Remote C–H Bond Functionalizations: Methods and Strategies in Organic Synthesis [1 ed.] 3527346678, 9783527346677

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Remote C H Bond Functionalizations

Remote C H Bond Functionalizations Methods and Strategies in Organic Synthesis

Edited by Debabrata Maiti Srimanta Guin

Editors Debabrata Maiti

Indian Institute of Technology Bombay Department of Chemistry Main Gate Rd, IIT Area 400076 Powai, Mumbai India

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Srimanta Guin

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Contents

1

Introduction 1 Uttam Dutta, Srimanta Guin, and Debabrata Maiti

2

Transition Metal-Catalyzed Remote meta-C–H Functionalization of Arenes Assisted by meta-Directing Templates 7 Yuzhen Gao and Gang Li Introduction 7 Template-Assisted meta-C–H Functionalization 9 Toluene Derivatives 9 Acid Derivatives 10 Hydrocinnamic Acid Derivatives 10 Phenylacetic Acid Derivatives 16 Benzoic Acid Derivatives 20 Amine and N-Heterocyclic Arene Derivatives 23 Aniline Derivatives 23 Benzylamine Derivatives 27 Phenylethylamine Derivatives 27 N-Heterocyclic Arene Derivatives 29 Sulfonic Acid Derivatives 33 Phenol Derivatives 40 Alcohol Derivatives 44 Silane Derivatives 50 Phosphonate Derivatives 51 Mechanistic Considerations 53 Conclusion 55 Abbreviations 56 References 57

2.1 2.2 2.2.1 2.2.2 2.2.2.1 2.2.2.2 2.2.2.3 2.2.3 2.2.3.1 2.2.3.2 2.2.3.3 2.2.3.4 2.2.4 2.2.5 2.2.6 2.2.7 2.2.8 2.3 2.4

3

3.1 3.2

C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis 59 Juntao Ye and Mark Lautens Introduction 59 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides 64

vi

Contents

3.2.1 3.2.1.1 3.2.1.2 3.2.1.3 3.2.2 3.2.3 3.2.4 3.2.5 3.3 3.3.1 3.3.2 3.3.3 3.4

4

4.1 4.2 4.2.1 4.2.2 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.4 4.5 4.6 4.7 4.8

5 5.1 5.2 5.2.1 5.2.2 5.2.3

ortho-Alkylation 64 ortho-Alkylation with Simple Alkyl Halides 64 ortho-Alkylation with Bifunctional Alkylating Reagents 70 ortho-Alkylation with Three-Membered Heterocycles 75 ortho-Arylation 77 ortho-Acylation and Alkoxycarbonylation 89 ortho-Amination 94 ortho-Thiolation 101 Pd(II)-Catalyzed C–H Functionalization of Arenes 101 C2-Functionalization of Indoles and Pyrroles 101 meta-C–H Functionalization of Arenes Containing an ortho-Directing Group 102 ortho-C–H Functionalization of Arylboron Species 105 Conclusions and Outlook 108 Acknowledgments 109 References 110 Directing Group Assisted meta-C–H Functionalization of Arenes Aided by Norbornene as Transient Mediator 115 Hong-Gang Cheng and Qianghui Zhou Introduction 115 meta-C–H Alkylation of Arenes 116 Amide as Directing Group 116 Sulfonamide as Directing Group 118 meta-C–H Arylation of Arenes 119 Amide as Directing Group 119 Sulfonamide as Directing Group 122 Tertiary Amine as Directing Group 122 Tethered Pyridine-Type Directing Group 123 Acetal-Based Quinoline as Directing Group 126 Free Carboxylic Acid as Directing Group 126 meta-C–H Chlorination of Arenes 127 meta-C–H Amination of Arenes 129 meta-C–H Alkynylation of Arenes 130 Enantioselective meta-C–H Functionalization 130 Conclusion 133 Abbreviations 134 References 134 Ruthenium-Catalyzed Remote C–H Functionalizations 137 Korkit Korvorapun, Ramesh C. Samanta, Torben Rogge, and Lutz Ackermann Introduction 137 meta-C–H Functionalizations 138 C–H Alkylation 138 C–H Benzylation 146 C–H Carboxylation 150

Contents

5.2.4 5.2.5 5.2.6 5.2.7 5.3 5.4 5.5

C–H Acylation 151 C–H Sulfonylation 151 C–H Halogenation 152 C–H Nitration 155 para-C–H Functionalizations 158 meta-/ortho-C–H Difunctionalizations 161 Conclusions 161 Acknowledgments 163 References 163

6

Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes 169 Georgi R. Genov, Madalina T. Mihai, and Robert J. Phipps Introduction 169 Non-covalent Interactions in Metal Catalyzed C—H Bond Functionalization 170 Overview of Iridium-Catalyzed Borylation 171 Non-covalent Interactions in Ir-Catalyzed Borylation 174 meta-Selective Borylation using Non-covalent Interactions 176 para-Selective Borylation using Non-covalent Interactions 181 Conclusions 186 References 186

6.1 6.2 6.3 6.4 6.5 6.6 6.7

7

7.1 7.1.1 7.2 7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 7.3 7.3.1 7.3.2 7.3.3 7.3.4 7.4

8

8.1

The Non-directed Distal C(sp2 )–H Functionalization of Arenes 191 Arup Mondal, Philipp Wedi, and Manuel van Gemmeren Introduction 191 Mechanisms 192 C–Het Formation 193 Borylation 193 Silylation 195 Amination 196 Oxygenation 200 Other C—Het Bond Forming Reactions 202 C—C Bond Forming Reactions 205 C–H-Arylation 206 Alkenylation/Olefination 207 Cyanation 209 Other C—C Bond Forming Reactions 212 Outlook 212 References 213 Transition Metal Catalyzed Distal para-Selective C–H Functionalization 221 Uttam Dutta and Debabrata Maiti Introduction 221

vii

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Contents

8.2 8.2.1 8.2.1.1 8.2.1.2 8.2.1.3 8.2.1.4 8.2.1.5 8.2.2 8.2.2.1 8.3 8.3.1 8.3.1.1 8.3.2 8.3.2.1 8.4 8.4.1 8.4.2 8.5

9

9.1 9.2 9.2.1 9.2.2 9.2.3 9.2.4 9.3 9.4 9.5 9.6 9.6.1 9.6.2 9.7

10

10.1 10.2

Template Assisted para-Selective C–H Functionalization 224 Palladium Catalyzed Methods 224 Alkenylation 224 Silylation 226 Ketonization 227 Acetoxylation 230 Cyanation 232 Rhodium Catalyzed Functionalization 233 Alkenylation 233 Steric Controlled and Lewis Acid-Transition Metal Cooperative Catalysis 233 Nickel Catalyzed Methods 234 Alkylation and Alkenylation 234 Iridium Catalyzed Methods 240 Borylation 240 Non-covalent Interaction Induced para-C–H Functionalization 242 Di-polar Induced Methods 242 Ion-Pair Induced Methods 243 Conclusion and the Prospect 244 Acknowledgments 246 References 246 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions 253 Koji Hirano and Masahiro Miura Introduction 253 Indole 253 C–H Functionalization at C4 Position 254 C–H Functionalization at C7 Position 258 C–H Functionalization at C5 Position 261 C–H Functionalization at C6 Position 261 (Benzo)Thiophene 262 Pyrrole 264 Pyridine 266 Miscellaneous Heteroarenes 271 Thiazole 271 Quinoline 271 Conclusion 272 References 273 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates 279 Ya Li, Qi Zhang, and Bing-Feng Shi Introduction 279 γ-C(sp3 )–H Functionalization of Aliphatic Acids 280

Contents

10.3 10.4 10.5 10.6

11 11.1 11.2 11.3 11.3.1 11.3.2 11.3.3 11.3.4 11.4 11.4.1 11.4.2 11.5

12

12.1 12.1.1 12.1.2 12.2 12.2.1 12.2.2 12.2.3 12.2.4 12.3 12.3.1 12.3.2 12.4 12.4.1 12.4.2

δ-/ε-C(sp3 )—H Bond Functionalization of Aliphatic Amines 288 γ-C(sp3 )—H Bond Functionalization of Aliphatic Ketones or Aldehydes 301 γ-/δ-C(sp3 )—H Bond Functionalization of Aliphatic Alcohols 305 Conclusions and Outlook 307 References 309 Radically Initiated Distal C(sp3 )–H Functionalization 315 Weipeng Li and Chengjian Zhu Introduction 315 Distal C(sp3 )–H Functionalization Promoted by Carbon-Centered Radicals 317 Distal C(sp3 )–H Functionalization Promoted by Nitrogen-Centered Radicals 325 Generation of Nitrogen Radical from N—X (X = F, Cl, Br, I) Bond 325 Generation of Nitrogen Radical from N—N Bond 328 Generation of Nitrogen Radical from N—O Bond 329 Nitrogen Radical Generated Directly from N—H Bond 331 Oxygen-Centered Radicals Initiate Distal C(sp3 )–H Functionalization 333 Oxygen Radical Generated from O—X (X = N, O) bond 333 Oxygen Radical Generated Directly from O—H Bond 336 Summary and Outlook 338 References 339 Non-Directed Functionalization of Distal C(sp3 )—H Bonds 343 Carlo Sambiagio and Bert U. W. Maes Introduction 343 Bond Dissociation Energy (BDE) of C—H Bonds 344 Scope of the Chapter 346 Reactions Occurring Without Formation of Metal–Carbon Bonds 346 Oxidations with Dioxiranes 346 Decatungstate-Photocatalyzed Remote Functionalization 348 Electrochemical Remote Functionalizations 353 Carbene Insertion into C—H Bonds 356 Reactions Occurring via Formation of Metal–Carbon Bonds 360 Pt-Based Shilov Chemistry 361 Rh- and Ir-Catalyzed C–H Borylation of (Functionalized) Alkanes 363 Altering Innate Reactivity by Polarity Reversal Strategies 367 Remote Functionalization of Aliphatic Amines via Quaternary Ammonium Salts 368 Remote Functionalization of Alcohols and Amides via Hydrogen Bond Interactions 376 Acknowledgments 378 References 378

ix

x

Contents

13

13.1 13.1.1 13.1.2 13.1.3 13.2 13.2.1 13.2.2 13.2.3 13.2.4 13.2.5 13.2.5.1 13.2.5.2 13.2.6 13.3 13.3.1 13.3.2 13.3.3 13.4 13.4.1 13.4.2 13.4.3 13.4.4 13.5 13.6

Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts 383 Miquel Costas Introduction 383 Bioinspired Catalysis as a Tool for Site Selective C—H Bond Oxidation 383 Typology of Bioinspired Catalysts 385 Site Selectivity in Aliphatic C–H Oxidation: Basic Considerations 387 Innate Substrate Based Aspects Governing Site Selectivity in C–H Oxidations 388 C—H Bond Strength 388 Electronic Effects 388 Steric Effects 391 Directing Groups 392 Stereoelectronic Effects 393 Hyperconjugation Effects 393 Strain Release and Torsional Effects 394 Chirality 395 Remote Oxidations by Reversal of Polarity 395 Remote Oxidation in Amine Containing Substrates by Protonation of the Amine Site 395 Remote Oxidation of Amide Containing Substrates by Methylation of the Amide Moiety 397 Remote Oxidation via Polarity Reversal Exerted by Fluorinated Alcohol Solvents 397 Remote Oxidations Guided by Supramolecular Recognition 401 Lipophilic Interactions 403 Lipophilic Recognition by Cyclodextrins 404 Ligand to Metal Coordination 406 Hydrogen Bonding 408 Selective Aliphatic C–H Oxidation at Dicopper Complexes 416 Conclusions 417 References 418 Index 423

1

1 Introduction Uttam Dutta, Srimanta Guin, and Debabrata Maiti Indian Institute of Technology Bombay, Department of Chemistry, Powai, Mumbai, 400076, India

Innovation and implementation of science and technology is a defining parameter to determine the progress of a civilization. Inquisitive minds are constantly devoted in empowering the human civilization by elegant discoveries and their subsequent applications in practical life. Organic chemistry, being a prime component of modern science, has served the human society in a way that has pronounced to be a boon for the present era. In one hand organic chemistry has unfolded the mechanistic intricacies of biorelevant reactivity, while on the other hand it has uncovered the methods to synthesize the molecular architecture that can either mimic the biological activity or can alter the same. Additionally, organic chemistry has profound industrial application including agrochemicals, food industry, dyes industry, polymer industry, and so on. As a whole, organic chemistry has become an inseparable component in our daily life. However, the genesis of these applications and large scale synthesis used to be initiated at synthetic laboratory. The ground breaking discoveries by erudite chemist have thus proved the intellectual supremacy of human race. However, the efficacy of synthetic methods is dependent on the step economy, atom economy, and environment benignity. Never ending aspiration to search such fruitful methods continues to challenge the chemist and inspire new chemical transformations. Accounting these existing literature precedents in the form of a concise summary, which would be the tutorial resources for future generation to accomplish successive progress, is undeniably one of the best efforts to intensify the expansion of chemical synthesis. C—H bond being the fundamental backbone of organic compounds, the potential of a C–H functionalization to amend a molecule overrides traditional routes on grounds of step and atom economy. This has triggered the development of various strategies with the aim to alter the physicochemical properties of specific compounds or add on molecular complexity. Irrespective of aliphatic or aromatic setup, the C—H bonds, vicinal to a functional group, are relatively easier to functionalize either by exploiting its acidity or by taking the advantage of its coordinating ability to the metal. Moving further toward distal positions, C–H functionalization is engrossed with several issues including the intrinsic inertness as well as regioselectivity due Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

2

1 Introduction

to the overabundance of multiple C—H bonds with subtle reactivity differences. Therefore, a curious quest was always followed to execute distal C–H functionalization with precise site selectivity. In its itinerary thus far, a number of elegant approaches have been conceived to install functional group at distal location with precise and predictable selectivity. In this book, an attempt is made to provide a broad overview on contemporary advancements in the field of distal C–H functionalization. Eminent researchers, who are known for their significant contributions in distinguished research areas, have penned down their collective efforts to outline a coherent and comprehensive discussion about different strategies for distal C–H functionalization. Chapter 2 introduces to the realm of directing group (DG) assisted distal arene meta-functionalization. Precise control on regioselectivity is one of the most important aspects in arene C–H functionalization. Arenes bearing heteroatom containing functionality, which is famously known as directing group (DG), were extensively exploited for proximal ortho-C–H activation. Extending such DG-assisted distal meta-functionalization strategy required proper template engineering that would ensure the meta-selective C–H activation. In this context, Yu and coworkers disclosed a “U”-shaped template for meta-selective alkenylation. Thereafter, Yu, Maiti, Tan, Li, and others embarked on exploring the scope of meta-functionalizations employing several templates. Gao and Li have collectively penned down in delineating a monograph on recent development of transition metal-catalyzed, template assisted distal meta-C–H functionalization. Chapter 3 deals with the involvement of the Catellani reaction for distal functionalization of (pseudo)halo arenes. Transition metal-catalyzed cross-coupling reactions have revolutionized the art of modern synthesis. While aryl halides or pseudohalides produced ipso-functionalized compounds, a new class of reactivity of aryl (pseudo)halide was developed by Catellani utilizing the combination of strained bicyclic olefin, norbornene (NBE), and palladium. A phenylnorbornylpalladium(II) (PNP) dimeric Pd-catalyst was successfully employed to furnish o,o′ -disubstituted vinylarenes starting from aryl iodides, alkyl iodide, and olefin in a regioselective manner. This Pd–NBE cooperative catalysis was expanded further for a diverse class of substrates including NH-indoles and NH-pyrroles, arenes bearing directing group (DG), and arylboron compounds by several eminent scientists. Several electrophiles were utilized for ortho-functionalization, and various nucleophiles were used as terminating reagent for ipso-functionalization. In Chapter 3, Juntao Ye and Mark Lautens have provided a vivid description about the development of arene C–H functionalization relying on Pd–NBE catalysis. The discussion was initially focused on the processes initiated with Pd(0) and subsequent discussion was made on the protocols initiated with Pd(II). However, a large part of Chapter 3 was devoted in portraying synthetic applicability of the Pd–NBE cooperative catalysis. The seminal work by Catellani on di-functionalization of aryl (pseudo)halides evolved in 1997. In later years, enormous efforts have been devoted in expanding the scope of this Pd–NBE cooperative catalysis in a relayed C–H activation process. In this context, Dong and Yu independently pioneered a directing group assisted meta-C–H functionalization utilizing the concept of Catellani reaction.

1 Introduction

An ortho-directing group was employed for initial ortho-C–H activation and subsequent palladium relay was realized in presence of NBE to accomplish meta-selective arene-C–H functionalizations. While the directing group (DG) assisted C–H functionalization was extensively studied for ortho-functionalization, aforementioned seminal reports opened up a new horizon in distal meta-C–H functionalization. Cheng and Zhou discussed about the recent advancements on directing group assisted meta-selective functionalization of arenes relying on NBE mediated Catellani type reaction. A detailed discussion was made on various functionalizations including alkylation, arylation, alkynylation, chlorination, and amination, which were achieved by anchoring different ortho-directing groups such as amides, amines, pyridine, or even free carboxylic acid. In Chapter 5, a comprehensive summary on ruthenium catalyzed distal metaand para-C–H functionalization was provided by Ackermann and coworkers. In last decades a number of handful synthetic protocols were developed to accomplish remote arene C–H functionalization by Ru-catalysis. Ru-catalyzed ortho-C–H ruthenation and subsequent ortho-functionalization were known in literature over few decades. In a sharp contrast, a unique catalytic reactivity to furnish meta-functionalized product from such ortho-ruthenated arenes was first observed by Frost and Ackermann in 2011 and 2013, respectively. In later years, Ackermann, Frost, Greaney, Zhang, and others successfully demonstrated a number of useful meta-functionalization methods relying on similar strategy. Ru-catalyzed para-selective functionalization was also included in Chapter 5 to retrospect the entire spectrum of Ru-catalyzed remote C–H functionalization. While Chapters 2–5 of this book were focused on discussing various approaches for distal arene C(sp2 )–H functionalization based on directing group assisted protocols, Catellani reactions, or via arene cyclo-ruthenation methods, in Chapter 6 Phipps and coworkers devoted their efforts in summarizing a complementary strategy for remote arene functionalization harnessing the non-covalent interactions. Although non-covalent interactions are prevalent in enzymatic reactions but translating such interaction in regioselective functionalization of small molecule in synthetic scale is rare. Despite the several challenges associated in controlling the site selectivity of arene functionalization, in recent years a number of elegant methods were developed by Smith, Kanai, Phipps, Chattopadhyay, and others. Phipps and his co-authors illuminated about the emergence of non-covalent interaction in distal arene-C–H functionalization in Chapter 6. Although use of directing group, transient mediator or non-covalent interactions have been popularized in recent years to harness the regioselective transformation of arenes. However, transition metal-catalyzed functionalization governed by the steric and/or electronic factors was cultivated over the century to mitigate the issues pertaining to the site-selectivity. Intrinsic biasness derived from the substituted functionality present in arenes or heteroarenes is considered to be the key component in defining the selectivity. While such strategy, precludes preinstallation of directing group or circumvent the complicated catalytic path involved in NBE mediated process, but were largely limited by the nature of substrate as well as usage of excess amount of arenes. However, prudent combination of catalyst, ligand, and reagent

3

4

1 Introduction

designing has been realized in recent years to enable regioselective functionalization of arenes or heteroarene with broad functional group tolerance. An exemplified discussion of such non-directed distal arene functionalization is made by van Gemmeren et al. in Chapter 7. The prime attention was paid in depicting the recent progresses on non-directed distal arene functionalization, where arenes were used as limiting reagent. In Chapter 8, Dutta and Maiti discussed about the recent progresses in the realm of distal arene para-C–H functionalizations. Distinction of energetically comparable C—H bonds to achieve regioselective C–H functionalization is one of prime focus of modern synthesis. In this regard, a number of strategies are known in the literature to perpetrate para-selective functionalization. Although electronic controlled Friedel–Crafts reaction being the early examples to promote para-C–H functionalization but this strategy is severely restricted with certain substrates and produced ortho-functionalized product as an unavoidable side product. Thus, the propulsive thrust in establishing strategies exists, which are not dependent on the electronic properties of the targeted substrate. The use of directing group, steric governance, non-covalent interactions, and radical initiation is cultivated to expand the scope of arene para-C–H functionalization. Chapter 8 is aimed to provide a comprehensive and exemplified discussion on directing group assisted, steric controlled, and non-covalent interactions promoted para-functionalizations to enlighten the scope of para-selective functionalizations beyond electronic control. Chapter 9 deals with heterocycle functionalizations at unusual positions. Heterocycles are prevalent structural core in pharmaceuticals, natural products, and agrochemicals. Regioselective C–H functionalization of heterocycles is of paramount importance as the derivatization of these heterocyclic cores can alter their inherent properties. However, C–H functionalizations of hetero-arenes are predominantly achieved at electronically biased positions. Therefore, standing against the innate inertness to attain selective C–H functionalization at unusual positions is of paramount importance in order to enrich the repertoire of heterocyclic compounds. The ever-expanding inquisitive minds have dedicated their efforts in finding and devising suitable methodology to promote site selective C–H functionalization of apparently inert C—H bonds present in heteroarenes. Hirano and Miura have elucidated these recent reports in Chapter 9. Recent progress on C–H functionalization of important heterocycles, namely, indole, (benzo)thiazole, pyrrole, pyridine, quinoline, and others is concisely recapitulated in Chapter 9. Unlike arene C(sp2 )–H functionalization, aliphatic C(sp3 )–H functionalization is relatively challenging due to its inherent inertness, low acidity, and overabundance with flexible long chain. Additionally, control over stereoselectivity is another important aspect to take care. Although functionalization of acidic C—H bonds adjacent to electron-withdrawing functional group or allylic and benzylic C—H bonds was exploited with electrophile, reciprocating such reactivity is impossible for remote C–H functionalization of long chain aliphatic substrates. However, the assistance from directing group enabled the delivery of functional groups at a desired position with uncompromised yield and selectivity. A vivid exemplification about the recent

1 Introduction

reports on directing group assisted remote functionalization of aliphatic substrates was presented by Li, Zhang, and Shi in Chapter 10. Chapter 11 by Li and Zhu articulates the recent progresses on radical initiated distal C(sp3 )–H functionalizations. Intramolecular hydrogen atom transfer process has provided a synthetically useful tool to promote regioselective functionalization of aliphatic substrates. Hofmann–Loffler–Freytag (HLF) reaction was considered as the pioneering invention in this realm. Although the potential of this strategy was realized lately in 2010, when a rapid growth was witnessed to promote radical initiated distal aliphatic functionalization via hydrogen atom transfer. In Chapter 11, comprehensive summary on different methods, synthetic applicability, and mechanistic intricacies are discussed from 2010 onwards. Chapter 12 is devoted in discussing non-directed functionalizations of aliphatic compounds, governed by innate reactivity. Although several challenges associated with the site selective functionalization of aliphatic substrates, constant up-search in finding suitable protocols either by tuning the innate reactivity of particular C—H bond present in the substrate or by controlling the reagent and catalyst has led to revolutionize the modern era of aliphatic C–H functionalization. Sambiagio and Maes have summarized the recent progress on non-directed aliphatic C–H functionalization at the remote position. Although a major part of aliphatic C–H activation was accomplished by directing group assisted strategy, Chapter 12 includes only non-directed aspect of aliphatic distal C–H functionalization. Chapter 12 was broadly divided into two parts: (i) the reaction involving distinct formation of metal–carbon bond and (ii) the reactions occurring without the metal–carbon bond formation. While the sojourn through transition metal-catalyzed distal C–H functionalization goes on in Chapters 2–12, in Chapter 13, Costas introduces to the territory of remote aliphatic C–H oxidation by bioinspired catalysis. Selective C–H oxidation is a routine task in biological system. The selectivity in enzymatic process is governed by the virtue of several interactions that enable the proper substrate trajectory and geometric orientation. Imitating such reactivity in laboratory synthesis is relatively challenging yet worthy to explore. Therefore, a persistent attempt to comprehend the mechanistic insight of biological reactivity and catalyst or ligand design was pronounced to furnish site selective functionalization of aliphatic substrate. A comprehensive survey on aliphatic C–H oxidation imparted by the bio-inspired catalysis is outlined by Costas in Chapter 13. The endless curiosities of human mind are the key to the technological advancements and evolution. This eternal truth has remained the essence for every piece of advancement since ancient times and will continue to remain persistent till times eternity. Modernization of scientific research in organic chemistry genre has shaped up in the form of C–H activation based protocols that has fostered a novel dimension in synthetic prospects and restructured the temperament of the scientific fraternity accordingly. This book besides providing a comprehensive scenario on the field of distal C–H activation also aims to inculcate cognizance among researchers of present and future generations to streamline and channelize their scientific understanding for the welfare of human civilization.

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7

2 Transition Metal-Catalyzed Remote meta-C–H Functionalization of Arenes Assisted by meta-Directing Templates Yuzhen Gao and Gang Li State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences (CAS), 155 West Yang-Qiao Road, Fuzhou, Fujian 350002, China

2.1 Introduction Site-selective C–H functionalization has emerged as an important synthetic methodology in organic synthesis in the past two decades [1–10]. For such synthetic methodology to be synthetically useful, precise control of the site-selectivity of C–H functionalization reactions is one of the most important issues required to be resolved due to the presence of several C—H bonds with similar reactivity in an organic molecule. Notably, meta-selectivity in C–H functionalization of arenes is one of the intriguing site selectivities that have been intensely studied in recent years [1–10]. Although thousands of methods for ortho-C–H functionalizations of arenes via proximity-induced cyclometallation have been reported, only a limited number of approaches have been disclosed in meta-C–H functionalizations of arenes. One of the representative approaches of meta-C–H functionalization of arenes is the directing template assisted remote meta-C–H functionalizations of arenes via geometry-induced metalation (Scheme 2.1a) [5–10]. ortho-C–H functionalization has been usually promoted by σ-chelation of the directing template. However, applying this chelation to meta-C–H functionalization is much more challenging since a strained cyclophane-like metallacycle might be involved in this transformation [11]. In 2012, the group of Yu and coworkers disclosed the first geometry-induced remote meta-C–H activation of toluenes and hydrocinnamic acids with a Pd(II) catalyst, which is assisted by two types of rationally designed nitrile-based templates that are covalently linked with toluenes or hydrocinnamic acids through an ether or amide bond (Scheme 2.1b) [11]. The presumable linear coordination mode of the nitrile-based chelating functionality (CF) in the U-shaped template that weakly coordinates to the palladium center in an end-on fashion is important for securing a possible less strained cyclophane-like pre-transition state. However, a more likely catalytic scenario is the weakly chelating template may “catch and release” the Pd(II) catalyst closely to the target meta-C—H bond, leading to a high effective concentration of the Pd(II) Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

8

2 Remote meta-C–H Functionalization

catalyst at the target meta-C—H bond without forming an 11- or 12-membered cyclophane-like palladacycle. (a) Template assisted meta-C–H activation X

Y

ortho (o) meta (m)

Lin

Pd or Rh cat. Ligand Coupling reagents

ke

r

CF

X m

H

FG

CF: chelating functionality

Y

Lin

ke

r

CF Template

FG: Functional group

(b) Seminal report's examples t-Bu

Linker

t-Bu

O 9

O NC

m H 1

i-Bu i-Bu

10 11

8

7

NC

6

12 3

2

N 4

5

CN

N C Pd H Cyclophane-like pre-transition state

(c) Substrate types: toluenes, acids, amines and N-heterocyclic arenes, sulfonic acids, phenols, alcohols, silanes, phosphonates (d) Dominant length from chelating atom to target C—H bond: 10–12 atoms, 9–11 bonds

Scheme 2.1 Directing template assisted meta-C—H bond functionalization. Related reviews: (a) Li et al. [5], Yang [6], Chattopadhyay and Bisht [7], Dey et al. [8], Ghosh and De Sarkar [9], and Dey et al. [10]; Source: (b) Modified from Leow et al. [11].

Inspired by this pioneering work, a series of directing template assisted remote meta-C–H activation reactions have been realized for a list of substrates including acids, amines, sulfonic acids, and so on (Scheme 2.1c). Notably, one of the key features of these reactions is the target C—H bond is usually 10–12 atoms away from the chelating atom of the template (Scheme 2.1b,d), although longer length was also possible. To date, three categories of CFs have been engineered including two nitrogen-based CN-containing (Scheme 2.2a) or heteroarene-containing (Scheme 2.2b) CFs and one oxygen-based CO2 H-containing CF (Scheme 2.2c). It should be noted that besides these three CFs that covalently attached to the substrate, two catalytic bifunctional templates that reversibly coordinate to the substrate were also reported recently and they are not classified in these categories [12, 13]. Another key feature of these reactions is that hexafluoroisopropanol (HFIP), which could also be used as an additive, appears to be the privileged solvent. Finally, N-acetyl glycine (Ac-Gly-OH), a mono-N-protected amino acid (MPAA), is often the ligand of choice for many of these reactions, although other MPAA ligands could also be utilized in some cases. Herein, we summarize important achievements that were disclosed until October 2019 in the field of directing template assisted meta-C–H functionalization of arenes with Pd or Rh catalysts since 2012. Different aspects of this type of methodology will be covered while discussing the works that are categorized by the substrate type.

2.2 Template-Assisted meta-C–H Functionalization

(a) R R

Rlink

Rlink

NC

NC

R

Rlink = OR, SiR12OR2, SO2R (b)

Rlink = OR, NR2, C2H4NR, SO2R, CHR2, COR

R O Rlink F

O N N

N

N O2N

Rlink = COR; OR, NHR

(c)

O

N

Me

HO

O

O

HO R R = H or F

F

Scheme 2.2 Three categories of chelating functionality (CF). (a) N-Based CN-containing CF; (b) N-based heteroarene-containing CF; (c) O-based CO2 H-containing CF.

Important mechanistic studies on this methodology will also be included. It is hoped that the reader will learn the key points, especially structural features, for rationally designing a feasible template for new substrates as well as developing new types of meta-C–H transformation after reading this chapter.

2.2 Template-Assisted meta-C–H Functionalization 2.2.1

Toluene Derivatives

In 2012, Yu and coworkers devised the first effective U-shaped nitrile-based directing template that was covalently linked to the toluene derivatives via a removable benzyl ether linkage (Scheme 2.3) [11]. Notably, the directing ability of the template was improved by installing two isobutyl templates at the α-position adjacent to the linearly chelating nitrile template due to the Thorpe–Ingold effect. This directing template efficiently enabled the meta-C–H olefination of a broad range of toluene derivatives using Pd(OPiv)2 as the catalyst and AgOPiv as the oxidant. It is worth mentioning that such remote C–H activation that possibly demanded a cyclophane-like 11-membered palladacycle was first ever disclosed. Remarkably, the intrinsic electronic and steric biases of the substrates were successfully overridden. Finally, the directing template was readily cleaved through hydrogenolysis with a Pd/C catalyst.

9

10

2 Remote meta-C–H Functionalization

R1

T

X

+

Pd(OPiv)2 (10 mol%) AgOPiv (3 equiv)

O

i-Bu

NC

R1 5 R2

4

3

t-Bu

T=

DCE, 90 °C 30–48 h

R2

H

t-Bu

T

X

i-Bu

Me F3C

T

CO2Et

Me

T

CO2Et

CO2Et

89% m/others = 91 : 9

86% m/others = 94 : 6

54% m/others = 98 : 2

Me

T T

F

T

T

O Me

CO2Et CO2Et 45% (mono), m/o = 95 : 5 44% (di), (m,m′)/others = 90 : 10

Scheme 2.3 et al. [11].

2.2.2

79% m/others = 96 : 4

61% m/others = 95 : 5

meta-C–H activation of toluene derivatives. Source: Modified from Leow

Acid Derivatives

2.2.2.1 Hydrocinnamic Acid Derivatives

In Yu’s seminal report, meta-C–H olefination of hydrocinnamic acid derivatives was also achieved using an easily synthesized and recyclable 2,2′ -azanediyldibenzonitrile directing template, which is now available from Sigma–Aldrich as the Yu–Li auxiliary [11]. This template was attached to several hydrocinnamic acids via a readily cleavable amide linkage (Scheme 2.4). It is worth mentioning that hydrocinnamic acids are core motifs of many drug molecules such as Baclofen. Notably, it was discovered that the MPAA ligand Ac-Gly-OH from the simplest amino acid significantly improved the yield of the reaction and improved the selectivity as well with the optimal HFIP solvent that was crucial for the full conversion of the substrate. It was found in subsequent reports that this set of novel reaction conditions was also highly effective for many of the directing templated assisted meta-C–H transformations. In this transformation, not only the intrinsic electronic biases of the substrate were overridden (9, 10), but also challenging steric hindrance was overcome by the template (11). Intriguingly, biaryl acid substrate that has the same length between the chelating nitrile group and the target meta-C—H bond as hydrocinnamic acid

2.2 Template-Assisted meta-C–H Functionalization T=

H

Pd(OAc)2 (10 mol%) CO2Et Ac-Gly-OH (20 mol%) X AgOAc (3 equiv) HFIP, 90 °C, 24 h

6

7

X

+ T

O

Me

CO2Et 9 87% m/others = 96 : 4

Scheme 2.4

O

N NC

O

F3C O

T

8 CO2Et

CF3

T

NC

DG T

O

T

Me

CO2Et

CO2Et

10

11

82% m/others = 95 : 5

49% (mono) m/p = 91 : 9 22% (di) (m,m′)/others = 94 : 6

O m1

CO2Et

12 45% (mono) m1/others = 95 : 5 48% (di) (m1,m1′)/others = 95 : 5

meta-C–H olefination of hydrocinnamic acid derivatives.

could also undergo meta-selective C–H olefination of the remote aryl ring (12). Finally, the directing template could be easily removed by hydrolysis under basic conditions at room temperature, leading to the meta-olefinated hydrocinnamic acids and the recycled directing template. In 2016, Maiti and coworkers disclosed a 2-hydroxybenzonitrile template for mono meta-selective olefination of hydrocinnamic acids via an ester linkage (Scheme 2.5a) [14]. Due to the less statistical availability of the coordinating nitrile group compared with the original 2,2′ -azanediyldibenzonitrile directing template, high mono-/di-selectivity could be obtained with this new template at lower reaction temperature using 1,2-dichloroethane (DCE) as the major solvent and HFIP as the minor solvent. Notably, hetero-di-olefination product could be afforded with a second meta-C–H olefination under similar reaction conditions using HFIP as the sole solvent (Scheme 2.5b). Most recently, Li and coworkers developed the first example of carboxy group assisted, remote meta-selective C(sp2 )–H activation with a PdII -catalyst via potential κ 2 coordination of the carboxyl, suppressing the ortho-C–H activation via the κ 1 coordination (Scheme 2.6a) [15]. Unlike the previous nitrogen-based CN-containing or heteroarene-containing templates, this is the first oxygen-based carboxyl-containing template, whose coordination geometry could be considered as a pseudo-linear coordination along the aryl–CO2 M bond similar to the nitrile-coordination geometry. Notably, hydrocinnamic acids could be meta-olefinated in a remote selective fashion, leaving the C—H bond ortho to the carboxy group on the same aryl intact, although carboxy group is well-known to be a good ortho-directing group (Scheme 2.6b). Moreover, tuning the electronic and

11

12

2 Remote meta-C–H Functionalization

T= X

+ T

R

Pd(OAc)2 (7 mol%) Ac-Gly-OH (21 mol%)

14

Ag2CO3 (2 equiv) DCE/HFIP (16/1) 65 °C, 48 h (excellent selectivity)

O

H 13

T

(a)

T

O

X O

NC

15 CO2Et

T

O

O T

O

T

MeO

CO2Et

COMe

SO2Ph

CO2Et

68%

66%

76%

52%

O

MeOC

+ T

(b)

CO2Et

O

T=

Pd(OAc)2 (10 mol%) COMe Ac-Gly-OH (30 mol%) Ag2CO3 (3 equiv) HFIP, 70 °C, 48 h 71%

O T

O

NC

CO2Et

Scheme 2.5 (a) 2-hydroxybenzonitrile template assisted mono meta-selective olefination of hydrocinnamic acids; (b) meta-selective hetero-di-olefination of hydrocinnamic acids. Source: (a) Modified from Modak et al. [14].

steric properties of the carboxy group by switching the hydrogen atom ortho to the carboxy group with a fluorine atom, the yield as well as the site selectivity could be improved to some extent (Scheme 2.6c). The possible presence of κ 2 coordination in assisting remote-selective C–H activation may inspire the exploration of novel site-selectivity of the carboxyl assisted C–H activation reactions. Besides Pd-catalysts, Rh-catalyst could also be used for olefination of hydrocinnamic acids. In 2017, Lu, Sun, Yu, and coworkers reported the first example of Rh(III)-catalyzed, directing template assisted remote meta-C–H olefination of hydrocinnamic acids via a postulated 12-membered macrocyclic intermediate (Scheme 2.7a) [16]. The directing template bearing a single nitrile group was slightly different from Yu’s seminal template. Moreover, molecular oxygen could be used as the terminal oxidant for this reaction. Subsequently, meta-C–H alkenylation of hydrocinnamic acids was also realized using alkynes, which are significantly less reactive than the polarized and reactive acrylate (Scheme 2.7b) [17]. Notably, transition metal-catalyzed meta-alkenylation using alkynes has not been successful with Pd catalysts in previous reports on the directing template strategy. In addition to meta-C–H olefination, meta-C–H arylation of hydrocinnamic acids was made possible using the directing template strategy. In 2013, Yu and coworkers reported the first example of Pd-catalyzed cross-coupling of meta-C—H bonds with arylboronic esters to afford meta-arylated hydrocinnamic acids derivatives

2.2 Template-Assisted meta-C–H Functionalization

Linker

O

H

X

p

Linker

H

H

H o1 m H [M] H

O

O

O

Intact H 2 κ -Coordination Geometry-driven Remote-selective C–H activation

N

Pd O

X = K+, Na+, etc.

H [M] κ1-Coordination Proximity-driven ortho-C–H activation

O

H

O

o2

Me

The working model

(a) O N

R

Me CO2H

O Mel K2CO3

m′

T

p

m

Me

TMe

Me

o1

CO2Me o2

R′

O

O

N

R

AgOPiv (3 equiv) silica gel HFIP, 80 °C, 24 h

H 16

R′ (2.0 equiv) Pd(OAc)2 (10 mol%) Ac-Phe-OH (20 mol%)

TMe

17

O

O TMe

TMe

TMe OMe

F

CO2Et

C6F5

59% (mono/di: 2.93/1) 67% m:others = 88 : 12 m:others = 91 : 9 m:o2 = 95 : 5

C6F5

C6F5

55% m:others = 89 : 11

76% (mono/di: 4.43/1) m:others = 93 : 7

(b) O N

R

Me CO2H

H

O Mel K2CO3

F

Me

CO2Et 75% (mono/di: 5.25/1) m:others = 91 : 9

p

m

O TMe Cl

TMe

C6F5 87% m:others = 91 : 9

N

R

Me

o1

R′

O

O

m′

AgOPiv (3 equiv) Silica gel HFIP, 80 °C, 24 h

TF

18

R′ (2.0 equiv) Pd(OAc)2 (10 mol%) Ac-Phe-OH (20 mol%)

CO2Me

19

F TF-Me Me

TMe

CO2Et 65% m:others = 82 : 18

O TMe

CO2Et 67% (mono/di: 2.94/1) m:others = 89 : 11

(c)

Scheme 2.6 (a) Proposed remote-selective C-H activation via κ2 coordination of the carboxyl. (b) Remote-selective meta-C–H olefination of hydrocinnamic acids. (c) Improved site-selectivity and reactivity with a modified carboxyl-containing template. Source: (a) Modified from Li et al. [15].

13

14

2 Remote meta-C–H Functionalization

X

R

+ T

[RhCp*Cl2]2 (5 mol%) Cu(CO2CF3)2·xH2O

T= F X

CF3CO2H, DCE O2, 100 °C, 48 h

O

H

T

N

O NC

21 CO Et 2

20 Br Br T

T

O

+ T

O R

H

O

T

MeO

CO2Et

69% m:others = 94 : 6

Ar X

T

O

CO2Et

CO2Et 78% m:others = 93 : 7

(a)

MeO

CONMe2

81% m:others = 95 : 5

[RhCp*Cl2]2 (5 mol%) AgSbF6 (20 mol%) Ag3PO4 (1 equiv) CH3CH2CO2H, DCE N2, 120 °C, 48 h

22

O

85% m:others = 97 : 3

T= F X T

N

O NC

R 23 Ar

Me Br T

T

O

MeO T

O

Ph

Ph

(b)

MeO

Ph 80% m:others = 93 : 7

70% m:others = 91 : 9

O

n-Pr

Me Ph

T

O

Ph 81% m:others = 95 : 5

Ph 72% m:others = 90 : 10

Scheme 2.7 (a) Rh(III)-catalyzed directing template assisted remote meta-C–H olefination of hydrocinnamic acids. (b) Rh(III)-catalyzed meta-C–H alkenylation of hydrocinnamic acids using alkynes. Source: (a) Modified from Xu et al. [16]; (b) Modified from Xu et al. [17].

(Scheme 2.8) [18]. A more electron-rich nitrile-based directing template with methoxy substitutions was found to better assist this reaction. Moreover, the privileged solvent HFIP and the MPAA ligand (Ac-Gly-OH) previously used for meta-C–H olefination of hydrocinnamic acid was still crucial for the reaction. Notably, tetrabutylammonium (TBA) salt tetrabutylammonium hexafluorophosphate (TBAPF6 ), which might prevent undesired agglomeration of Pd(0) species to give unreactive palladium black, dramatically improved the reaction yield. It is worth mentioning that biaryl compounds are import structural motifs that are frequently found in numerous pharmaceuticals and agrochemicals. Despite the success of meta-C–H arylation with arylboronic esters, meta-C–H arylation using low-cost aryl iodides proved to be challenging with the nitrile-based templates. Most recently, Li and coworkers achieved the first example of meta-C–H

2.2 Template-Assisted meta-C–H Functionalization

T=

Ar–Bpin (3 equiv) Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

R T

NC R

Ag2CO3 (2 equiv) CsF (2 equiv) TBAPF6 (3 equiv) HFIP, 70 °C, 24 h

O

H 24

T

N

O

Ar 25

Me

OMe

NC OMe

Me

Me

F3C T

T

O

T

O

T

O

CO2Me

CO2Me

CF3

OMe

85%

65%

60%

70%

O

Scheme 2.8 meta-C–H arylation of hydrocinnamic acids with arylboronic esters. Source: Modified from Wan et al. [18].

O N

R

Me CO2H

H TF

O

O

Me

MeI K2CO3

N

R Ar 26

F TF-Me O

O

CO2Me

Me CO2Me

m

TMe Cl

TMe CO2Me

O

Ag2CO3 (1.0 equiv) Cs2CO3 (0.5 equiv) HFIP, 100 °C, 24 h

F 18

Ar–I (2 equiv) Pd(OAc)2 (10 mol%) Ac-Phe-OH (20 mol%)

TMe

TMe CO2Me OMe

77% (mono/di: 2.21/1) m:others = 95 : 5

70% m:others = 98 : 2

51% m:others > 99 : 1

41% m:others = 95 : 5

Scheme 2.9 meta-C–H arylation of hydrocinnamic acids with aryl iodides. Source: Modified from Li et al. [15].

arylation of hydrocinnamic acid derivatives with aryl iodides assisted by the carboxyl-based template (Scheme 2.9) [15]. Notably, the site-selectivity is generally excellent with moderate to good yields. Moreover, aryl halides bearing an ortho-electron-withdrawing group (o-EWG) such as a methyl ester group were found to be most suitable with the reaction, which is possibly because that the combined electronic as well as weak coordinating effect of the o-EWG could facilitate oxidative addition with these aryl iodides.

15

16

2 Remote meta-C–H Functionalization

Finally, C–H deuteration and alkylation of hydrocinnamic acid derivatives were also possible using N-based heteroarene-containing templates, but only isolated examples were disclosed [19]. In short, the notable meta-C–H activation hydrocinnamic acid derivatives includes olefination and arylation with Pd(II) or Rh(III) catalysts, using nitrile-based or carboxyl-based templates. 2.2.2.2 Phenylacetic Acid Derivatives

The generality of the template strategy in accommodating potential macrocyclopalladation processes with smaller ring sizes was also investigated with phenylacetic acid derivatives. Notably, the Fujiwara–Moritani-type olefination is often used as the effective model reaction to test feasibility of a new substrate design of meta-C–H activation relation. In 2014, the Maiti group introduced a new category of nitrile-based phenolic directing template, which is now available from Sigma Aldrich as the Maiti–Bera–Modak (MBM) auxiliary, for meta-C–H olefination of phenylacetic acid derivatives via an ester linkage (Scheme 2.10) [20]. In this new class of substrates, a smaller 12-membered cyclic transition state was proposed for the palladation step than hydrocinnamic acid derivatives. With this easily synthesized and removable 2-hydroxybenzonitrile template, a broad range of phenylacetates were olefinated in a highly mono-selective as well as meta-selective fashion. Moreover, this protocol was also applied to drug molecules such as ibuprofen in a moderate yield and selectivity, products of which are difficult to access using conventional methods of diversification.

T R1

O

+

R2

H

CF3

27

T=

HFI O

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) R1 AgOAc (3 equiv) HFIP, 90 °C, 24 h

O NC

O R R = H, OMe

28 R2

(HFI)

CF3

(selectivity ratios: meta:other isomers) HFI O O

CO2Et

F

HFI O O

CO2Et

HFI O

Cl O

CO2Et

78% (11 : 1, R = OMe) 77% (26 : 1, R = OMe) 61% (14 : 1, R = OMe) 69% (26 : 1, R = H) 73% (11 : 1, R = H) 52% (14 : 1, R = H)

Scheme 2.10 [20].

F

HFI O O

COMe 79% (32 : 1, R = OMe) 71% (32 : 1, R = H)

meta-C–H olefination of phenylacetate. Source: Modified from Bera et al.

Simultaneously, Yu and coworker disclosed a protocol of the commercially available dibenzonitrile directing template assisted meta-C–H olefination of phenylacetic acid derivatives via an amide linkage [21]. Notably, N-formyl-protected glycine

2.2 Template-Assisted meta-C–H Functionalization

(Formyl-Gly-OH) was identified as the new ligand for this new class of substrate. Unlike previous protocols, weak base KH2 PO4 was required to use as the crucial additive. This reaction further demonstrates the good versatility of the template approach in accommodating potentially necessary macrocyclopalladation processes with different ring size for different classes of substrates (Scheme 2.11) [21]. R2

R2 T

R1

+

O

R3

Pd(OAc)2 (10 mol%) Formyl-Gly-OH (20 mol%)

R1

NC

O

KH2PO4 (50 mol%) AgOAc (3 equiv) HFIP, 90 °C, 24 h

H

T= T

N NC

30 R3

29

Me

OMe T

T

Cl

O

T

Me

O

CO2Et

CO2Et

86% m:others = 89 : 11

60% m:others = 96 : 4

T

Me

O

O

CO2Et

PO(OEt)2

82% m:others = 93 : 7

65% m:others = 95 : 5

Scheme 2.11 meta-C–H olefination of phenylacetic acid derivatives. Source: Modified from Deng et al. [21].

In 2017, the Maiti group developed the first rhodium-catalyzed meta-C–H olefination of phenylacetic acid frameworks with the assistance of 2-hydroxy-4-methoxy benzonitrile template (Scheme 2.12) [22]. The XPhos (2,4′ ,6′ -diisopropyl-1,1′ -bip T= T R1

O

+

R2

[{Rh(COD)Cl}2] (5 mol%) XPhos (10 mol%)

T O

R1

O

Cu(CO2CF3)2·xH2O (1 equiv) V2O5 (1 equiv) DCE, 120 °C, 36 h

H

NC OMe

32 R2

31 Br

OMe

Me

T

T

O

O

T O

F

CO2Et

CO2Et

CO2Et

70%

56%

52%

T

PhOC O

CO2Et 69% Ketoprofen derivative

Scheme 2.12 Rh-catalyzed meta-C–H olefination of phenylacetic acid derivatives. Source: Modified from Bera et al. [22].

17

18

2 Remote meta-C–H Functionalization

henyl-2-yldicyclohexylphosphine) was identified as the crucial ligand for this reaction. Substituents of phenylacetic acid esters at all positions of the arene ring were found to be tolerated. Synthetic application of this protocol was also expanded to the diversification of ketoprofen, a drug molecule containing a secondary α-methyl substituent. Besides nitrile-based templates, N-containing heteroarene-based templates also proved to be applicable for the phenylacetic acid frameworks (Scheme 2.13) [23]. In 2017, Yu and coworkers reported the a Pd-catalyzed meta-C–H olefination of phenylacetic acid scaffolds using a pyridine-based template via an amide linkage. A variety of phenylacetic acids, including cyclic and heterocyclic substrates, were efficiently meta-C–H olefinated in HFIP solvent without using additional ligand, opening new avenues for potential utility in C–H functionalization of advanced intermediates and late-stage modifications. Notably, the template could be used to extend the reaction scope to cross-coupling and iodination reactions (vide infra). R2 T 1

R

T=

R2

O

CO2Et

+

Pd(OAc)2 (10 mol%) AgOAc (3 equiv)

T

iPr

iPr

1

R

O

HFIP, 80 °C, 24 h

NH F

H

N

34 CO2Et

33 Me T O

CO2Et 91% m:others > 30 : 1

T

MeO O

CO2Et 91% m:others > 20 : 1

T F3C

O

CO2Et 53% m:others > 20 : 1

O EtO2C

T

5 N Ts

92% 5:others > 16 : 1

Scheme 2.13 Pyridine-based template assisted meta-C–H olefination of phenylacetic acid derivatives. Source: Modified from Jin et al. [23].

A novel N-containing pyrimidine-based template was also utilized to enable meta-C–H perfluoroalkenylation of phenylacetic acid derivatives by Werz, Zanoni, Maiti, and coworkers for the synthesis of organofluorine compounds (Scheme 2.14a) [24]. Notably, perfluoroalkenylation of drug molecule Ibuprofen was also possible with this protocol and the cleavage of the template is facile. Meanwhile, Wang, Zhou, and coworkers also reported a close protocol using olefin coupling partners other than perfluoroolefins such as acrylates (Scheme 2.14b) [25]. As mentioned earlier, pyridine-based template has been devised for meta-C–H olefination of phenylacetic acid scaffolds by the Yu group [23]. In the same report, it was also demonstrated that the meta-C–H activation with this template could be extended to meta-C–H cross-coupling with potassium trifluoroborate and

2.2 Template-Assisted meta-C–H Functionalization

R2 T R1

T=

R2 +

O

RF

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

T R1

O

Ag2CO3 (2.5 equiv) HFIP, 90 °C, 24 h

H

O

N

36 RF

35

N

Me T

Me O

T O

F

C4F9

T O

Me

C6F5

60% m:others = 20 : 1

T O

C2F4Br

41% m:others = 19 : 1

C4F9

78% m:others = 17 : 1

53% Ibuprofen derivatives

(a) R2 T R1

T=

R2

O

+

R

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

T R1

O

Ag2CO3 (2.5 equiv) HFIP, 90 °C, 24 h

H

N

37 R

35

O

N

Me T

Me O

CO2Et 70% m:others > 11 : 1

T Br

O

CO2Et 71% m:others > 10 : 1

T Me

O

CO2Et 67% m:others > 10 : 1

T Me

O

PO(OEt)2 83%

(b)

Scheme 2.14 (a) meta-C-H perfluoroalkenylation of phenylacetic acid derivatives. (b) meta-C-H alkenylation of phenylacetic acid derivatives with electron-deficient coupling partners. Source: (a) Modified from Brochetta et al. [24]; (b) Modified from Jiao et al. [25].

meta-C–H iodination with 1,3-diiodo-5,5-dimethylhydantoin (DIH) (Scheme 2.15) [23]. These results indicated that by tuning the distance and geometry a commonly used ortho-directing group (i.e. pyridyl) can be engineered to produce novel meta-directing templates for activating remote meta-C—H bonds. Deuterium-labeled compounds are widely used in pharmaceutical industry and kinetic studies of chemical reactions. However, deuterated compounds are often prepared with multistep synthetic routes. In 2019, by using the easily removable pyrimidine-based templates, Werz, Maiti, and coworkers realized the Pd-catalyzed meta-C–H deuteration of phenylacetic acid derivatives with easily available deuterium source such as deuterated acetic acid [26]. Notably, the method could be successfully been applied to several drug molecules such as Flurbiprofen

19

20

2 Remote meta-C–H Functionalization Pd(OAc)2 (10 mol%) NaB(3,5-CF3Ph)4 (20 mol%) ArBF3K (3 equiv) Ag2CO3 (2 equiv) R1 T R

R1 T R

CsF (2 equiv), KTFA (2 equiv) Bu4NBF4 (0.5 equiv) HFIP, air, 80 °C, 24 h

T=

O

iPr

Ar 38

NH F

O Pd(OAc)2 (10 mol %) TFA-Gly-OH (20 mol %) DIH (1 equiv)

H 33

R1

O

AgOAc (0.5 equiv) HOAc/HFIP (1 : 4), 80 °C, 24 h

I

(DIH: 1,3-diiodo-5,5-dimethylhydantoin)

Me

39

O

T

T Me

T

O

O

F

I

T O Me

CO2Me

N

T 33

R

iPr

CO2Me

69% 49% (mono), 13% (di) m:others > 20 : 1 m:others > 15 : 1

CF3 55%

61% m:others > 20 : 1

I Cl

T O

51% (mono), 26% (di) m:others > 20 : 1

Scheme 2.15 Pyridine-based template assisted meta-C–H arylation and iodination of phenylacetic acid derivatives. Source: Modified from Jin et al. [23].

(Scheme 2.16a). Simultaneously, Yu, Dai, and coworkers also achieved similar meta-C–H deuteration with a pyridine-based template (Scheme 2.16b) [19]. Finally, Pd-catalyzed meta-C–H allylation of phenylacetic acid derivatives has also been achieved with pyrimidine-based template utilizing synthetically inert unactivated acyclic internal olefins as allylic surrogates, but only limited examples were disclosed [27]. In short, meta-C–H transformation of phenylacetic acid derivatives includes olefination, arylation, iodination, and deuteration with Pd(II) or Rh(III) catalysts, using nitrile-based or N-heterocycle-based templates. 2.2.2.3 Benzoic Acid Derivatives

Benzoic acids are highly important structural motifs or precursors for drug molecules or natural products. Efficient diversification of benzoic acid derivatives is significantly desired in drug discovery. Benzoic acids were conventionally functionalized at the meta-position by electrophilic aromatic substitution under harsh conditions as they are generally deactivated toward electrophilic reactions. Though the meta-C–H activation strategy using directing templates has been successfully applied to many electron-rich/neutral arenes, it is generally less effective for electron-deficient arenes, possibly due to the low reactivity of electron-deficient arenes toward palladation in this type of reaction. Consequently, transition-metal-catalyzed meta-C–H activation of benzoic acids is considerably challenging. In early 2016, the Li group developed the first effective

2.2 Template-Assisted meta-C–H Functionalization

R2 T R1

O

T=

R2

Pd(OAc)2 (10 mol%) Ac-Gly-OH (10 mol%) [D4]acetic acid

T R1

H 40

O

O

80 °C, 24 h D 41

N

Me T

[96]

[93]

O

Me

T

F

[96]

91%

Me T

[93]

O

T

O

O

[93]

[99]

94%

97%

87% Flurbiprofen derivative

R2

T=

R2 Pd(OAc)2 (10 mol%) [D4]acetic acid

T O

T R1

O F

O

80 °C, 24 h

H 42

D 43

OMe

N Me

OMe T

[56]

O

[5]

F

[93]

(a)

R1

N

T

[91] [5]

[90]

[97]

88%

88%

F

O

[6]

T

[96]

F

[6]

O

[5]

T

[98]

Me

[5]

[96]

[98]

88%

88%

O

(b)

Scheme 2.16 (a) meta-C–H deuteration of phenylacetic acid derivatives pyrimidine-based templates. (b) meta-C–H deuteration of phenylacetic acid derivatives pyridine-based templates.

nosyl protected 2-cyano-phenylethylamine directing template that efficiently promoted the meta-C–H olefination of a broad range of electron-poor benzoic acid derivatives, regardless of the substitution patterns (Scheme 2.17) [28]. Remarkably, this protocol tolerated challenging highly electron-deficient tri-substituted benzoic acid derivatives. Such substitution pattern was not observed in previous transition-metal catalyzed meta-C–H functionalizations of (hetero)arenes through known approaches before the disclosure of this work (Scheme 2.17a). This result might imply that a matched directing template is important for meta-C–H functionalizations of different substrates regardless of electronic property of the substrate. Notably, molecular oxygen that is environmentally benign could be utilized as the terminal oxidant in this protocol. Instead, costly silver salt oxidants were predominantly used in almost all template assisted meta-C–H olefinations. Moreover, the mono-/di-olefination selectivity could be improved by switching the MPAA ligand. For example, a good ratio of mono over di-olefination could be achieved for the model substrate (44, R = H) by selecting Formyl-Gly-OH instead

21

22

2 Remote meta-C–H Functionalization T

O

+

R

Cu(OAc)2 (0.2–1.0 equiv) O2 (1 atm), HFIP (0.1 M) 80–90 °C, 24–48 h

R H

Ns N 45

T

O

T

R1

F

F Me

CO2Et 72%

(a)

Method a: LiOH·H2O (4.0 equiv) THF/MeOH/H2O rt, 1 h

NC CO2Et 46

CO2Et 92%

Ns N

O

T

O

Me

Cl

NC

T

O F

(b)

T=

R

44 O

T

O

Pd(OAc)2 (10 mol%) Ac-Gly-OH (60–100 mol%)

1

Method b: K2CO3 ( 2.5 equiv) EtOH, rt, 2 h

F

CO2Et

CONMe2

60%

60%

CO2R + CO2R 47, (R = H), 92% 49, (R = Et), 99%

H

Ns N NC

48, 88% (method a) 48, 93% (method b) (commercially available)

Scheme 2.17 (a) meta-C–H olefination of benzoic acids. (b) Removal of directing template. Source: Modified from Li et al. [28].

of Ac-Gly-OH as the ligand, though the yield was reduced a little bit. Finally, the sulfonamide chelating template, which is now available from Sigma-Aldrich as the Li–Li auxiliary, could be readily prepared in a large scale and easily cleaved from the product and recycled under very mild basic conditions (Scheme 2.17b). Moreover, using the aforementioned nosyl protected 2-cyano-phenylethylamine template, Li and coworkers also realized meta-C–H acetoxylation of electron-deficient benzoic acid derivatives bearing different substitution patterns (Scheme 2.18) [28]. Remarkably, the directing template could be readily cleaved with concomitant generation of a methyl ester. The methyl ester was then readily converted to a triflate, which could be used for accessing several synthetically useful meta-functionalized benzoic acid derivatives (Scheme 2.18b). In 2017, Houk, Yu, and coworkers also reported meta-C–H olefination of benzoic acid derivatives with a conformationally flexible nitrile-based template (Scheme 2.19) [29]. Notably, this new template was engineered through joint experimental and computational efforts. It was demonstrated that it was possible to computationally predict meta-selectivity of the devised templates with reasonable accuracy by using a Boltzmann distribution of all accessible C–H activation transition states. This newly designed optimal template, which favors a silver–palladium heterodimer low barrier transition state, enabled the Pd catalyzed meta-C–H olefination of benzoic acid derivatives with moderate-to-good yields and generally high regioselectivity. Notably, the authors found that kinetic experiments revealed

2.2 Template-Assisted meta-C–H Functionalization Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) PhI(OAc)2 (3.0 equiv)

T

O

R

T=

T

O

Ns N R

Ac2O (5.0 equiv) HFIP, 90 °C, N2, 24 h

OAc

44

NC

50 T

O

O

O

T

T

O

T

Me AcO

(a)

OAc

Me

T

F 61%

78%

81% (mono/di = 2.7 : 1)

OAc

OAc

CO2Me

O PhB(OH)2

(i) K2CO3, MeOH (ii) Tf2O, py., DCM

Pd(Ph3P)4, Na2CO3 DME/H2O, 95 °C

85% overall yield

AcO

53 CO2Me PhNH2

Pd(Ph3P)4 DMF, 100 °C

CO2Me

88% CO2Me CO (1 atm) MeO2C

(b)

100%

Ph 96% CO2Me

Zn(CN)2 NC

OAc F 63%

TfO

Pd(Ph3P)4, Et3N MeOH, DMF, 60 °C

54

Pd(Ph3P)4, Ph3P K2CO3, PhMe, 100 °C

TMS

NHPh 78% CO2Me

Pd(Ph3P)4, CuI Et3N, CH3CN, 80 °C 92%

TMS

Scheme 2.18 (a) meta-C–H acetoxylation of benzoic acids. (b) Elaboration of meta-functionalized benzoic acid derivatives. Source: Modified from Li et al. [28].

there was a fourfold increase in rate in the presence of MPAA ligand Ac-Val-OH. Finally, it was believed that the dialogue between synthetic and computational chemistry groups might inspire the development of novel templates for remote C–H activation.

2.2.3

Amine and N-Heterocyclic Arene Derivatives

2.2.3.1 Aniline Derivatives

Amine substituents on arenes are known strong ortho/para directors in electrophilic aromatic substitution reactions such as electrophilic palladation. Thus, to achieve meta-C–H activation of anilines is extremely challenging [30]. During engineering the meta-directing template for tetrahydroquinolines, Yu and coworkers found that a fluorine substituent in the auxiliary scaffold would induce a significant change in the conformation of the substrate (vide infra) [31]. Subsequently, a nitrile-based template bearing a fluorine was discovered (Scheme 2.20) [31], and this template

23

24

2 Remote meta-C–H Functionalization O

O

Pd(OAc)2 (10 mol %) Ac-Val-OH (20 mol %) NaOTs (1 equiv)

T

R

R1

+

T=

T

R

CN N Me

AgOAc (3 equiv) HFIP, 70 °C, 24 h

H

O

1 52 R

51 O Cl

O

OMe O T

T

CO2Et

CO2Et

61% m:others = 93 : 7

O

Me

Me

T

CONHMe

PO(OEt)2

92% m:others > 95 : 5

T

92% m:others > 95 : 5

68% m:others = 78 : 22

Scheme 2.19 meta-C–H olefination of benzoic acid derivatives with conformationally flexible nitrile-based template. Source: Modified from Fang et al. [29].

Me N T

X

Pd(OAc)2 (10 mol%) EWG Ac-Gly-OH (20 mol%)

+

R1 R2

H

AgOAc (3 equiv) HFIP, 90 °C, 24–48 h

53 Me N T

Cl

Me N T

Me N T

X

T=

O F O

R1 R2 54 EWG Me N T

Me

NC

H

Me N T

CO2Me CO2Et

CO2Et

78% 43% (mono) m:(o+p) = 99 : 1 m:(o + o′ + p) = 96 : 4 45% (di) (m,m′):others = 99 : 1

Scheme 2.20

CO2Et 82% m:(o + p) = 97 : 3

82% m:(o + o′ + p) = 99 : 1

meta-C–H olefination of aniline derivatives.

also favored the process of meta-C–H activation of anilines, successfully overriding the electronic bias toward possible ortho-palladation assisted by the amide directing group. Notably, the MPAA ligand Ac-Gly-OH and HFIP solvent were still the two key elements to enhance the reactivity and site selectivity of the reaction. In 2017, the group Li disclosed a novel template for anilines by incorporating readily available and inexpensive carbon dioxide into the nitrile-based carbamate template (Scheme 2.21a) [32]. A broad range of aniline derivatives, including tetrahydroquinoline, were efficiently meta-olefinated with palladium(II) acetate as

2.2 Template-Assisted meta-C–H Functionalization

NH2

(i) CO2, Cs2CO3, TBAI DMF, 2–3 h, rt

NsCl Ns N

O NC

R

Br

Ns

N

R H 55 Ns

N

55

R1 Pd(OAc)2 (10 mol%) Ac-Gly-OH (60 mol%)

T

AgCO3 (3 equiv) HFIP/DCE (1 : 1, v/v) 80 °C, 24 h

T

Ns

Br

N

Ns

T=

T

N

Me

O O

R R1

56

T

Ns

Br

N

T

NC

N

T

Me

CO2Et 94% (mono/di = 1/1)

NC

R

NC

(a)

O

Me

(ii)

R

N

Me

O

Me

O H

25

CO2Et 82%

CONMe2 73%

CH2O2Et 81%

(b)

Scheme 2.21 (a) synthesis of substrate from CO2 for meta-C–H activation of aniline. (b) meta-C–H olefination of aniline carbamates. Source: (a) Modified from Yang et al. [32].

the catalyst (Scheme 2.21b). Notably, the template could be easily removed under mild basic conditions. The practicality of substrate preparation, functional group tolerance, and easy removal of the template makes it a valuable method for the meta-C–H functionalization of anilines. In 2019, it was found that tertiary anilines were unreactive toward meta-C–H activation, possibly due to the unfavorable conformation resulted from the p–π conjugation between the lone-pair electrons of the nitrogen atom and the phenyl ring [33]. Thus, a template for tertiary anilines through a quaternary ammonium salt assembly was devised (Scheme 2.22). Assisted by this novel linkage of template, highly meta-selective C–H olefination of tertiary anilines was achieved with a range of substrates. The results indicated that the conformation of the substrate in the meta-selective C–H activation plays a vital role in the templated-assisted remote C–H functionalization apart from the distance and geometry of the template while being linked with the substrate. Besides meta-selective C–H olefination of aniline derivatives, meta-selective C–H acetoxylation, which proceeds via a different Pd(II)/Pd(IV) redox chemistry catalytic cycle as opposed to meta-C–H olefination, has also been achieved using different nitrile-based templates by the groups of Yu (Scheme 2.23a) [31] and Li (Scheme 2.23b) [32], respectively. By using the aforementioned templates for meta-C–H olefination for anilines, a range of aniline derivatives were

26

2 Remote meta-C–H Functionalization

R1

R2 T N OTf +

R3 R4

R

Pd(OAc)2 (10 mol %) Ac-Gly-OH (20 mol %) AgOAc (2 equiv)

R2 T N OTf

R1

T= O

R

HFIP, 80 °C, 36 h

R4

H 57 Me

Me T N OTf

O N

Me T N

T OTf

OHTf

MeO

OMe

Me T N OTf

NHCbz CO2Me

CO2Et

67%

Scheme 2.22

Me

CO2Et

CO2Et 62%

71%

72%

meta-C–H olefination of tertiary anilines. Me N T

X

NC

58

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) PhI(OAc)2 (2 equiv)

X

Me N T

Me N T

Me

OAc

O F

NC

OAc 59 Me N T

Br

OAc

60% m:o = 92 : 8

T= O

Ac2O (7 equiv) HFIP, 90 °C, 30–40 h

H 53

Me N T

Me

Me N T

Cl

OAc

66% m:o = 91 : 9

H

OAc

47% m:o = 98 : 2

64% m:o = 98 : 2

(a) Ns N X

T

Ns N X

Ac2O (5 equiv) HFIP, 90 °C, 24 h

H 55 Ns N

(b)

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) PhI(OAc)2 (3 equiv)

Me T

Ns N

Me

Me

O

T

O NC

OAc 60 Br

T

T=

Ns N

Me T

Cl

OAc

OAc

OAc

OAc

52%

63%

70%

66%

Ns N

T

Scheme 2.23 (a) meta-C–H acetoxylation of aniline amides. (b) meta-C–H acetoxylation of aniline carbamates. Source: (a) Modified from Tang et al. [31]; (b) Modified from Yang et al. [32].

2.2 Template-Assisted meta-C–H Functionalization

meta-acetoxylated with PhI(OAc)2 was the oxidant. It should be noted, however, the meta-C–H acetoxylation was generally less efficient than the meta-C–H olefination. 2.2.3.2 Benzylamine Derivatives

In 2014, Yu and coworkers reported the first meta-selective C–H acetoxylation of benzylamine derivatives using the template that previously worked for anilines (Scheme 2.24) [31]. The versatility of the reaction was demonstrated with both acyclic and cyclic benzylamines, although only a few examples were investigated. Notably, since 2-phenylpyrrolidine and 2-phenylpiperidine motifs are often found in medicinally important heterocycles, this meta-selective C–H acetoxylation method is a potentially powerful methodology for accessing diverse structures of medicinally importance.

N T H 61

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) PhI(OAc)2 (2 equiv)

T= N T

Ac2O (7 equiv) HFIP, 90 °C, 30–40 h

OAc 62

O F O

NC

H

Me N T

Me

OAc 54% m:o = 96 : 4

N T

Me

OAc 56% m:o = 98 : 2

N T

N T

OAc

OAc

51% m:o = 94 : 6

58% m:o = 96 : 4

Scheme 2.24 meta-C–H acetoxylation of benzylamine derivatives. Source: Modified from Tang et al. [31].

Besides meta-C–H acetoxylation of benzylamines, meta-C–H olefination was also reported by Xu, Xu, Jin, and coworkers through a quaternary ammonium salt assembly of the template for tertiary benzylamines [33]. Remarkably, this method was demonstrated to be applicable to several distal arene-tethered tertiary amine derivatives, although only a few examples of benzylamine derivatives were tested (Scheme 2.25). 2.2.3.3 Phenylethylamine Derivatives

In 2015, the group of Li achieved the first meta-C–H olefination of N-methyl-phenylethylamine derivatives using the 2-cyanobenzoyl group as the CF (Scheme 2.26) [34], followed by the isolated examples of meta-C–H olefination of tertiary phenylethylamine derivatives mentioned in Section 2.2.3.2 [33]. In presence of Pd(OAc)2 and Ac-Gly-OH under nitrogen atmosphere, the reaction proceeded smoothly with a broad scope of substrate, and the directing template is structurally

27

28

2 Remote meta-C–H Functionalization

R n

N

R′ OTf T

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv)

+

R n

R′ OTf T

N

T= O

CO2Et

HFIP, 80 °C, 36 h

H

CO2Et

NC

64

63 Me

Me N

T

Me

Me N

MeO2C

OTf

T

CO2Et

CO2Et

85%

84%

Me

Me N

3

T

Me 4

T

Me

CO2Et 83%

Me N

OTf 5

CO2Et

T

Me

Me N

OTf 6

CO2Et

79%

Me N Me T OTf

CO2Et 82%

Me N

OTf

MeO2C

Me N Me T OTf

OTf

OMe

OTf

T

CO2Et

75%

CO2Et

76%

72%

Scheme 2.25 meta-C–H olefination of tertiary benzylamines and distal arene-tethered tertiary amine derivatives.

X T

N

+ Me

H

R

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

T= X

AgOAc (3 equiv) DCE/HFIP, 80 °C N2, 24–48 h

T

65

N

Me N T

F3C

Me N T

Cl

Me NC

66 R Me N T

O

Me N T

Me

Cl

CO2Et 82% mono/di = 1.2 : 1

CO2Et 78%

CO2Et 74% mono/di = 2 : 1

PO(OEt)2 70%

Scheme 2.26 meta-C–H olefination of phenylethylamine derivatives. Source: Modified from Li et al. [34].

very simple and commercially available. Moreover, to increase the potential of application of direct C–H transformations in organic synthesis, using 2-cyanobenzoyl group as the common original directing functionality to access regiodivergent C–H activation was also demonstrated in a sequential remote-selective C–H olefination of 2-fluorophenylethylamine (Scheme 2.27). Notably, the first remote-selective C–H olefination occurs with the secondary amide 67 leaving the proximal aromatic

2.2 Template-Assisted meta-C–H Functionalization

C6F5 F

H N

Pd(OAc)2, Ac-Gly-OH Ag2CO3, O2, HFIP

O

O

F

N

t-Amyl-OH, 90 °C, 86%

NC

ortho-Olefination

67

intact 68

CO2Me

MeO2C

Me N NC

70

O

F

Pd(OAc)2, Ac-Gly-OH

Me N

O

NC

AgOAc, O2, HFIP DCE/HFIP, 90 °C, N2 73%

C6F5

C6F5 (i) LiHMDS, MeI 85% brsm (ii) Pd/C, H2 98%

meta-Olefination

F

H N H

69

C6F5

Scheme 2.27 Sequential remote-selective regiodivergent C–H olefination of 2-fluorophenylethylamine.

ortho-C—H bond intact in an ortho-selective manner and proceeds with an imidamide directing group that was formed through cyclization of the 2-cyanobenzoyl motif. The desired meta-directing template was reconstructed with methylation by using LiHMDS as the base to afford substrate 69 after hydrogenation. Finally, the second C–H olefination of 69 led to the production of tetra-substituted phenylethylamide 70 in a meta-selective manner under standard reaction conditions, enabling the building of molecular complexity in a concise manner. 2.2.3.4

N-Heterocyclic Arene Derivatives

Due to the prevalence of N-heterocycles in biologically important molecules, selective activation of a C—H bond of N-heterocyclic arenes is a conceptually intriguing and synthetically important challenge. For example, to selective activation of C—H bonds at C7 of bicyclic tetrahydroquinolines, a novel template will be required since a highly strained intermediate with a tricyclic cyclophane structure will be encountered. In 2014, Yu and coworkers found the template conformation was a critical factor in controlling remote meta- or ortho-selectivity, and when a fluorine substituent was introduced into the auxiliary, the conformation that favored the meta-selectivity would be dominant in the presence of the MPAA ligand Ac-Gly-OH (Scheme 2.28a) [31]. Intriguingly, when the substituents in the auxiliary scaffold were switched to methyl groups, high ortho-C–H activation at C7 of bicyclic tetrahydroquinolines was observed. With this new directing template by taking advantage of conformation control, remote meta-C–H olefination of tetrahydroquinolines was achieved in good yield and with high levels of site selectivity (Scheme 2.28b). Subsequently, Movassaghi, Yu, and coworkers developed a novel nitrile-based sulfonamide directing template for indolines, since previous directing template

29

30

2 Remote meta-C–H Functionalization Conformation-controlled meta-C–H activation

Ligand

Highly ortho-selective

Pd

Pd

N

8

Me O

7

N

Highly meta-selective

O

F

Me

Ligand

H

N

O

O CN

(a) N X 8

6

T +

Pd(OAc)2 (10 mol%) CO2Et Ac-Gly-OH (20 mol%)

N X

T=

H 71

F O

AgOAc (3 equiv) HFIP, 90 °C, 24–48 h Then HCl/EtOH

7

O

T NC

H

72 CO2Et Me

Cl F

EtO2C

N H

75% C7:C8 = 92 : 8

EtO2C

N H

71% C7:(C6 + C8) = 88 : 12

EtO2C

N H

N H

EtO2C 70% 53% C7:(C6 + C8) = 92 : 8 C7:C5 = 88 : 12

(b)

Scheme 2.28 (a) Conformation promoted meta-selective activation. (b) meta-C–H olefination of tetrahydroquinoline derivatives. Source: (a) Modified from Tang et al. [31].

for tetrahydroquinolines was not viable presumably due to that the aryl group of indolines is more electron rich and the new skeleton requires a different template to accommodate (Scheme 2.29a) [35]. The new electronically withdrawing sulfonamide linkage is crucial for the meta-selective C–H functionalization of electron-rich indolines that are otherwise highly reactive toward electrophilic palladation at the electron-rich C5-positions. With this new template and the established reaction conditions, a range of synthetically useful and advanced indoline analogues were efficiently olefinated at the C6 position, meta to the nitrogen atom. Moreover, the sulfonamide template could be removed at room temperature with magnesium turnings in methanol to afford meta-alkylated indoline derivatives through simultaneous reduction of the newly installed olefins (Scheme 2.29b). Based on the success of meta-C–H olefination of electron-rich indolines, the meta-C–H arylation of indolines under previously reported meta-C–H cross-coupling reaction conditions for hydrocinnamic acid derivatives was also achieved, demonstrating the versatility of this new template for diverse meta-C–H functionalizations of indolines (Scheme 2.30) [35]. Several indoline substrates reacted with arylboronic acid pinacol esters to afford meta-arylated indoline derivatives in synthetically useful yields. Since the meta-hydroxylated indolines are biologically important, meta-C–H acetoxylation of indolines using the well-established oxidation conditions was also

2.2 Template-Assisted meta-C–H Functionalization

R

R N T

X

+

7

5

R

T=

N T

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

S

X

AgOAc (3 equiv) HFIP, 55 °C, 24 h

6

H

O O

NC i-Bu i-Bu OMe

74 R

73

O N T

N T

Cl

CO2Et

H

Me

N T

CO2Et

75, 75% C6/others > 20 : 1

76, 67% C6/others > 20 : 1

H N T

Me

CONMe2

CO2Et

(±) –77, 81% C6/others > 20 : 1

(±)–78, 88% C6/others > 20 : 1

(a)

Mg0

N T

N H

MeOH, rt 89%

(b)

75

CO2Et

79

CO2Et

Scheme 2.29 (a) meta-C–H olefination of indoline derivatives. (b) Removal of directing template. Source: (a) Modified from Yang et al. [35]. Ar–Bpin (4 equiv) Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

X R

5

H

6

7

73

Ag2CO3 (2.5 equiv) CsF (2.5 equiv) TFAPF6 (3 equiv) HFIP, 100 °C, 36 h

N T

Me

T=

X

S

R Ar 80

N T

O O

NC i-Bu i-Bu OMe

Me O

F3C

N H T

N H T MeO2C

MeO2C (±)–81, 60%

Scheme 2.30 et al. [35].

N T

(±)–82, 53%

(±)–83, 51%

meta-C–H arylation of indoline derivatives. Source: Modified from Yang

31

32

2 Remote meta-C–H Functionalization

investigated (Scheme 2.31) [35]. It was found that although the meta-acetoxylated indolines were obtained as the major products, the meta-selectivity was much lower than olefination and para-acetoxylated indolines (∼10%) were also formed probably due to the electrophilic palladation at the electron-rich C5 position under the reaction conditions. It should be mentioned that the nonsubstituted indoline substrate was not compatible with these oxidation conditions, since the indoline was readily oxidized to give a mixture of unidentified compounds instead. Further investigation of this reaction to find better reaction conditions is required.

5

H

6

PhI(OAc)2 (2 equiv) HFIP/Ac2O (10 : 1) 70 °C, 24 h

N T

7

T=

Pd(OAc)2 (10 mol%) Ac-Gly-OH (30 mol%)

R

73

AcO 84

N T

Cl

NC i-Bu i-Bu Cl

Me

Me

N H AcO T (±)–85, 60% C6:C5 = 5 : 1

Scheme 2.31 et al. [35].

O O

S

R

N AcO T 86, 26% C6:C5 = 4 : 1

O Me N N H AcO AcO T T (±)–87, 63% (±)–88 74% C6:C5 = 6.6 : 1 C6:C5 = 5.8 : 1

meta-C–H acetoxylation of indoline derivatives. Source: Modified from Yang

In 2018, Yu and coworkers developed a novel simple ortho-sulfonyl benzonitrile template to achieve remote ortho or meta-C–H olefination of six different classes of N-heterocycles, including indoline, indole, and tetrahydroquinoline (Scheme 2.32) [37]. It was demonstrated that the site-selectivity could be predicted based on distance and geometry, and template-directed meta-C–H activation was possible through macrocyclopalladation processes with smaller ring size (10-membered organometallic ring for indoline and indole).

R H

N T

89

+

CO2Et

5 6

EtO2C

N EtO C 2 T

64% C6:C5 = 91 : 9

Scheme 2.32 et al. [36].

T=

Pd(OAc)2 (10 mol%) AgOAc (3 equiv) KH2PO4 (1 equiv) HFIP, 90 °C, 24 h

N T

EtO2C

NC

5

6

7

7

6

55% C6:C5 = 89 : 11

EtO2C

O

90

6

N T

O S

R

N T 46% C7:C6 = 91 : 9

O N T

EtO2C

75% C6:C7 > 95 : 5

meta-C–H olefination of N-heterocycles. Source: Modified from Dutta

2.2 Template-Assisted meta-C–H Functionalization

Stoichiometric installation of the template is not step-economic, or it would not be attached to the substrate while there is no appropriate functional group to form the covalent linkage. Thus, the design of a catalytic template that binds the substrate via a reversible coordination instead of a covalent linkage is very desirable. In 2017, Yu and coworkers reported a remarkable breakthrough for meta-C–H olefination of 3-phenylpyridines by using a catalytic pyridine-based bifunctional template (Scheme 2.33) [12]. In this reaction, the novel template coordinated two metal centers, one of which one reversibly anchored substrates near the catalyst. The other metal cleaved the meta-C–H selectively. Notably, unlike previous reaction conditions, the addition of the new copper acetate additive was crucial, since both the yield and the meta-selectivity would decrease greatly in the absence of copper acetate. Subsequently, Maiti and coworkers reported a novel nitrile-based bifunctional template for meta-C–H olefination of 3-phenylpyridines with Pd(acac)2 as the catalyst under similar reaction conditions (Scheme 2.34) [13]. Notably, this nitrile-based bis-amide template was easily prepared, which was beneficial for its application in the synthesis of complex molecular structures.

2.2.4

Sulfonic Acid Derivatives

In 2015, Maiti and coworkers developed the first meta-C–H activation of benzylsulfonic acid derivatives using aforementioned commercially available the 2-hydroxybenzonitrile directing template with high and controllable mono-selectivity (Scheme 2.35a) [38]. Thus, meta-selective homo-diolefination and sequential hetero-diolefination of benzylsulfonyl ester derivatives were made possibly with this protocol, providing a novel method for the synthesis of hetero-dialkenylated products that are difficult to access using conventional methods. Notably, the directing template could be converted to an alkenyl group using modified Julia olefination conditions (Scheme 2.35b). Subsequently, Maiti and coworkers also achieved the meta-C–H olefination of 2-phenethylsulfonic acid derivatives using the similar approach as the benzylsulfonic acid using the N-formyl glycine (For-Gly-OH) ligand (Scheme 2.36a) [14]. Notably, sequential meta-selective hetero-diolefination was also feasible with these substrates, and the deprotection and recovery of the directing template were successfully realized under basic conditions (Scheme 2.36b). In 2017, Maiti and coworkers disclosed the first pyrimidine-based template, which is effective for meta-C–H olefination of benzylsulfonyl and 2-phenethylsulfonyl esters, leading to an unconventional formation of α,β-unsaturated aldehydes with benzyl-protected allyl alcohols (Scheme 2.37) [39]. This novel pyrimidine-based template was also utilized for the production of β-aryl aldehydes and ketones, using allyl alcohols through meta-C–H alkylation of benzylsulfonyl and 2-phenethylsulfonyl esters. In the same year, the Maiti group introduced the novel 8-nitroquinoline-based directing template for meta-C–H functionalization of benzylsulfonyl esters via strong σ-coordination, ensuring the potential formation of a stable palladacycle

33

Ligand PyT (20 mol%) Pd(OAc)2 (30 mol%) Ac-Gly-OH (20 mol%)

R2 H +

R1

R

AgBF4 (1.0 equiv) Cu(OAc)2 (2.0 equiv) HFIP, 110 °C, 48 h, air

N Me

Scheme 2.33

61% m/o > 99/1 mono/di = 89/11

61% m/others > 94/6 mono/di > 96/4

m

O O O S NH HN S

R N

N

N

Ligand PyT F

OMe CO2Et

N

O

p o

R1

MeO CO2Et

N

R2

MeO

C6F5 N N

86% m/others > 90/10 mono/di > 99/1

meta-C–H olefination of 3-phenylpyridines. Source: Modified from Zhang et al. [12].

CO2Et N

40% m/o > 99/1 mono/di = 95/5

Ligand CNT (20 mol%) Pd(acac)2 (30 mol%) Ac-Gly-OH (20 mol%)

R2 H +

R1

R

N

Me

65% m/others = 10/1

Scheme 2.34

m

NC

CO2Et F

N

Ligand CNT

CN

Me

OMe

63% m/others = 23/1

O

NH HN

R

N

CO2Et N

O

p o

R1

Cl CO2Et

N

AgBF4 (1.0 equiv) Cu(OAc)2 (2.0 equiv) HFIP, 110 °C, 30 h

R2

76% m/others = 18 : 1

N

CO2Et N

65% m/others = 10 : 1

meta-C–H olefination of 3-phenylpyridines using nitrile-based bifunctional template. Source: Modified from Achar et al. [13].

36

2 Remote meta-C–H Functionalization O Pd(OAc)2 (10 mol%) S O CO2Et Ac-Gly-OH (20 mol%) + T Ag2CO3 (1.5 equiv) HFIP (3 equiv) DCE, 60 °C, 48 h

X H

O S O T

X

92 CO2Et

91

O S O T

CO2Et 82% mono/di = 7.2 : 1

Me

O S O T

O S O T

F

CO2Et

CO2Et

80%

76%

T= O NC

O S O T

Me

CO2Et 67%

(a) O S O O

(b)

NC CO2Et

Ph

PhCHO LDA, THF, –78 °C 73% CO2Et

Scheme 2.35 (a) meta-C–H olefination of benzylsulfonic acid derivatives. (b) Elaboration of product via olefination. Source: (a) Modified from Bera et al. [38].

(Scheme 2.38) [36]. The protocol enabled both meta-C–H olefination and acetoxylation, which could be scaled up and diversified to synthetically important compounds in late stage. In 2017, Maiti and coworkers also developed the XPhos-supported Rhodium catalysis of meta-C–H olefination of benzylsulfonic acids with the assistance of 2-hydroxy-4-methoxy benzonitrile template (Scheme 2.39) [22]. Complete mono-selectivity was observed for this reaction, and a range of olefins and substituents at all positions of the aryl ring were found to be tolerated. The development of efficient methods for the synthesis of organofluorine compounds is of great interest. Werz, Zanoni, Maiti, and coworkers achieved the first meta-C–H perfluoroalkenylation of benzylsulfonic acid derivatives using the pyrimidine-based template with several commercially available perfluoroolefins (Scheme 2.40) [24]. The substrate scope was broad and a high degree of compatibility with perfluoroolefins of different nature was also observed. In 2019, Paton, Maiti, and coworkers developed the Palladium(II)-catalyzed meta-selective C–H allylation of benzylsulfonyl esters using synthetically inert acyclic internal olefins as allylic surrogates (Scheme 2.41) [27]. The pyrimidine-based directing group proved to be the key factor to facilitate the olefin insertion by overcoming inertness of the typical unactivated internal olefins for meta-selective C–H activations. A broad scope of substrates with wide

2.2 Template-Assisted meta-C–H Functionalization O

O S

T

X

+

R

Pd(OAc)2 (10 mol%) For-Gly-OH (20 mol%)

O

O S

X

T=

T O

AgOAc (2 equiv) HFIP, 60 °C, 24 h

H 93

94 O

O S

T

O

O S

O

Cl

O S

T

NC

R

O

O S

T

T

Cl

CO2Et 75% mono:di = 7.3 : 1 (a) m:others = 7 : 1 O

O S

NC

(b)

SO2Ph

PO(OEt)2 55% m:others = 11 : 1

O

SO2Ph

CO2Et

65% m:others = 12 : 1

59%

O

O S

10% KOH in MeOH rt, 12 h 97%

OH

HO + NC

SO2Ph

Scheme 2.36 (a) meta-C–H olefination of 2-phenethylsulfonic acid derivatives. (b) Removal of directing template. Source: (a) Modified from Modak et al. [14].

functional-group tolerance was viable with this method to give good to excellent yields of products with exclusive E stereoselectivity. Direct transformation of a C—H bond to a carbon–heteroatom bond is highly important since their prevalence in complex natural products, pharmaceuticals, and agrochemicals. In 2016, Sunoj, Maiti, and coworkers achieved meta-C–H oxygenation of benzylsulfonyl esters by using an oxygenating agent PhI(OOCR3 )2 (Scheme 2.42) [40]. Notably, the formation of hydroxylated or acetoxylated molecules was obtained under similar reaction conditions with the variation of R (R = H, F) on the common agent PhI(OOCR3 )2 . Importantly, the approach had also been applied to the synthesis of unsymmetrically substituted phenols. In 2017, Maiti and coworkers disclosed a pyrimidine-based template assisted meta-C–H cyanation of benzylsulfonyl and 2-phenethylsulfonyl esters using stoichiometric amount of copper(I) cyanide as the cyanating agent (Scheme 2.43) [41]. The meta-cyano products are useful building blocks for synthesis of complex natural products as well as many drug molecules, and the synthesis of pharmaceutically valuable precursors was demonstrated by using this novel protocol. Deuterium-labeled compounds are important for pharmaceutical industry and kinetic studies of reaction mechanisms. In 2019, Werz, Maiti, and coworkers reported the Pd-catalyzed meta-C–H deuteration of benzylsulfonyl esters derivatives using readily available deuterium source such as deuterated acetic acid, assisted by readily removable pyrimidine-based template (Scheme 2.44) [26]. It

37

O

OBn

O S

n

T

Ag2CO3 (2.5 equiv) Cu2O (1 equiv) HFIP, O2, 80 °C, 36 h

O 95 O S

O

T

O 68% (m:others = 10 : 1)

Scheme 2.37

R H

S

74% (m:others = 10 : 1)

O S

O S

O R4

O 63% (m:others= 12 : 1)

O H 67% (m:others = 15 : 1)

Br

N

R2

O S

T

N Me

S

T

O O

O O O

O

R3

R

O

T

T=

T

n

96 O

T

Cl

Ag2CO3 (3.5 equiv) HFIP, O2, 80 °C, 30 h

n = 1, 2 T

O

R2 Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

T

n

O S

OH

O S

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

R

O

O

O

Me 74% (m:others = 10 : 1)

O 69% (m:others = 12 : 1)

meta-C–H olefination and alkylation of benzylsulfonyl and 2-phenethylsulfonyl esters. Source: Modified from Bag et al. [39].

2.2 Template-Assisted meta-C–H Functionalization R2 Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv) DCE:HFIP (1 : 1) rt to 80 °C, 24–48 h

SO2 T

R1

SO2 T

R1

T=

O

R2 N

98 O2N

Pd(OAc)2 (10 mol%) PhI(OAc)2 (4 equiv) Ac-Gly-OH (20 mol%)

H 97

SO2 T

R1

HFIP, Ac2O 80 °C, 24–36 h

OAc 99

Me

SO2 T

Br

SO2 T

F

F F

CO2Et

CO2Et 75% (mono:di = 10 : 1)

94%

SO2 T

SO2 T

Me

SO2 T

OAc

OAc

OAc

50%

64%

78%

Scheme 2.38 meta-C–H olefination and acetoxylation of benzylsulfonyl esters. Source: Modified from Dutta et al. [36].

O S O T

R

+

1

R

[{Rh(COD)Cl}2] (5 mol%) XPhos (10 mol%) Cu(CO2CF3)2·xH2O (1 equiv)

O S O T

R

V2O5 (1 equiv) DCE, 120 °C, 36 h

H

T=

OMe

O R1

100

CN

101 O S O T

O S O T

O S O T

Me

O S O T

MeOC CO2Et

CO2Et

69%

68%

SO2Ph 51%

53%

Scheme 2.39 Rh-catalyzed meta-C–H olefination of benzylsulfonyl esters. Source: Modified from Bera et al. [22].

was demonstrated that the template morphology was crucial for effectivity and selectivity of this remote C—H bond activation. Meanwhile, Yu, Dai, and coworkers also achieved an isolated example of meta-C–H deuteration of benzylsulfonyl esters using pyridine-based template. In 2017, the group of Maiti achieved an unprecedented meta-silylation and -germanylation of benzylsulfonyl esters by employing a nitrile-based phenolic directing template using readily available hexamethyldisilane as the silylating agent (Scheme 2.45) [42]. Notably, meta-silylation could be extended for 2-phenylethanesulfonic acids and 3-phenylpropane-1-sulfonic acid. Several

39

40

2 Remote meta-C–H Functionalization T= S

R1

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

T

O O +

RF

O O

Ag2CO3 (2.5 equiv) HFIP, 90 °C, 24 h

H

T

S

R1

O

N

103 RF

102

N

F T

Me

T S O O

S O O

C4F9

C4F9

69%

60%

F3 C

T S O O

F3C

T S O O

C2F4Br

C6F5

60%

63%

Scheme 2.40 meta-C–H perfluoroalkenylation of benzylsulfonyl esters. Source: Modified from Brochetta et al. [24].

S O O

R

O

Pd(OAc)2 (10 mol%) Ac-Nle-OH (20 mol%) Ag2CO3 (3 equiv)

T 1 + R

R2

T O

R

CuF2 (1 equiv) MeCN, 90 °C, 24 h

H

T=

O S

R2 N

102

104 O

O S

O

O

O S

T

O

T

F2HOC Me

Br

Me

Me

82% m:others = 18 : 1

Scheme 2.41 et al. [27].

Me 78% m:others = 14 : 1

T

T

Me

Me

O S

O S

N

R1

Me

Me Me

Me 66% m:others = 16 : 1

Me 71% m:others = 15 : 1

meta-C–H allylation of benzylsulfonyl esters. Source: Modified from Achar

examples of photosynthetic elaborations were attempted to demonstrate the synthetic utility, such as a formal synthesis of TAC101, a potential drug for the treatment of lung cancer.

2.2.5

Phenol Derivatives

In 2013, Yu and coworkers achieved an unprecedented meta-C–H functionalization of electron-rich phenol derivatives using the 2,2′ -azanediyldibenzonitrile directing template (Scheme 2.46), leading to a synthetically useful method for meta-functionalizing α-phenoxycarboxylic acids, the core structure of a fibrate class of drug molecules [43]. Remarkably, the selective C–H functionalization at the meta-positions of electron-rich phenol derivatives was especially useful since

2.2 Template-Assisted meta-C–H Functionalization

Pd(OAc)2 (10 mol%) Boc-Ala-OH (25 mol%)

X

Pd(OAc)2 (10 mol%) Formyl-Gly-OH (25 mol%)

H

O S O T

O S O T

F3CS

X

Scheme 2.42 et al. [40].

O S O T

S

n

Br

O S O T

OH 58% m/others = 20 : 1

meta-C–H oxygenation of benzylsulfonyl esters. Source: Modified from Maji

O Pd(OAc)2 (15 mol%) Ac-Gly-OH (30 mol%) Ag2CO3 (2 equiv)

T +

R n = 1, 2

MeO

51% m/others = 19 : 1

O

O

NC

OH

52% m/others = 17 : 1

71% m/others = 25 : 1

O O S O T

OH 106

F3CO

OAc

OAc

CuCN

CuCl (1 equiv) DCE:HFIP (10 : 1) 90 °C, 30 h

H

O

O

O S

T

O

T

n

O R CN

O S

T

T

Me CN 74% (m:others = 20 : 1)

T=

O S

N

N

108

107 S

T= OAc 105

PhI(TFA)2 (4 equiv) HFIP, 70 °C, 24 h

91

O

X

PhI(OAc)2 (4 equiv) HFIP, 70 °C, 24 h

O S O T

O S O T

CN

Cl

CN

77% 66% (m:others = 15 : 1) (m:others = 20 : 1)

S O

T

S

O CN

71% (m:others = 15 : 1)

O Me

T O

CN

76% (m:others = 10 : 1)

Scheme 2.43 meta-C–H cyanation of benzylsulfonyl and 2-phenethylsulfonyl esters. Source: Modified from Bag et al. [41].

it is orthogonal to previous electrophilic substitution of phenols in terms of regioselectivity. Notably, meta-C–H arylation of this class of phenol derivatives was also possible under the same meta-cross-coupling conditions of hydrocinnamic acids derivatives with arylboronic esters, although only a limited number of examples were demonstrated. Later in 2017, Zhou, Xu, and coworkers developed a nitrile-based organosilicon template assisted meta-C–H olefination of phenol derivatives in good yields with high meta-selectivities under similar reaction conditions (Scheme 2.47) [44]. Importantly, the organosilicon linkage could be easily cleaved under mild conditions, and

41

42

2 Remote meta-C–H Functionalization

Pd(OAc)2 (10 mol%) Ac-Gly-OH (10 mol%) [D4]acetic acid

T S O O

R

T= S

R

T O

O O

110 °C, 24–72 h

H 102

D 109

N

F D

[99]

S

T

O O

Me D

[99]

D

S

T

Cl

F

S

D

[87]

[86]

T

O O F

O O

Br

D

S

[85]

T

O O D

D

93%

91%

98%

Scheme 2.44 et al. [26].

[87]

N

[85]

97%

meta-C–H deuteration of benzylsulfonyl esters. Source: Modified from Bag

T= O OMe Pd(OAc)2 (10 mol%) O O Ac-Gly-OH (20 mol%) nS O nS O R R + Me3X XMe3 NC T T Ag2CO3 (3 equiv) R′ (X = Si, Ge) Na2SO4, HFIP, 45–70 °C T1: R′ = H; H n = 1, 2, 3 XMe3 T2: R′ = OMe 111 110 O O O O O T O S S O F S O S 1 S T1 T1 O O T1 T2 F F SiMe3 GeMe3 SiMe3 SiMe3 SiMe3 45% mono, 16% di

Scheme 2.45 et al. [42].

56%

52% mono, 19% di

45% mono, 10% di

45%

meta-C–H silylation and germanylation. Source: Modified from Modak

the directing template could be recovered under acidic conditions by using p-toluene sulfonic acid. Subsequently, Sun, Zhou, and coworkers achieved developed an Rh(III)-catalyzed meta-selective C–H olefination of phenol derivatives by using the same organosilicon template mentioned earlier (Scheme 2.48) [45]. A range of phenol derivatives and activated alkenes are viable in this reaction to produce meta-olefinated phenol products in good yields with high meta-selectivities. Recently, Xu, Jin, Yu, and coworkers developed bifunctional template assisted, palladium-catalyzed meta-selective C–H olefination of phenols (Scheme 2.49a), followed by nickel-catalyzed ipso-C–O activation and arylation (Scheme 2.49b) [46]. The sequential transformations could be carried out in a one-pot. Thus, this bifunctional template strategy allowed for the expedited synthesis of multiply substituted arenes. Notably, the novel template could be readily synthesized from inexpensive cyanuric chloride and was easily installed and smoothly removed. Finally, Maiti and coworkers also developed a Pd-catalyzed meta-C–H olefination of 2-phenyl phenol derivatives by using the 2-cyanobenzoyl group as the directing

2.2 Template-Assisted meta-C–H Functionalization

Me Me

O X T

Pd(OAc)2 (10 mol%) EWG Ac-Gly-OH (20 mol%) X AgOAc (3 equiv) HFIP, 90 °C, 24 h

+

O

H

O

Me Me

T

O

T= NC N NC

113 EWG

112 F

Me O

Me Me

T

O

Br

Cl

CO2Et

O

Me Me

T

O

F3C

CO2Et

Scheme 2.46

Me Me

O

Me Me

T

O

T

O

CO2Et

CONMe2

52% m:others = 96 : 4

84% m:others = 92 : 8

86% m:others = 98 : 2

O

82% m:others = 91 : 9

meta-C–H olefination of phenol derivatives.

T= T

O

R1

+

R

Pd(OAc)2 (10 mol% ) Ac-Gly-OH (20 mol%) AgOAc (2 equiv)

H

T

O

Et

Et

Si(iPr)2

R

DCE/HFIP (1 : 0.3) 60 °C, 24 h

114 O

O

T

CN

R1 115

T

O

T

T

O

MeO Br

CO2Et

CO2Et

73% m:others = 92 : 8

78% m:others = 91 : 9

CO2CH2CF3

PO(OEt)2 61% m:others = 95 : 5

56% m:others = 89 : 11

Scheme 2.47 Organosilicon template assisted meta-C–H olefination of phenol derivatives. Source: Modified from Mi et al. [44]. T= O

T +

R

R1

[RhCp*Cl2]2 (5 mol%) Cu(CO2CF3)2·xH2O (1 equiv) V2O5 (1 equiv) DCE, 120 °C, 36 h

H

O

T Et

R

Si(iPr)2 CN

R1

114

Et

115 O

T

O

T

O

T

O

T

Br Me

CO2Et 66% m:others = 90 : 10

CO2Et 57% m:others = 89 : 11

CN 61% m:others = 90 : 10

CO2CH2CF3 56% m:others = 88 : 12

Scheme 2.48 Rh(III)-catalyzed meta-C–H olefination of phenol derivatives. Source: Modified from Mi et al. [45].

43

44

2 Remote meta-C–H Functionalization T= T

O

+

R

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (1.5 equiv)

R1

R2

H

OMe

T

O

N R

HFIP, 80 °C, 36 h

N

R2 117

116

N

NC

R1

CO2Et O

T

O

T

O

Me

CO2Me CO2Et

F3C

81%

CO2Et 62%

T

T

Me

NHTFA

NPhth

O

CO2Me

59%

65%

(a) O

T +

R

ArB(OH)2

Ar

Ni(Xantphos)Cl2 (10 mol%) K3PO4 (7 equiv) Toluene, 110–120 °C, 24 h

R CO2Et

CO2Et 118

119 OMe

OMe

EtO2C

CO2Et F3C

(b)

90%

S

CO2Et 86%

CO2Et

CO2Et 75%

83%

Scheme 2.49 (a) meta-selective C–H olefination of phenols. (b) Nickel-catalyzed ipso-C–O activation and arylation. Source: (b) Modified from Xu et al. [46].

template that was once employed by Li and coworkers for meta-C–H olefination of phenylethylamines (Scheme 2.50) [47]. Although only a single 2-phenyl phenol substrate was utilized, the scope of the olefins was broad.

2.2.6

Alcohol Derivatives

Alcohols are important organic compounds widely found in many drug molecules. In 2013, Tan and coworkers reported a meta-C–H olefination of benzyl alcohols by using an effective bulky di-isopropyl silyl ether tethered nitrile-based template (Scheme 2.51) [48]. The template could be easily attached to the benzyl alcohol substrates and readily cleaved in situ with tetrabutylammonium fluoride (TBAF) under mild conditions, making the approach synthetically practical. Using the MPAA ligand Ac-Gly-OH in the presence of HFIP, a range of benzyl alcohols were meta-olefinated smoothly with all substitution patterns on the aromatic ring. Moreover, the template was applicable to both primary and secondary alcohols with equal efficacy. To expand the potential of achieving site selectivity in C–H activation via the recognition of distal and geometric relationship between existing chelating groups and C—H bonds of similar reactivity in organic molecules, Yu and coworkers

2.2 Template-Assisted meta-C–H Functionalization

O

T=

Pd(OAc)2 (10 mol%) Ac-Phe-OH (20 mol%)

T +

R

O

O

T

AgOAc (2 equiv) DCE:HFIP (7 : 1 v/v) 65 °C, 42 h, air

H

NC R 121

120

O

T

O

CO2Et

T

O

T

T

SO2Me

PO(OEt)2

65% m:o = 13 : 1

O

57%

SO2Ph

47% m:o = 12 : 1

61% m:o = 14 : 1

Scheme 2.50 meta-C–H olefination of 2-phenyl phenol derivatives. Source: Modified from Maity et al. [47].

m′ X

O

T +

(i) Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (3 equiv), HFIP (5 equiv) CO2Et DCE, 90 °C, 6–24 h X

m H

i-Pr Si i-Pr

T= OH

(ii) TBAF, rt, 1 h NC

122

123 CO2Et

s-Bu s-Bu

Me Me

OH

OH

OH

OH

MeO

CO2Et

CO2Et

51% (mono) m:others = 95 : 5 28% (di) mm′:others = 92 : 8

Scheme 2.51 et al. [48].

75% m/others = 95 : 5

CO2Et 51% (mono) m:others = 98 : 2 9% (di) mm′:others = 78 : 22

CO2Et 53% m/others = 96 : 4

meta-C–H olefination of benzyl alcohols. Source: Modified from Lee

engineered the first pyridine-based directing template that was effective for meta-C–H olefination of benzyl and phenyl ethyl alcohols (Scheme 2.52) [49]. This remarkable breakthrough is impressive, since the pyridyl group has only been extensively utilized to assist the ortho-C—H bond activation previously. Notably, this novel template also enabled a new meta-C–H iodination reaction by using DIH as the iodination reagent, which was not feasible with nitrile-based directing templates previously (Scheme 2.53). The aryl iodide products are synthetically useful intermediates, since they are amenable to a wide range of transformations such as the transition-metal-catalyzed cross-coupling reactions.

45

46

2 Remote meta-C–H Functionalization T= nO

X

+

T

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

R

T

AgOAc (3 equiv) HFIP, 80 °C, 18 h

H 124

O

nO

X

N

Me F

n = 1 or 2

125 R

Me Cl

O T

Me

O T

CO2Et

CO2Et

76% m/others > 20 : 1

O

O T

CONMe2

75% m/others > 20 : 1

65% m/others > 20 : 1

T

CO2Et 86% (mono/di = 1 : 1.4) m:others = 9 : 1

Scheme 2.52 meta-C–H olefination of benzyl and phenyl ethyl alcohols. Source: Modified from Chu et al. [49]. T= nO

X

T

AgOAc (0.5 equiv) HFIP/HOAc (4 : 1) 80 °C, 18 h

H 124 O

O

Pd(OAc)2 (10 mol%) TFA-Gly-OH (20 mol%) DIH (1.0 equiv)

O

T

T

T

n

O N

Me

I

X

n = 1 or 2

126 O

F

T

PhthN

O

T

Me I

Me

I

I

I

i-Pr 77% m:others > 20 : 1

Scheme 2.53

64% m:others = 5 : 1

47% m:o > 7 : 1

61% (mono), 8% (di) m:others = 5 : 1

meta-C–H iodination of benzyl and phenylethyl alcohols.

In 2017, Xu, Jin, and coworkers reported a Pd-catalyzed remote meta-C–H olefination of a wide range of arene-tethered alcohols such as 2-phenylethyl, 3-phenylpropyl alcohols, and their long-chain homologues (Scheme 2.54) [50]. This protocol would be potentially useful for late-stage modification and post-synthetic diversification of biologically active molecules for drug discovery. Density functional theory (DFT) computational studies were also performed to reveal that regioselectivity of this reaction resulted from both the C–N–Ag angles and gauche conformations of phenyl ether play. Subsequently, by using a different pyrimidine-based template that was used for meta-C–H cyanation of phenyl ethyl alcohols [41], Jayarajan, Maiti, and coworkers

2.2 Template-Assisted meta-C–H Functionalization

X

n

R

O

X

T +

R1

H 127 X = C, O, NBoc n = 0–8

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol %)

R

n

O

T

T= OMe

AgOAc (1.5 equiv) HFIP, 55 °C 128 R1

CN

O N

O 5

O

CO2Et 76% mono:di = 11 : 1

O

O

T

CO2Et 90% mono:di = 9 : 1

T

O

O

CO2Et 71% mono:di = 9 : 1

T

Me

O

T

SO2Ph 63%

Scheme 2.54 meta-C–H olefination of distal arene-tethered alcohols. Source: Modified from Zhang et al. [50].

achieved meta-C–H functionalizations of conformationally flexible long-chain arenes derived from alcohols (Scheme 2.55) [51]. The chain length could be up to 18 bonds between the target C—H bond and the chelating nitrogen atom of the directing template. Remarkably, this approach enabled diverse functionalizations include olefination, alkylation, cyanation, and acetoxylation. Moreover, the template could be readily cleaved by using ceric ammonium nitrate (CAN) under mild conditions (Scheme 2.56). It is worth noting that when perfluoroolefins were used, meta-C–H olefination was also feasible for these alcohol derivatives with different linker length under similar reaction conditions [24]. In 2019, Paton, Maiti, and coworkers developed the Palladium(II)-catalyzed meta-selective C–H allylation of alcohol derivatives using synthetically inert acyclic internal olefins as allylic surrogates, under the conditions discussed earlier for benzylsulfonyl esters (Scheme 2.57) [27]. Experimental and computational studies implied that the pyrimidine-based directing group was crucial this meta-selective C–H activation in determining the product selectivities. Notably, besides phenylethyl alcohols, alcohol derivatives with longer chain homologues could also be viable in this transformation. Recently, Wang, Kong, and coworkers developed the palladium-catalyzed meta-olefination of arene-tethered diols assisted by a pyrimidine-based template (Scheme 2.58) [52]. It was demonstrated this method could be used for the facile synthesis of various diol-based natural products such as coumarins. Moreover, removal of the template was easily realized by hydrolysis under acidic conditions. Finally, Yu, Dai, and coworkers also achieved meta-C–H deuteration of benzyl and phenyl ethyl alcohols with a pyridine-based template using easily available deuterium source such as deuterated acetic acid (Scheme 2.59) [19]. The template was linked to the substrate through a practical ester linkage that could be easily installed and cleaved. With high levels of D-incorporation at the meta-positions, this approach is potentially useful since deuterium-labeled compounds are important for mechanistic and metabolic studies.

47

R2 R1 Long chain

T

R R1 130 Long chain

T

R

OH

N

T

Pd(OAc)2 (15 mol%) Ac-Gly-OH (30 mol%) CuCN (3 equiv)

H 129

Ag2CO3 (3 equiv) Cu2O (2 equiv) HFIP, 110 °C, 30 h

Ac2O (4 equiv) HFIP, 100 °C, 24 h

131 T

R1 R2

T

O

132 Long chain

T

R CN 133

T

n

n n

T

n

OMe O

n = 3, 82% m:others = 15 : 1 n = 4, 68% m:others = 7 : 1 n = 5, 71% m:others = 5 : 1 n = 6, 70% m:others = 7 : 2

Scheme 2.55

R

Ag2CO3 (3.5 equiv) Cu2O (1 equiv) HFIP, 90 °C, 24 h

long chain R

Long chain

Pd(OAc)2 (15 mol%) Ac-Gly-OH (30 mol%)

O

Pd(OAc)2 (10 mol%) Ac-Gly-OH (25 mol%) PhI(OAc)2 (4 equiv)

OAc

N

T=

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv) DCE:HFIP = 10 : 1 80 °C, 18 h

R1

T

Me OAc

n = 2, 62% m:others = 13 : 1 n = 4, 55% m:others = 4 : 1 n = 6, 58% m:others = 4 : 1

O

n = 3, 76% m:others = 20 : 1 n = 5, 60% m:others = 9 : 2 n = 8, 55% m:others = 6 : 1 n = 10, 52% m:others = 9 : 2

CN

n = 2, 76% m:others = 20 : 1 n = 4, 65% m:others = 8 : 1 n = 5, 61% m:others = 4 : 1 n = 7, 57% m:others = 5 : 1

meta-C–H functionalizations of arenes with different linker lengths. Source: Modified from Jayarajan et al. [51].

2.2 Template-Assisted meta-C–H Functionalization

CAN (3 equiv)

O

N

OH

CH3CN, rt, 12 h 72%

N

CO2Me

CO2Me

Scheme 2.56

n

Removal of the pyrimidine-based template.

T=

Pd(OAc)2 (10 mol%) Ac-Nle-OH (20 mol%) Ag2CO3 (3 equiv)

T + R1

R2

R

O R

CuF2 (1 equiv) MeCN, 90 °C, 24 h

H

R2

134

Me

Me

Me

81% m:others = 15 : 1

Me

71% m:others = 15 : 1

63% m:others = 15 : 1

meta-C–H allylation of alcohol derivatives. Source: Modified from Achar

OH

O

O O

Me

Br Me

86% m:others = 20 : 1

Scheme 2.57 et al. [27].

T

Me OMe

Me

T +

R

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) R

H

AgF (3 equiv) Na2CO3 (2 equiv) HFIP, 100 °C, 24 h

n

n OH R

R1

137′

N

OR1

F3C

OR1

OR2

CO2Et

Scheme 2.58 et al. [52].

OR2

CO2Et

137a (62%); 137a′ (15%) m/others > 94/6

N

R1

OR2 OR1

OR1

O

R

OR2 Me

T=

T +

137

(n = 0, 1, 2)

Cl

N

R1

T

T

Me

136

N

135

T

n

T

n

CO2Et

137b (58%); 137b′ (8%) 137c (22%); 137c′ (4%) di: 10% m/others > 53/47 m/others > 90/10

CONMe2 137d (42%); 137d′ (15%) m/others > 95/5

meta-C–H olefination of arene-tethered diols. Source: Modified from Fang

49

50

2 Remote meta-C–H Functionalization

O R1

T=

R2

R2 n

Pd(OAc)2 (10 mol%) [D4]acetic acid

T

O R1

n

DCE 90 °C, 24 h

H 138 (n = 0, 1)

T F

O D 139

N

Me O

[95]

MeO

T

Me

[96]

O

[96]

Scheme 2.59

[10]

T

O

[95]

Me

MeO

80%

70%

2.2.7

O

[96]

Me

[95]

Me T

T

[10]

[96]

[95]

70%

61%

meta-C–H deuteration of alcohols. Source: Modified from Xu et al. [19].

Silane Derivatives

In 2016, Maiti and coworkers reported the Pd-catalyzed meta-C–H olefination of synthetically versatile benzyl silanes using a nitrile-based template (Scheme 2.60) [53]. Sequential olefinations through performing selective mono-olefination and bis-olefination were also demonstrated for synthesizing valuable 2,5- or 3,5-hetero divinylbenzene derivatives. Notably, the templated could be easily installed, and meta-olefinated toluene, benzaldehyde, and benzyl alcohols could be afforded while removing the silyl group with the template.

Si(i-Pr)2 + T

R

Pd(OAc)2 (7.5 mol%) Ac-Gly-OH (15 mol%) Ag2CO3 (2.5 equiv) R R′ DCE/TFE, 65 °C

H 140

T= Si(i-Pr)2 T

141

O NC

OMe

R'

Me Si(i-Pr)2 T

CO2Et

PO(OEt)2

82% Mono/di = 6.5 : 1

Scheme 2.60 et al. [53].

Si(i-Pr)2 T

73%

Si(i-Pr)2 T F3CS Me

CO2Et 63%

Si(i-Pr)2 T

CO2Et 81% Mono/di = 12 : 1

meta-C–H olefination of benzyl silanes. Source: Modified from Patra

Subsequently in 2017, Maiti and coworkers also developed a pyrimidine-based template assisted meta-C–H cyanation of benzyl silanes using copper(I) cyanide as the cyanating agent (Scheme 2.61a) [41]. The meta-cyano products are synthetically useful building blocks for preparing complex natural products as well as many drug

2.2 Template-Assisted meta-C–H Functionalization

molecules, and direct meta-C–H cyanation of benzyl silane and converting the silyl group to hydroxy group could be applied to the preparation of antidepressant drug citalopram (Scheme 2.61b). It is worth mentioning that meta-C–H allylation was also feasible with this template for benzyl silanes, although only limited examples were disclosed. i-Pr

Si

i-Pr

i-Pr Pd(OAc)2 (15 mol%) Ac-Gly-OH (30 mol%) Ag2CO3 (2 equiv)

T +

R

CuCN

H

i-Pr

S

i-Pr

i-Pr T

S

i-Pr

i-Pr T

S

T=

i-Pr T

O R

CuCl (1 equiv) DCE:HFIP (10 : 1) 90 °C, 30 h

142

S

CN

N

143 i-Pr

i-Pr T

S

i-Pr

i-Pr

S

N i-Pr T

T

F3CO CN

CN

78% (m:others = 20 : 1)

MeO

CN Cl 71% 65% (m:others = 20 : 1) (m:others = >20 : 1)

F3C

CN

74% (m:others = 18 : 1)

71% (m:others = 16 : 1)

CN

(a) i-Pr

Si

i-Pr

i-Pr T

Gram-scale

Si

i-Pr T

OH

(b)

O

KF, KHCO3 Me2N

H2O2

67% H

F

CN

77%

CN

CN Citalopram

Scheme 2.61 (a) meta-C–H cyanation of benzyl silanes. (b) Application of meta-C–H cyanation of benzyl silanes. Source: (a) Modified from Bag et al. [41].

2.2.8

Phosphonate Derivatives

In 2016, Bera, Maiti, and coworker achieved the first Pd(II)-catalyzed meta-C–H olefination of phosphonates at room temperature using the 2-cyanophenol template (Scheme 2.62) [54]. At elevated temperature, the reaction could be extended to meta-C–H hydroxylation or acetoxylation by varying the acetoxylating agent PhI(OCOR)2 . Notably, sequential di-meta-olefination would afford tri-alkenylated arenes that could be used in organic electronics as well as optoelectronics. Later in 2017, Maiti and coworkers achieved the meta-C–H alkylation of benzylphosphonates by using a pyrimidine-based template using allyl alcohols, leading to the formation of β-aryl aldehydes and ketones (Scheme 2.63) [39]. Notably, the generality of this meta-alkylation had been demonstrated in phenethylsulfonyl ester as well as phenethyl carbonyl scaffolds as discussed earlier. Moreover, meta-C–H cyanation of benzylphosphonates was also achieved by using the same pyrimidine-based template, albeit only two examples were disclosed [41]. Phosphonates are useful synthons in the synthetic chemistry, since they could be transformed readily to the versatile alkenyl product by well-established Horner–Wadsworth–Emmons reactions. And due to the importance of deuterium-

51

Pd(OAc)2 (10 mol%) Boc-Ala-OH (20 mol%)

R1

O P OEt Pd(OAc) (10 mol%) 2 T Ac-Phe-OH (20 mol%)

R

Ag2CO3 (2 equiv) HFIP, rt, 36 h R1 145

P OEt T

R H 144

O P OEt T

O P OEt T

P OEt T

Cl OAc

84%

Scheme 2.62

79%

67%

O

P OEt T

F

OAc

59%

meta-C–H functionalizations of phosphonates. Source: Modified from Bera et al. [54].

147

O Br P OEt T F

Me

OAc

NC

O P OEt T

R

O

Br

T=

OH 146

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) PhI(OAc)2 (2 equiv) Ac2O (2 equiv) HFIP, 80 °C, 24 h

O

MeOC CO2Et

PhI(TFA)2 (4 equiv) HFIP, 80 °C, 24 h

O

O P OEt T

R

O P OEt T

OH

OH

71%

65%

2.3 Mechanistic Considerations

P

P

T

Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%)

OH +

R1

R2

H

O P

EtO

O P

T

Me

EtO

Scheme 2.63

N

R2

O P

EtO

N

O P

T

Me

O Et 80% (m:others = 12 : 1)

O O 149

T

Me

T=

T

R1

Ag2CO3 (3.5 equiv) HFIP, O2, 80 °C, 30 h

148 EtO

O

EtO

O

EtO

T

Me

O

O

H 71% (m:others = 15 : 1)

O

Et 74% (m:others = 10 : 1)

Et 82% (m:others = 15 : 1)

meta-C–H alkylation of phosphonates. Source: Modified from Bag et al. [39].

labeled compounds for pharmaceutical industry and reaction mechanistic studies, efficient direct deuteration methods would be very valuable. Recently, Yu, Dai, and coworkers developed palladium-catalyzed meta-selective C–H deuteration of benzylphosphonates by using a pyridine-based directing template (Scheme 2.64) [19]. Notably, this method could be generally used for other substrates such as benzylsulfonates and benzyl alcohols via the practical ester linkage. T= O P T OEt

R

Pd(OAc)2 (10 mol%) [D4]acetic acid

R

80 °C, 24 h

H 150

Me

[96]

70%

Scheme 2.64

O F

D 151 O P T OEt

[96]

O P T OEt

O P T OEt

[94]

F

[94]

O P T OEt

[96]

MeO

72%

N F [93]

F

[96]

[95]

74%

68%

O P T OEt

meta-C–H deuteration of phosphonates. Source: Modified from Xu et al. [19].

2.3 Mechanistic Considerations The mechanisms of the aforementioned template assisted meta-C–H activation reactions are still not exactly very clear at present. However, detailed mechanistic investigations through computational and experimental mechanistic studies have been performed by such as the groups of Houk, Yu, and Wu, and the Maiti group to gain some hints of the reaction mechanism.

53

54

2 Remote meta-C–H Functionalization

The representative template assisted meta-C–H activation is olefination via Pd(II)/Pd(0) process with the nitrile-based directing template. Thus, a tentative catalytic cycle could be proposed for this reaction (Scheme 2.65). The catalytic process proceeds through five major steps: C–H activation, olefin binding and alkene migratory insertion, β-hydride elimination, reductive elimination, and re-oxidation of the Pd-catalyst. Computational study using density functional theory elucidated that the C–H activation step, which proceeds via a concerted metalation–deprotonation (CMD) pathway, was the rate- and regioselectivity-determining step [55]. However, unlike the presentation in Scheme 2.65, it was found that the C–H activation with the nitrile-based directing template occurred via a Pd–Ag heterodimeric transition state (Scheme 2.66). Moreover, the nitrile directing template coordinated with Ag an end-on fashion rather than the Pd metal center. The Pd was then linked with Ag by the bridging acetate ligand and delivered to the meta-C—H bond in the transition state, resulting in the observed high meta-selectivity. However, it is worth noting that not all the template assisted meta-C–H olefination required the use of silver salt, such as the meta-C–H olefination of benzoic acids by the Li group [28]. In addition, significant effects of distortions of the template were observed in the structural and distortion energy analysis of the transition states, which had help to devise the conformationally flexible directing template for benzoic acids by the groups of Houk and Yu in 2017 [29]. 2 Ag(0) 2 Ag(I)

[LPdII] H

Re-oxidation

C–H activation

L + [Pd0]

N C A

HX Reductive elimination [LPdII] N C

[LPdII] H X F

B

β-Hydride elimination

Olefin binding and migratory insertion

R C

N R

C

E

Scheme 2.65

R

N

C

[LPdII] D

Proposed catalytic cycle for meta-C–H olefination.

2.4 Conclusion

O H O O

Pd

C N

O

O

Ag

O Pd–Ag heterodimeric transition state Scheme 2.66

Proposed transition state through computational study.

Subsequently, Houk, Yu, Wu, and coworkers revealed the dual roles of the amino acid ligand in improving reactivity and selectivity through mass spectrometry (MS) and DFT calculations [56]. It was found that the amino acid ligand aced as both a dianionic ligand and a proton acceptor, leading to the stabilization of the monomeric Pd complexes and serving as the internal base for proton abstraction through a CMD pathway. Besides the MPAA ligand, the HFIP solvent is another key factor for most of the template assisted meta-C–H activation reactions. Although the exact role of HFIP is unknown at present, Maiti and coworkers proposed that the solvent HFIP could act as a coordinating ligand in the early stage of the reaction to promote the reaction through experimental and computational investigation [40, 54]. Moreover, they also found that the hydrogen-bonding between HFIP and the pyrimidine-based template was vital to decrease the basicity of the pyrimidine group and increase the π-acidity of the Pd center based on nuclear magnetic resonance (NMR) studies [51].

2.4 Conclusion Since 2012, the directing template approach has promoted a range of meta-selective C–H activation reactions with several classes of substrate. Three major classes of directing templates have been engineered by recognition of the geometry and distance between the directing atom and the target meta-C—H bonds. The number of transformation types also increases gradually since the first discovery of meta-C–H olefination. Despite the advances, the directing template strategy still suffers from several limitations. First, the transformation type is still limited, such as amination, fluorination, and alkynylation are not feasible at present. Thus, new protocols with possible new templates are needed. Second, it is not step-economic to link the template with the substrate with a covalent bond. Although breakthroughs in using catalytic amount of templates have been disclosed, these protocols were limited to special substrates and suffer from limitations such as high metal catalyst loadings and high molecular weights. Therefore, the discovery of more efficient systems using template through non-covalent interaction is highly desirable. Third, the

55

56

2 Remote meta-C–H Functionalization

high catalyst loading and the use of precious metal catalysts are not practical for the application of this method for large scale synthesis. The search for more effective catalytic protocols using low-cost metal catalysts and even in a low loading is well-worth investigating. In short, there are still many opportunities for exciting discoveries in the field of meta-C–H functionalization assisted by directing templates.

Abbreviations Ac Ala Ar Boc Bn Bu CAN cat. CMD DCE DG DIH DMF DMPU equiv EDG EWG Gly HFIP KIE L LDA m Me MPAA NMP o p Ph Phe Pin Piv Pr TBA TFA TBAPF6

acetyl L-alanine aryl tert-butyloxycarbonyl benzyl butyl ceric ammonium nitrate catalytic concerted metalation–deprotonation 1,2-dichloroethane directing template 1,3-diiodo-5,5-dimethylhydantoin N,N-dimethylformamide 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone equivalent electron-donating template electron-withdrawing template glycine hexafluoroisopropanol kinetic isotope effect ligand lithium diisopropylamide meta methyl mono-N-protected amino acid N-methylpyrrolidinone ortho para phenyl L-phenylalanine pinacol pivaloyl propyl tetrabutylammonium trifluoroacetic acid tetrabutylammonium hexafluorophosphate

References

TFE THF XPhos

trifluoroethanol tetrahydrofuran 2,4′ ,6′ -diisopropyl-1,1′ -biphenyl-2-yldicyclohexylphosphine

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59

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis Juntao Ye 1 and Mark Lautens 2 1 Shanghai Jiao Tong University, School of Chemistry and Chemical Engineering, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs and Frontiers Science Center for Transformative Molecules, 800 Dongchuan Road, Shanghai 200240, China 2 University of Toronto, Department of Chemistry, Davenport Laboratories, 80 St. George Street, Toronto ON M5S3H6, Canada

3.1 Introduction Substituted aromatic rings are ubiquitous scaffolds in bioactive natural products, pharmaceuticals, agrochemicals, and synthetic materials [1], and chemists have spent more than a century seeking ways to selectively functionalize simple aromatic starting materials to make value-added products. The development of selective and efficient C–H functionalization reactions of arenes represents an emerging field to achieve this objective. However, precise control of site selectivity remains a great challenge. While significant advances have been made in this area by taking advantage of covalently bound heteroatom-containing directing groups (DGs) [2, 3], additional synthetic steps are required for the installation and removal of such directing groups and thus lower the overall reaction efficiency. To circumvent this problem, an alternative strategy that relies on an in situ generated directing group, also known as transient directing group, has attracted increasing attention in recent years [4]. Aryl halides and pseudohalides are an important class of feedstock widely used by synthetic chemists for various transition metal-catalyzed cross-coupling reactions [5]. However, methods that allow for selective functionalization of aromatic C—H bonds of aryl halides and pseudohalides remain scarce. In 1997, Catellani et al. reported seminal studies on Pd-catalyzed ortho-C–H alkylation of aryl iodides where norbornene (NBE), a strained bicyclic alkene, was utilized as a transient mediator for this transformation (Scheme 3.1) [6]. By using a pre-formed phenylnorbornylpalladium(II) (PNP) dimer catalyst, simple iodoarenes 1 were converted to o,o′ -disubstituted vinylarenes 2 in a single step in the presence of an alkyl iodide and an olefin. Notably, both ortho- and ipso-positions of aryl iodides were simultaneously functionalized in a highly selective manner. A catalytic cycle that involves three oxidation states of palladium, i.e. Pd(0), Pd(II), and Pd(IV), was proposed by the authors (Scheme 3.2). Oxidative addition of Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

60

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

R2 I H

H

+ R1I

R2

+

PNP dimer (5 mol%)

R1

Cl

K2CO3 DMA, 20 °C

R1 = alkyl

R

Pd

R1

R 2

1

Cl

Pd

PNP dimer

Scheme 3.1 Catellani’s initial report on C–H functionalization of iodoarenes under Pd/NBE catalysis. Source: Modified from Catellani et al. [6].

H

R2 R1

I PdllX Pd0

R

R

Int6 H

R1

XPdll R1

PdlII

R2

R

R

Int1

2

R

Int5

X R1 PdIV

Int4

R

R

IPdll H

3

Pd0

R

Int2 Pdll

Base

R1–I

Int3

Base·HI

R ANP

Scheme 3.2 Proposed catalytic cycle for the ortho-C–H alkylation of aryl iodides under Pd/NBE catalysis.

Pd(0) to aryl iodide followed by intermolecular carbopalladation of NBE generate norbornylpalladium intermediate Int2, which places palladium in proximity to the ortho-C—H bond. Since syn-β-hydride elimination, a step commonly observed in a Heck reaction is not possible here due to the unique and rigid structure of the nobornyl moiety, an ortho-C–H metalation occurs with the aid of a base, forming the key arylnorbornylpalladacycle (ANP) Int3. This electron-rich ANP

3.1 Introduction

further reacts with alkyl iodides to form Pd(IV) species Int4, which undergoes reductive elimination to give the ortho-alkylated intermediate Int5. At this stage, a second ortho-alkylation would occur following the same sequence (Int2 → Int5) if the R group of iodoarene is hydrogen, otherwise, NBE extrusion via β-carbon elimination would occur due to the increased steric strain of Int5, giving rise to arylpalladium(II) species Int6, which then undergoes a traditional Heck reaction to afford the final vinylarene product 2 and regenerate the Pd(0) catalyst. It should be noted that the PNP dimer catalyst used by the authors could directly enter the catalytic cycle by reacting with an alkyl iodide and generate a Pd(0) species after one catalyst turnover. However, there are several drawbacks of using this catalyst: (i) its synthesis uses a toxic mercury reagent (PhHgCl) [7]; (ii) the product will be contaminated with an iodobenzene-derived by-product arising from the first catalytic cycle; (iii) ortho-substituted iodoarenes are not reactive under the reaction conditions. To circumvent these issues, in 1999 Catellani and Cugini developed a modified procedure for ortho-C–H alkylation of ortho-substituted iodoarenes by using Pd(OAc)2 (20 mol%) as catalyst [8]. This variant of the reaction suffered from low conversion and selectivity even when alkyl iodides and olefins were added slowly with syringe pump (Scheme 3.3). The major by-products are benzocyclobutene derivatives 3, which result from reductive elimination of the ANP intermediate Int3 as shown in Scheme 3.2. R2 I Pd(OAc)2 (20 mol%) NBE

R +

R1I

+

R2

K2CO3, KOAc DMA, 55 °C Slow addition

R1 = alkyl

Scheme 3.3

R1

R

+

4 8–76%

3

R

ortho-C–H alkylation of ortho-substituted iodoarenes under Pd/NBE catalysis.

Inspired by the pioneering work of Catellani, Lautens developed an annulative strategy for ortho-C–H alkylation of aryl iodides in 2000 by using olefin-containing alkyl bromides 5 as the alkylating reagents, providing a straightforward route to benzo-fused carbocycles 6 in one step (Scheme 3.4) [9]. Lautens developed a modified catalytic system, namely, the combination of a Pd(II) salt and a phosphine ligand R I R′

CO2Et

R +

Br n

CO2Et 5

Pd(OAc)2, TFP NBE, Cs2CO3 CH3CN, reflux

R′ n

6 25–93%

Scheme 3.4 Lautens’ modified reaction conditions for ortho-C–H alkylation of aryl iodides. Source: Modified from Lautens and Piguel [9].

61

Table 3.1

Bisfunctionalization of aryl (pseudo)halides under Pd(0)/NBE catalysis. Pd(0)

R

R X

Nu + E Y

R′

+ Nu Z

R′

Base

E

X = I, Br, OTf E Y

R1

X

or

A

R1 A = NR2 or O Alkylation

Section 3.2.1 Nu Z

R1

R

1

R1

ArB(OH)2 2

R

R1

CO2H

R1

Me Me OH

MeB(OH)2 B2Pin2

R2

Acylation and alkoxycarbonylation

Arylation Section 3.2.2

R1

R1

O

ArX

Section 3.2.3

PhCH2OH iPrOH iPrB(OH) 2 PhCH2Cl MeO(CH2)2OMe

R2 N OBz

Ts

Thiolation

Section 3.2.4

Section 3.2.5 H Het

R1R2NH

O R1

R1S R1Se

O Ar

H Fn R1 R2

H R3

R1 NR2

Ar

CH2CN Ar

R1

Amination

R1OH

CN

S

R1

3.1 Introduction

(Pd(OAc)2 and tri-2-furylphosphine [TFP] proved most effective). Moreover, Cs2 CO3 and CH3 CN were found to be the optimal base and solvent, respectively. This set of modified conditions not only improved the efficiency of this reaction significantly but also proved to be quite general in a wide variety of transformations (vide infra). Since then, the chemistry Pd(0)/NBE joint catalysis has been expanded significantly, initially largely by Catellani and Lautens and later by many others over the last two decades, allowing for introduction of a wide variety of functionalities into the ortho- and ipso-positions of aryl (pseudo)halides in a quite selective and efficient manner [10]. As shown in Table 3.1, ortho-C–H functionalization includes alkylation, arylation, acylation and alkoxycarbonylation, amination, and thiolation were achieved using different types of electrophilic reagents (E–X), which will be discussed in detail in Sections 3.2.1–3.2.5. For ipso functionalization, terminating reagents (Nu–Y) used so far include Heck acceptors, terminal and internal alkynes, arylboronic acids and bis(pinacolato)diboron, hydride transfer reagents (benzyl and isopropyl alcohol, alkyl boronic acids, benzyl chloride, 1,2-dimethoxyethane [DME], etc.), carbon nucleophiles (cyanids, enolates, carbenes, etc.), O-, N-, S-, and Se-containing nucleophiles, heteroarenes, fluorinated arenes, and even sp3 C—H bonds. Given that ortho-functionalized aryl–Pd(II) intermediate Int6 (see Scheme 3.2) shows electrophilic character, most of the terminating reagents used are nucleophilic in nature. Nevertheless, aromatic ketones and imines are two exceptions that were used as terminating reagents in ortho-arylation reactions (see Section 3.2.2). Moreover, the groups of Bach, Yu, Dong, Zhang, Zhou, and others have recently extended this chemistry to Pd(II) catalysis, enabling selective C–H functionalization of NH-indoles and NH-pyrroles, directing group (DG)-containing arenes, and

R

R

Pd(II)

N H

H

R1X

DG

DG Pd(II)

R

B

R1X = alkyl/aryl halide

R1

R2 Pd(II) R1X, R2Y w or w/o oxidant

R2 N OBz, ArOSO2Cl TIPS Br

R1

R

OR′ H

R

R′ R1X

H

R′O

1 R1 R X = alkyl/aryl halide

N H

R1

R′′

R1X = alkyl/aryl halide R1

R R2Y =

O O R2 N Ar O OBz , Ar R3, HX

Scheme 3.5 Pd(II)-initiated C–H functionalization of arenes under Pd/NBE catalysis. Source: Wegmann et al. [10e] and Cheng et al. [10h].

63

64

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

arylboron compounds (Scheme 3.5) [10e, h]. These aspects will be discussed in Sections 3.3.1–3.3.3. This review will provide a comprehensive summary of C–H functionalization of arenes under Pd/NBE catalysis and cover literature up to June 2019. We will first discuss Pd(0)-initiated reactions in Section 3.2 and then Pd(II)-initiated reactions in Section 3.3. Since the mechanistic aspect of Pd/NBE catalysis has been discussed in great detail in a 2010 monograph [10b] and by Catellani [10a, 11], this review will primarily focus on synthetic applications of this chemistry, although mechanistic discussion will be presented wherever necessary.

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides 3.2.1 3.2.1.1

ortho-Alkylation ortho-Alkylation with Simple Alkyl Halides

Since Catellani’s first report in 1997, ortho-alkylation of aryl (pseudo)halides using simple alkyl halides have been extensively studied and nicely summarized in several recent reviews [10g, i]. Therefore, the emphasis will be focused on seminal early work followed by recent developments in this area. In Catellani’s initial work using ortho-unsubstituted iodoarenes, two identical alkyl groups were introduced to the ortho and ortho′ positions (Scheme 3.1). To increase diversity of the vinylarene products, it is desirable to install two different groups at the ortho-positions using two alkylating reagents. Control of the selectivity proved to be very challenging. In 2003, Lautens achieved this goal by making one of the two alkylation events intramolecular and the other intermolecular. Specifically, iodoarene substrates 7 tethered with an alkyl iodide moiety were treated with an alkyl iodide and a Heck acceptor using their modified catalytic system (Pd(OAc)2 /PPh3 ), affording polysubstituted five- and six-membered bicyclic oxacycles 8 in moderate to good yields (Scheme 3.6) [12a]. In the absence of an external alkylating reagent, dimeric products 9 were obtained but simple monoalkylated adduct 10 was not detected. The authors proposed that intermolecular alkylation was likely the first step, based on steric considerations, followed by intramolecular alkylation and a Heck reaction. The same group later extended the methodology to the synthesis of tricyclic heterocycles 12 by installing two alkyl bromide moieties on the iodoarenes [12b, c]. A tricyclic mescaline analogue 13 was prepared by taking advantage of this strategy. Using Zn(CN)2 as the terminating reagent, tricyclic benzonitriles 14 were obtained under otherwise similar conditions [12d]. While primary alkyl iodides and bromides have been extensively used as alkylating reagents in Pd/NBE chemistry, no examples were reported for fluorinated alkyl halides until 2014. Liu and coworkers achieved an ortho-C–H trifluoroethylation of aryl iodides via Pd(0)/NBE catalysis (Scheme 3.7) [13]. With the aid of an electron-rich phosphine ligand (DavePhos), trifluoroethyl iodide was successfully

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

R′

EWG I

EWG I

n

O

+ RI

EWG

EWG

R

Pd(OAc)2/PPh3 NBE, Cs2CO3 DMF, 80 °C

n

O 8 37–87%

7

9

O

n

O 10

R′ = I or

EWG

R1

I

NH3Cl R1

Br m

X

X

n

Br

R 11 X = O, S, NTs, –CH2O–, –OCH2SiMe2–

Pd(OAc)2/PPh3 NBE, Cs2CO3, DME Microwave irradiation 190 °C

n

m

X

O

X

O OMe

R 12 19–85%

13 Mescaline analogue

I CN Br m

O

O R 11

n

Br

Pd(OAc)2/PPh3 Zn(CN)2

n

m

NBE, Cs2CO3, DME Microwave irradiation 150 °C

O

O R 14 56–88%

Scheme 3.6 ortho-Alkylation of ortho-unsubstituted iodoarenes with two different alkyl halides. Source: Modified from Pache and Lautens [12a].

R1

R I R′

+ CF3CH2I

Pd(OAc)2 DavePhos NBE, Cs2CO3 HOAc, DMI/CH3CN 110 °C

R R1 R′

CF3 15 36–82%

NMe2 PCy2

DavePhos

Scheme 3.7 ortho-C–H trifluoroethylation iodoarenes with trifluoroethyl iodide. Source: Modified from Zhang et al. [13].

alkylated at the ortho position, providing multisubstituted vinylarenes 15 in moderate to good yields. It should be noted that the change from ethyl iodide to trifluoroethyl iodide is nontrivial as it has been documented that both the oxidative addition of CF3 CH2 I to palladium catalyst and the reductive elimination of CF3 CH2 –Pd–aryl complex are very challenging steps [14]. Secondary alkyl iodides are another class of challenging alkylating reagents. Early on, Catellani observed that reactions with isopropyl iodide are very sluggish [8]. By tethering secondary alkyl halide moiety to iodoarene, a sequence involving intramolecular ortho-alkylation followed by intermolecular Heck reaction was developed by Lautens, giving rise to oxygen- and nitrogen-containing functionalized bicyclic heterocycles 17 under microwave irradiation conditions (Scheme 3.8). By using iodoarenes that contain a secondary alkyl iodide moiety and a terminating

65

R

R

I R1

+

X Y

Me 16 X = I, Br Y = O, NTs

R1

Pd(OAc)2/PPh3 NBE, Cs2CO3, DME Microwave irradiation 180 °C

Y

m

n

Y

20 X = I, Br Y = N, C; Z = S, CH

Pd(OAc)2/PPh3

Y

m

n

18

R = Me or H Scheme 3.8

R

NBE, Cs2CO3, DME Microwave irradiation 180 °C

R1

R n–1

Y

m

19 12–78%

ortho-Alkylation with racemic secondary alkyl iodides.

I R′

Y

NBE, Cs2CO3 DME or CH3CN Microwave irradiation 140–160 °C

I I

Pd(OAc)2 PPh3

I

+ R1

Z

Pd(OAc)2/PPh3

Z

X O

R

R

Me

I

Me 17 35–79%

R

Me

R2

NBE, Cs2CO3 CH3CN or DMF Sealed tube 90 °C

n

Y

m

21 29–90%

R R1 R′

R2 22 R1 42–99%

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

olefin or heteroarene, multi-fused heterocycles 19 and 21 could be prepared in a single step [15a, b]. The same group further developed a procedure for intermolecular ortho-alkylation with secondary alkyl iodides, affording sterically congested vinylarenes 22 in 42–99% yields [15c]. To provide further insight into the mechanism of reactions under Pd(0)/NBE catalysis, Lautens investigated the stereochemical outcome of reactions using enantioenriched secondary halides (Scheme 3.9). For reactions involving intramolecular alkylation, enantioenriched substrates (R)-16a and (S)-18a provided the corresponding bicyclic and tricyclic products 17a and 19a with almost complete retention of enantiopurity, although nitrogen containing substrate (R)-16b afforded the product 17b with obvious loss of enantiopurity [15a]. Furthermore, it was found that the reaction proceeded with overall inversion of configuration, suggesting that oxidative addition of secondary alkyl iodides to Pd(II) to form Pd(IV) species proceeds with overall inversion of configuration since reductive elimination typically occurs with retention of stereochemistry [16]. When enantioenriched secondary alkyl iodide 23 was treated with aryl iodide in an intermolecular fashion, complete transfer of stereochemical information was observed when acetonitrile was used as the solvent [15c]. Interestingly, when the reaction was carried out in dimethylformamide (DMF) under otherwise identical conditions, significant racemization was observed: 24 was obtained with only 40% ee, and the recovered alkyl iodide 23 was almost racemic. Me

Me I

OtBu

+

I

O

X

Me

CO2tBu

Pd(OAc)2/PPh3 NBE, Cs2CO3, DME Microwave irradiation 180 °C

Me X

(R)-17 X = O, 17a, 42%, 92% ee X = NTs, 17b, 55%, 63% ee

(R)-16 X = O, 16a, 96% ee X = NTs, 16b, 80% ee Me

CO2tBu

Me

I Pd(OAc)2/PPh3

I O

CO2tBu

NBE, Cs2CO3, DME Microwave irradiation 180 °C

(S)-18a 82% ee

(S)-19a 78%, 80% ee

OMe I

I + Me

OTBS

23 95% ee

Scheme 3.9

H

O

CO2tBu Pd(OAc)2 PPh3 NBE, Cs2CO3 CH3CN or DMF Sealed tube 90 °C Then TFA

OMe CO2H *

24

CH2OH

Me

53%, 94% ee (in CH3CN) 65%, 40% ee (in DMF)

ortho-Alkylation with enantioenriched secondary alkyl iodides.

67

68

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

While the aforementioned chirality transfer strategy provided a route to enantioenriched ortho-alkylated arenes, catalytical asymmetric ortho-alkylation under Pd/NBE catalysis would be a more efficient and attractive way for their synthesis. To this end, Gu and coworkers developed an asymmetric Catellani-type reaction involving an ortho-alkylation/ipso-Suzuki coupling sequence using chiral ligand L1, which contains axial chirality and P-center chirality, affording synthetically useful biaryl aldehydes 25 in moderate to excellent yields with up to 96% ee (Scheme 3.10) [17]. Interestingly, introducing an aldehyde moiety into both NBE and the arylboronic acids proved to be beneficial for improving the reaction efficiency, although the reasons remain unknown. R1

I

Cl

OC(O)Ar

R1 R

CHO

Pd(TFA)2/L1 (±)-NBE–CHO

+ CHO B(OH)2

K2CO3, MeCN 65 °C

NMe2 OC(O)Ar R 25 28–90% 76–96% ee

(±)-NBE–CHO =

P

L1

t Bu

i

Pr t Bu

CHO

Scheme 3.10 Asymmetric ortho-alkylation of iodoarenes under Pd/NBE catalysis. Source: Modified from Ding et al. [17].

In ortho-alkylation of iodoarenes, Heck acceptors, boronic acids, and cyanides are commonly used terminating reagents. Recent work from the groups of Liang [18], Zhou [19], Gu [20], and others [10g] have expanded the scope of terminating reagents for ortho-alkylation reactions (Scheme 3.11). In 2014, Liang and coworkers employed carbene precursors, in the form of N-tosylhydrazones 27, to terminate the intramolecular alkylation of iodoarenes 26. Polycyclic substituted vinylarenes 28 arise via an ortho-C–H alkylation/carbene migratory insertion/β-H elimination sequence [18a, b]. By using copper(I) iodide as a co-catalyst, electron-deficient polyfluoroarenes were successfully used as terminating reagents by the same group, affording polyfluoroarene-substituted benzofuran derivatives 31 in moderate to excellent yields [18c]. The authors proposed that polyfluoroaryl copper species formed in situ underwent transmetalation with ortho-alkylated aryl Pd(II) to give the final product after reductive elimination. While Lautens and coworkers utilized heteroarenes to terminate the reaction via intramolecular C–H insertion [21], intermolecular ipso-heteroarylation was not reported until 2015 when Zhou and coworkers found that NaOH could be used as the base for ipso-heteroarylation using benzoxazoles, oxazoles, and thiophenes with or without a copper(I) co-catalyst [19a]. The same group later used the same base for ipso-enolate coupling using methyl ketones and acetonitrile [19b]. In 2004, Catellani and coworkers utilized ipso-Sonogashira reactions to terminate ortho-alkylation reactions using aryl substituted terminal alkynes [22]; however, slow addition of both alkylating reagents and terminal alkynes was required to minimize the formation of by-products (34b and 34c) under their phosphine-free

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

Ar

Ar

X R Y

NNHTs

+

Ar Me Z n 27 26 X, Y = Br, I; Z = O, NTs n = 1, 2, 3 I

O 29 X = I, Br, Cl

n

R

Cs2CO3, dioxane 80 °C

Z

Fn

Int7

n

Z

Pd(OAc)2, TFP NBE

Y Z = O, S, NMe Y = N, CHO

R1 = alkyl X = Br, I

n

31 38–93%

Z

+

Z

O

R + R1X

Me

R

R R′

n

Cs2CO3, dioxane 120 °C

30

I

Pd

R

28 38–93%

Pd(OAc)2, 2-PyPPh2 CuI, NBE

R X

Ln

Fn

H +

Pd(OAc)2, PPh3 NBE, H2O

NaOH, NaI w or w/o CuBr MeCN, reflux

Y

R′ R1 32 43–85% R

R I R′

R1X R1 = alkyl X = Br, I

Scheme 3.11 reagents.

R2 or CH3CN

Me +

+

Pd(OAc)2, P(p-tol)3NBE NaOH, NaI 1,4-Dioxane, 90 °C

R′

R3

R1 33 R3 = R2C(O), CN 30–81%

Recent work on ortho-alkylation reactions using various terminating

conditions (Scheme 3.12). Zhou and coworkers recently found that the reaction efficiency could be improved without slow addition by employing Lautens’ modified conditions (TFP as ligand, Cs2 CO3 as base, and CH3 CN as solvent) [19c]. Gu and coworkers developed an alternative strategy for ipso-alkynylation by using 1,1-dimethyl-2-alkynyols 36 as masked terminal alkynes [20]. The alkoxypalladium species Int8, formed via anion exchange of 1,1-dimethyl-2-alkynyol with ortho-alkylated aryl Pd(II) species, underwent β-carbon elimination to generate alkynylpalladium intermediate Int9, which then delivers the final product 35 after reductive elimination. This strategy avoids the use of reactive terminal alkynes and greatly inhibits the formation of by-products. The first application of ortho-alkylation of iodoarenes under Pd/NBE catalysis in natural product synthesis was reported by Lautens and coworkers in 2013, who disclosed a route to (+)-linoxepin (Scheme 3.13) [23]. By using enantioenriched iodolactone 38 as the alkylating reagent and an acrylate as the terminating reagent, the key intermediate (−)-39 was obtained in 89% yield on gram scale, which then delivered the natural product in three steps.

69

70

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

Ar

Ar

I Pd(OAc)2 NBE

R1Br +

+

KOAc, DMA rt

Ar

R 1

1

R

R

+

+ Ar

R (Slow addition)

34b

R 34a

R 34c

R

R2

R I +

R′

R1X

+

R2

R1 = alkyl X = I, Br, Cl

Pd(OAc)2/TFP

H

R2 = alkyl, aryl, siyl

R I +

R′

R 1I

+ R2 36

1

R = alkyl

R

L Pd L

R′

O

R′

NBE, Cs2CO3, NaI MeCN, 90 °C

R1 35 38–86%

Me Me OH

R′

Cs2CO3, MeCN 100 °C

R1 35 57–93%

R2 = alkyl, aryl R

Me Me

Pd L R1 Int9

O R2

Me

R2

L

R′

R1 Int8

R2

R

Pd(OAc)2 P(p-MeO–C6H4)4 NBE, MgSO4

Me

Scheme 3.12 ortho-Alkylation/ipso-alkynylation reactions using terminal alkynes or 1,1-dimethyl-2-alkynyols. O O I

OMe 37

O

Br +

O

CO2tBu

O 38

O

Br

Pd(OAc)2/PPh2

H O

CO2tBu

I

O

H

O

H

NBE, Cs2CO3 DMF, 90 °C

3 steps

O

O OMe (–)-39 89%

O

O

OMe

O O

(+)-Linoxepin

Scheme 3.13 Total synthesis of (+)-linoxepin using ortho-alkylation/ipso-Heck coupling of iodoarene 37 as the key step. Source: Modified from Weinstabl et al. [23].

3.2.1.2

ortho-Alkylation with Bifunctional Alkylating Reagents

Since the first report of using olefin-containing alkyl bromides as a bifunctional alkylating reagent under Pd/NBE catalysis in 2000 [9], Lautens and Piguel have explored a wide variety of bifunctional alkylating reagents for the expedient synthesis of fused heterocycles. By using alkyl bromides bearing a heteroarene, such as indoles, pyrroles, azaindoles, pyrazoles, indazoles, thiophenes, and furans, as alkylating as well as terminating reagents, an array of heterocycles 40 were prepared

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

via ortho-alkylation and ipso-heteroarylation in a single step (Scheme 3.14) [21, 24]. R

R I

+

R′

Het

Br

Pd(II), TFP NBE, Cs2CO3 CH3CN, 90 °C

n

Het

R′ n

40 Cl

Me MeO

N

N

CO2Et

CF3

N

N

Cl

MeO

TsMeN

40a 93%

40b 75%

Me

N

N

MeO2C

40c 66%

40d 55%

Cl Me Me S

CF3 N 40e 94%

N

AcHN

Me S

Me O

O2N

Cl O

40f 70%

40g 66%

40h 53%

Scheme 3.14 ortho-Alkylation/ipso-heteroarylation of iodoarenes with heteroarene-tethered alkyl bromides. Source: Bressy et al. [21], Blaszykowski et al. [24a], Martins et al. [24b], Blaszykowski et al. [24c], Martins et al. [24d], Laleu and Lautens [24e].

Alkyl bromides containing other type of nucleophilic functionalities have also been used as bifunctional alkylating reagents (Scheme 3.15). For example, Lautens and coworkers employed bromoalkylamines 41 for the synthesis of indolines and tetrahydroquinolines 42 [25]. Using indole-containing alkyl bromides 43 as the alkylating reagents, Liang and coworkers achieved the synthesis of spiroindolenine derivatives 44 via an alkylation/dearomatization sequence [26a]. Notably, this study represents the first example of using a dearomatization process to terminate the reactions under Pd/NBE catalysis. The same group also demonstrated the application of cyclopentanone-containing alkyl bromides 45 for the synthesis of spirodihydroindenones 46 where intramolecular enolate coupling was utilized to terminate the reactions [26b]. By combining ortho-alkylation with redox-relay Heck reactions [27], Zhou and coworkers developed a novel approach for the construction of tetrahydronaphthalene and indanes derivatives 48 bearing a synthetically useful aldehyde moiety [28]. Olefinic alcohol-containing alkyl bromides or iodides 47 are also used as bifunctional reagents. The NBE derivative, 5-norbornene-2-carboxylic acid (NBE-CO2 H), was found to show much higher reactivity than NBE itself. Notably, by using the phosphoramidite ligand L2 developed by Carreira and coworkers [29], the authors achieved the asymmetric version of this reaction with moderate yield and enantioselectivity. Furthermore, the synthetic utility of this methodology was demonstrated in a four-step total synthesis of analgesic drug (±)-eptazocine. Alkyne-tethered alkyl bromides are another class of bifunctional reagents widely used for the expedient synthesis of various fused polycyclic compounds under

71

72

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

R

R I

R′

Br

+

NHAr

n

41 n = 1, 2

Pd(OAc)2, TFP NBE, Cs2CO3

I +

R′

n

42 24–86%

N H

CH3CN, 90 °C

R′

43

44 22–66% R2

R2

R I R′

+

Pd(OAc)2 P(m-Cl–C6H4)3

R1

Br

Cs2CO3, NBE THF, 60 °C

n

45 n = 1, 2

O

R′

Br

+

R1

R O

R′ n

46 22–74%

R I

R1

N

R

[Pd(π-allyl)Cl]2/TFP NBE, K2CO3

Br

R1

R′

CH3CN, 135 °C or microwave 180 °C

R

Ar N

OH

n

m

e 47 M m, n = 1 or 2

R Me

[Pd(π-allyl)Cl]2 XPhos NBE–CO2H

m CHO

R′

K2CO3, MeCN 70 °C

n

48 23–93%

NBE–CO2H = (±) CO2H I OH

+ Br

[Pd(π-allyl)Cl]2, L2 NBE or NBE–CO2H or N1

R

CHO ∗

K2CO3, MeCN 70 °C

R R = Me or H

17–58% 40–78% ee O

O P N O

N O

[Pd(π-allyl)Cl]2 XPhos NBE–CO2H

I

BnO +

OH

Br 47a Me

Scheme 3.15 catalysis.

K2CO3, MeCN 70 °C

Me

N1

L2

Me N 3 steps

BnO Me 48a 53%

CHO

HO Me (±)-Eptazocine

ortho-Alkylation using bifunctional alkylating reagents under Pd/NBE

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides R1 51 N

N I R

MeCN, 90 °C

49

N

NH

51

52 15–90%

53 20–90%

Br

R1

Pd(OAc)2/TFP NBE, K3PO4

I R

THF/DMF 65 °C 1 R = aryl, alkyl

54

Me I

R 56

55 63–92%

Int10

O Ph

Br Pd(OAc)2/TFP NBE, K3PO4 THF/DMF 65 °C

57 68%

Z

ZH n

R′ + I R

Ph 51a

O

N

R′

R

R

R1

R′

Ln R1 Pd R′

R1

or R

R1 = Ar

50

R1

N

PdCl2/TFP NBE, Cs2CO3

I

or

R

Br

Br R1 n = 1–3

58 Z = O, NBoc, CHCO2Et

Pd(OAc)2,TFP NBE Cs2CO3, DMF 90 °C

R1

R′ R

n

59 32–95%

Scheme 3.16 ortho-Alkylation of iodoarenes containing terminating functionality using alkyne-tethered alkyl bromides.

Pd/NBE catalysis (Scheme 3.16). When iodoarenes containing a terminating reagent at the ortho-position were alkylated with alkyne-tethered alkyl bromides, intramolecular alkylation followed by multiple intramolecular cyclizations would rapidly build up molecular complexity. Lautens and coworkers reported the first example in 2008 for the synthesis of tetracyclic fused pyrroles 52 from 1-(2-iodophenyl)-1H-pyrrole 49 and alkyne-tethered alkyl bromides 51 [30a]. Following the ortho-alkylation event, intramolecular carbopalladation onto the tethered alkyne occurs to give the vinyl palladium species Int10, which then undergo C–H functionalization at the adjacent electron-rich pyrrole ring. The same group later found 1-(2-iodobenzyl)-1H-pyrrole and -indoles 50 showed similar reactivity to give seven-membered-ring fused heterocycles 53 in 20–90% yields [30b]. Inspired by these studies, Luan and coworkers utilized an arene dearomatization process to capture the intermediate Int10, affording an array of interesting spiro-polycycles. Specifically, by using iodoarenes 54 bearing a 3-indolyl substituent at the ortho-position and bromoalkyl alkynes 51, spiroindolenine-containing pentacyclic products 55 were obtained in good yields in a single step [31a]. Based on preliminary mechanistic studies, the authors proposed that the final indole dearomatization step may involve an olefin coordination/insertion and β-hydride elimination sequence, which was further supported by the fact that benzofuran-containing substrate 56 also afforded the desired product 57 in 68%

73

74

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

yield under the standard reaction conditions. The same group further extended this methodology to iodoarenes 58, providing an easy access to spiro-polycyclic scaffold 59 in moderate to excellent yields [31b]. It is worth mentioning that in addition to phenol-derived substrates, naphthylamine- and naphthalene-based iodoarenes are also suitable substrates. For simple iodoarenes lacking a terminating functionality, reactions with bromoalkyl aryl alkynes lead to different types of tetrasubstituted helical alkenes depending on the structure of the aryl substituent (Scheme 3.17). For example, when simple bromoalkyl aryl alkynes 51 were used, NBE incorporation was observed to give helical alkenes 60 via the intermediacy of Int11 [32a]. Notably, when enantiopure bromoalkyl aryl alkynes were employed, chiral helical alkenes were obtained with almost complete retention of center-chirality, moderate induced helical chirality, and exclusive exo-facial selectivity. Interestingly, when an additional aryl or heteroaryl group was installed onto the terminal aryl ring, intramolecular C–H functionalization is favored over intermolecular NBE insertion for vinyl palladium species Int12, giving rise to structurally diverse and sterically crowded tetrasubstituted helical alkenes 62–65 [32b, c]. Complete retention of central-chirality and moderate helical chirality was also observed when enantiopure alkyl bromides were used. Ln

R1

R1

R +

R′

Br

H

61 99% ee

R

R2

R′

or

Scheme 3.17

R

64

1

Z R

or

R R′

63

R

N

R2

R′ 62

R1

or

R

Int12

R1

N

R2

R′

39–92% 97% to >99% ee 9 : 1 to 10 : 1 dr

R1

R1

Ln Pd R

Cs2CO3, CH3CN 90 or 120 °C

R2

Br

Int11

Ar

Pd(OAc)2 PPh3 or TFP NBE

Ar +

R2 R′

60 40–95% 94% to >99% ee 5 : 1 to 6.7 : 1 dr R1

I

R

R2

R′

51 ≥99% ee

R′

R

MeCN, 90 °C

R2

R

R1

Pd(OAc)2/TFP NBE, Cs2CO3

I

Pd

2

R2

R′ Z = O, S, NR3 65

ortho-Alkylation of simple iodoarenes with alkyne-tethered alkyl bromides.

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

3.2.1.3

ortho-Alkylation with Three-Membered Heterocycles

In addition to alkyl halides, strained three-membered heterocycles such as 2H-azirines [33], N-substituted aziridines [34], and epoxides [35] have also been utilized as alkylating reagents in Pd/NBE-catalyzed reactions by taking advantages of their ring strains. Lautens and coworker were the first to use this strategy for the synthesis of indoles 67 from iodoarenes and aryl-substituted 2H-azirines 66 (Scheme 3.18) [33]. Interestingly, when a large excess of 2H-azirines (4 equiv) were used, polycyclic dihydroimidazole heterocycles 68 were obtained as the major product. Mechanistically, oxidative addition of the N—C single bond to the aryl/NBE palladacycle affords Pd(IV) intermediate Int14 or Int15, which then R

R I +

R′

N

Pd(OAc)2 P(m-Cl–C6H4)3

66

NBE, Cs2CO3 MeCN, 90 °C

Ar

Ar

R′

67

or

Ar N

N Ar

R′

68 41–86% yields

67 54–95% yields

R

R

N

Tautomerization

R

H N

I

Ar

+ NBE + Cs2CO3

Int18 Pd0 R Pd

R N N

Ar Pd ANP

Int17

NBE

Ar 66

R R Pd N Ar

Pd Ar

Int13

N Int16 R R Pd δ

Pd δ

N Ar

δ

Nδ

Int14 Ar Int15

Scheme 3.18 Pd/NBE-catalyzed reactions of iodoarenes with aryl-substituted 2H-azirines. Ligand on palladium is omitted for clarity. Source: Modified from Candito and Lautens [33].

75

76

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

undergoes chemo-selective C—C bond formation to yield intermediate Int16. NBE extrusion followed by reductive elimination provides intermediate Int18, which then converts to the final indole products 67 through tautomerization. Tautomerization of intermediates may also occur at an earlier stage of the catalytic cycle. The dihydroimidazoles 68 might be formed via a Pd(0)-catalyzed formal [3 + 2] reaction of an azirine with the C—N double bond of intermediate Int18. In 2018, the groups of Liang [34a] and Zhou [34b] independently reported the use of aziridines as alkylating reagents (Scheme 3.19). In Liang’s work, aziridines 69 were used as both alkylating and terminating reagents, yielding indoline products 70 (R1 = H or alkyl) or a mixture of regioisomers 70 and 71 when 2-aryl-substituted aziridines (R1 = aryl) were utilized [34a]. When enantiopure aziridine (S)-69a was subjected to the reaction conditions in the presence of 1-iodonaphthalene, (R)-70a with retention of configuration and (S)-71a with inversion of configuration were

R

SO2Ar N

Pd(OAc)2 P(m-Cl–C6H4)3 NBE, K2CO3

69

w or w/o H2O Toluene/DME, 100–105 °C

I +

R′

R1

R R′

ArO2S

+

SO2Ar N

Ph (S)-69a Ar = 4-BrC6H4 >99% ee

Pd(OAc)2 P(m-Cl–C6H4)3 NBE, K2CO3 H2O Toluene/DME, 105 °C

Ph

(R)-70a 9% >99% ee, retention

Me N Pd

N

(S)-71a 43% >99% ee, inversion

N

Int20

EWG Ts N

EWG

R

Pd(OAc)2/TFP N1 (20 mol%)

R1

K2CO3, CH3CN 70 °C

72

EWG

R or

NTs

R′

R1

R1 = H, alkyl 41–90%

N

N1 O

NTs

R′

O

Scheme 3.19

ArO2S

N Ts

R

69

71 R1 Obseved when R1 = aryl

Ph

Int19

+

R′

N

Me

R′

+

SO2Ar N

+

N N Pd N Ts

I

R

70 16–93%

R1 = H, alkyl, aryl

I

SO2Ar N R1

Me

Pd/NBE-catalyzed reactions of iodoarenes with aziridines.

73

R1 R1 = aryl 40–63%

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

obtained without any loss of enantiopurity, suggesting that an SN 2 nucleophilic ring-opening of aziridines by the ANP is likely involved in this reaction. In an effort to isolate reaction intermediates, phenanthroline was added as a ligand and two key intermediates Int19 and Int20 were isolated and characterized by X-ray crystallography. This study provided further support to the key NBE extrusion step. In contrast with Liang’s work, Zhou and coworkers employed electron-deficient olefins to terminate this reaction, providing straightforward access to tetrahydroisoquinolines 72 or 73 via a Catellani reaction/aza-Michael addition sequence [34b]. Although NBE itself is a competent mediator for the reaction when it is used in large excess (3 equiv), readily available NBE derivative N1 proved to be more efficient and only 20 mol% is required to achieve comparable efficiency. The reaction is compatible with a wide variety of aryl iodides, electron-deficient olefins, and aziridines, providing tetrahydroisoquinoline products in moderate to excellent yields. Notably, when 2-aryl-substituted aziridines were used in place of 2-alkyl-substituted aziridines, switch of regioselectivity was observed to afford 1,4-cis-substituted tetrahydroisoquinolines 73. In the same year, the groups of Dong [35] and Zhou [36] also independently reported the use of epoxides 74 as alkylating reagents (Scheme 3.20). Dong found the combination of Buchwald’s Ruphos-Pd-G4 precatalyst (4–10 mol%) and an iso-propyl ester substituted NBE 75 (20 mmol%) was optimal, providing the desired 2,3-dihydrobenzofuran products 76 in moderate to excellent yields [35a]. The synthetic utility of this methodology was demonstrated in a three-step synthesis of the insecticide fufenozide in high yield. Notably, enantioenriched 2,3-dihydrobenzofurans with 31–42% ee could also be obtained by using enantiopure NBE catalyst (+)-75, which can be easily prepared using 2,10-camphorsultam as a chiral auxiliary [35b]. Almost at the same time, Zhou and coworkers reported the use of Pd/XPhos complex and the potassium salt of 5-norbornene-2-carboxylic acid 78 as catalysts for the same transformation [36a]. Notably, only 10 mol% of mediator 78 is required to achieve 48–97% yields of the reaction. Moreover, no extra base is needed in this protocol as the mediator 78 is also acting as a base. While epoxides are both alkylating and terminating reagents in the aforementioned reactions, the Zhou group also showed that electron-deficient olefins can be used as the terminating reagent to afford ortho-alkylation/ipso-Heck reaction products 79, providing an easy access to isochroman scaffolds 80 via a following oxa-Michael addition [36b]. It’s noteworthy that a methylated analogue of D4 agonist U-101387 81 could be prepared in just one step starting from the corresponding isochroman product. When bifunctional epoxides containing an olefin moiety were used, macrocycles 79a and 79b that are otherwise difficult to prepare could be obtained in a single step in synthetically useful yields.

3.2.2

ortho-Arylation

In the ortho-alkylation reactions of aryl halides, there is no selectivity issue in the reductive elimination of Pd(IV) species Int4 (R1 = alkyl) as sp2 –sp3 reductive elimination is more favored than sp3 –sp3 reductive elimination. However, in the

77

78

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

R

R I

O

+

R′

R1

(±)–74

RuPhosPd-G4 (±)–75 (20 mol%) NaOAc DMF, 120 °C

O

OMs Pd RuPhos

R1

R′

N H Me

76 44–99%

PCy2 Oi Pr

i PrO

RuPhosPd-G4 Me

O

I

OMe

Me Me

RuPhosPd-G4 (±)–75 (20 mol%)

+ O

NaOAc DMF, 120 °C

O

O

Me 2-steps

OMe

Me

O

N H

N

Me O

Fufenozide

R I

RuPhosPd-G4 (±)–75 (20 mol%)

O

+

R′

R1 (±)–74

NaOAc DMF, 120 °C

O R′

* * R1

(±)–75 CO2iPr

R I +

R′

O

R1

(±)–74

R

Pd(OAc)2 XPhos (±)–78 (10 mol%) NMP, 80 °C

O R′

+

O

R1 (±)–74

EWG (±)–78 (50 mol%) NMP, 60 °C

i Pr

i Pr Cy2P

R1 i Pr XPhos

76 48–97% EWG

R

Pd(OAc)2/XPhos

I

*

76 54–92% 31–42% ee

R

79 47–96%

EWG

R Cs2CO3

OH

R′

(±)–78 CO2K

CH3CN, 60 °C

R1

O

R′ 80

O Me

Me

N

N

SO2NH2

Me

O

NHMe

81

Scheme 3.20

79a 56%

O OH

O

O

R1

O

OH O

t Bu

O

Me

77 85%

Me

R

R′

RuPhos

(±)–75 CO2iPr

O

O NHMe

79b 42%

Pd/NBE-catalyzed reactions of iodoarenes with epoxides.

ortho-arylation reactions of aryl halides lacking an ortho substituent, exemplified by the homocoupling of 4-fluorobromobenzene 82, a mixture of regioisomers 83 and 84 resulting from aryl–norbornyl coupling and aryl–aryl coupling was obtained (Scheme 3.21) [37]. To circumvent this problem, Catellani and coworkers found that highly selective aryl–aryl coupling can be achieved simply by adding an ortho substituent in the iodoarenes. This observation, which was termed as the “ortho effect,” proved to be very general and have been widely applied in Pd/NBE-catalyzed reactions [10, 11]. The first example was reported in 2001 by Catellani et al. who used internal alkynes as the terminating reagents to afford phenanthrene derivatives 85 (Scheme 3.22) [38a]. Following this work, the same group used a wide variety of terminating reagents (R1 –Y), including olefins [38b], aryl boronic acids [38c], benzyl alcohol

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

Br Pd(PPh3)4 NBE BuOK, anisole 105 °C 45% (83/84 = 1/3)

2

t

F

+

F

F F

F

82

83

84

Br

F F

L

Pd

L

Ar PdBrL2

F

Int21

+ F

Ar

Ar = 4-FC6H4

Int22

PdBrL2

Int23

Scheme 3.21 Pd/NBE-catalyzed homocoupling of 4-fluorobromobenzene. Source: Modified from Catellani and Chiusoli [37].

R

I 2

R

+ R1

R2

R

Pd(OAc)2 NBE

+

K2CO3, TBAB DMF, 105 °C

R1

R

R

R2

R2

R1

85 33–93% I 2

R

+ R1 Y

Pd(OAc)2 NBE Base

R1 R R R2

R′ Ar R

R R 86 73–98%

R1 Y =

R′

H R

R 87 49–93% ArB(OH)2

R3

O R

R R 89 29–82%

R 88 48–87% PhCH2OH

X

R 90 62–82%

R2

R3 O

X

(X = O, S, NR)

Scheme 3.22 Pd/NBE-catalyzed homocoupling of ortho-substituted iodoarenes. Source: Modified from Catellani et al. [38a].

79

80

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

[38d], ketones [38e], and heteroarenes [38f], to functionalize the ipso position of iodoarenes, providing a new route to biaryls 86–90 with high efficiency. It is noteworthy that benzyl alcohol was found to be an efficient hydride donor for ipso-reduction to give 2,3′ -disubstituted biaryl derivatives 88 in moderate to good yields. To expand the diversity of biaryls that can be accessed via Pd/NBE catalysis, Catellani continued to investigate the cross-coupling of two different aryl halides, which is more challenging than the homocoupling reactions as up to four products may be formed (Scheme 3.23). Based on the mechanism of the reaction, one can assume that the selectivity might be improved if one of the two aryl halides has much higher reactivity toward Pd(0), while the other reacts preferentially with palladium(II) complex, i.e. the ANP Int3. Indeed, Catellani found that highly selective cross-coupling can be achieved by tuning the electronic property of the two aryl halides, that is, by using iodoarenes with an ortho electron-donating group (EDG) and aryl bromides with an electron-withdrawing group (EWG) [39]. Such a strategy proved to be very general in the presence of different types of terminating reagents such as electron-deficient olefins [39a], cyanide anion [39b], hydride donor [39c], and aryl boronic acids [39d], affording the corresponding cross-coupling biaryls 91–94 with high selectivity. Notably Lautens and coworkers found that DME could serve as a hydride donor when used as the solvent for the ortho-arylation/ipso-reduction reactions [39c]. R1 R1

R2 I

X

+

R2

R1

R2

R′ Pd/NBE

R′ + R2

R′

R′ +

+

R1

R1

R′ R2

X = I, Br EDG

Br

EDG I

+

R2 Pd/NBE

+ R2 Y

Base

R1

R1 R1 = EWG EDG

EDG

EDG EWG R1

91 13–83% R2 Y=

EWG

EDG H

CN

Ar R1

R1 92 31–94% K4[Fe(CN)6]·3H2O

93 33–95% Me

O

O

R1 94 61–90%

Me

ArB(OH)2

Scheme 3.23 Pd/NBE-catalyzed cross-coupling of iodoarenes with electron-poor bromoarenes.

In addition to bromoarenes bearing an EWG, bromoarenes with an ortho-chelating group have also been found to undergo selective cross-coupling of iodoarenes and bromoarenes (Scheme 3.24). In 2006, Catellani and coworkers reported such an example by treating ortho-substituted aryl iodides with 2-bromophenols 95 in

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

R I

OH + R1

R′

EWG

R

Br

Ar

EWG Pd(OAc)/NBE

O

R′

HO

K2CO3, DMF 80 °C

N H

H Ar = 1-naphthyl 97

R1 96 46–93% With 97 (25–50 mol%): 40–75%, 80–97% ee

95

R Br

R

OH +

I + R1

R′

Pd(OAc)2 DavePhos NBE

R2

Cs2CO3, DMF 100 °C

R3

98

R2

R′

R3 O

R1 99 46–89%

R

R R′ PdX OH

R2

R3

R1

R3

R′

XPd OH

R1 Int24

EtO2C

R2

I EtO2C

CO2Et Br I R + R1

OH

Cs2CO3, DMF 100 °C

Ar 100

Pd(OAc)2 P(o-tol)3 NBE

98

CO2Et

R Ar O R1 101 52–68%

Scheme 3.24 ortho-Arylation of iodoarenes using o-bromophenols and 1-bromo-2-naphthols in the presence of alkenes or alkynes.

the presence of an activated olefin, affording cross-coupling/oxa-Michael addition product 6H-dibenzopyran derivatives 96 in a single step [40a]. Given that 4-bromophenol and 2-bromoanisole did not react under the reaction conditions, the authors proposed that the chelating effect of the ortho-hydroxyl group is of critical importance for the reaction. By using cinchona alkaloid 97 as an organocatalyst, Zhou and coworkers recently achieved the asymmetric version of this reaction and dibenzopyran derivatives were obtained with 80–97% ee [40b]. Instead of using activated alkenes as terminating reagents, Luan and coworkers employed internal alkynes to couple with ortho-substituted iodoarenes and 1-bromo-2-naphthols 98 [41]. Following the crossing coupling and NBE extrusion steps, a sequence involving alkyne migratory insertion and arene dearomatization followed, leading to spirocarbocyclic products 99 in moderate to excellent yields via the intermediacy of Int24 and Int25. By introducing the alkyne moiety into aryl iodides, the two-component

81

82

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

reaction proceeded smoothly to provide biologically relevant polycyclic skeletons 101 in synthetically useful yields. Catellani showed N-containing functionality can also be utilized as the ortho-chelating group for selective unsymmetrical biaryl coupling (Scheme 3.25). For example, 5,6-dihydrophenanthridine derivatives 102 could be prepared from ortho-substituted aryl iodides, ortho-bromoarenesulfonylanilines, and activated olefins following a cross-coupling/aza-Michael addition sequence [42a]. Interestingly, when the substituent on nitrogen was changed to a trifluoroacetyl group, a retro-Mannich reaction occurred to provide phenanthridines 103 as the final products [42b]. Similarly, Malacria and coworkers found that dibenzoazepines 104 could be accessed from bromobenzylamines and aryl iodides in the presence of a Heck acceptor [43]. Notably, when an enolizable olefin such as methyl vinyl ketone was employed, imine derivatives 105 were obtained following a retro-Mannich reaction.

R I + R1

R

NHSO2R2 Br +

EWG

R Pd(OAc)/NBE

EWG

N

R′

K2CO3, TBAB CH3CN, 80 °C

R1

102 31–89% R I + R1

R′

NHCOCF3 Br +

SO2R2

R Pd(OAc)/NBE

COMe

N

R′

K2CO3, TBAB CH3CN, 80 °C

R1

103 40–93% EWG R1

R

Pd(OAc)/P(iPr)3 NH2 NBE

I R′

+ R2 Br

R

R

EWG

N

NH R′

R1

R1

or R′

K2CO3, DMF 130 °C

R2

R2 EWG = CN, CO2R3 104 32–75%

EWG = COMe 105 33–77%

Scheme 3.25 ortho-Arylation of iodoarenes using bromoarenes with N-containing chelating group in the presence of an activated alkene.

In the absence of an external terminating reagent, bifunctional aryl bromides or chlorides could be used to couple with aryl iodides to provide fused heterocycles in a single step under Pd/NBE catalysis (Scheme 3.26). In 2006, Catellani and coworkers demonstrated that 6-phenanthridinones 107 and their heterocyclic analogues could be accessed in 35–90% yields using amides of o-bromoarene- and heteroarenecarboxylic acids 106 as the arylating as well as the terminating reagents [44a]. Lautens and coworker reported the use of ortho-chloro-N-silylaldimines or N-silylketimines 108 as coupling partners of ortho-substituted aryl iodides,

O

R

NHR2

I

Br + R1

R′

MeCN or DMF 85 or 105 °C

R I

Cl

Pd(OAc)2/PPh3 NBE

108 R3 = TMS, TBDMS, H R1

R I

+ R2

R′

I R′

+

R2 NH S Br

R1

Scheme 3.26

R2

109 22–97%

MeCN 85–105 °C

111

R′

R N R′

Pd(OAc)2/PPh3 NBE

R2

R′

Br

Pd(OAc)2 PPh3 or Cy3PHBF4 NBE, Cs2CO3

R1

ortho-Arylation of iodoarenes using bifunctional aryl halides.

+

Cl R1

R Pd(OAc)2/PPh3 NBE, Cs2CO3 MeCN, 90 °C

119

R1 118 46–93%

Me

I R′

112 45–95%

O

R

O

R′

DME, 90–150 °C

R2 = H or OMe 117 O S R2

R1

R

+ R1

R′

OH R2

116 64–82%

I

(2) O2, 130 °C

Pd(OAc)2, PPh3 NBE, K2CO3

R3 114 66–99%

H2O, Cs2CO3 DME, 90 °C

O

R

R1

N

R2

R′

115

R

110

O

+ R1

R′

K2CO3, DMF105 °C

R1

O

R Cl

109 31–98%

(1) Pd(OAc)2/PPh3 NBE, Cs2CO3 NH2 DMF, 130 °C

Br

R

I

R2

Pd(OAc)2 NBE

R2

O

R

R′

Cs2CO3, MeCN 90 °C

OH

Br 113 R1, R2 ≠ H

R1

N

R

R2

+ R3

R1

R

+ R2

R'

O R′

R1

R1 I

R′ 107 35–90%

106 R3 N

R

R2 N

R Pd(OAc)2/PPh3 NBE, K2CO3

OH R′ 120 47–70%

R1

84

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

giving rise to phenanthridine derivatives 109 in moderate to excellent yields via ortho-arylation/ipso-amination followed by in situ desilylation [44b]. Interestingly, Malacria and coworkers found that the same products could be prepared from 2-bromobenzylamines 110 and aryl iodides under Pd/NBE catalysis followed by Pd(II)-catalyzed oxidative dehydrogenation [44c]. Recently, Chen and coworkers showed that NH-sulfoximines 111 could be coupled with ortho-substituted aryl iodides to yield polyheterocyclic sulfoximines 112 in good yields [44d]. In addition to nitrogen-containing functionalities, hydroxyl group of o-bromobenzyl alcohols 113 can also be utilized to terminate the reaction via C–O ring closure, providing 6H-dibenzopyrans 114 in modest to excellent yields [44e]. It should be noted that only tertiary alcohols are suitable substrates as β-H elimination occurs to give o-biaryl carbaldeydes or ketones for primary and secondary alcohols. While the ortho-functionalized aryl–Pd(II) intermediates formed after NBE extrusion can act as a electrophilic partner, and react with nucleophilic terminating reagents as shown earlier, Lautens found nucleophilic reactivity under certain reaction conditions. During their investigation of ortho-arylation of iodoarenes using carbonyl-containing aryl bromides and chlorides as the bifunctional coupling partners, the authors found that by using DME as the solvent and water as the additive, 2′ -chloroaryl ketones 115 coupled with ortho-substituted aryl iodides to afford 9H-fluoren-9-ols 116 via an ortho-arylation/ipso-1,2-addition sequence (Scheme 3.26) [44f]. When 2′ -bromoaryl aldehydes or esters 117 were employed, ipso-1,2-addition to the carbonyl groups has also been observed to provide 9H-fluoren-9-one 118 as the final products, although water is not required for these reactions. Interestingly, subtle variation of reactions conditions for 2′ -chloroacteophenones 119, i.e. by using anhydrous CH3 CN as the solvent instead of wet DME, electrophilic character of the ortho-arylated aryl–Pd(II) species was restored, providing phenanthren-9-ols 120 in 47–70% yields. o-Bromophenols have also been utilized as bifunctional reagents in ortho-arylation of iodoarenes; however, the reaction scope proved to be very limited and only dibenzofuran 121a and 121b were isolated as the major product (Scheme 3.27) [45]. Interestingly, hydroxybiphenyl products 122 were obtained as the main product for most of the substrates, indicating that NBE extrusion did not occur and an unusual β-H elimination from the palladium-bonded norbornyl group occurred, which was attributed by the authors to be due to the chelating effect of the phenolic group (Int27). It should be noted, however, the same authors had shown that NBE extrusion occurred readily to give 6H-dibenzopyran products 96 in the presence of activated olefins (Scheme 3.24), presumably because the presence of olefins inhibit the formation of Int27-type eight-membered palladacycle. In addition to using the aforementioned bifunctional arylating agents, aryl iodides containing a terminating functionality have also been employed for the one-step synthesis of fused heterocycles (Scheme 3.28). In 2010, Lautens and coworkers used this strategy for the rapid construction of benzomorpholine scaffolds 124 from amine-tethered iodoarenes 123 and electron-deficient bromoarenes [46]. Notably, when methyl-2-bromobenzoate was treated with iodoarene 123a, under the reaction conditions, the expected phenoxazine product further reacted with the

R

R OH

I +

Br

Pd(OAc)2 NBE K2CO3, DMF 120 °C

O R = Me, 121a, 45% R = CF3, 121b, 75% 121

R I R′

R Pd(OAc)2 NBE

+

PdBrL

R′

OH R1 Br

+L –HBr

K2CO3, DMF 105 °C

L H Pd L O

R′

R1 HO Int26

R

R

R1

R1 HO

Int27

95

Scheme 3.27

R′

ortho-Arylation of iodoarenes using o-bromophenols. Source: Modified from Motti et al. [45].

122 45–75%

Br O

NHR1 O

Br

n

I +R

2

NH2

n

Pd(OAc)2 P(m-ClC6H4)3 NBE, K2CO3

N

R1

I

N

+

I

124a 60%

HN

O

O

O

P N

3 steps

OHC

CO2tBu

N

N OHC

NO2

127 85% With L3 as the ligand: 65%, 88% ee

126

Scheme 3.28

123a

O2N

Cs2CO3 Dioxane, 85 °C

Br

O

CO2tBu

PdCl2/PPh3 NBE

125

N Pd(OAc)2 P(m-ClC6H4)3 NBE, K2CO3 MeCN, 135 °C

R2 124 9–62%

OHC

O

O

MeCN, 135 °C

R2 = EWG

123

CO2Me

ortho-Arylation of bifunctional iodoarenes under Pd/NBE catalysis.

128

(±)-Rhazinal (+)-Rhazinal

Me L3

Me

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

ortho-ester moiety to provide multicyclic δ-lactam 124a in 60% yield in one step. Gu and coworkers further demonstrated the high efficiency of this strategy in their total synthesis of rhazinal [47a]. By tethering an olefin moiety to a 2-iodopyrrole derivative 125, and using 1-bromo-2-nitrobenzene as the coupling partner, the key precursor 127 was obtained in 85% yield via a highly selective phenyl–pyrrole biaryl coupling followed by a Heck reaction. Interestingly, the authors noted that installation of an EWG, e.g. an aldehyde or ester group in the iodopyrrole substrate is very important for the success of this reaction. The same group further developed an asymmetric version of this reaction by using phosphoramidite L3 as the chiral ligand, affording optically active 127 in 65% yield with 88% ee, which was easily converted to (+)-rhazinal and four related natural products [47b]. While the “ortho effect” discovered by Catellani and coworkers proved to be very general in the transformations discussed earlier, the reason behind this interesting finding was not clear and has long been a matter of debate. Recent density functional theory (DFT) calculations by Derat, Catellani, and coworkers revealed that the ortho substituent (R) makes the formation of Pd(IV) intermediate Int28 energetically favored from the ANP (path a, Scheme 3.29) [11], thereby explaining the exclusive formation of aryl–aryl coupling products as sp2 –sp3 reductive elimination is disfavored over sp2 –sp2 reductive elimination [48]. On the other hand, in the absence of an ortho substituent in the aryl halides, a transmetalation pathway between two palladium(II) species, i.e. the ANP and the initially formed Ar–Pd(II)–X (X = I, Br), is more likely to be operative (path b, Scheme 3.29). As the energetic difference between aryl attack onto the aryl or norbornyl carbon of the ANP is quite small, both aryl–aryl coupling and aryl–norbornyl coupling have been observed via the intermediacy of Int30 and Int31, respectively. R

R

R≠H ArX

R Path a II

Pd ANP

IV

Pd X Ar Int28

Ar

PdII

Int29

Path b R=H Ar−Pd(II)−X

+ PdX Pd Ar Int30

Pd Ar PdX Int31

Scheme 3.29 Theoretical investigation on the origin of the “ortho effect.” Source: Modified from Maestri et al. [11].

This computational study nicely explained the experimentally observed “ortho effect,” however, deviation from the “ortho effect” has also been observed as certain chelating groups are able to offset the influence of the ortho substituent (Scheme 3.30). For example, while the reaction of ortho-substituted aryl iodides with N-sulfonylated or acetylated o-bromoanilines 129 afforded carbazoles 130

87

R R1 = COMe, SO2Ar

R

“ortho effect” sp2–sp2 R.E.

R

I R′ Pd/NBE

+

Br NHR1

PdIV NHR1 R

Int32

Br

R

I R′

Pd/NBE

+

R′

H2N Pd L Br Int34

R

R′ N H 131

R

CH2CONH2

R′

CONH2

Pd L

PdIV O NH2

CONH2

Br Int36

133

R

R Int35

With water added “ortho effect” sp2–sp2 R.E.

132

R2

R′

L Br

Br

R2

R′

Exception to “ortho effect” sp2–sp3 R.E.

R

R

R1 = H Exception to “ortho effect” sp2–sp3 R.E.

129

R2

130 Int33

R2

R2

R1 N

R′

R1HN

L

R′

R PdBrL

R′

R′

PdBrL

R

R′

PdLBr CONH2

R' CONH2

H2NOCH2C Int37

Scheme 3.30

Deviation from the “ortho effect.”

Int38

134

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

as expected [49a], Catellani and coworkers found that dihydrodibenzoazepine derivatives 131 were obtained when unprotected o-bromoanilines were employed [49b]. This observation indicates the formation of intermediate Int34, which, in turn, was formed via sp2 –sp3 reductive elimination rather than sp2 –sp2 reductive elimination from Pd(IV) species Int32. Based on DFT calculations, this exception to the “ortho effect” was attributed to the strong chelation of the NH2 group to palladium, which makes octahedral Pd(IV) complex distorted and as a result, sp2 –sp3 reductive elimination is energetically favored over sp2 –sp2 reductive elimination. At the same time, Malacria and coworkers also observed a deviation from the “ortho effect” when o-bromophenylacetamides 132 were used as the arylating reagents to yield NBE-containing dihydrophenanthrene products 133 [50]. Similarly, DFT calculations indicated that coordination of the oxygen atom from the amide functionality to palladium made sp2 —sp3 bond formation more favored from Pd(IV) species Int35. The intermediate thus formed underwent a direct C–H functionalization to afford the final products 133. Interestingly, when excess water (11 equiv relative to palladium) was added, the reaction pathway was restored to sp2 –sp2 reductive elimination generating intermediate Int37. However, instead of undergoing the commonly observed NBE extrusion, a Mizoroki–Heck-type dearomatization occurred to afford the spirocyclic compounds 134 in modest yields. DFT modeling suggested that water may replace phosphine ligand as the apical ligand in Pd(IV) species Int35, making sp2 –sp2 reductive elimination more favored. However, due to the minimal size of H2 O, deinsertion of NBE was not observed as this process is usually promoted by increased steric hindrance. While selective aryl–aryl coupling can be achieved by taking advantage of the “ortho effect,” it is highly desirable to expand the scope of aryl iodides to those without an ortho substituent. This long sought-after goal has been achieved recently by the groups of Yu and Dong (Scheme 3.31). In the work of Yu and coworkers, 2-carbomethoxynorbornene (NBE-CO2 Me) was identified as the mediator for the ortho-arylation of iodobenzene and 4-iodotoluene with themselves being the arylating reagent, affording ortho-bisarylated products in 60% and 84% yield, respectively [51]. In 2018, Dong and coworkers reported a new class of bridgehead-modified NBEs and applied them in the ortho-functionalization of ortho-unsubstituted aryl iodides [52]. It was found that NBE derivative 136 with an alkyl substituent at the bridgehead was an optimal mediator for the ortho-arylation of 3-isopropyliodobenzene using electron-poor bromoarenes as the arylating reagents. Notably, mono ortho-arylation could be achieved in these cases due to the increased steric hindrance of NBE mediator 136. While the two reports discussed herein demonstrated the feasibility of using substituted NBE to overcome the ortho substituent constraint, there is still much room for further improvement in terms of substrate scope and reaction efficiency.

3.2.3

ortho-Acylation and Alkoxycarbonylation

While ortho-alkylation and arylation of aryl halides and pseudohalides have been extensively studied under Pd/NBE cooperative catalysis, ortho-acylation was not

89

90

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis CO2Me Pd(OAc)2 NBE–CO2Me

I +

CO2Me

R

K2CO3, DMF 115 °C

R (3 equiv)

R

(1.2 equiv)

R R = H, 135a, 60% R = Me, 135b, 84% n

Br + R2 i Pr

CO2tBu

C7H15

R1

I

MeO2C NBE–CO2Me

CO2tBu

+

R1 = EWG

136

[Pd(π-allyl)Cl]2

R2

dppe, Cs2CO3 PhMe/dioxane, 100 °C

R1

i Pr

137 39–60 %

Scheme 3.31 Overcoming the “ortho effect” in ortho-arylation reactions by using substituted norbornenes.

possible until 2015 when the groups of Liang [53], Dong [54], and Gu [55] reported the ortho-acylation of aryl iodides. Notably, Liang and coworkers used pre-formed anhydrides 138 as the acylation reagent [53], while Gu and coworkers employed commercially available acyl chlorides 140 and water to generate anhydrides in situ [55a], providing the desired aryl ketones 139 in moderate to excellent yields using electron-deficient olefins as the terminating reagent (Scheme 3.32). It is worth mentioning that higher reactivity was observed for aromatic anhydrides as compared R2

R

R O

I + R1

R′

O O 138

R1

+

R2

PdCl2 TFP, NBE

R′

Cs2CO3, DME 90–100 °C

R1

139 46–90%

R

R2

R O

I R′

+

1

R

+

Cl

R2

140

R R′

Scheme 3.32 anhydrides.

R1 +

PdCl2 TFP, NBE Cs2CO3, H2O Dioxane, 100 °C

R1

O

Cl 141

O R

Cl

Pd(TFP)2Cl2 R3 Cs2CO3, dioxane 100 °C NBE,

O R2

R′ 139 41–95%

O I

O

Cl

R′ 142 O 57–90%

R3 R1 R2

ortho-Acylation of aryl iodides using pre-formed or in situ generated

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

with aliphatic anhydrides, especially for α-nonbranched aliphatic anhydrides. To circumvent this problem, Gu recently found mixed-anhydride 141, pre-formed from aliphatic carboxylic acid and commercially available 2,4,6-trichlorobenzoyl chloride (Yamaguchi reagent), exhibited high selectivity and reactivity in the ortho-acylation reaction. Densely functionalized aryl alkyl ketones 142 were produced in moderate to excellent yields [55b]. In contrast with Liang and coworkers’ [53] and Gu and coworkers’ [55a] work, Dong and coworkers employed a well-designed bifunctional anhydride, i.e. isopropyl carbonate anhydride 143, as the acylation reagent as well as the terminating hydride source for the ortho-acylation reaction, providing ipso-reduction aryl ketone products 145 in 19–86% yields (Scheme 3.33) [54]. Amide-substituted NBE 144 was used in place of NBE for higher yields and easier isolation of products. Notably, the same group achieved mono ortho-acylation of ortho-unsubstituted aryl iodides such as 3-iodotoluene using the newly developed bridgehead-modified NBE 136 [52].

R

R I

O +

R′

R1

O

H

O O 143

[Pd(π-allyl)Cl]2

144

TFP, Cs2CO3, NMe4Cl THF/MeCN, 85 °C

n

[Pd(π-allyl)Cl]2

I O

+ R Me

CO2tBu

O O

R

H CONHMe

R′

R1

145 O 19–86% CO2tBu

C7H15

O 136

TFP, Cs2CO3 PhMe/dioxane, 100 °C

R Me 146 54–84%

Scheme 3.33 ortho-Acylation of aryl iodides using norbornene derivatives as the mediator. Source: Modified from Dong et al. [54].

In addition to Heck acceptors, copper cyanide [56], arylpropiolic acids [57], benzoxazoles, and benzo[d]thiazoles [58] have also been utilized as terminating reagents in ortho-acylation reactions of iodoarenes, giving access to a wide variety of functional aromatic ketones in a single step (Scheme 3.34). To further increase the diversity of aryl ketone products accessible via ortho-acylation under Pd/NBE catalysis, the Gu group developed an elegant approach for the ortho-acylation of iodoarenes using thioesters 151 as a bifunctional acylation reagent (Scheme 3.35) [59a], affording ortho-acylation and ipso-thiolation products 152 in moderate to excellent yields. Notably, addition of group 11 metal salts such as CuI and Au(PPh3 )Cl significantly increased the yield of the reaction and probably promote the oxidative addition of the ANP with thioesters through the coordination of metal to the sulfur center. It’s worth mentioning that this work also represents the first example of using aryl sulfide anion as the terminating reagent in

91

92

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis R I

O

R′

+

1

R

1

R

O

R O

R′

+

R1

Cs2CO3, CH3CN 105 °C

R I

O

R′

+

R1

Scheme 3.34

O

N R1

O

R

R2

R′

R1

148 O 58–95%

X

R2

R1

147 O 27–99%

COOH Pd(OAc)2/TFP NBE

Cl

CN R′

Cs2CO3, H2O dioxane, 100 °C

R2

I

R

CuCN PdCl2/TFP NBE

O

R

R2 X

R′

PdCl2/TFP NBE/CuBr K2CO3 CH3CN, 100 °C

150 O 24–94%

R1 X = O, S

ortho-Acylation of aryl iodides using other types of terminating reagents.

R

R O

I R′

+ R1

PdCl2, TFP CuI, NBE

SAr 151

Cs2CO3, dioxane 120 °C

SAr R′

R

I R′

R1

152 O 39–94%

R O +

R1

SeR2 153

PdCl2, TFP NBE, K2CO3 DCP/DMI 100 °C

SeR2 R′

R1

154 O 36–91% R

R Cl

I R′

N

149

+ O

R N R1 155

2

Pd(OAc)2, PPh3 NBE, Cs2CO3 DCE, 95 °C

R′

R2 N

R1

156 O 30–99%

Scheme 3.35 ortho-Acylation of aryl iodides using bifunctional acylation reagents. DCP: 1,3-dichloropropane; DMI: 1,3-dimethyl-2-imidazolidone. Source: Modified from Sun et al. [59a].

Catellani-type reactions, providing an easy access to functionalized diaryl sulfides. Following on this work, the same group developed a protocol for the ortho-acylation and ipso-selenation of iodoarenes using selenoates 153 as the acylation as well as the terminating reagent, giving Se–aryl and Se–alkyl compound 154 in 36–91% yields [59b]. Interestingly, in contrast with the cleavage of the C(O)—S bond of thioates 151, addition of group 11 metal salts greatly diminished the yield of this

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

reaction. Jiao and coworkers demonstrated that aryl carbamoyl chlorides 155 can also be utilized as a bifunctional acylation reagent to afford phenanthridinones 156 in a single step [60]. In this instance, the aryl C–H functionalization serves as the terminating event. Not surprisingly, when olefin-containing bifunctional acylation reagents were used, benzo-fused cyclic ketones could be easily prepared in one step (Scheme 3.36). In Gu’s ortho-acylation of aryl iodides with aliphatic carboxylic acid derivatives, ring-fused ketones 158a–d were obtained in moderate to good yields [55b]. Recently, Dong, Wang, and coworkers utilized unsaturated carboxylic acid anhydrides 159 as the bifunctional acylation reagents to afford indenones 160 in synthetically useful yields [61]. Moreover, this methodology has been applied to the concise synthesis of natural products pauciflorol F and acredinone A. Notably, a new ortho-acylation/ipso-borylation protocol has been developed for the constructing of the pentasubstituted arene core 164, allowing for the total synthesis of acredinone A with two types of Pd/NBE-catalyzed ortho-acylation reactions. I

R3 R1 +

O n

R2

O O

n

O O 158a 69%

158 n = 1 or 2

[Pd(
-allyl)Cl]2 144 TFP

OCO2iPr

+ R1

O

Cs2CO3, dioxane 90 °C

Cl

O

I

R

R5

Pd(TFP)2Cl2, NBE

157 Cl n = 1 or 2

R R′

R4

Cl

R CONHMe

R2

R′

Cs2CO3, NMe4Cl dioxane/THF, 85 °C

R2 159

R = Pr, 158b, 51% R = Ph, 158c, 48% R = Bn, 158d, 56%

R1

O

160 43–88%

MeO O I

[Pd(
-allyl)Cl]2, TFP

OMe

+

OMe

O

MeO

O

MeO

O O

OH

HO

144, Cs2CO3, NMe4Cl

OMe

OMe MeO

HO

161 82%

OMe

OH

OH

Oi Pr

(±)-Pauciflorol F

OMe OMe

O

OMOM I

MeO OMOM

2O

NBS

OMe Me

CHO

OMe

[Pd(
-allyl)Cl]2, TFP 144, Cs2CO3

Me

OMe O OMe

OMe I

Me

2O

OMOM

[Pd(
-allyl)Cl]2, TFP 144, B2pin2, Cs2CO3

Br OMe O 163 83%

KHF2

OMe

OMOM

164 67%

OH MeO

O O

OMe Me

O MeO

Me MeO 2 steps

OMe (pin)B

OMe

4 steps

OMe

Me OMe O 162 70%

4 steps

Me

MeO OMOM

OMe

Me

KF3B O MeO

OMe

OMOM 165 83%

MeO

MeO OMe Me

OMe HO

Acredinone A

Scheme 3.36 Synthesis of benzo-fused cyclic ketones and natural products using unsaturated carboxylic acid anhydrides as the acylation reagents.

While Dong and coworkers demonstrated that carbonate-based unsymmetrical anhydrides are highly selective acylation reagents [54, 61], they

93

94

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

subsequently showed that selective cleavage of the carboxyl–O bond could be achieved by tuning the steric hindrance of carbonate anhydride reagents. A straightforward route to multi-functionalized aromatic carboxylic esters 167 was possible via Pd/NBE-catalyzed ortho-alkoxycarbonylation of iodoarenes using a new class of bulky carbonate anhydrides 166 (Scheme 3.37) [62]. Macrolactones such as 168 could be easily prepared form corresponding carbonate anhydrides containing an olefin moiety. Using isopropanol as a hydride donor, ortho-alkoxycarbonylation/ipso-reduction product 169 was obtained in 60% yield. Notably, ortho-aminocarbonylation could also be achieved using a carbamoyl anhydride, affording aryl amide 170 in 26% yield. Interestingly, under Gu’s ortho-acylation/ipso-selenation reaction conditions [59b], ortho-alkoxycarbonylation could also be achieved to give the corresponding α-alkoxycarbonyl selanes 172 in moderate yields. R

Me

O

I

O

+

R′

O O

R1

Me

O

Me

H

O Me

OEt

N

CO2Me

O 170 26%

169 60%

R

R

I R′

R1

NMe2

O

O

O 168 61%

O

167 O 37–83%

O HO Me

R′

Cs2CO3, dioxane, 80 °C

Me 166

Me

R2

NBE,

R2

R

Pd(MeCN)2Cl2/TFP

O +

R1O

SeR2 171

PdCl2, TFP NBE, K2CO3 DCP/DMI 100 °C

SeR2 R′

OR1

172 O 42–70%

Scheme 3.37 ortho-Alkoxycarbonylation of aryl iodides under Pd/NBE catalysis. Source: Modified from Wang et al. [62].

3.2.4

ortho-Amination

To further expand the scope of electrophiles under Pd/NBE catalysis and increase the diversity of the arene products, Dong and Dong developed an elegant approach for ortho-amination of iodoarenes using N-benzoyloxyamines 173 as electrophilic aminating reagents [63]. Isopropanol served as the terminating hydride source, which represents the first example of introducing a heteroatom at the ortho position of iodoarenes and provides aniline derivatives 174 in moderate to excellent yields

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

(Scheme 3.38). Aniline derivatives can also be prepared from aryl halides via the Buchwald–Hartwig reaction, where C—N bond formation takes place at the ipso position. This ortho-amination protocol provides a complementary route to aryl amines. The synthetic utility of this methodology was demonstrated in a two-step synthesis of 175, a key precursor used for the synthesis of P70S6 kinase inhibitor 176, from inexpensive 3-chloroanisole. Notably, the amine 175 was obtained in 88% yield as a single regioisomer, although a mixture of iodoarenes was used as the starting material. R I

R +

R′

1

2

R N OBz 173

R

Pd(OAc)2 P(4-MeOC6H4)3 NBE

H R′

i

PrOH, Cs2CO3 Toluene, 100 °C

Cl

174 50–99%

Cl

86%

MeO

R1

Cl I

NIS, In(OTf)3

N R2

MeO

BzO N

N Boc

+ Standard conditions

MeO 2.2 : 1 Used as a mixture

I

Cl

Cl

Me

175 88%

N

Boc

N NH

N

MeO

N

MeO

N 176 N

N

Scheme 3.38 Dong’s initial report on ortho-amination of iodoarenes with N-benzoyloxyamines.

Following on Dong’s work, different types of terminating reagents, including electron-deficient [64] or electron-rich olefins [65], arylboronic esters [66], methyl boronic acids [67], carbene precursors [68], bis(pinacolato)diboron [69], 1,1-dimethyl-2-alkynyols [70], propiolic acids [71], acetone [72], and cyanids [73], have been employed for ortho-amination of iodoarenes using N-benzoyloxyamines. A wide variety of functionalized aniline derivatives 177–185 can be prepared with high efficiency (Scheme 3.39). Given that bromoarenes are generally cheaper and more accessible than their iodide counterparts, Dong and coworkers further expanded the scope of ortho-amination reactions to aryl bromides (Scheme 3.40) [74]. By fine-tuning of the steric and electronic properties of phosphine ligands, a diverse range of terminating reagents 186a–186e were successfully applied in the ortho-amination of aryl and heteroaryl bromides to afford various functionalized aryl amines 187 in 30–88% yields. Since bromoarenes exhibit lower reactivity than iodoarenes toward Pd(0),

95

96

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

R EWG R

R′ CN

R′ N R2

185 29–93%

R

R1

Me R′ N 184 R2 40–98%

Zn(CN)2 or K4[Fe(CN)6]

R′

R

Me

R1 CO2H

R′ BnO

EWG

I

R1

R2

N OBz Pd(0)/NBE, Cs2CO3 +

R′

R

N 183 R2 16–96%

R1

NNHTs

B2Pin2

R

R R

R′

ArBPin or Me B(OH)2

Ar OH

R

178 44–94%

N R2

R1

R

or

R

OBn

R

O

Me

O

N 177 R2 54–90%

R1 N R2 R3 = Ar, 179, 20–94% R3 = Me, 180, 33–63% Ar

R′ BPin

R′ 182 63–70%

R3 R′

N R2

R1

181 36–88%

N R2

R1

Scheme 3.39 ortho-Amination of iodoarenes using N-benzoyloxyamines in the presence of various terminating reagents.

the authors also achieved sequential functionalization of the C—I and C—Br bonds of 2-bromo-6-iodoanisole 188 by merging classical iodoarene-based ortho-alkylation reaction with the bromoarene-based ortho-amination reaction, providing tetra- or penta-substituted arenes 190a and 190b in good yields. Iodoarenes containing a terminating functionality have also been utilized for ortho-amination reactions (Scheme 3.41). In 2018, Lautens and coworkers achieved an ortho-amination/ipso-amidation reaction of amide-tethered iodoarenes 191, thereby providing ortho-aminated dihydroquinolinones 192 via two sequential C—N bond-forming events [75]. Liang and coworkers developed an elegant approach for ortho-amination of iodoarenes 193 where direct arylation of unactivated C(sp3 )—H bond of a methyl group was, for the first time, utilized to terminate the reaction [76]. Key to the success of this reaction is the use of pivalic acid as an additive that enables a carboxylate ligand exchange following ortho-amination. The pivalate promotes arylation of the adjacent methyl C—H bonds via a concerted metalation deprotonation (CMD) process. Luan and coworkers reported the use of phenol-tethered iodoarenes 195 for the synthesis of diversely functionalized spiroindenes 196 in the presence of N-benzoyloxyamines and norbornadiene (NBD) [77]. Mechanistically, following the ortho-amination step, phenol dearomatization occurs instead of

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

R3 Y(186)

R R′

Br

Z

R1 +

R N OBz

Z = CH or N

R′

OMe I

Br + MeI 188 t BuO C 2

N R2

2

PCy2

DCypb R1 O PPh2 PPh2 DPEphos

Me OH O

CO2tBu

B

Me

B2Pin2 O

Me

OH 186a

Cy2P

R3

Z

187 30–88%

Me

H

=

R

Pd(OAc)2 DCypb or DPEphos NBE, Cs2CO3 1,4-Dioxane 90 °C

Me

Me R3Y

2

Ph 186b

186c t BuO C 2

186b Pd(OAc)2 TFP

186d

Br

NBE, Cs2CO3 1,4-Dioxane 100 °C

Me

186a or 186c Standard conditions

189 93% t BuO C 2

OMe

N OBz

O

OMe

186e

Ph

OMe

H Me

N 190a 74%

Me O

N 190b 61%

O

Scheme 3.40 ortho-Amination of aryl bromides using N-benzoyloxyamines. Source: Modified from Dong et al. [74].

NBD extrusion, presumably because the phenol dearomatization step is accelerated by the introduction of an amine group. Notably, preliminary studies on the asymmetric version of this reaction showed that products with up to 85% ee could be obtained using 2,2-dimethyl-α,α,α1 ,α1 -tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-derived chiral ligand L4. Very recently, Liang and coworkers developed a highly efficient method for the synthesis of 4-aminoindoles 198 from o-iodoaniline derivatives 197, N-benzoyloxyamines, and NBD [78]. From a mechanistic perspective, following the ortho-amination, intramolecular Buchwald–Hartwig coupling outcompetes NBD extrusion, leading to intermediate Int40. A subsequent retro-Diels–Alder reaction affords the final product 198. It was found that installing a sterically hindered substituent (such as tert-butyl) on the nitrogen atom of the o-iodoaniline is of critical importance, which, based on DFT calculations, makes ortho-C–H functionalization more favored than Buchwald–Hartwig coupling, following the initial NBD insertion step. Notably, this strategy shows high efficiency in the synthesis of complex, pharmaceutically relevant, and bioactive molecules. For example, the

97

98

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

O R′ I

191

O R1R2NOBz Pd(PPh3)4 3 NHR NBE Cs2CO3 Toluene, 110 °C

CO2R3 N

NR3 R′ 192 25–78%

N R2

R1

R′

R4 R5 I 193

H

tBuCO H, 2

194 29–78%

N

Ar Me Me

1 2

R′

R R NOBz Pd(OAc)2 P(4-MeOC6H4)3

I

195 +

Cs2CO3 DME, 100 °C

Me

Me R′ N R2

196 29–78%

O 196a 56%, 84% ee

I Z N 1 197 Z = CH or N

+

R1

R2 N OBz

N

N

R1

NHtBu 197a + Boc N

NBD standard conditions

O

P N

O

F

197a

N

O

NBD standard conditions

N OBz 199

R2

F

N 1 Int40 R

t N Bu

N 200 (90%)

Boc N

I

O

O

NHtBu +

N Z 198 R1 65–94%

O LnPd Z NHR1 Int39

O

I

Pd(OAc)2, PPh3 Cs2CO3, toluene 140 °C

R2

Ar

O

R2

O R1

R1

Ar L4 t Ar = p- Bu-C6H4

O 196b, 70% 5 : 1 dr, 85% ee O

R1

N R2

Ar

R1

NBD

R5

O

N

O

R4 N

R′

Cs2CO3 Toluene, 110 °C

O OH

R3O2C

R1R2NOBz Pd(OAc)2/PPh3 NBE

O HN N

3 steps

N

N N OBz

201

N t Bu 202 (81%)

Cl 203 GOT1 inhibitor

NH

Scheme 3.41 ortho-Amination of iodoarenes containing a terminating functionality using N-benzoyloxyamines.

antidepressant drug paroxetine was installed at the 4-position of an indole (200) in 90% yield. Moreover, GOT1 inhibitor 203, which is under investigation for the treatment of pancreatic ductal adenocarcinoma, was synthesized in only four steps from readily available starting materials. It is worth mentioning that 4-alkylindoles and 4-arylindoles could also be prepared in a similar way by using alkyl or aryl bromides as the electrophilic reagent. Mono ortho-functionalization of ortho-unsubstituted iodoarenes under Pd/NBE is very challenging as they tend to form double ortho functionalization products or NBE-incorporated by-products. Dong and coworkers made a breakthrough in this

3.2 Pd(0)-Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

I +

R′

2

1

R

R

N + OBz

3

R Y 186

R3

136 or 205, Cs2CO3 PhMe/dioxane 100 °C

Me O

R′ N 204 R2 35–84%

H H

H I

HO

N

Me 205

136

CO2

Me O O

tBu

H

N H t BuO

73% N

H

O

O

H O Strychnine

H

N OBz

O

H N

H

207 2C

N

H H

R1

Standard conditions

H

I N

Me

C7H15

206

Oestrone

Me

n

N OBz

O

Me O

H H

H

[Pd(π-allyl)Cl]2 RuPhos or dppe or TFP

H

H N

OH

H

H

H O 208

N

O

O

Standard conditions

H

H

O 209 H 56%

R O

O H Pd

ROCO Pd PdLn E Int44 Mono orthofunctionalization

R1 E Int43 Favored when R1 ≠ H

R1 Int41 Favored when R1 = H E

Pd

Ln

E

Int42 Double orthofunctionalization

Scheme 3.42 ortho-Amination of ortho-unsubstituted iodoarenes using bridgehead-substituted norbornenes as the mediator. Source: Modified from Wang et al. [52].

area by using bridgehead-modified NBEs 136 or 205 as the mediator, thereby providing a modular and step-economical route to mono ortho-functionalized arenes from ortho-unsubstituted iodoarenes (Scheme 3.42) [52]. Late-stage functionalizations of complex iodoarenes such as 206 and 208, which are derivatives of oestrone and strychnine, respectively, have also been demonstrated. Mechanistically, introduction of a substituent at the bridgehead position makes the formation of intermediate Int43 more favored over intermediate Int41 for steric reasons, thereby leading to intermediate Int44 via β-carbon elimination, which subsequently provides the desired mono ortho-functionalization product. In addition to making small molecules using Pd/NBE catalysis, Dong and coworker also achieved the synthesis of amine-functionalized arylacetylene-containing polymers, using a sequence involving ortho-amination and ipso-alkynylation (Scheme 3.43). Reacting diiodide 210 and dialkyne 211 with N-benzoyloxyamine gave rise to functional aromatic polymers 212 with different backbones [79]. Water-soluble poly(p-phenylene ethynylene) (PPEs) 215 were prepared in an efficient and selective manner where polymer backbones and side chains were constructed simultaneously from 4-iodophenylacetylene 213 [80].

99

100

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

R Z

I

I

X

R′

210 R = Me or H HO

R

Y

OH

N

212

Z

N OBz

O

O O

N

N

Y =

n-Octyl

Z

, R2 R2 = H or CN

O,

3

R

N

90% to >95% amination Mn = 5.6–21.0 Mn/Mw = 1.80–4.36 S N N

O ,

O

3

R′ R′ = Me or

Z = O or NR1

X =

Y

X

NBE, Cs2CO3 Toluene, 90 °C

211 Z

N

Pd(OAc)2 P(4-MeO-C6H4)3

n-Octyl

, R3 R3 = OR4 or CO2R5 Boc N

I N OBz

Boc N

N

Pd(OAc)2, P(4-MeO–C6H4)3 NBE, Cs2CO3

NH2

2Cl

NH HCl (xs)

Toluene, 90 °C 95%

CH2Cl2 rt, 99%

N

OH 213

214

NH N Boc

2Cl 215

NH2

Mn = 7500, Mn/Mw = 2.4 %amination >95%

Scheme 3.43 synthesis.

R R′

Application of ortho-amination/ipso-alkynylation of iodoarenes in polymer

O O I R1 S S + Ar 216 Ar = 4-MeC6H4 R Ar

R′

R2 Pd2(dba)3, TFP (±)-NBE–CHO K2CO3, THF 110 °C, dark

O S

O

R R2 R′ 217 47–98% R O

R′ Ar

S L

CHO (±)-NBE–CHO

O

Pd

Pd

L SR1 L Int45

S

R1

SR1 Int46

L

Scheme 3.44 ortho-Thiolation of iodoarenes using thiosulfonates as the thiolating reagent. Source: Modified from Cai and Gu [81].

3.3 Pd(II)-Catalyzed C–H Functionalization of Arenes

3.2.5

ortho-Thiolation

Introduction of a heteroatom at the ortho-position of iodoarenes, using Pd/NBE catalysis, is very challenging and had been limited to nitrogen. In early 2019, Gu and coworker reported an approach for ortho-thiolation of iodoarenes using thiosulfonates 216 as the thiolating reagent (Scheme 3.44) [81]. While the same group explored thioesters for ortho-acylation/ipso-thiolation reactions, selective reductive elimination of the Pd(IV) species Int45 to form a C(Ar)—SR bond was achieved. When thiosulfonates were used, tautomerization of the sulfonyl to a sulfinyl may occur in palladium(IV) species (Int45 → Int46).

3.3 Pd(II)-Catalyzed C–H Functionalization of Arenes 3.3.1

C2-Functionalization of Indoles and Pyrroles

All reactions discussed in Section 3.2 rely on a Pd(0) catalyst to initiate the reaction through oxidative addition of Pd(0) to an aryl halide. However, it was found that Pd(II) complexes could also be used to generate the aryl–Pd(II) species that undergoes carbopalladation with NBE. Bach and coworkers were the first to demonstrate the feasibility of this strategy in 2011. Specifically, the authors achieved 2-alkylation and arylation of NH-indoles 218 using PdCl2 (MeCN)2 or PdCl2 as the catalyst (Scheme 3.45) [82]. R2

R1

+ RX N H 218

PdCl2(MeCN)2 or PdCl2 NBE, Cs2CO3 DMA, H2O, 60–70 °C

RX = alkyl bromides or PhI

R1

R2 R N H 219 40–90%

Scheme 3.45 Pd(II)-catalyzed C2-functionalization of indoles. Source: Jiao and Bach [82a], Jiao et al. [82b], Potukuchi and Bach [82c], and Jiao and Bach [82d].

Mechanistically, ligand exchange between NH-indoles and Pd(II) affords N–Pd(II) species Int47, which then undergoes NBE insertion and C–H activation to form the five-membered palladacycle Int49. By using 1,10-phenanthroline as the ligand, the authors isolated the palladium complex 220 and characterized it by single crystal X-ray crystallography. Oxidative addition of alkyl or aryl halide to the palladacycle followed by reductive elimination and NBE extrusion affords intermediate Int52, which then furnishes the final product and regenerate the Pd(II) catalyst via protodepalladation (Scheme 3.46). Notably, this methodology was used as the key steps in the total synthesis of (±)-aspidospermidine, (±)-goniomitine, and several other natural products (Scheme 3.47) [82b]. Later, the same group extended this strategy to the 2-alkylation of free-NH pyrroles, providing 2-alkylpyrroles 225 in moderate to excellent yields (Scheme 3.48)

101

102

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis R2

R1

R2

R1 N H

R

N H

Pd(II)

HX R2

R1

R2

R1 R

N

N

II

Pd XL2 Int52

PdIIXL2 Int47

R2

R1 N

N

R PdIIXL2

N

Pd

N

Int48 L = 1,10-phenanthroline

R2

R1 N

PdIV

L N

L

PdII L

L Int50

Base

R2

R1

R X

PdIIXL2

N

220 X-ray

Int51

Scheme 3.46

R2

R1

RX

Int49

Proposed mechanism for the Pd(II)-catalyzed C2-functionalization of indoles.

[82d]. However, an electron-withdrawing substituent is required to avoid undesired N-alkylation. In 2018, Liu and coworkers used this approach to introduce a trifluoroethyl group at the 2-position of NH-indoles using trifluoroethyl iodide as the alkylating reagent (Scheme 3.49) [83]. Interestingly, dibenzoylmethane (dbm) was found to be the optimal ligand for this reaction, presumably due to the enhanced reactivity of the dbm-ligated palladacycle Int53 toward the unreactive trifluoroethyl iodide.

3.3.2 meta-C–H Functionalization of Arenes Containing an ortho-Directing Group Directed ortho-C–H palladation of arenes is a well-established method for the generation of aryl–Pd(II) species and thus could be utilized to initiate Catellani-type reactions. The groups of Yu [84] and Dong [85] were the first to achieve meta-C–H functionalization of arenes using this strategy in 2015. In Yu’s study, an amide directing group was utilized to achieve meta-C–H functionalization under Pd(II)/NBE catalysis. Using pyridine derivative L5 as the ancillary ligand, alkyl halides without

3.3 Pd(II)-Catalyzed C–H Functionalization of Arenes

N Et

PdCl2(MeCN)2 NBE, K2CO3

N H +

DMA, H2O 70 °C, Ar

Et Br

N H 221 65%

CO2Et

OTBS

+ I

N H 222 Aspidospermidine OH

OTBS Et

PdCl2 NBE, K2CO3 DMF/DMSO H2O, 60 °C, air

N H

Et

CO2Et

N H 223 73%

Et

H HN

CO2Et

N Et

224 Goniomitine

CO2Et

Scheme 3.47 Synthetic applications of the Pd(II)-catalyzed 2-alkylation of indoles. Source: Modified from Jiao et al. [82b].

R1

+ Br

2

R

N H R1 = CO2R or COR

Scheme 3.48 Bach [82d].

R2 R1 N H

PdCl2(MeCN)2 NBE KHCO3 DMA, 90 °C

R1

R2

N H 225 45–91%

Pd(II)-catalyzed 2-alkylation of pyrroles. Source: Modified from Jiao and

CF3CH2I Pd(acac)2, PhC(O)CH2C(O)Ph NBE KHCO3, DMF 100 °C

R1

R2

R2 R

R1 N H 226 13–82%

CH2CF3

N

O PdII O Int53

R

Scheme 3.49 Pd(II)-catalyzed 2-trifluoroethylation of indoles. Source: Modified from Zhang et al. [83].

β-hydrogens, and aryl iodides with ortho chelating groups could be employed as the alkylating and arylating reagents, respectively (Scheme 3.50) [84a]. Mechanistically, ortho-C–H palladation followed by NBE insertion generate palladacycle Int55, which then reacts with an alkyl or aryl halide to give intermediate Int56 via oxidative addition, reductive elimination, and NBE extrusion. Protodepalladation affords the final meta-C–H alkylated or arylated product 228. Later, the same group found that the combination of NBE derivative NBE–CO2 Me and quinoline ligand L6 was more efficient and general, allowing for the use of alkyl halides with β-hydrogens and aryl iodides without ortho chelating groups as the electrophiles [51].

103

R2

R2 Pd(OAc)2/L5 or L6 NBE or NBE–CO2Me

NHArF R1

+

O

227 ArF = 4-CF3–C6F4

RX

R = alkyl or aryl X = I or Br

NHArF R1

AgOAc DCE, TBME, or PhCF3 75–95 °C

CO2Me

O NBE–CO2Me

R 228 39–93% yield

OMe

Pd(II)/L

Pd(II)/L

N L5

H+

R2

2

R R1 H

R2

R1

N Pd ArF L Int54

NMe2

R1

N Pd ArF L Int56

R Int55

R2

EWG R

Z

Scheme 3.50 [85].

O L

+

Z = CH or N 229

O

RX

Pd

I R1

R

NHArF O

230

Pd(OAc)2/AsPh3 NBE, AgOAc CsOAc, LiOAc·2H2O Cu(OAc)2 H2O, HOAc PhCl, 100 °C

O

2

Me t Bu

N L6

O

Me

NMe2 EWG

R1 Z

R

231 31–80% yield

Pd(II)-catalyzed meta-C–H alkylation and arylation of arenes bearing an ortho-directing group. Source: Wang et al. [84a] and Dong et al.

3.3 Pd(II)-Catalyzed C–H Functionalization of Arenes

Almost at the same time, Dong et al. reported the use of a simple tertiary amine as the directing group for meta-C–H arylation using a related strategy (Scheme 3.50) [85]. Using commercially available AsPh3 as the ligand and a mixture of acetate salts as additives, N,N-dimethyl benzyl amine derivatives 229 react smoothly with aryl iodides containing an ortho EWG, affording the desired meta-arylated products 231 in moderate to good yields. Following the work of Yu and Dong, a variety of directing groups have been utilized for meta-C–H functionalizations. Alkylation, arylation, chlorination, amination, and alkynylation have been achieved (Scheme 3.51). These reactions were summarized in a recent review [10h] and thus will not be discussed herein. DG R

+ R1 X

Pd(II) NBE or 232 or NBE–CO2Me

DG CO2iPr 232 CO iPr 2

R

AgOAc

R1 n

R

R′

NHNs n = 0, 1

R

i Pr

HN O

R′

R′

O N i Pr

CO2H

R

R

Ar1 = 3,5-(CF3)2C6H3 R′

X O

NHR′

N O

R N

R1 R2

R R′ = COCF3 or Ns

R

O S O NHAr1

R3 X = CH2, NBoc, O

X

R N

Me

R′ = H or OTBS X = CH2, NBoc

Scheme 3.51 Pd(II)-catalyzed meta-C–H functionalization of arenes bearing an ortho-directing group.

In 2018, Yu and coworkers made a breakthrough in this area by using a chiral norbornene (+)-NBE–CO2 Me as the mediator, thereby achieving enantioselective remote meta-C–H arylation and alkylation (Scheme 3.52) [86]. Under the dual catalysis of Pd(II) and the chiral NBE, both benzylamines 233 and homobenzylamine derivatives 236 underwent a desymmetrization process to give the desired product in good yields with moderate to excellent enantioselectivity. Control experiments revealed that the (+)-NBE–CO2 Me is responsible for chiral induction while the chiral phosphoric acid 1,1′ -binaphthyl-2,2-diyl hydrogen phosphate (R)-BNDHP exerts a minor beneficial effect. In addition to desymmetrization, kinetic resolution of homobenzylamines 239 has also been achieved, albeit with slightly lower enantioselectivity.

3.3.3

ortho-C–H Functionalization of Arylboron Species

An alternative strategy to initiate the Catellani-type reaction using Pd(II) catalyst was independently reported by the groups of Zhang [87] and Zhou [88] in 2018,

105

Me Boc

N

Me

R′ Ar–I Pd(OAc)2/235 (+)-NBE–CO2Me

N

(R)-BNDHP AgOAc CHCl3, N2, 100 °C

R

R 233 R′ = H, Me

Boc

N

R′ N

Ns

R

R

R +

R1–X R1 = aryl, alkyl

R

AgOAc TBME, N2, 90 °C

Ns

Ns

Scheme 3.52 et al. [86].

R′ +

NH 239

R

1–X

R1 = aryl, alkyl

Pd(OAc)2/238 (+)-NBE–CO2Me

R

AgOAc TBME, N2, 90 °C

Ns

P

NH

237 R1 43–76% 72% to >98%

NH

O

O O

MeO2C (S) (+)-NBE–CO2Me

236

R

OH (R)

234 Ar 40–83% 40% to 98% ee

NH

CF3 N 235

Pd(OAc)2/238 (+)-NBE–CO2Me

R

F3C

OH

(R)-BNDHP

R

Ph

Me N 238

R′

R1 240 36–49% 76–86% ee, 17–37 s

Pd(II)-catalyzed enantioselective meta-C–H functionalization of arenes bearing an ortho-directing group. Source: Modified from Shi

3.3 Pd(II)-Catalyzed C–H Functionalization of Arenes

using arylboronic acids or esters as the starting materials (Scheme 3.53). Specifically, in the presence of a Pd(II)-catalyst and an oxidant such as Cu(OAc)2 and air, ortho-alkylation/ipso-Heck reaction of arylboronic acids or esters were achieved with NBE or NBE–CN being the mediator. Mechanistically, initial transmetalation of arylboronic acid or ester with Pd(OAc)2 generates an aryl–Pd(II) species, which then undergoes ortho-alkylation and ipso-olefination, in analogy to the traditional Pd(0)-catalyzed reactions. However, a stoichiometric amount of oxidant is required to regenerate the catalytically active Pd(II) species. Notably, by using aryl boronic ester 241 tethered with an aryl iodide moiety, Zhou demonstrated the orthogonal reactivity of this Pd(II)-catalyzed vs. the traditional Pd(0)-catalyzed Catellani reaction. With Pd(II), functionalization of the boro-containing aryl ring occurred while the iodo-containing aryl ring remained intact, leading to the formation of 242, which then underwent traditional Pd(0)-catalyzed ortho-alkylation to give the final product 243. EWG

R

Pd(OAc)2/PCy3 NBE

B(OH)2

+ R1–I

R′

Cu(OAc)2, BQ H2O, KOAc DMF, N2, 80 °C

R EWG R′ R1 47–93%

R B(OH)2

EWG

R′

+ R1–Br

or R

Pd(OAc)2 NBE–CN K2CO3 DMA, air, 30 °C

R EWG R′ R1

CN NBE–CN

39–97%

Bpin R′

I

+ Br

O

CO2Et 3

Bpin

CO2tBu Pd(OAc)2 NBE–CN

I O

CO2Et 3

K2CO3, DMA Air, 30 °C

242

241

CO2tBu

CO2tBu CO2t Bu Pd(OAc)2/Ph3P NBE, Cs2CO3, nBuI CH3CN, 90 °C

n

Bu

O

243

Scheme 3.53

CO2Et

3

CO2tBu

Pd(II)-catalyzed ortho alkylation of arylboronic acids or esters.

In 2019, Zhou and coworkers further extended this strategy to ortho-arylation of arylboronic esters to give rise to unsymmetrical biaryls 244 in moderate to excellent

107

108

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

yields (Scheme 3.54) [89]. Complementary substrate scope and functional group tolerance to the Pd(0)-catalyzed ortho-arylation reactions of aryl halides was noted (see Section 3.2.2). NBE derivative 245 proved to the optimal mediator for this transformation. R

1

Br

Bpin R′

+

R

EWG

R

Pd(OAc)2 245 K2CO3, DMF O3, 90 °C

EWG R1

R′

CO2Me 245 CO Me 2

244 30–97%

Scheme 3.54 Pd(II)-catalyzed ortho arylation of arylboronic esters. Source: Modified from Wang et al. [89].

In additional to ortho alkylation and arylation of arylboronic acids or esters, Dong and coworkers recently achieved Pd(II)-catalyzed ortho acylation and amination of aryl boroxines (Scheme 3.55) [90]. Instead of using Heck-acceptors as the terminating reagents, these reactions were terminated by a protodepalladation event, thereby avoiding the use of external oxidant as the overall transformations are redox-neutral. By taking advantage of orthogonal reactivity of the Pd(II)-catalyzed ortho acylation reaction and the Pd(0)-catalyzed ortho amination reaction, the authors demonstrated that the synthesis of compound 247 could be achieved via either Pd(II)-catalyzed ortho acylation followed by Pd(0)-catalyzed reductive ortho amination or the reverse.

3.4 Conclusions and Outlook In this chapter, we summarized the development of palladium-catalyzed NBE-mediated C–H functionalization of aromatic compounds since Catellani’s discovery in 1997 and the early work by Catellani and Lautens in the decade that followed. In the “second decade” this field has expanded significantly, i.e. from alkylation and arylation to acylation, alkoxycarbonylation, amination, and thiolation, from Pd(0) catalysis to Pd(II) catalysis, from NBE to various NBE derivatives, allowing for the construction of a wide variety of functionalized aromatic compounds in a highly efficient and selective manner. Despite these advances, there are still many unsolved problems and opportunities. For example, introduction of heteroatom at the ortho position and mono ortho-functionalization of ortho-unsubstituted iodoarenes are highly desirable but have met with only limited success. For Pd(II)-initiated reactions, future studies might focus on the use of native functionalities such as ketones and alcohols as the ortho-directing groups. Last but not the least, while work from the groups of Gu [17, 47b] and Yu [86] have demonstrated the feasibility of using a chiral ligand or chiral NBE mediator for asymmetric synthesis under Pd(0) or Pd(II) catalysis,

Acknowledgments

R

R BO

O

+

R′

Ar

Pd(TFA)2, AsPh3 NBE, K2CO3, CuI

O Ar

O

R′

BQ, 4 Å MS, Toluene, 100 °C

3

Ar

26–74% O R

R

X

BO

Pd(OPiv)2 P(OPh)3

+

R′

NBE, BQ CsI, Cs2CO2 Toluene, 100 °C

N OBz

3

R′ N X

57–66%

Me F Pd(II)-catalyzed ortho acylation

Pd(0)-catalyzed ortho amination

O

[B] = B(O)

68%

O

I

61%

Me Me

[B]

I

F

O R2N

246 99%

[B] = Bpin [B] = B(O)

O 247

O

Me [B]

Pd(0)-catalyzed ortho amination

R2N

O

Pd(II)-catalyzed ortho acylation

60%

[B] = Bpin

73%

64%

[B] = Bpin [B] = B(OH)2

Scheme 3.55 Pd(II)-catalyzed ortho acylation and amination of aryl boroxines. Source: Modified from Li et al. [90].

more studies are warranted so as to make more general and practical reactions. We anticipate that the chemistry of Pd/NBE catalysis will continue to expand over the next few decades.

Acknowledgments We thank the Natural Sciences and Engineering Research Council, the University of Toronto, “Thousand Youth Talents Plan” of China, and Shanghai Jiao Tong University for financial support. Mrs. Junfang Dong (Shanghai Institute of Organic Chemistry) is acknowledged for assistance with the preparation of the schemes. We would

109

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like to dedicate this chapter to Professor Marta Catellani on the occasion of her 75th birthday and to the 70th anniversary of Shanghai Institute of Organic Chemistry.

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4 Directing Group Assisted meta-C–H Functionalization of Arenes Aided by Norbornene as Transient Mediator Hong-Gang Cheng and Qianghui Zhou Wuhan University, College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), 299 Bayi Road, Wuhan 430072, China

4.1 Introduction The catalytic direct functionalization of ubiquitous but unreactive C—H bonds represents one of the most powerful strategies for efficient assembly of molecular complexity [1–3]. Therein, transition metal-catalyzed direct C–H functionalization of arenes is particularly attractive due to its high efficiency [4–8]. However, the development of practical and synthetically useful versions remains a significant challenge. Aside from identifying suitable reaction conditions that enable the activation of inert C—H bonds, these reactions should also proceed with perfect site selectivity. In this context, the “directing group” strategy is one of the most promising methods to address these challenges, whereby the preinstalled directing group can guide the metal catalyst to selectively activate the C—H bond. With the assistance of directing groups, transition metal-catalyzed ortho-C–H functionalization of arenes has been boomed in the past decades [9–11]. However, the meta-C–H functionalization of arene remains a big challenge. Until now, very limited strategies have been reported (Scheme 4.1), for instance, copper catalyzed meta-C–H arylations [12, 13], iridium catalyzed meta-C–H borylations [14–20], ruthenium catalyzed meta-C–H functionalizations [21–29], and use of specially designed U-shaped templates [30– 39]. Recently, inspired by the classical Pd(0)/norbornene (NBE) co-catalyzed Catellani reactions [40–51], Yu’s group and others developed an emerging concept of directing group assisted Pd(II)/NBE cooperative catalysis for meta-C–H functionalization of arenes, which has shown great promise (Scheme 4.2) [50–52]. As shown in Scheme 4.2, a catalytic cycle is proposed to explain this novel concept. The process is initiated by directing group assisted ortho-C—H bond activation of substrate 1 by the Pd(II) catalyst to give palladacyclic complex 4, which then undergoes carbopalladation with transient mediator NBE and meta-C–H activation to afford the key arylnorbornylpalladacycle (ANP) 6. Oxidative addition

Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

116

4 Directing Group Assisted meta-C–H DG Ho

Hp

(a)

Hm

DG

cat. [TM] Directing group assisted ortho-C–H activation

[TM]

+E–X

DG

functionalization E

Limited strategies reported: DG

DG

cat. [TM], +E–X

Ho

Hp Hm

E

Cu-catalyzed meta-C–H arylation Ir-catalyzed meta-C–H borylation Ru-catalyzed meta-C–H functionalization Templates directed meta-C–H functionalization

(b)

Scheme 4.1 Directing group assisted site-selective C–H functionalization of arenes. (a) ortho-C–H functionalization (well developed) and (b) meta-C–H functionalization (challenging).

of the electrophilic reagent E–X (2) to ANP 6, followed by reductive elimination leads to intermediate 8. Finally, the desired meta-C–H functionalized product 3 is produced by the expulsion of NBE from complex 8 via β-carbon elimination and the protodepalladation of the resulting complex 9. Notably, the Pd(II) catalyst is recovered after the redox-neutral protodepalladation step, which sets the stage for the next catalytic cycle. Overall, by taking advantage of the directed ortho-C–H palladation and the following NBE-mediated insertion/deinsertion relay, selective meta-C–H functionalization of the arene can be readily achieved. Owing to the efforts of Yu, Dong, Zhao, Shi, Ferreira, and others, amide, sulfonamide, tertiary amine, modified pyridine, modified quinolone, and even free carboxylic acid are successively utilized as directing group to cooperate with NBE-type transient mediator for meta-C–H functionalization of arenes. The use of this strategy in generating diversified derivatives of phenylacetic acid, β-arylethylamines, benzyl amines, anilines, and phenols have been illustrated. Herein, these results are summarized and categorized according to the types of meta-functionalizations, i.e. alkylation, arylation, chlorination, amination, and alkynylation. Particularly, the enantioselective meta-C–H functionalization of arenes enabled by chiral NBE-type mediator and Pd(II) cooperative catalysis will be discussed separately.

4.2 meta-C–H Alkylation of Arenes 4.2.1

Amide as Directing Group

Studies in this direction were initiated by Yu and coworkers in 2015, who elegantly uncovered an amide group assisted Pd(II)/NBE co-catalyzed meta-C–H alkylation of phenylacetic amides (Scheme 4.3) [52]. In the presence of a pyridine-based ligand 12, the palladium catalyst was relayed to the meta-position by the transient mediator-NBE after initial ortho-C–H activation. It was found that alkylating reagents without β-hydrogen, such as iodomethane, ethyl iodoacetate, and benzyl halides, were well tolerated in this reaction to give the meta-alkylated arenes 13 in

4.2 meta-C–H Alkylation of Arenes

R +

Hm 1

R

Pd(II)/[NBE] cooperative catalysis

DG E–X

DG

E

2 Electrophilic reagent

3 meta-C–H functionalized arenes R

E DG R

3

DG

Pd(II)Ln

H+

1

ortho-C–H activation

R

R

DG

DG

Pd(II) Ln E 9

4 Pd Ln

(II)

Norbornene insertion

Norbornene expulsion

NBE

R

R

DG

DG

Pd(II) 8

Ln

E

meta-C–H activation

Reductive elimination

DG

(IV)

Pd X E 7 Ln

5 Pd(II)

H

Ln

R R

Oxidative addition

DG (II)

E X 2

6

Pd Ln

Scheme 4.2 Proposed catalytic cycle of directing group assisted meta-C–H functionalization of arenes aided by the transient mediator norbornene. Source: Cheng et al. [50] and Wang and Dong [51].

good yields. In contrast, alkylating reagents containing β-hydrogen resulted in very poor yields. A follow-up study was conducted to overcome the aforementioned limitation by the same research group. They identified the combination of a more reactive NBE-derived mediator 2-carbomethoxynorbornene 15 (the Yu mediator) and the quinoline-type ligand 14 could successfully constitute a more general and efficient meta-C–H alkylation reaction compatible with a wide range of alkylating reagents (Scheme 4.4) [53].

117

118

4 Directing Group Assisted meta-C–H

Pd(OAc)2 (10 mol%) 12 (20 mol%)

R1 NHArF R

R2–I

+

O ArF = 4-(CF3)C6F4

NBE (1.5 equiv) AgOAc (3.0 equiv) DCE, 95 °C, 16 h

11

R1 OMe

NHArF R

O 2

R

N

O

12

13

10 OMe NPhth NHArF

OMe NHArF

Me

O

NHArF NHArF

F

Me

CH2CO2Et

Me 91%

O

O

O

CF3

86%

82%

71%

Scheme 4.3 meta-C–H alkylation of phenylacetic amide derivatives with NBE. Source: Modified from Wang et al. [52].

R1 R

NHArF + R2–I O ArF = 4-(CF3)C6F4

R1

Pd(OAc)2 (10 mol%) 14 (10 mol%) AgOAc (3.0 equiv) DCE, 75 °C, 16 h

11

NHArF R

tBu

O R2

Me

N

O

Me

14

13

CO2Me (±)

10

15 (1.5 equiv)

O

O n

93%

Bu

O NPhth

85%

NHArF

NHArF

NHArF

NHArF

Et

Me

Me

Me

Me

86%

O OTBS 84%

Scheme 4.4 meta-C–H alkylation of phenylacetic amide derivatives with Yu-mediator 15. Source: Modified from Shen et al. [53].

4.2.2

Sulfonamide as Directing Group

In 2017, the Yu group developed the sulfonamide group assisted meta-C–H alkylation of benzylsulfonamides with 15 as the mediator and isoquinoline 17 as the ligand, giving the corresponding products 18 in moderate to good yields. Notably, a broad spectrum of alkylating reagents was amenable to this protocol (Scheme 4.5) [54]. Recently, the Ding group reported a nosyl group assisted direct meta-C–H alkylation of phenylalanine derivatives (Scheme 4.6) [55]. By using another NBE derivative bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate 20 as the transient mediator and simple pyridine as the ligand, a number of meta-alkylated products 21 were generated in moderate to high yields. Notably, no racemization of the chiral substrate was observed during this procedure. It should be noted that in the aforementioned reported meta-C–H alkylation transformations, steric hindered secondary alkyl halides were all proved to be incompetent alkylating reagents.

4.3 meta-C–H Arylation of Arenes Pd(OAc)2 (10 mol%) O S O NHAr

1

R

Ar = 3,5-(CF3)2C6H3

+ R2–I 11

17 (20 mol%) 15 (1.5 equiv)

O S O NHAr

1

R

AgOAc (3.0 equiv)

N

R2 18

DCE,100 °C, 24 h

17

16 F

O S O

O S O NHAr

Me

NHAr nBu

O S O NHAr

Me

OTBS

60%

O S O NHAr

Me

( )6

Ph

72%

47%

Me

60%

Scheme 4.5 meta-C–H alkylation of benzylsulfonamide derivatives. Source: Modified from Cheng et al. [54]. Pd(OAc)2 (10 mol%) CO2Me R1

Pyridine (20 mol%) + R2–I

NHNs 11

19

NHNs Me

21

Br CO2Me

20

Me

CO2Me NHNs

NHNs

NHNs

CH2CO2Et

Et 79%

R2

CO2Me

CO2Me

CO2iPr CO2iPr

NHNs

20 (1.5 equiv) AgOAc (3.0 equiv) TBME, 80 °C, 24 h

F

OMe

CO2Me R1

27%

57%

CH2CO2Et 92%

Scheme 4.6 meta-C–H alkylation of nosyl-protected methyl ester of phenylalanine derivatives. Source: Modified from Liu et al. [55].

4.3 meta-C–H Arylation of Arenes 4.3.1

Amide as Directing Group

Following the success of previously described amide group assisted meta-C–H alkylation, Yu and coworkers exploited the more challenging meta-C–H arylation of phenylacetic amide derivatives (Scheme 4.7) [52]. Through a slight modification of the reaction conditions used for meta-C–H alkylation (see Scheme 4.3), meta-C–H arylation took place smoothly to afford the desired biaryls 23 in good yields. A plethora of aryl iodides containing ortho-coordinating groups and 3,5-bis(trifluoromethyl)-iodobenzene were demonstrated competent arylation reagents. Despite the success of meta-C–H arylation, this process only had a narrow substrate scope since the arylating reagents involved in the above reactions were limited to those with electron-withdrawing ortho-coordinating groups or multiple electron-withdrawing substituents. Consequently, development of a more general meta-arylation approach tolerable with common arylating reagents was highly

119

120

4 Directing Group Assisted meta-C–H

R1

NHArF + O ArF = 4-(CF3)C6F4

Ar X 22

O N Ar

TBME, 95 °C, 12 h

O

NHArF

NHArF

NHArF

NHArF

CO2Me

O

O Me F 3C

64%

O

12 Me

O

CO2Me

23

Me

O

O

OMe

NHArF R1

NBE (1.5 equiv) AgOAc (3.0 equiv)

10 Me

R2

Pd(OAc)2 (10 mol%) 12 (20 mol%)

R2

82%

CF3

48%

76%

Scheme 4.7 meta-C–H arylation of phenylacetic amide derivatives with NBE. Source: Modified from Wang et al. [52].

desirable. With the aid of quinoline ligand 14 and Yu mediator 15, the Yu group developed a general and efficient meta-selective C–H arylation procedure with a much broader scope of arylating reagents including simple phenyl iodide, para-, meta-substituted aryl iodides, and heteroaryl iodides (Scheme 4.8) [53].

NHArF +

Me

Pd(OAc)2 (10 mol%) 14 (20 mol%)

Me Ar X

NHArF

ArF = 4-(CF3)C6F4

PhCF3, 90 °C, 24 h

22

Bu

O

AgOAc (3.0 equiv)

O

Me t

Ar

N

O

Me

14

23

CO2Me ( ) 15 (3.0 equiv)

10a

Me

Me Me

NHArF NHArF

Me

NHArF NHArF

O O

O

Bn 73%

O

N

Cl Boc 86%

N Ts

80%

57%

Scheme 4.8 meta-C–H arylation of phenylacetic amide derivatives with Yu-mediator 15. Source: Modified from Shen et al. [53].

In 2016, Zhao, Shi, and coworkers reported a bidentated-directing group oxalyl amide assisted meta-C–H arylation of β-arylethylamine derivatives 24, using simple NBE as the transient mediator (Scheme 4.9) [56]. In this protocol, a wide range of aryl iodides bearing ortho-, meta-, or para-substituents were demonstrated to be suitable coupling partners, affording the corresponding biaryls in good yields.

4.3 meta-C–H Arylation of Arenes Pd(OAc)2 (10 mol%) NBE (1.0 equiv) AgOAc (1.5 equiv)

O

R1

HN

+

N(iPr)2

Ar X

OMe O

Ph

HN N(iPr)2

25

O N(iPr)2

S

HN

O

Me

O

N(iPr)2 O

HN Ph

O 81%

O

OMe

OMe

HN

N(iPr)2

Ar

Mesitylene, 100 °C, 24 h

22

O

HN

1-AdCO2H (0.5 equiv)

O 24

O

R1

N(iPr)2 O

Br

Me 83%

82%

87%

Scheme 4.9 meta-C–H arylation of β-arylethylamine derivatives. Source: Modified from Han et al. [56].

Later, the Shi group disclosed a selective interannular meta-C–H arylation of biaryl-2-trifluoroacetamide derivatives (Scheme 4.10) [57]. Notably, the incorporation of the trifluoroacetyl protecting group was found to be essential for the interannular selectivity, which might attribute to its electronic properties and binding ability. While the substrates reacted well with aryl iodides bearing an ortho electron-withdrawing group, the reactions with aryl iodides with meta- or para-substituents only had very low yields of the desired products. Under these circumstances, replacement of NBE to the Yu mediator 15 dramatically increased the reaction yields. Notably, the structurally well-defined dimeric palladacycle 28, consisting of two cyclopalladated trifluoroacetamino biaryl units connected by a trifluoroacetamide, was determined to be the key intermediate of this process.

O

R1 N H

CF3 + Ar X

AgOAc (3.0 equiv) DCE, 120 °C, 16 h, N2

R2

N H

CF3

F3C F3C

L

O N

R2

Pd

Ar 27

22

26

N Pd L O

O

Pd(OAc)2 (10 mol%) R1 4-Methoxypyridine (20 mol%) NBE or 15 (1.5 equiv)

28 (X-ray)

O N H

N H

CF3

N H

CF3

O CF3

MeO

O2N

N H Me

NO2

CO2Me

CO2Me Me

O

O

CF3 O

MeO Me

87%

68%

72%

51%

Scheme 4.10 meta-C–H arylation of biaryl-2-trifluoroacetamide derivatives. Source: Modified from Ling et al. [57].

121

122

4 Directing Group Assisted meta-C–H

4.3.2

Sulfonamide as Directing Group

In 2017, the Yu group showcased a Pd(II)/NBE cooperatively catalyzed meta-C–H arylation of nosyl-protected arylethylamines, phenylglycine esters, and 2-aryl anilines, with 4-Ac-pyridine 30 as the ligand and the common sulfonamide as the directing group (Scheme 4.11) [58]. This process was amenable not only to diversified aryl iodide arylating reagents but also to aryl bromide arylating reagents with ortho-coordinating groups. Remarkably, different from the previously reported cases that commonly necessitated the use of stoichiometric amount of mediator, only a catalytic amount (10–20 mol%) of NBE mediator was required to promote the meta-C–H arylation efficiently in the case of nosyl-protected arylethylamines, which represented the first example in this area.

( )n

R1

R2 + Ar X NHNs

n = 0, 1 29

Pd(OAc)2 (10 mol%) 30 (20 mol%) NBE (10–150 mol%) AgOAc (3.0 equiv) TBME, 80 °C, 24 h

31

NHNs

O

CO2Me

N H NHNs

iPr

CO2Me

CO2Me

92%

75%

R2

NHNs n = 0, 1

Ar

22

Cl CO2Me Me

( )n

R1

Ac

N 30 CO2Me

NHNs Me

CO2Me NHNs

CO2Me CO2Me

80%

70% (mono/di = 1/1)

Scheme 4.11 meta-C–H arylation of nosyl-protected aryl ethylamine, phenylglycine, and 2-aryl aniline derivatives. Source: Modified from Ding et al. [58].

In a related process, the same group achieved the meta-C–H arylation of benzylsulfonamide derivatives 16 through Pd(II)/NBE cooperative catalysis with 15 as the transient mediator and isoquinoline 17 as the ligand (Scheme 4.12) [54]. Apart from good functional-group tolerance, this process was also amenable to a wide variety of heteroaryl coupling partners. More importantly, the obtained meta-C–H arylated products are synthetically very useful since they can be readily converted to sodium sulfonates, sulfonate esters, sulfonamides, and styrenes through Julia-type olefination.

4.3.3

Tertiary Amine as Directing Group

In 2015, Dong and coworkers developed the tertiary amine assisted meta-arylation of arenes by Pd(II)/NBE cooperative catalysis (Scheme 4.13) [59]. It was worthy to note that the process was promoted by the ligand AsPh3 and an interesting “acetate cocktail” containing LiOAc⋅2H2 O, CsOAc, Cu(OAc)2 ⋅H2 O, and acetic acid. A range of

4.3 meta-C–H Arylation of Arenes

O S O NHAr

R1

Ar = 3,5-(CF3)2C6H3 16 O S O NHAr

Me

Pd(OAc)2 (10 mol%) 17 (20 mol%)

+ Ar X

15 (1.5 equiv) AgOAc (3.0 equiv)

22

Ar

DCE, 100 °C, 24 h

O S O NHAr

Me

O S O NHAr

R1

N 17

32

O S O NHAr

Me

Br O

O F

N 91%

92%

Scheme 4.12 meta-C–H arylation of benzylsulfonamide derivatives. Source: Modified from Cheng et al. [54]. Pd(OAc)2 (10 mol%) AsPh3 (25 mol%) NBE (2.0 equiv) AgOAc (2.5 equiv) PhCl, 100 °C, 24–36 h

Me N + Ar X Me

R1

Me N Me

R1

CsOAc (3.0 equiv) LiOAc·2H2O (1.0 equiv)

22

33

Ar

34

Cu(OAc)2·H2O (0.5 equiv) HOAc (15.0 equiv) “acetate cocktail” Me

NMe2

F3C

NMe2

MeO

NMe2 O

CO2Me

73%

CO2Me

55%

MeO

NMe2 O

OMe

N Me 53%

58%

Scheme 4.13 meta-C–H arylation of benzyl amine derivatives. Source: Modified from Dong et al. [59].

functional groups, as well as heteroarenes, were compatible under the optimal reaction conditions. However, an ortho electron-withdrawing substitution in aryl iodide was required to render it a competent coupling partner. Notably, the tertiary amine directing group can be facilely transformed into other synthetically useful functional groups.

4.3.4

O S O NHAr OMe

CHO 76%

63%

123

Tethered Pyridine-Type Directing Group

In 2016, Yu and coworkers reported the meta-C–H arylation of anilines, heteroaromatic amines, phenols, and 2-benzyl heterocycles by employing the versatile

124

4 Directing Group Assisted meta-C–H

3-acetylamino-2-hydroxypyridine 36a or its trifluoromethylated derivative 36b as the ligand and NBE or 15 as the transient mediator (Scheme 4.14) [60]. This reaction showed excellent substrate scope with respect to both (hetero)arene substrates and arylating reagents, as evidenced by more than 120 presented examples. Notably, the broad synthetic utility of this method in drug discovery was demonstrated by allowing the late stage meta-C–H arylation of a lenalidomide derivative 38 in good yield. Finally, it is worth mentioning that they also successfully developed the first silver-free version of meta-C–H arylation of anilines, which would significantly enhance the practicality of this strategy.

X R1

( )n

X = NBoc, O (n = 1) X = CH2 (n = 0)

R2

N

+

Ar

X R1

AgOAc (1.5 equiv)

R4

R

NHAc

R2

Ar

DCE, 100 °C, air, 24 h

22

( )n

N

I

R3 35

Pd(OAc)2 (10 mol%) 36a or 36b (20 mol%) NBE or 15 (1.5 equiv)

N OH 36a: R = H 36b: R = CF3

R3 37 R4

>120 examples Boc N S

Boc N

Me

Me

N MeO2C

N

N

93%

Boc

I

MeO2C N

O

+

O 38

Me

N

CO2Me

87% Pd(OAc)2 (10 mol%)

O 22a

80% DG

N

Boc

36a (20 mol%) 15 (1.5 equiv) AgOAc (3.0 equiv) DCE,100 °C, air, 24 h

NH

H

N MeO2C

Cl

98%

N

OMe

CO2Me

O

Me

OMe Me

DG

Me

Me

61% yield

N

O NH

O

O

CO2Me 39

Scheme 4.14 meta-C–H arylation of aniline, heterocyclic aromatic amine, phenol and 2-benzyl heterocycle derivatives, and synthetic application. Source: Modified from Wang et al. [60].

Similarly, by using a pyridine-type N-substitution as the directing group, the Yu group also realized meta-C–H arylation of benzylamine derivatives in 2017. The transformation was promoted by the Yu mediator 15 and pyridone-type ligands 41a or 41b to afford the corresponding meta-arylated products 42 in moderate to excellent yields. Gratifyingly, both heterocycle containing substrates and arylating reagents (aryl iodides) were compatible with this procedure (Scheme 4.15a) [61]. Importantly, the directing group could be readily removed through a two-step procedure to afford the N-Boc benzylamine derivatives 43, which would be further transformed into various important materials such as the RPR 128515 analogues 44 (Scheme 4.15b). By adopting the similar reaction conditions in Scheme 4.15, the meta-C–H arylation of masked aromatic aldehydes 45 with a tethered pyridine-type directing group

N

R1

Boc Me + Ar

N

22

40

Me

N

Boc Me

N

I

Pd(OAc)2 (5 mol%) 41a or 41b (7.5 mol%) 15 (1.5 equiv)

N

R1

Me

N

Boc

42

Me

N N

CF3

N OH 41a: R = H 41b: R = CF3

Ar

Me

N

Me

N

AgOAc (3.0 equiv) CHCl3, 100 °C, air, 24 h 60 examples

R

Boc

Me

Boc

N

Me

Boc

N

Me

S

91%

N Ts

Me

OCF3

CO2Me

87%

87%

67%

(a) Me Me

N N

Boc Me

Me

N H

NH2

Boc

NH

(1) MeI, 100 °C

NH2

(2) NaOH, 50 °C

Me

91% over 2 steps CO2Me

(b)

Scheme 4.15

42a

CO2H 43

O

N H

CO2Me

RPR 128515 analogue 44

(a) meta-C–H arylation of benzylamine derivatives. (b) Synthetic application. Source: (a) Modified from Wang et al. [61].

126

4 Directing Group Assisted meta-C–H Pd(OAc)2 (10 mol%)

OTBS R1

Me

N

+ Ar

41b (20 mol%) 15 (1.5 equiv)

I

OTBS

AgOAc (2.5 equiv) CHCl3, 100 °C, 16 h

N

OTBS

OTBS

Me N

Me N

N 70%

OTBS

F Me

MeO N

O2N Br

Ar 47

46

OTBS Me

CHO R1

Ar

22

45

TBAF Me 140 °C

R1

Me

N N

Me

O2N

Cl 66%

88%

45%

Scheme 4.16 meta-C–H arylation of masked aromatic aldehyde derivatives. Source: Modified from Wang et al. [61].

was achieved by the same group in 2018 (Scheme 4.16) [62]. It should be pointed out that a suitable length of the tether was essential to allow the critical migratory insertion step to proceed efficiently. In this process, a broad range of masked aryl aldehyde substrates and aryl iodides were identified as competent reactants to provide the corresponding masked biaryl aldehydes 46 in satisfactory yields. Importantly, 46 can be unmasked to yield biaryl aldehydes 47 in heated tetra-n-butylammonium fluoride (TBAF) solution.

4.3.5

Acetal-Based Quinoline as Directing Group

In 2017, Ferreira and coworker developed the meta-C–H arylation of benzyl alcohol-derived acetal substrates 48, which contained a unique acetal-based quinoline-type directing group quinolinyl acetal (QuA). This process was promoted by the distinct amino acid-derived ligand N-trifluoroacetylglycine 49 and the Yu mediator 15 (Scheme 4.17a) [63]. A wide variety of functional groups were tolerable in this process. Moreover, the meta-arylation could be combined with ortho-arylation or ortho-olefination to access polysubstituted arenes, thus providing a versatile platform for diversification of aromatic systems. Notably, the directing group QuA can be easily removed and recovered from the meta-arylated products under very mild reaction conditions (Scheme 4.17b).

4.3.6

Free Carboxylic Acid as Directing Group

In 2017, Yu and coworkers realized the more challenging auxiliary-free meta-C–H arylation of free arylacetic acids 52 by using the N-mono-protected 3-amino-2-hydroxypyridine-type ligand 53 and the Yu mediator 15 (Scheme 4.18) [64]. This reaction tolerated a number of aryl iodides as arylating reagent including those with non-coordinating substituents. The corresponding meta-arylated arylacetic acid-type products 54 were generated in moderate to high yields.

4.4 meta-C–H Chlorination of Arenes Pd(TFA) 2 (10 mol%) 49 (20 mol%) 15 (1.5 equiv)

OQuA + Ar X

R1

F3 C

AgOAc (4.0 equiv) o DCE, 100 C, 24 h

22

48

O

OQuA

R1

N CO2H H 49

Ar 50

QuA = O N

Me

MeO

OQuA

MeO

MeO

NTs

OQuA

OQuA

OQuA

CO2Et

CO2Me N

Bn 71%

(a)

75%

OQuA

R1

HCl (g), MeOH

OH

R1

(b)

O

+

23 oC, 24 h Ar 50

Boc

59%

47%

N MeO

Ar 51

QuA-OMe

Scheme 4.17 (a) meta-C–H arylation of benzyl alcohol derivatives. (b) Cleavage of QuA directing group. Source: (a) Modified from Li and Ferreira [63].

R2 CO2H

R1

+ Ar X

22

52

Me

Pd(OAc)2 (10 mol%) 53 (20 mol%) 15 (1.5 equiv)

R2

AgOAc (0.75 equiv) K2HPO4 (2.0 equiv)

Me

F3C Ar

HFIP, 100 °C, 24 h

54

CO2H

82%

Scheme 4.18 et al. [64].

CF3

91%

N

OH 53

CO2H

F OMe

NH

OPiv

F

CO2H

O

CO2H

R1

NO2

83%

CO2H Cl NO2

70%

meta-C–H arylation of free phenylacetic acids. Source: Modified from Li

4.4 meta-C–H Chlorination of Arenes Aryl chlorides are very important basic chemicals due to their wide synthetic utility in transition metal-catalyzed cross-coupling reactions. Among the various methods for aryl chloride preparation, the direct C–H chlorination of arenes is especially

127

128

4 Directing Group Assisted meta-C–H

attractive in terms of both atom economy and step economy. In 2016, Yu and coworkers reported a Pd(II)/NBE co-catalyzed meta-C–H chlorination of aniline and phenol derivatives with a tethered pyridine-type directing group (Scheme 4.19a) [65]. This highly efficient catalytic system exploited the unique aryl chlorosulfate 55 as the chlorination reagent, pyridine derivative 56 as the ligand, and 15 as the transient mediator. This protocol tolerated a series of substrates bearing diversified functional groups and delivered the corresponding meta-chlorinated products 57 in good to excellent yields. Gratifyingly, the substrates containing medicinally relevant heterocyclic motifs, such as indole, thiophene, and indazole derivatives, were also competent in this process. Moreover, the synthetic utility of this method was highlighted by transforming the meta-chlorinated products into a wide range of useful synthons, some of which were currently unable to access through direct meta-C–H functionalization strategy, for example, alkoxylation and borylation (Scheme 4.19b). Pd(PhCN)2Cl2 (10 mol%)

X R1

Me

N (X = NBoc, O)

iPr

56a or 56b (10 mol%) PhCN (20 mol%)

O S Cl O iPr O

+

OMe Me

Me

N

15 (1.5 equiv) AgOAc (2.0 equiv) Toluene/cyclohexane,

55

35

X R1 Cl

OMe Me 57

100 °C, N2, 14 h F O Cl

N H OH

N Boc N

MeS

Me

Me

N Cl

Boc N

Me

OMe

Me

Boc N DG

Me

OMe (b)

58

F

Cl

56a: R2 = CF3 56b: R2 = CN

F

Boc N

PinB Me

N

Me

OMe

MeOH, NaOtBu Dioxane, 100 °C 86% yield

OMe Me

Me

Boc N DG

Me

Cl 57a

Me

N

OMe 53%

Pd2(dba)3 (cat.) BuXPhos (cat.)

O

Cl

Cl

80%

t

Me Me

N

Me

87%

(a)

R2

F

60%

Pd(OAc)2 (cat.) XPhos (cat.) B2Pin2, KOAc Dioxane, 110 °C 71% yield

Boc N DG

Me

BPin 59

Scheme 4.19 (a) meta-C–H chlorination of aniline and phenol derivatives. (b) synthetic applications. Source: (a) Modified from Shi et al. [65].

Thereafter, the same group successfully extended this chemistry to benzylamine derivative 40a with an N-substituted pyridine-type directing group. The corresponding meta-chlorinated product 60 was obtained in 72% yield (Scheme 4.20) [61].

4.5 meta-C–H Amination of Arenes

Me

N

Boc

iPr

O S Cl O i Pr O

Me +

N

Pd(PhCN)2Cl2 (10 mol%) 56b (10 mol%) PhCN (20 mol%)

N

Boc Me

N

15 (1.5 equiv) AgOAc (2.0 equiv) Toluene/cyclohexane 100 °C, N2, 24 h

55

40a

Me

Cl 60: 72%

Scheme 4.20 meta-C–H chlorination of benzylamine derivative. Source: Modified from Wang et al. [61].

4.5 meta-C–H Amination of Arenes Aromatic amines are prevalent in bioactive natural products, agrochemicals, and pharmaceuticals [66, 67]. As such, the development of efficient synthetic methods for their synthesis is of great significance. In this context, transition-metal catalyzed direct C–H amination of arenes has emerged as an appealing approach. In 2016, Yu and coworkers demonstrated the first example of meta-C–H amination of aniline and phenol derivatives tethered with a pyridine-type directing group (previously, meta-C–H arylation of these substrates was realized, see Scheme 4.15) (Scheme 4.21) [68]. Through the cooperative catalysis of Pd(II) and 15 in combination with the bulky 3-amino-2-hydroxypyridine-type ligand 53, a large number of meta-aminated arene products (46 examples) were obtained in moderate to good yields. X R1

Me

N

+

OBz N 2 R R 2

(X = NBoc, O) 35

OMe Me

Boc N

Me

N N Me

61

O

N

81%

OAc 53%

OMe Me

62 Ph

O

OMe Me

Me

N R N R3 2

Ph

Me

N

Me

X R1

K3PO4 (3.0 equiv) AgOAc (2.0 equiv) DCM,100 °C, air, 24 h

Boc N

Me

OMe Me Me

Pd(OAc)2 (10 mol%) 53 (10 mol%) 15 (1.5 equiv)

O Me

N N N Boc

N

OMe

OMe

Me O 64%

Me

N

S

Me O 41%

Scheme 4.21 meta-C–H amination of aniline and phenol derivatives. Source: Modified from Wang et al. [68].

Shortly after, the same group successfully extended this meta-C–H amination chemistry to benzylamine derivative 40a and masked aryl aldehyde 45a both with a tethered pyridine-type directing group, through a minor modification of the previous reaction conditions. The corresponding meta-aminated products 63 and 64 were obtained in 65% and 52% yield, respectively (Scheme 4.22) [61, 62].

129

130

4 Directing Group Assisted meta-C–H

Me

N

Boc

N

Me

OBz +

N O 61a

40a (a)

(b)

N

Me

+

61a

Boc

N

Me

N O

63

OTBS Me

41b (40 mol%) 15 (1.5 equiv)

Me

45a

Me

K3PO4 (3.0 equiv) AgOAc (2.0 equiv) CHCl3, 100 °C, 24 h 65% yield Pd(OAc)2 (20 mol%)

OTBS

N

Pd(OAc)2 (20 mol%) 41b (20 mol%) 15 (1.5 equiv)

N

K3PO4 (3.0 equiv)

N

AgOAc (3.0 equiv) CHCl3, 100 °C, 24 h 52% yield

O

Me

64

Scheme 4.22 meta-C–H amination of benzylamine and masked aromatic aldehyde derivatives. Source: Wang et al. [61] and Farmer et al. [62].

4.6 meta-C–H Alkynylation of Arenes In 2016, Yu and coworkers reported the challenging unprecedented Pd(II)/NBE co-catalyzed meta-C–H alkynylation of anilines tethered with a pyridine-derived directing group, which has been the only example of meta-C–H alkynylation by now (Scheme 4.23) [68]. The incorporation of pyridine-based ligand 66, Yu mediator 15, and the additive LiF was found to be essential for reaction efficiency and selectivity (meta- vs. ortho-alkynylation). This transformation showed good functional group tolerance with regard to anilines. However, as to the alkynylating reagents, only the bulky silyl-protected alkynylbromides provided satisfactory results. Normal alkyl and aryl alkynyl bromides only led to trace amounts of the products.

4.7 Enantioselective meta-C–H Functionalization Enantioselective remote C–H functionalization is a long-standing challenge in asymmetric catalysis. In this context, the Yu group recently achieved an impressive breakthrough in this direction, regarding the first example of enantiopure NBE-enabled asymmetric meta-functionalization of arenes via a Pd(II)-initiated pathway. In the research, they reported the enantioselective meta-C–H arylation and alkylation of diarylmethylamines with a N-substituted pyridine-type directing group and homobenzylamines with a N-nosyl directing group, using the cooperative catalysis of the chiral Yu mediator (+)-15 and the Pd(II) complex (Scheme 4.24) [69]. As supported by the carefully designed mechanistic studies, the chiral differentiation of these processes relied on a fast, reversible, and racemic ortho-C–H activation followed by an enantioselective NBE insertion. Wherein, (+)-15 served

Pd(OAc)2 (10 mol%) 66 (30 mol%) 15 (2.5 equiv)

Boc N 1

R

Me

N

Br

+ TIPS

OMe

DCM, 100 °C, air, 24 h

Me

TIPS

65

35 Boc N

Me

Boc N

Cl

TIPS 72%

CF3

O OH

N 66

Me

Boc N

Ph Me

N

OMe Me

H N

F3C

67

Me

N

Me

N

LiF (2.0 equiv) AgOAc (1.5 equiv)

OMe

Scheme 4.23

Boc N R1

Me

N

OMe TIPS

Me

59%

Boc N

Me N N

Me

N

OMe TIPS

Me

61%

meta-C–H alkynylation of aniline derivatives. Source: Modified from Wang et al. [68].

OMe TIPS 53%

Me

132

4 Directing Group Assisted meta-C–H

R

n

Ar

DG

R′ DG H MeO2C n = 0 or 1

Ar

(R)

N

Ar

I

Me

N

N

DG

N R1

R1 69

Me Boc

N

Me

Boc

22

68

Boc

N

R2

Me

41b (15 mol%) (+)-15 (20 or 50 mol%) (R)-BNDHP (15 mol%) AgOAc (3.0 equiv) CHCl3, N2, 100 °C

R1

Me

R′ Aryl/alkyl

Pd(OAc)2 (10 mol%)

+

R1

Coupling

(+)-15

R2

N

* R

n

Ar

PdII CO2Me L L

(S)

(a) Me

Aryl/alkyl X (X = Br or I)

n

Pd(II), ligand

N

Boc

R′ N * R

Me

Me

Boc N

N Cl

CO2Me

CO2Me

Me

Me

N

Boc

N

N

N

Me Me

Me

Me Cl

Ar

Me

NTs CHO

(b)

64%, 84% ee

71%, 94% ee

Pd(OAc)2 (10 mol%) 72 (20 mol%) (+)-15 (20 or 50 mol%)

R Ns

R1 +

NH

70%, 84% ee

R2–X

AgOAc (3.0 equiv)

Me

Me

R Ns

(R2 = aryl, alkyl) TBME, N2, 90 °C 71

70

76%, 92% ee

R1

NH 73

Me

Me

NHNs

O2N

NsHN MeO2C

65%, 98% ee

48%, 84% ee

MeO2C NsHN Me

EtO2C

(c)

N 72

R2

MeO2C NHNs

Ph

Me

47%, 86% ee

c = 50%, s = 37

36%, 84% ee c = 36%, s = 18

Scheme 4.24 (a) Enantioselective meta-C–H activation. (b) Enantioselective meta-C–H arylation of diarylmethylamines. (c) Enantioselective meta-C–H arylation and alkylation of homobenzylamines. Source: Modified from Shi et al. [69].

both as the efficient transient mediator and as the only chiral source to control the stereoselectivity of the meta-C–H activation step (Scheme 4.24a). Enantioselective meta-C–H arylation of diarylmethylamines was realized through desymmetrization. The authors found that the use of (R)-BNDHP (1,1′ -binaphthyl-2,2′ -diyl hydrogen phosphate) as an additive could improve

4.8 Conclusion

the enantioselectivity of meta-C–H arylation of 68 (Scheme 4.24b). However, control experiments suggested that chiral mediator (+)-15 was solely responsible for the chiral induction while the chiral phosphoric acid has an appurtenant beneficial effect. A broad scope of arylating reagents (mainly aryl iodides plus 2-bromobenzoate), good functional group tolerance, and high enantioselectivities were observed. Additionally, asymmetric meta-C–H arylation and alkylation of N-nosyl homobenzylamines 70 were also achieved via either desymmetrization or kinetic resolution. Contrary to the broad scope of arylating reagents, the alkylating reagents presented were just ethyl iodoacetate and iodomethane (Scheme 4.24c). As to mechanistic studies, parallel kinetic isotope effect (KIEs) were measured to be 1.03 and 1.33 for ortho and meta-C—H bonds, respectively, indicating that neither C—H bond cleavage was the rate-determining step. The reaction rate was first order on [Ar–I], indicating that the reaction of ANP with aryl iodides was likely the rate-determining step. There is no doubt that these inspiring results obtained via the interplay of chiral mediator and Pd(II) complex will open up a new avenue for enantioselective remote C–H functionalization.

4.8 Conclusion Herein, we have summarized the directing group assisted meta-C–H functionalization of arenes through cooperative catalysis of NBE-type transient mediator and palladium(II) complex. Although this emerging strategy was just developed very recently, it has become a very powerful method for meta-C–H functionalization of various arene derivatives. Based on this chemistry, (hetero)arenes bearing a directing group are suitable substrates to undergo highly selective meta-C–H functionalizations, such as alkylation, arylation, chlorination, amination, and alkynylation, to provide the polysubstituted aromatics in a straightforward fashion. Despite the tremendous advances that have been made in this field over the past few years, there are still some challenges to be addressed. First, most of the directing groups of the suitable substrates have to be pre-installed through several synthetic operations. Moreover, its removal after meta-C–H functionalization also requires extra efforts. As such, it is highly desirable to develop much simpler and easily removable directing group, or even traceless directing groups that can be generated and removed in situ. Second, very limited NBE-type mediators are developed so far, among which only NBE and the Yu mediator can be widely used. In addition, stoichiometric quantities of mediator are usually required to achieve good reaction efficiency. Therefore, the development of general and powerful mediators that can promote the reaction catalytically is highly expected. Lastly, the development of chiral mediator and palladium complex co-catalyzed asymmetric meta-C–H functionalization of arenes will be another very important yet challenging direction for future investigations.

133

134

4 Directing Group Assisted meta-C–H

Abbreviations Ac Ad Ar Boc Bn BNDHP Bu Bz c cat. DCE DCM DG E ee equiv Et g HFIP L m Me NBE Ns o p Ph Phth Pin Piv Pr s TBAF TBME TBS TIPS TM Ts

acetyl adamantyl aryl tert-butyloxycarbonyl benzyl 1,1′ -binaphthyl-2,2′ -diyl hydrogen phosphate butyl benzoyl conversion catalytic 1,2-dichloroethane dichloromethane directing group electrophile enantiomeric excess equivalent ethyl gas hexafluoroisopropanol ligand meta methyl norbornene 2-nitrobenzenesulfonyl ortho para phenyl phthaloyl pinacol pivaloyl propyl selectivity tetra-n-butylammonium fluoride tert-butylmethylether tert-butyldimethylsilyl triisopropylsilyl transition metal 4-toluenesulfonyl

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137

5 Ruthenium-Catalyzed Remote C–H Functionalizations Korkit Korvorapun, Ramesh C. Samanta, Torben Rogge, and Lutz Ackermann Georg-August-Universität, Institut für Organische und Biomolekulare Chemie, Tammannstrasse 2, 37077 Göttingen, Germany

5.1 Introduction In contrast to numerous reports on ortho-selective C–H activations [1] of arenes, procedures for remote meta-/para-selective C–H functionalizations remain underdeveloped and were thus far largely realized through a limited number of viable strategies (Figure 5.1) [2]. Unfortunately, most approaches are either limited to specific substrates, requiring the construction of elaborate templates [3] and ligands [4], or restricted to the use of expensive iridium [5] and palladium catalysts [6]. In contrast, meta-C–H functionalizations under ruthenium catalysis can be achieved via remote C–H functionalization by cyclometalation. Proximity-induced, directing group-enabled ortho-selective C–H ruthenation leads to a considerable electronic bias at the arene ring [7] and consequently enables further functionalizations to take place at the remote para-position with respect to the Ru–C bond, thus resulting in the formation of overall meta-functionalized products (Figure 5.1e) [8]. In addition, the electronic effect of cyclometallic C–N bond allows transformations at the remote para-position, providing the corresponding para-substituted products (Figure 5.1h). The use of cyclometalated complexes was demonstrated by Roper/Wright in the stoichiometric nitration of ruthenium-benzene complexes [9]. Thereafter, the groups of Roper/Wright [10], van Koten [11], and Coudret [12] extended this method towards oxidative transformations and halogenations of cyclometalated ruthenium complexes in a stoichiometric fashion. Based on these reports on remote C–H functionalizations of ruthenium complexes, a number of protocols for ruthenium-catalyzed meta-selective C–H functionalizations of diverse substrates were developed within the last decade and allowed for the user-friendly construction of C–C as well as C–Het bonds, which will be discussed herein until November 2019.

Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

138

5 Ruthenium-Catalyzed Remote C–H Functionalizations meta-C−H activation (a)

(b)

O

Template

R

R

(c)

Ir

TM

R2

N H

Linker

N H O

NC

N Ir

1

R

(e)

(d)

R1

DG

N

R2 N Ru

H

Pd

para-C−H activation (g)

(f) Bulky catalyst

(h)

Ion-pair electrostatic Interactions

Template

R

R R

N

Ru

R TM Ir

O

N C

H

Ir

Figure 5.1 Strategies for remote meta-/para-selective C–H activation. (a) Steric control; (b) template assisted; (c) hydrogen bonding linker; (d) transient mediator; (e) remote σ-activator; (f) steric control; (g) template-assisted; (h) ruthenation.

5.2 meta-C–H Functionalizations 5.2.1

C–H Alkylation

The catalytic ortho-selective C–H alkylations of arene 1a with unactivated alkyl bromides 2 was first reported by the group of Ackermann in 2009 (Scheme 5.1a) [13]. Thereafter, the catalytic remote C–H functionalization via ortho-metalation was observed by the same group [14]. Ruthenium-catalyzed C–H alkylations with primary alkyl bromides afforded the ortho-alkylated product via chelation assistance. However, phenylpyridine 1b was reacted with 1-bromohexane (2) to deliver the ortho-alkylated product 3b along with the meta-decorated arene 3b′ , albeit in rather low yield (Scheme 5.1b). Thereafter, the group of Ackermann demonstrated the strategy of remote meta-C–H alkylations using secondary alkyl bromides 5 via carboxylate-assisted

5.2 meta-C–H Functionalizations (a) [RuCl2(p-cymene)]2 (2.5 mol%) 1-AdCO2H (30 mol%)

N H

+

n-Hex–Br

N n-Hex

K2CO3 NMP, 80 °C, 20 h

H 1a

H 3a: 68%

2

(b) [RuCl2(p-cymene)]2 (2.5 mol%) MesCO2H (30 mol%)

N H

+

n-Hex–Br

+

K2CO3 H2O, 100 °C, 20 h

H

2

H n-Hex

H OMe

OMe 1b

N

N n-Hex

3b: 45%

OMe 3b′: 7%

Scheme 5.1 Ruthenium catalysis for C–H alkylation with n-hexyl bromide. (a) Alkylation reaction in NMP and (b) in H2 O. Source: (a) Modified from Ackermann et al. [13]; (b) Modified from Ackermann et al. [14].

ortho-ruthenation, leading to the formation of meta-alkylated arenes 6 with excellent levels of position-selectivity (Scheme 5.2) [15]. Heteroarenes, such as pyridines, pyrimidines, and azoles, were successfully employed as the directing groups in the catalytic regime. Detailed mechanistic studies of this transformation were supportive of a reversible C–H ruthenation and a subsequent site-selective alkylation, which was proposed to proceed through the strong effect of the Ru–C(sp2 ) σ-bond. It is noteworthy that the enantiomerically enriched alkyl bromide (s)-5a led to the racemic product 6a (Scheme 5.2b). Moreover, the addition of the typical radical scavenger 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) fully inhibited the meta-C–H alkylation, providing strong support for a homolytic C–Br bond cleavage. In 2015, Ackermann and coworkers [16] and Frost and coworkers [17] contemporaneously reported on ruthenium-catalyzed tertiary C–H alkylations, occurring in the meta-position (Scheme 5.3). It was highlighted in Ackermann’s protocol that monoprotected amino acids (MPAA) were first employed as the ligand for ruthenium-catalyzed C–H activation (Scheme 5.3a). In addition, the applicability was not restricted to arenes 7 bearing pyridines or azoles as directing groups, but also removable pyrimidyl anilines were smoothly converted to the desired products 9 [16]. In addition to alkyl bromides 8a, commercially available and less reactive tertiary alkyl chlorides 8b were effective in Frost’s procedure (Scheme 5.3b) [17]. Both contributions provided further support for a radical pathway. Consequently, the following catalytic cycle was proposed by Ackermann and coworkers (Scheme 5.4) [16]. The catalytically active complex 10 initially undergoes a reversible ortho-C–H ruthenation to form intermediate 11. Subsequently, single-electron transfer to alkyl halide 8a followed by radical addition at the para-position with

139

140

5 Ruthenium-Catalyzed Remote C–H Functionalizations (a) R1 N

R

Br +

H

R3

Ar

R1 N

[RuCl2(p-cymene)]2 (2.5–5.0 mol%) MesCO2H (30 mol%)

2

R4

K2CO3 1,4-Dioxane, 100 °C, 20 h

H

R2

H Ar

R4 R3

4

5

6

N

N

N

N

N n-Pr

n-Pr

R OMe Me

R

R = n-Pr: 62% R = n-Bu: 70% R = n-Hex: 60%

76%

Me

Me

R = CF3: 55% R = CO2Me: 63%

50%

(b) [RuCl2(p-cymene)]2 (5.0 mol%) MesCO2H (30 mol%)

N Br

H

+ Me

n-Hex

H

H n-Hex OMe Me

OMe 1b

K2CO3 1,4-Dioxane, 100 °C, 20 h

N

(S)-5a

(rac)-6a: 53%

Scheme 5.2 Remote meta-C–H alkylations with secondary alkyl halides. (a) Scope of meta-C–H alkylations and (b) reaction with enantiomerically enriched alkyl bromide (s)-5a. Source: Modified from Hofmann and Ackermann [15].

respect to the Ru–C bond leads to radical intermediate 13. Then, rearomatization and hydrogen-atom abstraction furnishes the ruthenacycle intermediate 14, which undergoes proto-demetalation to deliver the alkylated product 9 and regenerates the catalytically active complex 10. Most of the protocols for ruthenium-catalyzed meta-C–H alkylations were until recently restricted to nitrogen-containing directing groups, such as 2-arylpyridines 1, that are difficult to modify or remove. In 2017, Ackermann and coworkers reported on a remote meta-C–H alkylation of imines 16 followed by hydrolysis, thus furnishing the meta-decorated ketones 17 (Scheme 5.5) [18]. In addition, the thus-obtained ketones 17 were easily transformed into a wealth of structural motifs, such as phenols, anilines, carboxylic acids, and indoles. Thereafter, azobenzenes 18 [19] and phenoxypyridines 20 [20] were also employed as transformable/removable directing groups in ruthenium-catalyzed remote C–H

5.2 meta-C–H Functionalizations

(a) DG

[RuCl2(p-cymene)]2 (2.5–5.0 mol%) Piv-Val-OH (30 mol%)

Br

H

+

Ar

R1

R2

H 7

R3

DG H Ar

K2CO3 1,4-Dioxane 100–120 °C, 16–20 h

R3 R2 R1

9

8a DG = heteroaryl, 2-pym-NH N

N

N N

NH

Me

N

N

NH

Me

t-Bu

F

R

60%

R = H: 53% R = Cl: 46% R = Br: 58%

N

t-Bu

OMe

F

78% O

72%

(b)

N

X +

H

Me

Me Me

H OMe 1b

[RuCl2(p-cymene)]2 (5.0 mol%) KOAc (50 mol%) K2CO3 or KOAc 1,4-Dioxane, 120 °C, 15 h

N H t-Bu OMe 9a

8 X = Br: X = Cl:

80% 71%

Scheme 5.3 meta-C–H Alkylations with tertiary alkyl halides. (a) Reactions of heteroarenes and removable N-pyrimidylanilines, and (b) of 2-phenylpyridines. Source: (a) Modified from Li et al. [16]; (b) Modified from Paterson et al. [17].

alkylations by the groups of Li/Yang and Li, thus providing access to meta-decorated anilines and phenols after the removal of the directing group (Scheme 5.6). As a consequence of the important role of organofluorine compounds in agrochemicals, pharmaceuticals, and material sciences, the cooperative action of phosphine and carboxylate ligands in ruthenium(II) catalysis enabled remote meta-C–H mono- and difluoromethylations using alkyl bromides 22, which were first presented by Ackermann and coworkers (Scheme 5.7) [21]. The group of Wang later reported on a dual ruthenium and palladium catalysis approach for remote mono- and difluoromethylations [22]. Thereafter, Frost and coworkers showed the efficacy of the cooperation of ruthenium(II) biscarboxylates with phosphine ligands or a palladium co-catalyst

141

142

5 Ruthenium-Catalyzed Remote C–H Functionalizations

N R3

R5

+

R2 15

N R2 R3

H

i-Pr

Me R4 9

X Piv

Br

R5

R2 R3

Ru

O

N H

H 1a

O 1

R

10

Proto-demetalation

+ K2CO3

H

KX + KHCO3 C–H ruthenation

8a i-Pr

Me Ru

O

N O

i-Pr

Me

R1

Ru NHPiv

R1

O

N

NHPiv

O

R4 R2 R3 14

H 11

Rearomatization

Radical addition i-Pr

Me [Ru(II)], KHCO3, KX

Ru

O

N [Ru(III)]X, K2CO3

O H R2

R3

R1

R4 R2 R3 12

NHPiv [Ru(III)]X

SET [Ru(II)]

R4

13

Br R2

R3

R4

8a

Scheme 5.4 Proposed catalytic cycle for remote C–H alkylations via ortho-ruthenation. Source: Modified from Li et al. [16].

for remote meta-C–H alkylations of α-halo carbonyl compounds 24a (Scheme 5.8a) [23]. The synergistic ruthenium catalysis could be applied not only to pyridines, pyrimidines, or removable pyrazoles as the directing groups, but also to transformable imidates, purines, and imines under milder conditions, as presented by Ackermann and coworkers (Scheme 5.8b) [24]. Very recently, Liang and coworkers exploited the cooperation of phosphine and carboxylate ligands in multicomponent ruthenium-catalyzed site-selective C–H functionalizations (Scheme 5.8c) [25]. Detailed mechanistic studies, such as reactions with radical scavengers or diastereomerically pure alkyl bromides, and radical clock experiments, were performed by Frost and coworkers [23], Ackermann and coworkers [24], and Liang and coworkers [25] and provided strong evidence for a radical mechanism as was earlier indicated [16]. In addition, Ackermann and coworkers presented electron paramagnetic resonance (EPR) experiments, which strongly support a homolytic C–X bond cleavage [24]. Furthermore, computational studies were

5.2 meta-C–H Functionalizations

TMP N

Me +

H

[RuCl2(p-cymene)]2 (5.0 mol%) 1-AdCO2H (30 mol%)

Br R1

Ar

R2

R3

K2CO3 PhCMe3, 120 °C, 20 h

H 16

H Ar

R3 R2 R1

17

8a Me

O

Me

O

H3 O

R

O

Me

O

Me

O

Me

t-Bu R

F

R = H: 71% R = OMe: 81% R = F: 74% R = Cl: 62%

Me N

R = Me: 73% R = Et: 70%

X X = O: 58% X = N: 70%

R

R = Me: R = Et: R = n-Pr: R = n-Hex:

84% 78% 77% 79%

Scheme 5.5 Remote meta-C–H alkylation with transformable/removable directing groups. Source: Modified from Li et al. [18].

(a) [RuCl2(p-cymene)]2 (5.0 mol%) PivOH (30 mol%)

Br N

+

N

Et

Et

H

K2CO3 1,4-Dioxane, 120 °C, 24 h

N

N

H Et

H 18

Et 19: 76%

5b

(b)

N H

+ Et

Et

H 20

[RuCl2(p-cymene)]2 (5.0 mol%) 1-AdCO2H (30 mol%)

Br

O

5b

K2CO3 C6H6, 120 °C, 24 h

N H

O

Et Et 21: 73%

Scheme 5.6 Remote meta-C–H alkylation with removable directing groups. (a) meta-Alkylations of azobenzenes 18 and (b) of phenoxypyridines 20. Source: (a) Modified from Li et al. [19]; (b) Modified from Li et al. [20].

143

144

5 Ruthenium-Catalyzed Remote C–H Functionalizations

(a) DG

[Ru(O2CMes)2(p-cymene)] (28, 10 mol%) P(4-C6H4CF3)3 (20 mol%)

O

H

+ Ar

Br

R2

7

O

Ar

Na2CO3 1,4-Dioxane 60 °C, 18 h

F R1

H

DG H

R2 F R1 23

22 F F N

N

CO2Et

R = H: 71% R = F: 72% R = Cl: 77%

N

CO2Et Me F R

F F

R

EtO2C

N

R = H: 60% R = F: 83%

N

N N R R = n-Bu: 78% R = Ph: 63%

(b)

N +

H

Br

CO2Et F F

H

[RuCl2(p-cymene)]2 (5.0 mol%) Pd(PPh3)4 (10 mol%) Ba(OAc)2 (15 mol%) Na2CO3 1,4-Dioxane 90 °C, 24 h

N H CO2Et F F

1a

22a

23a: 76%

Scheme 5.7 Ruthenium-catalyzed meta-C–H mono- and difluoromethylations. (a) Reactions by Ackermann and coworkers and (b) Wang and coworkers. Source: (a) Modified from Ruan et al. [21]; (b) Modified from Li et al. [22].

conducted by means of Fukui indices to rationalize the site-selectivity of the meta-C–C bond formation. Radical Fukui indices of ruthenium(III) species are suited to explain the site-selectivity of C–C bond formation at the para-position with respect to ruthenium, as presented by Ackermann and coworkers [24]. On the basis of these mechanistic studies, a plausible catalytic cycle was proposed by Ackermann, which commences with a reversible, carboxylate-assisted C–H ruthenation of arene 31 (Scheme 5.9). Subsequently, single-electron transfer occurs from ruthenacycle 32 to alkyl halides 24, leading to the formation of ruthenium(III) intermediate 33 and alkyl radical 34. Radical attack on the aromatic moiety at the position para to ruthenium forms ruthenacycle intermediate 35. Rearomatization followed by proto-demetalation delivers the desired meta-substituted product 37 and regenerates the catalytically active ruthenium(II) complex 30. It is noteworthy that the arene-ligand-free phosphine-coordinated ruthenacycle intermediate 32 was proposed in the catalytic cycle for the synergistic ruthenium(II)-catalyzed remote C–H functionalizations (Scheme 5.9). Further

5.2 meta-C–H Functionalizations (a) [RuCl2(p-cymene)]2 (5.0 mol%) MesCO2H (30 mol%) Pd(PPh3)4 (10 mol%) or PPh3 (20 mol%)

N O

H

+

Br

OEt

O

K2CO3 1,4-Dioxane, 120 °C, 15 h

H 1a

N H

OEt 25: 58%

24a

(b) R1 N

R2

(10 mol%) PPh3 (10 mol%)

O

H

+ Ar

Br

R4

R2

H

O

Ar

K2CO3 1,4-Dioxane, 40−60 °C, 20 h

H R3

H

R1 N

[Ru(O2CR5)2(p-cymene)]

R4 H R3

4

24b

26

R5 = Mes, Ad

n-Bu

R N

N

O

N

O

MeO2C N

R

N CO2Me

CO2Me n-Bu 63%

Br

N H

+

N i-Pr

n-Bu

R = H: 76% R = F: 73% R = OEt: 50%

(c)

CO2Me

CO2Me +

Br

CO2Et F F

H

R = H: 71% R = Br: 84%

[Ru(O2CMes)2(p-cymene)] (28, 10 mol%) P(4-C6H4CF3)3 (10 mol%)

N N

87%

N H

Na2CO3 1,4-Dioxane, 60 °C, 12 h

CO2Et MeO2C

1a

27

22a

F F

29: 65%

Scheme 5.8 Remote C–H alkylations with α-bromocarbonyl compounds. (a) Ruthenium catalysis by Frost and coworkers, (b) Ackermann and coworkers, and (c) Wang and coworkers. Source: (a) Modified from Paterson et al. [23]; (b) Modified from Korvorapun et al. [24]; (c) Modified from Wang et al. [25].

development in remote C–H alkylation was achieved by Ackermann and coworkers using well-defined arene-ligand-free [Ru(OAc)2 (PPh3 )2 ] as the catalyst (Scheme 5.10) [26]. Arenes 7 bearing heterocyclic directing groups, such as transformable oxazolines, removable pyrazoles, and biological relevant purines, were effortlessly converted to meta-alkylated products 9 under the catalytic regime with excellent levels of position-selectivity. Very recently, a breakthrough in remote meta-C–H alkylation was demonstrated by the group of Ackermann (Scheme 5.11) [27]. At ambient temperature, the excitation of ruthenium(II) intermediates in the remote meta-C–H alkylation by visible light led to the thus-formed excited state, which smoothly underwent single-electron

145

146

5 Ruthenium-Catalyzed Remote C–H Functionalizations

N

O N

H

H

R1

37

Mes

R2 R3

O

O

Proto-demetalation

Ru

O N

Ru

O

MesCO2H Mes

36

2

R

O

O

N

Ru

R1

KHCO3, KBr

Reversible C–H ruthenation

Mes

O

Ph3P

H

31

O

O L 30 (L = 31, PR3, OR2)

Ph3P

MesCO2H Mes O

O

O

Ph3P

O

L

R3

H O

32 R1

K2CO3

Mes

Mes

Rearomatization O

O Ru

Ph3P

N

Br 35

O

O

R2 R3

O Ru

HO R1

L N

R3 2 R 24

Br

O

Ph3P

SET

Br 33 R2

H . R3

34

R1

O

Scheme 5.9 Proposed catalytic cycle for the synergistic ruthenium-phosphine catalysis. Source: Modified from Korvorapun et al. [24].

transfer to alkyl halide 8a. It is noteworthy that the photoredox ruthenium catalysis was compatible with monosaccharide, menthol, and steroid 38a motifs. The photocatalytic reactions were performed under milder reaction conditions and without any additional exogeneous photocatalyst. Concurrently, Greaney and coworker reported on a remote C–H alkylation mediated by visible light (Scheme 5.12) [28]. Secondary and tertiary alkyl iodides 8c furnished the meta-decorated products 9b, while the selectivity switched from meta to ortho when primary alkyl halides were used. It was highlighted that the photocatalytic reactions were performed in 2-MeTHF as the solvent.

5.2.2

C–H Benzylation

In 2009, Ackermann and coworker first reported on ruthenium-catalyzed ortho-selective C–H benzylations using primary benzyl chlorides [29]. In consequence of the atom- and step-economical C–H/C–H activation [30] for the construction of new C–C bonds, the groups of Shi/Zhao [31] and Shi [32] reported on oxidative ruthenium-catalyzed meta-C–H benzylations of toluene derivatives

5.2 meta-C–H Functionalizations

DG

DG

Br

H

+

R1

Ar

R2

H

Ru(OAc)2(PPh3)2 (10 mol%) R3

H Ar

K3PO4 1,4-Dioxane, 100 °C, 18 h

R 7

N

8a

O

N

DG = heteroaryl, 2-oxazoline

9

F F

F F

EtO

N

EtO O

t-Bu Me

89%

O N

t-Bu

F

N i-Pr

62%

R3 2 1R

N

N O

N

O P EtO OEt

70%

N

N

N

O

O 60%

O

Me Me

Scheme 5.10 Remote C–H alkylations using an arene-ligand-free ruthenium complex. Source: Modified from Fumagalli et al. [26].

R1

N

+

H

[RuCl2(p-cymene)]2 (5.0 mol%) (C6H5O)2P(O)OH (30 mol%)

Br R2

Ar

R3

R4

H

R1

N H

K2CO3 1,4-Dioxane, 25−30 °C, 24 h Blue LEDs

Ar

8a

1

R4 R3 R2

38

(R4 = H, Alk) R N

N

N

Me O

N H O

Me

t-Bu R

63%

R = Me: 56% R = OMe: 54% R = F: 70%

H

H

O Me Me R = H: 69% R = Me: 60% R = OMe: 52%

38a: 64%

Scheme 5.11 Photo-induced ruthenium-catalyzed meta-C–H alkylations with alkyl bromides 8a. Source: Modified from Gandeepan et al. [27].

147

148

5 Ruthenium-Catalyzed Remote C–H Functionalizations

N

I

[RuCl2(p-cymene)]2 (10 mol%)

Me Me

KOAc, H2O 2-MeTHF, 28−30 °C, 24–48 h Blue LEDs

+ H

Me H 1a

N H t-Bu

8c

9b: 82%

Scheme 5.12 Remote meta-C–H alkylations under visible light irradiation. Source: Modified from Sagadevan and Greaney [28].

39 using di-tert-butylperoxide (DTBP) and heptafluoroisopropyl iodide (i-C3 F7 I) as the radical initiators, respectively (Scheme 5.13). Although pre-functionalized substrates are not necessary for the C–H/C–H activation, an excess of toluene derivative 39 is required in the catalytic transformations. Among the additive ligands, (±)-1,1′ -binaphthyl-2,2′ -diyl hydrogenphosphate (BNDHP) notably switched the site-selectivity of the oxidative C–H/C–H benzylations from ortho (40) to meta (41), as presented by Shi/Zhao (Scheme 5.13a) [31]. (a) Ru(PPh3)3Cl2 (4.0 mol%) Ferrocene (10 mol%)

N

Me

H

N +

H

DTBP 120 °C, 24 h

Me

RuCl3 (20 mol%) Ferrocene (10 mol%) Ligand (10 mol%) DTBP 130 °C, 24 h

N H

H

H 40 o:m = 83% : 5%

1a

41

39

Ligand

Yield of o:m

MesCO2H

16% : 53%

Piv-Val-OH

19% : 46%

(BnO)2PO2H

18% : 48%

(±)-BNDHP

5% : 83%

O

O P OH O

(±)-BNDHP

Me

(b) H

N +

H

Me

i-C3F7I Na2CO3 H2O 140 °C, 48 h

H

1a

[RuCl2(p-cymene)]2 (5.0 mol%) 4-ClC6H4CHO (50 mol%)

39

N H

Me

41: 60% mono/di = 2.8 : 1.0

Scheme 5.13 Oxidative ruthenium-catalyzed meta-benzylation with toluene derivatives. (a) C–H/C–H benzylations with DTBP and (b) with heptafluoroisopropyl iodide. Source: (a) Modified from Li et al. [31]; (b) Modified from Li et al. [32].

Very recently, major advances in site-selectivity control of C–H benzylations were achieved by the group of Ackermann using benzyl chlorides 42 [33]. The position-selectivity could switch from the ortho- (43) to the meta-positions (44) upon

5.2 meta-C–H Functionalizations

the addition of phosphine (Scheme 5.14). The cooperative action of ruthenium(II) biscarboxylates and phosphine ligands was effective for primary and secondary benzyl chlorides, delivering the meta-decorated products 44 with excellent levels of site-selectivity. It is noteworthy that this synergistic ruthenium manifold was fully compatible with biorelevant motifs, such as peptides 44a, nucleotides 44b, drug molecules 44c, and especially fully protecting group-free sugar 44d. R1 [Ru(OAc)2(p-cymene)] (10 mol%)

N Ar

Ar

K2CO3 1,4-Dioxane, 100 °C, 20 h

[Ru(OAc)2(p-cymene)] (10 mol%) PPh3 (10 mol%)

Cl

R2

N

+

H

H

H

43 91% (mono:di = 1.0 : 3.8) Me

Ar = 4-MeOC6H4

4

H Ar

42

44 Ar Me

S

Me

O O MeO2C

R2

N

K2CO3 1,4-Dioxane, 60−80 °C, 20 h

Ar

Ar

R1

N H

H N

O O

O

O Me Me

N

N

N i-Pr

N

44a: 74%

N

O O

N

HN

N i-Pr

O

N N

44b: 55% (from Uridine) HO OH

AcO AcO AcO

OH

HO

OAc

O O

O O N

EtO O EtO P O

O O

N O

Me Me 44c: 69% (from Gastrodin)

N N

N N i-Pr

N N

44d: 55% (from Salicin)

Scheme 5.14 Site-selectivity switch for ruthenium-catalyzed C–H benzylation. Source: Modified from Korvorapun et al. [33].

Here, mechanistic studies were conducted to rationalize the unique selectivity switch of this cooperative system [33]. Arene-free ruthenacycles with one or two phosphine ligands were shown to be effective in the remote meta-C–H benzylations. In addition, detailed computational molecular orbital analysis revealed a ligand-to-metal charge transfer to strongly stabilize the highly reactive triplet ruthenacycle 48 as the singlet species 49. The mechanistic findings and density functional theory (DFT) calculations have elucidated the following catalytic cycle (Scheme 5.15). Initially, carboxylate-assisted ortho-C–H ruthenation generates ruthenacycle 45, which undergoes single-electron transfer to benzyl chloride 42 to afford ruthenium(III) intermediate 46. Subsequently, the benzyl radical 47 attacks the arene moiety at the position para to ruthenium to deliver triplet species 48, which is stabilized as singlet ruthenacycle 49 by ligand-to-metal charge transfer. Finally, rearomatization and ligand exchange delivers the desired meta-benzylated product 51 and regenerates the catalytically active ruthenium(II) complex 45.

149

150

5 Ruthenium-Catalyzed Remote C–H Functionalizations 2-py [Ru(OAc)2(p-cymene)] + PPh3 +

H

1a 2-py

p-cymene + AcOH

H Ar

1a Ligand exchange

Cl 42

Single-electron transfer

PPh3 O Me Ru O N PPh3 50

KHCO3, KCl

Ar

PPh3 O Me Ru O N PPh3 45

51

Ar

H

PPh3 O Me Ru O N . H Cl H Ar 46 47

Rearomatization Radical addition

PPh3, K2CO3 PPh3 O Me Ru O N Cl 49

H Ar

PPh3 O Me Ru O N Cl 48

H Ar

Scheme 5.15 Proposed catalytic cycle for remote meta-C–H benzylations. Source: Modified from Korvorapun et al. [33].

5.2.3

C–H Carboxylation

Carboxylation reactions are useful tools for introducing a C-1 moiety into organic molecules [34]. The group of Greaney demonstrated selective carboxylation at the meta-position via a single-electron transfer process using RuCl3 ⋅nH2 O (53) [35] as the catalyst (Scheme 5.16) [36]. Ruthenium-catalyzed meta-C–C bond

RuCl3 ·nH2O

N +

H

CBr4

MeOH/1,4-dioxane (1 : 1) 85 °C, 16 h

H 1a

52

N

(53, 10 mol%) H

CO2Me 54: 59%

Scheme 5.16 Ruthenium-catalyzed remote C–H carboxylation. Source: Modified from Barlow et al. [36].

5.2 meta-C–H Functionalizations

formation followed by methanolysis was effective for arylheteroarenes, such as 2-arylpyridines (1a), 2-arylpyrimidines, and 6-arylpurines, thus furnishing metadecorated arenes 54.

5.2.4

C–H Acylation

Remote selective meta-C–H acylation was disclosed by Wang and coworkers using α-oxocarboxylic acid 55, as shown in Scheme 5.17 [37]. In the presence of a silver salt and persulfates, the activated ketoacids 55 underwent oxidative decarboxylation to deliver an acyl radical, which is the key intermediate in these ruthenium-catalyzed remote functionalizations. DG

Ru3(CO)12 (5.0 mol%) D-CSA (50 mol%)

O

H

OH

+

Ar H

Ar

7

Ag2CO3 Na2S2O8 TBME DCM, 100 °C, 48 h

O 55

DG H Ar

56

O Ar

DG = 2-py(m), pyr, purine

N

N

N

N

N

R Ph R

O

R = F: R = Cl: R = Br: R = CN:

75% 66% 52% 44%

Ph O R = Me: 67% R = Ph: 60% R = I: 61%

O 69%

O 52%

Scheme 5.17 Remote C–H acylation via oxidative decarboxylation. Source: Modified from Jing et al. [37].

5.2.5

C–H Sulfonylation

Carbon–heteroatom bond forming reactions via selective C–H bond activation have gained considerable attention over the last decade [38]. In an initial study, Frost and coworkers reported a meta-selective C–H sulfonylation of 2-phenylpyridines 1 using [RuCl2 (p-cymene)]2 and arylsulfonyl chlorides 57 (Scheme 5.18) [39]. An Ru–Caryl σ-bond formation by ortho-ruthenation assisted by the 2-pyridyl group takes place, which exerts a strong para-directing effect for the subsequent electrophilic sulfonylation. Later and based on mechanistic studies on meta-C–H alkylations, the mechanism of the meta-sulfonylation reaction was studied in more detail and revised [40]. Studies revealed that the C–H sulfonylation step is kinetically relevant and likely

151

152

5 Ruthenium-Catalyzed Remote C–H Functionalizations

N +

H Ar

O Cl S O

[RuCl2(p-cymene)]2 (5.0 mol%)

Ar

K2CO3 MeCN, 115 °C, 15 h

H 1

N H Ar

57

N

58

Ar

N

N

O S O

O S O

O S O

O S O R

R R = H: 70% R = t-Bu: 72% R = Br: 74%

Me 59%

R = Me: 56% R = OMe: 43%

Scheme 5.18 meta-C–H Sulfonylations of phenylpyridines 1 with sulfonyl chlorides 57. Source: Modified from Saidi et al. [39].

proceeds via a radical mechanism, while an electrophilic pathway can be ruled out (Scheme 5.19). This is in agreement with the previously proposed radical pathway for ruthenium-catalyzed meta-selective alkylation by the Ackermann group [16]. Dissociation of p-cymene takes place during the course of the reaction, and an arene-free ruthenium complex 60 has been suggested as the active catalyst for this reaction. As TsCl and 2-phenylpyridine (1a) played a significant role in the demetalation process, these studies are suggestive of the coordination of 2-phenylpyridine (1a) followed by a concerted C–H activation–demetalation to deliver the sulfonylated product 58 and regenerate the active catalyst 60. In addition, it is noteworthy that the yields for the meta-sulfonylation of 2-phenylpyridine (1a) with TsCl (57a) in the latter report [40] were significantly adjusted from 80% to 50%, compared with the identical reaction conditions published earlier [39]. In a recent report, Wang, Li, and coworkers reported an azoarene 18 directed ruthenium-catalyzed meta-selective sulfonylation (Scheme 5.20) [41]. The reaction could be performed on a gram scale and the product was reduced to the corresponding meta-sulfonylated aromatic amine.

5.2.6

C–H Halogenation

Aryl halides are valuable starting materials for numerous coupling reactions. In spite of a number of methods for ortho-selective C–H halogenations [38a, 42],

5.2 meta-C–H Functionalizations [RuCl2(p-cymene)]2 N K2CO3

C–H activation

KHCO3

1a

iPr

Me N

Ru

NCMe

59 ArSO2Cl p-cymene N N

+ KHCO3 58

57 [Ru(II)]

NCMe NCMe Ru NCMe

[Ru(III)Cl] ArSO2 61

NCMe 60

SO2Ar

Demetalation/ C–H activation

σ-meta-Activation

Radical addition

K2CO3 NCMe NCMe Ru N

N ArO2S

N H ArO2S

MeCN 64 MeCN

NCMe 62 K2CO3, [Ru(III)Cl]

Coordination N N 1a

NCMe NCMe Ru NCMe

ArO2S

NCMe NCMe Ru NCMe

KHCO3, KCl, [Ru(II)]

NCMe 63

Scheme 5.19 et al. [40].

Proposed catalytic cycle for meta-sulfonylation. Source: Modified from Marcé

general methods for direct meta-selective halogenations continue to be scarce. In 2015, the ruthenium-catalyzed meta-selective bromination of 2-phenylpyridine (1a) was achieved independently by Greaney and coworkers [43] and Huang and coworkers [44]. Greaney reported that [RuCl2 (p-cymene)]2 in combination with tetrabutylammonium tribromide (66) enabled the selective bromination (Scheme 5.21a). This protocol was further extended to the synthesis of meta-aryl or meta-alkenyl products by a one-pot bromination/Suzuki–Miyaura coupling or a one-pot bromination/Heck reaction. In the report by Huang, N-bromosuccinimide (NBS, 68a) was employed as a readily available bromine source for meta-C–H bromination under ruthenium catalysis (Scheme 5.21b). A plausible mechanism is initiated by ortho-ruthenation via a concerted metalation-deprotonation (CMD) [1o] C(sp2 )–H activation followed by a second C–H activation, which delivers

153

154

5 Ruthenium-Catalyzed Remote C–H Functionalizations

O Cl S O

N

[RuCl2(p-cymene)]2 (5.0 mol%)

N

+

N

Cs2CO3 MeCN, 110 °C, 24 h

H

N

H O S O

Me

H

18

65: 85%

57a

Me

Scheme 5.20

Azoarene-directed meta-sulfonation. Source: Modified from Li et al. [41].

(a) [RuCl2(p-cymene)]2 (5.0 mol%) MesCO2H (30 mol%)

N +

H

(n-Bu4N)Br3

H 1a

K2CO3 1,4-Dioxane, 110 °C, 20 h

N H Br 67a: 76%

66

(b) N +

H

NBS

DMA, 80 °C, 24 h Under air H 1a

68a

N

[RuCl2(p-cymene)]2 (5.0 mol%) H

Br 67a: 91%

Scheme 5.21 Ruthenium-catalyzed meta-bromination. (a) meta-Bromination with tetrabutylammonium tribromide (66) and (b) with N-bromosuccinimide (68a). Source: (a) Modified from Teskey et al. [43]; (b) Modified from Yu et al. [44].

a biscyclometalated ruthenium complex. Subsequently, the oxidative addition of NBS is followed by single-electron transfer (SET) bromination and thereafter protodemetalation releases the product and regenerates the catalyst. In an independent report by Ackermann and coworkers, synthetically useful, yet challenging purine bases 69 were selectively brominated at the meta-position under homogeneous or heterogeneous ruthenium catalysis (Scheme 5.22a) [45]. The silica-supported ruthenium catalyst Ru@SiO2 delivered the best results and can be recovered and reused for a number of times without loss of catalytic efficacy (Scheme 5.22b). The synthetic utility was showcased by introducing a pyrene motif as a fluorescent tag for fluorescent labeling of nucleobases. Later on, Maheswaran and coworkers disclosed a modified method for meta-selective C–H halogenations of arene 1a (Scheme 5.23a) [46]. A catalytic amount of the oxidant PhI(TFA)2 (20 mol%) was used and the method was extended

5.2 meta-C–H Functionalizations

(a) Br

H H N N R

+

RuCl3·nH2O (A) or Ru@SiO2 (B, 10 mol%)

NBS

N

H N

DMA, 80−100 °C, 20 h Under air

N 69

N R

68a

N N 70

R = i-Pr: R = n-Bu: R = Ph: R = Bn:

(b)

A: 77%, B: 70% A: 62%, B: 68% A: 53%, B: 50% A: 59%, B: 57%

70 60

Yield (%)

50 40 30 20 10 0 1

2

3

4

5

6

7

Run

Scheme 5.22 Homogeneous or heterogeneous ruthenium catalysts for meta-bromination. (a) Scope of meta-C–H bromination and (b) recycling and reuse of heterogeneous ruthenium catalyst B. Source: Modified from Warratz et al. [45].

to chlorination and iodination reactions, occurring with complete meta-selectivity. Very recently, Zhang and coworkers reported on meta-selective C–H chlorinations using N-chloro-2,10-camphorsultam (71) as chlorinating reagent under oxidative conditions (Scheme 5.23b) [47]. The reaction consists of Ru3 (CO)12 , an NHC ligand and PhI(TFA)2 as the oxidant in bromobenzene as the solvent at 95 ∘ C.

5.2.7

C–H Nitration

Methods for C–N bond formations are in high demand since nitro group-containing compounds are frequently found in medicinal chemistry and material sciences [48]. In 2016, Zhang and coworkers reported for the first time the meta-selective C–H nitration of arenes 7 using Cu(NO3 )2 ⋅3H2 O (72) (Scheme 5.24) [49]. The protocol comprises of Ru3 (CO)12 as the catalyst, oxone and AgTFA as oxidants and tetrabutylammonium acetate (TBA-OAc). Apart from pyridine, other N-heterocycles and ketimines were also employed as directing groups. Reduction of the nitro group to amines, followed by further transformations, led to the formation of Vismodegib,

155

156

5 Ruthenium-Catalyzed Remote C–H Functionalizations

(a) O

N

N X

+

H

[Ru(C5H5)(CO)2]2 (2.5 mol%) PhI(TFA)2 (20 mol%)

N H

PhMe, 110 °C, 5 h O

H 1a

X

68

67 X = Cl: 72% X = Br: 85% X = I: 76%

(b) Me

Me Ru3(CO)12 (7.5 mol%) IMes·HCl (20 mol%)

N

N

+

H

Cl H 1a

H

PhI(TFA)2 PhBr, 95 °C, 48 h

N

S O O

Cl

71

67b: 82% mono:di = 8 : 1

Scheme 5.23 Ruthenium-catalyzed meta-halogenation. (a) meta-Halogenation with N-halosuccinimides 68 and (b) meta-chlorination with N-chloro-2,10-camphorsultam (71). Source: (a) Modified from Reddy et al. [46]; (b) Modified from Fan et al. [47].

DG

DG Ru3(CO)12 (10 mol%)

H

+ Cu(NO3)2 ·3H2O

Ar

7

Ar

Oxone AgTFA (n-Bu)4NOAc DCE, 95 °C, 36 h

H 72

H NO2 73

DG = heteroarene R N

N

NO2

N

NO2

H

R R = Me: 76% R = CO2Me: 56%

H

N

NO2 Me

H

37% Me

N

79%

N

NO2 R = H: 72% R = F: 74%

O

Scheme 5.24

Ruthenium-catalyzed meta-nitration. Source: Modified from Fan et al. [49].

5.2 meta-C–H Functionalizations

an antineoplastic drug, and (R)-DRF053, a CDK/CK1 dual-specificity inhibitor, thereby demonstrating the synthetic utility of this method. A plausible mechanism includes the formation of biscyclometalated ruthenium complex 74 by ortho-C–H activation, followed by addition of the nitrogen dioxide radical on the arene para to the Ru–Caryl σ-bond, leading to intermediate 75, subsequent oxidation to 76 and, finally, protodemetalation to deliver the product and regenerate the catalyst (Scheme 5.25). N H NO2

N

73a

H N

CO N Ru

1a

Ru3(CO)12

CO

N

H

N Ru

CO

CO 2CO, H2O

O2N 76

74

NO2

CF3CO2H Cu(I) [O] N

Cu(II)

CO N

NO2

Ru

N2O4

CO Cu(O2CCF3)NO3

O2N H 75

CF3CO2Ag

AgNO3

H

NO2

AgNO2

Oxone

[Ag(II) NO2]

[O] Cu(NO3)2

H

NO2

Scheme 5.25 Proposed catalytic cycle for ruthenium-catalyzed meta-nitration. Source: Modified from Fan et al. [49].

Independently, Ackermann and coworkers disclosed a ruthenium-catalyzed metaselective nitration of 2-phenylpyridine (1a) using Ru3 (CO)12 as the catalyst, AgNO2 , and oxone as the oxidant (Scheme 5.26a) [45]. In a subsequent report by Zhang and coworkers, ketoximes 77 were successfully used as transformable auxiliaries [52] for meta-selective nitrations of arenes and a monomeric octahedral ruthenium(II) complex (80) was proposed as the active intermediate (Scheme 5.26b) [50]. Thereafter, a modified method was applied for the meta-nitration of

157

158

5 Ruthenium-Catalyzed Remote C–H Functionalizations

6-arylpurines 69a and nucleosides using sterically hindered trimesitylphosphine (Scheme 5.26c) [51]. (a) Ru3(CO)12 (10 mol%)

N + Cu(NO3)2 ·3H2O

H

AgNO2 Oxone DCE, 80 °C, 20 h

H 1a

N H NO2 73a: 62%

72

(b) OMe Me N +

H

AgNO3 PhI(TFA)2 DCE, 100 °C, 30 h Under O2

H 77 (c)

N

i-Pr

N

H +

AgNO3

69a

Ru3(CO)12 (7.5 mol%) PMes3 (30 mol%)

78

L Ru

CO

O

O CF3

NO2 79: 69%

PhI(TFA)2 DCE/HFIP (1 : 1) 100 °C, 48 h

N

CO MeO N Me

H

78

H

N

OMe N Me

Ru3(CO)12 (7.5 mol%)

80

O2N H N N i-Pr

N N

81: 74%

Scheme 5.26 Ruthenium-catalyzed remote C–H nitration. (a) meta-C–H Nitrations of 2-phenylpyridine (1a), (b) of protected oxime 77, and (c) of 6-phenylpurine 69a. Source: (a) Modified from Warratz et al. [45]; (b) Modified from Fan et al. [50]; (c) Modified from Fan et al. [51].

5.3 para-C–H Functionalizations In contrast to the significant advances in meta-selective C–H functionalizations under ruthenium catalysis, procedures for ruthenium-catalyzed para-C–H functionalization remain scarce. In 2011, Li and coworker reported on the para-selective, oxidative C–H/C–H alkylation of arenes 82 with cycloalkanes 83 under ruthenium catalysis (Scheme 5.27) [53]. While electron-deficient arenes, such as benzoic acid (84a) and acetophenone (84b), exclusively delivered the para-substituted products 84, a mixture of products was obtained for electron-rich arenes (84c). Ackermann and coworker presented the para-C–H oxygenation of anisoles 85 under ruthenium catalysis using phenyliodine bis(trifluoroacetate) (PIFA) as a mild oxidant (Scheme 5.28) [54]. Within a reaction time of only three hours, the desired products 86 were obtained in high yields, while the reaction without ruthenium catalyst did not provide any conversion. The groups of Frost [55] and Ackermann [24] independently disclosed ruthenium-catalyzed para-C–H alkylations of synthetically useful pyrimidylanilines 87 with α-bromo esters 24 (Scheme 5.29). The installation of a

5.3 para-C–H Functionalizations

R

Ru3(CO)12 (10 mol%) dppb (5.0 mol%)

R

+ ( )0–2 H

DTBP 135 °C, 12 h ( )0–2

82

83

CO2H

84 COMe

84a: 71% p:others = 92 : 8

84b: 83% p:others = 96 : 4

Cl

OMe

75% p:m:o = 51 : 9 : 40

84c: 47% p:m:o = 60 : 10 : 30

Scheme 5.27 Oxidative C–H/C–H activation for para-selective alkylations. Source: Modified from Guo and Li [53].

OMe

OMe [RuCl2(p-cymene)]2 (2.5 mol%)

H 85

PhI(TFA)2 DCE, 80 °C, 3 h

OH 86: 71% Without [Ru]: ---

Scheme 5.28 para-C–H Oxygenations of anisoles 85 under ruthenium catalysis. Source: Modified from Liu and Ackermann [54].

chloro-substituent in the 5-position of the directing group was found to suppress undesired di-functionalization and a number of diversely decorated arenes smoothly underwent the transformation. Based on experimental as well as computational studies, Frost proposed the formation of four-membered ruthenacycle 89 as the key intermediate. Thereafter, Zhao/Lan and coworkers [56] and Liang and coworkers [57] employed a similar ruthenium-catalyzed para-C–H functionalization approach for the synthesis of mono- and difluoroalkylated arenes using α-bromo-α-fluoro esters 22a (Scheme 5.30). While Zhao/Lan relied on the use of AgNTf2 in combination with carboxylic acid additives under rather harsh reaction conditions of 120–150 ∘ C, Liang opted for the use of well-defined [Ru(O2 CMes)2 (p-cymene)] (28) [15, 58] as the catalyst. In both protocols, electron-rich arenes usually delivered the desired products in high yield, whereas the introduction of electron-withdrawing substituents led to a significantly diminished reaction outcome. Although Zhao/Lan proposed the formation of ruthenacycle 94 via ortho-C–H ruthenation, no detailed explanation for the observed para-selectivity was put forward.

159

160

5 Ruthenium-Catalyzed Remote C–H Functionalizations

(a) Cl

N HN

N

Cl

N Br

CO2Me

+

Me Me

[RuCl2(p-cymene)]2 (5.0 mol%)

Ru N

R

N

N MeO2C Me Me 88: 55%

24c

87a

N

K2CO3 TBME, 120 °C, 16 h

H

i-Pr

Me

HN

O

R

HO H

89

(b) R

N HN

N

Br +

CO2Et

Me Me

[Ru(O2CMes)2(p-cymene)] (28, 10 mol%) PPh3 (10 mol%)

HN

N

K2CO3 m-Xylene, 120 °C, 20 h

H

EtO2C Me Me 90

24d

87

R

N

R = H: 33% R = Cl: 56%

Scheme 5.29 Ruthenium-catalyzed para-C–H alkylations with α-bromo esters. (a) para-Alkylations by Frost and coworkers and (b) Ackermann and coworkers. Source: (a) Modified from Leitch et al. [55]; (b) Modified from Korvorapun et al. [24]. (a) R

Piv

N

H

Br +

CO2Et F F

H

[RuCl2(p-cymene)]2 (5.0 mol%) AgNTf2 (20 mol%) 1-AdCO2H (20 mol%)

R

N

Piv H

K2CO3 DCE, 120 °C, 48 h F F 92: 87%

EtO2C

91

22a

(b) OMe N

Me

H

Br +

CO2Et F F

H

[RuCl2(p-cymene)]2 (5.0 mol%) AgNTf2 (20 mol%) Ac-Ile-OH (30 mol%)

Me

OMe N H

Na2CO3 DCE, 150 °C, 48 h

i-Pr

Me MeO N

Ru

O

Me F F 93: 86%

22a

NHPiv

H

EtO2C

77

R1

O

94

(c) N HN

N N

Br +

CO2Et F F

H

[Ru(O2CMes)2(p-cymene)] (28, 10 mol%)

HN

N

Na2CO3 PhMe, 120 °C, 18 h F F 95: 58%

EtO2C 87b

22a

Scheme 5.30 Ruthenium-catalyzed para-C–H mono- and difluoroalkylations. (a) Reactions of anilide 91, (b) of protected oxime 77, and (c) of N-(2-pyrimidyl)aniline 87b. Source: (a) Modified from Yuan et al. [56b]; (b) Modified from Yuan et al. [56a]; (c) Modified from Wang et al. [57].

5.5 Conclusions

O O S

H HN

N H

O Cl S O

[RuCl2(p-cymene)]2 (5.0 mol%)

HN

+

N H

Me

Li2CO3 PhMe, 120 °C, 24 h Me 96

57a

97: 65%

Scheme 5.31 para-C–H Sulfonylations of pyridines 96 under ruthenium catalysis. Source: Modified from Ramesh and Jeganmohan [59].

In 2017, Jeganmohan and coworker presented para-C–H sulfonylations of pyridylanilines 96 with sulfonyl chloride 57a under ruthenium catalysis, exclusively taking place at the C-5 position of the pyridine motif (Scheme 5.31) [59]. Under the optimized reaction conditions, a number of differently substituted pyridylanilines as well as sulfonyl chlorides were shown to be viable substrates, albeit the N-aryl substituent was required for the reaction to proceed.

5.4 meta-/ortho-C–H Difunctionalizations Compared with a stepwise procedure, sequential one-pot reactions represent a more sustainable alternative due to the reduction of chemical waste, work-up procedures, and purification steps [60]. Sequential remote meta-C–H alkylations followed by ortho-C–H functionalizations using a single-component ruthenium catalyst in a two-step, one-pot fashion were reported by the group of Ackermann, as shown in Scheme 5.32. The site-selective twofold C–H functionalization was applicable to removable ketimines 16a (Scheme 5.32a) [18], transformable oxazolines, pyrazoles, and, in particular, late-stage fluorescence labeling on purine molecules (99a) (Scheme 5.32b) [24]. Further development in the selective twofold C–H functionalization was achieved by the group of Li [61]. meta-C–H Sulfonylation/ortho-C–H chlorination of phenoxypyridine 100 with arylsulfonyl chlorides 57a under ruthenium catalysis led to the formation of decorated arenes 101 with high levels of chemo- and positional selectivity (Scheme 5.33).

5.5 Conclusions During the last decade, a number of effective protocols for site-selective C–H functionalizations have been developed. Among them, remote meta- or para-C–H transformations via chelation-assisted ortho-C–H ruthenation become a more interesting alternative due to the robustness and versatility of ruthenium catalysts. Particularly, the unique selectivity of ruthenium-catalyzed remote C–H activations results from the strong effect of Ru–Caryl bond, leading to the formation of

161

162

5 Ruthenium-Catalyzed Remote C–H Functionalizations

(a) TMP Me N

Br

H

Me

H3O

+ H F 16a

8d

TMP N Me

Br

H

Me

Me

O

[RuCl2(p-cymene)]2 (5.0 mol%) 1-AdCO2H (30 mol%)

Ar

K2CO3 PhCMe3, 120 °C, 20 h then ArBr 120 °C, 20 h Ar = 4-MeOC6H4

Me F 98a: 69%

Me

O

[RuCl2(p-cymene)]2 (5.0 mol%) 1-AdCO2H (30 mol%)

H3O

+

n-Hex

K2CO3 PhCMe3, 120 °C, 20 h then n-HexBr 120 °C, 20 h

H F 16a

Me F 98b: 56%

8d

(b) DG

[Ru(O2CR)2(p-cymene)] (10 mol%) PPh3 (10 mol%)

O

H

Br

+

Ar

R2 H R1

H 7

DG Ar

O

Ar

K2CO3 1,4-Dioxane, 40−60 °C, 20 h then ArBr, 120 °C, 20 h

R2 H R1 99

24b R = Mes, Ad N

R

N

O

N

O

CO2Me

CO2Me

n-Bu

CO2Me

n-Bu

R

52% (dr 1 : 1)

R = Me: 61% R = t-Bu: 61% R = OMe: 73%

Me

R = H: 58% R = OMe: 56%

n-Bu

n-Bu

MeO2C

MeO2C

N N i-Pr

N

N

N

Br

N

N

i-Pr 52%

N N

99a: 59%

Scheme 5.32 Sequential meta-C–H alkylation/ortho-C–H functionalizations in a one-pot fashion. (a) Twofold C–H activations of Ketimine 16a and (b) of heteroarenes 7. Source: (a) Modified from Li et al. [18]; (b) Modified from Korvorapun et al. [24].

References

N H

O Cl S O

O

[RuCl2(p-cymene)]2 (5.0 mol%)

+ H

100

Xylene 120 °C, 24 h

N Cl

O O S O

Me

57a

101: 83%

Me

Scheme 5.33 meta-C–H Sulfonylation/ortho-C–H chlorination of phenoxypyridine 100. Source: Modified from Li et al. [61].

meta-C–C or C–X bonds. The distinctive features of the ruthenium catalysis become more attractive to chemical industries, material sciences, and pharmaceutical chemistry in broadly applicable transformations, such as alkylations, benzylations, sulfonylations, halogenations, and nitrations. Furthermore, the excellent chemoand positional selectivities of ruthenium catalysis were reflected by the sequential meta-/ortho-C–H difunctionalizations. However, considerably more challenging remote C–H functionalizations are limited to strong nitrogen-directing groups, such as pyridines, pyrazoles, oxazolines, and imines. High reaction temperature and additional oxidants are mandatory in some C–H functionalizations. The development of methods for remote transformations under mild reaction conditions as well as a combination with photoredox catalysis or electrochemistry is expected to have a strong impact in the topical area of remote C–H functionalizations.

Acknowledgments Generous support by the DAAD (fellowship to K. K.), the Alexander von Humboldt foundation (fellowship to R. C. S.), and the DFG (SPP1807 and Gottfried Wilhelm Leibniz Prize to L. A.) is gratefully acknowledged.

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34 For selected reviews on transition metal-catalyzed carboxylations, see: (a) Tortajada, A., Juliá-Hernández, F., Börjesson, M. et al. (2018). Angew. Chem. Int. Ed. 57: 15948–15982. (b) Fujihara, T. and Tsuji, Y. (2018). Beilstein J. Org. Chem. 14: 2435–2460. 35 For selected examples of C–H activations with RuCl3 , see: (a) Ackermann, L., Althammer, A., and Born, R. (2008). Tetrahedron 64: 6115–6124. (b) Ackermann, L., Althammer, A., and Born, R. (2007). Synlett: 2833–2836. 36 Barlow, H.L., Teskey, C.J., and Greaney, M.F. (2017). Org. Lett. 19: 6662–6665. 37 Jing, K., Li, Z.-Y., and Wang, G.-W. (2018). ACS Catal. 8: 11875–11881. 38 For selected reviews on C–X formations, see: (a) Petrone, D.A., Ye, J., and ´ E., Lautens, M. (2016). Chem. Rev. 116: 8003–8104. (b) Zhao, X., Dimitrijevic, and Dong, V.M. (2009). J. Am. Chem. Soc. 131: 3466–3467. (c) Hartwig, J.F. (2008). Nature 455: 314–322. 39 Saidi, O., Marafie, J., Ledger, A.E.W. et al. (2011). J. Am. Chem. Soc. 133: 19298–19301. 40 Marcé, P., Paterson, A.J., Mahon, M.F., and Frost, C.G. (2016). Catal. Sci. Technol. 6: 7068–7076. 41 Li, G., Lv, X., Guo, K. et al. (2017). Org. Chem. Front. 4: 1145–1148. 42 Wang, L. and Ackermann, L. (2014). Chem. Commun. 50: 1083–1085. 43 Teskey, C.J., Lui, A.Y.W., and Greaney, M.F. (2015). Angew. Chem. Int. Ed. 54: 11677–11680. 44 Yu, Q., Hu, L., Wang, Y. et al. (2015). Angew. Chem. Int. Ed. 54: 15284–15288. 45 Warratz, S., Burns, D.J., Zhu, C. et al. (2017). Angew. Chem. Int. Ed. 56: 1557–1560. 46 Reddy, G.M., Rao, N.S., and Maheswaran, H. (2018). Org. Chem. Front. 5: 1118–1123. 47 Fan, Z., Lu, H., Cheng, Z., and Zhang, A. (2018). Chem. Commun. 54: 6008–6011. 48 (a) Nepali, K., Lee, H.-Y., and Liou, J.-P. (2019). J. Med. Chem. 62: 2851–2893. (b) Ono, N. (2001). The Nitro Group in Organic Synthesis. Weinheim: Wiley-VCH. 49 Fan, Z., Ni, J., and Zhang, A. (2016). J. Am. Chem. Soc. 138: 8470–8475. 50 Fan, Z., Li, J., Lu, H. et al. (2017). Org. Lett. 19: 3199–3202. 51 Fan, Z., Lu, H., and Zhang, A. (2018). J. Org. Chem. 83: 3245–3251. 52 (a) Gandeepan, P. and Ackermann, L. (2018). Chem 4: 199–222. (b) Zhao, Q., Poisson, T., Pannecoucke, X., and Besset, T. (2017). Synthesis 49: 4808–4826. 53 Guo, X. and Li, C.-J. (2011). Org. Lett. 13: 4977–4979. 54 Liu, W. and Ackermann, L. (2013). Org. Lett. 15: 3484–3486. 55 Leitch, J.A., McMullin, C.L., Paterson, A.J. et al. (2017). Angew. Chem. Int. Ed. 56: 15131–15135. 56 (a) Yuan, C., Zhu, L., Zeng, R. et al. (2018). Angew. Chem. Int. Ed. 57: 1277–1281. (b) Yuan, C., Zhu, L., Chen, C. et al. (2018). Nat. Commun. 9: 1189. 57 Wang, X.-G., Li, Y., Zhang, L.-L. et al. (2018). Chem. Commun. 54: 9541–9544. 58 Ackermann, L., Vicente, R., Potukuchi, H.K., and Pirovano, V. (2010). Org. Lett. 12: 5032–5035. 59 Ramesh, B. and Jeganmohan, M. (2017). Org. Lett. 19: 6000–6003.

References

60 For selected examples of twofold-C–H functionalizations, see: (a) Peglow, T.J., Costa, G.P.d., Duarte, L.F.B. et al. (2019). J. Org. Chem. 84: 5471–5482. (b) Zhang, W., Baudouin, E., Cordier, M. et al. (2019). Chem. Eur. J. 25: 8643–8648. (c) Hayashi, Y. (2016). Chem. Sci. 7: 866–880. (d) Yu, Y.-Q. and Xu, D.-Z. (2015). Synthesis 47: 1869–1876. (e) Li, B., Bheeter, C.B., Darcel, C., and Dixneuf, P.H. (2011). ACS Catal. 1: 1221–1224. (f) Ackermann, L., Born, R., and Álvarez-Bercedo, P. (2007). Angew. Chem. Int. Ed. 46: 6364–6367. 61 Li, G., Zhu, B., Ma, X. et al. (2017). Org. Lett. 19: 5166–5169.

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6 Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes Georgi R. Genov, Madalina T. Mihai, and Robert J. Phipps University of Cambridge, Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK

6.1 Introduction The functionalization of arenes at the distal (i.e. meta and para) positions is an area of particular challenge in C—H bond functionalization chemistry. The pioneering C–H activation methods that were based on cyclometallation mechanisms to enable reactivity naturally result in proximal functionalization at the arene ortho position. There have been a number of different approaches for functionalizing the arene meta and para positions, which have been extensively reviewed [1]. For example, ruthenium catalysis has been utilized extensively and typically operates via cyclometallation, but harnesses radical reactivity to functionalize meta to the original functionality (para to the ruthenium) in most cases [2]. Interestingly, recent reports have demonstrated how this can be diverted to the para position [3]. Copper catalysis together with iodonium salts has been used to achieve meta-selective arylation in the presence of an appropriate coordinating group [4]. Conversely, if the coordinating group is removed then para-selective arylation can be achieved on electron-rich arenes [5]. Iridium-catalyzed borylation, with its sterically-determined regioselectivity, naturally results in functionalization away from existing substituents, but often results in mixtures of regioisomers on mono-substituted and 1,2-disubsituted arenes [6] Perhaps the greatest number of developments in catalytic distal functionalization of arenes has arisen through use of palladium catalysis [7]. In pioneering work, Yu and coworkers first reported the use of an extended template design, which, through weak coordination, places the Pd at the arene meta position with great accuracy [8]. Since this report, there has been extensive research carried out resulting in many different template designs, which can operate in a breadth of different reactions. In addition, these stoichiometric templates can also be extended to enable para-selective reactions, proving the flexibility of this approach [9]. These various covalent template approaches have been subjected to a recent comprehensive review and will not be discussed in more detail here [10]. Yu and coworkers also developed a quite distinct strategy for meta-selective functionalization using palladium catalysis, Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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inspired by the Catellani reaction, and which operates as a relay C–H palladation process, ultimately delivering Pd to the meta position [11]. Similarly, over the past few years, this has led to a variety of modifications and refinements which will be covered in detail elsewhere in this book. In some of the most recent developments with regard to Pd-catalysis, templates have been developed, which are able to bind reversibly to the substrate through dative covalent bonds. These advances directly address a disadvantage of the aforementioned strategy, namely, that a stoichiometric amount of the template must be used. Here, by utilizing a reversible, dative covalent bond to connect the template to the substrate, the template can be used in catalytic amounts. The first example of this was demonstrated by Yu and coworkers in 2017 for the remote functionalization of phenylpyridines [12] and this has been followed by further reports from Maiti and coworkers [13]. This is a strategy that is clearly emerging and will be discussed in more detail in a different chapter of this book.

6.2 Non-covalent Interactions in Metal Catalyzed C—H Bond Functionalization Non-covalent interactions can be classified rather broadly as a molecular interaction that does not constitute a covalent bond. Common categorizations include hydrogen bonding, electrostatic interactions, hydrophobic effect, and aromatic interactions, among others [14]. While it has long been appreciated that non-covalent interactions play crucial roles in the mechanisms of enzyme catalysis, it is only relatively recently that synthetic chemists have harnessed these in the context of small molecule catalysis to control selectivity. This has been most extensively explored in the area of asymmetric organocatalysis, with great success [15]. This book is concerned with challenges of positional selectivity, and indeed there are instances where non-covalent catalysis has been applied to such challenges, with the focus being on the use of hydrogen bonding interactions in particular [16]. Pioneering examples include the site-selective oxygenation of sp3 C—H bonds. An early case was reported by Breslow et al. in 1997, which involved appendage of cyclodextrin units to the periphery of a manganese–porphyrin complex 1 [17]. Attractive non-covalent interactions between these units and matching functionality on a steroid substrate 2 resulted in self-assembly to place one specific C—H bond adjacent to the Mn metal center, resulting in highly selective C–H oxidation (Figure 6.1a). Another very notable example was reported by Crabtree, Brudvig, and coworkers in the oxidation of ibuprofen by a manganese catalyst 3 (Figure 6.1b) [18]. The ligands on the manganese metal complex possess carboxylate groups that engage in hydrogen bonding interactions with matched groups on the substrate. These interactions position a molecule of ibuprofen such that the benzylic C—H bond is in close proximity to the Mn center, resulting in selective activation at this position. Related manganese catalysts had been previously employed by Sames and coworkers; however in this earlier work the substrate was covalently attached to the manganese catalyst [19]. The Crabtree and Brudvig report is significant in that replacing the covalent attachment with a non-covalent interaction enables catalyst turnover.

6.3 Overview of Iridium-Catalyzed Borylation Oxidation of a steroid through self-assembly around Mn catalyst S

–O S 3

O R

S

NH

R=

O

O

9

N N

Mn

R

2

O

Binding group

6

N

Cyclodextrin

N

tBu

Binding group

Steroid Backbone

Linker 9

1

S

6

S

Mn

S

(a)

S

Porphyrin scaffold

Hydrogen bond-directed oxidation of ibuprofen using Mn catalyst

CO2H

0.1 mol% cat. 3 5 equiv NBu4 oxone

CO2H O

MeCN, 0 °C

53% conversion

Ibuprofen The other possible oxidation site O H

via

O O

N O

O H O H

O N N O Mn N Mn N O N N O

O H O N O

O

3

(b)

Figure 6.1 Site-selective sp3 C—H bond oxidation using Mn-based catalysts: (a) Breslow and coworkers’ self-assembly mediated oxidation of steroids; (b) Crabtree, Brudvig, and coworkers’ hydrogen bond-directed oxidation of ibuprofen. Source: (b) Modified from Das et al. [18].

Ligand–substrate non-covalent interactions have also been used to control regioselectivity in the hydroformylation of unsaturated carboxylic acids [20] and in hydrometalation processes [21]. In terms of control of regioselectivity in arene functionalization, the reaction that has been exclusively focused on to date, from the point-of-view of using non-covalent interactions to direct catalysis, has been Ir-catalyzed borylation.

6.3 Overview of Iridium-Catalyzed Borylation The initial research in the field of Ir-catalyzed C–H borylation was conducted for the borylation of alkanes, with the first examples of arene borylation being described in 1999 by Everson and Smith [22]. In this work benzene was borylated, catalyzed by a Cp* Ir complex 4 with strongly electron donating alkylphosphine

171

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6 Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes

Everson and Smith + BHPin

BPin

4 (17 mol%)

+ H2

150 °C, 120 h

53% yield

(a)

Me3P

Ir H BPin 4

Smith and Maleczka F + BHPin F

5 (2 mol%) 100 °C, 3 h

(b)

F

BPin + H2 F

Ph Ph PR3 P BPin Ir BPin P Ph Ph BPin 5

81% yield

Ishiyama, Miyaura, and Hartwig + B2Pin2

6 (3 mol%)

BPin + H2

80 °C, 16 h

(c)

COE N BPin Ir N BPin BPin 6

86% yield

Figure 6.2 Development progression of iridium-catalyzed borylation of arenes: (a) initial report; (b) use of phosphine ligands; (c) use of bipyridine ligands. Source: (b, c) Modified from Ishiyama et al. [6c].

ligands (Figure 6.2a). The efficiency of the process was greatly improved by Smith, Maleczka, and coworkers using bidentate phosphine ligands [6a] and even further by Ishiyama, Miyaura, Hartwig, and coworkers with bipyridine ligands (Figure 6.2b,c) [6c]. The latter utilized reaction conditions, which are currently regarded as standard for this transformation, with 4,4′ -di-tert-butylbipyridine (dtbpy) and 3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen) being typical ligands of choice [23]. Detailed mechanistic studies by Ishiyama, Miyaura, Hartwig, and coworkers led to the isolation of a Ir(dtbpy)(COE)(BPin)3 complex 7, which is believed to be the precursor to the active catalytic species [24]. Based on these findings, the mechanism of iridium-catalyzed arene C–H borylation using bipyridine ligands was proposed (Figure 6.3). The dimeric [Ir(COD)OMe]2 or [Ir(COD)Cl]2 precatalyst is broken down into monomers by coordination of the bidentate bipyridine after which the Ir(I) is oxidized by bis(pinacolato)diboron (B2 Pin2 ) to form the active catalyst precursor 7. Upon dissociation of COE a coordination site is made available (8), which allows oxidative addition into an arene C—H bond to give Ir(V) complex 9. Subsequent reductive elimination results in the desired C—B bond (11) and Ir(III) species 10, which undergoes ligand exchange with B2 Pin2 to regenerate the active catalyst 8. A remarkable feature of this transformation is the unique regioselectivity of the process. Classically the regioselectivity of arene chemistry is dictated by the electronics of the ring (e.g. Friedel–Crafts alkylation and acylation), while in many other

6.3 Overview of Iridium-Catalyzed Borylation

Me O Ir

COE BPin Ir N N

dtbpy Ir

PinB

B2Pin2

O

tBu

Me

BPin

PinB N BHPin

tBu

Ir

7 t

Bu

BPin N

BPin

t

Bu

R

8

H

B2Pin2

Ir(III)/Ir(V) catalytic cycle H N tBu

Ir

Oxidative addition R

BPin

H

N

PinB

BPin

N

tBu tBu

10

Ir

BPin N

BPin

tBu

9

Reductive elimination R PinB 11

Figure 6.3 Mechanism of iridium-catalyzed borylation of arenes, as proposed by Hartwig and coworkers.

C–H activation protocols the regiochemistry is primarily guided by directing groups and/or inherent stability of the formed metallocycles in the catalytic cycle. In contrast, the regioselectivity of iridium-catalyzed borylation of arenes is controlled by the steric demand of the substituents on the ring [6b]. For 1,3-disubstituted arenes the reaction can be considered inherently meta-selective to the substituents as typically only one regioisomer is obtained. The selectivity in this case is determined by the difficulty of the oxidative addition occurring ortho- to the arene substituents due to severe steric clashes with the three bulky BPin ligands on the active catalyst. In contrast, for mono-substituted or 1,2-disubstituted arenes, statistical mixtures of the borylated products are normally obtained, which remains one of the outstanding limitations of Ir-catalyzed borylation (Figure 6.4). It is for this reason that a focus of much recent research has been on developing catalyst or substrate-driven approaches to modulate regioselectivity in iridiumcatalyzed borylation. The earlier approaches involved using directing groups to

173

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6 Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes

R2 O O

B

Ir

B

O

N

N tBu

R1

O

B O

Bu

O

H

PinB

t

Ir

N

N

BPin

tBu

(a)

R2

2

R1 H

PinB N tBu

tBu

(b)

R1 R

BPin

H Ir

H

or

BPin

PinB

N BPin

N tBu

tBu

H Ir

BPin N

BPin

tBu

(c)

Figure 6.4 Considerations concerning the regioselectivity of iridium-catalyzed borylation: (a) the bulky nature of the active catalyst; (b) regioselectivity of 1,3-disubstituted substrates; (c) two possible regioisomers in case of 1,2-disubstituted arenes.

interact with the catalyst to direct borylation to the ortho position, which is typically disfavored by sterics in the absence of a directing group and a number of successful strategies have been utilized to this end, which have been amply covered in a recent authoritative review [25].

6.4 Non-covalent Interactions in Ir-Catalyzed Borylation The compatibility with non-polar solvents and the high functional group tolerance of Ir-catalyzed borylation make it an ideal reaction for exploring the utility of non-covalent directing strategies. The first advances in this area were made by Singleton, Maleczka, Smith, and coworkers in 2012 when they developed an ortho-selective borylation of N-Boc anilides, which was proposed to be enabled by a key hydrogen bonding interaction between the anilide NH and a BPin ligand on the approaching active catalyst (Figure 6.5a) [26]. This hypothesis was supported by DFT studies and also mechanistic experiments in which the hydrogen bond donor was removed. The following year the same authors reported a modified procedure in which free anilines are NH borylated in situ and subsequent C–H borylation was also ortho selective in certain circumstances. This was again attributed to a hydrogen bonding interaction between the NH of the substrate and the active

6.4 Non-covalent Interactions in Ir-Catalyzed Borylation Hydrogen bond-directed borylation of N-Boc Anilines at the ortho position:

BPin N

2 mol% [Ir(COD)OMe]2 4 mol% dtbpy

NHBoc

NHBoc BPin

0.2 equiv HBPin, B2Pin2, MTBE, 50 °C

BPin O

Ir

N H

via

B O

N H Boc

(a)

Ortho C–H borylation using electrostatic interactions between ligand surface and a boronate group:

1.1 equiv HBPin

1.5 mol% [Ir(COD)OMe]2 3.0 mol% dtbpy 0.7 equiv. B2Pin2

rt 5 min

Cyclohexane, 80 °C, 4 h

OH

OBPin

Cl

Cl

OH BPin

O

t-Bu δ+

N

H Ir

N

Cl >20 : 1 o:m 74% yield

(b)

O δ– O B

t-Bu

BPin BPin

BPin

Ortho C–H borylation of benzamides using a dual hydrogen bond donor ligand:

O

NH

1.5 mol% [Ir(COD)OMe]2 3.3 mol% Ligand 12

O

BPin

1.5 equiv HBPin, THF, 50 °C

(c)

O

NH N

N Ligand

HN 12

HN

75% conversion 16 : 1 ortho:others

Figure 6.5 Examples of ortho-selective borylation using non-covalent interactions between substrate and catalyst: (a) borylation of N-Boc anilides; (b) borylation of anilines; (c) borylation of benzamides. Source: (a) Modified from Roosen et al. [26]. (b) Modified from Chattopadhyay et al. [27]. (c) Modified from Bai et al. [28].

catalyst [29]. Later, detailed computational studies guided a refinement of the protocol, which enabled expansion of the scope of the “traceless” ortho-selective borylation of anilines to a wider substrate scope [30]. Further collaboration between the Singleton, Maleczka, and Smith groups has shown that phenols can also be amenable to ortho-selective borylation using a non-covalent approach. The ortho-selectivity was thought to arise due to an electrostatic interaction in the transition state between a partially positively charged bipyridine ligand and a partially negatively charged boronate ester, which was produced from O-borylation of the phenol in situ (Figure 6.5b) [27]. More recently Bheeter, Reek, and coworker have designed a bipyridine ligand 12 that incorporates two hydrogen bond donors in the form of an indole amide (Figure 6.5c) [28]. This ligand was found to deliver high levels of ortho-selectivity in borylation of secondary aromatic amides (see example). DFT studies suggest that in addition to the two expected hydrogen bonds; there is a third hydrogen bond present in the lowest energy transition state. This is between the N–H of the amide and an oxygen atom of a boryl group on the catalyst and demonstrates how powerful hydrogen bond networks can be in promoting typically challenging selectivity – the ortho position is normally very much disfavored in borylation on steric grounds.

175

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6 Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes

This book chapter is concerned with distal functionalization of arenes – the meta and para positions. Accordingly, approaches to access these two positions using non-covalent strategies will be addressed in the following two Sections 6.5 and 6.6.

6.5 meta-Selective Borylation using Non-covalent Interactions The first example of using non-covalent interactions to realize meta-selective iridium-catalyzed borylation was disclosed in 2015 by Kuninobu, Kanai, and coworkers [31]. In this case, the regioselectivity was achieved by developing a novel bipyridine ligand 13 bearing a urea functionality remote from the bipyridine ligand site. The urea was envisaged to act as a hydrogen bond donor in an interaction with a Lewis basic functional group on the substrate that would result in the iridium center being in close proximity to the meta C—H bond on the arene substrate. A number of ligands were evaluated in order to determine the ideal length for the linker between the bipyridine and the urea moiety (Figure 6.6a). Ultimately, ligand 13 was found to give the optimal meta:para ratio of 8.3 : 1 in the borylation reaction of N,N-dihexylbenzamide. Going forward, p-xylene was found to be a superior solvent to hexane and the substrate scope as explored included arenes possessing a variety of substitution patterns as well as other Lewis-basic functional groups apart from amides. This included esters, phosphonates and phosphine oxides, as well as several examples of heteroarenes (Figure 6.6b). In terms of probing the origin of selectivity, catalysts with the urea group located in different positions were inferior, demonstrating that an ortho-substituted arene in the bipyridine 5-position presumably results in the ideal spatial arrangement of the catalyst and substrate in the transition state leading toward meta-borylation. Mechanistic probes using methylated catalysts provided strong support for the urea acting as a hydrogen bond donor. A subsequent paper demonstrated that the reaction can be telescoped with a variety of methods for elaborating the BPin group, emphasizing the practicality of the transformation [32]. In an interesting later study from the same authors, rate differences were examined between ligands with and without the urea group [33]. As expected, the urea was found to significantly increase the rate of borylation. Additional modifications to the ligand design enabled the rate to be further increased. This included adding an electron-donating tert-butyl group onto one pyridine ring and a methyl group on the ortho-phenylene component, yielding ligand 17, in order to twist the dihedral angle of the ortho-phenylene and bipyridyl groups (Figure 6.7a). Following these modifications, the rate of borylation was found to be eight times faster than with ligand 13. This new ligand enabled the yield of a previously poorly-performing N-methyl amide substrate 18 to be increased from 20% to 85% (Figure 6.7b). The new ligand was demonstrated to perform with increased selectively in various inter- and intramolecular competitions between amide and ester directing groups. A later computational study by Unnikrishnan and Sunoj provided support for the crucial role played by the proposed hydrogen-bonding interactions for obtaining

6.5 meta-Selective Borylation using Non-covalent Interactions

0.75 mol% [Ir(COD)OMe]2 1.5 mol% ligand 13, B2Pin2

O NR2

N N

H

H

N

R

O N H via

8.3 : 1 (50%) 7.4 : 1 (31%) 1.4 : 1 (22%) 7.2 : 1 (31%) 3.9 : 1 (40%) 3.6 : 1 (31%)

R = Cy R = hex R = 4-(OMe)C6H4 R = 4-(CF3)C6H4 R = 4-(nBu)C6H4 R = 2,6-Me2C6H3

O

NR2

PinB

Hexane, 25 °C, 16 h

N

O

N H O

N Ir

NR2

N Ligand 13

(a) O

O Nhex2 PinB

PinB 8.3 : 1 m:p 50% yield

O Nhex2

CO2Me

4 PinB 5

>30 : 1 m:p >99% yield

OEt N

PinB

4.3 : 1 C4:C5 >99% yield

O

O

P OEt OEt PinB

P Cy Cy

16 :1 m:p 52% yield

>30 : 1 m:p 44% yield

(b)

Figure 6.6 Kuninobu, Kanai, and coworkers’ meta-selective borylation using bifunctional urea ligand: (a) ligand optimization; (b) selected examples from scope.

Ligand modification

O Cl

B2Pin2

p-Xylene, 25 °C, 1 h

O

NMe2

2 mol% [Ir(COD)OMe]2 3 mol% ligand,

Cl

NMe2

p-Xylene, 25 °C, 2 h

BPin

(a)

N N

14

N N

k [10–4 M/s] 0.55

H 13

N H

O N

tBu

N N 15

Cy

1.81

H

N H

O N

tBu

N

H

N

N H

Cy

O N

9.20 16, R = Cy 17, R = nHex 14.3

2.17

Application to challenging substrate

O Cl

B2Pin2

2 mol% [Ir(COD)OMe]2 3 mol% ligand, p-Xylene, 25 °C, 1 h

NHMe

NHMe

18 p-Xylene, 25 °C, 2 h

Ligand Yield (%)

O Cl

BPin

14 13 16 17

8 20 55 85

(b)

Figure 6.7 Kuninobu, Kanai, and coworkers’ urea containing ligand modification (a), enabling meta-selective borylation of challenging substrates (b).

R

177

178

6 Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes

meta-selectivity. Interestingly, their study suggested that this interaction is unlikely to be solely responsible for the high regioselectivity observed [34]. A series of other, weaker, but significant non-covalent interactions, such as C − H· · ·π, C − H· · ·O, C − H· · ·N, and N − H· · ·O between the substrate and ligand, were identified. The authors concluded that the combined network of non-covalent interactions is responsible for causing sufficient energy differentiation between the transition states leading to meta and para products, accounting for the excellent reported experimental selectivity outcomes. In 2016, our own group reported an ion-pair directed approach to achieve meta-regioselectivity in iridium-catalyzed arene borylation [35]. The hypothesis was that by installing a pendant sulfonate functionality onto a 5,5′ -dimethyl-2,2′ -bipyrine ligand, an ion-pairing interaction between this anionic group on the ligand and aniline or benzylamine-derived quaternary ammonium salts may be accomplished, guiding the Ir catalyst to the arene meta position (Figure 6.8a). Four sulfonated bipyridine ligands (19–22) of varying structure were evaluated in the borylation of quaternized 2-chlorobenzylamine 23 (Figure 6.8b). The results showed that the optimal design incorporated a methylene sulfonate group at the 5-position of the bipyridine ligand scaffold (ligand 19), giving a 10 : 1 meta:para ratio. Application of this ligand to a range of substituted aniline (11 examples) and benzylamine (13 examples) derived ammonium salts typically resulted in good to excellent levels of meta-selectivity (Figure 6.8c). This study was relatively rare in its use of ion-pairing interactions to control positional selectivity, as hydrogen bonds are more conventionally applied. Pioneering early work had been done in the area by Breslow et al.

Hypothesis for meta selectivity:

Ion pairing

meta activation

– Me Me N O O Me S O H Ir

N N

BPin

Four sulfonate ligands evaluated: – OTs

Me3N+

Cl

1.5 mol% [Ir(COD)OMe]2 3 mol% ligand 1.5 equiv B2Pin2 THF, 50 °C, 20 h

23

Bu4N+

N

11 Examples up to 20 : 1 m:p

(c)

Cl

Cl

PinB para

BPin SO3–

SO3–

Scope summary:

BPin

OTs

BPin

BPin N

NMe3 – OTs – (OTf)

–

Me3N+

meta

(b)

(a)

R

–

Me3N+ OTs

19 10 : 1 m:p R

20 3.5 : 1 m:p

SO3–

NMe3 – OTs

SO3–

Bu4N+

BPin 13 Examples up to 20 : 1 m:p

Bu4N+

N N

Bu4N+ N

N N

21 1.8 : 1 m:p

N

22 1.1 : 1 m:p

Figure 6.8 Sulfonated bipyridine ligands developed within the Phipps group, enabling control over regioselectivity through an ion-pairing interaction: (a) proposed transition state of the transformation; (b) evaluated ligand scaffolds; (c) scope summary.

6.5 meta-Selective Borylation using Non-covalent Interactions

Two carbons:

Cl

Three carbons:

+ NMe3

Cl

Cl + NMe3 – OTs

– OTs

BPin

Four carbons:

BPin

+ NMe3 – OTs

BPin

19: 89% yield, 12 : 1 m:p

19: 83% yield, 7.5 : 1 m:p

19: 53% yield, 4 : 1 m:p

(dtbpy: 1 : 2.9 m:p)

(dtbpy: 1 : 1.7 m:p)

(tmphen: 1 : 2.6 m:p)

Figure 6.9 Extending the chain length between the arene and ammonium groups and the effect on selectivity.

in the 1980s during studies on steroid functionalization, but selectivities had been modest [36]. In a subsequent study, we demonstrated that longer aliphatic chains could be incorporated between the ammonium group and the aromatic ring while still maintaining meta-selectivity in the borylation [37]. We had been concerned that the lack of directionality of the ion-pairing interaction, combined with more conformationally flexible substrates, may preclude useful levels of selectivity. Despite these fears, a range of quaternized phenethylamine and phenylpropylamine derived ammonium salts gave good results with the sulfonated bipyridine ligand 19 that had previously been optimal in with the shorter chain substrates (Figure 6.9). It should be noted though that if the methylene chain was extended further, to four carbons or more, the selectivity did reduce. This is in line with the expectation that the entropic cost to organize the transition state would become too great to yield high regioselectivity. We have also demonstrated that trimethylphosphonium salts perform very well in place of the corresponding trimethylammonium analogs [38]. Our group has subsequently shown that the sulfonated ligand 19, which proved so effective in the ion pair directed borylation is also able to perform well as a hydrogen bond acceptor under similar reaction conditions [39]. In this study we investigated arenes bearing an NH-amide able to act as a hydrogen bond donor and found that N-trifluoroacetylated benzylamines, phenethylamines, and phenylpropylamines all underwent borylation with high levels of meta-selectivity when the optimal ligand was utilized. As part of this study, we also surveyed a range of bipyridine ligands bearing neutral hydrogen bond acceptors (phosphine oxide, amide, and sulfoxide) but the sulfonate-bearing ligand was found to be optimal. A selection from the substrate scope is shown in Figure 6.10. Control experiments were carried out involving N-alkylated substrates, in which the selectivity was much reduced, providing support for the hypothesis that a hydrogen bond between ligand and substrate was crucial for obtaining high meta-selectivity. With longer chain lengths than three carbons the selectivity did decrease, as may be anticipated given the much greater flexibility. Given that the sulfonated bipyridine ligand has been demonstrated to be able to act in two modes to exert regiocontrol – hydrogen bonding and ion pairing – we designed several substrates that bear both an amide and a quaternary ammonium

179

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6 Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes Reaction overview: F3C

O

HN

1.5 mol% [Ir(COD)OMe]2 3.5 mol% ligand 19

n

R

F3C

N H

F3C

HN n

via

R

2.0 equiv B2Pin2, THF

PinB

n

H BPin Ir N N

O O O S

50 °C, 16 h

n = 1,2,3

R

O

O

PinB

BPin

Hydrogen bonding

meta selective borylation

(a) Examples from scope: Benzylamines F3C

Phenethylamines

F3C

O

HN

CF3

O

CF3 PinB

CF3

NH

O

HN

CF3

I PinB

O

NH

NH

O

N PinB

Phenylpropylamines O

CF3 NH

Cl PinB

F

PinB

COOMe PinB

90% yield

77% yield

68% yield

89% yield

97% yield

73% yield

13 : 1 m:p

8 : 1 m:p

6 : 1 m:p

13 : 1 m:p

9:1 m:p

20 : 1 m:p

(b)

Figure 6.10 Use of sulfonated bipyridine ligand to engage in hydrogen bond directed borylation with amide-containing substrates: (a) reaction overview and proposed transition state; (b) selected scope.

–

N+ OTs N H

A

– N+ OTs

O

16 : 1 A:B

– N+ OTs

CF3 NH

CF3

A B

O

O N H

CF3

A B 7 : 1 A:B

B 5 : 1 A:B

Figure 6.11 Substrates that present a competition between ion pair and hydrogen bond directed catalysis. Source: Modified from Mihai et al. [37].

group in a 1,2 orientation on the aromatic ring (Figure 6.11) [37]. These then present a competition in the borylation and pose the question – does ion pairing or hydrogen bonding prevail in terms of catalyst direction? As can be seen from the three substrates investigated, the major isomer occurred from borylation meta to the ammonium, highlighting the strong ability in this case of ion pairs to direct catalysis in comparison with the more commonly used hydrogen bonding. Building on their earlier work on para C–H borylation (see Section 6.6 for more detail), the Chattopadhyay group in 2018 reported a meta-selective borylation of aromatic amides (Figure 6.12a) [40]. Intriguingly, this was achieved by using the same L-shaped bipyridine ligand 24 that is used in the para-selective study when the substrates were aromatic esters (see later). The ligand is proposed to interact with

6.6 para-Selective Borylation using Non-covalent Interactions Reaction overview:

iPr N

O

iPr

1.5 mol% [Ir(COD)OMe]2 3.5 mol% ligand 24 4.5 mol% KOtBu

iPr N

O

iPr via

1.0 equiv B2Pin2, THF 80 °C, 12 h

Ligand 24

(a)

K+

[Ir] H N

81% yield

N

O– O

N

BPin 16 : 1 m:others

N

N R2 N

N HO

Examples from scope:

O

iPr N

iPr Cl

BPin

Br

84% yield 24 : 1 m:p

O

iPr N

O

iPr

F3 C

iPr N

O

iPr

iPr N

iPr

Ph BPin 89% yield 18 : 1 m:p

O

iPr N

iPr

N BPin 79% yield 15 : 1 m:p

F

BPin 78% yield 18 : 1 m:p

BPin 89% yield 18 : 1 m:p

(b)

Figure 6.12 Chattopadhyay’s meta C–H borylation of amides: (a) reaction overview; (b) selected examples. Source: (a) Modified from Bisht et al. [40].

the amide group via an electrostatic interaction involving an associated potassium cation. It was proposed that the hydroxyl group on the ligand is deprotonated under the reaction conditions to generate a potassium alkoxide, which can interact with the carbonyl group of the amide functionality in the substrate. It is proposed that this interaction could be responsible for positioning the meta C—H bond of the arene substrate in close proximity to the iridium center, for selective oxidative addition (Figure 6.12a, inset figure). A variety of tertiary amide substrates were demonstrated in the scope, including heterocycles (Figure 6.12b).

6.6 para-Selective Borylation using Non-covalent Interactions There have been notably fewer successful strategies to access the para position using Ir-catalyzed borylation. This could be attributed to the challenges of using directing templates or ligands for reaching further from a given functional group to this most distant site of reaction. The steric nature of the regioselectivity in borylation however can be used to favor selectivity at the para-position. Several research groups have elegantly exploited this property to achieve para-selectivity through incorporating increased steric bulk into the system. Saito et al. developed an approach based on a sterically very bulky phosphine ligand which worked well if the substrate possessed one sterically very large group [41]. Nakao and coworkers used a clever strategy

181

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6 Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes

Reaction overview: O

OEt

O

OEt

1.5 mol% [Ir(COD)OMe]2 3.5 mol% ligand 24

>30 : 1 p:m 92% yield

4.5 mol% KOt-Bu 1.0 equiv B2Pin2 THF, 50–80 °C, 12 h

N

O– K+

via N

N

BPin

N

N

O

[Ir] H N

N

HN

N

O

HO

OEt

24

(a)

Selected examples: CO2Et F

(b)

CO2Et Cl

BPin

BPin

91% yield para:others 28 : 1

93% yield para:others 20 : 1

CO2Et OMe

BPin 87% yield para:others 28 : 1

F

CO2Et F

BPin 72% yield para:others 99 : 1

CO2Et N

BPin 77% yield para:others 8:1

Figure 6.13 para C–H borylation by using an L-shaped ligand: (a) reaction overview and proposed transition state; (b) selected scope. Source: Modified from Hoque et al. [43].

involving a bulky Lewis acid catalyst in combination with the typical iridium catalyst [42]. The Lewis acid coordinates to an amide and so disfavors borylation at the meta position relative to the amide as it is so bulky. Given the topic of this chapter, the present section will focus on non-covalent strategies in greater detail. In 2017, the Chattopadhyay group introduced an interesting L-shaped ligand design (24) for directing C–H borylation to the para position of aromatic esters (Figure 6.13) [43]. The authors propose that the alcohol tautomer of the ligand undergoes deprotonation from the potassium alkoxide base present to form the potassium alkoxide salt. It is thought that the ligand is able to orient the substrate in the appropriate position for para-selective C–H activation by virtue of an electrostatic interaction between the alkoxide functionality now on the ligand and the ester group on the substrate. In support of this scenario the authors show that the addition of 18-crown-6 to the reaction dramatically reduces the selectivity, strongly suggesting that the potassium cation is crucial. Interestingly, optimization studies showed that when the potassium base is omitted, modest para selectivity could still be obtained. This suggests that hydrogen bonding interactions are able to impact the selectivity, but the extent is not as great as with the electrostatic interaction. It is intriguing that the same ligand under the same conditions gives the meta product with aromatic amides (see Section 6.5) and the reasons for this divergence with substrate functionality are not currently clear [40].

6.6 para-Selective Borylation using Non-covalent Interactions

New approach: attractive Substrate – counterion interaction anchors “steric shield,” forcing catalyst para

Previous strategies: meta-selective borylation using “attractive” Substrate – catalyst ion-pairing interaction – L

L

+

o

Metal - Reactivity

+

–

o Substrate

Substrate m

m p

meta within reach para too remote: Catalyst-directed approach challenging

p Para easily accessed

meta blocked Metal L

L

Figure 6.14 Use of a bulky cation to disfavor borylation at the meta position as compared with previous meta-selective approaches. Source: Adapted from Mihai et al. [44].

The strategies described so far have hinged on an attractive interaction between ligand and substrate to direct the reactive iridium catalyst typically to the ortho or meta positions. The greater distance to the para position makes such a strategy challenging to implement to obtain that isomer. The aforementioned work from Chattopadhyay and coworkers remains a rare example of that. In 2019 Phipps and coworkers [44], and Maleczka, Smith, and coworkers [45] independently developed an alternative strategy for para-selective borylation, which uses non-covalent interactions in a quite different manner. These two reports use a strategy in which the substrate is rendered anionic and then associated with a bulky tetrabutyl- or tetrapropylammonium cation. The hypothesis was that the cation should be bulky enough to act as a “steric shield” and disfavor borylation at the meta position and so only allow the catalyst to approach the para position (Figure 6.14). Both papers demonstrate that this is indeed very effective. Anilines and benzylamines can be converted to the corresponding sulfamate salts very readily and the requisite tetrabutylammonium cation introduced by simple cation exchange from the sodium sulfamate salt that is initially obtained. Phipps and coworkers showed that borylation of these using the standard borylation ligand dtbpy gave typically excellent para selectivity for both substrate classes (Figure 6.15). They then expanded their investigation to tetrabutylammonium sulfate salts of phenols and benzyl alcohols. These too gave para-selectivity although with at a slightly reduced level when compared with the earlier sulfamates. Finally, they examined intrinsically anionic aryl and benzyl sulfonates, which gave excellent results when used as the tetrabutylammonium salts. These were converted through to sulfonyl chlorides or sulfonamides following the borylation. To obtain insight into the hypothesis and gain more substantial evidence that the substrate countercation acts as a “steric shield,” a series of control experiments were

183

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6 Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes

Reaction and Proposed Transition State Overview

NBu4 O O O S 1.5–2.5 mol% [Ir(COD)OMe]2 X 3.0–5.0 mol% dtbpy

n

R

O

R

1.0–2.0 equiv B2Pin2 Dioxane, 70 °C, 16 h Then HCl/MeOH

n

N

X

OH

NH2 n or R

O O S

via

n

R

Steric shield

H BPin

BPin

X = NH, O

PinB

para selective borylation

N

Ir

BPin N

BPin

tBu

(a)

H

tBu

Selected Scope Anilines

Benzylamines

Aryl sulfonates (isolated after conversion to sulfonamides)

(isolated after conversion to amides)

NH2 Cl

NH2

NH2 CF3O

Br

BPin

BPin 84% yield >20 : 1 p:m

85% yield >20 : 1 p:m

NH2 CF3

O O S

Cl

BPin 72% yield >20 : 1 p:m

O

O O S

CF3O

BPin 72% yield 14 : 1 p:m

O

BPin

BPin

72% yield 10 : 1 p:m

67% yield 16 : 1 p:m

(b) Phenols

Benzyl alcohols

Benzyl Sulfonates (isolated after conversion to sulfonyl chlorides)

OH F

OH

OH I

CF3O

O O S OH

OH MeO

Br

O O S OH CF3

F BPin

BPin

BPin

BPin

72% yield

90% yield

69% yield

32% yield

BPin 70% yield

BPin 61% yield

9 : 1 p:m

9 : 1 p:m

14 : 1 p:m

>20 : 1 p:m

12 : 1 p:m

8 : 1 p:m

(c)

Figure 6.15 Phipps and coworkers’ “steric shield” strategy to controlling para-selective borylation of anilines, benzylamines, phenols, benzyl alcohols, and aryl and benzyl sulfonates.

performed where the size of the countercation was moderated through changing the alkyl chain lengths. Indeed, in line with the hypothesis substrates bearing smaller countercations provided diminished levels of para selectivity, while larger analogs demonstrated an increase in selectivity in comparison with tetrabutylammonium based compounds (Figure 6.16). In the manuscript from Maleczka, Smith, and coworkers, phenol-derived sulfate salts were used for optimization and the authors evaluated a selection of bipyridine ligands with varying electronics. This survey revealed that electron-rich bipyridines, particularly 4,4′ -dimethoxy-2,2′ -bipyridine, gave superior para selectivity compared with the more electron neutral ones such as dtbpy (Figure 6.17a). Substrates possessing tetrapropylammonium counterions were identified to result in slightly higher regioselectivities in comparison with tetrabutylammonium, in combination

6.6 para-Selective Borylation using Non-covalent Interactions O O S O

O O S O

1.5 mol% [Ir(COD)OMe]2 3.0 mol% tmphen

Cl

Cl

2.0 equiv B2Pin2 Dioxane, 70 °C, 16 h

NR4

NR4 BPin

N

N

N

3.5 : 1

4:1

8.6 : 1

Figure 6.16

N

N

10 : 1 para:meta selectivity

13 : 1

Stepwise increase of cation size across the benzylsulfonate substrate class.

Reaction overview

Ligand evaluation

R

R O N

N

R

p:m*

tBu H Me OMe

6:1 7:1 10 : 1 13 : 1

O O S X

NPr4 1.5–2.5 mol% [Ir(COD)OMe]2 3.0–5.0 mol% 4,4′-di-MeO–bpy

n

R

or

1.0–2.0 equiv B2Pin2 Dioxane, 40–60 °C, 16 h then HCl

n = 0: X = NH, O n = 1: X = O

n

R

BPin

BPin

para-Selective borylation

*In THF at 80 °C

(a)

OH

NH2 R

(b)

Selected scope †

Phenols OH F

Benzyl alcohols

Anilines OH

I

NH2 Cl

OH

NH2 MeO

F3CO

OH F3C

F BPin

BPin

78% yield 23 : 1 p:m

90% yield 22 : 1 p:m

BPin 95% yield 43 : 1 p:m

BPin 59% yield 20 : 1 p:m

BPin 69% yield 22 : 1 p:m

BPin 77% yield 9 : 1 p:m

(c)

Figure 6.17 Maleczka, Smith, and coworkers’ strategy to controlling para-selective borylation of anilines, phenols, and benzyl alcohols: (a) initial ligand evaluation; (b) general reaction scheme; (c) selected examples from scope. † Sulfamates used as tetrabutylammonium salts.

with the electron-rich ligand. Following this, the authors evaluated the scope using the methoxy-substituted ligand, and as a result, obtained typically higher para selectivity for these substrates than in the Phipps study, which had utilized dtbpy (Figure 6.17b). In this study a brief survey of aniline derived sulfamates was carried out in addition to the above mentioned phenol and benzyl alcohol-derived sulfates (Figure 6.17c).

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6 Harnessing Non-covalent Interactions for Distal C(sp2 )–H Functionalization of Arenes

6.7 Conclusions The great majority of methods for arene C–H activation have explored reactivity at the ortho position of the aromatic ring, with distal C–H functionalization posing a considerable challenge. In recent times a range of approaches have been developed in transition metal catalysis that allowed for functionalization not only at meta but also para positions of the arene. The increased interest within the synthetic community in using substrate–catalyst non-covalent interactions to modulate positional selectivity has led to a number of methods in which iridium-catalyzed borylation is successfully directed to distal position. Examples presented in this chapter demonstrate how powerful non-covalent interactions such as hydrogen bonding and electrostatic interactions can be in controlling this aspect of selectivity. We anticipate that their use will gradually be expanded to other transition metal-catalyzed processes in which regioselectivity challenges arise.

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35 Davis, H.J., Mihai, M.T., and Phipps, R.J. (2016). Ion pair-directed regiocontrol in transition-metal catalysis: a meta-selective C–H borylation of aromatic quaternary ammonium salts. J. Am. Chem. Soc. 138: 12759–12762. 36 (a) Breslow, R., Rajagopalan, R., and Schwarz, J. (1981). Selective functionalization of doubly coordinated flexible chains. J. Am. Chem. Soc. 103: 2905–2907. (b) Breslow, R. and Heyer, D. (1983). Directed steroid chlorination catalyzed by an ion-paired template. Tetrahedron Lett. 24: 5039–5042. 37 Mihai, M.T., Davis, H.J., Genov, G.R., and Phipps, R.J. (2018). Ion pair-directed C–H activation on flexible ammonium salts: meta-selective borylation of quaternized phenethylamines and phenylpropylamines. ACS Catal. 8: 3764–3769. 38 Lee, B., Mihai, M.T., Stojalnikova, V., and Phipps, R.J. (2019). Ion-pair-directed borylation of aromatic phosphonium salts. J. Org. Chem. 84: 13124–13134. 39 Davis, H.J., Genov, G.R., and Phipps, R.J. (2017). meta-Selective C–H borylation of benzylamine-, phenethylamine-, and phenylpropylamine-derived amides enabled by a single anionic ligand. Angew. Chem. Int. Ed. 56: 13351–13355. 40 Bisht, R., Hoque, M.E., and Chattopadhyay, B. (2018). Amide effects in C–H activation: noncovalent interactions with L-shaped ligand for meta borylation of aromatic amides. Angew. Chem. Int. Ed. 57: 15762–15766. 41 Saito, Y., Segawa, Y., and Itami, K. (2015). para-C–H borylation of benzene derivatives by a bulky iridium catalyst. J. Am. Chem. Soc. 137: 5193–5198. 42 Yang, L., Semba, K., and Nakao, Y. (2017). para-Selective C–H borylation of (hetero)arenes by cooperative iridium/aluminum catalysis. Angew. Chem. Int. Ed. 56: 4853–4857. 43 Hoque, M.E., Bisht, R., Haldar, C., and Chattopadhyay, B. (2017). Noncovalent interactions in Ir-catalyzed C–H activation: L-shaped ligand for para-selective borylation of aromatic esters. J. Am. Chem. Soc. 139: 7745–7748. 44 Mihai, M.T., Williams, B.D., and Phipps, R.J. (2019). para-Selective C–H borylation of common arene building blocks enabled by ion-pairing with a bulky countercation. J. Am. Chem. Soc. 141: 15477–15482. 45 Montero Bastidas, J.R., Oleskey, T.J., Miller, S.L. et al. (2019). para-Selective, iridium-catalyzed C–H borylations of sulfated phenols, benzyl alcohols, and anilines directed by ion-pair electrostatic interactions. J. Am. Chem. Soc. 141: 15483–15487.

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7 The Non-directed Distal C(sp2 )–H Functionalization of Arenes Arup Mondal 1 , Philipp Wedi 1 , and Manuel van Gemmeren 1,2 1 Max-Planck-Institute for Chemical Energy Conversion, Stiftstraße 34–36, 45470, Mülheim an der Ruhr, Germany 2 Universität Münster, Organisch-Chemisches Institut, Corrensstraße 40, 48149, Münster, Germany

7.1

Introduction

While a variety of directed arene C–H functionalization methods, including the use of transient mediators, templates, and non-covalent interactions, are now available to address the ever-growing need to access challenging positions by industry and research [1], many arenes do not contain a functional group suitable to activate the desired position [2]. Non-directed methods to access distal positions on simple arenes have been known for a long time, the electrophilic aromatic substitution reaction, which has been known since the nineteenth century, being a prime example [3]. As this early work has been extensively covered before, this chapter will focus on recent developments that have enabled novel transformations and selectivities through undirected C–H functionalizations of simple arenes [4, 5]. Without chelation by a directing group to facilitate the C–H functionalization, reactivity has to be achieved by catalyst and reagent design building upon the inherent reactivity defined by properties of the substrate [6]. This also enables tuning of the selectivity for remote positions of simple arenes, which are defined here as arenes without directing groups or strong electronic bias [7]. Similar to directed methods, a lot of research has focused on biased substrates. For example, in C–H activation heteroarenes and highly fluorinated arenes have been used, which have an inherent and predictable reactivity based on the unsymmetrical distribution of electron density in the ring [8]. This chapter covers non-directed methods on simple arenes with particular attention on synthetically useful procedures achieving the functionalization of arenes with the arene as limiting reagent, while keeping a high functional group

Arup Mondal and Philipp Wedi contributed equally to this work. Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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7 The Non-directed Distal C(sp2 )–H Functionalization of Arenes

tolerance and thus enabling a broad scope. Recent advances in catalyst, ligand, and reagent design to achieve the functionalization of distal positions from laboratory to industrial scale are discussed herein.

7.1.1

Mechanisms

As alluded to earlier, the non-directed functionalization of arenes in distal positions can be achieved through different reaction pathways. The first and simplest route is via an electrophilic aromatic substitution, where the regioselectivity of the product formation is determined by the relative stabilization of the competing Wheland intermediates and the transition states leading to their formation [9]. Thus, electron-donating substituents on the arene increase the reactivity and favor the formation of ortho and para isomers, whereas electron-withdrawing substituents reduce the reactivity and predominantly give meta isomers. A second non-directed strategy to access distal positions in arenes relies on radical processes, which can either be enabled using a radical initiator or through the use of photoredox catalysis [10–12]. Depending on the process at hand, the reactions can proceed through radical, radical cation, or radical anion intermediates and their regioselectivity is typically determined by the relative stabilization of the respective intermediates. While the aforementioned strategies do not inherently require the use of (transition)metal catalysts, such catalysts are at the center of a third approach, the use of C–H activation. In contrast to the term C–H functionalization, which covers all mechanisms by which a C–H bond in the substrate is converted to a functionalized bond, the term C–H activation has been defined by Shilov and coworker “to involve the formation of a defined organometallic intermediate that results from cleavage of the C–H bond (typically through an inner-sphere mechanism) where the reaction takes place in the coordination sphere of the metal” [13]. It should be noted, however, that the term C–H activation does not correspond to a single specific mechanism, but summarizes a variety of processes through which a C–H bond can be converted into an organometallic species [5, 14]: typical pathways include the electrophilic metalation, σ-bond metathesis, and the so-called concerted metalation-deprotonation (CMD) mechanism. The regioselectivity of C–H activation is determined by the combination of steric and electronic properties of the arene, the mechanism of C–H activation, and the sensitivity of the catalyst to these factors. This also implies that non-directed C–H functionalizations via C–H activation have the potential to give access to different isomers than simple aromatic electrophilic substitution or radical chemistry. A further factor to consider is the potential reversibility of the C–H activation step, since reversible C–H activation can shift the selectivity determining step to a later part of the catalytic cycle or enable thermodynamic rather than kinetic control of the regioselectivity. In the following parts of this chapter, synthetic methods for the non-directed distal C–H functionalization of arenes will be discussed, which, based on the different reaction mechanisms available, often offer complementary scopes and regioselectivity patterns.

7.2 C–Het Formation

7.2

C–Het Formation

The formation of carbon–heteroatom (Het) bonds is of fundamental importance in synthetic chemistry due to the prevalence of these motifs [15–18]. Historically the halogenation, nitration, and sulfonylation have been achieved by direct electrophilic aromatic substitution, while other transformations to carbon–silicon and carbon–boron compounds needed to be realized in a two-step process via prefunctionalization to the aryl halides [19]. Aryl amines were made by reduction of a nitro group or Buchwald–Hartwig amination of aryl halides [20–23]. Several powerful methods have emerged for direct C–H functionalization to form bonds between carbon and heteroatoms (boron, silicon, nitrogen, oxygen, and others) leading to shorter synthetic sequences [24].

7.2.1

Borylation

Building upon the work of Iverson and Smith, who achieved the first arene-limited borylation with a Cp* Ir complex in a C–H activation reaction [25], Maleczka, Smith, and coworkers greatly expanded the applicability through the introduction of 1,2-bis(diphenylphosphino)-ethane (Ligand 1) to their Ir-system in 2002 (Scheme 7.1) [26]. L2 Ir(Bpin)3 was proposed to be the active species in an IrIII /IrIV catalytic cycle. In a contemporary study the groups of Ishiyama, Hartwig, and Miyaura used 4,4′ -di-tert-butyl-2,2′ -bipyridine (Ligand 2) together with [Ir(OMe)(cod)2 ] as the Ir-precursor to borylate a range of electron-poor substrates, while using the arene as limiting reagent at room temperature [27]. For both methods, the regioselectivity is determined by steric factors giving the meta-products 2a, 2b, and 2c exclusively for 1,2- and 1,3-disubstituted arenes [28]. The sensitivity to the steric hindrance becomes evident from the yield decrease of almost 30% from 82% for the 1,2-dichlorobenzene (2a) to 53% for the 1,4-dichlorobenzene (2e). The H R

Bpin

Bpin source Conditions

Ligand 1 (4.0 mol%) HBPin (2.0–5.0 equiv)

2

1 Bpin

Cl

Maleczka and Smith: PPh2

M/S: [Ir(h5-C9H7)(cod)] (2.0 mol%)

R

Bpin

Cyclohexane or neat 100–150 °C, 4–25 h

Ph2P Ligand 1

R R

CO2Me

M/S: 2a, OMe 62% I/H/M: 2b, Cl 82% X Bpin

M/S: 2c, 95% I/H/M: 2c, 80% L

X M/S: 2d, F 81% I/H/M 2e, Cl 53%

Bpin Ir

L

Bpin Bpin

Ishiyama, Hartwig, and Miyaura:

t-Bu N

I/H/M: [{Ir(OMe)(cod)}2] (1.5 mol%) Ligand 2 (3.0 mol%) B2pin2 (0.5 equiv) Hexane, 25 °C, 8 h

N t-Bu Ligand 2

Active species L2IrIIIBpin3

Scheme 7.1 The iridium-catalyzed borylation developed by Maleczka, Smith, and coworkers [26], and by Ishiyama, Hartwig, Miyaura, and coworker [27].

193

194

7 The Non-directed Distal C(sp2 )–H Functionalization of Arenes

preference for the distal positions gives this method a different regioselectivity pattern compared with methods with aryl halides as intermediates and makes otherwise hard to access products available in a one-step process. In the case of unsymmetrical 1,4-disubstituted arenes, a selective ortho borylation is possible [29]. The use of bidentate ligands proved to be essential for this transformation with especially bipyridine ligands finding widespread application in borylation reactions. The role of the substituents on the ligand was investigated and the tert-butyl groups of Ligand 2 were found to increase solubility in nonpolar solvents as well as protect against self-borylation. Sakaki and coworkers conducted an investigation of the mechanism with theoretical methods and found the oxidative addition of the iridium trisboryl (L2 IrIII (Bpin)3 ) species into the C—H bond to be turnover-limiting [30], which was later experimentally confirmed by results of the Hartwig group [31]. The sensitivity to the steric environment can be explained by the bulkiness of the complex during the rate-determining C–H activation step which sets the regiochemistry. This makes the borylation a prime example for a sterically controlled method. While such methods are able to functionalize, meta-positions selectively in disubstituted arenes mixtures are expected, when para-positions become available. Only for arenes with substrate-specific electronic effects, a completely para-selective borylation could be achieved [29, 32]. Such para-selective reactions are highly desirable, since the typical mechanism for the metabolization of benzene-based drugs involves hydroxylation in the para position, such that a substituent in this position can improve pharmacokinetics [33]. Saito, Segawa, and Itami designed a sterically bulky diphosphine (Ligand 3) in 2015 to further increase the steric sensitivity of the Ir-catalyzed borylation and managed to achieve para/meta selectivities of up to 9 : 1 (Scheme 7.2) [34]. For monosubstituted alkenes a mixture of meta and para products was observed with the amount of para product increasing with the size of the substituent. While the borylation of ethylbenzene (2f) yielded meta as the major product with a ratio of 90 : 10, for tert-butylbenzene (2g) the product ratio improved to 31 : 68 favoring para. Disubstituted arenes could be functionalized to β-products 2h and 2i,

H

Bpin

B2pin2

R

Saito, Segawa, and Itami:

R

Conditions

2

1 Bpin

Bpin

t-Bu

Et 2f, 80% m : p = 68 : 31

β′

Me

Ligand 3, Ar = 3,5-Me-C6H3

Bpin

Bpin

O OMe

2h, 84% β sole product

P(Ar)2 P(Ar)2

Bpin β

Me

Me

MeO MeO

2g, 84% m : p = 10 : 90

Bpin

Scheme 7.2

[Ir(cod)OH]2 (1.5 mol%) Ligand 3 (3.0 mol%) B2pin2 (1.0 equiv) n-hexane, 85 °C, 20 h

2i, 86% β : β′ = 44 : 56

O 2j, 65% m : p = 21 : 79

Me3SiO

Et

Et

2k, 50% m : p = 9 : 91

The para-selective Ir-catalyzed borylation by Saito et al. [34].

7.2 C–Het Formation H

HSiMe(OTMS)2

R

[Si]

Conditions

3

1 [Si]

[Si]

OMe

Cheng and Hartwig:

R [Rh(coe)2OH]2 (1.0 mol%) Ligand 4 (2.2 mol%) HSiMe(OTMS)2 (2.0 equiv) Cyclohexene (2.0 equiv) THF, 45 °C, 12–36 h

MeO MeO

P(Ar)2 P(Ar)2

Ligand 4, Ar = 3,5-t-Bu2-4-MeO-C6H2

CF3

3a, 94% m : p = 20 : 80 3b, 82% m : p : di =77 : 22 : 1 β′

[Si]

[Si]

MeO

Me

Me

β α [Si]

CF3

CF3

OMe

Me

3c, 85% β sole product 3d, 93% β : β ′ = 14 : 86

Scheme 7.3

Cl

[Si] β

3e, 83% α : β = 98 : 2

3f, 78%

The Rh-catalyzed silylation developed by Cheng and Hartwig [48].

while in the case of the unsymmetrical disubstituted arene 2i the electronic bias of the molecule has little influence on the distribution of regioisomers. The boron compounds offer a rich follow-up chemistry and can readily be converted to aryl halides [35], phenols [36], benzonitriles [37], biphenyls [38], and nitro compounds [39] in one-pot reactions exploiting the sterically governed regioselectivity set by the Ir-catalyzed borylation giving access to otherwise challenging substitution patterns.

7.2.2

Silylation

Aryl silanes serve as important building blocks in organic synthesis and industrial processes with use in oxidation reactions [40], cross-coupling [41], and silicone synthesis [42]. They are notably more stable toward many common organic transformations than aryl boranes and may be prepared from less expansive starting materials [43]. In comparison to the borylation, early silylations saw limited application because for most silylation reactions a stoichiometric hydrogen acceptor is needed or silylation reagents with step-intensive synthesis had to be used. Despite still requiring an excess of the arene, the work by the groups of Curtis [44], Berry [45], Tsukada and Hartwig [46], and Murata [47] constituted significant advances toward the first arene-limited silylation. In 2014, Cheng and Hartwig reported an arene-limited Rh-catalyzed silylation, which used the diphosphine Ligand 4 that had previously been employed in Rh-catalyzed borylations (Scheme 7.3) [48]. The reaction utilizes the hydrosilane HSiMe(OTMS)2 instead of the previously often employed trialkylsilanes together with cyclohexene as the stoichiometric hydrogen acceptor providing unprecedented synthetic utility. The functionalization of monosubstituted arenes to the silanes 3a and 3b shows the influence of steric and electronic effects by substituents on the substrate. Where the reaction with 1,2-dimethylbenzene gave 3c as the sole product showing the similarity to the borylation, unsymmetrical arenes (3d,e) highlight the differences. The

195

196

7 The Non-directed Distal C(sp2 )–H Functionalization of Arenes

silylation proves to be more sensitive to electronic influences, favoring the more electron-rich position on the substrate. Despite this preference for electron-rich sites, even electron-poor substrates can be silylated in good yields (3f). In a follow-up mechanistic investigation, the authors propose a combined effect of the steric hindrance of the silane and rhodium catalyst as an explanation for the observed regiocontrol [49]. Like the borylation [31], the silylation is proposed to follow a C–H activation mechanism, but the hydrogenation of the hydrogen acceptor was found to be rate-limiting opposed to the C–H bond cleavage. The regioselectivity is thus not determined by the cleavage of the C–H bond, which can be reversible for electron-poor arenes, but the C–Si bond-forming reductive elimination in a process facilitated by increasing electron density at the metalated carbon atom. The functional group tolerance of the silylation was extended by Cheng and Hartwig in 2015 with the development of an Ir/phenanthroline system to include previously challenging substrates bearing Lewis basic functional groups such as nitriles, ketones and esters, and reducible groups, especially aryl halides, which suffered from protodehalogention of the carbon–halogen bond [50]. Initially, the synthetic utility was hindered by long reaction times, high temperatures, and inability to activate electron-rich arenes. Cheng, Hartwig, and coworker discovered a poisoning effect of the byproduct hydrogen, which masked the high reactivity of the catalyst [51]. By removing the hydrogen gas with a flow of nitrogen and using a sterically more encumbered 2,9-dimethylphenanthroline ligand, the synthetic value of the Ir-catalyzed silylation could be greatly extended to include many common functional groups and electron-rich arenes.

7.2.3

Amination

Arylamines are very important motifs in bioactive compounds, natural products, and pharmaceuticals and the development of methods to access these compounds has thus received much attention by the synthetic community [16–18]. Well-established methods to synthesize these compounds are the electrophilic nitration followed by reduction or Buchwald–Hartwig cross-coupling reactions [20–22, 52]. Despite the attractiveness of such methods and the advances in the direct C–H amination of heteroarenes [23, 53], the direct amination on simple arenes has remained highly challenging. In 2013, Ritter and coworkers reported a Pd-catalyzed aryl C–H imidation of arenes. The authors employed a bis-cationic Pd(II) complex as catalyst (Catalyst 1) and Ag(bipy)2 ClO4 as co-catalyst to conduct the desired transformation using N-fluorobenzenesulfonimide (NFBS) as the reagent. Control experiments showed that omitting either catalyst or co-catalyst led to 20 : 1)

i Pr

Si

i

Pr

DG4 CF3

Cl

Si

i Pr

DG4

F F

O

Me

O

15e, 82% (R3 = Et) (para:others >20 : 1)

Scheme 8.9

Me

15f, 75% (R3 = Et) (para:others 8 : 1)

O

Me

15g, 77% (R3 = Et) (para:others 16 : 1)

O

Me

15h, 67% (R3 = Et) (para:others >9 : 1)

Scope of para-ketonization.

Mechanistic investigation revealed C–H activation step as rate limiting for the catalytic process (kH /kD = 3.1 and PH /PD = 3.4). It was proposed that the initial path of the catalytic cycle was as similar as the Maiti’s previous para-selective silylation work (Scheme 8.10) [21]. Olefin coordination from vinyl ether and β-migratory insertion was followed by C–H activation via CMD pathway. Subsequently, β-hydride elimination resulted E. Finally, alkenylated ether underwent hydrolysis to furnish 15a. Two probable hydrolysis paths were proposed to be operative (Scheme 8.11). 8.2.1.4 Acetoxylation

Cyano based biphenyl template was further extended by Yu and coworkers to perform para-C–H acetoxylation reaction of benzoic acid in 2019 [23]. Benzoic acids are privileged class in pharmaceuticals, agrochemicals, and natural products. However, para-selective functionalization of benzoic acid is forbidden by several reasons, such as (i) the carboxylic group can act as the DG for native ortho-functionalization,

8.2 Template Assisted para-Selective C–H Functionalization i

i

Pr

Si

PdX2

Pr

O

DGp

Z

X

N H

i

i

Pr

Si

H 13a

N Z

Pr

Hydrolysis and tautomerization

O

A

O

i Pr

O

O

H N

O

N

H

Z

OMe

i Pr

O

N

Pd

N

O

OMe

E

Si

HX

EtO Pd

Pr

DGp

O

O

X

Me 15a

Si

O

Pd O

i

i Pr

OH

OMe

O

OMe

B

kH/kD = 3.1

O i

Z

i

Pr

Si

β-Hydride elimination

i Pr

Pr

Si

O

i Pr

O

CH activation

Z O 14

EtO Pd N D

OMe

Et HO

Pd N O

OMe

C

OMe

O

OMe

Olefin coordination and β-migratory insertion

Scheme 8.10

i

Pr

Si

Plausible catalytic cycle for para-ketonization reaction.

i Pr

DGp

i

Elimination pathway

Pr

solv

Path I O

Me 15a

Scheme 8.11

Si

i Pr

DG4

i

Pr

Si

Nucleophilic attack

i Pr

DGp

Path II H

O solv

H

O

Me 15a

Plausible hydrolysis pathways of para-alkenylated ether (E).

(ii) the benzoic acids are by virtue meta-directing for electrophilic aromatic substitution, (iii) the feasibility of C–H activation is prohibited the presence of carboxylic group due to its electron withdrawing effect. Despite the challenges, the Yu group developed a protocol for para-acetoxylation of benzamide derivatives (16) overriding the innate meta-selectivity of benzoic acid derivatives under palladium catalyzed conditions (Scheme 8.12).

231

232

8 Transition Metal Catalyzed Distal para-Selective C–H Functionalization

DGp O

DGp

O

DGp

Rn

HFIP, 80 °C, 36 h H

OAc 17 DGp

O

DGp

Cl

N

16 O

Me

Cl

Pd(OPiv)2 (10 mol%) PhIO, Ac2O Rn

N

O

DGp

O

DGp

Me F

Br

OAc

OAc

OAc

OAc

17a, 75% (para:meta 4 : 1)

17b, 64% (para:meta 4 : 1)

17c, 67% (para:meta >20 : 1)

17a, 35% (para:meta 9 : 1)

Scheme 8.12

para-Selective acetoxylation of benzoic acid derivative.

8.2.1.5 Cyanation

Very recently, in 2020, the group of Maiti reported palladium catalyzed template assisted para-selective cyanation [24]. Regioselective incorporation of cyano groups into arenes is significantly important not only because it is an important synthon in organic synthesis but also because it is a prevalent functional group in pharmaceuticals and natural products. However, Maiti group achieved such an important transformation by utilizing their previously developed cyano based D-shaped second generation DG. Despite the competitive binding between cyano-DG and metal cyanide, the cyanation reagent, and the catalyst poisoning capability of cyanide, a suitable catalytic system was realized to perform para-selective cyanation of toluene and phenol derivatives (Scheme 8.13). Substituted toluenes i

i Pr Pr Si X Y DGp

i

+

Rn H

Pr

i

Si

Rn

Ag2CO3 (2 equiv) HFIP, 90 °C, 24h

i

Pr

O DGp

Pr

i

Si

Me

Me CN

CN

i

Pr

O DGp

DGp

N CN OMe

X = CH2, Y = O for toluene scaffold X = O, Y = CH2 for phenol scaffold

18 i

Pd(OAc)2 (10 mol%) N-Ac-Gly-OH (20 mol%)

CuCN

i Pr Pr Si X Y DGp

19

Pr

i

Si

F

Pr

O DGp

i

i Pr Pr Si O DGp

OMe i

Me

i Pr Pr Si O DGp

F CN

CN

CN

19e, 60% 19a, 70% 19c, 61% 19b, 69% 19d, 55% (para:others–10 : 1) (para:others–15 : 1) (para:others–15 : 1) (para:others–10 : 1) (para:others–12 : 1)

Scheme 8.13

Scope of para-selective cyanation.

8.3 Steric Controlled and Lewis Acid-Transition Metal Cooperative Catalysis

(18a–18c) and phenols (18d, 18e) with distinct electronic property were well tolerated to offer the desired para-selective cyanation. Late stage modification of the products was demonstrated to strengthen the synthetic applicability of the protocol. Mechanistic investigation revealed PH /PD = 1, suggesting that a non-rate limiting C–H activation step was involved in the catalytic process. Partial para-deuteration was observed while the reaction was performed in deuterated HFIP (d2 -HFIP), which further supported the non-rate limiting reversible C–H activation. The experimental observation was also validated by computational study. Based on DFT study, [Cu(CN)(CO3 )]2− was believed to be the active cyanating reagent, which took part in ligand exchange with para-C–H palladated metallacycle via a four membered σ-bond metathesis transition state. This ligand exchange process was found to be most energy demanding transition state and believed to be rate limiting.

8.2.2

Rhodium Catalyzed Functionalization

8.2.2.1 Alkenylation

An unprecedented template assisted Rh-catalyzed para-selective alkenylation reaction was reported by Maiti and coworkers in 2019 [25]. Although Maiti’s D-shaped assembly was successfully employed for various para-selective functionalization under palladium catalysis, but the quest in exploiting other transition metal to permit para-selective functionalization led them to explore the catalytic potential of Rh as an alternative. Usage of Rh-catalytic conditions was beneficial in a number of ways; as it used cheaper oxidant and solvent, i.e. copper and DCE, alternate ligand system could be advantageous in asymmetric para-C–H functionalization. In this context, combination of [Rh(cod)Cl]2 catalyst and CuCl2 oxidant was employed successfully to achieve para-C–H alkenylation of toluene scaffolds (Scheme 8.14). Substituted toluene scaffolds bearing electron donating and electron withdrawing functionality were successfully utilized to showcase the generality of the protocol for para-selective alkenylation. para-Alkenylated compounds were further subjected for late stage modification. Mechanistically, Rh(I)/Rh(III) cycle was proposed, where Rh(III) was believed to be the active catalyst. Rh(III) promoted C–H activation and subsequently olefin coordination, migratory insertion, β-hydride elimination sequences were followed to generate the desired product. DFT calculation showed that the para-selectivity was exclusively dictated by the DG.

8.3 Steric Controlled and Lewis Acid-Transition Metal Cooperative Catalysis Steric effects are prevalent in biological system and enzymatic catalysis. Such steric factors are also successfully articulated to build up important organic frame work. While steric congestion prohibited to access a certain position of an organic molecule, conversely it enhanced the possibility in approaching other position, which could be against the innate reactivity. As far as metal catalyzed arene C–H

233

234

8 Transition Metal Catalyzed Distal para-Selective C–H Functionalization

i

Pr

i

Si

Pr

R2

R1

DGp

[Rh(cod)Cl]2 (5 mol%) CuCl2 (2 equiv), TFA (2 equiv)

Rn

i Pr

(2 equiv)

R2

R1

OMe 21

Si

i Pr

i Pr

DGp

Si

i Pr

i Pr

DGp

OMe i

Si

i Pr

Pr

DGp

CO2Et 21a, 75% (para:others = 12 : 1) Pr

Me

Si

SO2Ph 21b, 62% (para:others = 15 : 1)

i Pr

i

DGp Me

Pr

i

Si

Pr

DGp

CO2Et 21d, 64% (para:others = 5 : 1)

CO2Bn 21c, 65% (para:others = 14 : 1) i

i Pr

Pr

DGp

i

Si

F

Me

i

O

DGp N

20 Pr

DGp

i Pr

Rn

V2O5 (3 equiv) DCE, 120°C, 24 h

H

i

Si

Me

Si

Me

Pr

Me Me

DG5 Me Me H

F Me CO2Cy

H

CO2Et O

21e, 67% (para:others = >20 : 1)

Scheme 8.14

21f, 65% (para:others = >20 : 1)

H H

O

21g, 61% (para:others = 9 : 1)

Rhodium catalyzed para-selective alkenylation.

functionalization is concerned, the C–H metalation process can be manipulated either by the bulky ligand around the metal center or by the presence of pre-installed bulky substitution. However, rationalizing a prudent catalytic platform is an utmost challenge to override the innate reactivity of arenes, which eventually promote a site-selective C–H functionalization. Recent advancement in the realm of such steric controlled selective distal C–H functionalization is discussed in this section.

8.3.1

Nickel Catalyzed Methods

8.3.1.1 Alkylation and Alkenylation

Steric controlled C4-selective pyridine functionalization was reported by Hiyama, Nakao, and coworkers in 2010 [26]. Pyridines are prevalent structural core in pharmaceuticals, natural products, and ligand system in synthesis. However, pyridine functionalization is limited due to the presence of electron withdrawing sp2 -nitrogen atom, which offered innate inertness to the C—H bonds. Additionally, it can cause catalyst poisoning via strong coordination to metal center. Although pyridine C2-functionalizations are well known in the literature, example of distal C4-selective functionalization is scarce.

8.3 Steric Controlled and Lewis Acid-Transition Metal Cooperative Catalysis

Intrigued by Hiyama’s previous work on C2-functionalization of pyridine in combination of nickel catalyst, Lewis acid, and phosphine ligand, they embarked on pyridine C4-selective alkylation with alkene by controlling the electronic and steric factors of both Ni and Lewis acid catalyst (Scheme 8.15). Sterically encumbered Lewis acid (2,6-t Bu2 -4-Me-C6 H2 O)2 AlMe (MAD) and NHC ligand (IPr) attributed to the exclusive formation of C4 alkylation product. It was postulated that the para-selectivity was governed by the steric congestion derived from both the Lewis acid and the bulky ligand, what made the other pyridine C—H bond inaccessible. The reaction generality was examined with respect to terminal and internal alkenes and styrene derivatives. Expected C4 alkylated compounds (23) were obtained in good to excellent yield with exclusive selectivity. Nevertheless, a minor amount of branch alkylation product (23′ ) was also formed.

Rn

R1

+

N

Ni(cod)2 (5 mol%) IPr (5 mol%)

N

Rn

+

MAD (20 mol%) Toluene, 130 °C

H 22

Me 23 R1

N

N

N

Me tBu Al O O

t

SiMe3

9 Me 23a, 87% (in 5 h) (23 : 23′ – 95 : 5) N

23b, 91% (in 10 h) 23c, 83% (in 19 h) (23 : 23′ – 95 : 5) (23 : 23′ – 95 : 5)

Me

N

N

Scheme 8.15

Me

Bu

(2,6-tBu2-4-Me-C6H2O)2AlMe (MAD) i

i

Pr N i

9 Me 23e, 52% (in 9 h) (23 : 23′ – 95 : 5)

t

Bu

MeO2C

9 Me 23d, 12% (in 12 h) (23 : 23′ – 88 : 12)

R1 23′

tBu

Me

Me

N

Rn

N i

Pr

9 Me 23f, 89% (in 9 h) (23 : 23′ – 95 : 5)

Pr

Pr

IPr

C4-alkylation of pyridine in Ni/Al cooperative catalysis.

It was proposed that the 𝜂 2 -arenenickel complex A (Scheme 8.16) underwent oxidative addition with Ni(0). Due to the presence of pyridine coordinated bulky Lewis acid (MAD), C2—H and C3—H bonds were inaccessible. Therefore, kinetically favored C4—H bond selectively activated to produce B (Scheme 8.16). Subsequently, final C4-alkylated product, 23, was formed following olefin coordination, β-migratory insertion, and reductive elimination sequence. However, loss of deuterium was observed at C2 and C3 position, while d5 -22a was treated under standard reaction conditions (Scheme 8.17), ascribing that C2—H and C3—H bond also activated reversibly. But final irreversible reductive elimination was

235

236

8 Transition Metal Catalyzed Distal para-Selective C–H Functionalization

N

LA N

CH activation

R1

Reductive elimination

H

Ln

22

LA N

Ni

B Olefin coordination

Migratory insertion

H Ni L n

LA N C

Scheme 8.16 catalysis.

N

D D

D d5-22a >95.5% D

Scheme 8.17 catalysis.

R1

R1

Plausible mechanism for C4-alkylation of pyridine in Ni/Al cooperative

+ D

H Ni Ln

LA N

R1

D

D

LA = MAD Ln = IPr

NiL n A

N 23

H

Me 10

Ni(cod)2 (5 mol%) IPr (5 mol%)

D

MAD (20 mol%) Toluene, 130 °C, 9 h

D

N

D 89% D 62%

d4-23a

10 Me

Labeling experiment in C4-alkylation of pyridine in Ni/Al cooperative

not effectuated due to the steric congestion derived from MAD and IPr ligand, coordinated to Ni. Concurrently in 2010, Yap and coworkers disclosed C4-alkenylation via alkyne insertion by utilizing the Ni/Al cooperative catalytic platform [27]. An amino-linked NHC ligand was used to achieve the desired C4 selective functionalization in presence of AlMe3 as the Lewis acid and Ni(0) as catalyst (Scheme 8.18). Other Lewis acid such as dialkylzinc or borane was found to be inferior compared to the aluminum. The scope of the reaction was explored with respect to pyridine, quinoline, and their derivatives (Scheme 8.18). In all cases C4-alkenylation was found to be the major product in moderate to good yield. Similar to Hiyama’s work, it was postulated that a cooperative Ni–Al interaction, which provides required steric and electronic impetus to override C2 or C3 functionalization and therefore, C4 selectivity was obtained. Ni–Al cooperative catalysis was supported by an Ni(0)–Al(III) bimetallic complex isolation and characterization (26, Scheme 8.19). Pyridine was coordinated to the

8.3 Steric Controlled and Lewis Acid-Transition Metal Cooperative Catalysis Ni(cod)2 (5 mol%) Ligand (5 mol%)

Pr

N Rn

+

AlMe3 (20 mol%) Toluene, 130 °C

Pr

H

N

N

Rn

+ Pr Pr 25

24 N

N

N

Me

25′

Me

N

N

Pr

Pr

25a, 85% (25:25′–10:3)

25b, 56% (25:25′–1:0)

Scheme 8.18

N

Me Pr

Pr

Pr

Rn

Pr

MeO Pr

Pr

Me

Pr Pr

25c, 89% (25:25′–1:0)

HN

Ligand

tBu

25d, 56%

C4-alkenylation of pyridine in Ni/Al cooperative catalysis. AlMe 3 N t

Bu

Me N

N

N

Ni(cod)2 AlMe3

N H

+

Me Me

HN tBu

N

N Mes 26, X-Ray

Scheme 8.19

Mes N

Ni N N H

tBu

Ni–Al bimetallic intermediate bridged by pyridine.

Ni(0) via 𝜂 2 -coordination mode, which justifies the origin of C3 and C4 regioisomeric mixture. KIE was found to be 1.25, which suggested a not rate limiting C—H bond cleavage. Plausible catalytic cycle (Scheme 8.20) proceeded by the oxidative addition of C4—H bond to complex A. Subsequent alkyne coordination and insertion generated D. Final reductive elimination delivered 25. Thereafter, Nakao and coworkers reported para-selective alkylation of benzamide and aromatic ketone relying on similar nickel/Lewis acid cooperative catalytic system (Scheme 8.21) [28]. Innate inertness toward para-C–H functionalization of benzamide or aromatic ketone was successfully overridden by this protocol. Similar to Hiyama’s report, bulky Lewis acid (LA) co-catalyst [(2,6-t Bu2 −4-Me−C6 H2 O)2 AlMe (MAD)], and NHC-based ligand promoted the selective para-functionalization. The steric congestion offered from LA and ligand induced the regioselectivity. Substituted benzamides and aromatic ketones with distinct electronic properties were coupled successfully with terminal and internal olefin in para-selective manner. Mechanistic study revealed that the kH /kD value was 3.7 and a loss in deuterium was also observed in 23a-d5 , exclusively at para-position (Scheme 8.22). This

237

238

8 Transition Metal Catalyzed Distal para-Selective C–H Functionalization

N

LA N

LA = AlMe3 Ln = Me

H NiL n

N

A R1

Me

N 25

LA N

Ni

D

R1

CH activation H Ni Ln

24

Ln

LA N R1

B

R1

Alkyne coordination

R1

H Ni L n

LA N

R1

R1 C

Plausible mechanism for C4-alkenylation of pyridine in Ni/Al cooperative

R1

O R1

O

Ni(cod)2 (10 mol%) Ligand (10 mol%) R2

+

Rn

Rn

MAD (40 mol%)

H

R2

R1 = NR2 alkyl or aryl

t

27 Me

R3

t

Bu Me Bu Al O O

tBu

R3

NMe2

O

R3 N

Me MeO

R3

R3

28

N OMe

R3 R3

tBu

R3

Ligand R3 = 3,5-Me2-C6H3

(2,6-t-Bu2-4-Me-C6H2O)2AlMe (MAD)

O

Bu

H

Migratory insertion

Scheme 8.20 catalysis.

HN t

Ni(cod)2 + NHC AlMe3

R1 Reductive elimination

N

Me

O

NEt2 O

N

Me O Bpin

C11H23 SiMe(OSiMe3)2 28a, 67% 28b, 34% (para:others: 92 : 8) (para:others: >99 : 1)

28c, 94% (para:others: 96 : 4)

SiMe(OSiMe3)2 28d, 54% (para:others: 93 : 7)

Scheme 8.21 Scope of C4-alkylation of benzamide and aromatic ketone in Ni/Al cooperative catalysis. Source: Adapted from Okumura et al. [28].

8.3 Steric Controlled and Lewis Acid-Transition Metal Cooperative Catalysis

D

D

D

D

NEt 2

O

SiMe(OSiMe3)2

NEt 2

O

Ni(cod)2 (10 mol%) Ligand (10 mol%)

D

MAD (40 mol%)

D

NEt2

O

D

D

D

D

D

+ D

D/H

D

85% D SiMe(OSiMe3)2 -27a d d4-28a 5 Recovered; 65%

d5-27a

Scheme 8.22 catalysis.

Labelling experiment for C4-alkylation of benzamide in Ni/Al cooperative

observation suggested a reversible C–H activation step that was rate determining step of the catalytic cycle as well. Theoretical study was also in consistent with the experimental observation. The carbonyl group of the ketone or amide (27) coordinated to AlMe3 , which underwent para-selective C–H activation process with olefin coordinated Ni, A (Scheme 8.23). Thereafter, migratory insertion and reductive elimination afforded the compound 28e. The theoretical study involving propene as olefin and AlMe3 as co-catalyst revealed that AlMe3 as Lewis acid catalyst was crucial in determining the selectivity. NMe2

O

O NiLn

Me NMe2 27a

28e Me

Ln

AlMe3 O

Ln

NMe2

Me A Me

Ni

Ni Me E

NMe2

Ln Ln

AlMe3

Ni

O

Me

Scheme 8.23

AlMe3 O

B AlMe3 O

Ni Me

H B

NMe2

C

NMe2

Plausible mechanism for C4-alkylation of benzamide in Ni/Al cooperative.

Afterwards, a follow up para-alkylation of benzenesulfonamides was also disclosed by the same group in 2017 (Scheme 8.24) [29]. NHC based bulky ligand was used in association with (2,6-t Bu2 −4-Me−C6 H2 O)2 AlMe (MAD) as co-catalyst and bis(1,5-cyclooctadiene)nickel [Ni(cod)2 ] as catalyst to achieve the desired para-selective alkylation of sulfonamide using alkene as alkylating agent. Various aliphatic alkenes and vinylsilanes were successfully utilized for para-alkylation with

239

240

8 Transition Metal Catalyzed Distal para-Selective C–H Functionalization

O O S

O NEt 2 O S

NEt2

Ni(cod)2 (10 mol%) Ligand (10 mol%)

Rn

R2

+ H

MAD (40 mol%) R3

Me t Bu Al O O

t Bu

29 Me

t Bu

R3 N

Me MeO

R3

R3 N

OMe

R3 R 3

t Bu

R2 30

R3

R3

Ligand R3 = 3,5-Me2-C6H3

(2,6-t-Bu2-4-Me-C6H2O)2AlMe (MAD)

Scheme 8.24 para-C–H alkylation of sulfonamides by Ni–Al co-operative catalysis. Source: Adapted from Okumura et al. [29].

substituted benzene sulphonamides under the present protocol with commendable selectivity.

8.3.2

Iridium Catalyzed Methods

8.3.2.1 Borylation

Group of Nakao further embarked on developing para-selective borylation of pyridines and benzamides relying on similar cooperative strategy [30]. Presumably, para-selectivity was induced by the steric congestion derived from bulky Lewis acid, which was coordinated by the substrate, and sterically encumbered ligand around the metal center. While a combination of [Ir(cod)(OMe)]2 (1 mol%), 4,4′ -bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,2′ -bipyridine (vide infra) (2 mol%) in association with (2,6-t Bu2 –4-Me–C6 H2 O)2 AlMe (MAD) (20 mol%) was applied to effectuate para-C–H borylation of aromatic benzamides, 31 (Scheme 8.25), the [Ir(cod)(OMe)]2 (1 mol%), 4,4′ -di-tert-butyl-2,2′ -bipyridyl (dtbpy) (2 mol%), and isobutylaluminum bis(2,6-di-tert-butyl-4-bromophenoxide) NR2

O NR2

O

Rn

[Ir(cod)(OMe)]2 (1 mol%) Ligand (2 mol%) +

PinB BPin

H 31

BPin BPin

tBu

PinB

BPin

Me

tBu

(2,6-t-Bu2-4-Me-C6H2O)2AlMe (MAD)

Scheme 8.25

32ʹ

32

tBu

Me

+ R n

Rn

MAD (20 mol%) Hexane, rt, 18 h Me tBu Al O O

NR2

O

N

N

Ligand

para-Borylation of amide in Ir/Al co-operative catalysis.

8.3 Steric Controlled and Lewis Acid-Transition Metal Cooperative Catalysis

(iBABr, vide infra) (10 mol%) were altogether effective for C4-borylation of pyridine derivatives, 33 (Scheme 8.26). [Ir(cod)(OMe)]2 (1 mol%) Ligand (2 mol%)

N +

Rn

PinB BPin

N

33

i Bu

t Bu

O

34ʹ

34 t Bu

t Bu

Br

O t Bu

t Bu

N

(2,6-tBu2-4-Br-C6H2O)2Al iPr

Scheme 8.26

BPin

t Bu

Al Br

Rn BPin

iBABr (10 mol%) Hexane, rt, 6 h

H

N +

Rn

N

ligand

(iBABr)

C4-borylation of pyridine in Ir/Al co-operative catalysis.

Itami and coworkers reported a catalyst-controlled para-selective borylation in 2015 (Scheme 8.27) [31]. para-Selectivity was offered by the steric governance of the ligand. Electronically controlled para-functionalized protocols have been recently studied by Smith, Marder, Steel, Hartwig, and Ingleson group. Combination with [Ir(cod)OH]2 as catalyst, and sterically congested Xyl-MeO-BIPHEP as ligand provided 94% para-borylated trimethylphenylsilane (36a) with 88% para-selectivity. Several monosubstituted arenes were successfully employed to obtain the para-borylated product in good to excellent yields and synthetically useful selectivity. While the sterically encumbered triethylphenylsilane (35a) Me PinB BPin R

R

[Ir(cod)(OH)]2 (1.5 mol%) Xyl -OMe-BIPHEP (3 mol%)

Rn

+ Rn

Rn

Hexane, 85 °C, 20 h H

BPin

35

36

Me Me

R MeO BPin MeO

P

Me Me

P

36ʹ Me

Me Me

Xyl -OMe-BIPHEP Me

Me Me Si

O

Et

O

EtO

OEt

HO

OMe MeO

BPin 36a, 94% (36:36ʹ – 88:12)

Scheme 8.27 et al. [31].

BPin 36b, 64% (3 d) (36:36ʹ – 87:13)

BPin 36c, 58% (36:36ʹ – 71:29)

BPin 85%

Catalyst controlled para-borylation of arenes. Source: Adapted from Saito

241

242

8 Transition Metal Catalyzed Distal para-Selective C–H Functionalization

or quaternary carbon center bearing arenes (35b, 35c) produced the desired para-borylated compounds (36) in excellent para-selectivity. The less bulky group reduced the para-selectivity significantly, indicating that the steric repulsion between substituents and ligand played a pivotal role in controlling selectivity.

8.4 Non-covalent Interaction Induced para-C–H Functionalization 8.4.1

Di-polar Induced Methods

Non-covalent interactions play pivotal role in biological system. Translating such non-covalent interaction in transition metal catalyzed organic synthesis is significantly important. In recent past, concerted focus has been devoted in developing practical methods for transition metal catalyzed regioselective functionalization utilizing the unique non-covalent interactions. While particular focus is on distal para-C–H functionalization, Chattopadhyay and coworkers developed an iridium catalyzed para-selective borylation using a unique L-shaped template (37) in 2017 [12]. Non-covalent interaction between substrate and the L-shaped ligand (as outlined in 38, Scheme 8.28) was considered as the prime factor to govern the para-selectivity. A modified bipyridine ligand, defined as L-shaped ligand, was employed for para-selective borylation of ethyl benzoate with Ir-catalyst (Scheme 8.29). One part of the L-shaped ligand contains a quinolone moiety which is non-covalently linked to the ester group of the ethylbenzoate through an alkali cation (K+ in this case). Guided by this non-covalent interaction, para-C—H bond now selectively exposed to the bipyridine ligand core, which was the other part of the L-shaped ligand system. The Ir-catalyzed para-selective borylation condition was found to be amenable for substituted ethylbenzoate (39) irrespective of their electronic nature. Several heterocycles (40f) bearing ester moiety were transformed to the corresponding borylated compounds smoothly at distal position with acceptable yield and selectivity. However, the selectivity and yield of the reaction was significantly hampered while either free hydroxyl group of the 2-hydroxyquinoline

EtO N

IrLn

O

N

N

H

N

+ IrLn

N

HN O

H

37

Scheme 8.28

Proposed L-shaped template.

EtO

O 38

M O

8.4 Non-covalent Interaction Induced para-C–H Functionalization CO2Et Rn

CO2Et

[Ir(cod)(OMe)]2 (1.5 mol%) Ligand (3.5 mol%) +

PinB BPin

Rn

KO t Bu (4.5 mol%) THF, 50 – 80 °C, 12 h

H

BPin

39

40

CO2Et Me

CO2Et Me

CO2Et F HO

BPin

BPin

CO2Et F

CO2Et

BPin

BPin

CO2Et CO2Et

N

OH BPin

BPin

40a, 92% 40b, 70% 40c, 71% 40d, 72% 40e, 63% 40f, 77% (p:other – 923 : 1) (p:other – 99 : 1) (p:other – 99 : 1) (p:other – 99 : 1) (p:other – >96 : 1) (p:other – 8 : 1)

Scheme 8.29

Scope of para-borylation using L-shaped template.

(tautomeric form of quinolone ligand part) or K+ ion was absent, reinforcing the postulated non-covalent interaction driven regioselective para-C–H functionalization.

8.4.2

Ion-Pair Induced Methods

Non-covalent ion-pair interactions, in recent years, were extensively studied for direct C–H functionalization by the Phipps group. Such interaction was further extended to confer distal para-selective C–H borylation by the group of Smith and Maleczka [13]. Simultaneously at the same time, Phipps also disclosed a para-selective C–H borylation guided by the ion-pair interaction [14]. Phipps’s previous study pertaining to ion-pair interaction induced meta-C–H borylation was dealing with a counterion bearing the ligand. In oppose to that, a bulky counterion was envisaged to offer a steric shield toward the ortho- or meta-C—H bond in recent protocol. Thus, tetraalkylammonium counterion was realized for para-C–H borylation of sulfates, sulfonates, and sulfamates. In this regard, tetra-n-propylammonium sulfates (41) derived from phenols and benzyl alcohols were used in Smith’s protocol, whereas tetra-n-butylammonium cation offered better reactivity and selectivity for aryl sulfamate (43) (Scheme 8.30). Phipps’s protocol covered a broad class of substrate including tetra-n-butylammonium sulfate (45) derived from phenols and benzyl alcohols, sulfamate (47) derived from anilines and benzyl amines, aryl sulfonates, and benzyl sulfones (49) (Scheme 8.31). The requirement of steric congestion induced by the bulky ammonium counterion to overrule the ortho- or meta-selectivity was established experimentally in both the study. Thus, unsubstituted phenol sulfate, 41c offered para:meta-borylation only in 1.6 : 1 (para:meta) ratio under Smith’s conditions. This was possibly because the bulky ammonium counterion could block one of the meta-positions, therefore, other meta′ and para-position were equally accessible for metalation. Hence better para-selectivity was obtained when one of the ortho-position was substituted. Additionally, substrates 41d possessing meta-substitution furnished

243

244

8 Transition Metal Catalyzed Distal para-Selective C–H Functionalization O O n S O O–

nPr N nPr nPr n Pr

Rn

PinB BPin

+

H 41

OH n

[Ir(cod)OMe] (1.5 – 3.0 mol%) Ligand (3 – 6 mol%)

n = 0, 1

and O O S HN O–

Rn

and

Dioxane, 40 – 60 °C 10 – 36 h

BPin

Then 12 (M) HCl, 1 h

42

nBu N nBu nBu nBu

Rn BPin 44

MeO

+

Rn

NH2

OMe

Ligand

H 43

N

OH Me

OH

OH

N

OH

OH

F

CF3O

Cl

OH

NC BPin 42a, 57% (p:m – 11 : 1)

BPin 42b, 60% (p:m – 22 : 1)

NH2 MeO

BPin 42c, 98% (p:m – 1.6 : 1)

BPin 42d, 83% (p:m – 1 : 7)

BPin 42e, 79% (p:m – 22 : 1)

BPin 42f, 69% (p:m – 1.4 : 1)

NH2

NH2

NH2

F

Cl

F BPin 44a, 59% (p:m – 20 : 1)

Scheme 8.30

BPin 44b, 95% (p:m – 43 : 1)

BPin 44c, 53% (p:m – 2 : 1)

BPin 44d, 76% (p:m – 2.4 : 1)

para-C–H borylation using ion-pair interaction by Smith’s protocol.

meta′ -borylated product (42d) predominantly, indicating that this approach is unable to override the steric crowed at the para-position while it was sterically encumbered with a meta-substitution. However, according to the Phipps’ report, the desired para-selectivity was proportionally enhanced while the alkyl chain length in tetraalkylammonium counterion was gradually increased.

8.5 Conclusion and the Prospect Selective arene C–H functionalization is one of the celebrated classes in organic synthesis. Herein we summarize recent progress on distal para-selective C–H functionalization. Although Friedel–Crafts reaction is known over the century to partially expand the scope of para-functionalization, but there is always an urge to find a robust catalytic platform that can deliver only para-functionalized product as an outcome. In this chapter, we provided an overview pertaining to the strategies that has been evolved over the decades and applied in various field of organic

8.5 Conclusion and the Prospect O O n S O O

OH n n

Rn n

H 45

H O N n S O O Rn H 47 O

2. HCl/MeOH

Bu Nn Bu n Bu Bu

BPin 46 PinB BPin

1.

n Bu N n Bu n nBu Bu

Dioxane, 40 – 60 °C 10 – 36 h tBu

n

Rn H 49

Bu N n Bu n n Bu Bu

Br

t

N

Rn

H2SO4 then TFAA when n =1

BPin 48 O

Bu 2. POCl3 then piperidine

N

O S n N

Rn

Ligand BPin 50 OH

OH

NH2/NHCOCF3 n

[Ir(cod)OMe] (1.5 – 3.0 mol%) 2. HCl/MeOH Ligand (3 – 6 mol%) when n =0

n = 0, 1

O S n O

Rn

F

F3CO

O

NHCOCF3

NH2 F3C

S

O N

Cl

F BPin 46a, 80% (p:m – 9 : 1)

Scheme 8.31

BPin 46b, 74% (p:m – 5 : 1)

BPin 48a, 74% (p:m – 20 : 1)

BPin 48b, 72% (p:m – 14 : 1)

BPin 50a, 72% (p:m – 10 : 1)

para-C–H borylation using ion-pair interaction by Phipps protocol.

synthesis. In this regard, chemist has witnessed a huge resurgence in utilizing steric and electronic governance rendering either by the bulky ligand or from a pre-installed sterically encumbered substituent to achieve precise para-selectivity. Nevertheless, such substrate or catalyst dependency was overridden by template engineering. Notably, non-covalent interactions have been popularized in recent years in attaining para-selective C–H functionalization. A comprehensive discussion was made on these topics that have remolded the conventional synthetic route as well as expediting the scope of applications in pharmaceutical industries, material sciences, and agrochemicals. Despite the significant progress in this realm, there still remained many existing unsolved problems that required significant attention to diversify the scope of ensured para-selective functionalization and the broader applicability in industry as well as academia. The limitation pertaining to the template assisted functionalization is the pre-installation of DG and post-functionalization DG removal, which required additional synthetic steps. Electronic and steric controlled functionalizations are solely limited only to few arenes bearing highly electron donating functional groups. Additionally, a bulky ligand or substitution is the determining parameter to furnish para-selective product. Therefore, such strategies are highly restricted

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to a certain class of compounds. The non-covalent interactions are only explored for iridium catalyzed borylation process. Thus, development of robust protocol to alleviate the scope of functionalization for a diverse class of substrate without any steric or electronic bias is utmost important. To conceive such protocols, greater understanding about the mechanistic cycle is highly desirable. Therefore, the upsurge for new discoveries in the realm of selective para-C–H functionalization will undoubtedly be continued over next few decades.

Acknowledgments We are thankful to BRNS-India (BRNS-37(2)/14/06/2018) for financial support. Generous support from IIT Bombay and IITB-Monash Research Academy (fellowship to U.D.) is gratefully acknowledged.

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9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions Koji Hirano and Masahiro Miura Osaka University, Graduate School of Engineering, Department of Applied Chemistry, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan

9.1 Introduction Heteroaromatic compounds are privileged structural motifs in natural products, pharmaceutical agents, and organic functional materials. Accordingly, considerable attention has been focusing on the rapid and concise construction of multiply substituted heteroaromatics. Although traditional strategies largely rely on the prefunctionalization of starting substrates, such as halogenation and stoichiometric metalation, recent advances in the metal-mediated C–H activation can provide a more straightforward approach to the aforementioned target structure. The heteroarenes have usually electronic biases associated with the introduced heteroatoms, and the positional selectivity is generally controlled by the innate electronic nature of nuclei. However, chemists now developed new organometallic catalysts and directing groups to overcome such regioselective issues to enable the direct C–H functionalization at “unusual” positions. The newly developed protocols can access otherwise challenging C—H bonds to streamline synthesis of complex natural products and functional molecules based on the heteroaromatic cores. This chapter focuses on the recent development of this research filed: the reported procedures are categorized according to the heteroaromatic compounds to be functionalized, and their concept, reaction mechanism, and scope are briefly summarized.

9.2 Indole The indole is one of the most frequently occurring heterocycles in natural products and pharmaceuticals as well as the most reactive substrates in the C–H functionalization because of its high electron richness. Thus, numerous C–H functionalization reactions have been developed over the past two decades. In the indole skeleton, the N-containing five-membered pyrrole ring is more electronically biased than the Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions

six-membered benzene ring, and thus most C–H activation reactions occur selectively at the C2 or C3 position of pyrrole moiety (Scheme 9.1) [1].

FG Catalyst M N R

N R

N R

C–H functionalization

N R

FG

or

N R

Scheme 9.1 Innate electronic bias of indole based on resonance of pyrrole moiety and C–H functionalizations at “usual” C2 and C3 positions. Source: Sandtorv [1].

9.2.1

C–H Functionalization at C4 Position

One of the first examples for the palladium-catalyzed C–H functionalization at the “unusual” C4 position was observed by Yu and coworkers, where only one example with the tryptophan-type substrate was shown and alkenylation occurred at both C2 and C4 positions (Scheme 9.2) [2]. Inspired by Yu’s seminal work, Jia and coworkers developed the more general and highly C4-selective C–H alkenylation of tryptophan derivatives with olefins (Scheme 9.3) [3]. The reaction accommodated not only α,β-unsaturated esters but also phosphonate, sulfone, and styrene. The key to achieve the unusual C4 selectivity is the introduction of bulky tri(isopropyl)silyl (TIPS) group on the indole nitrogen as well as the use of NHTf directing group. CO2Me

CO2Me NHTf + N Tf

CO2Me

CO2Me

Pd(OAc)2 (10 mol%) AgOAc DCE/DMF (20 : 1) 130 °C, 48 h

NHTf N Tf

CO2Me 58%

Scheme 9.2 Seminal example of C–H functionalization of indole at unusual C4 position reported by Yu. DCE, 1,2-dichloroethane; Tf, trifluoromethanesulfonyl. Source: Modified from Li et al. [2].

Around the same time, Prabhu and coworker also reported the ruthenium-catalyzed highly C4-selective alkenylation with acrylates and styrenes by using the aldehyde directing group at the C3 position (Scheme 9.4) [4]. In this case, the benzyl group was found to be the optimal substituent on the indole nitrogen, but the unique C4-selectivity was retained even with the N-benzoyl substrate, which usually shows the C2-selectivity [5]. This result demonstrates the robustness of Ru catalyst–aldehyde directing group combination. The preferable formation of six-membered metallacycle over the five-membered one is believed to be responsible for the observed high C4 selectivity.

9.2 Indole R

CO2Me

CO2Me Pd(OAc)2 (10 mol%) AgOAc

NHTf +

R

NHTf

R = P(O)(OMe)2 80%

Toluene 100 °C, 16–72 h

N

N TIPS

TIPS Tf N Pd

CO2Me

R = CO2Me 88% R = SO2Ph 60% R = Ph 76%

CO2Me

NTf

Via

Pd

N tBu

O

O

Scheme 9.14 Cp* Rh(III)-catalyzed, pivaloyl-directed C7-selective C–H alkenylation of indoles: effects of steric bulkiness on nitrogen. Source: Modified from Xu et al. [16].

NHBoc R1

N O

CHO

[Cp*IrCl2]2 (4 mol%) AgNTf2 (16 mol%)

R2 + Ts N3 tBu

MeO

LiOAc (40 mol%)

CO2Et

N

DCE, 120 °C, 1–2 h Ts

NH

O

98%

N tBu Ts

NH

O

75%

N tBu Ts

NH

tBu

O 80%

Scheme 9.15 Iridium-catalyzed, pivaloyl-directed C7-selective C–H amidation of indoles with tosylazide. Boc, tert-butoxycarbonyl. Source: Modified from Song and Antonchick [17].

Around the same time, Shi and coworkers also identified the bulky P(O)(tBu)2 group to be highly promising C7-selective directing group in the palladium-catalyzed

259

260

9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions

oxidative direct arylation with arylboronic acids (Scheme 9.16) [18]. As observed in Scheme 9.14, the steric bulkiness plays a pivotal role to control the regioselectivity, but deuterium-labeling experiments suggest that the C–H activation occurs reversibly at both C3 and C7 positions, and the regioselectivity is thus determined in the C—C bond forming step. In addition to the arylation, the C7-selective alkenylation with acrylates was also possible with the assistance of the same P(O)(tBu)2 directing group.

N R + Ph B(OH)2 P R O

Pd(OAc)2 (10 mol%) 2-ClPy (20 mol%) Cu(OTf)2/Ag2O/CuO

Ph

Dioxane, 120 °C, 12 h

Ph

Ph + N R P R O

N R + P R O

N R P R O

Pd Via Pd

+ N tBu P tBu O

N tBu P tBu O

CO2Me

R = Et: decomposition R = iPr: 29% (0: 66 : 34) R = Cy: 26% (34 : 52 : 14) R = tBu: 82% (96 : 0 : 4)

N tBu P tBu O Pd(OAc)2 (10 mol%) L1 (20 mol%) Cu(OTf)2/CuO

Me F3C N tBu P tBu O

DCE, 80 °C, 24 h O2 (1 atm)

N

Me

O

L1

CO2Me 59%, 86% C7 selectivity

Scheme 9.16 Palladium-catalyzed C7-selective C–H arylation and alkenylation of indoles with P(O)(tBu)2 directing group. Source: Modified from Yang et al. [18].

Very recently, the same research group developed the more robust P(tBu)2 directing group for the C–H functionalization at the C7 position: under suitable Rh(I) catalysis, arylation, alkenylation, acylation, and even methylation were possible with the excellent C7 selectivity (Scheme 9.17) [19].

N P(tBu)2

Me

(PhCO)2O

Ac2O [RhCl(cod)]2 (2.5 mol%) NaHCO3

[RhCl(cod)]2 (2.5 mol%) NaHCO3

Toluene, 150 °C, 24 h

N

Toluene, 150 °C, 12 h

P(tBu)2

Ph

53%

95% N Ph

N P(tBu)2 Ph

93%

COOH

[RhCl(cod)]2 (2.5 mol%) Boc2O Toluene, 120 °C, 18 h

P(tBu)2

(PhCO)2O [RhCl(cod)]2 (5 mol%) NaHCO3, MS 4 A

N P(tBu)2

MeCN, 100 °C, 16 h Ph

O 61%

Scheme 9.17 Rhodium-catalyzed C7-selective C–H arylation, alkenylation, acylation, and methylation of indoles with P(tBu)2 directing group. Source: Modified from Qiu et al. [19].

9.2 Indole

9.2.3

C–H Functionalization at C5 Position

The catalytic regioselective C–H functionalization at the C5 position still remains a great challenge. Only one successful example is the copper-catalyzed direct arylation of 3-pivaloylindoles with diaryliodonium triflates (Scheme 9.18) [9], which is apparently based on the copper-catalyzed meta-selective C–H arylation originally developed by Gaunt and coworker [20]. According to the reported computational studies based on DFT [21], the reaction is believed to proceed via the Ar–Cu(III)-mediated Heck-type, four-membered cyclic transition state to form the observed C5-arylated indoles. O

O

tBu +

N Bn

Ph2IOTf

CuTC (10 mol%) 2,6-(tBu)2pyridine

tBu

Ph

Ph

Cu

O

tBu

via

CH2Cl2, 40 °C, 12 h 74%

N Bn

N Bn

Scheme 9.18 Copper-catalyzed C5-selective C–H arylation of 3-pivaloylindoles with diaryliodonium triflates. TC, 2-thiophenecarboxylate. Source: Modified from Yang et al. [9].

9.2.4

C–H Functionalization at C6 Position

The promising C6-selective C–H arylation was achieved by combination of the P(O)(tBu)2 directing group on the nitrogen and copper-catalyzed meta-selective arylation strategy (Scheme 9.19) [22], which are already mentioned in Schemes 9.16 and 9.18, respectively. Even in the presence of more electron-rich C–H at the C3 position, the high C6 selectivity was observed. The catalytic system was robust and compatible with various functional groups on the pyrrole as well as the benzene ring. CO2Me

R2 R1

CuO (10 mol%) + Ph2IOTf DCE, 80 °C, 12 h N tBu P tBu O

Ph 88%

N tBu Ph P tBu O

N tBu P tBu 79% O

MeO Ph

N tBu P tBu 72% O

Scheme 9.19 Copper-catalyzed, P(O)(tBu)2 -directed C6-selective C–H arylation of indoles with diaryliodonium triflates. Source: Modified from Yang et al. [22].

Recently, Frost and coworkers developed a completely different approach to the ruthenium-catalyzed C6-selective alkylation of indoles with α-haloesters (Scheme 9.20) [23]. The key to success is the introduction of acetic acid ester and pyrimidine moieties at the C3 and N positions, respectively. Either ester or pyrimidine alone did not provide any C–H alkylated products. The plausible reaction mechanism includes the dual ruthenacycle formation/redox active catalysis: the doubly pyrimidine- and ester-directed cyclometallation at the C2 position is

261

262

9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions

followed by electrophilic attack at the C6 position by the radical intermediate generated from the starting α-haloester and ruthenium catalysts to deliver the finally observed C6-alkylated indole. Computational studies rationally explain the higher nucleophilicity at the C6 position of ruthenacycle intermediate. OEt O N

Br

O [Ru(p-cymene)Cl2]2 (5 mol%) KOAc, AcOH

Unsuccessful substrates Me

O N EtO

N

N

O

Me

N

Dioxane, 120 °C, 16 h N

N

OEt

OEt

N

N H

N

80% OEt

OEt

More nucleophilic O Ru(II)

EtO

Br O

SET

EtO

Ru N O N

N

O Ru(II) Directed C–H activation

N N

N

Scheme 9.20 Ruthenium-catalyzed C6-selective C–H alkylation of indoles with α-haloester compounds: dual ruthenacycle formation/redox active catalysis. SET, single electron transfer. Source: Modified from Leitch et al. [23].

9.3 (Benzo)Thiophene Thiophene is one of the representative electron-rich heteroaromatics and frequently employed in organic functional materials such as organic field-effect transistors (OFETs). Thus, the C–H functionalization of thiophenes has also been studied well. Given the resonance structure of thiophene ring and higher acidity of C–H at the α-position [24], the α-position is considered to show the highest reactivity. Actually, in several seminal works, the α-selective C–H arylation with aryl halides was achieved under some transition metal catalysis (Scheme 9.21) [25]. In this context, Itami and coworkers first reported the palladium-catalyzed β-selective C–H arylation of thiophenes in the presence of strongly electron-withdrawing phosphite ligand, P[OCH(CF3 )2 ]3 (Scheme 9.22) [26]. Irrespective of steric and electronic nature of substituents on the thiophene, the good to high β-selectivity was observed. Additionally, the fused benzothiophene was also directly arylated at the β-position under identical conditions. Subsequently, the same research group developed an alternative oxidative palladium catalysis comprising Pd(OAc)2 /2,2′ -bipyridine (bpy)/2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), where more robust β-selectivity was achieved by using arylboronic acids as the aryl sources (Scheme 9.23) [27]. The observed high β-selectivity is attributed to the Heck-type carbopalladation pathway, which is supported by experimental and computational studies [28].

9.3 (Benzo)Thiophene

pKa values

Resonance effects

H 39.0 S

S

H 33.5

S

Early examples of C–H arylation of thiophenes R

R

Pd, Rh, Ir, etc. +

Ar

X

Ar S α-Selective

S R = Ar, alkyl, OR′, Cl

Scheme 9.21 Resonance, theoretical pK a values, and early examples of α-selective C–H arylation of thiophenes. Source: Modified from Okazawa et al. [25]. Ph I PdCl2 (5–10 mol%)

Ph

P[OCH(CF3)2]3 (10–20 mol%) Ag2CO3

R

Cl

m-Xylene, 130 °C, 12 h

S

Ph Ph

S

Ph

S

S 60%, 95% β selectivity

56%, >99% β selectivity 76%, 84% β selectivity

Scheme 9.22 Palladium-catalyzed β-selective C–H arylation of thiophenes with aryl iodides. Source: Modified from Ueda et al. [26]. Ph B(OH)2 Pd(OAc)2 (10 mol%) bpy (10 mol%) TEMPO

R

PhCF3, 80 °C, 12 h

S

Ph

Ph

Ph

Cl Ph S S S 53%, >99% β selectivity 68%, 94% β selectivity 92%, >99% β selectivity (in DCE) Ph

Ph N

Pd

N

R

Ph R

S

S +

Carbopalladation R

S

Pd

Major

Pd Ph Minor

R

β-Arylation

S

Deprotonation

R

S

Ph

α-Arylation

Scheme 9.23 Palladium-catalyzed β-selective C–H arylation of thiophenes with arylboronic acids. bpy, 2,2′ -bipyridine; TEMPO, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl. Source: Modified from Kirchberg et al. [27].

Following the aforementioned work by Itami, several catalysts for the highly β-selective C–H arylation of thiophenes appeared (Scheme 9.24). Oi and coworkers reported the palladium-catalyzed oxidative β-selective C–H arylation of thiophenes and benzothiophenes with ArSiMe3 . It is also noteworthy that the usually less reactive aryltrimethylsilanes showed uniquely higher reactivity than aryltrialkoxysilanes [29]. Glorius and coworkers also found the heterogeneous Pd catalysis for the highly β-selective C–H arylation [30a]. The first generation reaction system

263

264

9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions

Oi

Ph SiMe3

Ph

PdCl2(MeCN)2 (5 mol%) CuCl2

R

DCE, 80 °C, 16 h

S Glorius

Cl

S

Dioxane, 150 °C 48–72 h

EtOH, 60 °C, 22 h

Ph

S

p-Tol

I

R S

HFIP, 24 °C, 16 h

Cl

Ph HO

S

82%, >99% β selectivity

p-Tol

Pd2(dba)3·CHCl3 (2.5 mol%) Ag2CO3

90%, >99% β selectivity

Ph

48%, >99% β selectivity (10 mol%, Pd, 80 °C)

Larrosa

p-Tol Me

S

S 72%, >99% β selectivity p-Tol HO

S

S

80%, >99% β selectivity 65%, >99% β selectivity p-Tol

Br

S

Ph

S

S 74%, >99% β selectivity

Ph Cl

S 87%, 93% β selectivity MeO

Ph

S 89%, >99% β selectivity

Pd/C (5 mol%) S

S

Ph

Ph

Ph2IBF4 R

Ph

S

Ph

50%, >99% β selectivity 73%, 79% β selectivity

Ph Cl Pd/C (9.4 mol%) CuCl (10 mol%) Cs2CO3

R

Ph

p-Tol

Br Cl

S

48%, >99% β selectivity 77%, 98% β selectivity (at 50 °C)

65%, >99% β selectivity p-Tol

S 88%, >99% β selectivity

Scheme 9.24 Palladium-catalyzed β-selective C–H arylation of (benzo)thiophens reported by Oi, Glorius, and Larrosa. dba, dibenzylideneacetone; p-Tol, 4-methylphenyl.

was specific to the benzothiophenes, and simpler non-fused thiophenes cannot be accommodated. However, the readily available and cheap aryl chlorides can be used as the aryl donors. Later, the second generation system using the Ph2 IBF4 aryl donors and EtOH solvent allowed the simple thiophenes to be arylated at the β-position [30b]. Larrosa and coworkers developed the highly general β-selective palladium catalysis in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP): thiophenes as well as benzothiophenes were smoothly arylated with aryl iodides even at room temperature [31]. Among 33 substrates tested, the >97 : 3 β-selectivity was always observed only with one exception of 91% selectivity. Additionally, same as mentioned in the indole C–H functionalization, the C—H bond at the C4 position of benzothiophene is also accessible by using suitable directing groups at the C3 position. Representative examples are shown in Scheme 9.25 [10, 12].

9.4 Pyrrole The pyrrole is electronically rich heterocycles similar to the thiophene, and thus the C—H bond at the α position is usually most reactive. To get the unusual β selectivity, the steric control approach is generally applied. Smith and coworkers

9.4 Pyrrole

O

F3C

O

Me

F3C + Mes

S

I

SMe + S

Me

Pd(OAc)2 (10 mol%)

Ph

TFA, CH2Cl2, rt, 24 h

TfO

[Cp*RhCl2]2 (2.5 mol%) AgSbF6 (10 mol%) Cu(OAc)2·H2O

S 80% Ph SMe

DCE, 95 °C, 12 h S 92%

Scheme 9.25 Directed C4-selective C–H functionalization of benzothiophenes. Source: Bora and Shi [10] and Kona et al. [12].

[32] and Miyaura and coworkers [33], independently, reported the β-selective C–H borylation of N-TIPS pyrrole under rhodium and iridium catalysis, respectively (Scheme 9.26). The steric repulsion associated with the bulky TIPS group can guide the active iridium species to the more sterically accessible β position. Actually, in cases of smaller N-H and N-Me pyrroles, the high α selectivity was observed with the iridium catalyst. Smith Bpin

N

+

H Bpin

TIPS

Cp*Rh(η4-C6Me6) (2 mol%) N

C6H12, 150 °C, 41 h

TIPS 81%, >99% β selectivity

Miyaura

N

Bpin + pinB Bpin

TIPS

Octane, 80 °C, 16 h

Bpin N TIPS 79%, >99% β selectivity

Scheme 9.26 pyrroles.

cf.

[IrCl(cod)]2 (1.5 mol%) dtbpy (3 mol%) N

Bpin

H >99% α selectivity

N Me α:β = 76 : 24

Rhodium- and iridium-catalyzed β-selective C–H borylation of N-TIPS

The same strategy was also effective in the palladium-catalyzed β-selective alkenylation of pyrroles with acrylates (Scheme 9.27) [34]. According to the increasing steric bulkiness on the nitrogen, the β selectivity became higher. On the other hand, Yamaguchi, Itami, and coworkers developed the catalyst-controlled rhodium-catalyzed highly β-selective C–H arylation of simple N-Me and -Ph pyrroles with aryl iodides (Scheme 9.28) [35]. The use of highly electronically withdrawing and sterically demanding P[OCH(CF3 )2 ]3 ligand was critical for acceptable conversion and β selectivity. The rhodium catalyst was compatible with various functional groups on both the pyrroles and aryl iodides, and the β selectivity was

265

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9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions CO2Bn

N

+

CO2Bn

Pd(OAc)2 (10 mol%) tBuOOBz AcOH/DMSO/dioxane 35 °C, 24 h

R

R = Bn: 71%, β:α = 1 : 2.1 R = SEM: 69%, β:α = 1 : 2.3 CO2Bn R = Ac: 65%, β:α < 5 : 95 N R = Boc: 73%, β:α < 5 : 95 R R = Ts: 70%, β:α < 5 : 95 α-Alkenylation R = TIPS: 78%, β:α > 95:5

+ N R β-Alkenylation

Scheme 9.27 Palladium-catalyzed β-selective C–H alkenylation of N-TIPS pyrroles. SEM, [2-(trimethylsilyl)ethoxy]methyl. Source: Modified from Beck et al. [34].

R1 +

N

Ar

I

R2

RhCl(CO)L2 (3 mol%) Ag2CO3

Ar

Via

Rh

R1 N

Dioxane/m-xylene 150 °C, 19 h L = P[OCH(CF3)2]3

N

R2

>>

R2

N

Rh

R2 NO2

NO2 S

N Me

N Ph

N

EtO2C

Me

73%, 91% β selectivity 69%, 94% β selectivity 72%, 91% β selectivity

N Ph

44%, 94% β selectivity

Scheme 9.28 Rhodium-catalyzed β-selective C–H arylation of pyrroles with aryl iodides. Source: Modified from Ueda et al. [35].

uniformly high. Also in this catalysis, the steric factors in the C–H activation step are considered to play a pivotal role to control the regioselectivity.

9.5 Pyridine The pyridine is the relatively electron-deficient heterocycle, and thus its C–H activation is fundamentally more difficult than electron-rich thiophene and pyrrole. In early days, design of substrates and/or catalysts enabled the direct C–H functionalization at the C2 position proximal to the coordinating nitrogen. Some selected examples are illustrated in Scheme 9.29 [36]. In this context, Yu and coworkers developed the palladium-catalyzed highly C3-selective C–H arylation of pyridines with aryl halides (Scheme 9.30) [37a]. The combination of Pd(OAc)2 and 1,10-phenanthroline (phen) was necessary to obtain the good conversion and high C3 selectivity. The ligand-promoted, selective π-coordination of pyridine to Pd over the undesired σ-coordination is proposed to be the critical factor to achieve the C3 selectivity. Later, Itami and coworkers also developed the ligand-free palladium-catalyzed C3-selective C–H arylation with aryl triflates [37b]. Additionally, the Pd(OAc)2 /phen system catalyzed the C3-selective C–H alkenylation of pyridine with acrylates (Scheme 9.31) [38].

9.5 Pyridine

Bergman and Ellman Br

Me

+ Me

[RhCl(CO)2]2 (5 mol%)

N Me

53%

Me

[RhCl(CO)2]2 (5 mol%) PCy3·HCl (15 mol%)

+

tBu

N

Me

Me

N

Me

Dioxane, 190 °C, 24 h

THF, 165 °C, 13 h

Me

tBu

N 64%

Chatani +

Ni(cod)2 (5 mol%) PCy3 (10 mol%)

Ph2Zn

Toluene, 130 °C, 20 h

N

N

Ph

55% Baran +

AgNO3 (20 mol%) K2S2O8, TFA

Ph B(OH)2

CH2Cl2/H2O rt, 2–12 h

N Nakao +

Pr

Pr

N

N

Ph

68%, 66% C2 selectivity

Ni(cod)2 (3 mol%) P(iPr)3 (12 mol%) Me2Zn (6 mol%) Pr

N

Toluene, 50 °C, 24 h

Pr 95%, >99% C2 selectivity

Scheme 9.29 Early examples of C2-selective C–H functionalization of pyridines. Source: Modified from Berman et al. [36].

Yu + Ar

X

Pd(OAc)2 (5 mol%) Phen (15 mol%) Cs2CO3

N Solvent

OMe

140 °C, 68 h

CF3

N

N N N 70%, 90% C3 selectivity 72%, 92% C3 selectivity 90%, 94% C3 selectivity (X = Br) (X = I) (X = Br)

N N

Pd N

N

Pd N

Pd N

N

N

N

Itami Pd(OAc)2 (10 mol%) Cs2CO3

+ N Solvent

TfO

150 °C, 18 h

N 50%, 89% C3 selectivity

Scheme 9.30 Palladium-catalyzed C3-selective C–H arylation of pyridines with aryl (pseudo)halides. Phen, 1,10-phenanthroline. Source: Modified from Ye et al. [37a].

267

268

9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions CO2Et Pd(OAc)2 (10 mol%) Phen (13 mol%) Ag2CO3

R

CO2Et

DMF, 140 °C, 12 h air

N Solvent

Me

N

CO2Et N

73%, 86% C3 selectivity

F3C MeO

61%, 77% C3 selectivity

CO2Et N

70%, 91% C3 selectivity

Scheme 9.31 Palladium-catalyzed C3-selective C–H alkenylation of pyridines with acrylates. Source: Modified from Ye et al. [38].

The more promising C3 selectivity was obtained by using the suitable directing group. Yu and coworkers reported the palladium-catalyzed C3-selective C–H arylation with aryl bromides with the assistance of bulky amide directing group at the C4 position (Scheme 9.32) [39]. Me

Me

Via Me

Me

Pd(OAc)2 (10 mol%) PCy2tBu·HBF4 (10 mol%) Cs2CO3, MS 3 A

O NH +

Br

Me

NH

N Me

Toluene, 130 °C, 48 h N

N

O

O

Ar

Pd N

86%, >99% C3 selectivity

Scheme 9.32 Palladium-catalyzed directed C3-selective C–H arylation of pyridines with aryl bromides. Source: Modified from Wasa et al. [39].

Recently, Itami and coworkers developed the palladium-catalyzed, oxidant-controlled C2- and C3-selective dehydrogenative arylation of pyridines with benzoxazoles: in the presence of bulky organic oxidant, MesBr, the high C3 selectivity was observed, whereas the C2-arylated pyridine was obtained with the smaller benzyl bromide oxidant (Scheme 9.33) [40]. The origin of regioselectivity uniquely dependent on the oxidant still remains unclear, but this result provides a new aspect for the regiocontrolled C–H activation.

N

N

Pd(OPiv)2 (10 mol%) IMes HCl (10 mol%) BnBr, CsOPiv

N Solvent + N

170 °C, 17 h

O 74%, >99% C2 selectivity

Pd(OAc)2 (10 mol%) MesBr, CsOPiv

N O

170 °C, 17 h

N 68%, 72% C3 selectivity

O Me

Me N

Me Br

N

Me

Me Me

Me

IMes

Me

Me MesBr

Scheme 9.33 Palladium-catalyzed, oxidant-controlled C3- and C2-selective dehydrogenative arylation of pyridines with benzoxazoles. Source: Modified from Yamada et al. [40].

9.5 Pyridine

The C—H bonds at the C4 position are also accessible by using the amide-type directing group at the C3 position (Scheme 9.34) [39], which is similar to Scheme 9.32.

O N

Ar Br Pd(OAc)2 (10 mol%) PCy2 tBu·HBF4 (10 mol%) N Ph Cs CO , MS 3 A 2 3 N H Toluene, 130 °C, 48 h

O

O N H

Ph

N

O N H

Ph N

N H

Ph

OMe Me F 58%, 92% C4 selectivity 44%, >99% C4 selectivity 60%, 87% C4 selectivity

Scheme 9.34 Palladium-catalyzed directed C4-selective C–H arylation of pyridines with aryl bromides. Source: Modified from Wasa et al. [39].

Nakao, Hiyama, and coworkers developed the non-directed highly C4-selective C–H alkylation with alkenes under the Ni/Al cooperative catalysis (Scheme 9.35) [41]. The σ-coordination of pyridine nitrogen to the Lewis acidic MAD facilitates the C–H activation on the pyridine. Deuterium-labeling experiments suggest the reversible C–H activation at any positions, but the productive C—C bond forming process irreversibly occurs only at the C4 position, which is enabled by the steric repulsion between bulky ligand IPr and bulky Lewis acid MAD. The initially proposed mechanism included the formation of Ni–H species via oxidative addition of pyridine C–H to Ni(0), but recent computational studies based on DFT suggest that a ligand-to-ligand H transfer mechanism without any formation of the Ni–H species is more likely [42]. C11H23

N

iPr

Ni(cod)2 (5 mol%) IPr (5 mol%) MAD (20 mol%)

iPr N

N

iPr

C11H23

Toluene, 130 °C, 5 h

87%, >99% C4 selectivity 95 : 5 linear:branched selectivity

tBu tBu Me Al O O

Me

N tBu

iPr IPr

Me

tBu MAD

Scheme 9.35 Nickel/aluminum-catalyzed C4-selective C–H alkylation of pyridines with alkenes. Source: Modified from Nakao et al. [41].

Almost concurrently, Ong and coworkers reported the C4-selective C–H alkenylation with alkynes in the presence of similar Ni/Al cooperative catalysts (Scheme 9.36) [43]. The salient feature is the use of well-defined and bifunctional Pr

N

Pr

Me

Ni(cod)2 (10 mol%) NHC (20 mol%) Me3Al (20 mol%) Toluene, 80 °C, 16 h

N N

Me3Al

N

Pr 85%, 77% C4 selectivity

NHC Ni NHC

Me Pr

N

Me NHC

HN tBu

Isolated and characterized by X-ray

Scheme 9.36 Nickel/aluminum-catalyzed C4-selective C–H alkenylation of pyridines with alkynes and isolation of π-coordination complex. Source: Modified from Tsai et al. [43].

269

270

9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions

amino-substituted N-heterocyclic carbene (NHC) ligand, which also enabled the isolation of key C–H activation intermediate, π-coordination complex of Ni to pyridine. The same aluminum coordination strategy is also effective in the iridium-catalyzed C4-selective C–H borylation with pinB–Bpin (Scheme 9.37) [44]. Also in this case, the sterically controlled C4-selective C–H activation was proposed. [Ir(OMe)(cod)]2 (1 mol%) N

+ pinB Bpin

tBu tBu iBu Al O O

Br

dtbpy (2 mol%) iBABr (10 mol%)

N

Hexane, rt, 16 h

Bpin

tBu

76%, 92% C4 selectivity

Br

tBu

iBABr

Scheme 9.37 Iridium-/aluminum-catalyzed C4-selective C–H borylation of pyridines with pinB–Bpin. Source: Modified from Yang et al. [44].

The completely different approach to the C—H bond at the C4 position was reported by Matsunaga, Kanai, and coworkers: the alkylcobalt intermediate in situ generated from Co–H species and styrene undergoes the addition/elimination sequence at the C4 position of pyridine to finally deliver the corresponding C4-alkylated product (Scheme 9.38) [45a]. Later, Buchwald and coworkers developed the asymmetric version by using the Cu/chiral bisphosphine catalyst and hydrosilane as the hydride source [45b]. Although the detailed reaction mechanism including the regioselectivity issue still remains to be elucidated, this reaction can be good alternatives to the aforementioned nickel- and iridium-catalyzed, non-directed C–H activation at the C4 position. Matsunaga and Kanai

CoBr2 (1 mol%) LiBEt3H (20 mol%) Et3B (20 mol%) HMPA (30 mol%)

Ph

N

+

N Ph

Toluene, 70 °C, 20 h 91%, >94% C4 selectivity CoBr2 N

Ph

LiBEt3H

Co

Co

N

N

Ph

Ph

Co

H

Ph –Co

H Buchwald

Ph

Cu(OAc)2 (6 mol%) N

Ph +

(S,S)-Ph–BPE (6.6 mol%) (MeO)2MeSiH THF, rt, 20 h then air

Ph

N P

* Ph

P

Ph 62%, 90% ee, 96% C4 selectivity

Ph (S,S)-Ph–BPE

Scheme 9.38 Metal hydride-catalyzed C4-selective C–H alkylation of pyridines via addition/elimination pathway. HMPA, hexamethylphosphoric triamide. Source: Modified from Andou et al. [45].

9.6 Miscellaneous Heteroarenes

9.6 Miscellaneous Heteroarenes 9.6.1

Thiazole

The C–H functionalization of five-membered 1,3-azoles has also been well studies to date, because of their uniquely high reactivity associated with two heteroatoms in the one ring. In general, the C—H bonds at the C2 and C5 show higher reactivity than that at the C4 position. For example, thiazole underwent the palladium-catalyzed C–H arylation with iodobenzene at both the C2 and C5 positions to afford a mixture of C5-arylated and C2,C5-diarylated products (Scheme 9.39) [46]. Although the replacement of thiazole with the corresponding thiazole N-oxide uniquely increased the atomic contribution of highest occupied molecular orbital (HOMO) at the C2 position to perform the C2-selective C–H arylation [47], the selective access to the C4 position was the challenging task. In this context, Itami and coworkers developed the highly C4-selective C–H arylation of thiazoles with arylboronic acids (Scheme 9.40) [27]. Under the Pd(OAc)2 /phen/TEMPO catalysis same as that in Scheme 9.23, 2-phenylthiazole was arylated selectively at the C4 position even in the presence of conceivably more reactive C—H bond at the C5 position. Pd(OAc)2 (10 mol%) PPh3 (20 mol%) N +

N

Cs2CO3

I

Ph

DMF, 120 °C, 47 h

S

N +

Ph S

Ph Ph

35%

17% Pd(OAc)2 (5 mol%) L2 (10 mol%) PivOH (20 mol%) CuBr (10 mol%) K2CO3

O N

Toluene, 25 °C, 13 h

S

O N + Br

CO2Me

S

S

PPh2 CO2Me

Me2N

67%, >99% C2 selectivity

L2

Scheme 9.39 Early examples of C–H arylation of thiazoles at the C2 and/or C5 positions. Source: Modified from Pivsa-Art et al. [46].

N Ph

+

Ph B(OH)2

S

Pd(OAc)2 (10 mol%) Phen (10 mol%) TEMPO DMAc, 100 °C, 48 h

Ph

N Ph S

74%, 85% C4 selectivity

Scheme 9.40 Palladium-catalyzed C4-selective C–H arylation of thiazoles with arylboronic acids. Source: Modified from Kirchberg et al. [27].

9.6.2

Quinoline

The quinoline is the benzene-fused analog to the pyridine, and thus its regioselectivity under typical C–H activation conditions is generally similar to that of pyridine.

271

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9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions

One unique example is the rhodium-catalyzed C8-selective C–H arylation, which was reported by Chang and coworkers (Scheme 9.41) [48]. Although the detail is unclear, the key to achieve the unusual C8 selectivity is the use of IMes ligand. Other common NHCs such as IPr and IAd, and PCy3 resulted in lower yield and regioselectivity.

+ Ph Br N

Rh2(OAc)4 (5 mol%) Ligand (5 mol%) tBuONa Toluene, 95 °C, 24 h

N Ph

Me

IMes·HCl: 58%, >99% C8 selectivity (84%, >99% C8 selectivity w/ 3mol% catalyst) SIMes·HCl: 8%, 97% C8 selectivity IPr·HCl: 4%, 91% C8 selectivity IiPr·HBF4: 7%, 94% C8 selectivity IAd·HBF4: 20%, 67% C8 selectivity PCy3: 5%, 83% C8 selectivity

Me N

N

Me

N

N

N

N

Me Me Me SIMes

IiPr

IAd

Scheme 9.41 Rhodium-catalyzed C8-selective C–H arylation of quinolines with aryl bromides. Source: Modified from Kwak et al. [48].

The iridium-catalyzed C8-selective C–H silylation with hydrosilanes was also reported by Murai, Takai, and coworker (Scheme 9.42) [49]. The high C8 selectivity was achieved uniquely in the absence of any external nitrogen ligands, which are usually essential in the related iridium-catalyzed C–H silylation. Notably, such high regio- and chemoselectivity were limited to the silylation: attempts to apply the C–H borylation with pinB–Bpin under similar conditions provided an inseparable mixture of multiborylated products. The detailed mechanism still remains unclear, but the plausible key intermediate, quinoline-coordinated iridium complex was successfully isolated and characterized by X-ray analysis.

+

H SiEt3

N

tBu [IrCl(cod)]2 (10 mol%) C6H12, 60 °C, 24 h

N SiEt3 70%, >99% C8 selectivity

+ N

H SiEt3

Me

N Ir

tBu [IrCl(cod)]2 (2.5 mol%) THF, 70 °C, 2 h

N

Me

SiEt3 96%, >99% C8 selectivity

Cl

Isolated and characterized by X-ray

Scheme 9.42 Iridium-catalyzed C8-selective C–H silylation of quinolines with hydrosilanes. Source: Modified from Murai et al. [49].

9.7 Conclusion Heteroarenes are usually more electronically activated than simple benzenes because of the incorporated heteroatoms. However, the concurrently induced

References

electronic biases generally dominate the regioselectivity, and thus the C–H functionalization at the “unusual” positions are often more difficult than the benzene system even by using directing groups. As summarized in this chapter, new designs and concepts of organometallic catalysts as well as directing groups overcome such an innate regioselectivity issue. However, there still remain many challenges: for example, the C3-selective C–H arylation of furan seems to be a simple and easy transformation, but is still impossible. We believe that additional efforts by experimental and theoretical chemists address the regioselectivity problems in the C–H functionalization of heteroarenes and enable the discovery of new functional molecules as well as rapid synthesis of complex natural products and drug candidates based on the heteroarene scaffolds.

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10 Borah, A.J. and Shi, Z. (2017). Palladium-catalyzed regioselective C–H fluoroalkylation of indoles at the C4-position. Chem. Commun. 53: 3945–3948. 11 Okada, T., Sakai, A., Hinoue, T. et al. (2018). Rhodium(III)-catalyzed oxidative coupling of N-phenylindole-3-carboxylic acids with alkenes and alkynes via C4–H and C2–H/C2′ –H bond cleavage. J. Org. Chem. 83: 5639–5649. 12 Kona, C., Nishii, Y., and Miura, M. (2018). Thioether-directed selective C4 C–H alkenylation of indoles under rhodium catalysis. Org. Lett. 20: 4898–4901. 13 Ackermann, L. and Lygin, A.V. (2011). Ruthenium-catalyzed direct C–H bond arylations of heteroarenes. Org. Lett. 13: 3332–3335. 14 Paul, S., Chotana, G.A., Holmes, D. et al. (2006). Ir-catalyzed functionalization of 2-substituted indoles at the 7-position:nitrogen-directed aromatic borylation. J. Am. Chem. Soc. 128: 15552–15553. 15 Robbins, D.W., Boebel, T.A., and Hartwig, J.F. (2010). Iridium-catalyzed, silyl-directed borylation of nitrogen-containing heterocycles. J. Am. Chem. Soc. 132: 4068–4069. 16 Xu, L., Zhang, C., He, Y. et al. (2016). Rhodium-catalyzed regioselective C7-functionalization of N-pivaloylindoles. Angew. Chem. Int. Ed. 55: 321–325. 17 Song, Z. and Antonchick, A.P. (2016). Iridium(III)-catalyzed regioselective C7-sulfonamidation of indoles. Org. Biomol. Chem. 14: 4804–4808. 18 Yang, Y., Qiu, X., Zhao, Y. et al. (2016). Palladium-catalyzed C–H arylation of indoles at the C7 position. J. Am. Chem. Soc. 138: 495–498. 19 Qiu, X., Wang, P., Wang, D. et al. (2019). PIII -chelation-assisted indole C7-arylation, olefination, methylation, and acylation with carboxylic acids/anhydrides by rhodium catalysis. Angew. Chem. Int. Ed. 58: 1504–1508. 20 Phipps, R.J. and Gaunt, M.J. (2009). A meta-selective copper-catalyzed C–H bond arylation. Science 323: 1593–1597. 21 Chen, B., Hou, X.L., Li, Y.X., and Wu, Y.D. (2011). Mechanistic understanding of the unexpected meta selectivity in copper-catalyzed anilide C–H bond arylation. J. Am. Chem. Soc. 133: 7668–7671. 22 Yang, Y., Li, R., Zhao, Y. et al. (2016). Cu-catalyzed direct C6-arylation of indoles. J. Am. Chem. Soc. 138: 8734–8737. 23 Leitch, J.A., MuMullin, C.L., Mahon, M.F. et al. (2017). Remote C6-selective ruthenium-catalyzed C–H alkylation of indole derivatives via σ-activation. ACS Catal. 7: 2616–2623. 24 Shen, F., Fu, Y., Li, J.N. et al. (2007). What are the pK a values of C–H bonds in aromatic heterocyclic compounds in DMSO? Tetrahedron 63: 1568–1576. 25 For selected examples, see:(a) Okazawa, T., Satoh, T., Miura, M., and Nomura, N. (2002). Palladium-catalyzed multiple arylation of thiophenes. J. Am. Chem. Soc. 124: 5286–5287. (b) Yanagisawa, S., Sudo, T., Noyori, R., and Itami, K. (2006). Direct C–H arylation of (hetero)arenes with aryl iodides via rhodium catalysis. J. Am. Chem. Soc. 128: 11748–11749. (c) Join, B., Yamamoto, T., and Itami, K. (2009). Iridium catalysis for C–H bond arylation of heteroarenes with iodoarenes. Angew. Chem. Int. Ed. 48: 3644–3647. (d) Liégault, B., Petrov, I., Gorelsky, S.I., and Fagnou, K. (2010). Modulating reactivity and diverting

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selectivity in palladium-catalyzed heteroaromatic direct arylation through the use of a chloride activating/blocking group. J. Org. Chem. 75: 1047–1060. Ueda, K., Yanagisawa, S., Yamaguchi, J., and Itami, K. (2010). A general catalyst for the β-selective C–H bond arylation of thiophenes with iodoarenes. Angew. Chem. Int. Ed. 49: 8946–8949. Kirchberg, S., Tani, S., Ueda, K. et al. (2011). Oxidative biaryl coupling of thiophenes and thiazoles with arylboronic acids through palladium catalysis: otherwise difficult C4-selective C–H arylation enabled by boronic acids. Angew. Chem. Int. Ed. 50: 2387–2391. Steinmetz, M., Ueda, K., Grimme, S. et al. (2012). Mechanistic studies on the Pd-catalyzed direct C–H arylation of 2-substituted thiophene derivatives with arylpalladium bipyridyl complexes. Chem. Asian J. 7: 1256–1260. Funaki, K., Sato, T., and Oi, S. (2012). Pd-catalyzed β-selective direct C–H bond arylation of thiophenes with aryltrimethylsilanes. Org. Lett. 14: 6186–6189. (a) Tang, D.T.D., Collins, K.D., and Glorius, F. (2013). Completely regioselective direct C–H functionalization of benzo[b]thiophenes using a simple heterogeneous catalyst. J. Am. Chem. Soc. 135: 7450–7453. (b) Tang, D.T.D., Collins, K.D., Ernst, J.B., and Glorius, F. (2014). Pd/C as a catalyst for completely regioselective C–H functionalization of thiophenes under mild conditions. Angew. Chem. Int. Ed. 53: 1809–1813. Colletto, C., Islam, S., Juliá-Hernández, F., and Larrosa, I. (2016). Room-temperature direct β-arylation of thiophenes and benzo[b]thiophenes and kinetic evidence for a Heck-type pathway. J. Am. Chem. Soc. 138: 1677–1683. Tse, M.K., Cho, J.Y., and Smith, M.R. III, (2001). Regioselective aromatic borylation in an inert solvent. Org. Lett. 3: 2831–2833. Takagi, J., Sato, K., Hartwig, J.F. et al. (2002). Iridium-catalyzed C–H coupling reaction of heteroaromatic compounds with bis(pinacolato)diboron: regioselective synthesis of heteroarylboronates. Tetrahedron Lett. 43: 5649–5651. Beck, E.M., Grimster, N.P., Hatley, R., and Gaunt, M.J. (2006). Mild aerobic oxidative palladium (II) catalyzed C–H bond functionalization: regioselective and switchable C–H alkenylation and annulation of pyrroles. J. Am. Chem. Soc. 128: 2528–2529. Ueda, K., Amaike, K., Maceiczyk, R.M. et al. (2014). β-Selective C–H arylation of pyrroles leading to concise syntheses of lamellarins C and I. J. Am. Chem. Soc. 136: 13226–13232. (a) Berman, A.M., Lewis, J.C., Bergman, R.G., and Ellman, J.A. (2008). Rh(I)-catalyzed direct arylation of pyridines and quinolines. J. Am. Chem. Soc. 130: 14926–14927. (b) Lewis, J.C., Bergman, R.G., and Ellman, J.A. (2007). Rh(I)-catalyzed alkylation of quinolines and pyridines via C–H bond activation. J. Am. Chem. Soc. 129: 5332–5333. (c) Tobisu, M., Hyodo, I., and Chatani, N. (2009). Nickel-catalyzed reaction of arylzinc reagents with N-aromatic heterocycles: a straightforward approach to C–H bond arylation of electron-deficient heteroaromatic compounds. J. Am. Chem. Soc. 131: 12070–12071. (d) Seiple, I.B., Su, S., Rpdriguez, R.A. et al. (2010). Direct C–H arylation of electron-deficient

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38 39 40

41

42

43

44

45

46

47

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48 Kwak, J., Kim, M., and Chang, S. (2011). Rh(NHC)-catalyzed direct and selective arylation of quinolines at the 8-position. J. Am. Chem. Soc. 133: 3780–3783. 49 Murai, M., Nishinaka, N., and Takai, K. (2018). Iridium-catalyzed sequential silylation and borylation of heteroarenes based on regioselective C–H bond activation. Angew. Chem. Int. Ed. 57: 5843–5847.

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10 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates Ya Li, Qi Zhang, and Bing-Feng Shi Zhejiang University, Department of Chemistry, 38 Zheda Road, 310027, Hangzhou, China

10.1 Introduction Assembling valuable organic compounds in green and atom-economic approaches has long been the core goal of synthetic chemistry. Over the past two decades, direct C–H functionalization has progressively been developed into a powerful synthetic tool that could meet this goal by omitting the requirement for undesired prefunctionalization [1–6]. Apart from the reactivity issue caused by the intrinsic inertness of C—H bonds, another key problem within this field is selectivity, because C—H bonds are ubiquitous in organic molecules and difficult to differentiate [7–9]. The most powerful strategy to address this issue to date is directing group assisted transition-metal catalyzed C–H functionalization [10–20], where an exogenous or native directing group delivers the transition metal catalyst in close proximity to certain C—H bond and furnish high site-selective C—H bond activation (Scheme 10.1). For the activation of the more inert C(sp3 )—H bond, early organometallic findings indicate that five-membered cyclometallation is favored over other ring size [21], which has also been proven by countless examples of transition metal catalyzed functionalization of C(sp3 )—H bonds, such as β-C(sp3 )–H of carboxylic acid, γ-C(sp3 )–H of aliphatic amine, etc. (Scheme 10.2). However, this intrinsic selectivity also brings tremendous challenge for the activation of C(sp3 )—H bonds further away from the chelating atom X. With the efforts by many chemists, new methods and strategies for site-selective functionalization of distal C(sp3 )—H bonds through six- or over-six-membered C(sp3 )–H cyclometallation were developed over the past two decades. This short chapter focuses on recent advancements on auxiliary-directed transition-metal-catalyzed remote C(sp3 )–H functionalization of aliphatic compounds, and the relevant reports are sorted by the classifications of substrates.

Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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10 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates

X

[M] FG

H

X

FG ( )n

( )n

Coordination

Transformation

M X

H ()

X

Cyclometalation

M ()

n

n

X = chelating atom, such as N, O, S, … FG = aryl, alkyl, RO, R1R2N, halogen, …

Scheme 10.1

Directing group assisted transition metal-catalyzed C–H functionalization. X

M

X 5

X

H

H

M

R

H Favored five-membered metallacycle

FG

H

R H Classical approaches

R H H X

M R ( )n

n≥1

H

H

R FG Remote C–H functionalization ( )n

H

Disfavored six- or over-sixmembered metallacycle

Scheme 10.2

X

Directed metal-catalyzed site-selective C(sp3 )–H functionalization.

10.2 𝛄-C(sp3 )–H Functionalization of Aliphatic Acids The first fascinating outcome of catalytic γ-C(sp3 )–H functionalization of amino acids was reported by Corey group [22]. This approach was achieved by the combination of 8-aminoquinoline bidentate directing group and palladium catalysis [15, 19, 20, 23] In this report, L-valine, L-iso-leucine,, and L-tert-leucine derivatives were arylated at the γ-position in good yield. Excellent diastereoselectivity was obtained in the case of L-valine (Scheme 10.3). Aliphatic acids were also capable of affording the γ-C(sp3 )–H arylation products by using bidentate chelator. In 2017, D. Maiti and coworkers disclosed a palladium-catalyzed protocol for regioselective γ-C–H arylation of aliphatic acids (Scheme 10.4a) [24]. High mono-selective arylation was achieved by subjecting excess acid derived substrate to the reaction conditions, thus inhibit

10.2 γ-C(sp3 )–H Functionalization of Aliphatic Acids I

(4.0 equiv) MeO R1 R2 O H

MeO

R1 R1 O

Pd(OAc)2 (20 mol%) AgOAc (1.5 equiv)

NHQ NPhth

NHQ NPhth

Neat, 110 °C, 3.5 h

Q = 8-quinolyl Phth = phthanolyl MeO

Me

O

MeO

Me

NHQ NPhth 85%, dr > 20 : 1

O NHQ NPhth

87%

MeO

Me Me O NHQ NPhth 40% mono, 40% di

Scheme 10.3 Palladium-catalyzed γ-C(sp3 )–H arylation of amino acids. Source: Modified from Reddy et al. [22].

multi-arylation by competing coordination. Later in 2018, D. K. Maiti and coworkers developed a new 2-pyridone-based N,O-bidentate directing group that enables mono-selective γ-C(sp3 )–H arylation without requiring excess acid substrate (Scheme 10.4b) [25]. Using a combination of weakly coordinating directing group and well-designed ligand is growing as another convincing strategy for transition-metal-catalyzed C–H functionalization with the extensive efforts of Yu and coworkers [26]. In 2016, Yu group reported a ligand-enabled γ-C(sp3 )–H arylation of β-quaternary aliphatic acid and several amino acids [27]. The tricyclic quinoline ligand showed conspicuously promotion of the yield, without which no product could be detected (Scheme 10.5). Besides arylation, other carbon–carbon bond formation reactions were also realized. In 2011, Chatani and coworkers accomplished the first palladium-catalyzed directed alkynylation of C(sp3 )—H bonds of aliphatic acid derivatives (Scheme 10.6) [28]. Among the broad substrate scope, 3,3-dimethylbutyic amide afforded the remote γ-C(sp3 )–H alkynylated product, albeit with low yield. In 2013, Shi group developed the alkylation of unactivated alkyl C—H bonds with alkyl halides under palladium-catalyzed conditions and this new strategy enabled efficient production of various unnatural α-amino acids [29]. In this publication, N-protected L-valine derivative was subjected to the reactions and the desired γ-C(sp3 )–H alkylation product was given in moderate yield but high diastereoselective ratio (Scheme 10.7). Yu group achieved remote γ-C(sp3 )–H olefination and carbonylation of aliphatic acids with their representative weakly-coordinating amide directing group and quinoline-based ligand (Scheme 10.8) [30]. In this report, a series of β-quaternary aliphatic carboxylic acids and acrylates were reacted efficiently. Various richly functionalized valerolactams were synthesized via γ-olefination followed by intramolecular conjugate addition. The resulting lactam skeleton is crucial for

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10 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates

Maiti et al., 2017 ArI (0.3 equiv) Pd(PhCN)2Cl2 (10 mol%) AgOAc (3.0 equiv) CF3CO2Na (2.0 equiv)

R1 R2 O H

NHQ

t

Q = 8-quinolyl

BuOH, 150 °C, 24 h

Examples OHC

Br

NHQ

NHQ 66% mono:di > 25 : 1 OMe

NHQ 55% mono:di > 30 : 1 Ac

O

Me

O2N

O

NHQ (a)

Me Me O

Me Me O

67% mono:di > 25 : 1 tBu

NHQ

yields were based on Arl

OMe Me Me O

MeO2C

R1 R2 O Ar

O

NHQ

84%

NHQ

78%

55%

Maiti et al., 2018 R N

O

ArI (1.0 equiv) Pd(OAc)2 (10 mol%) AgOAc (3.0 equiv) CF3CO2Na (2.0 equiv)

Me Me HN H

1,4-Dioxane, 150 °C

O

Examples

Me N

O NC

O (b)

24 h, 79%

Ph

O

Me Me HN

O 24 h, 76%

Bn N

O MeO

Me Me HN

Me Me HN

Me MeHN Ar

Me N

O

R N

O

O 20 h, 69%

Scheme 10.4 Palladium-catalyzed γ-C(sp3 )–H arylation of aliphatic carboxamides. (a) Directed by 8-aminoquinoline. (b) Directed by 3-amino-1-methyl/benzyl-1H-pyridin-2-one. Source: (a) Modified from Dey et al. [24] and (b) Pati et al. [25].

the mono-selective γ-C(sp3 )–H activation. They also conducted a sequential and mono-selective carbonylation/olefination reaction to give richly γ-functionalized product (Scheme 10.9). Latest years, D. Maiti group has kept focus on distal C(sp3 )–H functionalization. In 2017, they reported palladium-catalyzed γ-C(sp3 )–H alkenylation of aliphatic acids using 8-amino quinoline as directing group (Scheme 10.10) [31]. Both acrylates and alkenyl iodides were compatible coupling partners. 4,4′ -Di-tert-butyl-2,2′ -bipyridine (dtbpy) ligand was added as an efficient promoter when acrylates were subjected to reaction conditions.

10.2 γ-C(sp3 )–H Functionalization of Aliphatic Acids

ArI (4.0 equiv) Pd(OAc)2 (10 mol%) L1 or L2 (40 mol%) Ag2CO3 (3.0 equiv)

R 1 R2 O H

t

NHArF R3

ArF =

F

AmylOH, 120 °C, 20 h

L1 =

F

Me tBu

F

N

F

Ph

NHArF R3

L2 =

Me

CF3

Me

Me Me O

R1 R1 O Ar

Me

O

N Me

Et Et O

NHArF

O

Ph Et O

NHArF

35% mono, 43% di

Me

NHArF

60%

45%

O Me

O Ph

NHArF 73%

Me

O N

Ph

NHArF NPhth Phth = phthanolyl 78%

O

NHArF

45% Me

NHArF

O

Me

F 3C

Me

O

86% (dr = 2 : 1) Me

NHArF NPhth 57%

O NHArF NPhth 85%

Scheme 10.5 Quinoline-ligand enabled palladium-catalyzed arylation of γ-C(sp3 )—H bonds. Source: Modified from Li et al. [27]. Br (1.5 equiv) TIPS Pd(OAc)2 (5 mol%) AgOAc (1.0 equiv) LiCl (1.0 equiv)

Me Me O H

NHQ

TIPS

Me Me O

PhMe, 110 °C, 15 h

NHQ 33% Isolated example

Scheme 10.6 Palladium-catalyzed γ-C(sp3 )–H alkynylation of 3,3-dimethylbutyic amide. Source: Modified from Ano et al. [28].

Despite the impressive progress made in remote C(sp3 )—H bond activation/C—C bond formation, achieving carbon–heteroatom bond formation was still rarely reported. Based on previous studies on distal C(sp3 )–H activations, D. Maiti group continued to develop the C(sp3 )–H silylation and germanylation of aliphatic carboxamides at the γ-position in 2017 (Scheme 10.11) [32]. A quinoline-based ligand was found to promote the reaction. Both aliphatic acids and α-amino acids

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10 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates

O (1.5 equiv)

I

Me H

OEt

Pd(OAc)2 (10 mol%) (BnO)2PO2H (30 mol%) Ag2CO3 (0.8 equiv)

O

NHQ NPhth

Me EtO

DCE/tBuOH, 90 °C, 12 h

O

NHQ NPhth

O

41%, dr = 17 : 1 Isolated example

Scheme 10.7 Palladium-catalyzed γ-C(sp3 )–H alkylation of L-valine derivative. Source: Modified from Chen et al. [29].

R3 (4.0 equiv)

O

R1

R2

H

Pd(OAc)2 (10 mol%) L2 (40 mol%) TEMPO (10 mol%) AgOAc (2.0 equiv) K2HPO4 (1.1 equiv) NaHCO3 ( 2.0 equiv)

O NHArF

C6F5CF3, O2 (1.0 atm), 120 °C

ArF & L2 were displayed in Scheme 10.5 Examples O

O NArF R1 R2

COR3

O

O

NArF Me Me

NArF CO2Et

87%

Et Me

NArF CO2Et

CO2Et Et

68%, dr = 56 : 44 O NArF

MeO

51%, dr = 55 : 45

O

O NArF

CO2Et

NArF CO2Et

Me

TFA

66%

51%, dr = 52 : 48 O

CO2Et N

O NArF

Me Me 77%

O NArF O

CO2Bn

75%

Me Me

NArF Ph

70%

Me Me

CN 73%

Scheme 10.8 Ligand-enabled palladium-catalyzed γ-C(sp3 )–H olefination and carboxylation. Source: Modified from Li et al. [30].

10.2 γ-C(sp3 )–H Functionalization of Aliphatic Acids Pd(OAc)2 (10 mol%) L2 (20 mol%) TEMPO (10 mol%) AgOAc (2.0 equiv) KH2PO4 (2.0 equiv) (tBuO)2 ( 2.0 equiv)

Me Me H CONHArF

Hexane, CO (1.0 atm) 150 °C, 20 h

CO2Me Me

O NArF Me Me

O

tBuOK

H

MeOH, rt

CONHArF 91%

61% O

CO2Me Me

NArF Pd(OAc)2/L2 CO2Et

Me

CO2Et CO2Me

LiHMDS

EtO2C

THF

68%

Scheme 10.9

CONHArF 93%

Sequential γ-C(sp3 )–H olefination and carboxylation.

were silylated and germanylated with good yield and high diastereoselectivity. The six-membered palladacycle was synthesized and characterized. Detailed mechanistic experiments were carried out, including palladacycle transformations and deuteration reactions. Preliminary density functional theory (DFT) studies revealed that the rate-determining step for silylation is oxidative addition, while for germanylation is reductive elimination. Later in 2018, D. Maiti and coworkers reported the highly regioselective γ-C(sp3 )–H thioarylation and selenoarylation of aliphatic acids by utilizing a similar reaction system (Scheme 10.12) [33]. To note, this protocol provides a convenient access to derive bioactive chalcogen-containing α-amino acids with excellent diastereoselectivity (up to 52 : 1). In their efforts to prepare synthetically useful pyrrolidones, Chen group disclosed palladium-catalyzed intramolecular amination of aliphatic acids using strongly coordinating bidentate auxiliaries (8-aminoquinoline and 2-pyridylmethyl amine) in 2013 [34]. It’s worthy of noting that several amino acid derivatives were compatible with this method, affording valuable α-amino-γ-lactams in good diastereoselectivity (Scheme 10.13). Under the optimized reaction conditions, only trace amount of γ-C(sp3 )–H acetoxylation byproduct resulted from competing intermolecular C–O reductive elimination could be detected. More importantly, the modified 8-amino-5-methoxyquinoline directing group could be easily removed in the presence of ceric ammonium nitrate (CAN) at ambient temperature without any loss of reactivity in the cyclization step. Notwithstanding the significant progress has been achieved in palladiumcatalyzed aliphatic C–H functionalization, high price of the catalyst has urged chemists to establish economically more attractive approaches. In 2015, Ge group reported the site-selective intramolecular amination of aliphatic amides assisted by 8-aminoquinoline catalyzed by base metal cobalt catalyst (Scheme 10.14). The method enabled a feasible synthesis of β- or γ-lactams with broad functional group tolerance and excellent diastereoselectivity [36]. In particular, for substrates bearing α-quaternary carbon, γ-benzylic C–H activation could compete over β-methyl

285

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10 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates CO2R3 (4.0 equiv) Pd(OAc)2 (10 mol%) dtbpy (40 mol%) Ag2CO3 (5.0 equiv) Na2CO3 (2.0 equiv)

R1 R2 O H

NHQ

R1 R1 O NHQ

1,4-Dioxane, 140 °C, 24 h

Q = 8-quinolyl Examples EtO2C

R3O2C

O Me Me O

O

O

Me Me O

NHQ

O

Me Me O

NHQ

61%

NHQ

61%

41%

Me O

Me H Me

Me

Me Me O

H Me

O

Me Me O

Me

NHQ

52% F

O

F F F F

n

F

O

Me Me O

F F F FF F

tBu

BuO2C

NHQ

NHQ

12%

37% I

R1 R2 O H

NHQ R3

BnO2C

R4 (2.0 equiv) Pd(OAc)2 (10 mol%) AgOAc (2.0 equiv)

NHQ

O

NHQ

Phth = phthanolyl 58% (dr > 20 : 1)

n

Pr

Me Me O

NHQ

NHQ

68% Me

O

NHQ NPhth

R1 R2 O R3

Me Me O

BnO

89%, mono:di = 2 : 1 Me

R4

PhMe, 80 °C, 24 h

Me Me O

O

CO2Et

O

66% MeO

Me

NHQ NPhth 24%

75%

O NHQ NPhth

Scheme 10.10 Palladium-catalyzed γ-C(sp3 )–H alkenylation of carboxylic acids. Source: Modified from Thrimurtulu et al. [31].

C–H to afford pyrrolidones as the major product. A two-step oxidative cleavage of directing group was also demonstrated to illustrate the utility of this method in organic synthesis. Despite the elegance of the above mentioned methods, the requirement to install and remove an exogenous directing group has greatly limited their application in organic synthesis. In this regard, direct functionalization of free carboxylic acid is a more interesting yet challenging topic in this area. Recently, researchers have found

10.2 γ-C(sp3 )–H Functionalization of Aliphatic Acids

R1 R2 O H

NHQ R3 Q = 8-quinolyl

(XMe3)2 (5.0 equiv) Pd(OPiv)2 (10 mol%) 2-Cl-quinoline (20 mol%) Ag2CO3 (3.0 equiv) NaHCO3 (2.0 equiv) t

BuOH, 130 °C, 24 h

Me

tBu

NHQ

NHQ R3

Me Me O Me3Si

R1 R1 O Me3X

O

Me3Si

Me3Si

NHQ NPhth

NHQ

71%

63% NO2

OMe

O

Phth = phthaloyl 69%, dr = 18 : 1 Ph O

Me O Me3Si

Me O NHQ

Me3Si 65%

NHQ 61%

54% Me

tBu

Me Me O

NHQ Ph

NHQ

71%

Me3Ge

Me3Si

O

Me3Ge

Me3Ge NHQ

57%

O

NHQ NPhth

69%, dr = 19 : 1

Scheme 10.11 Palladium-catalyzed γ-C(sp3 )–H silylation and germanylation of carboxylic acids. Source: Modified from Deb et al. [32].

ways to achieve alkyl β-C–H functionalization of free carboxylic acid and amino acid derivatives by introducing pyridine-based ligands [37–42]. In contrast, remote C(sp3 )—H bonds were seldom explored. In 2017, Yu group reported an isolated example of γ-C–H arylation of N-Phth protected L-tert-leucine in merely 23% yield using a combination of Pd-catalyst and pyridine-type ligand (Scheme 10.15) [39]. Later in 2019, D. Maiti and colleagues discovered that N-Ac protected glycine was an efficient ligand for palladium-catalyzed γ-C–H activation of free aliphatic carboxylic acids (Scheme 10.16) [43]. A range of aryl iodides, even those derived from complicated drug molecules, were effectively incorporated to free acids. This protocol exhibits excellent mono-selectivity at 90 ∘ C, and a sequential diarylation could be achieved by simply increasing the reaction temperature to 110 ∘ C. Chiral amino acids with bulky substitutions are among the most efficient chiral ligands for enantioselective C–H functionalization [44–46]. It has been proven that the side chain bulkiness of these ligands has significant impact on controlling the enantioselectivity. To open up an easy access to a series of these ligands, Shi group developed the remote γ-C–H arylation of tert-leucine derivatives (Scheme 10.17) [47]. N-Ac-tert-leucine ligand was proven crucial for this six-membered cyclopalladation. More importantly, oligopeptides bearing N-protected tert-leucine motif were also feasible substrates and deliver γ-C(sp3 )–H arylation of tert-leucine moiety

287

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10 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates

R1 R2 O H

NHQ

R3 Q = 8-quinolyl

(ArX)2 (5.0 equiv) Pd(OAc)2 (10 mol%) 2-Cl-quinoline (20 mol%) Ag2CO3 (3.0 equiv) NaHCO3 (2.0 equiv)

R1 R1 O ArX

THF, 130 °C, 24 h

NHQ R3

Me Me O O2N

Me Me O PhS

S

Me Me O NHQ

NHQ 77%

71%, mono:di = 2.8 : 1 Ac

MeO

O

PhS

Me O NHQ

PhS

Me

NHQ NPhth Phth = phthaloyl 52%

PhS

NHQ

NHQ 75%

Me

O NHQ NPhth

PhS

O NHQ NPhth

65% (overall yield) Me

tBu

Me Me O

60%

PhS

63%

Me Me O

PhSe

Me O NHQ

73%

PhS

NHQ

Cl

78%

tBu

S

O

PhSe

PhSe NHQ

48%

O NHQ NPhth

53%, dr = 25 : 1

Scheme 10.12 Palladium-catalyzed γ-C(sp3 )–H chalcogenation of carboxylic acids. Source: Modified from Guin et al. [33].

exclusively, despite the fact that peptide backbone are strong bidente directing group and might leads to quite different regioselectivity [50–53].

10.3 𝛅-/𝛆-C(sp3 )—H Bond Functionalization of Aliphatic Amines Aliphatic amines play a key role in the function of many biologically active molecules, but their synthesis and modification via transition-metal catalysis are challenging owing to the strong coordination ability. Over the past decade, with the aid of proper directing functionalities and ligands, direct transition-metal catalyzed C–H functionalization of aliphatic amine derivatives has gradually become a class of synthetically practical methods [54]. General methods afforded the γ-functionalized products with amine-based directing group via kinetically favored five-membered metallocycle.

10.3 δ-/ε-C(sp3 )—H Bond Functionalization of Aliphatic Amines

R2 R3 O

R1

H

N H

R4

DG

O PhthN

N N

Me

PhMe, 70–110 °C Ar, 24 h

R3

PhthN

N

N

N

N

Me

O N AcO

N

Me

3%

R

O

H

N

Me 77%

PhthN Std. conditions Et

N

Me 87%

N

83%

N

Et

Me

O

OMe N H

N 94%

tBuO

O

O PhthN

Me

N

82%, dr > 10 : 1

R1

R2

N

Me

O

N

Me

N

81%

PhthN

N DG

O PhthN

tBuO

85%, dr > 15 : 1 (Phth = phthaloyl) O

PhthN

R4

O

PhthN

O

Pd(OAc)2 (10 mol%) PhI(OAc)2 (2.5 equiv)

O

OMe N N

CAN (3.0 equiv) MeCN/H2O, rt, 5 h

PhthN

NH

Et

54% (R = H) + 33% (R = OAc)

65%

Scheme 10.13 Palladium-catalyzed γ-C(sp3 )–H intramolecular amination. Source: Modified from He et al. [34]. O H

NHQ R1

Co(OAc)2 (10 mol%) Ag2CO3 (2.5 equiv) PhCO2Na (0.5 equiv)

R2

Ph Q = 8-quinolyl

PhCl, 150 °C

Ph

Ph

N Q

Ph N Q R1

R2

O

Ph

N Q

Ph

N Q

N Q

Me Me

O

83%, dr = 1.1 : 1, γ 8%, β-methyl

Me

O

72%, dr > 20 : 1, γ 17%, β-methyl

O 86%

tBu

O 0%

Scheme 10.14 Cobalt-catalyzed γ-benzyl C(sp3 )–H dehydrogenative amination. Source: Modified from Li et al. [35].

The first δ-C(sp3 )–H functionalization of aliphatic amines was independently reported by Daugulis and Chen in 2012 [48, 49]. Both of the two groups employed picolinamide directing group, Pd(OAc)2 catalyst, and PhI(OAc)2 oxidant. Daugulis group synthesized a variety of pyrrolidines, indolines, and isoindolines under mild conditions (Scheme 10.18a). A mild cleavage of the directing group in the presence of LiEt3 BH was also demonstrated. Chen and coworkers utilized AcOH as additive, which promoted efficient synthesis of azetidines, pyrrolidines, and indolines (Scheme 10.18b) [49]. Based on the deuteration studies, they concluded the

289

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10 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates

O

O

N

H

p-Tol-I (2.5 equiv) Pd(OAc)2 (10 mol%) L3 (12 mol%) Ag2CO3 (2.0 equiv) K2HPO4 (1.0 equiv)

CO2H

N O p-Tol

HFIP, 100 °C, 24 h

Me Me

tBu

AcHN

O

N

L3

CO2H

tBu

Me Me 23%

Scheme 10.15 Ligand-enabled palladium-catalyzed γ-C(sp3 )–H arylation of N-Phth L-tert-leucine. Source: Modified from Chen et al. [39].

Ar–I (2.0 equiv) Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv) Na2HPO4 (0.5 equiv)

R1 R2 O OH

OH

HFIP, 90–110 °C, 24 h

H Examples

R1 R2 O

Me Me O

Me Me O

Ar

Me Me O OH

OH

Me Me O

OH

OH Br CHO

80%

CN

81% Me Me O

Me

73% O

OH Me

53% O

H H

OH

OH

Me O

Me

24%

81%

Me O

MeO

Me O OH

Ac 61%

NO2

NO2

O

0% Me O

MeO2C

OH

OH

O2N

Ac 66%

CO2Et 75%

Scheme 10.16 Palladium-catalyzed γ-C(sp3 )–H arylation of free aliphatic acids. Source: Modified from Dului et al. [43].

10.3 δ-/ε-C(sp3 )—H Bond Functionalization of Aliphatic Amines Ar–I (2.0 equiv) Pd(OAc)2 (10 mol%) Ac-tert-Leu-OH (20 mol%) Ag3PO4 (1.0 equiv) K2CO3 (1.0 equiv)

R1 R2 O H

OH

R1 R 2 O Ar

OH

HFIP, 70 °C, 24 h NPG

NPG CHO Cl

Me Me O

Me Me O OH

N

O

Me Me O OH

O

N

O

OH

O

N

O

O

NPhth = 56% MeO

Me Me O

MeO

Me Me O

OH N

O

O

Cl

N

O

O

O

OH O

N

H

Cl Cl

Cl

55%, mono:di = 6 : 1

76%, mono:di = 7 : 1 Ar–I (2.0 equiv) Pd(OAc)2 (15 mol%) Ac-tert-Leu-OH (30 mol%) Ag2SO4 (1.0 equiv) K2CO3 (1.0 equiv)

R Me O H

OH

HFIP, 70 °C, 24 h

NH

AA AA

NPhth O

Cyh OH

NPhth O

iBu

OH

Me Me O OH

PhthN MeO2C

HN

OH Me Me

47% H

PhthN NH

O

O

iPr

O OH

MeO2C

HN

Me Me 49%

O

Et

H O

Me Me 42%

NPhth O HN

MeO2C

35%

Ligand enabled monodentate vs. inherent bidentate

HN

OH NH

Me Me

53%, mono:di = 4 : 1

H O

R Me O Ar

O

HN

MeO2C

Me Me

Me

54%, mono:di = 4.5 : 1

AA AA

O

HN

PhthN MeO2C

Me Me O

OH

H

MeO2C

47%

66%, mono:di = 6 : 1 MeO

O OH

Me Me 34%

Scheme 10.17 Palladium-catalyzed γ-C(sp3 )–H arylation of N-protected tert-leucine and oligopeptides. Source: Modified from Liu et al. [47].

291

292

10 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates

O

N

Pd(OAc)2 (5.0 mol%) PhI(OAc)2 (2.0 equiv)

R1

HN

O

N N

R1

PhMe, 80–120 °C, 24 h 2

H

R

R3

R3

O

N N Me

Me Me

O

N

N

N Me

Me 40%

O

N HN H

O N

Me

(b)

82%, dr = 7 : 1

59%, dr > 10 : 1

36%, dr = 9 : 1

Pd(OAc)2 (5.0 mol%) PhI(OAc)2 (2.5 equiv)

R2

AcOH (10.0 equiv) PhMe, 110 °C, Ar, 24 h

O

N N

O

N N R3

O

N CO2Me

Me

Me

R1

CO2Me

N

CO2Me

R3

N

O

N

Me

Me

88%

(a)

O

N

R2

N

R1 R2

O

N CO2Me

N OAc

Me Me 86%

17%

72%, dr > 20:1

Scheme 10.18 Palladium-catalyzed intramolecular amination of C(sp3 )—H bonds at δ-positions. (a) Intramolecular δ-C(sp3 )–H amination by Daugulis et al. (b) Intramolecular δ-C(sp3 )–H amination by Chen et al. Source: (a) Modified from Nadres and Daugulis [48] and (b) He et al. [49].

order of relative reactivities of different aliphatic C—H bonds as follows: γ-methyl C—H > δ-methyl C—H > γ-methylene C—H bonds. They also employed a modified directing group that could be easily removed via intramolecular lactonization in this work. Later in 2017, Wu and coworkers developed picolinamide-assisted palladiumcatalyzed intramolecular C(sp3 )–H amination of aliphatic for constructing polycyclic N-containing heterocycles [55]. Under the promotion of microwave, the reaction could furnish good yield within four hours. Unconventionally, electron-deficient aryl iodides were used as oxidant to generate the Pd(IV) intermediates, however, the C-C reductive elimination was suppressed thus leading to C-N bond formation. Interestingly, several bridge-ring products were also synthesized via δ-C(sp3 )–H amination in moderate to good yields and acceptable chemo- and regioselectivity (Scheme 10.19).

10.3 δ-/ε-C(sp3 )—H Bond Functionalization of Aliphatic Amines

N HN

PdCl2 (10.0 mol%) Ag2CO3 (2.0 equiv) 1-Iodo-4-nitrobenzene (2.0 equiv) 2,6-Dimethoxylbenzoic acid (2.0 equiv) Na3PO4 (2.5 equiv)

O R1

O

N N

R1

TCE, MW, 140 °C, 2–4 h ( )n

2

R

R2

H

O

N N

O

N

O

N

N

N CO2Me

88% (δ-C–H arylation, 7%)

44% (γ-C–H amination, 50%)

OMe 43% (γ-C–H amination, 40%)

Scheme 10.19 Construction of polycyclic nitrogen-containing heterocycles via palladium-catalyzed directed δ-C–H amination of alkyl amines. Source: Modified from Zhao et al. [55].

Other directing groups were also found efficient to promote the remote C(sp3 )–H functionalization of amines. In 2014, Zhao group disclosed the intramolecular δ-C(sp3 )–H amination of aliphatic amine with an easily accessible oxalyl amide as directing group (Scheme 10.20) [56]. The novel auxiliary was proved powerful in distal C–H functionalization and facilitate the synthesis of five- to six-membered N-heterocycles. Deuteration study revealed that γ-C(sp3 )–H was deuterated in less than 2%, which showcased the favorable cleavage of remote C—H bonds of this directing group. In recent years, intermolecular carbon–carbon bond formation via remote C(sp3 )–H activation was also developed. In 2013, Chen group reported palladiumcatalyzed alkylation of aliphatic amine derivatives [57]. Simple dibenzyl phosphate (BnO)2 PO2 H was discovered as an crucial additive for this reaction. Within the scope of amines, norbornane derived substrates afforded multiple methylated products via sequential C(sp3 )–H activation, including one or two steps of δ-C(sp3 )–H methylation. The controllable selectivity was determined by the conformation of substrate and the reaction conditions (Scheme 10.21). This conformation determined δ-C(sp3 )–H activation has also inspired Wang and coworkers to explore the divergent synthesis of arylated anti-influenza virus A agents (a bicyclic amine) in 2014 [58]. Under the optimized conditions, both aryl iodides and aryl bromides were compatible coupling partners to give the corresponding δ-arylated anti-influenza virus A agents in high regioselectivity (Scheme 10.22). Prior to this work, an isolated example of δ-C(sp3 )–H arylation of linear aliphatic amine was reported by Daugulis group in 2013 [59]. A mixture of mono- and di-arylated products was obtained in low yield (Scheme 10.23). Very recently, D. Maiti group reported a practical method for δ-C(sp3 )–H arylation of aliphatic amines and amino acids [60]. A great many amines were

293

294

10 Directing Group Assisted Distal C(sp3 )–H Functionalization of Aliphatic Substrates

NiPr2

NiPr2

O

O

Pd(OAc)2 (5.0 mol%) PhI(OAc)2 (2.5 equiv)

R1

HN

O

O N

R1

Mesitylene, 100–140 °C, 24 h 2

H

R

R3

R3 NiPr2

NiPr2 O

O

NiPr2 O

O

N

N

NiPr2 O

O

R2

N

NiPr2 O

O

O

O

N

Me

Me Me

N CO2Me

Me 25%

Me 60%

Me

Me

Me

64%

62% NiPr2

NiPr2 O

O NH

91%

O Pd(OAc)2 (10 mol%) AcOD (10 equiv) Ar, 80 °C, 24 h

NiPr2

O

O N O Pd

H(D) NH

Ph

γ < 2%

H(D)

Disfavored

ε, 62%

Scheme 10.20 Palladium-catalyzed oxalyl amide directed δ-C–H amination of alkyl amines. Source: Modified from Wang et al. [56].

NHP P = picolinoyl

MeI (5.0 equiv) Pd(OAc)2 (10 mol%) (BnO)2PO2H (20 mol%) Ag2CO3 (2.0 equiv) PhMe/tAmylOH = 9 : 1 110 °C, Ar, 20 h

Me

Me NHP

CO2Me NHP

PhMe/tAmylOH = 9 : 1 110 °C, Ar, 20 h

+

NHP 77%

+ NHP

Me

6) focused on vinyl/aryl radical species. Second, the functionalization mainly occurs on tertiary, benzylic, or α-heteroatom C(sp3 )—H bonds. The high selective transformation of relative inactive secondary or methyl C(sp3 )—H bonds still meets great challenge. Third, similar to other methodologies for remote C(sp3 )–H activation, enantioselective version is still largely undeveloped. Nonetheless, these strategies are complementary to transition-metal mediated C–H insertion methods and together provide powerful protocols in the synthetic

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12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds Carlo Sambiagio 1 1 and Bert U. W. Maes 2 2 11 Eindhoven University of Technology, Department of Chemical Engineering and Chemistry, Den Dolech 2, 5612 AZ, Eindhoven, The Netherlands 22 University of Antwerp, Organic Synthesis Division, Department of Chemistry, Groenenborgerlaan 171, B-2020, Antwerp, Belgium

12.1 Introduction From a synthesis perspective, the efficient introduction and/or transformations of functional groups in an organic molecule are of utmost importance. While the transformation of existing functional groups into different moieties is well established, this approach suffers from the necessity of pre-installed functional groups. The functionalization of C—H bonds, ubiquitous in organic molecules, serves as an attractive alternative, as more sites are present in a typical organic compound which can be theoretically transformed in this manner. This offers more opportunity for increasing molecular complexity, and represents a greener alternative to reactions requiring pre-functionalizations, such as cross-couplings or nucleophilic substitutions. The functionalization of C—H bonds thus comes with the potentials of synthetic broadness, reduction of waste, and increase of atom economy. However, it also comes with significant challenges, in particular regarding the activation of the strong C—H bonds, and achieving selective functionalization in molecules with various similar bonds. Among the C—H bonds, Csp3 —H bonds represent the biggest challenge, as these are strong bonds, provide stereoisomers, and are more frequently occurring than Csp2 —H bonds in a typical molecule. Moreover, while in arenes selectivity can be achieved by exploiting the electronic effects (inductive and mesomeric) of existing functional groups, these effects, although present, are often less pronounced in aliphatic compounds, and limited to inductive activation. Therefore, alternative strategies for selective functionalization must be found. The most traditional way to functionalize aliphatic compounds involves the deprotonation of acidic C—H bonds adjacent to electron-withdrawing groups (EWGs), and their reaction with electrophiles. Weakly acidic C—H bonds adjacent to unsaturated C—C bonds (benzylic and allylic positions) or adjacent to heteroatoms can be instead functionalized via homolytic cleavage (see Section 12.1.1). These types of processes cannot be Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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labeled “remote” or “distal” functionalizations, as only C—H bonds adjacent to these existing functional groups can be involved. In this chapter these terms will be used to indicate functionalization processes involving C—H bonds at least at the β position with respect to a functional group or a heteroatom. To functionalize C—H bonds in remote positions and in a selective manner, transition metal catalysis in combination with directing groups (DGs) is commonly used. DGs are coordinating functional groups that act as “internal ligands” to bring a metal atom in proximity to a specific C—H bond [1]. This important strategy has been discussed in this book (Chapters 4 and 10). Another way to achieve site-selective functionalization at C—H bonds in remote positions to existing functionalities relies on molecular recognition and non-covalent interactions (of which biocatalysis is the ultimate version [2]), hereby bringing specific C—H bonds in proximity of the active center of the catalyst. This method allows functionalization of specific C—H bonds even within complex molecules [3]. In the absence of proximal activating functional groups (electronic effects), directing groups, or supramolecular interactions, the functionalization of aliphatic C—H bond is very challenging. A few strategies have been nonetheless developed to promote selective functionalization, based on tuning the innate reactivity of specific C—H bonds in the substrate and the characteristics of the reagent and/or the catalyst employed. The methods employed can be broadly divided in reactions occurring with or without the formation of a metal–carbon bond. Activation of C—H bonds that does not involve formation of a metal–carbon bond typically occurs via hydrogen atom transfer (HAT), i.e. homolytic cleavage of the C—H bond, either via free radicals or concerted mechanisms. These processes tend to be more sensitive to the thermodynamic properties of the C—H bond to be activated, and/or the stability of the radical formed, as discussed in Section 12.1.1. For reactions involving the formation of metal–carbon bonds, the properties of the organometallic intermediate formed are often more important than the properties of the C—H bond itself, and steric factors become crucial. This results in generally different selectivities [4]. Different mechanisms are possible for the different methodologies, and the basic mechanism for the reactions will be reported in the specific sections. However, a detailed discussion on the mechanistic aspects is outside the scope of this chapter, and the interested reader is referred to the literature referenced in this chapter.

12.1.1 Bond Dissociation Energy (BDE) of C—H Bonds The bond dissociation energy (BDE) of aliphatic C—H bonds, i.e. the energy required for the homolytic cleavage of these bonds, is considerably high, and consequently the cleavage is difficult to achieve. Most aliphatic C—H bonds, moreover, have very similar BDEs, and being very abundant in organic molecules, it is typically hard to differentiate between them in chemical transformations. Representative examples of BDE values for different classes of compounds are reported in Table 12.1. Generally speaking, as most of the C–H functionalization

12.1 Introduction

Table 12.1

Examples of BDEs of aliphatic C—H bonds [5].

C—H bond

BDE (kcal/mol)

Hydrocarbons [5a]

C—H bond

BDE (kcal/mol)

Amines (α to N) [5c]

CH4

105

CH3 CH2 CH2 NH2

93

CH3 CH3

101

(CH3 CH2 )2 NH

89 91

(CH3 )2 CH2

99

(CH3 CH2 )3 N

(CH3 )3 CH

97

Aldehydes [5a]

PhCH3

90

CH3 CHO

CH2 =CHCH3

89

Halides [5d] CH3 Br

102

95

CH3 Cl

100

(CH3 CH2 )2 O

95

CH3 F

101

(PhCH2 )2 O

85

Ethers (α to O) [5b] (CH3 )2 O

89

The CHs in bold represent those C—H bonds for which the BDE value is provided.

processes involve an electrophilic attack to the C—H bond, the more electron-rich a position is, the more likely it will be activated [4]. The introduction of a (partial) positive charge favors remote functionalizations, while the introduction of a (partial) negative charge in the molecule has the opposite effect, promoting functionalization in proximity to the charge location. The introduction of (partial) charges in a molecule is an important strategy to alter the innate reactivity of C—H bonds (affects the BDE of C–H bonds proximal to the charge), and is discussed in details in Section 12.4. The strength of a C—H bond can be influenced by different factors than electronics. Benzylic and allylic positions, as well as C—H bonds in positions α to a heteroatom, present lower BDE and are generally easier to activate than other bonds (Table 12.1). These C—H bonds are involved in hyperconjugative interactions with an adjacent π or non-bonding (lone pair) orbital, resulting in relatively easy activation and functionalization. As these C—H bonds are in proximity of a functional group, functionalizations at these positions will not be explicitly treated in this chapter, unless in competition with remote functionalization. Another type of hyperconjugation is that exerted by a cyclopropyl moiety on adjacent C—H bonds. Here the overlap between a σ C–C orbital of the cyclopropane and the σ* orbital of the adjacent C—H bond is responsible for the weakening of the latter. This effect is weaker than the above hyperconjugative effects, and strongly dependent of the geometry and conformation of the molecule, but is commonly observed [4a]. In the absence of activating or deactivating functionalities, a decreasing trend in BDEs from primary to tertiary C—H bonds (105–97 kcal/mol going from methane to tert-butane, Table 12.1) is observed, and functionalizations preferentially occur at tertiary positions over secondary or primary.

345

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12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds

The generalizations discussed in this section are valid for reactions that do not involve formation of metal–carbon bonds, and in the absence of steric or other effects. Steric effects are observed in many cases and depend on the mechanism of the activation process and the reagent and catalyst used. General discussion on steric effects can be found in the literature [4], and specific cases will be discussed in this chapter.

12.1.2 Scope of the Chapter Many different methodologies to achieve functionalization at remote Csp3 –H positions have been developed. It is impossible to discuss all the available methodologies in a single chapter, therefore we focused in this chapter on selected methods that have recently seen important developments and attracted the attention of researchers in the fields of catalysis and organic chemistry. We chose to broadly divide the methods into two main categories: reactions occurring without and with formation of metal–carbon bonds during the activation process. In the first category, we discuss methodologies such as the classical oxidation with dioxiranes, decatungstate photocatalysis, electrochemical functionalization, and carbene insertion into C—H bonds (Section 12.2). In the latter, the early Shilov-type chemistry and the more modern Rh-/Ir-catalyzed borylation of aliphatic C—H bonds are discussed (Section 12.3). Finally, Section 12.4 deals with the strategy of polarity reversal, a generally applicable method to alter the innate reactivity of C—H bonds in a molecule and promote remote functionalization.

12.2 Reactions Occurring Without Formation of Metal–Carbon Bonds 12.2.1 Oxidations with Dioxiranes The properties of dioxiranes as oxidants have been known for several decades, and the oxidation of a large variety of functionalities was reported already before the 1990s [6]. Dioxiranes such as dimethyldioxirane (DDO) and the more reactive methyl(trifluoromethyl)dioxirane (TFDO) are powerful electrophilic oxygen-transfer reagents, and are now routinely employed for oxidation reactions in relatively mild conditions, despite the disadvantages related to their instability and difficult handling. Oxidation with dioxiranes constitutes a unique example of uncatalyzed selective C–H oxidation of unactivated C—H bonds. Already in early reports it was observed that both DDO and TFDO could react with alkanes in a selective way, preferring tertiary positions to secondary, and secondary to primary. Interesting exceptions are constituted by norbornane and bicyclo[2.1.0]pentane, selectively functionalized at a secondary position instead of the tertiary bridgehead carbons (Scheme 12.1) [7]. In the latter case, the hyperconjugative properties of the cyclopropane ring determine the selectivity (see Section 12.1). In the case of linear alkanes without tertiary carbons, statistical functionalization at secondary carbons occurs, as exemplified by heptane (Scheme 12.1).

12.2 Reactions Occurring Without Formation of Metal–Carbon Bonds OH OH HO

HO 3 h, –20 °C, 74%

3 min, –20 °C, 98%

(TFDO)

Ph Me Et

OH

O O F3C

Retention of configuration

HO

5 min, –20 °C, 98%

H

Ph Me Et

OH

1 h, –23 °C, >98%, 72% ee

Alkane O

40% 18%

18 min, –20 °C, 98%

40%

OH OH 3°

3° 2°

2°

5 min, 0 °C, 79%

1.5 h, –20 °C, 77% (16% ketone)

70 min, –20 °C

Proposed concerted mechanism for the oxygen-transfer from TFDO to alkanes H O C F3C

Scheme 12.1

R Me

R C

O

H O

O C

R F3C

R C

R

R

Me

Examples of TFDO oxidations at tertiary and secondary C–H positions.

The negative radical clock tests and the reaction with chiral molecules with retention of configuration, together with other mechanistic evidence, demonstrate the absence of a free radical mechanism for the oxidation with dioxiranes. A concerted mechanism has been proposed for the reaction with alkanes, with the electrophilic oxygen insertion occurring along the O—O bond pointed toward the C—H bond (Scheme 12.1, bottom). This mechanism explains the stereoselectivity of the reaction observed in certain instances. The deviation from the typical regioselectivity of dioxirane methods in the absence of activating or deactivating functionalities in the molecule has been attributed to slight variations in the mechanism of the reaction [7a, 8]. Oxidations by dioxiranes in the presence of EWGs occurs, as expected, at remote positions from the functional group, according to the favorable BDE values of these positions (see also Section 12.4) [4a]. An important feature of TFDO is its selectivity in the reaction with steroid derivatives, where discrimination between different tertiary C–H positions is often achieved. For example, the hydroxylation of estrone acetate occurs selectively at the bridgehead tertiary benzylic C9, while in steroids with an acyclic tertiary position available, hydroxylation occurs preferentially at that site, e.g. C25 in cholestane and vitamin D2 derivatives (Scheme 12.2). The tert-butyl group in the alkyl chain is the most favorable functionalization position for electronic reasons (tertiary), but also has the lowest steric hindrance compared with the other available tertiary positions in the polycyclic structure, an important requisite considering the concerted mechanism of the reaction [7a]. Interestingly, C25 hydroxylations in these compounds do not occur with a range of other oxidants, including modern selective iron-catalyzed methods, as recently demonstrated by Lei and co-workers [9].

347

348

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds Estrone acetate Me O

(X = H, Br)

C9 OH

H

DDO, 20 °C, 22 h, 80%

Scheme 12.2

X

O Me OH

OH H

AcO

Me Me

Me Me

Me AcO

Vitamin D2 derivative

Cholestane derivatives

O

H

C25

O

TFDO, 0 °C, 1.7 h, 61%

C25 O

X

TFDO, –40 °C, 3 h, 80–85%

AcO

Selectivity of dioxirane C–H oxidation in steroid derivatives.

12.2.2 Decatungstate-Photocatalyzed Remote Functionalization In recent years, the functionalization of alkyl moieties via photocatalysis has received significant attention. In particular, Barton-type 1,5-HAT processes, together with other miscellaneous methods [10], have been employed to promote remote functionalization. Among the possible method, an interesting one is the use of decatungstate photocatalysis. The decatungstate anion is a tungsten-based polyoxometalate (POM) that is able to undergo either HAT or SET (single electron transfer) processes, depending on the substrate, under irradiation of UV light (350–400 nm, Scheme 12.3). In the case of alkanes and other aliphatic compounds, the HAT transfer mechanism is typically assumed. Contrarily to many other C–H activation reagents, which provide only one type of functionalization (e.g. oxygenation or borylation), an interesting feature of decatungstate photocatalysis is the possibility to form either C—C, C—N, C—O or C–halogen bonds directly, which makes it a versatile methodology in synthesis [11]. Hydrogen atom transfer from the decatungstate in simple alkanes normally follows the trends dictated by the BDE values, and typical functionalization ratios are in the order tertiary > secondary > primary. Several reports describe the use of decatungstate for the selective activation and functionalization of aliphatic compounds at activated C–H positions, such as benzylic [12], allylic [13], aldehyde C—H bonds [14], and α to ethers [14b, 15]. Although most of the functionalization reported with decatungstate involve such activated C—H bonds, a few interesting examples of remote functionalization of unactivated bonds have been reported. In 2014 Britton and co-workers reported the decatungstate-catalyzed fluorination of a variety of aliphatic esters using N-fluorobenzenesulfonimide (NFSI) as fluorinating agent. A certain degree of selectivity was observed, though with yields generally 3∘ . In this reaction the Pt(IV) acts as an oxidant to reoxidize the Pt(II) formed upon completion of the catalytic cycle, and the cleavage of the C—H bond was found to be the rate-determining step [47, 49]. Although this reaction can be explained in terms of oxidative addition and reductive elimination steps, other mechanistic possibilities have also been considered. Detailed discussion about the possible mechanisms at play in this reaction can be found in the literature [47, 49]. Despite the interesting reactivity demonstrated by the Shilov system, it presents several flaws that prevent its widespread use. The cost of the Pt catalyst, even when

361

362

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds Ar ROOC

H

R

Rh2L4 1%

N2

n

R

n

DCM, 39°C

Ar

H

COOR

1°

Br

Br

Br

1° 2°

3° H

COOCH2CCl3

H

82% (1° : 3° = 89 : 11) ee 90%

2°

TMSO COOCH2CBr3

80% (1° : 1° : 2° = 84 : 13 : 3) ee 95%

Br

H

COOCH2CBr3

90% (1° : 2° = 94 : 6) ee 98%

Br

1° 2° TMSO

Br H

2°

COOCH2CBr3

93% (1° : 1° : 2° = 93 : 4 : 3) ee 97% Stigmasteryl acetate

H

COOCH2CBr3

53% (1° : 2° = 84 : 16) ee 93%

H

3°

Rh2L4 = Ar

O Rh

Ar

H H

O Rh

H

AcO 44% (1° : 3° = 94 : 6) dr >100 : 1 Br

Scheme 12.17 bonds.

COOCH2CBr3 H

Ar

4

Ar = p-t-BuC6H4 Rh2[R-tris(p-t-BuC6H4)TPCP]4

Examples of selective carbene insertion into unactivated primary C—H

using alternative oxidants such as Cu(II) salts, is high, while the catalytic efficiency is generally low. Moreover, the selectivity obtained is modest, and the tendency to overoxidation has been demonstrated. Finally, issues with precipitation of metallic Pt (depending on the conditions) have been reported since the beginning. Some examples of selective C–H functionalization have been reported, but mostly in the presence of coordinating moieties in the substrate (directing groups) [50]. These initial discoveries are nonetheless very important, as they started a completely new line of research, involving experiments with a variety of different transition metal catalysts and associated mechanistic studies. This led to improved methodologies for C–H functionalization, such as the Pt-based catalytic process for methane oxidation [51], and the development of directing group-mediated functionalizations. However, despite these advancements, and the discovery of Pd-, Cu-, and Ir-promoted C–H activations, the corresponding functionalization is mostly not efficient or not selective in the absence of a directing group [47a].

12.3 Reactions Occurring via Formation of Metal–Carbon Bonds

12.3.2 Rh- and Ir-Catalyzed C–H Borylation of (Functionalized) Alkanes Among the methods involving formation of metal–carbon bonds for the functionalizations of alkanes and other aliphatic compounds in a selective way, metal catalyzed borylation reactions were shown to be of particular synthetic utility. These methods have recently acquired an important role in organic chemistry research, and numerous studies have been undertaken on directed and undirected borylation of Csp2 —H and Csp3 —H bonds [52]. Such interest in these methodologies can be partly attributed to the synthetic versatility of organoboranes, which can be easily transformed into a variety of functionalities. In this section we will describe the strategies for regioselective non-directed borylation of unactivated remote C—H bonds. Undirected borylations of benzylic positions [53], methylsilanes [54], and methane [55] do not fall in the scope of this chapter, and will therefore not be treated. In 2000, based on previous observation with stoichiometric metal complexes and photochemical reactions, Hartwig and co-workers reported a RhCp* -catalyzed borylation of linear alkanes using diboranes as reagents, and occurring selectively at primary carbons (Scheme 12.18). Among the primary methyl positions, it was observed that the least hindered was selectively functionalized, and slower reaction was observed for hindered methyl groups in the absence of other reactive sites (e.g. methylcyclohexane) [57]. The accepted catalytic cycle for this transformation involves an initial oxidative addition of the diborane to the Rh catalyst to give a Rh–bis(boryl) complex, followed by oxidative addition of the alkane, resulting in an Rh–alkyl intermediate, which finally undergoes reductive elimination to release the desired product. An analogous process can occur with the HBpin formed as a by-product. The mechanism reported in Scheme 12.19 accounts for both reactions with B2 pin2 and HBpin. Alkanes

Ethers/fluorides/amines

O B

O

Cat. 1 (5%): 5 h, 84% Cat. 2 (5%): 25 h, 88%

R

n

H

B2pin2, Rh cat.

Cat. 1: Cp*Rh(C2H4)2 Cat. 2: Cp*Rh(η4-C6Me6)

F

Second site O

B

Neat, 150 °C

O B

O

Cat. 1 (2.5%): 30 h, 73% Mixture 5 : 1 O B

O B O O Cat. 2 (5%): 24 h, 91%

O

Cat. 2 (5%), 140°C: 12 h, 83%

N

O B

O

O

Cat. 2 (6%): 80 h, 49%

Cat. 2 (5%): 24 h, 55%

Scheme 12.18 RhCp*-catalyzed selective borylation of primary, non-hindered Csp3 —H bonds in aliphatic compounds.

363

364

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds

R Bpin Reductive elimination

Y Bpin [Cp*Rh]H(X)

Oxidative addition

X–Bpin, R–H [Cp*Rh]L2

[Cp*Rh]H(X)(R)(Bpin)

X, Y = H or Bpin

Oxidative addition R H

Scheme 12.19

[Cp*Rh]H(X)(Y)(Bpin) Reductive elimination [Cp*Rh](X)(Bpin)

HY

General mechanism for the Rh-catalyzed C–H borylation of alkanes.

This transformation necessitates bulky ligands on the Rh catalysts, and the selectivity for non-hindered primary positions is determined mostly by steric reasons. In particular, it was later found that the formation of a primary Rh–alkyl species is favored over an analogous secondary Rh–alkyl species, and the energy barrier for the C—B bond formation is lower for primary than secondary carbons [58]. Different Rh catalysts proved effective for this transformation, provided that a bulky Cp* ligand was present. Some ligated organic species in the catalyst (e.g. ethylene in Catalyst 1, Scheme 12.18) led to side products and reduced the stability of the catalyst. Catalyst 2, featuring a hexamethylbenzene ligand, albeit less reactive, proved more stable, and was therefore preferred for following studies [57]. Both B2 pin2 and the resulting by-product HBpin (to a less extent) proved able to act as borylating agents. This is a general feature of these transformations, although the efficiency of HBpin as reactant is substrate-dependent [56]. B2 pin2 is most often used as limiting reagent, and yields above 100% are sometimes encountered in literature reports. This is an indication of the further reaction of the excess substrate with the HBpin by-product formed in situ. Subsequent research demonstrated that analogous selectivity at primary C–H carbons could be obtained for functionalized aliphatic compounds, including alkylamines, ethers, and alkyl fluorides (Scheme 12.18) [56]. For these compounds, no functionalization of methylenes, including those α to the heteroatom, was observed (halogens also have a slight weakening effect on the α C—H bond, see Table 12.1). The selectivity of borylation in heteroatom-containing molecules with more than one potential (primary) borylation site is dictated by different factors. With the Rh catalyst Cp* Rh(𝜂 4 -C6 Me6 ), it was observed that the reaction occurred preferentially at the primary C—H bonds closer to the heteroatom. For example, functionalization of the ethyl chain was favored over the butyl chain in butyl ethyl ether, and ethyl over propyl in tertiary amines (Scheme 12.20, top) [56]. Similar selectivity was observed using an electron-rich Ir catalyst subsequently developed (Scheme 12.20, bottom). For both amines and ethers, borylation at a primary β position (non-hindered) was favored over γ or δ (ethyl vs. propyl or butyl chains). This method is therefore complementary to the oxidation of ammonium ions, where functionalization occurs at

12.3 Reactions Occurring via Formation of Metal–Carbon Bonds

R

H

n

B2pin2, Cp*Rh(η4-C6Me6) 5%

N

O 1°, β

Neat, 150 °C

1°, δ

1°, β

β:δ = 4 : 1

1°, γ

β : γ = 1.5 : 1

B2pin2,

R

H

n

(η6-mes)Ir(Bpin)3 4%, Me4phen 2–4% Neat, 100–120 °C

Ethers

Amines O

O 1°, γ

1°, β

1°, β

146%, β : γ = 85 : 15

1°, δ

1°, α

O 1°, β

1°, β, hindered

1°, δ

O

1° , β

77%, α : β = 100 : nd

1°, α

1°, δ

1°, β

1°, γ

69%, γ : α = 96 : 4

N

O

1°, β, hindered

1°, β

84%, β : α = 100 : nd

112%, β(Et) : β(tBu) = 100 : nd

1°, α

N

N

130%, β : δ = 87 : 13

N 1°, γ

108%, β : γ = 83 : 17

1°, β

1°, δ

129%, β : δ = 86 : 14

70%, β : δ = 100 : nd

Scheme 12.20 Selectivity among different primary C—H bonds in Rh- and Ir-catalyzed borylation of ethers and alkylamines.

further positions (see Section 12.4.1). Methyl groups α to the heteroatom showed some differences: while for amines the α methyl was less reactive than the β, for ethers a similar reactivity was observed, albeit decomposition of α functionalized products led to lower observed yields. Hindered methyl groups showed no reactivity (Scheme 12.20) [59]. While the main reason for the selectivity towards primary C—H bonds over secondary and tertiary has to be found in the repulsive steric interactions between substrate and catalyst, the preference for primary carbon β to the heteroatom over those in further positions was proposed to be due to a particular transition state conformation, where the heteroatom in the amine or ether substrate lies directly above the boron atom in the catalyst, giving rise to weak interactions that promote the cleavage of β C—H bonds (see also Scheme 12.21) [59]. Despite the high selectivity for primary C—H bonds in linear alkanes, the Ir catalyst (𝜂 6 -mes)Ir(Bpin)3 in combination with 3,4,7,8-tetramethylphenanthroline (Me4 Phen) was found to promote borylation of a secondary C—H bond in cyclic ethers, in this case selectively at the β position to the oxygen atom (Scheme 12.21) [61]. Based on competition experiments, the authors proposed that the Lewis basicity of the oxygen atom in the substrates played a crucial role in the reaction, as functionalization proved favored for more basic substrates. The crucial role of the oxygen was demonstrated by the functionalization of cyclohexane, which required

365

366

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds

O B2pin2, (η6-mes)Ir(Bpin)34%, Me4phen 2–4%

O n

Neat, 120 °C, 14 h

O

O Bpin

Bpin

Bpin 83% O

90%

72%

Bpin OBz

Bpin Cyclohexane 39% (140 °C)

63% Initially suggested origin of the β selectivity: Six-membered transition state:

H N

O

Ir

N Bpin

Scheme 12.21

Lewis base/acid interaction

O

H

Bpin

N

Bpin

N

Ir

Bpin Bpin

Bpin

Selective borylation of secondary β C—H bonds in cyclic ethers.

increased temperature and catalyst loading, and gave considerably lower yields. A six-membered transition state, where the oxygen atom coordinated to the boron atom, was suggested to explain the selectivity (i.e. selectivity determined during the C–H activation step, Scheme 12.21, bottom) [61]. Recent theoretical mechanistic studies, however, attributed this selectivity to the reductive elimination instead, calculated to be the rate-determining step in the catalytic cycle [62]. The transition state for the reductive elimination was calculated to be lower in energy for the β functionalization than for the α, and the electronic properties of oxygen were deemed crucial in lowering the energy of this transition state. After the successful functionalization of cyclic ethers and cyclohexane, the borylation of secondary C—H bonds in cyclopropanes was also demonstrated by Hartwig and co-workers. The use of (𝜂 6 -mes)Ir(Bpin)3 in combination with 2,9-dimethylphenanthroline resulted in the borylation of functionalized cyclopropanes in good yields and trans diastereoselectivity, under even milder conditions than those necessary for the borylation of cyclic ethers (Scheme 12.22) [60]. The diastereomeric ratio (dr) observed is dependent on the steric bulk of the functionality present in the cyclopropane substrates, in line with the sterically-controlled substrate–catalyst interaction governing the selectivity. Further investigation on the borylation of unactivated C—H bonds have appeared since the first report of Hartwig and co-workers in the field [53b, 63]. Particularly worth noting is the observed acceleration of Ir-catalyzed borylations by catalytic amounts of bases such as KOtBu [64]. The role of the base was speculated to be the activation of the B2 pin2 reagent, thus accelerating its reaction with the catalyst, or alternatively the deprotonation of the ligand (Me4 Phen), altering the electronic properties of the catalyst.

12.4 Altering Innate Reactivity by Polarity Reversal Strategies

O

Br Bpin 81%, dr 97 : 3

R

B2pin2, (η6-mes)Ir(Bpin)3 4–6%, 2,9-Me2phen 4% THF, 90–100°C, 12 h

C10H21 Bpin

Bpin 96%, dr 96 : 4

57%, dr 90 : 10

EtOOC

MeOOC Bpin

NC

Bpin

52%, dr 85 : 15

76%, dr 83 : 17 MeOOC

NC Bpin

Bpin

MeOOC 67%, dr 76 : 24

Scheme 12.22

76%, dr 64 : 36

Ir-catalyzed borylation of secondary C—H bonds in cyclopropanes.

12.4 Altering Innate Reactivity by Polarity Reversal Strategies In recent years, apart from the development of new methods for selective functionalization of unactivated C—H bonds, strategies to alter the innate reactivity of aliphatic substrates have also been discovered. An important one is based on the activation of certain C—H bonds, or the deactivation of others by altering the electronic properties of the functional groups present in the substrates. This can be done by acid–base interactions or by hydrogen-bonding. These strategies have been collectively referred to as “polarity reversal” [65]. In the framework of C–H functionalization, these methods have been mostly applied to processes occurring via HAT, but they can be also be exploited for other methodologies, such as the Shilov oxidation method (vide infra). As the HAT reagents and metal species responsible for the cleavage of the C—H bonds are mostly electrophilic in nature, the polarity reversal concept will be illustrated for such reactions (Scheme 12.23). The interaction of an existing functional group in the substrate with a hydrogen bond donor or an acid (either Lewis or Brønsted) results in a (partial) positive charge on the functional group. The positive charge will generate an inductive electron-withdrawing effect on the proximal C—H bonds, which will become more electron-poor. This results in an increase of the BDE of these C—H bonds, and a more difficult cleavage by electrophilic species. The electron-withdrawing effect of the positive charge will extend to C—H bonds even further away than the α positions, and functionalization of remote, i.e. γ or δ, C—H bonds, is thus often observed. Several kinetic studies have been reported that demonstrate the deactivation of proximal C—H bonds towards HAT processes upon Brønsted and Lewis acids addition [66]. The effect in aliphatic substrates is

367

368

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds Hydrogen bond donor or Lewis/Brønsted acid

Deactivated toward electrophilic attack H–D

Y H D δ+ δ–

Deactivated toward electrophilic attack

Y H+

Effect exerted beyond the α position of Y

Y H

Functionalization at more remote positions Y = NH2,NHR, NR2,OH, OR, C(O)H, NHC(O)R, NRC(O)R

Hydrogen bond acceptor or base

Activated toward electrophilic attack A

Y H A δ– δ+

Activated toward electrophilic attack

YH B–

Scheme 12.23

Selective functionalization α to Y

Y

Y = CO2, O, NC(O)R, NH, NR

Activation and deactivation of C—H bonds via polarity reversal strategies.

significant in absolute values due to the full (or partial) positive charge present in the substrate, in comparison with EWGs featuring only dipoles. On the contrary, the generation of a (partial) negative charge on the functional group by the action of a hydrogen bond acceptor or by a base will result in a higher electron-density in the proximity of the functional group, making proximal C—H bonds more easily cleaved by electrophilic species. In this case, a decrease of the BDE values is observed. The BDEs of α C—H bonds for amines and alcohols upon protonation/deprotonation or upon coordination to metal ions (Lewis acids) have been calculated in several cases, showing considerable increase or decrease with respect to the neutral substrate (examples in Scheme 12.24) [67]. As this chapter is focused on remote functionalization, only examples of deactivation of proximal C—H bonds will be treated here. Examples of the activation of proximal positions (α functionalization) can be found in a recent review by Bietti [65b].

12.4.1 Remote Functionalization of Aliphatic Amines via Quaternary Ammonium Salts Aliphatic amines, amides, and other nitrogen-containing compounds are important moieties in organic synthesis, and their direct functionalization is therefore an important area of research. Nonetheless, selective C–H functionalization of such compounds presents several challenges. Non-directed C—H bond activation and

12.4 Altering Innate Reactivity by Polarity Reversal Strategies BDEs (kcal/mol–1) for neutral, deprotonated, and protonated butanol α, favoured 95.9

99.6

79.4

96.2 OH

102.5

γ, favoured

α, favoured

101.1

100.1

106.8

O 100.1

99.6

OH 2

n.d.

103.9

ΔG values (kcal/mol–1) for HAT between alcohols and ethers and the phenyl radical

–17.2

–19.4

O O

–37.7

–33.7 O

O

O

OH

O

O

O

O

Na

O

Scheme 12.24 Comparison of BDE values and/or ΔG values for HAT of C—H bonds under neutral and polarity reversal conditions.

functionalization in aliphatic amines and amides typically occurs at the α position to the N atom [68], as these bonds show the weakest BDE in the molecule (Table 12.1), while more remote C—H bonds show stronger BDEs and are more challenging to activate. Another important problem of N-containing molecules is that reaction with oxidants, necessary for the C–H activation, often results in N-oxidation, with formation of N-oxides. To achieve remote functionalization on these compounds, group-directed protocols are typically employed. Alternatively, the introduction of EWG groups on the N-moiety has the effect of strengthening the BDE of the C—H bonds in proximity to the nitrogen [4a]. However, only one EWG group (amides) is often not enough to promote remote functionalization, and the use of two EWG groups (imides) is necessary to achieve remote functionalization in the absence of any additive, basically limiting this method to primary amines [69]. Moreover, the introduction of an EWG group onto an amine requires two extra synthetic steps (introduction and cleavage), and is not always the most convenient way for synthetic purposes. Polarity reversal strategies are therefore used to achieve remote functionalization in aliphatic amines and amides, while suppressing functionalization at the α position. In particular, simple protonation is mostly used (Scheme 12.25), rather than hydrogen bond strategies. This method has also the advantage of suppressing N-oxidation, thanks to the formation of quaternary ammonium ions. Interestingly, while strong deactivation of proximal C—H bonds is observed in amines and amides, a much weaker effect is observed in alcohols or ethers, due to their lower basicity [66h]. Alteration of selectivity in such compounds can instead be more conveniently achieved via hydrogen bond methods (see Section 12.4.2). Several publications on selective remote functionalization of aliphatic amines and amides have now appeared, and while the basic principle remains the same, different acids, catalysts, and/or oxidative systems have been used to tune the selectivity of the different C—H bonds in the substrates. Most of the transformations reported with these methods are C–H oxidations to alcohols and ketones.

369

370

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds Neutral conditions:

N R

n

R

Acidic conditions:

O N R

n

Oxidation

R N R

n

R

O

(1) H+

n

(2) Oxidation

and/or

O N R R

n

via n

N R

R

R N R H

Scheme 12.25 Example of selectivity of C–H oxidation in aliphatic amines under neutral or acidic conditions.

An initial report on the selective oxidation of aliphatic amines came from Asensio’s group in 1993. In this seminal work the oxidation of a variety of aliphatic ammonium tetrafluoroborate salts with the reactive oxidant TFDO was investigated (Scheme 12.26) [70]. TFDO is known for its general selectivity toward tertiary C—H bonds, however, only tertiary C—H bonds in the γ or δ positions to the amine were functionalized, while primary and secondary C—H bonds were generally unreactive. More importantly, even tertiary C—H bonds in proximity to the heteroatom (α or β) could not be functionalized, due to the deactivating effect of the ammonium ion. Hexyl-, heptyl, and octylamine resulted instead in the selective formation of tetrahydropyridines; these products were suggested to derive from a selective ketone formation at the 𝜀 position, followed by intramolecular condensation. As more remote methylenes were oxidized preferentially in tetra-alkylammonium salts, the OH

HO O O

n

N R

R

(TFDO) F3C HBF4 (pH 2–3)

3°, δ

HO

98%, 3 h

3°, γ

N

NH2

3°, γ

98%, 5 h

N H 99%, 15 h

Unreactive substrates:

MeCN, 0 °C

NH2 3°, β

n n = 0–2

NH3

n

2°, ζ

NH2

3°, β NH2

2°, ε

O NH2

3°, α

N

n 90–95%, 8 h

ε

NMe3

NMe3

ζ:ε = 60 : 40

O

Scheme 12.26 Oxidation of remote tertiary and secondary C—H bonds in aliphatic amines by TFDO under acidic conditions.

12.4 Altering Innate Reactivity by Polarity Reversal Strategies

formation of such rings was proposed to be promoted by specific hydrogen bonding interactions between TFDO and the ammonium salts [70]. Following this methodology, and inspired by the work of Shilov and co-worker in the 1970s (see Section 12.3.1) [49a], Sanford and co-workers reported in 2015 the combination of Pt catalyst and CuCl2 as oxidant for the remote hydroxylation of aliphatic amines (Scheme 12.27) [71]. Ruled by steric hindrance and thermodynamic effects, Shilov chemistry is more selective towards primary C—H bonds [72], and completely different selectivity was observed than in the reaction with TFDO. By increasing the chain length in N-alkylpyrrolidines, generally higher yields of hydroxylated products were observed, whereas shorter chain lengths resulted in lower yields, but with higher selectivity (yields higher than 100% were due to the reoxidation of the Cu salt, used as limiting reagent, by atmospheric oxygen). These results reflect the overall deactivation of C—H bonds upon protonation, especially in the α and β positions. So far, this is the only example of functionalization of primary C—H bonds making use of this strategy. ζ

n

5 equiv

N R

K2PtCl4 5%, CuCl2 1 equiv R H2SO4 1.1 equiv

Piv

N

N

β

1°, η 65%, η:ζ = 5 : 1

H2O, 150 °C, 24–48 h

1°, γ

OH

OH

90%, γ:β = 14 : 1

Unreactive substrates (hindered): 1°, β

HN

1°, ε

N

β

β

OH

N α 25% β:α = >20 : 1

N

δ

OH γ

85% γ:β = 10 : 1

N

δ

OH

γ

126% δ:γ = 4 : 1

OH ε

N 73% ε:δ = 2 : 1

Selectivity

Scheme 12.27 Oxidation of remote primary C—H bonds in aliphatic amines via Pt-catalyzed Shilov chemistry.

Benzylic C—H bonds, although featuring relatively low BDEs and thus being cleaved more easily than other secondary C—H bonds, are still comparable with available α C–H in aliphatic amines with respect to BDE values (Table 12.1). Sanford and co-workers reported further remote oxygenation methods via an uncatalyzed reaction with potassium persulfate, and an iron-catalyzed reaction with tert-butyl hydroperoxide as oxidant (Gif chemistry) [73]. These protocols resulted in the selective functionalization of remote benzylic positions, even in the presence of tertiary C—H bonds or analogous benzylic and allylic positions in closer proximity to the

371

372

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds

N atom (Scheme 12.28). It is worth noting that a certain complementarity between these two methods was observed. For example, N,N-dimethyl-2-phenylethylamine could not be oxidized via Gif chemistry, whereas 57% of the ketone was obtained using persulfate. The use of persulfate resulted, in some instances, in mixtures of alcohols and ketones, whose ratio can be influenced by the amount of oxidant used. As such mixtures are often obtained in C–H oxygenation protocols, the potential selectivity tuning is of interest in synthesis. Finally, applications to the synthesis or modification of bioactive molecules such as Sedaminone and Melperone, were demonstrated with Gif oxidation [73b].

Ph

N R

n

R

K2S2O4 2 equiv, H2SO4 2.2 equiv.

NH2

O

n

N R

H2O, 80 °C, 2 h

Remote Bn

FeCl3 5%, tBuOOH, picolinic acid 12.5% R TFA 1.1 equiv. Pyridine/MeCN, rt, 48 h

β

NMe2 Ph

57% (4 equiv. K2S2O4)

O

O Ph

Ph ζ

N 47%

ζ

Ph

N NMe2

N 54% O

O

Unreactive substrates: α β Ph

NMe2

Ph 61% (alcohol:ketone = 0.94 : 1)

Ph

O

Ph

γ Sedaminone, 48%

N δ Melperone, 52%

F

Scheme 12.28 Oxidation of remote benzylic C—H bonds in aliphatic amines using potassium persulfate or Fe-catalyzed Gif oxidation.

In 2015 White and co-workers demonstrated the use of Fe(1,1′ -bis(2-pyridylmethyl)-2,2′ -bipyrrolidine [PDP]) complexes, previously developed for related C–H functionalizations [74], as possible catalysts for the C–H oxidation in amines and alkylpyridines at remote tertiary carbons [69a]. Brønsted acid HBF4 or Lewis acid BF3 ⋅Et2 O were used to activate these substrates (Scheme 12.29). Protonation by HBF4 is preferred in cases of hindered tertiary amines, while pre-formed amine-BF3 adducts proved more convenient for secondary and primary amines, due to their easier purification. The BF3 adduct, remained intact at the end of the reaction, could be cleaved by basic hydrolysis or by reaction with fluoride sources. A range of differently substituted 2- and 4-alkylpiperidines, common moieties encountered in drug-like molecules [68], were hydroxylated at remote tertiary positions in high yields, with ring hydroxylation (in γ) only obtained in case of no other available sites, due to the altered BDE values. Alkyl-substituted pyridines were also treated in the same manner. While several [75], including acid-promoted [76], functionalizations of alkylpyridines at the picolinic position have been recently reported, selective functionalization at a remote tertiary position

12.4 Altering Innate Reactivity by Polarity Reversal Strategies OH Fe(PDP) or Fe(CF3PDP) 5%, H2O2, HBF4 or BF3·Et2O 1.1 equiv R

N R

R

(SbF6)2

N Fe N

(+HBF4)

N H BF3 (preformed)

NCMe

N

N R

R = 2,6-diCF3Ph Fe(CF3PDP)

OH

MeCN

TfO

R

–COOEt –COOEt –CH2CN –CH2CN

Yield 55% 54% 58% 60%

Yield

–H –Me

(+HBF4)

Fe(PDP) or Fe(CF3PDP) 5%, H2O2, HBF4 or BF3·Et2O 1.1 equiv

N

HBF4 preformed HBF4 preformed

OH

or

NCMe

R

R

N

R=H Fe(PDP)

N

R

R or

MeCN R

OH

56% 52%

2–Pyridine 59% 3–Pyridine 50% 4–Pyridine 57%

N TfO

From Abiraterone acetate analog

N Me

H

N

H

Me

N

H

HO O

45% (ketone:alcohol = 2.5 : 1)

From Dextromethorphan derivative

H

AcO

H

OH 42% (alcohol:ketone = 6 : 1)

Scheme 12.29 Remote C–H oxidation of aliphatic amines using Fe(PDP) complexes in combination with hydrogen peroxide.

was obtained using Fe(PDP) complexes with HBF4 or BF3 activation, demonstrating interesting complementary chemoselectivity (Scheme 12.29) [69a]. The Fe(PDP) catalyst was further tested on the remote oxidation of C—H bonds in derivatives of Dextromethorphan and Abiraterone acetate, resulting in remote oxygenation products in 42–45% yield [69a]. Similar results and selectivity on alkylamines and alkylpyridines were obtained by Sigman, Du Bois, and co-workers using a Ru catalyst, employing periodic acid as oxidant and triflic acid as remote activator [77]. Fe(PDP) catalysis was later also investigated for the functionalization of amides by the White group. Although amides are inherently more electron-withdrawing than amines, they are significantly less basic, and remote oxidation via protonation is not necessarily achieved. In this case, not surprisingly, either Lewis or Brønsted acids proved inefficient, and methyl triflate was used as additive, giving imidate salts in situ and hereby promoting remote functionalization at tertiary and secondary C—H bonds in good yields (Scheme 12.30) [69b]. While the protonation of amine groups allows the functionalization of remote positions with higher selectivity with respect to proximal positions, the selectivity

373

374

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds

OH

O

59%

R= O

R

N

56% R=

O n

N R

MeOTf 1.2 equiv., Fe(PDP) or Fe(CF3PDP) 15–25% H2O2, AcOH R MeCN via

O R=

R N

n R= n = 1–4

OMe n

N R

OH

O R

N H

H O

O 43%

H

O

N Me

OTf H

52–55%

O

O

54–58%

O

55%

H N Me

54%

Scheme 12.30 Oxidation of remote tertiary and secondary C—H bonds in aliphatic amides via formation of imidate salts.

beyond a certain distance from the ammonium group is lost, as the inductive deactivating effect fades away with distance. This aspect has been addressed by research from Costas, Di Stefano, and Olivo, making use of manganese catalysis, also successfully used in a variety of oxidations with PDP or related ligands [78]. These authors reported a selective C8–C9 oxidation (ketones) in long chain aliphatic ammonium ions, under similar conditions to those employed by White and co-workers. Their approach was based on the supramolecular interaction of the protonated amine with a benzocrown (BC) ether moiety attached to the PDP ligand (PDP–BC), essential to bring the C8–C9 position in proximity to the Mn atom (Scheme 12.31) [79]. Oxidation at C8 and C9 in long-chain ammonium salts occurred, with this system, with much higher selectivity than at the other positions in the chain. The use of unsubstituted Mn(PDP) resulted in much lower selectivity and almost statistical distributions of products, especially in positions beyond C8 [79a]. A photochemical remote amine functionalization was recently reported by Schultz et al. (Scheme 12.32) [80]. Here the photochemical HAT chemistry of the decatungstate anion [11a] was employed to generate a radical at the β and γ positions of protonated (cyclic) amines, subsequently quenched by H2 O2 to give oxidized pyrrolidines, piperidines, and other amines. Importantly, with this methodology, no hydroxylation is obtained, and oxo-functionalized chains were obtained selectively. One-pot derivatization of the oxidized products furnished N-protected amines or newly formed imine functionalities. All the functionalizations reported so far were oxidations to alcohols or ketones. Although this is what most of the literature on the topic has been focused on until now, a publication from Renaud and co-workers demonstrates the possibility of C—C bond formation via protonation of propargylamines and subsequent radical

12.4 Altering Innate Reactivity by Polarity Reversal Strategies

C9

C8 NH3BF4

O O H H O O H NO O

C13–C10 C9

C8 C7–C5

1.5–6% 19% 26% 3–1% NH3BF4

N N

C11–C10 C9

OTf

7–9%

Mn

C8

OTf

N

C8 C7–C5

17% 21% 4–1%

N

NH3BF4 C9

C10

O O

Mn(PDP)

C9

C8 C7–C5

14% 18% 20% 6–1%

O O O

O

NH3BF4 C9

C8 C7–C5

16% 13% 5–0.5%

Mn(PDP–BC)

Scheme 12.31 Supramolecular interaction between Mn(PDP–BC) and long-chain alkylammonium ions allowing regioselective secondary C–H oxidation.

NaDT 1%, H2SO4 1.5 equiv., H2O2 2.5 equiv.

H N n

MeCN/H2O, rt, hv 360 nm, 2 h

43%

γ O

34%

Boc N γ O

H N γ

43%

H2 N 4–

H N or n

O

n

N R

COOH

O

NHBoc

43% NOBn

Me γ

COOMe 26%

DT (decatungstate) = [W10O32]4–

wO

[W10O32] *

HAT

hv

[W10O32]4–

R N

Derivatization

n

O

Boc N

Boc N β O

HSO4 H H N

H+ [W O ]5– 10 32

n

H2 N n

H2 N

H2 N HOO

n

O

n

Reoxidation

Scheme 12.32 Photochemical decatungstate-catalyzed oxidation of remote secondary C—H bonds in aliphatic amines.

375

376

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds EtO

N R R

AIBN 2 equiv PhSH2 equiv R CF3COOH 10 equiv

R N

R

R

SPh

82%

MeCN, reflux

R

R

R H N

R

PhS• R

R

Radical addition

R

63%

N

SPh

R

70%

R

R H N

R •

R

1,5-HAT

SPh

SPh

R H N

Translocation R

R

OEt

N

80%

R

N

R •

R

R Cyclization

R H N

R R

R R

SPh SPh

PhS H

SPh

Without acid: R R

R

R

R PhS•

N R

R

R

R R

N R

•

R

Complex mixture of products

Scheme 12.33 C—C bond formation via amine protonation and radical addition-translocation-cyclization (RATC).

addition-translocation-cyclization (RATC) initiated by AIBN and thiophenol (Scheme 12.33) [81]. In the absence of trifluoroacetic acid, a complex mixture of products derived from the formation of the undesired α radical was obtained. Suppression of homolytic α C–H activation resulted in high yields of the desired pyrrolidines.

12.4.2 Remote Functionalization of Alcohols and Amides via Hydrogen Bond Interactions The use of a hydrogen bond donor to alter the selectivity of C–H functionalization reactions is less exploited than actual protonation, and the effect observed is weaker, as only a partial positive charge is introduced in the system. A few examples of this method have been published. This is especially useful for weakly basic functionalities, such as alcohols and amides. In the case of alcohols, HAT processes normally result in the formation of ketones (oxidation of the C—O bond). The deactivation of the α C–H position will therefore alter not only the regioselectivity, but also the chemoselectivity of the process, preventing overoxidation of alcohols to ketones, which has potentially great use in synthesis. While a few examples of altered chemoselectivity in C–H oxidation have been reported by the use of strong hydrogen bond donors [82], the functionalization of remote positions in aliphatic alcohols has been more rarely investigated. Costas, Bietti, and co-workers reported in 2017 the use of Mn(MPC) catalysts for the oxidation of aliphatic alcohols, amines, and amides in both MeCN and HFIP (1,1,1,3,3,3-hexafluoro-2-propanol) as solvent. In MeCN the oxidation of alcohols

12.4 Altering Innate Reactivity by Polarity Reversal Strategies OH

Mn(TIPS–MCP) 0.5% H2O2, AcOH R n

O

MeCN or HFIP 0 °C, 1 h

OH

O

HO

MeCN HFIP

OH 70% / 0% 5% / 49%

MeCN HFIP

OH

O

OH OH

MeCN HFIP

60% / 1% 9% / 41%

76% / 0% 48% / 12% N

HO

Mn

OTf OTf

N

77% / 4% 8% / 56%

R1

OH MeCN HFIP

Scheme 12.34 alcohols.

R3

OH

OH MeCN HFIP

R2

N N

O O

R1

6% 0%

R3 R2

R1, R2 = H, R3 = Si(iPr)3 Mn(TIPS–MCP)

/ 0% / 75%

Effect of hydrogen bond donor HFIP on the selectivity of oxidation of

resulted selectively in the formation of the corresponding ketones, without further functionalization at remote positions in the aliphatic chain (Scheme 12.34). Under the same conditions, using HFIP, a strong hydrogen bond donor, remotely hydroxylated products (diols) were obtained, together with smaller amounts of ketones (Scheme 12.34). The formation of ketone is suppressed as a consequence of the BDE increase of the C–H bond α to the oxygen, due to hydrogen bonding. Although the results were dependent on the structure of the alcohols, a net preference for remote functionalization over alcohol oxidation was demonstrated [82b].

N n R

HO

Mn(TIPS–MCP) or Mn(DMM–PDP) 1% H2O2, AcOH

O

NH O Boc

R MeCN or HFIP –40 or 0 °C, 30 min O

OH O N H

R O

MeCN HFIP

MeCN HFIP

N H

R

OH O N H

N R

MeCN or HFIP, 0 °C enhanced yield of remote functionalization

N

22% / 3% 0% / 46%

R2 R3 N Mn

N

O

HO R

MeCN HFIP

n

R1

OTf OTf

N

35% / 0% 16% / 51%

Mn(TIPS–MCP) 1% R H2O2, AcOH

N Boc

N H 65% / 1% 0% / 62%

R1 R

R3 R2

R1, R3 = Me, R2 = OMe Mn(DMM–PDP)

H2N

HO

N H

OH

31% (MeCN)

6% (MeCN)

54% (HFIP)

44% (HFIP)

Scheme 12.35 Effect of hydrogen bond donor HFIP on the selectivity of oxidation of amides and amines.

377

378

12 Non-Directed Functionalization of Distal C(sp3 )—H Bonds

Under similar conditions, the oxidation of amides in acetonitrile furnished hydroxylated products almost exclusively at the α position to the nitrogen, as expected from the BDE trends (Scheme 12.35). In contrast, hydroxylation of the most remote available secondary or tertiary C—H bond was preferentially obtained when the reaction was conducted in HFIP (Scheme 12.35) [82b]. The effect of MeCN and HFIP on the remote hydroxylation of two model amines was also briefly investigated. In both amines tested, a larger amount of remote oxidation product was obtained from the reaction in HFIP, thus demonstrating the proximal deactivation effect exerted by the hydrogen bond donor (Scheme 12.35) [82b].

Acknowledgments This work has been supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions (FlowAct, Grant No. 794072, granted to CS), COST action CA15106 (CHAOS – C–H Activation in Organic Synthesis), the Research Foundation-Flanders (FWO) (BioFact Excellence of Science project Grant No. 30902231), and the Francqui Foundation.

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70 Asensio, G., Gonzalez-Nunez, M.E., Bernardini, C.B. et al. (1993). J. Am. Chem. Soc. 115: 7250–7253. 71 Lee, M. and Sanford, M.S. (2015). J. Am. Chem. Soc. 137: 12796–12799. 72 Lersch, M. and Tilset, M. (2005). Chem. Rev. 105: 2471–2526. 73 (a) Lee, M. and Sanford, M.S. (2017). Org. Lett. 19: 572–575. (b) Mbofana, C.T., Chong, E., Lawniczak, J., and Sanford, M.S. (2016). Org. Lett. 18: 4258–4261. 74 Chen, M.S. and White, M.C. (2007). Science 318: 783. 75 (a) Hruszkewycz, D.P., Miles, K.C., Thiel, O.R., and Stahl, S.S. (2017). Chem. Sci. 8: 1282–1287. (b) Itoh, M., Hirano, K., Satoh, T., and Miura, M. (2014). Org. Lett. 16: 2050–2053. (c) Liu, J., Zhang, X., Yi, H. et al. (2015). Angew. Chem. Int. Ed. 54: 1261–1265. (d) Sterckx, H., Sambiagio, C., Médran-Navarrete, V., and Maes, B.U.W. (2017). Adv. Synth. Catal. 359: 3226–3236. 76 a) De Houwer, J., Abbaspour Tehrani, K., and Maes, B.U.W. (2012). Angew. Chem. Int. Ed. 51: 2745–2748. (b) Sterckx, H., De Houwer, J., Mensch, C. et al. (2016). Beilstein J. Org. Chem. 12: 144–153. (c) Sterckx, H., Sambiagio, C., Lemière, F. et al. (2017). Synlett 28: 1564–1569. (d) Sterckx, H., De Houwer, J., Mensch, C. et al. (2016). Chem. Sci. 7: 346–357. 77 Mack, J.B.C., Gipson, J.D., Du Bois, J., and Sigman, M.S. (2017). J. Am. Chem. Soc. 139: 9503–9506. 78 Milan, M., Salamone, M., Costas, M., and Bietti, M. (2018). Acc. Chem. Res. 51: 1984–1995. 79 (a) Olivo, G., Farinelli, G., Barbieri, A. et al. (2017). Angew. Chem. Int. Ed. 56: 16347–16351. (b) Olivo, G., Capocasa, G., Lanzalunga, O. et al. (2019). Chem. Commun. 55: 917–920. 80 Schultz, D.M., Lévesque, F., DiRocco, D.A. et al. (2017). Angew. Chem. Int. Ed. 56: 15274–15278. 81 Soulard, V., Dénès, F., and Renaud, P. (2016). Free Radical Res. 50: S2–S5. 82 (a) Gaster, E., Kozuch, S., and Pappo, D. (2017). Angew. Chem. Int. Ed. 56: 5912–5915. (b) Dantignana, V., Milan, M., Cussó, O. et al. (2017). ACS Cent. Sci. 3: 1350–1358.

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13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts Miquel Costas Universitat de Girona, Grup de Química Bioinspirada, Supramolecular i Catàlisi (QBIS-CAT), Institut de Química Computacional i Catàlisi (IQCC), Departament de Química, Campus de Montilivi, 17071, Girona, Spain

13.1 Introduction 13.1.1 Bioinspired Catalysis as a Tool for Site Selective C—H Bond Oxidation The selective oxidation of aliphatic C—H bonds is a class of reactions of relevance in the metabolism of aerobic organisms, but its implementation in chemical synthesis is limited because of the lack of reagents to perform this transformation with satisfactory levels of selectivity. Selective oxidations in aerobic organisms are at the basis of multiple functions including the biosynthesis of molecularly complex metabolites such hormones, antibiotics, neurotoxins, and neurotransmitters, and the detoxification of xenobiotics or the triggering of signaling paths, to name a few (Scheme 13.1) [5–15]. Besides their biological relevance, these reactions feature remarkable aspects from the perspective of organic synthesis. They can operate in strong C—H bonds, recognized as poorly reactive sites against contemporary reagents, and reactions proceed under the mild conditions inherent to living organisms. Most important and singular is the selectivity exhibited by some of these reactions; C–H oxidations can take place with exquisite site, chemo- and stereoselectivity in the presence of multiple C—H bonds and also in the presence of a priori more reactive functional groups. The ability of enzymatic active sites to govern substrate trajectories and substrate orientation by virtue of a network of weak interactions account for this unique selectivity properties. The ability to control site selectivity in oxidation of aliphatic C—H bonds has an enormous potential in synthesis. A number of organic molecules contain alkyl chains with numerous non-equivalent aliphatic C—H bonds. Oxidation of a particular C—H bond installs functionality at this site and enables its further manipulation by conventional organic transformations. Therefore, methods that enable targeting

Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

384

13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts Iron dependent enzymes

OH H

15-β mutant P450 BM3 O2, NADH

H

H

OH

O

H H OH

H O

Testosterone

(a)

O H H

H

OH KshAB (Rieske oxygenase) O2, 2e–

O (b)

H

4-Androstene-3,17-dione

Prolyl hydroxylase (α-KG oxygenase) H

O

HO H

O2, 2-oxo-glutarate

(c)

Copper dependent enzymes HO (d)

NH2 O2, ascorbic acid

HO

H

pMMO H H

O

OH Dopamine-β-hydroxylase

H (e)

H

OH O

O2, NAD(P)H

HO NH2

HO

OH H H H

Scheme 13.1 Representative selective C–H oxidations taking place in nature. Source: (a) Adapted from Kille et al. [1]. (b) Adapted from Capyk et al. [2]. (c) Adapted from Bruick et al. [3]. (d) Adapted from Creveling et al. [4].

of different C—H bonds in a molecule can provide different products from the same precursor, opening diverse paths for subsequent elaboration [16, 17]. Iron-dependent hydroxylases are the largest and more diverse family of enzymes that participate in C–H oxidation reactions. Representative examples are shown in Scheme 13.1. Heme dependent oxygenases have been the most widely studied family, being cytochrome P-450 the paradigmatic example [5, 7]. More recently, diverse families of non heme iron dependent oxygenases including Rieske oxygenases [12, 18] and α-ketoglutarate dependent oxygenases [9, 13] are gaining attention. These enzymes do not contain the heme cofactor but

13.1 Introduction

instead iron centers ligated to the protein by means of carboxylate and imidazole residues. Despite of their structural diversity, the mechanism by which these enzymes activate O2 and oxidize aliphatic C—H bonds shares key mechanistic features (Scheme 13.2) [7, 19]; in first place, O2 is activated by means of its partial reduction, eventually splitting the O—O bond and forming hypervalent iron oxo reactive intermediates. This process requires the injection of two extra electrons either from an electron chain or from oxidation of a co-substrate. Alternatively, for some specific enzymes, 2e− oxidants such as peroxides may also be an alternative to yield the reactive iron–oxo species [6, 20]. In second place, oxidation of the C—H bond is initiated by a hydrogen atom transfer (HAT) from the substrate to the iron–oxo species. The consequence is that site selectivity in these reactions is governed by the relative HAT reactivity of the different C—H bonds of the substrate with the iron–oxo reactive species. H n+

Fe

O2 + 2e– or H2O2

O Fen+2

R

R″ R′

OH Fen+1 R

R″ R′

Fen+ + R

OH R″ R′

Hydrogen atom transfer

Scheme 13.2 Basic mechanistic scheme of C–H oxidation by mononuclear iron enzymes. Source: Ortiz de Montellano [7] and Costas et al. [19].

A second group of enzymes that has served as inspiration motif for the development of synthetic oxidation catalysts is copper dependent oxygenases. Mono and dicopper dependent oxygenases are known to participate in the oxidation of substrates containing strong aliphatic C—H bonds [14, 15]. Dopamine-β-hydroxylase (DβH) [4] and particulate methane monooxygenase (pMMO) [21] are paradigmatic examples (Scheme 13.1). Their mechanism of action is much less understood than in the case of iron oxygenases and most likely differs in a substantial manner. For example, it is highly unlikely that terminal copper–oxo type of species analogous to the iron oxos are formed. However, the basic mechanistic scheme of these enzymes also entails the reductive activation of O2 leading to powerful oxidizing species. The current understanding is that C–H functionalization by these enzymes, in analogy to iron dependent parents, also entails an initial HAT process. Consequently, governing site selectivity in aliphatic C–H oxidations requires understanding of the factors that govern HAT reactivity, as a first step toward the elaboration of methods that predictably alter the innate relative reactivity of the C—H bonds in a substrate.

13.1.2 Typology of Bioinspired Catalysts The unique C–H oxidation ability of metal dependent hydroxylases has prompted the development of small molecule synthetic catalysts that could emulate their

385

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13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

reactivity [5, 22–32]. Representative examples are shown in Scheme 13.3. Reproducing the typology of iron hydroxylases, two large groups of synthetic catalysts have been explored, differing in the type of ligands. Porphyrin complexes (Scheme 13.3a) were the first type of artificial C–H oxidation catalysts explored that exhibited reactivity and selectivity properties congruent with enzymatic oxidations, and solid support for the involvement of hypervalent metal–oxos in their reactions was established [5, 35]. Instead, early studies on non-porphyrinic iron catalysts resulted in reactions governed by free diffusing oxygen centered radicals in Fenton type of processes [36, 37]. More recently, iron coordination complexes based in polydentate ligands containing at least one nitrogen donor heterocycle (Scheme 13.3b) have been identified, which in combination with carboxylic acids give rise to powerful yet selective C–H oxidation catalysts [25, 38, 39]. Their easier structural modification in comparison with porphyrins has permitted their rapid elaboration by implementing elements that exert some control in their selectivity properties. Iron complexes based in phtalocyanins [40] and tetraamido macrocyclic ligands (TAML’s) Scheme 13.3c [33, 34], have been also explored as C–H oxidation catalysts. In the case of the latter, the tetraanionic nature of the ligand results in iron–oxo intermediates with a tamed electrophilic character, which translates into oxidation reactions with outstanding selectivity toward the weakest C—H bond. In parallel, strong evidence has also been gained that these catalysts devoid of the porphyrinic ligation can also operate via the formation of hypervalent iron–oxo species [29, 41–43]. On the other hand, from early studies in porphyrinic systems, it was rapidly recognized that other metals such as ruthenium and manganese share with iron mechanistic features in catalytic oxidation reactions and excellent catalytic activity [5]. Manganese complexes with non-porphyrinic ligands (Scheme 13.3b,d) have also been shown

(a)

(b)

(c)

Ar

O Cl

N N

N

Ar

M

Ar N

N N

N

M

N

O2N

L

N

N FeIII N N

L

O

O N O

Ar M = Fe, Mn, Ru

M = Fe, Mn, L = labile ligand

(d)

(e) N O N

Mn N

Scheme 13.3

N H3CCN Cu

N R

n = 1 or 2 R′

Basic typology of C–H oxidation catalysts discussed in this chapter.

13.1 Introduction

to exhibit excellent catalytic activity and in some cases improved performance with respect to the analog iron systems [44, 45]. Drawing an analogy to copper enzymes, binding and activation of O2 at copper coordination complexes (Scheme 13.3e), has been also explored in order to create selective C–H oxidation methods [31].

13.1.3 Site Selectivity in Aliphatic C–H Oxidation: Basic Considerations The term remote is quite ambiguous when applied to aliphatic C–H functionalization reactions. These are poorly reactive bonds and in contemporary organic chemistry they are not considered as “classical” functional groups susceptible to standard chemical manipulation. However, C–H functionalization reactions obviously operate in C—H bonds, which must be then considered functional groups. One should keep in mind though that aliphatic C—H bonds differ from classical functional groups because their electronic properties influence only in a modest manner (inductive effects) the reactivity of adjacent groups. Keeping these considerations in mind, in analogy to other type of transformations, one may refer to proximal C–H functionalizations to reactions that occur in C—H bonds adjacent to a “classical” functional group. In this scenario, remote C–H oxidations refer to those reactions where the site of C–H functionalization is not adjacent to the functional group. However, since organic molecules contain multiple aliphatic C—H bonds, a number of remote C–H oxidation products are in principle possible. Furthermore, C–H functionalization reactions may operate in molecules that contain non-equivalent C—H bonds but do not contain any classical functional group. The question becomes even more complex because the reactivity of aliphatic C—H bonds not only depends on its proximity or lack of proximity to a “classical” functional group, but also instead quite often the relative reactivity of the C—H bonds in a given molecule depends on the interplay of a number of factors. Some of these factors are inherent to the substrate, for example, bond dissociation energies of the different C—H bonds. Others instead may be dependent on the nature of the reagent and are susceptible to manipulation. For example, the steric demand of the oxidation catalysts may exert a preference for C—H bonds that are more accessible. Therefore, the use of the terms proximal and remote becomes ambiguous. In order to avoid this ambiguity, in this contribution we will discuss the different factors that govern site selectivity in aliphatic C–H oxidation reactions with bioinspired catalysts. The concepts of proximal or remote will be used only in some specific cases where a functional group exerts a dominating effect. The chapter will focus first in the innate properties of C—H bonds that affect their reactivity. Then, the use of reagents to modify the relative reactivity of C—H bonds by reversing the polarity of electron releasing groups will be discussed. The last part of the chapter focuses in substrate recognition phenomena exerted by catalysts in order to govern site selectivity.

387

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13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

13.2 Innate Substrate Based Aspects Governing Site Selectivity in C–H Oxidations There is a currently a fairly good understanding of the factors that exert an influence in the relative reactivity of C—H bonds in HAT initiated C–H functionalization reactions [46, 47]. Most of these factors were originally identified by White and coworker in bioinspired C–H oxidations with the Fe(pdp) system [38, 48, 49], and allowed certain degree of predictability in the site selectivity of the oxidations of this system. Notably, most of these factors are shared by a number of radical and radical-like reagents, pointing toward a common C–H activation/cleaving step [47]. This initial step corresponds to a HAT from the substrate to the electrophilic oxidant. The factors are discussed in the following lines.

13.2.1 C—H Bond Strength This parameter represents one of the major factors dictating their relative reactivity. The bond strength is measured by the homolytic bond dissociation energy (BDE), that is, the energy necessary to break a generic R—X bond [50]. Benzylic, allylic, and C—H bonds that are adjacent to an heteroatom are characterized by relatively low BDEs (85.4, 87.0, and 92.1 kcal/mol for ethylbenzene, cyclohexene, and tetrahydrofuran, respectively, Scheme 13.4). Instead, aliphatic C—H bonds exhibit higher BDEs, comprising between 96 and 101 kcal/mol, being tertiary C—H bonds the weakest, followed by methylenic sites, leaving primary C—H bonds as the strongest among the series. While numerous examples exist nowadays of the oxidation of tertiary and secondary aliphatic C—H bonds with bioinspired catalysts, oxidation of primary aliphatic C—H bonds remains exceedingly rare [40, 51]. Benzylic

Allylic

α-Heteroatom H

H O 85.4 kcal/mol

87.0 kcal/mol

H

92.1 kcal/mol

Aliphatic 2º

3º

H

H

96 kcal/mol

Activated C–H bonds

H

98 kcal/mol

1º H

101 kcal/mol

Non-activated C–H bonds Reactivity in HAT

Scheme 13.4

Relative reactivity of C—H bonds against HAT agents on the basis of BDE.

13.2.2 Electronic Effects High-valent metal–oxos are electrophilic species and therefore their reaction with C—H bonds, entailing an initial HAT step, proceeds preferentially at the most electron rich C—H bond, assuming that other factors such as BDE and sterics do not exert a strong bias toward a different site. Consequently, electron-withdrawing groups deactivate proximal C—H bonds and promote oxidation to take place at

13.2 Innate Substrate Based Aspects Governing Site Selectivity in C–H Oxidations (SbF6)2

(a) Fe(pdp) (5 mol%) 3 × AcOH (0.5 equiv) H H2O2 (1.2 equiv)

N N Fe NCCH3 N NCCH3 N

OH

CH3CN, rt, 30 min

Fe(pdp)

Substrate

Entry

Remote

1 2 3 4

H

Isolated yield % (rsm)a

Major product

Proximal H

HO

X=H X = OAc X = Br X=F

48 (29) 43 (35) 39 (32) 43 (20)

1:1 5:1 9:1 6:1

X

X = OAc X = Br

49 (21) 48 (17)

29 : 1 20 : 1

R

X = CH3 X = OCH3

52 (18) 56 (32)

>99 : 1 >99 : 1

H

X

5 6

H

7 8

H

H

H

X

X

HO

H

R

HO

H

O

Remote: proximal

O

a

rsm = % recovered starting material

(b) H

Fe(pdp) (5 mol%) 3 × AcOH (0.5 equiv) H2O2 (1.2 equiv) CH3CN, rt, 30 min

γ

δ

γ = 22% δ = 50%

Mn(dMMpdp) (1 mol%) H2O2 (3.5 equiv) AcOH (13 equiv)

(c) O R

N H

CH3CN, –40 °C, 30 min R

β

MeO

O

O

O

O

O MeO

H

γ

β

MeO2C

δ

β = 9% γ = 14% δ = 43%

γ

O

δ = 2% γ = 53%

OMe O

OH

O +

N H

R

OH N H

Yields Proximal

Remote

Norm. ratio Prox/rem

R = CH3

66%

1%

33 : 1

R = CF3

7%

77%

1 : 22

N N Mn OTf N OTf N

OMe Mn(dMMpdp)

Scheme 13.5 (a) Effect of EWGs on site-selectivity in the oxidation tertiary C—H bonds. (b) Effect of EWGs on site-selectivity in the oxidation secondary C—H bonds. (c) Impact of electronic character of the amide moiety in site-selectivity. Source: (b) Modified from Chen and White [48].

remote sites. For example, the series of substrates shown in Scheme 13.5a presents two tertiary C—H bonds susceptible to hydroxylation. The oxidation of these substrates with the Fe(pdp) catalyst and hydrogen peroxide was described by White and Chen. In the simple hydrocarbon, both sites are equally oxidized (entry 1) [49]. However, when electron-withdrawing groups such as halides, esters, or carboxyesters are present, oxidation occurs selectively at the remote tertiary C—H bond (entries 2–8). A related scenario is observed in the oxidation of methylenic

389

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13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

Fe(pdp) (15 mol%) H2O2 (3.6 equiv) AcOH (1.5 equiv)

4 2

3

O

O

O

+

+

CH3CN, 25 °C, 30 min 21%

(a)

32%

17% N

(SbF6)2 F3C F3C

N N

N N

NCCH3

Fe

N

N

Si N OTf

Fe

N

OTf

N

NCCH3

N

Fe(TIPSpdp)

N F3C

Si Fe(CF3pdp)

N

F3C

(b)

N

Fe(TIPSmcp) O Catalyst H2O2

O +

OH +

Total yield (%) Fe(pdp) Fe(CF3pdp)

(c)

Catalyst H2O2

C3

AcO

Fe(pdp) Fe(CF3pdp)

(d)

NHNs

AcO 2 1 O

AcO

O

: :

1 2 OH

+ OMe

NHNs

Fe(pdp) Fe(CF3pdp)

O

H

Catalyst H2O2

O

: :

1 4

72% 71%

H O O O

H O O O

O (+)-Artemisinin Fe(pdp)

(f)

Fe(

pdp)

2 1

OH

H O O O

+ H

O

CF3

OMe

NHNs

O

O

(e)

2 10

OH +

85% 79%

Catalyst OMe H2O2

: :

1 1

79% 77%

O H

O O

O

76%

2

:

1

57%

1

:

11

13.2 Innate Substrate Based Aspects Governing Site Selectivity in C–H Oxidations

chains; oxidation concentrates at the most remote methylenic site from the electron withdrawing (EW) group (Scheme 13.5b) [48]. In these cases, the terminal methyl site is not oxidized because the C—H bond is too strong. Amides constitute a particularly interesting case since they can have electrondonating or electron-withdrawing character, and this has been shown to effectively determine site-selectivity in manganese catalyzed oxidations with the Mn(dMM pdp) catalyst [52]. Scheme 13.5c shows the case where the proximal position is a methylenic site that competes with the oxidation of a tertiary C—H bond at a remote γ-position. In the reaction of the acetamide, the α-CH2 position is activated toward oxidation, and the proximal hydroxylated product is preferentially obtained in good yield, while the remote oxidized product is observed only in very low amount. This can be explained because of a stronger activation of the α-C—H bond, by the presence of the amide nitrogen atom, as compared with the remote tertiary C—H bond. On the other hand, the presence of the electron withdrawing group (EWG) trifluoroacetamide group led to a dramatic change in site selectivity, providing predominant formation of the product deriving from remote tertiary C—H bond hydroxylation in good yield. Along the same line, the corresponding phthalimide derivative undergoes exclusive oxidation at the remote position (65% yield), attesting the dominant effect of this powerful EWG.

13.2.3 Steric Effects C—H bonds at sterically hindered positions are less reactive than less-hindered counterparts. For example, the oxidation of 1,1-dimethylcyclohexane with the Fe(pdp) catalyst (Scheme 13.6a) concentrates in positions 3 and 4 that are oxidized in an approximate 1 : 1 statistically corrected ratio. Instead products from oxidation at C2 are obtained in reduced relative ratios [48]. Steric effects can modulate the relative reactivity of tertiary vs. secondary C—H bonds. Tertiary C—H bonds bear weaker C—H bonds than methylenic sites, but are sterically more congested. In certain cases, depending on the specific substrate and oxidant, steric effects may override bond dissociation energies in dictating relative reactivity, leading to preferential oxidation of the methylenic site. As representative examples (Scheme 13.6b), introduction of electronically deactivated aryl rings (Fe(CF3 pdp)) [53], or bulky tris-isopropylsylyl (TIPS) substituents (Fe(TIPS mcp)

Scheme 13.6 Catalyst dependent selectivity based in sterics. (a) Oxidation of 1,1-dimethylcyclohexane with the Fe(pdp) catalyst. (b) Schematic diagram of sterically bulky catalysts. (c–f) Relative ratios of products obtained with the Fe(pdp) and Fe(CF3 pdp) catalysts. Conditions for reaction (c) iterative addition; 3 × catalyst (5 mol%), AcOH (0.5 equiv), H2 O2 (1.2 equiv) in CH3 CN at room temperature, 30 minutes. Conditions for reactions (d) and (e) AcOH (0.5 equiv) in CH3 CN, catalyst (25 mol%) and H2 O2 (5 equiv) added during one hour by syringe pump at room temperature. Substrate recycled once. Conditions for (f) same as (d) and (e) but substrate was recycled twice (Fe(pdp)) and four times (Fe(CF3 pdp)). Source: (c) Modified from Gormisky and White [53].

391

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13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

and Fe(TIPS pdp)) on the pyridine rings of bis-amino–bis-pyridyl complexes forms highly methylene-selective oxidation catalysts [54, 55]. Substituents on position α of the pyridine ring may also increase steric congestion at the iron center, but catalyst stability is often critically compromised [39], with some notable exceptions [56, 57]. Representative examples of catalyst dependent selectivity based in sterics are shown in Scheme 13.6. In the oxidation of cis-1,2-dimethylcyclohexane (DMCH) (Scheme 13.6c) [53], Fe(CF3 pdp) exhibited enhanced selectivity toward secondary sites (10 : 1 2∘ /3∘ ratio), while the structurally related Fe(pdp) catalyst provided 2 : 1 2∘ /3∘ ratio. Reverse of site-selectivity was observed for some substrates. For example, oxidation of trans-4-methylcyclohexyl acetate (Scheme 13.6d) yields preferentially the tertiary alcohol as major product with Fe(pdp) (1 : 2 2∘ /3∘ ratio) but the C3 -ketone is the major product with Fe(CF3 pdp) was employed (2 : 1 2∘ /3∘ ratio). Along the same line, site selectivity in the oxidation of nosyl protected (+)-isoleucine (Scheme 13.6e), changed from 1 : 2 to 4 : 1 2∘ /3∘ ratio when changing from the former to the later catalyst. A notable example is the catalyst dependent selectivity observed in the oxidation of (+)-artemisinin (Scheme 13.6f). The oxidation produces two major products, (+)-10β-hydroxy-artemisinin (3∘ site) and (+)-9-oxo-artemisinin (2∘ site), which relative amount depends on the catalyst employed. While Fe(pdp) yields 1 : 2 2∘ /3∘ ratio, Fe(CF3 pdp) yielded 11 : 1 2∘ /3∘ ratio.

13.2.4 Directing Groups Directing groups channel reactivity toward a particular C—H bond overriding the presence of electronic, steric, and stereoelectronic factors. A carboxylic acid group on the substrate has been shown to direct the oxidation toward γ position in Fe(pdp) catalyzed oxidations, delivering five-member ring lactones [58, 59]. As a representative example, the oxidation of a 4-tert-butylcyclohexaneacetic acid ester and the corresponding acid derivative can be compared (Scheme 13.7). Oxidation of the ester affords the lactone product resulting from oxidation of the γ tertiary C—H bond in 9% yield, while the major product is the ketone arising from oxidation of a less sterically hindered secondary site on the cyclohexyl ring. In contrast, the carboxylic acid

tBu

CO2Me

Fe(pdp)(5 mol%) x 3 AcOH (0.5 equiv) H2O2 (1.2 equiv) CH3CN, rt, 30 min

24%

tBu

CO2H

x3

Fe(pdp) (5 mol%) H2O2 (1.2 equiv)

O

CO2Me + tBu

tBu O

O 32% O

CO2H + tBu

tBu

CH3CN, rt, 30 min 0%

O

O 54%

Scheme 13.7 Carboxylic acid directed C–H oxidation compared with oxidation of the corresponding ester.

13.2 Innate Substrate Based Aspects Governing Site Selectivity in C–H Oxidations

derivative provides exclusively the lactone product in 50% yield. When the same reaction is performed with a dioxirane, similar yields (1 : 1 ratio) for the two oxidation products were obtained for both the ester and carboxylic acid derivatives. Of notice, the powerful predictable nature of the γ-lactonization reaction has found application in total synthesis [60–64].

13.2.5 Stereoelectronic Effects 13.2.5.1 Hyperconjugation Effects

Groups that donate electron density from a filled orbital to the antibonding orbital of a C—H bond activate this C—H bond toward an HAT initiated oxidation. For example, the π-character in the C—C bonding orbitals of cyclopropanes populates σ* orbitals of adjacent C—H bonds, weakening and activating them toward oxidation (Scheme 13.8a) [48]. The lone-pair electrons of an ethereal oxygen can also donate electron density to the adjacent C—H bonds through hyperconjugative overlap activating them toward HAT. The electronic activating effect of the oxygen atom enables the selective oxidation of tetrahydrofuran and tetrahydropyran to give the corresponding lactone products.

H

Fe(pdp) (5 mol%) 3 x AcOH (0.5 equiv) H H2O2 (1.2 equiv)

O

CH3CN, rt, 30 min O

O

O δ

MeO

52%

δ = 62% ε = 11%

O O n n = 1, 41% n = 2, 47%

ε

(a)

O R

(b)

N H

Mn(dMMpdp) (1 mol %) H2O2 (3.5 equiv) AcOH (13 equiv) CH3CN, –40 °C, 30 min

O R

OH N H

O +

77%

R

O N H 13%

Scheme 13.8 Stereoelectronic effects in C–H oxidation reactions. (a) Catalytic oxidations with the Fe(PDP) system. (b) Catalytic oxidations with the Mn(dMM pdp) system. Source: Modified from Milan et al. [52].

Stereoelectronic effects also explain the preferential remote selectivity observed in the oxidation of α-methyl substituted amides (Scheme 13.8b) [52]. The introduction of a methyl group on the α-carbon increases the energy barrier required to reach the most suitable conformation for HAT where the α-C—H bonds are aligned with the amide π-system. Consequently, hydroxylation at α-C–H is disfavored and remote oxidation of the weaker tertiary C—H bond takes place.

393

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13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

13.2.5.2 Strain Release and Torsional Effects

These effects are most prominent in C—H bonds of cyclohexane rings. Release of 1,3-diaxial strain in the transition state occurs via planarization of the carbon centered radical that forms after HAT at an equatorial C—H bond. On the other hand, tertiary axial C—H bond deactivation can be rationalized in terms of an increase in torsional strain in the HAT transition state where the substituent is forced toward an unfavorable eclipsed interaction with the equatorial C—H bonds on the adjacent positions. The consequence of these effects is that equatorial C—H bonds of a given site are comparatively more reactive than axial counterparts [65]. An illustrative case is the oxidation of cis- and trans- isomers of 1,2-dimethylcyclohexane with the Fe(pdp) catalysts (Scheme 13.9a) [49]. The former substrate contains an axial and an equatorial tertiary C—H bond, while in the latter, the two tertiary C—H bonds are in axial position. Oxidation of cis-1,2-dimethylcyclohexane produces selectively the corresponding tertiary Fe(pdp) (5 mol%) 3 x AcOH (0.5 equiv) H2O2 (1.2 equiv)

+

HO

O

+ O

CH3CN, rt, 30 min 55%

9%

Fe(pdp) (5 mol%) 3 x AcOH (0.5 equiv) H2O2 (1.2 equiv)

+

CH3CN, rt, 30 min

O

6%

+ O

OH

(a)

29%

22%

28%

Deactivated axial C–H bond H

X

O Am

X

R

H

N H

trans +

Am

O

H

X

X

R

N H

H

Mn(tipsmcp) (5 mol%) AcOH (17 equiv) H2O2 (2.0–3.5 equiv)

X

O R

N H

>99% dr +

CH3CN, –40 °C, 30 min O

cis

X

From cis

Activated axial C–H bond O tBu

O N H

tBu

tBu

(b)

N H

68%

O

O tBu

O N H

H3 C 66%

N H

91%

75% CF3

O tBu

N H 84%

N H 96%

Scheme 13.9 (a) Strain release in C–H oxidations of 1,2-dimethyl substituted cyclohexanes. (b) Resolution of mixtures of cis/trans 4-substituted N-cyclohexylamides on the basis of strain release and torsional effects. Source: (a) Modified from Chen and White [49]. (b) Modified from Milan et al. [66].

13.3 Remote Oxidations by Reversal of Polarity

alcohol, presumably via oxidation at the equatorial tertiary C—H bond. Instead, oxidation of trans-1,2-dimethylcyclohexane produces products from oxidation of the tertiary site in comparable amounts with products from oxidation at C2 and C3 methylenic sites. Activating and deactivating torsional effects can be employed to selectively oxidize cis–trans mixtures of 4-substituted N-cyclohexylamides with manganese catalysts (Scheme 13.9b) [66]. Preferential oxidation of the equatorial C–H in cis-isomers leads to quantitative conversion of the cis-isomers to the corresponding 4-substituted-cyclohexanone, yielding the trans-isomers intact.

13.2.6 Chirality When chiral catalysts are employed in the oxidation of chiral organic molecules, matching–mismatching effects between the chirality of the two reagents may led to different selectivity profiles. Best yields for a product are dependent on the chirality of the catalyst, and thus this aspect needs to be considered when optimizing oxidation of chiral molecules [38, 67]. In specific cases, the impact is so important that the major product can be dependent in catalyst chirality. For example, oxidation of steroidal substrate trans-androsterone acetate (Scheme 13.10) proceeds predominantly at C6 with (S,S)-Fe(tips mcp) but at C12 with (R,R)-Fe(tips mcp) [54, 70]. O

C12

H H AcO

H

H

C6

CH3CN, 0°C, 30 min

H H AcO

H

trans-Androsterone acetate Catalyst (S,S)-[Fe(TIPSmcp)] (R,R)-[Fe(TIPSmcp)]

Scheme 13.10 acetate.

O

O Catalyst (3 mol%) H2O2 (2.5 equiv) AcOH (1.5 equiv)

O

H H

+ AcO

O(H)

50% 9%

H

H

H

16% 71%

Chirality dependent site selectivity in the oxidation of trans-androsterone

13.3 Remote Oxidations by Reversal of Polarity 13.3.1 Remote Oxidation in Amine Containing Substrates by Protonation of the Amine Site Nitrogen-containing molecules such as aliphatic amines (3∘ , 2∘ , 1∘ ), pyridines, and imides are a very important class of compounds, but oxidation of C—H bonds in amine containing substrate has traditionally represented a challenging problem for several reasons. In first place, amine oxidation is often easier than C–H oxidation. In addition, amines readily bind to metal centers, causing the deactivation of metal catalysts [71, 72]. Existing methods for the C(sp3 )–H functionalization of aliphatic

395

BF4

H+ or HBF4

N

N

or BF3·OEt2

N H

H

Amine

Ox

Remote C–H oxidation

N BF3

OH HO

HO

(1) HBF4

NH2

NH2

N H

98%

95%

(2) TFDO

99%

N

O

CF3

O

CF3

NH2 HO

(a)

HO

98%

98%

(1) HBF4 or BF3·OEt2 (2) Fe cat/H2O2/AcOH

OH OH N H 65% (31%)

β

γ

N H

OH

(b)

32% (24%) >20 : 1 γ/β

N n

N Fe N

H2N

N

N N

O

(SbF6–)2

F3C (SbF6)2

59% (25%)

56% (26%)

O N

OH N

NCCH3 NCCH3

N

N

Fe N

F3C NCCH3 NCCH3 CF3

OH

O

n = 1, 66% (18%) n = 2, 62% (16%)

F3C

56% (22%) (S,S)-Fe(pdp)

(S,S)-Fe(CF3pdp)

Recovering starting material rsm % in parentheses.

Scheme 13.11 Protonation or complexation driven remote C—H bond oxidation of amines. (a) Remote oxidation of amines with dioxiranes. (b) Remote oxidation of amines with metal catalysts. (c) Protonation conditions and metal catalysts employed in the remote oxidation of amines. Source: Asensio et al. [68] and Howell et al. [69].

13.3 Remote Oxidations by Reversal of Polarity

amines are scarce and involve both functionalization at the more activated C—H bond in α to the nitrogen atom [73–77] or the use of the nitrogen atom as a part of a directing group [78–80]. A simple solution to address this problem is the protonation of the basic nitrogen atom. Protonation introduces a positive charge, forming an ammonium cation, which is a strong electron-withdrawing group. Consequently, proximal C—H bonds are deactivated. In addition, protonation of the amine also avoids catalyst deactivation by preventing the binding of the amine to the metal center. Remote C–H reactions of protonated primary and secondary amines pioneered by Asensio et al. using dioxiranes as oxidants (Scheme 13.11) [68]. Ammonium salts were prepared in situ by adding tetrafluoroboric acid to the solution of the amine. The strong electron-withdrawing effect of the ammonium group directs oxidation to remote tertiary C—H bonds, leading to the formation of the corresponding aminoalcohols. Further precedent for the deactivating role of protonation in the HAT reactivity of C—H bonds adjacent to the nitrogen atoms was obtained from flash-photolysis kinetic studies of the HAT reaction between the protonated substrates and alkoxyl radicals [81]. The same strategy, entailing binding of the nitrogen atom to Lewis (BF3 ) or Brønsted acids (HBF4 ) was explored in the C(sp3 )–H oxidation of aliphatic and aromatic amine containing substrates with the Fe(pdp) catalyst (Scheme 13.11) [69]. Reaction with a Lewis or Brønsted acid (BF3 ) transforms the amine group into a very strong EWG, deactivating the α-C—H bonds toward oxidation and directing the reactions toward remote C—H bonds. Piperidines, pyridines, imides, and also primary amines are oxidized at remote tertiary or secondary positions with modest to high isolated yields and site-selectivity.

13.3.2 Remote Oxidation of Amide Containing Substrates by Methylation of the Amide Moiety In simple amides, C—H bonds in position α to the N atom are activated by hyperconjugation and are the most reactive sites in HAT initiated reactions [52]. However, remote C–H oxidation with the Fe(pdp) catalysts and H2 O2 can be accomplished by transforming the amide substrate into the corresponding amidate salt by reaction with methyl trifluoromethanesulfonate (Scheme 13.12) [82]. The amidate group is strongly electron-withdrawing and directs oxidation toward remote C—H bonds. The reaction displays a broad substrate scope covering tertiary amides, anilides, 2-pyridones, and carbamates.

13.3.3 Remote Oxidation via Polarity Reversal Exerted by Fluorinated Alcohol Solvents Fluorinated alcohol solvents such as trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) are very strong hydrogen bond donors (HBDs) that engage in strong hydrogen bonding to polar and electron rich, hydrogen bond acceptor (HBA) functional groups in the substrate (Scheme 13.13). This interaction increases

397

R′

R′ OTf Ox

MeOTf O

N R Amide

O

O

N

HO

O O

R

N R

OH

N

N

N N

OH 56%

R=

N Fe NCCH3 NCCH3 N

N

Fe

F3C NCCH3 NCCH3

N

CF3

52% (S,S)-Fe(pdp)

R = Me, 56% R = Et, 55% R = i-Pr, 52% O

H

O

H

O

O

H

N

Me

O

H

N

Me

O

43% (14%)

F 3C

(S,S)-Fe(CF3pdp)

56%

H N

O O O

N

55% (10%)

γ δ N

β

H

O

51% δ:γ = 5.3 : 1 (28%)

H O

N

H

H

32%

55% (8%)

Recovered starting material rsm % in parentheses.

Scheme 13.12

N

O

R

(SbF6–)2

F3C (SbF6)2

n n = 1, 60% n = 2, 55% n = 2, 52% (6%)

54% (8%) 55% (8%) 52% (6%) 52% (10%)

Remote C–H oxidation

(1) MeOTf (2) Fe cat/H2O2/AcOH (3) KI

O

N n

n = 1, n = 2, n = 3, n = 4,

58% (4%) 57% (6%) 54% (13%) 58% (7%)

N R Amidate

O

N O

n n = 1, n = 2, n = 3, n = 4,

MeO

Remote oxidation in amide and imide containing substrates. Source: Modified from Nanjo et al. [82].

O

13.3 Remote Oxidations by Reversal of Polarity

H

Activated toward HAT

H

H D Y

R

R

H

X•

–X H

Deactivated toward HAT

+ –

Y H D H

X•

–X H

R

Y H H

+

Y

R

H

–

D

O Y = OH, OR, NRCR, NH2,NHR, NR2 H D = TFE, HFIP

Scheme 13.13 Schematic representation of the HAT reaction of a methylenic site containing a functional group Y, by a hydrogen atom abstractor (X⋅), in the presence or absence of a strong hydrogen bond donor (HBD).

the extent of positive charge on the functional group, reversing the polarity of the proximal C—H bonds that are thus deactivated toward HAT [83]. By virtue of this effect, highly chemoselective aliphatic C—H bond oxidation of alcohol, ether, amine, and amide substrates, as well as product chemoselective oxidation of aliphatic hydrocarbons catalyzed by iron and manganese complexes, has been achieved, employing H2 O2 as the oxidant [36]. Oxidation of hydrocarbons in acetonitrile, the solvent commonly used in oxidation catalysis produces a mixture of alcohols and ketones, as shown in Scheme 13.14. Unless reactions are performed under a large excess of substrate, ketones are the major product because the first formed alcohols are more susceptible toward

H R

R′

O

OH

R

HFIP, 0 °C, 1 h

OH

OH

R′

+

R

R′

O

OH

O

O

59% (A:K 97:3 vs. 1 : 4)

OH

H

Mn(tipsmcp) (0.5 mol%) H2O2 (0.5 equiv) H AcOH (2 equiv)

72% (A:K 97 : 3 vs. 1 : 3 in ACN)

O

OH

O

56% (A:K 95 : 5 vs. 1 : 1)

HO

H

H

80% (A:K 95 : 5 vs. 1 : 1.5)

89% (A:K 98 : 2 vs. 1 : 3)

O

H

H

68% (A:K 97:3 vs. 1 : 1.5)

Scheme 13.14 Catalytic hydroxylation of methylenes in HFIP. Values in italics (orange) indicate the alcohol/ketone ratio observed when the reaction is conducted in acetonitrile.

399

400

13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

Mn(TIPSmcp)(0.5 mol%) H2O2 (0.5 equiv) AcOH (2 equiv)

OH R

R′

MeCN or HFIP 0 °C, 1 h

C–H selectivity MeCN 2%

5% 70%

R′ R

OH C–H selectivity HFIP

OH

32% 1%

OH

+

+

82%

R = OH 4% 52%

O

0%

OH

+

R=H 5% 14%

R′

R

O R

OH

O

OH

+

OH

13% 0%

49% 0%

OH

93%

OH

O

+ OH

0%

36% 80%

30% 0%

O

OH

+

+

OH

OH

8% 0%

9% 60%

2%

O

+

85%

41% 1% OH

OH

88%

56% 4%

8% 77%

5%

45% OH

Ether substrate O

+

O

OH

R 29%

R=H 1% 11%

R = OH 2% 6%

58% 7%

95%

Yields (with respect to H2O2) are shown below each of the products (purple: yields obtained in HFIP, green: yields obtained in MeCN).

Scheme 13.15 Comparative chemoselective C–H oxidation in alcohol and ether containing substrates in HFIP (red italics) and CH3 CN (green plain) solvent.

13.4 Remote Oxidations Guided by Supramolecular Recognition

oxidation than the hydrocarbon substrate. For example, in the oxidation of n-hexane (1 equiv) with the manganese catalysts Mn(tips mcp) and 0.5 equiv of H2 O2 , 2- and 3-hexanone account for 85% of the oxidized products (A:K ratio = 1 : 4). However, when the same reactions are performed in TFE and HFIP, 2- and 3-hexanol account for 89% and 97% of the products, respectively. Solvent hydrogen bonding to the first formed alcohol exerts a polarity reversal and consequent α-C—H bond deactivation. The increased product chemoselectivity toward the alcohol products observed on going from TFE to HFIP parallels solvent HBD ability. This effect was observed in a series of hydrocarbon substrates (see Scheme 13.14), resulting in the chemoselective hydroxylation of methylenic groups (95–98% selectivity), which contrasts with the dominant formation of the ketone in acetonitrile. An interesting consequence of this effect is the possibility to perform enantioselective hydroxylation of methylenic sites. Asymmetric hydroxylation of benzylic substrates with a manganese catalyst can be conducted in fluorinated alcohol solvents with product yields of chiral alcohols up to 46%, which compares favorably with results in the common solvent CH3 CN that provide low yields (5–6%) and moderate to good enantioselectivities (31–89% enantiomeric excess [ee]) [84, 85]. The polarity reversal exerted by fluorinated alcohol solvents enable chemoselective C–H oxidation in substrates containing polar, electron-rich functionalities, conventionally more reactive toward strong oxidants. For example, HFIP enables chemoselective C–H hydroxylation in substrates containing alcohol and ether functionalities (Scheme 13.15). Reactions lead to the predominant formation of diols and methoxyalcohols deriving from hydroxylation of remote unactivated C—H bonds, while products deriving from α-C—H bond oxidation were largely dominant when reactions were conducted in MeCN. Remote C–H oxidation in amide and amine substrates is also accomplished in reactions conducted in HFIP. Both functional groups are powerful hydrogen bonding acceptors, and α-C—H bonds become strongly deactivated by solvent hydrogen bonding leading to products resulting from oxidation of the most remote and least electronically deactivated methyne or methylenic site (Scheme 13.16).

13.4 Remote Oxidations Guided by Supramolecular Recognition A powerful strategy to introduce selectivity in C–H oxidation reactions is the decoration of a catalyst with a receptor able to non-covalently bind a substrate and orient specific C—H bonds toward the reactive metal center [86]. Binding should be weak and reversible in order to enable catalysis and prevent product inhibition, a recurrent problem in supramolecular catalysis. Interestingly, this approach finds ample precedent in nature since the use of weak interactions is at the basis of the high site selectivity exerted by a number of enzymes. In the following lines, we discuss the different systems that rely on this strategy on the basis of the nature of the receptor–substrate interactions.

401

402

13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

Catalyst (1 mol%) H2O2 (1.0–3.5 equiv) AcOH (13 equiv)

O R

N R′ H R = CH3, tBu

O

MeCN or HFIP –40 or 0 °C, 30 min

C–H remote selectivity MeCN

O

+

O

OH N H

1%

O

O

tBu

O

76%

1%a,b 62%a,c

100%

OH

+

N tBu

O 22%d 0%d

12%

R′ N H OH

OH N H

65%a,b 0%c

HN O

0%a,b 51%a,c

+

R

C–H remote selectivity HFIP

N H

35%a,b 16%a,c

0%

+

O

OH N H

O N O R′ H

R

3%d 46%a,d

100%

Yields (calculated with respect to the substrate) are shown below each of the products (green: yields obtained in MeCN, purple: yields obtained in HFIP). aIsolated yield. Reaction conditions: bMn(dMMpdp) (1 mol%), H O (3.5 equiv), AcOH (13 equiv), MeCN, –40 °C. cMn(TIPSmcp) 2 2 (1 mol%), H2O2 (3.5 equiv), AcOH (13 equiv), HFIP, 0 °C. dMn(dMMpdp) (1 mol%), H2O2 (1.0 equiv), AcOH (13 equiv), MeCN or HFIP, 0 °C.

(a) NH2

Mn(tipsmcp) (1 mol%) H2O2 (1 equiv) AcOH (13 equiv)

NH2

Solvent, 0 °C

OH

MeCN 6% HFIP 44%a OH N H

(b)

N H MeCN 31% HFIP 54%

Scheme 13.16 Comparative chemoselective C–H oxidation in amide and amine containing substrates in in HFIP (red italics) and CH3 CN (green plain) solvent. (a) Catalytic oxidation of amides in conventional (acetonitrile) vs fluorinated alcohol solvents. (b) Catalytic oxidation of amines in conventional (acetonitrile) vs fluorinated.

13.4 Remote Oxidations Guided by Supramolecular Recognition

13.4.1 Lipophilic Interactions Lipophilic interactions have been employed to promote remote hydroxylation of steroidal alcohols with porphyrin complexes [87]. When buried into a phospholipid bilayer in H2 O, an Mn(III) porphyrin complex (Chol Mn(porph)) (Scheme 13.17) decorated with four pendant steroids forms a hydrophobic pocket that can bind an orient an apolar substrate. Steroidal alcohols are recognized and positioned in such a manner that the polar hydroxyl group is oriented toward the aqueous phase while the apolar alkyl chain is directed toward the reactive manganese center. The

OH

OH

OH

O

O

H O

NH

N N

Mn

HN N N HN O

NH

O

OH OH Chol

Mn(Porph)

Single site oxidation

21

2 HO 3

23 24 H 20

18 22 25 12 17 27 11 16 1 199 13 8 14 15 10 4

5

Scheme 13.17

6

7

OH 26

Chol

Mn(Porph), [ O] HO

(0.8 TON)

Oxidation of cholesterol governed by lipophilic interactions.

403

404

13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

system performs highly regioselective oxidation of the C25 tertiary site delivering the corresponding alcohol in a nearly stoichiometric yield (0.8 TON). Unfortunately, catalytic conditions are only operative with simpler substrates but without any selectivity amplification [88].

13.4.2 Lipophilic Recognition by Cyclodextrins Breslow et al. pioneered the use of cyclodextrins (CDs) as supramolecular receptors [89, 90]. Covalently linked to metalloporphyrin complexes, CD’s recognize lipophilic tert-butylbenzene groups appended to the substrate, which becomes oriented in a manner that specific C–H groups are placed in proximity to the reactive metal center. This recognition thus translates into site-selectivity in catalytic C–H oxidation reactions (Scheme 13.18) performed in water media. Reversible binding enables catalysis. Representative examples of site-selective oxidations accomplished with these catalysts are shown in Tables 13.1 and 13.2. Single-product hydroxylation of two sites (C6 and C9) of elaborated steroids could be accomplished by careful positioning of the substrate recognizing CD’s units in the catalyst and of the recognized sites (tert-butylphenyl groups) in the substrate. A series of studies demonstrated that high site selectivity cannot be attained with a single recognition site and instead it requires substrate binding via multiple attachment points, ensuring precise orientation of the catalyst–substrate adduct. In addition, indiscriminate background oxidation, which will damage overall selectivity of the reactions, is prevented by the lack of reactivity for unbound substrates, which are only poorly soluble in water. A discussion on the C6 hydroxylation of the disubstituted androstanediol substrate S1 highlights important points on the catalyst design (Table 13.1) [91, 92]. While the simplest CD4 –Mn(porph) exhibited excellent site selectivity toward C6 hydroxylated product 𝛂-C6 OH, its activity was modest (Table 13.1, entry 1). Elaboration of the catalysts by introduction of halogen groups (entries 2–4) improves the stability and large turnover numbers can be obtained [93]. Replacement of one of the CD arms by a nitro group improves the activity of the catalyst (entry 5), presumably enhancing the electrophilicity of the metal–oxo species. In addition, introducing a pyridine arm that could intramolecularly bind to the manganese catalytic center eliminates the requirement for additional external ligands (R in Scheme 13.18, entry 6) and also translates into an enhancement in catalytic activity [94, 95]. Elaboration of α-C6 OH by introduction of different binding groups at specific positions (S2R ) results in exquisite recognition and hydroxylation at C9 (Table 13.2) [96]. Site-selective C9 hydroxylation requires binding of the substrate via three different points (see Scheme 13.18 for a model and Table 13.2). When only two binding sites are present in the substrate, reaction proceeds with poor yields and selectivities (entry 2). Models suggested that a tighter and more restrictive binding can be obtained with m-aryl substituted catalysts. The corresponding catalysts were prepared and displayed excellent C9 selectivity (entries 3 and 4). Overall, these systems display outstanding selectivities and activities in complex steroidal scaffolds. On the negative site, the excellent selectivity attained with these catalysts also translates into a substrate specificity that constitutes one of its main

(a)

(b)

Scheme 13.18 Geometry control in the oxidation of an androstenediol derivative. BG stands for binding group. (a) Key elements of substrate design are highlighted. (b) Schematic diagram of the catalysts with the bound substrate highlighting differences in binding between bis- and tris-derivatized androstanediol. (c) Sequence of protection–oxidation–deprotection employed in substrate S1.

406

13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

OH

OH

H HO

H

H

H HO

H

H

OH

Hydrolysis O

BG

O

BG

PhIO H BG

O

Catalyst

H

H

H

H2 O

S1

BG

O C6 O

BG =

N H

SO3

O

H

H

α-C6OH OH

(c)

Scheme 13.18

Continued

limitations in terms of practical application. In addition, the rather elaborate structure of the catalysts makes their further elaboration a complex synthetic task.

13.4.3 Ligand to Metal Coordination Coordination bonds with a metal center can be also employed as a tool to recognize and orientate substrates. By anchoring bipyridine moieties to the meso position, the resulting metalloporphyrin (bipy)4 –Mn(porph) (Scheme 13.19) is conveyed with the ability to bind Cu2+ ions. Decoration of a substrate with bidentate ligands able to also bind Cu2+ results in labile catalyst–Cu–substrate complexes where preorganization results in selective oxidation. Key to this design is the use of a highly labile metal ion, for which ligand exchange occurs at a faster rate than the one of the oxidation reaction, avoiding product inhibition. Competitive oxidation experiments showed that the recognized substrate was preferentially oxidized over compounds devoid of ligand moieties [97]. A representative example is shown in Scheme 13.19 where the oxidation of androstanediol derivatives S3 and S4 are displayed [98]. Oxidation of S3 mainly afforded C15 alcohol and ketone products (Scheme 13.19). Moving the binding site to C3 (substrate S4) shifted the oxidation toward C6. Oxidation of the non-coordinating analogs S3′ and S4′ produced a complicated mixture of products. Phosphonates can also be employed instead of bipyridines and are more resistant toward oxidation conditions [99]. By employing the fluorinated, F–(bipy)2 –Mn(porph) 𝛂C6 alcohol (32 turnover numbers [TONs]) was obtained with 90% selectivity in the oxidation of S5.

Table 13.1

Catalyst dependent selective oxidation of the androstanediol derivative S1.

S

S R

R R′ R R

R′ R

R R′

N

S

N

R′ R

R

N

R R′

R

F

Z

F

F

Z S

F N

S

S N

R′ R

F

R

Mn

F

N R R′

R

F

N

Z

Y F

R

F

N

F

N

Z

S

R = H, R′ = H, CD4–Mn(porph)

Y = NO2

R = F, R′ = H, F-CD4–Mn(porph)

Y=

R = F, R′ = Cl, X-CD4–Mn(porph)

Z

Z = H, m-CD4–Mn(porph)

NO2–CD3–Mn(porph)

O

N

H N

Z = F, PyF-m-CD4–Mn(porph) Py–CD3–Mn(porph)

O

BG

O

BG

PhI=O Catalyst H BG

Catalyst (loading)

O

H

H

TON

Conversion

H2O

H BG

O

H

O H

H α-C6OH

𝛂C6 OH yield

1

CD4 –Mn(porph) (10%)

4

40%

40%

2

F–CD4 –Mn(porph) (1%)

96

>99%

95%

3

F–CD4 –Mn(porph) (0.1%)

187

19%

19%

4

X–CD4 –Mn(porph) (0.1%)

356

36%

36%

5

NO2 –CD3 –Mn(porph) (0.1%)

2900

65%

65%

6

Py–CD3 –Mn(porph) (0.1%)

2200

50%

50%

Source: Breslow et al. [91, 92].

Z

Z N

Z N

N

S

S

Entries

Z

Mn

Z

F

S Z

N

N

F

R R′

Z

N Mn

N

S

408

13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

Table 13.2

C9 hydroxylation of the androstanediol derivative S2R . O R

O

R

C9

C3 BG O S2R Entries

PhIO H C15 C3 Catalyst, pyridine BG O C6 H2O H O BG H

Catalyst

R

OH H

H

C6 O BG

C15

αC9OHR

𝛂C9 OHR yield

TON

1

F–CD4 –Mn(porph)

BG

72

72%

2

F–CD4 –Mn(porph)

H

n.r.

n.r.a)

3

m-CD4 –Mn(porph)

H

2.5

2.5%

4

PyF –m-CD4 –Mn(porph)

H

90

90%

BG, binding group. a) 1 : 1 mixture with C15 alcohol. Source: Breslow et al. [96].

13.4.4 Hydrogen Bonding Hydrogen bonding between the catalyst and the substrate in apolar media may be also used as a tool for substrate recognition. A paradigmatical example is the supramolecular manganese catalyst designed by Crabtree, Brudvig, and coworkers that contains a Kemps triacid derivative covalently linked to a terpyridine ligand (Terpy–COOH), which in turn binds to the manganese center (Mn(terpy–COOH), Scheme 13.20) [100]. Two of the Mn-terpy units are linked via an Mn2 O2 core, leaving the –COOH groups available for binding/recognizing carboxylic acid containing carboxylic acids. Ibuprofen (S6) is regioselectively oxidized with tetrabutylammonium oxone (TBAO) as oxidant at the remote benzylic position, in close proximity to the Mn2 O2 group, as early suggested by molecular dynamic calculations. Oxidation afforded almost exclusively P6a (up to 71% conversion with 97% selectivity and 710 TONs, Table 13.3). Lacking the recognition motif, the parent complex (Mn2 (terpy)) produces two products P6a and P6b in a 3 : 1 ratio (77% selectivity, Table 13.3, entry 2). Remarkably, addition of excess acetic acid competes with the substrate for the carboxylic acid recognition site at the (Mn(terpy-COOH) catalyst, leading to the same selectivity observed for (Mn2 (terpy)) (Table 13.3, entries 4, 5) in the catalytic oxidation of ibuprofen. Moreover, oxidation of the ibuprofen methyl ester also takes place without any selectivity amplification. Oxidation of a cis/trans mixture of S7 (Scheme 13.21) results in the selective oxidation of the trans isomer (>99% selectivity, 18% conversion) [101]. This result can be explained by considering that only the trans isomer of S7 exposes the axial C—H bond to the reactive Mn2 O2 core, while the equatorial hydrogen of the cis isomer points away from of the active site. Furthermore, addition of sterically

N N

N

N

F

F

N

F

N

F N N

Mn

N

F N

N

Mn

N F

N

N

F

N N

N

F

(bipy)4–Mn(Porph)

F-(bipy)2–Mn(Porph)

O O

F

F

N

N

(a)

N

O O

N

bipy

N

15 (bipy)4–Mn(Porph) 0.5 equiv

O S3 (b)

PhIO 10 equiv, Cu 2 equiv CH3CN:DCM 1 : 1

O(H) O P3a 20% conversion, 17% (A + K)

Scheme 13.19 Control of selectivity by metal to ligand binding. (a) Metalloporphyrins bearing substrate recognition motifs. (b) Selective oxidation at C15 of an steroid guided by supramolecular recognition of a bipyridine ligand. (c) Selective oxidation at C4 of an steroid guided by supramolecular recognition of a bipyridine ligand. (d) Substrate used in control experiments.

O O

(bipy)4–Mn(porph) 0.2 equiv PhIO 60 equiv, Cu 1 equiv O N

N

CH3CN:DCM 1 : 1

O

O 6

bipy

O O(H)

S4

(c)

P4a 41% conversion, 41% (A + K) O

O O

O

O

O P ONa

O

O O

6

O 6 S3′ (d)

Scheme 13.19

Continued.

S4′

NaO

P ONa

O O 6 S5

ONa

13.4 Remote Oxidations Guided by Supramolecular Recognition

O H O

O

OH O

H

N MnII

N

N

N

O Cl

N

O MnIV

N

N

N

MnIV

N

N

O

N

O

O

N

O

H O

O

OH

Cl

O

O

H

O

O Mn2(terpy-COOH)·S6

Mn(terpy-COOH)(Cl)2

Scheme 13.20 Kemps triacid appended supramolecular catalyst and envisioned interaction with the substrate. Source: Modified from Das et al. [100]. Table 13.3

Oxidation of ibuprofen with the Mn2 (terpy–COOH) catalyst.

O

O

TBAO catalyst

HO

HO

O

O +

CD3CN S6 (ibuprofen) Entries

P6b

P6a

Catalyst

Additive Conversion TON

P6a selectivity

1

Mn2 (terpy–COOH)

—

50

50

97.5%

2a)

Mn2 (terpy)

—

53

53

77%

(terpy–COOH)b), c)

3

Mn2

—

71

710

96.5%

4

Mn2 (terpy–COOH)

AcOHd)

56

56

75%

5

Mn2 (terpy–COOH)

AcOHd)

58

58

77%

a) b) c) d)

% of total yield. 0.1% catalyst. CD3 CN as solvent instead of CH3 CN. In excess (4 equiv).

TBAO catalyst

H cis-S7

trans-S7 Catalyst

CO2H

CO2H

CO2H H +

CD3CN

Conversion

+

HO trans-S7

CO2H

HO

cis-S7

Yield (%)

Yield (%)

Mn2(terpy–COOH)

13%

12.9%

0.1%

Mn2(terpy)

19%

5.7%

5.7%

Mn2(terpy–COOH) (solvent CD3CN)

18%

17.9%

0.1%

Scheme 13.21

Competitive oxidation of a cis/trans mixture of S7.

411

412

13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

bulky, non-oxidizable carboxylic acids (p-tBu-benzoic acid), bind to the recognition motif, blocking the approach of other substrates to the active site, preventing their oxidation. Hydrogen bonding between a lactam ring and primary amides has been also used as recognition element to confer selectivity to Ru–porphyrin catalysts. The recognition site is a U-turn lactam ring ((Lactam)Ru(porph), Scheme 13.22) [102]. The directionality of the amide recognition, dictated by the chirality of the receptor, allows a differentiation of the two prochiral methylenes in spirocyclic

(a)

Favoured oxidation

H

N

F

N

F

H H

O

O H

Ar O N

M

N

N

F

Ar = F

Ar

F

N M = Ru(II), Mn(II)

Ar (Lactam)M(porph) (b) (1)

Cl

N O

Cl

O N H

(2) PCC or Swern oxidation

N H

S8

O O

N H

H N

PhIO (2 eq) O (Lactam)Mn(porph) 1% R CH Cl , 0 °C, 16 h 2 2 R

X

: H N

O R R

10

X

Conversion 29–97%

H N

+

OH S9

O

P8b

P8a 90

X

O

+

(Lactam)Ru(porph)

P9a

O R R

O P9b

22–68%, 87–99% ee

Scheme 13.22 Stereoselective C–H oxidation driven by recognition: enantiotopic C–H oxidation of spiroxindoles (top) and enantioselective C–H oxidation of 3,4-dihydroquinolones (bottom). Source: (a) Modified from Frost et al. [102]. (b) Frost et al. [102] and Burg et al. [103].

13.4 Remote Oxidations Guided by Supramolecular Recognition

oxindole substrates such as S8 (Scheme 13.22, top). This chiral recognition leads to enantiotopic differentiation and oxidation of one of the two methylenic sites [102]. Best yields were obtained by submitting the oxidation mixture obtained after catalytic oxidation to a subsequent oxidation with pyridinium chlorochromate (PCC) or Swern conditions, which transformed first formed alcohols into the final spyrolactones with moderate to good yields. Methylation of the amide N—H bond of the substrate, completely inhibited the reaction, demonstrating that recognition was necessary for the reaction to proceed. More recently, enantioselective C–H oxidation of a prochiral methylene in pharmaceutically relevant 3,4-dihydroquinolones (S9) was accomplished by using the same concept in an Mn–porphyrin catalyst (Scheme 13.22, bottom) [103]. The latter proved to be more effective catalyst than the Ru analog and also overoxidation of the first formed alcohol to the corresponding carbonyl product was limited. In CH2 Cl2 solution, substrate binding positions one of the two enantiotopic methylenic sites to the reactive manganese oxidant (likely an MnV —O species), resulting in site selective C–H hydroxylation, forming alcohol products with high levels of enantioselectivity (up to 99% ee). Again, alkylation of the amidic N—H bond leads to an almost racemic oxidation (5% ee) highlighting the key role of substrate recognition via hydrogen bonding with the amide. In a recent work [104] the Mn(pdp) complexes were evolved into supramolecular catalysts by attaching an 18-benzocrown-6-ether to the two pyridine binding arms of the ligand. Titration experiments showed that the resulting complex Mn(CR pdp) binds a molecule of protonated primary amine per unit of benzocrown, and that the interaction is reversible. Methylene groups of primary amines containing long alkyl chains (from C6 to C14) could be selectively oxidized. Amine binding to the receptor exposes remote C—H bonds at C8 and C9 to the oxidizing unit leading to a systematic enhancement of oxidation at these sites. For example, the selectivity for C8 and C9 positions increased from 53% to 81%, respectively, in decylammonium S19 oxidation (Scheme 13.23 and Table 13.4), and the same trend was observed for the series of linear amines from C9 to C14. Control experiments demonstrated that the selectivity enhancement arises from the supramolecular recognition. In first place, no selectivity toward C8 and C9 oxidation products was observed when the simple catalyst Mn(pdp) was employed. Reactions with Mn(CR pdp) lost the C8 and C9 selectivity when the interaction between the crown ether and the amine substrate was avoided. This could be done by adding a stronger guest (Ba2+ , Table 13.4, entry 3) or by methylation of the N—H bonds of S19 because alkylated amines do not effectively bind to the crown ether (Table 13.4, entries 4–5). Most interestingly, supramolecular recognition enables preferential oxidation of the recognized alkyl amine in front of substrates containing a priori more reactive C—H bonds, while an opposite selectivity was observed with Mn(pdp) complex [105]. This system is remarkable because it operates in non-activated methylenic sites, where C—H bonds are strong and apolar, very poorly reactive. But most important, differentiation between methylenic sites in linear alkyl chains is particularly difficult because they have very similar electronic and steric properties. This is best illustrated in control experiments performed with the Mn(pdp) complex, which

413

30

O

Non-NH3+

25

Yield (%)

20

O

O

H O H O H N

Dec-NH3+ Dodec-NH3+ Tetradec-NH3+

O BF4–

+

N

15

N

via 10

OAc Mn

N N

O

H H

C8 + C9 preferred oxidation

H H

5

O

0 4 (a)

6

8 10 Carbon oxidized

12

O

O (b)

O

O O

Scheme 13.23 Distribution of ketone products formed upon oxidation of linear amines (a) and (b) schematic representation of the supramolecular recognition phenomena.

13.4 Remote Oxidations Guided by Supramolecular Recognition

Table 13.4

Evidence on favor of a recognition-driven selectivity. O NH3BF4

NH (1) Mn(CRpdp) 1 mol%, H2O2 2.5 equiv, AcOH 22 equiv, CH3CN, 0 °C, 30 min

n=0 n=1 n=2 Entries

O n

n

(2) Et3N, Ac2O, extractions

C10-NH3+ C11-NH3+ C12-NH3+

Catalyst

Mainly C8 and C9 ketones

Substrate

Conversion Total yield

C8 + C9 selectivity

1

Mn(CR pdp) C10 -NH3 +

53%

36%

81%

2

+

43%

34%

53%

3a) Mn(CR pdp) C10 -NH3 +

47%

27%

58%

4 5

Mn(pdp) CR

C10 -NH3

Mn( pdp) C10 -NMeH2

+

Mn(pdp) C10 -NMeH2 +

9%

7%

50%

28%

26%

49%

a) 3 mol% of Ba(ClO4 )2 added as stronger guest.

shows basically statistic distribution of products resulting from oxidation at all the methylenic sites not affected by the polar deactivation exerted by the protonated amine moiety (C1–C4). Along a similar line, site selective oxidation of methylenic sites in linear diamines has been described with a ruthenium–porphyrin catalyst containing two 6-acylaminopyridyl-2-amide moieties as substrate recognition sites [106]. The two recognition sites are placed at two meso-phenyl groups at anti sites of the porphyrin. The two amine moieties at the undecamethyl-1,14-diamine substrate were derivatized with quinazoline-2,4-dione moieties (Scheme 13.24). The latter serves as the complementary hydrogen bonding motif for the 2,6-diacylaminopyridine sites because cyclic imides are known to bind tightly to 2,6-diacylaminopyridine via three hydrogen bonds. Oxidation of this substrate with the ruthenium catalyst (1 mol%) employing 2,6-dichloropyridine (3.3 equiv) as oxidant results in oxidation of the diamide substrate to yield monoketone products in 46–58% combined yields. Three major products are detected resulting from oxidation at C5 , C6 , and C7 . Interestingly, oxidation at C7 , the central site, initially envisioned as the preferred site because of its proximity to the reactive Ru—O unit is the main product of the reaction ([P5 ]/([P6 ] + [P7 ]) = 2.7–2.9).

415

416

13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

1

N

H

3

O

H

N

Ar

N

H

N

O

N

Ru

(a)

H

O

N

O

N

N

O

O N

13

Ar

N

N

11

9

7

5

O

N O

N

N

O

X

O Q

Q

Q

Q 4

7

4 O

7

Ru catalyst (1 mol%)

+

Cl

N

Cl

1,2-Dichloroethane

Q

14 O 3.3 equiv

Q

N

Q

P6

O Q

O

P7

Q 4

P5

7

46–58% yield, [P7]/([P6]+[P5]) = 2.7–2.9

N O

(b)

Scheme 13.24 Selective oxidation of diamines by a supramolecular porphyrin catalyst. (a) Schematic design of the supramolecular interaction. (b) Results of the catalytic reactions.

13.5 Selective Aliphatic C–H Oxidation at Dicopper Complexes O2 binding at activation reactions at copper dependent enzymes has also served as inspiration motif for the designing of catalysts that enable selective C–H oxidation at remote positions. Reactions of copper complexes with O2 may result in the formation of “CuO2 ” or “Cu2 O2 ” species where the O2 molecule has been reduced to the superoxide of peroxide level. In the case of dinuclear (CuII 2 (μ-O2 )) species, the O—O bond may be broken, forming highly electrophilic CuIII 2 (μ-O)2 species [107]. These reactions have been extensively observed in the studies of the interaction of O2 with copper coordination complexes, and resulted in the intramolecular oxidation of the ligand. More recently, proper ligands have been fused to organic molecules where the resulting aliphatic C–H oxidations result in products of synthetic interest. Remarkably, selectivities attached by some these reactions cannot be reached by other methods, making the biomimetic approach particularly relevant [108–110]. Pioneering work was done by Schönecker et al. describing that O2 reaction of a steroidal molecule derivatized with an iminopyridine ligand ligated to Cu(I) results in the regio- and stereoselective γ-hydroxylation in the 12β-position of a steroid, a notoriously difficult site [111, 112]. In the original report, the authors proposed that the reactions proceed via a dicopper(II) peroxide species, and consequently, they have a maximum yield of 50%. Later developments by Baran and coworkers led to the identification of conditions that permitted the Cu(II) ions to be reduced to

13.6 Conclusions R

H

Cu(CH3CN)4PF6 (I) or Cu(OTf)2 (II) (1.3 equiv)

R1 N N

H

OH

O

OH

H

OH

O

H I: 55% II: 73%

H

OH

O I: 94% II: 87% OH

O

OH

O

H

H AcO

H I: 40% II: 2% OH

O

O

H

H H I: 52% II: 51%

O

H H I: 80% II: 66%

HO

H H

n

O

H

OH

TBSO

N

O

Cu

H I: 62% II: 64%

MeO

H H

Cu

H H I: 90% II: 68%

BnO

O

R2

H

HO

N

R1 O

then sat. aq. Na4EDTA

R2 OH

H

H I: 46% II: 61%

H Ni-Pr2

H I: 32% II: 68%

Conditions: Cu (I or II, 1.3 equiv), sodium ascorbate (2.0 equiv), acetone/methanol (1 : 1, c = 0.15 M), 50 °C, O2.

Scheme 13.25 Schematic diagram of the selective oxidation of steroidal molecules with copper complexes along with the proposed mechanistic concept. Source: Modified from See et al. [113].

Cu(I) and reentering in the catalytic cycle, bypassing the stoichiometric 50% limit (Scheme 13.25) [113]. This improved substantially the system that could be then applied to a series of steroidal substrates. It is important to notice that the hydroxylation of the methylenic site takes place in a highly chemoselective manner, even in the presence of a priori more oxidizable functional groups. The value of this methodology has been demonstrated in its application to total synthesis. More recently, Garcia-Bosch and coworkers have shown that reactions can employ H2 O2 as oxidant and proceed under catalytic conditions [114].

13.6 Conclusions The current chapter describes different strategies to govern site selectivity in aliphatic C–H oxidation reactions with biologically inspired catalysts. Special emphasis has been devoted to discuss strategies to change the innate reactivity of the substrate, governing chemoselectivity to avoid a priori more reactive functional groups and activated C—H bonds. Strategies go from simple use of

417

418

13 Remote Oxidation of Aliphatic C—H Bonds with Biologically Inspired Catalysts

electron-withdrawing groups, the use of medium effects to exert polarity reversal and catalyst dependent designs where sterics and supramolecular recognition can be employed. Chemistry is still quite in its infancy since main of the systems described constitute proof of concepts that need to be further transformed into useful synthetic methodologies. The application of some of these methodologies in the preparation of complex organic molecules is growing in number and significance, attesting for the powerful reach of these methods.

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423

Index a Abiraterone acetate 373 acetate cocktail 122 acetone 95 acetonitrile 202 acetophenone 158 acetoxylation 36, 39 reactions 224 acetylated o-bromoanilines 87 acid derivatives benzoic acids 20–23 hydrocinnamic 10–16 phenylacetic 16–20 acredinone 93 acrylates 18 activated olefins 82 acyl chlorides 90 aerobic oxidation processes 353 aerobic remote oxidation 354 alcohol derivatives 44 aldehyde moiety 71 aliphatic C(sp3 )–H functionalization 4 alkoxypalladium species 69 alkylation and alkenylation 234 alkylation/dearomatization sequence 71 alkyl bromide moieties 64 alkyl bromides 71, 147 alkyl halides 144 alkyl hydroperoxide 335 2-alkylpyrroles 101 alkyl radical 144 2-alkyl-substituted aziridines 77 alkyl-substituted pyridines 372 alkyne-tethered alkyl bromides 71, 73, 74 alkynylpalladium intermediate 69 α-alkoxycarbonyl selanes 94 amide-substituted norbornene 91 amide-tethered iodoarenes 96

amine derivatives aniline derivatives 23–27 benzylamine derivatives 27 N-heterocyclic arene derivatives 29–33 phenylethylamine derivatives 27–29 amine-functionalized arylacetylenecontaining polymers 99 amine-tethered iodoarenes 84 4-aminoindoles 97 8-amino-5-methoxyquinoline 285 8-aminoquinoline bidentate 280 2-and 4-alkylpiperidines 372 androstanediol derivative 404, 407, 408 anhydrides 90 aniline derivatives 94, 95, 208 anilines 178, 183 anisoles 158 arene C(sp2 )–H functionalization 4 arene-free ruthenacycles 149 arene-limited non-directed carboxylation 210 arene-limited oxidative coupling 207 arene-tethered alcohols 46 artemisinin 392 aryl alkyl ketones 91 arylamines 196 aryl-aryl coupling 78, 87 aryl boronic acids 80, 108 aryl boronic esters 95 aryl boroxines 108 aryl carbamoyl chlorides 93 aryl diazonium initiated remote C(sp3)–H functionalization 319 aryl halides 59, 89 aryl iodides 82 aryl ketone products 91 aryl ketones 90 aryl-norbornyl coupling 78, 87

Remote C—H Bond Functionalizations: Methods and Strategies in Organic Synthesis, First Edition. Edited by Debabrata Maiti and Srimanta Guin. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

424

Index

arylnorbornylpalladacycle (ANP) 60, 77, 115 arylpalladium(II) species 61 arylpropiolic acids 91 6-arylpurines 157 2-arylpyridines 140 2-aryl-substituted aziridines 76 aryl-substituted 2H-azirines 75 aryl sulfamate 243 arylsulfonyl chlorides 161 aryl triazenes 317–318 aspidospermidine 101 asymmetric ortho-alkylation of iodoarenes under Pd/NBE catalysis 68 azaheterocycles 328 2,2′ -azanediyldibenzonitrile directing template 10, 11 aziridines 76 azoarene-directed meta-sulfonation 154 azobenzenes 140

b Baran’s electrochemical oxidation 353 Barton’s nitrite photolysis 315 Barton-type 1,5-hydrogen atom transfer processes 315, 348 benzocrown 413 benzocrown (BC) 374, 413 18-benzocrown-6-ether 413 benzo[d]thiazoles 91 benzofuran-containing substrate 73 benzo-fused carbocycles 61 benzo-fused cyclic ketones 93 benzoic acid derivatives 20 benzoic acids 158, 230 benzomorpholine scaffolds 84 benzothiophene 262 benzoxazoles 91 benzyl alcohols 53, 243 benzylamine derivatives 27 benzylamines 178, 183 benzyl chlorides 146, 148, 149 benzyl halides 116 benzylsulfonates 53 benzylsulfonyl esters 47 biaryl-2-trifluoroacetamide derivatives 121 bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate 118 bicyclo[2.1.0]pentane 346 bidentate (bisoxazoline) ligands 335 bifunctional acylation reagents 91, 93 bifunctional aryl bromides 82 bifunctional aryl halides 83

bioinspired catalysts aliphatic C–H oxidation 387 C–H bond oxidations 383–385 innate substrate of C–H oxidations C–H bond strength 388 chirality 395 directing groups 392–393 electronic effects 388–391 stereoelectronic effects 393–395 steric effects 391–392 bipyridine ligand 179 biscyclometalated ruthenium complex 157 bis(pinacolato)diboron 95 1,2-bis(diphenylphosphino)-ethane 193 3,5-bis(trifluoromethyl)-iodobenzene 119 (R)-BNDHP (1,1′ -binaphthyl-2,2′ -diyl hydrogen phosphate) 132 bond dissociation energy (BDE) 344–346, 388 boronic acids 68 bory 193 borylation 240 bridgehead-modified norbornenes 89, 91, 99 bridgehead-substituted norbornenes 99 bromine-catalyzed intramolecular C(sp3)–H amination reaction 326 α-bromo-α-fluoro esters 159 bromoalkylamines 71 2-bromoanisole 81 bromoarenes 80 bromobenzylamines 82 4-bromo-1,2-dimethylbenzene 202 α-bromo esters 158 1-bromohexane 138 2-bromo-6-iodoanisole 96 1-bromo-2-naphthols 81 1-bromo-2-nitrobenzene 87 2-bromophenols 80 4-bromophenols 81 Brønsted and Lewis acids addition 367 Buchwald–Hartwig coupling 97 Buchwald–Hartwig cross coupling reactions 196 Buchwald–Hartwig reaction 95 Buchwald’s Ruphos-Pd-G4 precatalyst 77

c carbazoles 87 carbene precursors 95 2-carbomethoxynorbornene (NBE-CO2 Me) 89 carbonate anhydrides 94

Index

carbonate-based unsymmetrical anhydrides 93 carbon–heteroatom formation amination 196–200 electrophilic aromatic fluorination 202–203 Lewis acid-catalyzed halogenation 202 nucleophilic 18 F-fluorination 203 oxygenation 200–202 silylation 195–196 thianthrenation 205 carboxylate-assisted C–H ruthenation of arene 144 carboxylate residue 385 carboxylic acids 386 catalyst-Cu-substrate complexes 406 catalytic cycle 115, 117, 139 catalytic pyridine-based bifunctional template 33 Catellani reaction/aza-Michael addition sequence 77 Catellani reactions 2, 3 Catellani-type reactions 68, 92, 105 C–C bond forming reactions alkenylation/olefination 208–210 C–H-arylation 206–208 C–H carboxylation of arenes 213 cyanation 210–213 C8–C9 oxidation 374 CD4 -Mn(Porph) 404 ceric ammonium nitrate (CAN) 47, 285 C–H acylation ruthenium catalysis 151 C–H alkylation ruthenium-catalyzed meta-selective C–H functionalizations alkyl bromides 147 alpha-bromocarbonyl compounds 145 arene-ligand-free ruthenium complex 147 benzylations 146–150 mono-and difluoromethylations 144 n-hexyl bromide 139 removable directing groups 143 secondary alkyl halides 140 tertiary alkyl halides 141 transformable/removable directing groups 143 via ortho-ruthenation 142 visible light irradiation 148

C–H carboxylation 150 of arenes 213 C–H deuteration 16 chelating functionality (CF) 8, 9 C–H functionalization of arenes under Pd/NBE catalysis 64 chirality 395 chlorides 82 cholestane 347 C–H sulfonylation ruthenium-catalysis meta/ortho selective C–H functionalizations 161 meta-selective C–H functionalizations 151 para-selective C–H functionalizations 161 cinchona alkaloid 81 cis trans mixture 408 cobalt-catalyzed γ-benzyl C(sp3 )–H dehydrogenative amination 289 concerted metalation deprotonation (CMD) mechanism 192, 208 pathway 54–55 process 96 copper-catalyzed direct arylation of 3-pivaloylindoles with diaryliodonium triflates 261 copper-catalyzed meta-selective arylation strategy 261 copper-catalyzed remote C(sp3)–H azidation of benzohydrazides 330 copper cyanide 91 copper dependent oxygenases 385 copper(I) iodide 68 coumarins 47 Cp*Rh(III) catalysis 259 cross-coupling/aza-Michael addition sequence 82 cross-coupling/oxa-Michael addition product 81 cross-dehydrogenative coupling 208 cross dehydrogenative coupling (CDC) 206 Curtin–Hammett principle 300 cyanide anion 80 cyanides 68, 95 cyano based biphenyl DG 224 2-cyanobenzoyl group 27 2-cyanophenol template 51 2-cyano-phenylethylamine 21 2-cyano-phenylethylamine template 22 cyclic ethers 365, 366 cycloalkanes 158

425

426

Index

cyclodextrins (CD) 404 cyclometalated complexes 137 cyclometallation 279 cyclopentanone-containing alkyl bromides 71 cyclopropane ring 346 cytochrome P-450 384

d dearomatization process 71, 73 decatungstate photocatalysis in aliphatic ketones and esters 352 aliphatic nitriles 352 fluorination and 18 F-fluorination of aminoacids 348, 350 HAT or SET 348 Ibuprofen derivative 350–351 N-fluorobenzenesulfonimide 348 steric and electronic effects 353 steric hindrance 354, 356 decylammonium 413 δ−/ε−C(sp3 )–H bond a of aliphatic amines amino acid derivatives 301, 303 cyclopalladation complex 298 iterative (hetero)arylation of 295, 297 mechanistic experiments and proposed catalytic cycle 300–302 palladium catalyst alkyl amines via transient directing strategy 299–300 anilines and aryl iodides 298 arylation of alkyl picolinamides 293–295 free amines 298–299 intramolecular amination 292 iodoarenes 295–296 methylated products 293–294 oxalyl amide 293–294 vs. pyrrolidines synthesis 292–293 remote arylation of anti-inluenza virus A agent 293–295 remote ε-C(sp3 )-H alkynylation of alkyl amine 295–297 picolinamide directing group 300–301 deuterium-labeled compounds 19, 37 Dextromethorphan 373 DG assisted para-functionalization 222 2,6-diacylaminopyridine 415 dialkyne 99 diaryliodonium salts (Ph2 IBF4 ) 207 diastereomeric ratios 358 diazoderivatives 357 dibenzoazepines 82

dibenzonitrile directing template 16 dibenzoylmethane (dbm) 102 dibenzyl phosphate 293 1,2-dichlorobenzene 194 1,4-dichlorobenzene 194 1,3-dichloropropane 92 2,3-dihydrobenzofuran products 77 dihydrodibenzoazepine derivatives 89 5,6-dihydrophenanthridine derivatives 82 3,4-dihydroquinolones 413 diiodide 99 1,3-diiodo-5,5-dimethylhydantoin (DIH) 45 diisopropylsilyl moiety 224 di-meta-olefination 51 1,2-dimethoxy benzene 199 1,2-dimethoxyethane (DME) 80 1,1-dimethyl-2-alkynyols 69, 70, 95 5,5′ -dimethyl-2,2′ -bipyrine ligand 178 dimethyldioxirane (DDO) 346 1,3-dimethyl-2-imidazolidone 92 dioxiranes 346–348 diphosphine 194 di-polar induced methods 242 directed C4-selective C–H functionalization of benzothiophenes 264 directed metal-catalyzed site-selective C(sp3 )–H functionalization 279, 280 directing group (DG) 2, 222 directing group assisted distal arene meta-functionalization 2 directing group assisted meta-C–H functionalization of arenes transient mediator norbornen catalytic cycle 115, 117 enantioselective meta-C–H functionalization 130–133 meta-C–H alkylation of arenes 116–119 meta-C–H alkynylation of arenes 130 meta-C–H amination of arenes 129–130 meta-C–H arylation of arenes 119–127 meta-C–H chlorination of arenes 127–129 directing group assisted site-selective C–H functionalization of arenes 116 directing group-assisted transition-metal catalyzed C–H functionalization 279

Index

directing template assisted meta-C–H bond functionalization 8 dirhodium catalyst 199 distal arene C(sp2 )–H functionalization 3 distal arene para-C–H functionalizations 4 distal arene-tethered tertiary amine derivatives 28 distal C(sp2)–H functionalization of arenes non-covalent interactions 169 non-directed methods 192 1,2-disubstituted aniline derivatives 204 1,2-disubstituted arenes 207 1,3-disubstituted arenes 173 di-tert-butyl azodiformate (DBAD) 338 4,4′ -di-tert-butylbipyridine (dtbpy) 172 4,4′ -di-tert-butyl-2,2′ -bipyridine 193 di-tert-butylperoxide (DTBP) 146 dopamine-β-hydroxylase (DβH) 385 drug molecules 149

e electrochemical fluorination 355 electrochemistry 332, 354 electron-deficient 95 arenes 20 bromoarenes 84 olefins 80 electron-donating group (EDG) 80 electron paramagnetic resonance (EPR) experiments 142 electron-poor trifluoromethyl benzene 198 electron-rich olefins 95 electron-withdrawing groups (EWGs) 343, 347 electrophilic oxygen-transfer reagent 346 electrophilic palladation 23 enantioenriched iodolactone 69 enantioenriched secondary alkyl iodide 67 enantioenriched secondary halides 67 enantioselective C–H oxidation 413 enantioselective meta-C–H functionalization 130 2e-oxidants 385 epoxides 75, 77 ethereal oxygen 393 ethyl iodoacetate 116 ethyl 2-(4-nitrophenyl)acetate 198

f Fe(CF3 pdp) 392 Fe (TIPS pdp) 392

Fe(CF3 pdp) catalyst 391 Fe(pdp) catalyst 373, 389, 391, 394 Fe(PDP) complexes 372–373 Fenton type 386 (Fe(TIPS mcp) 391 fluorinated alcohol solvents 397 4-fluorobromobenzene 79 Flurbiprofen 19 Friedel–Crafts acylation reactions 214 Friedel–Crafts reaction 4, 221 Friedel–Crafts type arylation process 207 Fujiwara–Moritani reaction 208 Fujiwara–Moritani-type olefination 16 Fukui analysis 204

g γ-C(sp3)–H functionalization of aliphatic acids cobalt catalyst 285 palladium catalysis 281 γ−C(sp3 )–H functionalization of aliphatic ketones/aldehydes 301 γ−/δ−C(sp3 )–H bond functionalization of aliphatic alcohols 305 germanylation 42 γ-fluoroleucine 350 goniomitine 101 Grignard reagent 321

h α-halo carbonyl compounds 142 α-haloesters 261 Hantzsch ester 329, 333 HAT transfer mechanism 348 2H-azirines 75 HBpin 363, 364 6H-dibenzopyran derivatives 81 6H-dibenzopyran products 84 6H-dibenzopyrans 84 Heck acceptors 63, 64, 68, 82, 91 Heck reactions 65, 71, 87, 208 helical alkenes 74 heme dependent oxygenases 384 heptafluoroisopropyl iodide 146 heteroarenes 139 heteroaromatic compounds indole 253–262 pyridine 266–270 pyrrole 264–266 quinoline 271–272 thiazole 271 (benzo)thiophene 262–264 heterocycle functionalizations 4

427

428

Index

hexafluoroisopropanol (HFIP) 8, 10, 11, 14, 18, 24, 44, 55, 224, 354 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) 256, 264, 376, 397 hexamethyldisilane 39, 226 HFIP 400, 401 9H-fluoren-9-ols 84 9H-fluoren-9-one 84 Hofmann–Loffler–Freytag (HLF) reaction 5, 315 Hofmann–Loffler reaction catalytic bromine-mediated 326 catalytic Iodine-mediated 325 visible-light-induced photoredox catalyzed 327 homobenzylamines 105 Horner–Wadsworth–Emmons reactions 51 1,5-H radical abstraction 315 hydride donor 80 hydrocinnamic acid derivatives 10, 16 hydrocinnamic acids 10–12, 16 hydrogen atom 315, 331 hydrogen atom transfer (HAT) 385 hydrogen atom translocation/atomtransfer radical cyclization (HAT/ATRC) 321 hydrogen bond acceptor (HBA) 397 hydrogen bond donors (HBD) 397 hydrogen bonding 408 1,5-hydrogen migration 317 1,5-hydrogen transfer 323 (+)10β-hydroxy-artemisinin 392 2-hydroxybenzonitrile directing template 33 2-hydroxybenzonitrile template 11, 16 hydroxybiphenyl products 84 hydroxylamine 199 hydroxylases 385 2-hydroxy-4-methoxy benzonitrile template 17, 36 hyperconjugation effects 345, 393 hypervalent metal-oxos 386

i ibuprofen 16, 18, 170, 408 ibuprofen derivative 350 imidazole residues 385 iminyl radicals 329–330 indanes derivatives 71 indenones 93 indole C–H functionalization reactions C4 position 254–258 C5 position 261

C6 position 261–262 C7 position 258–260 indole-containing alkyl bromides 71 indoles 73 indolines 71 intramolecular enolate coupling 71 intramolecular hydrogen-atom transfer (HAT) 5, 315 iodides 71 iodination of phenylacetic acid derivatives 20 iodoarenes 60, 65, 68, 73, 74, 96 iodobenzene 61 1-(2-iodobenzyl)-1H-pyrrole 73 iodomethane 116 1-iodonaphthalene 76 4-iodophenylacetylene 99 1-(2-iodophenyl)-1H-pyrrole 73 2-iodopyrrole derivative 87 iodopyrrole substrate 87 3-iodotoluene 91 ion-pair induced methods 243 ipso-Sonogashira reactions 68 ipso-thiolation products 91 (η6 -mes)Ir(Bpin)3 365, 366 iridium-catalysed borylation bipyridine ligands 172 mechanism of 173 non-covalent interactions in 174–176 regioselectivity of 173, 174 iridium-catalyzed amidation with tosylazides 259 iridium-catalyzed borylation 193, 195 iridium-catalyzed β-selective C–H borylation of N-TIPS pyrroles 265 iridium-catalyzed C7-selective C–H borylation, NH indoles 258 iridium catalyzed methods 241 iron complexes 386 iron dependent hydroxylases 384 iron hydroxylases 386 iron-oxo species 385 Ir/phenanthroline system 196 isopropanol 94 isopropyl carbonate anhydride 91

k ketimines 161 α-ketoglutarate dependent oxygenases 384 ketoprofen 18 ketoximes 157 KOtBu-mediated selective carbon-carbon coupling 319

Index

l lenalidomide derivative 124 Leuconoxine 322–323 Lewis acid catalyst 182 Lewis acid-catalyzed halogenation 202 ligand-enabled γ-C(sp3 )–H arylation of aliphatic ketones 304 ligand-promoted γ-C(sp3 )–H arylation of aliphatic aldehydes 305 ligand-substrate non-covalent interactions 171 Li-Li auxiliary 22 (+)-linoxepin 69, 70 lipophilic interactions 403 lipophilic recognition by cyclodextrins 404 L2 Ir(Bpin)3 193 L-iso-leucine derivative 280 L-tert-leucine derivatives 280 L-valine derivative 280

m macrocyclopalladation processes 16, 17, 32 macrolactones 94 Maiti–Bera–Modak (MBM) auxillary 16 manganese center (Mn(terpy-COOH) 408 manganese complexes 387 manganese porphyrin complex 170 Melodinine E 322–323 Mersicarpine 323 mesylation 202 meta-benzylated product 149 meta-bromination 155 meta-C–H acetoxylation of electron-deficient benzoic acid derivatives 22 of indoline derivatives 30, 32 meta-C–H activation of benzylsulfonic acid derivatives 33 meta-C–H activtion reation 16 meta-C–H alkylation of arenes benzylsulfonamide derivatives 119 phenylacetic amide derivatives 118 meta-C–H alkylation of benzylphosphonates 51 meta-C–H alkylation of phosphonates 53 meta-C–H alkynylation of arenes 130 meta-C–H allylation of alcohol derivatives 49 meta-C–H allylation of benzylsulfonyl esters 40 meta-C–H amination of arenes 129

meta-C–H arylation of arenes acetal-based quinolone, directing group 126 amide as directing group 119–121 free carboxylic acid, directing group 126–127 sulfonamide as directing group 122 tertiary amine as directing group 122–123 tethered pyridine-type directing group 123–126 of hydrocinnamic acids with arylboronic esters 14, 15 of hydrocinnamic acids with aryl iodides 14, 15 meta-C–H bond functionalization of arenes directing template assisted 8 mechanisms of 53–55 Pd or Rh catalysts 8 template assisted 9–53 meta-C–H chlorination of arenes 127 meta-C–H cyanation of benzylphosphonates 51 meta-C–H cyanation of benzylsulfonyl 37, 41 meta-C–H deuteration of alcohols 50 meta-C–H deuteration of benzylsulfonyl esters 39, 42 meta-C–H deuteration of phenylacetic acid derivatives 20 meta-C–H deuteration of phosphonates 53 meta-C–H functionalization of anilines 25 meta-C–H functionalization of benzylsulfonyl esters 33 meta-C–H functionalizations of phosphonates 52 meta-C–H hydroxylation/acetoxylation 51 meta-C–H iodination, benzyl and phenylethyl alcohols 45–46 meta-C–H olefination and alkylation of benzylsulfonyl 38 of aniline derivatives 24 of arene-tethered diols 49 of benzoic acid derivatives 24 of benzoic acids 54 of benzyl alcohols 44–45 of benzyl and phenyl ethyl alcohols 45–46 of benzylsulfonic acids 36 of benzylsulfonyl 33 catalytic cycle for 54 of distal arene-tethered alcohols 47

429

430

Index

meta-C–H olefination (contd.) of hydrocinnamic acid derivatives 10–16 of N-heterocycles 32 of N-methyl-phenylethylamine derivatives 27 of 2-phenethylsulphonic acid derivatives 33 of phenylacetate 16 of phenylacetic acid derivatives 17 pyridine-based template assisted 18 pyrimidine-based template assisted 18 of phenylacetic acid rhodiumcatalyzed 17 of phenylethylamine derivatives 27–29 of 2-phenyl phenol derivatives 45 of 3-phenylpyridines 34 of tertiary anilines 26 of tertiary benzylamines 27–28 toluene derivatives 9 meta-C–H oxygenation of benzylsulfonyl esters 41 meta-C–H perfluoroalkenylation of benzylsulfonic acid derivatives 36 meta-C–H perfluoroalkenylation of benzylsulfonyl esters 40 meta-C–H perfluoroalkenylation of phenylacetic acid derivatives 18 meta-C–H silylation 42 meta-decorated products 149 metal-carbon bonds reactions occurring via formation Pt-based Shilov chemistry 361–362 Rh-and Ir-catalyzed C–H borylation of (functionalized) alkanes 363–367 reactions occurring without formation carbene insertion 356–360 decatungstate-photocatalyzed remote functionalization 348–353 electrochemical remote functionalizations 353–356 oxidations with dioxiranes 346–348 metal catalyzed borylation reactions 363 metal-catalyzed C–H amination with organic azides 328 metalloporphyrin complexes 404 metalloporphyrin (bipy)4 -Mn(Porph) 406 meta-selective alkenylation 2 meta-selective borylation 176 meta-selective C–H acetoxylation method 27 meta-selective C–H acetoxylation of benzylamine derivatives 27

(5-phenylisoxazol-3-yl)(piperidin-1-yl) methanone 199 1-methoxynaphthalene 206 methyl benzoate 208 methyl boronic acids 95 methyl-2-bromobenzoate 84 methyl(trifluoromethyl)dioxirane (TFDO) 346–348, 354 methyl ester 22 methylsilanes 263, 363 methyl vinyl ketone 82 mixed-anhydride 91 Mizoroki–Heck-type dearomatization 89 Mn2 (terpy) 408 Mn(CR pdp) 413 Mn(pdp) complexes 413 Mn-porphyrin catalyst 413 Mn(III) porphyrin complex (CholMn(porph)) 403 mono-alkylarenes 210 mono and dicopper dependent oxygenases 385 mono-N-protected amino acid (MPAA) ligand 8, 10, 14, 23, 24, 55 monoprotected amino acids (MPAA) 139 mono-selective meta-C–H olefination of hydrocinnamic acids 11 multicyclic δ-lactam 87 multi-functionalized aromatic carboxylic esters 94

n N-acetyl glycine (Ac-Gly-OH) 8 N-alkoxyphthalimides 333–334 N-aminated dihydropyridine 329 naphthalene-based iodoarenes 74 naphthylamine 74 N-aryl-N ′ -chloromethyldiazoniabicyclo [2.2.2]octane salts 197 natural products 93 N-based heteroarene-containing templates 16 NBE-CO2 Me 103 NBE-derived mediator 2-carbomethoxynorbornene 117 N-benzoyloxyamines 94, 97, 99 N-benzoyloxyamines and norbornadiene (NBD) 96 N-bromosuccinimide 202 N-(4-chlorophenyl)-S-(trifluoromethyl) thiohydroxylamine 204 N-containing heteroarene-based templates 18

Index

N-containing pyrimidine-based template 18 N-cyclohexylamides 394–395 negative radical clock tests 347 N-fluorobenzenesulfonimide (NFBS) 196, 348 N-formyl-protected glycine (Formyl-Gly-OH) 17 NFSI 202 N-heterocyclic arene derivatives 29 NH-sulfoximines 84 nickel/aluminum-catalyzed C4-selective C–H alkylation of pyridines with alkenes 269 nitrile-based carbamate template 24 nitrile-based directing template 9 nitrile-based or N-heterocycle-based templates 20 nitrile-based phenolic directing template 16 nitrile-based templates 18, 23 nitrogen-containing molecules 395 nitrogen donor heterocycle 386 N,N-dihexylbenzylamide 176 non-arene-limited Fujiwara-Moritani reaction 209 non-covalent interactions induced para-C–H functionalization di-polar induced methods 242–243 ion-pair induced methods 243–244 iridium-catalysed borylation 171–174 in metal catalyzed C–H bond functionalisation 170–171 meta-selective borylation 176–181 para-selective borylation 181–185 non-directed fuctionalizations of aliphatic compounds 5 non-directed Fujiwara–Moritani reaction 208 non-directed methods carbon–heteroatom formation (Lewis)acid-catalyzed halogenation 202 amination 196–200 borylation 193–195 electrophilic aromatic fluorination 202 oxygenation 200–202 silylation 195–196 thianthrenation 205 carbon–heteroatom formationelectrophilic aromatic fluorination 203

C–C bond forming reactions alkenylation/olefination 208–210 C–H-arylation 206–208 C–H carboxylation of arenes 213–214 cyanation 210–213 mechanisms 192 non heme iron dependent oxygenases 384 non-oxidative coupling homocoupling 207 non-porphyrinic iron catalysts 386 norbornane 346 norbornene (NBE) 2 5-norbornene-2-carboxylic acid (NBE-CO2 H) 71 norbornene-containing dihydrophenanthrene products 89 norbornylpalladium intermediate 60 N-silylketimines 82 N-substituted aziridines 75 N-sulfonylated 87 N-tosylhydrazones 68 N-trifluoroacetylated benzylamines 179 N-trifluoroacetylglycine 126 nucleophilic 18 F-fluorination 203 nucleotides 149

o o-biaryl carbaldeydes or ketones 84 O-borylation 175 o-bromoarene-and heteroarenecarboxylic acids 82 o-Bromophenols 84 o-bromophenylacetamides 89 Odanacatib 350 oestrone 99 O–H bond 333, 336–338 o-iodoaniline derivatives 97 olefin-containing alkyl bromides 61 olefin-containing bifunctional acylation reagents 93 olefinic alcohol-containing alkyl bromides 71 olefins 84 organic field-effect transistors (OFETs) 262 organofluorine compounds 36, 141 organosilicon compounds 226 organosilicon template assisted meta-C–H olefination of phenol derivatives 41, 43 ortho-acylation/ipso-borylation protocol 93 ortho-acylation ipso-selenation reaction 94 ortho-acylation of aryl iodides aliphatic carboxylic acid derivatives 93 bifunctional acylation reagents 92

431

432

Index

ortho-acylation of aryl iodides (contd.) norbornene derivatives, mediator 91 pre-formed or in-situ generated anhydrides 90 terminating reagents 92 thioesters 91 ortho-acylation product 91 ortho-acylation reactions of iodoarenes 91 ortho-alkoxycarbonylation/ipso-reduction product 94 ortho-alkoxycarbonylation of aryl iodides 94 ortho-alkylated aryl Pd(II) species 69 ortho-alkylation/ipso-alkynylation reactions 70 ortho-alkylation/ipso-Heck coupling of iodoarene 70 ortho-alkylation/ipso-Suzuki coupling sequence 68 ortho-alkylation of iodoarenes 68 ortho-alkylation reactions 68 ortho-alkylation with enantioenriched secondary alkyl iodides 67 ortho-alkylation with racemic secondary alkyl iodides 66 ortho-aminated dihydroquinolinones 96 ortho-amination of iodoarenes bridgehead-substituted norbornenes 99 N-benzoyloxyamines 94–98 ortho-thiolation 101 ortho-aminocarbonylation 94 ortho-arylation/ipso-1,2-addition sequence 84 ortho-arylation/ipso-amination 84 ortho-arylation/ipso-reduction reactions 80 ortho-bisarylated products 89 ortho-bromoarenesulfonylanilines 82 ortho-C–H alkylation of aryl iodides Lautens’ modified reaction conditions 61 olefin-containing alkyl bromides 61 ortho-C–H functionalization 7 ortho-chloro-N-silylaldimines 82 ortho-C–H palladation 103 ortho-C–H trifluoroethylation iodoarenes with trifluoroethyl iodide 64, 65 ortho effect 78, 87–90 ortho-electron-withdrawing group (o-EWG) 15 ortho-functionalized arenes 99 ortho-functionalized aryl-Pd(II) intermediate 63

ortho-iodo(hetero)arylsulfonyl protected alcohols 319 ortho-substituted aryl iodides 82 ortho-substituted iodoarenes 61 ortho-thiolation 101 ortho-unsubstituted iodoarenes 99 ortho-xylene 202 oxa-Michael addition 77 oxidation with dioxiranes 346, 347 oxidative ruthenium-catalyzed meta-benzylation with toluene derivatives 148 oxidative transformations 137 9-oxo-artemisinin 392 oxygenases 385

p palladacycle 102, 103 palladacyclic complex 115 palladium-catalyzed C3-selective C–H alkenylation of pyridines with acrylates 266 C–H arylation of pyridines with aryl (pseudo)halides 266 C–H arylation with aryl bromides 268 palladium-catalyzed γ-C(sp3 )–H alkenylation of carboxylic acids 282, 286 alkylation of L|i-valine derivative 281 alkynylation of 3,-dimethylbutyic amide 283 arylation of a ketone 304 arylation of aliphatic carboxylic acids 280, 282 arylation of amino acids 281 arylation of N-Phth valine 287, 290 arylation of N-protected amino acid and oligopeptides 287, 291 chalcogenation of carboxylic acids 285 of free aliphatic acids 287, 290 intramolecular amination 285, 289 olefination and carbonylation ligand-enabled 284 sequential 282, 285 quinoline-ligand enabled 281 silylation and germanylation of carboxylic acids 283, 287 Palladium(II)-catalyzed meta-selective C–H allylation of alcohol derivatives 47 Palladium(II)-catalyzed meta-selective C–H allylation of benzylsulfonyl esters 36

Index

Palladium-catalyzed meta-selective C–H deuteration of benzylphosphonates 53 palladium-catalyzed meta-selective C–H olefination of phenols 42 palladium catalyzed methods template assisted para-selective C–H functionalization acetoxylation 230–232 alkenylation 224–226 cyanation 232–233 ketonization 227–230 silylation 226–227 palladium-catalyzed oxidative direct arylation with arylboronic acids 260 palladium/norbornene ((Pd/NBE)) catalysis Pd(II)-catalyzed C-H functionalization of arenes 101 palladium/norbornene (Pd/NBE) catalysis bisfunctionalizaztion of aryl (pseudo)halides 62 Catellani’s initial report on 60 ortho-C-H alkylation of aryl iodides 60 ortho-C-H alkylation of ortho-substituted iodoarenes 61 Pd(II)-initiated C-H functionalization of arenes 63, 64 Pd(0)-initiated reactions 64 para-alkylation of benzenesulfonamides 239 para-borylation of arenes 241 para-C–H borylation 180 para-C–H functionalization DG assisted 222 non-covalent interaction induced di-polar induced methods 242–243 ion-pair induced methods 243–244 rhodium catalyzed functionalization 233 steric controlled selective distal C–H functionalization 234 template assisted 224–233 para-selective borylation 181 para-selective C–H borylation 243 particulate methane monooxygenase (pMMO) 385 Pd-Ag heterodimeric transition state 54 Pd-catalyzed aryl C–H imidation of arenes 196 Pd(II)-catalyzed C–H functionalization of arenes

C2-functionalization of indoles and pyrroles 101–102 meta-C–H functionalization 102–105 ortho-C–H functionalization of arylboron species 105–108 Pd(0)-catalyzed C–H functionalization of aryl (pseudo)halides ortho-acylation and alkoxycarbonylation 89–94 ortho-alkylation alkyl halides 64–70 with bifunctional alkylating reagents 70–74 three-membered heterocycles 75–77 ortho-alkylation reactions 77–89 ortho-amination 94–100 Pd-catalyzed meta-C–H allylation of phenylacetic acid derivatives 20 Pd-catalyzed meta-C–H deuteration of phenylacetic acid derivatives 19 Pd-catalyzed meta-C–H olefination of phenylacetic acid 18 Pd-catalyzed meta-C–H olefination of 2-phenyl phenol derivatives 42 Pd(II)-catalyzed meta-C–H olefination of phosphonates 51 Pd-catalyzed remote meta-C–H olefination 46 Pd(IV) intermediate 87 Pd(II) salt 61 pentasubstituted arene 93 peptides 149 perfluoroalkenylation 18 perfluoroolefins 18, 36 peroxides 385 phenanthridine derivatives 84 phenanthridines 82 phenanthridinones 93 6-phenanthridinones 82 phenanthroline 77 phenethylamines 179 2-phenethylsulphonyl esters 33, 37, 38, 41 phenol derivatives 40 phenol-derived substrates 74 phenol-derived sulfate salts 184 phenol-tethered iodoarenes 96 phenoxazine product 84 α-phenoxycarboxylic acids 40 phenoxypyridines 140, 161 phenylacetic acid derivatives 16 phenylacetic acid esters 18 phenylacetic acid frameworks 18 phenylalanine derivatives 118

433

434

Index

phenylboronic acid (PhB(OH)2 ) 207 2-phenylethanesulfonic acids 39 2-phenylethyl 46 phenylethyl alcohols 47 phenylethylamine derivatives 27 phenylnorbornylpalladium(II) (PNP) 2, 59 2-phenylpiperidine 27 3-phenylpropane-1-sulfonic acid 39 3-phenylpropyl alcohols 46 phenylpropylamines 179 phenylpyridine 138 2-phenylpyridine 152 phenyl–pyrrole biaryl coupling 87 2-phenylpyrrolidine 27 phosphine-free conditions 69 phosphine ligand 63 phosphonate derivatives 51 3-phosphonatedquinolinone photocatalyst 335 phosphoramidite 87 phosphoramidite ligand 71 photochemical remote amine functionalization 374 photoredox/copper catalysis 335 photoredox ruthenium catalysis 146 phtalocyanins 386 picolinamide directing group 289, 300, 301 poisoning effect 196 polarity reversal activation and deactivation 368 alcohols and amides via hydrogen bond interactions 376–378 aliphatic amines via quaternary ammonium salts 368–376 Brønsted and Lewis acids addition 367 remote oxidation amide containing substrates by methylation 397 amine containing substrates by protonation 395–397 via fluorinated alcohol solvents 397–401 polycyclic substituted vinylarenes 68 polydentate ligands 386 polyfluoroarene-substituted benzofuran derivatives 68 polyheterocyclic sulfoximines 84 polyoxometalate (POM) 348 porphyrin complexes 386 porphyrinic ligation 386 porphyrins 386 propiolic acids 95

protodepalladation 103 pseudohalides 59, 89 pymidine-based template 49 pyridine 266 pyridine-based template assisted meta-C–H arylation 20 pyridine-based template assisted meta-C–H olefination of phenylacetic acid derivatives 18 pyridine derivative 102 pyrimidine-based template 47 pyrimidine-based template assisted meta-C–H olefination of phenylacetic acid derivatives 18 pyrimidylanilines 158 pyrrole 264

q quaternized 2-chlorobenzylamine 178 quinazoline-2,4-dione moieties 415 quinoline 271 quinoline ligand 103

r radical addition-translocation-cyclization (RATC) 374, 376 radical initiated distal C(sp3 )–H functionalizations 5 radical-mediated distal C(sp3)–H functionalization Hofmann–Loffler–Freytag (HLF) reaction 315 hydrogen-atom transfer (HAT) 322 hydrogen transfer 317 nitrogen-centered radicals alkyl radical 322–323 aryl iodide 318 aryl triazenes 317–318 hydrogen-atom transfer 322 1,5-hydrogen transfer 323 KOtBu-mediated selective carbon-carbon coupling 319 N–H bonds 332 N–N bond 328–329 N–O bond 329–331 N–X (X=F, Cl, Br, I) bond 325–328 radical arylation 319–320 using aryl diazonium salt reagents 317 vinyl radical 321–323 oxygen-centered radicals 333–338 radiochemical yields (RCYs) 203 regiodivergent C–H activation 28

Index

remote meta-para-selective C–H activation 138 remote oxidations reversal of polarity 395–401 supramolecular recognition hydrogen bonding 408–416 ligand to metal coordination 406–408 lipophilic interactions 403–404 lypophilic recognition by cyclodextrins 404–406 remote-selective C–H olefination 28 remote-selective meta-C–H olefination of hydrocinnamic acids 12 reticulated vitreous carbon (RVC) anode 354 retro-Diels–Alder reaction 97 retro-Mannich reaction 82 rhazinal 87 Rh-based chiral Lewis acid catalysis 334 Rh(III)-catalyzed meta-C–H alkenylation of hydrocinnamic acids 12 Rh-catalyzed meta-C–H olefination of benzylsulfonyl esters 39 Rh(III)-catalyzed meta-C–H olefination of phenol derivatives 43 Rh-catalyzed silylation 195 rhodium-catalyzed meta-C–H olefination of phenylacetic acid 17 rhodium catalyzed para-selective alkenylation 233 rhodium nitrenoids 199 Rh triphenylmethanecarboxylate complex Rh2 (TPA) 357 Rieske oxygenases 384 riphenylcyclopropanecarboxylate complex 357 Ritter’s electrophilic method 203 [Ru(bpy)3 ](PF6 )2 198 Ru-porphyrin catalysts 412 ruthenacycle 144, 149, 159 ruthenacycle intermediate 144 ruthenium-benzene complexes 137 ruthenium catalysis meta-C–H functionalizations acylation 151 alkylations 138–146 carboxylation reactions 150–151 C–H benzylations 146–150 halogenation 152–155 nitration 155–158 sulfonylation 151–152

meta-/ortho-C–H difunctionalizations 161 para-C–H functionalizations 158–161 ruthenium catalyzed distal meta and para-C–H functionalization 3 ruthenium-catalyzed meta-bromination 154 ruthenium-catalyzed meta-halogenation 155, 156 ruthenium-catalyzed meta-nitration 156, 157 ruthenium-catalyzed remote C–H nitration 158 ruthenium(II) complex 149, 157 ruthenium(III) intermediate 144

s Sclareolide 348, 354 Se-aryl and Se-alkyl compound 92 secondary α-methyl substituent 18 Selectfluor 202, 355, 356 selective aliphatic C–H oxidation at dicopper complexes 416 selective C–H oxidation 5 selenoates 92 sequential remote-selective regiodivergent C–H olefination of 2-fluorophenylethylamine 28, 29 Shilov oxidation method 367 Shilov system 361 Sigma Aldrich Li-Li auxiliary 22 Maiti–Bera–Modak (MBM) auxiliary 16 Yu-Li auxiliary 10 silane derivatives 50 silylation 195 spirocarbocyclic products 81 spirocyclic compounds 89 spirodihydroindenones 71 spiroindenes 96 spiroindolenine-containing pentacyclic products 73 spiroindolenine derivatives 71 spiro-polycycles 73 spiro-polycyclic scaffold 74 stereoelectronic effects steric controlled selective distal C—H functionalization nickel catalyzed methods alkylation and alkenylation 234–240 iridium catalyzed methods 240–242 steric effects 391 steric hindrance 347, 351, 354, 356

435

436

Index

steric shield 183, 184 steroid substrate 170 Stigmasteryl acetate 359 strain release 394 and torsional effects 394 strychnine 99 sulfamate 243 sulfonamide 118 sulfonamide chelating template 22 sulfonated bipyridine ligands 178, 179 sulfonated ligand 179 sulfonic acid derivatives 33 supramolecular catalysts 413 supramolecular recognition hydrogen bonding 408–416 ligand to metal coordination 406–408 lipophilic interactions 403–404 lypophilic recognition by cyclodextrins 404–406 synergistic ruthenium-phosphine catalysis 146

t TADDOL-derived chiral ligand 97 template assisted meta-C–H functionalization acid derivatives benzoic acids 20–23 hydrocinnamic 10–16 phenylacetic 16–20 alcohol derivatives 44–50 aniline derivatives 23–27 N-heterocyclic arene derivatives 29–33 phenol derivatives 40–44 phosphonate derivatives 51 silane derivatives 50–51 sulfonic acid derivatives 33–40 toluene derivatives 9–10 template assisted para-selective C—H functionalization palladium catalyzed methods acetoxylation 230–232 alkenylation 224–226 cyanation 232–233 ketonization 227–230 silylation 226–227 terpyridine ligand (Terpy-COOH) 408 tert-butylbenzene 195 tertiary amine 105 tertiary anilines 25 tertiary bridgehead carbons 346 tethered pyridine-type directing group 128

tetraalkylammonium counterion 243, 244 tetraamido macrocyclic ligands (TAML 386 tetrabutylammonium acetate (TBA-OAc) 155 tetrabutylammonium oxone (TBAO) 408 tetrabutylammonium (TBA) salt 14 tetracyclic fused pyrroles 73 tetrahydrofuran 393 tetrahydroisoquinolines 77 tetrahydronaphthalene 71, 295 tetrahydropyran 393 tetrahydroquinoline 24 tetrahydroquinolines 23, 30, 71 3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen) 172 tetra-n-butylammonium sulfate 243 tetra-n-butylamonium cation 243 tetra-n-propylamonium sulfates 243 thermal/photochemical decomposition 315 thiazole 271 thioates 92 2-thiocyanoimidazolium salts 210 thiofluoromethylation 205 thiophene 262 thiophenol 204 Thorpe–Ingold effect 9 three-membered heterocycles 75 titration experiments 413 Togni’s reagent 323, 329 toluene derivatives 9, 146 torsional effects 394 tosylation 202 trans-1,2-DMCH 392 transition metal catalysed distal C–H functionalization 5 transition-metal-catalyzed cross-coupling methods 206 transition metal-catalyzed cross coupling reactions 59 transition-metal-catalyzed meta-C–H activation of benzoic acids 20 transition-metal catalyzed meta-C–H functionalizations of (hetero) arenes 21 transition metal-Lewis acid co-operative catalytic process 222 tri-alkenylated arenes 51 triarylcyclopropanecarboxylate-based catalysts 358

Index

2,4,6-trichlorobenzoyl chloride 91 tricyclic benzonitriles 64 tricyclic mescaline analogue 64 triflation 202 trifluoroethanol (TFE) 397 tri-2-furylphosphine (TFP) 63 triiodide-mediated δ-amination of inert C–H bonds 326 tri(isopropyl)silyl (TIPS) 254, 391 tryptophan-type substrate 254

v vinyl azide 329 Vismodegib, 155 vitamin D2 derivatives 347

w water-soluble poly(p-phenylene ethynylene) (PPEs) 99

x

u

XPhos 17 Xphos 36

unsaturated carboxylic acid anhydrides 93 U-turn lactam ring ((Lactam)Ru(porph) 412

y Yu-Li auxiliary 10

437

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