Advances in Organic Synthesis [1 ed.] 9781681085647, 9781681085654

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Advances in Organic Synthesis (Volume 8) Edited by Atta-ur-Rahman, FRS Honorary Life Fellow, Kings College, University of Cambridge, Cambridge, UK

 

Advances in Organic Synthesis Volume # 8 Editor: Atta-ur-Rahman ISSN (Online): 2212-408X ISSN (Print): 1574-0870 ISBN (Online): 978-1-68108-564-7 ISBN (Print): 978-1-68108-565-4 ©2018, Bentham eBooks imprint. Published by Bentham Science Publishers – Sharjah, UAE. All Rights Reserved. First published in 2018.

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CONTENTS PREFACE ................................................................................................................................................ i LIST OF CONTRIBUTORS .................................................................................................................. ii CHAPTER 1 CATALYTIC TANDEM REACTIONS TRIGGERED BY THE INTRODUCTION OF A CARBONYL FUNCTION ........................................................................................................... Pascal D. Giorgi and Sylvain Antoniotti INTRODUCTION .......................................................................................................................... OXIDATION/HETERONUCLEOPHILE ADDITION .............................................................. OXIDATION/C-NUCLEOPHILE ADDITION .......................................................................... OXIDATION/SOPHISTICATED REACTIONS ........................................................................ CARBONYL INSTALLATION/REACTIONS ........................................................................... CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ............................................................................................................................... CHAPTER 2 SYNTHETIC APPLICATIONS OF BIFUNCTIONAL KNÖLKER TYPE IRON COMPLEXES AS (DE)HYDROGENATION CATALYSTS ............................................................. Raffaella Ferraccioli INTRODUCTION .......................................................................................................................... HYDROGENATION ...................................................................................................................... Knölker’s Iron Complex: Direct and Transfer Hydrogenation Reactions .............................. Switching Fe/OH Complex to Fe/SiH Complex: Transfer Hydrogenation of Alkyne and Alkene ..................................................................................................................................... In Situ Generated Knölker Type Iron Complexes .................................................................. (Cyclopentadienone)Iron Tricarbonyl Complexes: Direct Hydrogenation of Carbonyl Compounds .................................................................................................................... (Cyclopentadienone)Iron Tricarbonyl Complexes: Bicarbonate and CO2 Hydrogenation ............................................................................................................... Nitrile-Ligated (Cyclopentadienone)Iron Dicarbonyl Complexes: Hydrogenation of Carbonyl Compounds .................................................................................................... Hydrogenation under Water Gas Shift Reaction (WGSR) Conditions ................................... (Cyclopentadienone)Iron Tricarbonyl Complex: Aldehyde Reduction ......................... Heterobimetallic Knölker Type Complex: Benzaldehyde Reduction ............................ ASYMMETRIC HYDROGENATION ........................................................................................ Chiral Iron Complexes: Hydrogenation of C=O Bond ........................................................... Combining Achiral Knölker’s Complex and Chiral Additive: Hydrogenation of C=N Bond DEHYDROGENATION ................................................................................................................ Knölker’s Iron Complex: Alcohol Dehydrogenation ............................................................. (Cyclopentadienone) Iron Complexes: Alcohol Dehydrogenation ......................................... METHODS BASED ON DEHYDROGENATIVE ALCOHOL ACTIVATION ..................... Borrowing Hydrogen Methodology ........................................................................................ Carbon-Nucleophile: Carbon-Carbon Bond Formation .............................................. Nitrogen-Nucleophile: Carbon-Nitrogen Bond Formation .......................................... Heterocycle Synthesis via C-C and C-N Bond Formation ............................................ Dynamic Kinetic Resolution of Alcohols ............................................................................... CONCLUDING REMARKS ......................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST .........................................................................................................

1 1 4 10 13 18 23 24 24 24 24 32 32 35 35 38 39 40 45 45 47 47 48 49 49 52 55 55 56 58 58 58 61 66 70 73 74 74

ACKNOWLEDGEMENTS ........................................................................................................... 74 REFERENCES ............................................................................................................................... 74 CHAPTER 3 SUPERELECTROPHILIC ACTIVATION OF ALKYNES, ALKENES, AND ALLENES ................................................................................................................................................ Aleksander V. Vasilyev INTRODUCTION .......................................................................................................................... Superelectrophilic Activation of Alkynes ............................................................................... Superelectrophilic Activation of Alkenes ............................................................................... Superelectrophilic Activation of Conjugated Enynones ......................................................... Superelectrophilic Activation of Allenes ................................................................................ Superelectrophilic Activation of Trifluoromethyl Substituted Alkynes and Alkenes ............ CONCLUDING REMARKS ......................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ............................................................................................................................... CHAPTER 4 CHITOSAN AND ITS DERIVATIVES: SYNTHESIS STRATEGY AND APPLICATIONS ..................................................................................................................................... Tecia V. Carvalho, Raphaela V. Barreto, Alysson L. Angelim, Samantha Pinheiro Costa, Walderly M. Bezerra, Francisco E. A. Melo, Afrânio A. Craveiro, Gloria Maria, Marinho da Silva Sampaio, Gilberto Dantas Saraiva, Vicente de Oliveira Sousa Neto Vania M.M. Melo and Ronaldo Ferreira do Nascimento INTRODUCTION .......................................................................................................................... Source of Chitin and Chitosan in Nature ................................................................................ Chitosan Properties ................................................................................................................. Synthesis of Chitosan Derivatives .......................................................................................... Chitosan and its Derivatives: Antimicrobial Activity ............................................................. Importance of the Degree of Deacetylation (DD) of Chitosan ............................................... Antimicrobial Action by Chelating Capacity of Chitosan ............................................. Toxicity of Chitosan and Chitosan Derivatives ...................................................................... Environmental Application of Chitosan - Derivatives ............................................................ Entrapment of Bacterial Strains into Chitosan Beads for Bioremediation Application ......... Entrapment of Cells in Chitosan Beads .................................................................................. Chitosan/Derivatives for the Bioremediation of Oil-Polluted Seawater ................................. Chitosan: Alternative Application as Coagulation Aid .......................................................... Chitosan/Metal Oxides Nanocomposites ................................................................................ Chitosan: A Versatile Biocompatible Polymer ....................................................................... CONCLUDING REMARKS ......................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ............................................................................................................................... CHAPTER 5 SYNTHESIS OF N-CONTAINING HETEROCYCLES VIA HYPERVALENT IODINE(III)-MEDIATED INTRAMOLECULAR OXIDATIVE CYCLIZATION ........................ Jiyun Sun, Daisy Zhang-Negrerie, Yunfei Du and Kang Zhao THREE-MEMBERED RING ........................................................................................................ 2H-Azirine .............................................................................................................................. Aziridine ................................................................................................................................. Four-membered Ring ..............................................................................................................

81 81 82 88 91 99 102 114 115 115 115 115 121

122 122 122 123 128 131 136 143 144 144 147 156 158 161 161 161 162 162 162 163 175 176 176 177 177

Azetidines ...................................................................................................................... Four-membered β-Lactam ...................................................................................................... Five-membered Ring .............................................................................................................. Pyrrole Derivatives ....................................................................................................... Indole Derivatives ................................................................................................................... Azoles ............................................................................................................................ Six-membered Ring ................................................................................................................ Seven-membered Ring ............................................................................................................ Spiro- and Fused- Heterocycles .............................................................................................. CONCLUSION AND FUTURE PERSPECTIVE ....................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 6 ADVANCEMENTS IN IONIC LIQUIDS FOR THE FORMATION OF MORITA BAYLIS-HILLMAN ADDUCTS ........................................................................................................... Gitanjali Jindal, Navneet Kaur and Subodh Kumar INTRODUCTION .......................................................................................................................... Origin and Features of Morita Baylis-Hillman reaction ......................................................... Present Status in Context to Ionic Liquids .................................................................... Imidazolium-based Ionic liquids ................................................................................... CONCLUDING REMARKS ......................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ...............................................................................................................................

177 178 178 178 181 184 195 202 203 211 212 212 212 212 224 224 225 226 229 248 249 249 249 249

SUBJECT INDEX ................................................................................................................................... 255

i

PREFACE This volume of Advances in Organic Synthesis presents some recent exciting developments in synthetic organic chemistry. It covers a range of topics including important researches on novel approaches to the construction of complex organic compounds. The book should prove to be a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information in synthetic organic chemistry. The chapters are written by authorities in the field and are mainly focused on catalytic tandem reactions, synthetic applications of bifunctional Knölker type iron complexes, superelectrophilic activation processes, synthetic applications of chitosan, synthesis of N-containing heterocycles via hypervalent iodine(III)-mediated intramolecular oxidative cyclizations, and use of ionic liquids in formation of Morita Baylis-Hillman adducts. I hope that the readers will find these reviews valuable and thought provoking so that they may trigger further research in the quest for new developments in the field. I am grateful to Bentham Science Publishers for the timely efforts made by the editorial personnel, especially Mr. Mahmood Alam (Director Publications), Mr. Shehzad Naqvi (Senior Manager) and Dr. Faryal Sami (Assistant Manager).

Prof. Dr. Atta-ur-Rahman, FRS Honorary Life Fellow Kings College University of Cambridge Cambridge UK

ii

List of Contributors Afrânio A. Craveiro

Parque de Desenvolvimento Tecnológico, Av. Humberto Monte 2977, Campus do Pici, Universidade Federal do Ceará, PADETEC, CEP: 60440593, Fortaleza, CE, Brazil

Aleksander V. Vasilyev

Department of Chemistry, Saint Petersburg State Forest Technical University, Saint Petersburg, Russia Institute of Chemistry, Saint Petersburg State University, Saint Petersburg, Russia

Alysson L. Angelim

Biotrends Desenvolvimento Tecnológico, Av. Humberto Monte 2977, Campus do Pici, Universidade Federal do Ceará, Galpão 16, CEP:60440593, Fortaleza - CE, Brazil

Daisy Zhang-Negrerie

Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China

Francisco E.A. Melo

Departamento de Física, Universidade Federal do Ceará, CEP 60455-760, Fortaleza, CE, Brazil

Gilberto Dantas Saraiva

Departamento de Física, Universidade Estadual do Ceará-UECE, CEP, 63900-000, Quixadá, CE, Brazil

Gitanjali Jindal

Department of Chemistry, Panjab University, Chandigarh, Punjab, India

Gloria Maria Marinho da Silva Sampaio

Instituto Federal do Ceara - Mestrado em Tecnologia e Gestão Ambiental, CEP:60040-531, Fortaleza - CE, Brazil

Jiyun Sun

Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China

Kang Zhao

Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China

Navneet Kaur

Department of Chemistry, Panjab University, Chandigarh, Punjab, India

Pascal D. Giorgi

Université Côte d’Azur, CNRS, Institut de Chimie de Nice, France

Raffaella Ferraccioli

CNR-Istituto di Scienze e Tecnologie Molecolari, Via C. Golgi 19, 20133 Milano, Italy

Raphaela V. Barreto

Departamento de Ciências Animais, Universidade Federal Rural do SemiÁrido, Av. Francisco Mota, 572, Presidente Costa e Silva, CEP 59625900, Mossoró, RN, Brazil

Ronaldo Ferreira do Nascimento

Departamento de Química Analítica e Físico Química, Universidade Federal do Ceara- UFC, CEP: 60455-760, Fortaleza, CE, Brazil

Samantha Pinheiro Costa

Biotrends Desenvolvimento Tecnológico, Av. Humberto Monte 2977, Campus do Pici, Universidade Federal do Ceará, Galpão 16, CEP:60440593, Fortaleza - CE, Brazil

Subodh Kumar

Guru Nanak Dev University, Punjab, India

Sylvain Antoniotti

Université Côte d’Azur, CNRS, Institut de Chimie de Nice, France

iii Tecia V. Carvalho

Parque de Desenvolvimento Tecnológico, Av. Humberto Monte 2977, Campus do Pici, Universidade Federal do Ceará, PADETEC, CEP: 60440593, Fortaleza, CE, Brazil

Vania M.M. Melo

Laboratório de Ecologia Microbiana e Biotecnologia, Departamento de Biologia, Universidade Federal do Ceará. CEP: 60455-760, Fortaleza, CE, Brazil

Vicente de Oliveira Sousa Neto

Departamento de Química, Universidade Estadual do Ceará, CEP: 63900000, Quixadá, CE, Brazil

Walderly M. Bezerra

Laboratório de Ecologia Microbiana e Biotecnologia, Departamento de Biologia, Universidade Federal do Ceará. CEP: 60455-760, Fortaleza, CE, Brazil

Yunfei Du

Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China

Advances in Organic Synthesis, 2018, Vol. 8, 1-31

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CHAPTER 1

Catalytic Tandem Reactions Triggered by the Introduction of a Carbonyl Function Pascal D. Giorgi and Sylvain Antoniotti* Université Côte d’Azur, CNRS, Institut de Chimie de Nice, France Abstract: Catalysis has played a prominent role in recent decades allowing chemists to develop novel and efficient reactions in almost every class of chemical transformation. With the tuning of the catalysts’ steric and electronic properties, sophisticated reactions have been discovered, sometimes featuring several individual steps and resulting in one-pot formation of complex chemical structures with high atom-economy. With the increasing recognition of the importance of green and sustainable chemistry, the concept of step-economy has gained traction and one-pot multistep reactions have been developed. Current research in this area now focuses on the use of multiple catalysts within the same reactor to convert simple and available substrates into complex and valuable products. In this chapter, we review a selection of examples of catalytic tandem reactions triggered by the introduction of a carbonyl function either formed by oxidation of alcohols, hydroformylation, isomerisation or carbonylation. In particular, we emphasize nanocatalysis, the use of metal nanoparticles as catalysts. The in situ formation of reactive carbonyl electrophiles opens a wide array of possible subsequent reactions as illustrated in the following pages.

Keywords: Biocatalysis, Dual catalysis, Fine chemicals, Green chemistry, Metal nanoparticles, Multicatalysis, Nanocatalysis, One-pot reactions, Organocatalysis, Orthogonal multicatalysis, Oxidation, Sustainable chemistry, Tandem reactions. INTRODUCTION When green and sustainable chemistry principles were released in 1998 [1 - 3], a significant portion of the scientific community reacted with skepticism. Trendy science, useless chemistry, and inefficiency are examples of flaws attributed to green chemistry. About 20 years later, one can say that a significant shift has been made towards greener and more sustainable chemistry in most fields of the chemical sciences, both in academia and in industry. These efforts have been made around four pillars that are: 1) Waste diminution; 2) Resource management; * Corresponding author Sylvain Antoniotti: Université Côte d’Azur, CNRS, Institut de Chimie de Nice, Parc Valrose, 06108 Nice cedex 2, France; Tel: +33 (0) 4 92 07 61 72; Fax: +33(0) 4 92 07 61 51; E-mail: [email protected]

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

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3) Safety and innocuity of chemicals; and 4) Energy consumption. In many instances, catalysis has been shown to improve sustainability profiles by addressing multiple aspects of green chemistry. Indeed, catalysis, which is one of the twelve principles substituting stoichiometric promoters by catalytic entities, could also contribute to resource management of metals, lowering of energy requirements and waste prevention with the design of highly efficient and selective chemical processes [4 - 6]. An important principle when dealing with synthetic method development in organic chemistry is the principle of atom economy [7, 8], which eventually contributes to the even more important principle of waste prevention. Atom economy (AE) compares the molecular weight of the target product with the sum of the molecular weights of all the chemicals involved in the reaction, i.e. starting material(s), reagent(s) and in theory even solvent(s). Ideal reaction would have an AE score of 100% such as a thermal Diels-Alder cycloaddition performed in neat conditions, while a Wittig olefination would have a much lower AE score (Scheme 1).

Scheme 1. Comparison of Diels-Alder cycloaddition and Wittig olefination in terms of atom economy (solvents are not considered).

The recycling of solid or supported catalysts is also an important aspect of atom economy that is rarely considered. The same type of calculations could be made for multistep synthesis, but the overall cost for isolation and purification of intermediates is rarely considered. To save both time and resources, and in some favorable cases, to benefit from synergistic effects, new methods have emerged with several consecutive reactions occurring in the same reactor, ideally using only individual catalytic reactions. Multicatalytic reactions are designed for the synthesis of complex molecules in one single operation (one-pot) from suitable starting material(s) with the

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intervention of two or more catalysts [9]. The terminology of cascade, domino, or tandem processes may apply, depending on whether the reaction is intra- or intermolecular (Scheme 2). If it is necessary to change the conditions during the reaction, or to add another reaction partner after a certain period of time, the term sequential one-pot reaction would then be preferred [10]. Tandem processes are the most commonly reported examples of cascade reactions, either intra- or intermolecular, where one single catalyst is involved in two or more elementary steps occurring sequentially [11, 12].

Scheme 2. Examples of terminology applying in different examples of one-pot reactions.

In the case of multicatalytic processes, there are several classifications. In dual catalysis, two catalysts work together to activate the substrate molecule, while in cooperative dual catalysis, two catalysts independently activate two different substrate molecules, to allow for substrate coupling (Scheme 3). In other cases, a bifunctional catalyst could be used to activate two substrate molecules or two functional groups within the same substrate. Co-catalysis refers to processes where an ancillary catalyst is used to assist the recycling of the main catalyst, for example the Wacker process where copper salts are used to recycle palladium in its active. Finally, multicatalysis refers to one-pot processes where several catalysts work sequentially along a multistep reaction sequence without interfering with each other. All these processes have several advantages, one of the most important being the reduction of waste generation and/or energy consumption by avoiding work-up and purification procedures of the intermediates. In some cases, synergistic effects are observed, such as a favorable equilibrium shift when a thermodynamic

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product is formed in the late stages of the sequence. The key to success for the development of such reactions is a good understanding of the reaction mechanism of each step, and for kinetically controlled reactions, an evaluation of their relative rates.

Scheme 3. Different categories of multicatalytic reactions.

In this chapter, we present a selection of recent reports from the literature to illustrate multicatalytic processes that are based on the initial formation of a carbonyl functional group, with an emphasis on processes involving nanocatalysts, i.e. supported metal nanoparticles (NPs). Tandem processes where one or more reactions involve stoichiometric reagents or promoters, and flow chemistry multistep synthesis are outside the scope of this review. The reader might refer to previous review articles that specifically address the design of multifunctional nanocatalysts for tandem reactions [13], concurrent tandem catalysis [14], orthogonal tandem catalysis [15], tandem oxidative processes involving multimetallic nanoclusters [16], auto-tandem catalysis [17], enantioselective cooperative catalysis [18], asymmetric tandem catalysis [19], cascade reactions initiated by alcohols oxidation [20, 21], or biooxidation [22]. OXIDATION/HETERONUCLEOPHILE ADDITION Tandem and/or cascade reactions employing oxidation conditions for bi- or multicomponent heteronucleophile addition to in situ formed carbonyl compounds have been widely investigated in the past decade [23]. A key reason for the success of such one-pot multistep approaches is the generation of reactive intermediates that are immediately converted into complex products without requiring tedious and/or low yielding isolation procedures and avoiding degradation issues. These approaches result in very efficient and highly atom- and step-economical processes leading to the synthesis of valuable compounds, including esters, amides, and imines. Furthermore, metal NPs/O2 systems have been widely studied in the oxidation of alcohols, either bearing activating substituents (aryl, allyl) or relatively inert ones (alkyl), and generally allow primary alcohols to selectively lead to the corresponding aldehydes [24]. Catalytic protocols involving M NPs have thus been designed to oxidize various alcohols and convert them into diverse compounds in situ by heteronucleophile addition [25 - 30]. For example, a straightforward base-free oxidative esterification was

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proposed based on Au NPs-catalyzed oxidation of poorly reactive aliphatic octan1-ol to octyl octanoate, under a pressurized atmosphere of O2 [25]. It is worth noting that the selectivity of the reaction could be tuned towards acid or ester formation by changing the nature of the NPs’ support and changing the solvent from organoaqueous to aqueous. Thus, use of NiO as the support proved to be effective for the synthesis of octanoic acid with 97% selectivity, whereas replacing it with CeO2 produced the corresponding ester with a 66% yield and 79% selectivity (Scheme 4).

Scheme 4. Selective oxidation and oxidative esterification of aliphatic 1-octanol catalyzed by Au NPs.

The recyclability was tested by recovering the catalysts by centrifugation after the addition of ethyl acetate, washing and drying. A gradual decrease was observed but 85– 91% yields were still obtained after the sixth run. Interestingly, no change in the size of Au NPs was observed by TEM analysis performed on the catalyst after six cycles. In other instances, the Lewis acid-base character of the support was shown to be beneficial to the tandem process. For example, an Au-catalyzed oxidation/amine condensation/nucleophile addition protocol reported the synthesis of α-substituted phosphates involving aromatic alcohols, primary amines and hydrogenophosphates [31]. It is noteworthy that the amphoteric character of hydroxyapatite (HAP) support resulted in significant enhancements of the reaction efficiency. Subsequently, a tight cooperation was observed between Au NPs and the HAP surface in which the determining rate was optimized to limit side reactions. Thus, α–aminophosphonates were obtained with a yield up to 86%, in a one-pot three-component procedure in solvent-free conditions (Scheme 5).

Scheme 5. One-pot three component cascade reaction for the synthesis of α-aminophosphate catalyzed by AuNPs supported on hydroxyapatite (HAP).

Au/HAP catalyst could be reused 5 times with similar performance (95% conversion, 98% selectivity).

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In another example dealing with amide formation by oxidative amidation, the use of polymer-incarcerated carbon black-stabilized metal nanoparticles (PI/CB-M NPs) was the key to success [32]. The Au NPs-catalyzed oxidation of benzylic alcohols under O2 (1 bar) in the presence of a stoichiometric amount of NaOH was followed by the nucleophilic addition of the amine partner and further oxidation of the intermediate at the NP surface. The size of Au NPs appears to have a clear influence on the amide formation, and 18 examples were reported with up to 79% selectivity when using Au NPs with an average diameter of 7.2 nm (Scheme 6).

Scheme 6. Selective oxidative amidation catalyzed by medium-sized incarcerated PI/CB-Au NPs.

By combining supported catalysis and biocatalysis, a one-pot procedure of aerobic oxidation/reductive amination/direct amidation has been proposed based on an integrated AmP-CPG/Pd(0)-catalyzed benzyl alcohol oxidation, followed by catalytic reductive amination and a lipase-catalyzed acylation with an aliphatic carboxylic acid (Scheme 7) [33].

Scheme 7. General scheme of integrated heterogeneous oxidation/reductive amination/direct amidation via multiple relay catalysis.

The recycling of the catalyst could be performed 6 times for the reductive amination with conversion up to 90% at each cycle. An Au-catalyzed reductive hydrogen transfer/hydrolysis/nucleophile addition/dehydration process was proposed, based on the self-condensation of benzyl amines for the synthesis of imines. Interpretations of kinetic studies based on a Hammett plot showed a hydrogen transfer from the amine to the NPs surface, followed by the oxidation of the Au-H bond. After hydration of the imine moiety and the release of a molecule of ammonia, the corresponding aldehyde was obtained, immediately followed by the condensation of a second amine to produce the desired imine with a yield up to 86% (Scheme 8) [34 - 36].

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Scheme 8. Tandem oxidation of benzyl amines to imines catalyzed by Au NPs.

The catalysts could be recycled 8 times with the imine yield remaining at 73% at 8th run. The direct synthesis of quinoline derivatives from nitroarenes and aliphatic alcohols was proposed via an iridium-based reductive hydrogen transfer/condensation/dehydrogenation using sub-nanosized iridium clusters supported on TiO2 [37]. This protocol presented a high efficiency profile for the tandem reaction, allowing the catalyst to be recycled three times, while maintaining 100% activity. Mechanistic insights suggested that the dehydrogenation of the alcohol occurs first, followed by the hydrogen transfer generating the aminoarene and the aldehyde. Condensation of the amine with the aldehyde followed by ring closure with concomitant dehydration/dehydrogenation furnished the quinoline product. Surprisingly, the quality of TiO2 appeared to play an essential role in the condensation/cyclization, since more basic or more acidic supports did not produce similar product yields (Scheme 9).

Scheme 9. Ir sub-nanosized clusters-catalyzed hydrogen transfer/condensation/dehydrogenation.

Carbohydrates represent promising renewable feedstock chemicals that are easily accessible in huge amounts from lignocellulosic materials. Since biomass conversion is highly desirable, it is important to develop efficient and scalable reductive processes to refine these raw materials. A synthesis of valuable products from biomass conversion was proposed with the reduction of carbohydrates into γ-valerolactone and pyrrolidone. Au-catalyzed reduction/cyclisation of carbonyl compounds afforded the corresponding pyrrolidone, based on formate-mediated transfer reduction between levulinic acid (LA) and benzylamine. The reaction was used for the synthesis of 5-methyl-2-pyrrolidone, obtained in 97% yield [38]. It was proposed that formate used as a sole hydrogen source could act as a reducing reagent, in the presence of LA and the amine. This protocol was applied to a large variety of carbohydrate derivatives such as glucose, fructose, sucrose, and even

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starch and cellulose. Au/ZrO2-VS catalyst (VS standing for very small NPs: ca. 1.8 nm diameter) showed superior activity with respect to other solid catalysts for the selective production of pyrrolidone derivatives with ZrO2 support appearing to be the most tolerant of harsh acidic media (Scheme 10).

Scheme 10. Au-catalyzed pyrrolidone synthesis via biomass conversion.

Upon recycling experiments, results for the 5th run remained similar (95% yield, 99% selectivity). Octahedral MnO2 molecular sieve (OMS) was investigated as catalyst in the onepot tandem conversion of benzyl alcohol to 2-benzylidene-malononitrile, (E)chalcone, and 2,3-dihydro-1,5-benzothiazepine [39]. For example, the latter was formed by action of OMS-2-U, a material formed by hydrothermal synthesis in the presence of urea, resulting in tunnels of 3 × 3 structures (Scheme 11). In the presence of urea, the material obtained exhibited different physico-chemical properties compared with the control such as increased surface area (150 vs. 116 m2/g BET), slightly higher total pore volume (0.60 vs. 0.47 cm3/g), a higher number of acid sites (1.07 vs. 0.32 mmol/g NH3-desorbed) and a significantly higher number of basic sites (0.33 vs. 0.069 mmol/g CO2-desorbed).

Scheme 11. One-pot three-steps synthesis of 2,3-dihydro-1,5-benzothiazepine catalyzed by OMS-2-U under O2.

Recycling study showed that no significant decrease in the catalytic activity was observed even after five cycles. The carbonyl group could also be created by oxidation of a methyl group with the introduction of an external oxygen atom. For example, an efficient

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oxidation/oxidative esterification has been proposed based on a Cu-catalyzed aerobic oxidation of the Csp3-H bond of quinaldine, followed by an oxidative esterification leading to N-heteroaryl esters in 90% yield [40]. It was found that the methyl group had to be located at the 2-position, indicating the prominent role of nitrogen atom. A plausible mechanism was proposed as depicted in Scheme (12), in which the N-heteroaryl methyl group is first oxidized to the corresponding aldehyde, before being oxidatively coupled with the alcohol partner to produce the final N-heteroaryl ester.

Scheme 12. Copper-catalyzed oxidative esterification of activated methyl group in N-heteroaryl series.

Subsequently, an aryl ester synthesis catalyzed by Pd(II) salts was proposed via a double aromatic methyl oxidation/oxidative coupling (Scheme 13) [41]. As previously mentioned, the introduction of a directing group was essential to truly perform a cross-coupling reaction and to diminish homocoupling reactions. Notably, the reaction exhibited high selectivity upon the addition of Ag salts.

Scheme 13. Direct functionalization aromatic methyl groups and aryl ester synthesis.

The corresponding intermediate could then be oxidized by a peroxide species and lead to Pd(III) or Pd(IV) and a carbaldehyde intermediate, followed by the reductive elimination to the second palladacycle (Scheme 14). Subsequently, both oxidized partners would undergo a Kornblum-DeLaMare rearrangement to the first oxygenated diaryl hemiacetal intermediate, the structure of which was confirmed by MALDI-TOF MS, followed by a β-hydrogen elimination and reductive elimination leading to Pd(0) and the aryl ester product in 71% yield.

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Pd(0) would then be reoxidized to Pd(II) under AgCO3/O2.

Scheme 14. Plausible mechanism for tandem activation of aromatic methyl groups for benzyl ester synthesis (PA=2-pyridylacyl).

OXIDATION/C-NUCLEOPHILE ADDITION If heteronucleophile addition is known to be favored in the presence of lone pairs of electrons on the heteroatom (i.e. O, S, N), activated carbon atoms may also act as nucleophiles. Thus, the formation of C-C bonds can be envisaged, a valuable prospect for organic synthesis, using activated methylene, electron-rich arenes or other nucleophilic carbon atoms resulting in C-nucleophile addition. A straightforward protocol for biobased chemical feedstock valorization has been proposed with a sequential one-pot oxidation/aldolization protocol, based on furfuryl alcohol oxidation, catalyzed by Pd-NPs supported on mesoporous silica nanoparticles (MSNs), followed by an aldolization/crotonization sequence [42]. Interestingly, the aldolization, involving a large excess of acetone, could be

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catalyzed by a modified version of the silica support bearing aminomethyl units (MAP-MSN) within the pore framework (Scheme 15).

Scheme 15. Bicatalytic one-pot process for the oxidation/aldolization/crotonization of furfuryl alcohol with acetone catalyzed by Pd-MSNs & MAP-MSNs.

Upon recycling of the catalyst, an increase of the yield of furfural intermediate and a decrease of the yield of the final product were observed, suggesting a significant loss in activity of the second catalyst, possibly due to the oxidation of amine groups. This problem was solved by regeneration of the catalyst by using NaBH4, and a 73% conversion of furfuryl alcohol could be obtained, with a yield of 70% of product. The oxidation of allylic alcohols could be combined with a Heck coupling under the sole catalysis of Pd(OAc)2 [43]. The sequential addition of aryl iodide electrophiles together with 1.1 equiv. of Et3N was sufficient to yield β-aryl-αβ-unsaturated carbonyl products (Scheme 16).

Scheme 16. Oxidation/Heck coupling with aryl iodide of oct-1-en-3-ol catalyzed by Pd(OAc)2.

It is interesting to note that similar products could be obtained from allylic alcohols submitted to a Pd-catalyzed Heck reaction, the carbonyl group resulting from a β-hydride elimination furnishing an enol intermediate further isomerised to the corresponding carbonyl compound by keto-enol tautomerism, and not a direct initial oxidation of the alcohol functional group [44, 45]. An Ir-catalyzed domino borrowing-hydrogen transfer reaction/aldolization has been proposed for the direct double β-methylation of 1-phenylethanol derivatives with methanol as the primary source of carbon. Herein, the metal nanocluster catalyst presented a larger specific area and more corner sites where the catalyst activity is known to take place [46, 47]. Efficiency of the catalytic system in the presence of CsCO3 even allowed the alkylation to proceed with methanol as C1

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source, which is typically a difficult material to handle owing to its high dehydrogenation energy, in comparison to other alcohols. Moreover, aggregation of nanoclusters was avoided thanks to an alternative procedure using DMF as a stabilizer with no additives, making photoluminescent Ir nanoclusters easily observable. Mechanistic insights showed the involvement of an iridium hydride intermediate upon alcohol oxidation. The following aldol reaction results in the enone formation, immediately followed by the hydrogenation/reduction sequence to give the corresponding β-substituted alcohol with a 94% yield (Scheme 17) [48].

Scheme 17. Double β-methylation of 1-phenylethanol by methanol catalyzed by Ir nanoclusters.

Some strategies were proposed to implement more sophisticated reactions that rely on the initial oxidation of alcohols like a PCC oxidation/Wittig olefination of alcohols [49] or other stoichiometric oxidation processes as detailed in a recent review article [20]. Eventually, catalysis was introduced for the oxidation step for more powerful and sustainable one-pot processes. For example, a tandem oxidation/Wittig olefination sequence was described using manganese oxide octahedral molecular sieve (OMS) as heterogeneous catalyst (Scheme 18) [50]. The catalyst could be recycled four times, yet maintaining the conversion above 85%. A tandem oxidation/olefination in the presence of a copper catalyst was further developed using diazo reagents as an olefination partner [51]. The reaction could be performed with primary and secondary alcohols with TMSCHN2 and examples with other diazo reagents were provided. Interestingly, the integrity of chiral centers in vicinal position could be preserved (Scheme 19).

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Scheme 18. Oxidation/olefination with phosphorane of piperonyl alcohol catalyzed by MnO2 octahedral molecular sieve.

Scheme 19. Oxidation/olefination with diazo reagents of a protected aminoalcohol catalyzed by a copper(I) complex.

OXIDATION/SOPHISTICATED REACTIONS In this paragraph, we describe examples where the initial oxidation is followed by sophisticated reactions or complex sequences involving multiple C-heteroatom and/or C-C bond forming reactions. A new class of heterogeneous catalysts have been investigated for the sequential oxidation/asymmetric aza-Friedel-Craft reaction, between benzyl alcohols and N-aminoethylpyrroles, based on immobilized metal alloy nanoparticles (on PI/CB system, see below), themselves incarcerated in a new chiral hydrogenophosphate composite derived from (S)TRIP organocatalyst (IOC, Immobilized Organocatalyst-Coated). This elaborates that the catalyst was made via a method of pseudo-suspension, presenting a strong coordination between the layers of the framework and was amenable to orthogonal applications for the synthesis of piperazine derivatives obtaining yields of up to 90% with ees up to 91% (Scheme 20) [52]. Interestingly, the catalyst could be recycled and reused five times, while maintaining activity and enantioselectivity.

Scheme 20. Incarcerated heterogeneous oxidation/asymmetric addition for the synthesis of chiral piperazine derivatives.

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A spectacular integrated oxidation/olefination/asymmetric 1,4-addition was proposed based on an Au NPs-catalyzed oxidation of benzyl alcohol derivatives followed by a Horner–Wadsworth–Emmons olefination in a tandem process and, upon the addition of arylboronic acids, Rh NPs and a chiral diene, ending with an asymmetric arylation and the formation of chiral products (Scheme 21) [53]. Eleven examples were given with excellent ees up to >99%.

Scheme 21. Oxidation/olefination with a phosphonate/arylation of benzyl alcohol catalyzed by Au-Pd and Rh NPs.

PI/CB-Au/Pd catalyst could be recycled and reused after washing with a basic solution, and heating at 170 °C and similar yields were obtained. This reaction involved polymer-incarcerated carbon black-stabilized metal nanoparticles (PI/CB-M NPs), successfully used in many other nanocatalytic reactions [16, 26, 54 - 56]. PI/CB-Au/M could be recovered and reused up to 5 times without loss of activity upon pretreatment by washing with pure water, followed by a heating step at 170 °C to reactivate the catalyst. Heterogenized metal catalysts in the form of Pd NPs supported on aminopolymer–silica composite mesocellular foam (Pd0-AmP-MCF) were used in a sequence starting with the aerobic oxidation of selected alcohols further undergoing carbon-heteroatom or carbon-carbon bond formation reactions through aziridination, aza-Michael addition, or Wittig olefination [57, 58]. As an example, an enantioselective oxidation/Michael addition/carbocyclization reaction was developed (Scheme 22) [59]. An efficient enantioselective oxidative iminium cascade reaction has been proposed, based on a Ru-catalyzed oxidation of cinnamyl alcohol, followed by iminium formation and reaction with β-dicarbonyl nucleophiles in the presence of

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tetrapropylammonium perruthenate (TPAP) as a substrate-selective redox catalyst, that is tolerant to nitrogen-containing bases such as prolinol derivative α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether (Scheme 23) [60]. It is worth mentioning that this catalytic system allowed for the formation of benzimidazoles when phenylene diamine derivatives were used as nucleophiles.

Scheme 22. Enantioselective oxidation/Michael addition/carbocyclization of 3-phenylprop-2-en-1-ol catalyzed by Pd complex and Jorgensen’s catalyst.

Scheme 23. a) Asymmetric tandem oxidation/Michael addition/cyclization. b) Asymmetric tandem oxidation/ Michael addition.

The concept of borrowing-hydrogen has been developed recently for the direct functionalization of alcohols through an initial hydrogen abstraction to the corresponding carbonyl compound [61 - 65]. In the field of cooperative metal catalysis, a new borrowing-hydrogen transfer/asymmetric Michael addition protocol was recently reported, based on the combination of an iron catalyst

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(Knölker complex) and a prolinol catalyst, between 1,3-ketoester and allylic alcohol with trimethylamine N-oxide Me3NO as the hydrogen transfer agent. This dual cooperative bicatalytic borrowing hydrogen transfer was applied for the synthesis of β-chiral substituted alcohols obtained a yield up to 57% with 93% ee (Scheme 24) [66 - 68].

Scheme 24. Iron complex/prolinol derivative-catalyzed borrowing-hydrogen transfer/asymmetric Michael addition.

Experimental findings revealed that the reaction is triggered by the activation of a vacant site from the iron complex, formed after CO decoordination by Me3NO. The novel complex abstracts a hydrogen from the allylic alcohol, leading to the α,β-unsaturated aldehyde amenable to forming the chiral iminium intermediate. The bicatalytic process benefits from the thermodynamics of the Michael addition shifting the equilibrium to the formation of iminium. It was also suggested that the aldehyde lifetime significantly decreased after the liberation of the prolinol catalyst. In addition, high chemoselectivity was observed during the overall process since the transient iron hydride complex produced the more stable chiral β-alcohol with regeneration of the active iron catalyst. This example of dual activation is consistent with the principle of cooperative catalysis operating in a synchronous manner. Subsequently, a powerful borrowing-hydrogen transfer/asymmetric Michael addition/β-functionalization based on the same catalytic system, enhanced with an additional copper-catalyzed final step, was proposed for crotyl alcohol and dibenzoylmethane combination. It was found that an increase in the concentration of copper positively influenced the rate of the Claisen fragmentation, satisfying the enantioselective synthesis of the keto-ester with 82% yield and ees of up to 90% (Scheme 25) [69, 70]. A Pd(II)-catalyzed aerobic oxidation of various primary and secondary alcohols, either benzylic or aliphatic, could be combined in a one-pot process with a Rh(I)catalyzed methylenation with TMSCHN2 [71]. Interestingly, in a single example,

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a tricatalytic one-pot transformation was proposed, by adding a Ru-catalyzed ring-closing metathesis reaction to achieve the sequence (Scheme 26).

Scheme 25. Triple iron/copper/iminium catalysis for the enantioselective functionalization of crotyl alcohol.

Scheme 26. Oxidation/methylenation/RCM of an unsaturated secondary alcohol catalyzed by Pd, Rh and Ru complexes.

Au NPs supported on layered double hydroxides (LDH) were found to efficiently catalyze the one-pot synthesis of flavones via an intermolecular aldolization reaction between 2-hydroxyacetophenone derivatives and various aldehydes, followed by crotonization, hydroalkoxylation and dehydrogenation [72]. In the case of aromatic aldehydes, even the aldehyde partner could be generated in situ from the corresponding benzyl alcohols by oxidation (Scheme 27).

Scheme 27. Oxidation/aldolization/crotonization/hydroalkoxylation/dehydrogenation involving a benzyl alcohol derivative and 2-hydroxyacetophenone catalyzed by Au NPs/LDH.

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By combining Au NPs/O2 allylic alcohol oxidation [73] and base-catalyzed reactions, a bicatalytic one-pot oxidation/hetero-Michael addition/aldolization/ crotonization with salicylaldehydes and aminobenzaldehyde was proposed [74]. The reaction was found to be more effective in the presence if hydroperoxides such as H2O2 or TBHP as initiators, although their presence was not mandatory. Interestingly, 2-aminobenzaldehyde could be formed in situ from 2-aminobenzyl alcohol in a one-pot five-step sequence (Scheme 28).

Scheme 28. One-pot five-step sequence catalyzed by Au NPs and pyrrolidine to combine cinnamyl alcohol and aminobenzyl alcohol into substituted quinoline.

CARBONYL INSTALLATION/REACTIONS In an alternative to oxidative processes directed towards alcohols or other oxygenated substrates, a whole carbonyl function could be installed in a catalytic reaction, and subsequently undergo C-C bond formation. For example, the catalytic hydroformylation of olefins followed by aldol [75] or acyloin [76 - 78] condensation has been reported (Scheme 29).

Scheme 29. Hydroformylation/aldolization/crotonization/hydrogenation of but-1-ene with syngas and acetone catalyzed by a Rh complex and pyrrolidine.

Instead of CO/H2, CO alone could be used and combined with CuCl2 in a Pd(II)catalyzed aminochlorocarbonylation/In(III)-catalyzed Friedel-Crafts reaction of unsaturated amines [79]. This reaction was efficiently used in the total synthesis of the Tylophora alkaloids rusplinone, 13aα-secoantofine, and antofine (Scheme 30).

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Scheme 30. Aminochlorocarbonylation/In(III)-catalyzed Friedel-Crafts reaction of unsaturated protected amine catalyzed by Pd and In complexes.

Alternatively, the carbonyl function could be formed upon isomerization of a suitable substrate like in a Ca(II)-catalyzed Meyer-Schuster rearrangement of propargylic alcohols, followed, in this case, by an internal aldol condensation (Scheme 31) [80].

Scheme 31. Meyer-Schuster rearrangement/aldolization/crotonization of propargylic alcohols catalyzed by Ca(II) salts.

Independently, an Au-catalyzed domino 1,6-heteroenyne metathesis/Nazarov cyclization has been proposed for the synthesis of fused tri- and tetracyclic enones, catalyzed by Au(III) and AgSbF6. Mechanistic experiments proposed that the heteroenyne metathesis could produce a α,β-unsaturated tricyclic ketone intermediate upon successive interactions between π-complex A and concomitant migration of the oxygen atom from the carbonyl group to the triple bond. Nazarov cyclization would then occur in a domino-cascade sequence via the σ-complex B.Upon investigations into the scope of the process, it was shown that enynyl ketone bearing sterically hindered substituents such as t-Bu, naphthyl or gem methyl yielded in all cases the product with the best diastereomeric syn/anti ratio (6:1). The desired ketones were thus obtained with a yield of up to 80% and excellent selectivity (Scheme 32) [81].

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Scheme 32. Au-catalyzed diastereoselective tandem 1,6-heteroenyne metathesis/Nazarov cyclization.

Similarly, an In-catalyzed one-pot/four-step hydration/Knoevenagel condensation/ Michael addition/Conia-ene tandem reaction has been proposed for the direct synthesis of complex tetrahydrofuran derivatives containing a methylene unit, by fusion of alkynyl arylaldehydes and propargyl alcohols. Herein, the sequence is presented as follows: first the hydration of the triple bond would produce the corresponding 1,4-dicarbonyl intermediate, which may then undergo an intramolecular Knoevenagel condensation. Since complexation between indium cation and the diketone motif shifts the equilibrium towards the enolate form, thereby favoring the condensation, the corresponding α,β-unsaturated ketone is obtained, followed by the Michael addition of the propargyl alcohol to give the tethered ether intermediate, which finally lead to the indanone-fused 2-methylene tetrahydrofurans via a Conia-ene reaction. The latter step achieved excellent diastereoselectivities, leading to a desired product yield of up to 85% with a d.r. of up to 98:2 (Scheme 33) [82, 83].

Scheme 33. In(OTf)3-catalysed addition/Conia-ene protocol.

one-pot/four-steps

hydration/Knoevenagel

condensation/Michael

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Based on the same work, an Ag-catalyzed heteroenyne/Diels-Alder domino reaction has been investigated for the synthesis of indanone fused cyclohexene derivatives between ortho-carbonyl alkynyl arylaldehydes and dienes. In this case, the dienophile is generated in situ and then proceeds through a Diels-Alder cycloaddition with the enol form of the 1,3-diketone, which is highly activated by complexation with the silver salt. The cycloaddition is performed with high endo-selectivity. A plausible mechanism was proposed where the π-coordination of the Ag cation to the triple bond triggered a 5-exo-dig cyclization to produce an oxonium intermediate, which could then be converted to a carbonyl group upon hydrolysis. Favored by the presence of Ag salts, the enolate form would then attack the aldehyde through a Knoevenagel condensation and the formation of the desired indenone. A [4+2] cycloaddition reaction with the diene would then produce the desired tricyclic product. Surprisingly, in solvents such as dioxane and DCE, nonnegligible amounts of polycyclic side-products were formed via [3+2] dipolar cycloaddition to give a bridged bicycle followed by cyclopropane formation upon insertion of the Ag-carbenoid in the pendant olefin in a [2+1] cycloaddition (Scheme 34) [84].

Scheme 34. Ag-catalyzed heteroenyne/Diels-Alder domino reaction to indanone fused cyclohexene derivatives.

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Following the concept of auto-tandem catalysis [17], a tandem PdI2/KI-catalyzed oxidative carbonylation of propargyl amines was proposed for 2-oxazolidinone synthesis [85]. As a feature of auto-tandem catalysis, the overall mechanism can be described as the fusion of two catalytic cycles, both involving the same metal as the active species. The first oxidative aminocarbonylation of the triple bond would give a 2-ynamide intermediate, followed by the cyclocarbonylation to yield the oxazolidinone. Reactions were performed using a simple catalytic system consisting of PdI2/KI. Using the ionic liquid EmimEtSO4 as the solvent, the catalyst/solvent system could be recycled seven times without significant loss of activity leading to the desired product with a 74% yield (Scheme 35).

Scheme 35. Pd-catalyzed tandem oxidation/CO insertion in ionic liquid.

Two novel tandem hydroformylation/enantioselective aldolization reactions catalyzed by a rhodium complex and L-proline have been proposed for the synthesis of chiral 1,3-diol derivatives, formed upon NaBH4 reduction of chiral aldol products [86, 87]. Herein, under finely-tuned hydroformylation conditions, the compatibility between rhodium and proline catalysts was demonstrated, and homodimerization was avoided. The desired compound could be obtained with a 91% yield, ees of up to 94% and d.r. of 2:1. Moreover, the flexibility of the reaction conditions even allowed this strategy to be applied to the synthesis of a biologically active amine through a tandem hydroformylation/Mannich reaction, involving an arylamine, acetone and cyclopentene to form the desired optically active amine with a 48% yield and ee of up to 74% (Scheme 36) [88]. Last, a biocatalytic deracemization of secondary alcohols has been reported in a concurrent tandem oxidation/reduction reaction [89]. The initial step of this sequential process was a kinetic resolution of the alcohol by the selective oxidation of the (R)-alcohol to the corresponding ketone catalyzed by cells of Alcaligenes faecalis DSM 13975. The ketone intermediate was then

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enantioselectively reduced to the (S)-alcohol by an alcohol deshydrogenase with a cofactor recycling protocol. In comparison to kinetic resolution, this two-catalyst system provided a convenient and efficient approach for the synthesis of chiral alcohols with high yields and excellent enantioselectivity (Scheme 37).

Scheme 36. a) Rh-catalyzed tandem hydroformylation/enantioselective aldolisation reaction for the synthesis of chiral 1,3-diol. b) Rh-catalyzed tandem hydroformylation/enantioselective Mannich condensation for the synthesis of chiral keto-amine.

Scheme 37. Deracemization of secondary alcohols by tandem oxidation/enantioselective reduction by concurrent tandem biocatalysis.

CONCLUSION In summary, with the design of highly specific and selective catalysts, including nanocatalysts consisting of metal nanoparticles supported on modified inorganic materials, it is now possible to design complex multistep syntheses occurring in the same reactor without interference from the catalytic systems, or undesired

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side-reactions. These approaches were initially devoted to the synthesis of esters and amides by oxidative coupling of alcohols/amines. Later, more sophisticated reactions could be proposed, which combined C-C and C-heteroatom bond forming reactions in one-pot/4- or 5-step processes. These synthetic method developments are based on a robust understanding of the reaction mechanism of each separate reaction. Under these conditions, catalytic cycles can then be merged into highly efficient and step-economical processes. The complementarity of various types of catalysis, i.e. homogeneous catalysis, heterogeneous catalysis, nanocatalysis, organocatalysis and biocatalysis, and the consequent avoidance of deleterious interactions between the active species is often the key to success. In the most advanced examples presented herein, enantioselective reactions have been included in the sequence to provide valuable chiral products. In the near future, it is likely that increasingly complex products and processes will be developed, further improving the efficiency and sustainability of organic chemistry. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The author (editor) declares no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS This work was supported by the CNRS and the University Nice Sophia Antipolis. The French MESR is acknowledged for a doctoral fellowship to PDG. We are grateful to Dr. Abby Cuttriss for proofreading the manuscript. REFERENCES [1]

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CHAPTER 2

Synthetic Applications of Bifunctional Knölker Type Iron Complexes as (De)hydrogenation Catalysts Raffaella Ferraccioli* CNR-Istituto di Scienze e Tecnologie Molecolari, via C. Golgi 19, 20133Milano, Italy Abstract: Knölker type iron complexes, used directly or generated in situ, are suitable catalysts for (de)hydrogenation reactions enabling the synthesis of carbonyl derivatives, amines and alcohols of industrial and academic interest. Enantioselective hydrogenation of prochiral C=X double bonds (X: O, N) was achieved with up to 94% e.e. using iron-complexes bearing chiral ligands or Knölker’ complex in combination with a chiral additive. Knölker type complexes were also competent catalysts for sequential reactions based on temporary dehydrogenative alcohol activation including dynamic kinetic resolution of racemic secondary alcohols (99% e.e.) and borrowing hydrogen methodology. The latter method was applied to synthesize N-alkyl substituted amines, α-alkylated ketones and oxygen- or nitrogen-heterocycles.

Keywords: Alcohol, Amine, Asymmetric hydrogenation, Bifunctional catalyst, Borrowing hydrogen, Carbonyl compound, Dehydrogenation, Direct hydrogenation, Dynamic kinetic resolution, Heterocycle, Iron, Knölker’s complex, Metal-ligand cooperation, Transfer hydrogenation, Water-gas-shift reaction. INTRODUCTION Environmental concerns in chemistry have increased the demand for selective chemical processes with a minimum amount of waste. In that respect, hydrogenation and dehydrogenation reactions catalyzed by homogeneous metal complexes attract academic and industrial interests being considered “green synthetic tools”. Their application allows for the synthesis of versatile building blocks such as alcohols, amines and carbonyl compounds without using stoichiometric amounts of strong reducing or oxidizing agents (Scheme 1) [1, 2]. Corresponding author Raffaella Ferraccioli: CNR-Istituto di Scienze e Tecnologie Molecolari, via C. Golgi 19, 20133 Milano, Italy; Tel.: ++39-(0)2-503-14141; Fax.: ++39-(0)2-14139; E-mail: [email protected]

*

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

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Catalytic reduction of multiple polar bonds under H2 gas pressure (direct hydrogenation) allows for the construction of a new C−H bond through a 100% atom economy transformation (Scheme 1a). When hydrogen gas is replaced by easy to handle 2-propanol as hydrogen donor, environmentally friendly acetone is the only by-product of the reaction (transfer hydrogenation). Catalytic dehydrogenation of alcohols to carbonyl compounds can be considered as an extension of transfer hydrogenation reaction. It takes place through the cleavage of the C−H bond located alpha to the hydroxyl group in the presence of a hydrogen acceptor (Scheme 1b).

Scheme 1. Catalytic (de)hydrogenation reactions discussed in this chapter.

Catalytic hydrogenation implies H−H bond activation by a transition metal catalyst. Such an activation can occur (a) at the metal center without the participation of the ligand coordinated to the metal (Scheme 2a), (b) with both metal and ligand cooperation (Scheme 2b) [3, 4]. Cooperative action of both metal center and reactive center at the ligand in the process of bond activation is reminiscent of enzyme catalysis (hydrogenases), which operates under mild conditions [5].

Scheme 2. Simplified representation of H2 activation catalyzed by transition-metal catalysts (M-L); M = metal, L = ligand.

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A good number of metal catalysts used in (de)hydrogenation reactions operate according to a metal-ligand cooperation pathway. An interesting example is represented by Shvo’s catalyst, a dinuclear ruthenium complex supported by a tetraphenyl-substituted hydroxycyclopentadienyl ligand, developed in the mid1980s (Scheme 3) [6, 7]. Shvo’s catalyst is reported to form monomeric reducing and oxidizing species (S-r and S-o), upon dissociation in solution. Both species are catalytically active and interconvert with each other through the reaction with H2-donors or H2-acceptors (Scheme 3). The monomeric reductive species S-r is probably the first example of a “bifunctional catalyst” [3] containing two kinds of active hydrogen atoms: the first one is bound to the metal as a hydride (Ru−H) and the second one to the oxygen in its ligand as an acidic proton (O−H).

Scheme 3. Shvo’s catalyst (the box represents a free coordination site).

Shvo’s catalyst as well as the majority of bifunctional metal catalysts relies on precious metals [3, 4]. Low availability, high price and toxicity of noble metals are limiting factors to their employment, especially in industry. An important objective in the field of homogeneous catalysis is the development of catalysts based on economical and environmentally friendly metals [8]. Among them, iron plays a central role [9]: it is one of the most common elements in the earth’s upper crust and residual traces of iron are less toxic and more environmentally acceptable than precious metals. In 1999, Knölker and coworkers synthesized the bifunctional iron(II) complex 1, closely related to the reductive species of Shvo’s catalyst (Scheme 4) [10]. X-Ray structure determination of 1 suggested an η5-coordinated hydroxycyclopentadienyl ligand. NMR analysis in toluene-d8 showed no evidence of a diiron bridging hydride.

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Scheme 4. Knölker’s iron complex 1 and its related oxidative species (the box represents a free coordination site) (TMS = trimethylsilyl).

Complex 1 and the corresponding coordinatively unsaturated 16-electron ironspecies (Scheme 4) are reported to promote hydrogenation and dehydrogenation reactions like S-r and S-o species of Shvo’s catalyst, respectively [11]. This review is aimed to give the reader an overview of the synthetic applications of Knölker type complexes in (de)hydrogenation reactions. For this purpose, literature reports from early contributions until March 2017 have been reviewed. The examples selected from literature have been collected in four sections each representing the type of reaction in which iron complexes were involved as catalysts: symmetric and asymmetric hydrogenation (section 1 and 2), dehydrogenation (section 3) and methods based on dehydrogenative alcohol activation (section 4). HYDROGENATION Knölker’s Iron Complex: Direct and Transfer Hydrogenation Reactions Complex 1 was synthesized from tricarbonyl(η4-cyclopentadienone)iron complex 2a upon reaction with NaOH followed by the addition of phosphoric acid (Hieber reaction) (Scheme 5) [10]. The reaction of 2a with NaOH led to 1 and its deprotonated form 3 in a 13/1 ratio. Subsequent protonation with phosphoric acid drove the reaction to completion.

Scheme 5. Synthesis of complex 1 from tricarbonyl(η4-cyclopentadienone)iron complex 2a.

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In 2007, Casey and coworkers discovered the catalytic properties of 1 [12, 13]. NMR investigation of the stoichiometric reaction of acetophenone with 1 in toluene-d8 at room temperature showed the formation of the 1-phenylethanol complex A (R = Me) (Scheme 6a). Unfortunately, the latter could not be isolated as the reaction was incomplete: complex A was supposed to be labile undergoing reversible dissociation leading to 1-phenylethanol and the coordinatively unsaturated 16-electron iron complex B. Indeed, an added ligand L such as triphenylphosphine could irreversibly trap B leading to the complete formation of the free 1-phenylethanol and complex 4a-L (L = PPh3) (Scheme 6a).

Scheme 6. a) Stoichiometric reaction of 1 with carbonyl compounds (L = PPh3). b) Catalytic carbonyl hydrogenation. c) Outer-sphere mechanism of carbonyl hydrogenation.

Interestingly, the stoichiometric reduction of benzaldehyde gave the corresponding iron complex A in 90% NMR yield at room temperature after 10 min. X-Ray investigation of the isolated complex (R = H) showed that alcohol oxygen was coordinated to the metal and the hydrogen of the hydroxyl group interacted with the oxygen of cyclopentadienone carbonyl group by hydrogen bonding (Scheme 6a). NMR investigation of the stoichiometric reaction of benzaldehyde with 1 in the presence of external alcohols, as possible trapping agents of complex B, supported an outer-sphere mechanism involving the concerted transfer of both hydrogen atoms to aldehyde which did not coordinate to the metal (Scheme 6c) [13]. In addition, computational studies based on density functional theory calculations

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(DFT), confirmed that the outer-sphere mechanism was the pathway with the lowest energy barrier [14 - 17]. Stoichiometric carbonyl reduction was made catalytic when Casey and Guan observed that complex B could be intercepted by hydrogen leading to complex 1 (Scheme 6b) [12]. Hydrogen activation (B→1) was reported to be a thermodynamically favored process occurring through the heterolytic cleavage of H2 with Fe‒H/O‒H formation and Cp-ring aromatization (DFT studies) [14 - 17]. Direct catalytic hydrogenation could be extended to include electron-rich and electron-poor aromatic ketones (Scheme 7) [12]. A good chemoselectivity was observed: isolated alkyne and alkene, C−halogen bond, NO2 group, benzyl ether survived under hydrogenation conditions. 2-Acetylpyridine was easily hydrogenated despite the presence of the Py group which could bind iron and then inhibit the reaction (Scheme 7).

Scheme 7. Primary and secondary alcohol synthesis through carbonyl compound hydrogenation: selected examples.

It is worth mentioning that the use of Shvo’s catalyst in the carbonyl hydrogenation required harsher conditions in terms of reaction temperature (> 80° C) and H2-pressure (35 atm) [7]. The reason is probably due to the fact that the Shvo complex is a dimeric pre-catalyst which forms the monomeric reducing species upon reversible dissociation in solution. The reversibility of the hydrogen transfer process shown in Scheme 6a justified the use of a secondary alcohol as H2-donor to trap B and regenerate 1, thus closing the catalytic cycle (Scheme 6b). Indeed, acetophenone underwent selective catalytic transfer hydrogenation (87% isolated yield) in the presence of 2 mol% of 1, at 75 °C, in 2-propanol [12]. An industrially relevant application of transfer hydrogenation is the synthesis of γ-valerolactone (1 mol% of Fe-catalyst, 2-

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propanol, 5 mol% of NaHCO3, 100 °C, 95% isolated yield) from the biomassderived ethyl levulinate [18]. γ-Valerolactone is commonly employed as liquid fuel, additive, solvent and a synthetic organic building block. Switching Fe/OH Complex to Fe/SiH Complex: Transfer Hydrogenation of Alkyne and Alkene In 2014, Nakazawa developed a new class of bifunctional iron-complexes 5 in which the OH group on the ligand of 1 was replaced by the SiH group (Scheme 8a) [19]. Complexes 5, bearing a non-acidic active hydrogen atom, were inactive in the transfer hydrogenation of multiple, polar bonds. By contrast, one of them promoted transfer hydrogenation from 2-propanol to the multiple, apolar bond of an alkyne such as p-tolylacetylene (Scheme 8b). A mixture of the corresponding alkene and alkane was obtained. The latter was due to the hydrogenation of pmethylstyrene initially formed. The reaction is the first example of an unsaturated, apolar compound hydrogenation using an iron-catalyst structurally related to Knölker’s complex.

Scheme 8. Complexes 5 and their involvement in alkyne/alkene hydrogenation.

The authors claimed that the peculiar catalytic activity shown by 5a was ascribed to the polarity of the Si−H bond which is opposite to that of the O−H bond in complex 1. The stoichiometric reduction of p-tolylacetylene with 5a was suggested to occur through a stepwise hydrogen transfer to alkyne (Scheme 9). The initially formed 16-electron iron species C generated by CO ligand dissociation was believed to insert alkyne into the Fe−H bond leading to intermediate D. At this stage, the Si−H bond of the group tethered to the cyclopentadienyl ligand underwent oxidative addition, and the resulting species F reductively eliminated complex E and 4-methylstyrene. Hydrogen transfer from 2-propanol to both Fe and Si atoms of E regenerated complex C (Scheme 9). A similar catalytic cycle for alkene in place of alkyne accounts for alkane formation. Interestingly, the catalytic activity of 5b bearing a SiH group bonded to the ligand

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through a shorter tether, was significantly lower: alkyne hydrogenation gave only 8% of p-methylstyrene (GC-yield).

Scheme 9. Proposed alkyne hydrogenation mechanism.

In Situ Generated Knölker Type Iron Complexes Complex 1 (Rʹ = TMS) can be handled in air for a short period of time and has to be stored at -30 °C, under inert atmosphere [20]. Guan suggested that decomposition was triggered by the formation of a dimer favoring H2 elimination [21]. The resulting iron-complex subsequently underwent decomposition (Scheme 10). Apparently, the nature of Rʹ substituents affects complex stability. Dimer formation was thought to be disfavored by bulky substituents (Rʹ = TMS). By contrast, switching to phenyl substituents, the resulting hydride complex underwent rapid decomposition.

Scheme 10. Potential decomposition pathway of 1.

High sensitivity to air and moisture of complex 1 could hamper its synthetic application. The problem was circumvented by generating complex 1in situ from catalytically inactive, but stable iron complexes (i.e.2a, Scheme 5).

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So far, a good number of tricarbonyl-iron complexed cyclopentadienones and their carbo- and heterobicyclic analogues of general formula 2 were synthesized from simple and cheap precursors (Scheme 11). A commonly used approach is based on the [2+2+1] cycloaddition of the silylated terminal diynes and pentacarbonyliron (2 equiv) (Scheme 11a) [22, 23]. An alternative route is also possible. Complexes 2f-g were obtained in 50-69% yield by mixing a cyclopentadienone derivative and Fe2(CO)9 in boiling toluene with or without microwave irradiation (Scheme 11b) [24, 25]. Complexes 2 were stable enough to be purified by chromatography.

Scheme 11. Synthetic routes to complexes 2.

(Cyclopentadienone)Iron Tricarbonyl Complexes: Direct Hydrogenation of Carbonyl Compounds In 2013, Beller’s group found that complex 2a (Rʹ = TMS) (0.01 mol%) under Hieber base conditions (K2CO3, 0.05 mol%, aqueous solution) promoted the direct hydrogenation of acetophenone in very good yield (98% yield) and a TON of 3700 [26]. Comparable TON’s were obtained with 2a bearing SiEtMe2 or SitBuMe2 as Rʹ substituents: they were the highest TON number for the hydrogenation of carbonyl compounds with any iron-based catalysts.

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Aromatic, aliphatic aldehydes and ketones were competent substrates under optimized conditions: the corresponding primary and secondary alcohols were obtained in 76-98%. Notably, aromatic carbonyl compounds p-substituted by amide, ester, nitro or CF3 groups were also well tolerated (Scheme 12). Analogously, heteroaromatic aldehyde and ketones bearing indole, thiophene and furan rings underwent high-yielding transformations (82-97%).

Scheme 12. Aldehyde and ketone hydrogenation: selected examples.

α,β-Unsaturated aldehydes were chemoselectively hydrogenated: no traces of double bond hydrogenation products were observed (Scheme 13). Naturally occurring alcohols such as perillyl alcohol and geraniol were obtained in 91 and 98% yields, respectively.

Scheme 13. Chemoselective hydrogenation of allylic aldehydes.

In 2013, Renaud and coworkers reported on the direct hydrogenation of various carbonyl compounds in water using 2a and Me3NO as an activator (Scheme 14) [27]. Complex 2a activation occurred through the dissociation of one of the ironcoordinated CO ligand. Typically, the dissociation of CO is an endothermic process which becomes exothermic when it is assisted by an external oxidant (Me3NO) [17]. The reaction of 2a with Me3NO leads to CO2, NMe3 and complex B. The latter can be transformed in situ into the reductive active species 1 upon hydrogen activation (Scheme 6b).

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It is worth noting that challenging substrates such as 3-acetylpyridine and pacetylbenzonitrile were successfully hydrogenated in water using 2a or 2e, the latter containing an ionic moiety tethered to cyclopentadienone (Scheme 14). By contrast, the hydrogenation of p-acetylbenzonitrile with 1 (Rʹ = TMS) in toluene totally failed, as reported by Casey and coworkers [12]. A further example supporting the beneficial effect of water on both catalyst activity and reaction rate was the reduction of benzophenone (water: yield > 80%, 14 h). The same reaction promoted by 1 in toluene turned out to be slower and less selective (yield = 55%, 72 h) [12]. Several linear and cyclic water stable imines were also hydrogenated to the corresponding amines in 50-98% yields.

Scheme 14. Carbonyl hydrogenation in water: selected examples.

Esters are more challenging substrates than aldehydes and ketones. Complex 2a was a competent catalyst for trifluoroacetic ester reduction, under hydrogen pressure (Scheme 15) [28]. A catalytic amount of triethylamine (TEA) was also needed to avoid catalyst poisoning induced by trifluoroacetic acid accidentally generated by ester hydrolysis.

Scheme 15. Trifluoroacetate ester hydrogenation: selected examples.

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Various aromatic and aliphatic esters were quantitatively reduced to trifluoroethanol and the corresponding alcohols using a low catalyst loading (Scheme 15). Substrates with increased steric demand at the ester alkoxy group (R1 = isopropyl, cyclohexylmethyl, benzyl) were well tolerated by the catalyst system. Aromatic esters bearing R1 = Ph, p-Me, p-F were also competent substrates. On the other side, less activated esters such as ethyl difluoroacetates or simple acetates were totally inactive. Mechanistic proposal is based on two consecutive catalytic cycles as shown in Scheme 16. Initial ester reduction led to the hemiacetal which reversibly eliminated R1OH. The resulting aldehyde entered the second cycle undergoing hydrogenation to trifluoroethanol. Aldehyde hydrogenation step was easier and drove the whole reaction to completion.

Scheme 16. Proposed mechanism of ester hydrogenation.

The use of 2a/Me3NO as a catalytic system allowed Renaud and coworkers to perform the selective reductive amination of aliphatic aldehydes with primary and secondary alkyl amines, under H2 pressure (Scheme 17) [29], [17]. However, selectivity changed dramatically when one of the reaction partners was an aromatic compound. For instance, the reaction of citronellal with p-anisidine did not afford any product. On the other side, coupling aromatic aldehydes (i.e. 4-NO2, 4-F, 2-MeO-benzaldehyde) and N-methyl-benzylamine provided the expected products in low yields (16-23%) (Scheme 17). Selectivity improved significantly when 2a was replaced by complex 2f bearing a cyclopentadienone ligand containing heteroatoms (Scheme 17) [29]. The latter turned out to be more active in promoting the reaction under milder conditions. A cyclopentadienyl ligand with increased electron-density due to the presence of nitrogen atoms was believed to improve the stability of the corresponding 16-electron iron-complex of type B formed during the activation process. CO-bond IR analysis confirmed that

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a more significant electron density was present on the iron center of 2f, due to back donation. Furthermore, 2f fulfilled steric requirements necessary for catalyst stability: both phenyl substituents are almost perpendicular to the cyclopentadienone ligand (X-ray analysis) and create enough steric hindrance around the iron center to prevent dimerization of the corresponding active iron hydride complexes formed in situ [29].

Scheme 17. Reductive amination of aliphatic aldehydes: selected examples.

DFT investigation of the reactions catalyzed by 2a and 2f, respectively, indicated that in both cases the thermodynamically feasible hydrogen activation step (II→III) turned out to be the rate determining step (Scheme 18) [17], [29]. Comparative studies showed that energy barrier was lower in the presence of precatalyst 2f: hydrogen transfer to the C=O group of cyclopentadienone was easier as the calculated H····O(=C) distance in complex II (X = NMe; Rʹ = Ph) was found to be shorter. Imine coordination (III→IV) by means of hydrogen bonding interaction was followed by the hydrogenation step occurring through a concerted transition state V in which hydrogen atoms were simultaneously transferred to imine.

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Scheme 18. Proposed catalytic cycle for reductive amination catalyzed by 2.

(Cyclopentadienone)Iron Tricarbonyl Complexes: Bicarbonate and CO2 Hydrogenation Direct low pressure hydrogenation of abundant, cheap and relatively non-toxic carbon dioxide is an industrially important transformation as the formic acid formed can be used as carbon source, acid and reductant [30]. In 2015, Yan and Zhou were able to efficiently hydrogenate sodium bicarbonate (TON = 407) and CO2 (TON = 307) using pre-catalysts 2a (Rʹ = TMS) under Hieber base conditions (Scheme 19) [31]. Almost contemporarily, Renaud reported that complex 2f (0.01 mol%) promoted sodium bicarbonate reduction without activator (Me3NO), in DMSO/water (1/1) at 100 °C, under 50 bar of H2 (TON = 1246) [29].

Scheme 19. Carbon dioxide hydrogenation.

Nitrile-Ligated (Cyclopentadienone)Iron Hydrogenation of Carbonyl Compounds

Dicarbonyl

Complexes:

In 2012, Funk and coworkers were the first to use iron-complexes 4a-RCN, as pre-catalysts (Scheme 20) [32]. They were synthesized by oxidative decarbonylation of 2a in the presence of aliphatic or aromatic nitriles as ligands [13]. Although the resulting complexes contain a labile ligand, they were found to be air-stable solids and could be purified by chromatography.

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Scheme 20. Synthesis of 4a-RCN.

Complexes 4a-RCN were competent pre-catalysts for transfer hydrogenation of ketones and aldehydes with 2-propanol, at 85 °C [32]. Under reaction conditions, iron complexes underwent thermal ligand dissociation leading to complex B. The latter could be in situ converted into 1 upon hydrogen transfer from 2-propanol. Among pre-catalysts screened, 4a-MeCN (2 mol%) was the most selective. Aromatic aldehydes bearing aryl halides (p-Br, p-F), 2-methyl or 2,6-dimethyl substituents were well tolerated under reaction conditions. Linear and cyclic α,βunsaturated aldehydes were chemoselectively hydrogenated to the corresponding allylic alcohols (85-98% yields). On the contrary, the reduction of 4-phenyl3-buten-2-one afforded a mixture of saturated and unsaturated alcohols (ca. 1/2 ratio). Various aromatic and aliphatic ketones were also selectively reduced.

Scheme 21. Reductive amination catalyzed by 4-RCN.

While 4-RCN were completely inactive in the direct ketone and aldehyde hydrogenation, they were used to promote the reductive amination of citronellal and N-methylbenzylamine, under hydrogen pressure by the Renaud group, in

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2013 [17]. As shown in Scheme 21, iron complexes bearing a heteroatom in the backbone of the cyclopentadienone ligand were found to be more selective than those containing carbocyclic frameworks. In particular, the use of complex 4c-MeCN led to the desired amine with improved yield. The presence of an oxygen atom on the ligand backbone was believed to stabilize the corresponding complex of type-B, thus favoring subsequent hydrogen activation step. Hydrogenation under Water Gas Shift Reaction (WGSR) Conditions The water-gas shift reaction (WGSR) of CO and water in the presence of heterogeneous or homogeneous catalysts is an important industrial process to generate CO2 and H2. In other words, it is a cheap and readily accessible H2-source (Scheme 22) [33].

Scheme 22. The water-gas shift reaction (WGSR).

(Cyclopentadienone)Iron Tricarbonyl Complex: Aldehyde Reduction In 2012, the Beller group reported a rare combination of WGSR with aldehyde reduction both catalyzed by an iron catalyst such as 2a, in the presence of carbon monoxide and an inorganic base (Scheme 23) [34]. However, the attempt to include ketones as substrates failed.

Scheme 23. Iron-catalyzed aldehyde reduction under WGSR conditions.

The use of a base was necessary for the WGSR reduction of carbonyl compounds: the hydroxide anion generated in situ upon reaction of K2CO3 with H2O, was reported to react with one of the CO ligands coordinated to the iron center of 2a, thus triggering the in situ formation of the reductive iron(II) species.

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Aromatic aldehydes bearing either electron-donating or electron-withdrawing substituents in the ortho and para positions (i.e. CN, Cl, CF3, MeO, CF3O) gave the corresponding benzylic alcohols in good to excellent yields. Cyclic and branched aliphatic aldehydes were also well tolerated. α,β-Unsaturated aldehydes were chemoselectively reduced to the corresponding allyl alcohols. Scale-up experiment carried out on benzaldehyde (1 mmol→20 mmol) with 1 mol% of 2a led to the expected alcohol with full conversion and 86% isolated yield. Carbon monoxide could be replaced by paraformaldehyde [35]. Its employment as a carbon monoxide surrogate is advantageous being solid, relatively not toxic, inexpensive, not flammable and easy to handle. In this case no high-pressure equipment, but conventional glassware was needed. Selectivities (48-89%, GC yields) were comparable to those obtained using carbon monoxide. Heterobimetallic Knölker Type Complex: Benzaldehyde Reduction A new complex which incorporates copper into the metal-ligand bifunctional system of the original Knölker complex was found to be a suitable catalyst for benzaldehyde reduction, under WGSR conditions (Scheme 24a) [36].

Scheme 24. a) Synthesis of heterobimetallic complex 6. b) Simplified aldehyde reduction mechanism.

Guan and coworkers synthesized the air- and moisture-stable complex 6 from 2a and (IPr)CuOH, the latter being comparable to NaOH in terms of basicity and nucleophilicity [37]. The Fe/Cu complex in its solid state was reported to adopt the structure 6b in which the (IPr)Cu+ unit binds the Fe-H moiety rather than the oxygen atom (X-ray crystallography). By contrast, complex 6a was the dominant

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species upon solution in toluene-d8 or THF-d8 (Scheme 24a). The Fe/Cu complex (1.5 mol%) was applied as a catalyst to promote the reduction of benzaldehyde (1 equiv) using CO (6.4 atm) and water (20 equiv), in toluene at 100 °C (>99% conversion), without the use of any external base. A simplified version of the proposed mechanism is shown in Scheme 24b. Accordingly, benzaldehyde reduction occurred through concerted transfer of hydride and copper to C=O moiety. The resulting copper and iron complexes, namely (IPr)CuOCH2Ph and B, were reported to independently react with CO and H2O, respectively. Besides the expected benzyl alcohol, 2a and (IPr)CuOH were also formed. Then, Fe- and Cu-complexes recombined to afford 6, ready for a next catalytic cycle. ASYMMETRIC HYDROGENATION The capability of synthesizing enantiomerically pure compounds (i.e. pharmaceuticals, biologically active compounds, fragrances) is fundamental in organic chemistry. Asymmetric hydrogenation was one of the first methods used to prepare enantiomerically pure alcohols and amines. Several efforts have been devoted to develop the asymmetric hydrogenation of prochiral C=O and C=N bonds catalyzed by Knölker type catalysts [38]. The strategies used to achieve this task are based on a) the use of chiral iron pre-catalysts and b) the joint catalysis of achiral Knölker’s complex and a chiral additive. Chiral Iron Complexes: Hydrogenation of C=O Bond In 2011, Berkessel and co-workers synthesized the first chiral complex 4c-(R)Monophos or (S)-MonoPhos (Scheme 25) from 2c by photolytic or Me3NOmediated dissociation of the iron coordinated CO ligand in the presence of the chiral ligand [39]. The direct hydrogenation of acetophenone carried out in the presence of 4c-(R)-Monophos, under photolytic conditions afforded 1phenylethanol in 90% yield and modest enantioselectivity (31%, major enantiomer: (S)-configuration). It is useful to note that the activation of complex 4c-Monophos led to the formation of a hydride complex bearing a stereogenic iron atom (Scheme 25). 1H and 31P{1H} NMR investigations showed that a mixture of three active catalysts was formed upon activation of the chiral precatalyst, under hydrogen pressure. In addition to a small amount of the undesired achiral complex 1c, two chiral diastereoisomeric iron hydrides (1c:7:7a = 0.04:1:0.69 ratio) were observed. They might have different selectivities in the asymmetric hydrogenation of acetophenone, thus resulting in low e.e..

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Scheme 25. Activation of 4c-Monophos by irradiation with UV light and subsequent hydrogen uptake.

The Wills group was the first to synthesize iron-complexes bearing chiral cyclopentadienone ligands [40, 41]. An example is given by complexes 8 obtained through the intramolecular Pauson Kand cyclization of the corresponding enantiopure C2-symmetric diol and its benzyl and silyl ether derivatives mediated by Fe(CO)5 (Scheme 26a). Complexes 8 promoted the transfer hydrogenation of acetophenone with trimethylamine/formic acid, as H2-source. Besides the expected alcohol, a significant amount of the corresponding (R)-formate was formed. The latter derived from the formylation of the initially formed alcohol. However, asymmetric induction was modest: the best result (24% e.e.) was obtained using the more hindered silylated iron-complex (R1 = TBDPS) as a precatalyst (Scheme 26b).

Scheme 26. Synthesis and selectivity of chiral (cyclopentadienone)iron complexes 8 (TBDMS = tertbutyldimethylsilyl; TIPS = triisopropylsilyl; TBDPS = tert-butyldiphenylsilyl).

The presence of stereogenic carbon atoms on the five- or six-membered ring fused with cyclopentadienone did affect catalyst selectivity. However, their impact on the reaction transition state was low as they were too distant from the reduction center, according to the proposed outer-sphere mechanism.

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Switching catalyst to complex (R)-9 containing a BINOL-derived cyclopentadienone ligand allowed for the hydrogenation of acetophenone with e.e. ranging from 8 to 49% (Scheme 27) [42]. The transfer of stereochemical information from the catalyst stereo-axis to the substrate was more effective in the presence of bulky 3,3’-substituents (R1: OH; MeO) in the binphthol core.

Scheme 27. Synthesis and selectivity of (R)-9.

Catalyst selectivity was investigated using a variety of linear and cyclic ketones which were hydrogenated to the corresponding (S)- or (R)-alcohols with 22-100% of conversion and 13-77% e.e. (Scheme 28). Sterically hindered substrates gave the best e.e. (up to 77%), but lower conversions (25%). Up to now, enantioselectivity obtained with (R)-9 (R1 = MeO) was higher than that observed with any other reported chiral (cyclopentadienone)iron complex.

Scheme 28. Asymmetric hydrogenation of ketones with (R)-9.

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Combining Achiral Knölker’s Complex and Chiral Additive: Hydrogenation of C=N Bond In 2011, Beller and coworkers developed the asymmetric iron-catalyzed hydrogenation of prochiral ketimines by combining a catalytic amount of 1 and a BINOL-derived phosphoric acid (S)-10 (R1 = 2,4,6-iPr3C6H2) as an additive, under H2 pressure (Scheme 29) [43]. A variety of heteroaromatic and aromatic ketimines bearing electron-donating and electron-withdrawing groups in the meta- or paraposition showed good to high reactivity with yields in the range of 67-91% and high e.e. (88-93%). Slightly lower enantioselectivity (67-83%) was observed with linear and cyclic aliphatic imines. It is worth mentioning that the hydrogenation of the model N-(1-phenylethylidene)aniline catalyzed by Shvo’s catalyst led to the expected product in significantly lower e.e. (8%).

Scheme 29. Combining 1 and BINOL-derived phosphoric acid catalysis: asymmetric imine hydrogenation.

In situ31P NMR investigation of the stoichiometric reaction of (S)-10 (R1 = 2,4,6-iPr3C6H2) and 1 at the reaction temperature showed the formation of a supramolecular complex C, which suggested that the interaction between the two catalytic partners favored H2 release (Scheme 30). When the stoichiometric reaction occurred in the presence of the imine, a three-membered supramolecular complex D was formed as the major reaction product. Apparently, phosphoric acid played a dual role: in addition to imine activation, it was supposed to act cooperatively with 1 in promoting asymmetric hydrogenation.

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Scheme 30. Proposed reaction intermediate on the base of in situ31P NMR investigation.

Computational studies based on DFT calculations confirmed that hydrogenbonding interactions between iron-complex and phosphoric acid occurred throughout the catalytic cycle which was found to be a stepwise process starting with imine activation by proton transfer from the coordinated phosphoric acid (Scheme 31, E adduct) [44]. The resulting acid anion was coordinated both to the iminium salt and the iron(II)-complex (F adduct), thus enabling chirality transfer.

Scheme 31. Proposed mechanism for imine activation step on the basis of DFT calculations.

Catalyst combination of 1 and a chiral acid was further applied in the enantioselective reduction of substituted quinoxalines and benzoxazines [45]. The resulting products are interesting building blocks in the drug discovery process and important motif of many naturally occurring alkaloids. Both the C=N double bonds of 2-phenylquinoxaline were hydrogenated in the presence of Knölker’s complex and (R)-10 (R1 = 9-anthracenyl) as a chiral additive. The corresponding tetrahydro-2-phenylquinoxaline was formed with excellent e.r. and yield (Scheme 32). In addition, quinoxalines substituted in the 2-position by heteroaryl groups (2-furyl, 2-thienyl) and aryl groups bearing Me, MeO, CF3 and F substituents in the para or meta position were selectivity reduced

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in 90-97% isolated yields and with e.r. ranging from 80/20 to 95/5. The reduction of 2-alkyl-substituted substrates was achieved in high yield (94%) and with good e.r. (ca. 88/12).

Scheme 32. Enantioselective hydrogenation of a quinoxaline derivative.

Benzoxazines substituted in the 3-position by electron-donor and electronwithdrawing aryl groups gave slightly lower yield (67% to 90%) and e.e. (58% to 74%) compared to the corresponding quinoxalines (Scheme 33). It is worth noting that the combination of Knölker’s complex and a chiral phosphoric acid produced a catalytic system which is more selective compared to catalyst combination based on well-established Rh, Ru (Shvo’s catalyst) and Ir catalysts [45].

Scheme 33. Enantioselective hydrogenation of benzoxazine derivatives.

The enantioselective reductive amination of an alkyne was found to be an alternative method to access chiral amines [46]. In 2012, the Beller group reported on the cooperative Knölker’s complex/BINOL-derived phosphoric acid catalysis triggering the asymmetric reductive hydroamination of alkynes (Scheme 34a) [47]. Au-complex 11 was also used as a third catalyst to promote the intramolecular hydroamination of alkyne (i.e. phenylacetylene) with p-anisidine [48]. The resulting ketimine underwent asymmetric hydrogenation upon addition of 1 and (R)-10 (R1 = 2,4,6-iPr3C6H2) according to the mechanism proposed in Scheme 34b. Substrate scope investigation showed that mono-substituted alkynes bearing electron-rich or electron-poor aryl groups were well tolerated in the reaction with anisidine leading to the formation of the corresponding amines in 71-76% yield and 74-94% e.e.. By contrast, the reaction with aliphatic alkynes was less

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enantioselective (67-70% e.e.). Coupling a variety of electron-rich and-poor aniline derivatives with phenylacetylene afforded the corresponding chiral amines in excellent yields and high enantioselectivity (up to 94%).

Scheme 34. Enantioselective reductive hydroamination of alkynes.

DEHYDROGENATION The oxidation of alcohols to carbonyl compounds is a fundamental reaction in organic synthesis. Classical transformations are performed using stoichiometric amounts of chromium- or manganese-based oxidants, hazardous materials requiring special disposal. Transition-metal catalyzed oxidation of secondary alcohols using more friendly oxidants represents an important breakthrough in the field of green transformations [2]. Knölker’s Iron Complex: Alcohol Dehydrogenation As already reported, the stoichiometric reaction of 1 (Rʹ = TMS) with a carbonyl compound led to the alcohol/complex A through a reversible H2-transfer (Scheme 6a). In 2010, Guan envisioned that complex 1 could be used to catalyze the conversion of 1-phenylethanol to acetophenone by dehydrogenation in the presence of an efficient H2-acceptor such as acetone (Scheme 35) [21]. The proposed mechanism proceeds through the isopropyl alcohol complex A that is in equilibrium with the oxidative active species B formed upon release of 2propanol. The substrate binds B affording the new alcohol complex A′. The latter undergoes dehydrogenation releasing acetophenone and 1 ready for a new

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catalytic cycle (Scheme 35). Catalytic alcohol dehydrogenation is an efficient catalytic version of the Oppenauer oxidation [49] in which inexpensive acetone is the formal oxidant of the process.

Scheme 35. Secondary alcohol dehydrogenation: proposed mechanism.

Substrate scope investigation (Scheme 36) showed that electron-poor and -rich aromatic ketones were obtained in high yields. The reaction also worked well with cyclohexanol and a biologically relevant substrate like cholesterol which was chemoselectively oxidized. By contrast, the oxidation of 3β-hydroxy-steroids catalyzed by Shvo’s catalyst led to the corresponding α,β-enones [50]. Primary alcohols underwent oxidation with low conversion (20%). Apparently, the equilibria for alcohol oxidation favor R1CH2OH/acetone than R1COH/2-propanol. Only cinnamyl alcohol could be selectively oxidized as the formation of cinnamic aldehyde was favored by the high resonance energy gain. Interestingly, primary diols were converted into the corresponding cyclic esters: final lactone formation due to the oxidation of the hemiacetal intermediate drove the whole oxidation sequence to completion.

Scheme 36. Secondary alcohol dehydrogenation catalyzed by 1: ketone synthesis.

(Cyclopentadienone) Iron Complexes: Alcohol Dehydrogenation In 2010, Funk reported on the catalytic dehydrogenation of secondary alcohols

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using stable and easy to handle complexes 2a or 4a-MeCN (Scheme 37, A and B procedure) [20]. Thermal or Me3NO-induced ligand dissociation of 4a-MeCN or 2a led to the oxidative active species B. When Me3NO was used, the reaction was carried out in an open vessel to favor the elimination of Me3N formed during the reaction, the latter being a potential ligand of complex B. Both iron complexes promoted the oxidation of secondary benzyl/allylic alcohols in fear to very good yields. Secondary aliphatic alcohols were also well tolerated.

Scheme 37. Alcohol dehydrogenation using 2a or 4a-MeCN as pre-catalysts: selected examples.

Scheme 38. Alcohol oxidation catalyzed by complex 2h.

Complex 2h is a competent pre-catalyst for secondary alcohol dehydrogenation (Scheme 38) [51, 52]. In the presence of formaldehyde as a better H2 acceptor in comparison to acetone, a mixture of ketones and formates was obtained with very good conversions [51]. Formate formation was thought to occur through the formal dehydrogenative coupling of formaldehyde and alcohol, mediated by the iron complex.

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DEHYDROGENATIVE

ALCOHOL

Borrowing Hydrogen Methodology Alcohols are common and inexpensive starting materials containing a poor leaving group. Traditionally, their activation is based on the transformation of the OH group into a better leaving group (halide, acetate, carbonate, phosphate or sulfonate). An alternative method for alcohol activation under mild conditions relies on its temporary conversion to a carbonyl compound (aldehyde or ketones) by metal-promoted dehydrogenation (Scheme 39). The latter is more reactive and can be easily functionalized through the condensation with a carbon- or a nitrogen-nucleophile. The resulting unsaturated product formed upon water elimination, gets hydrogen back from the catalyst. Such a redox process promoting the formation of new carbon-carbon or carbon-nitrogen bonds is known as “borrowing hydrogen” (BH) methodology. Typical homogeneous catalysts promoting this reaction sequence are Iridium-, Ruthenium- and Rhodium-complexes [53].

Scheme 39. Transition metal-catalyzed borrowing hydrogen (BH) methodology.

Carbon-Nucleophile: Carbon-Carbon Bond Formation In 2015, the group of Darcel and Sortais developed the iron-catalyzed α-alkylation of ketones with benzyl alcohols in the presence of 2a/triphenylphosphine/Cs2CO3, as a catalytic system (Scheme 40) [54]. The inorganic base was reported to mediate the in situ formation of pre-catalyst 4-PPh3 from 2a by CO/PPh3 displacement. Then, the catalytically inactive complex 4-PPh3 was subsequently converted into the oxidative active 16-electron iron-PPh3 species, upon basepromoted CO ligand cleavage. According to the reaction mechanism proposed in Scheme 39, the starting ketone underwent a condensation with the aldehyde formed upon benzyl alcohol dehydrogenation. The carbon-carbon double bond of the resulting α,β-unsaturated ketone was chemoselectively hydrogenated leading to the product and the coordinatively unsaturated 16-electron iron-PPh3 complex

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ready for a new catalytic cycle. Coupling aryl ketones and benzyl alcohols with different electronic features gave the expected products in 36-72% yields (Scheme 40). Apparently, the success of the reaction relies on the bifunctional nature of iron complex. When 2a was replaced by Fe2(CO)9 as a pre-catalyst no reaction was observed even after longer reaction time.

Scheme 40. Ketone alkylation with benzyl alcohols.

Scheme 41. Coupling iron catalysis and asymmetric organocatalysis: chiral 3-alkylpentanol synthesis.

In 2014, Quintard and Rodriguez developed the enantioselective synthesis of chiral keto-alcohols, biologically active intermediates of natural products and fragrances, through a single synthetic operation using both 2a and chiral prolinol (Ocat) as a metal- and an organo-catalyst, respectively (Scheme 41) [55]. The reaction is an impressive example of a cascade process based on the synergistic combination of borrowing-H2 methodology and stereoselective C=C double bond addition. As shown in Scheme 42, iron-catalyzed crotyl alcohol activation is followed by the organocatalytic, enantioselective iminium Michael addition with 1,3-diketone, as C-nucleophile. Organocatalyst removal leads to the chiral βsubstituted aldehyde which easily undergoes carbonyl hydrogenation thus closing

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the “iron” catalytic cycle. The resulting linear alcohol intermediate was found to be in equilibrium with the cyclic chiral lactol bearing a COR2 group in the βposition. The latter underwent Claisen fragmentation providing the linear O-acyl product (Scheme 42). Kinetic studies indicated that the starting allylic alcohol behaved as a co-catalyst favoring the formation of the more reactive enol nucleophile through hydrogen bonding interactions (Scheme 42). This result prompted the authors to employ a Lewis acid as a third co-catalyst: better results in terms of yield and e.e. were obtained in the presence of a catalytic amount of Cu(acac)2 (Scheme 43) [56]. Improved enantioselectivity at the stage of iminium addition might be due to a better discrimination between the two diastereoisomeric transition states.

Scheme 42. Borrowing-H2 coupled with organocatalytic Michael addition: proposed mechanism.

Under triple iron/copper/organo-catalysis, nitroester and ketosulfone as Cnucleophiles were also well tolerated. When β-ketoesters were employed, diastereoisomeric mixtures (9/1 ratio) of chiral cyclic lactols were formed, Claisen fragmentation being disfavored either in the presence or in the absence of Lewis acid (Scheme 43) [56, 57]. Comparative studies showed that under triple catalysis, the reaction occurred with higher yield and stereoselectivity.

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Scheme 43. Triple Fe/Cu/prolinol catalysis: selected examples (MOM = methoxymethyl).

Nitrogen-Nucleophile: Carbon-Nitrogen Bond Formation N-Alkyl benzylamines. Benzyl amines are important targets, being present in a variety of drug molecules [58]. Feringa and co-workers were the first to synthesize N-alkyl substituted benzylamine derivatives through iron-catalyzed alkylation with alcohols [59, 60]. Two approaches were used to obtain the desired products. The first is based on the alkylation of benzylamines with primary alcohols, in toluene (Scheme 44, A-procedure) [59]. The second is based on the alkylation of primary alkyl amines with benzyl alcohols, in cyclopentyl methyl ether (CPME) (B-procedure) [60]. Comparative studies indicated that A-procedure was more efficient to synthesize electron-poor benzylamines, whereas Bprocedure worked better to obtain N-substituted electron-rich benzylamines. These results suggested two considerations: a) structurally different imine intermediates leading to the same product did not undergo isomerization, under reaction conditions, b) differences in reactivity might be due to differences in the imine hydrogenation rates. Benzyl alcohols were efficient alkylating agents also for linear and cyclic secondary aliphatic amines (Scheme 45a) [60]. The benzylation of morpholine and N-methyl benzylamine gave the corresponding tertiary benzylamines in good to high yields. Iron-catalyzed alkylation of 1-(2-pyrimidyl)piperazine with

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piperonyl alcohol led to Piribedil a dopamine antagonist used in the treatment of Parkinson’s disease, thus demonstrating the applicability of this method [59]. Alcohols containing heterocyclic units (thiophene, furan) were also competent substrates. In particular, the synthesis of furan-based pharmaceutically active antimuscarinic agents from 2,5-furandimethanol, one of the most important cellulose-derived platform chemicals, proved the synthetic utility of the method (Scheme 45b). Selective mono-amination of the diol with a secondary amine afforded the corresponding amino alcohol, direct precursor of active compounds [60].

Scheme 44. N-Alkyl substituted benzylamine synthesis (procedures A and B): selected examples.

Scheme 45. a) Benzylation of secondary aliphatic amines. b) Antimuscarinic agent synthesis.

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Interestingly, non-symmetric tertiary benzylamines were synthesized through the sequential alkylation of a primary aliphatic amine with two different alcohols, nbutanol and benzyl alcohol (Scheme 46). The success of the reaction relied on differences in reactivity between the alcohols used [60].

Scheme 46. Synthesis of non-symmetric tertiary aliphatic amines by sequential alkylation.

Aromatic amines. The Feringa group extended the procedure to include anilines and primary alcohols (Scheme 47) [59]. Substrate scope investigation showed that amine electronic and steric features dramatically affected selectivity. Anilines meta- or para-substituted by electron-donating groups and halides were selectively alkylated with 1-pentanol. Moving substituents from para to ortho position of the aromatic ring produced less selective transformations particularly with halide substituents. Anilines bearing electron-withdrawing groups (NO2, CN) did not react at all. Various primary aliphatic alcohols such as 1-octanol, ethanol, 2-phenylethanol and 1,2-ethanediol were also well tolerated in the reaction with p-anisidine. No reaction occurred with benzyl alcohol.

Scheme 47. Aniline alkylation with primary alcohols: selected examples.

Interestingly, in 2015 Wills and coworkers developed a protocol for the alkylation of anilines with benzyl alcohols [61]. The choice of iron pre-catalyst 2i was crucial for selectivity: aniline underwent alkylation in fair to high yields, with various benzyl alcohols (Scheme 48).

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Scheme 48. Aniline benzylation.

Secondary alcohols are less efficient than primary alcohols as alkylating agents as the transient ketone generated by alcohol activation undergoes slower amine condensation. In 2015, Zhao and coworkers found that the use of 1 in combination with a catalytic amount of silver fluoride as an additive, promoted the alkylation of p-anisidine with secondary alcohols (Scheme 49) [62]. The role of AgF was not completely clear. As a Lewis acid, it was believed to promote ketone/amine condensation and activate the resulting imine towards hydride transfer (hydrogenation step). Substrate scope investigation showed that linear and cyclic secondary aliphatic alcohols (2-octanol, 3-methyl-2-butanol, cyclohexanol, 2-propanol, αmethylbenzyl alcohol) were efficient alkylating agents of p-anisidine and primary or secondary aliphatic amines (benzylamine, piperidine, 30-51% yield).

Scheme 49. Aniline alkylation with secondary alcohols.

Allylic amines. In 2016, Sandararaju and coworkers reported that secondary cyclic amines (i.e. N-Boc-piperazine) were alkylated with allylic alcohols (cinnamyl alcohol, prenol, geraniol, farnesol) in satisfactory yields (Scheme 50) [63]. Amine scope investigation showed that five-, six-, seven-membered cyclic amines and acyclic dibenzylamines smoothly coupled with cinnamyl alcohol (Scheme 51).

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Primary amines such as p-methoxyaniline and benzylamine underwent selective mono-allylation in moderate yields, whereas double allylation occurred with the more basic n-propylamine. The synthesis of pharmaceutically interesting cinnarizine (antihistaminic drug) and naftifine (antifungal drug) proved the synthetic applicability of the methodology.

Scheme 50. Allylic amination: alcohol scope.

H NMR investigation of the reaction mixture (toluene-d8, 130 °C) demonstrated that allylic amination selectively proceeds through the α,β-unsaturated aldehyde intermediate generated through alcohol activation. These results ruled out the hypothesis of an alternative mechanism based on a π-allyl metal complex intermediate: it is well known that allyl alcohol could undergo nucleophilic substitution with amines, upon activation with a transition metal (Pd, Ru, Ir) and proper additives [64]. 1

Scheme 51. Allylic amination: amine scope.

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Heterocycle Synthesis via C-C and C-N Bond Formation Aza-heterocycles are present in a great number of natural and synthetic products such as drugs, catalysts and materials [65]. The application of borrowing hydrogen strategy led to the design of more sustainable and atom-economical heterocycle synthesis. Accessible substrates such as alcohols and amines are used, no stoichiometric activating agents are required, no waste is generated besides water [66]. Quinolines. Friedländer reaction is a classical methodology used to synthesize quinolines starting from 2-amino substituted aromatic carbonyl compounds and ketones containing a reactive α-methylene group [67]. Annulation occurs through an initial base- or acid-promoted condensation of the reaction partners followed by cyclization with water elimination. Main reaction drawbacks are represented by the possible formation of self-condensation products mostly due to instability of 2-amino substituted aromatic carbonyl compounds. Modified Friedländer quinoline syntheses based on Ru-, Rh-, Pd-, Cu-, Ir-catalyzed annulations via BH strategy have been recently reported [68]. In 2015, Darcel and coworkers developed the first iron-catalyzed synthesis of quinolines starting from more stable 2-aminobenzyl alcohol and acetophenone in the presence of 2a/triphenylphospine/tBuOK as a catalytic system, in toluene at 140 °C (Scheme 52) [54]. The oxidative active iron species I was believed to promote the slow oxidation of 2-aminobenzyl alcohol (Scheme 53). The resulting carbonyl compound underwent base-catalyzed condensation with the starting ketone. The α,β-unsaturated ketone formed underwent cyclization. It is useful to note that starting ketone also behaved as H2-scavenger capturing hydrogen from complex II to regenerate complex I (semi-borrowing hydrogen process).

Scheme 52. Quinoline synthesis.

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The reaction was successfully extended to include p-MeO, p-chloroacetophenone, propiophenone and α-tetralone as ketone partners.

Scheme 53. Proposed mechanism.

Pyrroles. Pyrrole synthesis through Hantzsch, Knorr and Paal-Knorr methods [69] make use of substrates containing ketone and amine functionalities which are involved in the formation of inter- and intramolecular C‒C and C‒N bonds. However, low substrate accessibility, limited scope, stoichiometric use of additives and harsh conditions could be limitations to synthetic application. Many efforts have been devoted to discover new routes to pyrrole derivatives taking advantage of catalytic C‒C and C‒N bond forming methodologies including borrowing hydrogen strategy [70]. In 2016, Barta and Yan converted easy accessible 2-butyne-1,4-diol (d1) or cis-2butene-1,4-diol (d2) to N-substituted pyrroles upon reaction with aromatic amines using 2a/Me3NO as a catalyst (Scheme 54) [71]. Comparative studies indicated that d1 selectively coupled with p-MeO and p-NMe2 substituted anilines, whereas p-Me and p-halo substituted anilines gave the best results upon reaction with d2 (Scheme 54a). The reaction with d1 worked well also with 3-picolylamine, 2furfurylamine and various electron-rich and electron-poor benzylamines (Scheme 54b). The reaction with other primary aliphatic amines such as cyclohexylamine, 2-phenethylamine and dodecylamine led to the corresponding pyrroles in moderate yields (33-41%). Interestingly, in all cases no significant over-reduction to pyrrolidines was observed under reaction conditions. In 2017, the Sundararaju group reported that variously substituted (E)- or (Z)-2butene-1,4-diols were coupled with amines to afford the corresponding mono- or di-substituted pyrroles (Scheme 55-57) [72]. While aliphatic amines turned out to be more competent substrates in the reaction with (E)-2-phenylbut-2-ene-1,4-diol, certain aniline derivatives and 2-aminopyridine were less efficient (Scheme 55).

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Among the aliphatic amines screened, isobutylamine, cyclohexylamine, sterically hindered tert-butyl amine and biologically interesting tryptamine led to the corresponding 3-phenyl-N-alkylpyrroles in moderate to good yields. 2Picolylamine, ortho- and para-substituted benzylamines gave the expected products in moderate to good yields. β- and γ-amino alcohols were also tested as primary amine sources: both gave the corresponding pyrroles without any oxidation of the alcohol group.

Scheme 54. N-aryl and N-alkyl pyrrole synthesis: selected examples.

Scheme 55. 3-Phenyl substituted pyrrole synthesis: selected examples.

The procedure was extended to include diamines and (E) or (Z)-diols: the resulting bis(pyrroles) were isolated in satisfactory yields (Scheme 56).

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Scheme 56. Synthesis of bis(pyrroles).

A variety of secondary trans-diols (R1: Me, iPr, Ph, naphthyl, 2-thienyl), which undergo dehydrogenation less easily compared to primary diols, were coupled with p-methoxybenzylamine affording the corresponding 2-substituted-N-PMBpyrroles (Scheme 57). As shown in Scheme 57, 2,4-disubstituted pyrroles were also obtained in decent yields from the corresponding di-substituted diols.

Scheme 57. Synthesis of 2- and 2,4-substituted pyrroles (PMB = p-methoxybenzyl).

Pyrrole formation mechanism. 2-Butyne-1,4-diols have been already involved in the synthesis of pyrroles via Ru-catalyzed BH methodology [73]. Inspired by these results, Barta and Yan proposed a mechanism for pyrrole formation starting with isomerization of 2-butyne-1,4-diol via iron-catalyzed H2-autotransfer (Scheme 58) [71]. Then, amine condensation with ketone intermediate (Z)-I led to (Z)-II containing an allylic hydroxyl group which was involved in a second catalytic H2-autotransfer isomerization. The resulting imine intermediate III underwent imino/enamino tautomerization, followed by cyclization to form pyrrole. When (E)-2-butene-1,4-diol was involved, Sundararaju and coworkers suggested that the reaction might proceed through iron-promoted allylic amination leading to the unsaturated aminoalcohol (E)-V (Scheme 59) [72]. The latter was supposed to undergo catalytic dehydrogenation affording the amino-aldehyde (E)-VI which provided the product by intramolecular condensation and concomitant H2O liberation.

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Scheme 58. Pyrrole formation from 2-butyne-1,4-diol: proposed mechanism.

Scheme 59. Pyrrole formation from (E)-2-butene-1,4-diols: proposed mechanism.

Azepanes, piperidines, pyrrolidines. Five-, six- and challenging seven-membered aza-heterocycles were synthesized in fair to very good yields from metasubstituted benzylamines and diols of different chain length (Scheme 60) [59]. Diols were involved in the amine double alkylation occurring inter- and intramolecularly. A complementary synthetic approach to such heterocycles relied on the use of benzyl alcohols and aminoalcohols as starting materials (Scheme 60). For instance, the reaction with 5-amino-1-pentanol afforded Nbenzylpiperidines in comparable yields [60].

Scheme 60. Pyrrolidine, piperidine and azepane synthesis.

Dynamic Kinetic Resolution of Alcohols An important method for the preparation of enantiomerically pure alcohols with

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excellent enantioselectivities is based on the kinetic resolution of racemic mixture using enzymes. The main drawback of the method is the yield of enantiomerically pure alcohol obtained which cannot exceed 50%. This limitation was overcome combining enzyme and transition metal catalysis (Scheme 61). Metal catalyst promotes the continuous racemization of the slow-reacting alcohol through a reversible hydrogen transfer process. In principle, a 100% yield of the enantiopure alcohol can be obtained via dynamic kinetic resolution (DKR).

Scheme 61. Enzymatic resolution under alcohol racemizing conditions: dynamic kinetic resolution.

Shvo’s complex [74] as well as other Ru-, Ir- and Pd-based catalysts have been successfully applied to DKR of racemic alcohols [75]. In 2016, Rueping and coworkers used Knölker’complex 1 (R′ = TMS) as a racemization catalyst in the DKR of secondary alcohols in the presence of Candida antarctica lipase B (CAIB) and p-chlorophenylacetate as the acyl donor, under inert atmosphere (Scheme 62) [76]. Various racemic 1-heteroarylethanol derivatives and 1arylethanols bearing p-tBu, p-Cl, p-Br, p-F, p-CF3, p- and m-MeO substituents were transformed into the corresponding enantioenriched acetates via DKR in very good yields and e.e.. While complex 1 was an efficient racemization catalyst, Rueping and coworkers found that the catalytic performances of some pre-catalysts of type 2 in the presence of Me3NO were not satisfactory. Even after prolonged heating, the racemization of (R)-1-phenyethanol was incomplete (e.e. > 0). The authors suggested that catalyst inactivation could be induced by Me3N generated from the reaction of 2 with Me3NO [20]. In 2017, Bäckvall and coworkers succeeded in DKR of racemic secondary alcohols by using 2a/Me3NO as a racemization catalyst, Candida antarctica lipase B (CAIB), in anisole or CPME as solvents (Scheme 63) [77]. Two additives were further employed to increase efficiency of the catalytic system: a catalytic amount of the ketone intermediate (R1-CO-R2) and a stoichiometric amount of an

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inorganic base (Na2CO3). A critical step of the racemization process was proved to be the re-addition of hydrogen to the ketone. A slight excess of it favored hydrogen transfer. At the same time, hydride transfer to R1-CO-R2 was found to be easier in the presence of Na2CO3 [39].

Scheme 62. DKR of racemic alcohols combining iron-complex 1 and lipase catalysis (PCPA = pchlorophenylacetate).

Chemoenzymatic DKR was applied to a number of secondary aliphatic alcohols. In terms of yield and enantioselectivity, the results obtained by the Bäckvall and Rueping groups were comparable (Scheme 62 and 63).

Scheme 63. Chemoenzymatic dynamic kinetic resolution using 2a.

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CONCLUDING REMARKS The number of synthetic applications reported in literature in the last decade proves that Knölker type iron complexes, used directly or generated in situ, are competent catalysts for (de)hydrogenation reactions leading to a variety of pharmaceutically and biologically interesting alcohol, amine and ketone derivatives. The employment of air- and moisture-stable complexes of type 2 or 4-L as pre-catalysts was decisive to exploit the catalytic potential of Knölker type iron complexes in synthetic applications. Tuning electronic and steric features of iron coordinated cyclopentadienone ligand of 2 opened new opportunities to enlarge substrate scope of (de)hydrogenation reactions. Iron complexes bearing chiral cyclopentadienone ligands were used as precatalysts to promote the asymmetric hydrogenation of prochiral C=O double bonds with promising enantioselectivity (up to 77%). Highly enantioselective hydrogenation of pro-chiral C=N double bonds was developed through the cooperative catalysis of achiral complex 1 and a chiral phosphoric acid. Moreover, coupling iron catalysis (1 or 2a) and biocatalysis allowed for obtainment of enantiopure benzylic alcohols (99% e.e.) through DKR of racemic secondary alcohols. Some recent results, although still preliminary, showed that switching 1 to Fe/SiH complex made possible, for the first time, the reduction of apolar multiple bonds of alkyne and alkene derivatives. The successful use of 2a and the heterobimetallic Fe/Cu-complex 6 in promoting catalytic aldehyde reduction using water and carbon monoxide or paraformaldehyde as a hydrogen source is an industrially relevant result. Complex 1 and mostly 2a were active catalysts for hydrogen autotransfer reactions enabling the selective alkylation of amines and ketones with inexpensive, non-toxic primary and secondary alcohols. Furthermore, five-, sixand seven-membered aza-heterocycles were built up in a single operation from easy available starting materials. Remarkably, the insertion of an enantioselective addition reaction step into BH process enabled the synthesis of pharmaceutically relevant intermediates with high enantio- and diastereoselectivity. It is interesting to note that catalytic activities of Knölker type complexes in the field of asymmetric hydrogenation and borrowing hydrogen methodology are unprecedented. In that respect, bifunctional iron-complexes can be considered complementary to the related Shvo complexes.

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CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The author (editor) declares no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS We thank Consiglio Nazionale delle Ricerche (CNR) for financial support. REFERENCES [1]

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CHAPTER 3

Superelectrophilic Activation of Alkynes, Alkenes, and Allenes Aleksander V. Vasilyev1,2,* Department of Chemistry, Saint Petersburg State Forest Technical University, Saint Petersburg, Russia 2 Institute of Chemistry, Saint Petersburg State University, Saint Petersburg, Russia 1

Abstract: Recent advances in organic synthesis based on superelectrophilic activation of alkynes, alkenes, allenes, and their trifluoromethyl substituted derivatives under the action of Brønsted superacids (CF3SO3H, FSO3H, HF), strong Lewis acids (AlCl3, AlBr3), conjugate Brønsted-Lewis superacids (CF3SO3H–SbF5, FSO3H–SbF5, HF–SbF5, HBr–AlBr3, HCl–AlCl3) or superacidic H+-zeolites are considered. These reactions proceed through an intermediate formation of carbocationic and other cationic species and lead to the formation of various functionalized compounds, carbocycles, heterocycles under mild conditions and in high yields of target products. In many cases, cationic reaction intermediates are detected and thoroughly studied by means of NMR in superacids (CF3SO3H, FSO3H), that help to prove reaction mechanisms.

Keywords: Acidic zeolites, Alkenes, Alkynes, Allenes, Brønsted superacids, Carbocations, Carbocycles, Cyclization, DFT calculations, Enynones, FriedelCrafts reactions, Heterocycles, Hydroarylation, Ionic hydrogenation, Lewis acids, NMR of cations, Superelectrophilic activations, Trifluoromethyl group, Vinyl triflates. INTRODUCTION Superelectrophilic activation is the generation of reactive carbocationic and other cationic intermediates from organic molecules under the action of Brønsted superacids (CF3SO3H, FSO3H, HF), strong Lewis (super)acids (AlCl3, AlBr3, SbF5) or combinations of Brønsted and Lewis superacids [1, 2]. Brønsted superacids are acids stronger than sulfuric acid H2SO4, which is characterized by Hammett acidity function value H0 -12. They have values of H0 less than -12, for instance, trifluoromethanesulfonic acid CF3SO3H (TfOH) (H0 -14) and fluorosulfonic acid FSO3H (H0 -15) [1]. Superacids have two main features: high Corresponding author Aleksander V. Vasilyev: Department of Chemistry, Saint Petersburg State Forest Technical University, Saint Petersburg, Russia; Tel: +78126709352; Fax: +78126709390; E-mail: [email protected] *

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

82 Advances in Organic Synthesis, Vol. 8

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protonating (ionizing) ability and extremely low nucleophilicity. This makes it possible to obtain not only mono-charged cations but also di-, tri- (and even more) cations, which possess enhanced electrophilic properties and are very reactive species. Low nucleophilicity of superacidic media suppresses interaction of the generated cations with acid counterions and allows direct reactions of cationic species with other nucleophiles, such as arenes, similar to a new carbon-carbon bond formation in Friedel-Crafts and other processes. One more unique advantage of liquid Brønsted superacids (CF3SO3H, FSO3H) is a possibility to generate stable cations at low (-100 – -40 °C) or room temperature and observe them by means of NMR, that sheds light on the reaction mechanisms. The general aspects and philosophy of phenomena of superacidity and superelectrophilic activation of organic compounds are discussed in books [1, 2]. Superelectrophilic activation is widely used in organic synthesis by carbon-carbon bond forming reaction through intermediate formation of carbo- and heterocations [3 - 5]. In this chapter, recent advances in superelectrophilic activation of alkynes, alkenes, allenes, and their trifluoromethyl substituted derivatives are considered. Protonation of unsaturated carbon-carbon bonds of such compounds in Brønsted superacids (or their coordination with strong Lewis acids) lead to carbocationic species, which may react in different ways. The perspectives of this methodology for organic synthesis to get new substances with practically valuable properties are shown. Reaction mechanisms are thoroughly discussed as well. Superelectrophilic Activation of Alkynes One of the useful transformations of alkynes in superacids is the addition of superacid molecules to the acetylene bond. Thus, esters of arylacetylenecarboxylic acids and arylacetylene ketones 1 in trifluoromethanesulfonic acid (TfOH) afford the corresponding vinyl triflates 2 [6, 7]. The reaction proceeds with initial formation of E-isomers of 2, as products of syn-addition of TfOH to the triple bond. Then under superacidic reaction conditions E-2 are isomerized into Z-(anti)2. In the same way, addition of FSO3H to compounds 1 gives vinyl fluorosulfonates [7]. Ar

COX

CF3SO3H

1 X = OMe, OEt, Me

TfO

CF3SO3H

COX Ar E-(syn) 2

Ar OTf = OSO2CF3 COX TfO Z-(anti) 2 (80-94 %)

Addition of TfOH to conjugated 1,5-diarylpent-2-en-4-yn-1-ones 3 proceeds very regioselectively to the acetylene bond only with the formation of E-/Z-isomers of dienyl triflates 4. The highest yields of 4 have been obtained with the use of the pyridine(10-33% vol.)–TfOH system [8].

Superelectrophilic Activation of Alkynes O Ar1

Ar

Advances in Organic Synthesis, Vol. 8 83

CF3SO3H, Py (10-33 % vol.)

OTf

O

Ar1 (2E,4Z)/(2E,4E)-4 (39-92 %) ratio of (2E,4Z) : (2E,4E) 1 - 4.1 : 1

r.t., 15 min

3

In neat TfOH, cross-conjugated enynones 5 form vinyl triflates 6 having predominantly Z-configuration at triflate double bond, that corresponds to antiaddition of TfOH to acetylene bond [9]. O Ar 5

O

CF3SO3H Ph

0 oC or r.t. 0.5-3 h

OTf

Ar

Ph

(1Z,4E)/(1E,4E)-6 (61-81 %) ratio of (1Z,4E) : (1E,4E) 4.8 - 8 : 1

Addition of TfOH to acetylene compounds 1, 3, 5 provides access to various vinyl triflates 2, 4, 6 which have a great value as substrates in cross-coupling reactions (Heck, Suzuki, Sonogashira, etc.). In many cases, the stereoselective formation of only E- or Z-isomer of vinyl triflates 2, 4, 6 can be achieved, that depends on the structure of starting compounds, reaction temperature and time [6 - 9]. Arylacetylenes 7 bearing various electron withdrawing substituents X may take part in Friedel-Crafts alkenylation of arenes [10 - 19]. This reaction proceeds through intermediate formation of vinyl dications 8 and lead to alkenes 9. The initially formed products of syn-hydroarylation of the triple bond 9 may be further converted into the corresponding anti-isomers under the reaction conditions depending on structure of substrate 9, reaction temperature and time [12, 13, 15]. This is a rather general reaction, which can be carried out in different Brønsted (FSO3H, CF3SO3H) and conjugate Brønsted-Lewis (HF–SbF5, FSO3H–SbF5, CF3SO3H–SbF5, HBr–AlBr3) superacids, or under the action of solid superacidic H+-zeolites [18]. X

Ar 7

H+(HY) -75 oC - r.t., 0.25 - 2 h

XH Ar 8

H

X = CO2H, CO2Alk, CONHAr, CN, COMe, COPh, COCO2Et, COCF3, PO(OEt)2, SO2Ph

Ar1H -2H+

Ar

X

Ar1 (syn-) 9 (up to 95 %)

HY

Ar1

X

Ar (anti-) 9

HY = FSO3H, CF3SO3H, HF-SbF5, FSO3H-SbF5, CF3SO3H-SbF5, HBr-AlBr3, H+-zeolites

Arylacetylenes ArC≡CX having aromatic ring with at least one methyl group are rather rich π-nucleophiles per se. In the absence of external aromatic nucleophiles,

84 Advances in Organic Synthesis, Vol. 8

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such substrates may undergo electrophilic attack from intermediate vinyl cations [10, 13]. Thus, compounds 10a-c furnish stereoselectively dimers E-11a-c in FSO3H at low temperature [13]. Me Me

Me Me

X

FSO3H -75- -50oC, 0.3-1h

Me Me

Me 10a-c

X

Me Me

X=COPh (a), COMe (b), PO(OEt)2 (c) X E-(syn-)11a (60 %), b(53 %), c(40 %)

Hydroarylation of acetylene bond under superelectrophilic activation may be conjugated with other reactions, for instance, ionic hydrogenation. Reaction of esters and amides of 3-phenylpropynoic acid 12 with AlX3 or HX-AlX3 (X = Cl, Br) in the mixture of benzene and cyclohexane affords 3,3-diphenylpropanoic acid derivatives 13 as a one-pot procedure [19].

COR +

Ph

+

12 R = OAlk, NAlk2

AlX3 or HX-AlX3 (X = Cl, Br) r. t., 3-15 h

Ph COR Ph 13 (45-94 %)

In the case of Brønsted-Lewis superacids HX-AlX3 (X = Cl, Br) O,C-diprotonation of 12 affords dication 14, alkenylates benzene leads to O-protonated alkene 15. The protonation of the latter at the double bond gives highly reactive superelectrophilic dication 16, which is able to take a hydride-ion from cyclohexane, that finally gives product of tandem hydrophenylation-ionic hydrogenation 13 [19]. For Lewis acids, the coordination of AlX3 (X = Cl, Br) with basic centers (C=C and C=O bonds) of 12 and 15 takes place, that leads to electrophilic activation of the corresponding intermediate species giving finally 13 [19]. Alkynes show a diversity of intramolecular reactions under superelectrophilic activation affording carbo- and hetero-cycles. 1,3-Diarylpropynones 17 are cyclized into 3-arylindenones 22 in various superacids [16, 20 - 23]. The reaction proceeds through the series of cationic intermediates 18-21. Initial O-protonated forms 18 of propynones 17 are not reactive. They were generated in FSO3H at -80

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°C and studied by NMR at these conditions (see ion 17a) [21, 22]. At higher temperature or with increasing acidity of reaction medium (CF3SO3H–SbF5, HF–SbF5), the second C-protonation occurs leading to reactive dications 19, which are cyclized into O-protonated indenones 20. These species in turn are protonated at the double bond under the superacidic reaction conditions and give stable O,C-dications 21, which were also characterized by NMR (see ion 21a) [22, 23]. Aqueous workup of reaction mixture results finally in the formation of indenones 22. HO O

2H+

Ph

Ph

R

12

H

14

1. H- (c-C6H12), -+C6H11

HO

HO Ph PhH -H+ Ph 15

R

R

Ph

+

H

R

Ph 16

Ph COR

Ph

2. H2O, -H+

R = OAlk, NAlk2

13

R

R OH

O

+

H

HO

H

H+

R

-H+

Ar Ar

Ar

17

18

19

+

H = acid: CF3SO3H, FSO3H, CF3SO3H-SbF5, HF-SbF5 OH

O

OH

+

H2O

H

-2H+ R

Ar 20

OH Ph

181.9 ppm

Ph 17a

R

Ar

21

13C NMR (FSO3H, -80 oC)

116.4 ppm

R

Ar

22 (43-95%)

 C NMR (CF3SO3H, -30 oC) 13

217.1 ppm

OH OMe

183.7 ppm

MeO

21a

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It is interesting to note, that 3-arylindenones 22 are easily regio- and stereoselectively photodimerized under exposure to day light with formation of [2+2]-syn-trans-adducts 23, which are isomers of truxone derivatives [23, 24]. O

O Et2O, h (day light)

H H O

r.t., 3 days Ar

Ar Ar 22

23 (67-72 %)

Aluminum halogenides (AlX3, X = Cl, Br) promote reactions of acetylene carbonyl compounds 24 and propargylic alcohols 25 with arenes furnishing indenes 34-37 [25 - 28]. Coordination of AlX3 at the carbonyl oxygen of substrates 24 activates the carbonyl carbon C1. This electrophilic center reacts with arenes leading to species 26, which are transformed into propargyl cations 27 [25, 27, 28]. The latter may be also generated from the corresponding propargyl alcohols 25 [26 - 28]. Cations 27 may be presented in allenyl mesomeric form 28. These two resonance forms 27 and 28 have two different reactive electrophilic carbon centers, C1 and C3, respectively, that in reactions with arenes affords two different products, viz., alkyne 29 (path a) or allene 30 (path b). The further protonation of compounds 29 and 30 gives the corresponding cations 31 and 32 (with the mesomeric form 33 for the latter). Cyclization of the species 31-33 leads to isomeric indenes 34-37. The influence of the electronic character of the substituents in mesomeric cations 27 and 28 on their consequent transformations was thoroughly analyzed [28]. It has shown that electron-donating substituents Ar, Ar1, and R capable of delocalizing positive charge favor the activation of the neighboring electrophilic center (C1 in 27 and C3 in 28) that guides the reaction via paths a or b, respectively. It should be noted, that electrophilic activation of carbonyl carbon in acetylene ketones 24 takes place only with strong Lewis acids AlX3 (X = Cl, Br). In Brønsted superacids hydroarylation of acetylene bond in ketones 24 solely proceeds without any reactions on the carbonyl group [13, 27]. In general, reaction of acetylene compounds 24 and 25 with arenes under the action of aluminum halogenides is an effective way to various indene derivatives [28]. Cyclization of arylacetylenecarboxylic acid derivatives 38, N-aryl amides (X = NH), aryl esters (X = O) or thioesters (X = S), results in the formation of heterocycles 39 of the series of quinolinones (X = NH) [29 - 33], coumarines (X = O) [34] or thiocoumarines (X = S) [35], respectively, under superelectrophilic activation.

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 87

O Ar

3

2

1

24

R = H, Me, Ph

R

AlX3

X = Cl, Br

Ar1H

Ar

H + AlX3 O R 2 1 1 Ar

3

26

- [AlX3OH]

-

Ar

3

-

2 1

Ar

3

2

1

28

Ar

Ar

-H+

Ar1

27

-

path a Ar2H

R 3

29

Ar1 H+ R Ar2

R

path b Ar2H

Ar2

R

Ar1

-H+

Ar

Ar1

Ar Ar 31

R

-H+

35

R3

R Ar1

R 30

Ar

Ar1

-H+

R Ar1

2

Ar

33

Ar2 36 Ar Ar2

R1

-H+

R

37

R2

Ar

Ar H+

38

Ar -H+

Ar2

Ar

R

Ar1

Ar1 2

H+

R2

34 R

-H+

32

X

Ar2

R

AlX3 - [AlX3OH]

Ar

2

25

OH R 1 1 Ar

R

O X = NH, O, S

X

O

H+ = acid: CF3SO3H, FSO3H, CF3SO3H-SbF5, AlCl3, AlBr3, H2SO4, H+-zeolites

39 (up to 98 %)

In the presence of arenes, amides 38 afford 4,4-diaryl-3,4-dihydroquinolinones 43 under the action of Brønsted superacids or AlX3 (X = Cl, Br) [17]. The intermediate dications 40 can react in the following concurrent directions. The first one is an intramolecular cyclization into quinolinones 39. The alternative reaction with arenes leads to compounds 41. The latter can be diprotonated to the cations 42 and cyclized into dihydroquinolinones 43. It should be noted that quinolinones 39 do not react with arenes with formation of compounds 43 under

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superelectrophilic activation. Aryl esters (X = O) or thioesters (X = S) 38 furnish the corresponding dihydro derivatives of coumarines or thiocoumarines in the same reactions with benzene [36]. Ar

Ar

Ar 2H

R N H

H

+

R

O

38

-2H+

OH 40

N H

R N H

39

O Ar'H+ H

Ar'H -2H+ H+ = acid: CF3SO3H, CF3SO3H-SbF5, AlCl3, AlBr3

Ar'

Ar' 2H

R 41

Ar

Ar

Ar

R

O

N H

Ar'

+

42

N H

OH

- 2H+

R N 43

O

H

Dihydroquinolinones 43 may be further transformed into the corresponding Nformyl derivatives 44, which react with benzene in Friedel-Crafts process in CF3SO3H affording N-diphenylmethyl substituted compounds 46. This reaction proceeds through intermediate formation of O,O-diprotanated species 45, in which superelectrophilic activation of N-formyl group takes place [17]. Ph

Ph R N 43

H

POCl3, DMF

O

Ph

Ph

Ph CF3SO3H

R N

PhH

R N

O

44 (30-39 %) O

Ph

Ph

45

OH OH

Ph

R N

O

Ph Ph 46 (36-80 %)

Superelectrophilic Activation of Alkenes Alkenes can be involved in reactions of electrophilic aromatic substitution in superacids. Protonation of cinnamides 47 in Brønsted superacids gives dications 48, which alkylate arenes with formation of amides 49 [32, 33, 37]. The carbonyl reduction in 49 affords 3,3-diarylpropylamines 50, which are known drugs. This sequence of the reactions is a novel and effective way to compounds 50, which are analogs of the known drugs [37].

Superelectrophilic Activation of Alkynes

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O Ar

47

NR1R2

OH

H+

Ar1

Ar1H

NR1R2 48 H+ = acid: CF3SO3H, FSO3H, AlBr3 Ar

O

NR1R2 49 (63-98 %)

Ar

LiAlH4 Ph NR1R2

Ph

Drugs: Diisopropamine (R1 = R2 = i-Pr) Fenpiprane (R1 = R2 = -(CH2)5-) Prozapine (R1 = R2 = -(CH2)6-) Fendiline (R1 = H, R2 = CHMePh)

Ar1 NR1R2 50 (61-90 %)

Ar

Such reactions on alkene side chains in heterocycles open possibilities for heterocyclic system modification. Thus, N- and C-styryltetrazoles 51 and 54 give products of hydroarylation 53 and 56 of double bond in reactions with arenes in CF3SO3H [38 - 40]. Reactive intermediates of these transformations are N,Cdiprotonated species 52 and 55. Ph

N N Ph

N N

N Ph

51 Ar

52

N N N 54

N Me

CF3SO3H

Ph

N

CF3SO3H

Ar

N N H

HN N 55

N

Ph

N N Ph 53 (67 %)

Ar

N N Me

Ar'H

Ph

N

PhH

N N Me N N 56 (40-95 %)

Ar'

Reactions of 5-styryl-3-aryl-1,2,4-oxadiazoles 57 with arenes in CF3SO3H, both at thermal and microwave conditions, lead to oxadiazoles 60 [41]. Protonation of 57 proceeds in two steps. At first stage, N4-protonated species 58 are formed. These cations are unreactive, they were studied by NMR in FSO3H at -80 °C (see data for 58a). Further C-protonation gives reactive dications 59, which indeed take part in the reaction [41]. In some cases, exchange of aryl groups in 49, 56, 60 has been observed under superacidic reaction conditions. Lowering reaction temperature (down to -80- -40 °C) allows to avoid these processes [37, 40, 41].

90 Advances in Organic Synthesis, Vol. 8 O N

1

Ar

N

Ar

Aleksander V. Vasilyev O N

CF3SO3H

N 58 H

Ar

57

Ar1

O N

CF3SO3H

N

Ar 59

 NMR (FSO3H, -80 oC)

H Ar2H

C 159.4 ppm

H9.10 ppm

O N

H Ph

Ar1





4N

H H7.53 ppm

Ar2 Ph N4 150 ppm

O N N

Ar

Ar1

60 (up to 97 %)

H H4 12.97 ppm

58a

Reaction of 1,1-dichloro-2-vinylcyclopropane 61 with arenes in CF3SO3H affords 3-aryl-1,1-dichloropent-1-enes 62 as the products of cyclopropane ring disclosure [42]. The same reaction of 1,1-dichloro-2-methyl-2-vinylcyclopropane 63 proceeds as a two-step procedure, including initial in situ generation of the corresponding triflate 64, followed by the reaction with arenes to give other 1,1dichloropent-1-enes 65. Amount of CF3SO3H and temperature are crucial factors for this reaction: good yields of the target alkenes 62 and 65 have been obtained with the use of 1 equivalent of the acid at low temperature -35 °C. In excess of CF3SO3H or at higher temperature, oligomeric materials have been obtained [42].

Cl Cl

Cl Cl 63

Me

+

CF3SO3H (1 eq.), CH2Cl2

ArH

Cl

-35 oC, 3 h

61

CF3SO3H (1 eq.), CH2Cl2 -35 oC, 10 min

Cl

Ar Me

62 (25-43 %)

Cl Me

Cl Me 64

OTf

ArH, CF3SO3H (1 eq.) CH2Cl2, -35 oC, 1 h

Cl Cl

Me Me Ar 65 (30-68 %)

Concerning the reaction mechanism, most probably, both reactions start from protonation of the double bond, giving rise to cyclopropyl-alkyl cation A [42]. The structure of these cations may be represented as non-classical bicyclobutonium ion B. In general, there is an equilibrium between several cyclopropyl-alkyl cations, such as A, C, and ion B. Finally, ring opening of species C leads to homo-allyl cations D, which may react in two different ways.

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Advances in Organic Synthesis, Vol. 8 91

The first reaction pathway is realized for 63 (R = Me) and includes a reaction with the triflate-ion, leading to compound 64. Upon being isolated and dissolved in TfOH, triflate 64 is transformed to cation D. Then, the latter reacts with arenes, yielding compounds 65. The second reaction pathway (R = H) for species D is isomerization into the more stable allyl cation E, which reacts with arenes, resulting in alkenes 62. 3

Cl Cl

1

3

3 +

2

H

R

Cl Cl

4

1

2

Cl R Me

4

1

Cl

4

A

Cl 2 3

4

Cl

Me

2 3 4

1

Cl

R D

R = Me Cl Cl 64 Me

3

ArH

Cl R

B

4

2

Me

C

Cl

ArH Me

- H+

1

Ar 2

Cl

3

4

Me

62

Cl 1

2

Cl 65 Me

4

1

E

CF3SO3-

2

R

Cl

~H R=H

1

Cl

Me

61 (R = H) 63 (R = Me)

1

3 2

3

4

Me

Ar

Me

OTf

Transformations of alkenes under superelectrophilic activation are widely used for the construction of various carbo- and heterocyclic systems. Thus, amines, containing allyl group and aromatic ring, undergo addition of HF to the double bond of allyl moiety or cyclization into aza-heterocycles in the HF-SbF5 system [43 - 45]. Alkene carboxylic acids in reactions with arenethiols in CF3SO3H under microwave irradiation afford thiochroman-4-ones [46]. Various solid acids, such as acidic zeolites, sulfated zirconia, heteropolyacids, are found to be effective for cyclization of 1-phenylprop-2-en-1-ones into indan-1-ones [47]. Superelectrophilic Activation of Conjugated Enynones Conjugated enynones possess three centers of basicity: carbonyl oxygen, and carbons of double and triple bonds. That may give electrophilic species with several reactive centers. Thus, protonation of 1,5-diphenylpent-2-en-4-yn-1-one 66a may proceed in several consecutive steps (Table 1) [8]. The first proton is bonded to the more basic carbonyl oxygen that affords cation A1. Then, protonation of the carbon-carbon triple or double bonds may occur leading to species B1 or C1 respectively, which in turn may be protonated to trication D1.

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Calculations of Gibbs free energies of these protonation reactions showed that the formation of cation A1 is energetically favorable with ΔG298 -71 kJ/mol (see reaction ΔG298 values in Scheme in Table 1). The second protonation, which leads to species B1 and C1, is unfavourable but the formation of cation B1 is less unfavourable. So, the second protonation should rather take place on the triple bond than on the double one for such conjugated enynones. Finally, trication D1 is very high in energy (see big positive ΔG298 values of the corresponding reactions). Its formation is unlikely due to thermodynamic reason DFT calculations of charge distribution, contribution of atomic orbital into LUMO and global electrophilicity indices ω species A1, B1, C1, and D1 show that compared to cation A1, dication B1 and C1 have higher values of electrophilicity indices and they are strong electrophiles (Table 1). Table 1. Selected electronic characteristics (DFT calculations) of cations A1, B1, C1, D1 derived from protonation of enynone 66a, and calculated Gibbs energies ΔG298 of protonation reactions (data from ref [8]). 2 5

Ph

4 3

1

O Ph

H3O+(-H2O) G -71 kJ/mol

2

Ph

1

4 3

5

OH

H3O+(-H2O)

Ph G 64 kJ/mol

Ph

4 3

G298 - Gibbs energy of reaction reactions are reversible, reversibility is not shown

C1

H3O+ G 19 kJ/mol (-H2O) Ph

OH 5

4

OH Ph

A1

66a

1

2 5

3 2

B1

Cation EHOMO, ELUMO, ω,a q(C1),b q(C3),b q(C5),b eV eV eV e e e

H3O+ G 104 kJ/mol (-H2O) H3O+(-H2O)

1

Ph

OH 5

Ph G 148 kJ/mol

4

3 2

1

Ph

D1

k(C1)LUMO, %с

k(C3)LUMO, %с

k(C5)LUMO, %с

A1

-6.92

-4.03

5.2

0.54

0.01

0.20

11

9

6

B1

-7.95

-4.65

6.0

0.58

-0.03

0.46

2

3

31

C1

-8.08

-4.98

6.9

0.65

0.04

0.28

9

14

12

19

15

D1 -8.21 -5.91 10.8 0.64 0.28 0.62 2 Global electrophilicity index ω = (EHOMO + ELUMO) 2/8(ELUMO - EHOMO). b Natural charges. c Contribution of atomic orbital into the molecular orbital. a

The comparison of the charge distributions in species A1, B1, C1 reveals that carbon C5 bears a large part of positive charge. Among these three species, dication B1 has the largest charge on C5 (0.46 e). Apart from that, this carbon in B1 gives the highest contribution (31%) in LUMO. These data show a coincidence of charge and orbital controls in the reactivity of carbon C5 in species B1. Thus, both calculated thermodynamic parameters (ΔG298 of reactions) and electronic characteristics (Table 1) indicate that dication B1, with an electrophilic

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 93

centre on carbon C5, is probably the main reactive species derived from enynones 66a under protonation. O Ar1

CF3SO3H

Ar

Ar

66

OH+

Ar1 B

OH+

TfO (2E,4Z)/(2E,4E)-E

Ar

R

OTf

OTf

Ar1

CF3SO3-

+

H OH

R

Ar

G H2O

OH

OH

R F

Ar

TfO

3

Ar

(2E,4E)-E'

- 2H+ - CF3SO3H Ar1 =

O

R O

R 67 (57-73 %)

Ar

Indeed, enynones 66 react with CF3SO3H at the acetylene bond, rather than at the double bond, giving the corresponding vinyl triflates 4 for 1-2 h (vide supra). Increasing reaction time till 60 h leads to formation of indanones 67 [8]. A plausible reaction mechanism for the formation of 67 includes generation of dication B. Reaction of the latter with the triflate ion gives the O-protonated form of dienyl triflate E, which upon hydrolysis affords triflate. Cation E, with a carbocationic center at C3 on the resonance form E′, may undergo cyclization into cation F. Under the superacidic reaction conditions, the latter is protonated with a formation of stable cation G. And finally, upon quenching with water cation G affords indanone 67. The formation of species E and G was proven by consequent generation of cations E1 and G1 from enynone 66a in CF3SO3H at room temperature after keeping reaction solution during 1 h and 60 h, correspondingly, that was monitored by 1H and 13C NMR (see selected 1H and 13C NMR signals for species E1 and G1) [8].

94 Advances in Organic Synthesis, Vol. 8

Aleksander V. Vasilyev

 NMR (CF3SO3H, r.t.) H 8.46 ppm

Ph 66a

O

CF3SO3H

Ph

r.t., 1 h

Ph

C 189.3 ppm OH+

H

Ph

TfO

C 167.8 ppm

H C 162.3 ppm

H 7.16 ppm (2E,4E)-E1

CF3SO3H r.t., 60 h  NMR (CF3SO3H, r.t.) C 222.0 ppm OTf H

H

G1

CH2 3.55, 4.09 ppm C 43.5 ppm OH

C 219.1 ppm

Ph

In the case of enynones 66 bearing an electron donating methyl group in the aryl ring conjugated with the acetylenic bond, one more reaction pathway leading to formation of “dimeric” structures 68 is observed [8]. The plausible mechanism of formation of compounds 68 consists of the following steps. The intermolecular substitution on ortho-position of the tolyl ring of Oprotonated triflate E by the carbon C5 of another species E gives cation H. The latter then protonated at C2 of the butadiene system leading to cation I, which undergoes a cyclization on the tolyl ring via C3 to give cation J. This species, in turn, is protonated in CF3SO3H with formation of the stable cation K. For instance, the cation K1 has been independently generated in CF3SO3H at room temperature and characterized by 1H and 13C NMR [8]. Finally hydrolysis of the reaction mixture gives compounds 68. An alternative way of formation of indenes 68 may be the initial formation of cations G (vide supra) followed by its FriedelCrafts reaction with species E leading to cation K.

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 95 R

O Me

O

CF3SO3H

Ar

OTf

Me

r.t., 12 h

O

66 Ar =

Me

Me

OH+ Ar 1

E 3

5

4

2

Me

R (2E,4Z) / (2E,4E)-68 (41-80 %)

R

OH

OTf

Ar

E

1

OTf 3

2

H+

OH

Ar

4 5

H

Me

Me Me OH

Ar

OTf

1 2

3 4

OH

OH

Ar

5

Me

OTf

Ar

Ar

I

J

Me

 NMR (CF3SO3H, r.t.) Me C 219.3 ppm OTf

Ph CH2 4.25, 4.68 ppm

H+ Me C 221.8 ppm

OH

OH

-H+

OH OH

OTf

Ar

OH

Ar

Ph

H H

Me C 52.83 ppm

C 200.4 ppm

K1

K

Me H 2O

-2H+

(2E,4Z)/(2E,4E)-68

&ontd.....

96 Advances in Organic Synthesis, Vol. 8

Aleksander V. Vasilyev Ar1(2)

O

O

CF3SO3H

Ar + Ar2H

Ar1

r.t., 12 h

66

R

66

Ar

Ar2(1)

2 H+

OH+

Ar1

Ar2H

Ar

B

69 (39-97 %)

-H+

CF3SO3H Ar2

OH+

OTf

OH+

2

Ar1

Ar E

Ar H -CF3SO3H

Ar1

Ar L

 NMR (CF3SO3H, r.t.) Ar1

C 222.4 ppm C 49.0 ppm

OH+

Ph H

C 219.1 ppm

OH+

Ar2

Ar L'

Ph

H

N1 CH2 4.09, 4.50 ppm

R

R

R

2

Ar

OH+ 1

Ar

Ar L

OH+

Ar1 M

Ar

H+

OH+

Ar1 N

Ar

H2O -2 H+

69

Enynones 66 in reactions with arenes in CF3SO3H furnish isomeric indenes 69 [43]. A plausible reaction mechanism for the formation of 69 includes formation of dication B, which undergoes an intermolecular substitution on arene Ar2H to give cation L. The latter may also be generated from dienyl triflate through its protonated form E. Two configurations (2E,4Z) and (2E,4E) are possible, corresponding to cations L and L′. They lead to the cyclic species M depending on whether the cyclization involves the aryl rings Ar1 or Ar2. The cation M is protonated to give stable dication N, precursor of the corresponding regioisomers 69 finally formed by aqueous quenching of the reaction mixture. Intermediate species N have been observed by NMR (see data on dication N1) [48].

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 97

In CF3SO3H or H2SO4, diaryl substituted cross-conjugated enynones 70 undergo addition of the acid to the triple carbon-carbon bond giving rise to the protonated forms 71 of corresponding vinyl triflates or sulfates. Vinyl triflates 73 are stable under aqueous work-up, whereas vinyl sulfates are hydrolyzed to α,β-unsaturated 1,3-diketones 74 (existing as conjugated enol forms). Extended reaction times lead to cyclization of 71 into dihydropyran-4-ones 72 [9]. O O

OH+ OX

XOH

Ar

Ar 70

71

Ph

1. XOH

(E/Z) Ph

XOH = CF3SO3H or H2SO4

2. H2O

O

H2O

Ph

Ar O 72 (22-95 %) OH O

OTf

Ar

Ph

or

Ar

Ph for X = SO3H 74 (28-92 %)

for X = Tf 73 (61-81 %)

Two main mechanisms involving either an intramolecular conjugated nucleophilic addition of the protonated enol 71, or a 6π electrocyclization of its tautomeric form 71′ may be proposed [9]. According to this mechanism, the cyclization of 71 into 75 takes place via the oxygen atom initially brought by the acid XOH and, therefore, requires elimination of “X+” (i.e. SO3H+ or Tf+). The ease of elimination directly affects the cyclization rate: while +SO3H can easily leave as SO3 and proton, the Tf+ group is probably derived as triflic anhydride Tf2O in a slower reaction, making the cyclization more difficult in TfOH. The derivatization of Tf+ is easier in the presence of more nucleophilic species such as H2SO4 or HSO3Cl, resulting in the faster conversions of 71 (X = Tf) into 72. OH+ AdN Ph

O X

Ar O

OH+

71 H+(XOH)

OH

Ph

Ar 75

Ar 6-electrocyclization

+

O X

-H+

-SO3, -H2SO4 (X = SO3H) Ph or -Tf2O (X = Tf)

Ph

O

Ar

72

X = Tf or SO3H

71'

A NMR study of the vinyl triflates and sulfates 71a-d in TfOH and H2SO4, presented in Table 2 [9], reveals that the real structures of these cationic species,

98 Advances in Organic Synthesis, Vol. 8

Aleksander V. Vasilyev

between the resonance structures 71 or 71', seem to depend on the X group and acidic medium XOH. For X = Tf (species 71a and 71b) it has been observed the formation of resonance form 71 rather than 71′. Cations 71a and 71b are the Oprotonated forms of the corresponding vinyl triflates, with chemical shifts of 190.6 ppm for the carbonyl carbon C3 in 13C NMR. The protonation of the carbonyl group is additionally supported by the large chemical shifts of H5 and C5, of respectively 8.86-8.93 ppm and 166.7-169.0 ppm in 1H and 13C NMR, pointing out a charge delocalization into Ar–C5H=C4H– fragment. Similar chemical shifts of around 167.6-168.0 ppm are observed for carbons C1 next to the OTf group. In contrast, for X = SO3H (species 71c, 71d, Table 2), in 13C NMR carbon C1 has larger chemical shifts of 184.9-188.0 ppm, which is now slightly more deshielded than C3 (182.6-183.4 ppm), while H5 and C5 have smaller chemical shifts of 7.998.14 ppm and 130.3-147.7 ppm in 1H and 13C NMR, respectively. This shows delocalization of the positive charge mainly over carbons C1 and C3, one may assume that the structure of such vinyl sulfates closer to the mesomeric form 71′. If triflates and sulfates have different structures, then one may suppose different cyclization mechanisms too: intramolecular nucleophilic addition for triflates (structure 71) and oxa-6π electrocyclization for sulfates (structure 71′). Table 2. Selected 1H and 13C NMR data of species 71a-d in TfOH or H2SO4 at room temperature (data from ref [9]).

O

OH+ OX

XOH

Ar

5 3

Ar

4

Ph

2

Ph

3 1

Ar

4

Ph

71a (in CF3SO3H): Ar = Ph, X = Tf 71b (in CF3SO3H): Ar = p-ClC6H4, X = Tf 71c (in H2SO4): Ar = p-ClC6H4, X = SO3H 71d (in H2SO4): Ar = p-NO2C6H4, X = SO3H

NMR Solvent

H NMR, δH, ppm

C NMR, δC, ppm

1

H (s)

H (d, J, Hz)

H (d, J, Hz)

2

2

71'a-d

71a-d

X = Tf or SO3H

Cation

OH OX+ 5

1

4

5

13

C

1

C2

C3

C4

C5

71a

CF3SO3H

7.47

7.56 (J 15.4)

8.93 (J 15.4)

167.6 109.9 190.6 120.8 169.0

71b

CF3SO3H

7.45

7.51 (J 15.4)

8.86 (J 15.4)

168.0 110.0 190.6 121.1 166.7

71c

H2SO4

6.60

6.86 (J 15.8)

7.99 (J 15.8)

184.9 97.9 183.4 119.3 130.3

71d

H2SO4

6.87

7.18 (J 16.0)

8.14 (J 16.0)

188.0 99.1 182.6 124.3 147.7

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 99

Superelectrophilic Activation of Allenes Reactions of allenes under the action of Brønsted or Lewis (super)acids give a lot of opportunities for synthesis of various hetero- and carbocycles [49 - 52]. 1(Diphenylphosphoryl)alka-1,2-dienes (phosphonoallenes) 76 in Brønsted (super) acids (TfOH, FSO3H, H2SO4) afford corresponding 1,2-oxaphosphol-3-enium ions 78 through an intermediate formation of O,C-diprotonated species 77 [49, 50]. Upon hydrolysis of reaction solution, cations 78 lead to the formation of phosphonoallyl alcohols 79. Under the acidic reaction conditions the cations 78 have been slowly transformed into O-protonated forms of dihydrophosphinoline 1-oxides 80, which give compounds 81 upon aqueous workup. Thus, varying reaction conditions one may achieve a selective formation of alcohol 79 (low temperature and short reaction time) or heterocycle 81 (high temperature and long reaction time). R1

R1

R2 2 H+

R2 Ph2P 2 OH R 77

R2

O PPh2

R2

H

76

H+ = Bronsted acid: CF3SO3H, FSO3H, H2SO4

R2

R2

- H+

R1 P HO Ph 80

- H+ R1

- H+ R1

+

R2 H2O, - H O 78

P O Ph 81 (34-95 %)

R1

H

Ph2P

R2

H2O

R2

R2 Ph2P R2 O HO 79 (47-94 %)

Cations 78 and 80 have been thoroughly studies by 1H, 13C and 31P NMR [50], see NMR data for transformation of 78a into 80a.  NMR (CF3SO3H, r.t.) H 7.78 ppm C161.3 ppm H Br Me Ph2P O

P 78.01 ppm

Me

CF3SO3H r.t., 14 days

 NMR (CF3SO3H, r.t.) H 7.63 ppm Me Me H C168.0 ppm Br

P HO

78a

80a

Ph

P 31.46 ppm

Phosphinoline oxides 81 can be directly obtained from phosphonoallenes 76 under the action of Lewis acid AlCl3 at room temperature just for 10 min.

100 Advances in Organic Synthesis, Vol. 8

Aleksander V. Vasilyev

Coordination of AlCl3 at oxygen atom and allene system gives species 82. Effect of AlCl3 may be explained by strong coordination of the Lewis acid at oxygen atom of the P=O group, that deactivates this oxygen for further electrophilic attack on it. As a result, formation of cation 78 and alcohol 79 is fully suppressed, and compounds 81 are formed as the only reaction product with AlCl3.

R1

R2

O PPh2

R2

 AlCl3 R2 

R1

2 AlCl3 Cl3Al

76

O

R2

P Ph

R2 -2 AlCl3

R1

R2

P O Ph 81 (50-98 %)

82

In the case of the presence of aryl substituents on allene system, intramolecular reactions on these aryl groups may occur. Phenyl substituted phosphonoallene 83 is transformed in CF3SO3H into diastereomeric cycles 87 and 88 through intermediate formation of plausible cationic intermediates 84-86 [51]. H

Me

CF3SO3H o

O PPh2

Ph

120 C, 4 h

83

Ph2P

Me H+

Me

- H+

OH

Ph2P OH

84

Me

Me

Ph

OH 86

Me +

-2 H+ P

85

P O

Ph 87 (9 %)

P Ph O 88 (32 %)

Diphenyl allenyl phosphonates 89 are cyclized into 2,5-dihydro-1,2-oxaphospol-2-ium ions 90 in Brønsted acids (CF3SO3H, H2SO4, FSO3H) [52]. These species have been studied by means of 1H, 13C, 31P NMR (see data for 90a). Upon hydrolysis of acidic solutions of 90, they are transformed into 2,5-dihydro-12-oxaphosphole-2-оxides 92 through intermediate formation of compounds 91. The cations 90 react with various nucleophiles (MeOH, EtOH, Et2NH, PhH) on the phosphorus atom. The obtained products 93 are very labile and undergo fast transformation into oligomeric materials [52].

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 101

R1 3

R

R1

2 O P(OPh)2 R

R1 2

R

CF3SO3H r.t., 15 min

O R3 P PhO OPh 90

89

R2

H2O

O R3 HO P PhO OPh

-H+

91

 NMR (CF3SO3H, r.t.) H 7.52 ppm H Me C164.3 ppm Me C116.0 ppm O Me P P 48.57 ppm PhO OPh 90a

R1

R1 R2 R3

O R3 P PhO OPh 90

-H+

P

O

PhO O 92 (85-90 %)

R1 R2 NuH

-PhOH

R2

3

R O Nu P PhO OPh 93

NuH = MeOH, EtOH, Et2NH, PhH

Contrary to Brønsted acids, under the action of Lewis acids AlX3 (X = Cl, Br), allenes 89 lead to another kind of heterocycles, 2,5-dihydrobenzo[f] [1, 2]oxaphosphepine-2-oxides 94. R1 3

R

R1 2

O P(OPh)2 R

AlCl3, CH2Cl2 r.t., 10 min

89 R2

R2

R2

R

R Ph

81

PhO P O O 94 (80-94 %)

[MCl2(NCR)2] 1

P O

R3

R2

HSiCl3 1

R2

P Ph 95 (83-87 %)

-2 NCR M = Pd, Pt

[MCl2(95)2] cis-/trans96 (82-94 %)

The obtained phosphaheterocycles 81 may be used as precursors for ligands for complexes of metals. Thus, reduction of 81 with HSiCl3 affords 1,4-

102 Advances in Organic Synthesis, Vol. 8

Aleksander V. Vasilyev

dihydrophosphinolines 95, which form various complexes 96 with Pd(II) and Pt(II) [53]. Superelectrophilic Activation of Trifluoromethyl Substituted Alkynes and Alkenes Protonation of trifluoromethyl (CF3) substituted alkynes, alkenes, allyl alcohols, enones in superacids gives rise to CF3-carbocations, which possess enhanced electrophilicity due to the electron withdrawing character of CF3 group. Such CF3-carbocations are highly reactive species, they may react very regio- and stereo- selectively. Protonation of CF3-alkynes 97 in CF3SO3H or FSO3H affords vinyl cations 98, which are able to effectively alkenylate a range of arenes giving alkenes 99 [54, 55]. However, under superacidic reaction conditions compounds 99 are protonated to form tertiary carbocations 100. These species are extremely stable in CF3SO3H even at room temperature and have been fully characterized by means of NMR (see cation 100a) [54]. Finally, upon quenching the reaction solution, cations 100 are either deprotonated or hydrated to afford E/Z-alkenes 101 or alcohols 102, respectively. Quenching with anhydrous MeCN or MeOH/MeONa affords alkenes 101 only. Workup of the reaction mixture with water, aqueous solutions of mineral acids or bases leads to the formation of mixtures of compounds 101 and 102.

Ar

CF3SO3H or FSO3H

CF3

–75oC - r.t. 0.5–1 h

97

CF3 Ar1H Ar1

Ar

H

-H+

98

CF3

Ar

Ar 99

 NMR (CF3SO3H, r.t.) F -58.6 ppm F3C

100a

Ph

C 39.7 ppm

CH2 C

Ph

H 4.90 ppm C 207.0 ppm

-H+

CF3 Ar1

Ar

E-,Z-101 (42–98%)

100

H2O

-H+ Ar1

CF3

1 H+ Ar

OH CF3

Ar 102 (18–50%)

The formation of the corresponding benzyl cations 104 takes place under protonation of E-/Z-2-halogeno-2-CF3 styrenes 103 (X = F, Cl, Br) in superacids [56, 57]. The structure of these electrophiles has been studied by means of NMR (see data for species 104a) and theoretical DFT calculations [57]. Accordingly to these data, in the case of bromo derivatives the formed cations, most probably,

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 103

exist as cyclic bromonium ions 104′. However in the cases of chloro and fluoro derivatives open forms 104 are more preferable. Subsequent reaction of these benzyl cations with arenes proceeds as Friedel-Crafts alkylation to afford 1,1diaryl-2-halo-3,3,3-trifluoropropanes 105 in high yields (up to 96%) as a mixture of two diastereomers D1 (1SR, 2SR) and D2 (1SR, 2RS). The compounds 105 have been easily converted into the corresponding mixtures of E-/Z-trifluoromethylated diarylethenes 106 by dehydrohalogenation with base (KOH or t-BuOK). This elimination proceeds stereoselectively giving Z-106 from D1-105 and E-106 from D2-105. CF3 Ar

CF3 Ar1H

CF3SO3H

X

Ar

103

-H+

X CF3

Ar

1 2

Ar

Base (KOH CF3 or t-BuOK) - HX X

105 (22-96 %) diastereomers D1: 1SR, 2SR D2: 1SR, 2RS

104 X = F, Cl, Br

Ar1

X

Ar1

CF3

Ar 106 (72-96 %) Z- from D1 E- from D2

104'

C 164.5 ppm H 8.04 ppm

F -73.28 ppm

CF3 MeO

CH CH

C 38.1 ppm

H 5.81 ppm

Br 104a

In some cases, the reaction can be complicated by the exchange of aryl groups in 105. However, this process has been suppressed by lowering reaction temperature (down to -10 °C) and using less amount of arene Ar1H [57]. Reactions of styrenes 107 and 109, bearing at the double bond fluorine and CF2Cl group, with arenes have also been investigated in CF3SO3H [57]. Activated by donating methoxyphenyl group, compound 107 is easily protonated at 0 °C and give the corresponding hydroarylation products 108. The key point is the stability of the C–Cl bond in compounds 107 under the superacidic conditions at 0 °C. On the other hand, deactivated C=C bond in para-chloro substituted styrene 109 is not protonated in CF3SO3H even at elevated temperature 60 °C. This styrene reacts only in a way of Friedel-Crafts reaction at C–Cl bond with arenes, followed by hydrolysis of two fluorine atoms under quench with water. Fluorinated

104 Advances in Organic Synthesis, Vol. 8

Aleksander V. Vasilyev

chalcones 110 are formed as a result of this reaction sequence. Reaction is highly stereoselective, leading predominantly to Z-isomer of 110. Such 2fluorochalcones are hardly available compounds. They are in great demand due to biological activity properties of chalcone derivatives. Ar

CF2Cl F

MeO

+

CF2Cl

CF3SO3H

ArH

F

0 oC, 1h MeO

Z-/E- 107

108 (58-96 %) O Ar

CF2Cl F

Cl

CF3SO3H

+ ArH

F

60 oC, 2h Cl

Z-/E- 109

Interaction of CF3-allyl alcohols 111 with Brønsted or Lewis acids proceed through intermediate formation of various electrophilic species. Coordination of oxygen with Lewis acid or protonation with Brønsted acid leads to species 112 or 113 correspondingly. Finally dehydroxylation of alcohols 111 results in formation of CF3-allyl cations 114, having two resonance forms 114′ and 114′′ with cationic centers on atoms C2 and C4, respectively. Due to electron-withdrawing character of CF3 group, these allyl cations react with arenes through 114′′ to form new C-C bond at C4 carbon. Intermediates 112 and 113 also possess highly electrophilic properties and may participate in reactions [58, 59]. H LA (Lewis acid)

Ar

4

3

2

4

Ar

OH

O

3

2

LA

-

CF3 1

112

-LA(OH)-

CF3

Ar

1

111

H

+

H (Bronsted acid) Ar

4

3

O 2

3

2

CF3 1

114

H CF3

4

-H2O

Ar

1

4

3

2

1

114'

113 Ar

4

3

114''

CF3

2

CF3 1

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 105

Indeed, reactions CF3-alcohols 111 with benzene, anisole, veratrole, ortho-xylene under the action of FeCl3 (room temperature) or FSO3H (-75 °C) lead exclusively to CF3-alkenes 115 with E-configuration [59]. The reaction proceeds at C4 carbon of 111 through species 114′′. FeCl3 (r.t.) or FSO3H (-75 oC)

OH 1

Ar

CF3

111

+ Ar H

Ar1 CF3

Ar

E-115 (28-75 %)

More π-donating polymethylated arenes (pseudocumene, mesitylene) afford only CF3-indanes 116 with predominant cis-orientation of substituents at positions 1 and 3 of indane ring. Meta- and para-xylenes show an intermediate behavior, they may form both CF3-alkenes and/or CF3-indanes [59]. OH Ar

CF3

111

H

O

+ Ar1H

FeCl3 (r.t.) or FSO3H (-75 oC)

CF3 R Ar cis-116 (23-81%)

X

Ar1

Ar1H 2 CF3 Ar 4 - HOX, -H+ 112 (X = FeCl3-),

Ar

117

Ar1

H+

CF3

Ar 118

113 (X = H)

CF3 -H+ CF3

- HOX Ar1

Ar1H Ar

4

2

114''

CF3

+

-H

R CF3

Ar 115

116

Ar

The plausible mechanisms of the investigated transformations consists of the following steps [59]. Species 112 or 113, having enough electrophilic center on C2, react with rather π-donating arenes, such as xylenes, pseudocumene, mesitylene, forming compounds 117. Further protonation of the formed alkene leads to cations 118, which are cyclized into indanes 116. It should be noted that compounds 115 in FeCl3- or FSO3H-promoted reactions are not cyclized into indanes 116, due to deactivation of double bond to protonation in alkenes 115 by electron withdrawing CF3 group. Directions of all these transformations of

106 Advances in Organic Synthesis, Vol. 8

Aleksander V. Vasilyev

alcohols 111 into different products 115, 116 depend on electrophilicity of species 112, 113, 114 and nucleophilicity of arenes. In some cases mixed mechanism can be realized leading to the formation of both 115 and 116. In the absence of arenes, as external π-nucleophiles, compounds 111 undergo electrophilic “dimerization” with formation of diastereomeric indanes 119 and 119′ [58]. R

R

CF3 R

H

H

OH FeCl3, CH2Cl2 r.t., 1 h

R

R

H

H

111 (R = H, Me, Cl)

119

H

OH + H CF3 CF3

OH H CF3

H

119'+119' (40-94 %)

119' CF3

R

R H

R

H

R H

H A1

111

CF3

114''

-H+

CF3

OH

CF3

H 119

CF3

R

H

OH

H

CF3

R

R

111

H R

R

H OH H H A2

CF3 CF3

H

-H+ H 119'

OH H CF3 CF3

The first stage of the reaction may involve formation of cationic intermediate 114′′. Next, the cationic center C4 of this species attacks the double bond of the starting alcohol 111 to form benzyl cations A1 and A2, that cyclize via the arene fragment to give the indanes 119 and 119′. A new C-C bond and four stereocenters are formed and the reaction is quite stereoselective because only two diastereomers are formed out of the eight possible. The configuration at atom C4 is the same for the diastereomers 119 and 119′. This reveals that the reaction between cation 114 and starting material 111 proceeds in a stereoselective manner.

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 107

2,4-Diaryl-substituted CF3-allyl alcohols 120 or their TMS-ethers in H2SO4 at room temperature in just 2 min are quantitatively cyclized into CF3-indenes 121 [60]. Reaction proceeds through an intermediate formation of the corresponding CF3-allyl cations, which are cyclized regioselectively at the allyl system carbon atom most remote from CF3 group on ring Ar1. Compounds 121 in solution of EtOAc in the presence of silica gel at room temperature for 4 h are quantitatively isomerized into other CF3-indenes 122, shift of double bond takes place. CF3

CF3 Ar 120

1

CF3

Ar

2

H2SO4, CH2Cl2 r.t., just 2 min cyclization quantitatively

OX X = H, SiMe3

silica gel, EtOAc 1 R r.t., 4 h isomerization Ar2 quantitatively

R1 121

122

Ar2

4-Aryl-1,1,1-trifluorobut-3-en-2-ones (CF3-enones) 123 react with arenes in Brønsted superacids (TfOH, FSO3H) to give, stereoselectively, trans-1,3-diaryl1-trifluoromethyl indanes 124 [61, 62]. These compounds have been investigated as potential ligands for cannabinoid receptors CB1 and CB2 types. The most potent compound 124a has shown sub-micromolar affinity for both receptor subtypes with a 6-fold selectivity toward CB2 receptor with no appreciable cytotoxicity toward SHSY5Y cells [62]. R R

O Ar

4

2

3

F3C

CF3 + 1

123

CF3SO3H 20 oC, 1 h R

Ar 124 (35-85 %) trans-diaryl

OMe F3C

OMe ligand for cannabinoid receptors CB1 and CB2

MeO

hCB1 Ki = 0.12 M

MeO 124a

Cl

hCB2 Ki = 0.75 M

108 Advances in Organic Synthesis, Vol. 8

Aleksander V. Vasilyev

The formation of indanes 124 indicates that both carbonyl carbon C2 and C4 (C=C bond) of starting substrates 123 participate in the reaction. The following reaction pathways for the transformation CF3-enones 123 into indanes 124 have been proposed [62]. The reaction of arenes with cation A' at carbon C4 can give compound 125, subsequent protonation leads to the formation of cation D. The latter can react further in two ways: intermolecularly, with the arene, to give rise to compound 126, or intramolecularly - to afford after cyclization indanol 127. Compounds 126 and 127 may also be obtained via the reaction of dication B with arene at C2 to result in the formation of cation E. Subsequent transformations of 126 and 127 can proceed with an intermediate formation of cations F and G, respectively, culminating the formation of indanes 124. O Ar

4

CF3

2

3

OH

123

4

Ar

1

B

+

H

4

2

E

F3C

-H+

Ar'

CF3

Ar

Ar' F

R

Ar

127

OH

CF3 Ar'

Ar H+ -H2O

H+ -H2O

OH

126

F3C

OH

CF3

2

Ar'

Ar'H

-H

R

4

Ar

-H+

H+

A

Ar

CF3

CF3 Ar'

+

OH Ar

2

OH

Ar'H

G

Ar Ar'H -H+

CF3

A'

F3C

-H+

Ar'H -H+

Ar'

R Ar' Ar

O

125

Ar'

H+ CF3

OH

Ar

D

CF3

Ar'H

124 Ar

-H+

There are two most likely reaction pathways: 1) through cation A to structures 125, D, 127, G, and 124; or 2) through cation B to structures E, 127, G, and 124. Cation G is one of the key intermediates of this reaction for both pathways. The addition of an aromatic molecule to the latter leads to trans-orientation of the bulky aromatic groups, probably due to steric reasons. One of the intermediates of this reaction, O-protonated froms A of 123, have been generated in FSO3H at -60-20 °C and characterized by means of NMR (see data for species A1) [62].

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 109

 NMR (FSO3H, -45 oC) H 7.98 ppm C 180.3 ppm

OH

H

C 150.4 ppm

Ph

CF3

C 116.9 ppm

A1

H

F -77.7 ppm

H 7.02 ppm

Brominated CF3-allyl alcohols 128 are promising precursors for generation of multicentered electrophiles under superelectrophilic activation [63]. Reaction of alcohols 128 with CF3SO3H gives rise to indenes 129 and indanones 130 as a result of intramolecular cyclization. Ratio of compounds 129/130 depends on reaction conditions. Thus, increasing the reaction time and temperature usually led to larger amount of indanones 130 or even to its exclusive formation [63]. Br

OH

Ar

CF3 Br E-/Z-128

CF3 CF3SO3H

R

R Br + Br 129 (21-90 %)

CF3 Br O 130 (10-58 %)

Plausible mechanism of this reaction includes the formation of O-protonated cation H, which is cyclized into indene 129. Subsequent protonation of the formed indene gives rise to cation I, which has been caught by NMR (see data for I1). Quench of the reaction mixture with water leads to deprotonation of cation I to afford indene 129. Alternatively, hydrolysis of I gives indanone 130. Reaction of dibromo-CF3-allyl alcohols 128 with arenes in CF3SO3H gives rise to dibromo- alkenes 131 as the main reaction products as a result of arylation of starting alcohols 128 on carbon C2. That reveals the participation of O-protonated species H in the reaction, rather than “pure” allyl cation. The reaction proceeds highly stereoselectively, in most cases only Z-isomers of 131 have been obtained, in which bromine atoms are located on one side of the double bond, in spite of the starting compounds 128 have been used as a mixture of E-/Z-isomers. During the study of this reaction, in some cases, an additional formation of indenes 132 from alcohols 128 has been observed.

110 Advances in Organic Synthesis, Vol. 8

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R

128

H+

R

OH2 Br Br

CF3 H

CF3 H+ - H+ 129 Br

 NMR (CF3SO3H, -20 oC) F -69.6 ppm F3C H H 4.72 ppm Me Br + H H 6.0 ppm

Br

OH + Ar1H CF3

Ar Br E-/Z-128

Br

Br

- H2O -H+

C 215.0 ppm

CF3

R

Br

Br O

130

trans-I1

Br CF3SO3H r.t., 1 h

R

Br - H+ H2O - HBr CF3 I

Ar

Ar1 CF3

R +

Br E-/Z-131 (26-87 %)

CF3 Br Ar1 132 (26-60 %)

Plausible reaction mechanism for the formation of compounds 131 and 132 includes the following stages [63]. Cations H have two different pathways to react. First one is the reaction with arene to afford alkenes 131. Another way proceeds as multistep domino sequence: a) cyclization into indenes 129; b) subsequent protonation of 129 to form cations I; c) the reaction of I with arene to form compounds J; d) protonation of benzylic C-Br bond in J with CF3SO3H resulted in formation of stable cations K (see NMR data for species K1); e) treatment of the reaction mixture with water gives finally indene 132 after proton abstraction. To show that indenes 132 are formed by arylation of compounds 129, their reactions with arenes in CF3SO3H have been also studied [63]. Indeed, indenes 132 have been isolated in good yields when this reaction has been performed at room temperature (10 min). However, almost in all cases the formation of nonbrominated indenes 133 has been observed as minor products. The highest yields of indenes 133 were achieved when electron rich arenes (m-xylene and pseudocumene) were used. These results can be rationalized as alternative way of transformation of stable cations K by loss of Br+ which is transferred to electron rich arene. Presumably, additional driving force for the debromination of K is

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Advances in Organic Synthesis, Vol. 8 111

caused also by steric hindrance between bromine and bulky ortho-methyl substituted aryl fragment at carbocationic center leading to exclusive or predominant formation of compounds 133. 128 H+ Ar1

Br Ar 131 Br

Br

Ar1H

CF3 -H2O -H+

CF3

OH2

Ar

CF3 Br

-H

CF3 Br 132

Br

129 Br

I

CF3

R

H2O

CF3 R

Br

-H2O +

H

R

H+

R

R

H+

-H+

Br

+

Ar1

Ar1H -H+ CF3 Br

-HBr

Ar1

K

Br

Ar1 Br

J

 NMR (CF3SO3H, r.t.) H 4.93 ppm H CF  -71.13 ppm 3

F

HH 6.39 ppm Br C 213.9 ppm Ph

CF3

R

Br + Ar1H 129

CF3SO3H r.t., 10 min

trans-K1 CF3

R

Ar1 132 (41-68 %)

Br

CF3

R Br +

Ar1 133 (39-85 %)

Monobrominated CF3-allyl alcohols 134 in reaction with arenes in CF3SO3H afford a mixture of regioisomeric brominated CF3-alkenes 135 and 136 [63]. This reaction proceeds very stereoselectively affording only Z-alkenes 135 and 136. OH 1 CF3 + Ar H

Ar Br Z-134

CF3SO3H

Ar1

Ar1 CF3 + Ar

-35 oC/ r.t., 1 h Ar Br

Z-135

Z-136

CF3 Br

135 + 136 (37-95 %)

112 Advances in Organic Synthesis, Vol. 8

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The arylation of alcohols 134 proceeds mainly at atom C4 with a predominant formation of alkene 135. The formation of two regioisomeric products can be explained in terms of formation of two types of electrophilic species. The corresponding O-protonated form of 134, oxonium ion L, reacts preferentially with arenes at carbon C2. On the other hand, the reaction of allyl cation M proceeds at carbon C4. H

O

+ Ar1 Ar

Ar 4

Ar1H

CF3

2

- H 2O

Br

- H+

Ar 4 Br

Ar1H

CF3

2

M

H

Ar1

- H 2O - H+ Ar

L

CF3 Br 135

CF3 Br

136

Treatment of bromoalkenes 131 and 135 with KOH in ethanol at room temperature for 24 h has resulted in the formation of the corresponding substituted CF3-allenes [63]. Ar1

Ar

CF3

Br

• Ar

Br E-/Z-131

CF3 (38-92 %)

Ar1 Ar

Ar1

Br

KOH, C2H5OH r. t., 24 h

CF3

KOH, C2H5OH r. t., 24 h

Br Z-135

Ar • Ar1

CF3

(37-57 %)

Monobromo- or dibromo- CF3-enones are cyclized in FSO3H at -60 °C into the corresponding indenols 139 through intermediate formation of O-protonated forms 138 having electrophilic center on carbon of protonated carbonyl group [64]. O

X

CF3 Br

FSO3H

OH

-60 oC, 2 h X

R 137

HO CF 3

R

X = H, Br

CF3 Br 138

Br

-H+ R

X 139 (14-96 %)

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 113

Monobrominated indenols 139 in reaction with benzene in CF3SO3H furnish CF3indenes 140 [64]. CF3

HO CF 3 CF3SO3H r.t., 1 h

Br +

R

Br

R

Ph 140 (54-70 %)

139

Plausible reaction mechanism includes the formation of indenyl cation 142 via protonation of 139 to form intermediate 141 and water elimination. Subsequent reaction of 142 with benzene gives intermediate 143. Protonation of the latter affords cation 144 that rearranges into a more stable species 145, deprotonation of which finally leads to indene 140.

139

H+

1

1 2

R

CF3

CF3

H2O CF 3 Br -H2O

2

3

R

141

PhH Br -H+

Br R 143

3

142

Ph H+

CF3 H2O

140

CF3 Br

-H+ R

~H

Br R

145 Ph

144 Ph

Contrary to monobromo derivatives 139 (X = H), reaction of dibromo-indenols 139 (X = Br) with benzene in CF3SO3H leads to formation of another kind of CF3-indenes 146 [64]. HO CF 3 Br

R 139

Br

CF3

+

CF3SO3H r.t., 1 h

Br

R

Ph Ph 146 (46-74 %)

This reaction proceeds by the following mechanism: indenyl cation 147 having most electrophilic С3 atom is formed at the first step. Indene 148 is a result of the

114 Advances in Organic Synthesis, Vol. 8

Aleksander V. Vasilyev

interaction of cation 147 with benzene. Subsequent elimination of HBr from 148 under superacidic conditions leads to cation 149 as a key intermediate. Finally, reaction with a second molecule of benzene takes place again at the position C3 of 149 to form 146. CF3

CF3 139

H+ -H2O

1 2

R

3

Br

PhH

Br

-H+

R

Ph Br 148

Br 147

H+ -HBr CF3 146

1

PhH -H+

2

R

Br

3

Ph

149

CF3-Substituted alkene carboxylic acids have been successfully used as precursors in the synthesis of trifluoromethylated thiochroman-4-ones [65], dihydrochalcones, aryl vinyl ketones and indanones [66]. CONCLUDING REMARKS Superelectrophilic activation of alkynes, alkenes, allenes, and their trifluoromethyl substituted derivatives is a useful and powerful tool in organic synthesis. These reactions allow to obtain alkenes, heterocycles of the series of quinoline, coumarine, thiocoumarine etc., various carbocycles (indanes, indenes, indanones) and their trifluoromethyl derivatives. Most of the reactions proceed with excellent regio- and stereo- selectivity, and in high yields of target products. A broad range of superacidic systems, based on Brønsted, Lewis, conjugate Brønsted-Lewis acids, or H+-zeolites, may be used for organic synthesis. Superacids (CF3SO3H, FSO3H, HF–SbF5) are able to activate carbon–carbon multiple bonds (C=C, C≡C) conjugated with strong electron-withdrawing substituents, as well as carbonyl carbon, which cannot be achieved in weaker acids (H2SO4, CF3CO2H). Liquid Brønsted superacids (CF3SO3H, FSO3H) remain indispensable for the study of intermediate cationic species by means of NMR, which gives opportunity to figure out the reaction mechanisms. Perspectives of the use of superacidic reagents in organic synthesis may lie in their application for the activation of polyunsaturated systems (dienes, diynes,

Superelectrophilic Activation of Alkynes

Advances in Organic Synthesis, Vol. 8 115

enynes, etc.) containing several π- (and additionally n-) basic centers leading to generation of reactive polycationic intermediates. The author hopes that this work will promote the chemistry of carbocations and motivate chemists to use superacidic reagents for purposes of organic synthesis. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The author (editor) declares no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS Declared none. REFERENCES [1]

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superelectrophilic hydroarylation of C=C bond and carbonyl reduction in cinnamides: synthetic rout to 3,3-diarylpropylamines, valuable pharmaceuticals. Tetrahedron, 2015, 71, 102-108. [http://dx.doi.org/10.1016/j.tet.2014.11.033] [38]

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CHAPTER 4

Chitosan and its Derivatives: Synthesis Strategy and Applications Tecia V. Carvalho1, Raphaela V. Barreto2, Alysson L. Angelim3, Samantha Pinheiro Costa3, Walderly M. Bezerra4, Francisco E. A. Melo5, Afrânio A. Craveiro1, Gloria Maria Marinho da Silva Sampaio6, Gilberto Dantas Saraiva7, Vicente de Oliveira Sousa Neto8, Vania M.M. Melo4 and Ronaldo Ferreira do Nascimento9,* Parque de Desenvolvimento Tecnológico, Av. Humberto Monte 2977, Campus do Pici, Universidade Federal do Ceará, PADETEC, CEP: 60440-593, Fortaleza, CE, Brazil 2 Departamento de Ciências Animais, Universidade Federal Rural do Semi-Árido, Av. Francisco Mota, 572, Presidente Costa e Silva, CEP 59625900, Mossoró, RN, Brazil 3 Biotrends Soluções Biotecnológicas, Av. Humberto Monte 2977, Campus do Pici, Universidade Federal do Ceará, Galpão 16, CEP:60440-593, Fortaleza-CE, Brazil 4 Laboratório de Ecologia Microbiana e Biotecnologia, Departamento de Biologia, Universidade Federal do Ceará. CEP: 60455-760, Fortaleza, CE, Brazil 5 Departamento de Física, Universidade Federal do Ceará, CEP 60455-760, Fortaleza, CE, Brazil 6 Instituto Federal do Ceara - Mestrado em Tecnologia e Gestão Ambiental, CEP:60040-531, Fortaleza-CE, Brazil 7 Departamento de Física, Universidade Estadual do Ceará-UECE, CEP: 63900-000, Quixadá, CE, Brazil 8 Departamento de Química, Universidade Estadual do Ceará, CEP: 63900-000, Quixadá, CE, Brazil 9 Departamento de Química Analítica e Físico Química, Universidade Federal do Ceara- UFC, CEP: 60455-760, Fortaleza, CE, Brazil 1

Abstract: This chapter provides a recent description of chemical synthesis, encapsulation of chitosan microspheres and the incorporation of microorganisms involving technological advances to bioremediation of inorganic and organic environmental pollutants as well as their antimicrobial activity. In addition, the potential of chitosan and their derivatives in the bioremediation of water polluted by oil spills, heavy metals, dyes, phenols and pesticides is explored.

Corresponding author Ronaldo Ferreira do Nascimento: Departamento de Química Analítica e Físico Química, Universidade Federal do Ceara- UFC, CEP: 60455-760, Fortaleza, CE, Brazil; Tel/Fax: +55 (85) 021 3366 9982; E-mail: [email protected] *

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

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Keywords: Antimicrobial Chitosan, Bacterial Consortium, Bioaugmentation, Bioremediation, Carboxymethyl Chitosans, Chitosan Beads, Chitosan- Metal composites, Grafted Chitosans, Pollutants, Synthesis of Chitosan Derivatives. INTRODUCTION Source of Chitin and Chitosan in Nature Chitin and chitosan are non-toxic, biodegradable and biocompatible polymers produced by renewable natural sources. After the cellulose, the chitin compound is the second most abundant polymer found in nature, being a structural polysaccharide found in different species like the cell walls in the fungi, the cuticle of insects, shells and the exoskeleton of crustaceans. Chitin is obtained from the crustacean shells by a chemical process of demineralization and deproteinization. Chitin contains acetyl groups (NHCOCH3), which is deacetylated with concentrated NaOH solution to produce chitosan. The chitosan is produced naturally and by chemical or physical hydrolysis with pendant acetyl groups on the polymer chitin chain. Chitin and chitosan consist of 2-acetamido-2-deoxy-D-glucopyranose and 2-amino-2-deoxy-D-glucopyranose units attached by bonds Glycosidic β. However, these polymers differ in the relative proportion of these units and solubility. Chitosan Properties Chitosan is a biopolymer of the polysaccharide type, generally obtained by the deacetylation (hydrolysis of the acetamide groups) of chitin from the exoskeletons of insects and crustaceans of great economic and environmental importance [1, 2]. In fact, the chitin deacetylation is rarely complete since chitosan is obtained when the extent of the reaction reaches about 60% (or more) [3]. The deacetylation degree (DD) of chitosan (percentage of amino groups present in the biopolymer), is responsible for defining not only its chemical identity but also determining its biological applications. The DD of chitosan usually varies from 70 to 95%, for a molecular weight of 10 to 103kDa, and depends on the chitin characteristics and on the chemical or biological methods used in the purification process [3, 4]. Regarding the solubility of the chitosan and its derivatives, it is important to mention that while the chitin is insoluble in most organic solvents, the deacetylated chitosan is readily soluble in the acid acetic, acid formic and acid lactic, as well as other dilute acid solutions at pH range of 2.0 to 6.0. The primary

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amines are positively charged under slightly acidic conditions, provide their solubility, unlike chitin, providing chitosan with bacteriostatic properties [5]. According to the literature, the higher DD of chitosan influence some of its chemical and biological properties, such as hydrophobicity, ability to undergo crosslinking by crosslinking agents, and solubility and viscosity [6, 7]. In addition, the chitosan has various biological properties, such as biocompatibility, non-toxic, biodegradable, adsorbable, bioactivity, antimicrobial activity (fungi, bacteria, viruses), antiacid, antiulcer, and antitumoral properties, blood anticoagulants, hypolipidemic activity, bioadhesiveness [8]. Synthesis of Chitosan Derivatives According to the literature [9], the chitosan derivatives can be classified into four main classes of materials: modified polymers, cross-linked chitosan, chitosanbased composites and membranes. In this chapter, only modified polymers (chitosan) will be discussed. The authors intend to show some routes of syntheses in a simplified way as well as the specific applications to the development of antibacterial compounds. The compounds derived from chitosan that will be approached in the next topic are Trimethyl Chitosan Chloride (TMC), Arginine-functionalized chitosan (CHT/ARG), and N-acetyl-l-cysteine -functionalized chitosan (CHT/NAC). (a) Trimethyl Chitosan Chloride (TMC): The TMC is a water-soluble chitosan derivative. It is a partially quaternized chitosan derivative. An important feature of this compound is its aqueous solubility over a wide pH range. This property has stimulated the search for new routes of TMC synthesis with a special interest in its application in drug transport. Experimentally, it has been demonstrated that TMC could, in fact, contribute effectively to increase the permeation of hydrophilic macromolecular drugs across the mucosal epithelia by opening the tight junctions. Synthesis of trimethyl chitosan chloride (TMC) - According to Polnok et al. [10], TMC can easily be synthesized by reductive methylation method. This route of synthesis requires only basic preparation conditions and suitable temperatures. It was observed that both the quaternization degree of the primary amino group and methylation of 3- and 6-hydroxyl groups were affected by the number of methylation processes and the base solution. It was observed that TMC with a high degree of quaternization showed more efficient permeation as compared with TMC with a low degree of quaternization [10]. Fig. (1) shows three synthetic

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routes proposed by (a) Sieval et al. [11] (b) Verheul et al. [12] and (c) Benediktsdottir et al. [13]. (a) HO

OM site 40-60 oC H 3 CO NaOH; Nal; NMP CH 3 l *One or more steps

O

O

NH 2

HO

O

O

x

HO

Chitosan OM site H 3CO O

N(CH 3 ) 3

O

-

O

+

N(CH 3 ) 3

HO

-

HO

H 3 CO

NaCl (aq)

O

+

Cl

N,N,N-trimethyl chitosan chloride (TMC) ND site Where: + x = N(CH 3) 3 ; N(CH 3) 2; NHCH 3; NH2 ; NHCOCH 3 +NT site

(b) HO

O H

O

O

H : 70 oC

C

NM site

HO

O

HO

H

C

N(CH 3 ) 2

HO

OH

HO

NMP:CH 3 l 40 oC

O

O

O

O

+ N(CH 3 ) 3

HO

ND Site

Chitosan

DMC HO

+ N(CH 3 ) 3

HO

O

O

O

O

+ N(CH 3 ) 3

Cl N,N,N-trimethyl chitosan chloride(TMC) TBDMS

HO i

O

NH 2

HO

HO HO

l-

(c)

HO

NaCl (aq)

O

O

i-

+ NT Site

HO

O

O

+ NH 3

ii

-O

Chitosan

O

O

NH 2

O

O Me

TBDMS

O

TBDMS

TBDMS

O

O

iii

O O TBDMS

NH 2

O O TBDMS

+ N

HO

O

H 3 C CH 3

iv

CH 3 l-

O HO

+ N

O

H 3 C CH 3

CH 3 Cl -

N,N,N-trimethyl chitosan chloride (TMC)

Fig. (1). Three synthetic routes to obtain TMC. They were proposed by (a) Sieval et al. [11] (b) Verheul et al. [12] and (c) Benediktsdottir et al. [13]. According to reference [31], it is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Sieval's method [11] can be performed in one or more steps. For the purpose of this chapter, we will only present the synthesis involving a single step. In this method, 2g of chitosan and 4.8g of potassium iodide were solubilized in 80mL of 1-methyl-2-prirrolidone (NMP) in a water bath at 60 ° C. Subsequently, after

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complete dissolution of the chitosan, 11 ml of 15% sodium hydroxide was added and then 11.5 ml of methyl iodide was added. Both were added with stirring. The mixture was stirred for 1 h. The product was precipitated using ethanol and subsequently isolated by centrifugation. Then, the material was dissolved in 40 ml of water, to which 250 ml of 1 M HCl in ethanol (96%) was added. thus exchanging the iodide for chloride. Fig.(1a) shows Sieval's method [11] to obtain TMC. A disadvantage of the Sieval's method [11] is that one obtains the Omethylated TMC. Verheul et al. [12], proposed a very interesting route for the preparation of TMC avoiding O-Methylation. There are two steps in Verheul´s method [12]. In this synthesis, initially, the dimethylated chitosan (DMC) is produced that later on is converted to trimethyl chitosan. According to [12], in the first step, a formic acid–formaldehyde methylation was used to synthesize N,N-dimethylated chitosan. Then formic acid was used both as the reducing agent and as a solvent because that allows chitosan to dissolve in the aqueous solution without the use of an acetate buffer. In Verheul´s method [12], 10g of chitosan was mixed with 30 ml of formic acid. Next, 40 ml of 37% formaldehyde and 180 ml of distilled water were added. The solution was heated to 70 °C under reflux and stirred using magnetic stirrer for 118 h. The second step is performed to ensure deprotonation of the tertiary amino groups of the DMC. In this step, 250mg of DMC and 2mL iodomethane were suspended in 50 ml NMP. The dispersion was stirred at 40 °C for the desired time and subsequently dropped in 150 ml of an ethanol/diethyl ether mixture (50/50). The precipitate (TMC) was isolated by centrifugation and washed extensively with diethyl ether. After drying overnight, the TMC was dissolved in 100 ml of an aqueous 10% NaCl solution and put on a shaker for a minimum of 18 h for ion-exchange. Fig. (1b) shows Verheul´s method to obtain TMC. (b) di-TBDMS Chitosan: Benediktsdottir´s method [13] uses di-TBDMS chitosan to obtain fully substituted N,N,N-trimethyl chitosan and highly substituted Nalkyl-N,N-dimethyl chitosan, avoiding O-methylation. This method involves protecting groups and is selective. The tert-butyldimethylsilyl (TBDMS) protection group is stable under a variety of reaction conditions but can be easily removed under strongly basic or moderate acidic conditions without affecting other functional groups. This synthetic strategy uses TBDMS to protect hydroxyl groups in chitosan, in which the TBDMS group is introduced to the mesylate salt of chitosan in a single step, at room temperature. This synthetic method results in apparently 100% O-protected chitosan material, with both the O-3 and O-6 groups protected (di-TBDMS chitosan).

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On the other hand, the method proposed by Sieval [11] and the method developed by Verheul [12] are not selective. They produce a heterogeneous mixture of Nmonomethyl-, N, N-dimethyl-, N, N, N-trimethyl- and O-methyl chitosan. Fig. (1c) shows Benediktsdottir´s method 13] to obtain TMC. A variety of researchers has been developed to investigate the mode of antimicrobial action of chitosan. However, the mechanism is still not fully understood. It is known that only the amino group has a fundamental importance in the mechanism of action. Possibly, the importance may be associated with their ability to form a positive charge (-NH3+) in pKa < 6.3. This property has led to intensive research into the development of amino-chitosans which are positively charged under physiological conditions and they have good water solubility. In the next topic, it will be discussed two amino-chitosans: chitosan/arginine (CHT/ARG) and chitosan/N-acetyl-l-cysteine (CHT/NAC). (c) Routes for chitosan/arginine (CHT/ARG) and chitosan/N-acetyl-l-cysteine (CHT/NAC): Arginine-functionalized chitosan is a chitosan derivative modified with arginine groups to different degrees of substitution. It is highly soluble in water due to the high pKa of the arginine guanidinium side chain (pKa = 12.48) which becomes positively charged under physiological conditions (pH = 7.0). According to Tang et al. [14], chitosan/arginine derivative presented antibacterial activity against gram-negative bacteria Pseudomonas fluorescens (P. fluorescens (ATCC 700830) and E. coli (ATCC 25922). They also studied the microbial action mode. In this work, they showed experimentally that only in acid conditions chitosan had antibacterial activities due to its low solubility at pH > 6.5. So, chitosan/arginine, soluble at pH ≈ 7.0, indicated that both substituted derivatives with substitution degrees (DS) = 6% and 30% inhibited significantly P. fluorescens and E. coli growth up to 24 h to concentrations ≥ 128 mg L−1 for P. fluorescens and ≥ 32 mg L−1 for E. coli. By experimental evidence it was possible to show that chitosan/ARG has higher antibacterial activity than natural chitosan due to unmodified increase in the membrane permeability. The authors used both fluorescent probes and field emission scanning electron microscopy (FESEM) methods. According to the authors the increase of membrane permeability by chitosan/ARG can be, in fact, attributed to the interaction between chitosan/ARG derivative and the bacteria [14]. Chitosan/arginine promotes 1-N-phenylnaphthylamine (NPN) uptake at pH ≈ 7 and it is likely that NPN uptake occurs through a similar mechanism upon exposure to either modified or unmodified chitosan polymers. The main advantage of a chitosan/arginine derivative is its polycationic feature at physiological pH. NPN is a hydrophobic fluorescence probe widely used to assess cell membrane permeability since its quantum yield increases greatly in hydrophobic environments compared to aqueous

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environments [14]. According to Xiao et al. [15], the chitosan/arginine was synthesized by an adapted method described in some reports [16, 17]. Initially, chitosan was dissolved in 2-(N-morpholino) ethane sulfonic acid sodium salt buffer solution (MES) (25 mM, pH 5.0). The authors used 1-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxysulfosuccinimide sodium salt (NHS) in MES buffer to promote activation of the carboxyl group of arginine. Activation The activation process was maintained for 2h. At a fixed molar ratio of EDC/NHS/arginine of 4:4:1, several mixtures were prepared by adding the activated arginine solution into the chitosan solution, and resultant mixtures were allowed to react at ambient temperature with stirring for 12, 24 and 48 h, respectively. The reactions were quenched by adding hydroxylamine and adjusting pH of reaction systems to 8.0 with the addition of a NaOH solution. The collected products were dialyzed against distilled water for 4 days and lyophilized. Fig. (2) shows the route for chitosan/arginine. HO O

O NH 2

HO Chitosan (CHT)

EDC/NHS Arginine

MES buffer

HO O HO

O

NH 2

NH C CH CH2 CH2 CH2

NH2

O Chitosan/arginine (CHT/ARG)

Fig. (2). Introduction of amino acid in chitosan structure (CHT/ARG). Printed according to [31].

Fernandes and co-workers [18] investigated the effect of the antimicrobial activity of the chitosan/N-acetyl-l-cysteine complex on Escherichia coli (CECT 101) and Staphylococcus. aureus (CECT 86). Chitosan/N-acetyl-l-cysteine complex was prepared from the carbodiimide-mediated reaction. By experimental data obtained

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from the Langmuir monolayer technique was possible to elucidate the interactions of both the chitosan as chitosan/N-acetyl-l-cysteine with the bacteria membrane using a cell membrane model. The anionic phospholipid dipalmitoylphosphatidylglycerol (DPPG) is a major component of gram-negative and grampositive bacteria. This negatively charged phospholipid (Fig. 3) interacts with the primary amines and sulfhydryl groups, which are believed to strongly account for its antibacterial activity. In this case, the microbial activity of thiolated chitosan was demonstrated to be primarily not only due to electrostatic interactions with DPPG, but also due to the uncharged amino and sulfhydryl groups of the biopolymer and/or the specific conformation of its macromolecules in solution [19]. The syntheses of chitosan/ cysteine involved a carbodiimide coupling reagent N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) for the immobilization of N-acetyl-l-cysteine (NAC). The pH of the chitosan solution was adjusted to 5 and then both NAC (400mM) and EDAC (50mM) were added. Then the system was stirred for 3 h at room temperature and dialyzed. O O O O

H

O

O P O-

OH O

OH

Fig. (3). Structure of Dipalmitoylphosphatidylglycerol (DPPG).

Fig. (4) shows the route for synthesis of chitosan/N-acetyl-l-cysteine (CHT/NAC). Chitosan and its Derivatives: Antimicrobial Activity Despite the helpful developments in medical and pharmaceutical technology, harmful bacteria, infecting millions of people annually, remain a great concern. According to Boucher [20]; the United States spends more than 120 billion USD per year for the treatment of infectious diseases. In this paper, it is emphasized that five billion USD of which is earmarked exclusively for the treatment of resistant pathogens. Another aspect that should be considered is that research into new antibiotics is not of interest to many large pharmaceutical companies, and different factors can be listed such as time-consuming, expensive with a reasonable estimate that is around one billion USD per year and risky, not to mention the short commercial life of such drugs (due to resistance acquisition by

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bacteria). One of the great challenges of the last decades in the health field has been the fight against infections. Certainly, the rise of resistant pathogens added to the relative delay in the production of antibacterial agents makes it even more difficult to combat microbial diseases [21]. HO O

O

NH 2

HO Chitosan (CHT) EDAC NAC HO O

O HO

NH

O C

CH

O

CH 2

NH

C

CH 3

SH Chitosan/N-acetyl-L-cysteine (CHT/NAC)

Fig. (4). Introduction of an acetyl amino acid to the amino group of chitosan Printed according to [31].

The chitosan compound has a broader spectrum of antimicrobial action than chitin. According to Gil and collaborators [22], this difference is due to the greater number of free amines present in chitosan, which can interact strongly with negative residues of the cell surface, inhibiting the microbial growth. According to Lim and Hudson [23], the degree of deacetylation, molecular mass, temperature, and pH are the factors that directly affect the chitosan antimicrobial activity. These state variables act by modifying the chemical structure of the polymer and consequently, as well as the potential of binding in the cell membranes. It is very important to know the mechanisms of antibacterial activity in the chitosan, nevertheless, several processes have been suggested for the exact form of action, which is not known yet. Among the proposed mechanisms, the most accepted are the interaction between positive charges of the chitosan with anionic molecules on the cell surface. This particular link causes vital changes in the membrane permeability and compromises bacterial metabolism. It may even

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lead to cell lysis [24, 25]. In the recent years, the microbial inhibition spectrum of the chitosan has been determined through important studies. The literature shows that this biopolymer has a broad bacterial spectrum, surpassing that of some chemical agents (Tables 1 and 2). In general, Grampositive bacteria present higher sensitivity to high molecular weight chitosan. The opposite is true for the Gram-negative, which can be inhibited by the change in the metabolism caused by the entry of the low molecular weight polymer, through the plasma membrane (Table 1) [26]. Some authors argue that this sensitivity is directly related to a number of anionic molecules on the cell surface [27]. Because of its low toxicity in mammals, the antimicrobial potential of chitosan has been extensively explored in the control of infectious agents [28-33]. Table 1. Chitosan minimum inhibitory concentration (MIC) against Gram-positive and Gram-negative bacteria. Adapted with permission from [28]. Strain

Gram reaction

MIC (ppm)

Corynebacterium michiganence

+

10

Escherichia coli

-

20

Micrococcus luteus

+

20

Staphylococcus aureus

+

20

Agrobacterium tumefaciens

-

100

Erwinia carotovora subsp.

-

200

Erwinia sp.

-

500

Pseudomonas fluorescens

-

500

Xanthomonas campestris

-

500

Klebsiella pneumoniae

-

700

Bacillus cereus

+

1000

Table 2. Chitosan minimum inhibitory concentration (MIC) against phytopathogenic fungi. Adapted with permission from [28]. Fungus

MIC (ppm)

Botrytis cinerea

10

Dreschtera sorokiana

10

Micronectriella nivalis

10

Fusarium oxysporum

100

Rhizoctonia solani

1000

Trichophyton equinum

2500

Piricularia oryzae

5000

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The antifungal potential of chitosan has been studied for treatments of Phytopathology caused by fungi present in the soil. Interestingly, in this kind of study the chitosan inhibits the growth of most fungicide-resistant microorganisms. In Table 2 is reported that chitosan at the concentration of 1 mg ml-1 inhibited the growth of several fungi, except Zygomycetes, which possess chitosan as the main constituent of the cell wall. According to Musumeci and co-workers [34], an antimicrobial agent is a “substance that kills or inhibits the development and the multiplication of microorganisms, such as bacteria, fungi, protozoa or viruses”. Among numerous materials having this feature, chitosan and its derivatives can be highlighted. The exact mechanisms of the antibacterial activities of chitosan and its derivatives are still unknown. It is known that chitosan's antimicrobial activity is influenced by a number of factors that act in and orderly and an independent fashion. According to Bui and co-workers [35] chitosan’s (and its derivatives) mechanisms of antimicrobial activity are believed to be similar to other cationic biocidal, following six steps: (1) bacterial cell surface adsorption; (2) cell wall diffusion; (3) cytoplasmic membrane adsorption; (4) cytoplasmic membrane disruption; (5) cytoplasmic constituents leakage; and (6) cell death [36]. Following this, some results related to the bacterial activity of chitosan and chitosan derivatives are presented. The polycationic structure of chitosan is a prerequisite for antibacterial activity. Thus, the electrostatic interaction between its polycationic structure and the predominantly anionic components of the microorganisms' surface (such as Gram-negative lipopolysaccharide and cell surface proteins) plays a primary role in the antibacterial activity. The trimethyl chitosan – TMC [37], derivative salt with permanent positive charges (obtained by the quaternization of the amino groups) gives to chitosan a cationic characteristic independent of the solvent pH, which can be better suited, mainly for food and medical applications [38]. In addition, quaternary chitosan derivatives like N,N,N-trimethyl chitosan (TMC) have superior antibacterial activity towards Gram-positive and Gram-negative bacteria as compared with chitosan and most other chitosan derivatives [39 - 41]. Fig. (5) shows the chemical structures of chitosan and N,N,N-trimethyl chitosan (TMC). Importance of the Degree of Deacetylation (DD) of Chitosan According to results from different works [39 - 41] it is not possible to take conclusion about how the degree of deacetylation of chitosan affects its antimicrobial activity property. This activity of chitosan was reported to be dependent on its degree of deacetylation (DD). Chitosan with higher DD, which

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has higher positive charge, would be expected to have stronger antibacterial activity. Researchers development by Jung and collaborators [42] suggested that chitosan with a high DD is commonly found to have greater antimicrobial activity towards various strains of fungi, Gram-positive bacteria and Gram-negative bacteria [42, 43] than does the lower deacetylated chitosan, particularly in the case of S. aureus and Escherichia coli (E. coli) [44, 45]. In Table 3, the DD and viscosity of chitosans used by Jung and co-workers in experimental studies can be seen. The objectives of the experimental research were to compare antibacterial activities of six acid-soluble chitosans (two different DD × three different viscosities) and two water-soluble chitosans (two different DD with a similar viscosity) against selected common foodborne spoilage and pathogenic bacteria (eight Gram-negative and six Gram-positive), and to identify chitosan that can be potentially used as a food preservative for extension of shelf-life of foods. Table 4 shows the antibacterial activities (log CFU mL) of 0.05% acid-soluble chitosan against eight gram-negative and six gram-positive bacteria. HO HO

O

O

O HO

N(CH 3 ) 3

HO

NH 2

Chitosan

O +

Cl

N,N,N-trimethyl chitosan chloride (TMC)

Fig. (5). TMC has positive charge in its structure. Chemical structures of chitosan, and N,N,N-trimethyl chitosan chloride. Adapted with permission from [31]. Table 3. Degree of deacetylation (DD) and viscosity of chitosans used in this experiment. Adapted with permission [42]. Chitosan

Acid-soluble

Water- soluble

Designationa

DD (%)

Viscosityb(mPa s)

D90-L

92.9

9.4

D90-M

89.6

47.4

D90-H

89.3

166.3

D99-L

98.8

17.9

D99-M

98.6

34.3

D99-H

99.2

77.6

D60

63.2

1.1

Remark

Oligomer

D80 80.0 1.3 Acetate The numbers after D indicate the value of degree of deacetylation; L, M, and H indicate low, medium, and high viscosity, respectively. b0.5% w⁄ v in 0.5% v ⁄ v acetic acid or in water. a

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Table 4. Antibacterial activities (log CFU mL)1) of 0.05% acid-soluble chitosans against eight gramnegative and six gram-positive bacteria. Adapted with permission from [42]. Bacteria Gram(-)

Gram(+)

Controla

Acid-soluble chitosana D90-La

D90-M

D90-H

D99-L

D99-M

D99-H

Pseudomonas fluorescens

8.33±0.01

ND

ND

ND

ND

ND

ND

Proteus vulgaris

9.27±0.05d

1.57±0.05a

ND

1.70±0.06b

ND

2.73±0.05c

ND

Erwinia carotovora

8.20±0.7d

0.30±0.06a

ND

ND

0.48±0.09a 2.76±0.03b

ND

Serratia marcescens

9.42±0.1e

1.91±0.06a 2.68±0.04c 1.96±0.08a 2.76±0.05d 2.20±0.08b 2.66±0.08c

Escherichia coli

9.13±0.05d

ND

2.08±0.05b

ND

1.88±0.05de

ND

2.15±0.08c

Vibrio parahaemolyticus

8.64±0.05c

1.61±0.11b

ND

ND

ND

0.60±0.08a

ND

Vibriovulnificus

8.49±0.02c

0.30±0.06a 2.63±0.03b

ND

ND

ND

ND

Salmonella Typhimurium

8.95±0.10d

8.52±0.06c 8.57±0.02c 8.32±0.01b

ND

ND

5.47±0.06a

Listeria monocytogenes

8.45±0.010b

ND

ND

0.60±0.08a

ND

ND

ND

Staphylococcus aureus

8.34±0.06b

ND

ND

0.85±0.08a

ND

ND

ND

Bacillus subtilis 7.95±0.010ND

ND

ND

ND

ND

ND

ND

Bacillus cereus

8.51±0.05b

0.70±0.08a

ND

ND

ND

0.78±0.05a

ND

Lactobacillus curvatus

8.42±0.08e

1.20±0.04c 1.59±0.02d 1.59±0.02d 0.78±0.07a 1.00±0.06b 1.04±0.0b

Lactobacillus plantarum

9.26±0.09f

2.02±0.03b 2.83±0.10c 3.14±0.03d 3.33±0.05e 1.59±0.03a

ND

Viable cells after incubation without (Control) or with 0.05% chitosan for 24 h at 37 C. Values are means ± SD of triplicate determinations. Means with different letters within each row indicate significant differences (P < 0.05). b See Table 1 for description of chitosans. ND, not detected.

a

o

However, some studies have reported different findings. Parker and collaborators [46] studied antimicrobial activity of hetero-chitosans and their oligosaccharides varying molecular weights. According to this work, the optimum activity was obtained with an intermediate (75%) DD, as compared with the DD values of 90% and 50%. Table 5 shows the minimum inhibitory concentration (MIC) of hetero-chitosans against eight different bacteria. In this research was investigated both bacteria: three Gram (+) and five Gram (-).

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Table 5. Minimum inhibitory concentration (MIC) of heterochitosans against eight different bacteria. Adapted with permission from [46]. MIC (mg/ml) Bacteria Gram (-) Gram (+)

90%

75%

50%

Escherichia coli

0.625

0.625

1.25

Salmolnella typhimurium

0.625

0.3125

0.625

Micrococcus luteus

0.625

0.625

1.25

Staphylococcus epidermidis

0.15625

0.15625

0.15625

Staphylococcus aureus

0.625

0.625

0.625

Bacillus subtilis

0.625

0.625

0.625

Bacillus cereus

0.625

0.625

0.625

Another study reported by Tsai and collaborators [47] (although the authors have concluded that the activity increased with increasing DD) draws attention towards the fact that no significant difference in the activity of the polymer with a varying DD (98–76%) against various bacteria and fungi was observed (Table 6). Table 7 shows both the degree of deacetylation and molecular weight of chitin and chitosan used by Tsai and collaborators [47]. Table 6. Minimal lethal concentrations (MLC)of chitosan obtained from shrimp shell treated microbiologically or chemically against various microorganisms.. Adapted with permission from [47].

Tested microorganisms

DD95 DD98 (MO)a (CH)b

MLC (p.p.m) DD76 DD47 DD53 DD74 b (CH) (MO)a (CH)b (MO)b

Bacteria, Gram (-) Aeromonas hydrophila CCRC 13881

500

1000

1000

1000

1500

2000

Aeromonas hydrophila YM1

500

500

500

500

>500 >.500

Escherichia coli CCRC 10674

100

100

100

100

500

200

Pseudomonas aeruginosa CCRC 10944

200

150

>200

200

>200

>200

Salmonella typhimurium CCRC 10746

1500

1500

1500

1500 >2000 >2000

Shigella dysenteriae CCRC 13983

200

200

>200

>200

>200

>200

Vibrio cholerae CCRC 13860

150

200

200

200

>200

>200

Vibrio parahemolyticus

100

100

150

100

>150

>150

Bacillus Cereus CCRC 10250

200

200

1000

500

1000

1000

Listeria monocytogenes LM- LM

100

150

150

150

150

150

Staphylococcus Aureus CCRC 12652

100

50

100

100

100

150

Bacteria, Gram (-)

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(Table ) contd.....

DD95 DD98 (MO)a (CH)b

Tested microorganisms

MLC (p.p.m) DD76 DD47 DD53 DD74 (CH)b (MO)a (CH)b b (MO)

Fungi Candida Albicans CCRC 20511

200

200

500

800

Fusarium oxysporum CCRC 32121

500

500

1000

500

Aspergillus fumigatus CCRC 30502

>2000 >2000

>2000

800

800

>2000 >2000

>2000 >2000 >2000

Aspergillus parasiticus CCRC 30117 >2000 >2000 >2000 >2000 >2000 >2000 DD95 (MO), DD74 (MO), DD47 (MO): 95%, 74%, or 47% deacetylated chitosan from microbiologically prepared chitin. b DD98 (CH), DD76 (CH), DD53 (CH): 98%, 76%, or 53% deacetylated chitosan from chemically prepared chitin. a

Table 7. Degree of deacetylation and molecular weight of chitin and chitosan obtained from shrimp shell treated chemically or microbiologically. Adapted with permission from [47]. Degree of deacetylation (%)

Molecular weigthd

35±5

ND

53±4

1.08 x 106

76±5

2.85 x 105

98±3

4.91 x 104

MO-chitina

32±6

NDc

MO-chitosanb

47±5

1.10 x 106

74±5

3.10 x 105

Materials

CH-chitin

a

c

CH-chitosan

b

95±4 5.10 x 104 CH-chitin, chemically prepared chitin; MO-chitin, microbiologically prepared chitin. b CH-chitosan, chitosan from alkaline deacetylation of CHchitin; MO-chitosan, chitosan from alkaline deacetylation of MO-chitin. c Average ± SE (n = 4). d Average of two measurements. ND, not determined. a

Thus, from these results, we come to the conclusion that there is a lack of agreement in these studies regarding the antibacterial effect of these structural features and their optimal combination. The mechanism of antimicrobial activity of chitosan has not yet been fully elucidated and validated, but several hypotheses have been proposed. The hypothesis that has been most accepted is a change in the cell membrane permeability due to interactions between the positively charged chitosan molecules and the negatively charged microbial cell membranes. This interaction leads to the leakage of proteinaceous and other intracellular constituents [48, 49]. Other mechanism proposed are more specifically focused and take into account

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differences in cell wall structure of bacteria. According to Jing and collaborators [50], differences in antibacterial activity of chitosan between Gram-positive and Gram-negative bacteria are likely due to the differences in cell wall structure. Fig. (6) shows the basic structure of both bacteria types: Gram-positive and Gramnegative [51]. The cell wall of gram-positive bacteria is entirely composed of peptide poly glycogen; chitosan could easily drill through the network of peptidoglycan and directly act on the cell membrane. The cell wall of gramnegative bacteria, however, is composed of an inner membrane of peptide poly glycogen and an outer membrane of lipopolysaccharide, lipoprotein, and phospholipid. The outer membrane of gram-negative bacteria functions as an efficient outer permeability barrier against macromolecules and could be responsible for preventing chitosan from reaching the cytoplasmic membrane. Thus, according to Coma and co-workers [52], chitosan generally showed a stronger antibacterial effect against gram-positive bacteria than gram-negative bacteria. Gram-Positive Bacterial Cell Wall

Gram-Negative Bacterial Cell Wall

Lipoteichoic Acid Outer Lipid Membrane

Peptidoglycan Cell Wall

Peptidoglycan Plasma Membrane

Plasma Membrane Alternating copolymer of b(1 4)-N-acetyl-O-glucosamine and N-acetylmuramic acid Pentaglycine cross-link

L-Ala-D-GluL-Lys-D-Ala-

tetrapeptide

Fig. (6). The basic structure of bacterial peptidoglycan and the cell wall structures of Gram-positive and Gram-negative bacteria (Printed from Glycobiology Analysis Manual, 2nd Edition from http://www.sigmaaldrich.com/technical-documents/articles/biology/glycobiology/peptidoglycans.html).

Antimicrobial Action by Chelating Capacity of Chitosan Metal ions that combine with cell wall molecules of the micro organism are crucial for the stability of the cell wall [53]. Additionally, the chitosan-metal complexes are prepared and exert strong antimicrobial activity. According to Rabea and collaborators [54], chitosan-mediated chelation of such metal ions has often been implicated as a possible mode of antimicrobial action.

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Not only does chelation plays a part in the acid condition, it is also able to combine divalent metal ions in neutral condition [55]. For example, the chitosan backbone has in your structure, multiple nucleophilic groups. This property requires suitable synthetic protocol in order to obtain the desired selectivity [56]. Jukka et al. [57] have demonstrated experimentally that there was greater reactivity of the amino groups when compared to the hydroxyl groups. On the other hand, the degree of selective substitutions varies greatly with the reaction condition. It was noted by the experiments that so many derivatives of chitosan obtained via grafting method were prepared to increase the amine content on the chitosan. However, the antibacterial activity of the product was decreased [58, 59]. H HO

Salicylaldehyde H

O

NH2

HO

OH

O

NH2

HO O

O

O

O

O

C

HO O

H

O

O

HO

O

O DA

DS

OH

NH2

OH

OH

HO OH

O

NH2

O HO

O

O

HO

NH2

HO

5-Nitrosalicylaldehyde

N

O

HO

O

C

HO O

O

O

O

O

O

N O

OH

O DA

DS

HO OH

NH2

HO N

OH

O

O OH

HO

O

5-Methoxysalicyladehyde

NH2

HO O

N

HO N O

O

O

O

HO OH

NH2

HO N

O

O

N O

OH

O DA

DS OH

Fig. (7). Structural representation of the ligands biopolymeric Schiff base, where (DD) = degree of deacetylation, (DS) = degree of substitution and (DA) = degree of acetylation. Adapted from [60].

Araújo and co-workers [60] developed a synthetic route for obtaining complexes of biopolymeric Schiff bases of salicylaldehydes and chitosan. Fig. (7) shows a ligand chitosan Schiff base and Fig. (8) shows complexes (a) Ni(II) and (b)Co(II). According to authors Schiff bases have been gaining prominence in coordination chemistry and have been considered an important class of ligands. From the Shiff bases, very stable complexes with several transition metals can be produced predominantly in oxidation states (II). Thus they have been extensively investigated regarding their biologic properties, as antitumor antifungal, antiviral,

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antimalarial, and antibacterial agents [61 - 63], as mimetic models for the transport of oxygen in metalloenzyme complexes, as well as, in other types of applications. De Araújo and collaborators studied biological activity and other possible uses of chitosan Schiff bases obtained from the reaction of chitosan with salicylaldehyde (CH), 5-methoxysalicylaldehyde (CMeO), and 5nitrosalicylaldehyde (CN) and their copper(II), nickel(II) and zinc(II) complexes (Fig. 8). All the compounds were characterized by usual methods such FT-IR and thermal analysis (TGA/DTG-DTA). Schiff bases were derived from salicylaldehydes substituted at position 5 on a chitosan matrix. a)

(1)EtOll. 10mL 40 oC (2)Ligand (L1. L2. L3). lmmol NaCH 3COO.3H2O. 2.2mmol. 40 oC. 10min (3)Ni(CH3COO)2.4H2O. lmmol. 4mL. 12h.OoC

Ni(CH3CO2)2.4H2O

H

HO

NH2

HO

N

HO O

O

H

H

O

NH2

HO

H

O

O

O

O

O

O

DA

DS

DD OH

OH

OH

H

O

O N

NH2

HO

H

O

O

N

HO O

OH

NH2

HO H

O

O

O

+

H

O

O

O

O

OH

OH

OH

b)

4’ 5’

3’

H

2’

H

O O

6’

1’

O

Co NH2

HO

HO

+N

H

O

O

O

O

DD OH

O

H H

O

O H

O

O

NH2

HO

H O

OH

O DA

DS OH

Fig. (8). Synthetic route to obtain the complexes (a) Ni(II) and (b)Co(II). Adapted from [60].

The synthesis proposed by Araújo et al. follows only two steps. The first step consists of the synthesis of the biopolymer Schiff base. In this step, an appropriate amount chitosan was suspended in 75 mL of 0.15 mol L-1 acetic acid for 12 h in a 25°C. The reactions were conducted at 55 ± 1 °C using an aldehyde to chitosan mol ratio of 3:2. This procedure resulted in a yellow compound. The second step consists in the synthesis of the biopolymer complexes of the Schiff base. In this step, 10mL of ethane was added to a round bottom flask at 40 ° C. Subsequently, 1.0 mmol of the ligand and 2.2 mmol of sodium acetate trihydrate were added. The mixture was heated for 10 minutes. Then 4mL of an aqueous solution of 1.0mM Zinc, Copper or Nickel acetate was added. The reaction mixture was then refluxed for 4 h, cooled to room temperature, and placed in a refrigerator for 12 h at 0°C. The resulting precipitate was collected by filtration and washed with methanol.

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Cytotoxicity studies were also performed by Araújo and coworkers. According to authors, the toxicity was investigated using an MTT assay performed with human HeLa cells for both biopolymeric Schiff bases and complex. Fig. (9) shows the composition of Schiff bases and the dependence of cell viability. It is observed by results that that ligand CMeO presented around 95%, ligands CN and CH were 85 and 80%, respectively of cell viability for cells analyzed. The cell viability of the copper(II), nickel(II) and zinc(II) complexes is also shown. 120

Cell viability / % control

100

80

60

40

Zn-CN

Zn-CMeO

Zn-CH

Ni-CN

Ni-CMeO

Ni-CH

Cu-CH

Cu-CMeO

Cu-CH

CN

CMeO

CH

0

Control

20

Fig. (9). Composition of Schiff bases and the dependence of cell viability. Printed with permission from [60].

The biopolymeric complexes of Cu-CN presented cytotoxicity above 100%. According to authors, an explanation to this result is that most likely this copper complex acts like micronutrient for these cells. Experimental data also showed that the complexes Cu-CMeO and Cu-CN showed great similarity in the cell viability assays when compared to their respective ligands. According to the results, the complexes Ni-CH Ni-CMeO and Zn-CH presented an average cell viability of c.a. 80%. The complexes of zinc Zn-CMeO and Zn-CN presented 70 and 50% of cytotoxicity, respectively. Authors concluded by cell viability studies that the Zn(II) complexes are the most cytotoxic, while the copper ones presented higher cell viability, suggesting selective use as cytotoxicity or viability is required in a specific application. The result obtained by electronic spectra suggested a square planar geometry for the Cu(II) and Ni(II) complexes.

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Anan and collaborators [64] synthesized a series of di and trivalent metals with a Schiff base derived from 4-hydroxysalicylaldehyde anchored on a chitosan matrix (Fig. 10). They characterized by FTIR, XRD, SEM images, ESR, RMN, elemental analysis and determined the dissociation and stability constants of these complexes. OH

a)

OH

1 6

b)

2

5

3

4

1 2

7

H

OH 6

N

OO

4 5

NH2

HO

N

HO

O

O

O

N

O

NH2

HO

N

DD

O N

O

O

O

DB

OH

NH2

HO

O

O

DS

OH

O

HO

N

O

OH

NH2

HO

O

O

O

DD

Schiff-base of chitosan:2CS-Hdhba

N

N O

O

O

O

N

O

O

DB

DS

OH

OH

OH

OH

OH

2 1 H O

NH2

HO O

N O

O

O

N O

DD OH

N

co NH2

O

N O

DS OH

NH2

HO

O DA

O

HO

O

OH

O

O

N O

DD OH

O O

O

N + H

N

H

OO

4

5

HO O

N

6

CI

N+

HO

O

3

N

O

O

NH2

NO

N O

DA

DS OH

O

OH

Fig. (10). (a) In the top: Structures of the Schiff base. Below: Complexes: palladium ; (b) metal(II) complexes of Co, and Zn. Adapted from [64].

In the synthesis strategy employed by the authors the 4hydroxysalicylidenechitosan Schiff-base (2CS-Hdhba) (Fig. 10) was obtained by a condensation reaction of 2,4-dihydroxybenzaldehyde with chitosan, and its metal complexes, [M(2CS-dhba)Cl2(H2O)2] (M(III) = Fe, Ru, Rh), [M*(2CSdhba)(AcO)(H2O)2] (M*(II) = Co, Ni, Cu, Zn), [Pd(2CS-dhba)Cl(H2O)] and [Au(2CSdhba) Cl2], were used in synthesis. The Schiff base (2CS-Hdhba) is negatively charged and it acts as a bidentate chelate. Both the azomethine nitrogen and the deprotonated 2-hydroxy centers with the pendant glucosamine hydroxy functionality take no part in the coordination process. The dissociation constants of 2CS-Hdhba and the stability constants of some of its metal complexes have

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been determined pH-metrically by authors. The authors show that the Schiff base and its complexes are thermally stable and with low crystallinity compared to free chitosan. Scanning Electron Microscope (SEM) data suggested that chitosan has a more regular surface and larger particle sizes than the Schiff-base modified chitosan and its complexes. The deprotonation constants of 2CS-Hdhba were found to be 10.12 and 9.25, and the stability constants of some of the reported metal ions complexes were found to be 5.72, 4.71, 5.25, 5.73, 5.89, 5.78 and 4.55 for Co(II), Ni(II), Cu(II) and Zn(II), Pd(II), Ru(III) and Rh(III), respectively. The authors also concluded that the structures involved are either octahedral or square planar geometries. Experimental evidence suggests that each structural geometry depends on the metal, being the Cu(II), Ni(II) and Zn(II) square planar and included an acetate anion in the coordination sphere. Nickel(II) complex of a tridentate Schiff base from a salicylaldehyde derivative on chitosan matrix was also prepared and structurally characterized regarding its supramolecular structure on the basis of XRD data revealing a distorted octahedral character for the complex [65]. Chitosan and its Hydrophilic/Hydrophobic Chain: Another important aspect which relates to the antimicrobial capacity of a compound is its interaction with water: compounds which interact actively with water are termed hydrophilic and compounds which do not are termed hydrophobic. This property becomes more evident when it is considered as the antimicrobial agents typically requiring water for the activity. The solubility of chitosan is strongly determined by the degree of its hydrophilic nature (Fig. 11). Originally, the chitosan has low solubility in water. This characteristic brings serious restrictions to the use of chitosan in various fields of science. Meantime chemical modifications with the introduction of polar groups have been developed as an effective way of improving the solubility of both chitosan and its derivatives in water [66 - 68]. Aiming to improve both the solubility as the antibacterial activity of chitosan, Xie, and collaborators [66] reported a novel synthetic route for the preparation of chitosan derivative with a quaternary amino salt. This quaternary derivative (Fig. 12) was obtained by treating hydroxyethyl chitosan (HECs) with chloroethylamine hydrochloride in sodium hydroxide solution. According to the authors, there was an improvement in the solubility of chitosan. The synthesis developed by Xie et al. [66] is divided into two steps. Initially, the chitosan is alkalized with NaOH solution (50% by mass) at -18 ° C for 48h. Subsequently, after thawing, 10mL of isopropyl alcohol was added. Then, chloroethanol was added with continuous stirring for 12 h at 80 ° C. After filtration, the solid product was washed with alcohol. Hydroxyethyl chitosan (HECs) yielded was dried in an oven at 60 °C. In the second step, five grams of HECs were added to the mixture

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of isopropyl alcohol (20mL) and 42% sodium hydroxide solution with stirring. After several minutes of reacting and under controlled temperature, chloroethylamine hydrochloride was added. After completion of the reaction, the pH was adjusted to 7 with 1M HCl. The ethylamine hydroxyethyl chitosan (EHCh) was washed, filtered and dried in the oven. Fig. (12) shows the synthesis of ethylamine hydroxyethyl chitosan (EHCh). O H3C

H

NH HO O

a)

HO O

O

H N

H

O

OH n n b) raw chitin (insoluble) chitosan(acid soluble) OH

increasing solubility

R HO O

c)

R N

R

O

O OH

H

R

n

quatemized chitosan (soluble)

H N

H

O O

d)

O n R substituted chitosan (soluble)

Fig. (11). Representation of chitin and chitosan derivatives. Adapted from [67].

This behavior can be attributed to ethylamine hydroxyethyl chitosan (EHCh) that decreased the intermolecular interactions, such as van der Waals forces, and then increased water solubility. Consequently, this resulted in the increase of its antibacterial capacity against Escherichia coli. Fig. (12) sets out the synthesis of (EHCh). Hydroxyethyl chitosan (HECh) was obtained in the first step. As observed the chitosan was treated with 2-chloroethanol in alkaline conditions. Then quaternary derivative was prepared by treating hydroxyethyl chitosan (HECh) with chloroethylamine hydrochloride in sodium hydroxide solution. The next topics a general approach on chitosan derivatives with their respective synthetics, route, and applications in various fields of science will be shown.

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HO O

O HO

O

NH2

(i) ClCH2CH2OH NaOH

OH

OH (ii) ClCH2CH2NH2 .HCl

O O

O HO

NH2

O O

O

O HCl.H2N

O

O

HN NH2.HCl

Fig. (12). The synthesis of ethylamine hydroxyethyl chitosan (EHCh). Adapted from [66].

Toxicity of Chitosan and Chitosan Derivatives Current studies show that chitosan is considered a biologically compatible polymer; in general, it is a non-toxic biocompatible material. This makes it a compound special in relation to biomedical applications [69 - 71]. These properties have been used by scientists to create formulations with potential in health. Despite numerous published studies, chitosan and derivatives are not yet approved by the FDA for drug delivery. As a result, few biotechnology companies are using these products [72]. Therefore, in this chapter, we will report some research involving the potential of chitosan and derivatives to be used in drug delivery in safe conditions. The water-insolubility of chitosan is disadvantageous for its wide application as an antibacterial agent, then the chemical modification of chitosan to produce soluble derivatives at neutral and basic pH is important. The chemical modification can be used to introduce various functional groups and control the hydrophobic, cationic and anionic properties. However, modifications made to chitosan may make it more or less toxic and residual chemical reagents should be carefully removed. However, researchers involving the toxicity of chitosan derivatives in biomedical applications are increasing. Chitosan, as biomaterials prepared from N-deacetylation of chitin, has attracted significant interest in

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biotechnology fields because of its well-known low toxicity, excellent biocompatibility and biodegradability. Meirong Huo and co-workers [72] obtained amphiphilically modified chitosan molecules with long alkyl chains as hydrophobic moieties and glycol groups as hydrophilic moieties (N-octyl-O-glycol chitosan) and for use as drug carriers. The biocompatibility and low toxicity of the chitosan derivatives (N-octylO-glycol chitosan) were confirmed by hemolysis, acute toxicity, and histopathological studies. The results indicated that these chitosan derivatives had some advantages over the commercially available, in terms of low toxicity levels and increased tolerated dose. Interesting review works involving toxicological aspects of chitosan and its derivatives are found in the literature [73]. Environmental Application of Chitosan - Derivatives This chapter provides a summary of recent results obtained using batch and column studies with chitosan-derivatives obtained during the treatment of water and wastewater for the removal of metal cations, dyes; phenols, for entrapment of bacterial strains, decontamination of oil-polluted sea water and other miscellaneous pollutants. However, there is still a consensus that there is a need to discover the practical utility of commercially developed adsorbents. Entrapment of Bacterial Strains into Chitosan Beads for Bioremediation Application The petroleum industry is the main cause responsible for the constant origination of most toxic pollutants, being these among other major inappropriate issues of humankind, facing in the coming years. The following toxic compounds, such as recalcitrant, mutagenic and carcinogenic, are being released into the environment, which causes acute and chronic illness, impacting and affecting the biota, leading to adverse effects in the ecosystem equilibrium [74, 75]. A recent example was the Gulf of Mexico spill, considered the largest recorded accident involving oil spill in the environment [76]. The environmental consequences of that spill are immeasurable. Nevertheless, the evaporation and the photooxidation from the petroleum spilled played a relevant role in the detoxification in the contaminated environments, at the end, the complete degradation is carried out by microorganisms. Bioremediation uses living organisms, usually microorganisms, to remove or reduce pollutants in the environment. Unlike physical and/or chemical processes, complete biodegradation (mineralization) is able to eliminate contaminants in the environment, having as final products carbon dioxide, water and microbial

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biomass [77]. The usage of immobilized microorganisms has been explored since it is more advantageous when compared to the use of free cells. Among the advantages are higher growth rate, higher catalytic stability, greater tolerance against large concentrations of toxic compounds, less susceptibility due to contamination of undesirable microorganisms, and the possibility of reuse for utilization in reactors [78 - 82]. In both situations, the use of microbial consortia has been emphasized due to the metabolic complementarity that improves the efficiency of recalcitrant compounds biodegradation [83]. Polyacrylamide, Polyethylene glycol, and polyurethane are several synthetic compounds and alginate, carrageenan, agar, collagen, chitin, as well as chitosan, are natural polymers that have been applied to matrices for the immobilization. However, natural polymers are more result oriented, due to their biocompatibility [84]. The natural polymers present biodegradability, lack of toxicity, physiological inertness and availability in nature. For instance, chitosan is one of the most promising materials for the cell immobilizations [85, 86]. The cell encapsulation process into the chitosan beads is performed by the solubilization of a different kind of polymer in a dilute organic acid (acetic acid or formic acid), in order to form a gel solution which may be added to the microbial biomass before the coagulation step in the alkali or ionotropic solutions. The production of biomaterials in different geometrical configurations can be done by the aforesaid procedure, leading to the production of beads, films or membranes [87]. Chitin and its derivative chitosan are recycled biologically in nature through microbial enzymes [88] including chitinase, chitosanase, and N-acetyl-β- Dglycosaminidase that act in synergy until the reduction of the polymers to the constituent monomeric units, characterizing the chitin cycle (Fig. 13). Bacterial species from Bacillus and Streptomyces as well as the fungi Mucor rouxii and Aspergillus spp. are excellent sources of chitin deacetylase and chitosanases [89, 90]. Chitinolytic enzymes are also found in plants, where they are involved in defense against pathogenic microorganisms [91]. The chitin and chitosan present many possible commercial applications of the products based on these polymers, which can be used in the food and cosmetic industries, in agriculture, in animal feed and in the treatment of effluents, where they can be used as chelating agents of metals, as flocculants and adsorbents of dyes, among others [92]. Due to its flocculation and coagulation properties,

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CHITIN DEACETILASE

CHITINASE LYSOZYME

CHITOSANASE

Chitin oligosaccharides N-ACETYLb-D-GLUCOSAMINIDASE

Chitosan

Chitosan Oligosaccharides b-D-GLUCOSAMINIDASE

N-Acetyl-Dglucosamine

D-glucosamine

Fig. (13). Chitin cycle in nature. Adapted with permission [88].

chitosan has been widely used for the removal of suspended solids, turbidity, and is even used for the selective separation of proteins. Because it is more economically attractive, chitosan stands out among other typical absorbents, such as active charcoal, for the removal of organic compounds and wastewater dyes [93] as well as fish farming effluent treatment [94]. Chitosan was successfully exploited in the coagulation of oils and greases dispersed in the waters of oil fields. Although it is not fully understood how chitosan acts in the absorption of oily substances, it is possible that it involves electrostatic attraction, as in inverse magnetic poles [95]. The abundant availability of chitosan in nature combined with its biocompatibility, biodegradability, hydrophilicity, and bioactivity justifies the growing interest in chitosan for the development of substrates for immobilization of cells, drugs, and biomolecules. The polymer is used as a raw material in the development of membranes, filters, microspheres, and nanospheres, which can be used in several applications. In this context, several applications using bacteria immobilized on chitosan have been investigated, such as the bioremediation of oil-polluted seawater, similarly, biodegradation of n-hexadecane by Bacillus subtilis spores encapsulated in chitosan beads crosslinked with glutaraldehyde. Bioremediation of crude oil polluted seawater by a hydrocarbon-degrading bacterial strain immobilized on chitin and chitosan flakes [96]; bioremediation of oil contaminated sediments in the shores (of Singapore) using osmocote mixed with chitosan to biodegradation of aliphatic and polycyclic aromatic hydrocarbons by native microorganisms [97]; degradation of heavy oil in an aqueous system by a Pseudomonas sp in the presence of chitosan [98].

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Entrapment of Cells in Chitosan Beads Cell immobilization is a general term used to describe different ways of attaching cells or molecules to polymer supports. Immobilization forms include flocculation, surface adsorption, and covalent attachment to carriers, crosslinking between cells, encapsulation, and entrapment in matrices. Among the previously mentioned methods, entrapment has emerged successfully, since it provides greater protection to the environmental variations and viability of microbial agents [87, 99, 100, 107]. In this process, the microbial cells are trapped inside a polymer matrix, which has pores of sufficient size to allow the diffusion of the substrate towards the cells, as well as the products generated by the cellular metabolism out of the matrix [81, 101]. Fig. (14) shows details of chitosan beads for highlighting its porosity.

A

B

C

D

Fig. (14). SEM micrography of chitosan bead (A); Bead surface details (B); Inner bead image (C) and Bead porosity (D). Printed with permission from [81].

Studies have shown that immobilized microorganisms are more effective as biodegradable agents than free cells. This advantage comes from the protection

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provided by the matrix against the toxicity of pollutants, optimizing the production of microbial metabolites responsible for xenobiotic mineralization reactions [101, 107]. Williams and Munnecke [102] reported the use of immobilized cells as a viable alternative to raising the productivity of substances of microbiological origin. This is because in systems with immobilized cells it is possible to obtain a larger mass of cells per volume unit compared to systems that use free cells. The semipermeable membrane is used for the cell entrapment, which may be performed by the involvement of the biological components. The enzymes/cells are free in the solution, however, they are restricted in the space. Regarding the large molecules that cannot leave the capsule (Proteins or enzymes) and the usage of the semipermeable membrane cannot cause an entrapment with other substrates and small products, which can pass through freely. The construction of a microcapsule ranging from 10-100 μm in diameter can be made by different materials [103]. The substrates used for immobilization are mostly insoluble in water and have a high molecular weight. In order to be considered ideal for immobilization of microbial cells, the polymeric matrix must have some characteristics, such as not being toxic to cells, high retention capacity of microorganisms, being inert chemically and biochemically, having mechanical resistance and high diffusivity of reagents and products to minimize the effects of mass transport in the process [104]. Many natural polymers have been used as support for cell immobilization. Algae polysaccharides such as agar, agarose, alginates, and carrageenans are classified as natural polymers, whereas polyacrylamide, polystyrene, polyurethane and alumina are synthetic polymers. The use of natural polymers may be in the form of homogeneous matrices or condensed with other reagents, such as glutaraldehyde. The preference for the use of these polysaccharides lies in the fact that they are abundant in nature, economically viable and present low toxicity, when compared to those of synthetic origin [105]. One of the first works to report the cell immobilization in chitosan was performed by Vorlop and Klein [106]. Since then there are few studies describing the utilization exclusive of chitosan as matrix for cell immobilization [107, 108]. As previously mentioned, chitosan does not have a uniform chemical entity, and variations in the degree of deacetylation and molecular mass may hinder the development of matrices. In addition, its proven antimicrobial potential makes it difficult to trap viable cells. However, studies with cells immobilized on heterogeneous matrices involving chitosan and other natural polysaccharides have been reported. In these cases, chitosan acts as a polymerizing agent, providing greater stability to the molecular arrangement of the support [109].

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One of the simplest methodologies for manufacturing chitosan beads is coagulation. In this technique, a solution of the polysaccharide dissolved in acid is dripped in alkaline solution for instant formation of the beads, through crosslinks formed in the polymer [110]. When only the coagulation in alkaline medium is not sufficient to promote the desired physical stability to the beads, they are subjected to cross-linking using glutaraldehyde. This process significantly reduces the solubility of chitosan in acidic medium by binding the free amines to the aldehyde group of the crosslinker (Fig. 15) and improves the resistance of this polymer to chemical and biological degradation [111]. OH H OH

H

O

NH2

OH

H

O

H

O

H

H

H

H

NH

H

H

O

H H

H

OH O

OH

O

H

NH2

H

NH2

H

NH2

OH H

H

O H

O

H

O

H

O

OH

NH

O OH

OH

OH

(H 2 C) 5 H

OH

H

H O OH

Fig. (15). Cross-linked chitosan structure with glutaraldehyde.

Beads preparation is a strategy to increase the adsorption capacity of chitosan, since beads have a surface area about 100 times greater than flaky chitosan. In addition, beads exhibit faster adsorption kinetics and ease of handling and operation. Biocompatible and biodegradable polymers are highly desirable compounds for the manufacture of micro and nanospheres conjugated or incorporated with other active components. Chitosan exhibits biocompatibility and biodegradability among other particular properties, which allow its manipulation in the aqueous acidic medium in order to lead to the formation of micro or nanospheres conjugated to compounds in which a slow, controlled release is desired or even to increase the efficiency of the absorption of active substances [112]. Another alternative for the immobilization of microorganisms in chitosan is the development of films and membranes. Chitosan films and membranes are prepared by drying a solution of chitosan in acid at room temperature for 30-36 h, after spreading the solution on the surface of a glass vessel. Chitosan films are also prepared by oven drying and infrared exposure. Depending on the drying

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method and the increments added to films and membranes, their physical properties such as tensile strength, elongation, and modulus of elasticity, or Young's modulus, are altered [113]. We have succeeded in immobilizing pure cultures of bacteria, spores and bacterial consortia following a thorough analysis of the susceptibility of bacterial candidate strains to the chitosan gel that will be used in the bead manufacture as well as to the harsh coagulation process, which predicts pH variation ranging from 3 to 9 in a short time. We also investigated whether the candidate strain produces chitosanase, and if so, is not chosen. The cell immobilization can be easily detected in the case of pigmented cells, as in the example shown in Fig. (16). In this case, we show the result of the immobilization of Staphylococcus saprophyticus, a Gram-positive coccus-shaped bacterium, which produces a yellow pigment, which makes the beads yellow, contrasting with spheres prepared only with chitosan that is white. The transverse sectioning of the sphere and its analysis by scanning electron microscopy (SEM) clearly shows the cocci inside the beads.

A

B

Fig. (16). A: Chitosan beads (white beads) and chitosan beads containing cells of Staphylococcus saprophyticus PFA001 immobilized (yellow beads). B: SEM micrography of S. saprophyticus inside the chitosan beads. Author photos.

It is worth noting that when the cell wall of S. saprophyticus was enzymatically removed and then entrapped in chitosan beads was observed that the beads were able to promote the emulsification of water-kerosene mixture, while the beads containing only chitosan were unable to (Fig. 17). The emulsifying activity was evaluated according to Iqbal and collaborators [114]. Briefly, 2 mL of kerosene was added to 2 mL water containing 2 ml of chitosan beads with and without entrapped biomass. The system was mixed for 2 min with a vortex and allowing it

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to stand for 24 h. The height of the emulsified layer (mm), divided by the total height of the liquid column (mm), was used to estimate the emulsification percentage.

Fig. (17). Chitosan beads in water-kerosene mixture Emulsification of kerosene promoted by Staphylococcus saprophyticus cell wall emulsifier entrapped in chitosan beads. Author photos.

Bacteria species of the genus Bacillus are recognized for secreting antibiotics, insecticides, biosurfactants, and enzymes [115]. They are also known by producing spores, a metabolically inert cell type, extremely resistant to aggressions of a physical and chemical nature. As spores store an intact copy of the bacterial chromosome it becomes potentially capable of originating a new vegetative cell when under optimal conditions, through the process of germination [116]. Chitosan is toxic to many bacteria, due to changes in normal cell membrane function. Unlike the vegetative cells, bacterial spores have many layers surrounding the cell membrane and these layers preserve the integrity of these cells against the antimicrobial action of chitosan. Melo and co-workers have tested the feasibility of the immobilization of the bacterial spores into the chitosan beads and the ability of the germinated cells to degrade the n-hexadecane for aiming at developing an innovative approach in the bioremediation. It is a material fact that the spores trapped in a medium supplemented with 1% of glucose germinated in vegetative cells, degrades almost 100% of the 1% nhexadecane. These stated trapped spores produced biosurfactant, as well as free

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cells within 48 h. It is important to note that during the biodegradation of the nhexadecane, the number of viable cells within the beads was maintained. However, the process of capturing bacterial spores can be made into the chitosan beads, overcoming the problems related to the stability and storage, as well as the long-term cell viability in the vegetative cells. Also, vegetative cells of Bacillus pumilus UFPEDA 831 were immobilized, a strain with special ability to degrade n-hexadecane, aiming bioremediation applications [107]. Fig. (18) shows details of the beads surface, porosity, and bacilli inside the beads. Fig. (19) compares the performance of the free and immobilized B. pumillus on chitosan beads throughout the n-hexadecane biodegradation process. It was observed that both groups reach the same biodegradation efficiency at 96 h. Although there is a delay of the immobilized cells relative to the free cells to metabolize the pollutant, this product presents several advantages over free cells such as ease of storage, transport, and applications. For using in reactors, the main advantage to be highlighted would be the possibility of the beads reuse.

SEM

: MY30.00kV

View field 150.50 mm

15 kV

WO 13.4000 mm DET: SE

15,000 X

A

20 mm

1 mm

VEGAN TESCAN ‘

Universidade Federal do Ceara

0001

JSM - 5600 LV

SEM : MY30.00kV WO 12.7770 mm DET: SE SEM MAG 2.50 X

B 10 mm

VEGAN TESCAN ‘

Universidade Federal do Ceara

C

Fig. (18). SEM micrography of the smooth surface observed on beads dried in an oven at 35 °C (A) and the porous surface of beads dried by lyophilization (B). Cell of Bacillus pumillus strain UFPEDA 831 inside the chitosan beads (C). Adapted with permission from [107].

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Residual Hexadecane %

100 90

Free-living Cells

80

Immobilised Cells

70 60 50 40 30 20 10 0

0

48

96

144

Time (hour) Fig. (19). Hexadecane degradation by free-living and immobilized cells of Bacillus pumillus strain UFPEDA 831 in chitosan beads at 0, 48, 96 and 144 h. Adapted with permission from [107].

Among the environmental clean-up technologies, the bioremediation stands out, due to the fact that it is more cost-effective, eco-friendly and efficient than many physical and chemical treatments [117]. Angelim and collaborators evaluated the advantages of immobilizing native bacteria from the oil-contaminated mangrove sediments in the chitosan beads, therefore using this product to accelerate the environmental recovery [107]. In order to achieve this, the authors carried out an exhaustive analysis of chitosan toxicity against each of the isolates to select who would remain in the consortium to be immobilized, as well as they evaluated the production of chitosanase by each isolate, intending to avoid damage to the beads. The process of the evaluation in the isolates after contacting with 3% (w/v) of the chitosan gel at pH 3.0, showed that among 17 candidate strains, 13 remained viable after 6 h of contact, 12 after 9 h of contact and only 3 after 24 h of contact demonstrating the toxic activity of chitosan against the majority of strains after 24 h. None of the selected isolates produced chitosanases. The immobilization step must not last more than 6h, in order to maintain the highest consortium in the member diversity, as discussed based on the above-stated results, being 6h sufficient to homogenize the biomass and chitosan gel, therefore subsequently allowing the beads to coagulate. We observed that the isolates were resistant to a coagulant solution. This solution was prepared with 1% (w/v) sodium tripolyphosphate (TPP) and pH 9.0. The biodiversity of the consortium immobilized in the chitosan beads is represented by a total of 13 from the remaining strains. The final composition of the consortium included Grampositives and Gram-negatives representatives: Xanthomonadaceae PETBA01,

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Martelella sp. PETBA03, Cytophaga sp. PETBA04, Sphingopyxis sp. PETBA06, Bhargavaea sp PETBA 08, Mesorhizobium sp. PETBA09, Mesorhizobium sp. PETBA10, Gordonia sp. PETBA11, Mesorhizobium sp. PETBA13, Pseudomonas sp. PETBA14, Gordonia sp. PETBA15, Gordonia PETBA16, and Gordonia PETBA19. This was the first work to report the immobilization of such bacterial diversity into chitosan beads for bioremediation application. The immobilized bacterial consortium was evaluated in the microcosm of sediments from the original oil-contaminated mangrove. The bacterial community was monitored by viable cells counts and by denaturing gradient gel electrophoresis (DGGE) during 90 days. At the end, the viability of bacterial strains confirmed the potential for selected bacteria entrapped in chitosan beads for bioaugmentation as shown in Fig. (20). 10 10

CFU/g of sodimcnt

10 9 10 8

b

10 7

a

ac

a b

bc

c ab

b ad

abd ad

a

c ad

c d

bc

NA CB CBC

10 6 10 5 10 4 10 3 10 2 10 1 0

7 15 30 60 90

0

7 15 30 60 90

Time (days)

0

7 15 30 60 90

Fig. (20). Monitoring the viable cells counts of bacterial consortium in microcosms of mangrove sediments under three conditions: natural attenuation (NA), chitosan beads (CB) and chitosan beads with immobilised bacterial consortium (CBC). Different letters between the times in the columns show significant differences (p < 0.05) for each individual treatment as demonstrated by the analysis of variance test (ANOVA) with Tukey’s post-test. Adapted with permission from [81].

Some factors are responsible for the main limitations in the success of the bioremediation [118], as in the case of the complexity in these environments. These factors are responsible for causing difficulties in predicting metabolic microbial activity in the situ, as well as in the process of adaptability and in the ecological competence. An emergent bioremediation approach for which a strategy is based on the entrapping of the indigenous bacterial consortia in the chitosan beads.

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The stimulating effect of the chitosan on the native bacterial community in the mangrove sediments was confirmed through the data from our study group [81], who provided the growth of the entrapped biomass in a favorable environment until indigenous microbiota degrade the matrix and release the bacterial cells. Therefore, chitosan beads meet dual functions, such as facilitating the introduction of cells into the environment (bioaugmentation) and providing carbon and nitrogen (biostimulation) at the end, benefiting the entire microbial community. Dellagnezze and collaborators carried out a experiment in mesocosm scale (3000 L) with seawater artificially polluted with crude oil. It was used a bacterial consortium composed of four metagenomic clones and the Bacillus subtilis strain CBMAI 707. The authors described that the aromatic compound degradation was more efficient with the immobilized cells than with the free cells, along biodegradation percentages reaching up to 99% in 30 days. Hsieh and co-workers have also demonstrated the advantages of the cell immobilization [79], when studying the degradation in the phenol by a Pseudomonas putida strain, entrapped in the chitosan beads inside Erlenmeyer flasks. The survival growth of the cells’and the degradation rates, were improved through the immobilization process, which increased the tolerance in the cells at a higher phenol concentration. The bacterial cells also remained stable and active for longer periods during bead reuse. A recent review of Bayat and collaborators [119] summarizes the effectiveness of immobilized cell in different supports for oil biodegradation. The authors highlight that immobilized cells are better, faster, and can stay for a longer period. Thinking of applications to the field, where it is imagined that a great amount of beads is required, we design and construct a machine capable of producing the order of tons of beads with immobilized microorganisms (Fig. 21). The machine has the capacity to produce up to one ton of beads in 22 cycles using 2 reservoirs of 50 L of chitosan gel. This equipment consists of an automatic mixing system and injector heads, which dispense the gel into the coagulation tank. Through the automated head system it is possible to form spheres with different diameters, with or without multiple coatings. This process represents an innovation and allows the production of spheres with mixed polymers, such as chitosan and alginate, which extends the possibilities of applications of these polymers and facilitates the process of microbial immobilization.

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A

C

Fig. (21). Chitosan beads production machine (MEQ) (A); Detail of the injector heads (B); and uniform aspect of the beads size (C). Author photos.

Chitosan/Derivatives for the Bioremediation of Oil-Polluted Seawater Chitosan derivatives when produced (as biosorbents) have attracted considerable attention because of the low cost and diversity of substituent functional groups that show significant potential for the removal of different aquatic pollutants. In this chapter, several chitosan derivatives, compiled from the literature, with efficient adsorption capacities for adsorption of various aquatic pollutants are presented. Thus, this chapter reports the main treatment results involving natural water and wastewater using chitosan derivatives for the removal of metal cations, dyes; phenols, different anions and other miscellaneous pollutants. The summary of the review provides the recent information obtained using batch studies and fixed-bed batch studies and adsorption supply, and the various mechanisms involved. It is clear that from the literature search that chitosan derivatives have shown good potential for the removal of various aquatic pollutants. However, there is still a need to discover the practical utility of adsorbents developed on a commercial scale. Since the beginning of research involving chitosan, particular attention has been given to the use of natural chitosan or its derivatives, using specific chelating agents to increase its performance as adsorbent material [120 - 129]. These adsorbents have been applied for the removal of inorganic and organic pollutants of

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industrial wastewaters. For example, toxic metals [130 - 134], dyes [135 - 137], phenols [138], and polycyclic aromatic hydrocarbons [139] have a potential impact on the environment and public health when they contaminate superficial and/or groundwater. In this context, the chitosan spheres due to their specific properties, such as cationic biopolymer, high adsorption capacity, macromolecular structure, abundance and low price, have been employed as purposes for bioremediation of oil-polluted seawater as well as an alternative method for the treatment of industrial effluents. Recently, chitosan natural and chitosan spheres were studied as an alternative adsorbent for bioremediation of oil-polluted seawater [140 - 142]. Claudio and co-workers investigated to evaluate the capacity of adsorption of crude oil spilled in seawater by chitin flakes, chitin powder, chitosan flakes, chitosan powder, and chitosan solution [141]. Results are presented in Table 8. The results showed that, although chitosan flakes had a better adsorption capacity by oil (0.379± 0.030 grams oil per gram of adsorbent), the biopolymer was sinking after adsorbing oil. Chitosan solution did not present such inconvenience, despite its lower adsorption capacity (0.013 ± 0.001 grams oil per gram of adsorbent). It was able to form a polymeric film on the oil slick, which allowed to restrain and to remove the oil from the samples of sea water. The authors also suggest that chitosan solution 0.5% has greater efficiency against oil spills in the alkaline medium than acidic medium. Table 8. Chitin flakes, chitin powder, chitosan flakes, chitosan powder, and chitosan solution evaluating the capacity of adsorption of crude oil spilled in simulated system containing seawater. Reproduced with the permission from [141]. Adsorbent

Oil Mass (g)

Adsorbent Amount (g; mL)

Chitin Flakes

3.06

9.19

52.24 ± 4.23

0.258 ± 0.022

Chitin Powder

3.18

9.25

49.35 ± 2.01

0.170 ± 0.004

Chitosan Flakes

3.16

6.09

72.75 ± 3.97

0.379 ± 0.030

Chitosan Powder

3.08

8.91

81.27 ± 13.39

0.281 ± 0.050

150.0 mL

60.52 ± 2.01

0.013 ± 0.001 g/mL

Chitosan Solution 3.08 n = performance in duplicate.

Adsorbed Oil Adsorption capacity (%) (g/g; g/mL)

Oliveira and cowokers [140] studied the removal of oil and grease (TOG) and organic matter (COD) in petrochemical wastewater using chitin and chitosan. The authors investigated the adsorbents efficiency in the wastewater petrochemical treatment for the system of fixed bed and the physicochemical parameters of the

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solutions were analyzed before and after the use in fixed bed, and the results obtained are shown in Table 9. Petrochemical wastewater treatment with fixed bed column system using chitin and chitosan adsorbents showed a performance of chitin and chitosan for the removal of oil and grease (TOG) about 90%. The turbidity removal from wastewater sample by the chitin and chitosan achieved 89% and 74%, respectively. The wastewater treatment with chitin showed high removal efficiency for organic matter (COD) with performance around 90%, and chitosan shows a low efficacy. Table 9. Results of the physical-chemical parameters of wastewater before and after treatment. Reproduced with the permission from [140]. Parameters

ERaw EComp EQTI EQTS

MLE Semace 154/2002

COD (mg L )

320.4

184.2

79.9

332.

200

TOG (mg L )

81.6

-

8.4

8.4

20

7.66

7.79

7.85

7.90

5-9

Conductivity (μs.cm ) 2.42

2.30

2.63

2.67

-

-1

-1

pH -1

Turbidity (NTU) 23.2 4.41 2.40 6.01 ERaw = raw wastewater EComp = effluent treated by the company, EQTI = effluent treated with chitin adsorbent EQTS = effluent treated with chitosan MLE = maximum limit established by environmental law (SEMACE 154/2002).

In addition, Vieira and co-workers [142] investigated crosslinking chitosan spheres as an adsorbent for oil diesel removal. The chitosan spheres were soaked with a diesel oil solution at different concentrations using a batch adsorption system. The equilibrium data were well described by the Langmuir model, showing that after chemical modification the maximum adsorption capacity increased significantly. These results show that bioadsorbed based on chitosan is promising for diesel oil removal from organics solutions which can be a good strategy for bioremediation. Chitosan: Alternative Application as Coagulation Aid The coagulation–flocculation is one of the most important processes in water treatment [143]. This process can be used as a pretreatment, after treatment or even a main treatment depending on the condition of water. Chitosan has been used as a single-component coagulant in various systems, such as clay suspensions [143 - 145] turbid waters [146, 147] and various industrial effluents [148, 149]. The key role of chitosan as a coagulant was reported to occur by a charge neutralization process (Fig. 22).

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A

B

Inter-particle Bridging

Charge Neutralization

C

‘Patch’ bridging

Fig. (22). Diagram showing the different mechanisms involved in coagulation-flocculation: (A) inter-particle bridging; (B) charge neutralization; and (C) “patch” adsorption. Printed with permission from [143]. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Other authors suggest that inter-bridging between particles occurs in combination with charges neutralization [144]. Since chitosan is positively charged and densely concentrated a “patch” mechanism was proposed. According to this mechanism, the flocculation promoted by chitosan can be attributed to the fact that the positive charges on chitosan are densely concentrated as compared to the negative charges in water where neutralization occurs in smaller regions in a stepwise fashion, thus leading to patches of charge neutralization [144]. The latter occurs by lowering the repulsive interactions between similarly-charged particles, which leads to the compression of the electric double layer. This effect leads to

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the destabilization of the dispersed system [149]. Since chitosan is a linear polysaccharide that possesses positive ionic charge in acidic media, it also works to bridge flocks together by electrostatic binding of several flocks with the opposite charge along different loci of the biopolymer chain. Evidence for charge neutralization was inferred from studies on chitosan dosage effects, where the removal of turbidity [148 - 150], lignocellulosic materials [151], total organic carbon (TOC) [152, 153] and color [154 - 156] increased with increasing dosage up to a point followed by a decrease due to the re-stabilization of the dispersed system. The latter is due to an increase in the positive charge to a point beyond the neutralization of the negative charge sites in the treated water, resulting in charge inversion [152]. The Fig. (23) shows how chitosan promotes the flocculation of both negative charge species (unmodified chitosan) and positive charge species (modified chitosan). It was discussed that chitosan is a positively charged polysaccharide in acidic media due to the protonation of the amino groups. It is interesting to note that, the pH of water and wastewater systems may be neutral or alkaline. In this case, chitosan has limited use due to its poor solubility above its pKa. For this reason, studies have investigated the modification of chitosan with anionic functional groups in place of some of the hydroxyl groups to allow for greater dissolution over a wider pH range (Fig. 23).

Self-assembly

Self-assembly

OH

Chitosan (unmodified) Chitosan (modified) Cationic species Anionic species

OH O

HO

NH 2

O O

HO n

NH O

O n

Chitosan

Fig. (23). Chitosan and modified chitosan as coagulant aid. Printed with the permission from [143]. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Hesami and collaborators [157] studied the removal of As(III) and As(V) with Fe(III) and chitosan as the coagulant and aid, respectively. Optimal removal of

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As(III) (80% -100%) was achieved at pH 7 using Fe(III) at a dosage of 60 mg.L-1, instead of chitosan as a bioflocculant. However, the addition of chitosan resulted in a smaller dosage of Fe(III). Studies with As(V) showed the same trend, but to a lesser degree, where a 5 -10% drop was observed upon chitosan addition. Chitosan/Metal Oxides Nanocomposites In addition, recently, chitosan based metal particles composites have been studied as an alternative adsorbent for wastewater treatment. Thus, Abdelaal and Mohameda [158] reported a modified sol-gel technique to prepare ZrO2 nanoparticles through impregnation of ZrO2 with chitosan. The composite photocatalyst of Pd/ZrO2 was characterized by XRD, TEM, UV-vis and BET. Also, the photocatalytic activity was investigated under visible light irradiation by using a thiophene solution as a model pollutant. Shahram and co-workers [159] studied the removal of permethrin pesticide from water using the chitosan-zinc oxide nanoparticles composite as an adsorbent. Tanhaei and co-workers [160] reported a new chitosan/Al2O3/magnetite nanoparticles composite adsorbent and applied as an adsorbent for removing methyl orange. Wang and co-workers [161] carried out the preparation and characterization of chitosan-poly(vinyl alcohol)/bentonite nanocomposites (CTS–PVA/BT) for adsorption of Hg(II). CTS–PVA/BT nanocomposites were synthesized by introducing bentonite (BT) into the CTS–PVA polymer matrix. The mesoporous nanocomposites thermally stable were efficient to Hg(II) removal of different mercuric salts with various initial concentrations and pH. Chitosan: A Versatile Biocompatible Polymer A particular attention has been focused on the biodegradable polymer chitosan because of their widespread use in bionanocomposite films field [162]. In this connection, these materials have attracted considerable attention, mainly due to the need to develop environmentally friendly materials. The recent progress made in this field of biodegradable polymers and composites is presented in different forms (films, gels, particles, membranes, or scaffolds) for a great number of applications, ranging from the biomedical field (e.g., drug delivery, tissue engineering) to industrial areas [162 - 167]. In addition, Fig. (24) shows the areas of chitosan versatility [167]. CONCLUDING REMARKS Chemical modifications of chitosan are used to incorporate various functional groups to control their hydrophobic, cationic and anionic properties. The progress of these researchers has been fairly rapid and has promoted the development of new chitosan derivatives which showed an unlimited application potential.

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Chitosan and some applications Biomaterial in medicine Drug delivery

NH2

HO

Adsorption property because functional groups

H

O

O

O

n OH

Film, Gels, Scaffolds Fig. (24). Chitosan – a versatile biocompatible polymer.

However, care should be taken with excess reagents (not consumed) in the derivatization process, which must be carefully removed to avoid toxic activities. In this chapter, we discussed several examples of strategies for the synthesis of chitosan derivatives, as well as their environmental applications involving the mobilization of pure cultures, bacterial consortia, bacterial spores in chitosan spheres for the degradation of hydrocarbons and bioremediation of oil-polluted seawater. Thus, a list of chitosan-derivatives from literature has been compiled and their adsorption capacities, for various aquatic pollutants, are presented and critically discussed regarding adsorbents for the removal of heavy metals, dyes, phenols, pesticides, applications in coagulation and antimicrobial activity. In conclusion, the chapter provides a summary of recent information obtained using batch and column studies and deals with various adsorption mechanisms involved. However, it is still evident from the literature that the progress in this area is quite rapid and the developed derivatives of chitosan exhibit an unlimited application potential to be used commercially. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The author (editor) declares no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS The authors thank the Brazilian agencies FINEP, CNPq, FUNCAP and CAPES

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CHAPTER 5

Synthesis of N-Containing Heterocycles via Hypervalent Iodine(III)-Mediated Intramolecular Oxidative Cyclization Jiyun Sun1, Daisy Zhang-Negrerie1, Yunfei Du1,2,* and Kang Zhao1,* Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China 2 Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China 1

Abstract: Hypervalent iodine(III) reagents, including iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, iodobenzene dichloride, hydroxy(tosyloxy)iodobenzene (Fig. 1), have been vastly used in various oxidative transformations in organic synthesis due to their low toxicity, commercial availability, ease of handling and environmental benignity. A striking feature of these hypervalent iodine(III)mediated approaches is that these transformations may not need the participation of any transition metals. Thus, the development of transition-metal-free method mediated by hypervalent iodine reagent for oxidative coupling reactions is a topic of great interest as such transformations represent an attractive alternative to the traditional transitionmetal-catalyzed oxidative reaction. Most strikingly, the hypervalent iodine has been utilized for the synthesis of a variety of biological interesting N-containing heterocyclic compounds including indoles, oxazoles, oxindoles, azirines, diazepin-2-ones, carbazolones, quinolin-2-ones, 1,4-benzodiazepines, spirooxindoles, etc under mild reaction conditions (Fig. 2). In this chapter, we highlight all the representative methodologies that have applied the common hypervalent iodine(III) reagents as oxidant in synthesizing the biologically interesting N-containing heterocyclic compounds through intramolecular oxidative C-C, C-N, C-O, N-N bond forming reactions as well as cascade reactions in some cases. The presentation is organized according to the ring sizes and the ring patterns of the intermediate (spiro vs. fused) formed during the intramolecular oxidative cyclization step. However, the application of hypervalent iodine(III) reagents together with the transition metals for the synthesis of N-containing heterocyclic compounds will not be discussed in this chapter.

Keywords: Cascade reaction, C-C bond formation, C-X(N, O, S)bond formation, Hypervalent iodine(III) reagent, Intramolecular cyclization, N-containing heterocycles, Oxidative reaction, Transition-metal-free, X-X(N, O, S) bond formation. * Corresponding authors Yunfei Du and Kang Zhao: Tianjin Key Laboratory for Modern Drug Delivery & HighEfficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; Tel: +86-2-27406121; Fax: +86-22-27404031; E-mail: [email protected]

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

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Fig. (1). General Scheme of Hypervalent Iodine(III)-Mediated Synthesis of N-Containing Heterocycles.

Fig. (2). Common-used Hypervalent Iodine(III) Reagents [1 - 15].

THREE-MEMBERED RING 2H-Azirine 2H-Azirines are a class of highly strained and reactive molecules containing C-N double bonds. Due to their presence in natural products [16 - 20] and also high synthetic potential as precursors for functionalized amino derivatives and Ncontaining heterocycles [1 - 15], this class of compounds has gained considerable attentions from synthetic chemists. In 2009, Zhao and Du reported two examples of synthesis of substituted 2Hazirines from enamines using hypervalent iodine(III) reagents via intramolecular oxidative cyclization (Scheme 1). When the R2 substituent is alkyl or aryl, 2Hazirines 2 were obtained in the presence of PIDA in 1,2-dichloroethane [21]. When R2 = H, treatment of enamines 1 with PhIO in 2,2,2-trifluoroethanol afforded 2-(2,2,2-trifluoroethoxy)-2H-azirines 3 [22]. The reaction is thought to undergo the formation of an imine ylide with subsequent nucleophilic attack on the nitrogen center by carbanion intermediate.

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Scheme 1. PIDA or PhIO-Mediated Synthesis of 2H-Azirines via Intramolecular Oxidative Cyclization of Enamines to 2H-Azirines.

Aziridine In 2010, Moriarty and co-workers realized a metal-free intramolecular aziridination of alkenyl sulfonyliminoiodanes 4 using hypervalent iodine(III) reagent instead of conventional metal catalysts such as Rh(II) and Cu(II). Reaction pathways involved formal [2 + 2] cycloaddition of the RSO2N=IPh group to the double bond followed by reductive elimination of PhI to give the sulfonylaziridine 5 (Scheme 2) [23].

Scheme 2. Synthesis of Aziridine via a PhIO-mediated Formal [2 + 2] Cycloaddition Aziridination.

Four-membered Ring Azetidines Hypervalent iodine(III) reagent-mediated [2 + 2] cycloaddition could also be applied to stereoselective construction of highly functionalized azetidines 9. Fan and co-workers realized functionalized azetidines synthesis in moderate to good yields with excellent diastereoselectivities. The reaction was postulated to proceed via a grind-promoted solvent-free Michael addition and a PhIO/Bu4NI mediated oxidative cyclization (Scheme 3) [24].

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Scheme 3. Synthesis of Azetidines via PhIO/Bu4NI-Mediated Oxidative Cyclization.

Four-membered β-Lactam In 2015, Maulide and Afonso et al. reported a C-H insertion of β-ketoamide substrates 10 to synthesize four-membered β-lactam 11 (Scheme 4) [25]. The reaction of substrates 10 and PIDA in the presence of NaH afforded an iodonium ylide Int-B, which allowed to bypass the use of either diazo precursors or metal catalysts.

Scheme 4. Synthesis of Four-membered β-Lactam via C-H Insertion of β-Ketoamide with PIDA in the Presence of Base.

Five-membered Ring Pyrrole Derivatives Pyrroles are a class of the most common five-membered N-containing heterocycles, representing a large number of natural products [26] and drug

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molecules [27]. Several methods for the synthesis of pyrrole derivatives with hypervalent iodine(III) reagents have been developed. In 2007, Fan and co-workers reported the δ-C(sp3)-H bond oxidation of sulfonamides 12 with PIDA/I2 under metal-free conditions. This reaction provides a useful route to pyrrolidine derivatives 13 (Scheme 5) [28]. An I2-initiated radical mechanism was proposed for this process.

Mechanism:

Scheme 5. Synthesis of Pyrrolidines Derivatives via PIDA/I2-Mediated Intramolecular C-H Bond Amination of Amides.

Scheme 6. Synthesis of Pyrrolidine-2,4-diones via Intramolecular C(sp3)−H Amination Mediated by PhI(OPiv)2/Brønsted Acids.

In 2012, an intramolecular C(sp3)−H amination mediated by hypervalent iodine(III) reagents to the pyrrolidine-2,4-diones 15 was reported (Scheme 6)

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[29]. This method offered a complementary approach to α-amination of carbonyl compounds. Later, Zhang and co-workers realized a PhIO-mediated intramolecular amination of homoallylic amines 16, and simultaneous 3-fluorination of pyrrolidines 17 using a widely adopted Lewis acid BF3·Et2O as an efficient fluorinating agent (Scheme 7) [30].

Mechanism:

Scheme 7. Synthesis of Pyrrolidines via Intramolecular Aminofluorination Reaction Using PhIO/BF3·Et2O.

Domínguez and co-workers developed a series of intramolecular amidation of substituted alkynes 18 in the presence of PIFA to render 5-aroyl- and 5-alkenoy-2-pyrrolidinone-type 19 (Scheme 8) [31 - 34]. The transformations from substituted alkynylamides to the corresponding pyrrolidinones give evidence that hypervalent iodine(III) reagent can activate alkyne moieties toward the intramolecular nucleophilic attack of the amide functional group. Hypervalent iodine(III) reagents have also been used to construct pyrrolidinones via C(sp2)-C(sp3) bond formation. α-Methylthio amide 20 underwent a Pummerertype rearrangement with PIFA, leading to the formation of 3methylthiopyrrolidinone 21 (Scheme 9) [35]. The reaction was proposed to proceed via the Pummerer reaction process with the intermediate formed by the attack of PIFA on the sulfur atom in 20, followed by simultaneous elimination of the α-proton and iodobenzene from the resultant sulfonium salt Int-A.

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Mechanism:

Scheme 8. PIFA-Mediated Construction of Substituted Pyrrolidinones.

Scheme 9. Construction of Pyrrolidinones via PIFA-Mediated C(sp2)-C(sp3) Bond Formation.

Indole Derivatives Owing to the ever expanding demand of both natural products and designed medicinal agents [36 - 39], methods to construct indole skeletons have been

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developed for many years. Hypervalent iodine(III) reagents-mediated metal-free transformations have been proven to be efficient approaches for the synthesis of indole derivatives. In 2006, the synthesis of N-arylated and N-alkylated indoles 23 from enamine derivatives 22 were realized through a PIFA-mediated intramolecular oxidative C(sp2)-N bond formation (Scheme 10, a) [40]. The same strategy was also applied to the synthesis of carbazolones [41] and chromeno[2,3-b]indol-11(6H)-ones [42] via I(III)-mediated intramolecular cyclization of 2-aryl enaminones. Later, a variety of functionalized indoles 25 were synthesized from N-aryl enamines 24 via PIDA-mediated oxidative C(sp2)-C(sp2) without the involvement of transition metals (Scheme 10, b) [43]. In 2014, Muñiz and co-workers prepared the indoles 27 form substrates 26 via C(sp2)-N based on sterically congested hypervalent iodine compounds of the family of Koser reagents, which refer to combination of iodosobenzene and 2,4,5tris-isopropylbenzene sulfonic acid (Scheme 10, c) [44].

Scheme 10. I(III)-Mediate Synthesis of Indole Skeletons.

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From the 28-type of substrates, Tellitu and Domínguez developed an approach for the synthesis of indoline derivatives 29. This method features PIFA-mediated difunctionalization of the alkene moiety with aniline and an additional hydroxy group, which was in situ generated at the terminal position of the original double bond (Scheme 11) [45]. The key step of this transformation is PIFA-mediated formation of a N-acylnitrenium ion Int-A and its succeeding intramolecular trapping by the olefin fragment.

Scheme 11. PIFA-Mediated Difunctionalization of the Alkene Moiety.

In 2013, Antonchick and co-workers realized PIFA-mediated azidoarylation of alkenes 30 under mild and metal-free reaction conditions leading to the biologically interesting 2-oxindoles 31 (Scheme 12) [46]. The cascade approach initiated by the addition of azidyl radical involved the cascade formation of C-N and C-C bonds. Hypervalent iodine(III) reagents with different ligands on the centered iodine atom could involve in diverse reactions. With the combination of PIDA and TBAI, a tandem cyclization/acetoxylation of O-acyl anilines 32 provided a useful route to 2-acetoxy indolin-3-ones 33 (Scheme 13) [47]. Through intramolecular C-H amination of N-substituted aminobiphenyls 34, Chang group and Antonchick group, respectively developed an approach to synthesize carbazoles 35 by using metal-free oxidant PIFA [48] and organocatalytic system (peroxyacetic acid and catalytic amount of ArI) (Scheme 14) [49].

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Scheme 12. Synthesis of 2-Oxindoles via PIFA-Mediated Azidoarylation of Alkenes.

Scheme 13. Synthesis of 2-Acetoxy Indolin-3-ones via Cyclization/Acetoxylation Mediated by PIDA/TBAI.

Scheme 14. Synthesis of Carbazoles with Hypervalent Iodine(III) Oxidative System.

Azoles Azoles are an important class of heterocycles because of their biological activities and various therapeutic applications. Their constructions are diverse, and the

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strategies include intramolecular oxidative cyclization through C-C, C-N, C-O, CS, N-O bond formation [50 - 54]. In 1996, Kotali and co-workers developed an approach to construct aminoindazole derivatives 37 from the o-aminoaryl ketone acylhydrazones 36 via PIDA-mediated N-N bond formation (Scheme 15) [55].

Scheme 15. PIDA-Mediated Synthesis of Aminoindazole Derivatives.

In 2006, Tellitu and Domínguez et al. reported the construction of indazolone derivatives 39 via PIFA-mediated N-N bond formation (Scheme 16) [56]. Upon the treatment of hypervalent iodine(III) reagent, N-arylamides 38 was oxidized to the corresponding N-acylnitrenium ions Int-A, which could be intramolecularly trapped by an amine moiety to furnish the final product by the formation of a new N-N single bond.

Scheme 16. PIFA-Mediated Synthesis of Indazolones.

Scheme 17. PIFA-Mediated Synthesis of 1H-indazoles via C-N bond formation.

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In 2016, the synthesis of 1H-indazoles 41 via PIFA-mediated oxidative C-N bond formation from easily accessible arylhydrazones 40 was developed (Scheme 17) [57]. In 2001, Moriarty and co-workers prepared 2-benzimidazolones 43a and 2benzoxazolones 43b by treating anthranilamides 42a or salicylamides 42b, respectively, with PIDA in the presence of potassium hydroxide (Scheme 18) [58]. The postulated mechanistic pathway suggested that substrates 42 bearing nucleophilic substituents XH at their β-position undergo Hofmann-type rearrangement to generate in situ isocyanate Int-A/B, which could undergo a sequential intramolecular nucleophilic attack by the XH group to afford the cyclized products.

Scheme 18. PIDA/KOH-Mediated Synthesis of 2-Benzimidazolones and 2-Benzoxazolones.

Benzimidazoles 45 could be prepared from amidine derivatives 44 through intramolecular oxidative C(sp2)-N bond formation mediated by various hypervalent iodine(III) reagents (Scheme 19), including PIDA [59 - 61], PIFA [62] and HTIB [63]. The transformation could also be realized via an organocatalytic systems, involving iodobenzene as a catalyst and mCPBA [64] or peroxyacetic acid [65] as terminal oxidant.

Scheme 19. I(III)-Mediated Intramolecular Oxidative C(sp2)-N Bond Formation of Amidine.

In addition to the benzimidazole products, pyrido[1,2-a]benzimidazoles 47 could also be obtained from N-aryl-2-aminopyridines 46 by adopting the same oxidative C(sp2)-N bond formation strategy (Scheme 20) [66].

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Scheme 20. Synthesis of Pyrido[1,2-a]benzimidazoles via I(III)-Mediated Oxidative C(sp2)-N Bond Formation.

In 2013, Zhu and co-workers developed an efficient method for the synthesis of pyrido[1,2-a]benzimidazoles 47 starting from readily available N-benzyl2-aminopyridines 48 in the absence of metal catalysts and additives (Scheme 21) [67]. The reaction was initiated by an PhI(OPiv)2-mediated ipso SEAr process followed by a solvent-assisted C-C bond cleavage. Sequential annulation was promoted by a second equivalent of PhI(OPiv)2 and the methylene group was oxidatively cleaved as an acetal.

Scheme 21. Synthesis of Pyrido[1,2-a]benzimidazoles via I(III)-Mediated Oxidative Rearrangement.

In 2014, Chiba and co-workers realized the intramolecular cyclization of Nallylamidines 49 and simultaneously diastereoselective anti-aminooxygenation or anti-diamination of alkenes with amidines by using hypervalent iodine(III) reagents such as PhI(OCOR)2 and PhI(NMs2)2, respectively (Scheme 22, a) [68]. Later, the anti-selective aminofluorination of alkenes with amidines with the same strategy was realized by the same group (Scheme 22, b) [69].

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Scheme 22. I(III)-Mediated Intramolecular Cyclization and Functionalization of Alkenes with Amidine in One Pot.

In 2006, Prakash et al. [70] reported the oxidation of 2-pyridyl and 2quinylhydrazones 52 with PIDA yielding the corresponding cyclized products 53, a special class of heterocycles with active antibacterial activities [71 - 75].

Scheme 23. Synthesis of 1,2,4-Triazoles via PIDA-mediated Intramolecular Oxidative Cyclization.

In 2012, Kumar and co-workers described a solvent-free method for oxidative cyclization of 2-pyridyl- and 2-quinolyl-hydrazones with PIFA and PIDA to the corresponding 3-aryl [1, 2, 4]triazolo[4,3-a]pyridines and 1-aryl [1, 2, 4]triazolo[4,3-a]quinolones [76]. And then, the same group also reported a hypervalent iodine(III)-mediated oxidative cyclization of arenecarbaldehyde-1,3Benzothiazol-2-yl hydrazones to construct 3-aryl-1,2,4-triazolo[3,4-b]-1,3benzothiazoles [77]. In 2014, Demmer and co-workers developed a one-pot, two-step reaction for the synthesis of benzo [4, 5]thiazolo[2,3-c] [1, 2, 4]triazoles 55, which featured an oxidative cyclization employing PIDA under mild conditions (Scheme 24) [78]. Firstly, the most nucleophilic lone pair on the double-bonded nitrogen of the hydrazine attacked PhI(OAc)2 to afford intermediate Int-A. The favorable orbital overlap of the aromatic lone pair of the nitrogen and the sp2-hybridized carbon of the hydrazone allowed for ring formation. Deprotonation by the acetate anion gave intermediate Int-C. Elimination with the release of PhI and acetate anion was aided by the nitrogen lone pair from the thiazole ring and subsequent rearomatization of Int-D by abstraction of a proton, leading to the desired benzo [4, 5]thiazolo[2,3- c] [1, 2, 4]triazoles 55.

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Scheme 24. PIDA-Mediated Synthesis of Benzo [4, 5]thiazolo[2,3-c] [1, 2, 4]triazoles

In 2012, it was reported that substrates N-(4-alkoxy-phenyl) and N-(4-acetamio-phenyl) benzamides 56 were converted to the benzoxazole products 56 via intramolecular oxidative C-O bond formation by using PIFA as oxidant and TMSOTf as catalyst (Scheme 25) [79].

Scheme 25. PIFA/TMSOTf-Mediated Synthesis of Benzoxazole Derivatives.

A similar strategy was applied to the synthesis of oxazoles 59 through a PIDAmediated intramolecular oxidative cyclization of enamide substrates 58 (Scheme 26) [80, 81]. It is worth noting that the previously discussed such transformations were realized by using transition metals [82, 83].

Scheme 26. Synthesis of Oxazoles from Enamides.

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As shown in Scheme 27, Fan and co-workers reported an intramolecular oxidative cyclization of benzoyl amides 60 to afford oxazolines 61via C(sp3)-O bond formation by using PhIO and a catalytic amount of tetrabutylammonium iodide (TBAI) [84].

Scheme 27. PhIO/TBAI-Mediated Synthesis of Oxazolines via Intramolecular Oxidative Cyclization of Benzoyl Amides.

In 1997, Varma et al. [85] reported the conversion of phenolic Schiff’s bases 62 into 2-arylbenzoxazoles 63 through PIDA-mediated direct C-O bond formation. This strategy has been applied to the synthesis of new pyrazolylbenzoxazoles and 2-aminooxazoles [86, 87].

Scheme 28. PIDA-Mediated Synthesis of 2-Arylbenzoxazoles via C-O Bond Formation.

In 2010, Saito and Hanzawa et al. reported PIDA-mediated oxidative cycloisomerization of propargylamide derivatives 64 in AcOH or AcOH-HFIP, affording the corresponding 2,5-disubstituted oxazoles 65 (Scheme 29) [88]. The cyclization of substrate 64 was initiated through the activation of the triple bond by PIDA. Proton transfer of Int-B followed by isomerization of Int-C afforded

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Int-D, during which the substitution of phenyliodonium group was displaced by AcOH. An alternative mechanism was proposed to involve the incorporation of acetoxy groups into the ketones via the alkynyliodonium intermediate like Int-E.

Scheme 29. PIDA-Mediated Synthesis of 2,5-Disubstituted Oxazoles.

In 2016, the synthesis of oxazolines and oxazines 67 was achieved via an intramolecular cyclization of N-allylamides, resulting from nucleophilic attack of the allylamine on the benzoxazin-4-one 66 (Scheme 30) [89]. The acylation of the original double bond could also be realized in one pot.

Scheme 30. PIDA-Mediated Synthesis of Oxazines via Intramolecular Cyclization to Synthesize Oxazolines and Oxazines

Oxidation of o-aminochalcones 68 using PIDA-KOH/MeOH was reported by Prakash and Varma et al. The reaction led to a facile synthesis of 3-(β-styryl)-21-benzisoxazoles 69 through oxidative N-O bond formation (Scheme 31) [90].

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Scheme 31. Synthesis of 3-(β-Styryl)-2,1-benzisoxazoles via Oxidation of o-Aminochalcones with PIDAKOH/MeOH.

The hypervalent iodine(III)-mediated intramolecular nitrile oxide cycloaddition (INOC) represents a convenient approach to fused heterocyclic ring system. In particular, Yao and co-workers applied the INOC reaction of 2allyloxybenzaldoximes 70 using Koser’s reagent in water to afford the corresponding tricyclic isoxazoline derivatives 71, which are potentially important pharmaceutical products (Scheme 32) [91]. Treatment of substrates 70 with hypervalent iodine(III) reagents could afford intermediate A, which was converted to the nitrile oxide B. An intramolecular [3+2] cycloaddition of nitrile oxide and the double bond afforded the isoxazoline derivative. This strategy could also be applied to synthesize certain complicated structures [92 - 94].

Scheme 32. I(III)-Mediated INOC Reaction to Tricyclic Isoxazoline.

In the presence of PhIO and I2, N- or O-centered radicals could be generated, respectively, from amides or alcohols [95 - 97]. In 2000, Suarez and co-workers reported the synthesis of homochiral 7-oxa-2-azabicyclo[2.2.1]heptane ring system 73 from specifically protected phosphoramidate derivatives of carbohydrates 72 under the conditions mentioned above. Mechanistic studies

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demonstrated a reaction path involving a hemolytic fragmentation of a hypothetical iodoamide intermediate B (Scheme 33) [97].

Scheme 33. PhIO/I2-Mediated Synthesis of Homochiral 7-Oxa-2-azabicyclo[2.2.1]heptane Ring System.

Scheme 34. Synthesis of Benzoxazoles via PIDA-Mediated C-O Bond Formation to Synthesize the Benzoxazole Derivatives.

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An interesting example of synthesis of benzoxazole amides was reported in 2016. The transformation follows a PIDA-mediated C-O bond formation leading to the benzoxazole derivatives 75 from substrate 74via sequential acylation and deacylation processes (Scheme 34) [98]. Due to oxidative dehydrogenation by PIDA, the expected C-S bond formation was replaced by C-O bond formation. In 2008, PIFA-mediated intramolecular cyclization of the thiobenzamides 76 resulting in the benzothiazoles 77via reactive intermediates of aryl radical cations was described (Scheme 35) [99]. From simple starting materials such as 78, 3substituted-5-arylamino-1,2,4-thiadiazoles 79 could be afforded through intramolecular oxidative S−N bond formations of imidoyl thioureas by PIFA (Scheme 36) [100].

Scheme 35. PIFA-Mediated Synthesis of Benzothiazoles.

Scheme 36. PIFA-Mediated Synthesis of 1,2,4-Thiadiazoles.

In 1993, Yang and Dai [101] reported an oxidation reaction of ketones (Nacylhydrazones) or aldehydes (N-acylhydrazones) 80 by PIDA in alcohol, affording 1,3,4-oxadiazolines 81 or 1,3,4-oxadiazoles 82, respectively, in excellent yields (Scheme 37). Symmetrical and unsymmetrical aldazines could also be efficiently converted to 2,5-disubstituted-1,3,4-oxadiazoles by oxidation with PIFA. N-Acylhydrazone was presumably generated as an intermediate which further reacted with PIFA to afford the cyclized product [102].

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Scheme 37. Synthesis of 1,3,4-Oxadiazolines and 1,3,4-Oxadiazoles via PIDA-Mediated Oxidation Reaction

Six-membered Ring N-Containing six-membered heterocycles are a class of the most important heterocycles due to their biological activities and potential as medicinal molecules. This class of molecules could be classified by the number of N atoms: pyridine, pyrimidine, paradiazine and fused ring compounds, such as (iso) quinoline and quinazoline and so on. In 1990, Kikugawa and co-workers reported an intramolecular oxidative C(sp2)-N bond formation in substrates 83, which contained a methoxyamide side chain on the aromatic ring, yielding the N-aryl-N-methoxyamides 84 (Scheme 38) via a nitrenium ion intermediate A [103]. This oxidative amidation protocol was later applied in many explorations of novel means to construct heterocyclic frameworks [104 - 107]. Experimental evidences support the ionic mechanism for this class of reactions, which proposes to involve the formation of the Nacylnitrenium intermediate from the reaction of the amide with hypervalent iodine(III) reagent [108].

Scheme 38. PIFA-Mediated Synthesis of N-Aryl-N-methoxyamides via An Intramolecular Oxidative C-N Bond Formation.

In 2017, a PhI-catalyzed synthesis of phenanthridinones 86/86’ from Nmethoxybenzamides 85 under mild conditions was developed (Scheme 39) [109]. Two mechanistic pathways were proposed.

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Except for the carboxamide substrates, this strategy could also be applied to the synthesis of sulfonylamides as shown in Scheme 40 [110, 111]. The ion-supported PhI-catalyzed cyclization of N-methoxy-2-arylethanesulfonamides 87 with mCPBA was carried out to form the corresponding N-methoxy-3,4-dihydro2,1-benzothiazine-2,2-dioxides 88 in moderate to good yields in 2,2,2trifluoroethanol.

Scheme 39. PhI/m-CPBA-Catalyzed Synthesis of Phenanthridinones from N-Methoxybenzamides.

In 2016, Muñiz and co-workers developed a convenient process to synthesize the same heterocyclic skeleton of N-methoxy-3,4-dihydro-2,1-benzothiazie-2,2-dioxides 89. The protocol consisted of iodine as catalyst, hypervalent iodine(III) as oxidant and exposure to visible light (Scheme 40) [112].

Scheme 40. I(III)-Mediated Synthesis of 3,4-Dihydro-2,1-benzothiazine-2,2-dioxides via Cyclization of NMethoxy-2-arylethanesulfonamides.

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The construction of spirocyclopropane quinolinediones 91 was realized through PIFA-mediated oxidative intramolecular cyclization of 2,2-disubstituted 2benzoylacetamides 90. The reaction pathway also involved the generation of Nacylnitrenium ion Int-A, which could be trapped with the aryl moiety (Scheme 41) [113].

Scheme 41. PIFA-Mediated Oxidative Intramolecular Cyclization to Construct the quinoline-2,4-dione Skeleton.

In 1996, Kita and co-workers reported a PIFA-induced intramolecular oxidative cyclization of substituted phenol ethers 92 bearing an alkyl azido side chain to afford quinone imine ketals 93 (Scheme 42) [114, 116]. Later, they applied a similar strategy to complete the synthesis of 7-methoxy-3,4-dihydropyrrolo[4,3,2-d,e] quinolin-8(1H)-one [115].

Scheme 42. PIFA-Induced Synthesis of Quinone Imine Ketals via Intramolecular Oxidative Cyclization of Substituted Phenol Ethers 92 Bearing An Alkyl Azido Side Chain.

In 2011, Lee and co-workers developed a synthesis of an oxazaspiroketalcontaining bissteroidal pyrazine 95 under the PIDA/I2 system (Scheme 43) [117]. The key transformations of this synthesis involved the stereoselective formation

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of oxazaspiroketal via aminyl-radical cyclization of a primary amine lacking a radical-stabilizing group via Suarez hypoiodite oxidation.

Scheme 43. PIDA/I2 System for Synthesis of Oxazaspiroketal-containing Bissteroidal Pyrazine.

I(III)-Mediated oxidative C(sp2)-C(sp2) bond formation was widely applied to the conversion of various biaryl substrates tethered by a relatively labile linker attached to the heterocycles [118, 119]. For example, Domínguez and co-workers described an efficient synthesis of benzo[c]phenanthridine 98 and phenanthridinone 99 from properly substituted benzylnaphthylamine 96 and naphthylbenzamide 97, respectively, through a PIFA-mediated intramolecular oxidative C-C bond formation between the two electron-rich phenyl rings (Scheme 44) [119].

Scheme 44. PIFA-Mediated Synthesis of Benzo[c]phenanthridine and Phenanthridinone.

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In 2013, Zhao & Du reported the syntheses of a variety of 3-arylquinolin-2-ones 101 from the N-methyl-N-phenylcinnamamides 100. The reactions involved an exclusive 1,2-aryl migration along with a metal-free oxidative C-C bond formation, mediated by PIFA in the presence of a Lewis acid (Scheme 45) [120]. Later on, on the basis of both the experimental results and density functional theory calculation, a revised mechanism involving an oxidative annulation, followed by an aryl migration, was reported (Scheme 46) [121]. The annulation of intermediate A is the regioselectivity determining step. Another metal-free synthesis of 3-arylquinolin-2-ones 104 from N,2-diarylacrylamides 105via phenyliodine(III) bis(2,2-dimethylpropanoate)-mediated direct oxidative C(sp2)C(sp2) bond formation was realized by the same group in 2016 (Scheme 47) [122].

Scheme 45. PIFA-Mediated Synthesis of 3-Arylquinolin-2-ones from N-Methyl-N-phenylcinnamamides through Oxidative C(sp2)-C(sp2) Bond Formation/1,2-Aryl migration.

Scheme 46. The Revised Mechanism for Explaining the Regioselectivity.

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Scheme 47. PhI(OCOtBu)2-direct Synthesis of 3-Arylquinolin-2-ones Through Oxidative C(sp2)-C(sp2) Bond Formation.

Construction and functionalization of bicyclic derivative 107 could be simultaneously realized by using a hypervalent iodine(III) reagent, PhI(OAc)NTs2, as oxidant from substrate N-benzoyl 2-acetylenyl aniline 106 (Scheme 48) [123].

Scheme 48. I(III)-Mediated Synthesis of 2-Phenyl-4H-benzo[d] [1, 3]oxazin-4-ylidene via Construction and Functionalization of Bicyclic Derivative.

Recently, electronic halocyclization and radical haloazidation of benzene-linked 1,7-dienes 108 for the synthesis of functionalized 3,1-benzoxazines 109 were reported (Scheme 49) [124]. The proposed mechanism suggested NBS acted as a halogen source and the combination of PIDA and TMSN3 gave the azido radical. In 2006, Aggarwal et al. reported a mild but efficient synthetic protocol for the construction of 2,3-diphenylquinoxaline-1-oxide skeleton 111 from benzilarylimino oximes 110 utilizing PIDA as an oxidizing agent. The reaction featured an oxidative C(sp2)-N bond formation between aryl with an oxime moiety in the side chain (Scheme 50) [125]. Recently, a series of new phosphorus heterocyclic compounds 113 were obtained through a PhI(OAc)2/I2-mediated tandem intramolecular oxidative C-H amination and iodization of phosphinamides 112 (Scheme 51) [126].

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Scheme 49. PIDA/TMSN3 System for Halocyclization and Haloazidation of 108.

Scheme 50. PIDA-Mediated Synthesis of 2,3-Diphenylquinoxaline-1-oxide.

Scheme 51. PIDA/I2-Mediated Synthesis of phosphorus heterocyclic compounds via Metal-free Tandem Intramolecular Oxidative C-H Amination and Iodization of Phosphinamides.

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Seven-membered Ring The indenocarboxamides 113 could be converted to the fused indeno-1,-diazepinones 114 through intramolecular oxidative C-N bond formations mediated by PIFA (Scheme 52) [106]. The key N-acylnitrenium species of Int-B type, stabilized by the electron-donating alkoxy group, were generated during the reaction of N-alkoxyamides with hypervalent iodine(III) reagent, and trapped intramolecularly by an aromatic group. Moreover, various PIFA-promoted intramolecular amidation reactions have been developed for the formation five-, six- and seven-membered heterocycles [127, 128].

Mechanism:

Scheme 52. PIFA-Mediated Synthesis of the Fused Indeno-1,4-diazepinones.

With similar strategies, 1,4-benzodiazepine skeleton 116 involving the biologically important compounds were conveniently constructed from 2(arylamino)benzamides 115 through PIDA-mediated oxidative C−N bond formation under mild reaction conditions (Scheme 53) [129].

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Scheme 53. PIDA-Mediated Synthesis of 1,4-Benzodiazepine via Oxidative C-N Bond Formation to Construct 1,4-Benzodiazepine Skeleton.

In 2014, Zhao & Du described a PIDA-mediated oxidative coupling of the two aryl groups in either 2-acylamino-N-phenylbenzamides or 2-hydroxy-Nphenylbenzamides 117 to afford the dibenzodihydro-1,3-diazepin-2-ones and dibenzo[d,f] [1, 3]oxazepin-6(7H)-ones 118, respectively (Scheme 54). The reaction sequence was postulated to involve an oxidative C(sp2)-C(sp2) aryl-aryl bond formation, C(sp2)-C/O bond cleavage and an intramolecular lactamization/lactonization. The unique feature of this conversion is the concomitant insertion of the ortho-substituted N or O atom into the tether [130].

Scheme 54. I(III)-Mediated Formation of Dibenzodihydro-1,3-diazepin-2-ones and Dibenzo[d,f] [1, 3]oxazepin-6(7H)-ones.

Spiro- and Fused- Heterocycles Since spiro-and bis-heterocycles are widely distributed in a large number of natural products, bioactive pharmaceuticals, and electronic materials [131 - 135], preparative routes to these compounds is of high importance.

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Oxidative dearomatization is one of the most important applications of hypervalent iodine(III) reagents. This strategy could be applied to the synthesis of a diverse variety of spiropyrroles and spiroindoles. In 2002, Ciufolini and coworkers realized oxidative spirocyclization of phenolic sulfonamides 119 to prepare the spiropyrroles 120 (Scheme 55) [136]. Later, Kikugawa and coworkers completed the synthesis of spirodienones 122 from N-methoxy-4-halogenophenyl)amides 121 with HTIB in trifluoroethanol (Scheme 56) [137].

Scheme 55. Synthesis of Spiropyrroles via Spirocyclization of Phenolic Sulfonamides.

Scheme 56. PIDA-Mediated Synthesis of Spirodienones from N-Methoxy-(4-halogenophenyl)amides.

Scheme 57. Synthesis of 1,2-Dispirodienones via PIDA-Mediated Phenolic Oxidation to 1,2Dispirodienones.

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Scheme 58. Iodocyclization of N-Arylpropynamides Mediated by Hypervalent Iodine.

Scheme 59. PIDA/TBAI-Mediated Tandem C-O/C-N Bonds Formation for Construction of Spiroheterocycles.

In 2013, Chabaud and Guillou reported a synthesis of 1,2-dispirodienones by hypervalent iodine-mediated phenolic oxidation of p-hydroxy acetanilides 123 [138]. A possible mechanism is depicted in Scheme 57. Intermediate A was proposed to evolve through two different pathways depending on the substitutions on the aromatic ring. For R1 = OMe, a 6-exo cyclization led to spirodienone 124. However, with other substrates (R1 = H), nucleophilic attack of the electron rich aromatic ring proceeded through a 5-exo cyclization to afford compound 125. Recently, Du and co-workers found that PIFA could act both as an oxidant and an iodination reagent in the iodocyclization of N-arylpropynamides 126 (Scheme 58) [139]. It is worth noting that the transformations selectively afforded spiro [4,

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5]trienone skeleton 127 depending on the substitution on the aromatic ring. Particularly, when substrates bearing a para-fluorine on the aniline ring, the spiro compounds were formed via an exclusive defluorination process. In recent years, research on construction of spiroheterocycles via carbon-hydrogen bond oxidation has grown rapidly. In 2011, Fan et al. [140] constructed the oxaaza spirobicycles 129 from substrates 128via PIDA/TBAI-mendiated tandem CO/C-N bond formation (Scheme 59).

Mechanism:

Scheme 60. Metal-free Synthesis of Spirooxindoles via PIFA-mediated Cascade Oxidation.

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In 2012, Zhao & Du reported a PIFA-mediated oxidative spirocyclization of N1,N3-diphenylmalonamides 130 to construct spirooxindoles 131 (Scheme 60) [141]. These processes involved PIFA-mediated metal-free oxidative C(sp2)-C(sp3) bond formation, and an intramolecular ring-closure reaction that took place between the phenyl ring in the side chain, assisted by the adjacent amino group and along with the cleavage of the O-I bond. The loss of proton in intermediate F as the final step furnished the spirooxindole. Later on, Gong and co-workers established an asymmetric organocatalytic direct C-H/C-H oxidative coupling reaction of N1,N3-diphenylmalonamides 132 (Scheme 61, a) [142], by using chiral iodobenzenes 134 as catalysts to give structurally diverse spirooxindoles 133 with high enantioselectivity. Later, they reported an enantioselective dearomatizative spirocyclization of 1-hydroxy-N-aryl2-naphthamide derivatives 135 by chiral iodobenzene catalysis 137 to assembly an all-carbon stereogenic center (Scheme 61, b) [143]. Spirooxindole derivatives 136 are afforded in good yields and with high to excellent levels of enantioselectivity.

Scheme 61. Chiral Organoiodine Catalysis-mediated asymmetric spirocyclization.

Zhao & Du also developed a series of PIFA-mediated cascade annulation of internal alkyne, affording the spiro-heterocycles (Scheme 62) [144, 145]. In case a, the process realized not only two sequential C-N/C-O bond formations, but also the insertion of a carbonyl oxygen in one pot. This conversion was initiated with

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Scheme 62. PIFA-Mediated Synthesis of Spiro-heterocycles via Cascade Annulation.

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Mechanistic Pathway for the Formation of the product 2p

Scheme 63. Asymmetric Synthesis of Spirofurooxindoles via Chiral Organoiodine Catalysis-mediated Asymmetric Spirocyclization.

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the reaction between 138 and PIFA, giving the cationic intermediate B after an intramolecular C-O bond formation. The combination of trifluoroacetate and positive-charged carbon center in B furnished the key intermediate C, the tosylamide moiety of which was oxidized to provide intermediate D. Intramolecular indolization, followed by ring-opening in the iminium G, afforded the iminium H, which underwent annulation to give the spirocyclic compound 139. A possible alternative pathway b involved the activation of the triple bond in 138 and the activation of the double bond in intermediate K by PIFA, respectively. Recently, a chiral aryliodine-mediated cascade process of C−O and C−C bond formations to construct diverse spirofurooxindoles 143 from alkyl 3oxopentanedioate monoamide derivatives 142 with high enantioselectivity was reported (Scheme 63) [146]. Firstly, substrate 1p reacted with the in situ iodine(III) reagent to give a C−I(Ph) bond intermediate B, which was subjected to enolation to form intermediate A through intramolecular C−O bond formation. Further oxidation of intermediate A led to the enantioselectivity-determining step of oxidative C−C bond formation, which afforded optically active product 2p. The product (R)-2p was formed in a more favored way owning to the aniline moiety in C facing away from the bulky substituent which consequently making the Si face of the 2-furanone moiety open to nucleophilic attack by the benzene ring. In 1991, Kita and coauthors reported a PIFA-mediated intramolecular ipso-trapping of phenol substrates 144 by the amide group in the side chain, leading to the corresponding spiro compounds 145 or bicyclic products 146 (Scheme 64) [147]. The cyclization product 146 could be obtained from the sequence of PIFA-mediated dearomatization and an intramolecular Michael-type addition of the amino group to the double bond of the dienone C. Such bicyclic products have been applied by Pitsinos et al. to the construction of the core structure in synthesis of scyphostatin [148]. In 2005, Feldman and co-workers reported sulfide substrate 147 to undergo a cascade oxidative cyclization to deliver the tetracyclic product 148 upon treatment of PhI(CN)OTf with N,N-diisopropylethylamine (DIPEA) (Scheme 65) [149]. This strategy has been successfully applied by Chen et al. to the total synthesis of dibromophakellstatin [150] and palau’amine [151]. In 2014, Chang and co-workers realized a cascade intramolecular oxidative diamination of olefins 149 by using PIDA as oxidant and a halide as additive, leading to the synthesis of a variety of bisindolines 150 (Scheme 66) [152].

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Scheme 64. PIFA-mediated Intramolecular of 144 to Prepare Spiro Compounds 145 or Bicyclic Products 146.

Scheme 65. PhI(CN)OTf-Mediated Synthesis of Tetracycle 148.

CONCLUSION AND FUTURE PERSPECTIVE The past several decades have seen much development and wide applications of hypervalent iodine(III) reagents in the syntheses of various heterocyles, for their low toxicity, oxidizing power, high chemoselectivity, while offering a transitionmetal-free process under mild reaction conditions. These heterocyclic compounds are important precursors of promising medicinal molecules. More and more known and novel heterocyclic compounds are foreseen to be synthesized through such hypervalent iodine-mediated intramolecular oxidative cyclizations.

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Mechanism

Scheme 66. PIDA-Mediated Synthesis of Bisindolines via Cascade Intramolecular Oxidative Deamination.

CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The author (editor) declares no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT We acknowledge the National Basic Research Project (#2014CB932201), National Natural Science Foundation of China (#21472136), Tianjin Research Program of Application Foundation and Advanced Technology (#15JCZDJC32900) for financial support. REFERENCES [1]

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[101] Yang, R-Y.; Dai, L-X. Hypervalent iodine oxidation of N-acylhydrazones and Nphenylsemicarbazone: an efficient method for the synthesis of derivatives of 1,3,4-oxadiazoles and DELTA.3-1,3,4-oxadiazolines. J. Org. Chem., 1993, 58, 3381-3383. [http://dx.doi.org/10.1021/jo00064a027] [102] Shang, Z.; Reiner, J.; Chang, J.; Zhao, K. Oxidative cyclization of aldazines with bis(trifluoroacetoxy)iodobenzene. Tetrahedron Lett., 2005, 46, 2701-2704. [http://dx.doi.org/10.1016/j.tetlet.2005.02.067] [103] Kikugawa, Y. Kawase, M. An Electrophilic Aromatic Substitution by N-Methoxyamides via Hypervalent Iodine Intermediates. Chem. Lett., 1990, 4, 581-582. [http://dx.doi.org/10.1246/cl.1990.581] [104] Herrero, M.T.; Tellitu, I.; Hernández, S.; Domínguez, E.; Moreno, I.; SanMartín, R. Novel applications of the hypervalent iodine chemistry. Synthesis of thiazolo-fused quinolinones. ARKIVOC, 2002, v, 31-37. [105] Romero, A.G.; Darlington, W.H.; Jacobsen, E.J.; Mickelsonl, J.W. Oxidative cyclization of acyclic ureas with bis(trifluoroacetoxy)iodobenzene to generate N-substituted 2-benzimidazolinones. Tetrahedron Lett., 1996, 37, 2361-2364. [http://dx.doi.org/10.1016/0040-4039(96)00291-2] [106] Herrero, M.T.; Tellitu, I.; Domínguez, E.; Moreno, I.; SanMartin, R. A novel and efficient iodine(III)mediated access to 1,4-benzodiazepin-2-ones. Tetrahedron Lett., 2002, 43, 8273-8275. [http://dx.doi.org/10.1016/S0040-4039(02)02019-1] [107] Correa, A.; Tellitu, I.; Domínguez, E.; Moreno, I.; Sanmartin, R. An efficient, PIFA mediated approach to benzo-, naphtho-, and heterocycle-fused pyrrolo[2,1-c][1,4]diazepines. An advantageous access to the antitumor antibiotic DC-81. J. Org. Chem., 2005, 70(6), 2256-2264. [http://dx.doi.org/10.1021/jo047872u] [PMID: 15760213] [108] Tellitu, I.; Urrejola, A.; Serna, S.; Moreno, I.; Herrero, M.T.; Domínguez, E.; SanMartín, R.; Correa, A. On the Phenyliodine(III)-Bis(trifluoroacetate)-Mediated Olefin Amidohydroxylation Reaction. Eur. J. Org. Chem., 2007, 3, 437-444. [http://dx.doi.org/10.1002/ejoc.200600782] [109] Liang, D.; Yu, W.; Nguyen, N.; Deschamps, J.R.; Imler, G.H.; Li, Y.; MacKerell, A.D., Jr; Jiang, C.; Xue, F. Iodobenzene-Catalyzed Synthesis of Phenanthridinones via Oxidative C-H Amidation. J. Org. Chem., 2017, 82(7), 3589-3596. [http://dx.doi.org/10.1021/acs.joc.7b00106] [PMID: 28245353] [110] Moroda, A.; Togo, H. Iodobenzene-Catalyzed Preparation of 3,4-Dihydro-1H-2,1-benzothiazine 2,2Dioxides from 2-Aryl-N-methoxyethanesulfonamides with m-Chloroperoxybenzoic Acid. Synthesis, 2008, 8, 1257-1261. [111] Ishiwata, Y.; Togo, H. Ion-supported PhI-catalyzed cyclization of N-methoxy-2-arylethanesulfonamides with mCPBA. Tetrahedron Lett., 2009, 50, 5354-5357. [http://dx.doi.org/10.1016/j.tetlet.2009.07.034] [112] Martínez, C.; Bosnidou, A.E.; Allmendinger, S.; Muñiz, K. Towards Uniform Iodine Catalysis: Intramolecular C-H Amination of Arenes under Visible Light. Chemistry, 2016, 22(29), 9929-9932. [http://dx.doi.org/10.1002/chem.201602138] [PMID: 27159628] [113] Zhang, Z.; Gao, X.; Li, Z.; Zhang, G.; Ma, N.; Liu, Q.; Liu, T. [Bis-(trifluoroacetoxy)iodo]benzenemediated Oxidative Intramolecular Cyclization of 1-Aroyl-N-arylcyclopropane-1-carboxamides and its Application to the Synthesize of Pyrrolo[3,2-c]quinolinones. Org. Chem. Front., 2017, 4, 1203-1207. [114] Kita, Y.; Egi, M.; Okajima, A.; Ohtsubo, M.; Takada, T.; Tohma, H. Hypervalent iodine(III) induced intramolecular cyclization of substituted phenol ethers bearing an alkyl azido sidechain-a novel synthesis of quinone imine ketals. Chem. Commun. (Camb.), 1996, 1491-1492. [http://dx.doi.org/10.1039/CC9960001491]

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CHAPTER 6

Advancements in Ionic Liquids for the Formation of Morita Baylis-Hillman Adducts Gitanjali Jindal1, Navneet Kaur1,* and Subodh Kumar2 1 2

Department of Chemistry, Panjab University, Chandigarh, Punjab, India Guru Nanak Dev University, Punjab, India Abstract: The reactions involving the carbon-carbon bond formation are the most significant and fundamental reactions in synthetic organic chemistry. Amongst such various types of reactions, Morita Baylis-Hillman (MBH) reaction has become one of the most constructive and popular routes for the production of functionalized molecules with vast utility and prospective. This reaction involves coupling of the activated alkenes with a variety of aldehydes under catalytic influence of tertiary bicyclic amines, phosphines or ionic liquids. The present significance of this reaction is credited to the fact that it leads to one-pot atom-economical construction of carbon-carbon bonds providing multifunctional molecules. Recently, ionic liquids are most extensively used for the synthesis of adducts of this reaction. This review is presented by the purpose of summarizing the various advances in ionic liquids and their use in this reaction.

Keywords: Activated alkenes, Aldehydes, Atom-economy, Chirality, DABCO, DBU, DMAP, Green chemistry, Imidazole, Ionic liquids, Microwave irradiation, Morita-Baylis-Hillman reaction, Multifunctional, Phosphine, Quinuclidine, Recyclable, Solvent-free, Tertiary-amine, Triazole. INTRODUCTION Carbon-carbon bond formation is a significant component of the synthetic organic chemistry. The recent advances in organic chemistry focus on the point that the development of any reaction highly depends on atom-economy, selectivity and functionalization and this criteria has been and continues to stand for the front position of research in organic chemistry. Several examples of such reactions and their applications exist in the literature. These include the aldol reaction [1, 2], Clasien reaction [3], Reformatsky reaction [4], Diels-alder reaction [5] and so on. Besides atom-economy and selectivity, present scenario of synthesis in organic * Corresponding author Navneet Kaur: Department of Chemistry, Panjab University, Chandigarh 160014, India; Tel: +91 172 2534430; Fax: +91 172 2545074; E-mail: [email protected]; [email protected]

Atta-ur-Rahman (Ed.) All rights reserved-© 2018 Bentham Science Publishers

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chemistry demands environment-friendly procedures and use of green catalysts to prevent harm to nature. Ionic liquids (IL), which are liquid at and below room temperature, serve this purpose. Amongst these, the MBH reaction [6 - 9] using ionic liquids has become one of the most useful and popular reactions, which fulfil all the above criteria. Origin and Features of Morita Baylis-Hillman reaction This reaction originated in 1972 with a German patent filed by A. B. Baylis and M. E. D. Hillman. This reaction (Scheme 1) involves coupling of the activated alkenes with a variety of aldehydes catalyzed by tertiary bicyclic amines, phosphines or ionic liquids. XH

X R

+

tert-amine

EWG

R'

or phosphine

EWG

R R'

EWG = COOR'', CONEt2, CN, COR'', CHO, PO(OEt)2, SO2Ph, SO3Ph, SOPh, etc. R = Alkyl, aryl, heteroaryl, etc.; R' = H, CO2R'', alkyl, etc. X = O, NCO2R'', NSO2Ar, etc. N tert-amine = N DABCO

N Indolizine

N Quinuclidine

Scheme 1.

This reaction shows great potential, but has been largely ignored by the scientists for a long time. It was only near the year 1980 that researchers in organic chemistry paid attention at this reaction and started analyzing various aspects and applications of this reaction. The great potential of MBH reaction may be attributed to; ●

● ●

●

●

Its operational simplicity in the one-pot atom-economical construction of carbon–carbon bonds providing densely functionalized molecules; Its interesting mechanistic aspects; The challenges and opportunities it offers in developing its asymmetric and intramolecular versions [10] and also The enormous applications [11] due to the proximity of the three chemospecific functional groups, A number of organic transformation methodologies and stereoselective

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processes, often leading to the synthesis of very useful molecules of medicinal importance [12]. Present Status in Context to Ionic Liquids Despite having enormous applications in synthetic organic chemistry, sometimes it suffers from the slow reaction rate. A large number of methods have been applied to accelerate the MBH reaction. Among these, the use of ionic liquids has become most important as the rate enhancement of MBH reaction in any protic solvent or lewis acid catalyst is ascribed to the participation of hydrogen bonding. Ionic liquids [13,14] are non-molecular solvents with melting points below 100 ºC, what means they are liquids in a wide temperature range. In addition, ILs that possesses melting points below to room temperature are commonly referred to as room temperature ionic liquids (RTILs). They represent a new class of solvents with non-molecular, ionic character. The ordinary liquids such as water and gasoline are predominantly made of electrically neutral molecules, while ionic liquids are largely made of ions and short lived ion pairs. These substances are variously called liquid electrolytes, ionic melts, ionic fluids, fused salts, liquid salts or ionic glasses. These are either organic salts or mixtures consisting of at least one organic component. The ionic bond is usually stronger than the van der Waals forces between the molecules of ordinary liquids. They have various properties which make them “green solvents” to be used in synthetic organic chemistry. ●

● ●

●

●

ILs have low to negligible vapour pressure at room temperature, so they do not generate volatile organic compounds to the atmosphere; They have very low flammability and easily recyclable; They are good solvents for a wide range of both inorganic and organic materials, and unusual combinations of reagents can be brought into the same phase; They are immiscible with a number of organic solvents and provide a nonaqueous, polar alternative for two-phase system. Hydrophobic ionic liquids can also be used as immiscible polar phases with water; They have high thermal stability, excellent chemical, electrochemical properties and are able to be stored for a long time without decomposition.

Due to their low volatile nature and high thermal, chemical and electrochemical ability they are termed as “green solvents” [15]. In a view to observe the influence of ionic liquids on the rate of the MBH reaction between various activated alkenes and electrophiles, a variety of ionic liquids have been synthesized by several research groups and it was seen that the rate has very much increased in the presence of ionic liquids. A large number of research articles and reviews [6 - 9] have been published

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during last 15 years, which have described the features and applications of this reaction. This chapter gives an overview of MBH reaction and advances in the ionic liquids used as catalysts in this reaction. MBH Mechanism in the Presence of an IL The reaction mechanism (Scheme 2) is supposed to be through the Michaelinitiated addition-elimination process. Route I IL

IL

O

IL OMe

O

H

H

Ph

OMe Ph

IL

O H

OMe

Ph

COOMe

Ph

Me

H

O

OH

O

IL

+ major

OH

O

Route II IL

IL

IL

O

O

OMe

H

O

IL O

O

+ MeO

OMe O

OMe

OMe

OMe MeO

O

O

I L

minor HO

OMe

OMe

Ionic Liqid (IL) contains 3o amine or phosphine which acts as a Lewis base.

Scheme 2.

Trio Requirement of the Reaction This reaction has been significantly improved during past few years with respect to the three essential components (Fig. 1), that is, the activated alkenes, alkynes, or allenes, electrophiles and catalysts.

Fig. (1). Essential components of MBH reaction.

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Therefore, a number of activated alkenes like alkyl acrylates [16,17], acrylonitriles [18,19], acrylamides [20], alkyl vinyl ketones [21], acroleins [22], vinyl sulfonates [23], vinyl phosphonates [24], etc. have been employed for the formation of a variety of MBH adducts when reacted with various electrophiles. Also, the electrophiles such as aldehydes, which include aliphatic, aromatic, heteroaromatic analogues [2, 25, 26], and α-keto esters [27], fluoroketones [28, 29], etc., have also been extensively studied for this reaction. The third important component of the reaction is the catalyst and variety of catalytic systems are available to be employed in this reaction such as imidazole [30], DBU [31], DMAP [32], DABCO, quinuclidine and indolizine [33], etc. (Fig. 2). OH

=S

Ph SO =

O

2 Ph

OH

G

G

OH

EWG

CHO

+ EWG = CHO

EWG = COMe RCHO (Electrophiles) R

+ Catalyst Et )2 (O G

=

PO

Activated alkenes : EW

OH

PO(OEt)2

R

EW

EWG = CONH2

EWG

SOPh

R

EW

EW

OH EWG = CN

SO2Ph

R

R

CN

R

OH

G

=C

OO

Me

COMe

OH COOMe

R

OH CONH2

R O

Electrophiles :

H

R

O

O R

CF3

X3C

O COOR

R

O COOR

EtOOC

COOEt

R = H, Alkyl, Aryl, etc.; X = H, Halide, NO2, etc. .. N N

N

Catalysts : N DBU

OH

O

N N .. N N N N DABCO Indolizine Quinuclidine 3-Hydroxyquinuclidine 3-Quinuclidone DMAP

Fig. (2). Types of Activated Alkenes, Electrophiles and Catalysts and the possible reactions.

This chapter has been further subdivided into following sections; ● ●

Imidazolium-based Ionic Liquids Pyridinium-based Ionic liquids

N N H Imidazole

Formation of Morita Baylis-Hillman Adducts ● ● ● ● ●

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Chiral derivatives of Ionic Liquids Quinuclidine-based Ionic liquids DABCO-based Ionic Liquids Triazolium-based Ionic Liquids Other Ionic Liquids

Imidazolium-based Ionic liquids Aggarwal et al. [34] performed Baylis–Hillman reaction in presence of 1, 8Diazabicycloundec-7-ene (DBU) catalyst, which is normally regarded as a hindered and non-nucleophilic base. Presence of DBU provided MBH adducts at much faster rates than other amine catalysts. Here, DBU acted as a base rather than a nucleophile, with diene enolate as reaction intermediate in comparison to a β-enolate (Scheme 3). O OH

O

O NR3

Ph

O

O Ph R3N

H

O

O

O

O R3N (1) Rate determining step O Ph

Scheme 3.

With DBU, the intermediate β-ammonium enolate (1) was stabilized through conjugation which increased its equilibrium concentration, and resulted in significantly enhanced rates. Later, they conducted the Baylis–Hillman reaction in the presence of an imidazolium-based [35] ionic liquid and obtained low yields due to direct addition of the deprotonated imidazolium salt to the aldehyde (Scheme 4). The modified ionic liquid 2 has been further used to promote MBH reaction, but, some of the original unsubstituted ionic liquid also reacted to form MBH product, leading to formation of mixture of products, 3 and 4 in 1:1.4 ratios (Scheme 5).

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N

N H

+

+

R3N

N

N

OH

N

Ph

R3NHCl PhCHO

N

2 R3N =

OH

N N

N

Scheme 4. N+ O OMe +

N 2

(1 equiv.)

O (1.5 equiv.)

OMe

OH Ph

OH

OH

O

Ph

OMe

OH

+

OMe

MeO

3

N (0.5 equiv.)

O

4

(1 : 1.4)

Scheme 5.

Afonso et al. [36] have reported the ionic liquid 1-n-butyl-3-methylimidazolium hexafluorophosphate, [bmim][PF6] (5), which has ability to accelerate the MBH reaction between benzaldehyde and methyl acrylate in the presence of DABCO, affording the desired products in moderate yields (39-72%) (Scheme 6). However, with aliphatic aldehydes, low yields (14-20%) of MBH adducts were obtained. Various lewis acids like Me2O.BF3, Et2O.BF3, SnCl4, LiClO4, Zn(OTf)2, Cu(OTf)2, Sc(OTf)3, La(OTf)3, Yb(OTf)3etc. were also used as additives to improve reaction rate. Only LiClO4 increased the rate to some extent (1.6 times), but the yields were decreased. DABCO (1 equiv) 5

O

O + R

H

OR'

OH

O

R

N

OR'

r. t., 24 h

N+ (5)

PF6-

14-72% CH=CH MeO R = nPr, iPr,

,

Cl ,

Me ,

O ,

, OMe

MeO R' = Me, t-Bu

Scheme 6.

OMe

,

Formation of Morita Baylis-Hillman Adducts

Advances in Organic Synthesis, Vol. 8 231

Kitazume et al. [37] investigated the first example of Michael additions via the MBH-type reaction that used 3-fluoromethylprop-2-enamide as a chiral auxiliary electrophile towards activated olefins in the DABCO-ionic liquid system. The reaction of (4S)-3-[(E)-4, 4, 4-trifluorobut-2-enoyl]-4-isopropyl-2-oxazolidinone (6) with activated vinyl moiety proceeded smoothly at 80oC to give the corresponding adducts 7 in moderate yields, however, albeit with low diastereoselectivity (Scheme 7). O EWG +

O N

CF3

CF3

O

GWE

DABCO

O N

O Ionic Liquid

EWG = CN, CO2Me, COMe

O

7 23-46%

6

dr = 50:50 to 55:45

N

Ionic Liquid =

N

N

PF6

N

BF4 N

N

[bmim][PF6](5)

OTf

[bmim][BF4](8)

[emim][OTf](9)

Scheme 7.

Afterwards, Ko et al. [38] studied the MBH reaction of benzaldehyde with methyl acrylate in various bmim-based ionic liquids (10) and found that [bmim][PF6] (10f) was the best, resulting in the maximum rate augmentation. A modest acceleration in the reaction rates was observed, when the ionic liquid was used in combination with Lewis acid or H-bond donors. Rate was increased by two-fold in mixtures of 10f, La(OTf)3 and 2, 2’, 2”-nitrilotris(ethanol) compared to the same reaction in acetonitrile solvent (Scheme 8). O N

O PhCHO +

10, La(OTf)3 HO [X]-

N

N 10

Scheme 8.

OMe

N OMe

10a. X = OAc 10b. X = OTf 10c. X = NTf2

Ph 10d. X = BF4 10e. X = SbF6 10f. X = PF6

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In view of the fact that there were problems associated with the use of imidazolium-based ionic liquids arising from the acidity of C-2 imidazolium cation, Hsu et al. [39] developed a novel 2-position substituted ionic liquid, [bdmim][PF6] (11) for the MBH reaction. In contrast to the commonly used [bmim][PF6] (5), which can react with the aldehydes under basic conditions, ionic liquid 11 was inert and gave the MBH adducts in better yields (Scheme 9). OH

O

O + R

H

OMe

2 equiv DABCO

O PF6

OMe

R

N

5 or 11, r. t., 24 h using 5; 18-69 % using 11; 27-99 %

N (11)

CH=CH MeO

Cl R =Et, n-Bu, CH3CH=CHI,

,

,

,

,

Cl

, OMe

Scheme 9.

Although, substitution at the 2-position of the imidazolium cation was considered to prevent the side reaction in the MBH reaction, Handy and Okello found that even the 2-methyl substituted imidazolium cation was not completely inert [40]. They reported that the 2-methyl group underwent slow proton exchange even in the presence of a weak base such as triethylamine (Scheme 10).

N N

Cl-

ClEt3N D2O

N CD3 N

k = 0.04 x 103 min-1

Scheme 10.

The acidic nature of the methyl group was further confirmed by analyzing the products obtained from attempted methylation of the imidazolium salt, 12. When 12 was treated with excess NaH and CH3I, the expected product (13) was not detected, rather the product 14 was obtained (Scheme 11). Wilhelm et al. [41] found that imidazolium salts (15), incorporating a phenyl ring at C-2, were suitable ionic liquids as solvent for quinuclidine-catalyzed MBH

Formation of Morita Baylis-Hillman Adducts

Advances in Organic Synthesis, Vol. 8 233

reactions of aldehydes with acrylates, cyclohexenone or acrylamide, whereby moderate to good yields of adducts were obtained (Scheme 12). ClN Cl-

HO

MeO

N

6 equiv NaH

N

10 equiv MeI

N 13 Cl-

12 N MeO

N 14

Scheme 11. O

O

OH

R

O

1 equiv quinuclidine

+ X

H

R

15, 48 h

N

X

NTf2-

N Ph

(15)

X = OMe, 38-66%; X = NH2, 48-49% (for R = Ph, 4-ClPh); X = (CH2)3, 45% (for R = Ph)

MeO R= , CH2CH2

Cl ,

, N

Scheme 12.

Since MBH reactions have been carried out with common ionic liquids, such as [bmim][X], gave lower to moderate yields. So, more recently, Tsai et al. [42] synthesized 1, 3-bis [2-(naphthalene-2-yloxy)propyl] imidazolium bromide (16), which promoted this reaction in the absence of solvents to yield the reaction adducts’ in high yields and lesser reaction time (Scheme 13). O

O + R1 R1

H

R2

= aryl, heteroaryl

Scheme 13.

OH

DABCO 16, r. t.

R1

O N

R2

R2 = CO2Me, 0.5-71 h, 47-98% R2 = CN, 0.1-29 h, 58-99%

O

N -

Br (16)

O

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Porto et al. [43] studied the effect of different catalytic conditions like ultrasound (US) at 0 oC, Ultrasound with an imidazolic ionic liquid at 0 oC or the ionic liquid catalyst at 0o and 50 oC for the MBH reaction both experimentally and by chemometry. It was observed that the use of ionic liquid at 0 oC with US (only stirring) results in high yield of 95% in only 30 min. However, the use of ionic liquid and ultrasound at 0 oC decreased the yield as depicted from contour surface obtained after statistical analysis of the results. On the contrary, combination of ionic liquid and US at 50 oC increased the rate as well as yield (89%) of MBH reaction. The slight less yields obtained as compared to using IL at 0 oC could be attributed to increase in disorder in the IL supramolecular structure at 50 oC. Thus strong synergic interactions were observed between IL & US, IL & temperature and US & temperature, with more pronounced effects when IL was associated with temperature (Scheme 14). XH

X R1

+

EWG

R2

Lewis Base catalytic

R1

EWG R2

EWG = COOR'', CN, COR'', CHO, PO(OEt)2, SO2Ph R1 = Alkyl or aryl ; R2 = H X = O, NCO2R'', NTS, NSO2Ar, etc.

Scheme 14.

Goncalves et al. [44] established the fact that unlike DABCO, hexamethylenetetramine (HMTA, 17) in combination with bmim type ionic liquids for MBH reactions between aromatic aldehydes and acrylonitrile or methyl acrylate, afforded the corresponding adducts in good yields (50–85%) in short reaction times (Scheme 15). Also, the ionic liquids could be recycled three times without any loss of activity. Some other kinds of imidazolium-based ionic liquids have also been developed for the MBH reaction. Kumar et al. [45] found that ionic liquid chloroaluminates, consisting of AlCl3 and N-1-butylpyridinium chloride (18) or 1-ethyl-3-metyl-1H-imidazolium chloride (19), as solvent could accelerate DABCO-catalyzed MBH reactions that were lethargic in the presence of other ionic liquids. In addition, the combination of 19 with AlCl3 was more efficient chloroaluminate ionic liquid than the 18 with AlCl3, as it comparatively provided higher yields in shorter time (Scheme 16).

Formation of Morita Baylis-Hillman Adducts

O R

EWG

R

5

H

N

OH

17, 100%

EWG

+

Advances in Organic Synthesis, Vol. 8 235

N

N N

(17) R

EWG

Time (d)

Yield (%)

-CO2Me

72

1.5

-CO2Me

63

2

OMe

-CO2Me

53

4

NO2

-CN

85

1

NO2

Scheme 15.

Cl O + R

H

EWG

OH

DABCO chloroaluminates

R

EWG

N

N

Cl

(18)

N (19)

Scheme 16.

R

EWG

chloroaluminates

Time (h)

Yield (%)

Ph

CO2Me

------

19

65

Ph

CO2Me

18.AlCl3 (60%)

11

75

Ph

CO2Me

19.AlCl3 (60%)

8

80

Ph

CN

------

9

82

Ph

CN

18.AlCl3 (60%)

5

93

Ph

CN

19.AlCl3 (60%)

6

95

2-MeOPh

CO2But

------

48

17

2-MeOPh

CO2But

18.AlCl3 (60%)

8

39

2-MeOPh

CO2Bu

19.AlCl3 (60%)

7

39

t

Santos et al. [46] performed on-line monitoring of the BH reaction in the presence of imidazolium ionic liquids (20), using electron-spray ionization mass spectroscopy in both the positive and negative ion modes to verify the

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supramolecular species responsible for the co-catalytic role of ionic liquids in MBH reaction (Scheme 17). The MS analysis and MS/MS dissociation studies confirmed that several supramolecular species formed by coordination of reagents and products as well as protonated forms of zwitterionic Baylis-Hillman intermediates with cations and anions of ionic liquid were efficiently transferred directly from the solution to the gas phase.

O

O

N + OCH3

S

N N DABCO

N CO2CH3

S

H

Me N

N H

OH

BunX20

-

X = BF4-, PF6-, CF3CO2(7 mol%)

Scheme 17.

de Souza et al. [47] described a new experimental protocol of MBH reaction in the water/ionic liquid media under microwave irradiation (Scheme 18). Different proportions of ionic liquids, 10d and 10f, and water were tested as solvents for the reaction between several aromatic aldehydes and Michael acceptors under microwave irradiation. The results showed that small amounts of ionic liquid mixed in water decreased the reaction time, keeping good yields. Ar-CHO

+

EWG

OH

water + 10d / 10f MW, 2 eq. DABCO 35 minutes

EWG = CN, COOCH3, CO2C(CH3)3

Ar

EWG

40-80 % yield

Scheme 18.

Chandramouli et al. [48] used catalytic amount of urotropine with ionic liquids for the preparation of Baylis-Hillman adducts under microwave irradiation (Scheme 19). They reported the synthesis of heterocyclics like coumarin and pyran derivatives in the presence of urotropine as inexpensive new tertiary amine with ionic liquid 10d in this reaction. Zhang et al. [49] reported a detailed theoretical study of the reaction of imidazolium cation [bmim]+ with benzaldehyde in the absence of DABCO, to understand side reaction mechanism involved in the BH reactions. In absence of DABCO, the high value of energy barrier indicated the stability of [bmim]+ cation. However, in the presence of it, the C-2 atom of [bmim]+ was observed to

Formation of Morita Baylis-Hillman Adducts Cl

O

O

+

O R

R 10d, Urotropine/ MW, 300W O O

OH

10d, Urotropine/ 140oC H

OH

10d, Urotropine/ 140oC

O O

Ar

Cl

O H

Advances in Organic Synthesis, Vol. 8 237

+ 10d, Urotropine/ MW, 300W O

O O

Ar O

Scheme 19.

be easily deprotonated, that decreased the positive charge on that atom. This increased the nucleophilic ability of C-2 atom, by which the overall energy barrier for the base-catalysed reaction was reduced, which indicated the increasing reactivity of [bmim]+ towards benzaldehyde under mild basic conditions. Thus, it was inferred that the imidazolium-based ionic liquids were non-innocent solvents under mild basic conditions and could lead to side reactions. Neto et al. [50] used the charge tagged acrylate derivative bearing an imidazolium tag to study MBH reaction via ESI-MS (MS) monitoring and effect of such tag on formation of intermediate complexes was affirmed by DFT calculations. The detailed calculations considering both IL effects and solvent, as well as the presence of proton donor, have emphasized that the H-shift was the ratedetermining step for MBH reaction, which might have occurred via pathways proposed by Aggarwal and McQuade as intramolecular H-transfer was found to be unfeasible process. Pyridinium-based Ionic Liquids Gong et al. [51] independently presented the application of pyridinium-based ionic liquid as recyclable solvent for the DABCO-catalyzed MBH reaction. Compared with the other commonly used imidazolium-based ionic liquids, the pyridinium-based ionic liquid N-1-ethylpyridinium tetrafluoroborate [EtPy][BF4] (21) was inert and the MBH reactions of aldehydes with methyl acrylate, MVK or acrylonitrile proceeded quickly in good yield. Zhao et al. [52] also examined HMTA (17)-catalyzed MBH reactions by using the ionic liquid (20) or N-butylpyridinium nitrate [BuPy][NO3] (22) as a reaction media. This gave excellent yields in short reaction times (Scheme 20). Their work [53] also reported that the Baylis-Hillman reaction could be carried out rapidly and cleanly in N-butylpyridinium tetrafluoroborate ([BuPy][BF4]) (23).

238 Advances in Organic Synthesis, Vol. 8

Jindal et al. NO2

OH R=

EWG

R

Pr, Me,

Cl

Cl

O2 N ,

,

,

,

OH

EWG = CN, CO2Me (21) 5-20 h

OH

17 (1.0 equiv) 53-90%

EWG = CN

O H

R

using 21: 0.5-10 h, 62-93%; using 22: 3-12 h, 42-86%

DABCO (1.0 equiv) +

EWG

CN

R

21 or 22

r. t. OH

EWG = CO2Me R

21, 2-12 h

CO2Me 58-83%

O2N R = Pr, Me,

Cl

Cl

O2 N ,

,

,

,

,

NO2 Cl

,

O 2N

21

BF4

, MeOPh

OH OH

Cl

N

,

N

NO3

22

N

BF4

23

Scheme 20.

Other pyridinium based ionic liquids, 24 and 25, synthesized by Zhao et al. [54] by the ultrasound assisted reaction of pyridine with acid (HCl and HBF4) and 3chloropropylene oxide at room temperature. Here, the acid provided the corresponding anionic component of the ionic liquids without requiring subsequent metathesis steps. These ionic liquids are successfully used in MBH reaction (Scheme 21). Zhao et al. [55] developed an efficient and versatile solvent-catalyst system, 26-H2O-DABCO, for the MBH reaction, which proceeded smoothly and showed significant acceleration effect (Scheme 22). This high activity was attributed to presence of hydroxyl group in the ionic liquid, 26. It was found that 1:3 ratio of 26:H2O composite system was most effective for MBH reaction in the presence of 15 mmol of DABCO.

Formation of Morita Baylis-Hillman Adducts

+

HX +

Advances in Organic Synthesis, Vol. 8 239

O

HO X N

ultrasound Cl

100W, 40 Hz 1.5 h, 76-86%

N X = Cl, BF4 OH

Cl

24: X = Cl; 25: X = BF4

O EWG = CO2Me

CO2Me R

R

25, 8-24 h

OH EWG = CN H

CN

EWG

+

R

DABCO 24 or 25

34-70%

using 24: 6-28 h, trace-82% using 25: 6-36 h, 21-85% Cl R= Cl

,

,

,

,

NO2

OMe

CHO

Scheme 21.

O

+

R

EWG

H2O/26

OH EWG

DABCO, r. t. R

H

Cl N

OH

26

Scheme 22.

Chiral Derivatives of Ionic Liquids For the first time, Thanh et al. [56] discussed the asymmetric induction caused by a chiral ionic liquid 27 as the source of chirality in an asymmetric MBH reaction. The enantioselectivity values obtained in the DABCO-catalyzed MBH reactions of aldehydes and methyl acrylate was up to 44% ee (enantiomeric excess, the absolute difference between the mole fraction of each enantiomer) by using 27 with chiral cations derived from (–)-N-methylephedrine as reaction media (Scheme 23). Importantly, the presence of the hydroxyl function on chiral ionic liquid 27 was favourable for the transfer of chirality. O

O R

H

+

OH

DABCO, IL-27 OMe

30oC, 4-7 days

R

O N

OMe

OTf

HO MeOPh

R=

, N

Scheme 23.

,

NO2

,

Cl

,

50-95% conv.; 36-87% yield; up to 44% ee

C8H17

Ph 27

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Subsequently, Headly et al. [57] synthesized chiral ionic liquids (28) containing two chiral centres in the side chain bonded to the 2-position of the imidazolium cation and different anions and then used them as chiral solvents for asymmetric MBH reactions, by which good yields and fair enantioselectivities were obtained (Scheme 24). O

O R1

H

+

OH

DABCO OR2

O

R1

28, 4oC, 7 d

N

N OR2

X HN OH

Cl

PhOMe

,

,

R1 = i-Pr,

CH2CH2

O2N ,

Ph

28a. X = BF4 28b. X = NTf2

,

R2 = OMe, Ot-Bu, (CH2)3

Scheme 24.

The presence of the hydroxyl and NH groups played an important role in the transfer of chirality via hydrogen bonding with the aldehyde substrate in a manner that C-C bond formation took place by the zwitterionic intermediate addition to the less hindered Re face of the aldehyde (Fig. 3). N N O

MeO O

OMe

OH

Ph

DABCO

H

+

O

Ph

O OMe

H O Ph

H H

N

O

N Ph

N NTf2 n-Bu

Fig. (3). Proposed mechanism for MBH reaction using 28a as solvent.

Leitner et al. [58] reported the first example of highly enantioselective asymmetric synthesis in which only the reaction medium induced chirality. Using a specifically designed ionic liquid (29) with a chiral anion as the only source of

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Advances in Organic Synthesis, Vol. 8 241

chirality, up to 84% ee was obtained in the aza-MBH reaction of N-Ts arylaldimines with methyl vinyl ketone (Scheme 25), which was comparable with values obtained with the best catalysts for the asymmetric aza-MBH reaction in conventional solvents (94% ee [59], 83% ee [60, 61]).

N

Ts

HN O

+

Ts

PPh3

O

O

O H

27 X

X

H O

[MtOA]

O

O B

71-84% ee

X = Br, Cl, NO2

O O [MtOA = methyltrioctylammonium] 29 O

Scheme 25.

Quinuclidine-Based Ionic Liquids Cheng et al. [62] investigated the ionic liquid-bound quinuclidine (30) catalyzed Baylis-Hillman reactions, where 30 was synthesized on the basis of biphasic strategy i.e. homogenous reaction and heterogeneous separation. The ionic liquidsupported catalyst 30 showed higher efficiency and gave high yields in comparison to the cases where other common homogeneous or heterogeneous catalysts were used (Scheme 26). Due to its easy separation from reaction medium, it could be readily recovered and reused six times without significant loss of catalytic activity.

1

R -CHO

+

R2

CH3OH (2.0 equiv.)

H N

OH

30 (0.3 equiv.) R1

32-98%

R2

C4H9n NH

N

N

BF430

Scheme 26.

Mi et al. [63] explored hydroxyl ionic liquid (31) as a novel support for Baylis–Hillman catalyst, where the hydroxyl group linked on 31 played an important role in activating aldehyde carbonyl and / promoting an intramolecular proton transfer, thus facilitating efficient catalysis under solvent-free conditions (Scheme 27). Ionic liquid (31) itself served as a protic additive to promote MBH reaction, thus completing the reaction in 0.5-25 hrs.

242 Advances in Organic Synthesis, Vol. 8

R1-CHO +

Jindal et al. H N

OH

R2

Catalyst (0.2 equiv) R1

solvent-free, r. t.

R2

HO

N H

N Br-

N 31

R1 = Alkyl, aryl, pyridyl, furyl R2 = -CO2CH3, -CO2C2H5, -CO2C4H9

Scheme 27.

DABCO-Based Ionic Liquids Liu et al. [64] prepared an efficient ionic catalyst, 1-butyl-4-aza-1-azoniabicyclo [2.2.2]octane chloride (32) and applied in the Baylis-Hillman reaction, which occurred readily at room temperature, resulting in high conversion and selectivity without activity loss even after seven recycling uses (Scheme 28). R-CHO

+

COOC2H5

OH 32 CH3OH, r. t.

R

COOC2H5 N

N

Cl

3-14 hrs with ~ 100% conversion 32 Cl

N

R= NO2 NMe2

OH

Scheme 28.

Zou et al. [65] developed a recyclable protic-ionic liquid solvent-catalyst system, DABCO-AcOH-H2O and used in the Balis-Hillman reaction of aromatic aldehydes, aliphatic aldehydes, and cinnamaldehydes with acrylates and acrylonitrile, showing comparable performance to free DABCO in traditional solvents (Scheme 29). The DABCO-AcOH-H2O solvent-catalyst system could be reused for at least five times without significant loss of activity. DABCO-AcOH-H2O

R-CHO

+

EWG

25oC

OH R

EWG

R = Aromatic, Aliphatic, cinnamaldehydes

Scheme 29.

Nehzad et al. [66] prepared a highly efficient non-imidazolium DABCO-based ionic liquid (33) for the synthesis of biologically active MBH adducts from

Formation of Morita Baylis-Hillman Adducts

Advances in Organic Synthesis, Vol. 8 243

activated ketones (Scheme 30). The results showed that the ionic liquid was very efficient in the reaction due to its operational simplicity, high yields, dual catalyst-solvent properties and excellent recyclability and re-usability. HO O

EWG +

R

H

OH 33 (1 ml), r. t.

time (h)

EWG

Pr

CO2Me

7

76

CN

7

73

Pr

N+

yield (%)

R

i

EWG

R

DBU (8 mol%)

33

BF4-

N

Scheme 30.

Triazolium-Based Ionic Liquids Jeong et al. [67] synthesized novel 1, 3-dialkyl-1,2,3-triazolium ionic liquids (34)via click reactions using 1-trimethylsilylacetylene and alkyl azides and they were found to be efficient reaction media for the Baylis-Hillman reaction (Scheme 31). These ionic liquids were chemically inert under basic conditions and more suitable media for the reactions involving bases than the common 1, 3dialkylimidazolium ionic liquids. O R

+ H

EWG

OH DABCO, r. t. 34

R

R = aryl, alkyl; EWG = CO2CH3, CN

EWG 33-99%

R1 N N N R 2 X 34 34a. R1 = C4H9; R2 = CH3 34b. R1 = CH2Ph; R2 = CH3 34c. R1 = R2 = C4H9 X = I, NTf2, OTf, PF6, BF4

Scheme 31.

Negron-Silva et al. [68] synthesized O- and S-functionalized 1, 2, 3-triazoliums (35a and 35b) by Cu(OAc)2 coupling of the benzyloxy- and thiophenoxy-alkynes with sodium azide in the presence of 4-chlorobenzylchloride to yield respective 1,2,3-triazoles, followed by N-alkylation with methyl iodide. These cations have been efficiently used as ionic liquids for Baylis-Hillman addition under mild conditions, with improved yields compared to ionic liquids based on imidazolium

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Jindal et al.

systems (Scheme 32). This improved yield was attributed to the stabilization of zwitterionic intermediates generated from the Michael addition of a nucleophilic Lewis base to an activated alkene. O

O + R

O

H

OH

DABCO R

35

I

N N

O

X

N Cl

O

35

H

35a. X = Ph-CH2O; 35b. X = Ph-S

Scheme 32.

Fall et al. [69] synthesized 1, 3, 4-trialkyl-1, 2, 3-triazolium ionic liquids (36-38)via click chemistry and used them for the MBH reaction (Scheme 33). It was found that ionic liquid 36c in CH2Cl2 and 1 equiv. of Yb(OTf)3 gave MBH adducts in 37 h with 53% yield. However, using 36c as solvent and DABCO as base, yield was improved to 80-88% yield. OH

HO

N n

36

OH HO

N N

HO N

X

OH

37

N N

N I

38

N N MeSO4

36a. n = 1; X = MeSO4 36b. n = 1; X = I 36c. n = 2; X = I O

OH EWG

H +

EWG

36b, r.t., 3 h DABCO (2eq.)

Cl

Cl EWG = COMe; CO2Et; CN

Scheme 33.

Other Ionic Liquids Lenardão et al. [70] used phenyl butyl ethyl selenonium tetrafluoroborate, (37) along with DABCO, as an acidic ionic liquid, in the Baylis-Hillman reaction of

Formation of Morita Baylis-Hillman Adducts

Advances in Organic Synthesis, Vol. 8 245

aldehydes and electron-deficient alkenes which afforded moderate to good yields and short reaction times (Scheme 34). OH EWG

+

RCHO

DABCO R

CH3CN, r. t.

C4H9

EWG

Se

C2H5

C6H5

BF4 37

Scheme 34.

Macaev et al. [71] prepared novel catalyst derived from the nitrile functionalized ionic liquids (38) and DMAP which promoted the Morita-Baylis-Hillman reaction of N-substituted isatines and the methyl acrylate with moderate up to high yields (Scheme 35). O R1 O

+

HO

1 38/DMAP, r. t. R

COOMe

Y N

n

CN 38

O

55-98%

N

COOMe

N

N

R2

R2 38a. n =1; Y = Br/Cl 38b. n = 1; Y = PF6 38c. n = 1; Y = BF4

CN

38d. n = 2; Y = Br/Cl 38e. n = 2; Y = PF6 38f. n = 2; Y = BF4

Scheme 35.

Zhao et al. [72] synthesized Poly (ethyleneglycol)-400 ionic liquid containing imidazolium cations (39) by atom-efficient reaction of 1, 2-dimethylimidazole with p-toluenesulfonate and used it for MBH reactions of a variety of aldehydes including e- deficient and e- rich aromatic aldehydes and aliphatic aldehydes (Scheme 36). OH R-CHO

+

EWG

39 / H2O R DABCO, r. t.

EWG

N

N

PEG

N

N 39

O S O

O

2

R = Aryl, Alkyl; EWG = CN, COOCH3

Scheme 36.

Kumar et al. [73] reported an eco-friendly and cost-effective method to generate MBH adducts upon microwave irradiation (MWI), where non-volatile polyethylene glycol-200 was used as reusable solvent (Scheme 37). MWI had a

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Jindal et al.

remarkable influence on PEG suspended DABCO catalyzed MBH reaction between aldehydes and ethyl acrylate, by which excellent yields were obtained in very short time of 90 s. O

O HCHO/DABCO (20mmol%)

HO

O

O

PEG-200, MW (300 W)

Scheme 37.

Yi et al. [74] developed and used the efficient and recyclable system, dimethyl amino pyridine-based ionic liquid (40)/water in the Morita–Baylis–Hillman reaction of aromatic aldehydes with acrylates (Scheme 38). The coupling reactions under the described basic reaction conditions proceeded quickly with good to excellent yields (80-97%). The ionic liquid could be reused at least five times without significant loss of activity.

R1-CHO

R2

+

DABCO, r. t.

N

OH

40 / H2O

R2

R1

OH N

40 O2N R1 =

NC

Cl ,

,

MeO

F ,

,

O ,

R2 = -CO2Me O

Scheme 38.

Hullio et al. [75] used nicotine-based task specific ionic liquid (41) as an alternative green and recyclable nucleophilic reagent for Morita-Baylis-Hillman reaction (Scheme 39). The presence of NTf2 (bis(trifluoromethane)sulfonimide) anion in the ionic liquid, 41, has ability to depress the melting point of salt and is having hydrophobic and weak coordination character, making it chemically and thermally more stable. Srivastava et al. [76] observed that BH reaction using ionic liquid [tmba][NTf2]/hydrotalcite clay (HTC) catalytic system was more reactive in terms of yield (51-68%) and reaction rate (24 h) than DABCO/acetonitrile system, which required more than 48 h for achieving same yield. This reaction system was also used for the synthesis of lactone ceramide analogoue from (S)-Garner aldehyde-methyl acrylate using BH reaction (Scheme 40).

Formation of Morita Baylis-Hillman Adducts

Advances in Organic Synthesis, Vol. 8 247

I N

N Hexyl

N

BnBr

Hexyl-I

N

Br

Br

CH2Ph

N Hexyl

(ii) LiNfT2

N

N

NfT2 (i) Ph3P N

41

CH2Ph

OH R-CHO

+

41 (0.3 equiv.)

CO2Me

CO2Me

R CH3OH (2 equiv.)

R = aliphatic and aromatic aldehydes

Scheme 39. O

O

O +

N

+

N

r. t., 24 h

CO2CH3

Boc

O

OH

[tmba][NTf2]/HTC

OH

N

CO2Me

CO2Me

Boc

Boc

syn

anti [tmba][NTf2] = trimethylammonium bis-trifluoromethanesulphonamide

Scheme 40.

Zhao et al. [77] prepared a variety of phosphonium ionic liquids (42) due to their superior thermal stability and inertness in weak basic reaction media and used DABCO and water-phosphonium ionic liquid catalyst-solvent system as MBH reaction media (Scheme 41). The results showed that this system effectively accelerated the reaction with high yields. XH

X R

+ R'

EWG

42

EWG R

R'

R = alkyl, aryl, heteroaryl; R' = H, CO2R, alkyl; X = O, NCOOR'', NSO2Ph, NPPh2 EWG = COOR, CONR2, CN, COR, CHO, PO(OEt)2, SO2Ph

(C4H8)3P-(CH2)nCH3 Br 42 42a. n = 1 42b. n = 2 42c. n = 3 42d. n = 7 42e. n = 9

Scheme 41.

Valizadeh et al. [78] used star-like polyionic-lewis base heterogeneous nanocatalyst (43) for the Baylis-Hillman reaction of benzyl- and methylacrylates with aryl aldehydes, which got completed at room temperature in 5.5-8 h with yield of 70-96% (Scheme 42).

248 Advances in Organic Synthesis, Vol. 8

Cl

O

nano SiO2

O

Jindal et al.

Me

Si

Me

Me

Me

N

N

N Cl

O

H

OH

R1

Me

O R1 R2

R2 R = CH3, CH2Ph

Me

O

43 r. t.

+

O

R2

Me

N

43

O

1

Me N

N Cl Me

Me

Me

O

Cl

Me

Cl

NO2

NO2 = NO2

CF3

CN

Scheme 42.

Kumar et al. [79] studied the kinetics and mechanism of the MBH reaction in certain ionic liquids possessing ethylsulfate anion [EtSO4]- and evaluated that the rate determining step was second order in aldehyde, but first order in acrylate and DABCO (Scheme 43). This is contrasting to the general observation according to which the rate determining step is first order in aldehyde, acrylate and DABCO in organic solvents. O H

OH

N

O

N +

O2N

OMe

OMe Solvents

O

O2N

Scheme 43.

It was further observed that MBH reaction could take place by two different mechanisms and balance amongst two has been maintained by the ionic environment used [80]. The measurement of rate constants and activation energy parameters demonstrated that change of reaction order from one to two was due to basic medium. The nature and basicity of the anion of ionic liquid was determinant factor in deciding the pathway of the reaction, where ionic liquids with more basic anions followed McQuade mechanism; while those with less basic ones followed hill and Issacs mechanism. CONCLUDING REMARKS The use of ionic liquids for MBH reaction has resulted in the development of a

Formation of Morita Baylis-Hillman Adducts

Advances in Organic Synthesis, Vol. 8 249

huge number of methodologies for the carbon-carbon bond formation. A comparison of the experimental procedures involving microwave irradiation with those of the room temperature formulation with a solvent-free condition revealed that the latter can be safely employed to obtain good to excellent yields. This reaction provides a great opportunity for the formation of a variety of molecules having biological importance in synthetic and medicinal chemistry. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The author (editor) declares no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS The authors are greatly thankful to DST PURSE-II (Grant no. 48/RPC) for the grant. REFERENCES [1]

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SUBJECT INDEX A 2-Acetoxy Indolin-3-ones 183, 184 Acetylene bond 82, 83, 84, 86, 93 Achiral Knölker’s complex 49, 52 Acidic 81, 91, 160 media 160 zeolites 81, 91 Acid(s) 35, 45, 52, 53, 60, 64, 81, 82, 84, 86, 100, 101, 104, 114, 125, 145, 183, 186, 199, 230, 231 Brønsted 100, 101, 104 formic 45, 125, 145 Lewis 60, 64, 81, 82, 84, 86, 100, 101, 104, 114, 199, 230, 231 peroxyacetic 183, 186 phosphoric 35, 52, 53 Acrylates 233, 242, 246, 248 Acrylonitrile 228, 234, 237, 242 Activation 16, 33, 41, 49, 50, 52, 53, 58, 65, 84, 86, 114, 127, 190, 210 electrophilic 84, 86 imine 52, 53 Active species, oxidative 55, 57 Alcohol activation 35, 58, 64, 65 dehydrogenative 35, 58 Alcohol dehydrogenation 55, 56, 57 secondary 56, 57 Alcohol oxidation 12, 57 Alcohols 1, 4, 7, 11, 12, 15, 16, 17, 18, 19, 22, 23, 32, 33, 41, 48, 49, 50, 51, 55, 56, 57, 58, 61, 62, 63, 64, 66, 70, 71, 73, 86, 99, 100, 102, 104, 106, 109, 112, 141, 142, 192, 194 crotyl 16, 17 expected 48, 50 furfuryl 11 isopropyl 55, 141, 142 oxidation of 1, 4 primary 4, 56, 61, 63, 64 propargylic 19, 86

Aldehyde reduction 47 Aliphatic aldehydes 41, 43, 44, 230, 242, 245 Aliphatic amines 62, 64, 67, 68 secondary 62, 64 Alkene(s) 183, 224, 225, 226, 227, 228, 244 moiety 183 activated 224, 225, 226, 227, 228, 244 Alkylation 11, 61, 63, 64 iron-catalyzed 61 sequential 63 Alkyl azido side chain 197 Allene system 100 Allyl cation 109, 112 Allylic 11, 16, 64, 65 alcohols 11, 16, 64 amination 65 Aluminum halogenides 86 Amides, benzoyl 190 Amino-chitosans 126 Aminoindazole derivatives 185 Aniline alkylation 63, 64 Antibacterial activities 126, 128, 129, 131, 132, 133, 136, 137, 141 Antimicrobial 121, 122, 123, 127, 128, 131, 132, 136, 162 activity 121, 123, 127, 128, 131, 132, 162 chitosan’s 131 chitosan 122 Antimuscarinic agent synthesis 62 Arginine-functionalized chitosan 123, 126 Aryl ester synthesis 9 3-arylindenones 84, 86 3-arylquinolin-2-ones 199, 200 Azetidines 177, 178

B Bacillus subtilis 133, 134 Baylis-Hillman reaction 237, 242, 243, 244, 247 Benzimidazoles 15, 186, 187 Benzothiazoles 194

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1,4-Benzodiazepine skeleton 202, 203 Benzoxazines 53, 54 Benzoxazole derivatives 189, 193, 194 Benzyl alcohol(s) 8, 13, 14, 17, 58, 59, 61, 63, 70 derivatives 14 Benzylamine 7, 61, 64, 65 Bicyclic products 210, 211 Bioaugmentation 122, 154, 155 Bioremediation 144, 146, 154, 156, 157, 162 Bisindolines 210, 212 Bond formation 58, 82, 203, 224, 249 aryl-aryl 203 carbon-carbon 58, 82, 224, 249 Brønsted superacids 81, 82, 88, 107

C Candida antarctica lipase 71 B (CAIB) 71 Cannabinoid receptors CB1 107 Carbon 14, 47, 48, 61, 73 -carbon bond formation reactions 14 monoxide 47, 48, 73 -nitrogen bond formation 61 Carbonyl 8, 11, 19, 21, 36, 37 42, 59, 86, 98 group 8, 11, 19, 21, 86, 98 hydrogenation 36, 37, 42, 59 Carbonyl compounds 7, 32, 33, 36, 40, 41, 45, 47, 55, 66, 180 substituted aromatic 66 Carboxymethyl chitosans 122 Cascade reaction 3, 4, 175 Catalysis 1, 2, 4, 11, 12, 22, 24, 34 auto-tandem 4, 22 homogeneous 24, 34 Catalyst combination 53, 54 Catalysts 1, 3, 5, 6, 7, 8, 11, 12, 13, 14, 16, 32, 34, 35, 42, 48, 49, 54, 58, 66, 67, 73, 186, 189, 196, 207, 227, 228, 229, 242 bifunctional 3, 32, 34 prolinol 16 Catalyst selectivity 50, 51

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Catalytic 8, 11, 15, 16, 22, 23, 24, 37, 38, 43, 45, 49, 53, 54, 56, 58, 59, 60, 66, 71, 73, 228, 241, 246 activity 8, 38, 73, 241 cycle 22, 24, 37, 38, 45, 49, 53, 56, 59, 60 system 11, 15, 16, 22, 23, 43, 54, 58, 66, 71, 228, 246 Cations, cyclopropyl-alkyl 90 Cells 22, 139, 145, 146, 147, 148, 150, 151, 152, 153, 154, 155 bacterial 155 entrapment 147, 148 immobilization 145, 147, 148, 150, 155 immobilized 148, 152, 153, 155 microbial 147, 148 vegetative 151, 152 viable 148, 152, 154 Chelating capacity of chitosan 136 Chelation, chitosan-mediated 136 Chiral 3-alkylpentanol synthesis 59 Chiral ionic liquid 239 Chitin and chitosan 122, 134, 135, 145, 157, 158 Chitosan 121, 123, 125, 126, 127, 128, 130, 131, 132, 133, 136, 138, 141, 143, 145, 149, 151, 153, 156, 160, 161 acid conditions 126 acid-soluble 132, 133 amount 138 chitosan and modified chitosan 160 action of 126, 151 chitosan antimicrobial activity 129, 135 beads in water-kerosene mixture emulsification 151 biodegradable polymer 161 cross-linked 123 derivative 145 dimethylated 125 di-TBDMS 125 flaky 149 functionalized 123 high molecular weight 130 microspheres 121 minimum inhibitory concentration 130 natural 126, 156 preventing 136

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Subject Index

quaternized 123 solubility of 141, 149 thiolated 128 toxicity 143, 153 trimethyl 125, 131 unmodified 160 water-soluble 123, 132 Chitosanase 145, 150, 153 produced 153 Chloroethylamine hydrochloride 141, 142 Cinnamaldehydes 242 Cinnamyl alcohol 14, 18, 56, 64 C-nucleophiles 59, 60 Complexes 23, 136 chitosan-metal 136 multistep syntheses 23 Composites, chitosan-based 123 Compounds, toxic 144, 145 Concentrations, minimum inhibitory 133, 134 Conjugated enynones 91, 92 Construction 200, 206 of spiroheterocycles 205, 206 Cross-linked chitosan structure 149 Cycloaddition 21, 40, 177, 192 Cyclohexane 84 Cyclohexylamine 67, 68 Cyclopentadienone 40, 42, 44, 45, 47, 50, 51, 56 Cyclopentadienone ligand 43, 44, 47 Cytotoxicity 139

D DABCO 229, 234, 236, 237, 239, 242, 247 -based ionic liquids 229, 242 -catalyzed MBH reactions 234, 237 Deacetylated chitosan 122, 132, 135 lower 132 Deacetylation 122, 129, 131, 132, 134, 135, 137, 148 alkaline 135 degree of 122, 129, 131, 132, 134, 135, 137, 148 Deacetylation degree (DD) 122, 131, 132, 133, 134, 137

Dehydrogenation 7, 17, 32, 35, 55, 69 reactions 32, 35 Denaturing gradient gel electrophoresis (DGGE) 154 Derivatives 21, 67, 81, 82, 114, 126, 178, 179, 181, 182 fused cyclohexene 21 indole 181, 182 pyrrole 67, 178, 179 substituted 81, 82, 114, 126 DFT calculations 53, 81, 92, 237 Diastereomers 103, 106 Dibenzodihydro-1,3-diazepin-2-ones 203 Dication, reactive 85, 89 Dienyl triflates 82, 93, 96 2,3-Dihydro-1,5-benzothiazepine 8 Dihydroquinolinones 87, 88 Dispersed system 160 DKR 71, 72, 73 Dual catalysis 1, 3 Dynamic kinetic resolution (DKR) 32, 70, 71, 72

E Electrophiles and catalysts 227, 228 Enamines 176, 177 Enantioselective 4, 16, 54, 55, 59, 207, 240 asymmetric synthesis 240 synthesis 16, 59 Enantioselectivity 13, 49, 51, 55, 72, 73, 207, 210 high 55, 207, 210 Enolate form 20, 21 Enynones 81, 92, 93, 94, 96 Escherichia coli 127, 130, 132, 133, 134, 142 Exoskeletons 122

F Field emission scanning electron microscopy (FESEM) 126

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G Glutaraldehyde 146, 148, 149 Grafted chitosans 122

H Heterochitosans 134 Heterocycle Synthesis 66 Heterogeneous catalysts 12, 13, 241 Hydrogenation 32, 33, 34, 35, 37, 38, 40, 41, 42, 43, 47, 49, 51, 52, 54, 73 asymmetric 32, 35, 49, 52, 54, 73 compound 37, 38 direct 32, 33, 41 reactions 32, 33, 34, 35, 73 Hydrogen 6, 7, 38, 42, 44, 46, 49 pressure 42, 46, 49 transfer 6, 7, 38, 44, 46 Hydrolysis 21, 93, 94, 99, 100, 103, 109, 122 Hydroxyapatite 5 Hydroxyethyl chitosan 141, 142, 143 ethylamine 142, 143 Hypervalent iodine, applications of 175, 204, 211

I Imidazole 224, 228 Imidazolium 232, 236, 240, 245 cation 232, 236, 240, 245 salts 232 Immobilization 128, 145, 146, 148, 149, 150, 151, 154 Indanones 21, 93, 109, 114 1H-indazoles 185, 186 Indole skeletons 181, 182 Indolizine 225, 228 Injector heads 155, 156 Intramolecular cyclization 87, 109, 175, 187, 191 Intramolecular cyclization 191 synthesis of oxazolines and oxazines 191 Intramolecular nitrile oxide cycloaddition (INOC) 192

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Intramolecular oxidative cyclization 190, 197 Ionic liquids 228, 229, 232, 234, 237, 240 imidazolium-based 228, 229, 232, 234, 237 synthesized chiral 240 Iron catalyst 15, 47 Iron tricarbonyl complexes 40, 45, 47

K Kerosene 150, 151 Kinetic resolution 22, 23, 32, 71, 72 dynamic 32, 71, 72 Knölker’s 32, 35, 38, 49, 52, 53, 54, 55 complex 32, 38, 49, 52, 53, 54 iron complex 35, 55 Knölker type 32, 35, 73 complexes 32, 35, 73 iron complexes 32, 73

M Mangrove sediments 154, 155 MBH 225, 226, 227, 228, 229, 230, 232, 233, 234, 236, 237, 238, 239, 240, 241, 244, 245, 248 adducts 228, 229, 230, 232, 244, 245 reaction 225, 226, 227, 229, 230, 232, 233, 234, 236, 237, 238, 240, 241, 244, 245, 248 asymmetric 239, 240 Membrane permeability 126, 129 Mesitylene 105 Mesoporous silica nanoparticles (MSNs) 10 Mesorhizobium sp 154 Metal complexes 140 Metal-ligand cooperation 32, 34 Metal nanoparticles 1, 23 Methodologies, organic transformation 225 Methyl acrylate 230, 231, 234, 237, 239, 245 Minimal 130, 133, 134, 135 lethal concentrations (MLC) 134, 135 inhibitory concentration (MIC) 130, 133, 134 Modified chitosan 141, 160

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Subject Index

Molecular sieve, octahedral 12, 13 Molecules anionic 129, 130 charged chitosan 135 Monophos 49 Morita Baylis-Hillman (MBH) 224 Multicatalysis 1, 3 Multicatalytic processes 3, 4

N N-alkyl pyrrole synthesis 68 Nanoparticles, chitosan-zinc oxide 161 N-aryl and N-alkyl pyrrole synthesis 68 N-aryl-N-methoxyamides 195 N-containing heterocyclic compounds 175 N-dimethylated chitosan 125 N-dimethyl chitosan 125 Nitrile oxide 192 N-methoxybenzamides 195, 196 N-methyl-N-phenylcinnamamides 199 NPs-catalyzed oxidation of benzyl alcohol derivatives 14 N-trimethyl chitosan 125, 131

O O-aminochalcones 191, 192 Octahedral molecular sieve (OMS) 8, 12, 13 Oil-polluted seawater 146, 156, 157, 162 O-Methylation, avoiding 125 O-Methyl chitosan 126 reactions 1, 3 three-steps synthesis 8 O-protected chitosan material 125 Orbital, atomic 92 Organocatalysis 1, 24, 59 Orthogonal multicatalysis 1 OTf-Mediated Synthesis of Tetracycle 211 Outer-sphere mechanism 36, 37, 50 Oxazaspiroketal-containing bissteroidal pyrazine 197, 198 Oxidation of o-aminochalcones 191, 192

Oxidative 5, 9, 175, 176, 185, 188, 189, 190, 197, 203, 210, 211 C-N bond formation 203 cyclization 176, 185, 188, 189, 190, 197, 210, 211 esterification 5, 9 reaction 175

P Pathogens, resistant 128, 129 Peptide poly glycogen 136 PhI-catalyzed synthesis of phenanthridinones 195 PhI/m-CPBA-catalyzed synthesis of phenanthridinones 196 PhIO/I2-mediated synthesis of homochiral 7Oxa-2-azabicyclo 193 PhIO-mediated synthesis of 2h-azirines 177 PhIO/TBAI-Mediated Synthesis of Oxazolines 190 Phosphinamides 200, 201 Phosphines 224, 225, 227 Phosphonoallenes 99 Phosphorus heterocyclic compounds 200, 201 PIDA-mediated 185, 189 intramolecular 189 N-N bond formation 185 PIDA-mediated synthesis of 189, 185, 190, 191, 204, 212 2-arylbenzoxazoles 190 aminoindazole derivatives 185 benzo 189 bisindolines 212 oxazines 191 spirodienones 204 PIFA-induced synthesis of quinone imine ketals 197 PIFA-mediated 183, 185, 194, 197 202 difunctionalization 183 formation 183 N-N bond formation 185 oxidative intramolecular cyclization 197 synthesis 194, 202

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PIFA-mediated synthesis of 185, 189, 194, 195, 198, 199, 208 1H-indazoles 185 3-Arylquinolin-2-ones 199 benzo 198 benzothiazoles 194 indazolones 185 N-Aryl-N-methoxyamides 195 spiro-heterocycles 208 benzoxazole derivatives 189 Piperidines 64, 70 Pollutants, aquatic 156, 162 Polymers, unmodified chitosan 126 Propargyl alcohols 20 Protonated forms 96, 97, 236 Protonation reactions 92 Pseudocumene 105, 110 P-tolylacetylene 38 Pyridinium-based Ionic Liquids 228, 237 Pyrrole(s) 67, 68, 69 formation mechanism 69 corresponding 67, 68 synthesis 67 substituted 68 Pyrrolidines 18, 67, 70, 180 Pyrrolidinones 180, 181

Q Quinone imine ketals 197 Quinoxaline(s) 53, 54, 224, 225, 228 Quinuclidine-based ionic liquids 229, 241

R Racemic alcohols 71, 72 Racemization catalyst 71 Realized functionalized azetidines synthesis 177 Reductive amination 6, 45, 46, 54 Reductive hydroamination 54, 55 Regioselectivity 199

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S Salicylaldehydes 18, 137, 138, 141 Saprophyticus 150 Schiff bases 137, 138, 139, 140, 141 composition of 139 ligand chitosan 137 Secondary alcohols 12, 16, 22, 23, 32, 37, 41, 55, 56, 64, 71, 73 synthesis 37 Semipermeable membranes 148 Shvo’s catalyst 34, 35, 37, 52, 54, 56 Sieval’s method 124, 125 Solvent 226, 238, 242 -catalyst system 238, 242 Spirocyclization 204, 207 Spirodienones 204, 205 Spiroheterocycles 205, 206 Spirooxindoles 175, 206, 207 Spiropyrroles 204 Stability constants 140, 141 Stereoselective 59, 104, 106, 225 Stoichiometric reaction 36, 52, 55 Structures, polycationic 131 Styrenes 103 Substitution 94, 96, 126, 137, 191, 205, 206, 232 intermolecular 94, 96 degrees 126 Substrate 3, 54, 56, 63, 64 molecules 3 scope investigation 54, 56, 63, 64 Sulfates, vinyl 97, 98 Sulfonamides, phenolic 204 Superacids 81, 82, 83, 84, 88, 102, 114 Superelectrophilic 81, 82, 84, 86, 88, 91, 109 activation 81, 82, 84, 86, 88, 91, 109 activations 81 Supramolecular species 236 Synthesis 2, 4, 5, 6, 7, 8, 13, 16, 17, 18, 19, 20, 21, 22, 23, 24, 32, 35, 37, 46, 48, 50, 51, 56, 62, 63, 65, 66, 69, 70, 73, 99, 114, 123, 124, 125, 128, 138, 140, 141, 142,

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Subject Index

143, 162, 175, 176, 177, 178, 179, 182, 183, 184, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 204, 205, 206, 210, 211, 121, 224, 226, 236, 242, 246 2-oxazolidinone 22 and selectivity of chiral 50 azepane 70 chemical 121 efficient 198 facile 191 hydrothermal 8 ketone 56 metal-free 199, 206 one-pot 17 quinoline 66 total 18, 210

T Thiocoumarines 86, 88, 114 Thioesters 86, 88 TMC synthesis 123 Total organic carbon (TOC) 160 Transfer hydrogenation 32, 33, 37, 38, 46, 50 Transfer hydrogenation reactions 33, 35 Transformation CF3-enones 108 Transformations 1, 17, 33, 41, 45, 55, 58, 63, 82, 86, 89, 99, 100, 105, 110, 175, 180, 182, 183, 186, 189, 194, 197, 205 alkenes 91 atom economy 33 chemical 1 consequent 86

fast 100 green 55 high-yielding 41 investigated 105 oxidative 175 reagents-mediated metal-free 182 selective 63 tricatalytic one-pot 17 Transition-metal-free 175, 211 Triazolium-Based Ionic Liquids 229, 243 Trifluoromethyl group 81 Trimethyl chitosan chloride 123

U Urotropine 236, 237

V Ɣ-valerolactone 7, 37, 38 Vinyl triflates 81, 82, 83, 93, 97, 98 corresponding 82, 93, 97, 98

W Water gas shift reaction (WGSR) 32, 47 Water-kerosene mixture emulsification 150, 151 Water-phosphonium ionic liquid 247 WGSR conditions 47, 48 Wittig olefination 2, 14

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et al.