Studies on Green Synthetic Reactions Based on Formic Acid from Biomass [1st ed.] 9789811576225, 9789811576232

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Springer Theses Recognizing Outstanding Ph.D. Research

Ming-Chen Fu

Studies on Green Synthetic Reactions Based on Formic Acid from Biomass

Springer Theses Recognizing Outstanding Ph.D. Research

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Ming-Chen Fu

Studies on Green Synthetic Reactions Based on Formic Acid from Biomass Doctoral Theses accepted by University of Science and Technology of China, Hefei, China

123

Author Dr. Ming-Chen Fu Department of Chemistry University of Science and Technology of China Hefei, Anhui, China

Supervisor Prof. Yao Fu University of Science and Technology of China Hefei, Anhui, China

ISSN 2190-5053 ISSN 2190-5061 (electronic) Springer Theses ISBN 978-981-15-7622-5 ISBN 978-981-15-7623-2 (eBook) https://doi.org/10.1007/978-981-15-7623-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Supervisor’s Foreword

I am pleased to see the doctoral thesis of my student Dr. Ming-Chen Fu being published as a part of the Springer Theses series. The thesis contains his many achievements in the field of green synthetic reactions based on formic acid from biomass as C1 sources during his Ph.D. candidature at the University of Science and Technology of China. Substituting “greener” and “renewable” or environmentally benign materials for hazardous and waste-generating reagents is an important task for both academic research and industrial production. Formic acid, which is a renewable bulk chemical with low toxicity, and is liquid and convenient for storage and transportation, has important applications in organic synthesis. Studies on green synthetic reactions based on formic acid not only enrich and develop the field of “C1 chemistry”, but accord with the development of green, sustainable chemistry. In this thesis, Dr. Fu first summarized the conversion of formic acid as a C1 source in various synthetic transformations, providing readers with an overview of the recent developments in this area, and projecting to the unresolved problems in future organic syntheses using formic acid as a C1 resource. Then, he developed the conceptually novel and synthetically valuable methods that use formic acid as a C1 source. First, Fu developed a newly described protocol using a boron-based catalyst [B(C6F5)3] in combination with silanes, aromatic amines, and aliphatic amines that could successfully react with formic acid to deliver a methylated product without using expensive transition-metal catalysts. In addition, formic acid can be used as a substitute for carbon monoxide in carbonylation reactions, thus avoiding the direct use of high-pressure carbon monoxide gas. In Chap. 3, Fu developed the first nickel-catalyzed hydrocarboxylation of various alkynes with formic acid in the catalytic amount of acetic anhydride, and various functionalized a, b-unsaturated carboxylic acids were obtained with high selectivity. Both terminal and internal alkynes are amenable substrates. In addition, b, c-unsaturated carbonyl compounds were used as the versatile building blocks, which can be synthesized by transition-metal-catalyzed carbonylation of allylic electrophiles, although carbonylation of allylic alcohols directly is still a challenge due to the poor leaving ability of the hydroxy group. Fu adopted the strategy of using acid anhydride to v

vi

Supervisor’s Foreword

activate the allylic alcohol in situ, and moreover to generate a mixed acid anhydride with formic acid to generate in turn carbon monoxide in situ by thermodecomposition. Thus, various b, c-unsaturated carboxylic acids were obtained successfully with excellent chemo-, regio-, and stereoselectivity. These works in the thesis provided a user-friendly and practical method to prepare 13C labeling of a, b-/b, c-unsaturated carboxylic acids. I hope these studies will bring further progress in the development of green synthetic reactions based on formic acid. Hefei, China June 2020

Prof. Yao Fu

Abstract

The development of “green” or environmentally benign sustainable methods, which utilize inexpensive and easily available feedstocks for an efficient organic synthesis, continues to be a major goal of chemical research. Substituting “greener” and renewable materials for hazardous and waste-generating reagents and precursors is thus a particularly important task for both academic research and industrial production. Formic acid (HCOOH), a renewable bulk chemical derived from the hydrolysis and oxidation of lignocellulose extracted from agricultural and forestry waste and energy crops, has biodegradability, low toxicity, and is convenient for storage and transportation. Due to its special structure, formic acid as a C1 building block has important applications in organic synthesis. Formic acid can be used as a formylation reagent, methylation reagent, and substitute for carbon monoxide (CO) used in carbonylation reactions. Thus, studies on green synthetic reactions based on formic acid not only enrich and develop the field of “C1 chemistry”, but also accord with the direction of the development of green sustainable chemistry. In the first chapter of this thesis, the conversion of formic acid as a C1 source in organic synthesis is reviewed. Formic acid can be used as an amine protecting group during peptide synthesis. In addition, it can be used for the N-methylation conversion of amines instead of methyl iodide, dimethyl sulfate, and other toxic methylation reagents. CO has been used widely as a carbonylation reagent in industrial processes. However, due to its high toxicity and flammability, the application of carbon monoxide in laboratory organic synthesis of fine chemicals is limited. Therefore, it is important to seek CO substitutes for carbonylation reactions. Recently, considerable efforts have been devoted to the development of formic acid as a CO surrogate. The corresponding aldehydes, ketones, or acids can be obtained through the reactions of formic acid with aryl halides, alkenes, alkynes, or aromatic hydrocarbons. N-methyl structural units are ubiquitous in pharmaceutical intermediates and fine chemicals. Precious metal catalysts, such as rhodium or platinum, can be used to catalyze the N-methylation conversion of amines with formic acid as a methylation reagent. In Chap. 2, we show that a boron-based catalyst [B(C6F5)3] in combination with poly(methylhydrosiloxane) can catalyze the straightforward N-methylation of vii

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Abstract

aromatic amines and aliphatic amines, using formic acid in the presence of a silane as reducing agent with high efficiency, selectivity, and functional group compatibility. In addition, the aromatic imines can also be converted directly through hydrogenation and N-methylation using this catalytic system. Hydrocarboxylation of alkynes is an important strategy for access to a, b-unsaturated carboxylic acids. Although the palladium-catalyzed hydrocarboxylation of acetylene with formic acid to produce acrylic acid has been developed, it remains a challenge to achieve the reaction between alkynes and formic acid using cheap metals to form various a, b-unsaturated carboxylic acids. In Chap. 3, we have demonstrated that the combination of Ni(II) salt with a bisphosphine ligand and a catalytic amount of acid anhydride can catalyze atom-economic hydrocarboxylation of a broad range of alkyne with formic acid. The operational simplicity, generality, and remarkable functional group compatibility make this reaction a user-friendly method of preparing functionalized a, b-unsaturated carboxylic acids. Some functional groups, which are sensitized in the reducing or acidic systems such as double bonds, aldehydes, cyano, esters, amides, boron esters, and carbonyl groups, can well be tolerated. Moreover, the reaction has a high yield at the gram scale and implies good prospects for industrial synthesis and application. b, c-Unsaturated carboxylic acids are important intermediates in the organic synthesis and chemical industries. Transition-metal-catalyzed reaction of allyl alcohol derivatives with carbon monoxide is an important method for preparing b, c-unsaturated carboxylic acids. In Chap. 4, we developed a method for preparing b, c-unsaturated carboxylic acids using palladium-catalyzed allyl alcohol with formic acid, without using high-pressure CO. The anhydride has a dual role: to activate the allylic alcohol and generate a mixed acid anhydride with formic acid to generate CO in situ. The reaction has excellent chemo-, regio-, and stereoselectivity, wide range of substrates, and good compatibility with various functional groups, providing a more practical method for the preparation of b, c-unsaturated carboxylic acids.







Keywords Formic acid Methylation Unsaturated carboxylic acids Hydrocarboxylation Carbonylation Carbon monoxide










Parts of this thesis have been published in the following journal articles: (1) Fu, M.-C.; Shang, R.*; Cheng, W.-M.; Fu, Y.* Boron-Catalyzed N-Alkylation of Amines using Carboxylic Acids. Angew.Chem. Int. Ed. 2015, 54, 9042. (2) Fu, M.-C.; Shang, R.*; Cheng, W.-M.; Fu, Y.* Nickel-Catalyzed Regio- and Stereoselective Hydrocarboxylation of Alkynes with Formic Acid through Catalytic CO Recycling. ACS Catal. 2016, 6, 2501. (3) Fu, M.-C.; Shang, R.*; Cheng, W.-M.; Fu, Y.* Efficient Pd-Catalyzed Regioand Stereoselective Carboxylation of Allylic Alcohols with Formic Acid. Chem. Eur. J. 2017, 23, 8818.

ix

Acknowledgements

The studies presented in this thesis have been conducted under the direction of my advisors Prof. Yao Fu and Prof. Rui Shang at the University of Science and Technology of China (USTC) during 2015–2018. These studies relate to the conversion of formic acid as a C1 source in green organic synthesis. I express my sincerest gratitude to my primary advisor, Prof. Yao Fu, whose kind guidance, enormous support, and insightful comments were invaluable during the course of my study. I also thank Prof. Rui Shang for his valuable discussions and help. All my research work during these past years was carefully guided by Prof. Rui Shang. His rigorous academic attitude and spirit of dedication spirit deeply influenced me and will be valuable for my future life and work. I am grateful to all the members of Prof. Fu’s research group at USTC for their good collaboration and for providing a good working atmosphere, and especially Prof. Wan-Min Cheng, Mr. Xingyu Li, Ms. Nan Dai, Mr. Guang-Zu Wang, Mr. Wei-Long Xing, Mr. Bin Zhao, Mr. Chao He, Ms. Ya-Nan Wu, Ms. Ya-Ting Wang, and Ms. Jia-Xin Wang, who supported me and contributed to the work provided in this thesis. I thank Ms. Ya-Ting Wang for her help in translating and editing this thesis for the publication in Springer Theses. Finally, but not least, I express my deepest appreciation to my family for nurturing me with their unconditional love and support.

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Contents

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source . . . 1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Reaction of Formic Acid with Amines . . . . . . . . . . . . . . . . . . . . . 1.2.1 N-Formylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2 N-Methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Reaction of Formic Acid with Aryl Halide . . . . . . . . . . . . . . . . . . 1.3.1 Synthesis of Aromatic Carboxylic Acids . . . . . . . . . . . . . . 1.3.2 Synthesis of Aromatic Aldehydes . . . . . . . . . . . . . . . . . . . 1.3.3 Carbonylation Coupling Reaction Involving Formic Acid and Aryl Halide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Reaction of Formic Acid with Olefin . . . . . . . . . . . . . . . . . . . . . . 1.4.1 Synthesis of Ester (Ketone) Compounds . . . . . . . . . . . . . . 1.4.2 Synthesis of Aliphatic Acids . . . . . . . . . . . . . . . . . . . . . . 1.4.3 Synthesis of Aliphatic Aldehydes . . . . . . . . . . . . . . . . . . . 1.5 Reaction of Formic Acid with Alkynes . . . . . . . . . . . . . . . . . . . . 1.6 Reaction of Formic Acid with Phenol (Alcohol) . . . . . . . . . . . . . . 1.6.1 Synthesis of Ketone (Ester) by Reaction of Formic Acid with Phenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.2 Synthesis of b, c-Unsaturated Carboxylic Acids by Reaction of Formic Acid with Allyl Alcohols . . . . . . . . . . 1.7 Reaction of Formic Acid with Arenes . . . . . . . . . . . . . . . . . . . . . 1.8 Conclusions and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 1 3 3 5 8 8 10

2 Boron-Catalyzed N-Methylation of Amines with Formic Acid 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1 Investigation of the Reaction Conditions . . . . . . . . . 2.2.2 Investigation of the Substrate Scope . . . . . . . . . . . .

27 27 29 29 31

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10 12 13 14 16 18 20 20 21 22 23 24

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2.2.3 Mechanistic Study . . . . . . . . . . . . . . 2.2.4 Application of This Catalytic System 2.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Experimental Part and Compound Data . . . . 2.4.1 Experimental Procedure . . . . . . . . . . 2.4.2 Characterization of the Products . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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33 33 35 35 35 36 41

3 Nickel-Catalyzed Hydrocarboxylation of Alkynes with Formic Acid Through Catalytic CO Recycling . . . . . . . . . . . . . . . . . . . 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Investigation of Reaction Conditions . . . . . . . . . . . . . 3.2.2 Exploring the Substrate Scope . . . . . . . . . . . . . . . . . 3.2.3 Gram-Scale Reactions . . . . . . . . . . . . . . . . . . . . . . . 3.2.4 Mechanistic Investigation . . . . . . . . . . . . . . . . . . . . . 3.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Experimental Part and Compound Data . . . . . . . . . . . . . . . . 3.4.1 Investigation of the Key Reaction Parameters . . . . . . 3.4.2 General Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3 Characterization of the Products . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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43 43 44 44 46 50 50 52 52 52 55 59 75

4 Efficient Pd-Catalyzed Regio- and Stereoselective Carboxylation of Allylic Alcohols with Formic Acid . . . . . . . . . . . . . . . . . . . . . 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1 Investigation of Reaction Conditions . . . . . . . . . . . . . . 4.2.2 Exploring of the Substrate Scope . . . . . . . . . . . . . . . . 4.2.3 Gram-Scale Synthesis . . . . . . . . . . . . . . . . . . . . . . . . 4.2.4 Mechanistic Investigation . . . . . . . . . . . . . . . . . . . . . . 4.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Experimental Part and Compound Data . . . . . . . . . . . . . . . . . 4.4.1 Investigation of the Key Reaction Parameters . . . . . . . 4.4.2 General Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.3 Characterization of the Products . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 1

Conversion of Formic Acid in Organic Synthesis as a C1 Source

Abstract The conversion of formic acid as a C1 source in organic synthesis is reviewed in this chapter, such as amine protecting group during peptide synthesis, methylated regent for amines, and CO surrogate in carbonylation reactions to deliever the corresponding aldehydes, ketones, or acids.

1.1 Background Over the past century, the rapid development of the global economy has largely depended on petroleum as the main chemical and energy source. However, with the continuous consumption of fossil resources and the increasing demand for energy by human society, finding new renewable resources to replace the nonrenewable fossil resources has become an imperative goal that our current society needs to strive toward. Biomass-derived feedstocks are abundant in nature and can be obtained from agricultural and forestry waste and from energy crops [1]. Moreover, the carbon source provided by these biomass-derived feedstocks does not intersect with petroleum or coal. Thus, biomass is regarded as a promising renewable carbon resource for preparing bulk chemicals in the future. Numerous studies have found that biomass can be used to obtain soluble carbohydrate molecules with high selectivity through the hydrolysis pathway, which can then be converted into a versatile biomassbased platform molecule [2]. Through the development of research into elementary chemical reactions, the efficient catalytic conversion of biomass-derived platform molecules into high value-added chemicals will greatly enhance the biomassbased chemical product library. Using relatively inexpensive and readily available raw materials and reagents in high-efficiency organic synthesis is a major research goal for the development of green sustainable chemistry [3]. Using “greener” and “renewable” raw materials to replace toxic or waste-producing reagents or precursor compounds is therefore an important task for the current academic research and industrial production [4].

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 M.-C. Fu, Studies on Green Synthetic Reactions Based on Formic Acid from Biomass, Springer Theses, https://doi.org/10.1007/978-981-15-7623-2_1

1

2

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source

Formic acid, a renewable bulk chemical that can be obtained through hydrolysis and oxidation of lignocellulose extracted from agricultural and forestry waste and from energy crops [5], has the advantages of low toxicity, biodegradability, and convenient storage and transportation. Formic acid can be used as a hydrogen source, and its hydrogen content is 4.4 wt% (5.22 MJ kg−1 ). Its energy content is at least 5 times higher than that of commercially available lithium-ion batteries. Thus, it has the potential to be designed as a portable hydrogen-carrying fuel cell with carbon dioxide as the main by-product (HCOOH → H2 + CO2 ), which does not pollute the environment. Moreover, formic acid can be obtained by hydrogenation of carbon dioxide, which broadens the reaction pathway for efficient conversion of carbon dioxide to produce liquid fuels and chemicals. Therefore, formic acid is likely to play the role of an energy carrier to replace fossil fuels in the future [6]. In the traditional method of using hydrogen as a reducing agent for multiple bonds, it is difficult to control the amount of hydrogen, and this often leads to excessive reduction of multiple bonds [7]. Moreover, hydrogen is flammable and explosive and is difficult to store and transport. Formic acid is liquid at room temperature and normal pressure, which is convenient for transportation and storage and is easy to measure. Therefore, formic acid has attracted widespread attention as a hydrogen source for reducing multiple bonds [8]. As such, formic acid is considered a basic organic chemical raw material and is widely used in tanning, medicine, and the textile, printing, and dyeing industries [9]. Due to its simple and specific structure, formic acid is also valued for synthetic utilization as a C1 source in organic chemical syntheses, including as a methylation (–CH3 ), formylation (–CHO), and carboxylation reagent (–COOH) (Scheme 1.1). Therefore, conducting basic applied research based on formic acid in organic reactions will not only enrich and develop the field of “C1 chemistry,” but also accord with the direction that has been developed for green sustainable chemistry. In this chapter, we focus mainly on the study of the reaction of formic acid as a C1 building block with various compounds such as amines, aryl halides, olefins, alkynes, and aromatic hydrocarbons.

CO2

- H2

N-CH3

+ H2 N-CHO Fomic Acid (HCOOH)

C-CHO Biomass-based carbohydrates (such as cellulose)

C-CO2H

Scheme 1.1 Application of biomass-based formic acid in green chemical synthesis

1.2 Reaction of Formic Acid with Amines

3

1.2 Reaction of Formic Acid with Amines 1.2.1 N-Formylation Formamide falls within an important class of organic intermediates in synthetic chemistry and is widely used in the synthesis of pharmaceutical molecules, such as substituted arylimidazoles, and nitrogen-bridged heterocyclic compounds. In addition, as a precursor for preparing N-methyl compounds, formamide is also used as an amino protecting group during peptide synthesis. A number of investigations on formylation for primary and secondary amines have been published. In 1995, Fieser’s group first applied formic acid to N-formylation to obtain N-methylformanilide using the N-methylaniline as the substrate [10]. Based on Fieser’s work, Choi and his team further optimized the reaction conditions by using a Dean–Stark trap and developed a practical method for N-formylation using an aqueous 85% formic acid in toluene. Both aromatic and aliphatic amines, and amino acid esters, are suitable substrates to give the desired N-formylation product smoothly (Scheme 1.2) [11]. In the work of Choi’s group, a large amount of toluene was needed as solvent. Hosseini-Sarvari and Sharghi have developed a novel and highly efficient solventfree method for N-formylation of amines with formic acid, using nontoxic, inexpensive, and biocompatible zinc oxide powder (Scheme 1.3) [12]. This protocol has many advantages, including high efficiency, not requiring specialized equipment, high product yields, and the possibility of reusing the catalyst.

or

R NH2

H N

R1

H N

toluene + HCOOH

R2

CHO 6

99%

N H

CHO

98%

reflux Dean-Stark

HO

CHO N 2 R R

R NH or CHO

CHO

1

N CHO

96%

CO2Bn

99%

Scheme 1.2 N-formylation of amine and formic acid without catalyst

R

H N

O

ZnO powder R'

+ HCOOH

70 oC, solvent-free

R

N

R'

R = aryl, alkyl R' = aryl, alkyl, H

Scheme 1.3 N-formylation of amine and formic acid catalyzed by ZnO powder

4

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source

In 2006, Bose’s group adopted a microwave-promoted method to achieve a rapid N-formylation of aliphatic and aromatic amines with aqueous formic acid [13]. The formamides were successfully obtained on a multiple gram scale in a few minutes without further purification by recrystallization (Scheme 1.4). Bhanage’s group found that by using formic acid/ethyl formate as a formylating agent, the N-formylation reaction can be successfully achieved without addition of catalysts and solvents, and the substrate is suitable for both aromatic and aliphatic amines [14]. As shown in Scheme 1.5, the possible reaction mechanism involves nucleophilic attack of the aniline on the electron-deficient carbonyl carbon in the formic acid or ethyl formate. The formed intermediate is further dehydrated or deethanolized to obtain the target product. N-formylation of amino acids or peptides with formic acid can be used for the protection of amine groups. In 2013, Kurosu’s group reported a mild and convenient N-formylation protocol by reacting various amino acids and peptides with formic acid in water media (Scheme 1.6). The protocol could selectively achieve the formylation of primary amines over secondary amines at a controlled temperature [15], and the author demonstrated this by selective formylation of the antibiotic daptomycin, which contains three different amino groups.

NH2

H N

HCOOH (aq.) MWI, 2 min 85%

MeO

CHO

MeO

Scheme 1.4 Microwave-promoted N-formylation of amine and formic acid

R

H N

O

Catalyst-free + HCOOR''

R'

R = aryl, alkyl R' = aryl, alkyl, H

+

Heat H

OR'

O R NH

H R N

H

N

H N OR' H HO R

O R NH2

R

Solvent-free 70 oC R'' = H, ethyl

- R'OH

Scheme 1.5 Catalyst- and solvent-free N-formylation of amines

OH OR' H

R'

1.2 Reaction of Formic Acid with Amines

5 X

X

condition A N H

N X = O or CH2 CHO

X = O or CH2

O O

O O

R2 R1 NH

O condition A or B R1 = alkyl, aryl, + amino acid r.t., 3 h H OH

R2 R1 = alkyl, aryl, R1 N amino acid CHO

(2 eq.) condition B O

5 eq. O N H

CO2R3 R3 = H or CH3

3

CO2R N R3 = H or CH3 CHO

OH N EDCl (2 eq.) NaHCO3 (10 eq.) CN H2O

OH N

CN (2 eq.)

EDCl (2 eq.) NaHCO3 (10 eq.) DMF-H2O (9:1)

Scheme 1.6 N-formylation of amino acids and peptides in water-containing solvents

1.2.2 N-Methylation N-methyl-substituted amine compounds are important type of structural units that play an important role in regulating the biological and pharmaceutical properties of life science molecules. In addition, N-methylamine compounds are key intermediates for bulk and fine chemicals and materials used widely in the manufacture of pharmaceutical molecules, agricultural chemicals, dyes, and polymers [16, 17]. Classic methods for methylation of amines mainly include using Eschweiler–Clarke methodology and need abundant formaldehyde through reductive amination or some activated methyl reagents, such as methyl iodide, dimethyl sulfate, dimethyl sulfoxide, or diazomethane. However, these conventional methylating reagents are toxic, and the application range of substrate is relatively limited. Thus, it is highly desirable to develop more environmentally acceptable and easy-to-handle, ecologically friendly methylated reagents for the preparation of N-methyl compounds. Formic acid, as one of the major products in biomass refining process, has the advantages of being nontoxic, biodegradable, and has good reactivity with amines. Thus, using formic acid as the C1 feedstock for the synthesis of N-methylamines is highly desired. In 2014, Beller’s group reported a general catalytic protocol for the N-methylation of amines using a commercially available platinum catalyst [Karstedt’s catalyst, Pt(CH2 =CHSiMe2 )2 O] combined with a bidentate phosphine ligand (dppp) and phenylsilane as a reductant. Using this protocol, various aromatic and aliphatic amines, both primary and secondary, have been converted to the corresponding Nmethylation product in good to excellent yield (Scheme 1.7). In addition, the catalytic system has good functional group compatibility, and ester, hydroxy, cyano, thiol, olefin, and even highly functionalized formamide groups can all be well tolerated [18]. In the same year, Cantat et al. realized the N-methylated reaction of aromatic amine with formic acid through a tandem pathway of formylation and hydrogen transfer based on ruthenium(II) catalysts in the absence of an external reducing agent [19]. Phosphine ligands (triphos) and additives (MSA or HNTf2 ) are essential for the successful occurrence of this reaction. When using methanesulfonic acid (MSA) as an additive in the reaction system, mono-substituted nitrogen methylation products are mainly generated. The use of the additive bis(trifluoromethanesulfonyl)imine

6

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source

R1R2NH or R1NH2 + HCOOH

CH3 N

PhSiH3, 18 h, r.t., nBu2O

CH3 N R1 CH3 H3C N

N CH3

N

87%

or

O

CH3 N

OH

CH3 1 N R R2

Karstedt's catalyst / dppp (1:1)

87%

70%

94%

Scheme 1.7 Platinum-catalyzed N-methylation of amine with formic acid

(HNTf2 ) is more favorable for the disubstituted nitrogen methylation products. In the reaction system, carbon dioxide and hydrogen are formed, and the author proposed a possible mechanism as shown in Scheme 1.8. Formic acid plays the role of a unique source of both carbon and hydrogen for the methylation of amines. In the presence of an acid promoter, formic acid firstly reacts with amine to form formamide which further hydrodehydrated under ruthenium catalysis to deliver imine intermediates. The final N-methylation product is obtained after the ruthenium-catalyzed formic acid reduction. In addition, there is another possible reaction route in which formic acid undergoes dehydrogenation catalyzed by the ruthenium catalyst, to deliver carbon dioxide and hydrogen, and then carbon dioxide and the amine react to form a formamide intermediate. Subsequently, corresponding catalytic conversion occurs via transfer hydrogenation to give the desired product. Although precious metals such as platinum and ruthenium have shown good catalytic activity in catalyzing the reaction of amine and formic acid to prepare Nmethyl compounds, from the standpoint of a long time scale, precious metals are similar to fossil resources in that their availability on earth is extremely limited.

H R1 N H + 6 HCOOH N H or R2 R2

Ru(COD)(methylallyl)2 (1.0 mol%) triphos (1.0 mol%), MSA (1.5 mol%) o

150 C, 24 h, THF -CO2, -H2O cat. [Ru]

HCOOH

R1 H3C N CH3 N H + 2 R R2

PPh2

triphos =

PPh2 PPh2

CO2 + H2

dehydrogenation

PhMeNH

u] . [R cat H2O O Me

N Ph

HCO2 or H2

H H

cat. [Ru] HCOOH transf er hydrogenation

Me

N Ph

H

CO2 + H2O Me cat. [Ru]

(transf er) hydrogenation

Scheme 1.8 Ruthenium-catalyzed N-methylation of amine with formic acid

N Ph

CH3

1.2 Reaction of Formic Acid with Amines

7

Therefore, it is of great importance to develop a method that utilizes inexpensive, low-toxic catalysts to achieve N-methylation of amines with high efficiency and selectivity. In 2015, Shang and Fu’s group [20] discovered that the boron-based catalyst [B(C6 F5 )3 ] combined with poly(methylhydrosiloxane) (PMHS), which is a cheap and environmentally friendly by-product of the silicone industry, is capable of catalyzing the N-methylation of a broad range of aromatic and aliphatic amines with formic acid with high efficiency and selectively. This reaction has the advantage of versatile substrates and tolerates a range of functional groups. In addition, imine substrates can achieve hydrogenation and N-methylation conversion in one pot using this catalytic system (Scheme 1.9). In 2017, He’s group reported a non-noble-metal copper-catalyzed protocol for reductive N-methylation of amines with formic acid using phenylsilane as reductant [21]. Primary amines, secondary amines, and imine are suitable substrates and give the desired product in moderate to good yield (Scheme 1.10). Compared with the homogeneous catalytic system, a heterogeneous catalytic system has the advantage that the catalyst can be recycled many times and still has high catalytic activity. Zhu et al. described a commercially available heterogeneous Pt/C catalyst capable of catalyzing the methylation of aromatic amines and imines

R1

NH2 or

R1

H N

B(C6F5)3 (0.5-1 mol%) R2

+ HCOOH

CH3 N R CH3

or

1

PMHS or PhSiH3 Bu2O, 100-120 oC

1

R

R2 N

CH3

n

CH3 N

CH3 N

OH

CH3 N

CN

87%

96%

SMe

S

CH3 N CH3

N

96%

CH3 N CH3

93%

88%

O

N

CH3 N CH3

85%

N CH3

82%

Ph

CH3 N Ph

Ph

N

Ph

substrate 94%

Scheme 1.9 Boron-catalyzed N-methylation of amine and formic acid

R1

NH2

or

1

R

H N

Cu(OAc)2 2

R

+ HCOOH

PhSiH3, nBu2O, 80 oC

CH3 1 N R CH3

Scheme 1.10 Copper-catalyzed N-methylation of amine and formic acid

or

R2 N R1 CH3

8

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source

Ar NH2 Ar

H N

+ HCOOH

1

R

Ar

N

R2

Pt/C, PhSiH3 toluene, 80 oC

CH3 N 1 R Ar

CH3 Ar N CH3

Ar

CH3 N R2

Scheme 1.11 Pt/C catalyzed N-methylation of amine and formic acid

using hydrosilane as a reductant [22]. A TON number of this reaction as high as 1700 was achieved, and the Pt/C catalyst retains its catalytic activity after recycling at least twice (Scheme 1.11).

1.3 Reaction of Formic Acid with Aryl Halide 1.3.1 Synthesis of Aromatic Carboxylic Acids Aromatic carboxylic acid structural units are ubiquitous in many natural products, pharmaceuticals, and pesticide chemicals [23]. In traditional methodologies, the preparation of aromatic carboxylic acids from aryl halogens is usually achieved through the pathway of palladium-catalyzed carbon monoxide (CO) gas insertion [24]. However, carbon monoxide gas is highly toxic and difficult to operate in the laboratory from the safety perspective. Thus, it is of great significance to develop a method without the direct use of carbon monoxide. In 2003, Cacchi’s group [25] first developed a new protocol for palladiumcatalyzed hydroxycarbonylation without using carbon monoxide. Aryl halogens, alkenyl halogens, and alkenyl trifluoromethanesulfonate are suitable substrates in this catalytic system and converted into the corresponding carboxylic acids in good to excellent yield (Scheme 1.12). Unfortunately, when aryl bromide was used as the substrate, the reaction result was not satisfactory under the conditions reported. This work revealed that the formic acetic anhydride, which was generated in situ by the reaction of the formate with acetic anhydride, is thermally unstable and undergoes further decarbonylation under the reaction conditions, thereby avoiding the addition of carbon monoxide. Replacing carbon monoxide in the carbonylation reaction

R X

+ MOOCH + Ac2O

R = aryl, vinyl X = I, Br, OTf M = Na, Li

Pd2(dba)3 EtNi Pr2, LiCl DMF, 80 oC

R COOH

Scheme 1.12 Palladium-catalyzed hydroxycarbonylation using formate with acetic anhydride

1.3 Reaction of Formic Acid with Aryl Halide

9

greatly reduces the difficulty of the laboratory palladium-catalyzed carbonylation reaction. The strategy of using a mixture of formate and anhydride as CO surrogates to avoid the direct use of carbon monoxide has greatly reduced the difficulty of the laboratory-based palladium-catalyzed carbonylation reaction. In 2006, a related study by Bessmernykh and Caille et al. [26] showed that using a combination of palladium(II) acetate with 1,1 -bis(diphenylphosphino)ferrocene (dppf) catalytic system, aryl and vinyl bromides were suitable substrates to give the corresponding acids in the presence of acetic anhydride and lithium formate as the source of carbon monoxide (Scheme 1.13). In 2013, Taaning and Skrydstrup’s group first achieved the Pd-catalyzed hydroxycarbonylation of aryl halides with substoichiometric carbon monoxide [27]. The preprepared palladium carbonyl complex (cat. [Pd]) provided both an active catalyst and the substoichiometric CO, thereby obviating adding additional CO. A series of aryl halides possessing electron-poor substituents and benzyl chloride were successfully converted to the corresponding carboxylic acids and phenylacetic acid compounds (Scheme 1.14). In the reaction above, the author proposed a possible mechanism as shown in Scheme 1.15. The air-stable acyl-palladium(II) precatalyst reacts with potassium formate to deliver the aryl acid and the substoichiometric amount of carbon monoxide in situ. Then, the aryl halide and Pd(0) simultaneously capture the carbon monoxide generated in situ through oxidation addition. The formic anhydride decomposes spontaneously upon heating to the desired product and carbon monoxide (Scheme 1.15, path a). Based on this cycle, any carbon monoxide depleting side reactions in this system, such as reductive carbonylation to the corresponding aldehyde (path b), would be unfavorable for the normal progress of the reaction. Pd(OAc)2/dppf R Br

+ HCO2Li

i

Pr2NEt, DMF, 120 oC

R COOH

R = aryl, vinyl

Scheme 1.13 Palladium-catalyzed hydroxycarbonylation of aryl or alkenyl bromides

X R

+ HCOOK

X = I, Br, Cl, CH2Cl

cat. [Pd] (1 mol%) dtbpf (1 mol%)

COOH R

Me-THF, 80 oC or Diglyme, 120 oC

or R

COOH

Scheme 1.14 Hydroxycarbonylation of aryl halides and benzyl chloride

Ar1 C (t Bu)3P Pd I O

cat. [Pd] =

10

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source

Ar X

LnPd0 CO

COAr

O

Path a

LnPd

Ar

O O

H

O2CH

HCOOK

CO Path b Ar-CHO

Ar-COOH

LnPd0 + CO2

Ar1-COOH

COAr1 LnPd

LnPd0 + CO

Halide Precatalyst

HCO2K

Scheme 1.15 Pd-catalyzed hydroxycarbonylation with substoichiometric CO addition [27]

I R

CHO

Pd(OAc)2, PCy3, Ac2O + HCOOH

Et3N, DMF, 80 oC, 6 h

R

Scheme 1.16 Palladium-catalyzed reductive carbonylation

1.3.2 Synthesis of Aromatic Aldehydes Recently, Wu et al. [28] reported a palladium-catalyzed reductive carbonylation of aryl iodides with formic acid as the formyl source (Scheme 1.16). By adding triethylamine as a base to the reaction system, the acyl-palladium formic acid complex can be selectively decarboxylated and then gives the desired aromatic aldehyde after reductive elimination (as in Scheme 1.15, path b). The elimination of carbon dioxide was confirmed in this work. Both aryl and heteroaryl iodides can react well in this catalytic system with moderate to excellent yields.

1.3.3 Carbonylation Coupling Reaction Involving Formic Acid and Aryl Halide The carbonylation coupling reaction is an important method for preparing ketones or esters by constructing carbon–carbon bonds. In recent years, a series of crosscoupling works involving aryl halide as substrate and formic acid as carbonylation reagent have been reported successively. Wu et al. [29] adopted the combination of formic acid and acetic anhydride to release CO in situ. The palladium-catalyzed

1.3 Reaction of Formic Acid with Aryl Halide

11

carbonylation Sonogashira coupling reaction was realized in one pot using the aryl iodide and terminal alkyne as the substrates, providing a simple and practical method for the synthesis of various alkynones (Scheme 1.17). In addition, the same group also realized the palladium-catalyzed carbonylation Suzuki coupling reaction using aryl halides and aryl boronic acids as substrates [30]. A series of diaryl ketones were obtained successfully by this method (Scheme 1.18). It is worth noting that although the acid anhydride is indispensable in the reaction system, the reaction was entirely suppressed when propionic anhydride or trifluoroacetic anhydride was used to replace the acetic anhydride in the reaction system. Using the same strategy, Wu et al. successfully achieved the synthesis of a series of phenolic benzoate compounds through palladium-catalyzed alkoxycarbonylation using aryl halogens and phenolic compounds as substrates [31] (Scheme 1.19a). It is worth noting that thiobenzoate can also be obtained when tert-butyl mercaptan is used instead of phenolic compounds (Scheme 1.19b). However, when using aliphatic alcohols, 4-methylthiophenol, and amine as substrates, the corresponding carbonylation coupling products could not be obtained. Aurones, as α, β-unsaturated ketone compounds, play an important role in many biologically active molecules and are widely used in antifungal, anticancer, and antioxidant drugs. In 2016, Wu’s group developed a general and convenient palladium-catalyzed carbonylation reaction of 2-iodophenol and terminal alkynes to deliver variety of aurone derivatives [32]. Notably, this is the first report on carbonylative synthesis of aurones using formic acid combined with acetic anhydride as the source of carbon monoxide (Scheme 1.20).

I

R2

R1

+

+ HCOOH

Pd(OAc)2 (3 mol%) PPh3 (6 mol%)

O R2

R1

Et3N, Ac2O toluene, 30 oC

Scheme 1.17 Carbonylation Sonogashira coupling reaction of aryl iodide, alkyne, and formic acid

X 1

R

X = I, Br

R2 +

B(OH)2 + HCOOH

Pd(OAc)2 (3 mol%) PPh3 (6 mol%)

O 1

R

K2CO3, Et3N, Ac2O toluene, 100 oC

Scheme 1.18 Palladium-catalyzed carbonylation Suzuki coupling reaction

R2

12

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source

X R1

(a)

R2 +

OH + HCOOH

O

R2 O

1

R

Et3N, Ac2O toluene, 80 oC

X = I, Br

I

(b)

Pd(OAc)2 (3 mol%) Xantphos (3 mol%)

SH

+

+ HCOOH

O

Pd(OAc)2 (3 mol%) Xantphos (3 mol%)

S

Et3N, Ac2O toluene, 80 oC

Scheme 1.19 Palladium-catalyzed carbonylation coupling reaction involving formic acid

O I R1

+

R2

+ HCOOH

Pd(PPh3)4 (3 mol%)

R2 R1

Et3N, Ac2O toluene, 80 oC

OH

O

Scheme 1.20 Palladium-catalyzed reaction of o-iodophenol, formic acid, and terminal alkyne

1.4 Reaction of Formic Acid with Olefin Searching for carbon monoxide surrogates for carbonylated addition of olefins has aroused great interest among many organic chemists [33]. Although the use of formate or its analogues for the synthesis of carbonyl compounds is a highly effective method, formic acid is easily decomposed into water and carbon monoxide under acidic conditions at high temperature; thus, development of the general method that using formic acid directly to participate in the reaction under mild conditions remains challenging. Through the unremitting efforts of chemists, the use of formic acid as a carbon monoxide substitute for transition-metal-catalyzed carbonylation of olefins to effectively prepare corresponding esters, carboxylic acids, or aldehydes has been realized (Scheme 1.21). O R

OR' or O

transition-metal catalyst R

+ HCOOH

R

OH or O

R

H

Scheme 1.21 Transition metal catalyzes hydrocarbonylation of formic acid with olefin [33]

1.4 Reaction of Formic Acid with Olefin

13

1.4.1 Synthesis of Ester (Ketone) Compounds The ester compounds have important applications in the chemical, pharmaceutical, and perfume industries. Therefore, transition-metal-catalyzed carbonylative esterification of olefins has great appeal in organic synthesis. In 2014, Jun’s group [34] reported the use of formate as a carbon monoxide substitute, and ruthenium-catalyzed the three-component reaction of olefins, alcohols, and formate to prepare ester compounds (Scheme 1.22). Both aryl olefins and alkyl olefins showed good applicability in this catalytic system, and primary aliphatic alcohols could be converted effectively to the desired product. The secondary or tertiary alcohols are less effective as substrates, but it is worth noting that when phenols were used instead of aliphatic alcohols, corresponding phenolic ester products could also be obtained. Except for the ruthenium catalyst, Shi’s group found that using a catalytic system composed of palladium acetate and triphenylphosphine [35], cyclization esterification of o-hydroxystyrene compounds could be achieved by adding HCOOH and HCOOPh, providing an effective method for the preparation of benzo five- and sixmembered ring lactones. In addition, when a chiral phosphine ligand (R)-(–)DTBMSEGPHOS is used instead of triphenylphosphine in this catalytic system, the cyclic lactone product could be obtained in high yield with 76% ee (Scheme 1.23). Transition-metal-catalyzed carbonylation of olefins is also an important method for the preparation of various carbonyl-containing compounds. In 2017, Shi’s group [36] reported an effective palladium-catalyzed sequential carbonylation of olefins to give various ketones and α, β-enones. The catalytic system was combined of palladium trifluoroacetate [Pd(TFA)2 ] with a bidentate phosphine ligand, and acetic anhydride was added as an additive to achieve the reaction of formic acid and two molecules of olefins. The intermediate of acyl-palladium complex was formed first through palladium-catalyzed carbonylation of olefins with formic acid. Then, the

R1

+ HCOONa +

Ru3(CO)12 (5 mol%) 2-pyridinemethanol (20 mol%)

R2 OH

O 1

R

O

o

170 C, 4 h O

O

O O

O

O

38%

67%

87%

O 94%

O

O

O t-Bu

O

38%

O

14%

Scheme 1.22 Ruthenium-catalyzed carbonylative esterification [34]

O O

4%

R2

14

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source OH

(a)

Pd(OAc)2 (5 mol%) PPh3 (20 mol%)

O

R2

+

R3

H

OPh

1

R

OH (b) Me

O

O

O

HCOOH (1 equiv) mesitylene 90 oC, 16 h

R3

R1

1

2

R

R

Pd(OAc)2 (2.5 mol%) (R)-(-)DTBM-SEGPHOS (5 mol%) HCOOPh (1.2 equiv)

O

or

R3 R2

O O

O

*

HCOOH (1 equiv) THF, 55 oC, 24 h

OMe t

O

PAr2 PAr2

O

Bu

t

Bu

Ar =

Me 90% (ee. 76% )

O (R)-(-)DTBM-SEGPHOS

Scheme 1.23 Palladium-catalyzed cyclization esterification of o-hydroxystyrene [35]

O

Pd(TFA)2, dppp + HCOOH

R

Ac2O, CH3CN

R

+ HCOOH

R

R

90 oC

60 oC O

O

Pd/L Ac2O

O or

R

R

R

H

R

PdH R O

R

PdH R

O R

R

Scheme 1.24 Carbonylation of olefins with HCOOH [36]

intermediate could be eliminated to deliver aldehyde compounds, or react further with another olefin, and following β-hydride elimination and/or reductive elimination to give ketone or enone products (Scheme 1.24).

1.4.2 Synthesis of Aliphatic Acids Simonato et al. [37] developed a method of the hydrocarbonylation of olefins and formic acid by IrI4 catalyzed to give aliphatic acids (Scheme 1.25). Formic acid plays the role of the carbon monoxide source, and the catalytic system has high activity. However, the reaction needed to be performed at a high temperature up to 190 °C, which greatly limits the application of this catalytic system. Subsequently, the same group [38] found that the hydrocarboxylation of olefins could also be processed smoothly when combining the use of the rhodium catalyst [RhCl(CO)2 ]2 and triphenylphosphine, with formic acid used as the carboxylation reagent. To inhibit formic acid reducing the active iridium catalyst to the inactive

1.4 Reaction of Formic Acid with Olefin

15 O

O +

H

IrI4 (0.8 mol%) OH

OH

AcOH, 190 oC, 2.5 h 100%

O H

H+ or heat CO + H2O

OH

Scheme 1.25 Iridium-catalyzed hydrocarboxylation of olefins with formic acid [37]

Ir4 (CO)12 , a large amount of acetic acid was required to be added to the previous iridium catalytic system. By contrast, this catalytic system does not require the addition of solvent, providing an effective method for laboratory-scale fine chemical synthesis (Scheme 1.26). Shi’s group developed an efficient palladium-catalyzed hydrocarboxylation of olefins with phenol formate and formic acid to prepare aliphatic acids under mild reaction conditions in 2014 [39] (Scheme 1.27). The isolated yield of desired product could be obtained above 80% when the amount of phenol formate was reduced to 0.2 equivalents in the reaction system. Control experiments showed that formic acid is essential for this reaction. No product was detected in the absence of formic acid; only a small amount the phenyl ester by-product was obtained. Relevant experiments to determine the mechanism indicated that phenol formate plays the role of carbon , H+ a)

HCOOH

+ CO + H2O

b)

CO + H2O COOH

, H+

H

Scheme 1.26 Rhodium-catalyzed hydrocarboxylation of olefins with formic acid [38]

O

R1 R2

R3 + H

O

Ph

Pd(OAc)2 (5 mol%) dppf (10 mol%) HCOOH (1.0-2.0 equiv) toluene, 90 oC, 24 h

R2 COOH

R1 R3

O COOH

O

COOH O

97%

84%

HN

COOH

AcO O 84%

80%

Scheme 1.27 Palladium-catalyzed hydrocarboxylation of olefins with formic acid [39]

16

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source O

[(allyl)PdCl]2 (0.5 mol%) DPEphos (2 mol%)

N R O

HCOOH (2.0 equiv) HCOOPh (0.2 equiv) toluene, 60-80 oC

O COOH

NH2NH2.H2O

N R

EtOH, reflux

COOH R NH2

O

Scheme 1.28 Palladium-catalyzed hydrocarboxylation of enamine for synthesis of β-amino acids [40]

monoxide source, thereby avoiding the use of toxic carbon monoxide. An electrondeficient α, β-unsaturated ester or α, β-unsaturated amine could also react well in this system, and the latter is cyclized in one step to generate a pyrrolidine-2,5-dione. Adopting the same strategy, the same group further realized the hydrocarboxylation of enamine compounds, providing a simple and practical method for the synthesis of β-amino acids (Scheme 1.28). As Cacchi’s group discovered [25], the formic acetic anhydride is thermally unstable and can further undergo decarbonylation without the use of toxic carbon monoxide. Inspired by this strategy, Shi’s group [41] used formic acid with a catalytic amount of acetic anhydride as cocatalyst and achieved an effective palladiumcatalyzed hydrocarboxylation of olefins using mild conditions. A broad range of carboxylic acids were obtained in good to excellent yields with high regioselectivity. The mechanistic studies suggested that formic acid firstly reacted with acetic anhydride to generate formic acetic anhydride (HCOOAc), which undergoes oxidative addition with Pd(0) delivery to a palladium hydride complex. The complex then inserted into an olefin with subsequent reductive elimination affords the product and regenerates the Pd(0) catalyst (Scheme 1.29). Although many studies on the palladium-catalyzed hydrocarboxylation of olefins with formic acid to form alkyl carboxylic acids have been reported, selective control of the carbonyl insertion of olefins at different sites remains a major challenge. Shi’s group found that different phosphine ligands have a considerable influence on the regioselectivity of hydrocarboxylation of olefins (Scheme 1.30). When styrenic compounds are used as substrates, carbonyl insertion at the benzyl site or at the terminal position can be performed selectively through the regulation of various ligands. When tris[4-(trifluoromethyl) phenyl] phosphine was used as ligand, a branched-chain carboxylic acid compound (benzyl insertion carbonyl) was mainly selectively obtained, and when tris(2-methoxyphenyl) phosphine was used as ligand, linear carboxylic acid compounds (terminally inserted carbonyl) were selectively formed.

1.4.3 Synthesis of Aliphatic Aldehydes Hydroformylation of olefins provides an effective method for synthesis of aliphatic aldehydes. Various transition-metal catalysts such as Ir, Ru, Co, Rh, and Pd have been

1.4 Reaction of Formic Acid with Olefin R1 R2

17 Pd(OAc)2 (3 mol%) Xantphos (3 mol%)

R3 + HCOOH (2.0 equiv)

COOH R1

Ac2O (20 mol%) PhCH3, 70 oC, 24 h

R3 R2

Ac2O HCOOH

COOH + HCOOAc

Ph

AcOH O

HCOOAc

Pd(0) Ph

OAc

Ph

Pd

O

OAc

Pd H

AcO

O

OAc Pd H CO

Pd(0) + CO + AcOH

Ph

Scheme 1.29 Proposed reaction mechanism for hydrocarboxylation [41]

COOH

Pd(OAc)2 (5 mol %) HCOOH (3.0 equiv) Ac2O (20 mol %)

Ar P up to > 20:1

Ar

Pd(OAc)2 (5 mol %) HCOOH (2.0 equiv) Ac2O (20 mol %) Ar

COOH

P

CF3 3

3

MeO

up to > 20:1

Scheme 1.30 Ligand-directed catalytic regioselective hydrocarboxylation of aryl olefins [42]

used with syngas (CO/H2 ) under high pressure in a traditional hydroformylation reaction [43]. Shi et al. developed an effective Pd-catalyzed regioselective hydroformylation of olefins using formic acid as the source of carbon monoxide under mild conditions (Scheme 1.31) [44]. The combination of HCOOH/Ac2 O avoided the use of syngas. Various aryl and alkyl olefins could be effectively hydroformylated to deliver the corresponding aldehydes with good yields. The experiments revealed that the ligand and additive have a dramatic effect on the hydroformylation reaction process. The unique ligand structure of 1,3-bis(diphenylphosphino) propane (dppp) favors the release of CO2 to give the aldehyde products rather than the corresponding reductive elimination to give the acid products. Moreover, the reaction has high regioselectivity for linear aldehydes with aryl olefins.

18

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source Pd(OAc)2 (5 mol%) dppp (10 mol%)

R2 3

R1

R

R2

+ HCOOH

CHO

CHO

R1

Bu4NI (2.5 mol%) Ac2O (3.0 equiv) 4 A MS, DCE, 80 oC

3

R

CHO

CHO CHO 4

85% l:b > 20:1

78% l:b > 20:1

65% l:b = 7:1

65%

Scheme 1.31 Pd-catalyzed regioselective hydroformylation of olefins with formic acid [44]

1.5 Reaction of Formic Acid with Alkynes Compared with the above carbonylation method of olefins with formic acid as carbon monoxide surrogates, while the carbonylation of alkynes can only be conducted by means of hydrocarboxylation to give the α, β-unsaturated carboxylic acid product, the hydroformylation of alkynes remains to be solved. The traditional method for hydrocarboxylation of alkyne is usually to feed carbon monoxide and hydrogen into the reaction system. By contrast, the production of α, β-unsaturated carboxylic acids by catalyzing the direct reaction of alkyne with formic acid is highly economical, avoiding the use of toxic carbon monoxide and greatly simplifying the operation. In 1993, Alper’s group [45] reported a palladium-catalyzed hydrocarboxylation of various terminal alkynes with formic acid in the presence of suitable phosphine ligands, and the corresponding α, β-unsaturated carboxylic acids were obtained in 60–90% yields. However, this method requires high-pressure CO (120 psi of CO gas pressure), which limits its application scope (Scheme 1.32).

R

H

+ HCOOH

CO gas, DME, 100-110 oC

HOOC

COOH

COOH

HOOC

Pd(OAc)2, PPh3, dppb

+ R α-

77% α :β = 89:11

β-

COOH

COOH TMS

Cl 96% α :β = 93:7

R

70% α :β = 21:79

Scheme 1.32 Palladium-catalyzed hydrocarboxylation of terminal alkynes

63% α :β = 0:100

1.5 Reaction of Formic Acid with Alkynes

19

In 2015, Zhou’s group [46] reported the first successful example of palladiumcatalyzed hydrocarboxylation of alkynes with formic acid using xantphos as the ligand. A catalytic amount of benzoic anhydride was used as a cocatalyst to generate carbon monoxide in situ. In this catalytic system, acetylene gas can be efficiently hydrocarboxylated with formic acid with high regioselectivity, providing a new approach to the important bulk chemical feedstock of acrylic acids. The putative mechanism is depicted in Scheme 1.33. First, acetylene is activated by the formation of a palladium complex, which reacts with formic acid to generate the intermediate B, then captures the carbon monoxide generated in situ from the mixed acid anhydride to deliver C, and then reductive elimination of C gives the anhydride D and regenerates the palladium catalyst. D decomposes to the acrylic acid and releases CO. From the perspective of green sustainable development chemistry, the development of inexpensive metal-catalyzed alkynes and formic acid to synthesize α, βunsaturated carboxylic acid is of great importance to the laboratory synthesis of fine chemicals. In 2016, Shang and Fu et al. [47] reported a method of combining the inexpensive nickel salt [Ni(acac)2 ] with a bidentate phosphine ligand (dppbz or dppen) to catalyze the hydrocarboxylation of alkynes with formic acid through carbonyl insertion, to provide a simple method for the preparation of various substituted acrylic compounds (Scheme 1.34). The reaction has good compatibility with various functional groups (such as halogens, trifluoromethyl, methoxy groups, indole, pyrrole, [Pd2(dba)3].CHCl3, Xantphos + HCOOH

COOH

Bz2O, THF, 100 oC

15 atm

TON = 350

R

LnPd0 O

H

O O

R

LnPd

R D O

R

R

H R

O

O

A

R

LnPd

CO

R

O R B

O

H

O

HCO2H

R' O

O R'

Scheme 1.33 Putative mechanism [46]

O

R'

H

O

R

O

R PdLn

C

R

OH

O

HCO2H

20

R1

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source

R2

cat. Ni(acac)2/ diphosphine +

R1, R2 = H, alkyl, aryl

HCO2H as low as 1.1 equiv

cat. Piv2O toluene, 100 oC

H 1

R

CO2H R2

42 examples, up to 95%

Ph2P

PPh2

Ph2P

PPh2

dppen

dppbz

Scheme 1.34 Nickel-catalyzed hydrocarboxylation of alkynes with formic acid

Ni(acac)2, di-[P] + HCOOH 10 atm

Ac2O, THF, 100 oC

S

COOH yield = 77% TON = 7700

Cy2P

PCy2 di-[P]

Scheme 1.35 Nickel-catalyzed reaction of acetylene and formic acid to produce acrylic acid

furan, three-membered rings, adamantane, and thioethers). In addition, it is worth noting that some functional groups that are unstable in reducing or acidic systems can also be well tolerated in this catalytic system, such as olefins, aldehydes, esters, amides, boron esters, carbonyls, and cyano groups. The yield of desired product is not greatly reduced when applied to gram-scale reactions, and so, the system had good application prospects in industrial synthesis. At the same year, Zhou’s group successfully realized that the catalytic conversion of acetylene and formic acid to acrylic acid using a combination of nickel salt with bidentate phosphine ligand [48] and the TON value is as high as 7700 (Scheme 1.35).

1.6 Reaction of Formic Acid with Phenol (Alcohol) 1.6.1 Synthesis of Ketone (Ester) by Reaction of Formic Acid with Phenol Benzofuranones are a class of valuable structure units that exist widely in pharmaceutical compounds and natural products and serve as the key moiety in numerous drug scaffolds and biological products. In 2016, Wu’s group [49] reported a palladiumcatalyzed carbonylative intramolecular synthesis of benzofuran-2(3H)-ones from 2hydroxybenzyl alcohol using formic acid as a carbonylation reagent (Scheme 1.36a) [49]. In addition, the same group used commercially available phenols and aldehydes as the substrates and also realized the synthesis of various types of benzofuran2(3H)-ones in moderate to good yields (Scheme 1.36b). Both aromatic and aliphatic aldehydes are applicable in this catalytic system [50].

1.6 Reaction of Formic Acid with Phenol (Alcohol) R2 (a)

21 O

R2

OH OH

1

R

O

Pd(PPh3)4, P(o-tolyl) + HCOOH

1

toluene, Ac2O, 100 oC

R

O Pd(PPh3)4 (5 mol%) P(o-tol)3 (20 mol%)

OH (b)

R1

+

O

R + HCOOH 2

TFA, Ac2O PhCl, 130 oC

O

O R2 R1

O

O

O

O

N

O

CN

C5H11 54%

70%

67%

Scheme 1.36 Synthesis of benzofuran-2(3H)-ones with formic acid as CO source

1.6.2 Synthesis of β, γ -Unsaturated Carboxylic Acids by Reaction of Formic Acid with Allyl Alcohols β, γ-unsaturated carboxylic compounds, containing both carbon–carbon double bonds and carboxylic acid functional groups, are “multifunctional” intermediates in synthetic organic chemistry, which can be easily converted into β, γ-unsaturated amides and β, γ-unsaturated esters. In addition, the double bonds can be selectively reduced to obtain saturated amides, esters, aldehydes, and alcohols. The transitionmetal-catalyzed reaction of allyl alcohol derivatives and carbon monoxide is an important method for the synthesis of β, γ-unsaturated carboxylic acids. From the perspective of atomic economy and operational feasibility, it is preferable to use allyl alcohol to directly react with formic acid as the source of carbon monoxide to prepare β, γ-unsaturated carboxylic acids. However, due to the poor desorption performance of the hydroxy structure in the allyl alcohol structure, the reaction often requires a high pressure of carbon monoxide to proceed [51]. In 2016, Shang and Fu’s group [52] reported palladium-catalyzed regio- and stereoselective carboxylation of allylic alcohols with formic acid to prepare β, γunsaturated carboxylic compounds (Scheme 1.37). In the reaction system, acid anhydride plays two important roles: On the one hand, it can react with allyl alcohol to weaken the bond energy of C–OH; on the other, the acid anhydride can react with formic acid to form a thermally unstable mixed anhydride, which generates carbon monoxide in situ, thereby avoiding the use of high-pressure CO. A bidentate phosphine ligand possessing a large bite angle (xantphos) plays a crucial role in the success of this transformation. Various β, γ-unsaturated carboxylic acids were

22

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source OH R1 R2

R2 or

+ HCOOH

R1

OH

COOH O

COOH

COOH

COOH

O B O

Pd2(dba)3 (0.5 mol%) R2 Xantphos (2 mol%) Ac2O (1.5 mmol) R1 toluene, 80 oC, 12 h

COOH

O 32%, E/Z =81/19

81%, E/Z =80/20

65%

84%

F COOH

COOH S 5

COOH

O

O COOH 60%

76%

66%

89%

F

Scheme 1.37 Pd-catalyzed carboxylation of allylic alcohols with formic acid

R2 OH R2

R1 or R1

+ HCOOH OH

Pd(OAC)2, Xantphos DCC, NaHCO3 1,4-dioxane, 60 oC

R1

COOH

Scheme 1.38 Synthesis of β, γ-unsaturated carboxylic acids reported by Peng and Wu et al

obtained successfully with excellent chemo-, regio-, and stereoselectivity, providing a practical method for preparing β, γ-unsaturated carboxylic acids. To achieve the same reaction as described above, Peng and Wu’s group [53] used dicyclohexylcarbodiimide (DCC) instead of acid anhydride to react with formic acid to generate carbon monoxide in situ. Various allylic alcohols were conveniently transformed into the corresponding β, γ-unsaturated carboxylic acids in the presence of Pd(OAc)2 and xantphos. In the reaction system, equivalent inorganic base was needed (Scheme 1.38).

1.7 Reaction of Formic Acid with Arenes The synthesis of aromatic carboxylic acids and their derivatives by carbonylation via C–H bond activation of arenes and various transition-metal complexes is of great importance. Various transition-metal complexes for catalyzed carbonylation of aromatic compounds in the presence of carbon monoxide have been studied extensively (Scheme 1.39) [54]. However, the direct hydrocarbonylation of arenes in the

1.7 Reaction of Formic Acid with Arenes

23 O

H

transition-metal catalyst

Nu

+ CO + NuH

Scheme 1.39 Carbonylation reactions involving aromatics

cat. Pd(OCOCF3)2 K2S2O8

(a) + HCOOH

CF3COOH/CH2Cl2 48 h, 50 oC

45% m-:p- = 17:83

Pd(OCOCF3)2 (10 mol%) ligand-[P] (11 mol%)

H (b)

COOH HO

+ HCOOH

R

C6H4(4-OMe) N P OTf N C6H4(4-OMe)

COOH R

K2S2O8 CF3COOH/(CF3CO)2O 48 h, 50 oC

COOH

COOH

COOH

53%

ligand-[P]

COOH

93%

t

Bu 86% o/m/p = 0:25:75

β α 86% α /β = 17:83

Scheme 1.40 Palladium-catalyzed hydrocarbonylation of arenes with formic acid

absence of carbon monoxide remains a challenge. Developing a method for hydrocarbonylation of arenes to deliver the corresponding aromatic carboxylic acids using formic acid as the direct source of carbon monoxide has good atomic economy. To our knowledge, Nozaki’s group [55] first achieved palladium(II)catalyzed sequential hydroxylation–carboxylation of biphenyl to give 4 -hydroxy4-biphenylcarboxylic acid using formic acid as the source of carbon monoxide (Scheme 1.40a). Subsequently, they found that different phosphine ligands have a strong effect on the selectivity [56], and that using suitable phosphine ligands could greatly improve the efficiency and selectivity of the aromatic ring hydrocarbonylation (Scheme 1.40b).

1.8 Conclusions and Perspectives In summary, we have reviewed the synthetic application of formic acid as a C1 source in the field of green organic chemistry, which includes mainly the reaction of formic acid with amines, aryl halides, alkenes, alkynes, and arenes. As seen from this review, formic acid, one of the main products produced in the process of biomass refining, has

24

1 Conversion of Formic Acid in Organic Synthesis as a C1 Source

the advantages of being renewable, easy to store in liquid state, and biodegradable. Thus, using formic acid as a methylation reagent or carbon monoxide surrogate for carbonylation to synthesize various organic intermediates and fine chemicals has great advantages. Developing green catalytic methods for formic acid as a C1 source currently remains a hot topic in organic synthesis research. Although formic acid as a C1 source has been studied widely, further development of methods for the efficient use of catalysts with formic acid, and broadening the types of reactions involving formic acid, is warranted. Examples are as follows. For example, improve the regioselectivity of carbonyl insertion sites when using formic acid as a carbonyl group reacting with asymmetric alkynes, design the special ligand to realize directly decarbonylative reactions of formic acid using inexpensive metal catalysts under mild conditions without the addition of anhydride additives. The catalytic system for carboxylation reactions of aromatic hydrocarbons with formic acid is narrow, and the reaction conditions harsh; thus, catalytic efficiency needs to be improved. Using formic acid and alkynes as the substrates to deliver α, βunsaturated aldehydes via carbonylative process also faces great challenges. The problems described above remain challenges and opportunities, and they deserve our continued in-depth research for developing novel catalytic systems to allow formic acid as a C1 source in green chemistry.

References 1. Bond JQ, Alonso DM, Wang D, West RM, Dumesic JA (2010) Integrated catalytic conversion of γ-valerolactone to liquid alkenes for transportation fuels. Science 327:1110–1114 2. Huber GW, Iborra S, Corma A (2006) Synthesis of transportation fuels from biomass: chemistry, catalysts, and engineering. Chem Rev 106:4044–4098 3. Li CJ, Trost BM (2008) Green chemistry for chemical synthesis. Proc Natl Acad Sci USA 105:13197–13202 4. Sheldon RA (2012) Fundamentals of green chemistry: efficiency in reaction design. Chem Soc Rev 41:1437–1451 5. Taccardi N, Assenbaum D, Berger MEM, Bösmann A, Enzenberger F, Wölfel R, Neuendorf S, Goeke V, Schödel N, Maass HJ, Kistenmacher H, Wasserscheid P (2010) Catalytic production of hydrogen from glucose and other carbohydrates under exceptionally mild reaction conditions. Green Chem 12:1150–1156 6. Yu WY, Mullen GM, Flaherty DW, Mullins CB (2014) Selective hydrogen production from formic acid decomposition on Pd–Au bimetallic surfaces. J Am Chem Soc 136:11070–11078 7. Broggi J, Jurcik V, Songis O, Poater A, Cavallo L, Slawin AMZ, Cazin CSJ (2013) The isolation of [Pd{OC(O)H}(H)(NHC)(PR3 )] (NHC=N-heterocyclic carbene) and its role in alkene and alkyne reductions using formic acid. J Am Chem Soc 135:4588–4591 8. (a) Boddien A, Mellmann D, Gärtner F, Jackstell R, Junge H, Dyson PJ, Laurenczy G, Ludwig R, Beller M (2011) Efficient dehydrogenation of formic acid using an iron catalyst. Science 333:733–1736. (b) Deng L, Li J, Lai DM, Fu Y, Guo QX (2009) Catalytic conversion of biomass–derived carbohydrates into γ-valerolactone without using an external H2 supply. Angew Chem Int Ed 48:6529–6532. (c) Bielinski EA, Lagaditis PO, Zhang Y, Mercado BQ, Würtele C, Bernskoetter WH, Hazari N, Schneider S (2014) Lewis acid-assisted formic acid dehydrogenation using a pincer-supported iron catalyst. J Am Chem Soc 136:10234–10237 9. Supronowicz W, Ignatyev IA, Lolli G, Wolf A, Zhao L, Mleczko L (2015) Formic acid: a future bridge between the power and chemical industries. Green Chem 17:2904–2911

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36. Chang WJ, Dai J, Li JF, Shi Y, Ren WL, Shi YA (2017) A facile approach to ketones via Pdcatalyzed sequential carbonylation of olefins with formic acid. Org Chem Front 4:1074–1078 37. Simonato JP, Walter T, Mtivier PJ (2001) Iridium–formic acid based system for hydroxycarbonylation without CO gas. Mol Catal A 171:91–94 38. Simonato JP (2003) New efficient catalytic system for hydroxycarbonylation without CO gas. J Mol Catal A 197:61–64 39. Wang Y, Ren W, Li J, Wang H, Shi Y (2014) Facile palladium-catalyzed hydrocarboxylation of olefins without external CO gas. Org Lett 16:5960–5963 40. Dai J, Ren W, Wang H, Shi Y (2015) A facile approach to β-amino acid derivatives via palladium-catalyzed hydrocarboxylation of enimides with formic acid. Org Biomol Chem 13:8429–8432 41. Wang Y, Ren WL, Shi Y (2015) An atom-economic approach to carboxylic acids via Pdcatalyzed direct addition of formic acid to olefins with acetic anhydride as a co-catalyst. Org Biomol Chem 13:8416–8419 42. Liu W, Ren WL, Li J, Shi Y, Chang WJ, Shi Y (2017) A ligand-directed catalytic regioselective hydrocarboxylation of aryl olefins with Pd and formic acid. Org Lett 19:1748–1751 43. Wang X, Buchwald SL (2011) Rh-catalyzed asymmetric hydroformylation of functionalized 1,1-disubstituted olefins. J Am Chem Soc 133:19080–19083 44. Ren W, Chang W, Dai J, Shi Y, Li J, Shi Y (2016) An effective Pd-catalyzed regioselective hydroformylation of olefins with formic acid. J Am Chem Soc 138:14864–14867 45. Zargarian D, Alper H (1993) Palladium-catalyzed hydrocarboxylation of alkynes with formic acid. Organometallics 12:712–724 46. Hou J, Xie JH, Zhou QL (2015) Palladium-catalyzed hydrocarboxylation of alkynes with formic acid. Angew Chem Int Ed 54:6302–6305 47. Fu M-C, Shang R, Cheng W-M, Fu Y (2016) Nickel-catalyzed regio- and stereoselective hydrocarboxylation of alkynes with formic acid through catalytic CO recycling. ACS Catal 6:2501–2505 48. Hou J, Yuan ML, Xie JH, Zhou QL (2016) Nickel-catalyzed hydrocarboxylation of alkynes with formic acid. Green Chem 18:2981–2984 49. Li HP, Ai HJ, Qi XX, Peng JB, Wu XF (2017) Palladium-catalyzed carbonylative synthesis of benzofuran-2(3H)-ones from 2-hydroxybenzyl alcohols using formic acid as the CO source. Org Biomol Chem 15:1343–1345 50. Qi XX, Li HP, Wu XF (2016) A convenient palladium-catalyzed carbonylative synthesis of benzofuran-2(3H)-ones with formic acid as the CO source. Chem Asian J 11:2453–2457 51. Li HQ, Neumann H, Beller M (2016) Palladium-catalyzed aminocarbonylation of allylic alcohols. Chem Eur J 22:10050–10056 52. Fu M-C, Shang R, Cheng W-M, Fu Y (2017) Efficient Pd-catalyzed regio- and stereoselective carboxylation of allylic alcohols with formic acid. Chem Eur J 23:8818–8822 53. Wu FP, Peng JB, Fu LY, Qi XX, Wu XF (2017) Direct palladium-catalyzed carbonylative transformation of allylic alcohols and related derivatives. Org Lett 19:5474–5477 54. Li X, Li X, Jiao N (2015) Rh-catalyzed construction of quinolin-2(1H)-ones via C-H bond activation of simple anilines with CO and alkynes. J Am Chem Soc 137:9246–9249 55. Shibahara F, Kinoshita S, Nozaki K (2004) Palladium(II)-catalyzed sequential hydroxylationcarboxylation of biphenyl using formic acid as a carbonyl source. Org Lett 6:2437–2439 56. Sakakibara K, Yamashita M, Nozaki K (2005) An efficient Pd(II)-based catalyst system for carboxylation of aromatic C-H bond by addition of a phosphenium salt. Tetrahedron Lett 46:959–962

Chapter 2

Boron-Catalyzed N-Methylation of Amines with Formic Acid

Abstract N-methyl-substituted amines have found wide applications in the synthesis of fine chemicals, agrochemicals, and materials and play an important role in regulating the biological and pharmaceutical properties of molecules used in the life sciences. In this chapter, we describe our development of a nonmetallic boron-catalyzed protocol for methylation of aromatic and aliphatic, both primary and secondary, amines, using formic acid as the methylation reagent with high efficiency and selectively. The method has a wide scope of substrates and good functional group compatibility. In addition, imines can be used for hydrogenative methylation conversion in one pot in the catalytic system.

2.1 Introduction N-methyl-substituted amines are an important class of organic intermediates that can be widely used in the synthesis of pharmaceutical molecules, agrochemicals, and dyes and can often be found in some biological active molecules (Scheme 2.1) [1]. Traditional methods for synthesis of methyl-substituted amines mainly use a reducing amine system (HCHO/reducing agent) [2] or an activated methyl reagent, such as methyl iodide, dimethyl sulfate, dimethyl sulfoxide, or diazomethane [3]. However, these activated methyl reagents are all toxic and their scope of substrates is narrow. Therefore, it is of great worth to develop safer, sustainable, and environmentally acceptable methylation reagents. In this regard, during the last decade, methanol and dimethyl carbonate have been of interest as green substitutes [4]. In recent years, using dioxide carbon as methylated agent has obtained wide attention for N-methylation of © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 M.-C. Fu, Studies on Green Synthetic Reactions Based on Formic Acid from Biomass, Springer Theses, https://doi.org/10.1007/978-981-15-7623-2_2

27

28

2 Boron-Catalyzed N-Methylation of Amines with Formic Acid

amines because it is abundant, nontoxic, and inexpensive, as exemplified by Beller, Cantat, and Leitner [5–8]. However, these operations often require high temperature or pressure conditions, which limit the application of these methods. Formic acid, one of the main products during the process of biomass refining [9], is regarded as a good potential liquid hydrogen storage material and a new C1 structural motif [10]. In recent years, numerous works have been reported using formic acid as the formylation reagent for synthesizing formamide with amines [11]. Formic acid has the advantages of being nontoxic, biodegradable, easy to work with and has good reactivity with amines. Thus, formic acid has many advantages as the methyl reagent for methylation of amines, and the research on N-methylation conversion using formic acid as the C1 feedstock with amines has attracted wide interest. Cantat et al. used a system of Ru(II) and phosphine ligands to achieve methylation of aromatic amines through a cascade of formylation/transfer hydrogenation processes [12]. In this work, formic acid plays the role of both a carbon and hydrogen source with higher atom economics. In 2014, Beller’s group reported a novel catalytic protocol for the methylation of amines with formic acid as methyl reagents, using Karstedt’s catalyst [Pt(CH2 =CHSiMe2 )2 O] and silanes as reducing agents [13]. Both aromatic amines and aliphatic amines can undergo methylation conversion to deliver the corresponding tertiary amines smoothly, including [N–13 C]-labeled drugs under mild conditions in good to excellent yields. Although the previously reported catalytic systems have shown good catalytic activity, the high price of the previously used metal catalysts limits their wide application on a large scale. Therefore, the development of a method that uses more economical elements with lower toxicity to catalyze N-methylation with high efficiency and selectivity is highly desired, such as using first-row transition metals or main group elements. In this chapter, we report a boron-based catalyst [B(C6 F5 )3 ], which is nontoxic and insensitive to water and air [14], to catalyze the straightforward methylation of amines with formic acid in the presence of silane as a reducing agent. Various types of primary and secondary amines can be smoothly methylated with good selectivity and good functional group compatibility. In addition, the catalytic system was successfully applied to the alkylation of amines with readily available carboxylic acids, providing a new method for the construction of C–N bonds.

O

CH3 N CH3

4-diphenhydramine

N

CH3 N CH3

Imipramine

Scheme 2.1 Drug molecules containing N–CH3 structure

t

Bu

N CH3

Butenafin

2.2 Results and Discussion

29

Table 2.1 Catalytic N-methylation of N-methylaniline using formic acid

Reaction conditions: N-methylaniline (0.2 mmol), PhSiH3 (4.0 equiv), catalyst (5 mol%), formic acid (2.3 equiv), nBu2 O (1.0 mL), 100 °C, 8 h. The GC yield was determined using dodecane as an internal standard. a Et3 B (1.0 mol/L in THF)

2.2 Results and Discussion 2.2.1 Investigation of the Reaction Conditions We first chose N-methylaniline (1a) as the model substrate and phenylsilane as a reducing agent. A series of transition-metal catalysts in the first row and boron-based catalysts were examined as shown in Table 2.1. When using the transition-metal catalysts, such as Fe3 (CO)12 , Co(acac)3 , and Zn(OAc)2 , no desired product was detected obviously (entries 1, 2, 4). When using Cu(OAc)2 as the catalyst, 12% yield of the desired product (2a) was obtained, and 15% of the formylation by-product was also detected (3a) (entry 3). Then, we tested various boron-based catalysts (entries 5–10) and found that 49% yield of the desired product could be obtained when using Et3 B as the catalyst, but BF3 ·OEt2 was found to be inactive. Boronic acids, which were previously reported to be effective for amide condensations and amide reductions, were totally ineffective for this one-pot amine methylation reaction. To our delight, when using B(C6 F5 )3 as the catalyst, N,N-dimethylaniline (2a) was obtained in quantitative yield. Other boric acid or boric acid esters failed to give the

30

2 Boron-Catalyzed N-Methylation of Amines with Formic Acid

Table 2.2 Screening of silanes and solvents

Reaction conditions: N-methylaniline (0.2 mmol), silane (4.0 equiv), B(C6 F5 )3 (1 mol%), formic acid (2.3 equiv), nBu2 O (1.0 mL), 100°C, 8 h. The GC yield was determined using dodecane as an internal standard. PMHS = poly(methylhydrosiloxane). a B (C6 F5 )3 (0.5 mol%)

desired product. The unique catalytic activity of B(C6 F5 )3 may be attributed to its ability to form an FLP with carbonyl groups to activate the silane and thus induce reductive C–N bond formation. Then, we investigated the effect of different reducing agents. As shown in Table 2.2, when using Et3 SiH as the reducing agent, N-formylation product (3a) was formed in 61% yield, and only 6% of 2a was detected, (EtO)3 SiH also failed to give the desired product. When using Et2 SiH2 or Ph2 SiH2 , the raw material 1a was basically completely converted, and the desired product was obtained in excellent yield (higher than 90%). It should be noted that when using poly(methylhydrosiloxane) (PMHS), which is a by-product of the silicone industry [15, 16], the yield of the target product 2a is as high as 98%. Compared with other silanes, PMHS is a cheap, stable, and environmentally friendly hydrosilane, which is more suitable to serve as a reducing agent for large-scale production [17]. Therefore, we chose PMHS as a reducing agent in the subsequent research. In addition, different solvents have great effect on the reaction outcome. We found that when using DMF as the solvent, the major product is N-formylation, and only a trace amount of the desired product was detected. The conversion dramatically decreased when using THF or diglyme as the solvent, while when using dioxane, nBu2 O, toluene, or mesitylene as the solvent, the catalytic system exhibited high activity. It is worth noting that when the amount of catalyst was reduced to 0.5 mol%, the desired product 1b could still be obtained in 95% yield.

2.2 Results and Discussion

31

Table 2.3 Selectively catalyzed mono- and bimethylation of aniline

Reaction conditions: aniline (0.2 mmol), PMHS (3.0 equiv), B(C6 F5 )3 (1 mol%) formic acid (n equiv), solvent (1.0 mL), 100°C, 3 h. GC yield was determined by using dodecane as an internal standard. a PMHS (8.0 equiv), 8 h

Subsequently, to selectively achieve the mono- and dimethylation of the primary amines, we conducted an in-depth study using aniline (4a) as the substrate by investigating the effect of the amount of silane and formic acid and different solvents (Table 2.3). We found that when 4.0 equivalent of formic acid and 8.0 equivalent of PMHS were used in the system, the aniline was converted in equivalent, and N,N-dimethylaniline (2a) was obtained in 97% yield (Table 2.3, entry 1). By screening the reaction time, the amount of formic acid, the reaction temperature, and different solvents, we found that when dioxane was used as the solvent, the ratio of the mono/bis methylated product is 62/6, and the substrate conversion rate was 75% (Table 2.3, entry 8).

2.2.2 Investigation of the Substrate Scope With the optimized conditions in hand, we next investigated the scope of this reaction using formic acid and various amine coupling partners. As shown in Table 2.4, various N-methylanilines could be successfully methylated in excellent yield. The electronic effect on the phenyl ring had no major effect on the reaction outcome (2b–2e). N-Ethyl and N-benzylaniline could also be successfully methylated with formic acid in excellent yield (2f, 2i). When using indoline as the substrate, the corresponding N-methylated product was obtained in high yield (2g). Besides the N-alkylated aniline, diphenylamine also underwent reaction smoothly to the desired product (2h). When using indole as the substrate, 1-methylindoline was obtained as

32

2 Boron-Catalyzed N-Methylation of Amines with Formic Acid

the major product, in which the double bond was hydrogenated during the reaction (2j). This reaction also has good functional group compatibility: Aryl chloride (2c), aryl bromide (2d), and ether (2e) were all well tolerated. It was surprising to find that even the nitro group (2k) and cyano group (2m) were well tolerated without any undesired reduction. A terminal alkene structure, which is sensitive to transitionmetal catalysis, also remained intact (2l). Although the combination of silane and borane catalyst could directly reduce alcohols to alkanes as reported previously [17], the unprotected alcohol group remained intact with 96% yield of the desired product after the reaction (2n). The ketone functionality was not compatible in this catalytic system, and instead, a high yield of the deoxygenated product was obtained (2o). Esters could be tolerated, at least partially, by reducing the amount of silane used (2p). Not only aromatic amines, but also aliphatic amines, are suitable substrates, because piperidine and morpholine were methylated in high yield (2q, 2r). The reaction is not limited to secondary amines, as it also works well for primary amines. As shown in Table 2.5, the reaction of anilines can give dimethylated products selectively. Steric bulk on the ortho position of the aniline is well tolerated (2s, 2t, 2u). Basic nitrogen-containing heteroaromatic amines are important structural motifs in pharmaceuticals [18]. Our method could also be applied to the methylation of nitrogen-containing heteroaromatic amines as demonstrated by the selective Table 2.4 Methylation of various secondary aminesa

a Reaction

conditions: amines (0.2 mmol), PMHS (4.0 equiv), B(C6 F5 )3 (0.5 mol%), formic acid (2.3 equiv), n Bu2 O (1.0 mL), 100°C, 8–10 h. Isolated yield. b PMHS (5.0 equiv), 8 h. c PMHS (3.5 equiv), 8 h. d 120 °C, 18 h

2.2 Results and Discussion

33

Table 2.5 Methylation of various primary aminesa

a Reaction

conditions: amines (0.2 mmol), PMHS (8.0 equiv), B(C6 F5 )3 (1.0 mol%), formic acid (4.0 equiv), n Bu2 O (2.0 mL), 100°C, 8–15 h. Isolated yield. b PhSiH3 (8.0 equiv)

demethylation of pyridin-2-amine and benzo[d]thiazol-2-amine in excellent yields (2v, 2w).

2.2.3 Mechanistic Study To understand further the possible pathway of N-methylation of primary and secondary amines with formic acid, several control experiments were conducted. As shown in Scheme 2.2, when N-methylformanilide (2a) was tested under the optimized conditions, it delivered the amine product quantitatively. However, under the same reaction conditions, when using formanilide (5a) as the substrate, three products were generated by GC detection: 66% N-methylaniline (1a), 14% N,N-dimethylaniline (2a), and 10% aniline (4a). In addition, when 2.3 equivalent of formic acid was added, formanilide (5a) was transferred quantitatively with the major product of 2a in 96% yield, and only a trace of 1a was detected. Based on these results and the previous literature [13], we considered the possible reaction pathways for this reaction: the formation of dimethylated product 2a by condensation of the initially formed 1a. In addition, the formamide 5a could react with 1a to form the intermediate N-methyl-N,N  -diphenylurea and then by reduction of this intermediate to give the desired product 2a.

2.2.4 Application of This Catalytic System When exploring the scope of substrates, we found an interesting example of an imine that could be reduced in situ and methylated in one pot (Scheme 2.3).

34

2 Boron-Catalyzed N-Methylation of Amines with Formic Acid B(C6F5)3 (0.5 mol%) CHO PMHS (4.0 equiv)

N 1)

n

N

CH3

o

Bu2O, 100 C, 8 h 2-2a

2-3a 0.2 mmol

99%

2) 2-5a 0.2 mmol H N 3)

H N

B(C6F5)3 (1 mol%) PMHS (5.5 equiv) CHO HCOOH (2.3 equiv) n Bu2O, 100 oC, 8 h

H N

CH3

+

2-1a

2-2a

3%

96% H N

B(C6F5)3 (0.5 mol%) CHO PMHS (4.0 equiv) n Bu2O, 100 oC, 8 h

CH3

+

2-1a 66%

2-5a 0.2 mmol

CH3 N CH3

CH3 N CH3 + 2-2a 14%

NH2

2-4a 10%

Scheme 2.2 Control experiments

N

B(C6F5)3 (0.5 mol%) PMHS (5.0 eq.)

O +

H

0.2 mmol

CH3 N

n

OH

Bu2O (1 mL) 100 oC, 8 h

2.3 eq.

94%

Scheme 2.3 Domino reductive methylation of imine

N-substituted lactams are an important class of organic structural intermediates that are widely used in the field of organic synthesis and pharmaceuticals [19]. Using cheap and readily available raw materials to synthesize this structural unit has great attraction. To our delight, we found that aniline can react with levulinic acid using this catalytic system and can deliver N-methylpyrrolidone and N-methylpyrrole selectively (Scheme 2.4).

N O 2-3b, 91%

B(C6F5)3 (1 mol%) PMHS (2.5 equiv)

O

NH2 +

toluene, 100 oC 0.2 mmol

B(C6F5)3 (1 mol%) PMHS (5 equiv) COOH toluene, 100 oC 0.34 mmol

Scheme 2.4 Selectively synthesis of N-methylpyrrolidone and N-methylpyrrole

N

2-3c, 86%

2.4 Experimental Part and Compound Data

35

O N H t

+ HCO2H

B(C6F5)3 (1 mol%) PhSiH3 (6 equiv) Bu2O, 120 oC, 20 h 91% yield

n

Bu

t

Bu

N CH3

Scheme 2.5 Synthesis of butenafine

Considering the toxicity and cost of transition-metal catalysts, the pharmaceutical industry prefers to use synthetic routes which avoid them. Notably, we successfully applied this method to the synthesis of N-(4-(tert-butyl)benzyl)-N-methyl-1(naphthalene-1-yl)methanamine (butenafine, an antifungal drug) [20] (Scheme 2.5), and using N-(4-(tert-butyl)benzyl)-1-naphthylcarboxamide as a substrate to react with formic acid, the reduction of amides and the methylation of amines can be achieved in one pot.

2.3 Conclusion In this chapter, we have reported that a boron-based catalyst can catalyze straightforward methylation of amines with formic acid in the presence of silane as a reducing agent under mild conditions. Both primary and secondary amines can be smoothly methylated with good selectivity and functional group compatibility. The application of this method was demonstrated by the one-pot, metal-free syntheses of butenafine.

2.4 Experimental Part and Compound Data 2.4.1 Experimental Procedure General procedure A: for the methylation reaction of primary amines: In a Schlenk tube under argon atmosphere, B(C6 F5 )3 (1.0 mol%, 1.1 mg) was dissolved in dry n Bu2 O (2.0 mL), and PMHS (8.0 equiv, 1.6 mmol) was added. Then, amines (1.0 equiv, 0.2 mmol) and HCO2 H (4.0 equiv, 0.8 mmol) were added via a syringe. The reaction mixture was stirred for 8 h at 100 °C. General procedure B: for the methylation reaction of secondary amines: In a Schlenk tube under argon atmosphere, B(C6 F5 )3 (0.5 mol%, 0.56 mg) was dissolved in dry n Bu2 O (1.0 mL), and PMHS (4.0 equiv, 0.8 mmol) was added. Then, amines (1.0 equiv, 0.2 mmol) and HCO2 H (2.3 equiv, 4.6 mmol) were added via a syringe. The reaction mixture was stirred for 8 h at 100 °C.

36

2 Boron-Catalyzed N-Methylation of Amines with Formic Acid

After completion, the mixture was diluted with ethyl acetate (5 mL), quenched with aqueous NaOH (3 M solution; 3 mL) carefully, and stirred for 3 h at room temperature. The yields were analyzed by GC using n-dodecane as internal standard. All catalytic reactions were performed at least twice to ensure reproducibility. To determine the isolated yield of the methylated amines, the mixture was extracted with ethyl acetate (three times) and the combined organic layers were dried over Na2 SO4 . The organic phase was filtered, concentrated, and purified by silica gel column chromatography to give the corresponding methylated amines.

2.4.2 Characterization of the Products N-ethyl-N-methylaniline [CAS Number: 613-97-8]: According to general procedure B, obtained in 98% yield as a yellow liquid (petroleum ether/ethyl ether = 100/1). (Reference: J. Am. Chem. Soc. 2013, 135, 1549.)

1 H NMR (400 MHz, CDCl3 ) δ 7.23 (m, 2H), 6.76–6.66 (m, 3H), 3.39 (q, J = 7.1 Hz, 2H), 2.90 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 149.06, 129.21, 116.19, 112.52, 46.92, 37.55, 11.22. 1-methylindoline [CAS Number: 824-21-5]: According to general procedure B, obtained in 94% yield as a yellow liquid (petroleum ether/ethyl ether = 100/1). (Reference: Angew. Chem. Int. Ed. 2014, 53, 12876.)

H NMR (400 MHz, CDCl3 ) δ 7.12–7.05 (m, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 3.29 (t, J = 8.1 Hz, 2H), 2.94 (t, J = 8.1 Hz, 2H), 2.76 (s, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 153.29, 130.37, 127.35, 124.30, 117.91, 107.36, 56.19, 36.38, 28.75. N-benzyl-N-methylaniline [CAS Number: 614-30-2]: According to general procedure B, obtained in 90% yield as a pale yellow liquid (petroleum ether/ethyl ether = 100/1). (Reference: Angew. Chem. Int. Ed. 2013, 52, 12156.) 1

2.4 Experimental Part and Compound Data

37

H NMR (400 MHz, CDCl3 ) δ 7.26–7.11 (m, 7H), 6.69–6.61 (m, 3H), 4.45 (s, 2H), 2.93 (s, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 148.68, 137.97, 128.13, 127.51, 125.81, 125.69, 115.48, 111.30, 55.58, 37.47. 3-chloro-N,N-dimethylaniline [CAS Number: 6848-13-1]: According to general procedure B, obtained in 86% yield as a pale yellow liquid (petroleum ether/ethyl ether = 100/1). 1

H NMR (400 MHz, CDCl3 ) δ 7.14 (t, J = 8.3 Hz, 1H), 6.69 (d, J = 6.8 Hz, 2H), 6.61 (d, J = 7.8 Hz, 1H), 2.95 (s, 6H). 13 C NMR (101 MHz, CDCl3 ) δ 150.41, 133.92, 128.91, 115.14, 111.16, 109.44, 39.35. HRMS (ESI) calcd for C8 H10 ClNH+ [(M + H)+ ] 156.0502, found 156.0576. 4-methoxy-N,N-dimethylaniline [CAS Number: 701-56-4]: According to general procedure B, obtained in 98% yield as a white solid (petroleum ether/ethyl ether = 100/1). (Reference: J. Am. Chem. Soc. 2013, 135, 1549.) 1

1 H NMR (400 MHz, CDCl3 ) δ 6.85 (d, J = 9.1 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 3.76 (s, 3H), 2.87 (s, 6H). 13 C NMR (101 MHz, CDCl3 ) δ 152.11, 145.65, 115.04, 114.64, 55.77, 41.94. N-methyl-N-phenylaniline [CAS Number: 552-82-9]: According to general procedure B, obtained in 86% yield as a brown liquid (petroleum ether/ethyl ether = 100/1). (Reference: Organometallics, 2014, 33, 1587.)

H NMR (400 MHz, CDCl3 ) δ 7.27 (t, 4H), 7.02 (d, J = 7.7 Hz, 4H), 6.95 (t, J = 7.3 Hz, 2H), 3.31 (s, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 149.00, 129.17, 121.25, 120.43, 40.23. N,N-dimethyl-4-nitroaniline [CAS Number: 100-23-2]: According to general procedure B, obtained in 84% yield as a yellow solid (petroleum ether/ethyl ether = 30/1). (Reference: Angew. Chem. Int. Ed. 2014, 53, 12876.) 1

38

2 Boron-Catalyzed N-Methylation of Amines with Formic Acid

H NMR (400 MHz, CDCl3 ) δ 8.05 (d, J = 9.4 Hz, 2H), 6.54 (d, J = 9.4 Hz, 2H), 3.05 (s, 6H). 13 C NMR (101 MHz, CDCl3 ) δ 154.14, 137.06, 126.13, 110.34, 40.35. N-allyl-N-methylaniline [CAS Number: 6628-07-5]: According to general procedure B, obtained in 96% yield as a brown oil (petroleum ether/ethyl ether = 100/1). (Reference: Angew. Chem. Int. Ed. 2014, 53, 474.) 1

H NMR (400 MHz, CDCl3 ) δ 7.26–7.22 (m, 2H), 6.78–6.65 (m, 3H), 5.90–5.79 (m, 1H), 5.20–5.12 (m, 2H), 3.92 (d, J = 5.1 Hz, 2H), 2.94 (s, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 148.43, 132.74, 128.08, 115.37, 115.12, 111.41, 54.25, 36.98. Ethyl 4-(dimethylamino)benzoate [CAS Number: 10287-53-3]: According to general procedure B, obtained in 68% yield as a white solid (petroleum ether/ethyl ether = 30/1). (Reference: Angew. Chem. Int. Ed. 2014, 53, 12876.) 1

H NMR (400 MHz, CDCl3 ) δ 7.92 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 8.9 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.04 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 167.03, 153.12, 131.22, 117.59, 110.85, 60.17, 40.20, 14.50. 3-(methyl(phenyl)amino)propanenitrile [CAS Number: 94-34-8]: According to general procedure B, obtained in 87% yield as a brown liquid (petroleum ether/ethyl ether = 30/1). (Reference: Chem. Eur. J. 2014, 20, 7878.) 1

H NMR (400 MHz, CDCl3 ) δ 7.30–7.25 (m, 2H), 6.79 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 8.2 Hz, 2H), 3.72 (t, J = 6.9 Hz, 2H), 3.03 (s, 3H), 2.57 (t, J = 6.9 Hz, 2H). 13 C NMR (101 MHz, CDCl3 ) δ 147.58, 129.52, 118.46, 117.73, 112.58, 48.99, 38.66, 15.21. 2-(methyl(phenyl)amino)ethanol [CAS Number: 93-90-3]: According to general procedure B, obtained in 96% yield as a yellow liquid (petroleum ether/ethyl ether = 50/1 to 30/1). (Reference: Angew. Chem. Int. Ed. 2013, 52, 12156.) 1

2.4 Experimental Part and Compound Data

39

H NMR (400 MHz, CDCl3 ) δ 7.28–7.23 (m, 2H), 6.83 (d, J = 8.1 Hz, 2H), 6.77 (t, J = 7.3 Hz, 1H), 3.81 (t, J = 4.7 Hz, 2H), 3.47 (t, J = 5.6 Hz, 2H), 2.97 (s, 3H), 1.87 (s, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 149.96, 129.25, 117.55, 113.29, 60.05, 55.69, 38.90. N,N,2,4,6-pentamethylaniline [CAS Number: 13021-15-3]: According to general procedure A, obtained in 93% yield as a yellow liquid (petroleum ether/ethyl ether = 100/1). 1

H NMR (400 MHz, CDCl3 ) δ 6.73 (s, 2H), 2.72 (d, J = 2.4 Hz, 6H), 2.17 (dd, J = 9.4, 2.2 Hz, 9H). 13 C NMR (101 MHz, CDCl3 ) δ 146.04, 135.92, 133.12, 128.39, 41.52, 19.63, 17.96. HRMS (ESI) calcd for C11 H17 NH+ [(M + H)+ ] 164.1361, found 164.1435. N,N-dimethyl-[1,1 -biphenyl]-2-amine [CAS Number: 6590-81-4]: According to general procedure A, obtained in 83% yield as a yellow liquid (petroleum ether/ethyl ether = 100/1). (Reference: Angew. Chem. Int. Ed. 2013, 52, 12156.) 1

H NMR (400 MHz, CDCl3 ) δ 7.52–7.45 (m, 2H), 7.34–7.26 (m, 2H), 7.23–7.11 (m, 3H), 6.97–6.88 (m, 2H), 2.45 (s, 6H). 13 C NMR (101 MHz, CDCl3 ) δ 150.18, 140.94, 133.07, 130.66, 127.60, 127.25, 127.00, 125.41, 120.39, 116.49, 42.29. N,N-dimethyl-2-(methylthio)aniline [CAS Number: 2388-50-3]: According to general procedure A, obtained in 88% yield as a yellow liquid (petroleum ether/ethyl ether = 100/1). 1

H NMR (400 MHz, CDCl3 ) δ 7.17–7.06 (m, 4H), 2.78 (s, 6H), 2.44 (s, 3H). C NMR (101 MHz, CDCl3 ) δ 150.97, 134.39, 124.94, 124.69, 124.02, 119.17, 44.38, 14.83. HRMS (ESI) calcd for C9 H13 NSH+ [(M + H)+ ] 168.0769, found 168.0841. N,N-dimethylbenzo[d]thiazol-2-amine [CAS Number: 4074-74-2]: According to general procedure A, obtained in 93% yield as a white solid (petroleum ether/ethyl ether = 20/1). 1

13

40

2 Boron-Catalyzed N-Methylation of Amines with Formic Acid

H NMR (400 MHz, CDCl3 ) δ 7.58 (t, J = 7.8 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 3.19 (s, 6H). 13 C NMR (101 MHz, CDCl3 ) δ 168.81, 153.13, 134.20, 125.99, 120.96, 120.63, 118.78, 40.23. HRMS (ESI) calcd for C9 H10 N2 SH+ [(M + H)+ ] 179.0565, found 179.0640. 1

In a Schlenk tube under argon atmosphere, B(C6 F5 )3 (1.0 mol%, 1.1 mg) was dissolved in dry toluene (2.0 mL), and PMHS (2.5 equiv., to obtain 3b; 5.0 equiv., to obtain 3c) was added. Then, amines (1.0 equiv, 0.2 mmol) and levulinic acid (0.34 mmol) were added via a syringe. The reaction mixture was stirred for 13 h at 100 °C. After completion, the mixture was diluted with ethyl acetate (5 mL), quenched with aqueous NaOH (3 M solution; 3 mL) carefully, and stirred for 3 h at room temperature. The yields were analyzed by GC using n-dodecane as internal standard. All catalytic reactions were performed at least twice to ensure reproducibility. To determine the isolated yield of the methylated amines, the mixture was extracted with ethyl acetate (three times) and the combined organic layers were dried over Na2 SO4 . The organic phase was filtered, concentrated, and purified by silica gel column chromatography to give the corresponding methylated amines. 5-methyl-1-phenylpyrrolidin-2-one [CAS Number: 6724-71-6]: obtained in 91% yield as a white solid (petroleum ether/ethyl ether = 50/1 → 20/1). (Reference: ACS Catal. 2014, 4, 3045.)

H NMR (400 MHz, CDCl3 ) δ 7.42–7.35 (m, 4H), 7.23–7.18 (m, 1H), 4.35–4.26 (m, 1H), 2.70–2.50 (m, 2H), 2.43–2.33 (m, 1H), 1.80–1.71 (m, 1H), 1.21 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 174.25, 137.57, 129.00, 125.77, 124.06, 55.64, 31.37, 26.76, 20.18. 2-methyl-1-phenylpyrrolidine [CAS Number: 33342-99-3]: obtained in 86% yield as a colorless liquid (petroleum ether/ethyl ether = 100/1). (Reference: Chem. Commun. 2014, 50, 8985.) 1

2.4 Experimental Part and Compound Data

41

H NMR (400 MHz, CDCl3 ) δ 7.22 (t, J = 7.8 Hz, 2H), 6.68–6.53 (m, 3H), 3.91–3.82 (m, 1H), 3.41 (dd, J = 11.8, 4.7 Hz, 1H), 3.15 (dd, J = 16.0, 8.0 Hz, 1H), 2.13–1.92 (m, 3H), 1.76–1.65 (m, 1H), 1.17 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 146.18, 128.13, 114.06, 110.69, 52.54, 47.11, 32.06, 22.25, 18.34. 1

In a Schlenk tube under argon atmosphere, B(C6 F5 )3 (1.0 mol%, 2.6 mg) was dissolved in dry n Bu2 O (1.0 mL), and PhSiH3 (6 equiv, 3.0 mmol) was added. Then, 8a (1.0 equiv, 0.5 mmol) and HCO2 H (2.3 equiv, 1.15 mmol) were added, and the reaction mixture was stirred 20 h at 120 °C. After completion, the mixture was diluted with ethyl acetate (5 mL), quenched with aqueous NaOH (3 M solution; 3 mL) carefully, and stirred for 3 h at room temperature. The mixture was then extracted with ethyl acetate (three times) and the combined organic layers were dried over Na2 SO4 anhydrous. Finally, the organic phase was filtered, concentrated, and purified by silica gel column chromatography to give the product (yellow solid, yield: 91%, petroleum ether/ethyl ether = 50/1). N-(4-(tert-butyl)benzyl)-N-methyl-1-(naphthalene-1-yl)methanamine: (Angew. Chem. Int. Ed. 2014, 53, 11010) 1 H NMR (400 MHz, CDCl3 ) δ 8.16–8.12 (m, 1H), 7.77–7.62 (m, 2H), 7.43–7.15 (m, 8H), 3.83 (s, 2H), 3.48 (s, 2H), 2.11 (s, 3H), 1.22 (s, 9H). 13 C NMR (101 MHz, CDCl3 ) δ 149.91, 136.36, 135.14, 133.97, 132.62, 128.88, 128.43, 127.95, 127.80, 127.47, 125.73, 125.61, 125.15, 124.98, 62.12, 60.52, 42.46, 34.54, 31.51.

References 1. Ali MF, El Ali BM, Speight JG (2005) Handbook of industrial chemistry: organic chemicals. McGraw-Hill, New York 2. Clarke HT, Gillespie HB, Weisshaus SZ (1933) The action of formaldehyde on amines and amino acids. J Am Chem Soc 55:4571–4587 3. Smith MB, March J (2001) Advanced organic chemistry, 5th edn. Wiley-Interscience, New York 4. Zhao Y, Foo SW, Saito S (2011) Iron/amino acid catalyzed direct N-alkylation of amines with alcohols. Angew Chem Int Ed 50:3006–3009 5. (a) Li Y, Fang X, Junge K, Beller M (2013) A general catalytic methylation of amines using carbon dioxide. Angew Chem Int Ed 52:9568–9571. (b) Li Y, Sorribes I, Yan T, Junge K, Beller M (2013) Selective methylation of amines with carbon dioxide and H2. Angew Chem Int Ed 52:12156–12160 6. (a) Jacquet O, Gomes CDN, Ephritikhine M, Cantat T (2012) Recycling of carbon and silicon wastes: room temperature formylation of N–H bonds using carbon dioxide and polymethylhydrosiloxane. J Am Chem Soc 134:2934–2937. (b) Tlili A, Frogneux X, Blondiaux E, Cantat

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7.

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9. 10. 11. 12. 13. 14.

15. 16.

17. 18.

19.

20.

2 Boron-Catalyzed N-Methylation of Amines with Formic Acid T (2014) Creating added value with a waste: methylation of amines with CO2 and H2 . Angew Chem Int Ed 53:2543–2545 Beydoun K, vom Stein T, Klankermayer J, Leitner W (2013) Ruthenium-catalyzed direct methylation of primary and secondary aromatic amines using carbon dioxide and molecular hydrogen. Angew Chem Int Ed 52:9554–9557 Das S, Bobbink FD, Laurenczy G, Dyson PJ (2014) Metal-free catalyst for the chemoselective methylation of amines using carbon dioxide as a carbon source. Angew Chem Int Ed 53:12876– 12879 Johnson TC, Morris DJ, Wills M (2010) Hydrogen generation from formic acid and alcohols using homogeneous catalysts. Chem Soc Rev 39:81–88 Enthaler S, von Langermann J, Schmidt T (2010) Carbon dioxide and formic acid—the couple for environmental-friendly hydrogenstorage? Energy Environ Sci 3:1207–1217 Allen CL, Williams JMJ (2011) Metal-catalysed approaches to amide bond formation. Chem Soc Rev 40:3405–3415 Savourey S, Lefevre G, Berthet JC, Cantat T (2014) Catalytic methylation of aromatic amines with formic acid as the unique carbon and hydrogen source. Chem Commun 50:14033–14036 Sorribes I, Junge K, Beller M (2014) General catalytic methylation of amines with formic acid under mild reaction conditions. Chem Eur J 20:7878–7883 Houghton AY, Hurmalainen J, Mansikkamäki A, Piers WE, Tuononen HM (2014) Direct observation of a borane–silane complex involved in frustrated Lewis-pair-mediated hydrosilylations. Nature Chem 6:983–988 Das S, Addis D, Zhou S-L, Junge K, Beller M (2010) Zinc-catalyzed reduction of amides: unprecedented selectivity and functional group tolerance. J Am Chem Soc 132:1770–1771 Hanada S, Tsutsumi E, Motoyama Y, Nagashima H (2009) Practical access to amines by platinum-catalyzed reduction of carboxamides with hydrosilanes: synergy of dual Si−H groups leads to high efficiency and selectivity. J Am Chem Soc 131:15032–15040 Addis D, Das S, Junge K, Beller M (2011) Selective reduction of carboxylic acid derivatives by catalytic hydrosilylation. Angew Chem Int Ed 50:6004–6011 Huang S, Wong JCS, Leung AKC, Chan Y-M, Wong L-L, Fernendez MR, Miller AK, Wu W-M (2009) Excellent correlation between substituent constants and pyridinium N-methyl chemical shifts. Tetrahedron Lett 50:5018–5020 Ogiwara Y, Uchiyama T, Sakai N (2016) Reductive amination/cyclization of keto acids using a hydrosilane for selective production of lactams versus cyclic amines by switching of the indium catalyst. Angew Chem Int Ed 55:1864–1867 (a) McNeely W, Spencer CM (1998) Butenafine. Drugs 55:405–412. (b) Singal A (2008) Butenafine and superficial mycoses: current status. Expert Opin Drug Metab Toxicol 4:999– 1005

Chapter 3

Nickel-Catalyzed Hydrocarboxylation of Alkynes with Formic Acid Through Catalytic CO Recycling

Abstract In this chapter, we describe the development of a protocol using the combination of Ni(II) salt, bisphosphine ligand, and a catalytic amount of acid anhydride, to achieve the hydrocarboxylation of various alkynes with formic acid with high selectivity and remarkable functional group compatibility, affording α, β-unsaturated carboxylic acids regio- and stereoselectively. Both terminal and internal alkynes are amenable substrates. A mechanism proceeding through carbon monoxide recycling in catalytic amount is demonstrated to be crucial for the success of this transformation.

R1 1

2

R2

R , R = H, alkyl, aryl

HCO2H

+

as low as 1.1 equiv

cat. Ni(acac)2/ diphosphine

H

CO2H

cat. Piv2O toluene, 100 oC

R1

R2

42 examples, up to 95%

high chemo- regio- and stereoselectivity

3.1 Introduction α, β-Unsaturated carboxylic acid is a key organic structural unit that plays an important role in the chemical, pharmaceutical, and perfumery fields. Transition-metalcatalyzed hydrocarboxylation of alkynes is an effective strategy to access α, βunsaturated carboxylic compounds [1]. In 1949, Reppe et al. reported the palladiumcatalyzed hydrocarboxylation of alkynes with carbon monoxide [2], but the reaction system requires high-pressure carbon monoxide, which is toxic, flammable, and difficult to handle. In 1999, Yamamoto’s group [3] reported the equivalent of bis(1,5-cyclooctadiene) nickel to achieve the hydrocarboxylation of alkyne with carbon dioxide under alkaline conditions. In 2011, Tsuji’s group [4] and Ma’s group [5], respectively, reported the hydrocarboxylation of alkyne with carbon dioxide to access α, β-unsaturated carboxylic acids using catalytic amounts of copper (II) © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 M.-C. Fu, Studies on Green Synthetic Reactions Based on Formic Acid from Biomass, Springer Theses, https://doi.org/10.1007/978-981-15-7623-2_3

43

44

3 Nickel-Catalyzed Hydrocarboxylation of Alkynes …

and nickel (0). However, a stoichiometric amount of active silanes or alkyl zinc as reducing agents is necessary in these reaction systems, which are sensitive to air and humidity. Formic acid, which can be produced from biomass and CO2 reduction, is potentially an ideal source for atom-efficient hydrocarboxylation of alkynes. Using formic acid as a substitute for carbon monoxide for carbonylation has been attracted widespread attention [6]. In 2015, Zhou et al. [7] reported a palladium-catalyzed hydrocarboxylation of alkynes with formic acid. However, the application of an inexpensive and ubiquitous first-row transition-metal catalyst to this process is still unexploited. Herein, we demonstrate that through the combination of an inorganic Ni(II) salt, a bisphosphine ligand (1,2-bis(diphenylphosphino)-benzene, dppbz) and a catalytic amount of acid anhydride, atom-economical hydrocarboxylation of alkynes with formic acid could proceed smoothly with high chemo-, regio-, and stereoselectivity. The inexpensive nickel-catalytic system is capable of catalyzing a broad range of terminal and internal alkynes with remarkable functional group compatibility. This work provides a new method to access various functionalized alkenyl carboxylic acids using inexpensive base-metal catalysis.

3.2 Results and Discussion 3.2.1 Investigation of Reaction Conditions We envisaged that using inexpensive nickel catalysts combined with suitable ligands, and by adding acid anhydride and formic acid to generate carbon monoxide in situ, it may be possible to achieve the hydrocarboxylation of alkyne with formic acid. However, nickel catalysts are easily poisoned by CO [8, 9], which leads to the loss of catalytic activity. Nevertheless, the use of suitable ligands can well stabilize the Ni–CO bond, thereby avoiding the problem of nickel catalysts being poisoned [10, 11]. Therefore, we postulated that suitable phosphine ligands and the concentration of carbon monoxide generated in situ in this catalytic system are critical for the successful hydrocarboxylation of alkyne. Our investigation into the key reaction-controlling parameters of hydrocarboxylation of alkyne is shown in Table 3.1. From the outset, diphenylacetylene was chosen as the model substrate. After careful optimization of all reaction parameters, the desired product (E)-2,3-diphenylacrylic acid was obtained in 95% yield when heating a mixture of diphenylacetylene (0.5 mmol), formic acid (1.0 mmol), air-stable Ni(acac)2 (5 mol%), dppbz (7 mol%), and pivalic acid anhydride (20 mol%) in toluene at 100 °C for 24 h. By contrast with other Ni-catalyzed hydrocarboxylation under basic conditions, this reaction proceeds under acidic conditions and affords the carboxylic acid product without follow-up acidification. The good chemo- and stereoselectivities of this transformation are noteworthy. Although formic acid was previously reported to act as a reducing agent to transfer hydrogenate alkyne to alkene [12], under our optimized conditions, alkene and alkane by-products were

3.2 Results and Discussion

45

Table 3.1 Key factors controlling the reaction Ni(acac)2 (5 mol %) dppbz (7 mol %) Ph + HCOOH Ph Piv2O (20 mol %) 3-1a toluene, 100 oC, 24 h 1.0 mmol 0.5 mmol

H Ph

COOH Ph

3-1b, 95%

Effect of nickel source (5 mol % of Ni. source instead of Ni(acac)2) none

NiBr2 diglyme

0%

11%

NiCl2

Ni(OTf)2

Ni(COD)2

15%

0%

84%

Effect of ligand (7 mol % of ligand instead of dpbz) 1,10-phen 0%

dppm

PPh3

< 5%

0%

dppb < 5%

dppen

dppf

56%

< 5%

dppe

dppp

25% Xantphos 0%

40% (88%a) Binap < 5%

Effect of acid anhydride (20 mol % of anhydride instead of Piv2O) Bz2O 89%

Tfa2O < 5%

Ac2O

Tf2O

85%

0%

not detected. The nickel catalyst selectively distinguishes the triple bond over the double bond because no further reduced aliphatic carboxylic acid or double hydrocarboxylated dicarboxylic acid was detected. This reaction has an excellent stereoselectivity without formation of any (Z)-2,3-diphenylacrylic acid. Nickel precursors have a substantial effect on the reaction outcome. As shown in Table 3.1, this reaction failed to give the desired product at all in the absence of the nickel catalyst. Using nickel precursors containing a halide counteranion has a deleterious effect, probably because of the competitive coordination of halide with formate anion to the catalyst center, although Ni(COD)2 also works as a good catalyst precursor. However, because of its air sensitivity, air-stable Ni(acac)2 is preferred. When using Ni(OTf)2 as the catalyst, only the by-product of alkyne hydrogenation was detected. The ligand plays a critical role for the reaction. As shown in Table 3.1, row 2, among all the ligands tested, 1,2-bis(diphenylphosphino)benzene (dppbz) gave optimal results. Monophosphine ligand or dinitrogen ligand was ineffective. It is also worth noting that the efficiency strongly depends on the backbone structure and bite angle of the bisphosphine ligands. The high ligand dependence may be ascribed to a suitable transeffect of the ligand to labilize the Ni–CO bond to facilitate CO insertion [13]. Acid anhydride as additive appears to be another crucial

46

3 Nickel-Catalyzed Hydrocarboxylation of Alkynes …

Table 3.2 Effect of the amount of acid anhydride Ni(acac)2 (10 mol %) dppp (20 mol %)

O Ph

Ph

+

3-1a, 0.5 mmol

H

OH

1.0 mmol

Ac2O (x mol %) toluene, 100 oC, 24 h

H Ph

COOH Ph 3-1b

x mol %

0

10

20

30

40

50

100

Yield of 1

0

65

88

64

30

50%) amount of acid anhydride gave no desired product. All these parameter studies supported a suitable ligand and subtly controlling the concentration of CO are two keys for the reaction, as described above in the working hypothesis.

3.2.2 Exploring the Substrate Scope With the understanding of this reaction, we next explored the scope of different alkynes. Firstly, various diarylacetylenes were tested as shown in Table 3.3. Only (E)-2,3-diarylacrylic acid was formed in this transformation without a (Z)-isomer being detected. The stereoconfiguration of 1i was confirmed by an X-ray diffraction analysis. Both electron-rich (1c, 1d, 1g, 1h) and electron-deficient (1e, 1f, 1i, 1k) diarylacetylenes delivered the hydrocarboxylation product in good yield. In addition, the catalytic system has good compatibility with aryl fluoride, aryl chloride, and aryl bromide. When using 1,2-di(naphthalen-1-yl)ethyne as the substrate, only 53% of desired product was obtained, probably because of steric hindrance (1j). 3,3 -(Ethyne-1,2-diyl)dibenzonitrile gave moderate conversion and yield, possibly because of the coordination effect of the cyano substituent (1k). In addition to diarylacetylenes, dialkyl alkynes are amenable substrates. The reaction of oct-4-yne gave (E)-2-propylhex-2-enoic acid in 95% yield (1l). It should be noted that the amount of formic acid could be reduced to 1.5 equivalent with slight decrease of the yield to 93%, but when reduced to 1.2 equivalent, only 73% yield of the desired product was obtained. Then, for the unsymmetrical alkynes, as shown in Table 3.4, such as aryl alkyl alkynes, the hydrocarboxylation affords the α-arylated alkenyl carboxylic acids as the major product. Dppen was chosen as the ligand because of its slightly better performance than dppbz. When 1-phenylpropyne was used as the substrate, the hydrocarboxylation product was obtained in as high as 97% yield, in which the

3.2 Results and Discussion

47

Table 3.3 Scope of symmetric alkynes Ni(acac)2 (5 mol%) dppbz (7 mol%)

O R

R

+

H OH Piv2O (20 mol%) (1.2-2.2 equiv) toluene, 100 oC COOH

COOH

F R

H

COOH

R

R

COOH

F

R 3-1g, 95%

3-1c, R = Me, 86%a 3-1d, R = OMe, 85%a 3-1e, R = Cl, 87% 3-1f, R = Br, 86%

3-1h, 70%

COOH

F3C

CF3 3-1i, 78%

COOH

COOH COOH NC

3-1j, 53%a

CN 3-1k, 46%

3-1l, 95%, 93%b , 73%c

Reaction conditions: alkyne (0.5 mmol), HCO2 H (2.2 equiv), Ni(acac)2 (5 mol%), dppbz (7 mol%), Piv2 O (20 mol%), toluene (1.0 mL), 100 °C, 24 h. Isolated yields. a dppp (10 mol%), HCO2 H (2.0 equiv). b HCO2 H (1.5 equiv). c HCO2 H (1.2 equiv)

α-carboxylated product is the major isomer (α/β = 1.9/1). This result reveals that in the hydrometallation step, nickel prefers the α-position of the aryl substituent. In addition, the ratio of the two regioisomers (α/β) is also affected by the steric effect of the alkyl substituent of the alkyne. Compared with product 2a, when 1phenylbutyne was used as substrate, the reaction gave excellent yield with a higher ratio of the two isomers (93% yield, α/β = 4.6/1). When using hex-1-yn-1-ylbenzene as a substrate, the yield of the hydrocarboxylated product (2c) was obtained with a slightly reduced yield and no further improvement in regioselectivity. These results suggested that the electronic effect on the aryl substituents slightly affects the yield but has no major effect on the regioselectivity. Although several investigators reported that heterocyclic substituted alkynes can considerably improve the regioselectivity

48

3 Nickel-Catalyzed Hydrocarboxylation of Alkynes …

Table 3.4 Scope and selectivity of unsymmetrical internal alkynes R

1

R

Ni(acac)2 (5 mol%) dppen (7 mol%)

O

2

+ H

OH

Piv2O (20 mol%) toluene, 100 oC

COOH Me

R

R1

C6H13

R2

COOH Bu

Ph

3-2d OMe 81% ( / = 82 : 18)

COOH

Bu

R1

R2

3-2b, R = Et 93% ( / = 82 : 18) 3-2c, R = Bu 85% ( / = 74 : 26)

COOH

H

+

COOH

Ph

3-2a 97% ( / = 65 : 35) 98% ( / = 62 : 38)a

HOOC

COOH

H

COOH

S BnO

CF3 3-2e, 96% ( / = 80 : 20)

3-2f, 76% ( / = 76 : 24) COOH

COOH Cy

Ph

3-2h, 57% ( / = 49 : 8)b

Ph Me 3-2i, 68% ( / = 97 : 3)

3-2g, 83% ( / = 84 : 16) COOH

BnO

3-2j, 98% ( / = 0 : 100)c

of hydrometallization [14], unfortunately, in our study, no matter whether the heterocyclic substituted alkyne or alkyl chain contained heteroatoms, the regioselectivity of hydrocarboxylated products was not improved substantially (2f, 2g). When the alkyne was substituted with a secondary alkyl group (2h), the α/β regioselectivity further increased, but with a decrease of the yield (57%, α/β = 6.1/1) due to steric hindrance. When (3-(benzyloxy)but-1-yn-1-yl)benzene was applied, good regioselectivity was achieved with moderate yield (2i, 68%, α/β = 90/10). Using 4,4dimethyl-2-pentyne as the substrate, the carboxylation site was completely selected at the position with less steric hindrance in excellent yield (2j, 98%, α/β = 0/100). From the results described above, it can be seen that the carboxylation takes place selectively on the α-position of the aryl substituent, and the steric hindrance effect of the alkyl substituent acts as an additional factor to determine the regioselectivity. For unsymmetrical alkyl-alkyl-substituted acetylenes, the steric effects act as the dominant factor. As shown in Table 3.5, the hydrocarboxylation reaction of terminal alkynes can also proceed well in this catalytic system. It should be noted that in the nickelcatalyzed hydrocarboxylation with CO2 to produce α, β-unsaturated carboxylic acids described in previous reports, terminal alkynes could not be used as suitable substrates [5, 15]. Table 3.5 summarizes the reaction results for terminal alkynes with formic acid. For terminal alkyl alkynes, branched selectivity can be achieved exclusively.

3.2 Results and Discussion

49

Table 3.5 Scope and selectivity of terminal alkynes Ni(acac)2 (5 mol%) dppbz (7 mol%)

O R

+ H OH (1.1-2.2 equiv)

b

COOH

R

I

Cl

Ph

Bu 3-3c 80%, 13%c

3-3e, 94%c / 99/1

3-3d 68%, 3%c

Br

COOH

NC

COOH

COOH

t-

3-3b, 79% / 99/1

3-3a, 93% (90% , 83% ) / 99/1

R

COOH

Ph a

COOH +

Piv2O (20 mol%) toluene, 100 oC

COOH

COOH

HOOC

COOH

O O

O

O O

d

3-3f, 64% 99/1

g, 50% 99/1

3-3h, 90% 99/1

HOOC

O

3-3i, 61% 99/1

R

COOH

3-3k, 91%,

99/1

COOH O

3-3p, 77% 99/1

O 3-3o, 83% 99/1

3-3n, 52%d 99/1

N N 3-3q, 88% 99/1

COOH

O

COOH N 3-3r, 74% 99/1

COOH

O Ph

S

COOH

O

R = cyclopropyl 3-3l, 89%b 1-adamantyl 3-3m, 92%b 99/1

COOH

O H 3-3j, 86% 99/1

COOH

O

O B O

O

O

COOH

O

O O

3-3s, 89% 99/1

However, when using the substrate with large steric hindrance on the α-position, a linear product was detected (3c, 93%, α/β = 80/13). For terminal aryl alkynes, when using phenylacetylene as the substrate, a branched product was obtained in moderate yield, only 3% yield of the linear product was detected (3d). The excellent functional group compatibility is highlighted in Table 3.5. Alkyl chloride (3e), cyano (3f), aryl iodide (3g), activated aryl bromide (3h), aryl pinacol boronate (3k), ester (3i, 3l, 3m), aryl aldehyde (3j), ketone with enolizable α-hydrogen (3i), alkene (3o), imide (3p), and sulfide (3n) were well tolerated. It is noteworthy that although aryl bromide and aryl iodide are susceptible to low-valent nickel species, substantial amounts of hydrodebromination or hydrodeiodination were not detected in our reaction system, which may be due to the CO poisoning effect on low-valent nickel species retarding oxidative addition to aryl halide, but also the acidic reaction conditions making lowvalent nickel species easily oxidized by formic acid. For some products with only

50

1)

3 Nickel-Catalyzed Hydrocarboxylation of Alkynes …

Ph

Ph

Ni(acac)2 (5 mol%) dppbz (7 mol%)

+ HCO2H

5 mmol (0.892 g)

7.5 mmol

Bz2O (15 mol%) toluene, 100 oC, 30 h

O 5 mmol (0.89 g)

Ph

Ph

3-1b, 94% (1.06 g)

Ni(acac)2 (5 mol%) dppbz (7 mol%)

O

2)

COOH

+

HCO2H 7.5 mmol

Bz2O (15 mol%) toluene, 100 oC, 30 h

O

COOH

O 3-3t, 81% (0.90 g)

Scheme 3.1 Gram-scale reactions

moderate yields, the starting materials were recovered (3i, 3n). Heteroaromatics, such as thiophene (2f), indole (3p), pyrrole (3r) and furan (3s) were well tolerated. It is worth noting that when the amount of formic acid was reduced to 1.1 equivalent, and the yield of the desired product did not decrease greatly (3a, 3l, 3m).

3.2.3 Gram-Scale Reactions To demonstrate further the utility of this hydrocarboxylation protocol, the gram-scale reactions were conducted for synthesis of α, β-unsaturated carboxylic acid. As shown in Scheme 3.1, the amount of formic acid could be reduced to 1.5 equivalents on the gram scale without decreasing the yield (1b, 94%). In addition, the cyclic alkene structure remained intact selectively after the reaction, and the desired product was obtained in high yield (3t), although alkenes can undergo hydrocarboxylation with formic acid in the palladium-catalyzed system [16, 17].

3.2.4 Mechanistic Investigation To shed further light on the mechanism of the protocol, isotope-labeling experiments were conducted as described in Scheme 3.2. The 13 C-labeled 2-methylenehexanoic acid was obtained in high yield with excellent 13 C incorporation when using H13 COOH as the substrate. In addition, the reaction conducted under CO2 atmosphere gave the desired product in high yield with excellent 13 C incorporation (>99% 13 C incorporation). These results suggest that the carboxylation process with CO2 is not likely involved in the reaction mechanism. Based on the results described above and previous reports, we proposed a possibility pathway of hydrocarboxylation reaction of alkynes with formic acid. As shown in Scheme 3.3, first, a Ni(0) species coordinates with alkyne (A) followed

3.2 Results and Discussion

51

H13CO2H

+

1.1 equiv

0.5 mmol entry

Ni(acac)2 (5 mol%) dppbz (7 mol%)

13COOH

Piv2O (20 mol%) toluene, 100 oC, 24 h

atmosphere

3-3u % 13C of 3u

yield (%)

1

Ar

91

> 99%

2

CO2

90

> 99%

Scheme 3.2 Isotope-labeling experiments

R

LnNi0 O

R

H

O O

R

LnNi

R D

R CO Recycling R

COOH

O

H R

O

O

Ni-Catalytic Cycle

C

R

H

HCO2H

O R

O O

H

O

R O

NiLn A

LnNi

CO

R

R

R'

HCO2H

B

(R'CO)2O CO concentration controlling

Scheme 3.3 Proposed reaction pathway

by hydrometallation to generate an alkenyl–Ni species (B) [18]. This alkenyl-Ni species can generate intermediate C through CO insertion. The carbon monoxide in the reaction system can originate from the decomposition of the mixed anhydride in situ obtained by the reaction of formic acid with anhydride [8, 16]. The concentration of CO was controlled by the amount of anhydride added. Then, the Ni(0) catalyst is regenerated and the acrylic anhydride (D) is delivered through reductive elimination. The acrylic anhydride (D) decomposes to the desired product and CO.

52

3 Nickel-Catalyzed Hydrocarboxylation of Alkynes …

3.3 Conclusion In this chapter, we have reported the first nickel-catalyzed hydrocarboxylation of a broad range of alkynes, including both internal and terminal alkynes with formic acid. The operational simplicity, generality, and remarkable functional group compatibility make this protocol a user-friendly method for the synthesis of functionalized α, βunsaturated carboxylic acids, including 13 C-labeled carboxylic acids. A mechanism through CO recycling in catalytic amount is critical for the success of the reaction. The desired products were obtained in high yields on a gram scale. The methodology using formic acid through catalytic CO recycling may find future applications in related nickel-catalyzed carbonylation reactions.

3.4 Experimental Part and Compound Data 3.4.1 Investigation of the Key Reaction Parameters See Tables 3.6, 3.7, 3.8, 3.9 and 3.10. Table 3.6 Screening of nickel catalysts Ph

Entry 1 2 3 4 5 6

Ph

+ HCO2H

Ni-source (5 mol%) dppbz (7 mol%) Piv2O (20 mol%) toluene, 100 oC, 24 h

Catalysts None NiBr2·diglyme NiCl2 Ni(OTf)2 Ni(COD)2 Ni(acac)2

H Ph

COOH Ph

Yield (%) 0 11 15 0 89 95

3.4 Experimental Part and Compound Data

53

Table 3.7 Screening of different solvents Ph

Ph

+ HCO2H

Ni(acac)2 (5 mol%) dppbz (7 mol%) Piv2O (20 mol%) solvent, 100 oC, 24 h

Solvents CH3OH THF 1,4-dioxane benzen toluene DMF DMSO

Entry 1 2 3 4 5 6 7

H Ph

COOH Ph

Yield (%) 0 99:1

Yield of 4-2a (%) 89 76

99:1, unless other wise noted. E/Z ratio determined by 1H NMR. a Formic acid (2.0 mmol), Ac2 O (2.0 mmol). b THF was used as solvent, 100 °C. c 4,6-bis(diphenyl phosphino)-10H-phenoxazine (L13) was used as ligand

84

4 Efficient Pd-Catalyzed Regio- and Stereoselective Carboxylation … OH

1.

HCOOH

+

5.0 mmol

Pd2(dba)3 (0.5 mol%) xantphos (2.0 mol%) Ac2O (15 mmol) toluene, 80 oC, 12 h

COOH

91%, 0.737 g

15 mmol OH

O

2.

+

B O

5.0 mmol

HCOOH

Pd2(dba)3 (0.5 mol%) xantphos (2.0 mol%) Ac2O (15 mmol) toluene (10 mL) 80 oC, 12 h

can be used for further modification

F

COOH

3.

+

HCOOH

F 5.0 mmol

B O

82%, 1.18 g, E:Z = 98:2

15 mmol

OH

F

COOH O

15 mmol

Pd2(dba)3 (0.5 mol%) xantphos (2.0 mol%) Ac2O (15 mmol) F toluene (10 mL) 80 oC, 12 h

O

NH N

[ref.18] N F 94%, 1.29 g

F

Pimozide

Scheme 4.2 Gram-scale reactions

(3u). However, when alkyl bromide was used, the yield was low because of the SN2 substitution side reaction with the acetate anion (3v). It was interesting to note that Shi et al. [13] reported that a terminal olefin can be effectively hydrocarboxylated and hydroformylated with formic acid and acetic anhydride using palladium catalysis, whereas, in our reactions, both terminal and internal olefins remained intact, probably due to the chemoselectivity induced by the different ligand system (3w).

4.2.3 Gram-Scale Synthesis In order to further clarify the synthetic utility of this protocol, we performed three gram-scale synthesis as shown in Scheme 4.2. It was gratifying that the reaction could be easily scaled up to gram scale without reducing its efficiency when using primary and secondary allylic alcohols as the substrates. Transmetallation of the aryl boronate does not allow arylation of an allyl palladium intermediate. Thus, a product possessing a useful boronate functionality was obtained in 82% isolated yield on gram scale and with high selectivity. In addition, we demonstrate the use of this reaction to prepare an important intermediate of a commercialized medicinal compound [18], pimozide, an antipsychotic drug for the treatment of Tourette’s syndrome.

4.2.4 Mechanistic Investigation The 13 C-labeling experiment was performed in order to further shed light on the mechanism of the protocol. As shown in Scheme 4.3, 13 C-labeled β, γ-unsaturated carboxylic acid was obtained with >99% 13 C incorporation when using 13 C-labeled formic acid under CO2 atmosphere. This confirms the mechanism of CO generation

4.2 Results and Discussion Ph

Ph

Pd2(dba)3 (0.5 mol%) xantphos (2.0 mol%) 13COOH + H Ac2O (1.5 mmol) toluene, 80 oC, 12 h 1.5 mmol CO2 atmosphere

OH

0.5 mmol

Scheme 4.3

85

13 C-labeling

13

C O

OH

87%, 13C (%) >99%

experiment

from formic acid rather than any carboxylation process with CO2 formed from dehydrogenation of formic acid. On the basis of these results and the study of Chap. 3, we depicted a possible reaction mechanism in Scheme 4.4. Firstly, allyl alcohol reacts with acetic anhydride to generate allyl alcohol acetate (B) in situ, then oxidative addition with Pd(0) to form the allyl palladium complex (C). Subsequently, coordination and insertion of C with CO, which was generated in situ from the reaction of formic acid with anhydride, afforded the complex E. After reduction elimination to obtain Pd(0) and mixed acid anhydride F, and finally, the intermediate F reacts with an acid to deliver the desired product G. One intriguing aspect of this reaction is the regio- and stereoconvergence. Ecinnamyl alcohol and α-vinylbenzyl alcohol yield the same allyl palladium species after oxidative addition. Thus, the selectivity mainly depends on the thermodynamically favorable CO-insertion step. According to the literature, a transition-metal or acid catalyst can catalyze the isomerization of an allylic alcohol into a thermodynamically stable isomer (α-vinylbenzyl alcohol to E-cinnamyl alcohol) [19]. Our control experiment also confirmed that in the absence of formic acid, both E-cinnamyl and avinylbenzyl alcohol can be smoothly converted into E-cinnamyl acetate, catalyzed by the palladium catalyst (Scheme 4.5a). Thus, the regioselectivity could be explained Ph

COOH G Ph

RCO2O

RCO2H

O

B

Pd(0)L

RCO2O - RCO2H

Ph

OH A

R

O

Ph

OOCR

O

F L Pd

Ph

L

O O

Ph

R

O E

Pd OOCR C O

O L OC Pd OOCR

RCO2H

Ph D

Scheme 4.4 Proposed reaction pathway

R

O

H

HCOOH + RCO2O RCO2H

86

4 Efficient Pd-Catalyzed Regio- and Stereoselective Carboxylation …

OH Ph

OH

+

0.25 mmol

Ph

OH

0.25 mmol

Ph 0.25 mmol

Pd2(dba)3 (0.5 mol%) xantphos (2.0 mol%) Ac2O (1.5 mmol) toluene, 80 oC, 12 h

Pd2(dba)3 (0.5 mol%) xantphos (2.0 mol%) + Ph OH Ac2O (1.5 mmol) toluene, 80 oC, 12 h 0.25 mmol

Ph

OAc

(a)

0.48 mmol

Ph

OAc

(b)

0.48 mmol

Scheme 4.5 Control experiments regarding regio- and stereoselectivity

by this thermodynamically favored isomerization. Considering that the diastereomers of the allylic alcohol may exhibit different reactivity in transition-metal-catalyzed allylic substitution reactions [3], a control experiment was performed to clarify the observed stereoconvergence. The results of this experiment indicated that a reaction using a mixture of Z- and E-cinnamyl alcohol afforded only E-cinnamyl acetate in the absence of FA (Scheme 4.5b). The results of this control experiment further indicated that stereoisomerization of cinnamyl acetate readily takes place in the presence of a palladium catalyst and, furthermore, is independent of the CO-insertion step.

4.3 Conclusion In this chapter, we have reported that biomass-derived formic acid can be used together with acetic anhydride to directly carboxylate allylic alcohols in the presence of a low loading of commercially available palladium catalyst, in order to prepare β, γ-unsaturated carboxylic acids with excellent chemo-, regio-, and stereoselectivity. Regio- and stereoisomers of allylic alcohols react in a convergent manner to afford products with high selectivity. It was discovered that a bidentate phosphine ligand possessing a large bite angle (xantphos, L10) plays a crucial role in the success of this transformation. Compared with established carbonylation methods, this reaction avoids the use of high-pressure CO gas and proceeds under mild acidic conditions, generating acetic acid as a by-product. We anticipate that the reaction we have developed could find future industrial application as a sustainable and user-friendly method of preparing functionalized β, γ-unsaturated carboxylic acids.

4.4 Experimental Part and Compound Data

87

4.4 Experimental Part and Compound Data 4.4.1 Investigation of the Key Reaction Parameters See Tables 4.4, 4.5, 4.6 and 4.7. Table 4.4 Screening of palladium catalysts OH

0.5 mmol

+ HCOOH 1.5 mmol

cat.[Pd] (0.5 mol%) xantphos (2.0 mol%) Ac2O (1.5 mmol) toluene (1 mL) 80 oC, 12 h

Entry

Cat. [Pd]

1 2a 3a 4a 5a 6a

Pd2(dba)3 Pd(OAc)2 Pd(acac)2 Pd(CF3COO)2 Pd(MesCOO)2 PdBr2

COOH

Yield (%) 89 76 0