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. 2024 Apr 12;26(16):3380–3385. doi: 10.1021/acs.orglett.4c00872

General Approach to Amides through Decarboxylative Radical Cross-Coupling of Carboxylic Acids and Isocyanides

Qing Yan †, Qing-Jia Yuan †, Andrey Shatskiy ∥, Gregory R Alvey ∥, Elena V Stepanova ∥,‡, Jian-Quan Liu †,*, Markus D Kärkäs ∥,*, Xiang-Shan Wang †,*
PMCID: PMC11059110  PMID: 38607963

Abstract

graphic file with name ol4c00872_0005.jpg

Herein, we report a silver-catalyzed protocol for decarboxylative cross-coupling between carboxylic acids and isocyanides, leading to linear amide products through a free-radical mechanism. The disclosed approach provides a general entry to a variety of decorated amides, accommodating a diverse array of radical precursors, including aryl, heteroaryl, alkynyl, alkenyl, and alkyl carboxylic acids. Notably, the protocol proved to be efficient for decarboxylative late-stage functionalization of several elaborate pharmaceuticals, demonstrating its potential applications.

The amide functionality constitutes a prominent element in nature. In addition to peptides and proteins, amides find applications in a variety of areas—from synthetic polymeric materials, such as nylon or polyacrylamides, to agrochemicals and pharmaceuticals (Figure 1a).1 Hence, it is not surprising that the development of new methods for amide bond formation remains a prominent goal in chemical synthesis. A common approach for amide bond formation is the exploitation of (super)stoichiometric quantities of activating agents (Figure 1b) through pre- or in situ activation of the carboxylic acid coupling partner.2 Thus, the rather low efficiency and questionable sustainability credentials associated with traditional amide coupling methodologies,3 especially at large scale, have stimulated renewed interest in the design of innovative atom efficient and benign catalytic approaches for amide bond formation through the use of nonconventional coupling partners.4

Figure 1.

Figure 1

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Amides and isocyanides in chemical synthesis and this work.

Isocyanides are widely used and versatile building blocks in chemical synthesis.5 They demonstrate carbene-like reactivity, similar to carbon monoxide, making them valuable for various synthetic transformations.6 Besides their established role in various polar reaction manifolds, isocyanides have also been extensively explored in radical settings. Specifically, radical cross-coupling reactions involving isocyanides have been predominantly observed as part of tandem cyclization reactions, playing a crucial role in the construction of diverse heterocyclic compounds such as indoles, quinolines, isoquinolines, quinoxalines, and phenanthridines. In contrast, transition-metal-catalyzed radical cross-coupling reactions of isocyanides without subsequent cyclization remain relatively rare.7 Consequently, broadening the available scope of direct radical reactions involving isocyanides is highly desirable.

Transition-metal-catalyzed decarboxylative radical cross-coupling reactions serve as a powerful tool for the construction of carbon–carbon and carbon–heteroatom bonds.8 However, only a handful of reports on radical cross-coupling reactions of carboxylic acids or their analogues with isocyanides have been disclosed. For example, Grimaud and co-workers reported the radical cross-coupling reaction of diazonium salts with isocyanides and carboxylic acids to generate imides.9 However, this reaction is associated with a limited scope and moderate yields of the isolated products (ca. 50%). Subsequently, the Jamison,10 Zhou,11 Yatham,12 and Li13 groups reported the oxidative decarboxylative cross-coupling of arylisocyanides with alkyl carboxylic esters or alkyl/aryl carboxylic acids to furnish alkyl/aryl-substituted aromatic aza-heterocycles, respectively (Figure 1c). Meanwhile, the oxidative decarboxylative radical cross-coupling of alkynyl carboxylic acids with isocyanides has been underexploited due to the high energy and short lifetime of the alkynyl radical.14 Silver exhibits proficient catalytic activity in radical reactions and isocyanide chemistry.15 As part of our interest in developing novel silver-catalyzed reactions involving isocyanides,16 herein we report a silver-catalyzed protocol for decarboxylative radical cross-coupling of various carboxylic acids with isocyanides, allowing general entry to decorated amides (Figure 1c).

In designing a general platform for accessing amides, we surmised that decarboxylative cross-coupling would serve as a suitable entry. Carboxylic acids are ubiquitous and can be exploited as versatile sources of radicals, making them competent and easily accessible cross-coupling partners. We envisioned that a metal catalyst could mediate decarboxylation to generate the desired carbon-centered radical. Then, this radical could engage with the isocyanide to furnish a radical that can be intercepted with a suitable oxygen-donating agent, ultimately producing the coveted amide.

The execution of our design commenced using 4-bromophenylisocyanide (1a) and cyclohexanecarboxylic acid (2a) as the model substrates to screen the reaction conditions (for a detailed discussion, see the Supporting Information). With a suitable set of reaction conditions established, the versatility of the developed protocol was explored (Scheme 1). A series of aromatic isocyanides engaged in the reaction with cyclohexanecarboxylic acid 2a to deliver the corresponding amide products 3b–3u in 64–89% yields. Among these, ortho-, meta-, and para-substituted aromatic isocyanides bearing either electron-donating (e.g., Me, MeO, and EtO) or electron-withdrawing (e.g., F, Cl, Br, and CF3) substituents could be efficiently converted to the desired products in high yields. A range of diversely functionalized aliphatic carboxylic acids were also effective in decarboxylative coupling with 4-bromophenylisocyanide 1a, furnishing expected products 3v–3ag in moderate to high yields (58–94%). Delightfully, a wide array of aryl and heteroaryl carboxylic acids were well-tolerated, allowing efficient access to corresponding amides 3ah–3as. Additionally, both aliphatic and heteroaromatic isocyanides 1v–1aa could engage in the reaction to provide the corresponding amides 3at–3ay (66–81%). Similarly, cinnamic and α-oxocarboxylic acids furnished the expected products 3az–3be with a high efficiency. Importantly, we found that alkynyl carboxylic acids were also compatible with the disclosed catalytic system, albeit with lower yields, providing a prominent entry to alkyne-based radical transformations. Unfortunately, conducting the reaction with methylenated isocyanides, including ethyl isocyanoacetate and TosMIC, only provided the imidazole products, which is in agreement with the results previously reported in the literature.17

Scheme 1. Scope of Carboxylic Acids and Isocyanides.

Scheme 1

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Reaction conditions: isocyanide 1 (0.5 mmol, 1.0 equiv), carboxylic acid 2 (1 mmol, 2.0 equiv), Ag2CO3 (0.10 mmol, 0.2 equiv), acetone (5.0 mL), H2O (250 μL), 60 °C, 8 h. All yields are of isolated products. PBP = 4-bromo-C6H4.

To demonstrate the applicability of the disclosed protocol for late-stage functionalization of bioactive molecules (Scheme 2), a range of pharmaceuticals, including abietic acid, ibuprofen, fenofibric acid, and telmisartan, were subjected to the optimized reaction conditions, smoothly furnishing the desired product 3bl–3bs in 56–83% yields. Employing N-protected amino acids as substrates also furnished the desired products (3bt–3bx) in good yield, demonstrating the robustness of the disclosed protocol. Additionally, we obtained the single crystal X-ray structure of product 3bn (CCDC no. 2291774), unequivocally confirming the identity of the product.

Scheme 2. Late-Stage Diversification of Pharmaceuticals, Natural Products, and Biomolecules.

Scheme 2

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For a better understanding of the reaction mechanism, a series of mechanistic experiments were carried out (Scheme 3). First, reacting isocyanide 1ab with benzoic acid 2n or phenylpropiolic acid 2af under optimal conditions furnished the corresponding tandem cyclized products, highlighting that the reaction proceeds through a free-radical process. Next, cyclohexanecarboxylic (2a), benzoic (2n), and phenylpropiolic acids (2af) were subjected to the optimized reaction conditions with 4-bromophenylisocyanide (1a) and 2 equiv of TEMPO as a radical scavenger. For all three reactions, formation of the amide product was completely inhibited, indicating that the reaction proceeds through a free-radical pathway. Additionally, TEMPO-based adduct 5 was isolated in 48% yield for reaction with benzoic acid. Further, control experiments with isotopically labeled benzoic acid ([13C]-2n) resulted in unlabeled product 3ah, demonstrating that the carbonyl carbon in the product derives from isocyanide.18 Conducting the reaction under the atmosphere of 18O-labeled dioxygen resulted in [18O]-3ah in 78% yield with a high degree of 18O-incorporation, while excluding oxygen inhibited the reaction (12% yield). Finally, the reaction between 2n and 1a in the presence of H218O did not yield any labeled product [18O]-3ah. Importantly, the latter suggests that in the disclosed reaction, water does not act as an oxygen source, in contrast to previously disclosed isocyanide-coupling reactions.19

Scheme 3. Mechanistic Considerations.

Scheme 3

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Based on the above mechanistic experiments and relevant literature precedents,6b,6c,15 a plausible mechanism for the disclosed reaction is proposed with 1a and 2n as the model substrates. First, isocyanide 1a coordinates to the silver catalyst to produce silver intermediate A. At the same time, decarboxylation of benzoic acid to phenyl radical B is mediated by a silver catalyst, as has been described for other transformations.20 Subsequently, phenyl radical B undergoes coupling with complex A (or free isocyanide) to produce radical imine adduct C, which is oxidized by O2 to produce peroxide intermediate D. This species presumably undergoes rapid silver-mediated interconversion to intermediate E. Finally, the protonation of intermediate E furnishes the desired product 3ah. In this sequence, the silver catalyst mediates the decarboxylation step either through a AgII/AgI catalytic cycle21 with oxygen as the terminal oxidant22 or enables this step through an inner-sphere AgI-promoted pathway.23

In conclusion, an appealing approach for free-radical coupling between carboxylic acids and isocyanides to yield a diverse collection of amides was realized through silver catalysis. The disclosed protocol displays good functional group tolerance, delivering the corresponding amide products in excellent yields for a majority of the evaluated substrates. The developed methodology also expands the currently known scope of use of isocyanides in free-radical chemistry, aiding the development of new catalytic systems.

Acknowledgments

Financial support from the Outstanding Youth Fund of Jiangsu Province (BK20211607), 2022 Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX22_2785), the Priority Academic Program Development of Jiangsu Higher Education Institutions, the Swedish Research Council (Grant No. 2020-04764), FORMAS (Grant No. 2019-01269), the Olle Engkvist Foundation, the Magnus Bergvall Foundation, KTH Royal Institute of Technology, and the Ministry of Education and Science of the Russian Federation (Program No. 075-03-2021-287/6) is gratefully acknowledged.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c00872.

  • Experimental procedures, X-ray crystallography data of 3bn as well as characterization data, and copies of NMR spectra for all obtained products (PDF)

  • FAIR data, including the primary NMR FID files, for compounds 3, 4, and 5 (ZIP)

Author Contributions

J.-Q.L., M.D.K., and X.-S.W. conceptualized and directed the project. Q.Y., Q.-J.Y., A.S., G.R.A., and E.V.S. designed, conducted, and analyzed the experiments described in this manuscript. All authors contributed to discussing the results and drafting the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ol4c00872_si_001.pdf (12MB, pdf)
ol4c00872_si_002.zip (45.8MB, zip)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol4c00872_si_001.pdf (12MB, pdf)
ol4c00872_si_002.zip (45.8MB, zip)

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

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