Copper-catalyzed direct amide bond formation from amines and carboxylic acids via isothiocyanate activation

Pinyong Zhong^a, Kunming Liu^a, Fumin Liao^a, Bin Huang^a, Min Yang*^b and Jin-Biao Liu*^a
aJiangxi Provincial Key Laboratory of Functional Molecular Materials Chemistry, Jiangxi University of Science and Technology, Ganzhou 341000, China. E-mail: liujinbiao@jxust.edu.cn
^bSchool of Pharmacy, Gannan Medical University, Ganzhou, 341000, China. E-mail: min_yang100@163.com

First published on 6th August 2025

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Introduction

Amide structures are pervasive components in a diverse array of substances, including natural products, pharmaceuticals, agrochemicals, polymers, and functional materials.¹ Within biological organisms, amide bonds are essential for linking amino acids to form the fundamental backbone of proteins. It has been established that a significant proportion – over a quarter – of identified drug molecules incorporate at least one amide bond within their molecular architectures.² Consequently, amidation reactions are integral to the synthesis of prospective novel pharmaceuticals. Furthermore, the amide group's intermediate reactivity and stability position it as a versatile intermediate in organic chemistry for the synthesis of a broad spectrum of other structural units, such as carboxylic acids, amines, nitriles, heterocycles, and esters.³ Additionally, amides are extensively employed as ligands and catalysts in organic synthesis.⁴

Traditionally, the formation of amide bonds is typically facilitated by preformed or in situ generated carboxylic acid derivatives, such as acyl chlorides, anhydrides, and active esters.⁵ These methods generally follow the strategy of modifying carboxylic acids at the hydroxyl (–OH) position to construct an efficient leaving group (Scheme 1, Path A).⁶ Although the aforementioned methods have been widely applied in relevant fields, they have certain limitations due to their usual involvement of a two-step reaction sequence or the requirement of toxic reagents.

Although a variety of strategies for the synthesis of amides have been developed, such as cyanohydrin hydrolysis, decarboxylation reactions, CO insertion, transamidation, etc.,⁷ the direct reaction of carboxylic acids with amines has long been considered the most ideal method for amide synthesis. This is because only water is produced as the sole byproduct, representing excellent atom economy. However, to overcome the energy barrier leading to the formation of ammonium carboxylate salts due to acid–base reactions, this process typically requires high temperatures.⁸ Numerous factors, including the pK_a value of the carboxylic acid, the basicity and nucleophilicity of the amine, and the stability of the ammonium carboxylate, collectively exert a significant influence on the yield of this acid–base reaction.⁹ Therefore, this reaction is typically conducted in the presence of Lewis acid catalysts such as titanium, aluminum, zirconium compounds, and organoborane derivatives.¹⁰ However, the necessity to remove water from the reaction system makes the reaction more complex in practical applications. The use of traditional coupling agents, such as DCC and EDC, effectively circumvents the disadvantages of high temperature and complicated operation.

Emerging amine activation strategies present a paradigm-shifting alternative by circumventing traditional carboxylic acid activation. This approach proves particularly valuable for preserving stereochemical integrity in α-chiral substrates like amino acids.¹¹ Current implementations employing isocyanides, N-(imidazolecarbonyl)amines, iminophosphoranes, and isothioureas demonstrate promising reactivity profiles (Scheme 1, Path B).¹² Nevertheless, persistent challenges including elevated temperature requirements, explosive intermediate formation, and multi-component reaction systems motivate the development of more operationally benign protocols. Our investigation focuses on redefining the role of isothiocyanates (ITC) in amidation chemistry. While established as reactants in classical transformations,¹³ their limited commercial availability and high cost prompted our exploration of aryl isothiocyanates as novel coupling reagents. Building upon our prior success in developing a photocatalytic amidation reaction between thioureas and carboxylic acids,¹⁴ we attempted to utilize isothiocyanates as coupling agents for the photocatalytic amidation of carboxylic acids with amines. However, extensive optimization under photocatalytic conditions failed to afford the target product. Consequently, our efforts were redirected toward a copper-catalyzed pathway. We herein describe an innovative, traceless route for the synthesis of amides and peptides wherein isothiocyanates serve as amine-activating coupling agents, rather than conventional reactants.

Results and discussion

In this study, benzoic acid (1a) and p-bromoaniline (2a) were first selected as template substrates, and phenyl isothiocyanate (ITC 1) was chosen as the coupling agent. An extensive optimization experiment of the reaction conditions was conducted. In the initial stage, with DMAP as the base, CuCl₂ as the catalyst, and DMF as the solvent, the target product 3a was successfully obtained with a yield of 58% (Table 1, entry 1). Notably, the by-product 4, generated from the direct coupling between isothiocyanate and carboxylic acid, was simultaneously formed with a yield of 30%. This result preliminarily confirmed the feasibility of the research method. Immediately afterwards, the coupling efficiency of different isothiocyanate reagents was evaluated (Table 1, entries 2–4). The reaction with ITC 2 bearing an electron-withdrawing nitro substituent failed to provide the target product. In contrast, phenyl isothiocyanates with electron-donating groups could improve the yield and selectivity of the reaction. To our delight, when ITC 4 was used as the coupling agent, the highest yield of 86% was achieved, along with excellent selectivity. Subsequently, a series of bases were thoroughly investigated (Table 1, entries 5–10). The research findings indicated that organic bases could effectively promote this reaction, and DMAP remained the best choice. In contrast, inorganic bases, regardless of their basicity, showed no promotional effect on the reaction. Thereafter, the impact of various polar and non-polar solvents, including DMSO, DCE, MeCN, and THF, on the reaction was examined (Table 1, entries 11–15), but no better results were obtained. Moreover, other catalysts such as CuCl, CuSO₄, and Cu(OAc)₂ were attempted, but none of them yielded better results than CuCl₂ (Table 1, entries 16–18). The reaction did not proceed smoothly in the absence of a copper catalyst (Table 1, entry 19). Additional optimization studies can be found in the SI.

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With the optimized reaction conditions established, we systematically investigated the substrate scope of this amide synthesis protocol using a diverse array of carboxylic acids and amines (Scheme 2). The reaction demonstrated excellent compatibility with benzoic acids bearing electron-donating groups, as exemplified by methyl-, 3,5-dimethyl-, and p-methoxy-substituted derivatives, which furnished amides 3b–3f in consistently high yields (76–92%). Notably, substrates containing strongly electron-withdrawing groups exhibited remarkable reactivity, with 4-nitrobenzoic acid being successfully converted into amide 3g in 74% yield. Halogenated benzoic acids (4-fluoro-, 4-chloro-, and 4-bromo-) were similarly effective, delivering the corresponding amides 3h–3j in excellent yields (83–90%). The protocol's versatility was further demonstrated through efficient transformations of 2-naphthoic acid and 3-thiophenecarboxylic acid, which afforded target products 3k and 3l with high efficiency.

Expanding our investigation to aliphatic systems, various cycloalkyl carboxylic acids proved to be competent substrates, yielding amides 3m and 3n in up to 92% efficiency. Particularly noteworthy was the successful conversion of cinnamic acid (containing an unsaturated C–C bond) into amide 3o in 95% yield, highlighting the method's tolerance for conjugated systems. The protocol maintained excellent performance across carboxylic acids of varying substitution patterns, as evidenced by the successful transformation of primary, secondary, and tertiary derivatives to amides 3p–3s. However, 2-oxo-2-phenylacetic acid was not suitable for this reaction. To underscore the practical utility of this methodology, we successfully applied it to the amidation of non-steroidal anti-inflammatory drugs (NSAIDs), with both ibuprofen and naproxen yielding functionalized derivatives 3t and 3u, respectively.

We next examined the scope of amine substrates, beginning with aromatic systems. Aniline, methyl-substituted anilines and p-anisidine provided amides 3v–3z in moderate to good yields (53–77%). Notably, halogenated anilines exhibited enhanced reactivity, delivering products 3aa–3ac in improved yields (75–83%). The methodology successfully accommodated extended aromatic systems, as demonstrated by the smooth conversion of 2-naphthylamine into 3ad in 92% yield. While the more challenging 3-nitroaniline afforded product 3ae in 45% yield, complete reaction failure was observed with 4-nitroaniline, with predominant recovery of the starting material presumably due to its diminished nucleophilicity. Importantly, substrates bearing sensitive functional groups—including 3-cyano and 3-acetamido benzoic acid derivatives—participated effectively to yield 3af (86%) and 3ag (75%), respectively. The protocol also accommodated sterically demanding substrates, as shown by the successful conversion of 2-biphenylamine into amide 3ah in 75% yield. For aliphatic amines, neither ethylamine nor benzylamine could undergo the reaction. Thus, the conversion of primary amines remains highly challenging, while the failure of secondary amines in the reaction was anticipated, as they cannot form carbodiimides.

To further demonstrate the synthetic potential of this methodology, we explored its application in late-stage functionalization of amino acids and peptides. A series of α-substituted glycine derivatives (bearing phenyl, benzyl, methyl, isopropyl, and dimethyl groups) underwent smooth transformation to products 3ai–3am in 55–86% yields. Moreover, the methodology proved particularly valuable for peptide modification, as evidenced by the successful conversion of α-carboxylic acid groups in short peptides into the corresponding amides (3an–3aq).

Notably, our experimental observations demonstrated that the introduction of K₂CO₃ during the reaction proved indispensable for specific substrates, including alkyl carboxylic acids, aryl amines bearing electron-donating groups, and amino acid derivatives. Based on our previous work,¹⁴ we hypothesize that this requirement originates from the necessity for enhanced alkalinity to drive the conversion of in situ generated N-acylurea intermediates derived from these substrates into the corresponding amide products.

Following successful implementation of diverse transformations, we conducted preliminary control experiments to gain mechanistic insights, as outlined in Scheme 3. Crucially, elimination of the isothiocyanate coupling reagent (ITC 4) under standard conditions completely abolished the formation of target product 3a, establishing its indispensable role in this transformation (Scheme 3a). Notably, replacement of 4-methoxyphenyl isothiocyanate with its isocyanate counterpart resulted in complete reaction failure, highlighting the unique sulfur-dependent nature of this process (Scheme 3b). Intriguingly, reactions conducted under an inert nitrogen atmosphere showed no product formation, suggesting essential involvement of molecular oxygen (Scheme 3c). To verify the hypothesized oxidative desulfurization pathway, we performed sulfate anion detection through barium chloride precipitation after standard reaction completion (detailed sulfate quantification is provided in the SI). The successful identification of sulfate species strongly supports that molecular oxygen serves as the crucial oxidant in this transformation.

Based on the mechanistic investigations, supported by literature precedents,^14,15 and combined with density functional theory (DFT) calculations, we propose a plausible reaction mechanism as illustrated in Scheme 4. Employing the model reaction system, 4-bromoaniline (2a) undergoes a nucleophilic addition reaction with 4-methoxyphenyl isothiocyanate to generate the thiourea intermediate 6. This species then undergoes deprotonation and coordinates with copper to form the complex 7. 7 undergoes oxidative desulfurization assisted by molecular oxygen, regenerating the copper catalyst while releasing sulfate ions and yielding carbodiimide 8 as the key reactive intermediate. Theoretically, due to the cumulative CN feature of the carbodiimide, the nucleophilic addition reaction of 1a to 8 will produce two isomers, 9 and 10. According to the calculation results, the latter has higher energy than the former. This difference demonstrates that the nitrogen atom at one end of the carbodiimide, to which the electron-donating group (EDG) aryl is attached, is more basic, leading to 10 being more stable than 9 and dominating in the tautomerization equilibrium.¹⁶ Subsequently, 10 initiates a Mumm rearrangement process, forming the N-acylurea species 11. Regarding the subsequent cyclization process, the transition state TS2 is 22.6 kcal mol⁻¹ lower in energy than TS2′, indicating that, kinetically, the direct hydrogen-atom transfer (HAT) between the intramolecular N atoms to release isocyanate 5 and yield amide 3a is unfavorable. A more favorable pathway is the elimination of isocyanate 5 via the six-membered ring transition state TS2 to obtain 12, and subsequently, 12 undergoes rearrangement to afford the target product, amide 3a.

Conclusions

This work establishes a copper-catalyzed traceless strategy for amide bond formation through transient activation of amines using isothiocyanates as coupling agents. The method operates under ambient conditions without requiring preactivation of carboxylic acids, achieving high efficiency and functional group tolerance. Key to the success is the generation of reactive carbodiimide intermediates via copper-mediated desulfurization of thioureas, which enables direct coupling with diverse non-activated carboxylic acids. The protocol demonstrates broad applicability to pharmaceuticals, peptides, and sterically demanding substrates, highlighting its potential for late-stage functionalization of bioactive molecules. Compared to traditional methods using toxic coupling agents under harsh conditions, this strategy combines copper catalysis, ambient operation, and low-toxicity isothiocyanate activation. This approach simplifies amide synthesis with improved sustainability, offering practical advantages for constructing complex molecules under environmentally benign conditions.

Data availability

The data supporting this article have been included as part of the SI: experimental procedures and the ¹H, ¹³C and ¹⁹F NMR spectra of all new products (PDF). See DOI: https://doi.org/10.1039/d5ob01008j.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was funded by the National Natural Science Foundation of China (21961014 and 22467002) and the Jinggang Scholars Program in Jiangxi Province.

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