Atom-economic dehydrogenative amide synthesis via ruthenium catalysis

Abstract

Recently, a class of dehydrogenative transformations for amide bond formation have been developed. These transformations are atom-economic and environmentally-benign processes with their respective starting materials of alcohols and amines, aldehydes and amines, as well as symmetrical esters and amines, showing a promising prospect for applications. These unique protocols have been reported using various ruthenium-based catalytic systems. However, challenges still exist in this area. For example, existing catalytic systems usually suffer from low efficiency, high catalyst loading, and lack of structural diversity.

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Cheng Chen

Cheng Chen (1984, China) received his BS (2006) and MS (2008) degrees with Professors Zhi-Ling Zhang and Dai-Wen Pang from Wuhan University, and he obtained his PhD at Nanyang Technological University with Professors Soon Hyeok Hong and Shunsuke Chiba (2008–2012). After having postdoctoral experience with Professor Yvan Six at Ecole Polytechnique (2012–2013) and with Professor Guang-Fu Yang at Central China Normal University (2013–2015), he became a researcher at State Key Laboratory of Advanced Technology for Materials Synthesis and Processing (Wuhan University of Technology) in 2016. His main research interests concern organometallic catalysis and its applications in synthesis of bioactive compounds.

Francis Verpoort

Francis Verpoort (1963, Belgium) received his DPhil from Ghent University in 1996. In 1998, he became a full professor at the same university. In 2008, he became an editor of Applied Organometallic Chemistry. Currently, he is also a chair professor at State Key Laboratory of Advanced Technology for Materials Synthesis and Processing (Wuhan University of Technology). Recently, he has been appointed as “Expert of the State” in the frame of “Thousand Talents” program, PR China. In 2015 he was selected as High level Expert of the Russian Federation. His main research interests concern organometallic material chemistry, catalysis, MOFs, water splitting, olefin metathesis, CO2 conversion, polymers.

Qiongyou Wu

Qiongyou Wu (born in 1975, China) received his BS degree from Fuyang Teachers College in 1998, and he obtained his PhD from the Department of Chemistry and Molecular Science, Wuhan University under the supervision of Professor Ling Peng (1998–2003). He was then moved to Central China Normal University and became an associate professor at the key laboratory of Pesticide & Chemical Biology, Central China Normal University in 2007. His main research interests concern rational design of green pesticide, organometallic catalysis and its applications in synthesis of heterocyclic compounds especially for pesticide related heterocycles.

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1. Introduction

The amide bond is one of the most fundamental functional groups in organic chemistry, and it plays a central role in elaboration and composition of biological systems.^1–6 Traditionally, amide synthesis could be achieved through reaction of activated carboxylic acids and amines.⁷ Besides, alternative strategies have also been reported.^8–14 These strategies are general and have been widely used. However, they usually require stoichiometric amounts of reagents and generate equimolar amounts of by-products as waste, which is not in accordance with the concept of “green and sustainable chemistry”.¹⁵ Recently, a few atom-economic and environmentally-friendly methods for amide bond formation have been developed via ruthenium catalysis (as shown in Fig. 1).^16–21 In this article, recent development of these methods and current challenges in this area are presented.

Fig. 1 Atom-economic transformations for ruthenium-catalyzed dehydrogenative amide synthesis.

2. Ruthenium-catalyzed direct amide synthesis from alcohols and amines

2.1. Catalyst development

Ruthenium-catalyzed amide formation directly from alcohols and amines is a highly atom-economic transformation that evolves dihydrogen gas as the only by-product (Fig. 2a).²² The generally accepted mechanism is described in Fig. 2b. An alcohol is initially oxidized to the corresponding aldehyde (or a ruthenium-bound aldehyde) which reacts with an amine to give a hemiaminal. Finally, the hemiaminal undergoes further oxidation to give the amide.

Fig. 2 Ruthenium-catalyzed amide formation directly from alcohols and amines and the generally accepted mechanism.

Murahashi and co-workers reported the pioneer work in 1991. In this report, five- and six-membered lactams were prepared from amino alcohols in an intramolecular process as depicted in Scheme 1.¹⁶

Scheme 1 Synthesis of lactams from amino alcohols.

Since 2007, various catalytic systems have been discovered for intermolecular amidation of alcohols with amines. Three well-defined ruthenium complexes were synthesized and utilized as the catalysts (Fig. 3).^22–24 Among them, the major breakthrough is the discovery of complex 1, a commercialized ruthenium PNN pincer complex (the Milstein catalyst), developed by the Milstein group (Fig. 3a).²² Notably, this is the first time to allow alcohol amidation with amines in an intermolecular fashion. In addition, the reaction could be performed under neutral conditions without any additive. Afterwards, complex 2, a well-defined N-heterocyclic carbene (NHC)-based ruthenium complex, was employed by Glorius et al. as a highly active catalyst for this transformation (Fig. 3b).²³ Recently, Hong and co-workers developed a hydride-based NHC–Ru complex 3 which catalyzed formation of various amides from alcohols and amines (Fig. 3c).²⁴

Fig. 3 Well-defined complexes 1–3 directly as catalysts.

As a matter of fact, many research groups prepared well-defined complexes for this reaction. However, these complexes were only active in the presence of a catalytic amount of base.^25–38 Hong and co-workers reported Ru–NHC complexes 4a–4e for this reaction (as shown in Fig. 4a).²⁵ When the activity was initially screened only with those complexes, no amide formation was observed. It was found that a strong base is required and 15–20 mol% of the base is optimal for the catalytic cycle to proceed. Later, replacement of the p-cymene ring with a benzene group led to the preparation of compound 5, which demonstrated similar activities with 4a–4d for amidation of alcohols and primary amines (Fig. 4b).²⁶ Interestingly, 5 showed superior activities for secondary amines especially sterically hindered ones.

Fig. 4 Well-defined complexes 4a–4e and 5 as precatalysts.

Madsen et al. also identified a catalytic system based on 4c, and optimized the conditions as 5 mol% 4c, 5 mol% PCy₃ as a supporting ligand and 10 mol% KOtBu (as shown in Fig. 5a).²⁷ With the proposition of Ru–NHC components as active species, the same group screened NHC-based olefin metathesis catalysts for the direct amidation of primary alcohols. The results indicated that complexes 6–7 were active in the presence of 10 mol% of KOtBu (Fig. 5b and c).²⁸

Fig. 5 Catalytic systems based on 4c, 6 and 7.

The Crabtree group reported a ruthenium diphosphine diamine complex 8 for the alcohol amidation.²⁹ Using complex 8 and KOH as catalyst, amide synthesis could be performed smoothly in an intramolecular pattern (Fig. 6a), while a moderate yield was obtained in case of intermolecular amide formation (Fig. 6b). Afterwards, another ruthenium diphosphine diamine complex 9, by which enhanced activity was observed for intermolecular amide synthesis, was prepared (Fig. 6c).³⁰

Fig. 6 Catalytic systems based on 8–9.

The Albrecht group reported 1,2,3-trazolium-derived carbene based ruthenium complexes 10 and 11 for the amide synthesis (Fig. 7).³¹ Although only moderate yields were obtained, potential application of 1,2,3-triazolidene ligands in the design of highly active homogeneous catalysts could be illustrated.

Fig. 7 Well-defined complexes 10–11 as precatalysts.

In order to obtain a higher electron density at the metal center, a benzimidazolylidene complex 12, which is expected to act as a stronger σ-donor and weaker π-acceptor compared with its imidazolylidene analogs, was successfully synthesized by Möller et al.³² This complex is highly active for amidation of alcohols with amines in the presence of a catalytic amount of KOtBu (Fig. 8a). Moreover, this complex exhibited exceptional air- and moisture-stability. Later, Huynh and co-workers also reported that a benzimidazolylidene complex 13 (5 mol%) and NaH (30 mol%) promoted the formation of amides from alcohols and amines (Fig. 8b).³³ Notably, selectivity of amide formation versus amine formation could be simply tuned by the choice of base and solvent (Fig. 9).

Fig. 8 Benzimidazolylidene complexes 12–13 as precatalysts.

Fig. 9 Selectivity of amide formation versus amine formation.

Very recently, the Bera,³⁴ Guan,³⁵ and Viswanathamurthi^36–38 groups successfully illustrated their ruthenium complexes for this transformation (as depicted in Fig. 10). A pyridine functionalized NHC-based ruthenium complex 14 (Fig. 10a) and a ruthenium PNP pincer catalyst 15 (Fig. 10b) could promote amide formation from alcohols and amines with aid of a base. In 2016, Viswanathamurthi et al. prepared a series of ruthenium complexes containing multidentate ligands for this reaction (Fig. 10c–e).

Fig. 10 Precatalysts 14–18.

Except well-defined ruthenium complexes, several in situ ruthenium based catalytic systems for the intermolecular amidation reactions have been developed (Fig. 11).^39–43 Madsen et al. reported the first example of an in situ generated NHC-based ruthenium catalytic system for direct amidation of alcohols (Fig. 11a).³⁹ Later the William group⁴⁰ and the Hong group^41–44 reported their respective catalytic systems (Fig. 11b–f).

Fig. 11 In situ generated catalytic systems.

2.2. Attempts for challenging substrates

Formamides are highly important in the synthesis of numerous valuable molecules. Ruthenium-catalyzed formamide formation via methanol activation constitutes a huge challenge. Glorius and co-workers advocated amide synthesis from methanol and an amine for the first time, even though styrene was used as a hydrogen acceptor (Scheme 2).²³ A more recent study by Hong et al. indicated that catalyst 3 could catalyze formamide synthesis from methanol and an amine without a hydrogen acceptor or base promoter (Scheme 3).^45,46

Scheme 2 Formamide synthesis via methanol activation.

Scheme 3 Formamide synthesis via methanol activation catalyzed by 3.

Although the above-mentioned catalytic systems showed outstanding activities for primary amines, only limited activity towards secondary amines has been observed. In order to overcome this challenge, Hong and co-workers developed a highly active precatalyst 5 for the direct amide synthesis from alcohols and secondary amines (Fig. 12a).²⁶ Notably, 5 demonstrated a promising activity even for sterically-hindered secondary amines (Fig. 12b). Later, Milstein et al. prepared ruthenium bipyridine-based pincer complexes 19 and 20 for activation of secondary amines (Scheme 4).⁴⁷

Fig. 12 Amide synthesis from alcohols and secondary amines catalyzed by precatalyst 5.

Scheme 4 Alcohol amidation with secondary amines catalyzed by 19 and 20.

2.3. Applications in peptide and polymer synthesis

In biological systems, numerous molecules such as proteins and peptides contain the amide linkage with complex structures. Therefore, it is of vital importance to conduct amide synthesis for more complicated systems. Milstein and co-workers evaluated the activity of complex 1 for peptide synthesis (Fig. 13).⁴⁸ Indeed, 1 catalyzes the conversion of various amino alcohols where R is a larger group than methyl to the corresponding cyclic dipeptides in good yields with liberation of H₂ (Fig. 13a). In the case of alaninol, the corresponding oligopeptide was formed (Fig. 13b). Moreover, an optically pure tricyclic peptide was readily achieved from (S)-pyrrolidin-2-yl-methanol in almost quantitative yield (Fig. 13c).

Fig. 13 Synthesis of oligopeptides and cyclic dipeptides catalyzed by 1.

Polyamides are among the most significant families of polymers. For the first time, Guan and co-workers reported the direct polyamidation from diols and diamines catalyzed by 1 (Fig. 14a).⁴⁹ To facilitate polymer formation, anisole or a combination of anisole and dimethyl sulfoxide was selected as the solvent system. In addition, due to the high selectivity of 1 toward primary amines, diamines bearing additional secondary amine groups were also successfully transformed to the respective polyamides, which are potentially valuable for gene delivery (Fig. 14b). After this work, the Milstein group⁵⁰ and the Möller group⁵¹ also reported similar polyamide synthesis from diols and diamines.

Fig. 14 Synthesis of polyamides from diols and diamines catalyzed by 1.

3. Ruthenium-catalyzed direct amide synthesis from aldehydes and amines

Ruthenium-catalyzed amide formation directly from aldehydes and amines has been highlighted as an attractive protocol for constructing the amide bond, and it has high atom economy that evolves dihydrogen gas as the sole by-product (Fig. 15a).¹⁶ Generally, the proposed mechanism is depicted in Fig. 15b. An aldehyde reacts with an amine to produce a hemiaminal intermediate, which is further oxidized to the corresponding amide in the presence of a ruthenium catalyst.

Fig. 15 Ruthenium-catalyzed amide formation directly from aldehydes and amines and the proposed mechanism.

In 1991, Murahashi et al. identified the first example for the amidation of aldehydes with amines (Scheme 5).¹⁶ Although only aromatic aldehydes and cyclic secondary amines were tolerated, it could be an inspiration for further researchers. Based on the above catalyst, the Hong group developed an improved catalytic system by introducing an NHC ligand and acetonitrile as a supporting ligand, which resulted in a broader substrate scope (Scheme 6).⁴³ Except cyclic secondary amines, primary amines could also be tolerated. Besides, both aromatic and aliphatic aldehydes could be employed.

Scheme 5 The first ruthenium-catalyzed direct amidation of aldehydes with amines.

Scheme 6 An improved catalytic system based on Murahashi's catalyst.

Since the aldehyde or ruthenium-bound aldehyde was proposed as the key intermediate for the direct amide synthesis from alcohols and amines, the Hong group tested the activities of their catalytic systems 21a–21c which showed excellent activities for alcohol amidation for the direct amidation of aldehydes (Fig. 16a). The results indicated that 21a–21c resulted in only low to moderate yields for the amide formation, with the corresponding imine as the major by-product (Fig. 16b).^25,41 Interestingly, the efficient amidation of aldehydes catalyzed by 21a can be realized by the addition of a catalytic amount of a primary alcohol (Scheme 7).²⁵ Inspired by the alcohol activation, the same group reported a modified catalytic system from 21b which is highly active for amide synthesis from aldehydes and amines (Scheme 8).⁵²

Fig. 16 Catalytic activities of 21a–21c for aldehyde amidation with amines.

Scheme 7 Efficient aldehyde amidation with amines via alcohol activation.

Scheme 8 An active catalytic system modified from 21b.

4. Ruthenium-catalyzed direct amide synthesis from esters and amines

Ruthenium-catalyzed amide formation directly from symmetrical esters and amines is another highly atom-economic transformation. Unlike conventional methods for ester amidation which generates an alcohol as by-product, only two molecules of H₂ were eliminated as waste (Fig. 17a).⁵³Fig. 17b illustrated the plausible reaction mechanism. With the aid of a ruthenium catalyst, reaction of a symmetrical ester and an amine occurs to give the amide product and an alcohol. The alcohol could then go through ruthenium-catalyzed alcohol amidation with the amine to afford another molecule of the amide, with the liberation of H₂.

Fig. 17 Ruthenium-catalyzed direct amide formation from esters and amines and the plausible mechanism.

The Milstein group pioneered this novel reaction by utilizing 1 as the catalyst under neutral conditions (Fig. 18a).⁵³ Later, during mechanistic investigation of alcohol amidation with secondary amines, Hong and co-workers observed the conversion of an ester intermediate to the amide product with help of their ruthenium catalyst 5 and an increased amount of a base (Fig. 18b).²⁶ Afterwards, a catalytic system, 5 mol% 3 and 15 mol% KOtBu, was found to be highly active for the reaction of benzylbenzoate and 3-phenyl-1-propylamine (Fig. 18c).²⁴ In addition, the Xiong group confirmed the feasibility of direct amide synthesis from esters and amines by the commercially available precatalyst 15 (Fig. 18d).⁵⁴

Fig. 18 Dehydrogenative amide synthesis from esters and amines.

5. Current challenges and perspectives

Although versatile ruthenium-based catalytic systems have been employed for the above-mentioned protocols, there are still many challenges in this area. Existing catalytic systems usually suffer from low efficiency, high catalyst loading, and lack of structural diversity, so they are only active for simple substrates and not suitable for industrial applications. To the best of our knowledge, there has been no report about the direct amidation of less nucleophilic sulfonamides. Limited yields have been obtained for aryl amines, sterically hindered substrates. Moreover, reactivity toward heterocyclic compounds and/or structurally complex molecules has been rarely studied. Therefore, in order to increase the practical value of these emerging methods in industrial production, it is crucial to focus on design and synthesis of catalytic systems which could show both excellent activity and broad substrate scope. Afterwards, more concentration should be given on applications of these protocols for synthesis of more valuable compounds such as bioactive compounds.

6. Conclusions

The amide bond demonstrates wide availability in pharmaceuticals, agrochemicals, materials and biological systems. In recent years, three environmentally benign and atom-economic protocols for dehydrogenative amide synthesis have been developed using a number of ruthenium-based catalytic systems. These processes meet the requirement of “green and sustainable chemistry”, exhibiting a bright future for industrial applications. However, current catalytic systems usually require high catalyst loading and are not be applicable for a wide range of substrates. Therefore, further research should be focused on development of highly active catalytic systems with much broader substrate scope and their applications in synthesis of useful molecules.

Acknowledgements

This research was supported by the National Natural Science Foundation of China (No. 21272091 and 21502062).

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