Catalytic Reductive N‐Alkylations Using CO₂ and Carboxylic Acid Derivatives: Recent Progress and Developments

Abstract

N‐Alkylamines are key intermediates in the synthesis of fine chemicals, dyes, and natural products, and hence are highly valuable building blocks in organic chemistry. Consequently, the development of greener and more efficient procedures for their production continues to attract the interest of both academic and industrial chemists. Reductive procedures such as reductive amination or N‐alkylation through hydrogen autotransfer by employing carbonyl compounds or alcohols as alkylating agents have prevailed for the synthesis of amines. In the last few years, carboxylic/carbonic acid derivatives and CO2 have been introduced as alternative and convenient alkylating sources. The safety, easy accessibility, and high stability of these reagents makes the development of new reductive transformations with them as N‐alkylating agents a useful alternative to existing procedures. In this Review, we summarize reported examples of one‐pot reductive N‐alkylation methods that use carboxylic/carbonic acid derivatives or CO2 as alkylating agents.

Homogeneous and heterogeneous catalytic reduction of amides and related compounds using molecular hydrogen

“…In addition, several interesting reductive transformations that imply the hydrogenation of an amide intermediate as a key step (via C-N or C-O cleavage) have been successfully developed. Many of those methods make use of CO 2 and carboxylic/carbonic acid derivatives as safe and stable starting materials that, in combination with molecular hydrogen, and amines as external nucleophiles, can give access for a variety of highly valuable chemical compounds 84 . In addition, other more energy-related applications have been studied.…”

“…Traditionally, N-alkylating methodologies imply the use of toxic reagents or are based on reductive methods employing hydrosilanes or hydroboranes, which suffer from low atom efficiency and tedious work-up procedures 119 . Therefore, the development of more sustainable protocols for their synthesis is highly desired 84 . In this respect, the N-methylation of amines using CO 2 /H 2 mixtures in the presence of a suitable catalyst system is interesting.…”

“…Following the same principle applied for the N-methylation of amines using CO 2 /H 2 mixtures, carboxylic/carbonic acid derivatives in combination with H 2 can be employed for a more general N-alkylation of amines-including ammonia- (Fig. 5b) 84 . Theoretically, in those hydrogenative processes as a first step an in situ amide formation takes place, followed by its hydrogenation through direct or indirect C-O cleavage.…”

“…In addition to the methylation of NH 3 , in the last 6 years, several research groups have contributed to achieve catalytic systems for the N -methylation of amines with CO 2 /H 2 (Fig. 5a, ii ) 84 . From the homogeneous side, only two examples have been reported simultaneously by the groups of Klankermayer 127 and Beller 128 .…”

“…This type of emerging protocols making use of safer, more stable, and highly accessible alkyl sources offer appealing alternatives to more traditional reductive alkylation methods employing toxic agents, carbonyl compounds, or alcohols via hydrogen autotransfer 119 . However, owing to the kinetic and thermodynamic stability of carboxylic acid derivatives, their application in such hydrogenative N-alkylation processes has been scarcely investigated 84 and its further implementation still remains an actual task. In fact, either from the homogenous or the heterogeneous side, just a few catalysts have been described 84 and these are, obviously, closely related with amide C–O hydrogenation catalysts vide supra.…”