Continuous-Flow Amide and Ester Reductions Using Neat Borane Dimethylsulfide Complex.

Sándor B Ötvös,C Oliver Kappe

doi:10.1002/cssc.201903459

Abstract

Reductions of amides and esters are of critical importance in synthetic chemistry, and there are numerous protocols for executing these transformations employing traditional batch conditions. Notably, strategies based on flow chemistry, especially for amide reductions, are much less explored. Herein, a simple process was developed in which neat borane dimethylsulfide complex (BH3⋅DMS) was used to reduce various esters and amides under continuous‐flow conditions. Taking advantage of the solvent‐free nature of the commercially available borane reagent, high substrate concentrations were realized, allowing outstanding productivity and a significant reduction in E‐factors. In addition, with carefully optimized short residence times, the corresponding alcohols and amines were obtained in high selectivity and high yields. The synthetic utility of the inexpensive and easily implemented flow protocol was further corroborated by multigram‐scale syntheses of pharmaceutically relevant products. Owing to its beneficial features, including low solvent and reducing agent consumption, high selectivity, simplicity, and inherent scalability, the present process demonstrates fewer environmental concerns than most typical batch reductions using metal hydrides as reducing agents.

Highlights

As a consequence of the ubiquity of alcohols and amines, carbonyl reductions are amongst the most crucial transformations in synthetic organic chemistry
BH3·DMS as reducing agent were pumped as separate streams, and the combined mixture was reacted while passing through a 12 mL perfluoroalkoxy alkane (PFA) coil (1.58 mm inner diameter), which was heated in an oil bath
According to earlier literature findings, reductions of esters with borane reagents require more stringent conditions than those of amides.[3b]. Methyl benzoate was selected as a simple model substrate to investigate the effects of reaction conditions on the continuous-flow reduction (Table 1)

Summary

Introduction

As a consequence of the ubiquity of alcohols and amines, carbonyl reductions are amongst the most crucial transformations in synthetic organic chemistry. Borane complexes have been applied in continuous-flow carbonyl reductions.[17] In these cases, borane reagents were used as 1–2 m solutions, involving low substrate concentrations and inherently low productivities. Borane reagents were used as 1–2 m solutions, involving low substrate concentrations and inherently low productivities Compared with those of aldehydes and ketones, continuous reductions of carboxylic acid derivatives have been less explored.[14]. This can be explained partly by the fact that LiAlH4 reductions are virtually incompatible with flow conditions, and that heterogeneous catalytic amide and ester hydrogenations are quite limited owing to the harsh conditions required.[3b, 6a].

Results and Discussion

Conclusion

Conflict of interest