HMPA-Catalyzed Transfer Hydrogenation of 3-Carbonyl Pyridines and Other N-Heteroarenes with Trichlorosilane.

Yun Fu,Jian Sun

doi:10.3390/molecules24030401

Abstract

A method for the HMPA (hexamethylphosphoric triamide)-catalyzed metal-free transfer hydrogenation of pyridines has been developed. The functional group tolerance of the existing reaction conditions provides easy access to various piperidines with ester or ketone groups at the C-3 site. The suitability of this method for the reduction of other N-heteroarenes has also been demonstrated. Thirty-three examples of different substrates have been reduced to designed products with 45–96% yields.

Highlights

IntroductionPiperidines are very important structural building blocks of numerous biologically active compounds, such as the Topo inhibitor, the Chk inhibitor, Tiagabine and Focalin XR [1]
The catalytic hydrogenation of pyridines provides one of the most straightforward methods to access piperidines [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18], it is essential to overcome some inherent challenges presented by catalyst deactivation and pyridine dearomatization
Various transition-metal catalyst systems have been studied for the direct hydrogenation of pyridines, but the metal-free catalytic reduction of pyridines is a great challenge [19,20,21,22,23,24]

Summary

Introduction

Piperidines are very important structural building blocks of numerous biologically active compounds, such as the Topo inhibitor, the Chk inhibitor, Tiagabine and Focalin XR [1]. Trichlorosilane with a Lewis base as an activator is a well-known unsaturated double bond reduction method. Its strength has been well demonstrated by others and ourselves in terms of of pyridines by use of this system still presents a great challenge, and no successful protocol has been asymmetric reduction of double bonds [31,32,33,34,35,36,37,38]. We found trichlorosilane could activate the imine substrate through of pyridines by use of this system still presents a great challenge, and no successful protocol has been coordination of the nitrogen atom. We envisioned that pyridines would be reduced by present a highly effective new method to reduce 3-carbonyl pyridines under an organic Lewis base trichlorosilane with a proper Lewis base activator.

Discussion

Substrate

Methods

H13 C-NMR

The Stereochemical Assignment of Disubstituted Piperidines

Conclusions