Highly-chemoselective step-down reduction of carboxylic acids to aromatic hydrocarbons via palladium catalysis.

Chengwei Liu,Chong-Lei Ji,Michal Szostak,Xin Hong,Zhi-Xin Qin

doi:10.1039/c9sc00892f

Abstract

Aryl carboxylic acids are among the most abundant substrates in chemical synthesis and represent a perfect example of a traceless directing group that is central to many processes in the preparation of pharmaceuticals, natural products and polymers. Herein, we describe a highly selective method for the direct step-down reduction of carboxylic acids to arenes, proceeding via well-defined Pd(0)/(ii) catalytic cycle. The method shows a remarkably broad substrate scope, enabling to direct the classical acyl reduction towards selective decarbonylation by a redox-neutral mechanism. The utility of this reaction is highlighted in the direct defunctionalization of pharmaceuticals and natural products, and further emphasized in a range of traceless processes using removable carboxylic acids under mild, redox-neutral conditions orthogonal to protodecarboxylation. Extensive DFT computations were conducted to demonstrate preferred selectivity for the reversible oxidative addition and indicated that a versatile hydrogen atom transfer (HAT) pathway is operable.

Highlights

The reduction of carboxylic acid derivatives represents one of the most fundamental transformations in synthetic chemistry and catalysis.[1]
We proposed that the direct reduction of carboxylic acids[9,10] to hydrocarbons via a heretofore unknown redox-neutral, decarbonylative[11,12,13,14,15] Pd(0)-catalyzed pathway could enable to use ubiquitous carboxylic acids as traceless activating groups, offering high level of predictability5a,b and functional group tolerance5e–g under redox-neutral conditions orthogonal to protodecarboxylation.[16]
A er extensive optimization, we found that the reduction of 4-Ph-benzoic acid in the presence of Pd(OAc)[2] (1 mol%), dppb (2 mol%, dppb 1⁄4 1,4-bis(diphenylphosphino)butane), piv2O (1.5 equiv., piv 1⁄4 2,2-dimethylpropanoyl), Et3N (1.5 equiv.) and Et3SiH (1.5 equiv.) as a hydride source afforded the desired reduction product in 97% yield on gram scale, attesting to the scalability of the method

Summary

Introduction

The reduction of carboxylic acid derivatives represents one of the most fundamental transformations in synthetic chemistry and catalysis.[1]. Aryl carboxylic acids are among the most abundant substrates in chemical synthesis and represent a perfect example of a traceless directing group that is central to many processes in the preparation of pharmaceuticals, natural products and polymers. We describe a highly selective method for the direct step-down reduction of carboxylic acids to arenes, proceeding via well-defined Pd(0)/(II) catalytic cycle.

Results

Conclusion