Chiral Aniline Synthesis via Stereospecific C(sp3)-C(sp2) Coupling of Boronic Esters with Aryl Hydrazines.

Venkataraman Ganesh,Adam Noble,Varinder K Aggarwal

doi:10.1021/acs.orglett.8b02615

Abstract

An enantiospecific coupling between alkylboronic esters and lithiated aryl hydrazines is described. The reaction proceeds under transition-metal-free conditions and is promoted by acylation of a hydrazinyl arylboronate complex, which triggers a N–N bond cleavage with concomitant 1,2-metalate rearrangement. Judicious choice of the acylating agent enabled the synthesis of ortho- and para-substituted anilines with essentially complete enantiospecificity from a wide range of boronic ester substrates.

Highlights

N itrogen-containing compounds are of immense importance in medicine, constituting 84% of all small-molecule drugs.[1]
We recently initiated a research program focused on developing alternative, transition-metal-free coupling strategies that proceed through 1,2-metalate rearrangements of in situ generated arylboronate complexes (Figure 2A).[7]
We showed that activation of heteroatoms of nitrogen- or oxygen-containing arylboronate complexes could induce a 1,2-metalate rearrangement to provide coupled products.[9−11] For example, we demonstrated that boronate complexes formed from ortho-lithiated benzylamines undergo acylation and 1,2-metalate rearrangement (Figure 2B)

Summary

Introduction

N itrogen-containing compounds are of immense importance in medicine, constituting 84% of all small-molecule drugs.[1]. The resulting aniline products are generated in high yield and with complete enantiospecificity for a range of structurally diverse boronic esters.

Results

Conclusion