Synthesis of \u03b1,\u03b2-unsaturated ketones through nickel-catalysed aldehyde-free hydroacylation of alkynes

Joon Ho Rhlee,Jeong Woo Lee,Kyungjae Myung,Jaehyun Park,Yung Sam Kim,Ho Seung Lee,Seok Ju Kang,Soochan Lee,Saikat Maiti,Jeong Kon Seo,Sung You Hong,Ismoili Ahror Bakhtiyorzoda,Wonyoung Choe

doi:10.1038/s42004-022-00633-3

Abstract

α,β-Unsaturated ketones are common feedstocks for the synthesis of fine chemicals, pharmaceuticals, and natural products. Transition metal-catalysed hydroacylation reactions of alkynes using aldehydes have been recognised as an atom-economical route to access α,β-unsaturated ketones through chemoselective aldehydic C–H activation. However, the previously reported hydroacylation reactions using rhodium, cobalt, or ruthenium catalysts require chelating moiety-bearing aldehydes to prevent decarbonylation of acyl-metal-hydride complexes. Herein, we report a nickel-catalysed anti-Markovnikov selective coupling process to afford non-tethered E-enones from terminal alkynes and S-2-pyridyl thioesters in the presence of zinc metal as a reducing agent. Utilization of a readily available thioester as an acylating agent and water as a proton donor enables the mechanistically distinctive and aldehyde-free hydroacylation of terminal alkynes. This non-chelation-controlled approach features mild reaction conditions, high step economy, and excellent regio- and stereoselectivity.

Highlights

Α,β-Unsaturated ketones are common feedstocks for the synthesis of fine chemicals, pharmaceuticals, and natural products
The catalytic hydroacylation of alkynes using aldehydes inherently provides an atom-economical process leading to the formation of enones
Though nondirected hydroacylation methods have been developed for alkenes or dienes[32,33,34,35,36], to our knowledge, there is no general hydroacylation method for unactivated terminal alkynes that lead to chelating moiety-free Eenones

Summary

Introduction

Α,β-Unsaturated ketones are common feedstocks for the synthesis of fine chemicals, pharmaceuticals, and natural products. The catalytic hydroacylation of alkynes using aldehydes inherently provides an atom-economical process leading to the formation of enones. A consecutive alkyne insertion and subsequent protodemetalation process may lead to hydroacylation product formation (Fig. 1c). We report a nondirected and aldehyde-free approach to afford E-enones via a nickel-catalyzed reductive pathway.

Results

Conclusion