Nickel-catalyzed remote and proximal Wacker-type oxidation

Binbin Liu,Lu Cheng,Mingxi Tan,Fangning Xu,Penghui Hu,Wei Han

doi:10.1038/s42004-018-0107-y

Abstract

Wacker oxidation chemistry is widely applied to oxidation of olefins to carbonyls in the synthesis of pharmaceuticals, natural products, and commodity chemicals. However, in this chemistry efficient oxidation of internal olefins and highly selective oxidation of unbiased internal olefins without reliance upon suitable coordinating groups have remained significant challenges. Here we report a nickel-catalyzed remote Wacker-type oxidation where reactions occur at remote and less-reactive sp3 C–H sites in the presence of a priori more reactive ones through a chain-walking mechanism with excellent regio- and chemo- selectivity. This transformation has attractive features including the use of ambient air as the sole oxidant, naturally-abundant nickel as the catalyst, and polymethylhydrosiloxane as the hydride source at room temperature, allowing for effective oxidation of challenging olefins. Notably, this approach enables direct access to a broad array of complex, medicinally relevant molecules from structurally complex substrates and chemical feedstocks.

Highlights

Wacker oxidation chemistry is widely applied to oxidation of olefins to carbonyls in the synthesis of pharmaceuticals, natural products, and commodity chemicals
These challenges inherently undermine the utility of Wacker chemistry because the vast majority of alkenes are unbiased internal olefins readily accessible from petroleum and renewable resources such as seed oils[10] and through well-established synthetic routes such as carbonyl olefination[11] and olefin metathesis[12]
Remote functionalization that allows direct bond formation at a distal and specific position other than the initial reactive site is a significant challenge[13,14,15,16,17,18,19,20,21], in remote Wacker-type oxidation. This is because the remote Wacker-type oxidation would involve transition-metal hydride addition of an alkene into the organometallic intermediate transition-metal alkyl, followed by a sequential β-hydride elimination/migratory-insertion iteration process reaching a specific remote sp[3] C–H position where oxidation occurs to liberate the desired single carbonyl product[13,14]; both the reductive transition-metal hydride and the unstable organometallic intermediate are commonly sensitive to oxidative conditions

Summary

Introduction

Wacker oxidation chemistry is widely applied to oxidation of olefins to carbonyls in the synthesis of pharmaceuticals, natural products, and commodity chemicals. We report a nickel-catalyzed remote Wacker-type oxidation where reactions occur at remote and less-reactive sp[3] C–H sites in the presence of a priori more reactive ones through a chain-walking mechanism with excellent regio- and chemo- selectivity This transformation has attractive features including the use of ambient air as the sole oxidant, naturally-abundant nickel as the catalyst, and polymethylhydrosiloxane as the hydride source at room temperature, allowing for effective oxidation of challenging olefins. Straightforward oxidation of olefins’ remote sp[3] C–H to valuable ketones serves as a more practical approach (For an example of Pd-catalyzed tandem isomerization–Wacker oxidation of allyl arenes, see ref. 35.)

Methods

Results

Conclusion