摘要：KEYWORDS:organocatalysis, deoxygenation,deoxygenativenucleophilic couplings (反应类型),C(sp3)-O, C(sp3)-N, C(sp3)-S, C(sp2)-C(sp3) (成键

转自：康龙化成

Deoxygenative Alcohol-nucleophile Couplingvia Carbocations

Léa Thai-Savard,1 Jason R. Zbieg,1and Jack A. Terrett1,2*

1 Discovery Chemistry, Genentech, Inc., South San Francisco, CA, USA;

2 Lead contact

—Chem. Catal., 2025, org/10.1016/j.checat.2024.101187.

Recommended by Bingbing Chang_ MC5

KEY WORDS: organocatalysis, deoxygenation,deoxygenative nucleophilic couplings (反应类型), C(sp3)-O, C(sp3)-N, C(sp3)-S, C(sp2)-C(sp3) (成键类型), alcohols, thiols, amides, carbamates, ureas, sulfonamides (原料), ethers, thiol ethers, amides, carbamates, ureas, sulfonamides (产物),deoxazole, NHC, carbocation precursors (其他)

ABSTRACT: Alcohols are one of the most ubiquitous and widely available functional groups, yet methods for their direct employment as electrophiles in nucleophilic couplings are limited. Due to the high energy barrier for hydroxide to function as a leaving group, preactivation of the alcohol is often required, necessitating multistep sequences. Here, Jack A. Terrett et aldisclose a mild catalytic alcohol activation strategy that enables the direct use of alcohols as carbocation precursors in nucleophilic coupling reactions. A diverse array of nucleophiles can be coupled, allowing for formation of C–O, C–S, C–C, and C–Nbonds. A feature of this platform is the exquisite selectivity, affording exclusively heterocoupledproduct despite the coupling of two traditionally nucleophilic substrates. Furthermore, this approach facilitates the routine synthesis of previously challenging privileged α-tertiary ethers.

Background

Scope of alcohols as carbocation precursors (selected)

Proposed mechanism

The direct employment of widely available alcohol feedstocks as synthons in nucleophilic couplings is a longstanding objective within the synthetic community. Traditional methods utilizing alcohols require the preactivation of one coupling partner due to the inherent mismatched electronics for C–O bond formation. Here, free alcohols are leveraged as carbocation precursors via in situ activation, reversing their traditional nucleophilic behavior and avoiding the need for prefunctionalization. The direct catalytic deoxygenative coupling of alcohols toward selective C–O heterocouplingis described. Mechanistic studies support the intermediacy of a discrete carbocation, which can be intercepted by a diverse array of simple nucleophiles. Application of this protocol toward natural products and complex active pharmaceutical ingredients is also demonstrated. The compatibility toward a large breadth of nucleophiles enables the construction of C–O, C–S, C–C, and C–N bonds in a single step, showcasing the broad applicability of this alcohol activation platform.

来源：新浪财经