摘要：ShihanGeng1, Changwei Jiang1,ZhaotingLi1,HongyeWang1,YihanGao1,ZirunWang2, Qiang Liu3, Ning Jiao1& Song Song1,4*

转自：康龙化成

Inorganic Iodide Catalyzed Alkylation of Amines with Primary Alcohols

Shihan Geng1, Changwei Jiang1, Zhaoting Li1, Hongye Wang1, Yihan Gao1, Zirun Wang2, Qiang Liu3, Ning Jiao1 & Song Song1,4*

1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191,

2 Beijing No. 4 High School, Beijing 100034,

3 Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100084,

4 Department of Pharmacy, Peking University First Hospital, Xicheng District, Beijing 100034

—CCS Chem. 2025, DOI: 10.31635/ccschem.025.202505864

Recommended by Yuquan Liu_PT

KEY WORDS:alkylation,amination (反应类型),alcohols, amines(原料),amines (产物), C(sp3)-N (成键类型),HI and NaHSO4(其他)

ABSTRACT:Alkylation of amines with readily accessible reagents is one of the most efficient strategies for synthesizing substituted amines. Primary alcohols, being widely abundant, are excellent electrophiles that can undergo dehydration to react with various nucleophilic reagents. However, using primary alcohols for direct alkylation of amines is challenging due to the kinetic and thermodynamic barriers associated with carbocation generation during alcohol dehydroxylation. Conventional approaches that involve the preactivation of primary alcohols to their derivatives (aldehydes, halides, or tosylates) suffer from poor step- and atom economy, limited functional group tolerance, or reliance on unstable metal complexes. In this work, we present a highly efficient method for the alkylation of amines using primary alcohols, catalyzed by the combination of HI and NaHSO4. This method leverages inexpensive catalysts and easily accessible alcohols as alkylation reagents, exhibiting excellent functional group tolerance and high catalytic reactivity. The method has been successfully applied to the alkylation of various amines, cascade construction of N-heterocycles, and late-stage concise synthesis of pharmaceuticals.

Previous work

This work

Proposed Mechanism

Substrate scope (selected examples)

Substrate scope (Alkylation of anilines with primary alcohol)

Prof. Song Song et al have developed an efficient alkylation of amines with various primary alcohols under redox neutral conditions. The simple inorganic iodide was demonstrated to be a highly efficient catalyst, while the NaHSO4 additive played a crucial role in promoting this alkylation. Mechanistic studies revealed the gradual generation of organic iodide from alcohol and the in-situ exchange of SO42−with iodide ion (I−), both of which were essential for an efficient alkylation process. This chemistry provides a practical protocol for the synthesis of various N-heterocycles and has been successfully applied in the late-stage synthesis of drugs. They anticipate that this strategy may pave the way for direct functionalization of inert primary alcohols.

来源：新浪财经