摘要：Division of Chemistry and ChemicalEngineering, California Institute of Technology, Pasadena, CA, USA

转自：康龙化成

Synthesis of Tertiary Alkyl Amines via Photoinduced Copper-catalysed Nucleophilic Subsitution

Hyungdo Cho, Xiaoyu Tong, Giuseppe Zuccarello, Robert L.Anderson & Gregory C. Fu

Division of Chemistry and ChemicalEngineering, California Institute of Technology, Pasadena, CA, USA

—Nature Chemistry, 2025,doi:10.1038/s41557-024-01692-w

Recommended by Depei Meng_MC4

KEY WORDS: Cucatalysis (反应类型),photo chemistry (反应类型),nucleophilic substitution (反应类型),C(sp3)-N (成键类型), Alkyl bromides, secondaryamines (原料), tertiary alkyl amines (产物), CuBr (催化剂)

ABSTRACT: Inview of the high propensity of tertiary alkyl amines to be bioactive, thedevelopment of new methods for their synthesis is an important challenge.Transition-metal catalysis has the potential to greatly expand the scope ofnucleophilic substitution reactions of alkyl electrophiles; unfortunately, inthe case of alkyl amines as nucleophiles, only one success has been describedso far: the selective mono-alkylation of primary amines to form secondaryamines. Here, using photoinducedcopper catalysis, we report the synthesis of tertiary alkyl amines fromsecondary amines and unactivatedalkyl electrophiles, two readily available coupling partners.

Tertiary Alkyl Amines

a,Bioactive tertiary alkyl amines.

b,Metabolically stable Csp3 -rich bioisosteres ofanilines.

c, Alkylation of secondary alkyl amines by unactivated secondary and tertiary electrophiles: no broadly applicable method.

d, Photoinduced copper catalysis under mild conditions.

Substrate Scope

The Proposed Catalytic Cycle

(For the sake of simplicity, all steps are shown as irreversible)

Summary and Comments

In conclusion, although tertiaryalkyl amines frequently occur in bioactive molecules, the alkylation of secondary alkylamines by hindered, unactivated alkyl electrophiles is afundamental challenge in synthetic organic chemistry that lacks a generalsolution. GregoryC. Fu’s group have developed a mild, versatile and efficient method that uses photoinduced transition-metal catalysis, specifically, by copper. Thisapproach complements other methods for accessing tertiary alkyl amines, both interms of stereoselectivity (forexample, versus reductive amination) and scope (for example, access to bioisosteres ofanilines).

总地来说，尽管叔烷基胺经常出现在生物活性分子中，但仍缺乏通用的解决方案通过受阻、未活化的烷基亲电试剂对仲烷基胺的烷基化合成叔烷基胺，是有机合成化学中的一个基本挑战。GregoryC. Fu课题组开发了一种温和、通用和高效的方法，该方法使用光诱导过渡金属（铜）催化。这种方法无论是在立体选择性（例如与还原胺化相比）还是底物范围（例如获得苯胺的生物等位体）方面，都可以和其他获得叔烷基胺的方法形成很好的互补。

来源：新浪财经