康 · 学术 | Reaction of the Day No. 1768

Deaminative Nucleophilic Substitution of Alkyl Amines

Ke Xiao 1,2, Yuang Cui 1,2, Xiaoping Chen 1,2, Guangliang Tu 1,2, Hui Lv1 & Xiaheng Zhang1*

1School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.

2These authors contributed equally: Ke Xiao, Yuang Cui, Xiaoping Chen, Guangliang Tu.

—Nat. Synt. 2026, doi: org/10.1038/s44160-026-01210-5.

Recommended by Bingbing Chang_MC5

KEY WORDS: Deamination, Deaminative nucleophilic substitution, late-stage functionalization (反应类型), C(sp3)-X, C(sp3)-O, C(sp3)-N, C(sp3)-S, C(sp3)-Se, C(sp3)-C(sp2) (成键类型), amines, alkyl nitroamines, HNO3 (原料), deaminative functionalization products (产物), nitroamines (其他).

ABSTRACT: Nucleophilic substitution is one of the most fundamental and widely used strategies for alkyl functionalization. For more than a century, such transformations have relied predominantly on alcohols and alkyl halides as the primary alkylating synthons. Here we report a nucleophilic substitution strategy that uses the unique reactivity of N-alkyl nitroamines, enabling alkyl amines to serve as a latent and readily available class of direct alkylation reagents. Through a systematic investigation of N-alkyl nitroamine reactivity, Prof. Xiaheng Zhang have developed a polarity-driven platform for direct deaminative functionalization, enabling broad nucleophilic substitution of alkyl amines to efficiently construct alkyl C?halogen, C?C, C?N, C?O and C?S bonds. The method accommodates primary, secondary and tertiary alkyl amines as well as benzylic amines. This strategy overcomes the intrinsic limitations of aliphatic diazonium chemistry and substantially expands the scope of nucleophilic substitution reactions hitherto inaccessible by conventional approaches.

Direct deaminative nucleophilic substitution of alkyl amines. a, Alkyl amines as building blocks in synthetic chemistry. b, Current progress in direct deaminative functionalization of alkyl amines. c, Deaminative nucleophilic substitution of alkyl amines (this work).

Scope of deaminative halogenation

Nucleophile scope of deaminative functionalization (selected examples)

Proposed mechanism

Summary and Comments

By unlocking the reactivity of alkyl nitroamines, Prof. Xiaheng Zhang have realized deaminative nucleophilic substitution of alkyl amines, thereby expanding the boundaries of alkyl functionalization well beyond the limitations of classical diazonium salt chemistry. This previously inaccessible polarity-driven deamination manifold establishes a versatile and general platform for alkyl functionalization. In contrast to conventional approaches, such as the Mitsunobu or classical nucleophilic substitution reactions, the present strategy offers a distinct advantage in accommodating sterically hindered tertiary alkyl centres. They anticipate that this deaminative functionalization chemistry will inspire widespread exploration and application across synthetic chemistry.