摘要：Céline Dorval 1, Adrian D. Matthews 1, Karina Targos 1, Sara N.Alektiar1, Dylan E. Holst1, Zhifeng Tan 1, MikkoMuuronen2, Justin B

转自：康龙化成

Unlocking Azole Chemical Space via Modular and Regioselective N-alkylation

Céline Dorval 1, Adrian D. Matthews 1 , Karina Targos 1 , Sara N. Alektiar1 , Dylan E. Holst1, Zhifeng Tan 1 , Mikko Muuronen2 , Justin B. Diccianni3 , José Enrique Gómez 4 , Kyana M. Sanders1 , Ilia A. Guzei1& Zachary K. Wickens1

1 Department of Chemistry, University of Wisconsin–Madison, Madison, WI, USA.

2 Analytical Development Synthetics, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.

3 Global Discovery Chemistry, Janssen Research & Development LLC, Spring House, PA, USA. 4 Global Discovery Chemistry, Janssen Research & Development, Janssen-Cilag, SA, Toledo, Spain

—Nature Chemistry. 2025, doi:10.1038/s41557-025-01891-z

Recommended by Depei Meng_MC4

KEY WORDS:azole alkylation,hydroazolation, regioselective (反应类型), C(sp3)─N (成键类型), alkenyl thianthrenium, azoles (原料), azolothianthrenium, N-alkyl azoles (产物), reversible C–N-bond-forming (其他)

ABSTRACT: Azoles are important synthetic targets due to their diverse applications in areas ranging from human health to food security. Accordingly, access to N-functionalized azoles is an essential goal in modern synthetic chemistry. Surprisingly, however, the relied-upon azole N-alkylation strategies fundamentally limit the structural diversity of these important compounds that can be synthesized and studied. Here we introduce an approach to prepare a broad array of important but difficult-to-access N-alkyl azole compounds. We accomplish this through the introduction of a base-catalysed hydroazolation of readily accessible alkenyl thianthrenium electrophiles. This strategy circumvents the classical challenge of azole alkylation regiocontrol through an unusual reversible C–N-bond-forming step that exploits the thermodynamic differences between azole N-alkylation isomers. This reaction furnishes a class of versatile azolothianthreniumbuilding blocks that provides a general platform to investigate diverse N-alkyl azole molecules. More broadly, the distinctive approach outlined through this project is poised to impact the design and development of diverse regioselective alkylation reactions.

Background and this work. b, Conventional azole N-alkylation methods suffer from major limitations. c, Our strategy leverages the hydroazolation of alkenylthianthreniumsalts to readily prepare previously challenging-to-access, densely functionalized N-alkyl azoles..

Influence of Brønsted base catalyst identity on azole N-alkylation yield and regioselectivity

Treatment of the minor N-regioisomer with the appropriate Brønsted base catalyst leads to its conversion to the major regioisomer

Substrate Scope: Generalization of the hydroazolation strategy

One-pot synthesis of densely functionalized azoles

Synthetic opportunities enabled by reversible hydroazolation. a, Preparation of an unreported N-isomer of butoconazole via the hydroazolation of an alkenylthianthrenium salt. b,Improved synthesis of a drug intermediate.

Synthetic opportunities enabled by reversible hydroazolation. c, Dynamic resolution of diastereomers in 1,2-azolothianthrenium substitution.d,Mechanistic scenario consistent with the dynamic resolution of diastereomers.

In conclusion, Céline Dorval  et al. have introduced an azole N-alkylationstrategy to prepare previously prohibitively difficult-to-access molecular structures. This reaction is highly N-regioselectivedue to an unusual, reversible C–N-bond-forming step that allows us to exploit the thermodynamic differences between N-alkyl azole isomers. Alkenylthianthrenium hydroazolation was found to be general across a wide range of azoles and related heterocycles. Without requiring purification, the resultant azolothianthrenium electrophiles undergo substitution reactions with a diverse array of abundant polar nucleophiles. Overall, this operationally simple one-pot protocol fundamentally expands the structural diversity of accessible N-alkyl azoles and is poised to impact the design and preparation of biologically active small molecules.

总地来说，Céline Dorval等人提出了一种唑类N-烷基化策略，用以制备以往难以获取的分子结构。该反应采用非常规的可逆碳氮键形成步骤，从而能够利用N-烷基唑异构体之间的热力学差异，使反应具备具有高度N-区域选择性。该烯基噻蒽鎓氢唑化反应适用于多种唑类及相关杂环化合物。无需后续纯化处理，所得唑鎓噻蒽盐亲电试剂即可与多种富电子极性亲核试剂发生取代反应。总体而言，这种操作简便的一锅法从本质上拓展了可制备N-烷基唑类化合物的结构多样性，有望对生物活性小分子的设计与合成产生深远影响。

来源：新浪财经