Rapid syntheses of N-fused heterocycles via acyl-transfer in heteroaryl ketones

• Published in: Nature communications Vol. 13; no. 1; p. 3337
• Main Authors: Ye, Dan, Lu, Hong, He, Yi, Zheng, Zhaojing, Wu, Jinghao, Wei, Hao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-06-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/403/933; 639/638/77/888; Biological activity; Bromides; Carbon - chemistry; Chemical reactions; Chromatography; Humanities and Social Sciences; Ketones; Ketones - chemistry; Knowledge management; multidisciplinary; Natural products; Nitrogen; Nitrogen - chemistry; Organic chemistry; Scaffolds; Science; Science (multidisciplinary); Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31063-3

The wide-ranging potencies of bioactive
N
-fused heterocycles inspire the development of synthetic transformations that simplify preparation of their complex, diverse structural motifs. Heteroaryl ketones are ubiquitous, readily available, and inexpensive molecular scaffolds, and are thus synthetically appealing as precursors in preparing
N
-fused heterocycles via intramolecular acyl-transfer. To best of our knowledge, acyl-transfer of unstrained heteroaryl ketones remains to be demonstrated. Here, we show an acyl transfer-annulation to convert heteroaryl ketones to
N
-fused heterocycles. Driven via aromatisation, the acyl of a heteroaryl ketone can be transferred from the carbon to the nitrogen of the corresponding heterocycle. The reaction commences with the spiroannulation of a heteroaryl ketone and an alkyl bromide, with the resulting spirocyclic intermediate undergoing aromatisation-driven intramolecular acyl transfer. The reaction conditions are optimised, with the reaction exhibiting a broad substrate scope in terms of the ketone and alkyl bromide. The utility of this protocol is further demonstrated via application to complex natural products and drug derivatives to yield heavily functionalised
N
-fused heterocycles.
Heteroaryl ketones are ubiquitous molecular scaffolds but seldom used as synthetic precusors. Here, the authors develop an acyl transfer-annulation to convert heteroaryl ketones to
N
-fused heterocycles, which are prevalent in bioactive molecules.