Premium
Rapid Assembly of Saturated Nitrogen Heterocycles in One‐Pot: Diazo‐Heterocycle “Stitching” by N–H Insertion and Cyclization
Author(s) -
Boddy Alexander J.,
Affron Dominic P.,
Cordier Christopher J.,
Rivers Emma L.,
Spivey Alan C.,
Bull James A.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201812925
Subject(s) - diazo , chemistry , combinatorial chemistry , image stitching , aryl , nitrogen , stereochemistry , organic chemistry , computer science , alkyl , artificial intelligence
Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2‐disubstituted azetidines, pyrrolidines, piperidines, and azepanes bearing ester and diverse aryl substituents. A one‐pot rhodium catalyzed N–H insertion and cyclization sequence uses diazo compounds to stitch together linear 1, m ‐haloamines ( m =2–5) to rapidly assemble 4 ‐, 5 ‐, 6 ‐, and 7 ‐membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including examples with diazo compounds derived from biologically active compounds. The products can be functionalized to afford α,α‐disubstituted amino acids and applied to fragment synthesis.