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.
Keywords: amino acids; cyclization; fragment synthesis; nitrogen heterocycles; rhodium catalysis.
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