Cross-coupling reactions with aromatic compounds have revolutionized organic synthesis and influenced enormously the synthesis of biologically active small molecules. Limitations in the solubility, pharmacokinetics, bioavailability, and originality of the resulting structures have led many scientists to evaluate saturated heterocycles including piperidines, morpholines, thiomorpholines, piperazines, and diazepanes as superior alternatives. Despite considerable effort, the preparation of such heterocycles onto by a convenient cross-coupling reaction has proven difficult to achieve (eq 1).In this report we disclose an alternative to the cross-coupling with saturated N-heterocycles using aldehydes as a synthetic handle. We have developed SnAP reagents for the preparation of N-unprotected, 3-substituted thiomorpholines by a convenient, operationally simple procedure. The mechanism of this process involves a copper (II)-mediated intramolecular radical cyclization onto an unactivated imine. The procedure was also expanded to the preparation of morpholines, piperazines, and other saturated N-heterocycles not currently served by existing methods (Figure 1).SnAP = Tin (Sn) Amine Protocol(1) Vo, C.-V. T.; Mikutis, G.; Bode, J. W. Angew. Chem. Int. Ed. 2013  , 52, 1705-1708.

SnAP reagents for the transformation of aldehydes into substituted saturated N-heterocycles � an alternative to cross-coupling reaction

247th National Meeting (2014)

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