One-Pot Synthesis of Aza-Diketopiperazines Enabled by Controlled Reactivity of N-Isocyanate Precursors.

Org Lett

Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON K1N 6N5, Canada.

Published: October 2015

A one-pot sequence for the synthesis of aza-diketopiperazines is reported, involving carbazate acylation with chloroacetyl chloride, SN2 with a primary amine, N-isocyanate formation, and cyclization. Nitrogen-substituted isocyanates (N-isocyanates) are a rare class of amphoteric isocyanate with high, but severely underdeveloped synthetic potential. This approach highlights that βN-acyl carbazates can act as blocked (masked) N-isocyanates, thus allowing a challenging intermolecular SN2 reaction of a primary amine to proceed while the N-isocyanate is "protected", and then cyclization once it is unmasked. Control experiments show that the alternate pathway--N-isocyanate substitution and then cyclization by an intramolecular SN2 reaction--is not operating.

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Source
http://dx.doi.org/10.1021/acs.orglett.5b02464DOI Listing

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