Abstract
A one-pot sequence for the synthesis of aza-diketopiperazines is reported, involving carbazate acylation with chloroacetyl chloride, S(N)2 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 beta N-acyl carbazates can act as blocked (masked) N-isocyanates, thus allowing a challenging intermolecular S(N)2 reaction of a primary amine to proceed while the N-isocyanate is "protected", and then cydization once it is unmasked. Control experiments show that the alternate pathway-N-isocyanate substitution and then cydization by an intramolecular S(N)2 reaction-is not operating.