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

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...

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Veröffentlicht in:	Organic letters 2015-10, Vol.17 (19), p.4898-4901
Hauptverfasser:	Ivanovich, Ryan A, Vincent-Rocan, Jean-François, Elkaeed, Eslam B, Beauchemin, André M
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container_issue	19
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container_title	Organic letters
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creator	Ivanovich, Ryan A Vincent-Rocan, Jean-François Elkaeed, Eslam B Beauchemin, André M
description	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.
doi_str_mv	10.1021/acs.orglett.5b02464
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title	One-Pot Synthesis of Aza-Diketopiperazines Enabled by Controlled Reactivity of N‑Isocyanate Precursors
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