Investigation of Masked N‐Acyl‐N‐isocyanates: Support for Oxadiazolones as Blocked N‐Isocyanate Precursors

• Published in: Chemistry : a European journal Vol. 27; no. 56; pp. 14051 - 14056
• Main Authors: Gagné‐Monfette, William, Vincent‐Rocan, Jean‐François, Lutes, Owen C., O'Keefe, Geneviève F., Jeanneret, Alexandria D. M., Blanger, Claire, Ivanovich, Ryan A., Beauchemin, André M.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 07.10.2021; Wiley Subscription Services, Inc
• Subjects: aza-peptides; Carboxylic acids; Catalysts; Chemistry; Chemistry, Multidisciplinary; Hydantoin; hydrazides; Isocyanates; nitrogen heterocycles; Nucleophiles; oxadiazolones; Physical Sciences; Precursors; Science & Technology; Substitutes; SOLID-PHASE SYNTHESIS; ONE-POT SYNTHESIS; AMINO; INHIBITION; aza-peptides; isocyanates; nitrogen heterocycles; CONCERTED CYCLOADDITIONS; oxadiazolones; hydrazides; AZA-PEPTIDE; AMIDE BOND FORMATION; PEPTIDE-SYNTHESIS; DERIVATIVES; AZAPEPTIDES
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202102301

In contrast to carbon‐substituted isocyanates that are common building blocks, N‐substituted isocyanates remain underdeveloped and reports on their N‐acyl derivatives (i. e. amido‐isocyanates) are exceedingly rare. Herein, amido‐isocyanates were investigated in the context of syntheses of aza‐tripeptide and hydantoins subunits starting from simple bench‐stable precursors. A key finding is that the amido‐isocyanate formed in situ cyclized to yield an oxadiazolone, and that under suitable reaction conditions this heterocycle is a traceless blocked (masked) N‐isocyanate. Using organic bases as catalysts and upon heating, oxadiazolone formation is observed, and various nucleophiles to provide the desired aza‐dipeptides or hydantoins in moderate to high yields. Further support for an amido‐isocyanate intermediate was obtained using carboxylic acids as nucleophiles, affording N‐acylhydrazide products. Masked synthesis: N‐isocyanates are reactive intermediates and their N‐acyl derivatives, amido‐isocyanates, are rare. Herein, their synthesis and reactivity are studied, supporting that under suitable conditions the amido‐isocyanate is in equilibrium with the parent oxadiazolone. Reactions with amino‐amides as nucleophiles form nitrogen‐rich products, either aza‐tripeptides or their parent hydantoins. Support for an isocyanate intermediate was also obtained using carboxylate ions as nucleophiles, affording N‐acylhydrazides.