A Solid-Phase Synthesis of N,N‘-Disubstituted Ureas and Perhydroimidazo[1,5-a]pyrazines via the Curtius Rearrangement

Abstract

An efficient method for trapping isocyanates, generated from the Curtius rearrangement, with resin-bound amines is reported. A commercially available carboxylic acid is treated with diphenylphosphoryl azide, followed by thermal rearrangement, cooling, and trapping in one pot. Cleavage from the resin gives an N, N'-disubstituted urea in excellent purity, as demonstrated with several heterocyclic and aliphatic carboxylic acids. Further utility is shown by preparing several novel perhydroimidazo[1,5-a]pyrazines.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

“…The Curtius rearrangement is a key step in the total synthesis of (+)‐zamoanolide, a tumor‐growth inhibitor 500. Solid‐phase Curtius rearrangements have also been described for the amine504 or carboxylic acid505 immobilized on the solid phase. The isocyanate 522 is first formed as an intermediate in a Curtius rearrangement before further transformation (Scheme 126).…”

Organische Azide – explodierende Vielfalt bei einer einzigartigen Substanzklasse

“…Bei der Totalsynthese von (+)‐Zamoanolid, einem Tumorwachstums‐Hemmstoff, ist die Curtius‐Umlagerung eine wichtige Synthesestufe 500. Auch eine Curtius‐Umlagerung am Träger wurde beschrieben, bei der Amine504 oder auch Carbonsäuren505 an der festen Phase immobilisiert werden konnten. Dabei wurde in einer vorherigen Stufe das Isocyanat 522 aus einer Curtius‐Umlagerung als Zwischenprodukt gebildet, das dann weiter umgesetzt wurde (Schema 126).…”

From Regioselective Condensation to Regioselective N‐Alkylation: A Novel and Environmentally Benign Strategy for the Synthesis of N,N′‐Alkyl Aryl Ureas and N,N′‐Dialkyl Ureas

“…However, isocyanates are highly toxic, hazardous, and unstable. As a result, much effort has been devoted to the synthesis of N , N ′‐alkyl aryl ureas and N , N ′‐dialkyl ureas based on in situ generation of the isocyanates through the rearrangement of some precursors,2–7 such as carbamates,2 acyl azides,3 carboxylic acids,4 hydroxamic acids,5 carbamic acids,6 and acetoacetanilide 7. However, these procedures often suffer from a tedious synthesis of the starting materials, the formation of high‐molecular‐weight side products, and low yields.…”