A Cascade Synthesis of Aminohydantoins Using In Situ‐Generated N‐Substituted Isocyanates

Abstract

Nitrogen-substituted isocyanates are rarely utilized but powerful building blocks for the development of cascade reactions in heterocyclic synthesis. These reactive amphoteric intermediates can be accessed in situ via an equilibrium that allows controlled reactivity in the presence of bifunctional partners such as α-amino esters. A cascade reaction has been carried out that forms 3-aminohydantoin derivatives using simple phenoxycarbonyl derivatives of hydrazides and hydrazones as precursors of N-substituted-isocyanates. This method allows rapid assembly of complex aminohydantoin derivatives, including analogues of medicinally-relevant compounds, using simple reactants.

Cascade reactions of nitrogen-substituted isocyanates: a new tool in heterocyclic chemistry

“…Herein, we discuss the first cascade reactions developed using amino-, imino- and amido-substituted N -isocyanates for the synthesis of heterocyclic molecules. In addition to previously communicated work toward saturated 5- and 6-membered azacycles and nitrogen-substituted hydantoins, 7 , 8 we report new cascade reactions furnishing important heteroaromatic cores incorporating the N–N–C O motif in several different orientations. N -Isocyanates were used to assemble 5- and 6-membered aromatic heterocycles including acyl-pyrazoles, acyl-phthalazinones and azauracils.…”

“…Recently, we reported such a cascade reaction using α-amino esters to rapidly assemble N -substituted hydantoins ( Scheme 3 ). 8 Since encouraging results were obtained for substitution reactions using amino-esters on blocked N -isocyanates ( Scheme 3 ), we rationalized that we could develop a new substitution/cyclization reaction cascade. This cascade was first investigated with amino-isocyanates since two different products could be formed depending on which nitrogen would cyclize.…”

Preise 2015 der Canadian Society for Chemistry

“…Beauchemin wurde in dieser Rubrik vorgestellt, als er einen AstraZeneca Excellence in Chemistry Award erhalten hatte 4a. Kürzlich erschien in Chemistry—A European Journal eine Arbeit von ihm über eine Kaskadensynthese von Aminohydantoinen 4b …”

Canadian Society for Chemistry Awards 2015

“…Beauchemin was featured here when he won an AstraZeneca Excellence in Chemistry Award 4a. He has recently reported in Chemistry—A European Journal on a cascade synthesis of aminohydantoins 4b …”