Diversity-oriented heterocyclic synthesis using divergent reactivity of N-substituted iso(thio)cyanates

Abstract

Carbon-substituted isocyanates and isothiocyanates are common building blocks in organic synthesis. In contrast, synthetic uses of N-substituted isocyanates and isothiocyanates are severely underdeveloped: few have been reported and their reactivity had not been compared. Herein, we compare the reactivity of blocked (masked) N-isocyanate and N-isothiocyanate precursors in cascade reactions. Divergent reactivity is observed with secondary propargylic and allylic systems, leading to new syntheses of imidazolones, thiazolidines, and a tool to form complex azomethine imines.

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

“…Finally, we performed exploratory attempts toward three related cascades. These proved rewarding as we showed that: (1) imidazolidinone ( 7p ) formation was possible if ring closure was achieved via 1,4-addition (rather than 1,2-addition), using an α,β-unsaturated amino-ester as reagent; (2) an N -isothiocyanate precursor also engaged in a related cascade 14 to form an amino-thiohydantoin ( 7q ); (3) amide-substituted hydantoin ( 7r ) could be synthesized using an amido-isocyanate precursor. Collectively, this data suggested that a variety of N -isocyanate precursors could engage in cascade reactions and display similar reactivity.…”

N-Propargylamines: versatile building blocks in the construction of thiazole cores

“…The desired N -isocyanates A are produced in situ upon heating or treatment with a base, in acetonitrile under microwave irradiation conditions ( Scheme 8 ). The reaction tolerated a variety of functional groups such as fluoro, cyano, hydroxy, and methoxy, allowing a further derivatization of the products [ 90 ].…”

N-Isocyanates, N-Isothiocyanates and Their Masked/Blocked Derivatives: Synthesis and Reactivity

“…While prior studies reported the reactivity of aminoisothiocyanates, the Beauchemin group investigated the reactivity of iminoisothiocyanates in the context of a cascade reaction with an aminoester, 65 and compared the reactivity in cascade reactions involving aminoisocyanates. 66 These reports are discussed in detail in the next section.…”

“…In addition to developing cycloaddition reactions, Beauchemin developed several cascade reactions using simple or amphoteric nitrogen nucleophiles. 65,66,77,78,80,81 This work also required improved control over N-isocyanate formation and reactivity.…”

“…Subsequent to this report highlighting the similar reactivity of N-isocyanates and N-isothiocyanates, the same research group reported the divergent reactivity of these reactive intermediates with propargylic amines (Scheme 37). 66 Indeed, while both reactive intermediates reacted readily with the nitrogen nucleophile, subsequent cyclization on the alkyne yielded different products, with the semicarbazone adducts of the iminoisocyanate cyclizing with their nitrogen atoms to form imidazolones, and the iminoisothiocyanate adducts cyclizing instead through the sulfur atom.…”