Synthesis of N-Styrenyl Amidines from α,β-Unsaturated Nitrones and Isocyanates through CO₂ Elimination and Styrenyl Migration

Abstract

A mild, metal-free, and modular route for the preparation of N-styrenyl amidines from N-aryl-α,β-unsaturated nitrones and isocyanates has been developed that accesses an initial oxadiazolidinone intermediate that can undergo CO(2) elimination and styrenyl migration. The use of a migration event to install N-styrenyl amidine substituents circumvents a limitation of traditional Pinner-type methods for amidine synthesis that require the use of amine nucleophiles. The modularity of the nitrone and isocyanate reagents provides access to a variety of differentially substituted N-styrenyl amidines. The scope and tolerance of the method are presented, and preliminary mechanistic data for the transformation are discussed.

The C=C Bond Decomposition Initiated by Enamine‐Azide Cycloaddition for Catalyst‐ and Additive‐Free Synthesis of N‐Sulfonyl Amidines

“…While the classical condensation of amines with amide acetals resulting from the treatment of amides with SOCl 2 , POCl 3 etc used to be frequently employed for amidine synthesis in early years, the driving force of developing environmentally benign synthetic methods has triggered the occurrence of many important new tactics providing amidine products. For example, the reactions involving direct activation of amides, the reactions involving decomposition of the in situ generation 1,2,3‐triazole ring given by copper‐catalyzed azide‐alkyne cycloaddition, the condensation of C=S bond with amine precursors, three‐component protocols involving the coupling of amine or precursors with amides and electrophiles, the Ag‐catalyzed activation of alkyne C≡C triple bond, the reactions involving nitrone/isocyanate [3+2] cycloaddition . And most prevalently, the oxidative imidation of the C−C bond on tertiary amines .…”

“…[2] While the classical condensation of amines with amide acetals resulting from the treatment of amides with SOCl 2 , POCl 3 etc used to be frequently employed for amidine synthesis in early years, [3] the driving force of developing environmentally benign synthetic methods has triggered the occurrence of many important new tactics providing amidine products. [9] And most prevalently, the oxidative imidation of the CÀ C bond on tertiary amines. [9] And most prevalently, the oxidative imidation of the CÀ C bond on tertiary amines.…”

Diastereoselective Synthesis of Nine‐Membered Heterocycles via the Cycloaddition and Sequential Rearrangement of N‐Vinyl Nitrones with Isocyanates

“…In previous work, (3+2) cycloadditions of N ‐alkyl or N ‐aryl nitrones with isocyanates have been shown to successfully afford five‐membered ring intermediates regioselectively, which were then able to undergo decarboxylation and migration to afford amidines or amides (Scheme ‐A) . In 2014, Anderson and co‐workers reported a new method for the synthesis of N ‐vinyl amidines from α,β ‐unsaturated N ‐aryl nitrones and isocyanates through CO 2 elimination and styrenyl migration (Scheme ‐B) . Although N ‐vinyl nitrones have rarely been used as synthetic intermediates, it was envisioned that the double bonds attached to the N ‐atom of the cycloadduct resulting from N ‐vinyl‐ α,β ‐unsaturated ketonitrone and isocyanate would undergo an aza‐Claisen rearrangement to afford nine‐membered heterocycles (Scheme ‐C).…”

“…In previous work, (3 + 2) cycloadditions of N-alkyl or N-aryl nitrones with isocyanates have been shown to successfully afford five-membered ring intermediates regioselectively, [9] which were then able to undergo decarboxylation and migration to afford amidines or amides (Scheme 1-A). [11] Although N-vinyl nitrones have rarely been used as synthetic intermediates, [12] it Scheme 1. [11] Although N-vinyl nitrones have rarely been used as synthetic intermediates, [12] it Scheme 1.…”

A Convenient Synthesis of Amidines via Cycloaddition–Decarboxylation of Isocyanates and Nitrones

“…11 In 2014, Anderson and co-workers developed a modular route to N-styrenylamidines by using N-aryl-,-unsaturated ni-trones as substrates. 12 This reaction allows access to an initial oxadiazolidinone intermediate, which then undergoes extrusion of CO 2 and styrenyl migration to provide a series of functionalized amidine products (Scheme 1c). However, this synthetic method largely relies on elaborately designed substrates that are not readily accessible.…”