Asmic Isocyanide [3 + 2] Cascade to Dihydrooxazoles and Dihydroimidazoles

Abstract

The versatile isocyanide building block Asmic, anisylsulfanylmethylisocyanide, reacts with aldehydes and ketones in a BF 3 •OEt 2 -mediated condensation to afford thioimidoyl-substituted 2,5-dihydrooxazoles. The condensation is distinguished from related base and transition-metal-catalyzed [3 + 2] processes in proceeding via the condensation of aldehydes and ketones with 2 equiv of an isocyanide followed by a molecular rearrangement that installs four new bonds. BF 3 •OEt 2 mediates an analogous condensation of Asmic with imines to generate N-substituted dihydroimidazoles. Mechanistically, BF 3 • OEt 2 activates the isocyanide to facilitate deprotonation evolving to a zwitterion that traps π-electrophiles in a formal [3 + 2] process. A second deprotonation−condensation with Asmic initiates a structural rearrangement involving a sulfanyl elimination− addition transposition sequence. The resulting dihydrooxazoles and dihydroimidazoles contain a thioimidate that serves as a diversification point for further elaboration.

Reactions Involving Multiple Isocyanide Insertions

“…When t butyl isocyanides 2 react with N-tosylhydrazones 214 in the presence of higher amounts of BF 3 , the t Bu group is selectively In 2020, Fleming et al synthesized thioimidoylsubstituted 2,5-dihydrooxazoles/dihydroimidazoles 230 in moderate to good yields (58-84%) via [3 + 2] condensation of π-electrophiles 224 with Asmics (anisylsulfanylmethylisocyanides) 225 using BF 3 .OEt 2 in CH 2 Cl 2 at 0 °C (Scheme 30). [46] To do so, first of all, the acidity of the methylene protons is increased via coordination of BF 3 with the carbon atom of isocyanides 225 whose subsequent base-induced deprotonation produces the zwitterions 226. Then, cyclization of zwitterions 226 with π-electrophiles 224 gives cyclic intermediates 227.…”

Recent Advances in [3+2]-Cycloaddition-Enabled Cascade Reactions: Application to Synthesize Complex Organic Frameworks

“…19,20 In 2020, Fraser F. Fleming et al have reported an asmic isocyanide aided [3+2] cascade reaction sequence for formation of dihydrooxazoles and dihydroimidazoles (Scheme 5). 20 The versatile building block isocyanide 19 reacts with aldehydes, ketones, and derivatives 20 in a BF 3 •OEt 2 -mediated condensation to afford thiomidoyl-substituted 2,5-dihydrooxazoles 21. Mechanistically, firstly boron trifluoride etherate coordinated to the carbon of isocyanide making the methylene protons more acidic as depicted in 22 (Scheme 5).…”

“…Isocyanides have a renowned history of serving as a quintessential precursor for the formation of bioactive complex heterocycles. 19,20 In 2020, Fraser F. Fleming et al have reported an asmic isocyanide aided [3+2] cascade reaction sequence for formation of dihydrooxazoles and dihydroimidazoles (Scheme 5). 20 The versatile building block isocyanide 19 reacts with aldehydes, ketones, and derivatives 20 in a BF 3 •OEt 2 -mediated condensation to afford thiomidoyl-substituted 2,5-dihydrooxazoles 21.…”

Boron Lewis acid-catalyzed formal insertion of isocyanides into a C–O bond of benzyl esters

“…Although transition-metal-catalyzed reactions of isocyanides have been widely investigated by numerous research groups all over the world, 4 reactions that involve isocyanides and boron Lewis acids are comparatively underexplored and have been mainly limited to stoichiometric reactions. 5 Therefore, the development of boron Lewis acid catalyzed transformations of isocyanides is highly desirable.…”