Development of Hydrogen Bond Donor Catalyzed Domino Protocols for the Synthesis of Functionalized Heterocycles

Abstract

The synthesis of highly functionalized five membered oxa- and aza-heterocycles has newlinebeen reported utilizing a Hydrogen-Bond Donor (HBD) Catalysis. In this regard, newlineepoxide was taken as a substrate and reacted with functionalized arylidene/alkylidene newlinemalononitrile derivatives in the presence of the newly designed HBD catalyst. In all the newlinecases the products 2,5-disubstituted tetrahydrofuran (2,5-THF) were obtained in good newlineto excellent yields with high diastereoselectivity (dr up to 99:1) as a single regioisomer. newlineThe stereochemistry at the 2- and 5-positions of the five membered ring has been newlineconfirmed by single crystal X-ray analysis and it is found to be cis as the major product. newlineThe same strategy has been further utilized to obtain substituted oxazolidines whenever newlinethe epoxide has been reacted with isocyanate as an electrophile. In order to induce the newlineenantioselectivity, chiral epoxide and chiral HDB catalyst have been introduced with newlineboth the electrophiles in the presence of the same reaction conditions to afford the single newlinestereoisomer of the final products. This synthetic methodology involves low catalyst newlineloading, ambient reaction condition and has been generalized with various substituents newlinepresent in the starting electrophiles to produce the resultant products in acceptable newlineyields and stereoselectivity. newlineFurthermore, a new and straightforward metal-free synthesis of fused or hybrid oxa newlineaza- heterocycles from substituted cis-2,5-THF derivatives under mild conditions is newlinediscussed. The reaction involves a hypervalent iodine mediated intramolecular CSP2-N newlinecoupling reaction under the ambient reaction conditions. This intramolecular C-N newlinecoupling methodology provides a powerful tool for the synthesis of fused or hydrid oxa newlineaza- heterocyclic compounds in good yields and stereoselective form. newline