One-Pot, Three-Component Synthesis of Chiral 4-Alkylidene-2-oxazolidin­ones

Abstract

A one-pot convenient access to chiral 2-oxazolidinones is described. Diethylzinc-mediated asymmetric alkynylation of aldehydes with propiolates in the presence of b-sulfonamide alcohol as the chiral ligand, followed by treatment with isocyanates, yielded chiral 4-alkylidene-2-oxazolidinones.Avid interest in modern organic chemistry has been directed toward the development of simple and convenient ways to access useful heterocyclic compounds under mild and environmentally friendly conditions. Multicomponent reactions (MCR) have recently emerged as a valuable tool for the preparation of chemical libraries of druglike heterocyclic compounds. 1 2-Oxazolidinones play prominent roles in daily life. They are widely used in pharmaceutical manufacturing, 2 agriculture, and industry, and as chiral auxiliaries in organic synthesis. 3 Among the many methods for the syntheses of 2-oxazolidinones, 4 the 5-exo cyclization of O-propargyl or O-allyl carbamates is one of the most attractive methods because it enables easy access to various substituted 2-oxazolidinones. The base-promoted cyclization of Opropargyl carbamates has long been established. 5 The intermolecular hydroamination of O-propargyl carbamates in the presence of a transition metal, such as Cu 2+ or Au + salt, has also been reported. 6 Baba and co-workers reported that the addition of allyltin reagents to a,b-unsaturated aldehyde, followed by treatment with isocyanates, gave 2-oxazolidinones in one-pot reactions. 7 Herein, we report the one-pot, three-component synthesis of chiral 4-alkylidene-2-oxazolidinones with aldehydes, propiolates, and isocyanates.Although the asymmetric alkynylation of carbonyl compounds by zinc acetylides is a well-known method for the synthesis of chiral propargyl alcohol derivatives, 8 the resulting zinc alkoxides have been scarcely used for further transformation as most zinc-oxygen bonds are hydrolyzed to propargyl alcohols despite their sufficient nucleophilicity. We devised a one-pot synthesis of chiral 2-oxazolidinones, which involved asymmetric alkynylation of aldehydes with propiolates, followed by treatment with isocyanates. Initial screening of the reaction conditions demonstrated that the conditions developed by Wang's group 9 gave the best results for our purpose.Diethylzinc-mediated (3.0 equiv) asymmetric alkynylation of cyclohexanecarbaldehyde (1.0 equiv) with ethyl propiolate (3.0 equiv) in the presence of Ti(Oi-Pr) 4 (30 mol%) and 1,2-dimethoxyethane (DME, 1.0 equiv) using b-sulfonamide alcohol (30 mol%) as the chiral ligand in toluene at room temperature, followed by treatment with tosyl isocyanate (3.2 equiv), afforded (R,E)-4-alkylidene-3-tosyloxazolidin-2-one 1a in 77% yield with good enantioselectivity 10 and complete E-stereoselectivity 11 (Table 1, entry 1). 12,13 To demonstrate the generality of this method, we examined the scope and limitations of the present one-pot synthesis (Table 1). The reaction with methyl or tert-butyl propiolates in place of ethyl propiolate also proceeded under the same conditions and ...