Bisphosphine-catalyzed mixed double-Michael reactions have been developed to afford β-amino carbonyl derivatives of oxazolidines, thiozolidines, and pyrrolidines in excellent yields and with high diastereoselectivities. Efficient reactions between amino acid-derived pronucleophiles, e.g., β-amino alcohols,β-amino thiols, and γ-amino diesters, as Michael donors and electron-deficient acetylenes, e.g., propiolates, acetylacetylene, and tosylacetylene, as Michael acceptors provided access to azolidines containing both diversity of substituents and asymmetry. This methodology-the first examples of mixed double-Michael reactions of acetylenes-is operationally simple and involves mild conditions. Mechanistically, it constitutes a rare example of the anchimeric assistance of bisphosphines in organocatalysis. Five-membered nitrogen atom-containing heterocycles are structural components of many natural products and pharmaceuticals; 1 in addition, many of them-for example, enantiopure azolidine derivatives-have been employed as synthetic intermediates, auxiliaries, ligands, and catalysts for asymmetric synthesis. 2 Consequently, there is a high demand for new methods for the efficient construction of optically active azolidine derivatives. 3 As part of a program aimed at developing phosphine-mediated annulation reactions, 4 we sought a novel route toward highly substituted and functionalized five-membered-ring nitrogen atom-containing heterocycles. In light of recent reports on the phosphine-catalyzed conjugate additions of electron-deficient olefins and acetylenes with alcohols, 5 herein we report a bisphosphinecatalyzed mixed double-Michael process 6 that generates azolidines (2; eq 1). Use of amino acid-derived pronucleophiles (1) as Michael donors and electron-deficient acetylenes as Michael acceptors provides efficient access to azolidines containing both diversity and asymmetry. Our initial evaluation of the proposed double-Michael addition began with the reaction between amino alcohol 1a and methyl propiolate (Table 1). Employing PPh 3 as the catalyst gave the desired double-Michael adduct 2a in 35% yield in addition to a 40% yield of the mono-Michael adduct 3a (entry 1). 7 Use of Ph 2 PEt led to a moderate improvement in the yield of the oxazolidine product 2a (entry 2), but none was formed from the reaction catalyzed by Me 3 P

General base-catalyzed double-Michael reactions of allenes with various dinucleophiles are described. The reactions are facilitated most efficiently by a catalytic amount of trimethylphosphine, affording six types of C2-functionalized benzannulated five-membered heterocycles: benzimidazolines, benzoxazolines, benzothiazolines, 1,3-benzodioxoles, 1,3-benzoxathioles, and 1,3-benzodithioles. This atom-economical reaction is operationally simple and provides the product heterocycles in good to excellent yields. Careful mechanistic studies unveiled the phosphine-triggered general base catalysis pathway. Furthermore, the double-Michael reaction can serve as an alternative method for the selective mono-ketalization of β-diketones.

Seven different types of benzannulated N-heterocycles—indolines, dihydropyrrolopyridines, benzimidazolines, dihydrobenzo-3,1-oxazines, benzomorpholines, tetrahydroquinolines, and tetrahydroisoquinolines—can be obtained from simple dinucleophiles and electron-deficient acetylenes in one synthetic step. This powerful methodology was made possible through the use of diphenylphosphinopropane (DPPP) as the catalyst, with acetic acid and sodium acetate used as additives in some cases. The benzannulated N-heterocycles were isolated in excellent yields under mild metal-free conditions; they were purified without the need for aqueous work-ups.

2-tert-Butyldiphenylsilylmethyl-substituted aziridine and the corresponding azetidine reacted efficiently with nitriles and carbonyl substrates to generate imidazoline, oxazolidine, and tetrahydropyrimidine products. The azetidine rearranged efficiently to the pyrrolidine skeleton involving migration of silicon under BF3.Et2O conditions. The tert-butyldiphenylsilylmethyl function, latent to CH2OH group, controlled not only the regioselectivity of aziridine and azetidine cleavage but also the relative stereochemistry of the substituents in the products derived from substituted aziridine.

We have prepared a previously unreported family of P-stereogenic [2.2.1] bicyclic chiral phosphines through straightforward syntheses starting from the natural product carvone. This design rationale prompted the development of an unforeseen C-dealkenylation reaction. We have applied these organocatalysts in the asymmetric syntheses of a bevy of pyrrolines, obtained in high yields and enantioselectivities, including a biologically active small molecule, efsevin.