We have developed an efficient bifunctional squaramide catalyst for the asymmetric tandem Michael addition–cyclization of malononitrile to functionalized nitroolefins. This organocatalytic asymmetric reaction provides convenient and valuable access to highly functionalized 2-amino-4H-chromene derivatives, which possess important biological activities, in good yields with moderate to high enantioselectivities (up to 95% ee).Figure optionsDownload full-size imageDownload as PowerPoint slide3-((S)-3-Phenyl-1-(piperidin-1-yl)propan-2-ylamino)-4-(3,5-bis(trifluoromethyl)phenylamino)cyclobut-3-ene-1,2-dioneC26H25F6N3O2[α]D20=-90.0 (c 1.0, DMSO)Source of chirality: l-PhenylalanineAbsolute configuration: (S)3-((S)-3-Methyl-1-(piperidin-1-yl)butan-2-ylamino)-4-(3,5-bis(trifluoromethyl)phenylamino)cyclobut-3-ene-1,2-dioneC22H25F6N3O2[α]D20=-85.0 (c 1.0, DMSO)Source of chirality: l-ValineAbsolute configuration: (S)3-((S)-3,3-Dimethyl-1-(piperidin-1-yl)butan-2-ylamino)-4-(3,5-bis(trifluoromethyl)phenylamino)cyclobut-3-ene-1,2-dioneC23H27F6N3O2[α]D20=-75.0 (c 1.0, DMSO)Source of chirality: l-tert-LeucineAbsolute configuration: (S)(R)-2-Amino-4-nitromethyl)-4H-chromene-3-carbonitrileC11H9N3O387% ee[α]D25=-21.5 (c 1.5, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (R)(R)-2-Amino-6-fluoro-4-nitromethyl-4H-chromene-3-carbonitrileC11H8FN3O374% ee[α]D25=-26.0 (c 1.0, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (R)(R)-2-Amino-6-chloro-4-nitromethyl-4H-chromene-3-carbonitrileC11H8ClN3O362% ee[α]D25=-40.5 (c 1.2, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (R)(R)-2-Amino-6-bromo-4-nitromethyl-4H-chromene-3-carbonitrileC11H8BrN3O376% ee[α]D25=-10.0 (c 0.8, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (R)(R)-2-Amino-6,8-dibromo-4-nitromethyl-4H-chromene-3-carbonitrileC11H7Br2N3O395% ee[α]D25=-10.0 (c 1.0, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (R)(R)-2-Amino-6-nitro-4-nitromethyl-4H-chromene-3-carbonitrileC11H8N4O560% ee[α]D25=-60.0 (c 1.0, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (R)(R)-2-Amino-6-methoxy-4-(nitromethyl)-4H-chromene-3-carbonitrileC12H11N3O441% ee[α]D25=-35.0 (c 1.0, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (S)(R)-2-Amino-6-methyl-4-nitromethyl-4H-chromene-3-carbonitrileC12H11N3O357% ee[α]D25=-25.0 (c 1.5, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (S)(R)-2-Amino-7-methyl-4-nitromethyl-4H-chromene-3-carbonitrileC12H11N3O362% ee[α]D25=-35.0 (c 1.0, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (R)(R)-2-Amino-8-methyl-4-nitromethyl-4H-chromene-3-carbonitrileC12H11N3O367% ee[α]D25=-16.7 (c 1.0, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (R)(R)-3-Amino-1-nitromethyl-1H-benzo[f]chromene-2-carbonitrileC15H11N3O381% ee[α]D25=-45.0 (c 1.5, CHCl3)Source of chirality: Asymmetric organocatalysisAbsolute configuration: (R)

A primary amine-thiourea organocatalyzed intramolecular Michael addition access was developed for the synthesis of trans-dihydrobenzofurans. Under the catalysis of an (R,R)-1,2-diphenylethylamine derived primary amine-thiourea bearing a glucosyl scaffold, the corresponding trans-dihydrobenzofurans were obtained in high yields with excellent level of enantioselectivities (94 to >99% ee). Moreover, an in situ isomerization occurring at high temperature gave good to excellent trans/cis ratios as well (trans/cis: 84/16–96/4).

Based on different chiral diamine skeletons, a series of bifunctional primary amine-thiophosphoramides were synthesized and screened as the catalysts for the asymmetric Michael addition of acetone to both aromatic and aliphatic nitroolefins. Under the catalysis of a thiophosphoramide derived from 1,2-diphenylethane-1,2-diamine, the corresponding adducts were obtained in high yields (up to >99%) with excellent enantioselectivities (97−99% ee) under mild reaction conditions. Moreover, the catalyst could be recovered via simple phase separation and reused at least five times without any loss of both catalytic activity and stereocontrol.

By employing a cinchonine-based thiourea as catalyst, highly enantioselective Michael addition reactions of 2-hydroxy-1,4-naphthoquinone to β,γ-unsaturated α-ketophosphonates were realized. The reaction afforded the corresponding β-substituted carboxylates in excellent yields with high levels of enantioselectivities (94−>99% ee) upon quenching the generated parent structures with DBU and MeOH as a second nucleophile.