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)

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)