Chiral bifunctional squaramide catalyzed asymmetric tandem Michael-cyclization reaction: efficient synthesis of optically active 2-amino-4H-chromene-3-carbonitrile derivatives

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).

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3-((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)