Enantioselective synthesis of 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles using squaramide as the catalyst

The organocatalyzed enantioselective synthesis of a series of chiral 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles was achieved using bifunctional squaramides as the catalysts. The tandem Michael addition–cyclization reaction of cyclohexane-1,3-diones and benzylidenemalononitriles gave the corresponding products in excellent yields (up to 99%) and moderate to good enantioselectivities (up to 83% ee). This investigation provides an efficient and useful process for the synthesis of chiral 2-amino-4H-chromenes.

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(R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4-phenyl-4H-chromene-3-carbonitrileC18H18N2O2ee = 67%[α]D25=+35.5 (c 0.53, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-4H-chromene-3-carbonitrileC18H17FN2O2ee = 58%[α]D25=+39.6 (c 0.53, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H-chromene-3-carbonitrileC18H17ClN2O2ee = 55%[α]D25=+39.6 (c 0.45, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-4-(4-bromophenyl)-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H-chromene3-carbonitrileC18H17BrN2O2ee = 83%[α]D25=+39.2 (c 0.49, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(4-methylphenyl)-5-oxo-4H-chromene-3-carbonitrileC19H20N2O2ee = 68%[α]D25=+22.1 (c 0.97, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-4H-chromene-3-carbonitrileC18H17N3O4ee = 42%[α]D25=+25.0 (c 0.93, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-4-(2-chlorophenyl)-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H-chromene-3-carbonitrileC18H17ClN2O2ee = 51%[α]D25=+47.3 (c 0.77, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(2-methylphenyl)-5-oxo-4H-chromene-3-carbonitrileC19H20N2O2ee = 65%[α]D25=+37.0 (c 0.74, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(3,4-dimethoxyphenyl)-5-oxo-4H-chromene-3-carbonitrileC20H22N2O4ee = 64%[α]D25=+21.1 (c 0.92, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(2-naphthyl)-5-oxo-4-phenyl-4H-chromene-3-carbonitrileC22H20N2O2ee = 54%[α]D25=+73.7 (c 0.92, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitrileC16H14N2O2ee = 55%[α]D25=+54.7 (c 0.74, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

C16H13FN2O2(R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-4H-chromene-3-carbonitrileee = 42%[α]D25=+42.9 (c 1.03, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitrileC16H13ClN2O2ee = 53%[α]D25=+24.7 (c 0.85, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-4-(4-bromophenyl)- 5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitrileC16H13BrN2O2ee = 49%[α]D25=+29.5 (c 0.80, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-4-(4-methylphenyl)-5-oxo-4H-chromene-3-carbonitrileC17H16N2O2ee = 54%[α]D25=+36.0 (c 0.85, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-4-(4-nitrophenyl)-5-oxo-4H-chromene-3-carbonitrileC16H13N3O4ee = 31%[α]D25=+42.2 (c 1.02, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-4-(2-chlorophenyl)-5,6,7,8-tetrahydro-5-phenyl-4H-chromene-3-carbonitrileC16H13ClN2O2ee = 34%[α]D25=+33.2 (c 0.86, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-4-(2-methylphenyl)-5-oxo-4H-chromene-3-carbonitrileC17H16N2O2ee = 49%[α]D25=+32.7 (c 1.12, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-4-(3,4-dimethoxyphenyl)-5-oxo-4H-chromene-3-carbonitrileC18H18N2O4ee = 53%[α]D25=+24.9 (c 0.85, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5,6,7,8-tetrahydro-4-(2-naphthyl)-5-oxo-4H-chromene-3-carbonitrileC20H16N2O2ee = 45%[α]D25=+61.5 (c 0.78, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-4,5,6,7-tetrahydro-5-oxo-cyclopenta[b]pyran-3-carbonitrileC15H12N2O2ee = 32%[α]D25=+6.9 (c 1.15, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

(R)-2-Amino-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrileC19H12N2O3ee = 6%[α]D25=+1.1 (c 0.75, acetone)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)