Facile synthesis of chiral 2-amino-4-(indol-3-yl)-4H-chromene derivatives using thiourea as the catalyst

The enantioselective Friedel–Crafts alkylation of indoles with iminochromenes catalyzed by a bifunctional thiourea organocatalyst was investigated. This reaction afforded chiral functionalized 2-amino-4-(indol-3-yl)-4H-chromenes in good yields (up to 87% yield) and with moderate to good enantioselectivities (up to 86% ee).

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(S)-2-Amino-4-(1H-indol-3-yl)-4H-chromene-3-carbonitrileC18H13N3Oee = 62%[α]D25=+45.3 (c 0.34, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(1H-indol-3-yl)-8-ethoxy-4H-chromene-3-carbonitrileC20H17N3O2ee = 39%[α]D25=+37.0 (c 0.20, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(1H-indol-3-yl)-6-chloro-4H-chromene-3-carbonitrileC18H12ClN3Oee = 43%[α]D25=-72.8 (c 0.53, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(1H-indol-3-yl)-6-bromo-4H-chromene-3-carbonitrileC18H12BrN3Oee = 63%[α]D25=-76.3 (c 0.64, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(1H-indol-3-yl)-6-methoxy-4H-chromene-3-carbonitrileC19H15N3O2ee = 60%[α]D25=-32.0 (c 0.50, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(1H-indol-3-yl)-8-methoxy-4H-chromene-3-carbonitrileC19H15N3O2ee = 72%[α]D25=+91.3 (c 0.80, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(1H-indol-3-yl)-6,8-dichloro-4H-chromene-3-carbonitrileC18H11Cl2N3Oee = 30%[α]D25=-19.3 (c 0.29, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(5-methyl-1H-indol-3-yl)-4H-chromene-3-carbonitrileC19H15N3Oee = 61%[α]D25=+60.8 (c 1.55, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(5-chloro-1H-indol-3-yl)-4H-chromene-3-carbonitrileC18H12ClN3Oee = 40%[α]D25=+19.8 (c 1.12, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(5-methyl-1H-indol-3-yl)-6-bromo-4H-chromene-3-carbonitrileC19H14BrN3Oee = 86%[α]D25=-79.8 (c 2.07, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(5-methyl-1H-indol-3-yl)-6-methoxy-4H-chromene-3-carbonitrileC20H17N3O2ee = 41%[α]D25=-35.2 (c 0.96, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-Amino-4-(5-methyl-1H-indol-3-yl)-8-methoxy-4H-chromene-3-carbonitrileC20H17N3O2ee = 68%[α]D25=+45.9 (c 1.09, EtOAc)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-N-(2-((2-((3,5-Bis(trifluoromethyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methylbutyl)-4-methylbenzenesulfonamideC24H23F6N3O4See = 99%[α]D25=+8.5 (c 1.10, acetone)Source of chirality: l-valinolAbsolute configuration: (S)

N-((1S,2S)-2-((2-((3,5-Bis(trifluoromethyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-1,2-diphenylethyl)-4-methylbenzenesulfonamideC33H25F6N3O4See = 99%[α]D25=+12.2 (c 0.98, acetone)Source of chirality: (1S,2S)-1,2-diphenylethylenediamineAbsolute configuration: (S,S)

N-((2S)-2-((2-(((1S)-(6-Methoxyquinolin-4-yl)((2S)-5-vinylquinuclidin-2-yl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-2-phenylethyl)-4-methylbenzenesulfonamideC39H41N5O5See = 99%[α]D25=-7.2 (c 1.19, acetone)Source of chirality: l-phenylglycinolAbsolute configuration: (S,S,S)