Highly enantioselective Mannich reactions of imines with tert-butyl acetoacetate catalyzed by squaramide organocatalyst

Highly enantioselective Mannich reactions of imines bearing a benzothiazole moiety with tert-butyl acetoacetate, catalyzed by a cinchona-based squaramide organocatalyst have been developed. The corresponding benzothiazole β-keto ester derivatives were obtained in high yields (up to 99%) and with excellent enantioselectivities (up to 98% ee).

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tert-Butyl 2-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)-3-oxobutanoateC22H24N2O3S58:42 dr, 98% ee (major), 98% ee (minor)[α]D25 = +9.6 (c 1.03, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)

tert-Butyl 2-(((6-methylbenzo[d]thiazol-2-yl)amino)(phenyl)methyl)-3-oxobutanoateC23H26N2O3S58:42 dr, 97% ee (major), 95% ee (minor)[α]D25 = +5.3 (c 1.28, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)

tert-Butyl 2-(((6-chlorobenzo[d]thiazol-2-yl)amino)(phenyl)methyl)-3-oxobutanoateC22H23ClN2O3S58:42 dr, 97% ee (major), 98% ee (minor)[α]D25 = +11.5 (c 1.26, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)

tert-Butyl 2-(((6-methoxybenzo[d]thiazol-2-yl)amino)(phenyl)methyl)-3-oxobutanoateC23H26N2O4S59:41 dr, 95% ee (major), 96% ee (minor)[α]D25 = +11.3 (c 1.44, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)

tert-Butyl 2-((benzo[d]thiazol-2-ylamino)(4-nitrophenyl)methyl)-3-oxobutanoateC22H23N3O5S64:36 dr, 89% ee (major), 95% ee (minor)[α]D25 = +21.0 (c 2.50, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)

tert-Butyl 2-((benzo[d]thiazol-2-ylamino)(p-tolylphenyl)methyl)-3-oxobutanoateC23H26N2O3S64:36 dr, 92% ee (major), 92% ee (minor)[α]D25 = −9.7 (c 1.62, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)

tert-Butyl 2-((benzo[d]thiazol-2-ylamino)(4-bromophenyl)methyl)-3-oxobutanoateC22H23BrN2O3S65:35 dr, 90% ee (major), 96% ee (minor)[α]D25 = +29.4 (c 2.31, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)

tert-Butyl 2-((6-chlorobenzo[d]thiazol-2-ylamino)(4-nitrophenyl)methyl)-3-oxobutanoateC22H22ClN3O5S57:43 dr, 95% ee (major), 95% ee (minor)[α]D25 = +21.8 (c 2.34, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)

tert-Butyl 2-((6-methylbenzo[d]thiazol-2-ylamino)(4-nitrophenyl)methyl)-3-oxobutanoateC23H25N3O5S64:36 dr, 94% ee (major), 94% ee (minor)[α]D25 = +39.0 (c 1.18, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)

tert-Butyl 2-((6-methoxybenzo[d]thiazol-2-ylamino)(2-methoxyphenyl)methyl)-3-oxobutanoateC24H28N2O5S98:2 dr, 83% ee (major)[α]D25 = +21.4 (c 1.02, CH2Cl2)Source of chirality: Asymmetric synthesisAbsolute configuration: major isomer (R,S)