Enantioselective synthesis of 6-substituted thiomorpholin-3-ones via asymmetric thia-Michael addition reactions using chiral bifunctional thiourea catalysts followed by intramolecular reductive cyclization

Herein we report the first practical and efficient method for the synthesis of chiral 6-substituted thiomorpholin-3-ones via asymmetric thia-Michael addition reactions between aryl/heteroaryl nitroalkenes and methyl 2-mercaptoacetate by using chiral thiourea catalysts followed by intramolecular reductive cyclization in good yields with selectivities up to 95% ee. The effects of solvent, temperature, substrate concentration, and catalyst loading on asymmetric thia-Michael addition reactions are discussed. The construction of these chiral thiomorpholin-3-ones by this synthetic route would expand upon diversity of the libraries of pharmaceutical interest.

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Methyl 2-((R)-2-nitro-1-(thiophen-2-yl)ethylthio)acetateC9H11NO4S2[α]D23 = −22.4 (c 1.0, CHCl3)Source of chirality: the carbon atom with four different substituents (Asymmetric thia-Michael addition reaction)Absolute configuration: (2R)

Methyl 2-((R)-1-(furan-2-yl)-2-nitroethylthio)acetateC9H11NO5S[α]D23 = −24.4 (c 1.0, CHCl3)Source of chirality: the carbon atom with four different substituents (Asymmetric thia-Michael addition reaction)Absolute configuration: (2R)

Methyl 2-((R)-2-nitro-1-(pyridin-2-yl)ethylthio)acetateC10H12N2O4S[α]D23 = −25.9 (c 1.0, CHCl3)Source of chirality: the carbon atom with four different substituents (Asymmetric thia-Michael addition reaction)Absolute configuration: (2R)

Methyl 2-((S)-2-nitro-1-(pyridin-3-yl)ethylthio)acetateC10H12N2O4S[α]D23 = −27.4 (c 1.0, CHCl3)Source of chirality: the carbon atom with four different substituents (Asymmetric thia-Michael addition reaction)Absolute configuration: (2S)

Methyl 2-((S)-2-nitro-1-phenylethylthio)acetateC11H13NO4S[α]D23 = −21.6 (c 1.0, CHCl3)Source of chirality: the carbon atom with four different substituents (Asymmetric thia-Michael addition reaction)Absolute configuration: (2S)

Methyl 2-((S)-1-(4-methoxyphenyl)-2-nitroethylthio)acetateC12H15NO5S[α]D23 = −25.2 (c 1.0, CHCl3)Source of chirality: the carbon atom with four different substituents (Asymmetric thia-Michael addition reaction)Absolute configuration: (2S)

Methyl 2-((S)-1-(naphthalen-2-yl)-2-nitroethylthio)acetateC15H15NO4S[α]D23 = −23.5 (c 1.0, CHCl3)Source of chirality: the carbon atom with four different substituents (Asymmetric thia-Michael addition reaction)Absolute configuration: (2S)

Methyl 2-((S)-1-(naphthalen-1-yl)-2-nitroethylthio)acetateC15H15NO4S[α]D23 = −24.9 (c 1.0, CHCl3)Source of chirality: the carbon atom with four different substituents (Asymmetric thia-Michael addition reaction)Absolute configuration: (2S)

(R)-6-(Thiophen-2-yl)thiomorpholin-3-oneC8H9NOS2[α]D23 = −21.4 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (6R)

(R)-6-(Furan-2-yl)thiomorpholin-3-oneC8H9NO2S[α]D23 = −18.2 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (6R)

(R)-6-(Pyridin-2-yl)thiomorpholin-3-oneC9H10N2OS[α]D23 = −19.1 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (6R)

(S)-6-(Pyridin-3-yl)thiomorpholin-3-oneC9H10N2OS[α]D23 = −19.2 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (6S)

(S)-6-Phenylthiomorpholin-3-oneC10H11NOS[α]D23 = −24.5 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (6S)

(S)-6-(4-Methoxyphenyl)thiomorpholin-3-oneC11H13NO2S[α]D23 = −22.8. (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (6S)

(S)-6-(Naphthalen-2-yl)thiomorpholin-3-oneC14H13NOS[α]D23 = −21.9 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (6S)

(S)-6-(Naphthalen-1-yl)thiomorpholin-3-oneC14H13NOS[α]D23 = −21.5 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (6S)