Synthesis of isatins with a chiral substituent at the nitrogen atom

(R)-Ethyl 2-(isatin-1-yl)propanoates 8a–c were prepared from the corresponding (R)-arylalanines by Sandmeyer’s method in high yield and good enantioselectivity (up to 99%). The key step of the process is the Mitsunobu reaction.

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Ethyl O-methanesulfonyl-(S)-2-hydroxypropanoateC6H12O5S[α]D20=-65 (c 1, CHCl3)Source of chirality: ethyl ester (S)-2-hydroxypropionic acidAbsolute configuration: (S)

Ethyl 2-(5-methylisatin-1-yl)propanoateC14H15NO4Ee ⩾ 30%[α]D20=-1.3 (c 3.8, CHCl3)Source of chirality: (S)-ethyl 2-(methanesulfonyl)propanoateAbsolute configuration: (R)

Ethyl (R)-N-(2-nitrophenylsulfonyl)-N-(4-bromophenyl)-2-aminopropanoateC17H17BrN2O6S[α]D20=-8.4 (c 3.2, CHCl3)Source of chirality: ethyl (S)-2-hydroxypropanoateAbsolute configuration: (R)

Ethyl (R)-N-(2-nitrophenylsulfonyl)-N-(4-phenyl)-2-aminopropanoateC17H18N2O6S[α]D20=+10.1 (c 3.27, CHCl3)Source of chirality: ethyl (S)-2-hydroxypropanoateAbsolute configuration: (R)

Ethyl (R)-N-(2-nitrophenylsulfonyl)-N-(4-methylphenyl)-2-aminopropanoateC18H20N2O6S[α]D20=+2.1 (c 3.27 CHCl3)Source of chirality: ethyl (S)-2-hydroxypropanoateAbsolute configuration: (R)

Ethyl (R)-N-(4-bromophenylamino)-propanoateC11H14BrNO2[α]D20=+67 (c 3.37 CHCl3)Source of chirality: ethyl (S)-2-hydroxypropanoateAbsolute configuration: (R)

Ethyl (R)-N-(4-phenylamino)-propanoateC11H15NO2[α]D20=+40 (c 2.71, CHCl3)Source of chirality: ethyl (S)-2-hydroxypropanoateAbsolute configuration: (R)

Ethyl (R)-N-(4-methylphenylamino)-propanoateC12H17NO2[α]D20=+49 (c 3.30, CHCl3)Source of chirality: ethyl (S)-2-hydroxypropanoateAbsolute configuration: (R)

(R)-Ethyl 2-(5-bromisatin-1-yl)propanoateC13H12BrNO4[α]D20=+2 (c 1.0, CHCl3)Ee ⩾ 97%Source of chirality: Ethyl (R)-N-(4-bromophenylamino)-propanoateAbsolute configuration: (R)

(R)-Ethyl 2-(isatin-1-yl)propanoateC13H13NO4[α]D20=+8 (c 1.0, CHCl3)Ee ⩾ 99%Source of chirality: Ethyl (R)-N-(4-phenylamino)-propanoateAbsolute configuration: (R)

(R)-Ethyl 2-(5-methylisatin-1-yl)propanoateC14H15NO4[α]D20=-4.3 (c 3.8, CHCl3)Ee ⩾ 99%Source of chirality: Ethyl (R)-N-(4-methylphenylamino)-propanoateAbsolute configuration: (R)