Alternative and complementary approaches to the asymmetric synthesis of C3 substituted NH free or N-substituted isoindolin-1-ones

Complementary synthetic approaches to enantiomerically pure C3 alkylated or arylated NH free or N-substituted isoindolinones have been developed. The key step is elaboration of diversely substituted 2-alkyl- and arylbenzylamines, which can be submitted to a bis-metallation process followed by interception with a carbonylating agent. They can be also converted into N-alkylbromobenzylcarbamates or into bromobenzyldicarbamates and the assembly of the titled compounds can be readily ensured by reliance upon the Parham cyclization process.

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(S)-1-Benzo[1,3]dioxol-5-ylethylamineC9H11NO2Ee >96%[α]D25=-24.8 (c 1.10, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (1S)

N-(S)-(1-Benzo[1,3]dioxol-5-ylethyl)-2,2-dimethylpropionamideC14H19NO3Ee >96%[α]D25=-86.2 (c 1.04, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (1S)

(S)-7-(2,2-Dimethylpropionyl)-6-methyl-6,7-dihydro-8H-1,3-dioxolo[4,5-e]isoindol-8-oneC15H17NO4Ee >96%[α]D25=+2.0 (c 1.05, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (6S)

(S)-6-Methyl-6,7-dihydro-8H-1,3-dioxolo[4,5-e]isoindol-8-oneC10H9NO3Ee >96%[α]D25=-12.4 (c 1.03, DMSO)Source of chirality: (S)-valinolAbsolute configuration: (6S)

(S)-1-Phenyl-1-(3,4,5-trimethoxyphenyl)methyl amineC16H19NO3Ee >96%[α]D25=+24.4 (c 1.06, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (1S)

(S)-[Phenyl-(3,4,5-trimethoxyphenyl)methyl] carbamic acid methyl esterC18H21NO5Ee >96%[α]D25=-3.4 (c 1.05, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (1S)

(S)-Methyl[phenyl-(3,4,5-trimethoxyphenyl)methyl]carbamic acid methyl esterC19H23NO5Ee >96%[α]D25=-11.2 (c 1.00, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (1S)

(S)-[(2-Bromo-3,4,5-trimethoxyphenyl)phenylmethyl]methylcarbamic acid methyl esterC19H22BrNO5Ee >96%[α]D25=-0.3 (c 1.01, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (1S)

(S)-5,6,7-Trimethoxy-2-methyl-3-phenyl-2,3-dihydro-1H-isoindol-1-oneC18H19NO4Ee >96%[α]D25=+5.7 (c 1.06, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (3S)

(S)-2-Methyl-1-(3,4,5-trimethoxyphenyl)propylamineC13H21NO3Ee >96%[α]D25=+3.5 (c 1.03, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (1S)

(S)-N,N-Di(methoxycarbonyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)propylamineC17H25NO7Ee >96%[α]D25=-48.1 (c 1.02, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (1S)

(S)-N,N-Di(methoxycarbonyl)-2-methyl-1-(2-bromo-3,4,5-trimethoxyphenyl)propylamineC17H24BrNO7Ee >96%[α]D25=+6.5 (c 1.06, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (1S)

(S)-3-Isopropyl-5,6,7-trimethoxy-2,3-dihydro-1H-isoindol-1-oneC14H19NO4Ee >96%[α]D25=-48.1 (c 0.9, CHCl3)Source of chirality: (S)-valinolAbsolute configuration: (3S)