Absolute configuration determination of 2-(2-oxo-3-indolyl)acetamide derivatives

We describe a reliable method for determining the absolute configuration of 2-(2-oxo-3-indolyl)acetamides based on analysis of the 1H NMR spectra of their phenylethylamide diastereomers. The conformational preferences for two diastereomeric amides were calculated by DFT, which matched well with the experimental results. X-ray diffraction analysis allowed us to validate the method.

Absolute configuration assignment by 1H NMR.Figure optionsDownload as PowerPoint slide

(3R,1′R)-N-(1′-Phenylethyl)-2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC20H22N2O2Ee >98% (by 1H NMR)[α]D20=+87.3 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3R,1′R)

(3S,1′R)-N-(1′-Phenylethyl)-2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC20H22N2O2Ee >98% (by 1H NMR)[α]D20=+160.2 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3S,1′R)

(3R,1′R)-N-(1′-Phenylethyl)-2-(1-methyl-3-ethyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC21H24N2O2Ee >98% (by 1H NMR)[α]D20=+73.0 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3R,1′R)

(3S,1′R)-N-(1′-Phenylethyl)-2-(1-methyl-3-ethyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC21H24N2O2Ee >98% (by 1H NMR)[α]D20=+143.1 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3S,1′R)

(3R,1′R)-N-(1′-Phenylethyl)-2-(1-methyl-3-benzyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC26H26N2O2Ee >98% (by 1H NMR)[α]D20=+29.1 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3R,1′R)

(3S,1′R)-N-(1′-Phenylethyl)-2-(1-methyl-3-benzyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC26H26N2O2Ee >98% (by 1H NMR)[α]D20=+177.7 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3S,1′R)

(3R,1′R)-N-(1′-Phenylethyl)-2-(1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC21H24N2O2Ee >98% (by 1H NMR)[α]D20=+74.8 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3R,1′R)

(3S,1′R)-N-(1′-Phenylethyl)-2-(1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC21H24N2O2Ee >98% (by 1H NMR)[α]D20=+145.8 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3S,1′R)

(3R,1′R)-N-(1′-Phenylethyl)-2-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC26H26N2O2Ee >98% (by 1H NMR)[α]D20=+66.7 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3R,1′R)

(3S,1′R)-N-(1′-Phenylethyl)-2-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl) acetamideC26H26N2O2Ee >98% (by 1H NMR)[α]D20=+146.3 (c 1, EtOH)Source of chirality: (R)-(+)-1-phenylethylamineAbsolute configuration: (3S,1′R)