Racemization-free synthesis of atropisomeric 1-phenylpyrrole based diamines using diphenylphosphoryl azide

An efficient, highly stereoconservative synthesis has been developed for the preparation of aniline derived 1-arylpyrrole-2-carboxamide atropisomers using diphenylphosphoryl azide (DPPA). The classical azide synthesis, involving reaction with active acylating agents prepared from axially chiral benzoic acid derivatives, showed significant racemization caused by intramolecular tricyclic isoimidium salt formation. In order to avoid the ring closure reaction, the azide synthesis was carried out with DPPA in a stereoconservative manner, and Curtius rearrangement followed by hydrolysis resulted in enantiopure products. The application of the novel racemisation-free synthetic method of axially chiral anilines from atropisomeric benzoic acid derivatives is demonstrated by the preparation of secondary as well as tertiary amines containing 2-(2-substituted-1H-pyrrole-1-yl)aniline type diamines.

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(Sa)-Methyl 2-[2-(dimethylcarbamoyl)-1H-pyrrol-1-yl]-3-(trifluoromethyl)benzoateC16H15F3N2O3ee ⩾99%[α]D25 = −97.1 (c 0.48, CHCl3)Source of chirality: synthesis from the optically active monoesterAbsolute configuration: (Sa)

(Sa)-Methyl 2-[2-(dibutylcarbamoyl)-1H-pyrrol-1-yl]-3-(trifluoromethyl)benzoateC22H27F3N2O3ee ⩾99%[α]D25 = −72.7 (c 0.34, CHCl3)Source of chirality: synthesis from the optically active monoesterAbsolute configuration: (Sa)

(Sa)-Methyl 2-[2-[methyl((S)-1-phenylethyl)carbamoyl]-1H-pyrrol-1-yl]-3-(trifluoromethyl)benzoateC23H21F3N2O3ee ⩾99%[α]D25 = −231.3 (c 0.52, CHCl3)Source of chirality: synthesis from the optically active monoesterAbsolute configuration: (Sa)

(Sa)-2-(2-Carbamoyl-1H-pyrrol-1-yl)-3-(trifluoromethyl)benzoic acidC15H13F3N2O3ee ⩾99%[α]D25 = −32.4 (c 0.50, CHCl3)Source of chirality: hydrolysis of the optically active esterAbsolute configuration: (Sa)

(Sa)-2-[2-(Dimethylcarbamoyl)-1H-pyrrol-1-yl]-3-(trifluoromethyl)benzoic acidC15H13F3N2O3ee ⩾99%[α]D25 = −176.2 (c 0.66, CHCl3)Source of chirality: hydrolysis of the optically active esterAbsolute configuration: (Sa)

(Sa)-2-[2-(Dimethylcarbamoyl)-1H-pyrrol-1-yl]-3-(trifluoromethyl)benzoic acidC17H17F3N2O3ee ⩾99%[α]D25 = −173.5 (c 0.82, CHCl3)Source of chirality: hydrolysis of the optically active esterAbsolute configuration: (Sa)

(Sa)-2-[2-(Dibutylcarbamoyl)-1H-pyrrol-1-yl]-3-(trifluoromethyl)benzoic acidC21H25F3N2O3ee ⩾99%[α]D25 = −182.6 (c 0.29, CHCl3)Source of chirality: hydrolysis of the optically active esterAbsolute configuration: (Sa)

(Sa)-2-[2-(Pyrrolidine-1-carbonyl)-1H-pyrrol-1-yl]-3-(trifluoromethyl)benzoic acidC17H15F3N2O3ee ⩾99%[α]D25 = −194.6 (c 0.49, CHCl3)Source of chirality: hydrolysis of the optically active esterAbsolute configuration: (Sa)

(Sa)-2-[2-[Methyl((S)-1-phenylethyl)carbamoyl]-1H-pyrrol-1-yl]-3-(trifluoromethyl)benzoic acidC22H19F3N2O3ee ⩾99%[α]D25 = −370.1 (c 0.32, CHCl3)Source of chirality: hydrolysis of the optically active esterAbsolute configuration: (Sa)

(Sa)-2-[2-(Benzylcarbamoyl)-1H-pyrrol-1-yl]-3-(trifluoromethyl)benzoic acidC20H15F3N2O3ee ⩾99%[α]D25 = −160.4 (c 0.22, CHCl3)Source of chirality: hydrolysis of the optically active esterAbsolute configuration: (Sa)

(Ra)-1-[2-Amino-6-(trifluoromethyl)phenyl]-N,N-dimethyl-1H-pyrrole-2-carboxamideC14H14F3N3Oee ⩾99%[α]D25 = −271.1 (c 0.69, CHCl3)Source of chirality: modified Curtius rearrangement of the optically active carboxylic acid followed by hydrolysisAbsolute configuration: (Ra)

(Ra)-1-[2-Amino-6-(trifluoromethyl)phenyl]-N,N-diethyl-1H-pyrrole-2-carboxamideC16H18F3N3Oee ⩾99%[α]D25 = −292.3 (c 0.36, CHCl3)Source of chirality: modified Curtius rearrangement of the optically active carboxylic acid followed by hydrolysisAbsolute configuration: (Ra)

(Ra)-1-[2-Amino-6-(trifluoromethyl)phenyl]-N,N-dibutyl-1H-pyrrole-2-carboxamideC20H26F3N3Oee ⩾99%[α]D25 = −355.6 (c 0.60, CHCl3)Source of chirality: modified Curtius rearrangement of the optically active carboxylic acid followed by hydrolysisAbsolute configuration: (Ra)

(Ra)-[1-[2-Amino-6-(trifluoromethyl)phenyl]-1H-pyrrol-2-yl](pyrrolidin-1-yl)methanoneC16H16F3N3Oee ⩾99%[α]D25 = −184.4 (c 0.68, CHCl3)Source of chirality: modified Curtius rearrangement of the optically active carboxylic acid followed by hydrolysisAbsolute configuration: (Ra)

(Ra)-1-[2-Amino-6-(trifluoromethyl)phenyl]-N-methyl-N-((S)-1-phenylethyl)-1H-pyrrole-2-carboxamideC21H20F3N3Oee ⩾99%[α]D25 = −512.3 (c 0.65, CHCl3)Source of chirality: modified Curtius rearrangement of the optically active carboxylic acid followed by hydrolysisAbsolute configuration: (Ra)

(Ra)-1-[2-Amino-6-(trifluoromethyl)phenyl]-N-benzyl-1H-pyrrole-2-carboxamideC19H16F3N3Oee ⩾99%[α]D25 = −123.5 (c 0.34, CHCl3)Source of chirality: modified Curtius rearrangement of the optically active carboxylic acid followed by hydrolysisAbsolute configuration: (Ra)

(Ra)-tert-Butyl-2-[2-[(diethylamino)methyl]-1H-pyrrol-1-yl]-3-(trifluoromethyl)phenylcarbamateC21H28F3N3O2ee ⩾99%[α]D25 = −212.2 (c 0.36, CHCl3)Source of chirality: modified Curtius rearrangement of the optically active carboxylic acid followed by reaction with tert-butanolAbsolute configuration: (Ra)

(Ra)-2-[2-[(Dimethylamino)methyl]-1H-pyrrol-1-yl]-3-(trifluoromethyl)anilineC14H16F3N3ee ⩾99% (HPLC)[α]D25 = −68.7 (c 1.31, CHCl3)Source of chirality: reduction of the optically active amido amineAbsolute configuration: (Ra)

(Ra)-2-[2-[(Diethylamino)methyl]-1H-pyrrol-1-yl]-3-(trifluoromethyl)anilineC16H20F3N3ee ⩾99% (HPLC)[α]D25 = −75.1 (c 0.85, CHCl3)Source of chirality: reduction of the optically active amido amineAbsolute configuration: (Ra)

(Ra)-2-[2-[(Dibutylamino)methyl]-1H-pyrrol-1-yl]-3-(trifluoromethyl)anilineC20H28F3N3ee ⩾99% (HPLC)[α]D25 = −32.1 (c 0.28, CHCl3)Source of chirality: reduction of the optically active amido amineAbsolute configuration: (Ra)

(Ra)-2-[2-(Pyrrolidin-1-ylmethyl)-1H-pyrrol-1-yl]-3-(trifluoromethyl)anilineC16H18F3N3ee ⩾99% (HPLC)[α]D25 = −50.0 (c 0.53, CHCl3)Source of chirality: reduction of the optically active amido amineAbsolute configuration: (Ra)

(Ra)-2-[2-[[Methyl((S)-1-phenylethyl)amino]methyl]-1H-pyrrol-1-yl]-3-(trifluoromethyl)anilineC21H22F3N3ee ⩾99% (HPLC)[α]D25 = −58.1 (c 0.25, CHCl3)Source of chirality: reduction of the optically active amido amineAbsolute configuration: (Ra)

(Ra)-2-[2-[(Benzylamino)methyl]-1H-pyrrol-1-yl]-3-(trifluoromethyl)anilineC19H18F3N3ee ⩾99% (HPLC)[α]D25 = −21.9 (c 0.56, CHCl3)Source of chirality: reduction of the optically active amido amineAbsolute configuration: (Ra)