Henry reaction catalyzed by new series of imidazolidine-4-one Cu-complexes

A series of 5-tert-butyl-2-(pyridine-2-yl)imidazolidine-4-ones have been prepared and their Cu(II) complexes studied as enantioselective catalysts of the asymmetric Henry reaction of various aldehydes with nitromethane. It was found that these compounds were effective catalysts for this reaction, with enantiomeric excesses being as high as 97%. The enantioselectivities of individual derivatives were different and depended on the substituents attached to stereogenic centers and the configuration of imidazolidine-4-one cycle. High enantiomeric excesses were obtained irrespective of the solvent used. The most effective derivative was chosen for preparation of the key intermediate for Salmeterol medical drug and an enantiomeric excess of 92% was obtained.

Figure optionsDownload as PowerPoint slide

(S)-2-Acetamido-2,3,3-trimethylbutanoic acid (−)-quinine saltC29H41N3O5[α]D20 = −112.7 (c 0.5, CH3OH)Source of chirality: asymmetric synthesis—resolution via diastereomers; (−)-quinineAbsolute configuration: (S) and (−)-quinine ((R)-(6-methoxyquinolin-4-yl)((2S,4S,8R)-8-vinylquinuclidin-2-yl)methanol)

(S)-2-Acetamido-2,3,3-trimethylbutanoic acidC9H17NO3[α]D20 = +32.4 (c 0.5, CH3OH)Source of chirality: asymmetric synthesis—resolution via diastereomersAbsolute configuration: (S)

(S)-2-Amino-2,3,3-trimethylbutanoic acid hydrochlorideC7H16ClNO2[α]D20 = −12.4 (c 0.5, CH3OH)Source of chirality: asymmetric synthesis—resolution via diastereomersAbsolute configuration: (S)

(S)-2-Amino-2,3,3-trimethylbutanamideC7H16N2O[α]D20 = −78.4 (c 0.2, CHCl3)Source of chirality: asymmetric synthesis—resolution via diastereomersAbsolute configuration: (S)

(S)-2-Amino-3,3-dimethylbutanamideC6H14N2O[α]D20 = +57.0 (c 1.06, CH3OH)Source of chirality: l-tert-leucineAbsolute configuration: (S)

(2R,5S)-5-tert-Butyl-5-methyl-2-(pyridine-2-yl)imidazolidine-4-oneC13H19N3O[α]D20 = +48.0 (c 1, CH3OH)Source of chirality: asymmetric synthesis, chromatographic separationAbsolute configuration: (2R),(5S)

(2S,5S)-5-tert-Butyl-5-methyl-2-(pyridine-2-yl)imidazolidine-4-oneC13H19N3O[α]D20 = −51.0 (c 1.03, CH3OH)Source of chirality: asymmetric synthesis, chromatographic separationAbsolute configuration: (2S),(5S)

(2R,5S)-5-tert-Butyl-2,5-dimethyl-2-(pyridine-2-yl)imidazolidine-4-oneC14H21N3O[α]D20 = −51.7 (c 1.01, CH3OH)Source of chirality: asymmetric synthesis, chromatographic separationAbsolute configuration: (2R),(5S)

(2S,5S)-5-tert-Butyl-2,5-dimethyl-2-(pyridine-2-yl)imidazolidine-4-oneC14H21N3O[α]D20 = +18.0 (c 1.01, CH3OH)Source of chirality: asymmetric synthesis, chromatographic separationAbsolute configuration: (2S),(5S)

(2R,5S)-5-tert-Butyl-2-methyl-2-(pyridine-2-yl)imidazolidine-4-oneC13H19N3O[α]D20 = −28.4 (c 0.5, CH3OH)Source of chirality: l-tert-leucine, chromatographic separationAbsolute configuration: (2R),(5S)

(2S,5S)-5-tert-Butyl-2-methyl-2-(pyridine-2-yl)imidazolidine-4-oneC13H19N3O[α]D20 = +5.6 (c 0.52, CH3OH)Source of chirality: l-tert-leucine, chromatographic separationAbsolute configuration: (2S),(5S)

(S)-2-(N-Pyridylmethylimino)-3,3-dimethylbutanamideC12H17N3O[α]D20 = +12.2 (c 1.03, CH3OH)Source of chirality: l-tert-leucineAbsolute configuration: (S)