Asymmetric cross-coupling of racemic α-bromo esters with aryl Grignard reagents catalyzed by cyclopropane-based bisoxazolines cobalt complexes

Four new cyclopropane-based bisoxazolines were synthesized and applied to cobalt-catalyzed cross-coupling reactions between racemic α-bromo esters and aryl Grignard reagents. The reaction afforded a series of chiral α-arylalkanoic esters with high yields and good enantioselectivities (up to 93% yield, 92:8 er). This research focuses on the cross-coupling between racemic α-bromopropanoate and p-isobutylphenyl Grignard reagent’s which provides ibuprofen ester efficiently. Furthermore, ibuprofen ester 7e was transformed into (S)-ibuprofen (99:1 er) via hydrolysis and recrystallization.

Figure optionsDownload as PowerPoint slide

(4S,4′S)-2,2′-((1S,2R)-3,3-Dimethylcyclopropane-1,2-diyl)bis(4-ethyl-4,5-dihydrooxazole)C15H24N2O2[α]D20 = −107.8 (c 1.13, CHCl3)Source of chirality: (S)-2-aminobutan-1-olAbsolute configuration: (4S,4′S)

(4S,4′S)-2,2′-((1S,2R)-3,3-Dimethylcyclopropane-1,2-diyl)bis(4-isobutyl-4,5-dihydrooxazole)C19H32N2O2[α]D20 = −141.6 (c 1.22, CHCl3)Source of chirality: (S)-2-amino-4-methylpentan-1-olAbsolute configuration: (4S,4′S)

(4S,4′S)-2,2′-((1S,2R)-3,3-Dimethylcyclopropane-1,2-diyl)bis(4-sec-butyl)-4,5-dihydrooxazole)C19H32N2O2[α]D20 = −125.4 (c 1.11, CHCl3)Source of chirality: (2S)-2-amino-3-methylpentan-1-olAbsolute configuration: (4S,4′S)

(4S,4′S)-2,2′-((1S,2R)-3,3-Dimethylcyclopropane-1,2-diyl)bis(4-phenethyl-4,5-dihydrooxazole)C27H32N2O2[α]D20 = −134.8 (c 1.36, CHCl3)Source of chirality: (S)-2-amino-4-phenylbutan-1-olAbsolute configuration: (4S,4′S)

(S)-2-(4-Isobutylphenyl)propanoic acid [(S)-ibuprofen]C13H18O2Er = 99:1[α]D20 = +52.3 (c 1.0, CHCl3)Source of chirality: Ligand 2bAbsolute configuration: (S)