Recyclable Cu(II)-macrocyclic salen complexes catalyzed nitroaldol reaction of aldehydes: A practical strategy in the preparation of (R)-phenylephrine

Abstract

Chiral macrocyclic salen ligands 1′–3′ derived from 1R,2R-(−)-1,2-diaminocyclohexane, 1R,2R-(+)-1,2-diphenyl-1,2-diaminoethane and (R)-(+)-1,1′-binaphthyl-2,2′-diamine with trigol bis aldehyde were prepared and characterized by microanalysis, 1H NMR, UV/Vis. spectroscopy, optical rotation and mass spectroscopy. Highly enantioselective nitroaldol reaction of various aromatic and aliphatic aldehydes with nitromethane in presence of several bases were carried out in the presence of in situ generated Cu(I)/Cu(II) complexes with chiral macrocyclic salen ligands 1′–3′ at RT. Excellent yields (up to 92% with respect to the aldehyde) of β-nitroalcohols with high enantioselectivity (ee, ∼95%) was achieved in case of 3-methoxy- and 4-nitrobenzaldehyde in ca. 30h with the use of chiral macrocyclic salen ligands 3′ with CuCl2·2H2O in presence of 2,6-lutidine as a base. Chiral macrocyclic salen catalyst 3 mediated nitroaldol process is recyclable (up to 8 cycles with no significant loss in its performance). This protocol is also used for the synthesis of enantiomerically pure (R)-phenylephrine (α1-adrenergic receptor agonist) via asymmetric nitroaldol reaction of 3-methoxybenzaldehyde in three steps.