Chiral recyclable Cu(II)-catalysts in nitroaldol reaction of aldehydes with various nitroalkanes and its application in the synthesis of a valuable drug (R)-isoproterenol

Chiral dimeric macrocyclic salen ligands 1'a-c and [H-4]salen 2'a-c derived from (1R,2R)-(-)-1,2-diaminocyclohexane, (1R,2R)-(+)-1,2-diphenyl-1,2-diaminoethane, and (R)-(+)-1,1'-binaphthyl-2,2'-diamine with 5,5'-(piperazine-1,4-diylbis(methylene)-bis-(3-tert-butyl-2-hydroxybenzaldehyde) were prepared. Cu(II) complexes 1a-c and 2a-c were generated in situ by the interaction of different source of copper(II) salts with chiral dimeric macrocyclic salen ligands 1'a-c and 2'a-c and used for asymmetric nitroaldol reaction of various aromatic and aliphatic aldehydes with various nitroalkanes at RT (27 +/- 2 degrees C). Excellent yields (98% with respect to the aldehyde) of beta-nitroalcohols with high enantioselectivity (ee, similar to 99%) was achieved in case of 2-fluorobenzaldehyde and nitromethane in ca. 20 h with the use of chiral dinuclear macrocyclic [H4]salen Cu(II)-2'a complex. This protocol also worked well with nitroethane and 2-nitropropane with several aldehydes to furnish the corresponding products in high yields and enantioselectivties for syn diasteriomers. Chiral dinuclear macrocyclic[H-4]salen catalysts Cu(II)-2'a 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)-isoproterenol (beta-adrenergic agonist) as a key step via asymmetric nitroaldol reaction of 3,4-dimethoxybenzaldehyde. To understand the mechanism of the catalytic nitroaldol reaction, the kinetic investigation was carried out with different concentrations of the catalyst Cu(II)-2'a, nitromethane, and 3-methoxybenzaldehyde as the representative substrate. The nitroaldol reaction of 3-methoxybenzaldehyde was first order with respect to the concentration of the catalyst and the nitromethane but did not depend on the initial concentration of the substrate. An appropriate mechanism of the nitroaldol reaction is proposed. (C) 2013 Elsevier B.V. All rights reserved.