Enantioselective Henry and Aza‐Henry Reaction in the Synthesis of (R)‐Tembamide Using Efficient, Recyclable Polymeric Cu^II Complexes as Catalyst

Abstract

Chiral copper(II) polymeric [H4]salen (salen=bis[(salicylidene)ethylenediaminato]) complexes CuII‐1–3 were generated in situ and used as efficient catalysts in the asymmetric Henry and aza‐Henry reaction of various aromatic and aliphatic aldehydes and N‐tosylimines in the presence of various nitroalkanes at room temperature (27±2 °C) for 20 hours. This group of polymeric [H4]salen complexes demonstrated excellent performance (product yield and enantiomeric excess ee up to 98 %) in the formation of β‐nitroalcohol by using nitromethane with low catalyst loading of 1 mol % (with respect to the monomeric salen unit) and high enantioinduction (ee 94 %) in the aza‐Henry product; β‐nitroamines were obtained with moderate yield (78 %). This catalytic system also worked well with nitroethane and 1‐nitropropane in the case of Henry reaction, to furnish the corresponding products in high yields and enantioselectivities for syn diastereomers. The CuII‐2 complex retained its performance at the gram level and was expediently recycled eight times with no significant loss in its performance. The kinetic study with CuII‐2 complex for the enantioselective aza‐Henry reaction of N‐Ts‐benzylimine (Ts=tosyl) revealed a first‐order dependence on catalyst and nitromethane concentration and was zero order with respect to the substrate. The product obtained was transformed straightforwardly to the pharmaceutically important enantiomerically pure (R)‐tembamide (β‐adrenergic agonist) drug in good yield by the asymmetric nitroaldol reaction of 4‐methoxybenzaldehyde in three successive steps.

Peer Review #2 of "One-pot multicomponent nitro-Mannich reaction using a heterogeneous catalyst under solvent-free conditions (v0.1)"

“…The second step involves the coordination of CuI to the imino nitrogen, thus activating the imine by formation of a positively charged nitrogen atom, making it a stronger electrophile. This type of activation is typical of copper catalysts used in the nitro-Mannich reaction [52]. Moreover, validity of the possible mechanism was shown by the fast reaction times and high yields obtained with electron-donating groups since these resulted in a greater electron density on the C=N, which helped the activation of the imine by coordinating with the Lewis acid Cu + catalyst.…”

“…Moreover, validity of the possible mechanism was shown by the fast reaction times and high yields obtained with electron-donating groups since these resulted in a greater electron density on the C=N, which helped the activation of the imine by coordinating with the Lewis acid Cu + catalyst. It was suggested that the CuI salt coordinates also to the nitroalkane oxygen, increasing its acidity and thus favouring deprotonation to form the reactive nitronate anion [52].…”

Chiral Salen Complexes for Asymmetric Heterogeneous Catalysis: Recent Examples for Recycling and Cooperativity

“…The polymer was recovered and reused ten times without showing any sign of reduced performance. In the same context, the authors prepared a polymer containing enantiopure copper[H 4 ]salen units, linked together with triazine‐piperazine acting also as basic units . After polymerization and reduction of the salen groups, formation of Cu‐salan derivatives was performed in‐situ for their use as catalysts in the Henry and aza‐Henry reactions.…”

“…In the same context, the authors prepared a polymer containing enantiopure copper[H 4 ]salen units, linked together with triazinepiperazine acting also as basic units. [53] After polymerization and reduction of the salen groups, formation of Cu-salan derivatives was performed in-situ for their use as catalysts in the Henry and aza-Henry reactions. The presence of the basic moieties of the spacer supported deprotonation of nitromethane to generate the active nucleophile, thus providing good results with a very low catalyst loading.…”

Biocatalytic Approach to Chiral β-Nitroalcohols by Enantioselective Alcohol Dehydrogenase-Mediated Reduction of α-Nitroketones

“…Extracts of Aegle marmelos, containing tembamide, have been used in the Indian traditional medicine as a control for hypoglycemia [43]. Most of the enantioselective procedures to (R)-tembamide involve the use of the corresponding amino alcohol (R)-2e as a key building block [44].…”