Salicylaldimine based copper ( II ) complex : a potential catalyst for the asymmetric Henry reaction

The chiral ligand synthesized from L-diphenylvalinol and salicylaldehyde is found to catalyse the asymmetric Henry reaction with copper(II)acetate monohydrate. Various nitroaldols were formed with 77-95% ee and good yield. The mechanism for the formation of a particular enantiomer is also discussed. The enantioselection in the formation of the chiral nitroaldol is discussed in terms of steric bulkiness of the catalytic system.


Introduction
Among the C-C bond forming reactions, the nitroaldol (Henry) reaction is one of the classical reactions in organic synthesis. 1It is well known that the nitroaldol products find increasing applications in pharmaceutical industries, in the synthesis of natural products, polyamino alcohols and polyhydroxylated amides.Generally, the nitroaldol reaction involves the addition of a nitronate ion to a carbonyl compound.The nitronate ion can be generated in situ by the deprotonation of a nitroalkane with an external base.The addition is facilitated either by a Lewis acid catalyst or by a suitable bifunctional catalyst, while the former activates the carbonyl partner, the latter works as a Lewis acid-Bronsted base which activates and bring both reactants together. 2The current study is to identify a weakly Lewis acidic system bearing moderately basic charged ligands that would facilitate the deprotonation of nitroalkanes for the Henry reaction to proceed.We felt that, divalent metal acetate-chiral ligand combination will meet these requirements because, acetate ion has been employed as a Bronsted base in the enantioselective nitroaldol reaction. 3atalysts for asymmetric Henry reaction reported so far are metal catalysts and organocatalysts.The metal catalysts include rare earth BINOL complexes, 4a dinuclear zinc catalysts, 4b Cu-bis(oxazoline) catalysts, 14a dual Lewis acid/amine chiral amino alcohol ligands, 4c tridentate-bis(thiazole) and bis(tetrazole) ligands, 4d diethylzinc triggered reactions, 4e ketoamino cobalt complexes, 4f metal complexes on solid support.4g The organocatalysts include guanidine derived bifunctional catalysts, 5a cinchona alkaloid derived catalysts 5b and silyl nitronates as activated nitroalkanes.5c Chiral Schiff bases have been used frequently in catalytic asymmetric synthesis. 6Schiff base type, particularly chiral salen ligands have attracted much attention because they can coordinate with a variety of transition metal ions to afford the corresponding stable chiral metal complexes.In general, these complexes are quite efficient catalysts for the asymmetric Henry reaction. 7mong them, the copper catalysed asymmetric Henry reaction performed at room temperature has captured much focus in recent years. 8Chiral copper complexes derived from -ONO type tridentate chiral ligands are of much interest and in most of the cases they afforded nitroaldols with impressive enantioselectivities. 9 Among the chiral Schiff bases, the amino acid derived ligands can catalyse the enantioselective Henry reaction under mild conditions.However, still there is scope for developing a cheap and efficient catalytic system which can work under mild reaction conditions with excellent enantioselectivity.The chiral Schiff base derived from L-phenylalaninol was found to catalyse the enantioselective Henry reaction in combination with copper(II) acetate. 10The salen ligands synthesized from L-valinol and Ldiphenylvalinol were reported to catalyse the enantioselective trimethylsilylcyanation of aldehydes by N. Oguni et al. in 1993. 11,12o the best of our knowledge there is no report for these salen ligands to catalyse the asymmetric Henry reaction.Hence in this paper, we report the synthesis of chiral Schiff bases from salicylaldehyde and L-valinol and L-diphenylvalinol and their potential with Cu(OAc)2.H2O to catalyse the asymmetric nitroaldol reaction.The mechanism of the catalytic cycle is also discussed in detail.

Scheme 1. Synthesis of imines 2a and 2b.
In order to test the ability of these ligands to induce enantioselectivity in the copper catalysed asymmetric Henry reaction (Scheme 2), nitromethane and benzaldehyde were made to react with 5 mol% of ligand 2a and the metal salt copper(II) acetate mono hydrate in an ethanolic medium at room temperature.No conversion, however, was observed under these conditions.This may be due to the poor Lewis acidity of the catalytic system, which is insufficient for the formation of nitronate anion.Then the Lewis acidity of the catalytic system was increased by adding additives.Triethylamine, which is a Lewis base, was tried as an additive.This resulted in the product (R)-(-)-2-nitro-1-phenylethanol in 60% yield with 40% enantiomeric excess.The enantioselectivity of the catalytic system was increased as expected.It is found that 1 mol% of triethylamine is sufficient for increasing the conversion of the reaction.The optimization of reaction conditions are given in table 1.

Scheme 2. Asymmetric nitroaldol reaction catalysed by 2b-Cu(OAc)2 complex.
In order to increase the enantiomeric excess of the product, the temperature was decreased from room temperature to 0 °C.As a result of this, the yield of the product was decreased to 6% but the enantiomeric excess remained the same (Table 1, entry 3).This indicates that, 0 °C is not providing the sufficient activation energy required for the substrates to react.Then the temperature was increased.The reaction was carried out under reflux conditions.But this condition resulted in the loss of enantioselectivity.The racemic nitroaldol product was formed in 60% yield (Table 1, entry 4.) The effect of temperature on the catalytic reaction clearly shows that, room temperature alone will provide the necessary stereo control for the ligand system which makes the process more selective.
In general, increase in the concentration of a catalytic system will increase the enantioselectivity of that particular asymmetric transformation.Hence, the catalytic amount of the ligand 2a-Cu(OAc)2.H2O was increased from 5 mol% to 10 mol%.With 10 mol% of the ligand 2a-Cu(OAc)2.H2O at room temperature, the enantiomeric excess of the nitroaldol was increased to 54% with full conversion (Table 1, entry 5).Hence, it was decided that 10 mol% of the ligand 2a with Cu(OAc)2.H2O is sufficient to carry out the asymmetric Henry reactions.In order to induce more enantioselectivity in the asymmetric Henry reaction, the effect of solvent on the enantioselectivity was studied by performing the reaction with different solvents.In the methanolic medium the conversion was 98%.The product (R)-(-)-2-nitro-1-phenylethanol was formed with 12% enantiomeric excess (Table 1, entry 6).With all other solvents like THF, acetonitrile, dichloromethane, chloroform, diethyl ether and toluene there is no conversion to the product nitroaldol.Then the reaction was done by taking nitromethane, which is one of the substrates as solvent (Table 1, entry 7).This led to decrease in the yield and enantioselectivity of the nitroaldol product.
Hence with ligand 2a, the maximum enantioselectivity that could be obtained was 54% under various reaction conditions.This may be due to the presence of primary alcohol moiety in ligand 2a which is not bulky enough to induce more enantioselectivity.The increase in the bulkiness of the ligand system may increase the enantioselectivity.Because, the ligand system may differentiate the two enantiotopic faces of the prochiral aldehyde, if there is a restricted rotation, which can be achieved with a bulky group in the place of methylene group in the amino alcohol part of the ligand 2a.Hence, the methylene group in the ligand 2a was replaced with diphenyl group, by synthesising L-diphenylvalinol 1b and the corresponding Schiff base 2b by condensing with salicylaldehyde.
Then, the ligand 2b-Cu(OAc)2.H2O was screened for the enantioselective Henry reaction.With 10 mol% of the ligand 2b-Cu(OAc)2.H2O the product (R)-(-)-2-nitro-1-phenylethanol was formed in 99% yield with 70% enantiomeric excess in ethanol medium at room temperature (Table 1, entry 8).Then the reaction was carried out under reflux conditions.The product nitroaldol was formed in 99% yield without any enantiomeric excess ( The reaction was carried out without adding triethylamine. The possible mechanism for the asymmetric Henry reaction catalysed by ligand 2b-Cu(OAc)2.H2O can be explained by taking the mechanistic pathway proposed by J.R. Pedro et al. 13 for their catalyst, which has almost similar structural environment as that of ligand 2b (Figure 1).First, the coordination of nitronate anion with copper takes place through the oxygen of the nitronate anion near salicylaldimine part (a).Benzaldehyde occupies the fourth equatorial position forming the distorted square planar intermediate (b).The attack of the nitronate anion on the carbonyl group of benzaldehyde takes place at the si face, via a stable six membered transition state.The product (R)-(-)-2-nitro-1-phenylethanol (c) was formed after work up (Figure 1).
With the optimised reaction conditions in hand, the scope of the reaction was explored by screening the catalytic system for the asymmetric Henry reaction of various substituted aldehydes and nitromethane (Table 2).The yield of all the nitroaldols was quantitative.High enantiomeric excess (77-95%) was observed for aldehydes bearing either electron withdrawing or electron donating groups. 14The results are shown in Table 2.All the nitroaldol products formed are in R-configuration

Conclusions
In conclusion, a new catalytic system for the copper(II) catalysed enantioselective Henry reaction between nitromethane and aromatic aldehydes has been developed.This system can be easily prepared because the chiral source L-valine is readily available.The salen ligand derived from L-diphenylvalinol and Cu(OAc)2.H2O system has been proven to be a good catalytic system for the asymmetric Henry reaction, by providing the corresponding nitroalkanols with good yield and high enantiomeric excess.Finally, the reaction can be carried out without the need of air and moisture exclusion which makes the catalyst more attractive.

General procedure for asymmetric Henry reaction
To an ethanolic solution of 2b (0.036 g, 0.1 mmol), Cu(OAc)2.H2O (0.012 g, 0.1 mmol) was added and stirred for 1 hr.To this nitromethane (0.154 g, 1 mmol) was added followed by the addition of triethylamine (0.01 ml, 1 mol%).Then benzaldehyde (0.212 ml, 1 mmol) was added drop wise and the reaction mixture was stirred for 24 hours at room temperature.After 24 hours, 1M HCl was added to the reaction mixture, and the solvent was evaporated.The aqueous layer was extracted with ethyl acetate.The resulted organic layer was dried over anhydrous sodium sulphate.The product nitroaldol was purified by column chromatography using silica gel as an adsorbent and 95:5 hexane:ethylacetate as an eluant.

Table 1 .
Asymmetric Henry reaction using benzaldehyde and nitromethane a The absolute configuration was assigned to the major enantiomer by comparison with the sign of the specific rotation given in the literature data.14a e a The ratio of ligand 2a / 2b-Cu(OAc)2.H2O: nitromethane: triethylamine: benzaldehyde was 0.1 mmol: 1 mmol: 0.01 mmol: 1 mmol.bIsolatedyield after column chromatography.cTheenantiomeric excess was determined by HPLC analysis using chiralcel OD-H column.d