Effect of Microwaves in the Chiral Switching Asymmetric Michael Reaction†

Highly enantioselective Michael reactions of malonates with cyclic enones are achieved in remarkably less time under microwave irradiation using newly developed heterobimetallic catalysts.


Introduction
Earlier, we have synthesized from readily a vailable salicylaldehyde and L -valine the novel chiral catalysts 1 and 2a-d, which displayed an interesting phenomenon of enantiomer switching in asymmetric reductions of prochiral ketones [1] and asymmetric Michael reactions [2] (Scheme 1). Catalytic asymmetric Michael reactions using chiral amines [3], alkaloids [4], polymer bound alkaloids [5], chiral crown ethers and bases [6], optically active Co (II) complexes [7], natural proteins [8] and amino alcohols [2] as catalysts have been extensively studied. A breakthrough in catalytic asymmetric Michael addition reactions was achieved with the introduction of heterobimetallic catalysts. In a series of reports Shibasaki and coworkers [9] elaborated the utility of such heterobimetallic catalysts of BINOL -La ( Al)-alkali metals in bringing about highly enantioselective Michael addition reactions, however, the Michael reaction usually requires prolonged reaction times.
It is well known that ultrasound or microwaves [10] can accelerate the reaction rates in normal reactions. We were interested in exploring such techniques in the Michael addition reaction and their effect on enantioselectivity. Accordingly we modified a domestic microwave oven to allow the reactions to be carried out in a flask attached to a reflux condenser using a wide variety of solvents as the fire hazard is significantly reduced compared to an open vessel system. When the asymmetric Michael reaction of cyclohexenone and diethyl malonate was carried out with the aluminium complex (3), the reaction was complete in 4 hours yielding the S-isomer in more than 80% ee, whereas the aluminium complex (4) gave the R -isomer in 60 % ee [2]. Interestingly the microwave assisted asymmetric Michael reaction using the aluminium complexes 3 and 4 was remarkably accelerated without altering the chiral switching nature (Scheme 2). Thus, cyclic enones when treated with vario us dialkyl malonates under microwave irradiation produced the adducts in less than 5 minutes. The results are presented in Table 1 Scheme 2 (n )  The results indicate that using microwaves comparable enantioselectivity could be achieved in a shorter period of time (2 min) in excellent yields. Also, chiral switching which occurred under room temperature conditions was reproduced under microwave conditions.

Scheme
The study was extended to include a cyclic α,β-unsaturated ketones and aldehydes (Scheme 3). The reaction times and yields are given in Table 2. Although the reaction was complete in a shorter period, resulting in 90 % yield of the Michael adduct, the expected enantioselectivity could not b e achieved. This may be attributed to the loss of rigidity in the acyclic system, since the same reaction when carried out under normal conditions also resulted in a racemic product. Table 2, Michael additions of acyclic α,β-unsaturated enone with dialkyl malonates under microwave irradiation. In order to prove the versatility of the catalyst and the application of microwaves, thiols were also used as Michael donors, which is a useful methodology for C -S bond formation (Scheme 4). The Michael adducts are obtained in very good yield within remarkably reduced reaction times (1 minute). Results are presented in Table 3.  The fact that the products obtained in the microwave assisted Michael reactions exhibit no change in the ee when compared with the same reaction carried out under normal conditions, indicates the "isoentropic" nature of these reactions.

Conclusions
The newly developed heterobimetallic catalysts along with the microwave technology provide better methodology for asymmetric Michael reaction for a variety of substrates in lesser reaction time.

Acknowledgements
One of the authors (S.V) thanks CSIR for financial assistance

General
The solvents and chemicals used in this work were obtained commercially and were purified using conventional methods. All reactions were carried out in a modified domestic Microwave oven (IFB model 750W). The NMR spectra were recorded on BRUKER 200 MHz instrument. Optical rotations were recorded using an Autopol polarimeter using CHCl 3 as solvent at 23°C using the sodium D-line monochromator (2580 A°)

Procedure for the modification of the domestic microwave oven
The commercial domestic microwave oven used in our laboratory was provided with a facility for inserting a reflux condenser and magnetic stirrer (Table 4).

General experimental procedure for Michael addition reaction using Al -Complex 3
In an oven dried side arm flask closed with a septum and containing LiAlH 4 (0.038 g, 1 mmol) in dry THF (2 mL) was added 3 (0.237 g, 1 mmol) in dry THF (3 mL) at room temperature. The resulting mixture was stirred for one hour. To the stirred solution 2-cyclohexenone (0.490g, 5 mmol) and diethyl malonate, (0.800 g, 5 mmol) were added and the mixture was irradiated in a microwave oven for the stipulated period of time. The reaction was quenched with dil. HCl and extracted with ethyl acetate (3x10 mL). The organic layer was washed with water, followed by saturated. NaHCO 3 solution. The combined organic layers were dried over anhydrous Na 2 SO 4 and the solvent were removed under reduced pressure to yield the product. (1.1 g. 90 % yield, [αD o ]=-2.3 o 78 % ee ). All the products were identified and characterized by their 1 H and 13 C-NMR spectral data and found identical with the literature reported values [11].