Simple and fast microwave-assisted ruthenium _ catalyzed direct aldol reaction

Article history: Received March 30, 2012 Received in Revised form April 5, 2012 Accepted 5 April 2012 Available online 6 April 2012 A microwave-assisted method was developed for the synthesis of aldol adducts using RuCl3.nH2O-BINAP as an efficient catalyst. Important advantages of this technology include environmentally benign condition, highly accelerated rate of the reaction with an improvement in the chemoselectivity and quality of the products. © 2012 Growing Science Ltd. All rights reserved.


Introduction
C-C bond formation is the essence of organic synthesis.An aldol reaction, represents one of the classical C-C bond forming processes, and its variants have been used extensively in many important syntheses [1][2][3] .There has been great demand to develop one-pot procedures 4 for successive reactions for the formation of several C-C bonds.The minimization of steps involved in multistep synthesis not only allows the reduction of waste but also results in the diminution of costs.The pursuit of all these synthetic targets with increasing complexity has resulted in the development of reactions that emphasize chemo-, regio-, diastereo-, and enantioselectivity.
An asymmetric aldol reaction is one of the most common methods for C-C bond formation in organic molecules 5 .It is extensively applied in the synthesis of carbohydrates, amino sugars, steroids, and other valuable chiral organic compounds.It provides an atom-economic approach to β-hydroxyl carbonyls, which make up a large family of chiral intermediates for the synthesis of biologically active substances and natural products [6][7][8][9][10] .
The development of a direct catalytic asymmetric aldol reaction, in which the pre-activation of nucleophiles is no longer needed, has been worthy of notice.On the other hand, metal-catalyzed reactions have made a great contribution to the recent growth of organic synthesis and a variety of synthetic methods have been reported using transition metal complexes in catalytic amounts [11][12][13] .Among the transition metal Lewis acids, Ru III salts are known to catalyze a variety of organic transformations, and the investigation of the chemistry of ruthenium continues to be an active area of organometallic chemistry 14,15 .
Here, we report a direct aldol reaction of ketones and aromatic aldehydes catalyzed by RuCl 3 .nH 2 O and chiral ligand under microwave condition.

Results and Discussion
The aldol reaction is one of the most important chemical reactions.Substantial effort has gone into its development using preformed enolates, resulting in a remarkable level of regio-and stereochemical control.In all of the catalytic asymmetric reactions, preconversion of the ketone moiety to a more reactive species is an unavoidable necessity.Thus, the development of a direct catalytic asymmetric aldol reaction is highly desirable in terms of atom economy.
In continuation of our research in environmentally benign [16][17][18] and microwave-assisted conditions 19 , we now report an operationally simple and fast method for the preparation of aldol products by one-pot condition reaction.We have previously reported this work 17 at room temperature that in all cases, the reaction produced the aldol products with longer reaction times (0.5-2.5 h).In this research, We decided to overcome the problem of somehow prolonged reaction times using microwave irradiation.Therefore, the direct aldol reaction of ketones with aromatic aldehydes using catalytic amount of RuCl 3 .nH 2 O and chiral ligand (BINAP) was irradiated in a 160 W microwave oven and proceeded smoothly to give the corresponding aldol adducts in good yields with moderate to good diastereoselectivity.
The reaction of propiophenone (1.5 mmol) and aldehyde (0.25 mmol) in a minimum amount of solvent was carried out in the presence of BINAP/Ru III chloride (0.010/0.009 mmol).Typical results of the aldol reactions, under optimized reaction conditions, are shown in Table 1..
A mechanistic pathway for the catalytic aldol reaction is proposed.Initially, ketone may be captured on the ruthenium complex by the synergic action (i) to form the corresponding rutheniumenolate (ii) which reacts with aldehyde (iii) to give the ruthenium-aldolate (iv).Finally, when ketone is incorporated, the aldol product is released to regenerate the intermediate ruthenium-enolate (ii).The chiral space derives from the conformational preferences of the BINAP moiety.The absolute configuration in many cases was assigned by comparison with the literature and assumed to be the same in the other cases.

Conclusions
We have developed a mild and efficient direct aldol reaction using simple substrates in the presence of RuCl 3 .nH 2 O-BINAP.Microwave technique offers clean, fast, and economic for the synthesis of aldol adducts 22 .Retro aldol reactions and self-condensation of aldehydes were prevented as well.Work is currently ongoing to develop an asymmetric variant of the reaction through incorporation of the other chiral system.Additionally, we have begun to explore the use of esters in the context of several aldol reactions.

Experimental
All solvents, organic and inorganic compounds were purchased from Merck and Fluka and used without further purification.All reactions were followed by TLC with detection by UV light.The isolation of pure products was carried out via preparative thin layer chromatography (silica gel 60 GF 254 , Merck).IR spectra were recorded on Shimadzu FTIR-8400S spectrometer. 1 H NMR spectra were obtained on a Bruker DRX-500 Avance spectrometer and 13 C NMR spectra were obtained on a Bruker DRX-125 Avance spectrometer.Samples were analyzed in CDCl 3 , and the chemical shift values are reported in ppm relative to TMS (tetramethylsilane) as the internal reference.

Table 1 .
Microwave-assisted ruthenium-catalyzed cross aldol reactions of aldehydes with ketones b Yields after purification by chromatography.c Identified by comparison with authentic sample