Surprises in the Study of Ruthenium-catalyzed

A convenient and diastereoselective method was developed for the synthesis of aldol derivatives in the presence of a catalytic amount of RuCl 3 .nH 2 O under solvent-free conditions. Aldol adducts were obtained in good yields and with high chemoselectivity in short reaction times. In this protocol, aromatic and heteroaromatic aldehydes readily participate as electrophilic crossaldol partners with a range of cycloalkanones as ketone donors.


INTRODUCTION
2][3][4][5] 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 stoichiometric or catalytic amounts. 6,7Among the transition metal Lewis acids, ruthenium salts and complexes display remarkable properties. 8,91][22][23][24] The reaction has proven to be a powerful and general method for the stereocontrolled construction of βhydroxy ketone derivatives and has relevant application in the synthesis of carbohydrates, amino sugars, steroids, natural heteroatomic molecules, fine chemicals and pharmaceuticals.There are several methods to synthesized aldol products.However, only few reports described the use of catalyst to perform the aldol reactions in the simple conditions.
Over the last thirty years, seminal research from the laboratories of Evans, 25 Heathcock, 26,27 Masamune 28 and Mukaiyama 29 have established this venerable reaction as the principal chemical method for the stereoselective construction of complex polyol architecture.Also, many efforts have been addressed towards the synthesis of organocatalysts that have produced systems able to afford very good stereoselectivities.[32][33][34] These observations prompted us to synthesize a series of aldol derivatives with complete diastereoselectivity using RuCl 3 .nH 2 O as an efficient catalyst via a convenient one-pot reaction under solvent-free conditions.It is worth noting that only a little amount of ruthenium catalyst was used, which represents a significant improvement over the conventional aldol reaction.

General
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.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 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.Elemental analyses were made by a Carlo-Erba EA1110 CHNO-S analyzer and agreed with the calculated values.The isolation of pure products was carried out via preparative thin layer chromatography (silica gel 60 GF 254 , Merck).

RESULTS AND DISCUSSION
Recently, we have examined an efficient protocol for the cross aldol reaction in the presence of RuCl 3 .nH 2 O/PPh 3 .In this protocol, the reaction of 1-(thiophen-2-yl)ethanone with aldehydes resulted aldol adducts in good yields without the formation of any side product. 35The study of the Ru III /PPh 3promoted aldol reaction urged us to investigate the aldolization of aryl alkyl ketones with aromatic and heteroaromatic aldehyds in the presence of RuCl 2 (PPh 3 ) 3 .Ru II -catalyzed cross aldol reaction proceeded at 80°C, furnishing a wide variety of âhydroxy ketones with moderate diastereos electivities. 36This led us to discover unexpected effects of the nature of chiral ligand on the Ru IIIcatalyzed aldolization of aromatic aldehyds with ketones.In this method, the aldol reaction proceeded smoothly, affording the corresponding product in good yields and complete diastereoselectivities. 37 In the present protocol, due to the importance of development of new diastereoselective methodologies in the synthesis of organic compounds with high chemoselectivity, we performed Ru III -catalyzed aldol reactions using various aldehydes and cycloalkanones without the use of chiral system in good yields with complete diastereoselectivity.In this method, all reactions were carried out by simply adding the ruthenium catalyst (RuCl 3 .nH 2 O) to a neat solution containing aldehyde and cycloalkanone at 15°C when the molar ratio of cycloalkanones and aldehydes was 3 (Scheme 1).The successful results of Ru IIIcatalyzed aldol reactions are given in Table 1.
By comparing the entries, for the heteroaromatic aldehydes 1 b-d, the reaction could complete within 1-3 h.For the aromatic aldehyde,  much longer reaction time was required.Although the activity of catalyst decreased when using aromatic aldehyde, it can be used at 2 mol% loading and only a slight excess of the ketone with respect to the aldehyde is required (3eq).This result provided a remarkable contrast to similar reactions, where a large excess of the donor carbonyl compound is mandatory to perform the reaction 37,[39][40][41][42][43][44][45][46] As far as the diastereomeric ratios are concerned, complete selectivities in favor of the syn products were observed in all the cases 3aa-ec.Configurational assignment of diastereoisomers was attributed by NOESY, 1 H NMR and IR.
It is a well understood phenomenon that the lower values of the 1 H NMR coupling constants of the carbinol protons than 1 Hz, for example 3cc, along with very weak correlation between the 1-H and 2-H (Figure 1) in the NOESY spectrum clearly indicate the relative stereochemistry of the aldol adduct in favor of the syn geometry.Also, in the IR spectrum of 3cc, the broad band of OH was observed with a maximum at 3500 cm -1 , which indicates the existence of hydrogen bonding of aldol adduct (Figure 2).In fact, the structure has been fixed in a special stereochemistry which dominated by hydrogen bonding observed in IR spectra and the tendency to minimize the steric crowding between the 5-Methylthiophen-2-yl and cycloheptanone rings.These results illuminate that 1-C, 2-C, 1-H and 2-H has the same chemical environment, that is to say 3cc is exclusively of syn stereochemistry.
The fact that all of the products shared almost the same NMR and IR patterns suggests the stereochemistry of these compounds to be identical.

CONCLUSION
In brief, the direct aldol reaction of various cycloalkanones with heteroaromatic and aromatic aldehydes using catalytic amount of RuCl 3 .nH 2 O without the use of chiral ligand proceeded smoothly under extremely mild conditions to give the corresponding aldol adducts in moderate to good yields with complete diastereoselectivity.The reaction can efficiently proceed at 15 °C with a small excess of ketone.From a practical and economic point of view this reaction condition is convenient with respect to most of other protocols where a large excess of ketone is used.Also, the chemoselective aldolization has shown good generality and enough activity without using any organic solvent.Further investigations focusing on the mechanism and full scope of related systems are currently underway and

Table 1 : Ruthenium-catalyzed cross aldol reactions of aldehydes with cycloalkanones 3aa-ec Entry a R Aldol Yield (%) b Time (h)
38All products were characterized by 1 H NMR,13C NMR and IR.bYields after purification by chromatography. cdentified by comparison with authentic sample.38