α-Keto Esters as Electrophiles for the Chalcogeno-Baylis-Hillman Reaction

Abstract

The Baylis-Hillman reaction of a-keto esters with a,bunsaturated ketones under the catalytic influence of dimethyl sulfide in the presence of titanium tetrachloride leading to the formation of 2-aryl-2-hydroxy-3-methylene-4-oxoalkanoates has been described.The Baylis-Hillman reaction is an emerging carbon-carbon bond forming reaction involving the coupling of activated alkenes with carbon electrophiles under the catalytic influence of tertiary amines (particularly DAB-CO) producing a novel class of multifunctional molecules and is of current interest. [1][2][3][4][5][6][7][8][9][10][11][12][13] In continuation of our interest in the development of the Baylis-Hillman reaction, 8-13 we herein report dimethyl sulfide catalyzed coupling of aketo esters with methyl vinyl ketone and ethyl vinyl ketone in presence of titanium tetrachloride thus providing a simple and convenient methodology for synthesis of 2-aryl-2-hydroxy-3-methylene-4-oxoalkanoates.The Baylis-Hillman reaction of a-keto esters with activated alkenes such as acrylates and acrylonitrile providing densely functionalized products with a quaternary carbon centre and the applications of these molecules in organic synthesis have been well documented in the literature. 14-18 During our work on the ongoing research program on the Baylis-Hillman reaction we required 2-aryl-2-hydroxy-3-methy-lene-4-oxoalkanoates. A literature survey reveals that Golubev and coworkers reported the DABCO catalyzed coupling of methyl vinyl ketone (mvk) with methyl trifluoropyruvate to provide methyl 2-hydroxy-3-methylene-4-oxo-2-trifluoromethylpentanoate in high yield. 17 However, our attempts to synthesize ethyl 2-hydroxy-2-phenyl-3-methylene-4-oxopentanoate via DABCO catalyzed coupling of methyl vinyl ketone with ethyl phenylglyoxylate (a-keto ester) were unsuccessful. 19 Recently Kataoka et al. 20,21 reported an interesting chalcogenoBaylis-Hillman reaction of aldehydes with different a,bunsaturated ketones in the presence of Lewis acid to provide the desired a-hydroxyalkylated enones in moderate to good yields. With a view to providing a convenient synthesis of 2-aryl-2-hydroxy-3-methylene-4-oxoalkanoates and also with a view to expanding the scope of chalcogeno-Baylis-Hillman reaction we have examined the possibility of coupling a, b-unsaturated ketones with a-keto esters under the catalytic influence of dimethyl sulfide in the presence of Lewis acid. During our studies in this direction, we have first carried out the reaction of ethyl phenylglyoxylate with methyl vinyl ketone (mvk) under various conditions. The best results were obtained when ethyl phenylglyoxylate (1) was treated with methyl vinyl ketone and a catalytic amount of dimethyl sulfide in the presence of titanium tetrachloride in dichloromethane at room temperature for one hour thus providing the desired ethyl 2-hydroxy-2-phenyl-3-methylene-4-oxopentanoate (6) in 73% yield. 22 Encour-aged by this result we have carried out the coupling reaction of representative a-keto esters 2-5 with methyl vinyl ketone (mvk) unde...

A Convenient Synthesis ofα-Halomethylene Aldols orβ-Halo-α-(hydroxyalkyl)acrylates Using the Chalcogeno-Baylis-Hillman Reaction

“…Slow evaporation of these solutions yielded crystals suitable for single crystal X-ray analyses. [6] Compound 1, [Cu(Et-N7-G-en)(H 2 O) 2 ][NO 3 ]Cl´(H 2 O) x , is a coordination polymer in which the metal ion adopts a square pyramidal configuration with a {3N:2O} coordination sphere ( Figure 1). The three nitrogen donor atoms are provided by Figure 1.…”

“…After various attempts to find a good catalyst, we developed a reaction catalyzed by chalcogenides and TiCl 4 , known as the chalcogeno-Baylis ± Hillman reaction. [3] This reaction has some merits, namely, that it is complete within an hour [4] and can be applicable to thioesters [5] and ketoesters, [6] for which the Baylis ± Hillman reaction gives unsatisfactory results. Dimethyl sulfide, cyclic chalcogenides, and bifunctional chalcogenides are used as the catalysts of the reactions.…”

Chalcogeno Morita−Baylis−Hillman Reaction of 2‐(Methylchalcogeno)phenyl Vinyl Ketones with Aldehydes, Ketones, and α‐Dicarbonyl Compounds

“…However, this is the first example of an enolizable α-diketone reacting as an electrophile under mild conditions in the MoritaϪ BaylisϪHillman reaction. [5b] The reaction of ethyl pyruvate (13c) with 3-buten-2-one did not give the expected adduct under various MoritaϪBaylisϪHillman reaction conditions, [10] while the reaction of 1 and 4 with 13c gave 14c and 15c in 70 and 74% yield, respectively (Entries 5 and 6). Reactions with methyl benzoylformate (13d) gave the products in low yields.…”

Methanolic trimethylamine mediated Baylis-Hillman reaction

“…Though the DABCO is the most commonly used tertiary amine catalyst in this fascinating reaction, several other tertiary amines such as 4-DMAP, 22 DBU, 23 3-hydroxyquinuclidine, 1-3 3-quinuclidone, 1-3 indolizine, 1-3 and pyrrolizidines 24 have been successfully employed as catalysts/ medium to perform this reaction. Several nonamine catalysts/systems such as dimethyl sulfide/TiCl 4 , 25,26 TiCl 4 , 27,28 trialkylphosphines and metal complexes such as RhH(PPh 3 ) 4 and RuH 2 (PPh 3 ) 4 have also been successfully utilized for coupling between activated alkenes and carbon electrophiles. [1][2][3] It is worth mentioning here the most recent work of Hu, who reported a remarkable rate acceleration in the Baylis−Hillman reaction in water−dioxane medium.…”