LiBr-Mediated, solvent free von Pechmann reaction: facile and efficient method for the synthesis of 2 H -chromen-2-ones

4-Substituted 2 H -chromen-2-ones were synthesized in high yields employing lithium bromide via von Pechmann condensation of phenols and β -keto esters under solvent free condition.


Introduction
2H-Chromen-2-ones (coumarins) continue to be investigated because of their importance to medicinal chemists due to a variety of biological activity.Associated with the coumarin scaffold are antibacterial, 1a antiviral, 1b anticancer 2b,c activity as well as inhibition of platelet aggregation 2a and inhibition of steroid 5a-reductase. 3Coumarins are used in drug and pesticidal preparations, 4 they have also found applications as photosensitizers, 5 fluorescent and laser dyes. 6ecause of the significance of these molecules the search for efficient syntheses is of considerable interest.Usual methods of their preparation are von Pechmann, 7 Knoevenagel, 8 Perkin, 9 Reformatsky, 10 and Wittig reactions. 11The von Pechmann reaction is simple and straight forward employing β-keto esters and substituted phenols together with an acid catalyst.
In the past, strong acids like H 2 SO 4 , 7a,b TFA, P 2 O 5 , AlCl 3 , Znl 2 , TiCl 4 , Bi(NO 3 ) 3 •5H 2 O, 12-13 ionic liquids, 14 sulfated zircona, 15 indium halides, 16a and palladium 16b have been used.Some of the catalyst used so far are harsh or hazardous, or have to be used in considerable excess; 7, 12c some are not very efficient in terms of time (up to several days 7a,b ), yield 7c (even when the catalyst is used in excess.7a,b,12a,14b ), or lead to the formation of side products 17 (Table 1).These shortcomings certainly demand the search for a safe, more convenient and efficient method.
We and others 18 have used LiBr as a mild Lewis acid 19 in many chemical transformations like Friedel-Crafts reaction, preparation of acylals, opening of epoxides, Knoevenagel condensation, Ehrlich-Sachs reaction, Biginelli condensation, and recently in the synthesis of dibenzo-[b]xanthenes and tetrahydrobenzo [a,j]pyrans.18g In most of these reported reactions, LiBr is reported to be a near neutral Lewis acid catalyst. 19In continuation of our studies we employed LiBr in the synthesis of coumarins via von Pechmann reaction under solvent free condition (Scheme 1).Phenols 1 and β-keto esters 2 reacted in the presence of LiBr without solvent at 75 °C within 15-40 min to furnish 2H-chromen-2-ones 3 (Table 2; 3ga, 3ha at 125 °C and 90 min).Microwave irradiation gave comparable yields at reduced reaction times of 2-5 min.All the products 3 were characterized by spectroscopic analyses (IR, 1 H NMR) and -with the exception of the novel products 3da, 3ea, and 3ia -by comparison with reported data.

Scheme 1
The catalyst efficacy is fairly general; an increased reaction time resulted in no significant improvement.It is worth mentioning that the present procedure showed no evidence for the formation of side products of the chromanone type. 17This procedure worked also at multi-gram levels (up to 0.1 mol).Various phenols 1 and three β-keto esters 2 (ethyl acetoacetate, ethyl 4-chloroacetoacetate, ethyl benzoylacetate) were successfully employed.Phenols 1 with an electron-donating group R 2 in meta position (position 3) generally gave high yields in shorter ARKAT USA, Inc.
reaction times (Table 2): enhancement of electron density at position 6 facilitates the electrophilic substitution.Phenol (1g) gave a lower yield of 3ga and required a higher temperature as well as a longer reaction time because of the lack of an electron-donating group.

Experimental Section
General Procedures.Melting points were determined in open capillaries, those of the known products 3 were compared with reported data.IR spectra were obtained with a Perkin-Elmer 237B infrared spectrometer (KBr discs).NMR spectra were recorded on a Varian Gemini 300 spectrometer with tetramethylsilane (TMS) as internal standard.Commercial grade LiBr was used as procured from Aldrich; all other chemicals were purified by distillation or crystallization prior to use.