UNPRECEDENTED ALKYLATION OF CARBOXYLIC ACIDS BY BORON TRIFLUORIDE ETHERATE

The alkylation of carboxylic acids by an ethyl moiety of boron trifluoride etherate in the absence of ethyl alcohol from the reaction system is unexpected and novel. Both aromatic and aliphatic carboxylic acids were clearly alkylated affording good yields in short reaction times with the exception of nicotinic acid that necessitated an overnight reaction. It was noted that while ortho-substituted hydroxyl groups of carboxylic acids investigated were not affected by alkylation, those of metaand para-substituted carboxylic acids were partially etherified. Furthermore, the alkylation reaction was found to be compatible with a range of functional groups such as halogens, amino and nitro groups except for the alkene function of undecylenic acid that underwent polymerisation with concomitant alkylation of its carboxylic acid function.


INTRODUCTION
The synthesis of ortho-acylphenols have aroused the interest of organic chemists not least ourselves because of their biological activities with many of the molecules present in an array of natural products [1].Many of them have served as synthons for the synthesis of biologically active chalcones, flavanones, naphthoquinones and pesticides [2][3].We got encouraged by reports of the synthesis of ortho-acylphenols catalysed by boron trifluoride [4] and that of deoxybenzoins from respective substituted phenols and phenyl acetic acids in the presence of boron trifluoride etherate (BTE) as Lewis acid catalyst and as solvent for the acylation reactions [5].Given that we had substantial quantities of BTE in stock, we decided to test the reaction of carboxylic acids with differently substituted phenols.In place of the anticipated acylphenols, all carboxylic acids were alkylated forming carboxylic acid ethyl esters.
Carboxylic acid esters are basic compounds in organic synthesis.They find applications as pharmaceuticals, agrochemicals, cosmetics, flavours, electronic materials and also serve as synthons for synthetic intermediates.Their synthesis is widely achieved by the classical Fischer-Speier esterification by which carboxylic acids react with alcohols in the presence of acid catalysts [6].This being a reversible condensation reaction, the desired esters can be obtained by using an excess of alcohol or by the azeotropic in situ removal of water.The formation of esters is not limited to the Fischer process alone but it can also be satisfactorily achieved by alkylation of carboxylic acids.A literature survey reveals different reaction conditions for the different alkylating agents such as orthoesters [7], N,N-dimethylformamide dialkyl acetals [8], triazene derivatives [9], o-dialkylisoureas [10], dimethylcarbonate [11], methylboronic acid [12], dimethylsulfoxide [13], methylsalicylate [14], terminal alkynes [15][16][17] and in situ generation of diazomethane, the latter reagent due to its explosive nature and cancer-causing properties has been largely replaced in recent years by trimethylsilyldiazomethane-hexane solution [18].The alkylation process has gained popularity and is being applied in laboratories and in some cases in industry.While reports of the esterification of carboxylic acids catalysed by BTE are known and take place in the presence of an alcohol [19][20][21], the alkylation of carboxylic acids by an ethyl moiety of BTE in the absence of ethyl alcohol from the reaction system is unexpected and to the best of our knowledge has not been reported and therefore forms the basis of this communication.

EXPERIMENTAL
General.All chemicals were obtained from commercial sources and were used without further purification unless stated otherwise.Products were characterised by 1 H-and 13 C-NMR spectroscopy using a Varian spectrometer at 400 and 100 MHz for proton and carbon-13 respectively.Spectra were recorded in CDCl 3 solutions employing TMS as an internal reference.All spectra are reported as  (ppm) values.

RESULTS AND DISCUSSION
The alkylation of carboxylic acids proceeded cleanly with good yields in the presence of boron trifluoride etherate as alkylating agent and solvent.The reactions were complete in 4 hours except for nicotinic acid which was refluxed overnight.Reported esterification of carboxylic acids catalysed by boron trifluoride or boron trifluoride etherate have all until now necessitated the presence of an alcohol [16].On the other hand, the alkylation of carboxylic acids by an ethyl moiety of BTE alone is unexpected and to our knowledge unprecedented.The alkylation reaction was compatible with a range of functional groups such as halogens, amino and nitro groups.While the alkene function of undecylinic acid 25 polymerized in the reaction process, the acid moiety of the molecule was nevertheless alkylated as revealed by its NMR spectrum.The carboxylic acid groups of compounds 6 and 9 were alkylated, their hydroxyl groups were partly etherified forming compound 6b and 9b, respectively, while the hydroxyl groups in 6a and 9a remained untouched.It is noteworthy that as the acid in compound 14 was alkylated, its ortho-substituted hydroxyl group was not.Furthermore, both hydroxyl groups in compounds 19 were not etherified.No significant trend can be deduced from the reactions to explain why ortho-substituted hydroxyl groups in compounds 14 and 19 were not etherified at all, whereas meta-and para-substituted hydroxyl groups in compounds 6 and 9 were partly etherified to form compounds 6b and 9b, respectively.In all cases, the hydroxyl group of the carboxylic acid is etherified faster than the alcohol function due to its higher acidity.Phthalic and isophthalic acids were completely alkylated to afford esters 21 and 20, respectively, without any trace of their mono ester formation.As we have established this alkylation reaction is not limited to aromatic compounds but can be extended to aliphatic carboxylic acid systems with good yields as demonstrated in compounds 22, 23, 24 and 25.
The hitherto described alkylation of carboxylic acids in both aliphatic and aromatic systems is thought to proceed according to the following reaction mechanism:

CONCLUSION
Although the alkylation of carboxylic acids by boron trifluorde etherate is a clean reaction, it is unlikely that it would become the method of choice due to the prohibitive cost of boron trifluoride etherate compared to the classical Fischer esterification reagents.Nevertheless it is a transformation worthy of note and might find applications under special circumstances in organic syntheses.