Pechmann Reaction Promoted by Boron Trifluoride Dihydrate

The Pechmann reaction of substituted phenols 1a-e with methyl acetoacetate (2) can be activated by boron trifluoride dihydrate (3) to give the corresponding 4-methylcoumarin derivatives 4a-e in excellent yield (98-99 %).


Introduction
The coumarin moiety is widespread in nature and its derivatives find applications as fragrances, pharmaceuticals and agrochemicals [1]. Some 4-methylcoumarins are also useful as antioxidants in lipid peroxidation [2]. Their 7-methoxy-and 7-ethoxy derivatives have remained the most selective inhibitors for the coumarin 7-hydroxylase (Coh) enzyme [3,4]. The main method for the synthesis of coumarins is the Pechmann reaction of substituted phenols of type 1 with methyl, 2, or ethyl acetoacetate in the presence of protonic acid (conc. H 2 SO 4 ), Lewis acids (AlCl 3 , ZnCl 2 , ZnCl 2 /Al 2 O 3 , ZrCl 4 etc.), dehydrating agents (P 2 O 5 ) or montmorillonite clay [5][6][7][8][9][10]. The mechanism of this condensation involves three reactions: hydroxyalkylation, transesterification, and dehydration, which occur concomitantly condensing the two reactants to form the coumarin heterocycle [5]. Recently, solid acid catalysis has been found effective in the synthesis of 7-hydroxy-4-methylcoumarin (4a), giving moderate yields (40-50 %) using commercially available solid acid catalysts (Amberlyst IR 120 or Nafion 417) [11]. In 1934 Meerwein and Pannwitz reported that by reaction of boron trifluoride with water two kinds of products are formed -boron trifluoride dihydrate (3) and boron trifluoride monohydrate (Scheme 1) [12]. The monohydrate is a fuming liquid, too unstable to be stored at room temperature. It loses one mole of BF 3 to form the dihydrate 3 (Scheme 1) [12]. The boron trifluoride monohydrate is a known superacid and several applications in organic syntheses have already been published [13][14][15][16][17]. In contrast to this, the dihydrate 3 is more stable and can be even distilled under reduced pressure. Meerwein and Pannwitz also described that the reaction of 3 with water is reversible and the starting compound could be recovered [12]. Although its crystal structure was determined [18] nothing was to be found in the literature about its chemistry, e.g. its application in organic synthesis, and to the best of our knowledge, the use of 3 as an activator for organic reactions has not been reported until now. The aim of the present work was to study the use of boron trifluoride dihydrate (3) as a promoting reagent for the Pechmann condensation.

Results and Discussion
The reaction of substituted phenols 1a-e with methyl acetoacetate (2) was carried out at room temperature and at 60 °C (Scheme 2).  (3) is not perceivably exothermic and no cooling is necessary. This could be an important advantage for industrial applications. Resorcinol (1a) gave 7-hydroxy-4-methylcoumarin (4a) in yields ranging from 90-95 % under stirring for 3 hours at 18-20 °C and almost quantitatively (99 %) after 20 minutes at 60 °C. Of all obtained coumarins only the product 4a is soluble in 3 at room temperature.
To isolate the products 4a-e, the reaction mixtures were poured into 50 g of crushed ice and the solids formed were collected by filtration. The boron trifluoride dihydrate (3) can be reused several times after mild evaporation of the aqueous phase under reduced pressure.

Conclusions
In summary, to the best of our knowledge the use of the boron trifluoride dihydrate (3) as an activator in organic synthesis is now reported by us for the first time. The title compound 3 can be used in the Pechmann condensation, giving substituted 4-methylcoumarins in excellent yields (98-99 %). The possibility of reusing 3 also provides a cheaper and easier method for the synthesis of 4.

General procedure
A mixture of the corresponding phenol 1a-e (30 mmol), methyl acetoacetate (2, 3.48 g, 30 mmol) and boron trifluoride dihydrate (3, 20.8 g, 200 mmol) was heated at 60 °C for 20 minutes. After cooling to room temperature, the mixture was poured into 50 g of crushed ice. The crystals formed were filtered off, washed with water and air dried to give crude, tlc-pure products 4a-e (POLYGRAM SIL G/UV 254 plates, solvent CH 2 Cl 2 :CH 3 COOC 2 H 5 9:1). If necessary the products can be recrystallized from the solvents given in Table 1.