Facile iron(III) chloride hexahydrate catalyzed synthesis of coumarins

A practical and inexpensive synthesis of coumarins, from phenols and  -keto esters, via the Pechmann reaction catalyzed by 10 mol% of FeCl 3 · 6H 2 O is described. The reaction was applied to transform phenols and  -keto esters into the corresponding coumarins in moderate to excellent yields.


Introduction
][17][18][19] The Pechmann reaction 20 is known as one of the most valuable methods for the synthesis of coumarins since it proceeds from simple starting materials, a phenol and a -keto ester, together with an acid catalyst.2][33] However, the development of practical, efficient and environmentally benign synthetic protocols for the synthesis of coumarins is greatly desirable.
Among the transition metal catalysts, iron is in many ways ideal, owing to its ready availability, low price and environmentally friendly character.5][36] A few examples of iron-catalyzed synthesis of 4-substituted coumarins through the Pechmann condensation have been demonstrated very recently [37][38] by employing anhydrous FeCl 3 as the active catalyst under microwave and ultrasonic irradiation as well as conventional heating 37 and in an ionic liquid medium. 38We envisioned that the use of an Fe(III) hydrate as a catalyst instead of anhydrous FeCl 3 would be an advantage, as it is cheap and easily available.There appear to be no reports of the use of such an iron hydrate in the Pechmann reaction.Herein, we report that iron(III) chloride hexahydrate can be used as an effective catalyst for the synthesis of coumarin derivatives by Pechmann condensation of phenols and -keto esters.

Results and Discussion
Initially, the reaction between resorcinol (1a) and methyl acetoacetate (2a) in the presence of iron salt catalyst was selected as a model system.Next, the effect of substituents on the reactivity of the phenol were investigated by the reaction of a variety of phenols and methyl acetoacetate (2a) (Table 2, entries 1-6).Phenols with a strong electron-donating group (R 1 ) at the meta position yielded the desired products in high yields (Table 2, entries 1-2).These good yields are the result of the presence of the increased electron density at position 6 where electrophilic substitution takes place.3,5-Disubstituted phenols 1c-1e with electron-donating groups gave the corresponding coumarins in lower yields, possibly because of the steric effect of the substituents at position 5 (Table 2, entries 3-5).In addition, 3,4-dimethoxyphenol (1f) showed low activity, leading to 3f in 44% yield (Table 2, entry 6).It was assumed that an electron-donating substituent at position 4 could decrease electron density at position 6.
Finally, the scope and limitations of the reaction were examined by employing various phenols and -keto esters (Table 2, entries 7-14).Apart from the substituent effects of the phenols, steric effects from substituents (R 4 , R 5 ) of -keto esters may play an important role in the reaction as seen more sterically hindered -keto esters affording lower yields of the corresponding products (Table 2, entries 7-9, 12-14).

Conclusions
We have developed a general and practical iron-catalyzed synthetic method for coumarin derivatives via the Pechmann reaction.A variety of phenols and -keto esters were converted into the corresponding coumarins in moderate to excellent yields.Notably, the reaction proceeds in the presence of a simple, commercially available and inexpensive iron catalyst.

Experimental Section
General.Melting points ( o C) were measured with a Gallenkamp melting point apparatus and are uncorrected.However, the melting point of 3l was determined by polarized light microscopy (Olympus BH-2) using a Mettler FP52 microfurnace and FP5 temperature controller. 1 H and 13 C NMR spectra were recorded on a Bruker AV400 spectrometer.Chemical shifts () are given in ppm and refer to TMS or the residual undeuterated solvent as the internal standard.The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, m = multiplet, dd = double doublet, br.s = broad singlet.ESI mass spectra were recorded on a Thermo Finnigan LCQ Advantage Mass Spectrometer.High Resolution Mass Spectrometry was performed with a MicroTOF LC , Bruker Daltonics.FTIR spectra were obtained with a Perkin Elmer FT-IR Spectrum GX.Flash chromatography was performed with Fluka silica gel 60 (70-230 mesh) in common glass columns.All chemicals were obtained from commercial suppliers, and were used without further purification.

Table 1 .
Optimization of the Pechmann reaction conditions aVarious reaction conditions in the presence of different catalytic amounts of FeCl 3 •6H 2 O in toluene at room temperature and under reflux were optimized (Table1, entries 1-5).It can be clearly seen from Table1that a high yield was achieved with the use of 10 mol% FeCl 3 •6H 2 O in toluene under reflux for 16 h without the need of an inert atmosphere (Table1, entry 3).However, a low yield was observed using ethanol as a solvent (Table 1, entry 6).A brief survey of other iron salts, such as FeSO 4 •7H 2 O and NH 4 Fe(SO 4 ) 2 •12H 2 O reveal that FeCl 3 •6H 2 O was the most active catalyst for the model reaction though NH 4 Fe(SO 4 ) 2 •12H 2 O showed significant activity (Table 1, entries 7-8).
b Isolated yield.

Table 2 .
Synthesis of coumarins via the Pechmann reaction catalyzed by FeCl 3 •6H 2 O a