Barium Dichloride as a Powerful and Inexpensive Catalyst for the Pechmann Condensation without Using Solvent

The development of procedures to prepare heterocycles is of vital importance in synthesis of organic compounds, especially the heterocycles which can be found in naturally occurring products [1]. Coumarin derivatives possess diverse biological properties. For example, some polycyclic coumarins such as calanolides [2] isolated from Calophyllum genus, and others have shown potent anti-HIV activity [3]. Numerous coumarins have been also used as drug in contemporary medicine. As can be seen in Figure 1, warfarin, acenocoumarol, and phenprocoumon are vitamin K antagonists which play an anticoagulant role in the treatment of thromboembolic disorders [4]. Besides, some coumarins are used as additives in food and cosmetics [5], optical brighteners [6], and dispersed fluorescent and laser dyes [7]. Due to the abovementioned properties of these heterocycles, their synthesis has attracted much attention of researchers. Coumarins have been synthesized by several methods. Some of them suffer from disadvantages such as harsh conditions, long reaction times, low yield of products, and use of expensive and toxic reagents or organic solvents [8–12]. In continuation of our study on catalyzed reactions [13], in this paper, a new application of barium dichloride as a Lewis acid catalyst in the synthesis of some coumarins is reported. 2. Results and Discussion


Introduction
The development of procedures to prepare heterocycles is of vital importance in synthesis of organic compounds, especially the heterocycles which can be found in naturally occurring products [1].Coumarin derivatives possess diverse biological properties.For example, some polycyclic coumarins such as calanolides [2] isolated from Calophyllum genus, and others have shown potent anti-HIV activity [3].Numerous coumarins have been also used as drug in contemporary medicine.As can be seen in Figure 1, warfarin, acenocoumarol, and phenprocoumon are vitamin K antagonists which play an anticoagulant role in the treatment of thromboembolic disorders [4].
Besides, some coumarins are used as additives in food and cosmetics [5], optical brighteners [6], and dispersed fluorescent and laser dyes [7].Due to the abovementioned properties of these heterocycles, their synthesis has attracted much attention of researchers.Coumarins have been synthesized by several methods.Some of them suffer from disadvantages such as harsh conditions, long reaction times, low yield of products, and use of expensive and toxic reagents or organic solvents [8][9][10][11][12].In continuation of our study on catalyzed reactions [13], in this paper, a new application of barium dichloride as a Lewis acid catalyst in the synthesis of some coumarins is reported.

Results and Discussion
Establishing the reaction based on solvent-free conditions obviously reduces pollution and brings down handling costs due to simplification of experimental procedure, workup technique, and saving in labour [14].
In 1883, Pechmann and Duisberg found that phenols condense with β-ketonic esters in the presence of sulfuric acid, giving coumarin (benzo-2-pyrone) derivatives [15].In fact, Pechmann condensation is a commonly method for the preparation of coumarin derivatives because it proceeds from simple precursor such as phenols and β-ketoesters.However, via the Pechmann condensation, coumarins with substitution on either pyrone or benzene ring or both are affordable in good-to-excellent yield.In this study, we found that the Pechmann cyclocondensation of phenols 1 with β-ketoesters 2 in the presence of barium dichloride as an efficient catalyst produces the substituted coumarins 3 under thermal and solvent-free conditions (Scheme 1).
In order to optimize the reaction conditions, we tested both various temperatures and amounts of the catalyst (BaCl 2 ) in the reaction of phloroglucinol (1a) with ethyl acetoacetate (2a) as a model reaction to investigate the effects of catalyst amount and temperature for the preparation of 5,7-dihydroxy-4-methylcoumarin (3a) (Scheme 2).
As shown in Tables 1 and 2, it can be concluded that the thermal-assisted model reaction is efficiently carried out by  adding catalytic amounts of barium dichloride (10 mol%) in solventless conditions at 100 • C. The excessive amounts of catalyst or higher temperature than 100 • C cannot improve the product yield.
After optimization of the reaction conditions, as can be seen in Table 3, in order to extend the scope of this reaction, various phenols such as resorcinol, pyrogallol, and phloroglucinol were successfully used for the efficient Pechmann reaction with different β-ketoesters.A wide variety of coumarins were obtained through this method in good-to-excellent yield in short reaction times (Table 2).a Refers to isolated yields.
In summary, the presented report demonstrates facile barium dichloride-catalyzed synthesis of coumarins via the Pechmann reactions.The important advantages of this method are the short reaction time, high yields, simple workup, the use of inexpensive and available catalyst, the nonchromatographic purification of products, that is, simple recrystallization from EtOH, and use of solvent-free conditions instead of organic solvents in accord with green chemistry criteria.

Experimental Section
3.1.General.The chemicals were purchased from Merck, Fluka, and Aldrich chemical companies.The reactions were monitored by TLC (silica-gel 60 F 254 , hexane: EtOAc).IR spectra were recorded on a FT-IR Shimadzu-470 spectrometer and the 1 H NMR spectra were obtained on a Bruker-Instrument DPX-400 and 500 Avance 2 model.

General Procedure for the Preparation of Coumarin 3.
A mixture of phenol 1 (1 mmol), β-ketoesters 2 (1 mmol), and barium dichloride (10 mol%) was heated and stirred at 100 • C.After completion of the reaction (controlled by TLC), the reaction mixture was cooled at room temperature and poured onto crushed ice.The solid product obtained was filtered off, washed with ice-cold water, and recrystallized from hot EtOH to obtain the pure product 3.

Table 1 :
The effect of catalyst amount on the synthesis of 3a at 100 • C under solvent-free conditions.
a Refers to isolated yields.

Table 2 :
The effect of temperature on the synthesis of 3a using BaCl 2 (10 mol%) under solvent-free conditions.

Table 3 :
Synthesis of some coumarin derivatives based on Pechmann condensation using barium dichloride at 100 • C under solvent-free conditions.
a Identified by comparison with authentic samples and their spectral data.b Refers to isolated yields.