Microwave assisted synthesis of benzophenone and acetophenone ethylene ketals

A simple and convenient synthesis of acetophenone and benzophenone ethylene ketals was elaborated by performing the reaction of ethylene glycol in toluene in the presence of PTSA, under microwave irradiation with simultaneous removal of the water so formed. Under these conditions 100 % conversion and high yields were obtained within short reaction times


Introduction
Recently we have reported the lithiation reactions of chloro substituted acetophenones and benzophenones protected as 1,3-dioxolanes (1, Scheme 1). [1,2]The lithio species 2 thus formed were treated with various electrophiles to give ortho-functionalized acetophenone derivatives 3, which provided precursors of a series of benzannelated heterocyclic systems 4.

Scheme 1
5][6][7][8] We were seeking a simple and environmentally benign synthesis of benzophenone and acetophenone ethylene ketals.Most of the reported methods that avoided the drawbacks of the traditional protection methods (eg.long reaction times) resulted in procedures having other undesired features (reagents hazardous to the environment, limited scope, etc.). [9]ome contradictory results have been published on the reaction of acetophenone and benzophenone with ethylene glycol without solvent in a microwave reactor.The irradiation of a mixture of acetophenone, ethylene glycol (∼10 equiv.)and PTSA (0.015 equiv.) in a "nonmodified domestic microwave oven" for two minutes has been described to afford the corresponding 1,3-dioxolan-2-yl derivative in 71 % yield. [10]This paper does not discuss the reaction of benzophenones under similar conditions.However, in another study, the mixture of acetophenone or benzophenone and ethylene glycol (2 equiv.)and PTSA (0.1 equiv.) was irradiated in a Prolabo (Synthewave ® ) oven for 30 minutes (the monitored temperature 120 ºC with a maximum emitted power of 120 W), a low conversion (20 %) was observed with acetophenone, whereas, benzophenone did not react at all. [11]Ketalization of some acetophenones with ethylene glycol has been described in a Teflon cylinder under microwave irradiation in the presence of water in 30-80 % yield, however, the results are not supported by sufficient evidence to be considered reliable. [12]n this paper we describe a simple and convenient synthesis of acetophenone and benzophenone ethylene ketals by performing the reaction of the starting materials with ethylene glycol in toluene in the presence of PTSA under microwave irradiation and with simultaneous removal of the so formed water.The apparatus used for the irradiations was the same as in the case of the traditional heating (eg.oil bath), except that the reaction flask was placed in the internal space of a microwave instrument (Figure 1).

Results and Discussion
The conversion of 4-chlorobenzophenone (5a) into the corresponding 1,3-dioxolan-2-yl derivative 6a [2] has been studied in detail.The mixture of ketone 5a (0.1 mol, Scheme 1), ethylene glycol (31.0 g, 27.9 mL, 0.5 mol), PTSA (0.57g, 0.003 mol) and toluene (140 mL) in a round bottomed glass vessel equipped with a Dean-Stark apparatus was irradiated with constant 500 W energy in a Milestone MicroSYNTH ® microwave reactor (Figure 1).Small samples were analysed by 1 H NMR to determine the conversion. [13]After 3 h the conversion was complete (Figure 2) and the crystalline product was isolated in 98 % yield.For comparison the reaction was also carried out under traditional conditions.A 42 % conversion was achieved after 3 h by refluxing the mixture without irradiation and completion of the reaction took 40 h.No superheating effect was observed under microwave conditions, as the boiling temperature was the same (113-114 °C) in both cases.
ARKAT USA, Inc.In order to obtain further information on the optimal reaction conditions we have also studied the effect of the ratio of toluene and ethylene glycol (v/v) in the reaction mixture on the conversion of benzophenone 5a to ketal 6a.Solutions of ketone 5a (0.1 mol) in various mixtures of toluene and ethylene glycol (0.5 mol) in the presence of PTSA (0.003 mol) were irradiated with a constant 650 W energy and small samples were analysed by 1 H NMR to determine the conversion.No significant difference was observed in the conversion when the volume of toluene was increased threefold (boiling temperature: 118-120 °C) or fivefold (boiling temperature: 113-114 °C) over the ethylene glycol (Figure 3).
In both cases 100 % conversion was achieved after 3h reaction time. [12]However tenfold (boiling temperature: 112-113 °C) excess of toluene decreased the rate of the reaction, it was completed only after 6 h.It is interesting to mention that the conversion exhibited a bell-shaped curve with a maximum at 90 min, when the reaction was carried out in a 1:1 (v/v) mixture of toluene and ethylene glycol.The return of the ketal to the starting ketone was accompanied with the formation of diethylene and triethylene glycol, which were detected in the reaction mixture by 1 H NMR. The initial boiling temperature (126 °C) increased to 157 °C after 90 min.
We investigated the influence of the power of irradiation on the reaction whilst keeping dilution ratios constant (ie.threefold).When applying 400, 650 and 800 W constant energies no significant difference was detected in the course of the reaction (Figure 4).We noted however that at least 400 W energy was required to keep the reaction mixture refluxing.However, over 800 W intensive foaming was observed.

Scheme 2
Reacting acetophenones 7a-e (0.1 mol, Scheme 3) and using the same amounts of ethylene glycol, PTSA and toluene as above, under irradiation with a constant 500 W energy and with azeotropic removal of the water, the conversion was complete after 2 h (boiling temperature: 118-120 °C).Ketals 8a-e were isolated with 94-98 % yield.Compounds 8a,c were characterized as per the literature [1] , while 8b,d,e are new compounds (see experimental section).7a-e 8a-e

Scheme 3
In conclusion, a convenient route to acetophenone and benzophenone ethylene ketals has been devised using microwave irradiation and simultaneous removal of the water.Contrary to the traditional methods, high yields were obtained within short reaction times.

Figure 1 .
Figure 1.Schematic drawing of the experimental apparatus.