An improved synthesis of 2,2⁻-((4-substituted phenyl) methylene) difurans by Ultrasound irradiation

1 Introduction

Organic compounds containing five-membered aromatic heterocyclic rings are widely distributed in nature and often play an important role in various biochemical processes (Suslick, 1998). Heterocyclic rings have played an important role in medicinal chemistry, serving as key templates central to the development of numerous important therapeutic agents (Meohi et al., 2005). As a result they are incorporated into new chemical entities by medicinal chemists. Furan and their derivatives belong to aromatic heterocyclic group, they are important structural fragment in many pharmaceutical and chemical compounds (Suslick, 1997).

Furan compounds have been found to show nematocidal, insecticidal, antibacterial, antifungal, antiviral and antioxidant activity (Gribble et al., 1985; Matsurnra et al., 1996).

The ultrasound has increasingly been used in organic synthesis in the last three decades (Safaei-Ghomi et al., 2007; Luche, 1999). Ultrasound effects on organic reactions are attributed to cavitations, a physical process that create, enlarge, and implode gaseous and vaporous cavities in an irradiated liquid (Du et al., 2006; Abedini and Mousavi, 2010; Doan et al., 2007; Wang and Pei, 2009). Cavitations induces very high local temperatures and pressure inside the bubbles, leading to a turbulent flow in the liquid and enhanced mass transfer. Ultrasonic irradiation in some organic reactions proceeds with facile reactions to provide high yields within a very short reaction time periods (Safaei-Ghomi and Alishahi, 2006).

In the present investigation we compared the traditional methods which direct the condensation of furan with aromatic benzaldehyde (40:1) catalyzed by trifluoroacetic acid (TFA) at room temperature for 30 min (Littler et al., 1999), the reaction is accelerated by ultrasonic irradiation. The procedure described here provides an interesting protocol for the synthesis of novel 2,2⁻-((4-substituted phenyl) methylene) difurans (Said et al., 2010).

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The classical methods require drastic conditions or prolonged reactions time, in adequate yields and use of huge quantity of catalyst or organic solvent limits their practical applications (Pereir et al., 2007).

In this paper, we wish to report an expedient procedure for the synthesis of 2,2⁻-((4-substituted phenyl) methylene) difurans from the condensation of aryl aldehydes with furan using (TFA) as a catalyst.

2 Result and discussion

Herein, we wish to disclose a new protocol for the synthesis of a variety of biologically important 2,2⁻-((4-substituted phenyl) methylene) difurans using two different methods.

We first examined the crude product distribution formed (Said et al., 2010), our previously reported condition for the synthesis of 2,2⁻-((4-substituted phenyl) methylene) difurans, which involves temperature for 30 min (Table 1). Analysis of the crude product by TLC showed three points.

In this study we sought to extend the work of Chang and Jonathan (Lee and Lindsey, 1994), in which 2,2⁻-((4-substituted phenyl) methylene) difurans (1–7) were purified by distillation. We found that removal of the O-confused methylene difuran required recrystallization after distillation.

Also, we improved a general method for the synthesis of 2,2⁻-((4-substituted phenyl) methylene) difurans (1–7) by using ultrasound irradiation. Application of ultrasound shortened the reaction time of the generation products from (25–30) min under classical conditions to (3–5) min (Table 1). Also the yields of products were enhanced by 20–30%. The progress of the reaction was monitored by TLC. The mixture was sonicated until the condensation has been completed. The 2,2⁻-((4-substituted phenyl) methylene) difurans (1–7) were obtained after removal of the solvent and purified by flash column chromatography (silica gel), eluting with dichloromethane.

In summary, we have developed a simple and efficient procedure for the synthesis of methylene difurans, using TFA as a catalyst.

In all cases, aromatic aldehydes with subsistent carrying either electron-donating or electron -withdrawing groups, reacted successfully and gave the products in high yields.

The structure of products (1–7) has been confirmed by elemental analyses, ¹H NMR, ¹³C NMR and IR. The elemental analysis for each compound was found consistent theoretical values for the corresponding compounds. Through studying IR spectra of all compounds, it noticed that the absorption of carbonyl group has disappeared which absorbs in (1720 cm⁻¹) also the absorption bands of (C–H stretching) of aldehyde disappeared in (2760–2860 cm⁻¹).

The ¹H NMR data and the assignment of the compounds are presented in Table 2, all these compounds showed two identical signals for the proton of methane and benzyl protons.

Table 2 ¹H NMR and ¹³C NMR data of prepared compound.

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Compounds	Substituent	1H NMR	13C NMR
1	4-H	(5.83, 1H, s, CH-methane), (7.3, 1H, d, Ha), (6.2, 1H, t, Hb), (5.7, 1H, d, HC), (7.1, 5H, m, ph)	(48.0, C-methane, 141.5-Ca, 110.5-Cb, 106.0-Cc, 153-Cd, 126-C4, 130-C2,3,5,6, 137-C1)
2	4-CH3	(5.8, 1H, s, CH-methane), (2.4, 3H, CH3), (7.2, 1H, d, H9), (6.2, 1H, t, Hb), (5.8, 1H, d, Hc), (6.9, 4H, m, ph)	(21.0, 4-CH3, 48.5,C-methane, 142-Ca, 111-Cb, 107-Cc, 153-Cd, 130-C2,3,5,6, 135-C1,4)
3	4-OCH3	(3.7, 3H, s, -CH3), (5.8, 1H, s, CH-methane), (7.2, 1H, d, Ha), (6.2, 1H, t, Hb), (5.7, 1H, d, Hc), (6.8, 2H, H3,5), (7.0, 2H, H2,6)	(47, C-methane, 57, O-CH3, 115-C3,5, 130-C1,2,6, 159-C4, 140-Ca, 110-Cb, 106-Cc, 153-Cd)
4	2-OCH3	(3.7, 3H, s, -CH3), (5.8, 1H, s, CH-methane), (7.2, 1H, d, Ha), (6.2, 1H, t, Hb), (5.7, 1H, d, Hc), (6.7, 1H, H6), (6.85, 1H, H5), (6.95, 1H, H4), (7.3, 1H, H3)	(37, C-methane, 56, O-CH3, 141-Ca, 110-Cb, 106-Cc, 153-Cd, 123-C1, 162-C2, 114-C3, 126-C4, 121-C5, 130-C6
5	4-F	(5.63, 1H, s, CH-methane), (7.06, 1H, d, Ha), (6.58, 1H, T, Hb), (5.88, 1H, d, Hc), (6.88, 4H, H2,3,5,6)	(43.1, C-methane, 133-Ca, 107-Cb, 106-Cc, 136-Cd, 113-C3,5, 117-C2,6, 129-C1, 158-C4)
6	4-NO2	(5.8, 1H, s, CH-methane), (7.2, 1H, d, Ha), (6.3, 1H, t, Hb), (5.9, 1H, d, Hc), (7.5, 2H, H2,6), (8.2, 2H, H3,5)	(47,C-methane, 141-Ca, 110-Cb, 106-Cc, 153-Cd, 121-C3,5, 130-C2,6, 135-C1, 159-C4)
7	2,4-Cl	(5.8, 1H, s, CH-methane), (7.2, 1H, d, Ha), (6.2, 1H, T, Hb), (5.9, 1H, d, Hc), (7.3, 1H, H3), (7.1, 1H, H5), (7.0, 1H, H6)	(38, C-methane, 141-Ca, 110-Cb, 106-Cc, 152-Cd, 136-C1, 135-C2, 129-C3,5, 132-C4,6)

3 Experimental

Column chromatography was performed on silica (Merck, 230–400 mesh). Furan was distilled at atmospheric pressure from CaH₂. CH₂Cl₂ (Fisher, reagent grade) was distilled from K₂CO₃. Trifluoro acetic acid was used as obtained from Aldrich. The 2,2⁻-((4-substituted phenyl) methylene) difurans are easily visualized upon exposure of thin layer chromatography to I₂ vapor. Sonication was performed in a TPC-25 ultrasonic cleaner (with a frequency of 30 kHz and a normal power 250 w). The elemental analyses (C, H and N) were obtained from a Carlo BBOT Model EA-68 analyzer. All the melting points are uncorrected and were determined in a capillary tube on electro thermal 9100 digital melting point apparatus. The IR Spectra of the compounds were recorded on a Thermo Mattson IR 300 using KBr pellets. The ¹H (300 MHz) and ¹³C (75 MHz) NMR spectra used tetramethylsilane (TMS) as internal standard and CDCl₃ or dimethylsulfoxide (DMSO) as solvent. Coupling constants (J) are quoted to the nearest 0.1 Hz. Chemical shifts (δ-scale) are quoted in parts per million and the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad.

4 General procedure for the synthesis of 2,2⁻-((4-substituted phenyl) methylene) difurans (1–7)

• Method A: Furan (40 equiv.) and the aryl aldehyde (1.0 equiv.) were added to a dry round-bottomed flask and degassed with a stream argon for a period as indicated in Table 1. TFA (0.5 equiv.) was then added, and the solution was stirred under argon at room temperature for (7 min) then quenched with (0.1 M) NaOH. Ethyl acetate was added; the organic phase was washed with water and dried (Na₂SO₄) the solvent was removed under vacuum to afford orange oil. Steam distillation typically gives oil which crystallized upon standing. Crystallization of the oil was slow so the oil was washed in a round-bottomed flask with ethyl acetate. Removal of the solvent under vacuum gave a solid product that was recrystallized two times from ethanol to give pure difuromethanes as a crystalline solid.

• Method B: A mixture of furan (25 equiv.), aldehyde (1.0 equiv) and (0.05 equiv.) of TFA was taken in ultrasonic bath for a period as indicated in Table 1, at room temperature and workup similarly as mentioned in method A. But after consumption of the starting material (TLC monitoring) the solvent was removed by rotary evaporator (50–60 °C) to yield dark oil. The dark oil was purified by flash column chromatography (silica gel 230–400 mesh, dichloromethane).