Green synthesis of trans -(4-chlorophenyl)-7-aryl-6,7-dihydro[1,3]dioxolo[4,5- f ][1]benzofuran-6-yl)methanones in an aqueous medium

Abstract

A three-component one-pot condensation of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide with benzo[1,3]dioxol-5-ol and an arylglyoxal in the presence of catalytic amounts of 1,4-diaza-bicyclo[2.2.2]octane in refluxing water gave a series of seven trans-(4-chlorophenyl)-7-aryl-6,7-dihydro[1,3]dioxolo[4,5-f][1]benzofuran-6-yl)methanones in excellent yield and in a short time.

Introduction

Multicomponent reactions (MCRs), by virtue of their convergence, productivity, facile execution and generally high yields, have attracted much attention in the area of combinatorial chemistry.^1–3 Many important heterocyclic syntheses are MCRs.

Dihydrofurans are important hetrocycles commonly found in a large variety of naturally occurring substances. ⁴ The development of new and efficient methods for their synthesis remains an area of current interest, and a whole series of new synthetic methods have appeared in the literature.^5–8 The synthesis of dihydrofurans has been reported by the condensation of an aryl aldehyde, a cyclic 1,3-diketone, 2-bromo-1-phenylethanone or 4-nitrobenzyl bromide and pyridine in the presence of 10 mol% sodium hydroxide in refluxing aqueous solution. ⁹ Recently, organic reactions in aqueous media have attracted a great deal of attention ¹⁰ as a result of increasing interest in the concepts of sustainability and green chemistry. ¹¹ Also, the latter synthesis used a procedure first described by Wang et al. ¹² in which they synthesised a series of dihydrofurans via the pyridine-catalysed reaction of phenacyl bromides with a series of aromatic aldehydes and 4-hydroxycoumarin in the presence of catalytic amounts of NaOH or Et₃N. Although many of the reported methods are effective, some of them suffer from disadvantages such as harsh reaction conditions, use of hazardous solvents, long reaction times, complex working and purification procedures, high catalyst loadings and moderate yields. Therefore, the development of a simple, mild and efficient method is still needed. In this work, we used 1,4-diaza-bicyclo[2.2.2]octane (DABCO) as an efficient catalyst to overcome these limitations.

DABCO has been used in many organic preparations as a good solid catalyst. ¹³ DABCO has received considerable attention as an inexpensive, eco-friendly, highly reactive, easy to handle and non-toxic basic catalyst for various organic transformations, affording the corresponding products in excellent yields with high selectivity. The reactions are environmentally friendly and the catalyst can be recycled in some cases. ¹⁴ As a part of our current studies on the development of new routes in organic synthesis,^15,16 in this study, we have used the procedure of Wang et al. ¹² and Khan et al. ⁹ to synthesise another class of dihydrofurans via a three-component condensation reaction of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide 2 with benzo[1,3]dioxol-5-ol 3 and an arylglyoxal 4 in the presence of catalytic amounts of DABCO (Scheme 1).

Scheme 1.

A three-component condensation reaction of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide 2 with benzo[1,3]dioxol-5-ol 3 and an arylglyoxal 4 in presence of catalytic amounts of DABCO.

Results and discussion

One of the starting materials for our synthesis, compound 2, was prepared by a literature method ¹⁷ (Scheme 2).

Scheme 2.

Synthesis of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide (2) by treatment of isoquinoline with 4-chlorophenacyl bromide (1) in acetonitrile.

A one-pot three-component reaction of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide 2 with benzo[1,3]dioxol-5-ol 3 and an arylglyoxal (4; R = various) in the presence of catalytic amounts of DABCO in refluxing water gave the pentacyclic products (5; R = various) in very good to excellent yields (Table 1).

Table 1.

Yields of a series of trans-(4-chlorophenyl)-7-aryl-6,7-dihydro[1,3]dioxolo[4,5-f][1]benzofuran-6-yl)methanones (5; R = various) prepared by refluxing a mixture of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide 2, benzo[1,3]dioxol-5-ol 3 and an arylglyoxal (4; R = various) in water in the presence of DABCO (Scheme 1).

5	Ar	Yield a (%)	m.p. (°C)
a	4-O2N C6H4	94	164–166
b	4-F C6H4	90	125–127
c	2-BrC6H4	85	113–115
d	4-Cl C6H4	90	118–120
e	2-Cl C6H4	88	105–108
f	4-HOC6H4	80	95–97
g	4-Br C6H4	86	132–134

a

Yields refer to the pure isolated products.

The structures of compounds 5a–g were deduced from their infrared (IR), ¹H NMR and ¹³C NMR spectra. The mass spectra of compounds 5a–g were fairly similar and displayed molecular ion peaks. In the ¹H NMR spectra, the two protons at the 2,3-position of the dihydrofuran ring appeared as two doublets at 5.37 and 6.09 ppm with vicinal coupling constants of 4.8 and 4.8 Hz, respectively. It has been documented that in cis-2,3-dihydrofurans, the vicinal coupling constant of the two methine protons is 7–10 Hz, while in trans-2,3-dihydrofurans the vicinal coupling constant is 2.8–6 Hz. So, we concluded that in our synthesis, the thermodynamically stable trans isomer of the 2,3-dihydrofuran derivatives had been formed. ⁹

A proposed mechanism for this reaction is shown in Scheme 3. The formation of the product can be explained as follows. The 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide 2 undergoes deprotonation in the presence of aqueous DABCO to give the reactive isoquinolinium ylide 6 at room temperature. Benzo[1,3]dioxol-5-ol 3 reacts with arylglyoxal 4 in the presence of DABCO to give the Knoevenagel product 7. This reacts instantly with the isoquinolinium ylide 6 to form the zwitterionic intermediate 8 which undergoes cyclization with the elimination of isoquinoline to give the desired product 5.

Scheme 3.

Suggested mechanism for formation of compound 5.

Experimental

Melting points were determined with an electrothermal 9100 apparatus. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyser. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionisation potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer. ¹H and ¹³C NMR spectra were recorded on a Bruker DRX-400 Avance spectrometer in CDCl₃ using tetramethylsilane (TMS) as internal standard. 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide 2 was prepared by a literature method. ¹⁷ Other chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification.

General procedure

To a magnetically stirred solution of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide 2 (1 mmol), benzo[1,3]dioxol-5-ol (1 mmol) 3 and an arylglyoxal (4; R = various) (1 mmol) in H₂O (10 mL) was added DABCO (15 mol %) in H₂O (5 mL). The mixture was refluxed for 2 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). After cooling to room temperature, the solid product was filtered off, recrystallized from ethanol to afford the pure products.

trans-(4-Chlorophenyl)-7-(4-nitrobenzoyl)-6,7-dihydro[1,3]dioxolo[4,5-f][1]benzofuran-6-yl)methanone (5a): White powder, m.p. 164–166 °C; IR (ν_max, cm⁻¹) KBr: 1667 and 1684 (C=O), 1510 and 1406 (NO₂); ¹H NMR: δ 5.37 (1H, d, J = 4.8 Hz, CH), 6.07 (2H, s, CH₂) 6.09 (1H, d, J = 4.8 Hz, CH), 6.47 (1H, s, CH), 7.23 (1H, s, CH), 7.64 (2H, d, J = 8.8 Hz, 2CH), 8.09 (2H, d, J = 8.8 Hz, 2CH), 8.36 (2H, d, J = 8.8 Hz, 2CH), 8.39 (2H, d, J = 8.8 Hz, 2CH) ppm.; ¹³C NMR: δ 53.9, 85.3, 100.9, 101.4, 113.7, 118.7, 123.8, 128.7, 130.1, 130.4, 132.3, 138.6, 142.8, 143.6, 146.3, 152.3, 155.7, 197.1, 199.3 ppm.; MS (m/z, %): 451 (7); Anal. calcd for C₂₃H₁₄ClNO₇: C, 61.14; H, 3.12; N, 3.10. Found: C, 61.25; H, 3.20; N, 3.01%.

trans-(4-Chlorophenyl)-7-(4-fluorobenzoyl)-6,7-dihydro[1,3]dioxolo[4,5-f][1]benzofuran-6-yl)methanone (5b): White powder; m.p. 125–127 °C; IR (ν_max, cm⁻¹) KBr: 1644 and 1678 (C=O); ¹H NMR: δ 5.31 (1H, d, J = 4.8 Hz, CH), 6.08 (2H, s, CH₂) 6.09 (1H, d, J = 4.8 Hz, CH), 6.59 (1H, s, CH), 7.14 (1H, s, CH), 7.35 (2H, d, J = 8.8 Hz, 2CH), 7.62 (2H, d, J = 8.8 Hz, 2CH), 8.07 (2H, d, J = 8.8 Hz, 2CH), 8.17 (2H, d, J = 8.8 Hz, 2CH) ppm.; ¹³C NMR δ 52.8, 83.8, 100.4, 101.8, 113.7, 115.4, 118.5, 128.3, 130.2, 130.5, 132.3, 132.5, 138.9, 143.6, 148.4, 155.6, 167.1, 197.1, 198.2 ppm.; MS (m/z, %): 424 (3); Anal. calcd for C₂₃H₁₄ClFO₅: C, 65.03; H, 3.32. Found: C, 65.14; H, 3.41%.

trans-(4-Chlorophenyl)-7-(2-bromobenzoyl)-6,7-dihydro[1,3]dioxolo[4,5-f][1]benzofuran-6-yl)methanone (5c): White powder; m.p. 113–115 °C; IR (ν_max, cm⁻¹) KBr: 1654 and 1688 (C=O); ¹H NMR: δ 5.32 (1H, d, J = 4.8 Hz, CH), 6.10 (2H, s, CH₂), 6.14 (1H, d, J = 4.8 Hz, CH), 6.59 (1H, s, CH), 7.17 (1H, s, CH), 7.33 (2H, t, J = 8 Hz, 2CH), 7.47 (2H, d, J = 8.8 Hz, 2CH), 7.57 (2H, d, J = 8 Hz, 2CH), 7.85 (2H, d, J = 8.8 Hz, 2CH) ppm.; ¹³C NMR: δ 53.6, 84.5, 100.6, 101.9, 112.7, 117.8, 122.3, 127.3, 127.6, 128.5, 130.2, 130.7, 132.4, 133.6, 138.38, 140.3, 143.2, 148.3, 155.7, 197.1, 199.2 ppm.; MS (m/z, %): 485 (5); Anal. calcd for C₂₃H₁₄BrClO₅: C, 56.88; H, 2.91. Found: C, 56.95; H, 3.05%.

trans-(4-Chlorophenyl)-7-(4-chlorobenzoyl)-6,7-dihydro[1,3]dioxolo[4,5-f][1]benzofuran-6-yl)methanone (5d): White powder; m.p. 118–120 °C; IR (ν_max, cm⁻¹) KBr: 1669 and 1688 (C=O); ¹H NMR: δ 5.32 (1H, 2d, J = 4.8 Hz, CH), 6.12 (2H, s, CH₂), 6.17 (1H, 2d, J = 4.8 Hz, CH), 6.57 (1H, s, CH), 7.25 (1H, s, CH), 7.99 (4H, d, J = 8.8 Hz, 4CH), 8.34 (4H, d, J = 8.8 Hz, 4CH) ppm.; ¹³C NMR: δ 53.8, 84.6, 100.7, 102.3, 112.6, 118.7, 127.5, 128.6, 130.3, 130.6, 134.6, 134.7, 138.7, 140.4, 143.2, 148.5, 155.7, 197.2, 198.7 ppm.; MS (m/z, %): 440 (8); Anal. calcd for C₂₃H₁₄Cl₂O₅: C, 62.60; H, 3.20. Found: C, 62.71; H, 3.11%.

trans-(4-Chlorophenyl)-7-(2-chloroenzoyl)-6,7-dihydro[1,3]dioxolo[4,5-f][1]benzofuran-6-yl)methanone (5e): White powder; m.p. 105–108 °C; IR (ν_max, cm⁻¹) KBr: 1680 and 1691 (C=O); ¹H NMR: δ 5.33 (1H, 2d, J = 4.8 Hz, CH), 6.10 (2H, s, CH₂), 6.15 (1H, 2d, J = 4.8 Hz, CH), 6.62 (1H, s, CH), 7.13 (1H, s, CH), 7.36 (2H, t, J = 8.0 Hz, 2CH), 7.46 (2H, d, J = 8.8 Hz, 2CH), 7.58 (2H, d, J = 8.0 Hz, 2CH), 7.87 (2H, d, J = 8.8 Hz, 2CH) ppm.; ¹³C NMR: δ 53.9, 85.2, 100.2, 101.8, 112.3, 118.6, 122.4, 128.1, 129.1, 129.8, 130.6, 132.3, 132.4, 134.6, 138.7, 140.2, 143.2, 148.1, 156.1, 197.9, 199.1 ppm.; MS (m/z, %): 440 (6); Anal. calcd for C₂₃H₁₄Cl₂O₅: C, 62.60; H, 3.20. Found: C, 62.74; H, 3.09%.

trans-(4-Chlorophenyl)-7-(4-hydroxybenzoyl)-6,7-dihydro[1,3]dioxolo[4,5-f][1]benzofuran-6-yl)methanone (5f): White powder; m.p. 95–97 °C; IR (ν_max, cm⁻¹) KBr: 3295 (OH), 1664 and 1683 (C=O); ¹H NMR δ 4.95 (1H, d, J = 4.8 Hz, CH), 6.02 (2H, s, CH₂), 6.17 (1H, d, J = 4.8 Hz, CH), 6.50 (1H, s, CH), 6.58 (1H, bs, OH), 6.87 (2H, d, J = 8.8 Hz, 2CH), 7.13 (1H, s, CH), 7.62 (2H, d, J = 8.8 Hz, 2CH), 7.89 (2H, d, J = 8.8 Hz, 2CH), 8.12 (2H, d, J = 8.8 Hz, 2CH) ppm.; ¹³C NMR δ 52.9, 84.9, 100.2, 101.8, 112.6, 115.7, 119.6, 128.6, 129.4, 131.1, 133.4, 136.5, 137.5, 143.2, 147.2, 156.1, 161.7, 196.9, 198.9 ppm.; MS (m/z, %): 422 (5); Anal. calcd for C₂₃H₁₅ClO₆: C, 65.34; H, 3.58. Found: C, 65.49; H, 3.70%.

trans-(4-Chlorophenyl)-7-(4-bromophenyl)-6,7-dihydro[1,3]dioxolo[4,5-f][1]benzofuran-6-yl)methanone (5g): White powder; m.p. 132–134 °C; IR (ν_max, cm⁻¹) KBr: 1667 and 1682 (C=O); ¹H NMR: δ 5.29 (1H, d, J = 4.8 Hz, CH), 6.09 (2H, s, CH₂), 6.13 (1H, d, J = 4.8 Hz, CH), 6.61 (1H, s, CH), 7.14 (1H, s, CH), 7.62 (2H, d, J = 8.8 Hz, 2CH), 7.71 (2H, d, J = 8.8 Hz, 2CH), 7.94 (2H, d, J = 8.8 Hz, 2CH), 8.10 (2H, d, J = 8.8 Hz, 2CH) ppm.; ¹³C NMR: δ 52.7, 84.6, 100.3, 101.7, 113.1, 119.2, 127.3, 129.1, 129.9, 132.4, 133.5, 136.9, 139.1, 140.1, 44.4, 147.7, 156.9, 196.8, 198.7 ppm.; MS (m/z, %): 485 (7); Anal. calcd for C₂₃H₁₄BrClO₅: C, 56.88; H, 2.91. Found: C, 56.97; H, 3.02%.