Synthesis of functionalized trans -2,3-disubstituted-hexahydrobenzofurans in an aqueous medium using triethanolamine as catalyst

Abstract

A one-pot, efficient synthesis of seven novel trans-2,3-diacylated hexahydrobenzofuran derivatives has been achieved via a three-component condensation of N-(1-benzyloxycarbonylmethyl)quinolinium bromide with 5,5-dimethyl-1,3-cyclohexanedione (dimedone) and an aromatic aldehyde in the presence of catalytic amounts of triethanolamine in water under reflux conditions. The attractive features of the method are excellent yields and high purity, short reaction times, easy work-up, and use of an inexpensive and non-toxic catalyst.

Introduction

Dihydrofurans are important heterocycles found in a large variety of naturally occurring substances. ¹ 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.^2–5 The synthesis of dihydrofurans has been achieved by reacting 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. ⁶ Recently, organic reactions in aqueous media have attracted a great deal of attention ⁷ as a result of increasing interest in the concepts of sustainability and green chemistry. ⁸ The latter synthesis used a procedure first described by Wang et al ⁹ in which they synthesized a series of dihydrofurans via the pyridine-catalyzed 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 continuation of our previous work on the synthesis of heterocyclic compounds^10–12 we decided to investigate the reaction of N-(1-benzyloxycarbonylmethyl)quinolinium bromide (2) with dimedone (3) and an aromatic aldehyde 4 in the presence of catalytic amounts of triethanolamine in water under reflux conditions (Scheme 1).

Scheme 1.

The reaction of N-(1-benzyloxycarbonylmethyl)-quinolinium bromide 2 with dimedone 3 and an aromatic aldehyde 4 in the presence of catalytic amounts of triethanolamine in water under reflux conditions.

Results and discussion

Using a previously reported method ¹³ we prepared in nearly quantitative yield one of the starting materials, N-(1-benzyloxycarbonylmethyl)quinolinium bromide (2), by treatment of quinoline with benzyl bromoacetate (1) in acetonitrile (Scheme 2).

Scheme 2.

Synthesis of N-(1-benzyloxycarbonylmethyl)-quinolinium bromide (2) by treatment of quinoline with benzyl bromoacetate (1) in acetonitrile.

A one-pot three-component reaction of N-(1-benzyloxycarbonylmethyl)quinolinium bromide (2) with dimedone (3) and an aromatic aldehyde 4 in the presence of catalytic amounts of triethanolamine in water under reflux conditions yielded the tetracyclic products 5 in excellent yields (Table 1).

Table 1.

Yields of a series of trans-2,3-diacylated tetrahydrobenzofuran-4-one derivatives (5; Ar = various) prepared from N-(1-benzyloxycarbonylmethyl)quinolinium bromide (2), dimedone (3) and an aromatic aldehyde 4 (Ar = various) (Scheme 1) ^a .

Entry	Ar	Product	Yield (%)	m.p. (°C)
1	4-ClC6H4	5a	91	145-147
2	4-FC6H4	5b	89	173-175
3	2, 4-ClC6H3	5c	90	165-167
4	2-O2N C6H4	5d	84	198-200
5	3, 4-ClC6H3	5e	85	170-172
6	2-FC6H4	5f	88	160-162
7	1-Thienyl	5g	87	184-186

a

Reaction conditions: Triethanolamine (20 mol%) was added to a stirred mixture of N-(1-benzyloxycarbonylmethyl)quinolinium bromide (2) (1 mmol) with dimedone (3) (1 mmol) and an aromatic aldehyde 4 (Ar = various) (1 mmol) in water (5 mL) and the mixture heated at reflux for 3 h.

b

Isolated yields.

The structures of compounds 5a–g were deduced from their IR, ¹H and ¹³C NMR spectra. The mass spectra of compounds 5a–g are fairly similar and display molecular ion peaks. In the ¹H NMR spectra, the two protons at the 2,3-position of the dihydrofuran ring display two doublets at 4.49 and 5.08 ppm with a vicinal coupling constant J = 4.8 Hz. It has been documented that in cis-2,3-dihydrofurans the vicinal coupling constant of the two methine protons is 7–10 Hz, whereas in trans-2,3-dihydrofurans the vicinal coupling constant is 2.8–6 Hz. ⁶ So we concluded that the thermodynamically stable trans isomers of 2,3-dihydrofuran derivatives were formed. A proposed mechanism for this reaction is shown in Scheme 3. The formation of the product can be explained as follows. The N-(1-benzyloxycarbonylmethyl)quinolinium bromide (2) undergoes deprotonation in the presence of aqueous triethanolamine to give the reactive quinolinium ylide 6. Dimedone (3) reacts with aromatic aldehyde 4 in the presence of triethanolamine to give the Knoevenagel product 7. This reacts instantly with the quinolinium ylide 6 to form the zwitterionic intermediate 8, cyclisation of which with the elimination of quinoline gives the tetracyclic 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 analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer. NMR spectra were obtained on a Bruker DRX-500 MHz spectrometer (¹H NMR at 500 Hz, ¹³C NMR at 125 Hz) in CDCl₃ using TMS as an internal standard. Chemical shifts (δ) are given in ppm and coupling constants (J) are given in Hz. N-(1-Benzyloxycarbonylmethyl)quinolinium bromide (2) was prepared by a literature method. ¹³ Other chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification.

Synthesis of trans-2,3-diacylated hexahydrobenzofuran derivatives; general procedure

Triethanolamine (20 mol%) in H₂O (5 mL) was added to a magnetically stirred solution of N-(1-benzyloxycarbonylmethyl)quinolinium bromide (1 mmol), dimedone (1 mmol) and an aromatic aldehyde (1 mmol) in H₂O (10 mL). The mixture was then refluxed for 3 h. The progress of the reaction was monitored by thin-layer chromatography. After cooling to room temperature, the solid product was filtered off and recrystallized from ethanol to afford the pure product.

Benzyl trans-3-(4-chlorobenzoyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5a): White powder; m.p. 145–147°C; IR (KBr) (ν_max, cm^–1): 1734, 1639; ¹H NMR: δ = 1.30 (3H, s, CH₃), 1.32 (3H, s, CH₃), 2.26 (2H, m, CH₂), 2.50 (2H, m, CH₂), 4.49 (1H, d, J = 4.8 Hz, H-3), 5.08 (1H, d, J = 4.8 Hz, H-2), 5.23 (2H, d, J = 12.5 Hz, CH₂), 7.25 (1H, d, J = 8.8 Hz, ArH), 7.29 (2H, d, J = 7.8 Hz, ArH), 7.37 (2H, d, J = 7.8 Hz, ArH), 7.43 (2H, d, J = 8.2 Hz, ArH), 7.44 (2H, d, J = 8.2 Hz, ArH) ppm; ¹³C NMR: δ = 29.6, 29.7, 34.1, 37.0, 50.1, 51.3, 66.8, 85.0, 109.8, 118.7, 127.8, 128.2, 128.4, 128.5, 129.0, 135.3, 140.1, 167.9, 170.2, 195.9 ppm; MS m/z (%): 438 (9). Anal. calcd for C₂₅H₂₃ClO₅: C, 68.41; H, 5.28; found: C, 68.55; H, 5.41%.

Benzyl trans-3-(4-fluorobenzoyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5b): White powder; m.p. 173–175°C; IR (KBr) (ν_max, cm^–1): 1739, 1637; ¹H NMR: δ = 1.17 (3H, s, CH₃), 1.23 (3H, s, CH₃), 2.26 (2H, m, CH₂), 2.50 (2H, m, CH₂), 4.30 (1H, 2d, J = 4.5 Hz, H-3), 4.99 (1H, 2d, J = 4.5 Hz, H-2), 5.11 (2H, 2d, J = 9.5 Hz, CH₂), 6.80 (2H, t, J = 8.5 Hz, ArH), 6.98 (2H, dd, J = 8.5 Hz, J = 5.2 Hz, ArH), 7.09 (1H, m, ArH), 7.20 (2H, d, J = 5 Hz, ArH), 7.32 (2H, d, J = 5 Hz, ArH) ppm; ¹³C NMR: δ = 29.6, 29.7, 34.2, 37.2, 50.8, 52.1, 66.9, 86.3, 108.8, 115.5 (d, J = 13 Hz, C^ortho), 128.2, 128.4, 128.7, 128.9 (d, J = 8 Hz, C^meta), 139.6 (d, J = 3 Hz, C^para), 140.4, 160.6 (d, J = 242 Hz, C^ipso), 169.1, 176.5, 196.9 ppm; MS m/z (%): 422 (7). Anal. calcd for C₂₅H₂₃FO₅: C, 71.08; H, 5.49; found: C, 71.19; H, 5.63%.

Benzyl trans-3-(2,4-dichlorobenzoyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5c): White powder; m.p. 165–167°C; IR (KBr) (ν_max, cm^–1): 1737, 1636; ¹H NMR: δ = 1.16 (3H, s, CH₃), 1.20 (3H, s, CH₃), 2.28 (2H, m, CH₂), 2.52 (2H, m, CH₂), 4.27 (1H, d, J = 6.5 Hz, H-3), 5.13 (1H, d, J = 6.5 Hz, H-2) 5.27 (1H, d, J = 12.5 Hz, CH₂), 7.02 (2H, d, J = 8.5 Hz, ArH), 7.11 (2H, d, J = 8.5 Hz, ArH), 7.19 (1H, m, ArH), 7.23 (1H, d, J = 2 Hz, ArH), 7.34 (1H, d, J = 2 Hz, ArH), 7.38 (1H, s, ArH) ppm; ¹³C NMR: δ = 29.6, 29.7, 34.2, 37.2, 50.3, 52.3, 66.9, 87.2, 108.0, 121.7, 128.6, 128.7, 129.1, 129.5, 129.9, 132.9, 134.5, 134.7, 139.7, 169.9, 177.2, 196.5 ppm; MS m/z (%): 472 (4). Anal. calcd for C₂₅H₂₂Cl₂O₅: C, 63.44; H, 4.68; found: C, 63.55; H, 4.80%.

Benzyl trans-3-(2-nitrobenzoyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5d): White powder; m.p. 198–200° C; IR (KBr) (ν_max, cm^–1): 1745, 1643, 1521, 1387; ¹H NMR: δ = 1.20 (3H, s, CH₃), 1.22 (3H, s, CH₃), 2.26 (2H, m, CH₂), 2.50 (2H, m, CH₂), 4.19 (1H, d, J = 5 Hz, H-3), 5.05 (1H, d, J = 5 Hz, H-2), 5.29 (2H, d, J = 10.8 Hz, CH₂), 7.22 (2H, d, J = 8.5 Hz, ArH), 7.30 (2H, d, J = 8.5 Hz, ArH), 7.35 (1H, d, J = 8.5 Hz, ArH), 7.50 (1H, t, J = 8.5 Hz, ArH), 7.55 (1H, t, J = 8.5 Hz, ArH), 7.91(1H, d, J = 8.5 Hz, ArH), 7.99 (1H, d, J = 8.5 Hz, ArH) ppm; ¹³C NMR: δ = 29.37, 29.66, 34.3, 37.6, 51.0, 52.3, 66.8, 86.7, 108.3, 127.6, 128.1, 128.6, 129.3, 129.4, 133.6, 134.8, 139.1, 141.0, 148.8, 168.5, 177.7, 193.5 ppm; MS m/z (%): 449 (10). Anal. calcd for C₂₅H₂₃NO₇: C, 66.81; H, 5.16; N, 3.12; found: C, 66.94; H, 5.26; N, 3.25%.

Benzyl trans-3-(3,4-dichlorobenzoyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5e): White powder; m.p. 170–172°C; IR (KBr) (ν_max, cm^–1): 1736, 1671; ¹H NMR: δ = 1.06 (3H, s, CH₃), 1.11 (3H, s, CH₃), 2.19 (2H, m, CH₂), 2.43 (2H, m, CH₂), 3.83 (1H, d, J = 7 Hz, H-3), 4.94 (1H, d, J = 7 Hz, H-2), 5.23 (2H, d, J = 12 Hz, CH₂), 6.71 (1H, d, J = 8.5 Hz, ArH), 6.76 (1H, d, J = 8.8 Hz, ArH), 7.29 (1H, d, J = 3.5 Hz, ArH), 7.44 (2H, d, J = 8 Hz, ArH), 7.71 (2H, d, J = 8 Hz, ArH), 8.05 (1H, t, J = 8 Hz, ArH) ppm; ¹³C NMR: δ = 29.3, 29.6, 34.1, 35.5, 51.1, 53.5, 67.4, 88.2, 110.3, 126.5, 126.7, 127.8, 128.2, 128.3, 128.6, 129.2, 133.6, 134.9, 136.3, 169.2, 176.4, 193.7 ppm; MS m/z (%): 472 (6). Anal. calcd for C₂₅H₂₂Cl₂O₅: C, 63.44; H, 4.68; found: C, 63.53; H, 4.83%.

Benzyl trans-3-(2-fluorobenzoyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5f): White powder; m.p. 160–162°C, IR (KBr) (ν_max, cm^–1): 1739, 1636; ¹H NMR: δ = 1.16 (3H, s, CH₃), 1.18 (3H, s, CH₃), 2.27 (2H, m, CH₂), δ = 2.48 (2H, m, CH₂), 4.74 (1H, d, J = 5 Hz, H-3), 5.13 (1H, d, J = 5 Hz, H-2), 5.28 (1H, d, J = 9.9 H_Z, CH), 6.83 (1H, t, J = 7 Hz, ArH), 7.10 (2H, m, ArH), 7.22 (1H, t, J = 7 Hz, ArH), 7.23 (1H, m, ArH), 7.34 (2H, d, J = 9 Hz, ArH), 7.62 (2H, d, J = 9 Hz, ArH) ppm; ¹³C NMR: δ = 29.4, 29.5, 34.2, 44.0 (d, ³J_C–F = 1.5 Hz), 50.8, 51.1, 66.8, 86.8, 107.7, 115.9 (d, J = 21 Hz, C^ortho), 123.8 (d, J = 3 Hz, C^para), 126.9, 127.5 (d, J = 8 Hz, C^meta), 128.2, 128.4 (d, J = 12 Hz, C^ortho), 128.7, 129.3 (d, J = 3 Hz, C^meta), 135.4, 159.7 (d, J = 243 Hz, C^ipso), 168.7, 170.0, 196.8 ppm; MS m/z (%): 422 (5). Anal. calcd for C₂₅H₂₃FO₅: C, 71.08; H, 5.49; found: C, 71.22; H, 5.65%.

Benzyl trans-3-(thiophen-2-carbonyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5g): White powder; m.p. 184–186°C; IR (KBr) (ν_max, cm^–1): 1744, 1643; ¹H NMR: δ = 1.07 (3H, s, CH₃), 1.17 (3H, s, CH₃) 2.29 (2H, m, CH₂), 2.52 (2H, m, CH₂), 4.29 (1H, 2d, J = 4 Hz, H-3), 5.15 (1H, 2d, J = 4 Hz, H-2), 5.32 (2H, d, J = 12.5 Hz, CH₂), 7.09 (2H, d, J = 7 Hz, ArH), 7.13 (2H, d, J = 7 Hz, ArH), 7.34 (1H, m, ArH), 7.40 (1H, d, J = 4.5 Hz, ArH), 7.65 (1H, d, J = 4.5 Hz, ArH), 7.78 (2H, d, J = 4.5 Hz, ArH) ppm; ¹³C NMR: δ = 29.0, 29.3, 35.0, 37.0, 50.8, 52.2, 66.9, 87.0, 109.9, 121.7, 123.6, 124.1, 127.1, 127.6, 128.3, 140.4, 148.3, 169.9, 176.7, 196.7 ppm; MS m/z (%): 410 (7). Anal. calcd for C₂₃H₂₂O₅S: C, 67.30; H, 5.40; found: C, 67.41; H, 5.54%.