The First Synthesis of 4-Unsubstituted 3-(Trifluoroacetyl)coumarins by the Knoevenagel Condensation of Salicylaldehydes with Ethyl Trifluoroaceto­acetate Followed by Chromene-Coumarin Recyclization

Abstract

A series of ethyl 6-substituted 2-hydroxy-2-(trifluoro­methyl)-2H-chromene-3-carboxylates was obtained in good yields via the Knoevenagel condensation of salicylaldehydes with ethyl trifluoroacetoacetate in the presence of piperidinium acetate. The subsequent recyclization of these chromenes proceeds smoothly in refluxing chlorobenzene in the presence of p-toluenesulfonic acid affording previously unknown 3-(trifluoroacetyl)coumarins in moderate to good yields.

Key words

ethyl trifluoroacetoacetate - salicylaldehydes - Knoevenagel condensation - 3-(trifluoroacetyl)coumarins - chromene-coumarin recyclization

References and Notes

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11

Typical Procedure for Preparation of 6 A mixture of salicylaldehyde (5.0 mmol), ethyl trifluoro­-acetoacetate (5.0 mmol) and piperidinium acetate (4 mg, 5 mol%) was refluxed in MeCN (10 mL) for 3-4 h and then diluted with H₂O (30 mL). The precipitate that formed was filtered, washed with warm H₂O (50 °C, 5 × 10 mL) and dried on air to give 6.
Data for Compounds 6a,d Compound 6a: colorless crystals; mp 102-103 °C (hexane). IR (mull): ν = 3294, 1686, 1635, 1607, 1576 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.40 (t, J = 7.2 Hz, 3 H, Me), 4.38 (q, J = 7.2 Hz, 2 H, OCH₂), 7.01-7.06 (m, 2 H, H-6, H-8), 7.26 (dd, J = 7.9, 1.7 Hz, 1 H, H-5), 7.39 (ddd, J = 8.2, 7.5, 1.7 Hz, 1 H, H-7), 7.50 (s, 1 H, OH), 7.78 (s, 1 H, H-4). ¹⁹F NMR (376 MHz, CDCl₃): δ (C₆F₆) = 74.50 (s, CF₃). ¹³C NMR (100 MHz, CDCl₃): δ = 14.02 (Me), 62.54 (CH₂), 95.29 (q, ² J _CF = 35.3 Hz, C-2), 114.74, 116.00 (CH), 117.55, 122.66 (q, ¹ J _CF = 292.0 Hz, CF₃), 122.68 (CH), 129.51 (CH), 133.94 (CH), 139.36 (CH), 152.62 (C-8a), 166.80 (C=O). Anal. Calcd for C₁₃H₁₁F₃O₄ (%): C, 54.18; H, 3.85; F, 19.77. Found: C, 54.20; H, 3.85; F, 19.82.
Compound 6d: light-yellow crystals; mp 120-120.5 °C (benzene). IR (mull): ν = 3230, 1686, 1619, 1578, 1527, 1345 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.43 (t, J = 7.2 Hz, 3 H, CH₃), 4.42 (q, J = 7.2 Hz, 2 H,OCH₂), 7.18 (br.d, J = 9.0 Hz, 1 H, H-8), 7.55 (s, 1 H, OH), 7.82 (s, 1 H, H-4), 8.23 (d, J = 2.6 Hz, 1 H, H-5), 8.29 (dd, J = 9.0, 2.6 Hz, 1 H, H-7). ¹⁹F NMR (376 MHz, CDCl₃): δ (C₆F₆) = 74.80 (s). ¹³C NMR (100 MHz, CDCl₃): δ = 13.82 (s, Me), 63.07 (s, OCH₂), 95.96 (q, ² J _CF = 35.8 Hz, C-2), 116.79 (s, CH), 117.13, 117.63, 122.11 (q, ¹ J _CF = 291.5 Hz, CF₃), 125.02 (CH), 128.81 (CH), 137.09 (CH), 142.79, 156.69 (s, C-8a), 165.98 (s, C=O). Anal. Cald for C₁₃H₁₀NF₃O₆ (%): C, 46.86; H, 3.03; F, 17.10; N, 4.20. Found: C, 46.73; H, 3.16; F, 16.97; N, 4.29.

14

General Procedure for Preparation of 7
A mixture of chromene 6 (0.5 mmol) and TsOH·H₂O (10 mg, 10 mol.%) was refluxed in chlorobenzene (5 mL) for 10-17 h and then concentrated to ca. 2 mL in volume. The resulting reaction mixture was dried in vacuo, dissolved in toluene (15 mL) and washed with H₂O (3 × 5 mL). Toluene solution was refluxed with a Dean-Stark trap for 5 h, the solvent was evaporated in vacuo and the residue was sublimed affording 7.
Data for Compounds 7a,d Compound 7a: pale yellow crystals; mp 117-118 °C. IR (mull): ν = 1752, 1696, 1605, 1558 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.38-7.45 (m, 1 H, H-8, H-6), 7.70 (dd, J = 7.8, 1.6 Hz, 1 H, H-5), 7.76 (ddd, J = 8.2, 7.6, 1.6 Hz, 1 H, H-7), 8.52 (s, 1 H, H-4). ¹⁹F NMR (376 MHz, CDCl₃): δ (C₆F₆) = 88.37 (s, CF₃). ¹³C NMR (100 MHz, CDCl₃): δ = 115. 65 (q, ¹ J _CF = 290.6 Hz, CF₃), 116.93 (CH), 117.24, 119.03, 125.49 (CH), 130.63 (CH), 136.25 (CH), 151.07 (C-4), 155.48 (C-8a), 155.90 (C-2), 178.36 (q, ² J _CF = 37.7 Hz, COCF₃). Anal. Calcd for C₁₁H₅F₃O₃ (%): C, 54.56; H, 2.08; F, 23.54. Found: C, 54.55; H, 2.30; F, 23.53.
Compound 7d: yellowish crystals; mp 115.5-116 °C (sublim.). IR (mull): ν = 1751, 1719, 1611, 1566, 1342 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.58 (dm, J = 9.1 Hz, 1 H, H-8), 8.58 (s, 1 H, H-4), 8.60 (dd, J = 9.1, 2.6 Hz, 1 H, H-7), 8.65 (d, J = 2.6 Hz, 1 H, H-5). ¹⁹F NMR (376 MHz, CDCl₃): δ (C₆F₆) = 88.16 (s). ¹³C NMR (100 MHz, CDCl₃): δ = 115.47 (q, ¹ J _CF = 290.1 Hz, CF₃), 117.15, 118.19, 118.53 (CH), 126.08 (CH), 130.06 (CH), 144.68, 149.00 (q, ⁴ J _CF = 1.2 Hz, C-4), 154.24 (s, C-8a), 158.55 (C-2), 177.96 (q, ² J _CF = 38.6 Hz, COCF₃). Anal. Calcd for C₁₁H₄NF₃O₅ (%): C, 46.01; H, 1.40; N, 4.88; F, 19.85. Found: C, 46.00; H, 1.15; N, 4.72; F, 19.94.