Benzannulation of Substituted 3-Alkoxycarbonylhex-3-en-5-ynoic Acids: A New Route to 4-Substituted 3,5-Dihydroxybenzoic Acids Derivatives

Abstract

A new regioselective pathway to 4-substituted 3,5-dihydroxybenzoic acids derivatives is described here. According to this procedure substituted propargylic aldehydes are converted into substituted 3-alkoxycarbonylhex-3-en-5-ynoic acids, which are in turn, treated with acetic anhydride in the presence of sodium acetate to give the substituted benzoic acids derivatives. The aromatic moiety constructed using the latter benzannulation reaction is formed in regioselective fashion and a range of substituents are tolerated.

Key words

annulations - cyclizations - phenols - regioselectivity - biaryls

References

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• 7b

  Propargylic alcohols 3b-i were oxidised with MnO₂ in CH₂Cl₂ at r.t.

• 8a Propargylic alcohols 3a and 3b are commercially available. Alcohol 3c was prepared from phenylacetylene by treatment with butyllithium followed by addition of formaldehyde. Alcohol 3h was prepared by palladium mediated coupling of (E)-β-bromostyrene with propargyl alcohol accordingly to the following reference: Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  4467 
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11

General procedure for the benzannulation of acids 6a-i to give phenols 7a-i:
Acids 6a-i (50 mmoles)were dissolved in acetic anhydride (48 mL, 0.5 mol). To this solution, anhyd sodium acetate (8.2 g, 0.1 mol) and hydroquinone (275 mg, 2.5 mmol) were added in one portion. The obtained heterogeneous mixture was heated at reflux for 2 h under a nitrogen atmosphere. After cooling to r.t., the acetic anhydride was removed in vacuo and the residue was treated with ethyl acetate (200 mL) and water (100 mL). The organic phase was separated, dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by chromatography and crystallisation to give phenols derivatives 7a-i.

12

All new compounds were fully characterised. Selected analytical data:
6f: Anal. Calcd for C₁₇H₁₈O₆: C, 64.14; H, 5.70. Found: C, 63.98; H, 5.72. Mp 135-136 °C (ethyl acetate); ¹H NMR (250 MHz, CDCl₃) δ 1.30 (3 H, t, J = 7.2 Hz), 3.70 (2 H, s), 3.88 (3 H, s), 3.90 (3 H, s), 4.25 (2 H, q, J = 7.2 Hz), 6.82 (1 H, d, J = 8.5 Hz), 6.95 (1 H, d, J = 1.7 Hz), 7.04 (1 H, s), 7.10 (1 H, dd, J = 8.5, 1.7 Hz); EI-MS m/z 319 (M⁺ + 1), 318 (M⁺), 289, 273, 259, 245, 229, 217, 214, 201, 185, 151, 128, 88; FT-IR(nujol): (cm^-1) 766, 807, 860, 1036, 1054, 1212, 1247, 1281, 1515, 1594, 1618, 1702, 2187.
6i: Anal. Calcd for C₁₃H₁₂O₄S: C, 59.08; H, 4.58; S, 12.13. Found: C, 59.15; H, 4.60; S, 12.20. Mp 92 °C (hexane-ethyl acetate); ¹H NMR (250 MHz, CDCl₃) δ 1.30 (3 H, t, J = 7.1 Hz), 3.68 (2 H, s), 4.25 (2 H, q, J = 7.1 Hz), 7.02 (1 H, s), 7.14 (1 H, dd, J = 5, 1 Hz), 7.30 (1 H, dd, J = 5, 3 Hz), 7.56 (1 H, dd, J = 3, 1 Hz); EI-MS m/z 264 (M⁺), 220, 205, 191, 163, 147, 135, 111, 83; FT-IR(nujol): (cm^-1) 763, 811, 1041, 1203, 1288, 1421, 1619, 1709, 2195.
7f: Anal. Calcd for C₂₁H₂₂O₈: C, 62.68; H 5.51. Found: C, 62.90; H, 5.55. Mp 109-110 °C (hexane-ethyl acetate);
¹H NMR (250 MHz, CDCl₃) δ 1.39 (3 H, t, J = 7.1 Hz), 2.02 (6 H, s), 3.85 (3 H, s), 3.92 (3 H, s), 4.39 (2 H, q, J = 7.1 Hz), 6.77-6.93 (3 H, m), 7.72 (2 H, s); EI-MS m/z 402 (M⁺), 360, 343, 318, 303, 273, 244, 214, 199, 183, 157, 131, 115, 95; FT-IR(nujol): (cm^-1) 758, 862, 911, 1030, 1200, 1227, 1258, 1309, 1523, 1586, 1605, 1719, 1770.
7i: Anal. Calcd for C₁₇H₁₆O₆S: C, 58.61; H 4.63; S, 9.20. Found: C, 58.50; H, 4.65; S, 9.25. Mp 100-101 °C (hexane-ethyl acetate); ¹H NMR (250 MHz, CDCl₃) δ 1.38 (3 H, t, J = 7.1 Hz), 2.08 (6 H, s), 4.38 (2 H, q, J = 7.1 Hz), 7.11 (1 H, dd, J = 4.3, 2 Hz), 7.34-7.39 (2 H, m), 7.72 (2 H, s); EI-MS m/z 348 (M⁺), 306, 289, 264, 250, 236, 219, 192, 163, 134, 111, 91; FT-IR(nujol): (cm^-1) 756, 868, 1043, 1198, 1208, 1307, 1562, 1719, 1768.