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.

annulations - cyclizations - phenols - regioselectivity - biaryls

References

1a Serra S. Fuganti C. Moro A. J. Org. Chem.  2001,  66:  7883 

1b Brenna E. Fuganti C. Serra S. J. Chem. Soc., Perkin Trans. 1  1998,  901 

1c Brenna E. Fuganti C. Perozzo V. Serra S. Tetrahedron  1997,  53:  15029 

2 Fuganti C. Serra S. J. Chem. Res., Synop.  1998,  638 

3 Brenna E. Fuganti C. Serra S. Synlett  1998,  365 

4a Fuganti C. Serra S. Tetrahedron Lett.  1998,  39:  5609 

4b Brenna E. Fuganti C. Serra S. Tetrahedron  1998,  54:  1585 

5a Brenna E. Fuganti C. Grasselli P. Serra S. Zambotti S. Chem.-Eur. J.  2002,  8:  1872 

5b Fuganti C. Serra S. Synlett  1999,  1241 

6a Serra S. Synlett  2000,  890 

6b Fuganti C. Serra S. J. Org. Chem.  1999,  64:  8728 

6c Fuganti C. Serra S. Synlett  1998,  1252 

7a Propargyl alcohol 3a was oxidised with chromium trioxide and sulfuric acid as described in the following reference: Veliev MG. Guseinov MM. Synthesis  1980,  461 

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 

8b Alcohols 3d-g and 3i were prepared by palladium mediated coupling of propargyl alcohol with 1-bromo-4-fluorobenzene, 1-bromo-2-chlorobenzene, 4-bromoveratrole, 4-nitro-1-iodobenzene and 3-bromothiophene, respectively; this method of preparation has been performed by a small modification of the method described in the following reference: Bleicher LS. Cosford NDP. Herbaut A. McCallum JS. McDonald IA. J. Org. Chem.  1998,  63:  1109 

9 For the preparation of this ylide see: Hudson RF. Chopard PA. Helv. Chim. Acta  1963,  46:  2178 

The Wittig reaction of ylide 5 with the aldehydes affords the 3-(E)-alkylidene-succinic acid monoalkyl esters in a highly stereoselective way; for previous studies on this reaction see:

10a Paquette LA. Schulze MM. Bolin D. J. Org. Chem.  1994,  59:  2043 

10b Röder E. Krauss H. Liebigs Ann. Chem.  1992,  177 

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.

13a Glüsenkamp KH. Büchi G. J. Org. Chem.  1986,  51:  4481 

13b For the preparation of the 3,5-dihydroxybenzoic acid (R = H) see: Weston AW. Suter CM. Org. Synth.  1941,  21:  27 

14a Kojima T. Ohishi T. Yamamoto I. Matsuoka T. Kotsuki H. Tetrahedron Lett.  2001,  42:  1709 

14b Hattori T. Takeda A. Suzuki K. Koike N. Koshiishi E. Miyano S. J. Chem. Soc., Perkin Trans. 1  1998,  3661 

14c Johnson MG. Foglesong RJ. Tetrahedron Lett.  1997,  38:  7001 

15a Occelli E. DePaoli A. Nathansohn G. Gazz. Chim. Ital.  1981,  111:  383 

15b Budzikiewicz H. Metlesics W. J. Org. Chem.  1959,  24:  1125