Divergent Synthesis of Linear and Angular Furocoumarin Acetic Acids from Phloroglucinol

Abstract

Linear and angular furocoumarins can be obtained starting from phloroglucinol in a versatile, simple, direct, and efficient way, as demonstrated in the divergent syntheses described here. The key step is the alkali-mediated rearrangement of 4-halomethylcoumarins to benzofuran-3-acetic acids via α,β-unsaturated acids and the key intermediates are benzodipyrones, which, depending on their substitution, can either give or fail to give the ring-contraction reaction.

Key words

Pechmann reaction - furocoumarin acetic acids - ring-contraction reaction - divergent synthesis

References and Notes

• 1 Santana L. Uriarte E. Roleira F. Milhazes N. Borges F. Curr. Med. Chem.  2004,  11:  3239 
• 2 Dalla Via L. Marciani-Magno S. Curr. Med. Chem.  2001,  8:  1405 
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• 4b Greenman WM, Grass JA, Talib S, Stassinopoulos A, Hei DJ, and Hearst JE. inventors; WO  9903976 A2 19990128.  ; Chem. Abstr. 1999, 130, 152548
• 4c Cook D, Merritt J, Nerio A, Rapoport H, Stassinopoulos A, Wollowitz S, and Matejovic J. inventors; WO  9830545 A1 19980716.  ; Chem. Abstr. 1998, 129, 136107
• 4d Kontogiorgis C. Hadjipavlou-Litina D. J. Enzyme Inhib. Med. Chem.  2003,  18:  63 
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7

A solution of 1 (300 mg, 2.4 mmol) in H₂SO₄ was stirred at r.t. for 20 min. Then, ethyl 4-chloroacetoacetate (1.60 mL, 1.95 g, 11.89 mmol) was added dropwise and the reaction was stirred at r.t. overnight. Ice (50 mL) was added, the solution was filtered, and the precipitate was washed with cold H₂O until the washings were pH 7. The residue was purified by silica gel column chromatography (hexane-EtOAc, 4:1 to 3:2) to afford 2 (16 mg, 2.5% yield), 3 (104 mg, 15.0% yield), and 4 (220 mg, 41.0% yield), all as pure white solids.
10-Chloromethyl-8H-8-oxofuro[4,3,2-e]pyran[3,2-g]coumarin(2): mp 243-244 °C. IR (KBr): 2960, 1684, 1639, 1590, 1390, 1208, 1109, 1074, 856 cm^-1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 4.93 (s, 2 H, CH₂Cl), 5.90 (d, J = 2.1 Hz, 2 H, H-2), 6.20 (t, J = 2.1 Hz, 1 H, H-3), 6.56 (s, 1 H, H-9), 7.03 (s, 1 H, H-6). MS: m/z (%) = 292 (2) [M + 2]⁺, 290 (15) [M⁺], 178 (86), 163 (69), 135 (10).
10-Chloromethyl-8H-8-oxofuro[4,3,2-d,e]pyran[3,2-h]coumarin(3): mp 266-267 °C. IR (KBr): 2960, 1684, 1639, 1590, 1390, 1208, 1109, 1074, 856 cm^-1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 5.11 (s, 2 H, CH₂Cl), 5.82 (d, J = 2.0 Hz, 2 H, H-4), 6.31 (t, J = 2.0 Hz, 1 H, H-3), 6.58 (s, 1 H, H-9), 7.03 (s, 1 H, H-6). MS: m/z (%) = 292 (0.5) [M + 2]⁺, 290 (3) [M⁺] , 220 (1.6), 142 (1.7), 104 (3), 79 (25), 54 (51), 46 (80), 33 (100).

9

Synthesis of 3,5-Bis(carboxymethyl)-4-hydroxyfuro[3,2- f ]benzofuran ( 5)
A mixture of 3 (100 mg, 0.344 mmol) in 0.1 N NaOH (10 mL) was stirred at 0 °C for 30 min. Then, 3 N HCl was added to give pH 6.0 at the same temperature. The resulting brown precipitate was filtered off and washed with cold H₂O until the washings were pH 7. The residue was purified by silica gel column chromatography (CH₂Cl₂-MeOH, 9:1 to 4:1) to give 5 (77 mg, 78.0%); mp 147 °C (dec.). IR (KBr): 3520, 2949, 2840, 1746, 1620, 1599, 1422, 1128, 1080, 830 cm^-1. ¹H NMR (DMSO-d ₆): δ = 3.74 and 3.77 (2 s, 2 + 2 H, 2 CH₂), 6.73 (s, 1 H, H-8), 7.67 and 7.69 (2 s, 1 + 1 H, H-2 and H-6), 9.99 (br s, 1 H, OH), 12.31 (br s, 2 H, 2 COOH). MS: m/z (%) = 290 (0.2) [M⁺], 261 (12), 247 (58), 231 (12), 203 (100), 201 (15), 164 (5).

10

6-Carboxymethyl-5-hydroxy-4-hydroxymethylfuro[3,2-g]coumarin (7): mp 290 °C (dec.). IR (KBr): 3550, 2930, 2800, 1715, 1595, 1430, 1100, 1080, 835 cm^-1. ¹H NMR (250 MHz, DMSO-d ₆): δ = 3.84 (s, 2 H, CH₂CO), 4.76 (s, 2 H, CH ₂OH), 6.05 (s, 1 H, H-3), 6.88 (s, 1 H, H-9), 7.96 (s, 1 H, H-7), 9.45 (br s, 1 H, OH), 11.05 (br s, 2 H, 2 OH). MS: m/z (%) = 291 (9) [M + 1]⁺, 290 (100) [M⁺], 272 (15), 246 (20), 205 (10).

11

9-Carboxymethyl-5-hydroxy-4-hydroxymethylfuro[2,3-h]coumarin (10): mp 285 °C (dec.). IR (KBr): 2949, 2840, 1716, 1599, 1432, 1108, 1088, 832 cm^-1. ¹H NMR (250 MHz, DMSO-d ₆): δ = 3.80 (s, 2 H, CH₂CO), 4.72 (s, 2 H, CH ₂OH), 6.08 (s, 1 H, H-3), 6.79 (s, 1 H, H-6), 7.58 (s, 1 H, H-8), 10.80 (br s, 3 H, 3 OH). MS: m/z (%) = 291 (8) [M + 1]⁺, 290 (100) [M⁺], 272 (18), 246 (9), 228 (15).