Divergent Synthesis of Linear and Angular Furocoumarin Acetic Acids from Phloroglucinol

Giovanna Delogu; Carmen Picciau; Elias Quezada; Lourdes Santana; Eugenio Uriarte

doi:10.1055/s-2007-984536

LETTER

Divergent Synthesis of Linear and Angular Furocoumarin Acetic Acids from Phloroglucinol

Giovanna Delogu*^a, Carmen Picciau^a, Elias Quezada^a,b, Lourdes Santana^b, Eugenio Uriarte^b
^a Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy
Fax: +39(070)6758553; e-Mail: delogug@unica.it;
^b Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain

Abstract

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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

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References and Notes

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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).

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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).

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).

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).