Synthesis of 4-Heteroaryl-Substituted Coumarins by Suzuki Cross-Coupling Reactions

Abstract

Palladium-catalyzed coupling of 4-trifluoromethylsulfonyloxycoumarins 1a-d with heteroarylboronic acids 2a-d under the Suzuki reaction conditions affords 4-heteroaryl-substituted ­coumarins in good to excellent yields.

coumarin - heteroarylboronic acids - neoflavonoid derivatives - palladium catalyst - tubulin

References

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General Procedure: A mixture of 4-trifluoromethyl-sulfonyloxycoumarin (0.15-0.4 mmol, 1 equiv), heteroarylboronic acid (1.3 equiv), K₃PO₄ (3.00 equiv), Bu₄NBr (0.1 equiv) and PdCl₂(dppf) (0.05 equiv) in dry MeCN (1-2 mL), under argon atmosphere, was heated at reflux until the 4-trifluoromethylsulfonyloxycoumarin was completely consumed (0.5-3 h, monitored by TLC). The mixture was diluted with H₂O and extracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄), and after distillation of the solvent, the residue was purified by column chromatography on silica gel (EtOAc-petroleum ether = 3:2) to give the corresponding products.

The heteroarylboronic acids 2a-c were obtained from Lancaster and used as received. The 2,4-dibenzyloxy-3,5-pyrimidylboronic acid (2d) was prepared by the procedure of:

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Selected Physical Data:
4-(3′-Quinolyl)-5,6,7-trimethoxycoumarin ( 3c): white needles; mp 155 °C. ¹H NMR: δ = 3.23, 3.77 and 3.95 (9 H, s, OCH₃), 6.16 (1 H, s, H-3), 6.75 (1 H, s, H-8), 7.62 (1 H, td, J = 7.4 and 1.1 Hz, H-5′), 7.78 (1 H, td, J = 7.4 and 1.5 Hz, H-6′), 7.88 (1 H, d, J = 8.3 Hz, H-7′), 8.13 (1 H, d, J = 2.2 Hz, H-8′), 8.18 (1 H, d, J = 8.3 Hz, H-4′), 8.89 (1 H, d, J = 2.2 Hz, H-2′). ¹³C NMR: δ = 56.4, 60.8 and 61.1 (OCH₃), 96.4, 106.7, 115.0, 127.0, 127.3, 128.0, 129.1, 130.1, 132.3, 133.2, 139.2, 147.0, 149.5, 150.8, 151.7, 151.9, 157.4, 160.2. MS: m/z (%) = 363 (100) [M⁺], 348 (56), 332 (10), 320 (14), 277 (12), 262 (13).
4-(2′-Furyl)-5,6,7-trimethoxycoumarin ( 4c): yellow needles; mp 116 °C; ¹H NMR: δ = 3.62, 3.83 and 3.92 (9 H, s, OCH₃), 6.35 (1 H, s, H-3), 6.51 (1 H, dd, J = 3.4 and 1.5 Hz, H-4′), 6.69 (1 H, s, H-8), 6.74 (1 H, d, J = 3.4 Hz, H-5′), 7.56 (1 H, d, J = 1.5 Hz, H-3′). ¹³C NMR: δ = 56.2, 61.1 and 61.8 (OCH₃), 96.3, 105.8, 111.4, 112.0, 113.4, 139.4, 142.9, 143.7, 149.9, 150.8, 151.8, 156.8, 160.6. MS: m/z (%) = 302 (100) [M⁺], 287 (18), 274 (20), 259 (100), 231 (13), 216 (23), 201 (19).
4-(4′-Methoxy-3′-pyridinyl)-5,6,7-trimethoxycoumarin ( 5c): white needles; mp 164 °C. ¹H NMR: δ = 3.31, 3.80, 3.93 and 3.98 (12 H, s, OCH₃), 6.05 (1 H, s, H-3), 6.72 (1 H, s, H-8), 7.77 (1 H, dd, J = 8.6 and 0.9 Hz, H-5′), 7.59 (1 H, dd, J = 8.8 and 2.5 Hz, H-6′), 8.14 (1 H, d, J = 2.5 Hz, H-2′). ¹³C NMR: δ = 53.5, 56.2, 60.8 and 61.0 (OCH₃), 96.4, 106.9, 107.6, 109.3, 114.3, 127.8, 138.6, 139.4, 144.5, 150.8, 151.7, 156.9, 160.2 (C2), 164.0 (C4′). MS: m/z (%) = 343 (100) [M⁺], 328 (54), 315 (8), 300(15), 257 (8).
4-(2′,4′-Dibenzyloxy-3′,5′-pyrimidinyl)-5,6,7-trimethoxycoumarin ( 6c): white needles; mp 139 °C. ¹H NMR: δ = 3.31, 3.63, and 3.89 (9 H, s, OCH₃), 5.48 (4 H, s, CH₂), 6.06 (1 H, s, H-3), 6.67 (1 H, s, H-8), 7.11-7.49 (10 H, m, ArH), 8.15 (1 H, s, H-6′). ¹³C NMR: δ = 56.3, 60.8 and 61.1 (OCH₃), 68.4 and 69.4 (CH₂), 96.2, 107.1, 114.4, 115.3, 127.2, 127.9, 128.0, 128.1, 128.3, 128.4, 135.6, 136.3, 139.0, 147.3, 150.7, 151.2, 154.4, 156.8, 160.3, 164.8, 167.9.