Synthesis of 3-Methoxyolivacine and Olivacine by Friedel-Crafts Reaction of Indole-2,3-dicarboxylic Anhydride with 2,4,6-Trimethoxypyridine

Abstract

1-Benzylindole-2,3-dicarboxylic anhydride (1) was reacted with 2,4,6-trimethoxypyridine in the presence of titanium(IV) chloride to give 3-(2,4,6-trimethoxynicotinoyl)indole-2-carboxylic acid (2) as the sole product in high yield, which could be converted to olivacine.

Keywords

indole - Friedel-Crafts reaction - Heck reaction - demethylation - olivacine

References

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14

Olivacine: mp >300 °C (MeOH) (lit.⁵ⁿ 318-326 °C). IR (nujol): ν = 3267 cm^-1. ¹³C NMR (DMSO-d ₆): δ = 158.0, 142.7, 144.2, 133.9, 132.8, 128.2, 126.0, 122.4, 121.6, 121.0, 119.7, 116.6, 116.2, 111.9, 111.2, 20.8, 12.3. ¹H NMR (270 MHz, CDCl₃): δ = 2.82 (3 H, s, 5-CH₃), 3.03 (3 H, s, 1-CH₃), 7.21-7.26 (1 H, m, aromatic proton), 7.47-7.55 (2 H, m, aromatic protons), 7.79 (1 H, d, J = 6.0 Hz, H-4), 8.25 (1 H, d, J = 6.0 Hz, H-3), 8.35 (1 H, d, J = 7.5 Hz, H-10), 8.89 (1 H, s, H-11), 11.20 (1 H, br s, NH). HRMS: m/z [M⁺] calcd for C₁₇H₁₄N₂: 246.1157. Found: 246.1138.

15

Reaction of Anhydride (1) with 2,4,6-Trimethoxypyri-dine: 1-Benzyl-3-(2,4,6-trimethoxynicotinoyl)-indole-2-carboxylic Acid (2).
To a solution of 1-benzylindole-2,3-dicarboxylic anhydride (1, 1.90 g, 7 mmol) and 2,4,6-trimethoxypyridine (2.40 g, 14 mmol) in CH₂Cl₂ (28 mL) was added titanium(IV) chloride (21 mL of a 1 M CH₂Cl₂ solution, 21 mmol) and the mixture was stirred for 18 h at r.t. To this reaction mixture H₂O was added and then the mixture was extracted with CH₂Cl₂. The combined extracts were washed with H₂O and dried over Na₂SO₄, then concentrated under reduced pressure to give a solid, which was purified by column chromatography (n-hexane-EtOAc) to afford 1-benzyl-3-(2,4,6-trimethoxy-nicotinoyl) indole-2-carboxylic acid (2, 3.02 g, 97%).
Analytical data of compound 2: mp 170-172 °C (n-hexane-EtOAc). IR (nujol): 1722, 1593 cm^-1. ¹H NMR (CDCl₃): d = 3.65 (3 H, s, OCH₃), 3.78 (3 H, s, OCH₃), 4.01 (3 H, s, OCH₃), 6.02 (1 H, s, H-5′), 6.09 (2 H, s, CH ₂Ph), 7.08-7.34 (8 H, m, aromatics), 7.46 (1 H, d, J = 8.0 Hz, H-4). Anal. Calcd for C₂₅H₂₂N₂O₆: C, 67.26; H, 4.95; N, 6.27. Found: C, 67.19; H, 5.01; N, 6.34.