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.

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

References

<A NAME="RU16004ST-1">1</A> Mosher CW. Crews OP. Acton EM. Goodman L. J. Med. Chem.  1966,  9:  237 

For reviews, see:

<A NAME="RU16004ST-2A">2a</A> Gribble GW. Synlett  1991,  289 

<A NAME="RU16004ST-2B">2b</A> Gribble GW. Advances in Heterocyclic Natural Product Synthesis   Vol. 1:  Pearson W. Jai Press Inc.; London: 1990.  p.43 

<A NAME="RU16004ST-2C">2c</A> Kansal VK. Potier P. Tetrahedron  1986,  42:  2389 

<A NAME="RU16004ST-2D">2d</A> Gribble GW. Saulnier MG. Heterocycles  1985,  23:  1277 

<A NAME="RU16004ST-2E">2e</A> Hewlins MJE. Oliveira-Campos A.-M. Shannon PVR. Synthesis  1984,  289 

<A NAME="RU16004ST-2F">2f</A> Sainsbury M. Synthesis  1977,  437 

<A NAME="RU16004ST-3">3</A> Gribble GW. The Alkaloids   Vol. 39:  Brossi A. Academic Press; New York: 1990. 

<A NAME="RU16004ST-4A">4a</A> Narasimhan NS. Gokhale SM. J. Indian Inst. Science  2001,  81:  135 

<A NAME="RU16004ST-4B">4b</A> Hall RJ. Marchant J. Oliveira-Campos AMF. Queiroz MJRP. Shannon PVR. J. Chem. Soc., Perkin Trans. 1  1992,  3439 

<A NAME="RU16004ST-4C">4c</A> Hogan I. Jenkins PD. Sainsbury M. Tetrahedron  1990,  46:  2943 

<A NAME="RU16004ST-4D">4d</A> Yokoyama Y. Okuyama N. Iwadate S. Momoi T. Murakami Y. J. Chem. Soc., Perkin Trans. 1  1990,  1319 

<A NAME="RU16004ST-4E">4e</A> Bäckvall J.-E. Plobeck NA. J. Org. Chem.  1990,  55:  4528 

<A NAME="RU16004ST-4F">4f</A> Naito T. Iida N. Ninomiya I. J. Chem. Soc., Perkin Trans. 1  1986,  99 

<A NAME="RU16004ST-4G">4g</A> Narasimhan NS. Gokhale SM. J. Chem. Soc., Chem. Commun.  1985,  86 

<A NAME="RU16004ST-4H">4h</A> Murakami Y. Yokoyama Y. Okuyama N. Tetrahedron Lett.  1983,  24:  2189 

<A NAME="RU16004ST-4I">4i</A> Naito T. Iida N. Ninomiya I. J. Chem. Soc., Chem. Commun.  1981,  44 

<A NAME="RU16004ST-4J">4j</A> Oikawa Y. Yonemitsu O. J. Chem. Soc., Perkin Trans. 1  1976,  1479 

<A NAME="RU16004ST-4K">4k</A> Besselievre R. Husson H.-P. Tetrahedron Lett.  1976,  1873 

<A NAME="RU16004ST-4L">4l</A> Kutney JP. Grierson DS. Heterocycles  1975,  3:  171 

<A NAME="RU16004ST-4M">4m</A> Wenkert E. Dave KG. J. Am. Chem. Soc.  1962,  84:  94 

<A NAME="RU16004ST-4N">4n</A> Schmutz J. Wittwer H. Helv. Chim. Acta  1960,  43:  793 

<A NAME="RU16004ST-5A">5a</A> Kutney JP. Noda M. Lewis NG. Monteiro B. Mostowicz D. Worth BR. Can. J. Chem.  1982,  60:  2426 

<A NAME="RU16004ST-5B">5b</A> Bergman J. Carlsson R. Tetrahedron Lett.  1978,  4055 

<A NAME="RU16004ST-6">6</A> Hibino S. Sugino E. J. Heterocycl. Chem.  1990,  27:  1751 

<A NAME="RU16004ST-7A">7a</A> Kametani T. Suzuki T. Ichikawa Y. Fukumoto K. J. Chem. Soc., Perkin Trans. 1  1975,  2102 

<A NAME="RU16004ST-7B">7b</A> Kametani T. Ichikawa Y. Suzuki T. Fukumoto K. Heterocycles  1975,  3:  401 

<A NAME="RU16004ST-8">8</A> Gribble GW. Saulnier MG. Obaza-Nutaitis JA. Ketcha DM. J. Org. Chem.  1992,  57:  5891 

<A NAME="RU16004ST-9A">9a</A> Haider N. Sotero E. Chem. Pharm. Bull.  2002,  50:  1479 

<A NAME="RU16004ST-9B">9b</A> Guillonneau C. Pierré A. Charton Y. Guilbaud N. Kraus-Berthier L. Léonce S. Michel A. Bisagni E. Atassi G. J. Med. Chem.  1999,  42:  2191 

<A NAME="RU16004ST-10A">10a</A> Miki Y. Hachiken H. Yanase N. J. Chem. Soc., Perkin Trans. 1  2001,  2213 

<A NAME="RU16004ST-10B">10b</A> Miki Y. Tada Y. Matsushita K. Heterocycles  1998,  48:  1593 

<A NAME="RU16004ST-10C">10c</A> Miki Y. Tada Y. Yanase N. Hachiken H. Matsushita K. Tetrahedron Lett.  1996,  37:  7753 

<A NAME="RU16004ST-11">11</A> Miki Y. Tsuzaki Y. Kai C. Hachiken H. Heterocycles  2002,  57:  1635 

<A NAME="RU16004ST-12">12</A> Miki Y. Hachiken H. Yoshikawa I. Heterocycles  1997,  45:  1143 

<A NAME="RU16004ST-13">13</A> Sengupta S. Leite M. Razslan DS. Quesnelle C. Snieckus V. J. Org. Chem.  1992,  57:  4066 

<A NAME="RU16004ST-14">14</A>

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.

<A NAME="RU16004ST-15">15</A>

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.