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.

Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids

“…In 2004, Miki et al reported the total synthesis of olivacine ( 28.10 ) and ellipticine ( 28.9 ) starting from common precursors, N -benzylindole-2,3-dicarboxylic anhydride ( 318.1 ) and 2,4,6-trimethoxypyridine ( 318.2 ) (Scheme ). , Previously, the same group had already reported a synthesis of ellipticine ( 28.9 ) starting from the same indole precursor 318.1 . − Friedel–Crafts acylation of 2,4,6-trimethoxypyridine ( 318.2 ) with N -benzylindole-2,3-dicarboxylic anhydride ( 318.1 ) in the presence of titanium(IV) chloride in dichloromethane afforded regioselectively the 3-acylindole-2-carboxylic acid 318.3 , which was transformed to ketone 318.4 by reaction with copper chromite in quinoline. , The ketone 318.4 was transformed to the monomethyl derivative 318.5 by regioselective methyl ether cleavage with 47% hydrobromic acid, treatment with triflic anhydride (Tf 2 O), and subsequent reaction of the corresponding triflate with MeMgBr in the presence of NiCl 2 (dppe) 2 (70% yield over 3 steps) . Regioselective O-demethylation of 318.5 by treatment with boron tribromide followed by reductive removal of the ketone oxygen atom with diborane and subsequent treatment with triflic anhydride (Tf 2 O) afforded the 4-pyridyl triflate 318.6 .…”

“…Debenzylation of 318.8 with 47% hydrobromic acid afforded 3-methoxyolivacine ( 318.9 ). After O-demethylation of 318.9 , the corresponding hydroxy derivative was transformed to the triflate, which on subsequent treatment with ammonium formate in the presence of Pd(PPh 3 ) 4 in hot methanol led to olivacine ( 28.10 ) …”

“…In 2004, Miki et al reported the total synthesis of olivacine (28.10) and ellipticine (28.9) starting from common precursors, N-benzylindole-2,3-dicarboxylic anhydride (318.1) and 2,4,6-trimethoxypyridine (318.2) (Scheme 318). 663,664 Previously, the same group had already reported a synthesis of ellipticine (28.9) starting from the same indole precursor 318.1. 665−667 Friedel−Crafts acylation of 2,4,6trimethoxypyridine (318.2) with N-benzylindole-2,3-dicarboxylic anhydride (318.1) in the presence of titanium(IV) chloride in dichloromethane afforded regioselectively the 3-acylindole-2carboxylic acid 318.3, which was transformed to ketone 318.4 by reaction with copper chromite in quinoline.…”

“…665−667 Friedel−Crafts acylation of 2,4,6trimethoxypyridine (318.2) with N-benzylindole-2,3-dicarboxylic anhydride (318.1) in the presence of titanium(IV) chloride in dichloromethane afforded regioselectively the 3-acylindole-2carboxylic acid 318.3, which was transformed to ketone 318.4 by reaction with copper chromite in quinoline. 663,664 The ketone 318.4 was transformed to the monomethyl derivative 318.5 by regioselective methyl ether cleavage with 47% hydrobromic acid, treatment with triflic anhydride (Tf 2 O), and subsequent reaction of the corresponding triflate with MeMgBr in the presence of NiCl 2 (dppe) 2 (70% yield over 3 steps). 663 Regioselective O-demethylation of 318.5 by treatment with boron tribromide followed by reductive removal of the ketone oxygen atom with diborane and subsequent with (1-ethoxyvinyl)tributyltin (318.7) followed by cyclization of the intermediate ethoxyvinyl derivative with 10% hydrochloric acid afforded 6-benzyl-3-methoxyolivacine (318.8) in 84% yield.…”

“…663,664 The ketone 318.4 was transformed to the monomethyl derivative 318.5 by regioselective methyl ether cleavage with 47% hydrobromic acid, treatment with triflic anhydride (Tf 2 O), and subsequent reaction of the corresponding triflate with MeMgBr in the presence of NiCl 2 (dppe) 2 (70% yield over 3 steps). 663 Regioselective O-demethylation of 318.5 by treatment with boron tribromide followed by reductive removal of the ketone oxygen atom with diborane and subsequent with (1-ethoxyvinyl)tributyltin (318.7) followed by cyclization of the intermediate ethoxyvinyl derivative with 10% hydrochloric acid afforded 6-benzyl-3-methoxyolivacine (318.8) in 84% yield. Debenzylation of 318.8 with 47% hydrobromic acid afforded 3-methoxyolivacine (318.9).…”