Manganese dioxide mediated one-pot synthesis of methyl 9H-pyrido[3,4-b]indole-1-carboxylate: Concise synthesis of alangiobussinine

The carboline ring system is an important pharmacophore found in a number of biologically important targets. Development of synthetic routes for the preparation of these compounds is important in order to prepare a range of analogues containing the carboline heterocyclic moiety. A manganese dioxide mediated one-pot method starting with an activated alcohol and consisting of alcohol oxidation, Pictet–Spengler cyclisation, and oxidative aromatisation, offers a convenient process that allows access to β-carbolines. This one-pot process for the preparation of methyl 9H-pyrido[3,4-b]indole-1-carboxylate has subsequently been used as the key step in the synthesis of alangiobussinine and a closely related analogue.

S2 toluene (65 mL) for 3 hours. The mixture was then heated under reflux overnight. The mixture was cooled and the solids were removed by filtration through Celite ® and washed with ethyl acetate (100 mL). The solvent was removed and the residue was purified by flash chromatography eluting with 5% methanol in dichloromethane to give β-carboline 6 (620 mg, 44%) as cream-coloured powder.

Table 1, entry b
Methyl glycolate (232 μL, 3 mmol) was added to a suspension of tryptamine (321 mg, 2 mmol), MnO 2 (1.7 g, 20 mmol) and 4 Å molecular sieves (2 g) in dichloromethane (20 mL). The mixture was stirred at room temperature for 3 hours under nitrogen. The mixture was then heated under reflux overnight. The mixture was cooled and the solids were removed by filtration through Celite ® and washed with ethyl acetate (30 mL). The filtrates were concentrated in vacuo and dried. The 1 H NMR of the crude mixture did not show any product.

Table 1, entry d
Tryptamine (1 g, 6.24 mmol), methyl glycolate (0.72 mL, 9.36 mmol) and 4 Å molecular sieves (6.24 g) and MnO 2 (8.14 g, 93.6 mmol) were stirred at room temperature in THF (65 mL) for 3 hours. The mixture was then heated under reflux overnight. The mixture was cooled and the solids were removed by filtration through Celite ® and washed with ethyl acetate (100 mL). The solvent was removed and the residue purified by flash chromatography eluting with 5% methanol in dichloromethane to give β-carboline 6 (633 mg, 45%).
The mixture was stirred at room temperature for 3 hours under nitrogen. The mixture was then heated under reflux overnight. The mixture was cooled and the solids were removed by filtration through Celite ® and washed with ethyl acetate (30 mL). The filtrates were concentrated in vacuo and dry loaded to a 10 g Biotage SP4 cartridge for chromatographic purification (solvent system: Hexane/ethyl acetate, gradient: 0% 4CV; 0-30% 10CV; 30% 6CV) to give β-carboline 6 (230 mg, 51%).
The mixture was stirred at room temperature for 3 hours under nitrogen. The mixture was then subjected to microwave irradiation at 170 °C for 10 minutes. The mixture was cooled and the solids were removed by filtration through Celite ® and washed with ethyl acetate (30 mL). The filtrates were concentrated in vacuo and dry loaded to a 10 g Biotage SP4 cartridge for chromatographic purification (solvent system: Hexane/ethyl acetate, gradient: 0% 4CV; 0-30% 10CV; 30% 6CV) to give βcarboline 6 (148 mg, 33%).

Table 1, entry h
Methyl glycolate (232 μL, 3 mmol) was added to a suspension of tryptamine (320 mg, 2 mmol), MnO 2 (1.7 g, 20 mmol), the 4 Å molecular sieves (2 g) and ZnCl 2 (273 mg, 2 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at room temperature for 3 hours under nitrogen. The mixture was then heated under reflux overnight. The mixture was cooled and the solids were removed by filtration through Celite ® and washed with ethyl acetate (30 mL). The filtrates were concentrated in vacuo. The NMR of the crude mixture did not show any product.

carboxamide (7)
Method A DMF (0.43 μL, 5.5 nmol) was added to a stirred suspension of lithium 9H-pyrido[3,4b]indole-1-carboxylate (120 mg, 0.55 mmol) and oxalyl chloride (0.24 mL, 349 mg, 2.75 mmol) in dry dichloromethane (10 mL). The mixture was refluxed for 6 hours (TLC of sample after addition to methanol showed total conversion to methyl ester; acid chloride hydrolyses on TLC to acid). Toluene (10 mL) was added and all the volatiles were distilled off in vacuo, yielding the acid chloride as an orange powder, which was immediately used in the next step without further purification. The residue was suspended in dry MeCN (20 mL) and added by syringe to a stirred suspension of S6 tryptamine (240 mg, 1.49 mmol) and dry Et 3 N (0.31 mL, 227 mg, 2.24 mmol) in dry MeCN (10 mL) at 0 °C. The reaction was stirred at room temperature overnight, subsequently concentrated in vacuo and the residue was triturated with H 2 O (1 mL) (10 g Biotage SP4 cartridge solvent system: MeOH/CH 2 Cl 2 , gradient: 0% 6CV; 0-10% 12CV) to yield the desired compound 7 (131 mg, 67%) as a cream-coloured powder.
Concentration in vacuo of fractions containing the product yielded an orange gum which was subsequently triturated with methanol (0.2 mL) and diethyl ether (1 mL) to yield compound 10 (152 mg, 60%) as a yellow solid.