Hydrochloric Acid → methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4-(3-hydroxypropyl)-7H-pyrrolo(2,3-d)carbazole-6-carboxylate

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Reaction Conditions

Reaction Steps

To methyl 1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5-carboxylate (5.0 g, 20 mmol) stirring in methanol (25 mL) was added enough methanol saturated with HCl to turn moist universal pH paper red. The methanol was evaporated at reduced pressure and to the residue was added H2O (50 mL) and 2-hydroxytetrahydropyran (2.2 g, 22 mmol) and the mixture was allowed to stir at 20° C. overnight. TLC (SiO2, 7.5% methanol/CH2Cl2,) of the mixture showed the formation of two products which were methyl 1,2,4,6-tetrahydro-11-β(4-hydroxybutyl)-3,10b-methanoazepino (4,5-b)indole-5-carboxylate and methyl 1,2,4,6-tetrahydro-11-α (4-hydroxybutyl)-3,10b-methanoazepino (4,5-b)indole-5-carboxylate (Rf 0.68 and 0.76, CAS, blue). The reaction mixture was basified (NH4OH), 10% (aq) and extracted three times with CH2Cl2. The organic extracts were dried (Na2SO4) and concentrated to a residue, which was immediately dissolved in THF (100 mL). To the THF solution was added benzyl bromide (2.5 mL, 21 mmol) and then the solution was heated to reflux and monitored by TLC until conversion to the mixture of 3-benzyl 1,2,4,6-tetrahydro-11-β(4-hydroxybutyl)-5-methoxycarbonyl-3,10b-methanoazepino (4,5-b)indolium bromide and 3-benzyl-1,2,4,6-tetrahydro-11-α(4'-hydroxybutyl)-5-methoxycarbonyl-3,10b-methanoazepino (4,5-b)indolium bromide (about 2h) was completed. At this point the THF was evaporated and replaced with methanol (100 mL) and diisopropyl ethyl amine (5.3 mL). Reflux was restarted until TLC showed complete disappearance of the above mixture of compounds. The methanol was evaporated and the residue chromatographed (SiO2, 5% methanol/CH2Cl2) to yield 5.7 g (67%) of methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4(3-hydroxy-propyl)-7H-pyrrolo(2,3-d)carbazole-6-carboxylate as a gum;TLC (SiO2, 7.5% methanol/CH2Cl2) Rf 0.86 (CAS, blue).

Provenance & Evidence