A new approach to the synthesis of ellipticines

Abstract

1,4-Dimethylcarbazole-3-carbaldehyde (2a) was condensed with aminoacetaldehyde diethyl acetal, and the Schiff's base was hydrogenated before conversion into the N-tosyl derivative (3a). The latter was cyclised in boiling dilute hydrochloric acid in dioxan to ellipticine [5,11-dimethyl-6H-pyrido[4,3-b]carbazole)(1a)(87%). N-Tosyl-3,4-dihydroellipticine (4) was shown to be an intermediate. Under the same conditions, m-methoxyanilinoacetaldehyde diethyl acetal (6a) gave a low yield (5%) of 6-methoxyindole, but its N-methyl derivative (6b) gave 4- and 6-methoxy-N-methylindoles in 11 and 32% yields, respectively.

Condensation of 6- methoxy-1-methylindole with hexane-2,5-dione in ethanol containing toluene-p-sulphonic acid gave 7-methoxy-1,4,9-trimethylcarbazole (9a)(58%) and 1,2,3,4-tetrahydro-7-methoxy-1,4-bis-(6-methoxy-1-methylindol-3-yl)-1,4,9-trimethylcarbazole (10), which on heating with toluene-p-sulphonic acid in boiling chloroform gave the carbazole (9a). Treatment of the latter (9a) with pyridinium bromide perbromide gave 6-bromo-7-methoxy-1,4,9-trimethylcarbazole (9b). Formylation of (9b) with N-methylformanilide and phosphoryl chloride gave a complex mixture of N-methylcarbazoles resulting in part from ipso-attack of the Vilsmeier etectrophile at C-6.

2,5-Dimethyl-4-acetamidobenzaldehyde (13) was condensed with aminoacetaldehyde diethyl acetal, and the-Schiff's base (14) formed was hydrogenated to 4′-(2,2-diethoxyethylaminomethyl)-2′,5′-dimethylacetanilide (15a). The N-tosyl derivative (15b) on boiling with dilute hydrochloric acid in dioxan gave only the corresponding aldehyde (16), but coupling of (15b) with p-bromoanisole under Goldberg conditions gave 4′-[N-(2,2-diethoxyethyl)tosylaminomethyl]-N-(4-methoxyphenyl)-2′,5′-dimethylacetanilide (17a)(75%). Similarly, (15b) coupled with m-bromoanisole gave 4′-[N-(2,2-diethoxyethyl)tosylaminomethyl]-N-(3-methoxyphenyl)-2′,5′-dimethylacetanilide (17b)(66%). Goldberg coupling of p-bromoanisole and 2,5-dimethylacetanilide gave N-(4-methoxyphenyl)-2′,5′-dimethylacetanilide (18a), which on irradiation afforded 4-acetyl-N-(4-methoxyphenyl)-2,5-dimethylaniline (18b), 2-acetyl-N-(2,5-dimethylphenyl)-4-methoxyaniline (18c), and 6-methoxy-1,4-dimethylcarbazole (2b).