Syntheses of 8 , 9 , 10 , 11-Tetrahydro-pyrido [ 3 , 2 , 1-jk ] carbazoles

Pyrido[3,2,1-jk]carbazol-6-one in its partial hydrogenated form is part of the heterocyclic skeleton of many natural products (e. g. strychnos alkaloids such as strychninolones and brucinolones, picrasidin Q and olivacin alkaloids). It possesses the biological interesting combination of an indole structure and of a 2-quinolone; Comparison with strychnos alkaloids shows that it has already four rings and two oxygen functions in the correct position.


General Aspects
Pyrido [3,2,1-jk]carbazol-6-one in its partial hydrogenated form is part of the heterocyclic skeleton of many natural products (e.g. strychnos alkaloids such as strychninolones and brucinolones, picrasidin Q and olivacin alkaloids).It possesses the biological interesting combination of an indole structure and of a 2-quinolone; Comparison with strychnos alkaloids shows that it has already four rings and two oxygen functions in the correct position.[1] .In the literature several syntheses for 2,3,4,9-tetrahydro-1H-carbazoles 1 (sometimes named incorrectly 1,2,3,4-tetrahydrocarbazoles) are described, starting either directly from cyclohexanones and phenylhydrazines, or from similar derivatives and intermediates; also the hydrogenation of carbazoles is described [2].For our purposes, which were directed to the easy and regioselective introduction of electron-pushing and pulling substituents, we started from phenylhydrazine derivatives such as 3-and 4-chlorophenylhydrazine, and cyclohexanone or methylcyclohexanone using the general type of a Fischer-Indole-Synthesis in glacial acetic acid.The yields were dependent on the electron and steric influence of the substituents in the aromatic ring and ranged between 40 and 85%.The cyclization to pyridocarbazoles (3 or 4) was achieved by thermal condensation with diethyl malonates at about 250 °C similar to the reactions investigated in the carbazoles series [3].The direction of the second step of the cyclization proceeded with R 2 = H and methyl to the electron rich and reactive aromatic ring and gave 3 by electrophilic aromatic substitution of the ketene intermediates of malonates as found in a series of similar reactions [4].Now the question raised if the cyclization of electron-deficient tetrahydrocarbazoles with R 1 = chloro gives the same pyridocarbazoles of type 3 starting from tautomers 1, or -if the reaction starts from the second possible carbazole tautomer of type 2 to give (at least as by-product) pyridocarbazoles of type 4. Careful work-up of the reaction mixture, however, gave in all cases only one detectable product of a pyridocarbazole (however, in lower yields), which could be assigned unequivocal to the structure of type 3 by 4a-Methyl-2,3,4,4a-tetrahydro-1H-carbazole 5 was obtained from 2-methylcyclohexanone and phenylhydrazine together with its 1-methyl isomer 6, probably via a rearrangement reaction, adopting known methods [5].Such a rearrangement hypothesis could explain why isomer 2 or its cyclization products 4 are not formed during the reaction from 1 to 3.

Synthesis
Both isomers, 5 and 6, have different properties (neutral and basic), which allows a simple separation e.g. by extraction in basic media.The ratio of both isomers can be influenced by the application of different acids, however the yields werde moderate.The influence of electron-pushing and pulling substituents such as methoxy or chloro was visible, surprisingly shifting to higher yields with the chloro substituent, and to lower yields with the methoxy group.
The cyclocondensation reaction of 5 with malonates at about 250 °C gave in moderate yields the pyridocarbazoles 7 by ring closure reaction at the more reactive enamine double bond (9a,1) at position 1; no cyclization reaction could be observed directed to the aromatic ring which should give pyridocarbazoles such as products 8; there was no influence observed in the ring closure reaction deriving from substituents R 1 .The structural assignment could be performed by 1 H-nmr spectral methods.The regioselective reduction of the enamine double bond in 4a-methyl-2,3,4,4a-tetrahydro-1H-carbazole 5 could be achieved with borohydride to give 4a-methyl-2,3,4,4a,9,9a-hexahydro-1H-carbazole mixture of two diastereomeric compounds visible in the isolated produ mainly the cis-isomer and in less than 5% the trans isomer).This mix separated and used for further reactions.
This ring system has already the correct hydrogenation degree as vis however in the reverse sequence.
Further reactions for functionalization of these pyridocarbazoles lead active compounds.This work is in progress.

Experimental
General procedure for the synthesis of tetrahydro-1H-carbazoles (1,5).To a suspension of anhydrous sodium acetate and the corresponding cyclohexanone in glacial acetic acid, the corresponding phenylhydrazine hydrochloride in glacial acetic acid was added in small portions.The reaction mixture was heated for some hours, then cooled, diluted with water and filtered (for 5, the reaction mixture was made alkaline and then extracted with diethylether and purified by distillation).