Syntheses, Substitution and Cyclization Reactions of 7a,8,9,10,11,11a-Hexahydro-pyrido[3,2,1-jk]carbazoles With a Strychnos Alkaloids Partial Structure

4a-Methyl-2,3,3,4a-tetrahydro-1 H-carbazole ( 3), obtained from phenylhydrazinium chloride and 2-methylcyclohexanone, was regioselectively reduced with sodium borohydride to 4amethyl-2,3,4,4a,9a-hexahydro-1 H-carbazole (4). Cyclocondensation of 4 with 2 molecules of diethyl malonate 5a gives 7-hydroxy-13a-methyl-9a,10,11,12,13,13a-hexah ydro-5H,8H-pyrano[2',3':4,5] pyrido[3,2,1-jk]carbazole-5,8-dione ( 6), which affords in a 2-step degradation 5-unsubsti tuted 4-hydroxy-11a-methyl-7a,8,9,10,11,11a-hexahydro-6 H-pyrido[3,2,1-jk]carbazol-6-one ( 9). Nitration forms the 5-nitro compound, which cyclized after chlorination a d azidation at position 4 on thermolysis to the furoxane 15. Cyclocondensation of 4 with phenylmalonate 5b forms 4-hydroxy-11amethyl-5-phenyl-7a,8,9,10,11,11a-hexahydro-6 H-pyrido[3,2,1-jk]carbazol-6-one ( 16a), which cyclized after chlorination and azidation at position 4 on t hermolysis to the indole derivative 19.


Introduction
Hexahydropyrido[3,2,1-jk]carbazol-6-one (blue structure part in A) is part of the heterocyclic skeleton of many natural products (e.g.Strychnos alkaloids A such as strychninolones and derivatives [2, 3a]).It possesses the biological interesting combination of the well-known indole structure [4] and the 4-hydroxy-2-pyridone structure, which can be found in many natural products (e.g.Flavipucin [5] with antibiotic activity).
Our synthetic approach to the hexahydropyridocarbazole system E started with the synthesis of 2,3,4,4a-tetrahydro-1H-carbazole (3) obtained from phenylhydrazine hydrochloride (1) and 2-methylcyclohexanone (2), which are brought to reaction directly in glacial acetic acid as soft acid and as solvent without releasing the free phenylhydrazine bases.The work-up includes the extraction of 3 with diethyl ether from the alkaline isomer mixture to isolate the crude so-called "basic product" as oil [9][10][11][12][13][14][15], which crystallizes on addition of hexane (Scheme 2).In the 1 H nmr spectra of 3 the 4a-methyl group shows a signal at 1.30 ppm.
The regioselective reduction of the enamine double bond in tetrahydrocarbazole 3 can be achieved with sodium borohydride to give 4a-methyl-2,3,4,4a,9,9a-hexahydro-1H-carbazole (4) as a mixture of two diastereomeric compounds [16].The spectral data show that in the isolated product mainly the cis isomer is present, and in less than 3% the trans isomer.This mixture was used for further reactions without separation.Hexahydrocarbazole 4 behaves in the following cyclocondensation reactions with malonates 5 like a N-substituted aniline [17].Cyclocondensation of 4 with excess diethyl malonate 5a in boiling diphenyl ether as solvent is directed after primary N-acylation in the first step to the aromatic ring.The thermally produced intermediate ketene derivative attacks the adjacent aromatic ring position.In the second step a further malonate molecule produces primarily with the intermediate 4-hydroxy-pyridocarbazolone an ester, and then the second thermal induced cyclization takes place directed to the enolized carbon of the 1,3-dicarbonyl moiety in the pyridone ring.This bis-condensation gives in good yields 7-hydroxy-13a-methyl-9a,10,11,12,13,13a-hexahydro-5H,8H-pyrano[2',3':4,5]pyrido[3,2,1-jk] carbazole-5,8-dione (6).The formed pyridocarbazole ring system of 6 has the correct hydrogenation degree as e.g.visible in strychnos alkaloids (formula A, Scheme 1), however the carbazole rings are arranged in the reverse sequence (see formula E, Scheme 1).
The reaction enthalpy in the formation of 15 is ∆H = -125 J/g, which is a rather high value, and must be taken into consideration when larger batches are thermolyzed.The structure of 15 is supported by IR data, which show that the azide signal of 14 at 2115 cm -1 is missing.The thermal cyclocondensation of hexahydrocarbazole 4 with diethyl phenylmalonate (5b) and diethyl benzylmalonate (5c) in boiling diphenylether as the solvent gives via reactive ketene intermediates [17] 4-hydroxy-hexahydropyridocarbazolones 16a,b.The spectral analyses show that the ring closure was again directed to the aromatic ring, visible by the lack of the fourth aromatic proton from the carbazole part.In this way, 4-hydroxy-5-substituted-7a,8,9,10,11,11a-hexahydro-6H-pyrido[3,2,1-jk] carbazol-6-ones 16a,b have been obtained in good yields (Scheme 6).
The DSC diagram of 4-azido-hexahydropyridocarbazolone 18 shows a cyclization range with 241.2°C onset and 241.8°C peak maximum, which allows to use dimethylformamide at reflux temperature as the suitable cyclization solvent.The reaction enthalpy in the formation of 19 is ∆H = -15.1 J/g which is rather low.At 246.3°C a melting point of the azide 18 is observed, which is identical with the melting

Conclusion
This investigation shows that the reduction of tetrahydrocarbazole 3 with sodium borohydride leads in good yields to hexahydrocarbazole 4. Cyclocondensation of 4 with diethyl malonate (5a) results in the formation of hexahydropyrano-pyridocarbazoledione 6 which was ring-opened to 5-acetyl derivatives 7 and 8. Thermal cyclization of the azide 18 was investigated by differential scanning calorimetry (DSC) and allowed the synthesis of hexahydro-indolo-pyridocarbazolone 19 under suitable conditions obtained from DSC data.

4 -
Hydroxy-hexahydropyridocarbazolone 9 with an reactive unsubstituted position 5 at the enolized dicarbonyl moiety can serve for the synthetic approach to electrophilic substitutions.Its synthesis includes a 2-step degradation of pyrano-hexahydropyridocarbazoledione 6 and follows a well established route which we have applied in a series of heterocycles containing the structural element of 4-hydroxypyridone[18].Best results in the ring opening are obtained when 6 is reacted with potassium hydroxide with glycol as the solvent because of a higher reaction temperature and short reaction time.