Modern Friedel-Crafts chemistry. Part 35. New synthetic approach to substituted indolo[2,1-a ][2]benzazepines and indolo[2,1-a ]isoquinolines via Friedel-Crafts cyclialkylations

Facile procedures for the construction of fused indole-containing heteropolycycles 1a-f and 2a-c have been developed. The methodology involves Friedel-Crafts cyclialkylations of heteoraryl alkanols in the presence of both Brönsted (PPA) and Lewis (AlCl 3 /CH 3 NO 2 ) acid catalysts. The starting alkanols 6a-f and 12a-c were smoothly obtained both by reactions of the corresponding carboxylic acid esters and the corresponding ketones with Grignard reagents. Overall, this approach allows for easy and efficient access to polycyclic indoles from easily synthesized precursors.

The indole scaffold 1 was obtained early by Kozikowski et al. 12,13 from the derived Nalkylindole and 2-bromobenzyl bromide in the presence of Pd(PPh3)4.Lee and co-workers 14,15 reported the synthesis of benzazepinoindoles via intramolecular Heck type reaction by applying intramolecular palladium-catalyzed arylation of indole-containing Baylis-Hillman adducts. 16rito et al. 17 reported the formation of alkaloids of berberine and dibenzopyrrocoline series via the palladium-catalyzed coupling of amide derived from o-halobenzylisoquinolines. On the other hand, Sharma et al. 18 reported interesting examples for the synthesis of benzazepinoindoles through the 7-endo trig Pictet-Spengler cyclization with various carbonyl compounds. 19ther strategies have been successfully applied in the synthesis of polyindoles.That included benzyne reactions 20 , oxidative couplings of 1-benzylisoquinoline 21 , enamine photocyclization 22 , silicon mediated ring closure of benzyl anion 23 , radical cyclization 24 and palladium-catalyzed couplings. 25aust et al. 5 failed to prepare the tetracyclic amine indoloisoquinoline (2) by the methodology of Kozikowski.However, they succeeded to obtain 2 via consecutive six-step reactions starting from 3-formylindoles in low overall yields.Other synthetic methodologies have been developed to generate these compounds by stepwise introduction or construction of the pyrrole and benzene rings. 26he development of new direct, concise and economical routes to this class of compound is currently a popular research area for both medicinal and synthetic organic chemists. 27,28In this paper, we applied our experience in Friedel-Crafts cyclialkylations [29][30][31][32][33][34][35][36] to offer unequivocal syntheses for both substituted 7,8-dihydro-6H-indolo[2,1-a][2]benzazepine (1) and 6,7-dihydroindolo[2,1-a]isoquinoline (2) via intramolecular ring closures of some synthesized heteroaryl alkanols.

Conclusions
We have developed new, simple and facile synthetic pathways for the construction of different indole-based substituted heteropolycycles via Friedel-Crafts cyclialkylation of heteroarylalkanols (6a-f and 12a-c) catalyzed by AlCl3/CH3NO2 and PPA.To the best of our knowledge, this is the first time that such novel substituted tetracycles (1a-f and 2a-c) have been described.The results show Friedel-Crafts cyclialkylations to be useful pathways to the syntheses of heteropolycycles.

Synthesis of heteroaryl ketones 9a,b. General procedure
To an ice-cold Grignard reagent obtained as usual 40 from Mg turnings (0.24 g, 10 mmol), alkyl or aryl halide (10 mmol) in ether (30 mL) was added with stirring a solution of nitrile 8 (2 g, 8 mmol) in benzene (30 mL) over 10 min.After complete addition, the solution was refluxed for 10 hr then it was poured with srirring into ice-cold hydrochloric acid (100 mL, 30%).The organic solvent was evaporated and the mixture was concentrated.The resulted mixture was then hydrolyzed by refluxing with a mixture of (benzene, 20 mL and HCl, 10 mL) for 10 h.The solution was cold and benzene layer was separated, while the aqueous layer was basified by vertually addition of solid Na 2 CO 3 with stirring and then extracted with benzene (230 mL).The combined benzene extracts were washed with water, dried over anhydrous Na2SO4 and the solvent was removed to afford the crude ketones 9a,b which were purified by crystallization.The spectral data of the ketones 9a,b are given below.(11)  To a stirred mixture of compound 3 (4.1g,20 mmol), anhydrous K2CO3 (1.6 g, 12 mmol) and a catalytic amount of potassium iodide (0.2 g) in dry acetone (30 mL) was added dropwise a solution of bromoacetone 10 (3.8g, 28 mmol) in dry acetone (20 mL) at reflux temperature.Reflux was continued for 10 h.The reaction mixture was concentrated to dryness and then transferred to ice water (100 mL).The separated solid was collected by filtration and crystallized from acetone to yield ketone 11 (

Cyclialkylation procedures
The procedures described earlier for cyclialkylation of arylalkanols with AlCl3/CH3NO2 30 and PPA 31 were essentially followed.Purification of the crude isolated products with flash column chromatography (basic alumina, EtOAc/n-hexane, 1/1) gave the pure product.The conditions and yields for the products 1a-f and 2a-c are shown in Tables 2 and 3 while the physical constants and spectral data of the products are given below.

Table 1 .
Optimum conditions for the synthesis of heteroarylalkanols 6a

Table 2 .
Cyclialkylation conditions and results of heteroarylalkanols

Table 3 .
Cyclialkylation conditions and results of heteroarylalkanols 12a-c