Modern Friedel-Crafts chemistry. Part 32. † Facile synthesis of some new fused heteropolycycles via direct intramolecular Friedel-Crafts cyclialkylations of suitable heteroarylalkanols

This study provides expedient methods for the synthesis of some novel fused heteropolycycles. Thus, a variety of fused di-, tri-and tetracyclic nitrogen and nitrogen-sulfur heteropolycycles 8, 9, 11 - 15 were smoothly synthesized by Friedel-Crafts intramolecular alkylations of heteroarylalkanols 1-7 in the presence of both Brönsted (PPA and PTSA) and Lewis (AlCl 3 /CH 3 NO 2 ) acid catalysts. The precursor alkanols were readily prepared by reaction of the corresponding carboxylic acid esters with methylmagnesium iodide. The structures of the compounds are established using both spectral and analytical data. A plausible carbocation mechanism is proposed to account for the results.


Introduction
A variety of methods have been developed for the synthesis of biologically and pharmacologically active heteropolycycles that bear quinoline or tetrahydroquinoline fragments. 1,2Among these methods, intramolecular Friedel-Crafts reactions (called cyclialkylations) 3 prompted by both Brönsted and Lewis acid catalysts proved to introduce powerful pathways for the facile construction of not only homo-but also heteropolycycles. 4,5n this paper, we introduce the construction of seven nitrogen and nitrogen-sulfur polycycles 8, 9, 11-15 containing fused quinoline, tetrahydroquinoline, acridine, phenothiazine and indole moieties via Friedel-Crafts cyclialkylations of seven new heteroarylalkanols 1-7 (Scheme 1).
† For preceding paper of the series see ref 19

Synthesis and cyclialkylation of 4-(acridin-9-yl)-2-methylbutan-2-ol (2)
The title alcohol was synthesized by addition of methymagnesium iodide to methyl 3-(acridin-9yl)propanoate. 7 Cyclialkylation of carbinol 2 was carried out using PPA and AlCl3/CH3NO2 catalysts in methylene chloride solvent.The product from PPA was shown to be pure  This alcohol was obtained in a series of two consecutive steps starting with 3-(1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoic acid. 9This acid was converted to its ethyl ester followed by addition of two equivalents of methylmagnesium iodide.Cyclialkylation of carbinol 4 was carried out in the presence of PPA, H3PO4 and PTSA catalysts.The products of reactions with all three catalysts were identical and were shown to be

Conclusions
In conclusion, we have developed a facile and efficient approach to synthesize seven new heteropolycycles 8, 9, 11-15 via intramolecular Friedel-Crafts cyclialkylations of seven new heteroarylalkanols 1-7.All together, the results of this study proved that Friedel-Crafts cyclialkylation can be considered as one of the most useful pathways to the synthesis of di-, triand higher condensed polycycles enclosing one or more heteroatoms.

Experimental Section
General.Melting points were measured on a digital Gallenkamp capillary melting point apparatus and are uncorrected.Infrared spectra were determined with a Shimadzu 470 Infrared spectrophotometer using KBr wafer and thin film techniques ( cm -1 ).

2-Methyl-1-(2-phenylquinolin-4-yl)propan-2-ol (5)
was obtained in a series of five consecutive steps starting with (2-phenylquinolin-4-yl)methanol. 10 A summary of the steps and of the involved product intermediates is given in the following: (i) Following standard literature procedure and reactant ratios, 14 a solution of thionyl chloride in dry benzene was added dropwise to an ice cooled stirred solution of (2-phenylquinolin-4yl)methanol in dry benzene over a period of five minutes.The reaction mixture was left to stir for ten more minutes, treated with aqueous ammonia until alkaline then the precipitated hydrochloride was decomposed by water to give (88%) of a crude solid product.(iii) Hydrolysis of (2-phenylquinolin-4-yl)acetonitrile to (2-phenylquinolin-4-yl)acetic acid was carried out by refluxing with ethanolic sodium hydroxide solution according to the literature procedure 13 to give (91%) of crude solid product.Crystallization from aqueous ethanol gave (81%) of pure (

Table 1 .
1jk]carbazole 8 as sole product.The results are presented in Scheme 2 and Table 1 (Entries 1 and 2).Cyclialkyltion conditions and results of heteroarylalkanols 1-7  ARKAT USA, Inc.
1H NMR spectra were recorded by 90 MHz Varian NMR spectrometer using the appropriate deuteriated solvent with TMS as internal standard.Chemical shifts (δ) and J values are reported in ppm and Hz, respectively.Elemental analyses were performed on a Perkin-Elmer 2400 Series II analyzer.The mass spectra were performed by JEOL JMS 600 spectrometer at an ionizing potential of 70 eV using the direct inlet system.Reactions were monitored by thin layer chromatography (TLC) using precoated silica plates (Kieselgel 60, F 254, E. Merck) visualized with UV light.
Flash column chromatography (FC) was performed on silica gel (230-400 mesh, E. Merck).All reagents were purchased from Merck, Sigma or Aldrich Chemical Co. and were used without further purification. ARKAT USA, Inc.