Friedel-Crafts chemistry. Part 40. An expedient novel synthesis of some dibenz-azepines, -azocines, 11 H -benzo[ f ]pyrido[2,3-b ]azepines and 6 H -benzo[ g ]pyrido[2,3-c ]azocines

A new synthetic approach for the synthesis of novel 5 H -dibenz[ b,f ]azepine, 5 H -dibenz[ b,f ]- azocine, 11 H -benzo[ f ]pyrido[2,3-b ]azepine and 6 H -benzo[ g ]pyrido[2,3-c ]azocine derivatives is reported. The key step of this methodology is based on Friedel-Crafts ring closure of nitrogen containing carboxylic acids and alkanols in the presence of AlCl 3 , P 2 O 5 or PPA catalysts in overall high yields. The starting carboxylic acids were prepared via an unequivocal synthetic pathway by the basic hydrolysis of trimethyloxindole followed by N -arylation reactions.

More recently Cho et al. 31 in an alternative strategy reported that treating of cyclic ketoximes fused to aromatic rings with diisobutylaluminum hydride (DIBALH) resulted in reductive ring-expansion reaction leading to a variety of five-to eight-membered bicyclic heterocycles.Majumdar et al. 32 synthesized several coumarin, pyrimidine and quinoline annulated-benzazocine derivatives from substituted allylamines via sequential aza-Claisen rearrangement and intramolecular Heck reactions.
Owing to the remarkable biological activities of dibenzfusedazepines and azocines there has been increasing interest in the development of easy, economic and efficient construction strategies of this class of heterocycles.
In order to obtain the tricyclic amines 12a-d, however, the best results obtained by the cycliacylation of the corresponding 2-[2-(N-aryl-N-tosylamino)-3-methylphenyl]-2-methylpropanoic acids (10a-d).Thus, the tosylated esters 8a-d were hydrolyzed with KOH in methanol furnished acids 10a-d.Ring closures of the latter tosylated acids to dibenzazepinones and dibenzazocinones 11a-d carried out in presence of AlCl3, P2O5 or PPA [36][37][38][39] followed by Wolff Kishner reduction 47 of the resulting ketones to give 12a-d in a high yields.The conditions and results for the cyclialkylation of alkanols 9a-d and acids 10a-d are depicted in Table 1 and Schemes 2 and 3.The structures of all new alcohols were appropriately established by both elemental and spectral analyses.
On the other hand, cyclialkylations of alcohols 9a-d to substituted azepines and azocines 12e-h were carried out in the presence of the same catalysts under varying conditions.A plausible mechanism accounted for the results is realized on the generation of tertiary carbocation by loss of water upon treatment of such alcohols with acidic catalysts.The resulting carbocation underwent ring closure to pentamethyl-substituted dibenzazepines and azocines (12e-h) in overall high reaction yields.The removal of the tosyl group occurred concurrently with the closure step as noted in other reported cases. 48In almost all cases, yields were over 80%.

Conclusions
In conclusion, the results presented here provide a novel, very attractive route to unknown tricyclic azepines and azocines were made accessible in excellent yields by short and convenient synthetic pathways.This reaction will be applicable to the synthesis of various organic compounds of medicinal interest.The simplicity of the processes, moderate cost and the results of this study proved that the development of Friedel-Crafts cyclialkylations in heterocyclic chemistry can be considered as one of the most useful pathways to the synthesis of such heteropolycycles.

Experimental Section
General.All reagents were purchased from Merck, Sigma or Aldrich Chemical Co. and were used without further purification.Melting points were measured on a digital Gallenkamp capillary melting point apparatus and are uncorrected.The IR spectra were determined with a Shimadzu 470 Infrared spectrophotometer using KBr wafer and thin film techniques ( cm -1 ).The 1 H NMR and 13 C NMR spectra were recorded on JEOL LA 400 MHz FT-NMR (400 MHz for 1 H, 100 MHz for 13 C) and on a Varian NMR (90 MHz) spectrometers using CDCl3 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 visualized with UV light.Flash column chromatography was performed on silica gel and basic alumina.

Synthesis of 2-(2-amino-3-methylphenyl)-2-methylpropanoic acid (5).
This acid was obtained in a series of three consecutive steps starting with commercial available o-toluidine.A summary of the steps and of the involved product intermediates is given in the following: (i) To an ice-cold stirred mixture of o-toluidine 1 (3.2 g, 30 mmol), anhydrous K2CO3 (12.5 g, 90 mmol) in dioxane (35 mL) was added a solution of 2-bromo-2-methylpropanoyl bromide 2 (7.6 g, 33 mmol) in dioxane (15 mL) over a period of 30 min.The reaction mixture was left to stir for 2 hr at room temperature and then heated in a steam bath at 80-90 C for additional 1 h.Afterwards, the reaction mixture was treated as in standard procedure to give (7.2 g, 94 %) of crude oily amide.Purification by flash column chromatography (basic alumina, EtOAc/nhexane, 1/1) gave (6.8 g, 89 %) of pure 2-bromo-2-methyl-N-o-tolylpropanamide (3) in the form of pale yellow oil; (ii) A mixture of amide 3 (6.4g, 25 mmol) and anhydrous AlCl3 (6.6 g, 50 mmol) was stirred for 1h at room temperature.After the evolution of HCl gas has been ceased, the reaction mixture was heated on a water bath for 1h, cooled to 0 C and quenched with ice-cold HCl solution (30 mL, 10%).Separation of the product following literature standard procedure gave (3.9 g, 89 %) of crude product.Crystallization from ethanol gave (3.6 g, 84 %) of pure (iii) A mixture of the oxindole 4 (3.5 g, 20 mmol) in ethanol (20 mL, 80%) and sodium hydroxide solution (10 N, 3.5 mL) was stirred under reflux for 8 h.The excess alcohol was removed by distillation and the residue was diluted with water (50 mL).The clear solution was cooled to 0 C and adjusted to pH 6-7 with HCl solution (40 mL, 20 %) and then left to stand at refrigerator for overnight.The precipitated acid was collected, washed and dried to give (3.4

Arylation of 2-(2-amino-3-methylphenyl)-2-methylpropanoic acid (6a-d).
A mixture of amino acid 5 (2 g, 10 mmol), K2CO3 (4.1 g, 30 mmol), aryl halide (PhBr or 2-bromopyridine or PhCH2Cl or 2-picolyl chloride) (10 mmol), pyridine (1 mL) and CuI (0.3 g) in anhydrous DMSO (15 mL) was heated with continuous stirring for 10 h at 100-10 C.Once the reaction was cooled, just enough NaOH solution (25 mL, 5%) was added to completely dissolve the product.Decolorizing carbon (5 g) was added and the mixture was boiled for 20 min and filtered by suction.The resulting filtrate was acidified using HCl solution (30 mL, 20%) until the pH 1-2.The resultant yellow precipitate was then filtered and recrystallized from ethanol gave the pure product.The yields and spectral data are given in the following: General procedure for the tosylation of esters 7a-d.To a cold solution of ester (7a, b, c or d) (10 mmol) and pyridine (10 ml) in dichloromethane (30 ml) was added p-toluenesulfonyl chloride (4.7 g, 25 mmol) slowly in small portions over 10 minutes.The reaction mixture was stirred at room temperature for 10 h and then heated for 1h on water bath at 80-90 °C.The reaction mixture was concentrated on water bath to ca. 15 ml, cooled to room temperature, diluted with water (100 mL) and extracted with AcOEt (3 × 30 mL).The combined organic layers were washed with HCl (2 × 30 mL, 5%), with NaHCO3 soln (3 × 30 mL) and finally with water.The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to afford crude residue.Purification of the residue by flash column chromatography (basic alumina, EtOAc/n-hexane, 3/1) provided the corresponding pure tosylated esters 8a-d.The yields and spectral data are given in the following: