Friedel-Crafts chemistry. Part 45: expedient new improved process for the synthesis of oxacarbazepine precursor 10,11-dihydro-10-oxo-5 H -dibenz[ b , f ]azepine via Friedel-Crafts cycliacylations

An unprecedented efficient methodology for the synthesis of 10,11-dihydro-10-oxo-5 H - dibenz[ b,f ]azepine via a three new synthetic pathways is described. The key steps of this approach are based on classical Friedel-Craft ring closures of three precursors 1-(2-( N -phenyl- N - tosylamino)phenyl)-2-bromoethanone, ethyl 2-(2-( N -phenyl- N -tosylamino)phenyl)acetate or 2-(2-( N -phenyl- N -tosylamino)phenyl)acetic acid, by using AlCl 3 /CH 3 NO 2 or AlCl 3 in dichloromethane. For the latter two precursors, P 2 O 5 in toluene worked also well. The precursors were easily obtained in a two-or three -step reaction sequence. Overall, the described approach allows easy and efficient access to the tricyclic dibenzoazepinone ring system from easily accessible starting materials.


Introduction
The synthesis of dibenzo[b,f]azepines has been the focus of interest of many investigations during recent years.They are important synthetic intermediates 1 exhibit interesting biological activities 2 while substituted or reduced dibenzo[b,f]azepine skeletons are the core structures of several natural products 3 and pharmaceuticals 4,5 such as oxcarbazepine, carbamazepine, imipramine, desipramine, clomipramine and trimipramine exhibiting a diverse medical functions as antiviral, antidepressant, antiepileptic, anticonvulasant, antimicrobial, antimalarial and anticancer activities 5 (Fig. 1).Among the related dibenzoazepine derivatives, 10,11-dihydro-10oxo-5H-dibenz[b,f]azepine 3 has a unique nitrogen-containing tricyclic structure which was the precursor in the develop of drug oxcarbazepine 6 (a second-generation of antiepileptic drug) sold under the trade name Trileptal ® .
In spite of the large number of published synthetic routes to iminostilbene 2 and its reduced derivative 1 7 , to date, only a limited number of synthetic strategies have been successfully applied to the preparation of dibenzoazepinone 3.This may be due to unfavorable entropic factors and transannular interactions encountered during the synthesis of medium-sized rings.The most important synthetic strategies leading to dibenzoazepinones are as follows.In 1964 Geigy 9 synthesised compound 3 via the addition of bromine to 5-acety-5H-dibenz[b,f]azepine followed by dehydrohalogenation and hydrolysis of the remaining bromide under basic conditions.This strategy was found to be general, as it provided several derivatives of dibenzoazepinones.Fouche et al. 10 disclosed a convenient one-step regioselective synthesis of dibenzoazepinone 3 derivatives via hydrolysis followed by oxidation of 10methoxydibenz[b,f]azepine.Later, Karusala et al. 11 and Gupta et al. 12 adopted the same strategy for the synthesis of 10-methoxy or 10-haloiminostilbene derivatives which involved sequential N-protection, halogenation and elimination sequence or alternatively by a dehydrohalogenation of a halomethoxyiminodibenzyl intermediate obtained by using 1,3-dihalodimethylhydantoin.By a different approach, Aufderhaar et al. 13 demonstrated a straightforward methodology for the construction of dibenzoazepinone 3 and consequently the synthesis of targeted oxcarbazepine 5 from iminodibenzyl by benzylic oxidation after a suitable N-functionalization. Lohse et al. 14 used a tandem remote metalation and cyclization of 2-carboxamido-2'-methyldiarylamines, prepared by palladium mediated Buchwald-Hartwig coupling of o-bromobenzamides with o-toluidine followed by N-deprotected and carbamoylated to afford oxcarbazepine 5. Other widely used methodologies for the synthesis of oxcarbazepine 5 are, epoxidation of iminostilbene followed by hydrogenation and oxidation reactions, 15 iron-catalyzed reduction and acid hydrolysis of 10nitroiminostilbene or its corresponding oximes respectively, 16 as the key steps in these approaches.Both of theses processes, described in detail in Scheme 1, are industrial procedures for the development of oxcarbazepine 5 at Novartis.Further synthetic approaches to compound 5 involved intramolecular Friedel-Crafts acylation of 2-carboxymethyldiarylamine intermediate to give 10-methoxyiminostilbene which upon carbamoylation and hydrolysis furnished 5. 17 Recently, a palladium-catalyzed sequential Narylations reactions of substituted 2-(2-bromophenyl)-1-(2-(tosylamino)phenyl)ethanone was recently reported. 18This strategy was applied to the synthesis of not only of oxcarbazepine 5 but also of several structural analogs which incorporate arene or heteroarene rings.
In recent communications we have demonstrated a very simple procedure for the synthesis of series of tricyclic keto derivatives of 10,11-dihydro-5H-dibenz[b,f]azepines (iminodibenzyls), 19,20 21 applied to the routine synthesis of difficult heterocyclic skeletons with the advantages of shorter reaction times and higher yields.In view of the above reports and in continuation of our interest in Friedel-Crafts ring closures 22 as expedient alternative synthetic routes of novel and known heterocyclic systems, herein, we report the synthesis of 10,11-dihydro-10-oxo-5Hdibenz[b,f]azepine 3 by three different facile synthetic routes starting with easily prepared precursors.

Results and Discussion
Our approaches to the desired 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine 3 involved three classical synthetic pathways (Scheme 2).Path 1, included the conversion of 1-(2bromophenyl)ethanone 17 23   The IR spectrum of ketone 19 showed the characteristic absorption band for C=O group as at 1683 cm -1 .The 1 H NMR spectrum for compound 19 displayed three signals.The aromatic protons appear at δ 6.84-7.34, the aliphatic acyclic protons of the methyl and methylene groups appear as two singlet at δ 2.47 and δ 4.48 respectively.The IR spectra of acid 25 showed a broad absorption band at 2700-2535 cm -1 for the OH group and a sharp band at 1717 cm -1 for the C=O group.The 1 H NMR data allowed an unambiguous results for the tosyl acid formation.Thus, the 1 H NMR spectrum displayed four signals, aromatic protons appear at δ 6.63-7.71while the aliphatic protons of the two CH 3 and CH 2 groups of the new acid appeared at δ 2.27 and 3.45 respectively.The singlet at δ 10.28 corespounds to the carboxylic acid OH group.
In the final step, cycliacylation of bromoketone 19 ester 24 or aryl acids 25 proceeded smoothly in the presence of AlCl 3 or FeCl 3 or AlCl 3 /CH 3 NO 2 or PPA (polyphosphoric acid) or P 2 O 5 catalysts 29 under different reaction conditions to provide tricyclic ketone 39 in good overall yields (Table 1 and Scheme 2).
From Table 1 it is evident that the cycliacylation of precursors 19, 24 and 25 to product 3 depends on the catalyst, solvent and temperature used.Overall the best results are in the presence of Lewis acid catalysts.For example, treatment of 19 with AlCl 3 /CH 3 NO 2 in DCM for 24 hours at room temperature are the mildest conditions with the highest yield of compound 3.For the cycliacylation of precursor 24 the use of AlCl 3 in DCM under reflux worked equally well (83% yield of 3) when compared to the use of P 2 O 5 in toluene under reflux (84% yield of 3).On one the other hand, cycliacylation of precursor 25 worked by far the best when carried out in the presence of P 2 O 5 in toluene under reflux (89% yield of 3).A plausible acylation mechanism that accounted for the cycliacylation of 24 and 25 is the generation of acyl carbocation 30 , either free or as an ion pair 31 which upon treatment with acidic catalysts losses water or alcohol.However, ring closures of 19 is explained to occur via an alkylation mechanism produce a primary carbocation. 32The resulting acyl carbocation or carbocation then undergoes ring closure to dibenzazepinone 3. The removal of the tosyl group occurs concurrently with the closure step as noted in other reported cases. 33t is noteworthy to comment about utility of Friedel-Crafts cycliacylations in the synthesis of medium-sized azacarbocycles which has received substantial support in the literature. 34These reactions were observed for the synthesis of tetracyclic thiazocines, pyrrolothienodiazocine and benzodiazocines (Fig. 2). 35The Friedel-Crafts reaction has been considered as one of the macrocyclization reactions (including carbocyclizations, macrolactonizations and macrolactamizations) for the synthesis of medium-sized rings characterized by small enthalpic cost and large entropic cost in the transition state but little to no entropic cost in the product cycle. 36Furthermore, elimination of transannular interactions in the synthesis of medium-sized rings comes at the cost of minimized Baeyer and Pitzer strains which in turn could be diminished by applying more strenuous conditions. 37The described approaches are an alternative to those previously reported for the synthesis of the dibenzazepinone ring system and provide the products in good yields with selectivity even during high temperatures and short reaction times.The results proved the significance of applying Friedel-Crafts ring closure reaction conditions for the synthesis of 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 CDCl 3 solvent with TMS as internal standard.Chemical shifts (δ) and J values are reported in ppm and Hz, respectively.The mass spectra were performed by JEOL JMS 600 spectrometer at an ionizing potential of 70 eV using the direct inlet system.Refractive index was measured using an Abbe refractometer at sodium D-line wavelength (589.3 nm) at 25 C ( 25 D n ).Elemental analyses were performed on a Perkin-Elmer 2400 Series II analyzer.Reactions were monitored by thin layer chromatography (TLC) using precoated silica plates visualized with UV light.Flash column chromatography was performed on silica gel or basic alumina.

Path 2. Hydrolysis of 1-phenylindolin-2-one (20).
To a refluxed solution of oxindole 20 (4.2 g, 20 mmol) in ethanol (20 mL, 90%), was slowly added NaOH solution (10 N, 5 mL) and reflux is continued for 6 h.The solution is cooled to about 30 °C and treated slowly with HCl solution (40 mL, 20 %).The obtained suspension is then left to stand at refrigerator for overnight.The crystals are collected by filtration, washed with water and dried giving (4.1 g, 92%) of crude acid.Crystallization from methanol gave (  (22) with aniline A mixture of acid 22 (2.1 g, 10 mmol), aniline (1.8 g, 20 mmol), K 2 CO 3 (3.4g, 25 mmol), pyridine (2 mL) and activated copper powder (0.4 g) was heated with continuous stirring for 8 h at 110-20 C.The resulting slightly brownish mixture was diluted with water (50 mL), filtered while hot and washed with water (40 ml).The filtrate was cooled to room temperature and extracted with hexane (3×20 mL).The aqueous layer was separated and decolorizing carbon (5 g) was added and then the whole mixture was boiled for 10 min then filtered on hot.The clear cold filtrate was acidified using HCl solution (30 mL, 20%) until the pH 1-2.The resultant precipitate was collected, washed with water and dried to give (1.8 g, 83%) of the crude acid.Recrystallization from ethanol gave the pure product that's physical and spectral data are similar to that obtained from path 2.
to 1-(2-(N-phenyl-N-tosylamino)phenyl)-2-bromoethanone 19 via two consecutive steps: (i) N-alkylation of ketone 17 with N-tosylbenzenamine 24 in the presence of K 2 CO 3 in DMF solution to give 1-(2-(N-phenyl-N-tosylamino)phenyl)ethanone (18) and (ii) bromination of the resulting ketone 18 with one equivalent of bromine in CHCl 3 afforded 2bromoketone 19.In the other two reaction paths, 2-(2-(phenylamino)phenyl)acetic acid (21) the key intermediate, obtained via Path 2, encompassed ring opening hydrolysis of 1-phenylindolin-2-one (20) 25 to acid 21 by refluxing with NaOH in ethanol and via Path 3 from the base catalyzed Ullmann 26 N-coupling reaction of 2-(2-bromophenyl)acetic acid (22)27 with aniline in the presence of K 2 CO 3 /Cu in pyridine at 110-20 C.In the next step, the resulting o-anilinoacetic acid 21 was esterified28 in the presence of ethanol and H 2 SO 4 under reflux to furnish ethyl 2-(2-(phenylamino)phenyl)acetate 23.The latter ester was converted to the N-tosylated ester 24 by reaction with tosyl chloride in pyridine which in turn was hydrolyzed with NaOH in methanol to carboxylic acid 25.The structures of all new compounds were appropriately established by both elemental and spectral analyses (IR, 1 H NMR, MS).