Imidoyl isothiocyanates in the synthesis of condensed heterocycles : preparation of some substituted benzotriazocines

By modification of the known literature procedures, the key intermediate product – Nphenyl(phenylimino)methylchloromethanimidoyl chloride 3 was prepared. Nucleophilic substitution reactions of the prepared imidoyl chloride with various secondary amines gave the corresponding intermediates, very useful for the syntheses of corresponding imidoyl isothiocyanates 5a-e. The subsequent cyclization reaction of these isothiocyanates afforded novel substituted 1,3,5-benzotriazocine derivatives 6a-e .


Introduction
As homologues of quinazoline, heterocyclic compounds such as 1,4-benzodiazepines and 1,5benzodiazocines, can be expected to display a number of similar properties.The presence of a larger heterocyclic ring engenders changes in the spatial arrangement and hence also the manifestation of different properties.The best way to visualize these differences is to compare the respective bioactivities.While quinazolines have been known to possess a wide scope of pharmacological properties in addition to being phyto-effective, benzodiazepines and benzodiazocines are better known as central nervous system agents.
These findings have stimulated our efforts to synthesize novel bioactive benzodiazocines.
The synthetic approach to the majority of benzodiazocines, azepines and azocines starts from anilines carrying a carbonyl group in the 2 position.Such a bifunctional substrate can serve as starting material for building up further rings, utilizing the available amino-or carbonyl group, and leading ultimately to fused 6-, 7-, or 8-membered rings.
For the preparation of 8-membered benzoannelated steps we selected the easily available [(4chlorophenyl)(phenylimino)methyl]carbonimidic dichloride 3, a starting material prone to further nucleophilic substitutions, and suitable for preparation of target heterocyclic rings.Radical chlorination of the N-formyl-N´-phenylbenzenecarboximidamide 2 afforded the key intermediate -[(4-chlorophenyl)(phenylimino)methyl]carbonimidic dichloride 3. The chlorination was carried out as a one-pot process, using sulfuryl chloride dissolved in thionyl chloride.In addition to serving as solvent, thionyl chloride had also a dehydrating effect.Under the above reaction conditions however, radical chlorination took not only place at the expected formamide carbon, but at one aromatic ring as well.Our observation and the structure of the isolated product was confirmed by 13 C and 1 H NMR spectra.Since the target dichloride 3 decomposes rapidly, it appeared more convenient for synthetic purposes to use it directly without purification.The quality of the crude product proved sufficient for the subsequent reaction.Numerous reactions of carboimidoyl dichlorides with nucleophiles, such as secondary amines, alcoholates, phenolates and thiols 5 , have been published.Using the propensity of carboimidoyl dichlorides to nucleophilic substitutions, we modified [(4chlorophenyl)(phenylimino)methyl]carbonimidic dichloride 3 by reactions with various secondary amines to the corresponding N-[(4-chlorophenyl)(phenylimino)methyl]-R-4-carboximidoyl chlorides 4a-e.The latter are usually prepared in inert solvents (benzene, toluene) in the presence of a base.In our hands the best results were achieved in anhydrous acetone with triethylamine as base.Using anhydrous acetone allowed us to filter off the triethylamine hydrochloride after completion of the reaction and use the acetone solution of substituted carboximidoyl chloride directly in the following reaction with potassium thiocyanate.

Results and Discussion
For analytical measurements the acetone solutions of 4a-e were, after filtering off the triethylamine hydrochloride, concentrated in vacuo and the crude product was purified by crystallization from acetonitrile.The last synthetic step involved a thermal intramolecular cyclization in boiling toluene of the freshly prepared N´´´-[(4-chlorophenyl) (phenylimino)methyl]-R-carboximidoyl isothiocyanates 5a-e.After completion of the reaction, isolation and purification of the product, the desired 2-(4chlorophenyl)-4-R-1,3,5-benzotriazocine-6(5H)-thiones 6a-e were obtained.
In conclusion, we have developed an efficient, mild and spontaneous method for synthesis of the rare 1,3,5-benzotriazocines, and provided further examples of the utility of imidoyl isothiocyanates in organic syntheses of benzazocines and their analogues.

Experimental Section
General Procedures.Melting points were determined using a Kofler hot-stage apparatus and are uncorrected.IR spectra of compounds in KBr pellets were measured with a Philips PV 9800 FTIR apparatus. 1H and 13 C NMR spectra were recorded on a Varian VXR 300 spectrometer in (CD 3 ) 2 SO and tetramethylsilane was used as an internal standard.Preparation on starting N-phenylbenzenecarboximidoyl chloride 1 was reported in Ref 6 .

General procedure for the preparation of N-[(Z)-(4-chlorophenyl)(phenylimino)methyl]-Rcarboximidoyl chloride 4a-e
To the solution of [(4-chlorophenyl)(phenylimino) methyl]carbonimidic dichloride 3 (2 g, 0.0055 mol) in dry acetone (10 mL) the equimolar amount of triethylamine (0.78 mL, 0.0055 mol) was added.The solution was cooled to 0°C, and the secondary amine (0.0055 mol) was added dropwise.The reaction mixture was stirred at room temperature for 2 h.The precipitated triethylamine hydrochloride was filtered off, the solvent was removed by distillation and the crude product was crystallized from acetonitrile.

General procedure for the preparation of N´´´-[(4-chlorophenyl)(phenylimino)methyl]-Rcarboximidoyl isothiocyanates 5a-e
To the acetone solution of the corresponding carboximidoyl chloride (0.0055 mol) cooled to -10°C, potassium thiocyanate (0.5 g, 0.0055 mol) in dry acetone (10 mL) was added dropwise.The reaction mixture was stirred at 0°C for 1 h.Precipitated KCl was filtered off, the solvent was removed under vacuum and the crude product was used in the next reaction without purification.