A Convenient, TiCl4/SnCl4-Mediated Synthesis of N-Phenyl or N-Aryl Benzamidines and N-Phenylpicolinamidines

A new, TiCl4-or SnCl4-mediated, solvent-free method was developed for the synthesis of N-Aryl benzamidines and N-phenylpicolinamidines, in moderate-to-good yield, using suitable amines and nitriles as starting materials.

In 1998, Zhou and Zhang published the results on such a subject that amidines were successfully prepared from nitriles and nitrocompounds in the presence of TiCl 4 /Sm in THF. They also reported that under same reaction conditions amidine formation was not observed by treatment of nitriles with amines [41]. Thus, it was of interest to study the reactions of nitrile and amine using TiCl 4 and SnCl 4 .

Results and Discussion
We would like to demonstrate in the present work that amidine could be prepared by coupling nitrile with amine in presence of TiCl 4 as well as SnCl 4 using neat condition in absence of samarium. At the beginning we studied the synthesis of amidine (Scheme 1, Table 1, and Entry 1) using benzonitrile and aniline as model substrates. In a typical experiment aniline (0.01 mol) and benzonitrile (0.01 mol) were heated at 100-110 • C with TiCl 4 or SnCl 4 (0.012 mol) for 3-4 hr to complete the reaction. The obtained black reaction mixture was then neutralised with NaOH solution and extracted with dichloromethane. Product was isolated simply by evaporation of the solvent at reduced pressure. The crude product was recrystallized from hexane. The obtained product was characterised by IR, NMR, and mass spectroscopy data and compared with authentic sample. Furthermore, the reaction was carried out for several substituted aryl amines and nitriles (Table 1) under the same conditions. It is distinct that both TiCl 4 and SnCl 4 were found to have a potential utility for the synthesis of amidine with good-tomoderate yields under mentioned reaction conditions. The mechanism we propose for the reaction is similar to the one reported for amidine using AlCl 3 [42] and is outlined in Scheme 2: at first the complex between nitrile and TiCl 4 was formed followed by nucleophilic addition of amine (2) on the more electrophilic carbon of nitriles to yield the amidine (3).
With these results in hand, we tested the scope and limitations of this process; we examined the coupling reaction of various substituted benzonitriles with heteroaromatic amine, that is, 2-aminopyridine, (Scheme 3 and Table 2) by performing the reaction with the well-established reaction conditions.
Similarly, to test the scope and limitations of this process; we examined the coupling reaction of various substituted anilines with heteroaromatic nitrile, that is, 2-cyanopyridine, (Scheme 4 and Table 3) by performing the reaction with the well-established reaction conditions.

Conclusion
In the summary, we have developed a solvent-free method of amidine formation from nitrile and amine using TiCl 4 or SnCl 4 in absence of expensive metal-like samarium. The reaction proceeded at 100-110 • C and was completed within 3-4 hrs. In conclusion the reaction was extremely simple to carry out, and the obtained yield of amidine was good to moderate. On the basis of yield, we may conclude that TiCl 4 is preferable catalyst over SnCl 4 .

Experimental
Melting points were determined by open capillary tube method and are uncorrected. Progress of the reaction was monitored by TLC (visualization was effected by exposure to UV light). Commercial reagents were used without purification for synthesis. Mass spectra were recorded on Thermo Finnigan (model-LCQ Advantage MAX) mass spectrometer. The IR spectra were recorded with KBr pellets on Perkin-Elmer Spectrum One Spectrometer. 1 H NMR spectra were recorded in CDCl 3 on a Bruker 300 DRX Avance instrument at 300 MHz.

Preparation of Amidines, 3a-o.
Benzonitrile (1.03 g, 0.01 mol) was taken in a dry round bottom flask and to this was added a 2-aminopyridine (0.94 g, 0.01 mol). The flask was heated, after fitting a dry condenser along with a guard tube, in an oil bath at a temperature range of 80-90 • C with stirring. After 30 min TiCl 4 (1.3 mL, 0.012 mol) or SnCl 4 (1.4 mL, 0.012 mol) was added to the flask. After addition, temperature was increased to 100-110 • C, and contents of the flask were heated for 3-4 hrs. The mixture was cooled to room temperature, and the solid, thus, formed was dissolved in hot water and made alkaline with 10% NaOH. This solution was extracted with a CH 2 Cl 2 (3 × 100 mL). Then organic layer was decolourized with activated charcoal and dried over anhydrous Na 2 SO 4 . After evaporating the solvent under reduced pressure, crude amidine was obtained. This crude product was recrystallized from hexane to get pure amidine.