A new, TiCl4-or SnCl4-mediated, solvent-free method was developed for the synthesis of
The amidine nucleus is found in a wide variety of biologically active molecules [
Amidines were used as important synthon in organic synthesis in the preparation of various heterocyclic compounds, such as pyridine [
Several synthetic strategies have been developed for the synthesis of amidines, in which the nucleophilic addition of amine to nitrile is the most popular. Generally, nitriles were activated to the intermediate salt in the presence of EtOH/HCl [
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 TiCl4/Sm in THF. They also reported that under same reaction conditions amidine formation was not observed by treatment of nitriles with amines [
We would like to demonstrate in the present work that amidine could be prepared by coupling nitrile with amine in presence of TiCl4 as well as SnCl4 using neat condition in absence of samarium. At the beginning we studied the synthesis of amidine (Scheme
SnCl4/TiCl4 catalysed coupling of substituted anilines with benzonitrile.
Entry no. | Amines | Amidinesa (isolated yield %) | M.P. °C (Lit.) | |
---|---|---|---|---|
by TiCl4 | by SnCl4 | |||
|
Aniline | 75 | 71 | 114–116 (116) |
|
2-Cl-Aniline | 65 | 67 | 108–110 |
|
4-F-Aniline | 64 | 63 | 86–88 |
aAll products were characterised by IR, NMR, and mass spectral data and in comparison with authentic samples.
The mechanism we propose for the reaction is similar to the one reported for amidine using AlCl3 [
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
SnCl4/TiCl4 catalysed coupling of 2-aminopyridine with substituted benzonitriles.
Entry no. | Amines | Nitriles | Amidinesa (isolated yield %) | M.P.°C (Lit.) | ||
---|---|---|---|---|---|---|
R | X | R′ | by TiCl4 | by SnCl4 | ||
|
H | N | H | 72 | 61 | 96 (97-98) |
|
H | N | 3-Cl | 63 | 68 | 114–116 |
|
H | N | 4-Cl | 69 | 63 | 162–164 |
|
H | N | 4-Br | 73 | 66 | 152–154 |
|
4-Br | N | H | 67 | 63 | 102–104 |
aAll products were characterised by IR, NMR, and mass spectral data and in comparison with authentic samples.
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
SnCl4/TiCl4 catalysed coupling of substituted anilines with 2-cyanopyridine.
Entry no. | Amines | Amidinesa (isolated yield %) | M.P. °C (Lit.) | |
---|---|---|---|---|
R | by TiCl4 | by SnCl4 | ||
|
H | 79 | 68 | 78–80 HCl Salt |
|
2-CH3 | 59 | 64 | 68–70 (68-69) |
|
4-CH3 | 64 | 61 | 54 (52-53) |
|
4-F | 78 | 69 | 72 (75-76) |
|
4-Cl | 66 | 60 | 80–82 (80–82) |
|
4-Br | 81 | 65 | 84–86 (85-86) |
|
3,4-Cl | 76 | 69 | 112 (112-113) |
aAll products were characterised by IR, NMR, and mass spectral data and in comparison with authentic samples.
In the summary, we have developed a solvent-free method of amidine formation from nitrile and amine using TiCl4 or SnCl4 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 TiCl4 is preferable catalyst over SnCl4.
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. 1H NMR spectra were recorded in CDCl3 on a Bruker 300 DRX Avance instrument at 300 MHz.
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 TiCl4 (1.3 mL, 0.012 mol) or SnCl4 (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 CH2Cl2
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,
1H NMR (CDCl3,