Reaction of Nitrilimines with 2-Aminopicoline , 3-Amino-1 , 2 , 4-Triazole , 5-Aminotetrazole and 2-Aminopyrimidine

The reaction of picoline derivatives 3-6 with hydrazonoylhalide 1a produced imidazo[1,2-a]pyridines 7-10, while the reaction of the same picoline derivatives with hydrazonoylhalide 1b afforded imidazo[1,2-a]pyridine-2-ones 11-13. The reaction of 1b, c with 3-amino-1,2,4-triazole 14 produced the acyclic adducts 18 and 19, respectively. Reaction of 1b, 1c with 5-aminotetrazole 20 produced the acyclic products 23 and 24, respectively. Finally, the reaction of 1b with 4, 6-dimethyl-2-aminopyrimidine 27 afforded compound 29 rather than its isomeric structure 28. The structure of the products was confirmed by the different spectroscopic analytical methods including IR, MS, 1HNMR and 13CNMR.


Introduction
Nitrilimines-generally generated in situ from hydrazonoyl halides are 1,3-dipolar species that are widely used for the synthesis of different heterocyclic systems via 1,3-dipolar cycloaddition reactions [1] [2], or cyclocondensation reactions [2].Nitrilimines with C-acetyl or ester moiety represent a dielectrophilic system that may react with dinucleophilic heterocyclic systems at the carbonyl carbon of the acetyl or ester group, and at the terminal carbon of the dipole leading to fused heterocyclic systems.Recent examples include; the synthesis of im-idazo [1,2-a]pyridines [3] [4] and their 2-one derivatives [4] from the reaction of nitrilimines with 2-amino-pyridine and imidazo [1,2-a]pyrazine from the reaction with 2-aminopyrazine [5].Their reaction with 2-cyanomethylben-zimidazole gave pyrrolo [1,2-a]benzimidazole [6] [7].The reaction of ethyl pyridine-2-acetate with nitrilimines having a C-acetyl moiety afforded the corresponding pyrrolo [1,2-a]pyridine, while their reaction with nitrilimines having a C-ester moiety afforded a cyclic adducts [8].Similarly, the reaction of nitrilimines with a C-ester moiety with 2-cyanomethylbenzimidazole, and 2-amniobenzimidazole afforded a cyclic adducts [8].In this work, we will investigate the reaction of nitrilimines with different amino heterocycles hoping to prepare new fused heterocyclic compounds that may be further tested for their biological activity.The following amino heterocycles will be used; aminopicolines, aminotriazole, aminotetrazole, aminoisoxazole and aminopyrimidine.

Experimental
1 H-NMR spectra were recorded at 300 or 400 MHz and 13 C-NMR spectra at 75 or 100 MHz on a Bruker AC300 or AC400 spectrometer.Chemical shifts are denoted in (ppm) relative to the internal solvent standard, TMS.ES-MS and HRMS were recorded on a Micromass LCT orthogonal acceleration time-of-flight mass spectrometer (positive and negative ion mode) with flow injection via a Waters 2790 separation module autosampler.FTIR spectra were recorded using Shimadzu 8201 spectrophotometer with KBr technique in region 4000 -400 cm −1 that was calibrated by polystyrene.Melting point determinations were made using a Stuart Scientific SMP1 apparatus and are uncorrected.All chemicals and solvents were used without further purification, as supplied by Sigma-Aldrich unless otherwise stated.Hydrazonoylhalides 1a-c were prepared using Japp-Klingman method according to reported literature procedure [9].

Results and Discussion
The reaction of picoline derivatives 3-6 with hydrazonoyl chloride 1a in THF in the presence of Et 3 N as a base at room temperature produced imidazo[1,2-a]pyridine 7-10 in 85% -90% yield, while the reaction of hydrazonylchloride 1b with substituted picolines 3-6 under the same reaction conditions afforded the expected imidazo[1,2-a]pyridine-2-ones 11-13 in 30% -70% yield (Scheme 1).The structure of the products was confirmed by the different spectroscopic analytical methods including IR, MS, 1 HNMR and 13 CNMR.
The reaction of 1 with 3-amino-1,2,4-triazole 14 in refluxing ethanol was reported by Shawali et al. to give imidazo [1,2-b] triazole 15 in very low yield [10].On the other hand, and under the same reaction conditions, Graf reported that the reaction of 14 with hydrazonylchloride 1 (X = Ar) afforded the acyclic adducts 16 [11].Treatment of 16 with refluxing AcOH/AcONa led to formation of the cyclic fused product 18 via loss of a molecule of NH 3 .The structure of 16 and 17 were determined by X-ray crystallography.
signment is based on the appearance of the NH 2 group and the C=O group in both IR and NMR spectra.Similar to Graf product, the reaction is proposed to occur at the N4 of the triazole 14.The fused heterocyclic system reported by Shawali [10] was not obtained.Attempt to cyclize compounds 18 and 19 using AcOH/NaOAc (Graf method) was unsuccessful.
Graf reported [12] that the reaction of hydrazonylhalides 1 with 5-aminotetrazole 20 in refluxing ethanol produced compounds 22 via the rearrangement accompanied by loss of hydrazoic acid (HN 3 ) from the intermediate cycloaddition product 21.In this work; the reaction of hydrazonyl halides 1b, 1c with 5-aminotetrazole 20 in THF in the presence of Et 3 N at room temperature afforded the acyclic adducts 23 and 24, respectively (Scheme 3).
The reaction of hydrazonylhalide 1a with 2-aminopyrimidine 25 was reported by Awadallah et al. [8] to produce the pyrimido [2,1-d] 1,2,3,5-tetrazine 26.The reaction of 1b with 4, 6-dimethyl-2-aminopyrimidine 27 in THE in presence of Et 3 N as a base at room temperature produced however, the acyclic adduct, 29.Two different possible isomeric structures are possible 28 and 29 (Scheme 4).The NMR data obtained provided an unambiguous confirmation that the actual obtained product is in fact compound 29 rather than compound 28.The assignment is based on the appearance of two CH 3 groups at the pyrimidine ring.In compound 28 these two CH 3 are identical as they are in the same chemical and electronic environment, so they should appear as one peak with an integration value corresponding to 6H.On the other hand, the two CH 3 groups in compound 29 are different and two peaks with equal integration are expected. 1HNMR spectra obtained supported structure 29 rather than 28.The mass spectra form compound 29 in both positive mode 234 [M+1] + and negative mode 232 [M-1] + is shown in Figure 1.

Conclusion
A new series of heterocyclic compounds was synthesized via the reaction of Nitrilimines with 2-aminopicoline, 3-amino-1,2,4-triazole, 5-aminotetrazole and 2-aminopyrimidine.The structures of the products were characterized by IR, 1 H-NMR, 13 C-NMR and MS.The melting points of the synthesized compounds are listed in Table 1.

Figure 1 .
Figure 1.Mass spectra for compound 29 in both positive and negative mode.

Table 1 .
The melting points of the synthesized compounds.