Synthesis of new derivatives of 2,3-dicyano-imidazo [1,2-a ]pyrimidine from 4-hydroxy-6-methylpyran-2-ones

The reactions of 2-amino-4,5-dicyanoimidazole 1 with lactone 2 in refluxing alcohol has been carried out for the first time and afforded imidazo[1,2-a ]pyrimidines 4 and 5a-d . Condensation of compound 1 with 3-acetyl-4-hydroxy-6-methylpyran-2-one in refluxing n-butanol afforded bis(imidazopyrimidine) derivative 6 . Reaction of hydrazine hydrate with ester 5 yielded the corresponding hydrazides 8 . Condensation of o-phenylenediamines 9 with compound 5 in refluxing xylene or with hydrazides by melting reagents afforded 2,3-dicyano-5-[benzimidazol-2-yl]methyl-7-methylimidazo[1,2-a ] pyrimidines 10a-d .


Introduction
In the past few years there has been a growing interest in the chemistry of imidazo [1,2-a]  pyrimidines, which is due to the extent of their applications in pharmacological science.Indeed they are known for their anxiolytic, 1 cardiovascular, 2 analgesic, 3,4 antihypertensive 4 and neuroleptic 5,6 properties.

Results and Discussion
The reaction of imidazole 1 with pyran-2-one 2 was carried out at reflux temperature in linear aliphatic alcohols for different time periods (24-48 hours).This allowed us to obtain two imidazopyrimidines (Scheme 1) namely the substituted acetic acid 4 and the corresponding esters 5a-d.Scheme 1. Reaction of imidazole 1 and pyran 2 in aliphatic alcohols.
The structures of the compounds 4 and 5a-d were obtained from their 1 H NMR, 13 C NMR and mass spectra, and X-ray crystallography.In the 1 H NMR spectra, besides the signals due to the ester groups, two singlets appear at δ 7.01-7.12and δ 3.93-3.95which could be attributed respectively to the pyrimidine protons and to the methylene groups α to the ester groups.The 13 C NMR spectra of 5a-d showed, in particular, a signal at δ (167.3 -168.6)which corresponds to the carbonyls of esters groups, as well as two signals at δ 43.7-43.8and δ 114.3-114.4due respectively to the methylene groups α to the ester groups and to C-6 of the bicyclic system.The results and yields are summarised in Table 1.A crystallographic study was also carried out on the compound 5a which provided further evidence for the proposed structures (Figure 1).As shown in Figure 1, the molecule of the product 5a is built up of two plane cycles.The cohesion of the molecules in crystal 5a is assured by their interpenetration.
It should be mentioned that the yields of the products 4 and 5 vary according to the nature of solvent employed in the reaction.The more sterically hindered alcohols give less of the ester.
The results obtained from the condensation of 1 and 2 allow us to propose a mechanism explaining the formation of the compounds 4 and 5a-d (Scheme 2).In fact, the attack of the amino group of aminoimidazole 1 on the C-6 of pyrone 2 leads to the intermediate We have also examined the condensation of 2-amino-4,5-dicyanoimidazole 1 with 4hydroxy-6-methylpyran-2-one 2 in t-butanol.Thus it was shown, after 24 h of reflux that the reaction is complete and leads exclusively to the formation of the compound 4 with a yield of 90 % .The structures of the compounds 6 and 7 were identified by NMR analysis, mass spectra and X-ray structure.The 1 H NMR spectrum of compound 6 shows a singlet at δ7.72 due to the pyrimidine proton and two singlets at δ 2.38 and δ 2.74 which could be attributed to the protons of the methyl groups.Further evidence was obtained from mass spectrum (FAB, MNBA) showing that two molecules of 2-aminoimidazole were involved during this reaction.The structure of the compound 6 was proven by X-ray diffraction study (Figure 2).

Scheme 4
The action of hydrazine hydrate on the esters 5a-d at reflux temperature in methanol gives the corresponding hydrazide 8 (Scheme 5).

Scheme 5. Synthesis of hydrazide 8.
The structure of compound 8 was established on the basis of 1 H NMR, mass and IR spectral data.The 1 H NMR spectrum shows in particular two signals at δ 9.47 and 4.01 which correspond respectively to the protons of the NH and NH 2 groups of the hydrazide.The IR spectrum revealed the presence of two characteristic bands around 3260 cm -1 and 3100 cm -1 which correspond respectively to the stretching ν NH and ν NH2 and a band between 1655 -1660 cm -1 attributed to the carbonyl group of hydrazide.
At these stage, we wanted to prepare new systems associating benzimidazole and imidazopyrimidine rings.To this end, we have examined the condensation of ophenylenediamines 9 with esters 5a at reflux temperature of xylene or with hydrazide 7 by fusion of the reagents.

Scheme 6
The 1 H NMR spectra of compound 10 shows the disappearance of the signals of the protons of the esters groups and reveal the presence of signals at δ 3.98-4.13and 7.46-7.50corresponding respectively to the protons of methylenes groups and to the aromatic protons of the benzimidazole ring.

Conclusions
We report in this work a novel method for the synthesis of new imidazopyrimidine derivatives, starting from 4-hydroxy-6-methylpyran-2-one and 3-acetyl-4-hydroxy-6-methylpyran-2-one.The synthesized compounds were characterized with elementary analysis, NMR, and mass spectrometry.

Experimental Section
General Procedures.All solvents for the spectroscopic measurements were of spectroscopic grade and were used without further purification.The chemicals for the synthesis were of reagent grade quality, procured from commercial sources, and used as received. 1H and 13 C NMR spectra ARKAT USA, Inc.
were recorded at room temperature on a Bruker Avance 300 instrument operating at a frequency of 300 MHz for 1 H and 75 MHz for 13 C. 1 H NMR spectra were referenced to tetramethylsilane (0.00 ppm) as an internal standard.Chemical shift multiplicities are reported as s = singlet, d = doublet, q = quartet and m = multiplet. 13C NMR spectra were referenced to the CDCl 3 (77.67ppm) signal.Mass spectra were detected in mass spectrometer using Fast-atom bombardment (FAB-MS) or Electrospray mass spectrometry (ES-MS) in positive mode.Infrared (IR) spectra were measured with a Perkin Elmer 1760x spectrometer.

Esterification of compound 4
The acid 4 (1.44g, 610 -3 mol) was dissolved in ethanol (23 mL) and concentrated sulphuric acid (1mL) was refluxed for 48 hours.The solution was cooled down and then ice (5g) was added to this solution under stirring.The solution was neutralised with ammoniac in order to make it strongly alkaline.The product 5b extracted with chloroform and recrystallised from ethanol to afford 5b in 80 % yield.
[A], which acts according to two competitive reactions.An esterification leads to the intermediate [B], which cyclises towards compounds 5a-d and an intramolecular cyclisation of [A] leads to the compound 4.

Scheme 2 .Scheme 3 .
Scheme 2. The proposed mechanism for the formation of the compounds 4 and 5.