Synthesis and Characterization of Novel Pyrimido [1,2-a] benzimidazole and its Derivatives

A few pyrimido[1,2-a] benzimidazole derivatives had been synthesized, derived from 4-amino-2-(4-chloro or bromophenyl) -1,2-dihydropyrimido[1,2-a] benzimidazole-3-carbonitrile (4 or 5) is made through one pot three components condensation reaction of 1H-benzimidazol-2-amine (1) with p-chloro or bromobenzaldehyde (2) and malononitrile (3). First part of these derivatives prepared by reaction compound (4 or 5) with acetic acid or propionic acid in presence POCl3 to give pyrmidino rings (6-9). Second part of derivatives were prepared by reaction compound (4 or 5) with benzoyl chloride or phenylisothiocyanate or cyclohexanone to give cyclic compounds (10-15) respectively. All these derivatives characterized by FT-IR and HNMR spectroscopy analysis in addition to physical properties.


INTRODUCTION
Pyrimidine-fused derivatives are an inextricable portion of RNA and DNA, play an important role in a variety of biological processes, and are chemically and biologically significant. As a pharmacophore, pyrimidine-condensed derivatives have many different biological actions, including anti-bacterial [1], anti-viral [2], antifungal [3], antimalarial (4), anti-inflammatory [5], anti-cancer [6], and anti-HIV [7]. For the synthesis of pyrimidine-fused analogues, many retrosynthetic techniques are available, which opens up many possibilities in the field of medicinal chemistry. Starting from their existence in biologically active resources has been recognized to elicit additive effect on molecules' bio-efficacy, scientists were interested in ring fused pyrimidine and its numerous derivatives [8]. Over the last few decades, significant development was achieved in the anticancer agents' development, with a large number of novel anticancer agents generated from both synthetic and natural sources. From heterocyclic compounds, pyrimidine-fused bicyclic heterocycles have antiviral, anti-cancer, and other biological activities [9]. Pyrido [2,3-d] pyrimidine derivatives (I), as shown in Figure 1, are one of the key components in developing new cytotoxic drugs that operate on cell cycle apoptosis induction via extrinsic or intrinsic pathways [10]. Pyrimidine derivative chemistry is significant in the fields of agriculture chemicals, drugs and a variety of biological activities. A great number of pharmacological investigations on pyrimidine and its derivatives have been conducted in recent 16 decades. Yet, additional research is needed to determine the biological chemicals' requirement. In medicinal chemistry, many approaches for pyrimidine synthesis, as well as their various reactions, create an enormous scope. These researches were aided by the fact that pyrimidines can be used as a core structure for a variety of biologically active compounds. A wide variety of pyrimidine derivatives were found to have antitumor [11], antimycobacterial [12], anticancer [13], antiviral [14], antimicrobial [15], anti-inflammatory [16] and analgesic activities [17].

Chemical materials
All solvents and reactants utilized in this research were reagent grade and were purchased from Sigma Aldrich and Fluka. In Germany, Stuarts, SMP30 Melting Points apparatus, melting points are specified in open capillary tubes and uncorrected. At the Dept. of Chemistry/Collage of Science/Univ. of Mustansiriyah, infrared spectra (FT-IR) were acquired with the use of Shimadzu FT-IR8400S spectrophotometer. 1HNMR spectra have been recorded on a Bruker, Ultra Shield 400Mhz, spectrometer (Switzerland) utilizing tetra-methylsilane (TMS) as internal standard and DMSO-d-6 as a solvent, in Turkey, all progress of the reactions and checking the purity were performed with thin layer chromatography (TLC) technique and revealed by mixture of nhexane and ethyl acetate (3: 2) as eluent in the staining jar and irradiation with UV light chromatograms.

Synthesis of 5-(4-chloro or bromophenyl)-4-imino-3-phenyl-3,4,5,6tetrahydrobenzo [4,5]imidazo[1,2a]pyrmido[5,4-e]pyrmidine-2(1H)-thione [12,13]
A mixture of compound [4,5] (0.003mol) and phenyl isothiocyanate (0.4g, 0.003mol) in pyridine (15ml) has been refluxed for a period of 18 hrs. In addition, the solid product created when pouring into ice-water has been gathered through filtration as well as washed by distilled water and after that recrystallized from ethanol for giving compounds [12], and [13] respectively. The compound's physical properties [12], and [13] are provided in Table 1. To a mixture of compound [4,5] (0.001mol) and cyclohexanone (10ml) placed in a round bottom flask connected to a reflux condenser, was added FeCl3 (0.16g, 0.001mol). The mixture was heated for 24 hrs at a temperature of 120°C under stirring. Following cooling to r.t, the remaining solids have been treated by NaOH solution (2 mol/L, 8ml), while such mixture has been heated at reflux for a period of 24 hrs. On cooling to r.t, the reaction mixture has been extracted with the CHCl3 (3x8ml), the organic layers have been combined and dried over Na2SO4. The solvent has been evaporated under decreased pressure and re-crystallized from the ethanol for the purpose of giving the compound [14,15], the physical characteristics have been listed in Table 1.

CONCLUSION
All pyrimido[1,2-a] benzimidazole derivatives had been synthesized with cyclization using different methods and reagents. Pyrimidine ring was prepared from reaction compounds containing an amine group adjacent to a cyano group with aliphatic carboxylic acids in presence pocl3 or with benzoyl chloride in pyridine or with phenyl isothiocyanate in pyridine or with cyclohexanone in presence ferric chloride.

ACKNOWLEDGMENT
Very thanks for Mustansiriyah University, College of Science, department of Chemistry for the facilities in this work.