Biginelli Synthesis of Novel Dihydropyrimidinone Derivatives Containing Phthalimide Moiety

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia Drug Exploration and Development Chair, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia Peptide Chemistry Department, Chemical Industries Research Division, National Research Centre, 12622 Dokki, Cairo, Egypt Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia


Introduction
Pyrimidines have played a vital role in the field of pharmaceutical chemistry [1]. Pyrimidines are important moiety because of their various pharmacological activities. Nifedipine, 4-aryl-1,4-dihydropyridines, was the first antihypertensive agent into the clinical medicine. For the treatment of various cardiovascular diseases, dihydropyridines are the most potent calcium channel modulators [2,3].
Substituted dihydropyrimidinone compounds show interesting biological properties, e.g., calcium channel blockers and antihypertensive agents [4,5]. ese compounds display a broad spectrum of biological activities such as anti-inflammatory, antitumor, antiviral, and antibacterial ones [6,7]. Dihydropyrimidinone compounds were first synthesized by Pietro Biginelli. e type of compounds is known as Biginelli compounds. e synthesis of this type of compounds involves the reacting of numerous aldehydes with urea and a beta-keto ester to give a tetrahydropyrimidinone.
Phthalimide analogues have been reported with large range of pharmacological activities that are anticonvulsant, anti-inflammatory, analgesic, and hypolipidemic [8][9][10][11]. Phthalimide analogues have been synthesized as tumor necrosis factor-α (TNF-α) inhibitors [12]. TNF-α plays an important role in certain physiological immune systems. It stimulates the inflammatory response leading to autoimmune disorders including rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriasis, and refractory asthma [13]. Extensive research on the phthalimide analogues has been reported in the literature [14][15][16][17]. e hybrid compounds containing these two important moieties (dihydropyrimidinone and phthalimide) may have a substantial therapeutic potential. In continuation of our work on dihydropyrimidinones, a series of novel phthalimide dihydropyrimidinone hybrids were synthesized by simple method and fully characterized by elemental analysis and spectral data [18,19] Scheme 1 depicts a reaction by which the dihydropyrimidinone derivatives of phthalimide were prepared. e dihydropyrimidinone derivatives (1−10) were synthesized by refluxing phthalic anhydride (I) (0.01 mol) and paraaminoacetophenone (II) (0.01 mol) in glacial acetic acid for 2 h. e reaction mixture was added to the ice cold water. e white product was precipitated and was filtered by vacuum filtration. e washing of the product was performed by ice cold water. e compound 2-(4-acetylphenyl)-1H-isoindole-1,3(2H)-dione (III) was obtained, which was recrystallized by ethanol. A mixture of (III) (0.02 mol) and dimethylformamide-dimethylacetal (DMF-DMA) (0.023 mol) was refluxed for 12 h without solvent on a heating mantle. After the completion of reaction, the reaction mixture was cooled to room temperature. Diethyl ether was added to precipitate the reaction mixture and vacuum filtration was performed. e obtained product enaminone, , was recrystallized from absolute ethanol.

Synthesis of the Dihydropyrimidinone Derivatives (1-10).
differently substituted benzaldehyde (0.01 mol), urea (0.01 mol), and glacial acetic acid (10 mL), was refluxed for 3 h. e precipitates (1-10) were obtained by adding ice cold water to the reaction mixture. e products were obtained by filtration under vacuum. e products were washed several times with water. e products were purified by recrystallization from glacial acetic acid and ethanol mixture. e physicochemical properties of compounds (1−10) are given in Table 1.

Results and Discussion
As   [20]. Compounds presented the D 2 O exchangeable broad singlet at δ 9.33-9.62 ppm and δ 10.12-10.31 ppm corresponding to the two NH protons. e H-4 protons of dihydropyrimidinone moiety and aromatic protons were observed at δ 5.43-6.17 and δ 6.59-8.41 ppm, respectively [21]. 13 C NMR spectra confirmed all the carbon atoms for compounds (1−10). Molecular weights of the compounds were confirmed by mass spectral data. Molecular ion peaks were observed in all compounds respective to their molecular weights. e composition of the synthesized compounds (1-10) was confirmed by spectral and elemental data. e possible reaction mechanism involves the acid catalyzed formation of iminium ion intermediate from the substituted aryl aldehydes and urea. Reaction of phthalimide enaminone by iminium ion yields ureidenone, which forms hexahydropyrimidine by cyclization. Final dihydropyrimidinone derivatives (1-10) were obtained by elimination of NH(CH 3 ) 2 group from hexahydropyrimidine in presence of glacial acetic acid (Scheme 2).

Conclusion
In conclusion, a series of novel dihydropyrimidinone derivatives containing phthalimide moiety were synthesized in good yield, at high level of purity, and in efficient manner from the enaminone, which was derived from phthalimide by simple and solvent-free method. e enaminone existed in the E-configuration. All the compounds were characterized and confirmed by different spectroscopic methods and elemental analysis.

Data Availability
Samples of the compounds (1-10) in pure form are available from the authors upon request.