A One-Pot Biginelli Synthesis and Characterization of Novel Dihydropyrimidinone Derivatives Containing Piperazine/Morpholine Moiety

Enaminones, 4-methyl-1-[4-(piperazin/morpholin-1-yl) phenyl] pent-2-en-1-one (IIa–b) were synthesized by refluxing 1-[4-(piperazin/morpholin-1-yl) phenyl] ethan-1-one (Ia–b) with dimethylformamide dimethylacetal (DMF–DMA) without any solvent. The three dimensional structure of enaminone (IIb) containing morpholine moiety was confirmed by single crystal X-ray crystallography. Finally, the dihydropyrimidinone derivatives (1–20) were obtained by reacting enaminones (IIa–b) with urea and different substituted benzaldehydes in the presence of glacial acetic acid. Dihydropyrimidinone derivatives containing piperazine/morpholine moiety were synthesized in a good yield by means of simple and efficient method.


Introduction
Pyrimidines scaffold have played a significant role in the area of medicinal chemistry [1]. Pyrimidines are important moieties because of their potential biological activities such as antitumor, antiviral, and antibacterial agents [2,3]. Dihydropyridines are the most potent calcium channel modulators available for the treatment of various cardiovascular diseases [4]. Dihydropyrimidines, also known as Biginelli's compounds, display various pharmacological activities [5]. Dihydropyrimidinone compounds were first synthesized by Pietro Biginelli. The process comprised of reacting numerous aldehydes with urea and a beta-keto ester to give a tetrahydropyrimidinone. Substituted dihydropyrimidinone compounds show interesting biological properties. Some of the analogs of dihydropyrimidine compounds are antitumor agents [6]. Dihydropyrimidinones have emerged as calcium channel blockers and antihypertensive agents [7]. These compounds exhibit a broad range of pharmacological activities, such as antibacterial, antitumor, antiviral, and anti-inflammatory [8].
The literature review suggested that molecules possessing these important scaffolds (piperazine/morpholine and dihydropyrimidinone) may have significant therapeutic activity. In the present disclosure, a series of novel piperazine/morpholine dihydropyrimidinone hybrids were prepared and analyzed by spectral data. Morpholine is an organic moiety containing nitrogen and oxygen in a heterocyclic six-membered ring, and is considered as an important building block in the field of medicinal chemistry. The linezolid antibiotic having a morpholine moiety is commercially available as antimicrobial agent. Timolol, moclobemide, emorfazone (anti-inflammatory drug and analgesic), phenadoxone (heptalgin, opioid analgesic), antidepressants reboxetine and gefitinib, fenpropimorph (fungicide) and antibacterial drugs finafloxacin and levofloxacin contain a morpholine moiety ( Figure 2). Morpholine derivatives are very much essential in the drug discovery process. Morpholine scaffolds are important, due to their variety of pharmacological activities [29][30][31][32][33][34][35].
The literature review suggested that molecules possessing these important scaffolds (piperazine/morpholine and dihydropyrimidinone) may have significant therapeutic activity. In

Chemistry
All the solvents were purchased from Merck (Kenilworth, NJ, USA). To check the purity of compounds, thin layer chromatography (TLC), was performed on silica gel 60 F254 coated plates (Merck). For performing FTIR, Perkin Elmer (Waltham, MA, USA) FT-IR spectrophotometer was used. Melting points were measured by Gallenkamp melting point apparatus. 1 H and 13 C NMR were recorded in Bruker (Billerica, MA, USA) NMR 500/700 MHz and 125/176 MHz spectrophotometer. The samples were run in DMSO-d6 with tetramethyl silane (TMS) as an internal standard. Molecular weights of compounds were determined in mass spectroscopy. The elemental analysis of compounds was performed by CHN Elementar (Analysensysteme GmbH, Langenselbold, Germany). The compound (IIb) was obtained as single crystal by reported method. Data were collected on a Bruker APEX-II D8 Venture area diffractometer. SHELXT was used to solve structure [41,42]. CCDC 1532829 contains the supplementary crystallographic data for the compound (IIb). These data can be obtained

Chemistry
All the solvents were purchased from Merck (Kenilworth, NJ, USA). To check the purity of compounds, thin layer chromatography (TLC), was performed on silica gel 60 F 254 coated plates (Merck). For performing FTIR, Perkin Elmer (Waltham, MA, USA) FT-IR spectrophotometer was used. Melting points were measured by Gallenkamp melting point apparatus. 1  weights of compounds were determined in mass spectroscopy. The elemental analysis of compounds was performed by CHN Elementar (Analysensysteme GmbH, Langenselbold, Germany). The compound (IIb) was obtained as single crystal by reported method. Data were collected on a Bruker APEX-II D8 Venture area diffractometer. SHELXT was used to solve structure [41,42]. CCDC 1532829 contains the supplementary crystallographic data for the compound (IIb). These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).

Conflicts of Interest:
The authors declare no conflict of interests.