Synthesis of novel highly substituted pyrimidines bearing furanyl thiazole nucleous

. A series of novel highly substituted pyrimidines bearing furanyl thiazole nucleous have been synthesized. In which reaction of guanidine nitrate with ketene dithioacetals 3c produced substituted pyrimidines 4d which further treated with various aromatic aldehydes to afford title compounds 5(a-t) . The chemical structures of the synthesized compounds were elucidated by 1 H NMR, 13 C NMR, FT-IR, elemental analysis, and mass spectral data.


INTRODUCTION
At very early period in the history of organic chemistry, pyrimidines ('m-diazine') were known as the breakdown products of uric acid. The first pyrimidine derivative to be isolated was alloxan in 1818 by Brugnatelli, oxidizing uric acid with nitric acid [1]. The name pyrimidine (combination of words pyridine and amidine) was first applied by Pinner. Pyrimidines are the most important six membered heterocyclic containing 2 nitrogen atoms at position 1 and 3. It is isomeric with two other forms of diazene. Nucleic acid hydrolysis produces several pyrimidines (uracil, thymine and cytosine). Of the 2 types of nucleic acid DNA and RNA, cytosine is found present in both DNA and RNA, while uracil present only in RNA and thymine only in DNA [2].

EXPERIMENTAL
Required all reagents were obtained commercially. Solvents were purified and dried before being used. All melting points were taken in open capillaries and are uncorrected. Thin-layer chromatography (TLC, on aluminium plates precoated with silica gel, 60F 254 , 0.25 mm thickness) (Merck, Darmstadt, Germany) was used for monitoring the progress of all reactions, purity and homogeneity of the synthesized compounds; eluent-hexane:ethyl acetate: (2:8). UV radiation and/or iodine were used as the visualizing agents. Elemental analysis (% C, H, N) was carried out by Perkin-Elmer 2400 series-II elemental analyzer (Perkin-Elmer, USA) and all compounds are within ±0.4% of theory specified. The IR spectra were recorded in KBr on a Perkin-Elmer Spectrum GX FT-IR Spectrophotometer (Perkin-Elmer, USA) and only the characteristic peaks are reported in cm -1 . 1 H NMR and 13 C NMR spectra were recorded in DMSO-d 6 on a Bruker Avance 400F (MHz) spectrometer (Bruker Scientific Corporation Ltd., Switzerland) using solvent peak as internal standard at 400 MHz and 100 MHz respectively. Chemical shifts are reported in parts per million (ppm). Mass spectra were scanned on a Shimadzu LCMS 2010 spectrometer (Shimadzu, Tokyo, Japan).

Synthesis of ketene dithioacetals 3c.
A 100mL conical flask equipped with magnetic stirrer and septum was charged with a solution of N-(4-(furan-2-yl)thiazol-2-yl)-4-methyl-3-oxopentanamide 2b, (10 mmol) in DMF (10 mL). Dried K 2 CO 3 (10 mmol) was added and the mixture was stirred for 2 h at room temperature. CS 2 (30 mmol) was added and the mixture was stirred for an additional 2 h at room temperature. Methyl iodide (20 mmol) was added at 0-5 o C and the mixture was stirred for 4 h before being poured onto water (40 mL). The precipitated crude product was purified by filtration followed by crystallization from EtOH. When the product was oil, the organic phase was extracted with Et 2 O (3 × 10 mL). The combined organic extracts were washed with H 2 O (2 × 10 mL), dried (MgSO 4 ), and concentrated in vaccuo to afford ketene dithioacetals directly used for the next step. .

General procedure for the synthesis of substituted pyrimidines 4d
To a well stirred mixture of guanidine nitrate (10 mmol) and sodium methoxide or sodium ethoxide (20 mmol) in methanol or ethanol was added the solution of ketene dithioacetals 3c (10 mmol) in methanol or ethanol within 10-15 min. The resulting reaction mixture was further stirred at rt for 15 min. then, reflux the reaction mixtures for 7h on water bath. After completion of the reaction, the mixture was poured onto ice cold water. Thus, the obtained solid was filtered, wash with water and dried it and crystallization from EtOH to afford analytically pure products 4d.

General procedure for the synthesis of substituted pyrimidines 5(a-t)
To a well stirred mixture of substituted pyrimidines 4d (10 mmol) and piperidine (2 drops) in ethanol (10 mL) was added various aromatic aldehyde (10 mmol). The resulting reaction mixture was further stirred at rt for 15 min. then, reflux the reaction mixtures for 4-5h on water bath. After completion of the reaction, the mixture was poured onto ice cold water. Thus, the obtained solid was filtered, wash with water and dried it and crystallization from MeOH to afford analytically pure products 5(a-t).
In the current study, all the pyrimidine derivatives 5(a-t) were obtained in good yields by the reaction of various aromatic aldehydes and substituted amino pyrimidines 4d in ethanol, using piperidine as catalyst, at reflux temperature.(Scheme 4). The mechanism (Scheme 5), in ketene dithioacetal system the carbonyl carbon and β-carbon atoms regarded as hard and soft electrophilic centers, since the carbonyl carbon is adjacent to the hard-base oxygen while the β-carbon is flanked by the soft-base methylthio groups. Thus, the binucleophile guanidine in the presence of base attacks on carbonyl carbon of systems and formed substituted amino pyrimidine 4d product by removal of water molecule followed by methylthio as good leaving group.
The identity of the product determined by 1 H NMR, 13 C NMR, FT-IR spectral data, and molecular weight of some selected compounds were confirmed by mass spectrometry. 1 H NMR (DMSO-d6) spectrum of 5a, molecule of interest, exhibited doublet peak at δ 1.103-1.189 ppm appeared for methyl protons of isopropyl group. Also exhibited multiplet at δ 3.223-3.202 ppm appeared for methine proton and singlet at δ 3.530 ppm of aromatic methoxy group. Aromatic protons as multiplets appeared at around δ 6.845-7.562 ppm Moreover, it exhibited two singlet peak δ 9.139 ppm appeared for methine proton and δ 10.288 ppm appeared for -NH-proton. The 13 C NMR spectrum is in consonance with the structure assigned. In the 13 C NMR spectra, signals around δ 163.20 ppm are attributed to carbonyl carbons and signals around δ 110.12-141.30 ppm are attributed to aromatic carbons of compound 5a. Moreover 5a exhibited a distinctive signal at δ 56.20 ppm for aromatic methoxy carbon, at δ 30.65 ppm for methine carbon, at δ 21.36 ppm for methyl carbon. The IR spectrum of compound 5a exhibited characteristic absorption band at 3,326 cm -1 for -NH-group. While 3,045 cm -1 for aromatic C-H stretching and 1,688 cm -1 for carbonyl C=O stretching. The mass spectra of compounds 5a and 5k, molecules of interest, detected the expected molecular ion signals corresponding to respective molecular formula, i.e., mass spectra of compounds 5a and 5k gave molecular ion peak at m/z 447.1 (M + 1) and m/z 461.1 (M + 1) corresponding to molecular formula C 23 H 21 N 5 O 3 S and C 24 H 23 N 5 O 3 S. The obtained elemental analysis values are in good agreement with theoretical data. Similarly, all these compounds were characterized on the basis of spectral studies. All spectroscopic data have been given in spectral data.