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Design, Synthesis and Spectral Characterization of Novel 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides
Design, Synthesis and Spectral Characterization of Novel 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides
Journal of the Korean Chemical Society. 2010. Feb, 54(1): 49-54
Copyright © 2010, The Korean Chemical Society
  • Received : September 16, 2009
  • Accepted : January 19, 2010
  • Published : February 20, 2010
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About the Authors
Vijayakumar Kanagarajan
Jayaraman Thanusu
Mannathusamy Gopalakrishnan
profmgk@yahoo.co.in

Abstract
A new series of novel 2-morpholino- N -(4,6-diarylpyrimidin-2-yl)acetamides 34 - 42 is synthesized by the condensation of 2-chloro- N -(4,6-diarylpyrimidin-2-yl)acetamides 25 - 33 with morpholine in the presence of anhydrous potassium carbonate. The synthesized compounds have been characterized by melting point, elemental analysis, MS, FT-IR, one-dimensional NMR ( 1 H & 13 C) spectroscopic data.
Keywords
INTRODUCTION
Pyrimidines being an integral part of nucleic acids and many chemotherapeutic agents display a wide range of pharmacological activities as bactericide, 1 fungicide, 2 phosphodiesterase inhibitor, 3 viricide, 4 and leishmancide. 5 Pyrimidines are the basic nucleus in nucleic acids and have been associated with a number of biological activities. 6 Substituted aminopyrimidine nuclei are common in marketed drugs such as anti-atherosclerotic aronixil, anti-histaminic thonzylamine, anti-anxielytic buspirone, anti-psoriatic enazadrem, and other medicinally relevant compounds. 7 Many pyrimidine derivatives have been found to be active against different forms of cancer. 8 Various method of synthesis and reactions of aminopyrimidines are reported. 9 - 11
Amides are well known for their therapeutic values. 12 The chemistry of chloro acetyl group has received significant attention through the years resulting in substantial advances both in the synthetic and medicinal aspects. N-Benzyl-β-chloropropionamide is a well-proven anticonvulsant agent 13 and is marketed under the trade name Hibicon and Hydrane. Chloroacetyl derivatives of some amines were found to exert diverse biological properties such as antiepileptic, 14 antiplasmodic, 15 antitumour, anti-MDR, 16 antimicrobial, 17 herbicidal, 18 mild stimulant and depressant activities. 19 Antibiotics like penicillins and cephalosporins have amide group. Novel bioactive natural compounds 20 are synthesized by the conversion of ketones into amides, since amide group is an important pharmacophores.
Many N-fuctionalized morpholines have found to posses diverse pharmacological activites. They are reported to exert a number of important physiological activities such as antidiabetic, 21 , 22 antiemetic, 23 , 24 platelet aggregation inhibitors and antihyperlipo-proteinemics, 21 bronchodilators and growth stimulants 25 and antidepressants. 26 These were also used in the treatment of inflammatory diseases, pain, migraine and asthma. 24
Recently, we exploited the synthesis of some novel structurally diverse heterocyclic compounds comprising pyrimidine nucleus such as 3,4-dihydropyrimidin-2(1 H )-ones 27 and - thiones and 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones, 28 morpholine nucleus namely (E)-1-4-morpholinophenyl)-3-aryl-prop-2-en-1-ones 29 and amide moiety such as 2,7-diaryl-[1,4]-diazepan-5-ones. 30 In the interest of above, we planned to synthesize a target molecule, 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides which unite biolabile 4,6-diarylpyrimidin-2-amines, chloroacetyl chloride and morpholine moieties together to furnish a new series of compounds.
RESULTS AND DUSCUSSION
A four-step synthetic route furnished the target compounds 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides 34 - 42 in good yields. A general schematic representation is given in 1 . The Claisen-Schmidt 31 condensation of equimolar quantities of appropriate acetophenone and appropriate benzaldehyde in the presence of sodium hydroxide gives E -1,3-diarylprop-2-en-1-ones 7 - 15 . When E -1,3-diarylprop-2-en-1-ones 7 - 15 are refluxed with guanidine nitrate in the presence of sodium hydroxide, 2-amino-4,6-diarylpyrimidines 32 16 - 24 are formed. Various substituted 2-chloro-N-(4,6-diarylpyridiarylpyrimidin-2-yl)acetamides 33 25 - 33 are synthesized by electrophilic substitution reaction of chloroacetyl chloride with the corresponding parent 2-amino-4,6-diarylpyrimidines 16 - 24 in the presence of triethyl amine as base and toluene as solvent. Then, condensation of 2-chloro-N-(4,6-diarylpyrimidin-2-yl)acetamides 25 - 33 with morpholine in the presence of anhydrous potassium carbonate furnished 2-morpholino-N-(4,6-diarylpyrimidin- 2-yl)acetamides 34 - 42 . The physical and analytical data for compounds 34 - 42 is given in 1 .
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Synthetic route for the formation of 2-morpholino-N-(4,6- diarylpyrimidin-2-yl)acetamides
The following nine compounds 34 - 42 are synthesized from the corresponding 2-chloro-N-(4,6-diarylpyrimidin-2-yl)acetamides 25 - 33 :
  • ❖2-morpholino-N-(4,6-diphenylpyrimidin-2-yl)acetamide34
  • ❖2-morpholino-N-(4-(4-methylphenyl)-6-phenylpyrimidin-2-yl)acetamide35
  • ❖N-(4(4-fluorophenyl)-6-phenylpyrimidin-2-yl)2-morpholinoacetamide36
  • ❖N-(4-phenyl-6-(4-methoxyphenyl)-pyrimidin-2-yl)2-morpholinoacetamide37
  • ❖N-(4-phenyl-6-(4-fluorophenyl)-pyrimidin-2-yl)2-morpholinoacetamide38
  • ❖N-(4-(4-methoxyphenyl)-6-(4-methylphenyl)pyrimidin-2-yl)2-morpholinoacetamide39
  • ❖N-(4,6-bis(4-fluorophenyl)pyrimidin-2-yl)2-morpholinoacetamide40
  • ❖N-(4-(4-fluorophenyl)-6-(4-methylphenyl)pyrimidin-2-yl)2-morpholinoacetamide41
  • ❖N-(4-(4-methylphenyl)-6-(4-fluorophenyl)pyrimidin-2-yl)2-morpholinoacetamide42
Physical and analytical data of compounds34-42
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Physical and analytical data of compounds 34-42
FT-IR absorption frequencies (cm-1) for selected functional groups of compounds34-42
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FT-IR absorption frequencies (cm-1) for selected functional groups of compounds 34-42
The structures of all the newly synthesized compounds are characterized by m.p.’s, elemental analysis, FT-IR, MS, onedimensional NMR ( 1 H and 13 C) spectra.
FT-IR spectrum of 2-morpholino-N-(4,6-diphenylpyrimidin-yl)acetamide 34 shows characteristic absorption frequency ( 2 ) observed at 3314cm -1 is due to N-H stretching vibrations of the amide group. The absorption frequency at 3193 ~3030 cm -1 is assigned to aromatic stretching vibration. The absorption frequency at 2920 ~ 2851 cm -1 is assigned to aliphatic stretching vibration. The band at 1682 cm -1 is due to the presence of amide C=O stretching frequency. The absorption band at 1360 ~ 1236 cm -1 is consistent with C-N stretching vibration. The absorption band at 1565 cm -1 is due to C=C stretching vibration. In addition, compound 34 displayed characteristic absorption bands (cm -1 ) in the regions 761 ~ 693 (aromatic ring stretching) and 1112 (C-O-C ether linkage in the morpholine ring); this gives positive evidence for the formation of compound 34 .
In the 1 H NMR spectrum of 34 , a singlet observed at 3.91 ppm for two protons is assigned to methylene protons. The singlet for H-5 proton is observed at 6.69 ppm. The amide proton resonates at 10.25 ppm. Two triplets are observed and they are due to the methylene protons O(CH 2 ) 2 and N(CH 2 ) 2 of morpholine ring. Among the triplets, one triplet observed in the region of 2.65 ~ 2.63 ppm corresponding to two protons and this signal is due to methylene protons N(CH 2 ) 2 of morpholine ring. Another triplet appeared in the region of 3.49 ~ 3.47 ppm, corresponding to two protons, which can be conveniently assigned to methylene protons O(CH 2 ) 2 of morpholine ring. The aromatic protons resonate in the region 8.20 ~ 7.30 ppm.
Proton NMR chemical shifts (δ, ppm) of compounds34-42
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Proton NMR chemical shifts (δ, ppm) of compounds 34-42
The 13 C resonance at 163.91 ppm is assigned to the amide group bearing carbon C-2 of pyrimidine moiety. The amide carbonyl carbon resonances at 169.40 ppm. The 13 C resonances observed at 164.72 and 101.27 ppm are due to the C-4 and C-5 carbons respectively. The 13 C resonances observed at 164.72 ppm is conveniently assigned to C-6 carbon. There are two 13 C resonances observed at 45.89 and 67.25 ppm. Among the two resonances, one 13 C resonance at 45.89 ppm is due to methylene carbon N(CH 2 ) 2 of morpholine ring and 13 C resonances at 67.25 ppm is unambiguously assigned to methylene carbon O(CH 2 ) 2 of morpholine ring. The methylene carbon attached to amide carbonyl carbon resonances at 66.23 ppm. The remaining 13 C signal at 137.38 ppm and 134.55 ppm are due to ipso carbons. The aromatic carbons are observed in the region of 130.30 ~ 126.87 ppm.
The 1H and 13 C NMR chemical shifts of all the newly synthesized compounds are furnished in 3 and 4 respectively.
Carbon NMR chemical shifts (δ, ppm) of compounds34-42
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Carbon NMR chemical shifts (δ, ppm) of compounds 34-42
CONCLUSION
In conclusion, we have synthesized a series of 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides 34 - 42 by a four step synthetic route in good yields and characterized by their physical and analytical data. The target molecules 34 - 42 have pharmacophoric group such as amide besides the presence of biologically active morpholine and pyrimidine nuclei. The biological screening studies are under progress to evaluate the antibacterial, antifungal, antioxidant and anticancer potencies of the newly synthesized of 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides 34 - 42 .
EXPERIMENTAL
Thin layer chromatography (TLC) was carried out to monitor the course of the reaction and purity of the product. All the reported melting points were taken in open capillaries and were uncorrected. IR spectra were recorded in KBr (pellet forms) on a Thermo Nicolet-Avatar-330 FT-IR spectrophotometer and important absorption values (cm -1 ) alone are listed. 1 H and 13 C NMR spectra were recorded at 400 MHz and 100 MHz respectively on Bruker Avance II 400 NMR spectrometer using DMSO- d as solvent. The ESI +ve MS spectra were recorded on a Bruker Daltonics LC-MS spectrometer. Satisfactory microanalysis was obtained on Carlo Erba 1106 CHN analyzer.
By adopting the literature precedent 1,3-diaryl-prop-2-en-1-ones 31 7 - 15 , 2-amino-4,6-diarylpyrimidines 32 16 - 24 and 2-chloro-N-(4,6-diarylpyrimidin-2-yl)acetamides 33 25 - 33 were synthesized.
- General method for the synthesis of 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides 34-42
A mixture of 2-chloro-N-(4,6-diarylpyrimidin-2-yl)acetamides 25 - 33 (0.005 mol), anhydrous potassium carbonate (0.01 mol) and morpholine (0.005 mol) in dry toluene was refluxed for about 8 ~ 10 h. After completion of the reaction, potassium carbonate was removed by filtration and excess of solvent was removed under reduced pressure. The obtained residues were purified by column chromatography using benzene and ethylacetate (1:1) mixture as eluent which afforded 2-morpholino- N-(4,6-diarylpyrimidin-2-yl)acetamides 34 - 42 in good yields.
Acknowledgements
Authors are thankful to NMR Research Centre, Indian Institute of Science, Bangalore for recording spectra. One of the authors namely V. Kanagarajan is grateful to Council of Scientific and Industrial Research (CSIR), New Delhi, Republic of India for providing financial support in the form of CSIR-Senior Research Fellowship (SRF) in Organic Chemistry.
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