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A new and efficient synthesis of 1 (4-subtitued phenyl)-3-(1-(6-(substitued-2-yl)pyrimidin-4-yl)piperidin-4-yl)ureas via green aqueous suzuki coupling
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A new and efficient synthesis of 1 (4-subtitued phenyl)-3-(1-(6-(substitued-2-yl)pyrimidin-4-yl)piperidin-4-yl)ureas via green aqueous suzuki coupling

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  • 1. Journal of Natural Sciences Research www.iiste.org ISSN 2224-3186 (Paper) ISSN 2225-0921 (Online) Vol.3, No.8, 2013 123 A New And Efficient Synthesis Of 1-(4-Subtitued Phenyl)-3-(1-(6- (Substitued-2-Yl)Pyrimidin-4-Yl)Piperidin-4-Yl)Ureas Via Green Aqueous Suzuki Coupling. Venkata Suryanarayana.Ch, V.Anuradha*, G. Jayalakshmi and G. Sandhya Rani. Department Of Chemistry, Vignan School Of P.G Studies, Acharya Nagarjuna University, Guntur, Andhra Pradesh, India-522005. E-mail: var_chemistry@rediffmail.com Graphical Abstract: N N ClCl NH NH O O Step-1 N N NCl NH Boronic acids /PdCl2(PPh3)2 /water/80o C Step-2 N N NG NH O O G = Aryl, Hetro aryl N N NG NH2 TFA/DCM Isocyanates TEA/DCM NN N G NH O NHStep-3 Step-4 Cs2CO3/ DMF R 1 2 3 5 R = COOMe, Cl, OMe O O 4 Abstract A New and efficient method for the synthesis of disubstituted pyrimidines has been described. Suzuki coupling of diversely substituted and tert-butyl (1-(6-chloropyrimidin-4-yl) piperidin-4-yl) carbamate with various arylboronic acids in the presence 10% of PdCl2 (PPh3)2 with 0.5 M (aq) Na2CO3 in water at 80 o C furnished the aforementioned products in 72-84% yields. The resulted compounds were deprotected and coupled with various aryl isocynates in presence of triethylamine in CH2Cl2 at ambient temperature yielded corresponding ureas (> 90%). As a result, twelve new compounds were synthesized; those are well characterized by 1 H NMR, 13 C NMR, and mass spectral analyses. Keywords: 4,6-dichloropyrimidine , Green Chemistry, Suzuki Coupling, PdCl2(PPh3)2, Triethylamine, aryl isocyanates. Introduction: Nitrogen containing heterocycles are widely found in nature and are integral part of several biologically active compounds.1 Pyrimidines belongs to the class of diazine family of heterocyclics. Many biologically active compounds including nucleic acids, nucleotides and corresponding nucleosides have pyrimidine as a core unit.2 It was reported that pyrimidines and their derivatives exhibited significant in vitro activity against unrelated DNA and RNA.3 In addition, pyrimidine derivatives were found to possess inhibition properties against polio herpes viruses, and as diuretics, antitumor agents, anti HIV agents, and for cardiovascular diseases.3 Furthermore, pyrimidines substituted with nitro group acted as novel allosteric enhancer of -aminobutyric acid receptor function.4 Moreover, heterocyclic compounds containing a CF3 group exhibits wide range of biological activities.5 Smith, et. al. utilized 2-methoxy bromo pyrimidine for the synthesis of 5-substituted pyrimidones as inhibitors for lipoproteion-associated phospholipase A.6 Recently, Hu et. al. reported that 2,4,5-trisubstituted pyrimidines as a new class of tubulin polymerization inhibitors.7 Given these remarkable biological properties, the synthesis of pyrimidines and their analogues has attracted much attention. Conventional synthesis of pyrimidines are well documented in the literature, those methods involves double condensation with elimination of water, alcohol or hydrogen halide between amino and carboxylic acid, acid chloride or condensation of amino to CN groups or to polarized double bonds without elimination.2,8 The palladium-catalyzed Suzuki coupling9 is an important and versatile method for carbon-carbon bond formation. It has been extensively explored for synthesis of unsymmetrical biaryls, as well as aryl pyrimidines.10 2,4-substitued and 4,6-disubstitued pyrimidines bonded to an saturated heterocyclic unit at C-2 position of pyridine ring and related compounds had attracted
  • 2. Journal of Natural Sciences Research www.iiste.org ISSN 2224-3186 (Paper) ISSN 2225-0921 (Online) Vol.3, No.8, 2013 124 much attention as potent 5-HT2A receptor ligands with fairly strong behavioural antagonistic activity.11 Previously we studied amines with aryl isocyanates and triethylamine in CH2Cl2 yielded corresponding ureas (100%).12 Herein, we report palladium-catalyzed Suzuki coupling for the synthesis of various 4,6-disubstituted pyrimidines from tert-butyl (1-(6-chloropyrimidin-4-yl) piperidin-4-yl) carbamate, arylboronic acids, and water. The formed compounds were de-protected and coupled with aryl isocynates to yielded corresponding ureas with excellent yields. N N O CF3 N S AcHN AMG 517 N N C2H5 NH2 Cl NH2 pyrimethamine N N NH2 NH2N trimethoprim N NH2N HO N 2-(2-amino-5-(1-methyl-1H-indol-5-yl) pyrimidin-4-yl)phenol Figure 1. Representative examples of pyrimidine containing biologically active compounds. Results and Discussion: Our work commenced with commercially available 4,6-dichloropyrimidine as an ideal starting material. We selected the synthon 1 on the basis of the following reasons: 1. the chloro group of compound 1 can be easily displaced with appropriately substituted amines in the presence of base. This is due to the electronegative nitrogen atoms induce polarization in the sigma bond frame work of pyrimidine ring.13,14 The resultant increase in electron deficiency at the 2, 4, and 6 positions makes these carbon atoms more susceptible to the nucleophilic attack. This nucleophilic attack is especially feasible when a displaceable halide is a substituent.13,14 2. The resultant chloro pyrimidines (2) could serve as ideal candidates for palladium-catalyzed Suzuki coupling, followed by depotection and reacted with aryl isocyanates yielded corresponding urea’s as excellent yields. As shown in Scheme 1, treatment of tert-butyl 1-(6-chloropyrimidin-4-yl)piperidin-4-ylcarbamate 2 with arylboronic acids, and 0.5 N aqueous sodium carbonate in water was degassed by bubbling with nitrogen gas for 15min and then added PdCl2(PPh3)2and the reaction mixture was heated to 80 o C for 30 minutes. The reaction mixture was cooled to room temperature, the resultant solid was filtered and solid was washed with water and air dried. The crude product was recrystalized from dichloromethane in petroleum ether to give 3a. The resultant new compounds (i.e., 3a-d) were well characterized by 1 H NMR, 13 C NMR, and mass spectral analysis (See, Experimental section). Scheme 1. Green aqueous Suzuki coupling of tert-butyl (1-(6-chloropyrimidin-4-yl) piperidin-4-yl) carbamate with boronic acids.
  • 3. Journal of Natural Sciences Research www.iiste.org ISSN 2224-3186 (Paper) ISSN 2225-0921 (Online) Vol.3, No.8, 2013 125 B O N N NCl H N O O N N NG H N O O PdCl2(PPh3)2 0.5M Na2CO3 H2O, 80 oC, 30min (60-85%) B OH OHS B OH HO S O B OH HOG= , , OH OH , 2 3a-d G-Aryl, Hetro aryl With these intermediates (i.e., 3a-d) in hand, out next aim was to explore these compounds for the synthesis of 4,6-disubstituted pyrimidine ureas by use the of aryl isocynates coupling. To the best of our knowledge, their synthesis has not been reported. Consequently, we planned to develop a general synthetic route for synthesis of diversely 4,6-disubstituted pyrimidine ureas using aryl isocynates with triethylamine in CH2Cl2 for 6h at ambient temperature as a key step as in Scheme 2. Scheme 2. Synthesis of 1-(4-Subtitued phenyl)-3-(1-(6-(Substitued-2-yl)pyrimidin-4-yl)piperidin-4-yl)ureas with substituted phenyl isocyanates. G-Aryl, hetro aryl N N NG NH2 Isocyanates TEA/DCM NN N G N H O N HStep-4 R 4 5 R - COOMe, Cl, OMe 5a-c, 6a-c, 7a-c and 8a-c Conclusion: In conclusion, we have showed that 1-(6-(Substitued-2-yl)pyrimidin-4-yl)piperidin-4-amine and aryl isocyanates as an ideal coupling partners for synthesis of peptide bond formation.. The required 1-(6-(Substitued-2- yl)pyrimidin-4-yl)piperidin-4-amines were prepared by treatment of tert-butyl 1-(6-(Substitued-2-yl)pyrimidin- 4-yl)piperidin-4-ylcarbamates and TFA in CH2Cl2.The precursor of later compounds were prepared by green aqueous suzuki coupling. As a result, we developed an efficient methodology for the synthesis of various 4,6- disubstituted pyrimidine ureas by coupling of 1-(6-(Substitued-2-yl)pyrimidin-4-yl)piperidin-4-amines with aryl isocyanates in the presence of triethylamine in CH2Cl2 at ambient temperature. . This established synthetic methodology allowed us to prepare the total twelve new 4,6- Disubstituted pyrimidine urea’s in high yields and under mild reaction conditions. Experimental Section: General: All reactions were carried out in oven-dried glassware (120 °C) under an atmosphere of nitrogen unless as indicated otherwise. Ethyl acetate and hexanes from Mallinckrodt Chemical Co. were dried and distilled from CaH2. Tetrahydrofuran from Chemlabs Chemicals Co. were dried by distillation from sodium and benzophenone under an atmosphere of nitrogen. Acetonitrile were purchased from qualigens Chemical Co and dimethylformamide were purchased from Merck. Analytical thin layer chromatography (TLC) was performed on percolated plates (silica gel 60 F254), which were purchased from Merck Inc. Purification by gravity column chromatography was carried out by use of Silicycle ultra pure silica gel (particle size 40–63 µm, 100–200 mesh). Purity of products was checked by High-resolution mass spectra (HRMS) obtained by means of Q-TOF micro mass spectrometer and HPLC (Waters 2695). Proton NMR spectra were obtained on a MR (400 MHz) and Vnmrs (300 MHz) spectrometer by use of dimethylsulfoxide-d6 (DMSO) as solvent and TMS as internal standard. Proton NMR chemical shifts were referenced to residual protonated solvents (2.5 ppm for dimethylsulfoxide). Carbon-13 NMR spectra were
  • 4. Journal of Natural Sciences Research www.iiste.org ISSN 2224-3186 (Paper) ISSN 2225-0921 (Online) Vol.3, No.8, 2013 126 obtained on a MR (100 MHz) and Vnmrs (75MHz) spectrometer by use of dimethylsulfoxide as the solvent and TMS as internal standard. Carbon-13 chemical shifts are referenced to the center of the DMSO septet (δ 39.5 ppm). Multiplicities are recorded by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; bs broad singlet; bd, broad doublet; J, coupling constant (hertz). Melting points were obtained with a Buchi MP-B540 melting point apparatus. General procedure for the preparation tert-butyl (1-(6-substituted pyrimidin-4-yl) piperidin-4- yl)carbamate (3a-d, Scheme 1): Tert-butyl (1-(6-(benzo[b]thiophen-2-yl) pyrimidin-4-yl) piperidin-4-yl) carbamate (3a). To a mixture of tert-butyl 1-(6-chloropyrimidin-4-yl)piperidin-4-ylcarbamate (0.5 g, 1.60 mmol, 1.0 eq), benzo[b]thiophen-2-yl- 2-boronic acid (0.314 g, 1.76 mmol, 1.1 eq), and 0.5 N aqueous sodium carbonate (0.687 g, 6.48 mmol in 12.96 mL water) (5.0 mL) was degassed by bubbling with nitrogen gas for 15min and then added PdCl2(PPh3)2 (0.066 g, 0.008 mmol, 0.05 eq), and the reaction mixture was heated to 80 o C for 30 minutes. The reaction mixture was cooled to room temperature, the resultant solid was filtered and solid was washed with water and purified by column chromatography by using silica gel (100-200 mesh). The obtained product was recrystalized from dichloromethane in petroleum ether to give (3a) 72% (0.474 g) yield as light yellow solid mp 152.1-154.5 o C; TLC Rf 0.15 (20% EtOAc in hexanes as the eluent); 1 HNMR (DMSO, 300MHz) δ 8.50 (s, 1H), 8.40 (s, 1 H, pyrimidine H), 7.98 (t, J = 2.7 Hz, 1H, Ar-H), 7.89 (t, J = 6.3 Hz, 1H, ArH), 7.51 (s, 1H pyrimidine H), 7.41 (dd, J = 2.7 Hz, 2 H, ArH), 6.87 (d, J = 7.8 Hz, 1 H,NH) 4.46 (d, J = 12.6 Hz, 2H), 3.56 (s, 1H), 3.09 (t, J=11.7 Hz, 2H), 1.80 (d, J= 10.2 Hz, 2H), 1.39 (s, 11H); 13 C NMR (DMSO, 300MHz) δ 168.9, 161.9, 152.81, 150.34, 141.1, 139.02, 124.41, 121.31, 117.46, 106.13, 80.73, 49.13, 48.18 124.74, 23.73, ; IR (KBr) 1684 (C=O), 1220 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C22H26N4O2S) requires m/z 410.1, found m/z 411.3. tert-butyl (1-(6-(thiophen-2-yl)pyrimidin-4-yl)piperidin-4-yl)carbamate(3b). 84% yield as yellow solid mp (recrystalized from dichloromethane in petroleum ether) 142.1-146.5 o C; TLC Rf 0.26 (20% EtOAc in hexanes as the eluent); 1 HNMR (DMSO, 300MHz) δ 8.50 (s, 1H), 8.41 (s, 1 H, pyrimidine H), 8.02 (d, J = 2.7 Hz, 1H,Ar-H), ), 7.69 (d, J = 4.8 Hz, 1 H, ArH), 7.28 (s, 1 H pyrimidine H), 7.19 (t, J = 4.2 Hz, 2H, ArH), 6.85 (d, J = 6.9 Hz, 1H,NH), 4.46 (d, J = 12.6 Hz, 2H), 3.56 (s, 1H), 3.09 (t, J = 11.7 Hz, 2H), 1.80 (d, J = 10.2 Hz, 2H), 1.39 (s, 11H); 13 C NMR (DMSO, 300MHz) δ 168.9, 161.9, 156.81, 154.3, 141.1, 129.02, 128.41, 127.31, 106.13, 80.73, 49.13, 48.18 124.74, 23.73, ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C18H24N4O2S) requires m/z 360.1, found m/z 361.3. tert-butyl 1-(6-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-ylcarbamate(3c). 78% yield as white solid mp (recrystalized from dichloromethane in petroleum ether) 118.1-124.5 o C; TLC Rf 0.3 (20% EtOAc in hexanes as the eluent); 1 HNMR (DMSO, 300MHz) δ 8.81 (s, 1 H, pyrimidine H), 7.54 (dd, J = 6.2 Hz, 2H), 7.402 (dd, J = 3.6 Hz, 2H, Ar-H), ), 7.26 (t, J = 11.4 Hz, 2H, ArH), 7.21 (s, 1 H pyrimidine H), 7.05 (td, J = 4.2 Hz, 2H, ArH), 6.85 (d, J = 6.9 Hz, 1H,NH), 4.46 (d, J = 12.6 Hz, 2H), 3.56 (s, 1H), 3.09 (t, J = 11.7 Hz, 2H), 1.80 (d, J = 10.2 Hz, 2H), 1.39 (s, 11H); 13 C NMR (DMSO, 300MHz) δ 168.9, 162.3, 160.81, 156.1, 154.3, 144.3, 131.1, 129.02, 116.7, 106.13, 80.73, 49.13, 48.18, 24.74, 23.73, ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C26H30N4O3) requires m/z 446.2, found m/z 447.1. tert-butyl (1-(6-(4-methoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)carbamate(3d). 82% yield as white solid mp (recrystalized from dichloromethane in petroleum ether) 132.1-136.5 o C; TLC Rf 0.3 (20% EtOAc in hexanes as the eluent); 1 HNMR (DMSO, 300MHz) δ 8.58 (s, 1H, pyrimidine H), 7.402 (dd, J = 3.6 Hz, 1H,Ar-H), 7.26 (t, J = 11.4 Hz, 1H, ArH), 7.21 (s, 1H pyrimidine H), 7.05 (td, J = 4.2 Hz, 1H, ArH), 6.85 (d, J = 6.9 Hz, 1H,NH), 4.46 (d, J = 12.6 Hz, 2H), 3.56 (s, 1H), 3.09 (t, J = 11.7 Hz, 2H), 1.80 (d, J = 10.2 Hz, 2H), 1.39 (s, 11H); 13 C NMR (DMSO, 300MHz) δ 168.9, 164.9, 162.81, 156.1,154.3, 131.1, 129.02, 116.7, 106.13, 80.73, 49.13, 48.18, 24.74, 23.73, ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C21H28N4O3) requires m/z 384.1, found m/z 385.2. General procedure for the preparation Synthesis of 1-(4-Subtitued phenyl)-3-(1-(6-(Substitued-2- yl)pyrimidin-4-yl)piperidin-4-yl)ureas(5a-c to 8a-c, Scheme 2). Methyl 4-(3-(1-(6-(benzo[b]thiophen-2-yl)pyrimidin-4-yl)piperidin-4-yl)ureido) benzoate(5a).To a mixture 1-(6-(4-methoxyphenyl)pyrimidin-4-yl)piperidin-4-amine (0.25 g, 0.806 mmol, 1.0 eq), methyl 4- isocyanatobenzoate (0.157 g, 0.886 mmol, 1.1 eq ), and triethylamine (0.083 g, 0.806 mmol, 1.0 eq) was taken in 5 mL of CH2Cl2, then the reaction mixture was stirred at ambient temperature for 6h.. The reaction mixture was diluted with CH2Cl2 and water, organic layer was separated, dried over sodium sulphate and concentrated under vacuum. The resultant solid was recrystalized from dichloromethane in petroleum ether yielded as light yellow solid 361 mg (92%) mp () 102.1-104.5 o C; TLC Rf 0.3 (10% MeOH in CHCl3 as the eluent); 1 HNMR (DMSO, 400MHz); δ 8.81 (s, 1H), 8.52 (s, 1 H), 8.42 (s, 1H), 7.99 (t, J = 2.0 Hz, 1H ), 7.88 (m, J = 2.0 Hz, 1 H), 7.82 (d, J =7.2 Hz, 2H), 7.50 (m, J = 2.0 Hz, 3H, ArH), 7.40 (dd, J = 3.6 Hz, 2H), 6.38 (d, J = 7.6 Hz, 1H), 4.40 (d ,J = 13.6 Hz, 2H), 3.79 (s, 4H), 3.20 (t, J = 11.2 Hz, 2H), 1.91 (t, J = 9.6 Hz, 2H), 1.37 (q, J = 10,4 Hz, 2H); 13 C NMR (DMSO, 300MHz) δ 165.9, 161.4, 158.0, 156.8, 154.0, 145.0, 143.3, 140.0, 139.8, 130.3, 125.5, 124.7,
  • 5. Journal of Natural Sciences Research www.iiste.org ISSN 2224-3186 (Paper) ISSN 2225-0921 (Online) Vol.3, No.8, 2013 127 123.4, 122.6, 121.6, 116.6, 97.7, 51.6, 46.4, 42.4, 40.1, 39.7, 39.5, 39.0, 38.8, 31.5 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C26H25N5O3S) requires m/z 487.1, found m/z 488.3. 1-(1-(6-(benzo[b]thiophen-2-yl)pyrimidin-4-yl)piperidin-4-yl)-3-(3-chlorophenyl)urea (5b). 96 % yield as yellow solid mp (recrystalized from dichloromethane in petroleum ether) 106.1-110.5 o C; TLC Rf 0.3 (10% MeOH in CHCl3 as the eluent); 1 HNMR (DMSO, 400MHz); δ 8.58 (s, 1H), 8.52 (s, 1 H), 8.42 (s, 1H ), 7.99 (dd, J = 2.8 Hz, 1 H), 7.88 (dd, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 7.40 (dd, J = 6.2 Hz, 2H), 7.16 (td, J = 8.4 Hz, 2H), 6.92 (d, J = 7.6 Hz, 1H), 6.30 (d, J = 7.2 Hz, 1H), 4.41 (d, J = 11.6 Hz, 2H), 3.82 (t, J = 4.0 Hz, 1H), 3.18 (t, J = 11.2 Hz, 2H), 1.92 (d, J=10.0 Hz, 2H), 1.37 (q, J = 10.4 Hz, 2H); 13 C NMR (DMSO, 300MHz); δ 161.4, 158.1, 156.9, 154.2, 143.4, 141.9, 140.0, 139.9, 133.0, 130.1, 130.0, 125.5, 124.7, 124.3, 123.3, 122.6, 120.6, 116.9, 115.9, 97.1, 46.4, 42.4, 40.3, 39.7, 39.5, 39.2, 38.9, 38.6, 31.5 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C24H22ClN5OS) requires m/z 463.98, found m/z 465.1 & 467.1. 1-(4-methoxybenzyl)-3-(1-(6-(benzo[b]thiophen-2-yl)pyrimidin-4-yl)piperidin-4-yl)urea (5c). 92% yield as white solid mp (recrystalized from dichloromethane in petroleum ether) 122.1-126.5 o C; TLC Rf 0.2.5 (10% MeOH in CHCl3 as the eluent);; 1 HNMR (DMSO, 400MHz); δ 8.50 (s, 1H), 8.40 (s ,1H), 7.99 (dd, J = 3.6 Hz, 1H), 7.87 (dd, J = 2.0 Hz, 1H), 7.51 (s, 1H), 7.40 (dd, J = 3.2 Hz, 2H), 7.16 (d, J = 7.6 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.14 (t, J = 5.6 Hz, 1H), 5.95 (d, J = 8.0 Hz, 1H), 4.37 (d, J = 11.6 Hz, 2H), 4.12 (d, J = 5.6 Hz, 2H), 3.72 (s, 4H), 3.14 (t, J = 11.6 Hz, 2H), 1.86 (d, J = 9.6 Hz, 2H), 1.27 (q, J = 9.6 Hz, 2H);13 C NMR (DMSO, 300MHz); δ 161.5, 158.2, 158.1, 157,4, 156.9, 143.5, 140.1, 139.9, 132.7, 128.4, 125.6, 124.8, 124.4, 123.4, 122.7, 113.6, 97.1, 55.0, 46.5, 42.5, 42.3, 40.3, 40.0, 39.7, 39.5, 39.2, 38.9, 38.6, 32.0 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ;HRMS (ES+ ) exact mass calculated for [M+H]+ (C26H27N5O2S) requires m/z 473.59, found m/z 474.6. Methyl 4-(3-(1-(6-(thiophen-2-yl)pyrimidin-4-yl)piperidin-4-yl)ureido) benzoate(6a). 93% yield as off white solid mp (recrystalized from dichloromethane in petroleum ether) 112.1-114.5 o C; TLC Rf 0.32 (10% MeOH in CHCl3 as the eluent); 1 HNMR (DMSO, 400MHz) δ 8.80 (s, 1H), 8.44 (s, 1H), 8.03 (d, J = 3.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H ), 7.69 (d, J = 5,2 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.31 (s, 1H), 7.18 (t, J = 4.4 Hz, 1H), 6.38 (d, J = 7.2 Hz, 1H), 4.36 (d, J = 12.8 Hz, 2H), 3.79 (s, 4H), 3.15 (t, J = 11.6 Hz, 2H), 1.91 (t, J = 10.4 Hz, 2H), 1.35 (q, J = 6.4 Hz, 2H); 13 C NMR (DMSO, 300MHz) δ 165.9, 161.5, 158.0, 156.9, 154.0, 145.0, 143.2, 130.3, 129.3, 128.3, 126.7, 121.6, 116.7, 95.9, 51.6, 46.4, 42.3, 40.3, 40.0, 39.7, 39.5, 39.2, 38.9, 38.6, 31.5 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C22H23N5O3S) requires m/z 437.51, found m/z 438.61. 1-(3-chlorophenyl)-3-(1-(6-(thiophen-2-yl)pyrimidin-4-yl)piperidin-4-yl)urea (6b). 97% yield as yellow solid mp (recrystalized from dichloromethane in petroleum ether) 102.1-106.5 o C; TLC Rf 0.25 (10% MeOH in CHCl3 as the eluent); 1 HNMR (DMSO, 400MHz); δ 8.58 (s, 1H), 8.43 (s, 1H), 8.03 (d, J = 3.2 Hz, 1H ), 7.69 (d, J = 4.0 Hz, 1H), 7.66 (s, 1H), 7.32 (s, 1H), 7.16-7.25 (m, J = 8.8 Hz, 3H), 6.92 (d, J = 8.0 Hz, 1H), 6.29 (d, J = 7.6 Hz, 1H), 4.36 (d, J = 13.2 Hz, 2H), 3.79 (t, J = 3.6 Hz, 1H), 3.14 (t, J = 11.4 Hz, 2H), 1.90 (d, J=10.0 Hz, 2H), 1.34 (q, J = 10.4 Hz, 2H); 13 C NMR (DMSO, 300MHz); δ 161.6, 158.1, 157.0, 154.3, 143.2, 142.0, 133.1, 130.3, 129.4, 128.4, 126.8, 117.0, 116.0, 96.0, 46.4, 42.4, 40.1, 39.9, 39.7, 39.5, 39.2, 39.0 38.8, 31.6 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C20H20ClN5OS) requires m/z 413.9, found m/z 415.1. 1-(4-methoxybenzyl)-3-(1-(6-(thiophen-2-yl)pyrimidin-4-yl)piperidin-4-yl)urea (6c). 94% yield as white solid mp (recrystalized from dichloromethane in petroleum ether) 142.1-146.5 o C; TLC Rf 0.25 (10% MeOH in CHCl3 as the eluent);; 1 HNMR (DMSO, 400MHz); δ 8.42 (d, J = 0.8 Hz, 1H), 8.02 (d ,J = 2.4 Hz, 1H), 7.68 (dd, J = 0.8 Hz, 1H), 7.29 7.20 (dd, J = 0.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.12 (t, J = 6.4 Hz, 1H), 5.93 (d, J = 8.0 Hz, 1H), 4.33 (d, J = 12.4 Hz, 2H), 4.12 (d, J = 6.0 Hz, 2H), 3.72 (s, 4H), 3.10 (t, J = 11.2 Hz, 2H), 1.84 (d, J = 10,0 Hz, 2H), 1.24 (q, J = 11.2 Hz, 2H);13 C NMR (DMSO, 300MHz); δ 161.5, 158.0, 157.2, 156.9, 143.2, 132.7, 129.3, 128.3, 126.7, 113.5, 95.9, 55.0, 46.4, 42.4, 42.2, 40.1, 39.9, 39.7, 39.4, 39.2, 38.8, 31.9 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ;HRMS (ES+ ) exact mass calculated for [M+H]+ (C22H25N5O2S) requires m/z 423.5, found m/z 424.6. Methyl 4-(3-(1-(6-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)ureido) benzoate(7a). 95% yield as white solid mp (recrystalized from dichloromethane in petroleum ether) 112.1-114.5 o C; TLC Rf 0.4 (10% MeOH in CHCl3 as the eluent); 1 HNMR (DMSO, 400MHz); δ 8.81 (s,1H), 8.57 (s, 1 H), 8.17 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H ), 7.50 (d, J = 8.4 Hz, 2H), 7.42 (t, J =7.2 Hz, 2H), 7.34 (s, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 8.0 Hz, 3H), 6.38 (d, J = 8.0 Hz, 1H), 4.40 (d ,J = 13.6 Hz, 2H), 3.79 (s, 4H), 3.16 (d, J = 5.2 Hz, 2H), 1.92 (d, J = 12.8 Hz, 2H), 1.39 (q, J = 11.2 Hz, 2H); 13 C NMR (DMSO, 300MHz); δ 165.9, 161.6, 159.6, 158.9, 157.0, 155.8, 154.0, 145.1, 131.1, 130.3, 128.9, 124.1, 121.6, 119.2, 118.0, 116.7, 97.9, 51.6, 46.3, 42.5, 40.3, 40.0, 39.7, 39.2, 38.9, 38.5, 31.5 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C30H29N5O4) requires m/z 523.5, found m/z 524.5.
  • 6. Journal of Natural Sciences Research www.iiste.org ISSN 2224-3186 (Paper) ISSN 2225-0921 (Online) Vol.3, No.8, 2013 128 1-(3-chlorophenyl)-3-(1-(6-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)urea (7b). 84% yield as yellow solid mp (recrystalized from dichloromethane in petroleum ether) 108.1-112.5 o C; TLC Rf 0.35 (10% MeOH in CHCl3 as the eluent); 1 HNMR (DMSO, 400MHz); δ 8.57 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H), 7.66 (t, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.16-7.23 (m, J = 6.4 Hz, 3H), 7.0 6-7.10 (m, J = 6.4 Hz, 4H), 6.92 (d, J = 3.2 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.39 (d, J = 10.8 Hz, 2H), 3.81 (d, J = 4.0 Hz, 1H), 3.15 (t, J = 10.8 Hz, 2H), 1.90 (d, J = 9.6 Hz, 2H), 1.37 (q, J = 10.4 Hz, 2H); 13 C NMR (DMSO, 300MHz); δ 161.8, 160.9, 158.5, 158.0, 155.9, 154.2, 141.9, 141.9, 133.0, 132.3, 130.2, 130.0, 128.7, 123.9, 120.5, 119.1, 117.9, 116.9, 115.9, 97.6, 46.4, 42.3 40.3, 40.0, 39.7, 39.2, 38.9, 38.6, 31.5 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C28H26ClN5O2) requires m/z 499.9, found m/z 501.1. 1-(4-methoxybenzyl)-3-(1-(6-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)urea (7c). 97% yield as white solid mp (recrystalized from dichloromethane in petroleum ether) 116.1-120.5 o C; TLC Rf 0.2 (10% MeOH in CHCl3 as the eluent);; 1 HNMR (DMSO, 400MHz); δ 8.53 (s, 1H), 8.18 (d, J = 8.4 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.29 (s, 1H), 7.15 (t, J = 7.6 Hz, 4H), 6.12 (t, J = 5.6 Hz, 1H), 6.14 (t, J = 5.6 Hz, 1H), 5.93 (d, J = 8.0 Hz, 1H), 4.35 (d, J = 12.4 Hz, 2H), 4.12 (d, J = 5.6 Hz, 2H), 3.72 (s, 3H), 3.10 (t, J = 11.6 Hz, 2H), 1.84 (d, J = 10.4 Hz, 2H), 1.27 (q, J = 10.4 Hz, 2H);13 C NMR (DMSO, 300MHz); δ 161.0, 160.7, 158.6, 158.4, 158.2, 157.8, 155.4, 152.0, 151.7, 132.9, 130.5, 130.1, 128.6, 125.0, 124.7, 120.1, 118.3, 117.1, 114.2, 113.9, 99.4, 67.2, 55.1, 46.1, 42.6, 32.3, 25.3; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ;HRMS (ES+ ) exact mass calculated for [M+H]+ (C30H31N5O) requires m/z 509.6, found m/z 510.7. Methyl 4-(3-(1-(6-(2-fluoro-4methoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)ureido) benzoate(8a). 93% yield as white solid mp (recrystalized from dichloromethane in petroleum ether) 132.1-134.5 o C; TLC Rf 0.4 (10% MeOH in CHCl3 as the eluent); 1 HNMR (DMSO, 400MHz); δ 8.81 (s,1H), 8.60 (s, 1 H), 7.82 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H ), 7.41 (dd, J = 3.6 Hz, 1H), 7.24 (t, J = 10.4 Hz, 1H), 7.15 (s, 1H), 7.04 (t, J = 5.2 Hz, 1H), 6.39 (d, J = 7.2 Hz, 1 H), 4.29 (d ,J = 10.0 Hz, 2H), 3.79 (s, 7H), 3.17 (d, J = 11.2 Hz, 2H), 1.91 (d, J = 10.4 Hz, 2H), 1.36 (q, J = 10.0 Hz, 2H); 13 C NMR (DMSO, 300MHz); δ 166.1, 160.3, 159.3, 158.8, 158.2, 157.7, 155.8, 155.0, 151.7, 151.5, 148.1, 145.3, 145.2, 130.4, 121.1, 119.4, 119.3, 119.1, 117.6, 117.3, 117.2, 116.7, 115.6, 56.0, 51.7, 45.6, 40.3, 40.0, 39.7, 39.5, 39.2, 38.9, 38.6, 31.6 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C25H26FN5O4) requires m/z 479.5, found m/z 480.6. 1-(3-chlorophenyl)-3-(1-(6-(2-fluoro-4-methoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)urea (8b). 96% yield as yellow solid mp (recrystalized from dichloromethane in petroleum ether) 142.1-146.5 o C; TLC Rf 0.35 (10% MeOH in CHCl3 as the eluent); 1 HNMR (DMSO, 400MHz); δ 8.61 (s, 1H), 8.57 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 7.40 (dd, J = 3.2 Hz, 1H), 7.16-7.43 (m, 4H), 7.06 (td, J = 4.0 Hz, 1H), 6.91 (td, J = 2.0 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 4.30 (d, J = 10.4 Hz, 2H), 3.80 (s, 4H), 3.17 (t, J = 10.8 Hz, 2H), 1.90 (d, J = 13.6 Hz, 2H), 1.35 (q, J = 10.8 Hz, 2H); 13 C NMR (DMSO, 300MHz);δ 161.2, 157.7, 155.9, 155.4, 154.2, 152.7, 141.9, 133.0, 130.1, 126.1, 125.9, 120.5, 117.3, 116.9, 116.8, 115.9, 114.4, 102.5, 102.4, 55.6, 46.2, 42.4 40.3, 40.0, 39.7, 39.5, 39.2, 38.8, 38.6, 31.4 ; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ; HRMS (ES+ ) exact mass calculated for [M+H]+ (C23H23ClFN5O2) requires m/z 455.9, found m/z 457. 1-(4-methoxybenzyl)-3-(1-(6-(2-fluoro-4-methoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)urea (8c). 95% yield as white solid mp (recrystalized from dichloromethane in petroleum ether) 134.1-138.5 o C; TLC Rf 0.2 (10% MeOH in CHCl3 as the eluent);; 1 HNMR (DMSO, 400MHz); δ 8.59 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 3.2 Hz, 1H), 7.24 (dd, J = 8.8 Hz, 1H), 7.13 (t, J = 8.4 Hz, 3H), 6.85 (t, J = 2.8 Hz, 2H), 6.12 (t, J = 6 Hz, 1H), 5.93 (d, J = 7.6 Hz, 1H), 4.26 (d, J = 12.4 Hz, 2H), 4.11 (d, J = 5.6 Hz, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.12 (t, J = 10.8 Hz, 2H), 1.84 (d, J = 2.8 Hz, 2H), 1.23 (q, J = 4.0 Hz, 2H);13 C NMR (DMSO, 300MHz); δ 161.0, 160.7, 158.6, 158.4, 158.2, 157.8, 155.4, 152.0, 151.7, 132.9, 130.5, 130.1, 128.6, 125.0, 124.7, 120.1, 118.3, 117.1, 114.2, 113.9, 99.4, 67.2, 55.1, 46.1, 42.6, 32.3, 25.3; IR (KBr) 1680 (C=O), 1225 (C-N) cm-1 ;HRMS (ES+ ) exact mass calculated for [M+H]+ (C25H28FN5O3) requires m/z 465.5, found m/z 466.6. Acknowledgments. The authors are highly thankful to Department of Chemistry, Vignan school of P.G studies, Acharya Nagarjuna University, Nagarjunanagar, Guntur, Andhra Pradesh, India for constant encouragement. Supporting Information Available: Copies of 1 H and 13 C NMR spectra for all the new compounds. References: 1. M. Gracia-Valverde and T. Torroba, Molecules, 2005, 10, 318 320 and references cited therein. 2. I. M. Lagoja, Chemistry & Biodiversity, 2005, 2, 1 50. 3. C. O. Kappe, Tetrahedron, 1993, 49, 69376963. 4. S. Urwyler, M. F. Pozza, K. Lingenhoehl, J. Mosbacher, C. Lampert, W. Froestl, M.Koller and K. Kaupmann, J. Pharmacol. Exp. Ther, 2003, 307, 322 330. 5. (a) H. Berber, M. Soufyane, M. Santillana-Hayat and C. Mirand, Tetrahedron Lett. 2002,43, 9233 9235 and
  • 7. Journal of Natural Sciences Research www.iiste.org ISSN 2224-3186 (Paper) ISSN 2225-0921 (Online) Vol.3, No.8, 2013 129 references cited therein; (b) K. V. Jain, T. S. Chitre, P. B. Miniyar, M.K. Kathiravan, V. S. Veer, S. R. Shahane and C. J. Shishoo, Current Science, 2006, 90,793 803. 6. H. F. Boyd, B. Hammond, D. M. B. Hickey, R. J. Ife, C. A. Leach, V. Ann Lewis, C. H.Macphee, K. J. Milliner, I. L. Pinto, S. A. Smith, I. G. Stanfield, C. J. Theobald and C. M.Whittaker, Bioorg. Med. Chem. Lett. 2001, 11, 701704. 7. F. Xie, H. Zhao, D. Li, H. Chen, H. Quan, X. Shi, L. Lou and Y. Hu, J. Med. Chem. 2011,54, 3200–3205. 8. A. Herrera, R. Martınez-Alvarez-A, M. Chioua, R. Chioua and A. Sanchez, Tetrahedron,2002, 58, 10053 10058. 9. N. Miyaura and A. Suzuki, Chem. Rev, 1995, 95, 2457 2483. 10. For representative reports and a recent review, see: (a) J. M. Schomaker and T. J. Delia, J.Org. Chem. 2001, 66, 7125 7128; (b). N. E. Leadbeater and M. Marco, Org. Lett, 2002, 4,2973–2976; (c) L. Liu, Y. Zhang and Y. Wang, J. Org. Chem. 2005, 70, 6122 6125; (d). S. Li, Y. Lin, J. Cao and S. Zhang, J. Org. Chem. 2007, 72, 40674072; (e) S. Bardhan, S.Wacharasindhu, Z. K. Wan and T. S. Mansour, Org. Lett, 2009, 11, 2511–2514 andreferences cited therein. 11.(a) M. J. Mokrosz, B. Duszynska, A. Klodzinska, A. Deren-Wesolek, E. Chojnacka Wojcik, T. C. Baranowski, I. M. Abdou, N. P. Redmore and L. Strekowski, Bioorganic & Medicinal chemistry Letters. 1997, 7, 1635-1638 and references cited therein. 12. Guo-Hua. Chu, Minghua. Gu, Joel. A. Cassel, Serge. Belanger, Thomas. M. Graczyk, Robert. N. DeHaven, Nathalie.Conway -James, Michael. Koblish, Patrick J. Little, Diane L.DeHaven-Hudins, Roland E.Dolle, Bioorganic and Medicinal Chemistry Letters, 2007, 17; nb7, 1951-1955. 13. J. Joule and K. Mills, Heterocyclic Chemistry. 5th edition, Oxford: Wiley Blackwell2010, 8 and references cited therein. 14. D, Brown, The Chemistry of Heterocyclic Compounds: The Pyrimidines, New York:Interscience, 1962,
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