A new and efficient synthesis of 1 (4-subtitued...

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: [email protected]

Graphical Abstract:

N N

ClCl NH

NH

O

O

Step-1

N N

NCl

NH Boronic acids

/PdCl2(PPh3)2

/water/80o C

Step-2N N

NG

NH O

O

G = Aryl, Hetro aryl

N N

NG

NH2

TFA/DCMIsocyanates

TEA/DCM

NN

N G

NH

O

NHStep-3 Step-4

Cs2CO3/ DMF

R

12

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 oC 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 1H NMR,

13C 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



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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

CF3NS

AcHN

AMG 517

N

N

C2H5 NH2

ClNH2

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 oC 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 1H NMR,

13C 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.



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125

B

O

N N

NCl

HN O

O

N N

NG

HN O

O

PdCl2(PPh3)2

0.5M Na2CO3

H2O, 80 oC, 30min

(60-85%)

B

OH

OHS

B

OH

HOS

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

NH

O

NH

Step-4

R

45

R - COOMe, Cl, OMe5a-c,6a-c,7a-c and8a-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



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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 oC 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 oC;

TLC Rf 0.15 (20% EtOAc in hexanes as the eluent); 1HNMR (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 oC; TLC Rf 0.26 (20% EtOAc in hexanes

as the eluent); 1HNMR (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 oC; TLC Rf 0.3 (20% EtOAc in hexanes as

the eluent); 1HNMR (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 oC; TLC Rf 0.3 (20% EtOAc in hexanes

as the eluent); 1HNMR (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 oC; TLC Rf 0.3 (10% MeOH in CHCl3 as the eluent);

1HNMR (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,



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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


+ (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 oC; TLC Rf 0.3 (10%

MeOH in CHCl3 as the eluent); 1HNMR (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


+ (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 oC; TLC Rf 0.2.5 (10%

MeOH in CHCl3 as the eluent);; 1HNMR (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 oC; TLC Rf 0.32 (10% MeOH in

CHCl3 as the eluent); 1HNMR (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


+ (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


CHCl3 as the eluent); 1HNMR (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


+ (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


CHCl3 as the eluent);; 1HNMR (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


+

(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 oC; TLC Rf 0.4 (10%

MeOH in CHCl3 as the eluent); 1HNMR (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.



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


CHCl3 as the eluent); 1HNMR (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


CHCl3 as the eluent);; 1HNMR (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


+

(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 oC; TLC Rf 0.4 (10%

MeOH in CHCl3 as the eluent); 1HNMR (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 oC; TLC Rf 0.35 (10%

MeOH in CHCl3 as the eluent); 1HNMR (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


+

(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 oC; TLC Rf 0.2 (10%

MeOH in CHCl3 as the eluent);; 1HNMR (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 1H and

13C NMR spectra for all the new compounds.

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