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

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

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.

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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

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]+
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]+
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,

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+
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+
(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+
(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+
(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
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+
(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);; 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+
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%
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]+

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
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+
(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);; 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+
(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%
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+
(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%
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+
(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.
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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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