A tandem and tunable Pd catalyzed C-N coupling of heteroarenols with ureas via C-OH bond activation

Article abstract of DOI:10.1016/j.tet.2014.10.036

At this circumstance for the first time, a facile and convenient method for heteroaryl ureas has been developed via a two-step process involving in situ C-OH activation followed by palladium catalyzed C-N coupling of heteroarenols with ureas, which show excellent functional group tolerance and give out rapid coupling in good to excellent yield.

Full text of DOI:10.1016/j.tet.2014.10.036

Tetrahedron 70 (2014) 9394e9404
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Tetrahedron
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A tandem and tunable Pd catalyzed CeN coupling of heteroarenols
with ureas via CeOH bond activation
*
Jignesh P. Dalvadi, Poojan K. Patel, Kishor H. Chikhalia
Department of Chemistry, School of Science, Gujarat University, Ahmedabad 380009, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2014
Received in revised form 29 September 2014
Accepted 15 October 2014
Available online 22 October 2014
At this circumstance for the first time, a facile and convenient method for heteroaryl ureas has been
developed via a two-step process involving in situ CeOH activation followed by palladium catalyzed CeN
coupling of heteroarenols with ureas, which show excellent functional group tolerance and give out rapid
coupling in good to excellent yield.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
CeOH activation
Pd catalyzed CeN coupling
Heteroarenols
Urea
One pot synthesis
1. Introduction
N-heteroaryl substituted ureas have drawn immense consider-
ation for the design of biologically relevant molecules with exten-
Pd-catalyzed cross-coupling reactions have qualified to being
the mainly consistent and prominent methodology for the creation
of CeN bond.1 The easy-going reaction condition, outstanding
functional group tolerance, and the quick synthesis continue this
reaction to being mandatory tools in organic chemistry.2 Numerous
efforts have also been framed to make the cross-coupling reactions
further relevant since the advance of this reaction. The pre-
activated substrates such as pseudo halides have to be most usu-
ally consumed in this cross-coupling reaction. In the focus of
scrutiny to heteroaryl halides are typically prepared from simply
accessible heteroarenols. These transformations to heteroaryl ha-
lides can be precious, often require harsh condition, toxic reagents,
and multistep syntheses. Annihilation of functionality or loss of
protecting group may be caused underneath these circumstances.3
As a result, straight CeOH bond activation of heteroarenols for
cross-coupling reaction is significantly preferred and receive
enormous attention in organic synthesis.4 The relevance of CeOH
bond containing compounds as electrophiles in cross coupling re-
action experience major defies like requirement of high bond dis-
sociation energy of inert CeOH bond and thermodynamically
dispute to cleavage inert CeOH bond. So, we have held core on the
affecting heteroarenols possess active CeOH bond.
sive biomedical appeal as therapeutics and are normally originated
as a functional moiety in natural product. According to reported
survey, N-heteroaryl urea seems to be crucial for biologically po-
tency in drugs (Fig. 1).5 They have assembled enormous planning
among chemists due to their wide array of biological activities. The
classical methods for the synthesis of N-heteroaryl substituted
ureas were prepared by the reaction of heteroaryl amines with
isocyanates.5,6 As common and conventional alternate route of
synthesis are of condensation of heteroaryl amines with carba-
mates.7 In this context, heteroaryl amines are prepared by amina-
tion reaction of hetero aryl chloride. In such cases, aminolysis
reactions are carried out under the typical conditions concern of
ammonium hydroxide (or ammonia), high temperature and pres-
sure, lengthened periods of time and sealed reactor etc., thus cre-
ating a prospective safety risk and also yielding at law quantity and
purity. Furthermore, both isocyantates and carbamates are highly
toxic, unstable, and typically require the make use of phosgene for
their synthesis.8 So, we have chosen the new and alternate way of
synthesis of N-heteroaryl urea derivatives by way of Palladium
catalyzed CeN couplings of heteroarenols with a variety of urea via
in situ CeOH bond activation.
As to the catalytic reaction of arylation of ureas, this is of sub-
stantial value for organic synthesis. In this fact, central progress of
Pd-catalyzed reaction has arisen for N-arylation of urea.9 These
intact reported outcomes impelled us to explore the application of
the Pd-catalyzed CeN coupling reaction of heteroarenols with
* Corresponding author. Tel.: þ91 942715529; e-mail address: chikhalia_kh@
yahoo.com (K.H. Chikhalia).
http://dx.doi.org/10.1016/j.tet.2014.10.036
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

J.P. Dalvadi et al. / Tetrahedron 70 (2014) 9394e9404
9395
Fig. 1. Urea based biological potential compounds.
different type of urea as coupling partners. However, to the best of
our knowledge, Palladium catalyzed CeN coupling reaction via in
situ CeOH bond activation between heteroarenols with weak nu-
cleophilic coupling partners various type of ureas has never been
reported.
In this article, we report a method for synthesis of N-heteroaryl
substituted urea derivatives via Pd-catalyzed CeN coupling re-
action of heteroarenols with ureas through in situ CeOH bond
activation.
ureas with new CeN bond formation. To the beginning of the in-
tensive study, we preliminarily examined this type of tandem re-
action of 4-quinazolinone with phenyl urea by the using
a combination of phosphonium coupling and Pd-catalyzed CeN
cross coupling. The CeOH bond of 4-quinazolinone were activated
in the presence of phosphonium reagent, base, and solvent at rt for
2 h. Then Pd catalyst, ligand, and phenyl urea were introduced and
the mixture was stirred at 100 ꢀC for 4 h. A series of phosphonium
reagents, bases, solvents, Palladium sources, and ligands were
screened for the feasibility of approach for a merger of both
couplings.
2. Result and discussion
The results of the reaction optimization are summarized in
Table 1. The coupling reactions were practically examined with
appearance and the disappearance of the active alkoxy phospho-
nium salt. The highest yield was achieved by utilizing two stan-
dard conditions: the phosphonium coupling condition (PyBroP,
Et3N, 1,4-dioxane) and the Pd-catalyzed CeN coupling condition
(Pd2(dba)3, Ligand L, (Fig. 2) Cs2CO3, 1,4-dioxane) (Table 1,
Entry 8).
In favor of assessment aim, familiar phosphonium salts were
examined for phosphonium Coupling. Among them, the Br-derived
reagents (PyBroP and BroP) were extreme more effectual than the
OBt-derived reagents (PyBOP, BOP, PyAOP) and other reagent HATU
possibly because the concluding simultaneously generated the
heterocycle-OBt ether as the side product, that almost close up the
cross-coupling reaction. PyBroP was accredited as outstanding for
In our preface exploration of a range conditions for direct syn-
thesis of N-substituted the model substrates. 4-quinazolinone was
first activated in situ with phosphonium reagent and then de-
velopment of condition for Pd-catalyzed CeN cross coupling were
explored. These were the essentially assortment of CeOH bond
activation by phosphonium coupling and subsequent Pd-catalyzed
CeN coupling with urea in one pot synthesis. We predicted that
underneath Pd heteroaryl urea derivatives, 4-quinazolinone and
phenyl urea were initially designated as the model substrates. As
catalyzed cross-coupling condition; the resultant heterocycles-
phoshphonium salt might chemically perform similar to some of
the known preactivated oxygen containing cross-coupling allies,
such as sulfonates. This would undertake Pd-catalyzed direct N-
heteroarylation of the ureas to afford the N-substituted heteroaryl

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J.P. Dalvadi et al. / Tetrahedron 70 (2014) 9394e9404
Table 1
Reaction optimizationa
(IIA)
(IIB)
(II)
Phosphonium coupling
Pd catalyzed CeN coupling
Entry
Phosphonium salt
Base
Solvent
Catalyst
Ligand
Base
Solvent
Yied %
1
2
3
4
5
6
7
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
BOP
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAC)2
Pd(dppf)Cl2
Pd(Ph3P)2Cl2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Xphos
Brettphos
Dppf
Josiphos
DPEphos
Xantphos
BINAP
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Ligand
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOtBu
K3PO4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane, H2O
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
53
56
40
43
38
59
35
89
97
37
59
42
39
34
60
54
50
46
39
33
62
77
41
33
8
8a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
BrOP
PyBOP
PyAOP
HATU
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CS2CO3
Toluene
DMF
t-BuOH
Toluene
DMF
t-BuOH
1. Phosphonium coupling: 4-quinazolinone (1 mmol), Phosphonium salt (1.50 mmol), triethyl amine (2.0 mmol), solvent (5.0 mL), rt, 2 h. 2. Pd catalyzed CeN coupling: Pd:
1.6 mol %, ligand: 5 mol %, base: 1.4 mmol, 100 ꢀC, 4 h.
a
1,4-dioxaneþH2O was used as 5:1 ratio. Water was added at Pd catalyzed CeN coupling condition.
solvent. The Pd-catalyzed CeN coupling reaction appeared to be
vigorous in presence of water. The presence of water was found to
have a significant impact on the conversion of some Buchwald-
Hartwig reactions as per previous report.10
About recognized the optimistic screening outcome; concen-
tration was curved to establish the extent and the generalization of
the process. We embarked on an exploration of the reaction scope
by varying heteroarenols for Pd catalyzed CeN coupling with ureas
by operating a feasible catalyst system based on optimized condi-
tion via in situ CeOH bond activation using PyBrop.The obtained
results resumed in Table 2 reveal that the optimized conditions
proved to be generalize for the coupling of phenyl urea with a range
of these heteroarenols. Complete conversion and good to excellent
Fig. 2. Ligand L (2-(3-(2-(diphenylphosphino)phenyl)-1H-pyrazol-1-yl)-4,6-dimethoxy-
isolated yields were observed for all the heteroarenols employed.
1,3,5-triazine).
Next, the prospect of variation in ureas including aromatic ureas,
benzylic urea, urea, and cyclic urea was also explored (Table 3).
the phosphonium coupling. In the next phase, regarding the Pd
source was also tested. Other Pd-catalyst provided less effective
catalyst system than Pd2(dba)3. With Pd2(dba)3 as the best reagent
of choice for Pd catalyzed CeN coupling. The outcome of different
bases on the reaction was inspected for viability of Pd catalyzed
CeN coupling approach. The highest yield was accomplished by
making use of Cs2CO3. In addition, different solvent systems were
also screened. 1,4-dioxane afford in highest yield contrast to other
Notably, aromatic ureas bearing either electron donating or elec-
tron withdrawing groups at ortho, meta, or para positions experi-
ence CeN bond formation commonly. Use of Cs2CO3 as the base in
optimized condition observed with the existence of a base sus-
ceptible functional group to be well tolerated. The beneficial of
Cs2CO3 that it is pleasant with functional group during reaction.11
Aromatic ureas containing electron withdrawing groups coupled
well with rational yields. While Aromatic ureas bearing electron

J.P. Dalvadi et al. / Tetrahedron 70 (2014) 9394e9404
9397
Table 2
Results of the reaction of a variety of heteroarenol with phenyl ureaa
Entry
Heteroarenol
Product
Yieldb (%)
1
97
95
91
2
3
4
5
89
90
6
7
93
85
8
90
a
Conditions: 1. Phosphonium coupling: 4-quinazolinone (1 mmol), PyBroP (1.5 mmol), and Et3N (2.0 mmol) in 1,4-dioxane (5 mL) at room temperature for 2 h; then 2. Pd
catalyzed CeN coupling: Pd2(dba)3 (3.3 mol %), phenyl urea(1 mmol), Ligand L (5 mol %) Cs2CO3(1.4 mmol), and water (1 mL) at 100 ꢀC for 4 h.
b
Isolated yield.
donating groups were successfully coupled and resulted into ex-
cellent yields. The CeN bond coupling reaction was studied for
coupling of benzyl urea and result was obtained as productively.
Finally, carrying out the coupling reaction was also effective with
cyclic urea as well as acyclic urea given that in slightly lower yields
the correspondingly bis-heteroarylated urea products. The catalyst
system was also capable to couple of benzene sulfonyl urea.
We sought to demonstrate utility of reaction to showcase such
a facile, efficient, and chemo-selective of CeOH bond activation in
the synthesis of biologically important nucleosides based compound
such as (Phenylethynyl)-1-deoxy-1-[6-[[[(4-methoxyphenyl)-amino]
carbonyl]amino]-9H-purin-9-yl]-N-ethyl-D-ribofuranuronamide.12
Which was known as A1 and A3 Adenosine receptor agonists. It
generally takes multi step to be synthesized. We felt that our

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J.P. Dalvadi et al. / Tetrahedron 70 (2014) 9394e9404
Table 3
Results of the reaction of 4-quinazolinone with a variety of ureasa
Entry
Urea
Product
Yieldb (%)
1
97
2
3
83
85
4
5
79
95
6
7
8
9
89
96
77
81

J.P. Dalvadi et al. / Tetrahedron 70 (2014) 9394e9404
9399
Table 3 (continued )
Entry
Urea
Product
Yieldb (%)
10
11
87
94
12
13
73
70
14
86
15c
77
69
16c
17
67
a
Conditions: 1. Phosphonium coupling: 4-quinazolinone (1 mmol), PyBroP (1.5 mmol), and Et3N (2.0 mmol) in 1,4-dioxane (5 mL) at room temperature for 2 h; then 2. Pd
catalyzed CeN coupling: Pd2(dba)3 (3.3 mol %), urea(1 mmol), Ligand L (5 mol %) Cs2CO3(1.4 mmol), and water (1 mL) at 100 ꢀC for 4 h.
b
Isolated yield.
c
1. Phosphonium coupling: 4-quinazolinone (1 mmol), PyBroP (1.5 mmol), and Et3N (2.0 mmol) in 1,4-dioxane (7 mL) at room temperature for 2 h; then 2. Pd catalyzed CeN
coupling: Pd2(dba)3 (6.6 mol %), urea(1 mmol), Ligand L (10 mol %) Cs2CO3(2.8 mmol), and water (1.5 mL) at 100 ꢀC for 4 h.
chemistry could assist the synthesis of this compound. Therefore,
we chose to resynthesize compounds by using the phosphonium
coupling, Pd-catalyzed CeN coupling and then sonogashira cou-
pling at sequence in one pot synthesis (Scheme 1).
Proposed the promising mechanism of the direct dehydrative
cross-coupling of 4-quinazolinone with phenyl urea via Pd
catalyzed phosphonium coupling and then CeN coupling
(Scheme 2). The triazine based phosphine ligand stabilized

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J.P. Dalvadi et al. / Tetrahedron 70 (2014) 9394e9404
(IIIA)
(III)
Scheme 1. One pot single step synthesis of (Phenylethynyl)-1-deoxy-1-[6-[[[(4-methoxyphenyl)-amino]carbonyl]amino]-9H-purin-9-yl]-N-ethyl-D-ribofuranuronamide.
Scheme 2. Plausible mechanism.

J.P. Dalvadi et al. / Tetrahedron 70 (2014) 9394e9404
9401
catalytically active Pd0 species. The tautomerization of 4-
quinazolinone to 4-quinazolinol in the presence of Et3N churn
out and then PyBroP generate the heterocycle-phosphonium
intermediate to activate of 4-quinazolinol (CeOH bond activa-
tion). Oxidative insertion of Pd0 catalyst to the CeO bond of the
heterocycle-phosphonium intermediate began catalytic and
turned out the adduct heterocycle-PdII-phosphonium species. As
a homogeneous-Pd species, this was followed by coordination of
phenyl urea to heterocycle-Pd II-phosphonium species. Ab-
straction of the hydrogen by Cs2CO3 and reductive elimination
produce the heteroaryl-urea product with regeneration of the
Pd0 catalyst.
N) were performed using a Heraeus Carlo Erba 1180 CHN analyzer
(Hanau, Germany).
4.3. Preparation of ligand L(2-(3-(2-(diphenylphosphino)
phenyl)-1H-pyrazol-1-yl)-4,6-dimethoxy-1,3,5-triazine)
3. Conclusion
In conclusion, we have developed the first Pd catalyzed CeN
coupling of heteroarenols with ureas via in situ CeOH bond ac-
tivation using phosphonium salt with a feasible, broad, and ex-
tremely efficient catalyst system. The flexible reaction condition
and straightforward exploitation cause to be an enormously ef-
fective methodology. The scope of the reaction has been shown to
tolerate both a diverse range of functionalized ureas and a variety
of heteroarenols in fair to good yields. The results would be of
immense attention because, of the perception used to improve
the synthetic efficiency in modern organic chemistry, the com-
bination of multi-step synthesis into a one-pot operation and/or
achieving he reaction has been standard as the especially effec-
tive way for atom-efficient and environmentally benign synthe-
sis. Consequently, these methods should find practical
applications in pharmaceuticals, functional materials, catalysts,
and coordination and supramolecular chemistry. Further in-
vestigations to inflate the scope of related reaction are currently
in progress. Henceforth, our future endeavored will also be de-
termined the consistent mechanism for this type of
transformation.
(IA)
(IB)
(L)
Compound (IA) and (IB) were synthesized according to the lit-
erature method without modification.14,15 IA (1.0 mmol), 2-chloro-
4,6-dimethoxy-1,3,5-triazine(1.0 mmol), and NaHCO3(1.0 mmol)
were placed in a 25-mL round-bottomed Schlenk flask. After the air
in the flask was replaced by nitrogen, dried and degassed Ethanol
(10 mL) was added. The mixture was stirred overnight under ni-
trogen atmosphere at reflux temperature. After being cooled to
room temperature, the solution was diluted by 10 mL of ethanol.
The solvent was evaporated under vacuum. The residue was puri-
fied with silica gel column chromatography and recrystallized from
n-hexane to afford ligand L.
1H NMR (400 MHz, DMSO-d6)
d ppm: 7.85e7.29 (m, 14H), 7.10 (t,
J¼7.2 Hz,1H), 6.64 (d, J¼1.5 Hz,1H), 3.85 (s, 6H). 13C NMR (100 MHz,
DMSO-d6)
d ppm: 172.45, 169.01, 152.33, 139.10, 138.00, 133.97,
4. Experimental section
4.1. Reagents
132.87, 132.66, 132.34, 130.77, 130.0, 129.89, 129.57, 126.90, 103.0,
55.0.
4.4. General procedure of reaction conditions screening
All reactions were carried out under a nitrogen atmosphere. Air-
and moisture-sensitive solvents and solutions were transferred via
syringe or stainless steel cannula. All chemicals were purchased
from sigma Aldrich, merck, and fluka. Solvents used were of ana-
lytical grade. Anhydrous potassium carbonate was stored in a ni-
trogen-filled glove-box, ground and was taken out in small
quantities and stored in a desiccator. Aryl ureas were prepared by
known methods.13 All reactions were routinely checked by TLC. TLC
was performed on aluminum-backed silica gel plates (silica gel 60
F254 grade, Merck DC) with spots visualized by UV light. Column
chromatography was performed on silica gel LC 60A
(70e200 micron).
To an oven dried flat-bottomed flask, which was equipped with
a magnetic stir bar, was charged with 4-quinazolinone (1 mmol),
phosphonium salt (1.50 mmol), triethyl amine (2.0 mmol)in dried
solvent (5.0 mL).The reaction was sparged with nitrogen for
15 min, stirred and heated to rt for 2 h. The reaction was then
recharged with phenyl urea (1.00 mol), base (1.4 mmol), ligand
(5 mol %), catalyst (3.3 mol %). The mixture was stirred at 100 ꢀC
for 4 h. After completion of the reaction, mixture was cooled to
room temperature and filtered through a pad of Celite eluting with
ethyl acetate. The filtrate was concentrated and purification of the
residue by silica gel column chromatography gave the desired
product.
4.2. Instrumental
4.5. General procedures coupling reactions
All compounds were characterized by 1H NMR, 13C NMR as well
as elemental analysis. Melting points were determined in open
capillaries on a Veego electronic apparatus VMP-D (Veego In-
strument Corporation, Mumbai, India) and are uncorrected. 1H
NMR and 13C NMR spectra were recorded on a Bruker400 MHz
model spectrometer usingDMSO-d6 as a solvent and TMS as in-
ternal standard with 1H resonant frequency of 400 MHz and 13C
resonant frequency of 100 MHz. The 1H NMR, 13C NMR chemical
shifts were reported as parts per million (ppm) downfield from
TMS (Me4Si). The splitting patterns are designated as follows; s,
singlet; d, doublet; t, triplet; m, multiplet. Elemental analyses (C, H,
To an oven dried flat-bottomed flask, which was equipped with
a magnetic stir bar, was charged with heteroarenol (1 mmol),
PyBroP (1.50 mmol), triethyl amine (2.0 mmol)in dried 1,4-dioxane
(5.0 mL).The reaction was sparged with nitrogen for 15 min, stir-
red and heated to rt for 2 h. The reaction was then recharged with
urea (1.00 mol), Cs2CO3 (1.4 mmol), ligand
L (5 mol %),
Pd2(dba)3(3.3 mol %), water (1 mL). The mixture was stirred at
100 ꢀC for 4 h. After completion of the reaction, mixture was
cooled to room temperature and filtered through a pad of Celite
eluting with ethyl acetate. The filtrate was concentrated and

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J.P. Dalvadi et al. / Tetrahedron 70 (2014) 9394e9404
purification of the residue by silica gel column chromatography
gave the desired product.
C12H12N4O: C, 63.15; H, 5.30; N, 24.55. Found: C, 63.14; H, 5.27; N,
24.57. mp 262 ꢀC.
4.7.6. 1-Phenyl-3-(pyrimidin-4-yl)urea. 1H NMR (400 MHz, DMSO-
4.6. Synthesis of (phenylethynyl)-1-deoxy-1-[6-[[[(4-methoxy-
phenyl)-amino]carbonyl] amino]-9H-purin-9-yl]-N-ethyl-D-
ribofuranuronamide
d6)
d
ppm: 9.50 (s, 1H), 8.79 (s, 1H), 8.41 (s, 1H), 8.08 (d, J¼9.0 Hz,
1H), 7.42 (d, J¼7.6 Hz, 2H), 7.23 (t, J¼7.5 Hz, 2H), 6.99 (t, J¼7.5 Hz,
1H), 6.40 (d, J¼9.0, 1H). 13C NMR (100 MHz, DMSO-d6)
d ppm:
158.62, 158.00, 156.60, 155.90, 141.00, 129.00, 121.42, 118.22, 109.10.
Anal. Calcd for C11H10N4O: C, 61.67; H, 4.71; N, 26.15. Found: C,
61.64; H, 4.75; N, 26.17. mp 243 ꢀC.
Compound (IIA) was synthesized using xanthosine according to
the literature method without modification.16 To an oven dried flat-
bottomed flask, which was equipped with a magnetic stir bar, was
charged with(IIIA) (1 mmol), PyBroP (3.00 mmol), triethyl amine
(4.0 mmol)in dried 1,4-dioxane (10 mL).The reaction was sparged
with nitrogen for 15 min, stirred and heated to rt for 2 h. The re-
action was then recharged with p-methoxy phenyl urea (1.00 mol),
Cs2CO3 (3.0 mmol), ligand L (6 mol %), Pd2(dba)3(3.5 mol %), water
(2 mL). The mixture was stirred at 100 ꢀC for 4 h. After completion
of the reaction, mixture was cooled to room temperature and then
added to CuI (2.5 mol %), ethynylbenzene (1 mmol), stirred and
heated to rt for 4 h. After completion of the coupling reaction,
mixture was filtered through a pad of Celite eluting with ethyl ac-
etate. The filtrate was concentrated and purification of the residue
by silica gel column chromatography gave the desired product in
77% yield.
4.7.7. 1-(5-Methyl-4H-pyrazol-3-yl)-3-phenylurea. 1H NMR (400
MHz, DMSO-d6)
d
ppm: 9.48 (s,1H), 8.30 (s,1H), 7.59 (d, J¼7.6 Hz, 2H),
7.43 (t, J¼7.6Hz, 2H), 6.69(t, J¼7.4Hz,1H), 3.43(s, 2H), 3.01 (s, 3H).13
C
NMR (100 MHz, DMSO-d6)
d ppm; 158.12, 156.48, 151.80, 141.05,
131.10,129.05,121.48, 33.05, 22.15.Anal. Calcd forC11H12N4O:C,61.10;
H, 5.59; N, 25.91. Found: C, 61.06; H, 5.60; N, 25.95. mp 211 ꢀC.
4.7.8. 1-(Benzo[d]thiazol-2-yl)-3-phenylurea. 1H NMR (400 MHz,
DMSO-d6)
d
ppm: 9.49 (s, 1H), 8.35 (s, 1H), 7.97 (d, J¼9.0 Hz, 1H),
8.00 (d, J¼9.0 Hz, 1H), 7.51 (m, 4H), 7.24 (d, J¼7.5 Hz, 2H), 6.94 (t,
J¼7.4 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d ppm: 156.40, 154.49,
151.02, 141.03, 133.11, 129.04, 125.10, 123.34, 121.48, 120.30, 118.11,
117.15. Anal. Calcd for C14H11N3OS: C, 62.43; H, 4.12; N, 15.60.
Found: C, 62.44; H, 4.17; N, 15.57. mp 232 ꢀC.
4.7. Characterization of coupling yield
4.7.9. 1-(2-Fluorophenyl)-3-(quinazolin-4-yl)urea. 1H NMR (400
MHz, DMSO-d6)
d ppm: 9.50 (s, 1H), 9.11 (s, 1H), 8.41 (s, 1H), 7.69
4.7.1. 1-Phenyl-3-(quinazolin-4-yl) urea. 1H NMR (400 MHz, DMSO-
(dd, J¼7.6, 5.7 Hz, 1H), 7.21 (m, 5H), 7.01 (td,J¼7.6, 5.8 Hz, 1H), 6.80
d6)
d
ppm: 9.45 (s, 1H), 9.12 (s, 1H), 8.27 (s, 1H), 7.64 (m, 2H), 7.40
(tdd, J¼7.7, 5.7, 2.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d ppm:
(m, 4H), 7.21 (t, J¼7.5 Hz, 2H), 6.96 (tt, J¼7.4, 2.0 Hz, 1H). 13C NMR
166.03, 155.53e155.35 (m), 154.05, 152.99, 152.10, 131.09 (d,
J¼8.4 Hz), 130.08, 128.99 (d, J¼19.8 Hz), 127.32, 126.30, 125.98 (d,
J¼2.9 Hz), 125.01, 122.74 (d, J¼7.6 Hz), 121.88 (d, J¼19.8 Hz), 113.12.
Anal. Calcd for C15H11FN4O: C, 63.83; H, 3.93; N, 19.85. Found: C,
63.86; H, 3.90; N, 19.83. mp 244 ꢀC.
(100 MHz, DMSO-d6)
d ppm: 166.00, 156.50, 154.00, 152.12, 141.15,
131.10, 129.07, 127.30, 126.34, 125.00, 121.41, 118.20, 113.15. Anal.
Calcd for C15H12N4O: C, 68.17; H, 4.58; N, 21.20. Found: C, 68.20; H,
4.52; N, 21.18. mp 238e239 ꢀC.
4.7.2. 1-Phenyl-3-(quinoxalin-2-yl) urea. 1H NMR (400 MHz,
4.7.10. 1-(3-Fluorophenyl)-3-(quinazolin-4-yl)urea. 1H NMR (400
DMSO-d6)
d
ppm: 9.49 (s, 1H), 9.20 (s, 1H), 8.38 (s, 1H), 7.83 (m,
MHz, DMSO-d6) d ppm: 9.52 (s, 1H), 9.13 (s, 1H), 9.46 (s, 1H), 7.83
2H), 7.60 (m, 2H), 7.46 (d, J¼7.6 Hz, 2H), 7.21 (t, J¼7.5 Hz, 2H),
(dt, J¼9.0, 2.0 Hz, 1H), 7.58 (m, 2H), 7.42 (m, 1H), 7.35 (td, J¼7.6,
6.91 (tt, J¼7.4, 2.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d ppm:
5.8 Hz, 1H), 7.19 (m, 1H), 6.83 (ddt, J¼11.0, 7.8, 2.1 Hz, 2H). 13C NMR
156.55, 156.00, 141.08, 137.99, 137.12, 134.15, 131.10, 129.02,
127.30, 126.34, 125.00, 121.45, 118.19. Anal. Calcd for C15H12N4O:
C, 68.17; H, 4.58; N, 21.20. Found: C, 68.20; H, 4.55; N, 21.16. mp
220e221 ꢀC.
(100 MHz, DMSO-d6) d ppm: 166.0, 164.02,161.52, 156.37, 154.00,
152.11, 140.91 (d, J¼7.6 Hz), 131.17, 130.03(d, J¼7.6 Hz), 127.33,
126.33, 125.08, 116.60 (d, J¼2.9 Hz), 113.18, 111.46 (d, J¼19.8 Hz),
106.64 (d, J¼19.8 Hz). Anal. Calcd for C15H11FN4O: C, 63.83; H, 3.93;
N, 19.85. Found: C, 63.82; H, 3.97; N, 19.81. mp 242 ꢀC.
4.7.3. 1-Phenyl-3-(thieno[2,3-d]pyrimidin-4-yl)urea. 1H NMR (400
MHz, DMSO-d6)
d
ppm: 9.50 (s, 1H), 9.17 (s, 1H), 8.28 (s, 1H), 7.78 (d,
4.7.11. 1-(4-Fluorophenyl)-3-(quinazolin-4-yl)urea. 1H NMR (400
J¼6.2 Hz, 1H), 7.67 (d, J¼6.2 Hz, 1H), 7.46 (d, J¼7.6 Hz, 2H), 7.30 (t,
MHz, DMSO-d6)
(dd,J¼7.6, 2.0 Hz, 1H), 7.53 (td, J¼7.5, 2.0 Hz, 1H), 7.36e7.28 (m, 4H),
6.97e7.06 (m, 2H). 13C NMR (100 MHz, DMSO-d6)
ppm: 166.04,
d ppm: 9.50 (s, 1H), 9.13 (s, 1H), 8.57 (s, 1H), 7.66
J¼7.6 Hz, 2H), 7.01 (t, J¼7.4 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d
ppm: 166.00, 156.00, 154.00, 152.12, 141.14, 129.05, 124.45, 122.15,
d
121.44, 121.00, 118.13. Anal. Calcd for C13H10N4OS: C, 57.76; H, 3.73;
N, 20.73. Found: C, 57.70; H, 3.75; N, 20.70. mp 217 ꢀC.
161.49, 159.00, 156.65, 154.04, 152.19, 139.71 (d, J¼2.9 Hz), 131.13,
127.29, 126.38, 125.07,119.63 (d, J¼8.4 Hz), 114.57 &114.37 (d,
J¼21 Hz), 113.20. Anal. Calcd for C15H11FN4O: C, 63.83; H, 3.93; N,
19.85. Found: C, 63.80; H, 3.96; N, 19.90. mp 247e248 ꢀC.
4.7.4. 1-Phenyl-3-(pyridazin-3-yl)urea. 1H NMR (400 MHz, DMSO-
d6)
d
ppm: 9.42 (s, 1H), 8.40 (s, 1H), 8.03 (d, J¼9.0 Hz, 1H), 7.89 (d,
J¼9.0 Hz, 1H), 7.61 (m, 1H), 7.51 (d, J¼7.6 Hz, 2H), 7.22 (t, J¼7.6 Hz,
4.7.12. 1-(2-Methoxyphenyl)-3-(quinazolin-4-yl)urea. 1H NMR (400
MHz, DMSO-d6) d ppm: 9.38 (s, 1H), 9.15 (s, 1H), 9.04 (s, 1H), 7.75
2H), 7.10 (t, J¼7.4 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d
ppm:
157.12, 156.49, 146.10, 141.03, 129.60, 129.00, 121.47, 118.17. 117.00.
Anal. Calcd for C11H10N4O: C, 61.67; H, 4.71; N, 26.15. Found: C,
61.63; H, 4.74; N, 26.19. mp 257 ꢀC.
(td, J¼7.6, 2.0 Hz, 1H), 7.48 (m, 2H), 7.40 (m, 1H), 7.20 (dd, J¼7.2,
2.1 Hz, 1H), 7.17e7.12 (m, 2H) 7.00 (dd, J¼7.8, 1.9 Hz, 1H), 3.75 (s,
3H). 13C NMR (100 MHz, DMSO-d6)
d ppm: 165.98, 156.62, 154.05,
153.05, 152.09, 131.08, 129.40, 127.38, 126.37, 125.30, 125.05, 124.13,
120.69, 113.74,113.17, 56.60. Anal. Calcd for C16H14N4O2: C, 65.30; H,
4.79; N, 19.04. Found: C, 65.33; H, 4.84; N, 19.00. mp 234 ꢀC.
4.7.5. 1-(4-Methylpyrimidin-2-yl)-3-phenylurea. 1H NMR (400 MHz,
DMSO-d6)
d
ppm: 9.47 (s,1H), 8.33 (s,1H), 8.22 (d, J¼9.0 Hz,1H), 7.21
(t, J¼7.5 Hz, 2H), 7.43 (d, J¼7.5 Hz, 2H), 7.0 (m, 2H) 2.72 (s, 3H). 13
C
NMR (100 MHz, DMSO-d6)
d
ppm: 169.00, 157.82, 156.58, 155.10,
4.7.13. 1-(3-Methoxyphenyl)-3-(quinazolin-4-yl)urea. 1H NMR (400
141.08, 129.04, 121.41, 118.19, 116.34, 25.15. Anal. Calcd for
MHz, DMSO-d6) d ppm:9.41 (s, 1H), 9.14 (s, 1H), 8.37 (s, 1H), 7.77

J.P. Dalvadi et al. / Tetrahedron 70 (2014) 9394e9404
9403
(dd, J¼7.6, 2.0 Hz, 1H) 7.50 (m, 2H), 7.34 (m, 2H), 7.22 (t, J¼8.0 Hz,
1H), 6.98 (dd, J¼8.0, 2.0 Hz, 1H), 6.60 (dd, J¼8.0, 2.0 Hz, 1H), 3.78 (s,
131.17, 127.36, 126.31, 126.77 (m), 125.00, 124.01, 119.70 (d,
J¼2.2 Hz), 113.21. Anal. Calcd for C16H11F3N4O: C, 57.83; H, 3.34; N,
17.15. Found: C, 57.85; H, 3.37; N, 17.20. mp 257 ꢀC.
3H). 13C NMR (100 MHz, DMSO-d6)
d ppm:166.05,159.15, 156.57,
153.99, 152.07, 141.27, 131.16, 129.67, 127.26, 126.39, 125.07, 116.36,
113.18, 113.09, 107.47, 56.57. Anal. Calcd for C16H14N4O2: C, 65.30; H,
4.79; N, 19.04. Found: C, 65.84; H, 4.58; N, 9.01. mp 230e231 ꢀC.
4.7.21. 1-Benzyl-3-(quinazolin-4-yl)urea. 1H NMR (400 MHz,
DMSO-d6)
J¼7.6 Hz, 1H), 7.71 (m, 2H), 7.51 (t, J¼7.5 Hz, 1H), 7.25e7.11 (m, 5H),
4.33 (s, 2H). 13C NMR (100 MHz, DMSO-d6)
ppm: 165.94, 155.51,
d ppm: 9.69 (s, 1H), 9.06 (s, 1H), 7.96 (s, 1H), 7.88 (d,
4.7.14. 1-(4-Methoxyphenyl)-3-(quinazolin-4-yl)urea. 1H NMR (400
d
MHz, DMSO-d6)
d
ppm: 9.40 (s, 1H), 9.10 (s, 1H), 8.90 (s, 1H), 7.70
154.05, 152.02, 141.14, 131.10, 128.32, 128.19, 127.38, 126.75, 126.31,
124.88,113.19, 45.00. Anal. Calcd for C16H14N4O: C, 69.05; H, 5.07; N,
20.13. Found: C, 69.08; H, 5.08; N, 20.08. mp 211e212 ꢀC.
(dd, J¼7.6, 2.0 Hz, 1H) 7.52 (m, 2H), 7.41 (d, J¼7.6 Hz, 2H), 7.30 (m,
1H), 6.83 (d, J¼7.6 Hz, 2H), 3.72 (s, 3H). 13C NMR (100 MHz, DMSO-
d6)
d ppm: 166.06, 159.98, 156.70, 154.08, 152.17, 137.57, 131.18,
127.36, 126.38, 125.00, 119.58, 114.38, 113.19, 56.57. Anal. Calcd for
4.7.22. 1,3-Di(quinazolin-4-yl)urea. 1H NMR (400 MHz, DMSO-d6)
C
16H14N4O2: C, 65.30; H, 4.79; N, 19.04. Found: C, 65.35; H, 4.77; N,
d
ppm: 9.73 (s, 2H), 9.10 (s, 2H), 7.75 (d, J¼7.8 Hz, 2H), 7.71 (d,
19.02. mp 237 ꢀC.
J¼7.8 Hz, 2H), 7.44e7.60 (m, 4H). 13C NMR (100 MHz, DMSO-d6)
d
ppm: 166.08, 156.78, 154.12, 152.08, 131.07, 127.27, 126.28, 124.06,
4.7.15. 1-(4-Cyanophenyl)-3-(quinazolin-4-yl)urea. 1H NMR (400
MHz, DMSO-d6)
J¼8.6 Hz, 2H), 7.79 (m, 2H), 7.69 (d, J¼8.6 Hz, 2H), 7.90 (d, J¼7.5 Hz,
1H), 7.44 (m, 1H). 13C NMR (100 MHz, DMSO-d6)
ppm:
113.18. Anal. Calcd for C17H12N6O: C, 64.55; H, 3.82; N, 26.57 Found:
C, 64.50; H, 3.84; N, 26.54. mp 200 ꢀC.
d ppm: 9.52 (s, 1H), 9.09 (s, 1H), 8.90 (s, 1H),8.20 (d,
d
4.7.23. 1,3-Di(quinazolin-4-yl)imidazolidin-2-one. 1H NMR (400
166.09,156.77, 154.09, 152.17, 142.44, 133.34, 131.11, 127.36, 126.38,
125.07, 119.15, 119.00, 113.17, 107.70. Anal. Calcd for C16H11N5O: C,
66.43; H, 3.83; N, 24.21. Found: C, 66.47; H, 3.89; N, 24.24. mp
218 ꢀC.
MHz, DMSO-d6)
d
ppm: 9.13 (s, 2H), 7.78 (d, J¼7.8 Hz, 2H), 7.64 (d,
J¼7.8 Hz, 2H), 7.24e7.49 (m, 4H), 4.15 (m, 4H). 13C NMR (100 MHz,
DMSO-d6)
d ppm: 165.97, 152.07, 154.04, 131.15, 127.37, 126.31,
125.09, 113.10., 156.86, 56.20, 42.66. Anal. Calcd for C19H14N6O: C,
66.66; H, 4.12; N, 24.55. Found: C, 66.64; H, 4.16; N, 24.60.
mp207 ꢀC.
4.7.16. 1-(Quinazolin-4-yl)-3-(p-tolyl)urea. 1H NMR (400 MHz,
DMSO-d6)
d ppm: 9.44 (s, 1H), 9.14 (s, 1H), 9.00 (s, 1H), 7.84 (d,
J¼7.6 Hz, 1H), 7.66 (m, 2H), 7.46 (t, J¼7.6 Hz, 1H), 7.21 (d, J¼7.8 Hz,
4.7.24. N-(Quinazolin-4-ylcarbamoyl)benzenesulfonamide. 1H NMR
2H), 7.00 (d, J¼7.8, 2H), 2.37 (s, 3H), 13C NMR (100 MHz, DMSO-d6)
(400 MHz, DMSO-d6)
d ppm: 9.06 (s, 1H), 8.87 (s, 1H), 7.67 (d,
d
ppm: 165.097, 156.65, 153.98, 152.09, 139.89, 137.57, 131.06,
J¼7.6 Hz, 2H), 7.47 (s, 1H), 7.25 (d, J¼7.6 Hz, 2H), 7.13 (m, 3H), 6.95
128.77, 127.26, 126.29, 125.07, 118.92, 113.21, 22.00. Anal. Calcd for
(m, 1H), 6.86 (t, J¼7.4 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d ppm:
C
16H14N4O: C, 69.05; H, 5.07; N, 20.13. Found: C, 69.10; H, 5.05; N,
165.79, 155.07, 153.91, 153.00, 141.00, 133.05, 131.50, 129.12, 127.10,
126.24, 124.57, 110.19, 105.81. Anal. Calcd forC15H12N4O3S: C, 54.87;
H, 3.68; N, 17.06. Found: C, 54.82; H, 3.71; N, 17.03. mp 208 ꢀC.
20.17. mp 225 ꢀC.
4.7.17. N-(4-(3-(Quinazolin-4-yl)ureido)phenyl)acetamide. 1H NMR
(400 MHz, DMSO-d6)
d ppm: 9.76 (s, 1H), 9.19 (s, 1H), 9.42 (s, 1H),
Acknowledgements
8.15 (s, 1H), 7.89 (d, J¼7.5 Hz, 1H), 7.73 (d, J¼7.8 Hz, 2H), 7.64 (m,
2H), 7.58 (d, J¼7.8 Hz, 2H),7.41 (m, 1H). 2.11 (s, 3H). 13C NMR
The authors are thankful to Dr. (Ms.) N. K. Shah, Head of the
Chemistry Department and Director of School of Sciences, Gujarat
University for all the support and facilities. The authors also express
their sincere thanks to the Oxygen health care for spectral analysis.
One author is also thankful to UGC for providing financial
assistance.
(100 MHz, DMSO-d6)
d ppm: 170.05, 166.04, 156.53, 153.95, 152.10,
139.02, 137.89, 131.11, 127.35, 126.35, 124.95, 119.10, 119.00, 113.17,
23.53. Anal. Calcd for C17H15N5O2: C, 63.54; H, 4.71; N, 21.79. Found:
C, 63.59; H, 4.67; N, 21.74. mp 219 ꢀC.
4.7.18. 1-(4-Morpholinophenyl)-3-(quinazolin-4-yl)urea. 1H NMR
(400 MHz, DMSO-d6)
d ppm: 9.43 (s, 1H), 9.20 (s, 1H), 8.76 (s, 1H),
Supplementary data
7.65 (m, 2H), 7.50 (d, J¼7.6 Hz, 2H), 7.41 (m, 1H), 7.28 (m, 1H), 6.87
(d, J¼7.6 Hz, 2H), 3.70 (t, J¼4.8 Hz, 4H), 3.28 (t, J¼4.8 Hz, 4H). 13
C
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.10.036.
NMR (100 MHz, DMSO-d6)
d ppm: 166.00, 156.47, 154.00, 152.12,
151.76, 136.06, 131.10, 127.30, 126.34, 125.00, 120.56, 118.40, 113.15,
67.00, 49.80. Anal. Calcd for C19H19N5O2: C, 65.32; H, 5.48; N, 20.04.
Found: C, 65.35; H, 5.50; N, 20.07. mp 249 ꢀC.
References and notes
1. (a) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599e1626; (b) Jiang,
L.; Buchwald, S. L. In Metal-catalyzed cross-coupling reactions, 2nd ed.; Meijere,
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Synlett 2006, 1283e1287.
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Dunetz, J. R. Chem. Rev. 2011, 111, 2177e2250.
4.7.19. 1-(4-Acetylphenyl)-3-(quinazolin-4-yl)urea. 1H NMR (400
MHz, DMSO-d6) d ppm: 9.47 (s,1H), 9.03 (s,1H), 8.64 (s, 1H), 7.94 (d,
8.2 Hz, 2H), 7.85 (d, 8.2 Hz, 2H),7.75 (d, J¼7.6 Hz, 1H), 7.62 (m, 2H),
7.41 (t, J¼7.6 Hz, 1H),2.60 (s, 3H). 13C NMR (100 MHz, DMSO-d6)
d
ppm: 197.86, 166.00, 156.76,1 54.03, 152.02, 141.53, 135.53, 131.13,
128.77, 127.35, 126.37, 125.02,118.65, 113.15, 25.77. Anal. Calcd for
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C
17H14N4O2: C, 66.66; H, 4.61; N, 18.29. Found: C, 66.63; H, 4.69; N,
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J. C.; Cai, C.; Sui, W. Z.; Murray, V. Chem. Commun. 2010, 1347e1349; (c) Li, S.;
Huang, J.; Chen, G.; Han, F. Chem. Commun. 2011, 12840e12842; (d) Zhao, Y.;
Wub, G.; Han, F. Chem. Commun. 2012, 5868e5870; (e) Bae, S.; Lakshman, M. K.
J. Am. Chem. Soc. 2007, 129, 782e789; (f) Kang, F.; Sui, Z.; Murray, W. V. J. Am.
Chem. Soc. 2008, 130, 11300e11302; (g) Kang, F.; Kodah, J.; Guan, Q.; Li, X.;
Murray, W. V. J. Org. Chem. 2005, 70, 1957e1960; (h) Wan, Z.; Wacharasindhu,
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18.25. mp 227 ꢀC.
4.7.20. 1-(Quinazolin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea. 1H
NMR (400 MHz, DMSO-d6) d ppm: 9.49 (s, 1H), 9.11 (s, 1H), 8.08 (s,
1H), 7.91 (d, J¼8.8 Hz, 2H), 7.82 (d, J¼7.5 Hz, 1H), 7.68 (m, 2H), 7.50
(d, J¼8.8 Hz, 2H),7.30 (m, 1H). 13C NMR (100 MHz, DMSO-d6)
d
ppm: 166.06, 156.81, 154.00, 152.13, 143.48, 132.54, 132.23,

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