Microwave assisted, ligand free, copper catalyzed reaction of aryl halides with phenyl urea

Article abstract of DOI:10.1016/j.cclet.2010.09.037

The ligand free coupling reaction of phenyl urea with different functionalized aryl halides in the presence of air stable Cu₂O and t-BuOK as a base gives symmetrical and unsymmetrical diarylureas in relatively high yields. This method is milder than the palladium catalyzed arylation and avoids the use of toxic phosphine ligand.

Full text of DOI:10.1016/j.cclet.2010.09.037

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 292–295
www.elsevier.com/locate/cclet
Microwave assisted, ligand free, copper catalyzed reaction of aryl
halides with phenyl urea
a
Sandip N. Gavade , Ravi S. Balaskar , Madhav S. Mane , Pramod N. Pabrekar ,
a
a
c
b
Murlidhar S. Shingare , Dhananjay V. Mane
a,
*
a
Organic Research Laboratory, S.C.S. College, Omerga 413 606 (MS), India
b
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004 (MS), India
c
V.G. Vaze College, Mulund(E), Mumbai 400081 (MS), India
Received 17 June 2010
Available online 24 December 2010
Abstract
The ligand free coupling reaction of phenyl urea with different functionalized aryl halides in the presence of air stable Cu
t-BuOK as a base gives symmetrical and unsymmetrical diarylureas in relatively high yields. This method is milder than the
2
O and
palladium catalyzed arylation and avoids the use of toxic phosphine ligand.
#
2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: Microwave assisted; Ligand free; Copper catalyze; Phenyl urea; Aryl halides
The transition metal catalyzed cross-coupling of aryl halides and amines provides an invaluable entry towards the
synthesis of a wide range of compounds, including pharmaceuticals and natural products. The copper catalyzed variant
has emerged as an important alternative that is most promising for large-scale industrial applications due to lower
catalyst cost and toxicity [1]. N-aryl- and N-heteroaryl-substituted ureas are important subunits present in a number of
naturally occurring compounds and have found numerous applications such as drugs, pesticides [2], antioxidants [2]
and anion binding receptors [3]. The most straightforward route for the synthesis of diarylureas include the reaction of
aromatic amines with isocyanates, phosgene or carbon monoxide, although widely used, this methodology has
numerous deficiencies: most notably, in low reaction yields resulting from instability of the isocyanates,
disproportionation leading to symmetrical ureas, and highly toxic reagents [2]. The development of palladium-
catalyzed C–N bond-forming processes [4] has supplanted classical amination reactions such as the Ullmann [5] and
related Goldberg reactions [6], which require very high temperatures, highly polar solvents, and a large excess
of the alkoxides [7]. Among these the palladium catalyzed reactions are very sensitive to functional groups such
as –OH, –NH , exogenous air or moisture and also very expensive compared to the copper reagent [8].
2
Brian has reported the palladium catalyzed amidation of urea with different aryl halides and bippyphos was found
to be a suitable ligand for these coupling reactions. However, this method suffers from the following disadvantages: (1)
the use of toxic phosphine ligands, (2) the palladium catalyst is expensive, and (3) the formation of substantial amounts
*
Corresponding author.
E-mail address: dr_dvmane@rediffmail.com (D.V. Mane).
1001-8417/$ – see front matter # 2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2010.09.037

S.N. Gavade et al. / Chinese Chemical Letters 22 (2011) 292–295
293
of N-phenylation products arising from aryl group exchange between the aryl group bound to the palladium and the
phenyl group of the bippyphos [9]. Belestkaya has reported that the electron poor ligand 3,5-(CF ) 2-xantphos is more
3
effective than xantphos and requires lower catalyst loading and gives higher yields of products than xantphos [10]. An
attempt by the same group for the arylation of urea using a copper catalyst was unsuccessful [10]. There have been
many reports recently on the arylation of different compounds such as amines [8], amides [10], hydrazides, [11] etc.
using copper catalysts in the presence of suitable ligands and without ligand [12]. Microwave-assisted organic
reactions have been applied to a wide range of reaction types, including aromatic nucleophilic substitution,
cycloaddition, and organometallic reactions [13]. It accelerates a variety of synthetic transformations via time- and
energy-saving protocols. As a part of our program to synthesize different biologically active molecules using copper
catalyzed coupling reactions, we carried out the following investigations and preliminary results are given below. We
report a ligand free, copper catalyzed amidation of aryl halides with phenyl urea.
1
. Experimental
1
.1. General procedure
A Biotage vial of 0.5–2.0 mL was filled with the substituted phenyl urea (1.0 mmol), phenyl iodide (1.5 mmol), t-
BuOK (1.5 mmol), Cu O (10 mol%), anhydrous N-methyl-2-pyrrolidone (NMP) (1 mL). The vial was degassed with
2
N , sealed, and irradiated at 100 8C for 20 min. Once cooled, the reaction mixture was quenched with water, extracted
2
with diethyl ether and dried over anhydrous MgSO . The solvents were removed under vacuum and the residue was
4
1
purified by silica gel chromatography. The identity and purity of the known products was confirmed by H and
1
3
C NMR spectroscopic analysis, and the new products were fully characterized. 3-Diphenylurea (carbanilide) (Table
1
1
4
1
, entry 1): white solid in 75% isolated yield. M.p. 237.5 8C; H NMR (400 MHz, DMSO-d ): d 8.63 (s, 2H), 7.45 (d,
6
1
H, J = 8.6, Hz), 7.27 (t, 4H, J = 7.9 Hz), 6.96 (t, 2H, J = 7.3 Hz). C NMR (101 MHz, DMSO-d ): d 151.9, 139.1,
3
6
+
28.2, 121.3, 117.7. HRMS (EI, m/z) calcd. for C H N O (M ) 212.25, found 212.21. N-(2-pyridinyl)-N -phenylurea
0
1
3 12 2
1
(
Table 1, entry 8): white solid in 80% isolated yield. M.p. 186–188 8C; H NMR (400 MHz, DMSO-d ): d 10.49 (s,
6
1
7
1
H), 9.42 (s, 1H), 8.27 (d, 1H, J = 3.9 Hz), 7.77–7.70 (m, 1H), 7.55–7.45 (m, 3H), 7.34–7.26 (m, 2H, J = 4.1, 11.7 Hz),
1
.05–6.97 (m, 2H). C NMR (101 MHz, DMSO-d ): d 152.2, 151.5, 146.3, 138.4, 138.0, 128.4, 122.0, 118.3, 117.0,
3
6
+
11.5. HRMS (EI, m/z) calcd. for C H N O (M ) 213.24, found 213.28.
1
2 11 3
2
. Results and discussion
To find the optimum conditions for the coupling of phenyl urea with aryl halide, the N-arylation of phenyl urea
1 mmol) with iodobenzene (1.5 mmol) was investigated with different solvents, bases and various Cu salts (10 mol%) at
various temperatures for 20 min. A series of copper catalysts were screened extensively. CuI, CuSO , Cu O, CuBr ,
(
4
2
2
CuBr, CuCl, Cu(OAc) , Cu(acac) and were found to be inferior to Cu O as catalysts for the C–N coupling reaction. No
2
2
2
reaction was observed without any copper source. The yields of product decreased when reducing or elevating reaction
temperatures. The yields of product were 77% and 74%, respectively, when the amount of catalyst Cu O was reduced to
2
2
reactions using K CO , K PO , or t-BuONa as the base had poor yields of the desired product. The optimal results were
0 mol% and 10 mol%. The reactions using t-BuOK as the base gave the desired product in good yields, while the
2
3
3
4
obtained when phenyl urea (1.0 mmol), aryl halide (1.5 mmol) and t-BuOK (1.5 mmol) as a base were allowed to react
with 10 mol% of Cu O stirred in N-methyl-2-pyrrolidone (NMP) at 100 8C for 20 min in a microwave. The product was
2
characterized on the basis of its spectral data and by comparison of its melting point with the literature [14].
To determine the applicability of the copper catalyzed N-arylation with respect to the aryl halides, the substrate
possessing electron withdrawing substituent such as CF , in the meta position (Table 1, entry 9), fluorine, nitro in the
3
para position (Table 1, entries 4 and 5) were obtained in excellent yields. Electron releasing substituents such as Me
and OMe in the para position (Table 1, entries 2 and 3) and in the ortho position (Table 1, entries 6 and 7) of the
aromatic rings gave good yields of the corresponding diarylureas. Reaction of the bulky aryl halides 1-
0
iodonaphthalene with phenyl urea gave N-(1-naphthyl)-N -phenylurea in a good yield (Table 1, entry 10). Reaction of
heteroaryl halides 2-iodopyridine (Table 1, entry 8) gave excellent yield; 3-iodopyridine (Table 1, entry 18) gave good
yield. No significant electronic effects were observed for substituted phenyl ureas based on the yields of reactions and
reaction times. Substrate possessing electron withdrawing fluorine in the para position (Table 1, entry 11) and electron

294
S.N. Gavade et al. / Chinese Chemical Letters 22 (2011) 292–295
Table 1
a
[TD$INLE]
The copper-catalyzed N-arylation of substituted phenyl urea with aryl iodide in the presence of t-BuOK at 100 8C in MW, NMP as a solvent.
.
b
Yield (%)
Entry
Aryl halide
Phenyl urea
Product
[TD$INLINE]
[
D
I
L
N
]
[TD$INLE]
1
2
75
68
[
T
D
$
I
N
L
I
N
E
]
[TD$INLE]
[DT$INLE]
[
T
D
$
I
N
L
I
N
E
]
[
$
N
I
E
[TD$INLE]
3
4
65
[TD$INLINE]
[
D
I
L
N
]
[TD$INLE]
8
0
[
T
D
$
I
N
L
I
N
E
]
[
$
N
I
E
[TD$INLE]
5
6
7
85
63
60
[TD$INLINE]
[
$
N
I
E
[TD$INLE]
[
T
D
$
I
N
L
I
N
E
]
[TD$INLE]
[DT$INLE]
8
0
[TD$INLINE]
[
D
I
L
N
]
[TD$INLE]
8
9
[
T
D
$
I
N
L
I
N
E
]
[TD$INLE]
[DT$INLE]
7
7
2
0
[
T
D
$
I
N
L
I
N
E
]
[
$
N
I
E
[TD$INLE]
10
[
T
D
$
I
N
L
I
N
E
]
[TD$INLE]
[DT$INLE]
1
1
1
2
62
7
2
[TD$INLINE]
[
$
N
I
E
[TD$INLE]
[
T
D
$
I
N
L
I
N
E
]
[TD$INLE]
[DT$INLE]
1
1
1
1
3
4
5
6
76
78
[
T
D
$
I
N
L
I
N
E
]
[
$
N
I
E
[TD$INLE]
7
0
[TD$INLINE]
[
D
I
L
N
]
[TD$INLE]
[TD$INLINE]
[
D
I
L
N
]
[DT$INLE]
77
79
[TD$INLINE]
1
1
7
[
D
N
I
E
[TD$INLE]
c
5
7
[
T
D
$
I
N
L
I
N
E
]
[
$
N
I
]
[TD$INLE]
8
a
2
Reaction condition: substituted phenyl urea (1.0 mmol), aryl halide (1.5 mmol), Cu O (10 mol%) and base t-BuOK (1.5 mmol), N-methyl-2-
pyrrolidone (1 mL per mmol), 100 8C, 20 min, MW.
Yield of isolated product after flash chromatography.
b
c
Time 30 min.

S.N. Gavade et al. / Chinese Chemical Letters 22 (2011) 292–295
295
releasing substituents such as Me and OMe in the para position (Table 1, entries 13 and 15) and ortho-positions (Table 1,
entries 16 and 17) of the aromatic rings also gave good to excellent yields of the corresponding substituted diarylureas.
Unfortunately, attempts to apply aryl bromides as arylating agents provided the target cross-coupling products in only
very low yields [15].
3
. Conclusion
In summary, we have developed an efficient and inexpensive catalytic system for the synthesis of symmetrical and
0
unsymmetrical N,N -diarylureas via the reaction of various aryl iodides with substituted phenyl urea using Cu O and
2
t-BuOK as a base. We believe that this is an excellent complement to the previously established palladium- and
copper-catalyzed N-arylation protocols. Due to its manipulation ease, low-cost, and benign character, the new copper
catalyst system described appears promising for large-scale applications.
Acknowledgment
Authors are thankful to Head of Department of Chemistry V.G. Vaze College, Mulund (E), Mumbai-81(MS), India
for providing the necessary laboratory facilities.
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