N-Phenylurea as an inexpensive and efficient ligand for Pd-catalyzed Heck and room-temperature Suzuki reactions

Article abstract of DOI:10.1016/j.tetlet.2006.10.124

N-Phenylurea was found to constitute a highly efficient, yet low-priced, phosphine-free ligand for the Pd-catalyzed Heck and room-temperature Suzuki reactions of aryl bromides and iodides with very high turnover numbers (ca. 10³-10⁴).

Full text of DOI:10.1016/j.tetlet.2006.10.124

Tetrahedron Letters 48 (2007) 163–167
N-Phenylurea as an inexpensive and efficient ligand for
Pd-catalyzed Heck and room-temperature Suzuki reactions
Xin Cui, Yuan Zhou, Na Wang, Lei Liu* and Qing-Xiang Guo*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
Received 12 August 2006; revised 20 October 2006; accepted 25 October 2006
Available online 21 November 2006
Abstract—N-Phenylurea was found to constitute a highly efficient, yet low-priced, phosphine-free ligand for the Pd-catalyzed Heck
and room-temperature Suzuki reactions of aryl bromides and iodides with very high turnover numbers (ca. 103–104).
ꢀ 2006 Elsevier Ltd. All rights reserved.
Reactions leading to the formation of C–C bonds are
central to the synthesis of complex organic molecules.
The potent utility of Pd-catalyzed transformations (such
as Heck and Suzuki reactions) in this regard has assured
their place at the forefront of modern synthetic technol-
ogies.1 These transformations, normally performed with
1–5 mol % of Pd catalyst along with phosphine ligands,
have already been widely utilized in the academic insti-
tutions. However, industrial applications of these trans-
formations are still rare, mainly due to the following two
problems.2 First, Pd is expensive, and contamination of
the product by Pd has to be tightly controlled. Second,
many phosphine ligands are even more expensive, and
they are not pleasant to work with as they are poison-
ous, air sensitive, and prone to degrade at elevated tem-
peratures. Accordingly, one of the current challenges in
the field is the development of high turnover-number
catalysts (HTC) that utilize inexpensive, preferentially
nonphosphine, ligands.
reactions. Compared to many of the previous phos-
phine-free ligands,3–19 an important advantage associ-
ated with the N-phenylurea ligand is that the catalyzed
reactions enjoy very high turnover numbers (ca. 103–
104). Moreover, equipped with the N-phenylurea ligand
we have achieved room-temperature Suzuki reactions,
which were accomplished previously either by using
complicated phosphine or heterocyclic carbene
ligands,20 or by using a relatively high load of Pd
(i.e., >1 mol %).21
To begin our study, we examined the Heck reaction
between bromobenzene and styrene in the absence or
presence of ureas (Table 1). It was found that without
any ligand the yield of the Heck reaction was as low as
15% after 10 h (entry 1). The addition of un-substituted
urea dramatically increased the yield to 73% (entry 2).
The addition of N-methylurea also increased the yield
to 70% (entry 3). Nonetheless, it was found that N,N0-
dimethylurea was not effective because its corresponding
yield was only 8% (entry 4). Surprisingly, we next found
that N-phenylurea was considerably more active than
the un-substituted urea in facilitating the Heck reaction.
A nearly quantitative conversion of the starting material
to the desired product could be achieved in only 2 h in
the presence of N-phenylurea (entry 5). Compared to
N-phenylurea, N,N0-diphenylurea, and N-phenyl-N0-
methylurea were not as effective because they required
a longer reaction time and their corresponding yields
were lower (entries 6–7).
To meet the challenge, a number of phosphine-free cat-
alysts have been examined for the Heck and Suzuki
reactions. Previously studied ligands include hetero-
cyclic carbenes,3 oxazolines,4 Schiff bases,5 diazabuta-
dienes,6 pyridines,7 hydrazones,8 pyrazoles,9 phen-
anthrolines,10 guanidines,11 quinolines,12 carbazones,13
tetrazoles,14 imidazoles,15 amino acids,16 amines,17 thio-
ureas,18 and surfactants.19 Here we report that N-phen-
ylurea can also constitute a highly efficient, yet a
low-priced, ligand for the Pd-catalyzed Heck and Suzuki
It is worth mentioning that previously Yao et al.
reported that Pd(OAc)2 by itself could effect the Heck
reaction at 140 ꢁC after a fairly long reaction time
*
Corresponding authors. Tel.: +86 5513607466; fax: +86 5513606689
(L.L.); e-mail: leiliu@ustc.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.124

164
X. Cui et al. / Tetrahedron Letters 48 (2007) 163–167
Table 1. Heck reaction between bromobenzene and styrenea
deprotonated. This mechanism appears to be consistent
with the observation that N-methylurea is less effective,
because N-methylurea is less acidic than N-phenylurea
by about 5 pKa units.23 This mechanism may also
explain why an additional substituent group on urea
decreases the activity because it can cause a steric
hindrance in the Pd complex (3).
Br
Pd(OAc)2 / ligand
+
K2CO3, DMF
Entry
1
Ligand
—
Time (h)
10
GC yield (%)
15
O
Further experiment revealed that N-phenylthiourea
completely hampered the Heck reaction (entry 8 in
Table 1). This can be explained by the possible forma-
tion of a highly stable bis-complex (4) due to the
strongly-coordinating sulfur atom. Moreover, it was
interesting to find that N-phenylacetamide and 2-phenyl-
acetamide could also facilitate the Heck reaction, albeit
with much less efficiency (entries 9–10). This finding may
be explained by the fact that the oxygen in the amide
complex (5) is neutral, and thereby not effective in stabi-
lizing the cationic Pd intermediate.
2
10
10
10
2
73
70
8
H2N
O
NH2
NH2
3
N
H
O
4
N
H
N
H
O
5
99
68
92
0
Ph
N
H
NH2
Thus, the above results demonstrated that N-phenylurea
was an efficient, yet inexpensive ligand for the Pd-cata-
lyzed Heck reaction. The addition of N-phenylurea not
only significantly increased the yield, but also dramati-
cally reduced the reaction time. In order to examine
the scope of the N-phenylurea mediated Heck reaction,
we next performed the Heck reactions between a variety
of aryl halide and two representative olefins, namely,
styrene and butyl acrylate (Table 2). It was found that
both the electron-rich (deactivated) and electron-poor
(activated) aryl bromides could be efficiently converted
to the desirable products in high yields. The TONs in
most of the cases were about 103, except for 2-bromo-
pyridine where almost no reaction was observed. A pos-
sible problem for 2-bromopyridine is that the pyridine
nitrogen coordinates to Pd strongly and slows down
the turnovers. Besides aryl bromides, aryl iodides could
also be successfully used under the same reaction condi-
tions. Nonetheless, Pd/N-phenylurea was not active
enough to handle an aryl chloride unless it was activated
by electron-withdrawing substituents (such as 4-NO2).
O
6
10
10
10
10
10
Ph
Ph
Ph
Ph
N
H
N
H
O
S
7
N
H
N
H
8
N
H
NH2
O
9
Ph
32
88
N
H
O
10
Ph
NH2
a Conditions: bromobenzene (0.5 mmol), styrene (0.75 mmol), K2CO3
(1 mmol), Pd(OAc)2 (0.1 mol %), Pd(OAc)2:ligand = 1:2, DMF
(1 mL), 130 ꢁC, under Ar.
(ca. 20–40 h).22 They proposed a mechanism in which
the acetate anion acted as a ligand in the rate-determin-
ing oxidative-addition step (see 1 in Fig. 1). Compared
to Yao’s mechanism, it appears that the dramatic effect
of N-phenylurea is due to the formation of N,O-biden-
tate complex (2), in which one of the N–H bond is
Having demonstrated that Pd/N-phenylurea provided
excellent conditions for the Heck reactions of various
aryl bromides and iodides, we next examined whether
N-phenylurea could also facilitate the Suzuki reactions.
To our great satisfaction, it was found that N-phenyl-
urea was active enough to promote the Suzuki reactions
at room-temperature (Table 3). Both electron-rich and
electron-poor aryl bromides could be successfully con-
verted to the desired product very rapidly (ca. 1–6 h)
at room-temperature. The reaction also tolerated both
the electron-rich (e.g., 4-MeO–C6H4–B(OH)2) and elec-
tron-poor (e.g., 4-MeOC–C6H4–B(OH)2) arylboronic
acids. Only 0.01 mol % of Pd was needed and therefore,
the turnover numbers were as high as 104. Furthermore,
aryl iodides were excellent substrates for the reaction,
although aryl chlorides could not be converted
effectively. It is worth noting that the room-temperature
Suzuki reactions were achieved previously either by
using expensive phosphine or heterocyclic carbene
ligands,20 or by using a relatively high load of Pd (i.e.,
>1 mol %).21 In comparison, the novel conditions
Steric
Ph
Ph
O
CH3
N
N
H
N
O
O
Pd2+
H2N
Ph
O
Pd2+
R
Pd2+
Ph
Br
Br
Ph
Br
1
2
3
Ph
S
N
R
H2N
neutral
Pd2+
H2N
Ph
O
Pd2+
S
NH2
Br
N
Ph
5
4
Figure 1. Proposed Pd intermediates in the catalysis.

X. Cui et al. / Tetrahedron Letters 48 (2007) 163–167
165
Table 2. Heck-type reactions between aryl halides and olefins facili-
tated by the N-phenylurea liganda
Table 2 (continued)
Entry ArX
R
Time (h) Yieldb (%)
Pd(OAc)2 (0.1 mol%),
F3C
Br
1-phenylurea (0.2 mol%)
CO2nBu
R
21
2
93
+
Ar
X
R
Ar
K2CO3, DMF, 130 oC
Entry ArX
1
R
Time (h) Yieldb (%)
22
20
0
N
N
Br
Br
Br
2
2
2
2
98
99
81
98
CO2nBu
23
24
20
2
<5
93
Br
Br
CO2nBu
2
Br
3
N
N
O2N
Br
I
Br
CO2nBu
25
26
2
4
98
75
CO2nBu
4
O2N
Br
Br
5
6
2
2
85
97
CO2nBu
CO2nBu
I
CO2nBu
CO2nBu
CO2nBu
27
28
29
30
31
32
33
34
2
6
99
84
93
97
99
0
Br
7
2
2
98
96
I
MeO
Br
8c
I
MeO
4
MeO
Br
Br
9c
2
2
99
97
CO2nBu
I
I
MeO
2
MeOC
MeOC
10
OHC
2
Br
CO2nBu
11
2
2
2
98
97
80
Cl
OHC
20
20
2
Br
12
Cl
Cl
MeOC
81
90
Br
CO2nBu
O2N
O2N
13
MeOC
NC
CO2nBu
Br
14
15
16
17
18
19
20
2
2
2
2
2
2
2
97
93
96
91
86
92
95
a Conditions: aryl halide (0.5 mmol), olefin (0.75 mmol), K2CO3
(1 mmol), DMF (1 mL), under Ar.
NC
Br
Br
CO2nBu
CO2nBu
CO2nBu
b Isolated yield.
c In these two reactions, 1 mol % of TBAB was used as the addictive.
described here are evidently advantageous from the
economic point of view.
NC
NC
Ph
Br
To conclude, in the present study we reported an inter-
esting finding that N-phenylurea was a highly efficient,
yet simple and inexpensive, phosphine-free ligand for
the Pd-catalyzed Heck and room-temperature Suzuki
reactions of aryl bromide and iodides.24,25 Due to the
high turnover numbers and mild conditions of the N-
phenylurea facilitated reactions, we believed that the
reaction conditions described here should be both
operationally simple and economically competitive in
practice. Moreover, the present finding raised interesting
Br
Br
Ph
Br
F3C

166
X. Cui et al. / Tetrahedron Letters 48 (2007) 163–167
Table 3. Suzuki reactions facilitated by the N-phenylurea liganda
Table 3 (continued)
Entry ArX
R
Time Yieldb
Pd(OAc)2 (0.01 mol%),
1-phenylurea (0.02 mol%)
B(OH)2
R
X
+
(h)
(%)
Ar
K2CO3, EtOH/H2O(1:1), r.t.
Ar
R
Cl
B(OH)2
B(OH)2
17
18
24
<5
Entry ArX
R
Time Yieldb
(h)
(%)
Cl
Br
B(OH)2
B(OH)2
1
2
99
24
<5
O2N
a Conditions: aryl halide (5 mmol), arylboronic acid (7.5 mmol),
K2CO3 (10 mmol), ethanol (7.5 mL), H2O (7.5 mL), under air.
b Isolated yield.
Br
2
2
4
2
97
95
98
Br
B(OH)2
3
questions as to the mechanism and further optimization
of urea-based ligands for transition metals. Studies in
this regards are actively pursued in our laboratory and
will be reported in due course.
MeO
B(OH)2
Br
4
MeO
Acknowledgement
Br
Br
B(OH)2
5
24
2
89
99
94
98
Me2N
This research was supported by the NSFC (Nos.
20332020 and 20472079).
B(OH)2
6
Me2N
MeO
Supplementary data
B(OH)2
Br
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.10.124.
7
2
MeOC
Br
B(OH)2
8
2
MeOC
MeO
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MeOC
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24. Typical experimental procedure for the Heck reaction: A
mixture of phenyl bromide (0.5 mmol, 0.053 mL), styrene
(0.75 mmol, 0.087 mL), Pd(OAc)2 (0.5 · 10ꢀ3 mmol,
0.11 mg), phenylurea (10ꢀ3 mmol, 0.14 mg), and K2CO3
(1 mmol, 0.138 g) in 1 mL of dry DMF was stirred under
Ar at 130 ꢁC for 2 h. After the mixture was washed by
water, extracted by ether and condensed, the residue was
purified by flash column chromatography (hexane) to
afford trans-stilbene (89.3 mg, 99%).
25. Typical experimental procedure for the Suzuki reaction: A
mixture of p-methylphenyl bromide (5 mmol, 0.615 mL),
phenyl boronic acid (7.5 mmol, 0.915 g), Pd(OAc)2 (0.5 ·
10ꢀ3 mmol, 0.11 mg), phenylurea (10ꢀ3 mmol, 0.14 mg),
and K2CO3 (10 mmol, 1.38 g) in methanol/H2O (7.5 mL/
7.5 mL) was stirred at room-temperature for 2 h. After the
mixture was washed by water, extracted by ether and
condensed, the residue was purified by flash column
chromatography (hexane) to afford biphenyl (75.9 mg, 99%).