Variation of xanthene-based bidentate ligands in the palladium-catalyzed arylation of ureas

Article abstract of DOI:10.1016/S0040-4039(03)01051-7

A series of xanthene-based bidentate ligands containing various substituents on diphenylphosphino groups were synthesized and tested in the palladium-catalyzed arylation reaction of urea with unactivated aryl bromides. It was found that both steric and electronic properties of the ligands have a pronounced effect on the yields and ratios of the products. Arylation of urea and phenylurea with unactivated aryl bromides in the presence of Pd₂dba₃·CHCl₃/3,5-(CF₃) ₂Xantphos and Cs₂CO₃ as base in dioxane at 100°C gave the corresponding N,N′-diarylureas in 62-98% yields.

Full text of DOI:10.1016/S0040-4039(03)01051-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4719–4723
Variation of xanthene-based bidentate ligands in the
palladium-catalyzed arylation of ureas
Alexey G. Sergeev, Galina A. Artamkina and Irina P. Beletskaya*
Moscow State University, Chemistry Department, Leninskie Gory, 119992, Moscow, Russia
Received 20 March 2003; revised 18 April 2003; accepted 23 April 2003
Abstract—A series of xanthene-based bidentate ligands containing various substituents on diphenylphosphino groups were
synthesized and tested in the palladium-catalyzed arylation reaction of urea with unactivated aryl bromides. It was found that
both steric and electronic properties of the ligands have a pronounced effect on the yields and ratios of the products. Arylation
of urea and phenylurea with unactivated aryl bromides in the presence of Pd2dba3·CHCl3/3,5-(CF3)2Xantphos and Cs2CO3 as base
in dioxane at 100°C gave the corresponding N,N%-diarylureas in 62–98% yields. © 2003 Elsevier Science Ltd. All rights reserved.
Arylureas have numerous applications such as drugs,1
pesticides,1 selective anion-binding receptors2 and poly-
mer materials.3 Common methods for the synthesis of
arylureas include the reactions of arylamines with iso-
cyanates or phosgene.1 Alternative routes to these sub-
stances include the reductive carbonylation of
nitroarenes4 or oxidative carbonylation of amines.5 It is
evident that most of these methods utilize hazardous
and toxic reagents.
allowed one to perform arylation of amides,7–10
sulfonamides8,9 and ureas11 under rather mild condi-
tions tolerating various functional groups. One of the
most powerful ligands used in such palladium-catalyzed
reactions is Xantphos.8–11 However, the utility of this
ligand is mainly limited to the amidation of electron-
deficient aryl halides. Reactions with unactivated aryl
halides usually require higher catalyst loadings and give
much lower product yields.8–11 In many cases, especially
when an electron donating group like methoxy is
present in the aryl halide, the reaction fails.8,10 Recently
we encountered a similar problem in the arylation of
urea: reactions with activated aryl bromides afforded
the corresponding N,N%-diarylureas in high yields,
whereas arylation of urea with p-bromotoluene pro-
ceeded with incomplete conversion, gave a low yield of
the desired product, and was accompanied with the
formation of N-phenylation products: N,N%-diphenyl-
and N-phenyl-N%-p-tolylurea.
Recently, the palladium-catalyzed arylation of amines
(Buchwald–Hartwig reaction)6 became a convenient
and efficient method for CꢀN bond formation. Even
more recent expansions in the scope of this method
Buchwald has recently reported an effective arylation of
amides both with activated and unactivated aryl halides
in the presence of a copper catalyst and diamine lig-
and.12 However, our attempts to carry out the arylation
of urea under these conditions were unsuccessful.
A catalytic cycle for the palladium-catalyzed amidation
reaction is presented in Scheme 1. Oxidative addition to
Pd(0) even of unactivated aryl bromides, takes place
under very mild conditions. For instance, the amination
of bromobenzene can be performed at room tempera-
ture in the presence of Xantphos ligand.13 Amidation of
unactivated aryl bromides requires harsher conditions
(100–110°C).8–10 Therefore it may be supposed that the
Scheme 1.
Keywords: palladium-catalyzed; ligands; amidation; aryl halides; urea.
* Corresponding author. Tel.: +7-095-939-3618; fax: +7-095-939-3618;
e-mail: beletska@org.chem.msu.ru
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01051-7

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A. G. Sergee6 et al. / Tetrahedron Letters 44 (2003) 4719–4723
ing various steric and electronic properties. Tuning of
steric and electronic properties of the ligands was
achieved by introducing acceptor and donor sub-
stituents into various positions of the phenyl rings of
the ligand and by replacing phosphorus atoms with
arsenic. The ligands were synthesized via metallation of
dimethylxanthene and subsequent addition of
diarylchlorophosphine (diphenylchloroarsine) at low
temperature.18
rate-determining steps in the amidation reaction of
unactivated aryl bromides involve either substitution of
halogen for amide or reductive elimination. The rate of
CꢀN bond forming reductive elimination decreases with
the increase of the donor ability of the substituent in
the aryl group bound to palladium.14 A considerable
deceleration of the stages following the oxidative addi-
tion can give way to side processes, such as an exchange
of the aryl group bound to palladium and the phenyl
group of the ligand in the PdL2(Ar)Br complex, result-
ing in N-phenylated side products. Such an exchange
process becomes more evident when electron-rich aryl
halides are employed (Fig. 1).8,9,11,15
The efficiency of the ligands obtained was investigated
in the reaction of p-bromotoluene with urea, which in
the presence of Xantphos proceeds with incomplete
conversion and gives low yield of N,N%-ditolylurea.
Reactions were carried out using Pd2dba3·CHCl3 as a
pre-catalyst, the appropriate ligand and Cs2CO3 as the
base at 100°C in dioxane. As can be seen from Table 1,
the variation of electronic properties of the ligands has
a significant effect on the conversion and product
yields. The conversion of the aryl halide increases on
changing the electron-donating ligand p-MeOXantphos
to Xantphos. When the electron-deficient ligand 3,5-
(CF3)2Xantphos was used, the conversion reaches 100%
in 2.5 h. The reactions with p-MeOXantphos and Xant-
phos are considerably slower and give equally low yields
of the N,N%-ditolylurea (6–7%). In the reaction with
3,5-(CF3)2Xantphos the yield was increased to 62% and
the N-phenylation process is substantially suppressed.
An unexpected result was obtained with ligands having
bulky aryl substituents. Reactions with both electron-
rich o-MeXantphos and electron-poor FluoroXantphos
proceeded with very low conversion (<10%). The ineffi-
ciency of o-MeXantphos in the palladium-catalyzed aryl-
ation of amides was recently reported by Buchwald.9 At
the same time, in the amination of aryl halides both
o-MeXantphos and Xantphos gave similar results.19 The
arsenic analog of Xantphos was also an inefficient lig-
and (entry 6).
For this reason aryl–aryl exchange and catalyst deacti-
vation represent urgent problems in the reactions of
amides and ureas with unactivated aryl bromides. Tak-
ing into account that the rate of reductive elimination
increases both with the decrease of electron density on
the palladium atom16 and with the increase of the steric
bulk of the ligand,17 one may expect that a bulky
phosphine ligand bearing electron-withdrawing sub-
stituents will be of key importance for a successful
amidation of unactivated aryl halides.
To test this supposition we synthesized a number of
bidentate ligands based on the Xantphos backbone hav-
Thus, among the synthesized ligands on the Xantphos
backbone the only efficient one for arylation of urea
Figure 1.
Table 1. Variation of xanthene-based ligands in the palladium-catalyzed arylation of urea with p-bromotoluenea
Entry
Ligand
Pd (mol%)
Time (h)
Conversion (%)b
Yield (%)
A
B
C
1
p-MeOXantphos
4
2.5
24
20
2.5
20
20
20
34
47
62
100
9
8
7
62
4
10
4
2
3
4
5
6
Xantphos
4
4
4
2.5
2.5
5
3,5-(CF3)2Xantphos
o-MeXantphos
FluoroXantphos
Xantharsine
5
8
a The reactions were carried out with 1 mmol of aryl halide, 0.65 mmol of urea, 1.25–2 mol% of Pd2dba3·CHCl3 (2.5–4 mol% Pd), 3.75–6 mol%
of the ligand, 1.4 mmol Cs2CO3 in 4 ml of dioxane at 100°C under argon to the point when the conversion of the aryl bromide (as shown by
GC) did not increase further.
b Corresponding diarylamines were formed as side products.

A. G. Sergee6 et al. / Tetrahedron Letters 44 (2003) 4719–4723
4721
para-isomers and give ortho-substituted ureas in 80–
98% yields. By contrast, in the presence of Xantphos the
reaction with o-bromochlorobenzene, besides di(o-
chlorophenyl)urea, (57%), gave a substantial amount of
(o-chlorophenyl)amine (35%) and in the reaction with
o-bromotoluene di(o-tolyl)amine becomes the main
product (77%). Thus, changing one ligand for another
may alter the course of the reaction. It is worth noting,
that the arylation of urea with p-bromochlorobenzene
and p-bromotoluene in the presence of 3,5-
with p-bromotoluene is 3,5-(CF3)2Xantphos. We utilized
this ligand for the arylation of urea with unactivated
aryl bromides.21
From the data presented in Table 2 one can clearly see
the advantages of using 3,5-(CF3)2Xantphos instead of
Xantphos. In the presence of this ligand it is possible to
carry out the arylation of urea with unactivated aryl
halides with yields of 62–98%. ortho-Substituted aryl
bromides react more readily than the corresponding
Table 2. Palladium-catalyzed arylation of urea with unactivated aryl bromides in the presence of 3,5-(CF3)2Xantphos and
Xantphosa

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A. G. Sergee6 et al. / Tetrahedron Letters 44 (2003) 4719–4723
of the main product. The amount of symmetrical ureas
increases with increased reaction time. Since the reac-
tion of urea with unactivated aryl halides proceeds
rather slowly, it is difficult to obtain unsymmetrical
diarylureas with electron donor substituents under these
conditions. However the use of 3,5-(CF3)2Xantphos
allowed us, in a number of cases, to obtain such ureas
in high yields (Table 3). The quantity of the catalyst
was increased to reduce the reaction time and hence to
suppress the disproportionation side reaction. Again,
the ortho-substituted aryl halides proved to be the most
reactive substrates as in the arylation reaction of urea.
The greater efficiency of 3,5-(CF3)2Xantphos compared
to Xantphos is evident from the reaction with o-bromo-
toluene (entries 5 and 6). Reaction in the presence of
Xantphos proceeds with low conversion and gives a
much lower yield of the product. In fact it proceeds
slower than the reaction with p-isomer of bromo-
toluene, this being in sharp contrast to the reactions in
the presence of 3,5-(CF3)2Xantphos.
(CF3)2Xantphos requires lower catalyst loadings and
results in higher product yields in comparison to the
reaction with Xantphos.
Thus, the use of 3,5-(CF3)2Xantphos as a ligand allowed
us to accomplish a series of reactions of urea both with
poorly activated and unactivated aryl bromides, which
in the presence of Xantphos gave much less satisfactory
yields of diarylureas. However, the scope of this elec-
tron-poor ligand also has some limitations: the reaction
of urea with p-bromoanisole even with 2.5 mol% of the
catalyst proceeds with low conversion. The use of a
stronger base, t-BuONa instead of Cs2CO3, did not
improve the result. It should be emphasized that o-
bromoanisole, under the same conditions, gave the
product in 80% yield. o-Bromo-N,N%-dimethylaniline
proved to be an unreactive substrate.
In a previous paper we reported the arylation of phenyl-
urea with activated aryl halides in the presence of
Xantphos to give unsymmetrical N-aryl-N%-phenylureas
in high yields.11 The reaction is accompanied by forma-
tion of symmetrical N,N%-diarylureas and N,N%-
diphenylurea, which arise from the disproportionation
In summary, we have found that the electron-poor
ligand 3,5-(CF3)2Xantphos allows the palladium-cata-
lyzed arylation of urea and phenylurea with unactivated
Table 3. Palladium-catalyzed arylation of phenylurea with unactivated aryl bromides in the presence of 3,5-CF3Xantphos and
Xantphosa

A. G. Sergee6 et al. / Tetrahedron Letters 44 (2003) 4719–4723
4723
aryl bromides in high yields. The reactions in the
presence of this ligand require lower catalyst loadings
and give higher yields of the products than those with
Xantphos.
13. Guari, Y.; van Strijdonck, G. P. F.; Boele, M. D. K.;
Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N.
M. Chem. Eur. J. 2001, 7, 475–482.
14. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852–860.
15. Kong, K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113,
6313–6315.
Acknowledgements
16. Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R.
G. Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley, CA,
1987; pp. 324–329.
17. Hartwig, J. F.; Richards, S.; Baran˜ano, D.; Paul, F. J.
Am. Chem. Soc. 1996, 118, 3626–3633.
The financial support of this work by the Russian
Foundation for Basic Research (Grant N 00-15-97406,
01-03-32518) is gratefully acknowledged.
18. Preparation of 3,5-(CF3)2Xantphos. To a mixture of 0.39
g (1.85 mmol) of 9,9-dimethylxanthene, 0.7 ml (0.54 g,
4.63 mmol) of TMEDA in 14 ml of heptane was added
2.75 ml (4.67 mmol) 1.67 M solution of n-BuLi in
petroleum ether (65–70°C). The mixture was refluxed for
30 min, cooled to −65°C and 2.28 g (4.62 mmol) of
bis[3,5-bis-(trifluoromethyl)phenyl]chlorophosphine20 in 7
ml of THF was added dropwise over a period of 20 min.
The reaction mixture was heated to room temperature
and stirred for 16 h. The mixture was diluted with
CH2Cl2 and washed with water. The organic layer was
then dried over MgSO4, evaporated to dryness in vacuo
and the residue was purified first by flash chromatogra-
phy eluting with EtOAc:petroleum ether (1:6). The solid
was then recrystallized from a mixture of MeOH:CHCl3
(10:1) to give 0.755 g of the product as a white crystal.
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1
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