Direct arylation of oxazole and benzoxazole with aryl or heteroaryl halides using a palladium-diphosphine catalyst

Article abstract of DOI:10.1016/j.jorganchem.2007.10.028

Through the use of PdCl(dppb)(C₃H₅) as a catalyst, a range of aryl bromides and chlorides undergoes coupling via C-H bond activation/functionalization reaction with oxazole or benzoxazole in good yields. This air-stable catalyst can be used at low loadings with several substrates. Surprisingly, better results in terms of substrate/catalyst ratio were obtained in several cases using electron-excessive aryl bromides than with the electron-deficient ones. This seems to be mainly due to the relatively low thermal stability of some of the 2-arylbenzoxazoles formed with electron-deficient aryl halides. With these substrates, in order to obtain higher yields of product, the reactions had to be performed at a lower temperature (100-120 °C) using a larger amount of catalyst. On the other hand, in the presence of the most stable products, the reactions were performed at 150 °C using as little as 0.2 mol% catalyst. Arylation of benzoxazole with heteroaryl bromides also gave the coupling products in moderate to high yields using 0.2-5 mol% catalyst. With this catalyst, electron-deficient aryl chloride such as 4-chlorobenzonitrile, 4-chloroacetophenone or 2-chloronitrobenzene have also been used successfully.

Full text of DOI:10.1016/j.jorganchem.2007.10.028

Available online at www.sciencedirect.com
Journal of Organometallic Chemistry 693 (2008) 135–144
www.elsevier.com/locate/jorganchem
Direct arylation of oxazole and benzoxazole with aryl or
heteroaryl halides using a palladium–diphosphine catalyst
a
a
a
b,
*
Fazia Derridj , Safia Djebbar , Ouassini Benali-Baitich , Henri Doucet
a
Laboratoire d’hydrome´tallurgie et chimie inorganique mole´culaire, Faculte´ de Chimie, U.S.T.H.B. Bab-Ezzouar, Alger, Algeria
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite´ de Rennes ‘‘Catalyse et Organometalliques’’, Campus de Beaulieu,
35042 Rennes, France
b
Received 1 June 2007; received in revised form 15 October 2007; accepted 18 October 2007
Available online 24 October 2007
Abstract
Through the use of PdCl(dppb)(C3H5) as a catalyst, a range of aryl bromides and chlorides undergoes coupling via C–H bond
activation/functionalization reaction with oxazole or benzoxazole in good yields. This air-stable catalyst can be used at low loadings with
several substrates. Surprisingly, better results in terms of substrate/catalyst ratio were obtained in several cases using electron-excessive
aryl bromides than with the electron-deficient ones. This seems to be mainly due to the relatively low thermal stability of some of the
2-arylbenzoxazoles formed with electron-deficient aryl halides. With these substrates, in order to obtain higher yields of product,
the reactions had to be performed at a lower temperature (100–120 °C) using a larger amount of catalyst. On the other hand, in the pres-
ence of the most stable products, the reactions were performed at 150 °C using as little as 0.2 mol% catalyst. Arylation of benzoxazole
with heteroaryl bromides also gave the coupling products in moderate to high yields using 0.2–5 mol% catalyst. With this catalyst, elec-
tron-deficient aryl chloride such as 4-chlorobenzonitrile, 4-chloroacetophenone or 2-chloronitrobenzene have also been used successfully.
Ó 2007 Elsevier B.V. All rights reserved.
Keywords: Aryl bromides; Catalysis; C–H activation; Oxazole; Palladium
1. Introduction
both in terms of atom-economy and inert wastes (Scheme
2). So far, most of the results were described using rela-
tively large amounts (in general 5 mol%) of simple palla-
dium salts or Pd associated with monodentate ligands
[7–9]. The first direct arylations of oxazole and benzoxazole
were reported by Ohta and coworkers in 1992 [7a]. They
observed the selective 2-arylation of benzoxazole using
three chloropyrazines in the presence of 5% Pd(PPh3)4 as
catalyst and KOAc as base. A few years after, Miura also
explored the arylation of benzoxazole with aryl halides
[7b]. The reaction of benzoxazole with bromo- and iodo-
benzene using Cs2CO3 or K2CO3 as bases in DMF using
5 mol% Pd(OAc)2 associated with PPh3 gave the 2-arylated
product in 58% and 95% yields, respectively. Tamagnan
et al. reported that benzoxazole reacts with bromoanilines
or 2,4-dimethoxybromobenzene using 5 mol% Pd(OAc)2
associated to the electron-rich and sterically hindered
ligand P(tBu)3 as catalyst to provide after 1 h at 150 °C
Aryloxazoles are very useful compounds due to their
biological or physical properties [1]. The palladium-cata-
lyzed Negishi [2], Stille [3] or Suzuki [4] cross-coupling
reactions are powerful method for the preparation of such
compounds (Scheme 1) [5]. However, these methods are
not very convenient due to the limited access to halooxaz-
oles or to organometallic derivatives of oxazoles. Moreover
these reactions provides an organometallic or salt (MX) as
by product.
Since a few years, very interesting results for the direct
coupling of aryl halides with oxazole derivatives via C–H
activation have been reported [6]. This reaction provides
only HX as by-product and therefore is very interesting
*
Corresponding author. Tel.: +33 2 23 23 62 80; fax: +33 2 23 23 69 39.
E-mail address: henri.doucet@univ-rennes1.fr (H. Doucet).
0022-328X/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2007.10.028

136
F. Derridj et al. / Journal of Organometallic Chemistry 693 (2008) 135–144
R2
R1
R2
R2
R1
N
O
N
O
N
O
[Pd]
[Pd]
MR3
Ar
X
R1
+
+
+
XMR3
ArMR3
ArX
M = Zn, Mg, Sn, B
Scheme 1.
R2
R1
R2
R1
generally expensive. The use of bromides or chlorides is more
attractive in terms of atom-economy, environment, available
substrates and cost, but their activation requires more ele-
vated reaction temperature. At elevated temperatures a fast
decomposition of the palladium complexes associated to
monophosphines generally occurs. In order to find more effi-
cient palladium catalysts for this coupling reaction, we have
prepared the PdCl(C3H5)(dppb) complex [12]. The idea was
that intermediate Pd(0) species have to be protected by inter-
nal ligation against decomposition pathways through under-
ligation and subsequent colloid and ‘‘Pd black’’ formation.
The presence of the bidentate ligand dppb on palladium
might also reduce the poisoning of the catalyst due to the
presence of heteroaromatics. We have already reported some
results for the direct coupling of furans with aryl bromides at
low catalyst loadings using a tetraphosphine ligand [13,14].
These results demonstrated that polydentate ligands associ-
ated to palladium are useful catalysts for the direct arylation
of heteroaromatics. Herein, we report that the catalyst
PdCl(C3H5)(dppb) provides a powerful system for the
cross-coupling of oxazole derivatives, such as benzoxazole
or oxazole with a wide variety of electronically and sterically
diverse aryl bromides and chlorides and also for heteroaryl
halides.
N
O
N
O
[Pd] or [Rh]
H
Ar
base
+
+
ArX
HX/Base
Scheme 2.
the desired 2-arylbenzoxazoles in good yields [8a] An other
bulky electron-rich phosphine, butyldi-1-adamantylphos-
phine (10 mol%) associated to 5 mol% Pd(OAc)2 was
employed for the coupling of a few aryl chlorides with
benzoxazole [8c]. The arylation of an oxazolopyridine at
low temperature has been reported recently. They observed
that 72% yield for the addition of iodobenzene to the oxaz-
olopyridine derivative could be obtained at 30 °C using
Pd(OAc)2 (5%)/PPh3. (20%), Cs2CO3 and acetone as reac-
tion conditions. A good yield of 76% was also obtained for
this reaction using Pd(PPh3)4 as catalyst. Sterically con-
strained dppf led to a lower yield of 52% while the use of
bulky ligands PCy3 or P(oTol)3 gave no product [8b]. The
arylation of benzoxazole in moderate to high yields with
aryl iodides using 5 mol% [RhCl(cyclooctene)]2 associated
to 40 mol% of PCy3 has also been reported recently [9].
Even if several other methods for the preparation of 2-aryl-
oxazoles have been reported [1,10,11], the direct coupling
of oxazole derivatives with aryl halides is a very promising
process for the preparation of such compounds.
2. Experimental
2.1. General remarks
If monophosphine ligands such as PPh3 or the air-sensi-
tive PCy3, PtBu3 or butyldi-1-adamantylphosphine have
been successfully used for the direct coupling of oxazole
derivatives with aryl halides, the efficiency of bidentate
phosphine ligands for such couplings has not been demon-
strated [8b]. Moreover, it should be noted that, so far, rel-
atively few aryl chlorides [8c] or electron-deficient aryl
bromides have been employed for this reaction. Therefore,
an effective and selective method using an air-stable cata-
lyst for the direct coupling of both electron-excessive and
electron-deficient aryl bromides or chlorides with these
challenging substrates using high substrate/catalyst ratios
is still subject to significant improvement.
All reactions were run under argon in Schlenk tubes
using vacuum lines. DMF analytical grade was not distilled
before use. Cesium carbonate (99+) was used. Commercial
aryl halides and oxazole derivatives were used without
1
purification. H and 13C spectrum were recorded with a
Bruker 200 MHz spectrometer in CDCl3 solutions. Chem-
ical shift are reported in ppm relative to CDCl3 (7.25 for 1H
NMR and 77.0 for 13C NMR). Flash chromatography
were performed on silica gel (230–400 mesh). GC and
NMR yields in the tables are conversions of the aryl halides
1
into the product calculated with GC and H NMR spec-
trum of the crude mixtures.
Most of the coupling reactions of heteroaryl derivatives
with aryl bromides via C–H activation were performed at ele-
vated temperature (140–150 °C) [6–8]. A few reaction with
aryl iodides were performed at 30 °C due to their easy oxida-
tive addition to palladium [8c], however, these substrates are
2.2. Preparation of the PdCl(dppb)(C3H5) catalyst [12]
An oven-dried 40 mL Schlenk tube equipped with a
magnetic stirring bar under argon atmosphere, was

F. Derridj et al. / Journal of Organometallic Chemistry 693 (2008) 135–144
137
charged with [Pd(C3H5)Cl]2 (182 mg, 0.5 mmol) and dppb
(426 mg, 1 mmol). 10 mL of anhydrous dichloromethane
were added, then the solution was stirred at room temper-
ature for twenty minutes. The solvent was removed in vac-
2.7. 4-Benzooxazol-2-yl-benzonitrile (4) (Table 1, entry 9)
From 4-bromobenzonitrile (0.182 g, 1 mmol), benzoxaz-
ole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd
complex (0.05 mmol), product 4 was obtained in 79%
(0.174 g) yield.
uum. The yellow powder was used without purification. 31
P
NMR (81 MHz, CDCl3) d = 19.3 (s).
1H NMR (200 MHz, CDCl3) d 8.30 (d, J = 8.2 Hz, 2H),
7.75 (m, 1H), 7.58 (m, 3H), 7.40 (m, 2H).
2.3. General procedure for coupling reactions
In a typical experiment, the aryl halide (1 mmol), oxa-
zole derivative (2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
PdCl(C3H5)(dppb) (see Tables 1–4) were dissolved in
DMF (5 mL) under an argon atmosphere. The reaction
mixture was stirred at 100–150 °C (see Tables 1–4) for
20 h. The solution was diluted with an H2O/KOH solution
1 M (20 ml), then the product was extracted three times
with CH2Cl2. The combined organic layer was dried over
MgSO4 and the solvent was removed in vacuo. The crude
product was purified by silica gel column chromatography.
2.8. 2-(4-Nitrophenyl)-benzooxazole (5) (Table 1, entry
10)
From 4-bromonitrobenzene (0.202 g, 1 mmol), benzox-
azole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
Pd complex (0.05 mmol), product 5 was obtained in 69%
(0.166 g) yield.
1H NMR (200 MHz, CDCl3) d 8.45 (d, J = 8.2 Hz, 2H),
8.40 (d, J = 8.2 Hz, 2H), 7.85 (m, 1H), 7.61 (m, 1H), 7.42
(m, 2H).
2.4. 1-(4-Benzooxazol-2-ylphenyl)-ethanone (1) (Table 1,
entry 1)
2.9. 2-(3,5-Bistrifluoromethylphenyl)-benzooxazole (6)
(Table 1, entry 11)
From 4-bromoacetophenone (0.199 g, 1 mmol), benzox-
azole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd
complex (0.05 mmol), product 1 was obtained in 61%
(0.145 g) yield.
From 3,5-bistrifluoromethylbromobenzene (0.293 g,
1 mmol), benzoxazole (0.238 g, 2 mmol), Cs2CO3 (0.650 g,
2 mmol) and Pd complex (0.05 mmol), product 6 was
obtained in 82% (0.272 g) yield.
1H NMR (200 MHz, CDCl3) d 8.38 (d, J = 8.5 Hz, 2H),
8.12 (d, J = 8.5 Hz, 2H), 7.83 (m, 1H), 7.64 (m, 1H), 7.40
(m, 2H), 2.70 (s, 3H).
1H NMR (200 MHz, CDCl3) d 8.69 (s, 2H), 8.03 (s, 1H),
7.80 (m, 1H), 7.61 (m, 1H), 7.39 (m, 2H).
13C NMR (50 MHz, CDCl3) d 159.8, 150.8, 141.6, 132.6
(q, J = 35.2 Hz), 129.2, 127.4, 126.3, 125.2, 124.5 (q,
J = 3.7 Hz), 121.5 (q, J = 273.0 Hz), 120.2, 110.9.
Anal. calc. for C15H7F6NO: C, 54.39; H, 2.13. Found:
C, 54.27; H, 2.41%.
2.5. 1-(4-Benzooxazol-2-ylphenyl)-propan-1-one (2) (Table
1, entry 3)
From 4-bromopropiophenone (0.213 g, 1 mmol), benz-
oxazole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
Pd complex (0.01 mmol), product 2 was obtained in 75%
(0.189 g) yield.
2.10. 2-(4-Fluorophenyl)-benzooxazole (7) (Table 1, entry
15)
1H NMR (200 MHz, CDCl3) d 8.32 (d, J = 8.5 Hz, 2H),
8.08 (d, J = 8.5 Hz, 2H), 7.76 (m, 1H), 7.56 (m, 1H), 7.36
(m, 2H), 3.01 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H).
13C NMR (50 MHz, CDCl3) d 200.0, 162.3, 151.3, 142.4,
139.2, 131.2, 128.8, 128.1, 126.1, 125.3, 120.7, 111.2, 32.4,
8.5.
From 4-fluorobromobenzene (0.175 g, 1 mmol), benzox-
azole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd
complex (0.05 mmol), product 7 was obtained in 78%
(0.166 g) yield.
1H NMR (200 MHz, CDCl3) d 8.28 (dd, J = 8.2, 5.5 Hz,
2H), 7.78 (m, 1H), 7.59 (m, 1H), 7.39 (m, 2H), 7.23 (t,
J = 7.6 Hz, 2H).
Anal. calc. for C16H13NO2: C, 76.48; H, 5.21. Found: C,
76.80; H, 5.25%.
2.6. 2-(4-Trifluoromethylphenyl)-benzooxazole (3) (Table
1, entry 5)
2.11. 2-(4-tert-Butylphenyl)-benzooxazole (8) (Table 1,
entry 16)
From
4-(trifluoromethyl)bromobenzene
(0.225 g,
From 4-t-butylbromobenzene (0.213 g, 1 mmol), benz-
oxazole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
Pd complex (0.01 mmol), product 8 was obtained in 80%
(0.201 g) yield.
1 mmol), benzoxazole (0.238 g, 2 mmol), Cs2CO3 (0.650 g,
2 mmol) and Pd complex (0.01 mmol), product 3 was
obtained in 84% (0.221 g) yield.
1H NMR (200 MHz, CDCl3) d 8.36 (d, J = 8.2 Hz, 2H),
7.81 (m, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.59 (m, 1H), 7.39
(m, 2H).
1H NMR (200 MHz, CDCl3) d 8.21 (d, J = 8.2 Hz, 2H),
7.78 (m, 1H), 7.59 (m, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.39
(m, 2H), 1.40 (s, 9H).

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F. Derridj et al. / Journal of Organometallic Chemistry 693 (2008) 135–144
2.12. 2-p-Tolylbenzooxazole (9) (Table 1, entry 18)
2.17. 3-Benzooxazol-2-yl-benzonitrile (14) (Table 2, entry
1)
From 4-bromotoluene (0.171 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd com-
plex (0.01 mmol), product 9 was obtained in 61% (0.128 g)
yield.
From 3-bromobenzonitrile (0.182 g, 1 mmol), benzoxaz-
ole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd
complex (0.05 mmol), product 14 was obtained in 81%
(0.178 g) yield.
1H NMR (200 MHz, CDCl3) d 8.17 (d, J = 8.2 Hz, 2H),
7.78 (m, 1H), 7.59 (m, 1H), 7.39 (m, 2H), 7.36 (d,
J = 8.2 Hz, 2H), 2.46 (s, 3H).
1H NMR (200 MHz, CDCl3) d 8.54 (s, 1H), 8.48 (d,
J = 8.2 Hz, 1H), 7.80 (m, 2H), 7.61 (m, 2H), 7.42 (m, 2H).
13C NMR (50 MHz, CDCl3) d 160.5, 150.7, 141.6, 134.3,
131.3, 130.9, 129.8, 128.4, 125.9, 125.0, 120.3, 117.8, 113.4,
110.8.
2.13. 2-(4-Methoxyphenyl)-benzooxazole (10) (Table 1,
entry 19)
Anal. calc. for C14H8N2O: C, 76.35; H, 3.66. Found: C,
76.20; H, 3.87%.
From 4-bromoanisole (0.187 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd com-
plex (0.01 mmol), product 10 was obtained in 85% (0.191 g)
yield.
2.18. 2-(3-Nitrophenyl)-benzooxazole (15) (Table 2, entry
3)
1H NMR (200 MHz, CDCl3) d 8.18 (d, J = 8.2 Hz, 2H),
7.80 (m, 1H), 7.59 (m, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.39
(m, 2H), 4.08 (s, 3H).
From 3-bromonitrobenzene (0.202 g, 1 mmol), benzox-
azole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
Pd complex (0.05 mmol), product 15 was obtained in
64% (0.154 g) yield.
1H NMR (200 MHz, CDCl3) d 9.10 (s, 1H), 8.59 (d,
J = 8.2 Hz, 1H), 8.37 (d, J = 8.2 Hz, 1H), 7.85–7.43 (m,
3H), 7.42 (m, 2H).
2.14. (4-Benzooxazol-2-ylphenyl)-dimethylamine (11)
(Table 1, entry 21)
From 4-bromo-N,N-dimethylaniline (0.200 g, 1 mmol),
benzoxazole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol)
and Pd complex (0.01 mmol), product 11 was obtained in
87% (0.207 g) yield.
2.19. 2-Benzooxazol-2-yl-benzoic acid methyl ester (16)
(Table 2, entry 4)
From methyl 2-bromobenzoate (0.215 g, 1 mmol), benz-
oxazole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
Pd complex (0.05 mmol), product 16 was obtained in
79% (0.200 g) yield.
1H NMR (200 MHz, CDCl3) d 8.13 (d, J = 8.2 Hz, 2H),
7.71 (m, 1H), 7.53 (m, 1H), 7.28 (m, 2H), 7.79 (d,
J = 8.2 Hz, 2H), 3.10 (s, 6H).
1H NMR (200 MHz, CDCl3) d 8.07 (d, J = 8.2 Hz, 1H),
7.80 (m, 2H), 7.60 (m, 3H), 7.40 (m, 2H), 3.87 (s, 3H).
2.15. 2-Naphthalen-2-ylbenzooxazole (12) (Table 1, entry
23)
2.20. 2-Benzooxazol-2-ylbenzonitrile (17) (Table 2, entry
5)
From 2-bromonaphthalene (0.207 g, 1 mmol), benzox-
azole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
Pd complex (0.01 mmol), product 12 was obtained in
88% (0.216 g) yield.
From 2-bromobenzonitrile (0.182 g, 1 mmol), benzoxaz-
ole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd
complex (0.05 mmol), product 17 was obtained in 79%
(0.174 g) yield.
1H NMR (200 MHz, CDCl3) d 8.79 (s, 1H), 8.35 (d,
J = 8.2 Hz, 1H), 7.98 (m, 2H), 7.83 (m, 2H), 7.58 (m,
3H), 7.35 (m, 2H).
1H NMR (200 MHz, CDCl3) d 8.44 (d, J = 8.2 Hz, 1H),
7.95–7.50 (m, 5 H), 7.42 (m, 2H).
13C NMR (50 MHz, CDCl3) d 163.1, 150.8, 142.1, 134.7,
132.9, 128.9, 128.7, 128.0, 127.8, 127.7, 126.8, 125.1, 124.6,
124.3, 123.9, 119.9, 110.5.
2.21. 2-(2,4-Difluorophenyl)-benzooxazole (18) (Table 2,
entry 6)
2.16. 2-Phenylbenzooxazole (13) (Table 1, entry 25)
From 2,4-difluorobromobenzene (0.193 g, 1 mmol),
benzoxazole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol)
and Pd complex (0.05 mmol), product 18 was obtained in
82% (0.190 g) yield.
From iodobenzene (0.204 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd com-
plex (0.01 mmol), product 13 was obtained in 82% (0.160 g)
yield.
1H NMR (200 MHz, CDCl3) d 8.22 (q, J = 7.5 Hz, 1H),
7.83 (m, 1H), 7.58 (m, 1H), 7.39 (m, 2H), 6.99 (m, 2H).
13C NMR (50 MHz, CDCl3) d 165.1 (dd, J = 168.7,
11.6 Hz), 160.5 (dd, J = 175.0, 12.2 Hz), 158.0, 150.2,
1H NMR (200 MHz, CDCl3) d 8.30 (m, 2H), 7.83 (m,
1H), 7.70–7.32 (m, 6H).

F. Derridj et al. / Journal of Organometallic Chemistry 693 (2008) 135–144
139
141.5, 131.7 (m), 125.4, 124.6, 120.2, 112.1 (dd, J = 21.9,
3.8 Hz), 112.0, 110.5, 105.3 (t, J = 25.4 Hz).
Anal. calc. for C13H7F2NO: C, 67.53; H, 3.05. Found:
C, 67.47; H, 3.17%.
2.27. 2-Thiophen-3-yl-benzooxazole (24) (Table 3, entry 3)
From 3-bromothiophene (0.163 g, 1 mmol), benzoxaz-
ole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd
complex (0.01 mmol), product 24 was obtained in 79%
(0.159 g) yield.
2.22. 2-(2-Fluorophenyl)-benzooxazole (19) (Table 2, entry
7)
1H NMR (200 MHz, CDCl3) d 8.17 (d, J = 2.9 Hz, 1H),
7.78 (d, J = 5.2 Hz, 1H), 7.73 (m, 1H), 7.53 (m, 1H), 7.42
(dd, J = 5.2, 2.9 Hz, 1H), 7.32 (m, 2H).
From 2-fluorobromobenzene (0.175 g, 1 mmol), benzox-
azole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd
complex (0.05 mmol), product 19 was obtained in 72%
(0.154 g) yield.
2.28. 2,5-Di(benzooxazole)thiophene (25) (Table 3, entry
5)
1H NMR (200 MHz, CDCl3) d 8.26 (t, J = 7.7 Hz, 1 H),
7.83 (m, 1H), 7.65 (m, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.45–
7.20 (m, 4H).
From 2,5-dibromothiophene (0.242 g, 1 mmol), benzox-
azole (0.476 g, 4 mmol), Cs2CO3 (1.300 g, 4 mmol) and Pd
complex (0.05 mmol), product 25 was obtained in 51%
(0.162 g) yield.
2.23. 2-Naphthalen-1-yl-benzooxazole (20) (Table 2, entry
8)
1H NMR (200 MHz, CDCl3) d 7.98 (s, 2H), 7.80 (m,
2H), 7.60 (m, 2H), 7.42 (m, 4 H).
From 1-bromonaphthalene (0.207 g, 1 mmol), benzox-
azole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
Pd complex (0.01 mmol), product 20 was obtained in
78% (0.191 g) yield.
2.29. 2-(6-Methylpyridin-2-yl)-benzooxazole (26) (Table 3,
entry 6)
1H NMR (200 MHz, CDCl3) d 9.47 (d, J = 8.2 Hz, 1 H),
8.43 (d, J = 8.2 Hz, 1 H), 8.03 (d, J = 8.2 Hz, 1H), 7.94 (d,
J = 8.2 Hz, 1H), 7.88 (m, 1H), 7.75–7.50 (m, 4 H), 7.40 (m,
2H).
From 2-methyl-5-bromopyridine (0.172 g, 1 mmol),
benzoxazole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol)
and Pd complex (0.05 mmol), product 26 was obtained in
78% (0.164 g) yield.
1H NMR (200 MHz, CDCl3) d 8.14 (d, J = 8.0 Hz, 1 H),
7.80 (m, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.64 (m, 1H), 7.37
(m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 2.70 (s, 3H).
2.24. 2-o-Tolylbenzooxazole (21) (Table 2, entry 9)
From 2-bromotoluene (0.171 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd com-
plex (0.01 mmol), product 21 was obtained in 79% (0.165 g)
yield.
2.30. 2-Pyridin-3-yl-benzooxazole (27) (Table 3, entry 7)
From 3-bromopyridine (0.158 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd com-
plex (0.01 mmol), product 27 was obtained in 84% (0.165 g)
yield.
1H NMR (200 MHz, CDCl3) d 8.19 (d, J = 8.2 Hz, 1H),
7.78 (m, 1H), 7.58 (m, 1H), 7.35 (m, 5 H), 2.84 (s, 3H).
2.25. 2-(2-Methoxyphenyl)-benzooxazole (22) (Table 2,
entry 10)
1H NMR (200 MHz, CDCl3) d 9.48 (d, J = 1.5 Hz, 1H),
8.78 (dd, J = 4.9, 1.5 Hz, 1H), 8.54 (dt, J = 8.1, 1.8 Hz,
1H), 7.82 (m, 1H), 7.64 (m, 1H), 7.49 (dd, J = 4.9,
8.1 Hz, 1H), 7.42 (m, 2H).
From 2-bromoanisole (0.187 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd com-
plex (0.01 mmol), product 22 was obtained in 61% (0.138 g)
yield.
2.31. 2-Pyridin-4-ylbenzooxazole (28) (Table 3, entry 9)
1H NMR (200 MHz, CDCl3) d 8.16 (d, J = 8.2 Hz, 1H),
7.81 (m, 1H), 7.58 (m, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.38
(m, 2H), 7.10 (m, 2H).
From 4-bromopyridine (0.158 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd com-
plex (0.01 mmol), product 28 was obtained in 82% (0.161 g)
yield.
2.26. 2-Thiophen-2-yl-benzooxazole (23) (Table 3, entry 1)
1H NMR (200 MHz, CDCl3) d 8.82 (d, J = 7.0 Hz, 2H),
8.07 (d, J = 7.0 Hz, 2H), 7.81 (m, 1H), 7.61 (m, 1H), 7.40
(m, 2H).
From 2-bromothiophene (0.163 g, 1 mmol), benzoxaz-
ole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd
complex (0.01 mmol), product 23 was obtained in 73%
(0.147 g) yield.
2.32. 2-Pyrimidin-5-ylbenzooxazole (29) (Table 3, entry
11)
1H NMR (200 MHz, CDCl3) d 7.88 (d, J = 3.6 Hz, 1 H),
7.75 (m, 1H), 7.55 (m, 2H), 7.37 (m, 2H), 7.18 (t,
J = 4.1 Hz, 1H).
From 5-bromopyrimidine (0.159 g, 1 mmol), benzoxaz-
ole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd

140
F. Derridj et al. / Journal of Organometallic Chemistry 693 (2008) 135–144
complex (0.05 mmol), product 29 was obtained in 82%
(0.162 g) yield.
1H NMR (200 MHz, CDCl3) d 7.98 (d, J = 8.5 Hz, 2H),
7.68 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.21 (s, 1H), 1.34 (s,
9H).
1H NMR (200 MHz, CDCl3) d 9.51 (s, 2H), 9.35 (s, 1H),
7.82 (m, 1H), 7.61 (m, 1H), 7.40 (m, 2H).
2.38. CAS Registry No.
2.33. 3-Benzooxazol-2-ylquinoline (30) (Table 3, entry 12)
1 37069-08-2; 3, 478247-76-6; 4, 838-33-5; 5, 840-58-4; 7,
397-54-6; 8, 5998-50-5; 9, 835-71-2; 10, 838-34-6; 11, 840-
57-3; 12, 14625-56-0; 13, 833-50-1; 15, 840-56-2; 16,
92533-24-9; 17, 54175-73-4; 19, 212758-52-6; 20, 3164-18-
9; 21, 32959-60-7; 22, 13459-17-1; 23, 23999-63-5; 24,
638213-72-6; 25, 2866-43-5; 26, 64819-72-3; 27, 2295-42-3;
28, 2295-47-8; 29, 39116-33-1; 30, 72435-72-4; 31, 20000-
53-7; 32, 840-37-9; 34, 126773-86-2.
From 3-bromoquinoline (0.208 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd com-
plex (0.01 mmol), product 30 was obtained in 78% (0.192 g)
yield.
1H NMR (200 MHz, CDCl3) d 9.73 (s, 1H), 8.98 (s, 1H),
8.16 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.81 (m,
2H), 7.63 (m, 2H), 7.41 (m, 2H).
2.34. 4-Benzooxazol-2-yl-benzoic acid methyl ester (31)
(Table 4, entry 4)
3. Results and discussion
First, we tested several reaction conditions for the cou-
pling of 4-tbutylbromobenzene with benzoxazole in the
presence of 1 mol% PdCl(dppb)(C3H5) [12] as catalyst.
The reaction using KOAc as base in DMF or DMAc at
150 °C gave no coupling product. Using similar reaction
conditions, K2CO3 led to a very low conversion and yield.
On the other hand, using Cs2CO3 as base in DMF, the
product 8 was obtained in 80% yield with complete conver-
sion of the aryl bromide. Moreover, the reaction was very
selective in 8. Therefore, for this study, DMF was chosen
as the solvent and caesium carbonate as the base. In order
to obtain high substrate/catalyst ratios, we generally per-
formed the reactions at relatively elevated temperatures:
100–150 °C.
To determine the electronic and steric influence of the
substituents on the aryl bromides on this coupling reaction,
we studied the reactivity of several para- meta- an ortho-
substituted aryl bromides with benzoxazole (Scheme 3,
Tables 1 and 2). Using the para-substituted electron-defi-
cient aryl bromides such as 4-bromoacetophenone, 4-
bromopropiophenone, 4-trifluoromethylbromobenzene or
4-bromobenzonitrile, the reactions could be performed
using as little as 0.2–1 mol% catalyst (Table 1, entries 3,
5–8). However, if the coupling reaction proceeds nicely at
150 °C, the stability of some coupling products appears
to be quite limited and the formation of side-products
due to partial degradation of 2–4 was observed in some
cases. Using a lower reaction temperature, the reactions
were generally cleaner, but the presence of 1–5 mol% cata-
lyst had to be used in order to obtain high yields of prod-
ucts 1, 2, 4 and 5 (Table 1, entries 1, 2, 4, 9, 10).
Surprisingly, 4-fluorobromobenzene was found to give
only traces of coupling product when the reaction was per-
formed at 150 °C. On the other hand, using lower temper-
atures of 100 and 120 °C, the expected product 7 was
obtained in 37% and 78% isolated yields, respectively
(Table 1, entries 11–14). The thermal stability of the prod-
ucts formed with electron-rich aryl bromides seems to be
higher and with 4-tbutylbromobenzene, 4-bromoanisole
or 4-N,N-dimethylaminobromobenzene, the reaction could
From methyl 4-chlorobenzoate (0.171 g, 1 mmol), benz-
oxazole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
Pd complex (0.05 mmol), product 31 was obtained in
70% (0.177 g) yield.
1H NMR (200 MHz, CDCl3) d 8.32 (d, J = 8.4 Hz, 2H),
8.18 (d, J = 8.4 Hz, 2H), 7.82 (m, 1H), 7.62 (m, 1H), 7.40
(m, 2H), 3.97 (s, 3H).
2.35. 2-(2-Nitrophenyl)-benzooxazole (32) (Table 4, entry
5)
From 2-chloronitrobenzene (0.158 g, 1 mmol), benzox-
azole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and
Pd complex (0.05 mmol), product 32 was obtained in
55% (0.132 g) yield.
1H NMR (200 MHz, CDCl3) d 8.13 (d, J = 8.4 Hz, 1 H),
7.91 (d, J = 8.4 Hz, 1H), 7.80 (m, 1H), 7.72 (m, 2H), 7.56
(m, 1H), 7.41 (m, 2H).
2.36. 2-Pyrimidin-2-yl-benzooxazole (33) (Table 4, entry 9)
From 2-chloropyrimidine (0.115 g, 1 mmol), benzoxaz-
ole (0.238 g, 2 mmol), Cs2CO3 (0.650 g, 2 mmol) and Pd
complex (0.05 mmol), product 33 was obtained in 74%
(0.146 g) yield.
1H NMR (200 MHz, CDCl3) d 8.91 (d, J = 4.9 Hz, 2H),
7.82 (m, 1H), 7.63 (m, 1H), 7.39 (t, J = 4.9 Hz, 1H), 7.37
(m, 2H).
13C NMR (50 MHz, CDCl3) d 160.0, 158.5, 155.7, 151.6,
142.1, 127.4, 125.7, 122.4, 122.0, 111.9.
Anal. calc. for C11H7N3O: C, 67.00; H, 3.58. Found: C,
67.18; H, 3.41%.
2.37. 2-(4-tert-Butylphenyl)-oxazole (34) [16] (Scheme 5)
Reaction performed in an autoclave. From 4-t-butylb-
romobenzene (0.213 g, 1 mmol), oxazole (0.138 g, 2 mmol),
Cs2CO3 (0.650 g, 2 mmol) and Pd complex (0.05 mmol),
product 34 was obtained in 69% (0.139 g) yield.

F. Derridj et al. / Journal of Organometallic Chemistry 693 (2008) 135–144
141
PPh2
Pd
PPh2
CH2CH=CH2
N
O
N
O
Cl
+
ArX
or
Ar
DMF, Cs2CO3, 100-150 °C, 20 h
1—
24, 26-33
Br
Br
O
O
N
S
S
N
25
Scheme 3.
Table 1
Palladium-catalyzed arylation of benzoxazole using para-substituted aryl bromides (Scheme 3)
Entry
Aryl bromide
Ratio substrate/catalyst
Temperature (°C)
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromopropiophenone
4-Bromopropiophenone
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
4-Bromobenzonitrile
20
100
100
150
100
150
150
150
150
100
100
100
150
150
100
120
150
150
150
150
150
150
150
150
150
150
1
1
100 (78)b
88
100 (61)
76
100 (84)
62
60 (45)
24
88 (79)
100 (69)
100 (82)
Traces
Traces
42 (37)
100 (78)
100 (80)c
44
67 (61)
100 (85)
72
96 (87)
15
100
100
20
100
500
100
500
20
20
20
20
100
20
2
2
3
3
4
4-Bromobenzonitrile
4-Bromobenzonitrile
4
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
a
4-Bromonitrobenzene
3,5-Bis(trifluoromethyl)bromobenzene
4-Fluorobromobenzene
4-Fluorobromobenzene
4-Fluorobromobenzene
4-Fluorobromobenzene
4-tButylbromobenzene
4-tButylbromobenzene
4-Bromotoluene
4-Bromoanisole
4-Bromoanisole
4-N,N-dimethylaminobromobenzene
4-N,N-dimethylaminobromobenzene
2-Bromonaphthalene
5
6
7
7
7
20
7
100
500
100
100
500
100
500
100
500
100
8
8
9
10
10
11
11
12
12
13
100 (88)
12
100 (82)
2-Bromonaphthalene
Iodobenzene
Conditions: catalyst: PdCl(C3H5)(dppb), aryl halide (1 mmol), benzoxazole (2 mmol), Cs2CO3 (2 mmol), DMF, 20 h, yields are GC and NMR
conversions, yields in parenthesis are isolated.
b
This reaction performed using PdCl(C3H5)(dppe) instead of PdCl(C3H5)(dppb) as catalyst led to 1 in 100% conversion and 74% yield.
This reaction performed using PdCl(C3H5)(dppe) instead of PdCl(C3H5)(dppb) as catalyst led to 8 in 100% conversion and 71% yield.
c
be performed at 150 °C without formation of side products
(Table 1, entries 15–21). Moreover, with these substrates,
high turnover numbers (TONs) of 220, 360 and 96 have
been obtained (Table 1, entries 16, 19 and 20). 2-bromo-
naphthalene or iodobenzene also gave the expected prod-
ucts in good yield using 1 mol% catalyst (Table 1, entries
22–24). In the presence of PdCl(dppe)(C3H5) instead of
PdCl(dppb)(C3H5) as catalyst, the coupling of 4-bromo-
benzophenone or 4-tbutylbromobenzene gave products 1
and 8 in similar yields (Table 1, entries 1 and 16). It should
be noted that, in the literature, the rare examples of palla-
dium-catalyzed couplings with benzoxazole were described
with electron-rich aryl bromides [8a] or aryl iodides [7].
Then, we examined the reactivity of meta- and ortho-
substituted aryl bromides with benzoxazole (Table 2).
Coupling reaction with 3-bromobenzonitrile or 3-bromoni-
trobenzene gave 14 and 15 in 81% and 64% yield, respec-
tively, using 5 mol% catalyst (Table 2, entries 1–3).
Sterically congested aryl bromides are also suitable sub-
strates for this reaction. ortho-Substituted electron-poor
methyl 2-bromobenzoate, 2-bromobenzonitrile, 2-fluorob-
romobenzene or 2,4-difluorobromobenzene gave the cou-
pling products using 5 mol% catalyst at 100 °C (Table 2,
entries 4–7). In the presence of the electron-rich aryl bro-
mides, 2-bromotoluene, 2-bromoanisole or 1-bromonaph-
thalene, 20–22 were obtained selectively. Moreover, no

142
F. Derridj et al. / Journal of Organometallic Chemistry 693 (2008) 135–144
Table 2
Palladium-catalyzed arylation of benzoxazole using meta- or ortho-substituted aryl bromides (Scheme 3)
Entry
Aryl bromide
Ratio substrate/catalyst
Temperature (°C)
Product
Yield (%)a
1
2
3
4
5
6
3-Bromobenzonitrile
3-Bromonitrobenzene
3-Bromonitrobenzene
Methyl 2-bromobenzoate
2-Bromobenzonitrile
2,4-
20
20
20
20
20
20
100
100
150
100
100
100
14
15
15
16
17
18
100 (81)
95
100 (64)
100 (79)
100 (79)
100 (82)
Difluorobromobenzene
2-Fluorobromobenzene
1-Bromonaphthalene
2-Bromotoluene
7
8
9
10
a
20
100
150
150
150
19
20
21
22
77 (72)
100
100
100
100 (78)
100 (79)
100 (61)
2-Bromoanisole
Conditions: catalyst: PdCl(C3H5)(dppb), aryl bromide (1 mmol), benzoxazole (2 mmol), Cs2CO3 (2 mmol), DMF, 20 h, yields are GC and NMR
conversions, yields in parenthesis are isolated.
formation of side-products was observed at 150 °C, and the
reactions could be performed with only 1 mol% catalyst.
Palladium chemistry involving heterocycles has its
unique characteristics stemming from the heterocycles’
inherently different structural and electronic properties in
comparison to the corresponding carbocyclic aryl com-
pounds [5]. Thiophene are p-electron excessive and pyri-
dines are p-electron deficient heterocycles. However, we
observed with 2-bromothiophene, 3-bromothiophene, 3-
bromopyridine or 4-bromopyridine high reactivities and
high yields of coupling products 23, 24, 27 and 28 in all
cases in the presence of 1 mol% catalyst. With 3- or 4-
bromopyridines satisfactory yields were also obtained
using as little as 0.2 mol% catalyst (Table 3, entries 1–4
and 7–10). A very similar reactivity was observed with 3-
bromoquinoline (Table 3, entry 11). On the other hand,
using 5-bromopyrimidine, the reaction performed at
150 °C gave only traces of product 29. Again, using a lower
reaction temperature (100 °C), the selective formation of
the expected product 29 was observed (Table 3, entry 11).
Using 2,5-dibromothiophene and 4 eq. of benzoxazole,
the diarylated thiophene derivative 25 was obtained in
51% yield (Table 3, entry 5). Due to their coordination or
fluorescent properties the direct formation of such com-
pounds should be very useful.
These results seem to indicate that, for this reaction, the
oxidative addition of the aryl bromide to palladium is
probably not the rate-limiting step of the reaction. In order
to have more insight of the reaction mechanism, we
performed a reaction using a mixture of 4-bromoanisole
and 4-trifluoromethylbromobenzene in the presence of
benzoxazole (Scheme 4). We observed after 1 h of reaction,
the formation of a mixture of 3 and 10 in a ratio 95:5
indicating a faster oxidative addition of 4-trifluoromethylb-
romobenzene to palladium. After 6 h, all the 4-trifluorom-
ethylbromobenzene and 37% of the 4-bromoanisole were
consumed and the ratio or products 3:10 was 80:20. How-
ever, we had observed in Tables 1–3 that relatively similar
TONs could be obtained with electron-deficient and elec-
tron-excessive aryl bromides. Therefore, the rate limiting
step of this reaction with aryl bromides might be the inser-
tion of palladium in the C–H bond of oxazole or the reduc-
tive elimination to form the product. When a mixture of
aryl bromides is employed, the most reactive aryl bromide:
4-trifluoromethylbromobenzene reacts more rapidly with
palladium than 4-bromoanisole, but the electronic
Table 3
Palladium-catalyzed arylation of benzoxazole with heteroaryl bromides (Scheme 3)
Entry
Aryl bromide
Ratio substrate/catalyst
Temperature (°C)
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
a
2-Bromothiophene
2-Bromothiophene
3-Bromothiophene
3-Bromothiophene
2,5-Dibromothiophene
2-Bromo-6-methylpyridine
3-Bromopyridine
3-Bromopyridine
4-Bromopyridine
4-Bromopyridine
5-Bromopyrimidine
3-Bromoquinoline
100
500
100
500
20
150
150
150
150
150
150
150
150
150
150
100
150
23
23
24
24
25
26
27
27
28
28
29
30
100 (73)
17
100 (79)
15
100 (51)b
100 (78)
100 (84)
61
100 (82)
62
20
100
500
100
500
20
100 (82)
92 (78)
100
Conditions: catalyst: PdCl(C3H5)(dppb), aryl bromide (1 mmol), benzoxazole (2 mmol), Cs2CO3 (2 mmol.), DMF, 20 h, yields are GC and NMR
conversions, yields in parenthesis are isolated.
b
Benzoxazole (4 mmol.), Cs2CO3 (4 mmol.), the formation of the monoarylated product was also observed in low yield.

F. Derridj et al. / Journal of Organometallic Chemistry 693 (2008) 135–144
143
N
N
O
PdCl(C3H5)(dppb) 0.2%
+
CF3
Br
Br
CF3
DMF, Cs2CO3, 150 °C, 20 h
O
1 eq.
1 eq.
A
B
3
4 eq.
+
N
O
OMe
OMe
10
Reaction
Ratio
Conversion Conversion
time (h)
3:10
of A (%)
73
of B (%)
2
95:5
75:25
72:28
4
6
100
37
40
20
100
Scheme 4.
properties of these aryl bromides does not accelerates the
other steps of the catalytic cycle.
chlorides 4-trifluoromethylchlorobenzene, 3- or 4-chloro-
benzonitrile, 4-chloroacetophenone, methyl 4-chlorobenzo-
ate or 2-chloronitrobenzene the products 1, 3, 4, 14, 31 and
32 were obtained in good yields together with a few side-
products (Table 4, entries 1–6). On the other hand, 2-chlo-
robenzonitrile or 3-chloropyridine led to 17 and 26 in low
yields (Table 4, entries 7 and 8). From 2-chloropyrimidine,
33 was obtained in high yield (Table 4, entry 9).
In the presence of oxazole, a selective 2-arylation with 4-
tbutylbromobenzene to give 34 in 69% yield was observed
using this catalytic system (Scheme 5). Under these reac-
tion conditions, the 5-arylation or the diarylation products
were not observed. Such selective 2-arylation of oxazole
derivative has already been observed but was limited to
reactive aryl iodides. With 4-iodoanisole under base-free
and ligandless conditions or iodobenzene using P(otol)3
as ligand the 2-arylated oxazoles had been obtained in
23% and 89% yields, respectively [15].
Then, we examined the reactivity of aryl chlorides for
the coupling with benzoxazole (Table 4). The generalisa-
tion of the use of chloride substrates for cross-couplings,
both at the laboratory scale and in the industry, would
be a considerable advantage for sustainable development
because of their lower cost, lower mass, and the wider
diversity of available compounds, as well as for the treat-
ment of the relatively inert chloride waste. Very few exam-
ples of couplings of aryl chlorides with benzoxazoles have
been reported in the literature. They were performed using
heteroaryl chlorides [7a] or with the bulky electron-rich
phosphine butyldi-1-adamantylphosphine, which is not
air-stable [8c]. As expected, the electronic properties of
the aryl chloride have an important effect on the reaction
rates. Using PdCl(dppb)(C3H5), the electron-deficient aryl
Table 4
Palladium-catalyzed arylation of benzoxazole with aryl chlorides (Scheme
3)
4. Conclusion
Entry Aryl chloride
Temperature Product Yield
(°C)
In summary, we have established that the PdCl(dppb)-
(C3H5) system provides an efficient catalyst for the
coupling of oxazole derivatives with electron-deficient or
electron-excessive aryl bromides and also with electron-
deficient aryl chlorides. To the best of our knowledge, this
work represents one of the most wide-ranging study
reported so far for the preparation of 2-aryloxazoles via
C–H activation/functionalization. In general, better results
were obtained for the coupling with electron-rich aryl
bromides than with the electron-poor ones. If the electronic
properties of aryl bromides appear to have a minor influ-
ence on the reactions rates, they seem to have a larger
(%)a
1
2
3
4
5
6
7
8
9
4-Trifluoromethylchlorobenzene 150
3
4
100 (71)
100 (77)
100 (74)
88 (70)
83 (55)
100 (62)
12
4-Chlorobenzonitrile
4-Chloroacetophenone
Methyl 4-chlorobenzoate
2-Chloronitrobenzene
3-Chlorobenzonitrile
2-Chlorobenzonitrile
3-Chloropyridine
150
120
120
120
120
150
150
120
1
31
32
14
17
26
33
18
100 (74)
2-Chloropyrimidine
a
Conditions: catalyst: PdCl(C3H5)(dppb) (0.05 mmol), aryl chloride
(1 mmol), benzoxazole (2 mmol), Cs2CO3 (2 mmol), DMF, 20 h, yields are
GC and NMR conversions, yields in parenthesis are isolated.
N
N
PdCl(C3H5)(dppb) 5%
DMF, Cs2CO3, 150 °C, 20 h
+
Br
tBu
tBu
O
O
69%
34
Scheme 5.

144
F. Derridj et al. / Journal of Organometallic Chemistry 693 (2008) 135–144
(d) G.L. Young, S.A. Smith, R.J.K. Taylor, Tetrahedron Lett. 45
(2004) 3797.
[4] For examples of palladium Suzuki coupling reactions with oxazoles
derivatives: E.F. Flegeau, M.E. Popkin, M.F. Greaney, Org. Lett. 8
(2006) 2495.
[5] For examples of palladium coupling reactions with heteroaromatic
substrates: J.J. Li, G.W. Gribble, Palladium in Heterocyclic Chem-
istry, Pergamon, Amsterdam, 2000.
[6] For reviews on palladium-catalyzed C–H activation of heteroaryls
see: (a) V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev. 102 (2002) 1731;
(b) D. Alberico, M.E. Scott, M. Lautens, Chem. Rev. 107 (2007) 174;
(c) T. Satoh, M. Miura, Chem. Lett. 36 (2007) 200.
[7] For examples of direct arylation of benzoxazole with aryl iodides: (a)
Y. Aoyagi, A. Inoue, I. Koizumi, R. Hashimoto, K. Tokunaga, K.
Gohma, J. Komatsu, K. Sekine, A. Miyafuji, J. Kunoh, R. Honma,
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influence on the stability of some products. With this Pd-
diphosphine catalyst, several reactions could be performed
with as little as 0.2% catalyst without further optimisation
of the reaction conditions. An other advantage of this reac-
tion is the remarkable functional group tolerance; substitu-
ents such as fluoro, trifluoromethyl, acetyl, methoxy,
amino, carboxylate, nitro or nitrile on the aryl halide have
been used. Several heteroaromatics were also employed
successfully. Moreover, the air-stability of this catalyst
makes this procedure very convenient. This methodology
should allow the synthesis in one step of several biologi-
cally active compounds or polydentate ligands useful in
organometallic chemistry.
(b) S. Pivsa-Art, T. Satoh, Y. Kawamura, M. Miura, M. Nomura,
Bull. Chem. Soc. Jpn. 71 (1998) 467.
Acknowledgements
[8] (a) D. Alagille, R.M. Baldwin, G.D. Tamagnan, Tetrahedron Lett.
46 (2005) 1349;
We thank CNRS for financial support.
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