Nickel-catalyzed direct arylation of azoles with aryl bromides

Article abstract of DOI:10.1021/ol900159a

Nickel catalyst systems for the direct C2 arylation of oxazoles and thiazoles have been developed. The catalyst systems are cost-efficient and allow the use of various aryl bromides in the C-H arylation of azoles.

Full text of DOI:10.1021/ol900159a

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1737-1740
Nickel-Catalyzed Direct Arylation of
Azoles with Aryl Bromides
Hitoshi Hachiya, Koji Hirano, Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity,
Suita, Osaka 565-0871, Japan
miura@chem.eng.osaka-u.ac.jp
Received January 25, 2009
ABSTRACT
Nickel catalyst systems for the direct C2 arylation of oxazoles and thiazoles have been developed. The catalyst systems are cost-efficient and
allow the use of various aryl bromides in the C-H arylation of azoles.
Since organic molecules containing heterocycle-aryl link-
ages are ubiquitously found in many natural products,
pharmaceuticals, and functional materials, the arylation
methods of heterocycles have received significant attention
in organic synthesis.1 The transition-metal-catalyzed cross-
coupling is one of the most reliable approaches to make the
linkages.2 On the other hand, recent advances in the metal-
mediated direct arylation of aromatic heterocycles with aryl
halides may provide an efficient access to the target
molecules because it can eliminate the preactivation steps
of the heterocycles.3 Although palladium4 and rhodium5
catalysts are known to catalyze the direct arylation of various
heteroerenes, for the realistic catalyst loading, the replace-
ment of these catalysts with other less expensive ones are
strongly desired. In 2007, Daugulis reported an effective
method for the copper-catalyzed direct arylation of hetero-
cycles with aryl iodides.6a,b Subsequently, Ackermann
described the copper-catalyzed direct arylation of 1,2,3-
triazoles.6c Our group also succeeded in the arylation of
benzazoles with aryl iodides mediated by copper salts.7 While
these reactions are cost-efficient, compared to the conven-
(1) (a) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359. (b) Corbet, J.-P.; Mignani, G. Chem. ReV.
2006, 106, 2651.
(2) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., eds.; Wiley-VCH: Weinheim, 2004. (b) Tsuji, J. Palladium
Reagents and Catalysts, 2nd ed.; Wiley: Chichester, 2004. (c) Cross-
Coupling Reactions; Miyaura, N., Ed.; Top. Curr. Chem. 219; Springer:
Berlin, 2002.
(3) Recent reviews: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
(c) Campeau, L. C.; Stuart, D. R.; Fagnou, K. Aldrichchim. Acta 2007, 40,
35. (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173.
(4) Recent works: (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 71, 3994. (b) Stuart, D. R.; Villemure, E.;
Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072. (c) Stuart, D. R.; Fagnou,
K. Science 2007, 316, 1172. (d) Chuprakov, S.; Chernyak, N.; Dudnik,
A. S.; Gevorgyan, V. Org. Lett. 2007, 9, 2333. (e) Zhang, Z.; Hu, Z.; Yu,
Z.; Lei, P.; Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48, 2415.
(f) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926. (g) Phipps,
R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (h)
Blaszykowski, C.; Aktoudianakis, E.; Alberico, D.; Bressy, C.; Hulcoop,
D. G.; Jafarpour, F.; Joushaghani, A.; Laleu, B.; Lautens, M. J. Org. Chem.
2008, 73, 1888. (i) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73,
7428. (j) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2008, 47, 1473. (k) Nandurkar, N. S.; Bhanushali,
M. J.; Bhor, M. D.; Bhanage, M. Tetrahedron Lett. 2008, 49, 1045. (l)
Cusati, G.; Djakovitch, L. Tetrahedron Lett. 2008, 49, 2499. (m) Potavathri,
S.; Dumas, A. S.; Dwight, T. A.; Naumiec, G. R.; Hammann, J. M.; DeBoef,
B. Tetrahedron Lett. 2008, 49, 4050.
(5) (a) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A.
Org. Lett. 2004, 6, 35. (b) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 4996. (c) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K.
J. Am. Chem. Soc. 2006, 128, 11748. (d) Lewis, J. C.; Berman, A. M.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493. (e)
Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2008, 130, 14926.
(6) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
15185. (c) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R.
Org. Lett. 2008, 10, 3081. See also: (d) Besselie`vre, F.; Piguel, S.; Mahuteau-
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10.1021/ol900159a CCC: $40.75
Published on Web 03/20/2009
2009 American Chemical Society

tional palladium- and rhodium-catalyzed processes, the
arylating reagents are limited to the corresponding aryl
iodides. Therefore, the C-H arylation with less reactive aryl
bromides and chlorides using inexpensive catalyst systems
still remains a challenge.8 Herein, we report the nickel-
catalyzed direct arylation of azoles. The catalysts comprise
common and bench-stable NiBr2 and 1,10-phenanthroline or
its derivative and allow the use of aryl bromides as the
coupling reagents.
as a byproduct (entry 6).9 Polar solvents such as NMP and
DMAc were ineffective (entries 7 and 8). With other
inorganic bases such as NaO-t-Bu, KO-t-Bu, and Cs2CO3,
no arylated product was obtained (not shown).
We next examined the direct arylation of benzothiazole
(1) with a variety of aryl bromides using NiBr2 and 1,10-
phenanthroline in diglyme (Table 2). Not only 4- and
Table 2. Nickel-Catalyzed Direct Arylation of Benzothiazole (1)
with Various Aryl Bromides (2)a
Initially, we chose benzothiazole (1), 4-bromotoluene (2a),
and NiBr2 as model substrates in combination with a nickel
source and screened various ligands, solvents, and bases. It
was found that treatment of 1 with 1.2 equiv of 2a in the
presence of 10 mol % of NiBr2, 12 mol % of 1,10-
phenanthroline, and 4.0 equiv of LiO-t-Bu in diglyme at 150
°C for 4 h afforded the C2-arylated benzothiazole 3a in 73%
yield (Table 1, entry 1). Using 5 mol of NiBr2 gave 3a in
Table 1. Nickel-Catalyzed C2 Arylation of Benzothiazole (1)
with 4-Bromotoluene (2a)a
entry
ligand
base
solvent 3a, yieldb (%)
1
1,10-phenanthroline LiO-t-Bu diglyme
1,10-phenanthroline LiO-t-Bu diglyme
73 (67)
48
21
2c
3
2,2′-bipyridine
LiO-t-Bu diglyme
4
2,2′:6′,2′′-terpyridine LiO-t-Bu diglyme
12
5
TMEDA
dppbz
LiO-t-Bu diglyme
LiO-t-Bu o-xylene
trace
63e
0
6d
7
1,10-phenanthroline LiO-t-Bu NMP
1,10-phenanthroline LiO-t-Bu DMAc
8
0
a A mixture of 1 (0.50 mmol), 2a (0.60 mmol), NiBr2 (0.050 mmol),
ligand (0.060 mmol), and LiO-t-Bu (2.0 mmol) was stirred in solvent (3.0
mL) for 4 h at 150 °C. b GC yield. Isolated yield is shown in parentheses.
c Reaction with NiBr2 (0.025 mmol, 5 mol %) for 6 h. d Reaction with
NiBr2·diglyme (0.050 mmol). e 2-Phenylbenzothiazole was also obtained
in 12% yield as a byproduct.
a A mixture of 1 (0.50 mmol), 2 (0.60 mmol), NiBr2 (0.050 mmol),
1,10-phenanthroline (0.060 mmol), and LiO-t-Bu (2.0 mmol) was stirred
in diglyme (3.0 mL) at 150 °C. b Isolated yield. c Isolation after the removal
of acetal protection upon teatment with a catalytic amount of p-TsOH in
boiling acetone/H2O (1:1). d Reaction with 1.0 mmol of thiazole (1′) instead
of benzothiazole (1) and 0.50 mmol of 2a.
48% yield (entry 2). Other bidentate and tridentate nitrogen
ligands such as 2,2′-bipyridine, N,N,N′,N′-tetramethylethyl-
enediamine (TMEDA), and 2,2′:6′,2′′-terpyridine also showed
catalytic activities albeit with lower product yields (entries
3-5). The use of a phosphine ligand, 1,2-bis(diphenylphos-
phino)benzene (dppbz) in o-xylene, led to the formation of
3a in a compatible yield, while it caused the transfer of
phenyl group from the phosphorus atom to 1 under the
reaction conditions to form undesired 2-phenylbenzothiazole
3-bromotoluenes (2a and 2b) but also sterically demanding
2-bromotoluene (2c) and 1-bromo-2,5-dimethylbenzene (2d)
reacted with 1 to give the corresponding arylated benzothia-
zoles in moderate to good yields (entries 1-4). The
naphthalene motif could also be introduced to 1 (entry 5).
(7) Yoshizumi, T.; Tsurugi, H.; Satoh, T.; Miura, M. Tetrahedron Lett.
2008, 49, 1598.
(8) Exceptionally highly reactive aryl bromides such as 2-bromopyridine
were available for use in the copper-catalyzed direct arylation. See
ref 6b.
(9) The use of other arylphosphines resulted in the same scramble.
Trialkylphosphines such as PCy3 showed no catalytic activities. Dppbz in
diglyme was unexpectedly not effective.
1738
Org. Lett., Vol. 11, No. 8, 2009

Table 3. Nickel-Catalyzed C2 Arylation of Benzoxazole (1) with 2-Bromotoluene (2c)a
entry
Ni source/ligand
NiBr2/1,10-phenanthroline
NiBr2·diglyme/1,10-phenanthroline
NiBr2·diglyme/1,10-phenanthroline
NiBr2·diglyme/2,9-dimethyl-1,10-phenanthroline hydrate
NiBr2·diglyme/2,9-dimethyl-1,10-phenanthroline hydrate
additive
none
solvent
5c, yieldb (%)
1
2
3
4
5
diglyme
o-xylene
o-xylene
o-xylene
o-xylene
8
35
44
73 (53)
58
none
Zn powder
Zn powder
none
a A mixture of 4 (1.0 mmol), 2c (0.50 mmol), Ni source (0.050 mmol), ligand (0.060 mmol), LiO-t-Bu (2.0 mmol), and additive (0.25 mmol) was stirred
in solvent (3.0 mL) for 4 h at 150 °C. b GC yield. Isolated yield is in parentheses.
Electron-rich and electron-deficient aryl bromides 2f-h as
well as electron-neutral ones participated in the reaction
(entries 6-8). Although carbonyl functions except for CN
(entry 9) were not tolerant under the basic conditions, acetal
protection was compatible, and the coupling product 3k was
obtained (entry 10). Simple thiazole (1′) instead of 1 was
also arylated (entry 11).
of 2-biphenylyl and 9-anthracenyl groups was available
(entries 6 and 7).
The nickel/phenanthroline catalyst systems could be ap-
plied to the direct arylation of 5-aryloxazoles. Upon treatment
of 5-phenyloxazole (6a) with 9-bromophenanthrene (2l), the
corresponding 2,5-diaryloxazole 7al was formed in excellent
We also attempted the direct arylation of benzoxazole (4)
with 2-bromotoluene (2c). However, the expected coupling
product 5c was obtained in only 8% yield under the standard
conditions (Table 3, entry 1). Thus, further optimization
studies were performed to achieve the reaction with ben-
zoxazole (4). Since the GC analysis confirmed that benzox-
azole decomposed at the early stage, the development of the
milder reaction conditions would be essential. To our delight,
the change of solvent to less polar o-xylene suppressed the
decomposition of 4. The improvement of catalyst solubility
in o-xylene by the replacement of NiBr2 with NiBr2·diglyme
increased the yield (entry 2). Moreover, an addition of Zn
powder further improved the yield to 44% (entry 3). After
some additional ligand investigations, bulkier 2,9-dimethyl-
1,10-phenanthroline hydrate was found to be optimal (entry
4). Even in the presence of this ligand, Zn powder was
required for satisfactory yield (entry 5). This is probably
because the effective generation of zerovalent nickel species
would be necessary in the initiation step of the catalytic cycle
(vide infra).10
Table 4. Nickel-Catalyzed Direct Arylation of Benzoxazole (4)
with Various Aryl Bromides (2)a
By using the modified conditions, we conducted the
reaction of benzoxazole (4) with an array of aryl bromides
(Table 4). As observed in the case of benzothiazole (1),
various substitution patterns were tolerated toward the
arylation. Notably, the reaction with 9-bromophenanthrene
(2l) proceeded very smoothly to produce the corresponding
biaryl 5l in high yield (entry 5). In addition, the installation
(10) In the reaction of benzothiazole (1), the addition of Zn powder
gave no effect on yield. Hence, the combination of 1 and LiO-t-Bu in
diglyme would reduce the divalent nickel source to the corresponding
zerovalent active species effectively (see Scheme 2).
(11) As observed in the reaction of benzoxazole (4), the addition of Zn
powder improved the yield. For example, without Zn powder, compound
7bl was obtained in 79% yield.
a A mixture of 4 (1.0 mmol), 2 (0.50 mmol), NiBr2·diglyme (0.050
mmol), 2,9-dimethyl-1,10-phenanthroline hydrate (0.060 mmol), LiO-t-Bu
(2.0 mmol), and Zn powder (0.25 mmol) was stirred in o-xylene (3.0 mL)
for 4 h at 150 °C. b Isolated yield.
Org. Lett., Vol. 11, No. 8, 2009
1739

yield (Scheme 1). The oxazole bearing an electron-withdraw-
ing group on the benzene ring 6b also efficiently reacted
with 2l.11
species 8 would be initially generated in situ accompanied
by the reduction of NiBr2 with the combination of benzothia-
zole (1) and LiO-t-Bu in diglyme.12 On the contrary, in the
case of the reaction with benzoxazole (4) in o-xylene, the
initiation step would be insufficient so that the additional
reductant, Zn powder, is required. Subsequent oxidative
addition of aryl bromide to the active Ni(0) 8 followed by
transmetalation with heteroaryllithium compound 1013 gives
the corresponding diarylnickel 11. Productive reductive
elimination furnishes the arylated benzazole and regenerates
the starting nickel complex 8 to complete the catalytic cycle.
In conclusion, we have developed the effective and
inexpensive nickel catalyst systems for the direct arylation
of azoles with aryl bromides. The results show the high
potential of nickel catalysts in the direct C-H functional-
ization of heterocycles. Further elaborations may be expected
to make this method of broader utility. The detailed
mechanistic studies and the development of related C-H
cleavage processes under nickel catalysis are currently
underway.
Scheme 1
We are tempted to assume the mechanism of the reaction
with benzazoles as follows (Scheme 2). A zerovalent nickel
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. We thank Mr.
Tomoki Yoshizumi (Osaka University) for the initial ex-
perimental assistance. We are grateful to Prof. Kenichiro
Itami (Nagoya University) for useful discussion.
Scheme 2
Supporting Information Available: Detailed experimen-
tal procedures and characterization data of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900159A
(12) In the reaction mixture, a small amount of the homocoupling product
of benzothiazole was detected by GC-MS analysis.
(13) Deprotonation of heterocyclic compounds with LiO-t-Bu was
suggested. Do, H.-Q.; Daugulis, O. Org. Lett. 2009, 11, 421 See also ref 6.
Nevertheless, at this stage, the pathway involving nickel-assisted proton
abstraction mechanism could not be completely excluded.
1740
Org. Lett., Vol. 11, No. 8, 2009