Nickel-catalyzed C-H arylation of azoles with haloarenes: Scope, mechanism, and applications to the synthesis of bioactive molecules

Article abstract of DOI:10.1002/chem.201101091

Novel nickel-based catalytic systems for the C-H arylation of azoles with haloarenes and aryl triflates have been developed. We have established that Ni(OAc)₂/bipy/LiOtBu serves as a general catalytic system for the coupling with aryl bromides and iodides as aryl electrophiles. For couplings with more challenging electrophiles, such as aryl chlorides and triflates, the Ni(OAc)₂/dppf (dppf=1,1′-bis(diphenylphosphino)ferrocene) system was found to be effective. Thiazoles, benzothiazoles, oxazoles, benzoxazoles, and benzimidazoles can be used as the heteroarene coupling partner. Upon further investigation, we discovered a new protocol for the present coupling using Mg(OtBu)₂ as a milder and less expensive alternative to LiOtBu. Attempts to reveal the mechanism of this nickel-catalyzed heterobiaryl coupling are also described. This newly developed methodology has been successfully applied to the syntheses of febuxostat (a xanthine oxidase inhibitor that is effective for the treatment of gout and hyperuricemia), tafamidis (effective for the treatment of TTR amyloid polyneuropathy), and texaline (a natural product having antitubercular activity). Copyright

Full text of DOI:10.1002/chem.201101091

FULL PAPER
DOI: 10.1002/chem.201101091
À
Nickel-Catalyzed C H Arylation of Azoles with Haloarenes: Scope,
Mechanism, and Applications to the Synthesis of Bioactive Molecules
Takuya Yamamoto,[a] Kei Muto,[a] Masato Komiyama,[b] Jꢀrꢁme Canivet,[a]
Junichiro Yamaguchi,[a] and Kenichiro Itami*[a]
Abstract: Novel nickel-based catalytic
N
LiOtBu. Attempts to reveal the mecha-
nism of this nickel-catalyzed hetero-
biaryl coupling are also described. This
newly developed methodology has
been successfully applied to the synthe-
ses of febuxostat (a xanthine oxidase
inhibitor that is effective for the treat-
ment of gout and hyperuricemia), tafa-
midis (effective for the treatment of
TTR amyloid polyneuropathy), and
texaline (a natural product having anti-
tubercular activity).
À
systems for the C H arylation of
azoles with haloarenes and aryl triflates
have been developed. We have estab-
lished
that
NiACHTUNGTRENNUNG(OAc)2/bipy/LiOtBu
serves as a general catalytic system for
the coupling with aryl bromides and io-
dides as aryl electrophiles. For cou-
plings with more challenging electro-
philes, such as aryl chlorides and tri-
flates, the NiACHTUNGTRENNUNG(OAc)2/dppf (dppf=1,1’-
bis(diphenylphosphino)ferrocene)
system was found to be effective. Thi-
Introduction
Functionalized 2-arylazoles are a class of heterobiaryl
compounds present in many biologically active natural prod-
ucts and pharmaceuticals (Scheme 1).[5–12] In 1992, Ohta and
Heterobiaryl compounds represent a predominant structural
motif in many natural products and bioactive molecules.[1]
The construction of these motifs has been established by
palladium- or nickel-catalyzed cross-coupling reactions of
aryl–metal compounds with aryl halides, namely the
Kumada–Tamao–Corriu, Negishi, Migita–Kosugi–Stille,
Suzuki–Miyaura, and Hiyama cross-coupling reactions.[2]
À
co-workers first reported a direct C H bond arylation
method that used a palladium catalyst. However, the meth-
odology was somewhat limited in substrate scope.[13] In
1998, Miura and co-workers made a breakthrough in this
area by devising a more general palladium-catalyzed direct
arylation protocol of azoles with haloarenes [Eq. (1)].[14]
À
À
Meanwhile, a transition-metal-catalyzed direct C H bond
Since these pioneering works in direct C H coupling, many
arylation[3] that avoids the need to prepare stoichiometric
amounts of aryl–metal reagent is finding increased use in
the preparation of heterobiaryl compounds. We have also
contributed to this area of research by developing various
research groups have been involved in finding new methods
for the synthesis of 2-arylazoles using palladium catalysts.[15]
Ellman, Bergman, and co-workers reported a rhodium-cata-
lyzed arylation of azoles with aryl bromides that is likely to
proceed through a different mechanism.[16]
À
direct C H bond arylation reactions that are catalyzed by
Rh, Ir, Cu, and Pd complexes.[4]
[a] T. Yamamoto, K. Muto, Dr. J. Canivet, Dr. J. Yamaguchi,
Prof. Dr. K. Itami
Department of Chemistry
Graduate School of Science
Nagoya University, Chikusa
Nagoya 464-8602 (Japan)
Fax : (+81)52-788-6098
In spite of their utility, palladium and rhodium catalysts
are expensive, even when used in catalytic amounts. In 2007,
E-mail: itami.kenichiro@a.mbox.nagoya-u.ac.jp
À
Daugulis and co-workers described a copper-catalyzed C H
[b] M. Komiyama
arylation of azoles with haloarenes that was an important
breakthrough in terms of catalyst cost.[17a] Subsequently,
Miura and co-workers reported similar results.[17b] Our goal
Pharmaceutical Development Research Laboratories
Teijin Pharma Limited
3-2, Asahigaoka 4-chome
À
has been to develop this type of C H arylation reaction in
an inexpensive and operationally simple manner, while
maintaining high reactivity and broad substrate scope. Con-
Hino, Tokyo 191-8512 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101091.
Chem. Eur. J. 2011, 17, 10113 – 10122
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10113

Scheme 1. 2-Arylated azoles in biologically active compounds.
sidering these factors, we searched for a novel catalyst, and
À
finally developed the nickel-catalyzed C H arylation of
azoles with aryl halides and triflates in 2009.[4e] It should be
mentioned that the group of Miura also came to a similar
conclusion almost simultaneously.[18] Since these discoveries,
nickel-catalyzed direct heterobiaryl couplings using arylsi-
lanes or arylboronic acids have been reported.[19,20]
In this article, we disclose: 1) a broad evaluation of sub-
À
strate scope and limitations of Ni-catalyzed C H arylation
of azoles with haloarenes; 2) the establishment of a new
protocol using MgACHTUNGTRENNUNG(OtBu)2 as a milder and less expensive al-
ternative to LiOtBu; 3) our attempts to reveal the mecha-
nism of this nickel-catalyzed coupling; and 4) the application
À
of Ni-catalyzed C H arylation to the synthesis of febuxostat
À
Scheme 2. Ni-catalyzed C H arylation of azoles with haloarenes.
(a xanthine oxidase inhibitor that is effective for the treat-
ment of gout and hyperuricemia),[5] tafamidis (effective for
the treatment of TTR amyloid polyneuropathy),[6] and texa-
line (a natural product having antitubercular activity).[12]
are some examples of variations from these early condi-
tions.[21]
In the absence of a nickel source, almost none of the de-
sired coupling was observed. Nickel complexes such as [Ni-
AHCTUNGTRENNUNG
Results and Discussion
À
Discovery of Ni-catalyzed C H arylation of azoles with
ACHTUNGTRENNUNG
halo
A
tive. We have also determined that bidentate nitrogen-based
ligands furnish efficient catalysts. Whereas bipy (64%), 4,4’-
(tBu)2bipy (70%), and phenanthroline (52%) promoted the
coupling, diphosphanes such as 1,2-bis(diphenylphosphino)-
ethane (dppe) and 1,1’-bis(diphenylphosphino)ferrocene
(dppf) were less efficient under these conditions. The cou-
pling proceeded in various ether solvents, with 1,4-dioxane
giving the best yield (72%), whereas toluene, N,N-dimethyl-
formamide (DMF), and N-methyl-2-pyrrolidinone (NMP)
nickel salts, ligands, and alkalinic additives in the reaction of
benzothiazole (1A) and iodobenzene (2a). After extensive
screening, we found that NiACHTNUTRGENNG(U OAc)2/2,2’-bipyridyl (bipy)
could serve as an efficient catalyst in the presence of
LiOtBu. For example, the cross-coupling product 2-phenyl-
benzothiazole (3Aa) was obtained in 64% yield when the
reaction was carried out in THF at 858C for 18 h, represent-
ing our “early” conditions (Scheme 2). Listed in Scheme 2
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Arylation of Azoles
FULL PAPER
Table 1. Scope of iodo- and bromoarenes in Ni
azole arylation.[a]
ACHTUNGRTEN(NUGN OAc)2/bipy-catalyzed
Table 1. (Continued)
Substrate 2
Product 3
Yield
[%][b]
28[d]
29
3Aw
3Ax
96
57
Substrate 2
Product 3
Yield
[%][b]
1
X=I
X=I
X=Br
X=I
X=Br
3Aa
3Aa
3Aa
3Ab
3Ab
80
51
62
90
82
2[c]
3
30[d]
31
3Ay
3Az
45
74
4
5
6
7
X=I
X=Br
3Ac
3Ac
71
63
32
3Aaa
3Aab
58
49
33[d]
8
9
X=I
X=Br
3Ad
3Ad
69
48
[a] Reagents and conditions: 1A (0.75 mmol), 2 (0.50 mmol), Ni
(0.05 mmol), bipy (0.05 mmol), LiOtBu (0.75 mmol), 1,4-dioxane (2 mL),
858C, 36 h. [b] Isolated yield of 3. [c] 1 mol% Ni(OAc)2 and bipy were
ACHTUNGTRENNUNG(OAc)2
10
3Ae
91
AHCTUNGTRENNUNG
used. [d] LiOtBu (1.00 mmol) was used. The reaction was carried out at
1208C.
11[d]
3Af
68
were unsuitable solvents. The choice of base additive turned
out to be most critical: when LiOtBu was replaced by other
12[d]
3Ag
71
bases such as NaOtBu, KOtBu, Mg
ACHTUNGTRENNUNG
Li2CO3, Cs2CO3, K3PO4, or 1,8-diazabicycloACHTUNGTRENNUNG
13
14
o-
m-
p-
o-
m-
p-
3Ah
3Ai
3Aj
3Ak
3Al
65
53
70
72
75
68
ene (DBU), almost none of the target product was pro-
duced. A dramatic difference between LiOtBu and its
sodium, potassium, and magnesium analogues is notable. In
view of efficiency, cost, simplicity, and stability, at this point,
15
16[d]
17
18
3Am
we identified NiACTHNUTRGNEUNG(OAc)2/bipy/LiOtBu/1,4-dioxane/858C as
19[d]
3An
65
our “standard” conditions for the coupling reaction using
aryl iodides and bromides. Upon further optimization of the
reaction, we found that the best conditions involved
1.5 equivalents of benzothiazole, 1.0 equivalent of iodoben-
zene, 10 mol% of NiACTHNUTRGNEUNG(OAc)2/bipy, and 1.5 equivalents of
LiOtBu in 1,4-dioxane at 858C for 36 h (80% yield).
20[d]
21
m-
p-
3Ao
3Ap
47
78
22
23
3Aq
3Ar
51
61
À
Scope of Ni-catalyzed C H arylation of azoles with halo-
arenes: We next examined the direct arylation of benzothi-
AHCTUNGTREGaNNNU zole with various haloarenes (Table 1). Bromobenzene and
24[d]
3As
61
substituted bromoarenes reacted with benzothiazole (1A) to
give the corresponding 2-arylated benzothiazoles 3Aa–Ad
in slightly lower yields compared with the iodoarene series
(Table 1, entries 3, 5, 7, and 9). For a series of monomethyl-
25
3At
3Au
91
73
AHCTUNGTREGaNNNU ted iodo- or bromobenzenes, the ortho-methyl substituted
substrates generally afforded higher product yields than
their meta- and para-substituted counterparts (Table 1, en-
tries 4, 6, and 8).[22] ortho-Phenyliodobenzene also displayed
high reactivity, giving the corresponding product 3Ae in ex-
cellent yield (Table 1, entry 10). Sterically more hindered 1-
iodo-2,6-dimethylbenzene also gave the corresponding prod-
uct 3Ag in good yield (Table 1, entry 12). Both electron-rich
and electron-deficient aryl iodides and bromides can be
used as aryl electrophiles (Table 1, entries 13–23). The cou-
pling of ester-containing iodoarenes, such as ethyl 4-iodo-
26[d]
27[d]
3Av
62
Chem. Eur. J. 2011, 17, 10113 – 10122
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10115

K. Itami et al.
benzoate, proceeded sluggishly to afford a mixture of the
target product and tert-butylated product in less than 5%
yield. This is most likely due to a transesterification reaction
with LiOtBu, which generates an ethoxide that inhibits the
coupling reaction. On the other hand, an iodoarene with an
amide moiety at the 4-position reacted smoothly with 1A
(Table 1, entry 24). Unfortunately, acylated and nitrated
Using these optimized conditions, the direct arylation of
benzothiazole (1A) with various aryl chlorides and triflates
was performed (Table 3). Compared with unsubstituted
À
Table 3. Ni
N
aryl chlorides and triflates.[a]
haloACHTUNGTRENNUNGarenes were ineffective aryl electrophiles under these
catalytic conditions, giving less than 5% yield. Presumably,
substrates having highly sensitive functional groups react
with LiOtBu and decompose under these conditions. For
some substrates, more forcing conditions, such as higher
temperatures and the use of 2.0 equivalents of LiOtBu, were
required to reach high levels of substrate conversion
(Table 1, entries 11, 12, 16, 19, 20, 24, 26–28, 30, and 33).
Heteroaryl iodides and bromides were also reactive
(Table 1, entries 29–33). Finally, this reaction can take place
with a catalyst loading as low as 1 mol% nickel (Table 1,
entry 2).
On the basis of these findings, we next aimed to extend
the scope of the reaction to include more challenging aryl
electrophiles such as aryl chlorides and triflates (Table 2).
Various nitrogen bidentate ligands, such as bipyridyls and
phenanthrolines, proved to be ineffective when using aryl
chlorides as haloarenes (Table 2, entry 1). Monodentate
phosphane ligands such as Ph3P, Cy3P, (tBu)3P, and XPhos
were also not effective. The application of bidentate phos-
phane ligands drastically increased the reaction yield; for
example, the use of bis(diphenylphosphino)butane (dppb)
gave 2-phenylbenzothiazole (3Aa) in 50% yield. Upon fur-
ther screening of ligands, it was found that the use of dppf
as the ligand slightly increased the yield, and 3Aa was gen-
Substrate 2
Product 3
Isolated
yield [%]
1
2
X=Cl
X=OTf
3Aa
3Aa
74
48
3
3Ab
85
4[b]
5
3Am
3An
3Aj
32
65
27
54
6[b]
7[b]
3Ax
8[b]
3Ay
54
9[b]
10
3Aac
3Az
44
58
63
11[b]
3Aad
[a] Reagents and conditions: 1A (0.75 mmol), 2 (0.50 mmol), NiACHTUNGTRENNUNG(OAc)2
(0.05 mmol), dppf (0.05 mmol), LiOtBu (0.75 mmol), 1,4-dioxane (2 mL),
1408C, 40 h. [b] LiOtBu (1.5 mmol) was used.
erated in 53%, even though the NiACHTNUTRGNEUNG(OAc)2/dppf system had
been found to be less effective (26% yield) with iodoben-
zene at 858C (see Scheme 2). Finally, when the amount of
LiOtBu was decreased from 3.0 to 1.5 equivalents and the
reaction was performed at 1408C for 40 h, 3Aa was isolated
in 74% yield.
chlorobenzene (Table 3, entry 1), o-methylchlorobenzene re-
acted with benzothiazole in a slightly higher yield (Table 3,
entry 3). This reactivity trend is similar to that observed
with iodo- and bromoarenes as haloarene substrates. Elec-
tron-poor and electron-rich aryl chlorides containing tri-
fluoromethyl, fluoride, and methoxy groups also participated
in this coupling (Table 3, entries 4–6). Heteroaryl chlorides
À
Table 2. Ligand screening for Ni-catalyzed C H arylation of benzothi-
ACHTUNGTRENNUNG
azole with chlorobenzene.[a]
also reacted smoothly under the action of Ni
catalyst (Table 3, entries 7–11).
ACHTUNGRTENN(UNG OAc)2/dppf
Finally, we explored the use of other azoles in the aryl-
ation reactions (Table 4). Gratifyingly, thiazoles (1A–E),
benzoxazole (1F), oxazoles (1G and 1H), and N-
methylbenzimidazole (1I) reacted smoothly under the influ-
ence of Ni(OAc)2/bipy/LiOtBu to furnish the corresponding
coupling products in moderate yields. However, we found
that the coupling of 1F showed poor reproducibility. After
reinvestigation of the catalyst precursor, we identified that
Ligand
GC yield of 3 [%]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
9
bipy
dppm
dppe
dppp
dppb
0
0
2
26
50
10
6
43
53
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
dppn
BINAP
Xantphos
dppf
the use of [Ni
provide reproducible results. These experiments indicate
that the production of active Ni0 species from the Ni
(OAc)2
precursor might be slower in the reaction with benzoxazole.
ACHTUNGTNERNUG(cod)2]/bipy instead of NiACHTUNGTRENN(UGN OAc)2/bipy would
[a] Reagents and conditions: 1A (0.75 mmol), chlorobenzene
(0.50 mmol), Ni(OAc)2 (0.05 mmol), ligand (0.05 mmol), LiOtBu
(1.5 mmol), 1,4-dioxane (2 mL), 1408C, 10 h.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
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Arylation of Azoles
FULL PAPER
[a]
Table 4. Scope of heteroarene coupling partners.[a]
Table 5. Effect of base on the Ni-catalyzed C H arylation in DMF.
À
Ligand
GC yield of 3Aa [%]
Product 3
Isolated
yield [%]
Product 3
Isolated
yield [%]
1
2
3
4
5
6
7
8
9
NaOtBu
KOtBu
<1
0
6
20
9
20
35
0
Ca
Ba(OtBu)2
(OMe)2
(OEt)2
(OtBu)2
A
E
80
61
Mg
Mg
Mg
ACHTUNGTRENNUNG
A
AHCTUNGTRENNUNG
69[b]
43
Mg(OH)2
MgH2
0
[a] Reagents and conditions: 1A (0.50 mmol), 2a (0.50 mmol), NiACHTUNGTRENNUNG(OAc)2
(0.05 mmol), bipy (0.05 mmol), base (1.0 mmol), DMF (2 mL), 1008C,
18 h.
57
53[c]
73[b]
47
using 1,4-dioxane as a solvent, sodium and potassium tert-
butoxides were again both ineffective. Interestingly, alkox-
ides of alkaline earth metals such as barium, magnesium,
and calcium were somewhat effective. Finally, we discovered
an acceptable solution in which the reaction was conducted
41
with two equivalents of MgACHTNUTRGNENG(U OtBu)2 in DMF to furnish the
corresponding product 3Aa in 35% yield.
With new conditions in hand, we then compared the reac-
tivity of aryl electrophiles under the action of MgACTHUNRGTNEUNG(OtBu)2 in
[a] Reagents and conditions: 1 (0.75 mmol), 2a (0.50 mmol), NiACTHNUTRGNEUNG(OAc)2
(0.05 mmol), bipy (0.05 mmol), LiOtBu (0.75 mmol), 1,4-dioxane (2 mL),
858C, 36 h. [b] LiOtBu (1.00 mmol) was used. The reaction was carried
out at 1208C. [c] Zn powder (0.50 mmol) was added.
DMF with those under LiOtBu in 1,4-dioxane. To this end,
benzothiazole (3A) was used as a fixed coupling partner
and various aryl electrophiles were classified as being “supe-
rior”, “equal”, or “inferior” by comparing the yields under
We also found that the addition of one equivalent of zinc
powder to our “standard” conditions gave reproducible re-
sults, presumably due to the rapid formation of active Ni0
species.[23] In the case of thiazoles and oxazoles, only the
monoarylated product was exclusively obtained. We also at-
Mg
mediated conditions (Table 6). For example, in the case of
bromobenzene, further optimization (1.5 equiv Mg(OtBu)2
ACHTUNGTERN(NUNG OtBu)2-mediated conditions to those under LiOtBu-
ACHTUNGTRENNUNG
and 1.5 equivalents benzothiazole were employed, and the
reaction time was extended to 36 h) allowed the yield of
3Aa to be increased to 57%, which is nearly as good as the
yield obtained when LiOtBu was used. Therefore, bromo-
benzene was classified as being “equal”. Haloarenes with
electron-neutral or electron-rich substituents, such as fluo-
ride, methyl, and methoxy groups, were also identified as
being “equal”. In contrast, ortho-substituted haloarenes,
chlorobenzene, and phenyl triflate were found to be “inferi-
or” substrates. On the other hand, electron-deficient haloar-
enes, such as iodopyridine, iodonitrobenzene, and ester-sub-
stituted iodobenzene, were found to be “superior” arylating
agents. Moreover, 4-nitroiodobenzene and ethyl 4-iodoben-
tempted the coupling reaction using imidazole, imidazoACHTUNTRGNEUNG[1,5-
a]pyridine, and caffeine, but the corresponding coupling
products were unfortunately obtained either in low yields or
in trace amounts (less than 25%).
A new protocol involving MgACHTNUGRTENUNG(OtBu)2: The studies men-
tioned above clearly demonstrate the potential use of nickel
catalysis to rapidly access a range of arylazoles. However,
we were not satisfied with the critical necessity of LiOtBu
(base) and 1,4-dioxane (solvent), which might limit the syn-
thetic applications of this approach. For example, the high
basicity and nucleophilicity of LiOtBu might be problematic
for some sensitive functional groups. In addition, 1,4-diox-
ane might not be suitable for dissolving very polar sub-
strates, which are often required during the syntheses of
pharmaceuticals and biologically active compounds. There-
fore, we planned to explore the use of new base additives
zoate were effective only for Mg
As a result, we established two useful sets of coupling condi-
tions for use with the Ni(OAc)2/bipy catalytic system.
Whereas the LiOtBu/1,4-dioxane system generally works
well for robust substrates, the Mg(OtBu)2/DMF system is, in
many cases, superior for substrates with base-sensitive func-
ACHTUNGERTN(NUNG OtBu)2-mediated reactions.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
À
for the nickel-catalyzed C H arylation in DMF (Table 5).
Reactions were carried out using various alkaline additives
tional groups. It should also be mentioned that MgACHTUNGTRENNUNG(OtBu)2
(2 equiv) under the action of Ni
(OAc)2/bipy catalyst in
is less expensive than LiOtBu.
DMF at 1008C for 18 h.[24] Similar to our previous screening
Chem. Eur. J. 2011, 17, 10113 – 10122
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10117

K. Itami et al.
À
Table 6. Comparison between LiOtBu/1,4-dioxane and Mg
ation.[a]
ACHTUNGTERNN(UNG OtBu)2/DMF systems in Ni-catalyzed C H aryl-
situ; 2) nickelation of an azole
II
ACHTUNGTRENNUNG
À
À
À
X to
(Het H) with Ar Ni
II
À
À
generate an Ar Ni Het spe-
cies; and 3) reductive elimina-
tion of an arylazole product
À
(Het Ar) with the regeneration
of Ni0 catalyst. It is quite clear
that a Ni0 species is involved in
catalysis because the coupling
also proceeds well using [Ni-
Superior
3; yield [%][b]
Equal
Inferior
3; yield [%][b]
2
2
3; yield [%][b]
2
3Am; 84 (68)
3Ax; 85 (57)
3Al; 75 (75)
3Ak; 33[d] (72)
(cod)2] as
a
nickel source
3Aa; 57[d] (62)
3An; 61 (65)
3Ae; 26[d] (91) (Scheme 2). However, details
were unclear regarding the ele-
mentary steps in the assumed
mechanism, such as 1) the
manner in which the Ni0 species
is produced from Ni
under the reaction conditions;
2) whether or not an Ar Ni
species is involved in the cata-
lytic cycle; and 3) the way in
3Aae; 29[c] (<1)
3Ab; 58[d] (90)
3Aat; 63 (91)
3Ao; 87 (47)
3Ad; 69 (69)
3Af; 57 (65)
ACHTUNGTRENNUNG(OAc)2
II
À
À
X
3Aaf; 48[f] (<1)
3Aa; <5 (74)
3Aa; <5 (48)
which azole nickelation occurs
3Ar; 73[e] (61)
II
À
À
to give Ar Ni Het species.
With these questions in mind,
we performed a number of ex-
periments to shed some light on
the mechanism of this reaction.
[a] Reagents and conditions: 1A (0.75 mmol), 2 (0.50 mmol), Ni
(OtBu)2 (0.75 mmol), DMF (2 mL), 1008C, 36 h. [b] The first yield indicates the yield under the new protocol
of Mg(OtBu)2 in DMF, and the second yield within parenthesis indicates the yield under the standard condi-
tions. [c] The reaction was carried out at 858C. [d] The reaction was carried out at 1208C. [e] DMSO was used
instead of DMF as solvent. [f] The product was obtained as a mixture of 3Aaf (33%) and tert-butyl ester
3Aaf’ (15%).
ACHTUNGRTEN(NUNG OAc)2 (0.05 mmol), bipy (0.05 mmol), Mg-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Generation of Ni0 species from
Ni
sumed that the active Ni0 spe-
cies could be generated from Ni(OAc)2 by the action of sac-
rificial azole (in a catalytic amount). In other words, it might
be possible that nickelation of two molar equivalents of
ACHTUNGRTEN(NUNG OAc)2: We initially pre-
À
Mechanistic studies on the Ni-catalyzed C H arylation of
azoles: Mechanistic studies on transition-metal-catalyzed
azole–haloarene couplings using palladium, rhodium, and
copper catalysts had been performed by Ellman,[3h] Daugu-
lis,[17c] and Zhuravlev.[25] According to these results, as well
as to our previous investigations, a likely mechanism fol-
lowed in the present coupling involves Ni0/NiII redox cataly-
ACHTUNGTRENNUNG
azole with NiACTHUNRGTNEUNG(OAc)2, followed by reductive elimination,
could afford the necessary Ni0 species along with an azole
dimer. To corroborate this hypothesis, we performed the ex-
periments shown in Scheme 4. As anticipated, the dimeriza-
sis (Scheme 3) and proceeds through: 1) oxidative addition
0
À
of an aryl electrophile (Ar X) to a Ni species generated in
Scheme 4. Dimerization of benzothiazole by the action of Ni
and LiOtBu. Reagents and conditions: 1A (0.75 mmol), Ni
(0.05 mmol), bipy (0.05 mmol), LiOtBu (0.75 mmol), 1,4-dioxane (2 mL),
1208C, 36 h. The yield of 4 is based on Ni(OAc)2.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
À
Scheme 3. A possible mechanism of nickel-catalyzed C H arylation of
azoles with haloarenes.
ACHTUNGTRENNUNG
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Chem. Eur. J. 2011, 17, 10113 – 10122

Arylation of Azoles
FULL PAPER
tion of benzothiazole (1A) occurred through the agency of
Ni
ACHTUNGTRENNUNG(OAc)2/bipy and LiOtBu to give the dimer 4 in 74% yield
(based on nickel). Interestingly, further investigations led to
the conclusion that both NiACHTNUTRGENNG(U OAc)2 and LiOtBu are required
for the dimerization to proceed.[24]
Deprotonation of azoles with LiOtBu: Having identified
that LiOtBu is critical for generating Ni0 species, we then
explored another assumed role of LiOtBu as a deprotonat-
ing agent of azoles within the catalytic cycle (nickelation
step). In early experiments, benzothiazole (1A) was depro-
tonated with n-butyllithium instead of LiOtBu and the
nickel-catalyzed reaction with iodobenzene (2a) was then
conducted. However, the expected coupling product 3Aa
was not obtained, and 1A completely decomposed under
the coupling conditions. In line with this observation, Itoh
and co-workers reported that the C2-lithiated benzothiazole
(Li-1A) is very unstable even at À508C.[26] To evaluate
whether the deprotonation is taking place during nickel cat-
alysis, we conducted the coupling in the presence of tBuOD
(Scheme 5). When 1A (1.5 equiv) was treated with 2a
Scheme 6. Reaction of phenylnickel bromide complex and benzothiazole.
[a] DMF was used as solvent.
72% and 84% yield, respectively (Scheme 6). This result al-
ludes to the possibility of a sequence of 1) oxidative addi-
tion, 2) azole nickelation, and 3) reductive elimination in
catalysis.
Possible pathways for azole nickelation and the importance
of the protonation/deprotonation shuttle: Although the
mechanism of nickel-catalyzed arylation of azoles with halo-
AHCTUNGTREGaNNNU renes is not yet entirety clear, a number of experiments are
consistent with the proposed Ni0/NiII catalytic cycle shown
in Scheme 3; namely, the Ni0/NiII redox catalysis consisting
of: 1) oxidative addition of ArX to Ni0, 2) azole nickelation
Scheme 5. Protonation/deprotonation shuttle.
producing Ar-Ni-Het, and 3) reductive elimination, generat-
0
À
ing heterobiaryl product Het Ar and Ni . It is of note that
LiOtBu and Mg
(OtBu)2 most likely play a critical role in
(1.0 equiv), Ni
G
the azole nickelation step, which should be involved both in
the product-generating catalytic cycle as well as in the gen-
(2.0 equiv), and tBuOD (2.0 equiv), in 1,4-dioxane at 1208C
for 10 h, 42% of recovered 1A was deuterated at the C2 po-
sition (coupling product 3Aa was formed in 44% yield). Al-
though this result clearly indicates that the deprotonation
occurs under the coupling conditions, a more important im-
plication may be the following. Taking the instability of C2-
lithiated benzothiazole (Li-1A) into account, one of the im-
portant factors of the Ni-catalyzed coupling would be the
existence of a pre-equilibrium between 1A and Li-1A. This
deprotonation/protonation shuttle should help to prevent
decomposition of Li-1A. We believe that a similar effect is
operating in the generation of Ni0 species (Scheme 4).
eration of catalytically active Ni0 species from Ni
ACTHNUTRGNEN(UG OAc)2.
We assume that the azole nickelation step might occur
through a concerted metalation–deprotonation of azole with
Ar-Ni-OtBu, which could possibly be generated either from
Ar-Ni-X and tert-butoxide (Path A in Scheme 7),[28] or
through tert-butoxide-mediated deprotonation of azole fol-
lowed by transmetalation of the generated azolyllithium (or
magnesium) with Ar-Ni-X (Path B in Scheme 7). If the
latter mechanism were operating, the current Ni-catalyzed
heterobiaryl coupling would be tantamount to an in situ
Kumada–Tamao–Corriu type coupling of metalated azoles
and aryl electrophiles. However, we must stress that even if
this is the case, the deprotonation/protonation shuttle of
azoles (which avoids azole substrate decomposition) is es-
sential for achieving the heterobiaryl coupling.[29] In this
regard, the present Ni-catalyzed azole arylation is not
merely an in situ Kumada–Tamao–Corriu type coupling.
Nickelation of azoles with Ar-NiII-X and subsequent reduc-
tive elimination: In the mechanistic picture shown in
Scheme 3, nickelation of azoles with Ar-NiII-X is the next
step after oxidative addition of Ar X to Ni species. Thus,
Ar-Ni
N
benzothiazole (1A) in 1,4-dioxane at 1208C (Scheme 6). Al-
though the coupling product was not observed under these
conditions, we found that the addition of either LiOtBu or
À
Applications of Ni-catalyzed C H arylation to the synthesis
of biologically active compounds: To illustrate the utility of
Mg
G
Ni-catalyzed azole arylation in the preparation of biological-
Chem. Eur. J. 2011, 17, 10113 – 10122
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www.chemeurj.org
10119

K. Itami et al.
coupling components (6 and 7) can be quickly derivatized in
one step from commercially available 4-methyl-5-thiazole-
carboxylic acid and 2-fluoro-5-iodobenzonitrile, respectively.
Tafamidis, which was first synthesized by Kelly and co-
workers,[6] is effective for the treatment of TTR amyloid
polyneuropathy (Scheme 9), and is currently well into
Phase II and III clinical trials for treating these diseases. We
attempted to couple a benzoxazole ester with 1,3-dichloro-5-
iodobenzene (9), expecting to achieve a more efficient syn-
thesis, however, the coupling did not proceed at all. After
some investigation, we found that changing the ester of ben-
zoxazole to an amide moiety solved this problem. The de-
sired direct arylation was thus achieved, and subsequent hy-
drolysis of the amide using HF/pyridine provided tafamidis
in 70% overall yield (Scheme 9).
As a third example in this project, the synthesis of a natu-
ral product, texaline, which has antitubercular activity,[12a]
was undertaken. Piguel and co-workers had already report-
ed the synthesis of texaline using a palladium-mediated
Scheme 7. Possible pathways of azole nickelation.
ly active compounds, we selected febuxostat, tafamidis and
texaline as aryl-substituted
azole targets.
Febuxostat is an inhibitor of
xanthine oxidase that has been
developed by Teijin Pharma as
a new drug for the treatment of
gout
and
hyperuricemia
(Scheme 8).[5] It has been 40
years since a drug of this kind
Scheme 9. Concise synthesis of tafamidis.
direct arylation method under microwave conditions in 57%
yield.[12c] We found that texaline could be obtained in a su-
perior 84% yield under the action of the Ni/bipy/LiOtBu
catalytic system in 1,4-dioxane at 1208C (Scheme 10).
Conclusion
Scheme 8. Concise synthesis of febuxostat.
We have developed an efficient nickel-catalyzed process for
À
the C H bond arylation of azoles with aryl electrophiles.
One of the important features of the present reactions is the
has been developed, and febuxostat has gained a lot of pop-
ularity; it has already been accepted for commercial use in
Europe, USA, and Korea. Therefore, the development of an
efficient synthesis of febuxostat is currently ongoing in pro-
utilization of inexpensive, air-stable Ni
ACHTUNGTRENNUNG
catalyst precursor.[30] We have established that Ni
ACHTUNGTRENNUNG
bipy/LiOtBu serves as a general catalytic system for the cou-
cess chemistry. Under the influence of Ni
lyst and LiOtBu, thiazole 6 and
iodoarene 7 underwent cross-
coupling in 1,4-dioxane at
1008C to furnish the corre-
G
pling using aryl bromides and iodides as aryl electrophiles.
sponding
coupling
product
(Scheme 8). The Mg
methylsulfoxide
ACHTUNGTRENNUNG
(DMSO)
system was equally effective for
the coupling. Subsequent treat-
ment with CF3CO2H afforded
febuxostat in 62–67% overall
yield. The synthesis is extreme-
ly efficient because both of the Scheme 10. Concise synthesis of texaline.
10120
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Arylation of Azoles
FULL PAPER
Current Chemistry, Vol. 219, Cross-Coupling Reactions: A Practical
Guide (Ed.: N. Miyaura), Springer, Berlin, 2002.
For coupling more challenging electrophiles, such as aryl
chlorides and triflates, the NiACHTNUGTRENUNG(OAc)2/dppf/LiOtBu system
turned out to be effective. Thiazoles, benzothiazoles, oxa-
zoles, benzoxazoles, and benzimidazoles can be used as the
heteroarene coupling partner. Upon further investigation,
we discovered a new protocol for the present coupling using
À
[3] For selected reviews on catalytic C H bond arylation of arenes, see:
a) L.-C. Campeau, K. Fagnou, Chem. Commun. 2006, 1253–1264;
b) O. Daugulis, V. G. Zaitsev, D. Shabashov, Q.-N. Pham, A. Lazare-
va, Synlett 2006, 3382–3388; c) D. Alberico, M. E. Scott, M. Lautens,
Chem. Rev. 2007, 107, 174–238; d) I. V. Seregin, V. Gevorgyan,
Chem. Soc. Rev. 2007, 36, 1173–1193; e) T. Satoh, M. Miura, Chem.
Lett. 2007, 36, 200–205; f) F. Kakiuchi, T. Kochi, Synthesis 2008,
3013–3039; g) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008, 949–957;
h) J. C. Lewis, R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2008,
41, 1013–1025; i) M. Miura, T. Satoh in Modern Arylation Methods
(Ed.: L. Ackermann), Wiley-VCH, Weinheim, 2009, pp. 335–361;
j) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2009,
121, 5196–5217; Angew. Chem. Int. Ed. 2009, 48, 5094–5115; k) L.
Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. 2009, 121,
9976–10011; Angew. Chem. Int. Ed. 2009, 48, 9792–9826.
MgACHTUNGTRENNUNG(OtBu)2 as a milder and less expensive alternative to
LiOtBu. A number of mechanistic experiments were in line
with the proposed Ni0/NiII redox catalysis proceeding
through: 1) oxidative addition of an aryl electrophile to Ni0
species generated in situ, 2) nickelation of an azole with ar-
ylnickel(II) species, and 3) reductive elimination of a hetero-
biaryl product with the regeneration of Ni0 catalyst. The effi-
cient and rapid syntheses of febuxostat, tafamidis, and texa-
line speak well for the potential of the present nickel cataly-
sis in a range of synthetic applications.
[4] For our recent achievements on this field, see: a) S. Yanagisawa, T.
Sudo, R. Noyori, K. Itami, J. Am. Chem. Soc. 2006, 128, 11748–
11749; b) S. Yanagisawa, T. Sudo, R. Noyori, K. Itami, Tetrahedron
2008, 64, 6073–6081; c) I. Ban, T. Sudo, T. Taniguchi, K. Itami, Org.
Lett. 2008, 10, 3607–3609; d) S. Yanagisawa, K. Ueda, T. Taniguchi,
K. Itami, Org. Lett. 2008, 10, 4673–4676; e) J. Canivet, J. Yamagu-
chi, I. Ban, K. Itami, Org. Lett. 2009, 11, 1733–1736; f) B. Join, T.
Yamamoto, K. Itami, Angew. Chem. 2009, 121, 3698–3701; Angew.
Chem. Int. Ed. 2009, 48, 3644–3647; g) J. Bouffard, K. Itami, Top.
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Jpn. 2010, 68, 1132–1141; i) K. Ueda, S. Yanagisawa, J. Yamaguchi,
K. Itami, Angew. Chem. 2010, 122, 9130–9133; Angew. Chem. Int.
Ed. 2010, 49, 8946–8949; j) S. Kirchberg, S. Tani, K. Ueda, J. Yama-
guchi, A. Studer, K. Itami, Angew. Chem. 2011, 123, 2435–2439;
Angew. Chem. Int. Ed. 2011, 50, 2387–2391; k) S. Yanagisawa, K.
Itami, ChemCatChem 2011, 3, 827–829; l) A. D. Yamaguchi, D.
Mandal, J. Yamaguchi, K. Itami, Chem. Lett. 2011, 40, 555–557.
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Kondo, Jpn. Kokai Tokkyo Koho 1994, 329647; Treatment study and
mechanism of febuxostat: b) M. A. Becker, H. R. Schumacher, Jr.,
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N. Joseph-Ridge, N. Engl. J. Med. 2005, 353, 2450–2461; c) K. Oka-
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[6] H. Razavi, S. K. Palaninathan, E. T. Powers, R. L. Wiseman, H. E.
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115, 2864–2867; Angew. Chem. Int. Ed. 2003, 42, 2758–2761.
[7] For isolation and biological activity of muscoride A, see: a) A. Na-
gatsu, H. Kajitani, J. Sakakibara, Tetrahedron Lett. 1995, 36, 4097–
4100; For the synthesis of muscoride A, see: b) P. Wipf, S. Venkatra-
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Experimental Section
À
General procedure for the nickel-catalyzed C H arylation of azoles with
haloarenes and LiOtBu: A 20 mL glass vessel equipped with a J. Young
O-ring tap, containing
a magnetic stirring bar and NiACHTUNGTNRUEGN(OAc)2·4H2O
(10.6 mg, 0.05 mmol) was dried with a heatgun under vacuum and filled
with argon after cooling to RT. To this vessel were added bipy or dppf
(0.05 mmol), LiOtBu (60.0 mg, 0.75 mmol), azole 1 (0.75 mmol), and hal-
oarene 2 (0.50 mmol), followed by anhydrous 1,4-dioxane (2.0 mL). The
vessel was sealed and then heated (85–1408C) in an eight-well reaction
block with stirring. After cooling to RT, the mixture was passed through
a short silica gel pad (EtOAc), the filtrate was concentrated, and the resi-
due was subjected to preparative thin-layer chromatography (hexane/
EtOAc) to afford a coupling product 3.
À
Typical procedure for the nickel-catalyzed C H arylation of azoles with
haloarenes and Mg
A
O-ring tap, containing
a
magnetic stirring bar and NiACHTUNGTRENNU(G OAc)2·4H2O
(10.6 mg, 0.05 mmol) was dried with a heatgun under vacuum and filled
with argon after cooling to RT. To this vessel were added bipy (7.8 mg,
0.05 mmol), MgACHTUNGTRENNUNG(OtBu)2 (127.9 mg, 0.75 mmol), 1A (101.3 mg,
0.75 mmol), and 2a (102.0 mg, 0.50 mmol), followed by anhydrous DMF
(2.0 mL) under a stream of argon. The vessel was sealed with an O-ring
tap and then heated at 1008C for 36 h in an 8-well reaction block with
stirring. After cooling the reaction mixture to RT, the mixture was con-
centrated under vacuum. The crude product was dissolved in EtOAc, fil-
tered through Celite, the filtrate was concentrated, and the residue was
subjected to preparative thin-layer chromatography (hexane/EtOAc) to
afford 3Aa (77.1 mg, 73%) as a light-tan solid.
[8] For isolation and biological activities of hennoxazole A, see: a) T.
Ichiba, W. Y. Yoshida, P. J. Scheuer, T, Higa, D. G. Gravalos, J.
Am. Chem. Soc. 1991, 113, 3173–3174; For the synthesis of hennox-
azole A, see: b) P. Wipf, S. Lim, J. Am. Chem. Soc. 1995, 117, 558–
559; c) P. Wipf, S. Lim, Chimia 1996, 50, 157–167; d) D. R. Williams,
D. A. Brooks, M. A. Berliner, J. Am. Chem. Soc. 1999, 121, 4924–
4925; e) F. Yokokawa, T. Asano, T. Shioiri, Tetrahedron 2001, 57,
6311–6327; f) T. E. Smith, W.-H. Kuo, V. D. Bock, J. L. Roizen, E. P.
Balskus, A. B. Theberge, Org. Lett. 2007, 9, 1153–1155; g) T. E.
Smith, W. H. Kuo, E. P. Balskus, V. D. Bock, J. L. Roizen, A. B. The-
berge, K. A. Carroll, T. Kurihara, J. D. Wessler, J. Org. Chem. 2008,
73, 142–150.
Acknowledgements
We thank Mr. Naoki Tsuchiya and Mr. Takumi Takeyasu for helpful dis-
cussions on the synthesis of febuxostat. This work was supported by a
Grant-in-Aid for Scientific Research from MEXT, and the Teijin Pharma
Award in Synthetic Organic Chemistry, Japan to J.Y.
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Chem. Eur. J. 2011, 17, 10113 – 10122
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K. Itami et al.
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À
[20] For selected recent examples of Ni-catalyzed C H functionalization,
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[21] Typically, anhydrous Ni
Ni(OAc)2·4H2O, which is less expensive (see Experimental Section).
When Ni(OAc)2·4H2O was used without pretreatment, 3Aa was ob-
ACHTUNGRTEN(NUNG OAc)2 is generated by the dehydration of
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tained in 23% yield.
[22] Higher reactivity of ortho-substituted halobenzenes might be as-
cribed to steric-induced acceleration in the product-forming reduc-
tive elimination step in the catalytic cycle (Scheme 2).
[23] Miura and co-workers also indicated such a phenomenon; see refer-
ence [18].
[24] See the Supporting Information for further details.
[25] R. S. Sꢄnchez, F. A. Zhuravlev, J. Am. Chem. Soc. 2007, 129, 5824–
5825.
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[15] For selected examples of the synthesis of 2-arylated azoles by Pd-
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[30] The price of representative catalyst precursors in arene arylation
(Strem Chemicals, 2009): Ni
for 500 g), [RuCl2A(p-cymene)]2 ($116 for 5 g), Pd
25 g), [RhCl(CO)2]2 ($610 for 2 g).
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
Received: April 10, 2011
Published online: July 8, 2011
10122
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Chem. Eur. J. 2011, 17, 10113 – 10122