C-H arylation and alkenylation of imidazoles by nickel catalysis: Solvent-accelerated imidazole C-H activation

Article abstract of DOI:10.1039/c5sc02942b

The first nickel-catalyzed C-H arylations and alkenylations of imidazoles with phenol and enol derivatives are described. Under the influence of Ni(OTf)₂/dcype/K₃PO₄ (dcype: 1,2-bis(dicyclohexylphosphino)ethane) in t-amyl alcohol, imidazoles can undergo C-H arylation with phenol derivatives. The C-H arylation of imidazoles with chloroarenes as well as that of thiazoles and oxazoles with phenol derivatives can also be achieved with this catalytic system. By changing the ligand to dcypt (3,4-bis(dicyclohexylphosphino)thiophene), enol derivatives could also be employed as coupling partners achieving the C-H alkenylation of imidazoles as well as thiazoles and oxazoles. Thus, a range of C2-arylated and alkenylated azoles can be synthesized using this newly developed nickel-based catalytic system. The key to the success of the C-H coupling of imidazoles is the use of a tertiary alcohol as solvent. This also allows the use of an air-stable nickel(ii) salt as the catalyst precursor.

Full text of DOI:10.1039/c5sc02942b

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DOI: 10.1039/C5SC02942B
Chemical Science
ARTICLE
C–H Arylation and Alkenylation of Imidazoles by Nickel Catalysis:
Solvent-accelerated Imidazole C–H Activation
Kei Muto,a Taito Hatakeyama,b Junichiro Yamaguchi,a* and Kenichiro Itamia,c*
Received 00th January 20xx,
Accepted 00th January 20xx
The first nickel-catalyzed C–H arylation and alkenylation of imidazoles with phenol and enol derivatives is described.
Under the influence of Ni(OTf)2/dcype/K3PO4 (dcype: 1,2-bis(dicyclohexylphosphino)ethane) in t-amyl alcohol, imidazoles
can undergo C–H arylation with phenol derivatives. The C–H arylation of imidazoles with chloroarenes as well as that of
thiazoles and oxazoles with phenol derivatives can also be achieved with this catalytic system. By changing the ligand to
dcypt (3,4-bis(dicyclohexylphosphino)thiophene), enol derivatives could also be employed as coupling partners achieving
the C–H alkenylation of imidazole as well as thiazoles and oxazoles. Thus, a range of C2-arylated and alkenylated azoles
can be synthesized using this newly developed nickel-based catalytic systems. The key to success of C–H coupling of
imidazoles is the use of tertiary alcohol as solvent. This also allows using air-stable nickel(II) salt as a catalyst precursor.
DOI: 10.1039/x0xx00000x
www.rsc.org/
inexpensive transition metal catalyst.7
Introduction
Imidazoles including benzimidazoles are recognized as
important chemical motifs since they are frequently found in a
range of natural products, and exploited as core structures in
pharmaceuticals, agrochemicals, and organic materials.
Because of high versatility of imidazole-containing compounds
(particularly C2-arylated and alkenylated imidazoles; Figure
1),1 functionalization and derivatization thereof are of
significant importance in synthetic organic chemistry.
Numerous synthetic methods to construct C2-aryl and alkenyl
imidazoles have been reported thus far. Although cyclization
and annulation reactions have found wide use, these methods
often suffer from multi-step reaction sequences.2 Transition
metal-catalyzed cross-coupling reactions of arylmetal
compounds and aryl halides have also been employed, albeit
requiring the pre-functionalization of metalated or halogenated
imidazoles prior to the coupling reactions.3
N
N
N
N
N
NC
OMe
OH
N
H
N
H
F
tomoxiprole
mefenidil
SB202190
O
O
O
HO
Br
Ir
N
N
N
N
N
N
N
NH
N
H
N
H
2
nortopsentin B
phosphorescent probe
termisartan
Figure 1. C2-Arylated and alkenylated imidazoles and benzimidazoles in
natural products, pharmaceuticals, and organic materials
.
In recent years, transition metal-catalyzed C–H
functionalization approach has attracted attention as it enables
rapid and straightforward synthesis of various functional
heteroarenes.4 Within this class of reactions, C–H arylation and
alkenylation of imidazoles using transition-metal catalysts have
been reported, mainly involving palladium5 and rhodium.6 In
2009, Daugulis and coworkers discovered a Cu-catalyzed C–H
arylation of imidazoles, which allowed the use of an
In our studies in catalytic C–H functionalization,8 we have
developed several unique nickel catalysts9 that facilitate the C–
H arylation of 1,3-azoles, such as oxazoles and thiazoles, with
haloarenes (C–H/C–X coupling)10, phenol derivatives (C–H/C–
O coupling)11, and arenecarboxylates (decarbonylative C–H
coupling)12. The advantage of our recent nickel-based catalytic
systems11 is not only its low cost, but also its ability to activate
and couple phenol derivatives (C–O electrophiles).13,14
However, imidazoles and benzimidazoles still remained as
challenging substrates for our nickel-catalyzed C–H coupling
campaign. Herein, we report the first general protocol for Ni-
catalyzed C–H arylation as well as alkenylation of imidazoles
(Figure 2).
This journal is © The Royal Society of Chemistry 20xx
Chem. Sci., 2015, 00, 1-3 | 1
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Page 2 of 7
ARTICLE
Journal Name
Previous Metal-catalyzed C–H Coupling of Imidazoles
resulted in lower yields than with K3PO4 (entries 7 and 8).
View Article Online
DOI: 10.1039/C5SC02942B
While we initially imagined that in situ-generated potassium
Cu
Pd
Rh
N
N
+
X
H
Ar
Ar
tertiary alkoxides might be the reactive species, this seems not
to be the case; the use of KOt-Bu completely shut down the
catalytic activity (entry 9). Regarding the ligand effect, PCy3
and an N-heterocyclic carbene ligand were inactive for the
present reaction (entries 10 and 11). Our thiophene-based
N
R
N
R
X = halogen
Previous Ni-Catalyzed C–H Coupling of Oxazoles and Thiazoles
Ni
N
N
+
X
H
Ar
Ar
diphosphine
ligand,
dcypt
(3,4-
Z
Z
bis(dicyclohexylphosphino)thiophene),17 as well as other dcype
derivatives such as L1 and L2 furnished 3Aa in moderate
yields (entries 12–14). To our delight, the replacement of
Ni(cod)2 to Ni(OTf)2 as pre-catalyst maintained the catalytic
activity (entry 15). Considering significant advantage of using
air-stable Ni(OTf)2, we decided to use Ni(OTf)2/dcype catalyst
and K3PO4 in t-AmylOH for further studies.
X = halogen OR, CO2Ph
Z = S, O
This Work: The first Ni-Catalyzed C–H Coupling of Imidazoles
Ni
N
N
+
X
H
Ar
Ar
N
R
N
R
X = Cl, OR
Figure 2. Transition metal-catalyzed C–H arylation of imidazoles and
benzimidazoles
Table 1. Screening of reaction conditions.[a]
.
Ni(cod)2 (10 mol%)
ligand (12-24 mol%)
base (3.0 equiv)
O
O
N
N
+
Me2N
H
N
Me
N
Me
Results and discussion
solvent
110 °C, 12 h
C–H Arylation of Imidazoles with Phenol Derivatives
Among the myriad nickel catalysts for C–H arylation
reported over the past decade from our group,10-12 Miura,15 and
Chatani,16 our Ni(cod)2/dcype (cod = 1,5-cyclooctadiene; dcype
= 1,2-bis(dicyclohexylphosphino)ethane) catalyst with Cs2CO3
as the base in 1,4-dioxane as the solvent is well suited for direct
coupling of 1,3-azoles and phenol derivatives (C–H/C–O
coupling). The selection of an appropriate ligand is crucial, as
this reaction proceeds only when dcype was used. In contrast,
this catalytic system was not affected by the choice of base and
solvent since C2-functionalized azoles could be formed in the
absence of base. Through several mechanistic investigations
including the isolation of a catalytic intermediate, kinetic
studies,11c and theoretical calculations,11d we had previously
identified the ligand effect and a plausible catalytic cycle for
the reaction. In particular, DFT calculations provided
significant insight regarding the mechanism of C–H nickelation
steps: the formation of a Cs-Ni cluster was found to play a key
roll to accelerate the C–H nickelation. However, experimentally
and computationally, it had also been revealed that new
catalytic conditions need to be developed for the C–H coupling
of imidazoles.
1A (0.40 mmol)
2a (1.5 equiv)
3Aa
entry
1
ligand
base
Solvent
1,4-dioxane
t-AmylOH
t-BuOH
3Aa (%)[b]
dcype
dcype
dcype
dcype
dcype
dcype
dcype
dcype
dcype
PCy3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
LiOt-Bu
KOt-Bu
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
0
83
70
0
2
3
4
1,4-dioxane
DMF
5
0
6
i-PrOH
0
7
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
44
59
0
8
9
10
11
12
13
14
15[c]
0
IPr·HCl
dcypt
L1
0
55
53
64
82
L2
dcype
With these considerations in mind, we focused on the
investigation of base and solvent effects by using N-
methylbenzimidazole (1A) and phenyl carbamate 2a as model
substrates (Table 1). Our previous Ni(cod)2/dcype-based
catalytic conditions employing Cs2CO3 and 1,4-dioxane
afforded no coupling products (entry 1). Intensive and thorough
investigation led to the discovery that the combination of
K3PO4 and t-amyl alcohol (t-AmylOH) could facilitate the C–H
arylation of 1A to afford 3Aa in 83% yield (entry 2). The
replacement of t-AmylOH with t-BuOH gave 3Aa in slightly
lower yield (entry 3). When the base and/or the solvent were
changed, the reaction efficiency was diminished. For example,
the use of aprotic solvents and secondary alcohol solvents was
completely ineffective for this reaction (entries 4–6).
Additionally, the reaction in the presence of Cs2CO3 or LiOt-Bu
S
P
P
P
P
dcype
dcypt
S
S
P
P
P
P
L1
L2
[a]
Unless otherwise noted, reaction conditions were as follows: 1A (0.40
mmol), 2a (1.5 equiv), Ni(cod)2 (10 mol%), ligand (bidentate: 12 mol%,
monodentate: 24 mol%), base (3.0 equiv), solvent (1.6 mL), 110 °C, 12 h. [b]
GC yield. [c] Ni(OTf)2 (10 mol%) was used.
2 | J. Name., 2012, 00, 1-3
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ARTICLE
Ni(OTf)2 (10 mol%)
dcype (12 mol%)
DOI: 10.1039/C5SC02942B
K3PO4 (3.0 equiv)
We then examined the substrate scope of Ni(OTf)2/dcype-
catalyzed C–H arylation (C–H/C–O coupling) of imidazoles 1
with carbamates of phenol derivatives 2 (Scheme 1). Several N-
substituted benzimidazoles such as N-benzyl (1B), phenyl (1C),
morpholinoethyl (1D), and methoxymethyl benzimidazoles
(1E) underwent C–H/C–O coupling to afford the corresponding
products in moderate to excellent yields. In addition to
benzimidazoles, imidazoles were also coupled with phenol
derivatives 2 successfully, although it was necessary to use
Ni(cod)2 as the catalyst precursor as well as a longer reaction
time. In general, the coupling proceeds smoothly with
substrates having electron-withdrawing groups on the phenyl
rings at the C5 position of imidazole ring. For example, the
View Article Online
O
N
N
+
Me2N
H
Ar
Z
Z
N
R
N
R
O
Ar
t-AmylOH
110 °C, 12–36 h
1A–1P
2a–2k
3
N
N
N
N
N
N
N
O
3Ba: 53%
3Ca: 88%
3Da: 84%
N
Me
N
N
N
N
Me
N
Me
Me
OMe
3Ea: 53%
3Fa: 65%
3Ga: 64%[b]
reaction
of
trifluoromethyl-substituted
5-arylimidazole
N
furnished triaryl 3La in superior yield (>95%) than that for
methyl-substituted triaryl 3Ka (65%). Although the reason
remains unclear at this stage, dcypt ligand gave better results
for the coupling of C4-substituted imidazoles (1N, 1O, and 1P).
Notably, triazole 1M also underwent C–H/C–O coupling with
2a to afford 5-phenyl N-methyl-1,2,4-triazole (3Ma) in 82%
yield. Regarding aryl electrophiles, a broad functional group
tolerance was observed. An amino group or nitrogen
heterocycle, which often behaves as a catalyst-deactivating
group, did not inhibit the reaction; 3Da, 3Ag, and 3Ah were
obtained in good to excellent yields. Although
transesterification took place with t-AmylOH when
ethoxycarbonyl-substituted phenol electrophile 2f was used, the
product 3Af was generated in good yield. Delightfully, we
could directly functionalize pilocarpine (1Q), which is a drug
for the treatment of dry mouth,18 in 69% yield without any
lactone opening or epimerization at the α-position of the
carbonyl group. It should be emphasized that this coupling
reaction proceeds with high regioselectivity at the C2 position
of the imidazole rings.
N
N
N
N
N
Me
Me
3Ha: 64%[b]
3Ib: 49%[b]
3Ja: 82%[b]
N
N
N
N
N
Me
N
Me
N
Me
Me
F3C
3Ka: 65%[b]
3La: >95%[b]
3Ma: 82%[b]
NC
O
N
N
RO
N
N
Me
N
Me
N
Me
R = Et and t-Amyl
3Pb: 93%[c][d]
3Nb: 87%[c]
3Ob: 72%[c]
Me
t-Bu
N
N
N
Me
OMe
N
Me
N
N
Me
Me
3Ac: 74%
3Ad: 74%
3Ae: 58%
O
O
NMe2
N
N
N
N
N
Me
N
Me
N
Me
3Af: 81%[e]
3Ag: 67%
3Ah: 95%
N
N
N
Ph
N
Me
N
Me
N
Me
3Ai: 92%
3Ab: >95%
3Aj: 91%
natural product derivatization
H
H
Me
N
O
O
N
pilocarpine derivative
3Qb: 69%
Scheme 1. Substrate scope of imidazole C–H arylation with phenol
[a]
derivatives. Unless otherwise noted, reaction conditions were as follows:
1 (0.40 mmol), 2 (1.5 equiv), Ni(OTf)2 (10 mol%), dcype (12 mol%), K3PO4 (3.0
equiv), t-AmylOH (1.6 mL), 110 °C, 12–36 h. [b] Ni(cod)2 (10 mol%) was used.
[c] Ni(cod)2 (10 mol%) and dcypt (12 mol%) was used. [d] Starting from ethyl 4-
imidazolecarboxylate 1P. (R = Et: 33%; t-Amyl: 60%). [e] Starting from methyl
3-((dimethylcarbamoyl)oxy)benzoate (2f).
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ARTICLE
Journal Name
Ni(OTf)2 (10 mol%)
dcypt (12 mol%)
K3PO4 (3.0 equiv)
View Article Online
DOI: 10.1039/C5SC02942B
O
O
N
N
C–H Alkenylation of Imidazoles with Enol Derivatives
With our previous success of Ni-catalyzed C–H
alkenylation of oxazoles with enol derivatives,11b,19 we
envisioned that alkenylation of imidazoles would be feasible
under Ni(OTf)2/diphosphine/K3PO4/t-AmylOH system. The use
of C–O alkenyl electrophiles for coupling reactions is
advantageous because they can be easily prepared from the
corresponding ketones and aldehydes. Motivated by the fact
that alkenyl group is a versatile platform in organic synthesis,
we next embarked on the development of C–H/C–O
alkenylation of imidazoles (Scheme 2). Although the coupling
reaction of 1A and 2k under Ni(OTf)2/dcype catalysis is
feasible, it provided alkenylated product 3Ak in only 41% yield.
While changes in base and solvent did not lead to the
improvement of the reaction yield, the Ni(OTf)2/dcypt catalyst
dramatically boosted the reaction efficiency, providing the
coupling product 3Ak in 87% yield.
+
Me2N
H
N
R
N
R
R
t-AmylOH
110 °C, 36 h
R
1
2l–2s
3
N
N
N
N
N
N
O
N
O
3Bk: 87%
3Dk: 80%
3Rk: 86%
OMe
N
N
N
N
N
Me
N
Me
Me
3Ak: 87%
3Al: 86%
3Am: 52%
MeO
F
Ni(OTf)2 (10 mol%)
ligand (12 mol%)
K3PO4 (3.0 equiv)
N
O
O
N
N
N
N
N
N
+ Me2N
H
Me
N
Me
N
Me
t-AmylOH
120 °C, 36 h
N
Me
Me
Me
1A (1.0 mmol)
2k (1.5 equiv)
3Ak
3An: 67%
3Ao: 66%
3Ap: 69%
Ligand
S
Me
N
N
P
P
P
P
N
Me
N
Me
dcype
41% yield
dcypt
87% yield
3Aq: 75%
3Ar: 29%
Scheme 2. Dramatic effect of dcypt ligand in the C–H alkenylation of
imidazoles.
[a]
Scheme 3. Scope of imidazole C–H alkenylation under Ni(OTf)2/dcypt.
Unless otherwise noted, reaction conditions were as follows: 1 (1.0 mmol), 2
(1.5 equiv), Ni(OTf)2 (10 mol%), dcypt (12 mol%), K3PO4 (3.0 equiv), t-
AmylOH (4.0 mL), 120 °C, 36 h.
It turns out that this newly discovered Ni(OTf)2/dcypt
catalytic system can effectively facilitate the imidazole C–H
alkenylation with broad scope (Scheme 3). As with the case of
biaryl couplings, several N-alkylated benzimidazoles (such as
1D and 1R) could couple with enol carbamates. Both enol
carbamates synthesized from α- and β-tetralones were reactive
under the Ni(OTf)2/dcypt catalyst to afford the coupling
products 3Al–3Ap. Cyclohexenyl benzimidazoles could be
synthesized from cyclohexanone derived electrophiles.
Aldehyde-derived enol derivative 2r also coupled with 1A, but
its rather fast decomposition under the reaction conditions
turned out to be somewhat problematic. It has been known that
C–OMe14a,e and C–F bonds20 could be cleaved with nickel
complexes, but these groups were completely tolerated in the
present Ni-catalyzed coupling reaction.
C–H Arylation of Imidazoles with Chloroarenes
While we mainly focused on the use of C–O electrophiles in
this study, it was found that the newly developed
Ni(OTf)2/dcype/K3PO4/t-AmylOH system is also effective for
the imidazole arylation with chloroarenes. As shown in Scheme
4, a range of imidazoles and benzimidazoles cross-coupled with
chlorobenzene derivatives under the standard conditions. N-
Methyl, phenyl, and benzyl benzimidazoles underwent C–H
arylation with chlorobenzene (4a) to deliver phenylated
imidazoles in good yield. N-Methyl and benzyl imidazoles also
reacted as well. Nitrile-substituted aryl chloride 4s furnished
the corresponding product 3As in good yield. Although the
reaction yield was low (26%), we could apply indomethacin
derivative 4t to the reaction to give 3At, but with significant
amounts of homodimerization by-product. Very interestingly,
the reactions of aryl iodides and bromides in turn resulted in
poor or zero yields of product.
4 | J. Name., 2012, 00, 1-3
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ARTICLE
Ni(OTf)2 (10 mol%)
dcype (12 mol%)
K3PO4 (3.0 equiv)
limited to the reaction of oxazoles, the presentVNiewi-AcrtaictlaelOynzliende
N
N
DOI: 10.1039/C5SC02942B
reaction in t-AmylOH was also applicable to thiazoles.
+
H
Cl
N
R
N
R
3
t-AmylOH
110 °C, 36 h
Ni(cod)2 (10 mol%)
dcype (12 mol%)
K3PO4 (3.0 equiv)
4
1
O
O
N
Z
N
Z
+
Me2N
H
N
N
N
N
N
N
t-AmylOH
110 °C, 36 h
Z = O, S
5
Me
2
6
Me
Me
Me
Me
N
S
N
S
N
3Aa: 81%
3Ba: 69%
3Ca: 86%
N
N
N
S
Me
CN
N
N
Me
N
Me
6Aa: 91%
6Ba: 54%
6Ak: 59%[b]
N
O
N
O
N
3Ga: 81%[b]
3Ha: 64%[b]
3As: 66%
Ph
O
O
O
N
O
6Ca: 56%
6Ci: 63%
6Da: 74%[c]
N
Me
N
OMe
Me
O
Scheme 6. C–H arylation and alkenylation of oxazoles and thiazoles under
[a]
Ni(OTf)2/dcype/K3PO4 in t-AmylOH.
Unless otherwise noted, reaction
conditions were as follows: 5 (0.40 mmol), 2 (1.5 equiv), Ni(OTf)2 (10 mol%),
O
[b]
indomethacin derivative
3At: 26%
dcypt (12 mol%), K3PO4 (3.0 equiv), t-AmylOH (1.6 mL), 110 °C, 36 h.
Ni(OTf)2 (10 mol%) and dcypt (12 mol%) was used. [c] Ni(OTf)2 (10 mol%) and
dcypt (12 mol%) was used.
Scheme 4. C-H arylation of imidazoles with chloroarenes under
[a]
Ni(OTf)2/dcype.
Unless otherwise noted, reaction conditions were as
follows: 1 (0.40 mmol), 4 (1.5 equiv), Ni(OTf)2 (10 mol%), dcype (12 mol%),
K3PO4 (3.0 equiv), t-AmylOH (1.6 mL), 110 °C, 36 h. [b] Ni(cod)2 (10 mol%) was
used.
Plausible Mechanism
We succeeded in developing new catalytic systems to
significantly expand the C–H/C–O coupling of 1,3-azoles with
phenol/enol-based electrophiles, but we feel that the basic
catalytic cycle under Ni(OTf)2/diphosphine/K3PO4/t-AmylOH
should be similar to those operating with previous conditions.
First, Ni(OTf)2 should be reduced to nickel(0) species by the
action of diphosphine (dcype or dcypt) and/or an imidazole
substrate to initiate a Ni(0)/Ni(II) redox cycle shown in Figure
2. Oxidative addition of C–O or C–Cl bond of electrophile to
Ni(0) A affords intermediate B. Then, base-promoted C–H
nickelation of imidazoles, followed by reductive elimination
would furnish the coupling products with regeneration of the
active Ni(0) species. Previously, we successfully isolated and
characterized intermediate B by using naphthalen-2-yl pivalates
as a C–O electrophile,11c which supports our hypothesized
catalytic cycle. The remaining question is how the new
conditions (particularly the activation modes of K3PO4 and t-
AmylOH) allowed imidazoles to participate in this catalytic
cycle. We are currently investing to uncover these phenomena
experimentally and theoretically.
C–H Arylation and Alkenylation of Other 1,3-Azoles.
The present catalytic protocols were found to be applicable
not only for imidazoles, but also for thiazoles and oxazoles.
While our previous catalyst employing Ni(cod)2/dcype/Cs2CO3
in 1,4-dioxane was effective for oxazoles and thiazoles (in
particular for benzo-fused substrates),11 coupling was not
efficient for relatively electron-rich azoles. For example, the
reaction of 4,5-dimethylthiazole (5A) with naphthyl carbamate
2b under the previous conditions furnished no coupling product.
Thus, we applied our new protocol with K3PO4 and t-AmylOH
to the reaction of previously unreactive azole 5A. Gratifyingly,
5A and 2b cross-coupled very smoothly under the present
conditions to furnish 6Ab in 90% yield (Scheme 5).
Me
Me
Me
Ni/dcype catalyst
N
S
O
O
N
S
+
Me2N
H
Me
5A
2b
6Ab
Previous conditions
Current conditions
Cs2CO3
1,4-dioxane
110 °C
K3PO4
t-AmylOH
110 °C
Figure 2. A plausible catalytic cycle.
trace
90%
Scheme 5. Comparison of previous and current conditions for the reaction
of thiazole 5A.
Depicted in Scheme 6 are the results of the Ni-catalyzed
reactions of other 1,3-azoles. In addition to thiazoles, oxazoles
were also found to be good substrates, generating the
corresponding coupling products in good yields. Although
previous alkenylation reactions with C–O electrophiles were
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PleasCehdeomnioctalaSdjcuisetnmceargins
Page 6 of 7
ARTICLE
Journal Name
5
6
7
8
For Pd-catalyzed C–H coupling of imidazoles, see: (a) J.
M.
View Article Online
N
OR
Joo, B. B. Touré and D. Sames, J. Org. Chem., 2010, 75, 4911;
DOI: 10.1039/C5SC02942B
Ar
P
P
Ar
(b) L.-C. Campeau, D. R. Stuart, J.-P. Leclerc, M. Bertrand-
Laperle, E. Villemure, H.-Y. Sun, S. Lasserre, N. Guimond, M.
Lecavallier and K. Fagnou, J. Am. Chem. Soc., 2009, 131,
3291; (c) D. Zhao, W. Wang, S. Lian, F. Yang, J. Lan and J. You,
Chem. Eur. J., 2009, 15, 13370.
N
R
Ni
A
O2Ct-Bu
OCONMe2
OR =
reductive
elimination
oxidative
addition
For Rh-catalyzed C–H coupling of imidazoles, see: (a) J.
C.
Lewis, S. H. Wiedemann, R. G. Bergman and J. A. Ellman, Org.
Lett., 2003, 6, 35; (b) J. C. Lewis, J. Y. Wu, R. G. Bergman and
J. A. Ellman, Angew. Chem. Int. Ed., 2006, 45, 1589; (c) J. C.
Lewis, A. M. Berman, R. G. Bergman and J. A. Ellman, J. Am.
Chem. Soc., 2008, 130, 2493; (d) J. C. Lewis, R. G. Bergman
and J. A. Ellman, Acc. Chem. Res., 2008, 41, 1013.
P
P
P
P
Ni
Ni
N
OR
Ar
Ar
RN
C–H
nickelation
C
B
For Cu-catalyzed C–H coupling of imidazoles, see: (a) H.-Q.
Do and O. Daugulis, J. Am. Chem. Soc., 2007, 129, 12404; (b)
H.-Q. Do, R. M. K. Khan and O. Daugulis, J. Am. Chem. Soc.,
2008, 130, 15185; (c) D. Zhao, W. Wang, F. Yang, J. Lan, L.
Yang, G. Gao and J. You, Angew. Chem. Int. Ed., 2009, 48,
3296; (d) O. Daugulis, H.-Q. Do and D. Shabashov, Acc. Chem.
Res., 2009, 42, 1074.
N
RO–H
H
N
R
Conclusions
(a) S. Yanagisawa, T. Sudo, R. Noyori and K. Itami, J. Am.
Chem. Soc., 2006, 128, 11748; (b) B. Join, T. Yamamoto and K.
Itami, Angew. Chem. Int. Ed., 2009, 48, 3644; (c) S.
Yanagisawa, K. Ueda, H. Sekizawa and K. Itami, J. Am. Chem.
Soc., 2009, 131, 14622; (d) K. Ueda, S. Yanagisawa, J.
Yamaguchi and K. Itami, Angew. Chem. Int. Ed., 2010, 49,
8946; (e) S. Kirchberg, S. Tani, K. Ueda, J. Yamaguchi, A.
Studer and K. Itami, Angew. Chem. Int. Ed., 2011, 50, 2387;
(f) K. Mochida, K. Kawasumi, Y. Segawa and K. Itami, J. Am.
Chem. Soc., 2011, 133, 10716; (g) D. Mandal, A. D.
Yamaguchi, J. Yamaguchi and K. Itami, J. Am. Chem. Soc.,
2011, 133, 19660; (h) K. Kawasumi, Q. Zhang, Y. Segawa, L. T.
Scott and K. Itami, Nat. Chem., 2013, 5, 739; (i) S. Tani, T. N.
Uehara, J. Yamaguchi and K. Itami, Chem. Sci., 2014, 5, 123;
(j) K. Ueda, K. Amaike, R. M. Maceiczyk, K. Itami and J.
Yamaguchi, J. Am. Chem. Soc., 2014, 136, 13226; (k) A. D.
Yamaguchi, K. M. Chepiga, J. Yamaguchi, K. Itami and H. M. L.
Davies, J. Am. Chem. Soc. 2015, 137, 644; (l) T. Kawakami, K.
Murakami and K. Itami, J. Am. Chem. Soc., 2015, 137, 2460;
(m) Y. Saito, Y. Segawa and K. Itami, J. Am. Chem. Soc., 2015,
137, 5193; (n) S. Suzuki, Y. Segawa, K. Itami and J. Yamaguchi,
Nat. Chem., 2015, 7, 227; (o) K. Ozaki, K. Kawasumi, M.
Shibata, H. Ito and K. Itami, Nat. Commun., 2015, 6, 6251.
For recent reviews on nickel-catalyzed reactions, see: (a) S. Z.
Tasker, E. A. Standley and T. F. Jamison, Nature, 2014, 509,
299; (b) J. Yamaguchi, K. Muto and K. Itami, Eur. J. Org.
Chem., 2013, 19.
In summary, we have established a general protocol for the
nickel-catalyzed C–H couplings of imidazoles. The newly
discovered conditions, employing
a catalytic amount of
Ni(OTf)2/dcype or Ni(OTf)2/dcypt and K3PO4 in t-AmylOH,
enable a direct C–C bond-forming reaction of imidazoles
including C–H/C–O arylations and alkenylations. The C–H
arylation of imidazoles with chloroarenes as well as that of
thiazoles and oxazoles with phenol/enol derivatives can also be
achieved with this catalytic system. The key to success in the
new nickel-catalyzed system is the choice of a tertiary alcohol
as solvent, as neither aprotic solvents nor secondary alcohols
were effective. We believe that the present method provides
significant opportunities to synthesize and derivatize valuable
functionalized imidazoles.
Acknowledgements
This work was supported by the ERATO program from JST (K.I.),
KAKENHI (25708005 to J.Y.) from MEXT, and a JSPS research
fellowship for young scientists (to K.M.). We thank Ryosuke
Takise (Nagoya University) for providing phosphine ligands.
ITbM is supported by the World Premier International
Research Center (WPI) Initiative, Japan.
9
10 (a) J. Canivet, J. Yamaguchi, I. Ban and K. Itami, Org. Lett.,
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11 (a) K. Muto, J. Yamaguchi and K. Itami, J. Am. Chem. Soc.,
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Chemical Science
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Journal Name
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