Direct C5-arylation reaction between imidazoles and aryl chlorides catalyzed by palladium complexes with phosphines and N-heterocyclic carbenes

Article abstract of DOI:10.1021/om200490k

Palladium(II) acetate complexes bearing phosphines and carbene ligands, Pd(L)(PR₃)(OAc)₂ (1a, R = Ph; 1b, R = Cy; L = 1,3-dibenzylimidazol-2-ylidene), were prepared by salt metathesis reactions of their chloro complexes with AgOAc in good yields. The electron-rich 1b was efficient in catalyzing C-5 direct arylation of imidazoles with aryl halides. Most significantly, the catalytic system allows a range of aryl chlorides as substrates. Microwave irradiation effectively promotes the reactions, with good yields obtainable in only 2 h. In combination with the classical method of C-C bond formation reactions, novel imidazole derivatives featuring biaryl and styryl subunits were successfully obtained from 1,4-dichlorobenzene and 1-bromo-4-chlorobenzene.

Full text of DOI:10.1021/om200490k

ARTICLE
pubs.acs.org/Organometallics
Direct C5-Arylation Reaction between Imidazoles
and Aryl Chlorides Catalyzed by Palladium Complexes
with Phosphines and N-Heterocyclic Carbenes
P. Vijaya Kumar, Wu-Shien Lin, Jiun-Shian Shen, Debkumar Nandi, and Hon Man Lee*
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan, Republic of China
S Supporting Information
b
ABSTRACT: Palladium(II) acetate complexes bearing phosphines and
carbene ligands, Pd(L)(PR3)(OAc)2 (1a, R = Ph; 1b, R = Cy; L = 1,3-
dibenzylimidazol-2-ylidene), were prepared by salt metathesis reactions of
their chloro complexes with AgOAc in good yields. The electron-rich 1b
was efficient in catalyzing C-5 direct arylation of imidazoles with aryl
halides. Most significantly, the catalytic system allows a range of aryl
chlorides as substrates. Microwave irradiation effectively promotes the
reactions, with good yields obtainable in only 2 h. In combination with the
classical method of CꢀC bond formation reactions, novel imidazole
derivatives featuring biaryl and styryl subunits were successfully obtained
from 1,4-dichlorobenzene and 1-bromo-4-chlorobenzene.
’ INTRODUCTION
Lately, Sames et al. also reported regioselective sequential
arylation of imidazole derivatives with aryl chlorides.27 Never-
theless, high palladium loadings (5 mol %) and sophisticated
phosphine ligands (usually expensive and unstable) are still
required. In view of all these previous reports, we have been
searching for a new effective catalytic system, allowing relatively
lower palladium loading (<3 mol %) to synthesize a range of C5-
arylated imidazole derivatives by direct arylation from aryl
chlorides. Since Pd(OAc)2 has been widely used in catalyzing
the arylation reactions9,12 and, as a matter of fact, the acetate
ligand may be directly involved in the intramolecular depro-
tonation at the C5 position,27 a preformed palladium acetate
complex bearing both phosphine and N-heterocyclic carbene
(NHC) ligands would be a desirable precatalyst (Chart 1). To
our knowledge, such a palladium acetate complex bearing both
monodentate phosphine and NHC ligands is unknown and in
fact, no relevant preformed palladium acetate complex bearing
any ligand has ever been employed in the regioselective direct
arylation reactions of imidazoles. In our target complexes, the
robust NHC ligand should stabilize the active Pd(0) intermedi-
ate, whereas the labile phosphine can provide a vacant coordina-
tion site readily.29 Herein, we report the synthesis of such novel
complexes, Pd(L)(PR3)(OAc)2 (1a, R = Ph; 1b, R = Cy; L = 1,3-
dibenzylimidazol-2-ylidene), and their catalytic application in
direct C5-arylation reactions between imidazoles and aryl ha-
lides. Using microwave heating, good yields can be achieved from
Arylated imidazoles constitute an important class of com-
pounds because of their diverse applications in pharmaceuticals,
drug candidates, and functional materials.1 The construction of
these heteroaromatic building blocks commonly involves palla-
dium-catalyzed cross-coupling reactions.2 Since the initial work
by Ohta and co-workers,3 transition-metal-catalyzed direct aryla-
tion reactions have been rapidly developing for the syntheses of a
wide range of heteroaromatic compounds.4ꢀ15 Such methodol-
ogy to construct biaryls without the need of a preliminary
organometallic reagent is highly desirable, because of the reduced
waste and fewer reaction steps. However, it is also quite challen-
ging, since a kinetically significant aryl CꢀH bond activation step
is involved. By far, Pd(OAc)2 associated with monodentate
phosphines or arsene ligands is the most common catalyst system
to prepare arylated imidazoles via direct arylations. Ligands such
as PPh3,16ꢀ20 AsPh3,21 PCy3,22,23 P(2-furyl)3,24,25 P(n-Bu)-
Ad2,26,27 and X-phos28 have been commonly employed. Pre-
formed precatalysts are also known but are relatively rare.3,29ꢀ32
It is quite common, however, in these catalyst systems that high
palladium loadings of 5ꢀ10 mol % are required. An exception is
the report by Doucet and co-workers on a range of C5-arylated
imidazole derivatives obtained under ligandless conditions at low
Pd(OAc)2 loading (0.01ꢀ0.5 mol %).33 However, either aryl
iodides or aryl bromides were needed as substrates. More readily
available aryl chlorides have been used only rarely because of the
high strength of the CꢀCl bond.26,27 In this regard, Daugulis
et al. reported relevant arylation reactions which allow access to a
wide variety of electron-rich heterocycles from aryl chlorides.26
Received: June 7, 2011
Published: September 16, 2011
r
2011 American Chemical Society
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a range of aryl chlorides in only 2 h with a moderate 2.5 mol %
palladium loading. In combination with classical CꢀC coupling
methodologies,34ꢀ36 the same catalytic system can deliver new
imidazole derivatives featuring biaryls and styryl motifs in a
concise manner.
complexes are within the expected range for similar com-
pounds.38ꢀ40
Preparation of C5-Arylated Imidazole Derivatives. The
catalytic performance of complexes 1a,b in direct arylation
reactions of imidazole derivatives with aryl halides was explored.
To optimize the reaction conditions, the coupling between
1-methylimidazole and 4-bromoacetophenone was taken as a
model reaction (Table 2). Taking into consideration previous
reports,24,33 the initial investigation began with the following
conditions: palladium precatalyst (2.5 mol %), 1-methylimida-
zole (1.5 equiv), 4-bromoacetophenone (1 equiv), KOAc as base
(2 equiv) in DMA at 140 ꢀC under conventional heating, and a
reaction time of 18 h. The general reactivity trend of imidazole is
that the C5 position is much more reactive than the C4 position.
Hence, in all these reactions, the C5-arylated compound 5-(4-
acetylphenyl)-1-methylimidazole (3) was formed as the major
product, the structure of which has been confirmed by an X-ray
diffraction study (Figure 2). Entries 1ꢀ3 in Table 2 demonstrate
that palladium acetate complexes 1a,b are both significantly more
effective than ligandless Pd(OAc)2 in catalyzing the reactions. A
yield of 66% can be obtained from 1b bearing electron-rich PCy3,
whereas complex 1a gives a somewhat lower yield (62%). Entry 2
also demonstrates a good C5 selectivity from 1b. While the C5-
arylated product can be obtained in 66% yield, no C-2 arylated or
homocoupled products from aryl halide were observed. How-
ever, a small amount of diarylated product 3B was also isolated
(15%). The influence of solvent on the reaction is crucial, as
demonstrated in entries 2 and 4; switching to DMF led to a
significant decrease in product yield. Switching the base from
KOAc to K2CO3 also results in a decrease in product yields
’ RESULTS AND DISCUSSION
Preparation of Palladium(II) Precatalysts. Complexes 1a,b
can be straightforwardly prepared by salt metathesis reactions
between the known complexes Pd(L)(PR3)Cl2 (2a, R = Ph ; 2b,
R = Cy)37 and AgOAc in 83 and 72% yields, respectively. These
complexes were characterized by elemental analysis, X-ray crys-
tallographic studies, and 1H, 13C{1H}, and 31P{1H} NMR
spectroscopy. HMBC spectra were also obtained to assist the
assignments of their 1D spectra (see Figures S1 and S2 in the
Supporting Information). The carbene resonances in 1a,b are
revealed as singlets at 157.4 and 160.0 pm, respectively, suggest-
ing the cis geometry of these complexes. The 31P NMR signals
for 1a,b were observed at 24.4 and 40.3 ppm, respectively.
Notably, complexes 1a,b possess the desirable feature of high
stability in air and in solution. They also have good solubility in
halogenated solvents. The cis geometry of palladium complexes
1a,b was unambiguously established by X-ray diffraction studies
(Figure 1 and Table 1). The Pd atoms in 1a,b adopt a distorted-
square-planar coordination geometry. Due to the steric bulk of
PCy3 being greater than that of PPh3, —C1—Pd1—P1 in 1b is
much wider than that in 1a (95.81(15) vs 89.31(13)ꢀ). The two
PdꢀO distances in 1a are similar in length. In contrast, the
PdꢀO distance trans to PCy3 is longer than that trans to carbene
in 1b (2.084(4) vs 2.062(4) Å), reflecting the greater trans
influence exerted by the electron-donating PCy3 in comparison
to that of the carbene. The Pdꢀcarbene distances in these
Table 1. Selected BondDistances(Å) andAngles(deg) of1a,b
1a
1b
Pd1ꢀC1
Pd1ꢀP1
Pd1ꢀO1
Pd1ꢀO3
1.976(4)
2.2675(17)
2.092(3)
2.086(3)
1.986(5)
2.2733(15)
2.062(4)
2.084(4)
Chart 1. Palladium(II) Precatalysts for Direct C5-Arylation
Reactions between Imidazoles and Aryl Chlorides
C1ꢀPd1ꢀP1
O1ꢀPd1ꢀP1
C1ꢀPd1ꢀO3
O1ꢀPd1ꢀO3
P1ꢀPd1ꢀO3
C1ꢀPd1ꢀO1
89.31(13)
95.56(10)
87.92(16)
88.18(13)
171.86(11)
171.34(16)
95.81(15)
86.68(12)
88.52(18)
88.15(16)
172.18(12)
171.6(2)
Figure 1. Molecular structures of 1a (left) and 1b (right) with 35% probability ellipsoids for non-H atoms. Hydrogen atoms are omitted for clarity.
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Table 2. Screening Precatalysts and Reaction Conditions for Direct Arylation of 1-Methylimidazole and 4-Bromoacetophenone
under Conventional Heatinga
entry
cat.
solvent
base
isolated yield, %
1
2
3
4
5
6
1a
1b
DMA
DMA
DMA
DMF
DMA
DMA
KOAc
KOAc
KOAc
KOAc
K2CO3
KOtBu
62b
66 (15)
18
Pd(OAc)2
1b
1b
1b
28
57 (6)
trace
a Reaction conditions: 3.7 mmol of 1-methylimidazole, 2.5 mmol of aryl halide, 5.0 mmol of base, 5 mL of solvent, 2.5 mol % of cat., 140 ꢀC, 18 h. The
isolated yield of 3B is given in parentheses. b 3 was isolated in pure form, but a mixture of other products, including 3B, was also formed.
Figure 2. Molecular structures of 3 (left) and 8 (right) with 50% probability ellipsoids for non-H atoms. The interplanar angles between the two
aromatic rings in 3 and 8 are 39.11(9) and 41.80(6)ꢀ, respectively.
(entry 2 vs 5), reflecting the importance of base solubility in the
deprotonation step of the catalytic cycle (vide infra).16 However,
even though KOtBu is the most soluble base in DMA, only a trace
amount of product was obtained (entry 6), suggesting that steric
hindrance might become significant.
Next, we investigated the reactions between 1,2-dimethylimi-
dazole and aryl halides under identical conditions (Table 4). In
general, higher yields were obtained with 1,2-dimethylimidazole
than with 1-methylimidazole using a similar set of aryl halides.
For example, a 53% yield of 5-(4-methoxyphenyl)-1,2-dimethy-
limidazole (11) was obtained from 4-bromoanisole (entry 4,
Table 4) using conventional heating, compared with a 46% yield
of the corresponding compound from 1-methylimidazole and
4-bromoanisole (entry 4, Table 3). It is clear that blocking the C2
position avoids C2-arylation reactions. It is noteworthy that, in
general, the Pd(OAc)2/2PPh3 catalyst system reported by Murai
and co-workers delivered yields superior to those for 1b in the
reaction of 1,2-dimethylimidazole with aryl bromides.16 For
example, a 85% GC yield of 11 was obtained by them after 24 h,
compared with a 53% isolated yield delivered by 1b after 18 h
of conventional heating. Importantly, the Pd(OAc)2/2PPh3
catalyst system is limited to aryl iodides and bromides, whereas
aryl chlorides can be successfully utilized by 1b. Under conven-
tional heating, the coupling reactions proceeded well with a range
of aryl chlorides to deliver good yields in the range of 50ꢀ72%
(entries 6ꢀ10). A reasonable 52% yield of 11 was obtained from
the highly electron rich 4-chloroanisole (entry 10). Consistently,
comparable yields again can be obtained from either aryl
bromides or their chloro analogues, reflecting again that the
rate-determining step is not the CꢀCl bond. Microwave-assisted
arylations were also carried out smoothly to afford 5-aryl-1,2-
dimethylimidazole with slightly better yields in just 2 h. A very
good yield of 5-(4-acetylphenyl)-1,2-dimethylimidazole (8) can
be obtained from the arylation reaction of 4-bromoacetophenone
Employing 1b as precatalyst under the optimized conditions of
base and solvent, we explored the scope of the reaction by
applying a range of aryl bromides or chlorides to react with
1-methylimidazole (Table 3). In addition to conventional heat-
ing, microwave irradiation was also performed to shorten the
reaction time.41 Entries 1ꢀ4 show that the catalytic system
utilized activated, unactivated, and deactivated aryl bromides,
effectively affording yields of products in the range of 45ꢀ66%. A
decent yield of 5-(4-methoxyphenyl)-1-methylimidazole (6) can
be obtained from the deactivated aryl bromide 4-bromoanisole
(46%, entry 3). Markedly, the catalyst system is also effective with
a range of aryl chlorides. A comparable yield can be achieved
from the electron-rich aryl chloride 4-chloroanisole (40%, entry 9).
Notably, using microwave heating, 1-methylimidazole was suc-
cessfully arylated with the same set of aryl halides, affording
slightly higher yields in just 2 h. Thus, a reasonable 46% yield of 6
can be obtained from 4-chloroanisole in a short time. Intrigu-
ingly, yields of product from aryl bromides are only slightly
higher than those from aryl chlorides. Because the oxidative
additions to Pd(0) are normally the fastest for bromides, it is
likely that the oxidative addition of the CꢀCl bond is not the
rate-determining step.26 It should be noted that, in each case,
small amounts of either C-2 arylated or diarylated products were
also obtained.
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Table 3. Direct Arylation of 1-Methylimidazole and Aryl Halides under Conventional and Microwave Heatinga
a Reaction conditions: 3.7 mmol of 1-methylimidazole, 2.5 mmol of aryl halide, 5.0 mmol of KOAc, 5 mL of DMA, 2.5 mol % of 2b, 140 ꢀC. Yields of
other products are given in parentheses. b C-2 arylated or diarylated products were not determined.
under microwave heating (90%, entry 1). The structure of 8 was
also successfully confirmed by a X-ray diffraction study
(Figure 2). A water molecule is present linking two molecules
The design of 1b involves a labile phosphine and a robust
carbene ligand L around palladium acetate. It would be important
to justify this strategy by comparing the activities of 1b with the
catalyst systems Pd(PCy3)2(OAc)2 and Pd(L)2(OAc)2 compris-
ing two PCy3 and two L ligands around the palladium centers.
of 8 with strong OH N hydrogen bonds (see Figure S3 and
3 3 3
Table S2 in the Supporting Information).
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Table 4. Direct Arylation of 1,2-Dimethylimidazole and Aryl Halides under Conventional and Microwave Heating.a
a Reaction conditions: 3.7 mmol of 1,2-dimethylimidazole, 2.5 mmol of aryl halide, 5.0 mmol of KOAc, 5 mL of DMA, 2.5 mol % of cat., 140 ꢀC.
Table 5 clearly shows that while 1b is very effective in catalyzing
the reaction between 1,2-dimethylimidazole and 4-chloroaceto-
phenone (entry 1), both in situ systems of Pd(PCy3)2(OAc)2 and
Pd(L)2(OAc)2 delivered much lower yields (entries 2 and 3).
Then, we investigated the activity of 1b in preparing bis-
imidazole derivatives by preforming double arylation using
1-bromo-4-chlorobenzene (14a) and 1,4-dichlorobenzene (14b),
which are in general challenging substrates for cross-coupling
reactions (Scheme 1). Under the conditions in Table 3, mono-
imidazole 15 was isolated in decent yields from the reac-
tion between 1,2-dimethylimidazole and 1,4-dihalobenzenes.
Interestingly, a symmetrical bis-imidazole product was not
formed on increase of the molar equivalents of 1,2-dimethylimi-
dazole or further reaction between 15 and 1,2-dimethylimida-
zole. An attempt to react 15 with imidazolyl[1,2-a]pyridine also
did not yield the unsymmetrical bis-imidazole product 17
(Scheme 1). These results can be explained by the fact that aryl
chloride 15 contains an imidazolyl moiety of two methyl
substituents, rendering it too electron rich for a further coupling
reaction to occur. We envisioned that reversing the reaction
sequence would lead to the formation of the desirable product
17, since the monoimidazole intermediate from the first arylation
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would be electron poor due to the electron-withdrawing prop-
erty of the imidazolyl[1,2-a]pyridine moiety and the subsequent
arylation involves the more nucleophilic 1,2-dimethylimidazole.
To our delight, the first arylation reaction between imidazolyl-
[1,2-a]pyridine and 14a,b afforded monoimidazole 16, which
smoothly underwent a further arylation reaction with 1,2-
dimethylimidazole to afford 17 in 73% yield.
therapeutic value.43 Thus, we are also interested in preparing
imidazole derivatives containing styryl motifs, which are also
unknown in the literature. In contrast to the double-arylation and
Suzuki coupling reactions described in Schemes 1 and 2,
electron-rich 15 can undergo Heck coupling reactions smoothly
with styryl compounds to give stilbenes 21a,b (Scheme 3).
Compound 1b was also proven to be an effective Heck catalyst.
The desirable stilbenes can be produced as well by reversing the
reaction sequence. Thus, stilbenes 22a,b were prepared by
carrying out the Heck coupling reaction first. Then their sub-
sequent arylation reactions with 1,2-dimethylimidazole and
imidazolyl[1,2-a]pyridine using 1b as precatalyst produced
21a,b and 23a,b, respectively, in pure form.
Mechanistic Aspects. A catalytic cycle for the direct
C5-arylation reaction catalyzed by 1b, analogous to that proposed by
Miura and co-workers,16 is shown in Scheme 4. It involves the 14-
electron Pd(0) intermediate A, which is an active catalytic species
and is presumably generated from the reduction of 1b by base.
Pd(0) complexes similar to A have been structurally character-
ized in the literature,44 and 14-electron Pd(0) species, [Pd(PP)]
(PP = 1,2-bis(dimethylphosphino)ethane, (P)-2,20-bis(dimethyl-
phosphino)-1,10-biphenyl), have been shown by theoretical
calculations to be reactive for the oxidative addition of aryl
halides.45 Notably, 12-electron monoligated Pd(0) species bear-
ing electron-rich and bulky phosphine or carbene have been
suggested as the active catalytic species in classical cross-coupling
reactions.46 However, due to the much smaller steric bulkiness in
L, in contrast to those in, for example, IMes or IPr carbenes,
intermediate A is more favorable than the monoligated species.
Normally, oxidative additions of aryl halides to Pd(0) are faster
for bromides. However, since intermediate A is electron rich,
bearing two good electron-donating ligands, the oxidative addi-
tion of unreactive aryl chlorides can also occur readily. As
demonstrated by the comparable yields obtained from aryl
bromides and chlorides in Tables 3 and 4, the oxidative addition
of a CꢀCl bond (average bond energy 339 kJ/mol) might not be
the rate-determining step.26 The probable rate-determining
CꢀH cleavage step (average bond energy 413 kJ/mol) can
occur via three possible routes: (1) an electrophilic aromatic
substitution, (2) a concerted metalationꢀdeprotonation (CMD)
mechanism, and (3) a Heck-type mechanism. On the basis of the
fact that the more nucleophilic 1,2-dimethylimidazole is more
Since the biaryl motif, featuring two six-membered aromatic
rings, is an important subunit in many bioactive and functional
molecules,9,42 we were interested in preparing imidazole deriva-
tives containing such a biaryl motif, which are, surprisingly,
unknown in the literature (Scheme 2). Notably, it was quite
desirable that 1b was also an effective catalyst for Suzuki coupling
reactions. Similar to the preparation of 17, the reaction sequence
is vital for obtaining the desirable triarylated products. Due to the
deactivating imidazole unit, Suzuki coupling reactions did not
occur between 15 and methoxyphenylboronic acids. Reversing
the reaction sequence by preparing biaryls 18a,b first from
1-bromo-4-chlorobenzene and an appropriate phenylboronic
acid and then their subsequent direct arylations with 1,2-
dimethylimidazole produced the desirable products 19a,b in
decent yields. Triaryl compounds 20a,b were similarly prepared
in pure forms via direct arylation reactions from biaryls 18a,b.
Stilbene derivatives, such as stilbenoid compounds, polyhy-
droxystilbenes, and their glucosides, have attracted considerable
attention because of their biological activities and potential
Table 5. Comparative Study: Different Precatalysts for Direct
Arylation of 1-2-Dimethylimidazole and 4-Chloroacetophe-
none under Conventional Heatinga
entry
cat.
isolated yield, %
1
2
3
1b
72
30
23
Pd(OAc)2/2PCy3
Pd(OAc)2/2(L HCl)
3
a Reaction conditions: 3.7 mmol of 1,2-dimethylimidazole, 2.5 mmol of
4-chloroacetophenone, 5.0 mmol of KOAc, 5 mL of DMA, 2.5 mol % of
cat., 140 ꢀC, 18 h.
Scheme 1. Double Arylation Reaction Using 1,4-Dihalobenzene as Substrate
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Scheme 2. Sequential Suzuki and Arylation Reactions
Scheme 3. Sequential Heck and Arylation Reactions
reactive than 1-methylimidazole, it is likely that the catalytic cycle
proceeds with an electrophilic aromatic substitution, involving the
Wheland intermediate C. After deprotonation, subsequent reduc-
tive elimination in D affords the arylated imidazole and regenerates
the active species. The cyclohexylphosphine acts as a labile ligand,
whereas the carbene ligand L acts as a robust spectator ligand
throughout the catalytic cycle.29 In agreement of the proposed
catalytic cycle, addition of 4ꢀ5 equiv of PCy3 (with respect to 1b)
to the catalytic system effectively stops all catalytic activity, suggest-
ing the importance of phosphine dissociation in the catalytic cycle.
’ CONCLUSIONS
For palladium-catalyzed direct arylation reactions of imida-
zoles, high palladium loading (>5 mol %) and use of reactive aryl
halides (bromides and iodides) as coupling partners were com-
monly found in the literature. In contrast, we have successfully
developed effective direct C5-arylation reactions of imidazoles
with aryl chlorides using a moderate loading (2.5 mol %) of the
preformed electron-rich 1b as precatalyst. We confirmed that the
installation of a robust carbene and a labile phosphine ligand on
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Scheme 4. Proposed Catalytic Cycle of the Direct C-5 Ar-
ylation Reaction of Imdazoles Catalyzed by 1b
Crystals suitable for X-ray crystallography were obtained by vapor
diffusion of ether into a THF solution of the compound.
Synthesis of Pd(L)(PCy3)(OAc)2 (1b). The compound was
prepared following a procedure similar to that for 1a. A mixtue of 2b
(2.00 g, 2.840 mmol) and silver acetate (1.42 g, 8.250 mmol) was used. A
yellowish compound was obtained. Yield: 1.53 g, 72%. Mp: 151ꢀ155 ꢀC
dec. Anal. Calcd for C39H55N2O4PPd: C, 62.19; H, 7.36; N, 3.72.
1
Found: C, 61.88; H, 7.48; N, 3.57. H NMR (300 MHz, CDCl3):
δ 1.06ꢀ1.83 (m, 33H, Cy H), 1.86 (s, 3H, CH3), 1.94 (s, 3H, CH3), 5.52
2
2
(d, JHH = 15.0 Hz, 2H, PhCHAHBN), 6.17 (d, JHH = 15.0 Hz, 2H,
PhCHAHBN), 6.61 (s, 2H, imi H), 7.24ꢀ7.35 (m, 10H, Ph H). 13C{1H}
NMR (75 MHz, CDCl3): δ 22.6 (CH3), 24.3 (Cy C), 26.7 (d, 3JPC
=
10.9 Hz, Cy C), 28.4 (Cy C), 34.1 (d, 1JPC = 23.5 Hz, Cy C), 54.3 (CH2),
120.3 (imi C), 127.5 (Ph C), 127.8 (Ph C), 128.0 (Ph C), 133.7 (Ph C),
160.0 (NCN), 176.6 (CO). 31P{1H} NMR (121 MHz, CDCl3): δ 40.3.
Crystals suitable for X-ray crystallography were obtained by vapor
diffusion of hexane into a THF solution of the compound.
General Procedure for Palladium-Catalyzed Direct Aryla-
tion. Typically, a mixture of aryl halide (2.5 mmol), imidazole
(3.7 mmol), KOAc (5.0 mmol), and Pd precatalyst (0.087 mmol) was
dissolved in DMA (5 mL) under a nitrogen atmosphere. The reaction
mixture was stirred at 140 ꢀC in a preheated oil bath for 18 h or under
microwave irradiation for 2 h. After the mixture was cooled, ethyl acetate
(10 mL) was added. The solution was poured into water (50 mL) and
extracted with ethyl acetate (3 ꢁ 25 mL). The combined extracts were
washed with brine, dried over anhydrous MgSO4, and evaporated to
dryness under vacuum to give the crude product, which was purified by
column chromatography. Compounds 4, 6, 8, 9, 11, and 13,33 6B,47 5,
5B, and 15,16 and 1048 were identified by comparison of NMR data with
those in the literature. Crystals of 3 and 8 suitable for X-ray crystal-
lography were obtained by vapor diffusion of ether into a THF solution
of the compound.
General Procedure for the Palladium-Catalyzed Suzuki
Coupling Reaction. In a typical reaction, a mixture of aryl halides (1.0
mmol), phenylboronic acid (1.5 mmol), Cs2CO3 (2.0 mmol), and
palladium(II) precatalyst (2.5 mol %) in 1,4-dioxane (2.5 mL) was
stirred under nitrogen at 80 ꢀC for 2 h. After the mixture was cooled,
ethyl acetate (25 mL) was added. The solution was filtered through a
short column of Celite. The solvent was completely removed under
vacuum to give a crude product, which was purified by column
chromatography. Compounds 18a49 and 18b50 were identified by
comparison of NMR data with those in the literature.
General Procedure for the Palladium-Catalyzed Heck
Coupling Reaction. A 50 mL round-bottom flask was charged with
aryl halide (1.0 mmol), alkene (1.2 mmol), anhydrous sodium acetate
(1.2 mmol), palladium precatalyst (2.5 mol %), and NMP (5 mL) under
nitrogen. The flask was heated with stirring in a preheated oil bath at
140 ꢀC for 18 h. After the mixture was cooled, ethyl acetate (25 mL) was
added. The solution was poured into water (50 mL) and extracted with
ethyl acetate (3 ꢁ 25 mL). The combined extracts were washed with
brine, dried over anhydrous MgSO4, and evaporated to dryness under
vacuum to give a crude product, which was purified by column
chromatography. Compounds 21a,b were identified by comparison of
NMR data with those in the literature.51
5-(4-Acetylphenyl)-1-methylimidazole (3). Light-yellow
solid. Mp: 119ꢀ121 ꢀC. 1H NMR (300 MHz, CDCl3): δ 2.61 (s, 3H,
CH3), 3.71 (s, 3H, NCH3), 7.19 (s, 1H, H4), 7.61 (s, 1H, H2), 7.48 (d,
3J = 7.8 Hz, 2H, Ar H), 8.00 (d, 3J = 7.8 Hz, 2H, Ar H). 13C{1H} NMR
(75 MHz, CDCl3): δ 26.5 (CH3), 32.9 (NCH3), 128.0, 128.8, 132.5,
134.2, 136.1, 140.0 (NCN), 197.3 (CdO). HRMS (EI; m/z): calcd for
C12H12N2O 200.0945, found 200.0949. Crystals suitable for X-ray
crystallography were obtained by vapor diffusion of ether into a
dichloromethane solution of the compound.
palladium acetate affords an effective precatalyst. Under microwave
heating, good yields of arylated products can be obtained in 2 h.
The same catalyst system was also versatile in catalyzing Suzuki
and Heck coupling reactions. On combination of these classical
methods of CꢀC bond formation reactions, we demonstrated
that a variety of novel imidazole derivatives containing biaryl and
styryl motifs were easily accessible from dihalobenzenes.
’ EXPERIMENTAL SECTION
General Information. All manipulations were performed under a
dry nitrogen atmosphere using standard Schlenk techniques. Solvents
were dried with standard procedures. Starting chemicals were purchased
from commercial sources and used as received. Compounds 2a,b were
prepared according to the literature procedure.37 Microwave irradiation
experiments were conducted in a Milestone Start S microwave system.
Reaction times refer to hold times at the temperature indicated in
Tables 3ꢀ5. The temperature was measured with an IR sensor on the
outside of the reaction vessel. 1H, 13C{1H}, and 31P{1H} NMR spectra
were recorded at 300.13, 75.48, and 121.49 MHz, respectively, on a
Bruker AV-300 spectrometer. Elemental analyses were performed on a
Thermo Flash 2000 CHN-O elemental analyzer. High-resolution mass
spectroscopy (HRMS) was measured on a Finnigan/Thermo Quest
MAT mass spectrometer at the National Chung Hsing University
(Taiwan).
Synthesis of Pd(L)(PPh3)(OAc)2 (1a). A mixture of 2a (2.00 g,
2.907 mmol) and silver acetate (1.46 g, 8.722 mmol) in acetonitrile
(20 mL) was stirred at room temperature for 12 h. The mixture was then
filtered through a short column of Celite. After removal of the solvent
under vacuum, the residue was washed with diethyl ether to afford a
yellowish solid. Yield: 1.78 g, 83%. Mp: 153ꢀ157 ꢀC dec. Anal. Calcd for
C39H37N2O4PPd: C, 63.72; H, 5.07; N, 3.81. Found: C, 63.64; H, 5.11;
N, 3.82. 1H NMR (300 MHz, CDCl3): δ 1.43 (s, 3H, CH3), 1.89 (s, 2H,
CH3), δ 4.53 (d, 2JHH = 14.1 Hz, 2H, PhCHAHBN), 5.92 (d, 2JHH = 14.1
Hz, 2H, PhCHAHBN), 6.31 (s, 2H, imi H), 6.97ꢀ7.47 (m, 25H, Ph H).
13C{1H} NMR (75 MHz, CDCl3): δ 23.3 (CH3), 54.1 (CH2), 120.8
(imi C), 128.2 (d, 3JPC = 4.9 Hz, Ph C), 128.4 (Ph C), 128.5 (d, 2JPC = 5.5
Hz, Ph C), 128.9 (Ph C), 129.2 (Ph C), 130.9 (d, 4JPC = 2.3 Hz, Ph C),
1
133.8 (Ph C), 134.0 (d, JPC = 3.5 Hz, Ph C), 157.4 (NCN), 176.5
3
(d, JPC = 31.2 Hz, CO). 31P{1H} NMR (121 MHz, CDCl3): δ 24.4.
5167
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Organometallics
ARTICLE
1-[4-[2-(4-Acetylphenyl)-3-methylimidazol-4-yl]phenyl-
]ethanone (3B). 1H NMR (300 MHz, CDCl3): δ 2.54 (s, 6H, CH3),
3.68 (s, 3H, NCH3), 7.24 (s, 1H, H4), 7.39ꢀ7.59 (m, 2H, Ar H),
7.65ꢀ7.84 (m, 2H, Ar H), 7.89ꢀ8.12 (m, 4H, Ar H). 13C{1H} NMR
(75 MHz, CDCl3): δ 26.5 (CH3), 26.5 (CH3), 34.2 (NCH3), 128.1,
128.4, 128.6, 128.7, 129.0, 134.1, 134.5, 135.1, 136.0, 136.7, 149.0, 197.2
(CdO), 197.3 (CdO). HRMS (EI; m/z): calcd for C20H18N2O2
318.1368, found 318.1363.
(s, 3H, OCH3), 6.80 (t, 3J = 6.7 Hz, 1H, py H), 6.94ꢀ7.12 (m, 2H, Ar H),
7.20 (dd, 3J = 15.9, 8.9 Hz, 1H, py H), 7.28ꢀ7.46 (m, 2H, Ar H), 7.51ꢀ7.85
(m, 6H, Ar H, py H, imi H), 8.41 (d, 3J = 7.0 Hz, 1H, py H). 13C{1H} NMR
(75 MHz, CDCl3): δ 55.4 (OCH3), 111.1, 112.4, 118.1, 120.8, 123.4, 124.1,
125.6, 127.4, 127.6, 128.9, 129.6, 130.2, 130.6, 132.5, 138.3, 146.0 (NCN),
156.3 (COCH3). HRMS (EI; m/z): calcd for C20H16ON2 300.1263, found
300.1266.
3-(40-Methoxybiphenyl-4-yl)imidazolyl[1,2-a]pyridine (20b).
1
1
4-(1-Methylimidazol-2-yl)benzonitrile (4A). H NMR (300
Brown solid. Mp: 186ꢀ188 ꢀC. H NMR (300 MHz, CDCl3): δ 3.85
(s, 3H, CH3), 6.82 (t, 3J = 6.8 Hz, 1H, py H), 7.00 (d, 3J = 8.5 Hz, 2H, Ar H),
7.09ꢀ7.34 (m, 1H, py H), 7.55ꢀ7.84 (m, 8H, Ar H, imi H, py H), 8.38
MHz, CDCl3): δ 3.77 (s, 3H, CH3), 7.00 (s, 1H, imi H), 7.13 (s, 1H, imi
H), 7.64ꢀ7.97 (m, 4H, Ar H). 13C{1H} NMR (75 MHz, CDCl3): δ 34.8
(CH3), 76.6, 77.1, 77.5, 111.9, 118.5, 123.7, 128.8, 129.2, 132.3, 134.7,
145.6. HRMS (EI; m/z): calcd for C11H9N3 183.0796, found 183.0788.
5-(4-Formylphenyl)-1-methylimidazole (7). Yellow solid.
Mp: 165ꢀ167 ꢀC. 1H NMR (300 MHz, CDCl3): δ 3.82 (s, 3H,
CH3), 7.57 (s, 1H, H4), 7.80 (d, 3J = 8.0 Hz, 2H, Ar H), 8.01 (d, 3J =
8.0 Hz, 2H, Ar H), 8.35 (s, 1H, H2), 10.06 (s, 1H, CHO). 13C{1H} NMR
(75 MHz, CDCl3): δ 34.0 (NCH3), 125.9, 128.8, 130.4, 132.7, 134.4,
135.8, 140.2 (NCN), 193.0 (CHO). HRMS (EI; m/z): calcd for
C11H10N2 186.0793, found 186.0789.
3
(d, J = 7.0 Hz, 1H, py H). 13C{1H} NMR (75 MHz, CDCl3): δ 55.3
(OCH3), 112.6, 114.3, 118.2, 123.4, 124.2, 127.4, 128.0, 128.3, 132.5, 132.8,
140.6, 146.1 (NCN), 159.4 (COCH3). HRMS (EI; m/z): calcd for
C20H16ON2 300.1263, found 300.1257.
1,2-Dimethyl-5-[4-[(E)-styryl]phenyl]imidazole (21a). Off-
1
white solid. Mp: 123ꢀ125 ꢀC. H NMR (300 MHz, CDCl3): δ 2.47
(s, 3H, CCH3), 3.55 (s, 3H, NCH3), 7.01 (br s, 1H, imi H), 7.12 (s, 2H,
overlapping Ph H and dCH), 7.25ꢀ7.43 (m, 5H, Ph H), 7.56 (d, 3J =
3
8.2 Hz, 2H, Ph H), 7.52 (d, J = 8.2 Hz, 2H, Ph H). 13C{1H} NMR
5-(3-Methoxyphenyl)-1,2-dimethylimidazole (12). Light-
(75 MHz, CDCl3): δ 13.3 (CCH3), 31.5 (NCH3), 126.6, 126.8, 127.7,
127.8, 128.7, 128.8, 128.9, 129.4, 136.9, 137.0. HRMS (EI; m/z): calcd
for C19H18N2 274.1470, found 274.1472.
1
brown solid. Mp: 60ꢀ62 ꢀC. H NMR (300 MHz, CDCl3, 25 ꢀC,
TMS): δ 2.52 (s, 3H, CCH3), 3.56 (s, 3H, NCH3), 3.82 (s, 3H, OCH3),
6.87ꢀ6.95 (m, 3H, Ar H), 7.02 (s, 1H, H4), 7.35 (t, 3J = 7.6 Hz, 2H, Ar
H). 13C{1H} NMR (75 MHz, CDCl3): δ 13.0 (CCH3), 31.5 (NCH3),
55.2 (OCH3), 113.6, 114.5, 121.0, 123.5, 129.7, 130.6, 133.7, 145.6
(NCN), 159.7 (COCH3). HRMS (EI; m/z): calcd for C13H14N2O
214.1106, found 214.1111.
5-[4-[(E)-2-(4-Methoxyphenyl)vinyl]phenyl]-1,2-dimethy-
limidazole (21b). Pale yellow solid. Mp: 218ꢀ220 ꢀC. 1H NMR (300
MHz, CDCl3): δ 2.46 (s, 3H, CCH3), 3.54 (s, 3H, NCH3), 3.82 (s, 3H,
OCH3), 6.83ꢀ7.16 (m, 5H, imi H, dCH, Ph H), 7.31 (d, 3J = 8.2 Hz,
2H, Ph H), 7.45 (d, 3J = 8.5 Hz, 2H, Ph H), 7.53 (d, 3J = 8.2 Hz, 2H, Ph
H). 13C{1H} NMR (75 MHz, CDCl3): δ 13.5 (CCH3), 31.5 (NCH3),
55.3 (OCH3), 114.1, 125.0, 125.7, 126.5, 127.8, 128.7, 128.8, 129.8,
137.2 (NCN), 159.4 (CO). HRMS (EI; m/z): calcd for C20H20N2O
304.1576, found 304.1570.
3-[4-[(E)-Styryl]imidazolyl[1,2-a]pyridine (23a). Pale yellow
solid. Mp: 157ꢀ159 ꢀC. 1H NMR (300 MHz, CDCl3): δ 6.82 (t, 3J = 6.4
Hz, 1H, py H), 7.10ꢀ7.32 (m, 4H, dCH, py H, Ar H), 7.37 (t, 3J = 7.3
Hz, 2H, Ar H), 7.54 (m, 4H, imi H, py H, Ar H), 7.61ꢀ7.81 (m, 4H, Ar
H), 8.37 (d, 3J = 7.0 Hz, 1H, py H). 13C{1H} NMR (75 MHz, CDCl3): δ
112.6, 118.3, 123.4, 124.3, 125.5, 126.6, 127.2, 127.7, 127.9, 128.0, 128.3,
128.7, 129.4, 132.6, 137.0, 137.1, 146.2 (NCN). HRMS (EI; m/z): calcd
for C21H16N2 296.1313, found 296.1320.
3-(4-Chlorophenyl)imidazolyl[1,2-a]pyridine (16). Off-
1
white solid. Mp: 117ꢀ119 ꢀC. H NMR (300 MHz, CDCl3): δ 6.81
(td, 3J = 6.9 Hz, 4J = 1.0 Hz, 1H, py H), 7.20 (ddd, 3J = 9.1 Hz, 3J = 6.7 Hz,
4J = 1.2 Hz, 1H, py H), 7.48 (s, 4H, Ar H), 7.62ꢀ7.70 (m, 2H, imi H,
3
4
py H), 8.26 (dt, J = 7.0 Hz, J = 1.2 Hz, 1H, py H). 13C{1H} NMR
(75 MHz, CDCl3): δ 112.7, 118.3, 123.1, 124.3, 124.5, 127.7, 129.1,
129.4, 132.7, 133.9, 146.2 (NCN). HRMS (EI; m/z): calcd for
C13H9ClN2 228.0454, found 228.0448.
3-[4-(2,3-Dimethylimidazol-4-yl)phenyl]imidazolyl[1,2-a]-
pyridine (17). Off-white solid. Mp: 184ꢀ186 ꢀC. 1H NMR (300 MHz,
CDCl3): δ 2.47 (s, 3H, CCH3), 3.58 (s, 3H, NCH3), 6.83 (t, 3J = 6.7 Hz,
1H, py H), 7.02 (s, 1H, imi H), 7.16ꢀ7.29 (m, 1H, py H), 7.49 (d, 3J =
7.6 Hz, 2H, Ar H), 7.56ꢀ7.77 (m, 4H, Ar H, py H, imi H), 8.37 (d, 3J =
7.0 Hz, 1H, py H). 13C{1H} NMR (75 MHz, CDCl3/DMSO-d6): δ 13.7
(CCH3), 31.6 (NCH3), 112.9, 118.0, 123.6, 124.6, 125.1, 125.7, 128.0,
128.3, 129.0, 130.0, 132.6, 132.9, 146.1 (NCN), 146.3 (NCN). HRMS
(EI; m/z): calcd for C18H16N4 288.1375, found 288.1383.
5-[4-(2-Methoxyphenyl)phenyl]-1,2-dimethylimidazole (19a).
Off-white solid. Mp: 127ꢀ129 ꢀC. 1H NMR (300 MHz, CDCl3): δ 2.47
(s, 3H, CCH3), 3.57(s, 3H, NCH3), 3.83 (s, 3H, OCH3), 6.92ꢀ7.11 (m, 3H,
imi H, Ph H), 7.27ꢀ7.43 (m, 4H, Ph H), 7.59 (d, 3J = 7.9 Hz, 2H, Ph H).
13C{1H} NMR (75 MHz, CDCl3): δ 13.3 (CCH3), 31.5 (NCH3), 55.5
(OCH3), 111.2, 120.9, 124.8, 128.2, 128.5, 128.9, 129.7, 129.8, 130.7, 138.1
(NCN), 156.4 (CO). HRMS (EI; m/z): calcd for C18H18N2O 278.1419,
found 278.1427.
3-[4-[2-(4-Methoxyphenyl)ethyl]phenyl]imidazolyl[1,2-a]-
pyridine (23b). Pale yellow solid. Mp: 187ꢀ189 ꢀC. 1H NMR (300
MHz, CDCl3): δ 3.83 (s, 3H, CH3), 6.81 (t, 3J = 6.7 Hz, 1H, py H), 6.91
3
(d, J = 8.8 Hz, 2H, Ph H), 6.96ꢀ7.23 (m, 3H, HCdCH, py H),
7.45ꢀ7.72 (m, 8H, py H, imi H, Ph H), 8.36 (d, 3J = 7.0 Hz, 1H, py H).
13C{1H} NMR (75 MHz, CDCl3): δ 55.3 (OCH3), 112.6, 114.2, 118.2,
123.4, 124.2, 125.6, 126.9, 127.8, 128.0, 128.9, 129.8, 132.5, 137.5, 146.2
(NCN), 159.5 (CO). HRMS (EI; m/z): calcd for C22H18N2O 326.1419,
found 326.1411.
X-ray Diffraction Studies. Data for compounds 1a,b, 3, and 8
were collected at 150(2) K on a Bruker APEX II equipped with a CCD
area detector and a graphite monochromator utilizing Mo Kα radiation
(λ = 0.710 73 Å). The unit cell parameters were obtained by least-
squares refinement. Data collection and reduction were performed using
the Bruker APEX2 and SAINT software.52 Absorption corrections were
performed using the SADABS program.53 All the structures were solved
by direct methods and refined by full-matrix least-squares methods
against F2 with the SHELXTL software package.54 All non-H atoms
were refined anisotropically. All H atoms were fixed at calculated
positions and refined with the use of a riding model. Crystallographic
data are given in Table S1 of the Supporting Information. CCDC files
783655 (1a), 783656 (1b 0.5C4H8O H2O), 783654 (3), and 786904
5-[4-(4-Methoxyphenyl)phenyl]-1,2-dimethylimidazole
(19b). Off-white solid. Mp: 204ꢀ206 ꢀC. 1H NMR (300 MHz, DMSO-
d6): δ 2.36 (s, 3H, CCH3), 3.56 (s, 3H, NCH3), 3.80 (s, 3H, OCH3),
6.90 (s, 1H, imi H), 7.04 (d, 3J = 8.5 Hz, 2H, Ph H), 7.48 (d, 3J = 8.2 Hz,
2H, Ph H), 7.69 (d, 3J = 8.2 Hz, 2H, Ph H), 7.65 (d, 3J = 8.8 Hz, 2H, Ph
H). 13C{1H} NMR (75 MHz, DMSO-d6): δ 13.9 (CCH3), 31.8
(NCH3), 55.7 (OCH3), 115.0, 126.0, 127.0, 128.2, 128.9, 129.3,
132.4, 133.1, 139.1, 146.4 (NCN), 159.5 (CO). HRMS (EI; m/z): calcd
for C18H18N2O 278.1419, found 278.1413.
3-(20-Methoxybiphenyl-4-yl)imidazolyl[1,2-a]pyridine (20a).
3
3
1
(8) contain supplementary crystallographic data for this paper. These
Brown solid. Mp: 107ꢀ109 ꢀC. H NMR (300 MHz, CDCl3): δ 3.84
5168
dx.doi.org/10.1021/om200490k |Organometallics 2011, 30, 5160–5169

Organometallics
ARTICLE
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’ ASSOCIATED CONTENT
S
Supporting Information. Tables, figures, and CIF files
b
giving additional characterization data and full crystallographic
data for 1a,b, 3, and 8. This material is available free of charge via
the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
*Tel: +886 4 7232105 ext. 3523. Fax: +886 4 7211190. E-mail:
leehm@cc.ncue.edu.tw.
’ ACKNOWLEDGMENT
We are grateful to the National Science Council of Taiwan for
financial support of this work. We also thank the National Center
for High-performance Computing of Taiwan for computing time
and financial support of the Conquest software.
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