Intermolecular versus Intramolecular Palladium-Catalyzed Direct Arylations between 1-(2-Bromobenzyl)imidazoles and Aryl Bromides

Article abstract of DOI:10.1002/adsc.201500332

Herein, we report on the sequential palladium-catalyzed intermolecular followed by intramolecular direct arylations of 1-(2-bromobenzyl)imidazoles. We found that, in the presence of 1 mol% palladium acetate and potassium acetate as base, the intermolecular reaction between 1-(2-bromobenzyl)imidazole derivatives and electron-deficient aryl bromides proceeded faster than the intramolecular reaction, allowing us to prepare medium-size polycyclic imidazoles after a second Pd-catalyzed intramolecular arylation. These iterative direct arylations allowed the synthesis of fused nitrogen-containing heterocycles with a 5- or 7-membered-ring in only two steps. Some reactions have also been performed as a one-pot procedure using 2 mol% of palladium acetate in the presence of a larger amount of base (3 equiv.).

Full text of DOI:10.1002/adsc.201500332

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DOI: 10.1002/adsc.201500332
Intermolecular versus Intramolecular Palladium-Catalyzed
Direct Arylations between 1-(2-Bromobenzyl)imidazoles and Aryl
Bromides
Xiaowen Xu,a,b Liqin Zhao,a Yiqun Li,b,* Jean-FranÅois SoulØ,a
and Henri Douceta,*
a
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS – UniversitØ de Rennes “OrganomØtalliques matØriaux et
Catalyse”, Campus de Beaulieu, 35042 Rennes, France
Fax: (+33)-(0)2-2323-6939; phone: (+33)-(0)2-2323-6384; e-mail: henri.doucet@univ-rennes1.fr
Department of Chemistry, Jinan University, Guangzhou 510632, Peopleꢀs Republic of China
b
E-mail: tlyq@jnu.edu.cn
Received: April 2, 2015; Revised: July 15, 2015; Published online: September 11, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500332.
Abstract: Herein, we report on the sequential palla- molecular arylation. These iterative direct arylations
dium-catalyzed intermolecular followed by intramo- allowed the synthesis of fused nitrogen-containing
lecular direct arylations of 1-(2-bromobenzyl)imida- heterocycles with a 5- or 7-membered-ring in only
zoles. We found that, in the presence of 1 mol% pal- two steps. Some reactions have also been performed
ladium acetate and potassium acetate as base, the in- as a one-pot procedure using 2 mol% of palladium
termolecular reaction between 1-(2-bromobenzyl)- acetate in the presence of a larger amount of base
imidazole derivatives and electron-deficient aryl (3 equiv.).
bromides proceeded faster than the intramolecular
reaction, allowing us to prepare medium-size poly- Keywords: arylation; catalysis; C H bond activation;
cyclic imidazoles after a second Pd-catalyzed intra- imidazoles; palladium
À
Introduction
stage for the development of increasingly viable syn-
theses of complex molecules.[3] On the other hand,
Medium-size heterocycles (e.g., 5-, 6-, or 7-membered only a few examples dealing with the synthesis of imi-
rings) fused to aryl rings are ubiquitous in pharma- dazoles fused to aryl rings have been described in the
ceuticals or natural products; therefore original and literature,[4] and no general method has been de-
efficient accesses to such medium-size building blocks scribed yet.
are needed. For example, carbamazine (Tegretol),
The first example of an intramolecular direct aryla-
which is an important antiepileptic drug, or Paullones, tion of imidazole derivatives was reported in 1991,
which constitute a class of CDK inhibitors, are both using 10 mol% Pd(OAc)2 in DMA in the presence of
synthesized using Pd-catalyzed intramolecular Heck both base and a phase-transfer agent (Figure 1a).[5]
or arylation reactions.[1] Indeed, palladium-catalyzed Later, the reaction of 1-(2-bromobenzyl)imidazole in
cross-coupling reactions (e.g., Suzuki–Miyaura, Ne- the presence of a palladium catalyst and a base af-
gishi, or Stille reactions, etc.) are powerful methodol- forded selectively cyclization at the C-5 position in
ogies for the C C bond formation. More recently, 77% yield (Figure 1b).[4c] Such a palladium-catalyzed
direct C H bond arylation has appeared as one of the intramolecular direct arylation has been used for the
À
À
most suitable methods for such transformations with synthesis of several fused nitrogen imidazole deriva-
the respect of the environment (i.e., there is only the tives.[4a,e,f,6] In 2014, Laha and co-workers reported
formation of HX associated with the base as side a one pot procedure, i.e, N-benzylation/intramolecular
À
products and there is no requirement to use sensitive C H arylation for the synthesis of annulated nitrogen
organometallic reagents).[2]
heterocycles from imidazole and 2-bromobenzyl bro-
During the past decade, remarkable progress in the mide (Figure 1c).[7] The C-2 intramolecular direct ary-
direct arylation of heteroarenes, electron-deficient lation has also been performed using CuI associated
arenes or arenes bearing directing groups has set the with 1,10- phenanthroline as catalytic system (Fig-
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zole (Figure 1e, conditions 2).[10] A low catalyst load-
ing, phosphine-free palladium procedure for similar
coupling reactions was also reported.[11] Other reac-
tion conditions including a specially designed ligand
were also reported.[12] A sequential intermolecular
direct arylation of imidazole derivatives has also been
performed by Murai for the efficient synthesis of un-
symmetrical 2,4,5-triarylated azoles,[13] and a one-pot
procedure for the symmetrical 2,5-diarylation of imi-
dazoles has been reported.[14] Pd/Cu catalytic systems
have been also developed for the direct C-2 arylation
of imidazole.[15]
To the best of our knowledge, the intermolecular
direct arylation of imidazoles substituted by a 2-bro-
mobenzyl group at N-1 has not been reported yet, al-
though sequential intermolecular direct arylation fol-
lowed by an intramolecular direct arylation would
provide an efficient two-step synthesis of complex
imidazoles fused to aryl rings (Figure 1f). Herein, we
report on the reactivity of 1-(2-bromobenzyl)(2-sub-
stituted)imidazole in Pd-catalyzed intermolecular
versus intramolecular direct arylations.
Results and Discussion
In the initial experiments, the intramolecular direct
arylation of 1-(2-bromobenzyl)imidazole using our
previous best reaction conditions for the direct inter-
molecular arylations of several heteroarenes was per-
formed
(Scheme 1).[16]
Using
2 mol%
of
PdCl(C3H5)(dppb) in the presence of 2 equiv. of
KOAc as base in DMA at 1508C, the cyclization reac-
tion took place regioselectively at the expected C-5
position to afford imidazo[5,1-a]isoindole (1b) in 76%
yield. A similar result was obtained using 2 mol% of
Pd(OAc)2 instead of PdCl(C3H5)(dppb) as catalyst,
albeit a lower yield of 63% in 1b was obtained. It is
important to note that, in both cases, the C-2 position
was not reactive as imidazo[2,1-a]isoindole (1a) was
not detected, even in trace amounts in the crude GC-
1
MS and crude H NMR analyses.
Figure 1. Previous examples of Pd or Cu-catalyzed intramo-
lecular or intermolecular direct arylations of imidazoles.
ure 1d).[8] On the other hand, Bellina and co-workers
reported an intermolecular highly regioselective C-5
arylation of 1-arylimidazoles with aryl bromides as
coupling partners using 5 mol% of Pd(OAc)2 associat-
ed to 10 mol% AsPh3 (Figure 1e, conditions 1).[9]
Then, they applied similar reaction conditions for the
Scheme 1. Pd-catalyzed direct intramolecular arylation of 1-
C-5 arylation of 1-benzylimidazole or 1-methylimida- (2-bromobenzyl)imidazole.
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Intermolecular versus Intramolecular Palladium-Catalyzed Direct Arylations
Table 1. Palladium-catalyzed successive intermolecular fol-
lowed by intramolecular direct arylations using 1-(2-bromo-
benzyl)imidazole.
conditions (i) – namely 1 mol% of Pd(OAc)2 and
2 equiv. of KOAc in DMA – in the presence of 4-bro-
mobenzonitrile as coupling partner. Interestingly, the
intermolecular arylation proceeded faster than the in-
tramolecular reaction to afford the C-5 arylated imi-
dazole 2 in 71% yield. Moreover, in the course of the
reaction, the cyclized product 1b or other fused nitro-
gen heterocycles were not detected in the crude mix-
ture. In a second step, using the conditions (ii)
–namely, 2 mol% PdCl(C3H5)(dppb) catalyst and
2 equiv. of KOAc in DMA – the imidazole fused to
aryl 3 was obtained in 86% yield (Table 1, entry 1).
The cyclization took place exclusively at the C-2 posi-
tion on imidazole to allow the formation of the 3-aryl-
imidazo[2,1-a]isoindole 3. When the reaction was con-
ducted using 2 mol% of Pd(OAc)2 as catalyst, a lower
yield in 3 was obtained. Having determined the best
À
conditions for these iterative C H bond arylations,
namely Pd(OAc)2-catalyzed intermolecular arylation
followed by PdCl(C3H5)(dppb)-catalyzed cyclization,
we turned our attention to the scope of aryl bromide
partners. Using 1-bromo-4-nitrobenzene as coupling
partner, the C-5 arylated imidazole 4 was obtained in
64% yield; then, it was cyclized into the 3-(4-nitro-
phenyl)-imidazo[2,1-a]isoindole 5 in good 72% yield
(Table 1, entry 2). When the reaction was performed
using 3-bromobenzonitrile, a similar reactivity trend
as with 4-bromobenzonitrile was observed, whereas
on using 2-bromobenzonitrile a slightly lower yield
for the intermolecular arylation was obtained
(Table 1, entries 3 and 4).
We also conducted the reaction with electron-rich
4-bromoanisole; however, no reaction occurred using
the conditions (i), while a complex mixture was ob-
served using conditions (ii) (Scheme 2).
Next, a one-pot procedure for the synthesis of 3-ar-
ylimidazo[2,1-a]isoindole derivatives from 1-(2-bro-
mobenzyl)imidazole and aryl bromides was investigat-
ed (Scheme 3). Best reaction conditions were found
to be 2 mol% of Pd(OAc)2 in the presence of 3 equiv.
[a]
1 mol%
of
Pd(OAc)2
was
used
instead
of
PdCl(C3H5)(dppb).
We investigated then the reactivity of 1-(2-bromo-
benzyl)imidazole in the presence an additional aryl
Scheme 2. Reactivity of 4-bromoanisole in palladium-cata-
lyzed intermolecular or intramolecular arylations with 1-(2-
bromide derivative (Table 1). Firstly we tested the bromobenzyl)imidazole.
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ring, after the intermolecular arylation by the activa-
3
À
tion of the C(sp ) H bond on C-2 methyl substituent,
2
À
or a 7-membered ring, after activation of C(sp ) H
bond on the C-5 phenyl ring during the cyclization
step, were possible. We firstly tested our conditions (i)
with this new substrate without additional aryl bro-
mide. As expected, 3-methylimidazo[5,1-a]isoindole
17, which results from the direct intramolecular aryla-
tion at C-5 position, was obtained in 77% yield
(Table 2, entry 1). Then, we set up the reaction in the
presence of 1.2 equiv. of 4-bromobenzonitrile
(Table 2, entry 2). As in the previous cases (Table 1),
the intermolecular C-5 direct 5-arylation of the imida-
zole unit proceeded faster than the intramolecular re-
action to afford the C-5 arylated imidazole 18 in 61%
yield without the formation of 17. In the second step,
18 was submitted to a direct cyclization using the re-
action conditions (ii). We were pleased to find that
only the product 19, which results from the activation
2
À
of the C(sp ) H bond of the aryl unit, was formed.
The 6-membered ring product derived from the acti-
vation of the C(sp ) H bond of the methyl substituent
3
À
was not detected. Under the same reaction conditions,
but using Pd(OAc)2 as catalyst, no reaction occurred.
In order to further demonstrate the scope of these
unique iterative direct arylations, we decided to inves-
tigated the reactivity of several other aryl bromides
for this two-step synthesis of 7-methyl-dibenzo[c,e]i-
midazo[1,5-a]azepine derivatives (Table 2, entries 2–
6). The use of 1-bromo-4-nitrobenzene as coupling
Scheme 3. Palladium-catalyzed one-pot direct intermolecu-
lar and intramolecular arylations using 1-(2-bromobenzyl)-
imidazole.
of KOAc in DMA at 1508C for 48 h. As seen previ- partner offered again the intermolecular C-5 arylated
ously (Table 1, entry 5), the key for the success of product 20, albeit in lower 51% yield. Then, the
2
À
these transformations lies in the use of electron-defi- direct cyclization took place at one of the C(sp ) H
cient aryl bromides as coupling partners, because they bonds of the C-5 aryl group to give the azepine 21 in
react faster with Pd(0) species than the 2-bromoben- 63% yield (Table 2, entry 3). Both reactions, intermo-
zyl unit preventing the formation complex mixtures. lecular arylation and cyclization, were found to be in-
Aryl bromides bearing trifluoromethyl, ethyl ester, sensitive to the steric hindrance as 2-bromobenzoni-
formyl, or propionyl substituents at the para position trile was coupled with 1-(2-bromobenzyl)-2-methyli-
were successfully coupled with 1-(2-bromobenzyl)imi- midazole in 73% yield, and the resulting product 22
dazole to allow the formation in one step of the fused was cyclized into 23 in 82% yield (Table 2, entry 4). 3-
imidazoles 10–13 in 62%, 67%, 71%, and 74% yields, Bromobenzonitrile was also coupled with 1-(2-bromo-
respectively. The direct intermolecular arylation with benzyl)-2-methylimidazole to afford the C-5 arylated
3-bromoacetophenone proceeded also faster than the imidazole 24 in 68% yield. Substrate 24 contains two
2
À
cyclization to afford the desired fused coupling prod- potential C(sp ) H bonds for the cyclization reaction.
À
uct 14 in 59% yield. The reaction was also performed However, only the less hindered C H bond was acti-
with 2-acetyl-5-bromothiophene, which gave again, in vated to afford the azepine 27 in good yield as
one step, the polyheterocycle 15 in good yield. The a single regioisomer (Table 2, entry 4). Finally, we
À
cyclization at imidazolyl C-2 position occurred after also performed these iterative C H bond arylations
the direct intermolecular direct arylation, while the using 2-acetyl-5-bromothiophene as coupling partner.
2
À
C(sp ) H on the thiophene ring was unreactive, as no Interestingly, the corresponding fused imidazole 26
other cyclic compound was detected. Similar reactivi- was obtained in only one step in 57% yield using only
ty was observed with 4-bromoisoquinoline to give the the reaction condition (i) (Table 2, entry 6). This
2
À
desired product 16 in 61% yield.
result suggests a higher reactivity of the C(sp ) H on
In order to get larger medium-sized heterocycles the thienyl ring than their aryl analogues. It is impor-
(i.e., 6- or 7-membered rings), we decided to investi- tant to note that in all cases the activation of the
3
À
gate the reactivity of 1-(2-bromobenzyl)-2-methylimi- C(sp ) H bond of the methyl group was never ob-
dazole (Table 2). Both formation of a 6-membered served, confirming that under these reaction condi-
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Intermolecular versus Intramolecular Palladium-Catalyzed Direct Arylations
Table 2. Palladium-catalyzed iterative direct arylations using
1-(2-bromobenzyl)-2-methylimidazole.
Table 2. (Continued)
[a]
1 mol%
of
Pd(OAc)2
was
used
instead
of
PdCl(C3H5)(dppb).
2
À
tions the C(sp ) H bond is more reactive than the
3
3
À
À
C(sp ) H bond. Such C(sp ) H bonds required nor-
mally a stronger base such as t-BuOK to be activat-
ed.[17]
We finally investigated the reactivity of 1-(2-bromo-
2
À
benzyl)-2-phenylimidazole in these iterative C(sp ) H
bond arylations. As expected, without a coupling part-
ner, the use of the reaction conditions (i) resulted in
cyclization at the imidazolyl C-5 position giving 3-
phenylimidazo[5,1-a]isoindole (27) in 79% yield
(Table 3, entry 1). On the other hand, using the same
reaction conditions but in the presence of 1.2 equiv. of
4-bromo-1-nitrobenzene, again the intermolecular
direct arylation proceeded exclusively to furnish the
desired C-5 arylated imidazole 28 in 59% yield. Then,
the intramolecular direct arylation of 28 using the re-
action conditions (ii) was investigated. Two potential
2
À
reactive C(sp ) H bonds for the Pd-catalyzed direct
cyclization reaction are present on this structure, i.e.,
one as previously, on the C-5 aryl group coming from
the coupling with the aryl bromide, and the second on
the phenyl group at the imidazole C-2 position. The
formation of the 7-membered ring product happened
2
À
exclusively via the activation of a C(sp ) H bond of
the C-5 aryl group to afford the azepine 29 in 63%
yield (Table 3, entry 2). The reaction was completely
2
À
regioselective, as the C(sp ) H bonds on the 2-phenyl
substituent were completely untouched. This regiose-
lectivity might be explained by the difference of acidi-
ty between these two C H bonds if a concerted met-
À
alation–deprotonation mechanism (CMD) is opera-
tive.[18] Then, the reactivity of a few other aryl bro-
mides has been studied. A similar reactivity was ob-
served using 4-bromobenzonitrile as coupling partner.
The coupling product 30 was isolated in 72% in the
first step, then it was cyclized into the corresponding
7-membered ring fused imidazole 31 in 81% yield
(Table 3, entry 3). The reaction was again insensitive
to the bulkiness of the aryl bromide partner, as 2-bro-
mobenzonitrile provided 32 and 33 in 67% and 79%
yields, respectively (Table 3, entry 4). In contrast with
the 2-methylimidazole derivatives, in which both the
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Table 3. Palladium-catalyzed successive direct arylations
using 1-(2-bromobenzyl)-2-phenylimidazole.
Scheme 4. Palladium-catalyzed intramolecular arylations
using 1-(2-bromobenzyl)-2,4,5-triphenylimidazole.
direct inter- and intramolecular arylations proceeded
in one-pot as single step using 2-acetyl-5-bromothio-
phene (Table 2, entry 6); the reaction with 2-phenyli-
midazole derivative proceed in two sequential steps
(Table 3, entry 5). Firstly using the conditions (i), only
the C-5 arylated imidazole 34 was isolated in 56%
yield without formation of any fused imidazole deriv-
ative. In a second step and using the conditions (ii),
34 was cyclized into 35 in excellent 85% yield. This
fused imidazole derivative results from the activation
2
À
of a C(sp ) H bond of the thienyl ring.
In order to get more insights on the regioselectivity
of this seven-membered cyclization, we prepared N-
(2-bromobenzyl)imidazole 36, which contains phenyl
groups at C-2 and C-5 positions. Unfortunately, using
our optimized conditions for palladium-catalyzed in-
tramolecular direct arylation, only the debrominated
product 37 was isolated in 86% yield without the for-
mation of any cyclized product (Scheme 4). This
result strongly suggests that an electron-deficient
arene is required to get a cyclization reaction. On the
other hand, we prepared 4,4’-(1-(2-bromobenzyl)imi-
dazole-2,5-diyl)dibenzonitrile (38) from 1-(2-bromo-
benzyl)imidazole using our previous “one-pot” proce-
dure.[16c] Product 38 was obtained in low yield and
could not be isolated in pure form, therefore, we de-
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Intermolecular versus Intramolecular Palladium-Catalyzed Direct Arylations
Figure 2. Proposed mechanism for Pd(OAc)2-catalyzed inter-
molecular arylation.
cided to perform the cyclization reaction on the crude
mixture. To our surprise, both regioisomers 39a and
39b were obtained in a 1:1 ratio. This result indicates
that the regioselectivity of the reaction is dictated by
the electronic properties of the aryl groups, namely
electron-deficient arenes react preferentially.
Figure 3. Proposed mechanism for PdCl(C3H5)(dppb)-cata-
lyzed intramolecular arylation.
Based on a previous report,[19] we proposed the fol-
lowing catalytic cycles for palladium-catalyzed itera- tion of electron-rich aryl bromides such as H to gener-
tive direct arylations using 1-(2-bromobenzyl)limida- ate the complex I. The C-2 unsubstituted position is
zoles (Figure 2 and Figure 3). The first catalytic cycle the most reactive under a CMD mechanism assisted
employs phosphine-free Pd(OAc)2, which is known to by the coordinated acetate and affords the intermedi-
preferentially react with electron-deficient aryl bro- ate N. In contrast, when the position 2 is substituted
mides.[20] After in-situ generation of Pd(0) species[21] by Me or Ph groups, the C H bond activation oc-
À
and using a suitable coupling partner, the oxidative curred on the most electron-deficient arene confirm-
addition chemoselectively occurred with aryl bromide ing a CMD mechanism. Finally, reductive elimination
B affording Pd(II) species C, whereas the partner A from the intermediate M or N takes place to generate
remained untouched owing to its electron-rich proper- the desired five- or seven-membered rings.
ties. Then, through a concerted metalation–deproto-
nation (CMD) mechanism, a regioselective activation
À
at C-5 position of the C H bond occurred via the in- Conclusions
termediate E due to its lower Gibbs free energies of
activation.[18] Finally, reductive elimination from the In summary, we have investigated the reactivity of
intermediate F takes place to generate the desired imidazoles bearing a 2-bromobenzyl substituent at the
arylated product G with regeneration of the Pd(0) N-1 position in the presence of aryl bromides for Pd-
catalyst.
catalyzed direct arylations. We were pleased to find
The second catalytic cycle concerning the intramo- that using electron-deficient aryl bromides, phos-
lecular arylation is similar to the mechanism proposed phine-free Pd(OAc)2 catalyst promotes the intermo-
by Echavarren and Maseras (Figure 3).[22] The use of lecular direct arylation of imidazoles at the C-5 posi-
PdCl(C3H5)(dppb) as catalysts – which could also gen- tion. Then, the resulting cross-coupling products were
erate in-situ Pd(0)[23] – promotes the oxidative addi- submitted
to
a
cyclization
reaction
using
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PdCl(C3H5)(dppb) as catalyst to furnish the desired Procedure B (Direct Intramolecular Arylation of
fused imidazole derivatives in only 2 steps. When the Imidazoles)
imidazole was not substituted at the C-2 position, the
To a 5-mL oven-dried Schlenk tube, imidazole derivative
cyclization occurred at this position to afford 3-(hetero)-
(1–0.2 mmol), PivOK (2 equiv.), DMA (2–4 mL) and
arylimidazo[2,1-a]isoindoles. When the C-2 position
PdCl(C3H5)(dppb) (2 mol%) were successively added. The
of the imidazole partner was blocked by Me or Ph
substituents, the cyclization occurred chemoselectively
reaction mixture was evacuated by vacuum-argon cycles (5
times) and stirred at 1508C (oil bath temperature) for 24–
48 h (see Tables and Schemes). After cooling the reaction
mixture to room temperature and concentration, the crude
mixture was purified to afford the desired arylated products.
Imidazo[5,1-a]isoindole (1): Following the procedure B
using 1-(2-bromobenzyl)imidazole (237 mg, 1 mmol), the
residue was purified by flash chromatography on silica gel
(pentane-Et2O, 90–10) to afford the desired compound 1;
2
À
at the C(sp ) H bond of the aryl ring coming from
the aryl bromide. By this method, 7-substitued diben-
zo[c,e]imidazo[1,5-a]azepines were synthesized in high
yields in only two steps. These results represent eco-
nomically attractive and environmentally friendly pro-
cedures for the synthesis of fused imidazoles deriva-
tives.
1
yield: 119 mg (76%). H NMR (400 MHz, CDCl3): d=7.72
(s, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H),
7.37 (t, J=8.1 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.18 (s, 1H),
5.00 (s, 2H). This is a known compound and the spectral
data are identical to those reported in literature.[4c]
Experimental Section
General Methods
4-[1-(2-Bromobenzyl)imidazol-5-yl]benzonitrile (2): Fol-
lowing the procedure A using 1-(2-bromobenzyl)imidazole
(237 mg, 1 mmol) and 4-bromobenzonitrile (182 mg,
1.2 mmol), the residue was purified by flash chromatography
on silica gel (pentane-Et2O, 90:10) to afford the desired
compound 2; yield: 240 mg (71%). 1H NMR (400 MHz,
CDCl3): d=7.61–7.57 (m, 3H), 7.53 (d, J=7.6 Hz, 1H), 7.35
(d, J=8.3 Hz, 2H), 7.25 (s, 1H), 7.21 (t, J=7.1 Hz, 1H),
7.14 (t, J=7.5 Hz, 1H), 6.68 (d, J=7.6 Hz, 1H), 5.22 (s,
2H); 13C NMR (75 MHz, CDCl3): d=140.0, 135.2, 133.8,
132.9, 132.3, 131.4, 129.8, 129.6, 128.2, 127.9, 127.7, 122.0,
118.1, 111.2, 49.1; elemental analysis: calcd. (%) for
C17H12BrN3 (338.21): C 60.37, H 3.58; found: C 60.56, H
3.69.
All reactions were carried out under an argon atmosphere
with standard Schlenk techniques. DMA was purchased
from Acros Organics and was not purified before use.
1H NMR spectra were recorded on
a Bruker GPX
(400 MHz) spectrometer. Chemical shifts (d) are reported in
parts per million relative to residual chloroform (7.28 ppm
1
for H; 77.0 ppm for 13C), coupling constants are reported in
1
Hertz. H NMR assignment abbreviations were used as fol-
lows: singlet (s), doublet (d), triplet (t), quartet (q), doublet
of doublets (dd), doublet of triplets (dt), and multiplet (m).
13C NMR spectra were recorded at 100 MHz on the same
spectrometer and reported in ppm. All reagents were weigh-
ed and handled in air.
4-(Imidazo[2,1-a]isoindol-3-yl)benzonitrile (3): Following
the procedure B using 4-(1-(2-bromobenzyl)imidazol-5-yl)-
benzonitrile (2) (150 mg, 0.44 mmol), the residue was puri-
fied by flash chromatography on silica gel (pentane-Et2O,
90:10) to afford the desired compound 3; yield: 98 mg
Preparation of the PdCl(C3H5)(dppb) Catalyst[24]
An oven-dried 40-mL Schlenk tube equipped with a magnet-
ic stirring bar under argon atmosphere, was charged with
[Pd(C3H5)Cl]2 (182 mg, 0.5 mmol) and dppb (426 mg,
1 mmol). 10 mL of anhydrous dichloromethane were added,
then, the solution was stirred at room temperature for
twenty minutes. The solvent was removed in vacuum. The
powder was used without purification; 31P NMR (381 MHz,
CDCl3): d=19.3 (s).
1
(86%). H NMR (400 MHz, CDCl3): d=7.92 (d, J=7.4 Hz,
1H), 7.75–7.70 (m, 4H), 7.66 (s, 1H), 7.57–7.48 (m, 2H),
7.43 (t, J=7.5 Hz, 1H), 5.14 (s, 2H); 13C NMR (100 MHz,
CDCl3): d=156.1, 141.5, 134.3, 133.3, 132.9, 129.3, 129.0,
128.9, 128.2, 124.3, 123.5, 120.4, 118.7, 110.2, 50.1; elemental
analysis: calcd. (%) for C17H11N3 (257.30): C 79.36, H 4.31;
found: C 79.59, H 4.09.
Procedure A (Direct Intermolecular Arylation of
Imidazoles)
1-(2-Bromobenzyl)-5-(4-nitrophenyl)imidazole (4): Fol-
lowing the procedure A using 1-(2-bromobenzyl)imidazole
(237 mg, 1 mmol) and 1-bromo-4-nitrobenzene (242 mg,
1.2 mmol), the residue was purified by flash chromatography
on silica gel (pentane-Et2O, 75:25) to afford the desired
compound 4; yield: 229 mg (64%). 1H NMR (400 MHz,
CDCl3): d=8.22 (d, J=8.4 Hz, 2H), 7.66 (s, 1H), 7.61 (dd,
J=1.6 and 7.7 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (s,
1H), 7.28 (dt, J=1.6 and 7.2 Hz, 1H), 7.21 (ddd, J=1.7, 7.3
and 7.9 Hz, 1H), 6.74 (d, J=7.7 Hz, 1H), 5.29 (s, 2H);
13C NMR (100 MHz, CDCl3): d=147.2, 140.6, 136.0, 135.4,
133.3, 131.4, 130.6, 130.0, 128.5, 128.2, 127.9, 124.2, 122.3,
49.5; elemental analysis: calcd. (%) for C16H12BrN3O2
(358.20): C 53.65, H 3.38; found: C 53.96, H 3.57.
To a 5-mL oven-dried Schlenk tube, aryl bromide (1 mmol),
imidazole derivative (1.5 mmol), KOAc (0.196 g, 2 mmol),
DMA (2 mL) and Pd(OAc)2 (2.2 mg, 0.01 mmol) were suc-
cessively added. The reaction mixture was evacuated by
vacuum-argon cycles (5 times) and stirred at 1508C (oil bath
temperature) for 16 h (see Tables and Schemes). After cool-
ing the reaction mixture to room temperature and concen-
tration, the crude mixture was purified by silica column
chromatography to afford the desired arylated products.
3-(4-Nitrophenyl)imidazo[2,1-a]isoindole (5): Following
the procedure B using 1-(2-bromobenzyl)-5-(4-nitrophenyl)-
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Intermolecular versus Intramolecular Palladium-Catalyzed Direct Arylations
imidazole (4) (150 mg, 0.42 mmol), the residue was purified
by flash chromatography on silica gel (pentane-Et2O, 90:10)
to afford the desired compound 5; yield: 84 mg (72%).
1H NMR (400 MHz, CDCl3): d=8.33 (d, J=8.8 Hz, 2H),
7.95 (d, J=7.7 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.74 (s,
1H), 7.58 (d, J=7.4 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.46
(t, J=7.4 Hz, 1H), 5.20 (s, 2H); 13C NMR (100 MHz,
CDCl3): d=156.5, 146.1, 141.5, 136.2, 134.0, 129.3, 129.0,
128.8, 128.4, 124.7, 124.2, 123.5, 120.6, 50.2; elemental analy-
sis: calcd. (%) for C16H11N3O2 (277.28): C 69.31, H 4.00;
found: C 69.54, H 4.29.
3-[1-(2-Bromobenzyl)imidazol-5-yl]benzonitrile (6): Fol-
lowing the procedure A using 1-(2-bromobenzyl)imidazole
(237 mg, 1 mmol) and 3-bromobenzonitrile (182 mg,
1.2 mmol), the residue was purified by flash chromatography
on silica gel (pentane-Et2O, 90:10) to afford the desired
compound 6; yield: 226 mg (67%). 1H NMR (300 MHz,
CDCl3): d=7.53 (s, 1H), 7.50–7.44 (m, 3H), 7.43–7.36 (m,
2H), 7.15–7.11 (m, 2H), 7.06 (dt, J=1.9 and 7.7 Hz, 1H),
6.64 (d, J=7.8 Hz, 1H), 5.14 (s, 2H); 13C NMR (100 MHz,
CDCl3): d=139.4, 135.0, 132.6, 132.1, 131.3, 131.0, 130.7,
130.5, 129.4, 129.3, 129.1, 127.8, 127.7, 121.9, 117.7, 112.6,
48.8; elemental analysis: calcd. (%) for C17H12BrN3 (338.21):
C 60.37, H 3.58; found: C 60.12, H 3.75.
110.1, 49.6; elemental analysis: calcd. (%) for C17H11N3
(257.30): C 79.36, H 4.31; found: C 79.41, H 4.68.
3-[4-(Trifluoromethyl)phenyl]imidazo[2,1-a]isoindole
(10): Following the procedure A using 1-(2-bromobenzyl)-
imidazole (237 mg, 1 mmol) and 4-bromobenzotrifluoride
(168 mL, 1.2 mmol), the residue was purified by flash chro-
matography on silica gel (pentane-Et2O, 95:5) to afford the
desired compound 10; yield: 186 mg (62%). 1H NMR
(400 MHz, CDCl3): d=7.92 (d, J=7.5 Hz, 1H), 7.75–7.69
(m, 4H), 7.62 (s, 1H), 7.56–7.48 (m, 2H), 7.42 (t, J=7.6 Hz,
1H), 5.14 (s, 2H); 13C NMR (100 MHz, CDCl3): d=141.5,
133.6, 132.3, 129.6, 129.3 (q, J=33.5 Hz), 129.1, 128.8, 128.8,
128.0, 126.1 (d, J=3.2 Hz), 124.4, 124.1 (q, J=273.5 Hz),
123.5, 120.3, 50.0; elemental analysis: calcd. (%) for
C17H11F3N2 (300.28): C 68.00, H 3.69; found: C 68.21, H
3.95.
Ethyl 4-(imidazo[2,1-a]isoindol-3-yl)benzoate (11): Fol-
lowing the procedure A using 1-(2-bromobenzyl)imidazole
(237 mg, 1 mmol) and ethyl 4-bromobenzoate (196 mL,
1.2 mmol), the residue was purified by flash chromatography
on silica gel (pentane-Et2O, 85:15) to afford the desired
compound 11; yield: 204 mg (67%). 1H NMR (400 MHz,
CDCl3): d=8.14 (d, J=8.1 Hz, 2H), 7.92 (d, J=7.3 Hz, 1H),
7.70 (d, J=8.1 Hz, 2H), 7.65 (s, 1H), 7.56–7.47 (m, 2H),
7.41 (dd, J=6.9 and 8.1 Hz, 1H), 5.15 (s, 2H), 4.43 (q, J=
7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=166.1, 155.5, 141.6, 134.2, 132.5, 130.4, 129.9,
129.6, 128.8, 128.8, 127.9, 123.8, 123.4, 120.3, 61.1, 50.0, 14.4;
elemental analysis: calcd. (%) for C19H16N2O2 (304.35): C
74.98, H 5.30; found: C 75.22, H 5.48.
3-(Imidazo[2,1-a]isoindol-3-yl)benzonitrile (7): Following
the procedure B using 3-[1-(2-bromobenzyl)imidazol-5-yl]-
benzonitrile (6) (150 mg, 0.44 mmol), the residue was puri-
fied by flash chromatography on silica gel (pentane-Et2O,
90:10) to afford the desired compound 7; yield: 96 mg
1
(84%). H NMR (400 MHz, CDCl3): d=7.88 (d, J=7.2 Hz,
1H), 7.85–7.82 (m, 2H), 7.59–7.56 (m, 3H), 7.54 (d, J=
7.1 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.41 (t, J=7.5 Hz, 1H),
5.10 (s, 2H); 13C NMR (100 MHz, CDCl3): d=155.6, 141.5,
132.2, 131.4, 130.3, 130.0, 129.4, 128.8, 128.6, 128.4, 128.1,
127.3, 123.5, 120.3, 118.5, 113.5, 49.8; elemental analysis:
calcd. (%) for C17H11N3 (257.30): C 79.36, H 4.31; found: C
79.11, H 4.54.
2-[1-(2-Bromobenzyl)imidazol-5-yl]benzonitrile (8): Fol-
lowing the procedure A using 1-(2-bromobenzyl)imidazole
(237 mg, 1 mmol) and 2-bromobenzonitrile (182 mg,
1.2 mmol), the residue was purified by flash chromatography
on silica gel (pentane-Et2O, 90:10) to afford the desired
compound 8; yield: 192 mg (57%). 1H NMR (300 MHz,
CDCl3): d=7.69 (dd, J=1.6 and 7.7 Hz, 1H), 7.62 (s, 1H),
7.55 (dt, J=1.5 and 7.7 Hz, 1H), 7.45 (tt, J=1.7 and 7.7 Hz,
2H), 7.31–7.27 (m, 2H), 7.20 (dt, J=1.5 and 7.5 Hz, 1H),
7.09 (dt, J=1.8 and 7.7 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H),
5.17 (s, 2H); 13C NMR (75 MHz, CDCl3): d=139.4, 135.0,
133.3, 132.9, 132.8, 132.5, 130.7, 130.6, 129.6, 128.9, 128.7,
128.5, 127.8, 122.4, 117.4, 113.4, 49.1; elemental analysis:
calcd. (%) for C17H12BrN3 (338.21): C 60.37, H 3.58; found:
C 60.42, H 3.69.
4-(Imidazo[2,1-a]isoindol-3-yl)benzaldehyde (12): Follow-
ing the procedure A using 1-(2-bromobenzyl)imidazole
(237 mg, 1 mmol) and 4-bromobenzaldehyde (222 mg,
1.2 mmol), the residue was purified by flash chromatography
on silica gel (pentane-Et2O, 85:15) to afford the desired
compound 12; yield: 184 mg (71%). 1H NMR (400 MHz,
CDCl3): d=10.04 (s, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.94 (d,
J=7.6 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.72 (s, 1H), 7.56
(t, J=7.7 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 7.44 (dd, J=7.3
and 7.7 Hz, 1H), 5.19 (s, 2H); 13C NMR (100 MHz, CDCl3):
d=191.1, 156.0, 141.6, 135.7, 134.7, 133.3, 130.6, 129.6, 129.5,
128.8, 128.1, 124.3, 123.4, 120.4, 50.2; elemental analysis:
calcd. (%) for C17H12N2O (260.30): C 78.44, H 4.65; found:
C 78.81, H 4.67.
1-[4-(Imidazo[2,1-a]isoindol-3-yl)phenyl]propan-1-one
(13): Following the procedure A using 1-(2-bromobenzyl)-
imidazole (237 mg, 1 mmol) and 4’-bromopropiophenone
(256 mg, 1.2 mmol), the residue was purified by flash chro-
matography on silica gel (pentane-Et2O, 85:15) to afford the
desired compound 13; yield: 213 mg (74%). 1H NMR
(300 MHz, CDCl3): d=8.03 (d, J=8.1 Hz, 2H), 7.89 (d, J=
7.5 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.63 (s, 1H), 7.51 (d,
J=7.8 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.39 (dd, J=7.0
and 7.6 Hz, 1H), 5.09 (s, 2H), 3.01 (q, J=7.2 Hz, 2H), 1.25
(t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=199.7,
155.5, 141.6, 135.1, 134.2, 132.6, 129.7, 129.5, 128.9, 128.7,
127.9, 123.9, 123.4, 120.2, 50.0, 31.7, 8.3; elemental analysis:
calcd. (%) for C19H16N2O (288.35): C 79.14, H 5.59; found:
C 79.27, H 5.74.
3-(Imidazo[2,1-a]isoindol-3-yl)benzonitrile (9): Following
the procedure B using 2-[1-(2-bromobenzyl)imidazol-5-yl]-
benzonitrile (8) (150 mg, 0.44 mmol), the residue was puri-
fied by flash chromatography on silica gel (pentane-Et2O,
90:10) to afford the desired compound 9; yield: 92 mg
1
(81%). H NMR (400 MHz, CDCl3): d=7.89 (d, J=7.5 Hz,
1H), 7.79 (d, J=7.7 Hz, 1H), 7.71–7.60 (m, 3H), 7.48–7.42
(m, 3H), 7.40–7.36 (m, 1H), 5.05 (s, 2H); 13C NMR
(100 MHz, CDCl3): d=155.6, 141.6, 134.4, 133.4, 133.2,
129.6, 128.7, 128.1, 127.9, 127.6, 127.2, 123.4, 120.3, 118.6,
1-[3-(Imidazo[2,1-a]isoindol-3-yl)phenyl]ethan-1-one (14):
Following the procedure A using 1-(2-bromobenzyl)imida-
zole (237 mg, 1 mmol) and 3’-bromoacetophenone (239 mg,
Adv. Synth. Catal. 2015, 357, 2869 – 2882
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Xiaowen Xu et al.
1.2 mmol), the residue was purified by flash chromatography
2-methylimidazol-5-yl]benzonitrile
(18)
(150 mg,
on silica gel (pentane-Et2O, 85:15) to afford the desired
compound 14; yield: 162 mg (59%). 1H NMR (300 MHz,
CDCl3): d=8.18 (t, J=1.7 Hz, 1H), 7.86 (t, J=8.1 Hz, 2H),
7.82–7.77 (m, 1H), 7.56 (s, 1H), 7.55–7.42 (m, 3H), 7.37 (t,
J=7.3 Hz, 1H), 5.10 (s, 2H), 2.66 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=197.6, 155.0, 141.6, 137.8, 131.5, 130.7,
129.8, 129.7, 129.3, 128.8, 128.6, 127.8, 127.1, 123.4, 120.1,
49.8, 26.6; elemental analysis: calcd. (%) for C18H14N2O
(274.32): C 78.81, H 5.14; found: C 79.04, H 4.86.
1-[5-(Imidazo[2,1-a]isoindol-3-yl)thiophen-2-yl]ethan-1-
one (15): Following the procedure A using 1-(2-bromoben-
zyl)imidazole (237 mg, 1 mmol) and 1-(5-bromothiophen-2-
yl)ethan-1-one (246 mg, 1.2 mmol), the residue was purified
by flash chromatography on silica gel (pentane-Et2O, 85:15)
to afford the desired compound 15; yield: 233 mg (83%).
1H NMR (400 MHz, CDCl3): d=7.93 (d, J=7.5 Hz, 1H),
7.69 (d, J=4.0 Hz, 1H), 7.65 (s, 1H), 7.57 (d, J=7.5 Hz,
1H), 7.52 (t, J=7.4 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.29
(d, J=4.0 Hz, 1H), 5.10 (s, 2H), 2.60 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=190.2, 155.1, 141.8, 141.8, 140.2,
133.4, 132.7, 129.4, 128.8, 128.1, 125.0, 123.6, 122.7, 120.5,
49.5, 26.5; elemental analysis: calcd. (%) for C16H12N2OS
(280.34): C 68.55, H 4.31; found: C 68.86, H 4.12.
3-(Isoquinolin-4-yl)imidazo[2,1-a]isoindole (16): Follow-
ing the procedure A using 1-(2-bromobenzyl)imidazole
(237 mg, 1 mmol) and 4-bromoisoquinoline (249 mg,
1.2 mmol), the residue was purified by flash chromatography
on silica gel (pentane-Et2O, 65:35) to afford the desired
compound 16; yield: 173 mg (61%). 1H NMR (400 MHz,
CDCl3): d=9.27 (s, 1H), 8.38 (s, 1H), 8.03 (d, J=7.6 Hz,
1H), 7.76 (s, 1H), 7.71–7.68 (m, 2H), 7.67–7.62 (m, 1H),
7.40 (d, J=7.9 Hz, 1H), 7.12 (t, J=7.7 Hz, 1H), 7.05 (t, J=
7.7 Hz, 1H), 6.67 (d, J=7.5 Hz, 1H), 5.05 (s, 2H); 13C NMR
(75 MHz, CDCl3): d=153.4, 144.6, 139.1, 135.4, 135.1, 132.9,
131.1, 130.9, 129.6, 128.9, 128.2, 127.9, 127.7, 127.6, 127.4,
124.3, 122.8, 120.9, 49.3; elemental analysis: calcd. (%) for
C19H13N3 (283.33): C 80.54, H 4.62; found: C 80.86, H 4.67.
3-Methylimidazo[5,1-a]isoindole (17): Following the pro-
0.55 mmol), the residue was purified by flash chromatogra-
phy on silica gel (pentane) to afford the desired compound
19; yield: 130 mg (87%). H NMR (400 MHz, CDCl3): d=
1
7.92 (s, 1H), 7.60 (s, 2H), 7.52 (t, J=7.4 Hz, 1H), 7.48 (dt,
J=1.9 and 7.2 Hz, 1H), 7.45–7.37 (m, 2H), 7.22 (s, 1H),
4.98 (d, J=14.2 Hz, 1H), 4.79 (d, J=14.1 Hz, 1H), 2.56 (s,
3H); 13C NMR (100 MHz, CDCl3): d=144.8, 137.8, 136.7,
136.1, 134.1, 133.7, 131.2, 131.1, 130.7, 129.4, 129.4, 129.1,
127.8, 126.6, 118.6, 111.3, 48.0, 13.2; elemental analysis:
calcd. (%) for C18H13N3 (271.32): C 79.68, H 4.83; found: C
79.74, H 4.81.
1-(2-Bromobenzyl)-2-methyl-5-(4-nitrophenyl)imidazole
(20): Following the procedure A using 1-(2-bromobenzyl)-2-
methylimidazole (377 mg, 1.5 mmol) and 1-bromo-4-nitro-
benzene (242 mg, 1.2 mmol), the residue was purified by
flash chromatography on silica gel (pentane-Et2O, 70:30) to
afford the desired compound 20; yield: 190 mg (51%).
1H NMR (300 MHz, CDCl3): d=8.16 (d, J=8.7 Hz, 2H),
7.62 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.31–7.25
(m, 2H), 7.21 (t, J=8.0 Hz, 1H), 6.56 (d, J=7.6 Hz, 1H),
5.16 (s, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
148.3, 146.9, 136.5, 135.2, 133.2, 131.7, 129.6, 129.0, 128.3,
128.0, 126.5, 124.2, 121.6, 48.3, 13.5; elemental analysis:
calcd. (%) for C17H14BrN3O2 (372.22): C 54.86, H 3.79;
found: C 54.97, H 3.86.
7-Methyl-2-nitrodibenzo[c,e]imidazo[1,5-a]azepine (21):
Following the procedure
B
using 1-(2-bromobenzyl)-2-
methyl-5-(4-nitrophenyl)imidazole
(20) (150 mg,
0.40 mmol), the residue was purified by flash chromatogra-
phy on silica gel (pentane) to afford the desired compound
21; yield: 73 mg (63%). 1H NMR (300 MHz, CDCl3): d=
8.54 (s, 1H), 8.28 (d, J=8.7 Hz, 1H), 7.76 (d, J=8.3 Hz,
1H), 7.63 (d, J=6.6 Hz, 1H), 7.56–7.40 (m, 3H), 7.29 (s,
1H), 5.02 (d, J=13.4 Hz, 1H), 4.83 (d, J=13.7 Hz, 1H),
2.58 (s, 3H); 13C NMR (100 MHz, CDCl3): d=146.8, 145.0,
137.7, 136.7, 135.9, 135.3, 130.8, 129.5, 129.4, 129.2, 127.8,
127.1, 125.5, 122.9, 48.0, 13.2; elemental analysis: calcd. (%)
for C17H13N3O2 (291.31): C 70.09, H 4.50; found: C 70.23, H
4.87.
cedure
A
using 1-(2-bromobenzyl)-2-methylimidazole
(251 mg, 1 mmol), the residue was purified by flash chroma-
tography on silica gel (pentane-Et2O, 80:20) to afford the
desired compound 17; yield: 131 mg (77%). 1H NMR
(400 MHz, CDCl3): d=7.51 (d, J=7.6 Hz, 1H), 7.42–7.30
(m, 2H), 7.24–7.17 (m, 1H), 7.07 (s, 1H), 4.82 (s, 2H), 2.43
(s, 3H). This is a known compound and the spectral data are
identical to those reported in literature.[25]
4-[1-(2-Bromobenzyl)-2-methylimidazol-5-yl]benzonitrile
(18): Following the procedure A using 1-(2-bromobenzyl)-2-
methyl-1H-imidazole (377 mg, 1.5 mmol) and 4-bromoben-
zonitrile (218 mg, 1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 90:10) to
afford the desired compound 18; yield: 214 mg (61%).
1H NMR (400 MHz, CDCl3): d=7.65–7.58 (m, 3H), 7.33–
7.26 (m, 3H), 7.24–7.18 (m, 2H), 6.54 (d, J=7.7 Hz, 1H),
5.14 (s, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
147.9, 135.2, 134.4, 133.1, 132.6, 132.0, 129.5, 128.4, 128.2,
128.0, 126.4, 121.5, 118.4, 111.1, 48.1, 13.4; elemental analy-
sis: calcd. (%) for C18H14BrN3 (352.24): C 61.38, H 4.01;
found: C 61.65, H 4.31.
2-[1-(2-Bromobenzyl)-2-methylimidazol-5-yl]benzonitrile
(22): Following the procedure A using 1-(2-bromobenzyl)-2-
methylimidazole (377 mg, 1.5 mmol) and 2-bromobenzoni-
trile (218 mg, 1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 90:10) to
afford the desired compound 22; yield: 257 mg (73%).
1H NMR (400 MHz, CDCl3): d=7.66 (dd, J=1.4 and 7.7 Hz,
1H), 7.50 (dd, J=1.5 and 7.8 Hz, 1H), 7.47 (dt, J=1.5 and
8.1 Hz, 1H), 7.37 (dt, J=1.4 and 7.7 Hz, 1H), 7.22 (s, 1H),
7.21–7.16 (m, 2H), 7.08 (ddd, J=1.9, 7.3 and 8.1 Hz, 1H),
6.43 (dd, J=1.7 and 7.8 Hz, 1H), 5.05 (s, 2H), 2.31 (s, 3H).
13C NMR (100 MHz, CDCl3): d=147.4, 135.3, 133.7, 133.3,
132.8, 132.7, 130.4, 129.3, 129.2, 129.1, 128.7, 128.2, 126.8,
121.6, 117.7, 113.4, 47.9, 13.6; elemental analysis: calcd. (%)
for C18H14BrN3 (352.24): C 61.38, H 4.01; found: C 61.22, H
3.91.
7-Methyldibenzo[c,e]imidazo[1,5-a]azepine-4-carbonitrile
(23): Following the procedure B using 2-[1-(2-bromobenzyl)-
2-methylimidazol-5-yl]benzonitrile
(22)
(150 mg,
0.55 mmol), the residue was purified by flash chromatogra-
7-Methyldibenzo[c,e]imidazo[1,5-a]azepine-2-carbonitrile
(19): Following the procedure B using 4-[1-(2-bromobenzyl)-
phy on silica gel (pentane) to afford the desired compound
23; yield: 122 mg (82%). H NMR (400 MHz, CDCl3): d=
1
2878
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Intermolecular versus Intramolecular Palladium-Catalyzed Direct Arylations
7.84 (dd, J=4.4 and 7.8 Hz, 2H), 7.56 (s, 1H), 7.53 (d, J=
7.5 Hz, 2H), 7.49–7.37 (m, 3H), 5.00 (d, J=14.2 Hz, 1H),
4.80 (d, J=14.2 Hz, 1H), 2.58 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=144.4, 138.2, 138.1, 136.6, 134.8, 133.9, 131.7,
130.6, 129.3, 129.1, 127.9, 127.3, 126.9, 125.8, 118.9, 112.0,
47.8, 13.2; elemental analysis: calcd. (%) for C18H13N3
(271.32): C 79.68, H 4.83; found: C 79.81, H 5.07.
3-[1-(2-Bromobenzyl)-2-methylimidazol-5-yl]benzonitrile
(24): Following the procedure A using 1-(2-bromobenzyl)-2-
methylimidazole (377 mg, 1.5 mmol) and 3-bromobenzoni-
trile (218 mg, 1 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 90:10) to
afford the desired compound 24; yield: 240 mg (68%).
1H NMR (400 MHz, CDCl3): d=7.52–7.45 (m, 2H), 7.42 (s,
1H), 7.37–7.32 (m, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.10 (d, J=
8.4 Hz, 1H), 7.08 (s, 1H), 6.44 (d, J=7.8 Hz, 1H), 5.04 (s,
2H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3): d=147.4,
135.3, 133.1, 132.1, 131.6, 131.5, 131.4, 131.2, 129.7, 129.5,
128.2, 127.9, 126.5, 121.6, 118.1, 113.1, 47.9, 13.5; elemental
analysis: calcd. (%) for C18H14BrN3 (352.24): C 61.38, H
4.01; found: C 61.57, H 4.31.
chromatography on silica gel (pentane-Et2O, 75:25) to
afford the desired compound 28; yield: 256 mg (59%).
1H NMR (400 MHz, CDCl3): d=8.18 (d, J=8.7 Hz, 2H),
7.59–7.52 (m, 3H), 7.51 (s, 1H), 7.45 (d, J=8.8 Hz, 2H),
7.43–7.40 (m, 3H), 7.27 (t, J=6.6 Hz, 1H), 7.17 (t, J=
7.3 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 5.35 (s, 2H); 13C NMR
(100 MHz, CDCl3): d=151.4, 147.1, 136.4, 136.2, 133.2,
132.7, 130.6, 130.0, 129.6, 129.5, 128.8, 128.7, 128.4, 128.2,
127.2, 124.2, 121.4, 49.6; elemental analysis: calcd (%) for
C22H16BrN3O2 (434.29): C 60.84, H 3.71; found: C 61.09, H
3.95.
2-Nitro-7-phenyldibenzo[c,e]imidazo[1,5-a]azepine (29):
Following the procedure B using 1-(2-bromobenzyl)-5-(4-ni-
trophenyl)-2-phenylimidazole (28) (150 mg, 0.35 mmol), the
residue was purified by flash chromatography on silica gel
(pentane, 100) to afford the desired compound 29; yield:
1
77 mg (76%). H NMR (400 MHz, CDCl3): d=7.98 (s, 1H),
7.82 (d, J=7.6 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.68 (d, J=
7.0 Hz, 2H), 6.65–6.47 (m, 7H), 7.42 (d, J=7.0 Hz, 1H),
5.24 (d, J=14.3 Hz, 1H), 4.81 (d, J=14.1 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=147.0, 138.0, 136.8, 136.1,
135.2, 132.4, 132.3, 130.8, 130.0, 129.8, 129.5, 129.4, 129.2,
128.8, 128.7, 127.9, 125.8, 123.0, 48.4; elemental analysis:
calcd. (%) for C22H15N3O2 (353.38): C 74.78, H 4.28; found:
C 74.96, H 4.41.
2-[1-(2-Bromobenzyl)-2-phenylimidazol-5-yl]benzonitrile
(30): Following the procedure A using 1-(2-bromobenzyl)-2-
phenylimidazole (213 mg, 1 mmol) and 4-bromobenzonitrile
(182 mg, 1.2 mmol), the residue was purified by flash chro-
matography on silica gel (pentane-Et2O, 75:25) to afford the
desired compound 30; yield: 298 mg (72%). 1H NMR
(400 MHz, CDCl3): d=7.60 (d, J=8.1 Hz, 2H), 7.57–7.52
(m, 3H), 7.44 (s, 1H), 7.42–7.37 (m, 5H), 7.26 (t, J=8.2 Hz,
1H), 7.16 (t, J=7.8 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H), 5.32
(s, 2H); 13C NMR (75 MHz, CDCl3): d=150.9, 136.1, 134.3,
133.0, 132.9, 132.5, 129.9, 129.4, 129.3, 128.7, 128.6, 128.5,
128.4, 128.0, 127.1, 121.2, 118.4, 111.4, 49.3; elemental analy-
sis: calcd. (%) for C23H16BrN3 (414.31): C 66.68, H 3.89;
found: C 66.81, H 3.63.
7-Methyldibenzo[c,e]imidazo[1,5-a]azepine-3-carbonitrile
(25): Following the procedure B using 3-[1-(2-bromobenzyl)-
2-methylimidazol-5-yl]benzonitrile
(24)
(150 mg,
0.55 mmol), the residue was purified by flash chromatogra-
phy on silica gel (pentane, 100) to afford the desired com-
pound 25; yield: 113 mg (76%). 1H NMR (300 MHz,
CDCl3): d=7.90 (d, J=1.9 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H),
7.70 (d, J=6.6 Hz, 1H), 7.59–7.38 (m, 4H), 7.20 (s, 1H),
5.00 (d, J=14.3 Hz, 1H), 4.80 (d, J=14.1 Hz, 1H), 2.57 (s,
3H); 13C NMR (75 MHz, CDCl3): d=144.3, 143.2, 140.1,
138.1, 136.4, 132.3, 131.0, 130.8, 130.7, 130.5, 129.3, 129.3,
127.8, 126.0, 118.3, 112.3, 47.9, 13.2; elemental analysis:
calcd. (%) for C18H13N3 (271.32): C 79.68, H 4.83; found: C
79.73, H 5.11.
1-(10-Methylbenzo[e]imidazo[1,5-a]thieno[2,3-c]azepin-2-
yl)ethan-1-one (26): Following the procedure A using 1-(2-
bromobenzyl)-2-methylimidazole (377 mg, 1.5 mmol) and 1-
(5-bromothiophen-2-yl)ethan-1-one (246 mg, 1.2 mmol), the
residue was purified by flash chromatography on silica gel
(pentane-Et2O, 70:30) to afford the desired compound 26;
7-Phenyldibenzo[c,e]imidazo[1,5-a]azepine-2-carbonitrile
(31): Following the procedure B using 4-[1-(2-bromobenzyl)-
1
yield: 168 mg (57%). H NMR (300 MHz, CDCl3): d=7.94
2-phenyl-imidazol-5-yl]benzonitrile
(30)
(150 mg,
(s, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.50–7.35 (m, 3H), 7.21 (s,
1H), 4.93 (s, 2H), 2.63 (s, 3H), 2.57 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=190.1, 145.1, 141.7, 136.7, 135.8, 134.6,
133.9, 132.8, 129.1, 128.9, 128.4, 128.3, 126.4, 126.3, 48.8,
26.6, 13.2; elemental analysis: calcd. (%) for C17H14N2OS
(294.37): C 69.36, H 4.79; found: C 69.61, H 4.58.
0.36 mmol), the residue was purified by flash chromatogra-
phy on silica gel (pentane, 100) to afford the desired com-
pound 31; yield: 98 mg (81%). H NMR (400 MHz, CDCl3):
1
d=7.96 (s, 1H), 7.83–7.71 (m, 2H), 7.70–7.64 (m, 2H), 7.61–
7.45 (m, 7H), 7.44–7.37 (m, 1H), 5.22 (d, J=14.3 Hz, 1H),
4.79 (d, J=14.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=
148.6, 137.9, 136.7, 136.1, 134.3, 133.4, 132.5, 131.2, 130.6,
130.0, 129.5, 129.4, 129.3, 129.2, 129.2, 128.7, 128.1, 127.8,
118.5, 111.4, 48.3; elemental analysis: calcd. (%) for
C23H15N3 (333.39): C 82.86, H 4.54; found: C 83.04, H 4.81.
2-[1-(2-Bromobenzyl)-2-phenylimidazol-5-yl]benzonitrile
(32): Following the procedure A using 1-(2-bromobenzyl)-2-
phenylimidazole (213 mg, 1 mmol) and 2-bromobenzonitrile
(182 mg, 1.2 mmol), the residue was purified by flash chro-
matography on silica gel (pentane-Et2O, 75:25) to afford the
desired compound 32; yield: 278 mg (72%). 1H NMR
(400 MHz, CDCl3): d=7.67 (d, J=8.2 Hz, 1H), 7.64–7.59
(m, 2H), 7.51 (t, J=7.7 Hz, 1H), 7.45–7.38 (m, 5H), 7.36 (d,
J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.18 (dd, J=7.0
and 8.4 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 6.58 (d, J=7.7 Hz,
3-Phenylimidazo[5,1-a]isoindole (27): Following the pro-
cedure
A
using 1-(2-bromobenzyl)-2-phenylimidazole
(213 mg, 1 mmol), the residue was purified by flash chroma-
tography on silica gel (pentane-Et2O, 90:10) to afford the
desired compound 27; yield: 184 mg (79%). 1H NMR
(400 MHz, CDCl3): d=7.97 (d, J=7.8 Hz, 2H), 7.60 (d, J=
7.6 Hz, 1H), 7.52–7.45 (m, 2H), 7.44–7.36 (m, 3H), 7.35 (s,
1H), 7.28 (t, J=7.6 Hz, 1H), 5.20 (s, 2H). This is a known
compound and the spectral data are identical to those re-
ported in the literature.[26]
1-(2-Bromobenzyl)-5-(4-nitrophenyl)-2-phenylimidazole
(28): Following the procedure A using 1-(2-bromobenzyl)-2-
phenylimidazole (213 mg, 1 mmol) and 1-bromo-4-nitroben-
zene (242 mg, 1.2 mmol), the residue was purified by flash
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Xiaowen Xu et al.
1H), 5.32 (s, 2H); 13C NMR (75 MHz, CDCl3): d=150.7,
135.7, 133.3, 132.5, 132.5, 130.6, 130.2, 130.2, 129.1, 129.0,
128.8, 128.6, 128.6, 127.8, 127.5, 121.3, 117.6, 113.5, 49.0; ele-
mental analysis: calcd. (%) for C23H16BrN3 (414.31): C
66.68, H 3.89; found: C 66.57, H 4.09.
8.8 Hz, 1H), 7.43–7.39 (m, 3H), 7.39–7.31 (m, 3H), 7.30–
7.22 (m, 5H), 7.21–7.17 (m, 1H), 7.12 (t, J=7.8 Hz, 1H),
6.84 (d, J=7.8 Hz, 1H), 5.15 (s, 2H); 13C NMR (75 MHz,
CDCl3): d=148.0, 138.2, 136.7, 134.2, 132.6, 130.8, 130.5,
130.4, 130.0, 129.0, 128.9, 128.9, 128.8, 128.7, 128.6, 128.1,
127.7, 127.4, 126.8, 126.5, 121.2, 48.7; elemental analysis:
calcd. (%) for C28H21BrN2 (465.39): C 72.26, H 4.55; found:
C 72.39, H 4.86.
7-Phenyldibenzo[c,e]imidazo[1,5-a]azepine-4-carbonitrile
(33): Following the procedure B using 2-(1-(2-bromoben-
zyl)-2-phenylimidazol-5-yl)benzonitrile
(32)
(150 mg,
1-Benzyl-2,4,5-triphenylimidazole (37): Following the pro-
cedure B using 1-(2-bromobenzyl)-2,4,5-triphenylimidazole
(36) (150 mg, 0.32 mmol), the residue was purified by flash
chromatography on silica gel (pentane-Et2O, 50:50) to
afford the desired compound 37; yield: 107 mg (86%).
1H NMR (400 MHz, CDCl3): d=7.65–7.55 (m, 4H), 7.38–
7.13 (m, 14H), 6.80 (d, J=7.5 Hz, 2H), 5.11 (s, 2H). This is
a known compound and the spectral data are identical to
those reported in the literature.[27]
4,4’-[1-(2-Bromobenzyl)imidazole-2,5-diyl]dibenzonitrile
(38): 4-Bromobenzonitrile (768 mg, 4 mmol), 1-(2-bromo-
benzyl)imidazole (237 mg, 1 mmol), CsOAc (1.303 g,
4 mmol) and Pd(OAc)2 (4.4 mg, 0.02 mmol), were dissolved
in DMA (5 mL) under an argon atmosphere. The reaction
mixture was stirred at 1508C for 96 h. After evaporation of
the solvent, the residue was filtered on a silica plug and di-
rectly use as it in the next reaction
7-(4-Cyanophenyl)dibenzo[c,e]imidazo[1,5-a]azepine-2-
carbonitrile (39a) and 7-(4-cyanophenyl)dibenzo[c,e]imida-
zo[1,2-a]azepine-2-carbonitrile (39b): Following the proce-
dure B using the crude mixture of 4,4’-[1-(2-bromobenzyl)-
imidazole-2,5-diyl]dibenzonitrile (38), the residue was puri-
fied by flash chromatography on silica gel (CH2Cl2-AcOEt,
80:20) to afford a mixture of the desired compounds 39a
and 39b in a 1:1 ratio; yield: 100 mg (28%). 1H NMR
(400 MHz, CDCl3): d=8.01 (q, J=9.5 Hz, 2H), 7.89 (dt, J=
2.2 and 6.7 Hz, 3H), 7.83 (d, J=9.1 Hz, 3H), 7.80–7.74 (m,
2H), 7.72 (s, 1H), 6.69 (s, 1H), 7.67 (d, J=7.6 Hz, 2H),
7.64–7.58 (m, 3H), 7.58–7.55 (m, 1H), 7.55–7.52 (m, 1H),
7.44 (d, J=2.0 Hz, 1H), 7.41 (d, J=7.2 Hz, 2H), 7.36–7.31
(m, 2H), 5.20 (d, J=14.3 Hz, 1H), 5.02 (d, J=14.7 Hz, 1H),
4.87 (d, J=14.2 Hz, 1H), 4.79 (d, J=14.4 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=148.5, 136.9, 136.1, 134.4,
134.0, 133.1, 132.9, 132.9, 132.8, 132.7, 132.6, 132.6, 132.5,
131.4, 131.2, 130.9, 130.8, 130.7, 130.4, 130.4, 129.8, 129.6,
129.5, 129.4, 129.4, 129.1, 129.1, 129.0, 128.8, 128.3, 127.7,
127.6, 125.5, 118.3, 112.2, 112.1, 48.7, 47.4; elemental analy-
sis: calcd. (%) for C24H14N4 (358.40): C 80.43, H 3.94;
found: C 80.58, H 4.11.
0.36 mmol), the residue was purified by flash chromatogra-
phy on silica gel (pentane, 100) to afford the desired com-
1
pound 33; yield: 96 mg (79%). H NMR (400 MHz, CDCl3):
d=7.86 (t, J=7.6 Hz, 2H), 7.80 (s, 1H), 7.67 (d, J=7.2 Hz,
2H), 7.61–7.51 (m, 5H), 7.48 (d, J=8.1 Hz, 1H), 7.46 (d, J=
8.1 Hz, 1H), 7.31 d, J=6.7 Hz, 1H), 5.23 (d, J=14.2 Hz,
1H), 4.80 (d, J=14.2 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d=147.9, 138.4, 138.2, 136.8, 134.9, 134.0, 131.5, 130.6, 130.5,
130.0, 129.4, 129.3, 129.2, 129.1, 128.7, 128.1, 127.9, 127.5,
119.0, 112.2, 48.0; elemental analysis: calcd. (%) for
C23H15N3 (333.39): C 82.86, H 4.54; found: C 83.13, H 4.68.
1-{5-[1-(2-Bromobenzyl)-2-phenylimidazol-5-yl]thiophen-
2-yl}ethan-1-one (34): Following the procedure A using 1-(2-
bromobenzyl)-2-phenylimidazole (213 mg, 1 mmol) and 1-
(5-bromothiophen-2-yl)ethan-1-one (246 mg, 1.2 mmol), the
residue was purified by flash chromatography on silica gel
(pentane-Et2O, 65:35) to afford the desired compound 34;
1
yield: 245 mg (56%). H NMR (400 MHz, CDCl3): d=7.63
(dd, J=1.5 and 7.8 Hz, 1H), 7.56 (s, 1H), 7.54–5.49 (m,
3H), 7.41–7.37 (m, 3H), 7.30 (t, J=7.2 Hz, 1H), 7.22 (dt,
J=1.3 and 7.5 Hz, 1H), 6.82 (d, J=3.9 Hz, 1H), 6.77 (dd,
J=1.9 and 7.6 Hz, 1H), 5.38 (s, 2H), 2.50 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=190.0, 151.0, 143.7, 138.9, 136.1, 133.1,
132.8, 130.8, 129.8, 129.4, 129.4, 128.7, 128.4, 128.2, 127.4,
127.0, 125.7, 121.3, 49.6, 26.5; elemental analysis: calcd. (%)
for C22H17BrN2OS (437.36): C 60.42, H 3.92; found: C 60.71,
H 4.17.
1-(10-Phenylbenzo[e]imidazo[1,5-a]thieno[2,3-c]azepin-2-
yl)ethan-1-one (35): Following the procedure B using 1-{5-
[1-(2-bromobenzyl)-2-phenylimidazol-5-yl]thiophen-2-yl}-
ethan-1-one (34) (150 mg, 0.34 mmol), the residue was puri-
fied by flash chromatography on silica gel (pentane-Et2O,
75–25) to afford the desired compound 35; yield: 104 mg
1
(85%). H NMR (400 MHz, CDCl3): d=7.97 (s, 1H), 7.71–
7.66 (m, 3H), 7.57 (t, J=6.9 Hz, 2H), 7.54–7.48 (m, 2H),
7.46 (dd, J=3.7 and 6.7 Hz, 3H), 5.00 (s, 2H), 2.64 (s, 3H);
13C NMR (75 MHz, CDCl3): d=190.1, 148.8, 142.0, 136.3,
136.1, 134.8, 134.0, 132.9, 129.8, 129.3, 129.1, 128.9, 128.7,
128.6, 128.5, 128.3, 127.6, 49.4, 26.6; elemental analysis:
calcd. (%) for C22H16N2OS (356.44): C 74.13, H 4.52; found:
C 74.32, H 4.65.
1-(2-Bromobenzyl)-2,4,5-triphenylimidazole (36): To a so-
lution of 2,4,5-triphenylimidazole (500 mg, 1.69 mmol) in
DMF (10 mL) was added at 08C NaH (100 mg, 2.53 mmol,
60% in oil) and the resulting solution was stirred at the
same temperature during 1 h. Then 2-bromobenzylbromide
(505 mg, 2.03 mmol) was added to the solution and the re-
sulting solution was heated at 658C during 2 h. After com-
pleted conversion, the reaction was quenched by addition of
water (10 mL) and the product was extracted with CH2Cl2
(3”10 mL). The residue was purified by flash chromatogra-
phy on silica gel (pentane-CH2Cl2, 50:50) to afford the de-
sired compound 36; yield: 723 mg (92%). 1H NMR
(400 MHz, CDCl3): d=7.66–7.60 (m, 4H), 7.46 (d, J=
Acknowledgements
We are grateful to the “Chinese Scholarship Council” for
a grant to Z. L. and to the “Jinan University short-term over-
seas research program” for a grant to X. X. We thank CNRS
and “Rennes Metropole” for providing financial support.
References
[1] a) J. H. Rigby, R. C. Hughes, M. J. Heeg, J. Am. Chem.
Soc. 1995, 117, 7834–7835; b) S. E. Gibson, N. Guillo,
2880
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 2869 – 2882

FULL PAPERS
Intermolecular versus Intramolecular Palladium-Catalyzed Direct Arylations
M. J. Tozer, Chem. Commun. 1997, 637–638; c) L. A.
Arnold, W. Luo, R. K. Guy, Org. Lett. 2004, 6, 3005–
3007; d) J. G. Avila-Zµrraga, A. Lujan-Montelongo, A.
Covarrubias-ZfflÇiga, M. Romero-Ortega, Tetrahedron
Lett. 2006, 47, 7987–7989; e) P. A. Donets, E. V. Van
der Eycken, Org. Lett. 2007, 9, 3017–3020; f) L. Joucla,
F. Popowycz, O. Lozach, L. Meijer, B. Joseph, Helv.
Chim. Acta 2007, 90, 753–763.
na, S. Cauteruccio, A. Di Fiore, R. Rossi, Eur. J. Org.
Chem. 2008, 5436–5445.
[11] J. Roger, H. Doucet, Tetrahedron 2009, 65, 9772–9781.
[12] a) S. Pivsa-Art, T. Satoh, Y. Kawamura, M. Miura, M.
Nomura, Bull. Chem. Soc. Jpn. 1998, 71, 467–473;
b) H. A. Chiong, O. Daugulis, Org. Lett. 2007, 9, 1449–
1451; c) O. Rene, K. Fagnou, Adv. Synth. Catal. 2010,
352, 2116–2120; d) F. Shibahara, E. Yamaguchi, T.
Murai, Chem. Commun. 2010, 46, 2471–2473; e) M.
Baghbanzadeh, C. Pilger, C. O. Kappe, J. Org. Chem.
2011, 76, 8138–8142; f) M. Baloch, R. J. Roy, D. Roy,
K. Beydoun, H. Doucet, RSC Adv. 2011, 1, 1527–1536;
g) P. V. Kumar, W.-S. Lin, J.-S. Shen, D. Nandi, H. M.
Lee, Organometallics 2011, 30, 5160–5169; h) F. Bellina,
M. Lessi, C. Manzini, Eur. J. Org. Chem. 2013, 5621–
5630; i) A. Mahindra, N. Bagra, R. Jain, J. Org. Chem.
2013, 78, 10954–10959; j) S. Guo, H. V. Huynh, Organo-
metallics 2014, 33, 2004–2011; k) H. Jung, S. Bae, H.-L.
Jang, J. M. Joo, Bull. Korean Chem. Soc. 2014, 35,
3009–3014; l) A. Jakab, Z. Dalicsek, T. Soos, Eur. J.
Org. Chem. 2015, 56–59.
[2] a) J. J. Li, G. W. Gribble, Palladium in Heterocyclic
Chemistry, Pergamon, Amsterdam, 2000; b) L. Acker-
mann, Modern arylation methods, Wiley, 2009.
[3] a) F. Bellina, S. Cauteruccio, R. Rossi, Curr. Org.
Chem. 2008, 12, 774–790; b) F. Kakiuchi, T. Kochi, Syn-
thesis 2008, 3013–3039; c) L. Ackermann, R. Vicente,
A. R. Kapdi, Angew. Chem. 2009, 121, 9976–10011;
Angew. Chem. Int. Ed. 2009, 48, 9792–9826; d) F. Belli-
na, R. Rossi, Chem. Rev. 2009, 109, 1082–1146; e) F.
Bellina, R. Rossi, Tetrahedron 2009, 65, 10269–10310;
f) 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; g) T. W. Lyons, M. S. Sanford,
Chem. Rev. 2010, 110, 1147–1169; h) E. M. Beck, M. J.
Gaunt, Top. Curr. Chem. 2010, 292, 85–121; i) J. Roger,
A. L. Gottumukkala, H. Doucet, ChemCatChem 2010,
2, 20–40; j) T. Satoh, M. Miura, Synthesis 2010, 3395–
3409; k) C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem. Commun.
2010, 46, 677–685; l) S. H. Cho, J. Y. Kim, J. Kwak, S.
Chang, Chem. Soc. Rev. 2011, 40, 5068–5083; m) N.
Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius,
Angew. Chem. 2012, 124, 10382–10401; Angew. Chem.
Int. Ed. 2012, 51, 10236–10254; n) B.-J. Li, Z.-J. Shi,
Chem. Soc. Rev. 2012, 41, 5588–5598; o) M. C. White,
Synlett 2012, 23, 2746–2748; p) S. I. Kozhushkov, L. Ac-
kermann, Chem. Sci. 2013, 4, 886–896; q) M. He, J.-F.
SoulØ, H. Doucet, ChemCatChem 2014, 6, 1824–1859;
r) R. Rossi, F. Bellina, M. Lessi, C. Manzini, Adv.
Synth. Catal. 2014, 356, 17–117; s) K. Yuan, J.-F. SoulØ,
H. Doucet, ACS Catal. 2015, 5, 978–991.
[4] a) H. S. Lee, S. H. Kim, S. Gowrisankar, J. N. Kim, Tet-
rahedron 2008, 64, 7183–7190; b) B. Delest, J.-Y. Tisser-
and, J.-M. Robert, M.-R. Nourrisson, P. Pinson, M.
Duflos, G. Le Baut, P. Renard, B. Pfeiffer, Tetrahedron
2004, 60, 6079–6083; c) N. Arai, M. Takahashi, M.
Mitani, A. Mori, Synlett 2006, 3170–3172; d) B. Lie-
gault, D. Lapointe, L. Caron, A. Vlassova, K. Fagnou,
J. Org. Chem. 2009, 74, 1826–1834; e) J. Koubachi, S.
Berteina-Raboin, A. Mouaddib, G. Guillaumet, Tetra-
hedron 2010, 66, 1937–1946; f) J. K. Laha, G. D. Cuny,
J. Org. Chem. 2011, 76, 8477–8482.
[13] F. Shibahara, T. Yamauchi, E. Yamaguchi, T. Murai, J.
Org. Chem. 2012, 77, 8815–8820.
[14] A. Takfaoui, L. Zhao, R. Touzani, J.-F. SoulØ, P. H. Dix-
neuf, H. Doucet, Tetrahedron 2014, 70, 8316–8323.
[15] a) F. Bellina, S. Cauteruccio, R. Rossi, Eur. J. Org.
Chem. 2006, 1379–1382; b) F. Bellina, C. Calandri, S.
Cauteruccio, R. Rossi, Tetrahedron 2007, 63, 1970–
1980; c) R. A. Altman, E. D. Koval, S. L. Buchwald, J.
Org. Chem. 2007, 72, 6190–6199; d) H.-Q. Do, R. M. K.
Khan, O. Daugulis, J. Am. Chem. Soc. 2008, 130,
15185–15192; e) J. Huang, J. Chan, Y. Chen, C. J.
Borths, K. D. Baucom, R. D. Larsen, M. M. Faul, J.
Am. Chem. Soc. 2010, 132, 3674–3675; f) B. Liegault, I.
Petrov, S. I. Gorelsky, K. Fagnou, J. Org. Chem. 2010,
75, 1047–1060; g) B. Liu, X. Qin, K. Li, X. Li, Q. Guo,
J. Lan, J. You, Chem. Eur. J. 2010, 16, 11836–11839;
h) F. Shibahara, E. Yamaguchi, T. Murai, J. Org. Chem.
2011, 76, 2680–2693; i) C. G. Baumann, S. De Ornellas,
J. P. Reeds, T. E. Storr, T. J. Williams, I. J. S. Fairlamb,
Tetrahedron 2014, 70, 6174–6187; j) T. Yamauchi, F. Shi-
bahara, T. Murai, J. Org. Chem. 2014, 79, 7185–7192.
[16] a) Y. Xu, L. Zhao, Y. Li, H. Doucet, Adv. Synth. Catal.
2013, 355, 1423–1432; b) I. Smari, L. Zhao, K. Yuan,
H. B. Ammar, H. Doucet, Catal. Sci. Technol. 2014, 4,
3723–3732; c) A. Takfaoui, L. Zhao, R. Touzani, P. H.
Dixneuf, H. Doucet, Tetrahedron Lett. 2014, 55, 1697–
1701; d) L. Zhao, T. Yan, C. Bruneau, H. Doucet,
Catal. Sci. Technol. 2014, 4, 352–360.
[5] T. Kuroda, F. Suzuki, Tetrahedron Lett. 1991, 32, 6915–
6918.
[17] G. Song, Y. Su, X. Gong, K. Han, X. Li, Org. Lett.
2011, 13, 1968–1971.
[6] K. C. Majumdar, P. Debnath, A. Taher, A. K. Pal, Can.
J. Chem. 2008, 86, 325–332.
[7] J. K. Laha, N. Dayal, S. Singh, R. Bhimpuria, Eur. J.
[18] S. I. Gorelsky, Coord. Chem. Rev. 2013, 257, 153–164.
[19] D. Lapointe, K. Fagnou, Chem. Lett. 2010, 39, 1118–
1126.
Org. Chem. 2014, 5469–5475.
[20] B. U. W. Maes, S. Verbeeck, T. Verhelst, A. EkomiØ, N.
von Wolff, G. Lef›vre, E. A. Mitchell, A. Jutand,
Chem. Eur. J. 2015, 21, 7858–7865.
[21] a) F. d’OrlyØ, A. Jutand, Tetrahedron 2005, 61, 9670–
9678; b) C. Amatore, A. Jutand, F. Lemaître, J. L.
Ricard, S. Kozuch, S. Shaik, J. Organomet. Chem. 2004,
689, 3728–3734; c) C. Amatore, A. Jutand, M. A.
M’Barki, Organometallics 1992, 11, 3009–3013.
[8] Y. Huang, W. Chen, D. Zhao, C. Chen, H. Yin, L.
Zheng, M. Jin, S. Han, Chin. J. Chem. 2013, 31, 1007–
1010.
[9] F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi, S.
Viel, J. Org. Chem. 2005, 70, 3997–4005.
[10] a) F. Bellina, S. Cauteruccio, A. Di Fiore, C. Marchetti,
R. Rossi, Tetrahedron 2008, 64, 6060–6072; b) F. Belli-
Adv. Synth. Catal. 2015, 357, 2869 – 2882
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2881

FULL PAPERS
Xiaowen Xu et al.
[22] D. Garcia-Cuadrado, P. de Mendoza, A. A. C. Braga, F.
Maseras, A. M. Echavarren, J. Am. Chem. Soc. 2007,
129, 6880–6886.
[25] Y. Xiao, L. Zhang, Org. Lett. 2012, 14, 4662–4665.
[26] F. Aldabbagh, M. A. Clyne, Lett. Org. Chem. 2006, 3,
510–513.
[23] C. Amatore, A. Jutand, A. Thuilliez, Organometallics
2001, 20, 3241–3249.
[24] T. Cantat, E. GØnin, C. Giroud, G. Meyer, A. Jutand, J.
[27] S. Samai, G. C. Nandi, P. Singh, M. S. Singh, Tetrahe-
dron 2009, 65, 10155–10161.
Organomet. Chem. 2003, 687, 365–376.
2882
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 2869 – 2882