Direct imidation to construct 1H-benzo[d]imidazole through Pd II-catalyzed C-H activation promoted by thiourea

Article abstract of DOI:10.1002/chem.200900154

A study was conducted to demonstrate the development of a method to construct 1H-benzo[d]immidazole through Pd^II -catalyzed intermolecular C-H activation starting from N-phenylbenziimidamide. The detailed mechanism investigations indicated that a palladacycle monomer or dimer was the key intermediate for this transformation, demonstrating that thiourea was first used to influence the efficiency of C-H activation. The method was found to construct 1H-benzo[d]immidazole through Pd^II -catalyzed intermolecular C-H activation extending the substrate scope widely. It also demonstrated the introduction of thiourea (tetramethylthiourea) (TMTU) for the first time as an additive to promote the efficiency of Pd^II catalysis for the direct C-H transformation. N-phenylbenziimidamide was also readily synthesized through the addition of aniline to benzonitrile according to the method to conduct the investigations.

Full text of DOI:10.1002/chem.200900154

DOI: 10.1002/chem.200900154
Direct Imidation to Construct 1H-Benzo[d]imidazole through PdII-Catalyzed
À
C H Activation Promoted by Thiourea
Qing Xiao, Wen-Hua Wang, Gang Liu, Fan-Ke Meng, Jia-Hua Chen, Zhen Yang,* and
Zhang-Jie Shi*[a]
A novel and straightforward method to construct 1H-ben-
zo[d]imidazole was developed b means of PdII-catalyzed in-
which not only the substrate scope was widely extended, but
also thiourea (tetramethylthiourea, TMTU) was introduced
À
tramolecular C H activation starting from readily available
for the first time as an additive to promote the efficiency of
II
À
N-phenylbenzimidamide. The detailed mechanism studies
indicated that a palladacycle monomer or dimer is the key
intermediate for this transformation and thiourea was first
the Pd catalysis for the direct C H transformation.
1H-benzo[d]imidazole (1a) is a unique structural unit of
many natural products and synthetic drugs.[5] This scaffold
can be obtained starting from benzene-1,2-diamine and its
derivatives.[6] Very recently, Ma and Buchwald made signifi-
cant contributions to constructing this useful scaffold
through Pd- or Cu-catalyzed tandem reactions starting from
amines and ortho-haloacetanilides,[7] which are readily avail-
able through the developed highly selective halogenation of
acetanilides.[8] Undoubtedly, the most straightforward
À
used to prompt the efficiency of C H activation.
Much attention has been paid to C N formation in the
past two decades. Many useful methods have been devel-
À
À
oped to construct C N bonds through transition-metal-cata-
lyzed amination/amidation from aryl halides.[1] Very recent-
À
ly, new methods have been developed to construct C N
bonds intra/intermolecularly through direct aromatic C H
functionalization. Among these investigations, Buchwald
and co-workers pioneered studies to construct a carbazole
À
À
method to construct this scaffold is to construct C N bond
À
directly through highly selective C H activation from the
II
À
core structure through Pd -catalyzed intramolecular C H
aniline derivatives (Scheme 1).
activation.[2] Shortly afterwards, Che, Yu, and co-workers re-
II
À
ported the intermolecular C N formation through Pd - or
II
[3]
À
Cu -catalyzed C H functionalization, respectively. When
we were preparing this manuscript, Buchwald and co-work-
À
ers reported a novel Cu-catalyzed direct C H functionaliza-
tion to produce benzimidazoles similar to our design. In
their report, steric hindered benzimidamides showed the ex-
cellent reactivities to facilitate this transformation.[4] Herein
À
Scheme 1. New strategies to construct benzoimidazole through C H acti-
vation.
we report a new method to construct 1H-benzo[d]imidazole
II
À
through Pd -catalyzed intramolecular C N formation, in
N-Arylbenzimidamide 2 was readily synthesized through
the addition of aniline to benzonitrile according to the refer-
enced method.[9] To verify our supposition, we first conduct-
ed the stoichiometric reaction starting from 2a in the pres-
ence of one equivalent of PdCl2. Gratifyingly, the palladacy-
cle dimer 3 was obtained, the structure of which was further
determined by X-ray crystallography. This dimer could fur-
ther undergo reductive elimination to form the designed
product 1a in DMSO in low yield in the presence of
NaOAc with the recovery of the starting material 2a in the
absence of any oxidants (Scheme 2). Although the efficiency
[a] Q. Xiao, W.-H. Wang, G. Liu, F.-K. Meng, Prof. Dr. J.-H. Chen,
Dr. Z. Yang, Prof. Dr. Z.-J. Shi
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of the Ministry of Education
College of Chemistry and Green Chemistry Center
Peking University, Beijing 100871,
Fax : (+86)106-276-0890
E-mail: zshi@pku.edu.cn
zyang@pku.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900154. It contains experi-
mental details and spectral data for products and some substrates.
7292
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Chem. Eur. J. 2009, 15, 7292 – 7296

COMMUNICATION
stronger electron-withdrawing
groups, such as nitro and CN,
completely shut down the trans-
formation. Aliphatic nitriles
and guanine derivatives were
not fit for this transformation
(entry 9). No observation of the
desired product 1k from N’-
phenylated N-phenylbenzimida-
mide 2k indicated that both
À
free N H groups are necessary
for this process.
Different aniline derivatives
were also surveyed (Table 3).
Similarly, electron-rich func-
tionalities were beneficial for
Scheme 2. First try towards 1a with stoichiometric palladacycle dimer 3.
of this transformation was quite low, we assumed that it is
theoretically reasonable to synthesize 1H-benzo[d]imida-
Table 1. Phenylation of 1a under different conditions.[a]
zoles (1) starting from N-phenylbenzimidamides (2) through
II
À
Pd -catalyzed, direct C H transformation directed by the
imino group with proper oxidants on the basis of these
ACHTUNGTRENNUNG
Cat. (10 mol%)
None
[O]
Additive
Solvent 2a
[%][c]
(1.0 equiv)[b] (20 mol%)
1
2
3
4
5
Cu
O2
Cu
O2
Cu
O2
N
TMTU
TMTU
TMTU
TMTU
TMTU
NMP
NMP
NMP
NMP
NMP
15
16
29
37
60
CTHUNGTRENNUNG
ACHTUNGTRENNUNG
Pd
Pd
U
N-methyl-2-pyrrolidone). During this transformation,
TMTU was used for the first time to promote the efficiency
À
in C H transformation as an additive, although thiourea has
A
CHTNUTRGENN(UG CH3CN)2] CuACHUTNGTRENNUNG
been broadly used as a ligand in different transformations.[10]
The yield decreased dramatically in the absence of TMTU,
which may arise from the stabilizing ability of TMTU to
O2
Cu
O2
A
U
ACHTUNGERTN(NUNG OAc)2/
PdII species (cf. entries 5 and 13). Interestingly, Cu
ACTHNUTRGEN(UNG OAc)2
6
7
8
A
(PhCN)2]
1,4-quinone TMTU
oxone
NMP
NMP
NMP
NMP
NMP
NMP
NMP
<5
10
21
7
6
<5
58
N
TMTU
TMTU
TMTU
TMTU
TMTU
TMTU
itself could promote this transformation, but the efficiency
was very low under our developed conditions (entry 1). It is
of great importance to note that DMSO is also a suitable
solvent and the desired product could be obtained in a good
yield. However, the impurity (dimethylsulfone) from DMSO
could not be separated after many trials (entry 20). Other
palladium species lowered the catalytic efficiency more or
less. Furthermore, different organic and inorganic oxidants
were tested, but failed for this transformation. In addition,
the catalyst loading could be decreased to 5 mol% with a
slightly lower yield.
The influence of substitutions on the nitrile moiety was
first investigated (Table 2). Only electron-donating groups
on phenyl ring were compatible with this transformation
(entries 2–7). When a strong electron-donating group was
introduced to benzonitrile fragment, the efficiency was en-
hanced even at low temperature (entries 4–6). The steric
effect did not affect the efficiency of this transformation. In
addition, ortho-substituents promoted the yield (entry 2). It
G
Cu
Cu
Cu
ACHTUNGERTN(NUNG OTf)2
ACHTUNGTRENNUNG
[e]
9
E
10
11
12
R
G
E
O2 (1 atm)
[f]
A
Cu
O2
Cu
O2
Cu
O2
Cu
O2
Cu
O2
Cu
O2
Cu
O2
Cu
O2
Cu
O2
N
/
13
14
15
16
17
18
19
20[d]
A
(PhCN)2]
none
NMP
30
E
TMTU
TMTU
TMTU
TMTU
TMTU
None
sBuOH <5
toluene <5
CH3CN 24
N
E
E
DMF
45
26
42
68
G
DMA
DMSO
DMSO
A
R
TMTU
[a] The reactions were carried out in 0.5 mmol scale of 1a in the presence
of the proper catalyst in 2 mL of different solvents. [b] The pressure of
dioxygen is 1 atm. [c] Isolated yields. [d] The product contained a small
amount of dimethylsufone, which could not be separated with general
methods. [e] 2 equiv. [f] 0.5 equiv.
À
is worth noting that C Cl was compatible with our reaction
conditions and thus offers great opportunity to further trans-
form into different functionalities. However, the efficiency
was lower even with high catalyst loading (entry 8). Other
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7293

Z. Yang, Z.-J. Shi et al.
Table 2. Selective imidazolation of substituted N-arylimidamides.[a]
Table 3. Selective imidazolation of substituted N-arylimidamides.[a]
2
1
Yield
[%][b]
1
2
Yield
[%][b]
1
60
71
59
64
75
63
1
2
67
2
61[c]
3
3
32
60
68
4[c]
5[c]
6[c]
4[c]
5
6
62c
65
53
7[c]
8[d]
9
72
40
0[e]
7[d]
8[d]
9
10
0
40ACHTUNGTRENNUNG(1:1)
[a] All the reactions were carried out under the following reaction condi-
tions: 2 (0.5 mmol), [PdCl2A(PhCN)2] (10 mol%), TMTU (20 mol%), and
Cu(OAc)2 (0.5 mmol) in NMP (2 mL) under O2 atmosphere (balloon
pressure) at 1008C. [b] Isolated yields.[c] 808C. [d] 20.0 mol% Pd-
(PhCN)2Cl2 was used. [e] R=Me, NHPh.
CTHUNGTRENNUNG
[a] All the reactions were carried out under the following reaction condi-
tions: 1 (0.5 mmol), [PdCl2A(PhCN)2] (10 mol%), TMTU (20 mol%), and
Cu(OAc)2 (0.5 mmol) in NMP (2 mL) under O2 atmosphere (balloon
pressure) at 1008C. [b] Isolated yields. [c] Four isomers were observed
with the same molecular weight by GC. [d] The reactions were carried
out at 808C.
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
this transformation. In contrast, electron-deficient substitu-
ents made the reactions less effective, which may arise from
the decreased electron density on phenyl ring. When the
nitro group was introduced into para-position, this reaction
was totally shut down. Interestingly, steric effect also play a
vital role in controlling the reactivity. Both para- and meta-
methylated substrates showed good reactivity, but the ortho-
methylated substrate evidently influenced the efficiency (cf:
entries 1–3). It is important to note that when substrates 1m
and 1q, with methyl and a fused five-membered carbon ring
substituents, respectively, were used, four isomers were ob-
served by GC that may arise from both the regioselectivity
products were isolated in 1:1 and 2:1 ratios, respectively,
when 1s and 1t served as the substrates with meta-substitu-
ents, in which the less hindered ortho-position was preferred
À
(entries 8 and 9). Similarly, the C Cl group survived well
(entry 9).
To clearly understand the mechanism, we further investi-
gated the effect of TMTU (Scheme 3). The dimer of palla-
dacycle 3 could be transformed into the palladacycle mono-
mer 4 with TMTU as a ligand. This complex could be trans-
formed into the desired product 1a in a good efficiency in
the presence of NaOAc as a base and in the absence of Cu-
ACHTUNGRTEN(NUNG OAc)2. In the presence of TMTU and NaOAc, palladacycle
dimer 3 could be transformed into desired product in 40%
isolated yield. Thus, TMTU may play an important role in
À
of the C N formation and the migration of C=N group (en-
tries 2 and 6). Interestingly, when substrate 1r with 5,6-di-
methoxy groups was used, only one isomer was isolated in a
good yield (entry 7). In comparison, two isomers of the
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Chem. Eur. J. 2009, 15, 7292 – 7296

Synthesis of the 1H-Benzo[d]imidazole Scaffold
COMMUNICATION
plays a role as a base to in re-
moving the proton of the imine
group to generate intermediate
5. After the reductive elimina-
tion to yield the desired prod-
uct 1, a Pd0 species is generat-
ed, which can be further oxi-
dized to PdII to finish this cata-
lytic cycle. The palladacycle
dimer 3 may also go through
the direct deprotonation and
reductive elimination to finish
this catalytic cycle according to
its observed weak reactivity.
The X-ray structures of inter-
mediates 3 and 4 strongly sup-
ported
During this catalytic cycle, Cu-
AHCTUNRTGEG(NUNN OAc)2 was assumed to play
these
hypotheses.
dual roles both as a base in re-
moving the proton of palladacy-
cle monomer or dimer and an
oxidant to oxidize Pd0 to PdII to
facilitate the catalytic cycle.
Scheme 3. Mechanistic studies for the direct imidation through palladacycles 3 and 4.
promoting the reductive elimination. Moreover, both dimer
and monomer could also be applied to this transformation
as catalysts under standard conditions. This evidence offers
strong support of the existence of palladacycles in the pro-
posed catalytic cycle (Scheme 4).
The catalytic ability of CuACHTNUGTRENNNUG
On the basis of these preliminary studies, this transforma-
tion was hypothesized to occur through imino-group-direct-
ed ortho-cyclopalladation to produce the palladacycle 3.
After the decomposition of the dimeric palladacycle to pro-
duce the monomer 4 in the presence of TMTU, the acetate
We have developed a novel method to construct the core
structure of 1H-benzo[d]imidazole through PdII-catalyzed
À
C H activation, starting from readily available N-phenyl-
benzimidamides under mild reaction conditions. This trans-
formation has a broad substrate scope. Different functionali-
ties survived well. Mechanistic studies strongly indicate that
a PdII species plays an important role in facilitating the cata-
lytic cycle via a palladacycle monomer or dimer as key inter-
mediates. During this transformation, TMTU was used for
the first time to promote the catalytic efficiency of the PdII-
À
catalyzed C H activation. This method offered the most
straightforward pathway to diversify the benzimidamides.
Experimental Section
General: The boiling point of petroleum ether was between 60–908C.
Silica gel (200–300 mesh) for purification was purchased from Qing Dao
Hai Yang Chemical Industry Co. of China. 1H and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively, with Varian Mercury 300 spec-
trometer or at 400 MHz and 100.6 MHz, respectively, with Brucker
ARX400 spectrometer. Mass spectrometric data were obtained using
ZAB-HS mass spectrometer and GCT-MS Micromass UK. NMP and
DMSO were dried over CaSO4 and freshly distilled. [PdCl
hydrous Cu(OAc)2, and TMTU were purchased from Acros Chemical
and used without further purification.
2ACHTUNGTRENN(UNG PhCN)2], an-
AHCTUNGTRENNUNG
General procedures for direct imidation to construct 1H-benzo[d]imid-
II
À
À
Scheme 4. Plausible mechanism for the C N formation of 1H-benzo[d]-
N
À
A
(1a) or its derivatives (0.5 mmol, 1.0 equiv), [PdCl
R
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7295

Z. Yang, Z.-J. Shi et al.
0.10 equiv), anhydrous Cu
(OAc)2 (0.5 mmol, 1.0 equiv), and TMTU
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NMP (2.0 mL) was added by syringe. The tube was sealed with a Teflon
lined cap, and the reaction mixture was degassed and refilled with O2 (re-
peated three times), then heated to 1008C in an oil bath for 24 h. After
the reaction was completed, saturated aq.Na2CO3 (5 mL) and ethyl ace-
tate (10 mL) were added to the mixture. The dark solid was removed by
filtration through Celite and the Celite bed was washed with 4ꢁ20 mL
ethyl acetate. In most cases, the combined filtrate was washed with water
(4ꢁ8 mL) and brine (10 mL). The organic phase was dried with Na2SO4
and concentrated. The residue was purified by silica gel chromatography
with a proper eluent. The purified material was dried under oil-pump
vacuum.
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Acknowledgements
Support of this work by the grant from NSFC (No. 20672006 and
20821062, GZ419) and the “973” programme from MOST of China
(2009CB825300) is gratefully acknowledged.
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À
À
Keywords: C H activation · C N formation · homogeneous
catalysis · palladium · thiourea
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Received: January 19, 2009
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Revised: May 5, 2009
Published online: June 23, 2009
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