Direct C—H Bond Activation of Benzoxazole and Benzothiazole with Aryl Bromides Catalyzed by Palladium(II)-N-heterocyclic Carbene Complexes

Article abstract of DOI:10.1002/cjoc.201800166

Herein, we report that a series of novel palladium(II)-NHC complexes (NHC=N-heterocyclic carbene) were synthesized. The structures of all novel complexes were characterized by ¹H NMR, ¹³C NMR, FT-IR spectroscopy and elemental analysis techniques. These palladium(II)-NHC complexes were tested as efficient catalysts in the direct C—H bond activation of benzoxazole and benzothiazole with aryl bromides in the presence of 1 mol% catalyst loading at 150 °C for 4 h. Under the given conditions, various aryl bromides were successfully applied as the arylating reagents to achieve the 2-arylbenzoxazoles and 2-arylbenzothiazoles in acceptable to high yields.

Full text of DOI:10.1002/cjoc.201800166

Direct C-H Bond Activation of Benzoxazole and Benzothiazole with Aryl
Bromides Catalyzed by Palladium(II)-N-Heterocyclic Carbene Complexes
Murat Kaloğlu,a,b Nazan Kaloğlua,b and İsmail Özdemir*a,b
a Department of Chemistry, Faculty of Science and Arts, İnönü University, 44280 Malatya, Turkey
b Catalysis Research and Application Center, İnönü University, 44280 Malatya, Turkey
*E-mail: ismail.ozdemir@inonu.edu.tr; Tel. and fax number: +90-422-341-0212.
Herein we report, a series of novel palladium(II)-NHC complexes (NHC = N-heterocyclic carbene) were synthesized. The structures of all
novel complexes were characterized by 1H NMR, 13C NMR, FT-IR spectroscopy and elemental analysis techniques. These
palladium(II)-NHC complexes were tested as efficient catalysts in the direct C-H bond activation of benzoxazole and benzothiazole with
aryl bromides in presence of 1 mol% catalyst loading at 150 °C for 4 h. Under the given conditions, various aryl bromides were
successfully applied as the arylating reagents to achieve the 2-arylbenzoxazoles and 2-arylbenzothiazoles in acceptable to high yields.
Keywords benzimidazolium bromide, benzoazoles, direct C-H bond activation, N-heterocyclic carbene, palladium
Introduction
derivatives have attracted the attention of many
research groups and biological activities have made
them popular synthetic targets.[10-12] The conventional
methods for the synthesis of 2-arylsubstituted
benzoxazoles and benzothiazoles typically involve three
main strategies: (i) Intermolecular cyclization of
2-amino(thio)phenol with amines (Scheme 1a),[13] (ii)
Intramolecular cyclization of halobenzanilides (Scheme
1b),[14] and (iii) Ring-opening-coupling-recyclization of
benzoxazole or benzothiazole with aromatic aldehydes
or benzoyl chloride (Scheme 1c).[15] These protocols
require high temperatures, which limits the substrate
scope with temperature-sensitive heterocyclic aryl
halides. Furthermore, in many cases these reactions
were performed in high boiling solvents, such as DMSO,
DMF, and NMP, which complicate product isolation.
Alternatively, 2-aryl-substituted benzoxazoles and
benzothiazoles can be prepared by direct arylation of
heterocycles through metal-catalyzed direct C-H bond
activation (Scheme 1d).[16-20] Since the direct arylation
has many advantages such as step-economy,
atom-economy, high efficiency, simple operation, and
mild reaction conditions, it represent an
environmentally, economically and potentially more
attractive strategy. Hence, the direct C-H bond
arylation of such compounds is receiving growing
attention in the context of organic synthesis. A variety
of electrophilic reagents including aryl halides[21-24], aryl
2-Arylsubstituted benzoazoles are an important
class of heterocyclic compounds that are widely found
in bioactive molecules,[1,2] pharmaceuticals[3,4] and
natural products,[5] due to their diverse biological and
pharmacological properties. In addition, these
compounds have become essential building blocks for
the synthesis of conjugated functional materials, such
as industrial dyes and plant growth regulators.[6] For
example,
benzothiazole
derivatives
are
the
pharmacophore of zopolrestat, which has been used for
the treatment of diabetes.[7,8] Benzoxazoles are also
well known for their biological activities, e.g. as an
antiinflammatory agent and antibacterial agent.[9]
Biologically active some benzoazoles are exemplified in
Figure 1.
organometallic reagents[25]
arenes[26]
,
unactivated simple
,
and phenol derivatives such as
triflates[19,27-28], mesylates[29], sulfamates[30] and acids[31]
have been employed for the transformation. Similarly,
arene sulfonyl chlorides[32] and arene diazonium salts[33]
are inexpensive and readily available arylating reagents.
Among these arylating reagents, especially aryl halides
have been employed as the most widely used arylating
reagents owing to their commercial availability and
substituted diversity.
Figure 1 Examples of biologically active benzoazole derivatives
Given the importance of benzoazoles, many
methods have been developed for the preparation of
these benzofused heterocyclic structures in recent
years. Specifically, benzoxazole and benzothiazole
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Scheme 1 Synthesis of 2-aryl-substituted benzoxazoles and
benzothiazoles
this work.
Palladium-catalyzed direct arylation reactions are
the most widely used method for the formation of
C(sp2)-C(sp2) bond,[34,35] but several contributions have
also been reported using ruthenium catalysis,[36-39] or
other transitions-metals.[40-42] Early examples of
palladium-catalyzed direct arylation were reported by
Ames et al.[43] Then, palladium-catalyzed direct aryla-
tion of an azole ring was first accomplished by Ohta et
al.[44] Later development in this area focused on
intermolecular direct arylation and expanded the
substrate scope to include various (hetero)arenes
containing directing groups and electron-deficient
Figure 2 Palladium(II)-NHC complexes (2a-f)
Results and discussion
Preparation of benzimidazolium bromides
The two novel benzimidazolium bromides 1a and 1b
were obtained by alkylation (RBr; R = CH2C6H3(Cl)2-3,4
and CH2C6H2(OCH3)3-3,4,5) of N-(2-(2-ethoxyphenoxy)-
ethyl)benzimidazole in 92% and 73% isolated yields,
respectively. The salts 1a and 1b were fully character-
1
ised by elemental analysis, H NMR and 13C NMR and
arenes.
Since
these
exciting
results,
the
FT-IR spectroscopies. The FT-IR spectra of the free lig-
ands showed a broad band at 1562 and 1566 cm-1,
which corresponds to the CN bond vibration of 1a and
1b, respectively. The signal of the NCHN proton ap-
pears in the expected range, at  = 11.53 and 11.46
ppm for 1a and 1b, respectively. Their 13C NMR spectra
display the characteristic singlet at  = 143.7 and 143.7
ppm for the NCHN carbon for 1a and 1b, respectively
(for the NMR and FT-IR spectrum of 1a and 1b, see SI,
pp S1-S4). The other benzimidazolium bromides used in
this study (1c-f) were synthesized as we previously de-
scribed.[58,59] Obtained spectroscopic values for the 1a
and 1b compounds are consistent with those found in
the literature for benzimidazolium salts.[39,53,55-57]
palladium-catalyzed direct arylation of (hetero)arenes
with aryl halides has proved to be a very powerful
method for the synthesis of a wide variety of arylated
heterocycles.[45-48] In this connection, recently we have
synthesized,
characterized,
and
carbene
investigated
(Pd-NHC)
palladium(II)-N-heterocyclic
complexes for catalytic activity in the direct C-H bond
activation of different (hetero)aromatic compounds
with aryl halides.[49-57] The strong σ-donating but poor
π-accepting ability of NHC ligands lead to the formation
of many stable palladium(II)-NHC complexes. Due to
activity, stability and selectivity of palladium(II)-NHC
complexes, they have been widely used as highly
reactive and rather selective catalysts for numerous
direct arylation reactions. Based on these findings and
our continuing interest in developing more efficient
and stable catalysts for direct arylation of benzoxazole
and benzothiazole with aryl halides, we now report the
preparation of the palladium(II)-NHC complexes 2a-f
(Figure 2) and its characterization. The application of
these novel palladium(II)-NHC complexes in the direct
C-H bond activation of benzoxazoles and
benzothiazoles with aryl bromides is also described in
Preparation of palladium(II)-NHC complexes
The six novel palladium(II)-NHC complexes 2a-f
were obtained in 55-75% yields by the reaction of the
corresponding benzimidazolium bromides 1a-f. The air-
and moisture-stable palladium(II)-NHC complexes are
yellow in colour and soluble in common organic sol-
vents such as acetone, dichloromethane, chloroform,
DMF, ethanol and acetonitrile. They were fully charac-
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terised by elemental analysis, 1H NMR and 13C NMR and
pp S5-S16). Also, the results of the elemental analysis
were in good agreement with the theoretical values.
Palladium(II)-NHC complexes exhibit a characteristic
v(NCN) band typically at between 1393-1410 cm-1. The
spectroscopic data are similar to those found for
described palladium(II)-NHC complexes in the
literature.[50-52,56,57] All the novel compounds were
prepared according to general reaction pathway
depicted in Scheme 2. The analytical data are in good
agreement with the compositions proposed for all the
novel compounds we prepared, and are summarized in
the Table 1.
1
infrared spectroscopies. In the H NMR and 13C NMR
spectra of the all palladium(II)-NHC complexes, loss of
the benzimidazolium H(2)-proton (NCHN) and
benzimidazolium C(2)-carbon (NCHN) signal suggests
the formation of the palladium(II)-NHC complexes. The
characteristic peak of the Pd-Ccarbene resonance for all
palladium(II)-NHC complexes were detected at
between  = 180.5-182.6 ppm, however, NMR studies
showed that all palladium(II)-NHC complexes were a
mixture of cis/trans isomers in an approximate 47:53
ratio (for the NMR and FT-IR spectrum of 2a-f, see SI,
Scheme 2 Synthesis of benzimidazolium bromides and palladium(II)-NHC complexes
Table 1 Physical and spectroscopic properties of the novel compounds
Isolated yield
(%)
M.p.
(oC)
FT-IR v(CN)
(cm-1)
H(2) 1H NMR
(ppm)
C(2) 13C NMR
(ppm)a
Compound
Molecular formula
1a
1b
2a
2b
2c
2d
2e
2f
C24H23BrCl2N2O2
C27H31BrN2O5
92
73
62
63
75
60
59
55
163-164
139-140
160-162
198-200
135-137
164-166
275-277
132-134
1562
1566
1393
1405
1410
1409
1399
1398
11.53
11.46
143.7
143.2
C48H44Br2Cl4N4O4Pd
C54H58Br2N4O10Pd
C42H50Br2N4O4Pd
C40H48Br2N4O6Pd
C58H68Br2N4O4Pd
C56H64Br2N4O4Pd
-
-
-
-
-
-
182.4 and 182.6
181.8 and 182.1
180.5 and 180.7
182.0 and 182.1
182.3 and 182.4
182.0 and 182.1
a As previously reported by several groups,[56,57,60-62] NMR data showed that all palladium(II)-NHC complexes were cis/trans mixtures.
Direct arylation of benzoxazole and benzothiazole with
aryl halides
KOAc as the base, since the DMAc/KOAc combination
has been commonly used for the direct arylation of
5-membered heterocycles.[63-66] A series of experiments
were carried out to study the effect of various reaction
parameters such as catalyst loading, reaction time and
reaction temperature. Selected results from our
experiments are summarized in Table 2.
Initially, to optimise the reaction conditions, we
selected the complex 2f as the model catalyst,
benzothiazole and 4-bromoacetophenone as a model
substrate. Also, we selected DMAc as the solvent, and
Table 2 Screening of the reaction condition for the palladium(II)-NHC-catalyzed direct arylation of benzothiazole with
4-chloroacetophenone and 4-bromoacetophenonea
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Entry
2f (mol-%)
X
Time (h)
Temperature (oC)
Yield (%)b,c
1
2
3
4
5
6
7
8
9
No
2
1
1
1
1
1
1
1
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
8
8
8
4
2
4
4
8
16
24
150
150
150
150
150
120
150
150
150
-
100 (86)
97 (82)
93 (79)
78 (64)
74 (58)
-
8 (-)
14 (<5)
20 (<10)
10
1
150
a Conditions: benzothiazole (2.0 mmol), aryl halide (1.0 mmol), KOAc (2.0 mmol), DMAc (2 mL). GC yields were calculated with respect
to aryl halide from the results of GC and GC-MS spectrometry with dodecane as internal standard. c Isolated yields were shown in
parentheses.
b
The
arylation
of
benzothiazole
with
procedure, using various aryl bromides under the
determined conditions (in presence of 1 mol% catalyst,
o
4-bromoacetophenone was first carried out at 150 C
for 8 h without the addition of 2f complex in order to
examine the effect of catalyst on the reaction. As at-
tempt, no products were formed without the addition
of 2f complex (Table 2, entry 1). In the presence of 2
mol% of 2f as the catalyst at 150 °C for 8 h, the
o
KOAc as the base, DMAc as the solvent at 150 C for 4
h). The reaction worked well for a wide variety of aryl
bromides such as bromobenzene, 4-bromotoluene,
4-bromoanisole,
4-bromobenzaldehyde,
and
4-bromoacetophenone, affording the 2-aryl substituted
benzoxazoles for 30 examples, and 2-aryl substituted
benzothiazoles for other 30 examples, and the results
are summarized in Table 3. Similar yields were obtained
for benzoxazole (48-85%) and benzothiazole (65-91%)
using the neutral aryl bromide such as bromobenzene
(Table 3, entries 1-6). When the reaction of
benzoxazole and benzothiazole with electron-rich aryl
bromides such as 4-bromotoluene and 4-bromoanisole
was investigated, the yields at between 68-92% and
61-87% for 4-bromotoluene with benzoxazole and
benzothiazole, respectively (Table 3, entries 7-12),
4-Bromoanisole gave also the 2-aryl substituted
C2-arylated
benzothiazole
derivative
namely,
2-(4-acetylphenyl)-benzothiazole was obtained full
conversion with 86% isolated yield (Table 2, entry 2).
When catalyst loading was decreased from 2 mol% to 1
mol% at 150 °C for 8 h, similar yield of product was also
observed (Table 2, entry 3). Encouragingly, the reaction
performed in the presence of 1 mol% palladium(II)-NHC
catalyst
at
150
oC
for
4
h
afforded
2-(4-acetylphenyl)-benzothiazole in 79% isolated yield
(Table 3, entry 4). Decreasing the reaction time from 4
h to 2 h had a detrimental effect on the yield (Table 2,
entry 5). Similarly, when the reaction temperature was
reduced from 150 °C to 120 oC in the presence of 1 mol% benzoxazole and benzothiazole with 50-88% and 60-83%
2f for 4 h, the yield decreased to 74% (Table 2, entry 6).
Finally, the best conditions leading to 93% yield (79%
isolated yield) of 4-bromoacetophenone with
2-(4-acetylphenyl)benzothiazole were obtained, when
the reaction was carried out in DMAc/KOAc
combination in the presence of 1 mol% 2f catalyst at
150 oC for 4 h (Table 2, entry 4). When the less reactive
4-chloroacetophenone was used as substrate in the
yields, respectively (Table 3, entries 13-18). The
coupling of benzoxazole and benzothiazole with
electron-poor
aryl
bromide
such
as
4-bromobenzaldehyde
also proceeds
nicely.
4-Bromobenzaldehyde gave the 2-aryl substituted
benzoxazole and benzothiazole with 75-95% and 71-92%
yields, respectively (Table 3, entries 19-24). The
electron-poor 4-bromoacetophe- none was also a good
substrate to afford the corresponding products
o
presence of 1 mol% of 2f catalyst at 150 C for 4 h, no
conversion was observed (Table 2, entry 7). Although
the reaction time was gradually increased from 4 h to
24 h, no significant increase in the conversion was
observed (8-20% yield) (Table 2, entries 8-10).
Therefore, no direct arylation of aryl chloride
compounds with benzoxazole or benzothiazole has
been performed.
2-(4-acetylphenyl)benzoxazole
and
2-(4-acetylphenyl)benzothiazole at between 78-96%
and 74-93% yields, respectively (Table 3, entries 25-30).
In general, the direct arylation of benzothiazole
exhibited more good yields than the direct arylation of
benzoxazole with a range of aryl bromides. But, it is
noteworthy that neither electron-withdrawing nor
electron-donating groups had a significant effect on the
overall yield of the reaction.
Then, we studied the scope and limitations of this
Table 3 Palladium(II)-NHC-catalyzed direct arylation of benzoxazole and benzothiazole with aryl bromidesa
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Yield (%)b,c
Entry
Aryl bromide
Catalyst
Product
Y = O
Y = S
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
79 (65)
73 (60)
48 (32)
64 (50)
76 (63)
85 (75)
84 (72)
89 (76)
68 (54)
79 (65)
72 (58)
92 (77)
71 (59)
67 (54)
50 (37)
68 (55)
83 (70)
88 (76)
82 (69)
75 (61)
75 (60)
86 (73)
90 (75)
95 (76)
83 (70)
88 (73)
78 (64)
89 (75)
93 (80)
96 (84)
84 (70)
68 (54)
78 (63)
65 (51)
85 (73)
91 (76)
82 (68)
61 (48)
74 (60)
69 (56)
73 (60)
87 (72)
75 (62)
82 (68)
60 (46)
76 (62)
79 (65)
83 (70)
82 (68)
71 (57)
73 (61)
81 (65)
86 (72)
92 (78)
89 (76)
81 (68)
74 (61)
85 (72)
89 (78)
93 (79)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
a Conditions: Pd-NHC, 2a-f (0.01 mmol), benzoxazole or benzothiazole (2.0 mmol), aryl bromide (1.0 mmol), KOAc (2.0 mmol), DMAc (2
mL), 150 °C, 4 h. b GC yields were calculated with respect to aryl bromide from the results of GC spectrometry with dodecane as internal
standard. c Isolated yields were shown in parentheses.
The palladium-catalyzed direct arylation of
benzoazoles with a variety of electrophilic reagents has
been previously described by many groups.[19-33] In
previous works, similar substrates have been employed
with higher catalyst loading (5-20 mol%) and higher
reaction time (5-48 h) has been chosen for the direct
arylation of benzoazoles in presence of palladium
catalysts.[21,22,24-26,29-32] But, in the present work the
catalyst loading was reduced to 1 mol%, and the
reaction time was shortened to 4 h. Moreover, in the
present study benzoxazole and benzothiazole can be
efficiently and selectively arylated at the 2-position by
palladium complexes bearing NHC ligands, and
satisfactory results were obtained as compared to
previously reported similar studies using aryl
halides.[21,22,24] When compared with our previous work,
in the present work, the reaction time was shortened
to 4 h and higher yields were obtained, whereas in pre-
vious work, the reaction was carried out in presence of
1.5 mol% palladium(II)-NHC catalyst, in NMP as the
solvent, K3PO4 as the base, at 130 oC. Also, the reaction
time was chosen as 48 h for arylation of benzoxazole
and benzothiazole with aryl bromides.[50] For example
aryl bromides were coupled with benzoxazole and
benzothiazole to give the desired product in 64-67%
and 54-72% yields only after 48 h respectively, whereas
in the present work the higher yields were obtained.
In the present work, when the performances of the
complexes 2a-f were compared in the direct C-H bond
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arylation of benzoxazole and benzothiazole, complex 2f
bearing NHC ligands with 2-(2-ethoxyphenoxy)ethyl
and 4-tert-butylbenzyl substituents exhibited better
catalytic activity than the others. We attributed these
performance differences to well-accordance electronic
and steric properties of the NHC ligand. It is known that
oxidative additions of electron-withdrawing substrates
to electron rich palladium-complexes and reductive
elimination of the product from large, sterically hin-
dered palladium-complexes proceed more readily.
Therefore, the presence of an NHC ligand bearing a
different second donating group such as ether side
chains on the metal may radically increase the catalytic
performance of the catalyst. The chelating nature of
these ligands promotes production of highly stable
complexes. The hemilabile part of such ligands is capa-
ble of reversible dissociation to produce vacant coor-
dination sites, allowing complexation of substrates
during the catalytic cycle. At the same time the
strong-donor carbene moiety remains connected to the
metal centre. In this direct C-H bond arylation, we be-
lieve that the bulky and electron-donor NHC ligands
bearing 2-(2-ethoxyphenoxy)ethyl substituents in com-
plexes 2a-f provide the synergetic steric and electronic
effects to confer the metal center the appropriate
properties to make optimum for the key steps of the
catalytic cycles.
palladium(II)-NHC complexes in organic synthesis. Also,
a more thoroughly investigations of further studies
aimed at expanding the substrate scope of the reaction
are underway.
Experimental
General methods
All manipulations were carried out under argon
using standard Schlenk line techniques. The solvents
used were purified by distillation over the drying agents
indicated and were transferred under argon. Elemental
analyses were performed by İnönü University Scientific
and Technological Research Center (Malatya, Turkey).
Melting points were measures in open capillary tubes
with an Electrothermal-9200 melting points apparatus.
FT-IR spectra were recorded on ATR (Attenuated Total
Reflection) sampling accessory in the range of 400-4000
cm-1
with
Perkin
Elmer
Spectrum
100
1
Spectrophotometer. Routine H NMR and 13C NMR
spectra were recorded using Bruker UltraShield 300
operating at 300 MHz (1H), 75 MHz (13C) and Bruker
AscendTM 400 Avance III HD operating at 400 MHz (1H),
100 MHz (13C) FT spectrometers in CDCl3. The NMR
studies were carried out in high-quality 5 mm NMR
tubes. The chemical shifts (δ) are reported in ppm
relative to tetramethylsilane (TMS). Coupling constants
(J values) are given in hertz. NMR multiplicities are ab-
breviated as follows: s = singlet, d = doublet, t = triplet,
q = quartet, pent = pentet, hext = hextet, m = multiplet.
1H NMR spectra are referenced to residual protiated
solvents (δ = 7.26 ppm for CDCl3), 13C chemical shifts
are reported relative to deuteriated solvents (δ = 77.16
ppm for CDCl3). All catalytic reactions were monitored
on an Agilent 6890N GC and Schimadzu 2010 Plus
GC-MS system by GC-FID (Flame Ionization Dedector)
with a HP-5 column of 30 m length, 0.32 mm diameter,
and 0.25 μm film thickness.
Conclusions
In summary, two novel benzimidazolium bromides
1a and 1b, and six novel palladium(II)-NHC complexes
2a-f were successfully synthesized and characterized by
1H NMR, 13C NMR and FT-IR spectroscopy, and
microanalysis techniques. In addition, we have
established that the synthesized palladium(II)-NHC
complexes are efficient catalysts for the direct C-H
bond activation of benzoxazole and benzothiazole with
aryl bromide derivatives. Under the determined
conditions, the reaction can tolerate various substrates.
For example, aryl bromides with electron-donating,
neutral, and electron-withdrawing substituents are all
proven to be suitable substrates. When compared to
previous reports,[21,22,24] satisfactory results were
obtained in presence of low catalyst loading in this
study. But, we can say that there is no significant
difference between 2a-f complexes on the catalytic
activity of direct arylation of benzoazole derivatives.
The only significant difference between these
complexes indicates that electronic and steric effects.
The performances and stabilities of this catalytic
system may be attributed to the ability of the
possibility of flexible substituents on 2a-f complexes,
which would rotate away from the axial site of the
palladium center. Finally, this transformation
represents an effective way to carry out the arylation
of benzoxazole or benzothiazole compounds, a task
that otherwise requires several synthetic steps or harsh
reaction conditions. Therefore, the results reported in
this paper provide an economical, convenient, and
alternative method for the direct C-H bond activation
of benzoazoles and will also enrich the chemistry of the
General procedure for the preparation of benzimidaz-
olium bromides
A chloroform (10 mL) solution of N-(2-(2-ethoxy-
phenoxy)ethyl)benzimidazole (1.41 g, 5.0 mmol) and
alkyl bromide (5.0 mmol) was stirred at 60 °C for 24 h.
After completion of the reaction, the solvent was re-
moved by vacuum and Et2O (15 mL) was added to ob-
tain a white crystalline solid, which was filtered off. The
solid was washed with Et2O (3×10 mL) and dried under
vacuum. The crude product was recrystallized from
EtOH/Et2O mixture (1:2, v/v) and dried under vacuum.
Benzimidazolium bromides 1a and 1b were isolated as
air- and moisture-stable white solids and were isolated
1
in 92% and 73% yields, respectively. For the H NMR,
13C NMR and FT-IR spectrums of the novel
benzimidazolium bromides 1a and 1b see SI, pp S1-S4.
1-(2-(2-Ethoxyphenoxy)ethyl)-3-(3,4-dichlorobenzyl)be
1
nzimidazolium Bromide (1a): Yield: 2.402 g, 92%; H
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NMR (300 MHz, CDCl3, 25 oC, TMS): δ (ppm) = 1.33 (t, 3J
General procedure for the preparation of
palladium(II)-NHC complexes
3
= 6.9 Hz, 3H, OCH2CH3), 3.96 (q, J = 7.0 Hz, 2H,
OCH2CH3), 4.57 (t, 3J = 4.5 Hz, 2H, NCH2CH2O), 5.18 (t, 3J
=
4.5 Hz, 2H, NCH2CH2O), 5.94 (s, 2H,
A suspension of the benzimidazolium bromides (1.0
mmol) and Pd(OAc)2 (0.50 mmol) in degassed DMSO (3
mL) was heated with vigorous stirring at 100 oC for 24 h.
Volatiles were removed in vacuo, and the residue was
washed with n-pentane (2×5 mL). The crude product
was dissolved with CH2Cl2 then filtered through a pad
of celite and silica gel (70-230 mesh) to remove the
unreacted Pd(OAc)2 and benzimidazolium bromide.
Then, the crude complex was crystallized from
CH2Cl2/Et2O mixture (1:2, v/v) at room temperature and,
completely dried under vacuum. All palladium(II)-NHC
complexes were isolated as air- and moisture-stable
yellow solids and were isolated in 55-75% yields. NMR
studies showed that all palladium(II)-NHC complexes
were a mixture of cis/trans isomers in an approximate
47:53 ratio, as determined by comparison of the
integral values of specific protons such as OCH2CH3 on
NCH2C6H3(Cl)2-3,4), 6.81-6.94 (m, 4H, arom. CHs,
NCH2CH2OC6H4(OCH2CH3)-2), 7.40-7.63 (m, 6H, arom.
CHs, NC6H4N and NCH2C6H3(Cl)2-3,4), 8.20 (d, 3J = 8.1 Hz,
1H, arom. CH, NC6H4N), 11.53 (s, 1H, NCHN). 13C NMR
(75 MHz, CDCl3, 25 oC): δ (ppm) = 15.0 (OCH2CH3), 48.3
(OCH2CH3), 50.4 (NCH2C6H3(Cl)2-3,4), 62.9 (NCH2CH2O),
68.1 (NCH2CH2O), 112.8, 113.0, 114.6, 115.3, 120.9,
122.6, 127.2, 128.0, 130.1, 130.9, 131.5, 132.5, 132.8,
133.4, 133.7, 147.1, 148.7 (arom. Cs, NC6H4N,
NCH2C6H3(Cl)2-3,4 and NCH2CH2OC6H4(OCH2CH3)-2),
143.7 (NCHN). Elemental analysis calcd (%) for
C24H23BrCl2N2O2 (Mr = 522.26 g.mol-1): C 55.19, H 4.44,
N 5.36; found (%): C 55.21, H 4.46, N 5.38.
1-(2-(2-Ethoxyphenoxy)ethyl)-3-(3,4,5-trimethoxybenz
yl)benzimidazolium Bromide (1b): Yield: 1.983 g, 73%;
1H NMR (300 MHz, CDCl3, 25 oC, TMS): δ (ppm) = 1.30 (t,
3J = 7.0 Hz, 3H, OCH2CH3), 3.80 and 3.84 (s, 9H,
NCH2C6H2(OCH3)3-3,4,5), 3.92 (q, 3J = 7.0 Hz, 2H,
OCH2CH3), 4.55 (t, 3J = 5.0 Hz, 2H, NCH2CH2O), 5.18 (t, 3J
1
the NHC ligand in the H NMR spectroscopy. For the 1H
NMR, 13C NMR and FT-IR spectrums of the novel
palladium(II)-NHC complexes (2a-f) see SI, pp S5-S16.
=
4.7 Hz, 2H, NCH2CH2O), 5.72 (s, 2H,
cis/trans-Dibromo-bis[1-(2-(2-ethoxyphenoxy)ethyl)-3-
NCH2C6H2(OCH3)3-3,4,5), 6.69-6.92 (m, 4H, arom. CHs,
NCH2CH2OC6H4(OCH2CH3)-2), 6.85 (s, 2H, arom. CHs,
NCH2C6H2(OCH3)3-3,4,5), 7.57-7.71 (m, 3H, arom. CHs,
(3,4-dichlorobenzyl) benzimidazol-2-ylidene]palladium
1
(II) (2a): Yield: 0.356 g, 62%; H NMR (400 MHz, CDCl3,
3
25 oC, TMS): δ (ppm) = 1.43 and 1.44 (t, J = 7.0 Hz, 6H,
3
3
NC6H4N), 8.17 (d, J = 8.0 Hz, 1H, arom. CH, NC6H4N),
OCH2CH3), 3.99 and 4.00 (q, J = 7.0 Hz, 4H, OCH2CH3),
11.46 (s, 1H, NCHN). 13C NMR (75 MHz, CDCl3, 25 oC): δ
(ppm) = 14.9 (OCH2CH3), 47.9 (OCH2CH3), 51.8
4.60 and 4.78 (t, J = 5.6 Hz, 4H, NCH2CH2O), 5.21 and
3
5.33 (t, 3J = 5.6 Hz, 4H, NCH2CH2O), 5.86 and 6.04 (s, 4H,
NCH2C6H3(Cl)2-3,4), 6.77-7.44 (m, 18H, arom. CHs,
(NCH2C6H2(OCH3)3-3,4,5),
56.8
and
60.8
(NCH2C6H2(OCH3)3-3,4,5), 63.8 (NCH2CH2O), 68.2
(NCH2CH2O), 106.0, 112.7, 113.1, 114.5, 115.1, 120.8,
122.6, 127.0, 127.1, 127.9, 130.9, 132.6, 138.6, 147.1,
148.7, 153.9 (arom. Cs, NC6H4N, NCH2C6H2(OCH3)3-3,4,5
and NCH2CH2OC6H4(OCH2CH3)-2), 143.2 (NCHN). Ele-
mental analysis calcd (%) for C27H31BrN2O5 (Mr = 543.46
g.mol-1): C 59.67, H 5.75, N 5.15; found (%): C 59.64, H
5.71, N 5.09.
NC6H4N,
NCH2C6H3(Cl)2-3,4
and
3
NCH2CH2OC6H4(OCH2CH3)-2), 7.56 (d, J = 7.8 Hz, 1H,
3
arom. CH, NC6H4N), 7.72 (d, J = 8.0 Hz, 1H, arom. CH,
3
NC6H4N), 7.82 (dd, J = 12.3, 8.1 Hz, 2H, arom. CH,
NC6H4N). 13C NMR (100 MHz, CDCl3, 25 C): δ (ppm) =
o
15.0 and 15.1 (OCH2CH3), 48.3 and 48.4 (OCH2CH3),
51.2 and 51.5 (NCH2C6H3(Cl)2-3,4), 63.9 and 64.0
(NCH2CH2O), 67.3 and 67.9 (NCH2CH2O), 110.4, 110.5,
112.1, 112.8, 112.9, 113.3, 113.6, 120.8, 120.9, 121.5,
121.6, 123.4, 123.5, 126.9, 127.1, 129.3, 129.6, 130.7,
130.9, 132.2, 132.3, 132.9, 133.0, 133.9, 134.0, 135.3,
135.5, 135.6, 135.7, 147.8, 147.9, 148.5, 148.6 (arom.
1-(2-(2-Ethoxyphenoxy)ethyl)-3-(n-butyl)benzimidazoli
um Bromide (1c): This benzimidazolium bromide was
synthesized according to published procedure.[58]
Cs,
NC6H4N,
NCH2C6H3(Cl)2-3,4
182.4 and
and
182.6
1-(2-(2-Ethoxyphenoxy)ethyl)-3-(2-methoxyethyl)benzi
midazolium Bromide (1d): This benzimidazolium
bromide was synthesized according to published
procedure.[58]
NCH2CH2OC6H4(OCH2CH3)-2),
(Pd-Ccarbene), (ratio of cis/trans isomers = 49:51). Ele-
mental analysis calcd (%) for C48H44Br2Cl4N4O4Pd (Mr =
1148.93 g.mol-1): C 50.18, H 3.86, N 4.88; found (%): C
50.29, H 3.97, N 4.94.
1-(2-(2-Ethoxyphenoxy)ethyl)-3-(2,3,4,5,6-pentamethy
lbenzyl)benzimidazolium
Bromide
(1e):
This
cis/trans-Dibromo-bis[1-(2-(2-ethoxyphenoxy)ethyl)-3-
benzimidazolium bromide was synthesized according to
(3,4,5-trimethoxybenzyl)benzimidazol-2-ylidene]palla
published procedure.[59]
dium(II) (2b): Yield: 0.374 g, 63%; H NMR (300 MHz,
1
o
3
CDCl3, 25 C, TMS): δ (ppm) = 1.35 and 1.42 (t, J = 7.0
Hz, 6H, OCH2CH3), 3.77 , 3.82, 3.85 and 3.87 (s, 18H,
1-(2-(2-Ethoxyphenoxy)ethyl)-3-(4-tert-butylbenzyl)be
nzimidazolium Bromide (1f): This benzimidazolium
bromide was synthesized according to published
procedure.[58]
3
NCH2C6H2(OCH3)3-3,4,5), 3.96 and 4.02 (q, J = 7.0 Hz,
3
4H, OCH2CH3), 4.67 and 4.84 (t, J = 5.5 Hz, 4H,
NCH2CH2O), 5.32 and 5.42 (t, 3J = 5.3 Hz, 4H,
NCH2CH2O),
5.97
and
6.11
(s,
4H,
This article is protected by copyright. All rights reserved.

NCH2C6H2(OCH3)3-3,4,5), 6.81 (s, 2H, arom. CHs,
NCH2C6H2(OCH3)3-3,4,5), 6.82-6.88 (m, 7H, arom. CHs,
NC6H4N and NCH2CH2OC6H4(OCH2CH3)-2), 6.99 (s, 2H,
arom. CHs, NCH2C6H2(OCH3)3-3,4,5), 7.19-7.33 (m, 7H,
arom. CHs, NC6H4N and NCH2CH2OC6H4(OCH2CH3)-2),
7.83 and 7.87 (d, 3J = 8.0 Hz, 2H, arom. CH, NC6H4N). 13C
NCH2CH2OC6H4(OCH2CH3)-2), 7.20-7.22 and 7.42-7.46
3
(m, 6H, arom. CHs, NC6H4N), 7.69 (d, J = 8.0 Hz, 2H,
arom. CH, NC6H4N). 13C NMR (100 MHz, CDCl3, 25 oC): δ
(ppm) = 15.0 and 15.1 (OCH2CH3), 48.1 and 48.2
(NCH2CH2OCH3), 48.4 and 48.5 (OCH2CH3), 59.1 and
59.2 (NCH2CH2OCH3), 64.1 and 64.2 (NCH2CH2O), 67.7
and 67.8 (NCH2CH2O), 71.5 and 71.6 (NCH2CH2OCH3),
111.0, 111.1, 111.5, 111.6, 112.9, 113.0, 113.5, 113.7,
120.9, 121.0, 121.5, 121.6, 123.0, 123.1, 135.1, 135.2,
135.3, 135.4, 148.0, 148.1, 148.6, 148.7 (arom. Cs,
NC6H4N and NCH2CH2OC6H4(OCH2CH3)-2), 182.0 and
182.1 (Pd-Ccarbene), (ratio of cis/trans isomers = 47:53).
Elemental analysis calcd (%) for C40H48Br2N4O6Pd (Mr =
947.07 g.mol-1): C 50.73, H 5.11, N 5.92; found (%): C
50.75, H 5.13, N 5.94.
o
NMR (75 MHz, CDCl3, 25 C): δ (ppm) = 15.0 and 15.1
(OCH2CH3), 48.1 and 48.3 (OCH2CH3), 52.6 and 52.8
(NCH2C6H2(OCH3)3-3,4,5), 56.4, 56.6, 60.7 and 60.9
(NCH2C6H2(OCH3)3-3,4,5), 63.9 and 64.0 (NCH2CH2O),
68.4 and 68.7 (NCH2CH2O), 104.8, 104.9, 110.9, 111.1,
111.9, 112.3, 112.8, 112.9, 113.2, 113.5, 120.8, 120.9,
121.5, 121.6, 123.2, 123.3, 131.1, 131.3, 133.9, 134.0,
135.5, 135.7, 137.4, 137.7, 147.9, 148.0, 148.5, 148.6,
153.5, 153.7 (arom. Cs, NC6H4N, NCH2C6H2(OCH3)3-3,4,5
and NCH2CH2OC6H4(OCH2CH3)-2), 181.8 and 182.1
(Pd-Ccarbene), (ratio of cis/trans isomers = 48:52). Ele-
mental analysis calcd (%) for C54H58Br2N4O10Pd (Mr =
1189.30 g.mol-1): C 54.54, H 4.92, N 4.71; found (%): C
54.56, H 4.95, N 4.73.
cis/trans-Dibromo-bis[1-(2-(2-ethoxyphenoxy)ethyl)-3-
(2,3,4,5,6-pentamethylbenzyl)benzimidazol-2-ylidene]
1
palladium(II) (2e): Yield: 0.339 g, 59%; H NMR (300
MHz, CDCl3, 25 oC, TMS): δ (ppm) = 1.24 and 1.46 (t, 3J =
6.9 Hz, 6H, OCH2CH3), 2.25, 2.27, 2.29, 2.35, 2.37 and
2.40 (s, 30H, NCH2C6(CH3)5-2,3,4,5,6), 3.51 and 4.03 (q,
cis/trans-Dibromo-bis[1-(2-(2-ethoxyphenoxy)ethyl)-3-
3
(n-butyl)benzimidazol-2-ylidene]palladium(II)
(2c):
3J = 7.0 Hz, 4H, OCH2CH3), 4.85 and 4.87 (t, J = 4.2 Hz,
1
o
3
Yield: 0.352 g, 75%; H NMR (400 MHz, CDCl3, 25 C,
4H, NCH2CH2O), 5.45 and 5.47 (t, J = 4.3 Hz, 4H,
3
TMS): δ (ppm) = 0.95 and 0.99 (t, J = 7.4 Hz, 6H,
NCH2CH2O),
6.35
and
6.38
(s,
4H,
3
NCH2CH2CH2CH3), 1.36 and 1.42 (t, J = 7.0 Hz, 6H,
NCH2C6(CH3)5-2,3,4,5,6), 6.28-6.47 (m, 4H, arom. CHs,
NCH2CH2OC6H4(OCH2CH3)-2), 7.71-6.95 (m, 8H, arom.
CHs, NC6H4N and NCH2CH2OC6H4(OCH2CH3)-2), 7.17
OCH2CH3), 1.51 and 1.52 (hext, 3J = 7.4 Hz, 4H,
3
NCH2CH2CH2CH3), 2.16 and 2.17 (pent, J = 7.4 Hz, 4H,
3
3
NCH2CH2CH2CH3), 3.92 and 3.98 (q, J = 7.0 Hz, 4H,
(dd, J = 12.4, 7.5 Hz, 2H, arom. CH, NC6H4N), 7.75 (dd,
OCH2CH3), 4.68 and 4.69 (t, 3J = 7.4 Hz, 4H,
3J = 7.6, 4.5 Hz, 2H, arom. CH, NC6H4N). 13C NMR (75
3
NCH2CH2CH2CH3), 4.71 and 4.72 (t, J = 4.4 Hz, 4H,
MHz, CDCl3, 25 oC): δ (ppm) = 15.0 and 15.3 (OCH2CH3),
NCH2CH2O), 5.24 and 5.25 (t, 3J = 4.3 Hz, 4H,
NCH2CH2O), 6.69-6.82 (m, 8H, arom. CHs,
NCH2CH2OC6H4(OCH2CH3)-2), 7.18-7.23 and 7.29-7.32
16.8,
16.9,
17.2,
17.6,
17.7
and
17.8
(NCH2C6(CH3)5-2,3,4,5,6), 47.8 and 47.9 (OCH2CH3), 51.3
and 51.4 (NCH2C6(CH3)5-2,3,4,5,6), 63.9 and 64.0
(NCH2CH2O), 68.4 and 68.7 (NCH2CH2O), 111.4, 111.5,
111.7, 111.8, 112.8, 112.9, 113.1, 113.4, 120.7, 120.9,
121.3, 121.4, 122.5, 122.9, 128.1, 128.2, 133.0, 133.1,
134.4, 134.5, 134.6, 134.7, 135.5, 135.6, 135.7, 135.8,
148.0, 148.1, 148.5, 148.6 (arom. Cs, NC6H4N,
3
(m, 6H, arom. CHs, NC6H4N), 7.73 (d, J = 8.0 Hz, 2H,
arom. CH, NC6H4N). 13C NMR (100 MHz, CDCl3, 25 oC): δ
(ppm) = 12.9 and 13.0 (NCH2CH2CH2CH3), 14.0 and 14.1
(OCH2CH3), 19.6 and 19.7 (NCH2CH2CH2CH3), 30.7 and
30.8 (NCH2CH2CH2CH3), 47.1 and 47.2 (OCH2CH3), 47.3
and 47.4 (NCH2CH2CH2CH3), 63.0 and 63.1 (NCH2CH2O),
66.7 and 67.1 (NCH2CH2O), 109.0, 109.1, 110.8, 111.1,
111.8, 111.9, 112.3, 112.4, 119.8, 119.9, 120.3, 120.4,
121.8, 121.9, 133.4, 133.5, 134.4, 134.5, 147.0, 147.1,
NCH2C6(CH3)5-2,3,4,5,6
NCH2CH2OC6H4(OCH2CH3)-2),
and
182.4
182.3
and
(Pd-Ccarbene), (ratio of cis/trans isomers = 47:53). Ele-
mental analysis calcd (%) for C58H68Br2N4O4Pd (Mr =
1151.43 g.mol-1): C 60.50, H 5.95, N 4.87; found (%): C
60.52, H 5.97, N 4.89.
147.5,
147.6
(arom.
Cs,
180.5
NC6H4N
and
180.7
NCH2CH2OC6H4(OCH2CH3)-2),
and
(Pd-Ccarbene), (ratio of cis/trans isomers = 49:51). Ele-
mental analysis calcd (%) for C42H50Br2N4O4Pd (Mr =
941.11 g.mol-1): C 53.60, H 5.36, N 5.95; found (%): C
53.62, H 5.37, N 5.97.
cis/trans-Dibromo-bis[1-(2-(2-ethoxyphenoxy)ethyl)-3-
(4-tert-butylbenzyl)benzimidazol-2-ylidene]palladium
1
(II) (2f): Yield: 0.308 g, 55%; H NMR (400 MHz, CDCl3,
25 oC, TMS): δ (ppm) = 1.15 and 1.18 (s, 18H,
3
cis/trans-Dibromo-bis[1-(2-(2-ethoxyphenoxy)ethyl)-3-
NCH2C6H4(C(CH3)3)-4), 1.35 and 1.40 (t, J = 7.0 Hz, 6H,
3
(2-methoxyethyl) benzimidazol-2-ylidene]palladium(II)
OCH2CH3), 3.91 and 3.97 (q, J = 7.0 Hz, 4H, OCH2CH3),
1
3
(2d): Yield: 0.284 g, 60%; H NMR (400 MHz, CDCl3, 25
4.73 and 4.81 (t, J = 5.1 Hz, 4H, NCH2CH2O), 5.30 and
3
oC, TMS): δ (ppm) = 1.36 and 1.42 (t, J = 7.0 Hz, 6H,
5.40 (t, 3J = 5.0 Hz, 4H, NCH2CH2O), 6.02 and 6.14 (s, 4H,
NCH2C6H4(C(CH3)3)-4), 6.67-6.88 (m, 8H, arom. CHs,
NCH2CH2OC6H4(OCH2CH3)-2), 7.01-7.06 and 7.17-7.32
(m, 14H, arom. CHs, NC6H4N and NCH2C6H4(C(CH3)3)-4),
OCH2CH3), 3.22 and 3.32 (s, 6H, NCH2CH2OCH3), 3.92
and 3.99 (q, 3J = 7.0 Hz, 4H, OCH2CH3), 4.06 and 4.12 (t,
3J = 5.8 Hz, 4H, NCH2CH2OCH3), 4.67 and 4.72 (t, 3J = 5.8
3
3
Hz, 4H, NCH2CH2O), 4.88 and 4.90 (t, J = 5.8 Hz, 4H,
7.70 (d, J = 8.0 Hz, 2H, arom. CH, NC6H4N). 13C NMR
3
o
NCH2CH2OCH3), 5.20 and 5.22 (t, J = 5.9 Hz, 4H,
(100 MHz, CDCl3, 25 C): δ (ppm) = 15.0 and 15.1
NCH2CH2O), 6.70-6.81 (m, 8H, arom. CHs,
(OCH2CH3), 31.3 and 31.4 (NCH2C6H4(C(CH3)3)-4), 34.5
This article is protected by copyright. All rights reserved.

and 34.6 (NCH2C6H4(C(CH3)3)-4), 48.6 and 48.7
(OCH2CH3), 52.7 and 52.8 (NCH2C6H4(C(CH3)3)-4), 63.9
and 64.0 (NCH2CH2O), 67.9 and 68.1 (NCH2CH2O), 110.9,
111.0, 112.1, 112.3, 113.4, 113.5, 113.9, 114.0, 115.6,
115.7, 120.8, 120.9, 123.0, 123.2, 125.6, 125.8, 127.9,
128.0, 132.3, 132.4, 135.9, 136.0, 147.6, 147.7, 148.6,
9
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151.0,
151.1
(arom.
Cs,
NC6H4N,
NCH2C6H4(C(CH3)3)-4 and NCH2CH2OC6H4(OCH2CH3)-2),
182.0 and 182.1 (Pd-Ccarbene), (ratio of cis/trans isomers
=
48:52). Elemental analysis calcd (%) for
C56H64Br2N4O4Pd (Mr = 1123.38 g.mol-1): C 59.87, H
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An oven dried 10 mL Schlenk tube was charged with
palladium(II)-NHC complex (0.01 mmol), benzoxazole or
benzothiazole (2.0 mmol), aryl bromide (1.0 mmol),
KOAc (2.0 mmol), and DMAc (2 mL) under argon. The
Schlenk tube was placed in a preheated oil bath at
150 °C for 4 h. Completion of the reaction, the solvent
was removed under vacuum and the residue was
charged directly onto a micro silica gel column. The
products were eluted by using n-pentane/Et2O mixture
(4:1, v/v). The yields were calculated by GC with
dodecane as internal standard.
Supporting Information
The supporting information for this article is
available
on
the
WWW
under
http://dx.doi.org/10.1002/cjoc.2017xxxxx.
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Acknowledgement
This work was financially supported by the
Technological and Scientific Research Council of Turkey
(TÜBİTAK-BOSPHORUS (France), Project no: 109T605)
and the İnönü University Research Fund (İÜBAP, Project
no: 2015/41).
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Scheme Captions
Scheme 1 Synthesis of 2-aryl-substituted benzoxazoles and benzothiazoles
Scheme 2 Synthesis of benzimidazolium bromides and palladium(II)-NHC complexes
Figure Captions
Figure 1 Examples of biologically active benzoazole derivatives
Figure 2 Palladium(II)-NHC complexes (2a-f)
Table Captions
Table 1 Physical and spectroscopic properties of the novel compounds
Table 2 Screening of the reaction condition for the palladium(II)-NHC-catalyzed direct arylation of benzothiazole with
4-chloroacetophenone and 4-bromoacetophenone
Table 3 Palladium(II)-NHC-catalyzed direct arylation of benzoxazole and benzothiazole with aryl bromides
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Direct C-H Bond Activation of Benzothiazole
and Benzoxazole with Aryl Bromides
Catalyzed by Palladium(II)-N-Heterocyclic
Carbene Complexes
Six new palladium(II)-NHC complexes with the general molecular formula
[PdBr2(NHC)2], (NHC = 1,3-dialkylbenzimidazol-2-ylidene) were synthesized. The
obtained complexes were fully characterized by analytical and spectral methods such as
elemental analysis, FT-IR, 1H NMR and 13C NMR. The catalytic activity of the all
palladium(II)-NHC complexes have been evaluated in the C-H bond activation of
benzoxazole and benzothiazole with aryl bromides in moderate to high yields.
Murat Kaloğlu; Nazan Kaloğlu and İsmail
Özdemir*
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