Direct synthesis of 2-substituted benzimidazoles: Via dehydrogenative coupling of aromatic-diamine and primary alcohol catalyzed by a Co complex

Article abstract of DOI:10.1039/d0nj03619f

A Co(ii) complex with a stable structure was designed and synthesized with quinalic acid and Co (OAc)2·4H2O. The single crystal structure of the complex was characterized by X-ray diffraction. A dehydrogenative coupling of aromatic diamines and primary alcohols was developed by using the Co(ii) complex as the catalyst to synthesize 2-substituted benzimidazole. A series of 2-substituted benzimidazoles were obtained with good to excellent yields under mild reaction conditions. In addition, a compound with inhibitory Parkinson's activity was synthesized on a gram-scale by using this method. Finally, the reaction mechanism was proposed and the energy changes in the reaction process were simulated by density functional theory (DFT).

Full text of DOI:10.1039/d0nj03619f

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Direct synthesis of 2-substituted benzimidazoles via
dehydrogenative coupling of aromatic-diamine and primary
alcohol catalyzed by Co Complex
Minghui Zuo a,b, Weihao Guo a,b, Yucheng Pang a,b, Rui Guo a,b, Chuanfu Hou a,b,Shouneng Sun a,b
,
a,b
a,b
a,b
Hongfeng Wu , Zhizhong Sun and Wenyi Chu
*
.4H
A Co (II) complex with stable structure was designed and synthesized with quinalic acid and Co (OAc)
2
2
O. The single
crystal structure of complex was characterized by X-ray diffraction. A dehydrogenative coupling of aromatic diamines and
primary alcohols was developed by using the Co (II) complex as the catalyst to synthesize 2-substituted benzimidazole. A
series of 2-substituted benzimidazole were obtained with good to excellent yields under mild reaction conditions. In
addition, a compound with inhibit Parkinson's activity was synthesized on the gram-scale by using the method. Finally, the
reaction mechanism was proposed and the energy changes in the reaction process were simulated by density functional
theory (DFT).
application limitations because they often require strong acidic
or alkaline conditions and stoichiometric oxidants and
INTRODUCTION
Benzimidazole, as an important class of biologically active
heterocyclic compounds, is an important structural unit of
many anticancer drugs, antiviral drugs, psychotropic drugs,
drugs for treating coronary heart disease, and drugs for
1
1-14
complicated catalysts,
as well as low atomic utilization and
poor functional group compatibility, and produce
1
1
5
stoichiometric salt waste. Therefore, it is an important goal
to develop synthetic method that is efficient,
environmentally friendly and avoiding multi-step operations.
a
1
6
2
,3
treating Alzheimer's disease.
Benzimidazole and its
In this case, transition metal-catalyzed dehydrogenation
coupling reaction of renewable alcohols with 1,2-
diaminobenzene become another synthetic method for
derivatives have good biological activity and have important
application value in anti-cancer, antibacterial and de-
worming.4 They are widely used in pharmaceutical and
pesticide fields, and can also be used as important organic
,5
1
7-21
benzimidazoles.
synthesis intermediates (Scheme 1), for example, 1-benzyl-2-
pyridin-2-yl)-1H-benzo[d]imidazole (anti-PD), benzimidazole
quinazoline (bacteriostatic). In addition, benzimidazole
compounds can emit characteristic fluorescence, which can be
used as a fluorescent chemical sensor to detect metal ions. For
example, bis-N-propylcyano-2-benzimidazole (fluorescent
material),8 3-(1H-benzo [d] imidazol-2-yl) thiophene-2-ol
fluorescent sensor). It is because of the significance and
application of benzimidazole that the synthesis of these
compounds is particularly important.
6
(
N
N
N
N
N
7
N
1-benzyl-2-(pyridin-2-yl)-1H-benzo[d]imidazole
benzimidazole quinazoline
NC
H
N
N
N
N
N
9
N
N
(
HO
CN
bis-N-propylcyano-2-benzimidazole
3-(1H-benzo[d]imidazol-2-yl)quinolin-2-ol
Benzimidazole and its derivatives are usually prepared by
condensation of 1, 2-diaminobenzene and carbonyl
derivatives.10 However, these processes are subject to
Scheme 1 Representative compounds with a benzimidazole
structure skeleton
2
2
In 2018, Kaliccharan Das and co-workers synthesized a series
of 2-substituted benzimidazole using o-phenylenediamine and
benzyl alcohol as substrates and Mn(I) NNS- donor Complex as
catalyst at 140°C (Scheme 2a). In the same year, Lin li and co-
a. Address here. School of Chemistry and Materials Science, Heilongjiang University,
Harbin 150080, P. R. China.
Address here. Key Laboratory of Chemical Engineering Process and Technology
for High-efficiency Conversion, College of Heilongjiang Province, Harbin 150080,
P. R. China (E-mail: wenyichu@hlju.edu.cn; Tel /Fax: +86-451-86609135)
b.
23
workers synthesized benzimidazole with o-phenylenediamine
and benzyl alcohol as substrates and Ru (II) NNN- donor
Complex as catalyst at 165°C (Scheme 2b). In 2019, Kaushik
2
4
Chakrabarti and co-workers
prepared 2-substituted
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benzimidazole with o-phenylenediamine and benzyl alcohol as ray
substrates using Ir(II) N,N-type catalysts at 120°C (Scheme 2c). (C10
In addition, some research groups have also achieved system and the space group P 2
synthesis of 2-substituted benzimidazole using visible light the complex contained a Co atom and two quinoline-2-
catalysis. For example, in 2018, Ameneh Eskandari and co- carboxylic acid (Ligand) units, and the Co atom consisted of
workers
derivatives at 80°C with o-phenylenediamine and benzyl oxygens (O1, O2, ) atoms. The novel Co (II) Complex as a
alcohol as substrates, Co(II)-TD@nTiO
NHPI as additive(Scheme 2d).
diffraction
analysis
OH) Complex crystallized in the monoclinic
/c. The molecular structure of
indicated
that
the
Co
View Article Online
DOI: 10.1039/D0NJ03619F
H
10NO ) (2C H
2 2 2 5
1
2
5
synthesized a series of benzimidazole and its two quinoline nitrogen (N1, and N2) atoms and two ketone
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as photocatalyst and catalyst for synthesis of
a
series of 2-substituted
benzimidazoles and their derivatives was evaluated in this
Although these works were effective, they were limited by paper. (NMR, FTIR, UV-Vis, elementary analysis and mass
noble metal catalysts and harsh reaction conditions, and most spectrometry data are in the support information)
of these metal complexes require Clip-on ligands, such as The structure of the complex is shown in the figure. The Co ion
tridentate NNS, PNN ligands and NNN ligands. These ligands in the complex forms
a
six-coordinated octahedral
are not only expensive and sensitive to air, but also difficult to configuration with the four O atoms and two N atoms of the
synthesize. The photocatalytic synthesis method was used to quinalidic acid ligand; the complex is a symmetrical structure
solve the problem of harsh reaction conditions, but the as a whole. (CShM=0.821, CShM value is calculated by Shape
synthesis steps of photocatalyst were also very complicated, software)
and the oxidant was added in the reaction process, which Co-O2 = 2.014 Å; vertical Co-O2 = 2.103 Å, it can be seen that
increased the operation steps of the reaction. the average value of atoms in the horizontal direction is
Based on the above problems, it is necessary to design and greater than the average value in the vertical direction, the
synthesize catalyst for the efficient synthesis of atoms at the level are far away from Co ions, which greatly
benzimidazoles. Therefore, Co (II) N, O Complex was designed increases the catalytic efficiency.
and synthesized, because cobalt is abundant and has good Figure 1 The molecular structure of Co (C10
catalytic activity and low pollution. At the same time, the Complex
synthesized Co (II) Complex was structurally stable in the air.
2
6,27
From a horizontal perspective, Co-N1 = 2.200 Å,
a
H
2 2 2 5
10NO ) (2C H OH)
The synthesized Co (II) Complex was used as the catalyst to
prepare a series of 2-substituted benzimidazole and its
derivatives with o-phenylenediamines and primary alcohols or
benzyl alcohols as substrates at room temperature (Scheme
2
e). In addition, the reaction mechanism was explored by the
energy changes of the whole reaction using DFT calculation.
(a) Dipankar Srimani's work
H
N
NH2
Cat.
H
OH
+
R
N
KOH 140o
C
N
R
Catalyst=
N
NH2
Mn SHEt
OC CO
Table 1 Optimization of the reaction conditions of o-
phenylenediamine and benzyl alcohol a
(b) Lin Li's work
NH2
H
N
H
H
Cat.
Catalyst=
N
N
+
HO
R
R
N
H
NH2
NH2
165oC.24h.
N
N
Ru
Cl
N
Catal.(mol%). Base.
Solvent. Time
N
OH
+
Ph3P
PHPh3
N
c
Thanh Binh Nguyen's work
NH2
NH2
H
Cat.
Argon
N
OH
OH
+
R
Catalyst=
N
NH
Yield
(%)
120oC 24h
R
Ir
Entry
Catal.(mol%)
Solvent
Base
Time(h)
NH2
N
N
b
Cl
(d) Jeshma Kovvuri's work
1
2
3
4
5
6
7
8
9
Complex(0.2mol)
CoCl
Co(OAc)
Complex(0.4mol)
Complex(0.6mol)
Complex(0.4mol)
Complex(0.4mol)
CH
CH
CH
CH
CH
3
3
3
3
3
CN
CN
CN
CN
CN
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
3
3
3
2
2
2
2
2
2
2
2
2
2
2
2
1
3
75%
35%
65%
92%
92%
75%
72%
70%
45%
46%
45%
50%
72%
93%
NH2
H
N
Co(II)-TD@nTiO2
+
R
2
NH2
Visible light NHPI 80o
N
R
C
2
(e) Our work
NH2
CO
3
H
O
Cat.
R.T. Air(O2)
N
+
HO
R
R
Catalyst=
O
Co N
O
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
N
O
2C2H5OH
N
NH2
DCM
DCE
Complex(0.4mol) Toluene
Scheme 2 The method for synthesis of 2-substituted
benzimidazoles
Complex(0.4mol)
Complex(0.4mol)
Complex(0.4mol)
Complex(0.4mol)
Complex(0.4mol)
Complex(0.4mol)
DMF
DMSO
1
1
1
1
1
0
1
2
3
4
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
KOH
Cs CO
Na CO
Na CO3
2
3
RESULTS AND DISCUSSION
The synthesized cobalt complex was characterized by X-ray
single crystal analysis. The ORTEP of the molecular structure of
2
3
2
a
o-phenylenediamine (1.0 mmol), benzyl alcohol (1.0 mmol),
Co(II) Complex (0.4 mol%), base (0.5 mmol), room
the Co (C10
2 2 2 5
H10NO ) (2C H OH) Complex was shown in Figure 1
b
temperature. Isolated yields.
and the crystal data was listed in the support information. X-
2
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Based on the initial experiments, o-phenylenediamine and
benzyl alcohol were used as the substrates to optimize the
reaction conditions, and results were summarized in Table 1.
Primordially, the Co (II) Complex was used as a catalyst to
afford corresponding product in 75% yield (Table 1, entry 1).
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OH
OH
OH
OH
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DOI: 10.1039/D0 N8 J 20 3619F
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H
F
F
N
85
88
80
89
86
88
N
H
Cl
Br
Other Co (II) catalysts were also investigated; CoCl
2
and Co
Cl
(
OAc) only gave the product in 35% and 65% yields,
2
N
respectively (Table 1, entries 2-3). Then the amount of the
complex catalyst was evaluated, when the complex was
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H
Br
0
.4mol% equivalent of the substrate, the yield of the reaction
reached 92%, but with the continuous increase of catalyst to
.6mol%, the yield showed no significant change (Table 1,
N
1
0
1
N
H
0
CH3
OH
H3C
entries 4-5).
N
Subsequently, reaction solvents were investigated.
Dichloromethane (DCM), 1,2-dichloroethane (DCE) and
toluene as the solvents gave the product in 75%, 72%, and 70%
yields, respectively (Table 1, entries 6-8). The use of N, N-
dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) 12
only gave lower yields in 45%, 46% (Table 1, entries 9-10),
1
N
H
NO2
NO2
N
OH
OH
OH
N
H
F
F
while the use of acetonitrile (CH
Table 1, entry 4). Then, different bases were investigated. The 13
use of Na CO gave a good yield in 92% (Table 1, entry 4), but
when KOH and Cs CO were used, the yields reduced to 45%
3
CN) gave a good yield in 92%
N
(
N
H
2
3
Cl
Cl
2
3
N
and 50%, respectively (Table 1, entries 11-12). Finally, it was
found that the reaction time was shortened to 1h, the yield
was reduced to 72%, and the yield of the target product was
not significantly improved by increasing to 3h (Table 1, entries
14
83
N
H
CH3
CH3
F
N
OH
1
5
6
90
91
1
3-14).
N
H
F
Table 2 Substrate scope of condensation cyclization of benzyl
alcohol and o-phenylenediamine a
N
OH
Cl
1
N
H
H
Cl
NH2
Co(II) Complex.
N
+
R1
OH
R1
OH
N
NH2
CH CN Na CO Air(O2)
N
R2
3
2
3
R2
O
17
83
H3CO
Ph
N
H
Entry
Substrates
Products
Yield(%)b
N
OH
Ph
18
19
20
88
76
73
N
H
N
1
2
3
4
5
6
H C
OH
OH
OH
75
3
N
H
N
OH
N
N
H
N
H
N
C H
2
72
68
65
79
92
5
C H
2 5
N
S
S
N
N
H
OH
OH
H
N
4
n-C H9
n-C H
H
N
4
9
N
21
90
91
H
H C
N
3
N
n-C H
OH
7 15
n-C H
7
15
H
N
OH
N
22
N
N
Cl
OH
OH
N
H
a
o-phenylenediamine (1.0 mmol), primary alcohol (1.0 mmol),
Co(II) Complex (0.4 mol%), CH
3
CN (10 ml), Na
at room temperature for 2h. Isolated yields.
2
CO
3
(0.5 mmol.),
N
b
N
H
Base on above experimental results, it was determined that
the optimal reaction system was o-phenylenediamine and
benzyl alcohol as the reaction substrates, Co (II) Complex as
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catalyst, CH CN as solvent, Na CO as base, at room
temperature for 2h.
View Article Online
DOI: 10.1039/D0NJ03619F
H
NH2
N
OH
Co (II) Complex
With the optimized reaction conditions in hand, we turned our
attention toward the scope of the substrates, and the results
were summarized in Table 2. Firstly, aliphatic alcohols
including ethanol, n-propanol, n-pentanol, n-octanol and
cyclohexylmethanol were used as the reaction reagents to
afford corresponding products with yields of 75%, 72%, 68%,
(a)
+
N
NH2
standard conditions
N
N
2
0 mmol, 2.16 g
20 mmol, 2.18 g
76%, 2.96 g
H
N
Benzyl bromide
CH3CN, KOH
(b)
N
N
0
1
2
3
4
5
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0
1
2
3
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0
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0
1
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3
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9
0
1
2
3
4
5
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7
8
9
0
N
N
N
6
5% and 79%, respectively (Table 2, entries1-5). Then,
1
0 mmol, 1.95 g
(80%, 2.28 g; total yield 61% )
aromatic alcohols were investigated. Benzyl alcohol without a
substituent gave the product in a yield of 92% (Table 2, entry6). Scheme 3 Application of synthesis of 1-benzyl-2-phenyl-1H-
For ortho-substituents, electron-withdrawing groups (-F, -Cl benzo[d]imidazole
and -Br) gave the corresponding product in 82%, 85% and 88% In order to further understand the reaction mechanism, the
yields, respectively (Table 2, entries7-9), meanwhile electron- following control experiments were carried out as shown in
donating group (-Me) gave a yield of 80% (Table 2, entry 10). Scheme 4.The reaction time was adjusted to 30, 60 and 90
For meta- substituents, electron-withdrawing groups (-NO
Cl) gave the corresponding products in 89%, 86% and 88% (benzylamine) aniline were 41%, 25% and 10%, respectively,
2
, -F, minutes, and the yields of the intermediate product 2-
-
yields, respectively (Table 2, entries11-13), electron-donating while the yields of 2-phenyl-1H-benzo (d) imidazole were 33%,
group (-Me) gave the corresponding product in 83% yield 54% and 77%, respectively (Scheme 4a). The results showed
(
Table 2, entry 14). For para-substituents, electron- that 2-(benzylideneamino) aniline is an important intermediate
withdrawing groups (-F, -Cl) gave the corresponding products for synthesis of 2-phenyl-1H-benzo (d) imidazole. Then the
in 90% and 91% yields, respectively (Table 2, entries15-16), control experiments were performed in different reaction
electron-donating groups (-OMe, -Ph) gave the yields of 83% atmospheres. It was found that the yields of the product were
and 88%, respectively (Table 2, entries17-18). In addition, obtained in 92% and 94% under air atmosphere and O
pyridin-2-ylmethanol and thiophen-2-ylmethanol also gave the atmosphere, while the reaction was inhibited under N
corresponding products in 76% and 73% yields (Table 2, atmosphere to afford only a yield of 5% (Scheme 4b).
entries19-20).
Therefore, O in air atmosphere is necessary in this reaction
According to the above experimental results, it was found that system.
the reactivity of aliphatic alcohols was not as high as that of Scheme 4 Control Experiments
aromatic alcohols. This is because aromatic alcohols are more
conducive to dehydrogenation than aliphatic alcohols to form
aromatic aldehydes. For the substituents of aromatic alcohols,
the reactivity of electron-withdrawing groups was higher than
that of electron-donating groups. This is because the electron
2
2
2
H
N
NH2
Co (II) Complex Air
N
(a)
+
OH
+
N
NH2
CH CN, Na CO , R.T.
3
2
3
NH2
Time (30 min)
Time (60 min)
Time (90 min)
Yield: 41%
Yield: 25%
Yield: 10%
33%
54%
77%
-withdrawing
groups
are
advantageous
to
the
H
N
NH2
NH2
Co (II) Complex,
OH
(b)
+
dehydrogenation of aromatic alcohols to form aromatic
aldehydes. In addition, the yield of ortho-substituents was
slightly lower than that of para- and meta-substituents due to
steric hindrance effect. Finally, when the substrates were
CH3CN, Na2CO3, R.T.
N
under Air atmosphere 92%
under O2 atmosphere 94%
under N2 atmosphere
5%
benzyl alcohol, different substituents of o-phenylenediamine On the basis of experimental results and previous literatures
1
4,26-27
were investigated. Both electron-donating group (-Me) and reported,
electron-withdrawing group (-Cl) afforded good yields of 90% substituted benzimidazole catalyzed by the Co(II) Complex is
and 91% (Table 2, entries 21-22).
described in Scheme 5. Initially, Co (II) Complex catalyzes
In order to further demonstrate the practicability of the benzyl alcohol (IMA) to form benzaldehyde (IMB) by a process
catalytic system, a gram-scale reaction of o-phenylenediamine of dehydrogenation. Subsequently, benzaldehyde reacts with
and pyridin-3-ylmethanol was implemented, the target o-phenylenediamine to obtain 2-(benzylideneamino) aniline
product 2-(pyridin-2-yl)-1H-benzo[d]imidazole was obtained in (IMC) by a coupling reaction, and furtherly reacts to form a
a plausible mechanism for synthesis of 2-
7
6% yield (Scheme 3a). Then, 2-(pyridin-2-yl)-1H- cyclic intermediate (IMD) by a cyclization. Finally, the cyclic
benzo[d]imidazole was used as raw material to synthesize 1- intermediate is furtherly catalyzed by Co (II) Complex to obtain
benzyl-2-phenyl-1H-benzo[d]imidazole, which has an inhibitory the product 2-phenyl-1H-benzo (d) imidazole (IME) by a
effect on Parkinson's biological activity.
2
8
According to process of dehydrogenation. During catalytic cycle, O2 in the
1-benzyl-2-phenyl-1H-benzo[d]- air atmosphere can oxidize the formed Co (I) Complex to
2
9,30-36
previous literatures,
imidazole was obtained in a low yield and complicated regenerate the catalyst Co (II) Complex.
conditions. Compared with the previously reported method,
our protocol is more convenient and efficiently to obtain the
target product with the total yield of 61% (Scheme 3b).
4
| J. Name., 2012, 00, 1-3
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confirms the rationality of the reaction mechanism (Figure 2
View Article Online
OH
O
DOI: 10.1039/D0NJ03619F
and Figure 3).
(IMA)
(IMB)
Co(II) Complex
Co(I) Complex
NH2
NH2
CONCLUSION
Air(O2)
Air(O2)
In summary, the stable Co (II) Complex was synthesized by
N
.
using cheap raw materials of quinalic acid and Co (OAc)
2
2
4H O.
NH2 (IMC)
Its single crystal structure was characterized by X-ray
diffraction. The Co (II) Complex was used as catalyst to directly
synthesize a series of 2-substituted benzimidazoles with o-
phenylenediamines and primary alcohol as the substrates
under mild reaction conditions. In addition, we discussed the
mechanism of the reaction and simulated the energy change
during the reaction by using density functional theory (DFT).
Our laboratory is designing cheaper and more efficient
catalysts and studying their applicability in other reactions.
0
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Co(I) Complex
Co(II) Complex
H
N
H
N
N
N
H
H
(IME)
(IMD)
Scheme 5 Proposed Mechanisms
Experimental
Synthesis of complex
2 2
Quinadinoic acid (1.0 eq, 1g) and Co (OAc) ·4H O (1.2 eq, 2.42g)
were mixed into a 100mL round bottom flask, then 30mL of
distilled water and 30mL of ethanol were added, and stirred at
room temperature for 30 minutes. Then the mixture was
o
transferred to a water bath, heated at 70 C for 4 hours and
filtered three times to obtain a clear solution. Finally, the clear
solution was divided into test tubes and volatilized. After 72
hours of diffusion with ether solvent, 0.95 g of pink
transparent crystals was obtained with a yield of 95%.
Catalytic reaction process
Figure 2 Optimized structures of reactants, intermediates and
products
Benzyl alcohol (1.0 mmol), o-phenylenediamine (1.0 mmol),
CH CN (10 mL), Na CO (0.5 mmol) and Co (II) Complex (0.40
3 2 3
mol%) were added into a 25 ml flask. The mixture was stirred
at room temperature for 2h. After the reaction was completed,
the reaction mixture was extracted 3 times with ethyl acetate
(
3×15 mL). The combined organic layer was dried with
anhydrous sodium sulfate. After removing the solvent by
rotary evaporation, the residue was purified by column
chromatography (petroleum ether / EA = 20: 1 as eluent).
Computational Method
The calculations were carried out by performing DFT by use of
the B3LYP functional with the 6-31G (d) basis set as
implemented in Gaussian 09 program package. All geometries
for the reactants, products, intermediates, and transition
states have been fully optimized. Vibrational frequency
calculations have been performed for each optimized structure
at the same level to identify the nature of all the stationary
Figure 3 Energy barrier diagram
In addition, based on the above reaction mechanism, the DFT
calculation method
changes of each reaction step to verify the correctness of the
reaction mechanism. IMB is formed by the release of hydrogen
from IMA through TS1 with relative energy of 22.8 Kcal/mol.
IMC is formed by the release of a molecule of H O from IMB points (local minimum or first-order saddle point).
through TS2 with relative energy of 16.1 Kcal / mol. IMC
2
4,37
was used to calculate the energy
2
generates IMD through TS3 with relative energy of 10 Kcal /
mol. Finally, IMD produces the target product IME by the Conflicts of interest
dehydrogenation through TS4 with relative energy of 11.8 Kcal
There are no conflicts to declare.
/
mol. Therefore, the DFT calculation method more specifically
This journal is © The Royal Society of Chemistry 20xx
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1. Z. F. Li, H. Song, R. Guo, M. H. Zuo, C. F. Hou, S. VNie.wSAurntic,leXO. nHlinee,
Acknowledgements
Z. Z. Sun and W. Y. Chu, Green Chem., 2019, 21, 3602-3605.
DOI: 10.1039/D0NJ03619F
This work was supported by Fund of Natural Science 22. K. Das, A. Mondal and D. Srimani, J Org Chem., 2018, 83,
Foundation of Heilongjiang Province of China (No. B2018012).
9
553-9560.
23. L. Li, Q. Luo, H. Cui, R. Li, J. Zhang and T. Peng,
ChemCatChem., 2018, 10, 1607-1613.
2
4. K. Chakrabarti, M. Maji and S. Kundu, Green Chem., 2019, 21,
Notes and references
1
999-2004.
1
. R. Hili and K. Y. Andrei, Nat Chem Biol., 2006, 6, 284-287.
25. A. Eskandari, M. Jafarpour, A. Rezaeifard and M. Salimi, New
J Chem., 2018, 42, 6449-6456.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2. D. A. Horton, G. T. Bourne and M. L. Smythe, Chem Rev., 26. S. Alvarez, P. Alemany, D. Casanova, J. Cirera, M. Llunell and
2003, 103, 893-930.
D. Avnir, Coord. Chem. Rev., 2005, 249, 1693–1708.
. N. R. Candeias, L. C. Branco, P. M. P.Gois, A. M. Afonso and A. 27. J. Cirera, E. Ruiz and S. Alvarez, Organometallics, 2005, 24,
F. Trindade, Chem Rev., 2009, 109, 2703-2802.
1556–1562.
. D. P. Jasmer, C. Yao, A. Rehman and S. Johnson, Mol Biochem 26. S. Rçsler, M. Ertl, T. Irrgang and R. Kempe, Angew Chem In
Parasit., 2000, 105, 81-90.
Ed., 2015, 54, 15046-15050.
5. S. Bhattacharya and P. Chaudhuri, Curr Med Chem., 2008, 15, 27. F. Bottaro and R. Madsen, ChemCatChem., 2019, 11,2707-
1762-1777.
2712.
. D. Almas, D. A. Alonso, E. Gomez, and C. N. Ajera, J Org 28. A. Morita, Y. Okuma, S. Kamei, F. Yoshii and T. Yam, Internal
Chem., 2009, 166, 163-6168.
Med., 2011, 50, 2163-2168.
. L. Unax, D. E Saios, S. Amaia, G. Montserrat, R. O. Borja and A. 29. B. Liu, Q. Guo, Y. Cheng, J. Lan and J. You, Chem Eur J., 2011,
Carmeo, Curr Drug Safety, 2013, 8, 63-68.
17, 13415-13419.
8. S. K. Gupta and S. S. Pancholi, J. Pharm. Sci. Res., 2010, 2, 30. X. M. Yan, X. R. Mao and Z. Z. Huang, Methods in Org Synth.,
2011, 83, 1371-1376.
3
4
6
7
228-231.
9
. J. Liu, Q. Lin, Y. M. Zhang and T. B.Wei, Sci China Chem., 2014, 31. A. Djemoui, A. Naouri, M. R. Ouahrani, D. Djemoui, S.
5
7, 1257-1263.
Lahcene, M. B. Lahrech, L. Boukenna, H. Albuquerque, L.
Saher, D. Rocha, F. L. Monteiro, L. A. Helguero, K. Bachari, O.
Talhi and A. Silva, Journal of Molecular Structure., 2020, 1204,
127487.
1
1
0. P. N. Preston, Chem Rev., 1974, 74, 279-314.
1. B. Blank, M. Stefan and K. Rhett, Adv Synth Catal., 2009, 351,
2903-2911.
12. S. Michlik and R. Kempe, Angew Chem In Ed., 2013, 52, 6326- 32. C. a Vallés-García, M. Cabrero-Antonino, S. Navalón, M.
6
329.
Álvaro, A. Dhakshinamoorthy and Hermenegildo García,
Journal of Colloid and Interface Science., 2020, 560 , 885–893.
33. A. Shaikh, O. Ravi, S. P. Ragini, N. Sadhana and S. R. Bathula,
Tetrahedron Lett., 2020, 61, 151356.
34. H. Lgaz, I.M. Chung, M. R. Albayati, A. Chaouiki, R. Salghi and
S. K. Mohamed., Arabian Journal of Chemistry., 2020, 13,
120–133.
1
1
3. Z. Xu, D. S. Wang, X. Yu, Y. Yang and D. Wang, Adv Synth
Catal., 2017, 359, 3332-3340.
4. M. Mastalir, G. Tomsu, E. Pittenauer, G. Allmaier and K.
Kirchner, Org Lett., 2016, 18, 3462-3465.
15. B. Katalin and P. C.Ford, Accounts Chem Res., 2014, 47, 1503-
512.
1
1
6. J. Fan, T. Wang, C. Li, R. Wang, X. Lei, Y. Liang and Z. Zhang, 35. A. Baldisserottob, M. Demurtasa, I. Lamprontic, M. Tacchinid,
Org Lett., 2017, 19, 5984-5987.
7. G. E. Dobereiner and R. H. Crabtree, Chem Rev., 2009, 110,
681-703.
D. Moia, G. Balbonia, S. Pacifcoe, S. Vertuanib, S.
Manfredinib and V. Onnis., Bioorganic Chemistry, 2020, 94,
103396.
1
18. S. Das, S. Mallick and S. Sarkar, J Org Chem., 2019, 84, 12111- 36. A. G. Uslua, T. G. Maza, A. Nocentinib, E. Banoglua, C.T.
1
2119.
Supuranb and B. Çalışkan., Bioorganic Chemistry, 2020, 95
103544.
37. H. Li, G. Lu, J. Jiang, F. Huang and Z. X. Wang,
Organometallics., 2011, 30, 2349-2363.
1
2
9. P. Daw, Y. Ben-David and D. Milstein, ACS Catal., 2017, 7,
7
456-7460.
0. J. Y. Song, X. Zhou, H. Song, Y. Liu, H. Y. Zhao, Z. Z. Sun and
W. Y. Chu, ChemCatChem., 2018, 10, 758-762.
6
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New Journal of Chemistry
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View Article Online
DOI: 10.1039/D0NJ03619F
Table of Contents Entry
H
N
NH2
Co(II) Complex.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
0
1
2
3
4
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9
0
1
2
3
4
5
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7
8
9
0
+
R1
OH
R1
NH2
R2
CH CN Na CO Air(O2)
N
3
2
3
R2
1
2
3
.Inexpensive Co-catalyst
.Wide scope of substrates
.Mild conditions
22 example products
65%-92% yield
A Co (II) complex with low price was designed and synthesized with quinalic acid and Co
.
(
OAc) 4H O. The catalyst was relatively easy to synthesize and did not require complex reaction
2
2
conditions. The single crystal structure of was characterized by X-ray diffraction. A
dehydrogenative coupling of aromatic diamines and primary alcohols was developed by using
the Co (II) complex as the catalyst to synthesize 2-substituted benzimidazole. In addition, we
discussed the mechanism of the reaction and simulated the energy change during the reaction
by using density functional theory (DFT). Finally, a compound with inhibit Parkinson's activity was
synthesized on the gram-scale by using the method.