Chemoselective Chan-Lam Coupling Reactions between Benzimidazoline-2-thiones and Arylboronic Acids

Article abstract of DOI:10.1021/acs.joc.9b01370

An efficient Chan-Lam-type methodology for the selective synthesis of S-arylbenzimidazoles and N,S-diarylbenzimidazoles was developed. The selectivity was controlled by varying the amount of the catalyst Cu(OAc)₂·H₂O, temperature, an

Full text of DOI:10.1021/acs.joc.9b01370

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Article
Chemoselective Chan-Lam Coupling Reactions between
Benzimidazoline-2-Thiones and Arylboronic Acids
Xing Liu, and Zhi-Bing Dong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01370 • Publication Date (Web): 22 Aug 2019
Downloaded from pubs.acs.org on August 22, 2019
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Chemoselective Chan-Lam Coupling Reactions between
Benzimidazoline-2-Thiones and Arylboronic Acids
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9
Xing Liu,a Zhi-Bing Dong* a,b
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aSchool of Chemistry and Environmental Engineering, Wuhan Institute of
Technology, Wuhan 430205, China.
bMinistry-of-Education Key Laboratory for the Synthesis and Application of Organic
Functional Molecules, Hubei University, Wuhan 430062, China
Email: dzb04982@wit.edu.cn
R2
H
N
R1
S
H
N
N
H
N
N
Cu(OAc)2 H2O (5%)
Bpy (10%)
Cu(OAc)2 H2O (50%)
Bpy (50%)
1
R1
S
R1
S
N
+
DMF, 30 o
open air
C
DMF/H2O = 1 : 3
80 oC, open air
R2
B(OH)2
R2
4
R2
3
2
mild conditions
one pot manner
C-S and C-N bond formation in one step
good selectivity
good substrate scope
H2O as reaction co-solvent
16 examples, yields up to 93%
14 examples, yields up to 95%
first example of double Chan-Lam coupling
obviates the use of equivalent catalyst
ABSTRACT
An efficient Chan-Lam-type methodology for the selective synthesis of
S-arylbenzimidazoles and N,S-diarylbenzimidazoles was developed. The selectivity
was controlled by varying the amount of the catalyst Cu(OAc)2•H2O, temperature and
solvent switching. These transformations feature a simple protocol, broad functional
group tolerance, high selectivity, and good to excellent yields. It is noteworthy that
these reactions represent the first examples of the application of the selective
Chan-Lam coupling.
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INTRODUCTION
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Benzimidazoline-2-thione derivatives represent a class of very important heterocyclic
organosulfur compounds widely used in the fields of medicine, agriculture, dye
industry, and functional materials.1 The heteroatom-containing aryl sulfide is
universal and serves as a critically important structural motif in certain biologically
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active
natural
products
and
drugs.2
The
tautomeric
nature
of
benzimidazoline-2-thiones make them a unique structural class due to the presence of
two adjacent nucleophilic nitrogen and sulfur atoms. According to the literature,
benzimidazole sulfides have attracted much attention from synthetic chemists mainly
for their wide range of biological activities (Figure 1).3
N
N
H
N
H
N
S
S
N
N
O
O
O
O
CF3
Ufiprazole
Prevacid
Cl
N
N
S
N
N
N
S
N
S
N
H2N
N
N
N
NHcPr
Heat shock protein (HSP)-90 inhibitor
Antiprotozoal
Figure 1. Some biologically active benzimidazole sulfides.
Given their importance, several synthetic strategies to access benzimidazole
sulfides have been developed (Scheme 1). General methods for the synthesis of
2-thio-substituted benzimidazoles include: nucleophilic addition of arylthiols on
pre-formed 2-halobenzimidazoles (path a),4 cross-coupling reactions between
benzimidazoline-2-thiones and aryl iodides or diaryliodonium triflates (path b),5 and
the S-arylation of benzimidazoles with diaryl disulfides (path c).6,3d Recently, Hajra
and co-workers reported the visible-light-mediated synthesis of 2-thiobenzimidazoles
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via oxidative coupling of benzimidazoline-2-thione with arylhydrazine (path d).7
However, these synthetic processes involve the requirement of stoichiometric strong
bases and/or high reaction temperatures, which somehow limit their synthetic
applications. Though significant progress has been achieved, protocols that are
environmentally benign, mild, and efficient are still highly valuable.
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H
N
H
N
Cl
S
N
N
H
IOTf
Ar2
Ar
SH
or
Path
b
ArI
a
Path
H
N
Ar
S
N
ArNHN
H2
Ar-S-S-Ar
c
Path
Path
H
N
d
H
N
H
S
N
N
H
Scheme 1. Existing synthetic strategies towards 2-thiobenzimidazoles.
The Chan-Lam coupling is a generally known efficient tool for the construction of
carbon-heteroatom bonds to proceed at ambient temperature as opposed to high
temperature transformations.8 Many efficient Chan-Lam-type coupling reactions of
aromatic and heteroaromatic NH-derivatives have been reported,9 while S-arylation
has received less attention as compared to N- or O-arylations. Difficulties in C-S bond
formation may be attributed to the sulfur species rapidly and irreversibly deactivating
the catalyst.10 Although several examples of Chan-Lam-type C-S coupling reactions
have been developed,11 the C-S bond formation between potentially ambiphilic
thiocarbonyl compounds and phenylboronic acids is rare (Scheme 2, previous
work).12 Recently, we disclosed an efficient Chan-Lam S-arylation of arylthioureas
with aryl boronic acids.13 To the best of our knowledge, to date Chan-Lam-type
mono- and bis-arylation of benzimidazoline-2-thiones with arylboronic acids was not
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reported. As part of our longstanding interest in organosulfur chemistry14 and our
expertise in the development of Chan-Lam chemistry,15 we anticipated that
chemoselective C-S and C-N bond formations with benzimidazoline-2-thiones via
Chan–Lam-type cross-coupling reactions could be feasible. Here, we disclose
un-precedented one-pot double and single Chan–Lam coupling reactions to access
diversely substituted bis- and mono-arylbenzimidazoles (Scheme 2, this work).
Unlike the previously reported work, the protocol here features broad substrate scope,
simple and mild reaction conditions, as well as good to excellent yields. Notably, the
use of an inorganic base and the exclusion of air and water were not required. The
selectivity was shown to be modulated by varying the amount of Cu(OAc)2•H2O,
temperature and solvent switching, which could be an attractive alternative approach
to accessing these important compounds.
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Classical Chan-Lam coupling
Cat. Cu(OAc)2 (equivalent)
Ar B(OH)2
Ar XR
RX
H
+
weak base, air, r.t.
X = N, O, S
Previous work :
Ph
Ph
Cu(OAc)2 (1.0 eq.)
EtO2C
EtO2C
NH
N
Ar B(OH)2
(4.0 eq.)
+
1,10-phenanthroline,
air, MW, 110 oC
Ar
N
S
N
S
H
H
R2
This work :
H
N
N
Bpy
N
R1
(50%),
S
R1
S
H2O
air
oC,
Cu(OAc)2
N
H
30
R2
(50%),DMF,
+
Cu(OAc)
B(OH)2
2
H
(10%),DMF/H
2O
H
(5%),
R2
N
Bpy
2O
R1
=
1
S
:
3,
oC,
80
N
air
R2
Scheme 2. Chan-Lam-type coupling reactions: (i) previous work; (ii) this work:
chemoselective C-S and C-N bond formations.
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RESULTS AND DISCUSSION
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Based on our earlier study,13 benzimidazoline-2-thione (1a; 0.5 mmol) and
phenylboronic acid (2a; 1.0 mmol) were used as substrates in the model reaction
(Table 1). When Cu(OAc)2•H2O (0.8 equiv) and 2,2'-bipyridine (Bpy; 0.8 equiv) were
tested as catalyst system in THF, N,S-diarylation product 3a and S-arylation product
4a were obtained in a trace amount and 65% yield, respectively (entry 1). On the
other hand, when dichloromethane was used as solvent, S-arylation product 4a was
obtained in 59% yield (entry 2). Interestingly, N,S-diarylation product 3a was
obtained as the sole product in 51% yield when DMF was used as a solvent (entry 3).
Based on these results, we focused on improving the yield of 3a by increasing the
amounts of Cu(OAc)2•H2O and 2a but satisfactory results were not obtained (entries 4
and 5). Similarly, the use of different mediators such as CuCl2, Cu(OAc)2•5H2O, and
Cu(OTf)2 did not facilitate this reaction (entries 6–8). In the same line, the use of
different ligands such as 1,10-phenanthroline, pyridine, and NEt3 proved that Bpy was
most effective (entry 4 vs entries 9-11). The yield of product 3a was improved to 76%
when an increased ratio 1a:2a was used (entry 4 vs entry 12). Replacement of DMF
by other solvents such as DMSO or toluene proved to be ineffective (entries 13 and
14). Somehow surprisingly, screening the catalyst and ligand loading gave product 3a
in 91% yield (entries 15-17). The optimal reaction conditions for the selective
formation of 3a were as follows: 3a:2a = 1:4, Cu(OAc)2•H2O (50 mol%), Bpy (50
mol%), DMF (3 mL), 30 oC, 3.5 h (Table 1, entry 15).
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Next, we examined the selective synthesis of mono-S-arylbenzimidazole 4a (Table
1, entries 18-25). Nishiura and co-workers reported that the addition of a certain
amount of water to a polar aprotic solvent (such as DMF) may improve the Chan-Lam
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coupling reaction.16 The adding of water makes the reaction proceed in heterogeneous
way, which might slow down the reaction speed, thus allows the reaction to give the
S-arylation selectivity, and decreasing the catalyst loading might also help the
selective synthesis. We anticipated that a decreased amount of the mediator and the
addition of water may favor the formation of 4a over the production of 3a. Hence, a
tentative experiment was carried out under the following conditions: 1a:2a = 1:1.5,
Cu(OAc)2•H2O (0.1 equiv), Bpy (0.2 equiv), DMF:H2O = 1:1 (Table 1, entry 18), and
product 4a was obtained in 80% yield. Further screening of the catalyst and ligand
loadings as well as the phenylboronic acid ratio (entries 19-21) were conducted.
Finally, the reaction temperature screening (80°C) and the modulation of solvent
(DMF : H2O = 1:3) gave the mono-S-arylbenzimidazole product 4a in 95% yield
(entry 23). The control experiments (entries 26-27) in THF with a low mediator
loading (entry 1 vs entry 26) and addition of water showed the parameter modulation
based on THF had no help for the yields (entry 23 vs entry 27).
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Table 1. Optimizing of the selective formations of 3a and 4aa
H
N
H
N
N
Chan-Lam conditions
+
S
S
S
+
PhB(OH)2
N
N
N
H
1a
2a
3a
4a
Entry
Ratio
(1a:2a)
1:2
Cat.
Ligand
Solvent
Temp.
(oC)
30
Yield
3a (%)b
trace
trace
51
Yield
4a (%)b
65
[Cu]
.
1
2
3
4
5
0.8 eq Cu(OAc)2 H2O
0.8 eq Bpyc
0.8 eq Bpy
0.8 eq Bpy
0.8 eq Bpy
1.0 eq Bpy
THF
CH2Cl2
DMF
.
1:2
0.8 eq Cu(OAc)2 H2O
30
59
.
1:2
0.8 eq Cu(OAc)2 H2O
30
0
.
1:3
0.8 eq Cu(OAc)2 H2O
DMF
30
71
trace
trace
.
1:3
1.0 eq Cu(OAc)2 H2O
DMF
30
64
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1:3
1:3
0.8 eq CuCl2
0.8 eq Bpy
0.8 eq Bpy
0.8 eq Bpy
0.8 eq 1,10-Phend
0.8 eq Pye
DMF
DMF
30
30
30
30
30
30
30
30
30
30
30
30
80
80
80
80
80
80
80
60
30
60
0
0
0
.
7
0.8 eq Cu(OAc)2 5H2O
0
8
1:3
0.8 eq Cu(OTf)2
DMF
0
56
0
0
.
9
1:3
0.8 eq Cu(OAc)2 H2O
DMF
trace
trace
0
.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
1:3
0.8 eq Cu(OAc)2 H2O
DMF
.
1:3
0.8 eq Cu(OAc)2 H2O
0.8 eq Et3N
0.8 eq Bpy
0.8 eq Bpy
0.8 eq Bpy
0.5 eq Bpy
0.4eq Bpy
DMF
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
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48
49
50
51
52
53
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60
.
1:4
0.8 eq Cu(OAc)2 H2O
DMF
76
57
0
trace
trace
0
.
1:4
0.8 eq Cu(OAc)2 H2O
DMSO
.
1:4
0.8 eq Cu(OAc)2 H2O
Toluene
.
1:4
0.5 eq Cu(OAc)2 H2O
DMF
91 (85)
87
0
0
.
1:4
0.4 eq Cu(OAc)2 H2O
DMF
0
.
1:4
0.1 eq Cu(OAc)2 H2O
0.1 eq Bpy
0.2 eq Bpy
0.1 eq Bpy
0.05 eq Bpy
0.1 eq Bpy
0.1 eq Bpy
0.1 eq Bpy
0.1 eq Bpy
0.1 eq Bpy
0.1 eq Bpy
0.2 eq Bpy
DMF
0
.
1:1.5
1:1.5
1:1.5
1:1.2
1:1.5
1:1.5
1:1.5
1:1.5
1:2
0.1 eq Cu(OAc)2 H2O
DMF:H2O= 1:1
DMF:H2O= 1:1
DMF:H2O= 1:1
DMF:H2O= 1:1
DMF:H2O= 1:2
DMF:H2O= 1:3
DMF:H2O= 1:4
DMF:H2O= 1:3
THF
trace
trace
--
80
.
0.05 eq Cu(OAc)2 H2O
87
.
0.05 eq Cu(OAc)2 H2O
47
.
0.05 eq Cu(OAc)2 H2O
--
61
.
0.05 eq Cu(OAc)2 H2O
0
93
.
0.05 eq Cu(OAc)2 H2O
0
95 (90)
79
.
0.05 eq Cu(OAc)2 H2O
0
.
0.05 eq Cu(OAc)2 H2O
0
61
.
0.1 eq Cu(OAc)2 H2O
trace
trace
45f
.
1:2
0.1 eq Cu(OAc)2 H2O
THF:H2O= 1:3
48g
aReaction conditions (for entries 1–17): [Cu], ligand, 1a (0.5 mmol), solvent (0.16 M, total 3 mL), open air, 3.5 h;
reaction conditions (for entries 18–25): [Cu], ligand, 1a (0.5 mmol), solvent (0.16 M, total 3 mL), open air, 18 h.
bIsolated yield; scaled-up (5mmol) yields are shown in brackets. cBpy = 2,2’-bipyridine. d1,10-Phen =
1,10-phenanthroline. ePy = pyridine. fopen air, 3.5 h. gopen air, 18 h.
Under the optimized conditions we explored the substrate generality for the selective
synthesis of N,S-diarylbenzimidazoles 3 (Table 2). A range of phenylboronic acids
containing electron-donating and electron-withdrawing groups were tolerated.
Halogen
substituted
arylboronic
acids
successfully
coupled
with
benzimidazoline-2-thione to give the desired products in moderate to good yields
(3b-3d). Arylboronic acids with electron-donating substituents such as methyl, ethyl,
methoxy, and isopropyl at the para- position afforded the corresponding products (3e,
3f, 3g, 3j) with good to excellent yields (81%-91%). Di-substituted
3,4-dimethylphenylboronic acid and 3,5-dimethylphenylboronic acid underwent the
coupling reation smoothly to give the corresponding products 3h and 3i in 93% and
82% yields, respectively. To our delight, 3,4-methylenedioxyphenylboronic acid and
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4-(methoxycabonyl)phenylboronic acid were also suitable for this transformation (3k
and 3l). It is a pity that 2-chloro-4-methylbenzeneboronic acid could not be converted
to desired di-substituted arylbenzimidazole product under the optimal reaction
conditions, and the mono-S-aryl benzimidazole 4k was obtained in 91% yield. The
effect of the substituent attached on the benzimidazoline-2-thione ring was examined,
and it showed that the electron donating benzimidazoline-2-thione was more reactive
than the electron withdrawing benzimidazoline-2-thione (3m vs 3n).
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Table 2. Substrate scope for the selective synthesis of N,S-diarylbenzimidazoles 3a
R2
H
N
Cu(OAc)2 H2O (50%)
Bpy (50%)
DMF, 30 oC, open air
B(OH)2
N
N
R1
S
R1
+
S
N
H
R2
1
2
3
R2
F
Cl
Br
N
N
N
N
N
S
N
N
S
S
S
N
3e
3d
, 88%
, 38%
3c
, 65%
3b
, 51%
F
Cl
Br
O
N
N
N
N
N
N
S
S
S
S
N
N
3g
3h
, 93%
, 91%
3f
, 81%
3i
, 82%
O
O
O
O
O
N
N
N
N
S
S
S
N
N
O
3j
3k
, 65%
, 86%
3l
, 67%
O
O
O
H
N
Cl
S
N
N
N
Cl
S
S
N
N
4k
3n
, 91%
, 30%
3m
, 78%
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.
a Reaction conditions: 1 (0.5 mmol), 2 (2.0 mmol), Cu(OAc)2 H2O (50 mol%), Bpy (50 mol%), DMF (3 mL), 30
oC, open air, 3.5-9 h; Isolated yield based on 1.
6
7
8
9
Next, we explored the substrate generality for the selective synthesis of
N-arylbenzimidazoles 4 (Table 3). Here again, a variety of phenylboronic acids
containing electron-donating and electron-withdrawing groups were tolerated. Both
electron-donating groups, such as methyl, methoxy, isopropyl, ethyl (4b-4e) and
electron-withdrawing groups, such as chloro, bromo, cyano (4g-4i) on the aromatic
ring gave the respective mono-S-arylation products in good to high yields (70-95%).
Due to the possible steric hindrance reason, the o-methyl and o-chloro compound
showed similar activity with good yields (4j, 4k), while no significant effect of steric
hindrance was observed when m-methyl and m-bromo groups were applied (4f, 4m).
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It
was
noteworthy
that
both
electron-rich
and
electron-deficient
benzimidazoline-2-thiones were suitable for this transformation (4n-4p). The
extension of this protocol was also applied to 2-mercaptobenzothiazole and
1,1-dimethyl-3-phenylthiourea, and the desired product 4q and 4r were obtained in
poor yields (28% and 33%, respectively).
Table 3. Substrate scope for the selective synthesis of S-arylbenzimidazoles 4a
H
N
H
N
Cu(OAc)2 H2O (5%)
Bpy (10%)
B(OH)2
R1
R1
S
S
+
N
N
H
DMF/H2O = 1 : 3,
80 oC, open air
R2
2
1
4
R2
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H
N
H
N
H
N
H
N
S
S
S
S
S
S
N
N
N
N
4e
4d
, 95%
4c
, 84%
4b
, 70%
, 93%
O
H
N
H
N
H
N
H
N
S
S
S
S
S
S
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N
N
N
N
4f
, 84%
4g
, 81%
4h
, 82%
4i
, 72%
Cl
Cl
Br
CN
H
N
H
N
H
N
H
N
N
N
N
N
O
Br
4j
, 80%
4k
4l
, 78%
, 52%
4m
, 92%
O
S
H
H
H
N
Br
N
N
S
S
N
N
N
4n
, 77%
4o
, 89%
4p
, 72%
N
N
S
S
S
N
4q
, 28%
4r
, 33%
a Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), Cu(OAc)2 H2O (5 mol%), Bpy (10 mol%), DMF : H2O = 1 : 3
.
(total 3 mL), 80 oC, open air, 18-24 h; Isolated yield based on 1.
In an additional experiment, S-arylbenzimidazole product 4k (cf. Table 2) was
obtained under the optimal conditions for the synthesis of N,S-diarylbenzimidazoles 3,
and 4a was isolated in 49 % yield in 2 h by using the double Chan-Lam reaction
conditions (control experiment shown in Scheme 3 as well). These indicate that the
S-arylbenzimidazole 4a is an intermediate for the double Chan-Lam reaction, and the
S-arylation is faster than the N-arylation. Product 4a was characterized by X-ray
crystallography (Scheme 3, CCDC 1905719), and this supports the fact that
S-arylation is more favored than the N-arylation.
H
H
PhB(OH)2 (4.0 eq)
Cu(OAc)2 H2O (50%)
N
N
S
S
N
Bpy (50%), DMF
30 oC, open air, 2h
N
H
4a
, 49%
X-Ray crystal of 4a
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Scheme 3. Control experiment under the “double” Chan-Lam reaction conditions:
S-aryl intermediate 4a was obtained.
6
7
8
Base on the above experimental results and previous literature reports,17,11a
a
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reaction mechanism for the mono- and bis-arylation of benzimidazoline-2-thiones
with boronic acids was proposed (Scheme 4). As for the assumed Cu(I/II/Ⅲ) catalysis
cycle, the intermediary Cu(I) complex would be oxidized under aerobic conditions.
For the S-arylation, aryl boronic acid would reacted with Cu(II) to form complex A.
The intermediate A was oxidized by Cu(II), forming an Cu(III) species B that would
react
with
the
tautomeric
form
of
benzimidazoline-2-thione
(2-mercaptobenzimidazole), the subsequent reductive elimination gave product 4 and
Cu(I). Finally, rapid aerobic oxidation of Cu(I) regenerates Cu(II). For the
bis-S/N-arylation, the S-arylation took place firstly to give mono-S-arylation product 4,
4 further reacted with B to give product bis-S/N-arylated product 3 and Cu(I) via
reductive elimination.
N
Ⅱ
Cu
N
1/2 O2
1/2 O2
ArB(OH)2
N
Ⅱ
-
Cu
Ar
N
CuI
CuI
A
H
N
Ar
N
CuII
CuI
Ar
Ar
S
S
N
N
4
3
H
H
N
H
N
N
Ar
S
SH
S
N
CuIII
N
H
N
-
Ar
N
N
4
B
Scheme 4. Proposed mechanism for the formation of 3a and 4a.
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CONCLUSION
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In summary, we describe herein an easy and efficient method for the controllable
synthesis of S-arylbenzimidazoles and N,S-diarylbenzimidazoles by using inexpensive
and commercially available arylboronic acids as well as Cu(OAc)2•H2O as catalyst.
The products were selectively formed in good to excellent yields by varying the
amount of Cu(OAc)2•H2O, temperature and solvent switching. The protocol features
good selectivity, easy performance, broad functional group tolerance, and good to
excellent yields. To the best of our knowledge, this is the first report of selective
synthesis of mono- and bis-S/N-arylbenzimidazoles performed by Chan-Lam reaction,
which might be useful and practical for the synthesis of some potentially biologically
active compounds.
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EXPERIMENTAL SECTION
The thione substrates 1 were prepared by using our previously reported method, see ref 14(e). All
other starting materials were purchased from commercial suppliers and used without
further purification unless otherwise stated. Yields refer to isolated compounds
1
estimated to be >95% pure as determined by H NMR and capillary GC analysis.
NMR spectra were recorded on a Bruker AM400 NMR instrument in CDCl3 and
DMSO-d6 using TMS as an internal standard. Chemical shifts are given in ppm and
coupling constants (J) are given in Hz. All melting points were determined on a
RY-1G melting point instrument without correction. High-resolution mass spectra
(HRMS) were recorded on a Finnigan MAT 95Q or Finnigan 90 mass instrument
(ESI). TLC was performed using aluminum plates coated with SiO2 (Merck 60, F-254)
and visualized with UV light at 254 nm. Column chromatography was performed on
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silica gel (200-300 mesh) with petroleum ether-EtOAc as eluent.
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Typical procedure for the synthesis of bis-arylbenzimidazoles 3 (TP1).
8
9
Benzimidazoline-2-thione 1a (0.5 mmol) and phenylboronic acid 2a (2.0 mmol),
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.
Cu(OAc)2 H2O (0.25 mmol), bipyridine (0.25 mmol) were added in a dried tube (open
to air) equipped with a magnetic stirring bar, DMF (3.0 mL) was then added. The
o
mixture was stirred at 30 C and checked by TLC until the starting material was
finished. The reaction was terminated with sat. NH4Cl solution (3 mL) and then
extracted with ethyl acetate. The crude solution was dried over anhydrous Na2SO4 and
evaporated under vacuum. The residue was purified by flash column chromatography
to afford the desired product 3a.
Typical procedure for the synthesis of mono-arylbenzimidazoles 4 (TP2).
Benzimidazoline-2-thione 1a (0.5 mmol) and phenylboronic acid 2a (0.75 mmol),
.
Cu(OAc)2 H2O (0.025 mmol), bipyridine (0.05 mmol) were added in a dried tube
(open to air) equipped with a magnetic stirring bar, DMF (0.75 mL) and H2O (2.25
o
mL) was then added. The mixture was stirred at 80 C and checked by TLC until the
starting material was finished. The reaction was terminated with sat. NH4Cl solution
(3 mL) and then extracted with ethyl acetate. The crude solution was dried over
anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash
column chromatography to afford the desired product 4a
Analytical data of the products
1-phenyl-2-(phenylthio)-1H-benzo[d]imidazole (3a)
According to TP1, the residue was purified by flash chromatography on silica gel
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(petroleum ether/ethyl acetate = 5:1) to give the target compound 3a as a colorless oil
5
6
1
(137 mg, yield = 91%; for 5mmol scale-up syntheses, 1283 mg, yield = 85%). H
7
8
9
NMR (400 MHz, CDCl3, TMS): δ (ppm) 5.59 (d, 1H, J = 8.0 Hz), 5.54-5.45 (m, 3H),
5.41 (d, 2H, J = 8.0 Hz), 5.37-5.35 (m, 2H), 5.29-5.26 (m, 3H), 5.19-5.11 (m, 2H),
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13
5.01 (d, 1H, J = 8.0 Hz). C NMR (100 MHz, CDCl3, TMS): δ (ppm) 154.1, 148.0,
142.0, 139.9, 137.4, 135.3, 135.0, 134.6, 134.4, 133.7, 132.4, 128.5, 127.8, 123.9,
115.1. HRMS (ESI) m/z [M+H]+ Calcd for C19H15N2S (303.0951), found: 303.0955.
1-(4-fluorophenyl)-2-((4-fluorophenyl)thio)-1H-benzo[d]imidazole (3b)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3b as a colorless oil
1
(86 mg, yield = 51%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.64 (d, 1H, J =
8.0 Hz), 7.30-7.26 (m, 2H), 7.22-7.08 (m, 6H), 6.96 (d, 1H, J = 8.0 Hz), 6.87 (t, 2H, J
= 8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 161.9 (d, J = 248 Hz), 161.5
(d, J = 248 Hz), 148.8, 142.0, 136.3, 134.0 (d, J = 9.0 Hz), 130.2 (d, J = 4.0 Hz),
128.3 (d, J = 8.0 Hz), 124.1 (d, J = 3.0 Hz), 122.4, 121.8, 118.4, 115.7 (d, J = 23.0
Hz), 115.5 (d, J = 23.0 Hz), 108.6. HRMS (ESI) m/z [M+H]+ Calcd for C19H13F2N2S
(339.0762), found: 339.0765.
1-(4-chlorophenyl)-2-((4-chlorophenyl)thio)-1H-benzo[d]imidazole (3c)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3c as a colorless oil
(120 mg, yield = 65%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.65 (d, 1H, J =
13
8.0 Hz), 7.38 (d, 2H, J = 12.0 Hz), 7.24-7.10 (m, 8H), 6.99 (d, 1H, J = 8.0 Hz). C
NMR (100 MHz, CDCl3, TMS): δ (ppm) 147.8, 142.0, 136.0, 134.1, 133.8, 132.7,
132.7, 128.9, 128.5, 128.1, 127.7, 127.6, 122.7, 122.0, 118.5, 115.9, 108.7. HRMS
(ESI) m/z [M+H]+ Calcd for C19H13Cl2N2S (371.0171), found: 371.0169.
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1-(4-bromophenyl)-2-((4-bromophenyl)thio)-1H-benzo[d]imidazole (3d)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3d as a colorless oil
1
10
11
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15
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(87 mg, yield = 38%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.66 (d, 1H, J =
8.0 Hz), 7.56 (d, 2H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.0 Hz), 7.21-7.11 (m, 6H), 7.01 (d,
13
1H, J = 8.0 Hz). C NMR (100 MHz, CDCl3, TMS): δ (ppm) 155.6, 147.5, 142.0,
135.9, 133.2, 132.8, 131.9, 131.4, 131.0, 128.4, 127.9, 122.7, 122.1, 122.1, 121.9,
118.5, 116.5, 108.8. HRMS (ESI) m/z [M+H]+ Calcd for C19H13Br2N2S (458.9161),
found: 458.9165.
1-(p-tolyl)-2-(p-tolylthio)-1H-benzo[d]imidazole (3e)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3e as a colorless oil
(145 mg, yield = 88%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.60 (d, 1H, J =
8.0 Hz), 7.19 (d, 2H, J = 8.0 Hz), 7.13 (d, 2H, J = 8.0 Hz), 7.08-7.04 (m, 3H), 7.00 (t,
13
1H, J = 8.0 Hz), 6.93 (t, 3H, J = 8.0 Hz), 2.27 (s, 3H), 2.13 (s, 3H). C NMR (100
MHz, CDCl3, TMS): δ (ppm) 154.2, 149.5, 142.0, 137.9, 137.6, 136.2, 132.0, 131.5,
129.1, 128.9, 128.4, 126.0, 125.3, 121.8, 121.3, 118.0, 114.4, 108.7, 20.1, 20.1.
HRMS (ESI) m/z [M+H]+ Calcd for C21H19N2S (331.1264), found: 331.1269.
1-(4-ethylphenyl)-2-((4-ethylphenyl)thio)-1H-benzo[d]imidazole (3f)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3f as a colorless oil
(145 mg, yield = 81%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.62 (d, 1H, J =
8.0 Hz), 7.22-7.17 (m, 4H), 7.10 (t, 3H, J = 8.0 Hz), 7.03 (t, 1H, J = 8.0 Hz), 6.96 (t,
3H, J = 8.0 Hz), 2.63-2.57 (m, 2H), 2.48-2.42 (m, 2H), 1.18 (t, 3H, J = 8.0 Hz), 1.05
(t, 3H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 155.5, 150.7, 145.3,
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145.0, 143.1, 137.4, 134.6, 133.3, 132.9, 129.0, 128.9, 128.5, 127.3, 126.8, 123.1,
122.6, 119.2, 115.6, 110.0, 28.7, 28.6, 15.5, 15.4. HRMS (ESI) m/z [M+H]+ Calcd for
C23H23N2S (359.1577), found: 359.1574.
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1-(4-methoxyphenyl)-2-((4-methoxyphenyl)thio)-1H-benzo[d]imidazole (3g)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3g as a colorless oil
(165 mg, yield = 91%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.60 (d, 1H, J =
8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 7.15-7.01 (m, 4H), 6.94 (d, 1H, J = 8.0 Hz), 6.89 (d,
13
2H, J = 8.0 Hz), 6.71 (d, 2H, J = 8.0 Hz), 3.73 (s, 3H), 3.64 (s, 3H). C NMR (100
MHz, CDCl3, TMS): δ (ppm) 159.2, 158.8, 150.6, 142.1, 136.7, 134.5, 127.7, 126.9,
121.8, 121.3, 119.1, 118.1, 113.9, 113.7, 108.6, 54.6, 54.3. HRMS (ESI) m/z [M+H]+
Calcd for C21H19N2O2S (363.1162), found: 363.1166.
1-(3,4-dimethylphenyl)-2-((3,4-dimethylphenyl)thio)-1H-benzo[d]imidazole (3h)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3h as a yellow oil
(166 mg, yield = 93%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.61 (d, 1H, J =
8.0 Hz), 7.13-7.07 (m, 4H), 7.02 (t, 1H, J = 8.0 Hz), 6.97-6.90 (m, 4H), 2.20 (s, 3H),
2.15 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
154.4, 149.6, 142.0, 136.9, 136.4, 136.3, 136.3, 133.3, 131.8, 129.8, 129.4, 129.3,
127.1, 125.4, 123.5, 121.6, 121.1, 117.9, 108.7, 18.6, 18.5, 18.4. 18.3. HRMS (ESI)
m/z [M+H]+ Calcd for C23H23N2S (359.1577), found: 359.1580.
1-(3,5-dimethylphenyl)-2-((3,5-dimethylphenyl)thio)-1H-benzo[d]imidazole (3i)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3i as a white soild
(147 mg, yield = 82%). mp: 112-114 oC. 1H NMR (400 MHz, CDCl3, TMS): δ (ppm)
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7.65 (d, 1H, J = 8.0 Hz), 7.11 (t, 1H, J = 8.0 Hz), 7.04 (t, 1H, J = 8.0 Hz), 6.97 (t, 2H,
J = 8.0 Hz), 6.89 (s, 2H), 6.75 (s, 3H), 2.21 (s, 6H), 2.09 (s, 6H). 13C NMR (100 MHz,
CDCl3, TMS): δ (ppm) 148.7, 142.0, 138.0, 137.5, 136.2, 134.1, 129.3, 129.3, 129.0,
128.8, 123.9, 121.8, 121.2, 118.1, 108.8, 20.0. 19.9. HRMS (ESI) m/z [M+H]+ Calcd
for C23H23N2S (359.1577), found: 359.1582.
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1-(4-isopropylphenyl)-2-((4-isopropylphenyl)thio)-1H-benzo[d]imidazole (3j)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3j as a colorless oil
(166 mg, yield = 86%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.64 (d, 1H, J =
8.0 Hz), 7.19 (d, 4H, J = 8.0 Hz), 7.11 (t, 3H, J = 8.0 Hz), 7.04 (t, 1H, J = 8.0 Hz),
6.98 (t, 3H, J = 8.0 Hz), 2.90-2.83 (m, 1H), 2.75-2.68 (m, 1H), 1.19 (d, 6H, J = 8.0
13
Hz), 1.08 (d, 6H, J = 8.0 Hz). C NMR (100 MHz, CDCl3, TMS): δ (ppm) 154.5,
149.4, 148.7, 148.3, 142.1, 138.1, 136.4, 132.0, 132.0, 126.5, 126.4, 126.2, 126.1,
125.9, 122.0, 121.5, 118.2, 114.4, 108.9, 32.9, 32.8, 23.0, 22.8. HRMS (ESI) m/z
[M+H]+ Calcd for C25H27N2S (387.1890), found: 387.1894.
1-(benzo[d][1,3]dioxol-5-yl)-2-(benzo[d][1,3]dioxol-5-ylthio)-1H-benzo[d]imidazol
e (3k)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3k as a white soild
(127 mg, yield = 65%). mp: 137-139 oC. 1H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.61 (d, 1H, J = 8.0 Hz), 7.13-7.05 (m, 2H), 6.99 (d, 1H, J = 8.0 Hz), 6.87 (d, 2H, J =
8.0 Hz), 6.81 (d, 1H, J = 8.0 Hz), 6.71 (t, 2H, J = 8.0 Hz), 6.61 (d, 1H, J = 8.0 Hz),
5.96 (s, 2H), 5.83 (s, 2H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 150.1, 147.6,
147.3, 147.1, 147.1, 142.0, 136.5, 127.7, 127.0, 121.9, 121.4, 120.2, 118.1, 113.1,
108.6, 107.8, 107.5, 107.3, 101.0, 100.5. HRMS (ESI) m/z [M+H]+ Calcd for
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C21H15N2O4S (391.0747), found: 391.0744.
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methyl 4-((1-(4-(methoxycarbonyl)phenyl)-1H-benzo[d]imidazol-2-yl)thio)benzo
ate (3l)
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According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3l as a colorless oil
(140 mg, yield = 67%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 8.09 (d, 2H, J =
8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz), 7.72 (d, 1H, J = 8.0 Hz), 7.35 (d, 2H, J = 8.0 Hz),
7.27-7.18 (m, 4H), 7.09 (d, 1H, J = 8.0 Hz), 3.88 (s, 3H), 3.79 (s, 3H). 13C NMR (100
MHz, CDCl3, TMS): δ (ppm) 166.1, 165.2, 164.9, 160.6, 145.9, 141.9, 138.0, 136.2,
135.6, 130.6, 130.0, 129.6, 129.3, 128.4, 126.1, 123.3, 122.5, 120.2, 118.7, 114.3,
109.1, 51.5, 51.2. HRMS (ESI) m/z [M+H]+ Calcd for C23H19N2O4S (419.1060),
found: 419.1064.
5,6-dimethyl-1-phenyl-2-(phenylthio)-1H-benzo[d]imidazole (3m)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3m as a white soild
(129 mg, yield = 78%). mp: 102-104 oC. 1H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.45 (s, 1H), 7.30 (d, 3H, J = 8.0 Hz), 7.15-7.12 (m, 4H), 7.04 (t, 3H, J = 4.0 Hz),
6.77 (s, 1H), 2.22 (s, 3H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
146.2, 140.6, 134.7, 134.6, 131.8, 130.7, 130.6, 130.3, 128.3, 128.0, 127.6, 126.6,
126.3, 118.5, 109.2, 19.3, 19.1. HRMS (ESI) m/z [M+H]+ Calcd for C21H19N2S
(331.1264), found: 331.1268.
6-chloro-1-phenyl-2-(phenylthio)-1H-benzo[d]imidazole (3n)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3n as a yellow oil
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(50 mg, yield = 30%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.64 (s, 1H),
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Hz), 6.93 (d, 1H, J = 8.0 Hz). C NMR (100 MHz, CDCl3, TMS): δ (ppm) 150.3,
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142.8, 134.8, 133.9, 131.7, 128.9, 128.6, 128.2, 128.2, 127.5, 127.2, 126.2, 122.5,
118.0, 109.5. HRMS (ESI) m/z [M+H]+ Calcd for C19H14ClN2S (337.0561), found:
337.0558.
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2-(phenylthio)-1H-benzo[d]imidazole (4a)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4a as a white soild
(107 mg, yield = 95%; for 5mmol scale-up syntheses, 1017 mg, yield = 90%). mp:
202-204 oC. 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) 12.78 (s, 1H), 7.58-7.41
13
(m, 7H), 7.19 (s, 2H). C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 151.8, 148.9,
140.5, 136.4, 136.4, 134.8, 133.4, 127.8, 126.8, 123.5, 116.2. HRMS (ESI) m/z
[M+H]+ Calcd for C13H11N2S (227.0638), found: 227.0642.
2-(p-tolylthio)-1H-benzo[d]imidazole (4b)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4b as a white soild
o
1
(112 mg, yield = 93%). mp: 174-176 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.65 (s, 1H), 8.00-7.14 (m, 8H), 2.32 (s, 3H). 13C NMR (100 MHz, DMSO-d6,
TMS): δ (ppm) 148.2, 139.8, 138.8, 134.7, 134.0, 132.8, 130.7, 128.6, 128.5, 127.3,
122.4, 21.1. HRMS (ESI) m/z [M+H]+ Calcd for C14H13N2S (241.0794), found:
241.0790.
2-((4-methoxyphenyl)thio)-1H-benzo[d]imidazole (4c)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4c as a white soild
o
1
(90 mg, yield = 70%). mp: 206-208 C. H NMR (400 MHz, DMSO-d6, TMS): δ
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(ppm) 12.43 (s, 1H), 7.57-7.36 (m, 4H), 7.13 (d, 2H, J = 8.0 Hz), 7.03 (d, 2H, J = 8.0
Hz), 3.80 (s, 3H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 160.5, 149.4,
144.2, 135.8, 122.5, 121.8, 120.2, 118.3, 115.7, 111.2, 55.8. HRMS (ESI) m/z [M+H]+
Calcd for C14H13N2OS (257.0743), found: 257.0747.
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2-((4-isopropylphenyl)thio)-1H-benzo[d]imidazole (4d)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4d as a white soild
o
1
(113 mg, yield = 84%). m.p: 207-209 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.69 (s, 1H), 7.56-7.15 (m, 8H), 2.94-2.87 (m, 1H), 1.21 (s, 3H), 1.19 (s, 3H).
13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 149.4, 147.9, 144.1, 135.8, 132.5,
128.1, 128.0, 122.8, 122.0, 118.6, 111.4, 33.6, 24.1. HRMS (ESI) m/z [M+H]+ Calcd
for C16H17N2S (269.1107), found: 269.1104.
2-((4-ethylphenyl)thio)-1H-benzo[d]imidazole (4e)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4e as a white soild
o
1
(121 mg, yield = 95%). mp: 189-191 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.67 (s, 1H), 7.46 (d, 4H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0 Hz), 7.17 (s, 2H),
2.64-2.58 (m, 2H), 1.18 (t, 3H, J = 8.0 Hz). 13C NMR (100 MHz, DMSO-d6, TMS): δ
(ppm) 148.0, 144.9, 134.7, 132.6, 129.5, 127.8, 127.3, 122.7, 122.0, 118.6, 111.3,
28.2, 15.8. HRMS (ESI) m/z [M+H]+ Calcd for C15H15N2S (255.0951), found:
255.0954.
2-((3,5-dimethylphenyl)thio)-1H-benzo[d]imidazole (4f)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4f as a white soild
o
1
(107 mg, yield = 84%). mp: 178-180 C. H NMR (400 MHz, DMSO-d6, TMS): δ
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(ppm) 12.71 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.15 (d, 4H, J = 12.0 Hz), 6.99 (s, 1H),
7.17 (s, 2H), 2.25 (s, 3H), 2.23 (s, 3H). 13C NMR (100 MHz, DMSO-d6, TMS): δ
(ppm) 147.6, 144.2, 139.3, 135.8, 130.7, 130.4, 129.7, 122.9, 122.0, 118.7, 111.4,
21.1. HRMS (ESI) m/z [M+H]+ Calcd for C15H15N2S (255.0951), found: 255.0957.
2-((4-chlorophenyl)thio)-1H-benzo[d]imidazole (4g)
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According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4g as a white soild
o
1
(105 mg, yield = 81%). mp: 220-222 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.82 (s, 1H), 7.60-7.50 (m, 5H), 7.44 (d, 1H, J = 8.0 Hz), 7.23-7.16 (m, 2H).
13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 146.7, 144.1, 135.8, 133.6, 133.5,
130.5, 130.0, 123.1, 122.1, 118.8, 111.5. HRMS (ESI) m/z [M+H]+ Calcd for
C13H10ClN2S (261.0248), found: 261.0253.
2-((4-bromophenyl)thio)-1H-benzo[d]imidazole (4h)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4h as a white soild
o
1
(125 mg, yield = 82%). mp: 213-215 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.84 (s, 1H), 7.63 (d, 3H, J = 8.0 Hz), 7.46 (d, 3H, J = 8.0 Hz), 7.21 (s, 2H).
13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 146.5, 144.1, 135.8, 133.7, 132.9,
131.2, 123.1, 122.1, 122.0, 118.8, 111.5. HRMS (ESI) m/z [M+H]+ Calcd for
C13H10BrN2S (304.9743), found: 304.9745.
4-((1H-benzo[d]imidazol-2-yl)thio)benzonitrile (4i)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4i as a white soild
o
1
(90 mg, yield = 72%). mp: 178-180 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 13.17 (s, 1H), 7.84 (d, 2H, J = 8.0 Hz), 7.67 (s, 1H), 7.55 (d, 3H, J = 8.0 Hz),
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7.26 (s, 2H). C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 144.2, 143.8, 140.4,
135.8, 133.5, 129.6, 123.7, 122.5, 119.3, 118.9, 111.9, 110.0. HRMS (ESI) m/z
[M+H]+ Calcd for C14H10N3S (252.0590), found: 252.0593.
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2-((2,4-dimethylphenyl)thio)-1H-benzo[d]imidazole (4j)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4j as a white soild
o
1
(102 mg, yield = 80%). mp: 177-179 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.51 (s, 1H), 7.51 (s, 1H), 7.41 (d, 2H, J = 8.0 Hz), 7.18 (s, 1H), 7.14 (d, 2H, J
13
= 8.0 Hz), 7.06 (d, 1H, J = 8.0 Hz), 2.34 (s, 3H), 2.30 (s, 3H). C NMR (100 MHz,
DMSO-d6, TMS): δ (ppm) 148.6, 144.3, 140.9, 139.6, 135.8, 134.8, 132.1, 128.2,
126.0, 122.5, 121.8, 118.3, 111.2, 21.1, 20.8. HRMS (ESI) m/z [M+H]+ Calcd for
C15H15N2S (255.0951), found: 255.0954.
2-((2-chloro-4-methylphenyl)thio)-1H-benzo[d]imidazole (4k)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4k as a white soild
o
1
(107 mg, yield = 78%). mp: 161-163 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.82 (s, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.34 (d, 1H, J = 8.0 Hz), 7.18 (t, 3H, J
= 8.0 Hz), 2.31 (s, 3H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 146.2, 144.2,
140.8, 135.8, 134.7, 133.7, 131.0, 129.4, 127.1, 123.0, 122.1, 118.7, 111.5, 20.7.
HRMS (ESI) m/z [M+H]+ Calcd for C14H12ClN2S (275.0404), found: 275.0408.
2-(benzo[d][1,3]dioxol-5-ylthio)-1H-benzo[d]imidazole (4l)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4l as a white soild
o
1
(70 mg, yield = 52%). mp: 185-187 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.49 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.19-7.13 (m, 4H), 7.00 (d, 1H, J = 8.0
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Hz), 6.11 (s, 2H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 149.2, 148.9,
148.5, 144.2, 135.8, 128.3, 122.6, 121.9, 121.6, 118.4, 114.1, 111.3, 109.6, 102.2.
HRMS (ESI) m/z [M+H]+ Calcd for C14H11N2O2S (271.0536), found: 271.0533.
2-((3-bromophenyl)thio)-1H-benzo[d]imidazole (4m)
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According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4m as a white soild
o
1
(140 mg, yield = 92%). mp: 144-146 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.93 (s, 1H), 7.70 (s, 1H), 7.57 (d, 2H, J = 8.0 Hz), 7.48 (d, 2H, J = 8.0 Hz),
13
7.37 (t, 1H, J = 8.0 Hz), 7.21 (d, 2H, J = 4.0 Hz). C NMR (100 MHz, DMSO-d6,
TMS): δ (ppm) 146.0, 144.1, 135.8, 134.4, 133.2, 131.9, 131.4, 130.3, 123.3, 122.7,
122.2, 118.9, 111.6. HRMS (ESI) m/z [M+H]+ Calcd for C13H10BrN2S (304.9743),
found: 304.9746.
5,6-dimethyl-2-(phenylthio)-1H-benzo[d]imidazole (4n)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4n as a white soild
o
1
(98 mg, yield = 77%). mp: 167-169 C. H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.64 (s, 1H), 7.43-7.31 (m, 7H), 2.29 (s, 6H). 13C NMR (100 MHz, DMSO-d6,
TMS): δ (ppm) 144.8, 143.0, 132.8, 130.7, 129.9, 128.1, 118.9, 111.5, 20.4. HRMS
(ESI) m/z [M+H]+ Calcd for C15H15N2S (255.0951), found: 255.0956.
6-methyl-2-(phenylthio)-1H-benzo[d]imidazole (4o)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4o as a white soild
o
1
(107 mg, yield = 89%). mp: 135-137 C. H NMR (400 MHz, DMSO-d6, TMS): δ
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(ppm) 12.71 (s, 1H), 7.47-7.24 (m, 7H), 7.01 (d, 1H, J = 8.0 Hz), 2.40 (s, 3H). C
NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 145.8, 144.6, 136.0, 132.2, 131.2, 130.0,
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128.4, 124.5, 123.6, 118.5, 111.2, 21.7. HRMS (ESI) m/z [M+H]+ Calcd for
C14H13N2S (241.0794), found: 241.0791.
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6-bromo-2-(phenylthio)-1H-benzo[d]imidazole (4p)
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According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4p as a yellow oil
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(109 mg, yield = 72%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.46 (t, 3H, J =
8.0 Hz), 7.22 (s, 5H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 149.4, 139.2,
136.9, 132.4, 128.8, 128.4, 128.0, 124.7, 116.4, 114.6, 114.5. HRMS (ESI) m/z
[M+H]+ Calcd for C13H10BrN2S (304.9743), found: 304.9740.
2-(phenylthio)benzo[d]thiazole (4q)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2:1) to give the target compound 4q as a colorless oil
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(34 mg, yield = 28%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.80 (d, 1H, J =
8.0 Hz), 7.66 (d, 2H, J = 4.0 Hz), 7.56 (d, 1H, J = 8.0 Hz), 7.44-7.37 (m, 3H), 7.32 (t,
1H, J = 8.0 Hz), 7.18 (d, 1H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
168.7, 152.8, 134.5, 134.3, 129.5, 128.9, 128.9, 125.1, 123.3, 120.9, 119.7. HRMS
(ESI) m/z [M+H]+ Calcd for C13H10NS2 (244.0249), found: 244.0245.
phenyl-N,N-dimethyl-N'-phenylcarbamimidothioate (4r):
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to give the target compound 4r as a yellow oil
(42 mg, yield = 33%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.13-7.04 (m, 7H),
6.85 (t, 1H, J = 8.0 Hz), 6.66 (d, 2H, J = 4.0 Hz), 3.01 (s, 6H). 13C NMR (100 MHz,
CDCl3, TMS): δ (ppm) 152.3, 150.3, 133.1, 129.9, 128.6, 128.0, 126.3, 121.9, 121.8,
39.4. HRMS (ESI) m/z [M+H]+ Calcd for C15H17N2S (257.1107), found: 257.1111.
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ACKNOWLEDGMENT
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We thank the foundation support from National Natural Science Foundation of China
(21302150), Chen-Guang program from Hubei Association for Science and
Technology, Ministry-of-Education Key Laboratory for the Synthesis and Application
of Organic Functional Molecules, Hubei University (KLSAOFM1810). We also
thank Prof. Wenjing Xiao at Central China Normal University for generous NMR
analysis support.
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Supporting Information: concise list of H and 13C NMR of products, X-ray
crystallography data and CIF file of 4a found in the SI.
REFERENCES
(1) (a) Beard, R. L.; Colon, D. F.; Song, T. K.; Davies, P. J.; Kochhar, D. M.;
Chandraratna, R. A. Synthesis and Structure-Activity Relationships of Retinoid X
Receptor Selective Diaryl Sulfide Analogs of Retinoic Acid. J. Med. Chem. 1996,
39, 3556-3563. (b) Liu, G.; Link, J.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen, B.;
Marsh, K. C.; Okasinski, G. F.; von Geldern, T. W.; Ormes, M. Discovery of
Novel p-Arylthio Cinnamides as Antagonists of Leukocyte Function-Associated
Antigen-1/Intracellular Adhesion Molecule-1 Interaction. 1. Identification of an
Additional Binding Pocket Based on an Anilino Diaryl Sulfide Lead. J. Med.
Chem. 2000, 43, 4025-4040. (c) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza,
R.; DeVries, P.; Leitza, S.; Reilly, E. B.; Okasinski, G. F.; Fesik, S. W.; von
Geldern, T. W. Novel p-Arylthio Cinnamides as Antagonists of Leukocyte
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Function-Associated Antigen-1/Intracellular Adhesion Molecule-1 Interaction. 2.
Mechanism of Inhibition and Structure-Based Improvement of Pharmaceutical
Properties. J. Med. Chem. 2001, 44, 1202-1210. (d) De Martino, G.; Edler, M. C.;
La Regina, G.; Coluccia, A.; Barbera, M. C.; Barrow, D.; Nicholson, R. I.; Chiosis,
G.; Brancale, A.; Hamel, E. New Arylthioindoles:ꢀ Potent Inhibitors of Tubulin
Polymerization. 2. Structure-Activity Relationships and Molecular Modeling
Studies. J. Med. Chem. 2006, 49, 947-954. (e) Chen, H.-Y.; Peng, W.-T.; Lee,
Y.-H.; Chang, Y.-L.; Chen, Y.-J.; Lai, Y.-C.; Jheng, N.-Y.; Chen, H.-Y. Use of
Base Control to Provide High Selectivity between Diaryl Thioether and Diaryl
Disulfide for C-S Coupling Reactions of Aryl Halides and Sulfur and a
Mechanistic Study. Organometallics 2013, 32, 5514-5522.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) (a) Carcanague, D.; Shue, Y.-K.; Wuonola, M. A.; Uria-Nickelsen, M.; Joubran,
C.; Abedi, J. K.; Jones, J.; Kühler, T. C. Novel Structures Derived from
2-[[(2-Pyridyl)methyl]thio]-1H-benzimidazole as Anti-Helicobacter pylori Agents,
Part 2. J. Med. Chem. 2002, 45, 4300-4309. (b) Huang, W.; Yang, G.-F.
Microwave-Assisted, One-Pot Syntheses and Fungicidal Activity of
Polyfluorinated 2-Benzylthiobenzothiazoles. Bioorgan. Med. Chem. 2006, 14,
8280-8285. (c) Huang, W.; Zhao, P.-L.; Liu, C.-L.; Chen, Q.; Liu, Z.-M.; Yang,
G.-F. Design, Synthesis, and Fungicidal Activities of New Strobilurin Derivatives.
J. Agr. Food. Chem. 2007, 55, 3004-3010. (d) Bennamane, N.; Zaïoua, K.;
Akacem, Y.; Kaoua, R.; Bentarzi, Y.; Bakhta, S.; Nedjar-Kolli, B.; Ouhab, L.
Synthesis of Benzimidazol-2-Thiones from Dimedone : An Unexpected
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cyclisation into a Five-Membered Ring. Org. Commun. 2009, 2, 49-59. (e) Shin, J.
M.; Sachs, G.; Cho, Y.-m.; Garst, M. 1-Arylsulfonyl-2-(Pyridylmethylsulfinyl)
Benzimidazoles as New Proton Pump Inhibitor Prodrugs. Molecules 2009, 14,
5247-5280.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) (a) Oksuzoglu, E.; Tekiner-Gulbas, B.; Alper, S.; Temiz-Arpaci, O.; Ertan, T.;
Yildiz, I.; Diril, N.; Sener-Aki, E.; Yalcin, I. Some Benzoxazoles and
Benzimidazoles as DNA Topoisomerase I and II Inhibitors. J. Enzym. Inhib. Med.
Ch. 2008, 23, 37-42. (b) Maske, P.; Lokapure, S.; Nimbalkar, D.; Disouza, J.
Synthesis and Antiprotozoal Activity of Nitro and Halogeno Substituted Some
Novel Mercaptobenzimidazole Derivatives. Der Pharma Chemica 2012, 4,
1283-1287. (c) Liu, H.; Jiang, X. Transfer of Sulfur: From Simple to Diverse.
Chem-Asian. J. 2013, 8, 2546-2563. (d) Bianxiang, Z.; Kai, C.; Lihua, Y.; Ruijie,
Z.; Lina, Z.; Ruixue, S. C-S Coupling Reaction of Heteroaromatic Compounds via
Copper Catalyst. Chin. J. Org. Chem. 2015, 35, 905-909. (e) Vessally, E.;
Mohammadi, R.; Hosseinian, A.; Didehban, K.; Edjlali, L. S-Arylation of
2-Mercaptobenzazoles: A Comprehensive Review. J. Sulfur Chem. 2018, 39,
443-463. (f) Maske, P.; Lokapure, S.; Nimbalkar, D.; Disouza, J. Synthesis and
Antiprotozoal Activity of Nitro and Halogeno Substituted Some Novel
Mercaptobenzimidazole Derivatives. Der Pharma Chemica 2012, 4, 1283-1287.
(g) Zhang, L.; Fan, J.; Vu, K.; Hong, K.; Le Brazidec, J.-Y.; Shi, J.; Biamonte, M.;
Busch, D. J.; Lough, R. E.; Grecko, R. 7’-Substituted Benzothiazolothio- and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
5
6
7
Pyridinothiazolothio-Purines as Potent Heat Shock Protein 90 Inhibitors. J. Med.
Chem. 2006, 49, 5352-5362.
8
9
(4) Allin, S. M.; Bowman, W. R.; Karim, R.; Rahman, S. S. Aromatic Homolytic
Substitution using Solid Phase Synthesis. Tetrahedron 2006, 62, 4306-4316.
(5) (a) Schwab, R. S.; Singh, D.; Alberto, E. E.; Piquini, P.; Rodrigues, O. E.; Braga,
A. L. C-S Cross-Coupling of Thiols with Aryl Iodides under Ligand-Free
Conditions using Nano Copper Oxide as a Recyclable Catalyst in Ionic Liquid.
Catal. Sci. Technol. 2011, 1, 569-573. (b) Sekar, R.; Srinivasan, M.; Marcelis, A.
T.; Sambandam, A. S-Arylation of Mercaptobenzimidazoles using Cu (I)
Catalysts-Experimental and Theoretical Observations. Tetrahedron Lett. 2011, 52,
3347-3352. (c) Panda, N.; Jena, A. K.; Mohapatra, S. Heterogeneous Magnetic
Catalyst for S-Arylation Reactions. Appl. Catal. A-Gen. 2012, 433, 258-264. (d)
Bianxiang, Z.; Lihua, Y.; Ruixue, S.; Yongqiang, K. Synthesis of Heterocyclic
Aromatic Sulfides under Microwave Irradiation. Chin. J. Org. Chem. 2016, 36,
352-357. (e) Zhang, B.; Kang, Y.; Yang, L.; Chen, X. A S-Arylation of
2-Mercaptoazoles with Diaryliodonium Triflates under Metal-Free and Base-Free
Conditions. ChemistrySelect 2016, 1, 1529-1532. (f) Tan, B. Y.-H.; Teo, Y.-C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ligand-Free
CuI-Catalyzed
Chemoselective
S-Arylation
of
2-Mercaptobenzimidazole with Aryl Iodides. Synlett 2018, 29, 2056-2060.
(6) Katritzky, A. R.; Akutagawa, K. A New Synthetic Method for the 2-Substitution
of N-Unsubstituted Benzimidazoles: Formaldehyde as a Versatile Protecting
Agent for Heterocyclic NH1. J. Org. Chem. 1989, 54, 2949-2952.
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(7) Kibriya, G.; Mondal, S.; Hajra, A. Visible-Light-Mediated Synthesis of
Unsymmetrical Diaryl Sulfides via Oxidative Coupling of Arylhydrazine with
Thiol. Org. Lett. 2018, 20, 7740-7743.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(8) (a) Lam, P. Y.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M.;
Combs, A. New Aryl/Heteroaryl C-N Bond Cross-Coupling Reactions Via
Arylboronic Acid/Cupric Acetate Arylation. Tetrahedron Lett. 1998, 39,
2941-2944. (b) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. Solid
Supported Arylheteroaryl C-N Cross-Coupling Reactions. Tetrahedron Lett. 1999,
40, 1623-1626. (c) Lam, P. Y.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P.
K. Copper-Catalyzed General C-N and C-O Bond Cross-Coupling with
Arylboronic Acid. Tetrahedron Lett. 2001, 42, 3415-3418. (d) Lam, P. Y.;
Vincent, G.; Bonne, D.; Clark, C. G. Copper-Promoted/Catalyzed C-N and C-O
Bond Cross-Coupling with Vinylboronic Acid and Its Utilities. Tetrahedron lett.
2003, 44, 4927-4931. (e) Qiao, J. X.; Lam, P. Y. Copper-Promoted
Carbon-Heteroatom Bond Cross-Coupling with Boronic Acids and Derivatives.
Synthesis 2011, 2011, 829-856.
(9) (a) Chen, S.; Huang, H.; Liu, X.; Shen, J.; Jiang, H.; Liu, H. Microwave-Assisted
Efficient Copper-Promoted N-Arylation of Amines with Arylboronic Acids. J.
Comb. Chem. 2008, 10, 358-360. (b) Rasheed, S.; Rao, D. N.; Das, P.
Copper-Catalyzed Inter- and Intramolecular C-N Bond Formation: Synthesis of
Benzimidazole-Fused Heterocycles. J. Org. Chem. 2015, 80, 9321-9327. (c)
Dar’in, D.; Krasavin, M. The Chan-Evans-Lam N-Arylation of 2-Imidazolines. J.
ACS Paragon Plus Environment