Cyclization of Thiopropargyl Benzimidazoles by Combining Iron(III) Chloride and Diorganyl Diselenides

Article abstract of DOI:10.1021/acs.joc.9b02276

A practical synthetic approach to the synthesis of 3-(organoselenyl)-imidazothiazines was developed. The methodology involved the regioselective 6-endo-dig cyclization of thiopropargyl benzimidazoles promoted by diorganyl diselenides and iron(III) chloride. The investigation to determine the best reaction conditions indicated the use of thiopropargyl benzimidazoles (0.25 mmol) with diorganyl diselenides (1.0 equiv) and iron(III) chloride (2.0 equiv) in dichloromethane at 40 °C for 30 min to be optimal. Under these conditions, the scope of the substrates was evaluated varying the structures of thiopropargyl benzimidazoles and diorganyl diselenides giving 28 3-(organoselenyl)-imidazothiazines in moderate to good yields. The reaction conditions were also applicable to diorganyl ditellurides; however, they did not work for diorganyl disulfides. The mechanism studies were carried out indicating that the cyclization proceeds via a cooperative action of diorganyl diselenides and iron(III) chloride, but a direct electrophilic cyclization, promoted by the in situ formed electrophilic organoselenium species, cannot be ruled out.

Full text of DOI:10.1021/acs.joc.9b02276

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Article
Cyclization of Thiopropargyl Benzimidazoles by
Combining Iron(III) Chloride and Diorganyl Diselenides
Tales A. C. Goulart, João A. G. Kazmirski, Davi Fernando Back, and Gilson Zeni
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02276 • Publication Date (Web): 06 Oct 2019
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Cyclization of Thiopropargyl
Benzimidazoles by Combining Iron(III)
Chloride and Diorganyl Diselenides
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†
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‡
†,
Tales A. C. Goulart, João A. G. Kazmirski, Davi F. Back and Gilson Zeni *
†Laboratório de Síntese, Reatividade, Avaliação Farmacológica e Toxicológica
‡
de Organocalcogênios and Laboratório de Materiais Inorgânicos, CCNE,
UFSM, Santa Maria, Rio Grande do Sul, 97105-900, Brazil
*E-mail: gzeni@ufsm.br
Abstract
A practical synthetic approach to the synthesis of 3-(organoselenyl)-
imidazothiazines was developed. The methodology involved the regioselective
6-endo-dig cyclization of thiopropargyl benzimidazoles promoted by diorganyl
diselenides and iron(III) chloride. The investigation to determine the best
reaction conditions indicated the use of thiopropargyl benzimidazoles (0.25
mmol) with diorganyl diselenides (1.0 equiv) and iron(III) chloride (2.0 equiv) in
0
dichloromethane at 40 C for 30 min to be optimal. Under these conditions, the
scope of the substrates was evaluated varying the structures of thiopropargyl
benzimidazoles and diorganyl diselenides giving twenty-eight 3-(organoselenyl)-
imidazothiazines in moderate to good yields. The reaction conditions were also
applicable to diorganyl ditellurides; however, they did not work for diorganyl
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disulfides. The mechanism studies were carried out indicating that the
cyclization proceeds via a cooperative action of diorganyl diselenides and
iron(III) chloride, but a direct electrophilic cyclization, promoted by the in situ
formed electrophilic organoselenium species, cannot be ruled out.
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Keywords: iron, cyclization, heterocycles, selenides, cyclization
Introduction
The metal-catalyzed cyclization reaction is a powerful method for the
preparation of carbo- and heterocycle compounds that are biologically active or
are used as potent building blocks in organic synthesis.1 Many excellent
reviews are available dealing with cyclization by using different metals, such as
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cobalt, gold, copper, iron, mercury, palladium, ruthenium, rhodium,
silver,10 platinum,11 and others.
In recent years, the necessity in the
development of most user-friendly systems in the synthesis of heterocycles
using environmentally, cost effective, green, and mild methodologies has grown
significantly.12 Therefore, to attend these requirements, iron salts have
appeared as a versatile alternative, due to their low price and toxicity.13 Thus,
catalytic amounts of iron salts have been widely used in many transformations
of organic synthesis, including the carbon-heteroatom bond formation.14
Recently, the cooperative action between iron(III) chloride and diorganyl
dichalcogenides was found to be an useful system to promote the cyclization of
unsaturated substrates.15 We have also developed significant improvements in
the use of this combination as cyclizing agents for the preparation of chalcogen-
heterocycles.16 In the following article, we described the cyclization of
thiopropargyl benzimidazoles 1 to 3-(organochalcogenyl)-imidazothiazines 2
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promoted by iron(III) chloride and diorganyl dichalcogenides (Figure 1). Up to
now, only few examples for the cyclization of thiopropargyl benzimidazoles have
been reported in the literature leading to imidazo-thiazoles via a 5-endo-dig
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mode.17
Because few reports on the cyclization of thiopropargyl
benzimidazoles via a 6-endo-dig mode are found in the literature, the
preparation of imidazothiazines is rare.18 The regiochemistry of this reaction is
influenced by the reaction conditions, especially by the temperature control,
thus the product formation depends on the thermodynamic versus kinetic
reaction control.17a
In addition, the cyclization with the concomitant
functionalization of the heterocycles is not reported (Figure 1). The substituted
imidazo-thiazoles have received much attention in different areas because they
are present in a large number of molecules with pronounced biological activity.19
In addition, many heterocycles having a thiazole group in the molecule present
structural and electronic properties.20
The main improvement of our
methodology is the use of diorganyl diselenides to both to promote the
cyclization and to functionalize the new heterocycles. It provides a useful and
valuable method for further functionalization by using the peculiar reactivity of
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the Csp -selenium bond. The organochalcogen compounds have attracted
much interest in the last decades because of their wide application in the
chemistry and biochemistry.21 They have become important in biochemistry
since their application to prevent liver necrosis in rats fed a selenium-deficient
22
23
Torula yeast, their application as a nutritionally important trace element and
because they are present as selenocysteine in the active center of hepatic rat
glutathione peroxidase.24 Organochalcogens have been used much more often
in the chemistry mainly because they promote a variety of stereoselective
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synthetic transformations including, α-deprotonation, transition-metal-catalyzed
cross-coupling, cyclization transmetallation, nucleophilic vinylic substitutions,
oxidation, and reduction.25
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N
N
N
S
N
N
N
S
2014
S
2004
2016
R1
K CO
R1
O
2
3
R N
2
"Pd"
"Pd"
N
N
N
N
N
"Hg"
S
"Pd"
S
S
N
H
Me
1976
2019
R1
R1
O
R1
FeCl3
R SeSeR
2
2
N
N
S
N
Suzuki Coupling
S
N
R1
SeR2
R1
Ar
This work
3
examples
0-62%
28 examples
4
2
0-90%
Figure 1. The cyclization reaction of thiopropargyl benzimidazoles reported.
Results and Discussion
In order to determine the best reaction conditions for the cyclization reactions,
we first prepared a series of thiopropargyl benzimidazoles 1 in a one-step
procedure from 1H-benzo[d]imidazole-2-thiol and propargyl bromide derivatives
(Table 1). The reaction consisted of mixing the reactants in acetone allowing to
react at room temperature for 16 h.18 Although, a number of thiopropargyl
benzimidazoles 1 were prepared in moderate to good yields, the reactions to
install substituents at the propargyl position failed.
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Table 1. Synthesis of thiopropargyl benzimidazoles 1a-l.
N
N
K CO (1 equiv)
2
3
SH
Br
+
S
S
acetone, r.t, 16 h
N
R1
N
H
H
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
5
6
7
8
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2
3
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9
0
1
2
3
4
5
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7
8
9
0
1a-j
R1
N
N
N
S
N
S
S
N
N
H
N
N
H
H
H
Ph
MeO
Cl
1a - 87%
1b - 70%
1c - 56%
1d - 38%
N
N
N
S
N
S
S
S
N
H
N
H
N
N
H
H
1
h - 77%
S
F
CF3
1f - 80%
1
e - 70%
1g - 80%
MeO
Ph
Ph
N
N
N
N
S
S
S
S
N
N
N
H
N
H
H
H
Ph
i - 28%
C H
4 9
C6H13
Ph
1j - 61%
1
1k - 52%
1l - 71%
We started the optimization studies adding diphenyl diselenide (1.0 equiv) to a
solution of iron(III) chloride in dichloromethane (3 mL), under nitrogen
atmosphere at room temperature. After 15 min, imidazole 1a (0.25 mmol) was
added. The resulting mixture was stirred for 30 min under room temperature.
This condition gave only trace amounts of imidazothiazines 2a, whereas the
starting material was recovered (Table 2, entry 1). We then carried out the
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reaction with 2 and 3 equiv of iron(III) chloride, which afforded 2a in 53 and 20%
yields, respectively (Table 2, entries 2 and 3). We credit the reduction in the
yield by using 3 equiv of iron(III) chloride to the decrease in the reactivity of
diphenyl diselenide by complexation with iron excess.15a We also observed that
the reaction did not take place under a catalytic amount of iron(III) chloride.
This result in association with the fact that the best yields were reached with 2
equiv suggests that iron(III) chloride should be required not only to activate the
triple bond to promote the cyclization, but also to prepare a selenium
electrophilic species (See the mechanism discussion and Scheme 3). In the
course of further optimization reactions, we observed that increasing the
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temperature to 40 C led to increase of the yield, whereas the variation of
iron(III) chloride under this temperature was not beneficial (Table 2, entries 4-6).
0
However, an even greater increase in the reaction temperature at 70 C did not
improve the reaction efficacy (Table 2, entry 7). Additional screening revealed
that the yield of 2a was not influenced by increasing the amount of diphenyl
diselenide to 1.5 equiv, although the reduction to 0.75 equiv led to obtain 2a in a
poor yield (Table 2, entries 8 and 9). Next, our experimental protocol turned to
the effect of solvents. Among the solvents tested, dichloromethane was the
most suitable for this reaction, whereas the other solvents, such as
dichloroethane, acetonitrile, ethanol, nitromethane, 1,4-dioxane, and toluene
were inferior (Table 2, entries 10-15). We subsequently examined the effect of
other iron salts on the cyclization of imidazole 1a. All iron salts, with different
ligand partner types in the iron complex, were completely inactive to promote
the cyclization. In these cases, the starting material was recovered (Table 2,
entries 16-20). The cyclization of imidazole 1a using diphenyl diselenide with
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other Lewis or Brønsted acids instead of iron salt, such as BF ∙OEt and PTSA
3
2
did not give the imidazothiazines 2a (Table 2, entries 21 and 22). Because the
cyclization using iodine and bromine giving the five membered product via a 5-
exo-dig mode is already described in the literature,26 we did not use these
cyclizing agents. Finally, neither running the reaction in more concentrated nor
more diluted solutions gave better yields than those obtained with 3 mL of
solvent (Table 2, entries 23 and 24). To determine the reaction time, we took
samples of the reaction mixture every 10 min over 2 h and analyzed by TLC
and CGMS, which showed that 30 min was the reaction time necessary to the
complete consume of the starting material. Based on the optimization studies,
we found that the best condition consisted of the addition of diphenyl diselenide
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
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4
4
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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
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
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8
9
0
(0.25 mmol) to a solution of iron(III) chloride (2 equiv) in dichloromethane (3
mL), under nitrogen atmosphere at room temperature. After 15 min,
thiopropargyl benzimidazole 1a (0.25 mmol) was added. The resulting mixture
was stirred for 30 min under room temperature.
Table 2. Effect of different reaction parameters for the preparation of 3-
phenylselenyl)-imidazothiazines 2a.a
(
N
N
N
PhSeSePh, conditions
S
S
N
H
1a
2a
Ph
SePh
Ph
entry
promoter
equiv)
solvent
temperature
(°C)
time
(h)
yield (%)
(
1
2
3
FeCl (1)
CH Cl
r.t.
r.t.
r.t.
24
0.5
0.5
>5b
53
3
2
2
2
2
FeCl (2)
CH Cl
3
2
FeCl (3)
CH Cl
20
3
2
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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
4
5
FeCl (2)
CH Cl
40
40
40
70
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
0.5
0.5
0.5
0.5
0.5
0.5
0.5
24
64
46
3
2
2
2
2
FeCl (2.5)
CH Cl
3
2
6
FeCl (1.5)
CH Cl
54
3
2
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
7
FeCl (2)
DCE
40
3
8
FeCl (2)
CH Cl
65c
53d
3
2
2
2
9
FeCl (2)
CH Cl
3
2
10
FeCl (2)
DCE
52
3
33b
11
12
13
FeCl (2)
CH CN
3
3
FeCl (2)
EtOH
24
>5b
30
3
FeCl (2)
CH NO
2
0.5
24
3
3
14
FeCl (2)
dioxane
toluene
CH Cl
-e
3
<5b
1
5
6
FeCl (2)
24
3
1
FeCl ·6H O (2)
24
-e
3
2
2
2
2
2
2
2
2
2
2
2
17
Fe(acac) (2)
CH Cl
24
-e
3
2
-e
18
19
20
FeCl ·4H O (2)
CH Cl
24
2
2
2
0
-e
-e
Fe (2)
CH Cl
24
2
Ferrocene (2)
PTSA (2)
CH Cl
24
2
21
CH Cl
24
-e
2
-e
2
2
3
BF ·OEt (2)
CH Cl
24
3
2
2
2
FeCl (2)
CH Cl
0.5
0.5
44f
3
2
24
FeCl (2)
CH Cl
21g
3
2
a
The reaction was performed by the addition of diphenyl diselenide (1.0 equiv) to a
solution of promoter in solvent (3 mL), under nitrogen atmosphere at room
temperature. After 15 min, imidazole 1a (0.25 mmol) was added. The resulting
mixture was stirred under temperature and time indicated in the table 1.
b
Traces of the product were isolated and the starting material was recovered.
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c
d
e
f
Reaction was carried out with PhSeSePh (1.5 equiv).
Reaction was carried out with PhSeSePh (0.75 equiv).
The starting material was recovered.
1
.5 mL of CH Cl was used.
2 2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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9
0
1
2
3
4
5
6
7
8
9
0
g
8
mL de CH Cl was used.
2 2
To determine the range of the optimized reaction conditions, further
experiments were carried out using other thiopropargyl benzimidazoles 1 as
well as other diorganyl dichalcogenides. The results are summarized in Tables
3
and 4. A wide range of thiopropargyl benzimidazoles bearing electron-
donating or electron-withdrawing groups on either aromatic ring of the imidazole
or directly bonded to the alkyne were compatible with these conditions. We
also studied the effect of different diorganyl dichalcogenides on the outcome of
the cyclization process. It was noted that the yields of the reaction with diaryl
diselenides did not follow an expected reactivity order. According to our
proposed mechanism (see the mechanism discussion and Scheme 3), we
estimated that the electron-deficient aromatic ring would become the selenium
atom more electropositive, which could increase the reactivity of diaryl
diselenides toward interaction with the carbon-carbon triple bond. However, the
results obtained did not indicate any relationship between the yields and
electronic effects of substituents on the diorganyl diselenides. Under the
optimized reaction conditions, a neutral diphenyl diselenide and an electron-
deficient aryl diselenide having chlorine atom gave 3-(organochalcogenyl)-
imidazothiazines 2a and 2b in good yields; however, diselenides having the
aromatic ring substituted with fluoro and trifluoromethyl gave only moderate
yields (Table 3, 2a-2d). In addition to give the product in moderate yield, the
9
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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
reaction with trifluoromethylphenyl diselenide suffered from lower selectivity
affording an inseparable mixture of six and five membered ring products. In the
case of diorganyl diselenides having electron-donating groups, the reaction
using 4-methoxyphenyl diselenide failed to cyclize the thiopropargyl
benzimidazole 1a, whereas 4-methylphenyl diselenide gave the corresponding
imidazothiazine 2f in 76% yield (Table 3, 2e and 2f). We assume that the
contrasting result obtained for 4-methoxyphenyl diselenide is because the
oxophilic character of iron(III) chloride led to the decomposition of diselenide
rather than promoting the formation of the species responsible for the
cyclization. The optimized conditions were also efficient to dialkyl diselenide,
which gave the corresponding imidazothiazine 2g in moderate yields (Table 3,
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
2g). Next, to determine the influence of substituents at the carbon-carbon triple
bond of the alkyne, we kept the diphenyl diselenide invariable. Thus, the
cyclization of thiopropargyl benzimidazole 1h, which has a terminal alkyne,
gave 40% yield of a 6:4 mixture of six and five membered, probably because of
the absence of substituents on the triple bond enables the cyclization to occur
on both C-1 and C-2 of the alkyne (Table 3, entry 2h). In the examples, which
have an alkyl chain directly bonded to the triple bond, the absence of pi (π)
bonds next to the alkyne could become the carbon-carbon triple bond less
reactive towards nucleophilic attack. However, under the optimized conditions
both benzimidazoles 1K and 1l gave the products in good yields, indicating that
the presence of alkyl groups at the alkyne did not influence the yields (Table 3,
2i and 2j). In all cases examined, with alkynes having aryl groups bearing
electron-donating or electron-withdrawing substituents, the cyclized products
were obtained in similar moderate yields, indicating that the cyclization was not
1
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significantly influenced by the electronic effects of the aromatic rings (Table 3,
2k-2p).
When additional reactions were carried out with thiopropargyl
benzimidazole having a methoxy group at the aromatic ring, the expected
imidazothiazine 2q was not formed (Table 3, 2q). However, extended the
reaction conditions to 4,5-diphenyl-imidazole derivative, the imidazothiazine 2r
was formed in 40% yield (Table 3, 2r). We found an additional limitation in this
methodology when the reaction of thiopropargyl benzimidazole 1a was reacted
under optimized reaction conditions in a larger scale (2 mmol). In this case, the
product 2a was obtained in 20% yield.
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
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
Table 3. Preparation of 3-(organochalcogenyl)-imidazothiazines 2a-r.a
N
N
N
FeCl (2 equiv)
R1
3
R1
R3SeSeR3
S
+
S
0
CH Cl , 40 C
N
H
2
2
1
2a-r
R2
SeR3
R2
3
entry
substrate
(R Se)
product/yield/time
2
N
N
S
S
N
N
(PhSe)
2
1
H
Ph
SePh
Ph
2a, 64% (0.5 h)
1a
N
S
N
1a
6 4 2
(p-Cl-C H Se)
2
Ph
Se
Cl
2b, 75% (0.5 h)
1
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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
N
N
S
1a
(p-F-C
6
H
4
Se)
2
3
Ph
Se
c, 46% (0.5 h)
F
2
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
N
N
N
S
+
S
N
CF3
1a
1a
1a
(
m-CF
3
-C
6
H
4
Se)
2
4
5
6
7
8
Ph
Se
Ph
Se
2d'
2
d
CF3
2
d + 2d', 50% (73/27); (0.5 h)
N
S
N
(
6 4 2
p-MeO-C H Se)
Ph
Se
OMe
2e, 0% (24 h)
N
N
S
(
6 4 2
p-Me-C H Se)
Ph
Se
2f, 76% (0.5 h)
N
S
N
1a
(BuSe)
2
Ph
SeBu
2g, 38% (1 h)
N
N
N
N
S
+
S
N
(PhSe)
2
S
N
H
H
H
SePh
SePh
2
h
2h'
1h
2h + 2h', 40% (60/40); (0.5 h)
1
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N
(PhSe)2
9
N
N
S
S
S
S
N
H
C H
4
9
SePh
C H
4
9
2
i, 68% (0.5 h)
1k
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
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
N
(PhSe)2
10
N
S
N
N
H
C H
6
13
SePh
C H
6
13
2
j, 74% (0.5 h)
1l
N
N
S
N
N
H
(
(
(
PhSe)
PhSe)
PhSe)
2
2
2
11
SePh
MeO
2k, 30% (0.5 h)
MeO
1
c
N
N
N
S
N
H
S
12
SePh
2l, 46% (0.5 h)
1
b
N
N
S
N
H
S
N
13
SePh
Cl
2m, 42% (0.5 h)
Cl
1
d
1
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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
N
N
N
S
N
H
S
(PhSe)
2
1
4
SePh
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
F
2
F
n, 46% (0.5 h)
1e
N
N
S
S
N
N
H
(PhSe)
2
15
SePh
F3C
F3C
2
o, 72% (0.5 h)
1f
N
N
N
N
N
S
S
+
S
N
H
(PhSe)
2
16
SePh
SePh
S
S
2
p
2p'
S
g
2p + 2p', 28% (84/16); (0.5 h)
1
MeO
MeO
N
N
N
S
S
N
(PhSe)
2
1
7
8
H
SePh
Ph
1i
N
2
q, 0% (0.5 h)
Ph
Ph
Ph
N
S
S
N
N
H
(PhSe)2
1
Ph
Ph
SePh
Ph
2
r, 40% (0.5 h)
1j
1
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a
The reaction was performed by the addition of diorganyl diselenides (1.0
equiv) to a FeCl (2.0 equiv) solution in dichloromethane (3 mL), under air
3
atmosphere, at room temperature. After 15 min, at this temperature,
thiopropargyl benzimidazoles 1 (0.25 mmol) were added. The resulting mixture
was stirred at room temperature for the time indicated in Table 3.
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
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
Furthermore, the optimal reaction conditions were then applied to other
combination of thiopropargyl benzimidazoles 1 with diorganyl diselenides in
which the cyclization proceeded in good yields, short reaction time and with
complete selectivity in favor of six membered imidazothiazines (Table 4, 2s-
2
ah). Concerning the use of other dichalcogenides, such as diorganyl
ditellurides and diorganyl disulfides, we found additional limitations in the
cyclization reactions. For example, the reaction with diphenyl ditelluride gave
the product 2af in poor yields and selectivity, whereas dibutyl ditelluride gave
the product; however, it decomposed in the purification process (Table 4, 2ag).
Probably the alkyl group directly bonded to the tellurium atom could undergo a
beta-telluroxide elimination, during the purification, promoting the
decomposition. Besides, the reaction with diphenyl disulfide did not give any
amount of desired product (Table 4, 2ah). Probably, because the strength of
the sulfur-sulfur bond hampers its cleavage by iron(III) chloride inhibiting the
formation of desired products.
The structural assignment of 3-
(organochalcogenyl)-imidazothiazines 2 was based on NMR analysis and
confirmed by the X-ray diffraction of three structures, which confirmed the
cyclization as a 6-endo-dig process (Supporting Information, Figures S1-3,
1
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3
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5
6
7
8
9
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
CCDC 1944844 for compound 2a, 1944845 for compound 2m and 1944843 for
compound 2l).
Table 4. Preparation of 3-(organochalcogenyl)-imidazothiazines 2s-ah.[a]
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
N
N
N
FeCl (2 equiv)
R1
3
R1
R3SeSeR3
S
+
S
0
CH Cl , 40 C
N
H
2
2
1
2s-ah
R2
SeR3
R2
3
Entry
Substrate
(R Se)
Product/Yield/Time
2
N
S
N
N
S
N
H
6 4 2
(p-Me-C H Se)
1
Se
2s, 44% (0.5 h)
1b
N
S
N
N
S
N
H
6 4 2
(p-F-C H Se)
2
Se
F
2t, 40% (0.5 h)
1b
N
N
S
S
N
N
H
(BuSe)
2
3
SeBu
2u, 55% (1 h)
1b
1
6
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N
N
N
S
S
S
S
S
S
N
H
(p-Me-C H Se)
2
6
4
4
5
6
7
8
Se
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
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
MeO
MeO
2
v, 20% (0.5 h)
1
c
N
N
S
N
N
H
(BuSe)2
SeBu
MeO
2
MeO
w, 50% (1 h)
1
c
N
N
N
N
H
S
(p-Me-C H Se)
2
6
4
Se
Cl
Cl
Cl
Cl
2x, 54% (0.5 h)
1
1
1
d
N
N
N
H
S
N
(p-Cl-C H Se)
2
6
4
Se
Cl
Cl
2
y, 55% (0.5 h)
d
N
N
S
N
N
H
(BuSe)2
SeBu
Cl
2
z, 46% (1 h)
d
1
7
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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
N
N
N
S
S
S
S
N
H
(p-Me-C H Se)
2
6
4
9
Se
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
F
F
F
F
2
aa, 90% (0.5 h)
1
1
1
e
N
N
S
N
N
H
(p-Cl-C H Se)
2
6
4
10
Se
Cl
F
2ab, 28% (0.5 h)
e
N
N
S
N
N
H
(BuSe)2
11
SeBu
F
e
2ac, 65% (1 h)
N
N
S
S
N
N
H
6 4 2
(p-Me-C H Se)
12
Se
F3C
CF3
1f
2ad, 70% (0.5 h)
N
N
S
S
N
N
(BuSe)
2
13
H
SeBu
F3C
CF3
1f
2ae, 53% (1 h)
1
8
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N
N
N
N
N
S
S
S
N
H
(PhTe)
2
+
1
4
TePh
TePh
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
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
2af
2af'
1
a
2af + 2af', 28% (87/13); (1 h)
N
N
S
S
N
N
H
(BuTe)2
15
TeBu
2ag, 0% (24 h)
1
a
N
N
S
S
N
N
H
(PhS)2
16
SPh
2ah, 0% (24 h)
1
a
a
The reaction was performed by the addition of diorganyl dichalcogenides (1.0
equiv) to a FeCl (2.0 equiv) solution in dichloromethane (3 mL), under air
3
atmosphere, at room temperature. After 15 min, at this temperature,
thiopropargyl benzimidazoles 1 (0.25 mmol) were added. The resulting mixture
was stirred at room temperature for the time indicated in Table 4.
We next, applied the optimized conditions to the cyclization of other
functionalized benzothiazoles and imidazoles, shown in scheme 1. For the
cyclization of 2-N-propargyl benzothiazole 3 the expected cyclized thiazo
pyrimidine 4 was not obtained. In this case, a complete decomposition of the
starting material was observed (Scheme 1, eq 1). The reaction of N-methyl
benzoimidazole derivatives 5 with iron(III) chloride and diphenyl diselenide was
1
9
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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
also investigated. Both thio and selenopropargyl-N-methyl benzoimidazoles
failed in the formation of cyclized products. The major products in these
reactions were the chlorovinyl chalcogenides 6a and 6b, which were probably
formed via an electrophilic addition of phenylselenyl chloride to the carbon-
carbon triple bond.
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
eq 1
S
N
H
N
S
N
FeCl (2 equiv)
3
+ (PhSe)2
N
0
CH Cl , 40 C, 30 min
2
2
3
4
Ph
not formed
SePh
Cl
Ph
eq 2
N
N
N
N
N
Y
N
FeCl (2 equiv)
3
Y
SePh
Ph
Y
+
(PhSe)2
0
CH Cl , 40 C, 30 min
2
2
Ph
5a, Y = S
6
a/6a' (E/Z)
6b/6b' (E/Z) Cl
a + 6a', Y = S, 30%; 6b + 6b', Y = Se, 30%
5
b, Y = Se
PhSe
Ph
6
Scheme 1. Cyclization of 2-N-propargyl benzothiazole 3 and N-methyl
benzoimidazole 5 derivatives.
Furthermore, a series of control experiments were performed to assist in the
proposed mechanism for this cyclization reaction. These results are shown in
scheme 2. Considering that iron complexes have been used to promote
27
reactions via a radical pathway, we conducted the cyclization of thiopropargyl
benzimidazole 1a, under optimized reaction conditions, in the presence of
TEMPO and hydroquinone as free radical scavengers. Because the reaction
yields were not altered in both cases, we assume that a radical mechanism,
which could involve the PhSe radical species, is improbable (Scheme 2, eq 1).
Next, to exclude that the HCl, released from FeCl , could act as the catalyst to
3
promote the cleavage of diphenyl diselenide and the cyclization, the
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thiopropargyl benzimidazole 1a was reacted with a mixture of diphenyl
diselenide and HCl . Under these conditions, 2a was not formed and the
(g)
thiopropargyl benzimidazole and diphenyl diselenide were recovered (Scheme
, eq 2). Subsequently, the reaction of thiopropargyl benzimidazole 1a with
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
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
iron(III) chloride under optimized reaction conditions, in the absence of diphenyl
diselenide led to a complete decomposition of 1a in benzoimidazole and
propargyl mercaptan (Scheme 2, eq 3). These last two experiments indicated
that the cooperative action between diphenyl diselenide and iron(III) chloride
are essential to promote the cyclization. We described that a mixture of copper
catalyst and diorganyl diselenide is highly active in promoting the cyclization of
unsaturated substrates.28 Thus, to eliminate the possibility that trace amounts
29
of copper, present as impurity in the iron(III) chloride, could act as the catalyst
in the present cyclization, we performed three experiments using diselenides
and copper as the catalyst. Compound 2a, however, was not obtained in any of
these reactions (Scheme 2, eq 4). Finally, to verify whether a selenium
electrophilic species, generated in situ from the reaction of diorganyl diselenide
with iron(III) chloride, could act as a promoter of the cyclization, we carried out
two experiments using phenylselenyl chloride and phenylselenyl bromide.
These reactions led to the formation of 2a in 42 and 46% yields, respectively
(Scheme 2, eq 5).
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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
eq 1
N
N
N
FeCl (2 equiv)
3
S
+ PhSeSePh
S
0
N
H
CH Cl , 40 C, 0.5 h
2
2
1a
Ph
SePh
Ph
TEMPO, 2a = 54%
hydroquinone, 2a = 67%
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
eq 2
N
N
HCl(g)
S
+ PhSeSePh
S
N
N
H
0
CH Cl , 40 C, 0.5 h
2
2
1a
2a
Ph
SePh
Ph
eq 3
N
N
FeCl (2 equiv)
SH
3
S
+
Ph
0
CH Cl , 40 C, 0.5 h
2
2
N
H
N
H
1a
Ph
eq 4
N
N
Cu O
2
S
+ PhSeSePh
S
0
CH Cl , 40 C, 12 h
N
H
2
2
N
1a
2a
Ph
SePh
Ph
Cu O (10 mol%) = n.r.
Cu O (20 mol%) = n.r.
Cu O (2 equiv) = n.r.
2
2
2
eq 5
N
0
N
CH Cl , 40 C, 0.5 h
2
2
S
S
+
PhSeCl
PhSeBr
S
N
N
H
1a
2a, 42%
Ph
SePh
Ph
eq 6
N
0
N
CH Cl , 40 C, 0.5 h
2
2
+
S
N
H
N
1a
2a, 46%
Ph
SePh
Ph
Scheme 2. Control experiments to support the proposed mechanisms.
On the basis of the above results, we can anticipate that a mixture of iron(III)
chloride and diorganyl diselenides must be the main promoter of this cyclization;
however, a direct action of organoselenyl chloride as the cyclizing agent can not
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be discarded. For these reasons, two mechanisms can be proposed for the
cyclization of thiopropargyl benzimidazoles 1 with diorganyl diselenides and
iron(III) chloride (Scheme 3). In the pathway a, it is shown the mechanism
involving a cooperative action of diorganyl diselenides and iron(III) chloride to
promote the cyclization of thiopropargyl benzimidazoles 1. It could include (i)
the interaction of iron(III) chloride with one selenium atom from diorganyl
diselenide activating the molecule towards a nucleophilic attack; (ii) the alkyne
coordination to the electropositive selenium atom to form the intermediary I; (iii)
nucleophilic anti-attack of the nitrogen atom on the activated triple bond leads to
the intermediate II; (iv) removal of the hydrogen by breaking the N-H, promoted
by the selenolate anion, restores the aromatic system and releases the 3-
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
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
(organochalcogenyl)-imidazothiazines 2 (Scheme 3, pathway a). We suppose
that the interaction of iron(III) chloride with sulfur and selenium atom in the
intermediaries I and II directs the attack on the C-1 of the triple bond leading to
products in a regioselective 6-endo-dig mode. In the pathway b, it is described
the mechanism via an electrophilic cyclization, which involves: (i) the initial
formation of selenium electrophilic species (RSeCl) by the reaction of diorganyl
diselenides with iron(III) chloride; (ii) the alkyne coordination to the RSeCl leads
to the seleniranium intermediate III; (iii) the subsequent nitrogen nucleophilic
intramolecular anti-attack at the activated triple bond affords the intermediary IV
and chloride ion; (iv) the removal of a hydrogen bonded to nitrogen by chloride
ion gives the cyclized product 2 (Scheme 3, pathway b).
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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
N
1
1
1
1
1
FeCl + R SeSeR
R SeCl
FeCl + R SeSeR
3
3
S
N
H
pathway b
pathway a
H
N
Ph
H
FeCl3
N
S
SeR1
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
S
N
Se
N
R1
III
I
Se
R1
Ph
Ph
-SeR1
H
N
H
FeCl3
N
S
S
N
SePh
Ph
N
IV
II
Ph
SeR1
Cl-
-SeR1
H
N
S
N
Ph
SeR1
HCl or -HSeR1
-
N
S
N
2
Ph
SeR1
Scheme 3. Proposed mechanism for the cyclization of thiopropargyl
benzimidazoles.
2
The high reactivity of the Csp -selenium bond becomes the 3-
(organochalcogenyl)-imidazothiazines extremely versatile substrates to
introduce different functional groups at the 3-position of thiazine ring, especially
via the formation of new carbon-carbon bonds.30 In order to prove the potential
of 3-(organochalcogenyl)-imidazothiazine derivatives as substrates for
increasing their molecular complexity, we tested the reactivity of these
compounds toward the palladium-catalyzed Suzuki cross-coupling reactions.
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Thus, the reaction of 3-(phenylselenyl)-imidazothiazines 2a with boronic acids
0
catalyzed by Pd(PPh ) in the presence of Cu(AcO) ·H O, in DMF at 80 C gave
3
4
2
2
the 3-aryl substituted imidazothiazines 7a-c in moderate yields (Scheme 4).
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
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
B(OH)2
N
N
N
N
Pd(PPh ) (40mol%)
3 4
S
S
.
+
Cu(OAc) H O (1.2 equiv)
2
2
R1
0
DMF, 80 C, 24 h
2a
7a-c
Ph
Ph
SePh
R1
1
1
1
7a, R = H, 60%; 7b, R = Me, 50%; 7c, R = OMe, 42%
Scheme 4. Reactivity of 2a towards palladium-catalyzed Suzuki cross-coupling
reactions.
Conclusion
In conclusion, we developed an iron(III) chloride/diorganyl diselenide-promoted
cyclization of thiopropargyl benzimidazoles leading to 3-(organoselenyl)-
imidazothiazines in moderate to good yields. The mechanism studies indicated
that the cyclization took place via a regioselective 6-endo-dig mode through a
cooperative action of diorganyl diselenides and iron(III) chloride; however, a
direct electrophilic cyclization promoted by the in situ formed electrophilic
organoselenium species cannot be ruled out. The main advantage of our
methodology is that different from other cyclizations of thiopropargyl
benzimidazoles current reported, our protocol allowed the preparation of the 6-
membered heterocycles with the concomitant insertion of a new functionality,
which becomes the heterocycles useful intermediates in many processes,
including the transition-metal-catalyzed carbon-carbon bond formation. Another
advantage is that the cyclization reaction generated the product with an
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1
1
1
1
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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
organoselenium moiety in the structure, which is important in terms of new
applications in synthesis and medicinal chemistry.
Experimental Section
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Materials and Methods
1
Proton nuclear magnetic resonance spectra ( H NMR) were obtained on a
NMR spectrometer at 400 MHz. Spectra were recorded in CDCl solutions.
3
Chemical shifts are reported in ppm, referenced to the solvent peak of CDCl or
3
tetramethylsilane (TMS) as the external reference. Data are reported as
follows: chemical shift (δ), multiplicity, coupling constant (J) in Hertz and
13
integrated intensity. Carbon-13 nuclear magnetic resonance spectra ( C NMR)
were obtained on a 400 NMR spectrometer at 100 MHz. Spectra were recorded
in CDCl solutions. Chemical shifts are reported in ppm, referenced to the
3
solvent peak of CDCl . Abbreviations to denote the multiplicity of a particular
3
signal are s (singlet), d (doublet), t (triplet), quart (quartet), quint (quintet), sex
77
(
sextet), dd (double doublet) and m (multiplet). The Se NMR experiment was
carried out using capillary tube with diphenyl diselenide as internal reference.
High resolution mass spectra were recorded on a mass spectrometer using
electrospray ionization (ESI). Column chromatography was performed using
Silica Gel (230-400 mesh). Thin layer chromatography (TLC) was performed
using Gel GF254, 0.25 mm thickness. For visualization, TLC plates were either
placed under ultraviolet light, or stained with iodine vapor, or acidic vanillin.
Most reactions were monitored by TLC for disappearance of starting material.
The following solvents were dried and purified by distillation from the reagents
indicated: tetrahydrofuran from sodium with a benzophenone ketyl indicator. All
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other solvents were ACS or HPLC grade unless otherwise noted. Air- and
moisture-sensitive reactions were conducted in flame-dried or oven dried
glassware equipped with tightly fitted rubber septa and under a positive
atmosphere of dry nitrogen or argon. Reagents and solvents were handled
using standard syringe techniques. The FeCl3 was used in 99.99% purity
purchased from commercial suppliers.
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
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2
3
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General procedure for the preparation of thiopropargyl benzimidazoles 1a-
18
l, 5a and 5b : Propargyl bromide (7.2 mmol; 1.2 equiv) and K CO (0.828 g; 6
2
3
mmol; 1 equiv) were added to a solution of the 1H-imidazole-2-thione (6 mmol)
in anhydrous acetone (40 mL) under nitrogen. The mixture was stirred at room
temperature for 16 h. After evaporation of the solvent, water (30 mL) and AcOEt
(30 mL) were sequentially added. The phases were separated and the organic
layers were washed with brine and dried over Mg SO . After filtration and
2
4
evaporation of the solvent, thiopropargyl benzimidazoles was purified by column
chromatography on silica gel by using a solution of hexane/AcOEt.
2
-((3-Phenylprop-2-yn-1-yl)thio)-1H-benzo[d]imidazole (1a)17b: The product
was isolated by column chromatography (hexane:ethyl acetate 90:10) as an
1
orange solid. Yield: 1.378 g (87%); mp 179-181 °C. H NMR (CDCl , 400 MHz):
3
δ (ppm) 7.59-7.54 (m, 2H), 7.34-7.19 (m, 8H), 4.28 (s, 2H). 13C{ H} NMR
1
(CDCl . 100 MHz): δ (ppm) 148.5, 138.9, 131.7, 128.5, 128.2, 122.7, 122.3,
3
114.4, 84.4, 84.0, 22.7. MS (EI, 70 eV; m/z (relative intensity)): 265 ([M+1], 19),
2
64 (100), 207 (27), 187 (11), 115 (31), 103 (19). HRMS calcd for C H N S
16
13
2
+
(ESI-TOF, [M + H] ): 265.0799. Found: 265.0812.
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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
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5
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5
5
5
5
5
5
5
5
6
2
-((3-(p-Tolyl)prop-2-yn-1-yl)thio)-1H-benzo[d]imidazole (1b): The product
was isolated by column chromatography (hexane:ethyl acetate 92:8) as a red
1
solid. Yield: 1.234 g (70%); mp 152-154 °C. H NMR (CDCl , 400 MHz): δ (ppm)
3
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
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8
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7.55-7.52 (m, 2H), 7.24-7.18 (m, 4H), 7.03 (d, J = 7.7 Hz, 2H), 4.24 (s, 2H), 2.29
s, 3H). 13C{ H} NMR (CDCl . 100 MHz): δ (ppm) 148.7, 138.6, 131.7, 129.0,
1
(
3
122.6, 119.4, 84.6, 83.5, 22.8, 21.4. MS (EI, 70 eV; m/z (relative intensity)): 279
([M+1], 20), 278 (100), 207 (20), 128 (15), 115 (23), 91 (14). HRMS calcd for
+
C H N S (ESI-TOF, [M + H] ): 279.0956. Found: 279.0948.
17
15
2
2-((3-(4-Methoxyphenyl)prop-2-yn-1-yl)thio)-1H-benzo[d]imidazole
(1c):
The product was isolated by column chromatography (hexane:ethyl acetate
1
90:10) as a red solid. Yield: 0.987 g (56%); mp 139-141 °C. H NMR (CDCl ,
3
400 MHz): δ (ppm) 7.54-7.52 (m, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.20-7.18 (m,
13
1
2H), 6.75 (d, J = 8.9 Hz, 2H), 4.24 (s, 2H), 3.75 (s, 3H). C{ H} NMR (CDCl .
3
100 MHz): δ (ppm) 159.9, 148.7, 133.2, 122.6, 114.7, 114.0, 84.5, 82.8, 55.3,
2.9. MS (EI, 70 eV; m/z (relative intensity)): 295 ([M+1], 19), 294 (100), 207
23), 192 (10), 103 (20), 77 (13). HRMS calcd for C H N OS (ESI-TOF, [M +
2
(
17
15
2
+
H] ): 295.0905. Found: 295.0905.
2-((3-(4-Chlorophenyl)prop-2-yn-1-yl)thio)-1H-benzo[d]imidazole (1d): The
product was isolated by column chromatography (hexane:ethyl acetate 92:8) as
1
a red solid. Yield: 0.679 g (38%); mp 169-171 °C. H NMR (DMSO-d , 400
6
MHz): δ (ppm) 7.50-7.48 (m, 2H), 7.41-7.35 (m, 4H), 7.16-7.14 (m, 2H), 4.43 (s,
H). 13C{ H} NMR (DMSO-d . 100 MHz): δ (ppm) 148.8, 133.9, 133.6, 129.3,
1
2
1
6
22.1, 121.4, 87.7, 81.9, 21.3. MS (EI, 70 eV; m/z (relative intensity)): 300
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(
[M+2], 33), 298 (100), 261 (16), 207 (52), 115 (39), 102 (42). HRMS calcd for
+
C H ClN S (ESI-TOF, [M + H] ): 299.0410. Found: 299.0415.
16
12
2
2
-((3-(4-Fluorophenyl)prop-2-yn-1-yl)thio)-1H-benzo[d]imidazole (1e): The
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
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6
7
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9
0
1
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7
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9
0
1
2
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7
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9
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0
product was isolated by column chromatography (hexane:ethyl acetate 92:8) as
1
a red solid. Yield: 1.184 g (70%); mp 185-187 °C. H NMR (DMSO-d , 400
6
MHz): δ (ppm) 7.51-7.49 (m, 2H), 7.42-7.39 (m, 2H), 7.18-7.13 (m, 4H), 4.42 (s,
2H). 13C{ H} NMR (DMSO-d . 100 MHz): δ (ppm) 162.3 (d, J = 247.4 Hz),
1
6
1
48.7, 134.0 (d, J = 8.7 Hz), 121.9, 118.87 (d, J = 3.6 Hz), 116.1 (d, J = 22.2
Hz), 85.9, 82.1, 21.3. MS (EI, 70 eV; m/z (relative intensity)): 283 ([M+1], 10),
82 (100), 207 (94), 133 (64), 102 (09), 75 (07). HRMS calcd for C H FN S
2
16 12
2
+
(ESI-TOF, [M + H] ): 283.0705. Found: 283.0705.
2
-((3-(3-(Trifluoromethyl)phenyl)prop-2-yn-1-yl)thio)-1H-benzo[d]imidazole
(1f): The product was isolated by column chromatography (hexane:ethyl
1
acetate 90:10) as an orange solid. Yield: 1.59 g (80%); mp 137-139 °C. H NMR
(CDCl , 400 MHz): δ (ppm) 10.53 (s, 1H), 7.61-7.53 (m, 2H), 7.53-7.44 (m, 2H),
3
.40-7.35 (m, 1H), 7.33-7.26 (m, 1H), 7.24-7.16 (m, 2H), 4.29 (s, 2H). 13C{ H}
1
7
NMR (CDCl . 100 MHz): δ (ppm) 148.4, 139.3, 130.8 (q, J = 32.3 Hz), 128.7,
3
128.4 (q, J = 3.9 Hz), 124.9 (q, J = 3.3 Hz), 123.7 (q, J = 273.0 Hz), 122.2,
1
14.4, 85.8, 82.7, 25.5. MS (EI, 70 eV; m/z (relative intensity)): 333 ([M+1], 21),
3
32 (100), 331 (23), 187 (23), 134 (17), 102 (21). HRMS calcd for C H F N S
17
12
3
2
+
(ESI-TOF, [M + H] ): 333.0673. Found: 333.0680.
2-((3-(Thiophen-3-yl)prop-2-yn-1-yl)thio)-1H-benzo[d]imidazole (1g): The
product was isolated by column chromatography (hexane:ethyl acetate 90:10)
1
as an orange solid. Yield: 1.296 g (80%); mp 169-171 °C. H NMR (CDCl , 400
3
2
9
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