The activity of magnesium/aluminum 'memory effect' reconstructed hydrotalcites in the microwave-assisted synthesis of 2-benzimidazolethiol and its alkylated derivatives

Article abstract of DOI:10.1055/s-0033-1339763

An efficient and practical methodology for the microwave-assisted synthesis of 2-benzimidazolethiol from 1,2-benzenediamine and carbon disulfide using reconstructed hydrotalcite is described. The corresponding mono- and dialkylated derivatives of 2-benzimidazolethiol were obtained generally in good to excellent yields after short reaction times. Reconstructed hydrotalcite proved to be an efficient and reusable heterogeneous base for the alkylation reactions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339763

PAPER
▌3281
paper
The Activity of Magnesium/Aluminum ‘Memory Effect’ Reconstructed
Hydrotalcites in the Microwave-Assisted Synthesis of 2-Benzimidazolethiol
and Its Alkylated Derivatives
Reconstructed Hydrotalcites in the Synthesis of 2-Benzimidazolethiols
Deysi Y. Cruz-Gonzalez,a Rodrigo González-Olvera,a Deyanira Angeles-Beltrán,a Guillermo E. Negrón-Silva,*a
Rosa Santillanb
a
Departamento de Ciencias Básicas, Universidad Autónoma Metropolitana-Azcapotzalco, Av. San Pablo 180, C.P. 02200 México D.F., México
Fax +52(55)53189000; E-mail: gns@correo.azc.uam.mx
b
Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740,
07000 México D.F., México
Received: 18.07.2013; Accepted after revision: 19.08.2013
hydroxide (KOH),9 among others, have been employed as
Abstract: An efficient and practical methodology for the micro-
restructuring agents.
wave-assisted synthesis of 2-benzimidazolethiol from 1,2-benzene-
diamine and carbon disulfide using reconstructed hydrotalcite is
described. The corresponding mono- and dialkylated derivatives of
2-benzimidazolethiol were obtained generally in good to excellent
yields after short reaction times. Reconstructed hydrotalcite proved
to be an efficient and reusable heterogeneous base for the alkylation
reactions.
Recently, reconstructed hydrotalcites have been used as
successful catalysts for esterification reactions,10 glycerol
carbonate synthesis,3 aldol condensations,2 the synthesis
of important compounds in the cosmetic and fragrance in-
dustries,8 and the isomerization of glucose into fructose.11
Our research group has successfully employed calcined
hydrotalcites in the macrolactonization of ω-hydroxy
acids12 and in the regioselective synthesis of silylated vic-
inal azidohydrins.13 More recently, we have also applied
both the parent and calcined hydrotalcites in cyanosi-
lylation reactions over pentacyclo[5.4.0.02,6.03,10.05,9]un-
decane-8,11-dione (PCU).14
Key words: hydrotalcite, heterogeneous bases, microwave irradia-
tion, heterocycles, alkylations
Layered double hydroxides (LDH), or hydrotalcite-like
compounds, have received considerable attention owing
to their structural properties, easy recovery after a reac-
tion, and interesting and modifiable properties as Lewis or
Brønsted bases. Hydrotalcites having the general formula
[Mg(1–x)Alx(OH)2](CO3)x/22–·nH2O are a class of double
layered anionic clay with brucite-like [Mg(OH)2] layers,
where magnesium cations are octahedrally coordinated
with hydroxide ions and share edges to form the layers.
When a magnesium cation is replaced by an aluminum
one, a positive charge is generated in the layer, which is
balanced by an anion, such as a carbonate or hydroxide
ion, located between the layers.1 Water molecules can also
be present in the interlayer space.2
Benzimidazole and 2-benzimidazolethiol are heterocyclic
rings of synthetic importance. They are present in many
compounds with pharmacological activities, such as anti-
microbial, antiviral, anti-inflammatory, antiulcer, antitu-
mor, antihypertensive, antihistaminic, and anticonvulsant
activity.15 Additionally, our group has reported that 2-
benzimidazolethiol is an efficient acidic corrosion inhibi-
tor of steel grade API 5L X52.16 We have also described
the preparation of 2-(benzylthio)-1H-benzimidazole em-
ploying hydrotalcites and its use as an efficient acidic cor-
rosion inhibitor of mild steel.17
Herein, we present a convenient and practical synthesis of
2-benzimidazolethiol and several alkylated derivatives
using reconstructed hydrotalcite as a reusable heteroge-
neous base. These products are promising acidic corrosion
inhibitors of steel.
Thermal decomposition of magnesium/aluminum
(Mg/Al) double layered anionic clay produces a high
Mg/Al mixed oxide surface area known as calcined hy-
drotalcite. The hydrotalcites thus calcined can be recon-
structed into the original brucite structure during
subsequent aqueous treatment, owing to a peculiar mem-
ory effect.3 The basic properties of the hydrotalcites
change in both processes: calcined hydrotalcites exhibit
strong Lewis base sites and the reconstructed compounds
show Brønsted base ones.4 To reconstruct hydrotalcites,
microwave or ultrasonic irradiation have been employed.5
Water,6 aqueous solutions of sodium bicarbonate
(NaHCO3),7 sodium hydroxide (NaOH),8 and potassium
2-Benzimidazolethiol (1) was prepared according to a
procedure reported in the literature.18 The refluxing of
1,2-benzenediamine and carbon disulfide in ethanol for
three hours in the presence of KOH (1.05 equiv) gave
product 1 in 59% yield (Table 1, entry 1). When the reac-
tion was carried out employing the parent (HTs), calcinat-
ed (HTc), and reconstructed (HTr) hydrotalcites (100 mg)
as bases under the same reaction conditions, the desired
product 1 was obtained in 68, 61, and 75% yield, respec-
tively (entries 2–4). Of these heterogeneous bases, the re-
action with HTr exhibited the best results.
SYNTHESIS 2013, 45, 3281–3287
Advanced online publication: 27.09.2013
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DOI: 10.1055/s-0033-1339763; Art ID: SS-2013-M0502-OP
© Georg Thieme Verlag Stuttgart · New York

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D. Y. Cruz-Gonzalez et al.
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Table 1 Base and Heating Effect on the Synthesis of 2-Benzimid-
azolethiol (1)
Table 2 Alkylation of 2-Benzimidazolethiol (1) with Benzyl Chlo-
ride in the Presence of Different Bases
NH2
N
N
base
N
base
Cl
SH
S
+
+
CS2
SH
EtOH
reflux
EtOH–H2O
reflux
N
H
N
H
N
H
NH2
1
2
1
Entrya
Base
Time
Yieldc (%)
Entrya
Base
Time
Yieldd (%)
1
KOH
HTs
HTc
HTr
3 h
3 h
59
68
61
75
76
84
1b
2b
3b
4b
5c
6c
7c
8c
NaOH
HTs
2 h
87
90
81
96
90
91
84
98
2
2 h
3
3 h
HTc
HTr
2 h
4
3 h
2 h
5b
6b
KOH
HTr
25 min
25 min
NaOH
HTs
20 min
20 min
20 min
20 min
a Reagents: 1,2-benzenediamine (1.0 g, 9.2 mmol), CS2 (0.61 mL,
10.1 mmol), and KOH (0.54 g, 9.6 mmol) or the specified hydrotalcite
(100 mg).
HTc
HTr
b Reaction conditions: 1,2-benzenediamine (0.5 g, 4.6 mmol), CS2
(0.30 mL, 5.0 mmol), KOH (270 mg, 4.8 mmol) or HTr (50 mg), and
microwave heating (30 W, 70 °C, using simultaneous air cooling).
c Isolated yield after purification.
a Reagents: 2-benzimidazolethiol (0.51 g, 3.4 mmol), benzyl chloride
(0.39 mL, 3.4 mmol), and NaOH (135 mg, 3.4 mmol) or the specified
hydrotalcite (135 mg).
b Conventional heating (reflux).
c Microwave heating (30 W, 70 °C, using simultaneous air cooling).
d Isolated yield after purification.
With the aim of improving the reaction conditions and the
product yield, we decided to carry out experiments using
microwave irradiation.19 When the reaction between 1,2-
benzenediamine and carbon disulfide was performed un-
der microwave irradiation, the desired product 1 was ob-
tained in 76% yield after only 25 minutes of reaction time
using KOH (entry 5). When the heterogeneous base HTr
was used under the same reaction conditions, product 1
was obtained in 84% yield (entry 6).
Having successfully synthesized 2-benzimidazolethiol (1)
and its benzylated derivative 2 using HTr, we decided to
extend the application of this heterogeneous base to the
synthesis of mono- and dialkylated derivatives of com-
pound 1.
As shown in Table 3, monoalkylated derivatives 3–5 were
prepared in a straightforward manner. The reaction of 2-
benzimidazolethiol (1) with the corresponding alkyl ha-
lides was performed using HTr under microwave irradia-
tion and resulted in the corresponding alkylated products
in good to excellent yields (entries 1, 3, and 5). In contrast,
when the same reactions were carried out using NaOH (1
equiv) under the established reaction conditions, the de-
sired products 3–5 were obtained in lower yields (entries
2, 4, and 6).
Following the encouraging performance of the hydro-
talcites in the synthesis of thiol 1, we decided to explore
the reaction of 1 with benzyl chloride to prepare alkylated
product 2. The reaction was carried out employing con-
ventional and microwave heating in the presence of
NaOH and the three hydrotalcites. The results are summa-
rized in Table 2 and compound 2 was obtained in good to
excellent yield (81–98%). The best result was obtained
with HTr and microwave heating (entry 8).
When we carried out the dialkylation of 2-benzimid-
azolethiol (1) with alkyl halides (2.3 equiv) in the pres-
ence of 260 milligrams of HTr, we obtained mixtures of
the mono- and dialkylated products, which were separated
by column chromatography. In all cases, the major prod-
ucts were the dialkylated compounds, products 6–10 ob-
tained in 61–85% yield, and the corresponding
monoalkylated compounds were obtained in 12–33%
yield (Table 4, entries 1, 3, 5, 7, and 9). The reactions with
NaOH (2 equiv) produced dialkylated compounds 6–10 in
50–75% yield, whereas the monoalkylated compounds
were obtained in 22–44% yield (entries 2, 4, 6, 8, and 10).
The outstanding advantages offered by hydrotalcites over
common bases, such as KOH, NaOH, NaHCO3, potassi-
um carbonate, and sodium methoxide, are their recovery
and reuse. In this regard, we tested the recyclability of
HTr in the reaction of thiol 1 with benzyl chloride to give
compound 2. The hydrotalcite was recovered by filtration
after washing with ethanol and drying at 80 °C for four
hours. The recovered HTr was used without further puri-
fication for the synthesis of benzylated product 2 in a sec-
ond run and displayed a very similar performance (94%
yield). This result showed that HTr could be recovered
without significant loss of activity.
Synthesis 2013, 45, 3281–3287
© Georg Thieme Verlag Stuttgart · New York

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Reconstructed Hydrotalcites in the Synthesis of 2-Benzimidazolethiols
3283
Table 3 Monoalkylation of 2-Benzimidazolethiol (1) Using Microwave Heating
N
N
base
R1
SH
+
X
S
EtOH
MW, 70 °C
R1
N
H
N
H
1
3–5
Entrya
Base
X
R
Time
Product
Yieldb (%)
1
2
3
4
5
6
HTr
Cl
Cl
Cl
Cl
Br
Br
4-ClC6H4CH2
4-ClC6H4CH2
2-pyridinylmethyl
2-pyridinylmethyl
CH2CH=CH2
25 min
25 min
30 min
30 min
35 min
35 min
3
3
4
4
5
5
98
51
94
83
77
67
NaOH
HTr
NaOH
HTr
NaOH
CH2CH=CH2
a Reagents: 2-benzimidazolethiol (0.51 g, 3.4 mmol), alkyl halide (3.4 mmol), and NaOH (135 mg, 3.4 mmol) or HTr (135 mg).
b Isolated yield after purification.
These results suggest that the deprotonation of the NH hy- of thiol 1 with iodobenzene carried out with HTr under
drogen (lower acidity than SH)20 is more efficient with mild reaction conditions gave compound 12, also in excel-
HTr, thereby favoring the formation of the dialkylated lent yield (Scheme 1), whereas the reported method re-
compounds.
quires copper(I) iodide at high temperatures.22
We then observed interesting enhanced performances of During our investigation, it was found that the reaction of
related reactions using HTr. For example, the nucleophilic 2-benzimidazolethiol (1) with propargyl bromide in the
addition of 2-benzimidazolethiol (1) to phenylacetylene presence of HTr at 70 °C did not produce compound 13
in the presence of NaOH (2 equiv) in ethanol under reflux after 20 minutes. Instead, tricyclic compound 14 was ob-
for 16 hours gave Z-alkene 11 (92% yield),21 whereas this tained in 95% yield (Scheme 2). The formation of product
product was obtained in excellent yield after 1 hour using 14 proceeds through acetylene–allene isomerization fol-
HTr and microwave heating (Scheme 1). The S-arylation lowed by intramolecular cyclization.23 The structure of
Table 4 Dialkylation of 2-Benzimidazolethiol (1) Using Microwave Heating
N
N
N
base
SH
X
R1
+
S
+
S
EtOH
MW, 70 °C
R1
R1
N
H
N
N
H
R2
6–10
1
Entrya
Base
HTr
X
R
Time
Dialkylated Yieldc (%) of
Yieldc (%) of mono-
product
dialkylated product alkylated product
1
2
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Bn
Bn
3.5 h
3.5 h
2 h
6
6
71
51
75
63
61
50
85
75
80
68
21
38
19
29
33
44
12
22
14
24
NaOH
HTr
3
4-ClC6H4CH2
4-ClC6H4CH2
7
4
NaOH
HTr
2 h
7
5
2-pyridinylmethyl
2-pyridinylmethyl
CH2C≡CH
5 h
8
6
NaOH
HTr
5 h
8
7b
8b
9
1.3 h
1.3 h
3 h
9
NaOH
HTr
CH2C≡CH
9
CH2CH=CH2
CH2CH=CH2
10
10
10
NaOH
3 h
a Reagents: 2-benzimidazolethiol (0.51 g, 3.4 mmol), alkyl halide (7.9 mmol), and NaOH (272 mg, 6.8 mmol) or HTr (260 mg).
b Microwave heating (150 W, 25 °C) employing the CoolMate system.
c Isolated yield after purification.
© Georg Thieme Verlag Stuttgart · New York
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3284
D. Y. Cruz-Gonzalez et al.
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silica gel 60 (230–400 mesh). Melting points were determined using
a Fisher-Johns apparatus and are uncorrected. Infrared (IR) spectra
were recorded on a Bruker Alpha FT-IR/ATR (attenuated total re-
flection) spectrometer. The NMR spectra were obtained using
JEOL ECA-500 (500 MHz) and JEOL Eclipse-400 (400 MHz)
spectrometers. Chemical shifts (δ) are given in ppm downfield from
TMS as an internal reference. The 13C NMR spectra of compounds
2, 3, 5, 6, and 8 were recorded overnight. High-resolution mass
spectra (HRMS) were recorded on JEOL JMS-SX 102a and Agile-
nt-MSD-TOF-1069A spectrometers. Microwave irradiation experi-
H
Ph
N
N
HTr
SH
S
Ph
EtOH
N
H
N
H
MW, 70 °C, 1 h
1
11 98%
iodobenzene
HTr
DMSO
MW, 70 °C, 1 h
ments were performed using
a Discover System (CEM
N
Corporation) single-mode microwave with standard sealed micro-
wave glass vials. Simultaneous air jet cooling (3–4 bar) during mi-
crowave irradiation was performed using a compressor. Microwave
irradiation experiments using liquid cooling were performed on a
CEM CoolMate employing a microwave-transparent cooling fluid
(Galden HT-55). Reaction temperatures were monitored using an
IR sensor on the outside wall of the reaction vials or a fiber-optic
probe protected by a sapphire immersion well inserted directly into
the reaction mixture. The nitrogen adsorption–desorption isotherm
of HTr was obtained at –196 °C on Micromeritics ASAP 2020
equipment. Powder X-ray diffraction (XRD) was performed using
a Philips X’Pert Instrument with Cu-Kα radiation (45 kV, 40 mA).
Compounds 2–6 and 10–14 are known heterocyclic compounds; di-
alkylated products 7–9 are new.
S
N
Ph
H
12 98%
Scheme 1 Microwave-assisted syntheses of products 11 and 12 in
the presence of reconstructed hydrotalcites
HTr
N
N
N
propargyl bromide
SH
S
N
H
EtOH
MW, 70 °C, 20 min
1
Me
14 95%
HTr
propargyl bromide
EtOH
MW (CoolMate)
25 °C, 20 min
Synthesis and Characterization of Reconstructed Hydrotalcite
A solution of NaOH (14 g, 0.35 mol) and Na2CO3 (12.8 g, 0.093
mol) in deionized H2O (100 mL) was added slowly dropwise using
an addition funnel to a 250-mL Erlenmeyer flask containing
Mg(NO3)2·6H2O (25.6 g, 0.1 mol) and Al(NO3)3·9H2O (18.7 g, 0.05
mol) in deionized H2O (70 mL). The white gel obtained was then
stirred and heated at 60 °C for 24 h. The resulting gel was allowed
to cool and was then washed with deionized H2O until a pH of 9 was
achieved. After vacuum filtration, the wet solid was dried at 120 °C
for 18 h in an oven to obtain dry HTs. Then, HTc was formed by
heating HTs (2 g) at 450 °C (10 °C·min–1) in a tubular furnace under
air flow for 8 h. To obtain HTr, HTc (1.0 g) was treated with an
MeOH–H2O mixture (1:1, 100 mL) for 4 h at 60 °C. Then, the solid
was recovered by filtration and dried at 110 °C (10 °C·min–1) for 1
h.
N
S
N
H
13 82%
Scheme 2 Microwave-assisted synthesis of products 13 and 14 in the
presence of reconstructed hydrotalcites
tricyclic compound 14 was confirmed by 1H and 13C NMR
spectroscopy. Signals for the CH3 and =CH moieties of
compound 14 appeared at δ = 2.56 and 6.20 ppm, respec-
tively, in the 1H NMR spectrum.
The XRD pattern of HTr showed peak intensities and the sharpness
of (0 0 3), (0 0 6), and (0 0 9) planes, which were directly propor-
tional to the crystallinity of the material. The degree of reconstruc-
tion could be estimated by comparing the peak intensities of (0 0 3),
(0 0 6), and (0 0 9) planes of each sample with those of the HTs sam-
ple after 4 h reconstruction time. The nitrogen adsorption–desorp-
tion isotherm of HTr showed a type II isotherm as defined by
IUPAC and a hysteresis loop type H3 under the same classification,
typical of slit-shaped pores. The HTr surface area, pore volume, and
pore size were 48.95 m2·g–1, 0.24 cm3·g–1, and 193.38 Ǻ, respec-
tively.
To prevent the formation of 14, we carried out a micro-
wave irradiation experiment with intense simultaneous
cooling using the CEM CoolMate system. After perform-
ing the reaction for 20 minutes at 25 °C, the desired prod-
1
uct 13 was obtained in 82% yield (Scheme 2). The H
NMR spectrum of alkyne 13 exhibited a singlet at δ = 3.17
ppm (≡CH) and a doublet at δ = 4.11 ppm (CH2) for the
propargyl fragment, whereas signals at δ = 20.3 (CH2),
74.6 (≡CH), and 80.6 (≡C) ppm appeared in the 13C NMR
spectrum.
2-Benzimidazolethiol (1)
To a suspension of HTr (50 mg) in EtOH–H2O (9:1, 5 mL) were
added 1,2-benzenediamine (500 mg, 4.6 mmol) and CS2 (0.30 mL,
380 mg, 5.0 mmol), and the mixture was placed in a microwave re-
actor (30 W, 70 °C, simultaneous air cooling) for 25 min. Then, HTr
was filtered off and washed with EtOH (10 mL). The EtOH used to
wash the HTr was combined with the filtered reaction mixture and
the whole was vacuum evaporated, and the resulting desired prod-
uct was purified by column chromatography (EtOAc–hexane,
10:90) and recrystallization (EtOH–H2O, 1:1).
In conclusion, we have successfully developed a conve-
nient and practical synthesis of 2-benzimidazolethiol and
several alkylated derivatives using HTr. This protocol of-
fers several advantages, such as using a reusable and effi-
cient heterogeneous base and notable process simplicity.
The compounds reported herein are presently being eval-
uated as acidic corrosion inhibitors of steel.
Yield: 580 mg (84%); white solid; mp 302–305 °C (Lit.18 303–304
°C).
Commercially available reagents and solvents were used as re-
ceived. Flash column chromatography was performed on Kieselgel
Synthesis 2013, 45, 3281–3287
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reconstructed Hydrotalcites in the Synthesis of 2-Benzimidazolethiols
3285
Monoalkylated 2-Benzimidazolethiols 2–5; General Procedure
A mixture of HTr (135 mg) in EtOH (7 mL) was placed in a micro-
wave tube having a magnetic stirrer. Subsequently, 2-benzimid-
azolethiol (1) (510 mg, 3.4 mmol) and an alkyl halide (3.4 mmol)
were added to the mixture, which was heated under microwave ir-
radiation (30 W, 70 °C, simultaneous air cooling) for the time given
in Table 2, entry 8, or Table 3. Then, HTr was filtered off and
washed with EtOH (10–15 mL). The EtOH used to wash the HTr
was combined with the filtered reaction mixture and the whole was
vacuum evaporated, and the residue was purified by column chro-
matography (EtOAc–hexanes, 20:80, 10:90, or 5:95) and/or recrys-
tallization (EtOH–H2O, 1:1).
13C NMR (125.7 MHz, DMSO-d6): δ = 34.4 (SCH2), 110.8 (ArCH),
117.9 (ArCH), 118.9 (=CH2), 121.9 (2 ArCH), 134.3 (=CH), 136.0
(Cipso), 144.2 (Cipso), 149.9 (N=C–S).
Dialkylated 2-Benzimidazolethiols 6–10; General Procedure
A mixture of HTr (260 mg) in EtOH (7 mL) was placed in a micro-
wave tube having a magnetic stirrer. Subsequently, 2-benzimid-
azolethiol (1) (0.51 g, 3.4 mmol) and an alkyl halide (7.9 mmol)
were added to the mixture, which was heated under microwave ir-
radiation [30 W, 70 °C, simultaneous air cooling, except in the case
of the formation of 9 (see below)] for the time given in Table 4.
Then, HTr was filtered off and washed with EtOH (10–15 mL). The
EtOH used to wash the HTr was combined with the filtered reaction
mixture and the whole was vacuum evaporated, and the residue was
purified by column chromatography (EtOAc–hexanes, 20:80,
10:90, or 5:95) and recrystallization (EtOH–H2O, 1:1).
2-(Benzylthio)-1H-benzimidazole (2)
The title compound was prepared from 1 (510 mg, 3.4 mmol) and
benzyl chloride (0.39 mL, 3.4 mmol) according to the above general
procedure.
1-Benzyl-2-(benzylthio)-1H-benzimidazole (6)
The title compound was prepared from 1 (0.51 g, 3.4 mmol) and
benzyl chloride (0.91 mL, 7.9 mmol) according to the above general
procedure.
Yield: 790 mg (98%); white solid; mp 183–184 °C (Lit.24 184–185
°C).
1H NMR (400 MHz, DMSO-d6): δ = 4.57 (s, 2 H, SCH2), 7.09–7.14
(m, 2 H, ArH), 7.21–7.32 (m, 3 H, ArH), 7.43–7.45 (m, 4 H, ArH),
12.58 (br s, 1 H, NH).
13C NMR (100.5 MHz, DMSO-d6): δ = 35.7 (SCH2), 111.0 (ArCH),
118.0 (ArCH), 122.0 (2 ArCH), 127.9 (ArCH), 129.0 (2 ArCH),
129.4 (2 ArCH), 136.0 (Cipso), 138.3 (Cipso), 144.2 (Cipso), 150.3
(N=C–S).
Yield: 790 mg (71%); white solid; mp 85–86 °C (Lit.27 93–93.5 °C).
1H NMR (500 MHz, CDCl3): δ = 4.64 (s, 2 H, SCH2), 5.23 (2 H,
NCH2), 7.09–7.12 (m, 2 H, ArH), 7.17–7.19 (m, 2 H, ArH), 7.22–
7.33 (m, 7 H, ArH), 7.39–7.43 (m, 2 H, ArH), 7.76 (d, J = 8.05 Hz,
1 H, ArH).
13C NMR (125.7 MHz, CDCl3): δ = 37.6 (SCH2), 47.7 (NCH2),
109.4 (ArCH), 118.6 (ArCH), 122.2 (ArCH), 122.3 (ArCH), 127.0
(2 ArCH), 127.8 (ArCH), 128.0 (ArCH), 128.8 (2 ArCH), 128.9 (2
ArCH), 129.2 (2 ArCH), 135.7 (Cipso), 136.3 (Cipso), 136.7 (Cipso),
143.7 (Cipso), 151.8 (N=C–S).
2-(4-Chlorobenzylthio)-1H-benzimidazole (3)
The title compound was prepared from 1 (510 mg, 3.4 mmol) and
4-chlorobenzyl chloride (540 mg, 3.4 mmol) according to the above
general procedure.
Yield: 800 mg (98%); white solid; mp 179–180 °C (Lit.25 180–181
°C).
1H NMR (500 MHz, DMSO-d6): δ = 4.52 (s, 2 H, SCH2), 7.06–7.12
(m, 2 H, ArH), 7.31–7.34 (m, 2 H, ArH), 7.36–7.48 (m, 4 H, ArH),
12.56 (br s, 1 H, NH).
1-(4-Chlorobenzyl)-2-(4-chlorobenzylthio)-1H-benzimidazole
(7)
The title compound was prepared from 1 (0.51 g, 3.4 mmol) and 4-
chlorobenzyl chloride (1.27 g, 7.9 mmol) according to the above
general procedure.
13C NMR (125.7 MHz, DMSO-d6): δ = 34.8 (SCH2), 110.9 (ArCH),
117.9 (ArCH), 122.0 (2 ArCH), 128.9 (2 ArCH), 131.2 (2 ArCH),
132.4 (Cipso), 136.2 (Cipso), 137.6 (Cipso), 144.2 (Cipso), 149.9 (N=C–
S).
Yield: 790 mg (75%); white solid; mp 74–75 °C.
IR (neat): 3053, 3024, 2919, 1713, 1490, 1322, 1092, 795, 734 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 4.58 (s, 2 H, SCH2), 5.32 (s, 2
H, NCH2), 7.06 (d, J = 8.5 Hz, 2 H, ArH), 7.11–7.17 (m, 2 H, ArH),
7.28–7.33 (m, 4 H, ArH), 7.40–7.45 (m, 3 H, ArH), 7.57–7.60 (m,
1 H, ArH).
13C NMR (125.7 MHz, DMSO-d6): δ = 35.5 (SCH2), 46.5 (NCH2),
110.4 (ArCH), 118.4 (ArCH), 122.4 (ArCH), 122.6 (ArCH), 128.9
(2 ArCH), 129.2 (2 ArCH), 129.3 (2 ArCH), 131.3 (2 ArCH), 132.6
(Cipso), 132.8 (Cipso), 135.8 (Cipso), 136.6 (Cipso), 137.3 (Cipso), 143.5
(Cipso), 151.3 (N=C–S).
2-(2-Pyridinylmethylthio)-1H-benzimidazole (4)
The title compound was prepared from 1 (510 mg, 3.4 mmol) and
2-pyridinylmethyl chloride hydrochloride (550 mg, 3.4 mmol) ac-
cording to the above general procedure.
Yield: 770 mg (94%); white solid; mp 100–101 °C (Lit.26 100–102
°C).
1H NMR (500 MHz, CDCl3): δ = 4.41 (s, 2 H, SCH2), 7.16–7.20 (m,
2 H ArH), 7.22–7.26 (m, 1 H, ArH), 7.35 (d, J = 7.8 Hz, 1 H, ArH),
7.54 (br s, 2 H, ArH), 7.67 (td, J = 7.7, 1.7 Hz, 1 H, ArH), 8.60 (d,
J = 4.3 Hz, 1 H, ArH), 13.04 (br s, 1 H, NH).
13C NMR (125.7 MHz, CDCl3): δ = 38.1 (SCH2), 110.7 (ArCH),
118.3 (ArCH), 122.1 (2 ArCH), 123.0 (ArCH), 123.8 (ArCH),
135.3 (Cipso), 138.0 (ArCH), 144.1 (Cipso), 149.1 (ArCH), 151.1
(N=C–S), 158.0 (Cipso).
HRMS-ESI-TOF: m/z [M + H]+ calcd for C21H16Cl2N2S: 399.0484;
found: 399.0487.
1-(2-Pyridinylmethyl)-2-(2-pyridinylmethylthio)-1H-benzimid-
azole (8)
The title compound was prepared from 1 (0.51 g, 3.4 mmol) and 2-
pyridinylmethyl chloride hydrochloride (1.29 g, 7.9 mmol) accord-
ing to the above general procedure.
Yield: 688 mg (61%); white solid; mp 81–82 °C.
2-(Allylthio)-1H-benzimidazole (5)
The title compound was prepared from 1 (510 g, 3.4 mmol) and allyl
bromide (0.29 mL, 3.4 mmol) according to the above general pro-
cedure.
Yield: 830 mg (77%); white solid; mp 134–135 °C (Lit.25 133.5–
135 °C).
1H NMR (500 MHz, DMSO-d6): δ = 3.91–3.93 (m, 2 H, SCH2),
5.05–5.08 (m, 1 H, =CH2), 5.25–5.30 (m, 1 H, =CH2), 5.92–6.01
(m, 1 H, =CH), 7.06–7.10 (m, 2 H, ArH), 7.41 (br s, 2 H, ArH),
12.52 (br s, 1 H, NH).
IR (neat): 3053, 3010, 2954, 2932, 1588, 1565, 1478, 1419, 985,
737 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.79 (s, 2 H, SCH2), 5.38 (s, 2 H,
NCH2), 6.77 (d, J = 7.85 Hz, 1 H, ArCH), 7.12–7.23 (m, 5 H,
ArCH), 7.45–7.50 (m, 2 H, ArCH), 7.56–7.60 (m, 1 H, ArCH),
7.70–7.73 (m, 1 H, ArCH), 8.52–8.56 (m, 2 H, ArCH).
13C NMR (125.7 MHz, CDCl3): δ = 39.0 (SCH2), 49.5 (NCH2),
109.5 (ArCH), 118.5 (ArCH), 121.0 (ArCH), 122.3 (ArCH), 122.4
(ArCH), 122.5 (ArCH), 122.8 (ArCH), 123.5 (ArCH), 136.4 (Cipso),
© Georg Thieme Verlag Stuttgart · New York
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D. Y. Cruz-Gonzalez et al.
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136.8 (ArCH), 137.1 (ArCH), 143.7 (Cipso), 149.66 (ArCH), 149.67
(ArCH), 151.7 (N=C–S), 155.5 (Cipso), 156.7 (Cipso).
HRMS-ESI-TOF: m/z [M + H]+ calcd for C19H16N4S: 333.1168;
mmol) were added to the mixture, which was heated under micro-
wave irradiation (30 W, 70 °C, simultaneous air cooling) for 1 h.
Then, HTr was filtered off and washed with EtOH (15 mL). The
EtOH used to wash the HTr was combined with the filtered reaction
mixture and the whole was vacuum evaporated, and the residue was
purified by column chromatography (EtOAc–hexanes, 20:80).
found: 333.1169.
1-(2-Propyn-1-yl)-2-(2-propyn-1-ylthio)-1H-benzimidazole (9)
The title compound was prepared from 1 (0.51 g, 3.4 mmol) and
propargyl bromide (0.70 mL, 7.9 mmol) according to the above
general procedure. The reaction was carried out under microwave
irradiation employing the CoolMate system (150 W, 25 °C).
Yield: 772 mg (98%); white solid; mp 200–201 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.17 (s, 2 H, ArH), 7.27–7.80
(m, 7 H, ArH), 12.79 (br s, 1 H, NH).
13C NMR (100.5 MHz, DMSO-d6): δ = 116.0 (2 ArCH), 122.7 (2
ArCH), 128.7 (ArCH), 130.2 (2 ArCH), 131.8 (2 ArCH, Cipso),
140.2 (2 Cipso), 147.2 (N=C–S).
Yield: 650 mg (85%); white solid; mp 70–71 °C.
IR (neat): 3268 (≡C–H), 2966, 2925, 2123 (C≡C), 1612, 1462,
1433, 737, 660 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 3.19 (s, 1 H, C≡CH), 3.42 (s,
1 H, C≡CH), 4.17 (s, 2 H, SCH2), 5.06 (s, 2 H, NCH2), 7.17–7.24
(m, 2 H, ArH), 7.55–7.59 (m, 2 H, ArH).
13C NMR (125.7 MHz, DMSO-d6): δ = 21.1 (SCH2), 33.6 (NCH2),
74.8 (≡CH), 76.5 (≡CH), 78.2 (C, alkyne), 80.3 (C, alkyne), 110.5
(ArCH), 118.6 (ArCH), 122.6 (ArCH), 122.8 (ArCH), 136.1 (Cipso),
143.3 (Cipso), 149.9 (N=C–S).
2-(2-Propyn-1-ylthio)-1H-benzimidazole (13)
A mixture of HTr (135 mg) in EtOH (7 mL) was placed in a micro-
wave tube having a magnetic stirrer. Subsequently, 2-benzimid-
azolethiol (1) (0.51 g, 3.4 mmol) and propargyl bromide (0.30 mL,
3.4 mmol) were added to the mixture, which was heated under mi-
crowave irradiation employing the CoolMate system (150 W, 25
°C) for 20 min. Then, HTr was filtered off and washed with EtOH
(15 mL). The EtOH used to wash the HTr was combined with the
filtered reaction mixture and the whole was vacuum evaporated,
and the residue was purified by column chromatography (EtOAc–
hexanes, 5:95) and recrystallization (EtOH–H2O, 1:1).
HRMS-ESI-TOF: m/z [M + H]+ calcd for C13H10N2S: 227.0637;
found: 227.0633.
1-Allyl-2-(allylthio)-1H-benzimidazole (10)
The title compound was prepared from 1 (0.51 g, 3.4 mmol) and al-
lyl bromide (0.68 mL, 7.9 mmol) according to the above general
procedure.
Yield: 520 mg (82%); white solid; mp 163–164 °C (Lit.23 164–165
°C).
1H NMR (500 MHz, DMSO-d6): δ = 3.17 (s, 1 H, ≡CH), 4.11 (d, J =
1.9 Hz, 2 H, CH2), 7.07–7.17 (m, 2 H, ArH), 7.37 (br s, 1 H, ArH),
7.51 (br s, 1 H, ArH), 12.64 (br s, 1 H, NH).
13C NMR (125.7 MHz, DMSO-d6): δ = 20.3 (CH2), 74.6 (≡CH),
80.6 (C, alkyne), 111.1 (ArCH), 118.1 (ArCH), 121.8 (ArCH),
122.4 (ArCH), 136.0 (Cipso), 144.1 (Cipso), 148.9 (N=C–S).
Yield: 540 mg (80%); colorless liquid.27
1H NMR (500 MHz, DMSO-d6): δ = 3.96–3.99 (m, 2 H, SCH2),
4.74–4.77 (m, 2 H, NCH2), 4.88–4.93 (m, 1 H, =CH2), 5.07–5.10
(m, 1 H, =CH2), 5.12–5.16 (m, 1 H, =CH2), 5.26–5.31 (m, 1 H,
=CH2), 5.86–6.02 (m, 2 H, =CH), 7.11–7.16 (m, 2 H, ArH), 7.39–
7.43 (m, 1 H, ArH), 7.52–7.56 (m, 1 H, ArH).
3-Methylbenzo[d]thiazolo[3,2-a]imidazole (14)
13C NMR (125.7 MHz, DMSO-d6): δ = 34.9 (SCH2), 46.1 (NCH2),
110.2 (ArCH), 117.7 (=CH2), 118.3 (ArCH), 118.9 (=CH2), 122.1
(ArCH), 122.2 (ArCH), 132.9 (=CH), 134.0 (=CH), 136.5 (Cipso),
143.5 (Cipso), 151.2 (N=C–S).
A mixture of HTr (135 mg) in EtOH (7 mL) was placed in a micro-
wave tube having a magnetic stirrer. Subsequently, 2-benzimid-
azolethiol (1) (0.51 g, 3.4 mmol) and propargyl bromide (0.30 mL,
3.4 mmol) were added to the mixture, which was heated under mi-
crowave irradiation (30 W, 70 °C, simultaneous air cooling) for 20
min. Then, HTr was filtered off and washed with EtOH (15 mL).
The EtOH used to wash the HTr was combined with the filtered re-
action mixture and the whole was vacuum evaporated, and the res-
idue was purified by column chromatography (EtOAc–hexanes,
10:90).
Yield: 610 mg (95%); white solid; mp 159–160 °C (Lit.23 159–161
°C).
1H NMR (500 MHz, CDCl3): δ = 2.56 (s, 3 H, CH3), 6.20 (s, 1 H,
=CH), 7.12 (t, J = 7.7 Hz, 1 H, ArCH), 7.27 (t, J = 7.7 Hz, 1 H,
ArCH), 7.61 (d, J = 8.1 Hz, 1 H, ArCH), 7.71 (d, J = 8.2 Hz, 1 H,
ArCH).
(Z)-2-(2-Phenylethenylthio)-1H-benzimidazole (11)
A mixture of HTr (80 mg) in EtOH (7 mL) was placed in a micro-
wave tube having a magnetic stirrer. Subsequently, 2-benzimidazo-
lethiol (1) (150 mg, 1 mmol) and phenylacetylene (0.14 mL, 1.25
mmol) were added to the mixture, which was heated under micro-
wave irradiation (30 W, 70 °C, simultaneous air cooling) for 1 h.
Then, HTr was filtered off and washed with EtOH (15 mL). The
EtOH used to wash the HTr was combined with the filtered reaction
mixture and the whole was vacuum evaporated, and the residue was
purified by column chromatography (EtOAc–hexanes, 20:80).
Yield: 840 mg (98%); white solid; mp 134–135 °C (Lit.21 130–132
°C).
1H NMR (400 MHz, DMSO-d6): δ = 6.88 (d, Jcis = 10.8 Hz, 1 H,
=CH), 7.16–7.18 (m, 2 H, ArH), 7.32 (d, Jcis = 10.7 Hz, 1 H, =CH),
7.33 (br s, 1 H, ArH), 7.43–7.60 (m, 6 H, ArH), 12.86 (br s, 1 H,
NH).
13C NMR (125.7 MHz, CDCl3): δ = 14.5 (CH3), 104.6 (=CH), 110.5
(ArCH), 119.1 (ArCH), 120.6 (ArCH), 123.2 (ArCH), 129.9 (Cipso),
130.3 (Cipso), 148.5 (N=C–S), 157.3 (=CMe).
13C NMR (100.5 MHz, DMSO-d6): δ = 111.5 (ArCH), 118.3
(ArCH), 120.0 (=CH), 122.4 (2 ArCH), 128.2 (=CH), 128.5
(ArCH), 129.0 (2 ArCH), 129.2 (2 ArCH), 136.3 (2 Cipso), 143.8
(Cipso), 147.8 (N=C–S).
Acknowledgment
The authors would like to thank Consejo Nacional de Ciencia y
Tecnología (CONACyT) (project 181448) for financial support.
GENS and RS wish to acknowledge the SNI (Sistema Nacional de
Investigadores) for the distinction of their membership and the sti-
pend received. We also wish to thank Rebeca Yépez for her techni-
cal assistance, Teresa Cortez for her help with NMR experiments,
and Dr. Delia Soto-Castro for her help with HRMS.
2-(Phenylthio)-1H-benzimidazole (12)
A mixture of HTr (100 mg) in dry DMSO (3 mL) was placed in a
microwave tube having a magnetic stirrer. Subsequently, 2-benz-
imidazolethiol (1) (0.3 g, 2 mmol) and iodobenzene (0.23 mL, 2
Synthesis 2013, 45, 3281–3287
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reconstructed Hydrotalcites in the Synthesis of 2-Benzimidazolethiols
3287
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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