AlCl3-Promoted Synthesis of 2-Mercapto Benzoheterocycles by Using Sodium Dimethyldithiocarbamate as Thiocarbonyl Surrogate

Article abstract of DOI:10.1002/ejoc.201800993

A simple, expeditious and high-efficiency synthetic method for the AlCl₃-mediated one-pot preparation of 2-mercapto benzoheterocycles (2-mercapto benzothiazoles, benzoxazoles and benzimidazoles) is described. By the treatment of a series of S, O and N heteroatoms containing bifunctional molecules with sodium dimethyldithiocarbamate in AlCl₃, the desired benzoheterocycles are obtained smoothly. The protocol can also be applied on the synthesis of a series of thiazolidine-2-thiones, imidazolidine-2-thiones. This novel synthetic approach has advantages such as ligand-free, high efficiency, short reaction time, readily available starting materials and simple experimental procedures.

Full text of DOI:10.1002/ejoc.201800993

A Journal of
Accepted Article
Title: AlCl3-Promoted Synthesis of 2-Mercapto Benzoheterocycles
by Using Sodium Dimethyldithiocarbamate as Thiocarbonyl
Surrogate
Authors: Xing Liu, Shi-Bo Zhang, and Zhi-Bing Dong
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800993
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800993
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10.1002/ejoc.201800993
European Journal of Organic Chemistry
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AlCl3-Promoted Synthesis of 2-Mercapto Benzoheterocycles by
Using Sodium Dimethyldithiocarbamate as Thiocarbonyl
Surrogate
Xing Liu,[a] Shi-Bo Zhang,[a] Zhi-Bing Dong* [a, b]
Dedication ((optional))
Abstract:
A
simple, expeditious and high-efficiency synthetic
Although there has been intense development of synthetic
methods for the preparation of 2-mercapto benzoheterocycles,
most of the reported procedures are only applicable for the
synthesis of one type of 2-mercapto benzoheterocycles.[5] The
known synthetic procedures are based on the direct use of
carbon disulfide (Figure 2a), which is a toxic and obnoxious
smelling thiocarbonyl surrogates, often requires drastic reaction
conditions.[6] Therefore, the pursuance of more convenient and
practical synthetic methods for these compounds still remains an
active research area. Several methods are available for the
synthesis of 2-mercapto benzoheterocycles. These compounds
are prepared through the reactions of various bifunctional
molecules with phenyl chlorothionocarbonate,[7] potassium
method for the AlCl3-mediated one-pot preparation of 2-mercapto
benzoheterocycles (2-mercapto benzothiazoles, benzoxazoles and
benzimidazoles) is described. By the treatment of a series of S, O
and N heteroatoms containing bifunctional molecules with sodium
dimethyldithiocarbamate in AlCl3, the desired benzoheterocycles are
obtained smoothly. The protocol can also be applied on the
synthesis of a series of thiazolidine-2-thiones, imidazolidine-2-
thiones. This novel synthetic approach has advantages such as
ligand-free, high efficiency, short reaction time, readily available
starting materials and simple experimental procedures.
ethylxanthate,[8]
isopropyl-xanthicacipotassium
salt,[9]
Introduction
respectively (Figure 2b). Although these thiocarbonyl surrogates
are effective for the synthesis of mercapto derivatives, there
exist some drawbacks such as long reaction time, tedious work
up procedures, commercially not available starting materials,
use of additional microwave oven that utility and applicability are
somehow limited. Therefore, the more expeditious and
environmentally benign protocols for these compounds are still
highly desirable.
Heterocyclic compounds containing mercapto group play
dominant role in drug discovery.[1] This heterocyclic compounds
are the core structural elements of many natural products and
approved pharmaceuticals.[2] It is already known that thioethers
of 2-mercapto benzoheterocycles are a class of compounds
endowed
with
broad
and
decisive
biological
and
pharmacological activities.[3] They are extensively useful as
fungicides, antiprotozoals, anticancer agents and enzyme
inhibitors (Figure 1).[4] It is thus necessary to develop simple and
effective synthetic methods for the construction of 2-mercapto
benzoheterocycles.
Figure 2. Some different strategies for the synthesis 2-mercapto
benzoheterocycles.
Figure 1. Bioactive benzofused N, O, S heterocycles.
Recently, construction of heterocycle thione with sulfur and
chloroform as thiocarbonyl surrogates was reported by Tan and
their co-workers.[10] For the continuous efforts on the study of C-
S bond formation and related research,[11] we have reported a
method for the synthesis of 2-mercapto benzoheterocycles by
using TMTD (Tetramethylthiuram disulfide) as thiocarbonyl
surrogates (Scheme 1a).[12] For the research extension, we
hereby wish to report an alternative protocol for the synthesis 2-
[a]
aSchool of Chemistry and Environmental Engineering, Wuhan
Institute of Technology, Wuhan 430205, China.
E-mail: dzb04982@wit.edu.cn
http://cee.wit.edu.cn/info/1052/1538.htm
Department of Chemistry, Ludwig-Maximilians-Universität,
Butenandtstrasse 5-13, 81377 München, Germany.
[b]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
mercapto
benzoheterocycles
by
using
sodium
dimethyldithiocarbamate as surrogates (Scheme 1b).
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10.1002/ejoc.201800993
European Journal of Organic Chemistry
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10
11
12
13c
14
15
16
17
18
S
S
S
S
S
O
O
NH
NH
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
THF
EtOH
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
80
10
10
10
10
30
20
60
30
60
51
56
54
82
81
83
76
73
56
100
100
120
100
120
100
120
100
aReaction conditions: 1 (1.0 mmol), 2 (2.5 mmol), cat. (10 mol %), solvent (2.0
mL). bIsolated yield based on 1a after column chromatography. cIn the
presence of AlCl3 (5 mol%).
Scheme 1. Our previous (a) and present (b) strategies towards the synthesis
of 2-mercapto benzoheterocycles.
With the optimal conditions in hand, we investigated the
substrate scope to obtain 2-mercapto benzofused heterocycles
(Table 2). Firstly, the scope of 2-aminothiophenols were
explored. Starting materials 1b and 1c reacted with sodium salt
2 successfully under the optimal reaction conditions to provide
the desired products 3b (95%) and 3c (45%), respectively
(entries 2-3). Subsequently, the scope of 2-aminophenol
derivatives were also surveyed. Electron-withdrawing substituted
2-aminophenol substrates furnished 3e, 3f and 3g in moderate
yield (entries 5-7). Electron-donating substituted 2-aminophenol
substrates gave 3h, 3j, 3k and 3l in good yield (entries 8, 10-
12) . The results indicated that electron-donating groups were
more favored (generally) for the reaction than electron-
withdrawing groups. Unfortunately, heterocycle substrate 1m
was not suitable for the transformation (entry 13). Finally,
substituted 1,2-phenylenediamines bearing electron-withdrawing
as well as electron-donating groups were submitted for
evaluation of their compatibility in this reaction. It could be seen
that the desired products were obtained in general moderate
yields (entries 14-21). It is noteworthy that heterocycle substrate
1v could be converted to the corresponding product 3v in 30%
yield (entry 22). To our delight, akyl-diamines 1w and 1x were
also suitable for the transformation to afford 3w and 3x in good
yields (entries 23-24). In general, the results allow the present
procedure to be used as an easy and useful protocol for the
preparation of 2-mercapto benzoheterocycles.
Results and Discussion
To establish the optimal reaction conditions, we commenced
our research by investigating the reaction using 2-
aminothiophenol and sodium dimethyldithiocarbamate 2 as
model substrates (Table 1). Initially, we treated 2-
aminothiophenol with sodium dimethyldithiocarbamate 2 in DMF
without any addition of cataylst. To our delight, we were able to
obtain 2-mercaptobenzothiazole in 64% yield after the reaction
mixture was stirred in DMF for 10 min at 120oC (entry 1).
Encouraged by this initial result, several potential “catalysts”
including CuCl2, Cu(OAc)2, Cu(OTf)2, CuSO4, FeCl3, AlCl3 were
examined to evaluate their effect in the reaction (entries 2-7),
and it revealed that AlCl3 was found to be superior in furnishing
the cyclized product in 94% yield (entry 7). Subsequently, to
evaluate the solvent effect, the reaction was studied by
performing the reaction in different solvents (entries 8-12). DMF
was
selected
as
the optimal
solvent,
giving
2-
mercaptobenzothiazole in excellent yield after 10 minutes (entry
7). Based on these promising results, we further optimized the
loading amount of AlCl3. 2-Mercaptobenzothiazole was obtained
in a lower yield (82%) when 5% equiv of AlCl3 was used (entry
13). Thus, the loading of 10 % equiv of AlCl3 was chosen to be
the optimal. Screening of the reaction temperature showed that
lower temperature led to lower yield, even when the reaction
time was prolonged to 30 min. (entry 14). The optimal reaction
conditions were also applied on the O and N heteroatoms
containing bifunctional substrates (2-aminophenol, 1,2-
phenylenediamine) to react with sodium salt 2, furnishing the
desired products in good yields (entries 15, 17).
Table 2. Synthesis of benzoheterocycles starting from substituted anilines and
sodium dimethyldithiocarbamate.a
Table 1. Optimization of the reaction conditions.a
Entry
1
Substrate 1
Product
Yield
(%)b
94
Entry
X
Catalyst
Solvent
Temp
(oC)
120
120
120
120
120
120
120
120
120
Time
(min)
10
10
10
10
10
10
10
Yieldb
(%)
64
83
82
81
78
76
94
3a
1a
1
2
3
4
5
6
7
8
9
S
S
S
S
S
S
S
S
S
--
CuCl2
Cu(OAc)2
Cu(OTf)2
CuSO4
FeCl3
AlCl3
AlCl3
AlCl3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
H2O
2
3
95
45
3b
3c
1b
1c
10
10
70
trace
toluene
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10.1002/ejoc.201800993
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4
83
55
19
20
21
58
3d
1d
1s
1t
3s
5
3e
3f
67
1e
6
55
60
3t
1f
54
7
1u
3u
3g
1g
22
23
30
8
69
1v
3v
1h
3h
3i
92
9
32
78
1w
3w
1i
65
10
24
3j
1x
1j
3x
aReaction conditions: 1 (1.0 mmol), 2 (2.5 mmol), AlCl3 (10 mol %), DMF (2.0
mL). bIsolated yield based on 1 after column chromatography.
11
88
75
3k
1k
A plausible reaction mechanism for this transformation is
proposed. Initially, AlCl3 coordinates with thiocarbonyl moiety of
12
sodium
dimethyldithiocarbamate
A,
enhancing
the
electrophilicity at carbonyl-carbon of A and facilitates amino-
group of bifunctional molecule B to attack at this position to
generate the intermediate dimethylphenylthiourea C. Secondly,
the intramolecular cyclization of C generates target product E,
which is the dynamical isomer of F (Scheme 2).
3l
1l
0
13
3m
1m
14
73
1n
3n
3o
15
1o
16
56
30
Scheme 2. The possible reaction mechanism.
1p
3p
17
49
53
Conclusions
1q
3q
3r
In summary, we have developed an AlCl3-promoted one-pot
synthesis of 2-mercapto heterocycles (benzothiazoles,
benzoxazoles, benzimidazoles, thiazolidine-2-thiones and
imidazolidine-2-thiones). The reactions were readily facilitated to
18
1r
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10.1002/ejoc.201800993
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193°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) 13.92 (brs, 1H),
7.47 (d, 1H, J = 8.0 Hz), 7.29-7.20 (m, 3H). 13C NMR (100 MHz, DMSO-
d6, TMS): δ (ppm) 180.5, 148.5, 131.6, 125.5, 124.2, 110.9, 110.4.
HRMS (ESI) m/z [M+H]+ Calcd for C7H6NOS (152.0165), found: 152.0162.
afford the desired compounds smoothly under easy conditions.
Features of this protocol are 1) easy performance, 2)
commercially available, inexpensive, easy-to-handle and
chemically stable thiocarbonyl surrogates, 3) the ability to
prepare
structurally
diverse
2-mercapto
heterocycles
5-Fluoro-benzooxazole-2-thiol (3e): According to TP, the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 3:1) to give the target compound 3e as a yellow solid (yield =
55%). m.p: 189-190°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm)
13.99 (brs, 1H), 7.50-7.47 (m, 1H), 7.10-7.02 (m, 2H). 13C NMR (100
MHz, DMSO-d6, TMS): δ (ppm) 181.6, 159.9 (d, 1C, J = 238 Hz), 144.9
(d, 1C, J = 1 Hz), 132.5 (d, 1C, J = 13 Hz), 111.1 (q, 1C, J = 38 Hz), 98.7
(d, 1C, J = 29 Hz). HRMS (ESI) m/z [M+H]+ Calcd for C7H5FNOS
(170.0071), found: 170.0075.
(benzothiazoles, benzoxazoles, benzimidazoles, thiazolidine-2-
thiones and imidazolidine-2-thiones).
Experimental Section
General remarks: All reagents were used without further purification,
which were purchased from commercial suppliers. All reactions were
performed in an IKA parallel reactor, and were monitored by TLC.
Column chromatography separations were carried out on silica gel (200-
300 mesh). Melting points were measured with an RY-1 m.p. machine
without adjustment. 1H NMR (in CDCl3 or DMSO-d6) and 13C NMR (in
CDCl3 or DMSO-d6) spectra were recorded using TMS as an internal
standard on a Bruker 400 AC NMR spectrometer. The high-resolution
mass spectra (ESI-HRMS) were determined on an Ion Spec (7.0 T)
spectrometer. Yields refer to the isolated compounds estimated to be
>95% pure as determined by 1H NMR and capillary GC analysis.
6-Chloro-benzooxazole-2-thiol (3f): According to TP, the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 3:1) to give the target compound 3f as a yellow solid (yield =
55%). m.p: 224-225°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm)
14.01 (brs, 1H), 7.72 (d, J = 4 Hz, 1H), 7.35-7.32 (m, 1H), 7.23 (d, J = 8
Hz, 1H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 180.9, 148.9,
130.9, 128.4, 125.6, 111.7, 111.0. HRMS (ESI) m/z [M+H]+ Calcd for
C7H5ClNOS (185.9775), found: 185.9772.
5-Bromo-benzooxazole-2-thiol (3g): According to TP, the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 3:1) to give the target compound 3g as a red solid (yield = 60%).
m.p: 283-284°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) 13.93 (brs,
1H), 7.47-7.41 (m, 3H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm)
181.0, 147.8, 133.3, 126.8, 117.4, 113.5, 112.1. HRMS (ESI) m/z [M+H]+
Calcd for C7H5BrNOS (229.9270), found: 229.9274.
Typical procedure (TP) for synthesis of 2-mercapto benzothiazoles,
benzoxazoles and benzimidazoles. (3a-3x): 1 (1.0 mmol), 2 (2.5 mmol)
and AlCl3 (0.1 mmol) were dissolved in DMF (2 mL) in a dried tube
equipped with a magnetic stirring bar and a septum. The reaction mixture
was then heated in an oil bath and checked by TLC until the starting
material was consumed (about 10-30min). Then the reaction mixture was
allowed to cool down to room temperature, quenched with water,
extracted with ethyl acetate, and dried over anhydrous Na2SO4. The
residue was purified by flash column chromatography to afford the
desired product.
4-Methyl-benzooxazole-2-thiol (3h): According to TP, the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 3:1) to give the target compound 3h as a white solid (yield =
69%) m.p: 218-219°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm)
13.93 (brs, 1H), 7.28 (d, J = 8 Hz, 1H), 7.15-7.06 (t, J = 8 Hz, 2H), 2.36 (s,
3H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 180.5, 148.3, 130.8,
126.4, 124.0, 121.5, 107.6, 16.5. HRMS (ESI) m/z [M+H]+ Calcd for
C8H8NOS (166.0321), found: 166.0328.
Benzothiazole-2-thiol (3a): According to TP, the residue was purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to
give the target compound 3a as a white solid (yield = 94%). m.p: 180-
182°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) 13.71 (brs, 1H),
7.59 (d, 1H, J = 4.0 Hz), 7.30-7.17 (m, 3H). 13C NMR (100 MHz, DMSO-
d6, TMS): δ (ppm) 190.2, 141.8, 129.9, 127.7, 124.7, 122.3, 112.9.
HRMS (ESI) m/z [M+H]+ Calcd for C7H6NS2 (170.9936), found: 170.9939.
7-Methyl-benzooxazole-2-thiol (3i): According to TP, the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 3:1) to give the target compound 3i as a red solid (yield = 32%).
m.p: 203-205°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) 13.76 (brs,
1H), 7.17 (t, J = 8 Hz, 1H), 7.05 (t, J = 8 Hz, 2H), 2.38 (s, 3H). 13C NMR
(100 MHz, DMSO-d6, TMS): δ (ppm) 180.3, 147.4, 131.2, 125.4, 125.3,
120.4, 108.3, 14.7. HRMS (ESI) m/z [M+H]+ Calcd for C8H8NOS
(166.0321), found 166.0323.
5-Chloro-benzothiazole-2-thiol (3b): According to TP, the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 3:1) to give the target compound 3b as a white solid (yield =
95%). m.p: 201-203°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm)
13.81 (brs, 1H), 7.67 (d, 1H, J = 8.0 Hz), 7.31-7.25 (m, 2H). 13C NMR
(100 MHz, DMSO-d6, TMS): δ (ppm) 191.3, 142.6, 132.2, 128.6, 124.4,
123.5, 112.3. HRMS (ESI) m/z [M+H]+ Calcd for C7H5ClNS2 (201.9547),
found: 201.9545.
5-Methyl-benzooxazole-2-thiol (3j): According to TP, the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 3:1) to give the target compound 3j as a white solid (yield = 78%).
m.p: 214-216°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) 13.94 (brs,
1H), 7.56 (d, J = 12 Hz, 1H), 7.25 (d, J = 4 Hz, 2H), 2.57 (s, 3H). 13C
NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 181.6, 147.7, 136.2, 132.6,
125.7, 111.9, 110.8, 22.2. HRMS (ESI) m/z [M+H]+ Calcd for C8H8NOS
(166.0321), found: 166.0316.
thiazolidine-2-thione (3c): According to TP, the residue was purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate 1:1) to
give the target compound 3c as a white solid (yield = 45%). m.p: 106-
108°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) 10.09 (brs, 1H),
3.87 (t, d = 8.0 Hz, 2H), 3.51 (t, d = 8.0 Hz 2H). 13C NMR (100 MHz,
DMSO-d6, TMS): δ (ppm) 199.4, 51.9, 33.3. HRMS (ESI) m/z [M+H]+
Calcd for C3H6NS2 (119.9936), found 119.9932.
5-tert-Butyl-benzooxazole-2-thiol (3k): According to TP, the residue
was purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 3:1) to give the target compound 3k as a red solid (yield = 88%).
m.p: 126-128°C; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 12.20 (brs,
Benzooxazole-2-thiol (3d): According to TP, the residue was purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to
give the target compound 3d as a white solid (yield = 83%). m.p: 192-
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10.1002/ejoc.201800993
European Journal of Organic Chemistry
FULL PAPER
1H), 7.34 (m, 3H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3, TMS): δ
(ppm) 181.4, 149.9, 147.3, 130.8, 122.4, 110.3, 108.2, 35.6, 32.1. HRMS
(ESI) m/z [M+H]+ Calcd for C11H14NOS (208.0791), found: 208.0788.
168.1, 132.9, 132.1, 130.6, 123.6, 110.0, 109.6, 21.4. HRMS (ESI) m/z
[M+H]+ Calcd for C8H9N2S (165.0481), found: 165.0479.
5,6-Dimethyl-1,3-dihydro-2H-benzoimidazole-2-thione (3t): According
to the TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate 1:1) to give the target compound 3t as a
brown solid (yield = 67%). m.p: 325-326°C; 1H NMR (400 MHz, DMSO-d6,
TMS): δ (ppm) 12.29 (brs, 2H), 6.92 (s, 2H), 2.19 (s, 6H). 13C NMR (100
MHz, DMSO-d6, TMS): δ (ppm) 167.4, 131.0, 131.0, 110.5, 20.0. HRMS
(ESI) m/z [M+H]+ Calcd for C9H11N2S (179.0638), found: 179.0643.
6-Methyl-benzooxazole-2-thiol (3l): According to the TP, the residue
was purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 3:1) to give the target compound 3l as a white solid (yield = 75%).
m.p: 208-210°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) 13.68 (brs,
1H), 7.24 (s, 1H), 7.03 (s, 2H), 2.3 (s, 3H). 13C NMR (100 MHz, DMSO-d6,
TMS): δ (ppm) 180.3, 148.7, 134.0, 129.2, 126.0, 110.6, 110.3, 21.3.
HRMS (ESI) m/z [M+H]+ Calcd for C8H8NOS (166.0321), found: 166.0324.
4-methyl-1,3-dihydro-2H-benzoimidazole-2-thione (3u): According to
the TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate 1:1) to give the target compound 3u as a
brown solid (yield = 54%). m.p: decomposed; 1H NMR (400 MHz, DMSO-
d6, TMS): δ (ppm) 12.58 (s, 1H), 12.46 (s, 1H), 7.02-6.88 (m, 3H), 2.35 (s,
3H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 168.2, 132.3, 131.9,
123.6, 122.8, 120.1, 107.4, 16.7. HRMS (ESI) m/z [M+H]+ Calcd for
C8H9N2S (165.0481), found: 165.0484.
1,3-Dihydro-2H-benzoimidazole-2-thione (3n): According to the TP,
the residue was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate 1:1) to give the target compound 3n as a white solid
(yield = 73%). m.p: 298-300°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.42 (brs, 2H), 7.00 (t, J = 4.0 Hz, 4H). 13C NMR (100 MHz,
DMSO-d6, TMS): δ (ppm) 169.1, 133.2, 123.3, 110.5. HRMS (ESI) m/z
[M+H]+ Calcd for C7H7N2S (151.0325), found: 151.0321.
5-Fluoro-1,3-dihydro-2H-benzoimidazole-2-thione (3o): According to
the TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate 1:1) to give the target compound 3o as a
white solid (yield = 56%). m.p: 284-286°C; 1H NMR (400 MHz, DMSO-d6,
TMS): δ (ppm) 12.61 (d, J = 8.0 Hz, 2H), 7.13-7.10 (m, 1H), 6.98-6.93 (m,
2H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 169.7, 160.1 (d, 1C,
J = 236 Hz), 133.2 (d, 1C, J = 13 Hz), 129.3, 110.5 (d, 1C, J = 10 Hz),
109.8 (d, 1C, J = 25 Hz), 97.4 (d, 1C, J = 28 Hz). HRMS (ESI) m/z
[M+H]+ Calcd for C7H6FN2S (169.0230), found: 169.0227.
1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-thione (3v): According to the
TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate 1:1) to give the target compound 3v as a
white solid (yield = 30%). m.p: 322-324°C; 1H NMR (400 MHz, DMSO-d6,
TMS): δ (ppm) 13.13 (brs, 1H), 12.71 (brs, 1H), 8.09 (d, J = 8.0 Hz, 1H),
7.47 (d, J = 8.0 Hz, 1H), 7.14-7.10 (m, 1H). 13C NMR (100 MHz, DMSO-
d6, TMS): δ (ppm) 170.2, 146.8, 142.7, 125.9, 118.6, 116.7. HRMS (ESI)
m/z [M+H]+ Calcd for C6H6N3S (152.0277), found: 152.0273.
imidazolidine-2-thione (3w): According to the TP, the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 1:1) to give the target compound 3w as a white solid (yield =
92%). m.p: 204-205°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm)
7.95 (brs, 2H), 3.48 (s, 4H). 13C NMR (100 MHz, DMSO-d6, TMS): δ
(ppm) 184.4, 45.1. HRMS (ESI) m/z [M+H]+ Calcd for C3H7N2S
(103.0325), found: 103.0321.
2-Thioxo-2,3-dihydro-2H-benzoimidazole-5-carbonitrile
(3p):
According to the TP, the residue was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate 1:1) to give the target
compound 3p as a white solid (yield = 30%). m.p: 315-316°C; 1H NMR
(400 MHz, DMSO-d6, TMS): δ (ppm) 12.95 (d, J = 20.0 Hz, 2H), 7.53-
7.51 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6,
TMS): δ (ppm) 171.0, 136.0, 132.7, 127.4, 119.7, 113.3, 110.6, 104.6.
HRMS (ESI) m/z [M+H]+ Calcd for C8H6N3S (176.0277), found: 176.0273.
octahydro-2H-benzoimidazole-2-thione (3x): According to the TP, the
residue was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate 1:1) to give the target compound 3x as a white solid
(yield = 65%). m.p: 159-161°C; 1H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 8.26 (brs, 2H), 3.02 (t, J = 4.0 Hz, 2H), 1.91 (d, J = 12.0 Hz, 2H),
1.68 (d, J = 8.0 Hz, 2H), 1.34-1.22 (m, 4H). 13C NMR (100 MHz, DMSO-
d6, TMS): δ (ppm) 186.9, 64.2, 29.2, 23.9. HRMS (ESI) m/z [M+H]+ Calcd
for C7H13N2S (157.0794), found: 157.0797.
5-Bromo-1,3-dihydro-2H-benzoimidazole-2-thione (3q): According to
the TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate 1:1) to give the target compound 3q as a
gray solid (yield = 49%). m.p: 302-303°C; 1H NMR (400 MHz, DMSO-d6,
TMS): δ (ppm) 12.65 (d, J = 16 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.09 (d,
J = 8.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) 169.4,
134.0, 132.0, 125.4, 114.8, 112.4, 111.5. HRMS (ESI) m/z [M+H]+ Calcd
for C7H6BrN2S (228.9430), found: 228.9434.
Acknowledgements
5-Methoxy-1,3-dihydro-2H-benzoimidazole-2-thione (3r): According to
the TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate 1:1) to give the target compound 3r as a
yellow solid (yield = 53%). m.p: 255-257°C; 1H NMR (400 MHz, DMSO-d6,
TMS): δ (ppm) 12.38 (d, J = 12.0 Hz,, 2H), 7.05 (d, J = 12.0 Hz, 1H), 6.72
(t, J = 8.0 Hz, 2H), 3.72 (s, 3H). 13C NMR (100 MHz, DMSO-d6, TMS): δ
(ppm) 168.0, 156.2, 133.4, 126.7, 110.5, 110.2, 94.9, 55.9. HRMS (ESI)
m/z [M+H]+ Calcd for C8H9N2OS (181.0430), found: 181.0425.
We thank the foundation support from National Natural Science
Foundation of China (21302150), foundation of Chen-Guang
program from Hubei Association for Science and Technology,
foundation of Chutian distinguished fellow from Hubei Provincial
Department of Education, foundation of Highend Talent
Cultivation Program from Wuhan Institute of Technology. Z.-B. D.
acknowledges the Humboldt Foundation and China Scholarship
5-Methyl-1,3-dihydro-2H-benzoimidazole-2-thione (3s): According to
the TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate 1:1) to give the target compound 3s as a
white solid (yield = 58%). m.p: 294-295°C; 1H NMR (400 MHz, DMSO-d6,
TMS): δ (ppm) 12.41 (brs, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 8.0
Hz, 2H,), 2.32 (s, 3H). 13C NMR (100 MHz, DMSO-d6, TMS): δ (ppm)
Council for
a fellowship. X. L. thanks the support of
Postgraduate Innovation Foundation (CX2017088) from Wuhan
Institute of Technology.
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10.1002/ejoc.201800993
European Journal of Organic Chemistry
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10.1002/ejoc.201800993
European Journal of Organic Chemistry
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Author(s), Corresponding Author(s)*
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Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm;
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not be less than 2 mm.))
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Cyclization: synthesis of 2-mercapto
benzoheterocycles*
X. Liu, S. B. Zhang, Z. B. Dong*
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AlCl3-Promoted Synthesis of 2-
Text for Table of Contents
Mercapto
Benzoheterocycles
by
Using
Sodium
as
Dimethyldithiocarbamate
Thiocarbonyl Surrogate
*one or two words that highlight the emphasis of the paper or the field of the study
A simple, expeditious and high-efficiency synthetic method for the AlCl3-mediated one-pot preparation of 2-mercapto
benzoheterocycles (2-mercapto benzothiazoles, benzoxazoles and benzimidazoles) is described. By the treatment of a series
of S, O and N heteroatoms containing bifunctional molecules with sodium dimethyldithiocarbamate in AlCl3, the desired 2-
mercapto benzoheterocycles were synthesized smoothly. The protocol can also be applied on the synthesis of a series of
thiazolidine-2-thiones, imidazolidine-2-thiones.
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