Three-Component Synthesis of 2-Alkylthiobenzoazoles in Aqueous Media

Article abstract of DOI:10.1055/s-0039-1690854

A highly efficient three-component protocol for the synthesis of the 2-alkylthiobenzoazoles is described. Tetramethylthiuram disulfide (TMTD) cyclized with o -aminothiophenols, generating the intermediate 2-mercaptobenzothiazoles, and the successive C-S coupling with halogenated alkanes afforded a series of 2-alkyl-substituted thiobenzothiazoles smoothly in a one-pot process. This procedure could also be utilized for the preparation of 2-alkyl-substituted thiobenzoxazoles and 2-alkyl-substituted thiobenzimidazoles. Inexpensive and easily available starting materials, metal catalyst-free, broad substrate scope, and water as solvent are the features of this protocol.

Full text of DOI:10.1055/s-0039-1690854

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–G
paper
A
en
J.-Q. Chen et al.
Paper
Synthesis
Three-Component Synthesis of 2-Alkylthiobenzoazoles in
Aqueous Media
Jin-Quan Chena
Jia Guob,c
Zhi-Bing Dong*a,b,c,d
S
key blocks of potential biologically and
pharmaceutically active compounds
S
N
N
S
0
0
0
0-
0
0
0
2-3
3
5
4-8
3
1
8
S
NH2
XH
H2O
X
R
Y
TMTD
+
a School of Chemistry and Environmental Engineering,
Wuhan Institute of Technology, Wuhan 430205,
P. R. of China
+
FG
FG
S R
K2CO3
Y = Cl, Br
N
Metal-catalyst-free
Water as solvent
One-pot procedure
X = S, O, NH
22 examples, yields up to 97%
dzb04982@wit.edu.cn
b Key Laboratory of Green Chemical Process, Ministry of
Education, Wuhan Institute of Technology, Wuhan
430205, P. R. of China
c Hubei Key Laboratory of Novel Reactor and Green Chem-
istry Technology, Wuhan Institute of Technology, Wuhan
430205, P. R. of China
X-ray crystal of 3p
d Ministry of Education Key Laboratory for the Synthesis
and Application of Organic Functional Molecules, Hubei
University, Wuhan 430062, P. R. of China
O
H
Received: 19.12.2019
Accepted after revision: 14.02.2020
Published online: 16.03.2020
H
N
N
S
NHMe
S
N
N
DOI: 10.1055/s-0039-1690854; Art ID: ss-2020-f0693-op
O
1
2
Abstract A highly efficient three-component protocol for the synthe-
sis of the 2-alkylthiobenzoazoles is described. Tetramethylthiuram di-
sulfide (TMTD) cyclized with o-aminothiophenols, generating the inter-
mediate 2-mercaptobenzothiazoles, and the successive C–S coupling
with halogenated alkanes afforded a series of 2-alkyl-substituted thio-
benzothiazoles smoothly in a one-pot process. This procedure could
also be utilized for the preparation of 2-alkyl-substituted thiobenzoxaz-
oles and 2-alkyl-substituted thiobenzimidazoles. Inexpensive and easily
available starting materials, metal catalyst-free, broad substrate scope,
and water as solvent are the features of this protocol.
antituberculotic activity
enzyme inhibitor
X
SR
N
X=O, S, NH
Cl
O
Cl
O
OH
H
N
Cl
N
N
N
S
Key words metal-free, synthesis, thiobenzoazole, water, thiuram
N
Cl
Cl
4
3
triclabendazole
Metal-free-promoted C–S bond formation has been a
subject of intense study due to the importance of sulfur-
substituted benzoheterocyclic compounds and their deriva-
tives, which are popularly applied as a variety of pharma-
ceutical agents and bioactive natural products.1–3 In partic-
ular, some sulfur-substituted benzoheterocyclic com-
pounds have been reported as antiviral, antimicrobial,
anticancer, antihelmintic, antifungal, antitubercular, anti-
diabetic, and antibacterial agents;4 therefore, organic
chemists have paid much attention to the synthesis of the
2-alkyl-substituted thiobenzoazoles, which are important
units of some biologically and pharmaceutically active mol-
ecules.5 Several examples are shown in Figure 1 to illustrate
the importance of these key blocks, such as compound 1
(antituberculotic active drug), compound 2 (inhibitor of 5-
lipoxygenase and cathepsin-D), timoprazole (3), and tri-
clabendazole (4). Furthermore, some of them have efficient
catalytic activity and are used in chemical reactions.6
bendamustine
Figure 1 Representative biologically active compounds containing 2-
alkyl-substituted thiobenzoazoles
There are a couple of ways to synthesize 2-alkyl-substi-
tuted thiobenzoazoles, such as the reaction of 2-aminoiodo-
benzenes with carbon disulfide and alkyl thiols,5b the reac-
tion of benzoheterocyclic thiols with alkyl halides,7–11 and
the reaction of benzoheterocycles with alkyl thiols or dial-
kyl disulfides (Scheme 1).12 However, these protocols have
some drawbacks such as high temperature, use of toxic re-
agents or large amount of organic solvents, and the require-
ment of stoichiometric metal catalysts. Therefore, more
convenient and environmentally friendly methods are still
desirable for these important compounds.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J.-Q. Chen et al.
Paper
Synthesis
I
NH2
CS2+RSH
toxic reagent
K2CO3, DMF
RSH/toluene, 120 °C
Cu(OAc)2·H2O/CuO
TMTD + RY
(cheap, environmentally benign)
/H2O
XH
transition metal
X
N
X
SR
R = alkyl
NH2
K2CO3, 80 °C, 3–5 h
metal-free catalyst
RSSR
N
CuO-nano + K2CO3
X = O, S, NH
This work
140 °C
DMF,
high temperature
organic solvent
S
RY, K2CO3, EtOAc, 170–174 °C
X
S
N
N
S
SH
N
S
X = O, S, NH
Y = Cl, Br
TMTD: tetramethylthiuram disulfide
Scheme 1 Synthetic methods for 2-alkylthiobenzothiazoles, 2-alkylthiobenzoxazoles, and 2-alkylthiobenzimidazoles
Furthermore, the strategies of tandem manner have at-
tracted a lot of attention from the organic chemists recent-
ly, since the intermediates separation is not necessary, it
Table 1 Optimization of the Reaction Conditionsa
may thus increase the efficiency of the performance.13–15
Thiuram reagents are cheap and commercially available or-
ganosulfur compounds with broad applications,16 they
could also be regarded as interesting reagents for the devel-
opment of new synthetic transformations.17 Recently, from
the green and environmental point of view, we reported
that tetramethylthiuram disulfide (TMTD) was a very use-
ful sulfur reagent for organic synthesis.18 As part of our ef-
forts in organosulfur chemistry and our progress in metal-
free synthesis,19 here we would like to demonstrate a con-
venient and efficient protocol for the synthesis of 2-alkyl-
substituted thiobenzoxazoles in a one-pot manner. The fur-
ther survey on alkane halides (this work) could illustrate its
good substrate adaptability, providing an easy, green, and
high-efficient way to establish molecular libraries for the
pharmaceutical industry. Thus, 2-aminophenols, 2-amino-
thiophenols, and 1,2-phenylenediamines react with TMTD
by cyclization under metal-free conditions in water giving
mercaptobenzoheterocycles, and the latter C–S bond for-
mation with alkyl halides could afford the final products
smoothly (Scheme 1).
The model reaction was carried out by using 2-amino-
thiophenol (1a), TMTD, and 1-bromobutane (2a) as starting
materials. 2-Aminothiophenol was mixed with TMTD in
water and heated at 120 °C for 2–3 hours, base and 1-bro-
mobutane were then added to this mixture before it was
heated again. By varying the species of the base, the base
loading, substrate ratio, reaction temperature, and solvents,
the reaction conditions were optimized, and the results are
layed out in Table 1. First, the effects of several bases, such
as K2CO3, Na2CO3, KOH, NaOH, and NaHCO3 on the reaction
were tested (Table 1, entries 1–5), and the results showed
that K2CO3 was the most suitable one, which gave the prod-
Br
S
NH2
SH
S
N
2a
S
N
+
S
N
S
base, solvent
S
TMTD
1a
3a
Entry
Base (equiv)
Solvent
Temp (°C )b Ratioc
Yield(%)d
1
2
K2CO3 (2.0)
Na2CO3 (2.0)
KOH (2.0)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
DMF
DMSO
100
100
100
100
100
100
100
100
100
120
80
1:0.6:2
1:0.6:2
1:0.6:2
1:0.6:2
1:0.6:2
1:0.6:2
1:0.6:2
1:0.6:1
1:0.6:3
1:0.6:2
1:0.6:2
1:0.6:2
1:0.6:2
1:0.6:2
1:0.6:2
1:0.6:2
70
41
61
63
30
43
59
48
68
45
85
68
79
71
N.R.
22
3
4
NaOH (2.0)
NaHCO3 (2.0)
K2CO3 (1.0)
K2CO3 (3.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
5
6
7
8
9
10
11
12
13
14
15
16
60
80
80
Toluene
CH2Cl2
80
80
a Reaction conditions: 1a (1.0 mmol), TMTD (0.6 mmol), 2a (1.0–3.0
mmol), base (1–3 equiv), solvent (2 mL); the mixture of 1a and TMTD was
stirred at 120 °C for 2–3 h, then a mixture of base and 2a was added subse-
quently.
b The temperature for the second step.
c Ratio of 1a/TMTD/2a.
d Isolated yield based on 1a after column chromatography. N.R. = no reac-
tion.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

C
J.-Q. Chen et al.
Paper
Synthesis
Having the optimized reaction conditions in hand, we
began to survey the substrate scope. First, the reactivity of
alkyl halides in the presence of 2-aminothiophenol was ex-
amined (Scheme 2). The reaction proceeded smoothly and
we could obtain the intended tandem reaction (cyclization,
then C–S formation) products in moderate to good yields.
Generally, 2-aminothiophenol and TMTD reacted better
with alkyl bromides than the ones with alkyl chloride. 1-
Bromobutane reacted with 2-aminothiophenol and TMTD,
furnishing the product 3a in 85% yield, while 1-chloro-
butane reacted with the corresponding starting material
giving the product 3a in 25% yield. There is obvious differ-
ence in the reactivity between primary alkyl halogen and
S
NH2
+
S
N
K2CO3
S
N
+
R-Y
S
R
N
S
H2O, 80 °C
SH
S
1
2
3
S
S
S
N
S
S
S
O
N
N
3a
3b
3c
Y = Br, 85%
Y = Cl, 25%
Y = Br, 87%
Y = Br, 56%
S
S
N
S
S
S
N
S
N
3f
3e
3d
Y = Br, 61%
Y = Br, 58%
Y = Br, 59%
Scheme 2 Synthesis of 2-(alkylthio)benzo[d]thiazoles starting from 2-
aminothiophenol, TMTD, and alkyl halides. Reagents and conditions: A
mixture of 2-aminothiophenol (1.0 mmol) and TMTD (0.6 mmol) in
H2O (2.0 mL) was stirred at 120 °C for 2–3 h, then K2CO3 (2.0 mmol)
and alkyl halide (2.0 mmol) were added to the reaction mixture, and
the mixture was stirred at 80 °C for 3–5 h.
S
NH2
O
N
K2CO3
S
N
+
+
R-Y
FG
S
R
FG
N
S
H2O, 100 °C
OH
S
S
1
2
3
O
N
O
N
O
S
S
N
3i
uct in 70% yield (entry 1). Next, the amount of K2CO3 was
selected (entries 1, 6, 7), and 2.0 equivalents of K2CO3 were
found to be the optimal loading amount. Then, the investi-
gation on substrate ratio (1a/TMTD/2a) was performed (en-
tries 1, 8, 9), and it was shown that a ratio of 1a/TMTD/2a =
1:0.6:2 was the best. In addition, reaction temperature
screening (for the second step) was examined (entries 1,
10–12), and 80 °C was found to be the most suitable one.
The subsequent control experiments showed that the most
suitable temperature to give 2-alkylthiobenzoxazole was
100 °C and the best reaction temperature to give 2-alkyl-
thiobenzimidazole was 80 °C. Finally, various solvents such
as H2O, DMF, DMSO, toluene, and CH2Cl2 were tested (en-
tries 11, 13–16), and H2O was found to be the best solvent
for this reaction. The best reaction conditions are shown in
entry 11 of Table 1.
3g
3h
Y = Br, 84%
Y = Cl, 70%
Y = Br, 76%
Y = Br, 84%
O
S
O
O
S
S
N
N
3l
Y = Br, 97%
N
3j
3k
Y = Br, 86%
Y = Br, 56%
O
N
O
S
O
S
N
S
N
Cl
3m
3n
Y = Br, 87%
3o
Y = Br, 83%
Y = Br, 81%
Scheme 3 Synthesis of 2-(alkylthio)benzo[d]oxazoles starting from 2-
aminophenols, TMTD and alkyl halides. Reagents and conditions: The
mixture of 2-aminophenol (1.0 mmol) and TMTD (0.6 mmol) in H2O
(2.0 mL) was stirred at 80 °C for 2–3 h, then K2CO3 (2.0 mmol) and alkyl
halide (2.0 mmol) were added to the reaction, and the mixture was
stirred at 100 °C for 3–5 h.
S
H
NH2
N
K2CO3
S
N
FG
+
+
Br
FG
S
R
N
S
H2O, 80 °C
NH2
N
S
1
2
3
H
N
H
N
S
S
N
F
N
3p
3q
Y = Br, 83%
Y = Br, 81%
H
H
N
N
S
N
S
Br
N
Cl
3r
Y = Br, 81%
3s
Y = Br, 61%
Scheme 4 Synthesis of 2-(alkylthio)-1H-benzo[d]imidazole starting from 2-arylenediamines, TMTD, and 1-bromobutane. Reagents and conditions: The
mixture of 2-arylenediamines (1.0 mmol) and TMTD (0.6 mmol) in H2O (2.0 mL) was stirred at 110 °C for 2–3 h, then K2CO3 (2.0 mmol) and 1-bro-
mobutane (2.0 mmol) were added to the reaction, and the mixture was stirred at 80 °C for 3–5 h.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

D
J.-Q. Chen et al.
Paper
Synthesis
secondary alkyl halogen in this reaction. 2-Bromobutane
gave the products 3e in 58% yield while 1-bromopropane
furnished the product 3b in 87% yield, and 1-bromo-3-
methylbutane gave the product 3f in 59% yield. To our de-
light, the methoxy- and alkenyl-substituted alkyl chain
were all suitable for the transformation under the standard
reaction conditions, and gave the corresponding products
3c and 3d in 56–61% yields.
Next, we checked the reactivity of the alkyl halides in
the presence of various 2-aminophenols and 2-phenylene-
diamines (Scheme 3 and Scheme 4). Likewise, the tandem
reaction proceeded smoothly and the intended products
were generated in good to excellent yields. The results in
Schemes 2–4 revealed that the protocol featured good sub-
strate compatibility, providing a convenient and easy way
for preparation of potential drug molecules in pharmaceu-
tical industry. To further confirm the structure of the de-
sired product, the product 3p was characterized by X-ray
crystallography (Figure 2).20
In summary, a simple, efficient, and one-pot protocol
for the preparation of 2-alkylthiobenzoazoles in water was
developed. By using 2-aminothiophenols, 2-aminophenols,
and 1,2-phenylenediamines as starting materials, the mer-
captobenzoheterocycles were synthesized by cyclization by
reacting with TMTD, and the latter C–S coupling generated
the final products in good yields. The features of this proto-
col are metal catalyst-free, easy performance, wide sub-
strates scope, and water as solvent, showing its practical
and useful value in organic synthesis. Further development
and related applications for this method are under investi-
gation in our lab.
Flash column chromatography was operated on silica gel with
PE/EtOAc as the eluent. TLC was adopted and visualized under UV
light. The RY-1G instrument was used to determine melting points of
target compounds. The HRMS (high-resolution mass spectra) was re-
corded on a Finnigan MAT 95Q mass instrument (ESI). A Bruker
AM400 NMR instrument was operated in CDCl3 to record the NMR
spectra.
2-(Butylthio)benzo[d]thiazole (3a); Typical Procedure
A mixture of 2-aminobenzenethiol (1a; 1.0 mmol) and TMTD (0.6
mmol) in H2O (2.0 mL) was heated at 120 °C for 2–3 h, then K2CO3 (2.0
mmol) and 1-bromobutane (2a; 2.0 mmol) were added to the reac-
tion mixture. The mixture was stirred at 80 °C and the reaction was
monitored by TLC (about 5 h). The reaction was then quenched with
aq NH4Cl, and extracted with EtOAc. The combined extracts were
dried (anhyd Na2SO4) and concentrated under vacuum. The crude ma-
terial was purified by column chromatography on silica gel (PE/EtOAc
10:1) to give 3a as a yellow oil; yield: 190 mg (85%).
Figure 2 X-ray crystal structure of 3p20
According to the above results and our previous work on
C–S formation,18 we propose a possible pathway as shown
in Scheme 5. TMTD A reacts with aniline B to generate in-
termediate thiourea C, the XH (X = O, S, NH) undergoes in-
tramolecular nucleophilic addition giving intermediate D.
The subsequent intramolecular elimination allows D to give
the intermediate E, which is in dynamic equilibrium with
the mercaptobenzoheterocycle F. Benzoheterocycle F pro-
cesses the latter SN2 pathway with alkyl halide to furnish
the final product G easily.
1H NMR (400 MHz, CDCl3/TMS):  = 7.76 (d, J = 8.0 Hz, 1 H), 7.62 (d, J =
8.0 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1 H), 3.23 (t, J =
8.0 Hz, 2 H), 1.72–1.65 (m, 2 H), 1.44–1.34 (m, 2 H), 0.85 (t, J = 8.0 Hz,
3 H).
13C NMR (100 MHz, CDCl3):  = 166.3, 152.3, 134.0, 124.9, 123.0,
120.3, 119.8, 32.2, 30.1, 20.8, 12.5.
HRMS (ESI): m/z [M + H]+ calcd for C11H14NS2: 224.0562; found:
224.0564.
..
S
..
NH2
XH
..
X
S
SH
S
N
+
FG
FG
FG
N
S
N
N
H
XH
N
N
S
H
B
A
C
D
X = S, O, NH
HN
R
X
N
X
X
RY,Y = Br, Cl
S
FG
SH
N
FG
S
FG
base
SN2 process
N
H
G
F
E
Scheme 5 Plausible reaction mechanism
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

E
J.-Q. Chen et al.
Paper
Synthesis
2-(Propylthio)benzo[d]thiazole (3b)
13C NMR (100 MHz, CDCl3):  = 166.2, 152.3, 134.1, 124.9, 123.0,
120.3, 119.8, 36.9, 30.6, 26.4, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H16NS2: 238.0719; found:
238.0714.
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3b as a
brown oil; yield: 181 mg (87%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.74 (d, J = 8.0 Hz, 1 H), 7.58 (d, J =
8.0 Hz, 1 H), 7.26 (t, J = 8.0 Hz, 1 H), 7.12 (t, J = 8.0 Hz, 1 H), 3.18 (t, J =
8.0 Hz, 2 H), 1.76–1.65 (m, 2 H), 0.94 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 166.2, 152.2, 134.0, 124.8, 123.0,
120.3, 119.8, 34.4, 21.6, 12.3.
2-(Butylthio)benzo[d]oxazole (3g)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 20:1) to give 3g as a
yellow oil; yield: 174 mg (84%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.49 (d, J = 4.0 Hz, 1 H), 7.30 (d, J =
8.0 Hz, 1 H), 7.16–7.07 (m, 2 H), 3.19 (t, J = 8.0 Hz, 2 H), 1.73–1.65 (m,
2 H), 1.43–1.34 (m, 2 H), 0.85 (t, J = 8.0 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C10H12NS2: 210.0406; found:
210.0409.
2-[(3-Methoxypropyl)thio]benzo[d]thiazole (3c)
13C NMR (100 MHz, CDCl3):  = 164.1, 150.7, 140.9, 123.1, 122.6,
117.2, 108.7, 30.9, 30.2, 20.7, 12.5.
HRMS (ESI): m/z [M + H]+ calcd for C11H14NOS: 208.0791; found:
208.0795.
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 50:1) to give 3c as a
pale yellow oil; yield: 135 mg (56%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.75 (d, J = 8.0 Hz, 1 H), 7.61 (d, J =
8.0 Hz, 1 H), 7.28 (t, J = 8.0 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1 H), 3.40 (t, J =
8.0 Hz, 2 H), 3.31 (t, J = 8.0 Hz, 2 H), 3.23 (s, 3 H), 2.02–1.95 (m, 2 H).
13C NMR (100 MHz, CDCl3):  = 165.8, 152.2, 134.1, 124.9, 123.0,
120.3, 119.8, 69.6, 57.5, 29.3, 28.2.
2-(Propylthio)benzo[d]oxazole (3h)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3h as a
pale yellow oil; yield: 146 mg (76%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.52 (d, J = 8.0 Hz, 1 H), 7.35 (d, J =
8.0 Hz, 1 H), 7.21–7.13 (m, 2 H), 3.21 (t, J = 8.0 Hz, 2 H), 1.84–1.71 (m,
2 H), 1.01 (t, J = 8.0 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C11H14NOS2: 240.0511; found:
240.0515.
2-(But-3-en-1-ylthio)benzo[d]thiazole (3d)
13C NMR (100 MHz, CDCl3):  = 164.2, 150.7, 140.9, 123.1, 122.7,
117.2, 108.7, 33.1, 21.7, 12.2.
HRMS (ESI): m/z [M + H]+ calcd for C10H12NOS: 194.0634; found:
194.0638.
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3d as a
yellow oil; yield: 135 mg (61%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.76 (d, J = 8.0 Hz, 1 H), 7.61 (d, J =
8.0 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.16 (t, J = 8.0 Hz, 1 H), 5.82–5.72
(m, 1 H), 5.06–4.98 (m, 2 H), 3.32 (t, J = 8.0 Hz, 2 H), 2.49–2.44 (m, 2
H).
2-(Isopentylthio)benzo[d]oxazole (3i)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3i as a
palm red oil; yield: 186 mg (84%).
13C NMR (100 MHz, CDCl3):  = 165.7, 152.2, 134.6, 134.1, 124.9,
1H NMR (400 MHz, CDCl3/TMS):  = 7.49 (d, J = 4.0 Hz, 1 H), 7.30 (d, J =
8.0 Hz, 1 H), 7.16–7.70 (m, 2 H), 3.20 (t, J = 8.0 Hz, 2 H), 1.71–1.56 (m,
3 H), 0.85 (d, J = 8.0 Hz, 6 H).
123.0, 120.4, 119.8, 115.8, 32.2, 31.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H12NS2: 220.0406; found:
220.0409.
13C NMR (100 MHz, CDCl3):  = 164.1, 150.7, 140.9, 123.1, 122.6,
2-(sec-Butylthio)benzo[d]thiazole (3e)
117.2, 108.7, 36.9, 29.3, 26.3, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H16NOS: 222.0947; found:
222.0945.
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3e as a
brown oil; yield: 130 mg (58%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.77 (d, J = 8.0 Hz, 1 H), 7.61 (d, J =
8.0 Hz, 1 H), 7.28 (t, J = 8.0 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1 H), 3.87–3.79
(m, 1 H), 1.76–1.59 (m, 2 H), 1.39 (d, J = 4.0 Hz, 3 H), 0.95 (d, J = 8.0 Hz,
3 H).
13C NMR (100 MHz, CDCl3):  = 165.6, 152.3, 134.2, 124.8, 123.1,
120.4, 119.8, 44.8, 28.6, 19.8, 10.3.
HRMS (ESI): m/z [M + H]+ calcd for C11H14NS2: 224.0562; found:
224.0566.
2-(But-3-en-1-ylthio)benzo[d]oxazole (3j)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3j as a
yellow oil; yield: 177 mg (86%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.49 (d, J = 8.0 Hz, 1 H), 7.30 (d, J =
8.0 Hz, 1 H), 7.17–7.08 (m, 2 H), 5.81–5.70 (m, 1 H), 5.06–4.98 (m, 2
H), 3.25 (t, J = 8.0 Hz, 2 H), 2.50–2.45 (m, 2 H).
13C NMR (100 MHz, CDCl3):  = 163.8, 150.7, 140.9, 134.3, 123.1,
122.7, 117.2, 116.0, 108.7, 32.2, 30.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H12NOS: 206.0634; found:
206.0636.
2-(Isopentylthio)benzo[d]thiazole (3f)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3f as a
brown oil; yield: 139 mg (59%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.77 (d, J = 8.0 Hz, 1 H), 7.63 (d, J =
8.0 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.16 (t, J = 8.0 Hz, 1 H), 3.24 (t, J =
8.0 Hz, 2 H), 1.72–1.57 (m, 3 H), 0.86 (d, J = 8.0 Hz, 6 H).
2-(sec-Butylthio)benzo[d]oxazole (3k)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3k as a
yellow oil; yield: 116 mg (56%).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

F
J.-Q. Chen et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3/TMS):  = 7.50 (d, J = 8.0 Hz, 1 H), 7.31 (d, J =
8.0 Hz, 1 H), 7.18–7.09 (m, 2 H), 3.84–3.75 (m, 1 H), 1.79–1.62 (m, 2
H), 1.42 (d, J = 8.0 Hz, 3 H), 0.96 (t, J = 8.0 Hz, 3 H).
2-(Butylthio)-1H-benzo[d]imidazole (3p)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3p as a
white solid; yield: 172 mg (83%); mp 133–135 °C.
13C NMR (100 MHz, CDCl3):  = 163.8, 150.5, 140.9, 123.1, 122.7,
1H NMR (400 MHz, CDCl3/TMS):  = 10.46 (s, 1 H), 7.46–7.44 (m, 2 H),
7.11–7.09 (m, 2 H), 3.22 (t, J = 8.0 Hz, 2 H), 1.65–1.58 (m, 2 H), 1.31–
1.22 (m, 2 H), 0.73 (t, J = 8.0 Hz, 3 H).
117.3, 108.7, 43.8, 28.5, 20.0, 10.2.
HRMS (ESI): m/z [M + H]+ calcd for C11H14NOS: 208.0791; found:
208.0798.
13C NMR (100 MHz, CDCl3):  = 150.2, 138.6, 121.1, 113.0, 31.4, 30.5,
2-(Butylthio)-6-methylbenzo[d]oxazole (3l)
20.7, 12.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H15N2S: 207.0950; found:
207.0955.
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3l as a
yellow oil; yield: 233 mg (97%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.34 (d, J = 8.0 Hz, 1 H), 7.09 (s, 1
H), 6.95 (d, J = 8.0 Hz, 1 H), 3.17 (t, J = 8.0 Hz, 2 H), 2.31 (s, 3 H), 1.72–
1.64 (m, 2 H), 1.43–1.34 (m, 2 H), 0.85 (t, J = 8.0 Hz, 3 H).
2-(Butylthio)-5-fluoro-1H-benzo[d]imidazole (3q)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 3:1) to give 3q as a
yellow solid; yield: 181 mg (81%); mp 99–101 °C.
13C NMR (100 MHz, CDCl3):  = 163.3, 151.0, 138.7, 132.9, 124.1,
1H NMR (400 MHz, CDCl3/TMS):  = 10.32 (s, 1 H), 7.37–7.34 (m, 1 H),
7.17–7.12 (m, 1 H), 6.89–6.84 (m, 1 H), 3.20 (t, J = 8.0 Hz, 2 H), 1.66–
1.58 (m, 2 H), 1.32–1.23 (m, 2 H), 0.75 (t, J = 8.0 Hz, 3 H).
116.6, 109.0, 30.9, 30.2, 20.7, 20.5, 12.5.
HRMS (ESI): m/z [M + H]+ calcd for C12H16NOS: 222.0947; found:
222.0945.
13C NMR (100 MHz, CDCl3):  = 158.3 (d, J = 237.0 Hz), 151.2, 138.4 (d,
J = 13.0 Hz), 134.8, 113.3 (d, J = 10.0 Hz), 109.2 (d, J = 25.0 Hz), 99.4 (d,
J = 26.0 Hz), 31.5, 30.5, 20.7, 12.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H14FN2S: 225.0856; found:
225.0851.
2-(Butylthio)-5-methylbenzo[d]oxazole (3m)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3m as a
palm red oil; yield: 222 mg (83%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.28 (s, 1 H), 7.17 (d, J = 8.0 Hz, 1
H), 6.90 (d, J = 8.0 Hz, 1 H), 3.19 (t, J = 8.0 Hz, 2 H), 2.32 (s, 3 H), 1.73–
1.65 (m, 2 H), 1.44–1.34 (m, 2 H), 0.85 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.0, 148.9, 141.1, 132.8, 123.5,
117.3, 108.0, 30.9, 30.2, 20.7, 20.3, 12.5.
2-(Butylthio)-5-chloro-1H-benzo[d]imidazole (3r)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 3:1) to give 3r as a
yellow solid; 194 mg (81%); mp 120–122 °C.
1H NMR (400 MHz, CDCl3/TMS):  = 7.43 (d, J = 4.0 Hz, 1 H), 7.33 (d, J =
8.0 Hz, 1 H), 7.10–7.07 (m, 1 H), 3.23 (t, J = 8.0 Hz, 2 H), 1.68–1.61 (m,
2 H), 1.37–1.28 (m, 2 H), 0.80 (t, J = 8.0 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H16NOS: 222.0947; found:
222.0945.
5-(tert-Butyl)-2-(butylthio)benzo[d]oxazole (3n)
13C NMR (100 MHz, CDCl3):  = 151.3, 138.8, 136.8, 126.9, 121.7,
113.6, 112.8, 31.4, 30.5, 20.7, 12.5.
HRMS (ESI): m/z [M + H]+ calcd for C11H14ClN2S: 241.0561; found:
241.0568.
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3n as a
brown oil; yield: 277 mg (87%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.54 (s, 1 H), 7.23–7.15 (m, 2 H),
3.19 (t, J = 8.0 Hz, 2 H), 1.74–1.66 (m, 2 H), 1.44–1.35 (m, 2 H), 1.25 (s,
9 H), 0.85 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.3, 148.7, 146.6, 140.8, 120.1,
113.9, 107.8, 33.8, 30.9, 30.7, 30.2, 20.7, 12.5.
5-Bromo-2-(butylthio)-1H-benzo[d]imidazole (3s)
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 3:1) to give 3s as a
brown solid; yield: 174 mg (61%); mp 110–112 °C.
1H NMR (400 MHz, CDCl3/TMS):  = 9.23 (s, 1 H), 7.59 (s, 1 H), 7.29 (d,
J = 8.0 Hz, 1 H), 7.20 (t, J = 8.0 Hz, 1 H), 3.21 (t, J = 8.0 Hz, 2 H), 1.67–
1.59 (m, 2 H), 1.34–1.25 (m, 2 H), 0.77 (t, J = 8.0 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H22NOS: 264.1417; found:
264.1412.
2-(Butylthio)-5-chlorobenzo[d]oxazole (3o)
13C NMR (100 MHz, CDCl3):  = 151.4, 139.4, 137.2, 124.3, 115.8,
114.3, 114.0, 31.4, 30.5, 20.7, 12.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H14BrN2S: 285.0056; found:
285.0059.
Following the typical procedure, the crude material was purified by
column chromatography on silica gel (PE/EtOAc 10:1) to give 3o as a
yellow oil; yield: 196 mg (81%).
1H NMR (400 MHz, CDCl3/TMS):  = 7.45 (s, 1 H), 7.20 (d, J = 8.0 Hz, 1
H), 7.07 (d, J = 8.0 Hz, 1 H), 3.19 (t, J = 8.0 Hz, 2 H), 1.73–1.66 (m, 2 H),
1.44–1.35 (m, 2 H), 0.86 (t, J = 8.0 Hz, 3 H).
Funding Information
13C NMR (100 MHz, CDCl3):  = 165.9, 149.2, 142.0, 128.6, 122.7,
The financial support from Hubei Key Laboratory of Radiation Chem-
istry and Functional Materials, Hubei University of Science & Technol-
ogy (2019-20KZ01), Ministry of Education Key Laboratory for the
Synthesis and Application of Organic Functional Molecules, Hubei
University (KLSAOFM1810), Science and Technology Department of
Hubei Province (2019CFB596), Key Laboratory of Hubei Province for
117.3, 109.2, 31.0, 30.1, 20.7, 12.5.
HRMS (ESI): m/z [M + H]+ calcd for C11H13ClNOS: 242.0401; found:
242.0403.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

G
J.-Q. Chen et al.
Paper
Synthesis
Coal Conversion and New Carbon Materials (WKDM202003) are all
greatly appreciated. J.-Q.C. thanks the support of Postgraduate Inno-
vation Foundation from Wuhan Institute of Technology (CX2019170).
(6) Zhang, H. F.; Liu, D. M.; Kang, T. T.; Wang, Y.; Zhang, X. X.; Zhu,
X. B. Chin. J. Org. Chem. 2016, 36, 1104.
(7) Zhang, T. H.; He, H. X.; Du, J. L.; He, Z. J.; Yao, S. Molecules 2018,
23, 2011.
W
u
h
a
n
I
nstituteof
T
e
c
h
n
o
l
o
g
y
(C
X
2
0
1
9
1
7
0)
(8) Gao, M. C.; Wang, M.; Zheng, Q. H. Appl. Radiat. Isotopes 2008,
66, 506.
(9) Dalal, D. S.; Pawar, N. S.; Mahulikar, P. P. Org. Prep. Proced. Int.
2005, 37, 539.
(10) Li, Y. W.; Gu, G. B.; Liu, H. Y.; Sung, H. Y.; Williams, L. D.; Chang,
C. K. Molecules 2005, 10, 912.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690854.
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n
(11) (a) Sih, J. C.; Graber, D. R. J. Org. Chem. 1983, 48, 3842.
(b) Klimesova, V.; Koci, J.; Pour, M.; Stachel, J.; Waisser, K.;
Kaustova, J. Eur. J. Med. Chem. 2002, 37, 409. (c) Hu, Y.; Chen, Z.
C.; Le, Z. G.; Zheng, Q. G. Synth. Commun. 2004, 34, 2039.
(d) Mésangeau, C.; Narayanan, S.; Green, A. M.; Shaikh, J.;
Kaushal, N.; Viard, E.; Xu, Y. T.; Fishback, J. A.; Poupaert, J. H.;
Matsumoto, R. R.; McCurdy, C. R. J. Med. Chem. 2008, 51, 1482.
(12) (a) Rosario, A. R.; Casola, K. K.; Oliveira, C. E. S.; Zeni, G. Adv.
Synth. Catal. 2013, 355, 2960. (b) Rafique, J.; Saba, S.; Frizon, T.
E. A.; Braga, A. L. ChemistrySelect 2018, 3, 12387. (c) Zhou, A. X.;
Liu, X. Y.; Yang, K.; Zhao, S. C.; Liang, Y. M. Org. Biomol. Chem.
2011, 9, 5456.
(13) (a) Bunce, R. A. Tetrahedron 1995, 51, 13103. (b) Winkler, J. D.
Chem. Rev. 1996, 96, 167. (c) Mayer, S. F.; Kroutil, W.; Faber, K.
Chem. Soc. Rev. 2001, 30, 332. (d) Parsons, P. J.; Penkett, C. S.;
Shell, A. J. Chem. Rev. 1996, 96, 195. (e) Eilbracht, P.; Bärfacker,
L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon, B. E.; Kranemann, C.
L.; Rische, T.; Roggenbuck, R.; Schmidt, A. Chem. Rev. 1999, 99,
3329. (f) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1. (g) Denmark, S.
E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
References
(1) (a) Yu, Y. F.; Li, Z. N.; Jiang, L. Phosphorus, Sulfur Silicon Relat.
Elem. 2012, 187, 632. (b) Liang, G. G.; Liu, M. C.; Chen, J. X.; Ding,
J. C.; Gao, W. X.; Wu, H. Y. Chin. J. Chem. 2012, 30, 1611. (c) Dan,
W. X.; Deng, H. J.; Chen, J. X.; Liu, M. C.; Ding, J. C.; Wu, H. Y.
Tetrahedron 2010, 66, 7384. (d) Guo, W. X.; Chen, J. X.; Wu, D. Z.;
Ding, J. C.; Wu, H. Y. Tetrahedron 2009, 65, 5240. (e) Liu, M. C.;
Lin, S. M.; Ding, J. C.; Gao, W. X.; Wu, H. Y.; Chen, J. X. Tetrahe-
dron 2013, 69, 2283.
(2) He, M. C.; Yan, Z. H.; Zhu, F. Y.; Lin, S. J. Org. Chem. 2018, 83,
15438.
(3) (a) Deligeorgiev, T.; Kaloyanova, S.; Lesev, N.; Vaquero, J. J. Ultra-
son. Sonochem. 2010, 17, 783. (b) Ranjit, S.; Lee, R.; Heryadi, D.;
Shen, C.; Wu, J. E.; Zhang, P. F.; Huang, K. W.; Liu, X. G. J. Org.
Chem. 2011, 76, 8999. (c) Dai, C.; Xu, Z. Q.; Huang, F.; Yu, Z. K.;
Gao, Y. F. J. Org. Chem. 2012, 77, 4414. (d) Yang, X. L.; Xu, Y. L.;
Chen, J. X.; Ding, J. C.; Wu, H. Y.; Su, W. K. J. Chem. Res. 2009, 11,
682.
(14) Murru, S.; Ghosh, H.; Sahoo, S. K.; Patel, B. K. Org. Lett. 2009, 11,
4254.
(15) Shi, L.; Liu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2011, 76,
4200.
(4) (a) Suresh, C. H.; Rao, J. V.; Jayaveera, K. N.; Subudhi, S. K. Int.
Res. J. Pharm. 2011, 2, 257. (b) Singh, M.; Singh, S. K.; Gangwar,
M.; Nath, G.; Singh, S. K. RSC Adv. 2014, 4, 19013. (c) Rao, A. J.;
Rao, P. V.; Rao, V. K.; Mohan, C.; Raju, C. N.; Reddy, C. S. Bull.
Korean Chem. Soc. 2010, 31, 1863. (d) Singh, S. P.; Segal, S. Indian
J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1988, 27, 941.
(e) Palmer, P. J.; Trigg, R. B.; Warrington, J. V. J. Med. Chem. 1971,
14, 248. (f) Pattan, S. R.; Suresh, C.; Pujar, V. D.; Reddy, V. V. K.;
Rasal, V. P.; Koti, B. C. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2005, 44, 2404. (g) Huang, S. T.; Hsei, I. J.; Chen, C.
Bioorg. Med. Chem. 2006, 14, 6106. (h) Akhtar, T.; Hameed, S.;
Al-Masoudi, N. A.; Loddo, R.; Colla, P. Acta Pharm. 2008, 58, 135.
(i) Yang, X. L.; Xu, C. M.; Lin, S. M.; Chen, J. X.; Ding, J. C.; Wu, H.
Y.; Su, W. K. J. Braz. Chem. Soc. 2010, 21, 37. (j) Hu, K.; Qi, L. J.;
Yu, S. L.; Cheng, T. X.; Wang, X. D.; Li, Z. J.; Xia, Y. Z.; Chen, J. X.;
Wu, H. Y. Green Chem. 2017, 19, 1740. (k) Yu, S. L.; Hu, K.; Gong,
J. L.; Qi, L. J.; Zhu, J. H.; Zhang, Y. T.; Cheng, T. X.; Chen, J. X. Org.
Biomol. Chem. 2017, 15, 4300.
(16) Enders, D.; Rembiak, A.; Liebich, J. X. Synthesis 2011, 281.
(17) (a) Zeng, M. T.; Xu, W.; Liu, M.; Liu, X.; Chang, C. Z.; Zhu, H.;
Dong, Z. B. Synth. Commun. 2017, 47, 1434. (b) Dong, Z. B.;
Wang, M.; Zhu, H.; Liu, X.; Chang, C. Z. Synthesis 2017, 49, 5258.
(18) Liu, X.; Liu, M.; Xu, W.; Zeng, M. T.; Zhu, H.; Chang, C. Z.; Dong,
Z. B. Green Chem. 2017, 19, 5591.
(19) (a) Cao, Q.; Peng, Y. H.; Cheng, Y.; Dong, Z. B. Synthesis 2018, 50,
1527. (b) Zhang, S. B.; Liu, X.; Gao, M. Y.; Dong, Z. B. J. Org. Chem.
2018, 83, 14933. (c) Dong, Z. B.; Liu, X.; Bolm, C. Org. Lett. 2017,
19, 5916. (d) Xu, W.; Zeng, M. T.; Liu, M.; Liu, S. S.; Li, Y. S.; Dong,
Z. B. Synthesis 2017, 49, 3084. (e) Zeng, M. T.; Xu, W.; Liu, X.;
Chang, C. Z.; Zhu, H.; Dong, Z. B. Eur. J. Org. Chem. 2017, 6060.
(f) Liu, M.; Zeng, M. T.; Xu, W.; Wu, L.; Dong, Z. B. Tetrahedron
Lett. 2017, 58, 4352.
(20) CCDC 1971891 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
(5) (a) Ali, M.; Ali, S.; Khan, M.; Rashid, U.; Ahmad, M.; Khan, A.; Al-
Harrasi, A.; Ullah, F.; Latif, A. Bioorg. Chem. 2018, 80, 472.
(b) Shi, L.; Liu, X. Q.; Zhang, H.; Jiang, Y. W.; Ma, D. J. Org. Chem.
2011, 76, 4200.
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