Copper(I)-Catalyzed Tandem One-Pot Synthesis of 2-Arylthiobenzothiazoles and 2-Arylthiobenzoxazoles in Water

Article abstract of DOI:10.1021/acs.joc.8b01644

An efficient tandem process for the preparation of 2-arylthiobenzothiazoles has been developed. By condensation of 2-aminobenzenethiol with tetramethylthiuram disulfide (TMTD), 2-mercaptobenzothiazoles was in situ generated, which susequently underwent coupling with iodobenzenes to give the desired 2-arylthiobenzothiazoles fluently in a one-pot manner. This method can also be used for the synthesis of 2-arylthiobenzoxazoles. Inexpensive metal catalyst and ligand, mild reaction temperature, and water as solvent make this protocol practically valuable and useful in organic synthesis.

Full text of DOI:10.1021/acs.joc.8b01644

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Article
Copper(I)-Catalyzed Tandem One-Pot Synthesis of 2-
Arylthiobenzothiazoles and 2-Arylthiobenzoxazoles in Water
Xing Liu, Shi-Bo Zhang, Hui Zhu, and Zhi-Bing Dong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01644 • Publication Date (Web): 11 Sep 2018
Downloaded from http://pubs.acs.org on September 11, 2018
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Copper(I)-Catalyzed
Tandem
One-Pot
Synthesis
of
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2-Arylthiobenzothiazoles and 2-Arylthiobenzoxazoles in Water
Xing Liu a ShiꢀBo Zhang,a Hui Zhu,a and ZhiꢀBing Dong* a,b
,
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aSchool of Chemistry and Environmental Engineering, Wuhan Institute of Technology,
Wuhan 430205, China.
bDepartment of Chemistry, LudwigꢀMaximiliansꢀUniversität, Butenandtstrasse 5ꢀ13,
81377 München, Germany.
Email: dzb04982@wit.edu.cn
ABSTRACT
An efficient tandem process for the preparation of 2ꢀarylthiobenzothiazoles has been
developed. By condensation of 2ꢀaminobenzenethiol with TMTD (tetramethylthiuram
disulfide), 2ꢀmercaptobenzothiazoles was in-situ generated, which susequently
underwent coupling with iodobenzenes to give the desired 2ꢀarylthiobenzothiazoles
fluently in a oneꢀpot manner. This method can also be used for the synthesis of
2ꢀarylthiobenzoxazoles. Inexpensive metal catalyst and ligand, mild reaction
temperature, and water as solvent make this protocol practically valuable and useful
in organic synthesis.
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INTRODUCTION
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Heteroaromatic compounds possessing organothio groups and their derivatives are
known to exhibit interesting biological activities.1 These compounds possess potential
application as anticancer, antimicrobial, antiviral, antitubercular, antihelmintic,
antidiabetic, antifungal, and antibacterial agent.2 Particularly, several
2ꢀthioꢀsubstituted mercaptoazoles such as 2ꢀarylthiobenzothiazoles have received
much attention due to their unique structure and their uses as radioactive amyloid
imagining agents,3 and anticancer agents.4 Some therapeutic agents containing this
core structure have been reported, including avarolꢀ3′ꢀthiobenzothizole (A), PPAR
receptor activator (B), cathepsinꢀD inhibitor (C) (Figure 1).5 It is thus necessary to
develop simple and ecoꢀfriendly synthetic methods for their preparations.
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Figure 1. Representative Biologically Active 2ꢀArylthiobenzothiazoles.
Classically, 2ꢀarylthiobenzothiazolesa are synthesized via the crossꢀcoupling
reactions of 2ꢀmercaptobenzothiazoles with aryl halides (Scheme 1, path A),6 or aryl
boronic acids,7 or Grignard reagents (Scheme 1, path B),8 and the nucleophilic attack
of arylthiols on preformed 2ꢀhalobenzothiazoles (Scheme 1, path C).9 However, the
preparation of 2ꢀarylthiobenzothiazoles with these methods depends largely on the
availability of the requisite, suitably substituted 2ꢀhalobenzothiazoles or
2ꢀmercaptobenzothiazoles. Several other methods are available for the synthesis of
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2ꢀarylthiobenzothiazoles, including the Sꢀarylation of benzothiazoles with diaryl
disulfides (Scheme 1, path D)10 or the direct functionalization of a heterocyclic CꢀH
bond with aryl thiols in the presence of a copper reagent (Scheme 1, path E).11
However, these copperꢀmediated reactions suffer from many drawbacks such as high
reaction temperature, the usual requirement of stoichiometric copper salts. In recent
years, oneꢀpot, tandem, cascade or domino strategies, whereby multiple bonds can be
constructed in a single reaction without the need to isolate the intermediates, are used
to improve the efficiency of a chemical reaction.12 Patel and coꢀworkers reported
Cu(I)ꢀcatalyzed sequential intraꢀ and intermolecular CꢀS bond formation using
dithiocarbamate salts (Scheme 1, path F)13 and an efficient cascade process from
2ꢀhaloaryl isothiocyanates and S nucleophiles (Scheme 1, path G).14 Ma and
coꢀworkers reported the synthesis of 2ꢀthioꢀsubstituted benzothiazoles in good yields
via a domino condensation (Scheme 1, path H).15 Although significant progress has
been achieved towards the synthesis of these compounds, the development of
environmentally benign, facile, cheaper, and efficient Sꢀarylation protocols is still
desirable.
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Thiuram reagents are cheap and commercially available organosulfur compounds
with broad applications as fungicides, animal repellants, and vulcanization
accelerators.16 Because they are readily available and could be regarded as interesting
reagents for the development of new synthetic transformations.17 On the other hand,
the development of environmentally friendly reaction medium, especially water, has
been paid much attention.18 Recently, we reported an efficient and practical method
for the oneꢀpot synthesis of 2ꢀmercaptoazoles by using thiuram reagent (TMTD) in
water.19 For the continuous efforts on the study of benzoheterocycle compounds,20 we
wish to report here an efficient tandem protocol in water for the synthesis of
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2ꢀarylthiobenzothiazoles and 2ꢀarylthiobenzoxazoles by using thiuram reagent
(TMTD) (Scheme 2). In this oneꢀpot arylation strategy, intermolecular CꢀN coupling
of TMTD (tetramethylthiuram disulfide) would yield intermediate A (Scheme 2),
which is then followed by an intramolecular CꢀS (or CꢀO) coupling, furnishing
2ꢀmercaptobenzothiazole (or 2ꢀmercaptobenzoxazole). Thus, the subsequent in-situ
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intermolecular
CꢀS
coupling
between
2ꢀmercaptobenzothiazole
(or
2ꢀmercaptobenzoxazole) and iodobenzene would generate 2ꢀarylthiobenzothiazole (or
2ꢀarylthiobenzoxazole) smoothly.
S
SH
ArX
+
N
X = I, Br, B(OH)2
NH2
S
N
ArMgBr or
ArZnBr
ArSH
CS2
+
+
SH
+
X
path A
path B
path H
NCS
+ ArSH
X
S
S
path G
Cl
+ ArSH
Ar
path C
N
S
N
X = I, Br
path F
path D
H
N
S
N
S M
ArI
path E
+
ArSSAr
+
S
X
X= I, Br
S
N
SH
ArSH
+
Scheme 1. Existing Synthesis Strategies towards 2ꢀArylthiobenzothiazoles.
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Scheme 2. Our Synthetic Strategy towards 2ꢀArylthiobenzothiazoles and
2ꢀArylthiobenzoxazoles.
RESULTS AND DISCUSSION
We selected 2ꢀaminobenzenethio, TMTD (tetramethylthiuram disulfide) and
iodobenzene as the starting material for the model reaction, and the screened reaction
conditions are summarized in Table 1. The reaction took place to give the desired
product 4a in 20% yield under the conditions shown in entry 1 (10 mol% CuI, 10 mol%
o
1,10ꢀphenanthroline, 2.0 equiv. of Na2CO3, 120 C in H2O). A slightly improved
result was observed by changing H2O to organic solvent DMF (entry 2). Since the
first step of the threeꢀcomponent reaction is the condensation of 2ꢀaminobenzenethiol
with TMTD, we envisioned that changing the operational procedure might be helpful
to increase the yield. Accordingly, 2ꢀaminobenzenethiol was reacted with TMTD at
o
120 C for 3 h and then CuI, iodobenzene, 1,10ꢀphenanthroline, Na2CO3 were added
before heating. This manipulation proved to be useful, providing the target molecular
4a in 80% yield (entry 3). Encouraged by this result, various bases were investigated,
and K2CO3 gave the best yield (entries 4ꢀ7). A number of other ligands were tested for
this reaction (entries 8ꢀ10), and the results showed that other ligands displayed poor
activity as compared with 1,10ꢀphenanthroline. Subsequently, several copper catalysts
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were investigated (entries 11ꢀ15), and CuBr was found to be the most effective
catalyst for the current reaction (entry 11). Other metal catalysts, such as iron, nickel,
or cobalt showed no catalytic activity (entries 16ꢀ18). 5 mol% of copper loading did
not affect the yield of the product (entry 19), while the yield of the product was
reduced to 48% when 5 mol% of 1,10ꢀphenanthroline was used (entry 20). The
screening of the base loading showed that 2.0 equiv. of K2CO3 was the optimal (entry
19 and entry 21). In addition, the yield dropped to 31% when the temperature was
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o
reduced to 60 C (entries 22ꢀ24). Thus, the optimal reaction conditions were set and
summarized in entry 23 (5 mol% of CuBr, 10 mol% of 1,10ꢀphenanthroline, 2.0 equiv.
of K2CO3 in water, heating at 80 oC).
Table 1. Reaction Conditions Screened for the Tandem Synthesis of
2ꢀArylthiobenzothiazole Starting from 2ꢀAminobenzenethiol, TMTD, and
Iodobenzenea
Entry
Catalyst
Base
Ligand
Temp. Yield
(oC)
120
120
120
120
120
120
(%)b
20
1
2
3
4
5
6
CuI
CuI
CuI
CuI
CuI
CuI
Na2CO3
Na2CO3
Na2CO3
K3PO4
K2CO3
KOH
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
23c
80
82
83
76
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CuI
CuI
tꢀBuOK
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1,10ꢀphen
Bpyd
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
81
41
trace
trace
87
82
84
82
80
0
8
9
CuI
Lꢀproline
DMEDAe
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10ꢀphen
1,10-phen
1,10ꢀphen
10
11
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22
23
24
CuI
10
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CuBr
Cu2O
.
CuCl2 2H2O
.
CuSO4 5H2O
.
Cu(OAc)2 H2O K2CO3
.
FeCl3 6H2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
.
NiCl2 6H2O
0
CoCl2
0
CuBr (5%)
CuBr (5%)
CuBr (5%)
CuBr (5%)
CuBr (5%)
CuBr (5%)
87
48f
83g
87
87
31
60
a
Reaction conditions: A (for entries 1ꢀ2): 1a (1.0 mmol), 2a (0.6 mmol), 3a (1.5 mmol), [Cat] (10 mol%), base
(2.0 equiv.), ligand (10 mol%), H2O (2 mL), 15 h, B (for entries 3ꢀ24): 1a (1.0 mmol), 2a (0.6 mmol), H2O, 120 oC,
3 h; then 3a (1.5 mmol), [Cat] (10 mol%), base (2.0 equiv.), ligand (10 mol%), 120ꢀ60 C, 8 h. b Isolated yield.
o
c
d
e
f
DMF as solvent. Bpy = 2,2'ꢀBipyridine, DMEDA = N,N'ꢀDimethylꢀ1,2ꢀethanediamine, Use of 5 mol%
1,10ꢀphenanthroline. g Use of 1.5 equiv. of K2CO3.
By using the above optimized conditions, we explored the substrates scope and
limitations of the threeꢀcomponent reaction (Table 2). Firstly, various aryl iodides
were surveyed and proved to be applicable for this transformation, giving the
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corresponding 2ꢀarylthiobenzothiazoles successfully. For the electronꢀdonating
methyl or methoxy groups, generally good yields were obtained (4b-4e). Due to the
possible steric hinderence, compound 4d and 4e were obtained in moderate yields (77%
and 63%). Substrates bearing electronꢀwithdrawing substituents also resulted in good
yields. Halides such as F, Cl, and Br yielded the desired products in 76ꢀ84% yield (4g,
4h, 4j, 4m, 4n), while strong electronꢀwithdrawing group (NO2, CN) gave relatively
low yields (4f, 4k). Meanwhile, 2ꢀaminoꢀ4ꢀchlorobenzenethiol was also applicable for
the transformation, giving the corresponding 2ꢀarylthiobenzothiazoles in good yields
(4o, 4p). In addition, heterocyclic compound, such as 3ꢀiodopyridine could also afford
the corresponding products 4q in good yield (73%), which showed the good substrate
compatibility of this protocol.
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Table 2. Formation of 2ꢀThiobenzothiazoles from 2ꢀAminobenzenethiols, TMTD and
Iodobenzenesa
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aReaction conditions: 1 (1.0 mmol), 2a (0.6 mmol), H2O (2 mL), 120 oC, 3 h; then 3 (1.5 mmol), CuBr (5 mol%),
1,10ꢀphenanthroline (10 mol%), K2CO3 (2.0 equiv.), 80 oC, 15 h. Isolated yield based on 1.
Subsquently, 2ꢀaminophenol was also tested in order to assess the versatility of the
method (Table 3). It was found that both electronꢀdeficient and electronꢀrich
2ꢀaminophenol were applicable for this transformation, and the desired
2ꢀarylthiobenzoxazoles 6a-6f were obtained in moderate to good yields (40ꢀ85%).
Similarly, we examined the reaction with a series of substituted iodobenzenes (6g-6p).
Both electronꢀrich and electronꢀdeficient aryl iodides were successfully transformed
under the optimized conditions, furnishing the desired products in moderate to good
yields (30ꢀ71%).
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Table 3. Formation of 2ꢀThiobenzoxazoles from 2ꢀAminophenols, TMTD, and
4
5
6
Iodobenzenesa
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aReaction conditions: 5 (1.0 mmol), 2a (0.6 mmol), H2O, 80 oC, 3 h; then 3 (1.5 mmol), CuBr (5 mol%),
1,10ꢀphenanthroline (10 mol%), K2CO3 (2.0 equiv.), 80 oC, 15 h. Isolated yields based on 5.
CONCLUSION
In summary, we have developed an efficient, operationally simple, and economically
attractive
copperꢀcatalyzed
tandem
reaction
for
the
synthesis
of
2ꢀArylthiobenzothiazoles. 2ꢀArylthiobenzoxazole derivatives can also be obtained
under the same reaction conditions. The protocol features inexpensive metal catalyst
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and ligand, mild reaction temperature, broad substrates scope, and water as solvent,
which makes it practically valuable and useful for the synthesis of some potential
pharmaceutically active compounds.
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EXPERIMENTAL SECTION
All starting materials were purchased from commercial suppliers and used without
further purification unless otherwise stated. Yields refer to isolated compounds
1
estimated to be >95% pure as determined by H NMR and capillary GC analysis.
NMR spectra were recorded on a Bruker AM400 NMR instrument in CDCl3 using
TMS as an internal standard. Chemical shifts are given in ppm and coupling constants
(J) are given in Hz. All melting points were determined on a RYꢀ1G melting point
instrument without correction. Highꢀresolution mass spectra (HRMS) were recorded
on a Finnigan MAT 95Q or Finnigan 90 mass instrument (ESI). TLC was performed
using aluminum plates coated with SiO2 (Merck 60, Fꢀ254) and visualized with UV
light at 254 nm. Column chromatography was performed on silica gel (200ꢀ300 mesh)
with petroleum etherꢀEtOAc as eluent.
Typical procedure for reaction of 2-aminobenzenethiols with TMTD and
iodobenzenes (TP1).
A mixture of 2ꢀaminobenzenethiol (1.0 mmol) and TMTD (0.6 mmol) in H2O (2.0
o
mL) was stirred at 120 C for 3 h before CuBr (5 mol%), iodobenzene (1.5 mmol),
1,10ꢀphenanthroline (10 mol%) and K2CO3 (2.0 equiv.) were added. The mixture was
stirred at 80 oC and checked by TLC until the starting material was finished (about 15
h). The reaction was terminated with sat. NH4Cl solution (3 mL) and then extracted
with ethyl acetate. The crude solution was dried over anhydrous Na2SO4 and
evaporated under vacuum. The residue was purified by flash column chromatography
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to afford the desired product 4a.
4
5
6
7
8
Typical procedure for reaction of 2-aminophenols with TMTD and iodobenzenes
(TP2).
9
A mixture of 2ꢀaminophenol (1.0 mmol) and TMTD (0.6 mmol) in H2O (2.0 mL) was
stirred at 80 oC for 3 h before CuBr (5 mol%), iodobenzene (1.5 mmol)
1,10ꢀphenanthroline (10 mol%) and K2CO3 (2.0 equiv.) were added. The mixture was
stirred at 80 oC and checked by TLC until the starting material was finished (about 15
h). The reaction was terminated with sat. NH4Cl solution (3 mL) and then extracted
with ethyl acetate. The crude solution was dried over anhydrous Na2SO4 and
evaporated under vacuum. The residue was purified by flash column chromatography
to afford the desired product 6a.
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Experiment data
2-(Phenylthio)benzo[d]thiazole (4a)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4a as a yellow oil
(211 mg, yield = 87%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.85 (d, 1H, J =
8.0 Hz), 7.66 (d, 2H, J = 8.0 Hz), 7.55 (d, 1H, J = 8.0 Hz), 7.43ꢀ7.30 (m, 4H), 7.17 (t,
1H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 169.4, 153.8, 135.4,
135.2, 130.3, 129.8, 129.8, 126.0, 124.2, 121.8, 120.7. HRMS (ESI) m/z [M+H]+
Calcd for C13H10NS2 (244.0249), found: 244.0257.
2-(p-Tolylthio)benzo[d]thiazole (4b)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4b as a yellow oil
1
(198 mg, yield = 77%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.75 (d, 1H, J =
8.0 Hz), 7.49 (d, 3H, J = 8.0 Hz), 7.26 (t, 1H, J = 8.0 Hz), 7.16ꢀ7.09 (m, 3H), 2.30 (s,
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3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 169.8, 153.0, 140.1, 134.5, 134.4,
129.7, 125.1, 125.1, 123.1, 120.7, 119.7, 20.4. HRMS (ESI) m/z [M+H]+ Calcd for
C14H12NS2 (258.0406), found: 258.0412.
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2-((3,4-Dimethylphenyl)thio)benzo[d]thiazole (4c)
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According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4c as a colorless
oil (222 mg, yield = 82%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.82 (d, 1H, J
= 8.0 Hz), 7.50ꢀ7.27 (m, 4H), 7.13 (t, 2H, J = 8.0 Hz), 2.22 (s, 3H), 2.20 (s, 3H). 13C
NMR (100 MHz, CDCl3, TMS): δ (ppm) 170.9, 154.1, 139.8, 138.6, 136.4, 135.5,
133.0, 131.2, 126.3, 126.1, 124.1, 121.8, 120.8, 19.8, 19.7. HRMS (ESI) m/z [M+H]+
Calcd for C15H14NS2 (272.0562), found: 272.0552.
2-((2-Methoxyphenyl)thio)benzo[d]thiazole (4d)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4d as a colorless
oil (210 mg, yield = 77%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.88 (d, 1H, J
= 8.0 Hz), 7.68 (d, 1H, J = 8.0 Hz), 7.61 (d, 1H, J = 8.0 Hz), 7.48 (t, 1H, J = 8.0 Hz),
7.37 (t, 1H, J = 8.0 Hz), 7.22 (t, 1H, J = 8.0 Hz), 7.04ꢀ6.97 (m, 2H), 3.80 (d, 3H, J =
4.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 169.9, 159.9, 154.1, 137.4,
135.6, 132.8, 126.0, 124.1, 121.7, 121.5, 120.8, 117.6, 112.0, 56.0. HRMS (ESI) m/z
[M+H]+ Calcd for C14H12NOS2 (274.0355), found: 274.0362.
2-(o-Tolylthio)benzo[d]thiazole (4e)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4e as a colorless
oil (162 mg, yield = 63%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.84 (d, 1H, J
= 8.0 Hz), 7.68 (d, 1H, J = 8.0 Hz), 7.56 (d, 1H, J = 8.0 Hz), 7.41ꢀ7.32 (m, 3H),
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7.26ꢀ7.17 (m, 2H), 2.47 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 169.9,
154.2, 143.2, 137.1, 135.5, 131.5, 131.3, 129.1, 127.5, 126.1, 124.2, 121.8, 120.8,
20.9. HRMS (ESI) m/z [M+H]+ Calcd for C14H12NS2 (258.0406), found: 258.0412.
2-((4-Nitrophenyl)thio)benzo[d]thiazole (4f)
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According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4f as a white solid
o
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(202 mg, yield = 70%). m.p.: 77ꢀ79 C. H NMR (400 MHz, CDCl3, TMS): δ (ppm)
8.09 (d, 2H, J = 8.0 Hz), 7.83 (d, 1H, J = 8.0 Hz), 7.64 (d, 3H, J = 8.0 Hz), 7.34 (t, 1H,
J = 8.0 Hz), 7.24 (t, 1H, J = 8.0 Hz), 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
162.0, 152.5, 146.9, 139.0, 135.3, 131.8, 125.8, 124.7, 123.6, 121.9, 120.3. HRMS
(ESI) m/z [M+H]+ Calcd for C13H9N2O2S2 (289.0100), found: 289.0108.
2-((4-Fluorophenyl)thio)benzo[d]thiazole (4g)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4g as a colorless
oil (220 mg, yield = 84%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.86 (d, 1H, J
= 8.0 Hz), 7.72ꢀ7.69 (m, 2H), 7.64 (d, 1H, J = 8.0 Hz), 7.39 (t, 1H, J = 8.0 Hz), 7.25 (t,
1H, J = 8.0 Hz), 7.15 (t, 2H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
169.6, 164.3 (d, J = 250 Hz), 154.1, 137.9 ( ), 135.6, 126.4, 125.3 (d, J = 4.0 Hz),
124.5, 122.1, 121.0, 117.4 (d, J = 22 Hz). HRMS (ESI) m/z [M+H]+ Calcd for
C13H9FNS2 (262.0155), found: 262.0146.
2-((4-Chlorophenyl)thio)benzo[d]thiazole (4h)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4h as a colorless
oil (230 mg, yield = 83%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.86 (d, 1H, J
= 8.0 Hz), 7.60 (t, 3H, J = 8.0 Hz), 7.36 (t, 3H, J = 8.0 Hz), 7.23 (t, 1H, J = 8.0 Hz).
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13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 168.1, 153.6, 136.7, 136.2, 135.4, 130.0,
128.2, 126.1, 124.4, 121.9, 120.7. HRMS (ESI) m/z [M+H]+ Calcd for C13H9ClNS2
(277.9860), found: 277.9865.
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2-((4-(Trifluoromethyl)phenyl)thio)benzo[d]thiazole (4i)
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According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4i as a colorless oil
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(264 mg, yield = 85%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.89 (d, 1H, J =
8.0 Hz), 7.74 (d, 2H, J = 8.0 Hz), 7.64 (t, 3H, J = 8.0 Hz), 7.38 (t, 1H, J = 8.0 Hz),
7.26 (t, 1H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 165.8, 153.7,
136.0, 135.4, 134.2, 131.8 (q, J = 33 Hz), 126.7 (q, J = 4.0 Hz), 126.6, 125.2, 123.8 (q,
J = 258 Hz), 121.1. HRMS (ESI) m/z [M+H]+ Calcd for C14H9F3NS2 (312.0123),
found: 312.0117.
2-((4-Bromophenyl)thio)benzo[d]thiazole (4j)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4j as a colorless oil
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(244 mg, yield = 76%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.85 (d, 1H, J =
8.0 Hz), 7.60 (d, 1H, J = 8.0 Hz), 7.53ꢀ7.48 (m, 4H), 7.35 (t, 1H, J = 8.0 Hz), 7.22 (t,
1H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 167.8, 153.6, 136.3,
135.4, 132.9, 128.9, 126.2, 125.0, 124.4, 121.9, 120.7. HRMS (ESI) m/z [M+H]+
Calcd for C13H9BrNS2 (321.9355), found: 321.9347.
4-(Benzo[d]thiazol-2-ylthio)benzonitrile (4k)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4k as a white solid
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(169 mg, yield = 63%). m.p.:94ꢀ96 C. H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.82 (d, 1H, J = 8.0 Hz), 7.64ꢀ7.53 (m, 5H), 7.34 (t, 1H, J = 8.0 Hz), 7.24 (t, 1H, J =
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8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 162.6, 152.4, 136.4, 135.0,
132.1, 131.9, 125.5, 124.3, 121.6, 120.1, 117.0, 111.8. HRMS (ESI) m/z [M+H]+
Calcd for C14H9N2S2 (269.0203), found: 269.0211.
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2-((2-Bromophenyl)thio)benzo[d]thiazole (4l)
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According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4l as a colorless oil
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(263 mg, yield = 82%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.91 (d, 1H, J =
8.0 Hz), 7.79ꢀ7.65 (m, 3H), 7.42ꢀ7.25 (m, 4H). 13C NMR (100 MHz, CDCl3, TMS): δ
(ppm) 166.8, 153.7, 136.7, 135.7, 134.0, 131.6, 131.6, 129.5, 128.5, 126.1, 124.5,
122.1, 120.8. HRMS (ESI) m/z [M+H]+ Calcd for C13H9BrNS2 (321.9355), found:
321.9361.
2-((2-Chlorophenyl)thio)benzo[d]thiazole (4m)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4m as a colorless
oil (213 mg, yield = 77%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.89 (d, 1H, J
= 8.0 Hz), 7.75 (d, 1H, J = 8.0 Hz), 7.64 (d, 1H, J = 8.0 Hz), 7.53 (d, 1H, J = 8.0 Hz),
7.41ꢀ7.36 (m, 2H), 7.32ꢀ7.23 (m, 2H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
166.7, 153.7, 138.8, 136.9, 135.6, 131.6, 130.6, 129.4, 127.8, 126.1, 124.5, 122.0,
120.8. HRMS (ESI) m/z [M+H]+ Calcd for C13H9ClNS2 (277.9860), found: 277.9855.
2-((3-Bromophenyl)thio)benzo[d]thiazole (4n)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4n as a colorless
oil (244 mg, yield = 76%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.89ꢀ7.84 (m,
2H), 7.65ꢀ7.55 (m, 3H), 7.38 (t, 1H, J = 8.0 Hz), 7.29ꢀ7.23 (m, 2H). 13C NMR (100
MHz, CDCl3, TMS): δ (ppm) 167.2, 153.6, 137.0, 135.5, 133.2, 133.1, 132.0, 131.0,
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126.2, 124.6, 123.1, 122.1, 120.8. HRMS (ESI) m/z [M+H]+ Calcd for C13H9BrNS2
(321.9355), found: 321.9362.
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5-Chloro-2-(phenylthio)benzo[d]thiazole (4o)
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According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4o as a white solid
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(194 mg, yield = 70%). m.p.: 72ꢀ74 C. H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.67 (d, 1H, J = 4.0 Hz), 7.58ꢀ7.55 (m, 2H), 7.39ꢀ7.30 (m, 4H), 7.05ꢀ7.02 (m, 1H).
13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 171.2, 153.7, 134.4, 132.6, 131.0, 129.7,
129.0, 128.3, 123.5, 120.6, 120.4. HRMS (ESI) m/z [M+H]+ Calcd for C13H9ClNS2
(277.9860), found: 277.9866.
5-Chloro-2-((4-chlorophenyl)thio)benzo[d]thiazole (4p)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4p as a white solid
(193 mg, yield = 62%). M.p.: 118ꢀ120 oC. 1H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.76 (d, 1H, J = 4.0 Hz), 7.57 (d, 2H, J = 8.0 Hz), 7.48 (d, 1H, J = 8.0 Hz), 7.37 (d,
2H, J = 8.0 Hz), 7.18ꢀ7.15 (m, 1H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
169.8, 153.6, 136.2, 135.6, 132.6, 131.3, 129.2, 126.8, 123.8, 120.8, 120.4. HRMS
(ESI) m/z [M+H]+ Calcd for C13H8Cl2NS2 (311.9470), found: 311.9476.
2-(Pyridin-3-ylthio)benzo[d]thiazole (4q)
According to TP1, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 4q as a brown
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solid (178 mg, yield = 73%). m.p.: 76ꢀ78 C. H NMR (400 MHz, CDCl3, TMS): δ
(ppm) 8.74 (s, 1H), 8.52 (s, 1H), 7.84 (d, 1H, J = 8.0 Hz), 7.70 (d, 1H, J = 8.0 Hz),
7.48 (d, 1H, J = 8.0 Hz), 7.24ꢀ7.10 (m, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ
(ppm) 165.6, 153.5, 152.4, 149.8, 141.3, 134.4, 126.4, 125.3, 123.6, 123.4, 121.0,
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119.8. HRMS (ESI) m/z [M+H]+ Calcd for C12H9N2S2 (245.0202), found: 245.0211.
2-(Phenylthio)benzo[d]oxazole (6a)
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According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6a as a yellow oil
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(159 mg, yield = 70%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.69ꢀ7.67 (m,
2H), 7.59ꢀ7.57 (m, 1H), 7.44ꢀ7.36 (m, 4H), 7.26ꢀ7.18 (m, 2H). 13C NMR (100 MHz,
CDCl3, TMS): δ (ppm) 163.2, 151.7, 141.8, 134.3, 129.7, 129.5, 127.0, 124.2, 124.2,
118.9, 109.9. HRMS (ESI) m/z [M+H]+ Calcd for C13H10NOS (228.0478), found:
228.0472.
5-Methyl-2-(phenylthio)benzo[d]oxazole (6b)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6b as a colorless
oil (169 mg, yield = 70%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.66ꢀ7.64 (m,
2H), 7.39ꢀ7.37 (m, 4H), 7.21 (d, 1H, J = 8.0 Hz), 6.99 (d, 1H, J = 8.0 Hz), 2.38 (s,
3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 162.0, 149.1, 141.1, 133.2, 133.1,
128.7, 128.5, 126.4, 124.3, 118.0, 108.4, 20.4. HRMS (ESI) m/z [M+H]+ Calcd for
C14H12NOS (242.0634), found: 242.0639.
6-Methyl-2-(phenylthio)benzo[d]oxazole (6c)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6c as a white solid
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(169 mg, yield = 70%). m.p.: 56ꢀ58 C. H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.67ꢀ7.64 (m, 2H), 7.46ꢀ7.39 (m, 4H), 7.16 (s, 1H), 7.04 (d, 1H, J = 8.0 Hz), 2.39 (s,
3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 162.3, 152.2, 139.8, 134.8, 134.2,
129.7, 129.6, 127.5, 125.5, 118.5, 110.3, 21.7. HRMS (ESI) m/z [M+H]+ Calcd for
C14H12NOS (242.0634), found: 242.0629.
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According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6d as a red oil (205
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mg, yield = 85%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.60 (t, 2H, J = 4.0
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Hz), 7.29 (s, 3H), 7.09 (d, 1H, J = 8.0 Hz), 7.03ꢀ6.95 (m, 2H), 2.50 (s, 3H). 13C NMR
(100 MHz, CDCl3, TMS): δ (ppm) 161.4, 151.6, 141.3, 134.0, 129.6, 129.5, 129.5,
127.8, 125.1, 124.2, 107.4, 16.5. HRMS (ESI) m/z [M+H]+ Calcd for C14H12NOS
(242.0634), found: 242.0642.
5-Fluoro-2-(phenylthio)benzo[d]oxazole (6e)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6e as a yellow oil
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(113 mg, yield = 46%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.68ꢀ7.66 (m,
2H), 7.43ꢀ7.40 (m, 3H), 7.27ꢀ7.23 (m, 2H), 6.94ꢀ6.88 (m, 1H). 13C NMR (100 MHz,
CDCl3, TMS): δ (ppm) 164.4, 158.9 (d, J = 239 Hz), 147.1, 141.8 (d, J = 13 Hz),
133.5, 129.0, 128.6, 125.6, 110.6 (d, J = 27 Hz), 109.1 (d, J = 10 Hz), 104.6 (d, J = 26
Hz). HRMS (ESI) m/z [M+H]+ Calcd for C13H9FNOS (246.0484), found: 246.0477.
5-Chloro-2-(phenylthio)benzo[d]oxazole (6f)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6f as a white solid
o
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(104 mg, yield = 40%). m.p.: 57ꢀ59 C. H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.69ꢀ7.67 (m, 2H), 7.54 (d, 1H, J = 4.0 Hz), 7.46ꢀ7.42 (m, 3H), 7.26 (t, 1H, J = 8.0
Hz), 7.18ꢀ7.15 (m, 1H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 164.2, 149.3,
142.0, 133.6, 129.1, 128.9, 128.7, 125.5, 123.3, 117.9, 109.6. HRMS (ESI) m/z
[M+H]+ Calcd for C13H9ClNOS (262.0088), found: 262.0081.
2-((4-Fluorophenyl)thio)benzo[d]oxazole (6g)
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According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6g as a colorless
oil (174 mg, yield = 71%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.68ꢀ7.65 (m,
2H), 7.58ꢀ7.56 (m, 1H), 7.37 (d, 1H, J = 8.0 Hz), 7.25ꢀ7.18 (m, 2H), 7.12 (t, 2H, J =
8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 162.8 (d, J = 250 Hz), 162.2,
162.2, 150.8, 140.9, 135.9 (d, J = 9.0 Hz), 123.3 (d, J = 12.0 Hz), 121.1 (d, J = 3.0
Hz), 118.0, 115.9 (d, J = 23 Hz), 109.0. HRMS (ESI) m/z [M+H]+ Calcd for
C13H9FNOS (246.0384), found: 246.0388.
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2-((4-Bromophenyl)thio)benzo[d]oxazole (6h)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6h as a colorless
oil (128 mg, yield = 42%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.49ꢀ7.43 (m,
5H), 7.28 (d, 1H, J = 8.0 Hz), 7.16ꢀ7.09 (m, 2H). 13C NMR (100 MHz, CDCl3, TMS):
δ (ppm) 161.5, 150.8, 140.7, 134.8, 131.8, 125.1, 123.6, 123.5, 123.4, 118.1, 109.0.
HRMS (ESI) m/z [M+H]+ Calcd for C13H9BrNOS (305.9583), found: 305.9589.
2-((4-Chlorophenyl)thio)benzo[d]oxazole (6i)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6i as a colorless oil
(78 mg, yield = 30%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.63ꢀ7.58 (m, 3H),
7.41ꢀ7.38 (m, 3H), 7.28ꢀ7.20 (m, 2H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
161.6, 150.8, 140.8, 135.3, 134.6, 128.8, 124.5, 123.4, 123.4, 118.1, 109.0. HRMS
(ESI) m/z [M+H]+ Calcd for C13H9ClNOS (262.0088), found: 262.0082.
2-((4-(Trifluoromethyl)phenyl)thio)benzo[d]oxazole (6j)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6j as a white solid
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(198 mg, yield = 67%). m.p.: 40ꢀ42 C. H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.67 (d, 2H, J = 8.0 Hz), 7.55ꢀ7.48 (m, 3H), 7.30ꢀ7.28 (m, 1H), 7.17ꢀ7.11 (m, 2H). 13C
NMR (100 MHz, CDCl3, TMS): δ (ppm) 160.5, 150.8, 140.6, 132.6, 131.3, 130.4 (q,
J = 32.0 Hz), 125.3 (q, J = 4.0 Hz), 123.7, 133.6, 122.6 (q, J = 270.0 Hz), 118.2,
109.1. HRMS (ESI) m/z [M+H]+ Calcd for C14H9F3NOS (296.0352), found: 296.0356.
2-((3-Bromophenyl)thio)benzo[d]oxazole (6k)
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According to TP2, the residue was purified by flash chromatography on silica gel
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(174 mg, yield = 57%). m.p.: 58ꢀ60 C. H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.81 (s, 1H), 7.58 (d, 2H, J = 4.0 Hz), 7.50 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0
Hz), 7.25ꢀ7.18 (m, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 161.1, 150.8,
140.8, 135.5, 131.8, 131.7, 129.8, 128.2, 123.5, 123.5, 122.1, 118.2, 109.1. HRMS
(ESI) m/z [M+H]+ Calcd for C13H9BrNOS (305.9583), found: 305.9578.
2-((2-Chlorophenyl)thio)benzo[d]oxazole (6l)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6l as a white solid
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(151 mg, yield = 58%). m.p.: 44ꢀ46 C. H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.78ꢀ7.76 (m, 1H), 7.63ꢀ7.60 (m, 1H), 7.54ꢀ7.52 (m, 1H), 7.42ꢀ7.24 (m, 5H). 13C
NMR (100 MHz, CDCl3, TMS): δ (ppm) 160.6, 150.8, 140.9, 137.1, 135.1, 130.2,
129.5, 126.7, 125.9, 123.4, 118.1, 109.1. HRMS (ESI) m/z [M+H]+ Calcd for
C13H9ClNOS (262.0088), found: 262.0081.
2-(o-Tolylthio)benzo[d]oxazole (6m)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6m as a colorless
oil (142 mg, yield = 59%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.59 (d, 1H, J
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= 4.0 Hz), 7.47 (d, 1H, J = 8.0 Hz), 7.29ꢀ7.23 (m, 3H), 7.16ꢀ7.08 (m, 3H), 2.37 (s,
3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 162.2, 150.8, 141.5, 141.0, 135.1,
130.2, 129.6, 126.1, 125.2, 123.3, 123.1, 117.9, 108.9, 20.0. HRMS (ESI) m/z [M+H]+
Calcd for C14H12NOS (242.0634), found: 242.0629.
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2-((4-Methoxyphenyl)thio)benzo[d]oxazole (6n)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6n as a colorless
oil (149 mg, yield = 58%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.61ꢀ7.55 (m,
3H), 7.35 (d, 1H, J = 8.0 Hz), 7.23ꢀ7.15 (m, 2H), 6.94 (d, 2H, J = 8.0 Hz), 3.79 (s,
3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 164.4, 161.2, 151.9, 142.1, 136.7,
124.3, 124.0, 118.9, 117.0, 115.3, 109.9, 55.4. HRMS (ESI) m/z [M+H]+ Calcd for
C14H12NO2S (258.0583), found: 258.0587.
2-((3,4-Dimethylphenyl)thio)benzo[d]oxazole (6o)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6o as a colorless
oil (168 mg, yield = 66%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.55 (d, 1H, J
= 8.0 Hz), 7.40 (t, 2H, J = 8.0 Hz), 7.32 (d, 1H, J = 8.0 Hz), 7.21ꢀ7.13 (m, 3H), 2.23
(s, 3H,), 2.22 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 164.1, 151.9,
142.1, 139.1, 138.2, 135.7, 132.3, 131.0, 124.3, 124.1, 123.4, 119.0, 110.0, 19.8, 19.7.
HRMS (ESI) m/z [M+H]+ Calcd for C15H14NOS (256.0792), found: 256.0798.
2-(p-Tolylthio)benzo[d]oxazole (6p)
According to TP2, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the target compound 6p as a colorless
oil (101 mg, yield = 42%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.57 (d, 3H, J
= 8.0 Hz), 7.38ꢀ7.35 (m, 1H), 7.24ꢀ7.17 (m, 4H), 2.37 (s, 3H). 13C NMR (100 MHz,
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CDCl3, TMS): δ (ppm) 162.8, 150.9, 141.0, 139.3, 133.6, 129.4, 123.3, 123.1, 122.3,
118.0, 108.9, 20.3. HRMS (ESI) m/z [M+H]+ Calcd for C14H12NOS (242.0634), found:
242.0639.
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ASSOCIATED CONTENT
The Supporting Information (1H, 13C NMR spectra for the products) is available free
of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: dzb04982@wit.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the foundation support from National Natural Science Foundation of China
(21302150), foundation of ChenꢀGuang 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 Council for a fellowship. X. L. thanks the support of Postgraduate
Innovation Foundation (CX2017088) from Wuhan Institute of Technology.
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