One-Pot Synthesis of 2-Benzyl/2-Allyl-Substituted Thiobenzoazoles Using Transition-Metal-Free Conditions in Water

Article abstract of DOI:10.1021/acs.joc.8b02136

A transition-metal-free protocol for the one-pot synthesis of 2-benzyl/2-allyl-substituted thiobenzoazoles in water was developed. The cyclization of 2-aminothiophenols, 2-aminophenols, and 1,2-phenylenediamines with tetramethylthiuram disulfide (TMTD) gave mercapto benzoheterocycles, and the subsequent C-S coupling with benzyl or allyl halides furnished the desired products in good to excellent yields. This method features transition-metal-free conditions with water as a solvent, an easy performance, mild reaction conditions, a wide substrate scope, and good to excellent yields, thus paving an efficient and useful way to establish a library of potentially active drug molecules.

Full text of DOI:10.1021/acs.joc.8b02136

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Article
One-pot Synthesis of 2-Benzyl/2-Allyl Substituted
Thiobenzoazoles Using Transition-metal-free Conditions in Water
Shi-Bo Zhang, Xing Liu, Ming-Yuan Gao, and Zhi-Bing Dong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02136 • Publication Date (Web): 26 Nov 2018
Downloaded from http://pubs.acs.org on November 26, 2018
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One-pot
Synthesis
of
2-Benzyl/2-Allyl
Substituted
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Thiobenzoazoles Using Transition-metal-free Conditions in
Water
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Shi-Bo Zhanga, Xing Liua, Ming-Yuan Gaoa, Zhi-Bing Donga,b*
aSchool of Chemistry and Environmental Engineering, Wuhan Institute of Technology,
Wuhan 430205, China.
bDepartment of Chemistry, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13,
81377 München, Germany.
Email: dzb04982@wit.edu.cn
ABSTRACT
A transition-metal-free protocol for the one-pot synthesis of 2-benzyl/2-allyl
substituted thiobenzoazoles in water was developed. The cyclization of
2-aminothiophenols,
2-aminophenols,
and
1,2-phenylenediamines
with
tetramethylthiuram disulfide (TMTD) gave mercapto benzoheterocycles, the
subsequent C-S coupling with benzyl or allyl halides furnished the desired products in
good to excellent yields. This method features transition-metal free, water as solvent,
easy performance, mild reaction conditions, wide substrate scope, and good to
excellent yields, thus paves an efficient and useful way to establish the library of
potentially active drug molecules.
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INTRODUCTION
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Phenyl heterocycles are key blocks in active drug molecules due to their
pharmaceutical activity in medicinal chemistry studies.1-4 Among these,
2-benzyl substituted thiobenzoazoles compounds are the skeleton of natural
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macromolecular compounds such as compound
1 (multidrug resistance in
cancer chemtherapy), compounds (proton-pump inhibitor which reduces
2
stomach acid), compound
3 (antagonizing the activity of CCR3 receptors), and
compound
4
(potential antifungal agent) (Fig.1).5-10 These compounds exhibit
excellent physiological activity, high bioselectivity and low physiological
toxicity in the fungal growth inhibition test.11 Thus, 2-benzyl substituted
thiobenzoazoles have been paid extensive attention by the synthetic and
medicinal chemists.12-16
Figure 1. Representative drugs containing 2-allyl and 2-benzyl substituted
thiobenzoazoles skeletons.
So far, there are numbers of ways to synthesize 2-benzyl substituted
thiobenzoazoles,17-20 while most of them use 2-mercaptobenzoic heterocycles as
starting materials, which greatly limits the suitability of the substrates. Furthermore,
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these methods suffer from disadvantages such as using organic solvents, the
requirement of stoichiometric metal catalysts and highly toxic reagents (Scheme 1).
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Scheme 1. Existing synthetic route and our strategy for the synthesis of 2-benzyl/2-
allyl substituted thiobenzoazoles.
In addition, tandem or one-pot synthetic strategies have received great attention
from the organic chemistry community in recent decades, because there is no need to
separate the intermediates, thus might increase the yields of the final products.21-23
Recently, we found that thiuram disulfides were very useful starting materials from an
environmental point of view,24 and also served as interesting vulcanization reagents
for the development of new synthetic transformations.25 Hereby, we would like to
report an efficient and useful method for the one-pot synthesis of 2-benzyl/2-allyl
substituted thiobenzoazoles using metal-free condition in water. The cyclization of
2-aminothiophenols,
2-aminophenols,
and
1,2-phenylenediamines
with
tetramethylthiuram disulfide (TMTD) give mercapto benzoheterocycles, and the
subsequent C-S coupling with benzyl or allyl halides might furnish the desired
products (Scheme 1).
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RESULTS AND DISCUSSION
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By taking the strategy mentioned above, 2-aminothiophenol (1a), tetramethylthiuram
disulfide (TMTD) and benzyl bromide (2a) were selected as substrates for the model
reaction. 2-Aminothiophenol was firstly treated with TMTD in water at 120 oC for 2 h,
base and benzyl bromide were then added before heating. The reaction conditions
were examined, and the results are summarized in Table 1. Firstly, various bases such
as KOH, NaOH, Na2CO3, K2CO3, Cs2CO3, NaHCO3, pyridine, triethylamine and
diethylamine were evaluated (entries 1-10) and K2CO3 was found to be the most
suitable base to give the product in 94% yield. Next, different reaction temperatures
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o
(for the second step) were screened (entries 4, 11-14) and 80 C was found to be the
most suitable temperature. The substrate ratio (1a : TMTD : 2a) was also explored
(entries 4, 15-17) and it revealed that 1a : TMTD: 2a = 1 : 0.6 : 1 was the optimal
substrate ratio. Furthermore, we studied the effects of solvents (entries 4, 18-22) and it
was found that water was the best solvent. The optimal reaction conditions were
summarized in entry 4.
Table 1. Reaction condition screening for the tandem synthesis of
2-arylthiobenzothiazole starting from 2-aminobenzenethiol, tetramethylthiuram
disulfide (TMTD), and benzyl bromide a
Entry
base
KOH
NaOH
T(oC)b
80
Ratioc
1:0.6:1
1:0.6:1
Solvent
H2O
Yield(%)d
1
2
89
86
80
H2O
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3
Na2CO3
K2CO3
Cs2CO3
NaHCO3
Pyridine
Triethylamine
Diethylamine
--
80
80
80
80
80
80
80
80
110
100
60
40
80
80
80
80
80
80
80
80
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:0.6
1:0.6:0.8
1:0.6:1.1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
1:0.6:1
H2O
H2O
H2O
76
94, 88e
84
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6
H2O
63
7
H2O
56
8
H2O
73
9
H2O
76
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H2O
80
K2CO3
H2O
93
K2CO3
H2O
91
K2CO3
H2O
73
K2CO3
H2O
51
K2CO3
H2O
43
K2CO3
H2O
75
K2CO3
H2O
95
K2CO3
DMF
DMSO
EtOH
MeOH
DMAc
90
K2CO3
60
K2CO3
18
K2CO3
13
K2CO3
73
a
Reaction conditions: 1a (1.0 mmol), TMTD (0.6 mmol) and 2a (1.0 mmol) in 2 mL of H2O, the mixture of 1a
and TMTD was stirred for 2-3 h before the base and 2a were added. b The temperature for the second step. c Mole
ratio of 1a : TMTD: 2a. d Isolated yield based on 1a. e A scaled-up reaction (10 mmol) was performed.
Having the optimized reaction conditions in hand, the substrates scope was
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surveyed. Firstly, we examined the reactivity of benzyl or allyl halides in the presence
of o-aminothiophenol (Table 2). In general, the desired tandem reaction (cyclization
then C-S coupling) products could be obtained in good to excellent yields. Benzyl
halides bearing with electron-donating groups, such as -OMe or –Me furnished the
products 3d and 3e in 90% and 92% yield, respectively. While electron-withdrawing
groups on benzyl ring gave the products (3b, 3c, 3f, 3g, 3h, 3l) in slightly lower yields.
Sensitive ester group on the aryl ring could be tolerated well (3g). Ethyl chloroacetate
(allyl-like structure) was also suitable for the C-S coupling to give the product 3k in
83 % yield. We were also pleased to find that the non-aromatic ring substrate could be
transformed to 3l in good yield (80%).
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Table 2. One-pot synthesis of 2-(benzylthio)benzo[d]thiazoles starting from
o-aminothiophenol and tetramethylthiuram disulfide (TMTD) a
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a Reaction conditions: A mixture of 1 (1.0 mmol) and tetramethylthiuram disulfide (0.6 mmol) in H2O (2.0 mL)
was stirred at 120 oC for 2-3 h, then K2CO3 (2.0 mmol) and 2 (1.0 mmol) were added and the mixture was stirred
at 80 oC for 1h.
Next, we investigated the reactivity of a set of benzyl halides in the presence of
o-aminophenols (Table 3). Similarly, the desired tandem reaction occurred smoothly
and gave the desired products in good to excellent yields. The ester group could be
also tolerated in the base condition (3t, 3u).
Table 3. One-pot synthesis of 2-(benzylthio)benzo[d]oxazoles starting from
o-aminophenols and tetramethylthiuram disulfide (TMTD) a
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a Reaction conditions: A mixture of 1 (1.0 mmol) and tetramethylthiuram disulfide (0.6 mmol) in H2O (2.0 mL)
was stirred at 80 oC for 2-3 h, then K2CO3 (2.0 mmol) and 2 (1.0 mmol) were added and the mixture was stirred at
80 oC for 1h.
Furthermore, the reactivity of a set of benzyl/allyl halides in the presence of
o-phenylenediamine was investigated (Table 4). The results showed that the desired
products were furnished successfully under the standard reaction conditions. Ethyl
chloroacetate was also submitted for the C-S coupling, but no product was obtained.
Table 4. One-pot synthesis of 2-(benzylthio)-1H-benzo[d]imidazole starting from
o-phenylenediamine and tetramethylthiuram disulfide (TMTD) a
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a Reaction conditions: A mixture of 1 (1.0 mmol) and tetramethylthiuram disulfide (0.6 mmol) in H2O (2.0 mL)
was stirred at 110 oC for 2-3 h, then K2CO3 (2.0 mmol) and 2 (1.0 mmol) were added and the mixture was stirred
at 80 oC for 1h.
Moreover, halogenated alkanes were also submitted for the tandem reactions.
Gratifyingly, the target products could be achieved in 50-70% yield (Table 5),
showing its broad substrate compatibility.
Table 5. One-pot synthesis of 2-(alkylthio)benzo[d]thiazole by using alkyl halides as
starting materials a
a Reaction conditions: A mixture of 1 (1.0 mmol) and tetramethylthiuram disulfide (0.6 mmol) in H2O (2.0 mL)
o
was stirred at 120 oC (X=S) or 80 C (X=O) for 2-3 h, then K2CO3 (2.0 mmol) and 2 (1.0 mmol) were added and
the mixture was stirred at 80 oC for 1h.
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The results obtained form Table 2-Table 5 showed that this protocol had good
substrate adaptability, which might provide an easy and convenient access to the
establishment of drug molecule library for the pharmaceutical industry.
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Based on the experimental results and our previous effort on the organosulfur
chemistry,24 a plausible reaction pathway is outlined in Scheme 2. Tetramethylthiuram
disulfide (TMTD) A reacts with aniline B to give intermediate thiourea C, and the XH
(X = O, S, NH) group of C undergoes intramolecular nucleophilic addition forming
intermediate D. D undergoes intramolecular elimination by removing dimethylamine
gas, forming mercapto benzoheterocycle E. The subsequent SN2 process with
benzyl/allyl bromide allow E to give the final C-S coupling product F smoothly.
Scheme 2. Plausible mechanism of the reaction.
CONCLUSION
In summary, we have developed a convenient, highly efficient and one-pot green
synthetic method for the synthesis of 2-benzyl/2-allyl substituted thiobenzoazoles in
water.
The
cyclization
of
2-aminothiophenols,
2-aminophenols,
and
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1,2-phenylenediamines with tetramethylthiuram disulfide (TMTD) gave mercapto
benzoheterocycles, and the subsequent C-S coupling with benzyl or allyl halides
furnished the desired products in good to excellent yields. This method features
transition-metal free, water as solvent, easy performance, mild reaction conditions,
wide substrate scope, and good to excellent yields, illustrating its practical synthetic
value in some potentially biologically active compounds, especially for the
establishment of molecule library. Further details and the development of related
applications for this protocol are under research in our laboratory.
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EXPERIMENTAL SECTION
General Procedures
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 or
DMSO-d6 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
RY-1G melting point instrument without correction. High-resolution 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, F-254)
and visualized with UV light at 254 nm. Column chromatography was performed on
silica gel (200-300 mesh) with PE (petroleum ether)-EtOAc as eluent.
Typical Procedure (TP) for Synthesis of 2-(benzylthio)benzothiazole (3a). A
mixture of 2-aminobenzenethiol (1a, 1.0 mmol) and tetramethylthiuram disulfide
o
(TMTD, 0.6 mmol) in H2O (2.0 mL) was stirred at 120 C for 2-3 h before K2CO3
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(2.0 mmol) and benzyl bromide (2a, 1.0 mmol) were added. The resultant mixture
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was heated at 80 C and checked by TLC until the starting material was finished
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(about 1h). The reaction was cooled down to room temperature, quenched with sat.
NH4Cl solution (5 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 3a.
Analytical data of products
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2-(Benzylthio)benzo[d]thiazole (3a).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3a as a colorless
1
oil (242 mg, 94%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.82 (d, J= 8.0 Hz,
1H), 7.67-7.64 (m, 1H), 7.38-7.31 (m, 3H), 7.28-7.16 (m, 4H), 4.52 (s, 2H). 13C NMR
(100 MHz, CDCl3, TMS): δ (ppm) 165.3, 152.1, 135.1, 134.3, 128.0, 127.6, 126.7,
125.0, 123.2, 120.5, 119.9, 36.7. HRMS (ESI) m/z [M+H]+ Calcd for C14H12NS2
(258.0406), found: 258.0403.
2-((4-Bromobenzyl)thio)benzo[d]thiazole (3b).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3b as a white solid
o
1
(278 mg 83%). Mp: (76-79 C). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.73(d,
1H, J= 8.0 Hz), 7.51 (d, J= 8.0 Hz, 1H), 7.24-7.20 (m, 3H), 7.11-7.06 (m, 3H), 7.42
(m, 2H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 165.84, 153.14, 135.59, 135.46,
131.83, 130.89, 126.21, 124.49, 121.80, 121.68, 121.15, 36.97. HRMS (ESI) m/z
[M+H]+ Calcd for C14H11BrNS2 (335.9511), found: 335.9514.
2-((4-Nitrobenzyl)thio)benzo[d]thiazole (3c).
According to TP, the residue was purified by flash chromatography on silica gel
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(petroleum ether/ethyl acetate = 15:1) to give the target compound 3c as a white solid
(242 mg, 80%). Mp: (89-91 oC). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 8.01 (d,
J= 12.0 Hz, 2H), 7.77 (d, J= 8.0 Hz, 1H), 7.61 (d, J= 8.0 Hz, 1H), 7.49 (d, J= 8.0 Hz,
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2H), 7.31 (t, J= 8.0 Hz, 1H), 7.20-7.14 (m, 1H), 4.52 (s, 2H). C NMR (100 MHz,
CDCl3, TMS): δ (ppm) 163.7, 151.8, 146.2, 143.4, 134.3, 128.9, 125.1, 123.5, 122.7,
120.5, 120.0, 35.3. HRMS (ESI) m/z [M+H]+ Calcd for C14H11N2O2S2 (303.0256),
found: 303.0251.
2-((3-Methoxybenzyl)thio)benzo[d]thiazole (3d).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 50:1) to give the target compound 3d as a yellow oil
(259 mg, 90%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.81 (d, J= 8.0 Hz, 1H),
7.65 (d, J= 8.0 Hz, 1H), 7.35-7.31 (m, 1H), 7.22-7.13 (m, 2H), 6.94 (d, J= 8.0 Hz,
2H), 6.74-6.71 (m, 1H), 4.48 (s, 2H), 3.69 (s, 3H). 13C NMR (100 MHz, CDCl3,
TMS): δ (ppm) 166.4, 159.7, 153.1, 137.6, 135.3, 129.7, 126.1, 124.3, 121.5, 121.4,
121.0, 114.6, 113.4, 55.2, 37.7. HRMS (ESI) m/z [M+H]+ Calcd for C15H14NOS2
(288.0511), found: 288.0516.
2-((2-Methylbenzyl)thio)benzo[d]thiazole (3e).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3e as a colorless
1
oil (250 mg, 92%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.89 (d, J= 8.0 Hz,
1H), 7.58 (d, J= 12.0 Hz, 1H), 7.30-7.23 (m, 2H), 7.14 (t, J= 8.0 Hz, 1H), 7.07-7.00
(m, 3H), 4.50 (s, 2H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
166.6, 153.2, 137.2, 135.3, 133.7, 130.7, 130.2, 128.2, 126.3, 126.1, 124.3, 121.6,
121.0, 36.0, 19.3. HRMS (ESI) m/z [M+H]+ Calcd for C15H14NS2 (272.0562), found:
272.0560.
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4-((Benzo[d]thiazol-2-ylthio)methyl)benzonitrile (3f).
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8
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3f as a yellow
9
o
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solid (249 mg, 88%). Mp: (63-65 C). H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.71 (d, J= 8.0 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.33 (s, 4H), 7.23 (t, J= 8.0 Hz, 1H),
13
7.19 (t, J= 8.0 Hz, 1H), 4.38 (s, 2H). C NMR (100 MHz, CDCl3, TMS): δ (ppm)
165.0, 152.9, 142.3, 135.4, 132.3, 129.8, 126.2, 124.6, 121.6, 121.1, 118.6, 111.4,
36.8. HRMS (ESI) m/z [M+H]+ Calcd for C15H11N2S2 (283.0358), found: 283.0351.
Methyl 4-((benzo[d]thiazol-2-ylthio)methyl)benzoate (3g).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3g as a colorless
solid (271 mg, 86%). Mp: (105-106 oC). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.86 (d, J= 8.0 Hz, 2H), 7.77 (d, J= 8.0 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.39 (d, J=
8.0 Hz, 2H), 7.29 (t, J= 8.0 Hz, 1H), 7.16 (t, J= 8.0 Hz, 1H), 4.49 (s, 2H), 3.77 (s, 3H).
13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 166.6, 165.5, 153.0, 141.7, 135.4, 129.9,
129.5, 129.1, 126.1, 124.4, 121.6, 121.0, 52.1, 37.1. HRMS (ESI) m/z [M+H]+ Calcd
for C16H14NO2S2 (316.0460), found: 316.0466.
2-((4-Fluorobenzyl)thio)benzo[d]thiazole (3h).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3h as a yellow
o
1
solid (246 mg, 89%). Mp: (47-49 C). H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.81 (d, J= 8.0 Hz, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.35-7.30 (m, 3H), 7.22-7.15 (m,
13
1H), 6.94-6.88 (m, 2H), 4.47 (s, 2H). C NMR (100 MHz, CDCl3, TMS): δ (ppm)
164.9, 162.4, 159.9, 152.0, 134.2, 131.0 (d, J = 3.2 Hz), 129.7 (d, J = 8.2 Hz), 125.0,
123.3, 120.4, 119.9, 114.5 (d, J = 21.6 Hz), 35.7. HRMS m/z [M+H]+ (ESI) Calcd for
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C14H11FNS2 (276.0311), found: 276.0308.
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2-((Naphthalen-1-ylmethyl)thio)benzo[d]thiazole (3i).
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8
9
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3i as a yellow oil
(256 mg, 83%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 8.01 (d, J= 8.0 Hz, 1H),
7.83 (d, J= 8.0 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.65 (d, J= 8.0 Hz, 1H), 7.58 (d, J=
8.0 Hz, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.42-7.23 (m, 4H), 7.16-7.08 (m, 1H), 4.96 (s,
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2H). C NMR (100 MHz, CDCl3, TMS): δ (ppm) 166.6, 153.2, 135.4, 134.0, 131.6,
131.5, 129.0, 128.1, 126.6, 126.1, 126.1, 125.4, 124.4, 123.7, 121.6, 121.1, 35.7.
HRMS (ESI) m/z [M+H]+ Calcd for C18H14NS2 (308.0562), found: 308.0560.
2-(Allylthio)benzo[d]thiazole (3j).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3j as a yellow oil
(183 mg, 88%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.75 (d, J= 8.0 Hz, 1H),
7.69 (d, J= 8.0 Hz, 1H), 7.27 (t, J= 8.0 Hz, 1H), 7.14 (t, J= 8.0 Hz, 1H), 5.92-5.85 (m,
13
1H), 5.27-5.22 (m, 1H), 5.06 (d, J= 8.0 Hz, 1H), 3.85 (d, J= 8.0 Hz, 1H). C NMR
(100 MHz, CDCl3, TMS): δ (ppm) 165.1, 152.0, 134.2, 131.2, 124.9, 123.1, 120.4,
119.8, 118.1, 35.1. HRMS (ESI) m/z [M+H]+ Calcd for C10H10NS2 (208.0249), found:
208.0244.
Ethyl 2-(benzo[d]thiazol-2-ylthio)acetate (3k).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3k as a yellow oil
(211 mg, 83%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.77 (d, J= 8.0 Hz, 1H),
7.67 (d, J= 8.0 Hz, 1H), 7.33 (t, J= 8.0 Hz, 1H), 7.24-7.18 (m, 1H), 4.19-4.14 (m, 2H),
13
4.09 (s, 2H), 1.21 (t, J= 8.0 Hz, 3H). C NMR (100 MHz, CDCl3, TMS): δ (ppm)
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167.2, 163.7, 151.8, 134.4, 125.0, 123.4, 120.6, 120.0, 61.0, 34.1, 13.0. HRMS m/z
[M+H]+ (ESI) Calcd for C11H12NO2S2 (254.0304), found: 254.0309.
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2-((4-Fluorobenzyl)thio)-4,5-dihydrothiazole (3l).
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According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3l as a yellow oil
1
(182 mg, 80%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.25-7.22 (m, 2H), 6.89
13
(t, J= 8.0 Hz, 2H), 4.23 (s, 2H), 4.12 (t, J= 8.0 Hz, 1H), 3.29 (t, J= 8.0 Hz, 1H). C
NMR (100 MHz, CDCl3, TMS): δ (ppm) 163.8, 162.2, 159.8, 131.5 (d, J = 3.3 Hz),
129.6 (d, J = 8.2 Hz), 114.3 (d, J = 21.5 Hz), 63.1, 34.8 (d, J = 39.2 Hz). HRMS (ESI)
m/z [M+H]+ Calcd for C10H11FNS2 (228.0311), found: 228.0312.
2-((Pyridin-2-ylmethyl)thio)benzo[d]thiazole (3m).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 15:1) to give the target compound 3m as a yellow oil
(188 mg, 73%). 1H NMR (400 MHz, CDCl3, TMS): 8.45 (d, J = 4.0 Hz, 1H), 7.78 (d,
J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz,
1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 4.64 (s,
2H). δ (ppm). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 165.0, 155.3, 151.9, 148.4,
135.7, 134.3, 124.9, 123.2, 122.3, 121.4, 120.4, 119.9, 38.0. HRMS (ESI) m/z [M+H]+
Calcd for C13H11N2S2 (259.0358), found: 259.0359.
2-(Benzylthio)benzo[d]oxazole (3n).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3n as a yellow oil
(218 mg, 90%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.50 (d, J= 8.0 Hz, 1H),
7.33-7.27 (m, 3H), 7.21-7.06 (m, 5H), 4.42 (s, 2H). 13C NMR (100 MHz, CDCl3,
TMS): δ (ppm) 164.6, 151.9, 141.9, 135.9, 129.1, 128.8, 128.0, 124.39 124.0, 118.5,
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109.9, 36.6. HRMS (ESI) m/z [M+H]+ Calcd for C14H12NOS (242.0634), found:
242.0637.
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2-((4-Bromobenzyl)thio)benzo[d]oxazole (3o).
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According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 15:1) to give the target compound 3o as a yellow oil
(256 mg, 80%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.45 (d, J= 4.0 Hz, 1H),
7.22 (t, J= 8.0 Hz, 3H), 7.13-7.01 (m, 4H), 4.28 (s, 2H). 13C NMR (100 MHz, CDCl3,
TMS): 164.1, 151.9, 141.8, 135.2, 131.8, 130.7, 124.4, 124.1, 121.9, 118.6, 110.0,
35.9. HRMS (ESI) m/z [M+H]+ Calcd for C14H11BrNOS (319.9739), found: 319.9731.
2-((4-Nitrobenzyl)thio)benzo[d]oxazole (3p).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3p as a white solid
o
(250 mg, 87%). Mp: (113-115 C). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 8.09
(d, J= 8.0 Hz, 1H), 7.58-7.51 (m, 3H), 7.36-7.33 (m, 1H), 7.23-7.15 (m, 2H), 4.51 (s,
13
2H). C NMR (100 MHz, CDCl3, TMS): δ (ppm) 162.2, 150.9, 146.3, 142.9, 140.5,
128.9, 123.4, 123.2, 122.8, 117.5, 108.9, 34.4. HRMS (ESI) m/z [M+H]+ Calcd for
C14H11N2O3S (287.0485), found: 287.0480.
2-((3-Methoxybenzyl)thio)benzo[d]oxazole (3q).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3q as a colorless
1
oil (242 mg, 89%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.68-7.65 (m,1H),
7.50-7.46 (m, 1H), 7.34-7.27 (m, 3H), 7.10-7.06 (m, 2H), 6.90-6.86 (m, 1H), 4.59 (d,
J= 4.0 Hz, 2H), 3.84 (d, J= 4.0 Hz, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
163.4, 158.7, 150.8, 140.8, 136.2, 128.7, 123.2, 122.9, 120.2, 117.3, 113.5, 112.4,
108.8, 54.1, 35.5. HRMS (ESI) m/z [M+H]+ Calcd for C15H14NO2S (272.0740), found:
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272.0747.
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2-((2-Methylbenzyl)thio)benzo[d]oxazole (3r).
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8
9
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3r as a yellow oil
(233 mg, 91%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.50 (d, J= 8.0 Hz, 1H),
7.29-7.26 (m, 2H), 7.16-7.00 (m, 5H), 4.45 (s, 2H), 2.30 (s, 3H). 13C NMR (100 MHz,
CDCl3, TMS): δ (ppm) 163.5, 150.7, 140.8, 136.0, 132.1, 129.5, 129.1, 127.2, 125.2,
123.2, 122.8, 117.3, 108.7, 33.8, 18.1. HRMS (ESI) m/z [M+H]+ Calcd for
C15H14NOS (256.0791), found: 256.0795.
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2-((4-Fluorobenzyl)thio)benzo[d]thiazole (3s).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3s as a yellow oil
(205 mg, 79%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.37 (d, J= 8.0 Hz, 1H),
7.17-7.14 (m, 3H), 7.04-6.94 (m, 2H), 6.76-6.72 (m, 2H), 4.25 (s, 2H). 13C NMR (100
MHz, CDCl3, TMS): δ (ppm) 164.3, 163.6, 161.1, 151.9, 141.8, 131.8 (d, J = 3.3 Hz),
130.8 (d, J = 8.1 Hz), 124.2 (d, J = 34.7 Hz), 118.5, 115.6 (d, J = 21.6 Hz), 109.9 ,
35.7. HRMS (ESI) m/z [M+H]+ Calcd for C14H11FNOS (260.0540), found: 260.0549.
2-((2-Chlorobenzyl)thio)benzo[d]oxazole (3t).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3t as a yellow oil
1
(237 mg, 86%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.45-7.41 (m, 2H),
7.22-7.17 (m, 2H), 7.10-6.98 (m, 4H) 4.47 (s, 2H). 13C NMR (100 MHz, CDCl3,
TMS): δ (ppm) 164.4, 152.0, 141.9, 134.4, 134.0, 131.3, 129.7, 129.4, 127.1, 124.3,
124.0, 118.5, 109.9, 34.3. HRMS (ESI) m/z [M+H]+ Calcd for C14H11ClNOS
(276.0244), found: 276.0240.
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Methyl 4-((benzo[d]oxazol-2-ylthio)methyl)benzoate (3u).
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6
7
8
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3u as a white solid
(252 mg, 84%). Mp: (83-85 oC). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.85 (d,
J= 12.0 Hz, 2H), 7.48 (d, J= 4.0 Hz, 1H), 7.39 (d, J= 8.0 Hz, 2H), 7.27 (d, J= 8.0 Hz,
1H), 7.15-7.06 (m, 2H), 4.42 (s, 2H), 3.75 (s, 3H). 13C NMR (100 MHz, CDCl3,
TMS): δ (ppm) 166.5, 163.9, 151.9, 141.8, 141.3, 129.9, 129.6, 129.0, 124.3, 124.0,
118.5, 109.9, 52.1, 36.0. HRMS (ESI) m/z [M+H]+ Calcd for C16H14NO3S (300.0689),
found: 300.0681.
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Methyl 4-(((6-methylbenzo[d]oxazol-2-yl)thio)methyl)benzoate (3v).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3v as a brown
solid (280 mg, 89%). Mp: (105-106 oC). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.87-7.84 (m, 2H), 7.40-7.37 (m, 2H), 7.26 (s, 1H), 7.16-7.12 (m, 1H), 6.91-6.87 (m,
13
1H), 4.41 (d, J= 4.0 Hz, 2H), 3.76 (d, J= 4.0 Hz, 3H), 2.29 (d, J= 8.0 Hz, 3H). C
NMR (100 MHz, CDCl3, TMS): δ (ppm) 165.4, 162.6, 149.0, 140.8, 140.3, 133.0,
128.8, 128.8, 128.4, 127.9, 123.9, 117.4, 108.1, 51.0, 34.9, 20.3. HRMS (ESI) m/z
[M+H]+ Calcd for C17H16NO3S (314.0845), found: 314.0849
2-((4-Bromobenzyl)thio)-6-(t-butyl)benzo[d]oxazole (3w).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3w as a white soild
(331 mg, 88%). Mp: (79-80 oC). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.53 (s,
1H), 7.28 (d, J= 8.0 Hz, 2H), 7.21-7.14 (m, 4H), 4.33 (s, 2H), 1.23 (s, 9H). 13C NMR
(100 MHz, CDCl3, TMS): δ (ppm) 164.0, 149.9, 147.9, 141.7, 135.3, 131.8, 130.7,
121.9, 121.6, 115.2, 109.1, 35.8, 34.9, 31.8. HRMS (ESI): m/z [M+H]+ calcd for
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C18H19BrNOS (376.0365), found: 376.0361.
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2-((Pyridin-2-ylmethyl)thio)benzo[d]oxazole (3x).
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8
9
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3x as a white solid
(184 mg, 76%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 8.48 (d, J= 4.0 Hz, 1H),
7.56-7.49 (m, 2H), 7.43 (d, J= 8.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.20-7.07 (m,
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3H), 4.61 (s, 2H). C NMR (100 MHz, CDCl3, TMS): δ (ppm) 163.4, 154.8, 150.9,
148.5, 140.7, 135.8, 123.2, 122.8, 122.2, 121.5, 117.3, 108.8, 37.1. HRMS (ESI) m/z
[M+H]+ Calcd for C13H11N2OS (243.0857), found: 243.0851.
2-(Benzylthio)-1H-benzo[d]imidazole (3y).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3y as a white solid
o
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(215 mg, 89%). Mp: (184-185 C). H NMR (400 MHz, DMSO-d6, TMS): δ (ppm)
12.54 (s, 1H), 7.45 (d, J= 8.0 Hz, 4H), 7.33-7.25 (m, 3H), 7.15-7.12 (m, 2H), 4.58 (s,
13
2H). C NMR (100 MHz, DMSO-d6, TMS): δ (ppm) δ 150.1, 138.1, 129.3, 128.9,
127.7, 121.8, 35.6. HRMS (ESI) m/z [M+H]+ Calcd for C14H13N2S (241.0794), found:
241.0790.
2-((4-Bromobenzyl)thio)-1H-benzo[d]imidazole (3z).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3z as a white solid
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(258 mg, 81%). Mp: (187-188 C). H NMR (400 MHz, DMSO-d6, TMS): δ (ppm)
12.53 (s, 1H), 7.51-7.40 (m, 6H), 7.14-7.12 (m, 2H), 4.55 (s, 2H). 13C NMR (100
MHz, DMSO-d6, TMS): δ (ppm) 149.8, 137.9, 131.7, 131.4, 129.3, 128.9, 121.9,
120.8, 34.8. HRMS (ESI) m/z [M+H]+ Calcd for C14H12BrN2S (318.9899), found:
318.9902.
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2-((2-Methylbenzyl)thio)-1H-benzo[d]imidazole (3za).
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According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3za as a white solid
(227 mg, 89%). Mp: (161-163 oC). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 9.43
(s, 1H), 7.74 (s, 1H), 7.34-7.12 (m, 6H), 4.60 (s, 2H), 2.44 (s, 3H). 13C NMR (100
MHz, CDCl3, TMS): δ (ppm) 148.8, 136.0, 133.2, 129.5, 129.0, 127.0, 125.2, 34.5,
18.1. HRMS (ESI) m/z [M+H]+ Calcd for C15H15N2S (255.0950), found: 255.0956.
2-((4-Methylbenzyl)thio)-1H-benzo[d]imidazole (3zb).
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According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 5:1) to give the target compound 3zb as a white solid
(227 mg, 89%). Mp: (164-167 oC). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 11.36
(s, 1H), 7.45-7.42 (m, 2H), 7.18-7.11 (m, 4H), 7.00 (d, J= 8.0 Hz, 2H), 4.42 (s, 2H),
2.22 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 148.9, 136.4, 132.4, 128.3,
127.8, 121.3, 36.1, 20.1. HRMS (ESI) m/z [M+H]+ Calcd for C15H15N2S (255.0950),
found: 255.0951.
2-(Allylthio)-1H-benzo[d]imidazole (3zc).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the target compound 3zc as a white
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solid (167 mg, 88%). Mp: (140-141 C). H NMR (400 MHz, DMSO-d6, TMS): δ
(ppm) 12.54 (s, 1H), 7.43 (s, 2H), 7.14-7.10 (m, 2H), 6.06-5.95 (m, 1H), 5.31 (d, J=
13
16.0 Hz, 1H), 5.11 (d, J= 8.0 Hz, 1H), 3.96 (d, J= 8.0 Hz, 2H). C NMR (100 MHz,
DMSO-d6, TMS): δ (ppm) 149.8, 134.2, 121.8, 121.8, 118.5, 34.3. HRMS (ESI) m/z
[M+H]+ Calcd for C10H10N2S (190.0565), found: 190.0566.
2-(sec-Butylthio)benzo[d]thiazole (3zd).
According to TP, the residue was purified by flash chromatography on silica gel
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(petroleum ether/ethyl acetate = 15:1) to give the target compound 3zd as a yellow oil
(156 mg, 70%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.79 (d, J= 8.0 Hz, 1H),
7.66 (d, J= 8.0 Hz, 1H), 7.32 (t, J= 8.0 Hz, 1H), 7.20 (t, J= 8.0 Hz, 1H), 3.88-3.83 (m,
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1H), 1.79-1.64 (m, 2H), 1.42 (d, J= 4.0 Hz, 3H), 0.98 (d, J= 8.0 Hz, 3H). C NMR
(100 MHz, CDCl3, TMS): δ (ppm) 166.7, 153.4, 135.3, 125.9, 124.2, 121.5, 120.9,
45.9, 29.7, 20.9, 11.4. HRMS (ESI) m/z [M+H]+ Calcd for C11H14NS2 (224.0562),
found: 224.0567.
2-(Butylthio)benzo[d]thiazole (3ze).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 15:1) to give the target compound 3ze as a yellow oil
(129 mg, 58%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.76 (d, J= 8.0 Hz, 1H),
7.62 (d, J= 8.0 Hz, 1H), 7.31-7.27 (m, 1H), 7.18-7.14 (m, 1H), 3.23 (t, J= 8.0 Hz, 2H).
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1.73-1.65 (m, 2H), 1.44-1.34 (m, 2H), 0.85 (t, J= 8.0 Hz, 3H). C NMR (100 MHz,
CDCl3, TMS): δ (ppm) 166.3, 152.2, 134.0, 124.9, 123.0, 120.3, 119.84, 32.2, 30.1,
20.8, 12.5. HRMS (ESI) m/z [M+H]+ Calcd for C11H14NS2 (224.0562), found:
224.0567.
2-(tert-Butylthio)benzo[d]oxazole (3zf).
According to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 15:1) to give the target compound 3zf as a yellow oil
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(103 mg, 50%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.30-7.28 (m, 1H),
13
7.23-7.14 (m, 3H), 2.12 (s, 9H). C NMR (100 MHz, CDCl3, TMS): δ (ppm) 170.7,
147.7, 124.1, 123.2, 109.4, 109.1, 50.6, 29.9. HRMS (ESI) m/z [M+H]+ Calcd for
C11H14NOS (208.0791), found: 208.0799.
2-(Butylthio)benzo[d]oxazole (3zg).
According to TP, the residue was purified by flash chromatography on silica gel
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(petroleum ether/ethyl acetate = 15:1) to give the target compound 3zg as a yellow oil
(118 mg, 57%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.49 (d, J= 8.0 Hz, 1H),
7.31 (d, J= 8.0 Hz, 1H), 7.18-7.08 (m, 2H), 3.20 (t, J= 8.0 Hz, 1H), 1.74-1.66 (m, 2H),
1.44-1.34 (m, 2H), 0.85 (t, J= 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3, TMS): δ
(ppm) 164.1, 150.6, 140.9, 123.1, 122.6, 117.2, 108.7, 30.9, 30.1, 20.7, 12.5. HRMS
(ESI) m/z [M+H]+ Calcd for C11H14NOS (208.0791), found: 208.0794.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications
website. Experimental procedures, characterization data, and 1H, 13C NMR spectra for
new compound (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: 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), Z.-B. D. acknowledges the Humboldt Foundation and China Scholarship
Council for a fellowship. S.-B. Z thanks the support of National College Students
Innovation and Entrepreneurship Training Program (201710490002, 201710490008) .
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