Copper-Catalyzed One-Pot Synthesis of Chalcogen-Benzothiazoles/Imidazo[1,2- a ]pyridines with Sulfur/Selenium Powder and Aryl Boronic Acids

Article abstract of DOI:10.1055/s-0037-1609758

An efficient and convenient copper-catalyzed oxidative chalcogenation of benzothiazoles and imidazo[1,2- a ]pyridines with sulfur/selenium powder and aryl boronic acids was developed. This procedure allows access to a wide range of structurally diverse arylchalcogen-substituted benzothiazoles/imidazo[1,2- a ]pyridines in good yields and with good functional group tolerance. A biological evaluation revealed that some of the obtained products exhibited in vitro antiproliferative activities on human-derived lung, stomach, esophageal, and breast cancer cell lines.

Full text of DOI:10.1055/s-0037-1609758

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–G
letter
A
en
T. Guo et al.
Letter
Synlett
Copper-Catalyzed One-Pot Synthesis of Chalcogen-Benzothi-
azoles/Imidazo[1,2-a]pyridines with Sulfur/Selenium Powder and
Aryl Boronic Acids
Tao Guo*a
YAr
Xu-Ning Weia
Ying-Li Zhub
Huan Chenc
Shu-Lei Han*c
Yong-Cheng Ma*b
N
[S8]
or
[Se]
[Cu]
N
[Cu]
N
R1
R1
R2
YAr
+ ArB(OH)2
H
N
S
N
R1
H
17 examples
up to 81% yield
16 examples
up to 83% yield
R1
R2
S
Y = S, Se
N
a College of Chemistry, Chemical and Environmental Engineer-
ing, Henan University of Technology, Zhengzhou, Henan
450001, P. R. of China
taoguo@haut.edu.cn
b Clinical Pharmacology Laboratory, Zhengzhou University
People’s Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan
450002, P. R. of China
c China National Tobacco Quality Supervision & Test Center,
No. 2 Fengyang Street, Zhengzhou, Henan 450001, P. R. of
China
Received: 23.02.2018
Accepted after revision: 15.04.2018
Published online: 16.05.2018
genation of both benzothiazoles and imidazo[1,2-
a]pyridines has been made using chalcogen agents such as
ArSH, ArSSAr, ArSO2Cl, ArSO2Na, ArSO2H, and ArSeSeAr
(Scheme 1a and b).5 For example, the Zeni group reported a
copper oxide nanoparticle-catalyzed synthesis of 2-(or-
ganochalcogen)thiazoles through direct C–H bond activa-
tion of benzothiazoles.6 Subsequently, Braga reported a
novel iodine-catalyzed chalcogenation of imidazo[1,2-
a]pyridines with diaryl disulfides and diselenides.7 Addi-
tionally, Wang developed an Eosin B-catalyzed direct sulfe-
nylation of imidazo[1,2-a]pyridines with sulfinic acids
through a photoredox process at room temperature.8 How-
ever, the use of the above chalcogen agents has some draw-
backs including unpleasant fumes, volatility, toxicity, cost,
and moisture sensitivity. In contrast, a more straightfor-
ward and attractive alternate is to employ sulfur and seleni-
um powder as stable and easily handled cross-coupling
partners to construct C–S/C–Se bonds, avoiding the need
for substrate pre-activation (Scheme 1c).9 For example, Ad-
imurthy and co-workers developed a facile approach to ar-
ylthio-substituted imidazo[1,2-a]pyridine derivatives from
aryl halide and sulfur using catalytic copper(I) iodide.10
Subsequently, Wu reported a protocol to access 2-aryl-
selanyl-benzothiazoles from aryl halides and Se powder
using CuCl2 as a catalyst.11 However, the need for an inert
environment limits its usage and the synthetic compounds
are rarely applied to biological activity estimation.
DOI: 10.1055/s-0037-1609758; Art ID: st-2018-w0122-l
Abstract An efficient and convenient copper-catalyzed oxidative chal-
cogenation of benzothiazoles and imidazo[1,2-a]pyridines with sul-
fur/selenium powder and aryl boronic acids was developed. This proce-
dure allows access to a wide range of structurally diverse arylchalcogen-
substituted benzothiazoles/imidazo[1,2-a]pyridines in good yields and
with good functional group tolerance. A biological evaluation revealed
that some of the obtained products exhibited in vitro antiproliferative
activities on human-derived lung, stomach, esophageal, and breast
cancer cell lines.
Key words benzothiazoles, imidazoheterocycles, chalcogenation, C–H
activation, copper
Heterocyclic compounds are important structural mo-
tifs in a number of bioactive compounds and are used as
crucial intermediates in the pharmaceutical industry.1
Among various heterocycles, benzothiazoles and imid-
azo[1,2-a]pyridines have received considerable research at-
tention due to the diverse pharmacological profile includ-
ing their use as antitumor agents, RSK2 inhibitors, anti-in-
flammatory, antiviral agent, and SIRT1 agonist.2 Moreover,
these heterocycles are essential building blocks in the syn-
thesis of functional materials such as charge transporters,
industrial dyes and plant growth regulators.3 Owing to the
merits of benzothiazole and imidazo[1,2-a]pyridine deriva-
tives, there is a strong incentive to develop new synthetic
strategies geared towards these heterocyclic classes.4
Recently, a system of ArB(OH)2 and S8 was used as an
ideal and useful sulfanylation method for C–S bond forma-
tion.12 Inspired by our longstanding interest in the develop-
ment and application of imidazo[1,2-a]pyridine derivatives
in medicinal chemistry,13 herein we disclose an efficient
and concise route to access 2-chalcogen-benzothiazoles
and 3-chalcogen-imidazo[1,2-a]-pyridines via copper-cata-
Additionally, the nature of the substituent at either the
2- or 3-position of benzothiazoles and imidazo[1,2-a]pyri-
dines has a profound influence on the biological and physi-
cal properties. Considering the importance of organochal-
cogenides (S, Se), scientific progress in the direct chalco-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

B
T. Guo et al.
Letter
Synlett
(a) Metal-catalyzed direct C-H bond chalcogenation (S, Se) of benzothiazoles and imidazo[1,2-a]pyridines with chalcogen reagents
YAr
N
[S]
or
[Se]
[Cu]
[Cu, Rh]
N
R1
R1
sources
R2
YAr
N
S
N
N
R1
R2
R1
N
S
[S], [Se]= ArSH, ArYYAr, ArSO2Cl, phenylthio)isobutyrophenone
(b) Metal free direct C-H bond chalcogenation of benzothiazoles and imidazo[1,2-a]pyridines with chalcogen reagents
YAr
[S]
or
[Se]
Metal free
sources
N
R1
R2
N
N
R1
R2
N
[S], [Se]= ArSH, ArYYAr, ArSO2Na, ArSO2H, sulfonothioates
(c) Direct C-H bond chalcogenation of benzothiazoles and imidazo[1,2-a]pyridines with sulfur/selenium powder
SAr
[S8]
or
[Se]
[Cu]
N
S
[Cu]
N
R1
R2
R1
YAr
+ ArX
N
S
N
N
R1
R2
R1
N
This work
(d) Cu-catalyzed oxidative chalcogenation of benzothiazoles and imidazo[1,2-a]pyridines
YAr
[S8]
or
[Se]
N
S
[Cu]
[Cu]
N
R1
R2
+ ArB(OH)2
R1
YAr
H
N
S
N
R1
H
N
R1
R2
N
Scheme 1 Representative methods for the chalcogenation of benzothiazoles and imidazo[1,2-a]pyridines
lyzed oxidative chalcogenation of imidazo[1,2-a]pyri-
dines/benzothiazoles with sulfur/selenium powder and aryl
boronic acids (Scheme 1d).
1,4-dioxane were employed (entries 16–18). Efforts to fur-
ther enhance the yield by changing the base and ligand pro-
duced little improvements. Notably, ligands and bases com-
monly used in Cu-catalyzed reactions such as bpy, 4,5-di-
azafluoren-9-one, K2CO3, and K3PO4, led to lower yields
under the current reaction conditions (entries 19–24). Fur-
ther modifications of reaction concentration and tempera-
ture did not improve the yield of 3a. Therefore, the condi-
tions employed in entry 15 were chosen as the optimized
reaction conditions.
We began our study by examining the reaction between
benzothiazole (1a), phenylboronic acid (2a), and elemental
sulfur (S8) in N,N-dimethylacetamide (DMAc) by using CuI
as catalyst at 130 °C (Table 1). Initially, various oxidants
were investigated and the choice of oxidant was crucial.
Only a trace amount of product was observed when H2O2
and O2 were used (entries 1 and 2). When the reaction was
carried out with TBHP and Mn(OAc)2, no product 3a was
obtained (entries 3 and 4). 2,3-Dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) was also an inefficient catalyst for this
transformation (entry 5). Among the various silver salts ex-
amined, Ag2CO3 was the most effective, and its use afforded
3a in 70% yield (entries 6–9). Furthermore, the effects of
various copper sources were examined. CuI was the opti-
mal catalyst. Notably, other catalysts such as Cu(OTf)2,
CuBr2, Cu(OAc)2, and CuCl2 led to significantly lower reac-
tion yields (entries 10–13). Next, different solvents were
tested using CuI as the catalyst and Ag2CO3 as the oxidant.
There was no advantage when dimethyl sulfoxide (DMSO)
was used as the solvent (entry 14). Shifting the solvent sys-
tem to N,N-dimethylformamide (DMF), 3a was isolated in
75% yield under the same conditions (entry 15). Further-
more, no improvements were observed when other sol-
vents such as N-methyl-2-pyrrolidinone (NMP), xylenes, or
Table 1 Optimization of the Reaction Conditions
B(OH)2
N
S
N
S
conditions
S8
S
+
+
1a
2a
3a
Entrya Catalyst
Oxidant
Base
Solvent
Yield (%)b
1
2
3
4
5
6
CuI
CuI
CuI
CuI
CuI
CuI
O2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
trace
trace
NR
H2O2
TBHP
Mn(OAc)2
DDQ
NR
11
Ag2CO3
70
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

C
T. Guo et al.
Letter
Synlett
With the optimized reaction conditions in hand, the
scope and generality of the chalcogenation reaction was in-
vestigated by using several structurally diverse benzothi-
azoles, arylboronic acids, and sulfur/selenium powder. The
results, summarized in Scheme 2, demonstrate that the re-
action has a high degree of functional group tolerance with
a broad substrate scope. Generally, aryl boronic acid bearing
both electron-donating (Me, Et) and electron-withdrawing
(F, Cl, Br) groups with meta and para substitution were
transformed into the 3-sulfanyl-benzothiazole derivatives
with yields ranging from 51 to 78%. Fortunately, 2-naphth-
ylboronic acid could also undergo this transformation to
furnish the corresponding product 3g using the CuI/Ag2CO3
system. Next, the effect of various benzothiazole compo-
nents on the reactions with aryl boronic acids were exam-
ined. As demonstrated from the yields of products 3h–k,
both electron-withdrawing and electron-donating func-
tionalities on the benzothiazole ring had little influence on
the reaction efficiency. Most importantly, the reactions of
benzothiazole, aryl boronic acid, and Se powder permitted
the efficient synthesis of selenation products 3l–p in 49–
60% yield. Unfortunately, aliphatic boronic acids such as n-
hexaneboronic acid were not suitable for the developed
transformation.
Entrya Catalyst
Oxidant
Base
Cs2CO3
Solvent
Yield (%)b
7
CuI
AgNO3
AgOAc
AgOTf
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMSO
DMF
33
8
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
NR
trace
21
9
CuI
10
11
12
13
14
15
16
17
18
19
20
21
22c
23d
24e
Cu(OTf)2
CuBr2
Cu(OAc)2
CuCl2
CuI
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
40
62
55
52
CuI
75
CuI
NMP
15
CuI
xylenes
1,4-dioxane
DMF
trace
NR
61
CuI
CuI
CuI
K3PO4
DMF
68
CuI
KHCO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
NR
NR
65
CuI
DMF
CuI
DMF
CuI
DMF
trace
a Reaction conditions: 1a (0.25 mmol), S8 (0.75 mmol), 2a (0.5 mmol), cat-
alyst (20 mol%), phen (20 mol%), oxidant (0.5 mmol), base (0.5 mmol) and
solvent (1 mL) in air reacted for 10 h.
Having established a simple approach for the copper-
catalyzed C–S/C–Se bond formation via C–H bond activa-
tion, we next investigated whether valuable 3-chalcogen-
imidazo[1,2-a]pyridines could be obtained using imid-
azo[1,2-a]pyridines as the coupling partner (Scheme 3).
b Isolated yield.
c Without ligand.
d bpy (20 mol%) was used.
e 4,5-Diazafluoren-9-one (20 mol%) was used.
R
B(OH)2
N
N
CuI, Ag2CO3
R1
R1
Y
S8/Se
+
+
Phen, Cs2CO3
DMF, air, 130 °C
S
S
R
1
2
3
Y = S, Se
Et
Br
F
Cl
N
N
S
N
S
N
S
N
N
S
S
S
S
S
S
S
S
S
3e,
65%
3a, 75%
3b,73%
3c, 78%
3d, 51%
3f, 57%
N
S
Br
Ph
Cl
N
S
N
S
N
N
S
F
S
S
S
S
H3CO
S
S
3i, 75%
3j, 83%
3k, 62%
3g, 64%
3h, 71%
Et
Br
N
N
N
S
N
N
S
Se
Se
Se
Se
Se
S
S
S
3l, 60%
3m, 50%
3n, 56%
3o, 49%
3p, 52%
Scheme 2 Chalcogenation of benzothiazoles with aryl boronic acids. Reaction conditions: 1 (0.25 mmol), S8/Se (0.75 mmol), 2 (0.5 mmol), CuI (20
mol%), phen (20 mol%), Cs2CO3 (0.5 mmol), Ag2CO3 (0.5 mmol) and DMF (1 mL) in air reacted for 10 h at 130 °C. Isolated yields are given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

D
T. Guo et al.
Letter
Synlett
R
N
B(OH)2
R1
CuI, Ag2CO3
Y
N
R2
R1
S8/Se
+
+
Phen, K2CO3
DMF, air, 130 °C
N
R2
R
N
4
2
5
Y = S, Se
Br
F
O2N
Cl
S
S
5f, 65%
S
S
N
S
S
S
N
N
N
N
N
N
OCH3
N
N
N
N
N
5e, 56%
5a, 70%
5b, 59%
5c, 76%
5d, 49%
S
S
S
N
N
S
N
N
S
N
N
N
NO2
N
N
N
N
N
S
F
Cl
5g, 74%
5h, 69%
5i, 42%
5j, 73%
5k, 78%
5l, 53%
Br
S
S
S
Se
S
N
N
N
N
N
N
N
N
S
N
N
5m, 75%
5n, 72%
5o, 81%
5p, 52%
5q, 51%
Scheme 3 Chalcogenation of imidazoheterocycles with aryl boronic acids. Reaction conditions: 4 (0.25 mmol), S8/Se (0.75 mmol), 2 (0.5 mmol), CuI
(20 mol%), phen (20 mol%), K2CO3 (0.5 mmol), Ag2CO3 (0.5 mmol) and DMF (1 mL) in air reacted for 10 h at 130 °C. Isolated yields are given.
B(OH)2
The reactions of imidazo[1,2-a]pyridine with different sub-
S
CuI, Ag2CO3
stituted aryl boronic acids containing F, Cl, Br, NO2 substitu-
S
+
S8
ents afforded the desired products 5a–e in 49–76% yields. It
should be noted that the boronic acids with a strongly
electron-withdrawing group (NO2) gave the desired product
5d in a markedly reduced yield of 49%. For the substituted
imidazopyridines, both the electron-donating and the
electron-withdrawing substituents were well tolerated,
showing no obvious electronic effect for this transforma-
tion. Additionally, when naphthyl, thienyl, and (E)-2-styryl-
substituted imidazo[1,2-a]pyridines were used, the desired
products 5j–l were obtained in 73, 78, and 53% isolated
yields, respectively. Cyclopropylimidazo[1,2-a]-pyridine
was also suitable for the present protocol, affording the ali-
phatic products 5m in 75% yield. Additionally, the copper-
induced sulfenylation protocol was applied to other imidaz-
oheterocycles, such as imidazo[2,1-b]thiazoles. To our de-
light, the reaction proceeded smoothly, providing 5p in 52%
yield. Moreover, it was gratifying to find that the selenation
reaction was viable in this protocol and provided 3-phenyl-
selanyl-imidazo[1,2-a]pyridine 5q in 51% yield.
Phen, Cs2CO3
DMF, air, 130 °C
6, 95%
2a
N
S
N
S
CuI
S
S
S
+
Phen, Cs2CO3
DMF, air, 130 °C
6
1a
3a, 78%
S
CuI
S
N
N
S
Ph +
Phen, K2CO3
DMF, air, 130 °C
N
Ph
N
4n
6
5n, 70%
Scheme 4 Control experiments
To further understand the possible mechanism of this
novel reaction, a series of control experiments were per-
formed (Scheme 4). Treatment of phenylboronic acid 2a
with S8, under the standard conditions, gave diphenyl disul-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

E
T. Guo et al.
Letter
Synlett
fide 6 in 95% yield. Furthermore, the reaction of 6 with 1a
or 4n gave the desired products 3a and 5n in 78 and 70%
yield, respectively. Based on the above experimental results
and on previous reports,10,12,14 two plausible mechanistic
pathways are proposed (Scheme 5). For the 2-chalcogen-
benzothiazole synthesis, initial deprotonation of benzothi-
azole produces a carbanion, which is in equilibrium with 2-
isocyanothiolate.15 The reactions of aryl boronic acids with
S8 and Se generate the disulfide and the diselenide 6,16
which further react with CuI to provide a Cu(III)-tetracoor-
dinated square planar sulfate I. Then, 2-isocyanothiolate re-
acts with the copper species to form key intermediate II.
Subsequent, intramolecular nucleophilic attack of the thio-
late sulfur on the activated isocyanide carbon of I affords 2-
benzothiazole-copper III. Finally, reductive elimination of
intermediate III furnishes the desired product 3 and regen-
erates the Cu(I) catalyst. The mechanism for the synthesis
of 3-chalcogen-imidazo[1,2-a]pyridines has also been in-
vestigated and matched the proposed pathway up to the
electrophilic attack of imidazoheterocycles, which affords
intermediate IV. Elimination and aromatization of IV gives
the corresponding product 5, CuI, and the thiol/selenol,
which can be oxidized to the dichalcogenides 6.
The antiproliferative activities for some of the com-
pounds were evaluated in vitro against a panel of five hu-
man-derived tumor cell lines using a conventional MTT as-
say. Compound 5-fluorouracil, a widely used clinical cancer
drug, was chosen as the positive control. The results show
that compounds 5a and 5k displayed antiproliferative activ-
ities against PC-9 and H1975 with IC50 values of 6.68±0.82
and 15.30±1.18 μM, respectively, which was better than the
positive control (Table 2). These results support our ap-
proach to devise novel antiproliferative drugs based on the
framework of 3-chalcogen-imidazo[1,2-a]pyridines.
In summary, we report a new, effective, straightforward,
and promising synthetic route to develop bioactive com-
pounds such as 2-chalcogen-benzothiazoles and 3-chalco-
gen-imidazo[1,2-a]pyridines, with good yields under mild
reaction conditions.17 This method uses odorless and stable
S8/Se as the sulfur/selenium source and aryl boronic acids
as reactants with functional group compatibility and a
–
N
S
N
S
HCO3
S–
–
I
2–
(lll)
+
N
CO3
C
CuL
1
II
YPh
–
+
N
HCO3
C–
S–
PhYH
Ph
I
N
S
(lll)
Cu
Y
Y
L
(lll)
L
Cu
YPh
I
III
I
Ph
N
S
Y
3
Y
YH
Y
LCuI
Ag2CO3, CuI
6
B(OH)2
+
S8 or Se
Y
N
N
2
Ph
5
Y = S, Se
Ph
Y
L
I
(lll)
Cu
Y
I
Ph
Y
(lll)Cu
L
I
N+
N
Y–
H
Ph
N
IV
Ph
N
Scheme 5 Proposed mechanism.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

F
T. Guo et al.
Letter
Synlett
Table 2 In Vitro Antiproliferative Activity of Products on H1975 (lung), PC-9 (lung), HGC-27 (stomach), EC-109 (esophageal), and MCF-7 (breast)
Compound
IC50 (μM)
H1975
PC-9
HGC-27
EC-109
MCF-7
3a
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
3e
>80
>80
61.68±1.79
>80
>80
3f
>80
>80
>80
3g
>80
>80
55.18±1.74
>80
>80
3k
>80
>80
>80
3n
50.66±1.70
>80
>80
42.00±1.62
45.72±1.66
31.32±1.36
>80
>80
3p
>80
>80
5a
>80
6.68±0.82
35.53±1.55
72.71±1.86
13.22±1.12
15.62±1.98
44.34±1.65
46.57±1.68
6.04±0.78
68.48±1.84
>80
5c
>80
>80
5g
16.50±1.21
17.20±1.23
53.92±1.73
15.30±1.18
43.31±1.63
49.26±1.69
22.38±1.35
57.25±1.76
44.03±1.64
47.96±1.68
19.48±1.29
27.26±1.44
40.63±1.61
33.88±1.53
6.49±0.81
32.99±1.52
46.43±1.67
15.44±1.19
17.07±1.23
13.78±1.13
5h
5j
5k
5-Fluorouracil
broad substrate scope. Importantly, some synthesized com-
pounds displayed antitumor activity by a MTT assay, sup-
porting the value of this method.
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Funding Information
Financial support from National Natural Science Foundation of China
(81502952), Open Project of Grain & Corn Engineering Technology
Research Center in State Administration of Grain (No. 24400042), Col-
leges and Universities Key Research Program Foundation of Henan
Province (No.17A150006), Science and Technology Foundation of
Henan Province (No.172102310621, 182102210091) and Fundamen-
tal Research Funds for the Henan Provincial Colleges and Universities
in Henan University of Technology (No. 2015QNJH08) are greatly ap-
preciated. The authors are also thankful to Jun Liu, Henan University
(3) (a) Furukawa, S.; Shono, H.; Mutai, T.; Araki, K. ACS Appl. Mater.
Interfaces 2014, 6, 16065. (b) Mutai, T.; Sawatani, H.; Shida, T.;
Shono, H.; Araki, K. J. Org. Chem. 2013, 78, 2482. (c) Douhal, A.;
Amat-Guerri, F.; Acuna, A. U. Angew. Chem. Int. Ed. Engl. 1997,
36, 1514. (d) Wan, J.; Zheng, C.-J.; Fung, M.-K.; Liu, X.-K.; Lee,
C.-S.; Zhang, X.-H. J. Mater. Chem. 2012, 22, 4502.
of Technology, for her assistance for the NMR analysis.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609758.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

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(17) General procedure: DMF (1 mL) was added into a flask charged
with benzothiazole (1; 0.25 mmol), S8 or Se (0.75 mmol), aryl
boronic acid (2; 0.5 mmol), CuI (0.05 mmol), phen (0.05 mmol),
Cs2CO3 (0.5 mmol), and Ag2CO3 (0.5 mmol). The mixture was
stirred at 130 °C in air for 10 h. Then, the reaction was cooled to
room temperature, diluted with ethyl acetate (20 mL) and
washed with H2O (10 mL). The aqueous layer was extracted
twice with ethyl acetate (5 mL) and the combined organic phase
was dried over Na2SO4. After evaporation of the solvents, the
residue was purified by flash column chromatography (silica
gel, PE–EtOAc, 15: 1 to 10: 1) to afford the desired products.
2-(Phenylthio)benzo[d]thiazole (3a): Purified by using a flash
chromatography column (PE/EtOAc, 15: 1); yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.88 (d, J = 8.4 Hz, 1 H), 7.75–7.73 (m,
2 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.52–7.46 (m, 3 H), 7.42–7.38 (m,
1 H), 7.28–7.24 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ = 169.8,
154.1, 135.7, 135.5, 130.6, 130.1, 130.1, 126.3, 124.5, 122.1,
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120.9; IR (KBr): 2922, 1581, 1456, 1425, 1309, 1236, 1080,
+
1007, 752 cm–1
;
HRMS m/z [M++H] calcd. for C13H10NS2
:
244.02492; found: 244.02441
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3-((4-Fluorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (5a):
Purified by using a flash chromatography column (PE/EtOAc,
5:1); white solid; mp 128–130 °C. 1H NMR (500 MHz, CDCl3):
δ = 8.27 (d, J = 7.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 2 H), 7.72 (d, J =
9.0 Hz, 1 H), 7.46–7.31 (m, 4 H), 6.99–6.86 (m, 5 H); 13C NMR
(125 MHz, CDCl3): δ = 161.7 (d, JC–F = 244.9 Hz), 151.5, 147.2,
133.4, 130.2 (d, JC–F = 3.6 Hz), 128.8, 128.6, 128.5, 127.7 (d, JC–F
=
7.8 Hz), 126.9, 124.5, 117.9, 116.7 (d, JC–F = 21.0 Hz), 113.3,
(16) (a) Yu, J.-T.; Guo, H.; Yi, Y.; Fei, H.; Jiang, Y. Adv. Synth. Catal.
2014, 356, 749. (b) Chen, C.; Xie, Y.; Chu, L.; Wang, R.-W.; Zhang,
X.; Qing, F.-L. Angew. Chem. Int. Ed. 2012, 51, 2492.
106.7; IR (KBr): 2924, 2852, 1489, 1346, 1219, 1080, 735 cm–1
;
HRMS: m/z [M++H] calcd. for C19H14FN2S+: 321.08562; found:
321.08527.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G