Copper-Catalyzed Double Thiolation to Access Sulfur-Bridged Imidazopyridines with Isothiocyanate

Article abstract of DOI:10.1021/acs.joc.9b00186

A copper(I)-catalyzed sulfur-bridged dimerization of imidazopyridines has been developed using isothiocyanate as the sulfur source. This method enables a switchable synthesis of bis(imidazo[1,2-a]pyridin-3-yl)sulfanes or bis(2-(imidazo[1,2-a]pyridin-2-yl)phenyl)sulfanes in the presence of 4-dimethylaminopyridine (DMAP) or K₂CO₃ when different imidazopyridines were employed. Under optimized conditions, a variety of sulfur-bridged imidazopyridines were obtained in good yields. Moreover, thiourea was proved to be the key intermediate under catalytic system A.

Full text of DOI:10.1021/acs.joc.9b00186

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Article
Copper-Catalyzed Double Thiolation to Access
Sulfur-bridged Imidazopyridines with Isothiocyanate
Lu-Lu Tian, Shuai Lu, Zhe-Hua Zhang, En-Ling Huang, Hua-
Ting Yan, Xinju Zhu, Xin-Qi Hao, and Mao-Ping Song
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00186 • Publication Date (Web): 20 Mar 2019
Downloaded from http://pubs.acs.org on March 20, 2019
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The Journal of Organic Chemistry
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Copper-Catalyzed Double Thiolation to Access Sulfur-bridged Im-
idazopyridines with Isothiocyanate
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Lu-Lu Tian, Shuai Lu, Zhe-Hua Zhang, En-Ling Huang, Hua-Ting Yan, Xinju Zhu,* Xin-Qi Hao,
and Mao-Ping Song*
College of Chemistry and Molecular Engineering, Zhengzhou University, No. 100 of Science Road, Zhengzhou, He-
nan 450001, P. R. China
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Supporting Information
ABSTRACT: A copper(I)-catalyzed sulfur-bridged dimerization of imidazopyridines has been developed using isothiocya-
nate as the sulfur source. This method enables a switchable synthesis of bis(imidazo[1,2-a]pyridin-3-yl)sulfanes or bis(2-
(imidazo[1,2-a]pyridin-2-yl)phenyl)sulfanes in the presence of DMAP or K2CO3 when different imidazopyridines were
employed. Under the optimized conditions, a variety of sulfur-bridged imidazopyridines were obtained in good yields.
Moreover, thiourea was proved to be the key intermediate under catalytic system A.
great achievement has been made for the syntheses7 and
INTRODUCTION
functionalizations8 of imidazo[1,2-a]pyridine scaffold.
Until now, direct C3 arylation, alkylation, carbonylation,
amination, alkoxyla
The construction of C-S bonds is of fundamental research
interest due to their wide applications in pharmaceuticals,
organic syntheses, and materials science.1 Accordingly, a
Scheme 1. Functionalizations of imidazopyridines
wide range of protocols have been developed to introduce
sulfur moiety onto target molecules.2 Traditionally, the
formation of C-S bonds usually involves cross-coupling
between organic halides and thiols.3 Recently, C-H func-
tionalization has also emerged as a powerful strategy to
construct C-S bonds, which is more atom economic and
environmentally benign. In this context, various thiol
surrogates, such as disulfide, thiols, sulfinic acids, aryl-
sulfonyl chlorides, sulfonyl hydrazides, sodium sulfinates,
and others, have been successfully utilized to access thi-
oether derivatives.4
On the other hand, imidazo[1,2-a]pyridines have at-
tracted considerable attention due to their significance in
natural products, medicinal chemistry, and materials sci-
ence.5 Meanwhile, imidazo[1,2-a]pyridines have been uti-
lized as abnormal N-heterocyclic carbene and pincer-type
ligand precursors, which exhibited application in catalysis
after coordinated with transition metals.6 Consequently,
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copper salts, such as CuCl, CuBr, and CuBr2, were investi-
1
2
3
4
5
6
7
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gated, which all led to decreased yields (Table 1, entries 5-
7). When DMF was replaced by other solvents, no im-
proved result was obtained (Table 1, entries 8-10). In an
attempt to improve reaction efficiency, reducing the us-
age amount of DMAP to 0.5 equivalent was beneficial,
which provided 3a in 71% yields (Table 1, entry 11). To fur-
ther improve the outcome, the temperature range was
o
modulated. Product 3a was isolated in 88% yield at 90 C
(Table 1, entry 12), whereas decreased yield was observed
at lower temperature (Table 1, entry 13). Moreover, when
10 mol% of copper salt was utilized, product 3a was iso-
lated in 26% yield (Table 1, entry 14). And 3a could not be
detected without CuI, indicating the necessity of copper
salt (Table 1, entry 15). Finally, when the reaction was car-
ried out under argon or oxygen atmosphere, decreased
yields were observed. The structure of 3a was further con-
firmed by X-ray diffraction (See the sup info).
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Table 1. Optimization of reaction conditionsa
tion, halogenation, phosphonation, and thiolation have
been well-developed to construct C-C9 and C-X10 (X = O,
N, P, S, F, etc.) bonds (Scheme 1a). Meanwhile, imid-
azo[1,2-a]pyridine-directed C-H amidation and cyanation
have also been developed (Scheme 1b).11 Recently, DMA
and DMSO have been utilized as the methylene sources
Entry
catalyst
base
solvent
yield (%)b
1
2
CuI
CuI
CuI
CuI
CuCl
CuBr
CuBr2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
-
1,10-phen
2,2’-bipyridine
DMAP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
dioxane
DMSO
DMF
DMF
DMF
DMF
DMF
29
59
to
access
bis(imidazo[1,2-a]pyridin-3-yl)methanes
(Scheme 1c).12 However, the methodology to access sulfur-
bridged imidazopyridines is rather limited.13 Considering
the importance of sulfur-containing and bis(heteroaryl)
compounds,1,14 it is higher desirable to develop an envi-
ronmentally benign strategy to prepare sulfur-bridged
imidazopyridines.
3
64
-
4
K2CO3
5
DMAP
20
6
DMAP
36
7
DMAP
62
As commercially available organic synthons, isothiocy-
anates have been utilized as thiocyanating agents15 and
are versatile synthetic intermediates for various heterocy-
cles.16,17 Meanwhile, the reaction involving cleavage of the
C=S bond of isothiocyanates accompanied with formation
of byproduct, such as CuS, Ag2S, or H2S, is reported.18-20 As
the continuation of our previous work in imidaz-
opyridines,9c,10f,h,11b,21 we herein reported a unique ap-
proach to access sulfur-bridged imidazopyridines utilizing
CuI as the catalyst.21 To the best of our knowledge, the
employment of isothiocyanates as the sulfur source has
not been reported.
8
DMAP
44
55
9
DMAP
10
11
12c,d
13c,e
14cf
15c
DMAP
20
DMAP (0.5 equiv)
DMAP (0.5 equiv)
DMAP (0.5 equiv)
DMAP (0.5 equiv)
DMAP (0.5 equiv)
71, 71c
88
75
26
NR
aReaction Conditions: 1a (0.2 mmol), 2 (0.3 mmol), Cu salt (20
mol %), base (3.0 equiv), solvent (2.5 mL), under air, T (oC), 12 h.
bIsolated yields. cDMF (0.5 mL). d90 oC. e80 oC. fCuI (10 mol %).
RESULTS AND DISCUSSION
With the optimized conditions in hand (Table 1, entry
12), the scope and generality of double C-H thiolation
reaction was evaluated (Scheme 2). Initially, the substrate
scope of 2-phenylimidazo[1,2-α]pyridines was investigated.
It was found that Various substitutions at the para, meta,
and ortho positions were well tolerated, affording the cor-
responding products 3a-m in 37-88% yields. However,
substrate bearing strong electron-withdrawing groups
(NO2 and CF3) at the para position failed to yield the tar-
Our investigation was started with 2-phenylimidazo[1,2-
α]pyridine 1a (0.2 mmol), isothiocyanatobenzene 2 (0.3
mmol), CuI (20 mol%), and 1,10-phen (3 equiv) in DMF
(2.5 mL). To our delight, the desired sulfur-bridged prod-
o
uct 3a was isolated in 29% yield at 100 C for 12 h (Table 1,
entry 1). Subsequently, various bases were screened, and
DMAP was proved to be the best choice to afford 3a in
64% yield (Table 1, entry 3). Next, the effect of different
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get products (not shown). When 2-naphthyl substituted
substrates were employed, only 14% yield was achieved
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6
7
8
for 3n. Subsequently, imidazopyridines bearing OCH3,
CH3, F, or COOMe on the various positions of pyridine
rings were also examined, which provided products 3o-t
in 21-86% yields. Also, disubstituted imidazopyridine
were employed to afford products 3u in 57% yield. When
2-furanyl and 2-thienyl substituted imidazopyridines were
utilized, 3v and 3w were isolated in 63% and 75% yields,
respectively. Moreover, phenylimidazo[2,1-b] thiazole was
also compatible to provide the sulfur-bridged product 3x
in 40% yield. Finally, when C2,C3-unsubstituted imidaz-
opyridine was treated with PhNCS, only C3 sulfur-bridged
product 3y was obtained in 48% yield. Interestingly, when
electron-rich aromatics N,N-dimethylaniline was utilized,
the corresponding product 3z was isolated in 18% yield.22
Finally, a gram-scale experiment was conducted to evalu-
ate the practical utility of the current protocol as a syn-
thetic tool. Unfortunately, product 3a was isolated in only
32% yield.
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Unexpected, when 2-(2-bromophenyl)imidazo[1,2-
a]pyridine 4a was utilized as the coupling partners, bis(2-
(imidazo[1,2-a]pyridin-2-yl)phenyl)sulfane 5a was isolated
in 19% yield (Table 2, entry 1). In the process to improve
the yield of 5a, various base and solvents were examined
(see the sup info), which revealed that K2CO3 (2 equiv)
and DMF (2.0 mL) are the best choice (Table 2, entry 6).
o
When the temperature was increased to 120 C, product
5a was obtained in 89% yield (Table 2, entry 7). Further
elevating temperature to 130 oC led to decreased yield
(Table 2, entry 8). Moreover, when the Cu catalyst loading
was decreased to 10 mol%, product 5a was isolated in 76%
yield (Table 2, entry 9). The struc ture of 5a was further
confirmed by X-ray diffraction (see the sup info).
Scheme 2. Substrate scope of imidazopyridinesa
aReaction Conditions: 1 (0.2 mmol), 2 (0.3 mmol), CuI (20
mol %), DMAP (0.5 equiv), DMF (0.5 mL), 90 C, 12 h, under air.
b24 h. c1a (1.2 g, 6 mmol), 2 (9 mmol).
o
Table 2. Optimization of reaction conditionsa
Entry
base
T (oC)
Yield (%)
1
DMAP
90
90
19
-
2
2,2’-bypr
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mol %), K2CO3 (2.0 equiv), DMF (2.0 mL), 120 oC, 12 h, under air.
3
4
K2CO3
90
90
24
17
c4d (1.0 g, 4.6 mmol), 2 (0.90 g, 6.9 mmol).
1
2
3
4
5
6
7
8
Cs2CO3
5
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
90
34
40
89
83
76
ceeded smoothly to deliver product 5j and 5k in 53% and
64% yields. Finally, the catalytic system could be applied
to 2-(2-bromophenyl)pyridine, which provide 5l in 95%
yield. Other simple aryl bromides without a directing
group, such as bromobenzene and 2-bromonaphthalene,
failed to yield the desired products. We also tried to syn-
thesize 5d for a gram-scale production, which unfortu-
nately gave the desired product in 42% yield.
6c
7c
8c
9c,d
90
120
130
120
aReaction Conditions: 1a (0.2 mmol), 2 (0.3 mmol), CuI (20
mol%), base (0.5 equiv), DMF (0.5 mL), under air, T (oC), 12 h.
bIsolated yields. cDMF (2.0 mL). dCuI (10 mol %).
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To explore the reaction mechanism, a set of control ex-
periments were carried out (Scheme 4). A symmetric thi-
ourea 6 could be produced from isothiocyanatobenzene 2
under catalytic system A. Without DMAP or CuI, the thi-
ourea intermediate 6 could not be detected (Scheme 4, eq
1). Meanwhile, iodo-substituted imidazopyridine 7 was
isolated in 16% under catalytic system A (Scheme 4, eq 2).
Moreover, coupling between 7 and 6 yielded the desired
product 3a in 66% yield (Scheme 4, eq 3). These results
indicate that 6 and 7 are probably the key intermediate in
the catalytic system A. By contrast, compound 6 and 8
could not be detected under catalytic system B (Scheme 4,
eqs 4 and 5). Also, reaction between 4a and 6 failed to
give product 5a under catalytic system B (Scheme 4, eq 6).
These results indicate that formation of 5a does not pro-
ceed through intermediate 6 and 8.
Next,
the
substrate
scope
of
2-(2-
bromophenyl)imidazo[1,2-a]pyridines 4 was investigated
(Scheme 3). At first, imidazopyridines 4b-e bearing OCH3,
CH3, or Cl substituent on the C6 and C7 positions gave
products 5b-e in 63-85% yields, while substrates with
strong electron-withdrawing groups such as C6-
substituted CF3 and C7-substituted NO2 remained unreac-
tive (not shown). Next, substitutions at the C2-benzene
ring of imidazopyridines were examined, which gave pa-
ra-substituted products 5f-h in 82-86% yields. However,
meta-substituted product 5i was isolated in 33% yield.
Also, imidazo-containing heterocycles pro
Scheme 3. Substrate scope of 2-(2-bromoaryl)imidazo[1,2-
a]pyridines
Scheme 4. Mechanistic studies
On the basis of above discussion and related reports,18-
20,23 a plausible mechanism was proposed for catalytic sys-
tem A (Scheme 5). At first, Cu(I) underwent oxidative
addition with iodo-substituted imidazopyridine 7 to yield
Cu(III) intermediate I. Subsequently, the abstraction of a
nitrogen proton from thiourea followed by nucleophilic
substitution in the presence of DMAP gave Cu(III) inter-
mediate II,24 which underwent reductive elimination to
provide CuI and intermediate III. Next, abstraction of a
second proton generated diphenylmethanediimine and
aReaction Conditions: 4 (0.2 mmol), 2 (0.3 mmol), CuI (20
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intermediate IV,18c,19 which was confirmed by MS analysis
oselective afford sulfur-bridged imidazopyridines via two
1
2
3
4
(see the supporting information). Finally, nucleophilic
attack of intermediate I by intermediate IV gave I- and
intermediate V, which underwent reductive elimination
to deliver the final product 3a and Cu(I) species.
proposed catalytic systems. Meanwhile, this protocol is
featured with broad substrate scope, good functional
group compatibility, and operational convenience. The
discovery of isothiocyanate as sulfur source may promote
the development of C-H thiolation.
5
On the other hand, catalytic system B also underwent
similar reaction pathway (Scheme 6). Oxidative addition
of Cu(I) with 4a gave N1-chelated Cu(III) intermediate
VI,11 which reacted with VII species to yield intermediate
VIII, which underwent reductive elimination to generated
intermediate IX and CuX. After release of PhNCO and
CO2, intermediate X would be generated. Reaction be-
tween intermediates X and VI would afford Cu(III) inter-
mediate XI, which underwent reductive elimination to
deliver product 5a, accompanied with the regeneration of
Cu(I).
6
7
8
9
EXPERIMENTAL SECTION
General Experimental Details. Unless otherwise men-
tioned, all materials were commercially obtained and
used without further purification. All procedures were
performed under the air atmosphere. Imidazo[1,2-
a]pyridines 1,25 2-(2-bromophenyl)imidazo[1,2-a]pyridines
4,26 and 2-(2-bromophenyl)pyridine27 are known com-
pounds and synthesized according to previously de-
scribed methods. 1,3-diphenylthiourea 628 and 3-iodo-2-
phenylimidazo[1,2-a]pyridine 729 are known compounds.
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Scheme 5. Proposed catalytic cycles for catalytic system A
13
1H NMR, C NMR, and 19F NMR spectra were recorded at
400 MHz or 600 MHz, 100 MHz or 151 MHz, and 565 MHz
respectively on a Bruker DPX instrument using Me4Si as
an internal standard. Chemical shift multiplicities are
represented as follows: (s = singlet, d = doublet, t = triple,
m = multiplet, dd = double doublet, td = triple doublet).
Melting points were measured on a WC-1 instrument and
uncorrected. New compounds for HRMS were tested on a
Waters Q-Tof Micro MS/MS System ESI spectrometer.
Procedure for bis(2-phenylimidazo[1,2-a]pyridin-3-
yl)sulfane (3a) synthesis. To a 10 mL sealed tube was
added 2-phenylimidazo[1,2-a]pyridine 1a (38.8 mg, 0.2
mmol), isothiocyanatobenzene 2 (40.5 mg, 0.3 mmol), CuI
(7.6 mg, 20 mol %), and DMAP (12.2 mg, 0.5 equiv) in
DMF (0.5 mL) under air. The reaction was heated at 90 oC
for 12 h, and then cooled down to room temperature.
Ethyl acetate (20 mL) was added and the mixture was
extracted with water (2 × 10 mL). The organic layer was
dried over anhydrous sodium sulfate and concentrated.
The residue was purified by preparative TLC on silica gel
plates using petroleum ether/EtOAc = 2/1 as the eluent to
give the corresponding product 3a.
Scheme 6. Proposed catalytic cycles for catalytic system B
Procedure
for
bis(2-(imidazo[1,2-a]pyridin-2-
yl)phenyl)sulfane (5a) synthesis. To a 10 mL sealed
tube was added 2-(2-bromophenyl)imidazo[1,2-a]pyridine
4a (54.4 mg, 0.2 mmol), isothiocyanatobenzene 2 (40.5
mg, 0.3 mmol), CuI (7.6 mg, 20 mol %), and K2CO3 (55.2
mg, 2.0 equiv) in DMF (2.0 mL) under air. The reaction
o
was heated at 120 C for 12 h, and then cooled down to
room temperature. Ethyl acetate (20 mL) was added and
the mixture was extracted with water (2 × 10 mL). The
organic layer was dried over anhydrous sodium sulfate
and concentrated. The residue was purified by preparative
TLC on silica gel plates using petroleum ether/EtOAc = 1/1
as the eluent to give the corresponding product 5a.
Procedure for 1,3-diphenylthiourea (6) synthesis. To a
10 mL sealed tube was added isothiocyanatobenzene 2
(40.5 mg, 0.3 mmol), CuI (7.6 mg, 20 mol %), and DMAP
(12.2 mg, 0.5 equiv) in DMF (0.5 mL) under air. The reac-
tion was heated at 90 oC for 12 h, and then cooled down to
CONCLUSION
In conclusion, a novel CuI-catalyzed double thiolation
of imidazopyridines using isothiocyanate as the sulfur
source has been disclosed. This methodology could regi-
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room temperature. Ethyl acetate (20 mL) was added and
(q, J = 7.7 Hz, 4H), 1.37 (t, J = 7.6 Hz, 6H). 13C{1H} NMR (151
1
2
3
4
5
6
7
8
the mixture was extracted with water (2 × 10 mL). The
organic layer was dried over anhydrous sodium sulfate
and concentrated. The residue was purified by preparative
TLC on silica gel plates using petroleum ether/EtOAc =
2/1 as the eluent to give the corresponding product 6.
Procedure for 3-iodo-2-phenylimidazo[1,2-a]pyridine
(7) synthesis. To a 10 mL sealed tube was added 2-
phenylimidazo[1,2-a]pyridine 1a (38.8 mg, 0.2 mmol), CuI
(7.6 mg, 20 mol %), and DMAP (0.5 equiv) in DMF (0.5
MHz, CDCl3) δ 151.0, 146.5, 145.2, 131.2, 129.5, 128.1, 126.2,
125.46, 117.3, 112.4, 107.3, 28.9, 15.8. HRMS (positive ESI):
[M + H]+ Calcd. For C30H26N4S+: 475.1951, Found: 475.1953.
Bis(2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)sulfane (3e). puri-
fied by preparative TLC on silica gel with petroleum
ether/EtOAc (2:1) as an eluent (Rf = 0.22); Light yellow
o
solid (33.1 mg, 74% yield); mp 263 – 264 C. 1H NMR (400
MHz, CDCl3) δ 8.02 (d, J = 8.2 Hz, 4H), 7.60 (d, J = 6.9 Hz,
2H), 7.48 (t, J = 8.9 Hz, 2H), 7.41 (d, J = 8.0 Hz, 4H), 7.10 –
7.06 (m, 2H), 6.35 (td, J = 6.8, 0.9 Hz, 2H), 2.52 (s, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 150.9, 146.5, 138.8, 130.9,
129.4, 129.3, 126.2, 125.4, 117.3, 112.5, 107.0, 21.5. HRMS (pos-
itive ESI): [M + H]+ Calcd. For C28H22N4S+: 447.1638,
Found: 447.1642.
9
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mL) under air. The reaction was heated at 90 C for 12 h,
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and then cooled down to room temperature. Ethyl acetate
(20 mL) was added and the mixture was extracted with
water (2 × 10 mL). The organic layer was dried over anhy-
drous sodium sulfate and concentrated. The residue was
purified by preparative TLC on silica gel plates using pe-
troleum ether/EtOAc = 2/1 as the eluent to give the corre-
sponding product 7.
Bis(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)sulfane
(3f). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.27); Light yel-
o
1
Bis(2-phenylimidazo[1,2-a]pyridin-3-yl)sulfane (3a) puri-
fied by preparative TLC on silica gel with petroleum
ether/EtOAc (2:1) as an eluent (Rf = 0.34); Light yellow
solid (36.8 mg, 88% yield; 0.40 g, 32% yield for scale-up
low solid (38 mg, 84% yield); mp 254 – 255 C; H NMR
(400 MHz, CDCl3) δ 8.13 – 8.08 (m, 4H), 7.58 – 7.59 (m,
2H), 7.51 (d, J = 8.9 Hz, 2H), 7.34 – 7.28 (m, 4H), 7.16 – 7.12
(m, 2H), 6.44 (td, J = 7.8, 1.0 Hz , 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 163.3 (JC-F = 247.6 Hz), 149.9, 146.5, 131.3 (JC-
o
1
synthesis); mp 251 – 252 C. H NMR (400 MHz, CDCl3) δ
8.12 – 8.10 (m, 4H), 7.63 – 7.60 (m, 4H), 7.58 – 7.55 (m,
4H), 7.50 (d, J = 8.9 Hz, 2H), 7.11 – 7.07 (m, 2H), 6.34 (td, J
= 247.6 Hz), 129.9 (JC-F = 3.3 Hz), 126.6, 125.1, 117.5, 115.7
F
(JC-F = 21.4 Hz), 112.8, 107.0. 19F NMR (376 MHz, CDCl3) δ -
13
= 6.9, 1.0 Hz, 2H). C{1H} NMR (101 MHz, CDCl3) δ 150.9,
112.14. HRMS (positive ESI): [M
+
H]+ Calcd. For
146.6, 133.8, 129.6, 128.9, 128.6, 126.3, 125.4, 117.4, 112.6, 107.5.
HRMS (positive ESI): [M + H]+ Calcd. For C26H18N4S+:
419.1325, Found: 419.1324.
C26H16F2N4S+: 455.1137, Found: 455.1138.
Bis(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)sulfane.
(3g). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.28); Light yel-
Bis(2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)sulfane
(3b). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (3:1) as an eluent (Rf = 0.23); Brown
solid (20.0 mg, 42% yield); mp 224 – 225 oC. 1H NMR (400
MHz, CDCl3) δ 8.08 (d, J = 9.0 Hz, 4H), 7.62 (d, J = 7.0 Hz,
2H), 7.48 (d, J = 9.0 Hz, 2H), 7.16 – 7.11 (m, 4H), 7.11 – 7.07
o
1
low solid (23.1 mg, 47% yield); mp 296 – 297 C. H NMR
(400 MHz, CDCl3) δ 8.10 – 8.06 (m, 4H), 7.62 – 7.57 (m,
6H), 7.51 (d, J = 9.0 Hz, 2H), 7.17 – 7.13 (m, 2H), 6.47 (td, J
13
= 6.8, 1.0 Hz, 2H). C{1H} NMR (101 MHz, CDCl3) δ 149.8,
146.6, 135.1, 132.3, 130.7, 129.0, 126.7, 125.1, 117.6, 113.0, 107.1.
HRMS (positive ESI): [M + H]+ Calcd. For C26H16Cl2N4S:
487.0545, Found: 487.0548.
13
(m, 2H), 6.40 (td, J = 6.8, 0.9 Hz, 2H), 3.96 (s, 6H). C{1H}
NMR (101 MHz, CDCl3) δ 160.2, 150.6, 146.5, 130.8, 126.3,
125.4, 117.2, 114.0, 112.5, 106.5, 55.5. HRMS (positive ESI): [M
+ H]+ Calcd. For C28H22N4O2S+: 479.1536, Found: 479.1542.
Bis(2-(4-(tert-butyl)phenyl)imidazo[1,2-a]pyridin-3-
Bis(2-(3-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)sulfane.
(3h). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.25); Light yel-
o
1
yl)sulfane (3c). purified by preparative TLC on silica gel
with petroleum ether/EtOAc (1:1) as an eluent (Rf = 0.55);
low solid (17.9 mg, 37% yield); mp 153 – 154 C. H NMR
(400 MHz, CDCl3) δ 7.74 – 7.72 (m, 2H), 7.64 – 7.63 (m,
4H), 7.55 – 7.49 (m, 4H), 7.14 – 7.09 (m, 4H), 6.40 (td, J =
6.9, 1.0 Hz, 2H), 3.95 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.7, 150.7, 146.5, 135.08, 129.7, 126.5, 125.5, 122.0,
117.4, 115.3, 114.3, 112.7, 107.5, 55.5. HRMS (positive ESI): [M
+ H]+ Calcd. For C28H22N4O2S+: 479.1536, Found: 479.1538.
Bis(2-(m-tolyl)imidazo[1,2-a]pyridin-3-yl)sulfane (3i). puri-
fied by preparative TLC on silica gel with petroleum
ether/EtOAc (1:1) as an eluent (Rf = 0.30); Light yellow
o
Light yellow solid (46.0 mg, 87% yield); mp 267 – 268 C.
1H NMR (600 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 4H), 7.63
(d, J = 7.8 Hz, 4H), 7.54 (d, J = 6.5 Hz, 2H), 7.48 (d, J = 8.8
Hz, 2H), 7.07 (t, J = 7.8 Hz, 2H), 6.27 (t, J = 6.5 Hz, 2H),
13
1.46 (s, 18H). C{1H} NMR (101 MHz, CDCl3) δ 152.1, 150.9,
146.5, 130.9, 129.3, 126.2, 125.5, 125.4, 117.3, 112.3, 107.7, 34.9,
31.5. HRMS (positive ESI): [M + H]+ Calcd. For C34H34N4S+:
531.2577, Found: 531.2582.
o
1
Bis(2-(4-ethylphenyl)imidazo[1,2-a]pyridin-3-yl)sulfane
(3d). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.25); Light yel-
solid (32.7 mg, 73% yield); mp 172 – 173 C. H NMR (400
MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 2H), 7.89 (s, 2H), 7.58
(d, J = 6.8 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 7.6
Hz, 2H), 7.12 – 7.07 (m, 2H), 6.36 (td, J = 6.9, 1.0 Hz, 2H),
2.52 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 151.0, 146.5,
138.3, 133.7, 130.1, 129.7, 128.5, 126.7, 126.3, 125.5, 117.3, 112.5,
o
1
low solid (26.0 mg, 55% yield); mp 209 – 210 C. H NMR
(400 MHz, CDCl3) δ 8.03 (d, J = 8.3 Hz, 4H), 7.58 (d, J =
6.9 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.0 Hz,
4H), 7.10 – 7.06 (m, 2H), 6.32 (td, J = 6.8, 1.1 Hz, 2H), 2.82
6
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HRMS (positive ESI): [M + H]+ Calcd. For C34H22N4S+:
107.4, 21.6. HRMS (positive ESI): [M + H]+ Calcd. For
C28H22N4S+: 447.1638, Found: 447.1641.
519.1638, Found: 519.1643.
1
2
3
4
Bis(2-(2-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)sulfane
(3j). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (3:1) as an eluent (Rf = 0.53); Light yel-
Bis(6-methoxy-2-phenylimidazo[1,2-a]pyridin-3-yl)sulfane
(3o) purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.42); Brown
solid (30.0 mg, 63% yield); mp 264 – 265 oC. 1H NMR (400
MHz, CDCl3) δ 8.50 (dd, J = 8.5, 1.3 Hz, 4H), 7.59 (t, J = 7.5,
4H), 7.47 – 7.41 (m, 6H), 6.90 (dd, J = 9.7, 2.5 Hz, 2H),
o
1
5
6
7
8
low solid (35.3 mg, 74% yield); mp 195 – 196 C. H NMR
(400 MHz, CDCl3) δ 7.56 – 7.49 (m, 8H), 7.19 – 7.08 (m,
6H), 6.45 – 6.41 (m, 2H), 3.84 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 157.5, 148.4, 146.4, 132.6, 130.6, 125.7, 124.9,
123.1, 120.6, 117.4, 112.2, 111.3, 109.9, 55.6. HRMS (positive
ESI):[M + H]+ Calcd. For C28H22N4O2S+: 479.1536, Found:
479.1541.
13
2.88 (s, 6H). C{1H} NMR (101 MHz, CDCl3) δ 149.9, 149.1,
143.5, 134.0, 128.9, 128.8, 128.8, 122.1, 117.6, 106.6, 106.1, 54.8.
HRMS (positive ESI): [M + H]+ Calcd. For C28H22N4O2S+:
479.1536, Found: 479.1537.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bis(2-(o-tolyl)imidazo[1,2-a]pyridin-3-yl)sulfane (3k). puri-
fied by preparative TLC on silica gel with petroleum
ether/EtOAc (1:1) as an eluent (Rf = 0.40); Light yellow
solid (36 mg, 81% yield); mp 202 – 203 C. H NMR (600
MHz, CDCl3) δ 7.50 (d, J = 8.6 Hz, 2H), 7.47 – 7.44 (m, 4H),
7.40 – 7.35 (m, 6H), 7.16 (t, J = 7.5 Hz, 2H), 6.45 (t, J = 6.7
Hz, 2H), 2.25 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ
151.9, 146.2, 137.9, 133.4, 131.8, 130.5, 129.0, 126.1, 125.5, 124.9,
117.2, 112.5, 109.5, 20.3. HRMS (positive ESI): [M + H]+
Calcd. For C28H22N4S+: 447.1638, Found: 447.1642.
Bis(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)sulfane
(3p). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.33); Light yel-
low solid (38.1 mg, 86% yield); mp 285 – 286 C. H NMR
(400 MHz, CDCl3) δ 8.18 – 8.16 (m, 4H), 7.65 – 7.61 (m,
4H), 7.57 – 7.53 (m, 2H), 7.41 – 7.37 (m, 4H), 6.93 (dd, J =
9.1, 1.6 Hz, 2H), 1.74 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3)
δ 150.3, 145.5, 134.1, 129.5, 129.4, 128.8, 123.7, 122.5, 116.5,
106.8, 17.8. HRMS (positive ESI): [M + H]+ Calcd. For
C28H22N4S+: 447.1638, Found: 447.1640.
o
1
o
1
Bis(2-(2-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)sulfane
(3l). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (2:1) as an eluent (Rf = 0.33); Light yel-
Bis(7-methoxy-2-phenylimidazo[1,2-a]pyridin-3-yl)sulfane
(3q). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.39); Light yel-
o
1
o
1
low solid (22.0 mg, 48% yield); mp 243 – 244 C. H NMR
(400 MHz, CDCl3) δ 7.70 (td, J = 7.4, 1.7 Hz, 2H), 7.60 –
7.51 (m, 6H), 7.40 – 7.33 (m, 4H), 7.17 – 7.13 (m, 2H), 6.47
(td, J = 6.9, 1.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
160.2 (JC-F = 250.1 Hz), 146.8, 146.2, 132.7, (JC-F = 2.4 Hz),
131.0 (JC-F = 8.2 Hz), 126.4, 124.6, 124.3, (JC-F = 3.6 Hz), 122.0
(JC-F = 13.9 Hz), 117.7, 116.3 (JC-F = 22.0 Hz), 112.8, 109.6. 19F
NMR (376 MHz, CDCl3) δ -113.04. HRMS (positive ESI): [M
+ H]+Calcd. For C26H16F2N4S+: 455.1137, Found: 455.1142.
Bis(2-(2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-
yl)sulfane (3m). purified by preparative TLC on silica gel
with petroleum ether/EtOAc (2:1) as an eluent (Rf = 0.25);
low solid (27.3 mg, 57% yield); mp 272 – 273 C. H NMR
(400 MHz, CDCl3) δ 8.52 – 8.49 (m, 4H), 7.60 – 7.57 (m,
4H), 7.47 – 7.41 (m, 6H), 6.89 (dd, J = 9.5, 2.4 Hz, 2H),
13
2.88 (s, 6H). C{1H} NMR (101 MHz, CDCl3) δ 149.9, 149.1,
143.5, 134.0, 128.9, 128.8, 128.8, 122.1, 117.6, 106.6, 106.1, 54.8.
HRMS (positive ESI): [M + H]+ Calcd. For C28H22N4O2S+:
479.1536, Found: 479.1537.
Bis(7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)sulfane
(3r). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.43); Yellow
1
solid (20.0 mg, 45% yield); mp 197 – 198 oC. H NMR (400
MHz, CDCl3) δ 8.11-8.09 (m, 4H), 7.63 – 7.59 (m, 4H), 7.56
– 7.52 (m, 2H), 7.40 (d, J = 7.0 Hz, 2H), 7.24 (s, 2H), 6.18
(dd, J = 7.0, 1.6 Hz, 2H), 2.26 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 150.7, 146.9, 137.7, 133.9, 129.5, 128.8, 128.6,
124.6, 115.9, 115.2, 106.8, 21.3. HRMS (positive ESI): [M +
H]+ Calcd. For C28H22N4S+: 447.1638, Found: 447.1641.
o
1
Yellow solid (36.4 mg, 80% yield); mp 232 – 233 C. H
NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.7 Hz, 2H), 7.62 (t, J
= 7.5 Hz, 2H), 7.57 – 7.53 (m, 4H), 7.43 (d, J = 6.9 Hz, 2H),
7.32 (d, J = 7.5 Hz, 2H), 7.20 – 7.16 (m, 2H), 6.46 (td, J =
6.8, 0.9 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.2,
145.6, 133.2, 132.9, 131.2,130.4 ( JC-F = 30.0 Hz), 129.0,
126.6( JC-F = 5.2 Hz), 126.0, 124.1, 123.6 ( JC-F = 274.7 Hz),
117.6, 112.7, 110.9. 19F NMR (376 MHz, CDCl3) δ -58.70.
HRMS (positive ESI): [M + H]+ Calcd. For C28H16F6N4S+:
555.1073, Found: 555.1076.
Dimethyl
3,3'-thiobis(2-phenylimidazo[1,2-a]pyridine-7-
carboxylate) (3s). purified by preparative TLC on silica gel
with petroleum ether/EtOAc (1:1) as an eluent (Rf = 0.60);
o
Light yellow solid (12.0 mg, 23% yield); mp 208 – 209 C.
1H NMR (400 MHz, CDCl3) δ 8.20 – 8.21 (m, 2H), 8.09 (dd,
J = 8.2, 1.7 Hz, 4H), 7.67 – 7.62 (m, 6H), 7.54 (dd, J = 7.2,
0.7 Hz, 2H), 6.94 (dd, J = 7.1, 1.6 Hz, 2H), 3.90 (s, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 165.2, 153.0, 145.6, 133.1,
129.6, 129.5, 128.9, 127.9, 124.9, 119.9, 111.9, 109.0, 52.7
HRMS (positive ESI): [M + H]+ Calcd. For C30H22N4O4S+:
535.1435, Found: 535.1440.
Bis(2-(naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)sulfane
(3n). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.30); yellow
o
1
solid (7.2 mg, 14% yield); mp 264 – 265 C. H NMR (400
MHz, CDCl3) δ 8.64 (s, 2H), 8.30 (dd, J = 8.5, 1.7 Hz, 2H),
8.10 (d, J = 8.5 Hz, 2H), 8.06 – 8.03 (m, 2H), 8.01 – 7.98 (m,
2H), 7.62 – 7.57 (m, 6H), 7.51 (d, J = 8.9 Hz, 2H), 7.08 –
7.03 (m, 2H), 6.16 (td, J = 6.9, 1.0 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 150.8, 146.7, 133.5, 133.3, 131.2, 128.9, 128.7,
128.3, 127.9, 126.9, 126.8, 126.6, 126.5, 125.3, 117.4, 112.7, 107.3.
Bis(8-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)sulfane
(3t). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.50); Brown
o
1
solid (34 mg, 76% yield); mp 216 – 217 C. H NMR (400
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MHz, CDCl3) δ 8.09 – 8.07 (m, 4H), 7.62 – 7.58 (m, 4H), Bis(2-(imidazo[1,2-a]pyridin-2-yl)phenyl)sulfane (5a). puri-
1
2
3
4
5
6
7
8
7.55 – 7.51 (m, 2H), 7.41 (d, J = 6.7 Hz, 2H), 6.86 (d, J = 6.9
fied by preparative TLC on silica gel with petroleum
ether/EtOAc (1:1) as an eluent (Rf = 0.21); Brown solid
(37.3 mg, 89% yield); mp 165 – 166 oC. 1H NMR (400 MHz,
CDCl3) δ 8.18 (dd, J = 7.9, 1.3 Hz, 2H), 8.06 (s, 2H), 8.01 (dd,
J = 5.8, 0.9 Hz, 2H), 7.59 (dd, J = 9.2, 0.6 Hz, 2H), 7.36 (td,
J = 7.8, 1.4 Hz, 2H), 7.30 – 7.27 (m, 2H), 7.22 – 7.18 (m, 2H),
7.13 – 7.09 (m, 2H), 6.69 (td, J = 6.8, 1.1 Hz, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 144.6, 143.0, 135.3, 133.2, 132.7,
130.8, 128.5, 127.6, 125.9, 124.7, 117.4, 112.3, 112.3. HRMS
(positive ESI): [M + H]+ Calcd. For C26H18N4S+: 419.1325,
Found: 419.1330.
13
Hz, 2H), 6.25 (t, J = 6.9 Hz, 2H), 2.51 (s, 6H). C{1H} NMR
(151 MHz, CDCl3) δ 150.5, 146.8, 134.2, 129.8, 128.7, 128.5,
127.3, 125.1, 123.2, 112.5, 107.9, 16.7. HRMS (positive ESI): [M
+ H]+ Calcd. For C28H22N4S+: 447.1638, Found: 447.1642.
Bis(6-fluoro-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)sulfane
(3u). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.51); Light yel-
o
1
low solid (27.3 mg, 57% yield); mp 272 – 273 C. H NMR
(600 MHz, CDCl3) δ 7.91 (d, J = 7.4 Hz, 4H), 7.46 – 7.39 (m,
8H), 7.00 (t, J = 7.9 Hz, 2H), 2.52 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 153.1 (JC-F = 238.9 Hz), 152.4 (JC-F = 2.4 Hz),
144.1, 139.4, 130.4, 129.4 (JC-F = 21.9 Hz), 118.2 (JC-F = 25.2 Hz),
117.6 (JC-F = 8.4 Hz), 112.8, 112.4, 108.9, 21.4.19F NMR (376
MHz, CDCl3) δ -138.14. HRMS (positive ESI): [M + H]+
Calcd. For C28H20F2N4S+: 483.1450, Found: 483.1451.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bis(2-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl)sulfane
(5b). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:2) as an eluent (Rf = 0.20); Light yel-
o
1
low solid (33.2 mg, 74% yield); mp 72 – 73 C. H NMR
(400 MHz, CDCl3) δ 8.8 (dd, J = 7.8, 1.3 Hz, 2H), 7.98 (s,
2H), 7.79 (s, 2H), 7.50 (d, J = 9.2 Hz, 2H), 7.38 – 7.34 (m,
2H), 7.29 – 7.27 (m, 2H), 7.22 – 7,17 (m, 2H), 6.98 (dd, J =
9.2, 1.5 Hz, 2H), 2.25 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 143.6, 142.6, 135.5, 133.0, 132.7, 130.7, 128.3, 127.9, 127.6,
123.6, 121.8, 116.6, 112.2, 18.1. HRMS (positive ESI): [M + H]+
Calcd. For C28H22N4S+: 447.1638, Found: 447.1643.
Bis(2-(furan-2-yl)imidazo[1,2-a]pyridin-3-yl)sulfane
(3v).
purified by preparative TLC on silica gel with petroleum
ether/EtOAc (3:1) as an eluent (Rf = 0.34); Light Brown
o
solid (25.2 mg, 63% yield); mp 235 – 236 C. 1H NMR (600
MHz, CDCl3) δ 8.18 (d, J = 6.9 Hz, 2H), 7.72 (s, 2H), 7.54 (d,
J = 9.1 Hz, 2H), 7.38 (d, J = 2.9 Hz, 2H), 7.16 (t, J = 7.6 Hz,
2H), 6.69 (s, 2H), 6.64 (t, J = 6.9 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 148.4, 147.0, 143.4, 141.8, 126.7, 125.0, 117.5,
113.3, 111.8, 110.7, 104.6. HRMS (positive ESI): [M + H]+
Calcd. For C22H14N4O2S+: 399.0910, Found: 399.0913.
Bis(2-(7-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl)sulfane.
(5c). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:2) as an eluent (Rf = 0.21); Light yel-
o
1
low solid (30.0 mg, 63% yield); mp 85 – 86 C. H NMR
(600 MHz, CDCl3) δ 8.18 (d, J = 7.9 Hz, 2H), 7.93 (s, 2H),
7.85 (d, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.27 (d, J =
7.5 Hz, 1H), 7.20 – 7.18 (m, 2H), 6.88 (s, 2H), 6.45 (dd, J =
7.4, 2.2 Hz, 2H), 3.84 (s, 6H). 13C{1H} NMR (151 MHz,
CDCl3) δ 158.0, 146.0, 142.4, 135.3, 132.9, 132.7, 130.5, 128.2,
127.6, 126.3, 111.3, 107.5, 94.4, 55.5. HRMS (positive ESI): [M
+ H]+ Calcd. For C28H22N4O2S+: 479.1536, Found: 479.1541.
Bis(2-(7-methylimidazo[1,2-a]pyridin-2-yl)phenyl)sulfane
(5d). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:2) as an eluent (Rf = 0.20); Light yel-
low solid (38.0 mg, 75% yield; 0.42 g, 42% yield for scale-
up synthesis); mp 76 – 77 oC. 1H NMR (400 MHz, CDCl3) δ
8.17 (dd, J = 7.9, 1.4 Hz, 2H), 7.99 (s, 2H), 7.91 (d, J = 6.9,
2H), 7.37 – 7.33 (m, 4H), 7.29 – 7.26 (m, 2H), 7.21 – 7.17 (m,
2H), 6.55 (dd, J = 6.9, 1.5 Hz, 2H), 2.37 (s, 6H).13C{1H} NMR
(101 MHz, CDCl3) δ 145.0, 142.6, 135.6, 135.5, 133.1, 132.7,
130.7, 128.3, 127.6, 125.1, 115.7, 114.9, 111.8, 21.4. HRMS (posi-
tive ESI): [M + H]+ Calcd. For C28H22N4S+: 447.1638, Found:
447.1644.
Bis(2-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)sulfane
(3w). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (1:1) as an eluent (Rf = 0.38); Light yel-
o
1
low solid (32.1 mg, 75% yield); mp 217 – 218 C. H NMR
(600 MHz, CDCl3) δ 8.15 (d, J = 1.5 Hz, 2H), 7.93 (d, J = 6.7
Hz, 2H), 7.55 (d, J = 4.8 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H),
7.29 (s, 2H), 7.13 (t, J = 7.8 Hz, 2H), 6.54 (t, J = 6.6 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 146.8, 145.2, 136.5, 127.9,
127.4, 126.7, 125.2, 117.3, 113.2, 104.5. HRMS (positive ESI):
[M + H]+ Calcd. For C22H14N4S3+: 431.0453, Found: 431.0458.
Bis(6-phenylimidazo[2,1-b]thiazol-5-yl)sulfane (3x). puri-
fied by preparative TLC on silica gel with petroleum
ether/EtOAc (1:1) as an eluent (Rf = 0.55); Light yellow
solid (17.0 mg, 40% yield); mp 228 – 229 oC. 1H NMR (400
MHz, CDCl3) δ 8.08 – 8.05 (m, 4H), 7.56 – 7.53 (m, 4H),
7.49 – 7.45 (m, 2H), 6.51 (d, J = 4.5 Hz, 2H), 6.49 (dd, J =
4.5 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 151.4, 151.3,
133.6, 128.6, 128.6, 128.5, 118.4, 112.6, 109.5. HRMS (positive
ESI): [M + H]+ Calcd. For C22H14N4S3+: 431.0453, Found:
431.0456.
Bis(imidazo[1,2-a]pyridin-3-yl)sulfane (3y). purified by
preparative TLC on silica gel with petroleum ether/EtOAc
(1:3) as an eluent (Rf = 0.24); Light yellow solid (12.6 mg,
48% yield); mp 258 – 259 oC. 1H NMR (600 MHz, CDCl3) δ
8.58 (d, J = 6.9 Hz, 2H), 7.99 (s, 2H), 7.62 (d, J = 9.0 Hz,
2H), 7.27 (t, J = 7.8 Hz, 2H), 6.97 (t, J = 6.6 Hz, 2H). 13C{1H}
NMR (151 MHz, CDCl3) δ 147.6, 140.4, 126.0, 123.9, 118.2,
113.4, 109.7. HRMS (positive ESI): [M + H]+ Calcd. For
C14H10N4S+: 267.0699, Found: 267.0700.
Bis(2-(7-chloroimidazo[1,2-a]pyridin-2-yl)phenyl)sulfane
(5e). purified by preparative TLC on silica gel with petro-
leum ether/EtOAc (3:1) as an eluent (Rf = 0.30); Brown
solid (37.2 mg, 77% yield); mp 203 – 204 oC. 1H NMR (600
MHz, CDCl3) δ 8.12 (d, J = 7.8 Hz, 2H), 8.10 (s, 2H), 8.00 (s,
2H), 7.56 (d, J = 9.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.29
(d, J = 7.9 Hz, 2H), 7.23 (t, J = 7.5 Hz, 2H), 7.12 (d, J = 9.5
Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 144.0, 142.9,
134.9, 133.2, 132.9, 130.8, 128.8, 127.8, 126.2, 123.6, 120.5, 117.8,
112.7. HRMS (positive ESI): [M
+
H]+ Calcd. For
C26H16Cl2N4S+: 487.0545, Found: 487.0550.
8
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2H), 7.19 – 7.16 (m, 2H), 6.79 (d, J = 4.5 Hz, 2H). 13C{1H}
bis(2-(imidazo[1,2-a]pyridin-2-yl)-5-
1
methoxyphenyl)sulfane.(5f) purified by preparative TLC
on silica gel with petroleum ether/EtOAc (1:1) as an eluent
(Rf = 0.21); Light yellow solid (40.0 mg, 84% yield); mp 196
NMR (151 MHz, CDCl3) δ 149.2, 144.9, 135.5, 132.6, 132.2,
130.1, 128.0, 127.6, 118.7, 112.5, 112.4. HRMS (positive ESI):
[M + H]+ Calcd. For C22H14N4S3+: 431.0453, Found:
431.0454.
2
3
4
– 197 C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.9, Hz,
o
5
6
7
8
2H), 8.02 – 8.00 (m, 4H), 7.59 (d, J = 9.1 Hz, 2H), 7.14 –
7.09 (m, 2H), 6.92 (dt, J = 8.6, 2.6 Hz, 2H), 6.85 (d, J = 2.6
Bis(2-(imidazo[1,2-b]quinolin-2-yl)phenyl)sulfane
(5k).
purified by preparative TLC on silica gel with petroleum
ether/EtOAc (1:2) as an eluent (Rf = 0.48); Brown solid
(33.2 mg, 64% yield); mp 209 – 210 oC. 1H NMR (600 MHz,
CDCl3) δ 8.57 (s, 2H), 8.27 (d, J = 7.0 Hz, 2H), 7.74 (d, J =
7.9 Hz, 2H), 7.70 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 8.9 Hz,
2H), 7.49 (t, J = 7.2 Hz, 2H), 7.44 (d, J = 9.4 Hz, 2H), 7.39 –
7.35 (m, 6H), 7.24 (d, J = 7.2 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 143.0, 142.1, 135.2, 133.0, 132.8, 132.6, 130.6,
128.9, 128.8, 128.3, 127.8, 126.4, 124.6, 123.3, 116.9, 115.4, 111.2.
HRMS (positive ESI): [M + H]+ Calcd. For C34H22N4S+:
519.1638, Found: 519.1643.
Bis(2-(pyridin-2-yl)phenyl)sulfane. (5l). purified by prepar-
ative TLC on silica gel with petroleum ether/EtOAc (1:1)
as an eluent (Rf = 0.43); Light yellow solid (32.4 mg, 95%
yield); mp 77 – 78 oC. 1H NMR (400 MHz, CDCl3) δ 8.58 –
8.57 (m, 2H), 7.54 (td, J = 7.7, 1.8 Hz, 2H), 7.45 (dd, J = 7.5,
1.7 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.29 – 7.25 (m, 2H),
7.24 – 7.17 (m, 4H), 7.13 – 7.09 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 158.0, 149.0, 142.0, 135.7, 135.1, 132.9, 130.4,
129.0, 127.1, 124.1, 121.9. HRMS (positive ESI): [M + H]+
Calcd. For C22H16N2S+: 341.1107, Found: 341.1111.
13
Hz, 2H), 6.69 (td, J = 7.5, 0.7 Hz, 2H), 3.71 (s, 6H). C{1H}
NMR (101 MHz, CDCl3) δ 159.5, 144.5, 142.9, 133.9, 131.9,
128.0, 125.8, 124.6, 117.6, 117.2, 113.7, 112.1, 111.6, 55.3. HRMS
(positive ESI): [M + H]+ Calcd. For C28H22N4O2S+: 479.1536,
Found: 479.1548.
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34
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bis(5-fluoro-2-(imidazo[1,2-a]pyridin-2-
yl)phenyl)sulfane.(5g) purified by preparative TLC on sili-
ca gel with petroleum ether/EtOAc (1:1) as an eluent (Rf =
0.20); Light yellow solid (37.0 mg, 82% yield); mp 139 –
o
1
140 C. H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 8.4, 6.1
Hz, 2H), 8.05 (d, J = 6.58 Hz, 2H), 8.00 (s, 2H), 7.60 (d, J =
9.3 Hz, 2H), 7.16 (ddd, J = 7.9, 6.7, 1.0 Hz, 2H), 7.00 (td, J =
9.1, 2.6 Hz, 2H), 7.00 (dd, J = 9.1, 2.6 Hz, 2H), 6.76 – 6.63
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.3 (JC-F
=
247.8 Hz), 144.6, 142.1, 134.5 (JC-F = 7.3 Hz), 132.5 (JC-F = 8.7
Hz), 131.6 (JC-F = 3.1 Hz), 125.9, 124.9, 119.1 (JC-F = 23.8 Hz),
117.4, 115.2 (JC-F = 21.5 Hz), 112.5, 111.9. 19F NMR (376 MHz,
CDCl3) δ -112.73. HRMS (positive ESI): [M + H]+ Calcd. For
C26H16F2N4S+: 455.1137, Found: 455.1147.
bis(5-chloro-2-(imidazo[1,2-a]pyridin-2-
1
1,3-Diphenylthiourea (6). White solid (23.4 mg, 68%). H
yl)phenyl)sulfane.(5h) purified by preparative TLC on sili-
ca gel with petroleum ether/EtOAc (1:1) as an eluent (Rf =
0.25); Light yellow solid (42.0 mg, 86% yield); mp 213 – 214
NMR (600 MHz, DMSO) δ 9.27 (d, J = 9.3 Hz, 2H), 7.47 (d,
J = 7.6 Hz, 4H), 7.27 (t, J = 7.6 Hz, 4H), 6.95 (td, J = 7.3, 0.8
Hz, 2H).13C{1H} NMR (101 MHz, DMSO) δ 152.5, 139.7,
128.7, 121.8, 118.2.
1
oC. H NMR (400 MHz, CDCl3) δ 8.13 (t, J = 8.4 Hz, 2H),
8.05 – 8.04 (m, 4H), 7.60 (t, J = 9.1 Hz, 2H), 7.35 (dd, J =
8.4, 2.1 Hz, 2H), 7.25 (d, J = 2.1, 2H), 7.18 – 7.14 (m, 2H),
6.74 (td, J = 6.8, 0.9 Hz, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 144.7, 141.9, 134.2, 134.0, 133.9, 132.0, 128.2, 125.9,
125.1, 117.5, 112.5, 112.3. HRMS (positive ESI): [M + H]+
Calcd. For C26H16Cl2N4S+: 487.0545, Found: 487.0551.
bis(4-fluoro-2-(imidazo[1,2-a]pyridin-2-
3-Iodo-2-phenylimidazo[1,2-a]pyridine (7). Yellow solid
1
(10.4 mg, 16%). H NMR (600 MHz, CDCl3) δ 8.21 (d, J =
6.9 Hz, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 9.0 Hz, 1H),
7.48 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.26 – 7.23
(m, 1H), 6.90 (t, J = 6.9 Hz, 1H). 13C{1H} NMR (151 MHz,
CDCl3) δ 148.2, 148.1, 133.6, 128.6, 128.4, 128.4, 126.5, 125.5,
117.6, 113.2, 59.5.
yl)phenyl)sulfane.(5i) purified by preparative TLC on silica
gel with petroleum ether/EtOAc (1:1) as an eluent (Rf =
0.31); Light yellow solid (15.0 mg, 33% yield); mp 202 – 203
ASSOCIATED CONTENT
Supporting Information
1
oC. H NMR (400 MHz, CDCl3) δ 8.11 (s, 2H), 8.05 (d, J =
6.7 Hz, 2H), 7.96 (dd, J = 10.2, 2.9 Hz, 2H), 7.61 (d, J = 9.3,
2H), 7.27 – 7.22 (m, 2H), 7.20 – 7.15 (m, 2H), 6.93 (td, J =
7.8, 2,9 Hz, 2H), 6.75 (td, J = 6.7, 0.8 Hz, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 162.3 (JC-F = 249.2 Hz), 144.6, 141.9,
137.4 (JC-F = 8.6 Hz), 134.5 (JC-F = 7.7 Hz), 128.0 (JC-F = 3.0
Hz), 126.0, 125.2, 117.5, 117.4(JC-F = 24.0 Hz), 115.7 (JC-F = 22.0
Hz), 112.6, 112.6. 19F NMR (376 MHz, CDCl3) δ -114.07.
HRMS (positive ESI): [M + H]+ Calcd. For C26H16F2N4S+:
455.1137, Found: 455.1148.
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and spectra data for 3 and 5 (PDF)
Singly-crystal X-ray diffraction data for compounds 3a and 5a
(CIF)
AUTHOR INFORMATION
Corresponding Author
Bis(2-(imidazo[2,1-b]thiazol-6-yl)phenyl)sulfane (5j). puri-
fied by preparative TLC on silica gel with petroleum
ether/EtOAc (1:2) as an eluent (Rf = 0.25); Light yellow
Email: zhuxinju@zzu.edu.cn
Email: mpsong@zzu.edu.cn
Notes
o
1
The authors declare no competing financial interest.
solid (23.0 mg, 53% yield); mp 230 – 231 C. H NMR (600
MHz, CDCl3) δ 8.10 (dd, J = 7.8, 1.0 Hz, 2H), 7.97 (s, 2H),
7.37 (d, J = 4.3 Hz, 2H), 7.35 – 7.33 (m, 2H), 7.25 – 7.24 (m,
ACKNOWLEDGMENT
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Page 10 of 12
Financial support from the National Natural Science Founda-
P.; Koeller, J.; Ackermann, L. Expedient C-H Chalcogena-
1
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3
4
5
6
7
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tion of China (Grant Nos. 21672192 and 21803059), the China
Postdoctoral Science Foundation (Grant Nos. 2016M602254
and 2016M600582), the Program for Science & Technology
Innovation Talents in Universities of Henan Province (Grant
No. 17HASTIT004), the Aid Project for the Leading Young
Teachers in Henan Provincial Institutions (Grant No.
2015GGJS-157), and the Natural Science Foundation of Henan
Province (Grant No. 182300410255) is gratefully appreciated.
tion of Indolines and Indoles by Positional-Selective Cop-
per Catalysis. ACS Catal. 2017, 7, 1030-1034. (j) Sun, P.;
Yang, D.; Wei, W.; Jiang, M.; Wang, Z.; Zhang, L.; Zhang,
H.; Zhang, Z.; Wang, Y.; Wang, H. Visible Light-Induced
C–H Sulfenylation using Sulfinic Acids. Green Chem. 2017,
19, 4785-4791. (k) Dou, Y.; Huang, X.; Wang, H.; Yang, L.;
Li, H.; Yuan, B.; Yang, G. Reusable Ccobalt-
Phthalocyanine in Water: Efficient Catalytic Aerobic Oxi-
dative Coupling of Thiols to Construct S-N/S-S Bonds.
Green Chem. 2017, 19, 2491-2495. (l) Guin, S.; Deb, A.; Do-
lui, P.; Chakraborty, S.; Singh, V. K.; Maiti, D. Promoting
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