Sulfite-Promoted C-H Fluoroalkyl Sulfuration of Imidazoheterocycles with Bromofluoroacetate and Elemental Sulfur

Article abstract of DOI:10.1055/s-0040-1707120

A transition-metal-free sulfite-promoted three-component C-H sulfuration between imidazoheterocycles, elemental sulfur, and bromofluoroacetate is developed. Sulfites, including Na ₂S ₂O ₄, NaHSO ₃, and Na ₂S ₂O ₃, are able to promote the formation of two C-S bonds in one step using elemental sulfur as a green sulfurating agent, allowing the rapid introduction of the synthetically useful S-fluoroacetate group into imidazoheterocycles. These new imidazoheterocycle derivatives bearing an S-fluoroacetate group can be easily modified to produce pharmaceutically attractive compounds.

Full text of DOI:10.1055/s-0040-1707120

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–J
paper
A
en
Y.-C. Gao et al.
Paper
Synthesis
Sulfite-Promoted C–H Fluoroalkyl Sulfuration of Imidazohetero-
cycles with Bromofluoroacetate and Elemental Sulfur
Yong-Chao Gaoa
N
N
N
Br
Na2S2O3
Ar
R
Ar
Het
R
NH2
Het
Zi-Hao Huanga
Zhao-Sheng Zhangb
Jin-Xin Xiea
Zi-Ning Cui*b,c
Ri-Yuan Tang*a,c
N
Ar
Het
S
+
N
+
N
F
CO2Et
S
S
H
F
F
transition-metal-free
C–H sulfuration
CO2Et
N
O
H
using inexpensive and safe sulfur agents
synthetically and pharmaceutically useful molecules
24 examples
up to 91% yield
3 examples
up to 80% yield
0
0
0
0-0
0
0
2-
5
7
6
4-8
8
5
8
a Department of Applied Chemistry, College of Materials and
Energy, South China Agricultural University, Guangzhou
510642, P. R. of China
rytang@scau.edu.cn
b State Key Laboratory for Conservation and Utilization of
Subtropical Agro-bioresources, Integrative Microbiology
Research Centre, Guangdong Province Key Laboratory of
Microbial Signals and Disease Control, South China Agricultural
University, Guangzhou 510642, P. R. of China
ziningcui@scau.edu.cn
c Lingnan Guangdong Laboratory of Modern Agriculture,
Guangzhou 510642, P. R. of China
Received: 05.03.2020
Accepted after revision: 22.04.2020
Published online: 18.05.2020
range of bioactivity.10 For example, the C–H sulfuration of
imidazopyridines using elemental sulfur by coupling with
aryl halides or boric acids has been extensively studied.8
However, the introduction of functionalized alkyl groups
into imidazopyridines via C–H sulfuration using elemental
sulfur has not been widely reported.9a–c
DOI: 10.1055/s-0040-1707120; Art ID: ss-2020-g0126-op
Abstract A transition-metal-free sulfite-promoted three-component
C–H sulfuration between imidazoheterocycles, elemental sulfur, and
bromofluoroacetate is developed. Sulfites, including Na2S2O4, NaHSO3,
and Na2S2O3, are able to promote the formation of two C–S bonds in
one step using elemental sulfur as a green sulfurating agent, allowing
the rapid introduction of the synthetically useful S-fluoroacetate group
into imidazoheterocycles. These new imidazoheterocycle derivatives
bearing an S-fluoroacetate group can be easily modified to produce
pharmaceutically attractive compounds.
In 2017, we developed an oxidative dual C–H sulfuriza-
tion of imidazopyridines with alkanes and ethers using ele-
mental sulfur.9a However, the scope and functionality of the
alkyl groups was limited. In order to improve the diversity
and functionality of alkylthio substituents on imidazohet-
erocycles, we employed functionalized haloalkanes and di-
alkyl azo substrates as alkyl sources to prepare a wide range
of alkylthio-containing imidazoheterocycles.9b,c However,
the incorporation of fluoroacetate groups into imidazopyri-
dines was unsuccessful using these alkyl sulfuration strate-
gies. The presence of fluorine- and sulfur-containing
groups in a molecule can have a profound impact on its
physical, chemical, and biological properties.11 Thus, effi-
cient and simple methods for the introduction of a fluoro-
acetate group into imidazopyridines via sulfuration are
highly desired. Very recently, we found that sulfite was able
to promote the N-fluoroalkylation of imidazole derivatives
with bromofluoroacetate or 2-bromo-2,2-difluoroacetate,
enabling access to a wide range of N-fluoroalkylimidazole
and N-difluoromethylimidazole thioketones (Scheme 1, eq
1).12 Based on these results, we envisioned that sulfite may
promote the C–H sulfuration between imidazoheterocycles,
elemental sulfur and bromofluoroacetate. In continuation
of our research concerning the C–H sulfuration of heterocy-
cles,9,12,13 we herein report a sulfite-promoted transition-
Key words sulfites, sulfides, elemental sulfur, C–H functionalization,
imidazoles
Sulfur-containing compounds have been widely used in
numerous medicines and agrochemicals.1,2 Incorporation of
sulfur-containing functional groups into bioactive mole-
cules is an effective method for the development of new
drugs and pesticides.1,2 Therefore, the development of sim-
ple and environmentally benign synthetic methods for the
preparation of sulfur-containing organic compounds has
received considerable attention.3 In recent years, nontoxic
and stable elemental sulfur has been used as an ideal sulfur
source for the construction of sulfur-containing com-
pounds.4 The sulfuration of C–H bonds using elemental sul-
fur is a straightforward and atom-economic strategy for the
coupling of functional groups with pharmaceutically useful
molecules via C–S bonds.5–9 Increasing attention has been
devoted to the C–H sulfuration of indoles7 and imidazohet-
erocycles,8,9 because these heterocycles possess a diverse
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y.-C. Gao et al.
Paper
Synthesis
metal-free C–H fluoroalkyl sulfuration between imidazo-
heterocycles, bromofluoroacetate, and elemental sulfur
(Scheme 1, eq 2).
Table 1 Optimization of the Reaction Conditionsa
N
N
Br
Ph
Ph
+
+
S
N
N
F
CO2Et
2a
F
S
H
Previous work
CO2Et
3
F
F
F
1a
F
F
CO2Et
(1)
F
N
N
Br
CO2Et
sulfite
N
N
Br
CO2Et
S
+
Entry
Sulfite (equiv)
Solvent
Temp (°C) Yield (%)
S
S
sulfite
N
N
1
2
HOCH2SO2Na (2)
Na2S2O4 (2)
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
120
120
120
120
120
120
120
120
120
120
140
100
80
16
50
64
65
5
This work: sulfite-promoted C–H sulfuration
N
Br
N
Na2S2O3
Ph
3
NaHSO3 (2)
Ph
(2)
S
+
+
N
N
F
CO2Et
4
Na2S2O3 (2)
–
H
S
F
5
CO2Et
6
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (1)
Na2S2O3 (3)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O3 (2)
Na2S2O4 (2)
NaHSO3 (2)
trace
0
Scheme 1 Sulfite-promoted synthesis of sulfur-containing compounds
7
CH2Cl2
Our studies began with the three-component sulfura-
tion of imidazopyridine 1a with elemental sulfur and ethyl
bromofluoroacetate (2a). Based on our previous work,12 dif-
ferent sulfites, including HOCH2SO2Na, Na2S2O4, NaHSO3,
and Na2S2O3, were used to examine the reaction in dioxane
at 120 °C (Table 1, entries 1–4). All of these sulfites proved
to be effective. HOCH2SO2Na gave the target product 3 in
16% yield (entry 1), Na2S2O4 and NaHSO3 afforded product 3
in moderate yields (entries 2 and 3), whilst Na2S2O3, a com-
mon medical antidote, was found to be the most efficient
agent for this transformation, giving product 3 in 65% yield
(entry 4). In the absence of sulfite, product 3 was obtained
in only 5% yield (entry 5), which proves the necessity of sul-
fite for an efficient transformation. Next, the solvent effect
was examined. Both DCE and CH2Cl2 were unsuitable sol-
vents for this reaction (entries 6 and 7). MeCN, THF, and ac-
etone were effective, but gave lower yields than that ob-
tained in dioxane (entries 8–10). We next found that the re-
action temperature markedly affected the transformation.
The reaction at 140 °C produced product 3 in 81% yield (en-
try 11). The product yield decreased sharply at a reaction
temperature below 120 °C. For example, the product was
obtained in 38% yield at 100 °C and no product formed at
80 °C (entries 12 and 13). These results indicate that a high
reaction temperature may facilitate the activation of ele-
mental sulfur. Using one equivalent of Na2S2O3 led to a de-
crease in the yield (entry 14).
A negligible change in the yield was observed when
more than two equivalents of Na2S2O3 was used (Table 1,
entry 15). In the presence of two equivalents of Na2S2O3,
there was no change in the yield of the desired product
when the reaction was carried out with 0.5 to 1 equivalents
of elemental sulfur (entries 16 and 17). Almost no change in
the yield was found when the reaction was conducted un-
der N2 (entry 18). However, pure oxygen was incompatible
with Na2S2O3, giving product 3 in a yield of 45% when the
reaction was carried out under an O2 atmosphere (entry
19). Without elemental sulfur, product 3 was still obtained
8
MeCN
36
49
15
81
38
0
9
THF
10
11
12
13
14
15
16b
17c
18c,d
19c,e
20f
21f
22f
acetone
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
140
140
140
140
140
140
140
140
140
70
80
82
82
81
45
42
0
0
a Reaction conditions: 1a (0.2 mmol), S (0.4 mmol, 2 equiv), 2a (0.4 mmol,
2 equiv), solvent (2 mL), 12 h.
b Sulfur (0.2 mmol, 1 equiv).
c Sulfur (0.1 mmol, 0.5 equiv).
d Reaction under N2.
e Reaction under O2.
f Reaction without elemental sulfur.
but only in 42% yield (entry 20). These results indicate that
Na2S2O3 is able to provide sulfur atoms for the sulfuration.14
However, neither Na2S2O4 nor NaHSO3 are the source of the
sulfur atoms for the reaction (entries 21 and 22).
With a metal-free C–H alkyl sulfuration procedure in
hand (see Table 1, entry 17), the substrate scope was inves-
tigated (Scheme 2). Initially, a range of 2-arylimidazopyri-
dines was subjected to the reaction with ethyl bromofluo-
roacetate. Substituents on the benzene or pyridine ring, in-
cluding methyl, methoxy, chloro, fluoro, cyano, and
hydroxymethyl were tolerated, giving the corresponding
products 3–15 in moderate to good yields. For example, the
synthetically useful hydroxymethyl group was tolerated to
give product 10 in 46% yield. Disubstituted substrates were
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

C
Y.-C. Gao et al.
Paper
Synthesis
also amenable to the reaction conditions, giving the desired
products 11–15 in moderate yields. However, the reaction
of 2-styrylimidazopyridine was problematic, and only gave
product 16 in 18% yield. This indicated that the styryl group
was not compatible with the reaction conditions. 2-Phenyl
imidazolium pyrimidine performed particularly well to
give product 17 in 91% yield. Imidazothiazoles were also
suitable for this reaction, giving products 18 and 20 in
moderate yields. The product yield decreased for imidazo-
thiazoles bearing a fluorine atom (products 19 and 21).
Next, ethyl 3-bromopropanoate was subjected to the reac-
tion with 2-phenylimidazopyridine, and the corresponding
product 22 was obtained in 60% yield. However, the reac-
tion of ethyl 2-bromo-2-methylpropanoate only gave prod-
uct 23 in 16% yield. The steric hindrance of the two methyl
groups may be a contributing factor to the low yield. It is
worth noting that fluorescent 2-(imidazo[1,2-a]pyridin-2-
yl)phenols bearing a hydroxy group were also suitable for
this transformation,15 affording the corresponding products
24 and 25 in 62% and 34% yields, respectively. The two
modified molecules emit green and yellow fluorescence un-
der 365 nm UV irradiation, respectively. Interestingly, an
imidazopyrimidine bearing a hydroxy group afforded prod-
uct 26 in 43% yield, which demonstrated pink fluorescence
under 365 nm UV irradiation. Fluorescent molecules pos-
sessing an acetate linker tend to be used in biological imag-
ing or fluorescence tracing. We found that 2-ethylimidazo-
pyridine was not suitable for this reaction. 5-Phenyl-1H-
imidazole, without a fused aromatic framework, was not
amenable to the reaction conditions. These results suggest
that the conjugate effect of the 2-aryl and the fused aromat-
ic ring is beneficial to increase the reactivity. Finally, ethyl
2-bromo-2,2-difluoroacetate was also subjected to the re-
action conditions but no reaction occurred.
Next, further modification of the ester group of product
3 was studied (Scheme 3). The hydrolysis of compound 3
was carried out to afford the carboxylic acid 27 in 91% yield.
Next, propargylamine, morpholine, and 2-aminothiazole
were reacted with compound 27 in the presence of EDCl [N-
(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochlo-
ride], HOBT (1-hydroxybenzotriazole), and DIPEA (N,N-di-
isopropylethylamine) to give the corresponding amides 28–
30 in good yields. Such drug-like compounds are of great in-
terest in medicinal chemistry.16
R4
N
N
R4
CO2R3
Na2S2O3 (2 equiv)
dioxane, 140 °C
R2
R2
R1
+
R1
R4
S
+
Br
N
N
n
R4
CO2R3
S
1
2
n
n = 0, 1
R3 = Me, Et
OH
N
N
N
N
N
N
R
N
N
O
3, R = H, 82%
4, R = Me, 87%
5, R = MeO, 79%
6, R = Cl, 76%
7, R = F, 65%
S
S
S
S
F
F
F
F
CO2Et
8, 73%
CO2Et
CO2Et
CO2Et
9, 60%
10, 46%
N
N
N
S
N
N
N
N
R
Ph
Ph
R2
N
N
F
Ph
11, R2 = MeO, R = Cl, 45%
S
S
S
12, R2 = MeO, R = MeO, 36%
13, R2 = Cl, R = MeO, 68%
14, R2 = Me, R = F, 67%
15, R2 = Me, R = CN, 51%
S
F
F
F
CO2Et
CO2Et
CO2Et
CO2Et
16, 18%
17, 91%
18, 58%
S
N
N
S
N
N
S
N
N
Ph
Ph
F
N
N
N
N
Ph
F
S
S
S
F
S
F
S
F
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
19, 20%
20, 55%
22, 60%
21, 23%
23, 16%
HO
N
HO
N
HO
N
N
N
N
N
F
S
S
S
F
F
F
CO2Et
CO2Et
CO2Et
25, 34%
24, 62%
26, 43%
Scheme 2 Scope of the reaction. Reagents and conditions: 1 (0.2 mmol), S (0.1 mmol, 0.5 equiv), 2 (0.4 mmol, 2 equiv), Na2S2O3 (0.4 mmol, 2 equiv),
dioxane (2 mL), 140 °C, 12 h.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

D
Y.-C. Gao et al.
Paper
Synthesis
N
N
N
EDCI (2 equiv)
HOBT (1.5 equiv)
DIPEA (1.5 equiv)
Ph
Ph
Ph
N
N
N
LiOH (3 equiv)
+
R
NH2
S
S
S
H2O–THF (1:1)
rt, 4 h
CH2Cl2, rt, 6 h
F
F
F
COOH
CO2Et
3
O
HN
27, 91%
R
Ph
N
Ph
Ph
N
N
N
F
S
O
S
O
H
N
N
N
S
N
F
HN
F
N
O
S
O
28, 80%
29, 72%
30, 67%
Scheme 3 Modification of the ester group
In order to elucidate the reaction pathway, the control
experiments shown in Scheme 4 were conducted. As
Na2S2O3 is able to supply sulfur atoms for the sulfuration
(see Table 1, entry 18), we speculated that Na2S2O3 may
generate elemental sulfur under the reaction conditions.
Thus, Na2S2O3 was stirred in dioxane at 140 °C for 12 hours.
As expected, elemental sulfur was obtained in 17% yield
(Scheme 4, eq 1). Next, the reaction between Na2S2O3 and
ethyl bromoacetate was studied. A key intermediate 31 was
observed in the ESI-MS (Scheme 4, eq 2) (see the Support-
ing Information). The accelerated debromination of ethyl
bromoacetate may involve intermediate 31.17 There is no
sulfuration product in the reaction of imidazopyridine 1a
with elemental sulfur or Na2S2O3 (Scheme 4, eq 3). To ex-
amine the formation of certain possible radical species in
the reaction, the radical trapping agent TEMPO (2,2,6,6-te-
tramethylpiperidinooxy) was added to the reaction. How-
ever, product 3 was still obtained in 70% yield and com-
pound 32 was not observed (Scheme 4, eq 4). This indicates
that the reaction may not involve a fluoroalkyl radical,18 be-
cause it can couple with TEMPO to form compound 32 as
mentioned in our previous report.18c
Based on our results (see Table 1 and Scheme 4) and
previous reports concerning C–H alkyl sulfuration using el-
emental sulfur,9a–c a possible reaction pathway has been
proposed (Scheme 5). The sulfite may undergo a nucleo-
philic reaction with bromofluoroacetate 2a to form inter-
mediate A.19 At high temperature, imidazopyridine 1a ex-
ists as the resonance structure B, which undergoes a nucle-
ophilic reaction with elemental sulfur to give intermediate
C. The polysulfide intermediate C may release S7 to afford
intermediate D. Next, intermediate D undergoes a nucleop-
hilic substitution with intermediate A to give intermediate
E. Finally, a hydrogen atom in intermediate E is abstracted
by a thiosulfate anion to provide the desired product 3. Sul-
fur possesses multiple valence states, and the formed reac-
tion species are complex. Further studies are therefore
needed to elucidate a more detailed reaction mechanism.
ONa
O
S
O
Br
Na2S2O3
NaBr
S
F
CO2Et
Ph
F
CO2Et
A
2a
N
N
N
heating
S8
Ph
Ph
N
N
N
dioxane
S
7
1a
B
Na2S2O3
S
(1)
S
C
140 °C, 12 h
17%
O
S7
O
S
F
N
N
Br
dioxane
O
N
Ph
Ph
(2)
A
S
N
Na2S2O3
N
+
Ph
CO2Et
H
F
CO2Et
N
140 °C, 4 h
ONa
O
S
S
31
observed on ESI-MS
S
F
2a
F
S
S
O
D
CO2Et
E
CO2Et
3
Ph
S
N
N
dioxane
N
N
(3)
(4)
+
Ph
Scheme 5 A possible reaction pathway
or
Ph
or
N
S
N
140 °C, 12 h
N
Na2S2O3
2
SH
not observed
1a
In summary, a metal-free sulfite-promoted alkylthion-
ation reaction of imidazopyridines and ethyl bromoacetate
using elemental sulfur has been developed. In the presence
of sulfite, a variety of imidazopyridines bearing an S-fluoro-
acetate group were successfully synthesized, which could
not be easily prepared via previously reported methods.9a–c
Further modification of the acetate enables the preparation
of different amides. We believe that these imidazohetero-
not observed
N
Na2S2O3 (2 equiv)
TEMPO (3 equiv)
Ph
N
O
N
Ph
+ S +
2a
+
N
F
dioxane
140 °C,12 h
F
S
CO2Et
32
not observed
1a
CO2Et
3, 70%
Scheme 4 Control experiments
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

E
Y.-C. Gao et al.
Paper
Synthesis
cycle derivatives will be of significant interest in medicinal
chemistry. Although progress on the C–H alkyl sulfuration
of imidazoheterocycles has been reported, this sulfuration
method is not suitable for the modification of indoles, pyr-
roles, and pyrazoles; research is currently ongoing to ad-
dress this situation. Additionally, the detailed chemical be-
havior between the sulfite and elemental sulfur is not un-
derstood and so further studies on the reaction mechanism
are needed.
13C NMR (151 MHz, CDCl3):  = 164.8 (d, JC–F = 28.7 Hz, 1 C), 152.0,
147.5, 138.6, 130.2, 129.0, 128.6, 127.1, 125.1, 117.4, 113.0, 95.2 (d,
JC–F = 235.6 Hz, 1 C), 62.5, 21.3, 13.5.
19F NMR (471 MHz, CDCl3):  = –158.52.
HRMS (ESI): m/z [M + H]+ calcd for C18H18FN2O2S: 345.10675; found:
345.10721.
Ethyl 2-Fluoro-2-{[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-
yl]thio}acetate (5)
Yield: 57 mg (79%); white solid; mp 114.0–114.8 °C.
IR (KBr): 2925, 1756, 1457, 1344, 1013, 759, 741 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.56 (d, J = 6.8 Hz, 1 H), 8.18 (d, J = 8.9
Hz, 2 H), 7.61 (d, J = 8.9 Hz, 1 H), 7.33–7.28 (m, 1 H), 6.98 (td, J = 8.9,
2.5 Hz, 2 H), 6.91 (td, J = 6.8, 1.2 Hz, 1 H), 5.91 (d, J = 51.4 Hz, 1 H),
3.97–3.87 (m, 1 H), 3.84 (s, 3 H), 3.72–3.60 (m, 1 H), 0.96 (t, J = 7.2 Hz,
3 H).
13C NMR (151 MHz, CDCl3):  = 164.7 (d, JC–F = 27.2 Hz, 1 C), 160.1,
151.7, 147.5, 123.0, 127.1, 125.6, 125.0, 117.3, 113.7, 112.9, 102.6,
95.2 (d, JC–F = 235.1 Hz, 1 C), 62.5, 55.3, 13.6.
1H and 13C NMR spectra were measured on a Bruker Avance-600 or
500 instrument (600 MHz for 1H, 151 MHz for 13C NMR, and 471 MHz
for 19F NMR) using CDCl3 or DMSO-d6 as the solvent. The 1H and 13C
NMR chemical shifts are referenced to internal Me4Si (0 ppm). Stan-
dard abbreviations are used to indicate multiplicities. Mass spectra
were measured on an Agilent GC-MS-5975C Plus spectrometer (EI).
LCMS (ESI) analysis was performed using an AB SCIEX, API3200.
HRMS (ESI) analysis was performed on a Thermo Scientific LTQ
Orbitrap XL instrument.
19F NMR (471 MHz, CDCl3):  = –158.53.
HRMS (ESI): m/z [M + H]+ calcd for C18H18FN2O3S: 361.10167; found:
361.10245.
Ethyl 2-Fluoro-2-[(2-phenylimidazo[1,2-a]pyridin-3-yl)thio]ace-
tate (3); Typical Procedure
A sealed tube (15 mL) with a Teflon cap was equipped with a magnet-
ic stir bar and charged with 1a (0.2 mmol), S8 (0.1 mmol) and ethyl
bromofluoroacetate (2a) (0.4 mmol) in dioxane (2 mL). The reaction
mixture was stirred at 140 °C for 12 hours. After the reaction was
complete, a saturated aqueous solution of NaCl (10 mL) was added to
the reaction mixture and the reaction products were extracted with
ethyl acetate (3 x 10 mL), and the combined organic layers were dried
over anhydrous Na2SO4 and evaporated under vacuum. The residue
was purified by flash column chromatography (petroleum ether/ethyl
acetate) to afford the desired product 3.
Ethyl 2-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]thio}-2-
fluoroacetate (6)
Yield: 56 mg (76%); yellow solid; mp 116.3–117.6 °C.
IR (KBr): 2925, 1756, 1457, 1344, 1094, 1013, 759, 741 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.58 (dd, J = 6.9, 1.1 Hz, 1 H), 8.17 (dt,
J = 8.4, 2.4 Hz, 2 H), 7.66 (dt, J = 9.0, 1.1 Hz, 1 H), 7.44 (dt, J = 8.4, 2.4
Hz, 2 H), 7.39-7.35 (m, 1 H), 6.96 (td, J = 6.9, 1.2 Hz, 1 H), 5.92 (d, J =
51.1 Hz, 1 H), 3.95–3.88 (m, 1 H), 3.73–3.57 (m, 1 H), 0.97 (t, J = 7.2
Hz, 3 H).
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 28.7 Hz, 1 C), 150.7,
147.5, 134.7, 131.5, 129.9, 128.5, 127.4, 125.1, 117.5, 113.3, 103.7,
95.0 (d, JC–F = 235.6 Hz, 1 C), 62.5, 13.6.
Yield: 54 mg (82%); white solid; mp 104.0–104.3 °C.
IR (KBr): 2982, 1755, 1466, 1344, 1048, 758, 696 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.62–8.57 (m, 1 H), 8.20 (d, J = 7.1 Hz, 2
H), 7.65 (d, J = 8.9 Hz, 1 H), 7.45 (t, J = 7.4 Hz, 2 H), 7.38 (t, J = 7.4 Hz, 1
H), 7.35–7.30 (m, 1 H), 6.93 (td, J = 6.8, 1.0 Hz, 1 H), 5.91 (d, J = 51.1
Hz, 1 H), 3.94–3.86 (m, 1 H), 3.64–3.54 (m, 1 H), 0.94 (t, J = 7.1 Hz, 3
H).
19F NMR (471 MHz, CDCl3):  = –158.62.
HRMS (ESI): m/z [M + H]+ calcd for C17H15FClN2O2S: 365.05213;
found: 365.05289.
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 28.7 Hz, 1 C), 151.9,
147.5, 133.0, 128.71, 128.66, 128.3, 127.2, 125.1, 117.5, 113.1, 103.6,
95.1 (d, JC–F = 234.0 Hz, 1 C), 62.4, 13.5.
19F NMR (471 MHz, CDCl3):  = –158.59.
HRMS (ESI): m/z [M + H]+ calcd for C17H16FN2O2S: 331.09110; found:
Ethyl 2-Fluoro-2-[(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-
yl)thio]acetate (7)
Yield: 45 mg (65%); white solid; mp 113.9–114.2 °C.
IR (KBr): 2937, 1755, 1464, 1342, 1178, 1035, 759, 739 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.58 (d, J = 6.9 Hz, 1 H), 8.24–8.19 (m, 2
H), 7.64 (d, J = 8.9 Hz, 1 H), 7.37–7.32 (m, 1 H), 7.20–7.07 (m, 2 H),
6.95 (td, J = 6.8, 1.2 Hz, 1 H), 5.91 (d, J = 51.2 Hz, 1 H), 3.96–3.87 (m, 1
H), 3.71–3.62 (m, 1 H), 0.97 (t, J = 7.1 Hz, 3 H).
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 28.7 Hz, 1 C), 163.1 (d,
JC–F = 249.2 Hz, 1 C), 151.0, 147.5, 130.5 (d, JC–F = 7.6 Hz, 2 C), 129.2 (d,
JC–F = 3.0 Hz, 1 C), 127.4, 125.1, 117.5, 115.3 (d, JC–F = 21.1 Hz, 2 C),
113.2, 103.3, 95.0 (d, JC–F = 235.6 Hz, 1 C), 62.5, 13.6.
331.09186.
Ethyl 2-Fluoro-2-{[2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl]thio}ace-
tate (4)
Yield: 60 mg (87%); yellow solid; mp 106.7–107.9 °C.
IR (KBr): 2924, 1755, 1463, 1343, 1027, 759, 741 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.61 (dd, J = 6.9, 1.1 Hz, 1 H), 8.11 (d, J =
8.2 Hz, 2 H), 7.65 (d, J = 8.9 Hz 1 H), 7.37–7.31 (m, 1 H), 7.28 (d, J = 7.9
Hz, 2 H), 6.95 (td, J = 6.8, 1.1 Hz, 1 H), 5.92 (d, J = 51.4 Hz, 1 H), 3.98–
3.87 (m, 1 H), 3.72–3.60 (m, 1 H), 2.40 (s, 3 H), 0.97 (t, J = 7.1 Hz, 3 H).
19F NMR (471 MHz, CDCl3):  = –112.77, –158.61.
HRMS (ESI): m/z [M + H]+ calcd for C17H15F2N2O2S: 349.08168; found:
349.08234.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

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Y.-C. Gao et al.
Paper
Synthesis
Ethyl 2-Fluoro-2-[(6-methoxy-2-phenylimidazo[1,2-a]pyridin-3-
19F NMR (471 MHz, CDCl3):  = –158.72.
yl)thio]acetate (8)
HRMS (ESI): m/z [M + H]+ calcd for C18H17FClN2O3S: 395.06270;
Yield: 53 mg (73%); brown solid; mp 114.9–115.7 °C.
found: 395.06354.
IR (KBr): 2929, 1755, 1474, 1354, 1246, 1176, 797, 613 cm–1
.
Ethyl 2-Fluoro-2-{[6-methoxy-2-(4-methoxyphenyl)imidazo-
[1,2-a]pyridin-3-yl]thio}acetate (12)
1H NMR (600 MHz, CDCl3):  = 8.38 (d, J = 7.5 Hz, 1 H), 8.25–8.12 (m, 2
H), 7.48–7.40 (m, 2 H), 7.38–7.32 (m, 1 H), 6.92 (d, J = 2.5 Hz, 1 H),
6.63 (dd, J = 7.5, 2.5 Hz, 1 H), 5.89 (d, J = 51.3 Hz, 1 H), 3.96–3.87 (m, 1
H), 3.86 (s, 3 H), 3.67–3.51 (m, 1 H), 0.95 (t, J = 7.2 Hz, 3 H).
Yield: 28 mg (36%); brown solid; mp 126.7–127.3 °C.
IR (KBr): 2928, 1755, 1476, 1354, 1246, 1176, 1023, 836 cm–1
.
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 28.7 Hz, 1 C), 159.8,
151.8, 149.1, 133.1, 128.50, 128.46, 128.3, 125.5, 107.9, 102.0, 95.3 (d,
JC–F = 232.5 Hz, 1 C), 62.4, 95.0, 55.7, 13.6.
1H NMR (600 MHz, CDCl3):  = 8.36 (d, J = 7.4 Hz, 1 H), 8.20–8.12 (m, 2
H), 7.01–6.95 (m, 2 H), 6.92 (d, J = 2.5 Hz, 1 H), 6.62 (dd, J = 7.5, 2.5 Hz,
1 H), 5.90 (d, J = 51.5 Hz, 1 H), 3.98–3.90 (m, 1 H), 3.87 (s, 3 H), 3.84 (s,
3 H), 3.72–3.63 (m, 1 H), 0.98 (t, J = 7.1 Hz, 3 H).
19F NMR (471 MHz, CDCl3):  = –158.57.
13C NMR (151 MHz, CDCl3):  = 164.7 (d, JC–F = 28.7 Hz, 1 C), 160.0,
159.8, 151.5, 148.9, 129.8, 125.6, 125.5, 125.4, 113.7, 107.7, 101.2,
95.4 (d, JC–F = 234.1 Hz, 1 C), 94.8, 62.4, 55.7, 55.3, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C18H18FN2O3S: 361.10167; found:
361.10255.
Ethyl 2-Fluoro-2-[(8-methyl-2-phenylimidazo[1,2-a]pyridin-3-
19F NMR (471 MHz, CDCl3):  = –158.53.
yl)thio]acetate (9)
HRMS (ESI): m/z [M + H]+ calcd for C19H20FN2O4S: 391.11223; found:
Yield: 41 mg (60%); brown solid; mp 72.7–73.4 °C.
391.11304.
IR (KBr): 2956, 1756, 1466, 1355, 1047, 1027, 752, 696 cm–1
.
Ethyl 2-{[6-Chloro-2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-
yl]thio}-2-fluoroacetate (13)
1H NMR (600 MHz, CDCl3):  = 8.45 (d, J = 6.7 Hz, 1 H), 8.20 (d, J = 8.2
Hz, 2 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.10 (d, J = 6.8
Hz, 1 H), 6.83 (t, J = 6.8 Hz, 1 H), 5.96–5.82 (m, 1 H), 3.95–3.87 (m, 1
H), 3.64–3.56 (m, 1 H), 2.65 (s, 3 H), 0.95 (t, J = 7.1 Hz, 3 H).
Yield: 54 mg (68%); brown solid; mp 136.4–138.0 °C.
IR (KBr): 2929, 1756, 1463, 1327, 1177, 1031, 836 cm–1
.
13C NMR (151 MHz, CDCl3):  = 164.7 (d, JC–F = 28.7 Hz, 1 C), 151.5,
147.8, 133.3, 128.9, 128.5, 128.3, 127.5, 125.9, 122.9, 113.1, 103.8,
95.0 (d, JC–F = 234.1 Hz, 1 C), 62.4, 29.7, 16.7, 13.6.
1H NMR (600 MHz, CDCl3):  = 8.59 (s, 1 H), 8.16 (d, J = 8.5 Hz, 2 H),
7.57 (d, J = 9.4 Hz, 1 H), 7.29 (dd, J = 9.4, 2.0 Hz, 1 H), 6.98 (d, J = 8.5 Hz,
2 H), 5.91 (d, J = 50.8 Hz, 1 H), 4.01–3.91 (m, 1 H), 3.85 (s, 3 H), 3.72–
3.62 (m, 1 H), 1.01 (t, J = 7.1 Hz, 3 H).
19F NMR (471 MHz, CDCl3):  = –158.92.
13C NMR (151 MHz, CDCl3):  = 164.5 (d, JC–F = 28.7 Hz, 1 C), 160.3,
152.4, 145.8, 129.9, 128.5, 125.1, 123.1, 121.4, 117.6, 113.8, 103.4,
94.8 (d, JC–F = 235.6 Hz, 1 C), 62.6, 55.3, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C18H18FN2O2S: 345.10675; found:
345.10714.
Ethyl 2-Fluoro-2-{[8-(hydroxymethyl)-2-phenylimidazo[1,2-a]-
19F NMR (471 MHz, CDCl3):  = –158.79.
pyridin-3-yl]thio}acetate (10)
HRMS (ESI): m/z [M + H]+ calcd for C18H17FClN2O3S: 395.06270;
Yield: 33 mg (46%); yellow oil.
found: 395.06335.
IR (KBr): 3365, 2926, 1754, 1355, 1026, 774, 754, 697 cm–1
.
Ethyl 2-Fluoro-2-{[2-(4-fluorophenyl)-6-methylimidazo[1,2-a]-
pyridin-3-yl]thio}acetate (14)
1H NMR (600 MHz, CDCl3):  = 8.54 (d, J = 6.8 Hz, 1 H), 8.26–8.16 (m, 2
H), 7.51–7.45 (m, 2 H), 7.43–7.38 (m, 1 H), 7.30–7.26 (m, 1 H), 6.95 (t,
J = 6.9 Hz, 1 H), 5.92 (d, J = 50.9 Hz, 1 H), 5.19–4.97 (m, 2 H), 4.33 (s, 1
H), 3.97–3.90 (m, 1 H), 3.67–3.56 (m, 1 H), 0.99 (t, J = 7.1 Hz, 3 H).
Yield: 49 mg (67%); white solid; mp 149.2–150.4 °C.
IR (KBr): 2926, 1754, 1463, 1337, 1158, 1016, 841 cm–1
.
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 28.7 Hz, 1 C), 151.1,
146.3, 132.7, 129.7, 128.8, 128.7, 128.3, 124.1, 113.2, 104.0, 94.9 (d,
JC–F = 234.1 Hz, 1 C), 62.5, 62.1, 13.6.
1H NMR (600 MHz, CDCl3):  = 8.35 (s, 1 H), 8.23–8.16 (m, 2 H), 7.53
(d, J = 9.1 Hz, 1 H), 7.18 (dd, J = 9.1, 1.7 Hz, 1 H), 7.15–7.10 (m, 2 H),
5.90 (d, J = 51.2 Hz, 1 H), 3.97–3.89 (m, 1 H), 3.76–3.56 (m, 1 H), 2.38
(s, 3 H), 0.98 (t, J = 7.1 Hz, 3 H).
19F NMR (471 MHz, CDCl3):  = –158.96.
13C NMR (151 MHz, CDCl3):  = 164.7 (d, JC–F = 27.2 Hz, 1 C), 163.0 (d,
JC–F = 249.2 Hz, 1 C), 150.7, 146.5, 130.4 (d, JC–F =7.6 Hz, 2 C), 129.4 (d,
JC–F = 3.0 Hz, 1 C), 123.1, 122.8, 116.8, 115.2 (d, JC–F = 21.1 Hz, 2 C),
102.8, 95.1 (d, JC–F = 235.6 Hz, 1 C), 62.5, 18.4, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C18H18FN2O3S: 361.10167; found:
361.10248.
Ethyl 2-{[2-(4-Chlorophenyl)-6-methoxyimidazo[1,2-a]pyridin-3-
yl]thio}-2-fluoroacetate (11)
19F NMR (471 MHz, CDCl3):  = –112.84, –158.81.
HRMS (ESI): m/z [M + H]+ calcd for C18H17F2N2O2S: 363.09733; found:
Yield: 36 mg (45%); yellow solid; mp 122.0–122.7 °C.
IR (KBr): 2926, 1732, 1374, 1017, 726 cm–1
.
363.09802.
1H NMR (600 MHz, CDCl3):  = 8.36 (d, J = 7.5 Hz, 1 H), 8.20–8.12 (m, 2
H), 7.44–7.36 (m, 2 H), 6.90 (d, J = 2.4 Hz, 1 H), 6.65 (dd, J = 7.6, 2.5 Hz,
1 H), 5.89 (d, J = 51.2 Hz, 1 H), 3.97–3.89 (m, 1 H), 3.87 (s, 3 H), 3.72–
3.59 (m, 1 H), 0.98 (t, J = 7.1 Hz, 3 H).
Ethyl 2-{[2-(4-Cyanophenyl)-6-methylimidazo[1,2-a]pyridin-3-
yl]thio}-2-fluoroacetate (15)
Yield: 37 mg (51%); yellow solid; mp 155.1–156.2 °C.
IR (KBr): 2927, 2229, 1756, 1506, 1338, 1049, 804 cm–1
.
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 28.7 Hz, 1 C), 159.9,
150.5, 149.1, 134.5, 131.6, 129.7, 128.5, 125.50, 125.48, 108.1, 102.2,
95.1 (d, JC–F = 235.6 Hz, 1 C), 94.9, 62.5, 55.7, 13.6.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

G
Y.-C. Gao et al.
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Synthesis
1H NMR (600 MHz, CDCl3):  = 8.57 (t, J = 1.4 Hz, 1 H), 8.49 (dt, J = 8.0,
1.2 Hz, 1 H), 8.38–8.35 (m, 1 H), 7.64 (dt, J = 7.7, 1.4 Hz, 1 H), 7.58–
7.52 (m, 2 H), 7.23 (dd, J = 9.1, 1.4 Hz, 1 H), 5.93 (d, J = 51.1 Hz, 1 H),
4.00–3.92 (m, 1 H), 3.79–3.60 (m, 1 H), 2.40 (s, 3 H), 1.00 (t, J = 7.1 Hz,
3 H).
13C NMR (151 MHz, CDCl3):  = 164.5 (d, JC–F = 28.7 Hz, 1 C), 149.0,
146.6, 134.6, 132.6, 131.9, 131.7, 130.9, 129.2, 123.7, 122.9, 118.8,
117.0, 112.6, 94.9 (d, JC–F = 235.6 Hz, 1 C), 62.6, 18.4, 13.6.
Ethyl 2-Fluoro-2-{[6-(4-fluorophenyl)imidazo[2,1-b]thiazol-5-
yl]thio}acetate (19)
Yield: 14 mg (20%); brown solid; mp 112.3–114.3 °C.
IR (KBr): 2982, 1754, 1468, 1250, 1046, 1025, 841 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.12–8.06 (m, 2 H), 7.66 (d, J = 4.4 Hz, 1
H), 7.11 (t, J = 8.7 Hz, 2 H), 6.91 (d, J = 4.5 Hz, 1 H), 5.91 (d, J = 50.9 Hz,
1 H), 4.02–3.93 (m, 1 H), 3.75–3.67 (m, 1 H), 1.00 (t, J = 7.1 Hz, 3 H).
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 27.2 Hz, 1 C), 162.8 (d,
JC–F = 247.6 Hz, 1 C), 152.3 (d, JC–F = 13.6 Hz, 1 C), 129.7 (d, JC–F = 7.6 Hz,
2 C), 129.3 (d, JC–F = 3.0 Hz, 1 C), 118.9, 115.3 (d, JC–F = 21.1 Hz, 2 C),
113.0, 104.2, 94.7 (d, JC–F = 234.1 Hz, 1 C), 62.6, 13.6.
19F NMR (471 MHz, CDCl3):  = –158.63.
HRMS (ESI): m/z [M + H]+ calcd for C19H17FN3O2S: 370.10200; found:
370.10269.
19F NMR (471 MHz, CDCl3):  = –113.15, –158.29.
HRMS (ESI): m/z [M + H]+ calcd for C15H13F2N2O2S2: 355.03810; found:
Ethyl (E)-2-Fluoro-2-[(2-styrylimidazo[1,2-a]pyridin-3-yl)thio]-
acetate (16)
355.03879.
Yield: 13 mg (18%); yellow solid; mp 131.7–133.4 °C.
IR (KBr): 1751, 1502, 1472, 1335, 1056, 814 cm–1
.
Ethyl 2-Fluoro-2-[(2-phenylbenzo[d]imidazo[2,1-b]thiazol-3-
1H NMR (400 MHz, CDCl3):  = 8.50 (d, J = 6.8 Hz, 1 H), 7.78 (d, J = 16.1
Hz, 1 H), 7.67–7.59 (m, 3 H), 7.43–7.33 (m, 4 H), 7.30 (t, J = 7.4 Hz, 1
H), 6.93 (t, J = 6.8 Hz, 1 H), 5.96 (d, J = 50.9 Hz, 1 H), 4.10–3.87 (m, 2
H), 1.05 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.8 (d, JC–F = 28.3 Hz, 1 C), 150.8,
147.9, 136.8, 133.4, 128.7, 128.3, 127.9, 127.0, 125.0, 117.5, 117.0,
113.0, 105.8, 95.0 (d, JC–F = 236.3 Hz, 1 C), 62.8, 13.7.
yl)thio]acetate (20)
Yield: 43 mg (55%); yellow solid; mp 103.9–104.5 °C.
IR (KBr): 2925, 1755, 1482, 1371, 1267, 1024, 748, 700 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.72–8.60 (m, 1 H), 8.22–8.12 (m, 2 H),
7.71 (ddd, J = 8.0, 4.1, 1.1 Hz, 1 H), 7.49–7.44 (m, 3 H), 7.41–7.33 (m, 2
H), 5.92 (d, J = 50.8 Hz, 1 H), 4.00–3.92 (m, 1 H), 3.66–3.57 (m, 1 H),
1.03 (t, J = 7.2 Hz, 3 H).
13C NMR (151 MHz, CDCl3):  = 164.5 (d, JC–F = 27.2 Hz, 1 C), 154.4,
151.5, 133.6, 132.9, 128.4, 128.29, 128.25, 127.8, 126.1, 125.1, 124.0,
116.0, 115.0, 94.5 (d, JC–F = 237.1 Hz, 1 C), 62.5, 13.7.
19F NMR (376 MHz, CDCl3):  = –157.73, 157.87.
HRMS (ESI): m/z [M + H]+ calcd for C19H18FN2O2S: 357.10681; found:
357.10663.
19F NMR (471 MHz, CDCl3):  = –163.15.
HRMS (ESI): m/z [M + H]+ calcd for C19H16FN2O2S2: 387.06317; found:
Ethyl 2-Fluoro-2-[(2-phenylimidazo[1,2-a]pyrimidin-3-yl)thio]-
acetate (17)
387.06412.
Yield: 60 mg (91%); green solid; mp 111.8–112.5 °C.
IR (KBr): 2926, 1750, 1612, 1493, 1342, 1047, 1028, 771 cm–1
.
Ethyl 2-Fluoro-2-{[2-(4-fluorophenyl)benzo[d]imidazo[2,1-b]thi-
1H NMR (600 MHz, CDCl3):  = 8.92–8.86 (m, 1 H), 8.68 (dd, J = 4.1, 2.0
Hz, 1 H), 8.31 (d, J = 7.5 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.42 (t, J = 7.4
Hz, 1 H), 7.04 (d, J = 6.8 Hz, 1 H), 5.96 (d, J = 51.1 Hz, 1 H), 4.00–3.84
(m, 1 H), 3.70–3.51 (m, 1 H), 0.95 (t, J = 7.1 Hz, 3 H).
azol-3-yl]thio}acetate (21)
Yield: 18 mg (23%); yellow solid; mp 119.3–119.8 °C.
IR (KBr): 2922, 1755, 1482, 1158, 840, 748 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.65 (d, J = 8.3 Hz, 1 H), 8.18–8.12 (m, 2
H), 7.71 (d, J = 8.0 Hz, 1 H), 7.48 (dd, J = 8.4, 1.2 Hz, 1 H), 7.41–7.36 (m,
1 H), 7.14 (t, J = 8.7 Hz, 2 H), 5.92 (d, J = 51.0 Hz, 1 H), 3.98 (m, 1 H),
3.70 (m, 1 H), 1.06 (t, J = 7.2 Hz, 3 H).
13C NMR (151 MHz, CDCl3):  = 164.5 (d, JC–F = 28.7 Hz, 1 C), 162.9 (d,
JC–F = 249.1 Hz, 1 C), 153.6, 151.6, 133.6, 130.09, 130.06 (d, JC–F = 7.6
Hz, 2 C), 130.0, 129.0 (d, JC–F = 3.2 Hz, 1 C), 126.2, 125.2, 124.1, 115.3
(d, JC–F = 21.1 Hz, 2 C), 114.9, 94.5 (d, JC–F = 237.1 Hz, 1 C), 62.6, 13.7.
13C NMR (151 MHz, CDCl3):  = 164.3 (d, JC–F = 28.7 Hz, 1 C), 153.1,
152.3, 150.4, 133.0, 132.2, 129.3, 129.0, 128.4, 109.6, 94.9 (d, JC–F
=
235.6 Hz, 1 C), 62.7, 13.5.
19F NMR (471 MHz, CDCl3):  = –157.44.
HRMS (ESI): m/z [M + H]+ calcd for C16H15FN3O2S: 332.08635; found:
332.08719.
Ethyl 2-Fluoro-2-[(6-phenylimidazo[2,1-b]thiazol-5-yl)thio]-
acetate (18)
19F NMR (471 MHz, CDCl3):  = –112.85, –163.12.
HRMS (ESI): m/z [M + H]+ calcd for C19H15F2N2O2S2: 405.05375; found:
Yield: 39 mg (58%); brown solid; mp 75.5–76.5 °C.
405.05466.
IR (KBr): 2923, 1749, 1457, 1251, 1028, 696 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.09 (d, J = 7.5 Hz, 2 H), 7.67 (d, J = 4.4
Hz, 1 H), 7.43 (t, J = 7.7 Hz, 2 H), 7.35 (t, J = 7.4 Hz, 1 H), 6.90 (d, J = 4.4
Hz, 1 H), 5.91 (d, J = 51.0 Hz, 1 H), 4.01–3.90 (m, 1 H), 3.76–3.60 (m, 1
H), 0.98 (t, J = 7.2 Hz, 3 H).
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 28.7 Hz, 1 C), 153.1,
152.4, 133.1, 128.3, 127.9, 118.9, 113.0, 104.5, 94.8 (d, JC–F = 234.1 Hz,
1 C), 62.5, 13.6.
Methyl 3-[(2-Phenylimidazo[1,2-a]pyridin-3-yl)thio]propanoate
(22)
Yield: 37 mg (60%); brown oil.
IR (KBr): 2854, 1736, 1465, 1439, 1344, 757 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.49 (dt, J = 6.8, 1.2 Hz, 1 H), 8.28–8.25
(m, 2 H), 7.65 (dt, J = 9.0, 1.1 Hz, 1 H), 7.49–7.44 (m, 2 H), 7.39–7.35
(m, 1 H), 7.29 (dd, J = 9.0, 1.3 Hz, 1 H), 6.93 (td, J = 6.8, 1.1 Hz, 1 H),
3.51 (s, 3 H), 2.89 (t, J = 7.0 Hz, 2 H), 2.38 (t, J = 7.0 Hz, 2 H).
13C NMR (151 MHz, CDCl3):  = 171.7, 150.3, 146.7, 133.6, 128.5,
128.3, 126.2, 124.4, 117.6, 112.8, 108.7, 51.8, 33.9, 30.1.
19F NMR (471 MHz, CDCl3):  = –158.30.
HRMS (ESI): m/z [M + H]+ calcd for C15H14FN2O2S2: 337.04752; found:
337.04828.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

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Y.-C. Gao et al.
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Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C17H17N2O2S: 313.10052; found:
313.10031.
1H NMR (600 MHz, CDCl3):  = 12.49 (s, 1 H), 8.94 (d, J = 6.7 Hz, 1 H),
8.68 (dd, J = 4.1, 1.8 Hz, 1 H), 8.56 (d, J = 6.8 Hz, 1 H), 7.34–7.28 (m, 1
H), 7.11 (dd, J = 6.8, 4.1 Hz, 1 H), 7.05 (d, J = 8.2 Hz, 1 H), 6.91 (t, J = 7.5
Hz, 1 H), 6.01 (d, J = 50.9 Hz, 1 H), 3.93 (m, 1 H), 3.59 (m, 1 H), 0.98 (s,
3 H).
Ethyl 2-Methyl-2-[(2-phenylimidazo[1,2-a]pyridin-3-yl)thio]pro-
panoate (23)
13C NMR (151 MHz, CDCl3):  = 164.1 (d, JC–F = 24.3 Hz, 1 C), 158.7,
152.7, 151.26, 148.3, 132.8, 131.6, 128.2, 118.7, 118.2, 115.0, 110.3,
101.5, 94.8 (d, JC–F = 236.9 Hz, 1 C), 62.9, 13.5.
19F NMR (471 MHz, CDCl3):  = –156.92.
HRMS (ESI): m/z [M + H]+ calcd for C16H15FN3O3S: 348.08127; found:
Yield: 11 mg (16%); yellow oil.
IR (KBr): 2954, 2925, 2854, 1736, 1465, 1439, 1344, 757, 694 cm–1
1H NMR (600 MHz, CDCl3):  = 8.52 (d, J = 6.8 Hz, 1 H), 8.26 (d, J = 7.6
Hz, 2 H), 7.67 (d, J = 8.9 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 2 H), 7.36 (t, J = 7.4
Hz, 1 H), 7.32–7.26 (m, 1 H), 6.89 (t, J = 6.8 Hz, 1 H), 3.68 (br s, 1 H),
3.51 (br s, 1 H), 1.25 (s, 6 H), 0.91 (t, J = 7.1 Hz, 3 H).
.
348.08224.
13C NMR (151 MHz, CDCl3):  = 173.4, 152.4, 146.9, 133.9, 128.9,
128.4, 128.2, 126.5, 125.0, 117.6, 112.5, 108.3, 61.4, 53.8, 29.7, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H21N2O2S: 341.13183; found:
2-Fluoro-2-[(2-phenylimidazo[1,2-a]pyridin-3-yl)thio]acetic Acid
(27)
A round-bottomed flask (50 mL) with a reverse plug was equipped
with a magnetic stir bar and charged with compound 3 (5 mmol),
LiOH (15 mmol), and THF/H2O (1:1, 10 mL). The reaction mixture was
stirred at room temperature for 4 hours. After the reaction was com-
plete, the mixture was acidified with HCl (1 mol/L), extracted with
ethyl acetate, and the combined organic layers dried over anhydrous
Na2SO4 and evaporated under vacuum. The residue was purified by
flash column chromatography (petroleum ether/ethyl acetate con-
taining 1/1000 of acetic acid) to afford the desired product 27.
341.13131.
Ethyl 2-Fluoro-2-{[2-(2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-
yl]thio}acetate (24)
Yield: 43 mg (62%); white solid; mp 114.3–116.6 °C.
IR (KBr): 3386, 2982, 1753, 1455, 1348, 1041, 755, 742 cm–1
.
1H NMR (600 MHz, CDCl3):  = 12.95 (s, 1 H), 8.68 (d, J = 6.7 Hz, 1 H),
8.62 (d, J = 7.0 Hz, 1 H), 7.63 (d, J = 8.9 Hz, 1 H), 7.47–7.39 (m, 1 H),
7.28 (t, J = 7.3 Hz, 1 H), 7.07–6.99 (m, 2 H), 6.92 (t, J = 7.4 Hz, 1 H), 5.98
(d, J = 51.2 Hz, 1 H), 3.98–3.58 (m, 2 H), 0.99 (s, 3 H).
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 27.2 Hz, 1 C), 158.6,
150.0, 145.3, 130.8, 128.1, 125.0, 118.6, 117.9, 116.6, 115.7, 113.9,
102.7, 95.2 (d, JC–F = 244.6 Hz, 1 C), 62.7, 13.6.
Yield: 1.38 g (91%); maroon solid; mp 196.8–199.6 °C.
IR (KBr): 3417, 1649, 1523, 1398, 763, 694 cm–1
.
1H NMR (600 MHz, DMSO-d6):  = 8.87 (s, 1 H), 8.19 (dd, J = 8.0, 1.9
Hz, 2 H), 8.09–7.94 (m, 2 H), 7.70–7.52 (m, 4 H), 6.59 (d, J = 50.0 Hz, 1
H).
13C NMR (151 MHz, DMSO-d6):  = 166.8 (d, JC–F = 27.2 Hz, 1 C), 150.7,
146.9, 133.4, 129.1, 128.71, 128.67, 128.3, 125.8, 117.3, 114.0, 104.6,
94.9 (d, JC–F = 231.0 Hz, 1 C).
19F NMR (471 MHz, CDCl3):  = –158.08.
HRMS (ESI): m/z [M + H]+ calcd for C17H16FN2O3S: 347.08602; found:
347.08685.
19F NMR (471 MHz, DMSO-d6):  = –158.37.
HRMS (ESI): m/z [M + H]+ calcd for C15H12FN2O2S: 303.05980; found:
Ethyl 2-Fluoro-2-{[6-fluoro-2-(2-hydroxyphenyl)imidazo[1,2-a]-
pyridin-3-yl]thio}acetate (25)
303.06052.
Yield: 25 mg (34%); yellow solid; mp 115.0–116.3 °C.
IR (KBr): 3384, 2923, 2853, 1735, 1455, 1260, 1049, 816, 801, 759 cm–
.
Amides 28–30; General Procedure
1
A round-bottomed flask (25 mL) with a reverse plug was equipped
with a magnetic stir bar and charged with CH2Cl2 (2 mL), compound
27 (0.2 mmol), the corresponding amine (0.24 mmol), EDCI (0.4
mmol), HOBT (0.3 mmol), and DIPEA (0.3 mmol). The reaction mix-
ture was stirred at room temperature for 6 hours. After completion of
the reaction, a saturated aqueous solution of NaCl (10 mL) was added
to the reaction mixture, and the reaction products were extracted
with ethyl acetate (3 x 10 mL). The combined organic layers were
dried over anhydrous Na2SO4 and evaporated under vacuum. The res-
idue was purified by flash column chromatography (petroleum
ether/ethyl acetate) to afford the desired product.
1H NMR (600 MHz, DMSO-d6):  = 12.19 (s, 1 H), 8.75–8.68 (m, 1 H),
8.37 (dd, J = 7.9, 1.6 Hz, 1 H), 7.90 (dd, J = 9.8, 5.0 Hz, 1 H), 7.69 (m, 1
H), 7.29 (m, 1 H), 6.97–6.89 (m, 2 H), 6.61 (d, J = 48.5 Hz, 1 H), 3.85 (m,
1 H), 3.53 (m, 1 H), 0.89 (t, J = 7.1 Hz, 3 H).
13C NMR (151 MHz, DMSO-d6):  = 165.1 (d, JC–F = 28.7 Hz, 1 C), 157.7,
154.0 (d, JC–F = 237.1 Hz, 1 C), 150.4, 143.0, 131.1, 128.7, 120.7 (d, JC–F
=
25.7 Hz, 1 C), 119.0, 117.9 (d, JC–F = 9.1 Hz, 1 C), 117.6, 116.5, 112.8 (d,
JC–F = 40.8 Hz, 1 C), 105.6, 94.8 (d, JC–F = 231.0 Hz, 1 C), 62.4, 13.7.
19F NMR (471 MHz, DMSO-d6):  = –137.46, –159.97.
HRMS (ESI): m/z [M + H]+ calcd for C17H15F2N2O3S: 365.07660; found:
365.07683.
2-Fluoro-2-[(2-phenylimidazo[1,2-a]pyridin-3-yl)thio]-N-(prop-
2-yn-1-yl)acetamide (28)
Ethyl 2-Fluoro-2-{[2-(2-hydroxyphenyl)imidazo[1,2-a]pyrimidin-
3-yl]thio}acetate (26)
Yield: 54 mg (80%); brown solid; mp 138.3–139.5 °C.
IR (KBr): 3297, 1683, 1528, 1467, 1442, 1344, 758, 696 cm–1
1H NMR (600 MHz, CDCl3):  = 8.60 (d, J = 6.8 Hz, 1 H), 8.25 (d, J = 7.4
Hz, 2 H), 7.65 (d, J = 8.9 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.4
Hz, 1 H), 7.35–7.29 (m, 1 H), 6.94 (t, J = 7.0 Hz, 1 H), 6.27 (d, J = 6.1 Hz,
1 H), 5.90 (d, J = 50.9 Hz, 1 H), 3.72 (m, 2 H), 2.08 (t, J = 2.6 Hz, 1 H).
.
Yield: 30 mg (43%); brown solid; mp 164.0–165.7 °C.
IR (KBr): 3357, 2924, 1742, 1609, 1338, 1260, 1025, 753, 595 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

I
Y.-C. Gao et al.
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Synthesis
13C NMR (151 MHz, CDCl3):  = 164.6 (d, JC–F = 24.2 Hz, 1 C), 152.2,
147.3, 132.9, 128.8, 128.6, 128.4, 127.3, 125.2, 117.5, 113.1, 103.3,
97.4 (d, JC–F = 238.6 Hz, 1 C), 77.8, 72.2, 29.0.
(2) (a) Jarrett, J. T. J. Biol. Chem. 2015, 290, 3972. (b) Konaklieva, M.
I.; Plotkin, B. J. Recent Pat. Anti-Infect. Drug Discovery 2006, 1,
177. (c) Zysman-Colman, E.; Leste-Lassere, P.; Harpp, D. N.
J. Sulfur Chem. 2008, 29, 309.
19F NMR (471 MHz, CDCl3):  = –160.25.
(3) For reviews on the construction of C–S bonds, see: (a) Ghaderi,
A. Tetrahedron 2016, 72, 4758; and references cited therein.
(b) Qiao, Z.; Jiang, X. Org. Biomol. Chem. 2017, 15, 1942. (c) Shen,
C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Chem. Soc. Rev.
2015, 44, 291.
HRMS (ESI): m/z [M + H]+ calcd for C18H15FN3OS: 340.09144; found:
340.09213.
2-Fluoro-1-morpholino-2-[(2-phenylimidazo[1,2-a]pyridin-3-
yl)thio]ethan-1-one (29)
(4) (a) Nguyen, B. T. Adv. Synth. Catal. 2017, 359, 1066; and refer-
ences cited therein. (b) Meyer, B. Chem. Rev. 1976, 76, 367.
(5) (a) Chen, F.-J.; Liao, G.; Li, X.; Wu, J.; Shi, B.-F. Org. Lett. 2014, 16,
5644. (b) Han, R.; Hillhouse, G. L. J. Am. Chem. Soc. 1998, 120,
7657. (c) Chen, C.; Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134,
12454. (d) Zhou, Z.; Liu, Y.; Chen, J.; Yao, E.; Cheng, J. Org. Lett.
2016, 18, 5268. (e) Chen, C.; Xie, Y.; Chu, L.; Wang, R.-W.; Zhang,
X.; Qing, F.-L. Angew. Chem. Int. Ed. 2012, 51, 2492. (f) Shibahara,
F.; Kanai, T.; Yamaguchi, E.; Kamei, A.; Yamauchi, T.; Murai, T.
Chem. Asian J. 2014, 9, 237. (g) Zhang, G.; Yi, H.; Chen, H.; Bian,
C.; Liu, C.; Lei, A. Org. Lett. 2014, 16, 6156. (h) Wang, Z.; Wang,
Y.; Zhang, W.-X.; Hou, Z.; Xi, Z. J. Am. Chem. Soc. 2009, 131,
15108. (i) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Org. Lett.
2013, 15, 4218. (j) Wang, M.; Fan, Q.; Jiang, X. Org. Lett. 2016, 18,
5756. (k) Feng, C.; Peng, Y.; Ding, G.; Li, X.; Cui, C.; Yan, Y. Chem.
Commun. 2018, 54, 13367. (l) Liu, Z.; Gao, R.; Lou, J.; He, Y.; Yu,
Z. Adv. Synth. Catal. 2018, 360, 3097.
(6) (a) Siva Reddy, A.; Kumara Swamy, K. C. Org. Lett. 2015, 17,
2996. (b) Arisawa, M.; Ichikawa, T.; Yamaguchi, M. Org. Lett.
2012, 14, 5318. (c) Huang, Y.; He, X.; Lin, X.; Rong, M.; Weng, Z.
Org. Lett. 2014, 16, 3284. (d) Weng, Z.; He, W.; Chen, C.; Lee, R.;
Tan, D.; Lai, Z.; Kong, D.; Yuan, Y.; Huang, K.-W. Angew. Chem.
Int. Ed. 2013, 52, 1548. (e) Paul, R.; Punniyamurthy, T. RSC Adv.
2012, 2, 7057. (f) Xiao, F.; Chen, S.; Li, C.; Huang, H.; Deng, G.-J.
Adv. Synth. Catal. 2016, 358, 3881.
Yield: 54 mg (72%); white solid; mp 156.0–157.7 °C.
IR (KBr): 2855, 1665, 1465, 1443, 1344, 1271, 1115, 758, 697 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.61 (d, J = 6.7 Hz, 1 H), 8.07 (d, J = 7.6
Hz, 2 H), 7.68 (d, J = 8.9 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.40 (t, J = 7.4
Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 6.96 (t, J = 6.8 Hz, 1 H), 6.02 (d, J =
53.0 Hz, 1 H), 3.51–3.11 (m, 8 H).
13C NMR (151 MHz, CDCl3):  = 162.3 (d, JC–F = 22.7 Hz, 1 C), 151.6,
147.3, 133.0, 128.94, 128.85, 128.5, 127.4, 125.2, 117.5, 113.4, 105.0,
97.4 (d, JC–F = 234.1 Hz, 1 C), 66.4, 66.1, 45.6, 45.7, 42.5.
19F NMR (471 MHz, CDCl3):  = –154.29, 154.40.
HRMS (ESI): m/z [M + H]+ calcd for C19H19FN3O2S: 372.11765; found:
372.11841.
2-Fluoro-2-[(2-phenylimidazo[1,2-a]pyridin-3-yl)thio]-N-(thi-
azol-2-yl)acetamide (30)
Yield: 52 mg (67%); brownish yellow solid; mp 126.8–128.4 °C.
IR (KBr): 2925, 1549, 1466, 1442, 1344, 1322, 1165, 1029, 758, 738,
695 cm–1
.
1H NMR (600 MHz, DMSO-d6):  = 12.67 (s, 1 H), 8.62 (d, J = 6.8 Hz, 1
H), 8.08 (d, J = 7.2 Hz, 2 H), 7.68 (d, J = 8.9 Hz, 1 H), 7.46–7.43 (m, 2 H),
7.33–7.27 (m, 3 H), 7.19 (d, J = 3.5 Hz, 1 H), 7.05 (t, J = 6.7 Hz, 1 H),
6.49 (d, J = 49.3 Hz, 1 H).
(7) For recent references on the sulfuration of indoles using ele-
mental sulfur, see: (a) Liao, Y.; Peng, Y.; Qi, H.; Deng, G.-J.; Gong,
H.; Li, C.-J. Chem. Commun. 2015, 51, 1031. (b) Liu, J.; Yan, X.;
Liu, N.; Zhang, Y.; Zhao, S.; Wang, X.; Zhuo, K.; Yue, Y. Org. Chem.
Front. 2018, 5, 1034. (c) Liu, J.; Zhang, Y.; Yue, Y.; Wang, Z.; Shao,
H.; Zhuo, K.; Lv, Q.; Zhang, Z. J. Org. Chem. 2019, 84, 12946.
(d) Lu, C.; Huang, H.; Tuo, X.; Jiang, P.; Zhang, F.; Deng, G.-J. Org.
Chem. Front. 2019, 6, 2738. (e) Thomas, J.; Jana, S.; Sonawane,
M.; Fiey, B.; Balzarini, J.; Liekens, S.; Dehaen, W. Org. Biomol.
Chem. 2017, 15, 3892.
(8) For recent references on the sulfuration of imidazoheterocycles
using elemental sulfur, see: (a) Li, J.; Li, C.; Yang, S.; An, Y.; Wu,
W.; Jiang, H. J. Org. Chem. 2016, 81, 7771. (b) Ravi, C.; Reddy, N.
N. K.; Pappula, V.; Samanta, S.; Adimurthy, S. J. Org. Chem. 2016,
81, 9964. (c) Shi, S.; Chen, J.; Zhuo, S.; Wu, Z.; Fang, M.; Tang, G.;
Zhao, Y. Adv. Synth. Catal. 2019, 361, 3210. (d) Wu, W.; Ding, Y.;
Xie, P.; Tang, Q.; Pittman, C. U. Jr.; Zhou, A. Tetrahedron 2017, 73,
2151. (e) Zhu, W.; Ding, Y.; Bian, Z.; Xie, P.; Xu, B.; Tang, Q.; Wu,
W.; Zhou, A. Adv. Synth. Catal. 2017, 359, 2215.
13C NMR (151 MHz, DMSO-d6):  = 163.6 (d, JC–F = 22.7 Hz, 1 C), 151.5,
147.2, 133.4, 130.1, 128.7, 128.5, 128.4, 127.9, 125.7, 117.4, 114.6,
113.7, 103.6, 95.3 (d, JC–F = 235.6 Hz, 1 C).
19F NMR (471 MHz, DMSO-d6):  = –162.67.
HRMS (ESI): m/z [M + H]+ calcd for C18H14FN4OS2: 385.05876; found:
385.05890.
Funding Information
We gratefully thank the Guangdong Basic and Applied Basic Research
Foundation (Grant No. 2019B151502052) for financial support.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707120.
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(9) For our publications on the sulfuration of imidazoheterocycles
using elemental sulfur, see: (a) Zhang, J.-R.; Liao, Y.-Y.; Deng, J.-
C.; Feng, K.-Y.; Zhang, M.; Ning, Y.-Y.; Lin, Z.-W.; Tang, R.-Y.
Chem. Commun. 2017, 53, 7784. (b) Zhang, J.-R.; Zhan, L.-Z.;
Wei, L.; Ning, Y.-Y.; Zhong, X.-L.; Lai, J.-X.; Xu, L.; Tang, R.-Y. Adv.
Synth. Catal. 2018, 360, 533. (c) Gao, Y.-C.; Huang, Z.-B.; Xu, L.;
Li, Z.-D.; Lai, Z.-S.; Tang, R.-Y. Org. Biomol. Chem. 2019, 17, 2279.
(d) Deng, J.-C.; Zhang, J.-C.; Li, M.-H.; Huang, J.-C.; Lai, Z.-S.;
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J