One-pot synthesis of imidazo[1,2-α]pyridine thioethers using imidazo[1,2-α]pyridines, arylsulfonyl chlorides and hydrazine

Article abstract of DOI:10.1080/10426507.2019.1686376

A one-pot reaction of making RS-substituted imidazo[1,2-α]pyridine derivatives by directly using aryl or alkylsulfonyl chloride and hydrazine was developed, selectively giving good yields of the expected products. Compared with previously reported methods

Full text of DOI:10.1080/10426507.2019.1686376

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
One-pot synthesis of imidazo[1,2-α]pyridine
thioethers using imidazo[1,2-α]pyridines,
arylsulfonyl chlorides and hydrazine
Jin Wang, Jie Zhu & Aihua Zhou
To cite this article: Jin Wang, Jie Zhu & Aihua Zhou (2019): One-pot synthesis of
imidazo[1,2-α]pyridine thioethers using imidazo[1,2-α]pyridines, arylsulfonyl chlorides
and hydrazine, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2019.1686376
To link to this article: https://doi.org/10.1080/10426507.2019.1686376
View supplementary material
Published online: 23 Dec 2019.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=gpss20

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1686376
One-pot synthesis of imidazo[1,2-a]pyridine thioethers using
imidazo[1,2-a]pyridines, arylsulfonyl chlorides and hydrazine
Jin Wang , Jie Zhu, and Aihua Zhou
Department of Pharmaceutical Engineering, Pharmacy School, Jiangsu University, Zhenjiang City, Jiangsu, China
ABSTRACT
ARTICLE HISTORY
Received 30 July 2019
Accepted 25 October 2019
A one-pot reaction of making RS-substituted imidazo[1,2-a]pyridine derivatives by directly using
aryl or alkylsulfonyl chloride and hydrazine was developed, selectively giving good yields of the
expected products. Compared with previously reported methods of using ArSO2NHNH2 as a sulfur
source, this method is much cheaper, more practical and convenient and enriches current meth-
ods to make thioether-containing compounds, providing a good example of green chemistry.
KEYWORDS
Imidazo[1,2-a]pyridine; sul-
fenylation; benzene
sulfonylhydrazine; hydrazine
GRAPHICAL ABSTRACT
Introduction
make ArS-substituted imidazo[1,2-a]pyridine derivatives
before,[14] the method uses arylsulfonyl hydrazines as starting
materials which are more expensive and less available than
arylsulfonyl chlorides, so considerable room for improvements
still exist.
Here, we report a more convenient method of directly using
arylsulfonyl chloride and hydrazines instead of arylsulfonyl
hydrazines to make ArS-substituted imidazo[1,2-a]pyridine
derivatives. The reaction is carried out in THF with good
product yields under environmentally friendly conditions.
Imidazo[1,2-a]pyridine structure is very important in drug dis-
covery,[1] because its core is the same as the structures of sev-
eral marketed drugs, such as Zolpidem and Alpidem.
Imidazo[1,2-a]pyridine derivatives also possesses other import-
ant bioactivities,[2] such as antiviral,[3] antigout,[4] anticancer
[5]
and Alzheimer’s disease.[6] Due to its importance in drug dis-
covery, different methods of synthesizing imidazo[1,2-a]pyri-
dine derivatives, particularly the synthesis of thioether
derivatives, have been reported.[7] Several methods to make
ArS- and MeS-substituted imidazo[1,2-a]pyridine derivatives
have been reported.[8] Typically ArSSAr,[9]ArSH,[10]
ArSO2NHNH2,[11] ArSO2Cl[12] and Ar-SO2Na[13] have been
used as sulfenylation agents to make ArS- and MeS-substituted
imidazo[1,2-a]pyridine derivatives in Scheme 1. Some of these
methods involve using transition metal salts as catalysts, or
Results and discussion
As arylsulfonyl chlorides can readily react with hydrazine to
give arylsulfonyl hydrazines in good yields, so we plan to
develop an one-pot three component reaction for directly
toxic solvents. Although ArSO2NHNH2 has been reported to making ArS-substituted imidazo[1,2-a]pyridine derivatives
CONTACT Aihua Zhou
ahz@ujs.edn.cn Department of Pharmaceutical Engineering,
Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang City,
Jiangsu, 212013, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1686376.
ß 2019 Taylor & Francis Group, LLC

2
J. WANG ET AL.
by using hydrazine, arylsulfonyls instead of using arylsul- 35% yield of expected product 3a (entry 1). Using Et3N,
Na2CO3, K2CO3 or NaHCO3 as a base in THF at 135 ꢀC
fonyl hydrazines in order to shorten reaction steps and sim-
generated 3a in a 42%, 0%, 0% or 75% yield (entry 2, 3, 4,
5), repectively. Using different solvents such as DMF, THF,
DMSO, EA or CH3CN without a base involved at 135 ꢀC,
the reaction afforded 3a in a 23%, 82%, 0%, 75% or 80%
yield (entry 6, 7, 8, 9, 10), resepectively. While employing
acetone or DCM generated 3a in trace amount or 45% yield
(entry 11, 12). Decreasing temperature from 135 ꢀC to
115 ꢀC reduced the reaction yield to 65% (entry 13). When
the reaction temperature dropped to 90 ꢀC, the reaction
yield was only 43% (entry 14).
Based on the above screening, the optimized reaction
conditions selected for the one-pot multicomponent reaction
using arylsulfonyl chloride and hydrazine to generate ArS-
substituted imidazo[1,2-a]pyridine derivatives are: imi-
dazo[1,2-a]pyridine (1.0 equiv.), arylsulfonyl chloride (1.5
equiv.), hydrazine (3.0 equiv.) and THF as the solvent at
135 ꢀC for 20 h.
plify starting materials. To achieve this goal, a suitable
reaction condition for this one-pot three component reac-
tion need to be found.
To screen for a suitable one-pot reaction condition for
making ArS-substituted imidazo[1,2-a]pyridine with arylsul-
fonyl chloride and hydrazine as reactants, 2-phenylimi-
dazo[1,2-a]pyridine 1a was selected as a representative
reactant, 4-methylbenzenesulfonyl chloride 2a and hydrazine
were used as the representative starting substrate materials.
Different reaction conditions were employed in order to
find out suitable reaction conditions. The experimental
results are demonstrated in Table 1.
The screening reaction started with using DABCO as a
base in THF solvent at 135 ꢀC, but the reaction only gave a
To further explore the scope of above reaction, several
imidazo[1,2-a]pyridine reactants with electron-donating and
electron-withdrawing functions were synthesized based on
the reported methods in literature. Then in one pot these
imidazo[1,2-a]pyridine analogs were reacted with hydrazine
and different arylsulfonyl chloride with various functional
groups on their benzene rings. Under the optimized condi-
tion found above, most reactions proceeded well, giving
good yields of the regioselective ArS-subsituted imidazo[1,2-
a]pyridine derivatives. The experimental results are shown
in Table 2. Isolated yields of most reactions ranged from
54% to 88%. Selected alkyl sulfonyl chlorides were also tried
for the reaction and gave good yields of the expected prod-
ucts of 3o, 3p, 3q.
On the basis of the present investigations and previous
reports on the reaction mechanism of imidazo[1,2-
Scheme 1. Previously reported synthetic methods versus our new method.
Table 1. Screening for suitable reaction conditions.a
Entry
Base
Temp (oC)b
Solvent
Yield (%)c
1
2
3
4
5
6
7
8
DABCO
Et3N
Na2CO3
K2CO3
NaHCO3
—
—
—
—
—
135
135
135
135
135
135
135
135
135
135
135
135
115
90
THF
THF
THF
THF
THF
DMF
THF
DMSO
EA
CH3CN
Acetone
DCM
THF
35
42
0
0
75
23
82
0
75
80
trace
45
65
43
9
10
11
12
13
14
—
—
—
—
THF
aReaction conditions: imidazo[1,2-a]pyridine (0.5 mmol, 1.0 equiv.), sulfonyl chloride (1.5 equiv.), hydrazine (3.0 equiv.), solvent (0.5 mL) in sealed pressure tube.
bReaction temperature: oil bath temperature.
cIsolated yield of 3a was based on the reactant imidazo[1,2-a]pyridine 1a. Reaction time: 20 h.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
Table 2. Synthesis of RS-substituted imidazo[1,2-a]pyridine derivatives using different sulfonyl chloride.a
3
aReaction conditions: imidazo[1,2-a]pyridine (0.5 mmol, 1.0 equiv.), sulfonyl chloride (1.5 equiv.), hydrazine hydrate (3.0 equiv.), solvent (0.5 mL) in sealed pres-
sure tube.
bIsolated yield of 3a was based on the reactant imidazo[1,2-a]pyridine 1a. Reaction time: 20 h.
a]pyridine with arylsulfonyl hydrazine,[15] a reaction mech- mode (MeOH as a solvent). The Supplemental Materials con-
anism is proposed in Scheme 2. Initially, aryl-or alkyl-sul- tain sample 1H and 13C NMR spectra for the products 3
fonyl chloride reacted quickly with hydrazine to afford (Figures S1–S34).
sulfonyl hydrazine. Under heat, sulfonylhydrazine underwent
the reaction to give reaction intermediate A, which reacted
General procedure for the synthesis of compounds 3a-q
with imidazo[1,2-a]pyridine to give final product 3a.
Hydrazine (3.0 equiv.) was added to a pressure tube with
THF (0.5 mL), sulfonyl chloride 2a (1.5 equiv.) was added
slowly under ice bath and stirred for 1 h. Then imidazo[1,2-
Experimental
a]pyridine 1a (0.5 mmol, 1.0 equiv.) was added into and the
mixture were stirred at 135 ꢀC. After 20 h, the reaction was
cooled down to room temperature, diluted with dichlorome-
thane (2 mL), washed with brine (1 mL), dried over anhyd-
rous Na2SO4 and concentrated under vacuum. The residue
was purified by flash chromatography (Petroleum ether:
EtOAc ¼40:1) on silica gel to give the desired product 3a as
a colorless oil in an 82% yield.
All reactions were carried out in sealed pressure tubes; stirring
was achieved with an oven-dried magnetic stirring bar.
Solvents were purified by standard methods unless otherwise
noted. Commercially available reagents were purchased from
Aladdin Company in China and used throughout without fur-
ther purification other than those detailed below. Flash column
chromatography was performed on silica gel (200-300 mesh).
All reactions were monitored by TLC analysis. Deuterated sol-
1
vents were purchased from Cambridge Isotope laboratories. H
and 13C NMR spectra were recorded on a Bruker DRX-400
spectrometer operating at 400 MHz and 100 MHz respectively.
2-Phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (3a)[16a]
HRMS spectrometry (LC-HRMS) was recorded on a LXQ FTIR: 2979, 2927, 1343, 1090, 1461, 1050, 882 cmꢁ1 1H-
;
Spectrometer (Thermo Scientific) operating in the ESI-TOF NMR (CDCl3, 400 MHz): d 8.28 (tt,J ¼ 7.0, 1.4 Hz, 3 H), 7.74

4
J. WANG ET AL.
Scheme 2. A proposed reaction mechanism.
(dd, J ¼ 9.0, 1.2 Hz, 1 H), 7.46 (dd, J ¼ 8.3, 6.7 Hz, 2 H), 7.42 7.34 (m, 4 H), 7.25 – 7.16 (m, 2 H), 6.99 – 6.85 (m, 3 H).
– 7.33 (m, 1 H), 7.29 (ddd, J ¼ 8.7, 6.8, 1.3 Hz, 1 H), 7.02 (d, 13C-NMR (CDCl3, 100 MHz): d 151.61, 147.21, 133.74,
J ¼ 8.1 Hz, 2 H), 6.99 – 6.89 (m, 2 H), 6.81 (td, J ¼ 6.8, 133.12, 132.07, 129.59, 128.77, 128.49, 128.32, 126.89,
1.2 Hz, 1 H), 2.25 (s, 3 H); 13C-NMR (CDCl3, 100 MHz): d 126.84, 124.35, 117.78, 113.30, 105.73. HRMS (ESI-TOF)
151.20, 147.04, 136.05, 133.52, 131.54, 130.24, 128.59, m/z calculated for C19H14ClN2Sþ 337.0561 (M þ H)þ,
128.45, 128.42, 126.59, 125.85, 124.52, 117.61, 113.02, found 337.0557.
106.87, 20.92. HRMS (ESI-TOF) m/z calculated for
C20H17N2Sþ 317.1107 (M þ H)þ, found 317.1105.
2-(3-(Phenylthio)imidazo[1,2-a]pyridin-2-yl)phenol
(3e)[16c]
2-Phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (3b)[16a]
FTIR: 3328, 3055, 3018, 2356, 1457, 1349, 1098, 734 cmꢁ1
;
FTIR:2979, 2923, 2338, 1591, 1466, 1047, 684 cm-1; 1H- 1H-NMR (CDCl3, 400 MHz): d 13.13 (s, 1 H), 8.64 (dd,
NMR(CDCl3, 400 MHz): d 8.15 (d, J ¼ 6.8 Hz, 1 H), 8.11 (d, J ¼ 8.0, 1.7 Hz, 1 H), 8.39 (dt, J ¼ 6.8, 1.2 Hz, 1 H), 7.70 (dt,
J ¼ 7.2 Hz, 2 H), 7.63 (d, J ¼ 9.0 Hz, 1 H), 7.33 (dd, J ¼ 8.3, J ¼ 9.0, 1.1 Hz, 1 H), 7.42 (ddd, J ¼ 9.0, 6.8, 1.3 Hz, 1 H), 7.35
6.6 Hz, 2 H), 7.21 (ddd, J ¼ 8.7, 6.8, 1.3 Hz, 2 H), 7.09 (dd, – 7.20 (m, 3 H), 7.20 – 7.14 (m, 1 H), 7.14 – 7.03 (m, 3 H),
J ¼ 8.3, 6.7 Hz, 2 H), 7.02 (t, J ¼ 7.2 Hz, 1 H), 6.92 – 6.86 (m, 6.96 (td, J ¼ 6.8, 1.2 Hz, 1 H), 6.89 (ddd, J ¼ 8.3, 7.2, 1.3 Hz,
2 H), 6.74 (t, J ¼ 6.8 Hz, 1 H). 13C-NMR (CDCl3, 100 MHz): 1 H). 13C-NMR (CDCl3, 100 MHz): d 158.44, 149.45, 144.66,
d 151.41, 147.12, 135.18, 133.33, 129.46, 128.63, 128.44, 134.41, 130.63, 129.56, 127.75, 127.48, 126.39, 125.85,
128.40, 126.72, 126.08, 125.58, 124.51, 117.64, 113.12, 124.24, 118.88, 117.73, 116.70, 116.13, 113.81, 105.47. HRMS
106.34. HRMS (ESI-TOF) m/z calculated for C19H15N2Sþ (ESI-TOF) m/z calculated for C19H15N2OSþ 319.0900
303.0950 (M þ H)þ, found 303.0944.
(M þ H)þ, found 319.0904.
3-((4-Methoxyphenyl)thio)-2-phenylimidazo
2-(4-Methoxyphenyl)-3-(phenylthio)imidazo[1,2-a]
[1,2-a]pyridine (3c)[16b]
pyridine(3f)[16d]
FTIR: 3027, 2928, 2855, 1460, 1347, 1086, 798 cmꢁ1
;
1H- FTIR: 2920, 2847, 2355, 1469, 1248, 1035, 744 cmꢁ1 1H-
;
NMR(CDCl3, 400 MHz): d 8.34 (d, J ¼ 6.8 Hz, 1 H), 8.26 (d, NMR(CDCl3, 400 MHz): d 8.27 (dt, J ¼ 6.9, 1.2 Hz, 1 H),
J ¼ 7.3 Hz, 2 H), 7.77 (d, J ¼ 9.0 Hz, 1 H), 7.48 (t, J ¼ 7.4 Hz, 8.24 – 8.17 (m, 2 H), 7.73 (dt, J ¼ 9.0, 1.1 Hz, 1 H), 7.37 –
2 H), 7.44 – 7.33 (m, 2 H), 7.02 (d, J ¼ 8.8 Hz, 2 H), 6.91 (td, 7.26 (m, 1 H), 7.26 – 7.17 (m, 2 H), 7.17 – 7.11 (m, 1 H),
J ¼ 6.8, 1.1 Hz, 1 H), 6.81 – 6.75 (m, 2 H), 3.75 (s, 3 H). 13C- 7.04 – 6.95 (m, 4 H), 6.85 (td, J ¼ 6.8, 1.2 Hz, 1 H), 3.85 (s,
NMR (CDCl3, 100 MHz): d 158.59, 150.59, 146.72, 133.19, 3 H). 13C-NMR (CDCl3, 100 MHz): d 160.02, 151.32, 147.08,
128.61, 128.43, 128.03, 126.71, 125.35, 124.49, 117.52, 115.17, 135.33, 129.66, 129.44, 126.59, 126.01, 125.95, 125.51,
114.06, 113.12, 107.96, 55.34. HRMS (ESI-TOF) m/z calculated 124.42, 117.39, 113.87, 112.91, 105.31, 55.28. HRMS (ESI-
for C20H17N2OSþ 333.1056 (M þ H)þ, found 333.1048.
TOF) m/z calculated for C20H17N2OSþ 333.1056 (M þ H)þ,
found 333.1066.
3-((4-Chlorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine
(3d)[16b]
5-Chloro-2-(3-(phenylthio)imidazo[1,2-a]pyridin-2-yl)
phenol(3g)[16c]
FTIR: 3038, 2922, 2857, 1470, 1347, 1086, 692 cmꢁ1; H-
1
NMR (CDCl3, 400 MHz): d 8.27 (dt, J ¼ 6.8, 1.2 Hz, 1 H), FTIR: 3352, 2975, 2909, 1407, 1050, 881 cmꢁ1
;
1H-NMR
8.24 – 8.16 (m, 2 H), 7.77 (dt, J ¼ 9.0, 1.1 Hz, 1 H), 7.51 – (CDCl3, 400 MHz): d 13.15 (s, 1 H), 8.68 – 8.63 (m, 1 H),

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
8.41 – 8.37 (m, 1 H), 7.72 – 7.65 (m, 1 H), 7.43 (ddd, J ¼ 8.7, 6-Bromo-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
5.7, 1.3 Hz, 1 H), 7.30 – 7.14 (m, 4 H), 7.10 – 7.03 (m, 2 H), (3l)[16d]
7.03 – 6.92 (m, 2 H). 13C-NMR (CDCl3, 100 MHz): d 157.12,
1
FTIR: 3028, 2928, 2869, 1477, 1349, 1080, 783 cmꢁ1; H-NMR
(CDCl3, 400 MHz): d 8.52 – 8.41 (m, 1 H), 8.26 – 8.19 (m,
2 H), 7.63 (dd, J¼ 9.4, 0.9 Hz, 1 H), 7.50 – 7.37 (m, 4H), 7.07
(d, J¼ 8.0 Hz, 2 H), 6.97 – 6.91 (m, 2H), 2.30 (s, 3H). 13C-
NMR (CDCl3, 100 MHz): d 151.67, 145.38, 136.40, 132.91,
130.90, 130.35, 130.10, 128.83, 128.49, 128.32, 125.97, 124.69,
118.25, 107.96, 107.73, 20.91. HRMS (ESI-TOF) m/z calculated
for C20H16BrN2Sþ 395.0212 (M þ H)þ, found 395.0218.
147.79, 144.50, 133.89, 130.29, 129.62, 127.71, 126.27,
124.25, 119.04, 118.27, 117.14, 116.77, 116.67, 114.04,
113.89, 106.44. HRMS (ESI-TOF) m/z calculated for
C19H14ClN2OSþ 353.0510 (M þ H)þ, found 353.0516.
2-(4-Chlorophenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine
(3h)[16b]
FTIR:3027, 2928, 2863, 1477, 1345, 1083, 786 cmꢁ1 1H-
;
6-Bromo-3-((4-bromophenyl)thio)-2-phenylimidazo[1,2-a]
NMR (CDCl3, 400 MHz):d 8.30 (dt, J ¼ 6.8, 1.2 Hz, 1 H),
8.25 – 8.15 (m, 2 H), 7.74 (dt, J ¼ 9.0, 1.1 Hz, 1 H), 7.42 (d,
J ¼ 8.6 Hz, 2 H), 7.36 (ddd, J ¼ 9.0, 6.8, 1.3 Hz, 1 H), 7.03 (s,
2 H), 6.91 (d, J ¼ 8.3 Hz, 3 H), 2.28 (s, 3 H). 13C-NMR
(CDCl3, 100 MHz): d 149.81, 146.94, 136.27, 134.57, 131.83,
pyridine(3m)[16d]
FTIR: 3040, 2945, 2859, 1480, 1340, 1084, 692 cmꢁ1 1H-
;
NMR (CDCl3, 400 MHz): d 8.42 (d, J ¼ 1.8 Hz, 1 H), 8.18
(dd, J ¼ 8.2, 1.6 Hz, 2 H), 7.50 – 7.41 (m, 4 H), 7.41 – 7.34
131.11, 130.28, 129.59, 128.64, 126.87, 125.87, 124.54, (m, 3 H), 6.89 (d, J ¼ 8.6 Hz, 2 H). 13C-NMR (CDCl3,
100 MHz): d 133.78, 132.66, 132.33, 130.56, 129.10, 128.59,
128.26, 127.74, 127.21, 124.51, 123.96, 120.24, 119.09,
118.37, 108.35. HRMS (ESI-TOF) m/z calculated for
C19H13BrN2Sþ 458.9161 (M þ H)þ, found 458.9167.
117.59, 113.22, 107.16, 20.89. HRMS (ESI-TOF) m/z calcu-
lated for C20H16ClN2Sþ 351.0717 (M þ H)þ, found 351.0721.
2-(4-Bromophenyl)-6-methyl-3-(phenylthio)imidazo[1,2-a]
pyridine(3i)[16d]
2-Methyl-3-(phenylthio)imidazo[1,2-a]pyridine (3n)[16d]
1
FTIR: 3028, 2929, 2859, 1470, 1345, 1084, 796 cmꢁ1; H-NMR
FTIR: 3041, 2925, 2849, 1483, 1341, 1083, 679 cmꢁ1 1H-
;
(CDCl3, 400 MHz): d 8.22 – 8.12 (m, 2 H), 8.06 (d, J¼ 1.5 Hz,
1 H), 7.70 (d, J¼ 9.1Hz, 1H), 7.49 – 7.32 (m, 5 H), 7.25 (dd,
J¼ 9.1, 1.7 Hz, 1 H), 6.88 (d, J¼ 8.6 Hz, 2 H), 2.36 (s, 3 H).
13C-NMR (CDCl3, 100 MHz):d 151.17, 146.05, 134.67, 132.97,
132.49, 130.26, 128.73, 128.48, 128.22, 126.99, 123.42, 122.06,
119.77, 117.01, 105.09, 18.43. HRMS (ESI-TOF) m/z calculated
for C20H16BrN2Sþ 395.0212(M þ H)þ, found 395.0218.
NMR (CDCl3, 400 MHz): d 8.07 (dt, J ¼ 6.8, 1.2 Hz, 1 H),
7.52 (dd, J ¼ 9.0, 1.2 Hz, 1 H), 7.18 (ddd, J ¼ 8.7, 6.8, 1.3 Hz,
1 H), 7.11 (dd, J ¼ 8.3, 6.7 Hz, 2 H), 7.06 – 6.99 (m, 1 H),
6.89 – 6.80 (m, 2 H), 6.73 (td, J ¼ 6.8, 1.2 Hz, 1 H), 2.50 (s,
3 H). 13C-NMR (CDCl3, 100 MHz): d 150.65, 145.93, 134.57,
128.22, 124.97, 124.88, 124.60, 123.29, 115.96, 111.56,
106.34, 12.96. HRMS (ESI-TOF) m/z calculated for
C14H13N2Sþ 241.0794 (M þ H)þ, found 241.0798.
6-Methyl-3-((4-nitrophenyl)thio)-2-phenylimidazo[1,2-a]
pyridine (3j)[16d]
6-Methyl-3-(methylthio)-2-phenylimidazo[1,2-a]
pyridine(3o)[16e]
1
FTIR: 3023, 2921, 2837, 1467, 1337, 1079, 778 cmꢁ1; H-NMR
(CDCl3, 400 MHz):d 8.14 – 8.09 (m, 3 H), 8.02 (d, J¼ 1.8 Hz,
1 H), 7.76 (d, J¼ 9.2 Hz, 1 H), 7.49 – 7.36 (m, 3 H), 7.30 (d,
J¼ 12.7 Hz, 2 H), 7.17 – 7.08 (m, 2 H), 2.37 (d, J¼ 1.1 Hz,
3H). 13C-NMR (CDCl3, 100 MHz): d 146.4, 146.1, 145.1, 132.6,
130.7, 129.0, 128.6, 128.2, 125.2, 124.7, 124.5, 124.0, 121.8,
117.3, 103.2, 22.7. HRMS (ESI-TOF) m/z calculated for
C20H16N3O2Sþ 362.0958(M þ H)þ, found 362.0962.
1
FTIR: 3057, 2922, 2360, 1338, 818, 776 699 cmꢁ1; H-NMR
(CDCl3, 400 MHz):d 8.36 – 8.26 (m, 3 H), 7.60 (dd, J ¼ 9.1,
0.9 Hz, 1 H), 7.53 – 7.46 (m, 2 H), 7.43 – 7.36 (m, 1 H), 7.17
(dd, J ¼ 9.1, 1.8 Hz, 1 H), 2.43 (d, J ¼ 1.2 Hz, 3 H), 2.28 (s,
3 H). 13C-NMR (CDCl3, 100 MHz): d 148.50, 145.28, 133.87,
129.10, 128.35, 128.17, 128.15, 122.56, 122.02, 116.93,
110.96, 18.45, 18.23. HRMS (ESI-TOF) m/z calculated for
C15H15N2Sþ 255.0950 (M þ H)þ, found 255.0952.
2-(4-Chlorophenyl)-6-methyl-3-(phenylthio)imidazo[1,2-a]
pyridine (3k)[16d]
3-(Methylthio)-2-phenylimidazo[1,2-a]pyridine(3p)[16e]
FTIR:3025, 2926, 2863, 1478, 1347, 1085, 786cmꢁ1;1H-NMR
(CDCl3, 400 MHz): d 8.22 – 8.14 (m, 2H), 8.09 (q, J¼ 1.3 Hz,
1 H), 7.65 (d, J¼ 9.1 Hz, 1 H), 7.44 – 7.36 (m, 2 H), 7.27 – 7.12
(m, 4 H), 7.03 – 6.95 (m, 2 H), 2.33 (s, 3 H). 13C-NMR (CDCl3,
100 MHz): d 149.93, 146.12, 135.19, 134.44, 131.95, 130.07,
129.50, 129.47, 128.59, 126.11, 125.45, 123.20, 122.20, 116.97,
105.95, 18.39. HRMS (ESI-TOF) m/z calculated for
C20H16ClN2Sþ 351.0717 (M þ H)þ, found 351.0707.
FTIR: 3066, 2922, 2364, 1345, 758, 695 cmꢁ1 1H-NMR
;
(CDCl3, 400 MHz):d 8.50 (dt, J¼ 6.9, 1.2 Hz, 1 H), 8.34 – 8.26
(m, 2H), 7.70 (dt, J¼ 9.0, 1.1 Hz, 1 H), 7.54 – 7.46 (m, 2 H),
7.44 – 7.37 (m, 1 H), 7.35 – 7.27 (m, 1 H), 6.96 (td, J¼ 6.8,
1.2Hz, 1H), 2.28 (s, 3H). 13C-NMR (CDCl3, 100 MHz): d
148.74, 146.27, 133.72, 128.39, 128.30, 128.27, 126.01, 124.26,
117.60, 112.78, 111.44, 18.18. HRMS (ESI-TOF) m/z calculated
for C14H13N2Sþ241.0794 (M þ H)þ,found 241.0792.

6
J. WANG ET AL.
3-(Ethylthio)-2-phenylimidazo[1,2-a]pyridine(3q)[16f]
FTIR: 3064, 2922, 2364, 1345, 7563, 694 cmꢁ1 1H-NMR
of Iodoimidazo[1,2-a]pyridines and Dihydrofuran. J. Med.
Chem. 2003, 46, 1449–1455. DOI: 10.1021/jm020339r. (c)
Moraski, G. C.; Miller, P. A.; Bailey, M. A.; Ollinger, J.; Parish,
T.; Boshoff, H. I.; Cho, S.; Anderson, J. R.; Mulugeta, S.;
Franzblau, S. G.; Miller, M. J. Putting TB to Rest:
Transformation of the Sleep Aid, Ambien and “Anagrams”
Generated Potent Anti-tuberculosis Agents. ACS Infect. Dis.
2015, 1, 85–90. DOI: 10.1021/id500008t.
;
(CDCl3, 400 MHz): d 8.55 (dt, J ¼ 6.8, 1.2 Hz, 1 H), 8.40-8.31
(m, 2 H), 7.70 (dt, J ¼ 9.0, 1.2 Hz, 1 H), 7.54-7.46 (m, 2 H),
7.45-7.37 (m, 1 H), 7.35-7.28 (m, 1 H), 6.94 (td, J ¼ 6.8,
1.2 Hz, 1 H), 2.72 (q, J ¼ 7.4 Hz, 2 H), 1.14 (t, J ¼ 7.4 Hz,
3 H). 13C-NMR (CDCl3, 100 MHz): d 149.4, 146.3, 133.8,
128.3, 128.3, 128.2, 126.0, 124.4, 117.5, 112.7, 110.1, 29.9,
14.8. HRMS (ESI-TOF) m/z calculated for C15H15N2Sþ
255.0950 (M þ H)þ, found 255.0951.
[3] (a) Barradas, J. S.; Errea, M. I.; D’Accorso, N. B.; Sepulveda,
C. S.; Damonte, E. B. Imidazo[2,1-b]thiazole carbohydrate
derivatives: Synthesis and antiviral activity against Junin virus,
agent of Argentine hemorrhagic fever. Eur. J. Med. Chem. 2011,
46, 259–264. DOI: 10.1016/j.ejmech.2010.11.012. (b) Juspin, T.;
Laget, M.; Terme, T.; Azas, N.; Vanelle, P. TDAE-Assisted
Synthesis of New Imidazo[2,1-b]Thiazole Derivatives as Anti-
infectious Agents. Eur. J. Med. Chem. 2010, 45, 840–845. DOI:
10.1016/j.ejmech.2009.10.048.
Conclusion
In summary, a new one-pot reaction of making RS-substi-
tuted imidazo[1,2-a]pyridine derivatives by directly using
aryl or alkylsulfonyl chloride and hydrazine was developed,
giving good yields of expected products 3a-3q. Compared
with previously reported methods of using ArSO2NHNH2 as
sulfur sources, this method is much cheaper, flexible and
convenient. This method is probably more suitable for a
large scale production. Further studies to expand the scope
of this methodology are under way.
[4] Hirayama, T.; Okaniwa, M.; Banno, H.; Kakei, H.; Ohashi, A.;
Iwai, K.; Ohori, M.; Mori, K.; Gotou, M.; Kawamoto, T.;
Yokota, A.; Ishikawa, T. Synthetic Studies on Centromere-
Associated Protein-E (CENP-E) Inhibitors: 2. Application of
Electrostatic Potential Map (EPM) and Structure-Based
Modeling to Imidazo[1,2-a]pyridine Derivatives as Anti-Tumor
Agents. J. Med. Chem. 2015, 58, 8036–8053. DOI: 10.1021/acs.
jmedchem.5b00836.
[5] (a) Xi, G. L.; Liu, Z. Q. Introducing Ferrocene into
Imidazo[1,2-a]Pyridine by Groebke Three-Component-Reaction
for Scavenging Radicals and Inhibiting DNA Oxidation.
Tetrahedron. 2015, 71, 9602–9610. DOI: 10.1016/j.tet.2015.10.
080. (b) Andreani, A.; Burnelli, S.; Granaiola, M.; Leoni, A.;
Locatelli, A.; Morigi, R.; Rambaldi, M.; Varoli, L.; Calonghi, N.;
Cappadone, C.; Farruggia, G.; Zini, M.; Stefanelli, C.; Masotti,
L.; Radin, N. S.; Shoemaker, R. H. New Antitumor Imidazo[2,1-
b]thiazole Guanylhydrazones and Analogues. J. Med. Chem.
2008, 51, 809–816. DOI: 10.1021/jm701246g. (c) Park, J. H.; El-
Gamal, M. I.; Lee, Y. S.; Oh, C. H. New Imidazo[2,1-b]Thiazole
Derivatives: Synthesis, In Vitro Anticancer Evaluation, and In
Silico Studies. Eur. J. Med. Chem. 2011, 46, 5769–5777. DOI:
10.1016/j.ejmech.2011.08.024. (d) Ali, A. R.; El-Bendary, E. R.;
Ghaly, M. A.; Shehata, I. A. Synthesis, In Vitro Anticancer
Evaluation and In Silico Studies of Novel Imidazo[2,1-
b]Thiazole Derivatives Bearing Pyrazole Moieties. Eur. J. Med.
Chem. 2014, 75, 492–500. DOI: 10.1016/j.ejmech.2013.12.010.
[6] Chen, C.; Bandoa, K.; Ashinoa, H.; Taguchi, K.; Shiraishi, H.;
Shima, K.; Fujimotoa, O.; Kitamuraa, C.; Morimotoa, Y.;
Kasaharaa, H.; Minamizawaa, T.; Jiang, C.; Zhang, M.-R.;
Suhara, T.; Higuchi, M.; Yamada, K.; Ji, B. Biological Evaluation
of the Radioiodinated Imidazo[1,2-a]Pyridine Derivative
DRK092 for Amyloid-Imaging in Mouse Model of Alzheimer’s
Disease. Neurosci. Lett. 2014, 581, 103–108. DOI: 10.1016/j.neu-
let.2014.08.036.
[7] (a) Rahaman, R.; Das, S.; Barman, P. Visible-Light-Induced
Regioselective Sulfenylation of Imidazopyridines with Thiols
Under Transition Metal-Free Conditions. Green Chem. 2018,
20, 141–147. DOI: 10.1039/C7GC02906C. (b) Maddi, R. R.;
Shirsat, P. K.; Kumar, S.; Meshram, H. M. N-Bromosuccinimide
Promoted Direct Thiolation of Imidazoheteroaryl C-H bonds
with Disulfides. Chem. Select. 2017, 2, 1544–1547. DOI: 10.
1002/slct.201601460.
[8] (a) Ravi, C.; Joshi, A.; Adimurthy, S. C3 Sulfenylation of N-
Heteroarenes in Water under Catalyst-Free Conditions. Eur. J.
Org. Chem. 2017, 2017, 3646–3651. DOI: 10.1002/ejoc.
201700487. (b) Zhu, W.; Ding, Y.; Bian, Z.; Xie, P.; Xu, B.;
Tang, Q.; Wu, W.; Zhou, A. One-Pot Three-Component
Synthesis of Alkylthio-/Arylthio-Substituted Imidazo[1,2-a]pyri-
dine Derivatives via C(sp2)–H Functionalization. Adv. Synth.
Catal. 2017, 359, 2215–2221. DOI: 10.1002/adsc.201601431.
[9] (a) Bettanin, L.; Saba, S.; Doerner, C. V.; Franco, M. S.; Godoi,
M.; Rafique, J.; Braga, A. NH4I-Catalyzed Chalcogen(S/Se)-
Functionalization of 5-membered N-heteroaryls Under
Disclosure statement
There are no conflicts to declare.
Funding
Aihua Zhou acknowledge Jiangsu University for financial sup-
port (1281290006).
ORCID
Jin Wang
Aihua Zhou
http://orcid.org/0000-0003-2978-100X
http://orcid.org/0000-0002-0998-6932
References
[1] (a) Liu, R.; Yu, X.; Wallqvist, A. Data-Driven Identification of
Structural Alerts for Mitigating the Risk of Drug-Induced
Human Liver Injuries. J. Cheminform. 2015, 7, 4. DOI: 10.1186/
s13321-015-0053-y. (b) Ilardi, E. A.; Vitaku, E.; Njardarson, J.
T. Data-Mining for Sulfur and Fluorine: An Evaluation of
Pharmaceuticals to Reveal Opportunities for Drug Design and
Discovery. J. Med. Chem. 2014, 57, 2832–2842. DOI: 10.1021/
jm401375q. (c) Ritchie, T. J.; Macdonald, S. J. Physicochemical
Descriptors of Aromatic Character and Their Use in Drug
Discovery. J. Med. Chem. 2014, 57, 7206–7215. DOI: 10.1021/
jm500515d. (d) Kucher, O. V.; Kolodyazhnaya, A. O.; Smolii,
O. B.; Nazarenko, N. K.; Kubyshkin, V.; Mykhailiuk, P. K.;
Tolmachev, A. A. Lipase Kinetic Enantiomeric Resolution of 1-
Heteroarylethanols. Tetrahedron: Asymmetry 2016, 27, 341–345.
DOI: 10.1016/j.tetasy.2016.02.012.
[2] (a) Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H.;
Prinsep, M. R. Marine natural products. Nat. Prod. Rep. 2015,
32, 116–211. DOI: 10.1039/C4NP00144C. (b) Gudmundsson,
K. S.; Williams, J. D.; Drach, J. C.; Townsend, L. B. Synthesis
and Antiviral Activity of Novel Erythrofuranosyl Imidazo[1,2-
a]pyridine C-Nucleosides Constructed via Palladium Coupling

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
Metal-Free Conditions. Tetrahedron. 2018, 74, 3971–3980. [13] Huang, X.; Wang, S.; Li, B.; Wang, X.; Ge, Z.; Li, R.
DOI: 10.1016/j.tet.2018.05.084. (b) Xiao, G.; Min, H.; Zheng, Z.;
Deng, G.; Liang, Y. Copper-Catalyzed Three-Component
Reaction of Imidazo[1,2-a]Pyridine with Elemental Sulfur and
Arylboronic Acid to Produce Sulfenylimidazo[1,2-a]Pyridines.
Chin. Chem. Lett. 2018, 29, 1363–1366. DOI: 10.1016/j.cclet.
2017.12.013. (c) Rafique, J.; Saba, S.; Rosrio, A. R.; Braga, A. L.
Regioselective, Solvent-and Metal-Free Chalcogenation of
Imidazo[1,2-a]Pyridines by Employing I2/DMSO as Catalytic
Oxidation System. Chem. Eur. J. 2016, 22, 11854–11862. DOI:
10.1002/chem.201600800. (d) Ji, X.; Zhou, S.; Chen, F.; Zhang,
X.; Tang, R. Direct Sulfenylation of Imidazoheterocycles with
Disulfides in an Iodine–Hydrogen Peroxide System. Synthesis.
2015, 47, 659–671. DOI: 10.1055/s-0034-1379941.
Iodine–Triphenylphosphine
Imidazoheterocycles with Sodium Sulfinates. RSC Adv. 2015, 5,
22654–22657. DOI: 10.1039/C4RA17237J.
Mediated
Sulfenylation
of
[14] Bagdi, A. K.; Mitra, S.; Ghosh, M.; Hajra, A. Iodine-Catalyzed
Regioselective Thiolation of Imidazo[1,2-a]Pyridines Using
Sulfonyl Hydrazides as a Thiol Surrogate. Org. Biomol. Chem.
2015, 13, 3314–3320. DOI: 10.1039/C5OB00033E.
[15] (a) Chowdhury, S. R.; Fadikar, P.; Hoque, I. UI.; Maity, S.
Catalyst-Free Regioselective Sulfenylation of Imidazoheterocycles
with Sulfonyl Hydrazides in Water. Asian J. Org. Chem. 2018, 7,
332–336. DOI: 10.1002/ajoc.201700670. (b) Yang, Y.; Zhang, S.;
Tang, L.; Hu, Y.; Zha, Z.; Wang, Z. Catalyst-Free Thiolation of
Indoles with Sulfonyl Hydrazides for the Synthesis of 3-
Sulfenylindoles in Water. Green Chem. 2016, 18, 2609–2613. DOI:
10.1039/C6GC00313C.
[16] (a) Iida, H.; Demizu, R.;Ohkado, R. Tandem Flavin-Iodine-
Catalyzed Aerobic Oxidative Sulfenylation of Imidazo[1,2-
a]Pyridines with Thiols. J. Org. Chem. 2018, 83, 12291–12296.
DOI: 10.1021/acs.joc.8b01878. (b) Huang, X.; Chen, Y.; Zhen,
S.; Song, L.; Gao, M.; Zhang, P.; Li, H.; Yuan, B.; Yang, G.
Cobalt-Catalyzed Aerobic Cross-dehydrogenative Coupling of
C-H and Thiols in Water for C-S Formation. J. Org. Chem.
2018, 83, 7331–7340. DOI: 10.1021/acs.joc.7b02718. (c) Ding,
Y.; Wu, W.; Zhao, W.; Li, Y.; Xie, P.; Huang, Y.; Liu, Y.; Zhou,
A. Generation of Thioethers via Direct C-H Functionalization
with Sodium Benzenesulfinate as Sulfur Source. Org. Biomol.
Chem. 2016, 14, 1428–1431. DOI: 10.1039/C5OB02073E. (d)
Wu, W.; Ding, Y.; Xie, P.; Tang, Q.; Pittman, M. U.; Zhou, A.
Synthesis of Imidazol[1,2-a]Pyridine Thioethers via Using
Sulfur Powder and Halides as Reactants. Tetrahedron. 2017, 73,
2151–2158. DOI: 10.1016/j.tet.2017.02.065. (e) Chen, Z.; Ren,
H.; Cao, G.; Zhang, F.; Li, H.; Xu, J.; Miao, M. Metal-Free
Mediated C-3 Methylsulfanylation of Imidazo[1,2-a]pyridines
[10] (a) Ravi, C.; Mohan, D. C.; Adimurthy, S. N-Chlorosuccinimide-
Promoted Regioselective Sulfenylation of Imidazoheterocycles at
Room Temperature. Org. Lett. 2014, 16, 2978ꢁ2981. DOI: 10.
1021/ol501117z. (b) Iida, H.; Demizu, R.; Ohkado, R. Tandem
Flavin-Iodine-Catalyzed Aerobic Oxidative Sulfenylation of
Imidazo[1,2-a]Pyridines with Thiols. J. Org. Chem. 2018, 83,
12291–12296. DOI: 10.1021/acs.joc.8b01878. (c) Hiebel, M. A.;
Berteina-Raboina, S. Iodine-Catalyzed Regioselective Sulfenylation
of Imidazoheterocycles in PEG400. Green Chem. 2015, 17,
937–944. DOI: 10.1039/C4GC01462F.
[11] Zhao, W.; Xie, P.; Bian, Z.; Zhou, A.; Ge, H.; Zhang, M.; Ding,
Y.; Zheng, L. Ammonium Iodide-induced Non-radical
Regioselective Sulfenylation of Flavones via
a
C-H
Functionalization Process. J. Org. Chem. 2015, 80, 9167–9175.
DOI: 10.1021/acs.joc.5b01602.
[12] (a) Ravi, C.; Mohan, D. C.; Adimurthy, S. Dual Role of
p–Tosylchloride: Copper–Catalyzed Sulfenylation and Metal
free Methylthiolation of Imidazo[1,2-a]pyridines. Org. Biomol.
Chem. 2016, 14, 2282–2290. DOI: 10.1039/C5OB02475G. (b)
Wang, D.; Guo, S.; Zhang, R.; Lin, S.; Yan, Z. TBAI–HBr
System Mediated Generation of Various Thioethers with
with Dimethyl Sulfoxide as
a Methylsulfanylating Agent.
Benzenesulfonyl Chlorides in PEG400
54377–54381. DOI: 10.1039/c6ra02302a. (c) Guo, T.; Wei, X.
Ammonium Iodide-Mediated Sulfenylation of 4-
. RSC Adv. 2016, 6,
Synlett. 2017, 28, 1795–1800. DOI: 10.1055/s-0036-1588419. (f)
Yuan, Y.; Cao, Y.; Qiao, J.; Lin, Y.; Jiang, X.; Weng, Y.; Tang,
S.; Lei, A. Electrochemical Oxidative C-H Sulfenylation of
Imidazopyridines with Hydrogen Evolution. Chin. J. Chem.
2018, 37, 49–52. DOI: 10.1002/cjoc.201800405.
Hydroxycoumarins or 4-Hydroxyquinolinones with a Sulfonyl
Chloride as a Sulfur Source. Synlett. 2017, 28, 2499–2504. DOI:
10.1055/s-0036-1589083.