Unconventional Reactivity with DABCO-Bis(sulfur dioxide): C–H Bond Sulfenylation of Imidazopyridines

Article abstract of DOI:10.1002/ejoc.202000112

This work highlights the unexpected and unprecedented outcome of the reactivity with DABCO-bis(sulfur dioxide). The use of this reagent led to the exclusive introduction of a sulfur atom on the C-3 position of imidazopyridines instead of a sulfone group.

Full text of DOI:10.1002/ejoc.202000112

A Journal of
Accepted Article
Title: Unconventional reactivity with DABCO-bis(sulfur dioxide) C-H
bond sulfenylation of imidazopyridines
Authors: Julie Le Bescont, Chloé Breton-Patient, and Sandrine Piguel
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000112
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000112
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.202000112
COMMUNICATION
Unconventional reactivity with DABCO-bis(sulfur dioxide):
C-H bond sulfenylation of imidazopyridines
[a,b]
[a,b]
[a,b]
Julie Le Bescont,
Chloé Breton-Patient,
and Sandrine Piguel*
[
a]
J. Le Bescont, C. Breton-Patient, Dr S. Piguel
Université Paris-Saclay, CNRS, Inserm,
9
1405, Orsay, France
E-mail: sandrine.piguel@curie.fr
https://science.curie.fr/recherche/biologie-et-chimie-des-radiations-cellulaires-et-cancer/cmbc/chimie-modelisation-reconnaissance-proteines/
[
b]
J. Le Bescont, C. Breton-Patient, Dr S. Piguel
Institut Curie, CNRS, Inserm
91402, Orsay, France
Supporting information for this article is given via a link at the end of the document.
Abstract: This work highlights the unexpected and unprecedented
outcome of the reactivity with DABCO-bis(sulfur dioxide). The use of
this reagent led to the exclusive introduction of a sulfur atom on the
C-3 position of imidazopyridines instead of a sulfone group. The
reaction methodology turned out to be robust, scalable and suitable
for various imidazopyridines and aryl iodides both bearing
substituents with different electronic and steric properties (38
examples). Beyond the fact that this synthetic method complements
the previously reported protocols for sulfenylation reactions, this
work is meant to underline the unconventional role of DABCO-
bis(sulfur dioxide).
8 2 2 3
S or Na S O (Scheme 1, eq b). This approach is more versatile
as it does not require a pre-activated sulfur-containing specie.
For example, Adimurthy et al reported an efficient sulfenylation
reaction with elemental sulfur and aryl halides using copper (I)
iodide as a catalyst whereas, simultaneously, Zhou et al used
[6]
sodium thiosulfate and extended their protocol to alkyl halides.
More recently, other coupling partners such as dialkyl azo
compounds and formamides were implemented in the C-H
sulfenylation reaction to give 3-cyano-alkyl- and 3-
[
7]
carbamothioyl- imidazopyridines respectively.
Introduction
The carbon-sulfur bond is prevalent in natural products and
synthetic compounds, playing a fundamental role in biochemical
processes of living organisms and finding applications in
pharmaceuticals and in materials sciences. Consequently, the
formation of the carbon-sulfur bond has become an essential
topic in both synthetic organic chemistry and biosynthesis,
leading to the development of a plethora of strategies depending
[
1]
on the sulfur sources and the nature of the substrates. In
addition, sulfur-containing compounds are valuable precursors in
the toolbox of the organic chemist for further transformations in
[
2]
particular, for carbon-carbon bond forming reactions.
Among the four imidazopyridine isomers, imidazo[1,2-a]pyridine
is the most common thanks to its wide variety of biological
[
3]
activities. This scaffold is a key element in a number of
prominent pharmaceutical marketed drugs such as the
worldwide known Zolpidem and Alpidem for treating insomnias
CuI
Phenantroline
tBuOK
Yield of 4a
[
4]
and associated sleeping disorders.
+
+
-
+
+
-
+
-
68%
In the last few years, the functionalization of the imidazo[1,2-
a]pyridine core has been the focus of intensive work, in
particular for the carbon-sulfur bond formation at the C-3
No reaction
No reaction
No reaction
+
+
position. Introduction of
a sulfur group on imidazo[1,2-
a]pyridines is usually based on two different and efficient
strategies, both being either metal-catalyzed or metal-free
processes. The first one relies on the use of an organic sulfur-
containing starting material such as thiols, disulfides, sulfonates
and sulfenyl chlorides (Scheme 1, eq a) with the drawback of not
+
-
Scheme 1. Main strategies for sulfenylation reactions.
[
5]
being environmentally friendly and easy to handle. The second
strategy involves a one-pot three-component reaction between
an imidazo[1,2-a]pyridine, an activated alkyl/aryl partner and the
sulfur, the latest being delivered via an inorganic source such as
Although sulfenylation reactions of imidazo[1,2-a]pyridines have
been well developed, the corresponding sulfonylation reaction is
more scarce despite the relevance of the sulfone moiety in
[
8]
pharmaceuticals and agrochemicals. During our initial studies
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000112
COMMUNICATION
of sulfonylation of C-H bonds by merging the reaction conditions
the optimum conditions for the sulfenylation process were shown
to be CuI (10 mol%), phenanthroline (10 mol%) and tBuOK (2.5
eq) in DMF at 140 °C for 24h.
of direct arylation of imidazo[1,2-a]pyridine derivatives reported
[
9]
by Cao and the use of 1,4-diazabicyclo[2.2.2]octane bis(sulfur
dioxide) adduct (DABCO∙(SO ), we came across an intriguing
observation. The reaction between 2-phenylimidazo[1,2-
a]pyridine 1, iodobenzene 2 and DABCO∙(SO in the presence
2 2
)
2
)
2
[a]
Table 1. Optimization of the sulfenylation reaction
of CuI, phenanthroline and tBuOK in DMF at 140°C did not lead
to the expected sulfonylated product 3 (Scheme 1, eq c). Instead,
the sulfenylation reaction took place furnishing exclusively the C-
[b]
Entry
Catalyst
Ligand
Base
Yield 4a
3
sulfenylated imidazo[1,2-a]pyridine 4a in 68% yield. First,
1
2
3
4
5
6
7
8
9
CuI
Phenanthroline
Phenanthroline
Phenanthroline
Phenanthroline
Phenanthroline
-
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
68%
54%
18%
41%
58%
47%
-
DABCO∙(SO is now very well-known SO -surrogate,
pioneered and re-named DABSO by the group of Willis, for the
direct incorporation of the sulfonyl group through transition
metal-catalyzed reactions or radical-based processes. Second,
this result was quite surprising with respect to Yang and Wang’s
work who described a similar reaction in 2018 , apart from a
copper(II) salt and no base, and reported the sulfonylated
product 3.
relevant spectra of the literature and the structure of 4a was
subsequently unambiguously confirmed by the absence of the
two infra-red absorption bands characteristic of the sulfone
moiety in the region of 1370-1190 and 1170-1110 cm .
Following this preliminary result, control experiments, where CuI,
phenanthroline and tBuOK were left out successively, were
carried out. Neither compound 3 nor compound 4a were formed,
the starting material being fully recovered. These preliminary
2
)
2
a
2
CuCl
CuBr
[
10]
[
e]
CuTC
Cu
[
11]
2
O
[
12]
The NMR spectrum of 4a was compared with
(IPr)CuCl
CuI
Triphenylphosphine
2,2’-Bipyridine
CuI
58%
52%
-
-1 [13]
[
f]
CuI
DMEDA
10
CuI
Phenanthroline
Phenanthroline
Phenanthroline
Phenanthroline
Phenanthroline
Phenanthroline
2 3 2 3
Cs CO or Na CO
11
CuI
tBuOLi
KOAc
30%
21%
results, highlighting the unusual reactivity of DABCO∙(SO
formally delivering only a sulfur atom instead of the SO group,
2 2
)
12
13
14
15
CuI
2
[
c]
prompted us to further explore in more details this
transformation.
For the optimization process, 2-phenylimidazo[1,2-a]pyridine 1
and iodobenzene 2 were selected as benchmark partners.
Screening of the copper sources and ligands revealed that the
CuI/phenanthroline duet was the most effective (Table 1, entry
CuI
tBuOK
tBuOK
tBuOK
-
[
d]
CuI
61%
18%
[g]
CuI
[
a] Unless otherwise noted, reaction conditions are: 2-phenylimidazo[1,2-
1
). Indeed, copper catalysts such as CuCl, CuBr, CuTC and
a]pyridine 1 (0.51 mmol), iodobenzene 2 (2 eq), DABCO∙(SO2)2 (2 eq), [Cu]
(10 mol%), ligand (10 mol%), base (2.5 eq), DMF (2 mL) at 140 °C for 24
hours. [b] Isolated yields. [c] reaction run at 110 °C for 60h. [d] reaction run
with CuI 5 mol% and phenanthroline 5 mol%. [e] CuTC: copper(I) thiophene-2-
carboxylate. [f] DMEDA: trans-N,N’-dimethylethylene-1,2-diamine. [g]
bromobenzene was used instead of iodobenzene.
Cu O, using phenanthroline as the ligand gave no improvement,
2
at best 58% yield (entries 2-5). The use of a N-heterocyclic
carbene copper(I) complex ((IPr)CuCl) showed a lower catalytic
activity furnishing 4a in a 47% yield (entry 6). Next, a brief
survey of the ligands was undertaken in which
triphenylphosphine failed to give compound 4a while nitrogen-
containing ligands such as 2,2’-bipyridine or trans-N,N-
dimethylcyclohexane-1,2-diamine showed moderate results
This optimized protocol was subsequently used to investigate
the reactivity of DABSO in the sulfenylation process with various
aryl iodides (Scheme 2). Both electron-rich and electron-
deficient aryl iodides led exclusively to the sulfenylated
compounds 4 in moderate to good yields with substitutions being
tolerated at each of the ortho-, meta-, and para-positions of the
phenyl ring. Steric effects did not influence the performance of
the reaction since sulfenylated products with ortho-substituents
were isolated between 45-70% yields. However, these
conditions were not compatible with strong electron-withdrawing
groups such as nitrile, nitro or ester with the exception of
compound 4p bearing a cyano group at the meta position. In all
cases, the 2-phenylimidazo[1,2-a]pyridine was mainly recovered.
Interestingly, the free amino group withstood the reaction
conditions as the product 4q was delivered in an appropriate
(
entries 7-9). Also, the use of tBuOK was found to be optimal
since reactions with Cs CO , Na CO , KOAc, tBuOLi were less
2
3
2
3
efficient or did not proceed (entries 10-12). DMF proved to be
the better solvent as reaction in DMSO, acetonitrile, dioxane,
dichloromethane or toluene resulted in no conversion.
Furthermore, the reaction proceeds only in DMF at 140 °C with
no reaction at 110 °C even after prolonged time (60h) (entry 13).
Switching from conventional heating to microwave irradiation, in
order to shorten reaction time, was detrimental to the process,
returning the starting material essentially unchanged (not
shown). Finally, when decreasing the catalyst loading to 5 mol%,
4a was obtained in a slightly lower yield (61%, entry 14). When
4
0% yield. In addition to the aryl group, benzyl bromide reacted
successfully to afford the benzyl sulfenylated derivative 4r in
3% yield.
bromobenzene was used as coupling partner, the yield dropped
drastically to 18% yield (entry 15). The reaction proved to be
also scalable since the sulfenylated compound 4a was obtained
in 66% yield on a 1.5 mmol scale. It is noteworthy that all the
tested conditions in the optimization step did not give a trace
amount of the expected sulfonylated product 3 in first-line. Thus,
8
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000112
COMMUNICATION
yield for each C-S bond). At this stage, no trace of
monosulfenylated compound was observed. Compared to
sulfenylation process, disulfenylation has never been explored
until very recently where Adimurthy et al. reported a copper-
catalyzed disulfenylation of imidazo[1,2-a]pyridine using
[
14]
elemental sulfur and aryl iodides.
The reaction conditions
were also further applied to 6-phenylimidazo[2,1-b]thiazole
which was successfully sulfenylated albeit in a moderate yield
(
6t, 49%).
Scheme 2. Scope of the sulfenylation reaction of 2-phenylimidazo[1,2-
a]pyridine with various aryl iodides.
Next, the reaction scope was further implemented with various
substituted imidazo[1,2-a]pyridines. In fact, the nature of the
substituents on the imidazo[1,2-a]pyridine core showed strong
effects on the outcome of the reaction. Substrates possessing 6-,
7-
and 8- electron-donating groups were successfully
sulfenylated at the C-3 position in good yields (Scheme 3).
Methyl or methoxy groups were well tolerated except when a
methyl group was present on the C-5 position of the imidazo[1,2-
a]pyridine. Indeed, a steric effect was predominant since the
yield of the reaction drastically dropped down to 17%. The
presence of a halogen atom was deleterious to the reaction
since the sulfenylated product 6e was isolated in a low yield
Scheme 3. Scope of the sulfenylation process with various substituted
imidazo[1,2-a]pyridines.
To gain some insights into the reaction mechanism, a few
control experiments were conducted. First, the radical
scavengers 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and
(
35%). Imidazo[2,1-a]isoquinoline was also reactive under the
optimal reaction conditions albeit in lower yield. Various 2-
arylimidazo[1,2-a]pyridines were also compatible with the
optimized conditions leading to the sulfenylated compounds in
moderate to good yields. In most cases, electron-donating (Me,
OMe, NMe ) and electron-withdrawing (CF , F) substituents on
2 3
the phenyl ring did not affect the outcome of the reaction,
2,6-di-tert-butyl-4-methylphenol (BHT) were added in the
standard conditions. Although the yield of the sulfenylated
product 4a dropped significantly when TEMPO was employed in
stoichiometric amount (scheme 4, eq a) and no trace of 4a was
observed with 3 eq of TEMPO, a radical pathway cannot be
strictly confirmed as this reagent can also act as an oxidant.
However, in the presence of BHT, the sulfenylated compound 4a
was still isolated in 54% yield, ruling out definitely the possibility
of a radical process. In addition, compound 4a was not detected
when the reaction was conducted with diphenyl sulfide,
phenylsulfinate or thiophenol, in standard conditions without
DABSO, indicating that these coupling partners might not be
intermediates in the mechanism (scheme 4, eq b). The
sulfenylated process was not affected either when running the
reaction under air or inert atmosphere, indicating that oxygen
does not serve as an oxidizing agent (although in some specific
cases it happened to be deleterious). At last, considering that
delivering the expected compounds 6k-6n in fairly good yields
(
3
52-70%, Scheme 3). Still, the cyano group led to a low yield (6o,
5%). Finally, imidazo[1,2-a]pyridine bearing naphthyl
substituent on the C-2 position led to 6p in a very good yield of
3%. In addition to aryl substituent on the C-2 position, 2-
a
7
methylimidazo[1,2-a]pyridine or 2-styrylimidazo[1,2-a]pyridine
were found suitable substrates providing the sulfenylated
compounds 6q and 6r in 61% and 40% yield respectively. In
these conditions, disulfenylation was also possible starting from
the unsubstituted imidazo[1,2-a]pyridine and the resulting
disulfenylated compound 6s was isolated in 19% yield
considering that two C-S bonds are formed in one pot (~44%
3
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European Journal of Organic Chemistry
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COMMUNICATION
the C-3 sulfonylated imidazopyridine 3 can be formed at first
followed by reduction of the sulfone moiety into sulfur, we first
synthesized compound 3 according to a protocol described by
[
8]
Zhu and Shao in 2018. Then, compound 3 was submitted to
our optimized reaction conditions at 140 °C in DMF (Scheme 4,
eq c). No sulfenylated imidazopyridine was formed, the sulfone
derivative 3 being fully recovered.
Scheme 5. Proposed mechanism for sulfenylation of imidazo[1,2-a]pyridines.
Conclusion
This work highlights the unusual reactivity with DABCO-
bis(sulfur dioxide). Instead of delivering a sulfone group to the
imidazopyridines as described in the recent work of Yang and
Wang, this reagent allowed the introduction of a sulfur atom at
the C-3 position of the imidazopyridines. We were able to show
that this was not an isolated result as the scope of the reaction
could be extended to imidazopyridines and aryl iodides both
bearing substituents with different electronic and steric effects.
The corresponding sulfenylated imidazopyridines were then
isolated in moderate to good yields. The method was also
applicable in large scale synthesis highlighting the robustness of
the procedure. Beyond the fact that this synthetic method
complements the previously reported protocols for sulfenylation
reactions, this work is meant to underline the unconventional
role of DABCO-bis(sulfur dioxide).
Scheme 4. Control experiments for investigating the reaction mechanism.
If DABCO∙(SO
exact behavior of the released SO
conditions, one can expect that disproportionation of SO
2
)
2
is now a very well-known SO
remains obscure. In our
in
can occur. This elemental sulfur would be
the key specie to deliver the sulfur atom as recently described in
2
-surrogate, the
2
2
[
15]
elemental sulfur S
8
[
6, 14, 16]
the literature.
However, the proposed mechanisms are
very heterogeneous regarding the reaction conditions and are
hardly generalized to our process with respect to preliminary
experiments carried out in this work. Although the reaction
mechanism still remains elusive, we can envisione the following
one which is consistent with previous reports on C-H bond
functionalization of nitrogen-containing heterocycles (Scheme
[
17]
5).
The sequence probably starts with a ligand exchange
between complex I and potassium tert-butoxide giving alkoxide
complex II as proposed by Hartwig et al. Then, deprotonation of
Experimental section
2
-phenyl imidazo[1,2-a]pyridine via intermediate III forms the
copper complex IV. simultaneous oxidative addition of
iodobenzene and insertion of sulfur, generated from the
disproportionation of SO results in four coordinated
General information. Commercially available reagents and
solvents were used without further purification. Yields refer to
isolated and purified products. Reactions were monitored by
Thin Layer Chromatography (TLC) carried out on 60F-254 silica
gel plates and visualized under UV light at 254 and 365 nm.
A
2
,
a
copper(III) intermediate V. A subsequent reductive elimination
furnishes the sulfenylated product and releases the Cu(I)
catalyst.
Column chromatography was performed on
a Combiflash
Companion using pre-packed silica 60 columns. Chemical shifts
1
13
(
δ) of H and C NMR are reported in ppm and residual non
deuterated solvents were used as references. Multiplicities are
designated by the following abbreviations: s = singlet, d =
doublet, t = triplet, q = quadruplet, bs = broad singlet, m =
multiplet. Melting points were measured with a Stuart SMP30.
High-resolution mass spectra (HRMS) were measured by a TOF
spectrometer, using electrospray ionization (ESI) or atmospheric
pressure photoionization (APPI) method. LCMS were performed
on a Waters spectrometer using Phenomenex Luna Omega 3
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000112
COMMUNICATION
µm Polar C18 100A column. MS were determined on a Waters
micromass ZQ spectrometer using electrospray ionization (ESI).
Substituted imidazo[1,2-a]pyridines were synthesized according
to literature from condensation of the corresponding -
bromoketones and 2-aminopyridines in refluxing EtOH with
7.49 – 7.28 (m, 4H), 7.16 (d, J=8.6 Hz, 2H), 6.92-6.84 (m, 3H)
1
3
C NMR (75 MHz, CDCl
3
): δ=151.7, 147.3, 133.8, 133.2, 132.1,
129.7, 128.8, 128.6, 128.4, 126.9, 126.9, 124.4, 117.9, 113.3,
+
+ [8]
105.8; MS (ES ): m/z (%) = 336.8 (100) [M + H] .
[
18]
NaHCO
3
.
2-styrylimidazo[1,2-a]pyridine was synthesized
2-phenyl-3-((4-(trifluoromethyl)phenyl)thio)imidazo[1,2-
[
19]
1
using a protocol described by Mohan et al.
a]pyridine (4f). Yellow solid (106 mg, 56%); H NMR (300 MHz,
CDCl
3
): δ=8.23 (d, J=6.8 Hz, 1H), 8.15 (d, J=6.8 Hz, 2H), 7.77 (d,
General procedure. To a sealed tube under argon atmosphere
were added imidazo[1,2-a]pyridine 1 (0.51 mmol, 100 mg),
DABSO (1.03 mmol, 247 mg), CuI (0.05 mmol, 10 mg), 1,10-
phenanthroline (0.05 mmol, 9 mg), t-BuOK (1.29 mmol, 144 mg)
and iodobenzene (1.03 mmol, 115 µL) in dry DMF (2 mL). The
tube was sealed and the reaction mixture was stirred at 140 °C
for 24 h in an oil bath. The mixture was cooled down to room
temperature and water (10 mL) was added. The mixture was
extracted with DCM (3 x 10 mL), the organic layer was dried with
J=9.0 Hz, 1H), 7.47-7.35 (m, 6H), 7.06 (d, J=8.2 Hz, 2H), 6.92 (t,
1
3
J=6.8 Hz, 1H); C NMR (75 MHz, CDCl
140.6 , 133.1 , 129.0 , 128.6 , 128.4 , 128.1 , 127.2 , 126.4 (q,
C-F = 3.7 Hz), 125.3 , 124.4 , 124.1 (d, JC-F = 271.9 Hz), 118.0 ,
3
): δ=152.2 , 147.5 ,
J
+
+ [8]
113.6 , 104.6; MS (ES ): m/z (%) = 370.8 (100) [M + H] .
2-phenyl-3-(o-tolylthio)imidazo[1,2-a]pyridine (4g). Yellow
1
solid (106 mg, 65%); H NMR (300 MHz, CDCl ): δ=8.22 – 8.13
3
(m, 3H), 7.76 (d, J=9.0 Hz, 1H), 7.46-7.32 (m, 4H), 7.20 (d,
J=7.4 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H), 6.89 (dt, J=13.7, 7.2 Hz,
4
anhydrous MgSO and evaporated under reduced pressure. The
1
3
crude was purified by chromatography with a gradient of
cyclohexane to cyclohexane/EtOAc 10% to afford the
sulfenylated product 4a in 68% yield.
1H), 6.42 (d, J=7.8 Hz, 1H), 2.52 (s, 3H); C NMR (75 MHz,
CDCl ): δ=151.7, 147.2, 134.9, 134.1, 133.4, 130.7, 128.6,
3
128.4, 128.4, 127.0, 126.7, 125.7, 124.5, 124.1, 117.7, 113.1,
+
+ [6a]
1
05.6, 19.9; MS (ES ): m/z (%) = 316.8 (100) [M + H] .
2
-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (4a). Yellow
1
solid (106 mg, 68%); H NMR (300 MHz, CDCl
3
): δ= 8.27 (d, J =
.8 Hz, 1H), 8.24 – 8.19 (m, 2H), 7.74 (d, J=9.0 Hz, 1H), 7.48 –
.30 (m, 4H), 7.25 – 7.09 (m, 3H), 7.00 (m, 2H), 6.86 (td, J = 7.5,
.7 Hz ,1H); C NMR (75 MHz, CDCl
33.4, 129.5, 128.7, 128.5, 128.5, 126.8, 126.1, 125.6, 124.6,
3-((2-methoxyphenyl)thio)-2-phenylimidazo[1,2-a]pyridine
1
6
7
0
1
1
(4h). Yellow solid (77 mg, 45%); H NMR (300 MHz, CDCl3):
δ=8.27 (d, J=6.8 Hz, 1H), 8.19 (d, J=7.0 Hz, 2H), 7.74 (d, J=9.0
Hz, 1H), 7.48 – 7.29 (m, 4H), 7.12 (td, J=7.7 Hz, 1.3 Hz, 1H),
6.91-6.84 (m, 2H), 6.69 (t, J=8.0 Hz, 1H), 6.39 (dd, J=7.7, 1.3 Hz,
13
3
): δ=151.5, 147.2, 135.3,
+
+
13
17.7, 113.2, 106.3; MS (ES ): m/z (%) = 302.7 (100) [M + H] .
1H), 3.94 (s, 3H); C NMR (75 MHz, CDCl ): δ=156.2, 151.9,
3
[
6a]
1
47.4, 133.5, 128.6, 128.5, 127.0, 126.7, 125.6, 124.9, 123.4,
+
121.7, 117.7, 113.0, 110.9, 105.4, 56.0; MS (ES ): m/z (%) =
+
[21]
2
-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (4b). Yellow
332.8 (100) [M + H] .
1
solid (113 mg, 77%); H NMR (300 MHz, CDCl
3
): δ=8.28 (d, J =
6
7
6
.8 Hz, 1H), 8.21 (d, J=7.0 Hz, 2H), 7.72 (d, J=9.0 Hz, 1H), 7.46-
3-((2-fluorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (4i).
1
.29 (m, 4H), 7.02 (d, J=8.2 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H),
Pink solid (115 mg, 70%); H NMR (300 MHz, CDCl ): δ= 8.30 (d,
3
13
.85 (t, J=6.5 Hz, 1H), 2.26 (s, 3H); C NMR (75 MHz, CDCl
3
):
J=6.8 Hz, 1H), 8.20 (d, J=7.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 1H),
δ=151.2, 147.0, 136.0, 133.5, 131.5, 130.2, 128.6, 128.4, 128.4,
7.47-7.33 (m, 4H), 7.18 – 7.02 (m, 2H), 6.94 – 6.82 (m, 2H),
6.61 – 6.49 (td, J=7.7 Hz, 1.0 Hz, 1H); C NMR (75 MHz,
+
13
1
26.6 125.8, 124.5, 117.6, 113.0, 106.8, 20.9; MS (ES ): m/z
+
[8]
(
%) = 316.8 (100) [M + H] .
CDCl ): δ=159.7 (d, J = 244.9 Hz), 152.1 , 147.4 , 133.2 , 128.8 ,
3
128.5 , 128.4 , 127.8 (d, J = 7.3 Hz), 127.3 (d, JC-F = 2.2 Hz),
3
-((4-methoxyphenyl)thio)-2-phenylimidazo[1,2-a]pyridine
126.9 , 125.1 (d, JC-F = 3.4 Hz), 124.6 , 122.4 (d, JC-F = 17.1 Hz),
1
+
(
4c). Yellow solid (139 mg, 81%); H NMR (300 MHz, CDCl
3
):
117.8 , 116.0 (d, JC-F = 20.8 Hz), 113.3 , 104.2; MS (ES ): m/z
+
[22]
δ=8.32 (d, J=6.8 Hz, 1H), 8.24 (d, J=7.1 Hz, 2H), 7.71 (d, J=9.0
Hz, 1H), 7.49 – 7.27 (m, 4H), 6.99 (d, J=8.8 Hz, 2H), 6.87 (t,
(%) = 320.7 (100) [M + H] .
1
3
J=6.6 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H) , 3.73 (s, 3H); C NMR
75 MHz, CDCl ): δ=158.6, 150.9, 147.0, 133.6, 128.6, 128.5,
28.5, 128.0, 126.6, 125.5, 124.6, 117.7, 115.2, 113.1, 107.9,
3-((2-chlorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (4j).
1
(
3
Yellow solid (97 mg, 56%); H NMR (300 MHz, CDCl ): δ=8.24
3
1
5
(d, J=6.8 Hz, 1H), 8.16 (d, J=7.8 Hz, 2H), 7.79 (d, J=9.0 Hz, 1H),
+
+ [20]
5.4; MS (ES ): m/z (%) = 332.8 (100) [M + H] .
7.49 – 7.32 (m, 5H), 7.08 (td, J=7.8, 1.5 Hz, 1H), 7.01 – 6.88 (m,
1
3
2
3
H), 6.40 (dd, J=7.9, 1.4 Hz, 1H); C NMR (75 MHz, CDCl ):
3
-((4-fluorobenzyl)thio)-2-phenylimidazo[1,2-a]pyridine (4d).
δ=152.3, 147.6, 134.4, 133.2, 131.2, 130.2, 128.9, 128.6, 128.41,
1
Yellow solid (120 mg, 73%) ; H NMR (300 MHz, CDCl
3
): δ=
127.7, 127.1, 127.0, 125.6, 124.6, 117.9, 113.4, 104.7; MS
+
+ [23]
8.28 (d, J = 6.8 Hz, 1H), 8.25 – 8.16 (m, 2H), 7.73 (d, J = 9.1 Hz,
(ES ): m/z (%) = 336.9 (100) [M + H] .
1
3
1
H), 7.51 – 7.30 (m, 4H), 7.05 – 6.83 (m, 5H); C NMR (75 MHz,
): δ=161.5 (d, JC-F = 246.0 Hz), 151.3 , 147.1 , 133.3 ,
30.1 (d, JC-F = 3.1 Hz), 128.7 , 128.5 , 128.3 , 127.6 (d, JC-F
.9 Hz), 126.7 , 124.3 , 117.7 , 116.6 (d, JC-F = 22.2 Hz), 113.2 ,
CDCl
3
2-phenyl-3-((3-(trifluoromethyl)phenyl)thio)imidazo[1,2-
a]pyridine (4k). Yellow solid (114 mg, 60%); mp 112-114 °C; H
1
1
7
1
=
NMR (300 MHz, CDCl ): δ= 8.25 (d, J=6.8 Hz, 1H), 8.17 (d,
3
+
+ [8]
06.6; MS (ES ): m/z (%) = 320.7 (100) [M + H] .
J=6.8 Hz, 2H), 7.76 (d, J=9.0 Hz, 1H), 7.49 – 7.35 (m, 6H), 7.32
–
7.24 (m, 1H), 6.99 (d, J=7.9 Hz, 1H), 6.91 (t, J=6.8 Hz, 1H);
C NMR (75 MHz, CDCl ): δ=152.2, 147.5, 137.1, 133.2, 132.2,
3
1
3
3
-((4-chlorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (4e).
1
Yellow solid (90 mg, 52%); H NMR (300 MHz, CDCl
3
): δ=8.23
131.8, 130.0, 128.9, 128.7, 128.5, 128.4, 127.1, 124.4, 123,
+
(
d, J=6.8 Hz, 1H), 8.18 (d, J=7.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 1H),
122.5, 118.0, 113.5, 104.9; MS (ES ): m/z (%) = 370.7 (100) [M
5
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000112
COMMUNICATION
+
+
[
H] ; HRMS (ESI-TOF): m/z calcd for C20
H
14
F
3
N
2
S: 371.0830
128.7, 128.5, 128.5, 126.5, 124.6, 122.3, 117.6, 116.2, 113.0,
108.7; MS (ES ): m/z (%) = 317.8 (100) [M + H] .
+
+
+ [21]
M+H] ; found: 371.0836.
2
-phenyl-3-(m-tolylthio)imidazo[1,2-a]pyridine (4l). Yellow
3-(benzylthio)-2-phenylimidazo[1,2-a]pyridine (4r). Brown
1
1
solid (129 mg, 80%); H NMR (300 MHz, CDCl
3
): δ=8.28 (d,
solid (136 mg, 84%); H NMR (300 MHz, CDCl
3
): δ=8.28 – 8.20
J=6.8 Hz, 1H), 8.24 – 8.19 (m, 2H), 7.74 (d, J=9.0 Hz, 1H), 7.48
(m, 2H), 8.07 (d, J=6.9 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.45 (t,
J=7.3 Hz, 2H), 7.41 – 7.36 (m, 1H), 7.23 – 7.15 (m, 1H), 7.09 –
7.03 (m, 3H), 6.95-6.89 (m, 2H), 6.67 (td, J=6.8, 0.9 Hz 1H),
–
7.30 (m, 4H), 7.09 (t, J=7.7 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H),
1
3
6
.90 – 6.83 (m, 2H), 6.77 (d, J=7.8 Hz, 1H), 2.23 (s, 3H);
): δ=151.4, 147.2, 139.5, 135.0, 133.5,
29.4, 128.7, 128.5, 128.4, 127.1, 126.7, 126.1, 124.6, 122.6,
C
1
3
NMR (75 MHz, CDCl
1
1
3
3.81 (s, 2H); C NMR (75 MHz, CDCl
3
): δ=150.0, 146.3, 137.0,
133.8, 128.6, 128.4, 128.3, 128.2, 127.3, 125.9, 124.1, 117.2,
+
+
+ [20]
17.7, 113.1, 106.5, 21.5; MS (ES ): m/z (%) = 316.8 (100) [M +
112.2, 109.3, 40.5; MS (ES ): m/z (%) = 316.8 (100) [M + H] .
+
[22]
H] .
8
-methyl-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (6a).
1
3
-((3-methoxyphenyl)thio)-2-phenylimidazo[1,2-a]pyridine
3
Yellow solid (120 mg, 74%); H NMR (300 MHz, CDCl ): δ=8.22
1
(
4m). Yellow solid (116 mg, 68%); m.p. 90-92 °C; H NMR (300
MHz, CDCl ): δ=8.28 (d, J=6.8 Hz, 1H), 8.23 – 8.16 (m, 2H),
.73 (d, J=9.0 Hz, 1H), 7.49 – 7.30 (m, 4H), 7.12 (t, J=7.9 Hz,
H), 6.88 (td, J=6.8, 0.8 Hz, 1H), 6.71-6.64 (m, 1H), 6.61-6.53
– 8.16 (m, 2H), 8.14 (d, J=6.8 Hz, 1H), 7.48-7.32 (m, 3H), 7.24-
7.16 (m, 2H), 7.16 – 7.09 (m, 2H), 7.03 – 6.96 (m, 2H), 6.78 (t,
J=6.8 Hz, 1H), 2.72 (s, 3H); C NMR (75 MHz, CDCl ): δ=151.2,
3
3
1
3
7
1
147.5, 135.6, 133.8, 129.5, 128.6, 128.5, 127.8, 126.0, 125.6,
1
3
+
(
m, 2H), 3.67 (s, 3H); C NMR (75 MHz, CDCl
3
): δ=160.4, 151.6, 125.5, 122.4, 113.1, 106.5, 16.9; MS (ES ): m/z (%) = 316.8
+
[8]
147.2, 136.7, 133.4, 130.4, 128.7, 128.5, 128.5, 126.8, 124.6,
(100) [M + H] .
+
117.8, 117.7, 113.2, 111.7, 111.3, 106.3, 55.3; MS (ES ): m/z
+
(
%) = 332.8 (100) [M + H] ; HRMS (ESI-TOF): m/z calcd for
7-methyl-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (6b).
+
1
C
20
H
17
N
2
OS: 333.1062 [M+H] ; found: 333.1050.
Yellow solid (119 mg, 73%); H NMR (300 MHz, CDCl ): δ=8.19
3
(
d, J=7.4 Hz, 2H), 8.13 (d, J=6.6 Hz, 1H), 7.49 (s, 1H), 7.46-7.33
3
-((3-fluorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (4n).
(m, 3H), 7.24-7.08 (m, 3H), 6.99 (d, J=7.6 Hz, 2H), 6.68 (d,
J=6.1 Hz, 1H), 2.43 (s, 3H); C NMR (75 MHz, CDCl ): δ=151.4,
3
1
13
Yellow solid (82 mg, 50%); H NMR (300 MHz, CDCl
3
): δ=8.25
(
7
d, J=6.8 Hz, 1H), 8.20 – 8.14 (m, 2H), 7.76 (d, J=9.0 Hz, 1H),
147.6, 138.0, 135.6, 133.6, 129.5, 128.6, 128.5, 128.4, 126.0,
+
.50 – 7.31 (m, 4H), 7.18 (td, J=8.0, 6.0 Hz, 1H), 6.93 – 6.87 (t,
125.6, 123.8, 116.3, 115.8, 105.5, 21.5; MS (ES ): m/z (%) =
13
+ [8]
J=6.8 Hz, 1H), 6.86 – 6.75 (m, 2H), 6.71 – 6.66 (m, 1H);
C
316.8 (100) [M + H] .
3
NMR (75 MHz, CDCl ): δ=163.4 (d, JC-F = 249.4 Hz), 151.8 ,
1
1
1
1
47.3 , 137.8 (d, JC-F = 7.1 Hz), 133.1 , 130.9 (d, JC-F = 8.4 Hz),
28.9 , 128.6 , 128.4 , 127.1 , 124.4 , 121.1 (d, JC-F = 3.0 Hz),
6-methyl-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (6c).
1
Yellow solid (98 mg, 60%); H NMR (300 MHz, CDCl ): δ=8.22 –
3
17.8 , 113.4 , 113.2 (d, JC-F = 21.5 Hz), 112.5 (d, JC-F = 24.3 Hz), 8.15 (m, 2H), 8.07 (s, 1H), 7.64 (d, J=9.1 Hz, 1H), 7.46-7.34 (m,
+
+ [22]
13
05.4; MS (ES ): m/z (%) = 320.7 (100) [M + H] .
3H), 7.25 – 7.12 (m, 4H), 7.04 – 6.97 (m, 2H), 2.31 (s, 3H);
NMR (75 MHz, CDCl ): δ=151.3, 146.2, 135.6, 133.5, 129.8,
129.4, 128.5, 128.4, 128.3, 125.9, 125.4, 122.9, 122.2, 117.0,
C
3
3-((3-chlorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (4o).
1
+
+ [13a]
Yellow solid (84 mg, 49%); H NMR (300 MHz, CDCl
3
): δ=8.25
105.6, 18.4; MS (ES ): m/z (%) = 316.8 (100) [M + H] .
(
d, J=6.8 Hz, 1H), 8.20 – 8.13 (m, 2H), 7.75 (d, J=9.0 Hz, 1H),
7
.50 – 7.32 (m, 4H), 7.12 (m, 2H), 7.02 (m, 1H), 6.91 (td, J=6.8,
5-methyl-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (6d).
13
1
0.8 Hz, 1H), 6.85 – 6.79 (m, 1H); C NMR (75 MHz, CDCl
3
):
Yellow solid (27 mg, 17%); H NMR (300 MHz, CDCl ): δ=8.01 –
3
δ=152.0, 147.5, 137.6, 135.5, 133.2, 130.6, 128.9, 128.6, 128.46, 7.95 (m, 2H), 7.63 (d, J=8.9 Hz, 1H), 7.41 – 7.33 (m, 3H), 7.28 –
1
27.1, 126.5, 125.4, 124.5, 123.6, 118.3, 113.5, 105.3; MS
7.18 (m, 3H), 7.12 (t, J=7.4 Hz ,1H), 6.97 (d, J=8.3 Hz, 2H), 6.56
(d, J=6.9 Hz, 1H), 2.97 (s, 3H); C NMR (75 MHz, CDCl3):
+
+ [21]
13
(
ES ): m/z (%) = 336.8 (100) [M + H] .
δ=154.1, 149.1, 140.6, 138.9, 133.7, 129.6, 129.1, 128.6, 128.3,
+
3
-((2-phenylimidazo[1,2-a]pyridin-3-yl)thio)benzonitrile (4p).
127.0, 125.6, 124.9, 116.3, 115.1, 107.1, 20.6; MS (ES ): m/z
(%) = 316.9 (100) [M + H] .
1
+ [22]
Yellow solid (48 mg, 29%); m.p. 113-115 °C; H NMR (300 MHz,
CDCl ): δ=8.23 (d, J=6.8 Hz, 1H), 8.15 (dd, J=8.1, 1.5 Hz, 2H),
.77 (d, J=9.0 Hz, 1H), 7.49 – 7.35 (m, 5H), 7.30 (t, J=7.8 Hz,
H), 7.26 (m, 1H), 7.19 – 7.13 (m, 1H), 6.93 (td, J=6.8, 1.0 Hz,
3
7
1
1
1
1
6-chloro-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (6e).
Yellow solid (60 mg, 35%); H NMR (300 MHz, CDCl ): δ=8.34 –
8.30 (m, 1H), 8.23 – 8.17 (m, 2H), 7.67 (d, J=9.4 Hz, 1H), 7.49 –
7.35 (m, 3H), 7.29 (dd, J=9.5, 2.0 Hz, 1H), 7.25 – 7.20 (m, 2H),
7.19 – 7.14 (m, 1H), 7.04 – 6.98 (m, 2H); C NMR (75 MHz,
1
3
1
3
H); C NMR (75 MHz, CDCl
30.1, 129.6, 129.5, 129, 128.6, 128.4, 128.3, 127.2, 124.1,
18.0, 118.0, 113.7, 113.6, 104.0 ; MS (ES ): m/z (%) = 327.9
3
): δ=152.3, 147.5, 137.9, 132.9,
+
13
+
(
100) [M + H] ; HRMS (ESI-TOF): m/z calcd for C20
H
14
N
3
S:
CDCl ): δ=152.3, 145.5, 134.7, 133.0, 129.7, 129.0, 128.6,
128.4, 128.2, 126.4, 125.8, 122.6, 121.7, 118.2, 107.3; MS
3
+
328.0908 [M+H] ; found: 328.0895.
+
+ [8]
(
ES ): m/z (%) = 336.9 (100) [M + H] .
4
-((2-phenylimidazo[1,2-a]pyridin-3-yl)thio)aniline (4q). White
1
crystals (65 mg, 40%); H NMR (300 MHz, CDCl
J=6.9 Hz, 1H), 8.29 – 8.23 (m, 2H), 7.70 (d, J=9.0 Hz, 1H), 7.45
t, J=7.2 Hz, 2H), 7.41 – 7.36 (m, 1H), 7.30 (ddd, J=9.0, 6.9, 1.3
Hz, 1H), 6.94 – 6.82 (m, 3H), 6.53 (d, J=8.5 Hz, 2H), 3.62 (s,
3
): δ=8.34 (d,
8-methoxy-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine
1
(6f). Brown solid (84 mg, 49%); H NMR (300 MHz, CDCl3):
(
δ=8.29 – 8.19 (m, 2H), 7.92 (d, J=6.7 Hz, 1H), 7.45-7.32 (m, 3H),
7.23 – 7.09 (m, 3H), 7.03 – 6.96 (m, 2H), 6.76 (t, J=7.2 Hz, 1H),
1
3
13
2H); C NMR (75 MHz, CDCl
3
): δ=150.5, 146.8, 145.6, 133.6,
6.61 (d, J=7.5 Hz, 1H), 4.07 (s, 3H); C NMR (75 MHz, CDCl3):
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000112
COMMUNICATION
δ=150.7, 149.1, 141.4, 135.4, 133.3, 129.5, 128.6, 128.5, 128.3,
CDCl
3
): δ=151.5, 147.1, 138.5, 135.3, 130.5, 129.4, 129.2,
+
1
26.1, 125.7, 117.3, 113.0, 107.4, 103.0, 56.1; MS (ES ): m/z
128.2, 126.6, 126.0, 125.5, 124.4, 117.5, 113.0, 105.9, 21.4; MS
+
[22]
+
+ [8]
(
%) = 332.8 (100) [M + H] .
(ES ): m/z (%) = 316.8 (100) [M + H] .
7
-methoxy-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine
3-(phenylthio)-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-
a]pyridine (6m). Yellow solid (99 mg, 52%); H NMR (300 MHz,
CDCl ): δ=8.35 (d, J=8.2 Hz, 2H), 8.31 (d, J=6.9 Hz, 1H), 7.75 (d,
3
1
1
(
6g). Pink solid (134 mg, 78%); H NMR (300 MHz, CDCl
δ=8.31-8.16 (m, 2H), 8.07 (d, J=7.5 Hz, 1H), 7.46-7.34 (m, 3H),
.24-7.18 (m, 2H), 7.16-7.10 (m, 1H), 7.04 – 6.99 (m, 3H), 6.57
3
):
7
J=9.0 Hz, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.42 – 7.32 (m, 1H), 7.25-
7.12 (m, 3H), 7.02 – 6.96 (m, 2H), 6.91 (td, J=6.8, 0.5 Hz, 1H);
1
3
(
dd, J=7.5, 2.5 Hz, 1H), 3.89 (s, 3H); C NMR (75 MHz, CDCl
3
):
1
3
δ=159.6, 151.2, 148.6, 135.6, 133.4, 129.5, 128.5, 128.4, 128.2,
3
C NMR (75 MHz, CDCl ): δ= 149.8, 147.3, 137.0, 134.7, 130.5,
+
126.0, 125.5, 124.9, 107.9, 104.8, 95.2, 55.8; MS (ES ): m/z (%)
130.1, 129.7, 129.6, 128.6, 128.5, 127.3, 127.1, 126.4, 126.4,
126.1, 125.7, 125.6, 125.3, 124.7, 124.6, 122.5, 118.0, 117.9,
+
[8]
=
332.8 (100) [M + H] .
+
+ [8]
1
13.6, 107.4; MS (ES ): m/z (%) = 370.7 (100) [M + H] .
7-methoxy-2-phenyl-3-((4-
(
trifluoromethyl)phenyl)thio)imidazo[1,2-a]pyridine
(6h).
Yellow solid (45 mg, 51%); m.p. 109-111 °C; H NMR (300 MHz,
CDCl ): δ=8.16 – 8.10 (m, 2H), 8.02 (d, J=7.5 Hz, 1H), 7.48 –
.36 (m, 5H), 7.10 – 7.02 (m, 3H), 6.60 (dd, J=7.5, 2.4 Hz, 1H),
2-(4-fluorophenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (6n).
Beige solid (115 mg, 70%); H NMR (300 MHz, CDCl ): δ=8.27
3
(d, J=6.8 Hz, 1H), 8.23-8.16 (m, 2H), 7.72 (d, J=9.0 Hz, 1H),
1
1
3
7
3
1
1
7.34 (t, J=7.8 Hz, 1H), 7.25-7.18 (m, 2H), 7.17 – 7.08 (m, 3H),
13
13
.90 (s, 3H); C NMR (75 MHz, CDCl
3
): δ=159.9, 152.0, 149.1,
6.99 (d, J=7.2 Hz, 2H), 6.88 (t, J=6.5 Hz, 1H); C NMR (75 MHz,
41.1, 133.3, 128.8, 128.6, 128.2, 126.4, 125.9, 125.2, 124.7,
3
CDCl ): δ= 164.8 , 161.5 , 150.6 , 147.6 , 135.1 , 130.2 (d, JC-F =
+
22.3, 108.3, 103.1, 95.5, 55.9; MS (ES ): m/z (%) = 400.9 (100)
8.2 Hz), 129.6 , 126.9 , 126.2 , 125.6 , 124.6 , 117.7 , 115.5 (d, J
+
+
[
M + H] ; HRMS (ESI-TOF): m/z calcd for C21
H
16
N
2
OF
3
S:
C-H= 21.5 Hz), 113.2 , 106.1; MS (ES ): m/z (%) = 320.7 (100) [M
+
+ [21]
4
01.0935 [M+H] ; found: 401.0932.
+ H] .
N,N-dimethyl-4-(2-phenyl-3-(phenylthio)imidazo[1,2-
a]pyridin-7-yl)aniline (6i). Yellow solid (62 mg, 46%); m.p. 251-
4-(3-(phenylthio)imidazo[1,2-a]pyridin-2-yl)benzonitrile (6o).
1
Yellow solid (58 mg, 35%); H NMR (300 MHz, CDCl
3
): δ=8.41-
1
2
1
2
2
1
1
4
53 °C; H NMR (300 MHz, CDCl
H), 7.59 (d, J=8.7 Hz, 2H), 7.48-7.34 (m, 3H), 7.26-7.19 (m,
H), 7.17-7.11 (m, 2H), 7.04 (d, J=7.5 Hz, 2H), 6.81 (d, J=8.8 Hz, J=6.9, 0.7 Hz, 1H); C NMR (75 MHz, CDCl
3
): δ=8.25-8.20 (m, 3H), 7.87 (s, 8.27 (m, 2H), 8.30 (d, J=6.9 Hz, 1H), 7.77-7.67 (m, 3H), 7.42 –
7.34 (m, 1H), 7.27-7.15 (m, 3H), 7.01 – 6.95 (m, 2H), 6.92 (td,
1
3
3
): δ=149.0, 147.3,
1
3
H), 3.03 (s, 6H); C NMR (75 MHz, CDCl
3
): δ=150.7, 147.9,
137.9, 134.4, 132.3, 129.7, 128.7, 127.4, 126.5, 125.7, 124.7,
+
40.0, 135.6, 133.5, 129.5, 128.5, 128.4, 128.3, 127.6, 126.0,
119.1, 118.0, 113.8, 111.9, 107.9; MS (ES ): m/z (%) = 327.8
+
+ [21]
25.6, 124.1, 112.6, 112.0, 105.4, 40.4; MS (ES ): m/z (%) =
(100) [M + H] .
+
22.2 (100) [M
+
H] ; HRMS (ESI-TOF): m/z calcd for
+
C
27
H
24
N
3
S: 422.1691 [M+H] ; found: 422.1683.
2-(naphthalen-2-yl)-3-(phenylthio)imidazo[1,2-a]pyridine (6p).
1
Beige solid (132 mg, 73%); H NMR (300 MHz, CDCl
3
): δ=8.72
2
-phenyl-3-(phenylthio)imidazo[2,1-a]isoquinoline
(6j).
Yellow solid (63 mg, 35%); m.p. 160-163 °C; H NMR (300 MHz,
CDCl ): δ=8.82 (d, J=7.8 Hz, 1H), 8.30 – 8.23 (m, 2H), 8.11 (d,
J=7.3 Hz, 1H), 7.77 – 7.73 (m, 1H), 7.73 – 7.67 (m, 1H), 7.66 –
(s, 1H), 8.39 (dd, J=8.6, 1.4 Hz, 1H), 8.33 (d, J=6.8 Hz, 1H),
7.94-7.88 (m, 2H), 7.87 – 7.82 (m, 1H), 7.78 (d, J=9.0 Hz, 1H),
7.51 – 7.44 (m, 2H), 7.37 (ddd, J=8.7, 6.9, 1.3 Hz, 1H), 7.24 –
7.19 (m, 2H), 7.18 – 7.13 (m, 1H), 7.08-7.03 (m, 2H), 6.90 (t,
1
3
13
7.60 (m, 1H), 7.50 – 7.42 (m, 2H), 7.41 – 7.34 (m, 1H), 7.25-
3
J=6.1 Hz, 1H); C NMR (75 MHz, CDCl ): δ=151.4, 147.3, 135.3,
1
3
7
.17 (m, 2H), 7.16-7.09 (m, 2H), 7.07 – 7.01 (m, 2H); C NMR
): δ=149.9, 145.1, 137.1, 135.8, 133.6, 130.4,
133.5, 130.9, 128.8, 128.1, 128.0, 127.7, 126.9, 126.5, 126.3,
+
(
75 MHz, CDCl
3
126.2, 126.0, 125.9, 124.6, 117.8, 113.3, 106.9; MS (ES ): m/z
+
[8]
129.5, 129.0, 128.5, 128.4, 128.3, 127.1, 126.1, 125.7, 123.8,
(%) = 352.9 (100) [M + H] .
+
123.7, 121.3, 113.7, 108.5; MS (ES ): m/z (%) = 352.9 (100) [M
+
+
H] ; HRMS (ESI-TOF): m/z calcd for C23
H
17
N
2
S: 353.1112
2-methyl-3-(phenylthio)imidazo[1,2-a]pyridine (6q). White
+
1
[
M+H] ; found: 353.1109.
cristals (76 mg, 61%); H NMR (300 MHz, CDCl ): δ=8.15 (d,
3
J=6.8 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.31-7.22 (m, 1H), 7.22-
2
-(4-methoxyphenyl)-3-(phenylthio)imidazo[1,2-a]pyridine
7.15 (m, 2H), 7.15-7.07 (m, 1H), 6.93 (d, J=7.6 Hz, 2H), 6.81 (t,
J=6.9 Hz, 1H), 2.58 (s, 3H); C NMR (75 MHz, CDCl ): δ=151.8,
3
1
13
(
6k). Yellow solid (94 mg, 55%); H NMR (300 MHz, CDCl
3
):
δ=8.26 (d, J=6.8 Hz, 1H), 8.20-8.13 (m, 2H), 7.71 (d, J=9.0 Hz,
147.1, 135.7, 129.4, 126.1, 126.0, 125.7, 124.4, 117.1, 112.7,
14.1; MS (ES ): m/z (%) = 240.8 (100) [M + H] .
+
+ [8]
1
H), 7.36 – 7.28 (m, 1H), 7.24 – 7.09 (m, 3H), 7.03 – 6.93 (m,
1
3
4
H), 6.89 – 6.81 (m, 1H), 3.83 (s, 3H); C NMR (75 MHz,
): δ=160.0, 151.3, 147.1, 135.3, 129.7, 129.5, 126.6,
26.0, 126.0, 125.5, 124.4, 117.4, 113.9, 112.9, 105.3, 55.3; MS
CDCl
3
(E)-3-(phenylthio)-2-styrylimidazo[1,2-a]pyridine (6r). Orange
1
1
oil (67 mg, 40%); H NMR (300 MHz, CDCl ): δ=8.19 (d, J=6.9
3
+
+ [8]
(
ES ): m/z (%) = 332.8 (100) [M + H] .
Hz, 1H), 7.82 (d, J=16.1 Hz, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.61 (d,
J=7.7 Hz, 2H), 7.47 (d, J=16.1 Hz, 1H), 7.40 – 7.10 (m, 7H),
1
3
3
-(phenylthio)-2-(p-tolyl)imidazo[1,2-a]pyridine (6l). Yellow
7.03 (d, J=8.0 Hz, 2H), 6.82 (t, J=6.8 Hz, 1H); C NMR (75 MHz,
CDCl ): δ=150.4, 147.8, 137.1, 135.2, 133.0, 129.5, 128.8,
128.3, 127.2, 127.2, 126.4, 126.3, 124.5, 118.3, 117.4, 112.9;
1
solid (120 mg, 73%); H NMR (300 MHz, CDCl
J=6.8 Hz, 1H), 8.11 (d, J=8.1 Hz, 2H), 7.72 (d, J=9.0 Hz, 1H),
3
): δ=8.26 (d,
3
+
+ [5b]
7.36 – 7.28 (m, 1H), 7.24 – 7.12 (m, 4H), 7.03 – 6.97 (m, 2H),
MS (ES ): m/z (%) = 328.9(100) [M + H] .
1
3
6.85 (td, J=6.8, 0.7 Hz, 1H), 2.38 (s, 3H); C NMR (75 MHz,
7
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European Journal of Organic Chemistry
10.1002/ejoc.202000112
COMMUNICATION
S. Hor, X. Liu, Chem. Soc. Rev. 2015, 44, 291-314; e) D.-
Q. Dong, S.-H. Hao, D.-S. Yang, L.-X. Li, Z.-L. Wang, Eur.
J. Org. Chem. 2017, 2017, 6576-6592.
a) S. G. Modha, V. P. Mehta, E. V. Van der Eycken, Chem.
Soc. Rev. 2013, 42, 5042-5055; b) L. Wang, W. He, Z. Yu,
Chem. Soc. Rev. 2013, 42, 599-621.
D. Vanda, P. Zajdel, M. Soural, Eur. J. Med. Chem. 2019,
181, 111569.
S. Z. Langer, S. Arbilla, J. Benavides, B. Scatton, Adv.
Biochem. Psychopharmacol. 1990, 46, 61.
a) M.-A. Hiebel, S. Berteina-Raboin, Green Chem. 2015,
2
,3-bis(phenylthio)imidazo[1,2-a]pyridine (6s). Brown solid
1
(
3
32 mg, 19%); H NMR (300 MHz, CDCl ): δ=8.20 (d, J=6.8 Hz,
1
1
1
H), 7.65 (d, J=9.0 Hz, 1H), 7.49-7.44 (m, 2H), 7.34 – 7.27 (m,
H), 7.27 – 7.21 (m, 2H), 7.20 – 7.16 (m, 3H), 7.16 – 7.12(m,
H), 7.03-6.98 (m, 2H), 6.87 (t, J=6.8 Hz, 1H); C NMR (75
): δ=148.1, 147.6, 134.6, 134.3, 131.0, 129.4, 129.1,
[
2]
13
[
[
3]
4]
MHz, CDCl
27.2, 126.8, 126.8, 126.6, 124.6, 117.8, 113.5; MS (ES ): m/z
3
+
1
+
(
%) = 334.8 (100) [M + H] ; HRMS (ESI-TOF): m/z calcd for
+
[14]
C
19
H
15
N
2
S
2
: 335.0677 [M+H] ; found: 335.0668.
[5]
17, 937-944; b) C. Ravi, D. C. Mohan, S. Adimurthy, Org.
Lett. 2014, 16, 2978-2981; c) J. Rafique, S. Saba, M. S.
Franco, L. Bettanin, A. R. Schneider, L. T. Silva, A. L.
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Adimurthy, J. Org. Chem. 2016, 81, 9964-9972; b) Y. Ding,
P. Xie, W. Zhu, B. Xu, W. Zhao, A. Zhou, RSC Adv. 2016,
6
-phenyl-5-(phenylthio)imidazo[2,1-b]thiazole (6t). Orange oil
1
(
76 mg, 49%); H NMR (300 MHz, CDCl
3
): δ=8.10 (d, J=7.1 Hz,
2H), 7.43 – 7.31 (m, 4H), 7.23 (d, J=7.6 Hz, 2H), 7.16 (d, J=7.2
[6]
13
Hz, 1H), 7.07 (d, J=7.2 Hz, 2H), 6.85 (d, J=4.5 Hz, 1H); C NMR
75 MHz, CDCl ): δ=152.7, 151.5, 135.9, 133.6, 129.5, 128.5,
28.3, 127.6, 126.2, 125.9, 118.1, 113.1, 107.8; MS (ES ): m/z
(
1
3
81932–81935.
+
[
[
7]
8]
a) Y. C. Gao, Z. B. Huang, L. Xu, Z. D. Li, Z. S. Lai, R. Y.
Tang, Org. Biomol. Chem. 2019, 17, 2279-2286; b) J. C.
Deng, J. R. Zhang, M. H. Li, J. C. Huang, Z. S. Lai, X. Y.
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+
[5b]
(
%) = 308.8(100) [M + H] .
N,N-dimethyl-4-(2-phenylimidazo[1,2-a]pyridin-7-yl)aniline
5i). Starting material for 6i. In a microwave tube under argon,
-chloro-2-phenylimidazo[1,2-a]pyridine (1.31 mmol, 300 mg, 1
eq), 4-(dimethylamino)phenylboronic acid (1.57 mmol, 260 mg,
.2 eq), sodium carbonate (5.25 mmol, 556 mg, 4 eq), tri-tert-
7854-7857.
(
7
Y. J. Guo, S. Lu, L. L. Tian, E. L. Huang, X. Q. Hao, X.
Zhu, T. Shao, M. P. Song, J. Org. Chem. 2018, 83, 338-
349.
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[
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2012, 14, 1688-1691.
butylphosphine tetrafluoroborate (0.079 mmol, 23 mg, 0.06 eq),
Tris(dibenzylideneacetone)dipalladium (0.026 mmol, 24 mg,
10]
a) B. Nguyen, E. J. Emmett, M. C. Willis, J. Am. Chem.
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Moreover, we were not able to reproduce Yang’s results.
In our hands, Yang’s condition did not allow any reaction,
the starting material being fully recovered. Further
investigation showed that the proton NMR spectra of the
sulfone 3 reported by Yang and Wang was not in
accordance with the one described, the same year, by Zhu
and Shao et al. (ref 8) who also provide a crystallographic
data to confirm their structure. Furthermore, by
comparison of the proton NMR spectra of our compound
2
0.02 eq) were solubilized in 8:1 DMF:H O (5 mL). The reaction
was heated by microwave irradiation at 110 °C for 1 h. After, the
reaction mixture was diluted with ethyl acetate (50 mL) and
washed with saturated sodium carbonate solution (3x50 mL) and
distilled water (3x50 mL). The organic layer was dried over
anhydrous sodium sulfate and the solvent was removed under
reduced pressure. The crude was dissolved in a minimum of
DCM and pentane was added until the formation of a precipitate.
The resulting solid was filtered, washed with pentane and dried
[
[
11]
12]
under vaccum to give the corresponding product as a yellow
solid (167 mg, 41%); m.p. 77-79 °C; H NMR (300 MHz, CDCl
δ=8.09 (d, J=7.0 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 7.82 (s, 1H),
1
3
):
4b with the one described by Yang and Wang who
claimed to have the sulfone moiety, we found that they
superimpose. To gain more evidence for the exact
structure of 4b, we did an IR spectra showing the absence
of the two very strong absorption bands characteristic
7
7
3
1
1
.78 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.44 (t, J=7.1 Hz, 2H), 7.37-
.28 (m, 1H), 7.07 (d, J=7.2 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H),
.02 (s, 6H); C NMR (75 MHz, CDCl ): δ=150.5, 146.7, 146.1,
3
37.9, 133.9, 128.7, 127.9, 127.4, 126.1, 126, 125.2, 112.7,
13
-
1
between 1370-1290 and 1170-1110 cm .Therefore, we
strongly believe that there is a misleading reading of the
analytic data from Yang and Wang throughout their
manuscript and that they obtained the sulfenylated
compounds instead, as we did in this work.
12.1, 112.0, 107.5, 40.4; HRMS (ESI-TOF): m/z calcd for
+
C
21
H
20
N
3
: 314.1657 [M+H] ; found: 314.1657.
[
13]
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la Recherche for a doctoral fellowship. This work has benefited
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Keywords: Nitrogen heterocycles • Sulfur • Copper •
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8
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European Journal of Organic Chemistry
10.1002/ejoc.202000112
COMMUNICATION
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9
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European Journal of Organic Chemistry
10.1002/ejoc.202000112
COMMUNICATION
C-H Sulfenylation
Exploring the unexpected reactivity of DABCO-bis(sulfur dioxide) on various imidazo[1,2-a]pyridines expanded the toolbox of the
sulfenylation reagent. Starting from three simple building blocks, this three-component transformation led to various C-3 sulfenylated
substituted imidazo[1,2-a]pyridines in moderate to good yields.
1
0
This article is protected by copyright. All rights reserved.