Copper-Catalyzed Multicomponent Reactions (MCRs) for Disulfenylation of Imidazo[1,2- a]pyridines Using Elemental Sulfur and Arylhalides and Intramolecular Cyclization of Haloimidazo[1,2- a]pyridines

Article abstract of DOI:10.1021/acs.joc.9b01632

Copper-catalyzed synthesis of disulfenylated imidazo[1,2-a]pyridines and indoles using elemental sulfur and haloarenes through one-pot, three component reaction by two C-S-C bond formations has been developed. The method has a broad substrate scope with a variety of substituted haloarenes. The conditions were also applied for the synthesis of benzothieno-imidazo[1,2-a]pyridines in excellent yields (99%) through intramolecular sulfenocyclization of 2-(2-halophenyl)imidazo[1,2-a]pyridines using sulfur powder.

Full text of DOI:10.1021/acs.joc.9b01632

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Note
Copper-Catalysed Multi-Component Reactions (MCR’s) for Disulfenylation
of Imidazo[1,2-a]pyridines using Elemental Sulfur and Arylhalides
and Intramolecular Cyclisation of Haloimidazo[1,2-a]pyridines
Rashmi Semwal, Chitrakar Ravi, Soumya Saxena, and Subbarayappa Adimurthy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01632 • Publication Date (Web): 23 Sep 2019
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Copper-Catalysed Multi-Component Reactions (MCR’s) for
Disulfenylation of Imidazo[1,2-a]pyridines using Elemental Sulfur and
Arylhalides and Intramolecular Cyclisation of Haloimidazo[1,2-a]pyridines
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Rashmi Semwal, Chitrakar Ravi, Soumya Saxena and Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals
Research Institute, G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA).
*E-mail: adimurthy@csmcri.res.in
Copper-catalyzed synthesis of disulfenylated imidazo[1,2-a]pyridines and indoles using
elemental sulfur and haloarenes through one-pot three component reaction by two C-S-C bond
formations has been developed. The method has a broad substrate scope with a variety of
substituted haloarenes. The conditions also applied for the synthesis of benzothieno-
imidazo[1,2-a]pyridines in excellent yields (99%) through intramolecular sulfenocyclization
of 2-(2-halophenyl)imidazo[1,2-a]pyridines using sulfur powder.
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Functionalised imidazo[1,2-a]pyridines are important structural motifs found in many
bioactive molecules.1 Particularly C-3 substituted imidazo[1,2-a]pyridine derivatives
necopidem, saripidem, and zolpidem are clinically used as neuroactive drugs including other
candidates such as alpidem, (as an anxiolytic agent), olprinone (the treatment of acute heart
failure), minodronic acid2 zolimidine (peptic ulcer),3 and optically active GSK812397 (HIV
infection).4 The biological profile is mainly dependent on the nature of the substituents and
introduction of sulfenyl groups on the azaheterocyclic rings that could impart marked
biological properties.5 Remarkable progress has been made by various groups6 on the synthesis
of sulfenylated imidazo[1,2-a]pyridine derivatives including our group.7 Most of the reported
methods are efficient, however they employed pre-prepared organic sulphur reagents such as
thiols or disulfides as source of sulfenylation which are hazardous to handle. To overcome the
use of thiols and disulfides, recently we have introduced a new concept of using elemental
sulfur as a benign source for sulfenylation of imidazo[1,2-a]pyridines via three component
coupling reactions with aryl halides.8 Immediately after our disclosure, many research groups
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reported the sulfenylation of imidazopyridines with elemental sulfur under diverse conditions.9-
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Compared to monosulfenylation of imidazo[1,2-a]pyridines, the direct disulfenylation of
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imidazopyridines using elemental sulfur and aryl halides have never been reported. However,
Zhou’s group observed one unexpected disulfenylated imidazopyridine in 45% yield when
elemental sulfur, iodine, PPh3, and benzyl alcohol were employed.11
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In continuation of our efforts on the development of new synthetic methods to access various
functionalised imidazo[1,2-a]pyridines7 we envisioned our studies on the disulfenylation of
imidazo[1,2-a]pyridines utilising elemental sulfur and aryl halides as a benign and sustainable
source (Scheme 1).
Scheme 1. Disulfenylation of imidazo[1,2-a]pyridines
Initially, we focused on the optimization of conditions for the disulfenylation of imidazo[1,2-
a]pyridine 1a via a three-component system, using elemental sulfur S8 (2a) and 4-iodo toluene
(3a) with CuI (10 mol %) and Na2CO3 as base at 100°C in dimethyl formamide (DMF) as
solvent (Table 1, entry 1). Under these conditions, the desired product 2,3-bis(p-
tolylthio)imidazo[1,2-a]pyridine 4a was isolated in 13% yield. With the feasibility of this
reaction, by increasing the reaction temperature (130°C) and catalyst loading (20 mol%), the
yield of desired product 4a was also increased up to 30% (Table 1, entries 2 and 3). But the
conditions were not efficient to achieve the desired yield of the product. When the reaction was
performed in other solvents, DMSO, water and mixture of DMF-H2O, no improvement in yield
was observed (Table 1, entries 4−6). Gratifyingly, a significant enhancement in yield (64%)
was observed by conducting the reaction with the combination of DMF and acetic acid (1:1
v/v) as solvent (entry 7). With this combination of solvent, marginal improvement in yield was
observed when the amounts of 2a/3a was increased to 1/1 ratios (entry 8). Further increasing
the amounts of 2a/3a to 1.25/1.25 ratios, no improvement in yield was observed (entry 9). We
then screened the reaction in different bases such as K2CO3, KOtBu, NaOtBu, DBU, DABCO,
among these bases (entries 10−14), the best yield of 4a was obtained with KOtBu as base (entry
11). No improvement in the yield was observed when the reaction performed with other copper
catalysts (i.e., CuBr, CuCl, CuBr2, and CuCl2) (Table 1, entries 15−18). The reactions
performed with lowering the reaction time, base and without catalyst, the yield of 3a was either
reduced or completely stopped (Table 1, entries 19−22).
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Table 1. Optimization of reaction conditions
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aReaction conditions: 1a (0.25 mmol; 1.0 equiv.), 2a/3a, base (4.0 equiv.), solvent (1:1) (1.0 mL), 24
h, isolated yields. bReaction time 18 h. cYield with 3.0 equiv. of base. dYield with 2.0 equiv. of base.
On the basis of the above optimum conditions (Table 1, entry 11), we next investigated the
generality of the disulfenylation of 1a with a variety of substituted haloarenes (Table 2).
Iodoarenes with various substituents (Me, tert-Bu, F, Cl, and CF3) reacted smoothly with 1a
and afford the corresponding disulfenylated imidazo[1,2-a]pyridines 4a–4f with yields ranging
from 71% to quantitative yield. The reaction of 1a was performed with corresponding 4-
bromoarene under the optimised conditions, low yield of 4a (43%) was observed. Under the
same conditions, (4-iodophenyl)boronic acid and 4-methoxybromobenzene gave the desired
disulfenylated products 4g and 4h in 47% and 45% yields respectively. The product 4g an
important intermediate used in various cross coupling reactions. The strong electron
withdrawing substrate (4-nitroiodobenzene) afford the product 4i in very low yield (15%).
However, the ortho and meta-substituted iodoarenes provided the good to excellent yields
(54%–94%) of desired products 4j–4l. The reaction of 1-iodonaphthalene with 1a, yield the
desired product 2,3-bis(naphthalen-1-ylthio)imidazo[1,2-a]pyridine 4m in moderate yield.
Further, to ascertain the versatility of the present methodology, methyl iodide and ethyl iodide
were subjected to the optimized conditions with 1a, but no desired disulfenylated product
formation was observed due to less stability of alkyl derivatives (4n and 4o). To check the
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feasibility of the method for scale up synthesis, one product 4c was obtained in 78% yield
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(1.735 gm) when the reaction performed at 5.0 mmol scale.
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To expand the scope of the present transformation, we explored the reactivity of 6-
chloroimidazo[1,2-a]pyridine 1b with various aryl iodides, and the results are compiled in
Table 3. In some cases, higher loading of copper catalyst was required for better results. The
reaction of 1b, with iodobenzene and substituted iodobenzenes having both electron donating
and withdrawing groups (-Me, -OMe, -tert-Bu, -F, -Br, -Cl, -B(OH)2) at various
(para/ortho/meta) position reacted smoothly under the optimized conditions and gave the
desired disulfenylated products 5b–5i in moderate to good yields (40–73%). Bulky 1-
iodonaphthalene was also reacted with 1b under the optimised conditions and afford the desired
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Table 2. Scope of aryl halides for the disulfenylation of 1aa
aConditions unless otherwise stated: 1 (0.25 mmol), aryl halides (4.0 equiv.; 1.0 mmol) S8 (4.0 equiv;
1.0 mmol), KOtBu (4.0 equiv.), CuI (20 mol%), DMF+AcOH (1:1) 1 mL, 130 °C, 24 h, isolated yield.
bYields obtained from bromo arenes derivative. cYield obtained at 5.0 mmol scale of 1a (1.735 g), nr=
no reaction.
disulfenylated product 5j in 55% yield. The reaction of 6-bromoimidazo[1,2-a]pyridine 1c with
representative iodoarenes were also performed under the optimised conditions and obtained the
corresponding products (5k-5m) in moderate yields (54–67%). Further, the present strategy
was extended to other important heterocyclic compounds such as indoles under the optimized
conditions. When N-methyl indole was reacted with 3- iodotoluene and 4-methoxy
iodobenzene, low yields of corresponding disulfenylated products 6a (40%) and 6b (20%) were
obtained. Other derivatives of indoles tested were not reactive under the present conditions.
As the handful of sulfenylated products were obtained through the formation of double C-S-C
bonds between aryl halides and heteroarenes, we hypothesised to subject the ortho-halo
derivatives
of
2-phenylimidazo[1,2-a]pyridines
713,
to
obtain
the
benzo[4',5']thieno[3',2':4,5]imidazo[1,2-a]pyridines 8 with the same optimised conditions
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(Table 4). To our delight, when 2-(2-bromophenyl)imidazo[1,2-a]pyridine 7a was subjected to
the optimised conditions, the intramolecular cyclised product 8a was obtained in 90% yield.
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Table 3. Disulfenylation of 6-chloroimidazo[1,2-a]pyridine and indolesa
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aConditions unless otherwise stated: 1b (0.25 mmol), S8 (4.0 equiv; 1.0 mmol), iodoarene (4.0 equiv.;
1.0 mmol), KOtBu (4.0 equiv.), CuI (40 mol%), DMF+AcOH (1:1) 1 mL, 130 °C, 24 h, isolated yield.
bFor products 6a and 6b N-methylindole (0.2 mmol) was used.
An improved yield (95%) of 8a was observed with ortho-iodo analogue 7b (Table 4, entry 2).
Similarly, the methyl substituted imidazo[1,2-a]pyridines 7c–7e were reacted smoothly, and
obtained the corresponding products 8b–8d in excellent yields.
One of the substrate 7e was performed with reduced amounts of S8 and base (two equivalents
each, w.r.t. 7e), the yield of the product 8d was reduced to 75% from 96% (entry 7, yield in
parenthesis). This reaction along with entries 20, 21 of the Table 1 suggest that, excess of S8
and base are necessary to uphold the yields of desired products in the present transformations.
Table 4. Intramolecular cyclisation of imidazo[1,2-a]pyridines (7)a
aConditions unless otherwise stated: 7 (0.25 mmol; 1.0 equiv.), S8 (4.0 equiv.; 1.0 mmol), KOtBu (4.0
eqv.), DMF+AcOH (1:1) 1.0 mL, 130 °C, 24 h, isolated yield. bYield obtained with two equivalents of
each S8 and KOtBu.
To get insight about the reaction mechanism, some selective experiments were performed
(Scheme 2). Initially, the reaction of 1a with elemental sulfur (S8) and iodobenzene 3b was
subjected to the optimized conditions in presence of radical scavenger TEMPO. Under these
conditions the desired product 4b was isolated in 70% yield (Scheme 2a). This reaction
indicates that, the present transformation is not going through radical path. The reaction of 1a
and thiophenol 9 was subjected to optimised conditions without S8 and aryliodide, 53 % of
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monosulfenylated product (10) formation was observed (Scheme 2b) along with
diphenyldisulfide 11. Further, 11 was reacted with 1a under the same conditions, 61% yield
of product 10 formation was observed (Scheme 2c). These reactions suggest that, under the
present conditions 9 may convert to 11 which reacts with 1a to give the product. Further, 3-
(phenylthio)imidazo[1,2-a]pyridine 10 was reacted with diphenyldisulfide 11 under the
optimised conditions, but product 4b formation was not observed (Scheme 2d). Finally, 2-
phenylimidazo[1,2-a]pyridine 12 and S8 was subjected to the optimised conditions without
iodoarene, the corresponding disulfide product 13 formation was observed (Scheme 2e).
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Scheme 2. Control experiments
Subjecting the reaction of 13 with iodoarene 3d to the standard conditions, 93% yield of
expected product 14 was obtained (Scheme 2f). When C-3 substituted imidazo[1,2-a]pyridines
10 and 15 where reacted with S8 and iodobenzene under the optimised conditions, the desired
products 16 and 4b were not detected (Scheme 2g). To confirm the role of acetic acid in the
present system, a reaction of 1a with elemental sulfur, iodobenzene 3b (4.0 equiv.), base (4.0
equiv.) and Cu(OAc)2 (1.5 equiv.) without acetic acid in the presence of 1mL of DMF at 130
℃ temperature was performed. Under these conditions, 4b was obtained in 70% yield. This
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reaction suggest that, under the present conditions CuI is oxidised to Cu(OAc)2 in the presence
of acetic acid. Hence AcOH plays a dual role as a solvent and as oxidising agent (Scheme 2h).
Further, one of the reaction was tested under inert atmosphere (N2 atmosphere) and the desired
product 4a was obtained in 85% yield, this indicates no role of external oxidant in the present
reaction system (Scheme 2i).
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Based on the control experiments and literature precedents,8,12-16 a plausible reaction
mechanism has been proposed (Scheme 3). Initially, the reaction of iodoarene and sulfur
powder in presence of copper iodide catalyst generates diphenyldisulfide 11 and copper acetate
in acetic acid medium, it may convert to thiophenol 9 and the copper intermediate A.12a Further
9 reacts with intermediate B, (which is generated through the reaction of 1a with Cu(AcO)2)12b
generates copper complex C. This copper complex C reacts with acetic acid and thiophenol in
the subsequent steps and give another intermediate E through transmetalated intermediate D.
Through reductive elimination of E, provide the desired disulfenylated product 4b.
Scheme 2. Plausible mechanism
In conclusion, we have developed a copper-catalysed multi-component reaction for the
selective synthesis of disulfenylated of imidazo[1,2-a]pyridines and indoles using elemental
sulfur and haloarenes by double C-S-C bond formations. The method has a broad substrate
scope with a variety of substituent groups on haloarenes. Under the same conditions, 2-(2-
halophenyl)imidazo[1,2-a]pyridine provided benzothieno-imidazo[1,2-a]pyridines in excellent
yields (99%) through intramolecular sulfenocyclization approach. To the best of our
knowledge this is the first report for disulphenylation of imidazo[1,2-a]pyridine by one-pot
multi component reaction.
Experimental Section
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General: All commercially available chemicals and reagents were used without any further
purification unless otherwise indicated. 1H and 13C NMR spectra were recorded at 600 MHz,
500 MHz, 150 MHz and 125 MHz unless stated. The spectra were recorded in CDCl3 as
solvent. Multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); m (multiplet);
dd (doublet of doublets), etc. and coupling constants (J) were given in Hz. Chemical shifts are
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reported in ppm relative to TMS as an internal standard. The peaks around delta values of H
NMR (7.26), and 13C NMR (77.0) are correspond to deuterated solvent chloroform respectively
1
[δ value around (1.5) in H NMR is of water. The Melting points for all solid products were
measured with MEL-TEMP instrument. Mass spectra were obtained using electron impact
(EI) ionization method. Progress of the reactions was monitored by thin layer chromatography
(TLC). All products were purified through column chromatography using silica gel 100-200
mesh size using hexane/ethyl acetate as eluent, unless otherwise indicated.
General Procedure
(A) Procedure for the synthesis of 2,3-bis(p-tolylthio)imidazo[1,2-a]pyridine (4a): The
imidazo[1,2-a]pyridine (1a) (29.5 mg, 0.25 mmol), elemental sulfur (2a) (32mg, 1 mmol), 4-
methyliodobenzne (3a) (218 mg, 1mmol,) using base potassium tert-butoxide (112.2 mg, 4.0
equiv.) with CuI (9.5 mg, 20 mol%) in catalytic amount and 1.0 mL of [DMF (0.5 mL)+
CH3COOH (0.5 mL)] were placed in screw capped reaction tube. The mixture was heated in
an oil bath at 130 ℃in a closed tube. After completion of the reaction, it was allowed to attain
room temperature, and then the mixture was poured into 20 mL of sodiumbicarbonate solution.
The product was extracted with EtOAc (50 mL X 3) and dried with anhydrous Na2SO4. The
solvent was removed under reduced pressure. The residue was purified by column
chromatography using 100-200 mesh silica gel in 15% EtOAc/hexane as eluents to obtain the
corresponding 4a (80.54 mg; 89% yield).
(B) Procedure for the synthesis of 6-chloro-2,3-bis(p-tolylthio)imidazo[1,2-a]pyridine
(5a): The 6-chloroimidazo[1,2-a]pyridine (1b) (38 mg, 0.25 mmol) was added to the elemental
sulfur (2a) (32mg, 1 mmol), iodobenzene (3b) (204 mg, mmol), base potassium tert-butoxide
(112.2 mg, 4.0 equiv.), CuI (19 mg, 40 mol%) in 1.0 mL of [(DMF (0.5 mL)+ CH3COOH (0.5
mL)] The resulting mixture was heated in a 130 °C oil bath with rapid stirring until the 6-
chloroimidazo[1,2-a]pyridine was consumed as determined by TLC. After completion of the
reaction, it was allowed to attain room temperature, and then the mixture was poured into 20
mL of sodiumbicarbonate solution. The product was extracted with EtOAc (50 mL X 3) and
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dried with anhydrous Na2SO4. The solvent was removed under reduced pressure. The residue
was purified by column chromatography using 100-200 mesh silica gel in 15% EtOAc/hexane
as eluents to obtain the corresponding 5a (57.96 mg; 63% yield).
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(C) Procedure for the synthesis of 2-(2-bromophenyl)imidazo[1,2-a]pyridine (7a):16
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470 mg (5.0 mmol) of 2-aminopyridine, 1990 mg (10 mmol) of 2′-Bromoacetophenone, CuI
10 mol% (95 mg), BF3·Et2O; 10 mol% (70.5 mg) and DMF (2 mL) were placed in a 25-mL
double-necked round-bottomed flask. The mixture was heated in an oil bath at 60 ℃ for 24 h
under an oxygen atmosphere (balloon). After completion of the reaction, it was allowed to
attain to room temperature and then the mixture was poured into 20 mL of sodium carbonate
solution. The product was extracted with DCM (50 mL×3) and dried with anhydrous Na2SO4.
The solvent was removed under reduced pressure. The left out residue was purified by column
chromatography using 100-200 mesh silica gel in 25% EtOAc/hexane as eluents to get the
product 7a, in 59% yield (805 mg). Experimental data were compared with reported and well
matched with literature data.18 The same method was applied for the preparation of other
starting substrates (7b-7e). The yields of 7b (55 % yield; 0.880 gm; 2.75 mmol), 7c (55 %
yield; 0.157 gm; 0.54 mmol), 7d (52% yield; 0.298 gm; 1.04 mmol), 7e (53 % yield; 0.456 gm,
1.59 mmol).
(D) Procedure for the synthesis of benzo[4',5']thieno[3',2':4,5]imidazo[1,2-a]pyridine
(8a): The 2-(2-bromophenyl)imidazo[1,2-a]pyridine (7a) (67.75 mg, 0.25 mmol) was added to
the mixture of elemental sulfur (2a) (32 mg, 1 mmol), base potassium tert-butoxide (112.2
mg, 4.0 equiv), catalyst CuI (9.5 mg, 20 mol%) in 1.0 mL of [DMF (0.5 mL)+ CH3COOH (0.5
mL)]. The resulting mixture was heated in a 130 ℃oil bath with rapid stirring. After completion
of the reaction, it was allowed to attain to room temperature and then the mixture was poured
into 20 mL of sodium carbonate solution. The product was extracted with DCM (50 mL×3)
and dried with anhydrous Na2SO4. The solvent was removed under reduced pressure. The
residue was purified by column chromatography using 100-200 mesh silica gel in 20%
EtOAc/hexane as eluents to obtain the corresponding 8a (50.4 mg; 90% yield).
Characterization data:
2,3-bis(p-tolylthio)imidazo[1,2-a]pyridine (4a)
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(Eluent: 15% EtOAc/hexane); 89% yield (80.54 mg),
brown solid; mp 104-106 ℃. 1H NMR (600 MHz, CDCl3
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8
) δ 8.19 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 9 Hz, 1H), 7.40
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(d, J = 7.8 Hz, 2H), 7.26 (dd, J = 9.0, 7.0 Hz, 1H), 7.06 (d, J = 7.8 Hz, 2H), 6.99
(d, J = 7.8 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.84 (t, J = 6.6 Hz, 1H), 2.29 (s,
3H), 2.25 (s, 3H);13C{1H} NMR (150 MHz, CDCl3 ) δ 148.3, 147.0, 137.3, 136.4,
131.7, 130.7, 130.0, 129.9, 129.7, 127.1, 126.4, 124.3, 117.3, 113.1, 112.6, 21.0,
20.8. HRMS-ESI (m/z) [M+Na]+calcd. For C21H18N2NaS2: 385.0809; Found:
385.0806.
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2,3-bis(phenylthio)imidazo[1,2-a]pyridine (4b)
(Eluent: 15% EtOAc/hexane); 97% yield (80.99 mg); brown
1
liquid; H NMR (600 MHz, CDCl3 ) δ 8.21 (d, J = 6.8 Hz, 1H),
7.64 (d, J = 9.0 Hz, 1H), 7.46 (d, J = 7.9 Hz, 2H), 7.33 – 7.29 (m,
1H), 7.26 (t, J = 6.6 Hz, 2H), 7.22 – 7.17 (m, 3H), 7.16 – 7.12 (m, 1H), 7.00 (d,
J = 8.1 Hz, 2H), 6.88 (t, J = 6.9 Hz, 1H).13C{1H}NMR (150 MHz, CDCl3) δ
130.9, 129.2, 128.9, 127.0, 126.7, 126.6, 126.4, 124.5, 117.6, 113.3. HRMS-ESI
(m/z) [M+H]+calcd. For C19H15N2S2: 335.0677; Found: 335.0662.
2,3-bis(4-(tert-butyl)phenyl)thio)imidazo[1,2-a]pyridine (4c)
(Eluent: 15% EtOAc/hexane); 99 % yield (110.38
mg); yellow solid; mp 144-146 ℃. 1H NMR (600
MHz, CDCl3) δ 8.20 (d, J = 7.2 Hz, 1H), 7.60 (d, J =
9 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.25 (t, J = 7.9 Hz,
1H), 7.20 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.82 (t, J = 6.6 Hz, 1H),
13
1.27 (s, 9H), 1.24 (s, 9H); C{1H} NMR (150 MHz, CDCl3) δ 150.2, 149.6,
148.3, 147.2, 131.1, 130.9, 130.3, 126.8, 126.3, 126.2, 125.9, 124.4, 117.4, 113.0,
112.6, 34.4, 34.3, 31.17, 31.12. HRMS-ESI (m/z) [M+Na]+calcd. For
C27H30N2NaS2: 469.1748; Found: 469.1772.
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2,3-bis(4-fluorophenyl)thio)imidazo[1,2-a]pyridine (4d)
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(Eluent:20% EtOAc/hexane); 93 % yield (86.02 mg);
yellow white solid; mp 94-96 ℃. 1H NMR (500 MHz,
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CDCl3) δ 8.20 (dd, J = 6.8, 1.1 Hz, 1H), 7.61 (dt, J =
9.1, 1.0 Hz, 1H), 7.48 (ddd, J = 6.8, 5.2, 2.2 Hz, 2H), 7.30 (ddd, J = 9.0, 6.8, 1.3
Hz, 1H), 7.04 – 6.99 (m, 2H), 6.96 (dd, J = 9.7, 7.8 Hz, 2H), 6.92 – 6.83 (m, 3H).;
13C{1H} NMR (150 MHz, CDCl3) δ 163.1 (d, J= 93.3 Hz), 161.5 (d, J= 92.9 Hz),
148.3, 147.2, 133.78 (d, J = 8.2 Hz), 129.3, 128.95 (d, J = 7.7 Hz), 128.4, 126.7,
124.1, 117.5, 116.4 (d, J= 22.5 Hz), 116.1 (d, J= 21.7 Hz), 113.4, 112.1. HRMS-
ESI (m/z) [M+H]+calcd. For C19H13 F2N2S2: 371.0488; Found: 371.0500.
2,3-bis(4-chlorophenyl)thio)imidazo[1,2-a]pyridine (4e)
(Eluent: 20% EtOAc/hexane); 77% yield (77.19 mg); white
crystalline solid; mp 104-106 ℃. 1H NMR (500 MHz, CDCl3) δ
8.18 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.43 – 7.35 (m,
2H), 7.36 – 7.29 (m, 1H), 7.25 – 7.17 (m, 2H), 7.16 – 7.09 (m,
2H), 6.89 (d, J = 8.5 Hz, 3H).; 13C{1H} NMR (150 MHz, CDCl3)
δ 147.8, 147.4, 133.3, 132.8, 132.5, 132.3, 132.1, 129.3, 129.0, 127.8, 126.9,
124.2, 117.6, 113.6, 111.9. HRMS-ESI (m/z) [M+H]+calcd. For C19H13Cl2N2S2:
402.9897; Found: 402.9917.
2,3-bis(4-(trifluoromethyl)phenyl)thio)imidazo[1,2-a]pyridine (4f)
(Eluent: 20% EtOAc/hexane); 71% yield (83.42 mg); yellow
solid; mp 104-106 ℃.1H NMR (500 MHz, CDCl3) δ 8.19 (d, J =
6.8 Hz, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H),
7.44 (d, J = 8.5 Hz, 2H), 7.42 – 7.33 (m, 3H), 7.02 – 6.90 (m,
3H).; 13C{1H} NMR (150 MHz, CDCl3 ) δ 146.9 (d, J= 126.4 Hz), 146.0, 138.4
(d, J= 37.7 Hz), 128.8, 127.9, 127.76 (dd, J = 39.4, 32.9 Hz), 126.4, 125.19 (d, J
= 2.7 Hz), 124.82 (d, J = 24.4 Hz), 123.8, 123.7, 123.4, 122.0, 121.8, 116.9, 113.0,
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110.8. HRMS-ESI (m/z) [M+H]+calcd. For C21H13F6N2S2: 471.0424; Found:
471.0405.
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((imidazo[1,2-a]pyridine-2,3-diylbis(sulfanediyl))bis(4,1
phenylene))diboronic acid (4g)
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(Eluent: 20% EtOAc/hexane); 71% yield (83.42 mg);
yellow solid; mp 104-106 ℃. 1H NMR (600 MHz, CDCl3)
δ 8.20 (d, J = 6.6 Hz, 3H), 7.65 (d, J = 9 Hz, 3H), 7.46 (d,
J = 7.2 Hz, 6H), 7.33 – 7.29 (m, 4H), 7.24 (d, J = 7.2 Hz,
5H), 7.22 – 7.16 (m, 9H), 7.14 (d, J = 7.8 Hz, 3H), 7.00 (d,
J = 7.8 Hz, 5H), 6.88 (t, J = 6.6 Hz, 3H).13C{1H} NMR (150 MHz, CDCl3) δ
147.9, 147.3, 134.4, 134.0, 130.9, 129.2, 128.9, 127.1, 126.7, 126.4, 124.4, 117.5,
113.3, 112.8. HRMS-ESI (m/z) [M+H]+calcd. For C19H16KB2N2O4S2: 461.0375;
Found: 461.0351.
2,3-bis (4-methoxyphenyl)thio)imidazo[1,2-a]pyridine (4h)
(Eluent: 20% EtOAc/hexane); 45% yield (44.32 mg);
brown liquid; 1H NMR (600 MHz, CDCl3) δ 8.23 (d,
J = 6.6 Hz, 1H), 7.58 (d, J = 9 Hz, 1H), 7.50 (d, J =
8.4 Hz, 2H), 7.25 (dd, J = 13.1, 5.7 Hz, 1H), 7.10 – 7.05 (m, 2H), 6.83 (t, J = 9
13
Hz, 3H), 6.76 – 6.72 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H).; C{1H} NMR (150
MHz, CDCl3) δ 159.4, 158.8, 148.9, 147.0, 134.3, 129.6, 126.2, 124.9, 124.2,
123.8, 117.4, 114.8, 114.6, 113.0, 112.7, 55.29, 55.26. HRMS-ESI (m/z)
[M+Na]+calcd. For C21H19N2O2S2:395.0888; Found: 395.0901.
2,3-bis(4-nitrophenyl)thio)imidazo[1,2-a]pyridine (4i)
(Eluent: 25% EtOAc/hexane); 15% yield (15.6
1
mg); brownish solid; mp 124-126 ℃. H NMR
(600 MHz, CDCl3) δ 8.20 (d, J = 6.6 Hz, 1H),
8.15 – 8.05 (m, 4H), 7.77 (d, J = 9.0 Hz, 1H), 7.49 (dd, J = 16.6, 9 Hz, 3H), 7.04
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(dd, J = 9, 3.6 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 148.3, 146.2, 143.6,
128.7, 128.0, 125.6, 124.5, 124.4, 124.0, 118.2, 114.5. HRMS-ESI (m/z)
[M+Na]+calcd. For C19H12N4NaO4S2: 447.0198; Found: 447.0194.
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2,3-bis(o-tolylthio)imidazo[1,2-a]pyridine (4j)
Eluent: 20% EtOAc/hexane); 91% yield (82.35 mg); yellow
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brown solid; mp 104-106 ℃. H NMR (600 MHz, CDCl3 ) δ
8.08 (d, J = 6.6 Hz, 1H), 7.62 (d, J = 9 Hz, 1H), 7.37 (d, J =
7.8 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.18 – 7.09 (m, 3H), 7.03
(dt, J = 19.5, 7.6 Hz, 2H), 6.88 (t, J = 7.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.35
(d, J = 7.8 Hz, 1H), 2.47 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3
) δ 148.4, 147.5, 139.1, 135.0, 133.4, 132.6, 132.1, 130.5, 130.2, 127.4, 126.5,
126.3, 126.2, 125.7, 124.7, 124.3, 117.3, 113.1, 110.8, 20.7, 19.7. HRMS-ESI
(m/z) [M+Na]+calcd. For C21H18 N2NaS2: 385.0809; Found: 385.0817.
2,3-bis(m-tolylthio)imidazo[1,2-a]pyridine (4k)
(Eluent: 20% EtOAc/hexane); 93% yield (84.16 mg);
brownish liquid. 1H NMR (600 MHz, CDCl3 ) δ 8.18 (d, J =
7.2 Hz, 1H), 7.62 (d, J = 9 Hz, 1H), 7.30 – 7.22 (m, 3H), 7.12
(t, J = 8.4 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.92 (d, J =
7.2 Hz, 1H), 6.84 (dd, J = 9.0, 4.4 Hz, 1H), 6.80 (d, J = 11.2 Hz, 1H), 6.79 (d, J
= 7.8 Hz, 1H), 2.23 (s, 3H), 2.18 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ
147.9, 147.3, 139.1, 138.6, 134.1, 133.8, 131.5, 129.0, 128.7, 128.0, 127.9, 127.2,
126.4, 124.5, 123.8, 117.5, 113.2, 113.0, 21.2. HRMS-ESI (m/z) [M+H]+calcd.
For C21H19N2S2: 363.0990; Found: 363.1003.
2,3-bis(3-bromophenyl)thio)imidazo[1,2-a]pyridine (4l)
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(Eluent: 20% EtOAc/hexane); 54% yield (66.01 mg); yellow
liquid;1H NMR (500 MHz, CDCl3) δ 8.37 (dd, J = 6.8, 1.1 Hz,
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8
1H), 7.84 (dd, J = 9.0, 1.0 Hz, 1H), 7.74 (t, J = 1.8 Hz, 1H), 7.58
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– 7.50 (m, 2H), 7.48 (ddd, J = 8.0, 1.8, 1.0 Hz, 1H), 7.45 – 7.40
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(m, 1H), 7.32 – 7.26 (m, 2H), 7.21 (t, J = 7.9 Hz, 1H), 7.10 (td, J
= 6.8, 1.1 Hz, 1H), 7.03 (ddd, J = 7.9, 1.7, 0.9 Hz, 1H). 13C {1H} NMR (150 MHz,
CDCl3) δ 147.6, 147.4, 136.6, 136.2, 133.0, 130.5, 130.1, 129.6, 129.1, 129.0,
127.1, 124.9, 124.4, 123.2, 122.7, 117.8, 113.8, 112.2. HRMS-ESI (m/z)
[M+H]+calcd. For C19H12Br2N2S2Na: 512.8706; Found: 512.8702.
3-(naphthalen-1-ylthio)-2-(naphthalen-2-ylthio)imidazo[1,2-a]pyridine (4m)
(Eluent: 15% EtOAc/hexane); 48% yield (52.08 mg); brown solid; mp 154-156
℃.1H NMR (500 MHz, CDCl3) δ 8.46 – 8.33 (m, 1H), 8.23
(d, J = 8.2 Hz, 1H), 7.89 (dd, J = 6.8, 0.8 Hz, 1H), 7.69 (t, J
= 8.2 Hz, 2H), 7.65 – 7.57 (m, 1H), 7.55 (d, J = 8.2 Hz, 1H),
7.50 – 7.35 (m, 4H), 7.26 (dd, J = 6.3, 3.3 Hz, 2H), 7.14 (t,
J = 7.7 Hz, 1H), 7.05 (dd, J = 8.5, 7.4 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 6.56 (t, J
= 6.8 Hz, 1H), 6.41 (d, J = 7.3 Hz, 1H) 13C{1H} NMR (150 MHz, CDCl3) δ 149.0,
147.5, 134.0, 133.9, 133.5, 132.3, 131.1, 130.8 130.1, 128.8, 128.5, 128.2, 126.5,
126.4, 126.39, 126.33, 125.9, 125.6, 125.5, 125.4, 124.3, 123.7, 123.2, 117.4,
113.1, 110.6. HRMS-ESI (m/z) [M+H]+calcd. For C27H19N2S2: 435.0990; Found:
435.0969.
6-chloro-2,3-bis(phenylthio)imidazo[1,2-a]pyridine (5a)
(Eluent: 15% EtOAc/hexane); 63% yield (57.96 mg); yellow
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solid; mp 120-122 ℃. H NMR (600 MHz, CDCl3) δ 8.25
(s, 1H), 7.56 (d, J = 9.6 Hz, 1H), 7.47 (d, J = 7.8 Hz, 2H),
7.29 – 7.24 (m, 4H), 7.22 (t, J = 8.3 Hz, 3H), 7.17 (t, J = 7.1
13
Hz, 1H), 7.03 (d, J = 7.8 Hz, 2H); C{1H} NMR (150 MHz, CDCl3) δ 149.4,
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145.7, 133.9, 133.3, 131.4, 129.4, 129.0, 127.9, 127.4, 126.8, 126.7, 122.3, 121.9,
117.9, 113.0. HRMS-ESI (m/z) [M+H]+calcd. For C19H14ClN2S2:369.0287;
Found: 369.0277.
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6-chloro-2,3-bis(p-tolylthio)imidazo[1,2-a]pyridine (5b)
(Eluent: 15%EtOAc/hexane); 73% yield (72.27 mg); yellow
solid; mp 134-136 ℃. 1H NMR (500 MHz, D2O) δ 8.25 (d, J
= 1.3 Hz, 1H), 7.56 (d, J = 9.5 Hz, 1H), 7.34 – 7.22 (m, 3H),
7.15 (t, J = 7.9 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 7.03 (d, J =
7.5 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.88 – 6.75 (m, 2H),
2.26 (s, 3H), 2.21 (s, 3H).; 13C{1H} NMR (150 MHz, CDCl3 ) 149.3, 145.6,
139.3, 138.7, 133.6, 133.1, 131.9, 129.1, 128.8, 128.7, 128.3, 127.8, 127.6, 127.5,
123.9, 122.4, 121.8, 117.8, 113.4 21.2. HRMS-ESI (m/z) [M+H]+calcd. For
C21H17ClN2NaS2: 419.0419; Found: 419.0421.
6-chloro-2,3-bis(4-fluorophenyl)thio)imidazo[1,2-a]pyridine (5c)
(Eluent: 15% EtOAc/hexane); 70% yield (70.70 mg); white
solid; mp 174-176 ℃. 1H NMR (500 MHz, D2O) δ 8.25 (d, J =
1.3 Hz, 3H), 7.54 (dt, J = 13.0, 3.8 Hz, 4H), 7.52 – 7.45 (m,
8H), 7.30 – 7.23 (m, 5H), 7.08 – 7.03 (m, 8H), 7.01 – 6.96 (m,
9H), 6.96 – 6.91 (m, 7H); 13C{1H} NMR (125 MHz, CDCl3 )
163.5 (d, J= 78.6 Hz), 161.6 (d, J= 83.7 Hz), 149.6, 145.5, 134.3, 134.2, 129.3,
129.2, 128.8, 128.6, 128.1, 127.7, 122.1, 117.8, 116.7 (d, J= 22.1 Hz), 116.3 (d,
J= 21.8 Hz), 112.5. HRMS-ESI (m/z) [M+Na]+calcd. For C19H11ClF2N2NaS2:
426.9918; Found: 426.9877.
2, 3-bis(4-(tert-butyl)phenyl)thio)-6-chloroimidazo[1,2-a]pyridine (5d)
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(Eluent: 15% EtOAc/hexane); 67% yield (80.40 mg);
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yellow solid; mp 134-136 ℃. H NMR (600 MHz, CDCl3
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8
9
) δ 8.27 (d, J = 1.5 Hz, 1H), 7.54 (d, J = 9.6 Hz, 1H), 7.43
(d, J = 7.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.28 – 7.21 (m,
3H), 7.01 (d, J = 8.4 Hz, 2H), 1.29 (s, 9H), 1.26 (s, 9H);
13C{1H} NMR (150 MHz, CDCl3) δ 150.6, 150.0, 149.7, 145.5, 131.5, 130.4,
129.6, 127.7, 127.0, 126.4, 126.1, 122.3, 121.6, 117.7, 113.0, 34.5, 34.4, 31.2,
31.1. HRMS-ESI (m/z) [M+H]+calcd. For C27H30ClN2S2: 481.1539; Found:
481.1521.
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(6-chloroimidazo[1,2-a]pyridine-2,3-diyl)bis(sulfanediyl)bis(4,1-
phenylene)diboronic acid (5e)
Eluent: 15% EtOAc/hexane); 45% yield (51.30 mg);
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yellow solid; mp 114-116 ℃. H NMR (600 MHz, CDCl3)
δ 8.25 (s, 1H), 7.56 (d, J = 9.6 Hz, 1H), 7.47 (d, J = 8.4 Hz,
2H), 7.29 – 7.23 (m, 5H), 7.22 (dd, J = 14.0, 5.1 Hz, 3H),
7.17 (d, J = 7.2 Hz, 1H), 7.05 – 7.01 (m, 2H). 13C{1H} NMR
(150 MHz, CDCl3) δ 149.3, 145.7, 133.9, 133.3, 131.3, 129.4, 129.0, 127.9,
127.4, 126.8, 126.7, 122.3, 121.9, 117.9, 113.0. HRMS-ESI (m/z) [M+Na]+calcd.
For C19H15B2ClN2O4S2Na: 479.0246; Found: 479.0241.
6-chloro-2,3-bis(o-tolylthio)imidazo[1,2-a]pyridine (5f)
(Eluent: 15% EtOAc/hexane); 70% yield (69.30 mg); yellow
solid; mp 150-152 ℃. 1H NMR (600 MHz, CDCl3) δ 8.15 (d, J
= 1.8 Hz, 1H), 7.55 (d, J = 9.6 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H),
7.27 – 7.23 (m, 1H), 7.20 – 7.13 (m, 3H), 7.07 (dd, J = 15.9, 9
Hz, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H), 2.48 (s, 3H), 2.41 (s,
13
3H); C{1H} NMR (150 MHz, CDCl3) δ 150.0, 145.9, 139.8, 135.2, 133.1,
132.9, 131.9, 130.7, 130.4, 127.9, 127.75, 126.8, 126.4, 126.0, 124.7, 122.2,
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121.7, 117.7, 111.0, 20.8, 19.8. HRMS-ESI (m/z) [M+H]+calcd. For C21H18
ClN2S2: 397.0600; Found: 397.0591.
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8
9
6-chloro-2,3-bis(m-tolylthio)imidazo[1,2-a]pyridine (5g)
10
11
12
13
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(Eluent: 15% EtOAc/hexane); 66% yield (65.34 mg); yellow
solid; mp 94-96 ℃.1H NMR (500 MHz, CDCl3) δ 8.27 – 8.22 (m,
1H), 7.53 (d, J = 9.5 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.25 – 7.19
(m, 1H), 7.10 (d, J = 7.9 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.97
(d, J = 8.1 Hz, 2H), 2.31 (s, 3H), 2.28 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3
) δ 149.4, 145.7, 139.4, 138.8, 133.7, 133.2, 132.0, 129.2, 128.8, 128.6, 128.3,
127.9, 127.6, 127.5, 124.0, 122.5, 121.8, 117.9, 21.33. HRMS-ESI (m/z)
[M+H]+calcd. For C21H18ClN2S2: 397.0600; Found: 397.0585.
6-chloro-2,3-bis(3-methoxyphenyl)thio)imidazo[1,2-a]pyridine (5h)
Eluent: 15% EtOAc/hexane); 50% yield (53.50 mg); semi
liquid; 1H NMR (600 MHz, CDCl3 ) δ 8.24 (s, 1H), 7.57 (d, J =
9.6 Hz, 1H), 7.32 – 7.23 (m, 1H), 7.16 (t, J = 7.2 Hz, 1H), 7.12
(dd, J = 11.1, 4.7 Hz, 1H), 7.07 – 6.99 (m, 2H), 6.75 (d, J = 8.4
Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.63 – 6.53 (m, 2H), 3.72 (s,
3H), 3.68 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3 ) δ 160.2, 159.7, 149.0, 145.7,
135.1, 134.6, 130.2, 130.1, 129.6, 128.09, 128.02, 123.3, 122.4, 121.9, 118.9,
117.9, 116.3, 116.27, 116.22, 113.2, 112.3, 55.1. HRMS-ESI (m/z) [M+H]+calcd.
For C21H18ClN2O2S2: 429.0498; Found: 429.0472.
2,3-bis(3-bromophenyl)thio)-6-chloroimidazo[1,2-a]pyridine (5i)
(Eluent: 15% EtOAc/hexane); 40% yield (52.30 mg); yellow
1
brown solid; mp 104-106 ℃. H NMR (500 MHz, CDCl3) δ
8.24 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.55 (t, J
= 1.5 Hz, 1H), 7.40 – 7.35 (m, 1H), 7.35 – 7.23 (m, 3H), 7.15
– 7.09 (m, 2H), 7.06 (t, J = 7.9 Hz, 1H), 6.90 – 6.83 (m, 1H).;
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13C{1H} NMR (150 MHz, CDCl3) δ 148.7, 145.9, 136.1, 135.4, 133.5, 130.7,
130.5, 130.2, 129.9, 129.6, 129.1, 128.6, 125.0, 123.4, 122.8, 122.5, 122.3, 118.2,
112.5. HRMS-ESI (m/z) [M+H]+calcd. For C19H12Br2ClN2S2: 524.8497; Found:
524.8478.
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6-chloro-3-(naphthalen-1-ylthio)-2-(naphthalen-2-ylthio)imidazo[1,2-
a]pyridine (5j)
(Eluent: 15% EtOAc/hexane); 55% yield (64.35 mg); white
yellow solid; mp 154-156 ℃. 1H NMR (500 MHz, CDCl3)
δ 8.51 – 8.44 (m, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.15 (d, J =
1.4 Hz, 1H), 7.89 – 7.82 (m, 2H), 7.80 – 7.74 (m, 1H), 7.72
(d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.57 (ddd, J = 11.8, 7.9, 1.1 Hz, 2H),
7.50 (d, J = 9.5 Hz, 1H), 7.46 – 7.39 (m, 2H), 7.29 (dd, J = 8.0, 7.4 Hz, 1H), 7.19
(dd, J = 9.5, 2.0 Hz, 1H), 7.13 – 7.06 (m, 1H), 6.59 – 6.52 (m, 1H); 13C{1H} NMR
(150 MHz, CDCl3 ) δ 150.4, 145.9, 134.08, 134.04, 133.7, 132.9, 130.8, 129.4,
129.2, 128.6, 128.3, 127.8, 126.6, 126.5, 126.0, 125.68, 126.64, 125.5, 123.7,
123.2, 122.3, 121.8, 117.8. HRMS-ESI (m/z) [M+H]+calcd. For C27H18ClN2S2:
469.0600; Found: 469.0602.
6-bromo-2,3-bis(phenylthio)imidazo[1,2-a]pyridine (5k)
(Eluent: 10% EtOAc/hexane); 54% yield (55.48 mg); yellow
solid; mp 160-162 ℃. 1H NMR (500 MHz, CDCl3) δ 8.35 (d, J
= 0.8 Hz, 1H), 7.51 (d, J = 9.4 Hz, 1H), 7.47 (d, J = 7.2 Hz,
2H), 7.35 (dd, J = 9.5, 1.7 Hz, 1H), 7.30 – 7.24 (m, 3H), 7.23 –
7.20 (m, 2H), 7.18 (d, J = 7.0 Hz, 1H), 7.03 (d, J = 7.4 Hz, 2H).13C{1H} NMR
(125 MHz, CDCl3) δ 149.2, 145.8, 133.9, 133.3, 131.4, 130.0, 129.4, 129.0,
127.4, 126.7, 124.5, 118.1, 112.8, 108.3. HRMS-ESI (m/z) [M+H]+calcd. For
C19H14BrN2S2: 412.9782; Found: 412.9763.
6-bromo-2,3-bis((4-fluorophenyl)thio)imidazo[1,2-a]pyridine (5l)
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(Eluent: 10% EtOAc/hexane); 62% yield (73.00 mg);
5
6
1
yellow semi solid; H NMR (500 MHz, CDCl3) δ 8.39 –
7
8
8.32 (m, 1H), 7.54 – 7.44 (m, 3H), 7.36 (dd, J = 9.4, 1.8 Hz,
9
1H), 7.10 – 7.03 (m, 2H), 6.99 (dd, J = 12.0, 5.1 Hz, 2H),
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13
6.94 (dd, J = 12.0, 5.2 Hz, 2H). C{1H} NMR (125 MHz,
CDCl3) δ 163.5 (d, J= 78.75 Hz), 161.6 (J= 78.12 Hz), 149.6, 145.7, 134.2, 130.1,
129.2, 128.9, 127.7, 124.3, 118.1, 116.7 (J= 22.25 Hz), 116.3 (J= 21.87 Hz),
112.3, 108.4. HRMS-ESI (m/z) [M+H]+calcd. For C19H12BrF2N2S2: 448.9593;
Found: 448.9570.
6-bromo-2,3-bis((3-methoxyphenyl)thio)imidazo[1,2-a]pyridine (5m)
(Eluent: 15% EtOAc/hexane); 67% yield (74.87 mg); yellow
1
semi solid; H NMR (500 MHz, CDCl3) δ 8.34 (dd, J = 1.7,
0.6 Hz, 1H), 7.52 (dd, J = 9.4, 0.5 Hz, 1H), 7.36 (dd, J = 9.5,
1.9 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H),
7.05 (s, 1H), 7.03 – 6.98 (m, 1H), 6.75 (ddd, J = 8.3, 2.5, 0.7
Hz, 1H), 6.72 – 6.67 (m, 1H), 6.61 – 6.57 (m, 1H), 6.56 (d, J = 2.1 Hz, 1H), 3.73
(s, 3H), 3.68 (s, 3H). C{1H} (125 MHz, CDCl3) δ 160.2, 159.7, 148.9, 145.8,
13
135.1, 134.5, 130.2, 129.7, 124.6, 123.4, 118.9, 118.1, 116.3, 113.3, 112.3, 108.4,
55.2. HRMS-ESI (m/z) [M+H]+calcd. For C21H18BrN2O2S2: 472.9993; Found:
472.9999.
1-methyl-2,3-bis(m-tolylthio)-1H-indole (6a)
(Eluent: 15% EtOAc/hexane); 40% yield (37.50 mg); yellow semi
1
liquid; H NMR (600 MHz, CDCl3 ) δ 8.02 (d, J = 7.8 Hz, 1H),
7.88 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8
Hz, 1H), 7.39 (s, 1H), 7.33 (dd, J = 16.7, 8.3 Hz, 2H), 7.30 – 7.23
(m, 3H), 7.17 (s, 1H), 7.10 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H);13C{1H}
NMR (150 MHz, CDCl3) δ 138.3, 138.2, 138.0, 127.0, 122.8, 122.7, 122.2, 121.0,
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120.9, 120.6, 120.4, 119.6, 119.5, 110.1, 109.7, 109.6, 32.9, 30.3, 30.2. HRMS-
ESI (m/z) [M+H]+calcd. For C23H21NNaS2: 398.1013; Found: 398.1019.
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2,3-bis(4-methoxyphenyl)thio)-1-methyl-1H-indole (6b)16
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(Eluent: 15% EtOAc/hexane); 20% yield (20.35mg); yellow
1
brown solid; mp 94-96 ℃. H NMR (200 MHz, CDCl3) δ 8.02
(d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.58 (dd, J = 9.9, 7.6
Hz, 2H), 7.35 (s, 2H), 7.31 (s, 2H), 7.23 – 7.04 (m, 3H), 6.71 (d,
J = 9 Hz, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 137.1, 127.2, 126.0, 121.7, 120.2, 119.1, 109.5, 109.2, 109.38 (d, J =
37.5 Hz), 32.8.
benzo[4',5']thieno[3',2':4,5]imidazo[1,2-a]pyridine (8a)19
(Eluent: 20% EtOAc/hexane); 90% yield (50.40); 95% yield
(53.20); brown solid; mp 134-136 ℃. 1H NMR (600 MHz,
CDCl3 ) δ 8.26 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 6.6 Hz, 1H), 7.85 (d, J = 7.8 Hz,
1H), 7.76 (d, J = 9 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.26
(t, J = 7.2 Hz, 1H), 6.91 (t, J = 6.6 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ
149.6, 146.0, 140.2, 129.1, 125.5, 125.4, 124.5, 124.3, 122.7, 121.7, 118.5, 112.2,
77.3, 77.1, 76.9.
10-methylbenzo[4',5']thieno[3',2':4,5]imidazo[1,2-a]pyridine (8b)19
Eluent: 20% EtOAc/hexane); 99% yield (58.90 mg); yellow solid; mp
1
170-172 ℃. H NMR (600 MHz, CDCl3 ) δ 8.31 (d, J = 7.8 Hz, 1H),
7.91 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1rH), 7.38 (t, J = 7.8
Hz, 1H), 7.00 (d, J = 6.4 Hz, 1H), 6.75 (dd, J = 9.3, 6 Hz, 1H), 2.71 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 149.9, 145.2, 139.9, 129.1, 128.2, 125.1,
124.1, 123.26, 123.20, 122.9, 121.9, 121.6, 111.9, 17.4.
9-methylbenzo[4',5']thieno[3',2':4,5]imidazo[1,2-a]pyridine (8c)19
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Eluent: 20% EtOAc/hexane); 89% yield (52.95 mg); yellow
5
6
1
white solid; mp 154-156 ℃. H NMR (600 MHz, CDCl3) δ 8.22
7
8
(d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 6.6 Hz, 2H),
9
13
7.39 (d, J = 7.2 Hz, 1H), 6.69 (d, J = 6.6 Hz, 1H), 2.42 (s, 3H); C{1H} NMR
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(150 MHz, CDCl3) δ 149.9, 145.5, 139.9, 135.6, 129.0, 125.2, 125.1, 124.1,
123.3, 121.9, 121.4, 116.6, 114.7, 21.5.
8-methylbenzo[4',5']thieno[3',2':4,5]imidazo[1,2-a]pyridine (8d)19
(Eluent: 20% EtOAc/hexane); 96% yield (57.12 mg); brownish
1
solid; mp 194-196. H NMR (600 MHz, CDCl3) δ 8.21 (dd, J =
7.9, 1.8 Hz, 1H), 7.80 (dd, J = 7.5, 5.4 Hz, 2H), 7.61 (dd, J = 9.1, 5.4 Hz, 1H),
7.51 – 7.44 (m, 1H), 7.37 (td, J = 7.3, 3.0 Hz, 1H), 7.04 (s, 1H), 2.32 (d, J = 7.6 Hz, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 148.4, 145.5, 140.0, 129.0, 127.5, 125.2,
124.1, 122.1, 121.8, 121.7, 121.4, 117.4, 18.1.
3-(phenylthio)imidazo[1,2-a]pyridine (10)7d
(Eluent: 20% EtOAc/hexane); white solid. mp 84-86 ℃. 1H NMR (500
MHz, CDCl3) δ 8.21 (d, J = 6.8 Hz, 1H), 7.98 (s, 1H), 7.71 (d, J = 9.0
Hz, 1H), 7.34 – 7.28 (m, 1H), 7.20 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 7.3
13
Hz, 1H), 7.02 – 6.96 (m, 2H), 6.87 (t, J = 6.8 Hz, 1H).; C{1H} NMR
(50 MHz, CDCl3) δ 148.0, 142.3, 135.1, 129.2, 126.15, 126.12, 124.2, 118.0,
113.1, 110.6.
1,2-bis(2-phenylimidazo[1,2-a]pyridin-3-yl)disulfane (13)20
(Eluent: 50 % EtOAc/hexane); yellow solid. m.p 240-242
1
℃. H NMR (200 MHz, CDCl3) δ 8.10 (d, J = 6.8 Hz, 1H),
7.64 (d, J = 6 Hz, 2H), 7.37 (d, J = 8.8 Hz, 1H), 7.24 – 7.00
13
(m, 4H), 6.74 (td, J = 6.8, 1.2 Hz, 1H). C{1H} NMR (50
MHz, CDCl3) δ 147.3, 131.9, 128.1, 127.8, 127.6, 124.3, 117.6, 112.9.
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3-(4-fluorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (14)8
5
6
7
8
9
(Eluent: 20% EtOAc/hexane); 80% yield (64 mg);
yellow solid. mp 134-136
.1H NMR (500 MHz,
℃
10
11
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CDCl3) δ 8.28 (dt, J = 6.8, 1.1 Hz, 1H), 8.23 – 8.17 (m,
2H), 7.73 (dt, J = 9.0, 1.0 Hz, 1H), 7.51 – 7.42 (m, 2H),
7.42 – 7.31 (m, 2H), 6.98 (ddd, J = 10.1, 5.1, 2.5 Hz, 2H), 6.95 – 6.84 (m,
3H).; C{1H} NMR (125 MHz, CDCl3) δ 162.5 (d, J= 236.9 Hz), 151.3,
13
147.0, 133.1, 130.0, 128.6, 128.4, 128.3, 127.6, 127.5, 126.7, 124.3, 117.7,
116.6 (d, J= 22.6 Hz), 113.1, 106.6.
Acknowledgements
CSIR-CSMCRI Communication No. 082/2019. We are thankful “Analytical Discipline
and Centralized Instrumental Facilities” for instrumentation facilities. R.S. is thankful
to Department of Science and Technology, Govt. of India for providing DST-INSPIRE
fellowship to her. We are also thanks to DST, Government of India (EMR/2016/000010
and EMR/2016/004944) for the research grants and CSIR-CSMCRI (MLP-027) for the
partial financial support.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
at DOI:xxx. Copies of NMR spectra for all compounds; COSY of compound 4e and
HRMS spectra for new compounds (PDF)
References
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