One-Pot Three-Component Synthesis of Alkylthio-/Arylthio- Substituted Imidazo[1,2-a]pyridine Derivatives via C(sp2)–H Functionalization

Article abstract of DOI:10.1002/adsc.201601431

Sulfenylation is an important transformation to generate C?S bonds in organic synthesis. Here, two three-component synthetic protocols have been developed by using imidazo[1,2-a]pyridine, inorganic, odorless S₈ and alcohols or arylboronic acids

Full text of DOI:10.1002/adsc.201601431

Title: One-pot Three-component Synthesis of Alkyl/Arylthioether-
Substituted Imidazo[1,2-α]pyridine Derivatives via C(sp2)-H
Functionalization
Authors: Wenhui Zhu, Yingcai Ding, Zhaogang Bian, Ping Xie, Baojun
Xu, Qiujie Tang, Wei Wu, and Aihua Zhou
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201601431
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10.1002/adsc.201601431
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201
One-pot Three-component Synthesis of Alkyl/Arylthioether-
Substituted Imidazo[1,2-α]pyridine Derivatives via C(sp2)-H
Functionalization
Wenhui Zhu,a,+ Yingcai Ding,a,+ Zhaogang Bian,a Ping Xie,b Baojun Xu,a Qiujie Tang,a
Wei Wu,a and Aihua Zhoua,*
a
Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang City, Jiangsu, 212013, China
Email: ahz@ujs.edn.cn
Jiangsu University Library, Jiangsu University, Zhenjiang City, Jiangsu, 212013, China
These authors contributed equally.
b
+
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201
recently, a sulfenylation method for imidazo[1,2-
generate C-S bonds in organic synthesis. Here, two three- α]pyridines with sulfur was reported.14 There are
Abstract: Sulfenylation is an important transformation to
component synthetic protocols were developed for using
imidazo[1,2-α]pyridine ， inorganic, odorless S8 and
alcohols or arylboronic acid as reactants to make alkyl/aryl-
S-substituted imidazo[1,2-α]pyridine derivatives via
C(sp2)-H functionalization. The reactions proceeded with
high efficiency and broad functional group tolerance,
affording regioselective products in good yields.
some shortcomings associated with these previous
methods. (1) Previous methods only afford MeS- and
ArS-substituted imidazo[1,2-α]pyridine derivatives.
They can’t make other alkyl-S-substituted derivatives
by direct C-H functionalization. (2) Most of these
sulfur agents are relatively expensive, odorless, and
unconvenient to prepare, so they are not suitable for
kilogram scale syntheses; (3) Some ArS-substituted
derivatives require prefunctionalized aromatic
reagents as the sulfur source. Herein, we reported two
different one-pot three-component protocols for
generating alkyl/aryl-S-substituted imidazo[1,2-
α]pyridine derivatives via
Keywords: sulfenylation; imidazo[1,2-α]pyridine; C(sp2)-
H functionalization；C-S bond
Sulfenylation is an important transformation to
generate C-S bonds in organic synthesis.1 The C-S
bond is also a common moiety among natural
products,2 marketed drugs,3 pesticides,4 and
polymers.5 Therefores, many chemists have
addressed developing more efficient methods to
construct C-S bonds, especially those methods which
can avoid using prefunctionalized reactants, smelly
and expensive sulfur agents,6 and expensive metal
catalysts. Particular attention is given to those new
methods which generate C-S bond via direct C-H
functionalization of reactants7.
It’s well-known that imidazo[1,2-α]pyridine is also
an privileged structure in drug discovery. This core
structure is associated with such biological activities,
as sedative-hypnotics, gout, anticancer and
Alzheimer’s disease.8 In order to find more efficient
drug candidates, much effort has been devoted to
generating their derivatives. Scheme 1 illustrates
several methods of constructing C-S bonds on
imidazo[1,2-α]pyridines that have been reported.
These methods generally involve using sulfur
agents such as ArSSAr,9 ArSH,10 ArSO2NHNH2,11
ArSO2Na,12 ArSO2Cl.13 All these sulfur agents are
relatively expensive, and some have powerful oders.
DMSO is also a sulfur agent, but only MeS-
substituted derivatives can be generated.13 Only
Scheme 1. Different routes for the synthesis of 2-
phenylimidazo[1,2-α]pyridine thioether derivatives.
C-H functionalization. Our methods simply use
alcohols or arylboronic acids as reactants and
odorless and cheap S8 as the sulfur source. Most of
1
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10.1002/adsc.201601431
Advanced Synthesis & Catalysis
these reactions proceeded with high efficiency,
affording regioselective products in good yields.
Our goal focuses on developing new sulfenylation
methods using odorless and cheap sulfur agents, such
as S8, Na2S or Na2S2O3. The substituent connected to
S at one end should also be derived from easily
available chemicals to make this sulfenylation
practical, environmentally friendly and efficient.
Initially, alcohol and inorganic S8 were chosen as
starting materials for reaction condition screening.
Different catalysts and inducers, solvents and
temperatures were screened (see Table 1).
solvent generated 2a in a 55% or 63% yield
respectively (entries 9 and 10). When DMSO was
used as the solvent, trace amounts of 2a was isolated
(entry 11), despite DMSO itself being a sulfur reagent.
The use of CuI (0.2 equiv.) as a catalyst with PPh3
also failed to generate 2a (entry 12) in DMF, but
Table 2. Generation of 2-phenylimidazo[1,2-α]pyridine
thioether derivatives using S8 and alcohols.[a]
Table 1. Sulfenylation screening reactions using S8 and
methanol.[a]
Entry
Inducers/
Catalyst
T
Solvent
Yield
[oC]
[b]
%
1
2
3
4
5
6
7
8
I2
I2
I2
I2
----
I2
I2
I2
I2
PPh3
60
90
DMF
DMF
DMF
DMF
DMF
----
EtOAc
Toluene
Dioxane
CH3CN
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
THF
15
45
75
40
0
50
60
40
55
63
trace
trace
20
10
5
PPh3
PPh3
----
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
----
----
----
PPh3
PPh3
PPh3
9
10
11
12[c]
13[c]
14
15
16
17
18
I2
I2
CuI
CuI
TBAI
NH4I
NH4I
CCl4
CCl4
30
0
0
[a]
Reaction conditions: 2-Phenylimidazo[1,2-α]pyridine
(0.5 mmol, 1.0 equiv.), methyl alcohol (3.0 equiv.), S8
(2.0 equiv.), inducer (1.0 equiv.), PPh3 (1.0 equiv.),
DMF (0.5 mL) under the air, 12h.
[b] Isolated yields are based on reactant 1a.
[c] CuI (0.2 equiv.)
To start the reaction, I2 and PPh3 were chosen as
reaction inducers in DMF at 60oC. The reaction
afforded the desired product 2a in 15% yield (entry 1,
Table 1). Increasing the temperature to 90oC led to a
45% yield (entry 2). Increasing reaction temperature
to 120oC gave a 75% yield (entry 3). Without using
PPh3, the reaction generated a 40% yield of expected
product 2a (entry 4). Without using I2, the reaction
didn’t afford 2a (entry 5). The combination of I2 and
PPh3 at 120oC afforded 2a in 50% yield under
solvent-free (entry 6) conditions. If I2 and PPh3 were
employed in ethyl acetate or toluene, the product 2a
was isolated in a 60 or 40% yield, respectively
(entries 7 and 8). Using dioxane or CH3CN as the
[a]
The reactions were carried out as follows: 2-
phenylimidazo[1,2-α]pyridine (0.5 mmol, 1.0 equiv.),
alcohol (3.0 equiv.), S8 (2.0 equiv.), I2 (1.0 equiv.),
PPh3 (1.0 equiv.), DMF (0.5 mL) at 120 oC, 12h.
[b] Isolated yields are based on reactant 1.
when no PPh3 was present, a 20% yield of 2a (entry
13) was obtained. Using tetrabutylammonium iodide
(TBAI) or NH4I as inducers, the reactions produced
2
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10.1002/adsc.201601431
Advanced Synthesis & Catalysis
only 10% or 5% yield of 2a, respectively (entries 14
and 15). Using the combination of NH4I/PPh3 in
DMF gave a 30% yield of 2a (entry 16). The
combination of CCl4 and PPh3 in DMF at 120oC
didn’t give 2a (entry 17). By changing solvent from
DMF to THF, the combination of CCl4 and PPh3 in
THF at 120oC did not afford 2a (entry 18). After the
above screening, the suitable conditions selected for
the sulfenylation are: 2-phenylimidazo[1,2-a]pyridine
(1.0 equiv.), alcohol (3.0 equiv.), S8 (2.0 equiv.), I2
(1.0 equiv.) and PPh3 (1.0 equiv.) in DMF as the
solvent at 120 oC.
reacted with dibenzyl disulfide, the BnS-substitued
product 2i was obtained in a 65% yield. In the
absence of I2 and Ph3P, the reaction give only a 10%
yield. This indicated that dibenzyl disulfide could be
a possible intermediate species involved in the
reaction. Based on the above experimental results and
previous reports,15 a plausible mechanism was
proposed below (Scheme 3).
Employing these selected reaction conditions,
different imidazo[1,2-α]pyridines were synthesized to
explore the scope of sulfenylation (Table 2). Several
alcohols were also chosen as reactants. Under these
conditions, all primary alcohols were suitable for
sulfenylation reactions, proceeding well and
generating good yields of regioselective alkyl-S-
substituted imidazo[1,2-α]pyridine derivatives. But
when secondary iso-propanol and tert-butanol were
used as starting materials, no thioether substitution
products were observed (Table 2, 2d, 2g, 2n, 2p).
One exception is diphenylmethanol (secondary
alcohol) which gave a 73% yield of the expected
product. An elimination reaction might occur using
secondary and tertiary alcohol. Allyl alcohol (Table 2,
2c) and the phenolic OH function on benzene ring
(Table 2, 2f) were tolerated in this sulfenylation
process. Neither interfered with the main
sulfenylation process. Electron-donating or electron-
withdrawing functions on pyridine ring also didn’t
cause any problems in this reaction. When
unsubstituted imidazopyridine as a starting material,
interestingly, the reaction gave the unexcepted
disubstituted thioether product with 45% yield (Table
2, 2r) as a main product.
Scheme 3. A plausible mechanism for the generation
of alkylthioether-substituted imidazo[1,2-α]pyridine
derivatives.
Alkyl iodide was probobly generated as an
intermediate during the reaction between alcohol and
I2/PPh3. This supposition is also consistent with why
using primary alcohols and diphenylmethanol as
reactants worked well for the sulfenylation process,
but using secondary or tertiary alcohols didn’t work.
An elimination reaction from a secondary alkyl
iodide to generate alkene would readily occur instead
of reacting with S8 to generate the disulfide. With
primary alcohols, the resultant RSSR then reacted
with I2 to give electrophilic RS-I which, in turn,
reacts with imidazo[1,2-α]pyridine 1 to give the RS-
substituted-2-phenylimidazo[1,2-α]pyridine thioether
derivatives.
To further expand the scope of this sulfenylation
reaction, arylboronic acids were also tested as
reactants instead of using alcohols. To find suitable
conditions for this sulfenylation, different catalysts,
bases, temperatures and solvents were also screened
(Table 3). The initial reaction was carried out using I2
and PPh3 at 120oC. However, only a 5% yield of
desired product was obtained after 20 h (Table 3,
entry 1). When CuBr and CuI were used with Na2CO3,
the yield increased slightly (entries 2 and 3). Using
.
CoCl2 6H2O as a catalyst afforded a 40% yield of
product 3a (entry 4). Using CH3CN or benzene as the
solvent afforded only low yield of 8% or 15% (entries
5 and 6). Lowering temperature to 100oC produced a
30% yield in DMF (entry 7). Raising temperature to
130oC gave a 50% yield (entry 8). Using K2CO3 as a
base instead of Na2CO3 increased the reaction yield to
Scheme 2. Control experiments.
63% (entry 9). The use of DBU as a base with
.
To explore the reaction mechanism, two designed
control experiments were conducted (Scheme 2). To
determine if radical intermediates were involved in
this sulfenylation process, TEMPO (2,2,6,6-
tetramethyl-piperidinooxy) was used as a radical
scavenger under the optimized conditions. In the
presence of TEMPO, the reaction still gave expected
2i in a 68% yield, indicating that the reaction was not
going through a radical pathway. When 1a was
CoCl2 6H2O did not generate any 3a (entry 10) in
DMF. Surprisingly, when DABCO was used as a
base (entry 11), an 85% yield was obtained.
Decreasing the catalyst loading to 0.2 equiv. afforded
a 92% yield (entry 12), but when the catalyst loading
was decreased to 0.1 equiv. ， the reaction yield
dropped to 80% (entry 13). When the reaction was
carried out under the argon atmosphere, the yield of
3a dropped to 60% (entry 14). Suggesting air plays a
3
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10.1002/adsc.201601431
Advanced Synthesis & Catalysis
role as an oxidant, but it is not the only oxidant.
hindrance reduced the yield to 20% (Table 4, 3o).
The substituent change on imidazo[1,2-α]pyridine
.
.
Changing catalyst from CoCl2 6H2O to FeCl2 4H2O or
FeCl3 afforded only a 45% or 55% yield, respectively
(entries 15 and 16). Based on these results, we
selected the following general reaction conditions: 2-
Table 4. Generation of 2-phenylimidazo[1,2-α]pyridine
thioether derivatives via C-H functionalization catalyzed
by CoCl2 using S8 and arylboronic acids.[a]
phenylimidazo[1,2-a]pyridine
(1.0
equiv.),
arylboronic acid (2.0 equiv.), S8 (1.5 equiv.),
.
CoCl2 6H2O (0.2 equiv.) and DABCO (2.0 equiv.) in
DMF as a solvent at 130 oC.
Table 3. Sulfenylation screening reactions using S8 and
arylboronic acid.[a]
Entry Catalyst
Base
PPh3
T
Solvent Yield
[%][b]
[oC]
1[c]
2
3
I2
CuBr
CuI
120 DMF
5
Na2CO3 120 DMF
Na2CO3 120 DMF
10
15
40
8
4
5
CoCl2.6H2O Na2CO3 120 DMF
CoCl2.6H2O Na2CO3 120 CH3CN
6
CoCl2.6H2O Na2CO3 120 Benzene 15
7
8
9
10
11
12[d]
13[e]
14[f]
15
CoCl2.6H2O Na2CO3 100 DMF
CoCl2.6H2O Na2CO3 130 DMF
30
50
63
0
85
92
80
60
45
55
CoCl2.6H2O K2CO3
CoCl2.6H2O DBU
130 DMF
130 DMF
CoCl2.6H2O DABCO 130 DMF
CoCl2.6H2O DABCO 130 DMF
CoCl2.6H2O DABCO 130 DMF
CoCl2.6H2O DABCO 130 DMF
FeCl2.4H2O DABCO 130 DMF
16
FeCl3
DABCO 130 DMF
[a]
Reaction
conditions:
2-phenylimidazo[1,2-
α]pyridine (0.5 mmol, 1.0 equiv.), arylboronic acid
(2.0 equiv.), S8 (1.5 equiv.), catalyst (0.5 equiv.),
base (2.0 equiv.), DMF (0.5 mL) under the air, 20h.
[b] Isolated yields are based on reactant 1a
.
[c] I2 (1.0 equiv.), addition: PPh3 (1.0 equiv.).
[d] CoCl2.6H2O (0.2 equiv.).
[e] CoCl2.6H2O (0.1 equiv.).
[f] Under the argon atmosphere
With these selected conditions in hand, several
arylimidazo[1,2-a]pyridines
with
different
substituents were synthesized and reacted with
different substituted arylboronic acids which
contained (-Me, -OMe, -Cl, -Br, -NO2) on their
phenyl ring. These results are presented in Table 4.
All these sulfenylation reactions proceeded well,
giving aryl-S-substituted imidazo[1,2-α]pyridine
derivatives in good yields. Furthermore, electron-
donating functions on imidazo[1,2-α]pyridine ring
gave somewhat higher yields than those with
electron-withdrawing functions. Furthermore, the
scope of arylboronic acid substrates was investigated.
Using a heteroaromatic boronic acid also gave a good
yield of the desired product 3n. When ortho-
chlorosubstituted arylboronic acid was used, its steric
[a]
The reactions were carried out as follows: 2-
phenylimidazo[1,2-α]pyridine (0.5 mmol, 1.0 equiv.),
arylboronic acid (2.0 equiv.), S8 (1.5 equiv.),
CoCl2.6H2O (0.2 equiv.), DABCO (2.0 equiv.), DMF
(0.5 mL) at 130oC, 20h.
[b] Isolated yields are based on reactant 1.
from an aryl to an alkyl function was also explored.
When 2-methylimidazo[1,2-α]pyridine was used as a
reactant, the reaction still gave a 70% yield of 3p.
4
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10.1002/adsc.201601431
Advanced Synthesis & Catalysis
To probe possible reaction mechanisms, TEMPO
In summary, two one-pot three-component
protocols which use easily available inorganic,
odorless S8 as a sulfur source, alcohols or arylboronic
acids as reactants were developed to make alkyl/aryl-
S-substituted imidazo[1,2-α]pyridine derivatives via
C-H functionalization. Both reactions proceeded well,
affording regioselective products in high yields under
relatively mild conditions. These two protocols are
practical and efficient, enriching currently known C-S
bond construction methods.
was used as a radical scavenger in a control reaction
(Scheme 4). A good yield was still obtained despite
the presence of this radical scavenger. This is
evidence that the reaction did not proceed through a
radical pathway. Previous literature showed that
arylboronic acids could react with S8 to generate
disulfides.16 With this in mind, we synthesized 1,2-
diphenyldisulfane, and reacted it with 1a under the
optimized conditions. As expected, a 60% yield of 3a
was isolated. This result suggested that 1,2-
diphenyldisulfane could be an intermediate in the
sulfenylation process.
Experimental Section
General experimental procedures
All reactions were carried out in round-bottom flasks;
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
further 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 solvents were purchased
from Cambridge Isotope laboratories. 1H- and 13C-
NMR spectra were recorded on a Bruker DRX-400
spectrometer operating at 400 MHz and 100 MHz
respectively. HRMS spectrometry (LC-HRMS) was
recorded on a LXQ Spectrometer (Thermo Scientific)
Scheme 4. Control reactions.
On the basis of our experimental results and those
of previous relevant mechanistic studies,17 we
propose the speculative but plausible reaction
pathway depicted in Scheme 5. Initially, in the
presence of base and CoCl2, arylboronic acid A
reacted with the cobalt dichloride catalyst to generate
arylcobalt complex intermediate B. Subsequently,
intermediate B reacts with S8 powder to give another
intermediate C, which might exist in equilibrium
diaryldisulfide. C then reacts with 1a to afford the
intermediate D which is deprotonated by base
(DABCO) or ArS- to give the intermediate E.
operating on ESI-TOF (MeOH as
a solvent).
Heterocyclic derivatives were synthesized according
to the literature.
General procedure for the synthesis of compounds
2a-r.
2-Phenylimidazo[1,2-α]pyridine 1a (0.5 mmol, 1.0
equiv.), S8 (2.0 equiv.) and methyl alcohol (3.0 equiv.)
were added to a dried flask with DMF (0.5 mL) ,
followed by the addition of I2 (1.0 equiv.) and PPh3
o
(1.0 equiv.). The mixture was stirred at 120 C. After
12 h, the reaction was cooled to room temperature,
diluted with ethyl acetate, washed with brine, dried
over anhydrous Na2SO4 and concentrated under
vacuum. The residue was purified by flash
chromatography (Petroleum ether: EtOAc = 30:1) on
silica gel to give the product 2a as a colorless oil in a
75% yield. The same procedure was applied to the
production of compounds 2a-r.
General procedure for the synthesis of compounds
3a-p.
2-Phenylimidazo[1,2-α]pyridine 1a (0.5 mmol, 1.0
equiv.), S8 (1.5 equiv.) and arylboronic acid (2.0
equiv.) were added to a dried flask with solvent DMF
(0.5 mL) , followed by the addition of CoCl2.6H2O
(0.2 equiv.) and DABCO (2.0 equiv.). The mixture
Scheme 5. A plausible mechanism for the generation of
arylthioether-substituted
derivatives.
imidazo[1,2-α]pyridine
o
was stirred at 130 C. After 20 h, the reaction was
Reductive elimination gives product 3a. The resultant
Co(I) from reductive elimination step was then
oxidized back to Co(II) by air or S8.
cooled to room temperature, diluted with ethyl acetate,
washed with brine, dried over anhydrous Na2SO4 and
concentrated under vacuum. The residue was purified
5
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10.1002/adsc.201601431
Advanced Synthesis & Catalysis
by flash chromatography (Petroleum ether: EtOAc
=25:1) on silica gel to give the product 3a as a
colorless oil in a 92% yield. The same procedure was
applied to the production of other compounds 3a-p.
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Author contributions
W.Z. and Y.D. contributed equally.
Acknowledgements
This investigation was generously supported by funds
provided by Jiangsu University (1281290006). We are very
grateful to Charles U. Pittman, Jr., Mississippi State
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Advanced Synthesis & Catalysis
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10.1002/adsc.201601431
Advanced Synthesis & Catalysis
COMMUNICATION
One-pot Three-component Synthesis of
Alkyl/Arylthioether-Substituted Imidazo[1,2-
α]pyridine Derivatives via C(sp2)-H
Functionalization
Adv. Synth. Catal. Year, Volume, Page – Page
Wenhui Zhu,a Yingcai Ding,a Zhaogang Bian,a Ping
Xie,b Baojun Xu,a Qiujie Tang,a Wei Wu,a and
Aihua Zhoua,*
8
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