Aerobic multicomponent tandem synthesis of 3-sulfenylimidazo[1,2-a] pyridines from ketones, 2-aminopyridines, and disulfides

Article abstract of DOI:10.1002/ejoc.201300905

An aerobic CeCl₃·7H₂O/NaI-catalyzed C-H functionalization reaction was developed for the synthesis of 3-sulfenylimidazo[1,2-a]pyridines from easily available ketones, 2-aminopyridines, and disulfides without DMSO or peroxide as an ox

Full text of DOI:10.1002/ejoc.201300905

Job/Unit: O30905
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Date: 20-08-13 11:30:48
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300905
Aerobic Multicomponent Tandem Synthesis of 3-Sulfenylimidazo[1,2-
a]pyridines from Ketones, 2-Aminopyridines, and Disulfides
Wenlei Ge,[a] Xun Zhu,[a,b] and Yunyang Wei*[a]
Keywords: Multicomponent reactions / Tandem reactions / C–H functionalization / Cerium / Sulfur / Ketones
An aerobic CeCl3·7H2O/NaI-catalyzed C–H functionalization
volves the formation of imidazo[1,2-a]pyridines followed by
reaction was developed for the synthesis of 3-sulfenylimid-
Friedel–Crafts sulfenylation in one pot under mild conditions.
azo[1,2-a]pyridines from easily available ketones, 2-amino- Both aryl and alkyl ketones afforded the desired products in
pyridines, and disulfides without DMSO or peroxide as an
oxidant. This three-component tandem reaction process in-
good to excellent yields without the presence of other addi-
tives.
lytic efficiency and environmentally friendly characters.[6]
Among the cerium(III) salts used, CeCl3 has emerged as a
cheap, nontoxic, water-tolerant, and very useful Lewis acid
catalyst that can promote reactions of electron-rich aza-aro-
matics with several electrophiles to form C–S, C–N, C–O,
and C–C bonds in both hydrated and anhydrous forms.[7]
It was found that the addition of NaI to CeCl3·7H2O is a
key step to expand the use of CeCl3·7H2O.[8] The
CeCl3·7H2O/NaI catalytic system is tolerated under aerobic
oxidative reaction conditions.
Introduction
Aerobic C–H bond functionalization is one of the most
important strategies in organic synthesis, and it provides an
efficient method to construct C–C and C–heteroatom (N,
S, and O, etc.) bonds.[1] This transformation is more econ-
omic and straightforward than traditional synthetic strate-
gies, as it can avoid prefunctionalization of the substrates.[2]
In this emerging field, highly efficient and selective forma-
tion of C–N and C–S bonds simultaneously in one-pot
through C–H bond functionalization is still an interesting
challenge.[3]
Recently, direct oxidative C–H functionalization was re-
alized in multicomponent reactions (MCRs),[4] which is one
of the most powerful, efficient, and atom-economical meth-
odologies in organic synthesis, especially for the preparation
of heterocyclic polyfunctionalized molecules. This strategy
has many advantages in comparison to the classical step-
by-step formation of individual bonds for a given target
molecule, including the preclusion of time-consuming mul-
tiple workup processes and the isolation of intermediates.
However, activation of C–H bonds in MCRs mainly de-
pends on the use of noble metal catalysts and equivalent
amounts of oxidants, such as peroxide, hypervalent iodide,
and so on.[5]
Imidazopyridine and its derivatives exist in a variety of
natural products and have attracted much attention because
of their important biological activities and broad utilization
in the pharmaceutical industry. For example, they can be
used as antiulcer agents, long-acting local anesthetics, an-
thelmintic or bacteriostatic agents, and fluorescent materi-
als.[9] They are also used in bioimaging probes and molecu-
lar sensors for molecular recognition because of their struc-
tural characters.[10] Generally, the pharmacological profile
is mainly dependent on the nature of the substituents, and
introduction of sulfenyl or selenyl groups on the aza-aro-
matic rings could impart marked biological properties to
the compounds; for example, 3-sulfenyl indoles, 3-sulfenyl
pyrroles, and 3-sulfenylimidazopyridines are of considerable
therapeutic value against a variety of diseases.[11] 3-Sulfenyl-
imidazopyridines are usually prepared by sulfenylation of
imidazopyridines prior-synthesized. The most direct and
applicable procedures involve the use of hypervalent-iodide
PIFA-promoted oxidative intermolecular C–S cross-cou-
pling reactions from imidazopyridines and aryl thiols [PIFA
= phenyliodine bis(trifluoroacetate); Scheme 1, Eq. (1)].[12]
Xigeng Zhou and co-workers reported an alternative
method for the synthesis of 3-sulfenylimidazopyridines by
sulfenylation of imidazopyridines by using disulfides cata-
lyzed by CuI under an air atmosphere in DMSO [Scheme 1,
Eq. (2)].[13] These methods use imidazopyridines as starting
Trivalent cerium ions have also been applied for MCRs
to construct heterocyclic aromatics, for example, pyrroles,
pyridines, and pyrimidones, as a result of their high cata-
[a] School of Chemical Engineering, Nanjing University of Science
and Technology,
Nanjing 210094, P. R. China
E-mail: ywei@mail.njust.edu.cn
Homepage: www.njust.edu.cn
[b] Department of Chemical Engineering, Yancheng Institute of
Industry Technology,
Yancheng, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300905.
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W. Ge, X. Zhu, Y. Wei
SHORT COMMUNICATION
materials in the presence of equivalent amounts of oxidants Table 1. Optimization of the reaction conditions for the sulf-
enylation of enones.[a]
to activate the C–H bonds. However, most imidazopyrid-
ines are not commercially available.
Entry Catalyst
[O]
Solvent
Yield
[%][b]
1
2
3
4
5
6
7
8
CeCl3·7H2O
O2
O2
O2
O2
air
N2
O2
O2
O2
O2
O2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DMC
0
74
63
93
29
Ͻ10
19
31
91
93
67
trace
Ͻ5
Ͻ5
51
Ͻ5
49
CeCl3·7H2O/I2
CeCl3·7H2O/HI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
NaI
Scheme 1. Strategies for the synthesis of 3-sulfenylimidazopyrid-
ines.
9
iPrOH
EtOH
glycol
10
11
12[c]
13[c]
14[c]
15[c]
16[c]
17[d]
18[e]
19
20
21[f]
Therefore, synthesis of 3-sulfenylimidazopyridines from
easily available substrates without the use of equivalent
amounts of oxidants and imidazopyridines prior-synthe-
sized is highly desirable. In our continuous work on C–S,
C–N, and C–O bond-forming reactions,[14] an aerobic oxi-
dative CeCl3·7H2O/NaI-catalyzed multicomponent reaction
was developed for the synthesis of 3-sulfenylimidazopyrid-
ines from ketones, 2-aminopyridines, and disulfides under
benign conditions [Scheme 1, Eq. (3)].
DMSO EtOH
Oxone
TBHP
DTBP
H2O2
O2
O2
O2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
61
0
Ͻ5
56
I2
O2
O2
CeCl3·7H2O/NaI(SiO2)
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a
(0.25 mmol), catalyst (10 mol-%), solvent (1 mL), 10 h, 80 °C, in a
35 mL sealed tube. [b] Yield of isolated product after column
chromatography. [c] 3 equiv. of the oxidant was used. [d] The reac-
tion was performed at 60 °C. [e] 5 mol-% of the catalyst was used.
[f] 3 mmol of CeCl3·7H2O/NaI (1.12 g/0.45 g) was supported on sil-
ica gel (5 g) and 10 mol-% of the catalyst (0.11 g) was used.
Results and Discussion
At the beginning of our investigation, readily available
acetophenone, 2-aminopyridine, and diphenyl disulfide
were selected as the model substrates to optimize the reac-
tion conditions, and the results are listed in Table 1. To our
delight, desired product 4a was obtained in 93% yield from at 60 °C instead of 80 °C, the yield of 4a decreased from
the model reaction under the catalysis of CeCl3·7H2O to- 93 to 49% (Table 1, entries 17 and 18). Blank experiments
gether with NaI as an additive under an O2 atmosphere in showed that NaI or I2 alone cannot catalyze the reaction
CH3CN (Table 1, entry 4). No product was detected with- (Table 1, entries 19 and 20). A silica gel supported catalyst
out the use of NaI (Table 1, entry 1). Other additives such was also tested under the optimized conditions, and the ac-
as I2 and HI afforded the desired product in 74 and 63% tivity of the catalyst decreased remarkably, and 4a was ob-
yield, respectively (Table 1, entries 2 and 3). Upon per- tained in only moderate yield (Table 1, entry 21).
forming the reaction in air instead of under an O2 atmo-
sphere, product 4a was isolated in 29% yield.
To extend the scope of this methodology, a variety of
ketones were allowed to react with 2-aminopyridine and di-
However, 4a was obtained in less than 10% yield if the phenyl disulfide under the optimized conditions. As can be
reaction was performed under a N2 atmosphere (Table 1, seen from Table 2, the tandem reactions of ketones with 2-
entries 5 and 6). Several kinds of solvents were then exam- aminopyridine and diphenyl disulfide generated the corre-
ined, and ethanol was the solvent of choice on the basis of sponding products in good to excellent yields. Electron-do-
the yield of desired product 4a (Table 1, entries 7–11; DMC nating and electron-withdrawing groups on the benzene
= dimethyl carbonate). Subsequently, several oxidants such rings of the aromatic ketones were tolerated. Aromatic
as DMSO, Oxone, tert-butyl hydroperoxide (TBHP), di- ketones bearing electron-donating groups (Table 2, prod-
tert-butyl peroxide (DTBP), and H2O2 were tested in the ucts 4b, 4d, 4e, 4i), such as CH3, OCH3, and phenyl gave
reaction. Only DTBP as the oxidant was able to deliver the slightly higher yields of the products than those bearing
desired product in moderate yield. With DMSO, Oxone, electron-withdrawing groups such as Cl, Br, and NO2
TBHP, and H2O2 as the oxidant instead of O2, less than (Table 2, products 4f–h). Acetophenone bearing a CH3
5% of the desired product was formed, along with several group at the ortho position of the aromatic ring afforded
byproducts (Table 1, entries 9–11). Reducing the dosage of the corresponding product in 90% yield, in comparison to
the catalyst from 10 to 5 mol-% led to a decrease in the the yield of 94% that was obtained if the CH3 group was
yield of 4a from 93 to 61%. Upon performing the reaction located at the para position of the aromatic ring. This result
2
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Aerobic Multicomponent Tandem Reaction
represents a slight ortho-position effect of acetophenone Table 3. The scope of disulfides for the synthesis of 3-sulfenylimid-
azopyridines under the optimized reaction conditions.[a,b]
(Table 2, products 4b and 4c). Under the present reaction
conditions, 1-acetylnaphthalene also underwent the tandem
reaction to generate 4j in 88% yield. 2-Acetylfuran, a het-
erocyclic ketone, was easily converted into desired product
4k in 85% yield, and to our delight, acetone was also trans-
formed to desired product 4l in 53% yield.
Table 2. The scope of ketones for the synthesis of 3-sulfenylimid-
azopyridines under the optimized reaction conditions.[a,b]
[a] Reaction conditions:
1
(0.5 mmol), 2a (0.5 mmol),
3
(0.25 mmol), catalyst (10 mol-%), solvent (1 mL), 10 h, 80 °C, in a
35 mL sealed tube. [b] Yields of the isolated products after column
chromatography are given. [c] 0.2 equiv. of the catalyst was used.
[d] N-Propylthiol succinimide instead of dipropyl disulfide was
used.
Without the use of disulfides, the CeCl3·7H2O/NaI
(0.1 equiv.) catalyzed reaction of ketones and 2-aminopyr-
idine easily afforded the intermediate imidazopyridines un-
[a] Reaction conditions:
1
(0.5 mmol), 2a (0.5 mmol), 3a der an O2 atmosphere. Although a variety of protocols have
been developed to form imidazopyridines,[15] most of them
require the addition of equivalent amounts of the transi-
tion-metal catalysts and oxidants, such as Ag2CO3,[16]
hypervalent iodide,[17] I2,[18] TBHP,[19] and so on. Notably,
the imidazopyridines could be isolated in high yields
(0.25 mmol), catalyst (10 mol-%), solvent (1 mL), 10 h, 80 °C, in a
35 mL sealed tube. [b] Yields of the isolated products after column
chromatography are given. [c] 1 (10 mmol), 2a (10 mmol), and 3a
(5 mmol) were used for a gram-scale experiment. [d] Reaction was
performed for 15 h. [e] 1.5 equiv. of acetone were used.
The three-component tandem reaction between aceto- through a simple workup process. In light of this and as a
phenone and 2-aminopyridine with various disulfides was result of the great importance of functionalized imidazopy-
investigated, and the results are summarized in Table 3. Di- ridines among natural compounds and pharmaceutical
sulfides bearing electron-donating R groups (Table 3, prod- products, we explored our procedure with several kinds of
ucts 4m and 4n) gave better yields than those bearing elec- substrates, and the results are listed in Table 4.
tron-withdrawing groups (Table 3, products 4o–q), which
Ketones bearing aryl groups were all converted into the
suggests that during the reaction, an electrophilic RS+ spe- desired imidazopyridines in satisfactory to excellent yields
cies may be formed. An electron-donating group attached (Table 4, products 5a–d). Excitingly, aliphatic ketones also
to R would be favorable for the formation of such a species. afford the desired imidazopyridines in moderate yields
Notably, dibenzyl disulfide was also converted into corre- (Table 4, products 5e–g). Other pyridine derivatives such as
sponding product 4r in 83% yield in the presence of 3-chloropyridin-2-amine and pyrimidin-2-amine also gave
0.2 equiv. of the catalyst (Table 3, product 4r). Alkyl di- the desired products in good yields (Table 4, products 5h
sulfides did not afford the desired product under the present and 5i).
reaction conditions. However, the use of N-propylthiol suc-
To explore the catalytic mechanism, some blank and par-
cinimide instead of dipropyl disulfide afforded the desired allel experiments were performed, and the results are listed
product in 86% yield (Table 3, product 4s). Under the opti- in Scheme 2. Under the optimized reaction conditions,
mized conditions, diphenyl diselenide was well tolerated, phenacyl iodine could not be oxidized to phenylglyoxal cat-
and the desired selenylation product was obtained in 89% alyzed by CeCl3·7H2O/NaI under an O2 atmosphere
yield (Table 3, product 4t).
(Scheme 2, pathway b). Moreover, the desired product was
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W. Ge, X. Zhu, Y. Wei
SHORT COMMUNICATION
Table 4. Synthesis of imidazopyridines under the optimized reac- (C),[20] which reacts with imidazopyridine to give intermedi-
tion conditions.[a,b]
ate D. Deprotonation of intermediate D gives the final
product [Scheme 3, Eq. (2)].
Scheme 3. Proposed mechanism for the synthesis of 3-sulfenylimid-
azopyridines.
Conclusions
[a] Reaction conditions:
1 (0.5 mmol), 2 (0.5 mmol), catalyst
An efficient and environmentally friendly CeCl3·7H2O/
NaI-catalyzed oxidative system based on a three-compo-
nent reaction in one pot has been developed for the synthe-
sis of 3-sulfenylimidazopyridines from ketones, 2-aminopyr-
idines, and disulfides. This tandem reaction process involves
a C–H bond functionalization strategy for the formation of
C–N and C–S bonds with O2 as the terminal oxidant. In
addition, imidazopyridines can also be formed under the
optimized reaction conditions without the use of disulfides.
A tentative reaction mechanism was proposed.
(10 mol-%), solvent (1 mL), 10 h, 80 °C, in a 35 mL sealed tube.
[b] Yields of the isolated products after column chromatography
are given. [c] The reaction was performed for about 20 h.
not isolated upon using phenylglyoxal instead of aceto-
phenone (Scheme 2, pathway c). These results clearly dem-
onstrate that phenacyl iodine may be an important interme-
diate in the formation of the imidazopyridines (Scheme 2,
pathway a). Furthermore, the intermediate imidazopyridine
efficiently reacted with disulfide to form the 3-sulfenylimid-
azopyridine end product in high yield under the optimized
conditions (Scheme 2, pathway d).
Experimental Section
General Procedure for the Synthesis of Silica-Supported
CeCl3·7H2O/NaI: Silica gel (5 g) was added to a mixture of
CeCl3·7H2O (1.12 g, 3 mmol) and NaI (0.45 g, 3 mmol) in MeCN
(100 mL), and the mixture was stirred overnight at room tempera-
ture. MeCN was removed under reduced pressure, and the resulting
mixture was stored in a bottle at room temperature.
General Procedure for the Synthesis of 3-Sulfenylimidazopyridines:
The ketone (0.5 mmol), 2-aminopyridine (0.5 mmol), and disulfide
(0.25 mmol) were dissolved in EtOH (1 mL) at 80 °C in a 35 mL
sealed tube, and then CeCl3·7H2O/NaI (0.05 mmol, 10 mol-%) was
added. The reaction proceeded under an O2 atmosphere for the
indicated time until complete consumption of the starting material
as indicated by TLC. The solution was diluted with EtOAc (10 mL)
and washed with H2O (3ϫ 10 mL). Then, the organic layer was
separated and concentrated under vacuum, and the crude product
was purified by recrystallization (petroleum ether/EtOAc, 3:1) or
column chromatography (petroleum ether/EtOAc, 5:1) to provide
analytically pure product 4.
Scheme 2. Parallel and blank experiments tested to explore the re-
action mechanism.
On the basis of the results obtained above, a tentative
mechanism is proposed to explain the reaction (Scheme 3).
To start, the iodide anion from NaI is oxidized to iodine
with O2 as the terminal oxidant in the presence of the
CeCl3·7H2O/NaI catalytic system [Scheme 3, Eq. (1)]. The
ketone is then α iodinated to phenacyl iodine (A) by iodine.
Nucleophilic attack of 2-aminopyridine on A affords inter-
mediate B. Intramolecular cyclization of B gives the inter-
mediate imidazopyridine with regeneration of NaI. The di-
General Procedure for the Synthesis of Imidazopyridines: The ketone
(0.5 mmol) and 2-aminopyridine (0.5 mmol) were dissolved in
EtOH (1 mL) at 80 °C in
a 35 mL sealed tube, and then
CeCl3·7H2O/NaI (0.05 mmol, 10 mol-%) was added. The reaction
proceeded under an O2 atmosphere for the indicated time until
sulfide reacts with I2 to form the RSI electrophilic species complete consumption of the starting material as indicated by
4
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Aerobic Multicomponent Tandem Reaction
[7]
[8]
a) B. V. S. Reddy, R. Jain, K. Bhargavi, M. Swain, J. S. Yadav,
Synthesis 2011, 2, 0337–0341; b) G. Bartoli, E. Marcantoni, M.
Marcolini, L. Sambri, Chem. Rev. 2010, 110, 6104–6143; c)
C. C. Silveira, S. R. Mendes, L. Wolf, G. M. Martins, Tetrahe-
dron Lett. 2010, 51, 2014; d) C. C. Silveira, S. R. Mendes, Tet-
rahedron Lett. 2007, 48, 7469–7471; e) D. C. Johnson II, T. S.
Widlanski, J. Org. Chem. 2003, 68, 5300–5309; f) G. Sabitha,
R. S. Babu, M. Rajkumar, J. S. Yadav, Org. Lett. 2002, 4, 343–
345.
a) E. Marcantoni, R. Cipolletti, L. Marsili, S. Menichetti, R.
Properzi, C. Viglianisi, Eur. J. Org. Chem. 2013, 132–140; b) G.
Bartoli, M. Bosco, A. Giuliani, E. Marcantoni, A. Palmieri,
M. Petrini, L. Sambri, J. Org. Chem. 2004, 69, 1290–1297; c)
G. Bartoli, M. Bartolacci, M. Bosco, G. Foglia, A. Giuliani, E.
Marcantoni, L. Sambri, E. Torregiani, J. Org. Chem. 2003, 68,
4594–4597; d) E. Marotta, E. Foresti, T. Marcelli, F. Peri, P.
Righi, N. Scardovi, G. Rosini, Org. Lett. 2002, 4, 4451–4453;
e) G. Bartoli, M. C. Bellucci, M. Petrini, E. Marcantoni, L.
Sambri, E. Torregiani, Org. Lett. 2000, 2, 1791–1793.
a) Y. Katsura, S. Nishino, Y. Inoue, M. Tomoi, H. Takasugi,
Chem. Pharm. Bull. 1992, 40, 371–380; b) B. Dubinsky, D. A.
Shriver, P. J. Sanfilippo, J. B. Press, A. J. Tobia, M. E. Rosen-
thale, Drug Dev. Res. 1990, 21, 277–289; c) J. E. Starrett, T. A.
Montzka, A. R. Crosswell, R. L. Cavanagh, J. Med. Chem.
1989, 32, 2204–2210; d) H. Tomoda, T. Hirano, S. Saito, T.
Mutai, K. Araki, Bull. Chem. Soc. Jpn. 1999, 72, 1327–1334;
e) J. C. Teulade, G. Grassy, R. Escale, J. P. Chapat, J. Org.
Chem. 1981, 46, 1026–1030; f) E. S. Hand, W. W. Paudler, J.
Org. Chem. 1980, 45, 3738–3745; g) A. J. Guildford, M. A. To-
metzki, R. W. Turner, Synthesis 1983, 987–989; h) M. H.
Fisher, A. Lusi, J. Med. Chem. 1972, 15, 982–985.
a) S. M. Hanson, E. V. Morlock, K. A. Satyshur, C. Czajkow-
ski, J. Med. Chem. 2008, 51, 7243–7252; b) M. H. Wiegand,
Drugs 2008, 68, 2411–2417; c) T. S. Harrison, G. M. Keating,
CNS Drugs 2005, 19, 65–89; d) K. S. Gudmundsson, J. D. Wil-
liams, J. C. Drach, L. B. Townsend, J. Med. Chem. 2003, 46,
1449–1455; e) J. J. Kaminsky, A. M. Doweyko, J. Med. Chem.
1997, 40, 427–436; f) T. Palani, K. Park, M. R. Kumar, H. M.
Jung, S. Lee, Eur. J. Org. Chem. 2012, 5038–5047; g) M. A.
Andriyankov, G. G. Skvortsova, V. K. Voronov, Zh. Org. Khim.
1983, 19, 2459; h) M. Bakherad, H. Nasr-Isfahani, A. Keivan-
loo, N. Doostmohammad, Tetrahedron Lett. 2008, 49, 3819–
3822; i) G. B. Barklin, L. P. Davies, P. W. Harrison, Aust. J.
Chem. 1995, 48, 1031–1038; j) Ya. G. Bal’on, M. D. Shul’man,
V. A. Smirnov, M. M. Yukhomenko, M. A. Yukhomenko, Zh.
Org. Khim. 1990, 26, 1566–1571.
a) D. Huang, J. Chen, W. Dan, J. Ding, M. Liu, H. Wu, Adv.
Synth. Catal. 2012, 354, 2123–2128; b) O. Saidi, J. Marafie,
A. E. W. Ledger, P. M. Liu, M. F. Mahon, G. Kociok-Köhn,
M. K. Whittlesey, C. G. Frost, J. Am. Chem. Soc. 2011, 133,
19298–19301; c) K. M. Schlosser, A. P. Krasutsky, H. W. Ham-
ilton, J. E. Reed, K. Sexton, Org. Lett. 2004, 6, 819; d) M.
Tudge, M. Tamiya, C. Savarin, G. R. Humphrey, Org. Lett.
2006, 8, 565–568.
TLC. The solution was diluted with EtOAc (10 mL) and washed
with H2O (3ϫ 10 mL). Then, the organic layer was separated and
concentrated under vacuum, and the crude product was purified
by recrystallization (petroleum ether/EtOAc, 5:1) or column
chromatography (petroleum ether/EtOAc, 5:1 to 2:1) to provide an-
alytically pure product 5.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra.
Acknowledgments
The authors are grateful to Nanjing University of Science and
Technology for financial support. This project was funded by the
Priority Academic Program Development of Jiangsu Higher Edu-
cation Institutions (PAPD).
[1] a) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111,
1780–1824; b) J. Wencel-Delord, T. Droge, F. Liu, F. Glorius,
Chem. Soc. Rev. 2011, 40, 4740–4761; c) O. Saidi, J. Marafie,
A. E. W. Ledger, P. M. Liu, M. F. Mahon, G. Kociok-Köhn,
M. K. Whittlesey, C. G. Frost, J. Am. Chem. Soc. 2011, 133,
19298–19301; d) X. Zhao, E. Dimitrijevic, V. M. Dong, J. Am.
Chem. Soc. 2009, 131, 3466–3467; e) X. Chen, K. M. Engle, D.
Wang, J. Yu, Angew. Chem. 2009, 121, 5196–5217; Angew.
Chem. Int. Ed. 2009, 48, 5094–5115; f) O. Daugulis, H. Q. Do,
D. Shabashov, Acc. Chem. Res. 2009, 42, 1074–1086; g) V. Rit-
leng, C. Sirlin, M. Pfeffer, Chem. Rev. 2002, 102, 1731–1770;
h) G. Dyker, Angew. Chem. 1999, 111, 1808–1822; Angew.
Chem. Int. Ed. 1999, 38, 1698–1712.
[2] a) H. Huang, X. Ji, W. Wu, L. Huang, H. Jiang, J. Org. Chem.
2013, 78, 3774–3782; b) A. Hajra, Y. Wei, N. Yoshikai, Org.
Lett. 2012, 14, 5488–5491; c) M. T. Barros, S. S. Dey, C. D.
Maycock, P. Rodrigues, Chem. Commun. 2012, 48, 10901–
10903; d) Y. Izawa, D. Pun, S. S. Stahl, Science 2011, 333, 209–
213; e) M.-O. Simon, S. A. Girard, C.-J. Li, Angew. Chem.
2012, 124, 7655–7658; Angew. Chem. Int. Ed. 2012, 51, 7537–
7540.
[3] a) J. Liu, P. Li, W. Chen, L. Wang, Chem. Commun. 2012, 48,
10052–10054; b) L. Shi, X. Liu, H. Zhang, Y. Jiang, D. Ma, J.
Org. Chem. 2011, 76, 4200–4204; c) H.-A. Du, R.-Y. Tang, C.-
L. Deng, Y. Liu, J.-H. Li, X.-G. Zhang, Adv. Synth. Catal.
2011, 353, 2739–2748; d) Y.-J. Guo, R.-Y. Tang, J.-H. Li, P.
Zhong, X.-G. Zhang, Adv. Synth. Catal. 2009, 351, 2615–2618.
[4] a) X. Li, Y. Zhao, H. Qu, Z. Mao, X. Lin, Chem. Commun.
2013, 49, 1401–1403; b) M. Rueping, C. Vila, Org. Lett. 2013,
15, 2092–2095; c) M. Shiri, Chem. Rev. 2012, 112, 3508–3549;
d) S. Duttwyler, C. Lu, A. L. Rheingold, R. G. Bergman, J. A.
Ellman, J. Am. Chem. Soc. 2012, 134, 4064–4067; e) H. Deng,
Z. Li, F. Ke, X. Zhou, Chem. Eur. J. 2012, 18, 4840–4843; f)
S. U. Dighe, S. Hutait, S. Batra, ACS Comb. Sci. 2012, 14, 665–
672; g) T. Zeng, W.-W. Chen, C. M. Cirtiu, A. Moores, G.
Song, C.-J. Li, Green Chem. 2010, 12, 570–573; h) L. Shi, X.
Liu, H. Zhang, Y. Jiang, D. Ma, J. Org. Chem. 2011, 76, 4200–
4204; i) Y. Shang, K. Ju, X. He, J. Hu, S. Yu, M. Zhang, K.
Liao, L. Wang, P. Zhang, J. Org. Chem. 2010, 75, 5743–5745;
j) B. B. Touré, D. G. Hall, Chem. Rev. 2009, 109, 4439–4486;
k) D. M. D’Souza, T. J. J. Müller, Chem. Soc. Rev. 2007, 36,
1095–1108.
[9]
[10]
[11]
[12]
a) C. Hamdouchi, J. D. Blas, J. Ezquerra, Tetrahedron 1999, 55,
541–548; b) C. Hamdouchi, C. Sanchez, J. Ezquerra, Synthesis
1998, 867–872; c) R. J. Bochis, L. E. Olen, M. H. Fisher, R. A.
Reamer, G. Wilks, J. E. Taylor, G. Olson, J. Med. Chem. 1981,
24, 1483–1487.
Z. Li, L. Hong, R. Liu, J. Shen, X. Zhou, Tetrahedron Lett.
2011, 52, 1343–1347.
a) W. Ge, Y. Wei, Synthesis 2012, 44, 934–940; b) W. Ge, Y.
Wei, Green Chem. 2012, 14, 2066–2070; c) W. Ge, X. Zhu, Y.
Wei, RSC Adv. 2013, 3, 10817–10822.
a) S. K. Guchhait, A. L. Chandgude, G. Priyadarshani, J. Org.
Chem. 2012, 77, 4438–4444; b) R. L. Yan, H. Han, C. Ma,
Z. Y. Ren, X. A. Gao, G. S. Huang, Y. M. Liang, J. Org. Chem.
2012, 77, 2024–2028; c) H. Cao, H. Y. Zhan, Y. G. Lin, X. L.
Lin, Z. D. Du, H. F. Jiang, Org. Lett. 2012, 14, 1688–1691;
d) O. N. Burchak, L. Mugherli, M. Ostuni, J. J. Lacapère, M.
[13]
[14]
[5] a) R. Y. Nimje, M. V. Leskinen, P. M. Pihko, Angew. Chem.
2013, 125, 4918–4922; Angew. Chem. Int. Ed. 2013, 52, 4818–
4822; b) F. Drouet, G. Masson, J. Zhu, Org. Lett. 2013, 15,
2854–2857.
[6] a) S. Chen, L. Li, H. Zhao, B. Li, Tetrahedron 2013, 69, 6223–
6229; b) D. Dhara, K. S. Gayen, S. Khamarui, P. Pandit, S.
Ghosh, D. K. Maiti, J. Org. Chem. 2012, 77, 10441–10449; c)
L. D. S. Yadav, R. Kapoor, Tetrahedron Lett. 2008, 49, 4840–
4844; d) D. S. Bose, L. Fatima, H. B. Mereyala, J. Org. Chem.
2003, 68, 587–590.
[15]
Eur. J. Org. Chem. 0000, 0–0
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Date: 20-08-13 11:30:48
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W. Ge, X. Zhu, Y. Wei
SHORT COMMUNICATION
Balakirev, J. Am. Chem. Soc. 2011, 133, 10058–10061; e) P. Liu,
C. L. Deng, X. S. Lei, G. Q. Lin, Eur. J. Org. Chem. 2011,
7308–7316; f) S. Mishra, R. Ghosh, Synthesis 2011, 3463; g)
N. Chernyak, V. Gevorgyan, Angew. Chem. 2010, 122, 2803–
2806; Angew. Chem. Int. Ed. 2010, 49, 2743–2746; h) H. Wang,
Y. Wang, C. Peng, J. Zhang, Q. Zhu, J. Am. Chem. Soc. 2010,
132, 13217–13219; i) E. Kianmehr, M. Ghanbari, M. N. Niri,
R. Faramarzi, J. Comb. Chem. 2010, 12, 41–44; j) A. Herath,
R. Dahl, N. D. P. Cosford, Org. Lett. 2010, 12, 412–415; k) M.
Aginagalde, Y. Vara, A. Arrieta, R. Zangi, V. L. Cebolla, A.
Delgado-Camón, F. P. Cossío, J. Org. Chem. 2010, 75, 2776–
[16] C. He, J. Hao, H. Xu, Y. Mo, H. Liu, J. Han, A. Lei, Chem.
Commun. 2012, 48, 11073–11075.
[17] a) T. J. Donohoe, M. A. Kabeshov, A. H. Rathi, I. E. D. Smith,
Org. Biomol. Chem. 2012, 10, 1093–1101; b) X. Wang, L. Ma,
W. Yu , Synthesis 2011, 2445–2453; c) M. Ueno, H. Togo, Syn-
thesis 2004, 16, 2673–2677; d) M. Ueno, T. Nabana, H. Togo,
J. Org. Chem. 2003, 68, 6424–6426.
[18] a) Z. Fei, Y.-P. Zhu, M.-C. Liu, F.-C. Jia, A.-X. Wu, Tetrahe-
dron Lett. 2013, 54, 1222–1226; b) A. J. Stasyuk, M. Banasiew-
icz, M. K. Cyran´ski, D. T. Gryko, J. Org. Chem. 2012, 77,
5552–5558.
2784; l) S. Kumar, D. P. Sahu, ARKIVOC 2008, 15, 88–98; m) [19] L. J. Ma, X. P. Wang, W. Yu, B. Han, Chem. Commun. 2011,
I. V. Seregin, A. W. Schammel, V. Gevorgyan, Org. Lett. 2007,
9, 3433–3436; n) A. R. Katritzky, Y. J. Xu, H. Tu, J. Org. Chem.
2003, 68, 4935–4937; o) C. Enguehard, J.-L. Renou, V. Collot,
M. Hervet, S. Rault, A. Gueiffier, J. Org. Chem. 2000, 65,
6572–6575; p) N. Katagiri, T. Kato, R. Niwa, J. Heterocycl.
Chem. 1984, 21, 407–412.
47, 11333–11335.
[20] a) Z. Li, J. Q. Hong, X. J. Zhou, Tetrahedron 2011, 67, 3690–
3697; b) X.-L. Fang, R.-Y. Tang, P. Zhong, J.-H. Li, Synthesis
2009, 24, 4183–4189.
Received: June 20, 2013
Published Online: ᭿
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Job/Unit: O30905
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Date: 20-08-13 11:30:48
Pages: 7
Aerobic Multicomponent Tandem Reaction
C–H Functionalization
W. Ge, X. Zhu, Y. Wei* .................... 1–7
Aerobic Multicomponent Tandem Syn-
thesis of 3-Sulfenylimidazo[1,2-a]pyridines
from Ketones, 2-Aminopyridines, and Di-
sulfides
Keywords: Multicomponent reactions
Tandem reactions / C–H functionalization /
Cerium / Sulfur / Ketones
/
Aerobic oxidative three-component tan-
dem formation of C–N and C–S bonds in
one-pot! A CeCl3·7H2O/NaI system is ef-
ficient for the synthesis of 3-sulfenylimid-
azo[1,2-a]pyridines through a C–H func-
tionalization strategy. Without the use of
disulfides,
a variety of imidazo[1,2-a]-
pyridines are obtained in good yields by us-
ing this protocol.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7