One-pot multicomponent cascade reaction of N,S-ketene acetal: Solvent-free synthesis of imidazo[1,2-a]thiochromeno[3,2-e]pyridines

Article abstract of DOI:10.1021/ol301441v

Unprecedented imidazo[1,2-a]thiochromeno[3,2-e]pyridines have been synthesized via a three-component cascade reaction under solvent-free conditions. This one-pot transformation involving multiple steps and not requiring the use of transition metal catalysts constructs three new C-C bonds, two C-N bonds, one C-S bond, and three new rings with all reactants efficiently utilized.

Full text of DOI:10.1021/ol301441v

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3470–3473
One-Pot Multicomponent Cascade
Reaction of N,S-Ketene Acetal:
Solvent-Free Synthesis of Imidazo-
[1,2-a]thiochromeno[3,2-e]pyridines
Ming Li,* Han Cao, Yong Wang, Xiu-Liang Lv, and Li-Rong Wen*
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and
Molecular Engineering, Qingdao University of Science and Technology,
Qingdao 266042, P. R. China
liming928@qust.edu.cn; wenlirong@qust.edu.cn
Received May 25, 2012
ABSTRACT
Unprecedented imidazo[1,2-a]thiochromeno[3,2-e]pyridines have been synthesized via a three-component cascade reaction under solvent-free
conditions. This one-pot transformation involving multiple steps and not requiring the use of transition metal catalysts constructs three new CꢀC
bonds, two CꢀN bonds, one CꢀS bond, and three new rings with all reactants efficiently utilized.
The solvent-free reaction (SFR)1 is an important syn-
thetic procedure from the viewpoint of green and sustain-
able chemistry. Carbonꢀcarbon and carbonꢀheteroatom
bond-forming reactions are central to organic synthesis.
Multicomponent reactions (MCRs)2 involving domino
processes are important for generating high levels of diversity
giving rise to complex structures by simultaneous forma-
tion of two or more bonds from simple substrates. Thus,
developing a new, environmentally benign MCR has been
recognized as one of the most important topics of green
chemistry.3
Imidazo[1,2-a]pyridine scaffolds represent an important
class of organic molecules that attract the interest of both
synthetic and medicinal chemists that are contained in
marketed drugs such as the clinical antiulcer compound
soraprazan,4 the PDE 3 inhibitor olprinone,5 the sedative
zolpidem,6 and inhibitors of TNF-R expression in T
cells.7 On the other hand, functionalized thiochromones
(1) (a) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso,
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C. A. M.; Trindade, A. F. Chem. Rev. 2009, 109, 2703. (b) Galvez, J.;
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2010, 12, 1370. (e) Ramachary, D. B.; Jain, S. Org. Biomol. Chem. 2011,
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Buriol, L.; Machado, P. Chem. Rev. 2009, 109, 4140. (h) Wang, G. W.;
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P. M. P. Eur. J. Org. Chem. 2009, 1859. (f) Ma, N.; Jiang, B.; Zhang, G.;
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Psychopharmacol. 1990, 46, 61.
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(b) Domling, A. Chem. Rev. 2006, 106, 17. (c) Wei, H. L.; Yan, Z. Y.;
Niu, Y. L.; Li, G. Q.; Liang, Y. M. J. Org. Chem. 2007, 72, 8600.
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Hong, D.; Lu, P.; Wang, Y. G. Org. Lett. 2011, 13, 1024.
r
10.1021/ol301441v
Published on Web 06/26/2012
2012 American Chemical Society

represent an important class of heterocycles and have been
tested and applied as drugs.8 Hence, the synthesis of the
imidazo[1,2-a]thiochromeno[3,2-e]pyridines could be a
valuable strategy to discover new bioactive compounds.
Functionalized ketene S,S-9 and N,S-acetals10 have
received much attention as versatile building blocks in
organic synthesis. Among them, β-ketothioamides (KTAs)
with general structures A and B have been proven to be
well-known synthons in the construction of hetero-
cyclic systems (Figure 1).11,12 Ethyl 2-(3-(2-haloaryl)-3-
oxopropanethioamido)acetates 1, as novel R-oxoketene
N,S-acetals with seven chemically distinct reactive
sites, show intriguing and fascinating structural features
and have a different reactivity profile from A or B. By
the special reactivity of ethyl 2-(3-(2-haloaryl)-3-oxopro-
panethioamido)acetates 1, we developed the three-component
reactions of 1 with aromatic aldehydes and malononitrile
or ethyl 2-cyanoacetate to construct imidazo[1,2-a]thio-
chromeno[3,2-e]pyridine moiety. In this process, at least
nine distinct reactive sites participated, which resulted in
the concomitant creation of six new bonds and three new
rings. Careful literature search shows that the synthetic
application of ethyl 2-(3-(2-haloaryl)-3-oxopropanethioamido)-
acetates 1 in MCRs has not been disclosed thus far.
Ethyl 2-(3-(2-haloaryl)-3-oxopropanethioamido) acet-
ates 1, required as the key cyclization precursors for the
three-component reaction, were readily obtained by the
previously reported procedure utilizing β-oxodithiocar-
boxylates with alkyl glycinate hydrochloride in the pre-
sence of Et3N in C2H5OH at room temperature.10e
Surprisingly, when methyl 3-(2-bromo-4-fluorophenyl)-
3-oxopropanedithioate was used to react with glycine ethyl
ester hydrochloride, ethyl 2-(3-(2-bromo-4-(methylthio)-
phenyl)-3-oxopropanethioamido)acetate 1e rather than
1e0 was obtained, in which a SNAr reaction of the fluoro
atom by the methylthio group took place accidentally
(Scheme 1).
Scheme 1. Unexpected Result for Synthesis of 1e
This unexpected result was also verified by the X-ray
diffraction analysis of the product 4bb (Figure 2). This
unprecedented observation is very rare.
Figure 1. Reactivity profile of KTA.
(8) (a) Geissler, J. F.; Roesel, J. L.; Meyer, T.; Trinks, U. P.; Traxler,
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Cheng, X.; Liang, F. S.; Shi, F.; Zhang, L.; Liu, Q. Org. Lett. 2009, 11,
93. (f) Singh, O. M.; Devi, N. S. J. Org. Chem. 2009, 74, 3141. (g) Nandi,
G. C.; Samai, S.; Singh, M. S. J. Org. Chem. 2010, 75, 7785. (h)
Chowdhury, S.; Nandi, G. C.; Samai, S.; Singh, M. S. Org. Lett. 2011,
13, 3762. (i) Nandi, G. C.; Samai, S.; Singh, M. S. J. Org. Chem. 2011,
76 (19), 8009.
Figure 2. X-ray structure of 4bb.
Initially, ethyl 2-(3-(2-bromophenyl)-3-oxopropanethio-
amido)acetate 1a, malononitrile 2a, and benzaldehyde 3a
were chosen as the model substrates to optimize reaction
conditionsincludingbases, solvents, and reaction tempera-
ture (Table 1).
ꢀ
(10) (a) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197. (b) Junjappa,
H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423. (c) Kumar,
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Asokan, C. V. Tetrahedron 2006, 62, 1708.
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J. Org. Chem. 2005, 70, 9644. (b) Venkatesh, C.; Singh, B.; Mahata,
P. K.; Ila, H.; Junjappa, H. Org. Lett. 2005, 7, 2169. (c) Mahata, P. K.;
Venkatesh, C.; Syam, K. U. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2003,
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7046. (e) Sundaram, G. S. M.; Venkatesh, C.; Syam, K. U. K.; Ila, H.;
Junjappa, H. J. Org. Chem. 2004, 69, 5760.
(12) (a) Wen, L. R.; Shi, Y. J.; Liu, G. Y.; Li, M. J. Org. Chem. 2012,
77, 4252. (b) Li, M.; Hou, Y. L.; Wen, L. R.; Gong, F. M. J. Org. Chem.
2010, 75, 8522. (c) Wen, L. R.; Sun, J. H.; Li, M.; Sun, E. T.; Zhang, S. S.
J. Org. Chem. 2008, 73, 1852. (d) Wen, L. R.; Ji, C.; Li, Y. F.; Li, M.
J. Comb. Chem. 2009, 11, 799. (e) Wen, L. R.; Li, Z. R.; Li, M.; Cao, H.
Green Chem. 2012, 14, 707.
Org. Lett., Vol. 14, No. 13, 2012
3471

Table 1. Optimization of Reaction Conditionsa
Table 2. Synthesis of Compounds 4
entry
base (equiv)
solvent temp (°C) time (h) yieldb (%)
entry
1, X, R1
2
3, R2
3a, H
4
yieldb (%)
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
reflux
reflux
6
NR
59
10
40
78
30
45
33
20
64
79
69
77
1
2
1a, Br, H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
2b
2a
2b
2a
2b
2a
2a
2a
2b
2b
2b
4a
4b
4c
78
82
80
79
73
71
85
80
75
86
83
82
77
76
86
81
80
83
80
81
78
61
66
70
77
63
68
81
77
87
84
89
80
Et3N (1.0)
5
1a, Br, H
3b, 4-F
Et3N (1.0)
C2H5OH reflux
5
3
1a, Br, H
3c, 4-Cl
Et3N (1.0)
THF
reflux
120
120
120
120
120
120
120
110
5
4
1a, Br, H
3d, 4-Br
3e, 4-CH3
3f, 4-OCH3
3g, 4-NO2
3j, 3-F
4d
4e
Et3N (1.0)
1.5
3
5
1a, Br, H
[bmim]OH (1.0)
[octmim]OH (1.0)
DBU (1.0)
6
1a, Br, H
4f
3
7
1a, Br, H
4g
4h
4i
3
8
1a, Br, H
DMAP (1.0)
3
9
1a, Br, H
3k, 3-OCH3
3b, 4-F
10 Et3N (0.5)
1.5
1.5
1.5
1.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
1a, Br, H
4j
11 Et3N (1.5)
12 Et3N (1.0)
13 Et3N (1.0)
1a, Br, H
3c, 4-Cl
4k
4l
1a, Br, H
3d, 4-Br
3e, 4-CH3
3f, 4-OCH3
3g, 4-NO2
3h, 2-Cl
3i, 3-Cl
130
1a, Br, H
4m
4n
4o
4p
4q
4r
1a, Br, H
a The mixture of 1a (1.0 mmol), 2a (1.0 mmol), and 3a (1.0 mmol) was
stirred in a flask in an oil bath. b Isolated yield.
1a, Br, H
1a, Br, H
1a, Br, H
1a, Br, H
3j, 3-F
No reaction occurred without addition of any base
in refluxing CH3CN for 6 h (entry 1), but when 1.0 equiv
of Et3N was added, the compound 2,6-dioxo-5-phenyl-
2,3,5,6-tetrahydro-1H-imidazo[1,2-a]thiochromeno[3,2-e]-
pyridine-4-carbonitrile 4a was obtained in 59% yield
(entry 2). Next, different solvents were tested in the pre-
sence of Et3N, but the results were unsatisfactory (entries 3
and 4). To our delight, however, a breakthrough result was
achieved when the reaction was carried out under solvent-
free conditions at 120 °C; 4a was formed in good yield
of 78%, and the reaction time was shortened to 1.5 h
simultaneously (entry 5). Thus, other various bases, such
as [bmim]OH, [octmim]OH, DBU, and DMAP, were
examined, and the results revealed that they all failed to
effectively promote the reactions; instead, the reactions
became sluggish and the yields of the corresponding pro-
ducts were lower than with Et3N (entries 6ꢀ9). Next,
changing the amount of Et3N (entries 10 and 11) and
changing the reaction temperature (entries 12 and 13) also
did not improve the yield of 4a. It could be concluded that
the optimum reaction conditions were solvent-free and
Et3N (1.0 equiv) as the base at 120 °C (entry 5).
1a, Br, H
3l, 3-Br
4s
1a, Br, H
3m, 2-Br
3k, 3-OCH3
3c, 4-Cl
4t
1a, Br, H
4u
4c
1b, Cl, H
1b, Cl, H
3c, 4-Cl
4k
4v
4w
4x
4y
4aa
4bb
4cc
4dd
4ee
4ff
1c, Cl, 4-Cl
1c, Cl, 4-Cl
1d, Cl, 5-Cl
1d, Cl, 5-Cl
1e, Br, 4-SMe
1e, Br, 4-SMe
1e, Br, 4-SMe
1e, Br, 4-SMe
1e, Br, 4-SMe
1e, Br, 4-SMe
3c, 4-Cl
3c, 4-Cl
3c, 4-Cl
3c, 4-Cl
3c, 4-Cl
3f, 4-OCH3
3g, 4-NO2
3c, 4-Cl
3g, 4-NO2
3f, 4-OCH3
a General conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), Et3N
(1.0 mmol), under solvent-free conditions, 120 °C, 1.5 h. b Isolated yield
after washing by ethanol.
electron-donating or electron-withdrawing substituents, the
reactions proceeded very smoothly in all cases.
It is noteworthy that all of the isolated products only
need washing with ethanol rather than column chromato-
graphy or recrystallization. This easy purification makes
this methodology facile, practical, and rapid to execute.
On the basis of the above experimental results, a plau-
sible reaction scenario for the synthesis of imidazo[1,2-a]-
thiochromeno[3,2-e]pyridines is depicted in Scheme 2.
First, an aldehyde 3 reacts with an acetonitrile derivative
2 through Knoevenagel condensation by Et3N catalysis to
give intermediate [A]; 1 was mediated by Et3N and depro-
tonated to form the anion of 1, which reacts with [A]
To test the generality of this process, the reactions of
five different 1aꢀe with 2a or 2b and various aromatic
aldehydes 3aꢀm were examined under the optimized con-
ditions, as shown in Table 2.
All reactions provided good to excellent yields and
afforded the corresponding products 4 as a racemic form.
For the precursors 1, aryl bromides showed higher reactivity
than aryl chlorides (compare entry 3 with 22, entry 11 with
23 in Table 2). However, for precursors 3 bearing either
3472
Org. Lett., Vol. 14, No. 13, 2012

group leads to imidazo[1,2-a]thiochromeno[3,2-e]pyridines
4 with elimination of HX.
Scheme 2. Plausible Scenario for the Reaction
In summary, we have successfully developed an efficient
one-pot multicomponent cascade to construct imidazo-
[1,2-a]thiochromeno[3,2-e]pyridines via Et3N-assisted an-
nulations under solvent-free conditions. The process
provides an opportunity to avoid the use of transition
metal catalysts, toxic solvents and resource consumption.
We found that this tandem process involves multiple
reactions, including Knoevenagel condensationꢀMichael
additionꢀN-cyclizationꢀrapid imineꢀenamine tautomer-
izationꢀintramolecular N-cyclizationꢀketoꢀenol tauto-
merizationꢀSNAr sequence. Undoubtedly, this domino
synthetic strategy provides a convenient and green way
to construct the target molecules in an atom-economic
manner. We hope this approach may be of value to others
seeking novel synthetic fragments with unique properties
for medicinal chemistry.
Acknowledgment. This work was financially supported
by the National Natural Science Foundation of China
(Nos. 21072110 and 20872074) and the Natural Science
Foundation of Shandong Province (No. ZR2010BM007).
through Michael addition to generate the intermediate [B].
Then the [B] undergoes a N-cyclization to give the inter-
mediate [C], which takes place a rapid imineꢀenamine
tautomerization to give [D]. Next, the intramolecular
N-cyclization of [D] with losing a molecule of C2H5OH
leads to the formation of imidazo[1,2-a]pyridine motif [E]
which undergoes ketoꢀenol tautomerization to give [F].
Finally, an intramolecular nucleophilic aryl substitution of
the o-halo of aryl group (SNAr) by attack of mercapto
Supporting Information Available. Experimental and
1
characterization details, H and 13C NMR spectra of
P-1e, 1e, and 4, and crystal data for compounds 4k and
4bb (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
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