One-pot combinatorial synthesis of 4-aryl-1 h -thiopyrano[3,4- b ]pyridine-5-one derivatives

Article abstract of DOI:10.1021/cc100017f

A simple and efficient method for the combinatorial synthesis of highly substituted thiopyrano[3,4-b]pyridin-5(4H)-one, thiopyrano[3,4-b]quinoline-4, 6(3H,5H)-dione, dithiopyrano[3,4-b:4′,3′-e]pyridine-4,6(1H,3H)- dione, and pyrazolo[3,4-b]thiopyrano[4,3-e]pyridin-5(1H)-one derivatives has been developed. The synthesis was achieved via one-pot multicomponent reaction of aromatic aldehyde, 2H-thiopyran-3,5(4H,6H)-dione and enamine (such as the derivatives of amine and 1,3-dicarbonyl compounds and 3-methyl-1-phenyl-1H- pyrazol-5-amine) in glacial acetic acid. This procedure features short reaction time, generally good to excellent yields, easily available starting materials, and operational simplicity. This chemistry provides an efficient and promising synthetic strategy to diversity-oriented construction of the thiopyrano[3,4-b]pyridine skeleton.

Full text of DOI:10.1021/cc100017f

472
J. Comb. Chem. 2010, 12, 472–475
One-Pot Combinatorial Synthesis of
4-Aryl-1H-thiopyrano[3,4-b]pyridine-5-one Derivatives
Chang-Sheng Yao, Cui-Hua Wang, Bei Jiang, and Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, Xuzhou Normal UniVersity, and Key Laboratory of
Biotechnology for Medicinal Plant, Xuzhou, Jiangsu, 221116, P.R. China
ReceiVed January 28, 2010
A simple and efficient method for the combinatorial synthesis of highly substituted thiopyrano[3,4-b]pyridin-
5(4H)-one, thiopyrano[3,4-b]quinoline-4,6(3H,5H)-dione, dithiopyrano[3,4-b:4′,3′-e]pyridine-4,6(1H,3H)-
dione, and pyrazolo[3,4-b]thiopyrano[4,3-e]pyridin-5(1H)-one derivatives has been developed. The synthesis
was achieved via one-pot multicomponent reaction of aromatic aldehyde, 2H-thiopyran-3,5(4H,6H)-dione
and enamine (such as the derivatives of amine and 1,3-dicarbonyl compounds and 3-methyl-1-phenyl-1H-
pyrazol-5-amine) in glacial acetic acid. This procedure features short reaction time, generally good to excellent
yields, easily available starting materials, and operational simplicity. This chemistry provides an efficient
and promising synthetic strategy to diversity-oriented construction of the thiopyrano[3,4-b]pyridine skeleton.
Introduction
remarkable potential of novel thiopyranopyridine derivatives
as a source of valuable drug candidates. However, only a
few thiopyrano[3,4-b]pyridine derivatives were synthesized
and their activities as KATP channel openers were reported.19
Besides, these synthetic methods suffer from long reaction
time, multiple steps, high temperature, unsatisfactory yields,
and limited diversity. Considering the biological significance
of fused S,N-heterocycles, it is valuable to synthesize the
compound library based on the important thiopyrano[3,4-
b]pyridine scaffold with high diversity for biomedical
screening. To continue our work on the multicomponent
synthesis of heterocyclic compound library with high diver-
sity,20 herein we report a new, convenient, diversity-oriented,
and highly efficient protocol for the synthesis of thiopy-
rano[3,4-b]pyridine collections via one-pot multicomponent
reactions under acidic conditions. This method uses readily
available raw materials such as aromatic aldehyde, am-
monium acetate, 3-methyl-1-phenyl-1H-pyrazol-5-amine,
1,3-dicarbonyl compounds including ethyl 3-oxobutanoate,
methyl 3-oxobutanoate, pentane-2,4-dione, 5,5-dimethylcy-
clohexane-1,3-dione, and 2H-thiopyran-3,5(4H,6H)-dione.
Multicomponent reactions (MCRs) are one-pot processes
in which three or more reactants come together in a single
reaction vessel to form a product containing substantial
elements of all the reactants.1 MCRs, leading to interesting
heterocyclic scaffolds, are particularly useful for the com-
binatorial chemistry as powerful tools2 because of their value
features such as atom-economy, environmental concerns,
straightforward reaction design, and the opportunity to
construct target compounds by the introduction of several
diversity elements in a single chemical operation.3 Therefore,
a great deal of current interest is focused on the development
of novel MCRs.4 For example, the most classical synthesis
of a 1,4-dihydropyridine (1,4-DHP) is a three-component
condensation reaction reported by Hantzsch in 1882.5 Hantz-
sch 1,4-dihydropyridines are an important class of drugs for
the treatment of cardiovascular diseases such as hypertension
and angina pectoris.6 Thus, in terms of designing and
screening new lead compounds, searching for new and facile
MCRs to prepare 1,4-DHPs with new functional substituents
is highly desirable work.7
Thiopyran and fused thiopyran derivatives exhibit various
kinds of biological activities, such as weed control8 and
antitumor activity.9 Pyridines are of interest because of the
occurrence of their saturated and partially saturated deriva-
tives in biologically active compounds and natural products,
for example, NAD nucleotides, pyridoxol (vitamin B6), and
pyridine alkaloids.10 Within a long-term research program
aiming at the synthesis of novel fused S,N-heterocycles,
thiopyranopyridines are of special importance because of
their biological activities,11 such as antitumor,12 antibacterial,
and fungicidal activity,13 neuroleptic activity,14 and signifi-
cant cytotoxicity.15-18 These examples clearly indicate the
Results and Discussion
We started by finding optimal conditions for the efficient
formation of the thiopyrano[3,4-b]pyridines via a one-pot
four-component reaction of aromatic aldehyde (1), 2H-
thiopyran-3,5(4H,6H)-dione (2), acyclic 1,3-dicarbonyl com-
pounds (3), and excess ammonium acetate (Scheme 1). To
search for the suitable reaction solvent, the model reaction
of 4-bromophenylaldehyde (1a, 1 mmol), 2H-thiopyran-
3,5(4H,6H)-dione (2, 1 mmol), ethyl 3-oxobutanoate (3a, 1
mmol), and ammonium acetate (excess) was conducted in
CH3CN, N,N-dimethylformamide (DMF), ethanol, CHCl3,
and glacial acetic acid, (Table 1, entries 1-5) at room
temperature, respectively. As shown in Table 1, the reaction
in glacial acetic acid (Table 1, entry 5) exhibits higher yield
* To whom correspondence should be addressed. Phone: 0086-516-
83500065. Fax: 0086-516-83500065. E-mail: laotu@xznu.edu.cn.
10.1021/cc100017f  2010 American Chemical Society
Published on Web 05/05/2010

Synthesis of 4-Aryl-1H-thiopyrano[3,4-b]pyridine-5-one
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 473
Table 2. Synthesis of Compounds 4 in Glacial Acetic Acid
without Catalyst
Scheme 1. Synthesis of 4-Aryl-1H-thiopyrano[3,4-b]pyridine
Derivatives 4
time
(h) products (%) Mp (°C)
yielda
entry
R1
R2
1
2
3
4
5
6
7
8
9
4-BrC6H4 (1a)
2-FC6H4 (1b)
3-FC6H4 (1c)
4-FC6H4 (1d)
2-ClC6H4 (1e)
3-ClC6H4 (1f)
4-ClC6H4 (1g)
2,4-Cl2C6H3 (1h)
3,4-Cl2C6H3 (1i)
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
6
8
6
7
7
6
6
7
7
9
9
8
7
7
8
9
8
8
9
9
8
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
86 260-261
84 258-260
85 250-252
84 255-257
85 224-226
84 218-220
82 274-276
87 251-253
83 245-246
81 237-240
85 194-196
82 240-242
87 239-240
84 202-204
81 246-247
80 216-218
80 251-253
82 245-248
81 207-209
80 249-252
83 220-221
84 227-229
81 255-257
83 231-233
80 227-229
81 237-239
80 249-252
82 242-243
80 218-220
81 173-175
10 3-NO2C6H4 (1j)
11 3,4,5-(CH3O)3C6H2 (1l) OEt
4aj
4ak
4al
Table 1. Solvent and Temperature Optimization for the
Synthesis of 4aa
12 4-(CH3)2NC6H4 (1m)
13 2-Thienyl (1n)
14 n-Propyl (1o)
15 C6H5 (1p)
16 4-BrC6H4 (1a)
17 2-FC6H4 (1b)
18 3-FC6H4 (1c)
19 2-ClC6H4 (1e)
20 4-ClC6H4 (1g)
21 4-NO2C6H4 (1k)
OEt
OEt
OEt
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
entry
solvent
T (°C)
time (h)
yielda (%)
4am
4an
4ba
4bb
4bc
4bd
4be
4bf
4bg
4bh
4ca
4cb
4cc
4cd
4ce
4cf
1
2
3
4
5
6
7
8
CH3CN
DMF
EtOH
CHCl3
HOAc
HOAc
HOAc
HOAc
r.t.
r.t.
r.t.
r.t.
r.t.
15
20
40
10
12
10
8
6
10
8
73
80
75
50
86
75
78
80
6
22 3,4,5-(CH3O)3C6H2 (1l) OCH3 10
a Isolated yields.
23 4-BrC6H4 (1a)
24 2-FC6H4 (1b)
25 3-FC6H4 (1c)
26 2-ClC6H4 (1e)
27 3-ClC6H4 (1f)
28 4-ClC6H4 (1g)
29 3,4-Cl2C6H3 (1i)
CH3
CH3
CH3
CH3
CH3
CH3
CH3
9
8
8
10
10
9
10
10
and greater reaction rate than other counterparts. So glacial
acetic acid was used as the solvent to synthesize the desired
products.
4cg
4ch
To further screen for the practical temperature for the
synthesis, the previous reaction was carried out in glacial
acetic acid at 15 °C, 20 °C, room temperature (25 °C), and
40 °C (Table 1, entries 5∼8), resulting in the isolation of
4aa in 75%, 78%, 86%, and 80% yields (Table 1, entries
5∼8), respectively. Therefore, room temperature was chosen
to synthesize the thiopyrano[3,4-b]pyridine derivatives.
Under the conditions described above, a range of valuable
structures of ethyl 4,5,6,8-tetrahydro-2-methyl-5-oxo-4-aryl-
1H-thiopyrano[3,4-b]pyridine-3-carboxylate (Table 2, entries
1-14) were synthesized in good to excellent yields within
a few hours. As expected, when methyl 3-oxobutanoate (3b)
and pentane-2,4-dione (3c) were used instead of ethyl
3-oxobutanoate (3a), the reaction gave the corresponding
products in good to excellent yields under the optimized
conditions (Scheme 1, Table 2). The structure of 4bb was
identified by IR and 1H NMR and further confirmed by X-ray
diffraction analysis (Figure 1).
30 3,4,5-(CH3O)3C6H2 (1l) CH3
a Isolated yields.
Figure 1. ORTEP drawing of 4bb.
As shown in Table 2, the effect of electronic nature of
the substituents on the aromatic ring did not show strong
influence on reaction yields. This protocol can be applied
not only to electron-rich and electron-deficient aromatic
aldehydes, but also to heteroaromatic aldehydes and aliphatic
aldehyde with moderate to excellent yields under the same
conditions, which highlighted the wide scope of this
condensation.
Scheme 2. Synthesis of 5-Aryl-1H-thiopyrano[3,4-b]quino-
line-4,6(3H,5H,7H,10H)-dione Derivatives 6
This sequence is also extended from acyclic 1,3-dicarbonyl
compounds to cyclic 1,3-dicarbonyl compounds, such as 5,5-
dimethylcyclohexane-1,3-dione (Scheme 2). To expand the
scope of amine substrates, ammonium acetate and primary
aromatic amines including aniline, p-toluidine, and 4-chlo-
roaniline were applied to this protocol. In all cases, the
desired reactions took place successfully to afford a series
of 5-aryl-1H-thiopyrano[3,4-b]quinoline-4,6(3H,5H,7H,10H)-
diones (6a-6s) in moderate to good yields. The results are
summarized in Table 3. The structure of 6k is confirmed by
X-ray diffraction analysis, and its crystal structure is shown
in Figure 2.
Actually, 2H-thiopyran-3,5(4H,6H)-dione is a cyclic
1,3-dicarbonyl compound with high reactivty. Setting

474 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Yao et al.
Table 3. Synthesis of Compounds 6 in Glacial Acetic Acid without Catalyst
entry
Ar
R
time (h)
products
yielda (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
4-BrC6H4 (1a)
4-ClC6H4 (1g)
H
H
H
H
H
H
H
H
13
12
14
14
13
13
14
12
13
13
12
13
12
14
13
12
15
15
14
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
75
72
70
75
73
71
70
74
80
75
78
74
76
75
77
76
78
78
74
265-267
266-268
240-241
254-257
228-230
233-235
155-157
246-249
221-223
260-261
270-271
281-283
257-259
248-250
239-241
262-264
242-244
233-235
226-229
3-NO2C6H4 (1j)
4-CH3C6H4 (1q)
3-CH3OC6H4 (1r)
4-CH3OC6H4 (1s)
3,4,5-(CH3O)3C6H2 (1l)
2-Thienyl (1n)
4-BrC6H4(1a)
3-FC6H4 (1c)
4-ClC6H4 (1g)
4-FC6H4 (1d)
2-ClC6H4 (1e)
3-ClC6H4 (1f)
3,4-Cl2C6H3 (1i)
3-NO2-4-OHC6H3 (1t)
4-CH3OC6H4 (1s)
3,4,5-(CH3O)3C6H2 (1l)
4-(CH3)2NC6H4 (1m)
C6H5
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
a Isolated yields.
Table 4. Synthesis of Compounds 7 in Glacial Acetic Acid
without Catalyst
time
(h)
yielda
(%)
entry
Ar
products
Mp (°C)
1
2
3
4
5
6
7
8
C6H5 (1p)
8
10
9
10
9
10
10
9
7a
7b
7c
7d
7e
7f
82
85
81
83
83
85
80
82
>300
4-BrC6H4 (1a)
2-FC6H4 (1b)
4-FC6H4 (1d)
4-ClC6H4 (1g)
3-CH3OC6H4 (1r)
4-CH3OC6H4 (1s)
2-Thienyl (1n)
285-287
298-300
272-275
251-253
258-259
286-289
>300
7g
7h
a Isolated yields.
Scheme 4. Synthesis of 4-Aryl-3-methyl-1-phenyl-4,6,8,9-
tetrahydropyrazolo[3,4-b]thiopyrano[4,3-e]pyridin-5(1H)-one
Derivatives 9
Figure 2. ORTEP drawing of 6k.
Scheme 3. Synthesis of 5-Aryl-5,7,9,10-tetrahydrodithio-
pyrano[3,4-b:4′,3′-e]pyridine-4,6(1H,3H)-dione Derivatives 7
Table 5. Synthesis of Compounds 9 in Glacial Acetic Acid
without Catalyst
molar ratio of 2H-thiopyran-3,5(4H,6H)-dione to aromatic
aldehyde at 2:1 means adding another equivalent 1,3-
dicarbonyl compound to the reaction system (Scheme 3).
So the pseudo four-component reactions were performed
in glacial acetic acid at 50 °C and the corresponding
dithiopyrano[3,4-b;4′,3′-e]pyridine products 7 were ob-
tained in good yields (Table 4). These heterocyclic
compounds encompass two thiopyranone rings and are
known to display a wide range of potential biological
activities including antimicrobial, antibacterial, and anti-
fungal activity, KATP activity, and the inhibition of
spontaneous bladder contractions.19
time
(h)
yielda
(%)
entry
Ar
products
Mp (°C)
1
2
3
2-ClC6H4 (1e)
4-BrC6H4 (1a)
2-FC6H4 (1b)
12
11
10
12
14
12
13
15
15
13
9a
9b
9c
9d
9e
9f
9g
9h
9i
86
82
81
85
84
81
85
83
85
80
262-264
191-194
255-257
233-235
215-217
178-181
218-221
211-214
239-241
226-228
4
C6H5 (1p)
5
6
7
8
9
10
3-ClC6H4 (1f)
4-ClC6H4 (1g)
4-CH3C6H4 (1q)
4-CH3OC6H4 (1s)
3,4,5-(CH3O)3C6H2 (1l)
2-Thienyl (1n)
9j
a Isolated yields.
ridin-5(1H)-one derivatives were obtained successfully in high
yields at room temperature (Table 5).
The structures of all of the synthesized compounds were
characterized by H NMR, IR, and HRMS spectra. The
structures of 4bb and 6k were established by X-ray diffrac-
In our continued study, we performed the reaction of aromatic
aldehyde(1), 2H-thiopyran-3,5(4H,6H)-dione(2), and 3-methyl-
1-phenyl-1H-pyrazol-5-amine(8) under the optimized conditions
(Scheme 4). To our pleasure, a series of novel 4-aryl-3-methyl-
1-phenyl-4,6,8,9-tetrahydropyrazolo[3,4-b]thiopyrano[4,3-e]py-
1
tion analysis further (Figures 1 and 2).

Synthesis of 4-Aryl-1H-thiopyrano[3,4-b]pyridine-5-one
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 475
N. J.; Qian, X. H. Green Chem. 2009, 11, 1414–1420. (e)
Syamala, M. Org. Prep. Proced. Int. 2009, 41, 1–68.
(8) Muehlebach, M.; Mathews, C. J.; Scutt, J. N.; Jeanmart,
S. A. M.; Govenkar, M. WO Patent WO 2009074314, 2009;
Muehlebach, M.; Mathews, C. J.; Scutt, J. N.; Jeanmart,
S. A. M.; Govenkar, M. Chem. Abstr. 2009, 151, 92857.
(9) Wentlanda, M. P.; Pernia, R. B.; Huang, J. I.; Powles, R. G;
Aldous, S. C.; Klingbeil, K. M.; Peverly, A. D.; Robinson,
R. G.; Corbett, T. H.; Jones, J. L.; Rake, J. B.; Coughlin, S. A.
Bioorg. Med. Chem. Lett. 1996, 6, 1345–1350.
(10) Balasubramanian, M.; Keay, J. G. In ComprehensiVe Hetero-
cyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. V. F., Eds.; Pergamon Press:: London, 1996; Vol. 5,
Chapter 6, pp 245-300.
(11) Vera, K. Collect. Czech. Chem. Commun. 1993, 58, 1195–
1197.
(12) (a) Yamato, M.; Takeuchi, Y.; Hashigaki, K.; Ikeda, Y.;
Chang, M. R.; Takeuchi, K.; Matsushima, M.; Tsuruo, T.;
Tashiro, T. J. Med. Chem. 1989, 32, 1295–300. (b) Croisy-
Delcey, M.; Huel, C.; Croisy, A.; Bisagni, E. Heterocycles
1991, 32, 1933–1945. (c) Croisy-Delcey, M.; Bisagni, E.
J. Med. Chem. 1983, 26, 1329–1333.
(13) El-Kanzi, N. A. A.; Soleiman, H. A.; Khalafallah, A. K.
Phosphorus, Sulfur Silicon Relat. Elem. 2007, 182, 1459–
1473.
(14) Rowland, D. A.; Gillepsie, R. J.; Ager, I. R.; Clements-Jewery,
S.; Garner, C. R. Eur. Patent EP 99303, 1984; Rowland, D. A.;
Gillepsie, R. J.; Ager, I. R.; Clements-Jewery, S.; Garner, C. R.
Chem. Abstr. 1984, 100, 209782.
(15) Varvaresou, A.; Tsotinis, A.; Papadaki-Valiraki, A.; Siatra-
Papastaikoudi, T. Bioorg. Med. Chem. Lett. 1996, 6, 861–
864.
(16) Skotnicki, J. S.; Steinbaugh, B. A.; Fitzgerald, J. J. J.; Kearney,
R. M.; Musser, J. H.; Adams, L. M.; Caccese, R. G.; Chang,
J. Y.; Gilman, S. C. Med. Chem. Res. 1991, 1, 245–252.
(17) Ganguly, A. K.; Friary, R. J.; Schwerdt, J. H.; Siegel, M. I.;
Smith, S. R.; Seidl, V. A.; Sybertz, E. J. U.S. Patent US
4810708, 1989; Ganguly, A. K.; Friary, R. J.; Schwerdt, J. H.;
Siegel, M. I.; Smith, S. R.; Seidl, V. A.; Sybertz, E. J. Chem.
Abstr. 1989, 111, 214470.
(18) Abelman, M.; Jiang, R.; Zablocki, J.; Koltun, D.; Boze, M.
WO Patent WO 2008079139, 2008; Abelman, M.; Jiang, R.;
Zablocki, J.; Koltun, D.; Boze, M. Chem. Abstr. 2008, 149,
128806.
(19) (a) Carroll, W. A.; Agrios, K. A.; Altenbach, R. J.; Buckner,
S. A.; Chen, Y. Y.; Coghlan, M. J.; Daza, A. V.; Drizin, I.;
Gopalakrishnan, M.; Henry, R. F.; Kort, M. E.; Kym, P. R.;
Milicic, I.; Smith, J. C.; Tang, R.; Turner, S. C.; Whiteaker,
K. L.; Zhang, H.; Sullivan, J. P. J. Med. Chem. 2004, 47,
3180–3192. (b) Altenbach, R. J.; Brune, M. E.; Buckner, S. A.;
Coghlan, M. J.; Daza, A. V.; Fabiyi, A.; Gopalakrishnan, M.;
Henry, R. F.; Khilevich, A.; Kort, M. E.; Milicic, I.; Scott,
V. E.; Smith, J. C.; Whiteaker, K. L.; Carroll, W. A. J. Med.
Chem. 2006, 49, 6869–6887. (c) Drizin, I.; Holladay, M. W.;
Yi, L.; Zhang, H. Q.; Gopalakrishnan, S.; Gopalakrishnan,
M.; Whiteaker, K. L.; Buckner, S. A.; Sullivan, J. P.; Carroll,
W. A. Bioorg. Med. Chem. Lett. 2002, 12, 1481–1484.
(20) (a) Jiang, B.; Tu, S. J.; Kaur, P.; Wever, W.; Li, G. G. J. Am.
Chem. Soc. 2009, 131, 11660–11661. (b) Jiang, B.; Hao, W. J.;
Wang, X.; Shi, F.; Tu, S. J. J. Comb. Chem. 2009, 11, 846–
850. (c) Han, Z. G.; Zhang, G.; Jiang, B.; Ma, N.; Shi, F.;
Tu, S. J. J. Comb. Chem. 2009, 11, 809–812. (d) Jiang, B.;
Cao, L. J.; Tu, S. J.; Zheng, W. R.; Yu, H. Z. J. Comb. Chem.
2009, 11, 612–616. (e) Hao, W. J.; Jiang, B.; Tu, S. J.; Wu,
S. S.; Han, Z. G.; Cao, X. D.; Zhang, X. H.; Yan, S.; Shi, F.
J. Comb. Chem. 2009, 11, 310–314. (f) Wang, X. S.; Wu,
J. R.; Zhou, J.; Tu, S. J. J. Comb. Chem. 2009, 11, 1011–1022.
Conclusion
In summary, we have developed a simple and efficient
method for the diversity-oriented synthesis of a series of
thiopyrano[3,4-b]pyridine derivatives via a one-pot multi-
component reaction in acidic media. This procedure features
shorter reaction time, generally good to excellent yields,
easily available starting materials, and operational simplicity
(only one pot).
Acknowledgment. We are grateful for financial support
by Natural Science Foundation of China (No.20672090 and
200810102050), the Major Basic Research Project of the
Natural Science Foundation of the Jiangsu Higher Education
Institutions (09KJA430003), Natural Science Foundation of
Xuzhou City (XM09B016), Graduate Foundation of Xuzhou
Normal University (09YLB030), and Qing Lan Project
(08QLT001).
Supporting Information Available. Representative ex-
perimental procedures, spectral data of compounds 4aa-4ch,
6a-6s, 7a-7 h, and 9a-9j, and crystallographic information
files (CIF) of 4bb and 6k. This material is available free of
charge via the Internet at http://pubs.acs.org.
References and Notes
(1) (a) Domling, A. Chem. ReV. 2006, 106, 17–89. (b) Orru,
R. V. A.; de Greef, M. Synthesis 2003, 1471–1499. (c) Hulme,
C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80. (d)
Montagne, C.; Shiers, J. J.; Shipman, M. Tetrahedron Lett.
2006, 47, 9207–9209.
(2) (a) Pokhodylo, N. T.; Matiychuk, V. S.; Obushak, M. D.
J. Comb. Chem. 2009, 11, 481–485. (b) Ghahremanzadeh, R.;
Sayyafi, M.; Ahadi, S.; Bazgir, A. J. Comb. Chem. 2009, 11,
393–396. (c) Zhang, L.; Lushington, G. H.; Neuenswander,
B.; Hershberger, J. C.; Malinakova, H. C. J. Comb. Chem.
2008, 10, 285–302. (d) Tu, S. J.; Zhang, X. H.; Han, Z. G.;
Cao, X. D.; Wu, S. S.; Yan, S.; Hao, W. J.; Zhang, G.; Ma,
N. J. Comb. Chem. 2009, 11, 428–432. (e) Wang, X. S.; Li,
Q.; Wu, J. R.; Tu, S. J. J. Comb. Chem. 2009, 11, 433–437.
(3) (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-
VCH: Weinheim, 2005. (b) Domling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168–3210. (c) Shaabani, A.;
Seyyedhamzeh, M.; Maleki, A.; Behnam, M.; Rezazadeh, F.
Tetrahedron Lett. 2009, 50, 2911–2913. (d) Adib, M.;
Sheibani, E.; Bijanzadeh, H. R.; Zhu, L. G. Tetrahedron 2008,
64, 10681–10686. (e) Sunderhaus, J. D.; Martin, S. F.
Chem.sEur. J. 2009, 15, 1300–1308.
(4) Toure, B. B.; Hall, D. G. Chem. ReV. 2009, 109, 4439–4486.
(5) (a) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1–82.
(b) Stout, D. M. Chem. ReV. 1982, 82, 223–243. (c) Eisner,
U.; Kuthan, J. Chem. ReV. 1972, 72, 1–42.
(6) (a) Toniolo, R.; Di, N. F.; Bontempelli, G.; Ursini, F.
Bioelectrochem. 2000, 51, 193–200. (b) Guengerich, F. P.;
Brain, W. R.; Iwasaki, M.; Sari, M. A.; Berntsson, P. J. Med.
Chem. 1991, 34, 1838–1844. (c) Janis, R. A.; Triggle, D. J.
J. Med. Chem. 1983, 26, 775–785. (d) Meyer, H. Annu. Rep.
Med. Chem. 1982, 17, 71–77.
(7) (a) Wan, J. P.; Gan, S. F.; Sun, G. L.; Pan, Y. J. J. Org. Chem.
2009, 74, 2862–2865. (b) Heydari, A.; Khaksar, S.; Tajbakhsh,
M.; Bijanzadeh, H. R. J. Fluorine Chem. 2009, 130, 609–
614. (c) Debache, A.; Ghalem, W.; Boulcina, R.; Belfaitah,
A.; Rhouati, S.; Carboni, B. Tetrahedron Lett. 2009, 50, 5248–
5250. (d) Shen, L.; Cao, S.; Wu, J. J.; Zhang, J.; Li, H.; Liu,
CC100017F