Efficient one-pot three-component synthesis of fused pyridine derivatives in ionic liquid

Article abstract of DOI:10.1021/co1000162

An efficient one-pot synthesis of fused pyridine derivatives (including pyrazolo[3,4-b]pyridine and pyrido[2,3-d]pyrimidine) by three-component reaction of aldehyde, acyl acetonitrile, and electron-rich amino heterocycles (including aminopyrazole and amin

Full text of DOI:10.1021/co1000162

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Efficient One-Pot Three-Component Synthesis of Fused Pyridine
Derivatives in Ionic Liquid
Zhibin Huang, Yu Hu, Yao Zhou, and Daqing Shi*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. China
S Supporting Information
b
ABSTRACT: An efficient one-pot synthesis of fused pyridine derivatives (including
pyrazolo[3,4-b]pyridine and pyrido[2,3-d]pyrimidine) by three-component reaction
of aldehyde, acyl acetonitrile, and electron-rich amino heterocycles (including
aminopyrazole and aminouracils) in ionic liquid is reported. This new protocol has the
advantages of environmental friendliness, higher yields, shorter reaction times, and convenient operation.
KEYWORDS: one-pot synthesis, pyridine derivatives, multicomponent reactions, ionic liquid
’ INTRODUCTION
great promise as an attractive alterative to conventional organic
solvents, and more attention has been currently focused on
organic reactions promoted by ionic liquids.9 They are non-
volatile, recyclable, nonexplosive, easily operable, and thermally
robust.10 There are many reports concerning the applications
of ionic liquid in organic reactions, such as Friedel-Crafts
reactions,11 Diels-Alder reactions,12 Heck reactions,13 Pechmann
condensations,14 Biginelli reactions,15 Beckmann rearrange-
ments,16 and other reactions.17 As part of our current studies
on the developments of new routes to heterocyclic systems in
ionic liquid,18 we herein described a facile synthesis of fused
pyridine derivatives (including pyrazolo[3,4-b]pyridine and
pyrido[2,3-d]pyrimidine) by three-component reaction of alde-
hyde, acyl acetonitrile, and electron-rich amino heterocycles
(including aminopyrazole and aminouracils) in ionic liquid
without any catalyst.
Multicomponent reactions (MCRs) in which several reac-
tions are combined into one synthetic operation have been
used extensively to form carbon-carbon bonds in the synthetic
chemistry.1 Such reactions offer a wide range of possibilities
for the efficient construction of highly complex molecules in a
single procedure step, thus avoiding the complicated purifica-
tion operations and allowing savings of both solvents and
reagents. Thus, they are perfectly amenable to automation for
combinatorial synthesis.2 In the past decade, there have been
tremendous development in three- and four-component reac-
tions and great effort continue to be made to develop new
MCRs.3
Pyrazole and its derivatives are gaining importance in medic-
inal and organic chemistry. They have displayed broad spectrum
of pharmacological and biological activities, such as antibacterial,
antidepressant, antihyperglycemic, anti-inflammatory, and anti-
tumor.4 In particular, condensed pyrazoles are known for various
biological activities, for example, pyrazolo[3,4-b]pyridines are
useful for treatment of a wide variety of stress-related illnesses,
such as depression, Alzheimer's disease, gastrointestinal disease,
anorexia nervosa, hemorrhaged stress, drug and alcohol with-
drawal symptoms, drug addition and infertility.5 Pyrido[2,3-d]-
pyrimidines represent a heterocyclic ring system of considerable
interest because of several biological activities associated with
this scaffold. Some analogues have been found to act as anti-
cancer agents inhibiting dihydrofolate reductases or tyrosine
kinases,6 while others are known as antiviral agents.7 Pyrazolo-
[3,4-b]pyridine derivatives are general prepared by reaction
of 5-aminopyrazole and substituted R,β-unsaturated nitriles in
organic solvent using triethylamine as catalyst,8 but most of them
suffer from drawbacks, such as lower yields and use of organic
solvent.
’ RESULTS AND DISCUSSION
To avoid the disadvantages such as volatility and toxicity than
many organic solvents inherently have, we employed RTILs
into the three-component reaction as a green medium. Initially,
the three-component reaction of 4-methylbenzaldehyde 1{1},
3-oxo-3-phenylpropanenitrile 2{1}, and 3-methyl- 1-phenyl-1H-
pyrazol-5-amine 3{1} as a simple model substrate was investi-
gated to establish the feasibility of the strategy and to optimize
the reaction conditions (Scheme 1). The effects of solvents and
reaction temperature were evaluated for this model reaction, and
the results are summarized in Table 1. The ionic liquid [bmim]Br
provided higher yields and shorter reaction times than those
using organic solvents (Table 1, entry 8 vs entries 1-5). The
bmim bromide also proved to be slightly superior to the
Received: September 26, 2010
Room temperature ionic liquids (RTILs), especially those
based on 1-alkyl-3-methylimidazolium cations, have shown
Revised:
Published: November 10, 2010
October 16, 2010
r
2010 American Chemical Society
45
dx.doi.org/10.1021/co1000162 ACS Comb. Sci. 2011, 13, 45–49
|

ACS Combinatorial Science
RESEARCH ARTICLE
Scheme 1. Model Reaction
Table 1. Optimization of Reaction Conditions
entry
solvent
T (°C)
time (h)
isolated yield (%)
1
acetone
60
70
80
60
100
90
90
90
r.t.
40
60
80
24
18
10
25
8
32
59
73
55
81
89
90
93
53
68
79
93
2
acetonitrile
ethanol
3
4
chloroform
DMF
5
6
[bmim]PF6
[bmim]BF4
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
6.5
6
7
8
5
9
20
14
8
10
11
12
5
analogous hexafluorophosphate or tetrafluoroborate ionic liquids
for this reaction (Table 1, entries 6 and 7). The yield of product
4{1,1,1} was improved and the reaction time was shortened as
the temperature was increased from room temperature to 80 °C,
with no further improvement observed at 90 °C (Table 1, entries
8-12). Therefore, the most suitable reaction temperature is
80 °C.
The optimized reaction conditions were then tested for library
construction with eighteen aldehydes 1{1-18}, three acyl
acetonitriles 2{1-3}, and four electron-rich amino heterocycles
3{1-4} (Figure 1). The corresponding fused pyridine deriva-
tives 4 were obtained in good yields at 80 °C in ionic liquid
[bmim]Br without any catalyst. The results are summarized in
Table 2. The protocol was effective with aromatic aldehydes
having either electron-withdrawing (nitro, halide) or electron-
donating groups (hydroxyl, alkoxyl) and also with heterocyclic
aldehydes and aliphic aldehydes.
R,β-Unsaturated aldehydes were found to be incompatible
with the three-component assembly reaction, as noted for the
combination of 3-phenylacrylaldehyde 1{18}, 3-oxo-3-phenyl-
propanenitrile 2{1}, and 6-amino-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione 3{2}. In this case, the desired tetrahydro-
pyrido[2,3-d]pyrimidine was not obtained. Instead, an efficient
side reaction between 1{18} and 3{2} occurred to give1,3-
dimethyl-5-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
was observed (Table 2, entry 46).
Figure 1. Diversity of reagents.
Although the detailed mechanism of this reaction remains
to be fully clarified, the formation of compounds 4 could
be explained by the reaction sequence in Scheme 2. First,
a Knoevenagel condensation reaction of aldehyde 1 with
acyl acetonitrile 2 is proposed to give the intermediate A.
Michael addition of electron-rich amino heterocycles 3 to
A should then occur to provide intermediate B, which under-
goes intramolecular cyclization and dehydration to give C.
In the last step, the intermediate product C is aromatized to
product 4.
The structures of all products 4 were characterized by IR, 1H
NMR, 13C NMR spectral data as well as HRMS analysis. The
structure of 4{13,2,1} was further confirmed by X-ray diffraction
analysis. The molecular structure of 4{13,2,1} is shown in
Figure 2.
46
dx.doi.org/10.1021/co1000162 |ACS Comb. Sci. 2011, 13, 45–49

ACS Combinatorial Science
RESEARCH ARTICLE
Table 2. Synthesis of Fused Pyridine Derivatives 4 in Ionic
Liquid [bmim]Br
entry
products
time (h)
isolated yield (%)
mp (°C)
1
4{1,1,1}
4{1,1,2}
4{1,1,4}
4{1,2,1}
4{1,2,2}
4{1,3,1}
4{2,1,1}
4{2,1,2}
4{2,1,4}
4{2,2,1}
4{2,2,2}
4{2,3,1}
4{3,1,1}
4{3,1,2}
4{4,1,1}
4{4,1,2}
4{4,2,2}
4{5,1,1}
4{5,1,2}
4{5,2,3}
4{5,2,4}
4{6,1,1}
4{7,1,1}
4{8,1,1}
4{8,1,2}
4{9,1,1}
4{9,2,1}
4{10,1,1}
4{10,1,2}
4{11,1,1}
4{12,1,1}
4{12,2,1}
4{13,1,1}
4{13,1,2}
4{13,2,1}
4{13,2,2}
4{14,1,1}
4{14,1,2}
4{14,2,1}
4{14,2,2}
4{15,1,1}
4{15,2,1}
4{16,1,1}
4{16,2,1}
4{17,1,2}
4{18,0,2}a
5
93
92
94
96
92
86
95
88
98
93
90
85
94
90
98
94
88
95
98
93
97
98
82
98
90
92
93
92
92
91
96
92
95
90
80
90
83
85
89
81
98
89
91
92
90
72
210-212
>300
2
5
3
5
249-250
210-211
>300
4
5
5
5
6
4
197-199
231-233
>300
7
5
8
5.5
5.5
5.5
5
9
252-254
244-246
>300
Figure 2. Crystal structure of 4{13,2,1}.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
Scheme 2. Proposed Mechanism for the Synthesis of Fused
Pyridines 4
4
180-182
216-218
269-270
206-208
246-248
>300
5.5
5
4.5
5
5
5.5
5.5
5
244-246
>300
177-178
266-268
204-206
186-188
176-178
270-272
226-228
201-202
192-194
226-227
275-276
210-212
265-267
191-192
257-258
210-212
275-276
174-176
269-270
201-203
246-248
138-139
200-202
156-158
163-164
>300
5.5
4.5
6
6
7
6.5
5.5
4
4.5
5.5
4.5
4.5
5
’ CONCLUSION
We have described an efficient one-pot three-component
reaction of aldehyde, acyl acetonitrile, and electron-rich amino
heterocycles, such as 5-aminopyrazole or 6-aminopyrimidine-
2,4-dione, for the synthesis of pyrazolo[3,4-b] pyridine and
pyrido[2,3-d]pyrimidine derivatives in ionic liquid. This method
has the advantages of higher yields, milder reaction conditions,
shorter reaction time, convenient procedure, and environmental
friendliness. Given the large number of commercially available
building blocks, the present method should be applicable to
synthesis of libraries with high diversity.
5
5
5
5
6
5
6
’ EXPERIMENTAL PROCEDURES
4.5
4.5
4.5
4.5
5
General Information. Commercial solvents and reagents
were used as received. Melting points are uncorrected. IR spectra
were recorded on Varian F-1000 spectrometer in KBr with
absorptions in cm-1. 1H NMR and 13C NMR were determined
on Varian-300 MHz or Varian-400 MHz spectrometer in
DMSO-d6 or CDCl3 solution. J values are in Hz. Chemical shifts
are expressed in parts per million downfield from internal
5
177-178
a The product is 1,3-dimethyl-5-phenylpyrido[2,3-d]pyrimidine-2,4-
(1H,3H)-dione.
47
dx.doi.org/10.1021/co1000162 |ACS Comb. Sci. 2011, 13, 45–49

ACS Combinatorial Science
RESEARCH ARTICLE
standard TMS. High-resolution mass spectra (HRMS) were
obtained using a time-of-flight mass spectrometry (TOF-MS)
instrument. X-ray crystallographic analysis was performed with a
Rigaku Mercury CCD/AFC diffractometer.
General Procedure for the Synthesis of Fused Pyridine
Derivatives 4. A dry 50 mL flask was charged with aldehyde 1
(1 mmol), acyl acetonitrile 2 (1 mmol), electron-rich amino
heterocycles 3 (1 mmol), and ionic liquid [bmim]Br (2 mL). The
mixture was stirred at 80 °C for 4-7 h to complete the reaction
(monitored by TLC), then 50 mL water was added. The solid
was filtered off and washed with water. The crude product was
purified by recrystallization from ethanol to give 4.
3-Methyl-1,6-diphenyl-4-(4-methylphenyl)-1H-pyrazolo[3,4-b]-
pyridine-5-carbonitrile 4{1,1,1}. mp: 210-212 °C. IR (KBr) ν:
2221, 1583, 1559, 1506, 1433, 1418, 1385, 1340, 1196, 1176,
1127, 775, 758, 706 cm-1. 1H NMR (DMSO-d6) δ: 2.10 (s, 3H,
CH3), 2.46 (s, 3H, CH3), 7.38 (t, J = 7.2 Hz, 1H, ArH), 7.45 (d,
J = 8.0 Hz, 2H, ArH), 7.56-7.61 (m, 7H, ArH), 7.94-7.96 (m,
2H, ArH), 8.22 (d, J = 8.4 Hz, 2H, ArH). HRMS [Found m/z
400.1688 (Mþ); Calcd for C27H20N4 M, 400.1688].
1,3-Dimethyl-2,4-dioxo-7-phenyl-5-(4-methylphenyl)-1,2,3,4-
tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile 4{1,1,2}. mp:
>300 °C. IR (KBr) ν: 2222, 1713, 1668, 1553, 1478, 1409, 1362,
1286, 1097, 817, 752, 716, 698 cm-1. 1H NMR (DMSO-d6) δ:
2.41 (s, 3H, CH3), 3.17 (s, 3H, CH3), 3.67 (s, 3H, CH3),
7.25-7.31 (m, 4H, ArH), 7.61-7.62 (m, 3H, ArH), 8.00-
8.02 (m, 2H, ArH). HRMS [Found m/z 382.1435 (Mþ); Calcd
for C23H18N4O2 M, 382.1430].
the Foundation of Key Laboratory of Organic Synthesis of
Jiangsu Province (No. JSK0812).
’ REFERENCES
(1) (a) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Maximiz-
ing Synthetic Efficiency: Multi-Component Transformations Lead The
Way. Chem.;Eur. J. 2000, 6, 3321–3329. (b) Tietze, L. F.; Modi, A.
Multicomponent Domino Reactions for the Synthesis of Biologically
Active Natural products and Drugs. Med. Res. Rev. 2000, 20, 304–322.
(c) D€omling, A.; Ugi, I. Multicomponent Reactions with Isocyanides.
Angew. Chem., Int. Ed. 2000, 39, 3168–3210. (d) Zhu, J. Recent Devel-
opments in the Isonitrile-Based Multicomponent Synthesis of Hetero-
cycles. Eur. J. Org. Chem. 2003, 1133–1144. (e) Orru, R. V. A.; de Greef,
M. Recent Advances in Solution-Phase Multicomponent Methodology
for the Synthesis of Heterocyclic Compounds. Synthesis 2003, 1471–
1499. (f) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Strategies for Heterocyclic Construction via
Novel Multicomponent Reactions Based on Isocyanides and Nucleo-
philic Carbenes. Acc. Chem. Res. 2003, 36, 899–907. (g) Simon, C.;
Constantieux, T.; Rodriguez, J. Utilisation of 1,3-Dicarbonyl Deriva-
tives in Multicomponent Reactions. Eur. J. Org. Chem. 2004, 4957–
4980. (h) Ramon, D. J.; Yus, M. Asymmetric Multicomponent Reac-
tions (AMCRs): The New Frontier. Angew. Chem., Int. Ed. 2005, 44,
1602–1634.
(2) Terrett, N. K. Combinatorial Chemistry; Oxford University Press:
New York, 1998.
(3) (a) Nair, V.; Vinod, A. U.; Rajesh, C. A Novel Synthesis
of 2-Aminopyrroles Using a Three-Component Reaction. J. Org. Chem.
2001, 66, 4427–4429. (b) List, B.; Castello, C. A Novel Proline-
Catalyzed Three-Component Reaction of Ketones, Aldehydes and
Meldrum's Acid. Synlett 2001, 1687–1689. (c) Shestopalov, A. M.;
Emeliyanova, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.; Niazim-
betova, Z. I.; Evans, D. H. One-Pot Synthesis of Substituted 6-Amino-
5-cyanospiro-4-(piperidine-4)-2H,4H-dihydropyrazolo[3,4-b]pyrans.
Org. Lett. 2002, 4, 423–425. (d) Bertozzi, F.; Gustafsson, M.; Olsson, R.
A Novel Metal Iodide Promoted Three-Component Synthesis of
Substituted Pyrrolidines. Org. Lett. 2002, 4, 3147–3150. (e) Yuan, Y.;
Li, X.; Ding, K. Acid-Free Aza Diels-Alder Reaction of Danishefsky's
Diene with Imines. Org. Lett. 2002, 4, 3309–3311. (f) Cheng, J. F.; Chen,
M.; Arrhenius, T.; Nadzen, A. A Convenient Solution and Solid-Phase
Synthesis of Δ5-2-Oxopiperazines via N-Acyliminium Ions Cyclization.
Tetrahedron Lett. 2002, 43, 6293–6295. (g) Huma, H. Z. S.; Halder, R.;
Kalra, S. S.; Das, J.; Iqbal, J. Cu (I)-Catalyzed Three Component
Coupling Protocol for the Synthesis of Quinoline Derivatives. Tetra-
hedron Lett. 2002, 43, 6485–6488. (h) Bora, U.; Saikia, A.; Boruah, R. C.
A Novel Microwave-Mediated One-Pot Synthesis of Indolizines via a
Three-Component Reaction. Org. Lett. 2003, 5, 435–438. (i) Dallinger,
D.; Gorobets, N. Y.; Kappe, C. O. High-Throughput Synthesis of
N3-Acylated Dihydropyrimidines Combining Microwave-Assisted Syn-
thesis and Scavenging Techniques. Org. Lett. 2003, 5, 1205–1208.
(4) (a) Hardy, C. R. The Chemistry of Pyrazolopyridines. Adv.
Heterocycl. Chem. 1984, 36, 343–409. (b) Orth, R. E. Biologically Active
Pyrazoles. J. Pharm. Sci. 1968, 57, 537–556. (c) Elnagdi, M. H.;
Elmoghayar, M. R. H.; Elgemeie, G. E. H. Chemistry of Pyrazolopyr-
imidines. Adv. Heterocycl. Chem. 1987, 41, 319–376. (d) Elnagdi, M. H.;
Elmoghayar, M. R. H.; Sadek, K. U. Chemistry of Pyrazoles Condensed
to Heteroaromatic Five- and Six-Membered Rings. Adv. Heterocycl.
Chem. 1990, 48, 223–299. (e) Liu, X. H.; Cui, P.; Song, B. A.; Bhadury,
P. S.; Zhu, H. L.; Wang, S. F. Synthesis, Structure and Antibacterial
Activity of Novel 1-(5-Substituted-3-substituted-4,5-dihydropyrazol-1-
yl)ethanone Oxime Ester Derivatives. Bioorg. Med. Chem. 2008, 16,
4075–4082. (f) Palaska, E.; Aytemir, M.; Uzbay, T.; Erol, D. Synthesis
and Antidepressant Activities of Some 3,5-Diphenyl-2-pyrazolines. Eur.
J. Med. Chem. 2001, 36, 539–543. (g) Kees, K. L.; Fitzgerald, J. J.; Steiner,
K. E., Jr; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb,
M. L. New Potent Antihyperglycemic Agents in db/db Mice: Syn-
thesis and Structure-Activity Relationship Studies of (4-Substituted
2-Amino-4-oxo-7-phenyl-5-(4-methylphenyl)-3,4-dihydro-
pyrido[2,3-d]pyrimidine-6-carbonitrile 4{1,1,4}. mp: 249-
250 °C. IR (KBr) ν: 3323, 3060, 2224, 1701, 1665, 1539, 1455,
1431, 1386, 1357, 1280, 1209, 1103, 908, 828, 789, 717, 694 cm-1
;
1H NMR (DMSO-d6) δ: 2.43 (s, 3H, CH3), 7.28 (s, 5H, ArH),
7.58-7.60 (m, 4H, ArHþNH2), 7.89-7.99 (m, 2H, ArH), 11.18
(s, 1H, NH). 13C NMR (DMSO-d6) δ: 21.66, 108.74, 114.13,
118.04, 128.48, 128.97, 129.69, 130.92, 134.85, 137.99, 138.17,
138.33, 141.37, 156.47, 158.73, 162.98, 164.96. HRMS [Found
m/z 353.1277(Mþ); Calcd for C20H1235ClN5O M, 353.1277].
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and spec-
b
troscopic characterization for compounds 4 and the X-ray crystal-
lographic information for compound 4{13,2,1}. This informa-
tion is available free of charge via the Internet at http://
pubs.acs.org/.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: dqshi@suda.edu.cn.
Author Contributions
Zhibin Huang and Daqing Shi conceived and designed the
experiments, Yao Zhou and Yu Hu performed the experiments,
Daqing Shi and Zhibin Huang co-wrote the manuscript and
supporting information.
’ ACKNOWLEDGMENT
This work were partially supported by the Major Basic
Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 10KJA150049) and
48
dx.doi.org/10.1021/co1000162 |ACS Comb. Sci. 2011, 13, 45–49

ACS Combinatorial Science
RESEARCH ARTICLE
benzyl)(trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem.
1996, 39, 3920–3928.
(5) Chen, Y. L. Pyrazolo- and Pyrazolopyridines Useful as CRF
Antagonists. Internation Patent WO 9534563 A1, 1995; Chem. Abstr.
1995, 124, 232447.
(17) (a) Wang, B.; Gu, Y.; Luo, C.; Yang, T.; Yang, L.; Suo, J. Pyrrole
Synthesis in Ionic Liquids by Peal-Knorr Condensation under Mild
Conditions. Tetrahedron Lett. 2004, 45, 3417–3419. (b) Yadav, J. S.;
Reddy, B. V. S.; Baishya, G.; Reddy, K. V.; Narsaiah, A. V. Conjugate
Addition of Indoles to R,β-Unsaturated Ketones Using Cu(OTf)2
Immobilized in Ionic Liquids. Tetrahedron 2005, 61, 9541–9544.
(c) Xu, L. W.; Li, L.; Xia, C. G.; Zhou, S. L.; Li, J. W. The First Ionic
Liquids Promoted Conjugate Addition of azide ion to R,β-Unsaturated
Carbonyl Compounds. Tetrahedron Lett. 2004, 45, 1219–1221.
(18) (a) Shi, D. Q.; Yang, F. Ionic Liquid as an Efficient Promoting
Medium for Synthesis of Bis-pyrazolo[3,4-b:40,30-e]pyridines. J. Chin.
Chem. Soc. 2008, 55, 755–760. (b) Shi, D. Q.; Ni, S. N.; Yang, F.; Shi,
J. W.; Dou, G. L.; Li, X. Y.; Wang, X. S. An Efficient Synthesis of
Polyhydroacridine Derivatives by the Three-Component Reaction of
Aldehydes, Amines and Dimedone in Ionic Liquid. J. Heterocycl. Chem.
2008, 45, 653–660. (c) Shi, D. Q.; Ni, S. N.; Yang, F.; Shi, J. W.; Dou,
G. L.; Li, X. Y.; Wang, X. S.; Ji, S. J. An Efficient Synthesis of Pyrimido-
[4,5-b]quinoline and Indeno[20,10:5,6]pyrido[2,3-d]pyrimidine Deriva-
tives via Multicomponent Reactions in Ionic Liquid. J. Heterocycl. Chem.
2008, 45, 693–702. (d) Shi, D. Q.; Ni, S. N.; Yang, F.; Ji, S. J. An Efficient
and Green Synthesis of 3,30-benzylidenebis(4-hydroxy-6-methylpyridin-
2(1H)-one) Derivatives through Multi-Component Reaction in Ionic
Liquid. J. Heterocycl. Chem. 2008, 45, 1275–1280. (e) Shi, D. Q.; Yang,
F.; Ni, S. N. A Facile Synthesis of Furo[3,4-e]pyrazolo[3,4-b]pyridine-
5(7H)-one Derivatives via Three-Component Reaction in Ionic Liquid
without Any Catalyst. J. Heterocycl. Chem. 2009, 46, 469–476. (f) Shi,
D. Q.; Zhou, Y.; Liu, H. An Efficient Synthesis of Pyrido[2,3-d]-
pyrimidine Derivatives in Ionic Liquid. J. Heterocycl. Chem. 2010, 47,
131–135.
(6) (a) Gangjee, A.; Adair, O.; Queener, S. F. Pneumocystis Carinii
and Toxoplasme Gondii Dihydrofolate Reductase Inhibitors and
Antitumor Agents: Synthesis and Biological Activities of 2,4-Diamino-5-
methyl-6-[(monosubstituted anilino) methyl]-pyrido[2,3-d]pyrimidines.
J. Med. Chem. 1999, 42, 2447–2455. (b) Gangjee, A.; Vasudevan, A.;
Queener, S. F.; Kisliuk, R. L. 2,4-Diamino-5-deaza- 6-substituted Pyrido-
[2,3-d]pyrimidine Antifolates as Potent and Selective Nonclassical
Inhibitors of Dihydrofolate Reductases. J. Med. Chem. 1996, 39, 1438–
1446. (c) Hamby, J. M.; Connolly, C. J. C.; Schroeder, M. C.; Winters,
R. T.; Showalter, H. D. H.; Panek, R. L.; Major, T. C.; Olsewski, B.; Ryan,
M. J.; Dahring, T.; Lu, G. H.; Keiser, J.; Amar, A.; Shen, C.; Kraker, A. J.;
Slintak, V.; Nelson, J. M.; Fry, D. W.; Bradford, L.; Hallak, H.; Doherty,
A. M. Structure-Activity Relationships for a Novel Series of Pyrido-
[2,3-d]pyrimidine Tyrosine Kinase Inhibitors. J. Med. Chem. 1997, 40,
2296–2303.
(7) Nasr, M. N.; Gineinah, M. M. Pyrido[2,3-d]pyrimidines and
Pyrimido[50,40;5,6]pyrido[2,3-d]pyrimidines as New Antiviral Agents:
Synthesis and Biological Activity. Arch. Pharm. 2002, 335, 289–295.
(8) (a) Quiroga, J.; Alvarado, M.; Insuasty, B.; Moreno, R.; Ravina,
E.; Estevez, I.; De Almeida, R. H. Synthesis of 5-Cyanopyrazolo-
[3,4-b]pyridines in the Reaction of 5-Amino-3-methyl-1-phenylpyrazole
with Arylidene Derivatives of Malonodinitrile and Ethyl Cyanoacetate.
J. Heterocycl. Chem. 1999, 36, 1311–1316. (b) Quiroga, J.; Cruz, S.;
Insuasty, B.; Abonia, R.; Cobo, J.; Sanchez, A.; Nogueras, M.; Low,
J. N. Synthesis and Structural Analysis of 5-Cyanodihydropyrazolo-
[3,4-b]pyridines. J. Heterocycl. Chem. 2001, 38, 53–60.
(9) (a) Dzyuba, S. V.; Bartsch, R. A. Recent Advances in Applications
of Room-Temperature Ionic Liquid/Supercritical CO2 Systems. Angew.
Chem., Int. Ed. 2003, 42, 148–150. (b) Wilker, J. S. A Short History
of Ionic Liquids-From Molten Salts to Neoteric Solvents. Green Chem.
2002, 4, 73–80.
(10) (a) Welton, T. Room-Temperature Ionic Liquids. Solvents for
Synthesis and Catalysis. Chem. Rev. 1999, 99, 2071–2084. (b) Dupont,
J.; de Souza, R. F.; Suarez, P. A. Z. Ionic Liquid (Molten Salt) Phase
Organometallic Catalysis. Chem. Rev. 2002, 102, 3667–3692.
(11) Earle, M. J.; Seddon, K. R.; Adams, C. J.; Roberts, G. Friedel-
Crafts Reactions in Room-Temperature Ionic Liquids. Chem. Commun.
1998, 2097–2098.
(12) (a) Fischer, T.; Sethi, A.; Welton, T.; Woolf, J. Diels-Alder
Reactions in Room-Temperature Ionic Liquids. Tetrahedron Lett. 1999,
40, 793–796. (b) Lee, C. W. Diels-Alder Reactions in Chloroaluminate
Ionic Liquids: Acceleration and Selectivity Enhancement. Tetrahedron
Lett. 1999, 40, 2461–2464. (c) Ludley, P.; Karodia, N. Phosphonium
Tosylates as Solvents for the Diels-Alder Reaction. Tetrahedron Lett.
2001, 42, 2011–2014.
(13) (a) Carmichael, A. J.; Earle, M. J.; Holbrey, J. D.; McCormac,
P. B.; Seddon, K. R. The Heck reaction in Ionic Liquids: A Multiphasic
Catalyst System. Org. Lett. 1999, 1, 997–1000. (b) Calo, V.; Nacci, A.;
Lopez, L.; Mannarini, N. Heck Reaction in Ionic Liquids Catalyzed by
a Pd-Benzothiazole Carbene Complex. Tetrahedron Lett. 2000, 41,
8973–8976.
(14) Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Coumarin
Syntheses via Pechmann Condensation in Lewis Acidic Chloroalumi-
nate Ionic Liquid. Tetrahedron Lett. 2001, 42, 9285–9287.
(15) Peng, J.; Deng, Y. Ionic Liquids Catalyzed Biginelli Reaction
under Solvent-Free Conditions. Tetrahedron Lett. 2001, 42, 5917–5919.
(16) (a) Ren, R. X.; Zueva, L. D.; Ou, W. Formation of ε-Capro-
lactam via Catalytic Beckmann Rearrangement Using P2O5 in Ionic
Liquids. Tetrahedron Lett. 2001, 42, 8441–8443. (b) Peng, J.; Deng, Y.
Catalytic Beckmann Rearrangement of Ketoximes in Ionic Liquids.
Tetrahedron Lett. 2001, 42, 403–405. (c) Wasserscheid, P.; Keim, W.
Ionic Liquids;New Solutions for Transition Metal Catalysis. Angew.
Chem., Int. Ed. 2000, 39, 3772–3789.
49
dx.doi.org/10.1021/co1000162 |ACS Comb. Sci. 2011, 13, 45–49