An efficient method for the one-pot, four-component benzaldehyde based synthesis of 3-methyl-1, 4-diphenyl-7,8-dihydro-1H-furo[3, 4-e]pyrazolo[3, 4-b]pyridin-5(4H)-ones catalyzed by alum in environment-friendly media

Article abstract of DOI:10.13005/ojc/300135

A mild and efficient method for the synthesis of 3-methyl-1, 4-diphenyl-7, 8-dihydro-1 H-furo[3, 4-e]pyra-olo[3, 4-b]pyridin-5(4H)-one derivatives via one-pot, four-component reaction of aromatic aldehydes, tetronic acid, 3-aminobut-2-enenitrile, and Phenylhydrazine is described using Alum as catalyst. The features of this procedure are mild reaction conditions, excellent yields, short reaction time, and operational simplicity.

Full text of DOI:10.13005/ojc/300135

ISSN: 0970-020 X
CODEN: OJCHEG
2014, Vol. 30, No. (1):
Pg. 279-284
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
An Efficient Method for the One-pot, Four-component
Benzaldehyde based Synthesis of 3-methyl-1,4-diphenyl-
7,8-dihydro-1H-furo[3,4-e]pyrazolo[3,4-b]pyridin-5(4H)-ones
Catalyzed by Alum in Environment-friendly Media
SADIF A. SHIRVAN1*,FEREYDOON KHAZALI1,
SARA HAYDARI DEZFULI1 and ALI BORSALANI2
1 Department of Chemistry, Omidiyeh Branch, Islamic Azad University, Omidiyeh, Iran.
2Department of Gas Engineering, Omidieh Branch, Islamic Azad University, Omidieh, Iran.
*Corresponding author E-mail: shiravan_sadif@yahoo.com
http://dx.doi.org/10.13005/ojc/300135
(Received: December 01, 2013; Accepted: January 17, 2014)
ABSTRACT
A mild and efficient method for the synthesis of 3-methyl-1,4- diphenyl-7,8-dihydro-1H-
furo[3,4-e]pyrazolo[3,4-b]pyridin-5(4H)-one derivatives via one-pot, four-component reaction of
aromatic aldehydes, tetronic acid, 3-aminobut-2-enenitrile, and phenylhydrazine is described using
Alum as catalyst.The features of this procedure are mild reaction conditions, excellent yields, short
reaction time, and operational simplicity.
Key words: Alum, Multicomponent Reactions (MCRs), Ionic liquids, benzaldehyde.
INTRODUCTION
(MCRs) have emerged as an efficient and powerful
tool in modern synthetic organic chemistry due to
their valued features such as atom economy, simpler
procedures and equipment, time and energy savings,
straightforward reaction design, and the opportunity
to construct target compounds by the introduction of
several diversity elements in a single chemical event.
MCRs, leading to interesting heterocyclic scaffolds,
are particularly useful for the construction of diverse
Application of multicomponent reactions
(MCRs) to the construction of natural product-based
libraries would be most beneficial to this area of
research. Such processes in which three or more
reactants are combined together in a single reaction
flask to produce a product. Up to seven starting
components have been used, and MCRs have
often been shown to produce higher product yields
than classical chemistry.Multi-component reactions
chemical libraries of ‘drug-like’ molecules1-9
.

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Tetronic acid (tetrahydrofuran-2,4-dione) pyridin-5(4H)-oneswasreportedviathree-component
is a promising convenient building block and reaction32, herein, we report a simple and efficient
compoundsin which tetronic acid fragment is fused method for the synthesis of these compounds with
to a heterocyclic systems attract specific attention. fused furo, pyrido and pyrazolo rings, through the
A large number of tetronic acid derivatives are one-pot four-component reaction in green media,
widespread in nature found in sponges, lichens, and using Alum as a catalyst at short reaction times with
molds, as well as in higher plants. Many exhibit a excellent yields.
wide array of biological properties such as antibiotic,
anticoagulant, antiepileptic, antifungal, insecticidal,
EXPRIMENTAL
analgesic and anti-inflammatory activities.Recently,
these compounds have also been reported as HIV-1 General remark
protease inhibitors10-21
.
All chemicals were purchased from
commercial providers and were used as received.
Polyfunctionalized heterocyclic compounds
play important roles in the drug discovery process, Physical measurements
and analysis of drugs in late development or on the
The progress of the reaction was monitored
market shows that 68% of them are heterocycles. by1H NMR spectra were recorded on a BRUKER
Therefore, it is not surprising that research in the DRX-300 AVANCE spectrometer at 300.13 MHz,
field of synthesis of polyfunctionalized heterocyclic Elemental analyses were performed using a Heracus
compounds has received special attention5.
CHN-O-Rapid analyzer, FT-IR on Nicolet 400D and
TLC.
Ionic liquids (ILs) have received vast
research interests in recent years. They exhibited Synthesis, spectral and analytical data of some
unique properties such as high ionic conductivity, representative compounds
wide electrochemical window, non-volatility, high
A mixture of tetronic acid (1 mmol),
thermal stability, nonflammability and miscibility with 3-aminobut-2-enenitrile (1 mmol) , phenylhydrazine
organic compounds, especially with the heterocyclic (1 mmol) and Catalyst (0.05 g) in ionic Liquid (0.2 g)
compounds as hydrophilicity, hydrophobicity, Lewis was stirred for 5 min at 70 °C. Then benzaldehyde
acidity, viscosity and density can be altered by the (1.2 mmol) was added to the mixture and stirred for
fine-tuning of parameters such as the choice of 15 min at this temperature. After cooling, the water
organic cation, inorganic anion and the length of (10 ml) was added to the reaction mixture and filtered.
alkyl chain attached to the organic cation (Fig. 1) The precipitate washed with water (10 mL) and EtOH
21-25. Because of these useful properties, ILs have (10 mL) to afford the pure product.
been applied in several areas, including catalysis,
electrochemistry, separation science for extraction 6,7-dihydro-4,9-diphenylfuro[3,4-b]quinoline-
of heavy metal ions, as solvents for green chemistry 1,8(3H,4H,5H,9H)-dione (1a)
and materials for optoelectronic applications26-30
.
IR(KBr, v,cm-1): 1737, 1674;1H NMR (300
MHz, DMSO-d6): δH (ppm) 1.69-1.89 (m, 2H, CH2),
Room temperature ionic liquids are 2.14-2.23 (m, 2H, CH2), 2.17-2.28 (m, 2H, CH2),
increasingly finding a range of laboratory, 4.56-5.02 (m, 2H, CH2),4.73 (s, 1H, CH), 6.88-7.80
developmental and technical applications, for (m, 10H, H-Ar). Anal. Calcd for C23H19NO3: C, 77.29;
example, as media for organic and inorganic H, 5.36; N, 3.92. Found C, 77.37; H, 5.24; N, 3.49.
chemical synthesis, materials productions, and
electrochemical devices23.
9-(4-bromophenyl)-4-phenyl-5, 6, 7, 9-
tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione
As a part of our research program, which (4e)
aims to develop new and environmentally friendly
IR(KBr, v,cm-1): 1751, 1667;1H NMR (300
methodologies for the preparation of heterocyclic MHz, DMSO-d6): δH (ppm) 1.73-1.92 (m, 2H, CH2),
compounds31, recently, synthesis of 3-methyl-1,4- 2.13-2.24 (m, 2H, CH2), 2.28-2.34 (m, 2H, CH2),
diphenyl-7,8-dihydro-1H-furo[3,4-e]pyrazolo[3,4-b] 4.53-4.59 (m, 2H, CH2),4.89 (s, 1H, CH), 6.88-7.80

SHIRVAN et al., Orient. J. Chem., Vol. 30(1), 279-284 (2014)
281
(m, 9H, H-Ar).Anal.Calcd for C23H18BrNO3:C, 63.32;
H, 4.16; N, 3.21. Found C, 63.37; H, 4.20; N, 3.16.
MHz, DMSO-d6): δH (ppm) 0.82 (s, 3H, CH3), 0.91 (s,
3H, CH3), 2.00-2.05 (m, 2H, CH2), 2.16-2.20 (m, 2H,
CH2), 2.40 (s, 3H, CH3), 4.45-4.52 (m, 2H, CH2), 4.65
(s, 1H, CH), 6.65-7.68 (m, 8H, H-Ar). Anal. Calcd for
C26H24BrNO3: C, 65.28; H, 5.06; N, 2.93. Found C,
65.31; H, 5.10; N, 2.90.
9-(4-methoxyphenyl)-4-p-tolyl-5,6,7,9-
tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione
(4f)
IR(KBr, v,cm-1): 1756, 1678;1H NMR (300
MHz, DMSO-d6): δH (ppm) 1.71-1.86 (m, 2H, CH2),
2.10-2.23 (m, 2H, CH2), 2.26-2.33 (m, 2H, CH2),
2.41 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 4.50-4.58 (m,
2H, CH2), 4.61 (s, 1H, CH), 6.64-7.76 (m, 8H, H-Ar).
Anal.Calcd for C25H23NO4:C, 74.79;H, 5.77;N, 3.49.
Found C, 74.74; H, 5.81; N, 3.45.
RESULTS AND DISCUSSION
In our first attempt, four-component reaction
of benzaldehyde, 1a tetronic acid, 2 3-aminobut-2-
enenitrile, 3 and phenylhydrazine, 4 was done in
various conditions. Additionally, different types and
amounts of catalysts were considered in order to
optimize the reaction conditions.We were pleased to
note the formation of 5a in excellent yield (98%).
9-(4-methoxyphenyl)-6,6-dimethyl-4-phenyl-
5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8
(3H,4H)-dione (4h)
IR(KBr, v,cm-1): 1745, 1689;1HNMR (300
MHz, DMSO-d6): δH (ppm) 0.84 (s, 3H, CH3), 0.95
(s, 3H, CH3), 2.02-2.08 (m, 2H, CH2), 2.17-2.23 (m,
2H, CH2), 3.70 (s, 3H, OCH3), 4.41-4.54 (m, 2H,
CH2),4.68 (s, 1H, CH), 6.85-7.81 (m, 9H, H-Ar).
Anal.Calcd for C26H25NO4:C, 75.16;H, 6.06;N, 3.37.
Found C, 75.12; H, 6.11; N, 3.33.
At first, we examined this simple model
reaction in the presence of a diverse types of lewis
and bronsted acids such as Alum, SSA, SnCl4,
ZnCl2, SnO2, p-TSA, CAN, and K-10 as a catalyst.
We also tested the reaction in different ionic liquids
media such as [Bmim]Br, [Bmim]Cl, [Bmim]CF3COO,
[Bmim]BF4, and [Bmim]PF6. It was found that only
trace amount of the target compound 5a was
obtained in the absence of catalyst. We have found
that use of Alum has a unique capability and best
promoter to enhance the reaction rate in [Bmim]PF6
medium (Scheme 1).
9-(4-bromophenyl)-6,6-dimethyl-4-p-tolyl-5,6,7,9-
tetrahydrofuro[3,4-b]quinoline 1,8(3H,4H)-dione
(4k)
IR(KBr, v,cm-1): 1750, 1683;1H NMR (300
N
N
PF6
N
N
BF4
(
)
n
n=1=[Bmim]PF6
n=3=[Hmim]PF6
n=5=[Octmim]PF6
[Bmim]BF4
Fig. 1: Chemical structure of the ionic liquids
Me
N
O
CHO
NHNH2
Me
O
[BMIM]PF6
CN
O
O
+
NH2
N
+
+
Alum
70 °C
20 min
N
H
O
Scheme1: Standard model reaction

282
SHIRVAN et al., Orient. J. Chem., Vol. 30(1), 279-284 (2014)
After optimizing the conditions, to delineate pot, four-component condensation of benzaldehydes,
this approach, particularly in regard to library 1(a-l) tetronic acid, 2 3-aminobut-2-enenitrile, 3 and
construction, as shown in Table 2 it was found phenylhydrazine, 4 with excellent yields in the ionic
that this procedure works with a wide variety of liquid media in the presence of Alum as a catalyst for
benzaldehydes. Corresponding 3-methyl-1,4- 20 min at 70 °C .Work-up gave products 5(a-l) 93%
diphenyl-7,8-dihydro-1H-furo[3,4-e]pyrazolo[3,4-b] to 98% yields. The results are summarized in Table
pyridin-5(4H)-ones 5 were synthesized by the one- 2. All the products 5(a-l) are Known compounds and
R
Me
N
O
NHNH2
Me
O
[BMIM]PF6
CN
O
O
RCHO
+
NH2
Alum
70 °C
20 min
+
+
N
N
H
O
1(a-l)
2
3
4
5(a-l)
Scheme 2: Synthesis of 3-methyl-1,4-diphenyl-7,8-dihydro-1H-
furo[3,4-e]pyrazolo[3,4-b]pyridin-5(4H)-ones
HN
O
Me
O
NHNH2
O
Me
O
[BMIM]PF6
CN
N
O
O
O
+
NH2
N
+
+
Alum
70 °C
20 min
N
O
H
N
H
6
2
3
4
7
Mp > 300 C
°
Yield 95%
O
Me
O
O
O
NHNH2
Me
O
[BMIM]PF6
CN
N
O
O
+
NH2
N
+
+
Alum
70 °C
20 min
N
O
H
8
2
3
4
9 Mp > 300 C
°
Yield 93%
Scheme 3: Replacement of aromatic aldehydes in the reaction
with tetronic acid, 3-aminobut-2- enenitrile
Table 1: Model Reaction, Conditions, andYields
Conditions
Catalyst
Time (min)
T.(°C)
Yield(%)
[Bmim]PF6
[Bmim]PF6
[Bmim]PF6
[Bmim]PF6
[Bmim]PF6
[Bmim]PF6
[Bmim]PF6
[Bmim]BF4
[Bmim]CF3CO2
[Bmim]Br
CAN
p-TSA
SnCl4
SSA
Alum
ZnCl2
SnO2
Alum
Alum
Alum
Alum
20
20
20
20
20
20
20
20
20
20
20
70
70
70
70
70
70
70
70
70
70
70
<50
66
<50
63
98
<50
<50
88
91
70
[Bmim]Cl
61

SHIRVAN et al., Orient. J. Chem., Vol. 30(1), 279-284 (2014)
283
were characterized by comparison of their melting
point data with authentic samples synthesised by
reported procedures30.
compounds, indoline-2,3-dione and acenaphthylene-
1,2-dione, were examined as the replacement of
aromatic aldehydes in the reaction with tetronic
acid, 3-aminobut-2-enenitrile, and phenylhydrazine,
(Scheme 3).
Subsequently, another active carbonyl
Table 2: 4,9-diphenyl-5,6,7,9-tetrahydrofuro
[3,4-b]quinoline-1,8(3H,4H)-dione derivatives5
Entry
5
R
Yielda (%)
Mp °C
Lit.bMp °C
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
4-CH3C6H4
4-BrC6H4
4-OHC6H4
3,4-OCH2OC6H3
4-CH3OC6H4
4-ClC6H4
4-FC6H4
3-ClC6H4
4-NO2C6H4
3,4-Cl2C6H3
2-ClC6H4
98
93
98
95
96
97
96
98
98
97
96
97
224-225
240-242
259-262
270-272
233-235
222-223
250
169-172
230-231
243-244
259-260
257
222-224
238-240
358-260
268-270
230-232
223-224
249-250
168-170
228-230
244-246
258-260
254-256
9
10
11
12
J
K
L
2,4-Cl2C6H3
a) Isolated Yields
b) Melting point data in authentic samples synthesised by reported procedures 30
.
In these reactions 3-methyl-1-phenyl-7,8-
dihydrospiro[furo[3,4-e]pyrazolo [3,4-b]pyridine-
4,3'-indoline]-2',5(1H)-dione and 3'-methyl-1'-
phenyl-7',8'-dihydro-2H-spiro[acenaphthylene-1,4'-
furo[3,4-e]pyrazolo[3,4-b]pyridine]-2,5'(1'H)-dione
were synthesized with excellent yields in the same
conditions.
pyrazolo[3,4-b] pyridin-5(4H)-ones in short reaction
time is reported. Using readily available starting
materials and Alum as a inexpensive and nontoxic
catalyst in environmentally friendly reaction media,
operational simplicity, excellent product yields and
easy work-up procedures are prominent among the
advantages of this new method.
CONCLUSION
ACKNOwLEDGEMENTS
In conclusion, a facile and green one-pot
four component procedure for the syntheses of
3-methyl-1,4-diphenyl-7,8-dihydro-1H-furo[3,4-e]
We gratefully acknowledge financial
support from the Research Council of Islamic Azad
University, Omidieh Branch.
REFERENCES
1.
2.
Multicomponent Reactions, J. Zhu, H. 3.
Bienayme, Eds. Wiley-VCH. Weinheim
D. J. Ramon, M. Yus,Angew. Chem., 44: 160
(2005).
Mehdi Forouzani and H.G. Bosra, Orient J.
Chem., 29(2): 573-578 (2013).
A .Domling, Chem. Rev., 106: 17 (2006).
2005.
4.
A. Basso, L. Banfi, R. Riva, G. Guanti, J. Org.
Chem., 70,575( 2005).
5.

284
SHIRVAN et al., Orient. J. Chem., Vol. 30(1), 279-284 (2014)
6.
I .Ugi, S.Heck, Comb.Chem.HighThroughput
Chem., 18: 199(1975).
Screening., 4: 1 (2001).
M. Shigemitsu, Bull. Chem.Soc.Jpn., 32: 692
(1959).
21.
B. E. Roggo, F. Petersen, R. Delmendo, H. B.
Jenny, H. H. Peter, J. Roesel, J. Antibiot., 47:
136(1994).
7.
8.
R. Gharamanzadeh, A. Bazgir, J. Hetrocycl. 22.
Chem., 47: 421 (2010).
R. Hagiwara, Y. Ito, J. Fluorine Chem., 105:
221 (2000).
9.
R. Gharamanzadeh, S. Ahadi, A. Bazgir, 23.
T. Welton, Chem. Rev., 99, 2071(1999).
M.J.Earle, K.R.Seddon, Pure Apple.Chem.,
72, 1391(2000).
H. Olivier, J. Mol. Catal. A. Chem., 146,
285(1999).
J. H. Davis, K. J. Forrester, T. Merrigan,
Tetrahedron Lett., 39: 8955 (1998).
J.G Huddleston, H.D.Willauer, R.P.Swatloski,
A. E. Visser, R. D, Rogers, Chem. Commun.,
1765 (1998).
A. Rosowsky, C. E. Mota, S. F. Queener, J.
hetrocyclic.Chem., 32: 335(1995).
A.E.Visser, R.P Swatloski, W.M.Reichert, R
Mayton, S. Sheff,A. Davis, Chem. Commun.,
135 (2001).
J.Hetrocycl.Chem., 51: 449 (2010).
N.K.Satti, A.K.Suri, O .P.Sun, Indian.J.Chem
B., 32: 978 (1993).
F.Effenberg,J.Syed,Tetrahedron:Asymmetry.,
9: 817 (1998).
24.
25.
26.
27.
10.
11.
12.
13.
14.
15.
16.
17.
L. J.Haynes, Plimmer, J. R. Quart. Rev., 14:
292 (1960).
S.V. Ley, M. L. Trudell, D. Wad worth,
Tetrahedron., 47: 8285 (1991).
B. E. Vanwagenen, J. H.Cardellina, 28.
Tetrahedron., 42: 1117 (1986).
R. A.Vishwakarma, R. S .K apil, S. P.Popli, 29.
Indian J. Chem., 26: 486(1987).
K. Luk, S. A. Readshaw, J. Chem. Soc., 11:
1641(1991).
30.
D. Haristoy, D. Tsiourvas, Chem. Mater., 15:
2079 (2003).
A. Shameli, A.H. Raeisi, B. Pourhasan, H.
Naeimi and M.M. Ghanbari, Orient J. Chem., 31.
28(2): 749-755 (2012).
A. Ibi, E.Yaniguchi, K. Maekawa, Agric. Biol.
Chem., 43: 1641(1979).
S. A. Shirvan, R. Ghahremanzadeh, M.
Mirhosseini Moghaddam, A. Bazgir, A. H.
Zarnani, M. M. Akhondi, J. Heterocyclic
Chem., 2011, (In Press).
18.
19.
20.
R. Brodersen, A. Kjaer, Acta Pharmacol. 32.
Toxicol., 2: 109 (1946).
F.R.Foden, J.McCormick, D.M.O’Man.,J.Med.
C. L. Shi, D. Q. Shi, S. H. Kim, Z. B. Huang,
Tetrahedron., 64: 2425 (2008).