γ-Alumina as a recyclable catalyst for the four-component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5- carbonitriles in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2011.03.036

γ-Alumina as an expedient and recyclable catalyst for the synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5- carbonitriles in water via a four-component reaction is established. Comparative study of the efficacy of γ-alumina, basic alumina and KF-alumina is also discussed. The method presented is mild, environment friendly, inexpensive and functionality tolerable to give the products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2011.03.036

Tetrahedron Letters 52 (2011) 2523–2525
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
c-Alumina as a recyclable catalyst for the four-component synthesis
of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitriles in aqueous medium
⇑
Hormi Mecadon, Md. Rumum Rohman, Mantu Rajbangshi, Bekington Myrboh
Department of Chemistry, North-Eastern Hill University, Permanent Campus, Umshing, Mawlai, Shillong 793022, India
a r t i c l e i n f o
a b s t r a c t
Article history:
c
-Alumina as an expedient and recyclable catalyst for the synthesis of 6-amino-4-alkyl/aryl-3-methyl-
2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles in water via a four-component reaction is established.
Comparative study of the efficacy of -alumina, basic alumina and KF-alumina is also discussed. The
Received 9 January 2011
Revised 3 March 2011
Accepted 8 March 2011
Available online 12 March 2011
c
method presented is mild, environment friendly, inexpensive and functionality tolerable to give the prod-
ucts in good to excellent yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Four-component reaction
c
-Alumina
Water
Multi-component reactions (MCRs), by virtue of their flexibility
Furthermore, alumina and alumina supported reagents, due to
their surface property and well defined porosity, act as proficient
catalysts and reagents for many important organic reactions.8
More importantly, alumina is eco-friendly and inexpensive.
Despite the available procedures we, therefore, decided to use
to rapidly assemble three or more reactants and converting them
into higher molecular weight compound in one-pot, have become
a powerful synthetic strategy in recent years.1 The synthetic utility
of such protocols is further made more attractive when the reac-
tions are carried out in aqueous medium.
the
c-alumina and improve further the existing methodologies
Pyrano[2,3-c]pyrazoles constitute one of the privileged hetero-
cyclic scaffolds known to exhibit important biological activities,
such as analgesic,2a anti-tumor, anti-cancer,2b anti-inflammatory
properties2c and also serve as potential inhibitors of human Chk1
kinase.3 Furthermore, heterocyclic compounds bearing 4H-pyran
units have played increasing roles in synthetic strategies to prom-
ising compounds in the field of medicinal chemistry.4 Junek and
Aigner5 first established the synthesis of pyrano[2,3-c]pyrazole
derivatives from 3-methyl-1-phenylpyrazolin-5-one and tetracya-
noethylene in the presence of triethylamine. Later on, a number of
synthetic approaches have also been made for the synthesis
pertaining to the synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitriles.
Thus, in conjunction with our continued research aimed at the
development of environmentally benign synthetic methodologies
using solid-support catalysts,9 we report herein the four-
component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-
dihy-dropyrano[2,3-c]pyrazole-5-carbonitriles using c-alumina as
catalyst in water (Scheme 1).
In continuation of this method, we further carried out a
comparative catalytic efficacy of -alumina, basic alumina and
c
potassium fluoride loaded alumina (KF-alumina) with selected
of
6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazoles
aldehydes for the same synthesis.
employing triethylamine,6a,6b piperazine6c and piperidine6d as
prominent catalysts. However, these syntheses have been achieved
through a two-component or three-component reaction except for
the works reported by Vasuki et al.6d and Gogoi and Zhao 7 where a
four-component synthesis has been accomplished. Although, the
reported methods are effective, they are confronted with certain
drawbacks of environment compatibility by the use of toxic and
expensive catalysts,6,7a which also lack recyclability.
NH2
NH2.H2O
R1
O
2
γ-alumina (30 mol%)
CN
CN
CN
O
+
R1
HN
O
O
1
H2O, reflux
N
NH2
4
5 a-t)
(
H
O
3
(61-90%)
⇑
Corresponding author. Tel.: +91 364 272 2612; fax: +91 364 255 0076.
E-mail address: bmyrboh@nehu.ac.in (B. Myrboh).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.036

2524
H. Mecadon et al. / Tetrahedron Letters 52 (2011) 2523–2525
Initially, the one-pot synthesis was optimized by heating a mix-
ture of ethyl acetoacetate (1) (2.0 mmol), hydrazine hydrate (2)
(2.5 mmol), 4-chlorobenzaldehyde (3e) (2.0 mmol) and malononit-
such as 2-nitrobenzaldehyde, 3-nitrobenzaldehyde and 4-nitro-
benzaldehyde (entries 10–12, Table 2).
Similarly, the scope of this methodology was extended to poly-
nuclear aldehydes such as 1-naphthaldehyde and 9-anthraldehyde.
In each case, the reaction underwent smoothly resulting in similar
good yields (products 5q and r, entries 17 and 18, Table 2). The
methodology was also found to be effective for the aliphatic alde-
hydes. Thus, butyraldehyde (3s) and propionaldehyde (3t) reacted
cleanly with substrates 1, 2 and 4 to give 6-amino-4-alkyl-3-
methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles 5s and t
in 83% and 70% yields, respectively (entries 19 and 20, Table 2).
The products obtained were fully characterized by 1H, 13C NMR,
IR, mass spectral and elemental analyses.13
rile (4) (2.0 mmol) in the presence of
c-alumina (10 mol %) in
water (10 mL) for 35 min which afforded 5e in 60% yield. The same
reaction when carried out with 15 mol % of the catalyst gave 5e
with an increased yield (71%). Thus, by varying the amount of
c
-alumina, optimization was arrived at 30 mol % which signifi-
cantly resulted in 90% yield of the product 5e (Table 1). In another
attempt, the catalyst recovered from the reaction after filtration
and washing with boiling ethyl acetate was used further for the
condensation of ethyl acetoacetate (1) (2.0 mmol), hydrazine hy-
drate (2) (2.5 mmol), 4-chlorobenzaldehyde (3e) (2.0 mmol) and
malononitrile (4) (2.0 mmol). Interestingly, the reaction was
observed to complete within 45 min giving 6e in 80% yield. The
recyclability of the catalyst and the results are shown in Table 1.
Subsequently, a series of 6-amino-4-aryl-3-methyl-2,4-dihy-
dropyrano[2,3-c]pyrazole-5-carbonitriles were prepared in the
Next, a comparative catalytic efficiency of
c-alumina, basic
alumina and KF-alumina for the synthesis of 5 was examined by
executing a series of reactions using 30 mol % each of the catalysts
with reference to the optimized reaction condition. It was observed
that the reactions performed with basic alumina exhibited low effi-
ciency with most of the products requiring column chromatogra-
phy purification. KF-alumina catalyzed reactions in ethanol as
solvent, on the other hand, did show comparable efficiency with
presence of
c-alumina (30 mol %) involving different aldehydes
after simple work-up and purification (5a–p, Table 2).12 Irrespec-
tive of the presence of electron withdrawing or donating substitu-
ents in the ortho, meta or para positions on the ring of various
aromatic aldehydes the reactions proceeded smoothly to furnish
the desired products in good yields (5a–p). Also, high yields of
the products were obtained for the electron poor benzaldehydes,
maximum yields almost equivalent to
tions (Table 3). The comparative catalytic activity was found to dis-
play an order of -alumina > KF-alumina > basic alumina in the
reaction. Here, the higher catalytic activity of -alumina may be
c-alumina catalyzed reac-
c
c
attributed to its amphoteric nature and the surface area available
for greater adsorption of the reactants on its surface.
Table 1
Notably, reactions in the presence of c-alumina catalyst were
Optimization of the reaction condition and the catalyst recyclability with compound
clean and all the products were obtained after simple filtration
and purification by recrystallization from ethanol and water except
for 5c, h, i and m (entries 3, 8, 9 and 13, Table 2) which were puri-
fied by column chromatography. The spectral study revealed the
formation of two enantiomers and the combined yields of the race-
mates are summarized in Table 2.
Although there is ambiguity on the reaction mechanism, we
presume that the formation of 6-amino-4-alkyl/aryl-3-methyl-
2,4-dihy-dropyrano[2,3-c]pyrazole-5-carbonitriles takes place
through a tandem Michael addition and Thorpe-Ziegler reaction
as described in earlier reports.6d,7 The amphoteric nature and high
5e
Entry
Reaction conditions
Yielda (%)
1
2
3
4
5
6
7
8
c
c
c
c
c
c
c
c
-Alumina (10 mol %), 35 min, refluxed
-Alumina (15 mol %), 35 min, refluxed
-Alumina (25 mol %), 35 min, refluxed
-Alumina (30 mol %), 35 min, refluxed
-Alumina (35 mol %), 35 min, refluxed
-Alumina (recycled once), 45 min, refluxed
-alumina (recycled twice), 60 min, refluxed
-alumina (recycled three times), 90 min, refluxed
60
71
83
90
89
80
50
20
a
Isolated yields.
surface area of c-alumina allow compound 6 to adsorb on its sur-
face10 to give complex 8c (steps-B–D) which facilitates Michael
addition of 8c to compound 7 giving intermediate 9 (step-E). Sub-
sequently, the Thorpe-Ziegler like intramolecular cyclization fol-
lowed by tautomerization affords product 5 (Scheme 2).
In summary, we have devised a green and facile method for
the synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyra-
Table 2
Synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-car-
bonitriles via Scheme 1
Entry
Substrate 3 (R1)
Product
5
Time
(min)
Yielda
(%)
Mpc (oC)
244–2466c
206–2086d
210-2126c
145–147
no[2,3-c]pyrazole-5-carbonitriles using c-alumina as the recycla-
ble catalyst and water as the solvent. A comparative study of
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
C6H5
5a
5b
5cb
5d
5e
5f
5g
5hb
5ib
5j
50
45
60
55
35
40
40
75
90
60
45
40
70
70
70
60
55
60
55
60
80
82
79
80
90
84
90
74
61
72
75
85
75
73
80
81
79
85
83
70
4-CH3C6H4
4-CH3OC6H4
2-ClC6H4
4-ClC6H4
3-BrC6H4
Table 3
234–2366c
222–2246b
178-18011
224–2266c
167–16911
220–222
Comparative study of
c-alumina, basic alumina and KF-alumina catalyst for the
synthesis of 5
4-BrC6H4
4-HOC6H4
Entry Product 5 Time (min)
Yielda (%)
4-N(CH3)2C6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
3-CH3O-4-HOC6H3
2,5-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
1-Naphthyl
9-Anthranyl
Butyryl
c
-Alumina Basic alumina KF-alumina
5k
5l
193-19511
251–2536c
235–2376c
210–212
1
2
3
4
5
6
7
8
9
5a
5b
5c
5e
5h
5k
5l
5m
5q
5r
50
45
60
35
75
45
70
70
55
60
70
80
70
77
75
80
82
79b
90
5mb
5n
5o
5p
5q
5r
73b
83
75b
88
192–1946d
209–2116d
200–202
74b
75
61b
70b
60b
67b
71b
72b
78
64b
71b
70
85
75b
79
72b
74
206–208
5s
5t
143–145
Propionyl
130–1326d
10
11
85
83
78
78
5s
a
b
c
Isolated yields.
Purified by column chromatography.
Literature references.
a
Isolated yields.
Purified by column chromatography.
b

H. Mecadon et al. / Tetrahedron Letters 52 (2011) 2523–2525
2525
R1
R1
O
CN
CN
N
Al2O3
Al2O3
N
O
NH2
+
+
+
HN
+
HN
NH2.H2O
H
Step-B
O
O
Step-A
NC CN
O
O
1
2
3
4
6
7
Al
8a
Step-C
R1
R1
O
R1
H
CN
CN
CN
NH2
CN
CN
N
N
HN
N
HN
HN
H
Step-F
Step-E
Step-D
N
N
H
O
O
O
5
9
Al
8c
Al
8b
Step-F = 1. cyclization, 2. tautomerization.
Scheme 2. Proposed mechanism for the formation of pyrano[2,3-c]pyrazoles.
7. Gogoi, S.; Zhao, C.-G. Tetrahedron Lett. 2009, 50, 2252.
c
-alumina, basic alumina and KF-alumina with the c-alumina
8. (a) Sánchez-Valente, J.; Hernández-Beltrán, F.; Guzmán-Castillo, M. L.; Fripiat, J.
J.; Bokhimi, X. J. Mater. Res. 2004, 19, 1499; (b) Keshavarz, A. R.; Rezaei, M.;
Yaripour, F. Power Tech. 2010, 199, 176; (c) Ionescu, A.; Allouche, A.; Jean-
Pierre, A. J. Phys. Chem. B 2002, 106, 9359; (d) Maggi, R.; Ballini, R.; Giovanni, S.;
Raffaella, S. Tetrahedron Lett. 2004, 45, 2297; (e) Blass, B. E. Tetrahedron 2002,
58, 9301. and the references cited therein..
displaying greater catalytic activity has also been shown. More
importantly, the present procedure offers mild, efficient and envi-
ronmentally benign strategy by the use of c-alumina which over-
comes the drawbacks of the reported methods.
9. (a) Mizar, P.; Myrboh, B. Tetrahedron Lett. 2008, 49, 5283; (b) Mizar, P.; Myrboh,
B. Tetrahedron Lett. 2009, 50, 3088; (c) Rohman, M. R.; Myrboh, B. Tetrahedron
Lett. 2010, 51, 4772.
Acknowledgments
10. Hasni, M.; Prado, G.; Rouchaud, J.; Grange, P.; Devillers, M.; Delsarte, S. J. Mol.
Catal. A 2006, 247, 116.
11. Kanagaraj, K.; Pitchumani, K. Tetrahedron Lett. 2010, 51, 3312.
12. General experimental procedure for the synthesis of 6-amino-4-alkyl/aryl-3-
H.M. thanks the UGC-India for the research fellowship under
the RGNF scheme. The authors thank the SAIF North-Eastern Hill
University for the spectral analyses.
methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles (5): To
a pre-stirred
mixture of ethyl acetoacetate (1) (0.26 mL, 2.0 mmol) hydrazine hydrate (2)
(0.13 mL, 2.5 mmol) in water (10 mL) was added aldehydes (3) (2.0 mmol) and
Supplementary data
malononitrile (4) (0.13 g, 2.0 mmol) followed by pre-calcinated
c-alumina
(30 mol %). The reaction mixture was then heated at 100 °C and allowed to stir
for 35–90 min. On completion of the reaction (monitored by TLC), it was cooled
and water was evaporated in vacuo. The residue was treated with boiling
Supplementary data (spectroscopic analytical data, 1H, 13C NMR
and mass spectra) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2011.03.036.
methanol–ethyl acetate (1:1) and filtered through
a sintered funnel and
washed thoroughly with the same solvent. The combined filtrate was
evaporated in vacuo to afford the crude product which was recrystallized
from ethanol/water (9.5:0.5), or purified by column chromatography over silica
gel (100–200 mesh) using methanol/dichloromethane (2:8) as the eluent to
afford pure compound 5.
Same procedure was followed for the reactions when basic alumina and
KF-alumina (30 mol %) were used as catalysts during the comparative
study.
References and notes
1. (a) Eilbracht, P.; Bärfacker, L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon, B. E.;
Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schimdt, A. Chem. Rev. 1999, 99,
3329; (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2009, 39, 3168; (c) Kappe, C.
O. Acc. Chem. Res. 2000, 33, 879.
2. (a) Kuo, S. C.; Huang, L. J.; Nakamura, H. J. Med. Chem. 1984, 27, 539; (b) Wang, J.
L.; Liu, D.; Zheng, Z. J.; Shan, S.; Han, X.; Srinivasula, S. M.; Croce, C. M.; Alnemri,
E. S.; Huang, Z. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7124; (c) Zaki, M. E. A.;
Soliman, H. A.; Hiekal, O. A.; Rashad, A. E. Z. Naturforsch., C 2006, 61, 1.
3. Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.; Robertson, A. G. S.; Surgenor, A.
E. Bioorg. Med. Chem. 2006, 14, 4792.
4. (a) Stachulski, A. V.; Berry, N. G.; Lilian Low, A. C.; Moores, S. L.; Row, E.;
Warhurst, D. C.; Adagu, I. S.; Rossignol, J. F. J. Med. Chem. 2006, 49, 1450; (b)
Sun, W.; Cama, L. J.; Birzin, E. T.; Warrier, S.; Locco, L.; Mosely, R.; Hammond, M.
L.; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2006, 16, 1468; (c) Elinson, M. N.;
Dorofeev, A. S.; Feducovich, S. K.; Gorbunov, S. V.; Nasybullin, R. F.; Stepanov, N.
O.; Nikishin, G. I. Tetrahedron Lett. 2006, 47, 7629.
13. Spectroscopic data for compound (5k): yellowish solid; IR mmax (KBr): 1076,
1169, 1348, 1407, 1527, 1600, 1653, 2196, 2932, 3118, 3217, 3469 cmÀ1 1H
;
NMR (400 MHz, (CD3)2CO): d (ppm) 1.92 (s, 3H, CH3), 4.79 (s, 1H, 4H), 6.20 (s,
2H, NH2), 7.55 (t, 1H, J = 8.0 Hz, Ar–H), 7.62 (d, 1H, J = 7.6 Hz, Ar–H), 8.00–8.03
(m, 2H, Ar–H), 11.34 (s, 1H, NH); 13C NMR (100 MHz, CDCl3 + DMSO-d6): d
(ppm) 9.70, 29.0, 56.5, 112.6, 120.2, 123.2, 128.4, 128.6, 135.7, 141.3, 146.3,
151.3, 154.6, 160.9; MS (ES+) calcd for C14H11N5O3 297.1 found m/z 297.9
(M+H)+, 319.9 (M+Na)+; CHN calcd for C14H11N5O3: C, 56.56; H, 3.73; N,
23.56%; found: C, 56.69; H, 3.69; N, 23.43% (Lit.).11 For compound (5s) yellow
solid; IR mmax (KBr): 1149, 1222, 1401, 1467, 1527, 1613, 2203, 2932,3120,
3190, 3390 cmÀ1 1H NMR (400 MHz, CDCl3 + DMSO-d6): d (ppm) 0.76–0.85
;
(m, 3H, CH3), 1.18–1.21 (m, 2H, CH2), 1.66–1.73 (m, 2H, CH2), 1.90 (s, 3H, CH3)
3.20–3.26 (m, 1H, 4H), 6.66 (s, 2H, NH2); 13C NMR (100 MHz, CDCl3 + DMSO-
d6): d (ppm) 9.8, 13.7, 19.8, 31.3, 36.5, 96.6, 112.8, 112.9, 139.5, 159.5, 171.5;
MS (ES+) calcd for C11H14N4O 218.1 found m/z 218.9 (M+H)+, 240.9 (M+Na)+;
CHN calcd for C11H14N4O: C, 60.53; H, 6.47; N, 25.67%; found: C, 60.41; H, 6.39;
N, 25.40%.
5. Junek, H.; Aigner, H. Chem. Ber. 1973, 106, 914.
6. (a) Sharanin Yu, A.; Sharanina, L. G.; Puzanova, V. V. Zh. Org. Khim. 1983, 19,
2609; (b) Sharanin, Y. A.; Sharanina, L. G.; Puzanova, V. V. J. Org. Chem. USSR
(Engl. Transl.) 1983, 221; (c) Peng, Y.; Song, G.; Dou, R. Green Chem. 2006, 8, 573;
(d) Vasuki, G.; Kumaravel, K. Tetrahedron Lett. 2008, 49, 5636.