L-Proline as an efficicent catalyst for the multi-component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles in water

Article abstract of DOI:10.1016/j.tetlet.2011.04.048

An efficient four-component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4- dihydropyrano[2,3-c]pyrazole-5-carbonitriles involving ethyl acetoacetate, hydrazine hydrate, malononitrile, and various aldehydes using l-proline (10 mol %) in water under mild reaction condition in excellent yields is established. A comparative study of l-proline with γ-alumina, basic alumina, and KF-alumina was also carried out. The generality and functional tolerance of this convergent and environmentally benign method is demonstrated.

Full text of DOI:10.1016/j.tetlet.2011.04.048

Tetrahedron Letters 52 (2011) 3228–3231
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
L-Proline as an efficicent catalyst for the multi-component synthesis
of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitriles in water
Hormi Mecadon, Md. Rumum Rohman, Iadeishisha Kharbangar, Badaker M. Laloo, Icydora Kharkongor,
⇑
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:
An efficient four-component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyra-
Received 1 February 2011
Revised 31 March 2011
Accepted 12 April 2011
Available online 18 April 2011
zole-5-carbonitriles involving ethyl acetoacetate, hydrazine hydrate, malononitrile, and various alde-
hydes using
established. A comparative study of
L
-proline (10 mol %) in water under mild reaction condition in excellent yields is
-proline with -alumina, basic alumina, and KF-alumina was also
L
c
carried out. The generality and functional tolerance of this convergent and environmentally benign
method is demonstrated.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Four-component reaction
L-Proline
Water
Environmentally benign
Multi-component reactions (MCRs) and improving the meth-
ods for multi-component reactions has been of considerable
interest in the current day research. As a one-pot reaction, MCRs
permit rapid access to combinatorial libraries of complex mole-
cules especially in drug discovery.1 The synthetic utility of such
protocols is, however, made more significant when the reactions
are carried out in water.
The synthesis of 4-H pyran unit bearing heterocyclic compounds
has been given much attention in the recent years as they constitute
important precursors to promising drugs in the field of medicinal
chemistry.2 Pyrano[2,3-c]pyrazoles are such heterocyles that have
shown analgesic,3a anti-tumor, anti-cancer,3b and anti-inflam
matory3c properties. Moreover, 4-(6-amino-2,4-dihydro-3,5-
dimethylpyrano[2,3-c]pyrazolol-4-yl)benzene-1,2-diol has been
reported as a potential inhibitor of human chk1 kinase.4 Junek
et al. 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.5a Gradually, a number
of methods have been developed for the synthesis of 6-amino-4-al-
kyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitr-
iles employing triethylamine,5a–d piperazine,5e and piperidine5f as
catalysts. Although, the reported methods are effective, they have
limited applicability by the use of toxic catalysts. Literature survey
also revealed the recent multi-component synthesis of 6-amino-4-al-
kyl/aryl-3-methyl- 2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitr-
iles catalyzed by cinchona alkaloid organocatalysts and per-6-
amino-b-cyclodextrin.6 Inspite of many reported methods for the
synthesis
of
6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyr-
ano[2,3-c]pyrazole-5-carbonitriles, the development of a new syn-
thetic strategy using easily accessible catalyst still attracts a lot of
attention because of the importance of these molecules especially
if they can overcome the drawbacks of some of the earlier
procedures.
Furthermore,
eco-friendly and proficient catalyst among the amino acids. The
versatile utility of -proline has been demonstrated by its appli-
L-proline has been reported to be an
L
cations in many important reactions and asymmetric transfor-
mations such as aldol,7 Michael,8 and Knoevenagel9 reactions.
Being amphoteric and soluble in water it can also facilitate
chemical transformations in concert, similar to enzymatic catal-
ysis.10 Moreover,
of its advantages, we have chosen
synthesize 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyr-
L
-proline is an inexpensive catalyst. In view
-proline as a catalyst to
L
ano[2,3-c]pyrazole-5-carbonitriles.
Therefore, as a part of our research aimed at the development
of synthetic methodologies using environmentally benign
catalysts through MCRs,11 we report herein, an alternative
protocol for the four-component synthesis of 6-amino-4-alkyl/
aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles
in the presence of
(Scheme 1).
L-proline (10 mol %) as a catalyst in water
⇑
Corresponding author. Tel.: +91 364 272 612; fax: +91 364 255 0076.
E-mail address: bmyrboh@nehu.ac.in (B. Myrboh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.048

H. Mecadon et al. / Tetrahedron Letters 52 (2011) 3228–3231
3229
Table 1
Further, this four-component condensation was also carried out
with selected aldehydes using -alumina, basic alumina, and
potassium fluoride loaded alumina (KF-alumina, 40% KF in Al2O3)
Optimization of the reaction condition for product 5a
c
Product
Reaction conditions
Yielda (%)
and the results compared with those obtained by using
as the catalyst.
As a preliminary test we investigated the conversion of a mix-
ture of ethyl acetoacetate (1) (2.0 mmol), hydrazine hydrate (2)
(2.5 mmol), benzaldehyde (3a) (2.0 mmol), and malononitrile (4)
L-proline
5a
5a
No catalyst, 1 h, reflux
0
50
L
L
L
L
L
-proline (5 mol %), 10 min, reflux
-proline (10 mol %), 10 min, reflux
-proline (15 mol %), 10 min, reflux
-proline (20 mol %), 20 min, reflux
-proline (10 mol %), 24 h, stirred at rt
5a
5a
5a
5a
90
91
86
10
(2.0 mmol) in water (4 mL) and refluxed in the presence of L-pro-
line (5 mol %) for 10 min which resulted in the formation of com-
pound 5a with 50% yield. However, when the same reaction was
refluxed with 10 mol % of the catalyst the yield significantly in-
creased to 90%. Optimization was finally arrived at 10 mol % when
not much variation in the yield was observed after increasing the
a
Isolated yields.
Table 2
Synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-car-
bonitriles via Scheme 1
amount of L-proline up to 20 mol % (Table 1). In another attempt,
when the reaction was carried out at room temperature, only a
trace amount of the product was formed. Similarly when the reac-
tion was refluxed without the catalyst the intermediates remain
unreacted even after prolonged heating.
Entry
Substrate 3 (R1)
Time (min)
Product 5c
Yielda (%)
1
2
3
4
5
6
7
8
C6H5
10
10
18
15
10
20
10
20
20
16
10
15
20
17
15
10
12
15
15
5a6b
5b6b
5c6b
5d6b
5e6b
5f5e
5g6b
5h6b
5i6b
5j
90
93
65b
92
94
75
92
85
68b
77
87
80
4-CH3C6H4
4-CH3O6H4
2-ClC6H4
4-ClC6H4
3-BrC6H4
The advantages and limitations of this methodology were inves-
tigated by reacting ethyl acetoacetate (1), hydrazine hydrate (2),
and malononitrile (4) with various substituted benzaldehydes (3)
to give 6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyra-
zole-5-carbonitriles (5a–p, Scheme 1).15 Irrespective of the pres-
ence of electron withdrawing or releasing substituents in the
ortho-, meta-, or para-positions, the reactions proceeded fairly well
and afforded the desired products in good to excellent yields (5a–
p, Table 1). Interestingly, electron poor benzaldehydes, such as 2-
nitrobenzaldehyde (3j), 3-nitrobenzaldehyde (3k), and 4-nitro-
benzaldehyde (3l) also furnished 6-amino-4-aryl-3-methyl-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitriles (5j-l) in high yields
(entries 10–12, Table 2).
4-BrC6H4
4-HOC6H4
9
4-N(CH3)2C6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
3-CH3O-4-HOC6H3
3,4-(CH3O)2C6H3
2,5-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
1-Naphthyl
9-Anthranyl
Butyryl
10
11
12
13
14
15
16
17
18
19
5k6b
5l6b
5m5e
5n
5o
5p
5q
5r
5s
b
76
81
87
81
80
87
69b
Similarly, the scope of this methodology was further extended to
the reaction of polynuclear aromatic aldehydes such as 1-naphthal-
dehyde (3q) and 9-anthraldehyde (3r) with 1, 2, and 4. In each case
the reaction underwent smoothly resulting in similar good yields
(products 5q and r, Table 2). The present protocol was also found
to be effective for the aliphatic aldehydes. Thus, butyraldehyde
(3s) reacted cleanly with substrates 1, 2, and 4 to give 6-
amino-4-butyranyl-3-methyl-2,4-dihydropyrano[2,3- c]pyrazole-
5-carbonitrile (5s) in 69% yield (entry 19, Table 2). All the products
obtained were fully characterized by 1H NMR, 13C NMR, IR, Mass
spectral, and elemental analyses.16
Notably, the reactions were clean and all the products were ob-
tained after filtration and washing with water and purification by
crystallization from ethanol and water except for 5c, 5i, 5m, and
5s which were purified by column chromatography. The yields of
the products are summarized in Table 2.
a
b
c
Isolated yields.
Purified by column chromatography.
Literature reference.
Table 3
Comparative study of L-proline,
the synthesis of 5 in water
c
-alumina, basic alumia, and KF-alumina catalysts for
Yielda (%)
Product Time (min)
c
-
Basic alumina KF-
alumina
L
-
Alumina
Proline
5a
5b
5c
5d
5e
5g
5h
5k
5n
5p
10
10
18
15
10
10
20
10
17
10
90
93
65b
92
94
92
85
87
81
81
55b
50b
42b
67
46b
45b
45b
60
40b
45b
30b
59
57b
62
55b
57b
62
52b
41
It is important to highlight that, the compounds 5a, 5d, 5g, and
5h were obtained by Nagarajan and Reddy from a neat four-com-
ponent reaction in 48–66% yields,12 whereas the present method
afforded the same compounds in 85–92%, which indicates that
our protocol is effective in comparison to some of the earlier re-
ported methods.
67
64
68
60
51b
37b
49b
46b
60b
58
51b
a
Isolated yields.
Purified by column chromatography.
b
Next, the same four-component condensation was carried out
replacing
L-proline with
c-alumina, basic alumina, and KF-alumina
(40% KF in Al2O3) for the comparative catalytic efficiency by
executing a series of reactions using 10 mol % each of the catalysts
keeping other parameters constant. It was observed that the
H2N NH2.H2O
O
2
R1
N
L-proline (10 mol%)
R1
H
reactions performed with c-alumina exhibited low efficiency with
+
N
O
N
HN
H2O, 10-20 min,
reflux
most of the products isolated in low yields (Table 3). On the other
hand, the basic alumina and KF-alumina catalyzed reactions
require column chromatography purification for most of the
products besides affording poor yields (Table 3). The comparative
3
N
4
O
NH2
O
O
5
1
Scheme 1.
catalytic activity was found to display an order: L-proline > c-alu-

3230
H. Mecadon et al. / Tetrahedron Letters 52 (2011) 3228–3231
Table 4
formation of enolate 10. Subsequent deprotonation and attack on
the Knoevenagel moiety 7 gives the Michael adduct 1113 which fi-
nally undergoes Thorpe–Ziegler type intramolecular cycliza-
tion5f,6a,14 followed by tautomerization to afford the product 5
(Scheme 2).
In summary, we have established the use of L-proline (10 mol %)
as a catalyst for the four-component synthesis of 6-amino-4-alkyl/
aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles
Three-component synthesis of 5 using L-proline or KF-alumina in ethanol
L-proline (10 mol%)
or
N
N
O
R1
4
N
O
KF-alumina
R1
H
HN
+
N
H
N
O
5
NH2
Ethanol, 10-30 min,
reflux
3
N
in water. A comparison of the catalytic efficiency of
alumina, basic alumina, and KF-alumina with the -proline exhibit-
ing greater activity has also been demonstrated. On the other hand,
KF-alumina also exhibited equally good catalytic activity as -pro-
L-proline, c-
L
6
L
line when the reaction was carried out in three-component fashion
in ethanol. On the whole, the work presented here is significant in
terms of yield, cost effectiveness, and eco-friendliness thus over-
coming drawbacks of some earlier procedures.
Product
Time (min)
Yielda (%)
KF-alumina
KF-alumina
L
-Proline
L
-Proline
5a
5b
5c
5e
5h
5k
5l
5m
5q
5r
10
10
20
10
20
18
15
20
15
12
12
15
25
10
30
30
20
20
16
18
87
90
63b
90
79
80
82
76b
81
90
80
87
Acknowledgments
61b
88
71b
76b
79
The authors thank the SAIF-NEHU for the spectral analyses.
H.M. thanks the UGC-India for the financial assistance under the
RGNF scheme.
72b
76
84b
Supplementary data
a
Isolated yields.
Purified by column chromatography.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.048.
b
References and notes
mina > basic alumina > KF-Alumina. Here, the higher catalytic
activity of -proline may be attributed to its water solubility and
L
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N.; Mondon, M.; Charbit, S.; Ficheux, H.; Schutze, F. U. S. Patent 2005, 6, 965,
039 B2.
amphoteric nature. The detailed comparative study of the catalysts
is summarized in Table 3.
In the study of catalytic activity in different solvents, we ob-
served that KF-alumina was most effective when the reaction is
three-component and ethanol was used as the solvent. Also, paral-
3. (a) Kuo, S. C.; Huang, L. J.; Nakamura, H. J. Med. Chem. 1984, 27, 539; (b) Wang, J.
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Sharanina, L. G.; Puzanova, V. V. Zh. Org. Khim. 1983, 19, 2609; (c) Sharanin, Yu.
A.; Sharanina, L. G.; Puzanova, V. V. J. Org. Chem. USSR (Engl. Transl.) 1983, 221;
(d) Al-Matar, H. M.; Khalil, K. D.; Adam, A. Y.; Elnagdi, M. H. Molecules 2010, 15,
6619; (e) Peng, Y.; Song, G.; Dou, R. Green Chem. 2006, 8, 573; (f) Vasuki, G.;
Kumaravel, K. Tetrahedron Lett. 2008, 49, 5636.
lel examination of both L-proline and KF-alumina as catalysts
(10 mol % each) in the condensation of readily available 3-
methyl-1H-pyrazol-5(4H)-one (6) with 3 and 4 in ethanol was
found to be equally competent with slight variation in time and
yields of the products (5) as shown in Table 4. In an attempt to re-
cover and reuse KF-alumina, we found that the recycled KF-alu-
mina (recycled after washing and drying) was not efficient
enough to further catalyze the reaction.
From the mechanistic point of view, it could be hypothesized
6. (a) Gogoi, S.; Zhao, C.-G. Tetrahedron Lett. 2009, 50, 2252; (b) Kanagaraj, K.;
Pitchumani, K. Tetrahedron Lett. 2010, 51, 3312.
that
L-proline, due to its amphoteric nature and high solubility,
ionizes in water to its Zwitter-ionic form 8 which facilitates the
N
O
N
H
H
O
O
HN
H
8
O
+
H2N NH2.H2O
O
O
O
N
N
H
6
O
H
1
2
H
N
O
9
O
R1
+
H
N
N
N
3
4
N
N
N
NH
R1
N
R1
O
R1
O
10
1. cyclization
2. tautomerization
7
H
HN
N
N
HN
O
NH2
N
H
N
O
5
11
O
Scheme 2. Proposed mechanism for the formation of 5.

H. Mecadon et al. / Tetrahedron Letters 52 (2011) 3228–3231
3231
7. He, L.; Tang, Z.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. Tetrahedron 2006, 62,
346.
8. Meghana, S. R.; Mahesh, K. P.; Swapnil, S. M.; Manikrao, M. S. J. Mol. Catal. A.
2005, 235, 267.
9. Sabitha, G.; Kumar, M. R.; Reddy, M. S. K.; Yadav, J. S.; Krishna, K. V. S. R.;
Kunwar, A. C. Tetrahedron Lett. 2005, 46, 1659.
solvent. Work-up was carried out by filtering the reaction mass and washing
thoroughly the residue with boiling mixture of ethyl acetate and methanol
(7:3) followed by removal of the combined filtrate under vacuum to give the
crude mass, which was purified by crystallization or column chromatography
as mentioned above.
16. Spectroscopic data for compound 5j. Yellow solid (460 g, 77%). Mp 220–222 °C.
1H NMR (400 MHz, CD3OD): dH 1.86 (s, 3H, CH3), 5.26 (s, 1H, 4H), 7.34 (d, 1H,
J = 8.0 Hz, Ar-H,), 7.46 (t, 1H, J = 7.6 Hz, Ar-H,), 7.63 (t, 1H, J = 7.6 Hz, Ar-H), 7.81
(d, 1H, J = 8.0 Hz Ar-H) ppm; 13C NMR (100 MHz, CDCl3 + DMSO-d6): dC 10.2,
29.0, 56.0, 99.0, 118.0, 120.3, 128.1, 129.0, 130.4, 135.2, 138.2, 154.8, 161.2,
165.1 ppm; IR mmax (KBr): 1048, 1159, 1351, 1403, 1492, 1525, 1638, 2187,
2870, 2927, 2963, 3167, 3316, 3373, 3413 cmÀ1; 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, 56.35; H, 3.71; N, 23.64%. For compound
(5r): yellow solid (610 mg, 87%). Mp 206–208 °C. 1H NMR (400 MHz,
CDCl3 + DMSO-d6): dH 1.43 (s, 3H, CH3), 5.96 (s, 2H, NH2), 6.27 (s, 1H, 4H),
7.49–7.52 (m, 3H, Ar-H), 7.93–8.09 (m, 3H, Ar-H), 8.40–8.50 (m, 2H, Ar-H), 8.67
(s, 1H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3 + DMSO-d6): dC 9.3, 29.2, 58.9,
98.2, 116.8, 120.1, 122.5, 124.1, 124.2, 124.4, 124.6, 126.2, 127.6, 129.0, 129.1,
130.4, 131.5, 135.6, 154.5, 160.4 ppm; IR mmax (KBr): 1069, 1394, 1487, 1600,
1639, 2190, 2925, 3040, 3118, 3184, 3317 cmÀ1; MS (ES+) calcd for C22H16N4O
352.1 found m/z 353.0 (M+H)+, 375.0 (M+Na)+; CHN calcd for C22H16N4O: C,
74.98; H, 4.58; N, 15.90%; found: C, 74.71; H, 4.72; N, 15.80%. For compound
(5s): yellow solid (300 mg, 69%). Mp 143–145 °C. 1H NMR (400 MHz,
CDCl3 + DMSO-d6): dH 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)
ppm; 13C NMR (100 MHz, CDCl3 + DMSO-d6): dC 9.8, 13.7, 19.8, 31.3, 36.5, 96.6,
112.8, 112.9, 139.5, 159.5, 171.5 ppm; IR mmax (KBr): 1149, 1222, 1401, 1467,
1527, 1613, 2203, 2932,3120, 3190, 3390 cmÀ1; 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.
10. List, B. Tetrahedron 2002, 58, 5573.
11. (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
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12. Nagarajan, A. S.; Reddy, B. S. R. Synlett 2002, 2009.
13. We thank the referee for suggesting this mechanism.
14. Gou, S.-B.; Wang, S. –X.; Li, J. –T. Synth. Commun. 2007, 37, 2111.
15. General experimental procedure for the synthesis of 6-amino-4-alkyl/aryl-3-
methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles (5). Method A: to
pre-stirred mixture of ethyl acetoacetate (1) (0.26 mL, 2.0 mmol), hydrazine
hydrate (2) (0.13 mL, 2.5 mmol) in water (4 mL) was added aldehydes (3)
a
(2.0 mmol) and malononitrile (4) (0.13 g, 2.0 mmol) followed by L-proline
(10 mol %). The reaction mixture was then refluxed for 10–20 min. On
completion of the reaction (monitored by TLC), it was cooled. The solid mass
was filtered through a sintered funnel and washed thoroughly with water. The
crude residue was crystallized 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.
The same procedure was followed when
c-alumina, basic alumina, and KF-
alumina were employed as catalysts. On completion of the reaction (monitored
by TLC), water was evaporated in vacuo. Work-up was carried out after diluting
the residue with boiling mixture of ethyl acetate and methanol (7:3) and
filtering off the catalyst followed by removal of the combined filtrate to give
the crude mass and purified by crystallization or column chromatography as
mentioned above.
Method B: method A was followed except for the ethanol (4 mL) used as