Synergetic effects of naturally sourced metal oxides in organic synthesis: a greener approach for the synthesis of pyrano[2,3-c]pyrazoles and pyrazolyl-4H-chromenes

Article abstract of DOI:10.1007/s11164-017-3197-8

Abstract: A clean and more economic protocol for the synthesis of pyrano[2,3-c]pyrazoles and pyrazolyl-4H-chromenes has been carried out using bael fruit ash (BFA) as a non-conventional natural catalyst in aqueous condition at ambient temperature. The catalyst was obtained from renewable resources by simple thermal treatment to dry rind of Aegle marmelos (Bael) fruit and formation of its active phase was confirmed by AAS, DSC-TGA, XRD, FT-IR, and SEM techniques. The BFA catalyst was found to be a green, highly active, easily biodegradable, and recyclable without loss of activity after the fifth run. The methodology provides an alternative platform to the conventional catalyzed process. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-017-3197-8

Res Chem Intermed
https://doi.org/10.1007/s11164-017-3197-8
Synergetic effects of naturally sourced metal oxides
in organic synthesis: a greener approach
for the synthesis of pyrano[2,3-c]pyrazoles
and pyrazolyl-4H-chromenes
Sachin K. Shinde1 Megha U. Patil1 Shashikant A. Damate1
Suresh S. Patil1
•
•
•
Received: 10 May 2017 / Accepted: 4 November 2017
Ó Springer Science+Business Media B.V., part of Springer Nature 2017
Abstract A clean and more economic protocol for the synthesis of pyrano[2,3-
c]pyrazoles and pyrazolyl-4H-chromenes has been carried out using bael fruit ash (BFA)
as a non-conventional natural catalyst in aqueous condition at ambient temperature. The
catalyst was obtained from renewable resources by simple thermal treatment to dry rind
of Aegle marmelos (Bael) fruit and formation of its active phase was confirmed by AAS,
DSC-TGA, XRD, FT-IR, and SEM techniques. The BFA catalyst was found to be a
green, highly active, easily biodegradable, and recyclable without loss of activity after
the fifth run. The methodology provides an alternative platform to the conventional
catalyzed process.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11164-
017-3197-8) contains supplementary material, which is available to authorized users.
&
Suresh S. Patil
sanyujapatil@yahoo.com
1
Synthetic Research Laboratory, PG Department of Chemistry, PDVP College, Affiliated to
Shivaji University, Kolhapur, Tasgaon, Dist-Sangli, MS 416312, India
123

S. K. Shinde et al.
Graphical Abstract
Keywords Pyrano[2,3-c]pyrazoles Á Pyrazolyl-4H-chromenes Á Multi-component
reactions Á Natural catalyst Á Aqueous medium Á Green chemistry
Introduction
The development of green and efficient chemical processes or methodologies such
as reaction in aqueous media, multi-component reactions (MCR) and reusable
catalysts-performed reactions for the synthesis of biologically active compounds is
one of the major challenges for chemists. These advantages comply with the
principles of green chemistry in terms of simplicity and synthetic efficiency over
conventional chemical reactions [1–3]. Functionalized pyrano[2,3-c]pyrazoles are
an important class of N-heterocycles because the core fragment is constituted by a
great variety of natural products and biologically active compounds. The synthesis
of pyrano[2,3-c]pyrazole and their derivatives have attracted much attention from
organic chemists due to their many pharmacological properties including anticancer
[4], antimicrobial [5], anti-inflammatory [6], insecticidal, and molluscicidal
activities [7], and are potential inhibitors of human Chk1 kinase [8].
A review of the literature revealed that Junek and Aigner first established the
synthesis of pyrano[2,3-c]pyrazole derivatives from 3-methyl-1-phenylpyrazolin-5-
one and tetracyanoethylene in the presence of triethylamine [9]. Wamhoff et al. [10]
synthesized various 6-amino-5-cyano-4-aryl-4H-pyrazolo[3,4-b]pyrans by the reac-
tion of arylidienemalononitrile with 3-methyl-pyrazoline-5-ones or by the conden-
sation of 4-arylidienepyrazoline-5-one with malononitrile. Sharanin et al. [11] have
123

Synergetic effects of naturally sourced metal oxides in…
developed a three-component reaction between pyrazolone, an aldehyde and
malononitrile in ethanol using triethylamine as the catalyst. Shestopalov et al. [12]
reported the synthesis of pyranopyrazoles via three-component condensation of
N-methylpiperidone, pyrazolin-5-one and malononitrile by a chemical as well as an
electrochemical method. Peng et al. [13] have reported a flash synthesis of 4H-
pyrano[2,3-c]pyrazoles in aqueous media under combined microwave and ultra-
sound irradiation. More recently, the highly functionalized pyrano[2,3-c]pyrazoles
were reported using a variety of reagents, such as a piperidine [14], glycine [15], L-
proline [16], imidazole [17], heteropolyacid [18], per-6-amino-b-cyclodextrin [19],
nanosized magnesium oxide [20], ionic liquid (IL) [21], silica-bonded n-propy-
lpiperazine sodium n-propionate [22], silica-bonded n-propyltriethylene-tetramine
[23], silica-grafted n-propyl-imidazolium hydrogen sulfate [(Sipim)HSO4] [24],
silica-bonded n-propylimidazolium chloride [(Sipim)Cl] [25] and Mg/Al hydrotal-
cite [26], bovine serum albumin (BSA) [27], Citrus limon (lemon juice) [28], IL-
[DMDBSI]2HSO4 [29], and magnetized water [30].
Surprisingly, only one method has been reported for the synthesis of 4-pyrazolyl-
4H-chromenes by a four-component reaction of hydrazine hydrate, ethyl acetoac-
etate, 2-hydroxybenzaldehyde and malononitrile in water [31]. This method is only
compatible with salicylaldehydes. However, despite the potential utility of the
methods published so far, they exhibit varying degrees of success as well as
limitations such as harsh reaction conditions, cost of the catalyst, long reaction
times, lack of catalyst recovery, and tedious reaction work-ups.
Performing organic reactions in water has attracted much attention over the past
decades due to its numerous advantages such as being considerably safe, non-toxic,
environmentally friendly, and cheap [32–34]. Nowadays, biosynthetic processes
involving bio-based catalysts have received much attention as viable alternatives for
the development of green protocols for organic transformations [35–39]. In this
regard, naturally sourced catalysts as part of the chemical process offer excellent
alternatives to chemically generated catalysts in being more environmentally
friendly technologies due to their ease of biodegradability, ability to act as catalysts,
low toxicity, and non-flammable properties. Again, due to their high natural
abundance, their production is potentially less expensive.
Therefore, the aim of the present work is to explore the synthetic utility of
naturally sourced catalysts in organic transformations. A plant, Aegle marmelos
(Linn.) Correa ex Roxb, belongs to the family Rutaceae, is locally known as bael in
India, and known from pre-historic timed [40]. The bael tree has its origin in the
Eastern Ghats and Central India, and is also found in tropical and subtropical
regions of the world. Every part of the bael tree such as the fruit, seed, bark, leaf and
root has medicinal [41], therapeutic and traditionallimportance [42]. Physico-
chemical studies have revealed that bael fruit is rich in mineral and vitamin contents
[43, 44].
In view of the above, and as a part of our on-going research on the development
of natural catalysts for organic transformations [45–48], to the best of our
knowledge we report here for first time a naturally sourced, relatively mild, less
expensive, non-toxic, non-corrosive, and bio-degradable catalyst (BFA) for one-pot
four-component synthesis of pyrano[2,3-c]pyrazoles and 4-pyrazolyl-4H-chromenes
123

S. K. Shinde et al.
under aqueous conditions at ambient temperature (Scheme 1). A very simple
protocol was followed in the reaction process. This strategy also provides a high
yield and good recyclability of the catalyst.
Experimental
All chemicals were of reagent grade and procured from Sigma-Aldrich, and were
used without any further purification. Analytical thin-layer chromatography (TLC)
was carried out on precoated Merck silica gel 60 F254 aluminum plates. Melting
points were recorded on a DBK programmable melting point apparatus and are
uncorrected. IR spectra were obtained using potassium bromide pellets ona Bruker
1
ALPHA FT-IR spectrometer. The H NMR and 13C NMR spectra of synthesized
compounds were recorded on a Bruker AC (300 MHz for 1H NMR and 75 MHz for
13C NMR) spectrometer using CDCl3 and DMSO as solvent. Chemical shifts (d) are
expressed in parts per million (ppm) values with tetramethylsilane as the internal
reference and coupling constants are expressed in hertz (Hz). Mass spectra were
recorded on a Shimadzu QP2010 GCMS with an ion source temperature of 280 °C.
The pH of aqueous solutions of BFA were measured using a pH meter (Pro-Lab
3000 laboratory pH meter). A SHIMADZU AA-7000 atomic absorption spec-
trophotometer (AAS) was used for elemental analysis by the flame emission
method. Thermal gravimetric analysis (TGA) curves were obtained using a TA SDT
Q600 V20.9 Build 20 instrument in the presence of static air at a linear heating rate
of 10 °C min-1 from 25 to 1000 °C. XRD was taken using a Brucker D2 Phaser. It
˚
was obtained in reflection mode with Cu Ka radiation (k = 1.5418 A) at 30 kV,
10 mA, a scan speed of 1.0 ° min,-1 and a scan range of 10°–90°. The data was
analyzed in the 2h/° range from 2° to 70° with the scanning step of 0.5 per s.
A JEOL (Tokyo, Japan) JSM-5200 scanning electron microscope was used for SEM
analysis.
Synthesis of pyrano[2,3-c]pyrazoles (5)
In a 25-mL round-bottom flask, a mixture of hydrazine hydrate 1 (1 mmol), ethyl
aceto acetate 2 (1 mmol), aldehydes 3a–s (1 mmol) and, molanonitrile 4 (1 mmol)
O
O
R
OEt
CN
O
2
R
H2N
NH2
N
NH
H
+
R
OH
CN
CN
1
4
H
3a-s
O
OH
CN
BFA catalyst (10 wt. %)
6a-n
R
N
N
H
O
7a-n
NH2
NH2
O
5a-s
H2O, RT/Stirr
Scheme 1 BFA-catalyzed synthesis of functionalized pyrano[2,3-c]pyrazoles and 4-pyrazolyl-4H-
chromenes
123

Synergetic effects of naturally sourced metal oxides in…
was stirred at room temperature using the BFA catalyst 10 wt% in water (2 mL) for
certain time periods as indicated in Table 2 (see ‘‘Results and discussion‘‘). The
reaction was monitored by TLC (ethyl acetate: hexane 1:9) and after elusion the
Merck silica gel 60 F254 aluminium plates were visualized under UV light. After
completion of the reaction, the reaction mixture was subjected to solvent extraction
using ethyl acetate (4 9 10 mL). The combined organic phase was washed with
water and dried (Na2SO4), and the solvent was removed under reduced pressure to
afford a crude product. The pure products were obtained in good yields by
recrystallization from 96% ethyl alcohol without any use of further purification. The
physical and spectroscopic data are consistent with the proposed structure and in
harmony with the literature values [14–30]. Eight newly synthesized compounds
1
were ascertained on the basis of FT-IR, H NMR and 13C NMR spectroscopic
techniques.
Synthesis of 4-pyrazolyl-4H-chromene (7)
In a 25-mL round-bottom flask, a mixture of hydrazine hydrate 1 (1 mmol), ethyl
aceto acetate 2 (1 mmol), salicylaldehydes 6a–n (1 mmol) and molanonitrile 4
(1 mmol) was stirred at room temperature using the BFA catalyst 10 wt% in water
(2 mL) for certain time periods as indicated in Table 3 (see ‘‘Results and
discussion’’). The reaction was monitored by TLC (ethyl acetate: hexane 1:9) and
after elusion the Merck silica gel 60 F254 aluminium plates were visualized under
UV light. After completion of the reaction, the appropriate work-up from the
method above was used.
Analytical and spectral data of unreported compounds
6-Amino-4-[4-(diethoxymethyl)phenyl]-3-methyl-2,4-dihydropyrano[2,3-c]pyra
zole-5-carbonitrile (5j)
Pale yellow solid; MP (°C): 284–286; IR (KBr): 3498, 3390, 3106, 2961, 2183,
1
1648, 1618, 1510, 1302, 1100, 758 cm-1. H NMR (300 MHz, CDCl3 ? DMSO-
d6) dH: 1.11 (t, 6H CH3), 1.76 (s, 3H, CH3) 3.50 (m, 4H, CH2), 4.58 (s, 1H, CH),
5.43 (s, 1H, CH), 6.88 (s, 2H, NH2), 7.14 (d, 2H, J = 7.5 Hz, Ar–H), 7.32 (d, 2H,
J = 7.5 Hz, Ar–H), 12.10 (s, 1H, NH) ppm; 13C NMR (75 MHz, CDCl3 ? DMSO-
d6) dC: 9.81, 15.20, 36.01, 57.08 60.88, 97.60, 100.97, 120.86, 126.63, 127.24,
128.37, 130.02, 135.68, 137.76, 144.42, 154.77, 160.93 ppm; MS/EI m/z: 354.1
(M?).
6-Amino-4-(3-ethoxy-4-hydroxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile (5l)
Yellow solid; MP (°C): 192–194; IR (KBr): 3568, 3465, 3390, 3000, 2946, 2177,
1654, 1615, 1536, 1406, 1130 cm-1. 1H NMR (300 MHz, CDCl3 ? DMSO-d6) dH:
0.96 (t, 3H, J = 6.5 Hz, CH3) 1.94 (s, 3H, CH3), 3.65 (q, 3H, J = 6.5 Hz, CH2),
5.49 (s, 1H, CH), 6.62 (s, 2H, NH2), 6.72 (d, 1H, J = 2.1 Hz, Ar–H), 6.88 (d, 1H,
123

S. K. Shinde et al.
J = 8.2 Hz, Ar–H), 7.16 (dd, 1H, J = 8.2, 2.1 Hz, Ar–H), 9.43 (bs, 1H, OH), 12.14
(s, 1H, NH) ppm; 13C NMR (75 MHz, CDCl3 ? DMSO-d6) dC: 9.90, 14.80, 29.64,
35.84, 57.71, 63.93, 97.97, 113.11, 115.57, 119.88,135.41, 145.58, 146.43, 154.80,
160.73, 169.71 ppm; MS/EI m/z: 312.1 (M?).
6-Amino-4-(3-bromo-4-fluorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile (5n)
Brown solid; MP (°C): 224–226; IR (KBr): 3458, 3310, 3084, 2938, 2195, 1644,
1
1618, 1510, 1483, 1170 cm-1. H NMR (300 MHz, CDCl3 ? DMSO-d6) dH:1.79
(s, 3H, CH3), 4.67 (s, 1H, CH), 6.97 (s, 2H, NH2), 7.21 (dd, 1H, J = 8.5 Hz, Ar–H),
7.32 (dd, 1H, J = 8.5, 2.3 Hz, Ar–H), 7.48 (d, 1H, J = 2.3 Hz, Ar–H), 12.17 (s,
1H, NH) ppm; 13C NMR (75 MHz, CDCl3 ? DMSO-d6) dC: 9.82, 35.15, 56.44,
97.01, 115.81, 117.68, 120.68, 128.95, 132.18, 135.89, 142.76, 155.49, 158.72,
161.03 ppm; MS/EI m/z: 348.0 (M?).
6-Amino-4-(2-bromo-5-fluorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile (5q)
Yellow solid; MP (°C): 251–253; IR (KBr): 3464, 3326, 3104, 2942, 2184, 1654,
1
1608, 1505, 1443, 1158 cm-1. H NMR (300 MHz, CDCl3 ? DMSO-d6) dH:1.77
(s, 3H, CH3), 5.04 (s, 1H, CH), 7.02 (s, 2H, NH2), 7.06 (d, 1H, J = 2.1 Hz, Ar–H),
7.11 (dd, 1H, J = 8.2, 2.1 Hz, Ar–H), 7.63 (d, 1H, J = 8.2 Hz, Ar–H), 12.28 (s,
1H, NH) ppm; 13C NMR (75 MHz, CDCl3 ? DMSO-d6) dC: 9.72, 36.27, 55.26,
96.37, 116.33, 117.55, 120.28, 134.56, 135.61, 144.99, 154.91, 160.15, 161.42,
163.40 ppm; MS/EI m/z: 348.0 (M?).
4,40-(Thiophene-2,5-diyl)bis(6-amino-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile) 14
Brown solid; MP (°C): Above 310; IR (KBr): 3589, 3354, 3245, 2922, 2139, 1640,
1
1558, 1503, 1289, 973 cm-1. H NMR (300 MHz, excess DMSO-d6) dH: 1.72 (s,
3H, CH3), 2.02 (s, 3H, CH3), 4.55 (s, 1H, CH), 4.57 (s, 1H, CH), 6.85 (s, 1H, Ar–H),
6.96 (s, 1H, Ar–H), 7.09 (s, 4H, NH2), 12.11 (s, 2H, NH) ppm; 13C NMR (75 MHz,
CDCl3 ? DMSO-d6) dC: 9.73(2C), 11.01(2C), 35.96(2C), 57.14(2C), 97.77(2C),
120.86(2C), 126.70(2C), 126.69(2C), 135.65(2C), 142.80(2C), 154.72(2C),
160.90(2C) ppm; MS/EI m/z: 432.1 (M?).
2-Amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-8-methoxy-4H-chromene-3-
carbonitrile (7h)
White solid; MP (°C): IR (KBr): 3422, 3365, 2919, 2198, 1665, 1611, 1525, 1402,
1
1332, 1250 cm-1. H NMR (300 MHz, DMSO-d6) dH: 1.94 (s, 3H, CH3), 3.77 (s,
3H, OCH3), 4.58 (s, 1H, CH), 6.68 (s, 2H, NH2), 6.94 (d, 1H, J = 3.6 Hz, Ar–H),
7.13 (dd, 1H,J = 8, 0.8 Hz, Ar–H), 7.28 (t, 1H,J = 8 Hz Ar–H), 10.11 (br s, 1H,
NH), 10.88 (br s, 1H, OH)ppm; 13C NMR (75 MHz, DMSO-d6) dC: 162.84, 160.10,
123

Synergetic effects of naturally sourced metal oxides in…
146.74, 137.91, 136.52, 124.34, 123.95, 120.11, 118.37, 110.11, 105.02, 55.92,
54.95, 28.83, 9.94 ppm; MS/EI m/z: 299.11 (M?).
2-Amino-8-bromo-6-chloro-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-4H-chromene-
3-carbonitrile (7m)
White solid; MP (°C): 244–246; IR (KBr): 3455, 3333, 2917, 2190, 1658, 1609,
1
1520, 1412, 1402, 825 cm-1. H NMR (300 MHz, DMSO-d6) dH: 2.04 (s, 3H,
CH3), 4.65 (s, 1H, NH2), 6.90 (s, 2H), 7.00 (s, 1H Ar–H), 7.61 (s, 1H, Ar–H), 9.78
(br s, 1H, NH), 11. 31 (bs, 1H, OH) ppm; 13C NMR (75 MHz, DMSO-d6) dC:
159.51, 159.14, 144.68, 136.67, 130.41, 128.00, 127.91, 127.15, 120.22, 109.98,
104.33, 55.17, 29.43, 9.84 ppm; MS/EI m/z: 379.97 (M?).
3-Amino-1-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-1H-benzo[f]chromene-2-
carbonitrile (7n)
White solid, MP (°C): 232–234; IR (KBr): 3441, 3294, 3169, 2182, 1661, 1584,
1
1405, 1224, 1085, 807 cm-1; H NMR (300 MHz, DMSO-d6) dH: 1.87 (s, 3H
CH3), 5.05 (s, 1H, CH), 6.75 (s, 2H, NH2), 7.21 (d, 1H, J = 8.8 Hz), 7.49–7.38 (m,
2H, Ar–H),7.88 (d, 1H, J = 7.6 Hz, Ar–H), 7.92 (d, 1H, J = 8.4 Hz, Ar–H), 10.01
(br s, 1H, NH), 11.27 (br s, 1H, OH) ppm; 13C NMR (75 MHz, DMSO-d6) dC:
159.65, 158.2, 146.44, 130.68, 130.53, 128.80, 128.45, 126.88, 124.75, 123.38,
120.96, 116.57, 115.17, 105.29, 56.40, 26.73, 9.71 ppm; MS/EI m/z: 319.11 (M?).
Results and discussion
Preparation and characterization of the catalyst
Collected dry fruits of Aegle marmelos (Fig. 1a) were authenticated by the
Department of Botany. The rind of the dried fruits were (5.0 g) manually broken
into small pieces (Fig. 1b) and used for ashing. In each case, the small pieces of the
fruits were taken in a cleaned silica crucible and burned in open air, which resulted
in fine soft ash (3.2 g). This ash was named as the BFA catalyst (Fig. 1c). The
alkalinity of BFA in water was measured and was found to be strongly alkaline with
pH 12.8.
Fig. 1 a Dry bael fruit, b pieces of bael fruit, c ash of bael fruit (BFA catalyst)
123

S. K. Shinde et al.
AAS is a very common and reliable technique for detecting metals and
metalloids in environmental samples. Therefore, the presence of elements in BFA
was determined by flame AAS using a hot filtration test. Results shows that BFA
contains major content of K (30.5%) along with Ca (13.9%), Mg (2.82%)), Na (2%),
P (2.4%), S (0.41%)), Cl (0.08)), B (0.09%), with small amounts of transition metals
like Mn (0.042%), Fe (0.345%), Cu (0.012%), and Zn (0.05%).
Thermal stability of the prepared catalyst was investigated by using a DSC-TGA
thermal analyser. The TGA result (Fig. 2) shows the temperatures at which the BFA
decomposed when heated in a controlled environment to avoid any misleading
oxidation reactions at a given temperature rate. The temperature ranged from 0 to
1000 °C depicting the decomposition of ash. Three distinct stages of weight loss
were observed. In the first step, minor weight loss at temperatures below 89.90 °C
was 2.246% occurred due to the loss of adsorbed moisture. Another weight loss
occurred in the second step between 89.90 and 278.56 °C and was 8.188%,
reflecting the decomposition of organic compounds such as carotenoids, alkaloids,
pectins, tannins, flavonoids, terpenoids and chlorides. In the third step, the 9.187%
weight loss between temperature range of 626.61–746.66 °C was due to the
decomposition of metal carbonates. Finally, 65.957% weight of residue remaining
after the temperature of 985.05 °C was due to metal oxides and silica.
The phase composition of the BFA catalyst is evident from X-ray diffraction
analysis (Fig. 3). The XRD patterns of PBF displayed very broad peaks at
2h = 11.08°, 14.10°, 16.00°, 17.09°, 17.70°, 19.43°, and 20.56° suggesting the
Fig. 2 DSC-TGA curves of the BFA catalyst
123

Synergetic effects of naturally sourced metal oxides in…
Fig. 3 X-ray diffraction patterns of parent beal fruit (a) and BFA catalyst (b)
amorphous nature of these materials. After the thermal treatment, the peaks at
2h = 28.05°, 28.46°, 29.78°, 40.62°, 44.65°, 48.38°, 59.08° and 65.89° corre-
sponded to the characteristic patterns of the metal carbonates. The peaks appearing
at 2h = 32.34°, 33.37°, 33.99°,41.80°, 42.92°, 53.57°, 62.32° were characteristic of
metal oxides. Metal hydroxides was also observed at 2h = 13.31°, 19.43°, 20.56°
and 21.94°. Therefore, this active phase of the catalyst was utilized for the
conversion of the reactant into the product.
In the FT-IR spectrum of BFA (Fig. 4), the observation of absorption bands at
698, 870, 1458, 2516 cm-1 are the characteristic peaks of carbonates, and the weak
absorption that occurred around 1795 cm-1 corresponds to C=O from carbonate.
Also the observation of a weak stretching broad band at 3155 cm-1 due to the small
1.0
0.8
0.6
3155
2926
0.4
572
0.2
870
0.0
4000
1053
1458
1500
3500
3000
2500
2000
1000
500
Wavenumber cm-1
Fig. 4 FT-IR spectra of Bthe FA catalyst
123

S. K. Shinde et al.
concentration of the OH group in the spectrum of BFA supports the formation of
metal hydroxides due to the absorption of moisture from the environment.
The shape and surface morphology of the BFA catalyst was studied by scanning
electron microscopy (SEM). Figure 5 clearly shows that the SEM images of the
BFA catalyst illustrate the porous nature of the prepared catalyst which provides a
smooth and soft surface area for catalyzing the reaction.
Catalytic performance
The catalyst is sourced from the thermal treatment of the rind of dry bael fruit,
which is a tree of Indian origin and known from pre-historic timexs. At the outset of
the protocol, our goal was to identify the catalytic activity of the BFA catalyst for
the synthesis pyrano[2,3-c]pyrazole derivatives, and we defined the following
criteria: a green solvent system, a low catalyst loading, relatively low reaction
temperature, and good reaction yield in a short reaction time. With these goals in
mind, the reaction conditions were optimized using hydrazine hydrate 1 (1 mmol),
ethyl acetoacetate 2 (1 mmol), 4-chlorobenzaldehyde 3b (1 mmol), and malonon-
itrile 4 (1 mmol) as model reactants reacting under different amounts of catalyst and
solvents at ambient temperature. The observed results are summarized in Table 1.
At first, the model reaction was examined under solvent-free conditions and in water
(2 mL) without any catalyst. It was found that the desired product, 5b, was not
observed on the TLC plate even after 2 h of stirring (Table 1, entries 6–7). As the
reaction requires a catalyst, the model reaction was performed using the BFA
catalyst by varying the catalytic amounts (2, 5, 10, 15, and 20 wt%) in water (2 mL)
and under solvent-free conditions. It was found that when increasing the amount of
the catalyst from 2 to 5 and 10 wt% in water, the yield also increased (Table 1,
entries 1–3). A further increase in the catalyst amount (above 10 wt%) surprisingly
reduced the yield (Table 1, entries 4–5), when the reaction was performed in 2 mL
Fig. 5 SEM images of the BFA catalyst
123

Synergetic effects of naturally sourced metal oxides in…
Table 1 Optimization of reaction conditions on the reaction of 1, 2, 3b and 4a
Entry
Catalyst (wt%)
Solvent (2 mL)
Time (min)
Yield (%)b
1
BFA (2)
BFA (5)
BFA (10)
BFA (15)
BFA (20)
–
Water
Water
Water
Water
Water
–
120
120
10
42
70
93
90
86
Nrc
Nrc
82
54
48
30
2
3
4
30
5
30
6
120
120
30
7
–
Water
EtOH
CH3CN
CH2Cl2
Toluene
8
BFA (10)
BFA (10)
BFA (10)
BFA (10)
9
30
10
11
60
60
aReaction conditions: hydrazine hydrate 1 (1 mmol), ethyl acetoacetate 2 (1 mmol), 4-chlorobenzalde-
hydes 3b (1 mmol), malononitrile 4 (1 mmol), catalyst (wt%), and solvent (2 mL) at room temperature
bIsolated yield
cNo reaction
water. Therefore, 10 wt% of BFA catalyst in 2 mL water is sufficient to remarkably
enhance the reactivity of the reactants (1 mmol each), and the corresponding
product 5b was obtained in 93% yield within 10 min (Table 1, entry 3).
We immediately undertook a study to examine the effect of thermal treatment on
the activity of the catalyst: a dried PBF powder was tested for the model reaction,
and the reaction did not proceed even at a prolonged reaction time in water and
solvent-free conditions (Table 1, entry 7). Optimization was carried out with
variation of the reaction medium. The preceding reaction was also examined in
different conventional organic solvents like EtOH, CH3CN, CH2Cl2, and toluene
and afforded low to moderate yields (Table 1, entries 8–11). Thus, the best yield,
cleanest reaction, and most facile work-up was achieved employing 10 wt% of BFA
in water (2 mL) at room temperature.
Therefore, to compare the catalytic activity of the BFA catalyst, the model
reaction was performed under optimized reaction conditions in the presence of
analytical grade alkali metal carbonates and metal oxides (Table 2, entries 1–8).
The result shows only trace amounts of the product were observed on TLC after 2 h.
(Table 1, entries 1 and 7), indicating that a synergetic effect of all alkali metal
carbonates and oxides along with transition metals (Mn, Fe, Cu and Zn ions) in BFA
provides a better catalytic activity for this transformation (Table 2, entry 8).
The dramatic acceleration of this reaction by the catalytic activity of BFA is
currently not well understood. Although we did not investigate the reaction
mechanism, a probable mechanistic rationale portraying the sequence of events for
this condensation reaction over BFA catalyst system is schematically shown by a
conceptual picture (Scheme 2). The BFA catalyst containing the mixture of metal
carbonates and oxides is soluble to some extent in water which was confirmed by
123

S. K. Shinde et al.
Table 2 Comparison of catalytic efficiency of alkali metal carbonates and oxides with BFA on the
reaction of 1, 2, 3b and 4a
Entry
Catalyst
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
K2CO3
Na2CO3
CaCO3
MgCO3
CaO
120
120
120
120
120
120
120
10
58
54
42
48
64
62
60
93
MgO
ZnO
BFA
aReaction conditions: hydrazine hydrate 1 (1 mmol), ethyl acetoacetate 2 (1 mmol), 4-chlorobenzalde-
hydes 3b (1 mmol), malononitrile 4 (1 mmol), catalyst (10 wt%), and water (2 mL) at room temperature
bIsolated yield
Scheme 2 Conceptual picture of pyrano[2,3-c]pyrazoles formation
conducting a hot filtration test, and detectable metals by dissolution were analyzed
by AAS. The report reveals very high oxide contents of K, Ca, Mg, and Na with
small amounts of Mn, Fe, Cu and Zn. The dissolution reaction of metal oxides
having active M2?, oxide and hydroxides provides a number of Lewis basic sites
(O2- and OH) along with Lewis acid sites (M2?) for the activation of reactants to
forward the reactions in the proper direction. In this reaction, the first is the
formation of pyrazolone 8 intermediate by reaction between 1 and 2, and
arylidenemalononitriles 9 by the Knoevenagel condensation between 3 and 4 on the
active sites of the catalytic surface. Intermediates 8 and 9 undergo subsequent
Michael addition to afford 10 which on intramolecular cyclization yields the
targeted pyrano[2,3-c]pyrazoles 5.
123

Synergetic effects of naturally sourced metal oxides in…
Next, we investigated the 100% reusability of the BFA catalyst. The reusability
of a catalyst is an important benefit for the scale-up the practical and industrial
applications. After complication of the reaction 5b, the product was extracted with
ethyl acetate from the reaction mixture. After extraction, it comes in the aqueous
phase and isolates the product from the reaction mass. The remaining aqueous
suspension was regenerated as the catalyst by concentring the excess of water. The
recovered catalyst was tested for its activity in further subsequent runs. The results
obtained in our experiment confirmed that the BFA catalyst could be reused for up
to five run cycles with only negligible loss of activity (Fig. 6).
Under the preceding optimized conditions, the scope and limitations of this new
MCR protocol were next investigated using a variety of structurally different
aromatic aldehydes 3a–s, and the results are summarized in Table 3. Gratifyingly,
we found that the BFA-catalyzed four-component reaction worked well for a wide
range of aromatic aldehydes carrying electron-donating and electron-withdrawing
substituents on the aromatic aldehydes and providex easy access to pyrano[2,3-
c]pyrazoles 5a–s in good to excellent yields. Notably, the reactions were clean and
all the products were easily extracted with ethyl acetate.
Next, the scope of this four-component reaction was achieved through a pseudo-
eight-component reaction with two equivalents of each of the building blocks, i.e.,
hydrazine hydrate 1, ethylacetoacetate 2, molanonitrile 4 and one equivalent of
dialdehyde such as terephthalaldehyde 11 and thiophene-2,5-dicarbaldehyde 12 in the
presence of 30 wt%BFA in water (2 mL) affording the sterically hindered product4,40-
(1,4-phenylene)bis(6-amino-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile) 13 and 4,40-(thiophene-2,5-diyl)bis(6-amino-3-methyl-2,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile) 14 with up to 90% yield in 25 min (Scheme 3). This
reaction can be considered as two four-component reactions occurring simultane-
ously. The reaction could not be controlled at the level of a single four-component
reaction. This new protocol clearly demonstrates that BFA is an excellent catalyst for
this one-pot pseudo-eight-component reaction in water.
A few derivatives of 4-pyrazolyl-4H-chromenes 7 have been reported in just one
publication [31]. Therefore, there is an urgent need to increase the scope of the
93
Fig. 6 Recyclability of the
catalyst
93
93
100
90
80
70
60
50
40
30
20
10
0
92
92
1
2
3
4
5
No. of runs
123

S. K. Shinde et al.
Table 3 Synthesis of pyrano[2,3-c]pyrazoles 5a–s using BFA-catalysta
Time Yield
(min) (%)b
Entry
1
Aldehydes (3)
Product (5)
Mp. (0C) (Lit.) [Ref.]
O
H
15
5
92
93
244–245 (245–246) [13]
234–236 (234–235) [13]
CN
HN
HN
N
3a
O
NH
2 5a
Cl
O
H
2
CN
Cl
3b
N
O
NH2
5b
Br
O
H
3
4
5
10
12
8
92
90
94
180–182 (180–183) [19]
168–170 (170–171) [19]
262–254 (251–252) [19]
CN
Br
HN
HN
HN
3c
N
N
N
O
F
NH2
5c
5d
5e
O
H
F
CN
3d
O
NH2
NO2
O
H
O2N
CN
3e
3f
O
NH2
OCH3
O
H
6
7
10
15
92
88
210–212 (212–213) [19]
224–226 (223–224) [19]
MeO
CN
HN
HN
N
O
NH2
5f
OH
O
H
HO
CN
3g
N
O
NH2
5g
123

Synergetic effects of naturally sourced metal oxides in…
Table 3 continued
Time Yield
(min) (%)b
Entry
8
Aldehydes (3)
Product (5)
Mp. (0C) (Lit.) [Ref.]
CH3
O
H
20
90
86
174–176 (175–176) [19]
Me
CN
NH
HN
3h
N
O
N
2 5h
H3C
CH3
O
H
Me
9
30
20
162–164 (162–165) [19]
N
CN
Me
HN
3i
N
O
NH2
5i
EtO
OEt
O
H
MeO
10
90
284–286 [New]
CN
OMe
HN
3j
N
O
NH2
5j
Cl
O
O
O
Cl
H
11
12
13
14
14
10
10
12
94
92
92
92
154–156 (156–158) [19]
192–194 [New]
Cl
CN
Cl
HN
3k
N
O
NH2
5k
OH
O
H
HO
CN
OEt
HN
3l
N
O
NH2
5l
OH
O
H
232–234 (233–235) [13]
224–226 [New]
HO
CN
OMe
HN
N
3m
O
F
NH2
5m
5n
O
Br
H
F
CN
Br
HN
N
3n
O
NH2
123

S. K. Shinde et al.
Table 3 continued
Time Yield
(min) (%)b
Entry
Aldehydes (3)
Product (5)
Mp. (0C) (Lit.) [Ref.]
O
Cl
CN
H
15
8
94
92
94
246–248 (245–246) [13]
220–222 (220–223) [16]
251–253 [New]
Cl
HN
HN
N
N
O
O
NH
3o
3p
2 5o
O
NO2
CN
H
16
17
10
10
NO2
NH2
5p
5q
F
O
F
H
Br
CN
Br
HN
HN
HN
N
3q
O
NH2
O
S
O
O
S
CN
18
19
25
30
86
90
174–176 (175–177) [19]
190–192 (190–191) [19]
H
3r
3s
N
O
NH2
5r
O
CN
H
N
O
NH2
5s
aReaction conditions: hydrazine hydrate 1 (1 mmol); ethyl acetoacetate 2 (1 mmol); 2-hydroxyaldehydes
6a–s (1 mmol); malononitrile 4 (1 mmol); BFA (10 wt%); water (2 mL); room temperature
bIsolated yield
123

Synergetic effects of naturally sourced metal oxides in…
O
O
2
OEt
CN
2
H2N
2
2
4
NH2
+
CN
1
BFA (30 wt.%)
Water/RT, Stirr
OHC
CHO
OHC
CHO
S
12
11
CN
H2N
O
CN
NC
NH2
O
NC
H2N
NH2
S
O
O
N
N
N
N
N
H
N
H
N
H
N
H
13
14
Scheme 3 One-pot pseudo-eight-component reaction in water
substrate. To recognize the efficiency and scope of the proposed method for the
synthesis 4-pyrazolyl-4H-chromenes 7 via one-pot, four MCRs of hydrazine hydrate
1, ethyl acetoacetate 2, and malononitrile 4 was reacted with salicylaldehydes 6 in
the presence of 10 wt5% BFA catalyst in water at ambient temperature. The results
are incorporated in Table 4, which indicate that various aromatic aldehydes
possessing electron-donating as well as electron-withdrawing substituent on their
aromatic rings afforded the desired 4-pyrazolyl-4H-chromenes 7 in higher yields
within short reaction times.
Compares the efficiency of our method for the synthesis of pyrano[2,3-
c]pyrazoles with other reported works (Table 5). Each of these methods has its own
advantages, but some of them suffer from disadvantages such as very poor yield,
long reaction time, use of organic solvents and the employment of expensive
catalysts, none from natural sources. So the present method furnishes a naturally
sourced catalyst, a green reaction medium, with a shorter reaction time, while a
small quantity of this inexpensive and readily available catalyst is sufficient to
obtain good yieldx of the expected product.
Conclusion
In the present research, we have developed a green, highly efficient and eco-friendly
protocol for one-pot four-component synthesis of pyrano[2,3-c]pyrazoles and
4-pyrazolyl-4H-chromenes using BFA as a non-conventional catalyst under aqueous
medium at ambient temperature. The advantages of the reported method the use of
123

S. K. Shinde et al.
Table 4 Synthesis of 4-pyrazolyl-4H-chromenes 7 (a–n) using BFA-catalysta
Entry
1
Salicyaldehydes (6)
Product (7)
Time (min) Yield (%)b
N
NH
O
H
OH
CN
15
86
OH
6a
O
NH2
7a
N
NH
O
OH
Cl
H
2
3
5
5
94
90
Cl
Br
CN
OH
6b
O
NH2
7b
7c
N
NH
NH
O
OH
CN
Br
H
OH
6c
O
NH2
N
O
OH
CN
O2N
H
4
5
6
5
92
92
90
O2N
HO
OH
6d
O
NH2
7d
7e
N
NH
O
OH
CN
HO
H
10
15
OH
6e
O
NH2
N
NH
O
H
OH
CN
OH
6f
O
NH2
7f
N
NH
O
OH
CN
MeO
H
7
10
5
92
90
MeO
OH
6g
O
NH2
7g
N
NH
O
OH
CN
H
8
OH
O
NH2
OMe
6h
OMe
7h
123

Synergetic effects of naturally sourced metal oxides in…
Table 4 continued
Entry
9
Salicyaldehydes (6)
Product (7)
Time (min) Yield (%)b
N
NH
O
H
OH
CN
15
84
OH
6i
O
NH2
7i
N
NH
NH
O
OH
H
10
11
10
15
86
90
CN
OH
O
6j
O
NH2
7j
N
OH
CN
Cl
Br
H
Cl
Br
OH
O
6k
6l
O
NH2
7k
N
NH
OH
CN
H
12
10
92
OH
O
NH2
Br
Br
7l
N
NH
O
OH
CN
Cl
H
Cl
13
14
10
15
94
90
OH
O
NH2
Br
6m
Br
7m
N
NH
O
OH
CN
H
OH
6n
O
NH2
7n
123

S. K. Shinde et al.
Table 5 Screening of some reported catalysts with the present protocol for the synthesis of 4b
Entry Catalyst
Reaction condition
Time (min) Yield (%) References
1
Piperidine (5 mol%)
Water, r.t.
5–10
5–20
10
89
89
[14]
2
Glycine (2 mol%)
Water, r.t.
[15]
3
L-proline (10 mol%)
Imidazole (50 mol%)
Per-6-ABCD (0.8 mol%)
Nano MgO (50 mg)
Ionic liquid (25 mol%)
Water, reflux
Water, 80 °C
Solvent-free, r.t.
Acetonitrile, r.t.
Solvent-free, r.t.
94
[16]
4
20
90
[17]
5
01
[ 99
97
[19]
6
05
[20]
7
30
85
[21]
8
Mg/Al hydrotalcite (0.1 g) Ethanol, r.t.
240
120
86
[26]
9
BSA (60 mg)
Water–ethanol (7:3), r.t.
88
[27]
10
11
12
13
Lemon Juice (1 mL)
Water–ethanol (9:1), 90 °C 45
94
[28]
[DMDBSI]Á2HSO4 (10%) Water, 60 °C
Magnetized water (4 mL) 25 °C
12
20
5
90
[29]
92
[30]
BFA (10 wt%)
Water, r.t.
93
This work
na atural catalyst obtained from renewable resources having a high catalytic activity
in water, short reaction time, excellent yields, and simple work-up, and an easy
separation of products. Utilization of a natural material as a source of a catalyst not
only provides an opportunity to catalyze organic reactions but also addx value to the
waste generated. Thus, this catalyst is a better and more practical alternative for
green processes.
Acknowledgements The author S.K.S. is grateful to the Council of Scientific and Industrial Research
(CSIR), New Delhi for the award of Senior Research Fellowship (SRF). The authors are grateful to the
Indian Institute of Chemical Technology (IICT), Hyderabad, for NMR analysis.
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