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Nanosized magnesium oxide as a highly effective heterogeneous base catalyst for the rapid synthesis of pyranopyrazoles via a tandem four-component reaction
*Corresponding author at: Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 76169, Iran. Tel.: +98 341 322 1451; fax: +98 341 322 1452 hsheibani@mail.uk.ac.ir (Hassan Sheibani)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Available online 25 June 2010
Abstract
A four-component reaction of hydrazine hydrate or phenyl hydrazine, ethyl 3-alkyl-3-oxo propanoate, aldehydes and malononitrile has been achieved in the presence of nanosized magnesium oxide as a highly effective heterogeneous base catalyst to produce of 6-amino-3-alkyl-4-aryl-5-cyano-1,4-dihydropyrano[2,3-c]pyrazole derivatives in excellent yields and in a short experimental time. This method is simple and rapid for focusing a pyrano ring with a pyrazole ring.
Keywords
Four-component
Ethyl 3-alkyl-3-oxo propanoate
Malononitrile, 6-amino-3-alkyl-4-aryl-5-cyano-1,4-dihydropyrano[2,3-c]pyrazole
6-Amino-3-alkyl-4-aryl-5-cyano-1,4-dihydropyrano[2,3-c]pyrazole
1 Introduction
Tandem C–C bond formations are convenient methods for synthesis of heterocyclic compounds from relatively simple starting materials in a convergent way (Tietze et al., 2006; Montgomery, 2004; Miura and Murakami, 2007; Denmark and Thorarensen, 1996; Ji et al., 2008). These transformations are usually operated in one-pot without the need for intermediate workups or purifications. In particular, the development of tandem reactions for the efficient construction of small molecules is an important goal in combinatorial chemistry from the viewpoints of operational simplicity and assembly efficiency. Hence, the development of multi-component reaction protocols for the synthesis of heterocyclic compounds has attracted significant interest from pharmaceutical groups. Pyranopyrazoles are an important class of heterocyclic compounds. They find applications as pharmaceutical ingredients and biodegradable agrochemicals (Bonsignore et al., 1993; Wang et al., 2000). The first reported pyranopyrazole was synthesized from the reaction between 3-methyl-1-phenylpyrazolin-5-one and tetracyanoethylene (Junek and Aigner, 1973). Various 6-amino-5-cyano-4-aryl-4H-pyrazolo[3,4-b]pyrans were synthesized by the reaction of arylidienemalononitrile with 3-methyl-pyrazol-ine-5-ones or by the condensation of 4-arylidienepyrazoline-5-one with malononitrile (Wamhoff et al., 1993; Tacconi et al., 1980).
Sharanin Yu et al. (1983) have developed a three-component reaction between pyrazolone, an aldehyde and malononitrile in ethanol using triethylamine as the catalyst. Vasuki and co-workers reported an efficient four-component reaction protocol for the synthesis of pyranopyrazole derivatives in the presence of a catalytic amount of bases such as piperidine, pyrrolidine, morpholine and triethylamine at ambient temperature (Gnanasambandam Vasuki and Kumaravel, 2008). We have recently reported a one-pot three-component synthesis of 5-cyano-1,4-dihydropyrano[2,3-c]pyrazole derivatives which were catalyzed by magnesium oxide (MgO) as heterogeneous base catalyst in acetonitrile (Sheibani and Seifi, 2008; Sheibani et al., 2009; Sheibani and Babaei, 2010). Heterogeneous catalysts are advantageous over conventional homogeneous catalysts as they can be easily recovered from the reaction mixture by simple filtration and can be reused after activation, thereby making the process economically viable. Among the heterogeneous basic catalysts, magnesium oxide is a versatile material used as catalyst for several base-catalyzed organic transformations (Hattori, 1995), toxic waste remediation, and as additive in refractory, paint, and superconductor products (Ding et al., 2001).
2 Results and discussion
In the present work, we report an efficient one-pot, four-component reaction protocol for the synthesis of pyranopyrazole derivatives in the presence of nanosized magnesium oxide as a highly effective heterogeneous base catalyst at room temperature. This protocol offers flexibility in tuning the molecular complexity and diversity. The reactions proceeded to completion almost instantaneously, and pure product was obtained, without using any chromatographic techniques, simply by recrystallization from ethanol (Scheme 1).
The MgO catalyst is generally prepared by the decomposition of various magnesium salts or magnesium hydroxide[Mg(OH)2, brucite]. However, the MgO formed by this method usually exhibits relatively large grain sizes, inhomogeneous morphologies, and small surface areas. These structural and textural features limit its application as a catalyst. Several novel methods such as controlled precipitation, solgel route, sol–gel followed by hypercritical drying, amorphous citrate method, and preparation under hydrothermal conditions, have been reported in literature for preparation of nanosized MgO particles (Wang et al., 1997; Koper et al., 1997). These methods are highly advantageous in terms of the crystallite size and shape, surface area, and surface basic characteristics of the synthesized MgO particles.
The particle size and surface morphology of synthesized MgO by wet chemical procedure depend upon several factors such as the rate of hydrolysis of magnesium salts, temperature, type of base, concentration of the salt, and drying and calcination steps. Proper choice of these parameters can lead to particles of uniform morphology and size. In this study, we have prepared nanosized MgO catalyst on basis of method which was reported by Dalip Kumar and co-workers and used it successfully in the synthesis of dihydropyrano[2,3-c]pyrazoles. The treatment of hydrazine hydrate 1a or phenyl hydrazine 1b, ethyl 3-alkyl-3-oxopropanoates 2, aldehydes 3 and malononitrile 4 resulted in 5-cyano-1,4-dihydropyrano[2,3-c]pyrazole derivatives 5 in the presence of commercially available MgO and nanosized magnesium oxide (MgO) as base catalysts (Table 1). The catalytic activity of the synthesized nanosized MgO particles was compared with the commercially available MgO catalyst. As shown in Table 1 the activity of the nanosized MgO was much faster as compared to the commercial MgO catalyst. This is in agreement with a recent report where an increase in the initial activity was observed in case of nanoparticles as compared to the bulk catalyst (Valdes-Solis et al., 2006). In order to examine the solvent effect, we used solvents such as water, ethanol and acetonitrile in the four-component reactions of benzaldehyde, hydrazine hydrate 1a or phenyl hydrazine 1b, ethyl acetoacetate or ethyl 3-oxo-hexanoate and malononitrile 4 in the presence of nanosized magnesium oxide (MgO) as model reactions to investigate the effects of solvent for preparing compounds 5a and 5g, respectively. The four-component condensation in ethanol required relatively longer reaction time and afforded moderate yields of the product. In each case, the substrates were mixed together with 0.05 g catalysts agitated with 10 mL solvent. The results are shown in Table 2. As shown in Tables 1 and 2 yield of the reaction is markedly affected by the catalyst and solvent, and optimum results were obtained when reactions were treated in acetonitrile and in the presence of nanosized magnesium oxide (MgO).
Compd no.
R
R′
Ar
Commercial MgO
Nanosized MgO
m.p., °C (Ref.)
Time (min)
Yield (%)
Time (min)
Yield (%)
5a
H
CH3
C6H5
90
83
10
97
243–245 (Peng et al., 2006)
5b
H
CH3
2-ClC6H4
90
83
12
93
246–248 (Peng et al., 2006)
5c
H
CH3
4-ClC6H4
50
85
5
97
233–235 (Peng et al., 2006)
5d
H
CH3
3-BrC6H4
100
75
17
90
220–222 (Peng et al., 2006
5e
H
CH3
4-NO2C6H4
120
70
25
90
249–252 (Peng et al., 2006)
5f
H
CH3
4-CH3OC6H4
150
70
43
89
208–210 (Peng et al., 2006)
5g
Ph
CH3
C6H5
150
83
12
95
166–168 (Jin et al., 2006
5h
Ph
CH3
4-CH3C6H4
165
85
20
93
176–178 (Jin et al., 2006)
5i
Ph
CH3
4-CH3OC6H4
165
75
15
90
169–170 (Jin et al., 2006)
5j
Ph
CH3
4-ClC6H4
100
87
5
96
144–146 (Jin et al., 2006)
5k
Ph
CH3
2,4-Cl2C6H3
75
88
10
92
182–184 (Jin et al., 2006)
5l
Ph
CH3
4-BrC6H4
175
76
23
88
184–185 (Sheibani and Babaei, 2010
5m
Ph
Propyl
4-ClC6H4
100
88
12
92
181–182 (Sheibani and Babaei, 2010)
5n
Ph
Iso-propyl
4-ClC6H4
100
87
15
93
172–173 (Sheibani and Babaei, 2010)
5o
Ph
Iso-propyl
2,4-Cl2C6H3
60
85
10
95
188–189 (Sheibani and Babaei, 2010)
Compd. no.
Solvent
Time (min)
Yield (%)
5a
H2O
20
90
5a
CH3CH2OH
35
80
5a
CH3CN
10
97
5g
H2O
25
85
5g
CH3CH2OH
45
75
5g
CH3CN
12
95
Mechanistically, the reaction occurs via initial formation of arylidenemalononitrile in quantitative yield by the Knoevenagel addition of malononitrile to the aldehyde and followed by loss of water molecules. The Knoevenagel condensations of malononitrile with aldehydes in the presence of magnesium oxide (MgO) as a catalyst have been extensively studied and the rate of these reactions are very fast (Sheibani and Babaei, 2010). The formation of the product 5 is proposed to involve the following tandem reactions: pyrazolone 6 formation by reaction between 1 and 2, Knoevenagel condensation between 3 and 4, Michael addition of pyrazolone 6 to arylidenemalononitrile 7, followed by cyclization and tautomerization (Scheme 2).
The compounds 5a–o are known in the literature. The IR spectra and melting point of all known compounds were consistent with those reported in the literature (Sheibani and Babaei, 2010; Peng et al., 2006; Jin et al., 2006). The IR spectra of these compounds showed the presence of CN at region 2235–2238 cm−1 and two sharp bands at 3500–3450 and 3390–3380 cm−1 due to asymmetric and symmetric vibrations of the NH2 group. The 1H and 13C NMR and mass spectra were also in accordance with the proposed structures.
In conclusion, we have described an efficient route for generation of pyranopyrazoles via a tandem four-component reaction in the presence nanosized magnesium oxide (MgO) as a highly effective heterogeneous base catalyst. We believe that the operational simplicity of the present process combined with the efficiency of this method will make it potentially attractive for further library construction.
3 Experimental
The (arylhydrazono)-propan-2-ones 1 were known and prepared according to a general procedure (Koper et al., 1997). Melting points were determined on an Gallenkamp melting point apparatus and are uncorrected. IR spectra were measured on a Mattson 1000 FT-IR spectrometer. 1H NMR and 13C NMR spectra were recorded on a BRUKER DRX-500 AVANCE spectrometer at 500 and 125.77 MHz, respectively. MS spectra were recorded on a Shimadzu QP 1100EX mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer.
3.1 Preparation of nanosized MgO
The MgO nanoparticles were synthesized by precipitation of the magnesium hydroxide gels in aqueous solution using Mg (NO3)2 as salt and liquid ammonia as the precipitating agent. Initially, the pH of 200 mL of distilled water was adjusted to 10.5 by addition of liquid ammonia. To this solution, 0.1 M magnesium nitrate solution was added dropwise with continuous stirring. The rate of addition of the salt solution was kept at 20 mL/h. During the addition, the pH of the mixture decreased due to hydrolysis of the salt. The pH was maintained at 10.5 by controlled addition of liquid ammonia solution. After completion of the precipitation procedure, the mixture was stirred at room temperature for 12 h, filtered, repeatedly washed with distilled water, dried at 120 °C, and calcined at 500 °C for 2 h (Kumar et al., 2007).
3.2 General procedure for the preparation of 6-amino-4-aryl-3-alkyl-5-cyano-1,4-dihydropyra-no[2,3-c]pyrazole derivatives (5a–o)
To a stirred solution of hydrazine hydrate 96% (0.107 g, 2 mmol) or phenyl hydrazine (0.216 g, 2 mmol), ethyl 3-alkyl-3-oxopropanoate (2 mmol), aldehyde (2 mmol), malononitrile (0.132 g, 2 mmol) and MgO (50 mg) in acetonitrile (15 mL) were added successively at room temperature with vigorous stirring for the time reported in Table 1 (the progress of the reaction being monitored by TLC and hexane/ethyl acetate was used as an eluent). After completion of the reaction the catalyst was separated from the reaction mixture by centrifugation. The excess acetonitrile was removed by evaporation and then was poured into ice cold water; the crude product was filtered, dried and recrystallized from 96% ethanol.
3.3 Spectral data for selected compounds
3.3.1 6-Amino-5-cyano-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole (5a)
White crystals, mp. 243–245°C; νmax(KBr): 3450, 3370 (NH2), 2195 (CN), 1645 (C⚌N), 1610, 1605 (Ar) cm−1; δH (500 MHz, DMSO-d6): 12.16 (s, 1H, NH), 7.45–7.16 (m, 5H, ArH), 6.95 (s, 2H, NH2), 4.62 (s, 1H, 4-H), 1.80 (s, 3H, CH3) ppm.
3.3.2 6-Amino-5-cyano-3-methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole (5g)
Pale yellow crystals, mp. 168–170 °C; νmax(KBr): 3472, 3320 (NH2), 2205 (CN), 1660 (C⚌N), 1590 (Ar) cm−1; δH (500 MHz, DMSO-d6): 7.16–7.32 (m, 10H, ArH), 6.95 (s, 2H, NH2), 4.68 (s, 1H, 4-H), 1.93 (s, 3H, CH3) ppm.
3.3.3 6-Amino-4-(4-chlorophenyl)-5-cyano-1-phenyl-3-propyl-1,4-dihydropyrano[2,3-]pyrazole (5m)
Pale yellow crystals, mp. 181–182 °C; νmax(KBr): 3456, 3312 (NH2), 2210 (CN), 1656 (C⚌N), 1586 (Ar) cm−1; δH (500 MHz, DMSO-d6): 7.83–7.30 (9H, m, arom), 7.24 (2H, s, NH2), 4.73 (1H, s, CH), 2.14 (1H, m, Ha on C 1 of propyl), 2.05(1H, m, Hb on C1 of propyl), 3.5 (1H, m, Ha on C2 of propyl), 1.22 (1H, m, Hb on C2 of propyl), 1.83 (3H, t, CH3) ppm.
Acknowledgements
The authors express appreciation to the Shahid Bahonar University of Kerman Faculty Research Committee Fund for its support of this investigation.
References
- Eur. J. Med. Chem.. 1993;28:517.
- Chem. Rev.. 1996;96:137.
- Chem. Mater.. 2001;13:435.
- Tetrahedron Lett.. 2008;9:5636.
- Chem. Rev.. 1995;95:537.
- Org. Lett.. 2008;10:3919.
- ARKIVOC. 2006;xi:176.
- Chem. Ber.. 1973;106:914.
- Chem. Mater.. 1997;9:2468.
- Tetrahedron. 2007;63:3093.
- Chem. Commun. 2007:217.
- Angew. Chem. Int. Ed.. 2004;43:3890.
- Green Chem.. 2006;8:573.
- Org. Khim.. 1983;19:2609.
- Synth. Commun.. 2010;40:257.
- Catal. Lett.. 2008;126:275.
- Synth. Commun.. 2009;39:1055.
- J. Prakt. Chem.. 1980;322:831.
- Domino Reactions in Organic Synthesis. Weinheim, Germany: Wiley-VCH; 2006.
- Catal. Today. 2006;116:354.
- Synthesis. 1993;11:1129.
- J. Phys. Chem. B. 1997;101:7448.
- Z. Proc. Natl. Acad. Sci. USA. 2000;97:7124.
