Electro-Organic Synthesis of Nanosized Particles of 2-Amino-pyranes

Article pubs.acs.org/IECR

Electro-Organic Synthesis of Nanosized Particles of 2-Amino-pyranes Somayeh Makarem,† Ali Reza Fakhari,*,† and Ali Asghar Mohammadi*,‡ †

Department of Chemistry, Faculty of Sciences, Shahid Beheshti University, G. C., P.O. Box 19396- 4716, Evin, Tehran, I. R. Iran. Chemistry and Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, I. R. Iran

‡

S Supporting Information *

ABSTRACT: We have developed a convenient and efficient method for the electrosynthesis of nanosized particles of 2-aminopyrane derivatives through the reaction of aromatic aldehyde or isatin against malononitrile and 1,3-dicarbonyl compound inside an undivided cell where sodium bromide was present as electrolyte in propanol medium. This procedure resulted in efficient and selective formation of the products. one,20 this electrocatalytic methodology has fabricated nanosized particles of 2-amino-pyrane compounds and synthesized them all in one step, whereas previously this process required two stages: one for synthesizing organic compounds and another for the fabrication of the nanosized particles.21−24

1. INTRODUCTION In recent years, pyranes and their derivatives have attracted serious interest due to their useful biological properties such as cosmetics1 pigments, anti-inflammatory,2 antipyretic,3 antibacterial,4 antiviral,5 anticancer,6 anticoagulant,7 and application as potential biodegradable agrochemicals.8 Additionally they are also present in natural alkaloids thus the synthesis of this heterocyclic nucleus is of much current importance. In previous reports,9−11 these compounds have been synthesized in two steps: in the first step unsaturated nitriles or unsaturated carbonyl compounds are synthesized, and then they are used in the reaction with 1,3-dicarbonyl compounds or cyanoacetic acid derivatives. The one-pot method of synthesis based on three-component condensation of carbonyl compound (aldehydes, ketones, isatines) and CH acids (1,3-dicarbonyl compounds, substituted pyrazolin-5-ones, benzoannelated 3-oxo-2H-pyrroles, 3-oxo2H-thiophenes, resorcinol, and others) with cyanoacetic acid derivatives (cyanoacetic esters, malononitrile) is widely used recently.9,12−14 This electrochemical procedure is advantageous for a multicomponent reaction in utilizing simple equipment, an undivided cell that would be of value for a large-scale process due to its catalytic nature, and the use of cheap and environmentally friendly chemical reagent-electricity. Size reduction is a fundamental unit operation having important applications in pharmacy.15 It helps to improve solubility and bioavailability, reduce toxicity, enhance release, and provide better formulation opportunities for drugs. In most of the cases, size reduction is limited to micrometer size range, for example, various pharmaceutical dosage forms like powder, emulsion, suspension, etc. Drugs in the nanometer-size range enhance performance in a variety of dosage forms. Major advantages of nanosizing include (i) increased surface area, (ii) enhanced solubility, (iii) increased rate of dissolution, (iv) increased oral bioavailability, (v) more rapid onset of therapeutic action, (vi) less amount of dose required, (vii) decreased fed/fasted variability, and (viii) decreased patient-topatient variability.16,17 In connection with the authors’ ongoing work on electroorganic synthesis, benzofurans18 and 2-amino-4H-chromenes,19 nanosized particles of 3-hydroxy-3-(1H-indol-3-yl) indolin-2© 2012 American Chemical Society

2. RESULTS AND DISCUSSION Pursuing our studies on the multicomponent reactions of resorcinol with malononitrile16 and aromatic aldehydes by the catalytic amount of electro-generated base in an undivided cell in this effort, after screening several parameters such as solvents and current, it was found that dry propanol at a current density of 10 mA cm−2 (I = 50 mA, electrode surface = 5 cm2) promotes the synthesis of some new 2-amino-pyranes efficiently by the reaction of 1,3-diketones (1a−c) with malononitrile (2) and aldehydes (3) or isatins (11) in an undivided cell in the presence of NaBr as an electrolyte (Scheme1 and Table1) Surprisingly, we have found that these products are nanoparticles. SEM micrographs of template synthesized nanoparticles obtained by powder are shown in Figure 1. The average particle size, DSEM, is ∼100 nm. The size and the form of aggregates depend on the condition of preparation. Although we do not know exactly the nanoparticle formation mechanism, we think existence of the Mg2+ in the solution maybe prevents the aggregation of the products.25−27 An attempt was made to prepare nanosized particles of 2amino-pyrane derivatives from 1,3-diketones (1a−c) with malononitrile (2) and aldehyde (3) or isatin (11) derivatives to extend the scope of the reaction. Hence, a number of nanosized particles of 2-amino-pyrane derivatives were participated with good yields. The optimized results are summarized in Table 2. Strong literature review shows that there are many articles that support the proposed mechanism as follow:31−34 Deprotonation of an alcohol at the cathode leads to the Received: Revised: Accepted: Published: 2200

May 9, 2011 December 5, 2011 January 2, 2012 January 2, 2012 dx.doi.org/10.1021/ie200997b | Ind. Eng.Chem. Res. 2012, 51, 2200−2204

Industrial & Engineering Chemistry Research

Article

Scheme 1. Formation of 2-Amino-pyranes

Table 1. Comparison Effect of Different Solvent and Current on the Reaction of 4-Hydroxycoumarin (1a), Malonitrile (2), 4-Fluorobenzaldehyde (3b) to Afford the 2-Amino-4-(4fluorophenyl)-4,5-dihydro-5-oxopyrano[3,2-c]chromene-3carbonitrile (8b)a

a

current (mA)

electricity passed (F/ mol)

time (min)

solvent

yield (%)b

20 50 20 50

3.0 2.8 3.0 2.8

240 90 240 90

EtOH EtOH n-PrOH n-PrOH

75 75 85 85

Table 2. Results Obtained in the Reaction of a Series of Representative Aldehydes or Ketones with Malononitrile and 1,3-Diketones (1a−c)a

2

For all reactions, 0.5 mmol of NaBr, iron cathode (5 cm ), magnesium anode (5 cm2), and r.t were used. bIsolated yields based on 4-hydroxycoumarin.

entryb

R

yield (%)

Mp (°C)

lit Mp (°C)

8a 8b 8c 9a 9b 9c 10a 10b 14a 14b

3-NO2 4-F H 4-Br 3-NO2 4-F 4-Br 4-NO2 5-NO2 5-Br

87 85 80 92 94 90 85 84 93 95

82 dec 271 165 165 265 282 180 120dec 268dec >280

262−26428 256−25828

230−23129 239−24029 335−33730

a

For all reactions, 0.5 mmol of NaBr, iron cathode (5 cm2), magnesium anode (5 cm2), and room temperature were used. b Isolated yields based on 1,3-dicarbonyl compounds. Time of reaction is 90 min.

electrode in solution. The subsequent reaction between the alkoxide anion and malonitrile gives rise to malonitrile anion. The aldehyde 3 condenses with malononitrile anion 2 with elimination of hydroxide to afford 2-benzylidene-malonitrile derivative 5 (Scheme 2). The condensation of enol (1a−c) with 5 gives the intermediate 6 which cyclizes by the nucleophilic attack of the O− group on the cyano moiety and produces the intermediate 7. Finally the products (8−10) are formed from intermediate 7 (Scheme 3). This hypothesis is supported by the following fact. When isatin (11) containing no C(4)H acidic moiety is introduced into system; spiro[pyrano(3,2-c)chromen]-(1′H)-2′-one-3-carbonitrile are formed. (Scheme 4) The structure of the compounds (8−10, 14) was deduced from 1H NMR, 13C NMR, and IR spectral data, whereas the molecular weights were confirmed by mass spectroscopy. IR

Figure 1. SEM images of nanosized particles of 2-amino-4a,5,6,10btetrahydro-6-methyl-4-(3-nitrophenyl)-5-oxo-4H-pyrano[3,2-c]quinoline-3-carbonitrile.

formation of alkoxide anion. We could see H2 production at cathode electrode when we only have alcohol and supporting 2201

dx.doi.org/10.1021/ie200997b | Ind. Eng.Chem. Res. 2012, 51, 2200−2204


Article

previously synthesized pyranes containing similar moieties.12−15 The IR spectra of spiroheterocycles (14a−b) contain the absorption band of the amide group with the endocyclic nitrogen atom of the isatin moiety at νCON ∼1740 cm−1. The 1 H NMR spectra of pyranes (8−10) contain characteristic signals of the protons of the C(4) H at ∼4.50 ppm. The spectra of spiro heterocycles contain no signal of the C(4) H group but exhibit signals of protons of the isatin moiety at ∼11 ppm. Investigation of the effects of the parameters such as concentration, current density, electrode materials, temperature, solvent, and electrolyte is very important and time consuming. In this work we only want to report formation of these products. Our research about of the effect of parameters on size and morphology of the products is in progress.

Scheme 2. Formation of Benzylidene−Malonitrile Derivatives

Scheme 3. Formation of the Products through Intermediate 7

3. EXPERIMENTAL SECTION 3.1. Apparatus and Reagents. Controlled-current coulometry and preparative electrolysis were performed using a SAMA potentiostate/galvanostate (Isfahan, Iran). The working electrodes were on an iron cathode (5 cm2) and a magnesium anode (5 cm2). NMR spectra were recorded on a Bruker DRX-300 Avance instrument. The IR spectra were recorded on a Bruker IFS-66 FT-IR spectrophotometer. Mass spectra were obtained using a QP-1100 EX Shimadzu GC-MS (EI at 70 eV) and Agilent Technologies 5937 mass-selective detector. Scanning electron microscopy (SEM) was run with axl30 scanning electron microanalyzer (Philips, Netherlands) at an acceleration voltage of 20.0 kV. The melting point of the product was obtained using an electrothermal melting point apparatus (UK), model 9200. All compounds were commercially available, obtained from Merck, and used without further purification. 3.2. Typical Procedure for Preparation of 2-amino-4(4-fluorophenyl)-4,5-dihydro-5-oxopyrano[3,2-c]chromene-3-carbonitrile (8b). A mixture of 1 mmol 4hydroxycoumarin (1a), malononitrile (2), and 4-fluorobenzaldehyde (3b) and NaBr (0.05 g, 0.5 mmol) in anhydrous propanol (25 mL) was stirred and electrolyzed in an undivided cell equipped with an iron cathode (5 cm2) and magnesium anode (5 cm2) at room temperature, under constant current density 10 mA/cm2 (I = 50 mA). After the completion of the reaction (monitored by thin-layer chromatography, ethyl acetate/n-hexane 1/1), the solvent was evaporated under reduced pressure, and then 20 mL ethanol (80%) was added to the reaction mixture. The resulting solid was separated by centrifugation. The product (8b) was collected for analysis. C19H11FN2O3; mp 271 °C; IR 3368, 3334, 2195, 1718, 1672 cm−1; 1H NMR (DMSO-d6, 300 MHz) δ = 8.16 (d, 2H, J = 8.7 Hz, Ar−H), 7.89 (d, 1H, J = 8.0 Hz), 7.73 (t, 1H, J = 8.4 Hz, Ar−H), 7.46−7.60 (m, 6H, 4Ar−H and NH2), 4.67 (s, 1H, CH); 13C NMR (DMSO-d6, 75 MHz) δ = 195.44, 160.06, 158.49, 154.43, 152.73, 151.23, 147.06, 133.68, 129.64, 125.24, 124.20, 123.08, 117.11, 113.34, 103.24, 57.19, 37.24; MS (m/z, %) 334 (M+, 10), 294 (4), 278 (18), 239 (100), 214 (5), 140 (7), 121 (25), 77 (7), 92 (20), 63 (4).

Scheme 4. Formation of Spiro[pyrano(3,2-c)chromen](1′H)-2′-one-3-carbonitrile

4. CONCLUSION In conclusion, for the first time we have developed a novel, practically convenient, easy, and ecologically safe method for the synthesis of nanosized particles of 2-amino-pyranes using a green chemical protocol. The use of electricity as a green catalyst not only gives high yield of nano particles but also

spectra of pyranes 8−10 and 14 exhibit the characteristic absorption bands of the enaminonitrile or enaminocarbonyl moieties at νNH2 3175−3478 and νCN 2184−2211. An analogous pattern was observed in the IR spectra of the 2202



Article

(14) Heravi, M. M.; Jani, B. A.; Derikvand, F.; Bamoharram, F. F.; Oskooie, H. A. Three component, one-pot synthesis of dihydropyrano[3,2-c]chromene derivatives in the presence of H6P2W18O62. 18H2O as a green and recyclable catalyst. Catal. Commun. 2008, 10, 272−275. (15) Azzam, E. M. S.; Kandile, N. G.; Badawi, A. M.; Sami, R. M. Influence in the surface activity for some cationic thiol surfactants using their nanostructures. J. Dispersion Sci. Technol. 2011, 32, 1325− 1331. (16) Pison, U.; Welte, T.; Giersig, M.; Groneberg, D. A. Nanomedicine for respiratory diseases. Eur. J. Pharmacol. 2006, 533, 341−350. (17) Behera, A. L.; Patil, S. V.; Sahoo, S. K.; Sahoo, S. K. Nanosizing of drugs: A promising approach for drug delivery. Pharm. Sin. 2010, 1, 20−28. (18) Fakhari, A. R.; Nematollahi, D.; Shamsipur, M.; Makarem, S.; Hosseini Davarani, S. S.; Alizadeh, A. A.; Khavasi, H. R. Electrochemical synthesis of 5,6-dihydroxy-2-methyl-1-benzofuran-3-carboxylate derivatives. Tetrahedron 2007, 63 (18), 3894−3898. (19) Makarem, S.; Mohammadi, A. A.; Fakhari, A. R. A multicomponent electro-organic synthesis of 2-amino-4H-chromenes. Tetrahedron Lett. 2008, 49, 7194−7196. (20) Makarem, S.; Fakhari, A. R.; Mohammadi, A. A. Electro-organic synthesis of nano-sized particles of 3-hydroxy-3-(1H-indol-3-yl) indolin-2-one derivatives. Monatsh. Chem. 2012, DOI: 10.1007/ s00706-011-0693-1. (21) Alessi, P.; Cortesi, A.; Kikic, I.; Foster, N. R.; Macnaughton, S. J.; Colombo, I. Particle production of steroid drugs using supercritical fluid processing. Ind. Eng. Chem. Res. 1996, 35, 4718−4726. (22) Cortopassi, A. C.; Kuo, K. K.; Ferrara, P. J.; Wawierna, T. M.; Essel, J. T. Synthesis of nano-sized rdx using an ultra-high-pressure ress system. Int. J. Energetic Mater. Chem. Propulsion 2008, 7, 39−54. (23) Thakur, R.; Gupta, R. B. Production of hydrocortisone microand nano-particles using supercritical anti-solvent with enhanced mass transfer. Chem. Eng. Commun. 2006, 193 (3), 293−305. (24) Abdolmohammadi, S.; Balalaie, S. Novel and efficient catalysts for the one-pot synthesis of 3,4-dihydropyrano[c]chromene derivatives in aqueous media. Tetrahedron Lett. 2007, 48, 3299−3303. (25) Merisko-Liversidge, E. M. M.; Liversidge, G. G. Drug nanoparticles: formulating poorly water-soluble compounds.Toxicol. Pathol. 2008, 36, 43−48. (26) Mercero, J. M.; Matxain, J. M.; Lopez, X.; Fowler, J. E.; Ugalde, J. M. Aluminum (III) interactions with the side chains of aromatic aminoacids. Int. J. Quantum Chem. 2002, 90, 859−881. (27) Reddy, A. S.; Sastry, G. N. Cation [M = H+, Li+, Na+, K+, Ca2+, Mg2+, NH4+, and NMe4+] interactions with the aromatic motifs of naturally occurring amino acids: a theoretical study. J. Phys. Chem. A 2005, 109, 8893−8903. (28) Balalaie, S.; Abdolmohammadi, S.; Bijanzadeh, H. R.; Amani, A. M. Diammonium hydrogen phosphate as a versatile and efficient catalyst for the one-pot synthesis of pyrano[2,3-d]pyrimidinone derivatives in aqueous media. Mol. Divers 2008, 12, 85−91. (29) Karimi, A. R.; Sedaghatpour, F. Novel Mono- and Bis(spiro-2amino-4H-pyrans): Alum-catalyzed reaction of 4-hydroxycoumarin and malononitrile with isatins, quinones, or ninhydrin. Synthesis 2010, 10, 1731−1735. (30) Heber, D.; Stoyanov, E. V. Synthesis of functionalized 4H-pyran and cyclohexanone derivatives via three-component reactions of dimethyl acetonedicarboxylate, aromatic aldehydes, and malononitrile. Synthesis 2003, 227−232. (31) Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M.; Ilovaisky, A. I.; Feducovich, S. K.; Belyakov, P. A.; Nikishin, G. I. Catalysis of salicylaldehydes and two different CH acids with electricity: first example of an efficient multicomponent approach to the design of functionalized medicinally privileged 2-amino-4H-chromene scaffold. Adv. Synth. Catal. 2008, 350, 591−601. (32) Elinson, M. N.; Merkulova, V. M.; Ilovaisky, A. I.; Demchuk, D. V.; Belyakov, P. A.; Nikishin, G. I. Electrochemically induced multicomponent assembling of isatins, 4-hydroxyquinolin-2(1H)-one

provides a procedure that does not use harmful organic solvents.

■

ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures and IR, 1H NMR, 13C NMR, and mass spectra for compounds 8, 9, and 14. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*Tel./Fax: +98-21-22431661. E-mail: [email protected] (A.R.F.); [email protected] (A.A.M.).

■ ■

ACKNOWLEDGMENTS We gratefully acknowledge financial support from the Research Council of Shahid Beheshti University. REFERENCES

(1) Ellis, G. P. The chemistry of heterocyclic compounds. In Chromenes, Chromanes and Chromeones; Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, 1977; p 13. (2) Luchini, A. C.; Rodrigues-Orsi, P.; Cestari, S. H.; Seito, L. N.; Wiataicenis, A.; Pellizzon, C. H.; Stasi, L. C. D. Intestinal antinflammatory activity of coumarin and 4-hydroxycoumarin in the trinitrobenzenesulphonic acid model of rat colitis. Biol. Pharm. Bull. 2008, 31, 1343−1350. (3) Stern, P.; Dezelic, M.; Kosak, R. Analgetic and antipyretic action of vitamin K and dicoumarol with special consideration of 4hydroxycoumarin. Naunyn Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1957, 232, 356−359. (4) Chohan, Z. H.; Shaikh, A. U.; Rauf, A.; Supuran, C. T. Antibacterial, antifungal and cytotoxic properties of novel Nsubstituted sulfonamides from 4-hydroxycoumarin. J. Enz. Inhib. Med.Chem. 2006, 21, 741−748. (5) Kirkiacharian, B. S.; Clercq, E.; Kurkjian, R.; Pannecouque, C. New synthesis and anti-HIV and antiviral properties of 3-arylsulfonyl derivatives of 4-hydroxycoumarin and 4-hydroxyquinolone. J. Pharm. Chem. 2008, 42, 265−270. (6) Velasco-Velázquez, M. A.; Agramonte-Hevia, J.; Barrera, D.; Jiménez-Orozco, A.; García-Mondragón, M. J.; Mendoza-Patiño, N.; Landa, A.; Mandoki, J. 4-Hydroxycoumarin disorganizes the actin cytoskeleton in B16−F10 melanoma cells but not in B82 fibroblasts, decreasing their adhesion to extracellular matrix proteins and motility. Cancer Lett. 2003, 198, 179−186. (7) Shapiro, S.; Sherwin, B. Thromboembolization. II. The use of dicumarol (3,3′-methylenebis (4-hydroxycoumarin) in embolization. Report of five cases. N. Y. State J. Med. 1943, 43, 45−52. (8) Hafez, E. A. A.; Elnagdi, M. H.; Ali Elagamey, A. G.; El-Taweel, F. M. A. A. Nitriles in heterocyclic synthesis: Novel synthesis of benzo[c]-coumarin and of benzo[c]pyrano[3,2-c]quinoline derivatives. Heterocycles 1987, 26, 903−907. (9) Shestopalov, A. M.; Emeliyanova, Yu. M. Selected Methods for Synthesis and Modification of Heterocycles; Kartsev, V. G., Ed.; IBS Press: Moscow, 2003; Vol. 2, p 363. (10) Piao, M. Z.; Imafuku, K. Convenient synthesis of aminosubstituted pyranopyranone. Tetrahedron Lett. 1997, 38, 5301−5302. (11) Shaker, R. M. Synthesis and reactions of some new 4Hpyrano[3,2-c]benzopyran-5-one derivatives and their potential biological activities. Pharmazie 1996, 51, 148−151. (12) Shestopalov, A. M.; Niazimbetova, Z. I.; Evans, D. H.; Niyazymbetov, M. E. Synthesis of 2-amino-4-aryl-3-cyano-6-methyl5-ethoxycarbonyl-4H-pyrans. Heterocycles 1999, 51, 1101−1107. (13) Balalaie, S.; Abdolmohammadi, S.; Bijanzadeh, H. R.; Amani, A. M. Diammonium hydrogen phosphate as a versatile and efficient catalyst for the one-pot synthesis of pyrano[2,3-d]pyrimidinone derivatives in aqueous media. Mol. Divers 2008, 12, 85−91. 2203



Article

and malononitrile: a convenient and efficient way to functionalized spirocyclic [indole-3,4_-pyrano[3,2-c]quinoline] scaffold. Mol. Divers 2010, 14, 833−839. (33) Elinson, M.; Nilovaisky, A. I.; Merkulova, V. M.; Demchuk, D. V.; Belyakov, P. A.; Ogibin, Y. N.; Nikishin, G. I. The electrocatalytic cascade assembling of isatins, malononitrile and N-alkyl barbiturates: An efficient multicomponent approach to the spiro[indole-3,5_pyrano[2,3-d]pyrimidine] framework. Electrochim. Acta 2008, 53, 8346−8350. (34) Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.; Gorbunov, S. V.; Nasybullin, R. F.; Stepanov, N. O.; Nikishin, G. I. Electrochemically induced chain transformation of salicylaldehydes and alkyl cyanoacetates into substituted 4H-chromenes. Tetrahedron Lett. 2006, 47, 7629−7633.

2204


Electro-Organic Synthesis of Nanosized Particles of 2-Amino-pyranes

Recommend Documents