Facile lemon juice catalyzed green and efficient synthesis of a series of new classes of 5-(fluorinatedbenzylidene)-2-thioxo-1,3-thiazolidin-4-ones (3a–e), 5-methyl-4-(fluorinatedbenzylidene)-2-phenylpyrazolidin-3-ones (5a–e), and 2,2-dimethyl-5-(fluorinatedbenzylidene)-1,3-dioxane-4,6-diones (7a–e) by the reaction of fluorinated aromatic aldehydes with active methylene compounds is reported. Lemon juice is natural acid catalyst which is readily available, cheap, nontoxic, and ecofriendly. This method is experimentally simple, clean, high yielding, green, and with reduced reaction times. The product is purified by simple filtration followed by washing with water and drying process. Some of the synthesized compounds have been evaluated “in vivo” for their analgesic activity and all the synthesized compounds are characterized by IR, 1H NMR, 13C NMR, 19F NMR, and mass spectral studies. 1. Introduction The steady growth of interest in the synthesis of heterocyclic compounds is connected with their raised biological activity and also with the fact that these compounds make possible the development of novel materials of unique properties. Pyrazolone is a biologically important scaffold associated with multiple pharmacological activities such as antimicrobial [1], anti-inflammatory [2], analgesic [3], antidepressant [4], anticonvulsant [5], antidiabetic [6], antihyperlipidemic [7], antiviral [8], antitubercular [9], antioxidant [10], and anticancer activites [11, 12]. The synthesis of pyrazolone and its derivatives has engrossed substantial attention from organic and medicinal chemists for many years as they belong to a class of compounds with proven utility in medicinal chemistry. One very interesting and promising class of heterocycles is the 4-thiazolidinone ring system. It represents a class of chemical products with interesting pharmacological and biological activities [13–18] including antidiabetic, antitubercular, anti-HIV, antiparasitic, hypnotic, and anathematic agents. Furthermore, the reactivity of the Meldrum’s acid (2,2-dimethyl-1,3-dioxan-4,6-dione) as a methylene active compound was explored about 40 years after its preparation, when the structure was correctly attributed by Davidson and Bernhard [19] assigning the acidic proton to the central carbon, and its high acidity is still object of study [20]. It is known that the Meldrum’s acid undergoes standard Knoevenagel condensation with aromatic and heteroaromatic aldehydes furnishing the corresponding arylidene derivatives, which are versatile substrates for different kinds of reactions [21,
References
[1]
？. G. Kü？ükgüzel, S. Rollas, H. Erdeniz, M. Kiraz, A. Cevdet Ekinci, and A. Vidin, “Synthesis, characterization and pharmacological properties of some 4-arylhydrazono-2-pyrazoline-5-one derivatives obtained from heterocyclic amines,” European Journal of Medicinal Chemistry, vol. 35, no. 7-8, pp. 761–771, 2000.
[2]
S. A. F. Rostom, I. M. El-Ashmawy, H. A. Abd El Razik, M. H. Badr, and H. M. A. Ashour, “Design and synthesis of some thiazolyl and thiadiazolyl derivatives of antipyrine as potential non-acidic anti-inflammatory, analgesic and antimicrobial agents,” Bioorganic and Medicinal Chemistry, vol. 17, no. 2, pp. 882–895, 2009.
[3]
S. Khode, V. Maddi, P. Aragade et al., “Synthesis and pharmacological evaluation of a novel series of 5-(substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines as novel anti-inflammatory and analgesic agents,” European Journal of Medicinal Chemistry, vol. 44, no. 4, pp. 1682–1688, 2009.
[4]
M. Abdel-Aziz, G. E. A. Abuo-Rahma, and A. A. Hassan, “Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities,” European Journal of Medicinal Chemistry, vol. 44, no. 9, pp. 3480–3487, 2009.
[5]
Z. S. Quan, R. L. Li, and Y. Z. Ling, “Study of the relationship between structure and anticonvulsant activities of 5-substituted-1-butry-3-pyrazolidinones and their synthesis,” Acta Pharmaceutica Sinica, vol. 27, no. 9, pp. 711–716, 1992.
[6]
N. Das, A. Verma, P. K. Shrivastava, and S. K. Shrivastava, “Synthesis and biological evaluation of some new aryl pyrazol-3-one derivatives as potential hypoglycemic agents,” Indian Journal of Chemistry B, vol. 47, no. 10, pp. 1555–1558, 2008.
[7]
G. A. Idrees, O. M. Aly, G. E. A. A. Abuo-Rahma, and M. F. Radwan, “Design, synthesis and hypolipidemic activity of novel 2-(naphthalen-2-yloxy)propionic acid derivatives as desmethyl fibrate analogs,” European Journal of Medicinal Chemistry, vol. 44, no. 10, pp. 3973–3980, 2009.
[8]
G. Ouyang, Z. Chen, X. Cai et al., “Synthesis and antiviral activity of novel pyrazole derivatives containing oxime esters group,” Bioorganic and Medicinal Chemistry, vol. 16, no. 22, pp. 9699–9707, 2008.
[9]
D. Castagnolo, F. Manetti, M. Radi et al., “Synthesis, biological evaluation, and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis: part 2. Synthesis of rigid pyrazolones,” Bioorganic and Medicinal Chemistry, vol. 17, no. 15, pp. 5716–5721, 2009.
[10]
K. B. Umesha, K. M. L. Rai, and M. A. Harish Nayaka, “Antioxidant and antimicrobial activity of 5-methyl-2-(5-methyl-1,3-diphenyl-1H-pyrazole-4-carbonyl)-2,4-dihydro-pyrazol-3-one,” International Journal of Biomedical Science, vol. 5, no. 4, pp. 359–368, 2009.
[11]
R. Tripathy, A. Ghose, J. Singh et al., “1,2,3-Thiadiazole substituted pyrazolones as potent KDR/VEGFR-2 kinase inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 6, pp. 1793–1798, 2007.
[12]
H. Park, K. Lee, S. Park et al., “Identification of antitumor activity of pyrazole oxime ethers,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 13, pp. 3307–3312, 2005.
[13]
R. Murugan, S. Anbazhagan, and S. S. Narayanan, “Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3 + 2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives,” European Journal of Medicinal Chemistry, vol. 44, no. 8, pp. 3272–3279, 2009.
[14]
S. Chandrappa, C. V. Kavitha, M. S. Shahabuddin et al., “Synthesis of 2-(5-((5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid derivatives and evaluation of their cytotoxicity and induction of apoptosis in human leukemia cells,” Bioorganic and Medicinal Chemistry, vol. 17, no. 6, pp. 2576–2584, 2009.
[15]
E. W. Brooke, S. G. Davies, A. W. Mulvaney et al., “Synthesis and in vitro evaluation of novel small molecule inhibitors of bacterial arylamine N-acetyltransferases (NATs),” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 15, pp. 2527–2530, 2003.
[16]
S. Ozkirimli, F. Kazan, and Y. Tunali, “Synthesis, antibacterial and antifungal activities of 3-(1,2,4-triazol-3-yl)-4-thiazolidinones,” Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 24, no. 2, pp. 447–452, 2009.
[17]
S. Chandrappa, S. B. Benaka Prasad, K. Vinaya, C. S. Ananda Kumar, N. R. Thimmegowda, and K. S. Rangappa, “Synthesis and in vitro antiproliferative activity against human cancer cell lines of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-diones,” Investigational New Drugs, vol. 26, no. 5, pp. 437–444, 2008.
[18]
A. Verma and S. K. Saraf, “4-Thiazolidinone—a biologically active scaffold,” European Journal of Medicinal Chemistry, vol. 43, no. 5, pp. 897–905, 2008.
[19]
D. Davidson and S. A. Bernhard, “The structure of Meldrum's supposed β-lactonic acid,” Journal of the American Chemical Society, vol. 70, no. 10, pp. 3426–3428, 1948.
[20]
K. Byun, Y. Mo, and J. Gao, “New insight on the origin of the unusual acidity of Meldrum's acid from αβ-initio and combined QM/MM simulation study,” Journal of the American Chemical Society, vol. 123, no. 17, pp. 3974–3979, 2001.
[21]
B. Chen, “Meldrum's acid in organic synthesis,” Heterocycles, vol. 32, no. 3, pp. 529–597, 1991.
[22]
L. F. Tietze and U. Beifuss, “The knoevenagel reaction,” in Comprehensive Organic Synthesis, vol. 2, pp. 341–394, 1991.
[23]
B. Pita, E. Sotelo, M. Suárez et al., “Pyridazine derivatives. Part 21: synthesis and structural study of novel 4-aryl-2,5-dioxo-8-phenylpyrido[2,3-d]pyridazines,” Tetrahedron, vol. 56, no. 16, pp. 2473–2479, 2000.
[24]
F. C. Brown, C. K. Bradsher, and S. M. Bond, “Some 5-substituted rhodanines,” Industrial & Engineering Chemistry, vol. 45, pp. 1030–1032, 1953.
[25]
K. Ramkumar, V. N. Yarovenko, A. S. Nikitina et al., “Design, synthesis and structure-activity studies of rhodanine derivatives as HIV-1 integrase inhibitors,” Molecules, vol. 15, no. 6, pp. 3958–3992, 2010.
[26]
J. Iwao and K. J. Tomino, “Synthesis of pyrazolo [3, 4-b] pyridine by knovengel condensation,” Pharmaceutical Society of Japan, vol. 76, pp. 748–755, 1956.
[27]
B. A. Alekseenko, T. E. Gorizdra, and S. N. Baranov, “Synthesis and structure of noncondensed bicyclic thiazolidino-4-one derivatives,” Khimiya Geterotsiklicheskikh Soedinenii, vol. 5, pp. 230–231, 1969.
[28]
G. G. Allan, D. Maclean, and G. T. Newbold, “Condensation products of rhodanine, and keto-acids,” Journal of the Chemical Society, pp. 5132–5153, 1952.
[29]
F. C. Brown, C. K. Bradsher, S. G. McCallum, and M. Potter, “Rhodanine derivatives of ketones,” Journal of Organic Chemistry, vol. 15, no. 1, pp. 174–176, 1950.
[30]
M. M. Chowdhry, D. M. P. Mingos, A. J. P. White, and D. J. Williams, “Syntheses and characterization of 5-substituted hydantoins and thiazolines - Implications for crystal engineering of hydrogen bonded assemblies. Crystal structures t of 5-(2-pyridylmethylene)-hydantoin, 5-(2-pyridylmethylene)-2-thiohydantoin, 5-(2-pyridylmethylene)thiazolidine-2,4-dione, 5-(2-pyridylmethylene)rhodanine and 5-(2-pyridylmethylene)pseudothiohydantoin,” Journal of the Chemical Society, Perkin Transactions 1, vol. 1, no. 20, pp. 3495–3504, 2000.
[31]
R. V. Hangarge, D. V. Jarikote, and M. S. Shingare, “Knoevenagel condensation reactions in an ionic liquid,” Green Chemistry, vol. 4, no. 3, pp. 266–268, 2002.
[32]
S. S. Shindalkar, B. R. Madje, and M. S. Shingare, “Microwave induced, solvent-free Knoevenagel condensation of 4-oxo-(4H)-1-benzopyran-3-carbaldehyde with Meldrum's acid using alumina support,” Indian Journal of Chemistry B, vol. 45, no. 11, pp. 2571–2573, 2006.
[33]
S. Santosh, B. R. Shindalkar, R. V. Madje, P. T. Hangarge, M. K. D. Patil, and M. S. Shingare, “Borate zirconia mediated Knoevenagel condensation reaction in water,” Journal of the Korean Chemical Society, vol. 49, pp. 377–380, 2005.
[34]
S. S. Shindalkar, B. R. Madje, and M. S. Shingare, “Ultrasonically accelerated Knoevenagel condensation reaction at room temperature in distilled water,” Indian Journal of Chemistry B, vol. 44, no. 7, pp. 1519–1521, 2005.
[35]
N. B. Darvatkar, A. R. Deorukhkar, S. V. Bhilare, and M. M. Salunkhe, “Ionic liquid-mediated knoevenagel condensation of Meldrum's acid and aldehydes,” Synthetic Communications, vol. 36, no. 20, pp. 3043–3051, 2006.
[36]
J. M. Khurana and K. Vij, “Nickel nanoparticles catalyzed chemoselective Knoevenagel condensation of Meldrum's acid and tandem enol lactonizations via cascade cyclization sequence,” Tetrahedron Letters, vol. 52, no. 28, pp. 3666–3669, 2011.
[37]
S. Ghosh, J. Das, and S. Chattopadhyay, “A novel light induced Knoevenagel condensation of Meldrum's acid with aromatic aldehydes in aqueous ethanol,” Tetrahedron Letters, vol. 52, no. 22, pp. 2869–2872, 2011.
[38]
A. M. Dumas, A. Seed, A. K. Zorzitto, and E. Fillion, “Triphenylphosphine mediated Knoevenagel condensation of Meldrum's acid with aromatic aldehydes,” Tetrahedron Letters, vol. 48, pp. 7072–7276, 2007.
[39]
K. Gong, Z. He, Y. Xu, D. Fang, and Z. Liu, “Green synthesis of 5-benzylidene rhodanine derivatives catalyzed by 1-butyl-3-methyl imidazolium hydroxide in water,” Monatshefte fur Chemie, vol. 139, no. 8, pp. 913–915, 2008.
[40]
K. F. Shelke, S. B. Sapkal, B. R. Madja, B. B. Shingate, and M. S. Shingare, “Ionic liquid promoted an efficient synthesis of 5-arylidene-2, 4-thiazolidinedione,” Bulletin of the Catalysis Society of India, vol. 8, pp. 30–34, 2009.
[41]
J. Zhou, Y. Song, F. Zhu, and Y. Zhu, “Facile synthesis of 5-benzylidene rhodamine derivatives under microwave irradiation,” Synthetic Communications, vol. 36, no. 22, pp. 3297–3303, 2006.
[42]
K. Bourahla, A. Derdour, M. Rahmouni, F. Carreaux, and J. P. Bazureau, “A practical access to novel 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones via sulfur/nitrogen displacement under solvent-free microwave irradiation,” Tetrahedron Letters, vol. 48, no. 33, pp. 5785–5789, 2007.
[43]
S. Patil, S. D. Jadhav, and U. P. Patil, “Natural acid catalyzed synthesis of schiff base under solvent-free condition: as a green approach,” Journal of Applied Sciences Research, vol. 4, no. 2, pp. 1074–1078, 2012.
[44]
H. L. Yale, “The trifluoromethyl group in medicinal chemistry,” Journal of Medicinal and Pharmaceutical Chemistry, vol. 1, no. 2, pp. 121–133, 1959.
[45]
P. C. Appelbaum and P. A. Hunter, “The fluoroquinolone antibacterials: past, present and future perspectives,” International Journal of Antimicrobial Agents, vol. 16, no. 1, pp. 5–15, 2000.
[46]
F. M. D. Ismail, G. B. D. Michael, and J. Michael, “Modulation of drug pharmacokinetics and pharmacodynamics by fluorine substitution,” Chemistry today, vol. 27, no. 3, pp. 18–21, 2009.
[47]
H. Sachdeva, D. Dwivedi, K. Arya, S. Khaturia, and R. Saroj, “Anti-inflammatory activity, and QSAR study of some Schiff bases derived from 5-mercapto-3-( -pyridyl)-4H-1,2,4-triazol-4-yl-thiosemicarbazide,” Medicinal Chemistry Research, 2013.
[48]
A. Dandia, H. Sachdeva, and R. Singh, “Improved synthesis of 3-spiro indolines in dry media under microwave irradiation,” Synthetic Communications, vol. 31, no. 12, pp. 1879–1892, 2001.
[49]
H. Sachdeva, D. Dwivedi, and S. Khaturia, “Aqua mediated facile synthesis of 2-(5/7-fluorinated-2-oxoindolin-3-ylidene)-N- (4-substituted phenyl) hydrazine carbothioamides,” Research Journal of Pharmaceutical, Biological and Chemical Sciences, vol. 2, no. 2, pp. 213–219, 2011.
[50]
H. Sachdeva and D. Dwivedi, “Lithium-acetate-mediated biginelli one-pot multicomponent synthesis under solvent-free conditions and cytotoxic activity against the human lung Cancer Cell line A549 and Breast Cancer cell line MCF7,” The Scientific World Journal, vol. 2012, Article ID 109432, 9 pages, 2012.
