One-Pot Three-Component Synthesis of Bispyrazole-thiazole-pyran-2-one Heterocyclic Hybrids

Abstract

A new series of some interesting bispyrazole-thiazole-pyran-2-one heterocyclic hybrids has been efficiently synthesized via a one-pot catalyst-free three-component reaction of α-bromoacetylated pyran-2-one derivatives, thiosemicarbazide, and polysubstituted-1-(1H-pyrazol-4-yl)butane-1,3-diones. This multicomponent procedure has been advantageously applied to prepare a structural diversity of hetero­cyclic hybrids characterized by extensive 1D and 2D NMR spectroscopic studies.

Key words

pyrazoles - thiazoles - pyran-2-ones - chromen-2-ones - three-component synthesis - 1D and 2D NMR

• References and Notes

• 1a Spino C. Dodier MS. Sotheeswaran S. Bioorg. Med. Chem. Lett. 1998; 8: 3475
• 1b Basile A. Sorbo S. Spadaro V. Molecules 2009; 14: 939
• 1c McGlacken GP. Fairlamb IJ. S. Nat. Prod. 2005; 22: 36
• 1d Lee JS. Mar. Drugs 2015; 13: 1581
• 2a Egan D. O'Kennedy E. Moran E. Cox D. Prosser E. Thornes RD. Drug Metab. Rev. 1990; 22: 503
• 2b Hatem AA. Tilal E. Abdullah A. Mohamed IA. Khalid AA. Abdul-Rahman MA. Eur. J. Med. Chem. 2013; 70: 358
• 2c Starks CM. Russell BW. Norman VL. Rice SM. O’Neil-Johnson M. Lawrence JA. Eldridge GR. Phytochemistry 2014; 98: 216
• 2d Behrami A. Dobroshi F. J. Chem. Pharm. Res. 2015; 7: 1087
• 2e Ratnakar RK. Rao SP. Jitender DG. Poornachandra Y. Ganesh KC. Bioorg. Med. Chem. Lett. 2014; 24: 1661
• 2f Jun M. Bacay AF. Moyer J. Webb A. Carrico-Moniz D. Bioorg. Med. Chem. Lett. 2014; 24: 4654
• 2g Talhi O. Schnekenburger M. Panning J. Pinto DG. C. Fernandes JA. Paz FA. A. Jacob C. Diederich M. Silva AM. S. Bioorg. Med. Chem. 2014; 22: 3008
• 2h Veselinović JB. Matejić JS. Veselinović AM. D. Sokolović D. Biol. Nyssana 2016; 7: 167
• 3a Fahr E. Pharm. Ztg. 1982; 127: 163
• 3b Altomare C. Perrone G. Zonno MC. Evidente A. Pengue R. Fanti F. Polonelli L. J. Nat. Prod. 2000; 63: 1131
• 3c Altomare C. Pengue R. Favilla M. Evidente A. Visconti A. J. Agric. Food Chem. 2004; 52: 2997
• 3d McGlacken GP. Fairlamb I. J. Nat. Prod. Rep. 2005; 22: 369
• 3e Aiqun L. Xiaoming L. Yuchun F. Tianjiao Z. Qianqun G. Weiming Z. J. Antibiot. 2008; 61: 245
• 4a Lee S. Park SB. Org. Lett. 2009; 11: 5214
• 4b Orrego-Hernández J. Cobo J. Portilla J. Eur. J. Org. Chem. 2015; 5064
• 5a Nasr MN. A. Said SA. Arch. Pharm. 2003; 336: 551
• 5b Ahasan NB. Rabiul MI. Bangladesh J. Pharm. 2007; 2: 81
• 5c Shankaraiah N. Devaiah V. Reddy KL. Juvekar A. Sen S. Kurian N. Zingde S. Bioorg. Med. Chem. Lett. 2008; 18: 14681
• 5d Nadia RM. Nahed YK. Amin FF. Ahmed AE. Der Pharma Chemica 2010; 2: 400
• 5e Santhosh RM. Sravanthi S. Manjula A. Vittal RaoB. Madhava RB. Sridhar B. Bioorg. Med. Chem. Lett. 2012; 22: 5272
• 6a Gupta P. Gupta JK. Halve AK. Int. J. Pharm. Sci. Res. 2015; 6: 2291
• 6b Yu-Ying H. Kimiyoshi K. Hiroyuki T. Masayuki K. Fung FW. Tetrahedron Lett. 2011; 52: 3786
• 6c Jania DH. Patela HS. Kehariab H. Modic CK. Appl. Organomet. Chem. 2010; 24: 99
• 7a Sugiura S. Ohno S. Ohtani O. Izumi K. Kitamikado T. Asai H. Kato K. J. Med. Chem. 1977; 20: 80
• 7b Sakya SM. Rast B. Tetrahedron Lett. 2003; 44: 7629
• 8a Siddiqui N. Arhad MF. Waquar A. Shamsher AM. Int. J. Pharm. Sci. Drug. Res. 2009; 1: 136
• 8b Patt WC. Hamilton HW. Taylor MD. Ryan MJ. Taylor DG. J. Connolly CJ. C. Doherty AM. Klutchko SR. Sircar I. Steinbaugh BA. Batley BL. Painchaud CA. Rapundalo ST. Michniewicz BM. Olson SC. J. J. Med. Chem. 1992; 35: 2562
• 8c Barreca ML. Balzarini J. Chimirri A. De Clercq D. De Luca L. Holtje HD. Holtje M. Monforte AM. Monforte P. Pannecouque C. Rao A. Zappala MJ. J. Med. Chem. 2002; 45: 5410
• 8d Dinkar M. Chandewar AV. Mahendra RS. Der Chem. Sinica 2011; 2: 137
• 8e Nepali K. Sharma S. Sharma M. Bedi PM.S. Dhar KL. Eur. J. Med. Chem. 2014; 77: 422
• 9a Ben Mohamed S. Rachedi Y. Hamdi M. Le Bideau F. Dejean C. Dumas F. Eur. J. Org. Chem. 2016; 2628
• 9b Bouherou H. Saidoun A. Abderrahmani A. Abdellaziz L. Rachedi Y. Dumas F. Demenceau A. Molecules 2017; 2: 57
• 10a Rachedi Y. Hamdi M. Speziale V. Synth. Commun. 1989; 19: 3427
• 10b Aït-baziz N. Rachedi Y. Chemat F. Hamdi M. Asian J. Chem. 2008; 4: 2610
• 11 Aït-Baziz N. Rachedi Y. Silva AM. S. Arkivoc 2010; (10) : 86
• 12 Rachedi Y. Hamdi M. Sakellariou R. Spesiale V. Synth. Commun. 1991; 21: 1189
• 13a Gelin S. Chantegrel B. Nadi A. J. Org. Chem. 1983; 48: 4078
• 13b Bendaas A. Hamdi M. Sellier N. J. Heterocycl. Chem. 1999; 36: 1291
• 14a Siddiqui N. Arshad M. Khan S. Acta Pol. Pharm. Drug Res. 2009; 66: 1617
• 14b Hikem-Oukacha D. Rachedi Y. Hamdi M. Silva AM. S. J. Heterocycl. Chem. 2011; 48: 31
• 15 General Procedure for the Synthesis of Bispyrazole-thiazole-pyran-2-one Hybrids 13a–d, 14, 15a-c, 15e and 16An equimolar mixture of the appropriate 3-(2-bromoacetyl)-pyran-2-one 10 or 12 (1 mmol), thiosemicarbazide 11 (91 mg, 1 mmol), and diketo-phenylpyrazoles (6a–e or 9, 1 mmol) was heated to reflux in absolute ethanol (10 mL) with vigorous stirring for 30–45 min. After completion of the reaction as indicated by TLC (using a 3:1 mixture of CHCl₃/EtOH as eluent), the products were collected by filtration and then washed with hot ethanol to afford pure products.
• 16 3-{2-[3′-(4-Chlorophenethyl)-5′-hydroxy-5-methyl-1′-phenyl-1′H,2H-(3,4′-bispyrazol)-2-yl]thiazol-4-yl}-4-hydroxy-6-methyl-2H-pyran-2-one (13b)C₃₀H₂₄ClN₅O₄S, white solid, 0.50 g (85%), mp 299–301 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.21 (s, 3 H, 6-CH ₃), 2.32 (s, 3 H, 5^b-CH₃), 2.76 (br s, 4 H, H-1^c and H-2^c), 5.97 (s, 1 H, H-5), 6.40 (s, 1 H, H-4^b), 7.00 (d, J = 8.2 Hz, 2 H, H-2′′′,6′′′), 7.08 (d, J = 8.2 Hz, 2 H, H-3′′′,5′′′), 7.28–7.31 (m, 1 H, H-4′′), 7.45–7.49 (m, 2 H, H-3′′,5′′), 7.64–7.66 (m, 2 H, H-2′′,6′′), 7.90 (s, 1 H, H-5^a), 11.53 (s, 1 H, 5′-OH), 12.53 (s, 1 H, 4-OH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.8 (5^b-CH₃), 19.8 (6-CH₃), 28.4 (C-1^c), 33.2 (C-2^c), 91.5 (C-4′), 94.5 (C-3), 101.1 (C-5), 111.5 (C-5^a), 113.6 (C-4^b), 122.8 (C-2′′,6′′), 126.5 (C-4′′), 128.2 (C-3′′′,5′′′), 129.2 (C-3′′,5′′), 130.4 (C-2′′′,6′′′), 130.8 (C-4′′′), 135.3 (C-3^b), 138.8 (C-1′′), 140.3 (C-1′′′), 144.4 (C-4^a), 149.7 (C-3′), 152.4 (C-5^b), 160.6 (C-2^a), 161.8 (C-2), 162.9 (C-6), 165.1 (C-5′), 168.3 (C-4) ppm. HRMS-ESI⁺: m/z calcd for [C₃₀H₂₄ClN₅O₄S + H]⁺: 586.1310; found: 586.1313.
• 17 4-Hydroxy-3-{2-[5′-hydroxy-3′,5-dimethyl-1′-phenyl-1′H,2H-(3,4′-bispyrazol)-2-yl]thiazol-4-yl}-6-methyl-2H-pyran-2-one (14)C₂₃H₁₉N₅O₄S, white solid, 0.44 g (95%), mp 235–237 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.07 (s, 3 H, 3′-CH₃), 2.20 (s, 3 H, 6-CH₃), 2.32 (s, 3 H, 5^b-CH₃), 6.01 (s, 1 H, H-5), 6.49 (s, 1 H, H-4^b), 7.26–7.30 (m, 1 H, H-4′′), 7.44–7.48 (m, 2 H, H-3′′,5′′), 7.66–7.68 (m, 2 H, H-2′′,6′′), 7.94 (s, 1 H, H-5^a), 11.55 (s, 1 H, 5-OH), 12.74 (s, 1 H, 4-OH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.8 (5^b-CH₃and 3′-CH₃), 19.8 (6-CH₃), 91.8 (C-4′), 94.6 (C-3), 101.1 (C-5), 111.8 (C-5^a), 113.2 (C-4^b), 122.5 (C-2′′,6′′), 126.2 (C-4′′), 129.2 (C-3′′,5′′), 135.7 (C-3^b), 138.9 (C-1′′), 144.4 (C-4^a), 147.1 (C-3′), 152.5 (C-5^b), 160.7 (C-2^a), 161.8 (C-2), 162.9 (C-6), 165.3 (C-5′), 168.5 (C-4) ppm. HRMS-ESI⁺: m/z calcd for [C₂₃H₁₉N₅O₄S + H]⁺: 462.1231; found: 462.1230.
• 18 3-{2-[5′-Hydroxy-3′-(4-methoxyphenethyl)-5-methyl-1′-phenyl-1′H,2H-(3,4′-bispyrazol)-2-yl]thiazol-4-yl}-2H-chromen-2-one (15e)C₃₄H₂₇N₅O₄S, white solid, 0.36 g (60%), mp 265–267 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.34 (s, 3 H, 5^b-CH₃), 2.71 (br s, 4 H, H-1^c and H-2^c), 3.51 (s, 3 H, 4′′′-OCH₃), 6.42 (br s, 2 H, H-5 and H-4^b), 6.56 (d, J = 8.5 Hz, 2 H, H-3′′′,5′′′), 6.91 (d, J = 8.4 Hz, H-2′′′,6′′′), 7.06–7.09 (m, 1 H, H-6), 7.28–7.32 (m, 1 H, H-4′′), 7.38–7.40 (m, 1 H, H-8), 7.45–7.49 (m, 2 H, H-3′′,5′′), 7.53–7.57 (m, 1 H, H-7), 7.86–7.88 (m, 2 H, H-2′′,6′′), 7.96 (s, 1 H, H-4), 8.09 (s, 1 H, H-5^a), 11.68 (s, 1 H, 5′-OH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.9 (5^b-CH₃), 29.7 (C-1^c), 33.2 (C-2^c), 55.1 (4′′′-OCH₃), 92.2 (C-4′), 112.8 (C-4^b), 113.8 (C-3′′′,5′′′), 116.4 (C-8), 116.8 (C-5^a), 119.1 (C-4^a), 120.7 (C-3), 121.2 (C-2′′,6′′), 124.9 (C-6), 125.8 (C-4′′), 128.5 (C-5), 129.5 (C-2′′′,6′′′), 129.6 (C-3′′,5′′), 132.3 (C-7), 133.5 (C-1′′′), 135.3 (C-3^b), 139.3 (C-4), 139.4 (C-1′′), 144.8 (C-4^a), 150.9 (C-3′), 151.7 (C-5^b), 152.8 (C-8^a), 157.7 (C-4′′′), 159.0 (C-2), 160.3 (C-2^a), 161.7 (C-5′) ppm. HRMS-ESI⁺: m/z calcd for [C₃₄H₂₇N₅O₄S + H]⁺: 602.1857; found: 602.1858.
• 19 3-{2-[5′-Hydroxy-3′,5-dimethyl-1′-phenyl-1′H,2H-(3,4′-bispyrazol)-2-yl]thiazol-4-yl}-2H-chromen-2-one (16)C₂₆H₁₉N₅O₃S, white solid, 0.35 g (72%), mp 248–250 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.09 (s, 3 H, 3′-CH₃), 2.34 (s, 3 H, 5^b-CH₃), 6.42 (br s, 1 H, H-5), 6.50 (s, 1 H, H-4^b), 7.06–7.10 (m, 1 H, H-6), 7.32 (s, 1 H, H-4′′), 7.37–7.39 (m, 1 H, H-8), 7.47–751 (m, 2 H, H-3′′,5′′), 7.52–7.56 (m, 1 H, H-7), 7.89–7.91 (m, 2 H, H-2′′,6′′), 8.06 (s, 1 H, H-4), 8.11 (s, 1 H, H-5^a), 11.72 (s, 1 H, 5′-OH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.8 (5^b-CH₃and 3′-CH₃), 91.9 (C-4′), 112.7 (C-4^b), 116.4 (C-8), 116.9 (C-5^a), 119.1 (C-4a), 120.8 (C-3), 121.1 (C-2′′,6′′), 124.9 (C-6), 125.9 (C-4′′), 128.4 (C-5), 129.7 (C-3′′,5′′), 132.4 (C-7), 135.4 (C-3^b), 139.2 (C-4), 139.5 (C-1′′), 144.8 (C-4^a), 149.3 (C-3′), 151.7 (C-5^b), 152.8 (C-8a), 159.0 (C-2), 160.60 (C-2^a), 162.0 (C-5′) ppm. HRMS-ESI⁺: m/z calcd for [C₂₆H₁₉N₅O₃S + H]⁺: 482.1281; found: 482.1274.