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Ionic liquid-promoted multi-component reaction: novel and efficient preparation of pyrazolo[3,4-b]pyridinone, pyrazolo[3,4-b]-quinolinone and their hybrids with pyrimidine nucleoside

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Abstract

The utilization of an ionic liquid, [bmim][BF4] as both reaction medium and promoter for a multi-component reaction of aldehyde (1) and 5-amino-3-methyl-1-phenylpyrazole (2) with Meldrum acid (3) or dimedone (5) is studied. From this reaction, pyrazolo[3,4-b]pyridinone (4) and pyrazolo[3,4-b]quinolinone (6) derivatives were prepared in high yields. This novel procedure showed such advantages as environmentally benign nature, enhanced efficiency, simple operation process, and mild reaction conditions. As an application, the procedure was successfully used in the preparation of a set of pyrimidine nucleoside–pyrazolo[3,4-b]pyridine and pyrazolo[3,4-b]quinolinone hybrids with potential biological activities.

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Abbreviations

MCRs:

Multi-Component reactions

[bmim]BF4 :

1-Butyl-3-methylimidazolium tetrafluoroborate

[bmim]PF6 :

1-Butyl-3-methylimidazolium hexafluorophosphate

TLC:

Thin-layer chromatography

NMR:

Nuclear magnetic resonance

MS:

Mass Spectrometer

EtOH:

Ethanol

THF:

Tetrahydrofuran

DMSO:

Dimethyl sulphoxide

m p:

Melting point

r. t.:

Room temperature

References

  1. Dömling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106: 17–89. doi:10.1021/cr0505728

    Article  PubMed  CAS  Google Scholar 

  2. Hulme C, Gore V (2003) Multi-component reactions: emerging chemistry in drug discovery ‘from xylocain to crixivan’. Curr Med Chem 10: 51–80. doi:10.2174/0929867033368600

    Article  CAS  PubMed  Google Scholar 

  3. Zhu J (2003) Recent developments in the isonitrile-based multicomponent synthesis of heterocycles. Eur J Org Chem 1133–1144 doi:10.1002/ejoc.200390167

  4. Ngouansavanh T, Zhu J (2007) IBX-mediated oxidative Ugi-type multicomponent reactions: application to the N and C1 functionalization of tetrahydroisoquinoline. Angew Chem Int Ed 46: 5775–5778. doi:10.1002/anie.200701603

    Article  CAS  Google Scholar 

  5. Laurent EK, Gizolme M, Grimaud L, Oble J (2006) Direct access to heterocyclic scaffolds by new multicomponent Ugi-smiles couplings. Org Lett 8: 4019–4021. doi:10.1021/ol061605o

    Article  CAS  Google Scholar 

  6. Trost BM (1995) Atom economy—a challenge for organic synthesis: homogeneous catalysis Leads the Way. Angew Chem Int Ed Engl 34: 259–281. doi:10.1002/anie.199502591

    Article  CAS  Google Scholar 

  7. Weber L (2002) The application of multi-component reactions in drug discovery. Curr Med Chem 9: 2085–2093

    CAS  PubMed  Google Scholar 

  8. Ranke J, Stolter S, Strömann R, Arning J, Jastorff B (2007) Design of sustainable chemical products—the example of ionic liquids. Chem Rev 107: 2183–2206. doi:10.1021/cr050942s

    Article  CAS  PubMed  Google Scholar 

  9. Stolte S, Matzke M, Arning J, Böschen A, Pitner WR, Welz-Biermann U, Jastorff B, Ranke R (2007) Effects of different head groups and functionalised side chains on the aquatic toxicity of ionic liquids. Green Chem 9: 1170–1179. doi:10.1039/b711119c

    Article  CAS  Google Scholar 

  10. Afonsa CAM, Branco LC, Candeias NR, Gois PMP, Lourenco NMT, Mateus NMM, Rosa JN (2007) Efficient catalyst reuse by simple dissolution in non-conventional media. Chem Commun 2669–2679 doi:10.1039/b607483a

  11. Parvulescu VI, Hardacre C (2007) Catalysis in ionic liquids. Chem Rev 107: 2615–2665. doi:10.1021/cr050948h

    Article  CAS  PubMed  Google Scholar 

  12. Ehlert FJ, Ragan P, Chen A, Roeske WR, Yamamura HI (1982) Modulation of benzodiazepine receptor binding: insight into pharmacological efficacy. Eur J Pharmacol 78: 249–253. doi:10.1016/0014-2999(82)90246-1

    Article  CAS  PubMed  Google Scholar 

  13. Sanghvi YS, Larson SB, Willis RC, Robins RK, Revankar GR (1989) Synthesis and biological evaluation of certain C-4 substituted pyrazolo[3,4-b]pyridine nucleosides. J Med Chem 32: 945–951. doi:10.1021/jm00125a004

    Article  CAS  PubMed  Google Scholar 

  14. Elnagdi MN, Rifaat M, Elmoghayar H, Sadek KU (1990) Chemistry of pyrazoles condensed to heteroaromatic five- and six-membered rings. Adv Heterocycl Chem 48: 223–299. doi:10.1016/S0065-2725(08)60340-2

    Article  CAS  Google Scholar 

  15. Hardy CR (1984) The chemistry of pyrazolopyridines. Adv Heterocycl Chem 36: 343–409. doi:10.1016/S0065-2725(08)60117-8

    Article  CAS  Google Scholar 

  16. Dias LRS, Santos MB, de Albuquerque S, Castro HC, de Souza AMT, Freitas ACC, Divaio MAV, Cabral LM, Rodrigues CR (2007) Synthesis, in vitro evaluation, and SAR studies of a potential antichagasic 1H-pyrazolo[3,4-b]pyridine series. Bioorg Med Chem 15: 211–219. doi:10.1016/j.bmc.2006.09.067

    Article  CAS  PubMed  Google Scholar 

  17. Witherington J, Bordas V, Gaiba A, Garton NS, Naylor A, Rawlings AD, Slingsby BP, Smith DG, Takle AK, Ward RW (2003) 6-Aryl-pyrazolo[3,4-b]pyridines: potent inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorg Med Chem Lett 13: 3055–3057. doi:10.1016/S0960-894X(03)00645-0

    Article  CAS  PubMed  Google Scholar 

  18. Lin RH, Connolly PJ, Lu YH, Chiu G, Li SJ, Yu Y, Huang SL, Li X, Emanuel SL, Middleton SA, Gruninger RH, Adams M, Fuentes-Pesquera AR, Greenberger LM (2007) Synthesis and evaluation of pyrazolo[3,4-b]pyridine CDK1 inhibitors as anti-tumor agents. Bioorg Med Chem Lett 17: 4297–4302. doi:10.1016/j.bmcl.2007.05.029

    Article  CAS  PubMed  Google Scholar 

  19. Falcó JL, Lloveras M, Buira I, Teixidó J, Borrell JI, Méndez E, Terencio J, Palomer A, Guglietta A (2005) Design, synthesis and biological activity of acyl substituted 3-amino-5-methyl-1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-ones as potential hypnotic drugs. Eur J Med Chem 40: 1179–1187. doi:10.1016/j.ejmech.2005.06.008

    Article  PubMed  CAS  Google Scholar 

  20. Pinto DJP, Orwat MJ, Quan ML, Han Q, Galemmo RA Jr, Amparo E, Wells B, Ellis C, He MY, Alexander RS, Rossi KA, Smallwood A, Wong PC, Luettgen JM, Rendina AR, Knabb RM, Mersinger L, Kettner C, Bai S, He K, Wexler RR, Lam PYS (2006) 1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. Bioorg Med Chem Lett 16: 4141–4147. doi:10.1016/j.bmcl.2006.02.069

    Article  CAS  PubMed  Google Scholar 

  21. Bell MR, Ackerman JH (1990) Pyrazolo[3,4-b]quinolines and their use as antiviral agents. U.S. Patent 4,920,128

  22. Janos RA, Triggle DJ (1983) New developments in calcium ion channel antagonists. J Med Chem 26: 775–785. doi:10.1021/jm00360a001

    Article  Google Scholar 

  23. Sagitullina GP, Lisitskaya LA, Vorontsova MA, Sagitullin RS (2007) Facile synthesis of substituted 1H-pyrazolo[3,4-b]pyridines. Mendeleev Commun 17: 192–193

    Article  CAS  Google Scholar 

  24. Quiroga J, Alvarado M, Insuasty B, Moreno R, Ravina E, Estevez I, de Almedia RH (1999) Synthesis of 5-cyanopyrazolo[3,4-b]pyridines in the reaction of 5-amino-3-methyl-1-phenylpyrazole with arylidene derivatives of malonodinitrile and ethyl cyanoacetate. J Heterocycl Chem 36: 1311–1316. doi:10.1002/jhet.5570360533

    Article  CAS  Google Scholar 

  25. Quiroga J, Hormaza A, Insuasty B, Marquez M (1998) Reaction of 5-amino-1-aryl-3-methylpyrazoles with benzylidene derivatives of Meldrum’s acid: synthesis and characterization of pyrazolo[3,4-b]pyridinones. J Heterocycl Chem 35: 409–412. doi:10.1002/jhet.5570350225

    Article  CAS  Google Scholar 

  26. Quiroga J, Kruz S, Insuasty B, Abonia R, Nogueras M, Sanchez A, Cobo J, Low JN (2001) Synthesis and structural analysis of 5-cyanodihydropyrazolo[3,4-b]pyridines. J Heterocycl Chem 38: 53–60. doi:10.1002/jhet.5570380108

    Article  CAS  Google Scholar 

  27. Zhu S, Tu S, Li T, Zhang X, Ji S, Zhang Y (2005) Synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenylpyridino-[2,3-c]pyrazole under microwave irradiation. Chin J Org Chem 25: 987–990 (in Chinese)

    CAS  Google Scholar 

  28. Tu S, Zhu S, Shao Z, Zou X, Ji S, Zhang Y (2005) One-step synthesis of 4-aryl-3-methyl-6-oxo-1-phenyl-4,5,6,7-tetrahydropyrido[2,3-c]pyrazole under microwave irradiation. Chin J Org Chem 25: 1552–1555 (in Chinese)

    CAS  Google Scholar 

  29. Tu S, Wang Q, Zhang Y, Xu J, Zhang J, Zhu X, Shi F (2007) Design and synthesis of new and significative bifunctional compounds containing two pyrazolo[3,4-b]pyridine nucleis through multicomponent reaction under microwave irradiation. J Heterocycl Chem 44: 811–814. doi:10.1002/jhet.5570440409

    Article  CAS  Google Scholar 

  30. Paul S, Gupta M, Gupta R, Loupy A (2001) Microwave assisted solvent-free synthesis of pyrazolo[3,4-b]quinolines and pyrazolo[3,4-c]pyrazoles using p-TsOH. Tetrahedron Lett 42: 3827–3829. doi:10.1016/S0040-4039(01)00505-6

    Article  CAS  Google Scholar 

  31. Quiroga J, Insuasty B, Hormaza A, Saitz C, Jullian C (1998) Synthesis of 4-aryl-4,7,8,9-tetrahydro-6H-pyrazolo[3,4-b]quinolin-5-ones. J Heterocycl Chem 35: 575–578. doi:10.1002/jhet.5570350313

    Article  CAS  Google Scholar 

  32. Hua GP, Xu JN, Tu SJ, Wang Q, Zhang JP, Zhu XT, Li TJ, Zhu SL, Zhang XJ (2005) Facile three component one-pot synthesis of 5-aryl-1,5,6,7,8,9-hexahydro-2H-pyrazolo[5,4-b]quinolin-6-one derivatives under microwave irradiation. Chin J Org Chem 25: 1610–1614 (in Chinese)

    CAS  Google Scholar 

  33. Fan X, Hu X, Zhang X, Wang J (2004) Ionic liquid promoted Knoevenagel and Michael reactions. Aust J Chem 57: 1067–1071. doi:10.1071/CH04060

    Article  CAS  Google Scholar 

  34. Fan X, Hu X, Zhang X, Wang J (2005) InCl3·4H2O Promoted green preparation of xanthenedione derivatives in ionic liquids. Can J Chem 83: 16–20. doi:10.1139/v04-155

    Article  CAS  Google Scholar 

  35. Fan X, Li Y, Zhang X, Qu G, Wang J (2006) A novel and green version of the Passerini reaction in an ionic liquid ([bmim][BF4]). Can J Chem 84: 794–799. doi:10.1139/V06-070

    Article  CAS  Google Scholar 

  36. Zhang X, Fan X, Niu H, Wang J (2003) An ionic liquid as a recyclable medium for the green preparation of α, α’-bis(substituted benzyli- dene)cycloalkanones catalyzed by FeCl3· 6H2O. Green Chem 5: 267–269. doi:10.1039/b212155g

    Article  CAS  Google Scholar 

  37. Fan X, Zhang X, Zhou L, Keith KA, Prichard MN, Kern ER, Torrence PF (2006) Toward orthopoxvirus countermeasures: a novel heteromorphic nucleoside of unusual structure. J Med Chem 49: 4052–4054. doi:10.1021/jm060404n

    Article  CAS  PubMed  Google Scholar 

  38. Fan X, Zhang X, Zhou L, Keith KA, Prichard MN, Kern ER, Torrence PF (2006) 5-(dimethoxymethyl)-2’-deoxyuridine: a novel gem diether nucleoside with anti-orthopoxvirus activity. J Med Chem 49: 3377–3382. doi:10.1021/jm0601710

    Article  CAS  PubMed  Google Scholar 

  39. Fan X, Zhang X, Zhou L, Keith KA, Prichard MN, Kern ER, Torrence PF (2006) Assembling a smallpox biodefense by interrogating 5-substituted pyrimidine nucleoside chemical space. Antiviral Res 71: 201–205. doi:10.1016/j.antiviral.2006.04.015

    Article  CAS  PubMed  Google Scholar 

  40. Fan X, Zhang X, Zhou L, Keith KA, Prichard MN, Kern ER, Torrence PF (2006) A pyrimidine-pyrazolone nucleoside chimera with potent in vitro anti-orthopoxvirus activity. Bioorg Med Chem Lett 16: 3224–3228. doi:10.1016/j.bmcl.2006.03.043

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. School of Chemistry and Environmental Sciences, Henan Key Laboratory for Environmental Pollution Control, Henan Normal University, Xinxiang, Henan, 453007, People’s Republic of China

    Xinying Zhang, Dongfang Li, Xuesen Fan, Xia Wang, Xiaoyan Li, Guirong Qu & Jianji Wang

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  1. Xinying Zhang
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  2. Dongfang Li
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  3. Xuesen Fan
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  4. Xia Wang
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  5. Xiaoyan Li
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  6. Guirong Qu
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  7. Jianji Wang
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Correspondence to Xuesen Fan or Guirong Qu.

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Zhang, X., Li, D., Fan, X. et al. Ionic liquid-promoted multi-component reaction: novel and efficient preparation of pyrazolo[3,4-b]pyridinone, pyrazolo[3,4-b]-quinolinone and their hybrids with pyrimidine nucleoside. Mol Divers 14, 159–167 (2010). https://doi.org/10.1007/s11030-009-9168-2

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  • DOI: https://doi.org/10.1007/s11030-009-9168-2

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