Solution-Phase and Solid-Phase Synthesis of 1-Pyrazol-3-ylbenzimidazoles

Jaime Portilla; Jairo Quiroga; Rodrigo Abonía; Braulio Insuasty; Manuel Nogueras; Justo Cobo; Ernesto G. Mata

doi:10.1055/s-2008-1032030

PAPER

Solution-Phase and Solid-Phase Synthesis of 1-Pyrazol-3-ylbenzimidazoles

Jaime Portilla^a, Jairo Quiroga*^a, Rodrigo Abonía^a, Braulio Insuasty^a, Manuel Nogueras^b, Justo Cobo^b, Ernesto G. Mata*^c
^a Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360, Cali, Colombia
e-Mail: jaiquir@gmail.com;
^b Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
^c Instituto de Química Orgánica de Síntesis (CONICET - UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
Fax: +54(341)4370477; e-Mail: mata@iquios.gov.ar;

Abstract

All articles of this category

Abstract

The facile solution and solid-phase synthesis of 1-pyrazol-3-ylbenzimidazoles from 4-fluoro-3-nitrobenzoate derivatives and 5(3)-amino-3(5)-subtituted-1H-pyrazoles is reported. The key step is the unexpected nucleophilic aromatic displacement of the activated fluorine by the exocyclic amino group of the pyrazole ring leading to 4-pyrazolylamino-3-nitrobenzoate derivatives, which are easily converted into the corresponding 1-pyrazol-3-ylbenzimidazoles in very high isolated yield. These novel methodologies would be very useful for the generation of libraries of diverse 1-heteroaryl derivatives of benzimidazoles.

Key words

solid-phase synthesis - combinatorial chemistry - heterocycles - benzimidazoles - pyrazoles

Full Text

References

1a Combinatorial Chemistry and Molecular Diversity in Drug Discovery Gordon EM. Kerwin JF. Wiley; New York: 1998.

1b Bunin BA. The Combinatorial Index Academic Press; London: 1998.

1c Obrecht D. Villalgordo JM. Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries Elsevier; New York: 1998.

1d Terrett NK. Combinatorial Chemistry Oxford University Press; Oxford: 1998.

1e Combinatorial Chemistry Fenniri H. Oxford University Press; Oxford: 2000.

2a Seneci P. Solid-Phase Synthesis and Combinatorial Technologies Wiley; New York: 2000.

2b Obrecht D. Villalgordo JM. Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries Elsevier; New York: 1998.

2c Solid-Phase Organic Synthesis Burgess K. Wiley; New York: 2000.

2d Solid-Phase Organic Synthesis Czarnik AW. Wiley; New York: 2001.

2e Zaragoza DF. Organic Synthesis on Solid Phase 2nd ed.: Wiley-VCH; Weinheim: 2002.

3 Mazur S. Jayalekshmy P. J. Am. Chem. Soc. 1979, 101: 677

4a Dolle RE. J. Comb. Chem. 2003, 5: 693

4b Dolle RE. J. Comb. Chem. 2004, 6: 623

4c Dolle RE. J. Comb. Chem. 2005, 7: 739

4d Dolle RE. Le Bourdonnec B. Morales GA. Moriarty KJ. Salvino JM. J. Comb. Chem. 2006, 8: 587

5 Al-Muhaimeed H. J. Int. Med. Res. 1997, 25: 175

6 Richter JE. Am. J. Gastroenterol. 1997, 92: 34

7 Cheng JB. Cooper K. Duplantier AJ. Eggler JF. Kraus KG. Marshall SC. Marfat A. Masamune H. Shirley JT. Tickner JE. Umland JP. Bioorg. Med. Chem. Lett. 1995, 5: 1965

8a Thomas AP. Allott CP. Gibson KH. Major JS. Masek BB. Oldham AA. Ratcliffe AH. Roberts DA. Russell ST. Thomason DA. J. Med. Chem. 1992, 35: 877

8b Kubo K. Inada Y. Kohara Y. Sugiura Y. Ojima M. Itoh K. Furukawa Y. Nishikawa K. Naka T. J. Med. Chem. 1993, 36: 1772

9 Kugishima H. Horie T. Imafuku K. J. Heterocycl. Chem. 1994, 31: 1557

10a Evans BE. Rittle KE. Bock MG. DiPardo RM. Freidinger RM. Whitter WL. Lundell GF. Veber DF. Anderson PS. Chang RSL. Lotti VJ. Cerino DJ. Chen TB. Kling PJ. Kunkel KA. Springer JP. Hirshfield J. J. Med. Chem. 1988, 31: 2235

10b Nicolaou KC. Pfefferkorn JA. Roecker AJ. Cao G. Barluenga S. Mitchell HJ. J. Am. Chem. Soc. 2000, 122: 9939

10c Patchett AA. Nargund RP. Ann. Rep. Med. Chem. 2000, 35: 289

10d Falcó JL. Piqué M. González M. Buira I. Méndez E. Terencio J. Pérez C. Príncep M. Palomer A. Guglietta A. Eur. J. Med. Chem. 1992, 27: 39

11a Quiroga J. Portilla J. Serrano H. Abonía R. Insuasty B. Nogueras M. Cobo J. Tetrahedron Lett. 2007, 48: 1987

11b Sortino MA. Delgado P. Juárez SF. Quiroga J. Abonía R. Insuasty B. Nogueras M. Rodero L. Gariboto FM. Enriz RD. Zacchino SA. Bioorg. Med. Chem. 2007, 15: 484

11c Insuasty H. Estrada M. Cortés E. Quiroga J. Insuasty B. Abonía R. Nogueras M. Cobo J. Tetrahedron Lett. 2006, 47: 5441

11d Quiroga J. Cisneros C. Insuasty B. Abonía R. Nogueras M. Sortino M. Zacchino S. J. Heterocycl. Chem. 2006, 43: 463

11e Quiroga J. Cruz S. Insuasty B. Abonía R. Nogueras M. Cobo J. Tetrahedron Lett. 2006, 47: 27

11f Quiroga J. Portilla J. Insuasty B. Abonía R. Nogueras M. Sortino M. Zacchino S. J. Heterocycl. Chem. 2005, 42: 61

12a Delpiccolo CML. Mata EG. Tetrahedron: Asymmetry 2002, 13: 905

12b Delpiccolo CML. Fraga MA. Mata EG. J. Comb. Chem. 2003, 5: 208

12c Delpiccolo CML. Mata EG. Tetrahedron Lett. 2004, 45: 4085

12d Delpiccolo CML. Méndez L. Fraga MA. Mata EG. J. Comb. Chem. 2005, 7: 331

12e Méndez L. Delpiccolo CML. Mata EG. Synlett 2005, 1563

12f Testero SA. Mata EG. Org. Lett. 2006, 8: 4783

12g Méndez L. Testero SA. Mata EG. J. Comb. Chem. 2007, 9: 189

For synthesis of 1-pyrazolyl benzimidazol-2-thione and related compounds, see:

13a Ahabchane NH. Essassi EM. Lopez L. Bellan J. Lamandé L. C. R. Acad. Sci., Ser. IIc 2000, 3: 313

13b Ahabchane NH. Essassi EM. Bellan J. Lopez L. Lamandé L. Phosphorus, Sulfur Silicon Relat. Elem. 2001, 173: 175

14 For a review on the solid-phase synthesis of benzimidazole, see: Kamal A. Reddy KL. Devaiah V. Shankaraiah N. Rao MV. Mini Rev. Med. Chem. 2006, 6: 71

For displacement of 4-fluoro-3-nitrobenzene derivatives by anilines, phenols and imidazoles, see:

15a Ankala SV. Fenteany G. Synlett 2003, 825

15b Kundu B. Sawant D. Chhabra R. J. Comb. Chem. 2005, 7: 317

16 The structures of methyl 3-nitro-4-(5-phenyl-1H-pyrazol-3-ylamino)benzoate (6a) and methyl 4-(5-amino-3-phenyl-1H-pyrazol-1-yl)-3-nitrobenzoate (4a) were established by ¹H and ¹³C NMR spectroscopy and corroborated by X-ray crystal structure analysis, see: Portilla J. Mata EG. Cobo J. Low JN. Glidewell Ch. Acta Crystallogr. 2007, C63: o510

17 Compound 4 was obtained only when the reaction was performed at high temperature, probably such heating favored a charge transfer from the amino group to the pyrazole ring, see: Quiroga J. Insuasty B. Rincón R. Larrahondo M. Hanold H. Meier H. J. Heterocycl. Chem. 1994, 31: 1333

18 The structures of methyl 3-nitro-4-(5-methyl-1H-pyrazol-3-ylamino)benzoate (6b) and methyl 1-(5-methyl-1H-pyrazol-3-yl)-1H-benzimidazole-5-carboxylate (1ba) were corroborated by X-ray crystal structure analysis, see: Portilla J. Mata EG. Nogueras M. Cobo J. Low JN. Glidewell Ch. Acta Crystallogr. 2007, C63: o38

19a Soliman R. Habib NS. Ashour FA. El-Taibei M. Boll. Chim. Farm. 2001, 140: 140 ; Chem. Abstr. 2001, 136, 167321

19b Essassi EM. Salem M. Bull. Soc. Chim. Belg. 1985, 94: 755 ; Chem. Abstr. 1986, 105, 191007

19c Habib NS. Soliman R. Ashour FA. El-Taiebi M. Pharmazie 1997, 52: 844 ; Chem. Abstr. 1997, 128, 61463