Download PDF
Synlett 2006(19): 3267-3270  
DOI: 10.1055/s-2006-956487
LETTER
© Georg Thieme Verlag Stuttgart · New York

Highly Regioselective Synthesis of 1-Aryl-3,4,5-Substituted Pyrazoles

Francis Gosselin*a, Paul D. O’Shea*a, Robert A. Webstera, Robert A. Reamerb, Richard D. Tillyerb, Edward J. J. Grabowskib
a Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 route transcanadienne, Kirkland, Québec, H9H 3L1, Canada
Fax: +1(514)4284936; e-Mail: francis_gosselin@merck.com;
b Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Further Information

Publication History

Received 10 August 2006
Publication Date:
23 November 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

A highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles based on the condensation of 1,3-diketones with arylhydrazines is described. The reaction proceeds at room temperature in N,N-dimethylacetamide and furnishes pyrazoles in 59-98% yields.

Key words

1,3-diketones - arylhydrazines - cyclocondensation - regioselectivity - amide solvents

    References and Notes

  • 1 Penning TD. Talley JJ. Bertenshaw SR. Carter JS. Collins PW. Docter S. Graneto MJ. Lee LF. Malecha JW. Miyashiro JM. Rogers RS. Rogier DJ. Yu SS. Anderson GD. Burton EG. Cogburn JN. Gregory SA. Koboldt CM. Perkins WE. Seibert K. Veenhuizen AW. Zhang YY. Isakson PC. J. Med. Chem.  1997,  40:  1347 
    CrossrefPubMedSearch in Google Scholar
  • 2 Pruitt JR. Pinto DJP. Galemmo RA. Alexander RS. Rossi KA. Wells BL. Drummond S. Bostrom LL. Burdick D. Bruckner R. Chen H. Smallwood A. Wong PC. Wright MR. Bai S. Luettgen JM. Knabb RM. Lam PYS. Wexler RR. J. Med. Chem.  2003,  46:  5298 
    CrossrefSearch in Google Scholar
  • 3 Rinaldi-Carmona M. Barth F. Héaulme M. Shire D. Calandra B. Congy C. Martinez S. Maruani J. Néliat G. Caput D. Ferrara P. Soubrié P. Brelière JC. Le Fur G. FEBS Lett.  1994,  350:  240 
    CrossrefSearch in Google Scholar
  • 4 Haque TS. Tadesse S. Marcinkeviciene J. Rogers MJ. Sizemore C. Kopcho LM. Amsler K. Ecret LD. Zhang DL. Hobbs F. Slee A. Trainor GL. Stern AM. Copeland RA. Combs AP. J. Med. Chem.  2002,  45:  4669 
    CrossrefSearch in Google Scholar
  • 5a Gilchrist TL. Heterocyclic Chemistry   2nd ed.:  Wiley; New York: 1992.  Chap. 8. p.294 
    Search in Google Scholar
  • For reviews on pyrazoles see:
  • 5b Elguero J. In Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Pergamon Press; Oxford: 1996.  p.1 
    Search in Google Scholar
  • 5c Elguero J. In Comprehensive Heterocyclic Chemistry II   Vol. 5:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1985.  p.167 
    Search in Google Scholar
  • 6a Katritzky AR. Wang M. Zhang S. Voronkov MV. J. Org. Chem.  2001,  66:  6787 
    CrossrefSearch in Google Scholar
  • 6b Wang X.-J. Tan J. Grozinger K. Betageri R. Kirrane T. Proudfoot JR. Tetrahedron Lett.  2000,  41:  5321 
    CrossrefSearch in Google Scholar
  • 6c Wang X.-J. Tan J. Grozinger K. Tetrahedron Lett.  2000,  41:  4713 
    CrossrefSearch in Google Scholar
  • 6d Wang X.-J. Tan J. Zhang L. Org. Lett.  2000,  2:  3107 
    CrossrefSearch in Google Scholar
  • 6e Huang YR. Katzenellenbogen JA. Org. Lett.  2000,  2:  2833 
    CrossrefSearch in Google Scholar
  • 6f Paulson AS. Eskildsen J. Vedsø P. Begtrup M. J. Org. Chem.  2002,  67:  3904 
    CrossrefSearch in Google Scholar
  • 6g Singh SK. Reddy MS. Shivaramakrishna S. Kavhita D. Vasudev R. Babu JM. Sivalakshmidevi A. Rao YK. Tetrahedron Lett.  2004,  45:  7679 
    CrossrefSearch in Google Scholar
  • 6h Deng X. Mani NS. Org. Lett.  2006,  8:  3505 
    CrossrefSearch in Google Scholar
  • 6i Peruncheralathan S. Yadav AK. Ila H. Jujappa H. J. Org. Chem.  2005,  70:  9644 
    CrossrefSearch in Google Scholar
  • 6j Perunchalathan S. Khan TA. Ila H. Junjappa H. J. Org. Chem.  2005,  70:  10030 
    CrossrefSearch in Google Scholar
  • 6k Nielsen J. Persson T. Org. Lett.  2006,  8:  3219 
    CrossrefSearch in Google Scholar
  • 7 For example: DMAc: ε = 37.78, µ = 3.72 D; EtOH: ε = 24.55, µ = 1.69 D; AcOH: ε = 6.15, µ = 1.74 D; In Lange’s Handbook of Chemistry   13th ed.:  Dean JA. McGraw-Hill; New York: 1985.  Chap. 10. p.103-116  
  • 9 Stonehouse J. Adell P. Keeler J. Shaka AJ. J. Am. Chem. Soc.  1994,  116:  6037 
    CrossrefSearch in Google Scholar
8

Pyrazoles obtained by condensation of arylhydrazine hydrochloride salts with 1,3-diketones often gave isolable solvates of DMAc that could be broken to give pyrazoles by simple recrystallization from i-PrOH-H2O.

10

Representative Procedure: To a solution of 4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione (1b; 1.47 g, 5 mmol) in N,N-dimethylacetamide (20 mL) at r.t. was added phenylhydrazine hydrochloride (723 mg, 5 mmol), followed by 10 N HCl (250 µL, 50 mol%). The mixture was let to stir for 24 h at r.t., cooled to 0 °C and H2O (20 mL) was slowly added. After diluting with toluene (30 mL), the organic layer was washed with H2O (3 × 20 mL) and concentrated to a brown oil that crystallized. The crystals were washed with cold heptane (3 × 5 mL) to give phenyl-3-(trifluoromethyl)-5-(4-bromophenyl)-1H-pyrazole(2j) as colorless crystals; yield: 1.36 g (74%); mp 103.7-105.4 °C. 1H NMR (500 MHz, CDCl3): δ = 7.44 (d, J = 7.4 Hz, 2 H), 7.36 (m, 3 H), 7.28 (m, 2 H), 7.07 (d, J = 7.4 Hz, 2 H), 6.74 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 143.4, 143.3 (q, J = 39 Hz), 138.9, 131.9, 130.2, 129.2, 128.7, 128.0, 125.4, 123.4, 121.1 (q, J = 269 Hz), 105.6. LRMS: m/z calcd for C16H10BrF3N2: 367.16; found [M - 1]: 366.8. Pyrazoles could also be readily purified by column chromatography using 5-20% EtOAc-hexanes as eluent.