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

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 
• 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 
• 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 
• 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 
• 5a Gilchrist TL. Heterocyclic Chemistry   2nd ed.:  Wiley; New York: 1992.  Chap. 8. p.294 
• 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 
• 5c Elguero J. In Comprehensive Heterocyclic Chemistry II   Vol. 5:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1985.  p.167 
• 6a Katritzky AR. Wang M. Zhang S. Voronkov MV. J. Org. Chem.  2001,  66:  6787 
• 6b Wang X.-J. Tan J. Grozinger K. Betageri R. Kirrane T. Proudfoot JR. Tetrahedron Lett.  2000,  41:  5321 
• 6c Wang X.-J. Tan J. Grozinger K. Tetrahedron Lett.  2000,  41:  4713 
• 6d Wang X.-J. Tan J. Zhang L. Org. Lett.  2000,  2:  3107 
• 6e Huang YR. Katzenellenbogen JA. Org. Lett.  2000,  2:  2833 
• 6f Paulson AS. Eskildsen J. Vedsø P. Begtrup M. J. Org. Chem.  2002,  67:  3904 
• 6g Singh SK. Reddy MS. Shivaramakrishna S. Kavhita D. Vasudev R. Babu JM. Sivalakshmidevi A. Rao YK. Tetrahedron Lett.  2004,  45:  7679 
• 6h Deng X. Mani NS. Org. Lett.  2006,  8:  3505 
• 6i Peruncheralathan S. Yadav AK. Ila H. Jujappa H. J. Org. Chem.  2005,  70:  9644 
• 6j Perunchalathan S. Khan TA. Ila H. Junjappa H. J. Org. Chem.  2005,  70:  10030 
• 6k Nielsen J. Persson T. Org. Lett.  2006,  8:  3219 
• 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 

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.