An Efficient Synthesis of Tetrasubstituted Pyrazoles

Abstract

An efficient method for the preparation of 1,3,4,5-tetrasubstituted pyrazoles promoted by butyllithium and palladium(0) cross-coupling reactions is described. Advantages of this new method include high yields and mild reaction conditions, which tolerate functional groups such as esters.

Key words

pyrazoles - metallation - cross-coupling - palladium

References

• 1 Zhang J. Didierlaurent S. Fortin M. Lefrançois D. Uridat E. Vevert JP. Bioorg. Med. Chem. Lett.  2000,  10:  2575 
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• 3 Wu T.-T, and Scribner AW. inventors; W.O. Patent  0164651.  ; Chem. Abstr. 2001, 135, 226990
• 4 Luethy C, Nebel K, and Wenger J. inventors; W.O. Patent  0130782.  ; Chem. Abstr. 2001, 134, 340513
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General Procedure for Pyrazoles 2. To a stirred solution of pyrazole 1 (1 equiv, typically 2.7 mmol) in dry THF (10 mL) under nitrogen at -78 °C was added dropwise BuLi (1 equiv). The mixture was allowed to warm to -45 °C, stirred at this temperature for 1 h and then cooled to -78 °C. The electrophilic reagent (1.1 equiv) dissolved in THF (5 mL) was added to the solution and the temperature was warmed to 25 °C. After TLC analysis, an aq solution of NH₄Cl was added, the mixture was extracted with EtOAc, the organic layer was washed with H₂O, dried (MgSO₄) and evaporated. The residue was purified by flash chromatography on silica gel (eluent: CH₂Cl₂-MeOH, 95:5) to give the pyrazoles 2.

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General Procedures for Pyrazoles 3
Method A: To a stirred solution of pyrazole 2b (1 equiv, typically, 1mmol) and tetrakistriphenylphosphine palladium (0.05 equiv) in toluene-MeOH (4/1, 5 mLmmol^-1 of 2b) under nitrogen was added a 2 M aq solution of Na₂CO₃ (2 equiv), copper(I) iodide (0.05 equiv) and the arylboronic acid (2 equiv). The mixture was refluxed for 12 h, after cooling to r.t., water was added, the mixture was then extracted with EtOAc, the organic layer was washed with H₂O, dried (MgSO₄) and evaporated. The residue was purified by flash chromatography on silica gel (eluent: CH₂Cl₂-MeOH, 95:5) to give the pyrazoles 3a-c.
Method B: For this method the zinc chloride pyrazole 2c was not isolated. After TLC analysis showed completion of reaction, a solution of tetrakistriphenylphosphine palladium (0.05 equiv) and halogenated aromatic compound (1 equiv) in dry THF (5 mL) was added. The mixture was refluxed for 12 h and then cooled to r.t. A 10% aq solution of HCl (10 mL) was added. The mixture was then extracted with EtOAc, the organic layer was washed with H₂O, dried (MgSO₄) and evaporated. The residue was purified by flash chromatography on silica gel (eluent: CH₂Cl₂-MeOH, 95:5) to give the pyrazoles 3d,e.
Method C: A solution of pyrazole 2b (1 equiv, typically
1 mmol), copper(I) iodide (0.05 equiv), K₂CO₃ (1.3 equiv), palladium(II) acetate (0.05 equiv), triphenylphosphine
(0.2 equiv) and the olefin (1.2 equiv) in dried DMF (3 mLmmol^-1 of 2b) was heated at 140 °C for 10 h in a sealed tube. After cooling, the mixture was poured into H₂O
(20 mL), extracted with CH₂Cl₂, the organic layer was washed with H₂O, dried (MgSO₄) and evaporated. The residue was purified by flash chromatography on silica gel (eluent:CH₂Cl₂-MeOH, 95:5) to give the pyrazoles 3f-j.