One-pot synthesis of N-arylpyrazoles from arylhalides

Organic Letters

Volumn 11, Issue 10, 2009, Pages 2097-2100

  Gerstenberger, Brian S ^a   Rauckhorst, Mark R ^a   Starr, Jeremy T ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HALOGENATED HYDROCARBON; PYRAZOLE DERIVATIVE;

ARTICLE; CATALYSIS; CHEMICAL STRUCTURE; CHEMISTRY; COMBINATORIAL CHEMISTRY; SYNTHESIS;

CATALYSIS; COMBINATORIAL CHEMISTRY TECHNIQUES; HYDROCARBONS, HALOGENATED; MOLECULAR STRUCTURE; PYRAZOLES;

EID: 66149125218     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol900515a     Document Type: Article

References (18)

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11. For an example of the state of the art, CuI-catalyzed N-arylation of pyrazole or 3-methyl-1H-pyrazole proceeded in 71% and 50% yield, respectively, after 40 h reaction time. Regioselectivity of arylation of 3-methyl-lH-pyrazole was 5:1 favoring the opposite regioisomer to the analogous example in our own work (Table 1, entry 4). See: Zhu, L.; Li, G.; Luo, L.; Guo, P.; Lan, J.; You, J. J. Org. Chem. 2009, 74, 2200-2202.
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14. Representative Procedure: 4-Chloro-l-(4-fluorophenyl)-lH-pyrazole (8). To a solution of 4-fluoroiodobenzene (222 mg, 1.0 equiv) in THF (4 mL) at -78 °C was added n-BuLi (2.5 M in hexanes, 0.42 mmol, 1.05 equiv). The reaction was stirred for 5 min, and then di-tert-butyl azodicarboxylate (242 mg, 1.05 equiv) in THF (1 mL) was added in one portion. The reaction changed from slightly yellow to amber color. The reaction was removed from the ice bath and allowed to warm to room temperature over 30 min. To the reaction mixture was added 2-chloroma-lonaldehyde (118 mg, 1.05 equiv) followed by 4 N HC1 in dioxane (∼5 mL). The reaction changed from an amber color to light yellow with the addition of the acid. The reaction was then heated to 80 °C for 10 min (the reaction turned dark amber color) then cooled to room temperature. The reaction was neutralized with sodium bicarbonate to pH ∼7 and extracted with ethyl acetate (5 mL × 3). The organic layer was dried with sodium sulfate, filtered, and concentrated to give an amber oil, which by TLC showed only one major spot above baseline (8:2 heptane/ethyl acetate). The reaction was purified via silica gel chromatography to give an off-white solid (125 mg, 64%).
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18. We occasionally observed formation of N-butylpyrazoles as side products of unreacted n-BuLi addition to DBAD. Although we did not pursue this avenue of research, we believe the scope may extend beyond aryl and heteroaryl substrates.