Substitution of Two Fluorine Atoms in a Trifluoromethyl Group: Regioselective Synthesis of 3‐Fluoropyrazoles

Abstract

Fluorine atoms in vinylic and allylic positions are highly versatile substituents. [1] Among the compounds bearing these fluorine atoms, 2-trifluoromethyl-1-alkenes and 1,1-difluoro-1-alkenes are attractive as building blocks for organic syntheses. [2] Because these fluoroalkenes are electron-deficient, they inherently react with nucleophiles instead of electrophiles. 2-Trifluoromethyl-1-alkenes are subjected to nucleophilic attack at the carbon atom in the position g with respect to the fluorine substituents (Scheme 1 A). [2] Succes-Supporting information for this article is available on the WWW under http://dx.

Introduction of Fluorine and Fluorine‐Containing Functional Groups

“…Similarly, trifluoromethylstyrene derivatives can rearrange to geminal difluoroalkenyl amines528 after the addition of lithium amide or allylic alkyl difluoroalkenes529 or organolithium reagents (Scheme ). More recently, the addition of substituted hydrazine nucleophiles to trifluoromethylstyrene followed by intramolecular cyclization was shown to yield various 3‐fluoropyrazole products 530. Trifluoromethyl tosylhydrazones rearrange to difluoroalkenes with 2.5 equivalents of n BuLi or methyllithium through extrusion of N 2 gas and tolylsulfinate (Scheme ) 517.…”

Selective Incorporation of Fluorine in Pyrazoles

“…Under similar conditions, they condensed (2,2,2-trifluoroethyl)hydrazine with 1,3-diketone 3 to prepare N-(2,2,2-trifluoroethyl)pyrazoles 4a and 4b. [32] Fused-ring N-fluoroarylpyrazole systems have also been prepared and examples are shown in Scheme 2. Song and Zhu condensed highly fluorinated arylhydrazines and trifluoromethylated 1,3-diketones 5 under neutral to acidic conditions to give regioisomeric N-fluoroarylpyrazoles 6a and its Scheme 1.…”

“…An added benefit to this synthesis is the unusual incorporation of fluorine at the 3 position of the pyrazole. [32] Fused-ring N-fluoroarylpyrazole systems have also been prepared and examples are shown in Scheme 2. Molteni and co-workers used microwave radiation to condense cycloalkane-1,3-diones 11 with fluorinated hydrazines to achieve fused-ring pyrazoles 12 in yields ranging from 66-87 %.…”

Einführung von Fluor und fluorhaltigen funktionellen Gruppen

“…B. LAH, Organolithiumreagentien und Lithiumenolate, in 1,1-Difluoralkene überführt werden (Schema 140). [530] Trifluormethyltosylhydrazone lagern sich durch Umsetzung mit 2.5 ¾quivalenten nBuLi oder Methyllithium unter Abspaltung von Stickstoffgas und Tolylsulfinat zu Difluoralkenen um (Schema 141). Au-katalysierte Fluorcyclisierung von Propargylketonen.…”

“…Vor kurzem wurde eine Reihe von 3-Fluorpyrazolen durch Addition substituierter Hydrazinnucleophile an Trifluormethylstyrol und nachfolgende intramolekulare Cyclisierung hergestellt. [530] Trifluormethyltosylhydrazone lagern sich durch Umsetzung mit 2.5 ¾quivalenten nBuLi oder Methyllithium unter Abspaltung von Stickstoffgas und Tolylsulfinat zu Difluoralkenen um (Schema 141). [517] Außerdem induziert nBuLi die Ringçffnung von Chlordifluormethylepoxiden zu 1,1-Difluorallylalkoholen.…”