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

Abstract

Replacing the fluorine: 3‐Fluorinated pyrazoles were regioselectively synthesized by sequential substitution reactions of 2‐trifluoromethyl‐1‐alkenes (see scheme). SN2′‐type reactions of 2‐trifluoromethyl‐1‐alkenes with deprotonated tert‐butoxylcarbonyl‐ or arylhydrazines afforded 1,1‐difluoro‐1‐alkenes, which were tosylated and then treated with NaH to give the desired 3‐fluoropyrazoles.

Vinylogous Reactivity of Enol Diazoacetates with Donor–Acceptor Substituted Hydrazones. Synthesis of Substituted Pyrazole Derivatives

“…12 Pyrazoles having functionality installed at the C-3 or C-5 position have attracted a significant amount of attention. 13 Numerous methodologies have been reported for pyrazole syntheses, 14 and the Knorr condensation reaction of dicarbonyl compounds is the most prevalent approach for pyrazole synthesis. 15 However, this classic condensation between α,γ-diketoesters and hydrazines is hampered by low regioselectivity 16 and general synthetic processes for functionalized pyrazoles having structural diversity and complexity continue to be needed.…”

Review of recent advances in CF bond activation of aliphatic fluorides

“…Based on this fact, Ichikawa reported the regioselective synthesis of 3-fluoropyrazoles by substitution of two fluorine atoms in an allylic trifluoromethyl group (Scheme 22d) [54]. This transformation includes the following two steps: 1) the S N 2'-type reaction of 2-trifluoromethyl-1-alkenes with lithio-or sodiohydrazines gives 1,1-difluoro-1-alkenes and 2) the cyclization of tosylated 1,1-difluoro-1-alkenes affords 3-fluoropyrazoles.…”

A General Synthesis of α‐Trifluoromethylstyrenes through Palladium‐Catalyzed Cross‐Couplings with 1,1,1‐Trifluoroacetone Tosylhydrazone

“…[10] Very interestingly, the intramolecular version of this reaction with ortho-substituted a-trifluoromethylstyrenes has enabled the synthesis of a wide variety of heterocycles bearing di-and trifluorinated onecarbon units through nucleophilic cyclizations, depending on the reaction conditions, [11] and even monofluorinated heterocycles. [12] Moreover, a-trifluoromethylstyrenes can also participate as dienophiles and dipolarophiles in cycloaddition reactions, [13] and serve as an entry into the biologically relevant 2,2,2-tri-…”