Fluorine-Sacrificial Cyclizations as an Access to 5-Fluoropyrazoles

Abstract

Methyl 3‐methoxy‐2‐trifluoromethylacrylate 1, readily prepared by Wittig reaction from methyl 3,3,3‐trifluoropyruvate, has been treated with a number of aryl‐ (or hetaryl‐) hydrazines. Under mild base‐catalysis, the resulting 3‐hydrazinoacrylates 6 undergo consecutive hydrogen fluoride elimination and intramolecular nucleophilic addition to afford methyl 1‐(het)aryl‐5‐fluoropyrazole‐4‐carboxylates 7. 5‐Aminopyrazoles 8 have been obtained by direct reaction of the ester 7a with a lithium amide, whereas 5‐fluoro‐1‐phenylpyrazole‐4‐carboxamides 10 have been formed by condensation of the 5‐fluoro‐1‐phenylpyrazole‐4‐carboxylic acid 9 with amines.

The Organometallic Approach to Molecular Diversity − Halogens as Helpers

“…Neither subsequent functionalization (yield after carboxylation: 11%) nor, if desired, reductive removal of the halogen causes any special problems, although yields are often poor (Scheme 25). [79] Whoever prepares 1-methyl-5-(trifluoromethyl)pyrazole will receive 1-methyl-3-(trifluoromethyl)pyrazole (46) as an extra. Fortunately, the two isomers can readily be separated at the stage of their precursors.…”

“…Bromine as a ''hydrogen-protective'' and activating group: shifting the site of deprotonation from the 4-to the 3-position in 1-phenyl-5-(trifluoromethyl)pyrazole The 4-bromo compound 47 obtained upon bromination reacts with LIDA once more at the 5-position, as evidenced by electrophilic trapping (with carbon dioxide, for example; yield: 89%). [79] With butyllithium, however, a halogen/metal exchange takes place at the 4-position (affording the corresponding acid in 85% yield after carboxylation; Scheme 26). [79] Scheme 26.…”

“…[79] With butyllithium, however, a halogen/metal exchange takes place at the 4-position (affording the corresponding acid in 85% yield after carboxylation; Scheme 26). [79] Scheme 26. 4-Bromo-1-methyl-3-(trifluoromethyl)pyrazole: hydrogen/metal exchange at the 5-position and halogen/metal exchange at the 4-position As pointed out in the Introduction, the controlled regiodivergent functionalization of core materials constitutes the cornerstone of our Shrapnel sequences concept.…”

Fluorinated Five‐Membered Nitrogen‐Containing Heterocycles

“…139 Schlosser developed a "fluorine sacrificial" route to 5-fluoropyrazoles. 140 Treatment of methyl 3-methoxy-2-trifluoromethyl-2-propenoate with aryl or heteroaryl hydrazines resulted in nucleophilic displacement of the methoxy group. Under weakly basic conditions, cyclization occurred with fluorine elimination to give 1-(het)aryl-4-carboxymethyl-5-fluoropyrazoles 126 in moderate yields.…”

Brominated 4‐(Trifluoromethyl)pyrimidines: A Convenient Access to Versatile Intermediates

“…Germany, 2004) by reaction with phosphorus tribromide. The analogous condensation of urea with 3-bromo-4-ethoxy-1,1,1-trifluoro-3-buten-2-one [22] produced tars rather than the expected 5-bromo-4-(trifluoromethyl)-2(1H)-pyrimidinone (5), which is a potential precursor of 5-bromo-4-(trifluoromethyl)pyrimidine (2). Heating thiourea together with ethyl 4,4,4-trifluoroacetoacetate gave 2-thioxo-6-(trifluoromethyl)-2,3-dihydropyrimidin-4(1H)-one [14] (81%).…”