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Switchable Reactivity: The Site‐Selective Functionalization of Trifluoromethyl‐Substituted Pyrazoles
Author(s) -
Schlosser Manfred,
Volle JeanNoël,
Leroux Frédéric,
Schenk Kurt
Publication year - 2002
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/1099-0690(200209)2002:17<2913::aid-ejoc2913>3.0.co;2-d
Subject(s) - trifluoromethyl , chemistry , lithium diisopropylamide , pyrazole , metalation , deprotonation , regioselectivity , ring (chemistry) , medicinal chemistry , reagent , stereochemistry , organic chemistry , catalysis , ion , alkyl
Modern organometallic methods enable the regioflexible conversion of simple heterocyclic starting materials into families of isomers and congeners. Depending on the choice of the reagent, 1‐methyl‐5‐(trifluoromethyl)pyrazole ( 1 ) undergoes deprotonation and subsequent carboxylation mainly or exclusively at either the 4‐position of the heterocycle or at the nitrogen‐attached methyl group. Similarly, 1‐phenyl‐5‐(trifluoromethyl)pyrazole ( 5 ) and 3‐methyl‐1‐phenyl‐5‐(trifluoromethyl)pyrazole ( 8 ) are selectively attacked by lithium diisopropylamide at the heterocyclic 4‐position and by butyllithium concomitantly at the 4‐position and the ortho position of the phenyl ring. In contrast, metalation of 1‐methyl‐3‐(trifluoromethyl)pyrazole ( 2 ) occurs only at the 5‐position, whatever the organometallic or metal amide base. Further sites become accessible to functionalization if bromine is introduced into the heterocyclic or aromatic ring. This has been demonstrated with 4‐bromo‐1‐methyl‐5‐(trifluoromethyl)pyrazole ( 3 ), 4‐bromo‐1‐methyl‐3‐(trifluoromethyl)pyrazole ( 4 ), 4‐bromo‐1‐methyl‐5‐(trifluoromethyl)pyrazole ( 7 ) and 1‐(2‐bromophenyl)‐5‐(trifluoromethyl)pyrazole ( 6 ). (© Wiley‐VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)