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Exploring Structural Opportunities: The Regioflexible Substitution of 1,3‐Difluorobenzene
Author(s) -
Schlosser Manfred,
Heiss Christophe
Publication year - 2003
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/ejoc.200300354
Subject(s) - chemistry , triethylsilane , carboxylation , deprotonation , electrophile , electrophilic substitution , halogen , fluorine , medicinal chemistry , lewis acids and bases , substitution reaction , silylation , bromine , stereochemistry , organic chemistry , catalysis , ion , alkyl
To demonstrate the superiority of modern organometallic methods, the inexpensive starting material 1,3‐difluorobenzene has been selectively converted into the three benzoic acids and all seven bromobenzoic acids containing the two fluorine atoms in homovicinal positions. The 2,6‐difluorobenzoic acid ( 1 ) was prepared in a one‐pot reaction consisting of direct metallation and carboxylation. The key step on the route to the bromobenzoic acid 4 was a deprotonation‐triggered bromine migration from the 2‐ to the 4‐position. All other products were attained through (2,6‐difluorophenyl)triethylsilane ( 11 ). Consecutive deprotonation of the sites adjacent to the fluorine atoms, followed by appropriate electrophilic substitution, provided not only the acid 7 but also the dibromo and iodobromo derivatives 13 and 23 . These in turn gave the isomers 14 and 24 upon base‐mediated migration of the heaviest halogen, which made the acids 8 and 10 directly accessible. The regiocontrolled monodebromination of intermediate 14 afforded (4‐bromo‐2,6‐difluoro)triethylsilane ( 15 ), which opened the route to the acids 3 and 5 (by carboxylation and protodesilylation) and to acid 9 (by carboxylation and bromodesilylation). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)