Exploring structural opportunities: The regioflexible substitution of 1,3-difluorobenzene

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 contg. the two fluorine atoms in homovicinal positions. 2,6-Difluorobenzoic acid was prepd. in a one-pot reaction consisting of direct metalation and carboxylation. The key step on the route to the 3-bromo-2,6-difluorobenzoic acid was a deprotonation-triggered bromine migration from the 2- to the 4-position. All other products were attained through (2,6-difluorophenyl)triethylsilane. Consecutive deprotonation of the sites adjacent to the fluorine atoms, followed by appropriate electrophilic substitution, provided not only 5-bromo-2,4-difluorobenzoic acid but also 3,5-dibromo-2,6-difluorophenyltriethylsilane and its 5-iodo analog. These in turn gave 3,4-dibromo-2,6-difluorophenyltriethylsilane (I) and its 4-iodo analog upon base-mediated migration of the heaviest halogen, which made 2-bromo-4,6-difluorobenzoic acid and 2-bromo-3,5-difluorobenzoic acid directly accessible. The regiocontrolled monodebromination of intermediate I afforded (4-bromo-2,6-difluoro)triethylsilane, which opened the route to 3,5-difluorobenzoivc acid and 4-bromo-2,6-difluorobenzoic acid by carboxylation and protodesilylation and to 4-bromo-325,6-difluorobenzoic acid by carboxylation and bromodesilylation. [on SciFinder (R)]

Published in:
European Journal of Organic Chemistry, 23, 4618-4624
CAN 140:128121 25-17 Benzene, Its Derivatives, and Condensed Benzenoid Compounds Institut de Chimie moleculaire et biologique Ecole Polytechnique Federale, BCh,Lausanne,Switz. Journal 1434-193X written in English. 372-18-9 (1,3-Difluorobenzene) Role: RCT (Reactant), RACT (Reactant or reagent) (prepn. of difluorobenzoic acids by substitution of 1,3-difluorobenzene); 348-57-2P (1-Bromo-2,4-difluorobenzene); 461-96-1P (1-Bromo-3,5-difluorobenzene); 64248-56-2P (1-Bromo-2,6-difluorobenzene); 184910-37-0P; 651027-02-0P (2,6-Difluoropenyltriethylsilane); 651027-03-1P; 651027-04-2P; 651027-05-3P; 651027-06-4P; 651027-07-5P; 651027-08-6P; 651027-09-7P; 651027-10-0P; 651027-11-1P; 651027-12-2P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. of difluorobenzoic acids by substitution of 1,3-difluorobenzene); 385-00-2P (2,6-Difluorobenzoic acid); 455-40-3P (3,5-Difluorobenzoic acid); 1583-58-0P (2,4-Difluorobenzoic acid); 28314-81-0P (3-Bromo-2,6-difluorobenzoic acid); 28314-83-2P (3-Bromo-4,6-difluorobenzoic acid); 183065-68-1P (4-Bromo-2,6-difluorobenzoic acid); 651026-98-1P (3-Bromo-2,4-difluorobenzoic acid); 651026-99-2P (2-Bromo-4,6-difluorobenzoic acid); 651027-00-8P (4-Bromo-3,5-difluorobenzoic acid); 651027-01-9P (2-Bromo-3,5-difluorobenzoic acid) Role: SPN (Synthetic preparation), PREP (Preparation) (prepn. of difluorobenzoic acids by substitution of 1,3-difluorobenzene)
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 Record created 2006-03-03, last modified 2018-01-27

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