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)]