A systematic comparison between 1,3‐difluorobenzene, 1,3‐dichlorobenzene, and 1,3‐dibromobenzene did not reveal major differences in their behavior towards strong bases such as lithium diisopropylamide or lithium 2,2,6,6‐tetramethylpiperidide. Thus, all 2,6‐dihalobenzoic acids 1 are directly accessible by consecutive treatment with a suitable base and dry ice. In contrast, (2,6‐dichlorophenyl)‐ and (2,6‐bromophenyl)triethylsilane (2a and 2b) were found to undergo deprotonation at the 5‐position (affording acids 3 and, after deprotection, 4), whereas the 1,3‐difluoro analog is known to react at the 4‐position. The 2,4‐dihalobenzoic acids 7 were selectively prepared from either the silanes 2 (by bromination at the 4‐position, metalation and carboxylation of the neighboring position, followed by desilylation and debromination) or the 1,3‐dihalo‐2‐iodobenzenes 8 (by base‐promoted migration of iodine to the 4‐position followed by iodine/magnesium permutation and subsequent carboxylation). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

In a case study, 1,2,3-trifluorobenzene was functionalized at each of the two vacant positions (producing the benzoic acids 1 and 2) and, in addition, bromine was introduced into all available positions (producing the benzoic acids 3−5). The required regioflexibility was achieved by applying novel orAt first glance, 1,2,3-trifluorobenzene hardly qualifies as a good example for demonstrating the merits of the organometallic approach to the creation of molecular diversity. [1] Having just two regiochemically distinct sites unoccupied, any deprotonation/functionalization sequence can give rise to not more than two isomers. To make our exercise in regioflexibility more demanding, we have therefore allowed for the presence of an additional substituent by targeting both the two trifluorobenzoic acids 1 and 2 and also the three bromo derivatives 3Ϫ5. The chart shown below summarizes the transformations involving the bromo-, iodo-, or triethylsilyl-substituted trifluorobenzenes 6Ϫ14. Details will be specified in the subsequent sections.The ortho-lithiation of 1,2,3-trifluorobenzene with secbutyllithium in tetrahydrofuran at Ϫ75°C has already been reported.[2] Subsequent carboxylation and neutralization afforded 2,3,4-trifluorobenzoic acid (1) in 94% yield.In contrast, a multi-step procedure was required to prepare 3,4,5-trifluorobenzoic acid (2). Treatment of the metalated species with elemental bromine gave 1-bromo-2,3,4-trifluorobenzene (7; 95%), which was converted into (5-bromo-2,3,4-trifluorophenyl)triethylsilane (8; 92%) upon subsequent reaction with lithium diisopropylamide (LIDA) and chlorotriethylsilane. Heating silane 8 with bromine for [a] 36 h in refluxing tetrachloromethane produced 1,5-dibromo-2,3,4-trifluorobenzene (9; 93%). The dibromo compound 9 (95%) was also formed when the bis(silane) 6, resulting in 91% yield from the twofold repetitive reaction

Upon treatment of various aryllithium intermediates with 1,2-dibromobenzene or 1-bromo-2-iodobenzene, dissymmetrical ortho,ortho'-di-, triand even tetrasubstituted bromo-or iodobiaryls become readily available. The crucial steps in all these reactions were the nucleophilic addition of the organolithium precursor to a transient aryne species released from it by b-elimination of a lithium halide and, stabilization of the resulting 2-biaryllithium intermediate by in situ transfer of bromine or iodine from the starting material. This straightforward transition metal-free access to biaryls allows the preparation of highly valuable halobiaryls on a gram scale in excellent yields. These precursors can be subsequently functionalized by highly regioselective halogen/metal permutations into a vast variety of target molecules. This was demonstrated in the synthesis of several mono-and diphosphine ligands.

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)

(2,6-Dichlorophenyl)- and (2,6-dibromophenyl)trialkylsilanes undergo hydrogen/metal interconversion preferentially at the 4- rather than 3-position. However, the organometallic species generated by such a "meta metalation" are thermodynamically less stable (i.e., more basic) than those that would result from an ordinary "ortho metalation". This was demonstrated by equilibration experiments based on permutational halogen/metal interconversion. A new buttressing effect can explain the unprecedented regioselectivity. It is supported by X-ray structures that reveal marked deformations of the benzene ring in halophenylsilanes. [structure: see text]