The conversion of 2,2‐difluoro‐1,3‐benzodioxole, an exceptionally acidic arene, via a 4‐lithiated intermediate into more than three dozen new derivatives was conceived as a case study. The lithiated species was trapped by C0‐electrophiles (4‐toluenesulfonyl azide, fluorodimethoxyborane, iodine), C1‐electrophiles (carbon dioxide, N,N‐dimethylformamide, formaldehyde, dimethyl sulfate), C2‐electrophiles (oxalic acid diesters, oxirane), C3‐electrophiles (oxetane), and higher alkyl iodides. The resulting carboxylic acid 1a may be treated with organolithium compounds to afford ketones (e.g. 10) and the aldehyde 9 can be condensed with nitromethane or acetic anhydride under basic conditions. If not oxidized with chromium trioxide to the corresponding carboxylic acids, the alcohols 2b, 2c, and 2d can be transformed into the corresponding bromides (12) or sulfonates (13). Their condensation with nitrogen‐containing C0‐nucleophiles (hydroxylamine, sodium azide, potassium phthalimide), C1‐nucleophiles (potassium cyanide), and C2‐nucleophiles (acetonitrile) opens a convenient access to the amines 3. Other reactions gave, despite a proven track record in other areas, only moderate yields. (© 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]

Although proton abstraction from the 4‐position of 2,2‐difluoro‐1,3‐benzodioxole occurs with exceptional ease, lithiation of the more‐remote 5‐position can only be brought about if no oxygen‐adjacent site remains unoccupied. Thus, unlike 4‐bromo‐2,2‐difluoro‐1,3‐benzodioxole (1), (7‐bromo‐2,2‐difluoro‐1,3‐benzodioxol‐4‐yl)triethylsilane (5b) does react with lithium diisopropylamide to generate an intermediate that isomerizes instantaneously by heavy‐halogen migration. Upon neutralization and carboxylation, 5‐bromo‐2,2‐difluoro‐1,3‐benzodioxole (8) and 5‐bromo‐2,2‐difluoro‐1,3‐benzodioxole‐4‐carboxylic acid (3) are formed nearly quantitatively. A similar basicity gradient‐driven heavy‐halogen migration can be accomplished starting from 2,2‐difluoro‐4,7‐diiodo‐1,3‐benzodioxole (11). These results procure a deeper insight in the acidifying effects of fluoroalkoxy groups and their distance dependence. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

2, 2, 2, 3, 3, 2,4,5-trifluorophenol and 2,3,4-trifluorophenol were converted into all 18 possible di-or trifluorinated hydroxybenzoic acids (1a-c, 4a-c, 9a-c, 12a,b, 14a-c, 17a,b, 18a,b), all of them new compounds. The phenolic hydrogen atom was replaced by a methoxymethyl or, less frequently, by a triisopropylsilyl group, which exerted an ortho activating or ortho shielding effect, respectively. Sites flanked by two electronegative substituents (fluorine, alkoxy) were deprotonated with particular ease. They had to be silenced by the reversible attachment of a metalation-blocking trimethylsilyl group or of a metalation-deflecting chlorine atom if the metal was to be introduced elsewhere. In all cases but one, the stage was thus set for an intramolecular competition between metalation at an oxygen-adjacent or a fluorine-adjacent site. It proved indeed possible to secure the desired regioflexibility in either way by relying on an appropriate substrate-reagent matching. This demonstrates once more the potential of the organometallic approach to diversity-oriented synthesis.The three fluorophenols represent milestones in the development of the organometallic approach to diversity-oriented synthesis. 1,2 The ortho and para isomers, after protection of the free phenols as anisoles 3 or methoxymethyl ethers 4 were found to undergo perfectly site-controlled metalation (and subsequent carboxylation) at either the oxygen-or halogen-adjacent position depending on the mechanism-matched choice of the reagent. The meta isomer acted as one of the first substrates to illustrate the concept of regioexhaustive functionalization by its transformation into each of the four possible fluorohydroxybenzoic acids (Scheme 1). 2 Under these circumstances it deemed us worthwhile to extend our studies to difluorophenols and trifluorophenols. Most of such compounds are commercial if often expensive. On the other hand, many of them can be efficaciously prepared from cheap starting materials such as 1,2-difluorobenzene, 1,4-difluorobenzene, 1-bromo-3,5-difluorobenzene and 1-bromo-2,4,5-trifluorobenzene by hydrogen/metal or halogen/metal permutation followed by dimethoxyborylation 5,6 and oxidation.As demonstrated below, it proved possible to introduce a metal atom into any vacant position of five difluorophenols and two trifluorophenols selected as model compounds. The organometallic intermediates thus generated were always intercepted by carbon dioxide and only occasionally also by other electrophiles (in particular, chlorinating and silylating reagents). It is nevertheless tacitly understood that in the same way as the 18 fluorinated hydroxybenzoic acids described below were accessed, aldehydes, alcohols, amines, sulfonic acids, phosphonic acids and countless other functionalized products could be made. 7

Starting from the inexpensive 2,2-difluoro-1,3-benzodioxole or its 5-bromo derivative, two new atropisomeric bisphosphines have been prepared which, after racemate resolution, exhibit attractive features as ligands for enantioselective catalysts. The key step in their synthesis is a low temperature Ullmann reaction. An improved protocol secures coupling yields of 70-80%.