A Homologous Series of O‐ and N‐Functionalized 2,2‐Difluoro1,3‐benzodioxoles: an Exercise in Organometallic Methodology

Abstract

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)

CF3‐Bearing Aromatic and Heterocyclic Building Blocks

“…* Carbon dioxide is arguably the most popular trapping reagent that is used to quench organometallic intermediates. However, dozens if not hundreds of other electrophiles could serve the same purpose [82] and thus make many new structural patterns readily available. Besides carboxylic acids and their derivatives, carboxaldehydes, ketones, alcohols, phenols, thiols, sulfinic and sulfonic acids, amines, azides, nitriles, phosphines, phosphinous, phosphinic, and phosphonic acids can thus be accessed to quote just a few of the most prominent product classes.…”

Deprotonation‐Triggered Heavy‐Halogen Migrations as a Key to the Structural Elaboration of 2,2‐Difluoro‐1,3‐benzodioxole

“…The preparation of 4-bromo-2,2-difluoro-1,3-benzodioxole and 2,2-difluoro-4-iodo-1,3-benzodioxole are described in ref. [8] (spec. on p. 460).…”

“…Monolateral halogen/metal permutation followed by carboxylation gave 2,2-difluoro-7-iodo-1,3-benzodioxane-4-carboxylic acid (12; 64%). The same acid 12 was formed in 64% yield when the organolithium precursor was generated by incubating 2,2-difluoro-4-iodo-1,3-benzodioxole [8] with LIDA in tetrahydrofuran for 2 h at Ϫ100°C. LIDA-promoted deprotonation of the diiodo compound 11 triggered a heavy-halogen migration.…”

“…2,2-Difluoro-1,3-benzodioxole, the key intermediate for the manufacture of an important herbicide, [5,6] provided us with a prototypical model substrate because its exceptionally strong inherent acidity makes lithiation at the 4-position, [5Ϫ7] and the subsequent introduction of a wide range of electrophiles at this site, extremely facile. [8] The main objective of the present work was to probe the proton mobility at the heteroatom-remote 5-position relative to the 4-position.…”

“…We chose 4-bromo-2,2-difluoro-1,3-benzodioxole (1) [8] to serve as the test compound. If it behaves as an ordinary 1-bromo-2,3-dialkoxyarene, deprotonation by a lithium dialkylamide should occur simultaneously at the halogen-and oxygen-adjacent positions because bromine or chlorine atoms and alkoxy or aryloxy substituents belong to the least-acidifying neighboring groups.…”