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

Abstract

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)

Relative Basicities of ortho-, meta-, and para-Substituted Aryllithiums

“…We have drawn attention to the exceptional acidity of 2,2-difluoro-1,3-benzodioxole already on previous occasions and have demonstrated how this property can be advantageously exploited for synthetic purposes. ,− This heterocyclic unit sets indeed a new record mark (ΔΔ G = −8.7 kcal/mol) as the lithiated species is still 2.5 kcal/mol less basic than 2-(trifluoromethoxy)phenyllithium (Scheme ).…”

“…All isomers of methoxy-, chloro-, fluoro-, trifluoromethyl-, or trifluoromethoxy-substituted bromobenzenes and iodobenzenes are commercial (Acros Organics, B-2440 Geel, Aldrich-Fluka, CH-9479 Buchs, and Apollo Scientific, Stockport UK-SK6 2QR). The same holds for 4-bromo-2,2-difluoro-1,3-benzodioxole, whereas the 4-iodo analog had to be prepared according to a literature procedure. , …”

The 2×3 Toolbox of Organometallic Methods for Regiochemically Exhaustive Functionalization

“…Trimethylsilyl groups have been sporadically used in earlier work to deactivate otherwise more‐acidic sites. However, as they may undergo deprotonation themselves,51, 52 it is often deemed advisable to replace them with triethylsilyl46, 47, 53 or, occasionally, even with triisopropylsilyl17 groups.…”

Der 2×3‐Werkzeugkasten der metallorganischen Methoden zur regiochemisch erschöpfenden Funktionalisierung

“…Trimethylsilyl‐Gruppen sind schon früher gelegentlich genutzt worden, um ansonsten acide Positionen zu inaktivieren. Da sie jedoch selbst zur Deprotonierung neigen,51, 52 scheint es oft ratsam, sie durch Triethylsilyl‐Gruppen46, 47, 53 oder gelegentlich sogar Triisopropylsilyl‐Gruppen17 zu ersetzen.…”