A Versatile Organocatalytic Approach for the Synthesis of Enantioenriched gem‐Difluorinated Compounds

Abstract

The combination of a practical and highly enantioselective organocatalytic reaction, which allows the stereoselective introduction of a benzodithiol group, with a fluorination step, gives a new and effective strategy for the stereoselective synthesis of difluorinated building blocks. The benzodithiol group is a versatile and chameleonic group that can be further functionalized before fluorination, giving customized and tailored useful synthetic strategies. As an example of the application of this facile strategy, the effective enantioselective synthesis of difluoroarundic acid is described.

Electrophilic Trapping of Semibenzenes

“…Following these encouraging results, we evaluated two more electrophiles, namely, tropylium tetrafluoroborate and 1,3-benzodithiolylium tetraborate . For tropylium tetrafluoroborate, we found that once again, the solvent is critical for the reaction outcome, with DMF yielding full conversion of the semibenzene and full selectivity toward the trapped product in less than 30 min, whereas MeCN, acetone, and CH 2 Cl 2 gave very poor selectivity (Table S1).…”

“…Following these encouraging results, we evaluated two more electrophiles, namely, tropylium tetrafluoroborate 19 and 1,3-benzodithiolylium tetraborate. 20 For tropylium tetrafluoroborate, we found that once again, the solvent is critical for the reaction outcome, with DMF yielding full conversion of the semibenzene and full selectivity toward the trapped product in less than 30 min, whereas MeCN, acetone, and CH 2 Cl 2 gave very poor selectivity ( Table S1 ). We chose 1,3-benzo dithiolylium tetrafluoroborate as the next electrophile since a similar reactivity to tropylium tetrafluoroborate has been reported for this carbocation, 19d making it a promising candidate to further increase the scope of this newly discovered transformation.…”

From QCA (Quantum Cellular Automata) to Organocatalytic Reactions with Stabilized Carbenium Ions

“…In the presence of tertiary amines, 16 forms carbene, which then dimerizes to tetrathiofulvalene derivatives 101. On the other hand, alkylation without the presence of an inorganic base is also possible, and the procedure was fully optimized 103…”

“…In fact, this group can also stabilize negative charges, and by lithiation, the protected intermediates obtained in high enantiomeric excess after the organocatalytic alkylation, could be easily alkylated. Benzodithiol can be also used as a synthetic equivalent of the CO and CF 2 groups,103 as we have recently shown (Scheme ). Using this straightforward methodology, it is possible to install the CF 2 unit near stereogenic centers for the synthesis of complex difluorinated molecules 104…”