Achirality electrophilic fluorinating

Shibata et al. [2,6] further extended this Cinchona alkaloid-mediated asymmetric transfer fluorination reaction to substrates with activated methylene groups, including acyclic (3-cyanoesters, cyclic (3-ketoesters, and oxindole substrates. Representative products, along with the optimal Cinchona alkaloids for these reactions, are shown in Scheme 13.3. Reaction conditions for the acyclic (3-cyanoesters and the cyclic (3-ketoesters used both (a) Selectfluor as the achiral electrophilic fluorine source in MeCN/CHaCla (3 4) at — 80 C and (b) dihydroquinidine acetate (DHQDA) in stoichiometric quantities. The oxindole substrates required the use of stoichiometric bis-Cinchona alkaloids, (DHQlaAQN or (DHQDlaPYR, to obtain useful yields and selectivities. Reactions of these substrates were run in MeCN at 0°C and also employed Selectfluor as the achiral electrophilic fluorine source. 

FIGURE 44.2. Examples of achiral electrophilic fluorinating agents. 

Fig. 1. Achiral neutral N-fluoro reagents for electrophilic fluorination.

The hrst organocatalytic asymmetric C-F bond-forming reactions occurred via transfer fluorination. This method utilized an achiral electrophilic source of fluorine, usually Selectfluor or A-fluorosulfonimide, in conjunction with a stoichiometric amount of a chiral amine, in all cases a Cinchona alkaloid. The fluorine was thus initially transferred from the achiral amine source to the chiral amine, resulting in the in situ generation of a new, chiral electrophilic source of fluorine. Upon subsequent addition of an achiral substrate, the fluorine was transferred from the chiral amine to the substrate. 

These reagents generally lead to good to excellent enantiomeric excesses. Their downside, however, is that they are too expensive for general use. Most current research on enantioselective, electrophilic fluorination relies on the less expensive achiral reagents shown in Figure 7.1, in conjunction with standard organic or metal-based, chiral catalysts. 

Baudequin, C. Loubassou, J.-F. Plaquevent, J.-C. Cahard, D. Enantioselective Electrophilic Fluorination A Study of the Fluorine-Transfer from Achiral N-F Reagents to Cinchona Alkaloids. J. Fluorine Chem. 2003, 122,189-193. 

These reagents are used either in diastereoselective electrophilic fluorinations for which the stereoselectivity is directed intramolecularly by an enantiopure substrate, often of natural origin, or having a temporary attached chiral auxiliary or in enantioselective electrophilic fluorinations of achiral substrates with the aid of a chiral reagent or catalyst. 

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