From Bifunctional to Trifunctional (Tricomponent Nucleophile–Transition Metal–Lewis Acid) Catalysis: The Catalytic, Enantioselective α-Fluorination of Acid Chlorides

Abstract

We report in full detail our studies on the catalytic, asymmetric α-fluorination of acid chlorides, a practical method that produces an array of α-fluorocarboxylic acid derivatives in which improved yield and virtually complete enantioselectivity are controlled through electrophilic fluorination of a ketene enolate intermediate. We discovered, for the first time, that a third catalyst, a Lewis acidic lithium salt, could be introduced into a dually-activated system to amplify yields of aliphatic products, primarily through activation of the fluorinating agent. Through our mechanistic studies (based on kinetic data, isotopic labeling, spectroscopic measurements, and theoretical calculations) we were able to utilize our understanding of this “trifunctional” reaction to optimize the conditions and obtain new products in good yield and excellent enantioselectivity.

Enantioselective Nucleophile-Catalyzed Synthesis of Tertiary Alkyl Fluorides via the α-Fluorination of Ketenes: Synthetic and Mechanistic Studies

“…1 The catalytic enantioselective α-fluorination of carbonyl compounds has been a subject of particular interest, 2 and an array of versatile methods have been described for the generation of such secondary alkyl fluorides. 3,4 In contrast, except in the case of doubly activated molecules, 2,5 there has been limited progress in the development of effective processes that furnish tertiary α-fluorocarbonyl compounds, 6−8 and we are not aware of any methods that directly afford esters, 9 with the exception of kinetic resolutions. 10 Here, we establish that a planar-chiral nucleophilic catalyst ( PPY* ) can achieve the coupling of a ketene, 11 an electrophilic fluorine source, 12 and an alkoxide, thereby providing such tertiary alkyl fluorides with high enantioselectivity (eq 1).…”

Cooperation of Non‐covalent Interactions and Coordination in Catalysis

“…The cooperation of coordination, hydrogen, and halogen bonding is observed in asymmetric α-fluorination of aliphatic acyl chlorides [37]; the catalytic system is based on a combination of the chiral nucleophile benzoylquinine and a transition metal LA cocatalyst, such as [PdCl 2 (PPh 3 ) 2 ]; an alkali metal LA salt (LiClO 4 ); N-fluorodibenzenesulfonamide (NFSi); and a variety of nucleophiles, for example, methanol and aromatic amines, in the presence of the Hünig base (Scheme 18.20). Under these conditions, aliphatic acyl chlorides are deprotonated by the Hünig base producing 2-substituted ethenones, which react with the chiral nucleophile benzoylquinine and [PdCl 2 (PPh 3 ) 2 ] leading to dually activated enolates I.…”

6.06 Synthesis of Fluorides

“…135 A synergistic trifunctional catalytic system combining a palladium catalyst, a chiral nucleophile, and an alkali metal catalyst was used to accomplish the enantioselective α-fluorination of acid chlorides (Scheme 36). 136 The cinchona alkaloid-based nucleophile works cooperatively with the palladium catalyst to form a chiral zwitterion amide-enolate intermediate from the acid chloride for subsequent fluorination. The alkali metal catalyst is hypothesized to activate NFSI through cation chelation of the sulfonyl oxygens, activating NFSI for nucleophilic attack by the chiral enolate.…”