Metal-Free Catalytic Asymmetric Fluorination of Keto Esters Using a Combination of Hydrogen Fluoride (HF) and Oxidant: Experiment and Computation

Abstract

A chiral iodoarene organocatalyst for the catalytic asymmetric fluorination has been developed. The catalyst was used in the asymmetric fluorination of carbonyl compounds providing the products with a quaternary stereocenter with high enantioselectivities. Chiral hypervalent iodine difluoride intermediates were generated in situ by treatment of the catalyst with an oxidant and hydrogen fluoride as fluoride source. As such the -fluorination of a carbonyl compound was achieved with a nucleophilic fluorine source. A combined computational and experimental approach provided insight into the reaction mechanism and the origin of enantioselectivity.

Synthesis of Annulated Indolines by Reductive Fischer Indolization

“…When using only 1.1equiv of both reagents (conditions a), the yield of product 9g was significantly lower (31 %). Inspired by this result, we have investigated substituted indanones 10 h-j.W ith an acceptor substituent, the expected CF 3functionalized indoline derivative 9h was obtained in 86 % yield from startingm aterial 10 h [25] (entry 8). Contrastingly,t he donor-substitutedc ongener 10 i [23] yielded the respective product 9i in only 25 %y ield (entry 9), whichc ould be the consequenceo fr educed electrophilicity of the carbonyl group.…”

“…All spectroscopic data are in accordance with the literature. [25] C 13 H 11 F 3 O 3 (272.22 gmol À1 ).…”

Enantioselective Iodine(I/III) Catalysis in Organic Synthesis

“…The kinetic study of the reaction revealed that the ee of the product is invariable over the course of the fluorination indicating that no racemization is involved. The yields remained moderate for this fluorination, but the enantioselectivities were significantly improved, giving up to 92% ee for the fluorinated species 53 (Scheme ) . An interesting feature of this work consisted in the rationalization of the observed enantioselection by computational chemistry.…”

“…After the enantioselective oxidation of the activated alkene by the chiral hypervalent iodine, the reductive substitution of the iodine(III) catalyst allows the insertion of diverse nucleophiles at the α‐position of the carbonyl . Accordingly, different selective α‐oxidative C–H functionalization reactions (oxygenation, halogenation, amination or fluorination) have been accomplished. The development of suitable enantioselective iodine catalysis has allowed for the introduction of stereogenic centers with defined absolute configuration.…”

Hypervalent Iodine Reagents by Anodic Oxidation: A Powerful Green Synthesis

“…Hypervalent iodine reagents are widely used in modern organic synthesis. [1][2][3][4] These reagents have tremendous synthetic applications,i ncluding difunctionalization of olefins and cyclopropanes, [5][6][7] oxidative couplings, [8][9][10] phenol dearomatizations, [11,12] oxidative formation of heterocycles, [13][14][15][16] aminations, [17,18] halogenations, [19][20][21] arylations, [22][23][24] and rearrangements. [25][26][27][28] In addition, aw ider ange of stereoselective transformationsw as achieved with high degree of stereocontrol using chiral hypervalent iodine reagents and catalytic systems of chiral iodoarenes and terminal oxidants.…”