The Role of Trichloroacetimidate To Enable Iridium-Catalyzed Regio- and Enantioselective Allylic Fluorination: A Combined Experimental and Computational Study

Abstract

Asymmetric allylic fluorination has proven to be a robust and efficient methodology with potential applications for the development of pharmaceuticals and practical synthesis for 18F-radio­labeling. A combined computational (dispersion-corrected DFT) and experimental approach was taken to interrogate the mechanism of the diene-ligated, iridium-catalyzed regio- and enantio­selective allylic fluorination. Our group has shown that, in the presence of an iridium­(I) catalyst and nucleo­philic fluoride source (Et3N·3HF), allylic trichloro­acet­imidates undergo rapid fluoride substitution to generate allylic fluoride products with excellent levels of branched-to-linear ratios. Mechanistic studies reveal the crucial role of the trichloro­acet­imidate as a potent leaving group and ligand to enable conversion of racemic allylic trichloro­acet­imidates to the corresponding enantio­enriched allylic fluorides, via a dynamic kinetic asymmetric transformation (DYKAT), in the presence of the chiral bicyclo­[3.3.0]­octadiene-ligated iridium catalyst.

Iridium‐Catalyzed Enantioselective Allylic Substitutions of Racemic, Branched Trichloroacetimidates with Heteroatom Nucleophiles: Formation of Allylic C−O, C−N, and C−S Bonds

“…[39] Xray crystallographic analysis confirmed the formation of a pentacoordinated π-allyliridium(III) species with η 1 -(σ-coordination) of the trichloroacetamide nitrogen to the iridium metal. [39] In addition, a neutral iridium metal center was involved in the π-allyliridium(III) intermediate instead of a more electrophilic cationic iridium complex as previously reported in other iridium-catalyzed asymmetric allylic substitutions. [43,44] Based on these previous studies, we propose [IrCl (R,R)-L] 2 (L = bicyclo[3.3.0]octadiene) catalyzed allylic substitution with heteroatom nucleophiles to undergo dynamic kinetic asymmetric transformation (DYKAT).…”

“…Experiments employing deuterium labeled allylic substrates have been utilized to investigate mechanisms of retention or inversion of stereochemistry. [39,45] In our study, both cis-alkene deuterium labeled substrate (R)-42 and (S)-42 were synthesized and submitted to the reactions with 4methoxybenzoic acid 1 f and aniline 13 e employing [IrCl(R,R)-L] 2 catalyst (Scheme 2). The substitution of These results are consistent with a retention-inversion pathway illustrated in Figure 2.…”

“…Recently, our group showed that in the presence of a chiral bicyclo[3.3.0]octadiene‐ligated Ir catalyst and Et 3 N ⋅ 3HF as a nucleophilic fluoride, racemic branched allylic trichloroacetimidates undergo rapid asymmetric fluorination [37–39] . Our studies on the chiral diene‐ligated iridium catalyst in the fluorination lead us to question whether this iridium‐trichloroacetimidate system could be capable of constructing C−O, C−N, and C−S bonds in an enantioselective fashion.…”

“…Recently, our group showed that in the presence of a chiral bicyclo[3.3.0]octadiene-ligated Ir catalyst and Et 3 N • 3HF as a nucleophilic fluoride, racemic branched allylic trichloroacetimidates undergo rapid asymmetric fluorination. [37][38][39] Our studies on the chiral dieneligated iridium catalyst in the fluorination lead us to question whether this iridium-trichloroacetimidate system could be capable of constructing CÀ O, CÀ N, and CÀ S bonds in an enantioselective fashion. Herein, we report a new strategy involving the chiral diene-ligated Ir-catalyzed asymmetric substitutions of racemic, branched allylic trichloroacetimidates with a wide range of heteroatom nucleophiles (Figure 1b).…”

Asymmetric Methods for Carbon‐Fluorine Bond Formation

“…Outer‐sphere attack of fluoride on the more stable η 3 ‐allyl iridium complex yields the final product. Importantly, the trichloroacetamide byproduct does not compete with fluoride [43c] …”