Mechanism of Copper(I)‐Catalyzed Allylic Alkylation of Phosphorothioate Esters: Influence of the Leaving Group on α Regioselectivity

Abstract

The mechanism of Cu(I) -catalyzed allylic alkylation and the influence of the leaving groups (OPiv, SPiv, Cl, SPO(OiPr)2 ; Piv: pivavloyl) on the regioselectivity of the reaction have been explored by using density functional theory (DFT). A comprehensive comparison of many possible reaction pathways shows that [(iPr)2 Cu](-) prefers to bind first oxidatively to the double bond of the allylic substrate at the anti position with respect to the leaving group, and this is followed by dissociation of the leaving group. If the leaving group is not taken into account, the reaction then undergoes an isomerization and a reductive elimination process to give the α- or γ-selective product. If OPiv, SPiv, Cl, or SPO(OiPr)2 groups are present, the optimal route for the formation of both α- and γ-substituted products changes from the stepwise elimination to the direct process, in which the leaving group plays a stabilizing role for the reactant and destabilizes the transition state. The differences to the energy barrier for the α- and γ-substituted products are 2.75 kcal mol(-1) with SPO(OiPr)2 , 2.44 kcal mol(-1) with SPiv, 2.33 kcal mol(-1) with OPiv, and 1.98 kcal mol(-1) with Cl, respectively; these values show that α regioselectivity in the allylic alkylation follows a SPO(OiPr)2 >SPiv>OPiv>Cl trend, which is in satisfactory agreement with the experimental findings. This trend mainly originates in the differences between the attractive electrostatic forces and the repelling steric interactions of the SPO(OiPr)2 , SPiv, OPiv, and Cl groups on the Cu group.

Unraveling Organocuprate Complexity: Fundamental Insights into Intrinsic Group Transfer Selectivity in Alkylation Reactions

“…Path A (i.e., attack from the α-carbon of CH 3 , Scheme ) is possible, but the S N 2 reaction may also take place from two nucleophilic positions on the allyl group (Scheme ): Path B (α-carbon, eq 11) or Path B2 (γ-carbon, eq 12). For 9 in Path C, OA ( TSOA ) followed by TSRE1 or TSRE2 is possible; however, coupling pathways via the Cu(III) intermediate are more numerous due to the possibility of higher denticity π-allyl intermediates (eqs 13–17, Scheme ). ,,, …”

Beyond classical sulfone chemistry: metal- and photocatalytic approaches for C–S bond functionalization of sulfones

“…In contrast, when di-alkylcuprate species of the type [R 2 Cu] − are the productive intermediates, the α-addition is facilitated. 85 This fact explains that under catalytic conditions, in which a Grignard reagent is mixed with the substrate with catalytic amounts of copper, the γ-product is typically observed which results from the addition of [RCuX] − . This behavior has also been explored for other Cu-catalysed allylic substitution reactions.…”

Synthesis of the natural product descurainolide and cyclic peptides from lignin-derived aromatics

“…24 Also, the influence of leaving groups on the regioselectivity of the reaction (branched versus linear) has previously been studied. 25 It was found that allylic carbonate (±)-14a was unstable on storage and purification on silica giving numerous compounds, one of which was the linear isomer 15 (Scheme 3). 26,27 It was therefore decided to use an electron-withdrawing substituent on the phenolic oxygen which led to the preparation of the stable pivolate-protected (±)-14b from 13, via alcohol (±)-2b, (Scheme 3).…”

“…The thermal ellipsoid plot for anti-(±)-41 is shown at 50% ellipsoid probability. 25 The linear peptides 42 and 43 (amino acid sequence: AXIGFPVG where X = (±)-5 or (±)-6 after removal of the Fmoc group respectively) were synthesised using a solid-phase peptide synthesis (SPPS) strategy. A preloaded Gly-2chlorotrityl chloride resin was used to couple N-Fmoc protected amino acids (±)-5 and (±)-6 with seven other naturally occurring amino acids (Scheme 11).…”