The syn/anti‐Dichotomy in the Palladium‐Catalyzed Addition of Nucleophiles to Alkenes

Abstract

In this review the stereochemistry of palladium-catalyzed addition of nucleophiles to alkenes is discussed, and examples of these reactions in organic synthesis are given. Most of the reactions discussed involve oxygen and nitrogen nucleophiles; the Wacker oxidation of ethylene has been reviewed in detail. An anti-hydroxypalladation in the Wacker oxidation has strong support from both experimental and computational studies. From the reviewed material it is clear that anti-addition of oxygen and nitrogen nucleophiles is strongly favored in intermolecular addition to olefin–palladium complexes even if the nucleophile is coordinated to the metal. On the other hand, syn-addition is common in the case of intramolecular oxy- and amidopalladation as a result of the initial coordination of the internal nucleophile to the metal.

Palladium catalyzed oxidative aminations and oxylations: where are we?

“…When an alkene coordinates to a PdX 2 complex, the electronic character of the olefin π-system changes enabling two main and mutually excluding reaction paths, namely nucleopalladation [1][2][3][4][5][6] or C-H allylic activation [7][8][9][10][11][12] to provide an electrophilic η 3 -allylpalladium complex. Other reactions and intermediates are also accessible depending upon the nature of the starting alkene and/or the reaction conditions (Scheme 1) [13].…”

Palladium-catalysed anti-Markovnikov selective oxidative amination

“… 1 – 7 Oxidative amination, also known as the aza-Wacker oxidation, differs from hydroamination reactions in that it retains the degree of unsaturation in the product, allowing for further elaboration of this functionality. 3 – 7 As terminal amines are prevalent in pharmaceuticals, especially distal to polar functionalities, 8 the development of an anti-Markovnikov selective aza-Wacker oxidation of unactivated alkenes would represent a significant advance. Such a process would constitute a novel approach to the remote, anti-Markovnikov amination of organic molecules, and represent a new, powerful disconnection in organic synthesis.…”

“…Due to both steric repulsion and the inherent electronic bias of nucleophile addition to alkenes, known as Markovnikov’s rule, this selectivity is not generally favored for an intermolecular aminometalation. 6 , 7 However, several strategies have been successfully employed to reverse this inherent selectivity. One approach uses activated alkenes that can form π-benzyl or [M]-enolate intermediates ( Figure 1a ).…”

“…We envisioned utilizing a palladate catalyst, which could promote a selective trans -nucleopalladation by saturating the coordination sites with excess halide, as seen in the Wacker oxidation ( Figure 1d ). 7 , 30 During the trans -aminopalladation step, a relatively large nucleophile would be kinetically biased to approach the alkene to form the less hindered C–N bond, leading to the desired anti-Markovnikov product. 28 , 29 , 31 – 33 While the trans -aminopalladation with cationic palladium catalysts are known to occur to afford the Markovnikov constitutional isomer, 34 , 35 we hypothesized that the electronic differentiation between the double bond carbons, which leads to Markovnikov’s rule, would be minimized with a less electrophilic anionic palladate catalyst, leading to a more sterically biased transformation.…”

Catalytic Enantioselective Functionalization of Unactivated Terminal Alkenes

“…44 With the stereochemical outcome of the Wacker process being sensitive to catalyst structure and reaction conditions, a complete understanding of the stereochemical features of the Henry process is not currently established. 45 …”