Palladium Catalyst is The Key in Wacker Reaction Innovation

In the chemical industry, the Wacker process for converting ethylene to acetaldehyde is one of the important industrial processes based on transition metal catalysis. At the same time, chemists have also developed an efficient method to convert monosubstituted terminal alkenes to methyl ketones based on the Pd^II-catalyzed oxidation process, and it has been widely used in the total synthesis of bioactive molecules.

Recently, a general method for the conversion of 1,1-disubstituted alkenes to ketones has been successfully developed by designing the Pd^II/Pd^IV catalytic cycle and incorporating 1,2-alkyl/Pd^IV dyotropic rearrangement as a key step. The reaction is suitable for both linear terminal alkenes and methylenecycloalkanes, and is also tolerant of alkyl halides, aryl halides, alkyl tosylate, hydroxyl, carboxylic acid, ester groups, lactones, amides, ketone, α, β-unsaturated ketone and other functional groups.

First, the researchers chose 7-methylenetridecane as the template substrate to optimize the reaction conditions and obtain the best reaction conditions: that is, Pd(MeCN)₄(BF₄)₂ (10 mol%) as the catalyst, Selectfluor ( 1.2 equiv) as the oxidant and MeCN/H2O (v/v=4:1) as the solvent at room temperature for 2h, the ketone product can be obtained with a yield of 75%. Control experiments show that the anion BF₄^- in Selectfluor plays an important role in determining the reaction pathway of Pd^IV species, while Pd(MeCN)₄(BF₄)₂ has higher Lewis acidity, which in turn promotes the coordination of metals and double bonds and subsequent hydroxypalladation reaction. Subsequently, the researchers investigated the range of substrates, and the results showed that symmetrical 1,1-disubstituted alkenes, methylenecyclobutane, functionalized methylenecyclohexane and methyleneadamantanone substituted with different functional groups can be compatible with this reaction, the corresponding ketone products were obtained in good yields. Similarly, asymmetric 1,1-disubstituted alkenes can also achieve this conversion smoothly, but due to the selective migration of more substituted carbons, C3-substituted cyclopentanones, cyclohexanones, cycloheptanones and cycloheptanones product are obtained. Furthermore, trans-1-methylenedecalin was regioselectively converted to the corresponding ketone in 57% yield, while linear asymmetric terminal alkenes were rearranged to ketones with low selectivity.

Given the low regioselectivity of linear asymmetric terminal alkenes, researchers attempted to study the targeting effect of common organic functional groups. In fact, when 4-methyl-4-pentenoic acid was reacted under standard conditions, the carboxyethyl shifted product (major), 5-oxohexanoic acid, was obtained in 72% yield, and the regioselectivity was significantly improved after the introduction of substituents at the α-position of the carboxylic acid. Similarly, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, and N-Ts piperidine-3-carboxylic acid derivatives also afforded the corresponding δ-oxocarboxylic acids in excellent yields and regioselectivities.

Next, the researchers carried out a series of synthetic applications, specifically: 1) under standard conditions, nokatone was converted into two isomeric ketones; 2) L-menthone-derived substrates and bicyclic compounds were respectively expanded the corresponding ketone products were obtained by ring reaction; 3) The regioselective ring expansion reaction of α-Sandonian derivatives was carried out, and the product was obtained in 62% yield. At the same time, it can be seen from the X-ray diffraction single crystal structure of the product that the alkyl group has migrated while maintaining its absolute configuration, which further shows that this is a coordinated migration process.

Reference

1. Oxidative rearrangement of 1,1-disubstituted alkenes to ketones
   Qiang Feng, Qian Wang, Jieping Zhu