Synthesis Wacker reaction

The two reactions shown below are examples of the use of the Wacker reaction in multistep synthesis. In the first case, selectivity is achieved between two terminal alkene units on the basis of a difference in steric accessibility. Both reactions use a reduced amount of Cu(I) salt. In the second reaction this helps to minimize hydrolysis of the acid-sensitive dioxolane ring. 

Oxidative addition consumes one equivalent of expensive Pd(OAc)2 in most cases. However, progress has been made towards the catalytic oxidative addition pathway. Knolker s group described one of the first oxidative cyclizations using catalytic Pd(OAc)2 in the synthesis of indoles [19]. They reoxidized Pd(0) to Pd(II) with cupric acetate similar to the Wacker reaction, making the reaction catalytic with respect to palladium [20]. 

With oxo synthesis, Wacker-type oxidations of alkenes is one of the older homogeneous transition-metal-catalyzed reactions [1], The most prominent example of this type of reaction is the manufacture of acetaldehyde from ethylene. This well-known reaction, which has been successfully developed on an industrial scale (Wacker process), combines the stoichiometric oxidation of ethylene by palladium ) in aqueous solution with the in situ reoxidation of palladium(O) by molecular oxygen in the presence of a copper salt (Eqs. 1 -4) [2]. 

The Wacker reaction provides a method for the preparation of 1,4-dicarbonyl compounds, by formation of an enolate, allylation with an allyl halide, followed by palladium-catalysed oxidation of the terminal alkene. The product 1,4-dicarbonyl compounds can be treated with base to promote intramolecular aldol reaction (Robinson annulation - see Section 1.1.2) to give cyclopentenones. Thus, in a synthesis of pentalenene, Wacker oxidation of the 2-aUyl ketone 115 gave the 1,4-diketone 116, which was converted to the cyclopentenone 117 (5.115). ... 

Scheme 16.10 Diamine synthesis within aza-Wacker reactions.

The chemistry of the Wacker reaction is not limited to ethylene, but may be extended to a wide range of alkenes, and is useful throughout organic synthesis." For the synthesis of complex molecules, the Wacker... 

In fact, Wacker type oxidations (largely applied for aldehyde synthesis, acetoxylation reactions) can be considered as an intra or, more probably according to the recent literature, as an out-of-sphere nucleophilic attack on a palladium-olefin 7r-complex. 

The Wacker reaction is an important process at the industrial level but several applications of related reactions have been reported in natural products synthesis. 

Wacker reaction originally referred to the oxidation of ethylene to acetaldehyde by oxygen in water in the presence of a palladium catalyst. The total synthesis of mycalamide A by Sohn et al. made use of a palladium-catalyzed tandem cycli-zation sequence to construct the pederic acid framework (Scheme 7.8) [17]. The reaction proceeded by the initial Wacker reaction of enol ether 31 to generate o-alkylpalladium species 32, which underwent an intramolecular Heck reaction to form the pyran ring 33. 

Asymmetric variants of these reactions are highly interesting since they provide access to chiral heterocycles. A recent comprehensive study by Stahl and coworkers reports the synthesis of various enantiopure [Pd( 4-C1)C1(NHC)]2 complexes and their application in asymmetric aza-Wacker cyclisations. The reactions generally proceed with low yields or enantioselectivity [43]. The best enantio-selectivity (63%) was achieved using complex 28 (Table 10.8). 

Several Pd-catalyzed domino processes start with a Tsuji-Trost reaction, a pal-ladation of alkynes or allenes [5], a carbonylation [6], an amination [7] or a Pd(II)-cat-alyzed Wacker-type reaction [8]. A novel illustrious example of this procedure is the efficient enantioselective synthesis of vitamin E [9]. 

The most important reaction based on Pdn-catalysis is the Wacker oxidation [171], which is used industrially for the synthesis of acetaldehyde, starting from ethane. This process can be combined with a Heck reaction and has been used by Tietze and coworkers [172] for an efficient enantioselective synthesis of vitamin E (6/1-... 

The latest example of a Pdn-catalyzed Wacker/Heck methodology was published by Rawal and coworkers. During the total synthesis of mycalamide A, an inter-molecular Wacker oxidation with methanol acting as nucleophile and a subsequent ring closure via Heck reaction led to a tetrahydropyran moiety in a 5.7 1 diastereom-eric mixture [184]. 

When Wacker-type reactions are performed under a CO atmosphere, the (3-H elimination pathway can be suppressed in favor of CO insertion and subsequent nucleophilic cleavage of the acyl metal species.399 This alkoxycarbonylation process has found widespread utility, particularly in the synthesis of five- and six-membered oxacyclic natural products. For example, the THF core of tetronomycin was prepared by the Pd-catalyzed alkoxycarbonylation of 4-alkenol derivatives (Equations (117) and (118)), where stereocontrol was achieved by utilizing either the directing ability of a free hydroxyl or the conformational bias imposed by a bulky silyl ether.420 Additional examples making... 

Water and carbon monoxide can produce dihydrogen in situ (shift reaction), as has been shown in the synthesis of diethylketone (pentan-3-one) from ethene, CO and water in the presence of palladium(II) salts, triphenylphosphine and acids [37], Ether chain ends have been observed in some polymerization reactions [40] and low molecular weight products can also contain an ether moiety as an end group. Most likely ether chain ends are not formed by attack of alcohol at coordinated ethene in a Wacker type reaction, since this is usually followed by fast (3-hydride elimination. Instead we propose that a palladium-... 

A development of the last two decades is the use of Wacker activation for intramolecular attack of nucleophiles to alkenes in the synthesis of organic molecules [9], In most examples, the nucleophilic attack is intramolecular, as the rates of intermolecular reactions are very low. The reaction has been applied in a large variety of organic syntheses and is usually referred to as Wacker (type) activation of alkene (or alkynes). If oxygen is the nucleophile, it is called oxypalladation [10], Figure 15.4 shows an example. During these reactions the palladium catalyst is often also a good isomerisation catalyst, which leads to the formation of several isomers. 

The formation of carbon-carbon bonds by palladium-promoted reactions has been widely used in organic synthesis [114-116]. A major advantage is that most of these coupling reactions can be performed with catalytic amounts of palladium. Palladium(II)-catalyzed reactions, e.g., the Wacker process, are distinguished from palladium(O)-catalyzed reactions, e.g., the Heck reaction, since they require oxidative regeneration of the catalytically active palladium(II) species in a separate step [117]. Several groups have applied palladium-mediated and -catalyzed coupling reactions to the construction of the carbazole framework. 

More recently, the same group achieved a simple, highly stereocontrolled total synthesis of (+)-hirsutic acid (Scheme LXXIX) ". This chirally directed effort developed subsequent to reaction of dl-728 with (+)-di-3-pinanylborane, alkaline hydrogen peroxide oxidation, chromatography, PCC oxidation, and hydrogenolysis. The dextrorotatory hydroxy ketone 729 was nicely crafted into keto aldehyde 730 from which 720 was readily obtained. Once again, the Wacker oxidation played an instrumental role in annulation of the third five-membered ring. The remainder of the asymmetric synthesis was completed as before. 

In comparable reaction conditions as Pd +Cu +Y, Pd + and Cu2+ exchanged pentasil and ferrierite zeolites show a different type of activity [31]. The main products formed by propylene oxidation on these catalysts are acrolein and propionaldehyde below 120°C and 2-propanol above 120 C. Above 150°C consecutive oxidation of 2-propano1 to acetone is observed. The catalytic role of Pd and Cu in the 2-propanol synthesis is proposed to follow the Wacker concept. It is striking that when Pd + and Cu2+ are exchanged in 10-membered ring zeolites, oxidation of a primary carbon atoms seems possible, as acrolein and propionaldehyde are obtained from propylene. 

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