Wacker terminal alkene

The Wacker reaction can also be applied to laboratory-scale syntheses.104 When the Wacker conditions are applied to terminal alkenes, methyl ketones are formed.105... 

This regiochemistry is consistent with the electrophilic character of Pd(II) in the addition step. Solvent and catalyst composition can affect the regiochemistry of the Wacker reaction. Use of /-butanol as the solvent was found to increase the amount of aldehyde formed from terminal alkenes, and is attributed to the greater steric requirement of /-butanol. Hydrolysis of the enol ether then leads to the aldehyde. 

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. 

The reaction rate is half-order in palladium and dimeric hydroxides of the type shown are very common for palladium. The reaction is first order in alcohol and a kinetic isotope effect was found for CH2 versus CD2 containing alcohols at 100 °C (1.4-2.1) showing that probably the (3-hydride elimination is rate-determining. Thus, fast pre-equilibria are involved with the dimer as the resting state. When terminal alkenes are present, Wacker oxidation of the alkene is the fastest reaction. Aldehydes are prone to autoxidation and it was found that radical scavengers such as TEMPO suppressed the side reactions and led to an increase of the selectivity [18],... 

Anodic oxidation is used to promote the recycling of palladium(il) in the Wacker process for the conversion terminal alkenes to methyl ketones. Completion of the catalytic cycle requires the oxidation of palladium(O) back to the palla-dium(li) state and this step can be achieved using an organic mediator such as tri(4-bromophenyljamine. The mediator is oxidised at the anode to a radical-cation and... 

In 1960, Moiseev and coworkers reported that benzoquinone (BQ) serves as an effective stoichiometric oxidant in the Pd-catalyzed acetoxylation of ethylene (Eq. 2) [19,20]. This result coincided with the independent development of the Wacker process (Eq. 1, Scheme 1) [Ij. Subsequently, BQ was found to be effective in a wide range of Pd-catalyzed oxidation reactions. Eor example, BQ was used to achieve Wacker-type oxidation of terminal alkenes to methyl ketones in aqueous DMF (Eq. 3 [21]), dehydrogenation of cyclohexanone (Eq. 4 [22]), and alcohol oxidation (Eq. 5 [23]). In the final example, 1,4-naphthoquinone (NQ) was used as the stoichiometric oxidant. 

The well-known Wacker oxidation of terminal alkenes to methylketones has been used for many years on a large scale. It requires a catalytic amount of Pd(II) together with stoichiometric CuCl2 under aerobic conditions. But it is hmited by palladiiun decomposition and chlorinated byproducts. Therefore, a lot of research has been devoted to modifying the reaction, but most of the time copper cocatalysts were necessary. Another problem is the often observed cleavage of the double bond and the production of aldehydes. 

Higher alkenes can also be converted to methyl ketones with the Wacker catalyst, but the rates and selectivities are lower. Improved procedures use basic406,407 or alcoholic solvents 408 Tsuji and coworkers used the PdCl2/CuCl catalyst in DMF for the synthesis of a variety of natural products and fine chemicals.409 Only terminal alkenes are ketonized under these conditions, even when the substrate contains other functional groups.395... 

In fact, the role of copper and oxygen in the Wacker Process is certainly more complicated than indicated in equations (151) and (152) and in Scheme 10, and could be similar to that previously discussed for the rhodium/copper-catalyzed ketonization of terminal alkenes. Hosokawa and coworkers have recently studied the Wacker-type asymmetric intramolecular oxidative cyclization of irons-2-(2-butenyl)phenol (132) by 02 in the presence of (+)-(3,2,10-i -pinene)palladium(II) acetate (133) and Cu(OAc)2 (equation 156).413 It has been shown that the chiral pinanyl ligand is retained by palladium throughout the reaction, and therefore it is suggested that the active catalyst consists of copper and palladium linked by an acetate bridge. The role of copper would be to act as an oxygen carrier capable of rapidly reoxidizing palladium hydride into a hydroperoxide species (equation 157).413 Such a process is also likely to occur in the palladium-catalyzed acetoxylation of alkenes (see Section 61.3.4.3). 

The synthetic applications of the palladium-catalyzed oxidation of alkenes to ketones have recently been reviewed.639 Improvements in the Wacker palladium-catalyzed ketonization of terminal alkenes have been obtained using phase-transfer catalysis,641 polyethylene glycol642 or phosphomolybdovanadic acids.643... 

One of the earliest uses of palladium(II) salts to activate alkenes towards additions with oxygen nucleophiles is the industrially important Wacker process, wherein ethylene is oxidized to acetaldehyde using a palladium(II) chloride catalyst system in aqueous solution under an oxygen atmosphere with cop-per(II) chloride as a co-oxidant.1,2 The key step in this process is nucleophilic addition of water to the palladium(II)-complexed ethylene. As expected from the regioselectivity of palladium(II)-assisted addition of nucleophiles to alkenes, simple terminal alkenes are efficiently converted to methyl ketones rather than aldehydes under Wacker conditions. 

Terminal alkenes can be selectively oxidized to aldehydes by reaction with oxygen, using a palladium-copper catalyst in tertiary butanol (equation 35)160. This reaction is contrary to the normal oxidation process which yields a ketone as the major product. The palladium(II) oxidation of terminal alkenes to give methyl ketones is known as the Wacker process. It is a very well established reaction in both laboratory and industrial synthesis161162. The Wacker oxidation of alkenes has been used in the key step in the synthesis of the male sex pheromone of Hylotrupes bajulus (equation 36)163. 

Oxidation of allylic andhomallylic acetates (cf. 10,175-176).1 This system is an efficient catalyst for oxygenation of terminal alkenes to methyl ketones (Wacker process). Similar oxidation of internal olefins is not useful because it is not regioselective. However, this catalyst effects oxygenation of allylic ethers and acetates regioselectively to give the corresponding /i-alkoxy ketones in 40-75% yield. Under the same conditions, homoallylic acetates are oxidized to y-acetoxy ketones as the major products. 

The Pd-catalyzed conversion of terminal alkenes to methyl ketones is a reaction that has found widespread use in organic chemistry [87,88]. These reactions, as well as the industrial Wacker process, typically employ CuCh as a co-catalyst or a stoichiometric oxidant. Recently Cu-free reaction conditions were identified for the Wacker-type oxidation of styrenes using fBuOOH as the oxidant. An NHC-coordinated Pd complex, in-situ-generated (I Pr)Pd(OTf)2, served as the catalyst (Table 5) [101]. These conditions min-... 

This combination of reagents h s been used to oxidize terminal vinyl groups to methyl ketones and is known as the Wacker oxidation. The nucleophile is simply water, which attacks the activated alkene at the more substituted end in an oxypalladation step. (3-Hydride elimination from the resulting a-alkyl palladium complex releases the enol, which is rapidly converted into the more stable keto form. Overall, the reaction is a hydration of a terminal alkene that can tolerate a range of functional groups. 

In a synthesis of the immunosuppressant Sanglifehrin A, two hydroxyl groups and a ketone were mutually protected as an acetal [Scheme 1.33].60 The ketone was generated by a Wacker oxidation of the terminal alkene 33.1 whereupon it was immediately converted to the bicyclic acetal 33.2 on treatment with acid. The acetal 33.2 survived the many steps required to elaborate the complex intermediate 33.3 but its stability was to exact a price the synthesis languished on the cusp of completion until conditions were found to hydrolyse the acetal without insult to the remaining delicate functionality. Hie three functional groups were eventually reclaimed in a modest 33% yield by interrupting the hydrolysis at 50% completion. 

The Wacker process is carried out in an aqueous medium containing hydrochloric acid. In addition to ethylene, Smidt and coworkers carried out the oxidation of other alkenes in an acidic aqueous solution of PdCh to prepare carbonyl compoimds. After this report, a few studies on the oxidation of higher alkenes were carried out in organic media. In general, terminal alkenes are converted to methyl ketones rather than aldehydes (equation 1). 

The industrial Wacker process is carried out in aqueous hydrochloric acid using PdClj/CuCh as the catalyst under oxygen pressure. The oxidation of higher terminal alkenes under the same conditions is slow and sometimes accompanied by undesired by-products formed by the chlorination of carbonyl com-poimds by CuCh, and isomerization of double bonds. Earlier examples of oxidation of various alkenes, mainly in aqueous solutions, have been tabulated.The pseudo-first-order rate constants for oxidation of various alkenes, relative to the value for cycloheptene, with PdCb in the presence of benzoquinone in aqueous solution have been rqwrted. An accelerating effect of surfactants such as sodium lauryl sulfate on the stoichiometric oxidation of higher alkenes in an aqueous solution has been reported. 

PdCl2/CuCl2/02 (Wacker oxidation) (palladium chloride/cupric chloride/oxygen) Sulpholane/water RT to 100 terminal alkenes-> methyl ketones... 

The Wacker process is an example of a homogeneously catalyzed reaction that occurs in water. The overall reaction involves the conversion of ethylene into acetaldehyde, or terminal alkenes into ketones (Eq. 28). The... 

Acid chlorides, via (CH3)2CuLi addition (see Section 7.5) Terminal alkenes, using the Wacker process ... 

The oxidation of terminal alkenes to the corresponding 2-alkanones (Wacker reaction cf. Section 2.4.1) has also been carried out under PTC conditions. This process is catalyzed by a PT agent and PdCl2 in the presence of CUCI2 (reoxidant eq. (6)) [84]. The reaction is very sensitive to the nature of the PT catalyst only quaternary salts of type Me3N" (Ci2-Ci4-alkyl) Br are effective. 

For the oxidation of terminal alkenes to methyl alkyl ketones, RhCl3 and RuCls as well as their complexes may be used instead of PdCl2. In these cases, symmetrical quaternary ammonium salts are also effective. However, under these conditions, the isomerization of alkenes occurs simultaneously with the oxidation [85]. The biphasic Wacker reaction can also be carried out under IPTC conditions using a- or /i-CD as the PT agent [86, 87]. 

The asymmetric total synthesis of the putative structure of the cytotoxic diterpenoid (-)-sclerophytin A was accomplished by L.A. Paquette and co-workers/ At the beginning of the synthesis, a bicyclic intermediate was subjected to the Wacker oxidation to oxidize its terminal alkene into the corresponding methyl ketone. The oxidation took place in high yield, although the reaction time was long. The spectra obtained for the final product (proposed structure) did not match that of the natural product, consequently a structural revision was necessary. 

The antiviral marine natural product, (-)-hennoxazole A, was synthesized in the laboratory of F. Yokokawa." The highly functionalized tetrahydropyranyl ring moiety was prepared by the sequence of a Mukaiyama aldol reaction, cheiation-controiied 1,3-syn reduction, Wacker oxidation, and an acid catalyzed intramolecular ketalization. The terminal olefin functionality was oxidized by the modified Wacker oxidation, which utilized Cu(OAc)2 as a co-oxidant. Interestingly, a similar terminal alkene substrate, which had an oxazole moiety, failed to undergo oxidation to the corresponding methyl ketone under a variety of conditions. 

The first synthesis of the hexacyclic himandrine skeleton was achieved by L.N. Mander and co-workers. The last six-membered heterocycle was formed via an intramolecular Wacker-type oxidation in which the terminal alkene side-chain reacted with the secondary amine functionality. The oxidation was conducted in anhydrous acetonitrile to insure that the Pd-alkene complex was substituted exclusively by the internal nucleophile. The resulting six-membered enamine was then hydrogenated and the MOM protecting groups removed to give the desired final product. 

The Wacker oxidation works well for terminal alkenes, too. The products are methyl ketones, not aldehydes, as expected from Markovnikov attack of H2O on the Pd-alkene tt complex. 

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