Alkenes Wacker-type reactions

The reaction is highly exothermic as one might expect for an oxidation reaction. The mechanism is shown in Figure 15.1. Palladium chloride is the catalyst, which occurs as the tetrachloropalladate in solution, the resting state of the catalyst. Two chloride ions are replaced by water and ethene. Then the key-step occurs, the attack of a second water molecule (or hydroxide) to the ethene molecule activated towards a nucleophilic attack by co-ordination to the electrophilic palladium ion. The nucleophilic attack of a nucleophile on an alkene coordinated to palladium is typical of Wacker type reactions. 

Wacker-type reactions are Pd(II)-catalyzed transformations involving heteroatom nucleophiles and alkenes or alkynes as electrophiles [108]. In most of these reactions, the Pd(ll) catalyst is converted to an inactive Pd(0) species in the final step of the process, and use of stoichiometric oxidants is required to effect catalytic turnover. For example, the synthesis of furan 113 from a-allyl-P-diketone 112 is achieved via treatment of the substrates with a catalytic amount of Pd(OAc)2 in the presence of a stoichiometric amount of C uC F [109]. This transformation proceeds via Pd(lt) activation of the alkene to afford 114,... 

When media other than water are used, different but related processes operate. Thus, the oxidation of ethylene in acetic acid can be directed to give vinyl acetate, ethylene glycol acetate, or 2-chloroethyl acetate [9]. Similarly, the synthesis of acetals or ketals can be achieved in an alcoholic medium [10]. Although the oxidation of alkenes in such a medium is closely parallel to the Wacker process, the chemistry of these reactions is far beyond the scope of this section, which is limited to Wacker-type reactions in aqueous media, and will not be discussed here. 

Finally, the C—C bond formation by the reaction of 7r-complexes of Pd derived from alkenes, dienes, and other 7r-compounds with enolates and related carbon nucleophiles a la Wacker reaction (Method VI in Scheme 1) provides yet another alternative, as exemplified by the results shown in Scheme For a more general discussion of the C—C bond formation via Wacker-type reaction of Pd rr-complexes with carbanions, the reader is referred to Sect. V.3.4. 

The cyclization of ort/zo-allyl phenols was reported by Murahashi in the late 1970s. The reaction of the 2-(2-cyclohexenyl)phenol (Equation 16.110) was one of the early examples of Wacker-type reactions with alcohol nucleophiles and has been re-investigated in more recent years with chiral catalysts. Intramolecular reactions of alkene-ols and alkenoic acids form cyclic ethers and lactones. These reactions were reported by Larock and by Annby, Andersson, and co-workers, and examples are shown in Equations 16.111 and 16.112. °° ° The use of DMSO as solvent was important to form the lactone products. More recently, reactions with alcohols were reported by Stoltz to form cyclic ethers by the use of pyridine and related ligands in toluene solvent. - The type of ligand, whether an additive or the solvent, is crucial to the development of these oxidative processes. However, the features of these ligands that lead to catalysis are not well understood at this time. 

Unlike the cases of alkenes, Wacker-type intermolecular oxypalladation reactions of alkynes have not been extensively investigated, although their intramolecular cyclization reactions have been developed into synthetically useful procedures (Sects. V3.2). In principle, they can proceed by a few alternative paths shown for the cases of terminal alkynes in Scheme 14. In reality, however, alkynyl C—H activation by Pd to give alkynylpalladium derivatives shown in Scheme 3 may well be the dominant path, as suggested by the carbonylative oxidation of terminal alkynes to give alkynoic acid esters shown in Scheme 15. Oxidative dimerization of alkynes is a potentially serious side reaction. Further systematic investigation of this fundamentally important process appears to be highly desirable. 

B.ix.a. Wacker-Type Reactions. The Wacker oxidation of an alkene bound to a macro-porous polystyrene resin yielded the expected methylketone whereas an alkene bound to a low-crosshnked Merrifield resin gave no product (Scheme 35). The results correlate with the relative permeability of each of these resins toward the aqueous solvent employed. It is interesting to note that the catalytic version of this process gave nearly the same yield as the stoichiometric reaction. 

Hegedus et al. have thoroughly studied the homogeneous hydroamination of olefins in the presence of transition metal complexes. However, most of these reactions are either promoted or assisted, i.e. are stoichiometric reactions of an amine with a coordinated alkene [98-101] or, if catalytic, give rise to the oxidative hydroamination products, as for example in the cyclization of o-allylanilines to 2-alkylindoles [102, 103], i.e. are relevant to Wacker-type chemistry [104]. 

A survey of Wacker-type etherification reactions reveals many reports on the formation of five- and six-membered oxacycles using various internal oxygen nucleophiles. For example, phenols401,402 and aliphatic alcohols401,403-406 have been shown to be competent nucleophiles in Pd-catalyzed 6- TZ /fl-cyclization reactions that afford chromenes (Equation (109)) and dihydropyranones (Equation (110)). Also effective is the carbonyl oxygen or enol of a 1,3-diketone (Equation (111)).407 In this case, the initially formed exo-alkene is isomerized to a furan product. A similar 5-m -cyclization has been reported using an Ru(n) catalyst derived in situ from the oxidative addition of Ru3(CO)i2... 

As indicated under section 2.2. the overall result is the same as that of an insertion reaction, the difference being that insertion gives rise to a yw-addition and nucleophilic attack to an anri-addition. Sometimes the two reaction types are called inner sphere and outer sphere attack. There is ample proof for the anti fashion the organic fragment can be freed from the complex by treatment with protic acids and the organic product can be analysed [19], Appropriately substituted alkenes will show the syn or anti fashion of the addition. The addition reaction of this type is the key-step in the Wacker-type processes catalysed by 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. 

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. 

Palladium-catalyzed, Wacker-type oxidative cycHzation of alkenes represents an attractive strategy for the synthesis of heterocycles [139]. Early examples of these reactions typically employed stoichiometric Pd and, later, cocat-alytic palladium/copper [140-142]. In the late 1970s, Hegedus and coworkers demonstrated that Pd-catalyzed methods could be used to prepare nitrogen heterocyles from unprotected 2-allylanilines and tosyl-protected amino olefins with BQ as the terminal oxidant (Eqs. 23-24) [143,144]. Concurrently, Hosokawa and Murahashi reported that the cyclization of allylphenol substrates can be accomplished by using a palladium catalyst with dioxygen as the sole stoichiometric reoxidant (Eq. 25) [145]. 

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 field of homogeneous palladium catalysis traces its origin to the development of the Wacker process in the late 1950s (Eq. 7) [83]. Since this discovery, palladium-catalyzed reactions have evolved into some of the most versatile reactions for the synthesis of organic molecules [84,85]. Palladium-catalyzed Wacker-type oxidation of alkenes continues to be an active field of research [86-88], and several recent applications of NHC-coordinated Pd catalysts have been reported for such reactions. 

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-... 

In Fig. 4.35 the nucleophile depicted is anionic, but Nu may also be a neutral nucleophile, such as an amine or H2O. There are many alkene complexes of middle and late transition elements which undergo this type of reaction, e.g. M = Pd2+, Pt2, Hg2+, Zn2+, FeCp(CO)2+. The addition reaction of this type is the key step in the Wacker-type processes catalyzed by palladium. 

A Pd-catalyzed oxidative cyclization of phenols with oxygen as stoichiometric oxidant in the noncoordinating solvent toluene has been developed for the synthesis of dihydrobenzo[ ]furans (Equation 136). Asymmetric variants of this Wacker-type cyclization have been reported by Hayashi and co-workers employing cationic palladium/2,2 -bis(oxazolin-2-yl)-l,l -binaphthyl (boxax) complexes <1998JOC5071>. Stoltz and co-workers have reported ee s of up to 90% when (—)-sparteine is used as a chiral base instead of pyridine <2003AGE2892, 2005JA17778>. Attempts to effect such a heteroatom cyclization with primary alcohols as substrates, on the other hand, led to product mixtures contaminated with aldehydes and alkene isomers, which is in contrast to the reactions with the Pd(ii)/02 system in DMSO <1995TL7749>. 

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 application of ethylene in Heck reactions often shows different activities from other alkenes, because of Wacker-type side reactions. It was found, however, that iodo- and acceptor-substituted bromoarenes are cleanly converted in aqueous media to the corresponding styrenes utilizing a palladium-TPPMS complex [13], Furthermore, high purity o- and p-vinyltoluenes were prepared on a large scale (in... 

Palladium catalysts are widely used in liquid phase aerobic oxidations, and numerous examples have been employed for large-scale chemical production (Scheme 8.1). Several industrially important examples are the focus ofdedicated chapters in this book Wacker and Wacker-type oxidation of alkenes into aldehydes, ketones, and acetals (Scheme 8.1a Chapters 9 and 11), 1,4-diacetoxylation of 1,3-butadiene (Scheme 8.1b Chapter 10), and oxidative esterification of methacrolein to methyl methacrylate (Scheme 8.1c Chapter 13). In this introductory chapter, we survey a number of other Pd-catalyzed oxidation reactions that have industrial significance, including acetoxylation of ethylene to vinyl acetate (Scheme 8. Id), oxidative carbonylation of alcohols to dialkyl oxalates and carbonates (Scheme 8.1e), and oxidative coupling of dimethyl phthalate to 3,3, 4,4 -tetramethyl biphenylcarboxy-late (Scheme 8.1f). 

The maintenance of a supported liquid layer in gas-phase reactions is also important in other heterogeneous catalytic applications, such as the Bayer/Hoechst process for vinyl acetate manufacture. However, in these systems, the catalytic metal is reduced to the metallic state, leading to significant mechanistic differences from the formally related homogeneous Wacker-type alkene oxidation/acetoxylation processes (section 11.7.7.3). 

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