Alkene Wacker-type process

While the Mori-Ban indole synthesis is catalyzed by a Pd(0) species, the Hegedus indole synthesis is catalyzed by a Pd(II) complex. In addition, the Mori-Ban indole synthesis is accomplished via a Pd-catalyzed vinylation (a Heck recation), whereas the Hegedus indole synthesis established the pyrrole ring via a Pd(II)-catalyzed amination (a Wacker-type process). Hegedus conducted the Pd-induced amination of alkenes [430] to an intramolecular version leading to indoles from o-allylanilines and o-vinylanilines [291-293, 295, 250, 251]. Three of the original examples from the work of Hegedus are shown below. 

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. 

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. 

In catalytic reactions involving Pd(II) salts, carboxypalladation yields an alkylpal-ladium species that can often undergo (3-H elimination instead of protonolysis. Subsequently, Stoltz and coworkers demonstrated that Wacker-type processes can also afford lactones under oxidative conditions (Scheme 2.35). The proposed mechanism involves Pd(II) coordination to the alkene, followed by oxypalladation and (3-H elimination. After elimination of HX to form Pd(0), aerobic oxidation is required to regenerate a Pd(II) species. The net result is olefin transposition to an adjacent position [80]. 

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. 

Early mechanistic studies have indicated that the oxypalladation step in the Wacker process proceeds through an <37z/z-pathway,399 although recent deuterium-labeling experiments have shown the viability of a yy/z-mechanism involving insertion of a metal-coordinated oxygen into the alkene.400,401 For example, with excess chloride ion present, the Wacker-type cyclization of a deuterated phenol system occurred in a primarily //-pathway, whereas the oxypalladation step favored a yy/z-mode in the absence of excess chloride ion (Scheme 16). Thus, either mechanism may be operative under a given set of experimental conditions. 

Asymmetric induction has also been achieved in the cyclization of aliphatic alcohol substrates where the catalyst derived from a spirocyclic ligand differentiates enantiotopic alcohols and alkenes (Equation (114)).416 The catalyst system derived from Pd(TFA)2 and (—)-sparteine has recently been reported for a similar cyclization process (Equation (115)).417 In contrast to the previous cases, molecular oxygen was used as the stoichiometric oxidant, thereby eliminating the reliance on other co-oxidants such as GuCl or/>-benzoquinone. Additional aerobic Wacker-type cyclizations have also been reported employing a Pd(n) system supported by A-heterocyclic carbene (NHC) ligands.401,418... 

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. 

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-... 

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,... 

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]. 

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. 

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). 

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. 

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. 

In the investigation of Wacker-type oxidations catalyzed by Ru porphyrins, Che and coworkers [36] realized a tandem process in which Ru porphyrin 45 first catalyzed oxidation of terminal alkene 39 to aldehyde 40, followed by a reaction in the same vessel with EDA in the presence of PhsP to generate the conjugated ester 41 in high yield (Scheme 18), Subsequently, they developed an aerobic protocol [37] that allowed the same tandem process to be run using only air as the oxidant. 

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. 

Lead tetraacetate initiates a similar type of oxidation with terminal alkenes, in the presence of acid, to give an aldehyde hy selective oxidation of the terminal carhon. l Ajj example is the conversion of styrene to phenylacetaldehyde in 98% yield. Palladium chloride (PdCl2) reacts with terminal alkenes, in the presence of oxygen and copper salts, to give a methyl ketone (this reaction is called the Wacker process and is discussed in sec. 12.6.A). It is more useful than the LTA oxidation. Oxidation of terminal alkenes with LTA leads to the aldehyde, whereas oxidation with PdCl2 leads to the methyl ketone. The PdCl2 oxidation is illustrated hy conversion of 402 to 403 in 77% yield, in Ikegami s synthesis of coriolin. ... 

Throughout this chapter, stabilized cations have been used for a variety of transformations. The Wacker process involved alkenes but when the alkene has an allylic position, a new type of organometallic can be formed with palladium reagents. 1-Propene, for example, reacts to give a Jt-allyl metal complex such as 338, stabilized by back-donation from the metal atom. Substitution reaction of this Jt-allyl complex with a suitable nucleophile will generate the allylic species, 339, where X is the nucleophile. Early work by Hiittel and Christ lS and also Volger l established that jt-allyl complexes could be prepared, but often in very poor... 

---