Wacker-type alkene oxidation

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]. 

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-... 

Table 5 Wacker-type oxidation of alkenes employing (I Pr)Pd(OTf)2...

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 first asymmetric Wacker-type oxidation of alkenes using a chiral Pd(II) complex was described by Hosokawa and Murahashi [41]. A copper salt catalyzed the air reoxidation of Pd(0) to Pd(II). 

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-type addition is the anti-addition of (most commonly) a heteroatom and a Pd(II) species across a C-C double bond. The Wacker-type oxidations are Pd(II)-catalyzed transformations involving heteroatom nucleophiles and alkenes or alkynes as electrophiles.27 In most of these reactions, the Pd(II) 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 33 from a-allyl-p-diketone 32 is achieved via treatment of the substrates with a catalytic amount of Pd(OAc)2 in the presence of a stoichiometric amount of CuCh-28 This transformation proceeds via Pd(II) activation of the alkene to afford 34, which undergoes nucleophilic attack of the enol oxygen onto the alkene double bond to provide alkylpalladium complex 35. p-Hydride elimination of 35 gives 36, which undergoes... 

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). 

As illustrated in Scheme 9.9, the proposed mechanism of forming phthalides and iso-coumarins involves orthopalladation of the carboxylic acid, subsequent alkenylation and nucleophihc cyclization or Wacker-type oxidative cyclization. The observed differences in product distributions from the reactions using n-butyl acrylate and styrene suggest that the electronic nature of the alkene plays an important role in product formation, although the exact origin of the difference remains unclear. 

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. 

Organopalladium derivatives containing Pd(II) can serve as sources of carbocationic species. Both alkene-Pd Tr-complexes and oxypalladated intermediates in the Wacker oxidation reactions can therefore generate carbocationic intermediates, which may then undergo anionotropic rearrangements (Scheme 6). In fact, it is rather remaikable that, despite the well-known involvanent of alkene-Pd Tr-complexes and oxypalladated intermediates, the Wacker-type oxidation of alkenes is relatively free from various possible rearrangement reactions. 

Terminal alkenes can be transformed into predominately linear and -configured allylic acetates using 1,4-benzoquinone in the presence of catalytic quantities of Pd(OAc)2 and a mixture of DMSO and acetic acid as solvent (eq 74). Wacker-type oxidation products are not observed, perhaps as a result of the stabilization, by DMSO, of a charged intermediate in the catalytic cycle. ... 

Michel BW, Steffens LD, Sigman MS (2011) On the mechanism of the palladium-catalyzed tert-butylhydroperoxide-mediated wacker-type oxidation of alkenes using quinoline-2-oxazoline ligands. J Am Chem Soc 133(21) 8317-8325... 

Scheme 5 Proposed mechanism for the Wacker-type oxidation of alkenes with N2O catalyzed by metallorganic-POM hybrid catalyst [160]...

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. 

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... 

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... 

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. 

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). 

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