Oxidative Heck reactions

Abstract This chapter highlights the use of iV-heterocyclic carbenes as supporting ligands in arylation reactions different than the more common cross-coupling reactions, including C-F bond activation, catalytic arylation, homocoupling, direct arylation and oxidative Heck reactions. 

Scheme 7.13 Proposed mechanism of the oxidative Heck reaction with as oxidising agent...

Table 7.2 Chiral NHC-Pd(II) complexes in asymmetric oxidative Heck reaction...

Palladium(0)-catalyzed cross-coupling of aryl halides and alkenes (i.e., the Heck reaction) is widely used in organic chemistry. Oxidative Heck reactions can be achieved by forming the Pd -aryl intermediate via direct palladation of an arene C - H bond. Intramolecular reactions of this type were described in Sect. 4.1.2, but considerable effort has also been directed toward the development of intermolecular reactions. Early examples by Fu-jiwara and others used organic peroxides and related oxidants to promote catalytic turnover [182-184]. This section will highlight several recent examples that use BQ or dioxygen as the stoichiometric oxidant. 

The useful and selective reactivity of arylboronic acids makes them favorite building blocks for many modern organic chemistry applications. Arylboronic acids also serve as highly useful arylpalladium precursors in palladium(II)-catalyzed oxidative Heck reactions. Andappan et al. developed a microwave-accelerated protocol for oxidative Heck couplings using cop-per(II) acetate as the palladium reoxidant [52]. The method proved to be... 

Scheme 14. Example for the oxidative Heck reaction of an arene.

Tsuji s group coupled 2-methylfuran with ethyl acrylate to afford adduct 15 via a Pd-catalyzed Fujiwara-Moritani/oxidative Heck reaction using tert-butyl peroxybenzoate to reoxidize Pd(0) to Pd(II) [30]. The palladation of 2-methylfuran takes place at the electron-rich C(5) in a fashion akin to electrophilic aromatic substitution. The perbenzoate acts as a hydrogen acceptor. 

An interesting application of the Fujiwara-Moritani/oxidative Heck reaction for the synthesis of benzo furans was recently reported by the Stoltz lab [31]. A variety of allyl phenyl ethers (all containing electron-rich aryl components) react with 10 mol% palladium acetate, 20 mol% ethyl nicotinate, 20 mol% sodium acetate, and one equivalent of benzoquinone at 100°C to provide benzofurans in 52-79% yield (e.g. 16—>17). The mechanism of this transformation begins with arene palladation of Pd(II) followed by olefin insertion, p-hydrogen elimination, and olefin isomerization to the thermodynamically favored benzofuran product. The resulting Pd(0) species is then oxidized to Pd(ll) thus regenerating the active catalyst. 

Scheme 39 Fujiwara s application of the oxidative Heck reaction to various heterocycles...

The intramolecular Fujiwara-Moritani/oxidative Heck reaction was applied to the synthesis of functionalized benzo[fe]furans and dihydrobenzo[h]furans in 50-80% yields, and 15 examples are given in the article <04AG(E)6144->. Ionic liquid ([bmimJBF4) was found to be an effective solvent for the PdCl -catalyzed intramolecular Heck reaction to realize benzofurans <04TL6235>. Another palladium-catalyzed intramolecular Heck reaction between vinyl triflate and benzo[(j]furan was utilized to construct the seven-membered ring based (-)-frondosin B <04T9675>. 

In addition to the industrial apphcations, in Scheme 8.1, other reactions have been the focus of extensive research and development. For example. Chapter 12 surveys the research efforts directed toward Pd-catalyzed oxidative carbonylation of phenol affords the important monomer, diphenyl carbonate (Scheme 8.2a). Other reactions of potential industrial significance highlighted in this chapter include the oxidation of alcohols to aldehydes and ketones (Scheme 8.2b), oxidative coupling of arenes and carboxylic acids to afford aryl esters (Scheme 8.2c), benzylic acetoxylation (Scheme 8.2d), and oxidative Heck reactions (Scheme 8.2e). The chapter concludes by highlighting a number of newer research developments, including ligand-modulated catalytic oxidations, Pd/NO cocatalysis, and alkane oxidation. 

The initial discovery of the oxidative Heck reaction was reported by Fujiwara and Moritani in 1967 when they disclosed the coupling of styrene with benzene in the presence of acetic acid and PdCl2 to give traws-stilbene and a-methylbenzyl acetate (Eq. (8.20)) [92]. Attempts to achieve catalytic turnover were made by adding Cu or Ag salts, but oidy 1-2 TONs were obtained [93]. 

Aerobic oxidative Heck reactions also proceed between olefins and other aryl nucleophiles such as aryl tin and aryl boron reagents (Eq. (8.22)). This field started by utilizing aryl tin reagents and electron-deficient alkenes with stoichiometric base additives such as NaOAc [100], but has been significantly improved by... 

Valuable ligand effects have been observed in oxidative Heck reactions. Arenes with weak directing groups benefit from the use of amino acid ligands such as acetylated isoleucine (Ac-Ile-OH), which promote C-H activation via proton... 

Direct functionalization of the C2 position of thiophene can be accomplished through an oxidative-Heck reaction employing palladium(II) acetate in the presence of silver carbonate. The resulting products are obtained in good to high yields with the trans-alkene isomer being favored. Typically less than 10% branched coupling products were observed (not shown). ... 

Oxidative Heck reaction of acetanilides with n-butyl acrylates. 

Table 2.6 Oxidative Heck Reaction of Acetanilides With n-Butyl Acrylates ...

KIEs determination for mechanochemicai oxidative Heck reaction. 

Soon after, Cui, Wu, and co-workers reported a highly efficient oxidative Heck reaction for the synthesis of planar chiral ferrocene derivatives (Scheme 5.10). By employing a similar catalytic system, all kinds of 2-alkenylated ferrocene derivatives were easily accessed via Pd/MPAA catalyzed asymmetric C—H bond functionalization. It was suggested that the Pd° species was oxidized to Pd at the end of the catalytic cycle by Ai,Ai-dime-thylaminomethylferrocenium which is generated from Ai,Ai-dimethylamino-methyl-ferrocene oxidized by air. 

Scheme 5.10 Pd-catalyzed asymmetric oxidative Heck reaction reported by Wu and Cui.

In addition to the several reports of intermolecular Fujiwara-Moritani reactions, there have been a nnmber of examples of intramolecular reactions, both stoichiometric and catalytic in palladinm. In considering an intramolecular oxidative Heck reaction, one can again draw a direct analogy to the classical Heck reaction (Figure 9.3). In the standard Heck reaction, a halogenated arene nndergoes an oxidative addition by palladium(0), followed by alkene insertion and jS-hydride elimination. In an oxidative version, a C—H bond of... 

Since that initial example of an intramolecular oxidative Heck reaction using stoichiometric palladium salts, there have been relatively few appUcations described in the literature. One notable exception is the use of palladium(II)-mediated cyclizations of anilinoquinones to construct carbazole-l,4-quinones (Scheme 9.11) [37]. Furukawa et al. [37a] first described the oxidative cyclization of anilinoquinones 72 and 74 to form pyrayaquinone A (73) and pyrayaquinone B (75) respectively. 

Corey and coworkers [45] later described the application of this reaction in the total synthesis of okaramine N (Scheme 9.16). Bisindole 110 was oxidatively cyclized using stoichiometric Pd(OAc)2 to form compound 111 in 38% yield. Although the yield was modest, the dihydroindoloazocine product could be elaborated in just two steps to afford okaramine N. This remarkably rapid synthesis highlights the efficacy of the palladium(II)-mediated oxidative Heck reaction to construct complex ring systems that can immediately expedite natural product synthesis. 

Much like the initial investigations into intramolecular oxidative Heck reactions utilizing stoichiometric palladium salts, much of the early work toward catalytic variants focused on cyclizations of anilinoquinones (Scheme 9.18) [37e, 47]. Knolker and O Sullivan [37e] reported the first example of an intramolecular oxidative Heck cyclization catalytic in... 

Since that initial report, a number of cyclizations on similar compounds have been described (Scheme 9.19). Akermark et al. [47a] illustrated that fcrt-butyl hydroperoxide can be used as a stoichiometric reoxidant in these reactions in their syntheses of murrayaquinone A (79) and other structural analogues. Knolker et al. [47c] demonstrated that the Pd(OAc)2/Cu(OAc)2 oxidation system can be utilized to access carbazole-l,4-quinone 121 in good yield, which was used as an intermediate in the synthesis of carbazoquinocin C. In 1999, Akermark and coworkers [47d] reported an intriguing example of an intramolecular oxidative Heck reaction of aniUnoquinone species 122 using molecular oxygen as the sole stoichiometric oxidant, affording 123 in 89% yield. 

In 2003, Ferreira and Stoltz [48] described an aerobic palladium(II)-catalysed intramolecular oxidative Heck reaction to form annulated indoles. The core annulated indole smicture is prevalent in a number of biologically active natural products, including pax-illine, penitrem A, and yuehchukene (Figure 9.5). Because indoles are susceptible to oxidative decomposition, carefully optimized conditions had to be developed that were compatible with the substrate and product indole species. 

In order to elucidate the mechanism of this reaction, a substrate probe was designed. Diastereomerically pure indole 140 was synthesized and subjected to the aerobic oxidative cyclization (Scheme 9.20). Annulated indole 141 was produced as a single diastereomer. The outcome of this reaction strongly suggested a mechanism involving initial palladation of the indole, followed by alkene insertion and )3-hydride elimination (an intramolecular Fujiwara-Moritani reaction). If the reaction proceeded by alkene activation followed by nucleophilic attack of the indole, then the opposite diastereomer would have been observed. This experiment confirmed that an oxidative Heck reaction pathway was operative in this aerobic indole annulation. 

As in the palladium(II)-catalysed indole annulation, a diastereomerically pure substrate was designed to help elucidate the mechanism of the benzofuran and dihydrobenzo-furan syntheses (Scheme 9.21). When aryl allyl ether 163 was treated with the palladium oxidation catalyst, dihydrobenzofuran 164 was produced as an exclusive di-astereomer in 60% yield. This observation confirmed that an oxidative Heck reaction pathway, featuring arene palladation, alkene insertion and /3-hydride elimination, was operative. 

In 2006, Lu and coworkers [53] described a method for the synthesis of carbazoles using the palladium(ll)-catalysed oxidative Heck reaction (Scheme 9.25). Indole 177 was subjected to catalytic Pd(OAc)2 and 2.1equiv of benzoquinone to afford carbazole 178 in 88% yield. Because the alkene is 1,1-disubstituted, a 5-exo cyclization mode (as seen in Ferreira and Stoltz s [48] indole annulation) is unproductive, and a 6-endo cyclization ultimately occurs. The putative intermediate is then believed to be oxidized to the aromatic carbazole by the excess benzoquinone. When indole 179, featuring a terminal alkene, was treated with these oxidative conditions, a mixture of products from 6-endo cyclization (180) and 5-exo cyclization (and subsequent isomerization and [3+2] cycloaddition, 181) was observed. A variety of substituted carbazoles were obtained by this palladium(n)-catalysed oxidative cyclization. 

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