Oxidative Heck

Oxidative Heck arylation of enamides with arylboronic acids, using oxygen gas as a reoxidant for Pd(0) and 2,9-dimethyl-1,10-phenanthroline as a chelating regiocontrolling ligand, yielded a (= internally) arylated reaction product as the major compound with a very good a//3 selectivity [92]. Microwave irradiation with prepressurized sealed vials proved useful in reducing the reaction time (Scheme 82). 

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...

The Heck cyclization of bromopyrrole 77 and the corresponding oxidative Heck cyclization of desbromopyrrole 78 was studied <06SL3081>. While the Heck cyclization of 77 led to a mixture of [3.3.l]bicycle 79 and [3.2.2]bicycle 80 under a variety of conditions, the oxidative Heck cyclization of 78 led solely to the desired building block 79. The latter has previously been utilized in a total synthesis of dragmacidin F. 

Another example involves dioxygen-promoted regioselective oxidative Heck aryla-tions of electron-rich alkenes with arylboronic acids (Scheme 4.12c). For this, two types of microwave reactors have been used. In a single-mode instrument (1 mmol run 25 mL vessel), the Heck arylation was performed by first pre-pressurizing the... 

A very recent addition to the already powerful spectrum of microwave Heck chemistry has been the development of a general procedure for carrying out oxidative Heck couplings, that is, the palladium)11)-catalyzed carbon-carbon coupling of arylboronic acids with alkenes using copper(II) acetate as a reoxidant [25], In a 2003 publication (Scheme 6.6), Larhed and coworkers utilized lithium acetate as a base and the polar and aprotic N,N-dimethylformamide as solvent. The coupling... 

Scheme 6.6 Oxidative Heck coupling of boronic acids and alkenes using copper(ll) acetate as a reoxidant.

Carbon Dioxide Stomatal activity is affected by carbon dioxide, and it may affect plant sensitivity to oxidants. Heck and Dunning reported a decrease in sensitivity of tobacco to ozone if the tobacco was exposed to added carbon dioxide at 500 ppm immediately before and during exposure to ozone (22% injury with added carbon dioxide, and 66% injury without). If this is a general plant response, the carbon dioxide now added to greenhouses to increase productivity may also increase resistance of the plants to oxidant pollutants. 

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.

Fig. 19. Cationic intermediates in the oxidative Heck arylation of l-vinyl-2-pyrrolidinone by p-tolylboronic acid observed by ESI(+)-MS 18. ...

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. 

More recently, there has been an emphasis on designing direct arylation reactions that occur under milder conditions and lower temperatures. Since the initial findings concerning the use of Pd(II) catalysts in oxidative Heck type transformations and directed palladations, it has been shown that utilization of these highly electron deficient Pd(II) catalysts can enhance the rate of the key electrophilic... 

There are two typical mechanisms generally applied for palladium-catalyzed C-H alkenylation. First, the oxidative Heck mechanism, initially proposed by Fujiwara and Moritoni [63]. 

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

An early example of a natural product synthesis featuring an indole C-H bond alkenylation was report by Trost and co-workers (Scheme 54). Using stoichiometric Pd(II)-salts in combination with silver tetrafluoroborate, they were able to mediate a oxidative Heck process onto the bicyclic amino-alkene. Using a reductive work-up to reduce the Pd-C bond, they were able to complete a synthesis of ibogamine [76]. 

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>. 

Heck reactions can be carried out on halo- or the readily available mercuri-derivatives, the latter requiring the use of one equivalent of palladium.In addition, due to their susceptibility to electrophilic substitution, oxidative Heck couplings (proceeding via in situ palladation) have found use in uracil chemistry, as shown above. 

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. 

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