Fujiwara-Heck reaction

After the finding of the coupling reaction via C—H activation, the couphng of olefins and aromatic halides by palladium catalysts was found as described in Part IV thus, these reactions are known as the Fujiwara arylationt or the Fujiwara-Heck reaction. fi i... 

An important route for the C-H activation of arenes and heteroarenes is through electrophilic metallation of an aromatic ring, followed by reaction with an alkene. There are numerous simple examples with arenes and heteroarenes reacting with alkenes under palladium catalysis." This has been referred to as the dehydro-genative Heck reaction and the oxidative Heck reaction, as well as the Fujiwara reaction, or Fujiwara-Heck reaction. Both benzene 3.4 and its derivatives (Schemes 3.6 and 3.7) and heteroarenes (Schemes 3.8 and 3.9) can be used. While the reaction has been carried out with a stoichiometric amount of palladium, catalytic processes, with an added oxidant are widespread. 

The lone pair of pyridine can be employed to direct C-H activation for C-C bond formation. If the palladium intermediate is intercepted in a Fujiwara-Heck reaction, the olefination product 3.168 undergoes conjugate addition of the pyridine nitrogen to the newly formed alkene giving a pyridinium ion product 3.169 (Scheme 3.66). ... 

FUJI WAR A Lanthanide (Yb) reaction 136 FUJIWARA Aiylation, caiboxylation 137 FUJIWARA - HECK Coupling 138... 

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>. 

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]. 

Similar to mercuration, Pd(OAc)2 undergoes facile palladation of aromatic com-povmds. The palladation product 162 is an unstable intermediate. It can be isolated only when stabilized by chelation. The palladation products of aromatics as reactive intermediates undergo three reactions. The reaction with alkenes to afford styrene derivatives 164 is the first one. Pd(II)-promoted alkenylation of aromatic compovmds, discovered by Fujiwara, is a stoichiometric Heck reaction. The second one is homocoupling to form biaryls. The acetoxylation of aromatic rings is the third reaction. These latter two reactions are treated in Chapter 2.7. 

Pd-catalyzed hydroarylation of alkynes via aromatic C—bond activation has been reported by Fujiwara. The reaction offers a good synthetic method of arylalkenes, which are usually prepared by Heck reaction of alkenes. Electron-rich arenes bearing more than one OH, OMe, and alkyl groups react with electron-deficient alkynes [6], The reaction proceeds with a catalytic amount of Pd(OAc)2 in trifluoroacetic acid (TEA) at room temperature. Hydroarylation of ethyl propiolate (15) with / -dimethoxybenzene yielded ethyl (Z)-3-(2,5-dimethoxyphenyl)-2-propenoate (16). Mesitylene (17) is an active arene and the reaction of 17 with 3-butyn-2-one (18) afforded the imsaturated ketone 19 which has f-form [7]. 

The first waste-free vinylation of arenes under C—H activation is as old as the Mizoroki-Heck reaction itself already in 1967, Moritani and Fujiwara [6] revealed a stoichiometric reaction of styrene-palladium(II) chloride dimers with benzene in the presence of acetic acid to give stilbenes in a modest 24% yield. During this process, the palladium(II) precursor is reduced to palladium(O), so that the key to closing the catalytic cycle was to add an efficient reoxidation step to regenerate an active palladium(II) species. One year later, the same group presented a first approach, substoichiometric in palladium. 

Oxidative Heck-Type Reactions (Fujiwara-Moritani Reactions)... 

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... 

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. 

Oxidative Heck-Type Reactions (Fujiwara-Moritani Reactions) 373 Table 9.2 The palladium-catalysed oxidative cyclization of aryl allyl ethers oxidant studies. 

In 1972, Heck showed, independently, that aryl, benzyl and styryl halides would react with alkenes in the presence of a hindered amine as organic base at a lower reachon temperature of 100 °C (Scheme 1.16) [51, 66]. A detailed overview on the modem aspects of Mizoroki-Heck reactions, as well as their oxidative variants (Fujiwara reactions), is provided by Martin Oestreich and Verena Trepohl in Chapter 7. 

This transformation, often termed the oxidative Mizoroki-Heck reaction, was actually reported by Moritani and Fujiwara [5] prior to pubUcation of the initial descriptions of the Mizoroki-Heck reaction [1, 2]. During the early years, the oxidation of palladium(O) by molecular oxygen required copper(II) as a redox mediator, although in recent years modified protocols were developed (see Section 7.4.2.1) [113],... 

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