Arenes palladation

Two mechanisms of reaction appear possible depending upon the reactants. Initial palladation of other the alkene or the arene may occur alkene palladation is proposed to occur initially in reactions of chlorinated alkenes.2-3 Alkenes without strongly electron-withdrawing chloride substituents and moderately reactive arenes generally react via an initial arene palladation, and the reaction takes the route shown in Scheme l.4... 

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. 

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. 

A variety of Lewis-basic nonbonding electron donors including amino, imino, azo, amido, phosphino, and sufldo groups readily participate in the arene palladation, as indicated by the results shown in Scheme 1.[ H12] Ethers and other oxygenated groups... 

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. 

Palladation, cyclobutadiene cobalt units, 7, 70 ortho-Palladations, arene chromium tricarbonyls, 5, 240 5-PalladatricycIo[4.1.0.0]heptanes, preparation, 8, 292 Palladium calix[4]arenes, as first- and second-sphere ligands,... 

Direct palladation of C-H bonds can be achieved by treatment of, for example, electron-rich arenes with Pd(II) salts (see also Section8.11). After cross-coupling via reductive elimination the resulting Pd(0) must be reoxidized to Pd(II) if Pd-catalysis is the aim [85], Reoxidation of Pd(0) with Cu or Ag salts (as in the Wacker process) is not always well suited for C-C bond-forming reactions [86], but other oxidants, for example peroxides, have been used with success (Scheme8.9). The required presence of oxidants in the reaction mixture limits the scope of these reactions to oxidation-resistant starting materials. 

Palladation of an arene is a very facile reaction when, before the C-H activation step, coordination of palladium to a nearby ligand functionality in the molecule occurs. The first report of a stoichiometric intramolecular palladation is probably the reaction of diazobenzene and palladium chloride by Cope in 1967 [6a], Intramolecular palladation is a widespread reaction that has often been used as a starting point for synthesizing new molecules using insertion reactions in the arylpal-... 

Perchloric acid increased the electrophilicity of Pd(II). A strong parallel between palladation and mercuration of aromatic hydrocarbons was drawn.568 (The effect of strong acids in increasing the electrophilicity of metal acetates has been discussed earlier.) Arylmercury complexes are relatively stable and do not afford biaryl readily. Analogous arylthallium(III) complexes only afford biaryls on photolysis in the presence of arenes via the following sequence ... 

The primary method of direct palladation begins with Pd and proceeds by either electrophilic aromatic substitution or oxidative addition of an arene C-H bond (equation 2) In both cases, loss of H-X leads to an aryl-Pd-X derivative. Simple arenes can undergo palladation, but lead to isomers in the absence of a strongly directing substituent. The process is usually done in a stepwise manner, with isolation of the aryl-Pd-X intermediate. It is not easily made catalytic various reoxidation recipes are used for conversion of Pd° to Pd in other applications, but none has been found satisfactory here. 

Oxidative addition of Pd(0) into Ar-X bond 2) Nortoomene mediated Pd(ll)-Pd(IV) cycle generates atylpalladium(ll) intermedaite VI i) Heck reaction between arylpalladium(ll) complex I and norbomene generates II ii) Directed ortho-palladation on arene forms III... 

In 2007, the Fagnou group achieved a much more practical and selective Ar-H/ Ar-H cross-coupling [50]. Electron deficient palladium(II) complexes can react via an electrophilic C-H activation mechanism with good selectivity for electron rich arenes. In contrast, Fagnou [51] recently showed that complimentary reactivity to this is displayed by some ArPd(II) complexes that react through a proton-transfer-palladation mechanism, and that they depend on arene C-H acidity rather than arene nucleophilicity (Scheme 31). 

In the cross-coupling reaction, starting from the simple arene (with directing group), palladation by a Pd(II) salt would lead to the formation of the palladacyclic complex (Ar1Pd(II)L) (Scheme 3). After the transmetallation and reductive elimination processes, the biaryl product is obtained together with Pd(0). If the Pd(0) can be further oxidized to Pd(II) catalyst, a catalytic cycle will be formed. By accomplishing this, arenes (C-H) are used to replace the aryl halides (C-X). Similarly, arenes (C-H) can be used to replace the aryl metals (C-M). 

Myers AG, Tanaka D, Mannion MR (2002) Development of a decarboxylative palladation reaction and its use in a Heck-type olefination of arene carboxylates. J Am Chem Soc 124 11250-11251... 

Alkenylation and arylation. Alkenyl triflates are highly active in intramolecular alkenylation of both electron-rich and electron-poor arenes. 2-Alkynylbiaryls give 9-aIkylidenefluorenes via palladation of the o -position [the benzene ring bearing electron-withdrawing group(s)]. ... 

Another Wacker-type oxidation is the oxidative cyclization reaction, which is the intramolecular union of two arenes with formal loss of H2 promoted by a Pd(II) species [typically Pd(OAc)2].33-36 In an early example of this transformation, treatment of diphenylamines 45 with Pd(OAc)2 in acetic acid yielded carbazoles 46.37 The role of acetic acid in such oxidative cyclization processes is to protonate one of the acetate ligands, which affords a more electrophilic cationic Pd(II) species, thereby promoting the initial electrophilic palladation of the aromatic ring. 

The first step of this reaction is the palladation of the arene. Olefin insertion into the Ar-Pd bond is then possible [12] ... 

Subsequent studies revealed that the pre-activation of the arene was not required when an oxidant was present (15) [134, 135]. While the mechanism has yet to be fully investigated, preliminary studies have ruled out both radical and electrophilic palladation pathways. 

Arenes, especially electron-rich ones, and five-membered-ring heteroaromatic compounds have been found to react with alkynes in the presence of Pd(II) or Pt(II) species in acidic solvents to give the corresponding hydroaryl-ation products (Eqs. 68 and 69) [155-158]. The mechanism proposed for the reaction involves aromatic palladation to form ArPd(II) species, as in the Fujiwara-Moritani reaction [10], insertion of an alkyne,and protonolysis of the... 

The palladation of arenes can be used for direct thermal functionalization. A palladium acetate/phenanthroline catalyst in the presence of acetic acid and under a CO atmosphere converts naphthalene into naphthoic acid with up to 91% selectivity for the )8-isomer. The reaction proceeds at 115 °C over 24-72 h. Ligands other than phenanthroline are less effective. Even saturated hydrocarbons are not inert to activation by palladium. In stoichiometric reactions, Pd(OAc)2 in CF3COOH as solvent at 80 °C reacts with methane to give CF3COOMe and Pd(0) as in equation (32), and adamantane gives 1-adamantyltrifluoroacetate. Since the esters can be hydrolyzed, the overall reaction corresponds to the reaction of the hydrocarbon with water to give alcohols shown in equation (33). Arenes are... 

There is support for the occurrence of Pd(IV) species in the acetoxylation of arenes,t with the most recent proposal shown in Scheme 17, consistent with demonstrated palladation of benzene, for example, by Pd(02CMe)2/SEt2 to form... 

It was demonstrated by Heck in the late 1960s that arylpaUadium salts, prepared by trans-metallation of organomercury compounds, constitute useful reactants in various vinylic substitution reactions.f t Independently, Moritani, Fujiwara, and colleagues conducted similar vinylic substitutions, but generated the organopalladium intermediates by direct electrophilic palladation of arenes.t ° In these reactions the palladium(II) salt employed is reduced to paUadium(O) (Scheme ). ... 

Oxidative couplings of simple arenes, whose reactivity is comparable with benzene itself, to biaryls have been performed with stoichiometric palladium salts [2-5], Biphenyl (8) is obtained in high yield from two molecules of benzene by the influence of palladium(II) acetate or mixture of palladium(II) chloride (1 eq.) and sodium acetate (2 eq.). The reaction apparently involves the electrophilic palladation of benzene to give phenylpalladium(ll) acetate (370) which further reacts with the... 

Unlike the previously discussed Fujiwara-Moritani reactions, which involve the electrophilic palladation of arenes, another category of Fujiwara-Moritani reactions exists that takes advantage of the directing ability of a neighbouring functional group. De Vries and coworkers [32] have reported a selective palladium(ll)-catalysed oxidative coupling of anilides with alkenes through C-H bond activation at room temperature. It was found that acetanilide (54) reacts with -butyl acrylate (4d) in the presence of 2 mol% Pd(OAc)2,... 

Other parameters of the palladium(n)-catalysed benzofuran synthesis were explored. Ultimately, it was found that the ideal system employed a 2 1 ligand/palladium ratio (10mol% Pd(OAc)2 and 20mol% ethyl nicotinate) and a substoichiometric amount (20mol%) of NaOAc at 100 °C. With this system in hand, a variety of substituted benzo-furans were accessed (Figure 9.7). The reaction was limited to electron-rich aryl systems the palladation event required a sufficiently nucleophilic arene in order to occur. The aryl subunit, however, tolerated an array of alkyl and alkoxy substitution patterns within the... 

First, the interaction of a Lewis acidic palladium 11) complex with a C(sp —H bond of an electron-neutral or electron-rich (het)arene might result in its electro-phiUc palladation (173 175 Scheme 7.42), a fundamental process later referred to as electrophilic C—H bond activation. In contrast, the oxidative addition of a C(sp )—X bond to palladium(O) is favored for electron-poor (het)arenes, thus providing an orthogonal entry into Mizoroki-Heck chemistry. After C—H activation, convenhonal alkene insertion (175 176) and P-hydride elimination (176 177) eventually lead to the formation of catalytically inactive palladium(O). In order to achieve catalytic turnover, however, paUadium(O) must be reoxidized to palladium(II). 

In this chapter, the transition of metal catalyzed carbonylative activation of C-H bonds has been discussed. This area is dominated by Pd, Ru and Rh catalysts, whereas the ability of other metals, such as Cu and Fe, have still not been explored. From the reaction mechanism point of view, the first step is the palladation of arene to produce an Ar-Pd bond, and then be followed by CO insertion. 

An interesting palladium-catalysed oxidative arylalkylation of aromatic acrylamides (282) with MeCN that proceeds through a dual C-H bond cleavage of both arene and acetonitrile and affords indolinones (283) has been reported. Mechanistic studies revealed a fast Heck-type arylation of the C=C bond and a rate-limiting C-H activation of the acetonitrile. The initial palladation of the aromatic moiety apparently proceeds with the assistance of the amide group. ... 

An interesting Pd-catalyzed diene carboamination reaction that involves urea-directed C—H activation was recently reported [56]. For example, treatment of N-aryl urea 63 with an activated diene in the presence of 10 mol% Pd(0 Ac) 2,50 mol% TsO H, AC2O, and benzoquinone provided 64 in 90% yield (Eq. (1.29)). The transformation is initiated by directed palladation of the arene by a palladium tosylate complex (formed... 

A new three-component reaction incorporating an aryl iodide, an aryl bromide, and an acrylate to give ortho-aryl-substituted cinnamates 201 recently also developed by Catellani et al. (Scheme 8.48) [361], proceeds only in the presence of norbornene and involves an intermediate norbornylpalladium complex and palladation of an arene ring. 

Aromatic ketimines as well as aldimines are viable substrates for ortho amidation, carbamoylation, and sulfamidation. Not only aromatic, but also aliphatic oximes were converted into the amides regioselectively in high yields. It was suggested that the reaction proceeds by the oxidation of the amide to a nitrene species, which then inserts into the ortho-palladated arene. An alternative mechanism, which involves a Pd-nitrene or Pd(IV) species, was also considered for this reaction. 

Despite the plausibility of the mechanisms shown in Schemes 1 and 2, palladation of arenes and other C—H compounds can also be and may have to be interpreted differently. As in the mechanistic discussion of oxidative addition in Sect IL3.1 (Scheme 6), the crucial requirements in the activation of a o--bond by Pd may just be a combination of (i) binding of Pd via tt- or o--complexation and (ii) oxidative addition of a proximal cr-bond, specifically C— H bond here. Such mechanisms for benzyl and alkynyl C— H activation are shown in Scheme 3. The critical difference between Schemes 2 and 3 is that, in the latter, there is no element of j8-elimination. A wide variety of o-palladation reactions observed with heterosubstituted arenes, such as those shown in Scheme 4, are more readily explained by the mechanism shown in Scheme 3 than that in Scheme 2. 

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