C-H palladations

In 2013, a C-H activation route to dibenzopentalenes was discovered by the Itami group (Scheme 2.16) [49]. Through a series of electrophilic palladations and insertions, the diphenyldibenzopentalene 14i was constructed in 52% yield. Notably, this method obviates the need for ortho-functionalized precursors as in prior examples. Over the course of a mechanistic study, it was found that the first C-H palladation event was sensitive to the electronic nature of the substrate and the subsequent alkyne insertion proceeded irrespective of it. Electron-poor / -trifluoromethyl-substituted tolans were excellent substrates (14m, 79% yield), and /w-substituted tolans were decent as well (14n, 53% yield 14o, 66% yield) however, / -methoxy-substituted tolans provided no product. 

In ensuing contributions, phenyl oximes, anilides and 2-phenyl-benzothiazoles have been successfully opened up as substrates. The group of Yu proposed a mechanism " for the acylation of pivaloyl anilides (Scheme 1.40) on the basis of deuterium labeling experiments (Ath/Atd =3.6 for the C-H palladation), a Hammett correlation study with a series of meta-substituted pivaloyl anilides, and the studies of Li et al. with pre-formed Pd complexes. ... 

The reaction starts with the thermal generation of tert-butoxy radicals that subsequently abstract a hydrogen atom from the carbonyl group of the aldehyde. The generated acyl radicals oxidize the palladacycles into either a Pd(IV) complex or a dimeric Pd(III) species which are generated by a rate-determining C-H palladation step. Reductive elimination liberates the product and closes the catal5rtic cycle. 

Simple palladium(II) salts such as chloride and acetate efficiently catalyse aerobic oxidative A-alkylation of amines and amides with alcohols. This method is suitable for a variety of sulfonamides, amides, aromatic and heteroaromatic amines as well as benzylic and heterobenzylic alcohols with a low loadings of the catalyst (0.5-1 mol%) and the alcohols. A selective carbon-carbon double bond assisted o-C-H olefination is catalysed by palladium(II) acetate. The terminal oxidant is oxygen. Addition of TFA is essential for any meaningful yield. (PdOCOCF3)+ has been proposed as the active catalyst. The observed large difference in the inter- and intra-molecular KIE values implied that the coordination of the C=C bond occurs before C-H palladation in the catalytic cycle consequently, a mechanism involving the initial coordination of allylic C=C bond to (PdOCOCF3)+ followed by selective o-C-H bond metalation has... 

After initial C-H palladation, reaction with the acetic anhydride gives an intermediate which yields the product, (117), after reductive elimination. Reaction in methanol or ethanol without added acetic anhydride gives the corresponding alkoxy-substituted products. 

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. 

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. 

Scheme 8.9. Formation of C-C bonds via intermediate palladation of C-H bonds [86-88],...

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-... 

Alkyl aryl ketones are known to be arylated at the a-position of the alkyl groups, via the corresponding enolates, by treatment with aryl halides in the presence of palladium catalysts [4, 9]. The ortho arylation of alkyl aryl ketones is also possible. For example, in the reaction of benzyl phenyl ketones with bromobenzenes, the arylation first occurs at the benzylic position the ortho positions are then arylated via C-H bond cleavage (Eq. 8) [15]. The ortho arylation is believed to occur after coordination of the enol oxygen to ArPd(II), which is followed by ortho palladation as in the reaction of 2-phenylphenols shown in Scheme 2. 

Two closely related yet distinct pathways can be proposed for the arylation of C-H bonds based on coordination-directed C-H bond activation (1) cyclometalation with an MXn fragment followed by transmetalation with Ar-M and reductive elimination, or (2) cyclometalation with an ArMX fragment followed by reductive elimination (Scheme 1). Analogously, two catalytic cycles can be written for the current transformation. The first one would be Cycle 1 which proceeds via cyclo-palladation (with Pd(OAc)2) followed by transmetalation (Scheme 3). An alterna-... 

Metallacycles have also been prepared from two molecules of alkenes or alkynes or from palladated o-alkyl- or aryl- substituted aryls by C-H activation. Metallacycles usually have five- or six-membered ring structures, and four-membered metallacycles have been shown to be intermediates in metathesis (Chapter 6). 

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. 

In some cases it is possible to control the site of palladation, choosing either an sp or sp C-H bond for insertion. When A -thiobenzoylpyrrolidine is treated with Pd in methanol, cyclometalation takes place at the aryl C-H, directed by one of the lone pairs on S (equation 73). When the same reaction is carried out in HMPA, an aUcyl C-H bond reacts. The reason for this change of reactivity with change of the solvent is not known. Certainly, different palladium complexes will be present in the two solvents. 

Presumably, the oxidative cyclization of 1 commences with direct palladation at the orfAo-position, forming o-arylpalladium(II) complex 3 in a fashion analogous to a typical electrophilic aromatic substitution (this notion is useful in predicting the regiochemistry of oxidative cyclizations). The mechanism of the second formal C—H bond functionalization step is not fully elucidated, but may occur either via (a) an intramolecular carbopalladation reaction (migratory insertion) followed by czHft-P-hydride elimination from 4 (Path A) (b) by o-bond metathesis (through a four-centered transition state) followed by reductive elimination (Path B) (c) by electrophilic aromatic substitution followed by C—C bond-forming reductive elimination (PathC) [9]. 

Electronic properties of the substrate often activated C-H bonds are targeted, for example, with electron rich heteroarenes electrophilic palladation is favored at the most nucleophilic position and relies on the inherent reactivity of the system. Similarly if a proton-transfer pathway is under operation, activation is favoured on the most acidic C-H bond. 

A final common arylation mechanism also involves C-H bond palladation with a Pd(II) catalyst, but then a transmetallation with an organometallic such as a boronic acid. Reductive elimination to form the desired product also releases Pd(0) and this species must be oxidized back to the active Pd(II) catalyst. A key aspect of this process is developing an oxidative system that does not result in homo-coupling of the aryl boronic acid (Scheme 9). 

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 first step, it was proposed that the highly electrophilic Pdn(TFA)2 catalyst affected selective electrophilic C-H bond activation exclusively on the electron rich indole. This generated an indole-Pd(II) complex I, which was able to selectively activate the benzene via a transfer-palladation pathway, which is controlled by C-H acidity. Reductive elimination afforded biaryl C-C bond formation and released Pd(0) which required oxidation to regenerate the active Pd(II) catalyst. 

C-H activation on benzene via proton transfer-palladation controlled by C-H acidity... 

Utilization of activated C-H bonds in heteroaromatic compounds is particularly suited to these transformations, where the key C-H activation step involves electrophilic palladation at an electron deficient Pd(II) catalyst. Fujiwara et al. 

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). 

A hypothesis of sequential C-H bond activation reactions at Pd(II) and Pd(IV) was proposed after extensive mechanistic studies. As shown in Scheme 12, the catalytic cycle begins with palladation of the 2-arylpyridine substrate to produce the Pd(II) complex I. Oxidation of complex I with oxone affords the Pd(IV) species II, which occurs another C-H activation to give the intermediate III. Reductive elimination of III leads to the coupling product and regeneration of Pd(II) salts. 

Oxidations of pyridopyrimidines are rare, but the covalent hydrates of the parent compounds undergo oxidation with hydrogen peroxide to yield the corresponding pyridopyrimidin-4(3H)-ones.ss Dehydrogenation of dihydropyrido[2,3-d]pyrimidines by means of palladized charcoal, rhodium on alumina, or 2,3-d i c h I or o - 5,6 - di cy ano -p - benzo -quinone (DDQ) to yield the aromatic derivatives have been reported. 138 Thus, 7-amino-5,6-dihydro-l,3-diethylpyrido[2,3-d]-pvri-midine-2,4(l //,3/7)-dione (177) is aromatized (178) when treated with palladized charcoal in refluxing toluene for 24 hours. 

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