Palladium-catalyzed substitution mechanism

The generally accepted mechanism of the palladium-catalyzed substitution reaction is shown in Scheme 1. For a more detailed discussion, the reader is referred to the original chapter [1], A number of papers which probe the enanti-odetermining step for specific ligands have been published over the past four years but will not be discussed further [15-28]. The effect of catalyst loading [29], the ionization of I with different Pd° complexes [30,31], the mechanism of the q3-q -q3 isomerization [32] of intermediate II, and the behavior of the ole-fin-Pd(O) complex III have been studied [33]. 

The palladium catalyzed reactions of substituted vinylallenes with unactivated 1,3-butadienes proceeded with high selectivity133. A multistep mechanism, involving several palladacycles, was proposed to explain the high selectivities observed. 

The mechanism of the Zn chloride-assisted, palladium-catalyzed reaction of allyl acetate (456) with carbonyl compounds (457) has been proposed [434]. The reaction involves electroreduction of a Pd(II) complex to a Pd(0) complex, oxidative addition of the allyl acetate to the Pd(0) complex, and Zn(II)/Pd(II) transmetallation leading to an allylzinc reagent, which would react with (457) to give homoallyl alcohols (458) and (459) (Scheme 157). Substituted -lactones are electrosynthesized by the Reformatsky reaction of ketones and ethyl a-bromobutyrate, using a sacrificial Zn anode in 35 92% yield [542]. The effect of cathode materials involving Zn, C, Pt, Ni, and so on, has been investigated for the electrochemical allylation of acetone [543]. 

Particularly interesting is the reaction of enynes with catalytic amounts of carbene complexes (Figure 3.50). If the chain-length between olefin and alkyne enables the formation of a five-membered or larger ring, then RCM can lead to the formation of vinyl-substituted cycloalkenes [866] or heterocycles. Examples of such reactions are given in Tables 3.18-3.20. It should, though, be taken into account that this reaction can also proceed by non-carbene-mediated pathways. Also Fischer-type carbene complexes and other complexes [867] can catalyze enyne cyclizations [267]. Trost [868] proposed that palladium-catalyzed enyne cyclizations proceed via metallacyclopentenes, which upon reductive elimination yield an intermediate cyclobutene. Also a Lewis acid-catalyzed, intramolecular [2 + 2] cycloaddition of, e.g., acceptor-substituted alkynes to an alkene to yield a cyclobutene can be considered as a possible mechanism of enyne cyclization. 

A variety of substituted seven-membered annulated pyrroles can be synthesized in a one-step process in good yields from readily accessible N-bromoalkyl pyrroles 75 and aryl iodides. The synthesis is based on a palladium-catalyzed/ norbornene-mediated sequential coupling reaction involving an aromatic sp C-H functionalization as the key step. The proposed mechanism suggests that orffzo-alkylation with the formation of intermediate 76 most likely precedes aryl-heteroaryl coupling (Scheme 15 (20060L2043)). 

Yamamoto has proposed a mechanism for the palladium-catalyzed cyclization/hydrosilylation of enynes that accounts for the selective delivery of the silane to the more substituted C=C bond. Initial conversion of [(77 -C3H5)Pd(GOD)] [PF6] to a cationic palladium hydride species followed by complexation of the diyne could form the cationic diynylpalladium hydride intermediate Ib (Scheme 2). Hydrometallation of the less-substituted alkyne would form the palladium alkenyl alkyne complex Ilb that could undergo intramolecular carbometallation to form the palladium dienyl complex Illb. Silylative cleavage of the Pd-G bond, perhaps via cr-bond metathesis, would then release the silylated diene with regeneration of a palladium hydride species (Scheme 2). 

Palladium-catalyzed coupling reactions of the Heck type have in many instances involved indole and pyrrole derivatives. Although the mechanisms are complex, organopalladium species are implicated (84H(22)1493). Vinylation of A-substituted-3 -iodoindoles with amidoacrylate groups provides a useful functionalization of indoles (Scheme 81) (90JOM(39l)C23). Yields are improved in intramolecular reactions, e.g. (406 — 407) and (408 — 409) <92H(34)219,91CPB2830). 

The Heck reaction is a palladium-catalyzed C-C bond-forming procedure that joins benzylic, vinylic, and aryl halides or the corresponding triRates with alkenes or alkyncs. The result is an alkenyl-or aiyl-substituted alkene. The mechanism below is assumed to apply to the Heck reaction.18... 

In the alkyne dimerization catalyzed by palladium systems, all proposed mechanisms account for an alkynyl/alkyne intermediate with cis addition of the alkynyl C-Pd bond to the alkyne in a Markovnikov fashion, in which the palladium is placed at the less-substituted carbon, both to minimize steric hindrance and to provide the most stable C-Pd bond (Scheme 2a). The reverse regioselectivity in the palladium-catalyzed dimerization of aryl acetylenes has been attributed to an agostic interaction between the transition metal and ortho protons of the aromatic ring in the substrate (Scheme 2b) [7, 8],... 

The scope of this reaction appeared to be limited to dialkylamides and electron-neutral aryl halides. For example, nitro-, acyl-, methoxy-, and dimethylamino-substituted aryl halides gave poor yields upon palladium-catalyzed reaction with tributyltin diethylamide. Further, aryl bromides were the only aryl halides to give any reaction product. Vinyl bromides gave modest yields of enamines in some cases. Only unhindered dialkyl tin amides gave substantial amounts of amination product. The mechanism did not appear to involve radicals or benzyne intermediates. 

In general, the telomerization reaction is defined as the dimerization of two molecules of a 1,3-diene in the presence of an appropriate nucleophile HX to yield substituted octadienes [216,217]. This reaction allows us to assemble simple starting materials in a 100% atom efficiency [218] and to easily prepare useful intermediates in the total synthesis of natural products [219,220] and industrial precursors [221], In light of numerous studies, the mechanism of the palladium-catalyzed telomerization reaction is well understood [222,223]. It is accepted that one strongly bound and sterically hindered ligand on the metal center is desirable to generate highly active species, characteristics fulfilled by (NHC)-Pd(O) complexes. 

Facing all the mechanism-related peculiarities of the thermally induced rearrangement it was consequential to try to shift the reaction toward one end of the mechanistic spectrum. The first steps in that direction were undertaken by Hiroi et ah in 1984 they reported on a palladium-catalyzed variant of the reaction [49]. With enantiomerically enriched sulfinates 61 (Scheme 16) they found a much faster reaction as compared to the uncatalyzed one, allowing a reduction of the reaction temperature down to - 78 °C ( ). The stereospecificity of the rearrangement depended heavily on the substitution pattern (between 28 and 92%) and was traced back to the intermediacy of a configurationally stable ri -jt-allylpalladium species whose configuration was influenced by the S centro chirality. Unfortunately, due to difficulties in the preparation of enantiomerically pure 2-alkenylsulfinates (see above), the ee values of the resulting allylic sulfones were quite low. 

This classification is illustrated in Scheme 365. The synthesis of imidazoles under this classification is rare mainly due to the difficulty of C-C bond formation. A palladium-catalyzed coupling of imines 1415, 1417 and acid chloride 1416 to synthesize substituted imidazoles 1418 belongs to this category of ring formation. AT-Alkyl and AT-aryl imines can be used, as can imines of aryl and even nonenolizable alkyl aldehydes. A plausible reaction mechanism involving 1,3-dipolar cycloaddition with miinchnones is illustrated in Scheme 366 <2006JA6050>. 

Amatore, C., Jutand, A., Suarez, A. Intimate mechanism of oxidative addition to zerovalent palladium complexes in the presence of halide ions and its relevance to the mechanism of palladium-catalyzed nucleophilic substitutions. J. Am. Chem. Soc. 1993,115, 9531-9541. 

The most important class of allylic substitutions are palladium-catalyzed reactions with so-called soft nucleophiles such as stabilized carbanions or amines, and with few exceptions, the enantioselective transformations discussed in this chapter belong to this category. The mechanism of these reactions has been firmly established and a detailed picture of the catalytic cycle can be drawn [1, 2,3,4,5,6,13,14,15]. The course of allylic substitutions catalyzed by metals other than palladium is less clear and information about the intermediates involved is scarce. 

The generally accepted mechanism of palladium-catalyzed allylic substitutions is shown in Scheme 1. An allylic substrate 1, typically an acetate or a carbonate, reacts with the catalyst, which enters the catalytic cycle at the Pd(0) oxidation level. Both Pd(0) and Pd(II) complexes can be used as precatalysts, because Pd(II) is easily reduced in situ to the active Pd(0) form. Presumably, the reaction is initiated by formation of a Ji-complex which eliminates X to produce an (ri -allyl)palladium(II) complex. The product of this oxidative addition can... 

In the absence of nucleophiles, the intermediate allyl complexes are stable and can be isolated. This is an attractive, quite unique feature of palladium-catalyzed allylic substitutions, because in most catalytic processes it is difficult to isolate or even merely detect intermediates of the catalytic cycle. The vast amount of data on the structure and reactivity of (allyl)palladium complexes that is available, has led to valuable insights into the mechanism of allylic substitutions and the origin of enantioselection in reactions with chiral catalysts (see Sect. 7). 

Scheme 3 A plausible electrophilic aromatic substitution mechanism for palladium-catalyzed direct arylation...

The stereochemical outcome was in agreement with a mechanism for the palladium-catalyzed cyclization/carboalkoxylation of a substituted alkene (Scheme 47) that involves outer-sphere attack of the indole on the palladium-olefin complex I which, coupled with loss of HCI, would form the alkylpalladium intermediate II. 1,1-Migratory insertion of CO into the Pd-C bond of II with retention of stereochemistry would form the acyl-palladium complex III, which could undergo methanolysis to release c/.v-product and form a palladium(0) complex. Oxidation with Cu(II) would then regenerate the active Pd(II) catalyst. 

Palladium-catalyzed direct (hetero)arylations of indolizines proceeded in a highly efficient and regioselective manner (Scheme 9.42) [103], Mechanistic studies strongly supported an electrophilic substitution-type mechanism for this transformation. 

The Intimate Mechanism of Replacement in Square-Planar Complexes Platinum(II)-Catalyzed Substitutions of Platinum(IV) Complexes Kinetics of Nickel, Palladium and Platinum Complexes Isomerization Mechanisms of Square-Planar Complexes Anomalies in Ligand Exchange Reactions for Platinum(II) Complexes Inorganic Reaction Mechanisms The CIS and trans Efiects of Ligands... 

On the basis of the analysis of the stereochemical outcome of oxidatively induced palladium-catalyzed C(sp )-0 forming reactions leading to substituted tetrahydrofurans, it was suggested that high valent alkyl palladium intermediates can react via a concerted three-center reductive elimination mechanism to form C (sp )-O bonds [31]. No characterization of these presumed high valent species or mechanistic studies of their reactions have been carried out. 

Internal alkynes will also readily undergo palladium-catalyzed annulation by functionally substituted aromatic or vinylic halides to afford a wide range of heterocycles and carbocycles. However, the mechanism here appears to be quite different from the mechanism for the annulation of terminal alkynes. In this case, it appears that the reaction usually involves (1) oxidative addition of the organic halide to Pd(0) to produce an organopalladium(II) intermediate, (2) subsequent insertion of the alkyne to produce a vinylic palladium intermediate, (3) cyclization to afford a palladacycle, and (4) reductive elimination to produce the cyclic product and regenerate the Pd(0) catalyst (Eq. 28). 

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