Palladium directed alkylations

Important features favoring the reductive elimination reaction have been discussed based on theoretical and experimental studies [128-130]. The reductive elimination of an azohum salt from a palladium NHC alkyl complex (Fig. 13) proceeds under direct formation of Pd° in an exothermic process with a low activation barrier [128]. The coligands at the palladium atom play an important role. It has been shown that the Caikyi-Pd-CNHC angle becomes more acute during the reductive elimination to allow for an optimal orbital overlap of the groups to be... 

Direct alkylation of allylic alcohols is effected with palladium complexes but under harsh reaction condi-... 

Table 7. Charge-Directed Palladium-Assisted Alkylation of Vinyl y-Rulyro-lactones with Sodium Dimethyl Malonate...

Unlike the platinum analogs, direct observation of palladium(IV) alkyls has been limited to those with nitrogen-based ligands such as 2,2 -bipyridine and a-diimines [49]. However, reductive elimination from palladium(IV) complexes has... 

Examples of direct alkylation of indoles under classical Friedel-Crafts conditions with strong Lewis acids are sparse. This fact probably reflects the tendency of indole to undergo oligomerization with such reagents (Sect. 2.2). The successful conditions for direct indole alkylation usually involve reagents that can generate carbocations under mild conditions, such as benzylic and allylic systems. Palladium-mediated allylations provide another approach. 

Intramolecular palladium-catalyzed alkylations of (hetero)arenes have been pioneered by Wong and Song [25], who described in 1994 a direct benzylation of furans within a domino sequence starting with the intermolecular Suzuki- Miyaura coupling of furylboroxines with o-bis(bromomethyl)arenes (Scheme 19.14). Mixtures of the cross-coupled product and the corresponding homocoupled furan were almost always obtained. 

The same group reported an extension of the direct alkylation of (benz)oxazoles with various alkyl bromides and chlorides by using the stronger base lithium tert-butoxide (Scheme 19.23) [38]. 5-Aryloxazoles containing electronically diverse substituents such as CFj and OMe were also alkylated successfully. Various linear alkyl chains were introduced, such as phenylpropyl, citronellyl, or octyl, affording interesting lipophilic molecules. The optimized reaction conditions failed to apply to benzothiazoles, and the authors had to turn their attention to nickel catalysis to achieve the corresponding alkylation (Section 19.2.3). Experiments were run to understand the reaction mechanism that presumably involves Sj 2-type oxidative addition of the alkyl halide to palladium(O) followed by transmetallation by the in situ-lithiated (benz)oxazole (Scheme 19.24). 

Scheme 19.23 Palladium-catalyzed direct alkylation of (benz)oxazoles.

Unactivated olefins are inert toward attack of nucleophiles. When complexed to palla-dium(II) salts, stabilized carbanions (p/(j, = 10-17) react intermolecularly with these olefinpalladium(II) complexes to generate alkylpalladium complexes. Alkylation occurs predominantly at the 2-position after a reductive or /3-elimination procedure or an insertion reaction with carbon monoxide. Nonstabilized carbanions attack the palladium directly, forming aUcylpalladium complexes that lead to alkene alkylation products at the 1-position. All these reactions required stoichiometric amounts of palladium salts. 

A carboxylic acid-directed palladium-catalyzed alkylation of benzoic acids with alkyl halides to provide benzolactones was reported by Yu and coworkers in 2009 (Scheme 3.20) [44]. The reaction is rather general to a wide scope of substrates and gives the desired products in moderate to excellent yields. 

Alkenyl zirconium complexes derived from alkynes form C—C bonds when added to aHyUc palladium complexes. The stereochemistry differs from that found in reactions of corresponding carbanions with aHyl—Pd in a way that suggests the Cp2ZrRCl alkylates first at Pd, rather than by direct attack on the aUyl group (259). 

Direct elimination of a carboxylic acid to an alkene has been accomplished by heating in the presence of palladium catalysts.Carboxylic esters in which the alkyl group has a P hydrogen can be pyrolyzed, most often in the gas phase, to give the corresponding acid and an alkene. No solvent is required. Since rearrangement and other side reactions are few, the reaction is synthetically very useful and is often carried out as an indirect method of accomplishing 17-1. The yields are excellent and the work up is easy. Many alkenes have been prepared in this manner. 

Fagnou and co-workers reported on the use of a palladium source in the presence of different phosphine ligands for the intramolecular direct arylation reaction of arenes with bromides [56]. Later, they discovered that new conditions employing palladium complex 27 promoted the direct arylation of a broad range of aryl chlorides to form six- and five-membered ring biaryls including different functionalities as ether, amine, amide and alkyl (Scheme 7.11) [57]. 

However, the practical, direct synthesis of functionalized linear polyolefins via coordination copolymerization olefins with polar monomers (CH2 = CHX) remains a challenging and industrially important goal. In the mid-1990s Brookhart et al. [25, 27] reported that cationic (a-diimine)palladium complexes with weakly coordinating anions catalyze the copolymerization of ethylene with alkylacrylates to afford hyperbranched copolymers with the acrylate functions located almost exclusively at the chain ends, via a chain-walking mechanism that has been meticulously studied and elucidated by Brookhart and his collaborators at DuPont [25, 27], Indeed, this seminal work demonstrated for the first time that the insertion of acrylate monomers into certain late transition metal alkyl species is a surprisingly facile process. It spawned almost a decade of intense research by several groups to understand and advance this new science and to attempt to exploit it commercially [30-33, 61]. 

The key intermediate 124 was prepared starting with tryptophyl bromide alkylation of 3-acetylpyridine, to give 128 in 95% yield (Fig. 37) [87]. Reduction of 128 with sodium dithionite under buffered (sodium bicarbonate) conditions lead to dihydropyridine 129, which could be cyclized to 130 upon treatment with methanolic HC1. Alternatively, 128 could be converted directly to 130 by sodium dithionite if the sodium bicarbonate was omitted. Oxidation with palladium on carbon produced pyridinium salt 131, which could then be reduced to 124 (as a mixture of isomers) upon reaction with sodium boro-hydride. Alternatively, direct reduction of 128 with sodium borohydride gave a mixture of compounds, from which cyclized derivative 132 could be isolated in 30% yield after column chromatography [88]. Reduction of 132 with lithium tri-f-butoxyaluminum hydride then gave 124 (once again as a mixture of isomers) in 90% yield. 

The palladium(n)-catalyzed direct carbonylation proceeds with remarkable site selectivity to afford a variety of five- or six-membered benzolactams from A-alkyl-cc-arylalkylamines in a phosphine-free catalytic system using Pd(OAc)2 and Cu(OAc)2 in an atmosphere of CO gas containing air (Equation (90)).118... 

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

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