Palladium intermolecular alkylation

Intermolecular bis-silylation of highly strained bicyclopropylidene with hexaorganodisilanes proceeds at 70 °C in the presence of the palladium// r/-alkyl isocyanide catalyst (Equation (34)).102... 

While optimizing the reaction conditions, Lautens found that cyanation took place with many intermediates in the Catellani reaction sequence, as all non-palladacycle palladium(II) species in the sequence underwent cyanation (Scheme 29). Through optimization experiments, the target product could be obtained in good to excellent yields from either tethered or intermolecular alkyl bromides and iodides (Scheme 30). As alkyl chlorides are more widely commercially available, lower in cost, and more stable than the corresponding alkyl bromides or iodides, Lautens reported a method to incorporate alkyl chlorides as reaction partners. This study eventually led to the use of benzyl chlorides, a-chloroesters, and a-chloroamides as coupling partners, which were far too reactive as the analogous bromides or iodides. 

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. 

Contrary to heteroarenes, only few examples of intermolecular alkylations of the less reactive arenes have been reported. In a seminal example, perylene bisimides have been meta-alkylated with various alkyl halides under palladium catalysis and using CS2CO3 as the base (Scheme 19.25) [39]. The C-H activation step was again proposed to occur through the base-induced CMD mechanism (Scheme 19.18), and the exclusive functionaU2ation at the meta position can be correlated to the higher acidity of the meta C-H bond, as already shown in the related C-H arylation of electron-deficient arenes [29b,c]. 

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I],... 

The first palladium-catalyzed formation of aryl alkyl ethers in an intermolecular fashion occurred between activated aryl halides and alkoxides (Equation (28)), and the first formation of vinyl ethers occurred between activated vinyl halides and tin alkoxides (Equation (29)). Reactions of activated chloro- and bromoarenes with NaO-Z-Bu to form /-butyl aryl ethers occurred in the presence of palladium and DPPF as catalyst,107 while reactions of activated aryl halides with alcohols that could undergo /3-hydrogen elimination occurred in the presence of palladium and BINAP as catalyst.110 Reactions of NaO-/-Bu with unactivated aryl halides gave only modest yields of ether when catalyzed by aromatic bisphosphines.110 Similar chemistry occurred in the presence of nickel catalysts. In fact, nickel catalysts produced higher yields of silyl aryl ethers than palladium catalysts.108 The formation of diaryl ethers from activated aryl halides in the presence of palladium catalysts bearing DPPF or a CF3-subsituted DPPF was also reported 109... 

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. 

Intermolecular, enantioselective Heck reactions require a cyclic olefin as substrate, since syn carbopal-ladation of a cyclic olefin results in a geometrically defined a-alkyl-palladium compound. By necessity, the subsequent syn dehydropalladation must take place away from the newly formed chiral centre, thereby affording a chiral product. 

The final modes of enantioselective allyl alkylations catalyzed by palladium involve the use of chiral nucleophiles447 and chiral leaving groups.448-449 Chiral enamines were found to undergo allylation in 100% optical yield in an intramolecular case and in up to 50% optical yield in intermolecular reactions (equation 358). 

A simple method for the direct catalytic allylic alkylation of aldehydes and cyclic ketones has been developed.26 The direct catalytic highly chemo- and regio-selective intermolecular a-allyhc alkylation reaction has been mediated by an unprecedented combination of palladium and enamine catalysis which furnishes a-allylic alkylated aldehydes and cyclic ketones in high yield. 

The first detailed study of alkyl to aryl palladium migrations, reported in 2004, involved homobenzylic to phenyl migration (Table 5) [58], The process was demonstrated using aryl iodides tethered to an olefin. An additional hap, either intramolecular arylation or intermolecular Heck olefination, was used to hap the migrated palladium. The reaction gives high yields of the desired polycyclic products. 

White and co-workers also reported an intermolecular oxidative allylic alkylation reaction using a similar palladium(II) complex 50 (Scheme 29) [52]. 

Palladium Catalysts Palladium catalysts are effective and powerful for C—H bond functionalization. Carbene precursors and directing groups are commonly used strategies. Generally, sp3 C—H bond activation is more difficult than sp2 C—H bond activation due to instability of potential alkylpalladium intermediates. By choosing specific substrates, such as these with allylic C—H bonds, palladium catalytic systems have been successful. Both intramolecular and intermolecular allylic alkylation have been developed (Scheme 11.3) [18]. This methodology has presented another alternative way to achieve the traditional Tsuji-Trost reactions. 

Two types of reactions are summarized in this section (i) the intermolecular carbopalladation leads to a Pd functionality such as alkyl-, alkenyl-, or allylpalladium complexes, which is intramolecularly trapped by a heteroatom (again Wacker-type processes are mechanistic alternatives) (ii) the palladium catalyst is not directly involved in the hetero-cyclization step, but the carbopalladation builds up a suitable functionality or changes bond angles so that the heterocyclization can take place. 

While the intermolecular reactions of butadiene and related methyl or simple alkyl-substituted dienes have been investigated extensively, relatively few examples of the Pd-catalyzed linear dimerization of higher dienes have been reported. Brun and co-work-ers in an isolated paper reported that, under palladium catalysis, reaction of methyl 2,4-pentadienoate (Scheme 9, 28) affords the linear dimer 29 in high yield (95%). Two aspects of this reaction are of particular interest, (i) The dimerization yields essentially only the tail-to-tail dimer 29, not the head-to-tail or head-to-head isomers (30 or 31, respectively). This is in contrast to the behavior of alkyl-substituted dienes under similar conditions vide infra), (ii) Although no details are given, the authors imply that 29 is... 

Many examples exist of synthetically useful intermolecular paUadium-catalyzed arylations of Jt-excessive heterocycles [4, 7, 50-56]. The reaction has also been extended to the direct arylation of pyridine, diazine and azole N-oxides with aryl halides [57]. Interestingly, tuning the ligand and base allows selective sp or sp activation of alkyl pyridine or pyrazine N-oxides [58], Palladium-catalyzed sp activation of alkylanines [59] and benzyUc arylation of benzoxazoles has also been described [60]. 

Nucleophilic attack of stabilized carbon nucleophiles on coordinated olefins is also known. Hegedus developed the alkylation of olefins shown in Equation 11.31. The (olefin)palladium(II) chloride complexes did not react with malonate nucleophiles, but the triethylamine adduct does react with this carbon nucleophile to provide the alkylation product. This reaction has recently been incorporated into a catalytic alkylation of olefins by Widenhoefer. - Intramolecular reaction of the 1,3-dicarbonyl compounds with pendant olefins in the presence of (GHjCNl PdCl occurs to generate cyclic products containing a new C-C bond (Equation 11.32). Some intermolecular reactions with ethylene and propylene have also been developed by this group. Deuterium labeling studies (Equation 11.32) have shown that the addition occurs by external attack on the coordinated olefin. ... 

Unfortunately, under these conditions the aUyUc amino add was obtained not via Claisen rearrangement, but an intermolecular palladium-catalyzed allyUc alkylation. For ejample, in reactions of crotyl esters two regioisomers are obtained. This fact, as well as the nearly complete lack of diastereoselectivity in the newly generated amino add of 25 synlanti 2 1) is a dear indication for an intermolecular process and the appearance of Tt-allylpaUadium intermediates. 

In addition to directed and intramolecular C-H alkylations, palladium-catalyzed intermolecular C-H alkylations have been reported. In this case, the regioselec-tivity of the C-H bond cleavage is controlled by the natural reactivity of the (hetero)arenes, which corresponds to the longest C-H bond, often correlating with the most acidic C-H bond, in the CMD mechanism [31]. 

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. 

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