Pd-catalyzed alkylation

As an e.xtension of the oxidative carbonylation with alkyl nitrites, malonate can be prepared by the oxidative carbonylation of ketene (583)[524], Also, the acetonedicarboxylate 585 is prepared by the Pd-catalyzed, alkyl nitrite-mediated oxidative carbonylation of diketene (584)[525],... 

It is noteworthy that ZnEt2 has been used as a base in enantioselective allylic substitutions. A remarkable increase in ee was observed when ZnEt2 was used instead of KH, NaH, LiH, LDA, or BuLi in the Pd-catalyzed alkylations of allylic acetates by enolates of malonic esters and related compounds.403 In contrast, application of ZnEt2 was not as very effective as in similar iridium-catalyzed allylic alkylations.404... 

Pd-catalyzed alkylations are generally rare because of the ease with which [3-hydride elimination occurs. However, alkylation of 2,4-dichloropyrimidine with trimethylaluminum in the presence of Pd(Ph3P)4 was achieved without detectable (3-hydride elimination. The preference for coupling at the 4-position was maintained for the formation of 2-chloro-4-methylpyrimidine (78), which then underwent an additional cross-coupling with triisobutylaluminum to afford 2,4-dialkylpyrimidine 79 [51]. 

The kinetic resolution of the racemic allylic acetates rac-3ab, rac-ldb, rac-lab, and rac-lbb with thiocarboxylate ions and BPA were investigated in more detail (Scheme 2.1.4.22). The acetates were selected instead of the corresponding carbonates in order to avoid the competing formation of the corresponding allylic alcohols (vide supra). All reactions were carried out in CH2CI2/H2O (9 1) using 2 mol% of Pd(0)/L and 8 mol% of BPA. Termination of the reaction of the pen-tenyl acetate rac-3ab with KSAc at 35% conversion showed the operation of highly selective kinetic resolution (entry 4). However, 50% conversion of the substrate could be achieved neither at room nor at reflux temperature. This is in contrast to the reactivity of carbonate roc-3aa (cf. Table 2.1.4.14, entry 1) and perhaps reflects the lower reactivity of allylic acetates in Pd-catalyzed alkylation. This... 

Application of the Pd-catalyzed alkylation of hydrogencarbonate to the meso-biscarbonate 29 gave the allylic alcohol 30 in 87% yield with 96% ee (Scheme 2.1.4.31). Alcohol 30 has been converted via the silyl ether 31 and alcohol 32 to ketone 33, the enantiomer of which is an important building block for the synthesis of prostaglandins [40]. Since both BPA and mt-BPA are readily available, access to ent-33 is also provided. 

Natural products synthesized via Pd-catalyzed alkylation since 1995 are listed in Table 6, and representative schemes including some crucial cross-coupling steps are shown in Schemes 69-72. 

TABLE 6. Natural products synthesized via Pd-catalyzed alkylation, homopropargylation and homobenzylation... 

SCHEME 76. Pd-catalyzed alkylation of organozincs with primary alkyl electrophiles... 

SCHEME 77. Pd-catalyzed alkylation of alkenylzirconocene chlorides with primary alkyl bromides... 

Compared to oxabenzonorbomenes, oxabicyclo[2.2.1]heptenes or oxabicyclo[3.2.1] octenes are less reactive substrates, and the Pd-catalyzed alkylative ring-opening process with organozinc reagents generally required heating in 1,2-dichloroethane at reflux. The addition of Zn(OTf)2 dramatically improved the rate of the reaction which could be carried out in CH2C12 at room temperature, as illustrated for the conversion of 83 to the... 

Due to the failure of ammonia in this reaction, a variety of alternative strategies to prepare primary alkyl amines utilizing Pd catalysis have been investigated.196-198-200 4,4 -Dimethoxybenzhydrylamine (DMB 8) reacts with allyl acetates under Pd° catalysis and can be debenzylated with formic acid to yield a primary amine (equation 57).200 Similarly, p-toluenesulfonamides196-197 and azides can be conveniently converted to amines following their participation in the Pd-catalyzed alkylation. 

New versatile Pd-catalyzed alkylation of indoles 523 via nucleophilic allylic substitution provides 3-allylindoles 524 in good to excellent yields (Scheme 107) <20040L3199 and references therein>. The regioselectivity of the reaction... 

Xia and Kozikowski developed a palladium-catalyzed bicycloannulation route (Scheme 4-4) to racemic HA from 2a in 40% overall yield. The three-carbon bridge was more efficiently introduced by Pd-catalyzed alkylation of 2a with 2-methylenepropane-l,3-diyl diacetate on both sides of the ketone carbonyl. Compared with (—)-HA (IC50 for AChE inhibition 0.047 pM), the racemate exhibited an IC50 of 0.073 pM, which is, within error, as expected if the unnatural enantiomer is inactive. 

Trost, B.M., and Oslob, J.D. 1999. Asymmetric Synthesis of (—)-Anatoxin-a via an asymmetric cyclization using a new ligand for Pd-catalyzed alkylations. JAm Chem Soc 121, 3057-3064. 

Novel bicyclic (92) and tricyclic (93ab) hydrophosphoranes have been synthesized and shown to form complexes with PdCl2(COD), PdCl2(RCN)2, and Pd(allyl)Cl2 containing an open form of the phosphoranes. The Pd-catalyzed alkylation of 1,3-diphenylallyl acetate (94) with dimethyl malonate gave (95) in up to 74% ee using complexes of (92) or (93ab). " ... 

As discussed in Section 1.2.3, some bidentate phosphines, such as dppf and dppp, have displayed distinct advantages in the Pd-catalyzed alkylation using secondary alkylmetals. 

The Pd- or Ni-catalyzed reaction of tiialkylsilylmethylmetals containing Zn or Mg provides a novel regio- and stereo-controlled route to allylsilanes [82-84] (Scheme 1-26). Another useful application of Pd-catalyzed alkylation is the / -substitution reaction of zinc homoenolates [85-89] (Scheme 1-27) and higher homologues [90]. 

Scheme 4.24 Cinchona alkaloid derived phenyl selenides in Pd-catalyzed alkylation of dimethyl malonate with l,3-diphenyl-2-propenyl acetate.

Palladium Catalysts Yu s group has carried out systematic studies on Pd-catalyzed alkylations of aryl C—H bonds. Stille-type cross-coupling reactions have been developed by directed C—H activation (Equation 11.30) [68]. The reaction rate is enhanced by benzoquinone and microwave irradiation. Significantly, carboxylic acid functionality can be used as an efficient directing group for aryl C— H bond activation (Equation 11.31) [69]. The reaction conditions can be applied to the carboxylation of vinyl C— H bonds. The possible intermediacy of a palladacycle has been confirmed by NMR spectra and X-ray crystallography. 

An estimation of considerably pure electronic effect of the substituent on the allyl terminus has been made by the Pd-catalyzed alkylation of... 

Chiral phenylsulfenyl derivatives of ferrocenyl-oxazoline were used as chiral ligands in the Pd-catalyzed alkylation of 1. The highest ee (98%) of (R)-2 was obtained with 7 as a ligand (Scheme 3). 

Chiral oxazoline ligands 24a,bearing a chiral sulfinyl group provided enantiose-lectivity of (5)-2 with 88% or 55% ee, respectively, in the Pd-catalyzed alkylation of 1 with dimethyl malonate using [Pd(7r-allyl)Cl]2, BSA, and KOAc in dichloromethane... 

In this section, those Pd-catalyzed alkylation reactions that involve the use of either saturated or remotely unsaturated (i.e., S-, e-, and beyond) alkylmetals will be reviewed, with focus on their reactions with alkenyl and aryl electrophiles. For other Pd-catalyzed reactions of alkylmetals, readers are referred to the sections indicated below. Pd-catalyzed alkylation reactions of homoallyl-, homopropargyl-, or homobenzylmetals with alkenyl and aryl electrophiles possess a special synthetic significance in that they offer alternative... 

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