Halides as electrophiles

Alternatively, alkylation of 4-benzyl-2-(trifluoromethyl)-5(2//)-oxazolone 16 in the presence of mild base using active alkyl halides as electrophiles occurs at C-4 " Subsequent aminolysis of a 4,4-dialkyl-5(4f/)-oxazolone like 17 gave an Al-(trifluoroacetyl)-a,a-dialkylglycine amide 18 that was used to prepare important peptides incorporating an a,a-dibenzylglycine unit (Scheme 7.5). 

The first successful preparation of lithium ethyl acetate was using the base lithium hexam-ethyldisilazanide12,14 at — 78 CC in tetrahydrofuran. The much greater stability of the lithium salt as compared to the previously prepared13 sodium ethyl acetate was noted and used in the reaction with carbonyl compounds12. The attack of alkyl halides as electrophiles on the lithium salts of esters, prepared by the action of lithium cyclohexylisopropylamide on the esters at low temperatures in tetrahydrofuran, furnished the a-alkylated products in yields of 50 -90%16,17. 

Nakamura and coworkers showed that the addition reaction of zincated hydrazone to vinylmagnesium halide as electrophile gives the s/r1-geminated organodimetal reagent (Scheme 37). The reaction pathway can be considered as a metalla-aza-Claisen-type... 

Jensen and Rickborn35 have criticised the use of relative reactivities of mercuric salts in reactions such as (15) as a basis for the deduction of reaction mechanism. They point out that, whereas cyclic transition states involving mercuric halides as electrophiles must, of necessity, be four-centred (e.g. (XIV)), the electrophiles mercuric acetate and mercuric nitrate could give rise to six-centred transition states (e.g. (XV)) that might be energetically more favoured than the four-centred. 

Sulfonates such as mesylates or tosylates are readily prepared from alcohols under mild conditions, and are therefore attractive alternatives to halides as electrophiles. Although sulfonates often undergo clean displacement by nucleophiles, alternative reaction pathways are accessible to these intermediates, which can lead to unexpected results. If the nucleophile used is strongly basic, metalation instead of displacement of the sulfonate can occur. Some potential reactions of such metalated sulfonates include fragmentation into sulfenes and alcoholates, or into sulfmates and carbonyl compounds, or self-alkylation (Scheme4.15). 

Recently, the bis(methylthio)methylene imine of pseudoephedrine glycinamide was shown to undergo diastereoselective alkylation at 23 °C with lithium terf-butoxide or sodium ethoxide as base and various alkyl halides as electrophiles (eq 21 ). This procedure was used to prepare enantiomerically enriched a-amino acids. 

In addition, the lithium enolate derived from pseudoephedrine propionamide has been shown to undergo highly diastereoselective Mannich reactions with p-(methoxy)phenyl aldimines to form enantiomerically enriched a,p-disubstituted p-amino acids (Table 10). As observed in alkylation reactions using alkyl halides as electrophiles, lithium chloride is necessary for the reaction of aldimines. With respect to the enolate, the stereochemistry of the alkylation reactions is the same as that observed with... 

Copper derivatives, in the form of cuprates (RCu(X)Li), are usually prepared in situ from lithium, magnesium or zinc compounds, by reaction with a Cu(I) sonrce snch as CnCN. They are often used to improve conversions using, for example, an acid chloride or an allylic halide as electrophile - a number of examples appear in other sections of this book. They are also nsefnl as the organometallic partners in some crosscoupling reactions (using cobalt catalysts). ... 

Nucleophilic substitutions of benzyl halides as electrophiles with Ph3P or BU3P as nucleophiles have been conducted under solvent-free conditions with accurate control of the power and temperature using a monomode reactor (Synthewave S402). The results were carefully compared under similar conditions with either MW or A activation [137] (Eq. (50), Table 4.12) ... 

Herein, a survey of the literature up to mid 2007 is provided, covering catalytic arylation and alkenylation reactions of alkenes with metals other than palladium. The review summarizes Mizoroki-Heck-type reactions employing organic (pseudo)halides as electrophiles (Scheme 10.1), while oxidative Mizoroki-Heck-type reactions [6] are beyond the scope of this review (Chapters 4 and 9). Valuable transition-metal-catalysed arylation reactions of alkenes employing stoichiometric amounts of organometallic compounds as... 

As an alternative to the use of aryl halides as electrophiles, Miura and coworkers [59] employed aroyl chlorides in rhodium-catalysed decarbonylative Mizoroki-Heck-type... 

The potential of iridium-catalysed arylations of alkenes with organic halides as electrophiles has thus far not been explored further. However, a notable iridium-catalysed arylation of alkenes with organosilicon reagents was disclosed recently [15]. 

Unsaturated thioethers represent a valuable alternative to organic halides as electrophilic partners in nickel-catalyzed cross-coupHng reactions with C(sp )-organozincs [284]. As in the case of aryl- and heteroarylzinc hahdes, high-yielding cross-coupling between an array of thiomethylated N-heterocycles and benzyl- or... 

The use of nonactivated secondary alkyl halides as electrophiles in a copper-catalyzed direct alkylation of benzoxazoles has been described. Although methods exist for the direct alkylation of aromatic heterocycles, such as radical alkylations " and coupling of heterocycles with alkyl electrophiles, such methods are restricted to the incorporation of primary alkyl groups only. Secondary alkyl groups can be introduced by metal-catalyzed hydroarylation of olefins but in these cases examples are usually confined to activated alkyls such as benzyl or allyl. 

The catalytic system copper/L19 gives moderate diastereoselectivities (see examples in Scheme 50) in a tandem CA electrophilic trapping process, using allyl, benzyl and propargyl halides as electrophiles. 

In pathway II, trans-lQ leads to 14 (either directly or by the intermediary of 15) via an acyclic transition state (see B) in an associative Y-for-R substitution. Reductive elimination then completes the catalytic loop. Espinet and Echavarren have proposed that pathway 1 is favored for conditions involving organic halides as electrophiles and a solvent with moderate coordinative ability towards palladium. Pathway II would be favored for good leaving groups like triflates and in presence of solvents with good coordinative ability for palladium. 

In addition to the use of alkyl halides as electrophiles, the Myers asymmetric alkylation method was also found to... 

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