Nucleophilic alkyl substitution allylic halides

Allylic amination of allyl halides can also be achieved using lithium and potassium bis(trimethylsilyl)amides [34] and potassium 1,1,3,3-tetramethyldisilazide [35] as the nucleophiles. It has been found that for the reaction of alkyl-substituted allyl chlorides using lithium bis(trimethylsilyl)amides as the nucleophile the allylic amination proceeds smoothly in a SN2 fashion to give /V,Af-disilylamines in high yields when silver(I) iodide was used as an additive. Other metal complexes such as copper ) iodide and other silver(I) salts can also be used as additives for the reaction. 

Lithiated propynyltrimethylsilane has been used as a substitute for the anion HC=CCHf as a highly nucleophilic species (strongly basic and polarizable) it reacts smoothly with alkyl- and allyl halides to give predominantly acetylenic products [105] ... 

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

Finally, attack of phosphorus nucleophiles such as trialkyl phosphites and dialkyl phenylphosphonites onto doubly activated allyl halides yields 2-phosphono- (339) and 2-phosphino-substituted electrophilic cyclopropanes (340) respectively . The formation of these cyclopropanes is explained by the formation of phosphonium-substituted cyclopropanes (341) followed by expulsion of an alkyl halide moiety (equation 107). It is... 

Since the original preparation of the allylic sulfide involved nucleophilic attack on an allylic halide 39, the more stable allylic sulfide - the one with the more highly substituted alkene 40 - is formed and this is inevitably and usefully transformed into the less stable allylic alcohol 45. The reaction is more useful still because the intermediate allylic sulfoxide 41 may be alkylated before rearrangement and this gives the unsymmetrically substituted ZT-al ly lic alcohols 47. These reactions... 

Alkyl halides that show a Dn + An mechanism (Ingold terminology SnI) in nucleophilic aliphatic substitutions can be used as electrophilic reagents in C-alkyla-tions of diazoalkanes. An example is the synthesis of ethyl 2-diazopent-4-enoate (9.18) by reaction of ethyl silver diazoacetate with 3-iodoprop-l-ene (allyl bromide) (9-14, 66% Schollkopf and Rieber, 1969). 

Allylation of Stabilized Anions. Electrophilic 7r-allyl Pd(0) complexes can be generated from Pd(dba)2 and functionalized allylic acetates, carbonates, halides, etc. These complexes are susceptible to reaction with a range of stabilized nucleophiles, such as malonate anions. Alkylation usually occurs at the less-substituted allylic terminus. Silyl-substituted r-allyl complexes undergo re-gioselective alkylation at the allyl terminus farthest removed from the silyl group (eq 14). ... 

Another interesting application of allyl halides in Pd-catalyzed allylic alkylations utilizes substituted 1-alkenylcyclopropyl chlorides (Scheme 12.38). These allylic chlorides, as well as the more reactive, analogous tosylates, react with soft nucleophiles, such as malonates, in a highly regioselective manner [17d,e, 72]. The attack at the ii-allylpalladium intermediate takes place preferentially at the allylic position distal to the cyclopropyl substituent, providing access to a variety of synthetically useful methylenecydopropane derivatives. 

In Sjj2 reactions of aUg l halides, the order of reactivity is RI > RBr > RCl > RF. Alkyl iodides are considerably more reactive than allyl fluorides, often by factors as great as 10 . All l-halo-2,4-dinitrobenzenes, however, react at approximately the same rate in nucleophilic aromatic substitutions. Account for this difference in relative reactivities. 

Alkyl halides are usually considered to be less suitable for double carbonylation because of the possibility of the direct reaction of alkyl halides with nucleophiles and of instability of alkyl-transition metal complexes involved in the catalytic process. However, allylic halides were found amenable to double carbonylation promoted by zerovalent palladium complex. It is well known that allylic halides undergo ready oxidative addition with a Pd(0) species to produce Tj -allylpalladium halide complexes. Thus, it was reasoned that the double carbonylation process might be realized if CO insertion into the aUyl-palladium bond proceeds before attack of amine on the 17 -allylpaUadium halide takes place. On the basis of fundamental studies on the behavior of i7 -allylpalladium halide complexes with CO and secondary amines, double carbonylation processes of substituted aUyl halides to give a-keto amides in high yields have recently been achieved (Eqs. 15 and... 

Again, the double-headed arrow indicates that the actual state of the ion is between the two resonance forms. Attack by an electron-rich nucleophile may occur at either of the two positive carbons, making allyl halides more susceptible to nucleophilic substitution of the halogen than ordinary alkyl halides. 

Nucleophilic Substitution on Alkyl Halides by Heteroatoms. A number of more or less activated alkyl halides, such as benzyl halides and allyl halides, undergo substitution reactions mediated by AgBp4 in the presence of a heteroatom nucleophile. For example, treatment of pentamethylcyclopentadienyl bromide with AgBp4 in the presence of a nucleophile gives the corresponding substituted product (eq 2). Thiols, amines, and alcohols have been used as nucleophiles. ... 

Activation of C-X Bonds. Even more important than carbonyl activation, ZnBr promotes substitution reactions with suitably active organic halides with a variety of nucleophiles. Alkylation of silyl enol ethers and silyl ketene acetals using benzyl and allyl halides proceeds smoothly (eq 13). Especially useful electrophiles are a-thio halides which afford products that may be desulfurized or oxidatively eliminated to result in a,p-unsaturated ketones, esters, and lactones (eq 14). Other electrophiles that have been used with these alkenic nucleophiles include Chloromethyl Methyl Ether, HC(OMe)3, and Acetyl Chloride... 

Secondary alkyl halides Sjvj2 substitution occurs if a weakly basic nucleophile is used in a polar aprotic solvent, E2 elimination predominates if a strong base is used, and ElcB elimination takes place if the leaving group is two carbons away from a carbonyl group. Secondary allylic and benzyiic alkyl halides can also undergo S l and El reactions if a weakly basic nucleophile is used in a pro tic solvent. 

Alkyl halides can be hydrolyzed to alcohols. Hydroxide ion is usually required, except that especially active substrates such as allylic or benzylic types can be hydrolyzed by water. Ordinary halides can also be hydrolyzed by water, if the solvent is HMPA or A-methyl-2-pyrrolidinone." In contrast to most nucleophilic substitutions at saturated carbons, this reaction can be performed on tertiary substrates without significant interference from elimination side reactions. Tertiary alkyl a-halocarbonyl compounds can be converted to the corresponding alcohol with silver oxide in aqueous acetonitrile." The reaction is not frequently used for synthetic purposes, because alkyl halides are usually obtained from alcohols. 

The method is quite useful for particularly active alkyl halides such as allylic, benzylic, and propargylic halides, and for a-halo ethers and esters, but is not very serviceable for ordinary primary and secondary halides. Tertiary halides do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and elimination predominates. The reaction can also be applied to activated aryl halides (such as 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, " and to activated alkenes such as acrylonitrile. The latter is a Michael type reaction (p. 976) with respect to the alkene. 

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