Alkyl halides electrophilicity

In 1974, Hegedus and coworkers reported the pa]ladium(II)-promoted addition of secondary amines to a-olefins by analogy to the Wacker oxidation of terminal olefins and the platinum(II) promoted variant described earlier. This transformation provided an early example of (formally) alkene hydroamination and a remarkably direct route to tertiary amines without the usual problems associated with the use of alkyl halide electrophiles. 

The prime functional group for constructing C-C bonds may be the carbonyl group, functioning as either an electrophile (Eq. 1) or via its enolate derivative as a nucleophile (Eqs. 2 and 3). The objective of this chapter is to survey the issue of asymmetric inductions involving the reaction between enolates derived from carbonyl compounds and alkyl halide electrophiles. The addition of a nucleophile toward a carbonyl group, especially in the catalytic manner, is presented as well. Asymmetric aldol reactions and the related allylation reactions (Eq. 3) are the topics of Chapter 3. Reduction of carbonyl groups is discussed in Chapter 4. 

In addition to alkylation with alkyl halides, electrophilic amination has been achieved with di-(/< /r-butyl) azodi-carboxylate <2004HCA1016>, and reactions with aldehydes have generated alcohol derivatives <1999JOC8668, 2003TL671>. Dialkylation at the 5-position has also been achieved <1998TA3881>. 

First, we recall that ethers can be prepared by substitution reactions of alkoxide anion nucleophiles with alkyl halide electrophiles—the Williamson ether synthesis. The two ways to prepare the target ether are as follows ... 

Because of the contribution of structures such as the one on the right to the resonance hybrid, the a-carbon of an enamine is nucleophilic. However, an enamine is a much weaker nucleophile than an enolate anion. For it to react in the SN2 reaction, the alkyl halide electrophile must be very reactive (see Table 8.1). An enamine can also be used as a nucleophile in substitution reactions with acyl chlorides. The reactive electrophiles commonly used in reactions with enamines are ... 

Aromatic rings are usually not good enough nucleophiles to react with alkyl halides. If Lewis acids are added to improve the electron sink, then electrophilic aromatic substitution occurs via the carbocation if it is more stable than secondary (an SnI viewed from the electrophile). With Lewis acids and methyl, primary, or secondary alkyl halides, electrophilic aromatic substitution usually occurs via direct displacement of the leaving group (an Sn2 viewed from the electrophile). 

Scheme 3.33 [204,210]. A limitation of this method is the failure of the organolithium to react efficiently with alkyl halide electrophiles.

The iron-catalyzed alkylation of hetero(arenes) has also been described by employing a similar metallation strategy (Scheme 19.34) [54]. Furan, thiophene, and pyridine proved to be successftd heteroaromatic partners with both primary and secondary alkyl halide electrophiles. Electron-deficient arenes were also efficiently alkylated, but less acidic substrates such as tetrafluoroanisole failed to provide the desired alkylated product... 

Ethers are frequently prepared via the Williamson ether synthesis, which involves the reaction of an alkyl halide electrophile (RX) with an alkoxide nucleophile (R O ). As usual, the Sn2 backside attack is sensitive to sterics, and the E2 elimination reaction is expected to compete here since alkoxides are strong bases. The Sn2 substitution can be expected to give good yields of the ether if the halide is on a methyl, primary, allylic, or benzylic carbon. Simple alkoxides may be commercially available otherwise, the alkoxide can be prepared from the corresponding alcohol by treatment with a strong base (NaH) or a metal (Na or K). 

Disconnection of an ether TM occurs at either C-0 bond, leading to an alkoxide nucleophile and alkyl halide electrophile. This Williamson ether synthesis involves an Sn2 mechanism, so minimization of steric hindrance is the main consideration when determining which disconnection to make in the retrosynthesis. 

The retrosynthesis begins by disconnecting the C-O bond that can be formed more easily, typically via an Sn2 mechanism. Since formation of the C-O bond at the aromatic ring would be more challenging, the disconnection shown is made instead to give a primary alkyl halide electrophile and a phenoxide nucleophile. Each of these compounds can be prepared from the corresponding alcohols, as required, and phenol can be synthesized from benzene via the phenyl diazonium salt. 

In Part A we learned that an alkyl halide (e g., R—X) serves very well as an electrophile in reaction with the nucleophile HC=C . Though lithium and Grignard reagents are good nucleophiles, for reasons we will not discuss they do not give good product yields in reactions with alkyl halide electrophiles. 

Memorization Task 16.7 Lithium diaikyi cuprates react best with alkyl halide electrophiles. 

Alkyl halides by themselves are insufficiently electrophilic to react with benzene Aluminum chloride serves as a Lewis acid catalyst to enhance the electrophihcity of the alkylating agent With tertiary and secondary alkyl halides the addition of aluminum chlonde leads to the formation of carbocations which then attack the aromatic ring... 

Secondary alkyl halides react by a similar mechanism involving attack on benzene by a secondary carbocation Methyl and ethyl halides do not form carbocations when treated with aluminum chloride but do alkylate benzene under Friedel-Crafts conditions The aluminum chloride complexes of methyl and ethyl halides contain highly polarized carbon-halogen bonds and these complexes are the electrophilic species that react with benzene... 

Because electrophilic attack on benzene is simply another reaction available to a carbocation other carbocation precursors can be used m place of alkyl halides For exam pie alkenes which are converted to carbocations by protonation can be used to alkyl ate benzene... 

Friedel-Crafts alkylation (Section 12 6) An electrophilic aro matic substitution in which an aromatic compound reacts with an alkyl halide in the presence of aluminum chloride An alkyl group becomes bonded to the nng... 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

Electrophilic attack on the sulfur atom of thiiranes by alkyl halides does not give thiiranium salts but rather products derived from attack of the halide ion on the intermediate cyclic salt (B-81MI50602). Treatment of a s-2,3-dimethylthiirane with methyl iodide yields cis-2-butene by two possible mechanisms (Scheme 31). A stereoselective isomerization of alkenes is accomplished by conversion to a thiirane of opposite stereochemistry followed by desulfurization by methyl iodide (75TL2709). Treatment of thiiranes with alkyl chlorides and bromides gives 2-chloro- or 2-bromo-ethyl sulfides (Scheme 32). Intramolecular alkylation of the sulfur atom of a thiirane may occur if the geometry is favorable the intermediate sulfonium ions are unstable to nucleophilic attack and rearrangement may occur (Scheme 33). 

This reaction illustrates a stereoselective preparation of (Z)-vinylic cuprates, which are very useful synthetic intermediates. They react with a variety of electrophiles such as carbon dioxide, epoxides, aldehydes, allylic halides, alkyl halides, and acetylenic halides they undergo... 

Soft electrophiles will prefer carbon, and it is found experimentally that most alkyl halides react to give C-alkylation. Because of the n character of the HOMO of the anion, there is a stereoelectronic preference for attack of the electrophile approximately perpendicular to the plane of the enolate. The frontier orbital is ip2, with electron density mainly at O and C-2. The tpi orbital is transformed into the C=0 bond. The transition state for an 8 2 alkylation of an enolate can be represented as below. 

The Friedel-Crafts reaction is a very important method for introducing alkyl substituents on an aromatic ring. It involves generation of a carbocation or related electrophilic species. The most common method of generating these electrophiles involves reaction between an alkyl halide and a Lewis acid. The usual Friedel-Crafts catalyst for preparative work is AICI3, but other Lewis acids such as SbFj, TiC, SnCl4, and BF3 can also promote reaction. Alternative routes to alkylating ecies include protonation of alcohols and alkenes. 

Variations and Improvements on Alkylations of Chiral OxazoUnes Metalated chiral oxazolines can be trapped with a variety of different electrophiles including alkyl halides, aldehydes,and epoxides to afford useful products. For example, treatment of oxazoline 20 with -BuLi followed by addition of ethylene oxide and chlorotrimethylsilane yields silyl ether 21. A second metalation/alkylation followed by acidic hydrolysis provides chiral lactone 22 in 54% yield and 86% ee. A similar... 

The 2-substituted 1,3-benzodithioles 57 are readily lithiated and react as acyl anions with various electrophiles, including alkyl halides, aldehydes, ketones. 

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