Alkyl halides reaction with enolates

Because enolate anions ffle sources of nucleophilic car bon, one potential use in organic synthesis is their- reaction with alkyl halides to give a-alkyl derivatives of aldehydes and ketones ... 

Enolates react with alkyl halides to form a new CC bond. A mixture of stereoisomers may result. For example, each of the reactions shown below gives two products, with the major product constituting > 90% of the mixture. 

Under the conditions of the Birch reduction, IV-Boc amides such as 60 can be reductively alkylated in high yields, presumably via a dianion intermediate which is protonated by ammonia at C-5 leaving an enolate anion at C-2 <96JOC7664>. Quenching the reaction with alkyl halides or ammonium chloride then affords the 3-pyrrolines 61. 

These reactions consist of two steps. The first is the formation of a stabilized anion—usually (but not always) an enolate—by deprotonation with base. The second is a substitution reaction attack of the nucleophilic anion on an electrophilic alkyl halide. All the factors controlling SnI and Sn2 reactions, which we discussed at length in Chapter 17, are applicable here, step l formation of enolate anion step 2 alkylation (SN2 reaction with alkyl halide)... 

When ethoxide is used as a base to abstract a-proton, it could react with the alkyl halide (Sn2) to form ether. However, the acid-base equilibrium with the diketone prefers the more stable, less basic enolate over the ethoxide, essentially consuming the ethoxide. Thus, the very stable enolates from 1,3-dicarbonyl compounds are able to undergo Sn2 reactions with alkyl halides without competition from the alkoxide catalyst. 

The synthetic utility of alkylation of enolates is utilized in the syntheses of malonic ester (3.3) and acetoacetic ester (3.2). For example, carbanion generated from malonic ester undergoes an Sn2 reaction with alkyl halide to yield alkyl-substituted malonic ester. The monosubstituted malonic ester still has an active hydrogen atom. The second alkyl group (same or different) can be introduced in a similar manner. Acid-catalyzed hydrolysis or base-catalyzed hydrolysis of mono- or disubstituted derivative of malonic ester followed by acidification gives the corresponding mono- or disubstituted malonic acid, which on decarboxylation yields the corresponding monocarboxylic acid (Scheme 3.3). 

The a-protons of iron acyl complexes are acidic and these can be deprotonated with Lithium diisopropylamide (LDA) or with n-butyllithimn. Thus the corresponding enolates are readily functionalized and undergo reaction with alkyl halides, aldehydes, disulfides, trimethylsilyl chloride, and epoxides to afford the corresponding a-derivatized products. " Early work on racemic complexes revealed that these transformations occur in a highly diastereoselective fashion,... 

Similar information is available for other bases. Lithium phenoxide (LiOPh) is a tetramer in THF. Lithium 3,5-dimethylphenoxide is a tetramer in ether, but addition of HMPA leads to dissociation to a monomer. Enolate anions are nucleophiles in reactions with alkyl halides (reaction 10-68), with aldehydes and ketones (reactions 16-34, 16-36) and with acid derivatives (reaction 16-85). Enolate anions are also bases, reacting with water, alcohols and other protic solvents, and even the carbonyl precursor to the enolate anion. Enolate anions exist as aggregates, and the effect of solvent on aggregation and reactivity of lithium enolate anions has been studied. The influence of alkyl substitution on the energetics of enolate anions has been studied. ... 

Enolates can be alkylated by reaction with alkyl halides (in an SN2 reaction with primary and secondary alkyl halides). These reactions produce new carbon-carbon bonds. 

Cyclic cobalt-acyl complexes can be deprotonated, and subsequent reaction of these enolates with aldehydes gives predominantly the anti/threo product (Scheme 63). Rhenium-acyl complexes can be deprotonated in the same manner. These lithium enolates can be alkylated or can react with [M(CO)5(OTf)] (M = Re, Mn) to give the corresponding enolates (Scheme Many transition metal enolates of type (21) or (22) are known, - but only a few have shown normal enolate behavior , e.g. aldol reaction, reaction with alkyl halides, etc. Particularly useful examples have been developed by Molander. In a process analogous to the Reformatsky reaction, an a-bromo ester may be reduced with Smia to provide excellent yields of condensation products (Scheme 65) which are generated through intermediacy of a samarium(III) enolate. ... 

Alkylation reactions via the tin(IV) enolate intermediate were also achieved with a protocol analogous to the above-mentioned aldol reaction (Scheme 9). By preforming the tin(IV) enolate under neutral free radical conditions, subsequent reactions with alkyl halides formed a-alkylated ketone products. This radical reaction... 

The HMPT used as a co-solvent in the procedure described below [1] has a double function. Reaction of methyl crotonate with LDA in a THF-hexane mixture gives rise to predominant conjugate addition of the base. HMPT causes such an enormous increase of the kinetic basicity of LDA, that abstraction of a proton becomes the only reaction. Since ester enolates are relatively weak nucleophiles in reactions with alkyl halides, elevated temperatures are needed to achieve alkylation... 

There are two major reactions of enolates (1) displacement reactions with alkyl halides or other suitable electrophiles and (2) nucleophilic addition to carbonyl compounds. Reaction of 58 with butanal to give 59 and reaction of 61 with bromopentane to give 62 are simple examples of each process. Enolate anions function as carbon nucleophiles and their reactions are fundamentally the same as those discussed in Section 8.3.C for acetylides. Although there are interesting differences, treating an enolate anion as a carbon nucleophile is very reasonable. 

In ether and THF, 0-alkylation is a much less serious problem in reactions with alkyl halides. With the possible exception of iodomethane, the use of lithium enolates in ether solvents leads to C-alkylation as the major product in virtually all cases. When the enolate carbanion center is sterically hindered, however, O-alkylation can be a problem, even in THF or ether. There are some reagents that prefer 0-alkylation, with silyl halides, and anhydrides being the most common. Both of these O-alkylation reactions will be discussed in Section 9.3.C. 

You can think of ds-fused rings as looking like a butterfly or an open book. The key to stereoselectivity in their reactions is that everything happens on the outside (on the cover of the book—the exo face). Nucleophiles add to carbonyl groups from the outside, enolates react with alkyl halides or Michael acceptors on the outside, and alkenes react with peroxyacids on the... 

As sources of nucleophilic carbon, enolates can be alkylated at the a carbon by reaction with alkyl halides. 

In Chapter 22 (Section 22.7.4), malonate derivatives were easily converted to the corresponding enolate anion, and reaction with alkyl halides or other electrophilic species gave the C3-alkylated product. Indeed, if 102 is treated with sodium metal (or NaH, LDA, etc.), enolate anion 103 is formed it reacts with an alkyl halide such as benzyl bromide (PhCH2Br) to give 104. If 104 is heated with aqueous sodium hydroxide and then treated with aqueous HCI, phthalic acid (35) and the amino acid phenylalanine (57) are formed as the final products. 

Whereas dibutylboron enolates may be used as specific enolates in aldol condensations, their reactions with alkyl halides are relatively poor. However, the addition of one equivalent of lithium 2-dimethylaminoethoxide results in site-specific mono-a-alkylation in excellent yield. Organotin enamines add to electrophilic alkenes such as acrylonitrile. The use of an optically active... 

In contrast to the reaction of enolate anions with alkyl halides, which require an equivalent of base, alkylation by conjugate addition is catalytic in base. 

The alkylation of enolates 12 with alkyl halides under /A -topicity (meaning that (5)-12 is attacked from its Si-face) was plausibly explained by assuming that the Re-fAce is shielded by the (deprotonated) hydroxymethyl residue at the pyrrolidine skeleton. Remarkably, the opposite stereochemical outcome was observed in the reaction of enolate 12 with epoxides, as experienced by Askin and coworkers. In the combination of enolates derived from the enantiomeric amides (S)- and (1J)-11 with chiral epoxides, the configuration of stereogenic a-carbonyl center is widely determined by the chiral auxiliary [13]. 

The most common representatives of alkenyliron complexes are iron-substituted enones and enals. They are prepared from Fp-anions and P-halovinyl ketones and aldehydes (Scheme 4-30), ° and they can be further functionalized via their enolates and reaction with alkyl halides or mesylates. ... 

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