Halides, alkyl enolate anions

Alkyl halides by reaction with the enolate anion derived from diethyl acetamidomalonate... 

The equatorial orientation of the newly introduced alkyl group may be controlled in both (3) and (6) by stereoelectronic and steric factors. The attack of the enolate anions (2) and (5) by the alkyl halide proceeds in a plane that is perpendicular to the plane of the enolate system. Products result from attack at the less hindered a- or -face, respectively... 

Weiss ° treated 16-dehydro- (6), 17a-acetoxy- (8), 17a-hydroxy- (9) and 17a-bromopregnan-20-one (11) with a solution of lithium, barium, calcium or sodium in liquid ammonia and reacted the intermediate enolate anion (7) with the appropriate alkyl halide. 

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 ... 

OL Alkylation of aldehydes and ketones (Section 18.15) Alkylation of simple aldehydes and ketones via their enolates is difficult. p-Diketones can be converted quantitatively to their enolate anions, which react efficiently with primary alkyl halides. 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

The problem of nitrogen alkylation of enamines, which one encounters with alkyl halides, is of no consequence in alkylations with positively activated olefins, since the generation of amonium salts can be expected to be reversible in these cases. Thus such enamine alkylations are obviously attractive to the synthetic chemist. Their particular importance, however, arises from avoidance of the serious obstacles often found with parallel enolate anion reactions. 

The reactive species is the corresponding enolate-anion 4 of malonic ester 1. The anion can be obtained by deprotonation with a base it is stabilized by resonance. The alkylation step with an alkyl halide 2 proceeds by a Sn2 reaction ... 

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. 

In the example shown, alkylation of the ketone is readily accomplished using such a two-stage process with 1 mol of alkyl halide. Note that the specificity of this reaction relies on one of the a-carbons having no acidic hydrogens, so that only one enolate anion can be formed. 

Diethyl malonate can be converted into its enolate anion, which may then be used to participate in an Sn2 reaction with an alkyl halide (see Section 10.7). Ester hydrolysis and mild heating leads to production... 

In contrast to the reaction of an enolate anion with an alkyl halide, which requires one equivalent of base, conjugate addition of enolates can be carried out with a catalytic amount of base. All the steps are reversible. 

Trifluoroalamne cannot be prepared by alkylation of a glycine anion with tri-fluoromethyl halides, since these electrophiles are not able to alkylate enolates. Other approaches have been reported using various substrates, but none is really satisfying. The three main ones are ... 

Exercise 17-27 If methyl iodide gives mainly C-alkylation with the enolate anion of 2-propanone, which of the following halides would you expect to be candidates to give O-alkylation tert-butyi chloride, phenylmethyl chloride, 3-chloropropene, neo-pentyl chloride ... 

The anions of esters such as ethyl 3-oxobutanoate and diethyl propanedioate can be alkylated with alkyl halides. These reactions are important for the synthesis of carboxylic acids and ketones and are similar in character to the alkylation of ketones discussed previously (Section 17-4A). The ester is converted by a strong base to the enolate anion, Equation 18-18, which then is alkylated in an SN2 reaction with the alkyl halide, Equation 18-19. Usually, C-alkylation predominates ... 

The direct a-alkylation of monoketones normally employs reaction of an alkyl halide or sulfonate with the enolate anion produced using a strong base. This method can be satisfactorily used with symmetrical ketones, which are to be dialkylated with a dihalide, and with intramolecular cyclization reactions, where the formation of five- and six-membered rings is often favored over the formation of three-, four-, seven-, and eight-membered rings (M. Mous-seron, 1937 W.S. Johnson, 1963). Regioselective alkylation of dianions according to Hauser s rule (see p. 9f.) is usually also a satisfactory procedure (F.W. Sum, 1979). 

The disconnection is of the newly formed C-C bond 14a and is not the same as 8a. The synthons are represented by the enolate anion and a carbon electrophile. We saw alkyl halides in this role in chapter 13 but in the next 10 chapters we shall be mostly interested in combining enol(ate)s with carbonyl compounds. 

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 ... 

Because an enolate anion is an intermediate in these reductions, it can be used in synthesis in much the same manner as enolate anions that are generated by deprotonation (see Section 20.3). Thus, the addition of an alkyl halide to the reaction mixture after the reduction has been completed results in the alkylation of the enolate anion ... 

However, the enolate anion can be generated specifically at the 2 position by reduction of 3-methyl-2-cyclohexenone. Addition of the alkyl halide results in the formation of a single alkylation product as illustrated in the following equation ... 

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)... 

Looking back on the history of ketone dianion chemistry, one soon notices that dianion species, derived from / -keto esters, have been in continuous steady use in organic synthesis3,4, as shown in Scheme 2. Thus, ethyl acetoacetate can be converted to the corresponding ketone o a -chainon via consecutive proton abstraction reactions. The resulting dienolate anion reacts with a variety of alkyl halides to give products, resulting from exclusive attack at the terminal enolate anions. 

It is unusual to think of a carbonyl compound as an acid, but the protons a to a carbonyl group can be removed by a strong base. Protons a to two carbonyl groups are even more acidic in some cases, acidity approaches that of phenols. This acidity is the basis for a-substitution reactions of compounds having carbonyl groups. Abstraction by base of an a proton produces a resonance-stabilized enolate anion that can be used in alkylations involving alkyl halides and tosylates. 

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