Halides, alkyl, reaction with enolate anions

Enolate anions react with alkyl halides by an S]v2 reaction to give alkylated carbonyl compounds. 

A p-keto ester can be hydrolyzed to a P-keto acid, and heating leads to decarboxylation. Malonic acid derivatives, as well as P-ketone acids decarboxylate upon heating 63,109, 111, 135. Enolate anions react with alkyl halides by an S]v2 reaction to give alkylated carbonyl compounds 65, 67, 70, 84, 108, 116, 127,... 

Enamines resemble enols because both have an increased electron density at a structurally related a carbon atom. The electron density at the a carbon atom in enamines is greater than that in enols because nitrogen is less electronegative than oxygen and releases an electron pair more readily. As a result, enamines are more nucleophilic than enols, and they are useful intermediates in alkylation reactions. We recall that enolate anions react with alkyl halides to give a-alkylated carbonyl compounds (Section 23.6), but uncharged enols are not sufficiently nucleophilic to be alkylated. Alkylation of the more nucleophilic enamine produces an iminium ion. 

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. ... 

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 ... 

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)... 

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. ... 

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 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. 

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. 

Carbanion-enolates are nucleophiles that react with alkyl halides (or sulfonates) by typical S 2 reactions, Carbanion-enolates are best formed using lithium diisopropylamide (lda), (r-Pr)2N Li, in tetrahydrofuran. This base is very strong and converts all the substrate to the anion. Furthermore, it is too sterically hindered to react with RX. 

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 ... 

Under the same conditions simple etiolates react vigorously with alkyl halides (which must be primary) to give mono- and polyalkylated products. The reactivity of the simple enolate is greater and cannot be controlled at room temperature. However, if the alkylation is carried out at low temperature, the reaction can be controlled and smooth monoalkylation of simple enolates can be achieved. The same is true for the alkylation of acetylide anions, which must be carried out at low temperature for successful alkylation. 

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 ... 

Compared with several synthetically important anions, ester enolates are rather poor nucleophiles in conversions with alkyl halides and epoxides [4], reactions that have a relatively high activation energy barrier. Yields of the alkylation products are often rather low (especially in reactions with secondary alkyl bromides and iodides) due to the occurrence of condensation of the alkylation product with unreacted enolate. Improved results in alkylations may be obtained when using the very polar DMSO or HMPT as co-solvent [1] under these conditions only C-alkylation products are formed. 

In the conversion of 66 to 67, we saw that HMPA was used as an additive. Another useful ingredient in many alkylation reactions is hexamethylphosphorus triamide [HMPT, (Me2N)3P], which coordinates with the enolate anion, diminishing the aggregate state and increasing reactivity. This additive also enhances the polarity of the solvent and thereby enhances the facility of the Sn2 alkylation step (sec. 2.7.A.i). The use of an additive such as HMPA or HMPT is very common when the enolate anion reacts slowly and/or the halide is relatively unreactive. Other acid derivatives such as lactones can react with LDA to give an enolate anion, which then reacts with alkyl halides in the usual manner. 

A nickel-catalyzed ene cyclization (sec. 11.13) has been reported that uses Ni(cod)2- The reaction proceeds by initial formation of a ac-allylnickel complex, which facilitates the intramolecular ene reaction with an allylic amine unit. l jt-Allylnickel complexes can be used in coupling reactions with both aryl and alkyl halides. Enolate anions react with nickel(O) reagents to form a complex that subsequently couples to aryl iodides. Semmelhack s final step in the synthesis of cephalotaxinone (446) treated 445 with Ni(cod)2 to... 

Sulfonylation of aroylmalonates gives enol derivatives (175) because sul-fonyl chlorides are even harder than acyl chlorides. The a-alkoxy-/3-oxosulfone anions form sulfonyl reductone derivatives on reaction with ClCHjOMe or aroyl chlorides (163). This behavior is in direct contrast to the C-alkylation with alkyl halides. 

The acyl addition and acyl substitution reactions of enolate anions presented in this chapter clearly show that enolate anions are nucleophiles. In Chapter 11 (Section 11.3), various nucleophiles reacted with primary and secondary alkyl halides via Sn2 reactions. Enolate anions also react with alkyl halides via 8 2 reactions in what is known as enolate alkylation. 

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