Extended enolates Alkylation

The Y appendage of 2-cyclohexenone 191 cannot be directly disconnected by an alkylation transform. (y-Extended enolates derived from 2-cyclohexenones undergo alkylation a- rather than y- to the carbonyl group). However, 191 can be converted to 192 by application of the retro-Michael transform. The synthesis of 192 from methoxybenzene by way of the Birch reduction product 193 is straightforward. Another synthesis of 191 (free acid) is outlined in... 

Treatment of the potentially electrophilic Z-xfi-unsaturated iron-acyl complexes, such as 1, with alkyllithium species or lithium amides generates extended enolate species such as 2 products arising from 1,2- or 1,4-addition to the enone functionality are rarely observed. Subsequent reaction of 2 with electrophiles results in regiocontrolled stereoselective alkylation at the a-position to provide j8,y-unsaturated products 3. The origin of this selective y-deproto-nation is suggested to be precoordination of the base to the acyl carbonyl oxygen (see structures A), followed by proton abstraction while the enone moiety exists in the s-cis conformation23536. 

Reaction of Z-a./j-unsaturated iron-acyl complexes with bases under conditions similar to those above results in exclusive 1,4-addition, rather than deprotonation, to form the extended enolate species. However, it has been demonstrated that in the presence of the highly donating solvent hexamethylphosphoramide, y-deprotonation of the -complex 6 occurs. Subsequent reaction with electrophiles provides a-alkylated products such as 736 this procedure, demonstrated only in this case, in principle allows access to the a-alkylatcd products from both Z- and it-isomers of a,/j-unsaturated iron-acyl complexes. The hexamethylphosphoramide presumably coordinates to the base and thus prevents precoordination of the base to the acyl carbonyl oxygen, which has been suggested to direct the regioselective 1,4-addition of nucleophiles to -complexes as shown (see Section 1.1.1.3.4.1.2.). These results are also consistent with preference for the cisoid conformations depicted. 

The effect of variation of the counterion or phosphane ligand on the alkylation of these extended enolates remains unexplored. Electrophiles that have been successfully reacted with extended enolate species to generate new C —C bonds are limited to primary iodoalkanes and (bromomethyl)benzene (see Table 8)71. 

In addition, we were able to extend the tandem hetero Michael addition/a-ester-enolate alkylation protocol by an intramolecular variant via a Michael-initiated ring closure (MIRC) reaction leading to diastereo- and enantiomerically pure trans-configured 2-amino-cycloalkanoic acids 30 (Scheme 1.1.7) [14c,d]. 

This methodology can be extended to alkylation of (3-silyl-a-alkyl enolates the diastereoselectivity is dependent on the size of the a-alkyl substituent, decreasing as the size of the alkyl group is increased (equation I). 

The asymmetric alkylation of other prochiral enolates has also been studied, and good results have been obtained provided that the intermediate enolate is stabilised by conjugation. For example, the extended enolate derived from 15 has been trapped with a range of alkylating agents to give a-alkylated esters such as 16 in 98% ee (Scheme 5) [12]. 

Aza-enolate alkylation is so successful that it has been extended from aldehydes, where it is essential, to ketones where it can be a useful option. Cyclohexanones are among the most electrophilic simple ketones and can suffer from undesirable side-reactions. The imine from cyclohexanone and cyclohexylamine can be deprotonated with LDA to give a lithium aza-enolate. In this example, iodomethylstannane was the alkylating agent, giving the tin-containing ketone after hydrolysis. 

Asymmetric Mannich reactions.24 Our enolate alkylation methodology has been subsequently extended to include asymmetric Mannich reactions. The Mannich reaction can be viewed as an imino analogue of the aldol reaction and is a very common synthetic method for the preparation of P-aminoketones. 

An important family of disconnections follows. The alkylations represented by 4c(i), 4c(ii) and 4c(iii) belong to extended enolate chemistry and you will learn to call the synthons 9,10 and 11 the a, y and a extended enolates. Synthons 9 and 11 react in the normal d2 position but 10 has d4 reactivity. There are obvious questions of regioselectivity in this family. This chemistry will not be discussed further in this chapter as it is the subject of chapter 11. 

Introduction The extended enolate problem Kinetic and thermodynamic control Wittig and Horner-Wadsworth-Emmons Reactions Extended Aza-Enolates Extended Lithium Enolates of Aldehydes Summary a-Alkylation of Extended Enolates Reaction in the y-Position Extended Enolates from Unsaturated Ketones Diels-Alder Reactions Extended Enolates from Birch Reductions The Baylis-Hillman Reaction The Synthesis of Mniopetal F... 

The dilithium derivatives 19 of carboxylic acids 17 are much more inclined to alkylation at the y position7 to give 20 though a-alkylation is by no means uncommon,8 while extended enolates 22 of amides such as 21 occupy a midway position, ratios of 23 24 varying from 67 33 to 98 2 for different R groups. In both these last two examples the metal can be exchanged for copper to improve y-selectivity, as it seems copper favours conjugate addition both for nucleophiles and for electrophiles.9... 

Alkylation is essentially irreversible, so thermodynamic products are difficult to make, but the aldol reaction is reversible, and the proportion of reaction at the y position of ester 11 and acid 17 derivatives in aldol reactions increases both with temperature and time. Hence the a-aldol 27 is the product with the extended enolate of ester 11 if the reaction is worked up at low temperatures. At higher temperatures the y-aldols 25 and -26 are the only products,10 the lactone 25 coming from cyclisation of Z-26. 

To summarise a-alkylation of extended enolates of esters, acids, and aldehydes with alkyl halides or Michael acceptors can be accomplished reliably by kinetic methods. These reactions are particularly suited to producing quaternary centres between C=0 and C=C functional groups. Aldol reactions are not so reliable, but can be controlled by temperature in some cases, and by Wittig approaches in others. We now need to look at ways of getting reaction at the y-position. 

Under more equilibrating conditions such as alkoxide bases in alcohol solution or amide bases in liquid ammonia, enolisation occurs to give the extended enolate 83 which is then alkylated in the a-position by alkyl halides. At first this seems the most difficult combination to achieve thermodynamic enolisation followed by kinetically controlled addition of an electrophile, but it is in fact a common result achieved with a variety of bases. Examples include the synthesis of pentethylcyclanone 100, an anti-tussive drug, by alkylation of the enone 103, the aldol dimer of cyclopentanone. Disconnection at the branchpoint to the available alkyl halide 102 X = Cl requires a-alkylation of the extended enolate 101 derived from the cyclopentanone aldol dimer27 103. This is easily achieved by sodium amide in toluene.28... 

Reaction in the a- or y-positions (i.e. from the extended enolate) is again best controlled by enamines or silyl enol ethers, both being formed under equilibrating conditions.20,29 Enones such as 104 give the enamine 105 and the silyl enol ether 107 from which the lithium enolate 108 can be made. Both these intermediates give a-alkylated products 106 or 109. Direct reaction of 104 with LDA would of course give the a lithium enolate. 

Simple Birch reduction of benzoic acid 131 gives initially an intermediate that can be represented as dianion 132. Proton transfer from C02H to the less stable of the two anions gives the enolate 133 that you will recognise as a (doubly) extended enolate with one a- and two y-positions. Alkylation occurs at the a-position to give 134. This is a useful way to construct a quaternary centre on a six-membered ring the two remaining alkenes can be further developed in many ways.36... 

Birch reduction of aromatic heterocycles is equally rewarding if more challenging mechanistically. The pyridine diester 138 is reduced to an intermediate that could be drawn as 139. Both anions are extended enolates but one has the charge delocalised onto the nitrogen atom and so is less reactive than the other. Alkylation occurs at the a-position38 to give 140. 

It is obviously easier to prepare symmetrical enaminones such as 64 by this method but these can be desymmetrised by enolate alkylation to give, say, 65 before conjugate substitution leads to the final product 66. The yields are reasonable for a three-step process and the middle step gives the product 65 of y-alkylation of an extended enolate (see chapter 11). 

Synthetic applications. This aj3-unsaturated ester (1) is converted by lithium diisopropylamide (LDA) into the extended enolate (a), which undergoes alkylation at the a-carbon atom to give a product with a potential carbonyl group on the y-carbon atom. Under the same conditions a second alkyl group... 

The y-extended enolate anion derived from (40) can in principle undergo intramolecular alkylation at either the a- or the y-position to yield (41) or (42) respectively. Piers etal. have shown that careful choice of the reaction conditions can lead to almost exclusive formation of the desired isomer. ... 

A recently published synthesis of /3-vetivone (245) makes use of the hitherto rarely observed y-alkylation of a y-extended enolate anion [e.g. (244) — (245)]. As might be expected, deprotonation of (244) normally leads to the alternative a-alkylation product (246). However, by careful choice of experimental conditions which might be expected to bring about rapid equilibration of all possible enolate anions, the Curtin-Hammett principle is made to apply, and (245) is formed in high yield. Another route to the spirovetivane sesquiterpenes makes use of an acyloin condensation to construct the five-membered ring. ... 

We recall that enolates undergo condensation reactions with the carbonyl carbon atom of aldehydes (Section 21.7). Enolates tend to react to give alkylation at carbon. A similar reaction occurs between the phenolate ion and formaldehyde. Because both C-2 and C-4 are nucleophilic, two possible condensation products may result. The following reaction shows condensation at C-4, producing a conjugation-extended enolate. Subsequent tautomerization generates the enol form, which is a phenol. Solvent-mediated proton transfer also occurs, giving a phenoxide rather than the more basic (and less stable) alkoxide ion. 

It might be supposed that this technique could be readily extended to alkylation of p-diketones, such as cyclohexane 1,3-dione, 17.34. These are certainly easy to deprotonate, but the alkylation reaction can present some problems (Figure 17.40). The extent of the 0-alkylation depends on the base used, the solvent (the alkoxide is naked in DMSO, but heavily solvated in methanol) and the electrophile. We describe enolate anions as ambident nucleophiles, since they can react either at carbon or oxygen. RO" is a hard nucleophile and reacts best with hard electrophiles such as... 

This method for preparing 2-phenyl-1-pyrroline, and assorted 2-substituted 1-pyrrolines, is one of the best currently available, particularly because it reproducibly affords clean materials. Generally, the procedure is amenable to various aromatic esters 2 it has also been applied successfully to aliphatic esters (Table I).3 An advantage of this method is the use of readily available, inexpensive N-vinyl-pyrrolidin-2-one as a key starting material. This compound serves effectively as a 3-aminopropyl carbanion equivalent. The method illustrated in this procedure has been extended to include the synthesis of 2,3-disubstituted pyrrolines. Thus, alkylation of the enolate of the intermediate keto lactam, followed by hydrolysis, leads to various disubstituted pyrrolines in good yields (see Table II).3... 

Again, this produces a favourable tertiary carbocation. Loss of a proton gives the required alkene. Note that potentially three different carbons could lose a proton. The reaction shown generates the most stable product this has the maximum number of alkyl substituents and also benefits from extended conjugation. We then get another aldol-type reaction. The enolate anion is produced from the ethyl chloroacetate, and simple addition yields an anion that is subsequently protonated. 

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