Ester enolate substitution

Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide)... 

The critical carbon-carbon bond forming step requires nucleophilic substitution on an alkyl halide by an ester enolate Methyl halides are more reactive than... 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

Schemes 28 and 29 illustrate Curran s synthesis of ( )-hirsutene [( )-1]. Luche reduction58 of 2-methylcyclopentenone (137), followed by acetylation of the resulting allylic alcohol, furnishes allylic acetate 138. Although only one allylic acetate stereoisomer is illustrated in Scheme 28, compound 138 is, of course, produced in racemic form. By way of the powerful Ireland ester enolate Clai-sen rearrangement,59 compound 138 can be transformed to y,S-unsaturated tm-butyldimethylsilyl ester 140 via the silyl ketene acetal intermediate 139. In 140, the silyl ester function and the methyl-substituted ring double bond occupy neighboring regions of space, a circumstance that favors a phenylselenolactonization reac-...

The addition of the lithium enolates of methyl acetate and methyl (trimelhylsilyl)acetate to ( + )-(S)-2-(4-methylphenylsulfinyl)-2-cycloalkenones gives, after desulfurization, (/ -substituted cycloalkenones. A higher level of selectivity is observed with the a-silyl ester enolate and in the cyclohexenone series13. The stereochemical outcome is rationalized by assuming attack on a ground-state conformation analogous to that in Section 1.5.3.2.1. 

Entries 3 to 6 are examples of ester enolate alkylations. These reactions show stereoselectivity consistent with cyclic TSs in which the hydrogen is eclipsed with the enolate and the larger substituent is pseudoequatorial. Entries 4 and 5 involve SN2 substitutions of allylic halides. The formation of the six- and five-membered rings, respectively, is the result of ring size preferences with 5 > 7 and 6 > 8. In Entry 4, reaction occurs through a chairlike TS with the tertiary C(5) substituent controlling the conformation. The cyclic TS results in a trans relationship between the ester and vinylic substituents. 

SRNl substitution include ketone enolates,183 ester enolates,184 amide enolates,185 2,4-pentanedione dianion,186 pentadienyl and indenyl carbanions,187 phenolates,188 diethyl phosphite anion,189 phosphides,190 and thiolates.191 The reactions are frequently initiated by light, which promotes the initiating electron transfer. As for other radical chain processes, the reaction is sensitive to substances that can intercept the propagation intermediates. 

By reaction of a base with compound 251, attack of the ester enolate at the adjacent nitrile occurs, to give the amino-substituted thienoindolizine 252 <1987CL2043> (Equation 34). 

Whereas reaction of the cyano-substituted indolizine 251 with a base results in the tf-fused product (Equation 34), the diester 255 reacts to give only the Afused product 256 <1987CL2043> (Equation 37). Similarly, when the acylindolizines 257 are prepared (Equation 38), very small amounts of the thienoindolizines are found in the product mixture. When such indolizines are substituted with both cyano and keto groups, treatment with a base gives a mixture of products resulting from reaction of the ester enolate with either of these electrophiles <1989BCJ119> (Equation 39). 

Further variations of the Claisen rearrangement protocol were also utilized for the synthesis of allenic amino acid derivatives. Whereas the Ireland-Claisen rearrangement led to unsatisfactory results [133b], a number of variously substituted a-allenic a-amino acids were prepared by Kazmaier [135] by chelate-controlled Claisen rearrangement of ester enolates (Scheme 18.47). For example, deprotonation of the propargylic ester 147 with 2 equiv. of lithium diisopropylamide and transmetallation with zinc chloride furnished the chelate complex 148, which underwent a highly syn-stereoselective rearrangement to the amino acid derivative 149. 

More recently, a study pertaining to the condensation of lithium ester enolates with substituted imines has appeared (eq. [66]) (79). Although monosubstituted enolates (Rj = H R2 = Ph, N=C(OLi)Ph] afforded moderate yields (35-45%) of trans-lactam 87, disubstituted enolates (Rj = OLi, CH3 R2 = Ph, CH3) afforded good yields (66-91%) of lactam products. The authors concluded from their study that the condensation step was probably reversible. 

Extensive investigations have been directed toward the development of chiral ester enolates that might exhibit practical levels of aldol asymmetric induction. Much of the early work in this area has been reviewed (111). In general, metal enolates derived from chiral acetate and propionate esters exhibit low levels of aldol asymmetric induction that rarely exceed 50% enantiomeric excess. The added problems associated with the low levels of aldol diastereoselection found with most substituted ester enolates (cf. Table 11) further detract from their utility as effective chiral enolates for the aldol process. Recent studies have examined the potential applications of the chiral propionates 121 to 125 in the aldol condensation (eq. [94]), and the observed erythro-threo diastereoselection and diastere-oface selection for these enolates are summarized in Table 31. For the six lithium enolates the threo diastereoselection was found to be... 

A further attempt has been made to develop a predictive model for chirality transfer achieved through alkylation reactions of ester enolates which feature chiral auxiliaries. " Hippurate esters (30) derived from (lI , 25 )-trani-2-(p-substituted phenyl)cyclohexanols were found, on reaction with benzyl bromide, to give (31) with predominantly the S configuration at the alkylation centre but with no correlation between the degree of stereoselectivity (20-98%) and the electron density on the aromatic ring. 

The reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

Therefore, in principal, condensation of a primary amine with an enantiomerically pure ketone should allow asymmetric synthesis of a-substituted primary amines. This approach has been applied to the synthesis of a-amino acids, for example, using the imine prepared from a-amino esters and (l.S, 2,S ,5,S )-2-hydroxy-3-pinanone, via an amino-substituted ester enolate anion with some success39 40. Application of this approach to simple primary amines has seldom been reported. 

An interesting variation of this methodology was developed whereby zinc enolates 127 were employed giving 2-ester-substituted pyrrolidines 128-13060c. The enolates 127 were obtained via transmetallation of lithium ester enolates 126 with ZnBr2 (equation 59). 

Substituted allyl alcohols can be prepared on insoluble supports under mild conditions using the Baylis-Hillman reaction (Figure 7.2). In this reaction, an acrylate is treated with a nucleophilic tertiary amine (typically DABCO) or a phosphine in the presence of an aldehyde. Reversible Michael addition of the amine to the acrylate leads to an ester enolate, which then reacts with the aldehyde. The resulting allyl alcohols are valuable intermediates for the preparation of substituted carboxylic acids [43,44],... 

Table 8. Stereoselective Ester Enolate [2,3] Wittig Rearrangement of Substituted Methyl (Z)-2-[(4,4,4-Trifluorobut-2-enyl)oxy]acetates (Z)-25 to y.ti-U nsaturated anti-( )-a-Hydroxy-/3-(trifluoromethyl) Esters (E)-2617...

Various groups have reported that additions of a-hetero substituted ester enolates to a,3-enones are temperature dependent, l40 c but, in general, the 1,2 to 1,4-equilibration of a-seleno and a-thio substituted ester adducts occurs at lower temperature than the a-oxo substituted ester adducts. In contrast to the simple ester enolates, the a-hetero substituted ester enolates are extremely useful for functionalization of alicyclic a,(3-enones with the tandem conjugate addition-electrophile trapping protocol, as shown... 

In contrast to the ester enolates, the a.O-carboxylic dianions are intrinsically more reactive and their use in conjugate reactions is thus limited. Typically, a-substituted-a.O-carboxylic dianions add exclusively to a,(3-unsaturated esters155a and nitroalkenes,155b while additions to ot,(3-enones are sensitive to the substitution pattern of the enones.155c>d Notable is the conjugate addition of dihydrobenzoic acid dianions (207), from Birch reduction of benzoic acids, to oi,3-unsaturated esters (Scheme 77).155e... 

The addition of Grignard reagents or organolithiums (alkenyl, alkyl, alkynyl, allyl or aryl) to nitroenamines (281)213 was reported by Severin to afford P-substituted-a-nitroalkenes.214 b Similarly, ketone enolates (sodium or potassium), ester enolates (lithium) and lactone enolates (lithium) react to afford acr-nitroethylidene salts (294) which, on hydrolysis with either silica gel or dilute acid, afford 7-keto-a,(3-unsaturated esters or ketones (295)2l4c-d or acylidene lactones (296).214 Alternatively, the salts (294, X s CH2) can be converted to -y-ketoketones (297) with ascorbic acid and copper catalyst. 

What is needed in the synthesis of C is a two-carbon nucleophile (or its equivalent) which is less basic titan an enolate so elimination is not competitive. If product C is recognized as an acetic acid derivative, then the following analysis can be made. A malonate ion used as the carbon nucleophile is much less basic than a simple ester enolate and hence undergoes substitution readily but does not promote elimination effectively, particularly in secondary systems. 

The synthesis of monocyclic p-lactams via the ester-enolate imine condensation route has been reported to be carried out utilizing triazene esters (Scheme 54), [141], Esters were attached to benzylamine resin by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates were reacted with various imines to give polymer-bound p-lactams in different substitution patterns. Traceless cleavage from the triazene linker yielded the desired p-lactams. 

The possibility of the triazene linking system for the ester-enolate imine condensation was initially investigated on model compounds 110 and 111 (Scheme 35). Dibenzyltriazene 110 was used as a model compound for monobactam derivatives and prepared by diazotization of hippuric acid methyl ester. Dibenzyltriazene 111 was used as a model compound for 3-phenyl-substituted azetidin-2-ones and prepared by diazotization of 2-(4-aminophenyl)-propionic acid methyl ester and conversion with dibenzylamine in 64% overall yield. The low yields of /V-unsub-stituted lactams, during the model studies, hint at a problematic transfer to solid support. 

---