Ester enolates reacting with esters

We recall that the conjugate base of an aldehyde must react with the aldehyde, which is present in a significantly greater concentration, to make an aldol condensation possible. A similar condensation reaction, called the Claisen condensatioii, occurs when low concentrations of ester enolates react with esters (Section 22.15). If an ester reacts vdth a very strong base, such as hthium diisopro-pylamide (LDA), high concentrations of the ester enolate form, and no ester would remain for a bimolecular self-condensation reaction. The ester enolate yield is stoichiometric when LDA is used as the base because diisopropylamine is a much weaker acid than an ester. Furthermore, LDA is a sterically hindered nucleophile, so it does not react with the electroplulic carbon atom of the ester. 

Ester enolates react with 3,3,3-trifluoropropene by an Sf,2 -ty pe process to gi ve 5 5 difluoro-4-pentenoic acid esters [130] (equation 112)... 

P-Lactams. In the presence of (CH3)2A1C1, lithium ester enolates react with enolizable aldimines to afford p-lactams in 60-95% yield as a mixture of cis- and trans-isomers. ... 

The ester enolates react with bromine or iodine at — 78° to give a-halogenated esters in high yield ... 

Pyrrole-2-carboxylates. The ester enolate reacts with vinyl sulfones by way of conjugate addition and displacement. 

Ester enolates react with imines to give, as intermediates, metallo-P-amino esters (Scheme 18). Depending on the particular substitution pattern and reaction conditions, these species either undergo spontaneous cyclization or can be isolated as their proto forms and then cyclized, usually according to Breckpot procedure [67]. 

The ester enolate reacts with the imine, yielding a lithium amide. 

In the late nineteenth century, Ludwig Claisen (Germany 1851-1930) treated an ester with a base the isolated product was a P-keto ester. This product results from the enolate anion of one molecule of the ester condensing with a second molecule via an acyl substitution reaction (Chapter 16, Section 16.8). In a typical experiment, ethyl 2-methyl propionate (60) is treated with a specialized base (sodium triphenylmethide, 19) in diethyl ether and stirred at room temperature for 60 hours. This reaction mixture is then acidified with glacial acetic acid (i.e., 100% acetic acid) the final isolated product is ethyl 2,2,4-tri-methyl-3-oxopentanone (61) in 74% yield. It is clear that when an ester enolate reacts with another ester, the product is a -keto ester and the reaction is now called the Claisen condensation. 

When an ester enolate reacts with an aldehyde or a ketone, the product is a hydroxy-ester. This disconnection is shown for both partners. If the reaction is turned around, the reaction of an enolate derived from an aldehyde or a ketone and then with an ester gives a keto-aldehyde or a diketone. Both disconnections are shown. The enolate alkylation reaction involves disconnection of an alkyl halide fragment from an aldehyde, ketone, or ester. In addition, the malonic acid and acetoacetic acid syntheses have unique disconnections. 

Zinc ester enolates react with (1) to give the corresponding A Boc a-amino carboxylic esters in moderate yield (eq 3). In contrast, diethyl a-cuprophosphonates give WBoc a-amino phos-phonic esters in acceptable yields (eq 4). ... 

The sterically demanding r-butyl ester enolate reacts with aeylimidazoles to provide /3-keto esters (eq 5)T ... 

The ester enolate reacts with another molecule of ester to form a carbon-carbon bond in a nucleophilic addition reaction that gives a tetrahedral intermediate. 

For acyclic systems, the anti diastereoselectivity of the (i )-enolates is lower than the syn diastereoselectivity of comparable (Z)-enolates. For example, carboxylic acid esters, which form predominantly ( )-enolates, react with aldehydes with high anti selectivity only in those cases where bulky aromatic substituents are in the alcoholic part of the ester22 25. 

Mechanistically, a-methylenecyclopentenone (2-391) reacts with ester enolate 2-392 in a Michael addition to give the enolate 2-393, which is then trapped with an aldehyde 2-394 generating the alcoholate 2-396. This eventually cyclizes through lactonization to afford 2-397 in good yield. The products 2-397 are obtained as single diastereomer thus, it can be assumed that the aldol reaction proceeds via the six-membered chair-like transition state 2-395. 

Monoaddition to esters. The reagent formed from RMgX and LDA (1 1) reacts with esters or amides to give enolates of ketones, which can be trapped by ClSi(CH,)v This technique provides a synthesis of artemisia ketone (1) by an aldol... 

In the aldol-Tishchenko reaction, a lithium enolate reacts with 2 mol of aldehyde, ultimately giving, via an intramolecular hydride transfer, a hydroxy ester (51) with up to three chiral centres (R, derived from rYhIO). The kinetics of the reaction of the lithium enolate of p-(phenylsulfonyl)isobutyrophenone with benzaldehyde have been measured in THF. ° A kinetic isotope effect of fee/ o = 2.0 was found, using benzaldehyde-fil. The results and proposed mechanism, with hydride transfer rate limiting, are supported by ab initio MO calculations. 

Further investigation with various silyl ketene acetals is summarized in Table 6. Silyl ketene acetals derived from various esters were reacted with /V-benzyloxy-carbonylamino sulfones 1 in the presence of 0.5-1 mol% Bi(0Tf)3-4H20. The corresponding (3-amino esters 24 were obtained in moderate to good yields (Table 6). Silyl enolates derived from esters as well as thioesters reacted smoothly to give the adducts. The /V - be n z v I o x v c ar bo n v I a m i n o sulfone derived from n-butvraldehyde lp led to moderate yields of (3-amino esters when reacted with (thio)acetate-derived silyl ketene acetals (Table 6, entries 1 and 2). A very good yield was obtained when the same sulfone was subjected to a tetrasubstituted silyl ketene acetal (Table 6, entry 3). The latter afforded moderate to good yields of (3-amino esters 24 with phenylacetaldehyde, / -tolu aldehyde, and o-tolualdehyde-derived sulfones (Table 6, entries 4-6). 

Attempts to react enol(ate)s of esters with aliphatic aldehydes are doomed as the aldehyde will simply condense with itself. If the ester is replaced by a malonate 60, there is so much enol(ate) from the (5-dicarbonyl compound that the reaction is good. This style of aldol reaction is often called a Knoevenagel reaction10 and needs only a buffered mixture of amine and carboxylic acid. The enol reacts with the aldehyde 61 in the usual way and enolisation of the product 62 usually means that dehydration occurs under the conditions of the reaction. 

The C=0 double bond of esters is usually not electrophilic enough to be olefinated by P ylides. Only formic acid esters can react with Ph3P—CH2 and then they give enol ethers of the structure H—C(=CH2)—OR. a,/l-Unsaturated esters can sometimes react with P ylides but this then results in a cyclopropanation similar to that which occurs with S ylides (Figure 9.3), not in an olefination giving an enol ether. 

Silyl enolates react with acyl cation equivalents to give the C- and/or O-acylated products (Equation (90)).333 Fluoride-catalyzed reaction using acyl fluorides is valuable for O-acylation of silyl enolates derived from aldehydes and ketones.334 CuCl also promotes the 0-acylation with acyl chlorides.335 The CuCl-promoted reaction of ester silyl enolates results in exclusive (7-acylation. Combined use of BiCfl and Znl2 (or Nal) effects catalytic (7-acylation of ketone silyl enolates with acyl chlorides. 

Bu3SnLi adds to ,/3-unsaturated esters, and the resulting Li-enolate reacts with 3-methyl-2-butenal to afford 7-hydroxyalkyl tins which are treated with BF3-OEt2 to produce vinyl cyclopropane carboxylic esters (chrysanthemic acid) (Equation (111)).280... 

Enolates derived from 2-phenylselanyl esters can react with various electrophiles. The Michael addition of the enolate formed from /-butyl 2-phenylselanyl propanoate 129 to furanone 130 followed by iodination afforded the key intermediate 131 for the total synthesis of (—)-avenaciolide 132 (Scheme 33).213... 

There is no danger of self-condensation with zinc enolates as they do not react with esters. But they do react cleanly with aldehydes and ketones to give aldols on work-up. You will appreciate that the use of zinc enolates is therefore special to esters you cannot make a zinc enoiate from a 2-bro-moaldehyde or an a-bromoketone as then you would get self-condensation. 

The ester enolates react at 20° in the presence of DMSO with a variety of organic halides to give good yields of the corrc.sponding alkylated esters ... 

The next stage is an intramolecular Claisen ester condensation. We can easily discover which enolate reacts with which ester by drawing the starting material in the shape of the product. The alternatives are three- or sbt-membered rings five-membered rings are more stable than three- and more rapidly formed than six-membered. Under the reaction conditions there is no stereochemistry as the product exists as a stable conjugated enolate ion (p. 724). 

A feature distinguishing Reformatsky enolates from base-generated enolates is that zinc enolates add to highly hindered as well as to easily enolizable ketones, such as cyclopentanones, thus avoiding formation of condensation products. Moreover, there is no danger of a Claisen-type self-condensation since zinc-enolates do not react with esters but react readily with aldehydes and ketones to furnish aldol-type products. 

With all this boron enolate chemistry it is easy to forget some of the older enolate methods that are still available. The use of an ester containing a hindered phenolic group has been seen before in Chapter 21 to control the formation of trans enolates so that anti aldol products may be produced. It is used here to couple two fragments in just that way. Ester 271 reacts with the hindered base LiTMP (in combination with LiBr) to give trans enolate 272 which was combined with aldehyde 273 to give49 the aldol adduct 274. 

---