Esters enolate acylation

Mixed Claisen condensations (Section 21.3) Diethyl carbonate, diethyl oxalate, ethyl formate, and benzoate esters cannot form ester enolates but can act as acylating agents toward other ester enolates. 

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. 

Triple bonds can give enol esters or acylals when treated with carboxylic acids. Mercuric salts are usually catalysts, and vinylic mercury compounds... 

Scheme 2.15. Acylation of Ester Enolates with Acyl Halides, Anhydrides, and Imidazolides... 

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. Entry 7 is an example of formation of a (3-ketoesters by reaction of magnesium enolate monoalkyl malonate ester by an imidazolide. Acyl imidazolides also are used for acylation of ester enolates and nitromethane anion, as illustrated by Entries 8, 9, and 10. (V-Methoxy-lV-methylamides are also useful for acylation of ester enolates. 

These reactions accomplish the same overall synthetic transformation as the acylation of ester enolates, but use desulfurization rather than decarboxylation to remove the anion-stabilizing group. Dimethyl sulfone can be subjected to similar reaction sequences.232... 

In lipase-catalyzed transesterifications, frequent use of enol esters as acyl agents has been seen [1, 5], since the leaving unsaturated alcohol irreversibly tautomerizes to an aldehyde or a ketone, leading to the desired product in high yields. The polymerization of divinyl adipate and 1,4-butanediol proceeded in the presence of lipase PF at 45 °C [39]. Under similar reaction conditions, adipic acid and diethyl adipate did not afford the polymeric materials, indicating the high polymerizability of bis(enol ester) toward lipase catalyst. 

The value of 2-acyl-1,3-dithiane 1-oxides in stereocontrolled syntheses has been extended to the enantioselective formation of (3-hydroxy-y-ketoesters through ester enolate aldol reactions <00JOC6027>. 

The method described here belongs to a group of recently developed procedures comprising the spontaneous intramolecular acylation of active derivatives of metalated p-hydroxy alkanoates. These compounds are available by reactions of carbonyl compounds with ester enolates prepared from S-phenyl alkanethioates6 or phenyl alkanoates,15 as well as by Reformatsky16 or Darzens17 reactions of carbonyl compounds with phenyl a-halo alkanoates. 

Acylation of ester enolates can also be carried out with more reactive acylating agents such as acid anhydrides and acyl chlorides. These reactions must be done in inert solvents to avoid solvolysis of the acylating agent. The preparation of diethyl benzoylmalonate (entry 1 in Scheme 2.14) is an example employing an acid anhydride. Entries 2-5 illustrate the use of acyl chlorides. Acylations with these more reactive compounds can be complicated by competing O-acylation. /V-Mcthoxy-iV-methylamidcs are also useful for acylation of ester enolates. 

Acyl imidazolides have also been used for acylation of ester enolates and nitromethane anion, as illustrated by entries 9 and 10 in Scheme 2.14. 

C-Acylations of C,H-acidic compounds have also been realized on insoluble supports. The few examples that have been reported include the C-acylation of support-bound ester enolates with acyl halides [9], Claisen condensations of polystyrene-bound ketones with benzoic acid esters, the C-acylation of nitriles with acyl nitriles or anhydrides, and the C-acylation of phosphonates with acyl halides (Entries 5-9, Table... 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

Previously, Ireland-Claisen ester-enolate rearrangement of the corresponding a-propionyloxy-allylsilane led to model system 5.44 Therefore, elaboration to 4 via rearrangement of 15 was pursued. To complete our retrosynthetic analysis, a plausible route to 15 was devised, involving straightforward homologation of 2P,3a-disubstituted cyclohexanone 17 to cyclohexene-carboxaldehyde 16, which in turn undergoes silylanion addition and subsequent acylation (Eq. 8). 

Sn-chelated glycine ester enolates have been proved efficient nucleophiles for highly stereoselective 1,4-additions toward nitroalkenes.37 In the presence of acyl halides the tin also acts as a reducing agent of the nitronate intermediates, giving direct access to nitriles in a one-pot protocol. 

The ring closure of 1,5-keto-acids and their derivatives is a widely used strategy for the synthesis of 2A-pyran-2-ones <1984CHEC, 1996CHEC-II>. The 1,5-keto acid derivatives are typically formed in situ with concomitant ring closure to form 2//-pyran-2-ones. There are three main approaches to access the prerequisite 1,5-keto acid derivatives, namely (i) reaction of an ester enolate with a 2-acyl vinyl cation equivalent, (ii) the reaction of a ketone enolate... 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

A Claisen condensation is the acylation of an ester enolate by the corresponding ester. By deprotonating an ester with MOR, only a small concentration of the ester enolate is generated and this enolate is in equilibrium with the ester (cf. Table 13.1). The mechanism of the Claisen condensation is illustrated in detail in Figure 13.57 for the example of the condensation of ethyl butyrate. Both the deprotonation of the ester to give enolate A and the subsequent acylation of the latter are reversible. This acylation occurs via a tetrahedral intermediate (B in Figure 13.57) just like the acylations of other nucleophiles (Chapter 6). The equilibrium between two molecules of ethyl butyrate and one molecule each of the condensation product C and ethanol does not lie completely on the side of the products. In fact, Claisen condensations go to completion only... 

Acylations of ester enolates with different esters are called crossed Claisen condensations and are carried out—just like normal Claisen condensations-in the presence of a stoichiometric amount of alkoxide, Na, or NaH. Crossed Claisen condensations can in principle lead to four products. In order that only a single product is formed in a crossed Claisen condensation, the esters employed need to be suitably differentiated one of the esters must be prone to enolate formation, while the other must possess a high propensity to form a tetrahedral intermediate (see example in Figure 13.59). 

---