Halo esters Darzens’ reaction

Darzens glycidic ester condensation generally involves the condensation of an aldehyde or ketone 2 with the enolate of an a-halo ester 1 which leads to an a,P-epoxy ester (a glycidic ester) (3). Thus the reaction adds two carbons to the electrophile however, the reaction has been primarily developed as a one-carbon homologation method. That is, subsequent to the condensation, the ester is saponified and decarboxylation ensues to give the corresponding aldehyde or ketone 5.2... 

There have been two general approaches to the direct asymmetric epoxidation of carbonyl-containing compounds (Scheme 1.2) ylide-mediated epoxidation for the construction of aryl and vinyl epoxides, and a-halo enolate epoxidation (Darzens reaction) for the construction of epoxy esters, acids, amides, and sulfones. 

Darzens reactions between the chiral imine 52 and a-halo enolates 53 for the preparation of nonracemic aziridine-2-carboxylic esters 54 (Scheme 3.17) were studied by Fujisawa and co-workers [61], It is interesting to note that the lithium enolate afforded (2K,3S)-aziridirie (2i ,3S)-54 as the sole product, whereas the zinc enolate give rise to the isomer (2S,3i )-54. The a-halogen did not seem to affect the stereoselectivity. 

Aldehydes and ketones condense with a-halo esters in the presence of bases to give ot,p-epoxy esters, called glycidic esters. This is called the Darzens condensation. The reaction consists of an initial Knoevenagel-type reaction (16-41), followed by an internal Sn2 reaction (10-13) ° ... 

The Darzens reaction, which is described on p T 253, is a good example of eyclisation to give a three-membered ring. The enolate of an a-halo ester, e.g. (27), adds to a ketone to give (26) v,/hieh cannot be isolated as it cyclises so readily. 

Darzens reaction, the reaction between a carbonyl compound and an a-halo ester in the presence of a base, consists of an initial aldol-type addition and a subsequent intramolecular Sn2 reaction, forming an epoxide as its final product. Its high stereoselectivity thus relies on the stereoselectivity of the nucleophilic addition of an a-halo ester onto the carbonyl substrate, which can be either an aldehyde or a ketone. 

S Darzen s 1 a-Halo ester XCH — COOR Aldehyde, ketone Epoxidation (Sn reaction) follows... 

Glycidic esters can easily be converted to aldehydes (2-40). The reaction has been extended to the formation of analogous aziridines by treatment of an imine with an a-halo ester or an a-halo N,N-disubstituted amide and f-BuOK in the solvent 1,2-dimethoxy-ethane.636 However, yields were not high. Acid-catalyzed Darzens reactions have also been reported.637 See also 6-61. 

The Darzens Reaction is the condensation of a carbonyl compound with an a-halo ester in the presence of a base to form an a,p epoxy ester. 

An intriguing route to ethylamino epoxides through a Darzens-type reaction has been reported <07CC2500>. Rather than the typical a-halo ester, this method uses an a-ammonium azetidinium salt 12 as the leaving group. This method provides the aminoethyl substituted epoxide 13 in excellent yield. 

Treatment of a, ) -unsaturated ketones with a-halo esters often results in oxirane (205) formation (Darzens reaction). However, the reaction of the dienone 203 with ethyl bromoacetate (204) produces the bicyclo[4.1.0]heptenone derivative 206 (equation 55) ... 

Darzens condensation. Hinckley found that the condensation of a-halo esters with ketones when effected with sodium hydride dispersion proceeds smoothly and without usual side reactions. 

The Darzens glycidic ester condensation involves the condensation of an aldehyde or ketone with an a-halo ester, in the presence of a base, to afford an a,3 epoxy ester (a glycidic ester ). The first synthesis of a glycidic ester was reported by Erlenmeyer in 1892 and is illustrative of the general reaction, as shown in equation (1). The reaction was subsequently developed and generalized by Darzens. Glycidic esters, in addition to undergoing transformations normally associated with epoxides, afford upon hydro-... 

Normally, the Darzens reaction of simple a-halo esters is carried out under anhydrous conditions, since in aqueous media or under phase-transfer catalysis conditions the esters are prone to hydrolysis. Saponification can be largely prevented by using r-butyl esters, but this strategy also poses potential problems, as hydrolysis of the resulting glycidic ester is often the next stage of a synthetic process. Recently, a procedure has been developed in which a-chloro esters are deprotonated by treatment with potassium... 

Darzens-type reactionThe Darzens reaction2 of a-halocarbonyl compounds with an aldehyde requires a base, which can promote side reactions. Darzens reactions can proceed under neutral conditions when effected with this neutral reagent (I cquiv.). Presumably, the reaction proceeds via an organotin(lV) enolate. When the reaction is conducted in THF, the rron.v-epoxidc is generally favored, but addition of HMPA can favor cis-sclectivity. ci.v-Selectivity is also favored in reactions of aliphatic aldehydes. The Darzens-type reaction can also be extended to or-halo esters, particularly in the presence of Bu4NF or LiBr. 

Route (b) requires a reagent for the carbene (6) and the halo ester (7) is used in the Darzens reaction.A carbene is not in fact an intermediate. 

Darzens synthesis of glycidic thiol esters. Standard conditions for the Dar-zens reaction of a-halo esters use sodium alkoxides as the base and the corre-... 

B.vi. Tbe Darzens Glycidic Ester Condensation. When an a-halo ester is treated with base and the resulting enolate anion condensed with a carbonyl derivative, the product is an alkoxide. This nucleophilic species can displace the halogen intramolecularly to produce an epoxide, which forms the basis of a classical reaction known as the Darzens glycidic ester condensation. 13S Reaction of ethyl a-chloroacetate and sodium ethoxide, in the presence of benzaldehyde. generated the usual alkoxide (221). Intramolecular displacement... 

The reaction of a-halo esters with carbonyl compounds in the presence of sodium ethoxide leads to 2-(ethoxycarbonyl)oxiranes (Darzens 1904). They are known as glycidic esters. In the first step, the a-halo ester is deprotonated by the base to the corresponding carbanion. This nucleophile adds to the carbonyl compound in a rate-determining step. Finally, the halogen atom is intramolecularly substituted, e.g. ... 

The Damns reaction. The synthesis of glycidic esters by the condensation of carbonyl compounds with a-halo esters, known as Darzens reaction [259], has been used in phosphorus... 

The formation of a,P-epoxy carboxylic esters from carbonyl compounds and a-halo esters is not just an undesired side reaction, but is also an important synthetic method known as Darzens reaction. 

The Darzens condensation is one of the older methods (1904) for the synthesis of thiee-membered heterocycles. It is most commonly the reaction of a 2-halo ester with a carbonyl derivative in the presence of base. The following examples of the Darzens condensation show how it is applied to the synthesis of oxacy-clopropane and azacyclopropane rings. Suggest a reasonable mechanism for each of these reactions. 

---