Halo ester

This reaction involves the condensation of an aldehyde or ketone with an a-halo ester in the presence of a basic condensing agent (sodium ethoxlde, sodamide, finely divided sodium or potassium iert.-butoxide) to give a glycldio (or ap-epoxy) ester. Thus acetophenone and ethyl chloroacetate yield phenyl-methylglycidic ester (I) ... 

Analysis Either way round will do, so let s arbitrarily chose ketone and a-halo ester ... 

Synthesis Our problems are not yet oyer because if we combine ketone and a-halo ester in base, quite a different reaction occurs. Can you draw a mechanism for it ... 

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

Condensations of aldehydes or ketones with a-halo esters give a,P-epoxy esters. This is called the Dar2ens condensation. 

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... 

An a ,/3-epoxycarboxylic ester (also called glycidic ester) 3 is formed upon reaction of a a-halo ester 2 with an aldehyde or ketone 1 in the presence of a base such as sodium ethoxide or sodium amide. Mechanistically it is a Knoevenagel-type reaction of the aldehyde or ketone 1 with the deprotonated a-halo ester to the a-halo alkoxide 4, followed by an intramolecular nucleophilic substitution reaction to give the epoxide 3 ... 

Good yields are usually obtained with aromatic aldehydes or ketones. Aliphatic aldehydes are poor substrates for the ordinary procedure, but react much better if the halo ester is first deprotonated with lithium diisopropylamide (LDA) in tetrahydrofuran at -78 °C, prior to addition of the aldehyde. 

Instead of a-halo esters, related reactants can be used e.g. the a-halo derivatives of ketones, nitriles, sulfones and A,A-disubstituted amides. The Darzens condensation is also of some importance as a synthetic method because a glycidic acid can be converted into the next higher homolog of the original aldehyde, or into a branched aldehyde (e.g. 5) if the original carbonyl substrate was a ketone ... 

By reaction of an imine 6 with a a-halo ester 2, an aziridine derivative 7 can be obtained " ... 

The classical Reformatsky reaction consists of the treatment of an a-halo ester 1 with zinc metal and subsequent reaction with an aldehyde or ketone 3. Nowadays the name is used generally for reactions that involve insertion of a metal into a carbon-halogen bond and subsequent reaction with an electrophile. Formally the Reformatsky reaction is similar to the Grignard reaction. 

By reaction of an a-halo ester 1 with zinc metal in an inert solvent such as diethyl ether, tetrahydrofuran or dioxane, an organozinc compound 2 is formed (a Grignard reagent-like species). Some of these organozinc compounds are quite stable even a structure elucidation by x-ray analysis is possible in certain cases ... 

The organozinc compound 2 is less reactive than an organomagnesium compound the addition to an ester carbonyl group is much slower than the addition to an aldehyde or ketone. Nevertheless the addition of 2 to the carbonyl group of unreacted a-halo ester 1 is the most frequently observed side-reaction ... 

The carbonyl substrate 3 to be reacted with the organozinc compound 2 can be an aldehyde or ketone that may contain additional functional groups. With a vinylogous halo ester—i.e. a y-halocrotyl ester—the corresponding y-crotylzinc derivative is formed. 

In general the Stork reaction gives moderate yields with simple alkyl halides better yields of alkylated product are obtained with more electrophilic reactants such like allylic, benzylic or propargylic halides or an a-halo ether, a-halo ester or a-halo ketone. An example is the reaction of 1-pyrrolidino-l-cyclohexene 6 with allyl bromide, followed by aqueous acidic workup, to yield 2-allylcyclohexanone ... 

Trialkylboranes react rapidly and in high yields with a-halo ketones,a-halo esters, a-halo nitriles, and a-halo sulfonyl derivatives (sulfones, sulfonic esters, sulfonamides) in the presence of a base to give, respectively, alkylated ketones, esters, nitriles, and sulfonyl derivatives. Potassium tert-butoxide is often a suitable base, but potassium 2,6-di-tert-butylphenoxide at 0°C in THF gives better results in most cases, possibly because the large bulk of the two tert-buXy groups prevents the base from coordinating with the R3B. The trialkylboranes are prepared by treatment of 3 mol of an alkene with 1 mol of BH3 (15-16). With appropriate boranes, the R group transferred to a-halo ketones, nitriles, and esters can be vinylic, or (for a-halo ketones and esters) aryl. " °... 

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) ° ... 

Reaction of halo esters or diazo esters with boranes... 

Reaction between nitriles, zinc, and a-halo esters (Blaise)... 

Condensation between aldehydes and a-halo esters, ketones, or... 

Condensation between aldehydes or ketones and ot-halo esters... 

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. 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allyl and benzyl halides, a-halo esters, a-halo ethers, and a-halo ketones are the most successful alkylating agents. The use of enamines for selective alkylation has largely been supplanted by the methods for kinetic enolate formation described in Section 1.2. 

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

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