Aldehydes with halo esters

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) ... 

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. 

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. 

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. 

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) ° ... 

Usually, after hydrolysis, the alcohol is the product, but sometimes (especially with aryl aldehydes) elimination follows directly and the product is an olefin. By the use of Bu,P along with Zn, the olefin can be made the main product,454 making this an alternative to the Wittig reaction (6-47). Since Grignard reagents cannot be formed from a-halo esters, the method is quite useful, though there are competing reactions and yields are sometimes low. A similar reaction (called the Blaise reaction) has been carried out on nitriles 455... 

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 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... 

Indium-mediated Barbier-type reaction of glyoxal monoacetal with bromomethyl acrylonitrile or bromomethyl-acrylate gives a masked a-hydroxy aldehyde (Equation (48)).91 The reaction of 3-bromo-2-chloro-l-propene, an aldehyde, and indium in water gives the corresponding homoallyl alcohol, which upon ozonolysis in methanol furnishes a / -hydroxy ester. The overall reaction is equivalent to the Reformatsky reaction, which cannot be realized by a direct indium-mediated reaction of an ct-halo ester with an aldehyde in water (Scheme 59).235... 

The condensation of aldehydes and ketones with halo esters may lead directly to olefinic acids and esters by dehydration of the intermediate /S-hydroxy compounds (Reformatsky). ° More often, the hydroxy esters are isolated and purified prior to dehydration (method 103). 

Other halogenated compounds have been substituted for the halo esters. Aromatic a-halo ketones have been condensed with aromatic aldehydes to give a,/3-epoxy ketones. ... 

Many other groups may be present in the alcohol or phenol during alkylation. Dimethyl sulfate and chlorohydrins give chloro ethers. Halo ethers are also prepared by the action of this reagent on halogenated phenols, e.g., w-bromoanisole (91%)- Phenolic aldehydes are converted in excellent yields to alkoxy aldehydes with dimethyl sulfate or alkyl p-toluenesulfonates. The conversion of a phenolic ketone to an alkoxy ketone is illustrated by the preparation of p-methoxypropiophenone (88%). Phenolic acids, esters, and cyanides, and nitrophenols respond favorably to this method for methylation. The sodium salt of mandelic acid, C H, CHOHCOOH, is methylated with dimethyl sulfate to furnish, after acidification, a-methoxyphenylacetic acid (42%). ... 

The Reformatsky reaction is very similar to 16-24. An aldehyde or ketone is treated with zinc and a hahde the hahde is usually an a-halo ester or a vinylog of... 

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