7- Halo esters, preparation

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... 

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. " °... 

An alternative route starting from serine 73 or threonine 68 74 makes use of diethoxy-triphenylphosphorane. Attempts to asymmetrically synthesize (25)-aziridine-2-carboxylic acid (1) by treating a, 3-dibromopropanoates with chiral amines 75 or by the Staudinger reaction from oxirane-2-carboxylic acid ester 70,76 leads to optically impure products, whereas 3-alkyl derivatives of tert-butyl aziridine-2-carboxylates can be prepared with high cis-selectivity from a-halo ester enolates and jV-trimethylsilyl imines. 77 Moreover, when optically... 

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... 

Although alkylations of enolates with a-halo ester compounds are quite effective in singular cases, these reactions often proceed with poor yield and selectivity. Therefore the siloxycyclopropane route is to be considered even for large scale preparations of relatively simple y-oxoesters. Synthesis of rather sensitive formyl esters (entries 9, 13, 16, 17) or the stereoselective generation of /ranj-substituted cyclic y-oxoesters as mentioned above can hardly be achieved with comparable efficiency by other methods. 

Zinc alkyls and aryls are reactive to air and water and their reactions are similar to, bnt less vigorons than, those of Grignard reagents, from which they differ in the important respect that they do not react with CO2 and are nsnally prepared in an atmosphere of this gas. Zinc may be nsed to generate, in effect, the nncleophile CH2CO2R from a-halo esters that can then react with carbonyl componnds as in the well-known Reformatsky reaction ... 

The method has been used for the preparation of dihalides, e.g., 1,9-dichlorononane (93%) unsaturated halides, e.g., 11-undecylenyl chloride (83%) halo ethers, e.g., /3-ethoxyethyl chloride (80%) halo ketones, e.g., desyl chloride (79%) halo esters, e.g, methyl a-chloropropionate (71%) halo cyanides, e.g., phenylchloroacetonitrile (80%) and aminoalkyl halides,An interesting isomerisation has been observed in liberating 2-diethylamino-l-chloropropane from its hydrochloride salt l-diethylamino-2-chloropropane is formed. ... 

The method has been of particular value in the preparation of difunctional compounds. For example, the action of elemental halogen on sodium acetylides or alkynylmagnesium halides gives 1-halo-1-alkynes (70-90%). t Also, halo esters, phenols, or acids result when the appropriate aromatic mercurial is treated. Sometimes p-toyl-sulfonyl chloride is substituted for chlorine gas. p-Iododimethylaniline is easily made in 42-54% yield by the reaction of p-dimethylaminophenyl-lithium and iodine. ... 

Various derivatives of fiuan and pyran are cleaved to give open-chain di- and poly-functional compounds. Fission to give dihalides, halo alcohols, and halo esters is described elsewhere (method 34). Hydrogenation and hydrogenolysis reactions lead to hydroxy compounds, as in the preparation of 5-hydroxy-2-pentanone and 1,4-pentanediol from methyl-... 

RC = CCH,X — RCX = C==CH,. /S.y- and 7,S-Acetylenic alcohols can be transformed to the halides in better yields by an alternative procedure, which consists in their esterification with p-toluenesulfonyl chloride and subsequent cleavage of the ester by the action of sodium iodide, lithium chloride, or calcium bromide in an appropriate solvent (60-90%). Halo ethers are prepared by the action of phosphorus tribromide on hydroxy ethers, as in the preparation of /3-ethoxyethyl bromide (66%). In a similar manner, /3-halo esters have been prepared without appreciable dehydration of the /3-hydroxy ester (40-60%). The reaction of cyanohydrins leads to a-halo nitriles. Treatment of 2-nitro-l-propanol with phosphorus pentachloride gives l-chloro-2-nitropropane (47%). ... 

Several acids have been esterified by reaction with propene, " isobutylene, and ttimethylethylene. " The reaction is reversible and catalyzed by sulfuric acid or boron trifluoride. The optimum conditions for maximum conversion are low reaction temperature, large quantity of catalyst, and anhydrous conditions. " By this method, the keto ester, t-butyl o-benzoyl benzoate, " and the halo esters, f-butyl and isopropyl trichloroacetates,have been prepared. 

Benzofurans and benzothiophenes are sometimes obtained by condensation of active methylene and aldehyde groups in ortho substituents on the benzene ring. " The starting materials in the furan series are conveniently prepared in situ torn phenolic aldehydes and a-halo ketones or CL-halo esters. 

Chiral a-halo esters (72a) and (72b) and a-halo imide (72c) have been prepared in high diastereomeric purity by the use of Oppolzer s chiral auxiliary (71a) and (71b) and Evans chiral auxiliary (71c), respectively. The reactions of (72a), (72b) and (72c) with azide ion proceeded with inversion of configuration (Scheme 30). In the latter reaction, the use of NaNs (DMF or DMSO, 0 C) has been reported to afford 2-5% epimerization. The azides thus prepared were transformed into the corresponding amino acids with high chemical and optical yields. 

In the same way as enantiomerically pure a-halo ketones, a-halo esters have been prepared in high diastereomeric excesses by asymmetric halogenation of silyl ketene acetals generated from chiral esters So, a successfull procedure was first introduced in 1985, by W. Oppolzer (refs. 8,9), using derivatives of camphor-10-sulfonic acid as chiral auxiliaries (Fig. 4). 

Finally, free a-chloro acids have been prepared in high enantiomeric excess by chlorination of silyl keteneacetals using D-(+)-glucose diacetonide as chiral auxiliary (refs. 13,14). The most outstanding features of this very efficient chiral auxiliary are the cheapness, and the easy hydrolysis of the final a-halo esters, that allows the removal of the chiral auxiliary under nonracemising conditions moreover, this compounds is non toxic and is commercially available. 

The Reformatsky reaction is most commonly conducted in a single step by addition of a mixture of a-halo ester and carbonyl substrate to a suspension of zinc in a suitable solvent. This one-stage procedure clearly minimizes any problems due to instability of the Reformatsky reagent. Since 1953, solutions of the reagent have occasionally been prepared, with varying degrees of success, by reaction of the a-halo ester with zinc in an initial separate step of a two-stage procedure. 

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