Halo esters formation

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... 

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. 

The fifth method involves the simultaneous formation of the N1-C2 and Nj-Cg bonds, thus enabling the facile introduction of Ni-substituents by the use of primary amines as reactants. An example of this approach is the tandem acylation-alkylation of an amine with a suitable halo-ester (see Figure 1 for numbering sequence). 

During studies on the use of amidines as azomethine ylide sources, Jones et al. (67-69) reported in a series of papers the application of their general strategy to an asymmetric process. Quatemization of the dihydroimidazole 214 with an a-halo ester followed by DBU-induced ylide formation and subsequent cyclization furnished a range of nitrogen heterocycles in a one pot generation and cyclization protocol (70) (Scheme 3.73). 

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. 

Halo esters can be formed by addition of halogen atoms and ester groups to an alkene. Alkene carboxylic acids give a tandem reaction of formation of a halonium ion followed by intramolecular displacement of the carboxylic group to give a halo lactone. This tandem addition of X and OCOR is called... 

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) ... 

If a hapten does not contain free carboxyl, such group(s) may often be introduced. Alkylation of oxygen or nitrogen substituents with halo-esters, followed by hydrolysis of the ester, is frequently used for this purpose (Kabakoff, 1980). For steroids, carboxyl groups may be introduced to the hydroxyl or keton groups, through the formation of hemisuccinate esters or (carboxymethyl)oximes, respectively. 

Formation of 1,2,4-oxadiazines occurs by acid-catalyzed ring expansion of a-aziridino oximes and dioximes, and by 1,3-dipolar cycloaddition of arylcarbonitrile oxides and 2-acyl-2//-azirines (Section 6.14.10). Preparation of l,2,4-oxadiazin-5-ones can be achieved by ring closure of A-carboxymethyl and A-alkoxycarbonylmethyl amidoximes (Section 6.14.9.1.1), by the acid-catalyzed condensation of arylaldehydes with O-alkyl-A-acylhydroxylamines (Section 6.14.9.2.3.1), and by reaction of A-hydroxyureas or amidoximes with a two-carbon fragment such as an a-halo ester or an acyl halide (Section 6.14.9.2.2.1). 

According to a general definition, the Reformatsky reaction can be taken as subsuming all enolate formations by oxidative addition of a metal or a low-valent metal salt into a carbon-halogen bond activated by a vicinal carbonyl group, followed by reaction of the enolates thus formed with an appropriate electrophile [23]. The insertion of metallic zinc into a-halo esters is historically the first and still the most widely used form of this process although Zn may be beneficially replaced but other metals and reducing metal salts in certain cases. 

Another related method uses the anion of nitroalkanes in a reaction with halo-esters. Nitromethane reacted with lithium diisopropylamide to form the nitro enolate and then with methyl 3-chloropentanoatc to give 4.110. Reduction of the nitro group with ammonium formate gave methyl 2-phenyl-3-aminopropanoate, 4.111. 

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. 

In yeast, the reduction of P-ketoesters is carried out by dehydrogenase complexes that can individually afford either the (l)- or the (d)configuration (36e). Therefore inhibition of the (L)cnzyme will provide (D)-products and vice versa. Nakamura et al. [52] reported that addition of allyl alcohol or a,P-unsaturated carbonyls resulted in the formation of (D)-hydroxyesters 137, thereby inhibiting the (L)-enzyme. To shift the product formation toward the t-side 138 a-halo esters can be used. Thus, the best results were obtained with a-chloroacetates. In this way, the additive serves as a switch between the formation of the enantiomeric P-hydroxy esters 137 and 138. 

A large variety of methods is applicable to the formation of isolated double bonds. This permits selection of reagents compatible with other functionality present. Alcohol dehydration, ester elimination and other nonreductive p eliminations are the most common methods. Reductive elimination of halo-hydrins, vic-dihalides, etc., and of a variety of ketone derivatives has also been used. 

Oxidadve cross-conphng reactions of alkylated derivatives of activated CH compounds, such as malonic esters, acetylacetone, cyanoacetates, and ceitain ketones, v/ithnitroalkanes promoted by silver nitrate or iodine lead to the formation of the nitroalkylated products. This is an alternative way of performing Spj l reactions using cr.-halo-nitroalkanes. 

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