Halo ketones nucleophilic substitution

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 ... 

The stabilization of reaction intermediates RCjq and RC q to form dihydrofullerene derivatives can also be achieved by intramolecular nucleophilic substitutions (SjJ), if R contains a leaving group. As shown by Bingel [31], the generation of a carbon nucleophile by deprotonation of a-halo esters or a-halo ketones leads to a clean cyclopropanation of Cjq. 

Next, a nucleophilic substitution reaction at saturated carbon. a-Halo ketones are excellent electrophiles and react rapidly with nucleophiles, such as this secondary amine, by the S 2 mechanism (Chapter 17). All that remains is to reduce the ketone and the acid to alcohols and remove the benzyl protecting group (both discussed in Chapter 24). 

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

Substituted bicyclo[ .1.0]alkanes may also be obtained by condensation of secondary amines with 2-halo ketones. A variety of nucleophilic reactions can be carried out on the intermediate cyclopropaniminium salt (Scheme 108). Competing alkene... 

The Hantzsch synthesis involves three intermediate steps. In the first, the halogen atom of the or-halo aldehyde or a-halo ketone is nucleophilically substituted. The resulting iS-alkyliminium salt 2 undergoes a proton transfer (2 -> 3) cyclization produces a salt of a 4-hydroxy-4,5-dihydrothiazole 4 which is converted into a 2,5-disubstituted thiazole 1 in protic solvents by an acid-catalysed elimination of water. 

Shreeve et al. have synthesized a range of new ionic liquids based on oxazoli-dine, morpholine and 1,2,4-triazole. These have been found to be good solvents for the Cu(I)-mediated nucleophilic trifluoromethylation of benzyl bromide [155]. Nucleophilic substitution has also been carried out on alkenes in the form of 2-tosyltropone, where the tosyl group was substituted for a chloride in [BMIM][BF4] [156]. Aminopyridines [157] and aminopyrimidines [158] react with a-halo ketones to form imidazopyridines and imidazopyrimidines. These reactions have been investigated in [Bp4] and [PFs]" ionic liquids and found to give fester reaction rates than in organic solvents [159]. 

This reaction was first reported by Hantzsch and Weber in 1887. It is the formation of thiazole derivatives by means of condensation of a-haloketones (or aldehydes) and thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis. In addition, other names, including the Hantzsch synthesis, Hantzsch reaction, and Hantzsch thiazole reaction are also used from time to time. Besides thioamides, other thio-ketone derivatives such as thiourea, dithiocarbamates, and ketone thiosemicarbazone can also condense with a-halo ketones (or aldehydes) to form thiazoles. This reaction occurs because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas, and normally gives excellent yields for simple thiazoles but low yields for some substituted thiazoles, as of dehalogenation. This reaction has been proven to be a multistep reaction, and the intermediates have been isolated at low temperatures, in which the dehydration of cyclic intermediates seems to be the slow step. It is found that a variety of reaction conditions might result in the racemized thiazoles that contain an enolizable proton at their chiral center, and it is the intermediate not the final product that is involved in the racemization. Therefore, some modifications have been made to reduce or even eliminate the epimeriza-tion upon thiazole formation. In addition, this reaction has been modified using a-tosyloxy ketones to replace a-haloketones. ... 

T. Lee et. al. [167] reported a series of 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivatives (168) from solid-phase s)mthesis. Thorpe-Ziegler type cyclization of solid supported cyanocarbonimidodithioate with a-halo ketones gave thiazole resin, which were transformed to the preferred thiazolop5rridine resin by the Friedlander procedure under microwave irradiation conditions. After oxidation of sulfides to sulfones, nucleophilic desulfonative substitution with amines 4elded the target thiazolo[4,5-b]pyridine derivatives. 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

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