5-Haloketones

The synthesis and detailed characterization of 4-bromo-2,3-dioxobutyl deriv- 

Additional bromo-2,3-dioxobutyl nucleotide affinity labels, (a) 2-(4-Bronio-2,3-dioxobu-tylthio)-l,A -ethenoadenosine 2, S -diphosphate (b) 2-(4-bromo-2,3-dioxobutylthio)-l,W -etheno-adenosine S -diphosphate and (c) 2-(3-broino-2-oxopropylthio)-l,iV -ethenoadenosine 5 -diphos-phate. 

The same 2-BDB-TeA 2, 5 -DP was also found to inactivate the NADP -specific glutamate dehydrogenase from Salmonella typhimurium. The rate of inactivation exhibited a nonlinear dependence on the reagent concentration, indicative of reversible binding prior to irreversible modification (J9). The presence of NADPH or NADP in the reaction mixture completely prevented inactivation, suggesting that 2-BDB-TcA 2, 5 -DP also functioned as an affinity label of the coenzyme site in this NADP -specific dehydrogenase. 

Bromopyruvate was first used as an affinity label of pyruvate binding sites by Meloche (45), and its application has been extended to a number of enzymes (23). By analogy, 3-bromo-2-ketoglutarate (BrKG) was synthesized as an affinity label of a-ketoglutarate binding sites by Mantsala and Zalkin (46) and shown 

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Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

The condensation of a-haloketones with monosubstituted alkyl or aryl-selenoureas (25) leads to 2-alkylamino- (26. 27) or 2-arylaminOselana-zoles (28) while disubstituted selenoureas give 2-(dialkylamino) selenazoles (26. 27) (Table X-3a). 

The only method that yields the 2-unsubstituted thiazoie derivatives directly involves the condensation of a-haloketones with thioformamide. As in the case of previously reported a-haloaldehydes, yields are better when more reactive bromoketones are used instead of a-chloroketones. Cyclization can be achieved by adding ketones dissolved in dioxane in small quantities to the thioformamide formed in situ at below 40°C. The temperature is kept below 70°C during the addition, and then the... 

By condensing a-haloketones with diacetylaminothioacetamide (13), Pyl et al. (533) obtained the corresponding 2-aminomethylthiazoles (15) after hydrolysis (Scheme 8). 

These products are used as starting material for the preparation of 2-substituted thiazol-4-ylacetic acids. a-Benzoyloxythiopropionamide and a-benzoyloxy-a-benzoylthioacetamide condensed with an equimolar amount of an a-haloketone in alcoholic solution yield the following compounds (409, 419, 569) 24, Rj = CH3, PhCO, R2 = Me... 

In the reverse reaction, thioheteroaryl amides reacted under reflux in alcohol with haloketones or aldehydes to give the corresponding 2-heteroarylthiazole derivatives (238, 271, 482, 550, 751, 765, 776, 781). 2,2 -Bithiazoles (4,4 -disubstituted) have been obtained in 80 to 90% yield by cyclocondensation of 1 mole rubeanic acid with 2 moles of a-bromoketones in polyphosphoric acid at 95 to 135 C (780). Some multiheteroaryl substituted thiazoles have been also reported (704). 

The mechanism of the Hantzsch s synthesis was studied at a very early stage by several authors. The intermediates were generally assumed to be open-chain a-thioketones, but in a series of papers by Murav eva and Schukina (470, 490) the isolation of hydroxythiazolines from the reaction between a-haloketones and a variety of thioureas was reported. 

The reaction of N-methyl-(p-dimethylamino)thiobenzamide (99) with a number of a-haloketones and a-bromoheptaldehyde gave stable 4-hydroxythiazolinium salts (100), which could be subsequently dehydrated by methanolic hydrogen chloride to the thiazolium salts (101), (Scheme 44) (622). 

In a similar way, the a-haloketones gives the corresponding 2-thiomethyl-3-ethylthia2olium salts (722). 

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar parts of thiourea (103) and a-haloketones or aldehydes to yield the corresponding 2-aminothiazoles (104a) or their 2-imino-A-4-thiazoline tautomers (104b) with no by-products (Method A, Scheme 46). 

The 2-aminothiazoles are extracted with ether after alkalinization of the reaction mixture. The yields are almost theoretical with a-haloketones and lower with a-haloaldehydes. 

In many cases, the a-haloketone does not appear to be an intermediate in this reaction, since reagents such as sulfur trioxide, sulfuric, or 60% nitric add lead to 2-aminothiazole but with lower yields (11 to 43%). Formamidine disulfide [-S-C(=NH)NH2]2, a product of the oxidation of thiourea, seems to be the intermediate in this reaction, since upon treatment with ketones, it gives 2-aminothiazole (604). However, the true mechanism of this reaction has not yet been completely elucidated. 

Aminolhtazoles were synthetized from thiourea by three methods Method A, from a-haloketones or aldehydes designated as (Cl) or (Br) Method B, from ketones and iodine (fj) or bromine (Btj) Method C, from iodomercuriketones. Method D consists in condensing ketones with cyanamid and sulfur. 

Compound 132 condensed with 1 or 2 moles of aliphatic or aromatic a-haloketones in acetonic or alcoholic solution yielded either the corresponding 2-thiazolythiourea (133) (559, 753, 797) or sym-substituted bis(2-thiazolyl)amine (134) (Scheme 64 and Table 11-19) (430, 553, 653). 

Aromatic amines react with 1-haloketones or 1-hydroxyketones to yield substituted indoles. This reaction is known as the Bischler indole synthesis (30). 

Hantzsch and Feist Syntheses. The Hant2sch synthesis of pyrroles iavolves condensation of an a-haloketone (10) with a p-keto ester (6) ia the presence of ammonia or an amine (22). 

The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

FAWORSKI WALLACH Rearrangement Reanangement of a-haloketones or a,a -dihalokeiones to acids or acrylic adds (via cyclopropanones). 

MATTOX KENDALL Dehydrohaiogenation Dehydrohaiogenatton of a haloketones with 2,4 dinitrophenylhydrazine or LiCI DMF... 

Reaction ol a haloketones with tnalkylphosphite to give ketophosphonate or vinylphosphate... 

Conversion of a-haloketones to olefins using hydrazine (via enedlitnides C-C-N NH). Also reduction of o,3-epoxy ketones to allyl alcohols. 

It is believed that a reactive ground-state species, the zwitterion A, is an intermediate and that it rearranges to the observed product. To test this mechanism, generation of species A by nonphotochemical means was undertaken. a-Haloketones, when treated with strong base, ionize to such dipolar intermediates. Thus, the bromoketone 6 is a potential precursor of intermediate A ... 

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