With Haloketones

As distinct from the reactions of dicarbonyl compounds, the reaction of a-halo ketones with 1,2-DABs proceeds with the formation of noncyclised products (Welton 1999 Wasserscheid and Keim 2000 Wilkes 2002 Zerth et al. 2003  

Kumar and Pawar 2004 Gu et al. 2005) formed by reaction with the carbonyl group only, or with dihydroquinoxaline derivatives (Das et al. 2007 Chou et al. 2011). Thus, these reactions are usually carried out in the presence of oxidants or under conditions that promote oxidation (Wu and Ede 2001 Singh et al. 2004 Das et al. 2007 Madhav et al. 2009 Meshram et al. 2010 Chou et al. 2011). 

It should be noted that the reaction route and the structure of products formed from compounds containing both diketone and a-halocarbonyl fragments depend on the solvent. For example, the reaction of 3-chloro-l,3- 

Ar = Ph, CgH4F-4, CgH4CI-4, CgH4Br-4, CgH4l-4, CgH4N02-4 13 examples, 70-98% 

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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). 

A series of 3-alkyl- and 3-aryl-7/7-furo[3,2- ]-l-benzopyran-7-ones 78 (linear furocoumarins) was synthesized and evaluated for their photochemical and nonphotochemical crosslink formation with DNA as well as for their spectro-photometric and fluorescent properties, lipophilicity, and ability to photobleach A, A -dimethyl-/)-nitrosoaniline (RNO) after irradiation with UVA light <2002AP187>. The synthesis of the linear furocoumarins (Scheme 10) was a modification of a previously published method in which 7-hydroxy-2//-l-benzopyran-2-ones 76 were converted into / -ketoethers 77 by alkylation with haloketones under phase-transfer catalysis conditions. Base-catalyzed intramolecular condensation and subsequent acidification gave the corresponding 78. A molecular complex between each one of these fluorescent furocoumarins and DNA was observed, but only compounds with a 3-Me or 3-Ph group showed UVA irradiation-induced crosslink formation. 

Reaction of amidoximes with -haloketones or 1,2-dibromoalkanes in the presence of base leads to the l-oxa-2,4-diazine system for example, the -aminopropionamidoxime 679 and bromoacetone yield 680 (Scheme 294) . 

An important reaction is that with haloketones. 2,5-Dibromo-l,4-benzoquinone... 

The striking successes achieved by Shaw (1970a) and his coworkers with haloketone derivatives of N-tosyl-phenylalanine and a-N-tosyl-lysine as affinity labels for chymotrypsin and trypsin, respectively, have stimulated their use in a large number of affinity labels. Haloketones are potentially reactive with all the nucleophilic amino acid residues in proteins. Examples of residues modified by haloketones include methionine (Sigman et al. 1970), glutamate (Visser et al. 1971), cysteine (Porter et al. 1971), histidine (Schoellman and Shaw 1963) and serine (Schroeder and Shaw 1971). 

Since epoxides potentially will react with a variety of amino acids, many products may be formed if they are incorporated into affinity labels. However at present affinity labels containing epoxides have been shown to modify either glutamate or aspartate residues in pepsin, lysozyme, those phosphate isomerase and j -glucosidase. The only other residue which has as yet been modified by epoxides is methionine 192 of chymotrypsin. In general, the other possible products should be similar in stability to derivatives formed by haloketones. Therefore the methods for identification of the amino acid derivatives formed by reaction with epoxides closely parallel those described in connection with haloketones ( 5.3.2). 

Diaminopyrimidines or l-aminopyrimidine-2-thiones were found to be suitable molecular fragments for the synthesis of heterocycles. Thus, l,6-diamino-2-oxo-4-hydroxypyrimidine (65) underwent cyclocondensation with dimethyl oxalate yielding 8-hydroxy-277,3/f,6/f-pyrimido[l,6-i)][l,2,4]triazine-2,3,6-trione (66) (Equation (12)) <85JHC1317>. Similarly, the reactions of the 2-thione (67) with haloketones gave pyrimido[2,l-fe][l,2,4]thiadiazines (68) (Equation (13)) <71IJC404>. 

Successful application of affinity labeling, with haloketones or any other class of reagent, typically requires four types of endeavors (1) search for suitable reagents (2) demonstration that inactivation results from an active-site-directed process (3) characterization of the covalently modified protein (4) determination of the relationship of the results to the mechanism of the enzyme-catalyzed reaction. 

Inhibition or Pboteolytic Enzymes with Haloketone Derivatives op Amino Acids and Peptides ... 

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... 

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). 

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). 

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

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