Isomeric haloketones

The above mechanism is supported by the fact that the same ester 2.35 is formed from the isomeric haloketones 2.33 and 2.34 (Scheme 2.26). 

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 derivative from an isomeric fused system has been described as a sedative-hypnotic compound. The synthesis starts by condensation of the aminopicoline 32 with the haloketone 33. The resulting pyrrolo[l,2-a]pyridine 34 then undergoes a Mannich reaction with formaldehyde and dimethylamine to give the aminomethylated derivative 35. After quatemization of the di-methylamino group in 35 with methyl iodide, the ammonium group is displaced by cyanide to... 

In connection with route A, the formation of sulfones from sulfinates and a-haloketones on the one hand, and of isomeric enol sulfonates on the other (cf. Section III. A.4), should be pointed out. 

An example of a sugar-derived chiral -haloketone is offered by 24. When ulosyl bromide 24 is coupled to acetaldehyde in a Grignard-type process, a mixture of isomeric adducts is formed, where the 50% is represented by 25, possessing the (R) configuration at the hydroxy ethyl substituent (equation 21). The same protocol is applied in an efficient nucleophilic C-glycosidation reaction of 24 with galactose-derived aldehyde 26 to give 27 (equation 22)20. 

Important related studies have been published by House, tJ- u and by Naqvi end co-workers,1218 on the subject of magnesium bromide-initiated epoxide isomerization. Their results, discussed in section IV.2.A, suggest that abnormal addition of Qrignard reagents to dicyelio a-haloketones does not proceed by way of an ephemeral poxide intermediate, in accordance with the view expressed previously by Gciesman and Akawie.4 4... 

Classic work by Loftfield on the Favorskii reaction showed that cyclopropanones are intermediates in the base-induced rearrangement of a-haloketones (l heme 4). Isolation of such an intermediate was accomplished in the reaction of the sterically hindered a-bromodineopentyl ketone (9) with potassium p-chlorophenyldimethylcarbinolate. The identity of the product (10), rrans-2,3-di-t-butylcyclopropanone, was established by independent synthesis of 1,3-di-t-butylallene oxide (11) which underwent valence isomerization to (10) ... 

Reactions of Miscellaneous Haloketones and Acid Chlorides - Photochemical chlorocarbonylation of the polycyclic tetradecane (196) results in the formation of mixture of isomeric acid chlorides which, on treatment with... 

An ingenious procedure for replacing sulfur in a thiolactam by a -CH COR group involves alkylation of sulfur with an a-haloketone, followed by sulfur extrusion either with triphenyl phosphine or by heating in DMF (with or without added sodium ethoxide). Th reaction has been successfully applied thus far to isoqu oline-l(2H)-thione, quinazoline-4(3H)-thlone, and 6-mercaptopurine. A closely related intramolecular sulfur displacement reaction with intriguing synthetic potential is Illustrated by the conversion of the S-alkylation product from 6-chloropurine ribonucleosld gand cysteine to the isomeric N-alkylated product by treatment with alkali. 

The triazine (82) reacts with a-haloketones in aqueous sodium hydroxide to give the products (83). These compounds dehydrate to yield (84) not the isomeric (85) [93JHC293]. 

The mechanism for the Hantzsch pyrrole synthesis begins with enamine formation. Condensation of ammonia (or an ammonia surrogate) and 3-ketoester 2 gives intermediate A. Intermediate A then undergoes dehydration and tautomerization (B) to produce enamine C. Michael addition of enamine C and a-haloketone 1 gives D, which forms E via P-elimination. Intramolecular nucleophilic substitution then generates F, which undergoes rapid isomerization to form the desired pyrrole 3. 

McPhee and Klingsberg were the first to suggest that the reaction proceeds via symmetrical intermediate, as the same rearranged ester was formed starting from two isomeric a-haloketones differing in the halogen s position a or a to the carbonyl ... 

The opposite configuration notation of the product alcohols are due to the CIP sequence rules. The directions of the asymmetric induction are consistent to afford (R)- isomers by si facial addition of hydride for both aliphatic and al-kylaromatic ketones. However, for a-haloketone and a-ketoester, re facial addition of hydride provides (S)-isomeric alcohols. The direct comparison of K-xylide asymmetric reductions reveals that the reagent resembles very closely to that of K-glucoride. 

In the reaction of P-ketoesters with a-haloketones, the possible competition between C-alkylation (followed by reaction of the Paal-Knorr type) and aldol addition (followed by reaction of the Feist-Benary type) can result in mixtures of isomeric furans. Regioselec-tivity can, however, sometimes be controlled by the reaction conditions, as, for instance, in the interaction of chloroacetone with acetoacetate, leading to the furan-3-carboxylates 66/67 ... 

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