A-Bromomethyl ketones

Aryl methyl ketones have been obtained [4, 5] by a modification of the cobalt-catalysed procedure for the synthesis of aryl carboxylic acids (8.3.1). The cobalt tetracarbonyl anion is converted initially by iodomethane into the methyltetra-carbonyl cobalt complex, which reacts with the haloarene (Scheme 8.13). Carboxylic acids are generally obtained as by-products of the reaction and, in several cases, it is the carboxylic acid which predominates. Unlike the carbonylation of haloarenes to produce exclusively the carboxylic acids [6, 7], the reaction does not need photoinitiation. Replacement of the iodomethane with benzyl bromide leads to aryl benzyl ketones in low yield, e.g. 1-bromonaphthalene produces the benzyl ketone (15%), together with the 1-naphthoic acid (5%), phenylacetic acid (15%), 1,2-diphenylethane (15%), dibenzyl ketone (1%), and 56% unchanged starting material [4,5]. a-Bromomethyl ketones dimerize in the presence of cobalt octacarbonyl and... 

Bromomethyl ketones.l Reaction of (dibromomethyl)lithium (1) with esters and then with BuLi (excess) generates the enolate (a) of a bromomethyl ketone. Quenching with acidic ethanol gives the bromomethyl ketone (2) in 70-85% yield. Quenching with A O generates bromo enol acetates. 

In order to classify the reactive building blocks, we grouped them into mono-and bidentate nucleophiles (e.g. amines, alcohols, thioureas, isothioureas, amidi-nes, amidrazones), into their mono- and bis-acceptor counter parts (e.g. alkyl halides, a-bromomethyl ketones, a-alkinyl ketones), and into donor-acceptor species (e.g. isocyanates, isothiocyanates, 2-azido benzoic acids215), as depicted in Figure 40. 

Silyl enol ethers react with bromomethyl methyl ether in the presence of a catalytic amount of SnBrg to yield a-bromomethyl ketones (Eq. 9) [18]. Other tin halides such as SnFg and SnClg can be used successfully in the reaction. 

The Hantzsoh reaction discovered in 1889 remains one of the most reliable routes to thiazoles and several applications of this reaction appeared during the past year <05JOC8991 05JA15644 05T1257>. This approach has been used twice to form both thiazole rings of the cyolopeptide dendroamide A <05H(65)95>. The first thiazolation of a-bromomethyl ketone 2 with thioamide 1 results in the formation of thiazole 3, which is converted into thioamide 4. This compound undergoes the second thiazolation with 5 to furnish oxazolyl bis-thiazole 6, a precursor to dendroamide A. 

Thiazolin-4-one derivative 29 in hydrazino-hydrazono tautomeric equilibrium is synthesized by cyclization of l,2-diaza-l,3-butadiene 27 with aryl thioamide 28. Subsequent hydrolytic removal of the NH-Boc-hydrazo protecting group provided 5-acetyl-4-hydroxythiazole derivative 30a, which undergoes a-bromination to give a-bromomethyl ketone 30b. This bromide is used to prepare polyfunctionalized 4,5 -bithiazol-4 -ol derivatives via the Hantzsch thiazole synthesis <04SL2681>. 

In a later development, it was found that tin(II) triflate catalyses the interaction of a bromomethyl ketone and a (l-formylalkyl)phosphonic diester to give the (3-bromo-2-hydroxy-4-oxoalkyl)phosphonic ester this is convertible into the epoxide with Et3N in benzene (Scheme 33 " . 

The 3-j3-D-arabinofuranosyl pyrazole derivative (33) has been synthesized from D-mannose by the procedure outlined in Scheme 9 on deprotection with ammonia, (33) epimerized to the -D-ribofuranosyl isomer. 2,5-Anhydro-D-allonic acid derivatives have been used to synthesize the C- ym-triazoloribo-nucleosides (34) and (35) by condensation with heterocyclic hydrazine derivatives. The diazoketone (36), prepared conventionally from the acid, has been used to prepare the thiazole analogue (37) of ribavirin via the intermediate a-bromomethyl ketone (38) by condensation with an imido-thio-oxalic acid derivative,and the indazole nucleoside analogue (39) by cyclization with benzyne (Scheme 10). An acyclic diazoketone analogously prepared from D-ribonic acid similarly gave a C-ribonyl-indazole with benzyne, which could be... 

Selenium dioxide a-Ketocarboxylic acid esters from a bromomethyl ketones... 

Reaction of labeled aryl halomethyl ketones with amines furnishes j8-amino[ C] ketones. If e.p. amines are employed, subsequent reduction of the keto group with achiral reducing agents produces diastereomeric mixtures of )8-amino alcohols. The individual diastereomers can usually be separated by achiral chromatographic methods, or if these fail chiral HPLC procedures or salt formation with a chiral acid (e.g. dibenzoyl-L-tartaric acid) may prove successful. This pathway was followed for the preparation of [ C]dilevalol (12), an antihypertensive agent (Figure 6.8). Within this synthetic sequence the reaction of the a-bromomethyl ketone 8 with e.p. (7 )-Wbenzyl-(l-methyl-3-phenyl)propylamine (2)... 

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