Bromomethyl ketone

Caution This preparation must be carried out in an efficient hood. Bromomethyl ketones are highly lachrymatory and are skin irritants. 

The following reaction sequence converts esters to bromomethyl ketones. Show the intermediates that are involved in each step of the sequence. 

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... 

Reaction of tetrasulfur tetranitride with aryl and alkyl bromomethyl ketones (288) in refluxing chlorobenzene gives 3,5-diaroyl and 3,5-diacyl-l,2,4-thiadiazoles (98) in yields of 17-60% (Equation (44)) <92JHC1433>. 

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. 

C-Terminal ketone derivatives of peptides have been used as effective inhibitors for a variety of proteases including serine, cysteine, and aspartyl proteases. 271 This class of peptides includes diazomethyl ketones (Section 15.1.2), halomethyl ketones (Section 15.1.3), and fluoromethyl ketones (Section 15.1.4). In general, the A -amino group and side chain must be protected. The diazomethyl ketones serve as good intermediates for conversion into chloromethyl and bromomethyl ketones. Fluoromethyl ketones, the most widely known class of peptide haloketones, can also be prepared from diazomethyl ketones or by halogen-exchange reactions. Other methods for the synthesis of fluoromethyl ketones are described in Section 15.1.4. 

The diazomethyl ketone functional group was first observed to be an affinity label by Buchanan and co-workers who showed that the antibiotic azaserine, an O-diazoacetyl derivative, 9 inhibited an enzyme in the biosynthesis of purine by alkylation of a cysteine residue. 10 The acid protease pepsin was then observed to be inhibited by peptidyl diazomethyl ketones in the presence of copper ions with the resulting esterification of an aspartate residue. 11 Two peptidyl diazomethyl ketones, Z-Phe-CHN2 and Z-Phe-Phe-CHN2, were found to irreversibly inactivate papain, a cysteine protease. 12 Since these reports, many peptidyl diazomethyl ketones have been prepared primarily as inhibitors of various cysteine proteases. 7 Peptidyl diazomethyl ketones are also synthetic intermediates and have been used to prepare chloromethyl ketones (Section 15.1.3), 13 bromomethyl ketones (Section 15.1.3), acyloxymethyl ketones, 14 and (i-peptides. 15 A few peptidyl diazoalkyl ketones have been reported. 16,17 ... 

Peptidyl bromomethyl ketones (Scheme 2) are synthesized by the same method used to prepare chloromethyl ketones (Scheme 1) namely, the reaction of peptidyl diazomethyl ketones with HBr. 16-18 This reaction proceeds readily for either chloromethyl or bromomethyl ketones, although a contaminant, the N-methylated compound, is usually observed in the final reaction product. 1 A variation of this method involves the use of LiBr, which facilitates the formation of acid-sensitive protected amino acids. 1 As with the chloromethyl synthesis, only Z and Boc should be used to protect the amino acids. 3 Although the reaction of diazo ketones with HBr is well known and relatively simple, only a few compounds have been synthesized (Table 2). 

Table 2 Peptidyl Bromomethyl Ketones Synthesized by Reaction of HBr with Peptidyl Diazomethyl...

Unlike the synthesis of chloromethyl and bromomethyl ketones, iodomethyl ketones cannot be synthesized simply by reacting a diazomethyl ketone with HI, since this reaction generally leads to the formation of the methyl ketone instead. To resolve this difficulty, iodomethyl ketones 8 are generally synthesized by reacting a chloro- or bromomethyl ketone 7 with Nal in acetone (Scheme 3).[1 3]... 

Bromination of the methyl group can be restricted to monosubstitution when the reaction is carried out in acidic media. The mechanism involves protonation of the carbonyl-oxygen, followed by proton loss to give the enol. After monobromination, protonation of the bromoketone is less favourable owing to the presence of the electron-withdrawing halogen atom. Further enolisation does not occur therefore and halogenation ceases (contrast the behaviour of methyl ketones on bromination under alkaline conditions, p. 667) the product is an aryl bromomethyl ketone or phenacyl bromide. 

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. 

The ethylene acetals of aryl bromomethyl ketones alkylated sodium benzenetellurolate as expected11. 

Alkylation of the salicylamide 375 with aryl bromomethyl ketones 376, followed by the acid-mediated cyclocondensation of intermediates 377 under DeanStark reflux conditions give the oxazepinones 378 in high yield (Scheme 203) C2002BML2367, CHEC-III(13.09.9.1)272>. 

Bromomethyl ketones. Aldehydes can be converted into bromomethyl ketones by reaction with the anion of bromomethyl phenyl sulfoxide to form a p-hydroxy-a-bromo sulfoxide followed by pyrolysis in xylene or diglyme (equation I). ... 

BROMOMETHYL KETONES Bromo-methyl phenyl sulfoxide. 

The side chain of His-57 is close enough to that of Ser-195 for a hydrogen bond to form between N-3 and the oxygen of the serine hydroxyl group. N-1 is shielded from solvent molecules. N-3 is selectively alkylated by the chloromethyl ketone and bromomethyl ketone inhibitors of serine proteases. These have the structure, R—C—CH2— X, where X... 

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. 

Besides bromoacetone, other bromomethyl ketones (BrCH2COR) can be used if they are available. Bromination is best carried out with cupric bromide as the reagent, and on ketones in which R contains no a-hydrogens to compete with those on methyl acetophenone, for example, or methyl /er/-butyl ketone. 

Alkylation of pyrathione 71a-b with arenyl bromomethyl ketones R COCHjBr (R = Ph, 4-BrC6H4, 4-MeOC6H4, 4-MeC6H4, 2-naphthyl, 2-thienyl, PhCH = CH) gives pyrylium bromides 72 in 60-95% yields (Scheme... 

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