Bromine with ketones

A commonly used alternative to the direct bromination of ketones is the halogenation of enol acetates. This can be carried out under basic conditions if necessary. Sodium acetate, pyridine or an epoxide is usually added to buffer the reaction mixture. The direction of enolization is again dependent upon considerations of thermodynamic and kinetic control therefore, the proportion of enol acetates formed can vary markedly with the reaction conditions. Furthermore, halogenation via enol acetates does not necessarily give the same products as direct halogenation of ketones 3. 23... 

Bromination of 5j5-3-ketones yields the equatorial 4 -bromo compounds (22) as the thermodynamic or kinetic products,although the presence of a considerable amount of 2-bromo isomer has been reported in bromination with phenyltrimethylammonium bromide-perbromide. This is in keeping with other evidence that enolization of 5j5-3-ketones is not specifically directed to C-4. Cleaner results would probably be obtained via thermodynamic enol acelylation. ... 

Bromination with A-bromosuccinimide generally gives the same result as bromination with free bromine or hypobromous acid. The reaction is considered to proceed with a small concentration of free bromine and does not generate an appreciable concentration of acid. Conditions are therefore mild. In addition, A-bromosuccinimide has been used to brominate the allylic position of a, -unsaturated ketones in the presence of free-radical promoters or with irradiation, and thus gives access to dienones by dehydro-halogenation, for exaraple " ... 

A -Bromosuccinimide has been used in combination with benzyl alcohol for the bromination of ketones ... 

The key structural features of compound 1 are the chiral cis-diaryl benzox-athiin fused ring system, two phenols, and one phenol ether linkage with the pyrrolidinylethanol. Originally, SERM 1 was prepared by medicinal chemists from a key ketone intermediate 5 shown in Scheme 5.1. Compound 5 was prepared in four steps with rather low yield [4a], Among these steps, the high temperature de-methylation step and the use of extremely toxic MOM-C1 were not particularly suitable for scale-up. The ketone 5 was then brominated with PhMe3NBr3 (PTAB) and coupled with thiophenol 7 to produce adduct 8. The key step of the synthesis was the conversion of adduct 8 to cis-diaryl benzoxathiin 9 under the Kursanov-Parne reaction conditions (TFA/Et3SiH). This novel reaction allowed the formation... 

With ketones such as (94), that have alternative groups of a-H atoms to attack, two questions arise (a) which group, the CH2 or the CH3, is attacked preferentially, and (b) when one H has been substituted by halogen, will a second halogen become attached to the same or to the other a-carbon atom. So far as (a) is concerned, it is found that bromination of, for example, MeCH2COCH3, yields 1- and 3-bromobutanones in virtually equal amount (both these bromoketones then undergo very rapid further reaction, cf. p. 296). The inductive effect exerted by a simple alkyl group, R, thus appears to have relatively little effect on the acidity of H, or on the... 

However, intramolecular O-alkylation can be performed under particular conditions leading to of annelation of a seven-membered heterocycle. Japanese researchers (170) prepared the corresponding seven-membered cyclic nitronates (50a-c) in good yields by the reaction of triethylamine with brominated aryl ketones (49a-c) containing the nitromethyl group in the ortho position. 

Boron trifluoride etherate, co-catalyst, 53, 30, 32 a-Bromination, selective of aralkyl ketone, 53, 111 Bromine, with 3-chlorocyclo-butanecarboxylic acid and mercuric oxide to give 1-bromo-3-chlorocyclobutane, 51, 106... 

When the same reaction is performed with adamantanone dinitrophenylhydrazone (DNP) or adamantanone O-mcthyloxime (OMO), the yields of 2,2-difluoroadamantanc are 65 and 50%, respectively. 4-tert-Butylcyclohexanone is converted via its azine, DNP or OMO into 4-tert-butyl-l.l-difluorocyclohexanc in 65, 75 or 50% yield, respectively. Similar results are obtained with aliphatic straight-chain ketones. Decan-2-one azine and decan-2-one DNP can be transformed into 2,2-difluorodecane in 60 and 80% yield. Deactivated aromatic rings, e.g. in 3-nitroacetophenone, do not undergo bromination with bromine trifluoride and the action of 2 equivalents of bromine trifluoride on 3-nitroacetophenone O-methyloxime results in 90% yield of 1-(1. l-difluorocthylj-S-nitrobenzene.122... 

Magnesium-mediated elimination of bromine monofluoride has been reported in the reaction of 2-bromo-2-chloro-l,l,l-trifluoroethane with ketones, e.g. reaction of 5 with octan-2-one. 

Anhydrous tetrahydrofuran contributes to the selectivity of the reagent because of the stability of Brf in this solvent. Moreover, tetrahydrofuran acts as a buifer by reaction with the liberated hydrobromic acid which is why PTT in tetrahydrofuran can also be very useful if the molecule bears acid-sensitive functions. It must be emphasized that anhydrous tetrahydrofuran must be used because small amounts of water can greatly retard the rate of bromination of ketones with resulting decreased selectivity. 

Bromination of ketone 58 could not be accomplished. The alcohol was therefore acetylated with acetic anhydride in pyridine at rt, which gave 87% of a 9 1 mixture of 59 and enol acetate 60. The enol acetate was the... 

A simple method for introducing a triple bond into an organic compound is to treat an appropriate dihalide with a strong base. Since vicinal dihalides (usually the bromide) are readily formed by reaction of bromine with an alkene, and geminal dihalides from aldehydes or ketones with phosphorus pentachloride, the method is a useful general procedure for the preparation of terminal and non-terminal alkynes from readily available starting materials. 

We used this strategy in chapter 6 under two-group C-X disconnections where bromination of ketones was the usual functionalisation. More relevant here are conversions of carbonyl compounds into 1,2-dicarbonyl compounds by reaction with selenium dioxide SeC>2 or by nitrosation. So acetophenone 57 gives the ketoaldehyde10 58 with SeC>2. These 1,2-dicarbonyl compounds are unstable but the crystalline hydrate 59 is stable and 58 can be reformed on heating. Since aromatic ketones such as 57 would certainly be made by a Friedel-Crafts reaction the disconnection 58a is not between the two carbonyl groups and offers an alternative strategy. 

Let us now consider the synthesis of isoxazole 4.28, a drug for the treatment of bronchial asthma. The most direct preparation of isoxazolyl ketone 4.24 is the cycloaddition of unstable bromonitrile oxide 4.22 (prepared in situ by dehydrobromination of 4.21) with acetylenic ketone 4.23. Observe the regioselectivity of this reaction. Both electron-donating and electron-withdrawing groups on the acetylenic components in such cycloadditions tend to occur at the C5 position in the final isoxazole and not at C4. Bromination of ketone 4.24 affords bromoketone 4.25 which is 4.23 n... 

Cyclization of enone (9) in hexane with boron trifluorideetherate in presence of 1,2-ethanedithiol, followed by hydrolysis with mercury (II) chloride in acetonitrile, yielded the cis-isomer (10) (16%) and transisomer (11) (28%). Reduction of (10) with lithium aluminium hydride in tetrahydrofuran followed by acetylation with acetic anhydride and pyridine gave two epimeric acetates (12) (32%) and (13) (52%) whose configuration was determined by NMR spectroscopy. Oxidation of (12) with Jones reagent afforded ketone (14) which was converted to the a, 3-unsaturated ketone (15) by bromination with pyridinium tribromide in dichloromethane followed by dehydrobromination with lithium carbonate and lithium bromide in dimethylformamide. Ketone (15), on catalytic hydrogenation with Pd-C in the presence of perchloric acid, produced compound (16) (72%) and (14) (17%). The compound (16) was converted to alcohol (17) by reduction with lithium aluminium hydride. 

Alcohols are converted to alkyl iodides by reaction with A A-diethyl-aniline/borane/iodine. Reductive iodination is observed when this system reacts with ketones or with carboxylic acids934,935. Direct reduction of aromatic aldehydes to benzyl bromide is reported by Le Corre and coworkers, who have brominated benzaldehydes and acetophenones in presence of a trimethylamine/borane complex and have obtained benzyl bromides and a-bromoethylbenzenes, respectively936. See also Reference937. 

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