Bromination of ketones

Regioselective bromination of ketones at the mote highly substituted a-position is effected by photocatalytic bromination in the presence of 1,2-epoxycyclohexane (37). 

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... 

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

Evidence that carbanion intermediates, e.g. (44), are involved is provided by carrying out the decarboxylation in the presence of bromine. This is without effect on the overall rate of the reaction but the end-product is now Me2CBrN02 rather than Me2CHN02— under conditions where neither Me2C(NO2)CO20 nor Me2CHN02 undergoes bromination. The bromo product (45) arises from rapid attack of Br2 on the carbanion intermediate (44), which is thereby trapped (cf. the base-catalysed bromination of ketones, p. 295) ... 

Bromination of ketone 303 gives monobromide 304a and dibromide 304b (65JOC1523) whereas the electrochemical fluorination of parent compound 2 (84JAK59204192) provides a second, smooth path to perfluoro derivative 54 already mentioned. 

Another reaction in which the cleavage of a carbon-hydrogen bond is important is the bromination of ketones. In the bromination of ethyl acetoacetate and 2-carboethoxycyclopentanone, it was shown that multivalent cations are catalysts. In the latter reaction, cupric, nickelous, lanthanum, zinc, plumbous, manganous, cadmium, magnesium, and calcium ions were effective (45). One can interpret the effect of the metal ion in terms of its catalysis of the proton transfer from the ester to a base, whether the reaction is carried out in dilute hydrochloric acid solution (acid-catalyzed bromination) or in acetate buffer (base-catalyzed bromination). 

Phenyltrimethylammonium bromide perbromide (PhMe3N Br3) was introduced as a reagent for the bromination of cyclic ketals81 (see section IV) but it has also been utilized for the selective bromination of ketones containing double bonds.82 The same claim has been made for cupric bromide as a brominating agent 83 yields are not good, however, and in methanol, the solvent usually employed, the formation of methoxy-substituted products is a common side reaction (cf. ref. 84, 85). 

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. 

The base-promoted bromination of ketones is a second-order process, first order in ketone and first order in base dius v = /c ketone base. The bromine concentration does not appear in die rate law that is, the reaction is zero order in [Br2]. 

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... 

The key step in the synthesis was bromination of ketone 59, followed by hydrogenation to liberate the free guanidine, which underwent an intramolecular Sn2 reaction to form the tetrahydropyrimidine ring B. Further hydrogenation reduced the ketone to yield 42% of 63 containing the fully functionalized tricyclic system and protected hydroxymethyl-uracil side chain of cylindrospermopsin. Hydrolysis of the pyrimidine of 63 in concentrated hydrochloric acid at reflux and selective monosulfation completed the synthesis of cylindrospermopsin. 

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. 

Bromination of ketone 3.17 gives 3.18 which can be converted to azide 3.19. Hydrogenation of 3.19 in the presence of hydrochloric acid affords aminoketone hydrochloride salt 3.20. Such aminoketones are often isolated as the corresponding salts because the free aminoketones are prone to dimerisation, having both nucleophilic and electrophilic centres. (For a common alternative preparation of aminoketones, see the Knorr pyrrole synthesis, Chapter 2.) Liberation of the free base of 3.20 in the presence of the acid chloride affords amide 3.21 which is cyclised to oxazole 3.22. Ester hydrolysis then affords the biologically-active carboxylic acid 3.23. 

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... 

Notice that the acid catalyst is regenerated at the end of the reaction. The reaction need not be carried out in an acidic solvent, or even with a protic acid at all. Lewis acids make excellent catalysts for the bromination of ketones. This example with an unsymmetrical ketone gives 100% yield of the bromoketone with catalytic AICI3 in ether as solvent. 

Bromination of ketones can be carried out with molecular bromine in a carboxylic acid solution. Give a mechanism for the reaction. 

The rate of the reaction is not proportional to the concentration of bromine [Br2]. Suggest an explanation. Why is the bromination of ketones carried out in acidic and not in basic solution ... 

Acetic acid, CH3CO2H Used as a solvent for the reduction of ozonides with zinc (Section 7.9) and the a-bromination of ketones and aldehydes with Br2 (Section 22.3). 

While bromine itself can be used to effect a-bromination of ketones, the Itydrogen bromide produced can be detrimental. o The addition of acid scavengers such as 1,2-epoxycyclohexane (equation 1)1 or potassium perchloratecan, however, lead to good yields in the more difficult cases. As with copper(II) salts, the conditions for elemental bromine also favor substitution at the more highly substituted carbon atom. 

A thoughtful reader would have noticed that, while plenty of methods are available for the reductive transformation of functionalized moieties into the parent saturated fragments, we have not referred to the reverse synthetic transformations, namely oxidative transformations of the C-H bond in hydrocarbons. This is not a fortuitous omission. The point is that the introduction of functional substituents in an alkane fragment (in a real sequence, not in the course of retrosynthetic analysis) is a problem of formidable complexity. The nature of the difficulty is not the lack of appropriate reactions - they do exist, like the classical homolytic processes, chlorination, nitration, or oxidation. However, as is typical for organic molecules, there are many C-H bonds capable of participating in these reactions in an indiscriminate fashion and the result is a problem of selective functionalization at a chosen site of the saturated hydrocarbon. At the same time, it is comparatively easy to introduce, selectively, an additional functionality at the saturated center, provided some function is already present in the molecule. Examples of this type of non-isohypsic (oxidative) transformation are given by the allylic oxidation of alkenes by Se02 into respective a,/3-unsaturated aldehydes, or a-bromination of ketones or carboxylic acids, as well as allylic bromination of alkenes with NBS (Scheme 2.64). 

The halogenation of positions adjacent to a carbonyl group takes place via the electrophilic attack of a halonium ion on the enol. Thus the bromination of ketones may be carried out with bromine in acetic acid. 

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