A-bromination of ketones

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 compound is a brominating agent similar to pyridinium bromide perbromide but more stable. It is very soluble in tetrahydrofurane and is employed in this solvent for the a-bromination of ketones and cyclic ketals, for example ... 

Bromination. The reagent is useful for selective a-bromination of ketones. It is converted into N,N-dimethylcyanoacetamide, which can be recycled. 

SCHEME 13.33. Enamine-catalyzed asymmetric a-bromination of ketones. 

Synthesis of 2-amino oxazole analogues (Method I) a-Bromination of ketones 33 using copper (11) bromide followed by the treatment with excess urea in tert-butanol, and finally trimethylsilyl bromide (TMSBr)-mediated removal of the phos-phonate diethyl ester produced oxazole phosphonie aeids 34 [77] (Scheme 12.8). 

Method II) a Bromination of ketones 35 using eopper (II) bromide and cyclisa-tion of the resulting bromide with excess R2CONH2 in tert-butanol followed by TMSBr-mediated removal of the diethyl ester gave oxazoles 36 [77],... 

Interconversion a results in logical synthons, alkoxy anion TM 5.4a and acyl cation TM 5.4b. The reagent for anionic synthon is a-hydroxy ketone, available by a-bromination of ketone followed by hydrolysis of halogen. Now we observe that disconnection b offers a more simple solution. Since the reagent for TM 5.4c is a-haloketone, this intermediate can be directly acylated by carboxylate anions to TM 5.4. The complete synthetic proposal for TM 5.4 is presented in Scheme 5.12. Synthesis of enantiomerically pure a-alkylcarboxylic acids is discussed in Sect. 3.6.3. 

Moreover, this catalytic oxidative bromination using cat. NHiVOs/AlBrs/Oa system can be applied to the a-bromination of ketones (Table 2.2) [188]. The hromina-tion reaction of p-keto esters such as ethyl benzoylacetate occurs to give mouo- or dibromination products depending on the amount of AlBr3 (entries 1 and 2). Substitution at a-position leads to the formation of the monobrominalion product (entry 3). 4 -Methoxyacetophenone is converted to the monobromide together with the dibromide. Bromination reaction of 4 -chloroacetophenone affords the monobromide as a major product (entry 4). The trihalo compound is obtained from... 

As in the chlorination case, (4/ ,5/ )-4,5-diphenyhmidazohdine has been apphed for the a-bromination of ketones. The best brominating agent was again the compound 101b, with the presence of benzoic acid in the reaction mixture being compulsory. The brominated ketones were isolated with up to 91% ee, after reduction to the corresponding alcohols [131],... 

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 ... 

Carboxylic acids, a-bromination of 55, 31 CARBOXYLIC ACID CHLORIDES, ketones from, 55, 122 CARBYLAMINE REACTION, 55, 96 Ceric ammonium nitrate [Ammonium hexa mtrocerate(IV)[, 55, 43 Chlorine, 55, 33, 35, 63 CHROMIUM TRIOXIDE-PYRIDINE COMPLEX, preparation in situ, 55, 84 Cinnamomtnle, a-phenyl- [2-Propeneni-tnle 2,3-diphenyl-], 55, 92 Copper(l) iodide, 55, 105, 123, 124 Copper thiophenoxide [Benzenethiol, copper(I) salt], 55, 123 CYCLIZATION, free radical, 55, 57 CYCLOBUTADIENE, 55, 43 Cyclobutadieneiron tricarbonyl [Iron, tn-carbonyl(r)4-l,3-cyclo-butadiene)-], 55,43... 

Djerassi et al. have already demonstrated the use of pyridinium hydrobromide perbromide for efficient a-bromination of steroid ketones (ref. 23). Cacchi et al. 

Ketimines, enamines from, in ketones alkylation, 54, 48 Ketone, aralkyl, selective a-bromination of, 53, 111 Ketone, a,a -dibromodineopen-tyl-, preparation of, 54,... 

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. 

The reaction of unsaturated hydrocarbons with bromine is synthetically important. Unsaturated fatty acids have been electrobrominated in an acetic acid/acetonitrile medium and at platinum electrodes [128]. The mechanism and rate constant for the process with oleic, erucic, and linoleic acid were elucidated. The a-bromination of a,f-unsaturated ketones has been reported [129] on the basis of the electrolysis of a substrate/CF3COOH/CuBr/Et4NOTs/ MeCN reaction system. CuBr is present as a catalyst. 

Carbon monoxide, 57, 11 Carbonyl compounds, 56, 36 Carboxylic acids, a-bromination of, 55, 31 CARBOXYLIC ACID CHLORIDES, ketones from, 55, 122 CARBYLAMINE REACTION, 55, 96 Carcinogens, list of. 56, 128 58, 168 Carveol, 56, 106 Carveol acetate, 56, 106 Catechols, 58, 125... 

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). 

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