Bromination of enolates

Bromination of enol acetates of aldehydes with subsequent reaction of the brominated product with methanol furnishes a novel synthesis of a-bromoaldehyde acefbls. 

Molecular bromine is normally used to prepare bromoketones, but some interesting results have been obtained by the use of cupric bromide in boiling tetrahydrofuran [153]. The reagent is remarkably selective and does not attack C=C double bonds. Its action may be to provide bromine at such low concentration as to permit selective bromination of enols under kinetic control. As an alternative, cupric bromide could conceivably act directly as a source of electrophilic bromine. 

This should remind you of the bromination of enols in Chapter 21. 

Avoidance by choice of oxygenated starting materials Oxidation through Lithiation and Ort/ro-Lithiation Hydroxylation of Pyridines by ortho-Lithiation Synthesis of Atpenin B Introducing OH by Nucleophilic Substitution Part II - Oxidation of Enols and Enolates Direct Oxidation without Formation of a Specific Enol Selenium dioxide Nitrosation with nitrites Nitrosation with stable nitroso compounds Indirect Oxidation with Formation of a Specific Enol Enone Formation Pd(II) oxidation ofsilyl enol ethers Bromination of enols in enone formation Sulfur and selenium compounds in enone formation Asymmetric Synthesis of Cannabispirenones... 

Bromination of lithium enolates Bromination of enol ethers... 

Ketones can be converted to a-imidoketones by a one-pot cascade reaction, whereby A-bromosuccinimide provides both electrophilic bromine (for a-bromination of enolate) and nucleophilic nitrogen in conjugation with diazabicyclo[5.4.1]undec-7-ene (DBU) as activator. ... 

A classical reaction leading to 1,4-difunctional compounds is the nucleophilic substitution of the bromine of cf-bromo carbonyl compounds (a -synthons) with enolate type anions (d -synthons). Regio- and stereoselectivities, which can be achieved by an appropiate choice of the enol component, are similar to those described in the previous section. Just one example of a highly functionalized product (W.L. Meyer, 1963) is given. 

Rates of enolization can be measured in several wt s. One method involves determining the rate of halogenation of the ketone. In the presence of a sufficient concentration of bromine or iodine, halogenation is much faster than enolu ation or its reverse and can therefore serve to measure the rate of enolization ... 

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... 

Two surprising observations were made in the course of this work first that the enol acetate (5) is stable under the conditions for formation of (6) from (4) second, that the course of the buffered bromination of (5) depends on the conditions used. Thus, in the presence of epichlorohydrin, (7) is the sole isomer produced, whereas in pyridine-acetic acid approximately equal amounts of (7) and (8) are formed. It was suggested that this difference is inherent in the mechanism and not a result of isomerization of (7) to (8) during the course of the reaction. 

In general bromination of 20-ketones is directed to the introduction of functionality at C-21. However, on occasion 17-bromo compounds are required for dehydrobromination to A -20-ketones, although these are generally obtained in other ways. Kinetic enolization of a 20-ketone gives the A °-enol, whereas the thermodynamic product is the A kjsomer. An interesting enolate trapping reaction has been used recently to prepare 16-methyl-A -20-ketones ... 

In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

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. ... 

A convenient synthesis of A -3-ketones in the 5 5 series uses DDQ in one step. This introduction has to be done indirectly because of the unfavorable direction of enolization. In this scheme, advantage is taken of the equilibrated formylation at C-2 of 5i5-3-ketones. Dehydrogenation of the 2-formyl derivative (72) proceeds rapidly with DDQ and deformylation is achieved in the presence of a homogeneous catalyst. A related approach involves preparation of the 2i -bromo-5i5-3-ketone by bromination of the 2-formyl compound (72). ... 

Bromination of the enolate anion from the reaction of 3j -acetoxypregna-5,16-dien-20-one (1) with methylmagnesium bromide in the presence of cuprous chloride affords (after treatment with sodium iodide to dehalo-genate any 5,6-dibromide) a mixture of 17a-bromo- and 17)5-bromo-16a-methyl compounds (11) and (12) in a ratio 9 1. The 17a-iodides can be obtained in an analogous reaction. 

Fluorination of an enamine, enol ether, or enol acetate with CF3OF gave 60-70% yields of fluoroketone (708). Bromination of an endiamine gave the bis-imonium salt (647). 

The rx bromination of carbonyl compounds by Br2 in acetic acid is limited tc aldehydes and ketones because acids, esters, and amides don t enolize to a suffi cient extent. Carboxylic acids, however, can be a brominaled by a mixture of Br and PBr3 in the HeJI-Volhard-Zelinskii (HVZ) reaction. 

Carbonyl compounds are in a rapid equilibrium with called keto-enol tautomerism. Although enol tautomers to only a small extent at equilibrium and can t usually be they nevertheless contain a highly nucleophilic double electrophiles. For example, aldehydes and ketones are at the a position by reaction with Cl2, Br2, or I2 in Alpha bromination of carboxylic acids can be similarly... 

Zeroth-order kinetics. The rate of bromination of acetone in acidic aqueous solution is governed by the enolization step. With [(CH3>2CO]o s> [B lo, the reaction rate is... 

When a substituent is able to resonantly stabilize the positive charge of the ionic intermediate, there is no bromine bridging and the intermediate is an open P-bromocarbocation. These carbocations have been shown to occur in the bromination of a-methylstilbenes (ref. 9), 1 and 2, and of a variety of enol ethers (ref. 10) and acetates (ref. 11). 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

This ester was prepared by bromination of glutaconaldehyde enol benzoate. 

There are also procedures in which the enolate is generated quantitatively and allowed to react with a halogenating agent. Regioselectivity can then be controlled by the direction of enolate formation. Among the sources of halogen that have been used under these conditions are bromine,125 (V-chlorosuccinimide,126 trifluoromethanesul-fonyl chloride,127 and hexachloroethane.128... 

Formal isomerization of the double bond of testosterone to the 1-position and methylation at the 2-position provides yet another anabolic/androgenic agent. Mannich condensation of the fully saturated androstane derivative 93 with formaldehyde and di-methylamine gives aminoketone 94. A/B-trans steroids normally enolize preferentially toward the 2-position, explaining the regiospecificity of this reaction. Catalytic reduction at elevated temperature affords the 2a-methyl isomer 95. It is not at all unlikely that the reaction proceeds via the 2-methylene intermediate. The observed stereochemistry is no doubt attributable to the fact that the product represents the more stable equatorial isomer. The initial product would be expected to be the p-isomer but this would experience a severe 1,3-diaxial non-bonded interaction and epimerize via the enol. Bromination of the ketone proceeds largely at the tertiary carbon adjacent to the carbonyl (96). Dehydrohalogenation... 

The very small p- and m-values observed for the fast bromination of a-methoxystyrenes deserve comment since they are the smallest found for this electrophilic addition. The rates, almost but not quite diffusion-controlled, are amongst the highest. The sensitivity to polar effects of ring substituents is very attenuated but still significant that to resonance is nil. These unusually low p-values for a reaction leading to a benzylic carbocation are accompanied by a very small sensitivity to the solvent. All these data support a very early transition state for this olefin series. Accordingly, for the still more reactive acetophenone enols, the bromination of which is diffusion-controlled, the usual sensitivity to substituents is annulled. 

The determination of the lifetime of the ionic intermediates using the azide-clock method has been however useful in showing that electrophilic addition of Br2 can occur, even through a fully concerted mechanism, definable as SN2-like. Bromination of cyclic enol ethers (glycals) 8-10 in methanol in the presence of... 

Experiment.—One drop of ferric chloride solution is added to a few drops of an aqueous solution of acetylacetone. The reaction characteristic of enols takes place. If now the solution is cooled in ice and dilute bromine water is rather quickly added, the red colour of the iron enolate disappears for a short time and then returns rapidly. 

Thus it has been possible to show that in the bromination of acetone, a process which has been found to be unimolecular, not the normal keto-form, but the tautomeric enol-form reacts. The enol-form is present, in equilibrium with the keto-form, in amount too small to be measured. As soon as this amount has reacted a further quantity is formed and the process is repeated. That the reaction is unimolecular follows from the fact that it is the rate of rearrangement (I) which is measured, whilst the reaction of the enol with bromine (II) takes place with immeasurable rapidity (Lapworth). 

---