Enolate bromination

Whereas methods of synthesising tetronic acids are plentiful, no one method has received general approval. The simplest tetronic acids have been the hardest to prepare readily in reasonable quantity. Zimmet et a/.155 have revived Kummler s method for the preparation of tetronic acid itself, the cyclization of a,y-dibromoacetoacetic ester being achieved simply by heat. A similar and very effective cyclization (Scheme 37) of a brominated enol... 

Bromine Enol form of acyl chloride Bromide Conjugate acid of... 

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. 

Participation by the oxygen lone pairs is responsible for the rapid attack on the carbon-carbon double bond of an enol by bromine We can represent this participation explicitly... 

Writing the bromine addition step m this way emphasizes the increased nucleophilicity of the enol double bond and identifies the source of that increased nucleophilicity as the enolic oxygen... 

Rapid halogenation of the a carbon atom takes place when an enolate ion is generated m the presence of chlorine bromine or iodine... 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

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 ... 

The distribution of a-bromoketones formed in the reaction of acetylcyclopentane with bromine was studied as a function of deuterium substitution. On the basis of the data given below, calculate the primaiy kinetic isotope effect for enolization of... 

Enolization is the rate-determining step in the halogenation of normal ketones. Where alternate directions for enolization exist, the preferred direction (and hence the position of kinetic bromination) depends on the substituents and stereochemistry. Furthermore, the orientation of the bromine introduced depends on stereochemical and stereoelectronic factors. 

The most familiar example of these effects is the enolization of A B cw-and A B fra j-3-ketones. Thus, in the 5a-series enolization towards C-2 is favored, while in 5jS-compounds enolization towards C-4 predominates. This preference is attributed to relief of nonbonding interactions in the enol form. Brominations are generally run in the presence of acid in order to... 

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. ... 

The selectivity is probably impaired by bromination at C-2 and C-9. Bromination under buffered conditions of the A -enol acetate prepared from acetic anhydride with perchloric acid catalysis may give better results. See also ref. 55 for a similar bromination. 

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. 

The sensitivity of this ketol side chain to acid or base requires careful control of the hydrolysis of the epoxyacetate. Alternatively, the enol acetate can be brominated and the resulting bromo ketone converted to the 21-acetoxy-20-ketone ... 

The mechanism presumably involves partial opening of the ketal to permit enol formation, followed by bromination and reclosing of the ketal ... 

As in the acid-catalyzed halogenation of aldehydes and ketones, the reaction rate is independent of the concentration of the halogen chlorination, bromination, and iodination all occur at the same rate. Fomnation of the enolate is rate-detemnining, and, once fomned, the enolate ion reacts rapidly with the halogen. 

Each act of proton abstraction from the a carbon converts a chiral molecule to an achiral enol or enolate ion. The 5/) -hybridized carbon that is the chirality center in the starting ketone becomes 5/) -hybridized in the enol or enolate. Careful kinetic studies have established that the rate of loss of optical activity of 5cc-butyl phenyl ketone is equal to its rate of hydrogen-deuterium exchange, its rate of bromination, and its rate of iodina-tion. In each case, the rate-detennining step is conversion of the starting ketone to the enol or enolate anion. 

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