Enolates bromination

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 formation of the acyl chloride with SOCl2 and the conversion of the a-bromoacyl chloride into the bromoester with MeOH are simple nucleophilic substitutions at the carbonyl group, just like the synthesis of esters from acyl chlorides in Chapter 12. The intermediate stage, the bromination of the very easily enolized acyl chloride, is a typical enol bromination. 

If the ketone is unsymmetrical, this reaction will occur on the more substituted side, for the same reason that acid-catalysed enol bromination gives the more substituted a-bromocarbonyl compound (see the box on p. 536). 

Stereoselective enolate bromination as an approach to a-halo carboxylic acids and a-aminoketones.32 a-Haloketones are useful synthetic intermediates,33 and may be derived from enolates by treatment with sources of electrophilic halide. This methodology has been applied by others34,35 as a stereoselective approach to chiral a-aminoacids. 

Only moderate diastereoselectivity is observed in enolate bromination in these systems, using N-bromosuccinimide as the source of halogen. In this case only, equilibration at the new asymmetric center in the products appears to take place, limiting the available stereoselectivity <95T1285>. 

Unfortunately, the hydrazino esters or amides required inconveniently high pressures for their hydrogenolysis (500 psi Schemes 8.25a and b). An improvement involved the direct azidation of the same enolates using arylazide derivatives, which were found to undergo reactions with enolate nucleophiles to provide a C-sulfonyltriazene intermediate which could be decomposed to the a-azido ester (Scheme 8.25c) [110]. Alternatively, azides may be obtained by enolate bromination followed by Sn2 azide displacement note that these techniques are stereochemically complementary. Similar chemistry has also been accomplished using 10-suIfonamidoisobomyl chiral auxiliaries (Scheme 8.25d) [111]. 

In the first step of the HVZ reaction, PBr3 converts the carboxylic acid into an acyl bromide by a mechanism similar to the one by which PBr3 converts an alcohol into an alkyl bromide (Section 12.3). (Notice that in both reactions PBr3 replaces an OH with a Br.) The acyl bromide is in equilibrium with its enol. Bromination of the end forms the a-brominated acyl bromide, which is hydrolyzed to the a-brominated carboxylic acid. 

Reactions.—An intermediate (71) has been isolated from the bromina-tion of alcohols using triphenylphosphine dibromide in dimethylformamide (Scheme 12). This implies that these reactions are closely related to the Vilsmeier reaction, and further evidence for this view comes from the isolation of a formylated product (72) from the analogous reaction of cholest-5-ene-3)8,4jS-diol (73). The other product (74) appears to be the result of an enol-bromination of the 3-ketone. Two related reactions which substantiate this are the mild reaction between pentane-2,4-dione and triphenylphosphine dibromide in DMF, to give (75), and the formation of 1-chlorocyclohex-l-ene (76) from cyclohexanone and a solution of... 

After deprotonation of its conjugate acid, the a-bromoacyl chloride reacts with a molecule of the starting carboxylic acid to give the product plus another molecule of acyl chloride, which then undergoes enolization, bromination, and so on. 

Bromination of lithium enolates Bromination of enol ethers... 

Stereoselective a-halogenation of enolates is an important approach for the generation of synthetically versatile, chiral building blocks. By use of an auxiliary approach, the acylated oxazolidinone derivatives developed by Evans have been showcased in diastereoselective enolate brominations (Scheme 3.33) [125]. Enolization of 226 (BujBOTf, amine base) and exposure of the boron enolate to NBS affords 228 in 95 5 dr. A key application of the bromo imides is their facile conversion into azides upon treatment with tetramethylguanidinium azide (229). The resulting azides such as 230 (dr=95 5) can readily be elaborated into chiral a-amino acids (see also Chapter 10). 

---