Enols: bromination derivatives

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

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... 

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. 

N-Iodosuccinimide reacts with enol acetates derived from ketones to give a-iodoketones, and the reaction has found application in the steroid field/ The iodination of the enol acetates seems to proceed by an ionic mechanism, and preliminary work indicates that N-iodosuccinimide is not capable of at least some of the radical-chain iodinations analogous to radical-chain brominations brought about by N-bromosuccinimide. ... 

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]. 

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). 

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). ... 

Very little is known concerning the simple, monocyclic 3-hydroxy-furans (cf. reference 15). Both the oxo and hydroxy forms of the substituted 3-hydroxyfurans 26 and 27 (R = H, CcHn) have been isolated/ but the individual tautomers slowly undergo interconversion. The enol forms give a positive reaction with ferric chloride, react rapidly with bromine, and form a peroxide with oxygen. From chemical evidence, the benzo derivatives of 3-hydroxyfuran, 28 and 29, appear to exist predominantly in the oxo form, and this is further supported by ultraviolet spectral data. Stefanye and Howard- ... 

In the following the reaction is outlined for an a-bromination. The reaction mechanism involves formation of the corresponding acyl bromide 3 by reaction of carboxylic acid 1 with phosphorus tribromide PBr3. The acyl bromide 3 is in equilibrium with the enol derivative 4, which further reacts with bromine to give the a -bromoacyl bromide 5 ... 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives. Acyl halides can be a brominated or chlorinated by use of NBS or NCS and HBr or HCl. The latter is an ionic, not a free-radical halogenation (see 14-2). Direct iodination of carboxylic acids has been achieved with I2—Cu acetate in HOAc. " ° Acyl chlorides can be a iodinated with I2 and a trace of HI. Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium A-isopropylcyclohexylamide in THF and treatment of this solution at -78°C with... 

L-dihydroxy-succinic acid (L(dexiro)-tartaric acid, CXIII). This result establishes the position of the double bond between C4 and C5 and demonstrates that C4 carries only one hydrogen atom while C5 has attached to it the enolic hydroxyl group. Treatment of the enol CXI with ethereal diazomethane gives 5-methyl-A4-D-glucosaccharo-3,6-lactone methyl ester (CXIY) which upon further methylation with silver oxide and methyl iodide yields 2,5-dimethyl-A4-D-glucosaccharo-3,6-lactone methyl ester (CXV). When the latter is subjected to ozonolysis there is formed oxalic acid and 3-methyl-L-threuronic acid (CXVI). Oxidation of this aldehydic acid (CXYI) with bromine gives rise to a monomethyl derivative (CXVII) of L-ilireo-dihydroxy-succinic acid. 

A detailed examination of OSO4 reactions with A -steroids has been reported." The A-ring conformation of the reactant or derived complex is important in determining the stereoselectivity of these reactions, and the major role of the proximate substituents is to anchor the appropriate conformation favouring a- or /3-attack. Studies on the stereochemistry of electrophilic attack on cholest-5-en-3-one continue." As with bromine chloride," appreciable /3-attack occurs and the 5/3,6j8-epoxide was isolated along with the previously reported 5a,6a-epoxide and the Baeyer-Villiger product, the A-homo-enol lactone (58). Base-catalysed... 

A synthesis of the B-ring aromatic corticosteroid (286), the analogue of cortex-olone, started with the previously reported B-ring aromatic norpregnane (285). Development of the corticosteroid side-chain employed bromination of the 17a-hydroxy-20-oxo-derivative with trimethylphenylammonium bromide perbromide. " Reaction of perchloryl fluoride with the mixed enol ethers (287) and (288) provided, after hydrolysis, the 17a-fluoro-20-oxo-compound (290) and the 21-fluoro-20-oxo-compound (291). In contrast, the enamine (289) led only to the 17a,21-difluoro-20-oxo-compound. A series of 17a-acyloxy-21-deoxy-... 

Bromide 280 (derived by bromination of silyl enol ether 270) undergoes both zinc- and cerium-mediated cleavage under mild and essentially neutral conditions, and was used to prepare the nucleoside-containing C-glycoside 282 (Scheme 73) [ 112,113], The aldehyde 281 used in this transformation was exceptionally sensitive to basic conditions which completely precluded use of a conventional enolate obtained by deprotonation of ketone 265 (Sect. 4.3.1). 

Careful investigation of the bromination reaction of 3 keto steroids, which leads ultimately to 2,4-dibromo derivatives (see, for example, S-2-5-3), revealed that the sequence starts with the formation of a 2a bromo derivative, a futher demonstration of the preferred enolization of the carbonyl group toward the 2 position. 

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