Bromination stereochemistry

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). 

Entries 1 and 2 in Scheme 2.9 are typical of concerted syn addition to alkene double bonds. On treatment with peroxyacetic acid, the Z-alkene affords the cis-oxirane, whereas the -alkene affords only the iraws-oxirane. Similarly, addition of dibromocarbene to Z-2-butene yields exclusively l,l-dibromo-cw-2,3-dimethylcyclopropane, whereas only 1,1-dibromo-/ra 5-2,3-dimethylcyclopropane is formed from -2-butene. There are also numerous stereospecific anti additions. Entiy 3 shows the anti stereochemistry typical of bromination of simple alkenes. 

The study of the stereochemical course of organic reactions often leads to detailed insight into reaction mechanisms. Mechanistic postulates ftequently make distinctive predictions about the stereochemical outcome of the reaction. Throughout the chapters dealing with specific types of reactions, consideration will be given to the stereochemistry of a reaction and its relationship to the reaction mechanism. As an example, the bromination of alkenes can be cited. A very simple mechanism for bromination is given below ... 

According to this mechanism, a molecule of bromine becomes complexed to the double bond of the alkene, and reorganization of the bonding electrons gives the product. This mechanism can be shown to be incorrect for most alkenes on the basis of stereochemistry. Most alkenes give bromination products in which the two added bromines are on opposite sides of the former carbon-carbon double bond. The above mechanism does not account for this and therefore must be incorrect... 

The stereochemistry of chlorination can be explained in similar terms. Chlorine would be expected to be a somewhat poorer bridging group than bromine because it is less polarizable and more resistant to becoming positively charged. Comparison of the data for bromination and chlorination of E- and Z-l-phenylpropene confirms this trend (see Table 6.2). Although anti addition is dominant in bromination, syn addition is slightly preferred... 

The stereochemistry of both chlorination and bromination of several cyclic and acyclic dienes has been determined. The results show that bromination is often stereo-specifically anti for the 1,2-addition process, whereas syn addition is preferred for 1,4-addition. Comparable results for chlorination show much less stereospeciftcity. It appears that chlorination proceeds primarily through ion-pair intermediates, whereas in bromina-hon a stereospecific anfi-l,2-addition may compete with a process involving a carbocation mtermediate. The latter can presumably give syn or anti product. 

The stereochemistry of addition is usually anti for alkyl-substituted alkynes, whereas die addition to aryl-substituted compounds is not stereospecific. This suggests a termo-iecular mechanism in the alkyl case, as opposed to an aryl-stabilized vinyl cation mtermediate in the aryl case. Aryl-substituted alkynes can be shifted toward anti addition by including bromide salts in the reaction medium. Under these conditions, a species preceding the vinyl cation must be intercepted by bromide ion. This species can be presented as a complex of molecular bromine with the alkyne. An overall mechanistic summary is shown in the following scheme. 

Further evidence for a bromine-bridged radical comes from radical substitution of optically active 2-bromobutane. Most of the 2,3-dibromobutane which is formed is racemic, indicating that the stereogenic center is involved in the reaction. A bridged intermediate that can react at either carbon can explain the racemization. When the 3-deuterated reagent is used, it can be shown that the hydrogen (or deuterium) that is abstracted is replaced by bromine with retention of stereochemistry These results are also consistent with a bridged bromine radical. 

This stereochemistry can be explained in terms of a bromine-bridged intermediate. 

This result shows than the initially added trichloromethyl group has little influence on the stereochemistry of the subsequent bromine atom-abstraction. The intermediate 2-(trichlor-omethyl)cyclohexyl radical presumably relaxes to the equatorial conformation faster than bromine-atom abstraction occurs. In contrast with addition to A -octahydronaphthalene, the addition is exclusively /ran -diaxial ... 

The /rans-fiised decalin system is conformationally rigid, and the stereochemistry of the product indicates that the initial addition of the trichloromethyl radical is from the axial direction. This would be expected on stereoelectronic grounds, because the radical should initially interact with the n orbital. The axial trichloromethyl group then shields the adjacent radical position enough to direct the bromine abstraction in the trans sense. 

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. 

In spite of these rationali2ations, the stereochemistry of ketone halogenation retains some puzzling features. For example, the effect of a 2-methyl substituent on the direction of bromination at C-2 is unexpected. 

R = 4-C6H5-C6H4 Table 2. Stereochemistry of lonie Addition of Bromine [7] ... 

Table 3. Stereochemistry of Free-Radical Bromine Addition [5] 4-H02CCgH4CF=CFX 4-H02CCgH4CFBtCFXBr...

Allylic bromination of pregnenolone acetate with dibromodi-methylhydantoin affords the 7-bromo compound (155) of undefined stereochemistry. Dehydrobromination by means of collidine followed by saponification affords the 5,7 endocyclic cis,cis-diene, 156. This compound contains the same chromophore as ergosterol, a steroid used as a vitamin D precursor. The latter displays a complex series of photochemical reactions among the known products is lumisterol, in which the stereochemistry at both C9 and Cio is inverted. Indeed, irradiation of 156 proceeds to give just such a product (158). This reaction can be rationalized by... 

When the halogenation reaction is carried out on a cycloalkene, such as cyclopentene, only the trews stereoisomer of the dihalide addition product is formed rather than the mixture of cis and trans isomers that might have been expected if a planar carbocation intermediate were involved. We say that the reaction occurs with anti stereochemistry, meaning that the two bromine atoms come from opposite faces of the double bond—one from the top face and one from the bottom face. 

How does the formation of a bromonium ion account for the observed anti stereochemistry of addition to cyclopentene If a bromonium ion is formed as an intermediate, we can imagine that the large bromine atom might "shield" one side of the molecule. Reaction with Br ion in the second step could then occur only from the opposite, unshielded side to give trans product. 

HC1, HBr, and HI add to alkenes by a two-step electrophilic addition mechanism. Initial reaction of the nucleophilic double bond with H+ gives a carbo-cation intermediate, which then reacts with halide ion. Bromine and chlorine add to alkenes via three-membered-ring bromonium ion or chloronium ion intermediates to give addition products having anti stereochemistry. If water is present during the halogen addition reaction, a halohydrin is formed. 

Bromine and chlorine also add to alkynes to give addition products, and trans stereochemistry again results. 

Regioselective addition of bromine azide to dienes 38 at 25 °C gave the 1,4-adducts 39 or the 1,2-adducts 40 as thermodynamically favored products, their ratios depending on the substituent R on the terminal carbon (Scheme 2.12). These adducts were easily converted into vinylaziridines 41 on treatment with trimethyl-phosphite, although the stereochemistries of 39, 40, and 41 are unclear [23]. 

Treatment of a-alkoxy-substituted iron acyl complexes 20 with bromine in the presence of an alcohol produces free acetals 22 with loss of stereochemistry at the center derived from the a-carbon of the starting complexl2,49. Electron donation from the alkoxy group allows formation of the oxonium intermediate 21, which is captured by the alcohol to generate the product acetal. 

This symposium addressed several important issues in bromine chemistry. A major part has been devoted to stereochemistry and mechanism of electrophilic bromination of olefins. Other topics included new selective methods of bromination and oxybromination, brominations in presence of solid supports and catalysts, organobromine compounds as synthons, recent developments in brominated fire retardants and toxicological and environmental aspects of brominated compounds. 

Next we studied high temperature bromination of benzobarrelene at 150 C. NMR analysis indicated that the reaction mixture was very complex and consisted of at least ten products. After repeated column chromatography combined with fractional crystallization we have been able to separate 18 compounds (Scheme 6). Four of them were bromoalcohol compounds 18, 12, 22 and 2fl. After high temperature bromination we expected three isomeric non-rearranged products with benzobarrelene skeleton and isolated 22, 22, and 24 in yields of 34, 9.3, and 6.2 %, respectively. Because of the very close structural similarity we were not able to make a clear-cut differentiation between the stereochemistry of 22 and 24-Therefore, we carried out an X-ray analysis (ref. 9) of the isomer 22-... 

Some years ago, we tackled (ref. 7) the particular question of bromine bridging, related mainly to stereochemistry, postulating that bromonium ions and bromo-carbocations are formed in separate pathways as shown in Scheme 3. The relative rates of reaction by these pathways depend on the olefin structure. As demonstrated later... 

Apart from information on stereochemistry, bromine bridging does not provide a priori any rule regarding regio- and chemoselectivity. Therefore, we systematically investigated (ref. 3) these two selectivities in the bromination of ethylenic compounds substituted by a variety of more or less branched alkyl groups (Scheme 4). 

Interestingly, both the cytosolic and the lysosomal enzyme regained most of their activity on prolonged standing after they had been inactivated to the extent of 98% with bromoconduritol F. The rate of reactivation was larger at pH 6 than at pH 4.6. It was concluded that a labile ester-bond had been formed in the inactivation reaction. From the stereochemistry of the hydroxyl groups and the bromine substituent, it could have been with the carboxyl group presumed to act as acid catalyst in the activation of substrate or epoxide (see Scheme 6). 

Bromination of 4-r-butylcyclohexene in methanol gives a 45 55 mixture of two compounds, each of composition CuH21BrO. Predict the structure and stereochemistry of these two products. How would you confirm your prediction ... 

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... 

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