Formation of Bromohydrin

In the formation of bromohydrin, bromine bonds at the least substituted carbon (from nucleophilic attack by water), and the hydroxyl group bonds at the more substituted carbon (i.e., the carbon that accommodated more of the positive charge in the bromonium ion). 

Laboratory scale bromination of alkenes in homogeneous solution using an undivided cell is adaptable to the formation of epoxides, bromohydrins or dibromides depending on the conditions [64]. Epoxides are generated using an initially neutral solution and a low concentration of bromide ions. The reaction sequence is similar to that of Scheme 2.3. Formation of bromohydrins requires dilute hydrobromic acid as the supporting electrolyte. Dibromides are obtained using a concentrated solution of sodium bromide as electrolyte. 

Several examples of halohydrin formation from styrene derivatives and saccharides catalyzed by CPO are reviewed by Adam and coworkers [23], Formation of bromohydrin derivatives of some saccharides can be of interest for the preparation of bioactive compounds [72]. 

The discovery of w-pentenyl glycosides (NPGs) [12], was derived from an observation made by Mootoo and Fraser-Reid in a completely unrelated project [13], Attempted formation of bromohydrin 5 by reaction of 4 with NBS in 1% aqueous acetonitrile led, instead to bro-momethyl tetrahydrofuran 6 (O Scheme 2) [14]. To rationalize this transformation (4 6), the authors invoked a 5-exo-cyclization [15] of the pyranosidic oxygen in 7 leading to cationic intermediate 8, and thence to oxocarbenium ion 9, that upon capture of H2O led to hemiac-etal 6. The overall result of the process had been a, nonhydrolytic, electrophilic unravelling of the glycosidic-type bond in 4. 

Fig. 3. Top Diastereospecific formation of bromohydrin. Center Regiospecific bromina-tive oxidation of 1,3-di-tert.butyl-indol. Bottom Enantioselective oxygenation of thioanisol by bromoperoxidase from the brown alga A nodosum (left) and the red alga C. pilulifera (right). The VClPO from the fungus C. inaequalis produces a racemate.

Figure 11.6 Formation of bromohydrins and epoxides from olefins in water.

Partial formation of a-bromoketones from ketones with formation of bromohydrins from oxido compounds... 

An example of the intermolecular halo-O-functionaliza-tion, which involves the opening of the halonium intermediate with a water molecule, appears in Usami et a/. s synthesis of (+)-pericosine A 26." In Usami et al. s report, the enantioselective formation of bromohydrin intermediate 25 was derived from the enantioenriched cyclohexadiene 24 (Scheme 42.9). (+)-pericosine A 26 has been demonstrated to be an inhibitor of protein kinase epidermal growth factor receptor (EGFR) and human topoisomerase II as well as an antitumor agent against P388 in vivo ... 

Several cortisone derivatives with glucocorticoid effects are most active, if they contain fluorine in the 9or-position together with an Il(9-OH group. Both substituents are introduced by the cleavage of a 9,11 -epoxide with hydrogen fluoride. The regio- and stereoselective formation of the -epoxide is achieved by bromohydrination of a 9,11-double bond and subsequent alkali treatment (J. Fried, 1954). 

FIGURE 6 13 Mechanism of bromohydrin formation from cyclopentene A bridged bromonium ion is formed and is attacked by a water molecule from the side opposite the carbon-bromine bond The bromine and the hydroxyl group are trans to each other in the product... 

The formation of a bromohydrin via the addition of hyprobromous acid to olefins complements the above mentioned route. This reagent adds to the double bond in a tm/w-diaxial manner, the addition being initiated by the attack of a positive bromonium ion from the less hindered side. The... 

Overall, the stereospecificity of this method is the same as that observed in per-oxy acid oxidation of alkenes. Substituents that are cis to each other in the alkene remain cis in the epoxide. This is because formation of the bromohydrin involves anti addition, and the ensuing intranolecular- nucleophilic substitution reaction takes place with inversion of configuration at the carbon that bear s the halide leaving group. 

Mechanism of bromohydrin formation by reaction of an alkene with Br2 in the presence of water. Water acts as a nucleophile to react with the intermediate bromonium ion. 

Show the stereochemistry of the epoxide (see Problem 11.42) you would obtain by formation of a bromohydrin from frnm-2-butene, followed by treatment with base. 

The influence of 1,2-asymmctric induction on the exchange of diastereotopic bromine atoms has also been investigated22,23. Thus, treatment of the / -silyloxydibromo compound 15 with butyllithium at — 110°C in the presence of 2-methylpropana led to products 17-19 after the reaction mixture was warmed to 20 °C. The distribution of the products indicates that the diastereomeric lithium compounds 16 A and 16B were formed in a ratio of 84 16, with 16A being kinetically favored by 1,2-asymmetric induction. Formation of the m-configurated epoxide (cis,anti-18) was slowed to such an extent that its formation was incomplete and a substantial amount of the parent bromohydrin 17 remained. The analogous m.yyn-configurat-ed epoxide was not observed. Presumably for sterie reasons, the parent bromohydrin did not cyclize to the epoxide but instead led to the ketone 1923. 

In 1975, van der Baan and Bickelhaupt reported the synthesis of imide 37 from pyridone 34 as an approach to the hetisine alkaloids, using an intramolecular alkylation as the key step (Scheme 1.3) [23]. Beginning with pyridone 34, alkylation with sodium hydride/allyl bromide followed by a thermal [3,3] Claisen rearrangement gave alkene 35. Next, formation of the bromohydrin with A -bi omosuccinimide and subsequent protection of the resulting alcohol as the tetrahydropyranyl (THP) ether produced bromide 36, which was then cyclized in an intramolecular fashion to give tricylic 37. 

The anti stereospecificity of epoxidation by the peracid is interpreted as due to association of the reagent with the allylic hydroxyl group which directs the entering oxygen atom to the same face of the molecule. The stereospecificity of bromohydrin formation is explicable in terms of steric approach control involving initial attack of the bulky bromine atom on the face opposite to the benzylic hydroxyl group (7). 

An especially interesting example of micelle-mediated specificity is the observation that formation of rrans-dibromide or mwis-bromohydrin from cyclohexene and Br2 (27) is affected not only by CTABr, but also by the... 

Pulse radiolysis experiments have shown that "OH radical adds preferentially at C5 of the uracil moiety, giving rise to the reducing 5-hydroxy-5,6-uracil-6-yl radical. Interestingly, the two cis diastereomers of 6-hydroperoxy-5-hydroxy-5,6-dihydrouridine, two of the expected final products of the latter radicals in aerated aqueous solutions, have been prepared by trifluoroacetic acid treatment of uridine (3, R = H, = ribose) in the presence of H202 (equation 14). The mechanism of the reaction that involves transient formation of an epoxide-type intermediate followed by nucleophilic attack by a perhy-droxyl group at C6 presents similarities with the substitution of thymine bromohydrin by... 

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