In oxymercuration-demercuration

Rearrangements of the carbon skeleton seldom occur in oxymercuration-demercuration. 

In oxymercuration—demercuration, the net orientation of the addition of the elements of water, H — and — OH, is in accordance with Markovnikov s rule. The H — becomes attached to the carbon atom of the double bond with the greater number of hydrogen atoms. 

Ammonia can be added to double bonds (even ordinary double bonds) in an indirect manner by the use of hydroboration (15-16) followed by treatment with NH2CI or NH2OSO2OH (12-29). This produces a primary amine with anti-Markovnikov orientation. An indirect way of adding a primary or secondary amine to a double bond consists of aminomercuration followed by reduction (see 15-3 for the analogous oxymercuration-demercuration procedure), for example. 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

Oxymercuration-demercuration is a useful laboratory method for the synthesis of small quantities of alcohol. Like the catalytic hydration reaction, this process is an example of Markovnikov addition. It s a useful procedure because it tends to result in high yields and rearrangements rarely occur. 

A synthetic neuraminic acid derivative having a methyl ether group at 0-4 (Neu5Ac4Me) was synthesized by Beau and coworkers101,102 by using an oxymercuration-demercuration reaction.103 The metabolic behavior of this compound will be described in Sections V and VI. 

Mechanism. The reaction is analogous to the addition of bromine molecules to an alkene. The electrophilic mercury of mercuric acetate adds to the double bond, and forms a cyclic mercurinium ion intermediate rather than a planer carbocation. In the next step, water attacks the most substituted carbon of the mercurinium ion to yield the addition product. The hydroxymercurial compound is reduced in situ using NaBH4 to give alcohol. The removal of Hg(OAc) in the second step is called demer-curation. Therefore, the reaction is also known as oxymercuration-demercuration. 

Complicating side reactions may occasionally occur - as in the oxymercuration-demercuration of styrene to 1-phenylethanol for which experimental details are also given. In this case evidently some organomercurial compounds survive the reductive stage, and their subsequent decomposition during final distillation complicates the isolation of the pure product. 

Neutral cyclodextrins have been used as chiral phase-transfer catalysts for an interesting inverse phase-transfer catalysis reaction [50]. The Markovnikovhydration of the double bond by an oxymercuration-demercuration reaction has been demonstrated in the presence of cyclodextrins as chiral phase-transfer catalysts to obtain products in low to moderate enantioselectivity (Scheme 7.16). The mercuric salts are water-soluble, and remain in the aqueous phase, whereas the neutral alkenes prefer an organic phase. A neutral cyclodextrin helps to bring the alkenes into the aqueous phase in a biphasic reaction, and also provides the necessary asymmetric environment. 

Oxymercuration-demercuration of an unsymmetrical alkene generally gives Markovnikov orientation of addition, as shown by the oxymercuration of propene in the preceding example. The mercurinium ion has a considerable amount of positive charge on both of its carbon atoms, but there is more of a positive charge on the more substituted carbon atom, where it is more stable. Attack by water occurs on this more electrophilic carbon, giving Markovnikov orientation. The electrophile, +Hg(OAc), remains... 

Similarly, oxymercuration-demercuration of 3,3-dimethylbut-l-ene gives the Markovnikov product, 3,3-dimethylbutan-2-ol, in excellent yield. Contrast this unrearranged product with the rearranged product formed in the acid-catalyzed hydration of the same alkene in Section 8-4B. Oxymercuration-demercuration reliably adds water across the double bond of an alkene with Markovnikov orientation and without rearrangement. 

Of the methods we have seen for Markovnikov hydration of alkenes, oxymercuration-demercuration is most commonly used in the laboratory. It gives better yields than direct acid-catalyzed hydration, it avoids the possibility of rearrangements, and it does not involve harsh conditions. There are also disadvantages, however. Organomercurial compounds are highly toxic. They must be used with great care and then must be disposed of properly. 

Water, alcohols, hydroperoxides or carboxylates can be added regioselectively to a,/ -unsaturat-ed carbonyl compounds by the oxymercuration demercuration protocol. In this sequence, the oxymercuration step yields the -addition product. Depending on whether the demercura-tion is performed with retention or inversion of configuration, two sets of diastereomeric pairs of enantiomers (racemic mixtures) are obtained. 

The products obtained from the oxymercuration-demercuration of alkenylacetates under standard conditions (NaBH4/NaOH 3 M) are diols. However, the yields are significantly lower than with methoxy-and hydroxy-alkenes because of competitive deoxymercuration.Increasing the amount of base results in major increases in the yield of hydrated products. A less basic procedure has been developed, which allows for the survival of the acetate group. 

A number of demercurations of RHgX or RHgOR use tributyltin, or triphenyltin hydride,but complete removal of tin residues can sometimes be difficult NaBH4 reduction is then preferred. De-oxymercuration has also been observed during demercuration. The presence of anhydrous sodium acetate avoided this side reaction with PhsSnH, and the use of tributyltin hydride instead of NaBH4/NaOH in the demercuration of peroxymercurials led to much improved yields of peroxides (Scheme 33). 

Cyclizations are also used to create glycosidic linkages. In the example given in Scheme 4.63, the E (303) and Z (304) enol ethers were obtained from the reaction of the aldehyde 301 with the phosphonate 302 [636]. Oxymercuration-demercuration of 303 and 304 gave the (3-linked (305) and a-linked (306) KDO disaccharides, respectively. 

The two-stage process of oxymercuration-demercuration is fast and convenient, takes place under mild conditions, and gives excellent yields—often over 90%. The alkene is added at room temperature to an aqueous solution of mercuric acetate diluted with the solvent tetrahydrofuran. Reaction is generally complete within minutes. The organomercurial compound is not isolated but is simply reduced in situ by sodium borohydride, NaBH4. (The mercury is recovered as a ball of elemental mercury.)... 

Thallium(i) azide and iodine converted 5a-cholest-2-ene into a mixture of three isomeric iodo-azides. Reaction of either a 17-methyleneandrostane (77) or a 17-methylandrost-16-ene (78) with thallium triacetate gave mixtures of the allylic acetates (79), (80), and (81). Oxymercuration-demercuration was more selective in giving, after acetylation, the 16/8-acetoxy-17-methylene compound (80) as the main product. 

Scheme 4.4 Examples of oxymercuration/demercuration in organic and aqueous media.

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