Halogen-metal exchange reduction

The typical reactions of halogenothiophenes can be classified under the following headings nucleophilic displacement, halogen-metal exchange, reductive dehalogenation and formation of thienyl radicals. 

Dechlorination, debromination, demethylthiolation, and demethylsulfonylation of triazole 1-oxides 448 are all formally related to halogen-metal exchange and can also be regarded as reduction processes favored by the formation of a stabilized anion. 

In addition to deprotonation with strong bases, halogen-metal exchange, or trans-metalation, a-heteroatom-substituted carbanions can also be prepared by 1,5-hydro-gen transfer to vinyl radicals, followed by reduction [204, 205] (Scheme 5.21) or by a related intramolecular 1,4-proton transfer [206]. 

The equilibria mean that n-BuLi can be used to form organolithiums from aryl halides at low temperature (the subsequent reaction of ArLi with the BuX formed in the exchange is slow6) r-BuLi will form organolithiums from primary alkyl halides.7 The formation of secondary organolithiums by halogen-metal exchange is difficult,9 and reductive lithiation is usually preferable. 

It is essential, for successful retention of stereochemistry, to form the organolithiums by halogen-metal exchange, and not by reductive lithiation. While transmetallation of cis- and trans-24 with BuLi, quenching the organolithium 25 with ethylene oxide, gives complete retention of stereochemistry in 26. Owing to the intervention of radicals, reductive lithiation leads to considerable (but not total) epimerisation ... 

The more flexible tether embodied in bispyridocarbazoles 321 and 322 was synthesized by Roques and colleagues (779) as shown in Scheme 50. The bischloro tether 319 was prepared from 4-bromopyridine (316) by halogen-metal exchange, condensation with 4-cyanopyridine, and Wolff-Kishner reduction of the resulting ketone 317. Catalytic hydrogenation, chlorination, and then alkylation of 320 with 319 gave the desired bispyridocarbazoles (321, 322). An important discovery in this research is that the methosulfate salts impart excellent water solubility to the bispyridocarbazoles. 

The first attempt to prepare dialkyl 1-aIkynyIphosphonates by a Michaelis-Becker reaction was reported in 1965, " Only octyne is produced when 1-bromooctyne is allowed to react with sodium diethyl phosphite in liquid ammonia, the coproduct being diethyl phosphoramidate. It seems likely that reduction of the bromo compound occurs by a halogen-metal exchange, with the resulting diethyl bromophosphate being immediately converted into diethyl phosphoramidate by the hquid anunonia. ... 

The phosphonylation of the l-(triisopropylsilyl)-3,3-difluoro-3-bromopropyne with sodium diethyl phosphite in THF at -10°C affords the desired difluorophosphonate in only 21% yield, the major byproduct being the difluoropropyne obtained through reductive debromination. The mechanism presumably involves an initial halogen-metal exchange reaction, followed by the electrophilic attack of the bromophosphate on the resulting difluoropropargyl an ion. 

The two segments were joined by addition of the lithium reagent derived from halogen-metal exchange of iodide 395 to aldehyde 391 to produce a mixture of diastereomeric alcohols 396. As simple reductive deoxygenation proved... 

Ci Lithiated Anomeric Carbanions by Reduction Scheme 3.2.1 Glycosidic Halogen-Metal Exchanges... 

The transient anomeric lithiation shown in Scheme 3.2.1 differs from standard halogen-metal exchanges in that a reductive mechanism is involved. The use of reductive methods, illustrated in Figure 3.2.2, is complimentary to the exploitation of metal exchange reactions for the formation of glycosidic nucleophiles in that strategies towards selectivity in the anomeric stereochemistry become available. 

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