Halogens directed lithiation

Carbocyclic substitution can also be achieved by first introdueing a reactive organomelallic substituent. Preparation of organolithium reagents can be done by one of the conventional melhods. especially halogen-metal exchange or directed lithiation. Table 14.2 gives examples. 

The direct lithiation of a 2-substituted 1,2,3-triazole has not been reported. Halogen-metal exchange of 4,5-dibromotriazole with n-butyllithium at — 80 °C occurs smoothly and the subsequent reaction of the lithium intermediate (244) with various electrophiles except aldehydes gives the 4-bromo-5-substituted triazoles (245) (Scheme 46). The corresponding 1-substituted 4,5-dibromo-1,2,3-triazole undergoes a similar reaction at the 5-position . 

S235). Examples of halogen directed metallation include the lithiation of 5-bromopyrimidine (345) or chloropyrazine (346) by LDA. 3-Halopyridines are also lithiated regiospecifically at C-4, but pyridyne formation is then rapid. 

Notably, treatment of 2-(p-bromophenyl)-3,3-dimethyl-1 -methylenecyclopropane with BuLi in TFIF followed by HgCl2 led to mercuration of the aromatic ring (equation 302). This indicates that lithium-halogen exchange at the aromatic ring is preferable to direct lithiation of the three-membered ring372. 

Competing deprotonation a to the halogen is a typical problem when heterosubstituents are in a position to direct lithiation to this position. So, for example, while both 125 and 126 transmetallate cleanly,107 the E and Z isomers of 127 and 128 behave quite differently, with deprotonation of 127 leading to carbene formation and capture of f-BuLi while 128 undergoes transmetallation.108 Clean transmetallation to an E vinyllithium can be achieved in this case by the use of the iodide (129) or by replacing one of the alkoxy groups of the acetal (130). 

Careful choice of reaction conditions allows 2-lithiation even in the presence of groups susceptible to attack by the reagent. At — 100°C in THE 4,5-dicyano-l-methylimidazole forms the 2-lithio compound at — 80°C butyllithium attacks one of the nitrile functions <92JHCI09I>. Even 4- and 5-chloroimidazoles can be 2-lithiated, as can 4-bromoimidazole, but when the 2-position is blocked halogen-metal exchange and direct lithiation can occur elsewhere <94JMC332>. 

The use of halogen to direct lithiation can be combined with the ability to snbseqnently displace the halogen with a nncleophile. ... 

Bromine and iodine also direct lithiations, but isomerisation - halogen dance (see discussion in 17.4.2) - can be a problem, however advantage can be taken of the isomerisation (to the more stable hthio-derivative) in suitable cases. In the example below, the more stable lithio compound is that in which the formally negatively charged ring carbon is located between two halogen-bearing carbon atoms. ... 

The complications associated with direct lithiation of thienopyridines have already been discussed, but lithio derivatives in both series are readily available by halogen-metal interchange at low temperature. 

Directed lithiation. 2-Arenesul gioselective fashion, furnishing thio 157-96%). 3-Halopyridines, includm lithiation and regioselective reaction that 3-chloro-4-iodopyridine generate t-BuLi. Halogen dance is also obsersx Vinyl esters are silylated at the esters of silyl ketones. The regiosel and the ability of the lithio derivative tion with suitable acceptors are expio cyclopentenones. ... 

Directed lithiation. 2-Arenesulfonyl benzamides are deprotonated in a re-gioselective fashion, furnishing thioxanthen-9-one 10,10-dioxides in good yields (57-96%). 3-Halopyridines, including the iodo compounds, manifest directed o-lithiation and regioselective reaction (at C-4) with electrophiles. It should be noted that 3-chloro-4-iodopyridine generates 3,4-pyridyne on treatment with either BuLi or f-BuLi. Halogen dance is also observed. ... 

When pyridine is heated to 165 °C in MeONa-MeOD, H-D exchange occurs at all positions via small concentrations of deprotonated species, at the relative rates a (3 7, 1 9.3 12. However, using the combination n-butyllithium/potassium t-butoxide, efficient formation of 2-pyridylpotassium or 4-pyridylpotassium has been achieved." Some pyridines have been selectively lithiated at C-2 via complexes with hexafluoroacetone " complexation removes the lone pair (cf. section 5.5.1) and additionally provides inductive and chelation effects to assist the regioselective metallation. In practice, simple lithiopyridines are generally prepared by metal-halogen exchange, however the presence of chlorine or fluorine, or other substituents which direct ortho metallation, allows direct lithiation (section 5.5.1). 

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