Halogen-metal exchange reagents

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

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. 

Scheme 7.2. Preparation of Organolithium Reagents by Halogen-Metal Exchange... 

Several examples of intramolecular additions to carbonyl groups by organo-lithium reagents generated by halogen-metal exchange have been reported, such as the two examples shown below. What relative reactivity relationships must hold in order for such procedures to succeed ... 

Annulation of aryl halides with ortho side chains bearing a pendant electi ophilic moiety via treatment with an organolithium reagent, involving halogen-metal exchange and subsequent nucleophilic cyclization to form 4- to 7-membered rings. 

The preparation of aryllithium reagents can also be performed by using t-butyllithium in a halogen-metal exchange, and aqueous potassium ferricyanide as an oxidant. 

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