Metallated indoles

Nucleophilic aromatic substitution reactions of nitro-substituted thiophenes have been utilized to prepare biologically active thiophenes including reverse transcriptase <02H(57)97> and nitric oxide synthase <02JHC857> inhibitors. The addition-elimination reaction of 2-chloro-3-nitrothiophene (56) with metallated indole 57 afforded 58 which was transformed into the corresponding thiophene-fused azepino[5,4,3-cd]indoles 59 <02H(57)1831>. 

With a Ka value of 16.97, indole possesses an NH-acidity similar to that of pyrrole. Indole reacts, therefore, with sodamide in liquid ammonia, with sodium hydride in organic solvents, with Grignard reagents and with -butyllithium to give 1-metalated indoles. 

There are also procedures for allylation with halides using zinc [91], gallium or cadmium [92] metal. These reactions are thought to proceed through a metallated indole formed in situ. Consistent with this interpretation, 1-methylindole does not react. With the gallium reagent, 3-methylindole gives the 2-allyl product. 

Entry Base Conditions M Metalated indole Yield (%) Ref. 

Metalated indoles, indazoles, benzimidazoles, and azaindoles and their synthetic applications 13S2343. 

Knochel and colleagues discussed metalated indoles, indazoles, benzimidazoles, and azaindoles (13S2343). Davies and Spangler reviewed the reactions of indole with metal-bound carbenoids (13AHC43). The electrophilicity of indole (13OBC5206) and the challenges of the C4 pre-nylation of indole has been recently reviewed (13SL1025). 

With a pKa-value of 16.97, indole is a very weak NH-acid similar to pyrrole. Therefore, indole is deprotonated by NaNH2 in liquid NH3, by NaH and by organometalHcs Hke RMgX and RLi forming 1-metalated indoles 2, for example ... 

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