Reactions of Indolyl-C-X Compounds

Gramine and, especially, its quaternary salts are useful synthetic intermediates in that they are easily prepared and the dimethylamino group is easily displaced by nucleophiles - reactions with cyanide and acetamidomalonate ° anions, and boronic acids with rhodium(I) catalysis, are typical. 

Utilising tri-n-butylphosphine to displace the dimethylamino group generates, in situ, a zwitterion which, by proton transfer, becomes a Wittig intermediate and thus can be utilised to prepare 3-vinyl-indoles.  

A related sequence is involved in the lithium aluminium hydride reduction of indol-3-yl-carbinols (which can be obtained from the corresponding ketones using milder reducing agents), with formation of the alkyl-indole. This constitutes a useful synthesis of 3-alkyl-indoles. The one-pot conversion of 3-formylindole into 3-cyanomethylindole with a mixture of sodium cyanide and sodium borohydride probably involves a comparable elimination from the cyanohydrin, then reduction.  

Yet another use for (A-protected) grammes is conversion into 3-bromo-indoles this involves P-bromination and then retro-Mannich loss of the original substituent. Combined with the directing ability of the original dimethylamino group (20.5.1) this provides a route to 4-substituted 3-bromo-indoles. 

Although indolylic halides are generally unstable and not synthetically useful, A-acylated derivatives are much more stable, can be prepared by side-chain radical substitution, and can be utilised in nucleophilic substitution processes.  

---