Gramine salts, displacement

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Another useful reagent for the 3-aLkylation of indole is the /V,/V-dimethy1foTma1 diminium ion, which forms the useful intermediate gramine [87-52-5] (9). The C-3 substituent can subsequendy be modified by displacement of the dimethylarnino group by a nucleophile. Alternatively, gramine can be converted to its quaternary salt prior to substitution. A variety of carbanions can function as the nucleophile. 

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethyl-aminomethylindole (gramine) (153) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 60). Indole-2,3-quinodimethanes, generated from 2-methylgramine as shown in Scheme 61, undergo intermolecular cycloaddition reactions with dienophiles to yield carbazole derivatives (82T2745). 

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethylaminomethyl-indole (gramine) (353) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 62). 

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. 

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