Substitution of the Dimethylamino Group in Gramines and One-Pot Cyclization to Tetrahydro-ß-carbolines Using a Triazine-Based Activating Agent.

A new method for the substitution of 3-[(dimethylamino)methyl]indoles (gramines) with malonate-based nucleophiles was developed using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) as the activating agent for the dimethylamino group. The reaction was completed in 1.5-6 h at room temperature in the presence of a tert-amine base and lithium salt. CDMT afforded superior results to methyl iodide, a common activating agent for the dimethylamino group in Mannich bases, particularly in the reactions of 1-substituted gramines. The reactivity of the possible intermediates, bis(indol-3-ylmethyl)dimethylammonium salts, was examined to obtain mechanistic insights on the reaction. This substitution method with CDMT enabled the sequential transformation of gramines: substitution with ( N-alkylidene)aminomalonates followed by the Pictet-Spengler reaction under acidic conditions afforded 1,2,3,4-tetrahydro-ß-carboline derivatives in one pot.

Imido-substituted triazines as dehydrative condensing reagents for the chemoselective formation of amides in the presence of free hydroxy groups.

In this paper, we discuss the synthesis of imido-substituted chlorotriazines and demonstrate their use in dehydrative condensation reactions. Chemoselective amide-forming reactions of amino alcohols using succinimido-substituted chlorotriazine (2A) proceeded smoothly. Occasionally, nonselectivity was problematic during the synthesis of hydroxy-substituted amides. Moreover, it was noteworthy that this method was applicable to hydroxy-substituted carboxylic acids that could have formed a lactone or an ester during the carboxylic acid activation step. The imido-substituted chlorotriazine (2A) was superior to the amido-substituted chlorotriazine and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in terms of reaction rates and yields.