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

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

Hikaru Fujita, Riho Nishikawa, Ozora Sasamoto, Masanori Kitamura, Munetaka Kunishima

J Org Chem. 2019 Jul 5;84(13):8380-8391.

PMID: 31199147

Abstract:

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-β-carboline derivatives in one pot.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP51066741	Dimethylammonium iodide		51066-74-1	Price

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