An Improved Synthesis of α-Carbolines under Microwave Irradiation

Abstract

[reaction: see text]. Alpha-carbolines are interesting core structures for designing DNA-interacting small molecules. However, these compounds are not commercially available and their synthetic methods are low yielding or time consuming. The shortest synthetic route, the modified Graebe-Ullmann reaction, has been optimized by using microwave heating in four different types of apparatus to give shorter reaction times and enhanced yields. Optimized conditions enabled the preparation of a small library of alpha-carbolines.

Synthesis and structure-activity relationship studies of novel 3,9-substituted α-carboline derivatives with high cytotoxic activity against colorectal cancer cells

“…The initial synthesis of the 3-substituted α-carbolines proceeded through the acid-catalyzed decomposition of a 1-(2-pyridyl)benzotriazole and cyclization of the indole ring, a modification of the Graebe–Ullmann carbazole synthesis [28, 29]. The starting material 1,2,3-benzotriazole ( 1 ) was reacted with methyl 6-chloronicotinate ( 2 ) to form methyl 6-(1,2,3-benzotriazol-1-yl)nicotinate ( 3 ).…”

The Graebe–Ullmann Carbazole‐Carboline Synthesis

“…This research team extended this method to the synthesis of α-carbolines (equation 3) [47]. This research team extended this method to the synthesis of α-carbolines (equation 3) [47].…”

An intramolecular inverse electron demand Diels–Alder approach to annulated α-carbolines

“…This procedure was improved upon and exploited for decades [37–40]. Later, reversing the roles of the benzene and pyridine rings, with the former as the nucleophile and latter as electrophile through the diazonium salt, led to improved yields in the indole ring closure [41], as did microwave promotion of the original methodology [42]. Nitrene insertion chemistry of appropriately substituted 3-arylpyridines also found application [43–44], and likewise falls into the category of indole ring closure onto an existing substituted pyridine, though in this case with the formation of the C–N bond.…”