Deprotometalation-Iodolysis and Direct Iodination of 1-Arylated 7-Azaindoles: Reactivity Studies and Molecule Properties

Abstract

Five protocols were first compared for the copper-catalyzed C-N bond formation between 7-azaindole and aryl/heteroaryl iodides/bromides. The 1-arylated 7-azaindoles thus obtained were subjected to deprotometalation-iodolysis sequences using lithium 2,2,6,6-tetramethylpiperidide as the base and the corresponding zinc diamide as an in situ trap. The reactivity of the substrate was discussed in light of the calculated atomic charges and the pKa values. The behavior of the 1-arylated 7-azaindoles in direct iodination was then studied, and the results explained by considering the HOMO orbital coefficients and the atomic charges. Finally, some of the iodides generated, generally original, were involved in the N-arylation of indole. While crystallographic data were collected for fifteen of the synthesized compounds, biological properties (antimicrobial, antifungal and antioxidant activity) were evaluated for others.

Aromatic Iodides: Synthesis and Conversion to Heterocycles

“…Another way to predict the outcome of aromatic electrophilic substitution (SEAr) reactions [1], such as iodination, relies on Fukui's concept (in a reaction with an electrophile, an aromatic compound reacts at its carbon with the highest amplitudes of the highest occupied molecular orbital (HOMO) coefficient-in absolute value) [2]. For example, calculating the amplitudes of these coefficients for 1-(3,5-dimethylphenyl)-7-azaindole and 1-(2-thienyl)-7-azaindole by applying Hückel's theory [3,4] indicates a favored reaction at C3 and C5′, respectively, in accordance with the experimental results [5] (products 1 and 2; Figure 1). From various 6-aminoquinoxalines [6], iodination similarly occurred at C5, as predicted by the amplitudes of the HOMO coefficients (see examples in Figure 2).…”