Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

Abstract

A novel, versatile approach for the synthesis of unsymmetrical 3,3'-diindolylmethanes (DIMs) with a quaternary carbon center has been developed via iodine-catalyzed coupling of trifluoromethyl(indolyl)phenylmethanols with indoles. In contrast to previously reported methods, the new procedure is characterized by chemoselectivity, mild conditions, high yields, and scalability to obtain gram amounts for biological studies. Selected compounds were found to display affinity for cannabinoid receptors, which are promising drug targets for the treatment of inflammatory and neurodegenerative diseases.

2,2,2‐Trifluoroethanol‐mediated hydroarylation of fluorinated alkynes with indoles: Application to diindolylmethanes

“…[ 36 ] We recently reported the trifluoromethyl‐substituted 3,3ʹ‐DIMs as ligands for cannabinoid receptors, which are promising drug targets for the treatment of inflammatory and neurodegenerative diseases. [ 31 ]…”

“…As part of our ongoing efforts to produce bioactive indole derivatives, [26][27][28][29][30][31] we describe an efficient synthesis of numerous β-trifluoromethyl indole-3-acrylates in trifluoroethanol (TFE) at room temperature (rt) without the use of any catalysts or additives (see Scheme 1b). Atom economy, high yields, a broad substrate scope, and multiscale synthesis are advantages of this process.…”

“…are promising drug targets for the treatment of inflammatory and neurodegenerative diseases. [31] To understand the reaction mechanism of hydroarylation, we performed control experiments (Scheme 3). As depicted in Scheme 3, the reaction of N-methylindole (1m) with 2a was investigated under the optimized reactions (see entry 10 in Table 1).…”

Design, synthesis, and structure–activity relationships of diindolylmethane derivatives as cannabinoid CB2 receptor agonists

“…Competition binding assays were performed using the nonselective CB receptor agonist radioligand [ 3 H](−)‐cis‐3‐[2‐hydroxy‐4‐(1,1‐dimethylheptyl)phenyl]‐trans‐4‐(3‐hydroxypropyl)cyclohexanol ([ 3 H]CP55,940, final concentration 0.1 nM) as previously described. [ 38,46,47 ] Membrane preparations of CHO cells stably expressing either human CB 1 or CB 2 receptor were used (CB 1 : 30 μg of protein/well and CB 2 : 16 µg of protein/well) for all of the radioligand binding experiments. Stock solutions of the DIM derivatives were prepared in DMSO.…”

“…EC 50 0.290 µM) exhibited an increase in agonistic activity compared to lead compound 4 (Figure 5). Surprisingly, introducing larger substituents like 4,4′-dibromo (44) 4,4′-dicyano (46), or 4-chloro,4′-bromo (157) increased the potency of the DIM derivatives in the β-arrestin assays dramatically yielding EC 50 values of 0.0450, 0.0149, and 0.0385 µM, respectively.…”