Friedel–Crafts Reaction of Acylsilanes: Highly Chemoselective Synthesis of 1-Hydroxy-bis(indolyl)methanes and 1-Silyl-bis(indolyl)methanes Derivatives

Abstract

A novel double Friedel–Crafts reaction of acylsilanes in water is described. This strategy enables synthesis of bis(indolyl)methane derivatives with 1-hydroxy or 1-silyl substituents in moderate to high yield. Compared to the 1-silyl-bis(indolyl)methane derivatives from indole substrate, 1-hydroxy-bis(indolyl)methane derivatives were synthesized from the 5-hydroxyindole, and the hydrogen bonds in the 5-hydroxyindole play a crucial role in regulating the reaction selectivity.

Synthesis and Cheminformatics-Directed Antibacterial Evaluation of Echinosulfonic Acid-Inspired Bis-Indole Alkaloids

“…While reviewing the literature for synthetic methods reporting other C-1″ hydroxy bis-indoles, we encountered a study reporting the synthesis of 16 α-hydroxy bis(3′indolyl) indoles via an acid-catalysed double Friedel–Crafts strategy [ 17 ]. Using 5-hydroxyindole, camphorsulfonic acid, and tert -butyldimethylsilane (TBS) glyoxylate in water, the authors proposed a reaction mechanism in which selectivity for α-hydroxy bis-indole formation was attributed to an intermolecular hydrogen bond between C-3 TBS-substituted 5-hydroxyindole and water.…”

“…Using 5-hydroxyindole, camphorsulfonic acid, and tert -butyldimethylsilane (TBS) glyoxylate in water, the authors proposed a reaction mechanism in which selectivity for α-hydroxy bis-indole formation was attributed to an intermolecular hydrogen bond between C-3 TBS-substituted 5-hydroxyindole and water. After this, a Brook rearrangement occurs to form the 3-TBS 5-hydroxyindole azafulvenium, followed by the loss of TBS and coupling with another 5-hydroxyindole to form α-hydroxy bis(3′indolyl) compounds 3o′ , 5a – n, and 5ab′ ( Figure 3 and Figure S45 ) [ 17 ]. Given the challenges installing and maintaining a hydroxyl group at C-1″ encountered during our work, along with the difficulties reported by other research groups [ 19 , 20 ], we carefully examined the published experimental NMR and MS data reported for the 16 synthetic indoles [ 17 ].…”

“…It is regrettable that neither a 13 C DEPT nor HSQC NMR experiment was utilised during the characterisation of the synthetic bis-indoles 3o′ , 5a – n , and 5ab′ . Such readily available NMR experiments would have likely revealed the true structural identities of the aforementioned synthetic indoles and avoided inaccuracies associated with the author’s proposed reaction mechanism (Brook rearrangement) and results of their acid-catalysed double Friedel–Crafts reaction with acylsilanes [ 17 ].…”

“…The synthesis of the bis-indoles presented herein also led to the re-examination of 16 synthetic bis(3′-indolyl) alkaloids ( 3o′ , 5a – n , and 5ab′ ) [ 17 ]. This series of synthetic bis-indoles were assigned as α-hydroxy bis(3′-indolyl) alkaloids.…”

“…Bioactivity classifications used for cheminformatic analysis of marine indole alkaloids. References [ 1 , 3 , 14 , 17 ] are cited in the Supplementary Materials.…”