Post-Ugi Acid-Catalyzed Fragmentation and Trapping: An Unprecedented Approach towards Novel Bis(indolyl)acetamides

This article is dedicated to Professor Anamik K. Shah on the occasion of his 70^th birthday.

Abstract

An unprecedented post-Ugi Brønsted acid catalyzed fragmentation followed by in situ trapping of the alkylideneindolenine intermediate by indole nucleophiles was developed to furnish novel bis(indolyl)acetamides. The amide fragment formed during this acid-catalyzed fragmentation of the Ugi adduct was also isolated and characterized. The carboxylic acid and amine components of the Ugi reaction were carefully chosen to permit a simple water wash for the removal of the amide fragment to obtain the desired bis(indolyl)acetamides in a pure form.

Key words

Ugi reaction - indoles - multicomponent reaction - bisindolylacetamides - fragmentation

Publication History

Received: 18 April 2024

Accepted after revision: 15 May 2024

Accepted Manuscript online:
15 May 2024

Article published online:
28 May 2024

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• 10 Amides 8a–h; General Procedure The appropriate Ugi adduct (1 equiv) and substituted indole (1 equiv) were treated with 30 mol% HCl in MeOH at rt until the reaction was complete (TLC, hexane–EtOAc, 7:3). The mixture was then poured into crushed ice and stirred for 5–10 min. The solid that separated was collected by filtration, washed with ice-cold H₂O, and purified by column chromatography. N-(tert-Butyl)-2,2-di-1H-indol-3-ylacetamide (8a) Prepared according to the general procedure from Ugi adduct 5e (0.377 g, 1 mmol, 1 equiv) and indole (0.117 g, 1 mmol, 1 equiv) to give a light-orange solid; yield: 0.297 g (86%); mp 140–142 °C; TLC R_f = 0.4 (EtOAc–hexane, 3:7; UV). IR (ATR): 3393, 3073, 2963, 1650, 1514, 1454, 1417, 1392, 1362, 1337, 1216, 1095, 1009, 792, 739 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.3 (s, 2 H), 7.5 (d, J = 7.9 Hz, 2 H), 7.25–7.23 (m, 2 H), 7.1 (t, J = 7.5 Hz, 2 H), 7.0 (t, J = 7.5 Hz, 2 H), 6.6 (s, 2 H), 5.9 (s, 1 H), 5.1 (s, 1 H), 1.2 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.4, 136.5, 126.6, 123.8, 121.9, 119.4, 119.1, 114.2, 111.5, 51.3, 43.7, 28.6. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₃N₃NaO: 368.1739; found: 368.1769.