Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

Summary

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Brønsted acid catalysis.

Abstract

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Brønsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.

Introduction

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry¹. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry². Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively (Figure 1)^3-9. Often these oxidative coupling reactions require synthetic....

Protocol

1. Synthesis of Tetrahydrocarbazole Hydroperoxides

1. The formation of the hydroperoxide is slowed down if the tetrahydrocarbazole is very colored. In this case, purify it by recrystallization using toluene/pentane or by column chromatography to get a colorless starting material. For purification by column chromatography, pack a column with a lower layer of silica gel and an upper layer of alumina. Put the tetrahydrocarbazole on top of the column and elute with toluene. All the unwanted yellow and black colored byproducts are adsorbed on the column and colorless tetrahydrocarbazole is eluting. Immediately evaporate the solvent and store the purified white pro....

Results

Synthesis of 1-(5-nitroindolin-1-yl)-2,3,4,9-tetrahydro-1H-carbazole (4a):

Synthesized according to Method A, R_f = 0.63 (hexane/ethyl acetate 70:30).

Purification: Purify the product by using Method A, workup variant A1 (steps 2.4, 2.5, 2.6). Orange solid, Yield: 95%.

¹H NMR (500 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.97 (dd,

Discussion

In summary, we could demonstrate that a C-H bond in tetrahydrocarbazoles can be conveniently functionalized to generate C-N-coupling products in a two-step procedure.

The first step is a well-known photocatalyzed oxidation of tetrahydrocarbazole (1) or its derivatives with elemental oxygen^17,19, giving a hydroperoxide 2. If performed in toluene, the hydroperoxide products precipitate and can be conveniently isolated by filtration. Further purificati.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
1,2,3,4-Tetrahydrocarbazole	Sigma Aldrich	T12408	If coloured, purification may be necessary. See Protocol 1.1
Methanol	Sigma Aldrich	322415	99.8% purity
4-Nitroaniline	Acros Organics	128371000	99% purity
Trifluoroacetic acid	Sigma Aldrich	T6508	99% purity
Acetic acid	J. T. Baker	JTB RS 426960101	99-100% purity
Aniline	Merck	8222560100
4-Aminobenzonitrile	Sigma Aldrich	147753	98% purity