A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

Summary

3-Aroyl-N-hydroxy-5-nitroindoles were synthesized by cycloaddition of 4-nitronitrosobenzene with a conjugated terminal alkynone in a one-step thermal procedure. Preparation of the nitrosoarene and of the alkynones were adequately reported and respectively through oxidation procedures on the corresponding aniline and on the alkynol.

Abstract

We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ketones. The reactions were carried out achieving indoles without any catalyst and with excellent regioselectivity. No traces of 2-aroylindole products were detected. Working with 4-nitronitrosobenzene as starting material, the 3-aroyl-N-hydroxy-5-nitroindole products precipitated from the reaction mixtures and were isolated by filtration without any further purification technique. Differently from the corresponding N-hydroxy-3-aryl indoles that, spontaneously in solution, give dehydrodimerization products, the N-hydroxy-3-aroyl indoles are stable and no dimerization compounds were observed.

Introduction

Aromatic C-nitroso compounds¹ and alkynones² are versatile reactants that are continuously and deeply used and studied as starting materials for the preparation of high valuable compounds. Nitrosoarenes play an ever-growing role in the organic synthesis. They are used for many different purposes (e.g., hetero Diels-Alder reaction^3,4, Nitroso-Aldol reaction^5,6, Nitroso-Ene reaction⁷, synthesis of azocompounds^8,9

Protocol

1. Preliminary preparation of the Jones Reagent

1. Add 25 g (0.25 mol) of chromium trioxide using a spatula in a 500 mL beaker that contains a magnetic stirring bar.
2. Add 75 mL of water and keep the solution under magnetic stirring.
3. Add slowly 25 mL of concentrated sulfuric acid with careful stirring and cooling in an ice-water bath.
   NOTE: Now the solution is ready and is stable and usable for many oxidation procedures; the concentration of the solution prepared by this procedure is 2.5 M.

2. Synthesis of 1-phenyl-2-propyne-1-one

1. Add 75 mL of acetone in an open-air round bottom flask tha....

Results

The preparation of 4-nitronitrosobenzene 2 was achieved by oxidation of 4-nitroaniline 1 by reaction with potassium peroxymonosulfate as reported in Figure 6. The product 2 was obtained in 64% yield after recrystallization in MeOH (twice) with 3-5% contamination of 4,4'-bis-nitro-azoxybenzene 6. The structure of product 2 was confirmed by ¹H-NMR (Figure 7). ¹

Discussion

The reaction for the indole synthesis between nitrosoarenes and alkynones shows a very high versatility and a strong and wide application. In a previous report, we could generalize our synthetic protocol working with different C-nitrosoaromatics and substituted terminal arylalkynones or heteroarylalkyones⁷². The procedure shows a deep substrate survey and a high functional group tolerance and both electron-withdrawing groups and electron-donor groups were present both in nitrosoarene and .......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
4-Nitroaniline	TCI Chemicals	N0119
Acetone	TCI Chemicals	A0054
1-Phenyl-2-propyne-1-ol	TCI Chemicals	P0220
Celite 535	Fluorochem	44931
Dichloromethane	TCI Chemicals	D3478
Sodium hydrogen carbonate	Sigma Aldrich	S5761
Sodium chloride	Sigma Aldrich	746398
Sodium sulfate anhydrous	Sigma Aldrich	239313
Oxone	TCI Chemicals	O0310
Methanol	TCI Chemicals	M0628
Toluene	TCI Chemicals	T0260
Chromium Trioxide	Sigma Aldrich	236470
Dichloromethane anhydrous	TCI Chemicals	D3478
Hexane anhydrous	TCI Chemicals	H1197