Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes

Summary

A persulfate-promoted metal-free benzannulation of α,β-unsaturated compounds and alkynes in water toward the synthesis of unprecedented polyfunctionalized benzenes is reported.

Abstract

Benzannulation reactions represent an effective protocol to transform acyclic building blocks into structurally varied benzene skeletons. Despite classical and recent approaches toward functionalized benzenes, in water metal-free methods remains a challenge and represents an opportunity to expand even more the set of tools used to synthesize polysubstituted benzene compounds. This protocol describes an operationally simple experimental setup to explore the benzannulation of α,β-unsaturated compounds and alkynes to afford unprecedented functionalized benzene rings in high yields. Ammonium persulfate is the reagent of choice and brings notable advantages as stability and easy handling. Moreover, the use of water as a solvent and the absence of metals impart more sustainability to the method. A modified workup procedure that avoids the use of drying agents also adds convenience to the protocol. The purification of the products is performed using only a plug of silica. The substrate scope is currently limited to terminal alkynes and α,β-unsaturated aliphatic compounds.

Introduction

Functionalized benzenes are arguably the most employed precursors in synthetic organic chemistry^1,2. They figure in the mainstream of pharmaceuticals, natural products and functional organic materials. Powerful approaches have been reported for the construction of polysubstituted benzene derivatives and among them, well-established methods as aromatic nucleophilic or electrophilic substitution³, cross-coupling reactions⁴ and directed metalation⁵ are prevalent approaches. Nevertheless, the widespread application of these strategies may be h....

Protocol

CAUTION: Consult Material Safety Data Sheets (MSDS) prior to the use of the chemicals in this procedure. Use appropriate personal protective equipment (PPE), including safety glasses, a lab coat, and nitrile gloves as several reagents and solvents are toxic, corrosive, or flammable. Carry out all reactions in a fume hood. Liquids used in this protocol are micropipette transferred.

1. Benzannulation reaction employing alkynes and α,β-unsaturated compounds

1. Add 2.0 mL of distilled water to a 15 mL-test tube (1 cm diameter) containing a stir bar. Sequentially, add phenylacetylene (220 μL, 2.00 mmol, 2.0 equiv.), 2-cyc....

Results

Polysubstituted benzene (3b, Figure 1) was isolated as a colorless oil (0.2741 g, 0.920 mmol, 92% yield) using our protocol. The structure and purity can be assessed in the ¹H and ¹³C NMR spectra presented in Figure 2 and Figure 3. Peaks for the aromatic protons on the central benzene ring (δ 8.37 and δ 7.72 ppm) were used as diagnostic signals for the formation of the product.

Discussion

The method reported herein was designed to be a very simple and mild experimental setup for the synthesis of polyfunctionalized benzenes in water¹⁵. Under our conditions we could observe excellent yields for the products through the use of ammonium persulfate. A freshly prepared persulfate aqueous solution should be used; however, solid ammonium persulfate can also be employed with no loss in yield. Attention to the temperature of the reaction medium is mandatory. An increase in 10 °C beyond .......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Ammonium persulfate	Vetec	276
Chloroform-D, (D, 99.8%)	Sigma Aldrich	570699-50G
2-cyclohexen-1-one >95%	Sigma Aldrich	C102814-25ML
Ethyl Acetate, 99.9%	Synth	01A1010.01.BJ	ACS
Hexanes, 98.5%	Synth	01H1007.01.BJ	ACS
Phenylacetylene 98%	Sigma Aldrich	117706-25ML
Silica Gel (SiO2)	Fluka	60738-5KG	pore size 60 Å, 35-70 μm particle size
Thin-layer chromatography plates	Macherey-Nagel	818333	0.20 mm silica gel 60 with fluorescent indicator UV254