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 hampered by limited substrate scope, overreaction and regioselectivity issues.

Tandem cyclization reactions represent a very attractive alternative to classical methods for rapid construction of functionalized benzenes in an atom-economical fashion^6,7,8. Within this framework, benzannulation reactions represent a suitable protocol to effectively transform acyclic building blocks into valuable benzene skeletons. This class of reaction is a versatile methodology featuring a variety of chemical feedstocks, mechanisms and experimental conditions^9,10,11.

The objective of our study is to develop a simple and practical protocol for a benzannulation reaction to generate unprecedented functionalized benzene rings. Toward this end, we set out to explore a metal-free, persulfate mediated benzannulation in water employing cheap chemical feedstocks (α,β-unsaturated compounds and alkynes).

Several advantages over methods reported in the literature can be pointed out. Metal-free transformations have all necessary attributes to meet the requirement of sustainable development. Just to mention few, there is no need for costly and challenging removal of metal trace amounts from the desired products; the reactions are less sensitive to oxygen and moisture making its manipulation easier and the overall process is normally less expensive¹². Persulfate salts are stable, easy to handle and generate only sulphate as the byproduct, thus adding momentum to the green chemistry initiative to minimize waste pollution¹³. Water is considered a suitable green solvent for organic reactions: it is non-toxic, non-flammable, has a very low odor and is available at a low cost. Even water-insoluble organic compounds can be employed using "on water"¹⁴ aqueous suspensions and these straightforward synthetic protocols have been gaining increasing attention during the years.

Our optimized reaction conditions and simple workup/purification procedure provide access to several functionalized benzene rings that offer a wealth of opportunities for further functionalization.

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-cyclohexen-1-one (96.8 μL, 1.00 mmol, 1.0 equiv.) and ammonium persulfate (1.5 mL of a freshly prepared aqueous solution 1.3 M, 2.00 mmol, 2 equiv.).
2. Cap the tube using a rubber septum and insert a needle in it to avoid eventual pressure buildup during the heating.
3. Place the tube in an aluminum heating block on a hotplate and heat it at 85 °C under vigorous stirring (1150 rpm) for 8 h.
4. To follow the progress of the reaction, take a 50 μL-aliquot of the reaction medium and transfer it to a 1.5 mL-conical vial. Add 50 μL of ethyl acetate to the vial and shake it. Collect the organic top layer with a capillary tube and analyze it by TLC.
   NOTE: Reaction progress is checked by TLC comparing the disappearance of the α,β-unsaturated compound spot to the appearance of the product under the UV light (254 nm). TLC analysis is performed with silica-coated glass plates and developed with 92:8 hexanes/ethyl acetate. R_f values: phenylacetylene = 0.68; 2-cyclohexen-1-one = 0.23; product 3e = 0.26.
   CAUTION: Phenylacetylene and 2-cyclohexen-1-one are flammable, acutely toxic and mild irritants. Ammonium persulfate is corrosive and may irritate the mucous membranes.

2. Extraction workup and purification

1. Cool the reaction mixture to room temperature and add ethyl acetate (1 mL) to the test tube. Stir the suspension for ca. 1 min and then centrifuge the suspension at 2,336 × g at room temperature for 1 min. Remove the organic top layer using a Pasteur pipette and transfer it to a round bottom flask. Repeat this step twice.
   NOTE: The centrifugation step avoids the use of drying agents and readily breaks any eventual emulsion.
2. Concentrate the solution under reduced pressure using a rotary evaporator to obtain a crude oil.
3. Add 55 mL of a mixture of hexanes/ethyl acetate at the ratio of 92:8 into a Becker containing 7.5 g of SiO₂ (pore size 60 Å, 35-70 μm particle size, for flash chromatography). Stir the flask to obtain a homogeneous slurry. Transfer the slurry to a column (40 mm internal diameter) and pack the column eluting the solvent. If necessary, elute once again to remove any bubbles from the stationary phase.
4. Dissolve the crude oil in a minimal amount of ethyl acetate, and then transfer this solution to the column. Using the same 55 mL of a mixture 92:8 hexanes/ethyl acetate, elute the material, collecting the column effluent in test tubes and following by TLC to obtain the desired pure product.
5. Concentrate the solution under reduced pressure on a rotary evaporator and remove the final volatiles under high vacuum for at least 1 h. Analyze a sample of the purified product by ¹H and ¹³C NMR using CDCl₃.
   CAUTION: Ethyl acetate and hexanes are flammable. SiO₂ powder is a respiratory irritant.

Representative 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.

6,8-diphenyl-3,4-dihydronaphthalen-1(2H)-one (3b). R_f = 0.26 (92:8 hexanes/ethyl acetate); ¹H NMR (500 MHz, Chloroform-d): δ 8.37 (d, J = 2.26 Hz, 1H), 7.72 (d, J = 2.26 Hz, 1H), 7.67 (dd, J = 8.28, 1.51 Hz, 2H), 7.49-7.37 (m, 8H), 2.89 (t, J = 6.02 Hz, 2H), 2.72 (ap t, J = 6.02 Hz, 2H), 2.09 (quint, J = 6.02 Hz, 2H). ¹³C NMR (125MHz, Chloroform-d): δ 23.19, 28.01, 39.02, 124.86, 127.00, 127.46, 127.64, 128.35, 128.85, 129.19, 133.17, 133.41, 139.13, 139.78, 140.81, 142.51, 198.60. HRMS m/z (ESI): calcd. for C₂₂H₁₉O [M+H]⁺ 299.1436, found 299.1420.

Several polysubstituted benzene rings were prepared in high yields using our protocol (Figure 1).¹⁵ All the products were analyzed by ¹H and ¹³C NMR, as well as high-resolution mass spectrometry (HRMS) in order to fully characterize them.

GC analysis can be used as an alternative method for the detection of the products; although, TLC analysis works efficiently as well. All the products are UV-active and stain in the presence of basic KMnO₄ aqueous solution. A plug of silica is adequate for the purification of products.

Optimal yields were obtained when employing a ratio of 2:1 for alkynes and α,β-unsaturated compounds, respectively; 2 equiv. of ammonium persulfate and 85 °C as reaction temperature. In the optimization process, the reaction between phenylacetylene 1a and fumaronitrile 2a was chosen as a model reaction (Table 1). Increasing the amount of the α,β-unsaturated compound led to an inferior result (Table 1, entry 3). Variations of the amount of (NH₄)₂S₂O₈ were tested and in every scenario a decrease in the production of 3a was observed (Table 1, entries 4 and 5). Changing the reaction temperature to 25 °C resulted in a complete shutdown of the reactivity (Table 1, entry 6). Increasing the reaction temperature to 95 °C did not enhance the yield (Table 1, entry 7).

Figure 1: General scheme and scope of the transformation. General conditions: 2 mL of water, 1 (2.0 mmol), 2 (1.0 mmol), (NH₄)S₂O₈ (2.0 mmol, aqueous solution 1.3 M), 85 °C, 8 h. Yields of the isolated products. ^aUsing 4.0 mmol of (NH₄)S₂O₈, 24 h reaction time. This figure has been modified from de Souza et al.¹⁵ Please click here to view a larger version of this figure.

Figure 2: ¹H NMR of 3b. Spectrum obtained in CDCl₃ at 400 MHz. This figure has been modified from de Souza et al.¹⁵. Please click here to view a larger version of this figure.

Figure 3: ¹³C NMR of 3b. Spectrum obtained in CDCl₃ at 400 MHz. This figure has been modified from de Souza et al.¹⁵. Please click here to view a larger version of this figure.

Figure 4: Proposed reaction mechanism. This figure has been modified from de Souza et al.¹⁵. Please click here to view a larger version of this figure.

Entrya	Ratio 1a:2a	NH4S2O8	Temperature	Yield (%)b
		(Equiv)	(T, °C)
1	1:1	2.0	85	69
2	2:1	2.0	85	90
3	1:2	2.0	85	65
4	2:1	1.0	85	56
5	2:1	3.0	85	72
6	2:1	2.0	25	0
7	2:1	2.0	95	88
aGeneral conditions for the optimization: In the sequence, 1.0 mL of water, 1a (0.5 or 1.0 mmol), 2a (0.5 or 1.0 mmol), (NH4)2S2O8, 8 h. bYield of the isolated product.

Table 1. Optimization of the reaction conditions. This table has been modified from de Souza et al.¹⁵

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 the optimized temperature (85 °C) has a deleterious effect on the yield (Table 1, entry 7)¹⁵. Reaction time can be increased without prominently affecting the yield. During the reaction, a needle must be inserted in the septum to relieve eventual pressure in the tube.

We noticed that the reaction involving the electron-rich alkyne 1-ethynyl-4-methoxybenzene was sluggish, thus we decided to use 4 equiv. of ammonium persulfate during 24 h of reaction time to reach an adequate yield (3d, Figure 1).

The workup in this protocol involves a centrifugation step and an extraction step using ethyl acetate. The centrifugation step makes the whole process of isolation much easier since any eventual emulsion formed can be broken promptly. It also avoids the use of drying agents as the separation of the aqueous and organic phases happens more efficiently. We have chosen ethyl acetate for sustainable reasons¹⁶; nevertheless, other common solvents for extraction can be used as well.

We observed no challenging purifications for the products; thus, a plug of silica was employed making the whole process more operationally and economically attractive. Most products were purified using 92:8 (hexanes/ethyl acetate). (3d, Figure 1) was purified using 80:20 (hexanes/ethyl acetate) and (3e, Figure 1) was purified using 90:10 (hexanes/ethyl acetate).

This straightforward protocol furnishes an array of functionalized benzene rings in high yields; however, the method is currently limited to terminal alkynes and α,β-unsaturated aliphatic compounds.¹⁵ Internal alkynes failed to provide the targeted products. In the reaction employing 4-phenylbut-3-yn-2-ol, a formal reduction of the triple bond occurred during the transformation whereas dimethyl but-2-ynedioate gave a cyclotrimerization product. The aromatic α,β-unsaturated ketone 4-phenylbut-3-en-2-one indeed gave the product but it was not separable employing only a plug of silica. As we were aiming to employ the lowest as possible amount of silica and solvents and consequently reduce the E-factor¹⁷, we ranked this substrate as unsuccessful in order to preserve the sustainability of the transformation. Currently, we are investigating modifications in the procedure in order to reach also these substrates.

We then suggested a possible reaction mechanism for the conversion (Figure 4, using phenylacetylene and methyl vinyl ketone as representative substrates). An aqueous solution of (NH₄)₂S₂O₈ under heating produces sulfate radical (Figure 4, step I). Such radical is prone to add to phenylacetylene providing radical B and styrene coming from radical B (Step II). Methyl vinyl ketone, radical B and styrene participate in a 3-component reaction to give radical C (Step III). Cyclization of C furnishes radical D (Step IV). Elimination of radical R yields olefin E (Step V) and further aromatization allows the formation of the targeted product (Step VI).

In summary, our protocol is a convenient method to explore the metal-free benzannulation reaction in water fulfilling the demands of sustainable chemistry and advocating in favor of operationally simple experimental setups.

Materials

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