Benzeneseleninic Acid in the Photo-Catalyzed Hydroxy-Selenylation of Styrenes ^†

Abstract

We established a new visible-light-mediated protocol for the regioselective β-hydroxyselenylation of olefins, employing benzeneseleninic acid as substrate. Regarding a novel approach, the benzeneseleninic acid emerges as an efficient and affordable reagent to be used as an electrophilic selenium source that can be easily converted to selenium-based radical species under visible-light conditions. In this sense, the photocatalytically formed PhSe• radical can react directly with unsaturated substrates, including alkenes, to access a new C–Se bond and a carbon-centered radical intermediate, which finally is trapped by a hydroxyl radical species, delivering the β-hydroxyselanyl compounds. Thus, despite the versatile utilities in organic synthesis, such as building blocks, the β-hydroxyselanyl compounds have demonstrated important biological activities. Based on that, we concentrated our efforts on developing a robust, effective, and environmentally benign methodology for their preparation. The optimal condition involves the reaction between styrene and 1.0 equivalent of phenylseleninic acid, in the presence of 5.0 mol% of eosin Y, as a cheap and easily available photocatalyst, with DMSO promoting the reaction medium. Satisfactorily, the system was irradiated with blue LED light for 2 h, to deliver the desired products in good yields.

1. Introduction

β-hydroxyselanyl derivatives have valuable structural functions, appearing in a variety of drug candidates, biologically active compounds and advanced organic synthetic materials [1,2]. They also act as an important synthetic intermediate for the construction of natural products, such as pancratistatin [3], sphingosine [4], and schweinfurthin B [5]. Additionally, β-hydroxy selenides have been employed smoothly as substrate to access allylic alcohols [6], olefins [7], bromohydrins [8], and oxygen-containing heterocycles [9].

There are, in the literature, several methods to prepare these compounds. The most conventional involves the ring-opening reactions of epoxides with the selenolate anions (RSe⁻), which can be generated in situ from diselenides [10] or from elemental selenium [11]. However, long reaction times, limited substrate scope and poor regioselectivity are among the common drawbacks found in these protocols. Thus, recently, several alternative protocols for synthesis of β-hydroxy selenides have been emerging. Among them, the regioselective direct hydroxyselenation of active olefins, with diselenides [12,13,14,15], has proven to be a highly effective and robust strategy to prepare β-hydroxy selenides. However, the use of benzeneseleninic acids, as a bench-stable electrophilic Se-based source, is still scarce [16].

On the other hand, the use of alternative energy sources has become a remarkable factor in organic synthesis, in order to circumvent the use of oil-based energies. In this context, several methods involving the hydroxyselenation of olefins have been using alternative energy sources, including microwave irradiation [17], ultrasonic irradiation [18], and electricity [19].

Based on that, herein is described a robust, effective, and environmentally benign methodology for preparation β-hydroxyselenylation of olefins, employing benzeneseleninic acids as bench-stable Se-based electrophile, under a photocatalytic system.

2. Results and Discussion

Firstly, in a reaction flask were added benzeneseleninic acid (1) (0.3 mmol), styrene (2) (1.0 equiv.), the organic photocatalyst eosin Y (5 mol%) and dimethylsulfoxide (DMSO, 1.0 mL). The resulting mixture was stirred for 1 h, at room temperature, under blue LED (light-emitting diode) irradiation. At the end, the desired product 3 was obtained in 65% yield (

Table 1. Optimization of reaction conditions ^a.

Entry	Solvent	Time (h)	Yield 3 (%) b	Yield 4 (%) b
1	DMSO	1	65	Trace
2	DMSO	2	73	11
3	DMSO	4	65	16
4	DMSO	24	56	21
5	DCM	2	-	18
6	MeCN	2	14	21
7	THF	2	15	4
8	PEG 400	2	7	Trace
9	DMF	2	25	4
10	Ethyl Acetate	2	9	-
11 c	DMSO	2	13	Trace
12 d	DMSO	2	44	5
13 e	DMSO	2	-	-

Reaction conditions. ^a In a specific reaction tube were added 0.3 mmol of benzeneseleninic acid (1), 0.3 mmol of styrene (2), 5 mol% of Eosin Y, as a photocatalyst, and solvent (1.5 mL). The mixture reaction was stirred at the room temperature under blue LED (light-emitting diode) light irradiation (50 W). The reactions were monitored by TLC (thin-layer chromatography). ^b Isolated yields obtained by chromatographic column. ^c Reaction performed with 3 mol% of Eosin Y. ^d Reaction performed with 10 mol% of Eosin Y. ^e Reaction performed without Eosin Y.

, entry 1). Parallelly, a trace amount of β-selenoketone 4 was obtained as byproduct. Then, in order to drive the reaction toward the product 3, longer reaction times were evaluated (Table 1, entries 2–4). In 2 h, the product 3 was obtained in 73%, with an overall yield of 84%. However, a slight decrease in the reaction selectivity was observed when the mixture was irradiated for 4 h, affording an overall yield of 81% with 65% of the product 3. Thus, based on these observations, 2 h was elected as the best reaction time to obtain compound 3 efficiently. Thus, a range of different organic solvents were employed to promote the reaction medium; however, none of them delivered better results (Table 1, entries 5–10).

Thus, eosin Y was employed in 3 and 10 mol%, however, the access to the product 3 has been negatively affected (Table 1, entries 11–12). Finally, in order to prove that the use of eosin Y is mandatory for the reaction success, an experiment was carried out in the absence of catalyst, in which almost all substrates were recovered at the end (Table 1, entry 13). In addition, it was possible to observe the formation of a small amount of diphenyl diselenide, resulting from benzeneseleninic acid oxidation. Based on that, the best reaction condition was defined by reacting the substrates 1 and 2 for 2 h, in the presence of DMSO and under blue LED light irradiation at room temperature, affording the desired β-hydroxy selenide 3 in 73% yield (Table 1, entry 3).

3. Conclusions

In conclusion, we have developed a simple and efficient approach for the β-hydroxyselenylation of styrenes, employing benzeneseleninic acids, as an efficient Se-based source, presenting a good regioselectivity toward the β-hydroxy selenide 3. It is worth mentioning that some studies are still occurring in our laboratory, including the influence of other wavelength sources and the reaction substrate scope, as well as the search for evidence to clarify each step of the reaction mechanism.

4. General Information

The reactions were irradiated by blue LED light (50 W) and monitored by TLC (thin-layer chromatography) carried out on pre-coated TLC sheets ALUGRAM^® Xtra SIL G/UV254 by using UV light as a visualization agent and the mixture of 5% vanillin in 10% H₂SO₄ under heating conditions as a developing agent. The purification was performed by flash chromatography, employing Merck silica gel (particle size 63–200 μm) as a stationary phase. Hydrogen nuclear magnetic resonance spectra (¹H NMR) were obtained at 400 MHz on Bruker Ascend 400 spectrometer. The spectra were recorded in CDCl₃ solutions. The chemical shifts are reported in ppm, referenced to tetramethysilane (TMS) as the external reference. Hydrogen coupling patterns are described as singlet (s), doublet (d), triplet (t), doublet of doublets (dd), and multiplet (m). Coupling constants (J) are reported in Hertz. Carbon-13 nuclear magnetic resonance spectra (¹³C NMR) were obtained at 100 MHz on Bruker Nuclear Ascend 400 spectrometer. The chemical shifts are reported in ppm, referenced to the solvent peak of CDCl₃

General procedure for synthesis of β-hydroxyselanyl compound 3a: In a specific reaction tube was added 0.3 mmol of benzeneseleninic acid (1), 0.3 mmol of styrene (2), 5 mol% of photocatalyst Eosin Y and 1.0 mL of DMSO. The reaction was stirred for 2 h at room temperature under blue LED visible light. After the reaction time, the solvent was completely removed under vacuum to give the crude. The product was purified by column chromatographic using silica gel as the stationary phase and a mixture of ethyl acetate and hexane (20:80) as the mobile phase. The desired compound 3 and the by-product 4 were characterized by NMR analysis.