Synthesis of 2-sulfenylindenones by visible-light-mediated addition of sulfur-centered radicals to 1,3-diarylpropynones

Abstract A novel, visible-light-mediated method for the synthesis of 2-sulfenylindenones from easily available thiophenols (2.0 equiv.) and 1, 3-diarylpropynones (1.0 equiv.) in the presence of eosin Y (0.02 equiv.) under air atmosphere has been developed. The reaction proceeded smoothly, for a wide range of derivatives of thiophenols and 3-diarylpropynones, to give the expected products in moderate to good yields. Compared with traditional methods, this method is more convenient and avoids using stoichiometric amounts of I2 and K2S2O8. Graphical Abstract


Introduction
Indenones are important structural motifs in a great number of pharmaceuticals and biologically active molecules, [1][2][3][4] they also serve as versatile intermediates in organic and pharmaceutical synthesis. [5,6] Hence, numerous methodologies have been developed for the synthesis of these structural motifs. Amongst the various approaches to produce indenones, the most commonly used methodologies are the intramolecular Friedel-Crafts-type-cyclizations or the addition of Grignard reagents to indandiones. [7,8] In comparison, Palladium or rhodium-catalyzed annulations of internal alkynes with 2halophenyl carbonyl compounds [9][10][11] or their equivalents [12][13][14][15][16][17] provided more direct strategy for the synthesis of substituted indenones. Recently, the cyclization of 1, 3-diarylpropynones triggered by superacids [18][19][20] has been shown to be an efficient method for the synthesis of indenones. The cyclization can also be triggered by sulfur-centered radicals generating from the reaction of manganese(III) acetate with arylthiols, as reported by the groups of Zou. [21,22] Very recently, similar tandem radical processes have been developed for the construction of indenones. [23][24][25] Professor Zhang has described an efficient approach to the synthesis of 2-sulfenylindenone derivatives through a tandem annulation of arylpropynols with disulfides, [23] the reaction pathway involves one-pot tandem Meyer-Schuster rearrangement of arylpropynols and successive radical cyclization with disulfides. But, the reaction necessitated stoichiometric amounts of I 2 and K 2 S 2 O 8 . While significant progress has been made in the construction of indenone skeletons, the development of new practical and general protocol for the synthesis of diverse multisubstituted indenones is still strongly desired.
As a clean, inexpensive and sustainable energy source, visible light has shown wide application prospects in organic synthesis. [26][27][28][29][30][31] From the viewpoint of energy efficiency, mild reaction conditions, synthetic simplicity, step and cost economy and the environment, the chemical transformations initiated by visible light (k ¼ 400-700 nm) sources have attracted considerable attention over a decade. [32] However, the visiblelight-driven catalytic radical cyclization of 1,3-diarylpropynones has not been uncovered. Herein, we describe a method for the synthesis of 2-sulfenylindenones derivatives from 1, 3-diarylpropynones and thiophenols under visible-light (green LEDs: k max ¼ 535 nm) photocatalyzed conditions (Scheme 1). In addition, a tentative mechanism is described for the reaction.

Results and discussion
Cheap, environmentally friendly and commercially available eosin Y and 1a, 3-diphenylpropynone (4a) and thiophenol, respectively, were chosen as photocatalyst and model substrates to optimize the reaction conditions. The optimization processes included wavelength of radiation source, solvents, catalyst, and its quantity and atmosphere. When a hexane solution containing 1, 3-diphenylpropynone (1.0 equiv.), thiophenol (2.0 equiv.), and a catalytic amount of eosin Y (2.0 mol%) was irradiated by white LEDs in an open vessel under ambient conditions for 20 h, the desired 3-phenyl-2-(phenylthio)-1H-inden-1-one was obtained in 27% yield ( Table 1, entry 1). Encouraged by these initial results, we optimized the reaction conditions further to increase the reaction yield. Interestingly, the yield of product enhanced to 38% when the reaction was performed with blue LEDs (k max ¼ 450 nm, Table 1, entry 2). It was gratifying that the desired product could be selectively produced in 58% yield when the reaction was performed with green LEDs (k max ¼ 535 nm, Table 1, entry 3). In contrast, the yield of product was lowered to 21% when the reaction was irradiated with a xenon lamp ( Table 1, entries 4). However, no product was detected in a dark environment (Table 1, entry 5). Afterward, the influence of solvents on the formation of 3-diarylpropynones was explored. The investigation revealed that DMSO was the most effective medium to promote the reaction with 82% yield (Table 1, entry 6) while the use of other solvents resulted in lower yields (Table 1, entries 6-10) even after 36 h of irradiation. In addition, several other photocatalysts including rose bengal, fluorescein, rhodamine, and eosin B were also investigated ( Table 1, entries [11][12][13][14]. Compared to eosin Y, these catalysts display much less efficiency toward the reaction. However, no product was observed without photocatalyst (Table 1, entries 15). With an increase in the catalyst amount from 2.0 mol% to 4.0-6.0 mol%, the reaction was accelerated obviously, but the yield was not improved (  Under the optimized reaction conditions, the reactions of a variety of substituted 1, 3-diarylpropynones 1 with thiophenol 2a were carried out ( Table 2). Several diarylpropynones bearing substituents at the ortho-and para-position of benzoyl, as well as alkyne part, were used in the reaction. The results shown in Table 2 indicate that electron-donating substituents on the benzoyl of 1,3-diphenylpropynones favored the reactions (Table 2, entries 1, 6, and 10), whereas electron-withdrawing groups on the benzoyl slightly disfavored the reactions ( Table 2, entries 3-5 and 7-9). The MeO group at the ortho-or para-positions of the benzoyl ring gave similar yields ( Table 2, entries 2 and 10). Electron-donating or electron-withdrawing groups on the alkyne part also gave moderate yields ( Table 2, entries 11-17).
Next, the scope of thiophenols was examined. As shown in Table 3, thiophenols bearing electron-donating or withdrawing groups were applicable to the coupling with moderate to good yields (Table 3). However, a strong dependence on the position of the substituents was observed (Table 3, entries 1, 4, 7, and 8). For example, a reaction with para-methyl substituted thiophenol afforded higher yield than ortho-methyl substituted thiophenol (Table 3, entries 1 and 7).
To gain insight into the mechanistic profile, a series of control experiments were conducted (Scheme 2). Initially, the present transformation was completely inhibited when a stoichiometric amount of a radical scavenger TEMPO was added into reaction system under the standard conditions and a TEMPO-trapped complex (4-MePhS-TEMPO) was detected by LC-MS analysis, most of 1a and 2b have been recovered. Thus, suggesting that this transformation might involve a radical process (Scheme 2a). Furthermore, the reaction did not proceed under an argon atmosphere, which indicates that air (O 2 ) is essential for the present transformation (Scheme 2b). Furthermore, when the reaction of 1a and p-Tolyl disulfide was carried out under the standard conditions, no desired product was obtained (Scheme 2c).
On the basis of the experimental results and the previous reports, [23][24][25]34,35] we proposed a tentative mechanism, as shown in Scheme 3. Initially, the excited state EY Ã was produced from Eosin Y under visible-light irradiation. A single-electron transfer (SET) from the excited state of EY Ã to thiol 2a gave the radical cation A and EY À radical anion. The oxidation of EY À by oxygen (air) would lead to the formation of the ground state Eosin Y and O 2 À , subsequently, the deprotonation of the radical cation A by O 2 À produced the thiyl radical B and hydroperoxide radical species. The thiyl radical B reacted with the carbon atom of the alkynyl to generate the radical C. Subsequently, C underwent intramolecular cyclization followed by hydrogen radical loss to afford the desired product.

Conclusion
In summary, we have developed a novel, visible-light photoredox catalysis for the conversion of a mixture of thiophenols and 1, 3-diarylpropynones into 2-sulfenylindenones. This method has some advantages such as easy operation, atom economy, good functional group tolerance, greenness and requires a very small quantity of non-metal catalyst. Further investigation focused on expanding the scope of substrates of this method is currently in progress. Synthesis of 3-phenyl-2-(phenylthio)-1H-inden-1-one; typical procedure

Experimental
To an oven-dried round, bottom flask equipped with a magnetic stir bar was charged with eosin Y (2.0 mol% in respect to amount of 1a), 1a (0.21 g, 1 mmol), 2a (0.22 g, 2 mmol) and DMSO solvent. The mixture was stirred a few minutes to mix well and then the flask was irradiated under a 5W green LED bulb at a distance of 5 cm. After stirring at room temperature for 20 h (The progress of the reaction was monitored using TLC), the solvent was removed under reduced pressure and the residue was then diluted with water. The aqueous solution was extracted (three times) with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous MgSO 4 , filtered, and concentrated. The residue was purified using column chromatography [SiO 2 column chromatography (petroleum ether (bp 60-90 C)/EtOAc ¼ 50:1)] to give 3-phenyl-2-(phenylthio)-1H-inden-1-one (0.26 g, 82%). Supplementary data Supporting information associated with this article can be found via the "Supplementary Content" section of this article's webpage.

Funding
We are grateful to the Fujian Province Young and Middle-aged Teacher Education Research Project (JAT160655), Innovation Training Program for College Students (201813470007), and the Fuzhou University Zhicheng College, for the support of this work.