2020, Vol.49, No.7

An efficient thioxanthone synthesis from benzoic acid esters is disclosed. Various thioxanthones were prepared by iridium-catalyzed C–H borylation of benzoic acid esters followed by copper-catalyzed deborylthiolation and direct acid-mediated cyclization. We also achieved a synthesis of benzo-fused thioxanthones through a transformation of an aryne intermediate having an ester moiety.

Thioxanthones have gained attention from a broad range of researchers as synthetic intermediates for organosulfur compounds, photoredox catalysts, photoinitiators, and bioactive compounds such as lucanthone (Figure 1A).1 Despite the importance of thioxanthone derivatives, it is not easy to synthesize thioxaothones by conventional methods through copper-mediated S-arylation with aryl halides followed by cyclization of carboxylic acids under acidic conditions (Figure 1B).1,2 In particular, a synthesis of multisubstituted thioxanthones including π-extended ring-fused thioxanthones is quite limited due to the poor accessibility of the corresponding thiols, the narrow substrate scope of S-arylation, and the harsh reaction conditions requiring an excess amount of strong acids. Therefore, a facile synthetic method enabling preparation of diverse thioxanthones from simple starting materials is desired. Herein, we describe a thioxanthone synthesis from easily available benzoic acid esters through formal ortho-C–H thiolation followed by direct trifluoromethanesulfonic acid (TfOH)-mediated cyclization (Figure 1C).

Based on our continuous efforts toward organosulfur chemistry,3 we planned to develop a novel synthetic route for thioxanthones from benzoic acid esters and thiosulfonates. Recently, an odorless user-friendly diaryl sulfide synthesis catalyzed by copper has been developed using a thiosulfonate as a sulfur surrogate.3a,3c Considering the broad substrate scope of the sulfide synthesis, we envisioned that the iridium-catalyzed ortho-borylation of benzoic acid esters4 followed by the copper-catalyzed deborylthiolation and direct cyclization would afford a wide variety of thioxanthone derivatives.57 Since halogeno groups would be tolerated in these transformations, a combination between this thioxanthone synthesis and subsequent cross-coupling chemistry will remarkably expand synthesizable thioxanthones.

Firstly, we conducted ortho-borylation of benzoic acid esters 1a1c according to a report4 by Smith and coworkers and attempted the copper-catalyzed deborylthiolation of the resulting arylboronic acid pinacol esters 2a2c with thiosulfonates 3a3c (Figure 2). As a result, after the selective borylation of benzoic acid esters 1a1c with a catalytic amount of [(MeO)Ir(cod)]2 and SIPBz (Figures 2A and 2B), a variety of 2-(arylthio)benzoic acid esters 4a4f were successfully prepared in high to excellent yields (Figure 2C). Particularly, the copper-catalyzed deborylthiolation using thiosulfonates having not only electron-donating methoxy and methyl groups but also electron-withdrawing chloro, fluoro, and bromo groups took place without a significant decrease in the efficiencies.

We then screened the reaction conditions for direct cyclization from 2-(arylthio)benzoic acid esters to thioxanthones without obtaining benzoic acids (Table 1). The results showed that TfOH8 facilitated the direct construction of the thioxanthone skeleton from ester 4a. We found that 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)9 dramatically promoted the TfOH-mediated intramolecular Friedel–Crafts-type reaction among various solvents tested (Entry 6 vs Entries 1–5). It is worthy to note that the cyclization also proceeded at room temperature (Entry 7). On the other hand, the cyclization using concentrated sulfuric acid or trifluoroacetic acid instead of TfOH resulted in failure (Entries 8 and 9). Good accessibility of benzoic acid esters 4 is a significant advantage of this method, while benzoic acids possessing arylthio groups at the ortho position have been used in the conventional methods for the formation of thioxanthone skeleton.

Table 1. Optimization of the reaction conditions
Table 1. Optimization of the reaction conditions
Entry Acid Solv. Temp. Yield/%a
1 TfOH MeCN 100 °C 13
2 TfOH MeNO2 100 °C 38
3 TfOH ClCH2CH2Cl 100 °C 21
4 TfOH toluene 100 °C 36
5 TfOH CF3CH2OH 65 °C 13
6 TfOH HFIP 65 °C 98 (97)b
7 TfOH HFIP rt 80
8 conc. H2SO4 HFIP 65 °C 0
9 CF3CO2H HFIP 65 °C 0

a 1H NMR yields. bIsolated yield.

A variety of disubstituted thioxanthones were successfully prepared by the acid-mediated ring-closure (Figure 3). Indeed, the cyclization of 2-(4-anisylthio)-6-methoxybenzoic acid ester 4b proceeded smoothly to afford thioxanthone 5b in good yield. Benzoic acid ester 4c having an electron-deficient 4-chlorophenylthio group was also applicable providing 2-chloro-8-methoxythioxanthone (5c) in moderate yield. Treatment of fluoro- and bromo-substituted 2-(4-tolylthio)benzoic acid esters 4d and 4e with TfOH furnished the corresponding thioxanthones 5d and 5e, respectively, in high yields. Furthermore, thioxanthone 5f having a transformable chloro and bromo groups was successfully synthesized in high yield leaving these functional groups untouched.

Consecutive palladium-catalyzed cross-coupling reactions of thioxanthone 5f bearing a chloro and a bromo group were accomplished (Figure 4).10 Treatment of thioxanthone 5f with 3-thienylboronic acid (6a) in the presence of potassium phosphate and a catalytic amount of (amphos)2PdCl2 in dioxane and water resulted in the selective C–C bond formation at the bromo group in good yield.11 The second cross-coupling of resulting thioxanthone 7 with 4-tolylboronic acid (6b) was prompted by a second-generation Pd–XPhos precatalyst to yield thioxanthone 8 efficiently.12 The wide viability of the cross-coupling chemistry will serve in the rapid construction of a diverse thioxanthone library.

We then developed a synthetic method of ring-fused thioxanthones 13 through 4-(methoxycarbonyl)benzyne intermediate (I) (Figure 5).13,14 According to our previous reports, treatment of a mixture of 4-(methoxycarbonyl)-2-iodophenyl triflate (9) and 2,5-dimethylfuran (10) with trimethylsilylmagnesium chloride15 and following aromatization with sodium iodide and trimethylsilyl chloride16 afforded methoxycarbonyl-substituted naphthalene 11 in good yields. The resulting ester 11 was successfully borylated by the iridium-catalyzed C–H activation in a regioselective manner. Following deborylthiolation with thiosulfonates 3a3c afforded sulfides 12a12c efficiently. Finally, TfOH-promoted cyclization of sulfides 12a12c occurred smoothly to furnish a range of benzothioxanthones 13a13c having methyl, methoxy, and chloro groups in good yields. In addition, benzothioxanthone 13a emitted significant blue-green fluorescence under excitation at 440 nm.17 Considering the versatility of aryne intermediates by a wide variety of transformations, various multisubstituted thioxanthones would be synthesized via aryne reactions with diverse arynophiles.

In summary, we have developed a novel method to prepare thioxanthone derivatives from benzoic acid esters and thiosulfonates. The synthetic utility of this method was clearly shown by the thioxanthone synthesis on the basis of the consecutive cross-coupling approach and synthetic aryne chemistry. Further studies are underway to disclose the detailed scope and limitations of this thioxanthone synthesis, examine structure–fluorescence relationship, and synthesize highly π-extended compounds.

This work was supported by JSPS KAKENHI Grant Numbers JP19K05451 (C; S.Y.), JP17J08217 (JSPS Research Fellow; K.U.), JP18H02104 (B; T.H.), and JP18H04386 (Middle Molecular Strategy; T.H.); the Naito Foundation (S.Y.); the Japan Agency for Medical Research and Development (AMED) under Grant Number JP19am0101098 (Platform Project for Supporting Drug Discovery and Life Science Research, BINDS); and the Cooperative Research Project of Research Center for Biomedical Engineering.

Supporting Information is available on https://doi.org/10.1246/cl.200190.