Ruthenium-catalyzed C–H activation of thioxanthones

Abstract

Thioxanthones – being readily available in one step from thiosalicylic acid and arenes – were used in ruthenium-catalyzed C–H-activation reaction to produce 1-mono- or 1,8-disubstituted thioxanthones in good to excellent yields. Scope and limitation of this reaction are presented.

Introduction

Thioxanthones (Figure 1) belong as a unique member to the large group of benzoannelated heterocycles [1]. They have found extensive use in biomedical applications (drugs and other bioactive compounds [2–5]) and material sciences, e.g., as photosensitizers (e.g., isopropylthioxanthone or diethylthioxanthone) [6–8] or as ligands [9–10]. Despite the widespread occurrences, there are only few modular syntheses reported so far and photosensitizing materials are often used as undefined mixtures. In addition, functionalization reactions for thioxanthones, such as C–C-bond formations [11–12], are underdeveloped [13]. For example, there are only a handful of 1,8-dialkyl/aryl-functionalized thioxanthones known [14–16], while more than 500 1-substituted thioxanthones are reported according to Scifinder. In contrast, xanthone chemistry aiming at a high degree of substitution seems to be well explored [17–18].

Figure 1.

Thioxanthone (1a).

This fact motivated us to extend existing methods [14–15] for the synthesis of substituted thioxanthones. We were intrigued by the fact that carbonyl-substituted arenes can undergo a smooth C–H activation and alkylation in the presence of metal catalysts [19] (for general reviews see [20–21]). However, there are only few examples [14–15] with sulfur-containing heterocycles as in general sulfur inhibits the catalytic activity of many transition metal catalysts [22].

Results and Discussion

Synthesis of functionalized thioxanthones

The required thioxanthones 1 were prepared using standard procedures [1,23]. For certain examples, optimizations of the standard protocol were required (Table 1 and Supporting Information File 1).

Table 1.

Synthesis of substituted thioxanthones from thiosalicylic acid.^a

Entry	Arene 3	Thioxanthone 1	Yieldb
1	3b	1b	57
2	3c	1c	9
3	3e	1e	87
4	3h	1g	25

^aFor conditions see Supporting Information File 1; ^bisolated yields.

In case of methoxyarenes this method was not successful due to a partial ether cleavage catalyzed by hot sulfuric acid. In this case, methylation (Me₂SO₄, K₂CO₃) of the hydroxythioxanthones 1c, 1e and 1g provided the required methyl ethers 1d, 1f and 1h, respectively in good yields (80, 85 and 95%), Scheme 1.

Scheme 1.

Route to methoxyarenes 1d, 1f, and 1h.

Ru-catalyzed C–H activation

Following the precedence for other carbonyl compounds, we used the protocol of Murai et al. [19] to investigate the use of thioxanthones in this C–H-alkylation reaction (Scheme 2). For recent examples and reviews, also for related rhodium-catalyzed systems, see [24–38].

Scheme 2.

Ru-catalyzed C–H activation of thioxanthones. Conditions: 6 mol % RuH₂(CO)(PPh₃)₃, toluene, 135 °C, 12 h.

It should be noted that already in the pioneering work there are also examples using sulfur heterocycles such as thiophene derivatives [19]. Gratifyingly, the reaction of dimethyl-substituted thioxanthone 1b with the model olefin neohexene (3,3-dimethyl-1-butene, 4a) was successful and the product 1ba was obtained in 65% yield (Table 2, entry 4). This and all the products obtained exhibit exclusively n-alkylation – branched alkyl chains originating from addition at the 2-position were not found. Other olefins like 1-hexene (4b) or 3-phenylpropene (4c) also worked smoothly (Table 2, entries 5 and 6). In addition, the silyl-substituted olefin 4d was also successfully used in this reaction (Table 2, entry 7). The product 1bd is formed in good yield, however, it is prone to hydrolysis thus the isolated yield of the pure product was rather low. In contrast to literature precedence for other carbonyl compounds [19], other olefins (styrene, vinyl/allyl ethers, perfluoroalkylethenes) failed since they polymerize during the reaction.

Table 2.

C–H activation.

Entry	Thioxanthone	Alkene (equiv)	Product	Yield [%]a
1	1a	4a (1.2 equiv)	1aa	47
			1aabis	20
2	1a	4b (6 equiv)	1abbis	43
3	1a	4c (1.2 equiv)	1ac	7
4	1b	4a (3 equiv)	1ba	65
5	1b	4b (3 equiv)	1bb	66
6	1b	4c (3 equiv)	1bc	27
7	1b	4d (3 equiv)	1bd	55b
8	1h	4a (3 equiv)	1ha	83
9	1h	4b (3 equiv)	1hb	65

^aIsolated yields; ^bcrude yield close to quantitative, but product prone to hydrolysis.

Extension of the unsymmetrical heterocycle system 1b to the unsubstituted thioxanthone (1a) was also successful: Depending on the amount of alkene, mono- (Table 2, entry 3) or 1,8-disubstituted thioxanthones such as 1aa_bis or 1ab_bis were isolated (see Table 2, entries 1 and 2). In addition, other thioxanthones such as 1h are also suitable substrates (Table 2, entries 8 and 9).

However, other thioxanthones such as a phenanthrene-annelated thioxanthone (not shown) failed to give the desired products due to insolubility of the starting materials.

Conclusion

We have presented a C–H-activation route towards the preparation of functionalized thioxanthones. Despite the fact that mono- and disubstituted thioxanthones can be found starting from the parent system, the selectivity can be controlled using different stoichiometries. It should be noted that alkoxy and silyl functionalities are tolerated in the reaction.

Experimental

The catalyst RuH₂(CO)(PPh₃)₃ was prepared according to literature [19] and stored under Argon with exclusion of water.

General procedure for C–H activation

In a sealed Schlenk pressure tube, 1.00 mmol of the thioxanthone, 0.060 mmol (55 mg) RuH₂(CO)(PPh₃)₃, 1.2 to 6 mmol of the olefin and 2 mL toluene were stirred and heated to 135 °C for 12 h. After cooling, the solvent was evaporated under reduced pressure and the residue submitted to column chromatography on silica gel using cyclohexane/ethyl acetate as eluent.

Supporting Information

File 1

Characterization data and spectra for compounds 2 and 3.