Ruthenium-catalyzed C–H activation of thioxanthones

  1. 1 and
  2. 1,2
1Department of Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
2Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
  1. Corresponding author email
Associate Editor: K. Itami
Beilstein J. Org. Chem. 2015, 11, 431–436. https://doi.org/10.3762/bjoc.11.49
Received 09 Feb 2015, Accepted 14 Mar 2015, Published 02 Apr 2015
Full Research Paper
cc by logo
PDF
Album
Supp Info
Cite

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.

Keywords: C–H activation; metal catalysis; thioxanthones

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].

[1860-5397-11-49-1]

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

[Graphic 1]
Entry Arene 3 Thioxanthone 1 Yieldb
1 [Graphic 2]
3b 		[Graphic 3]
1b 		57
2 [Graphic 4]
3c 		[Graphic 5]
1c 		9
3 [Graphic 6]
3e 		[Graphic 7]
1e 		87
4 [Graphic 8]
3h 		[Graphic 9]
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.

[1860-5397-11-49-i1]

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].

[1860-5397-11-49-i2]

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.

[Graphic 10]
Entry Thioxanthone Alkene (equiv) Product Yield [%]a
1 [Graphic 11]
1a 		[Graphic 12]
4a
(1.2 equiv) 		[Graphic 13]
1aa 		47
      [Graphic 14]
1aabis 		20
2 [Graphic 15]
1a 		[Graphic 16]
4b
(6 equiv) 		[Graphic 17]
1abbis 		43
3 [Graphic 18]
1a 		[Graphic 19]
4c
(1.2 equiv) 		[Graphic 20]
1ac 		7
4 [Graphic 21]
1b 		[Graphic 22]
4a
(3 equiv) 		[Graphic 23]
1ba 		65
5 [Graphic 24]
1b 		[Graphic 25]
4b
(3 equiv) 		[Graphic 26]
1bb 		66
6 [Graphic 27]
1b 		[Graphic 28]
4c
(3 equiv) 		[Graphic 29]
1bc 		27
7 [Graphic 30]
1b 		[Graphic 31]
4d
(3 equiv) 		[Graphic 32]
1bd 		55b
8 [Graphic 33]
1h 		[Graphic 34]
4a
(3 equiv) 		[Graphic 35]
1ha 		83
9 [Graphic 36]
1h 		[Graphic 37]
4b
(3 equiv) 		[Graphic 38]
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 1aabis or 1abbis 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

Supporting Information File 1: Characterization data and spectra for compounds 2 and 3.
Format: PDF Size: 2.0 MB Download

Acknowledgements

This work was supported by Joint-Lab IP3, the collaboration between KIT and BASF. We thank Dr. Thierry Muller (formerly KIT, now Clariant) and Dr. Michael Wörner (KIT) for fruitful discussions in the outset of this project.

References

  1. Nelson, A. Sci. Synth. 2003, 14, 787.
    Return to citation in text: [1] [2]
  2. Woo, S.-W.; Kang, D.-H.; Kim, J.-S.; Lee, C.-S.; Lee, E.-S.; Jahng, Y.-D.; Kwon, Y.-J.; Na, Y.-H. Bull. Korean Chem. Soc. 2008, 29, 471. doi:10.5012/bkcs.2008.29.2.471
    Return to citation in text: [1]
  3. Lima, R. T.; Sousa, D.; Choosang, K.; Pakkong, P.; Palmeira, A.; Paiva, A. M.; Seca, H.; Cerqueira, F.; Pedro, M.; Pinto, M. M.; Sousa, E.; Vasconcelos, M. H. Ann. Oncol. 2013, 24 (Suppl. 1), i26. doi:10.1093/annonc/mdt045.14
    Return to citation in text: [1]
  4. Lockhart, A. C.; Calvo, E.; Tolcher, A. W.; Rowinsky, E. K.; Shackleton, G.; Morrison, J. G.; Rafi, R.; VerMeulen, W.; Rothenberg, M. L. Am. J. Clin. Oncol. 2009, 32, 9. doi:10.1097/COC.0b013e318178331b
    Return to citation in text: [1]
  5. Paiva, A. M.; Pinto, M. M.; Sousa, E. Curr. Med. Chem. 2013, 20, 2438. doi:10.2174/0929867311320190004
    Return to citation in text: [1]
  6. Karasu, F.; Arsu, N.; Jockusch, S.; Turro, N. J. J. Org. Chem. 2013, 78, 9161. doi:10.1021/jo401386t
    Return to citation in text: [1]
  7. Balta, D. K.; Temel, G.; Goksu, G.; Ocal, N.; Arsu, N. Macromolecules 2012, 45, 119. doi:10.1021/ma202168m
    Return to citation in text: [1]
  8. Malval, J.-P.; Jin, M.; Morlet-Savary, F.; Chaumeil, H.; Defoin, A.; Soppera, O.; Scheul, T.; Bouriau, M.; Baldeck, P. L. Chem. Mater. 2011, 23, 3411. doi:10.1021/cm200595y
    Return to citation in text: [1]
  9. Breslow, R.; Mehta, M. P. J. Am. Chem. Soc. 1986, 108, 6417. doi:10.1021/ja00280a065
    Return to citation in text: [1]
  10. Breslow, R.; Guo, T. Tetrahedron Lett. 1987, 28, 3187. doi:10.1016/S0040-4039(00)95467-4
    Return to citation in text: [1]
  11. Zinad, D. S.; Feist, H.; Villinger, A.; Langer, P. Tetrahedron 2012, 68, 711. doi:10.1016/j.tet.2011.10.095
    Return to citation in text: [1]
  12. Zinad, D. S.; Hussain, M.; Akrawi, O. A.; Villinger, A.; Langer, P. Tetrahedron Lett. 2011, 52, 3451. doi:10.1016/j.tetlet.2011.04.102
    Return to citation in text: [1]
  13. Karasu, F.; Arsu, N.; Yagci, Y. J. Appl. Polym. Sci. 2007, 103, 3766. doi:10.1002/app.25467
    Return to citation in text: [1]
  14. Gupta, S. K.; Weber, W. P. Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 1999, 40, 62.
    Return to citation in text: [1] [2] [3]
  15. Niesert, C.-P.; Pawlowski, G.; Gries, W.-K.; Przybilla, K.-J. Mit Silikonen kompatible Photoinitiatoren und diese enthaltende lichtempfindliche Gemische. Eur. Pat. Appl. 0705865 A1, April 1, 1996.
    Return to citation in text: [1] [2] [3]
  16. Schaarschmidt, A. Justus Liebigs Ann. Chem. 1915, 409, 59. doi:10.1002/jlac.19154090106
    Return to citation in text: [1]
  17. Gérard, E. M. C.; Bräse, S. Chem. – Eur. J. 2008, 14, 8086. doi:10.1002/chem.200801507
    Return to citation in text: [1]
  18. Masters, K.-S.; Bräse, S. Chem. Rev. 2012, 112, 3717. doi:10.1021/cr100446h
    Return to citation in text: [1]
  19. Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993, 366, 529. doi:10.1038/366529a0
    Return to citation in text: [1] [2] [3] [4] [5]
  20. Jean-Gerard, L.; Jazzar, R.; Baudoin, O. In Metal-Cross Coupling Reactions and more; de Meijere, A.; Bräse, S.; Oestreich, M., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2014; Vol. 3, p 1427.
    Return to citation in text: [1]
  21. Dyker, G., Ed. Handbook of C-H Transformations: Applications in Organic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2005; Vol. 2.
    Return to citation in text: [1]
  22. Badano, J. M.; Quiroga, M.; Betti, C.; Vera, C.; Canavese, S.; Coloma-Pascual, F. Catal. Lett. 2010, 137, 35. doi:10.1007/s10562-010-0336-x
    Return to citation in text: [1]
  23. Okabayashi, I.; Kimura, M.; Fujiwara, H.; Kato, A. Chem. Pharm. Bull. 1987, 35, 2545. doi:10.1248/cpb.35.2545
    Return to citation in text: [1]
  24. Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992. doi:10.1126/science.287.5460.1992
    Return to citation in text: [1]
  25. Yamamoto, Y. Chem. Soc. Rev. 2014, 43, 1575. doi:10.1039/C3CS60369E
    Return to citation in text: [1]
  26. Chinchilla, R.; Nájera, C. Chem. Rev. 2014, 114, 1783. doi:10.1021/cr400133p
    Return to citation in text: [1]
  27. Trejos, A.; Odell, L. R. Sci. Synth. 2013, 3, 345.
    Return to citation in text: [1]
  28. Hussain, H.; Green, I. R.; Ahmed, I. Chem. Rev. 2013, 113, 3329. doi:10.1021/cr3004373
    Return to citation in text: [1]
  29. Engle, K. M.; Yu, J.-Q. J. Org. Chem. 2013, 78, 8927. doi:10.1021/jo400159y
    Return to citation in text: [1]
  30. Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Tetrahedron 2012, 68, 5130. doi:10.1016/j.tet.2012.05.040
    Return to citation in text: [1]
  31. Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta 2012, 45, 31.
    Return to citation in text: [1]
  32. Mei, T.-S.; Kou, L.; Ma, S.; Engle, K. M.; Yu, J.-Q. Synthesis 2012, 44, 1778. doi:10.1055/s-0031-1289766
    Return to citation in text: [1]
  33. Leyva-Pérez, A.; Corma, A. Angew. Chem., Int. Ed. 2012, 51, 614. doi:10.1002/anie.201101726
    Return to citation in text: [1]
  34. Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236. doi:10.1002/anie.201203269
    Return to citation in text: [1]
  35. Fedorov, A. Yu.; Nyuchev, A. V.; Beletskaya, I. P. Chem. Heterocycl. Compd. 2012, 48, 166. doi:10.1007/s10593-012-0980-8
    Return to citation in text: [1]
  36. Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. doi:10.1021/cr100280d
    Return to citation in text: [1]
  37. Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. doi:10.1039/c1cs15083a
    Return to citation in text: [1]
  38. Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293. doi:10.1021/cr100198w
    Return to citation in text: [1]

© 2015 Wagner and Bräse; licensee Beilstein-Institut.
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)