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

Bräse, S.

Wagner, D.

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Danny Wagner

Stefan Bräse

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Ruthenium-catalyzed C–H activation of thioxanthones

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431Ruthenium-catalyzed C–H activation of thioxanthonesDanny Wagner1 and Stefan Bräse*1,2Full Research Paper Open AccessAddress:1Department of Chemistry, Karlsruhe Institute of Technology,Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany and 2Institute ofToxicology and Genetics, Karlsruhe Institute of Technology, CampusNorth, Hermann-von-Helmholtz-Platz 1, 76344Eggenstein-Leopoldshafen, GermanyEmail:Stefan Bräse* - braese@kit.edu* Corresponding authorKeywords:C–H activation; metal catalysis; thioxanthonesBeilstein J. Org. Chem. 2015, 11, 431–436.doi:10.3762/bjoc.11.49Received: 09 February 2015Accepted: 14 March 2015Published: 02 April 2015Associate Editor: K. Itami© 2015 Wagner and Bräse; licensee Beilstein-Institut.License and terms: see end of document.AbstractThioxanthones – 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 thisreaction are presented.IntroductionThioxanthones (Figure 1) belong as a unique member to thelarge group of benzoannelated heterocycles [1]. They havefound extensive use in biomedical applications (drugs and otherbioactive compounds [2-5]) and material sciences, e.g., asphotosensitizers (e.g., isopropylthioxanthone or diethylthioxan-thone) [6-8] or as ligands [9,10]. Despite the widespread occur-rences, there are only few modular syntheses reported so far andphotosensitizing materials are often used as undefined mixtures.In addition, functionalization reactions for thioxanthones, suchas C–C-bond formations [11,12], are underdeveloped [13]. Forexample, there are only a handful of 1,8-dialkyl/aryl-functional-ized thioxanthones known [14-16], while more than 5001-substituted thioxanthones are reported according to Scifinder.In contrast, xanthone chemistry aiming at a high degree ofsubstitution seems to be well explored [17,18].Figure 1: Thioxanthone (1a).This fact motivated us to extend existing methods [14,15] forthe synthesis of substituted thioxanthones. We were intriguedby the fact that carbonyl-substituted arenes can undergo asmooth C–H activation and alkylation in the presence of metalcatalysts [19] (for general reviews see [20,21]). However, thereare only few examples [14,15] with sulfur-containing hetero-Beilstein J. Org. Chem. 2015, 11, 431–436.432Scheme 2: Ru-catalyzed C–H activation of thioxanthones. Conditions: 6 mol % RuH2(CO)(PPh3)3, toluene, 135 °C, 12 h.cycles as in general sulfur inhibits the catalytic activity of manytransition metal catalysts [22].Results and DiscussionSynthesis of functionalized thioxanthonesThe required thioxanthones 1 were prepared using standard pro-cedures [1,23]. For certain examples, optimizations of the stan-dard protocol were required (Table 1 and Supporting Informa-tion File 1).In case of methoxyarenes this method was not successful dueto a partial ether cleavage catalyzed by hot sulfuric acid. Inthis case, methylation (Me2SO4, K2CO3) of the hydroxy-thioxanthones 1c, 1e and 1g provided the required methyl ethers1d, 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 activationFollowing the precedence for other carbonyl compounds, weused the protocol of Murai et al. [19] to investigate the use ofthioxanthones in this C–H-alkylation reaction (Scheme 2). Forrecent examples and reviews, also for related rhodium-catalyzedsystems, see [24-38].It should be noted that already in the pioneering work there arealso examples using sulfur heterocycles such as thiophenederivatives [19]. Gratifyingly, the reaction of dimethyl-substi-Table 1: Synthesis of substituted thioxanthones from thiosalicylicacid.aEntry Arene 3 Thioxanthone 1 Yieldb13b 1b5723c 1c933e 1e8743h 1g25aFor conditions see Supporting Information File 1; bisolated yields.tuted thioxanthone 1b with the model olefin neohexene (3,3-dimethyl-1-butene, 4a) was successful and the product 1ba wasobtained in 65% yield (Table 2, entry 4). This and all the prod-Beilstein J. Org. Chem. 2015, 11, 431–436.433Table 2: C–H activation.Entry Thioxanthone Alkene (equiv) Product Yield [%]a11a4a(1.2 equiv)1aa471aabis2021a4b(6 equiv)1abbis4331a4c(1.2 equiv)1ac741b4a(3 equiv)1ba65ucts obtained exhibit exclusively n-alkylation – branched alkylchains originating from addition at the 2-position were notfound. Other olefins like 1-hexene (4b) or 3-phenylpropene (4c)also worked smoothly (Table 2, entries 5 and 6). In addition, thesilyl-substituted olefin 4d was also successfully used in thisreaction (Table 2, entry 7). The product 1bd is formed in goodyield, however, it is prone to hydrolysis thus the isolated yieldof the pure product was rather low. In contrast to literatureprecedence for other carbonyl compounds [19], other olefins(styrene, vinyl/allyl ethers, perfluoroalkylethenes) failed sincethey polymerize during the reaction.Extension of the unsymmetrical heterocycle system 1b tothe unsubstituted thioxanthone (1a) was also successful:Depending on the amount of alkene, mono- (Table 2, entry 3) or1,8-disubstituted thioxanthones such as 1aabis or 1abbis wereBeilstein J. Org. Chem. 2015, 11, 431–436.434Table 2: C–H activation. (continued)51b4b(3 equiv)1bb6661b4c(3 equiv)1bc2771b4d(3 equiv)1bd55b81h4a(3 equiv)1ha8391h4b(3 equiv)1hb65aIsolated yields; bcrude yield close to quantitative, but product prone to hydrolysis.isolated (see Table 2, entries 1 and 2). In addition, otherthioxanthones such as 1h are also suitable substrates (Table 2,entries 8 and 9).However, other thioxanthones such as a phenanthrene-annelatedthioxanthone (not shown) failed to give the desired productsdue to insolubility of the starting materials.ConclusionWe have presented a C–H-activation route towards the prepar-ation of functionalized thioxanthones. Despite the fact thatmono- and disubstituted thioxanthones can be found startingfrom the parent system, the selectivity can be controlled usingdifferent stoichiometries. It should be noted that alkoxy andsilyl functionalities are tolerated in the reaction.ExperimentalThe catalyst RuH2(CO)(PPh3)3 was prepared accordingto literature [19] and stored under Argon with exclusion ofwater.General procedure for C–H activationIn a sealed Schlenk pressure tube, 1.00 mmol of the thioxan-thone, 0.060 mmol (55 mg) RuH2(CO)(PPh3)3, 1.2 to 6 mmolof the olefin and 2 mL toluene were stirred and heated to135 °C for 12 h. After cooling, the solvent was evaporatedBeilstein J. Org. Chem. 2015, 11, 431–436.435under reduced pressure and the residue submitted to columnchromatography on silica gel using cyclohexane/ethyl acetate aseluent.Supporting InformationSupporting Information File 1Characterization data and spectra for compounds 2 and 3.[http://www.beilstein-journals.org/bjoc/content/supplementary/1860-5397-11-49-S1.pdf]AcknowledgementsThis work was supported by Joint-Lab IP3, the collaborationbetween 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.References1. Nelson, A. Sci. Synth. 2003, 14, 787.2. 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.2008.29.2.4713. 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/mdt045.144. 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.0b013e318178331b5. Paiva, A. M.; Pinto, M. M.; Sousa, E. Curr. Med. Chem. 2013, 20,2438. doi:10.2174/09298673113201900046. Karasu, F.; Arsu, N.; Jockusch, S.; Turro, N. J. J. Org. Chem. 2013, 78,9161. doi:10.1021/jo401386t7. Balta, D. K.; Temel, G.; Goksu, G.; Ocal, N.; Arsu, N. Macromolecules2012, 45, 119. doi:10.1021/ma202168m8. 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/cm200595y9. Breslow, R.; Mehta, M. P. J. Am. Chem. Soc. 1986, 108, 6417.doi:10.1021/ja00280a06510. Breslow, R.; Guo, T. Tetrahedron Lett. 1987, 28, 3187.doi:10.1016/S0040-4039(00)95467-411. Zinad, D. S.; Feist, H.; Villinger, A.; Langer, P. Tetrahedron 2012, 68,711. doi:10.1016/j.tet.2011.10.09512. Zinad, D. S.; Hussain, M.; Akrawi, O. A.; Villinger, A.; Langer, P.Tetrahedron Lett. 2011, 52, 3451. doi:10.1016/j.tetlet.2011.04.10213. Karasu, F.; Arsu, N.; Yagci, Y. J. Appl. Polym. Sci. 2007, 103, 3766.doi:10.1002/app.2546714. Gupta, S. K.; Weber, W. P.Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 1999, 40, 62.15. Niesert, C.-P.; Pawlowski, G.; Gries, W.-K.; Przybilla, K.-J. MitSilikonen kompatible Photoinitiatoren und diese enthaltendelichtempfindliche Gemische. Eur. Pat. Appl. 0705865 A1, April 1, 1996.16. Schaarschmidt, A. Justus Liebigs Ann. Chem. 1915, 409, 59.doi:10.1002/jlac.1915409010617. Gérard, E. M. C.; Bräse, S. Chem. – Eur. J. 2008, 14, 8086.doi:10.1002/chem.20080150718. Masters, K.-S.; Bräse, S. Chem. Rev. 2012, 112, 3717.doi:10.1021/cr100446h19. Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;Sonoda, M.; Chatani, N. Nature 1993, 366, 529. doi:10.1038/366529a020. Jean-Gerard, L.; Jazzar, R.; Baudoin, O. In Metal-Cross CouplingReactions and more; de Meijere, A.; Bräse, S.; Oestreich, M., Eds.;Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2014; Vol. 3,p 1427.21. Dyker, G., Ed. Handbook of C-H Transformations: Applications inOrganic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,2005; Vol. 2.22. 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-x23. Okabayashi, I.; Kimura, M.; Fujiwara, H.; Kato, A. Chem. Pharm. Bull.1987, 35, 2545. doi:10.1248/cpb.35.254524. Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y.Science 2000, 287, 1992. doi:10.1126/science.287.5460.199225. Yamamoto, Y. Chem. Soc. Rev. 2014, 43, 1575.doi:10.1039/C3CS60369E26. Chinchilla, R.; Nájera, C. Chem. Rev. 2014, 114, 1783.doi:10.1021/cr400133p27. Trejos, A.; Odell, L. R. Sci. Synth. 2013, 3, 345.28. Hussain, H.; Green, I. R.; Ahmed, I. Chem. Rev. 2013, 113, 3329.doi:10.1021/cr300437329. Engle, K. M.; Yu, J.-Q. J. Org. Chem. 2013, 78, 8927.doi:10.1021/jo400159y30. Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Tetrahedron 2012, 68, 5130.doi:10.1016/j.tet.2012.05.04031. Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta 2012,45, 31.32. Mei, T.-S.; Kou, L.; Ma, S.; Engle, K. M.; Yu, J.-Q. Synthesis 2012, 44,1778. doi:10.1055/s-0031-128976633. Leyva-Pérez, A.; Corma, A. Angew. Chem., Int. Ed. 2012, 51, 614.doi:10.1002/anie.20110172634. Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F.Angew. Chem., Int. Ed. 2012, 51, 10236. doi:10.1002/anie.20120326935. Fedorov, A. Yu.; Nyuchev, A. V.; Beletskaya, I. P.Chem. Heterocycl. Compd. 2012, 48, 166.doi:10.1007/s10593-012-0980-836. Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.doi:10.1021/cr100280d37. Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.2011, 40, 4740. doi:10.1039/c1cs15083a38. Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.doi:10.1021/cr100198wBeilstein J. Org. Chem. 2015, 11, 431–436.436License and TermsThis is an Open Access article under the terms of theCreative Commons Attribution License(http://creativecommons.org/licenses/by/2.0), whichpermits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.The license is subject to the Beilstein Journal of OrganicChemistry terms and conditions:(http://www.beilstein-journals.org/bjoc)The definitive version of this article is the electronic onewhich can be found at:doi:10.3762/bjoc.11.49

Ruthenium-catalyzed C-H activation of thioxanthones

Ruthenium-catalyzed C-H activation of thioxanthones

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