Regioselective Double C–H Functionalization of Arenes via Aryl Thianthrenium Salt Analogues

Abstract

Directed C–H functionalization reactions are powerful tools for the rapid and selective syntheses of complex molecules. However, many existing C–H functionalization reactions require the presence of a preinstalled directing group that has to be either a part of the molecule or introduced onto an existing functional group. Here, we report analogues of thianthrene that can also function as directing groups for intermediate directed C–H functionalization and thereby permit regioselective 2,4- and 3,4-aromatic C–H difunctionalization of simple arenes in yields of 22–33% over three steps.

Key words

sulfonium salts - C–H functionalization - directing group - linchpin - palladium catalysis

• References and Notes

• 1a Boursalian GB, Ham WS, Mazzotti AR, Ritter T. Nat. Chem. 2016; 8: 810
• 1b Berger F, Plutschack MB, Riegger J, Yu W, Speicher S, Ho M, Frank N, Ritter T. Nature 2019; 567: 223
• 1c Xu P, Zhao D, Berger F, Hamad A, Rickmeier J, Petzold R, Kondratiuk M, Bohdan K, Ritter T. Angew. Chem. Int. Ed. 2020; 59: 1956
• 1d Berger F, Ritter T. Synlett 2021; 33: 339
• 2a Meng G, Lam NY, Lucas EL, Saint-Denis TG, Verma P, Chekshin N, Yu J.-Q. J. Am. Chem. Soc. 2020; 142: 10571
• 2b Zhang L, Ritter T. J. Am. Chem. Soc. 2022; 144: 2399
• 3a Olah GA. Acc. Chem. Res. 1971; 4: 240
• 3b Mkhalid IA, Barnard JH, Marder TB, Murphy JM, Hartwig JF. Chem. Rev. 2010; 110: 890
• 3c Sambiagio C, Schönbauer D, Blieck R, Dao-Huy T, Pototschnig G, Schaaf P, Wiesinger T, Zia MF, Wencel-Delord J, Besset T, Maes BU. W, Schnürch M. Chem. Soc. Rev. 2018; 47: 6603
• 4 Juliá F, Shao Q, Duan M, Plutschack MB, Berger F, Mateos J, Lu C, Xue X.-S, Houk K, Ritter T. J. Am. Chem. Soc. 2021; 143: 16041
• 5a Dick AR, Hull KL, Sanford MS. J. Am. Chem. Soc. 2004; 126: 2300
• 5b Dick AR, Kampf JW, Sanford MS. J. Am. Chem. Soc. 2005; 127: 12790
• 5c Lyons TW, Sanford MS. Chem. Rev. 2010; 110: 1147
• 5d Ackermann L. Chem. Rev. 2011; 111: 1315
• 5e Leow D, Li G, Mei T.-S, Yu J.-Q. Nature 2012; 486: 518
• 6 Ishiyama T, Takagi J, Ishida K, Miyaura N, Anastasi NR, Hartwig JF. J. Am. Chem. Soc. 2002; 124: 390
• 7a Hartwig JF. Acc. Chem. Res. 2012; 45: 864
• 7b Chang W, Chen Y, Lu S, Jiao H, Wang Y, Zheng T, Shi Z, Han Y, Lu Y, Wang Y. Chem 2022; 8: 1775
• 8a Saito Y, Segawa Y, Itami K. J. Am. Chem. Soc. 2015; 137: 5193
• 8b Haines BE, Saito Y, Segawa Y, Itami K, Musaev DG. ACS Catal. 2016; 6: 7536
• 9a Dai H.-X, Li G, Zhang X.-G, Stepan AF, Yu J.-Q. J. Am. Chem. Soc. 2013; 135: 7567
• 9b Fernandez GE, Maiti D, Tantillo DJ. Chem. Eur. J. 2023; 29: e202300124
• 10a Rani G, Luxami V, Paul K. Chem. Commun. 2020; 56: 12479
• 10b Kaltenberger S, van Gemmeren M. Acc. Chem. Res. 2023; 56: 2459
• 11a Patra T, Bag S, Kancherla R, Mondal A, Dey A, Pimparkar S, Agasti S, Modak A, Maiti D. Angew. Chem. Int. Ed. 2016; 55: 7751
• 11b Pimparkar S, Bhattacharya T, Maji A, Saha A, Jayarajan R, Dutta U, Lu G, Lupton DW, Maiti D. Chem. Eur. J. 2020; 26: 11558
• 11c Bag S, Jana S, Pradhan S, Bhowmick S, Goswami N, Sinha SK, Maiti D. Nat. Commun. 2021; 12: 1393
• 12 Lapointe D, Fagnou K. Chem. Lett. 2010; 39: 1118
• 13a Kalyani D, Deprez NR, Desai LV, Sanford MS. J. Am. Chem. Soc. 2005; 127: 7330
• 13b Stowers KJ, Sanford MS. Org. Lett. 2009; 11: 4584
• 14a Shi BF, Maugel N, Zhang YH, Yu JQ. Angew. Chem. Int. Ed. 2008; 47: 4882
• 14b Shi B.-F, Zhang Y.-H, Lam JK, Wang D.-H, Yu J.-Q. J. Am. Chem. Soc. 2010; 132: 460
• 14c Rakshit S, Grohmann C, Besset T, Glorius F. J. Am. Chem. Soc. 2011; 133: 2350
• 14d Rousseau G, Breit B. Angew. Chem. Int. Ed. 2011; 50: 2450
• 14e Li G, Leow D, Wan L, Yu JQ. Angew. Chem. 2013; 52: 1245
• 15a Lee S, Lee H, Tan KL. J. Am. Chem. Soc. 2013; 135: 18778
• 15b Farmer ME, Wang P, Shi H, Yu J.-Q. ACS Catal. 2018; 8: 7362
• 15c Ali W, Saha A, Ge H, Maiti D. JACS Au 2023; 3: 6: 1790
• 15d Goswami N, Sinha SK, Mondal P, Adhya S, Datta A, Maiti D. Chem 2023; 9: 989
• 16 Bag S, Patra T, Modak A, Deb A, Maity S, Dutta U, Dey A, Kancherla R, Maji A, Hazra A, Bera M, Maiti D. J. Am. Chem. Soc. 2015; 137: 11888
• 17 10-Aryl-4-isopropoxy-10-phenyl[1,4]benzoxathiino[3,2-b]pyridin-10-ium Triflates 3a–c; General Procedure Under an ambient atmosphere, a 25 mL oven-dried round-bottomed flask was charged with the S-oxide 1 (2.50 mmol, 1.00 equiv), dry CH₂Cl₂ (10–15 mL, 0.17–0.25 M) and arene (2.63–12.5 mmol, 1.05–5.00 equiv) and the mixture was cooled to 0 °C in water/ice bath. TfOH (2.20 equiv + 1.00 equiv per basic functional group) was added to the stirred mixture in the flask. For very electron-rich arenes (e.g., 1,2-dimethoxybenzene) the use of the acid was avoided. Subsequently, trifluoroacetic anhydride (7.5 mmol, 3.0 equiv) was added in one portion at 0 °C. The mixture was stirred at 0 °C for 30 min and then warmed gradually to 25 °C and stirred for 18 h. Sat. aq NaHCO₃ (15 mL) was added dropwise, and the resultant mixture was stirred vigorously for 5 min at 25 °C, then poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL), and the organic layers were combined, washed with 3% aq KOTf (20 mL) and H₂O (20 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was then purified by column chromatography (silica gel CH₂Cl₂–MeOH or CH₂Cl₂–i-PrOH). The resulting highly viscous oil was placed in a 100 mL round-bottomed flask, and hexanes (70 mL) were added together with a large magnetic stirrer bar; the mixture was then stirred vigorously for 16 h at 25 °C. The resulting solid was collected by filtration on a paper filter, washed with hexanes (~25 mL), and dried in vacuo. 10-(4-Ethylphenyl)-4-isopropoxy[1,4]benzoxathiino[3,2-b]pyridin-10-ium Triflate (3a) Colorless solid: yield: 784 mg (61%), R_f = 0.42 (CH₂Cl₂–MeOH, 9:1). ¹H NMR (600 MHz, CDCl₃, 23 °C): δ = 8.38 (d, J = 5.4 Hz, 1 H), 8.22 (dd, J = 8.1, 1.5 Hz, 1 H), 7.83 (ddd, J = 8.5, 7.3, 1.5 Hz, 1 H), 7.68 (dd, J = 8.5, 1.2 Hz, 1 H), 7.63–7.58 (m, 2 H), 7.53 (ddd, J = 8.1, 7.3, 1.3 Hz, 1 H), 7.41–7.35 (m, 2 H), 7.30 (dd, J = 5.3, 0.6 Hz, 1 H), 4.94–4.85 (m, 1 H), 2.66 (q, J = 7.6 Hz, 2 H), 1.52 (d, J = 6.1 Hz, 3 H), 1.49 (d, J = 6.0 Hz, 3 H), 1.18 (t, J = 7.6 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃, 23 °C): δ = 155.2, 152.6, 149.9, 149.4, 139.6, 136.7, 132.8, 131.3, 130.3, 128.0, 127.6, 126.7, 121.0 (q, J = 320.6 Hz), 120.5, 113.6, 105.6, 74.3, 29.0, 21.7, 21.6, 14.9. ¹⁹F NMR (565 MHz, CDCl₃, 23 °C): δ = –78.17. (HRMS-ESI): m/z [M – OTf]^∙+calcd for C₂₂H₂₂N₁O₂S₁: 364.1366; found: 364.1366; deviation: 0.0 ppm.
• 18 Cheng G.-J, Yang Y.-F, Liu P, Chen P, Sun T.-Y, Li G, Zhang X, Houk K, Yu J.-Q, Wu Y.-D. J. Am. Chem. Soc. 2014; 136: 894
• 19 Olefination of 10-Aryl-4-isopropoxy-10-phenyl[1,4]benzoxathiino[3,2-b]pyridin-10-ium Triflates; General Procedure Under an ambient atmosphere, a 20 mL glass vial containing a Teflon-coated magnetic stirrer bar and equipped with Schlenk-line adapter was charged with the appropriate salt 3a–c (0.50 mmol, 1.0 equiv), Pd(OAc)₂ (0.05 mmol, 0.10 equiv), N-acetylglycine (0.25 mmol, 0.5 equiv), Ag₂CO₃ (1.5 mmol, 3.0 equiv), HFIP (10 mL, 0.05 M), and butyl acrylate (1.0 mmol, 2.0 equiv). The vial was tightly closed and transferred to a preheated metal block at 100 °C, where the mixture was stirred for 24 h. The vial containing the reaction mixture was covered with aluminum foil to eliminate light. After 24 h, the color of the mixture changed from yellow to black. The mixture was then allowed to cool to 25 °C and filtered through a sintered glass filter. The filter cake was washed with CH₂Cl₂ (90 mL) and the resulting solution was filtered again using filter paper to remove the suspended solids. The filter paper was washed again with an additional amount of CH₂Cl₂ (50 mL), and the solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CH₂Cl₂–MeOH or CH₂Cl₂–i-PrOH) to remove nonpolar impurities and afford a mixture of the starting material and product 4a–c. To quantify the product formation, the mixture was dissolved in CDCl₃ and trichloroethylene (45 μL, 66 mg, 0.5 mmol, 1.0 equiv) was added as an internal standard. The ¹H NMR resonances of the vinyl proton of the product at δ = 6.5–6.7 ppm were integrated relative to the ¹H NMR resonances of the vinyl proton of trichloroethylene (δ = 6.46 ppm), and the NMR yield of 4a–c was calculated and the resulting mixture was used in further transformations.
• 20a Sinha SK, Bhattacharya T, Maiti D. React. Chem. Eng. 2019; 4: 244
• 20b Bhattacharya T, Ghosh A, Maiti D. Chem. Sci. 2021; 12: 3857
• 21 Fairlamb IJ. S, Kapdi AR, Lee AF, McGlacken GP, Weissburger F, de Vries AH. M, Schmieder-van de Vondervoort L. Chem. Eur. J. 2006; 12: 8750