4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO), a Versatile Precursor for Trifluoromethyl-Substituted Heteroarenes – a Short Synthesis of Celebrex^® (Celecoxib)

Abstract

4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO) serves as a trifluoromethyl-containing building block for the preparation of trifluoromethyl-substituted thiophenes, furans, pyrrols, and piperazines. Key steps are an addition–elimination reaction to ETFBO followed by the thiazolium-catalyzed Stetter reaction. The scope of this chemistry was demonstrated in a new synthetic approach towards the COX-2 selective, nonsteroidal anti-inflammatory drug Celebrex^® (celecoxib).

Key words

antiinflammation - heteroarenes - Stetter reaction - organocatalysis - trifluoromethyl group

• References and Notes

• 1 Wang J. Sánchez-Roselló M. Aceña JL. del Pozo C. Sorochinsky AE. Fustero S. Soloshonok VA. Liu H. Chem. Rev. 2014; 114: 2432
• 2a Purser S. Moore PR. Swallow S. Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 2b Müller K. Faeh C. Diederich F. Science 2007; 317: 1881
• 3 Böhm H.-J. Banner D. Bendels S. Kansy M. Kuhn B. Müller K. Obst-Sander U. Stahl M. ChemBioChem 2004; 5: 637
• 4 Hagmann WK. J. Med. Chem. 2008; 51: 4359
• 5 Kuhn DG. Kamhi VM. Furch JA. Diehl RE. Lowen GT. Kameswaran V. Pestic. Sci. 1994; 41: 279
• 6 Kirk KL. Org. Process Res. Dev. 2008; 12: 305
• 7 Gerstenberger MR. C. Haas A. Angew. Chem., Int. Ed. Engl. 1981; 20: 647
• 8 Zhou Y. Wang J. Gu Z. Wang S. Zhu W. Aceña JL. Soloshonok VA. Izawa K. Liu H. Chem. Rev. 2016; 116: 422
• 9 Schlosser M. Angew. Chem. Int. Ed. 2006; 45: 5432
• 10 Sato K. Tarui A. Omote M. Ando A. Kumadaki I. Synthesis 2010; 1865
• 11 Burton DJ. Yang Z.-Y. Tetrahedron 1992; 48: 189
• 12 Eisenberger P. Gischig S. Togni A. Chem. Eur. J. 2006; 12: 2579
• 13a Fisher R. Lund A. WO 2006059103, 2006
• 13b Braun M. WO 2010037688, 2010
• 14 Frank R. Bahrenberg G. WO 2013045452, 2011
• 15 Takabe F. Fukumoto S. WO 2007088876, 2007
• 16 Zhu S. Qin C. Wang Y.-L. Chu Q. J. Fluorine Chem. 1999; 99: 183
• 17 Matsumoto N. Takahashi M. Tetrahedron Lett. 2005; 46: 5551
• 18 Zhang D. Yuan C. Eur. J. Org. Chem. 2007; 3916
• 19 Linderman RJ. Jamois EA. Tennyson SD. J. Org. Chem. 1994; 59: 957
• 20 Andrew RJ. Mellor JM. Tetrahedron 2000; 56: 7267
• 21 Talley JJ. Penning TD. Collins PC. Rogier DJ. Malecha JW. Miyashiro J. Bertenshaw SR. Khanna IK. Granets MJ. Rogers RS. Carter JS. Docter SH. Yu SS. WO 1995015316, 1995
• 22a Andrew RJ. Mellor JM. Tetrahedron 2000; 56: 7261
• 22b Andrew RJ. Mellor JM. Reid G. Tetrahedron 2000; 56: 7255
• 23 Nenajdenko VG. Krasovsky AL. Lebedev MV. Balenkova ES. Synlett 1997; 1349
• 24 Sanin AV. Nenajdenko VG. Smolko KI. Denisenko DI. Balenkova ES. Synthesis 1998; 842
• 25 Gorbunova MG. Gerus II. Kukhar VP. J. Fluorine Chem. 1993; 65: 25
• 26 Reddy MV. R. Billa VK. Pallela VR. Mallireddigari MR. Boominathan R. Gabriel JL. Reddy EP. Bioorg. Med. Chem. 2008; 16: 3907
• 27 Stetter H. Schreckenberg M. Angew. Chem., Int. Ed. Engl. 1973; 12: 81
• 28 Jesberger M. Davis TP. Barner L. Synthesis 2003; 1929
• 29a McCormack PL. Drugs 2011; 71: 2457
• 29b Kumar V. Kaur K. Gupta GK. Gupta AK. Kumar S. Recent Pat. Inflammation Allergy Drug Discovery 2013; 124
• 30a Anumula RR. Gilla G. Alla S. Akki TR. Bojja Y. US 7919633, 2011
• 30b Ambati VR. R. Garaga S. Mallela SP. S. Meenakshisunderam S. WO 2010095024, 2010
• 31 Oh LM. Tetrahedron Lett. 2006; 47: 7943
• 32 4-[5-p-Tolyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide (Celecoxib®) (22) (E)-1,1,1-Trifluoro-4-p-tolylbut-3-en-2-one (2a, 856 mg, 4.00 mmol, 1.0 equiv) and 4-hydrazinylbenzenesulfonamide hydrochloride (21, 941 mg, 4.20 mmol, 1.05 equiv) were heated in 10 mL of EtOH for 18 h at 90 °C. After cooling to r.t. the reaction was terminated by addition of a sat. NH₄Cl solution. The mixture was extracted twice with EtOAc, the combined organic extracts were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The crude material was dissolved in 50 mL toluene, equipped with activated MnO₂ (3.48 g, 40.0 mmol, 10 equiv), and sonicated for 18 h at r.t. The mixture was then filtered over Celite^® with the aid of 100 mL EtOAc. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (PE–EtOAc = 2:1 to 1:1) to give the title compound 22 (1.03 g, 2.70 mmol; 68% yield) as a colourless solid. ¹H NMR (400 MHz, CDCl₃, CHCl₃= 7.26 ppm): δ = 2.39 (s, 3 H, CH₃), 4.91 (s, 2 H, NH₂), 6.76 (s, 1 H, pyrazol-H), 7.13 (m, 2 H, ArH), 7.20 (m, 2 H, ArH), 7.50 (m, 2 H, ArH), 7.92 (m, 2 H, ArH) ppm. ¹³C NMR (200 MHz, CDCl₃, CDCl₃ = 77.2 ppm): δ = 21.3, 106.4, 122.4, 125.6, 127.6, 128.7, 129.8, 139.8, 141.3, 142.6, 144.0, 144.3, 145.3 ppm. HRMS: m/z calcd for C₁₇H₁₅O₂F₃N₃S [M + H⁺]: 382.0832; found: 382.0839.