Access to Functionalized α-Trifluoromethyl-α-aminophosphonates via Intermolecular Ene–Yne Metathesis

Abstract

An efficient approach to a new family of highly functionalized P analogues of α-trifluoromethyl-substituted phenylalanine and its homologues using ruthenium-catalyzed intermolecular ene–yne metathesis as a key step of the reaction sequence has been developed. The method includes cross metathesis of α-alkynyl-α-trifluoromethyl-α-aminophosphonates with alkenes under catalysis by second-generation Grubbs carbene complex to afford the corresponding aminophosphonates with 1,3-diene backbone followed by one-pot Diels–Alder reaction–aromatization step.

Key words

alkynes - diynes - cross-metathesis - aminophosphonates - catalysis

• References and Notes


For some selected reviews on metathesis, see:
• 1a Fürstner A, Davies PW. Chem. Commun. 2005; 2307
• 1b Nicolaou KC, Bulger PG, Sarlah D. Angew. Chem. Int. Ed. 2005; 44: 4490 ; Angew. Chem. 2005, 117, 4564
• 1c Binder JB, Raines RT. Curr. Opin. Chem. Biol. 2008; 12: 767
• 1d van Otterlo WA. L, de Koning CB. Chem. Rev. 2009; 109: 3743
• 1e Cossy J, Arseniyadis S, Meyer C. Metathesis In Natural Product Synthesis . Wiley-VCH; Weinheim: 2010
• 1f Prunet J. Eur. J. Org. Chem. 2011; 3634
• 1g Kress S, Blechert S. Chem. Soc. Rev. 2012; 41: 4389

For reviews on RCEYM, see:
• 2a Mori M. Materials 2010; 3: 2087
• 2b Villar H, Frings M, Bolm C. Chem. Soc. Rev. 2007; 36: 55
• 2c Mori M. Adv. Synth. Catal. 2007; 349: 121
• 2d Diver ST. Coord. Chem. Rev. 2007; 251: 671
• 2e Hansen EC, Lee D. Acc. Chem. Res. 2006; 39: 509
• 2f Diver ST, Giessert AJ. Chem. Rev. 2004; 104: 1317
• 2g Diver ST, Griffiths JR. Ene-yne Metathesis . In Olefin Metathesis: Theory and Practice . Grela K. Wiley; Chichester: 2014

Leading papers on ene–yne cross-metathesis:
• 3a Kinoshita A, Sakakibara N, Mori M. Tetrahedron 1999; 55: 8155
• 3b Rodríguez-Conesa S, Candal P, Jimenez C, Rodríguez J. Tetrahedron Lett. 2001; 42: 6699
• 3c Chatterjee AK, Choi T.-L, Sanders DP, Grubbs RH. J. Am. Chem. Soc. 2003; 125: 11360
• 3d Galan BR, Giessert AJ, Keister JB, Diver ST. J. Am. Chem. Soc. 2005; 127: 5762
• 3e Giessert AJ, Diver ST. Org. Lett. 2005; 7: 351
• 3f Mix S, Blechert S. Org. Lett. 2005; 7: 2015
• 3g Middleton MD, Peppers BP, Diver ST. Tetrahedron 2006; 62: 10528
• 3h Clark DA, Kulkarni AA, Kalbarczyk K, Schertzer B, Diver ST. J. Am. Chem. Soc. 2006; 128: 15632
• 3i Clark DA, Basile BS, Karnofel WS, Diver ST. Org. Lett. 2008; 10: 4927
• 3j Murelli RP, Catalan S, Gannon MP, Snapper ML. Tetrahedron Lett. 2008; 49: 5714
• 3k Kalbarczyk KP, Diver ST. J. Org. Chem. 2009; 74: 2193
• 4a Kukhar VP, Hudson HR. Aminophosphonic and Aminophosphinic Acids – Chemistry and Biological Activity. Wiley; Chichester: 2000
• 4b Ordonez M, Sayago FJ, Cativiela C. Tetrahedron 2012; 68: 6369
• 4c Troev KD. Chemistry and Application of H-Phosphonates. Elsevier; Amsterdam: 2006
• 4d Naydenova ED, Todorov PT, Troev KD. Amino Acids 2010; 38: 23
• 4e Kafarski P, Lejczak B. Phosphorus, Sulfur Silicon Relat. Elem. 1991; 63: 193
• 4f Hiratake J, Oda J. Biosci. Biotechnol. Biochem. 1997; 61: 211
• 4g Alonso E, Solis A, del Pozo C. Synlett 2000; 698
• 4h Kafarski P, Lejczak B. Curr. Med. Chem. 2001; 1: 301
• 5 Smith AB. III, Yager KM, Taylor CM. J. Am. Chem. Soc. 1995; 117: 10879
• 6a Hirschmann R, Smith AB. III, Taylor CM, Benkovic PA, Taylor SD, Yager KM, Sprengeler PA, Benkovic SJ. Science 1994; 265: 234
• 6b Allen JG, Atherton FR, Hall MJ, Hassall CH, Holmes SW, Lambert RW, Nisbet LJ, Ringrose PS. Nature (London, U.K.) 1978; 272: 56
• 6c Atherton FR, Hassall CH, Lambert RW. J. Med. Chem. 1986; 29: 29
• 6d Reddy SS, Sankar AU. R, Raju CN, Rao VK. S. Afr. J. Chem. 2008; 61: 97
• 6e Maier L, Diel PJ. Phosphorus, Sulfur Silicon Relat. Elem. 1991; 57: 57
• 7a Ojima I. Fluorine in Medicinal Chemistry and Chemical Biology. Wiley-Blackwell; Chichester: 2009
• 7b Schlosser M. Angew. Chem. Int. Ed. 2006; 45: 5432
• 7c Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
• 7d Hird M. Chem. Soc. Rev. 2007; 36: 2070
• 7e Kirk KL. Org. Process Res. Dev. 2008; 12: 305
• 7f O’Hagan D. Chem. Soc. Rev. 2008; 37: 308
• 7g Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 8a Lundgren RJ, Stradiotto M. Angew. Chem. Int. Ed. 2010; 49: 9322
• 8b Nie J, Guo H.-C, Cahard D, Ma J.-A. Chem. Rev. 2011; 111: 455
• 9 Turcheniuk KV, Kukhar VP, Rӧschenthaler G.-V, Aceña JL, Soloshonok VA, Sorochinsky AE. RSC Adv. 2013; 3: 6693
• 10 Vorobyeva DV, Karimova NM, Vasilyeva TP, Osipov SN, Shchetnikov GT, Odinets IL, Rӧschenthaler G.-V. J. Fluorine Chem. 2010; 131: 378
• 11 Vorobyeva DV, Karimova NM, Odinets IL, Rӧschenthaler G.-V, Osipov SN. Org. Biomol. Chem. 2011; 9: 7335
• 12 Zotova MA, Vasilyeva TP, Peregudov AS, Osipov SN. J. Fluorine Chem. 2012; 135: 33
• 13 Zotova MA, Vorobyeva DV, Dixneuf PH, Bruneau C, Osipov SN. Synlett 2013; 24: 1517
• 14a Kotha S, Halder S, Brahmachary E. Tetrahedron 2002; 58: 9203
• 14b Kotha S, Bansal D, Singh K, Banerjee S. J. Organomet. Chem. 2011; 696: 1856
• 14c Kotha S, Waghule GT. J. Org. Chem. 2012; 77: 6314
• 15 Typical Procedure for Cross-Metathesis Reaction A solution of the corresponding alkyne-containing amino phosphonate (0.5 mmol) in dry CH₂Cl₂ (5 mL) was placed in a flame-dried Schlenk tube (80 mL). The tube was cooled to –78 °C, and the solution was degassed by applying vacuum and argon flow sequentially. The corresponding alkene (2.5 mmol) and Grubbs second-generation catalyst (20 mg, 0.025 mmol, 5 mol%) were added, and the resulting suspension was vacuumized to a residual pressure of 1.33·10^–4 bar. The tube was closed, warmed to r.t., and the resulting red solution was stirred for 4 h. Then the solvent was removed under vacuum, and the crude product was purified by column chromatography. Selected Data for 4e (E-Isomer) ¹H NMR (600 MHz, CDCl₃): δ = 7.45 (d, J = 7.4 Hz, 2 H, H_arom.), 7.42–7.32 (m, 7 H, H_arom.), 7.25 (t, J = 7.3 Hz, 1 H, H_arom.), 6.82 (d, J = 16.3 Hz, 1 H, CH), 6.72 (d, J = 16.3 Hz, 1 H, CH), 5.52 (d, J = 8.9 Hz, 1 H, NH), 5.22–5.09 (m, 4 H, CH₂ + OCH₂), 4.34–4.20 (m, 4 H, 2 OCH₂), 2.78–2.63 (m, 2 H, CH₂), 2.63–2.48 (m, 2 H, CH₂), 1.44–1.34 (m, 6 H, 2 CH₃). ¹³C NMR (151 MHz, CDCl₃): δ = 154.10 (d, J = 11.5 Hz), 145.34, 137.37, 135.91, 130.45, 128.61, 128.61, 128.47, 128.38, 128.26, 127.49, 126.51, 124.88 (qd, J = 287.1, 4.5 Hz), 116.95, 67.30, 64.27 (d, J = 2.3 Hz), 64.22 (d, J = 2.3 Hz), 62.42 (dq, J = 151.9, 28.1 Hz), 28.46, 26.37, 16.41 (d, J = 5.7 Hz), 16.37 (d, J = 5.8 Hz). ¹⁹F NMR (282 MHz, CDCl₃): δ = 7.54 (d, J = 4.1 Hz, 3 F, CF₃). Anal. Calcd for C₂₆H₃₁F₃NO₅P (%): C, 59.43; H, 5.95; N, 2.67. Found: C, 59.69; H, 6.05; N, 2.78.
• 16 General Procedure for One-Pot Diels–Alder–Aromatization Reaction To a flame-dried Schlenk tube solution of the corresponding 1,3-diene (0.3 mmol) and dimethyl acetylenedicarboxylate (85 mg, 0.6 mmol) in dry toluene (5 mL) was loaded. The resulting mixture was cooled to –30 °C, and a solution was degassed by applying vacuum and an argon flow sequentially. The resulting mixture was refluxed for 20 h, then it was cooled to r.t. and DDQ (81 mg, 0.36 mmol) was added. The resulting red solution was heated at 80 °C for 4 h. After cooling to r.t. the solvent was removed under reduced pressure, and the resulting brown oil was fractionated by column chromatography to afford the desired product. Selected Data for 6f ¹H NMR (600 MHz, CDCl₃): δ = 7.70 (d, J = 0.9 Hz, 1 H, H_arom.), 7.44–7.32 (m, 5 H, H_arom.), 7.28 (s, 1 H, H_arom.), 5.50 (d, J = 8.4 Hz, 1 H, NH), 5.17 (d, J = 12.2 Hz, 1 H, OCH₂Ph), 5.13 (d, J = 12.2 Hz, 1 H, OCH₂Ph), 4.34–4.19 (m, 4 H, 2 OCH₂), 3.94 (s, J = 4.0 Hz, 3 H, CO₂CH₃), 3.90 (s, 3 H, CO₂CH₃), 3.02–2.94 (m, 1 H, CH₂), 2.82–2.65 (m, 2 H, CH₂), 2.63–2.52 (m, 3 H, 2CH₂), 1.61–1.55 (m, 2 H, CH₂), 1.42–1.34 (m, 8 H, CH₂ + 2CH₃), 0.94 (t, J = 7.4 Hz, 3 H, CH₃). ¹³C NMR (151 MHz, CDCl₃): δ = 169.91, 166.46, 154.07 (d, J = 11.1 Hz), 142.54, 140.84, 135.87, 133.91, 132.91, 128.59, 128.40, 128.26, 128.16, 127.66, 124.76 (qd, J = 286.8, 5.0 Hz), 67.32, 64.32 (d, 2 C, J = 7.2 Hz), 62.26 (dq, J = 151.8, 28.3 Hz), 52.43, 52.39, 33.50, 32.97, 30.51, 29.84, 22.59, 16.37 (d, J = 5.2 Hz), 16.33 (d, J = 5.2 Hz), 13.87. ¹⁹F NMR (282 MHz, CDCl₃): δ = 7.26 (d, J = 4.3 Hz, 3 F, CF₃). ³¹P NMR (121 MHz, CDCl₃): δ = 16.79 [q, J = 4.5 Hz, 1 P, PO(OEt)₂]. Anal. Calcd for C₃₀H₃₉F₃NO₉P (%): C, 55.81; H, 6.09; N, 2.17. Found: C, 55.78; H, 6.05; N, 2.22.