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Arene / Heteroarene Trifluoromethylation : Recent Advances

Arene / Heteroarene Trifluoromethylation : Recent Advances. Daniela Sustac October 19, 2011. On the properties of CF 3. Fluorine = most electronegative element in the periodic table; CF 3 = similar electronegativity to Oxygen (3.5); CF 3 = 2 ½ the volume of a Me group;.

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Arene / Heteroarene Trifluoromethylation : Recent Advances

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  1. Arene/HeteroareneTrifluoromethylation:Recent Advances Daniela Sustac October 19, 2011

  2. On the properties of CF3 • Fluorine = most electronegative element in the periodic table; • CF3 = similar electronegativity to Oxygen (3.5); • CF3 = 2 ½ the volume of a Me group; • Introduction of F or CF3 in a molecule substantially alters its properties: lipophilicity, metabolic stability, bioavailability; • No known natural products (so far) that contain a CF3 group; • Nearly 20% drugs and 35% agrochemicals on market today contain one of more fluorine atoms. (a) Shibata, N.; Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6, 65. (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (c) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975. (d) Shimiza, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214. (e) McClinton, M.A.; McClinton, D.A. Tetrahedron1992, 48, 6555.

  3. CF3 Synthesis: Brief Overview Other methods of direct replacement at C: Trifluoromethylationsthrough C-C bond forming reactions (a) Swarts, F. Acad. Roy. Belg. 1892, 3, 474. (b) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975.

  4. Nucleophilic Trifluoromethyl Reagents • Commercially available (Aldrich, $164 for 5 mL); • Initial synthesis: • CBrF3 (Halon 1301) ozone depleting substance, banned (Montreal protocol); • Alternative synthesis by Prakash: • Side note: CF3Br vs. CF3I vs. CF3H • C-I bond breaks more easily in water than C-Br; • CF3H ozone depleting potential <1/1000 than CF3Br; • 1 ton CF3H = 11 700 tons CO2. (a) Ruppert, I.; Schlich, K.; Volgang, W. Tet. Lett. 1984, 25, 2195. (b) Prakash, G.K.S.; Krishnamurti, R.; Olah, A.G. J. Am. Chem. Soc.1989, 111, 393. (c) Prakash, G.K.S.; Hu, J.; Olah, A.G. J. Org. Chem. 2003, 68, 4457. (d) Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W.R. Org. Lett. 2001, 3, 4271. (e) Wikipedia

  5. Electrophilic Trifluoromethyl Reagents • Extremely difficult to generate +CF3 ; • Two classes of reagents: 1 g $107.50 (Aldrich) (a) Shibata, N.; Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6, 65. (b) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975. (c) Yagupolskii, L.M.; Kondratenko, N.V.; Timofeeva, G.N. J. Org. Chem. USSR1984, 20, 103. (d) Umemoto, T. Chem. Rev2006, 96, 1757. (e) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46, 754.

  6. Radical Trifluoromethyl Reagents • CF3I in presence of sodium dithionite (Na2S2O4) • Trifluoromethylsulfonyl derivatives activated in presence of peroxides • N-trifluoromethyl-N-nitrosotrifluoromethanesulfonamide (a) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975. (b) Langlois, B.R.; Laurent, E.; Roidot, N. Tet. Lett.1992, 33, 1291. (c) Umemoto, T.; Ando, A. Bull. Chem. Soc. Jpn. 1986, 59, 447.

  7. Outline • RadicalTrifluoromethylations (Yamakawa, Baran) • Pd-MediatedTrifluoromethylations(Grushin, Sanford, Yu, Buchwald) • Cu-MediatedTrifluoromethylations(Vicic, Amii, Hartwig, Qing, Buchwald) • Ag-MediatedTrifluoromethylations (Sanford)

  8. Radical Trifluoromethylation Using CF3I • In general, low to moderate yields, poor regioselectivity; • Radical formed is electrophilic in nature, thus it reacts better with electron rich arenes; • Electron poor arenes are sluggish; • Method is simple and mild. Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98.

  9. Proposed Mechanism (a) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98. (b) Uraguchi, D.; Yamamoto, K.; Otsuka, Y.; Tokuhisa, K.; Yamakawa, T. Appl. Catal. A: Gen 2008, 342, 137. (c) Bravo, A.; Bjornvik, H.-R.; Fontana, F.; Liguori, L.; Mele, A.; Minisci, F. J. Org. Chem. 1997, 62, 7128.

  10. Innate Trifluoromethylation of Heterocycles • Innate: functionalization of the inherently reactive positions of the substrate; • Programmed: substrate prefunctionalization /directing groups. (a) Ji, Y.; Brueckl, T.; Baxter, R.D.; Fujiwara, Y.; Seiple, I.B.; Su, S.; Blackmond, D.G.; Baran, P.S. Proc. Natl. Acad. Sci. 2011, 108, 14411. (b) Langlois, B.R.; Laurent, E.; Roidot, N. Tet. Lett. 1991, 32, 7525.

  11. Reaction Optimization Ji, Y.; Brueckl, T.; Baxter, R.D.; Fujiwara, Y.; Seiple, I.B.; Su, S.; Blackmond, D.G.; Baran, P.S. Proc. Natl. Acad. Sci. 2011, 108, 14411.

  12. Mechanistic Considerations • EPR studies support radical mechanism; • CF3H observed by 19F NMR. Ji, Y.; Brueckl, T.; Baxter, R.D.; Fujiwara, Y.; Seiple, I.B.; Su, S.; Blackmond, D.G.; Baran, P.S. Proc. Natl. Acad. Sci. 2011, 108, 14411.

  13. Positional Selectivity (a) Ji, Y.; Brueckl, T.; Baxter, R.D.; Fujiwara, Y.; Seiple, I.B.; Su, S.; Blackmond, D.G.; Baran, P.S. Proc. Natl. Acad. Sci. 2011, 108, 14411. (b) Seiple, I.B.; Su, S.; Rodriguez, R.A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A.L.; Baran, P.S. J. Am. Chem. Soc. 2010, 132, 13194.

  14. Pd-MediatedTrifluoromethylations: Winning Over a Difficult Reductive Elimination

  15. Reductive Elimination from Pd(II): Proof of Concept • Other ligands (dppe, dppb, tmeda) ineffective. Grushin, V.V.; Marshall, W.J. J. Am. Chem. Soc. 2006, 128, 12644.

  16. Reductive Elimination from Pd(IV): Proof of Concept • What about a PdIV species? • Look for X-type ligands that will undergo slower reductive elimination than CF3. No Ar-F or Ar-OTf observed by F NMR. Ball, N.D.; Kampf, J.W.; Sanford, M.S. J. Am. Chem. Soc. 2010, 132, 2878.

  17. Pd(II) Catalyzed ortho-Trifluoromethylation Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648.

  18. Pd(II) Catalyzed Trifluoromethylation of Aryl Chlorides • Stoichiometric transmetallation/reductive elimination studies identify TESCF3 and CsF (28%); • Further optimization identifies KF as the ideal fluoride source and renders the process catalytic. Jin Cho, E.; Senecal, T.D.; Kinzel, T.; Zhang, Y.; Watson, D.A.; Buchwald, S.L. Science2010, 328, 1679.

  19. Substrate Scope • High tolerance of functional groups (esters, amides, acetals, nitriles, ethers, heteroarenes); • Limitations: aldehydes, ketones, free –NH or –OH; • Ortho –substituted arenes exhibit low conversions with BrettPhos, but improved yields with RuPhos. Jin Cho, E.; Senecal, T.D.; Kinzel, T.; Zhang, Y.; Watson, D.A.; Buchwald, S.L. Science2010, 328, 1679.

  20. Mechanistic Insights Jin Cho, E.; Senecal, T.D.; Kinzel, T.; Zhang, Y.; Watson, D.A.; Buchwald, S.L. Science2010, 328, 1679.

  21. Trifluoromethylation of Indoles • Moderate to good yields with electron neutral and EDG groups; • Poor yields with EWG; • Radical mechanism rejected since TEMPO increases the yield; • Competition experiments: indoles with EDG react faster than with EWG; Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem. Eur. J. 2011, 17, 6039.

  22. Cu-MediatedTrifluoromethylations: Understanding an Elusive “CuCF3” Species

  23. Early Stoichiometric Studies • Most of the early procedures unreliable, low temperatures and expensive reagents, competing Ullmann coupling, elusive “CuCF3” species. (a) Wiemens, D.M.; Burton, D.J. J. Am. Chem. Soc. 1986, 108, 832. (b) Urata, H.; Fuchikami, T. Tet. Lett. 1991, 32, 91.

  24. Synthesis of a “CuCF3” Complex • First isolated “Cu-CF3” complex; • Silylation of unsaturated NHC backbone; • Upon heating, decomposes to LCu-CF2CF3. • Catalytic conditions through the addition of KOtBu not feasible, since the reaction of KOtBu and TMSCF3 is too fast. Dubinina, G.G.; Furutachi, H.; Vicic, D.A. J. Am. Chem. Soc. 2008, 130, 8600.

  25. Early Example of Catalytic Cu Trifluoromethylation • Order of reactivity: I>Br>Cl; • EWG react well, no examples with EDG; • Radical scavenging studies (dinitrobenzene) suggest against a radical mechanism; • Instead, difluorocarbene pathway is proposed; • Attempts to trap difluorocarbene with an alkene (to form cyclopropane) unsuccessful. Chen, Q.Y.; Wu, S.-W. J. Chem. Soc., Chem. Commun. 1989, 705.

  26. Cu/L Catalysis Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.

  27. Stoichiometric Cu (Hartwig) • Copper reagent tolerates a large variety of functional groups; • Under Amii’s conditions, EDG unreactive and electron neutral fairly sluggish; • Hartwig points out that the catalytic active species in Amii’s case CANNOT BE the [(phen)CuCF3] (upon testing the above substrates under Amii’s conditons, only low yields were obtained); • Hartwig’s system is NOT catalytic. Morimoto, H.; Tsubogo, T.; Litvinas, N.D.; Hartwig, J.F. Angew. Chem. Int. Ed. 2011, 50, 3793.

  28. Continued Morimoto, H.; Tsubogo, T.; Litvinas, N.D.; Hartwig, J.F. Angew. Chem. Int. Ed. 2011, 50, 3793.

  29. Oxidative Trifluoromethylation (Qing) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060.

  30. Oxidative Trifluoromethylation (Buchwald) Senecal, D.T.; Parsons, A.T.; Buchwald, S.L. J. Org. Chem. 2011, 76, 1174.

  31. Trifluoromethylation of Unactivated Olefins (Buchwald) • Possible pathways for allylic trifluoromethylation: • Screening of different Cu salts and electrophilic trifluoromethylation reagents identified Togni’s reagent as promising hit; Parsons, A.T.; Buchwald, S.L Angew. Chem. Int. Ed. 2011, 50, 9120.

  32. Trifluoromethylation of Unactivated Olefins (Buchwald) • Final optimized conditions: • Not compatible with: branched or cyclic olefins. Parsons, A.T.; Buchwald, S.L Angew. Chem. Int. Ed. 2011, 50, 9120.

  33. Trifluoromethylation of Unactivated Olefins (Buchwald) • Alternate mechanism: Parsons, A.T.; Buchwald, S.L Angew. Chem. Int. Ed. 2011, 50, 9120.

  34. Trifluoromethylation of Unactivated Olefins (Wang) Wang, X.; Ye, Y.; Zhang, S.; Feng, Y.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, asap.

  35. Proposed Mechanism(s) Wang, X.; Ye, Y.; Zhang, S.; Feng, Y.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, asap.

  36. Ag-MediatedTrifluoromethylations

  37. Ag-Mediated Trifluoromethylation • Initial studies: • Optimization: AgOTf in presence of KF; • 14 examples, limited to EDG. Ye, Y.; Hee Lee, S.; Sanford, M.S. Org.Lett. 2011, asap.

  38. Mechanistic Studies • Possible radical pathway (recall TMSCF3 is a nucleophilic source of CF3, has never been shown to form a radical): • Radical scavenging: nitrobenzene no effect, TEMPO 7% yield (ambiguous); • Different ratios obtained: against a radical mechanism; • Mechanism still TBD. (a) Ye, Y.; Hee Lee, S.; Sanford, M.S. Org.Lett. 2011, asap. (b) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98

  39. Conclusion • Important advances in trifluoromethylation reactions in the past 20 years; • In spite of these, a general, inexpensive, mild method still required.

  40. Romania (1918 – 1940) Bran Castle Vlad the Impaler (Vlad Tepes) Ruler of Wallachia (1431 – 1476)

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