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Arene/Heteroarene Trifluoromethylation: Recent Advances Daniela Sustac October 19, 2011.

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Presentation on theme: "Arene/Heteroarene Trifluoromethylation: Recent Advances Daniela Sustac October 19, 2011."— Presentation transcript:

1 Arene/Heteroarene Trifluoromethylation: Recent Advances Daniela Sustac October 19, 2011

2 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; Introduction of F or CF 3 in a molecule substantially alters its properties: lipophilicity, metabolic stability, bioavailability; No known natural products (so far) that contain a CF 3 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. Tetrahedron 1992, 48, 6555.

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

4 Nucleophilic Trifluoromethyl Reagents Commercially available (Aldrich, $164 for 5 mL); Initial synthesis: CBrF 3 ozone depleting substance CBrF 3 (Halon 1301) ozone depleting substance, banned (Montreal protocol); Alternative synthesis by Prakash: CF 3 Br vs. CF 3 I vs. CF 3 H Side note: CF 3 Br vs. CF 3 I vs. CF 3 H C-I bond breaks more easily in water than C-Br; CF 3 H ozone depleting potential <1/1000 than CF 3 Br; 1 ton CF 3 H = tons CO 2. (a) Ruppert, I.; Schlich, K.; Volgang, W. Tet. Lett. 1984, 25, (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, (d) Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W.R. Org. Lett. 2001, 3, (e) Wikipedia

5 Electrophilic Trifluoromethyl Reagents Extremely difficult to generate + CF 3 ; Two classes of reagents: (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. USSR 1984, 20, 103. (d) Umemoto, T. Chem. Rev 2006, 96, (e) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46, g $ (Aldrich)

6 Radical Trifluoromethyl Reagents CF 3 I CF 3 I in presence of sodium dithionite (Na 2 S 2 O 4 ) 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, (c) Umemoto, T.; Ando, A. Bull. Chem. Soc. Jpn. 1986, 59, 447.

7 Outline Radica Radical Trifluoromethylations (Yamakawa, Baran) Pd-Mediated Pd-Mediated Trifluoromethylations (Grushin, Sanford, Yu, Buchwald) Cu-Mediated Cu-Mediated Trifluoromethylations (Vicic, Amii, Hartwig, Qing, Buchwald) Ag-Mediated Ag-Mediated Trifluoromethylations (Sanford)

8 CF 3 I Radical Trifluoromethylation Using CF 3 I 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, (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,

12 Mechanistic Considerations EPR studies support radical mechanism; CF 3 H observed by 19 F 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,

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, (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,

14 Pd-Mediated Pd-Mediated Trifluoromethylations: 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,

16 Reductive Elimination from Pd(IV): Proof of Concept What about a Pd IV species? Look for X-type ligands that will undergo slower reductive elimination than CF 3. 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 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. Science 2010, 328, Stoichiometric transmetallation/reductive elimination studies identify TESCF 3 and CsF (28%);

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. Science 2010, 328, 1679.

20 Mechanistic Insights Jin Cho, E.; Senecal, T.D.; Kinzel, T.; Zhang, Y.; Watson, D.A.; Buchwald, S.L. Science 2010, 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-Mediated Cu-Mediated Trifluoromethylations: Understanding an Elusive “CuCF 3 ” Species

23 Early Stoichiometric Studies (a) Wiemens, D.M.; Burton, D.J. J. Am. Chem. Soc. 1986, 108, 832. (b) Urata, H.; Fuchikami, T. Tet. Lett. 1991, 32, 91. Most of the early procedures unreliable, low temperatures and expensive reagents, competing Ullmann coupling, elusive “CuCF 3 ” species.

24 Synthesis of a “CuCF 3 ” Complex First isolated “Cu-CF 3 ” complex; Silylation of unsaturated NHC backbone; Upon heating, decomposes to LCu-CF 2 CF 3. Catalytic conditions through the addition of KOtBu not feasible, since the reaction of KOtBu and TMSCF 3 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)CuCF 3 ] (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-Mediated Ag-Mediated Trifluoromethylations

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 Radical scavenging: nitrobenzene no effect, TEMPO 7% yield (ambiguous); Different ratios obtained: against a radical mechanism; Mechanism still TBD. Possible radical pathway (recall TMSCF 3 is a nucleophilic source of CF 3, has never been shown to form a radical): (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; inexpensive 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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