Arene/Heteroarene
Trifluoromethylation: Recent
Advances
Daniela Sustac
October 19, 2011
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. Tetrahedron 1992, 48, 6555.
CF3 Synthesis: Brief Overview
Other methods of direct replacement at C:
Trifluoromethylations through 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.
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:
(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
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.
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.
USSR 1984, 20, 103. (d) Umemoto, T. Chem. Rev 2006, 96, 1757. (e)
Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46,
754.
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.
Outline
• Radical Trifluoromethylations (Yamakawa, Baran)
• Pd-Mediated Trifluoromethylations (Grushin, Sanford, Yu,
Buchwald)
• Cu-Mediated Trifluoromethylations (Vicic, Amii, Hartwig,
Qing, Buchwald)
• Ag-Mediated Trifluoromethylations (Sanford)
Radical Trifluoromethylation Using CF3I
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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.
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.
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.
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.
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.
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.
Pd-Mediated Trifluoromethylations:
Winning Over a Difficult Reductive
Elimination
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.
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.
Pd(II) Catalyzed ortho-Trifluoromethylation
Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648.
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. Science 2010, 328, 1679.
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.
Mechanistic Insights
Jin Cho, E.; Senecal, T.D.; Kinzel, T.; Zhang, Y.; Watson, D.A.; Buchwald, S.L. Science 2010, 328, 1679.
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.
Cu-Mediated Trifluoromethylations:
Understanding an Elusive “CuCF3”
Species
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.
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.
Early Example of Catalytic Cu
Trifluoromethylation
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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.
Cu/L Catalysis
Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.
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);
Morimoto, H.; Tsubogo, T.; Litvinas, N.D.; Hartwig, J.F. Angew. Chem. Int.
• Hartwig’s system is NOT catalytic.
Ed. 2011, 50, 3793.
Continued
Morimoto, H.; Tsubogo, T.; Litvinas, N.D.; Hartwig, J.F. Angew. Chem. Int. Ed. 2011, 50, 3793.
Oxidative Trifluoromethylation (Qing)
Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060.
Oxidative Trifluoromethylation (Buchwald)
Senecal, D.T.; Parsons, A.T.; Buchwald, S.L. J. Org. Chem. 2011, 76, 1174.
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.
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.
Trifluoromethylation of Unactivated Olefins
(Buchwald)
• Alternate mechanism:
Parsons, A.T.; Buchwald, S.L Angew. Chem. Int. Ed. 2011, 50, 9120.
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.
Proposed Mechanism(s)
Wang, X.; Ye, Y.; Zhang, S.; Feng, Y.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, asap.
Ag-Mediated Trifluoromethylations
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.
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
Conclusion
• Important advances in trifluoromethylation reactions in the
past 20 years;
• In spite of these, a general, inexpensive, mild method still
required.
Romania (1918 – 1940)
Bran Castle
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Ruler of Wallachia
(1431 – 1476)