Transition Metals Mediated Fluorination of Arenes and Heteroarenes

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1 Transition tals diated luorination of Arenes and eteroarenes t-bu i-pr C t-bu S P i-pr i i-pr 2 L o-s

Why Would You Want to luorinate an Arene?

i-pr 2 Lipitor Lexapro S i-pr 2 C 3 Crestor Junuvia C Zetia

between 2001 and 2011 ~30% of pharamaceuticals contain at

2 Why Would You Want to luorinate an Arene? Aryl fluorides are present in a wide range of pharmaceuticals i-pr 2 Lipitor Lexapro S i-pr 2 C 3 Crestor Junuvia C Zetia Levaquin 40 fluroine containing drugs introduced to market between 2001 and 2011 ~30% of pharamaceuticals contain at least one fluorine atom ustero, S.; Soloshonok, V. A.; Liu,. et al. Chem. ev. 2014, 114, 2432.

3 Why Would You Want to luorinate an Arene? Tradition methods are not compatible with complex functionality Balz-Schiemann 2 a 2, B B 4 - Δ - 2 Lenz-Wallach 2 a 2, anhydrous Δ - 2 not isolated S Ar EWG Cl M DMS/DM, 200 C EWG Mild methods for the selective introduction of fluorine to complex molecules remains challenging Müller, K.; aeh, C.; Diederich,. Science 2007, 317, Purser, S.; Moore, P..; Swallow, S.; Gouverneur, V. Chem. Soc. ev. 2008, 37, 320.

4 Transition tals diated luorination of Arenes and eteroarenes 1. Palladium Catalyzed Processes The challenges facing transition metal catalyzed fluorination irst example of C bond formation by reductive elimination Buchwalds catalytic fluorination using nucleophilic fluoride 2. Copper Catalyzed and diated Processes Copper mediated halogen exchange Sanford's catalytic fluorination of aryl iodoniums Sanford's Chan-Evans-Lam 3. Silver Catalyzed and diated Processes xidative fluorination of aryl nucleophiles artwig's Chichibabin inspired fluorination of heteroarenes 4. itter's oxidative fluorination of aryl nickel complexes 5. itter's radical fluorination of aryl potassium trifluoroborates Paquin, J-. et al. Chem. ev. 2015, 115, eumann, C..; itter, T. Angew. Chem. Int. Ed. 2015, 54, 2.

5 Challenges acing Transition tal Catalysis eductive elimination to from the C bond is kinetically difficult L L M Ar problem step L L M Ar energy ΔG L L M ormal oxidation of fluoride Competing reductive elimination involving the ligand had been a long standing problem Grushing, V. V. Chem. Eur. J. 2002, 45, Grushin, V. V.; Marshall, W. J. rganometallics. 2007, 26, 4997.

6 Palladium diated Aryl Bond ormation eductive elimination from a highly oxidising metal center proved to be fruitful B mol% (Ac) 2 C 6 6, µν, 110 C, 1h 1 2 Key chanistic ypothesis II L L " + " IV L ed. Elim. L L + II ull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, uruya, T.; Kaiser,. M.; itter, T. Angew. Chem. Int. Ed. 2008, 47, uruya, T.; itter, T. J. Am. Chem. Soc. 2008, 130,

7 Palladium diated Aryl Bond ormation eductive elimination from a highly oxidising metal center proved to be fruitful 2 S Py B() 2 Ac then Selectfluor 50 ºC, 30 min (IV) intermediate observed spectrascopically and isolated 4 L o-s o-s bserved in solution Air and moisture stable orange solid ull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, uruya, T.; Kaiser,. M.; itter, T. Angew. Chem. Int. Ed. 2008, 47, uruya, T.; itter, T. J. Am. Chem. Soc. 2008, 130,

8 Palladium diated Aryl Bond ormation eductive elimination from a highly oxidising metal center proved to be fruitful 2 S Py B() 2 Ac then Selectfluor 50 ºC, 30 min (IV) intermediate observed spectrascopically and isolated L o-s 4 o-s 50 ºC 94% Yield 150 ºC 97% Yield ull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, uruya, T.; Kaiser,. M.; itter, T. Angew. Chem. Int. Ed. 2008, 47, uruya, T.; itter, T. J. Am. Chem. Soc. 2008, 130,

9 Palladium diated Aryl Bond ormation eductive elimination from a highly oxidising metal center proved to be fruitful 2 S Py B() 2 Ac then Selectfluor 50 ºC, 30 min (IV) intermediate observed spectrascopically and isolated S 4 o-s Ar tridentate co-ordination of the pyridyl-sulfonamide ligand ull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, uruya, T.; Kaiser,. M.; itter, T. Angew. Chem. Int. Ed. 2008, 47, uruya, T.; itter, T. J. Am. Chem. Soc. 2008, 130,

10 Palladium diated Aryl Bond ormation eductive elimination from a highly oxidising metal center proved to be fruitful S S 2 Ar Trigonal prism More electron rich (IV) center aster E Sulfonamide ligand - basal Significant +ve charge on center in TS itter, T.; Goddard, W. A. III et al. J. Am. Chem. Soc. 2010, 132, 3793.

11 Palladium diated Aryl Bond ormation C activation Limited Substrate Scope Tf Ar f itter technology Controllable regioselectivity but stiochiometric in Palladium Electrophilic luorine sources are derived from 2 gas Expensive Ideal eaction But reductive elimination from (II) is much more challenging X cat. " - " ull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, uruya, T.; Kaiser,. M.; itter, T. Angew. Chem. Int. Ed. 2008, 47, Wang, X.; i, T. -S.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131, Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J. Q. Angew. Chem. Int. Ed. 2011, 50, 9081.

12 Palladium diated Aryl Bond ormation eductive elimination from (II) is challenging Ph 3 P Ph 3 P Ph I Ag C 6 C66, 6, sonication, sonication, 7820 to ºC 20 ºC Ph 3 P Ph 3 P Ph toluene, 2, 120 ºC no C bond formation Ph 3 P 2 Ph 2 air and moisture stable for 6 months at room temperature Ph 2 PPPh 2 (0) chanism Ph Ph PPh 3 Ph PPh 3 Ph 3 P Ph PPh 3 Ph 2 P Ph Ph PPh 3 Ph 3 P PPh 2 PPh 3 PPh 2 Ph 3 P PPh 2 Ph 3 P Ph 2 P Ph P Ph PPh 3 Ph 3 P PPh 2 Ph 3 P 2 Ph 2 PPPh 2 (0) raser, S. L.; Antipin, M. Y.; Khroustalyov, V..; Grushin, V. V. J. Am. Chem. Soc. 1997, 119, Grushin, V. V. rganometallics, 2000, 19, Grushin, V. V.; Acc. Chem. es. 2010, 43, 160. Grushin, V. V.; Marshall, W. J. rganometallics. 2007, 26, 4997.

13 Palladium diated Aryl Bond ormation eductive elimination from (II) is challenging Ar L L Ar Ph 3 P Ph 3 P Ar Ar L Ar L After working on this problem for ~10 years "ur work has shown that conventional tertiary phosphines, which are most widely used for catalysis, are unlikely to be useful for the desired C bond formation at the metal center" -Grushin 2007 Buchwald 2008 Tf 6 mol% tbubrettphos 2 mol% [(cinnamyl)cl] 2 Cs, Ph, 110 ºC, 12h tbubrettphos PtBu 2 Grushin, V. V.; Marshall, W. J. rganometallics. 2007, 26, Watson, D. A.; Su, M.; Teverovskiy G.; Zhang, Y.; Garcia-ortanet, J.; Kinzel, T.; Buchwalk, S. L. Science, 2008, 325, Grushin, V. V.; Acc. Chem. es. 2010, 43, 160.

14 Palladium diated Aryl Bond ormation eductive elimination from (II) is challenging Ar L L Ar Ph 3 P Ph 3 P Ar Ar L Ar L After working on this problem for ~10 years "ur work has shown that conventional tertiary phosphines, which are most widely used for catalysis, are unlikely to be useful for the desired C bond formation at the metal center" -Grushin 2007 Buchwald 2008 Tf 6 mol% tbubrettphos PtBu 2 tbubrettphos 2 mol% [(cinnamyl)cl] 2 Cs, Ph, ºC, ºC, 12h 12h Grushin, V. V.; Marshall, W. J. rganometallics. 2007, 26, Watson, D. A.; Su, M.; Teverovskiy G.; Zhang, Y.; Garcia-ortanet, J.; Kinzel, T.; Buchwald, S. L. Science, 2008, 325, Grushin, V. V.; Acc. Chem. es. 2010, 43, 160.

15 Palladium diated Aryl Bond ormation Buchwald 2008 Tf Tf 66 mol% tbubrettphos 22 mol% [(cinnamyl)cl] 2 2 Cs, Ph, Ph, ºC, 12h ºC, 12h tbubrettphos PtBu 2 PAdm 2 PAdm 2 PtBu 2 PAdm 2 n-bu n-bu tbubrettphos 2008 AdmBrettPhos 2013 Arylated ockphos Ligand AlPhos 2015 Aryl and select eteroaryl Triflates Aryl and etereoaryl Triflates Bromides emoves the induction period Aryl bromides now work Aryl and etereoaryl Bromides at room temperature Watson, D. A.; Su, M.; Teverovskiy G.; Zhang, Y.; Garcia-ortanet, J.; Kinzel, T.; Buchwald, S. L. Science, 2008, 325, Lee,. G. G.;.; Milner, P. J.; Buchwald, S. L. rg. Lett. 2013, 15, Milner, P. J.; Lee, Kinzel,. G. G.;.; T.; Milner, Zhang, P. Y.; J.; Buchwald, S. S. L. L. J. J. Am. Chem. Soc. 2014, 136, Sather, A. C.; Lee,. G. G.;.; De La osa, V. Y.; Yang, Y.; Muller, P.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, Milner, P. J.; Yang, Y.; Buchwald, S. L. rganometallics. 2015, 34, 4775.

16 Palladium diated Aryl Bond ormation Interesting bservations ational Ligand Design The reaction suffers from an induction period with destruction of the ArTf susbtrate Stoichiometric Studies Demonstrated Ligand Modification nbu Tf nbu t-bu t-bu P PtBu 2 xn. Cond. PtBu 2 nbu tbubrettphos unctionalized Ligand Watson, D. A.; Su, M.; Teverovskiy G.; Zhang, Y.; Garcia-ortanet, J.; Kinzel, T.; Buchwald, S. L. Science, 2008, 325, Maimone, T. J.; Milner, P. J. Kinzel, T.; Zhang, Y.; Takase, M. K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, Milner, P. J.; Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, Sather, A. C.; Lee,. G.; De La osa, V. Y.; Yang, Y.; Muller, P.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137,

17 Palladium diated Aryl Bond ormation Interesting bservations ational Ligand Design Certain substrates lead to a mixture of regioisomers Tf 3 equiv. Cs 2.5 mol% [(cinnamyl)cl] mol% arylated tbubretphos nbu Ph, 120 ºC, 12h nbu nbu 70% Yield 1.5:1 rr Tf 3 equiv. Cs 2.5 mol% [(cinnamyl)cl] mol% arylated tbubretphos D D nbu Ph, 120 ºC, 12h 1 equiv tbud nbu nbu nbu nbu 30% 3% 14% 8% 2,6-dideutared aryl triflates show improved regioselecitivity compared to there non deuterated analogues Watson, D. A.; Su, M.; Teverovskiy G.; Zhang, Y.; Garcia-ortanet, J.; Kinzel, T.; Buchwald, S. L. Science, 2008, 325, Maimone, T. J.; Milner, P. J. Kinzel, T.; Zhang, Y.; Takase, M. K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, Milner, P. J.; Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, Sather, A. C.; Lee,. G.; De La osa, V. Y.; Yang, Y.; Muller, P.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137,

18 Palladium diated Aryl Bond ormation t-bu P t-bu nbu Tf t-bu P t-bu nbu t-bu P t-bu nbu t-bu P t-bu Tf nbu Cs Cs Supressing Palladium Benzyne formation should improve regioselectivity CsTf t-bu P t-bu nbu CsTf

19 Palladium diated Aryl Bond ormation ational Ligand Design igh reaction temperatures required for reductive elimination Adm Ar Adm P nbu Internal -bonding interaction stabilizes fluoride ligand retards reductive elimination Adm Ar Adm P nbu This complex reductively eliminates at room temperature! Sather, A. C.; Lee,. G.; De La osa, V. Y.; Yang, Y.; Muller, P.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137,

20 State of the art technology Palladium diated Aryl Bond ormation Tf 3 equiv. Cs 2 mol% CD( AlPhos) 2 Ph or 2-T, rt, 96h >100:1 rr S 82% yield 89% yield C 3 C 2 Et 95% yield C 2 Phth C 2 81% yield 96% yield 92% yield Sather, A. C.; Lee,. G.; De La osa, V. Y.; Yang, Y.; Muller, P.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137,

21 Transition tals diated luorination of Arenes and eteroarenes 1. Palladium Catalyzed Processes The challenges facing transition metal catalyzed fluorination irst example of C bond formation by reductive elimination Buchwalds catalytic fluorination using nucleophilic fluoride 2. Copper Catalyzed and diated Processes Copper mediated halogen exchange Sanford's catalytic fluorination of aryl iodoniums Sanford's Chan-Evans-Lam 3. Silver Catalyzed and diated Processes xidative fluorination of aryl nucleophiles artwig's Chichibabin inspired fluorination of heteroarenes 4. itter's oxidative fluorination of aryl nickel complexes 5. itter's radical fluorination of aryl potassium trifluoroborates Paquin, J-. et al. Chem. ev. 2015, 115, eumann, C..; itter, T. Angew. Chem. Int. Ed. 2015, 54, 2.

22 Copper Catalyzed Aryl Bond ormation eactions I'm not going to talk about in depth Copper diated artwig 2012 I (tbuc) 2 CuTf (3 equiv) Ag (2 equiv) DM, 140 ºC, 22h artwig 2013 Conditions nearly identical to Sanford's + B 4 - Tf Cu BPin (tbuc) 2 CuTf (2 equiv) Ag (2 equiv) T, 50 ºC, 18h Cu(III) observed spectrascopically Mass Spec 19 and 1 M ier, P. S.; artwig, J.. J. Am. Chem. Soc. 2012, 134, ier, P. S.; Luo, J.; artwig, J.. J. Am. Chem. Soc. 2013, 135, 2552.

23 Copper Catalyzed Aryl Bond ormation eactions I'm not going to talk about in depth Copper diated Sanford B 4 - B 3 K (tbuc) 2 CuTf (2 equiv) EtAc, 80 ºC, 12h Sanford 2013 B 3 K Cu(Tf) 2 (4 equiv) K (4 equiv) C, 60 ºC, air, 20h Ye, Y.; Schimler, S. D.; anley, P. S.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, Ye, Y.; Sanford, M. S J. Am. Chem. Soc. 2013, 135,

24 Copper Catalyzed Aryl Bond ormation All of these methods are super stoichiometric in copper Copper luoride is prone to disproportionation Cu Cu 2 Cu Insoluable Catalytic deadend Complexation can stabilized Cu(I) fluorides but heating induces disproportionation Sanford 2013 irst thod Catalytic in Copper B 4-20 mol% Cu(Tf) 2 40 mol% 18-crown-6 I equiv K DM, 60 ºC, 3h Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rg. Lett. 2013, 15, Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rganometallics 2014, 33, 5525.

25 Sanford 2013 irst thod Catalytic in Copper Copper Catalyzed Aryl Bond ormation B 4-20 mol% Cu(Tf) 2 40 mol% 18-crown-6 I equiv K DM, 60 ºC, 3h B 4 - I + 20 mol% Cu(Tf) 2 40 mol% 18-crown equiv K t-bu DM, 60 ºC, 3h t-bu 73% Yield >1% Yield without [Cu] 2% Yield 40% Yield I The ratio of products in the absence of copper is strongly dependent on substrate electronics t-bu Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rg. Lett. 2013, 15, Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rganometallics 2014, 33, Grushin, V. V.; Demkina, I. I.; Tolstaya, T. P. J. Chem. Soc., Perkin Trans , 505.

26 Sanford 2013 irst thod Catalytic in Copper Copper Catalyzed Aryl Bond ormation B 4-20 mol% Cu(Tf) 2 40 mol% 18-crown-6 I equiv K DM, 60 ºC, 3h Cu(I) is formed in situ Concentration of fluoride is kept low due to insolubility of K in DM Transition State for xidative Addition Cu I Tf s 3 C S Cu I s 2 Cu I s Cu I s ΔG 9.7 kcalmol kcalmol kcalmol kcalmol -1 Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rg. Lett. 2013, 15, Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rganometallics 2014, 33, Grushin, V. V.; Demkina, I. I.; Tolstaya, T. P. J. Chem. Soc., Perkin Trans , 505.

27 Copper Catalyzed Aryl Bond ormation I + B 4 - s Is Cu - apid oxidative addition Cu Is Catalytic Cycle Copper I s aster then Cu(I) disproportionation aster than backgroup reaction Cu 18-Crown-6 allows for concentration of fluoride in solution to be controlled Cu Is Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rg. Lett. 2013, 15, Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rganometallics 2014, 33, 5525.

28 Transition tals diated luorination of Arenes and eteroarenes 1. Palladium Catalyzed Processes The challenges facing transition metal catalyzed fluorination irst example of C bond formation by reductive elimination Buchwalds catalytic fluorination using nucleophilic fluoride 2. Copper Catalyzed and diated Processes Copper mediated halogen exchange Sanford's catalytic fluorination of aryl iodoniums Sanford's Chan-Evans-Lam 3. Silver Catalyzed and diated Processes xidative fluorination of aryl nucleophiles artwig's Chichibabin inspired fluorination of heteroarenes 4. itter's oxidative fluorination of aryl nickel complexes 5. itter's radical fluorination of aryl potassium trifluoroborates Paquin, J-. et al. Chem. ev. 2015, 115, eumann, C..; itter, T. Angew. Chem. Int. Ed. 2015, 54, 2.

29 Silver diated Aryl Bond ormation Silver (II) as a site for C bond formation M 5 mol% Ag equiv Selectfluor 2.0 equiv ac 3, 1.0 equiv atf acetone, 65 ºC, SnBu 3 AgTf Ac atf Ag Ag(II) Silver Catalytic Cycle Bu 3 SnC 2 Ag Ag(I) Ac 72% yield + Cl + + Cl 60% yield uruya, T.; Strom, A. E.; itter, T. J. Am. Chem. Soc., 2009, 131, 1662 uruya, T.; itter, T. rg. Lett, 2009, 11, 2860 Pingping, T.; uruya, T.; itter, T. J. Am. Chem. Soc., 2010, 132, 12150

30 Silver diated Aryl Bond ormation Silver (II) as a site for C bond formation M 5 mol% Ag equiv Selectfluor 2.0 equiv ac 3, 1.0 equiv atf acetone, 65 ºC, SnBu 3 AgTf adical scavengers did not impede the reaction Addition of water lead to preferential phenol formation atf Bu 3 SnC 2 Ag Ag(II) Silver Catalytic Cycle Ag Ag(I) Ag + + Cl 47% yield + Cl + + Cl Addition of AgTf 84% yield uruya, T.; Strom, A. E.; itter, T. J. Am. Chem. Soc., 2009, 131, 1662 uruya, T.; itter, T. rg. Lett, 2009, 11, 2860 Pingping, T.; uruya, T.; itter, T. J. Am. Chem. Soc., 2010, 132, 12150

31 Silver diated Aryl Bond ormation Silver (II) as a site for C bond formation artwig 2013 Pyridines and Diazenes Ag 2 (2 equiv) C, 20 ºC, 1h Ag 2 Ag Ag Boc Et Ac 2 C Cl Cl 74% yield 75% yield 67% yield ier, P. S.; artwig, J.. Science. 2013, 342, 956

32 Transition tals diated luorination of Arenes and eteroarenes 1. Palladium Catalyzed Processes The challenges facing transition metal catalyzed fluorination irst example of C bond formation by reductive elimination Buchwalds catalytic fluorination using nucleophilic fluoride 2. Copper Catalyzed and diated Processes Copper mediated halogen exchange Sanford's catalytic fluorination of aryl iodoniums Sanford's Chan-Evans-Lam 3. Silver Catalyzed and diated Processes xidative fluorination of aryl nucleophiles artwig's Chichibabin inspired fluorination of heteroarenes 4. itter's oxidative fluorination of aryl nickel complexes 5. itter's radical fluorination of aryl potassium trifluoroborates Paquin, J-. et al. Chem. ev. 2015, 115, eumann, C..; itter, T. Angew. Chem. Int. Ed. 2015, 54, 2.

33 ickel diated Aryl Bond ormation ickel will actually undergo oxidative addition into simple unactivated Ar bonds 1973 MgBr 0.05 mol% icl(dppp) T, rt, 24h 92% yield C X bond formation fron ickel (II) is unknown. i II Br Br 2 Br i III or Br i IV Br Br Br dppe Ph Ph P Br P Ph Ph 90% yield i II Br Br Amii,.; Uneyama, K. Chem. ev. 2009, 109, Kiso, Y.; Tamao, K.; Kumada, M. J. rganomet. Chem. 1973, 50, C12. iggs, A. T.; Zinn, P. J.; Simmons, S. J.; Sanford, M. S. rganometallics, 2009, 21, Camasso,. M.; Sanford, M. S. Science, 2015, 347, Lee, E.; ooker, J. M.; itter, T. J. Am. Chem. Soc., 2012, 134,

34 xidative luorination of ickel Aryl Complexes ickel diated Aryl Bond ormation 2 S i Py I p-tol TBAT, C, 0 ºC, 1 min 2 + (Tf ) 2 Ph Ph 65% yield 2 S i Py Ar S i III/IV Ph Ph xidation state of intermediate is unknown Amii,.; Uneyama, K. Chem. ev. 2009, 109, Kiso, Y.; Tamao, K.; Kumada, M. J. rganomet. Chem. 1973, 50, C12. iggs, A. T.; Zinn, P. J.; Simmons, S. J.; Sanford, M. S. rganometallics, 2009, 21, Camasso,. M.; Sanford, M. S. Science, 2015, 347, Lee, E.; ooker, J. M.; itter, T. J. Am. Chem. Soc., 2012, 134,

35 xidative luorination of ickel Aryl Complexes ickel diated Aryl Bond ormation 2 S i Py I p-tol TBAT, C, 0 ºC, 1 min 2 + (Tf ) 2 Ph Ph 65% yield Boc Boc Boc [i] aqueous crown-6 iodonium, C, 23ºC, 1 min Boc Boc 18 Boc 18 L-DPA 15% CY Amii,.; Uneyama, K. Chem. ev. 2009, 109, Kiso, Y.; Tamao, K.; Kumada, M. J. rganomet. Chem. 1973, 50, C12. iggs, A. T.; Zinn, P. J.; Simmons, S. J.; Sanford, M. S. rganometallics, 2009, 21, Camasso,. M.; Sanford, M. S. Science, 2015, 347, Lee, E.; ooker, J. M.; itter, T. J. Am. Chem. Soc., 2012, 134,

36 xidative luorination of ickel Aryl Complexes ickel diated Aryl Bond ormation 2 S i Py I p-tol TBAT, C, 0 ºC, 1 min 2 + (Tf ) 2 Ph Ph 65% yield i II + Tf Tf i i II Tf Amii,.; Uneyama, K. Chem. ev. 2009, 109, Kiso, Y.; Tamao, K.; Kumada, M. J. rganomet. Chem. 1973, 50, C12. iggs, A. T.; Zinn, P. J.; Simmons, S. J.; Sanford, M. S. rganometallics, 2009, 21, Camasso,. M.; Sanford, M. S. Science, 2015, 347, Lee, E.; ooker, J. M.; itter, T. J. Am. Chem. Soc., 2012, 134,

37 xidative luorination of ickel Aryl Complexes ickel diated Aryl Bond ormation 2 S i Py I p-tol TBAT, C, 0 ºC, 1 min 2 + (Tf ) 2 Ph Ph 65% yield i II S + C 3 Tf Tf i C 3 Tf i II C 3 diamagnetic species observed in situ Amii,.; Uneyama, K. Chem. ev. 2009, 109, Kiso, Y.; Tamao, K.; Kumada, M. J. rganomet. Chem. 1973, 50, C12. iggs, A. T.; Zinn, P. J.; Simmons, S. J.; Sanford, M. S. rganometallics, 2009, 21, Camasso,. M.; Sanford, M. S. Science, 2015, 347, Lee, E.; ooker, J. M.; itter, T. J. Am. Chem. Soc., 2012, 134,

38 Transition tals diated luorination of Arenes and eteroarenes 1. Palladium Catalyzed Processes The challenges facing transition metal catalyzed fluorination irst example of C bond formation by reductive elimination Buchwalds catalytic fluorination using nucleophilic fluoride 2. Copper Catalyzed and diated Processes Copper mediated halogen exchange Sanford's catalytic fluorination of aryl iodoniums Sanford's Chan-Evans-Lam 3. Silver Catalyzed and diated Processes xidative fluorination of aryl nucleophiles artwig's Chichibabin inspired fluorination of heteroarenes 4. itter's oxidative fluorination of aryl nickel complexes 5. itter's radical fluorination of aryl potassium trifluoroborates Paquin, J-. et al. Chem. ev. 2015, 115, eumann, C..; itter, T. Angew. Chem. Int. Ed. 2015, 54, 2.

39 adical luorination of Arenes itters Catalytic Palladium Chemistry Unexpected chanism: no reductive elimination at the metal B 3 K Selectfluor, a cat. [ terpy](b 4 ) 2 C, 40 ºC, 15 min Logical Catalytic Proposal Cl Ar II + + Ar IV II Stoichiometric Studies Suggest an Alternate chanism Mazzotti, T..; Campbell, M. G.; Tang, P.; Murphy, J. M.; itter, T. J. Am. Chem. Soc., 2013, 135,

40 adical luorination of Arenes itters Catalytic Palladium Chemistry Unexpected chanism: no reductive elimination at the metal B 3 K Selectfluor, a cat. [ terpy](b 4 ) 2 C, 40 ºC, 15h 3+ 3 B 4 coordinatively saturated (III) complex isolated Isolated (III) Intermediate Mazzotti, T..; Campbell, M. G.; Tang, P.; Murphy, J. M.; itter, T. J. Am. Chem. Soc., 2013, 135,

adical luorination of Arenes Cl [(terpy) 2 II ] 2+ + + + B 3 SET Sodium luoride required to mop up B 3 generated [(terpy) 2 II ] 2+ B 3 K Palladium Catalytic Cycle

41 adical luorination of Arenes Cl [(terpy) 2 II ] B 3 SET Sodium luoride required to mop up B 3 generated [(terpy) 2 II ] 2+ B 3 K Palladium Catalytic Cycle [(terpy) 2 III ] 2+ Cl + B 3 K SET [(terpy) 2 III ] 2+ B 3 K + Cl Mazzotti, T..; Campbell, M. G.; Tang, P.; Murphy, J. M.; itter, T. J. Am. Chem. Soc., 2013, 135,

42 adical luorination of Arenes Cl [(terpy) 2 II ] B 3 SET Sodium luoride required to mop up B 3 generated [(terpy) 2 II ] 2+ B 3 K Palladium Catalytic Cycle [(terpy) 2 III ] 2+ Cl + o organometallic intermediates SET [(terpy) 2 III ] 2+ B 3 K C bond not formed via reductive elimination B 3 K + Cl Mazzotti, T..; Campbell, M. G.; Tang, P.; Murphy, J. M.; itter, T. J. Am. Chem. Soc., 2013, 135,

43 Transition tals diated luorination of Arenes and eteroarenes 1. Palladium Catalyzed Processes The challenges facing transition metal catalyzed fluorination irst example of C bond formation by reductive elimination Buchwalds catalytic fluorination using nucleophilic fluoride 2. Copper Catalyzed and diated Processes Copper mediated halogen exchange Sanford's catalytic fluorination of aryl iodoniums Sanford's Chan-Evans-Lam 3. Silver Catalyzed and diated Processes xidative fluorination of aryl nucleophiles artwig's Chichibabin inspired fluorination of heteroarenes 4. itter's oxidative fluorination of aryl nickel complexes 5. itter's radical fluorination of aryl potassium trifluoroborates Paquin, J-. et al. Chem. ev. 2015, 115, eumann, C..; itter, T. Angew. Chem. Int. Ed. 2015, 54, 2.

44 Conclusions eductive elimination to from the C bond is kinetically difficult L L M Ar problem step L L M Ar igh oxidation state metal center (IV), Ag(II), i(iii) acilitates problematic step Limited to organometallic nucleophiles and molecules with directing groups (II) catalysis allows the use of more diverse aryl halide electrophiles Ligand design incredibly important to get high efficiency Cu(I)/Cu(III) catalysis Cu prone to disproportionation ighly reactive electrophiles enable catalysis but shortening reaction times

45 Sanford 2013 irst thod Catalytic in Copper Copper Catalyzed Aryl Bond ormation B 4-20 mol% Cu(Tf) 2 40 mol% 18-crown-6 I equiv K DM, 60 ºC, 3h Cu(I) is formed in situ Concentration of fluoride is kept low due to insolubility of K in DM Transition State for xidative Addition Cu I Tf s 3 C S Cu I s 2 Cu I s Cu I s ΔG 9.7 kcalmol kcalmol kcalmol kcalmol -1 Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rg. Lett. 2013, 15, Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rganometallics 2014, 33, Grushin, V. V.; Demkina, I. I.; Tolstaya, T. P. J. Chem. Soc., Perkin Trans , 505.

46 Copper Catalyzed Aryl Bond ormation Barrier to oxidative addition to the I s bond is ~ 4 kcal mol -1 higher in energy Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rg. Lett. 2013, 15, Ichiishi,.; Canty, A. J.;Yates, B..; Sanford, M. S. rganometallics 2014, 33, 5525.

Recent Advancement in Ag Mediated C-F Bond Formation. Chem 535 Literature Seminar Jiabao Zhang 02/21/2017

Recent Advancement in Ag Mediated C-F Bond Formation. Chem 535 Literature Seminar Jiabao Zhang 02/21/2017 ecent Advancement in Ag diated C- Bond ormation Chem 535 Literature Seminar Jiabao Zhang 02/21/2017 1 Why Would You Want luorination? igh redox potential: block possible metabolic oxidation. 2 Why Would