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

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1 ecent Advancement in Ag diated C- Bond ormation Chem 535 Literature Seminar Jiabao Zhang 02/21/2017 1

2 Why Would You Want luorination? igh redox potential: block possible metabolic oxidation. 2

3 Why Would You Want luorination? igh redox potential: Zetia s Discovery (cholesterol lowering). 3

4 Why Would You Want luorination? Increase Potency via luorination oxidize 1 st generation of Zetia ED 50 : 2.2 mg/kg/day luorination 84% activity demethylation 22% activity luorinated lead compund ED 50 : 0.7 mg/kg/day, 3 fold increase Burnett, A.D. et al. J. d. Chem. 1998, 41,

5 Why Would You Want luorination? igh redox potential: igh electronegativity: affects drugs permeability and absorption Zetia s Discovery. 5

6 Why Would You Want luorination? igh redox potential: igh electronegativity: Zetia s Discovery Selective 5T 1D eceptor Ligand. 6

7 Why Would You Want luorination? Increase Bioavailability via luorination EC 50 = 0.3 nm pka = 9.7 Very low bioavailablity <1% EC 50 = 0.9 nm pka = 8.7 easonable bioavailablity 14% Castro, L. J. J. d. Chem. 1999, 42,

8 Why Would You want luorination? C Cl Lipitor Iressa C 3 Zetia 2 Junuvia C 2 Lexapro Levaquin ~20% of pharamaceuticals contain at least one fluorine atom ustero, S.; Soloshonok, V. A.; Liu,. et al. Chem. ev. 2014, 114,

9 Why Would You Want luorination? igh redox potential: igh electronegativity: Zetia s Discovery Selective 5T 1D eceptor Ligand 18 s long t 1/2 ~2hrs: useful tool in positron emission tomography (PET). 9

10 Why Would You Want luorination? igh redox potential: igh electronegativity: Long half-time Zetia s Discovery Selective 5T 1D eceptor Ligand 18 ludeoxyglucose. 10

11 Why Would You Want luorination? igh redox potential: igh electronegativity: Long half-time Zetia s Discovery Selective 5T 1D eceptor Ligand Schmitz, A. et al. J. Spinal Disord. Tech. 2000, 13,

12 Why Would You Want luorination? igh redox potential: igh electronegativity: Long half-time Zetia s Discovery Selective 5T 1D eceptor Ligand 18 ydrophobicity and strong carbon-fluorine bond: application in material ludeoxyglucose. 12

13 Why Would You Want luorination? igh redox potential: igh electronegativity: Long half-time Zetia s Discovery Selective 5T 1D eceptor Ligand Strong carbon-fluorine bond 18 C C n ludeoxyglucose Polytetrafluoroethylene (Teflon). 13

14 Traditional thods are ot Compatible with Complex unctionality Balz-Schiemann 2 a 2, B B ºC - 2 S Ar luorination EWG LG M EWG LG 200 ºC -LG EWG LG = 2 +, Cl, 2, Drawbacks: explosive intermediate; harsh conditions (a 2, high T); limited scopes. Liang, T.; eumann,. C.; itter, T. Angew. Chem. Int. Ed. 2013, 52,

15 Carbon-eteroatom Bond ormation Enabled by Transition tal Catalysis Bond Energy M: transition metal L: ligand C- 116 kcal/mol (shorter bond, high electronegativity) Y 3. eductive elimination M n L n 1. xidative addition X C- 99 kcal/mol C kcal/mol Y M n+2 Ln X M n+2 Ln C-C 83 kcal/mol C- 73 kcal/mol 2. Transmetalation Y-M' Y=,, Y M n+2 Ln X-M' uruya, T.; Kamlet, S. A.; itter, T. ature, 2011, 473,

16 Modern thods to Introduce C- Bond Pd(Ac) 2 (10 mol%) [Py]B 4 ( eq) C 3 C, C 3 C 6 5 microwave, 150 ºC, h Pro: C- to C- Tf Pd(Tf) (10 mol%) [ 3 Py]Tf ( eq) MP (0.5 eq) DCE, 120 ºC Tf Cons: igh temp Directing group needed Tf + Cs [(cinnamyl)pdcl] 2 (2 mol%) t-bubrettphos toluene, ºC, 12h Pro: ucleophilic fluorination Cons: igh temp Basicity of fluoride + i-pr i-pr 1.2 eq i-pr Cs (3.0 eq) toluene, ºC 3-20 h Sanford, M. S. et al. J. Am. Chem. Soc. 2006, 128, Yu, J. Q. et al. J. Am. Chem. Soc. 2009, 131, Buchward, S. L. et al. Science 2009, 325, itter, T. et al. J. Am. Chem. Soc. 2011, 133, i-pr 16

17 utline-ag diated C- Bond ormation üø C- Mild bond condition; formation enabled by single-electron redox process. üø C- Great bond functional formation group inspired tolerance; by a classic amination. üø C- eadily bond scalable formation to gram promoted scale. by metal-metal cooperation. Ag (I) Cl 2B 4 Ag I Catalyst SnBu 3 ac 3 Ag (II) SET Ag (III) Ag ax X=Tf or C 3 Ag II Ln Ag II tal-metal cooperation Bu 3 Sn(C 3 ) Ag I. Ag I m n C 2 -C Cl P 6 Cl 2P 6 17

18 eductive Elimination to orm the C- Bond is Challenging igh electronegativity Small size M n+2 Ln Ease of reductive elimination (.E.) C- > C- > C- L L M Ar difficult step L L M Ar- ow to facilitate the C- bond formation? Grushin, V. V. Acc. Chem. es. 2010, 43,

19 Ag Assisted Single e - redox Process Alkyl radical redox potential -1.8eV ammond s postulate Ag II to Ag I redox potential -0.5eV ernst Equation G=-nE G=~-30kcal/mol eaction will be very exothermic ibas, X. et al. at Commun. 2014, 5,

20 Single e - edox VS Two e - edox M: transition metal L: ligand M: transition metal L: ligand Y M n L n X + M n L n 1. xidative addition Y M n+2 Ln 3. eductive elimination X M n+2 Ln M n+2 Ln M n+1 Ln 2. Transmetalation Y-M' Y=,, Y M n+2 Ln X-M' ' 20

21 Decarboxylative luorination of Aliphatic Carboxylic Acid C Ag 3 (cat) Selectluor Cl 2B 4 Selectluor n-c Br 8 p-cl-c 6 11 p-cl-c % Ph Et 47% Ph 73% p-cl-c % 77% 84% 60% n-c 8 17 Bz 84% 92% 67% Yin,.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134,

22 Decarboxylative luorination of Aliphatic Carboxylic Acid 2 C Ag 3 (cat) C 2 Selectluor 2 C 95% Ag (I) Cl 2B 4 Ag 3 (cat) 2 C C 2 Selectluor 2 C 70% adical Probe Ag (II) Ag (III) C 2 Ag 3 (cat) Cl Selectluor Cl 40% C 2 -C Proposed chanism of Silver Catalyzed Decarboxylative luorination Yin,.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134,

23 adical Phosphonofluorination of Unactivated Alkenes Ag 3 (20 mol%) Selectluor 2 eq P(Et) 2 2 eq 3 2 P(Et) 2 1 Cl 2B 4 Selectluor Et 2 C Et 2 C P(Et) 2 Zhang, C.; Li, Z.; Zhu, L.; Yu, L.; Wang, Z.; Li. C. J. Am. Chem. Soc. 2013, 135, Ph P(Et) 2 P(Et) 2 C 3 79% 82% 66% P(Et) 2 P(Et) P(Et) 2 2 Br 85% 92% C P(Et) 2 53% P(Et) 2 86% 50% TBDPS 70% P(Et) 2 23

24 adical Phosphonofluorination of Unactivated Alkenes P(Et) 2 adical Probe Ag (I) Catalyst Cl 2B 4 9 P(Et) 2 Ag 3 (20 mol%) Selectluor 2 eq P(Et) 2 2 eq 9 47% Cl B 4 P(Et) 2 Ag(II) Ag(III) 2 C C 2 Ag 3 (20 mol%) Selectluor 2 eq P(Et) 2 P(Et) 2 2 eq + 2 C C 2 P(Et) 2 P(Et 2 ) 2 C 53% 26% P(Et) 2 C 2 Zhang, C.; Li, Z.; Zhu, L.; Yu, L.; Wang, Z.; Li. C. J. Am. Chem. Soc. 2013, 135,

25 adical Aminofluorination of Unactivated Alkenes X Ar Ag 3 (10 mol%) Selectluor 2 eq X Ar Cl 2B 4 Selectluor Cl Cl C Ac Ac 80% 65% 55% 75% Cl 75% 84% 90% 51% Zhang, C.; Li, Z.; Zhu, L.; Yu, L.; Wang, L.; Li, C. J. Am. Chem. Soc. 2013, 135,

26 utline-ag diated C- Bond ormation ü C- bond formation enabled by single-electron redox process. Ag (I) Cl 2B 4 S S transfer unprecedented but Cl, Br transfer is well known. Strong oxidant Yield: 80% SI Weak oxidant Yield: 0% Adding TEMP Ag (II) Ag (III) C 2 -C Well-established in literature Anderson, J. M.; Kochi, J. K. J. Am. Chem. Soc. 1970, 92, Severin, K. Curr. rg. Chem. 2006, 10,

27 luorination of Pyridines Inspired by a Classic Amination eaction Chichibabin eaction a 2 a 2 - a 2 ational Design for the fluorination M M - M ier, S. P.; artwig,. J. Science. 2013, 342,

28 luorination of Pyridines Inspired by a Classic Amination eaction Ag 2 3 eq rt, 1hr X Et =Ph, 88% =Et, 94% = t Bu 50% X=, 57% X=Cl, 41% X=Br, 43% =Ph, 59% =Et, 73% =Et 2 83% 62% Cl Ac 57% 51% 94% 83% ier, S. P.; artwig,. J. Science. 2013, 342,

29 luorination of Pyridines Inspired by a Classic Amination eaction Ag 2 3 eq rt, 1hr Chichibabin eaction a 2 a 2 - a 2 Ag -2Ag Ag 2 - Ag 2 Ag Proposed mechanism 2 eq of Ag 2 present in the mechanism, while another 1 eq can increase the yield. ier, S. P.; artwig,. J. Science. 2013, 342,

30 eductive Elimination Promoted by tal-tal Interaction 1) Increasing electrophilicity of metal center is a common way to promote.e. (e.g. π acids) Bu Pent 2 Zn I 3 C i II 10 mol% 3 C i II possible intermediate Bu Bu Pent w/ π-acid 70% yield, 1h w/out π-acid, 20% 15h 2) tal-metal cooperations are known to inhibit oxidative addition. Ph S P Ph C 2 Au I Au I C 2 S P Ph Ph I 2 Ph S P Ph C 2 Au I Au III C 2 I S P Ph Ph I Giovannini,.; Studemanan,.; Knochel, P. Angew. Chem. Int. Ed. 1998, 37, ackler, J. P. Inorg. Chem. 2002, 41,

31 Ag (I) diated C- Bond ormation SnBu 3 AgTf (2.0 eq) -TEDA-P 6 (1.2 eq) Sn: Yield B: Yield AgTf (2.0 eq) Selectluor (1.05 eq) B() 2 Cl 2X X=P 6 -TEDA-P 6 X=B 4 Selectluor Ph 82% 82% 83% 82% 76% 84% 73% 73% 79% 75% C C Boc 73% 85% 77% 71% 76% 77% 72% 70% 81% 75% uruya, T.; Strom, A. E.; itter, T. J. Am. Chem. Soc. 2009, 131, uruya, T.; itter, T. rg. Lett. 2009, 11,

32 Ag (I) Catalyzed Late Stage luorination SnBu 3 Ag (I) catalyst Et 2 C -TEDA-P 6 (1.5 eq) Et 2 C Et 2 C 1 2 2a Ag (I) catalyst Base (2.0 eq) Additive Temp Time Yield 2 Yield 2a 10 mol% AgTf none none 65 º C 3 h 30% 68% Tang, P.; uruya, T.; itter, T. J. Am. Chem. Soc. 2010, 132,

33 Ag (I) Catalyzed Late Stage luorination SnBu 3 Ag (I) catalyst Et 2 C -TEDA-P 6 (1.5 eq) Et 2 C Et 2 C 1 2 2a Ag (I) catalyst Base (2.0 eq) Additive Temp Time Yield 2 Yield 2a 10 mol% AgTf none none 65 º C 3 h 30% 68% 5 mol% Ag 2 ac 3 none 65 º C 3 h 87% 9% Tang, P.; uruya, T.; itter, T. J. Am. Chem. Soc. 2010, 132,

34 Ag (I) Catalyzed Late Stage luorination SnBu 3 Ag (I) catalyst Et 2 C -TEDA-P 6 (1.5 eq) Et 2 C Et 2 C 1 2 2a Ag (I) catalyst 10 mol% AgTf 5 mol% Ag 2 Base (2.0 eq) none ac 3 Additive none none 5 mol% Ag 2 ac eq atf 5 mol% Ag 2 1 mol% Ag 2 1 mol% Ag 2 ac 3 ac 3 ac eq atf 5.0 eq 1.0 eq atf 1.0 eq atf 5.0 eq Tang, P.; uruya, T.; itter, T. J. Am. Chem. Soc. 2010, 132, Temp Time 65 º C 3 h 65 º C 3 h 65 º C 3 h 65 º C 3 h 90 º C 18 h 90 º C 18 h Yield 2 Yield 2a 30% 68% 87% 9% 90% 5% 92% 2% 92% 2% 75% 20% 34

35 Ag (I) Catalyzed Late Stage luorination SnBu 3 Ag 2 (5.0 mol%) atf (1.0 eq) ac 3 (2.0 eq) -TEDA-P 6 (1.5 eq) Ø great G tolerance Ø gram-scale Ø cheap catalyst Ph flavanone 90% maculosin 78% Tang, P.; uruya, T.; itter, T. J. Am. Chem. Soc. 2010, 132, Bz Bz Bz Bz estrol-17-b-d-lactoside heptabenzote 80% Ac Ac DPA 78% C 2 Boc estrone 81% Br C 88% 76% 78% 77% 89% Boc Ac quinine Leu-enkephalin 75% Bz Bz 83% Bz 72% Ac 35

36 Ag (I) Catalyzed C- Bond ormation SnBu 3 Ag 2 (5.0 mol%) atf (1.0 eq) -TEDA-P 6 (1.5 eq) Ag I Catalyst SnBu 3 ac 3 Stoichiometric study Another 1 eq of AgTf increases yield significantly ax X=Tf or C 3 2 Ag II Ln Ag II Bu 3 Sn(C 3 ) Ag I. Ag I m n Ag 1 eq AgTf -TEDA-P 6 Ag AgTf 47% 84% Cl P 6 Cl 2P 6 1, 19 M observed Tang, P.; uruya, T.; itter, T. J. Am. Chem. Soc. 2010, 132,

37 uture Direction I. More mechanistic details should be studied a) The evidence for the presence of Ag(III), Ag(II)-Ag(II) complex; b) urther study of the radical mechanism II. Take advantage of the current platform to introduce new bonds 3 AgSC 3 (2.5 eq) 3 CS as 2 8 (4.0 eq) 1 2 AgP 6 AgP 6 SnBu 3 C 3 B() TAS C 2 3 TAS C 3-30 ºC -30 ºC Guo, S.; Zhang, X.; Tang, P. Angew. Chem. Int. Ed. 2015, 54, uang, C.; Liang, T.; arada, S.; Lee, E.; itter, T. J. Am. Chem. Soc. 2011, 133,

38 Summary ü C- bond formation enabled by single-electron redox process. ü C- bond formation inspired by a classic amination. ü C- bond formation promoted by metal-metal cooperation. Ag (I) Cl 2B 4 Ag I Catalyst SnBu 3 ac 3 Ag ax X=Tf or C 3 Bu 3 Sn(C 3 ) Ag (II) Ag (III) Ag II Ln Ag II Ag I n. Ag I m C 2 -C Cl P 6 Cl 2P 6 38

39 Acknowledgements Prof. Marty Burke Prof. Jefferson Chan Prof. Paul ergenrother The Burke Group CEM 535 Class Audience 39

40 Back-up Sides Saturday, ebruary 11,

41 Back-up Sides 41

42 Pd-Catalyzed Arene C- luorination Tf 10 mol% Pd(Tf) equiv [ 3 Py]Tf 0.5 equiv. MP DCE, 120 C Tf [ 3 Py]Tf Tf Br Tf Tf 3 C Tf Tf Tf Tf 83% 60% 81% 58% 68% 71% Difluorination: Tf dissociation L n Pd II Tf C-C rotation L n Pd II Tf Wang, X.; i, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,

43 Back-up Sides Saturday, ebruary 11,