Fron%ers in Chemistry Seminar
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1 Fron%ers in Chemistry eminar Transi%on Metal- Catalyzed Func%onaliza%on of C sp3 via C- bond ac%va%on Presented by: Jared T. ammill Wipf Group Mee%ng University of PiGsburgh eptember 22, 2012 Jared Wipf Group Page 1 of 73 9/28/2012
2 utline A. Introduction B. C sp3 C- Bond Functionalization A. C- Bond Formation B. C- Bond Formation C. C-C Bond Formation D. C-X Bond Formation C. Conclusions and Future Directions Jared Wipf Group 2 Jared Wipf Group Page 2 of 73 9/28/2012
3 What is Transition Metal-Catalyzed C- activation? [M] C C [M] -X -[M] C = C,,,, B, halogen Definition: The use of transition metals to increase the reactivity of a C- bond by replacement of the strong C- bond with a more readily functionalized C-[M] bond. Chem. ev. 1997, 97, Jared Wipf Group 3 Jared Wipf Group Page 3 of 73 9/28/2012
4 Advantages of C- ac%va%on nly requires prefunctionalization of one precursor Traditional C 2 FG 2 C FG 1 C FG 2 C 1 FG 1 C 1 C 2 C- activation C 2 FG C C FG C 1 C 1 C 2 cience, 2006, 312, Jared Wipf Group 4 Jared Wipf Group Page 4 of 73 9/28/2012
5 Advantages of C- ac%va%on Transition Metal Cataysis: FG Fe, h, u, Cu Pt, Pd FG Changing Metal we can get reactivity at 1º, 2º, and 3º C- bonds While many transition metals have been used today I will focus on Pt, Pd, Fe, h, u Jared Wipf Group 5 Jared Wipf Group Page 5 of 73 9/28/2012
6 Challenges of C- ac%va%on Inertness of alkanes Formerly known as paraffins, derived from the latin parum affinis (without affinity), products more reactive than M Ubiquitous nature of C- bonds electivity challenging: little difference in reactivity between C- bonds C BDE (kcal/mol) pka ( 2 ) pka s were reproduced from BDE s were reproduced based on Jared Wipf Group Chem. ev. 1997, 97, Jared Wipf Group Page 6 of 73 9/28/2012
7 Background C- Inser%on 1962: Chatt (dmpe) 2 u ap Initally proposed structure u(dmpe) 2 dmpe = Me 2 PC 2 C 2 PMe 2 Me 2 P Me 2 P P PMe 2 u u P PMe 2 PMe 2 Actual structure J. Chem. oc. 1962, 2545 J. rganomet. Chem. 2004, 689, : hilov Pt II D + D 1982: Bergmann J. Phys. Chem. 1969, 73, 1525 Ir Me 3 P hv Ir Me 3 P C- insertion Ir Me 3 P Jared Wipf Group cience, 1984, 223, Jared Wipf Group Page 7 of 73 9/28/2012
8 utline A. Introduction B. C sp3 C- Bond Functionalization A. C- Bond Formation B. C-C Bond Formation C. C- Bond Formation D. C-X Bond Formation C. Conclusions and Future Directions Jared Wipf Group 8 Jared Wipf Group Page 8 of 73 9/28/2012
9 hilov Chemistry C 4 [M] 3 C [M] FG 3 C FG Functionalization of Methane Methane = main constituent of natural gas eed way to functionalize for transport (gas à liquid) eed to use for synthesis of fine chemicals hilov chemistry C 4 Pt II (cat.) Pt IV (stoich) C 3 Methanol = industrial M for plastics and paints Poor efficiency Jared Wipf Group ature, 2007, 446, ew J. Chem. 1983, 7, Jared Wipf Group Page 9 of 73 9/28/2012
10 hilov Chemistry Mechanism: Cl 2 Pt II 2 Cl + C 4 - Cl Cl 2 Pt II 2 C 3 C 3 Cl 2 *Pt IV Cl 6 2- *Pt II Cl 4 2- xidation C 3 Cl Pt IV 2 2 Cl C 3 Key observation: toichiometric amount of Pt (needed for oxidation) Jared Wipf Group 10 Jared Wipf Group Page 10 of 73 9/28/2012
11 Current tate of the Art C 4 Pt II Cl Cl 2 4, 180 ºC C % Mechanism: Pt II X X C 4 -Cl Pt II C 3 X 2 4 Cat. Pt w/ 2 4 for x. C Ligand stabilized Pt II In Conc ºC >50 h 2 4 X Pt C IV 3 X X X = Cl, 4 Jared Wipf Group cience, 1998, 280, Jared Wipf Group Page 11 of 73 9/28/2012
12 White s Pd II Allylic C- Ac%va%on elective Allylic C- Insertion: Ph Pd(Ac) 2 (10 mol%) 'C 2 (2-4 equiv) BQ (1.5 equiv), air dioxane, 72 h, 45 ºC A ' C B ' examples: 53-77% yield 16:1 to 46:1 A:B BDE (kcal/mol) pka ( 2 ) J. Am. Chem. oc. 2005, 127, 6970 Ph Ph Pd(Ac) 2 (10 mol%) 'C 2 (2-4 equiv) BQ (2 equiv), air dioxane, h, 45 ºC ArB() 2 (1.5 equiv) 4-7 h, 45 ºC ' Ar 13 examples: 53-77% yield >20:1 E:Z >20:1 internal:terminal Jared Wipf Group J. Am. Chem. oc. 2006, 128, Jared Wipf Group Page 12 of 73 9/28/2012
13 Mechanism of Allylic C- Ac%va%on Electrophillic Pd II /Pd 0 Catalysis xidation BQ = ' L n Pd 0 eductive Elimination L n Pd II Ac L n Pd II ' L n Pd II C- Activation Ac 'C 2 Ligand Exchange Jared Wipf Group 13 Jared Wipf Group Page 13 of 73 9/28/2012
14 Complex Product Allylic C- PMP PMP a b Ph Ph Pd(Ac) 2 1. p- 2 Bz, BQ, 45 ºC 2. Li 3. K 2 C 3, Me 71% combined yield PMP at. Chem., 2009, 1, 547 Jared Wipf Group 14 Jared Wipf Group Page 14 of 73 9/28/2012
15 6- Deoxyerthronolide B PMP a b Ph Ph Pd(Ac) 2 BQ, 45 ºC PMP (56%, 2 recycles) > 40:1 dr TBAF breaks chelation to acid (outer sphere vs. inner sphere) "chelate" "non-chelate" Ph Ph Pd(Ac) 2 TBAF, BQ, 45 ºC PMP Pd vs. Pd (44% 2 recycles) 1:1.3 dr Jared Wipf Group at. Chem., 2009, 1, Jared Wipf Group Page 15 of 73 9/28/2012
16 xazoline Directed C- ac%va%on Direct the Palladium where to go: Pd(Ac) 2 (10 mol%) Ac Ac 2, MeCtBu 69% Pd(Ac) 2 (10 mol%) Ac Ac 2, MeCtBu 71% Pd(Ac) 2 (10 mol%) Ac Ac 2, MeCtBu Ac 50% Jared Wipf Group Angew. Chem. Int. Ed. 2005, 44, Jared Wipf Group Page 16 of 73 9/28/2012
17 anford s xime Me Pd(Ac) 2 (10 mol%) Me Ac PhI(Ac) 2 Ac/AC 2 75% Me Pd(Ac) 2 (10 mol%) PhI(Ac) 2 Ac/AC 2 Ac Me 75% Me Pd(Ac) 2 (10 mol%) Me Ac PhI(Ac) 2 Ac/AC 2 81% Jared Wipf Group J. Am. Chem. oc. 2004, 126, Jared Wipf Group Page 17 of 73 9/28/2012
18 Directed C- ac%va%on Pd II /Pd IV Catalysis Me C- Activation Ac Me Ac Pd II (Ac) 2 Me Pd II LL eductive Elimination Me Ac Ac Pd IV L PhI(Ac) 2 xidative L PhI Jared Wipf Group 18 Jared Wipf Group Page 18 of 73 9/28/2012
19 White s Fe C- ac%va%on (bf 6 ) 2 Piv Fe(,-PDP) (5 mol%) Ac (0.5 equiv) 2 2 (1.2 equiv) C 3 C, rt Piv 51% >99:1 dr Fe CC 3 CC 3 Fe(,-PDP) Jared Wipf Group cience, 2007, 318, 783 cience, 2010, 327, 566 at. Chem., 2011, 3, 216 cience, 2012, 335, 807 J. Am. Chem. oc. 2012, 143, Jared Wipf Group Page 19 of 73 9/28/2012
20 White s Fe C- ac%va%on (bf 6 ) 2 L n Fe III Fe CC 3 CC 3 L n Fe III LnFe III Fe(,-PDP) - L n Fe IV L n Fe V - Jared Wipf Group 20 Jared Wipf Group Page 20 of 73 9/28/2012
21 Predictable selec%vity General reactivity trends mirror BDE: 1º 2º 3º << <! EWG < " < EWG Want: electron rich, 3º C- bonds Does it work? Jared Wipf Group cience, 2007, 318, Jared Wipf Group Page 21 of 73 9/28/2012
22 Predictable selec%vity General reactivity trends mirror BDE: 1º 2º 3º << <! EWG < " < EWG Want: electron rich, 3º C- bonds Does it work: remote proximal remote:proximal X X X = Ac, X = Br, 5:1 9:1 X X X = Ac X = Br 29:1 20:1 = C 3 = C 3 >99:1 >99:1 Jared Wipf Group cience, 2007, 318, Jared Wipf Group Page 22 of 73 9/28/2012
23 Methylene reac%vity selec%vity Fe(,-PDP) (5 mol%) Ac (0.5 equiv) 2 2 (1.2 equiv) C 3 C, rt Yield 56% electivity 1.1:1 tereoelectronic Me 2 C Me 2 C Me 2 C 72% 2:1 teric Me 2 C Me 2 C Me 2 C 69% 3.5:1 70% 10:2:1 79% 1:1:1 Electronic 62% 9:1:1 41% Jared Wipf Group cience, 2010, 327, Jared Wipf Group Page 23 of 73 9/28/2012
24 Methylene reac%vity selec%vity Fe(,-PDP) (5 mol%) Ac (0.5 equiv) 2 2 (1.2 equiv) C 3 C, rt Yield 56% electivity 1.1:1 tereoelectronic Me 2 C Me 2 C Me 2 C 72% 2:1 teric Me 2 C Me 2 C Me 2 C 69% 3.5:1 70% 10:2:1 79% 1:1:1 Electronic 62% 9:1:1 41% Jared Wipf Group cience, 2010, 327, Jared Wipf Group Page 24 of 73 9/28/2012
25 Methylene reac%vity selec%vity Fe(,-PDP) (5 mol%) Ac (0.5 equiv) 2 2 (1.2 equiv) C 3 C, rt Yield 56% electivity 1.1:1 tereoelectronic Me 2 C Me 2 C Me 2 C 72% 2:1 teric Me 2 C Me 2 C Me 2 C 69% 3.5:1 70% 10:2:1 79% 1:1:1 Electronic 62% 9:1:1 41% Jared Wipf Group cience, 2010, 327, Jared Wipf Group Page 25 of 73 9/28/2012
26 Methylene reac%vity selec%vity Ac Fe(,-PDP) (5 mol%) Ac (0.5 equiv) Ac Ac 2 2 (1.2 equiv) C 3 C, rt 50% 11:1 DFT calculation à 3º C- bonds equal electronically electivity comes from sterics Jared Wipf Group cience, 2010, 327, Jared Wipf Group Page 26 of 73 9/28/2012
27 Methylene reac%vity selec%vity Ac Fe(,-PDP) (5 mol%) Ac (0.5 equiv) Ac Ac 2 2 (1.2 equiv) C 3 C, rt 50% 11:1 1 Fe(,-PDP) (5 mol%) Ac (0.5 equiv) 2 2 (1.2 equiv) C 3 C, rt 54% + 1 recycle 2X = sterically or electronically deactivated 3º C- Jared Wipf Group cience, 2010, 327, Jared Wipf Group Page 27 of 73 9/28/2012
28 verriding inherent selec%vity eme on-eme (bf 6 ) 2 Fe DG Fe DG Fe(,-PDP) General selectivity: E - rich, sterically accessible, 3º C- bonds Can we direct C- oxidation to less reactive groups? Jared Wipf Group J. Am. Chem. oc. 2012, 143, Jared Wipf Group Page 28 of 73 9/28/2012
29 Yes we can! t-bu C 2 Fe(,-PDP) (5 mol%) Ac (0.5 equiv) 2 2 (1.2 equiv) C 3 C, rt t-bu t-bu = Me 9% 36% = 54% -- C 2 Fe(,-PDP) (5 mol%) Ac (0.5 equiv) 2 2 (1.2 equiv) C 3 C, rt = Me = 2% 58% Jared Wipf Group J. Am. Chem. oc. 2012, 134, Jared Wipf Group Page 29 of 73 9/28/2012
30 Yes we can! Fe(,-PDP) (5 mol%) Ac (0.5 equiv) 2 2 (1.2 equiv) C 3 C, rt L n Fe C- Abstraction L n Fe hydroxyl rebound L n Fe Jared Wipf Group J. Am. Chem. oc. 2012, 134, Jared Wipf Group Page 30 of 73 9/28/2012
31 artwig s Ir Catalysis 3,4,7,8-Me 4 phen [Ir(cod)Me] 2 (0.5 mol%) Et 2 i Et 2 i [Ir(cod)Me] 2 (0.5 mol%) 3,4,7,8-Me 4 phen (1.2 mol%) 1 2 Et 2 i (1.2 equiv) KC 3, 2 2, TF/Me, 50 ºC 1 2 iet 2 Me 1 2 Ac 2, Et 3 C 2 Cl 2, rt 1 2 Ac Ac Tamao-Fleming xidation ature, 2012, 483, 70 Jared Wipf Group 31 Jared Wipf Group Page 31 of 73 9/28/2012
32 cope * ** [Ir(cod)Me] 2 (0.5 mol%), Et 2 i 2, rt then [Ir(cod)Me] 2 (0.5 mol%) 3,4,7,8-Me 4 phen (1.2 mol%) norbornene (1.2 equiv), TF, ºC 2. KC 3, 2 2, TF/Me, 50 ºC 3. Ac 2, Et 3, C 2 Cl 2, rt 1 2 Ac X Ac X = Cl** X = Br** X = CF 3 ** Ac 72% 72% 72% C Ac = t-bu = Me = Et2 = ipr Ac 71%** 71%* 53%* 69%* Ac = TIP** = TB** Ac 73% 55% Ac Ac Ac Ac 53%* 69%* ature, 2012, 483, 70 Jared Wipf Group 32 Jared Wipf Group Page 32 of 73 9/28/2012
33 cope * ** [Ir(cod)Me] 2 (0.5 mol%), Et 2 i 2, rt then [Ir(cod)Me] 2 (0.5 mol%) 3,4,7,8-Me 4 phen (1.2 mol%) norbornene (1.2 equiv), TF, ºC 2. KC 3, 2 2, TF/Me, 50 ºC 3. Ac 2, Et 3, C 2 Cl 2, rt 1 2 Ac Cbz Ac *60% Ac 76%* Ac 70%* Ac Ac Ac Ac Ac Ac Bu Ac 68%* 70%* 60%** (8:2 dr) Jared Wipf Group ature, 2012, 483, Jared Wipf Group Page 33 of 73 9/28/2012
34 C- oxygentaion ummary 1º C- Bonds Directed Pd or Ir catalysis Me º C- Bonds Allylic or Directed Pd catalysis Me 3º C- Bonds elective Fe cataylsis 1º 2º 3º << <! EWG < " < EWG Jared Wipf Group 34 Jared Wipf Group Page 34 of 73 9/28/2012
35 utline A. Introduction B. C sp3 C- Bond Functionalization A. C- Bond Formation B. C- Bond Formation C. C-C Bond Formation D. C-X Bond Formation C. Conclusions and Future Directions Jared Wipf Group 35 Jared Wipf Group Page 35 of 73 9/28/2012
36 C- Bond forma%on 1) eed to preoxidize C- bond for either displacement or reductive exchange 2) eliance on protection/deprotection to mask polar/acidic nature of nitrogens Breslow 1968: Cl Cl Zn Cyclohexane ZnCl 2 +! sulfonyl nitrene Early work of Gellman and. Breslow ( ) Tet. Lett., 1968, 51, 5349 i Pr IPh ML n C 3 C i Pr MLn = Mn(TPP)Cl Fe(TPP)Cl [Fe(cyclam)Cl 2 ]Cl FeCl 3 h 2 (Ac) 4 16% 77% 42% 16% 86% Jared Wipf Group Top Curr. Chem. 2010, 292, Jared Wipf Group Page 36 of 73 9/28/2012
37 Du Bois s h itrenoid h 2 (Ac) 4 (2 mol%) PhI(Ac) 2 Mg 1 2 Cbz X 1 2 X =, 2,, 3 3º 90% 86% C 2 Me 80% 2º TB 75% 78% pening: Cbz Ph C 3 C, rt Cbz Ph 88% Cbz Ph C 2 Me KAc DM, 40 ºC Cbz Ph Ac C 2 Me Jared Wipf Group J. Am. Chem. oc. 2001, 123, Jared Wipf Group Page 37 of 73 9/28/2012
38 Du Bois s h itrenoid h 2 (Ac) 4 (2 mol%) PhI(Ac) 2 Mg 1 2 Cbz X 1 2 X =, 2,, 3 2º C- Bond selectivity derived from chair-like T: u Favored u Disfavored Jared Wipf Group J. Am. Chem. oc. 2001, 123, Jared Wipf Group Page 38 of 73 9/28/2012
39 h itrenoid 2 1 K 2 C 3 Ts h 2 (TPA) 4 (5 mol%) acetone, rt h % 84% 64% Ph 60% From Allylic ubstrates: n-pr 67% 79% 62% Jared Wipf Group J. Am. Chem. oc. 2005, 127, Jared Wipf Group Page 39 of 73 9/28/2012
40 Du Bois s allylic solu%on u 2 (hp) 4 Cl 2 (2.5 mol%) PhI(C t 2 Bu) 2 5 Å M, C 2 Cl 2 Insertion (I) + Aziridine (A) 35% 2:1 (I/A) Ph 66% 8:1 (I/A) i 3 i Pr 71% 20:1 (I/A) 75% 20:1 (I/A) [u 2 (Ac) 24 Cl] C 6 5 Cl, reflux Cl u u Jared Wipf Group J. Am. Chem. oc. 2011, 133, Jared Wipf Group Page 40 of 73 9/28/2012
41 u itrenoid a radical approach tepwise biradical formation and recombination: Ph 2 u 2 (hp) 4 Cl (2.5 mol%) PhI(C 2 t Bu) 2 5 Å M, C 2 Cl 2 Ph o ring-opening 2-3% cis-trans isomerization Picosecond radical lifetime u 2 (hp) 4 Cl (2.5 mol%) 2 PhI(C t 2 Bu) 2 Ph D 5 Å M, C 2 Cl 2 D Ph + Ph D k /k D = 4.9 upports radical abstraction ebound mechanism Jared Wipf Group J. Am. Chem. oc. 2011, 133, Jared Wipf Group Page 41 of 73 9/28/2012
42 White s Fe Catalysis 2 Fe cat (10 mol%) AgbF 6 (10 mol%) allylic + 3º 1 2 PhI(Ac)2 (2 equiv) PhMe/MeC (4:1) rt 6 h 2 2 bf 6 Fe X [FePc] bf 6 Yields superior to h 2 (Ac) 4 and o aziridination observed Jared Wipf Group J. Am. Chem. oc. 2012, 134, Jared Wipf Group Page 42 of 73 9/28/2012
43 Fe Catalyst cope 2 Fe cat (10 mol%) AgbF 6 (10 mol%) allylic + 3º 1 2 PhI(Ac)2 (2 equiv) PhMe/MeC (4:1) rt 6 h 2 2 Ph Ph 70% d.r. 3.5:1 53% d.r. 3:1 >20:1 E/Z retained 66% d.r. 17:1 45% d.r. 97:3 72% >20:1 (allyl/3º) 62% 5:1 (allyl/benzy) Ph 53% 7:1 selectivity sterics Jared Wipf Group J. Am. Chem. oc. 2012, 134, Jared Wipf Group Page 43 of 73 9/28/2012
44 Intermolecular h itrenoid Troc Ts Cl 3 C 1 2 Troc h 2 (TPA) 2 (5-6 mol%) K 2 C 3 Troc Troc 1 2 Troc Troc Troc 92% 86% 68% 68% 61% 35% rg. Lett. 2007, 9, 639 Jared Wipf Group 44 Jared Wipf Group Page 44 of 73 9/28/2012
45 Cu Catalysis C- Bond forma%on Ts 2 /PhI(Ac) 2 or PhI=Ts Ts ab 4 Ts 10 mol% Cu(CF 3 3 ) 2 C 2 Cl 2, 40 ºC TF, rt Ts 86% Ts 42% Cl Ts Ts + 40% 35% Ts Ts Ts 85% 52% 70% pening: Ts Ts Ts Jared Wipf Group 90% 94% 92% rg. Lett., 2007, 9, Jared Wipf Group Page 45 of 73 9/28/2012
46 Cu itrenoid Cu(CF 3 3 ) 2 PhI=Ts or PhI(Ac) 2 + Ts 2 Ts itrene Formation PhI Ts=Cu(CF 3 3 ) 2 Ts Cu(CF 3 3 ) 2 Concerted C- Insertion Jared Wipf Group rg. Lett., 2007, 9, Jared Wipf Group Page 46 of 73 9/28/2012
47 Baran s Cu Catalysis iger- Type F-TEDA-PF 6 1. CuBr 2 (0.25 equiv) Zn(Tf) 2 (0.5 equiv) 2. a (1 equiv) 1 4 MeC, rt, 1-2 h 3 MeC/ 2 (1:1) 80 ºC, 2 h Ac 4 3 Mechanism (itter xn): Cl PF 6 - PF 6 - F F-TEDA-PF 6 {CuBr 2, F - TEDA + } Cu n+1 MeC {CuBr 2 TEDA + } +F Cu n n = 1 or 2 Jared Wipf Group J. Am. Chem. oc., 2012, 134, Jared Wipf Group Page 47 of 73 9/28/2012
48 Baran s Cu Catalysis iger- Type F-TEDA-PF 6 1. CuBr 2 (0.25 equiv) Zn(Tf) 2 (0.5 equiv) 2. a (1 equiv) 1 4 MeC, rt, 1-2 h 3 MeC/ 2 (1:1) 80 ºC, 2 h Ac 4 3 cope: M Product (Yield) M Product (Yield) Ac (91%) (65%) Ac (61%) Ac Ac (90%) n Bu n Bu Ac (53%) Ac (51%) Jared Wipf Group J. Am. Chem. oc., 2012, 134, Jared Wipf Group Page 48 of 73 9/28/2012
49 Che s Directed Pd Catalysis Me Pd(Ac) 2 (5 mol%) K 2 2 8, DCE Me Pd II LL 2 2 (p-cl-c 6 4 ) Me 2(p-Cl-C64) M amide Product yield Me 2 2 (p-cl-c 6 4 ) Me 2 (p-cl-c 6 4 ) 88% Me Me 2 CCF 3 89% CCF 3 2 (p-cl-c 6 4 ) Me 2 2 (p-cl-c 6 4 ) Me 93% Me 2 2 (p-cl-c 6 4 ) Me 2 (p-cl-c 6 4 ) 76% Jared Wipf Group 2 2 (p-cl-c 6 4 ) 79% 2 (p-cl-c 6 4 ) J. Am. Chem. oc. 2006, 128, Jared Wipf Group Page 49 of 73 9/28/2012
50 White s Pd Catalyst Ph Ph Pd(Ac) 2 (10 mol%) DIPEA MeC 2 Ts (2 equiv) BQ (2 equiv), air dioxane, h, 45 ºC Ts Me Me 2 C Ts Me 61% Ac Ts Me 64% Ts Me 54-89% = EWG, EDG Bn Ts Me 76% Ts Me 48% C 2 Ts = Me = Bn = t-bu = Fm 84% 87% 69% 55% Jared Wipf Group J. Am. Chem. oc. 2009, 131, Jared Wipf Group Page 50 of 73 9/28/2012
51 Allylic C- Mechanism Electrophillic Pd II /Pd 0 Catalysis xidation Ph L n Pd II Ph C- Activation BQ = + 2 Ac L n Pd 0 L n Pd II L n u Functionalization u = Me pk a ~ 3.5 Ts DIPEA + u DIPEA + - Ac - u Ac DIPEA + u Jared Wipf Group J. Am. Chem. oc. 2009, 131, Jared Wipf Group Page 51 of 73 9/28/2012
52 C- Amina%on ummary 1º C- Bonds Directed Pd catalysis Me 2º C- Bonds Directed Fe, h, u, or Cu Catalysis L n M 1 2 Allylic h, u, Pd Catalysis 3º C- Bonds Directed Fe, h, u, or Cu Catalysis L n M L n M Troc Jared Wipf Group 52 Jared Wipf Group Page 52 of 73 9/28/2012
53 utline A. Introduction B. C sp3 C- Bond Functionalization A. C- Bond Formation B. C- Bond Formation C. C-C Bond Formation D. C-X Bond Formation C. Conclusions and Future Directions Jared Wipf Group 53 Jared Wipf Group Page 53 of 73 9/28/2012
54 Davies s Carbenoid Approach 2 C 2 Me Ar + n h 2 (-DP) 4 (1 mol%) n = 1 n = 2 n C 2 Me Ar 72%, 96% ee 80%, 95% ee u u 2 Ar Ar = p-(c )C C 2 Me Ar h 2 (-DP) 4 (1 mol%) C 2 Me Ar h 2 (-DP) 4 74%, 98% ee 2 C 2 Me Ar + h 2 (-DP) 4 C 2 Me (1 mol%) Ar 60%, 68% ee Jared Wipf Group J. Am. Chem. oc. 2000, 122, Jared Wipf Group Page 54 of 73 9/28/2012
55 C- carbon bond forma%on 2 h 2 hl n + h h or h Chem. ev. 2010, 110, 704 Chem. oc. ev. 2011, 40, 1857 Jared Wipf Group 55 Jared Wipf Group Page 55 of 73 9/28/2012
56 C- carbon bond forma%on 2 h 2 (4-MEX) 4 C 2 Cl 2, 71% = Me, t Bu = Me, t Bu 2 Piv h 2 (CCPh 3 ) 4 CCl 4 TB Piv >75% (-)-tetrodotoxin Jared Wipf Group cience 2006, 312, 67 J. Am. Chem. oc. 2003, 125, Chem. Eur. J. 1998, 6, Jared Wipf Group Page 56 of 73 9/28/2012
57 White s C- C- C forma%on Ph Ph Pd(Ac) 2 (10 mol%) dioxane:dm (4:1) DMBQ/Ac 45 ºC, 3.5 h Pd II uc: Linear (L) uc uc Branched (B) = Me = Me = C 2 Me = CF 3 2 C 2 Me 50% 1.7:1 (L:B) 61% 3:1 (L:B) 61% 10:1 (L:B) 65% 12:1 (L:B) = TB = Me = CF 3 2 C 2 Me 62% 5:1 (L:B) 58% 3:1 (L:B) 59% >20:1 (L:B) Me 2 C Tf C 2 Me 2 Me 63% 7:1 (L:B) 2 C 2 Me 42% 1:5 (L:B) C 2 Me Zn dust conc. aq Cl C 2 Me 2 Me r.t., 20 min 99% 2 Jared Wipf Group J. Am. Chem. oc. 2008, 130, Jared Wipf Group Page 57 of 73 9/28/2012
58 Yu s C- C- C forma%on 1 2 Me Pd(Ac) 2 (10 mol%) B() 2 (1.6 equiv) K 2 C 3, Ag 2 BQ, t-bu 70 ºC, 18 h 1 2 Me CA 1 2 Me Ph 85% Me = C 2 Me 62% = CC 3 41% Can use air in place of Ag 2 Me Ph 75% Me 60% Et Me i Bu 58% Me Me 40% Jared Wipf Group Me Me 52% 41% J. Am. Chem. oc. 2008, 130, Jared Wipf Group Page 58 of 73 9/28/2012
59 Yu s C- C- C forma%on 1 2 Ar + C 2 Bn [Ar = C 6 F 5 ] Pd(Ac) 2 (10 mol%) LiCl (2 equiv) Cu(Ac) 2 (1.1 equiv) AgAc (1.1 equiv) DMF, 120 ºC 12 h, Ar C 2 Bn 1 2 Bn 2 C Ar Ar Bn 2 C Bn 2 C Ar 84% Ar Me Bn 2 C Ar Bn 2 C 87% 66% 61% J. Am. Chem. oc. 2010, 132, 3680 Jared Wipf Group 59 Jared Wipf Group Page 59 of 73 9/28/2012
60 anford s C- C- C forma%on + C 2 Et Pd(MeC) 4 (BF 4 ) 2 (10 mol%) 4 [PMo 11 V 40 ] (3 mol%) atf (10 mol%) Ac, 110 ºC, air EWG Et 2 C Tf - Et 2 C Tf - Et 2 C Tf - Et 2 C BF 4 - Et 2 C BF 4-89% 70% 43% (dr = 2.4:1) 3 C 2 Et 49% (dr = 1:1) J. Am. Chem. oc. 2011, 133, 6541 Jared Wipf Group 60 Jared Wipf Group Page 60 of 73 9/28/2012
61 anford s C- C- C forma%on + C 2 Et Pd(MeC) 4 (BF 4 ) 2 (10 mol%) 4 [PMo 11 V 40 ] (3 mol%) atf (10 mol%) Ac, 110 ºC, air Et 2 C Tf - Et 2 C BF 4 - Pt 2 (10 mol%) 1 atm M Et 12 h, rt Et 2 C Et 2 C BF 4 - ab 4 (2.5 equiv) Et, 0 ºC Et 2 C 75% 81% 2.3:1 cis:trans Et 2 C BF 4 - DBU (2 equiv.) 1 h, rt C 2 Et = Me = 85% 95% Jared Wipf Group J. Am. Chem. oc. 2011, 133, Jared Wipf Group Page 61 of 73 9/28/2012
62 Yu s C- C- C forma%on + Ph B Pd(Ac) 2 (10 mol%) Ag 2 C 3, K 2 P 4 aac, t-bu 130 ºC, 3 h Ph Ph Ph Ph Bn(C 2 ) 3 Me 2 C(C 2 ) 2 Ph 38% 30% 30% 20% + Ar-I Pd(Ac) 2 (10 mol%) Ag 2 C 3, K 2 P 4 aac, t-bu 130 ºC, 3 h Ar A + Ar Ar B = Me Ar = Ph 70% 5:2 (A:B) = (C 2 ) 3 Bn Ar = Ph 45% 5:1 (A:B) = i Bu Ar = Ph 62% 4:1 (A:B) = (C 2 ) 2 C 2 Me Ar = Ph 42% 5:1 (A:B) Jared Wipf Group J. Am. Chem. oc. 2007, 129, Jared Wipf Group Page 62 of 73 9/28/2012
63 alogen Directed C- C- C Forma%on Ar X I Pd(Ac) 2 (10 mol%) K 2 C 3, nbu 4 Br DMF, o C, 4 d Ar 37-59% Yield Angew. Chem. Int. Ed. 2003, 33, 103 Br C 2 Et Pd(Ac) 2 (10 mol%) P(o-tol) 3, K 2 C 3 (2 equiv) DMF, 150 o C, 30 min 93% Yield C 2 Et Angew. Chem. Int. Ed. 2003, 42, 5736 Z X 1 2 Pd (0) /P 3 base, 140 ºC Z examples 47-96% X = Cl, Br Z = no atom, C 2, -, C= Jared Wipf Group 1 = alkyl 2 =, C 2 Me, C J. Am. Chem. oc. 2010, 132, Jared Wipf Group Page 63 of 73 9/28/2012
64 Fagnou s C- C- C forma%on X Br Pd(Ac) 2 (10 mol%) PCy 3 -BF 4 (10 mol%) carbonate base, PiV Mesitylene, 150 ºC, 16 h X Me F 76% 56% 70% 62% 71% Jared Wipf Group J. Am. Chem. oc. 2010, 132, Jared Wipf Group Page 64 of 73 9/28/2012
65 C- C- C forma%on L n Pd 0 Br eductive Elimination Fast x. Add. Fast Pd L n Me 2 PCy 3 Pd Cy 3 P Br CsPiv CsBr + PCy3 Pd Cy 3 P Me 2 Pd Cy 3 P Pd Cy 3 P Ligand Exchange Fast if Piv - :Pd >3:1 Jared Wipf Group Concerted Metalation-Deprotonation low J. Am. Chem. oc. 2010, 132, Jared Wipf Group Page 65 of 73 9/28/2012
66 Buchwald s C- C- C forma%on X + X = Br or Cl Pd(Ac) (1 mol%) Ligand 2 3 a t Bu, olvent Typical solvents: toluene, TF, dioxane Typical rxn temperatures: ºC A PCy 2 P( t Bu) 2 B Me n Bu o Ligand 93% o Ligand 46% A 93% A 61% C 2 Et C 2 Me Et Et 2 t Bu A 64% Jared Wipf Group A 85% A 70% B 92% B 76% J. Am. Chem. oc. 2000, 122, Jared Wipf Group Page 66 of 73 9/28/2012
67 C- C- C forma%on Enolate equivalents work too: Ar 2 1 Pd 0 ArX 1 2 ime 3 3 M L n (Ar)Pd 2 1 L n (Ar)Pd 2 1 L n Pd X Ar M = Zn, Cu MX 2 1 Chem ev. 2010, 132, 1360 Angew. Chem. Int. Ed. 2010, 49, 676 Jared Wipf Group 67 Jared Wipf Group Page 67 of 73 9/28/2012
68 C- C bond forma%on summary 1º C- Bonds Directed Pd catalysis Z X Pd 1 2 Ar 1 2 Me 2º C- Bonds Directed Pd or h Catalysis Pd 2 C 2 Me Allylic, Pd Catalysis 3º C- Bonds Directed Pd, h, Catalysis C 2 Me Pd 2 Jared Wipf Group 68 Jared Wipf Group Page 68 of 73 9/28/2012
69 utline A. Introduction B. C sp3 C- Bond Functionalization A. C- Bond Formation B. C- Bond Formation C. C-C Bond Formation D. C-X Bond Formation C. Conclusions and Future Directions Jared Wipf Group 69 Jared Wipf Group Page 69 of 73 9/28/2012
70 Yu s C- C- I forma%on 1 2 t Bu Pd(Ac) 2 (10 mol%) I 2, PhI(Ac) 2 C 2 Cl 2, 24 ºC I 1 2 t Bu n t Bu Pd(Ac) 2 (10 mol%) I 2, PhI(Ac) 2 C 2 Cl 2, 24 ºC n I t Bu I 1 2 t Bu 1, 2 = Me or Et 88-92% t Bu n I n = % t Bu 67% I t Bu t Bu 98% I t Bu t Bu 32% I I xa 65% 99:1 dr I TB xa 62% 93:7 dr I t Bu xa 83% 91:9 dr Ph xa I 98% 99:1 dr Angew. Chem. Int. Ed. 2005, 44, 2112 Jared Wipf Group 70 Jared Wipf Group Page 70 of 73 9/28/2012
71 ummary C- xygenation Pt, Pd, Fe, Ir DG 1 2 DG C- Amination Cu, h, u Pd, Fe DG 1 2 DG 1 2 L n M C- C-C Formation Pd, h Z X DG 1 2 Pd 2 C 2 Me Jared Wipf Group 71 Jared Wipf Group Page 71 of 73 9/28/2012
72 Conclusion and Future Direc%ons ot Topic >600 journal articles (not reviews) published since 2000 Ground work has been laid Continued mechanistic elucidation à rational catalyst design ew catalysts/ligands igher levels of predictable selectivity Implementation in complex molecule synthesis If we can find ways to use C- bonds as versatile functional groups we can revolutionize the rules that have influenced our strategies for assembling molecules over the last 100 years. Jared Wipf Group Chem. oc. ev. 2011, 40, Jared Wipf Group Page 72 of 73 9/28/2012
73 Transi%on Metal- Catalyzed Func%onaliza%on of C sp3 C- bond ac%va%on Thanks for your attention! Questions? Jared Wipf Group 73 Jared Wipf Group Page 73 of 73 9/28/2012
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