Palladium-Catalyzed xygenation of Unactivated sp 3 C- Bonds Pd(Ac) 2 5 mol% PhI(Ac) 2 1.1 eq. Pd 2 Ac Desai, L. P.; ull, K. L.; Sanford *, M. S. University of Michigan J. Am. Chem. Soc. 2004, 126, ASAP (Web Release 16 th July 2004) David Amantini @ Wipf Group 1 Current Literature 24 th July 2004 7/29/04
xidation of Unactivated sp 3 C- Bonds: A Challenge in rganic Synthesis - REACTIVITY ( C- bond dissociation energy in methane 104 kcal mol -1 ) - SELECTIVITY ( C- bond dissociation energy in methanol: 93 kcal mol -1 ). while in ature Mycobacterium phlei Stearic acid leic acid Rhizopus nigricans David Amantini @ Wipf Group 2 Current Literature 24 th July 2004 7/29/04
Chemical Routes for the Intramolecular xidative Functionalization of Unactivated sp 3 C- Bond a) Reactions based on heteroatom centered radicals b) Reactions based on Rhodium-mediated carbene and nitrene sp 3 C- bond insertions c) Reactions based on transition metal-mediated sp 3 C- bond activation David Amantini @ Wipf Group 3 Current Literature 24 th July 2004 7/29/04
Reactions Based on eteroatom-centered Radicals offmann-loeffler-freytag Reaction R 1 Cl R 2 1., Δ 2. R 1 R2 offmann, A. W. Ber. 1883, 16, 558. Corey, E. J.; ertler, W. R. J. Am. Chem. Soc. 1958, 80, 2903. Arigoni, D. and coworkers J.Am. Chem. Soc. 1958, 80, 2905. Barton`s itrite Photolysis Ac Ac hν Barton, D.. R. and coworkers J.Am. Chem. Soc. 1960, 82, 2640 Breslow`s Remote xidation hν Breslow, R. and coworkers J. Am. Chem. 1973, 95, 3251 Jung, M. E.: Johnson, T. W. J. Am. Chem. Soc. 1997, 119, 12412 David Amantini @ Wipf Group 4 Current Literature 24 th July 2004 7/29/04
Reactions Based on Rhodium-Mediated Carbene and itrene sp 3 C- Bond Insertions 2 TBS Rh 2 (CCPh 3 ) 4 1.5 mol% TBS Cl 2 A B C Rh 2 (CCF 3 ) 4 10 mol% PhI(Ac) 2, Mg Cl 2 D (-)-Tetrodotoxin inman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598. For a Review on the Use of Rh-Mediated Intramolecular C- Insertion in atural Products Syntheses see: Taber, D. F.; Stiriba, S.-E. Chem. Eur. J. 1998, 4, 990 and references therein. David Amantini @ Wipf Group 5 Current Literature 24 th July 2004 7/29/04
Reactions Based on Transition Metal-Mediated sp 3 C- Bond Activation: the Shilov Reaction R + Pt (II) xidant R-Y Y =, Cl,.. R- + (II) Pt (II) Pt R + R Y xidant Reduced xidant Y (IV) Pt R Shilov, A. E.; Shul`pin, G. B. Chem. Rev. 1997, 97, 2879. Stahl, S. S. and coworkers Angew. Chem., Int. Ed. 1998, 37, 2180. Sen, A. and coworkers J. Am. Chem. Soc. 2001, 123, 1000. David Amantini @ Wipf Group 6 Current Literature 24 th July 2004 7/29/04
Unactivated sp 3 C- Bond xidative Functionalization by Group 10 Metals PRBLEMS: a) arsh reaction conditions: no applications to complex organic molecules b) Low T c) Low functional group tolerance d) Low level of regioselectivity TE KEY: The use of substrates containing coordinating functional groups that can bind the metal catalyst and direct the oxidation process to a specific sp 3 C- bond within the molecule. David Amantini @ Wipf Group 7 Current Literature 24 th July 2004 7/29/04
Unactivated sp 3 C- Bond xidative Functionalization by Group 10 Metals: Stoichiometric Version 2 DMF 100 o C Br 2 Br Ag 2 C 3 Toluene 2 1. CCl 3 CCl 2. ame, 3. 2, Pd/C 2 90% 70% 88% cex 1. Ph Ts, Toluene 2. [Me 2 Pt(µ-SMe 2 )] 2 30% Me Pt Me Ph cex Tf DCM Pt Me cex Tf CF 3 C 2 70 o C - C 4 Pt cex Tf KC 2 1. Pd/C, C, C 42% 3 steps quantitative dr 4.4 / 1 (PLC separation) cex Sames, D. and coworkers J. Am. Chem. Soc. 2002, 124, 6900. 2 2. a, then Cl 45 % (-)-Rhazinilam For other Stoichiometric Examples see: Sames, D. and coworkers J. Am. Chem. Soc. 2002, 124, 11856. Gribble, G. W. and coworkers J. rg. Chem. 2000, 65, 6278. David Amantini @ Wipf Group 8 Current Literature 24 th July 2004 7/29/04
Unactivated sp 3 C- Bond xidative Functionalization by Group 10 Metals: Catalytic Version K 2 PtCl 4 5 mol% α-aminoacid CuCl 2 7 eq. 2 160 o C 10h oxidized α aminoacid 1. Boc 2 2. Ac product Entry Substrate Products Distribution γ / δ Yield (%) 1 L-Valine C 2 27 2 Boc Boc 3 1 2 L-orvaline 2 C 2 Boc Boc C 2 BoC 3 21 2 1 1 3 L-Leucine 2 C 2 Boc C 2 BoC C 2 BoC 4.5 15 22 4 1 4 L-Proline C 2 REACTI Sames, D. and coworkers J. Am. Chem. Soc. 2001, 123, 8149. For an another Catalytic example see: Sames, D. and coworkers J. Am. Chem. Soc. 2002, 124, 13372. David Amantini @ Wipf Group 9 Current Literature 24 th July 2004 7/29/04
Authors Precedent Paper: A ighly Selective Catalytic Method for the xidative Functionalization of C- Bonds Substrate Pd(Ac) 2 1-6 mol% PhI(Ac)2 1.1-1.6 eq. Ac or C 3 C 100 o C 12-20 h Product Entry Product Yield (%) Entry Product Yield (%) Ac 1 Ac 86 5 54 2 88 6 72 Ac Ac 3 Ac 80 7 52 Ac 4 Ac Ph Ac 62 8 Ph 47 Sanford, M. S. and coworkers J. Am. Chem. Soc. 2004, 126, 2300. David Amantini @ Wipf Group 10 Current Literature 24 th July 2004 7/29/04
(I) Palladium-Catalyzed xygenation of Unactivated sp 3 C- Bonds Pd(Ac) 2 5 mol% PhI(Ac)2 1.1 eq. Ac R R` Ac -Ac 2 1-1 100 o C 1.5-3.5 h R R` Entry Substrate Product Yield (%) 1 Ac 74 Ac 2 78 3 Ac 39 4 REACTI 5 REACTI Sanford, M. S. and coworkers J. Am. Chem. Soc. 2004, 126,ASAP. David Amantini @ Wipf Group 11 Current Literature 24 th July 2004 7/29/04
(II) Palladium-Catalyzed xygenation of Unactivated sp 3 C- Bonds Substrate Pd(Ac) 2 5 mol% PhI(Ac)2 1.1-3.2 eq. Ac -Ac 2 1-1 80-100 o C 5 min- 12h Product Entry Substrate Product Yield (%) Entry Substrate Product Yield (%) 1 Ac 61 5 42 Ac Ac 2 Me Me 75 6 66 Ac 3 Me Me Ac Ac 81 7 44 4 Me Me Ac Ac 86 8 81 Sanford, M. S. and coworkers J. Am. Chem. Soc. 2004, 126,ASAP. David Amantini @ Wipf Group 12 Current Literature 24 th July 2004 7/29/04
(III) Palladium-Catalyzed xygenation of Unactivated sp 3 C- Bonds ypothesized Mechanism (II) Pd L C L C Pd (II) - L C Y xidant Reduced xidant Y L Pd (IV) C Y Y David Amantini @ Wipf Group 13 Current Literature 24 th July 2004 7/29/04
Summary - An efficient and highly β selective sp 3 C- bond oxidative functionalization for -methyl oximes and pyridines have been described. - The level of regioselectivity displayed by the described methodology is unprecedented. - The mild reaction conditions used along with the selectivity displayed, make the methodology a significant potential synthetic tool. - Future work aimed to elucidate the scope and the mechanism of the transformation described would be of particular interest for the synthetic community. David Amantini @ Wipf Group 14 Current Literature 24 th July 2004 7/29/04