Allylic Substitution Reactions! Group Meeting Literature Presentation! Alexanian Research Group! 15 May 2014! ! Njamkou N. Noucti! “Game Changers”! Born in 1927 in Shiga, Japan! Kyoto University (B.S., 1951) ! Columbia University, Gilbert Stork (Ph.D, 1960)! ! Toray Industries, Inc. (1962–1974)! Tokyo Institute of Technology (1974–1988)! Okayama University (1988–1996)! Jiro Tsuji! Kurashiki University of Science and the Arts (1996–1999)! Born in 1941 in Philadelphia, Pennsylvania ! Pennsylvania University (B.S. 1962)! Massachusetts Institute of Technology, Herbert House (Ph.D, 1965)! ! University of Wisconsin–Madison (1965–1987)! Stanford University (1987–Present)! Barry M. Trost! 2! Introduction! “Palladium–catalyzed substitution reactions involving substrates that contain a leaving group in an allylic position”! occur via #–allylmetal intermediates! Pd LG + Nu Nu Historically catalyzed by Palladium but now known with Ir, Mo, W, Ru, and Rh! Allyl fragment in allylic substitution reactions is electrophilic ! NOT TO BE CONFUSED WITH! " Cross–coupling reactions! X MXn + Nucleophilic allyl M = B, Si, Sn, Mg, Zn M = Cl, Br, I, OTs fragments: not allylic " Allylations/Crotylations! substitution O OH reactions! MXn + R R H M = Li, Mg, Sn, Si, B Cr, Ti, Zn, Zr 3! Why Transition–Metal Catalysis?! R R LG + Nu R Nu + SN2 or SN2'! Nu Uncatalyzed allylic substitution reaction! 1) Selectivity (SN2 vs SN2’) is difficult to control without a !catalyst! ! 2)" Transition–metals allow reaction to proceed at lower temperatures! 3)" Catalyzed reactions facilitate asymmetric variants! 4! Outline! !!!!Outline! ! 1." Introduction! 2." History and early developments! 3." Palladium–catalyzed reactions! 4." Iridium–catalyzed reactions! 5." Hard nucleophiles! 6." Conclusion! Topics not covered! Further reading! ! ! Asymmetric Allylic Alkylations! Chem Rev. 1996, 96, 395–422.! Reactions not catalyzed by Ir or Pd! Chem. Rev. 2003, 103, 2921–2943.! Applications in total synthesis! 5! History! n Wacker–Smidt (1959):! via: [Pd] PdCl , CuCl R O OH R 2 2 R H2O, HCl H O2 or air n Jiro Tsuji (1965):! " Carbon nucleophiles can also attack palladium–olefin complexes! O O O O Cl O O Na, EtOH Pd + EtO OEt + EtO OEt Pd DMSO Cl EtO OEt Smidt, J. et. al. Angew. Chem. 1959, 71, 176–182.! Smidt, J. et. al. Angew. Chem. 1959, 71, 626.! Smidt, J. et. al. Angew. Chem. 1962, 74, 93–102.! Tsuji, J. et. al. Tet. Lett. 1965, 4387–4388.! 6! History! n Trost (1972):! CO2Et CO Et CO Et 2 C2H5 C2H5 2 CO2Et CO Et Cl O O Na, PPh3 2 + CO2Et + + nC3H7 Pd Pd nC3H7 THF or DMF Cl EtO OEt 37% yield 23% yield 8% yield " 9:1 preference for the less substituted end of π–allyl system ! " Soft anions favor attack at least substituted end of π–allyl system! SO Me C2H5 C2H5 2 O O Na, PPh Cl 3 + S CO2Et nC3H7 Pd Pd nC3H7 MeO OEt THF or DMF Cl 80% yield Trost, B. et. al. J. Am. Chem. Soc. 1973, 95, 292–294. ! 7! Synthesis of π–Allyl Intermediate! n Olefin oxidation:! " Requires isolation of the PdCl2 Na2CO3 or palladium–allyl intermediate! NaCl, AcOH, NaOAc Cl Pd " Not amenable to one–pot allylic DCM Pd Cl substitution reaction! " Stoichiometric in palladium! n Functionalized allylic starting materials:! " Atkins (1970)! Pd(acac)2 (0.5 mol %) PPh3 (0.5 mol %) HNEt2 OH NEt2 50 ºC Pd 95% yield OH " Hata (1970)! Pd(PPh3)2 (0.002 mol %) maleic anhydride (0.004 mol %) HNEt2 OPh NEt2 85 ºC Pd OPh quantitative yield Atkins, K. E. et. al. Tetrahedron Lett. 1970, 3821–2824.! Hata, G. et. al. J. Chem. Soc. D, Chem. Comm. 1970, 1932–1933. ! 8! Reaction Substrates! Pd LG + Nu Nu n Nucleophiles:! Soft, carbon nucleophiles! Heteroatom nucleophiles! Hard, carbon nucleophiles! pKa < 25! pKa > 25! EWG R 1 2 EWG EWG R1 R2 N R R H HS HO R = H, alkyl, aryl, vinyl EWG = CN, NO , SO R, 2 2 EWG = CN, NO2, SO2R, SOR, CO R, COR 2 SOR, CO2R, COR n Allylic electrophile:! OCO2Me OP(O)(OEt)2 OAc Cl most common OSO2Me NO2 NR2 OR less common 9! Substrate Scope! R2 Pd2dba3–CHCl3 (2.5 mol %) R2 PPh3 (8 mol %) 3 3 R OCO2Me + Nu R Nu THF, 30 ºC R1 R1 CO2Et CO Me CO2Me 2 Ph CO2Et O O O 92% yield 91% yield 90% yield CO2Et CO2Me AcO CO2Et O 86% yield 77% yield Tsuji, J. et. al. J. Org. Chem. 1985, 1523–1529.! 10! Substrate Scope! Pd2dba3–CHCl3 (2.5 mol %) dppe (10 mol %) OCO2allyl + Nu Nu THF, 65 ºC NO2 CN CN Ph 76% yield 91% yield 73% yield O O CN THPO 29% yield 0% yield trace yield " Simple ketones and unactivated carbon centers are unreactive! Tsuji, J. et. al. J. Org. Chem. 1985, 1523–1529.! 11! Proposed Mechanism! Nu 0 OCO R Pd Ln 2 nucleophilic attack! oxidative addition! Pd OCO R Pd 2 Nu deprotonation! decarboxylation! ROH CO2 NuH Pd OR " Alkoxide base generated in–situ via decarboxylation of Pd–carbonate intermediate! Tsuji, J. et. al. J. Org. Chem. 1985, 1523–1529.! 12! Mechanistic Details! n Oxidative addition occurs with inversion of configuration:! CO2Me CO2Me [Pd] OAc [Pd] n Soft nucleophile attacks the allyl fragment with inversion of configuration! CO Me 2 CO2Me CO2Me NaCH(CO2Me)2 + [Pd] CH(CO2Me)2 (MeO2C)2HC " Hard nucleophiles attack the metal center. Reductive elimination occurs with retention of configuration! Kobayashi, Y. et. al. J. Org. Chem. 1996, 61, 5391–5399.! Tsuji, Y. et. al. Organometallics 1998, 17, 4835–4841.! 13! Iridium–Catalyzed Reactions! n Iridium–catalyzed reactions lead to substitution at the most substituted carbon center.! O O [Ir(COD)Cl]2 (2 mol %) nPr Ligand (16 mol %) CO2Et nPr OAc + EtO OEt + THF, Temperature nPr EtO C CO Et CO2Et Na H 2 2 2 equiv A B Entry Ligand Temperature Reaction Time % yield A:B 1 PnBu3 reflux 16 h 0 -- 2 PPh3 reflux 16 h 6 24:76 3 P(OiPr)3 reflux 9 h 44 53:47 4 P(OEt)3 reflux 3 h 81 59:41 5 P(OPh)3 rt 3 h 89 96:4 " Electron–poor phosphine ligands give selective reactions! Takeuchi, R. et. al. Angew. Chem. Int. Ed. Engl. 1997, 263–265.! 14! Regiochemical Explanation! n Regioselectivity of allylic substitution reaction controlled by three factors:! ! !!1. Steric Interactions between incoming nucleophile and allylic terminus! ! !!2. Charge distribution of #–allyl ligand on metal center! ! Most influential !!3. Stability of the resulting alkene–metal complex! with iridium! nPr nPr nPr nPr Nu vs.! vs.! [Ir] [Ir] Nu [Ir] [Ir] A! B! A! B! A is the more stable cation; S 2 attack positions N A is the more stable transition–metal complex! nucleophile on most substituted carbon! Takeuchi, R. et. al. Angew. Chem. Int. Ed. Engl. 1997, 263–265.! Cramer, R. et. al. J. Am. Chem. Soc. 1967, 89, 4621–4626.! Åkermark, B. et. al. Organometallics 1984, 3, 679–682.! 15! Substrate Scope! nPr [Ir(COD)Cl]2 (2 mol %) CO2Et P(OPh) (16 mol %) 3 nPr nPr OR + NaCH(CO2Et)2 + CO2Et THF, rt EtO2C CO2Et 2 equiv A B Entry R Reaction Time % yield A:B 1 Ac 3 h 89 96:4 2 CO2Me 1 h 94 97:3 3 H 2 h 100 96:4 4 C(O)CF3 5 h 70 95:5 n Quaternary centers can also be synthesized:! nBu CO2Et [Ir(COD)Cl]2 (2 mol %) OAc NaCH(CO2Et)2 P(OPh)3 (16 mol %) + Me + CO2Et Me nBu 2 equiv THF, rt EtO2C CO2Et Me nBu A 80 % yield B A:B = 0:100 Takeuchi, R. et. al. Angew. Chem. Int. Ed. Engl. 1997, 263–265.! 16! Nitrogen Nucleophiles! L = [Ir(COD)Cl]2 (1 mol %) L (2 mol %) Ph Ph OCO Me 1 2 Me 2 + NHR R O Ph THF, rt 1 2 NR R P N O Ph Me OMe N HN HN HN Ph Ph Ph Ph O 83% yield 84% yield 80% yield 88% yield 97% ee 95% ee 94% ee 96% ee (run at 50 ºC) N N N Ph Ph Ph 75% yield 91% yield 92% yield 97% ee 96% ee 97% ee Hartwig, J. et. al. J. Am. Chem. Soc. 2002, 124, 15164–15165.! 17! Unactivated Alkene Substrates! L1 = O PhNH2 Pd(OAc)2 (5 mol %) K PO NHPh OBz 3 4 N L1 (5.5 mol %) L2 (5 mol %) N BzO tBu R + 2 R R L2 = Solvent, 65 ºC O O temporary P functional group (COD)Ir N Ph Ph NHPh NHPh NHPh NHPh O O Cl C7H15 53% yield 68% yield 68% yield 60% yield 89% ee 92% ee 95% ee 88% ee NHPh NHPh NHPh NHPh O TBSO S MeO2C Tol F 65% yield O 53% yield 58% yield 77% yield 97% ee 89% ee a 88% ee 95% ee a oxidation run at 80 ºC.! Hartwig, J. et. al. J. Am. Chem. Soc. 2013, 135, 17983–17989.! 18! Unactivated Alkene Substrates! L1 = O PhNH2 Pd(OAc)2 (5 mol %) K PO NHPh OBz 3 4 N L1 (5.5 mol %) L2 (5 mol %) N BzO tBu R + 2 R R L2 = Solvent, 65 ºC O O temporary P functional group (COD)Ir N Ph Ph N NHPh NHBn TBSO N O O C7H15 N TBSO 53% yield 51% yield TBSO 89% ee 89% ee 55% yield O 90% ee 51% yield EtO2C CO2Et 89% ee Tol S O OPh TBSO TBSO TBSO 55% yield 50% yield 50% yield 90% ee 90% ee 88% ee a oxidation carried out at 80 ºC.! Hartwig, J. et. al. J. Am. Chem. Soc. 2013, 135, 17983–17989.! 19! Oxygen Nucleophiles! L = [Ir(COD)Cl]2 (3 mol %) L (6 mol %) Me 30 % aq.