Allylic Substitution Reactions! Group Meeting Literature Presentation! Alexanian Research Group! 15 May 2014! ! Njamkou N. Noucti! “Game Changers”! Jiro Tsuji! 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)! 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 π–allylmetal intermediates! LG + Pd 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! MXn + M = B, Si, Sn, Mg, Zn X M = Cl, Br, I, OTs Allylations/Crotylations! MXn M = Li, Mg, Sn, Si, B Cr, Ti, Zn, Zr + O R OH H Nucleophilic allyl fragments: not allylic substitution reactions! R 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! Asymmetric Allylic Alkylations! Reactions not catalyzed by Ir or Pd! Applications in total synthesis! ! Further reading! Chem Rev. 1996, 96, 395–422.! Chem. Rev. 2003, 103, 2921–2943.! ! 5! History! n Wacker–Smidt (1959):! via: R PdCl2, CuCl2 R H2O, HCl O2 or air [Pd] O OH R H n Jiro Tsuji (1965):! Carbon nucleophiles can also attack palladium–olefin complexes! O Cl O Pd Pd Cl O Na, EtOH + EtO OEt DMSO 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.! EtO O O OEt + EtO O OEt 6! History! n Trost (1972):! CO2Et C2H5 C2H5 Cl nC3H7 Pd Cl O Pd CO2Et CO2Et nC3H7 + O OEt EtO CO2Et Na, PPh3 CO2Et THF or DMF + CO2Et + 23% yield 37% 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! C2H5 C2H5 Cl nC3H7 Pd Cl Pd O nC3H7 + MeO S SO2Me O Na, PPh3 OEt THF or DMF CO2Et 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 palladium–allyl intermediate! PdCl2 Na2CO3 or NaCl, AcOH, NaOAc Cl Not amenable to one–pot allylic substitution reaction! Pd Pd DCM Cl Stoichiometric in palladium! n Functionalized allylic starting materials:! Atkins (1970)! OH Pd(acac)2 (0.5 mol %) PPh3 (0.5 mol %) 50 ºC HNEt2 Pd NEt2 95% yield OH Hata (1970)! OPh Pd(PPh3)2 (0.002 mol %) maleic anhydride (0.004 mol %) 85 ºC HNEt2 Pd OPh Atkins, K. E. et. al. Tetrahedron Lett. 1970, 3821–2824.! Hata, G. et. al. J. Chem. Soc. D, Chem. Comm. 1970, 1932–1933. ! NEt2 quantitative yield 8! Reaction Substrates! LG Pd + Nu Nu n Nucleophiles:! Soft, carbon nucleophiles! Heteroatom nucleophiles! pKa < 25! Hard, carbon nucleophiles! pKa > 25! EWG EWG1 EWG2 R1 EWG = CN, NO2, SO2R, SOR, CO2R, COR N H R2 HS R R HO R R = H, alkyl, aryl, vinyl EWG = CN, NO2, SO2R, SOR, CO2R, COR n Allylic electrophile:! OCO2Me OSO2Me OP(O)(OEt)2 NO2 OAc NR2 Cl most common OR less common 9! Substrate Scope! Pd2dba3–CHCl3 (2.5 mol %) PPh3 (8 mol %) R2 R3 OCO2Me + Nu R2 R3 THF, 30 ºC R1 R1 CO2Et CO2Me CO2Me Ph CO2Et O 92% yield Nu O O 91% yield CO2Et CO2Et 90% yield CO2Me AcO O 86% yield Tsuji, J. et. al. J. Org. Chem. 1985, 1523–1529.! 77% yield 10! Substrate Scope! OCO2allyl Pd2dba3–CHCl3 (2.5 mol %) dppe (10 mol %) + Nu NO2 Nu THF, 65 ºC CN CN Ph 76% yield O 91% yield CN 73% yield O 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 OCO2R Pd0Ln nucleophilic attack! oxidative addition! Pd OCO2R Pd 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! CO2Me CO2Me NaCH(CO2Me)2 [Pd] CO2Me + 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 nPr OAc + O EtO [Ir(COD)Cl]2 (2 mol %) Ligand (16 mol %) OEt THF, Temperature Na H nPr CO2Et + nPr EtO2C 2 equiv CO2Et CO2Et B A 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 9h 44 53:47 4 P(OEt)3 reflux 3h 81 59:41 5 P(OPh)3 rt 3h 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 π–allyl ligand on metal center! ! !3. Stability of the resulting alkene–metal complex! ! ! nPr [Ir] A! vs.! Most influential with iridium! nPr nPr [Ir] vs.! Nu [Ir] B! A is the more stable cation; SN2 attack positions nucleophile on most substituted carbon! nPr A! Nu [Ir] B! A is the more stable transition–metal complex! 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 OR + NaCH(CO2Et)2 [Ir(COD)Cl]2 (2 mol %) P(OPh)3 (16 mol %) nPr CO2Et EtO2C THF, rt 2 equiv + nPr CO2Et CO2Et A B Entry R Reaction Time % yield A:B 1 Ac 3h 89 96:4 2 CO2Me 1h 94 97:3 3 H 2h 100 96:4 4 C(O)CF3 5h 70 95:5 n Quaternary centers can also be synthesized:! OAc + Me nBu NaCH(CO2Et)2 2 equiv THF, rt Me + CO2Et EtO2C A Takeuchi, R. et. al. Angew. Chem. Int. Ed. Engl. 1997, 263–265.! CO2Et nBu [Ir(COD)Cl]2 (2 mol %) P(OPh)3 (16 mol %) 80 % yield A:B = 0:100 CO2Et Me nBu B 16! Nitrogen Nucleophiles! Ph OCO2Me + NHR1R2 L= [Ir(COD)Cl]2 (1 mol %) L (2 mol %) Ph THF, rt Me O P N O Me NR1R2 Ph Ph OMe HN HN Ph HN Ph 84% yield 95% ee O 88% yield 96% ee N 75% yield 97% ee Ph Ph 80% yield 94% ee Ph N N Ph 91% yield 96% ee Hartwig, J. et. al. J. Am. Chem. Soc. 2002, 124, 15164–15165.! 83% yield 97% ee (run at 50 ºC) N Ph 92% yield 97% ee 17! Unactivated Alkene Substrates! L1 = O + BzO2tBu R PhNH2 K3PO4 OBz L2 (5 mol %) Pd(OAc)2 (5 mol %) L1 (5.5 mol %) Solvent, 65 ºC NHPh N R R temporary functional group N L2 = O O P N (COD)Ir Ph Ph NHPh NHPh O O NHPh NHPh Cl C7H15 53% yield 89% ee 68% yield 92% ee 68% yield 95% ee 60% yield 88% ee NHPh NHPh O TBSO 65% yield 97% ee a oxidation NHPh NHPh Tol MeO2C S O 53% yield 89% ee a F 58% yield 88% ee 77% yield 95% ee run at 80 ºC.! Hartwig, J. et. al. J. Am. Chem. Soc. 2013, 135, 17983–17989.! 18! Unactivated Alkene Substrates! L1 = O + BzO2tBu R PhNH2 K3PO4 OBz L2 (5 mol %) Pd(OAc)2 (5 mol %) L1 (5.5 mol %) R R temporary functional group Solvent, 65 ºC NHPh N N L2 = O O P N (COD)Ir Ph Ph NHPh N NHBn N TBSO C7H15 TBSO 53% yield 89% ee 51% yield 89% ee Tol S O TBSO 55% yield 90% ee OPh TBSO 50% yield 90% ee N O TBSO 55% yield 90% ee O a oxidation O EtO2C CO2Et 51% yield 89% ee TBSO 50% yield 88% ee carried out at 80 ºC.! Hartwig, J. et. al. J. Am. Chem. Soc. 2013, 135, 17983–17989.! 19! Oxygen Nucleophiles! R OCO2tBu + TESOK 2 equiv [Ir(COD)Cl]2 (3 mol %) L (6 mol %) 30 % aq. NaOH in MeOH or TBAF DCM, rt L= Me O P N O Me R OH Ph Ph OH OH R R=H 88% yield 97% ee = CF3 78% yield 98% ee = OMe 75% yield 95% ee OH X X X=S =O 62% yield 50% yield 99% ee 97% ee OH Ph 65% yield X=S =O 67% yield 60% yield 98% ee 99% ee OTES Me 97% ee Carreira, E. et. al. Angew. Chem. Int. Ed. 2006, 45, 6204–6207.! 65% yield 95% ee 20! Oxygen Nucleophiles! OTf R Ph C2 or C3 (1 mol %) OCO2Me + KHCO3 DMF/H2O 10:1 O P O Ir OH H3C N H2C Ar CH3 Ar C2: diene = dbcot, Ar = Ph C3: diene = dbcot, Ar = 2–MeOC6H4 Ph Ph Ph3CO OH C3 86% yield 95% ee OH C2 92% yield 95% ee C7H15 OH C3 90% yield 93% ee Helmchen, G. et. al. J. Am. Chem. Soc. 2011, 133, 2072–2075.! OH C3 74% yield 89% ee OH C3 77% yield 95% ee 21! Mechanistic Details! L1 L1 Ir [(COD)IrCl]2 + 2 L1 O P O H3C Ph + Base CH3 N Ir O P O H2C HBase N Ph Ph Ir – L1 CH3 H2C + L1 not catalytically active! does not react with allylic reagents! CH3 N Ph Ph B A O P O Ph C e–! 18 Active species! 16 e–! CH3COCO2 R OCO2Me R Ir O P O H2C N Ph Ir Nu H2C CH3 Ph Nu D Silver salts lead directly to complex D! Nucleophile attacks more substituted carbon atom! Hartwig, J. et. al. J. Am. Chem. Soc. 2003, 125, 14272–14273.! Helmchen, G. et. al. Chem. Eur. J. 2009, 15, 11087–11090.! O P O N Ph R CH3 Ph E L1 = Me O P N O Me Ph Ph 22! Regiochemical Explanation! K4b–K4e: R’ = OMe! !a: R = C6H5, X = ClO4! !b: R = C6H5, X = SbF6! !c: R = CH3, X = ClO4! !d: R = CH3, X = SbF6! !e: R = CH3, X = CF3SO3! ! K4f: R’ = H! !f: R = CH3, X = CF3SO3! Ir bond to C1A is longer than Ir bond to C3A! Preferred attack of a nucleophile at weaker (longer) Ir–C bond! Helmchen, G. et. al. Chem. Eur. J. 2010, 16, 6601–6615.! 23! Hard Nucleophiles! n Few examples of hard nucleophiles in allylic substitution reactions:! Hard nucleophiles can react with ester functionality of allylic substrate! R O O + OH Nu + Nu R O unwanted reactivity with hard nucleophiles! n Rare example with vinyl Grignard:! + OAc ProliNOP: PdCl2(ProliNOP) (5 mol %) BrMg TMS THF, 10 ºC TMS 85% yield 30% ee N Ph2P O PPh2 Poor enantioselectivities typically obtained with hard nucleophiles.! Buono, G. et. al. Tetrahedron Lett. 1990, 31, 77–80.! 24! Proposed Mechanism! Nu Pd0Ln OAc reductive elimination! oxidative addition! [Pd] [Pd] OAc Nu M OAc M Nu ligand exchange! n Hard nucleophiles attack the metal center and not the allyl fragment! 25! “Softening” Hard Nucleophiles! n Traditionally hard nucleophiles can be “softened” with activating agents:! X X=N X=C Toluene and 2–methyl pyridine (pKa > 25) traditionally! considered hard nucleophiles! CH3 pKa = 34 pKa = ~44 Trost (2008)! OPG n + N R Catalyst N BF3•OEt2 n R H Walsh (2011)! CH3 OPG R2 + n R2 Catalyst [Cr] R1 Trost, B. et. al. J. Am. Chem. Soc. 2008, 130, 14092–14093.! Walsh, P. J. et. al. J. Am. Chem. Soc. 2011, 133, 20552–20560.! n R1 26! Boron Activating Agent! OPG N 1.5 equiv R + LiHMDS (3.5 equiv) BF3•OEt2 (1.3 equiv) [(η3–C3H5)PdCl]2 (2.5 mol %) L (6.0 mol %) O N Dioxane, rt R H PPh2Ph2P L Ph N N 94% yield 92% ee N N Me H 85% yield, >19:1 d.r. 94% ee a a LiHMDS Ph N >99% yield 96% ee N >99% yield 95% ee N H 98% yield 98% ee H N Me Me 99% yield, >19:1 d.r. 94% ee a O NH HN Br 80% yield, 4:1 d.r. 98% ee a H NMeBoc 70% yield, 13:1 d.r. 98% ee a (3.0 equiv), 1.0 equiv BuLi, BF3OEt2 (1.0 equiv), [(η3–C3H5)PdCl]2 (2.5 mol %), L (6 mol %), dioxane, rt.! Trost, B. et. al. J. Am. Chem. Soc. 2008, 130, 14092–14093.! Trost, B. et. al. J. Am. Chem. Soc. 2009, 131, 12056–12057.! 27! Chromium Activating Agent! OPiv CH3 R + Pd(COD)Cl2 (5 mol %) Xantphos (7.5 mol %) LiN(SiMe3)2 (3 equiv) NEt3 (1 equiv) THF, rt Cr(CO)3 R Cr(CO)3 Cl MeO MeO Cr(CO)3 96% yield Cr(CO)3 Cr(CO)3 45% yield 80% yield Cr(CO)3 no reaction n Chromium activating agent easily removed with sunlight and air:! OPiv CH3 Cr(CO)3 + same as above hν, air R Cr(CO)3 Walsh, P. J. et. al. J. Am. Chem. Soc. 2011, 133, 20552–20560.! R R=H 92% yield R = OMe 73% yield 28! Conclusion! “Palladium–catalyzed substitution reactions involving substrates that contain a leaving group in an allylic position”! occur via π–allylmetal intermediates! LG + Pd Nu Nu Mild reaction conditions! Tolerates a variety of nucleophiles ! Compatible with many leaving groups ! Regio–, diastereo–, and enantioselective! Early development: Mechanis5c contribu5ons: Jiro Tsuji Barry M. Trost John F. Hartwig Günter Helmchen 29!
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