M.C. White, Chem 153 JE-Allyl chemistry -347- Week of December 2. 2002 Olefin geometry clature of o the internal PdLn anti disfavored swnT: favored For sterically hindered olefins, the rate anti/syn isomerization is often slow relative to Nu attack, thus the initial lefin geometry is preserved in the product Trost JACS 1980(102)4730 CO,Me geranyl acetate(E 92%, only E somer observed So Ph by NMr neryl acetate( 2)OAc 78%, only the ZCO2Me observed by Nmr SOPh terically unhindered olefins, the rate of isomerization may be rapid and favors the syn T-allyl intermediate. This feature can used to synthesize stereodefined ionalized e olefins from terminal olefins Pd(Ppha) cat 个幽R八N OAc *Na 77%. the e (cis trans, 9: 1) exclusively
M.C. White, Chem 153 π-Allyl chemistry -347- Week of December 2, 2002 Olefin geometry OAc CO2Me SO2Ph CO2Me SO2Ph Na OAc CO2Me SO2Ph geranyl acetate (E) 92%, only E isomer observed by NMR Pd(PPh3)4 cat. 78%, only the Z isomer was observed by NMR neryl acetate (Z) THF For sterically unhindered olefins, the rate of isomerization may be rapid and favors the syn π-allyl intermediate. This feature can used to synthesize stereodefined, functionalized E olefins from terminal olefins. OAc CO2Me Na SO2Ph Pd(PPh3)4 cat. Nu 32% Nu 30% + + regioisomer (38%) (cis:trans, 9:1) THF R OAc CO2Me Na SO2Ph Pd(PPh3)4 cat. THF R Nu 77%, the E isomer was formed exclusively Trost JACS 1980 (102) 4730. For sterically hindered olefins, the rate anti/syn isomerization is often slow relative to Nu attack, thus the initial olefin geometry is preserved in the product: R R R H OAc OAc PdLn H R H H PdLn H R PdLn H R R Nu R Nu Z E anti: disfavored syn: favored η3/η1 η1/η3 Nu Nu anti/syn nomenclature of η3 π-allyl is relative to the internal H of the allyl group Z E PdLn anti/syn isomerization
M.C. White, Chem 153 JE-Allyl chemistry -348 Week of December 2. 2002 Regioselective electronic demands based large distribution of the n-allyl intermediate: allylmetal complexes steric demands of the nucleophile: path a is favored for may be thought of as allyl cations bulky nucleophiles. Pd catalysts bonded to zerovalent metals. The generally lead to reaction at the least hindered terminus of the allyl MIL preferentially stabilized at the more substituted position, therefore path b is the favored site of nucleophilic attack Trost JACS1984(106)6837 COMe CO,Me neryl acetate(2 OAc R=COMe 37: 63 (linear: branched) 90:10 Trost JOC1976(41)3215
M.C. White, Chem 153 π-Allyl chemistry -348- Week of December 2, 2002 Regioselectivity Factors influencing regioselectivity in metal-mediated allylic substitutions: RS MIILn RL Me Nu a steric demands of the nucleophile: path a is favored for bulky nucleophiles. Pd catalysts generally lead to reaction at the least hindered terminus of the allyl fragment. RS M0Ln RL Nu b Me electronic demands based on the charge distribution of the π-allyl intermediate: allylmetal complexes may be thought of as allyl cations bonded to zerovalent metals. The positive charge should be preferentially stabilized at the more substituted position, therefore path b is the favored site of nucleophilic attack based on electronic considerations. Nu Rs RL Me M0Ln steric demands of the metal: Path b is favored because it results in the least sterically hindered zerovalent M-olefin complex. LnM0 R Nu s RL Me Trost JACS 1984 (106) 6837. Pd mediated catalysis: sterics of the nucleophile dominate the regioselectivity: CO2Me R Na OAc CO2Me R Pd(PPh3)4 cat. neryl acetate (Z) THF R = CO2Me 37:63 (linear: branched) SO2Ph 90:10 CO2Me R + Trost JOC 1976 (41) 3215
M.C. White, Chem 153 UE-Allyl chemistry -349 Week of December 2. 2002 Carbon and oxygen spirocycles yclizations CO,Et O,Et Pd(PPh3) 7 mol% COet NaH,THF,65°C note that attack at the least sition results in a bridgehead olefin: Ln(Oac)Pd Pd(PPh3)47 mol% NaH. THF. 65C CO,Me CO,Me >99% Godleski JOC 1982(47)383 OrMe cis-fused decalin systems RO,O CO RO2C COrR=E NaH. THF. 65%C NaH. THF 65C CO,R CO,R Aco complements the Robinson annulation 75%.>98%cis >98%cis approach which generally leads to Backwall TL 1989(30)61 reyiew on cyclizations: Trost. ACIEE 1989(2811173 Macrocyclizations occur readily Regioselectivity favors substitution at the least sterically hindered carbon, particularly when bulky nucleophiles are used. TESO, OTES OTES LOTUS H3C Pdzdbas 10 mol% TESO OtBu OMe HO THF.40°C.12h 80% for IMSC Sorenson JACS2002(124)4552 (+}FR82877
M.C. White, Chem 153 π-Allyl chemistry -349- Week of December 2, 2002 Carbon and oxygen spirocycles: Cyclizations OAc CO2Et CO2Et CO2Et CO2Et OAc O CO2Me O CO2Me O CO2Me Ln(OAc)PdII Pd(PPh3)4 7 mol% NaH, THF , 65oC 66% note that attack at the least sterically hindered position results in a bridgehead olefin: Pd(PPh3)4 7 mol% NaH, THF , 65oC >99% Godleski JOC 1982 (47) 383. O TESO OTES TMSO O Ot-Bu O O OMe O OTMS O O-tBu TESO OTES 19-membered ring formation Pd2dba3 10 mol% THF, 40oC, 12h 80% O O O H H CH3 H CH3 H OH H3C HO CH3 H H H H (+)-FR182877 Macrocyclizations occur readily. Regioselectivity favors substitution at the least sterically hindered carbon, particularly when bulky nucleophiles are used. Sorenson JACS 2002 (124) 4552. cis-fused decalin systems: AcO O CO2R Pd2dba3/PPh3 cat NaH, THF, 65oC RO2C CO2R H H E E O E >98% cis complements the Robinson annulation approach which generally leads to trans-fused rings. AcO O CO2R CO2R RO2C = E Pd2dba3/PPh3 cat NaH, THF, 65oC O E E E H H 75%, >98% cis Backvall TL 1989 (30) 617. review on cyclizations: Trost ACIEE 1989 (28) 1173
M.C. White, Chem 153 JE-Allyl chemistry -350 Week of December 2. 2002 Efficient route to Cephalotaxine core via iterative pd-mediated cvclizations Pd(PPh3)4(8 mol%) EtyN,CH3CN,50°C 85% Aco readily accessible, simple starting materials nBuNOAc CH3CN/DMF/H20 NpD H 80% Br Tietze acide199735:1011241125
M.C. White, Chem 153 π-Allyl chemistry -350- Week of December 2, 2002 O O Br NH2 + I AcO O O Br H N AcO O O Br N Pd(PPh3)4 (8 mol%) Et3N, CH3CN, 50 oC 85 % O O N H O O Br NH LnPd O O PdLn N Br O O N H LnPd Br P Pd(OAc) oTol oTol 2 nBu4NOAc CH3CN/DMF/H2O 80 % 6 mol% readily accessible, simple starting materials Efficient route to Cephalotaxine core via iterative Pd-mediated cyclizations Tietze ACIEE 1997 35:10 1124-1125
M.C. White/Q Chen, Chem 153 兀- Allyl chemistry351 Week of December 2. 2002 Anti attack of allenes on(T-allylpalladium complexes Pd(dba 2 mol% CH3CN or Toluene Pdl PdLn E=CO,Me Pd(dba To support the proposed mechanism involving the intermediate (aT-allyl)palladium complex shown above, the authors no reaction demonstrate that the corresponding trans-allylic pivalate does f-BucOr CH3CN or not react under identical reaction conditions Toluene The authors speculate that the electron-withdrawing nature of the dba ligand increases the electrophilicity of the allyl group of the(a-allyl)palladium intermediate, and thus renders the allyl group susceptible to nucleophilic attack by the electron-rich double bond of the allene. Pd(dba trans attack HVE of allene (dba)Pd trans t-BucOr HLE E=COMe Pd(dba)z cis olefin β hydride elimination Cl Cl The pathway via trans attack on the allene is blocked upon the addition of LiCl. The authors rationalize this result by invoking the formation of a Pd-ate complex in which the dba ligand has been replaced with chloride anions. This intermediate(a-allyllpalladium complex lacking electron-withdrawing ligands alternatively undergoes olefin insertion followed by B-hydride elimination to give the corresponding cis-fused bicycle Tietze ACIEE 35: 101124-1125
M.C. White/Q. Chen, Chem 153 π-Allyl chemistry -351- Week of December 2, 2002 Anti attack of allenes on (π-allyl)palladium complexes Tietze ACIEE 1997 35:10 1124-1125. t-BuCO2 · E E Pd(dba)2 2 mol% CH3CN or Toluene · PdLn PdLn E E E E E = CO2Me E H E H 76 % yield t-BuCO2 · E E E = CO2Me Pd(dba)2 2 mol% CH3CN or Toluene no reaction The authors speculate that the electron-withdrawing nature of the dba ligand increases the electrophilicity of the allyl group of the (π-allyl)palladium intermediate, and thus renders the allyl group susceptible to nucleophilic attack by the electron-rich double bond of the allene. To support the proposed mechanism involving the intermediate (π-allyl)palladium complex shown above, the authors demonstrate that the corresponding trans-allylic pivalate does not react under identical reaction conditions · E E t-BuCO2 E = CO2Me Pd(dba)2 1 eq. Pd(dba)2 1 eq. LiCl 4 eq. · E E · E E (dba)Pd Pd Cl Cl E H E H E H E H (dba)Pd trans attack of allene E E H E H E cis olefin insertion H H Pd Cl Cl 88% 90% β-hydride elimination trans cis The pathway via trans attack on the allene is blocked upon the addition of LiCl. The authors rationalize this result by invoking the formation of a Pd-ate complex in which the dba ligand has been replaced with chloride anions. This intermediate (π-allyl)palladium complex lacking electron-withdrawing ligands alternatively undergoes olefin insertion followed by β-hydride elimination to give the corresponding cis-fused bicycle