M.C. White/Q Chen, Chem 153 Q&A-342 Week of december 2. 2002 An interesting synthesis of cyclopropanes has been recently reported by gri Propose a mechanism for this transformation. Pd dba)3, TFP NHMe P KCO3, DMF TFP= 68% NMe NHMe reductive elimination oxidative addition Pdln Attack of amide at central carbon of NMe NAMe Wacker-like process KHCO3 InsertIo CNHMe CO3 NAMe Insertion Attack of nucleophiles at the central carbon of(n-allyl)palladium complexes is much less common than attack at the termini. Central attack results in the formatic of a palladacyclobutane, which in the absence of a good leaving group can undergo reductive elimination to form a cyclopropane and regenerate pd(o) Grigg, R. Eur J. Org. Chem. 2001, 707-712
M.C. White/Q. Chen, Chem 153 Q&A -342- Week of December 2, 2002 NMe O Ln Pd K2CO3 NHMe O PdLn I O P PdLn NHMe O I NMe O I NHMe O I NHMe O An interesting synthesis of cyclopropanes has been recently reported by Grigg. Propose a mechanism for this transformation. + Pd2(dba)3, TFP K2CO3, DMF 68% TFP = 3 PdLn insertion Attack of amide at central carbon of the π-allyl is considered to be a Wacker-like process. Grigg, R. Eur. J. Org. Chem. 2001, 707-712. NHMe O PdL2 I NMe O oxidative addition insertion reductive elimination Attack of nucleophiles at the central carbon of (η3-allyl)palladium complexes is much less common than attack at the termini. Central attack results in the formation of a palladacyclobutane, which in the absence of a good leaving group can undergo reductive elimination to form a cyclopropane and regenerate Pd(0). KHCO3 KI
M.C. White/Q Chen, Chem 153 Q&A-343 Week of december 2. 2002 Murai has described the synthesis of butanolides from a three component coupling shown below Propose a mechanism for this process Ru3 CO12(2.5 mol%) RuCO3 cO reductive elimination The authors propose that the o, -chelate ruthenium complex reacts with ethylene to form a metallacycle in which the Ru-s bond remains intact Murai,S.JACS1999,7160-7161
M.C. White/Q. Chen, Chem 153 Q&A -343- Week of December 2, 2002 N S O Me N S O Me N S Me OCRu O OC CO N S O O Me N S O O Me CO Murai has described the synthesis of butanolides from a three component coupling shown below. Propose a mechanism for this process. Ru3CO12 (2.5 mol%) tol., 140 °C, 20h "RuCO3" Murai, S. JACS 1999, 7160-7161. ethylene (3 atm) CO (5 atm) S O N Me Ru "σ,σ-chelate ruthenium complex" The authors propose that the σ,σ-chelate ruthenium complex reacts with ethylene to form a metallacycle (CO)3 in which the Ru-S bond remains intact. S O N Me Ru (CO)3 S N Me Ru (CO)2 O O reductive elimination CO insertion O M M O
M.C. White, Chem 153 JE-Allyl chemistry -344 Week of December 2. 2002 Allylic substitutions via metal -allyl intermediates Highly regio-and stereoselective allylic substitutions are possible with metal mediated reactions LMcat X=OAc(most common Pd(most common) OCO,Me Moo wo FeO Nio halide, epoxide, sulfone I rh Nu= soft carbanions(malonate) roatom nucleophiles O, N organometallics(main group M" LUMO of allyl cation MIXL ML L HOMO of neutral ligand allyl cation ne representation of a metal T-allyl has the metal in its reduced form and the allyl ligand with a full positive charge ML Mo+2L NuMa+L Consideration of the LUMO of an allyl cation indicates that nucleophilic attack is most likely at the terminal positions of the allyl group
M.C. White, Chem 153 π-Allyl chemistry -344- Week of December 2, 2002 X X = OAc (most common) OCO2Me halide, epoxide, sulfone MnLm cat M = Pd0 (most common) Mo0, W0, Fe0, Ni0, IrI, RhI Nu Nu = soft carbanions (malonate) heteroatom nucleophiles O, N organometallics (main group) Nu Highly regio- and stereoselective allylic substitutions are possible with metal mediated reactions Allylic substitutions via metal π-allyl intermediates General mechanism: MnLm X Mn+2Lm X MnLm One representation of a metal π-allyl has the metal in its reduced form and the allyl ligand with a full positive charge. Consideration of the LUMO of an allyl cation indicates that nucleophilic attack is most likely at the terminal positions of the allyl group. HOMO of allyl cation LUMO of allyl cation Nu or Mn+2Lm X Nu MnLm Nu Nu Mn+2(X)Lm OA L neutral ligand Nu
M.C. White, Chem 153 JE-Allyl chemistry -345 Week of December 2. 2002 Mechanism Double inversion mechanism is thought to operate for Pd allylic substitutions that proceed with net retention. This mechanism operates with stabilized oft" C nucleophiles such as malonates, sulfonylacetates and may operate in part for amines MeO, Cr Pd(PPh, )cat. Merc MeOr CO,Me net retention THF reflux Pd(oac conaton MeO MeO,C- via SN2 VS SN2 b/c plated and shown to undergo COMe of Pd's sensitivity nucleophilic substitution with THF reflux Trost JOC. 1976(19)3215 vidence for double retention has been established in one case of Mo mediated allylic substitution RE (CH(CO, Me)) Kocovsky JACS 1995(117)6130 CO,Me
M.C. White, Chem 153 π-Allyl chemistry -345- Week of December 2, 2002 Substitution with net retention. Mechanism MeO2C OAc Pd(PPh3)4 cat. CO2Me CO2Me Na MeO2C CO2Me CO2Me PPh3 THF, reflux 92% net retention Trost JOC 1976 (19) 3215. OAc inert towards Pd0- catalyzed allylic substitution Mo(CO)6 15 mol% toluene, 100oC CO2Me CO2Me Na MoII(OAc)Ln OA CO2Me CO2Me Na NaOAc ligand exchange MoII(CH(CO2Me)2)Ln CO2Me CO2Me 96% RE Kocovsky JACS 1995 (117) 6130. Evidence for double retention has been established in one case of Mo mediated allylic substitution. MeO OAc 2C OAc MeO2C SN2 MeO2C LnPdII (OAc) OAc MeO2C LnPd0 Pd(PPh3)4 cat. CO2Me CO2Me Na MeO2C CO2Me CO2Me PPh3 MeO2C LnPdII (-OAc) CO2Me CO2Me PPh3 PPh3 Double inversion mechanism is thought to operate for Pd allylic substitutions that proceed with net retention. This mechanism operates with stabilized "soft" C nucleophiles such as malonates, sulfonylacetates and may operate in part for amines. = Thought to proceed via SN2 vs. SN2' b/c of Pd's sensitivity towards sterics. THF, reflux 92% net retention ionization Pd0Ln Pd π-allyl intermediates have been isolated and shown to undergo nucleophilic substitution with inversion
M.C. White, Chem 153 JT-Allyl chemistry -346 Week of December 2. 2002 Mechanism Substitution with immersion CO,Me Pd(dba) THF. 50C CO,B leOC LaPd(cn CO2Bn Meo2C lmPd CO,Bn Stille!S198410483 BuaSnCI Amine nucleophiles: CO,M Pd(PPh3)43-8 mol% COmE CO,Me THF rt 2N NHR NHR 81%(2: 3 identity of major isomer is not specified) MeO,C Meog -OAc) MeO2c F +(-OAc NpD(OAc) L.Pall Trost JOC 1979(44)3451
M.C. White, Chem 153 π-Allyl chemistry -346- Week of December 2, 2002 CO2Me Cl Pd(dba)2 n-Bu3Sn CO2Bn THF, 50oC CO2Me CO2Bn Pd0Ln LnPdII MeO (Cl) 2C n-Bu3Sn CO2Bn n-Bu3SnCl LnPdII MeO2C CO2Bn RE 87% OA via SN2 Mechanism Substitution with inversion: Stille JACS 1984 (106) 4833. CO2Me OAc H2N OMe OMe Pd(PPh3)4 3-8 mol% THF, rt CO2Me NHR CO2Me NHR + 81% (2:3 identity of major isomer is not specified) (OAc) MeO2C LnPdII Pd0Ln MeO2C (-OAc) LnPdII + NH2R MeO2C (-OAc) LnPdII (+NH2R) Amine nucleophiles: Trost JOC 1979 (44) 3451
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