1-allyl metals introduction - allyl metals x mx virtually all transition metals can form خ·3-allyl...

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  • MX2

    Allyl Metals

    X

    MX

    Virtually all transition metals can form η3-allyl complexes, but few are synthetically useful. Pd is most widely studied and has broad utility. Allyl complexes of Rh, Ir, Ru and Mo are becoming more important and display reactivity differences that are complimentary to Pd. These are usually quite stable (but still reactive), and their formation is typically preferred over other posibilities.

    + M(n)

    n = 0, 1

    oxidative addition M(n+2)X MgX + MX2

    transmet.

    η1-allyl

    η3-allyl

    H base

    –X

    R/H M + insertion

    M

    R/H

    MX R/H/Nuc

    M

    Nuc

    R/H M C+ insertion

    MX

    R/H

    M

    R/H

  • Pd(0)L2

    Allyl Metals Once formed the allyl palladium intermediate is available for a wide range of subsequent transformations.

    LPd(0)

    X

    Pd(II) X L(SN2 or SN2')

    Pd(II) X

    L

    Pd(II)L2Nuc Nuc

    "reductive elimination"

    +L –X–

    Nuc

    Pd(II) R

    L

    R M

    R + Pd(0)L

    transmetallation

    oxidative addition

    Pd(II) X

    –L, +

    insertion Pd(II)X

    H Pd X+

    BHE

    LPd(0) – HX

    (inversion)

    (retention)

    (inversion)

    (net inversion)

    (net retention)

    phosphine ligands are normally used

  • Pd Catalyzed Allylic Alkylation The electrophile A wide range of leaving groups have been used all with varying rates of reaction and synthetic utility/ease of installation.

    XR Pd(0)

    R

    Pd + X

    X = Br, Cl, –OAc, –OCOR, –OP(OEt)2, –OSR, OPh, OH, R3N+, NO2, SO2Ph, CN O O O

    OR

    most commonly used

    R

    Pd O

    basic

    R R

    Pd basicO OR

    O

    RO

    + CO2

    R R

    Pd not basic

    O O

    O

    O

    selective reactions possible: Cl > OCO2R > OAc >> OH

  • Pd Catalyzed Allylic Alkylation The electrophile – regioselectivity Because Pd proceeds through η3-allyl intermediate, it does not matter which isomer is used as the starting material. Other metals may behave differently.

    R

    X

    XR Pd(0)

    R

    PdX

    Pd(0)

    With Pd nucleophiles usually attack at less-substituted end. Can vary with ligands and other metals.

    R

    PdX

    Nuc R

    Nuc

    NucR

    minormajor

    Stereoselectivity

    With chiral substrates high levels of stereoselectivity are observed. Overall retention of configuration is the result of a "double inversion".

    R1

    X

    R2 Pd(0)

    (inversion)

    R1

    PdX

    R2 Nuc R1

    Nuc

    R2 R2

    Nuc

    R1 or

    (inversion)

  • Pd Catalyzed Allylic Alkylation The nucleophile Typical carbon nucleophiles are relatively soft, stabilized carbanions. The anion can be pregenerated, or made in situ in the presence of an added base. Some of the leaving groups can serve as this base.

    R

    PdX R

    Z Y Z, Y = CO2R, COR, SO2Ph, CN, NO2

    Z Y Y

    Z

    Intramolecular examples are kown and work well. Can be used to make rings from 3–11+ members.

    Silyl enol ethers can also be used.

    R

    PdX R

    OTMS

    R2

    O

    R2

  • Pd Catalyzed Allylic Alkylation

    O O

    H

    Me

    PhO2C

    cat. Pd(PPh3)4 (–)CH(CO2Me)2

    THF, 95% Me

    CO2MeMeO2C

    H CO2Ph

    HO

    O J. Am. Chem. Soc. 1981, 103, 1864. complete chirality transfer

    O

    O

    SO2Ph

    PhO2S

    OTBS

    O

    Pd(OAc)2 P(Oi-Pr)3

    O

    O

    OTBS

    OHPhO2S SO2Ph

    Tetrahedron Lett. 1986, 27, 5695.

    26-membered ring

    C5H11 CHO

    HCN

    Ac2O C5H11 OAc

    CN 5% Pd(PPh3)4 THF, rt

    COMeMeO2C C5H11 CN

    COMeMeO2C

    67% Tetrahedron Lett. 1981, 22, 2573. EWG controls regioselectivity

  • PdL*

    Allylic Alkylation–Stereoselectivity Acyclic allyl Pd intermediates are dynamic. This has important consequences with regard to regio- and stereoselectivity.

    OAc

    Pd(0)L* PdL*

    (SN2)

    Nuc

    fast rxn (SN2)σ-allyl π-allyl

    Nuc

    PdL*PdL* σ-allyl π-allyl

    PdL*

    H

    H

    σ-allyl

    H

    H

    PdL*

    σ-allyl

    Nuc slow rxn

    diastereomeric, different rxn ratesracemic

    high ee

    R1

    OAc

    R1 Pd(0)L*

    racemic

    R1R1

    PdL* one isomer

    (enantiotopic ends)

    Nuc

    high ee

    R1

    Nuc

    R1

    disubtituted acyclic – both enantiomers give same intermediate

    π→σ→π isomerization

    results in "enantioface exchange"

  • Allylic Alkylation–Stereoselectivity The π→σ→π isomerization pathway is not available to cyclic systems, but asymmetric induction has been acheived. Erosion of enantioenrichment is observed with chiral substrates and achiral catalysts at high metal loadings.

    H

    R

    PdL*

    H

    R

    PdL*

    H

    R

    PdL*

    LnPd

    H

    R

    PdL*

    "diastereoface exchange" Pd(II)L is leaving group for

    Pd(0)L attack

  • Allylic Alkylation–Stereoselectivity Desymmetrization of meso substrates is quite common. In these cases, the chiral catalyst can choose between the enantiotopic leaving groups.

    OAcAcO Pd(0)L*

    Z Y (achiral)

    Pd(0)L*

    YZ AcO

    Z

    Y (R) (S)OAc

    Z

    Y (R) (S)

    The remaining allylic leaving group is available for a second reaction with an achiral catalyst.

    AcO Z

    Y

    Pd(0)L

    Nuc Nuc

    Z

    Y

    AcO Z

    Y

    Pd(0)L

    Nuc

    Z

    Y

    Nuc Nuc

    Notice the tether alters the regioselectivity

  • Enantioselective Allylic Alkylation Several different ligands have been used to impart asymmetry. The Trost ligands have demonstrated the widest utility.

    Reviews: Chem. Rev. 1996, 96, 395. Acc. Chem. Res. 2006, 39, 747.

    HNNH OO

    PPh2 Ph2P

    (S,S)-Trost Ligand

  • Enantioselective Allylic Alkylation

    I

    OH

    OH

    Me

    OCO2Me CN

    (±)

    1% Pd2(dba)3, 2.7% (R,R)-Trost

    CH2Cl2, rt, 97%, dr 92/8 I OR

    OR a. 10% PdCl2(CH3CN)2 HCO2H, PMP, DMF, 50 ºC

    b. Ac2O, Et3N, DMAP, CH2Cl2 81% yield, 87% ee

    Me CN

    O

    OAc

    Me

    Me CN

    J. Am. Chem. Soc. 2002, 124, 11616.

    OBz

    BzO SO2PhO2N

    (η3-allyl-PdCl)2 (S,S)-Trost

    NaHCO3, THF 87%, >99% ee

    NO

    SO2Ph

    O

    J. Am. Chem. Soc. 1998, 120, 1732

  • Enantioselective Allylic Alkylation

    NH

    O

    O

    O OH

    2.5% Pd2(dba)3 7.5% Trost

    Cs2CO3, THF, rt 87%, 82% ee

    OHHO NPhth

    J. Am. Chem. Soc. 1996, 118, 6520.

    Cl 0.026% [(allyl)PdCl]2

    0.054% Ligand

    NaCH(CO2Me)2, THF 93% yield, 95% ee

    CO2Me

    MeO2C 1. NaOH, Δ 2. KI, I2, NaHCO3 recrystallization

    3. DBU, THF

    O

    O

    H H

    >99.9% eeAngew. Chem. Int. Ed. 2002, 41, 4054.

    P N

    O

    t-Bu2-Biph Ph

    Mn(CO)3

    ligand OMe

    OMe

    OCO2Me

    OMe

    OMe

    NTs

    Pd2(dba)3 BINAPO

    TsNHallyl THF, rt

    80%, 86% ee

    J. Org. Chem. 1997, 62, 3263.

  • Allylic Alkylation via Transmetallation Used less frequently than other nucleophiles. Allylic acetates are not great substrates, but can work. Transmetallation is slowed due to tight coordination of acetate, and reductive elimination is slower with allyl groups than other alkyl/aryl groups.

    Reactivity acheived with polar solvents (DMF), "ligandless" Pd [Pd2(dba)3, PdCl2(MeCN)2], and excess LiCl (facilitate transmetallation). Organostannanes work well (transmetallation facile relative to RB(OR)2). Reaction occurs on less substituted end, with net inversion of configuration (R.E. occurs with renention).

    TESO TESO

    Me

    OTES

    Me SnMe3

    AcO N

    OMe OH

    MeMe Me

    O

    +

    TESO TESO

    Me

    OTES

    Me Me

    OH

    Me N

    O OMe

    Me

    Pd2(dba)3 LiCl, DIEA

    NMP, 40 ºC 86%

    configuration maintained

    skipped diene J. Am. Chem. Soc. 2003, 125, 5393.

  • Allylic Alkylation via Transmetallation Works better with allylic chlorides/carbonates and vinyl epoxides. Chlorides reactive enough that phosphines can be used.

    MeO2C

    MeO2C

    SnBu3 O

    Me +

    Pd cat 1

    H2O, DMF, rt

    Pd cat 2

    H2O, DMF, rt (with Na salt of malonate)

    MeO2C OH

    MeO2C

    Me

    MeO2C SnBu3 MeO2C

    Me OH

    up to 93%

    up to 92%

    Pd cat 1: PdCl2(MeCN)2, Pd(cod)Cl2, Pd2(dba)3, Pd(bpy)Cl2

    Pd cat 2: Pd(PPh3)4, Pd(dba)(dppf), Pd(dba)(PPh3)2, Pd(dba)(AsPh3)2 Tetrahedron Lett. 1996, 37, 6591.

    N

    S

    O CO2CHPh2

    Cl

    NH O

    Bn Pd2(dba)3, P(2-furyl)3

    THF, 65 ºC

    MeO SnBu3

    N

    S

    O CO2CHPh2

    NH O

    Bn OMe

    Tetrahedron Lett