stille, suzuki, and sonogashira couplings cross-coupling ...· suzuki coupling suzuki coupling is

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  • Stille, Suzuki, and Sonogashira CouplingsCross-Coupling reactions:

    R-X + R'-M

    catalyst

    R-R' + M-X

    R, R' are usually sp2 hybridized

    X= I (best), OTf, Br, Cl

    M=Sn, B, Zn, Zr, In

    Catalyst= Pd, sometimes Ni

    Example:

    BrH3C + SnBu3

    Pd(0)

    H3C + Bu3SnBr

    Mechanism:Pd(II)

    Pd(0)Ln

    BrH3C

    Pd(II)LnBrH3C

    oxidative addition

    SnBu3

    transmetallation

    RDS

    Pd(II)LnH3C

    PdL L

    R'

    R

    trans

    PdL R'

    L

    Rcis

    initially:

    reductive eliminationfrom cis complex

    Bu3SnBr

    Stille Reaction

  • General Cross-Coupling Reactions

    Oxidative addition initially gives rise to a cis complex that rapidly isomerizes to a trans complex

    PdL I

    L

    R

    R-I

    PdL2 fast

    PdR I

    L

    L

    -hydride elimination occurs for Csp3 halides other than methyl:

    H Pd(II)LnX + HPd(II)L2X

    Both oxidative addition and reductive elimination occur with retention of double bond configuration

    Transmetallation is usually the rate-determining step, except where poor halide leaving groups (Cl) are used; thenoxidative addition is RDS.

    Order of ligand transfer from Sn:

    > >R

    >benzyl

    > alkyl

    Stille-specific conditions:Catalyst: Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3Large rate enhancements are often observed with poorly electron donating ligands: (furyl)3P, Ph3AsCuI can dramatically increase the reaction rate due to coppers free-ligand scavenging ability:

    I

    +SnBu3

    Pd2(dba)3 5mol%

    PPh3 (20mol%)

    mol% CuI relative rate 0 1 10 114

    JOC, 1994, 5905.

  • Stille Cross-CouplingThe use of aryl chlorides requires special conditions:

    Cl

    +SnBu3

    Pd2(dba)3 5mol%

    P(t-Bu)3CsF

    dioxane, 100C

    H3CO

    OEtOEt

    H3CO

    ACIEE, 1999, 2411Sn->Cu transmetallation increases the rate of cross-coupling reaction:

    ONf

    SnBu3

    Nf=SO2(CF2)3CF3

    +OHR Pd(PPh3)4 (10mol%)

    LiCl (6 eq), CuCl (5eq)

    DMSO, 60C

    OHR

    92%

    JACS, 1999, 7600

    Coupling of Acid Chlorides:

    O

    Cl

    +

    H2N

    Bu3Sn O

    O

    BnPdCl(PPh3)2CuI, THF, 50C

    H2N

    O

    O

    O

    JOC, 1993, 343

    Benzylic coupling:

    O

    Br

    R

    OTHP

    Bu3Sn+

    Pd(PPh3)4 (10mol%)

    CHCl3, reflux OR

    OTHP65%

    JOC, 1993, 165

  • Preparation of Aryl and Vinyl Stannanes

    From Organolithium reagents via directed ortho-lithiation:

    OMOM

    1. t-BuLi

    2. Bu3SnCl

    OMOM

    SnBu3

    Chem. Rev. 1990, 923.

    NBr R

    ((CH3)3Sn)2

    Pd(PPh3)4NBu3Sn R

    TL 1997, 4737.

    Prep of vinyl stannanes:

    OTHP

    CH3

    Bu3SnH

    AIBN

    OTHP

    CH3Bu3Sn

    OTHP

    CH3

    SnBu3

    +

    85 : 15

    a radical reaction, reversible, giving a thermodynamic ratio of productsJACS, 1976, 222.

    Alternatively,

    O

    OH

    I

    CH3

    Bu3Sn

    SnBu3

    PdCl2(CH3CN)2, 5mol%O

    OHCH3

    Bu3Sn

    69% Synlett, 1997, 771

  • Alternative Preparations of Vinyl Stannanes

    OEt

    EtO

    H

    Bu3Sn(Bu)CuCnLi2

    THF; CH3OH

    OEt

    EtO SnBu3

    TL, 1991, 6337.

    CH3

    EtO

    H

    BuLi; Bu3SnClCH3

    EtO

    SnBu3

    Cp2Zr(H)Cl CH3

    EtO

    SnBu3

    Zr(Cl)Cp2

    H2O CH3

    EtO

    SnBu3

    syn hydrozirconation

    HZ-vinyl stannane

    TL, 1992, 5861OEt

    EtO

    H

    Bu3Sn(Bu)CuCnLi2

    THF;Br

    OEt

    EtO SnBu3

    TL, 1991, 6337

    BrR

    OH

    t-BuLi (3 eq)

    Bu3SnCl Bu3SnR

    OH

    JACS, 1999, 7600

    Vinyl stannanes react cleanly with iodine to form vinyl iodides with retention of stereochemistry:

    R

    TBSO

    TBSO

    Pd(PPh3)2Cl2Bu3SnH

    CH2Cl2, 0C

    R

    TBSO

    TBSO

    SnBu3

    I2, DCM

    R

    TBSO

    TBSO

    I

    JACS, 1998, 3935

  • Suzuki Coupling

    Suzuki Coupling is the reaction of vinyl or aryl boronic acids with aryl and vinyl halides or triflatesusing a palladium catalyst. Example:

    B(OH)2 + CHO OHCBr

    Pd(OAc)2 (0.3 mol%)

    PPh3 (0.9 mol%)

    Na2CO3,(1.2 eq)

    iPrOH, H2O

    heat

    Mechanistic difference with Stille Coupling: Boron ate complexes are involved in transmetallation:

    RL2Pd

    O

    Ar

    B

    OH

    OH

    H

    RL2PdX

    HO-

    RL2PdOH

    ArB(OH)2

    Again Oxidative Addition and Reductive Elimination occur with retention of configuration

    Reactivity of Leaving Groups: I> OTf > Br >>Cl

    Rates of reductive elimination: aryl-aryl> alkyl-aryl > alkyl-alkyl

    The additive thallium hydroxide (TlOH) accelerates the rate of coupling by facilitating hydroxyl-halogen exchangeat Pd: JACS, 1987, 4756.

  • Transfer of primary alkyl groups utilizing the Suzuki coupling:

    Fe

    CN

    9-BBNB

    CN

    O

    Br

    PdCl2(dppf)

    K2CO3DMF, THF, 50C

    O

    CN

    JACS, 1989, 314

    PPh2

    PPh2

    Pd

    Cl Cl

    Ph2PPPh299

    large "bite" angle of dppf is believed to furnish a catalyst with a morefavorable ratio of rate constants for reductive elimination vs. !-hydride eliminiation

    dppf

    JACS, 1984, 249

    Buchwalds room temperature cross-coupling of Aryl chlorides:

    Cl

    O

    MeO

    (HO)2B

    O

    Pd(OAc)2 1mol%

    KF (3 eq), THF

    P(t-Bu)2

    O

    MeO

    O

    ACIEE, 1999, 2413

    91%

    2 mol%

  • Synthesis of Boronic Acids

    Li

    1. B(Oi-Pr)3

    2. HCl/Et2OB(OiPr)2

    OTfO2N

    B B

    O

    OO

    O

    PdCl2(dppf) 3 mol%

    KOAc, DMSO, 80C

    BO2N

    O

    O

    86%

    JOC, 1995, 7508

    Organometallics, 1983, 1316

    H1. n-BuLi

    2. B(OiPr)3

    B(OiPr)2

    H2, Lindlar

    B(OiPr)2

    H

    OBO

    H

    THF, 70C

    B O

    O

    80%

    JACS, 1972, 4370

    TL 1988, 2631, 2635.

    I(iPc)2BH

    CH3CH2OH

    B(OEt)2

    I

    H

    syn-hydroboration

    syn- hydroboration

    HO

    HO

    B

    I

    H

    O

    O

    B

    H

    O

    OEtZnI

    PdCl2(dppf)

    1mol%

    Chem. Lett, 1993, 1429.

  • Comparison of the Stille and Suzuki couplingsThe two methods are comparable, but the higher cost and toxicity of stannanes makes the Suzuki preferable.

    OMe

    NO2

    OTf

    Sn(Me)3

    Pd2(dba)3P(o-tol)3LiCl

    OMe

    NO2

    OMe

    NO2

    80%82%

    B(OH)2

    Pd(PPh3)4K3PO4DMA, 85C

    When alkyl boranes and stannanes are in the same molecule, the organoboron group reacts preferentially under basic conditions

    O

    Br

    B SnMe3

    PdCl2(dppf)

    K3PO4, DMF

    O

    SnMe3

    88% Synlett, 1991, 687

    Heterocycles, 1998, 1513

    Recently, triorganoindium reagents have been found to cross-couple with aryl and vinyl halides in anAtom-efficient manner, transferring all three organic ligands from indium. Indium is environmentally benign.

    CO2Et

    Br

    In

    CO2Et

    + 1/3 eq.

    1 mol% Pd(0)

    THF, 60C

    92%JACS, 2001, 4155

  • Sonogashira Coupling

    Sonogashira Coupling is the coupling of terminal alkynes with aryl and vinyl halides in the presence of A palladium (0) catalyst, a Cu(I) co-catalyst, and an amine

    X + R

    PdCl2(PPh3)2

    CuI, Et2NHR

    XR

    R'

    R''

    + R'''

    PdCl2(PPh3)2

    CuI, Et2NH

    R

    R'

    R''

    R'''

    Pd(0)Ln

    Pd(II)X

    oxidative addition

    transmetallation

    RDSPdL L

    R

    trans

    PdL

    L

    R cis

    reductive eliminationfrom cis complex

    CuX

    RX

    R

    L

    L

    Cu R'

    H R'

    CuI

    R2NH

    R'

    R'

    R R'

    copper(I)coordination toalkyne enhancesacidity:

  • Examples of Sonogashira Coupling

    CO2H

    CH3

    I+

    PdCl2(PPh3)2CuI, DMF

    CH3

    CO2H

    HO

    +I

    OCH3

    PdCl2(PPh3)2CuI, DMF HO

    H3CO87%

    JOC, 2001, 6037

    TL, 2002, 4703

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