Organometallic Coupling Reactions The Heck Reaction Organometallic Coupling Reactions The Heck...

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Transcript of Organometallic Coupling Reactions The Heck Reaction Organometallic Coupling Reactions The Heck...

  • C549 R.M. Williams

    Organometallic Coupling Reactions

    The Heck Reaction The Heck reaction involves the use of Pd(0) catalysts that mediate the net insertion of nucleophiles into

    metal carbon s-bonds which are produced by oxidative addition processes. The most synthetically useful transformations involves the insertion of CO and alkenes into metal carbon s-bonds. This reaction is generally limited to organic substrates lacking b-hydrogen atoms since, reductive elimination is a facile process which usually occurs under the conditions for oxidative addition. The catalytic cycle for the Heck reaction, involving CO insertion is shown below.

    R-X Pd(0)

    R-Pd(II)-X

    R Pd(II)-X O CO

    (insertion)

    (oxidative addition)

    H-Pd(II)-X

    HX

    R Nu O

    (reductive elimination)

    Nu-H

    Examples of the CO insertion process are given below.

    OTf

    O O H

    Me

    Me

    Me Me

    Pd(OAc)2, Ph3P

    CO, MeOH, Et3N

    CO2Me

    O O H

    Me

    Me

    Me Me

    NHBn

    Br

    Pd(OAc)2, Ph3P

    CO, Et3N NBn O63%

    75%

    The olefin insertion process is similar and involves coordination of the olefin p-system to the Pd(II) intermediate followed by insertion and b-H-elimination. Typical catalysts used are: ((Ph)3P)4Pd, *Pd(dba)2, PdCl2L2 + DIBAH; Pd(OAc) 2 + reducing agent (such as Ph3P). *Note Pd)dba)2 :

    O OPd = Pd(dba)2

  • R-X Pd(0)

    R-Pd(II)-X

    R Pd(II)-X (coordination)

    (oxidative addition)

    H-Pd(II)-X

    HX (reductive elimination)

    Z

    Z = H, R, Ph, CN, CO2R, OMe, OAc, NHAc Z

    (less substituted)

    Pd X

    Z

    R

    H H

    ZR

    b-H-elimination (cis)

    An elegant example of the olefin insertion reaction was published by Rawal in the total synthesis of strychnine as shown below:

    N

    N

    O

    I OTBS

    N

    N

    O

    OHH

    1. Pd(OAc)2, K2CO3

    Bu4NCl, DMF 2. 2N HCl, THF

    71% isostrychnine

    Rawal, V.H.; Iwasa, S., J.Org.Chem., 1994, 59, 2685~2686

    The Stille Cross-Coupling Reaction

    A major advance in the field of Pd-catalyzed cross-coupling reactions was developed by J.K Stille and co-workers and involves the use of vinyl and aryl stannanes with activated vinylic or aryl halides or triflates. The catalytic cycle for the Stille reaction is shown below:

    Pd(II) R1Sn(R2)3

    R1-R1 Pd(0)Ln

    R3-Pd(II)Ln-X

    R3-X

    R1Sn(R2)3XSn(R2)3

    R3-Pd(II)Ln-R1

    R1-R3

    Several examples of the Stille reaction cast in complex polyfunctional molecules are illustrated below:

    O

    SnBu3 TfO

    Me Me

    Pd(PPh3)4

    LiCl 75%

    + O Me Me

    pleraplysillin-1

    Scott, W.J.; Crisp, G.T.; Stille, J.K., J.Am.Chem.Soc., 1984, 106, 4630~4632

    Stille and co-workers published an impressive demonstration of the Stille coupling reaction in a total synthesis of D9(12)-capnellene. This synthesis also features two sequential Nazarov cyclization reactions to construct the fused five-membered rings.

  • Me Me

    O

    Me

    Tf2O

    base 85%

    Me Me

    OTf

    Me

    Me3Sn SiMe3

    CO, Pd(PPh3)4

    Me Me

    Me

    O

    SiMe3

    BF3-OEt2

    tol., D

    Me Me O

    Me (Nazarov)

    1. L-selectride

    2. Tf2NPh

    76%70% 87%

    Me Me OTf

    Me

    Me3Sn SiMe3

    CO, Pd(PPh3)4 86%

    Me Me

    Me

    O

    SiMe3 BF3-OEt2

    tol., D (Nazarov)

    80%

    Me Me

    Me

    O

    H

    H Me Me

    Me H

    H1. H2, Pd/C

    2. Ph3P=CH2

    D9(12)-capnellene

    Crisp, G.T.; Scott, W.J.; Stille, J.K., J.Am.Chem.Soc., 1984, 106, 750~7506

    O

    O Me

    Me Me

    SnBu3 TfO Me

    Me CO, Pd(MeCN)2Cl2

    LiCl, DMF

    O

    O Me

    Me Me

    Me

    Me

    O

    Gyorkos, A.C.; Stille, J.K.; Hegedus, L.S., J.Am.Chem.Soc., 1990, 112, 8465~8472

    24%

    jatrophone

    When the halide is allylic, coupling occurs from the least hindered termini as shown by the two examples below:

    Me Me

    Me

    Cl

    allylic halides (typically Cl) couple at the least hindered termini:

    Pd(dba)2, P(Ph)3

    PhSnBu3

    Me Me

    Me

    90%

    Me

    Me CHO

    Cl

    Pd(dba)2, P(Ph)3

    (p-OMe)PhSnBu3 87%

    Me

    Me CHO

    OMe

    Alkenyl chlorides are generally not used in the Stille coupling reaction due to low reactivity, whereas alkenyl bromides and iodides are very useful coupling partners. Some examples are illustrated below:

  • Pd(PPh3)2Cl2, THF

    PhSnMe3 80%

    Me Br

    O

    Ph

    I

    Me Br

    O

    Ph

    n-Bu I Bu3Sn OH+

    Pd(MeCN)2Cl2 n-Bu OH

    78%

    O

    O SiMe2Ph

    OMOM

    OTBS

    O

    O SiMe2Ph

    Br OMOM

    OTBS

    SnBu3 Pd(AsPh3)2Cl2

    80%

    Perhaps one of the most spectacular illustrations of the Stille coupling reaction can be found in the total synthesis of rapamycin reported by Nicolaou and co-workers as shown below. This reaction involves a daring double Stille cross-coupling and macrocyclization directly providing the natural product.

    O

    I

    Me OMe

    Me

    O

    O N

    O H

    OH

    OMe

    Me

    Me

    O Me Me

    OH

    MeO

    O

    I

    Me

    Me

    Bu3Sn SnBu3

    Pd(MeCN)2Cl2 i-Pr2NEt, DMF, THF

    O Me

    OMe

    Me

    O

    O N

    O H

    OH

    OMe

    Me

    Me

    O Me Me

    OH

    MeO

    O

    Me

    Me

    Nicolaou, K.C.; et al., J.Am.Chem.Soc., 1993, 115, 4419

    ~ 46%

    rapamycin

    Biaryl couplings. The Stille reaction is a very powerful method to prepare biaryl cross-coupling reactions. The ease of preparation of the aryl triflates from the corresponding phenol, make this a very useful method. Some of the examples below illustrate this.

    OH

    NO2

    + Tf2O pyridine

    OTf

    NO2

    MgBr

    OMe

    + Bu3SnCl THF

    SnBu3

    OMe

    PdCl2(PPh3)2

    LiCl, DMF

    OMe

    NO2

    Stille, J.K.; Echavarren, A.M.; Williams, R.M.; Hendrix, J.A., Org.Syn., 1992, 71, 97~106.

  • OO

    O

    O

    Me NH3+ OH

    Me HO

    HO HO

    O O

    N O

    N H

    H

    O N H

    O N

    OH H

    O

    Me

    Me

    NHMe H

    H H

    OHOH

    N O

    H HO2C

    H

    N O

    Cl

    Cl

    H2N O

    HO

    HO H H

    HH H H

    HO HO OH

    H2N CO2H H2N CO2H

    H H

    7

    5

    ACTINOIDIC ACID

    7

    5

    6 4 2

    VANCOMYCIN

    CHO

    Br OMe

    1. KCN, NaHSO3, MeOH, H2O 2. conc. HCl, diox., 16 h

    3. SOCl2, MeOH; then NaHCO3 4. Pb(OAc)4, MeOH, CH2Cl2 5. aq. HCl, MeOH, rt., 16 h 6. (BOC)2O

    Ph

    NH2

    OHH

    OMe Br

    tBOCHN H

    CO2Me

    (96% er)

    0.4 eq. Pd(PPh3)4 , 0.4 eq. CuBr diox., D

    CHO Me3Sn

    OMeMeO

    44-51% 44% overall

    MeO

    tBOCHN H

    CO2Me

    CHO

    OMe MeO

    1.

    MeOH, rt.; 2 eq. TMSCN 2. conc. HCl, diox., rt. 16 h 3. SOCl2, MeOH 4. (BOC)2O, NaHCO3, H2O CHCl3

    Ph

    NH2

    OHH

    50%

    MeO

    tBOCHN H

    CO2Me

    OMeMeO

    MeO2C NH

    OHPh

    H

    H

    +

    MeO

    tBOCHN H

    CO2Me

    OMeMeO

    MeO2C NH

    OHPh

    H

    H

    1. Pb(OAc)4 , CH2Cl2 MeOH

    2. conc. HCl, D 76%

    MeO

    H2N H

    CO2H

    OMeMeO

    HO2C NH2 H

    1. 48% HBr, D, 12h 2. Dowex-50

    40%

    OH

    H2N H

    CO2H

    OHHO

    HO2C NH2 H

    Actinoidic Acid

    (atropisomer mixture)

    (atropisomer mixture)

    (atropisomer mixture)

    Williams, R.M.; Amino, Y. (unpublished)

    Acyl halide couplings. Acid chlorides tend to couple with stannanes in the presence of a palladium catalyst and few limitations are apparently associated with this reaction. There are also examples of this reaction in the absence of apalladium (and in some cases the yields are higher than in the presence of Pd!). Two examples are shown below:

    acyl halide couplings:

    COCl

    COCl +

    SnMe3

    SnMe3

    BnPd(PPh3)2Cl

    THF 62%

    O

    O

    Degl'Innocenti, A., et al., Synthesis, 1991, 267

    O Cln-C5H11 SnBu3

    n-Bu

    O

    Pd(PPh3)4

    THF, D O

    O n-Bu

    n-C5H11

    Linderman, et al., J. Am. Chem. Soc., 1990, 112, 7438

    77%

  • The Suzuki Coupling

    Suzuki has brought a major advance to the field of Pd-mediated coupling reactions through the demonstration that alkylboranes can serve as organic donors provided base is used in the reaction. Most significantly, aqueous base can be used and this constitutes one of the few synthetically useful C-C coupling reactions mediated by transition metals that can be conducted in water.

    R1 BY2 + R2X Pd(0)

    base R1 R2

    BY2 = B(OR)2, 9-BBN, B(CHCH3CH(CH3)2)2 X = Cl, Br, I, OTf base = Na2CO3, NaOEt, TEA, K3PO4

    R'-X Pd(0)

    R'-Pd(II)-X

    R' Pd(II)-OR

    (oxidative additi