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Mechanism and Scope of Palladium-Catalysed C-N and C-O Bond

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Mechanism and Scope of Palladium-Catalysed C-N and C-O Bond Powered By Docstoc
					 Mechanism and Scope of
Palladium-Catalysed C-N and
     C-O Bond Formation


   A Presentation by Matthew Helm
                           Background
Carbon-Carbon bond forming catalysis, using transmetallation:


                            Pd(0) cat.
                     ArX                       ArR
                                RM


Analogous Carbon-Nitrogen or Carbon-Oxygen bond forming catalysis:



                            Pd(0) cat.
              ArX                                     ArNR 2
                         MNR2 or HNR2

                           Pd(0) cat.
              ArX                                     ArNR 2
                         MOR or ROH
    First Intermolecular Carbon-Nitrogen
               Bond Formation
In 1983 Kosugi et al. published report of intermolecular carbon-nitrogen bond
formation. Only electron neutral aryl bromides gave products in good yields.
Vinyl Bromides and aryl bromides containing electron donating or electron
withdrawing groups gave products in low yields.



R                                                         R
                                  [(o-MeC6H4)3P)2PdX2
           Br    +   Bu3SnNR2                                              NR2 +   Bu3SnBr




Only Unhindered dialkyl amides gave good yields of amination products. It
was reported the mechanism did not appear to involve radicals or benzyne
intermediates.

                M. Kosugi, M. Kameyama, T. Migita, Chem. Lett. 1983, 927
     First Intramolecular Carbon-Nitrogen
                 Bond formation
First example of palladium(0) mediated carbon-nitrogen bond formation using
stoichiometric quantities of palladium(0) was reported by Boger in 1984
                 O                O                                  O             O

                          N                                               N
          EtO                           OEt                    EtO                     OEt

                                              Pd(PPh3)4
                H2N
                                                                     HN
                Br




     eq. Pd(PPh3)4            Solvent            Temperature/oC           Time/h         Yield/%

          1.0            THF(sealed tube)                 80               20                 50
          1.2            THF(sealed tube)                 80               21                 81
          1.5            THF(sealed tube)                 80               21                 84
          1.2                 Dioxane                     100              20                 50
          1.5                 Dioxane                     100              24                73-80
          1.2                 Toluene                     100              24                 43
         0.01            THF(sealed tube)                 80               24                 0

                      D. L. Boger, J. S. Panek, Tetrahedron Lett. 1984, 3175
   Catalytic examples using amino stanannes
Work reported by J. Hartwig:

                                                     [(o-MeC6H4)3P)2PdX2
     R                Br     +      Bu3SnNMe2                                        R        NMe2
                                                               75-85%



Catalytic cycle:                                                      L2PdX2


                                                         L(NHR2)PdX2
                                     L2Pd       reduction/  R=Me,Et
                                                dissoc.

                           ArNR 2
                                            L-Pd                  ArBr


                                                                                L        Ar
                                    NR2                   Br                        Pd
                       L     Pd                                Pd-L            Br        Br
                                    Ar                    Ar                        Pd
                                            n=1,2                              Ar        L




                                     BrSnBu3         R2NSnBu3


                   F. Paul, J. Patt, J. F. Hartwig, J. Am. Chem. Soc. 1998, 5969.
  Catalytic examples using amino stanannes

Work reported by S. Buchwald:
                                                 R''
                                                                    Br
                                                                               R''
                            o
    Bu3Sn-NEt2 + HNRR'    ~80 C    Bu3Sn-NRR'                                             NRR'
                         -HNEt2                    1-2.5 mol% Pd cat.
                                                     Toluene, 105oC


Examples:
                                            Ph                                       Ph

             EtO2C                   N                 Me2N                      N


                            88 %                                        81 %


                            H

                            N                                            N


                          66 %                                     55 %

                     A. S. Guram, S. L. Buchwald, J. Am. Chem. Soc. 1994, 7901.
      Achieving the Same Chemistry Without
            the use of Tin Reagents?
Work reported by J. Hartwig:
                                                  L2Pd or L2PdCl2
                   ArBr + HNRR'                                               ArNRR'
                                                    LiN(SiMe3)2
                                                    L=P(o-tol)3
Catalytic cycle:
                        L2PdCl2     reduction       L2Pd


                           ArNR 2
                                                    L-Pd               ArBr


                                                                                L        Ar
                          Ar           NR2                       Br                 Pd
                                  Pd                                  Pd-L     Br        Br
                           L                                     Ar                 Pd
                                                           H
             HN(TMS)2 + LiBr                                                   Ar        L
                                             Ar            NR2
                                                    Pd
                                                                      HNR2
                                                L          Br
                                  LiN(TMS)2


                       J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 3609.
     Achieving the Same Chemistry Without
           the use of Tin Reagents?
 Work reported by S. Buchwald:
                                                  cat. Pd2(dba)3
                                                  P(o-tolyl)3
                            I     +               NaOtBu
                                      HNRR'                                     NRR'
                                                  Dioxane
             R                                                     R
                                                  65oC or 100oC




 Tested a variety of aryl iodides with primary and secondary amines:

         I MeO             I Cl                    I
                                                                                  O
                                                                       H
                                                                       N   HN          HNBu2   HN
 I        MeO
                                                                                  O
                                              O
                                                          H2N                          NH2
                     I I                                                                       n-Hexyl-NH2

                                              NBu2




Good yields for all, 59-79%, except for when primary amines were used with Aryl
iodides not next to an ortho- substituent

                  J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 1996, 1133.
                Intramolecular Cyclisations.
                                        NHR

                                       n           Pd cat.
                                                                                        n
                                                                                 N
                             Br                                                  R
                                                      t
                                    R = Bn, COMe, CO Bu and SO2Tol

  R       n                                      Conditions                                 Yield/%
  Bn      1                                  (i)Et2N-SnBu3                                    87
                              (ii)10 mol% PdCl2(P(o-tolyl)3)2, toluene, 100 oC
  Bn      2                                  (i)Et2N-SnBu3                                    72
                              (ii)10 mol% PdCl2(P(o-tolyl)3)2, toluene, 100 oC
  Bn      3                                  (i)Et2N-SnBu3                                    61
                              (ii)10 mol% PdCl2(P(o-tolyl)3)2, toluene, 100 oC
  Bn      1                       10 mol% Pd(PPh3)4, toluene, K2CO3, 100 oC                   92
  Bn      2                       10 mol% Pd(PPh3)4, toluene, K2CO3, 100 oC                   87
  Bn      3                       10 mol% Pd(PPh3)4, toluene, K2CO3, 100 oC                   89
C(O)Me    1         5 mol% Pd2(dba)3, 20 mol% P(2-furyl)3, Cs2CO3, toluene, 100oC, 8h         99
C(O)Me    2         5 mol% Pd2(dba)3, 20 mol% P(2-furyl)3, Cs2CO3, toluene, 110oC, 21h        44
C(O)tBu   1         5 mol% Pd2(dba)3, 20 mol% P(2-furyl)3, Cs2CO3, toluene, 100oC, 23h        87
SO2Tol    1           2 mol% Pd2(dba)3, 8 mol% P(o-tolyl)3, K2CO3, toluene, 100oC, 5h         88
SO2Tol    2          2 mol% Pd2(dba)3, 8 mol% P(o-tolyl)3, K2CO3, toluene, 100oC, 14h         87


              J. P. Wolfe, R. A. Rennels, S. L. Buchwald, Tetrahedron, 1996, 7525.
                        Catalyst Development
Buchwald found dramatic improvements in yield and substrate generality by
using BINAP as the ligand
Catalyst loadings are also significantly reduced


                                                 PPh2

                                    Ph2P




No longer need substituents ortho- to the halide to achieve good yields when
using primary amines
                                                            R        Mol% Pd   Reaction time/h   Yield/%
        Br              Pd2(dba)3               NHR
                        BINAP                            n-hexyl       0.5           2             88
                        NaOtBu                             Bn          0.5           4             79
             +   RNH2
                        Toluene
                        80oC                               Bn          0.05          7             79
                                                        Cyclohexyl     0.5           18            83

Compared with 35% when using P(o-tolyl)3 and R = n-hexyl
             J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. Soc. 1996, 7215.
               BINAP Reaction Mechanism
                                            Pd2(dba)3 + BINAP



                                             (BINAP)Pd(dba)


                            ArNRR'
                                                (BINAP)Pd              ArBr




                     (BINAP)Pd(Ar)[NRR']                      (BINAP)Pd(Ar)(Br)

                        t
               NaBr + HO Bu
                                                     NHRR'

                                              (BINAP)Pd(Ar)(Br)
                                        t
                                     NaO Bu


Believed to proceed via a different mechanism to the cycle involving P(o-tolyl)3
The phosphine does not appear to dissociate before oxidative addition or
coordination of the amine
                     Catalyst development
Hartwig developed a dppf based system that shows enhanced catalytic qualities

                                                PPh2
                                      Fe
                                                      PdCl2

                                                P
                                                Ph2

Good for primary amines and works on electron deficient aryl halides

        R                                  5mol% (DPPF)PdCl2     R
                                   t             DPPF
                     X + H2NR + NaO Bu                                        NHR
                                                  THF
                                               100oC/~3h


Concepts highlighted by Hartwig:
• “The catalytic cycle involves bis-(phosphine) intermediates”
• “Sterically encumbered phosphines are not necessary for high-yielding ,
  intermolecular amination of aryl halides”
• “Favourable selectivity for reductive elimination over b-hygrogen elimination
  results from chelation and large bite angle, rather than from steric effects”

                 M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1996, 1133.
                                  Mechanistic Aspects
Some chelating ligands favour decomposition of ligand backbone via C-P bond
cleavage as apposed to any C-N bond formation.
                                                 PPh2
                   Ph3P           NAr 2
                             Pd            +                                         + HNAr 2 + Pd(0)
                        Ph        PPh3                                        PPh2
                                                 PPh2
                                                                          93 %



DPPP, DPPBz and DPPEn all failed to produce stable amido complexes and no
aryl amine products were observed


                                                  PPh2
Ph3P        N(tolyl)2
                        DPPF
                                          Fe               Ph          85oC
       Pd                                                                        Ph-N(Tolyl)2 + (DPPF)2Pd + (PPh3)4Pd
                                                      Pd               PPh3
 Ph         PPh3                                                                      90 %
                                                           N(tolyl)2
                                                  P
                                                  Ph2
                                               54 %


Works with both aryl bromides and aryl iodides. Works using both primary
aryl- and alkylamines with aryl halides with either edg’s, ewg’s and ortho-
substituents
      Coupling of Secondary Acyclic Amines
                                                                                                     Bu
                                                   0.25 mol% Pd2(dba)3
                             Br                     0.75 mol% Ligand                                 N
                                                                       t                                    Bu
                                                    1.4 equiv. NaO Bu
                                   +    Bu2NH
                                                           toluene
         t-Bu                                               80oC                 t-Bu



                      NMe2                                                      NMe2                         OMe

                   PPh2                          PPh2                         PPh2                        PPh2
           Fe                          Fe                      Fe                            Fe


                   PPh2
    (rac)-BPPFA                    FcPPh2                  (rac)-PPFA                   (rac)-PPF-OMe
   Ligand          Time/h         Conversion/%          Ratio of product/reduced SM     GC yield/%       Isolated yield/%
  P(o-tolyl)3        48                 90                           12.6:1                 83                   77
   BINAP             48                 98                           1:5.2                  8                    -
    DPPF             48                 100                          1:4.9                  9                    -
 (rac)-BPPFA         48                 100                          1.7:1                  18                   -
   FcPPh2            48                 100                          3.0:1                  54                   -
 (rac)-PPFA          24                 100                          12.5:1                 92                   89
(rac)-PPF-OMe        5                  100                          39:1                   97                   93


                  J. Marcoux, S. Wagaw, S. L. Buchwald, J. Org. Chem. 1997, 1568.
                      Coupling of Aryl Triflates
Buchwald:
                                               2 mol% Pd(OAc)2
                                              BINAP or Tol-BINAP
                                                       t
                                                   NaO Bu
                           OTf   +   HNRR'                                          NRR'
                                                   Toluene
            R                                         o
                                                    80 C               R




Hartwig:
                                                1-5 mol% Pd(OAc)2
                                             3-10 mol% BINAP or DPPF
                                                               t
                                                 1.5 equiv. NaO Bu
                           OTf   +   HNRR'                                          NRR'
                                                      Toluene
            R                                             o
                                                       85 C            R




  Both systems use electron rich and electron poor aryl triflates with primary
  and secondary amines (cyclic and acyclic)

                       J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 1997, 1264.
            J. Louie, M. S. Driver, B. C. Hamann, J. F. Hartwig J. Org. Chem. 1997, 1268.
N-Allylation of Anilines Using Allyl Alcohols
 Palladium-Catalysed N-allyation of anilines using allyl alcohols in the
 presence of Titanium(IV) isopropoxide


                                                     R            R

           R
                         HO
                                                                 +
                          Pd(OAc) 2, PPh3                NH             N
                                 i
                          Ti(OPr )4, MS 4A
                NH2



                                                         A              B
                           R                 Yield / %        A/B
                          4-Me                  76            87 : 13
                          4-Cl                  70            87 : 13
                         4-OMe                  56            91 : 9
                        3,5-OMe                 67            87 : 13
                         2,4-Me                 82            90 : 10
                       2-Me, 4-Cl               86            91 : 9

                      W. Chung, S. Yang, Tetrahedron lett. 1999, 953.
Intermolecular Markovnikov Hydroamination
      of vinylarenes with alkylamines
                                                                                   NRR'
                                              5 mol% Pd(O2CCF3)2
                                                 10 mol% DPPF
                                                20 mol% CF3SO3H
     HNRR'     +     R                                               R
                                                          o
                                              Dioxane, 120 C, 24 h




                      Via:                              HNRR'




                                      (DPPF)Pd
                                          OTf

                                                                              Bn           n-hexyl
                                                  HN                     HN          HN
Amines:   HN             O    HN         NR
                                                                         Me           Me
                                                          n = 1,2


  Products formed in 43-79 % yield
                   M. Utsunomiya, J. F. Hartwig, J. Am. Chem. Soc. 2003, 14286.
    Sequential Petasis Reaction / Palladium
  Catalysed Carbonylation / Amination Process
One pot process involving sequential addition of reagents


      X                 O         OR                            X

 Ar                 +                                     Ar
              NH2                                                       N         CO2R
                        O         H
          + R1B(OH)2




          O                                                         X

                        R1                                 Ar
                                      CO (1 atm), Pd(0)                     H            Allene (1 atm), Pd(0)
                                                                            N      R1                            Ar
 Ar       N                                                                                                           N      R1

                        CO2R                                                    CO2R
                                                                                                                          CO2R




                             A. Thayaparan, V. Sridharan, R. Grigg, Tetrahedron lett. 2003, 9017.
   Sequential Petasis Reaction / Palladium
 Catalysed Carbonylation / Amination Process
Examples of compounds formed:

                                   OMe



               O                           O                  O
                                                                              O

               N                           N                      N

                           CO2Et                      CO2Et               CO2Et
               60 %                            56 %               59 %




                                     OMe


           N                                    N             N
                                                                              O

                   CO2Et                              CO2Et           CO2Et
               61 %                            72 %               50 %
     Synthesis of Enamines and Imines
                                                     Pd(OAc) 2/BINAP or
                                                                                             R2
                                                      Pd2(dba)3/BINAP
        R1              Br
                                      R2        R3          NaOtBu                   R1      N
                              +            N
                                           H                Toluene                                R3


Examples:


                                  O

                   N                                         N                                           N



            96 %                                        96 %                                      75 %

                                           O
                                                         O                       O                       O
                              N



                                                         N                       N                       N

                                               Bn                 BnO                     C7H15

                       95 %                          86 %                 96 %                    96 %

       M. Fernández, F. Aznar, C. Valdés, J. Barluenga, Chem. Eur. J. 2004, 494.
                         Other Developments
•   Palladium catalysed carbon-nitrogen have been achieved using resin bound
    techniques:
    Examples using resin bound aryl halides and aryl amines have shown for
    Buchwald-Hartwig coupling. Other processes including asymmetric allylic
    amination have been achieved using resin-supported Palladium complexes.

•   Buchwald-Hartwig reactions have been conducted using microwave chemistry.

•   The Hydroamination of amination of allenes using Palladium catalysis.

•   As well as Aryl Triflates, Aryl Nonaflates and Sulfonates.

•   Aqueous Amination has been demonstrated:


            R                                0.5 mol% Pd2(dba)3
                                                                  R
                                                             o
                                             KOH, Water, 100 C
                        Cl   +   HNR''R'''                            NR''R'''
                                              3-18 h, 84-96 %
                     V. Farina, Y. D. Ward, Tetrahedron lett. 1996, 6993.
                 K. Chapman, C. A. Willoughby, Tetrahedron lett. 1996, 7181.
                  Y. Uozumi, H. Tanaka, K. Shibatomi, Org. lett. 2004, 281.
X. Huang, K. W. Anderson, L. Jiang, A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2003, 6653.
   K. W. Anderson, M. Mendez-Perez, J. Priego, S. L. Buchwald, J. Org. Chem. 2003, 9563.
    R. A. Dommisse, G. L. F. Lemiere, K. T. J. Loones, B. U. W. Maes, Synlett 2003, 1822.
             Carbon-Oxygen bond formation
Buchwald reported formation of 5, 6 and 7 membered oxygen containing heterocycles
                                         3-5 mol% Pd(OAc)2
                    X                4-6 mol% tol-BINAP or dppf                   O
                            R            K2CO3 or NaOtBu                                  R'
                                R'
                                             Toluene
                                                                                          R
                                            80-100oC
                                OH                                                    n
                        n


Mechanism:

                                               Pd(0)              ArBr
                            O


                                Pd
                        O
                                                                                          OH



                                                       OH                Pd(II)

                   Base + HBr                          Pd                Br
                                                            Br



                                     Base


             M. Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1996, 10333.
                  Intermolecular C-O Bond Formation
     Hartwig’s Investigation into the chemistry of palladium aryl alkoxo complexes:

                          X = t-Bu
                          PPh3-d15
                                           Ph-Ph + t-Bu                           t-Bu +             t-Bu + Pd(0)
                                o
                           25-80 C


                      X
                          X = CH(O)
                           PPh3-d15                                     t
                                                                   O Bu + Pd(0)
                               o
                           25-80 C
(DPPF)Pd                                   O
            t
           O Bu
                          X = t-Bu                                 X
                          PPh3-d15                                           o
                                                                        20-75 C
                                                                                                NRR' + Pd(0)
                           HNRR'                                    92-100 %
                            t
                           - BuOH      (DPPF)Pd
                                                   NRR'


      Catalytic aryl ether formation:
                                                           cat. Pd(0)
                                                             DPPF
                  X                   Br   +   NaOtBu                       X     OtBu + NaBr
                                                            Toluene
                                                               o
                                                          100 C / 3h



                             G. Mann, J. F. Hartwig, J. Am. Chem. Soc. 1996, 13109.
  Expansion of the Scope of the Reaction
Buchwald’s system demonstrated applicability to wider variety of alcohol substrates
              X                                                1.5 mol% Pd2(dba)3           OR'
                                                               3.6 mol% Tol-BINAP
  R               +   1.2 equiv. R'OH   +    2.0 equiv. NaH                             R
                                                                    Toluene




These are the alcohols used, the yield of the ether products is between 53-84 %
                      OH

                                                                        t
                                        OH          Ph         OH   NaO Bu       MeOH

                                               OH             OH            OH




                                  OH                                        O




              M. Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 3395.
                             Catalyst development
Hartwig developed method that works with unactivated aryl halides
NaO                          t-Bu
                                                                               t-Bu                                 OMe
                                                               Cat. L/[Pd]
                         +
                  OMe                                  Br
                                                                                                        O

      L = DtBPF, 45 %; L = BINAP, DPPF, P(o-tolyl)3, 0 %; L = P(tBu)3, 27 %; L = PhP(tBu)2, <5 %, FcP(tBu)2, 83 %
                                     t                              FcP(t-Bu)2 =
                                    D BPF =

                                                    P(t-Bu)2                        P(t-Bu)2
                                     Fe                                  Fe


                                                    P(t-Bu)2
                                O                                                          O
Examples:
                                                                  Ph
                                                        OMe
                                     o
                      Cl = 9 h, 80 C, 82 %
                                                                                   12 h, 110 oC, 63 %
                      Br = 12 h, 80 oC, 85 %                            O
                                                            OMe

                                                O



                                                                                         O
                                         24 h, 110oC, 81 %                    3 h, 80oC, 78 %


       G. Mann, C. Incarvito, A. L. Rheingold, J. F. Hartwig, J. Am. Chem. Soc. 1999, 3224.
                          Catalyst Development
      New ligand systems developed by Buchwald for the formation of
      oxygen heterocycles:

                                         P(t-Bu)2


               P(t-Bu)2                                                       P(t-Bu)2              PCy2

                   X                                      X                              Me2N




      1X=H                           3                           4X=H                           7
      2 X = NMe2                                                 5 X = NMe2
                                                                 6 X = i-Pr
Some of these ligands used catalytic reaction:
                                                2 mol% Pd(OAc)2
                                                   2.5 mol% L
                                   OH           1.5 equiv Cs2CO3
                                                     Toluene
                                                      o
                          Br                        70 C, 24 h                            O


                   L = 1, 81 %; L = 3, 81 %; L = 4, 51 %; L = 7, <5 %

              M. Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 2001, 12202.
                       Catalyst Development
Catalyst system used to form 5, 6 and 7 membered rings using 2-3 mol% Pd(OAc)2,
1.5 equiv. Cs2CO3 and 2.5-3.5 mol% 1 or 4 in 65-85 % yield. Cyclisation achieved
with heteroatoms already present in tether chain, an example of this is shown below.
                                OH

                       O                                              O
                                     n-Bu   A, B or C


                       Br                                             O       n-Bu

                      96 % ee                                A = 80 %, 95 % ee
                                                             B = 95 %, 90 % ee
                                                             C = 69 %, 94 % ee

          A = Pd(OAc)2/5, Cs2CO3; B = Pd2(dba)3/5, t-BuONa; C = Pd(OAc)2/1, Cs2CO3


Medicinal target formed using methodology:
                       O

                                     H
                                     N              O             O
                       O
                                                                          .   HCl

                                                                  O
     Room Temperature Catalytic Formation
              of Aryl Ethers
Observation of catalyst degradation by Hartwig led to the development of a more
active catalyst system

                                                                                      P(t-Bu)2

                      P(t-Bu)2                  5 mol% Pd(OAc)2     Ph       Fe     Ph
             Fe                  +   PhCl               t
                                                    NaO Bu
                                                   25-110 oC      Ph                  Ph

                                                                             Ph
                                                                    85 %, Ph5FcP(t-Bu)2

Catalytic system:
                                        5 mol% Pd(dba)2/Ph5FcP(t-Bu)2
                        ArX + NaOR                                       Ar-O-R
                                                      Toluene

                           Ar = Ph, o-Tol, m-OMe-C6H4, p-OMe-C6H4, p-NO2-C6H4
                                            t
                                        R = Bu, TBS and C6H4OMe


          Q. Shelby, N. Kataoka, G. Mann, J. F. Hartwig, J. Am. Chem. Soc. 2000, 10718.
            Q. Shelby, N. Kataoka, G. Mann, J. F. Hartwig, J. Org. Chem. 2002, 5553.
     Room Temperature Catalytic Formation
              of Aryl Ethers
Intermolecular examples:
                                                    MeO



                Ot-Bu                    OTBS                          Ot-Bu    O2N                     Ot-Bu


 X = Br, RT, 17 h, 96 %   X = Br, RT, 14 h, 79 %      X = Br, RT, 9 h, 98 %         X = Br, RT, 19 h, 77 %
                                                      X = Cl, RT, 5 h, 93 %                   o
                                                                                    X = Cl, 80 C, 6 h, 92 %




  Intramolecular examples:


                                                           n                             n


                               O                         O                             O
                  o                     n = 1, RT, 5 h, 59 %            n = 1, RT, 15 h, 77 %
               80 C, 0.5 h, 58 %
                                        n = 2, RT, 0.5 h, 64 %          n = 2, RT, 10 min, 93 %
    Oxygen Nucleophiles in Palladium
     Catalysed Allylic Substitutions
                                                 2.5 mol% Pd2(dba)3-CHCl3           O
                      AcO         O
                                                          5 mol% dppe
R                                                          KF/alumina
                  +                      OEt                                              OEt
                                                           THF, RT
             OH
                                                                                    OAr
        R = o-CHO, o-CO2Me, o-CO2CH2Ph, o-CN, m-NHCOMe, m-OMe, p-OMe, p-CHO, p-Cl



                                                                                    R''
                                               0.5 equiv. Et2Zn
                  OAc                                                         O
                                               5 mol% Pd(OAc)2
                                                 7.5 mol% L
                             +   HOR''
    R                   R'                         THF, RT              R           R'



                                 L=



                                               P(t-Bu)2

             O. Roy, A. Riahi, F. Hénin, J. Muzart, Tetrahedron 2000, 8133.
                             H. Kim, C. Lee, Org. lett. 2002, 4269.
    Addition of Acidic OH Groups across Dienes

                                            1 mol% [Pd(PPh3)4]
                                 +   ROH                                           OR
                                             Toluene, RT, 24 h



Works for aryl alcohols and carboxylic acids in 44-73 %. Also works with acyclic dienes.


                             O                                       O




                                             t-Bu                                       t-Bu
                       63 %, E/Z 88:12                           59 %, E/Z 89:11

                 OMe

                         O
                                                                         O
               MeO

                                           t-Bu                              O
                             62%                                 41 %, E/Z 85:15


            M. Utsunomiya, M. Kawatsura, J. F. Hartwig, Angew. Chem. Int. Ed. 2003, 5865.
Stereoselective Synthesis of Tetrahydrofurans
 Wolfe reported generation of Tetrahydrofurans with 4 possible stereocentres
                      R3                                                           R1
                                                     1 mol% Pd2(dba)3                        O
    R1                            OH                                                                        R4
                                       +   R6Br      2 mol% DPE-Phos                *    *         *
                                                                             R6
                                                                    t
                                                      2 equiv. NaO Bu                                       R5
                       R4        R5
                 R2                                   THF, 65 oC, 2 h                    *         *
                                                                                        R2             R3

           R1 = H or Me                    R2 + R3 = H or Ph                 R4 + R5 = H, Me, Ph



   R6Br = Ph                      Br         Me                         Br    MeO                            Br




                            Br
           Ph
                                                    Br

                                                                              Br
                                 MeO
                                                               Br

                      M. A. Rossi, J. P. Wolfe, j. Am. Chem. Soc. 2004, 1620.
               Stereoselective Synthesis of
                    Tetrahydrofurans
Stereoselective examples:
                                     O                                                 O
                                             Ph



         MeO                                            Me
                                                                               Ph

                    62 %, >20:1 dr                                 51 %, 18:1 dr

                                                             O




                           MeO
                                                                  Ph

                                         84 %, 2:1 dr
                                                                                   O
                   H           O                                           H
                                                                          H
        Ph
                                               MeO
                                                                                           H


                55 %, 5:1 dr                                     69 %, >20:1 dr
                       Stereoselective Synthesis of
                            Tetrahydrofurans
                                                          H        R
                                                                                              H           H
     Mechanism:                                      O                                                O
                                                                               R'                             R

                                               R1              H
                                                          Pd
                                                                    Br               Ar
                                   A                 Ar                                   Not observed




                                                                                Ar            H       R
R1                            OH                Ar        H        R
                                                                                     O
                                                                               Pd
                                       B       Pd
                                                     O
                      R                                                         R1                H
          t                                                    H
     + NaO Bu + LnPd(Ar)Br                      R1
                                                                                          H
              C
                   H                                          H                               H           H
                              R'                                          R'                          O
                                                                               R'                             R
     R        O                            R         O
                  Pd                                      Pd
                       Ar H                                        Ar H
          H                                     H                                    Ar
                                                                                              Observed
                            Natural Products
There are many natural products and medicinal targets containing Carbon-Nitrogen
and Carbon-Oxygen bonds.

Sequence of intermolecular Buchwald-Hartwig, oxidative cyclization and Stille
coupling used to form product shown below

                                  HO


                                                     OH




                                        N
                                        H
                             HO



                             Carbazomadurin A



                       J. Knöll, H. Knölker, Chem. Commun. 2003, 1170.
                              Natural Products

Intramolecular Buchwald-Hartwig coupling:


                                                                O

                                O

                                     HN
                                                       N
                                    HO

                                              H

                                                  NH
                                          N

                                                       i
                                                           Bu
                                          O

                                     (-) - Asperlicin

               F. He, B. M. Foxman, B. B. Snider, J. Am. Chem. Soc. 1998, 6417.
                               Natural Products
Intramolecular Aryl ether formation in natural products and medicinal targets.

                               HO




                                                O


                                                           OH
                                    (+) - Heliannuol D

                           O

                                      H
                                      N               O               O
                           O
                                                                            .   HCl

                                                                      O
                                           MKC-242

    H. Kishuku, T. Yoshimura, T. Kakehashi, M. Shindo, K. Shishido, Heterocycles, 2003, 125.
            M. Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 2001, 12202.
                          Reviews
                    J. F. Hartwig, Synlett, 1998, 329.
            J. F. Hartwig, Angew. Chem. Int. Ed. 1998, 2047.
      U. Radhakrishnan, Y. Yamamoto, Chem. Soc. Rev. 1999, 199.
             R. Stürmer, Angew. Chem. Int. Ed. 1999, 3307.
D. Prim, J. Campagne, D. Joseph, B. Andrioletti, Tetrahedron, 2002, 2041.

				
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