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Select Organotransition Metal Coupling Reactions: C-C Bond Formation

Since the 1970's, organometallic mediated carbon-carbon and carbon heteroatom bond forming reactions have been of increasing importance in organic synthesis. Benefits include:reactions are catalytichigh functional group tolerancestructurally defined catalytic center allowing for regio and stereo

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Select Organotransition Metal Coupling Reactions: C-C Bond Formation

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    1. Select Organotransition Metal Coupling Reactions: C-C Bond Formation

    3. We will narrow our focus to four widely used reactions: 1) Stille Coupling, 2) the Heck reaction, 3) Suzuki coupling. Before that, we need to define terms Metal center – the transition metal to which the ligand and substrates reversibly coordinate. We will only explore palladium and ruthenium transition metals Ligands – species which donate or accept electron density to and from the metal center. Two common phosphine-based electron donating ligands are triphenylphosphine (PPh3) and tricyclohexylphosphine (PCy3).

    4. Pd(0)-Catalyzed C-C bond formation Although many palladium mediated C-C bond forming reactions are known, we will only explore the Stille, Heck, and Suzuki reactions. These are illustrative of organopalladium chemistry. Pd(0) complexes are common to each of these reactions and are often prepared in situ via a complete pre-equilibrium where air stable palladium salts(Pd(OAc)2, PdCl2, etc.) are reduced to Pd(0). Pd(0)(PPh3)4 is also directly used under inert atmosphere Many new catalysts can run in mixed water/organic solvent systems, minimizing the amount of organic waste - “green chemistry”

    5. Example Organopalladium reactions

    6. The Stille, Heck, and Suzuki reactions all proceed through a Pd(0) catalytic cycle that involve at least three main steps: Oxidative Addition Transmetalation or Insertion Reductive Elimination or b-hydride elimination Stille catalytic cycle, for example

    7. Oxidative Addition For the R-X reactants the X can be a Br or I or another good leaving group such as a sulfonate ester (-O-SO2CF3 = OTf) I > OTf > Br >> Cl For the R-X reactants the most reactive R groups are vinyl, aryl, and allyl Saturated alkyl halides are less reactive and require different reaction conditions. Aryl or vinyl chlorides are often sluggish to react It is called oxidative addition because the oxidation state of the palladium is from (0) to (II)

    10. At the end of the cycle the organic product is formed: either R-R’, or R-A=B, and the catalytically active d18 Pd(PPh3)4 is regenerated to start another cycle. The catalytic cycle involves the formation of carbon-palladium bonds, but unlike many other organometallic species these bonds are unaffected by most functional groups: alcohols, amines, carboxamides, esters, ketones, aldehydes and carboxylic acids.

    11. Stille Coupling

    12. Stille Coupling Oxidative addition is a two electron process Stereochemistry may be maintained on sp2 hybridized alkenyl halides and triflates

    13. Stille Coupling Cis and trans vinyl bromide substrate are synthetically accessible via organoboron chemistry

    14. Stille Coupling Transmetallation (M= Sn) also occurs with retention of configuration and is usually rate limiting Transmetalation co-catalysts are often used

    15. The transmetallation is an exchange reaction between the palladium intermediate and C-Metal where the C becomes bonded to the palladium and Metal-X is released. Transmetallation occurs when compounds where Metal = a main group element (B & Sn, typically) react with the d16 palladium intermediate.

    16. Reductive elimination In the final step of a Stille coupling, the two carbon fragments are joined together forming a new C-C bond. The stereochemistry of the precursors is often preserved in the products. Reductive elimination regenerates the Pd(0) catalytic species and restarts the catalytic cycle

    17. Stille Coupling - example

    18. Heck Reaction

    19. Heck Reaction - mechanism

    20. Heck Reaction - mechanism

    21. Heck Reaction - mechanism

    22. ß-Hydride elimination also occurs with syn stereochemistry. In a Heck reaction, H-X (a strong acid) is sequestered by a base to regenerate the active catalytic species

    23. Heck Reaction - Scope Both carbocyclic and heterocyclic halides can be coupled. Terminal acetylenes are good coupling agents

    24. Suzuki Coupling The Suzuki coupling uses an aryl or vinyl boronic acid (or esters) and a aryl or vinyl bromide or iodide (or triflate). The mechanism is similar to Stille coupling Oxidative insertion, transmetalation, reductive elimination

    25. The reaction requires an oxygen base: this is usually an alkoxide, but also carbonates, and phosphates have been used. Using 9-BBN reagents, alkyl groups can be transferred using Suzuki coupling Intramolecular reactions are also possible:

    26. Both the oxidative addition and the transmetallation steps occur with retention – the method is especially suited for the stereoselective synthesis of conjugated dienes:

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