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Oxidative Coupling

Oxidative Coupling. Scott Dufour. Oxidative coupling of aromatic or heterocyclic compounds provides a method for creating aryl-aryl bonds Sometimes, it can be cheaper faster or easier than palladium based routes 1

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Oxidative Coupling

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  1. Oxidative Coupling Scott Dufour

  2. Oxidative coupling of aromatic or heterocyclic compounds provides a method for creating aryl-aryl bonds • Sometimes, it can be cheaper faster or easier than palladium based routes1 • Continual advances in the nature of the oxidant and precisely defined reaction conditions have led to increasing levels of control upon C-C bond formation • Chemoselective C-C vs. C-O bonding, regioselective bonding and stereoselective biaryl bond formation can be now be achieved in many well defined systems

  3. Oxidants • Most recently, the hypervalent iodine complexes: phenyliodine (III) diacetate (PIDA), and phenyliodine(III) bis(trifluoroacetate) (PIFA) have been applied leading to an efficient , highly regioselective, mild non toxic alternative to heavy metals • Vanadium Complexes (VOCl3, VOF3), Thallium and Lead have been found to be reliable oxidative coupling agents; prevented over-oxidations, and enhanced regio selectivety of C-C bond formation between aryl rings • Iron (III) reagents were among the first tested and still have a wide following today; in the synthesis of triphenylenes it has been found the FeCl3 offers the best route of synthesis to these wide range of systems

  4. Hypervalent Iodine2 • Intramolecular biaryl formation using tether strategy has been demonstrated • The key is to use BF3*Et2O to enhance the electrophilicity of the iodine reagent

  5. Mechanistic View • Evidence supports the formation of a single electron transfer complex2

  6. Natural product chemistry led to the coupling of a tricyclic compound (norbelladine derivative) which illustrates the mechanism of using a phenolic substrate for oxidative coupling3 • It was observed that only (CF3)2CHOH at -40 C worked well (70% yield), solvents like CH3CN, benzene, CH2Cl2 gave unsatisfactory results (less than 50% yield)3

  7. Vanadium4 • Uang and co-workers have published a catalytic version of Vanadium Oxidative coupling, where dioxygen oxidizes V(IV) to V(V) without interfering in the coupling • VOCl3 has been used by Kumar in 1999 to synthesize triphenylene structures by oxidative coupling5 • Unsymmetrical triphenylene derivatives. can be obtained in a 50% yield using biaryl substrates

  8. Thallium and Lead6 • Reliable, regio selective • Thought to proceed through a phenoxium cation intermediate, though mechanistic details remain obscure • Benzil derivatives can be synthesized through this oxidative cyclization

  9. Iron(III)1 • First reagents tested • Reagent solubility is an issue • THF, MeNO2, dispersion in water (90%+ yield!) • Bushby, has found that FeCl3/CH2Cl2/methanol provides a superior route to triphenylenes1 • The proposed mechanism is one that involves a repeated cycle of one-electron oxidation, carbon-carbon bond forming and deprotonation steps

  10. Dialkoxylbenzene derivatives owe their extent of oligomerisation to the substitution pattern on their ring. • Meta-dialkoxybenzenes give polymers at their ortho site • Para-dialkoxybenzenes give predominately dimers, presumably because the products contain free 4, 4` sites which lead to bi-products • When those sites are blocked with Br, the yield of the biphenyl is much improved

  11. Ortho-dialkoxybenzenes give cyclic trimers • Blocking the 4-position with a Br forces the reaction to stop at the biphenyl stage in an 85% yield • Oxidation of a mixture of aromatic compounds can be achieved where aromatic A can be mixed with aromatic B to form A-B and not B-B or A-A

  12. Triphenylene Based Liquid Crystalline Polymers7 • These triphenylene cores can have functional polyester end groups • Multigram quantities of pure material are elusive; mixtures of products are produced and their structures are ill defined; extensive chromatography limits quantity. • Bushby has explored a Universal rational synthesis to these problems

  13. The key step is the oxidative coupling of biphenyl with a 1,2-dialkoxybenzene using Fe(Cl3) followed by a methanol reductive work up • Each of the polymers produced gave off white solids which gave clean NMR spectra • This method allows for single isomer main chain polymeric discotic liquid crystals to be prepared on an unprecedented scale

  14. Conclusion • From the continuous effort in the advancement of oxidative aryl coupling, issues such as chemo -, regio- and setereoselectivity now have clear well defined solutions, that have been empirically proven • By using inorganic combined with organic chemistry, researchers can approach oxidative coupling in an elegant way, rather than using “sledgehammer chemistry” • Further research should provide even more selective and universal methods to fashion the link between two aromatic units

  15. References • 1. N. Boden, Bushby Oct 2000 Tet. Letters 41 • 2. Oxidative Aryl Coupling Reactions in Synthesis, pg 483 • 3. H. Tohma, Y. Kita, Tetrahedron, 2001,57, 345 • 4. Oxidative Aryl Coupling Reactions in Synthesis, pg 499 • 5. Oxidative Aryl Coupling Reactions in Synthesis, pg 502 • 6. Oxidative Aryl Coupling Reactions in Synthesis, pg 506 • 7. A.N. Cammidge, R. Bushby, J. Am.Chem Soc. 1995, 117, 924-927

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