Sequential palladium-catalysed C- and N-arylation reactions as a practical and general protocol for the synthesis of the first series of oxcarbazepine analogues
After the optimisation of the synthetic route to OXC, we found in the literature an interesting study on the effect of the addition of small amounts of water in the palladium-catalysed amidation reactions. As in our case, the role of water was especially determining when the base was cesium carbonate and the solvents were either toluene or 1,4-dioxane. See:
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Dallas A.S., and Gothelf K.V. J. Org. Chem. 70 (2005) 3321
The only related example reported in the literature was developed by Hartwig's research group and involves the palladium-catalysed α-arylation of 2-acetylthiophene with bromobenzene, rendering the corresponding product in 68% yield. See:
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Hamann B.C., and Hartwig J.F. J. Am. Chem. Soc. 119 (1997) 12382
For a selection of the reaction conditions employed in the optimisation of this step, see the Supplementary data of this paper.
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The tendency of the sulfur atom to strongly coordinate with palladium is well-established. It is anticipated that poisoning the catalyst in this manner will inhibit the reaction progress and therefore account for the long reaction times required for these transformations. See:
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Mowery D.L., Graboski M.S., Ohno T.R., and McCormick R.L. Appl. Catal., B 21 (1999) 157
For additional information on the reaction conditions employed, see the Supplementary data of this paper.
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For an excellent review on the use of polyhalogenated heterocycles in different cross-couplings reactions, and a rational explanation of the electronic behaviour of each of the carbons bearing an halogen, see:
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Schröter S., Stock C., and Bach T. Tetrahedron 61 (2005) 2245
The reported examples for the α-arylation of heteroaromatic ketones often require the use of the more active triflates as the arylating agents to succeed. See:
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Muratake H., Hayakawa A., and Natsume M. Tetrahedron Lett. 38 (1997) 7577