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Issue 24, 2006
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Insights into the mechanism of the site-selective sequential palladium-catalyzed cross-coupling reactions of dibromothiophenes/dibromothiazoles and arylboronic acids. Synthesis of PPARβ/δ agonists

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Abstract

A reactivity study, aided by NMR spectroscopy, allowed a mechanistic rationale to be postulated for the palladium-catalyzed regioselective coupling of arylboronic acid (and arylstannane where feasible) at the position next to the sulfur atom in functionalized dibromothiophenes and dibromothiazoles. The analysis of the NMR spectra (using 19F from the boronic acid CF3 group and 31P from the phosphine of the catalyst as probes) of the entire reaction starting from the dibromoheterocycles allowed the qualitative proposal that the transmetalation is the rate-limiting step for both sequential substitution processes. The extremely facile oxidative addition at the C–Br bond next to the sulfur atom of the heterocycle instead determines the positional selectivity. An additional Stille reaction then replaced the second halogen, providing the trisubstituted heterocyclic scaffolds of PPAR ligands, which displayed PPARβ/δ agonist activity, as revealed by reporter assays in living cells.

Graphical abstract: Insights into the mechanism of the site-selective sequential palladium-catalyzed cross-coupling reactions of dibromothiophenes/dibromothiazoles and arylboronic acids. Synthesis of PPARβ/δ agonists

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Publication details

The article was received on 24 Aug 2006, accepted on 26 Oct 2006 and first published on 13 Nov 2006


Article type: Paper
DOI: 10.1039/B612235C
Citation: Org. Biomol. Chem., 2006,4, 4514-4525
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    Insights into the mechanism of the site-selective sequential palladium-catalyzed cross-coupling reactions of dibromothiophenes/dibromothiazoles and arylboronic acids. Synthesis of PPARβ/δ agonists

    R. Pereira, A. Furst, B. Iglesias, P. Germain, H. Gronemeyer and A. R. de Lera, Org. Biomol. Chem., 2006, 4, 4514
    DOI: 10.1039/B612235C

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