Insights into the mechanism of the site-selective sequential palladium-catalyzed cross-coupling reactions of dibromothiophenes/dibromothiazoles and arylboronic acids. Synthesis of PPARbeta/delta agonists.
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 PPARbeta/delta agonist activity, as revealed by reporter assays in living cells.
Pereira
Raquel
R
Departamento de Química Orgánica, Universidade de Vigo, 36310, Vigo, Spain.
Furst
Audrey
A
Iglesias
Beatriz
B
Germain
Pierre
P
Gronemeyer
Hinrich
H
de Lera
Angel R
AR
D002384:Catalysis; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047494:PPAR delta / Q000819:agonists*; D048068:PPAR-beta / Q000819:agonists*; D010165:Palladium / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry*; D013876:Thiophenes / Q000737:chemistry*
D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; D013876:Thiophenes; D010165:Palladium