The palladium-catalyzed cross-coupling reaction of iodinanes (iodonium salts and iodanes) with organoboron compounds to form carbon-carbon bonds was achieved at ambient temperature under aqueous conditions in the absence of base. Coupling of phenylboronic acid with diphenyliodonium tetrafluoroborate in the presence of Pd(PPh(3))(4) (0.2 mol %) or Pd(OAc)(2) (0.2 mol %) under aqueous conditions gave biphenyl in almost quantitative yield. Under the same conditions, substituted boronic acids, boronates, and trialkylboranes were readily coupled with diaryl-, alkenyl-, and alkynyliodonium salts. Finally, the iodanes ArI(OH)OTs underwent cross-coupling with boronic acids, boronates, and trialkylboranes to afford biphenyls and aryl-substituted alkenes.
A facile methodology effective in obtaining a set of compounds monofluorinated at various positions (fluorine scan) by chemical synthesis is reported. Direct and nonselective fluorination reactions of our lead compound 1a and key intermediate 2a worked efficiently to afford a total of six monofluorinated derivatives. All of the derivatives kept their physicochemical properties compared with the lead 1a and one of them had enhanced Raf/MEK inhibitory activity. Keeping physicochemical properties could be considered a benefit of monofluorinated derivatives compared with chlorinated derivatives, iodinated derivatives, methylated derivatives, etc. This key finding led to the identification of compound 14d, which had potent tumor growth inhibition in a xenograft model, excellent PK profiles in three animal species, and no critical toxicity.
Copper-catalyzed cross-and carbonylative coupling reactions have been achieved in the reaction of a variety of alkynyliodonium salts with arylboronic acids and organostannanes under the mild reaction conditions in high yield. Our investigation shows that the alkynylidonium tetrafluoroborates are more efficient than those of triflates and tosylates.
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