Abstract
Simultaneous introduction of two different palladium (pre)catalysts, one tuned to promote oxidative addition to (hetero)aryl bromide and another to activate terminal alkyne substrate, leads to productive Pd–Pd transmetalation, subsequent reductive elimination, and formation of disubstituted alkyne. This conceptually novel rational design of copper-free Sonogashira reaction enabled facile identification of the reaction conditions, suitable for the synthesis of alkyl, aryl, and heteroaryl substituted alkynes at room temperature with as low as 0.125 mol % total Pd loading.
Highlights
Contrary to a previous belief, it has been recently postulated by us[19,20] and others[21] that the mechanism of copper-free alkynylation operates through a process that resembles copper cocatalyzed variant, but the role of copper is played by palladium (Scheme 2)
General Representation of Bicyclic Mechanism of Copper-Free Alkynylation That Is Synergistically Catalyzed by Two Pd Species. This is exemplified by the synthesis of many Food and Drug Administration (FDA) approved active pharmaceutical ingredients (APIs),3a,d including Terbinafine (Sandoz, squalene epoxide inhibitor),[5] Ponatinib (Ariad Pharmaceuticals, tyrosine-kinase inhibitor),[6] Tazarotene (Allergan, receptor-selective retinoid),[7] and Eniluracil (GlaxoSmithKline, dihydropyrimidine dehydrogenase inactivator).[8]
Letter introducing a single palladium source/ligand combination that has so far been exclusively applied for the copper-free alkynylation.[3,4]
Summary
Contrary to a previous belief, it has been recently postulated by us[19,20] and others[21] that the mechanism of copper-free alkynylation operates through a process that resembles copper cocatalyzed variant, but the role of copper is played by palladium (Scheme 2). It features simultaneous introduction of two different palladium (pre)catalysts into the reaction mixture, one tuned to facilitate oxidative addition to aryl halide in Pd1Cycle, and another one to activate terminal alkyne in Pd2-Cycle.
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