Accessing a Biologically Relevant Benzofuran Skeleton by a One-Pot Tandem Heck Alkynylation/Cyclization Reaction Using Well-Defined Palladium N‑Heterocyclic Carbene Complexes

Well-defined palladium N-heterocyclic
carbene (NHC) complexes were employed in the one-pot tandem Heck alkynylation/cyclization
sequence for preparing biologically relevant benzofuran compounds
under copper-free conditions in a time-efficient step-reduced fashion.
In particular, a series of binuclear palladium complexes, 1b–1e and 2b–2e, of the alkyl-bridged NHC ligands, namely, {1,1′-di-R1-4,4′-R2-di-1,2,4-triazoline-5,5′-diylid-2-ene]
(R1 = i-Pr; R2 = −(CH2)2–, −(CH2)3−), and their mononuclear analogues, trans-(NHC)­PdBr2(pyridine) (3b) and cis-(NHC)­PdBr2(PPh3) (3c), successfully
catalyzed the one-pot tandem Heck alkynylation/cyclization reaction
of 2-iodophenol with a variety of terminal alkyne substrates, yielding
2-substituted benzofuran derivatives. The mononuclear complexes 3b and 3c were nearly half as active as the representative
dinuclear analogue 1c under analogous reaction conditions,
thereby implying that, at the same mole percent of the palladium loading,
the monometallic 3b and 3c and the bimetallic 1c complexes were equally effective as catalysts. The two
sites of the bimetallic complex 1c performed as two separate
independent catalytic sites, displaying no cooperativity effect in
the catalysis. Finally, the practical utility of the aforementioned
catalysts was demonstrated for a representative catalyst 1c through the convenient synthesis of a key intermediate, 3-[2-(benzo­[d]­[1,3]­dioxol-5-yl)-7-methoxybenzofuran-5-yl]­propan-1-ol,
in a total-synthesis protocol of the natural product Egonol.