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Benzofuran derivatives R 0070 Synthesis of Benzo[b]furans by Palladium-NHC Catalyzed Ring Closure of o-Bromobenzyl Ketones. -Based on a ring-closure of ketones (IV), an interesting synthetic approach to benzofuran derivatives is described. -(FARAGO, J.; KOTSCHY*, A.; Synthesis 2009, 1, 85-90; Inst. Chem., Eoetvoes Lorand Univ., H-1117 Budapest, Hung.; Eng.) -Mais 19-104

The palladium-catalyzed ring closure of aryl o-bromobenzyl ketones, easily accessible from aromatic aldehydes and 2-bromobenzyl bromide, provides a straightforward route to 2-arylbenzofurans. A study of the ring closure revealed that a heterocyclic carbene based catalyst provides the best results.In nature's collection of biologically active heterocycles, benzo[b]furan derivatives 3 constitute a major group. Their broad range of biological activities and significant pharmacological potentials have generated extensive and enduring efforts toward the synthesis of this important heterocyclic compound class 4 and its representatives in nature. 5 It is not surprising therefore that there is an ever increasing number of synthetic approaches toward the construction of the benzofuran core. The major synthetic strategies involve the cyclization of o-ethynylphenols, 5c,6 the oxidative cyclization of o-vinylphenols, 5a,7 the cyclization of phenoxy ketones, 8 and cyclizations through olefin formation. 9 A more recent approach is based on aromatic nucleophilic substitution as the ring-forming process. d-Halogenated carbonyl compounds and their imine analogs (e.g., orthohalobenzyl ketones and imines) are in equilibrium with their enol and enamine forms, respectively, which are ideally suited for cyclization through a transition-metal-catalyzed C-O or C-N coupling (Scheme 1). Copper 10 catalysts were successfully applied to the synthesis of benzofurans in such an approach, and the analogous palladium-catalyzed ring closure of 1-(o-bromobenzyl)-3,4-dihydroisoquinolines to form the dibenzopyrrocoline skeleton has also been published. 11 Willis and co-workers studied the palladium-catalyzed synthesis of benzofurans and reported 12 that the palladium-DPEphos {bis[2-(diphenylphosphino)phenyl] ether} system in toluene catalyzes the ring closure. Interestingly, the analogous Xantphos-based [Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] system was found to be ineffective.Our present work was aimed at establishing if there are any other palladium-based catalysts that lead to the efficient formation of benzofurans from o-bromobenzyl ketones. From the several routes leading to our key intermediates (e.g., hydration of alkynes, 10c arylation of ketones 12 ) we envisaged the synthesis of the aryl o-bromobenzyl ketones through a sequence of well-established transformations utilizing aromatic aldehydes and 2-bromobenzyl bromide as building blocks.A literature procedure 13 was followed to convert a series of aromatic aldehydes 1a-h into their thioketal derivatives 2a-h by use of propane-1,3-dithiol in the presence of a catalytic amount of nickel(II) chloride (Scheme 2) in dichloromethane. As expected, all reactions worked well and gave the desired 2-aryldithianes 2a-h in excellent yields (Table 1).We utilized the thus prepared dithianes 2a-h as acyl anion equivalents (Scheme 2). Their deprotonation with butyllithium proceeded readily and the anions that formed were quenched by reaction with 2-bromobenzyl bromide (3) (Scheme 2). A...