A New Approach to 2,3-Disubstituted Benzo[b]furans from o-Alkynylphenols via 5-endo-dig-Iodocyclisation/Palladium-Catalysed Reactions

Abstract

The 5-endo-dig-iodocyclization of o-alkynylphenols with iodine in the presence of NaHCO 3 at room temperature produces functionalised 2-substituted-3-iodobenzo[b]furans, which are useful synthetic intermediates for the preparation of 2,3-disubstituted benzo[b]furans via palladium-catalysed reactions.

Synthesis of 2,3-Disubstituted Benzo[b]furans by the Palladium-Catalyzed Coupling ofo-Iodoanisoles and Terminal Alkynes, Followed by Electrophilic Cyclization

“…In order to form a furan moiety, the oxygen of the methoxy group has to undergo a five endo-dig attack on the carbon-carbon triple bond. The failure to undergo the desired cyclization in entries 19,20,21,22 and 25 is possibly due to more favorable formation of a "vinylic" cation on the carbon of the triple bond next to the aryl group bearing the methoxy group, instead of on the more remote carbon (see the later mechanistic discussion). Similarly, a methoxy group para to the triple bond increases the electron density on the distal end of the triple bond (Figure 1), which favors electrophilic attack at that position and disfavors a five endo-dig cyclization.…”

Highly Potent Naphthofuran‐Based Retinoic Acid Receptor Agonists

“…[16,[31][32][33] Common electrophiles [31,34] activate the alkyne for intramolecular addition of the oxygen lone pair. Iodine has been most useful in this regard, [31] but other activators such as NIS, ICl, and PhSeCl [31,33] work equally well.…”

“…This reactivity pattern is also observed upon activation of the alkyne with transition metals. [35][36][37] We first selected the conditions reported by Arcadi et al, [16,17] which use solutions of I 2 in alcohols (ethanol, methanol) in the presence of sodium bicarbonate. Using methyl ethers such as 7, the substrates favored by Larock and colleagues, [31] starting materials were recovered.…”

“…For a straightforward entry into the collection of arotinoids with a naphthofuran scaffold (a study expanded to benzofuran analogues as well) we used the iodine-induced 5-endo-dig cyclization of o-methoxynaphthyl-(and o-methoxyphenyl)ethynyl benzoates. [16,17] Diverse aryl, alkenyl, and alkynyl substituents were then appended using Suzuki/Sonogashira coupling reactions. Remarkably, all the steps including the final saponification were carried out with short reaction times and high yields using microwave irradiation.…”

“…The synthesis of 8 would, in turn, be based on a 5-endo-dig cyclization of the precursors o-phenylalkynyl ethers 7 (or the corresponding phenol, R = H), [16,17] themselves acquired via a Sonogashira coupling reaction [18,19] of the o-haloaryl alkyl ethers. In addition, we extended the study to the corresponding di-tert-butylbenzofuran positional isomers 12 and 15 given the fact that di-tert-butylphenyl- [20][21][22][23] and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene [11] are the most popular structural surrogates of the trimethylcyclohexene hydrophobic ring of native retinoids.…”