Bismuth(iii)-catalyzed cycloisomerization and (hetero)arylation of alkynols: simple access to 2-(hetero)aryl tetrahydrofurans and tetrahydropyrans

Abstract

2-(Hetero)aryl tetrahydrofurans and tetrahydropyrans were successfully synthesized using Bi(OTf)3-catalyzed hydroalkoxylation (cycloisomerization) of alkynols (via 5 or 6 exo-dig cyclization) and intermolecular (hetero)arylation. This reaction involves a highly efficient cascade process, where initially the alkynol undergoes a cycloisomerization step via activation of the triple bond and generates the oxocarbenium ion, which subsequently participates in the (hetero)hydroarylation step with electron-rich arenes. Simple to complex suitably functionalized alkynols (4-pentyn-1-ols and 5-hexyn-1-ols) and electron-rich aromatic compounds were found to be reliable substrates in this cascade transformation and furnished a wide range of oxygen heterocycles. This practical tandem process provides a means to build libraries related to pharmacologically active molecules and natural product like scaffolds.

Divergent Synthesis of Oxepino-Phthalides and [5,5]-Oxaspirolactones through [2 + 2 + 2]- and [2 + 3]-Annulation of Alkynyl Alcohols with α-Ynone-Esters

“…Other Brønsted acid catalysts p -TsOH, PPTS, AcOH, TFA, and 1.0 N HCl (aqueous), were incompatible with this transformation (see Table S1). Next, the screening of other π- and σ-activating catalysts (BiCl 3 , InCl 3 , FeCl 3 , AgOTf, AuCl, PPh 3 AuCl-AgOTf, Pd(P(Ph) 3 ) 4 and Pd(OAc) 2 ) delivered only 5aa in low to moderate yield (12–48% yield) as we observed in our earlier investigations (see Table S1). , However, RuCl, RhCl(PPh 3 ) 3 , and NiCl 2 (known to facilitate [2 + 2 + 2]-cycloaddition) failed to promote this reaction (see Table S1).…”

“…With optimal reaction conditions in hand, we set out to investigate the reaction scope concerning 4-pentyn-1-ols 1 (possessing primary hydroxyl and terminal alkyne groups) and α-ynone-esters 3 . The reactions of cyclohexane- and cyclopentane-derived 4-pentyn-1-ols , with diverse α-ynone-esters having phenyl, p -tolyl, p -ethylphenyl, p -flourophenyl, and p -nitrophenyl substituents cleanly furnished corresponding oxepino-phthalides 4aa-ae , 4ba-bd in good yields (75–82%). Similarly, annulation of gem-dimethyl- and gem-diphenyl-substituted 4-pentyn-1-ols with various α-ynone-esters delivered respective oxepino-phthalides 4ca-4cd , 4da-dd in good yields (71–80%).…”

“…While the precise reaction mechanism requires further investigation, based on results obtained in this work (scheme – ) and earlier reports, − we propose plausible mechanistic pathways for this Brønsted acid-catalyzed [2 + 2 + 2]- and [2 + 3]-annulation cascades (Scheme ).…”

“…Phthalides have been used as key intermediates in synthesizing pharmaceuticals, natural products, and heat-resistant polymers. Further, many natural products possessing [5,5]-oxaspirolactones were isolated recently and known to display prominent biological profiles. ,, …”

Metal‐Free Intramolecular Hydroalkoxylation of Alkyne: Recent Advances

“…A tandem hydroalkoxylation and intermolecular Friedel-Crafts alkylation protocol was reported by Kontham et al for the synthesis of THF/THP-derivatives 61 (Scheme 37). [48] The mechanism followed intermolecular 5/6-exo-dig hydroalkoxylation of various alkynols 62 for the synthesis of exocyclic enol ether Int-H. The exocyclic enol ether Int-H upon trapping with substituted benzene 63 formed substituted THF/THPderivatives 61.…”