Time and Temperature Dependent Palladium-Catalyzed Stereo- and Regioselective Alkoxy-arylation of Triple Bonds: Synthesis of (E)/(Z)-1,1-Disubstituted-3-(1-Phenylalkylidene)-1,3-dihydroisobenzofurans

Abstract

The development of synthetic strategies enabling the stereo- and regio-selective synthesis of organic molecules is indispensable in the pharmaceutical industry. This work describes a stereo- and regioselective synthesis of (E)/(Z)-1,1-disubstituted-3-(1-arylalkylidene)-1,3-dihydroisobenzofurans catalyzed by palladium. The DHIBFs are achieved from readily available aryl bromides and ortho-alkyne tertiary alcohols via intermolecular aryl Heck coupling and intramolecular oxo-cyclization of the suitably situated hydroxyl group. Significantly, it was demonstrated that a Z-isomer was formed as a substantial isomer at 80 °C for 6 h, whereas the stable E-isomer was the predominant one at slightly vigorous conditions (100 °C for 12 h). In addition, careful observation has also led to the realization that this double isomerization from Z- to E-isomer was triggered in the NMR tube itself in CDCl3 at room temperature. Significantly, this protocol, for the first time, enabled the synthesis of heavily substituted dihydroisobenzofurans, especially, bearing a tetra-substituted double bond.

Development of novel transition metal-catalyzed synthetic approaches for the synthesis of a dihydrobenzofuran nucleus: a review

“…In 2021, Sreenivasulu and Satyanarayana 74 envisioned a Pd-catalyzed, regio- and stereo-selective construction of Z / E isomers of 1,3-dihydroisobenzofurans 108 & 109 via the aryl Heck coupling of o -substituted tertiary alcohols 106 and substituted aryl bromides 107 . It is a temperature and time-dependent strategy, in which Z -isomer 108 was formed at 80 °C after 4–6 hours of reaction, whereas stable E -isomer 109 was attained at 100 °C after 8–12 hours of reaction (Scheme 18).…”

Recent Advances Towards the Synthesis of Dihydrobenzofurans and Dihydroisobenzofurans

“…The construction of (E)/(Z)-1,1-disubstituted-3-(1-phenylalkylidene)-1,3-dihydroisobenzofurans 181/182 utilizing Pd-catalyzed stereo-and regio-selective alkoxy-arylation of triple bonds was reported by Satyanarayana et al in 2021. [122] The DHIBFs 181/182 were synthesized from o-alkyne tertiary alcohols 179 and aryl bromides 180, respectively, via intermolecular and intramolecular aryl Heck coupling and oxo-cyclization of hydroxyl group as shown in Schemes 59 and 60. The stable Eisomer was detected slightly at robust circumstances of 100 °C for 12 hours, whereas the Z-isomer was created at 80 °C for 6 hours.…”

Recyclable Aliphatic Nitrile-Template Enabled Remote meta-C–H Functionalization at Room Temperature

“…These DGs coordinate with the core metal atom and preferentially route it to the nearest feasible C–H bond in the molecule, resulting in a five- or six-membered metallacyclic transition state with great site selectivity. In this setting, synthetic organic chemists are constantly creating and finding novel DGs and catalysts to achieve C–H bond functionalization beyond proximity. − …”