Chemoselective Flow Hydrogenation Approaches to Diversify the Cytotoxic Tetrahydroepoxyisoindole Carboxamide Scaffold

Abstract

An Intramolecular Diels-Alder cycloaddition reaction between a furan diene and an alkynic dienophile was performed within a flow hydrogenator fitted with an inert titanium column at 150 8C, no H 2 , under 100 bar pressure. A single column pass (t R = 1.6 min) afforded % 55% conversion to the tetrahydroepoxyisoindole carboxamide scaffold with a product turnover of % 0.035 g/h, a 95% improvement over batch procedures. The cycloaddition protocol is performed in water and ethanol, and does not require catalysts or other additives. Quantitative hydrogenation of the resulting dual p-bonds within the oxabicyclo system was effected with either a 10% Pd/Al 2 O 3 or 10% Pd/CaCO 3 catalyst at 20 8C, 20 bar, with full H 2 whereas utilisation of a Raney Ni catalyst under these conditions resulted in a quantitative mono-olefin reduction of the C4-C5 double-bond. With regard to di-olefin reduction, a degree of stereoselectivity was observed with the aforementioned palladium-based catalysts yielding exclusive formation of (R) configuration at C7 while utilisation of a 5% Pt/C (sulfided) catalyst at temperatures below 60 8C promoted the formation of the (S)isomer at C7. Hence this work further highlights that flow-hydrogenation provides unprecedented convenience for establishing robust protocols to effect chemoselective transformations.

Greener Synthesis of Pristane by Flow Dehydrative Hydrogenation of Allylic Alcohol Using a Packed-Bed Reactor Charged by Pd/C as a Single Catalyst

“…We believe that the present flow protocol would be useful in designing a simplified flow-production process of pristane. It should be stated that, although flow hydrogenations of a variety of organic compounds have widely been developed [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], there were no reports on flow dehydrative hydrogenation of allylic alcohols before this work.…”

“…We believe that the present flow protocol would be useful in designing a simplified flow-production process of pristane. It should be stated that, although flow hydrogenations of a variety of organic compounds have widely been developed [18][19][20][21][22][23][24][25], there were no reports on flow dehydrative hydrogenation of allylic alcohols before this work. a variety of organic compounds have widely been developed [18][19][20][21][22][23][24][25], there were no reports on flow dehydrative hydrogenation of allylic alcohols before this work.…”

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

“…In 2018, Gordon and co-workers optimised a continuous-flow protocol for the development of new drug compounds. The authors exploited an H-Cube ® Pro system, which can provide high pressures and temperatures, to facilitate an intramolecular DA reaction [ 450 ]. The apparatus allowed access to the key intermediate 526 in higher throughput than the previously optimised batch mode (0.002 g h −1 vs 0.035 g h −1 ).…”

Recent Progress in Continuous‐Flow Hydrogenation

“…According to some reports, flow reactions could contribute to Diels–Alder reactions. Therefore, an intramolecular Diels–Alder (IMDA) cycloaddition reaction and chemoselective flow hydrogenation were used in the synthesis of the cytotoxic tetrahydroepoxyisoindole carboxamide scaffold (Scheme ) by Gordon and co‐workers . The intermediate was synthesized via the IMDA reaction between the alkyne dienophile and furan diene of 91 with an inert Ti column at 150 °C under 100 bar H 2 pressure.…”