Copper-catalyzed regioselective dehydrogenative alkoxylation of morpholinonyl alkenols: application to the synthesis of spirotricyclic dihydropyrans and of trans-fused bicyclic morpholines

Abstract

A base-free, regioselective, and atom-economical approach to morpholine-fused dihydropyrans, by Cu-catalyzed intramolecular dehydrogenative alkoxylation of allylic morpholinols, is described.

Serendipitous synthesis of 2-alkenyl- and 2-aryl-4-thiazolidinones using dithiodiglycolic anhydride

“…There is a relative paucity in flexible and reliable approaches to 2-alkenyl-4-thiazolidinones, despite their potential as versatile building blocks for the preparation of medicinal agents. For example, the appendage of an alkenyl motif to the skeleton of a thiazolidinone could pave the way for harnessing several reactivity modes, including hydroarylation, 18 oxoamination, 19 metathesis, 20 trifluoromethylation, 21 halolactonization, 22 dehydrogenative alkoxylation, 23 and dehydrative coupling. 24 It was recognized that successful implementation of the planned strategy would hinge on our ability to (i) achieve site-selective, (1,2- vs. 1,4-attack of the pendant thiol on the α,β-unsaturated imine), and (ii) control the E / Z geometry of the alkene.…”

Weak-Coordination in C–H Bond Functionalizations Catalyzed by 3d Metals

“…Later in 2019, Zou and co-workers developed a copper-catalyzed efficient protocol for the synthesis of coumestans from readily available 2-hydroxyl-3-arylcoumarins via cross dehydrogenative C–O coupling reactions (Scheme c) . The authors successfully implemented this versatile protocol in the synthesis of various natural products such as coumestrol, 9-methoxy-coumestrol, 8,9-dimethoxy-coumestrol, medicagol, and flemichapparin C. In a similar note, copper-catalyzed dehydrogenative C–H alkoxylation of morpholinolyl alkenols were accomplished by Beng and his co-workers using di- tert -butyl peroxide (DTBP) as an oxidant (Scheme d) . The protocol was extended for the synthesis of various spiro-tricyclic dihydropyrans and of trans -fused bicyclic morpholines with good yields.…”

“…205 The authors successfully implemented this versatile protocol in the synthesis of various natural products such as coumestrol, 9-methoxy-coumestrol, 8,9dimethoxy-coumestrol, medicagol, and flemichapparin C. In a similar note, copper-catalyzed dehydrogenative C−H alkoxylation of morpholinolyl alkenols were accomplished by Beng and his co-workers using di-tert-butyl peroxide (DTBP) as an oxidant (Scheme 105d). 206 The protocol was extended for the synthesis of various spiro-tricyclic dihydropyrans and of transfused bicyclic morpholines with good yields. Notably, 6-endo cyclization was preferred over the 5-exo cyclization irrespective of the substituents present in the alkenes.…”

Progress and prospects in copper-catalyzed C–H functionalization

“…A copper-catalyzed oxidative alkoxylation of allylic morpholinols 213 for the synthesis of morpholinone-fused quaternary dihydropyrans 213 was established. 94 This highly regioselective reaction was carried out using 20 mol% of CuCl as the catalyst along with 2 equiv. of di-tert-butylperoxide (DTBP) as suitable oxidant in DMF (Scheme 82).…”