Metal-free one-pot synthesis of 2-substituted and 2,3-disubstituted morpholines from aziridines

Abstract

SummaryThe metal-free synthesis of 2-substituted and 2,3-disubstituted morpholines through a one-pot strategy is described. A simple and inexpensive ammonium persulfate salt enables the reaction of aziridines with halogenated alcohols to proceed via an SN2-type ring opening followed by cyclization of the resulting haloalkoxy amine.

Recent applications of aziridine ring expansion reactions in heterocyclic synthesis

“…144 This group has used a simple and inexpensive reagent ammonium persulfate as an oxidant for aziridine ring-opening with 2-haloethanols. Use of optically pure aziridines in reactions led to the synthesis of chiral morpholines in 95-99% ee but in low to moderate yields.…”

Domino Ring-Opening Cyclization of Activated Aziridines with Indoles: Synthesis of Chiral Hexahydropyrroloindoles

“…Many interesting synthetic routes have been developed for this purpose, e.g., [3 + 2] cycloaddition, electrophilic addition/cyclization, cyclopropanation/ring opening/iminium cyclization (CRI reaction), Fischer indolization, copper catalyzed cyclization of iodo-tryptophans and organocatalytic cascade addition-cyclization, etc . Aziridines , have also been exploited for the synthesis of pyrroloindolines . In 2010, Nakagawa used the annulation protocol to synthesize physostigmine starting from skatole and activated aziridine in the presence of a Lewis acid .…”

Double Functionalization of Styrenes by Cu‐Mediated Assisted Tandem Catalysis

“…We then added an oxidant as a trigger to convert the Cu‐catalyst to stronger Lewis acidic species to promote the ring‐opening reaction (entries 2 and 3). In contrast to PhI(OAc) 2 , (NH 4 ) 2 S 2 O 8 was effective for the smooth and complete consumption of the aziridine intermediate to give the desired product 3a with 62 % yield . After screening of various oxidants and Cu‐catalysts, Cu(pyr) 4 (OTf) 2 proved to be the most suitable (entry 4).…”