Dehydrochlorination proceeded uneventfully to provide enol ether 32 in 71% yield. Incorporating a methyl substituent at the 5-position of the morpholine proved more challenging: analogous reaction of (S)-2-benzylaminopropan-1-ol (33) with rac-epichlorohydrin (5) unexpectedly afforded 6-regioisomer 30 in 74% yield, again as a ~2:1 mixture of diastereomers; 65 the desired 2,5-disubstituted regioisomer 34 was not observed (Scheme 7). LCMS analysis of the first step in both reactions revealed the formation of a 1:1 mixture of two chlorohydrin diastereoisomers (35 from 31, and 36 from 33), consistent with both enantiomerically pure aminoalcohols reacting similarly with the racemic epoxide. This observation suggested the formation of the 2,6-regioisomer from 33 was occurring in the second step of the reaction. Performing this step at different temperatures (150 °C, 170 °C and 190 °C) had no impact on the outcome; however, the stoichiometry of acid did. Using 1.0 equiv. of 98% H2SO4 led to exclusive formation of the undesired 2,6-disubstituted regioisomer 30. Using 2.0 equiv. of acid, both morpholine regioisomers were observed in a 2:1 ratio, with the 2,6-regioisomer now the minor product. Formation of this regioisomer was suppressed completely when 4.0 (or greater) equiv. of acid were employed; 67,68 under these conditions, morpholine 34 was obtained in 62% yield. We propose chlorohydrin 36 reacts with sulfuric acid to provide the corresponding ammonium sulfate 37. In the presence of a base (for example, sulfate), deprotonation of the ammonium species provides tertiary amine 38 which can form aziridinium species 39 by intramolecular displacement of sulfate. Intramolecular ring-opening of aziridinium ion 39 by the pendant alcohol is disfavored on Scheme 6. Formation of 5-and 6-methyl-substituted 2-chloromethyl morpholines and proposed mechanism of isomerization of 36 to 35 geometric grounds; however, Cossy and co-workers have reported the intermolecular reaction of aziridinium ions with sulfuric acid. Notably, ring-opening by sulfate occurs regioselectively at the more substituted carbon. Thus, irrespective of the starting aminodiol, this pathway delivers the same ammonium sulfate species 40. To form the morpholine product, sulfate transfer affords ammonium sulfate 41 which can now be intercepted directly by the pendant alcohol to afford morpholine product 30. Scheme 7. Formation of 6-methyl-substituted morpholine exocyclic enol ether 32 of chloronium ion 42 and intramolecular ringopening by the pendant alcohol provides an alternative route to the same chloromethyl-substituted morpholine product 30. In the presence of excess acid, we tentatively propose that the amine in 36 is effectively permanently protonated, suppressing formation of aziridinium species 39 and hence the pathway for isomerization (Scheme 6).