Synthesis of 3-Methoxyazetidines via an Aziridine to Azetidine Rearrangement and Theoretical Rationalization of the Reaction Mechanism

Abstract

The synthetic utility of N-alkylidene-(2,3-dibromo-2-methylpropyl)amines and N-(2,3-dibromo-2-methylpropylidene)benzylamines was demonstrated by the unexpected synthesis of 3-methoxy-3-methylazetidines upon treatment with sodium borohydride in methanol under reflux through a rare aziridine to azetidine rearrangement. These findings stand in contrast to the known reactivity of the closely related N-alkylidene-(2,3-dibromopropyl)amines, which are easily converted into 2-(bromomethyl)aziridines under the same reaction conditions. A thorough insight into the reaction mechanism was provided by both experimental study and theoretical rationalization.

The chemical fate of paroxetine metabolites. Dehydration of radicals derived from 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine

“…The calculated energy barrier for 5 → 9 is 64.7 kJ mol −1 higher than the corresponding barrier for cyclodehydration 5 → 8. This is in line with earlier studies showing that the energy barrier for azetidine ring formation in aminoalcohols 48 or aminohalides 49 can be quite substantial (up to 200 kJ mol −1 ).…”

Recent applications of aziridine ring expansion reactions in heterocyclic synthesis

“…A novel aziridine to azetidine rearrangement protocol has been developed by the conversion of 2-bromomethyl-2-methylaziridines 37. 36 Treatment of aziridines 37 with sodium borohydride is suggested to form a bicyclic intermediate 38 that undergoes reaction with methanol to form the azetidines 39 (Scheme 13). The cyclization of aziridines 37 to the bicyclic intermediate 39, which is in contrast with the well-known chemistry of 2-(bromomethyl)aziridines 37 bearing no additional substituent at C-2-position, was interpreted as the Thorpe-Ingold effect due to the gem-disubstitution at the aziridine carbon atom, resulting in a more favorable geometric positioning of the nucleophilic nitrogen atom with respect to the halogenated carbon atom.…”

Synthesis of 3-functionalized 3-methylazetidines

“…The proposed pathway concurs with the previously reported synthesis of 3-methoxy-3-methylazetidines 3 (R 1 = CH 2 Ar, R 2 = Me, Scheme 3) comprising the smooth ring expansion of 2-bromomethyl-2-methylaziridines 2 via bicyclic aziridinium intermediates 14 upon heating in methanol in the presence of NaBH 4 . 7 In the same study, it has been shown that 3-methoxy-3-methylazetidines 3 can also be obtained starting from 3-bromoazetidines 4 applying the same reaction conditions (NaBH 4 , MeOH, Δ). The latter transformation served as a starting point to thoroughly investigate the synthetic potential of 3-bromo-3-methylazetidines for the preparation of novel 3-substituted azetidines.…”

“…7 Until then, the peculiar rearrangement of 2-(halomethyl)aziridines to 3-haloazetidines had been observed in the literature in only two specific cases. MeOH, Ar Scheme 1.…”

“…7 Aziridine 8 was prepared by reductive cyclization of α,β-dibromoaldimine 7a (R = 4-MeC 6 H 4 CH 2 ), obtained via bromination of 2-methylpropenal 5 and subsequent condensation with 4-methylbenzylamine in the presence of titanium(IV) chloride and triethylamine. 7 In the same work, it has been shown that 3-methoxy-3-methylazetidines 3 were obtained upon treatment of imines 7 (R = CH 2 Ar) with sodium borohydride in methanol under reflux. Considering this smooth imine 7 (R = CH 2 Ar) to azetidine 3 transformation, different reaction conditions were evaluated to obtain 3-bromoazetidine 9 directly from imine 7a.…”