N-Amino-N-methylmorpholinium Salts: Highly Active Aziridination Reagents for Chalcones

Abstract

A highly effective aziridination reagent, based on Nmethylmorpholine, is reported which effects rapid conversion of chalcones to N-unfunctionalised aziridines at room temperature.Aziridines are highly attractive synthetic intermediates, 2 largely because they can undergo ring opening with a variety of nucleophiles to give functionalised amine products. 3,4 However, alkene aziridination, particularly asymmetric aziridination, is far less well developed than the closely related epoxidation. 5-8 We were attracted by the report of Xu in 2002 that enones can be aziridinated by hydrazinium salt 1 in the presence of NaH (Scheme 1). 9 By analogy with an earlier study, 10 this chemistry was assumed to proceed by deprotonation of 1 to give an N-N ylid (aminimine), which then undergoes Michael addition to the enone followed by ring closure to give the aziridine. An advantage of the method is that it affords N-unsubstituted aziridines which allows flexibility in further functionalising the nitrogen with a choice of activating group. We reasoned that this process had potential for asymmetric aziridination if chiral hydrazinium salts were employed. However, the strong base and carcinogenic solvent employed in this work were unattractive, as were the relatively long reaction times. Therefore, we undertook a study of alternative reaction conditions and report here the discovery of two new base systems as well as a more reactive hydrazinium salt that is particularly convenient to prepare. Scheme 1We began by testing the Xu nitrate salt 1 (2 equiv) for aziridination of chalcone with alternative bases and solvents. Early studies showed that it was possible to use NaOH in MeCN, but the yield of aziridine was low (17% after 18 h). Therefore we prepared alternative hydrazinium nitrate salts by amination of several cyclic amines. While the hydrazinium salts derived from N-methylpyrrolidine and N-methylpiperidine gave comparable or lower yields of aziridine, we were delighted to find that the N-methylmorpholinium nitrate salt 2a (Scheme 2), prepared by amination of N-methylmorpholine (Scheme 2), effected aziridination of chalcone in 95% yield after only three hours under the NaOH/MeCN conditions (Scheme 3). While this result was encouraging, particularly in identifying the reactivity of the morpholine framework, we felt that the procedure used to prepare the hydrazinium nitrate salt 2a from N-methylmorpholine was inconvenient since it required reaction with hydroxylamine-O-sulfonic acid (HOSA) and Ba(NO 3 ) 2 over extended time periods at raised temperatures. Therefore, we were pleased to find that the corresponding iodide salt could be more readily prepared simply by treatment of commercially available N-aminomorpholine 3 with one equivalent of iodomethane in THF at 0°C. The hydrazinium iodide salt 2b was isolated after filtration as a white solid in 77% yield and can be further purified by recrystallisation from EtOH. Under the same NaOH/MeCN conditions, the iodide 2b afforded a slightly lower yield of aziridine than nitrate 2a (Schem...

Nucleophilic reactivities of tertiary alkylamines

“…Tertiary alkylamines are generally used as Brønsted bases in organic synthesis 1–2. On the other hand, many reactions are known, where tertiary amines act as nucleophilic catalysts 3–32. 1,4‐Diazabicyclo[2.2.2]octane (DABCO, 1e ) and quinuclidine ( 1f ), for example, are common catalysts in Baylis–Hillman reactions7 and in cyclopropanations of Michael acceptors 8 .…”

Aminopyridinium iodide as a NH transferring agent for the synthesis of 2-aroyl-3-aryl aziridines

“…A possible general mechanism involving the N-N ylide is proposed to satisfactorily elucidate the generation of Ketoaziridines. A comparison of this procedure with previous work [24][25][26][27][28][29] on the synthesis of N-H ketoaziridines shows that simple one-pot, not expensive starting material and easy workup are the advantage of this direct N-H insertion method.…”

“…The search for the direct aziridination of olefins to prepare N-unsubstituted aziridines is currently an attractive field of research [24][25][26][27][28]. Despite work reported on the synthesis of ketoaziridines, novel and widely applicable methods for the synthesis of them are still in demand.…”

“…Recently, a few method has been reported that tertiary amines such as N-methylmorpholin [25], 1,4-diazabicyclo[2.2.2]octane (DABCO) [26,27]. Quinine chiral tertiary amine [28] and Troger s base [29] can prepare amine imide which reacts with chalcone to give desire aziridinyl ketones (Scheme 1).…”

Asymmetric Aziridination of Chalcone Promoted by Binaphthalene-Based Chiral Amines

“…20 We have found that chiral hydrazinium salts may be easily prepared and isolated from our binaphthylderived amines. For example, we were able to prepare hydrazinium salt (S)-23 from amine (S)-5 in 77% yield simply by stirring the tertiary amine with 1.1 equivalents of DppONH 2 in dichloromethane overnight; filtration then gave the pure salt (S)-23 (Scheme 7).…”