molecules Article ArticleAlkylative Aziridine Ring-Opening Reactions Alkylative Aziridine Ring-Opening Reactions Jieun Choi, Taehwan Yu and Hyun-Joon Ha * Jieun Choi, Taehwan Yu and Hyun-Joon Ha * Department of Chemistry, Hankuk University of Foreign Studies, Yongin 17035, Korea; [email protected] (J.C.); [email protected] (T.Y.) Department of Chemistry, Hankuk University of Foreign Studies, Yongin 17035, Korea; * Correspondence: [email protected]; Tel.: +82-31-330-4369 [email protected] (J.C.); [email protected] (T.Y.) * Correspondence: [email protected]; Tel.: +82-31-330-4369 Abstract: In this study, the highly strained three-membered aziridine ring was successfully acti- Abstract:vated as theIn thisaziridinium study, the ion highly by alkylation strained three-memberedof the ring nitrogen aziridine with ringa methyl, was successfully ethyl or allyl activated group, whichas the aziridiniumwas followed ion by by ring alkylation opening of with the ring external nitrogen nucleophiles with a methyl, such ethylas acetate or allyl and group, azide. which Such wasalkylative followed aziridine by ring ring opening opening with provides external an nucleophiles easy route such for the as acetatesynthesis and of azide. various Such N-alkylated alkylative amine-containingaziridine ring opening molecules provides with anconcomitant easy route introduction for the synthesis of an exte ofrnal various nucleophileN-alkylated at either amine- its αcontaining- or β-position. molecules with concomitant introduction of an external nucleophile at either its α- or β-position. Keywords: aziridine; non-activated; aziridinium ion; alkylative; ring-opening; amine; regioselectivityKeywords: aziridine; non-activated; aziridinium ion; alkylative; ring-opening; amine; regioselectivity 1. Introduction Aziridine, a nitrogen-containing three-membered ring,ring, hashas high ring strain similar to oxirane and cyclopropane [[1–12].1–12]. However, the non-activatednon-activated aziridine-bearingaziridine-bearing electron donating group at the ring nitrogen is relatively stable and inert toward almost all nucle- ophiles. It It should should be be activated properly as an aziridinium ion or its equivalent prior to ring-opening reaction, as shown in Scheme1 1[ 13[13,14].,14]. Citation: Choi, J.; Yu, T.; Ha, H.-J. AlkylativeCitation: Choi, Aziridine J.; Yu, Ring-Opening T.; Ha, H.-J. Y Y Alkylative Aziridine Ring-Opening HN Y HN Y R Reactions. Molecules 2021, 26, 1703. Nu: N R Nu: N https://doi.org/10.3390/moleculesReactions. Molecules 2021, 26, x. Nu Nu or H R Y = EWG Y = EDG R Nu 26061703https://doi.org/10.3390/xxxxx Activated azir idine Nu: Academic Editor:editor: Marek M. Y = Electron Attracting Group (EWG) M.Kowalczuk Kowalczuk E E Y Non-activated aziridine N R Received: 2 March 2021 Y = Electron Donating Group (EDG) E = Electrophile Accepted: 15 March 2021 Published: 18 March 2021 Scheme 1. Nucleophilic ring opening of activated and non-activated aziridines.aziridines. Publisher’s Note: MDPI stays neutralneu- The reactivityreactivity ofof non-activated non-activated aziridine aziridine provides provides an an opportunity opportunity to introduce to introduce another an- withtral with regard regard to jurisdictional to jurisdictional claims in functionalother functional group group into the into ring the nitrogen ring nitrogen during during activation activation of the aziridine of the aziridine ring. Electrophiles ring. Elec- publishedclaims in published maps and maps institutional and insti- affil- fortrophiles the activation for the activation of non-activated of non-activated aziridine by aziridine bond formation, by bond formation, including carbon–carbonincluding car- iations.tutional affiliations. andbon–carbon carbon–silicon, and carbon–silicon, and by Lewis and acid by (LA) Lewis coordination acid (LA) with coordination lone pair electronswith lone at pair the aziri-elec- dinetrons ring at the nitrogen aziridine can ring yield nitrogen aziridinium can ionsyield or aziridinium their equivalents ions or [15 their]. These equivalents electrophiles [15]. includeThese electrophiles haloalkanes, include acyl halides, haloalkanes, trialkylsilyl acyl halides, halides andtrialkylsilyl most Lewis halides acids and [16 most–19]. Lewis How- − ever,acids most[16–19]. aziridinium However, ions most are aziridinium quite reactive ions towardare quite the reactive counter toward anion the (X counterin Scheme anion2 ) Copyright: © 2021 by the authors. Li- released(X- in Scheme from reagents2) released of electrophiles from reagents as aof nucleophile electrophiles to beas brokena nucleophile down [20to –be24 ].broken Intro- Copyright:censee MDPI,© Basel, 2021 Switzerland. by the authors. This Licensee MDPI, Basel, Switzerland. ductiondown [20–24]. of a specific Introduction group with of a concomitant specific group breakage with concomitant of the ring opening breakage by anof externalthe ring article is an open access article distrib- nucleophile is a challenging problem to be solved to boost the synthetic utility of aziridine. Thisuted under article the is terms an openand conditions access article of opening by an external nucleophile is a challenging problem to be solved to boost the To make this possible, the aziridinium ion should be stable as it is a quaternary ammonium distributedthe Creative Commons under theAttribution terms (CC and synthetic utility of aziridine. To make this possible, the aziridinium ion should be stable salt enduring the strain of a three-membered aziridine ring until the external nucleophile conditionsBY) license of(http://creativecom- the Creative Commons as it is a quaternary ammonium salt enduring the strain of a three-membered aziridine reacts for ring opening [25,26]. It means that the nucleophilicity of the counter anion from Attributionmons.org/licenses/b (CC BY)y/4.0/ license). (https:// ring until the external nucleophile reacts for ring opening [25,26]. It means that the nucle- creativecommons.org/licenses/by/ theophilicity reagent of of the the counter electrophile anion from should the be reagent weak enoughof the electrophile for the aziridinium should be ion weak to survive.enough 4.0/). This is a key requirement for the external nucleophile added to the reaction media that Molecules 2021, 26, x; doi: FOR PEER REVIEW www.mdpi.com/journal/molecules Molecules 2021, 26, 1703. https://doi.org/10.3390/molecules26061703 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 1703 2 of 13 Molecules 2021,, 26,, xx FORFOR PEERPEER REVIEWREVIEW 2 of 13 for the aziridinium ion to survive. This is a key requirement for the external nucleophile leadsadded to to ring the opening reaction at media either that its α leads- or β to-position ring opening in a regioselective at either its manner,α- or β-position as shown in in a Schemeregioselective2. manner, as shown in Scheme 2. − SchemeScheme 2.2. AziridineAziridine ringring openingopening eithereither by by a a counter counter anion anion (X (X−−)) ofof anan electrophileelectrophile or or by by an an external exter- nal nucleophile (Nu:) added directly to the reaction vessel. nucleophilenal nucleophile (Nu:) (Nu:) added added directly directly to the to reactionthe reaction vessel. vessel. 2.2. ResultsResults andand DiscussionDiscussion EveryEvery electrophileelectrophile providesprovides anan aziridiniumaziridinium ionion withwith uniqueunique characteristicscharacteristics thatthat leadsleads toto ring-openingring-opening reactionsreactions inin distinctivedistinctive regiochemicalregiochemical pathways;pathways; eithereither “a”“a” oror “b”“b” inin SchemeScheme3 3,, as as summarized summarized in in our our previous previous publication publication [ [27].27]. TheThe ringring substituentsubstituent RR andand thethe −- nucleophilenucleophile (Nu (Nu-)) applied applied inin thethe reactionreaction vessel vessel are are also also crucial crucial to to determine determine regiochemical regiochemi- pathwayscal pathways [27, 28[27,28].]. SchemeScheme 3.3. AziridineAziridine ring opening in eith eitherer ways ways “a” “a” or or “b”. “b”. Activation Activation with with an an alkyl alkyl group group from from anan electrophileelectrophile ((EXEX)) toto makemake thethe aziridiniumaziridinium ionion inin thethe bracket,bracket, followedfollowed byby aziridineaziridine ring-openingring-opening − reactionsreactions withwith anan externalexternal nucleophilenucleophile ((NuNu−−)) for for alkylative alkylative aziridine aziridine ring ring opening. opening. OurOur previousprevious studystudy [[27,28]27,28] showedshowed thatthat thethe reactionreaction ofof aziridineaziridine ((11)) bearingbearing aa 2-2- methylbenzylmethylbenzyl groupgroup as as an an electron-donating electron-donating group group (EDG) (EDG) at theat the ring ring nitrogen nitrogen with with methyl me- trifluoromethylsulfonatethyl trifluoromethylsulfonate (MeOTf) (MeOTf) can provide can provide stable stable aziridinium aziridinium ions suchions such as 2 (Eas =2 Me,(E = − − XMe, = TfO X = TfO) (Scheme−) (Scheme3). Among 3). Among all electrophiles all electrophiles applicable applicable to the activation to the activation of non-activated of non- aziridine,activated theaziridine, alkyl group the alkyl is a group good applicant is a good withapplicant numerous with numerous advantages. advantages. It can provide It can a goodprovide chance a good to introduce chance to a introduce new alkyl groupa new atalkyl the ringgroup nitrogen at the ring and nucleophilesnitrogen and either nucleo- at thephilesα- oreitherβ-carbon