One-Pot Synthesis of Triazolobenzodiazepines Through
Total Page：16
File Type：pdf, Size：1020Kb
Communicationmolecules One-Pot Synthesis of Triazolobenzodiazepines CommunicationThrough Decarboxylative [3 + 2] Cycloaddition of One-Pot Synthesis of Triazolobenzodiazepines ThroughNonstabilized Decarboxylative Azomethine [3 Ylides + 2] Cycloaddition and Cu-Free ofClick NonstabilizedReactions Azomethine Ylides and Cu-Free Click Reactions Xiaoming Ma 1,†, Xiaofeng Zhang 2, †, Weiqi Qiu 2, Wensheng Zhang 3, Bruce Wan 2, Jason Evans 2 and Wei Zhang 2,* Xiaoming Ma 1,†, Xiaofeng Zhang 2,†, Weiqi Qiu 2, Wensheng Zhang 3, Bruce Wan 2, Jason1 School Evans of Pharmaceutical2 and Wei Zhang Engineering2,* and Life Science, Changzhou University, Changzhou 213164, China; [email protected] 1 School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou 213164, China; 2 Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA [email protected] 02125, USA. [email protected] (X.Z.); [email protected] (W.Q.); [email protected] 2 Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, (B.W.); [email protected] (J.E.) USA; [email protected] (X.Z.); [email protected] (W.Q.); [email protected] (B.W.); 3 [email protected] of Science, Jiaozuo (J.E.) Teachers’ College, 998 Shanyang Road, Jiaozuo 454100, China; 3 [email protected] of Science, Jiaozuo Teachers’ College, 998 Shanyang Road, Jiaozuo 454100, China; [email protected] ** Correspondence:Correspondence: [email protected]; [email protected]; Tel.: Tel.: +1-617-287-6147 +1-617-287-6147 † These These authors authors contribute contributedd equally equally to to this this work. work. Received: 16 January 2019; Accepted: 5 February 2019; Published: 8 February 2019 Received: 16 January 2019; Accepted: 5 February 2019; Published: 8 February 2019 Abstract: A one-pot synthesis of triazolobenzodiazepine-containing polycyclic compounds is Abstract:introduced.A The one-pot reaction synthesis process ofinvolves triazolobenzodiazepine-containing a decarboxylative three-component polycyclic [3 + 2] compounds cycloaddition is introduced.of nonstabilized The reactionazomethine process ylides, involves N-propargylation, a decarboxylative and three-componentintramolecular click [3 + reactions. 2] cycloaddition of nonstabilized azomethine ylides, N-propargylation, and intramolecular click reactions. Keywords: one-pot synthesis; decarboxylative [3 + 2] cycloaddition; nonstabilized azomethine Keywords:ylides; clickone-pot reaction synthesis; decarboxylative [3 + 2] cycloaddition; nonstabilized azomethine ylides; click reaction 1. Introduction 1. Introduction Triazolobenzodiazepines and related scaffolds are privileged heterocyclic systems for Triazolobenzodiazepines and related scaffolds are privileged heterocyclic systems for biologically biologically active molecules, such as benzodiazepine-bearing bretazenil [1], midazolam [2]; active molecules, such as benzodiazepine-bearing bretazenil [1], midazolam [2]; protease inhibitors [3], protease inhibitors [3], alprazolam [4], estazolam [5], and triazolam [6] (Figure 1). Due to their alprazolam [4], estazolam [5], and triazolam [6] (Figure1). Due to their medicinal significance, the medicinal significance, the development of synthetic methods for triazolobenzodiazepine-bearing development of synthetic methods for triazolobenzodiazepine-bearing compounds continuously compounds continuously attracts the attention of organic and medicinal chemists [7–9]. attracts the attention of organic and medicinal chemists [7–9]. Figure 1. Biologically active triazolobenzodiazepine-related molecules. Figure 1. Biologically active triazolobenzodiazepine-related molecules. Highly efficient and atom economic synthesis such as one-pot reactions and multicomponent reactionsHighly (MCRs) efficient have and gained atom increasing economic popularity synthesis in such the synthesizing as one-pot reactions of complex and molecules multicomponent including triazolobenzodiazepine-typereactions (MCRs) have gained compounds increasing [10 popularity–15]. For example, in the synthesizing the Martin group of complex reported molecules a cascade reductiveincluding triazolobenzodiazepine-type amination and intramolecular compounds [3 + 2] cycloaddition [10–15]. For reactionexample, sequence the Martin for group triazole-fused reported 1,4-benzodiazepines (Scheme1A) [ 10,11]. The Djuric group modified the van Leusen imidazole synthesisMolecules 2019 to, develop24, x; an intramolecular azide-alkyne cycloaddition for imidazole-www.mdpi.com/j and triazole-fusedournal/molecules benzodiazepine compounds (Scheme1B) [ 12]. The Kurth group reported a Lewis acid-catalyzed Molecules 2019, 24, 601; doi:10.3390/molecules24030601 www.mdpi.com/journal/molecules MoleculesMolecules 2019 2019, ,24 24, ,x x 22 ofof 88 aa cascadecascade reductivereductive aminationamination andand intramolecularintramolecular [3[3 ++ 2]2] cycloadditioncycloaddition reactionreaction sequencesequence forfor triazole-fusedtriazole-fused 1,4-benzodiazepines1,4-benzodiazepines (Scheme(Scheme 1A)1A) [10,[10,11].11]. TheThe DjuricDjuric groupgroup modifiedmodified thethe vanvan LeusenLeusen imidazoleimidazole synthesissynthesis toto developdevelop anan intramolecularintramolecular azide-alkyneazide-alkyne cycloadditioncycloaddition forfor imidazole-imidazole- andand triazole-fusedtriazole-fusedMolecules 2019, 24 benzodiazepine,benzodiazepine 601 compoundscompounds (Schem(Schemee 1B)1B) [12].[12]. TheThe KurthKurth groupgroup reportedreported aa LewisLewis2 of 7 acid-catalyzedacid-catalyzed MCRMCR forfor imidazole-imidazole- andand triazole-fusedtriazole-fused benzodiazepinesbenzodiazepines throughthrough sequentialsequential [3[3 ++ 2]2] cycloadditioncycloaddition andand cycloadditiocycloadditionn reactionsreactions (Scheme(Scheme 1C)1C) [13].[13]. IntroducedIntroduced inin thisthis paperpaper isis aa newnew MCR for imidazole- and triazole-fused benzodiazepines through sequential [3 + 2] cycloaddition sequencesequence involvinginvolving decarboxylativedecarboxylative intermolecularintermolecular [3[3 ++ 2]2] cycloadditioncycloaddition ofof nonstabilizednonstabilized and cycloaddition reactions (Scheme1C) [ 13]. Introduced in this paper is a new sequence involving azomethineazomethine ylidesylides followedfollowed byby NN-propargylation-propargylation andand intramolecularintramolecular [3[3 ++ 2]2] cycloadditioncycloaddition forfor decarboxylative intermolecular [3 + 2] cycloaddition of nonstabilized azomethine ylides followed by triazolobenzodiazepinestriazolobenzodiazepines (Scheme (Scheme 1D).1D). N-propargylation and intramolecular [3 + 2] cycloaddition for triazolobenzodiazepines (Scheme1D). SchemeScheme 1. 1. Atom AtomAtom economic economic economic synthesis synthesis of of triazolobenzodiazepines. triazolobenzodiazepines. 1,3-Dipolar1,3-Dipolar cycloadditioncycloaddition ofof primaryprimary aminoamino esters,esters, aldehydes,aldehydes, andand and activatedactivated alkenesalkenes isis aa well-establishedwell-established three-componentthree-componentthree-component reaction reactionreaction [16– 21[1[1].6–21].6–21]. The azomethine TheThe azomethineazomethine ylides derived ylidesylides from derivedderived deprotonation fromfrom deprotonationof iminium ions of are iminium CO R-stabilized ions are CO ylides2R-stabilized A (Figure ylides2A) [ 22 A– (Figure30]. In recent2A) [22–30]. years, ourIn recent lab has years, reported our deprotonation of iminium2 ions are CO2R-stabilized ylides A (Figure 2A) [22–30]. In recent years, our lablaba series hashas reportedreported of azomethine aa seriesseries ylides ofof azomethine azomethine A-based [3 ylidesylides + 2]cycloadditions A-basedA-based [3[3 + + 2] 2] for cycloadditions cycloadditions diverse heterocyclic forfor diversediverse scaffolds heterocyclicheterocyclic [31–35], scaffoldsscaffoldsincluding [31–35],[31–35], one-pot [3includingincluding + 2] and clickone-potone-pot reactions [3[3 ++ 2] for2] and triazolobenzodiazepinesand clickclick reactionsreactions forfor triazolobenzodiazepines [triazolobenzodiazepines32]. Compared to the reactions [32].[32]. ComparedComparedof stabilized toto ylides thethe reactionsreactions A, cycloadditions ofof stabilizedstabilized of nonstabilized ylidesylides A,A, cycloadditionscycloadditions ylides B are less ofof explorednonstabilizednonstabilized (Figure ylidesylides2B) [ 36BB –areare42 ]. lessless We α exploredexploredhave recently (Figure(Figure reported 2B)2B) the[36–42].[36–42]. synthesis WeWe ofhavehave-trifluoromethyl recentlyrecently reportedreported pyrrolidines thethe synthesissynthesis through decarboxylativeofof αα-trifluoromethyl-trifluoromethyl [3 + 2] α pyrrolidinespyrrolidinescycloaddition throughthrough of nonstabilized decarboxylativedecarboxylative azomethine [3[3 ++ ylides 2]2] cyclcycl Boaddition derivedoaddition from ofof nonstabilizednonstabilized-amino acids azomethine [azomethine43]. Presented ylidesylides in this BB derivedderivedpaper is from afrom new αα application-amino-amino acidsacids of nonstabilized [43].[43]. PresentedPresented azomethine inin thisthis paperpaper ylides is inis a thea newnew one-pot applicationapplication [3 + 2] and ofof nonstabilized clicknonstabilized reactions azomethineazomethinefor triazolobenzodiazepines. ylidesylides in in thethe one-potone-pot [3[3 + + 2] 2] and and click click reactionsreactions forfor triazolobenzodiazepines. triazolobenzodiazepines. Figure 2. Azomethine ylides from amino esters or amino acid. FigureFigure