pharmaceuticals

Review Synthesis of Imidazole-Based Medicinal Molecules Utilizing the van Leusen Imidazole Synthesis

Xunan Zheng 1,2, Zhengning Ma 1,3 and Dawei Zhang 1,*

1 College of Chemistry, Jilin University, Changchun 130012, China; [email protected] (X.Z.); [email protected] (Z.M.) 2 College of Plant Science, Jilin University, Changchun 130062, China 3 Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China * Correspondence: [email protected]; Tel.: +86-431-8783-6471



Received: 10 February 2020; Accepted: 1 March 2020; Published: 3 March 2020


Abstract: Imidazole and its derivatives are one of the most vital and universal heterocycles in medicinal chemistry. Owing to their special structural features, these compounds exhibit a widespread spectrum of significant pharmacological or biological activities, and are widely researched and applied by pharmaceutical companies for drug discovery. The van Leusen reaction based on tosylmethylisocyanides (TosMICs) is one of the most appropriate strategies to synthetize imidazole-based medicinal molecules, which has been increasingly developed on account of its advantages. In this review, we summarize the recent developments of the chemical synthesis and bioactivity of imidazole-containing medicinal small molecules, utilizing the van Leusen imidazole synthesis from 1977.

Keywords: van Leusen; TosMICs; imidazole; synthesis

1. Introduction Imidazole ring, which is widely found in natural products and medical molecules, is one of the most prominent, five-membered, nitrogen-containing, heterocyclic scaffolds. Furthermore, imidazole-based heterocyclic compounds, which possess a vital position in medicinal chemistry, have been playing a central role in the treatment of numerous types of diseases, and new derivatives for medicinal use are being energetically developed worldwide [1–5]. Due to the peculiar structural characteristic of imidazole scaffold with a worthy electron-rich feature, it is advantageous for imidazole groups to combine with various receptors and enzymes in biological systems, through diverse weak interactions, thereby showing a variety of biological activities. At present, a legion of imidazole-containing compounds with high a medical potential as a clinical drug have been widely used to treat diverse types of illnesses, such as antibacterial [6,7], antifungal [8,9], anti-inflammatory [10,11], antiviral [12,13], anti-parasitic [14,15], anticancer [16,17], antihistaminic [18,19], and enzyme inhibition [20,21]. Imidazole and its derivatives encompass a vast range of medical activities, as shown in the following Table1.

Pharmaceuticals 2020, 13, 37; doi:10.3390/ph13030037 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2020, 13, 37 2 of 19 PharmaceuticalsPharmaceuticals 2020 20, 1320, ,x 13 FOR, x FOR PEER PEER REVIEW REVIEW 2 of 219 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 2 of 19 PharmaceuticalsPharmaceuticals 20202020 20,, 131320,, ,,xx 13 FORFOR,, xx FORFOR PEERPEER PEERPEER REVIEWREVIEW REVIEWREVIEW 22 ofof 2 1919 of 19 TabTable 1.le Various 1. Various pharmacological pharmacological activities activities and andchemical chemical structures structures of imidazole of imidazole-based-based molecules molecules. . Table 1.TabVariousle 1. Various pharmacological pharmacological activities activities and and chemical structures structures of imidazole of imidazole-based-based molecules molecules.. TabTablele 1.1.le Various 1. Various pharmacological pharmacological activities activities and andchemical chemical structures structures of imidazoleimidazole of imidazoleimidazole--based-based molecules molecules.. .. PharmacologicalPharmacological Activities Activities ChemicalChemical Structures Structures PharmacologicalPharmacological Activities Activities Chemical Chemical Structures Structures PharmacologicalPharmacological Activities Activities A A ChemicalChemical Structurestructures Structures Cl Cl PharmacologicalPharmacological Activities Activities A ChemicalChemical Structures Structures Cl A A Clll Cll 1 1 OH OH 1 OH Cl Cl 2 2 1 1 N NOH OH 2 1 1 O2N O2N COHH3 COHH3 Cl O N N CH Clll Cll 22 2 AntibacterialAntibacterial 2 N N 3 HN HNN ClN Cl O22N O2N N CNH33 CH3 Antibacterial 2 2 N 3 3 HN N AntibacterialAntibacterialAntibacterial HN HNN N AntibacterialAntibacterial MetroMneiNdtraoznoiNdleazole HN HNN N Metronidazole MeettrrMoonneiiidttdrraoaznzooiidllleeazolle 1 1 2 2 1 2 N 11 N 1 N 22N 2 N N N N N N NN NN NN NN N N N ONH OH N ONH N N OH OH OH OH 4 4 AntifungalAntifungal 3 3 4 AntifungalAntifungal 3 44 4 AntifungalAntifungal 3 3 PhenPhetheynliemthidyalizmoildeazole BifonBiazfonleazole Phenethylimidazole Bifonazole eenneet enemt aazmzooeeazo e oonnaazzooneeazo e PhenPhetthheyyn3lililiemtthiiiddya3lilizmoiildlleazolle Biffon4Biazffoonlll4eazolle 3 4 6 6 5 5 N 33N 3 44 4 O O 6 5 Cl CNl N N O 6 6 5 5 Cl N N N O O Clll Cll N N N N N N NNON O N N N N N N NO F F N NO O AntiAnti-inflammatory-inflammatory F Anti-inflammatory F F SO2NHSO22NH2 Anti-inflammatoryAntiAnti--inflammatoryinflammatory-inflammatory H COH CO SO NH 3 3 SO2 NHSO2 NH H3CO m coxm xSO22NHSO222NH2 H3C H3C7 7 H COH COCi iCi ibico ib H C H33COH3COCimicoxib 3 7 x x H 3C H3C7 7 Ciiimiii5coCcoiimxiiibiibco5 xiib 33 3C77 6 77 6 5 6 H3C 5H5 3C 5 66 6 CH3 CH3 A A 7 7 H3C H C H CH3 A 7 H33C H3CCH CH A A 7 7 CH33 CH3 A A 7 7 N N S S N S N N O O N NN SN S N O O S S Cl Cl N N O H N H N N Cl NN SN S O O 2 2O N N NS HN HN H2N O O N N Clll Cll N 8 8 AntiviralAntiviral H N H NO O N NS HNS 8 Antiviral H22N H2ON O N N HN HN Antiviral O Cl Cl HN HN 88 8 AntiviralAntiviral Cl O O O2N O2N N N Clll Cll O N N 2 O22N O2N CNapraCvNairpirnaevirine 2 2 Capravirine CaaprrCaavaviprrirrnnaeevirrine 8 8 C p C7aiipii a7 ii ii e 8 7 88 8 77 7 N8 N8 N N N 10 10 O N O NN N 10 9 9 2 2N 10 10 9 O2N N N 10 10 O 2N O2NN N 9 9 O22N O2N H3C H3C N N AntiparasiticAntiparasitic H3C N N N Antiparasitic H C H C N N AntiparasiticAntiparasiticAntiparasitic H33CNH3C N N N N Antiparasitic N NN O O O2N O2N O O N N N NimoNiramzoolerazole O2 N O N morazo eO O O22N O2N Ni l 9 9 Nimoo1Nirr0aamzzooo1lllrere0azolle 9 10 N N 99 9 O O 1100 10 N O NH2 NH2 NO2 NO 12 12 11 N N 2 O ONH2 11 N NNO2 NH NH CH CH 12 11 NO NO NH22NH2 3 3 12 12 N NO22NO2 N N CH 12 12 11 11 N N O O N N NNNN 3N N N CH33CH3 O CH3 CH3 N N N N N 3 3 N NN NN NNCHN3 CH3 AnticancerAnticancer O CHO3 NH N NNNN N Anticancer OH OH CH CH H CH3 CH33CH3 HN N CH CH AnticancerAnticancerAnticancer OH N N CH33CH3 Anticancer OH OH H H MiOsoH nMiOidHsoaznoidleazole DacaDrbacaazirnbeazine Misonidazole Dacarbazine MisosoMinn11iiiddsoaazzn11ooiidllleeazolle DacaacaD12rrbacabaazzi12irirnnbeeaziine 11 D 12Db i b i 1111a 11a 1212 12 O O 14 14 a O 14 13 13 aa a 1414 14 13 a a O O 13 13 N CNH3 CH3 13 13 N CH3 N N N CNH CH AntihistaminicAntihistaminic N N CNH33 CH3 N N O O N N N O Antihistaminic N N N N O O AntihistaminicAntihistaminicAntihistaminic NH N N O O He me N N rox arnox an HN MN thiMethipimp epip NH H Cip Cifp if H MHethimepip Ciproxifan Pharmaceuticals 2020, 13, x FOR PEER REVIEW H He mee me HN N rrooxx aaronnx an 3 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW Metthihi1M3meetthipp1iimi3ppepiip H H Ciiippr1oC4xiiiipffar1on4xiiffan 3 of 19 13 H H 14 1133 13 1144 14 A CH3 15 A CH3 15 16 N 16 N N N N N N N Enzyme inhibitor N O EnzymeEnzyme inhibitor inhibitor N O

NO2 NO2 15 16 15 16

OwingOwing to the to thesignificant significant pharmacological pharmacological or biologicalor biological activities activities and and the theenormous enormous medicinal medicinal valuevalue of imidazole of imidazole-based-based molecul molecules, thees, thesynthes synthesis ofi sthe of theimidazole imidazole-skeleton-skeleton small small molecul molecule haes habeens been paidpaid attention attention to by to pharmaceuticalby pharmaceutical chemists chemists and and organic organic synthesis synthesis researchers researchers. However. However, there, there is is stillstill a need a need for afor simple a simple and and efficient efficient way way to construct to construct the theimidazole imidazole heterocyclic heterocyclic skeleton skeleton. In .recent In recent decades,decades, there there have have been been numerous numerous classical classical strategies strategies for forsynthesizing synthesizing this th ringis ring compound compound in the in the laboratorylaboratory, including, including van van Leusen Leusen imidazole imidazole synthesis synthesis [22], [22], Debus Debus-Radziszewski-Radziszewski imidazole imidazole synthesis synthesis [23],[23], Wallach Wallach imidazole imidazole synthesis synthesis [24] [24], etc., etc.Among Among these these synthetic synthetic strategies, strategies, it is it well is well-known-known that that the thevan van Leusen Leusen imidazole imidazole synthesis synthesis based based on TosMICson TosMICs, which, which is the is thecycloaddition cycloaddition reaction reaction, is one, is one of of the themost most convenient convenient and and attractive attractive protocols protocols for thefor thepreparation preparation of imidazole of imidazole-based-based small small molecules molecules, , duedue to its to excellentits excellent advantages advantages like like simple simple manipulation manipulation, easily, easily obta obtainedined raw raw materials materials and and a wide a wide rangerange of substrates, of substrates, which which has hasbeen been developed developed rapidly rapidly in the in thepast past decades decades (Scheme (Scheme 1). 1).

R1 3 2 R1 R (H) 3 Base R 2 1 2 + R (H) Base NR R CH 1NR 2 + N 3 R CH NR Tos NC R (H) 3 Tos NC N R (H) N Scheme 1. General van Leusen imidazole synthesis. Scheme 1. General van Leusen imidazole synthesis.

TosMIC,TosMIC, one one of theof themost most significant significant reactants, reactants, has hasmany many good good features features at room at room temperature, temperature, includinincluding beingg being a stable a stable solid solid and and being being odorless odorless and and colorless. colorless. Since Since it was it was introduced introduced and and applied applied in organicin organic synthesis synthesis by theby theDutch Dutch professor professor van van Leusen Leusen in 1972, in 1972, this this reagent reagent is also is also known known as vanas van Leusen’sLeusen’s reagent. reagent. Up Upto n toow, now, TosMIC TosMIC and and its derivativesits derivatives have have been been recognize recognized asd one as one of the of themost most significsignificant antbuild building ingblocks blocks in nitrogen in nitrogen heterocyclic heterocyclic synthesis, synthesis, which which have have been been fruitfully fruitfully employed employed especiallyespecially in the in thepreparation preparation of imidazole of imidazole-based-based heterocycle heterocycles [25s –[2529]–.29] . Therefore,Therefore, this this review review will will summarize summarize the thedevelopments developments of theof thesynthesis synthesis of imidazoleof imidazole-based-based moleculemolecules, utilizings, utilizing the thevan van Leusen Leusen imidazole imidazole synthesis synthesis, based, based on TosMIon TosMICs fromCs from 1977 1977. It is. It expected is expected thatthat this this review review article article will will be beneficialbe beneficial for fornew new opportunities opportunities to search to search for afor reasonable a reasonable design design for for lessless toxic toxic and and higher higher bioactive bioactive imidazole imidazole-containing-containing drug drugs. s.

2. General2. General van van Leusen Leusen Imidazole Imidazole Synthesis Synthesis In 1977,In 1977, van van Leusen Leusen et al. et firstal. first published published that that TosMIC TosMIC and and aldimine aldimine under undergo ago base a base-induced-induced 1 2 cycloadditioncycloaddition reaction reaction in a in proton a proton solvent solvent, meanwhile,, meanwhile, the theeffects effects of R of and R1 and R on R2 theon theform formationation of 17 of 17 werewere qualitatively qualitatively analyzed. analyzed. They They discovered discovered that that α- tosylbenzylα-tosylbenzyl isocyanate isocyanate and and α- tosylethylα-tosylethyl isocyanateisocyanate 18 could18 could form form 1,4,5 1,4,5-trisubstituted-trisubstituted imidazoles imidazoles 19 (Scheme19 (Scheme 2). 2)Based. Based on onthe thevarious various advantagesadvantages of this of this reaction, reaction, it is it widely is widely named named as the as thevan van Leusen Leusen imidazole imidazole synthesis synthesis [22]. [22].

R1 R3 2 R1 R3 base R 2 1 2 + base NR R CH 1 NR 2 + - N R3 R CH NR Tos NC TosH- R3 Tos NC TosH N N R3=H,Me,Ph R3=H,Me,Ph 17 18 19 17 18 19 Scheme 2. The first example of van Leusen imidazole synthesis. Scheme 2. The first example of van Leusen imidazole synthesis.

As shownAs shown in Scheme in Scheme 3, the 3, thevan van Leusen Leusen imidazole imidazole synthesis synthesis allo allows thews thepreparation preparation of imidazole of imidazole throughthrough [3 + [3 2] + cycloaddition 2] cycloaddition reaction reaction from from aldimines aldimines and and a reaction a reaction with with TosMICs, TosMICs, which which contain contain reactivereactive isocyanide isocyanide carbon carbons, actives, active methylene methylene, and, and leaving leaving groups groups such such as C2N1 as C2N1 “3- atom“3-atom synthon”. synthon”. Pharmaceuticals 2020, 13, x FOR PEER REVIEW 3 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 3 of 19

A CH3 15 A CH3 15 16 N N 16 N N N N N N Enzyme inhibitor N O Enzyme inhibitor N O

NO2 NO2 Pharmaceuticals 2020, 13, 37 15 16 3 of 19 15 16

Owing to the significantsignificant pharmacological or biological activities and the enormous medicinal value of of imidazole imidazole-based-based molecul molecules,es, the the synthes synthesisis of the of theimidazole imidazole-skeleton-skeleton small small molecul moleculee has been has paidbeen attention paid attention to by pharmaceutical to by pharmaceutical chemists chemists and organic and organic synthesis synthesis researchers researchers.. However However,, there is stillthere a isneed still for a needa simple for aand simple efficient and way efficient to construct way toconstruct the imidazole the imidazole heterocyclic heterocyclic skeleton. In skeleton. recent decades,In recent there decades, have there been have numerous been numerous classical classicalstrategies strategies for synthesizing for synthesizing this ring this compound ring compound in the laboratoryin the laboratory,, including including van Leusen van imidazole Leusen imidazole synthesis synthesis [22], Debus [22-],Radziszewski Debus-Radziszewski imidazole imidazolesynthesis [23],synthesis Wallach [23], imidazole Wallach imidazole synthesis synthesis [24], etc. [ 24Among], etc. Amongthese synthetic these synthetic strategies, strategies, it is well it is-known well-known that thethat van the Leusen van Leusen imidazole imidazole synthesis synthesis based based on TosMICs on TosMICs,, which which is the is thecycloaddition cycloaddition reaction reaction,, is one is one of theof the most most convenient convenient and and attractive attractive protocols protocols for for the the preparation preparation of of imidazole imidazole-based-based small small molecules molecules,, due to its excellent advantages like simple manipulation manipulation,, easily obta obtainedined raw materials and a wide range of substrates, which has been developed rapidly in the past decades (Scheme(Scheme1 1).).

R1 3 2 R1 R3(H) Base R2 1 2 + R (H) Base R N R1CH NR2 + N 3 R CH NR Tos NC R3(H) Tos NC N R (H) N Scheme 1. General van Leusen imidazole synthesis. Scheme 1 1.. GeneralGeneral van van Leusen Leusen imidazole imidazole synthesis synthesis..

TosMIC, one of the most significant significant reactants, has many good good features features at at room room temperature, temperature, includinincludingg being a stable solid and being odorless and colorless. Since Since it it was introduced and applied inin organic synthesis by by the the Dutch professor professor van van Leusen Leusen in in 1972, 1972, this this reagent reagent is is also known as as van Leusen’s reagent. reagent. Up Up to to n now,ow, TosMIC TosMIC and its derivatives have been recognize recognizedd as as one of the most sigsignificantnificant build buildinging blocks in nitrogen heterocyclic synthesis, which have been fruitfully employed especially in the preparation of imidazole imidazole-based-based heterocyclesheterocycles [[2525––2929]].. Therefore, this review will summarize the developments of the synthesis of imidazole-basedimidazole-based moleculemolecules,s, utilizing the van Leusen imidazole synthesis synthesis,, based on TosMI TosMICsCs from 1977.1977. It is expected thatthat this this review article will be be beneficial beneficial for new opportunities to to search search for a a reasonable design for for lessless toxic toxic and and higher bioactive imidazole imidazole-containing-containing drugs.drugs. 2. General van Leusen Imidazole Synthesis 2. General van Leusen Imidazole Synthesis In 1977, van Leusen et al. first published that TosMIC and aldimine undergo a base-induced In 1977, van Leusen et al. first published that TosMIC and aldimine undergo a base-induced cycloaddition reaction in a proton solvent,solvent, meanwhile, thethe eeffectsffects ofof RR11 and R2 on the form formationation of 17 cycloaddition reaction in a proton solvent, meanwhile, the effects of R1 and R2 on the formation of 17 were qualitatively analyzed. They discovered that α-tosylbenzyl isocyanate and α-tosylethyl isocyanate were qualitatively analyzed. They discovered that α-tosylbenzyl isocyanate and α-tosylethyl 18 could form 1,4,5-trisubstituted imidazoles 19 (Scheme2). Based on the various advantages of this isocyanate 18 could form 1,4,5-trisubstituted imidazoles 19 (Scheme 2). Based on the various reaction, it is widely named as the van Leusen imidazole synthesis [22]. advantages of this reaction, it is widely named as the van Leusen imidazole synthesis [22].

R1 R3 2 R1 R3 base R2 R1CH NR2 + base R N 1 2 + os - N R3 R CH NR T NC -TosH R3 Tos NC TosH N N R3=H,Me,Ph R3=H,Me,Ph 17 18 19 17 18 19 Scheme 2 2.. TheThe first first example of van Leusen imidazole synthesis synthesis.. Scheme 2. The first example of van Leusen imidazole synthesis.

As shown in Scheme 33,, thethe vanvan LeusenLeusen imidazoleimidazole synthesissynthesis allowsallows thethe preparationpreparation ofof imidazoleimidazole throughAs shown [3 + 2] in cycloaddition Scheme 3, the reaction van Leusen from imidazole aldimines synthesis and a reaction allows with the preparation TosMICs, which of imidazole contain through [3 + 2] cycloaddition reaction from aldimines and a reaction with TosMICs, which contain reactive isocyanide carbon carbons,s, active methylene methylene,, and and leaving leaving groups groups such such as as C2N1 C2N1 “3- “3-atomatom synthon”. synthon”. reactiveThe cyano isocyanide moiety can carbon be as, gradual active methylene cycloaddition, and to leaving polarize groups a double such bond as C2N1 under “3- aatom base synthon”. condition. The elimination of p-TosOH forms the intermediate 4-tosyl-2-imidazoline to produce the target 1,4,5-trisubstituted imidazoles 19, accompanied by the elimination of p-TosOH, which is negative to the obtained 1,5-disubstituted imidazoles. Pharmaceuticals 2020, 13, x FOR PEER REVIEW 4 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 4 of 19

TheThe cyanocyano moietymoiety cancan bebe aa gradualgradual cycloadditioncycloaddition toto polarizepolarize aa doubledouble bondbond undeunderr aa basbasee condition.condition. TheThe eeliminationlimination ofof pp--TosTosOOHH foforrmmss thethe intermediateintermediate 44--tosyltosyl--22--imidazolineimidazoline toto produceproduce thethe targettarget 1,1,4,4,55-- trisubstituted imidazoles 19, accompanied by the elimination of p-TosOH, which is negative to the Pharmaceuticalstrisubstituted2020 imidazoles, 13, 37 19, accompanied by the elimination of p-TosOH, which is negative to4 ofthe 19 obtainobtaineded 1,51,5--disubstituteddisubstituted imidazoleimidazoless..

R1 O + 2 R 1 O + R 2 NH2 R + R NH2

3 3 3 R1 R 3 R 3 R 3 R 1 ase Tos R N os R ase os R - R2 R Tos N base Tos N R1 N Tos N Tos N base Tos N -TosH R2 T os N base os + R 1 N 2 C Tos N base Tos N os N T N C T N C + R N R C T H N R3 C C R2 R 3 3 3 1 1 N 1 N R R 3 R 3 R 1 N R 1 R 1 N R R R N R N 2 R N 2 N 2 R2 R2 R 2 R2 R2 Ⅰ R Ⅳ 18 Ⅰ Ⅱ Ⅲ Ⅳ 19 18 Ⅱ Ⅲ Ⅳ 19

Scheme 3. Mechanism of van Leusen imidazole synthesis. SchemeScheme 3 3.3.. MechanismMechanism ofof van van Leusen Leusen imidazole imidazole synthesis synthesis.synthesis.. 3. Developments of the van Leusen Imidazole Synthesis 3.3. DDevelopmentsevelopments ofof thethe vanvan LeusenLeusen ImidazoleImidazole SynthesisSynthesis In 1995, Frankowski and co-workers were reported to lead the known D-xylo-pentodialdose to InIn 1995,1995, FrankowskiFrankowski andand coco--workersworkers werewere reportedreported toto leadlead thethe knownknown DD--xyloxylo--pentodialdosepentodialdose toto form imidazo-L-xylo-piperidinose derivatives, based on a sequential eight-step reaction. In this process, formform imidazoimidazo--LL--xyloxylo--piperidinosepiperidinose derivativesderivatives,, basedbased onon aa sequentialsequential eighteight--stepstep reactionreaction.. InIn thisthis the imidazole-base molecule was obtained through a van Leusen reaction as a key step. As shown processprocess,, thethe imidazoleimidazole--basebase moleculemolecule waswas obtainedobtained throughthrough aa vanvan LeusenLeusen reactionreaction asas aa keykey step.step. AsAs shownin Scheme in Scheme4, applying 4, applying this van this Leusen van methodology,Leusen methodology,20 and TosMICand TosMIC18 were transformed were transformed into the shownshown inin SchemeScheme 4,4, applyingapplying thisthis vanvan LeusenLeusen methodology,methodology, 2020 andand TosMICTosMIC 1818 werewere transformedtransformed intoimidazole the imidazole derivative derivative21. At last, removal. At last, ofremoval the protecting of the protecti group gaveng group to the gave target to product the target22, whichproduct is intointo thethe imidazoleimidazole derivativederivative 2121.. AtAt last,last, rremovalemoval ofof thethe protectiprotectingng groupgroup gavegave toto thethe targettarget productproduct a kind, which ofbicyclic is a kind azasugar of bicyclic and azasugar a glycosidase and a inhibitorglycosidase [30 ].inhibitor [30]. 2222,, whichwhich isis aa kindkind ofof bicyclicbicyclic azasugarazasugar andand aa glycosidaseglycosidase inhibitorinhibitor [30].[30].

BnO OH B nO HO OH O B O HO OHC O O . - , N O steps OH OHC O 1 .t -BuOK,DME N O steps OH + Tos NC t u , + T os NC 1. B OK, DM,E HN O T NC 2 .POCll3 Et3N DME O O N BnO O 2.P l3 ,Et3 N,DME HN B nO . OC, 3e 3 , O O N N B O 3 .NH3 ,MeOH ,DME N 3 NH3 MeOH DME N 20 18 21 22 20 18 21 22 21 22 Scheme 4 4.. TheThe van van Leusen methodology as the key step to synthesize glycosidase inhibitor 22. SchemeScheme 44.. TheThe vanvan LeusenLeusen methodologymethodology asas thethe keykey stepstep toto synthesizesynthesize glycosidaseglycosidase inhibitorinhibitor 2222..

In 1998,1998, thethe Sisko Sisko group group synthesized synthesized the the 1,4,5-trisubstituted 1,4,5-trisubstituted imidazole imidazole25, which 25, which displayed display potented bindingIn 1998, with p38the MAPSisko kinase, group a synthesized recently discovered the 1,4,5 protein-trisubstituted kinase that imidazole participates 25 in, which an inflammation displayed potentpotent bindingbinding withwith p38p38 MAPMAP kinase,kinase, aa recentlyrecently discovereddiscovered proteinprotein kinasekinase thatthat participateparticipatess inin anan inflammationregulatory mechanism. regulatory Asmechan shownism in. As Scheme shown5, 1,4,5-trisubstitutedin Scheme 5, 1,4,5-trisubstituted imidazole 24 imidazolewas accessed was by inflammationinflammation regulatoryregulatory mechanmechanismism.. AsAs shownshown inin SchemeScheme 5,5, 1,4,51,4,5--trisubstitutedtrisubstituted imidazoleimidazole 2424 waswas accesseda novel and by a facile novel protocol, and facile based protocol on the, based reaction on the of anreactionα-ketoaldimine of an α-ketoaldimine23 with an aryl-substituted with an aryl- accessedaccessed byby aa novelnovel andand facilefacile protocolprotocol,, basedbased onon thethe reactionreaction ofof anan αα--ketoaldimineketoaldimine 2323 withwith anan arylaryl-- TosMICsubstituted reagents TosMIC18 asreagents the key step as the [31 ].key step [31]. substitutedsubstituted TosMICTosMIC reagentsreagents 1818 asas thethe keykey stepstep [31].[31].

H H NH NH N N

O F O O F O N F O N N N H3C N N H3C H3C steps N K CO H3 s e s H2N N N + K2CO3 3C N t p H2 N N N + K2CO3 N 2 N NH NH Tos NC Tos NC F F F F 23 18 24 25 23 18 24 25 Scheme 5. SynthesisSynthesis of imidazole 25 exhibitexhibitinging potent binding with p38 MAP kinase kinase.. SchemeScheme 5.5. SynthesisSynthesis ofof imidazoleimidazole 2525 exhibitexhibitinging potentpotent bindingbinding withwith p38p38 MAPMAP kinasekinase.. In 2000, they also described an active and gentle procedure for preparing multisubstituted InIn 2000,2000, theythey alsoalso describeddescribed anan activeactive andand gentlegentle procedureprocedure forfor preparingpreparing multimultisubstitutedsubstituted imidazoles in one-pot, from an aryl-substituted TosMIC and a generated imine, in situ. One of the imidazolesimidazoles inin oneone--potpot,, fromfrom anan arylaryl--substitutedsubstituted TosMICTosMIC andand aa generatedgenerated imineimine,, inin situsitu.. OneOne ofof thethe reactions is shown in Scheme 6 6,, cycloadditioncycloaddition ofof imineimine 28, prepared prepared imine in situ from a 40% aqueous reactionsreactions isis shownshown inin SchemeScheme 66,, cycloadditioncycloaddition ofof imineimine 2828,, preparedprepared imineimine inin situsitu fromfrom aa 40%40% aqueousaqueous sosolutionlution ofof pyruvaldehyde pyruvaldehyde26 and and amine amine27, then,, then ketone, ketone29 was prepared was prepared in DMF, usingin DMF aryl-substituted, using aryl- sosolulutiontion ofof pyruvaldehydepyruvaldehyde 2626 andand amineamine 2727,, thenthen,, ketoneketone 2929 waswas preparedprepared inin DMFDMF,, usingusing arylaryl-- substitutedTosMIC 18 andTosMIC K2CO 183 and, with K2CO a 75%3, with yield. a 75% Surprisingly, yield. Surprisingly, when the when reaction the reaction was carried was outcarried at 0 out◦C, substituted TosMIC 18 and K2CO3, with a 75% yield. Surprisingly, when the reaction was carried out atthe 0 product°C, the product29 was blendedwas blend withed 15–20% with 15 of– the20% 1,4-disubstituted of the 1,4-disubstituted imidazole imidazole30 [32]. [32]. atat 00 °C°C,, thethe productproduct 2929 waswas blendblendeded withwith 1515––20%20% ofof thethe 1,41,4--disubstituteddisubstituted imidazoleimidazole 3030 [32].[32].

Pharmaceuticals 2020, 13, 37 5 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 5 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 5 of 19

CO Et CO Et CO2Et CO2Et N 2 N 2 F N N O F CO2Et O CO2Et O O N 2 O O N DMF K2CO3 N N + DMF N + K2CO3 N + N + N + + O N N O NCO2Et Tos NC N N NH2 NCO Et Tos NH2 2 T NC F F F F 26 27 28 18 29 30 26 27 28 18 29 30 Scheme 6. Synthesis of ketone 29 and 1,4-disubstituted imidazole 30. Scheme 6. SynthesisSynthesis of ketone 29 and 1,4 1,4-disubstituted-disubstituted imidazo imidazolele 30.

In the same year, thethe VanelleVanelle groupgroup convertedconverted 6-nitropiperonal 6-nitropiperonal into into the the methylimine methylimine31 31through through a acondensation condensation reaction reaction with with methylamine methylamine in ethanol. in ethanol. The moleculeThe molecule with imidazolewith imidazole ring 32 ringwas 32 formed was formed by reacting equimolar quantities of TosMIC 18 and aldimine 31 with K2CO3 in methanol formedby reacting by reacting equimolar equimolar quantities quantities of TosMIC of TosMIC18 and aldimine18 and aldimine31 with K312 COwith3 in K methanol2CO3 in methanol solvent, solventunder a, under refluxing a refluxing condition. condition. Then, through Then, through the classical the classical Knoevenagel Knoevenagel reaction, reaction, compound compound33 were 33 wereobtained, obtained which, which displayed display an eedffective an effectivein vitro leishmanicidal in vitro leishmanicidal bioactivity (Schemebioactivity7). (Scheme Compound 7). C33aompound, higher in33a vitro, highleishmanicidaler in vitro leishmanicidal bioactivity, might bioactivity lead to a, might promising lead significant to a promising therapeutic significant agent (Schemetherapeutic8)[ 33agent]. (Scheme 8) [33].

O O O O 2 steps O O K CO 2 steps O 2 3 O H + os K2CO3 O + Tos NC O N O N O H T NC CH3OH N N C CH3 CH3OH N N 1 O C N CH reflux N N R1 N 3 refllux H3C H3C R H3C H3C H R2 H R2 31 18 32 33 31 18 32 33 Scheme 7. Synthesis of the potential significant therapeutic agent 33. SSchemecheme 7. SynthesisSynthesis of of the the p potentialotential significant significant therapeutic agent 33.

O O O O N N N H N CH3 3C CH3 H3C 3 H H NO2 NO2 a 33a 33 SSchemecheme 8. High in vitro leishmanicidal activity of compound 33a. Scheme 8. High in vitro leishmanicidal activity of compound 33a. From 20052005 toto 2006,2006, inin orderorder to to access access unusual unusual imidazole-based imidazole-based heterocyclic heterocyclic structures, structures, a seriesa series of experimentalFrom 200 results5 to 20 were06, in reportedorder to byaccess the Graciasunusual and imidazole Djuric group.-based heterocyclic structures, a series of experimental results were reported by the Gracias and Djuric group. Initially, they they reported reported a anew new protocol protocol employing employing the the van van Leusen Leusen three three-component-component reaction reaction and and theInitially, ring-closing they reported metathetical a new reactionprotocol inemploying a sequence the method, van Leusen to form three a- fusedcomponent bicyclic reaction imidazole and the ring-closing metathetical reaction in a sequence method, to form a fused bicyclic imidazole ring. Thering. general The general method method is shown is shown in Scheme in Scheme 9 9(top (top),), the the reaction reaction underwent underwent smoothly withwith thethe Thecondensation general method reaction is of shown 4-pentenal in Scheme34 andallylamine 9 (top), the35 , inreaction DMF atunderwent room temperature, smoothly to with give the condensation reaction of 4-pentenal 34 and allylamine 35, in DMF at room temperature, to give the imine in situ, which was followed by the addition of the TosMIC reagent 18 and a base base,, to access the iminevan Leusen in situ, imidazole which was product followed36 inby high the addition yield. Next, of the a ring-closingTosMIC reagent metathesis 18 and (RCM)a base, reactionto access was the van Leusen imidazole product 36 in high yield. Next, a ring-closing metathesis (RCM) reaction was performed through the second second-generation-generation Grubbs catalyst to get imidazole 37 and their derivatives performed(Scheme9, top)through [34]. the second-generation Grubbs catalyst to get imidazole 37 and their derivatives (Scheme 9, top) [34]. NextNext,, they developed a concise route of fused imidazo azepine analog analogss via the stepwise van LeusenNext/intramolecular, they developed enyne a concise metathesis route synthesis. of fused Theimidazo condensation azepine reactionanalogs ofvia 4-pentenal the stepwise34 withvan Leusen/intramolecular enyne metathesis synthesis. The condensation reaction of 4-pentenal 34 with butbut-2-yn-1-amine-2-yn-1-amine 3838in in DMF DMF at at room room temperature temperature gives give thes iminethe imine in situ, in and situ, then and adds then phenyl adds TosMICphenyl 18butand-2-yn K-1CO-amineto access38 in DMF the van at Leusenroom temperature imidazole product gives the39 inimine high in yield. situ, Subsequentand then adds cyclization phenyl TosMIC 218 and3 K2CO3 to access the van Leusen imidazole product 39 in high yield. Subsequent TosMIC 18 and K2CO3 to access the van Leusen imidazole product 39 in high yield. Subsequent cyclizationvia the intramolecular via the intramolecular enyne metathesis enyne reactionmetathesi resultss reaction in the res formationults in the offormation the cyclized of the product cyclized40 cyclizationcontaining thevia dienethe int functionalramolecular group enyne and metathesi their derivativess reaction (Scheme results 9in, bottom) the formation [35]. of the cyclized product 40 containing the diene functional group and their derivatives (Scheme 9, bottom) [35].

Pharmaceuticals 2020, 13, 37 6 of 19 PharmaceuticalsPharmaceuticals 20202020,, 1133,, xx FORFOR PEERPEER REVIEWREVIEW 66 ofof 1919 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 6 of 19

H N H22N H2N .. -- , Ph 35 Ph 1 p TssOH,CH2Cl2 Ph 35 Ph 1. p- Ts OH, CH2Cl2 Ph 35 Ph N 1.p T OH CH.2Cl2 , N 2.Grubbs cat.,,CH Cl N K2CO3 , DMF N N 2. Grubbs cat., CH2 Cl2 N N K2CO3 , DMF N rubbs cat H 2 l 2 N N K2CO3 DMF N 2 G C 2C 2 N 3366 3377 PPhh 36 37 OHC + Ph + OHC + os + OHC + TTos NNCC + Tos NC H N CH3 3344 1188 H2 N CH3 H 2N CH3 34 18 2 CH Ph CH33 .. -- , Ph CH 38 CH Ph 1 p TssOH,CH2Cl2 Ph CH3 38 3 Ph 1. p- T OH, CH2Cl2 CH 3 38 Ph N 1.p TsOH CH.2Cl2 N 3 ,, N . ru s cat.,, N N KK2CCOO3 DDMMFF N 22.GGrubbbbs cat.,CCHH2CCll2 N N K 2CO 3 , DMF NN 2 Grubbs cat CH 2Cl 2 N 2 3 N 2 2 3399 4400 39 40 Scheme 9. SynthesisSynthesis ofof thethe fusedfused bicyclicbicyclic 37 andand thethe fusedfused imidazoimidazo azepineazepine derivativesderivatives 40.. SchemeScheme 9.9. SynthesisSynthesis of of the the fused fused bicyclic 3737 and the fused imidazo azepine derivatives 4040. In latelate 2005, 2005, they they also also reported reported a facile a facile route route of fused of triazolofused triazolo imidazole imidazole derivatives derivatives via a sequential via a InIn latelate 2005,2005, ttheyhey alsoalso reportedreported aa facilefacile routeroute ofof fusedfused triazolotriazolo imidazoleimidazole derivativesderivatives viavia aa vansequential Leusen van/alkyne–azide Leusen/alkyne cycloaddition–azide cycloaddition reaction. The reaction use of. an The azide use functionalityof an azide functionality on the aldehyde on the41 sequentialsequential vanvan Leusen/alkyneLeusen/alkyne––azideazide cycloadditioncycloaddition reactionreaction.. TheThe useuse ofof anan azideazide functionalityfunctionality onon thethe aldehydeand an alkyne 41 and functionality an alkyne functionality on the amine on42 thegives amine the bifunctional42 gives the bifunctional raw material raw for material the van Leusenfor the aldehydealdehyde 4141 andand anan alkynealkyne functionalityfunctionality onon thethe amineamine 4242 givgiveses thethe bifunctionalbifunctional rawraw materialmaterial forfor thethe vanreaction Leusen resulting reaction in substrateresulting 43in. substrate Subsequent 43. cyclization Subsequent through cyclization the intramolecular through the intramolecular alkyne–azide vanvan LeusenLeusen reactionreaction resultingresulting inin substratesubstrate 4343.. SubsequentSubsequent cyclizationcyclization throughthrough thethe intramolecularintramolecular alkynecycloaddition–azide cycloaddition will form the fusedwill form triazolo the fused imidazole triazolo skeletons imidazole44 (Scheme skeleton 10s 44)[36 (Scheme]. 10) [36]. alkynealkyne––azideazide cycloadditioncycloaddition willwill formform thethe fusedfused triazolotriazolo imidazoleimidazole skelskeletonetonss 4444 (Scheme(Scheme 10)10) [36].[36].

1 1 R 1 RR1 R1 n ramo ecu ar 1 R iinttramollecullar R an ranmeo--aezcuear N 3 3 ialtky ne lazidle R3 N CHO R 3 , R 3 N lky - id 3 N N N CHO R , R3 N3 aclkcyonae azidoen R3 N N 1 H NH2 3 K2CO3 DMF R 3 cy clloaddiittiion R N R 1 C O + NH2 + R K2CO3, DMF N3 c yc oa dd on N R + 2 NH2 + K2CO3 DMF y l dditi 2 R1 + R 2 R 2 N R2 + N R N3 R NN N R2 N 3 Tos NC N 3 Tos NC N N NN Tos NC N 2 N R 2 N R2 4411 4422 1188 4433 R 4444 41 42 18 43 44 Scheme 10. SynthesisSynthesis o ofoff fused fused triazolo triazolo imidazole imidazolesimidazoless 44.. SchemeScheme 10.10. Synthesis of fused triazolo imidazoles 4444. Then in in 2006, 2006, they they continued continued to to publish publish the the methods methods for for the the fused fused imidazole imidazole ring ring synthesis synthesis by ThenThen inin 2006,2006, theythey continuedcontinued toto publishpublish thethe methodsmethods forfor thethe fusedfused imidazoleimidazole ringring synthesissynthesis byby usingby using thethe tandem tandem van van Leusen/RCM, Leusen/RCM, van van Leusen Leusen/enyne/enyne metathesis, metathesis, van LeusenLeusen/alkyne–azidealkyne–azide usingusing thethe tandemtandem vanvan Leusen/RCM,Leusen/RCM, vanvan LeusenLeusen/enyne/enyne metathesis,metathesis, vanvan LeusenLeusen//alkynealkyne––azideazide cycloadditioncycloaddition,, or van Leusen//HeckHeck reaction,reaction, respectively.respectively. cycloadditioncycloaddition,, oror vanvan LeusenLeusen/Heck/Heck reactionreaction,, respectivelyrespectively.. Firstly, they synthesizedsynthesized fused imidazo-pyridineimidazo-pyridine and imidazo-azepineimidazo-azepine derivatives by using a Firstly,Firstly, theythey synthesizedsynthesized fusedfused imidazoimidazo--pyridinepyridine andand imidazoimidazo--azepineazepine derivativesderivatives byby usingusing aa sequential van Leusen // intramolecular Heck route route.. The The imidazole imidazole 4747 andand 49 were access accesseded via the sequentialsequential vanvan LeusenLeusen// intramolecularintramolecular HeckHeck routeroute.. TheThe imidazoleimidazole 4747 andand 4949 werewere accessaccesseded viavia thethe ccondensationondensation r reactioneaction between an appropriate aldehyde aldehyde-containing-containing vinylogous bromide bromide 45 and an ccondensationondensation rreactioneaction betweenbetween anan appropriateappropriate aldehydealdehyde--containingcontaining vinylogousvinylogous bromidebromide 4545 andand anan aamine-containingmine-containing double bond 4646,, respectivelyrespectively.. T Then,hen, preformation of the imine, the the desired desired TosMIC TosMIC aaminemine--containingcontaining doubledouble bondbond 4646,, respectivelyrespectively.. TThenhen,, preformationpreformation ofof thethe imine,imine, thethe desireddesired TosMICTosMIC reagent 18 and K 2CO 3 were added, and the cyclization was allowed to proceed at room temperature to reagentreagent 1818 andand KK22COCO33 werewere added,added, andand thethe cyclizationcyclization waswas allowedallowed toto proceedproceed atat rroomoom temperaturetemperature reagent 18 and K2CO3 were added, and the cyclization was allowed to proceed at room temperature toget get imidazo-[1,5- imidazo-[1,5a]pyridine-a]pyridine48 48or or imidazo[1 imidazo[1 ,5- a,5]azepine-a]azepine50 50(Scheme (Scheme 11 )[11)37 [37]. ]. toto getget imidazoimidazo--[1,5[1,5--aa]]pyridinepyridine 4848 oror imidazimidazo[1o[1 ,5,5--aa]]azepineazepine 5050 (Scheme(Scheme 11)11) [37[37].].

r r AAr AAr Ar Ar R Brr R B Heck (CH2)n R Br Heck (CH2)n Heck R N (CH2)n NN (CCHH2)n R N N N (CH 2)n R N N ( 2)n NN N N OHC R Ph 47 48 OHC Arr R(Ph) K2CO3 47 48 H A R (Ph ) K2CO3 47 48 O C Ar + H2N (CH2)n + ( ) K2CO + H2N (CH2)n + os 3 r + H2N (CH2)n + TTos NNCC DMF BBr Tos NC DMF Br DMF r r AAr AAr 4455 4466 1188 Ar Br Ar 45 46 18 Br PPhh Br MMWW PPhh Ph MW Ph NN NN NN N NN N N N

4499 5500 49 50 Scheme 11. Synthesis of the fused imidazole rings 48 and 50. Scheme 11. SynthesisSynthesis ofof thethe ffusedused imidazoleimidazole ringringss 48 andand 50.. SSchemecheme 11.11. Synthesis of the fused imidazole rings 4848 and 5050.

Pharmaceuticals 2020, 13, 37 7 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 7 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 7 of 19 Next, they described an elegant method to obtain a fused imidazole ring, employing the van Next,Next, they described anan elegant method to obtain a fused imidazole ring,ring, employing the van LeusenNext three, they-component described areactionn elegant, followedmethod to by obtain Pd/Cu a fused catalyzed imidazole intramolecular ring, employing C-arylation. the van Leusen three-componentthree-component reaction, reaction followed, followed by Pd /byCu catalyzedPd/Cu catalyzed intramolecular intramolecularC-arylation. C Meanwhile,-arylation. MLeuseneanwhile, three an-othercomponent available reaction protocol, followed to form 5,6 by-dihydroimidazo[2,1 Pd/Cu catalyzed- a]intramolecular-isoquinoline system C-arylation. 53, via anotherMeanwhile, available another protocol available to protocol form 5,6-dihydroimidazo[2,1-a]-isoquinoline to form 5,6-dihydroimidazo[2,1-a]-isoquinoline system 53 ,system via a radical 53, via aM radicaleanwhile, cyclization another reactionavailable of protocol tethered to a formryl halides 5,6-dihydroimidazo[2,1 onto the imidazole-a] ring-isoquinoline, was also systempublish 53ed., via In cyclizationa radical cyclization reaction ofreaction tethered of tethered aryl halides aryl ontohalides the onto imidazole the imidazole ring, was ring also, was published. also publish Ined. their In theira radical article cyclization, the imidazole reaction precursors of tethered were aryl accessed halides ontothrough the imidazolean alkylation ring ,chemistry was also ,publish and theed. van In article,their article the imidazole, the imidazole precursors precursors were accessedwere accessed through through an alkylation an alkylation chemistry, chemistry and the, and van the Leusen van Leusentheir article reaction, the wasimidazole used to precursors assemble imidazolewere accessed follow throughed by a an transition alkylation metal chemistry catalyzed, and C– theC bond van reactionLeusen reaction was used was to assemble used to assemble imidazole imidazole followed byfollow a transitioned by a metaltransition catalyzed metal C–C catalyzed bondframework C–C bond fLeusenramework reaction (Scheme was 12)use [38].d to assemble imidazole followed by a transition metal catalyzed C–C bond (Schemeframework 12 )[(Scheme38]. 12) [38]. 1 R 1 R1 R3 R R3 R3 N 3 . , N R 3 1. K CO DMF N N 1 + NH2 + R3 . 2 3 , N R 1CHO + NH2 R 1 K2CO3, DMF N R H NH2 + 1. K-2CO3 DMF R1CHO + X +Tos NC 2. C-Arylation C O 2 Tos NC 2. C-Arylation R 2 X Tos r at on R2 =X , NC 2 C A yl i 2 R X=Br ,I R 2 X Br I R2 X=Br,I R 51 52 18 53 51 52 18 53 51 52 18 53 Scheme 12. Synthesis of fused imidazole rings 53. Scheme 12. Synthesis of f fusedused imidazole ring ringss 53. InIn 2006, Dömling’sDömling’s groupgroup reported reported that that substituting substituting pyrroloimidazoles pyrroloimidazoles56 were56 were assembled assembled by vanby In 2006, Dömling’s group reported that substituting pyrroloimidazoles 56 were assembled by vanLeusen Leusen multicomponent multicomponent reaction reaction (MCR) (MCR) of TosMIC of TosMIC18, indole 18, indole carbaldehydes carbaldehydes54, and 54 primary, and primary amines van Leusen multicomponent reaction (MCR) of TosMIC 18, indole carbaldehydes 54, and primary amines55. They 55 were. They interested were interest in bioactivityed in bioactivity of the products of the product and theses and imidazole-containing these imidazole-containing skeletons amines 55. They were interested in bioactivity of the products and these imidazole-containing skeletonwere screeneds were screened in a phenotypic in a phenotypic assay for assay neurite for outgrowth.neurite outgr Theowth. test The results test results indicated indicat thated these that skeletons were screened in a phenotypic assay for neurite outgrowth. The test results indicated that thesesmall small molecules molecules would would serve serve as useful as useful chemical chemical probes probes to research to research neurite neurite growth growth and and might might be these small molecules would serve as useful chemical probes to research neurite growth and might beused used as aas therapeutic a therapeutic application application for axonfor axon regeneration regeneration of lesions of lesions of the of human the human spinal spinal cord andcord brain and be used as a therapeutic application for axon regeneration of lesions of the human spinal cord and brain(Scheme (Scheme 13)[39 13)]. [39]. brain (Scheme 13) [39].

R O R O O R N O O N N O N N N ase O N N + + base N N + R NH2 Tos NC base O N + R NH2 + Tos NC b N R NH2 + Tos NC DCM O DCM O CHO DCM H CHO 54 55 18 56 4 54 55 18 56 56 Scheme 13. SynthesisSynthesis of of chemical chemical probe probess 56.. Scheme 13. Synthesis of chemical probes 56. Based on their previous research, they also reported a novel synthesis route of potential Based on their previous research, they also reported a novel synthesis route of potential aspartyl-- aspartyl-proteaseBased on their inhibitors previous inresearch, 2007. In they their also method, reported 1,4,5-trisubstituted a novel synthesis 1-(4-piperidyl)-imidazolesroute of potential aspartyl- protease inhibitors in 2007. In their method, 1,4,5--trisubstitutedtrisubstituted 11--(4(4--piperidyl)--imidazolesimidazoles 59 couldcould protease59 could inhibitors be obtained in through2007. In their an isocyanide-based method, 1,4,5-trisubstituted van Leusen 1 MCR-(4-piperidyl) of α-substituted-imidazoles TosMICs 59 could18, be obtained through an isocyanide--based van Leusen MCR of α--substitutedsubstituted TosMICsTosMICs 18,, aldehydesaldehydes 57bealdehydes, obtainedand 4-aminopiperidine57 through, and 4-aminopiperidine an isocyanide 58 (Scheme-based58 14)(Scheme van[40] .Leusen 14)[ 40MCR]. of α-substituted TosMICs 18, aldehydes 57, and 4-aminopiperidine 58 (Scheme 14) [40].

R2 R2 3 R2 R 3 R1 N R3 base R1 N , N R1 CHO + R2 NH + R base R1 N 2= , N R1 CHO + R2 NH2 + os - obsase R 2= N , N R1 CHO + R2 NH2 + Tos NC -T SO2H N R2= 2 Tos NC -TosSO2H 3 N R HN O O T NC TosSO2H R 3 N NH O O R3 H O O 57 58 18 R 59 57 58 18 59

SSchemecheme 14. SynthesisSynthesis of of potent potentialial aspartyl aspartyl-protease-protease inhibitor inhibitorss 59.. Scheme 14. Synthesis of potential aspartyl-protease inhibitors 59. In 2009, a range of 1,5-disubstituted-4-methylimidazole preparations were reported by Fodili InIn 2009,2009, a rangerange of 1,5--disubstituted--4--methylimidazole preparations were reported by Fodili and co-workers.In 2009, a range Compounds of 1,5-disubstituted63 were prepared-4-methylimidazole from acetimine preparations analogs 62 were, which reported were by obtained Fodili and co--workers.. Compounds 63 were prepared fromfrom acetimine analogss 62,, which were obtained fromfrom andfrom co dehydroacetic-workers. Compounds acid 60 and 63 were primary prepared amine from61. Theseacetimine were analog enableds 62, to which react were with obtained TosMIC from18 in dehydroacetic acid 60 and primary amine 61.. These were enabled toto reactreact withwith TosMICTosMIC 18 inin thethe presencedehydroaceticthe presence of catalytic of acid catalytic 60 amounts and amounts primary of ofbismuth amine bismuth 61triflate.. triflate. These A were Aplausible plausible enabled mechanism mechanism to react withwas was TosMICput put forward forward 18 in that the presence of catalytic amounts of bismuth triflate. A plausible mechanism was put forward that involvinvolved the firstfirst formationformation ofof anan imidazolineimidazoline intermediate,intermediate, followedfollowed byby methyl migration,, and then subsequentinvolved the aromatization first formation provided of an imidazoline access to the intermediate, target imidazole followed ring by (Scheme methyl 15)migration [41]. , and then subsequent aromatization provided access to the target imidazole ring (Scheme 15) [41].

Pharmaceuticals 2020, 13, 37 8 of 19

involved the first formation of an imidazoline intermediate, followed by methyl migration, and then Pharmaceuticals 2020, 13, x FOR PEER REVIEW 8 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 8 of 19 Pharmaceuticalssubsequent aromatization2020, 13, x FOR PEER provided REVIEW access to the target imidazole ring (Scheme 15)[41]. 8 of 19 R H3C OH O OH N R OH3C N H C N OH O OH N R OH3 OH O OH N - u , OH N CH3 CH3 t-B NH2, Bi(OTf)3 N CH + H + os t BuNH Bi OTf N 3 R NH2 C 3 T NC - u 2, ( )3 CH + CH + os t B NH2 Bi(OTf)3 NR H C O O 3 R NH2 H C O O 3 T NC CH3OH 3 + R NH 3 + Tos NC H3C O O R H C O O 2 H C O O CH3OH H R 3 3 CH OH 3C O O H3C O O H3C O O 3 H3C O O 60 61 62 18 63 60 61 62 18 63 60 61 62 18 63 Scheme 15. Synthesis of 1,5-disubstituted-4-methyl imidazoles 63. Scheme 15. Synthesis of 1,5-disubstituted-4-methyl imidazoles 63. SchemeScheme 15. SynthesisSynthesis of of 1,5 1,5-disubstituted-4-methyl-disubstituted-4-methyl imidazoles imidazoles 6363.. In 2012, Hulme and Moliner reported a novel synthesis of two pharmacological relevant classes InIn 2012, 2012, Hulme and MolinerMoliner reportedreported a a novel novel synthesis synthesis of of two two pharmacological pharmacological relevant relevant classes classes of of moleculesIn 2012, Hulmeforming and the Molinerimidazoquinox reported aline a novel scafflod synthesis 66 and of 68 two, respectively. pharmacological This method relevant involves classes ofmolecules molecules forming forming the the imidazoquinox imidazoquinox aline aline sca scafflodfflod 66 66and and68 68,, respectively.respectively. ThisThis method involves ofthe molecules use of 1,2 forming-phenylenediamines the imidazoquinox 64 and aline glyoxylic scafflod acid 66 derivatives,and 68, respectively. namely ethylThis methodglyoxylate involves 65 or thethe use of 1,2 1,2-phenylenediamines-phenylenediamines 6464 andand glyoxylic acid acid derivatives, namely namely ethyl ethyl glyoxylate glyoxylate 6565 oror thebenzylglyoxamide use of 1,2-phenylenediamines 67, along with TosMIC64 and glyoxylic18 in a microwave acid derivatives,-assisted namely van Leusen ethyl threeglyoxylate-component 65 or benzylglyoxamidebenzylglyoxamide 6767,, along along with with TosMIC TosMIC 18 in a microwave-assistedmicrowave-assisted van Leusen three three-component-component benzylglyoxamidecondition. Then there 67, alongwas a withdeprotection TosMIC –18cyclization in a microwave step to- assistedform tw vano biological Leusen three-activity-component-enticing condcondition.ition. T Thenhen there there was was a a deprotection deprotection–cyclization–cyclization step step to form twotwo biological-activity-enticingbiological-activity-enticing condimidazoquinoxalineition. Then there families was a (Schemedeprotection 16) [42].–cyclization step to form two biological-activity-enticing imidazoquinoxalineimidazoquinoxaline families families (Scheme (Scheme 16)16)[ [42].42]. imidazoquinoxaline families (Scheme 16) [42]. O O O O CHO O CHO O65 CHO HN 65 HN 65, HN N DMF,MW O N DMF,MW O N DMF MW O N N NH2 66 N NH2 O 66 Tos NC + NH2 + O 66 Tos NC + + O Tos NC + NHBoc + N CHO NHBoc NH CHO NHBoc HN CHO 18 64 H 18 64 18 64 67 N 67 N . 67 . . N N , or r t overn t 1. DMF, MW . . igh H2N N 1. DMF, MW, or r.t,. overnight H N N 12. D10M%FTFMAW, DoCr Er ,t MovWernight H2N 2. 10%TFA, DCE, MW 2 N 2 10%TFA DCE MW N N 68 68 68 Scheme 16. Synthesis of biologically enticing imidazoquinoxaline 66 and 68. SchemeScheme 16. 16. SynthesisSynthesis of of biologically biologically enticing enticing imidazoquinoxaline imidazoquinoxaline 6666 andand 6868.. Scheme 16. Synthesis of biologically enticing imidazoquinoxaline 66 and 68. InIn 2016, 2016, the the Pirali’ Pirali’ss group group reported reported a method a method for synthesizing for synthesizing 4-PI analogues 4-PI analogues via the viavan theLeusen van In 2016, the Pirali’s group reported a method for synthesizing 4-PI analogues via the van Leusen MCR,LeusenIn which2016, MCR, the is which Pirali’by far iss groupthe by farmost reported the direct most a method directmethod method for for synthesizing obtaining for obtaining functionally4-PI analogues functionally rich via imidazole the rich van imidazole. Leusen. This MCR, which is by far the most direct method for obtaining functionally rich imidazole. This MCR,transformationThis transformation which is can by be canfar used bethe usedto most synthesize to synthesizedirect four method different four diforfferent seriesobtaining series of compounds offunctionally compounds—1,4,5-trisubstituted—1,4,5 rich-trisubstituted imidazole. This and transformation can be used to synthesize four different series of compounds—1,4,5-trisubstituted and transformation1,5and-, 1,5-,1,4- and 1,4- and4,5 can-disubstituted 4,5-disubstituted be used to synthesize imidazoles imidazoles four 71 .different 71M.eanwhile Meanwhile, series, 4,5 of- 4,5-diaryldiaryl compounds imidazoles imidazoles—1,4,5 were-trisubstituted were analy analyzedzed byand by a 1,5-, 1,4- and 4,5-disubstituted imidazoles 71. Meanwhile, 4,5-diaryl imidazoles were analyzed by a 1,53Da 3D- ,quantitative 1,4 quantitative- and 4,5 -structuredisubstituted structure-activity-activity imidazoles relationshi relationship 71. pM (SAR)eanwhile (SAR).. Based Based, 4,5 -diarylon on their their imidazoles docking docking scorewere score analyand and synthetic zed by a 3D quantitative structure-activity relationship (SAR). Based on their docking score and synthetic 3Dfeasibility,feasibility, quantitative thethe compoundscompounds structure- were activitywere selected, selected, relationshi synthesized, synthesizedp (SAR) and,. andBased biologically biologically on their evaluated. evaluated.docking score Compared Compared and synthetic with with 4-PI, 4- feasibility, the compounds were selected, synthesized, and biologically evaluated. Compared with 4- feasibility,PI,the the IDO1 IDO1 inhibitor the inhibitor compounds products produc were throughts throughselected, this this synthesized experimental experimental, and method methodbiologically have have enhanced evaluated. enhanced the Compared the potency. potency Bothwith. Both 4 in- PI, the IDO1 inhibitor products through this experimental method have enhanced the potency. Both PI,inenzymatic enzymatic the IDO1 and inhibitorand cellular cellular produc assays, assays,ts the through the most mostactive this active experimental compounds compounds showedmethod showed lowerha lowerve enhanced micromolar micromolar the potency, potency potency, but. Both but no in enzymatic and cellular assays, the most active compounds showed lower micromolar potency, but innodetectable enzymatic detectable cellular and cellular cellular toxicity. toxicity assays, The. The analysis the analysis most displayed active display compounds thated athat putative a showed putative hydrogen lower hyd rogenmicromolar bond betweenbond potency,between the Ser167 butthe no detectable cellular toxicity. The analysis displayed that a putative hydrogen bond between the noSer167of thedetectable proteinof the protein cellular and the and toxicity NH the of NH. theThe of imidazole analysisthe imidazole display ring mightringed mightthat be responsiblea beputative responsible hyd forrogen thefor improvementthe bond improvement between of the of Ser167 of the protein and the NH of the imidazole ring might be responsible for the improvement of Ser167thepotency, potency, of togetherthe togetherprotein with and with favorable the favorable NH interactionsof the interactions imidazole with withring the partially mightthe partially be occupied responsible occupied pocket for pocket the B. The improvement B. results The results above of the potency, together with favorable interactions with the partially occupied pocket B. The results theabovesuggested potency, suggest that togethered the that 4,5-disubstituted the with 4,5 favorable-disubstituted imidazole interactions imidazole framework with framework the might partially givemight occupied a newgive orientationa new pocket orientation B. for The the resultsfor design the above suggested that the 4,5-disubstituted imidazole framework might give a new orientation for the abovedesignof IDO1 suggest of inhibitors, IDO1ed inhibitors that in the future 4,5, in- disubstituted(Schemefuture (Scheme 17)[ 43imidazole]. 17) [43]. framework might give a new orientation for the design of IDO1 inhibitors, in future (Scheme 17) [43]. design of IDO1 inhibitors, in future (Scheme 17) [43]. 2 . , ≠ , R2 a R1 R2≠H R3 3 1 R a. 1, 2 , 3 R van eusen R 2 . R1= R, ≠2H≠ R, 3 R3 L MCR R1 NR ab R1, RH2 RH≠, RH3 R 1 + 2 + 3 van Leusen MCR 1 N . 1= , 2 , 3 R CHO R NH2 R v n u n R b. R2=H, R1≠H, R3 R1 H + 2 + Tos NC a Le se MCR N bc R1=H R2≠H R3 1 C O R2 NH2 + 3 N c. 2= , 1 , 3 R CHO + R NH Tos NC R .. R3=H,, R1≠, H2,≠ R 2 Tos N 3 N cd. R2=H R1 RH≠RH3 C R3 N 3= , 1, 2 69 70 18 R 71 d. R3=H, R1, R2≠H 69 70 18 71 d R H R R H 7 7 69 0 18 1 Scheme 17. SynthesisSynthesis of of p potentialotential IDO1 IDO1 inhibitors 71.. Scheme 17. Synthesis of potential IDO1 inhibitors 71. Scheme 17. Synthesis of potential IDO1 inhibitors 71. At the same year, the Suresh group developed a direct, sequential, copper-catalyzed N- At the same year, the Suresh group developed a direct, sequential, copper-catalyzed N- arylationAt the–condensation same year, reaction the Suresh utilizing group chiral developed cyclic 1,2 a-diamines direct, sequential73 and ortho, copper-haloaryl-catalyzed aldehydes N- arylation–condensation reaction utilizing chiral cyclic 1,2-diamines 73 and ortho-haloaryl aldehydes arylationor ketones–condensation 72. The corresponding reaction utilizing chiral tricyclicchiral cyclic 1,4- benzodiazepines1,2-diamines 73 and 74 wereortho synthesized-haloaryl aldehydes in high or ketones 72. The corresponding chiral tricyclic 1,4-benzodiazepines 74 were synthesized in high or ketones 72. The corresponding chiral tricyclic 1,4-benzodiazepines 74 were synthesized in high

Pharmaceuticals 2020, 13, 37 9 of 19

At the same year, the Suresh group developed a direct, sequential, copper-catalyzed Pharmaceuticals 2020, 13, x FOR PEER REVIEW 9 of 19 NPharmaceuticals-arylation–condensation 2020, 13, x FOR PEER reaction REVIEW utilizing chiral cyclic 1,2-diamines 73 and ortho-haloaryl aldehydes9 of 19 PharmaceuticalsPharmaceuticals 20202020,, 1133,, xx FORFOR PEERPEER REVIEWREVIEW 99 ofof 1919 or ketones 72. The corresponding chiral tricyclic 1,4-benzodiazepines 74 were synthesized in high yield. Subsequently, 1,4-diazapine 75 was converted into a novel tetracyclic N-fused ImBDs through yieldyield.yield.. Subsequently, Subsequently, 1 1,4-diazapine1,4,4--diazapinediazapine 757575 waswaswas converted converted into into a a novel novelnovel tetracyclic tetracyclictetracyclic NN--fused-fusedfused ImBDs ImBDs through through vyieldan Lusen. Subsequently, imidazole 1s,4ynthesis-diazapine (Scheme 75 was 18) converted [44]. into a novel tetracyclic N-fused ImBDs through vvanvanan Lusen Lusen imidazole imidazole s synthesissynthesisynthesis (Scheme (Scheme 18)1818))[ [44].[44].44]. N N H NN CuI H OHC CuuI N HH N OHC * NH2 a CCu,II * N eraz ne * N OOHHCC ** NNHH2 N a2CO3,,DMSO ** NN pip erazi ne ** NN + * NH22 NNa 2CCOO3,DDMMSSOO * piperaz ni e * + Na22CO33 DMSO + Tos NC ppipi-peraziine ++ * ++ Tooss NC t -BuOH X * NH C4H12N2 * N + TTos NNCC t--B℃uOH * N R X R * NH2 C4H12N2 ** N R t Buu℃O,H * N XX R * NH 2 CC4HH℃12,NN2 * NH R 1t20B℃℃O,,2Hh ** NH RR RR NH22 1240℃℃12,8h2 NH RR 112200 ,22hh NH R 120℃,,8h HH 120 2h HH 112200 88hh 72 73 74 18 75 7722 7733 7744 1188 7755 72 73 74 18 75 SchemeScheme 18. 18. SynthesisSynthesis ofof NN--fusedfused ImBDsImBDs 7575.. SchemeScheme 18.18. SynthesisSynthesis of of NN---fusedfusedfused ImBDs ImBDs 7575.. A range of 5 5-aryl-1-alkylimidazole-aryl-1-alkylimidazole deriva derivantesntes 7979 were synthetized by utilizing the van Leusen AA rangerange ofof 55--arylaryl--11--alkylimidazolealkylimidazole derivaderivanntestes 7979 werewere synthetizedsynthetized byby utilizingutilizing thethe vanvan LeusenLeusen MCR by Bojarski and co co-workers,-workers, in 2017. The The v vanan Leusen reaction was performed by the stepwise MCRMCR byby BojarskiBojarski andand coco--workersworkers,, inin 2017.2017. TheThe vvanan LeusenLeusen reactionreaction waswas performedperformed byby thethe stepwisestepwise cycloaddition of of TosMIC TosMIC 18 to the polarization double bond of a preformedpreformed imine 78.. Imidazole is is cycloadditioncycloaddition ofof TosMICTosMIC 1818 toto thethe polarizationpolarization doubledouble bondbond ofof aa preformedpreformed imineimine 7878.. ImidazoleImidazole isis synthetized by by the elimination of p--TosOH,TosOH, from the cycliccyclic intermediate.intermediate. Then Then,, aromatic aldehydes synthetizedsynthetized byby thethe eliminationelimination ofof pp--TToosOHsOH,, fromfrom thethe cycliccyclic intermediate.intermediate. ThenThen,, aromaticaromatic aldehydesaldehydes bind to the appropriate amine. All compounds were highly selectiv selectivee to 5 5-HT5A.-HT5A. These compounds bindbind toto thethe appropriateappropriate amine.amine. AllAll compoundscompounds werewere highlyhighly selectivselectivee toto 55--HT5A.HT5A. TheseThese compoundscompounds wewerere metabolicallymetabolically stablestable in in human human liver liver microsome, microsome showed, showed less less toxicity toxic inity HEK-293 in HEK- and293 and HepG2 HepG2 cells wewerere metabolicallymetabolically stablestable inin humanhuman liverliver microsomemicrosome,, showshoweded lessless toxictoxicityity inin HEKHEK--293293 andand HepG2HepG2 cellsand wereand we water-solublere water-soluble (Scheme (Scheme 19)[45 19)]. [45]. cellscells andand wewerere waterwater--solublesoluble (Scheme(Scheme 19)19) [45].[45]. base 1 + CH base N R 1 CHO H3C NH2 1 3 + Tos NC baassee H C N N R1 CHO + H C NH R 1 N CHH3 + Tos b H3 N NN R 1 CHO ++ H33C NH22 R1 N CCH3 ++ Tos NNCC H 3CC N R CHO H3C NH2 R 1 N 3 Tos NC H33C N 1= - - R N R indol -3 -yl 1 11== n o- - R R R 1 = ini-ddoll-33-yyll - - R11 R 5in-mdoelth3oyxlyindol -3 -yl R 1 5--methoxyindo-l-3--yl R 55mmeetthhooxxyyininddooll33yyll 76 77 78 18 79 76 77 78 18 79 76 77 778 18 79 76 77 8 18 79 SchemeScheme 19. 19. SynthesisSynthesis ofof 55--HT7HT7 rreceptoreceptor aagonistsgonists 7979.. SchemeScheme 19.19. SynthesisSynthesis ofof 55 5-HT7--HT7HT7 rr receptoreceptoreceptor a agonistsagonistsgonists 7979.. InIn 2019, 2019, they they also also synthesized synthesized a arange range of of fluorinated fluorinated indole indole-imidazoles-imidazoles to tofind find more more effective effective 5- InIn 2019,2019, theythey alsoalso synthesizedsynthesized aa rangerange ofof fluorinatedfluorinated indoleindole--imidazolesimidazoles toto findfind moremore effectiveeffective 55-- HT75-HT7 receptor receptor selective selective agonists agonists as as molecular molecular probes. probes. As As shown shown in in Scheme Scheme 20, 20 ,the the target target compounds compounds HT7HT7 receptorreceptor selectiveselective agonistsagonists asas molecularmolecular probes.probes. AsAs shownshown inin SchemeScheme 20,20, thethe targettarget compoundscompounds 82 were obtained from the relevant relevant indole indoless undergoing the formylati formylationon process and the stepwise van 8282 werewere obtainedobtained fromfrom thethe relevantrelevant indoleindoless undergoingundergoing thethe formylatiformylationon processprocess andand thethe stepwisestepwise vanvan Leusen imidazole synthesis with with TosMIC 18. Meanwhile, they indicated indicated that that compound 82a mmightight LeusenLeusen imidazoleimidazole synthesissynthesis withwith TosMICTosMIC 1818.. Meanwhile,Meanwhile, theythey indicatedindicated thatthat compoundcompound 82a82a mmightight be a potential analgesic or a long long-sought-sought tool tool for for studying the the receptor receptor effect effect of 5 5-HT7,-HT7, base basedd on the bebe aa potentialpotential analgesicanalgesic oror aa longlong--soughtsought tooltool forfor studyingstudying thethe receptorreceptor effecteffect ofof 55--HT7HT7,, basebasedd onon thethe antianti-nociceptive-nociceptive function o onn a m murineurine model of neuropathic pain (Scheme 2121))[ [46].46]. antianti--nociceptivenociceptive functionfunction oonn aa mmurineurine modelmodel ofof neuropathicneuropathic painpain (Scheme(Scheme 21)21) [46].[46]. 4 1 R 4 R 1 R4 N N R1 O 1R 4 N N 2 R 1 O R 1R N NN R R OO K CO R1 N 1= , 2= , , , , 2 2 3 R 1 R 1=H ,F R CF ,OCF ,OEt ,F , R22 4 K2CO3 2 R 1= , 2= 3, 3, , , RR + R 4 NH + Tos NC KK2CO3 R 2 R1=H,F R 2 2= = CF3,OCF3,OEt,F, + R4 NH2 + os 2CO3 R2 RR3=HH,FF RR CCF,F3 rO,O,CCFF3 eOO,EEttFF + R 4 NH 2 ++ TTos NNCC e RR2 R 3=H ,F Cl ,B3 r,I ,OM3e,CN 3 N + R NH22 Tos NC M OH R33==H,,F C,l,Br,,,I,OMe,,CN R 3 MeeOH RR4=HHeFF, CCllBBrIIOOMMeCCNN R3 NHN MMeOOHH 3 N R 4=M e,Et R 3 NH R 3 R44==Me,,Et R H R3 NHN RR MMeEEtt H RR3 NH HH 80 81 18 82 8800 8811 1188 8822 80 81 18 82 SchemeScheme 20. 20. SSSynthesisynthesisynthesis of of 5 5-HT75--HT7HT7 receptor receptor low low-basicitylow--basicitybasicity agonists agonists 8282... SchemeScheme 20.20. SSynthesisynthesis ofof 55--HT7HT7 receptorreceptor lowlow--basicitybasicity agonistsagonists 8282.. Et Et N N EEtt N NN F NN N FF I F I II N N NHN - HH AGH -1H92 AGH--192 AAGGHH119922 82a 82aa 8822a Scheme 21. A potential analgesic 82a. SchemeScheme 21.21. AA potentialpotential analgesicanalgesic 82a82a.. SchemeScheme 21.21. AA potentialpotential analgesicanalgesic 82a82a.. In 2017, Sharma and co-workers developed a brief, novel, and simple operational van Leusen InIn 2017,2017, SharmaSharma andand coco--workersworkers developeddeveloped aa briefbrief,, novelnovel,, andand simplesimple operationaloperational vanvan LeusenLeusen methodIn .2017, They Sharma presented and theco- workersfirst van developed Leusen process a brief , towardsnovel, and synthesis simple operationalof high functionalized van Leusen methodmethod.. TheyThey presentedpresented thethe firstfirst vanvan LeusenLeusen processprocess towardstowards synthesissynthesis ofof highhigh functionalizedfunctionalized dihydrodibenzo[b,f]imidazomethod. They presented the[1,2 first-d][1,4]thia/oxazepine van Leusen process 86towards, by synthesisreacting of TosMIChigh functionalized 18 and dihydrodibenzo[b,f]imidazodihydrodibenzo[b,f]imidazo[1,2[1,2--d][1,4]thia/oxazepined][1,4]thia/oxazepine 8686,, byby reactingreacting TosMICTosMIC 1818 andand

Pharmaceuticals 2020, 13, 37 10 of 19

In 2017, Sharma and co-workers developed a brief, novel, and simple operational van Leusen

Pharmaceuticalsmethod.Pharmaceuticals They 20202020,,presented 1133,, xx FORFOR PEERPEER the REVIEWREVIEW first van Leusen process towards synthesis of high functionalized1010 ofof 1919 dihydrodibenzo[b,f]imidazo[1,2-d] [1,4] thia/oxazepine 86, by reacting TosMIC 18 and dibenzo[b,f] [1,4] dibenzo[b,f][1,4]thia/oxazepinesthiadibenzo[b,f][1,4]thia/oxazepines/oxazepines 85, which were 8585 obtained,, whichwhich werewere from obtainedobtained compound fromfrom83 compoundcompoundand 84, under8383 andand a 8484 basic,, underunder condition aa basicbasic condition(Schemecondition 22 (Scheme(Scheme)[47]. 22)22) [47].[47].

2 R2 22 R RR2 u ,, -- ro ne XH CHO CCuCCll,LL PProlliine X XH CHO -- , X 3 , XX 3 t- BuuONaa, DMF R3 KOH, ACN X R3 ++ 11 t BuONa DMF R KOH ACN R + RR1 ++ os + TTos NNCC .. .., NH l MW 1 44 rr. t., 5m inn 1 4 NH22 Cl ℃MW, R1 N R4 r t 5min R1 R4 R 2 Cl 120 ℃, 20min R N R R N R R ((120 20min)) N os ( ) TTos 11== ,, 44== RR1=HH,CCll RR4=CCll NN 2= , = , R2= Cl, CF X= S, O R Cl CF33 X S O 3= ,, 3 R3= NO2, CF3 R NO2 CF3 8833 8844 8855 1188 8866 83 84 85 18 86 SchemeScheme 22. 22. SynthesisSynthesis ofof highlyhighly functionalizedfunctionalized moleculesmolecules 8686..

InIn 2018, 2018, thethethe WeaverWeaverWeaver group groupgroup reported reportedreported that thatthat two twotwo corresponding correspondingcorresponding series seriesseries of molecules ofof moleculesmolecules based basebase ondd the onon SAR thethe SARSARdesign— designdesignN1-substituted——NN11--substitutedsubstituted 5-indoleimidazoles 55--indoleimidazolesindoleimidazoles and N 1-substitutedandand NN11--substitutedsubstituted 5-phenylimidazoles 55--phenylimidazolesphenylimidazoles were accessed. werewere accessedTheaccessed latter.. The (andThe latterlatter more (and e(andfficient) moremore series efficient)efficient) were obtainedseriesseries werewere by anobtainedobtained accidental byby rearrangementanan accidentalaccidental rearrangemrearrangem of imines thatentent are ofof imineimineintermediatess thatthat areare in intermediateintermediate the van Leusen inin thethe imidazole vanvan LeusenLeusen synthesis imidazoleimidazole reaction. synthesissynthesis The one-pot reaction.reaction. synthesis TThehe oneone of--potpot compounds synthesissynthesis ofof89 compoundscompoundsin two steps 8989 utilizing inin twotwo the stepssteps van utilizutiliz Leuseniingng imidazolethethe vanvan LeusenLeusen synthesis imidazoleimidazole process synthesissynthesis is shown processprocess in Scheme isis shownshown 23. First, inin SchemeSchemeimine formation 2323.. First,First, between imineimine formationformation 2-indolecarboxaldeyde betweenbetween 22--indolecarboxaldeydeindolecarboxaldeyde87 and the appropriate 8787 andand benzyl thethe amineappropriateappropriate88 took benzylbenzyl place, which then reacted with TosMIC 18 and K CO to give indoleimidazoles.2 3 They have also conducted amineamine 8888 tooktook place,place, whichwhich thenthen reactedreacted withwith2 TosMICTosMIC3 1818 andand KK2COCO3 toto givegive indoleimidazoles.indoleimidazoles. TheyThey havehaveSAR studiesalsoalso conductedconducted on their SARSAR novel studiesstudies and more onon theirtheir potent novelnovel compounds. andand moremore Compounds potentpotent compounds.compounds.92 were CC synthesizedompoundsompounds 9292 starting werewere synthesizedsynthesizedfrom known startingstarting amine 91 fromfromand knownknown aromatic amineamine aldehyde 9191 andand90 aromaticaromatic(Scheme aldehyde24aldehyde). These 9090 inhibitors (Scheme(Scheme represent 24).24). TheThesese a promisinginhibitorsinhibitors representrepresentfuture for a thea promisingpromising development futurefuture of IDO1forfor thethe inhibitors developmentdevelopment with specific ofof IDO1IDO1 physical inhibitorsinhibitors and chemicalwithwith specificspecific properties physicalphysical that andand are chemicalchemicaleasy to synthesize propertiesproperties [48 thatthat]. areare easyeasy toto synthesizesynthesize [48].[48].

XX RR XX X DMFF KK2CO 3 + DMF XX N K2CO3 R CHO + R CH 2NH 2 X N ++ Tooss NC ℃ R CHO RCH2NH2 + Tos NC ℃ N 6600 N N NH NH N H NN H HH == r or NN XX=BBr or HH 877 88 18 89 87 88 18 89 SchemeScheme 23. 23. OneOneOne-pot--potpot ss synthesisynthesisynthesis ofof potentialpotential IDO1IDO1 inhibitorsinhibitors 8989..

r AAr XX XX DMF K CO Arr r ++ DMF N X K22CO33 Ar N N AArCCHHOO + N X ++ Tooss NC 2 3 N N + Tos NC H HH2NN NN H 2 H N H NN N HH 9900 9911 1188 9922 90 91 18 92 Scheme 24. One-pot synthesis of potential IDO1 inhibitors 92. SchemeScheme 24.24. OneOne--potpot ssynthesisynthesis ofof potentialpotential IDO1IDO1 inhibitorsinhibitors 9292.. In the same year, Kondaparla et al. synthetized a range of short chain 4-aminoquinoline-imidazole InIn thethe samesame year,year, KondaparlaKondaparla etet al.al. synthetizedsynthetized aa rangerange ofof shortshort chainchain 44--aminoquinolineaminoquinoline-- derivatives 95 using two steps, in one-pot, via the van Leusen MCR standard method. The detailed imidazoleimidazole derivativesderivatives 9595 usingusing twotwo stepssteps,, inin oneone--pot,pot, viavia thethe vanvan LLeuseneusen MCRMCR standardstandard methodmethod.. TheThe synthetic protocol for the synthesis of target compounds 95 is shown in Scheme 25, compound 94 detaileddetailed syntheticsynthetic protocolprotocol forfor thethe synthesissynthesis ofof targettarget compoundscompounds 9595 isis shownshown inin SchemeScheme 25,25, as amine was utilized to react with TosMIC 18 and acetaldehyde 93 through a multicomponent compoundcompound 9494 asas amineamine waswas utilizedutilized toto reactreact withwith TosMICTosMIC 1818 andand acetaldehydeacetaldehyde 9393 throughthrough aa cyclisation reaction. In the end, all synthesized compounds were screened against the chloroquine multimulticomponentcomponent cyclisationcyclisation reaction.reaction. InIn thethe end,end, aallll synthesizedsynthesized compoundscompounds werewere screenedscreened againstagainst sensitive and chloroquine-resistant strains of Plasmodium falciparum. In this study, substitution thethe chloroquinechloroquine sensitivesensitive andand chloroquinechloroquine--resistantresistant strainsstrains ofof PlasmodiumPlasmodium falciparumfalciparum.. InIn thisthis studystudy,, on the N-(2-(1H-imidazol-1-yl)ethyl)-7-chloroquinolin-4-amine moiety had greatly influenced the substitutionsubstitution onon thethe NN--(2(2--(1(1HH--imidazolimidazol--11--yl)ethylyl)ethyl))--77--chloroquinolinchloroquinolin--44--amineamine moietymoiety hahadd greatlygreatly antiplasmodial bioactivity [49]. influencedinfluenced thethe antiplasmodialantiplasmodial biobioactivityactivity [49].[49].

Pharmaceuticals 2020, 13, 37 11 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 11 of 19 PharmaceuticalsPharmaceuticals 20202020,, 1133,, xx FORFOR PEERPEER REVIEWREVIEW 1111 ofof 1919 R RR NH2 NNHH22 N N N N NN HN HHNN , NH K2CO3,, DMF NNHH CHO + + os KK2℃CCOO3 DDMMFF CHO ++ ++ T NC 2 , 3 H3C CHO TTooss NNCC 90℃℃,, overnight HH33CC Cl N 9900 oovveerrnniigghhtt CCll NN N Cl NN CCll 93 94 18 95 93 944 118 955 93 9 8 9 Scheme 25. One-pot synthesis of antiplasmodial compounds 95. SchemeScheme 25. 25. OneOneOne-pot--potpot synthesissynthesis ofof antiplasmodialantiplasmodial compoundcompound compoundsss 9595.. In the same year, Laali and co-workers reported that an available route provided access to InIn the the same same year, year, Laali and co co-workersco--workersworkers reported reported that that a anann available available route route provided provided access access to to various C5-substituted imidazoles 97, 98, and 99, through one-pot tandem via the van Leusen-Suzuki, variousvarious C5 C5-substitutedC5--substitutedsubstituted imidazoles imidazoles 9797,,, 9898,, andand 9999,,, throughthrough through oneone one-pot--potpot tandemtandem tandem viavia via thethe the vanvan van LeusenLeusen Leusen-Suzuki,--Suzuki,Suzuki, van Leusen-Heck, and van Leusen-Sonogashira methods, respectively. Imidazolium-ILs as solvents, vanvan Leusen Leusen-Heck,Leusen--Heck,Heck, andand vanvan LeusenLeusen Leusen-Sonogashira--SonogashiraSonogashira methodmethod methods,ss,, respectivelyrespectively respectively... II Imidazolium-ILsmidazoliummidazolium--ILsILs asas solventssolvents solvents,,, along with piperidine piperidine-appended-appended imidazolium [PAIM][NTf [PAIM][NTf2]] as as task task-specific-specific basic basic IL IL and facile alongalong withwith piperidinepiperidine--appendedappended imidazoliumimidazolium [PAIM][NTf[PAIM][NTf22]] asas tasktask--specificspecific basicbasic ILIL andand facilefacile aldimines 96, and TosMIC 18 in the mild condition, were employed in their article (Scheme 26) [50]. aldiminesaldimines 96, 96, and and TosMIC TosMIC 1818 inin the the mild mild condition condition,condition,, werewere employedemployed ininin theirtheirtheir articlearticlearticle (Scheme(Scheme(Scheme 26 2626)[)) [50].[50].50]. R RR N NN N Suzuki NN SSuuzzuukkii Ar/Het AArr//HHeett Ar Het rr/ e 97 AA //HHett 9977 R RR N NN N NN R r e N RR Ar/H t NN [BMIM][X] Heck AAr//HHeett + os [[BBMMIIMM]][[XX]] HHeecckk r e ++ Tos NC A /H t H TTos NNCC [PAIM][NTf2] AArr//HHeett HH PPAAIIMM NNTTff Br [[ ]][[ 22]] BBrr R 98 96 18 9988 9966 1188 RR R RR N Sonogashira NN N SSoonnooggaasshhiirraa NN Ar/Het AArr//HHeett

R 99 RR 99 99 Scheme 26. SSynthesisynthesis of of C5 C5-substituted-substituted imidazoles imidazoles 97,, 98,, and 99.. SchemeScheme 26.26. SSynthesisynthesis ofof C5C5--substitutedsubstituted imidazolesimidazoles 9797,, 9898,, andand 9999.. InIn the late 2018, Guan and co co-workers-workers developed a novel and high highlyly efficient efficient synthesis of InIn thethe latelate 2018,2018, GuanGuan andand coco--workersworkers developeddeveloped aa novelnovel andand highhighlyly efficientefficient synthesissynthesis ofof polysubstituted 1H1-imidazo-[4,5-H-imidazo-[4,5c] quinoline-c] quinoline derivatives derivatives through thethrough stepwise vanthe Leusenstepwise/Staudinger van/ polysubstitutedpolysubstituted 11HH--imidazoimidazo--[4,5[4,5--cc]] quinolinequinoline derivativesderivatives throughthrough thethe stepwisestepwise vanvan Leusen/Staudinger/azaaza-Wittig/carbodiimide-mediated-Wittig/carbodiimide cyclization-mediated method. cyclization Azides 102 methodwere accessed. Azides by102 the were van access Leusened Leusen/Staudinger/azaLeusen/Staudinger/aza--Wittig/carbodiimideWittig/carbodiimide--mediatedmediated cyclizationcyclization methodmethod.. AzidesAzides 102102 werewere accessaccesseded byreaction the van of 2-azidobenzaldehyde Leusen reaction of 2100-azidob, amineenzaldehyde101, and TosMIC 100, amine18. Then, 101 1, Hand-imidazole-[4,5- TosMIC 18.c ]T quinolinehen, 1H- byby thethe vanvan LeusenLeusen reactionreaction ofof 22--azidobazidobenzaldehydeenzaldehyde 100100,, amineamine 101101,, andand TosMICTosMIC 1818.. TThenhen,, 11HH-- imidazole103 was formed-[4,5-c] q byuinoline a tandem 103 aza-Wittigwas formed reaction by a tandem with isocyanate,aza-Wittig reaction in a moderate with isocyanate to good, yield in a imidazoleimidazole--[4,5[4,5--cc]] qquinolineuinoline 103103 waswas formedformed byby aa tandemtandem azaaza--WittigWittig reactionreaction withwith isocyanateisocyanate,, inin aa moderate(Scheme 27 to)[ good51]. yield (Scheme 27) [51]. moderatemoderate toto goodgood yieldyield (Scheme(Scheme 27)27) [51].[51].

2 R2 R 22 RR22 N RR N NN N NN N CHO NN - CHO K2CO3 ne pot NN 1 CHO 2 1 O -- 1 R + R NH + Tos NC KK22CCOO33 R OOnneeppoott R RR11 ++ 22 ++ ooss , RR11 11 N RR NNHH TT NNCC CH3OH,,DME N RR N NHR3 3 CCHH33OOHHDDMMEE 3 33 NN3 reflux NN3 NN NNHHRR 3 rreefluuxx 3 100 101 18 fl 102 103 1 1 1 1 1 2 1 10000 1001 188 1002 10033 Scheme 27. SSynthesisynthesis of of polysubstituted polysubstituted quinoline quinoline derivatives 103.. SchemeScheme 27.27. SSynthesisynthesis ofof polysubstitutedpolysubstituted quinolinequinoline derivativesderivatives 103103.. InIn 2019, Lammi et al.al. reported reported an an imidazolyl peptidomimetic peptidomimetic,, which which has has shown p proproteinroprotein InIn 2019,2019, LammiLammi etet al.al. reportedreported anan imidazolylimidazolyl peptidomimeticpeptidomimetic,, whichwhich hashas shownshown pproproteinroprotein cconvertaseonvertase subtilisinsubtilisin/Kexin/Kexin 9 9 (PCSK9) (PCSK9 inhibitor) inhibitor bioactivity bioactivity in the in micromolarthe micromolar dosage dosage range. range. As shown As cconvertaseonvertase ssubtilisin/Kexinubtilisin/Kexin 99 ((PCSK9PCSK9)) inhibitorinhibitor biobioactivityactivity inin thethe micromolarmicromolar dosagedosage range.range. AsAs shownin Scheme in Scheme28, the first 28, imidazolethe first imidazole derivative derivative105 was accessed 105 was in accessed good yield, in good starting yield from, startingp-anisaldehyde from p- shownshown inin SchemeScheme 28,28, thethe firstfirst imidazoleimidazole derivativederivative 105105 waswas accessedaccessed inin goodgood yieldyield,, startingstarting fromfrom pp-- anisaldehyde104, methylamine 104, 77methylamine, and TosMIC 7718, and. Then, TosMIC compound 18. Then105, wascompound treated 105 with wasn-butyllithium treated with and n- anisaldehydeanisaldehyde 104104,, methylaminemethylamine 7777,, andand TosMICTosMIC 1818.. ThenThen,, compoundcompound 105105 waswas treatedtreated withwith nn-- butyllithium and DMF as a formylating reagent at low temperatures, to obtain the aldehyde butyllithiumbutyllithium andand DMFDMF asas aa formylatingformylating reagentreagent atat lowlow temperaturetemperatures,s, toto obtainobtain thethe aldehydealdehyde

Pharmaceuticals 2020, 13, x FOR PEER REVIEW 12 of 19 derivative 106 in high yield. The target compounds 107a RIm13 and 107b RIm14 were accessed via a quasiPharmaceuticals-iterative2020 protocol, 13, 37 , with the emphasis on the alternating van Leusen three-component reactions12 of 19 with two formylation steps. In the end, they found that RIm13 represents currently one of the most potentPharmaceuticals proprotein 2020, 1convertase3, x FOR PEER subtilisin/kexin REVIEW 9/low-density lipoprotein receptor, (PCSK9/LDLR12 of )19 protein−proteinPharmaceuticalsDMF as a formylating 2020 interaction, 13, x FOR reagent PEER of small REVIEW at lowmolecules temperatures, (Scheme to 28) obtain [52]. the aldehyde derivative 106 in12 highof 19 yield.derivative The target106 in compounds high yield. 107aThe target RIm13 compounds and 107b RIm14 107a wereRIm13 accessed and 107b via RIm14 a quasi-iterative were accessed protocol, via a derivativewith the emphasis 106 in high on the yield alternating. The target van compounds Leusen three-component 107aH C RIm13 and reactions 107b RIm14 with two were formylation accessed C steps.viaHO a quasi-iterative protocol, with the emphasis on the alternating3 van Leusen three-componentH3C reactions N N quasiIn the-iterative end, theyCHO protocol found that, with RIm13 the emphasis represents on currentlythe alternating one of Nvan the Leusen most potent three proprotein-component convertase reactions with two formylation steps. In the end, they found that RIm13 .represents - , , -currently ℃ one of theN most K2CO3 1 n BuLi THF 78 withsubtilisin two /formylationkexin 9+/low-densityCH Nsteps.H + In lipoprotein the end, they receptor, found (PCSK9 that RIm13/LDLR) represents protein proteincurrently interaction one of the of smallmost potent proprotein convertase3 2 Tos subtilisin/kexinNC 9/low-density lipoprotein. . . receptor, (PCSK9/LDLR) H CO 2 DMF, r t − potentmolecules3 proprotein (Scheme convertase28)[52]. subtilisin/kexinDMF H C9/Olow-density lipoprotein receptor, (PCSK9/LDLR) protein−protein interaction of small molecules3 (Scheme 28) [52]. H3CO protein−protein104 interaction77 of small18 molecules (Scheme1 028)5 [52]. 106 CHO H3C NHCH H C N 3 3 CHO CHO H3C H C N N N5 ℃ 3 N K CO N . n- u , , - N CHO + + 2 3 N 1 B Li THF 78 CH3NH2 N . - , , - ℃ N Tos NC K2CO3 1 n. BuLi, T.H.F 78 H3CO + CH NH + N2 DMF r t 3 2 Tos NC DMF HMCeO . . . H CO 3 N 2 DMF, r t H3CO 3 DMF H CON 104 77 18 3 10R5 H3CO 106 104 77 18 N 105 106 H3CO NHCH3 NH5CH3 = N 107a RIm 13 R CHN2Ph 5 N 107b RIm 14 R=CH CH Ph N Me N2 2 N N Me N N R Scheme 28. Synthesis of inhibitory activityN molecules 107a and 107b. N R H3CO N In 2020, Rashamuse and co-workersH3CO described a microwave-assisted cycloaddition of TosMIC = 107a RIm 13 R CH2Ph 18 with imines and aldehydes to form 1-substituted 5 -aryl = -1H-imidazoles. Imidazoles 110 were also 110077abRRImIm1134RR=CCHHPChH Ph 2 2 2 obtained in a one-pot, two-steps reaction with10 7ab yieldRIm 1 4comparableR=CH CH Ph to that obtained through step-by- 2 2 step irradiation of aldehydeSchemeScheme 28.28.108 SynthesisSynthesis and aliphatic ofof inhibitoryinhibitory amine activityactivity 109, with moleculesmolecules a neat 107a 107amicrowave andand 107b107b .at. 60 °C for 4 min, followed by the additionScheme of 28. TosMIC Synthesis 18 of, K inhibitory2CO3, and activity CH3CN, molecules and the 107a reaction and 107b mixture. was placed underIn Inmicrowave 2020,2020, RashamuseRashamuse conditions andand (Scheme co-workersco-workers 29) [53]. describeddescribed aa microwave-assistedmicrowave-assisted cycloadditioncycloaddition ofof TosMICTosMIC 1818with withMoreoverIn 2020, iminesimines Rashamuse, the andand antibacterialaldehydes aldehydes and co to toproperties-workersform form1-substituted 1- substituteddescribed of these fragments a 5-aryl-15 microwave-aryl-1HH in-imidazoles.-imidazoles. vitro-assisted were cycloaddition ImidazolestestedImidazoles by the 110110 minimumof were wereTosMIC alsoalso inhibitory18obtainedobtained with imines inconcentrationin a a one-pot, one and-pot aldehydes two-steps, two(MIC)-step tobio reactions formreactionassay. 1 - withThesubstituted with results ayield a yield show comparable5-aryl comparableed-1 Hthat-imidazoles. to the thatto MIC that obtained valueobtainedImidazoles throughof compound thro 110ugh step-by-step were step 110a also-by - againstobtainedirradiationstep irradiati Staphylococcus in ofa aldehydeoneon of-pot aldehyde , aureustwo108-andstep was108 aliphatics reaction and15.6 aliphatic μg amine with/mL, 109awhileamine yield, with 110b109comparable a, neat withdisplay microwave a neat toed that amicrowave similar obtained at 60 ◦ CMIC forat thro 60 4value min, ugh°C for followedstepagainst 4 -min,by - stepby the irradiati additionon of of aldehyde TosMIC 10818,K andCO aliphatic, and CHamineCN, 109 and, with the a reaction neat microwave mixture at was 60 placed°C for 4 under min, Bacillusfollowed cereus by, theand addition indicate dof that TosMIC these2 compounds183 , K2CO3, 3and might CH be3CN, further and developedthe reaction to mixture specifically was target placed microbialfollowedmicrowaveunder microwave pathogensbyconditions the addition conditions (Scheme (Scheme of TosMIC30 (Scheme )29. )[53 18]. 29), K [53].2CO3 , and CH3CN, and the reaction mixture was placed underMoreover microwave, the conditions antibacterial (Scheme properties 29) [53]. of these fragments in vitro were tested by the minimum N inhibitoryMoreover concentration, the antibacterial (MIC) biopropertiesassay. The of theseresults fragments showed thatin vitro the MICwere valuetested of by compound the minimum 110a CHO 2 , inhibitory concentration (MIC) bioassay.R The results showK2COed3 C Hthat3CN the MIC valueN of compound 110a against Staphylococcus aureus+ was 15.6+ μg/omLs , while 110b displayed a similar MIC value against NH2 T NC 2 againstBacillus Staphylococcus cereus, and indicate aureusd thatwas these15.6 μgcompounds/mL, while might 110bM be Wdisplay furthered developed a similarR toMIC specifically value against target 1 1 Bacillusmicrobial cereus pathogens, andR indicate (Schemed that 30 )these. compounds might be further Rdeveloped to specifically target microbial pathogens (Scheme108 30).1 09 18 110 N Scheme 29. 110 Scheme 29. SynthesisSynthesis of of a anovel novel class class of of potential potential inhibitors inhibitors of of microbial microbial pathogen pathogenN 110. . CHO 2 , R K2CO3 CH3CN N CHO + NH 2 + Tos NC , Moreover, the antibacterial properties2R N of these fragmentsK2CO3 CHin3CN vitroN were testedN 2 by the minimum + + os MW R NH2 T NC 2 inhibitory concentrationR1 (MIC) bioassay. The results showedMW that the MICR1 valueR of compound 110a 1 N N 1 against StaphylococcusR aureus108 was 15.6109µg/mL, while18 110b displayed a similarR MIC110 value against Bacillus H3C H3C cereus, and indicated that108 these compounds109 might18 be further developed to specifically110 target microbial Scheme 29. SynthesisH3C of a novel class of potentialH3C inhibitors of microbial pathogen 110. CH3 CH3 pathogensScheme (Scheme 29. 30 Synthesis). of a novel class of potential inhibitors of microbial pathogen 110. a 110 N 110b N N N Scheme 30. AntimicrobialN compounds 110a and 110bN . N N H3C H3C H C H C In 2014, the Bunev groupH33C reported a novel processH33C for the synthesis of 1,4,5-trisubstituted CH3 CH3 H3C H3C imidazole-containing trifluoromethylCH3 group 112, which CcontainH ed two-component condensation 110a 3 110b a 110 110b Scheme 30. Antimicrobial compounds 110a and 110b. Scheme 30. Antimicrobial compounds 110a and 110b. Scheme 30. Antimicrobial compounds 110a and 110b. In 2014, the Bunev group reported a novel process for the synthesis of 1,4,5-trisubstituted imidazoleIn 2014,-containing the Bunev trifluoromethyl group reported group a novel 112 , processwhich containfor theed synthesis two-component of 1,4,5- trisubstitutedcondensation imidazole-containing trifluoromethyl group 112, which contained two-component condensation

Pharmaceuticals 2020, 13, x FOR PEER REVIEW 13 of 19

reaction, N-aryltrifluoroacetimidoyl chlorides 111 reacted with TosMIC 18, as well as sodium hydride inPharmaceuticals dry THF at2020 room, 13, 37temperature, under argon atmosphere (Scheme 31, top) [54]. 13 of 19 Then, in 2019, they also previously described a procedure, in which 1-imidoylbenzotriazoles [N- aryl-1-(1H-benzotriazol-1-yl)-2,2,2-trifluoroethan-1-imines] 113 reacted with TosMIC 18, according to In 2014, the Bunev group reported a novel process for the synthesis of 1,4,5-trisubstituted Pharmaceuticalsthe van Leusen 2020, 13 , xreaction FOR PEER to REVIEW obtain a good yield of 1-aryl-4-(4-methylbenzenesulfonyl)13 of -195- imidazole-containing trifluoromethyl group 112, which contained two-component condensation (trifluoromethyl)-1H-imidazoles 114, which is difficult to access. The yield of 114 almost did not reaction, N-aryltrifluoroacetimidoyl chlorides 111 reacted with TosMIC 18, as well as sodium hydride reaction,depend onN- aryltrifluoroacetimidoylthe substituent in the N chlorides-aryl fragment 111 react of edinitial with imidoylbenzotriazole TosMIC 18, as well as 11sodium3 (Scheme hydride 31, in dry THF at room temperature, under argon atmosphere (Scheme 31, top) [54]. inbottom) dry THF [55]. at room temperature, under argon atmosphere (Scheme 31, top) [54]. Then, in 2019, they also previously described a procedure, in which 1-imidoylbenzotriazoles [N- aryl-1-(1H-benzotriazol-1-yl)-2,2,2-trifluoroethanN-1-imines]CF3 113 reacted with TosMIC 18, according to R the van Leusen reaction to obtain a good Clyield of To1s-arylN-4-(4-methylbenzenesulfonyl)-5-

(trifluoromethyl)-1H-imidazoles 114, which is1 1difficult1 to access. TheN yield of 114 almost did not , F C depend on the substituent in the N-aryl fragmentNaH THF of initial imidoylbenzotriazole3 R 113 (Scheme 31, r. ., bottom) [55]. t 2h N 112 Tos NC + N N CF3 N R Ar 18 os N ClN T F3C Tos 111 NN 1,13 F C NaH THF 3 R . ., Nar Ht 2ThHF F C N . . 3 r r t 1h A N 112 Tos NC + N 114 N r Scheme 31. Synthesis18 of imidazoles 112 and 114A containing the trifluoromethyl group. Scheme 31. Synthesis of imidazoles 112 andN 114 containing the trifluoromethyl group. F3C Tos Then, in 2019, they also previously described a procedure, inN which 1-imidoylbenzotriazoles A possible mechanism for synthesis of the1 imidazole13 -containing trifluoromethyl group is shown [N-aryl-1-(1H-benzotriazol-1-yl)-2,2,2-trifluoroethan-1-imines], 113 reacted with TosMIC 18, according NaH THF F C N in Scheme 32. Initially, deprotonation of TosMIC with sodium3 hydride forms stabilized carbanion 18, to the van Leusen reaction to obtain ar good. . yield of 1-aryl-4-(4-Ar methylbenzenesulfonyl)-5- which attacks the carbon–nitrogen bond’s carbont 1h atom of 115, to give the intermediate adduct 116. (trifluoromethyl)-1H-imidazoles 114, which is difficult to access.114 The yield of 114 almost did not Elimination of the R ion from the latter generates intermediate 117, which undergoes intramolecular depend on the substituent in the N-aryl fragment of initial imidoylbenzotriazole 113 (Scheme 31, cyclization Schemeand lead 31s. toSynthesis imidazole of imidazoles 118. 112 and 114 containing the trifluoromethyl group. bottom) [55]. r A possible mechanism for synthesis of the imidazole-containing trifluoromethylA group is shownr A possible mechanism for synthesisA rof the imidazole-containingr trifluoromethyl group is shownA F3C R A in Scheme 32. Initially, deprotonationN of TosMIC with sodium hydrideF3 formsC N stabilized carbanionF3C 18, in Scheme 32. NInitially,aH deprotonation of TosMIC with sodiumN hydride forms stabilized carbanionN 18, os Tos NC + whichT attacksNC - the carbon–nitrogen bond’s carbonos atom of 115,- to giveH the intermediate adduct 116. which attacks theH2 carbon–nitrogenF3 CbondR’s carbonT atom of 115, toR give the intermediateC adduct 116. os N Tos N EliminationElimination of of the the R R ion ion from from the the latter latter generate generatess intermediate intermediateNC 111177,, which whichT undergoes undergoes intramolecular intramolecular cyclizationcyclization and and lead leadss to to 1imidazole imidazole8 11118181..5 116 117 118 Scheme 32. A possible mechanism for the synthesis of imidazole-containing trifluoromethyl group. r A r Ar r A F3C R A N F3C N F3C 4. Other van LeusenNaH Imidazole Synthesis N N Tos NC - Tos NC + H F C R Tos - H 2 3 R C N In 2015, Fodili and collaborators described NCthe synthesisT osof Na 1,4-disubstitutedTos 5- methylimidazole 121. As18 shown in Scheme115 33, compound116 121 was prepared117 by reacting enamine118 1 19 with TosMIC 18, under the presence of tert-butylamine and a catalytic amount of bismuth (III) triflate SchemeScheme 3 32.2. AA possible possible mechanism mechanism for for the the synthesis synthesis of of imidazole imidazole-containing-containing trifluoromethyl trifluoromethyl group. group. in methanol. In this research, it was the first example of a usual rearrangement in the van Leusen imidazole4. Other van synthesis Leusen and Imidazole showed Synthesis that the imidazole ring system can be prepared through reaction 4. Other van Leusen Imidazole Synthesis with TosMIC and a tautomeric enamine, to form a secondary ketamine. The possible mechanism In 2015, Fodili and collaborators described the synthesis of a 1,4-disubstituted 5-methylimidazole involvesIn 2015,the formation Fodili ofand the vancollaborators Leusen imidazoline described intermediate the synthesis, followed of aby 1,4a C-–disubstitutedC bond cleavage 5- 121. As shown in Scheme 33, compound 121 was prepared by reacting enamine 119 with TosMIC 18, methylimidazoleand then subsequent 121. tosylAs shown substitution in Scheme [56]. 3 3, compound 121 was prepared by reacting enamine 119 under the presence of tert-butylamine and a catalytic amount of bismuth (III) triflate in methanol. with TosMIC 18, under the presence of tert-butylamine and a catalytic amount of bismuth (III) triflate In this research, it was the first example of a usual rearrangement in the van Leusen imidazole synthesis in methanol. In this research, it was the first example of a usual rearrangement in the van Leusen and showed that the imidazole ring system can be prepared through reaction with TosMIC and a imidazole synthesis and showed that the imidazole ring system can be prepared through reaction tautomeric enamine, to form a secondary ketamine. The possible mechanism involves the formation of with TosMIC and a tautomeric enamine, to form a secondary ketamine. The possible mechanism the van Leusen imidazoline intermediate, followed by a C–C bond cleavage and then subsequent tosyl involves the formation of the van Leusen imidazoline intermediate, followed by a C–C bond cleavage substitution [56]. and then subsequent tosyl substitution [56].

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O HN O HN OH N O OH N N S N CH3S - Bi(OTf)3 CH + u + Bi(OTf)3 3 + t -BuNH2 + Tos NC . . t B NH2 Tos NC e ,r. ., CH MeOH,r.t.,48h H3 S H3C O O M OH t 48h H3C O O CH3 S H3C O O H3C O O 119 120 18 121 119 119 120 18 121 Scheme 33. The first example of an unusual rearrangement in the van Leusen imidazole synthesis. Scheme 3 33.3. The first first example of an unusual rearrangement in the van Leusen imidazole synthesis.

InIn 2019,2019, thethe the Suresh Suresh group group demonstrated demonstrated the the formationformation formation of of imidazoles imidazoles inin in thethe the presence presence of water of water as aas solventsolvent a solvent and and a base a base-free--freefree conditioncondition condition... TheThe Thereactionreaction reaction ofof dihydrodihydro of dihydro β--carbolinecarbolineβ-carboline iminesimines imines 122 122 andand p-- toluenesulfonylmethylptoluenesulfonylmethyl-toluenesulfonylmethyl isocyanidesisocyanides isocyanides 18 formed18formedformed thethe thecorrespondingcorresponding corresponding substitutedsubstituted substituted N--fusedfusedN-fused imidazoimidazo imidazo 6,116,11-- dihydro6,11-dihydro β--carbolinecarbolineβ-carboline derivativesderivatives derivatives 123,, with123 good, with yields good under yields mild under and green mild conditioncondition and green (Scheme(Scheme condition 334)) [57].(Scheme[57]. 34)[57].

General van Leusen imidazole reaction: General van Leusen imidazole reaction: 3 1 R3 R R3 R1 1 2 + Base R R1CH NR2 + Base R2 R CH NR Tos NC R2 N R3 Tos NC or an c so ven N R3 g i lv t organic solvent N N ' Suresh's work: Suresh's work: R2 R2 R2 R2 R3 N R3 No base N N No base N 1 + R1 N R1 + Tos NC , . . R1 N R Tos NC H O, r.t. 2h N N H2O r t 2h N HN 2 H R3 H H R3 122 18 123 122 123 18 Scheme 34. The base-free van Leusen imidazole synthesis of cyclic imines in water. Scheme 3 34.4. The base base-free-free van Leusen imidazole synthesis of cyclic imines in water. A possible mechanism for the present metal- and base-free imidazole framework is shown in A possible mechanism for the present metal-- and base--freefree imidazoleimidazole frameworkframework iiss shownshown inin Scheme 35. Initially, the precursor dihydro β-carboline imine 122 acts as a base that captures proton Scheme 35.. Initially,Initially, thethe precursorprecursor dihydrodihydro β--carbolinecarboline imineimine 122 acts as a base thatthat capturescaptures protonproton from TosMIC 18, to provide a C-nucleophile, which would add to the dihydro β-carboline imine 122, fromfrom TosMICTosMIC 18,, toto provideprovide aa CC--nucleophile,, whichwhich wouldwould addadd toto thethe dihydrodihydro β--carbolinecarboline imineimine 122,, and then be cyclized to form the intermediate 125 through the intermediate 124. Another molecule of the and then be cyclizedcyclized toto formform thethe intermediateintermediate 125 throughthrough thethe intermediateintermediate 124.. Another molecule of starting dihydro β-carboline imine 122 captures a proton from intermediate 125, then removes the tosyl thethe startingstarting dihydrodihydro β--carbolinecarboline imineimine 122 capturecapturess aa proton from intermediate 125,, thenthen removeremovess thethe group, which might result in the construction of imidazole derivative 123. Subsequently, the product tosyltosyl groupgroup,, which mightight resultresult inin thethe constructionconstruction of imidazole derivative 123.. Subsequently,Subsequently, thethe imidazole 123 might also act as a base following the rational reaction mechanism, as described in product imidazole 123 mightight also act as a base followingfollowing thethe rationalrational reactionreaction mechanismmechanism,, as Scheme 35. described in Scheme 35..

R2 R2 R2 R2 R2 H R2 H C H H N Tos N C N N N Tos N N C N N C N H R N N N H R N N H 1 N 1 N 1 N H R1 H R1 H Tos R R1 H R Tos R H R H Tos R R H R Tos 122 122 18 124 122 125 122 18 124 125

R2 R2 - -TosH N TosH + N 122 + N 122 N N 1 N R1 H R R H R 123 123 Scheme 3 35.5. AA possible possible mechanism mechanism for for the the base base-free-free van Leusen imidazole synthesis synthesis.. Scheme 35. A possible mechanism for the base-free van Leusen imidazole synthesis.

At the same year,, Necardo et al. foundfound an unusual multicomponent synthesis of 4--tosyltosyl--1-- arylimidazoles 127,, byby cconsidering aryl azides as thethe electrophilicelectrophilic partnerspartners forfor thethe TosMICTosMIC 18--

Pharmaceuticals 2020, 13, 37 15 of 19

At the same year, Necardo et al. found an unusual multicomponent synthesis of 4-tosyl-1- PharmaceuticalsPharmaceuticals 20 202020, ,1 133, ,x x FOR FOR PEER PEER REVIEW REVIEW 1515 ofof 1919 arylimidazoles 127, by considering aryl azides as the electrophilic partners for the TosMIC 18-mediated mediatedvanmediated Leusen vanvan cycloaddition. LeusenLeusen cycloadditioncycloaddition In this transformation,.. InIn thisthis transformation,transformation, it is the first itit example isis thethe firstfirst of example theexample reaction ofof the ofthe two reactreact TosMICionion ofof twomoleculestwo TosMICTosMIC participating moleculesmolecules participatparticipat in van Leuseninging ininimidazole vanvan LeusenLeusen synthesis imidazoleimidazole (Scheme synthesissynthesis 36)[ (Scheme58(Scheme]. 3366)) [58[58]]..

RR

NN33 -- , ttBBuuOOKK,DDMMFF NN ++ 22 TTooss NNCC ℃℃ .... NN 00 ttoorrtt 3300mminin RR TTooss 112266 1188 112277 SchemeScheme 36.36. SynthesisSynthesisSynthesis ofof of 127127127 byby vanvan LeusenLeusen imidazoleimidazole synthesissynthesis withwith twotwo TosMICTosMIC TosMIC...

AA plausibleplausible scenario scenario for for th thethee MCR MCR is is shown shown in in SchemeScheme 3737.. In In In thethe the initiationinitiation initiation stepstep step,,, thethe the TosMICTosMIC TosMIC anionanion attacksattacks NN---333 ofof of thethe the azideazide azide 128128128 tototo produceproduce produce intermediateintermediate intermediate 129129129.. Then,.Then, Then, NN--N11 -1 interceptsintercepts intercepts thethe the isocyanideisocyanide isocyanide inin a ina 66- a- endo6-endo-trigendo--trigtrig cyclizationcyclization cyclization toto toformform form anionanion anion 130130130,, whichwhich, which isis quenched isquenched quenched byby by aa protonproton a proton sourcesource source toto give togive give 131131131.. OwingOwing. Owing toto itstoits itsinstability,instability, instability, compoundcompound compound 131131131 processesprocessesprocesses aa [4 a[4 [4 ++ +2]2]2] cycloreversioncycloreversion cycloreversion toto to formform formationationation 132132132,, ,withwith with aa a lossloss loss of of nitrogen.nitrogen. Subsequently, Subsequently, the tthehe imine imineimine of ofof132 132132passes passpass througheses throughthrough anattack anan attackattack by a secondbyby aa secondsecond molecule moleculemolecule of the TosMIC ofof thethe TosMICanion,TosMIC followed anion, anion, followed followed by ring by by closure, ring ring closure closure to produce,, to to produc produc133.ee At 133 133 this.. At At point, this this point, point, after after after protonation, protonation, protonation, intermediate intermediate intermediate134 134regains134 regainsregains aromaticity aromaticityaromaticity via aviavia base-assisted aa basebase--assistedassisted mechanism, mechanimechanism withsm,, withwith the expulsionthethe expulsionexpulsion of the ofof mostthethe mostmost acidic acidicacidic proton protonproton and andlossand oflossloss hydrogen ofof hydrogenhydrogen cyanide cyanidecyanide and sulfinate. andand sulfinatsulfinat Undere.e. strong UnderUnder basic strongstrong condition, basicbasic excessconditionconditiont-BuOK,, excessexcess deprotonates tt--BuOKBuOK deprotonatesthedeprotonates newly formed thethe newlynewly hydrogen formedformed cyanide, hydrogenhydrogen avoiding cyanide,cyanide, the release avoidingavoiding of toxicthethe releaserelease HCN. of Itof istoxictoxic worth HCN.HCN. noting ItIt isis that worthworth the notingtwonoting molecules thatthat thethe two oftwo TosMIC molemoleculescules partake ofof TosMICTosMIC in the reaction partakepartake mechanism inin thethe reactionreaction in two mechanismmechanism different in paths,in twotwo withdifferentdifferent the second pathpaths,s, molecule in Scheme 37 undergoing a fragmentation resulting in the incorporation of a C H into the withwith thethe secondsecond moleculemolecule inin SSchemecheme 3737 undergoingundergoing aa fragmentationfragmentation resultingresulting inin thethe incorporationincorporation− ofof atargeta C−HC−H molecule.intointo thethe targettarget molecule.molecule.

NN NN HH NN OO OO -- NN NN ttBBuuOOHH NN OO N 112288 N SS CCHH33 NN SS CCHH33 NN SS CCHH33 OO NN NN OO NN NN OO NN NN OO SS NNCC OO 112299 113300 113311

HH33CC rreetrtroo 44++22 1188 HH [[ ]] NN22 NN HH NN NN OO NN OO OO OO SS SS NN OO NN SS N OO NN OO NN SS CCHH33 NN N OO ++ ++ OO CCHH33 OO CCHH33 HHCCNN SS SS 113322 OO SS OO OO OO OO -- ttBBuuOOKK NN SS CCHH33 OO

CCHH33 CCNN HH33CC HH33CC HHCC 33 113355 113344 113333 1188 SchemeSchemeScheme 37. 37. AA plausibleplausible scenario scenario for for thethe vv vananan LeusenLeusen imidazoleimidazole imidazole synthesissynthesis synthesis withwith with twotwo two TosMICTosMIC TosMIC moleculesmolecules molecules...

InIn 2019, 2019, the the one one-potone--potpot three three-componentthree--componentcomponent van van Leusen Leusen chemistry chemistry wa waswass us useduseded for for the thethe DNA DNA-encodedDNA--encodedencoded librarieslibraries (( (DELs)DELDELs)s) synthesissynthesis byby the the Staz Staz group, group, which which provid providedprovideedd the thethe first firstfirst publishedpublished DNA DNA-compatibleDNA--compatiblecompatible approachapproach to to form form unusual unusual highly highly functionalized functionalized imidazoles. imidazoles. TheThe The targettarget DELDEL productionproduction productionsss 138138 werewere obtainedobtained from fromfrom thethe aldehydealdehyde functionalized functionalizedfunctionalized DNA DNADNA molecule moleculemolecule136 136136, amine,, amineamine137 137137, and,, andand TosMIC TosMICTosMIC derivatives derivativesderivatives18 1818by byby the thethe van vvan Leusenan LeusenLeusen reaction. reactionreaction Moreover,.. Moreover,Moreover, a wide aa widewide variety varietyvariety of amines, ofof amines,amines, commercial commercialcommercial TosMIC TosMICTosMIC molecules moleculesmolecules and andandaldehyde aldehydealdehyde as the asas variety thethe varietyvariety element elementelement in the threeinin thethe ingredients threethree ingredientingredient heterocyclizationss heterocyclizationheterocyclization were investigated werewere investigatedinvestigated under an underunderoptimized anan condition,optimizedoptimized respectively. condition,condition, respectively. Thisrespectively. transformation ThisThis transformationtransformation meaningfully expanded meaningfullymeaningfully the application expandexpandeded of vanthethe applicationapplicationLeusen imidazole ofof vvanan synthesisLeusenLeusen imidazoleimidazole and DNA synthesissynthesis compatible andand chemistries DNADNA compcomp (Schemeatibleatible chemistrieschemistries 38)[59]. (Scheme(Scheme 3388)) [[5959].].

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2 O O R 3 O N R ase DNA 1 + 2 + b N N R R NH2 . DNA H Tos NC aq DMA N R1 H R3 136 137 18 138 SchemeScheme 38 38.. DNADNA-compatible-compatible v vanan Leusen Leusen imidazole imidazole heterocyclization. heterocyclization. 5. Conclusions 5. Conclusions In summary, under the in-depth research and application in imidazole-based medicinal chemistry In summary, under the in-depth research and application in imidazole-based medicinal and the progress in other disciplines—such as cell biology,molecular biology,pharmacology,and organic chemistry and the progress in other disciplines—such as cell biology, molecular biology, chemistry—an increasing number of imidazole-containing drugs with lower toxic, better efficacy, pharmacology, and organic chemistry—an increasing number of imidazole-containing drugs with superior pharmacokinetic characteristics, effective pathologic probes and diagnostic agents would lower toxic, better efficacy, superior pharmacokinetic characteristics, effective pathologic probes and be used in clinics. This could make remarkable contributions for the protection of mankind’s health. diagnostic agents would be used in clinics. This could make remarkable contributions for the Therefore, the van Leusen imidazole synthesis based on TosMICs will play an increasingly central protection of mankind’s health. Therefore, the van Leusen imidazole synthesis based on TosMICs part in the synthesis of bioactive compounds as clinic drugs in drug design and synthesis. We could will play an increasingly central part in the synthesis of bioactive compounds as clinic drugs in drug focus on the changing of the various aldimine groups and TosMIC derivatives in the van Leusen design and synthesis. We could focus on the changing of the various aldimine groups and TosMIC reaction to modify the imidazole derivatives in future. Above all these have clearly indicated the derivatives in the van Leusen reaction to modify the imidazole derivatives in future. Above all these infinite potentiality of van Leusen imidazole synthesis in medicinal chemistry. Additionally, we hope have clearly indicated the infinite potentiality of van Leusen imidazole synthesis in medicinal this review would build a full foundation and reference source which would open up new thoughts chemistry. Additionally, we hope this review would build a full foundation and reference source for researchers to focus on in imidazole-based medicinal molecule design and synthesis chemistry. which would open up new thoughts for researchers to focus on in imidazole-based medicinal moleculeAuthor Contributions: design and synthesisAll authors chemistry. wrote the paper. All authors have read and agreed to the published version of the manuscript. AuthorFunding: Contributions:Financial support All authors of this researchwrote the provided paper. All by authors the Science have and read Technology and agreed Planning to the published Project of version the Jilin ofProvince the manuscript. (20160414015GH) is greatly acknowledged.

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