Recent Advances in the Synthesis of Oxazole-Based Molecules Via Van Leusen Oxazole Synthesis

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Review Recent Advances in the Synthesis of Oxazole-Based Molecules via van Leusen Oxazole Synthesis

Xunan Zheng 1,2, Wei Liu 3,* and Dawei Zhang 1,*

1 College of Chemistry, Jilin University, Changchun 130012, China; [email protected] 2 College of Plant Science, Jilin University, Changchun 130062, China 3 Department of Pesticide Science, Plant Protection College, Shenyang Agricultural University, Shenyang 110866, China * Correspondence: [email protected] (W.L.); [email protected] (D.Z.); Tel.: +86-188-1775-2588 (W.L.); +86-431-8783-6471 (D.Z.) Academic Editors: Anna Carbone and Fabio Bertozzi Received: 2 March 2020; Accepted: 23 March 2020; Published: 31 March 2020

Abstract: Oxazole compounds, including one nitrogen atom and one oxygen atom in a ﬁve-membered heterocyclic ring, are present in various biological activities. Due to binding with a widespread spectrum of receptors and enzymes easily in biological systems through various non-covalent interactions, oxazole-based molecules are becoming a kind of signiﬁcant heterocyclic nucleus, which have received attention from researchers globally, leading them to synthesize diverse oxazole derivatives. The van Leusen reaction, based on tosylmethylisocyanides (TosMICs), is one of the most appropriate strategies to prepare oxazole-based medicinal compounds. In this review, we summarize the recent advances of the synthesis of oxazole-containing molecules utilizing the van Leusen oxazole synthesis from 1972, aiming to look for potential oxazole-based medicinal compounds, which are valuable information for drug discovery and synthesis.

Keywords: van Leusen; TosMICs; oxazole; synthesis

1. Introduction The oxazole ring, with one nitrogen atom and one oxygen atom, which are widely displayed in natural products and synthetic molecules, is known as a prime skeleton for drug discovery. On the account of structural and chemical diversity, oxazole-based molecules, as a central scaffold, not only enable different types of interactions with various receptors and enzymes, showing broad biological activities, but also occupy a core position in medicinal chemistry, showing their enormous development value and they favored the discovery of newer potential therapeutic agents [1–5]. Consequently, a wide variety of oxazole-containing compounds, as clinical drugs or candidates, have been frequently employed, which play a vital role in the treatment of diverse types of diseases like antibacterial [6–8], antifungal [9–11], anti-inflammatory [12–14], antiviral [15–17], anti-tubercular [18–20], anticancer [21–23], anti-parasitic [24–26], antidiabetic [27–29], and so on. The marketed drugs containing the oxazole ring system with medicinal value are being actively exploited worldwide. Various pharmacological activities and chemical structures of oxazole-based molecules are enumerated in the following Table1.

Molecules 2020, 25, 1594; doi:10.3390/molecules25071594 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 18 Molecules 2020, 25, x FOR PEER REVIEW 2 of 18 Table 1. The pharmacological activities and chemical structures of typical oxazole-based molecules. Table 1. The pharmacological activities and chemical structures of typical oxazole-based molecules. Molecules 2020MoleculesMolecules, 25Pharmacological, 1594 2020 2020, ,25 25, ,x x FOR FOR PEER PEER REVIEW REVIEW 22 of of 18 218 of 18 MoleculesPharmacological 2020, 25, x FOR PEER REVIEW Chemical Structures 2 of 18 Molecules 2020Activities, 25, x FOR PEER REVIEW Chemical Structures 2 of 18 TableTableActivities 1. 1. The The pharmacological pharmacological activities activities and and chemical chemical structures structures of of typical typical oxazole-based oxazole-based molecules. molecules. Table 1. TheTable pharmacological 1. The pharmacological activities activities and chemical and chemical structures structures of typicalof typical oxazole-based oxazole-based molecules. molecules. TablePharmacological 1. The pharmacological activities and chemical structures of typical oxazole-based molecules. Pharmacological Chemical Structures PharmacologicalActivities Chemical Structures PharmacologicalPharmacologicalActivities Chemical Structures Activities ChemicalChemical Structures Structures ActivitiesActivitiesAntibacterial Antibacterial

AntibacterialAntibacterial Antibacterial AntibacterialAntibacterial

Antifungal Antifungal

AntifungalAntifungal AntifungalAntifungal Antifungal

Anti- Anti- inflammatory inflammatory

Anti-Anti- Anti-inﬂammatoryAnti- inflammatoryinflammatory inflammatoryAnti- inflammatory

Antiviral Antiviral

AntiviralAntiviralAntiviral Antiviral Antiviral

Antitubercular Antitubercular Antitubercular

AntitubercularAntitubercular Antitubercular Antitubercular

AnticancerAnticancer MoleculesAnticancer 2020, 25, x FOR PEER REVIEW 3 of 18 Molecules 2020, 25, x FOR PEER REVIEW 3 of 18

AnticancerAnticancer Anticancer Anticancer Antiparasitic AntiparasiticAntiparasitic

AntidiabeticAntidiabetic Antidiabetic

Due to the diversity of therapeutic response profiles, the chemical synthesis of oxazole and its derivativesDue to hasthe becomediversity a ofkey therapeu objectivetic andresponse has dr profiles,awn much the chemicalattention synthesisof current of pharmacologists oxazole and its andderivatives chemists has around become the a globekey objective to be explored and has exha drawnustively much for attention the benefit of currentof mankind. pharmacologists Until now, manyand chemists ingenious around oxazole the syglobenthesis to bemethodologies explored exha haveustively been for developed, the benefit including of mankind. the van Until Leusen now, reactionmany ingenious [30], Cornforth oxazole reaction synthesis [31], methodologies Fisher reacti onhave [32], been Doyle developed, reaction [33],including Dakin–West the van reaction Leusen [34],reaction as well[30], asCornforth Robinson–Gabriel reaction [31], reaction Fisher [35],reacti etc..on [32],Among Doyle these reaction synthetic [33], Dakin–Weststrategies, it reactionis well- known[34], as thatwell the as vanRobinson–Gabriel Leusen oxazole reaction synthesis, [35], based etc.. on Among tosylmethylisocyanides these synthetic strategies, (TosMICs), it isis one well- of theknown most that convenient the van Leusen and attractive oxazole protocols synthesis, for based the preparationon tosylmethylisocyanides of oxazole-based (TosMICs), molecules, is owingone of tothe its most excellent convenient virtues and like attractive simple operation,protocols for easily the preparationobtained raw of materials,oxazole-based and amolecules, broad substrate owing scope,to its excellent and it has virtues been like developed simple operation, rapidly in easily the pastobtained decades. raw Itmaterials, is worth and mentioning a broad substratethat the pharmacologicalscope, and it has activity been developedoxazole-based rapidly compounds in the past11, 16 decades. and 25 inIt Tableis worth 1 can mentioning be obtained that by vanthe Leusenpharmacological reaction as activity a key step.oxazole-based compounds 11, 16 and 25 in Table 1 can be obtained by van LeusenTosMIC, reaction a kindas a keyof the step. most significant reactants, has many good features at room temperature includingTosMIC, stable a kind solid, of theodorless, most significant and colorless. reactants, Since has it manywas introduced good features and at applied room temperature in organic synthesisincluding bystable the Dutchsolid, odorless,professor andvan Leusencolorless. in Since1972, thisit was reagent introduced is also andknown applied as van in Leusen’s organic reagent.synthesis Today, by the TosMICDutch professor and its devanrivatives Leusen have in 1 972,been this recognized reagent isas also one knownof the mostas van significant Leusen’s buildingreagent. Today,blocks in TosMIC organic and synthesis its de andrivatives a great have deal been of reaction recognized scenarios, as one which of the have most been significant fruitfully employedbuilding blocks in the in preparation organic synthesis of pyrrole-, and a imidazol great deale-, of and reaction oxazole-based scenarios, five-membered which have been heterocyclic fruitfully moleculesemployed [36–40].in the preparation General van of Lepyrrole-,usen synthesis imidazol basee-, and on TosMICsoxazole-based is summarized five-membered in Scheme heterocyclic 1. molecules [36–40]. General van Leusen synthesis base on TosMICs is summarized in Scheme 1.

Molecules 2020, 25, x FOR PEER REVIEW 3 of 18

Antiparasitic

Antidiabetic

Molecules 2020, 25, 1594 3 of 18

Due to the diversity of therapeutictherapeutic response profiles,profiles, the chemical synthesis of oxazole and its derivatives has become a key objective and has drawndrawn muchmuch attentionattention of currentcurrent pharmacologistspharmacologists and chemists around the globe to be explored exhaustivelyexhaustively for the benefitbenefit of mankind. Until Until now, now, many ingenious oxazole synthesissynthesis methodologies have been developed, including the van Leusen reaction [[30],30], CornforthCornforth reaction reaction [31 [31],], Fisher Fisher reaction reaction [32 [32],], Doyle Doyle reaction reaction [33 ],[33], Dakin–West Dakin–West reaction reaction [34], as[34], well as aswell Robinson–Gabriel as Robinson–Gabriel reaction reaction [35], etc.. [35], Among etc.. Among these syntheticthese synthetic strategies, strategies, it is well-known it is well- thatknown the that van the Leusen van Leusen oxazole oxazole synthesis, synthesis, based based on tosylmethylisocyanides on tosylmethylisocyanides (TosMICs), (TosMICs), is one is one of the of mostthe most convenient convenient and and attractive attractive protocols protocols for the for preparation the preparation of oxazole-based of oxazole-based molecules, molecules, owing owing to its excellentto its excellent virtues virtues like simple like operation,simple operation, easily obtained easily obtained raw materials, raw materials, and a broad and substrate a broad scope, substrate and itscope, has been and developedit has been rapidly developed in the rapidly past decades. in the Itpast is worth decades. mentioning It is worth that thementioning pharmacological that the activitypharmacological oxazole-based activity compounds oxazole-based11, 16 compoundsand 25 in Table 11,1 16 can and be 25 obtained in Table by 1 van can Leusen be obtained reaction by asvan a keyLeusen step. reaction as a key step. TosMIC, a kindkind ofof thethe mostmost significantsignificant reactants,reactants, has many good features at room temperaturetemperature including stablestable solid, solid, odorless, odorless, and and colorless. colorless. Since Since it was it introducedwas introduced and applied and applied in organic in synthesis organic bysynthesis the Dutch by professorthe Dutch van professor Leusen van in 1972, Leusen this reagentin 1972, isthis also reagent known is as also van known Leusen’s as reagent. van Leusen’s Today, TosMICreagent. andToday, its derivativesTosMIC and have its beenderivatives recognized have asbeen one recognized of the most as significant one of the building most significant blocks in building blocks in organic synthesis and a great deal of reaction scenarios, which have been fruitfully organic synthesis and a great deal of reaction scenarios, which have been fruitfully employed in the employed in the preparation of pyrrole-, imidazole-, and oxazole-based five-membered heterocyclic preparation of pyrrole-, imidazole-, and oxazole-based five-membered heterocyclic molecules [36–40]. molecules [36–40]. General van Leusen synthesis base on TosMICs is summarized in Scheme 1. General van Leusen synthesis base on TosMICs is summarized in Scheme1.

Scheme 1. General van Leusen synthesis base on tosylmethylisocyanides (TosMICs). Scheme 1. General van Leusen synthesis base on tosylmethylisocyanides (TosMICs). Based on our previous research, we have published two reviews about the van Leusen reaction Based on our previous research, we have published two reviews about the van Leusen reaction for the preparation of pyrrole- and imidazole-based molecules [41,42]. Therefore, this review, which for the preparation of pyrrole- and imidazole-based molecules [41,42]. Therefore, this review, which covers the literature from 1972, will summarize the recent advances of the synthesis of oxazole-based covers the literature from 1972, will summarize the recent advances of the synthesis of oxazole-based molecules utilizing the van Leusen oxazole synthesis as an important part of van Leusen reaction, which molecules utilizing the van Leusen oxazole synthesis as an important part of van Leusen reaction, is the [3+2] cycloaddition reaction based on TosMICs. Meanwhile, it is expected that this review article which is the [3+2] cycloaddition reaction based on TosMICs. Meanwhile, it is expected that this willMolecules be beneﬁcial 2020, 25, x FOR for freshPEER REVIEW opportunities to search for a reasonable design for oxazole-containing drugs.4 of 18 review article will be beneficial for fresh opportunities to search for a reasonable design for oxazole- 2.containing General vandrugs. Leusen Oxazole Synthesis In 1972, 1972, van van Leusen Leusen et etal. al.first ﬁrstdiscovered discovered a nove al novelchemical chemical strategy strategy for the formation for the formation of oxazole- of oxazole-basedbased heterocyclic heterocyclic ring systems. ring systems. In this In study, this study, 5-substituted 5-substituted oxazoles oxazoles 2929 werewere obtained obtained from aldehydes 2828and and TosMIC TosMIC25 25as as a precursor a precursor in a in one-pot a one-pot reaction reaction under under mild condition,mild condition, which iswhich widely is knownwidely known as the van as the Leusen van Leusen oxazole ox synthesisazole synthesis (Scheme (Scheme2)[30]. 2) [30].

Scheme 2. The first ﬁrst example of van Leusen oxazole synthesis.

As shown in Scheme 3 3,, thethe vanvan LeusenLeusen oxazoleoxazole synthesissynthesis allowsallows thethe preparationpreparation ofof 5-5- substitutedsubstituted oxazole through a two-step [3[3+2]+2] cycloaddition cycloaddition reac reactiontion from from aldehydes with TosMICs under a base condition. In this process, the TosMIC contains reactive isocyanide carbons, active methylene, and leaving groups as C2N1 “3-atom synthon”. After adding the deprotonated TosMIC to the aldehyde and bond formation between the resulting hydroxy group and the isocyano group, an oxazoline results as an intermediate. Then, with concomitant elimination of -TosH, the intermediates are given to the obtained 5-substituted oxazoles.

Scheme 3. Mechanism of van Leusen oxazole synthesis.

3. Developments of the van Leusen Oxazole Synthesis In 1999, the Ganesan group developed a synthetic route of the 5-aryloxazoles 31. They utilized a new polystyrene-SO2-CH2-NC with polystyrene-SH resin as starting material in three steps for the preparation of an immobilized sulfonylmethyl isocyanide 25’, in order to illustrate the isocyanide resin’s potential. This protocol was similar to the solution-phase preparation of TosMIC or related analogues. Then, they used a quaternary ammonium hydroxide ion exchange resin to catalyze the reaction of TosMIC 25 with aromatic aldehydes 30 to generate the 5-aryloxazoles 31. By analysis, they anticipated that polymer-supported-TosMIC (PS-TosMIC) and tetrabutylammonium hydroxide would be a realistic solid-phase replacement for other applications of TosMIC (Scheme 4) [43,44].

Scheme 4. Synthesis of 5-aryloxazoles 31.

In 2000, Sisko’s group found that van Leusen reaction of aryl-substituted TosMIC reagents with aldehydes had not been relatively explored. Hence, they surmised these reactions should be

Molecules 2020, 25, x FOR PEER REVIEW 4 of 18 Molecules 2020, 25, x FOR PEER REVIEW 4 of 18 2. General van Leusen Oxazole Synthesis 2. General van Leusen Oxazole Synthesis In 1972, van Leusen et al. first discovered a novel chemical strategy for the formation of oxazole- basedIn heterocyclic1972, van Leusen ring etsystems. al. first discoveredIn this study, a nove 5-substitutedl chemical strategy oxazoles for the29 formationwere obtained of oxazole- from aldehydesbased heterocyclic 28 and TosMIC ring systems. 25 as a Inprecursor this study, in a one-pot5-substituted reaction oxazoles under mild29 were condition, obtained which from is widelyaldehydes known 28 and as the TosMIC van Leusen 25 as oxa precursorazole synthesis in a one-pot (Scheme reaction 2) [30]. under mild condition, which is widely known as the van Leusen oxazole synthesis (Scheme 2) [30].

Scheme 2. The first example of van Leusen oxazole synthesis. Scheme 2. The first example of van Leusen oxazole synthesis. As shown in Scheme 3, the van Leusen oxazole synthesis allows the preparation of 5- substituted oxazoleMoleculesAs 2020shownthrough, 25, 1594in a Scheme two-step 3, [3+2]the van cycloaddition Leusen oxazole reac sytionnthesis from allowsaldehydes the preparation with TosMICs of 5- under substituted a4 base of 18 condition.oxazole through In this a process, two-step the [3+2] TosMIC cycloaddition contains reac reactivetion from isocyanide aldehydes carbons, with activeTosMICs methylene, under a baseand leavingcondition. groups In In this as process, C2N1 “3-atom the TosMIC synthon”. contains After reactivere adactiveding isocyanidethe deprotonated carbons, TosMIC active methylene,to the aldehyde and andleaving bond groups formation as C2N1C2N1 between “3-atom“3-atom the synthon”.synthon”. resulting After hydroxy ad addingding group the anddeprotonated the isocyano TosMIC group, to thean oxazoline aldehyde resultsand bondbond as an formationformation intermediate. between between Then, the the resultingwith resulting concomitant hydroxy hydroxy groupelimination group and theand of isocyano -TosH,the isocyano the group, intermediates group, an oxazoline an oxazolineare results given toasresults the an intermediate.obtained as an intermediate. 5-substituted Then, withThen, oxazoles. concomitant with concomitant elimination elimination of -TosH, of -TosH, the intermediates the intermediates are given are togiven the obtainedto the obtained 5-substituted 5-substituted oxazoles. oxazoles.

Scheme 3. Mechanism of van Leusen oxazole synthesis. Scheme 3. Mechanism of van Leusen oxazole synthesis. Scheme 3. Mechanism of van Leusen oxazole synthesis. 3. Developments Developments of the van Leusen Oxazole Synthesis 3. Developments of the van Leusen Oxazole Synthesis In 1999, thethe GanesanGanesan groupgroup developeddeveloped aa synthetic synthetic route route of of the the 5-aryloxazoles 5-aryloxazoles31 31. They. They utilized utilized a In 1999, the Ganesan group developed a synthetic route of the 5-aryloxazoles 31. They utilized anew new polystyrene-SO polystyrene-SO2-CH2-CH2-NC2-NC withwith polystyrene-SHpolystyrene-SH resinresin asas startingstarting materialmaterial inin threethree steps for the preparationa new polystyrene-SO of an immobilized2-CH2-NC sulfonylmethylwith polystyrene-SH isocyanide resin 25’as star,, in tingorder material to illustrate in three the steps isocyanideisocyanide for the resin’spreparation potential. of an This Thisimmobilized protocol protocol was wassulfonylmethyl similar similar to to the the isocyanide solution-phase 25’, in preparation preparationorder to illustrate of of TosMIC TosMIC the isocyanide or related analogues.resin’s potential. Then, Then, Thisthey they protocolused used a a quaternary was similar ammonium to the solution-phase hydroxide hydroxide ion ionpreparation exchange of resin TosMIC to catalyze or related the reactionanalogues. of TosMIC Then, they 25 with used aromatic a quaternary aldehydes ammonium 30 to generate hydroxide the 5-aryloxazolesion exchange resin31.. By By to analysis, analysis, catalyze they they the anticipatedreaction of TosMIC thatthat polymer-supported-TosMIC polymer-supported-TosMIC 25 with aromatic aldehydes (PS-TosMIC) 30(PS-TosMIC) to generate and tetrabutylammoniumandthe 5-aryloxazoles tetrabutylammonium 31. hydroxideBy analysis, hydroxide would they wouldbeanticipated a realistic be a realisticthat solid-phase polymer-supported-TosMIC solid-phase replacement replacement for other for applications(PS-TosMIC) other applications of and TosMIC tetrabutylammoniumof TosMIC (Scheme (Scheme4)[43,44 4)]. [43,44].hydroxide would be a realistic solid-phase replacement for other applications of TosMIC (Scheme 4) [43,44].

Scheme 4. Synthesis of 5-aryloxazoles 31. Scheme 4. Synthesis of 5-aryloxazoles 31. In 2000, Sisko’s group found that van Leusen reaction of aryl-substituted TosMIC reagents with MoleculesIn 2000, 2020, 25 Sisko’s, x FOR groupPEER REVIEW found that van Leusen reaction of aryl-substituted TosMIC reagents 5with of 18 aldehydes had not been relatively explored. Hence, they surmised these reactions should be particularly aldehydesIn 2000, had Sisko’s not groupbeen relativelyfound that explored.van Leusen Henc reactione, they of aryl-substitutedsurmised these TosMIC reactions reagents should with be concise,particularly require concise, mild reactionrequire condition,mild reaction and becondition, tolerant ofand a vastbe tolerant range of of functional a vast range groups. of Then,functional they aldehydes had not been relatively explored. Hence, they surmised these reactions should be groups. Then, they proved through the experiment that similar cycloaddition reactions with available proved through the experiment that similar cycloaddition reactions with available and multifunctional aldehydesand multifunctional proceed smoothly aldehydes to generateproceed smoothly a wide variety to generate of interesting a wide oxazolevariety compoundsof interesting with oxazole high yield.compounds For example, with high methylketone yield. For example,33 could methylketone be obtained in 33 a goodcould yieldbe obtained from pyruvaldehyde in a good yield32 fromand aryl-substitutedpyruvaldehyde 32 TosMIC and aryl-substituted reagent 25 (Scheme TosMIC5)[45 reagent]. 25 (Scheme 5) [45].

Scheme 5. Synthesis of methylketone 33 via aryl-substituted TosMIC reagent. Scheme 5. Synthesis of methylketone 33 via aryl-substituted TosMIC reagent.

In 2005, Chakrabarty et al. described a van Leusen route of 3/2-formylindoles with TosMIC to prepare corresponding indolyloxazoles and stable indolyl primary enamines. This reaction was provided in refluxing methanol and could complete quickly in 3–6 h. Besides the expected 5-(3- indolyl)oxazoles products, the novel rearranged indolyl primary enamines might be also formed. As shown in Scheme 6, two different results were obtained from substituted indole derivatives 34a on one hand and from 34b on the other hand. Specifically, each of 34a furnished two products, viz. 35 and 36, respectively. On the contrary, each of 34b furnished only one type of products 36. Likewise, as shown in Scheme 7, each of 37a generated two products 38 and 39, each of 37b furnished only one product 38. However, by testing 37c, the result was that the final product was only 39. [46]. As to the mechanism of the formation of compound 36, the intermediate products in the process of carboxylic acids through nitriles form aldehydes and ketones with TosMIC 25. Then, the lone pair of electrons on the indolic nitrogen triggers the protonation (from methanol) of the enamidic double bond, resulting in the indoleninium species. Subsequently, a 1,2-shift of the tosyl group with simultaneous neutralization of the indoleninium cation, followed by the loss of a proton, gives rise to the intermediate. A nucleophilic attack by methanol, followed by the loss of a molecule of methyl formate and subsequent protonation, gives rise to the enamines 36.

Scheme 6. The reaction of 3/2-formylindoles with TosMIC and 34.

Scheme 7. The reaction of 3/2-formylindoles with TosMIC and 37.

In 2007, Kotha and co-workers reported that both C2-symmetric and C3-symmetric oxazole derivatives were synthesized through the stepwise Suzuki–Miyaura cross-coupling and the van Leusen synthesis. In this process, the raw materials of bis- and triscarboxaldehydes could be offered

Molecules 2020, 25, x FOR PEER REVIEW 5 of 18 particularly concise, require mild reaction condition, and be tolerant of a vast range of functional groups. Then, they proved through the experiment that similar cycloaddition reactions with available and multifunctional aldehydes proceed smoothly to generate a wide variety of interesting oxazole compounds with high yield. For example, methylketone 33 could be obtained in a good yield from pyruvaldehyde 32 and aryl-substituted TosMIC reagent 25 (Scheme 5) [45].

Molecules 2020, 25, 1594 5 of 18 Scheme 5. Synthesis of methylketone 33 via aryl-substituted TosMIC reagent.

In 2005, Chakrabarty Chakrabarty et et al. al. described described a avan van Leus Leusenen route route of of3/2-formylindoles 3/2-formylindoles with with TosMIC TosMIC to prepareto prepare corresponding corresponding indolyloxazoles indolyloxazoles and and stable stable indolyl indolyl primary primary enamines. enamines. This Thisreaction reaction was wasprovided provided in refluxing in refluxing methanol methanol and could and could complete complete quickly quickly in 3–6 in h. 3–6 Besides h. Besides the expected the expected 5-(3- indolyl)oxazoles5-(3-indolyl)oxazoles products, products, the novel the novel rearranged rearranged indolyl indolyl primary primary enamines enamines might might be also be also formed. formed. As Asshown shown in Scheme in Scheme 6, 6two, two different di fferent results results were were obtained obtained from from substituted substituted indole indole derivatives derivatives 34a on one hand and from 34b on the otherother hand.hand. Specifically, Specifically, each of 34a34a furnishedfurnished twotwo products,products, viz.viz. 35 and 36,, respectively.respectively. OnOn thethe contrary, contrary, each each of of34b 34bfurnished furnished only only one one type type of of products products36 .36 Likewise,. Likewise, as asshown shown in in Scheme Scheme7, each7, each of of37a 37agenerated generated two two products products38 38and and39 39,, each each of of 37b37b furnishedfurnished onlyonly one product 38. HoweverHowever,, by testing 37c,, thethe resultresult waswas thatthat thethe finalfinal productproduct waswas onlyonly 3939.[ 46[46].]. As to the mechanism of the formation of compound 36,, the the intermediate intermediate products products in the process process of carboxylic carboxylic acids acids through through nitriles nitriles form form aldehydes aldehydes and and ketones ketones with with TosMIC TosMIC 25. 25Then,. Then, the lone the lonepair pairof electrons of electrons on the on indolic the indolic nitrog nitrogenen triggers triggers the protonation the protonation (from methanol) (from methanol) of the enamidic of the enamidic double bond,double resulting bond, resulting in the inindoleninium the indoleninium species. species. Subsequently, Subsequently, a 1,2-shift a 1,2-shift of ofthe the tosyl tosyl group group with simultaneous neutralizationneutralization ofof thethe indoleniniumindoleninium cation, cation, followed followed by by the the loss loss of of a proton,a proton, gives gives rise rise to tothe the intermediate. intermediate. A A nucleophilic nucleophilic attack attack by by methanol, methanol, followed followed by by the the lossloss ofof aa moleculemolecule ofof methyl formate and subsequent protonation,protonation, gives riserise toto thethe enaminesenamines 3636..

Scheme 6. TheThe reaction reaction of of 3/2-formy 3/2-formylindoleslindoles with TosMIC and 34..

Scheme 7. TheThe reaction reaction of of 3/2-formy 3/2-formylindoleslindoles with TosMIC and 37..

In 2007, Kotha and co-workers reported that both C2-symmetric and C3-symmetric oxazole In 2007, Kotha and co-workers reported that both C2-symmetric and C3-symmetric oxazole derivatives were synthesized through the stepwise Suzuki–Miyaura cross-coupling and the van Leusen derivatives were synthesized through the stepwise Suzuki–Miyaura cross-coupling and the van synthesis. In this process, the raw materials of bis- and triscarboxaldehydes could be offered through Leusen synthesis. In this process, the raw materials of bis- and triscarboxaldehydes could be offered a Suzuki–Miyaura cross-coupling reaction of corresponding arylboronic acid reagents. Then, the aldehydes were further treated with TosMIC 25 in the presence of K2CO3 in refluxing methanol to deliver the corresponding oxazole derivatives. The different products were generated surprisingly through changing the position and number of aldehyde groups. Specifically, when trialdehyde derivatives 40 were treated with TosMIC 25 in a typical reaction condition, the corresponding C3-symmetric oxazole derivatives 41 were generated (Scheme8, path A). After confirming 41, they also prepared other C3- and C2-symmetric oxazole derivatives 43 (Scheme8, path B) and 45 through changing the substrates 42 and 44, respectively (Scheme8, path C) [47]. Molecules 2020, 25, x FOR PEER REVIEW 6 of 18 Molecules 2020, 25, x FOR PEER REVIEW 6 of 18 through a Suzuki–Miyaura cross-coupling reaction of corresponding arylboronic acid reagents. Then, the aldehydes were further treated with TosMIC 25 in the presence of K2CO3 in refluxing methanol the aldehydes were further treated with TosMIC 25 in the presence of K2CO3 in refluxing methanol to deliver the corresponding oxazole derivatives. The different products were generated surprisingly through changing the position and number of aldehyde groups. Specifically, when trialdehyde derivatives 40 were treated with TosMIC 25 in a typical reaction condition, the corresponding C3- derivatives 40 were treated with TosMIC 25 in a typical reaction condition, the corresponding C3- symmetric oxazole derivatives 41 werewere generatedgenerated (Scheme(Scheme 8,8, pathpath A).A). AfterAfter confirmingconfirming 41,, theythey alsoalso prepared other C3- and C2-symmetric oxazole derivatives 43 (Scheme 8, path B) and 45 through preparedMolecules 2020 other, 25, 1594 C3- and C2-symmetric oxazole derivatives 43 (Scheme 8, path B) and 45 through6 of 18 changing the substrates 42 andand 44,, respectivelyrespectively (Scheme(Scheme 8,8, pathpath C)C) [47].[47].

SchemeScheme 8.8. Synthesis of C 2- and C3-symmetric-symmetric oxazole oxazole derivatives derivatives 4141,, 4343,, and and 45.. Scheme 8. Synthesis of C2- and C33-symmetric oxazole derivatives 41, 43, and 45.

In 2009, Yu and co-worker developed a van Leusen reaction to synthesize the 4,5-disubstituted In 2009, Yu and co-worker developed a van Leusen reactionreaction toto synthesizesynthesize thethe 4,5-disubstituted4,5-disubstituted oxazoles in a one-pot manner. The special characteristic of this reaction was the ionic liquid as solvent. oxazoles in a one-pot manner. The special characteristic of this reaction was the ionic liquid as solvent. The target oxazole products 48 were generated from TosMIC 25, various aldehydes 46 and aliphatic The target oxazole products 48 werewere generatedgenerated fromfrom TosMICTosMIC 25,, variousvarious aldehydesaldehydes 46 andand aliphaticaliphatic halides 47. This reaction had a high yield and a broad substrate scope. Since the electron withdrawing halides 47.. ThisThis reactionreaction hadhad aa highhigh yieldyield andand aa broadbroad susubstrate scope. Since the electron withdrawing group could facilitate the reaction, aromatic aldehydes substrates with electron withdrawing group group could facilitate the reaction, aromatic aldehydes substrates with electron withdrawing group exhibited higher reactivity. It is noteworthy that this reaction is eco-friendly and economical, since the exhibited higher reactivity. It is noteworthy that this reaction is eco-friendly and economical, since ionic liquids can be recovered and reused as solvent for six runs without conspicuous loss of yield the ionic liquids can be recovered and reused as solvent for six runs without conspicuous loss of yield (Scheme9)[ 48]. (Scheme 9) [48].

Scheme 9. A one-pot synthesis of 4,5-disubstituted oxazoles 48 in ionic liquid. Scheme 9. A one-pot synthesis of 4,5-disubstituted oxazoles 4848 inin ionicionic liquid.liquid. From 2011 to 2018, the Šindler–Kulyk group reported a series of reactions to synthesize the From 2011 to 2018, the Šindler–Kulyk group reported a series of reactions to synthesize the 5- 5-substituted oxazole compounds. substituted oxazole compounds. In 2011, they described a novel approach for the synthesis of naphthoxazole and fused In 2011, they described a novel approach for the synthesis of naphthoxazole and fused heterobenzoxazole derivatives. In this report, the starting 5-(aryl/furyl/thienyl/pyridyl ethenyl) heterobenzoxazole derivatives. In this report, the starting 5-(aryl/furyl/thienyl/pyridyl ethenyl) oxazoles 50 were obtained through a van Leusen process between the corresponding α,β-unsaturated oxazoles 50 werewere obtainedobtained throughthrough aa vanvan LeusenLeusen processprocess betweenbetween thethe correspondingcorresponding α,,β-unsaturated aldehydes 49 and TosMIC 25 in a good yield. Then, the intermediate oxazoles underwent UV irradiation aldehydes 49 andand TosMICTosMIC 25 inin aa goodgood yield.yield. Then,Then, thethe intermediateintermediate oxazolesoxazoles underwentunderwent UVUV in aerobic condition in the presence of iodine, transforming into the naphthoxazoles 51 and other fused

heterobenzoxazoles (Scheme 10, method A) [49]. In 2014, they also synthesized the novel trans-5-(2-vinylstyryl)oxazole 53 through the van Leusen reaction between trans-3-(2-vinylphenyl) acrylaldehyde 52 and TosMIC 25. The trans-3-(2-vinylphenyl) acrylaldehyde 52 was prepared through the Wittig reaction of ovinylbenzaldehyde and (formylmethylene) triphenylphosphorane. For the preparation of 5-(2-vinylstyryl) oxazole by this route, 3-(2-vinylphenyl) acrylaldehyde was needed. As the configuration of the starting aldehyde 52 Molecules 2020, 25, x FOR PEER REVIEW 7 of 18 irradiation in aerobic condition in the presence of iodine, transforming into the naphthoxazoles 51 and other fused heterobenzoxazoles (Scheme 10, method A) [49]. In 2014, they also synthesized the novel trans-5-(2-vinylstyryl)oxazole 53 through the van Leusen reaction between trans-3-(2-vinylphenyl) acrylaldehyde 52 and TosMIC 25. The trans-3-(2- vinylphenyl)Molecules 2020, 25 acrylaldehyde, 1594 52 was prepared through the Wittig reaction of ovinylbenzaldehyde7 and of 18 (formylmethylene) triphenylphosphorane. For the preparation of 5-(2-vinylstyryl) oxazole by this route, 3-(2-vinylphenyl) acrylaldehyde was needed. As the configuration of the starting aldehyde 52 for the van Leusen reaction with TosMIC 25 was in trans configuration,configuration, the obtained corresponding product 5-(2-vinylstyryl)oxazole 53 retainedretained thethe transtrans configurationconfiguration (Scheme(Scheme 1010,, methodmethod B)B) [[50].50]. The same group synthesized the required p- and and o-substituted-substituted 5-arylethenyloxazoles 5-arylethenyloxazoles 55 from the corresponding αα,β,β-unsaturated-unsaturated aldehydes aldehydes54 54and and the the TosMIC TosMIC25 through 25 through the van the Leusen van Leusen reaction reaction under undera typical a typical reaction reaction condition condition in 2018. in To 2018. further To broaden further thebroaden substrate the substrate scope of naphtho scope of [1– naphthod]oxazoles, [1– dother]oxazoles, 5-(arylethenyl)oxazoles other 5-(arylethenyl)oxazoles55 were prepared 55 were from prepared the corresponding from the corresponding aryl-substituted aryl-substitutedα-unsaturated αaldehydes-unsaturated54 and aldehydes TosMIC 5425 and. This TosMIC process 25. This took process place as took depicted place above,as depicted treating above, with treating TosMIC with in TosMICone-step in synthesis one-step through synthesis the through van Leusen the van reaction Leusen (Scheme reaction 10 ,(Scheme method 10, C) [method51]. C) [51].

Scheme 10.10. SynthesisSynthesis of of naphthoxazoles naphthoxazoles and and fused fused heterobenzoxazoles heterobenzoxazoles 5151,, trans-5-(2- trans-5-(2- vinylstyryl)oxazole 53, and 5-(arylethenyl)oxazoles 55..

In 2011, 2011, Hamon Hamon and and co-workers co-workers adopted adopted a aconver convergentgent process process based based on on the the cross-coupling cross-coupling of 2,6-bis(oxazol-5-yl)of 2,6-bis(oxazol-5-yl) pyridine pyridine 57 57andand 2-bromopyridine 2-bromopyridine 5858 derivativesderivatives through through the the double double C-H activation ofof thethe oxazoleoxazole rings,rings, to to perform perform the the synthesis synthesis of of oligo-heteroaryles. oligo-heteroaryles. As As shown shown in Schemein Scheme 11, precursor11, precursor57 was57 was obtained obtained under under the the van van Leusen Leusen oxazole oxazole synthesis synthesis condition condition withwith TosMICTosMIC 25 and pyridine-2,6-dicarbaldehyde 5656 asas starting starting material material which which was was afforded aﬀorded through through the theoxidation oxidation of 2,6- of lutidine.2,6-lutidine. The The Pd Pdcatalyzed catalyzed coupling coupling of of5757 andand 2-bromopyridine 2-bromopyridine 5858 underunder known known condition condition to to form the pentaheteroarylepentaheteroaryle BOxaPy BOxaPy59 59in in a 45%a 45% yield. yield. To generateTo generate TOxaPy TOxaPy61 unambiguously, 61 unambiguously, another another novel processnovel process was devised was indevised which in terminal which oxazole terminal moieties oxazole were moieties synthesized were fromsynthesized the corresponding from the pentacycliccorresponding bisformyl pentacyclic intermediate bisformyl60 intermediate(Scheme 12). 60 The (Scheme key step 12). for The the key synthesis step for of the TOxaPy synthesis61 was of TOxaPythe classic 61 van was Leusen the classic oxazole van synthesisLeusen oxazo betweenle synthesis aldehyde between60 and aldehyde TosMIC 25 60, givingand TosMIC the target 25, giving ligand TOxaPythe target61 ligandin a 50% TOxaPy yield. 61 In in thisa 50% process, yield. itIn is this worth process, mentioning it is worth that mentioning the ligand TOxaPythat the 61ligandhas TOxaPyan unprecedented 61 has an binding unprecedented behavior binding with quadruplexes, behavior with which quadruplexes, shows a good which potential shows for a further good potentialapplication for in further the anticancer application drug in discoverythe anticancer [52]. drug discovery [52].

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Scheme 11. Synthesis of BOxaPy 59. Scheme 11. Synthesis of BOxaPy 59. Scheme 11. Synthesis of BOxaPy 59.

Scheme 12. Synthesis of potential anticancer drug TOxaPy 61. Scheme 12. SynthesisSynthesis of potential anticancer drug TOxaPy 61. Scheme 12. Synthesis of potential anticancer drug TOxaPy 61. In 2012, 2012, Zhang Zhang et et al. al. developed developed a straightforward a straightforward and and efficient efficient synthetic synthetic method method to form to form5-(3- In 2012, Zhang et al. developed a straightforward and efficient synthetic method to form 5-(3- 5-(3-indolyl)-oxazolesindolyl)-oxazoles 64, further64, further used to used synthesize to synthesize a class a of class products of products which were which similar were similarto the natural to the indolyl)-oxazolesIn 2012, Zhang 64 , etfurther al. developed used to synthesize a straightforward a class of and products efficient which synthetic were methodsimilar to to the form natural 5-(3- naturalproduct product pimprinine. pimprinine. The reaction, The reaction, which which was in was a inmixture a mixture of DME of DME and and methanol methanol as as solvent solvent with productindolyl)-oxazoles pimprinine. 64, furtherThe reaction, used to which synthesize was in a classa mixture of products of DME which and weremethanol similar as tosolvent the natural with TosMIC 2525 fromfromcompound compound62 62,, a affordedfforded 5-(1 5-(1HH-indol-3-yl)oxazole-indol-3-yl)oxazole63 63in in a 66%a 66% yield yield in in the the presence presence of TosMICproduct 25pimprinine. from compound The reaction, 62, afforded which 5-(1 wasH -indol-3-yl)oxazolein a mixture of DME 63 andin a 66%methanol yield asin thesolvent presence with theof the ion exchangeion exchange resin resin of Ambersep of Ambersep®900(OH).®900(OH). By this By way, this they way, synthesized they synthesized a sequence a of sequence pimprinine of ofTosMIC the ion 25 exchangefrom compound resin of 62 Ambersep, afforded ®5-(1900(OH).H-indol-3-yl)oxazole By this way, 63they in asynthesized 66% yield ina thesequence presence of analoguespimprinine and analogues then tested and theirthen anti-fungaltested their® activities.anti-fungal The activities. biological The testing biological showed testing that showed some of that the pimprinineof the ion exchangeanalogues resinand thenof Ambersep tested their900(OH). anti-fungal By activities.this way, The they biological synthesized testing a showedsequence that of productssome of the display products a broad display spectrum a broad anti-fungicidal spectrum activityanti-fungicidal against plantactivity pathogens against growing.plant pathogens At last, somepimprinine of the analogues products anddisplay then atested broad their spectrum anti-fungal anti-fungicidal activities. The activity biological against testing plant showed pathogens that theygrowing. found At that last, seven they offound the products that seven showing of the strongerproducts activity showing were stronger affirmed activity as the were most affirmed prospective as growing.some of theAt last,products they founddisplay that a broadseven ofspectrum the prod anti-fungicidalucts showing stronger activity activityagainst wereplant affirmed pathogens as candidatesthe most prospective for further study.candidates Further for structuralfurther study. optimization Further of structural pimprinine optimization analogues wasof pimprinine being well thegrowing. most Atprospective last, they candidatesfound that forseven further of the study. products Further showing structural stronger optimization activity were of affirmedpimprinine as atanalogues present, was alongside being morewell at precise present, biological alongside testing more of precise compounds biological with testing a high of biological compounds activity, with in a analoguesthe most prospective was being well candidates at present, for alongsidefurther study. more Furtherprecise biologicalstructural testingoptimization of compounds of pimprinine with a orderhigh biological to define theiractivity, classes in order of fungicidal to define activity their classes better of (Scheme fungicidal 13)[ activity53]. better (Scheme 13) [53]. highanalogues biological was beingactivity, well in atorder present, to define alongside their clmoreasses precise of fungicidal biological activity testing better of compounds (Scheme 13) with [53]. a high biological activity, in order to define their classes of fungicidal activity better (Scheme 13) [53].

Scheme 13. Synthesis of potential artiﬁcial compound 64. Scheme 13. Synthesis of potential artificial compound 64. Scheme 13. Synthesis of potential artificial compound 64. In 2013, Lee et al. publishedScheme 13. aSynthesis protocol of for potential the marine artificial natural compound product 64. streptochlorin. N-Boc protectedIn 2013, aldehydes Lee et 65al. werepublished reacted a withprotocol TosMIC for 25thethrough marine anatural van Leusen product reaction streptochlorin. in the presence N-Boc of protectedIn 2013, aldehydes Lee et al.65 werepublished reacted a protocolwith TosMIC for the 25 marinethrough natural a van Leusen product reaction streptochlorin. in the presence N-Boc protectedK2COIn3 as2013, basealdehydes Lee in methanol, et al.65 werepublished providing reacted a protocolwith the desired TosMIC for oxazolethe 25 marinethrough compound natural a van66 Leusen product. It was reaction interestingstreptochlorin. in the that presence theN-Boc Boc protectionof K2CO3 as group base in got methanol, lost during providing this transformation. the desired oxazole To compensate compound forthe 66. undesiredIt was interesting deprotection that the of ofprotected K2CO3 as aldehydes base in methanol, 65 were reacted providing with the TosMIC desired 25 oxazole through compound a van Leusen 66. It reactionwas interesting in the presence that the of K2CO3 as base in methanol, providing the desired oxazole compound 66. It was interesting that the

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Boc protection group got lost during this transformation. To compensate for the undesired thedeprotection Boc protective of the group, Boc protective it was reprotected group, it was at thereprotectedN-1 position at the to N give-1 position compound to give66. compound Then, further 66. studyThen, further was continued study was on continued this basis. on In this order basis. to In construct order to aconstruct series of a streptochlorin-based,series of streptochlorin-based, focused analogfocused library, analog as library, well as as the well screening as the ofscreening additional of bioactivities,additional bioactivities, researchers researchers are now focusing are now on thefocusing further on extension the further of extension the functional of the group functional tolerance group and tolerance substrate and scope substrate of the scope above of describedthe above syntheticdescribed sequencessynthetic sequences and the evaluation and the evaluati for additionalon for additional bioactivities bioactivities (Scheme 14 (Scheme)[54]. 14) [54].

N O N CHO O CHO K2CO3 X + Tos NC K2CO3 X + Tos NC MeOH N MeOH N NBoc NBoc Boc Boc 65 25 66 65 25 66 Scheme 14. The marine natural product streptochlorin analogue 66.. Scheme 14. The marine natural product streptochlorin analogue 66. In 2015, the Georgiades group reported a new synthetic route, which contained only seven steps, In 2015, the Georgiades group reported a new synthetic route, which contained only seven steps, to synthesize the unusual ‘propeller-like’ pyridyl-oxazole architecture with alternating pyridines and to synthesize the unusual ‘propeller-like’ pyridyl-oxazole architecture with alternating pyridines and oxazole rings. This method utilized the van Leusen reaction for the construction of oxazole moieties oxazole rings. This method utilized the van Leusen reaction for the construction of oxazole moieties with aldehydes as starting materials, two Pd(II)/Cu(I)-mediated cross-coupling reactions including with aldehydes as starting materials, two Pd(II)/Cu(I)-mediated cross-coupling reactions including C-H activation of oxazoles for the construction of C-C bonds between bromopyridine intermediates C-H activation of oxazoles for the construction of C-C bonds between bromopyridine intermediates and oxazole derivatives. As shown in Scheme 15, 1,3-dipolar cycloaddition progress was carried out and oxazole derivatives. As shown in Scheme 15, 1,3-dipolar cycloaddition progress was carried out on two ketone moieties of 67 withwith thethe reagentreagent TosMICTosMIC 2525,, underunder thethe conditioncondition ofof KK22COCO33 as base in on two ketone moieties of 67 with the reagent TosMIC 25, under the condition of K2CO3 as base in reﬂuxing methanol, making an eﬃcient transformation of 67 into the target tris-oxazole compound refluxing methanol, making an efficient transformation of 67 into the target tris-oxazole compound 68 [55]. 68 [55].

Scheme 15. Synthesis of ‘propeller-like’ anticancer biomolecular target 68.. Scheme 15. Synthesis of ‘propeller-like’ anticancer biomolecular target 68. In 2016, Shah et al. invented a preparation method of flexible tripodal 1,3-oxazoles through In 2016, Shah et al. invented a preparation method of flexible tripodal 1,3-oxazoles through utilizing 1,3,5-trimethyl-benzene as a substrate for transformation into the C -sym-metric scaffolds. utilizing 1,3,5-trimethyl-benzene as a substrate for transformation into the C3-sym-metric scaffolds. utilizing 1,3,5-trimethyl-benzene as a substrate for transformation into the C3-sym-metric scaffolds. The tris-aldehyde substrates were synthesizedsynthesized fromfrom 1,3,5-tris(bromomethyl)-2,4,6-trimethylbenzene1,3,5-tris(bromomethyl)-2,4,6-trimethylbenzene throughThe tris-aldehyde coupling withsubstrates different were phenolic synthesized aldehydes from under 1,3,5-tris(bromomethyl)-2,4,6-trimethylbenzene a basic condition in a high yield. Then, the through coupling with different phenolic aldehydes under a basic condition in a high yield. Then, the van Leusen reaction was used to construct the oxazole rings betweenbetween tris-aldehyde substrates 69 and TosMICvan Leusen25 with reaction K CO wasin used refluxing to construct methanol, the oxazole giving therings desired between 5-substituted tris-aldehyde tris-oxazoles substrates 6970 andin a TosMIC 25 with K22CO3 in refluxing methanol, giving the desired 5-substituted tris-oxazoles 70 in a good goodTosMIC yield 25 (Schemewith K2CO 16)[3 in56 refluxing]. methanol, giving the desired 5-substituted tris-oxazoles 70 in a good yield (Scheme 16) [56].

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Scheme 16. Synthesis of flexible ﬂexible tripodal 1,3-oxazoles 70 as molecular scascaffolds.ﬀolds.

In 2016, Vinary KumarKumar andand co-workersco-workers described a novel modifiedmodified van Leusen protocol for the preparation of 5-(het)aryl oxazoles 73.. They used substituted (het) aryl methyl alcohols 71 or benzyl bromides 7272 asas thethe startingstarting materialsmaterials whichwhichwere were converted converted to to aldehyde aldehyde through through in-situ in-situ oxidation oxidation in in a ®® propylphosphonica propylphosphonic anhydride anhydride (T3P (T3P®)–DMSO)–DMSO oror DMSODMSO media,media, respectively.respectively. Then,Then, thethe homologoushomologous aldehyde reacted with TosMIC 2525,, givinggiving thethe oxazolesoxazoles underunder thethe aqueous-alcoholicaqueous-alcoholic KOHKOH conditioncondition with the yieldsyields rangingranging fromfrom 61%61% toto 90%.90%. This is the firstfirst substrate-modifiedsubstrate-modified van Leusen reaction which can proceed under a mildmild reactionreaction condition,condition, and it is toleranttolerant of variousvarious functional groups with a high yield. This method is also efficient efficient an andd eco-friendly, and the products are easily purifiedpurified

(Scheme 1717))[ [57].57].

Scheme 17. A novel modified van Leusen strategy for the synthesis of 73. Scheme 17. A novel modified van Leusen strategy for the synthesis of 73. In the following year, the Ponomarenko group invented various synthetic routes for the In the following year, the Ponomarenko group invented various synthetic routes for the preparation of linear phenyloxazoles and their trimethylsilane (TMS) group substituted derivatives, preparation of linear phenyloxazoles and their trimethylsilane (TMS) group substituted derivatives, which could serve as the novel luminescent dye under a mild condition, by a combination of the which could serve as the novel luminescent dye under a mild condition, by a combination of the van van Leusen process and direct C-H arylation reaction. At the first step of method A, symmetric Leusen process and direct C-H arylation reaction. At the first step of method A, symmetric 1,4-bis(1,3- 1,4-bis(1,3-oxazol-5-yl)benzene 75 was generated from terephthaloyl aldehyde 74 and TosMIC 25 under oxazol-5-yl)benzene 75 was generated from terephthaloyl aldehyde 74 and TosMIC 25 under the the typical van Leusen condition. In the method B, 1-bromo-4-(trimethylsilyl)benzene was lithiated at typical van Leusen condition. In the method B, 1-bromo-4-(trimethylsilyl)benzene was lithiated at the the first step to obtain (trimethylsilyl)benzaldehyde 77. After that, aldehyde 77 was translated into first step to obtain (trimethylsilyl)benzaldehyde 77. After that, aldehyde 77 was translated into 5- 5-substituted 4-(trimethylsilyl)phenyloxazole 78 with TosMIC 25 under the van Leusen condition. The substituted 4-(trimethylsilyl)phenyloxazole 78 with TosMIC 25 under the van Leusen condition. The target linear products 76 and 79, were generated at the following steps by direct C-H arylation process target linear products 76 and 79, were generated at the following steps by direct C-H arylation process with 4-substituted bromobenzene derivatives and 1,4-paradibromobenzene, with the yield of 80%, with 4-substituted bromobenzene derivatives and 1,4-paradibromobenzene, with the yield of 80%, 74%, and 84%, respectively (Scheme 18). 74%, and 84%, respectively (Scheme 18). The synthetic scheme of the two kinds of linear phenyloxazoles was exhibited, in which The synthetic scheme of the two kinds of linear phenyloxazoles was exhibited, in which method method A (Scheme 18) comprises fewer reaction stages compared with the preparation of the exact A (Scheme 18) comprises fewer reaction stages compared with the preparation of the exact 1,4-bis(5- 1,4-bis(5-phenyloxazol-2-yl)benzene (POPOP) structure (Scheme 18, method B). Due to the concise and phenyloxazol-2-yl)benzene (POPOP) structure (Scheme 18, method B). Due to the concise and efficient synthesis and excellent optical properties as well as high photo- and thermo- stability, the efficient synthesis and excellent optical properties as well as high photo- and thermo- stability, the novel luminescent dyes might find broad application in organic photonics [58]. novel luminescent dyes might find broad application in organic photonics [58].

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Scheme 18. Synthesis of POPOP structural isomers 76 and 79. Scheme 18. Synthesis of POPOP structural isomers 76 and 79.

InIn 2017,2017, Mahdavi’sMahdavi’sScheme groupgroup 18. describeddescribed Synthesis of anan POPOP eefficientﬃcient structural protocolprotocol isomers forfor thethe 76 formationandformation 79. ofof oxazoles.oxazoles. ThisThis approach proceeded through through a a unique unique van van Leusen Leusen reaction reaction in in the the presence presence of oftriethylamine triethylamine and and β- βcyclodextrin-cyclodextrinIn 2017, (Mahdavi’sβ (-CD)β-CD) with with group water water described as as solvent. solvent. an Theefficient The reaction reaction protocol was was forformed formed the formationbetween diverseof oxazoles. aldehydealdehyde This substratesapproach proceeded80 and TosMIC through 25 ina uniquea system van of LeusenEt3N and reaction β-CD atin 50°Cthe presence in water. of It triethylamine was clearly assured and β- substrates 80 and TosMIC 25 in a system of Et3N and β-CD at 50 ◦C in water. It was clearly assured thatthatcyclodextrin thethe oxazoleoxazole (β-CD)81 81was was with formed formed water in in anas an excellentsolvent. excellent yieldThe yield reaction through through thewas the analysis formed analysis of between the of reactionthe reactiondiverse mixtures. mixtures.aldehyde This novelThissubstrates novel approach 80approach and improves TosMIC improves the 25 vanin the a Leusensystem van Leusen reactionof Et3 Nreac and greatlytion β-CD greatly since at 50°C thesince catalytic in the water. catalytic amounts It was amounts clearly of base assuredof can base be usedcanthat be the to used promoteoxazole to promote 81 the was reaction the formed reaction at lowin an at temperatures lowexcellent temperatures yield and through water and water can the bean can actedalysis be acted asof athe greenas reaction a green media mediamixtures. for this for reactionthisThis reaction novel (Scheme approach (Scheme 19)[ 59improves19)]. [59]. the van Leusen reaction greatly since the catalytic amounts of base can be used to promote the reaction at low temperatures and water can be acted as a green media for this reaction (Scheme 19) [59].

Scheme 19. Synthesis of 81 by modified van Leusen reaction using green media. Scheme 19. Synthesis of 81 by modified van Leusen reaction using green media. In 2017, Kotha and co-workers published a new application of a van Leusen synthesis. In this In 2017, Kotha and co-workers published a new application of a van Leusen synthesis. In this work, the van LeusenScheme synthesis19. Synthesis was of used81 by asmodified a key stepvan Leusen to construct reaction a series using ofgreen five-membered media. oxazole work, the van Leusen synthesis was used as a key step to construct a series of five-membered oxazole heterocycles, giving the star shaped molecules containing diverse heterocycles integrated with several heterocycles,In 2017, Kothagiving and the co-workersstar shaped published molecules a newcontaining application diverse of a heterocyvan Leusencles synthesis.integrated In with this variations 83. The tri-aldehyde substrates 82 were synthesized from heterocycle derivatives through severalwork, the variations van Leusen 83. synthesisThe tri-aldehyde was used substrates as a key st82ep were to construct synthesized a series from of five-memberedheterocycle derivatives oxazole the Vilsmeier–Haack reaction under K2CO3 and methanol condition in a medium yield. This step had throughheterocycles, the Vilsmeier–Haack giving the star reactionshaped undermolecules K2CO co3 andntaining methanol diverse condition heterocy in acles medium integrated yield. withThis a broad substrate scope since the furan or thiophene derivatives could be synthesized equally. Then, stepseveral had variations a broad 83substrate. The tri-aldehyde scope since substrates the furan 82 or were thiophene synthesized derivatives from heterocycle could be synthesized derivatives the tri-aldehyde substrates 82 were treated with TosMIC 25, transforming into the targeted oxazole equally.through theThen, Vilsmeier–Haack the tri-aldehyde reaction substrates under 82 K were2CO3 andtreated methanol with TosMIC condition 25 in, transforming a medium yield. into This the products 83 through a van Leusen route (Scheme 20). In this work, the authors also investigated targetedstep had oxazole a broad products substrate 83 scopethrough since a van the Leusen furan routeor thiophene (Scheme derivatives20). In this work,could thebe authorssynthesized also the fluorescent behavior of these molecules containing π-conjugated systems. The results indicated investigatedequally. Then, the the fluorescent tri-aldehyde behavi substratesor of these82 were molecules treated withcontaining TosMIC π-conjugated 25, transforming systems. into Thethe that the C3-Symmetric molecules containing furan moieties possessed a stronger fluorescence than resultstargeted indicated oxazole productsthat the C833-Symmetric through a van molecules Leusen routecontaining (Scheme furan 20 ).moieties In this work, possessed the authors a stronger also thiophene-substituted star-shaped compounds [60]. fluorescenceinvestigated thanthe fluorescentthiophene-substi behavitutedor of star-shaped these molecules compounds containing [60]. π-conjugated systems. The results indicated that the C3-Symmetric molecules containing furan moieties possessed a stronger fluorescence than thiophene-substituted star-shaped compounds [60].

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Scheme 20. Synthesis of C3-symmetric-symmetric star-shaped star-shaped molecules 83. Scheme 20. Synthesis of C3-symmetric star-shaped molecules 83. In 2017, Civcir et al. found a new application of the van Leusen reaction. In this work, a series of designedIn 2017, new Civcir molecules et al. containingfound a new thiophene-based, application of the furan-based van Leusen oxazole, reaction. isoxazole, In this work, and isothiazole a series of moietiesdesigned werenew molecules synthesizedsynthesized containing through thiophene-based, thethe vanvan LeusenLeusen furan-based reaction.reaction. By oxazole, following isoxazole, this reaction, and isothiazole oxazole derivativesmoieties were 85 with synthesized corresponding through heterocyclic the van Leusen cores, werereaction. provided By following through thethis reaction reaction, of suitableoxazole 2-formylderivatives substitutedsubstituted 85 with corresponding furan furan or thiopheneor thiophene heterocyclic derivatives derivatives cores,84 werewith 84 TosMICprovided with 25TosMIC through(Scheme 25the 21 ,(Schemereaction top). Additionally, of21, suitable top). theAdditionally,2-formyl three ringsubstituted the systems three offuranring furan systems or or thiophene of furan 87orderivatives thiophenewhich had 8784 the whichwith oxazole hadTosMIC rings the oxazol substituted25 (Schemee rings87 substituted at21, their top). 2- and87Additionally, at 5-positions, their 2- theand were three 5-positions, also ring successfully systems were of also obtainedfuran succe or thiophene fromssfully the obtained di-formyl 87 which from substrates had thethe oxazoldi-formyl86 (Schemee rings substrates 21substituted, bottom). 86 This(Scheme87 at reaction their 21, 2-bottom). was and suitable 5-positions, This reaction for di wereﬀerent was also suitable aldehydes succe forssfully withdifferent furanobtained aldehydes or thiophene from with the sincefurandi-formyl bothor thiophene thesesubstrates oxazole since 86 syntheticboth(Scheme these 21, methods oxazole bottom). occurredsynthetic This reaction withmethods good was occurred tosuitable excellent withfor yielddifferent good [61 to]. aldehydes excellent yield with [61].furan or thiophene since both these oxazole synthetic methods occurred with good to excellent yield [61].

Scheme 21. SynthesisSynthesis of heterocyclic systems derivatives 85 and 87 based on TosMIC. Scheme 21. Synthesis of heterocyclic systems derivatives 85 and 87 based on TosMIC. At the same year, the Georgiades group found that oligomeric chemical compounds composed At the same year, the Georgiades group found that oligomeric chemical compounds composed by successive N,O-heteroaromatic rings, could be introduced for products with useful and mild by successiveAt the same N, Oyear,-heteroaromatic the Georgiades rings, group could found be thatintroduced oligomeric for chemicalproducts compoundswith useful composedand mild properties as alternative substances for biomolecular recognition. Thereupon, they developed a propertiesby successive as alternativeN,O-heteroaromatic substances rings, for biomolecularcould be introduced recognition. for products Thereupon, with they useful developed and mild a synthetic method based on van Leusen reaction, along with oxazoles which were formed by C-H syntheticproperties method as alternative based on substa van ncesLeusen for reaction, biomolecular along recognition.with oxazoles Thereupon, which were they formed developed by C-H a activation and following by their C-C cross-coupling to 2-bromopyridines in order to collect a class activationsynthetic methodand following based onby vantheir Leusen C-C cross-coupling reaction, along to 2-bromopyridineswith oxazoles which in order were toformed collect by a classC-H of variable-length, ‘head-to-tail’-connected, pyridyl-oxazole ligands. For constructing the skeleton ofactivation variable-length, and following ‘head-to-tail’-connected, by their C-C cross-coupling pyridyl-oxazole to 2-bromopyridines ligands. For constructing in order to the collect skeleton a class of of oligomers, one of the main chemical methods was to establish which was from the conversion oligomers,of variable-length, one of the‘head-to-tail’-connected, main chemical methods pyridyl-oxazole was to establish ligands. which For was constructing from the theconversion skeleton of of aldehyde moieties 88, 90, and 92 to oxazoles 89, 91, and 93 with TosMIC 25 in methanol, under aldehydeoligomers, moieties one of the88, main90, and chemical 92 to oxazolesmethods 89was, 91 to, andestablish 93 with which TosMIC was from25 in themethanol, conversion under of stepwise van Leusen synthetic oxazole. The studies inspected the effect to link with asymmetry stepwisealdehyde van moieties Leusen 88 synthetic, 90, and oxazole. 92 to oxazoles The studies 89, in91spected, and 93 the with effect TosMIC to link 25with in asymmetry methanol, ratherunder rather than symmetry of the ligands’ ingredient units, as well as the impact of ligand length, and thanstepwise symmetry van Leusen of the synthetic ligands’ oxazole.ingredient The units, studies as well inspected as the the impact effect of to ligand link with length, asymmetry and results rather of results of these parameters, including target affinity, target stabilization, and target conformational thesethan symmetryparameters, of the including ligands’ ingredienttarget affinity, units, astarg wellet asstabilization, the impact of andligand target length, conformational and results of modification. Through designing, these molecules representing new access into a series of rotationally modification.these parameters, Through including designing, target these affinity, molecules target representingstabilization, new and access target into conformational a series of flexible oligoaryl compounds, on account of limited rigidity and adaptability to the target surface and rotationallymodification. flexible Through oligoaryl designing, compounds, these on molecules account of representinglimited rigidity new and accessadaptability into toa theseries target of multivalent bonding ability, might be wonderfully suited to target sites of G-quadruplexes from those surfacerotationally and flexible multivalent oligoaryl bonding compounds, ability, on mightaccount be of limitedwonderfully rigidity suited and adaptability to target tosites the oftarget G- exploited by the more traditional intercalator-type ligands. Notably, they would focus on the basis of quadruplexessurface and multivalentfrom those exploitedbonding byability, the more might trad beitional wonderfully intercalator-type suited ligands.to target Notably, sites of they G- the potential function of these structures for anticancer purposes (Scheme 22)[62]. wouldquadruplexes focus on from the basisthose of exploited the potential by the function more tradof theseitional structures intercalator-type for anticancer ligands. purposes Notably, (Scheme they 22)would [62]. focus on the basis of the potential function of these structures for anticancer purposes (Scheme 22) [62].

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N N O CHO O CHO N N 2 steps N N N N K2CO3 K2CO3 + Tos NC K CO N 2 steps N + Tos NC K CO N MeOH2 3 N O MeOH2 3 O N CHO+ Tos NC N O + Tos NC MeOH N O MeOH O N CHO O N N N N 88 25 89 90 25 91 88 25 89 90 25 91

N CHO N N CHO N O N N N N O N O N O 3 steps O K2CO3 O 3 steps + Tos NC N K2CO3 N + Tos NC MeOH N N MeOH N N N N O O O O N N N N 92 25 93 92 25 93 Scheme 22. 22. SynthesisSynthesis of ‘head-to-tail’-connected of ‘head-to-tail’-connected asymmetric asymmetric pyridyl-oxazoles pyridyl-oxazoles 93 for anticancer93 for Scheme 22. Synthesis of ‘head-to-tail’-connected asymmetric pyridyl-oxazoles 93 for anticancer anticancerpurposes. purposes. purposes.

5 In 2018,2018, LaaliLaali reportedreported that that facile facile synthesis synthesis of of multiple multipleC5 C-substituted-substituted oxazoles oxazoles derivatives derivatives95, 9596,, In 2018, Laali reported that facile synthesis of multiple C5-substituted oxazoles derivatives 95, and96, and97. These97. These products products were were obtained obtained from thefrom oxazole the oxazole intermediates intermediates through through the van Leusenthe van reaction, Leusen 96, and 97. These products were obtained from the oxazole intermediates through the van Leusen followedreaction, byfollowed the sequential by the sequential van Leusen–Suzuki, van Leusen–Suzuki, van Leusen–Heck, van Leusen–Heck, and van Leusen–Sonogashira and van Leusen– reaction, followed by the sequential van Leusen–Suzuki, van Leusen–Heck, and van Leusen– couplingSonogashira reactions, coupling respectively. reactions, respectively. This method This was characterizedmethod was characterized through employing through imidazolium employing Sonogashira coupling reactions, respectively. This method was characterized through employing ionicimidazolium liquids (imidazolium-ILs)ionic liquids (imidazolium-ILs) as solvent and piperidine-appendedas solvent and piperidine-appended imidazolium [PAIM][NTf imidazolium2] as imidazolium ionic liquids (imidazolium-ILs) as solvent and piperidine-appended imidazolium task-speciﬁc[PAIM][NTf2 base.] as task-specific This reaction base. could This proceed reaction successfully could proceed with readilysuccessfully available with aldehydesreadily available94 and [PAIM][NTf2] as task-specific base. This reaction could proceed successfully with readily available TosMICaldehydes25 94in aand one-pot TosMIC manner 25 in witha one-pot a high manner yield. Thiswith reactiona high yield. had greatThis reaction potential had for thegreat IL potential solvents aldehydes 94 and TosMIC 25 in a one-pot manner with a high yield. This reaction had great potential whichfor the couldIL solvents be recycled which and could reused be recycled (Scheme and 23 )[reused63]. (Scheme 23) [63]. for the IL solvents which could be recycled and reused (Scheme 23) [63].

Scheme 23. Synthesis of C5-substituted oxazoles 95, 96, and 97. Scheme 23. Synthesis of C5-substituted oxazoles 95, 96, and 97. Scheme 23. Synthesis of C5-substituted oxazoles 95, 96, and 97. In 2019, Lechel et al. found a novel oxazole-functionalization of pyrimidine derivatives. In their study,In they 2019, found Lechel that et aal. van found Leusen a novel synthesis oxazole-functionalization of 98 with TosMIC 25 ofcould pyrimidine occur and derivatives. give oxazole In 99theirin In 2019, Lechel et al. found a novel oxazole-functionalization of pyrimidine derivatives. In their thestudy, K COthey andfound a methanolthat a van system Leusen in synthesis high yield. of 98 The with synthesis TosMIC of25 the could novel occur pyrimidine and give derivativeoxazole 99 study,2 they3 found that a van Leusen synthesis of 98 with TosMIC 25 could occur and give oxazole 99 99in thecontaining K2CO3 and three a methanol diﬀerent heterocyclicsystem in high substituents yield. The wassynthesis unprecedented of the novel and pyrimidine remarkable, derivative which 99in thecontaining K2CO3 and three a methanol different systemheterocyclic in high substi yield.tuents The synthesiswas unprecedented of the novel and pyrimidine remarkable, derivative which 99 containing three different heterocyclic substituents was unprecedented and remarkable, which

Molecules 2020, 25, 1594x FOR PEER REVIEW 14 of 18 Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 14 of 18 indicated the flexibility and an application of this reaction in constructing the multi-substituted indicatedcomplexindicated molecules thethethe ﬂexibility flexibilityflexibility (Scheme and andand an 24) an applicationan [64]. applicationapplication of this ofof reactionthisthis reactionreaction in constructing inin constructingconstructing the multi-substituted thethe multi-substitutedmulti-substituted complex moleculescomplex molecules (Scheme 24(Scheme)[64]. 24) [64].

Scheme 24. Synthesis of pyrimidine derivative 99. Scheme 24.24. Synthesis of pyrimidine derivative 9999.. In the same year, Zarganes–Tzitzikas et al. developed the van Leusen reaction from formylphenylboronicInIn thethe samesame year,year, ester Zarganes–TzitzikasZarganes–Tzitzikas 100. They found that etet al.althe.. developeddevelopedwidespread developed the the theapplicability vanvan van LeusenLeusen of oxazolesreaction reaction in fromfrom the formylphenylboronicpreparationformylphenylboronic of drugs also ester ester justified 100.. They They the evaluationfoundfound found thatthat that of thethe the the widespreadwidespread compatibility applicabilityapplicability of these aromatic ofof oxazoles oxazoles heterocycles in in thethe preparationwithpreparation the Cu-mediated ofof drugsdrugs alsoalso oxidative justifiedjustified 18 F-fluorination thethe evaluationevaluation method. ofof thethe compatibilitycompatibility The oxazole ofof substituted thesethese aromaticaromatic arylboronic heterocyclesheterocycles ester 18 withderivativeswith thethe Cu-mediatedCu-mediated 101 were formed oxidativeoxidative through 1818F-fluorinationF-fluorination the van Leusen method. multicomponent The oxazole substituted reaction between arylboronic a 4- esteror 3- derivativesformylphenylboronic 101101 werewere formedformedester formed 100 throughthroughthrough and TosMIC thethe the vanvan van 25 LeusenLeusenunder Leusen microwave multicomponentmulticomponent multicomponent assisted reactionreaction reaction(MW-assisted) betweenbetween between condition. aa 4-4- a 4-oror or3-3- 3-formylphenylboronicTheformylphenylboronicformylphenylboronic intermediates 101 esteresterwere ester 10018100F-fluorinated andandand TosMICTosMIC TosMIC through 2525 underunder a Cu-mediated microwave microwave assisted oxidative assisted (MW-assisted) (MW-assisted) reaction. Both condition. condition.p- and m- 18 ThepositionThe intermediates fluorinated 101101 molecules werewerewere 1818F-fluorinatedF-fluorinated 102 were successfully through through a aCu-mediated radiolabeled. Cu-mediated oxidative The oxidative 4-fluorinated reaction. reaction. Both product Both p-- andandp -102a and m-- mpositionreached-position afluorinated higher fluorinated maximum molecules molecules radiochemical 102102 werewerewere conversion successfullysuccessfully successfully (RCC) radiolabeled.radiolabeled. radiolabeled. of 67% than TheThe Thethe 4-fluorinated 4-fluorinated3-fluorinated 4-fluorinated productproduct 102b102a reachedwhich had a a higher higher the maximum maximum maximum RCC radiochemicalradiochemical radiochemical of 38% (Scheme conversionconversion conversion 25) [65]. ((RCC) (RCC) of 67% of 67%than thanthe 3-fluorinated the 3-fluorinated product product 102b 102bwhichwhich had the had maximum the maximum RCC RCCof 38% of (Scheme 38% (Scheme 25) [65]. 25)[ 65].

Scheme 25. Synthesis of p- and m-position products 102. Scheme 25. Synthesis of p-- and and m-position-position products products 102.. In 2019, Yasaei and co-workers described a synthesis of 5-(2-chloroquiolin-3-yl)oxazole 104. The synthesisInIn 2019, proceeded Yasaei andand through co-workersco-workers a describedvandescribed Leusen aa synthesissynthesis route procedure ofof 5-(2-chloroquiolin-3-yl)oxazole5-(2-chloroquiolin-3-yl)oxazole between 2-chloroquinoline-3- 104104... The The synthesiscarbaldehydes proceededproceeded 103 and through through TosMIC a van a25 Leusen .van The routeLeusenoxazole procedure intermedroute betweenprocedureiate was 2-chloroquinoline-3-carbaldehydes efficientlybetween subjected2-chloroquinoline-3- to the Pd- 103catalyzedcarbaldehydesand TosMIC amidation 10325. andand The process TosMIC oxazoleTosMIC with intermediate 25 isocyanides.. TheThe oxazoleoxazole was to formintermed eintermedﬃciently 3-(oxazol-5-yl)quinoline-2-carboxamides.iateiate subjected waswas efficientlyefficiently to the Pd-catalyzed subjectedsubjected toto amidation thethe Pd- Pd-As processcatalyzedshown in with amidationScheme isocyanides 26, process subjecting to form with 3-(oxazol-5-yl)quinoline-2-carboxamides.2-chloroquinoline-3-carbaldehyde isocyanides to form 3-(oxazol-5-yl)quinoline-2-carboxamides. 103 and As TosMIC shown 25 in Schemeto the van As26, subjectingshownLeusen inreaction Scheme 2-chloroquinoline-3-carbaldehyde condition 26, subjecting generated 2-chloroquinoline-3-carbaldehyde 5-(2-tosylquinolin-3-yl)oxazole103 and TosMIC 25 to the 103 van104 andand Leusenin TosMICTosMICa 83% reaction yield 25 toto conditionafter thethe vanvan8 h generated(SchemeLeusen reaction 26) 5-(2-tosylquinolin-3-yl)oxazole [66]. condition generated 5-(2-tosylquinolin-3-yl)oxazole104 in a 83% yield after 8 h (Scheme 104 inin a26a 83%83%)[66 ].yieldyield afterafter 88 hh (Scheme(Scheme 26)26) [66].[66].

Scheme 26. Synthesis of 5-(2-tosylquinolin-3-yl)oxazole 104 . In 2020, RashamuseScheme et al. reported 26. Synthesis a MW-assisted of 5-(2-tosylquinolin-3-yl)oxazole van Leusen synthesis. 104104 They.. synthesized a series In 2020, Rashamuse et al. reported a MW-assisted van Leusen synthesis. They synthesized a of unusual 5-aryl-4-tosyl-4,5-dihydro-1,3-oxazoles and 5-aryl-1,3-oxazole compounds 106 through seriesIn of 2020, unusual Rashamuse 5-aryl-4-tosyl-4,5-dihydro-1 et al. reported a MW-assisted,3-oxazoles van and Leusen 5-aryl-1,3-oxazole synthesis. They compounds synthesized 106 a a MW-assistedIn 2020, Rashamuse cycloaddition et al. with reported TosMIC a MW-assisted25 and imines van or Leusen aldehydes synthesis. as starting They materials. synthesized This a throughseries of a unusualMW-assisted 5-aryl-4-tosyl-4,5-dihydro-1 cycloaddition with TosMIC,3-oxazoles 25 and iminesand 5-aryl-1,3-oxazole or aldehydes as starting compounds materials. 106 reactionseries of had unusual both a high5-aryl-4-tosyl-4,5-dihydro-1 yield, eﬃciency, and a broad,3-oxazoles substrate and scope. 5-aryl-1,3-oxazole They extended compounds the MW-assisted 106 throughThis reaction a MW-assisted had both a cycloaddition high yield, efficiency, with TosMIC and a 25 broad and iminessubstrate or aldehydesscope. They as extended starting materials. the MW- versionthrough of a theMW-assisted van Leusen cycloaddition reaction of commercially with TosMIC available 25 and imines TosMIC or andaldehydes aldehyde as starting to form materials. of a small Thisassisted reaction version had of both the vana high Leusen yield, reaction efficiency, of commercially and a broad substrate available scope. TosMIC They and extended aldehyde the to MW-form varietyThis reaction of 5-aryl-1,3-oxazoles had both a high106 yield,with efficiency, anhydrous and methanol a broad substrate as solvent scope. (Scheme They 27 )[extended67]. the MW- assistedof a small version variety of of the 5-aryl-1,3-oxazoles van Leusen reaction 106 ofwith commercially anhydrous availablemethanol TosMICas solvent and (Scheme aldehyde 27)[67]. to form of a small variety of 5-aryl-1,3-oxazoles 106 withwith anhydrousanhydrous methanolmethanol asas solventsolvent (Scheme(Scheme 27)[67].27)[67].

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Scheme 27. Synthesis of inhibitor of microbial pathogen 106..

4. Conclusions In summary, underunder thethe in-depthin-depth researchresearch andand applicationapplication in oxazole-based medicinal chemistry and thethe progressprogress in in other other related related disciplines disciplines such such as as cell cell biology, biology, molecular molecular biology, biology, pharmacology, pharmacology, and organicand organic chemistry, chemistry, the synthesis the synthesis of oxazole-based of oxazole-based drugs willdrugs be will still anbe activestill an field active in medicinalfield in medicinal research andresearch development and development industries industries for a long for time. a long In the time. future, In the increasing future, increasing researcher researcher interests would interests be focusedwould be on focused the design, on the synthesis, design, synthesis, bioactive bioact evaluation,ive evaluation, and action and mechanism action mechanism of unusual of typesunusual of oxazole-basedtypes of oxazole-based heterocyclic heterocyclic compounds compounds with completely with completely novel chemical novel sca chemicalffold, which scaffold, are helpfulwhich are for overcominghelpful for drugovercoming resistances, drug increasing resistances, bioactivities, increasing and bioactivities, will make remarkable and will contributionsmake remarkable to the preventioncontributions and to protection the prevention of human and health.protection Hence, of human we could health. focus Hence, on changing we could the focus starting on changing materials includingthe starting di ffmaterialserent aldehydes including and different TosMICs aldehy to modifydes and oxazole-containing TosMICs to modify derivatives, oxazole-containing or utilizing aderivatives, new synthesis or utilizing technology a new like synthesis the MW-assisted technology condition like the MW-assisted to improve the condition synthesis to eimprovefficiency, the or unitingsynthesis other efficiency, typical nameor uniting reaction other to synthesizetypical name the reaction special and to synthesize complex oxazole-based the special and compounds complex inoxazole-based the future. Abovecompounds all, these in the have future. clearly Above and stronglyall, these suggestedhave clearly the and infinite strongly potentiality suggested of vanthe Leuseninfinite oxazolepotentiality synthesis of van in Leus medicinalen oxazole chemistry. synthesis Additionally, in medicinal we chemistry. hope that Additionally, this review will we buildhope athat full this foundation review will and build reference a full source, foundation which an willd reference open up source, new thought which forwill researchers open up new to focusthought on oxazole-basedfor researchersmedicinal to focus on molecule oxazole-based design medici and synthesisnal molecule chemistry. design and synthesis chemistry.

Author Contributions: All authors wrote the paper. All authors read andand approvedapproved thethe ﬁnalfinal manuscript.manuscript.

Funding: Financial support of this research provided by thethe Science and Technology PlanningPlanning Project of Jilin Province (20160414015GH) is greatly acknowledged. Province (20160414015GH) is greatly acknowledged. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflicts of interest. References References 1. Zhang, H.Z.; Zhao, Z.L.; Zhou, C.H. Recent advance in oxazole-based medicinal chemistry. Eur. J. Med. 1. Zhang, H.Z.; Zhao, Z.L.; Zhou, C.H. Recent advance in oxazole-based medicinal chemistry. Eur. J. Med. Chem. 2018, 144, 444–492. [CrossRef][PubMed] Chem. 2018, 144, 444–492. 2. Kaur, R.; Palta, K.; Kumar, M.; Bhargava, M.; Dahiya, L. Therapeutic potential of oxazole scaffold: A patent 2. Kaur, R.; Palta, K.; Kumar, M.; Bhargava, M.; Dahiya, L. Therapeutic potential of oxazole scaffold: A patent review (2006–2017). Expert Opin. Ther. Pat. 2018, 28, 783–812. [CrossRef][PubMed] review (2006–2017). Expert Opin. Ther. Pat. 2018, 28, 783–812. 3. Kakkar, S.; Narasimhan, B. A comprehensive review on biological activities of oxazole derivatives. BMC 3. Kakkar, S.; Narasimhan, B. A comprehensive review on biological activities of oxazole derivatives. BMC Chem. 2019, 13.[CrossRef][PubMed] Chem. 2019, 13, doi:10.1186/s13065-019-0531-9. 4. Chiacchio, M.A.; Lanza, G.; Chiacchio, U.; Giofre, S.V.; Romeo, R.; Iannazzo, D.; Legnani, L. Oxazole-based 4. Chiacchio, M.A.; Lanza, G.; Chiacchio, U.; Giofre, S.V.; Romeo, R.; Iannazzo, D.; Legnani, L. Oxazole-based compounds as anticancer agents. Curr. Med. Chem. 2019, 26, 7337–7371. [CrossRef] compounds as anticancer agents. Curr. Med. Chem. 2019, 26, 7337–7371. 5. Aljaar, N.; Gujjarappa, R.; Al-Refai, M.; Shtaiwi, M.; Malakar, C.C. Overview on recent approaches towards 5. Aljaar, N.; Gujjarappa, R.; Al-Refai, M.; Shtaiwi, M.; Malakar, C.C. Overview on recent approaches towards synthesis of 2-keto-annulated oxazole derivatives. J. Heterocycl. Chem. 2019, 56, 2730–2743. [CrossRef] synthesis of 2-keto-annulated oxazole derivatives. J. Heterocycl. Chem. 2019, 56, 2730–2743. 6. Škedelj, V.; Perdih, A.; Brvar, M.; Krofliˇc,A.; Dubbée, V.; Savage, V.; O’Neill, A.J.; Solmajer, T.; Bešter-Rogaˇc,M.; 6. Škedelj, V.; Perdih, A.; Brvar, M.; Kroflič, A.; Dubbée, V.; Savage, V.; O’Neill, A.J.; Solmajer, T.; Bešter- Blanot, D.; et al. Discovery of the first inhibitors of bacterial enzyme d-aspartate ligase from Enterococcus Rogač, M.; Blanot, D.; et al. Discovery of the first inhibitors of bacterial enzyme d-aspartate ligase from faecium (Aslfm). Eur. J. Med. Chem. 2013, 67, 208–220. [CrossRef] Enterococcus faecium (Aslfm). Eur. J. Med. Chem. 2013, 67, 208–220. 7. Li, N.N.; Xu, Y.T.; Xia, Q.; Bai, C.G.; Wang, T.Y.; Wang, L.; He, D.D.; Xie, N.N.; Li, L.X.; Wang, J.; et al. 7. Li, N.N.; Xu, Y.T.; Xia, Q.; Bai, C.G.; Wang, T.Y.; Wang, L.; He, D.D.; Xie, N.N.; Li, L.X.; Wang, J.; et al. Simplified captopril analogues as NDM-1 inhibitors. Bioorgan. Med. Chem. Lett. 2014, 24, 386–389. [CrossRef] Simplified captopril analogues as NDM-1 inhibitors. Bioorganic Med. Chem. Lett. 2014, 24, 386–389. 8. Patil, P.C.; Tan, J.; Demuth, D.R.; Luzzio, F.A. 1,2,3-Triazole-based inhibitors of Porphyromonas gingivalis 8. Patil, P.C.; Tan, J.; Demuth, D.R.; Luzzio, F.A. 1,2,3-Triazole-based inhibitors of Porphyromonas gingivalis adherence to oral streptococci and biofilm formation. Bioorgan. Med. Chem. 2016, 24, 5410–5417. [CrossRef] adherence to oral streptococci and biofilm formation. Bioorganic Med. Chem. 2016, 24, 5410–5417. 9. Tomi, I.H.R.; Tomma, J.H.; Al-Daraji, A.H.R.; Al-Dujaili, A.H. Synthesis, characterization and comparative 9. Tomi, I.H.R.; Tomma, J.H.; Al-Daraji, A.H.R.; Al-Dujaili, A.H. Synthesis, characterization and comparative study the microbial activity of some heterocyclic compounds containing oxazole and benzothiazole moieties. study the microbial activity of some heterocyclic compounds containing oxazole and benzothiazole J. Saudi Chem. Soc. 2015, 19, 392–398. [CrossRef] moieties. J. Saudi Chem. Soc. 2015, 19, 392–398. 10. Pedras, M.S.; Abdoli, A. Metabolism of the phytoalexins camalexins, their bioisosteres and analogues in the plant pathogenic fungus Alternaria brassicicola. Bioorganic Med. Chem. 2013, 21, 4541–4549.

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