molecules Review ReviewStyrylpyrazoles: Properties, Synthesis and Styrylpyrazoles:Transformations Properties, Synthesis and Transformations Pedro M. O. Gomes, Pedro M. S. Ouro, Artur M. S. Silva * and Vera L. M. Silva *

PedroLAQV-REQUIMTE, M. O. Gomes Department, Pedro M.of Chemistry, S. Ouro, Artur University M. S. of Silva Aveiro, * 3810-193and Vera Aveiro, L. M. Portugal; Silva * LAQV-REQUIMTE,[email protected] (P.M.O.G.); Department [email protected] of Chemistry, University(P.M.S.O.) of Aveiro, 3810-193 Aveiro, Portugal; [email protected]* Correspondence: (P.M.O.G.); [email protected] [email protected] (A.M.S.S.); (P.M.S.O.) [email protected] (V.L.M.S.); Tel.: +351-234-370714 (A.M.S.S.); * Correspondence:+351-234-370704 (V.L.M.S.) [email protected] (A.M.S.S.); [email protected] (V.L.M.S.); Tel.: +351-234-370714 (A.M.S.S.); +351-234-370704 (V.L.M.S.) Academic Editor: Derek J. McPhee Academic Editor: Derek J. McPhee


Received: 21 November 2020; Accepted: 9 December 2020; Published: date
 Received: 21 November 2020; Accepted: 9 December 2020; Published: 12 December 2020 Abstract: The pyrazole nucleus and its reduced forms, pyrazolines and pyrazolidine, are privileged Abstract:scaffolds inThe medicinal pyrazole chemistry nucleus and due its to reduced their rema forms,rkable pyrazolines biological and activities. pyrazolidine, A huge are number privileged of scapyrazoleffolds inderivatives medicinal have chemistry been duestudied to their and remarkablereported over biological time. activities.This review A hugearticle number gives an of pyrazoleoverview derivatives of pyrazole have derivatives been studied that and contain reported a styryl over time. (2-arylvinyl) This review group article linked gives anin overviewdifferent ofpositions pyrazole of derivativesthe pyrazole that backbone. contain Although a styryl (2-arylvinyl) there are studies group on linked the synthesis in different of positionsstyrylpyrazoles of the pyrazoledating back backbone. to the 1970s Although and even there earlier, are this studies type onof compound the synthesis has ofrarely styrylpyrazoles been studied. dating This timely back toreview the 1970s intends and to even summarize earlier, this the type properties, of compound biological has rarely activity, been studied.methods Thisof synthesis timely review and intendstransformation to summarize of styrylpyrazoles; the properties, thus, biological highlighti activity,ng the interest methods and of synthesishuge potential and transformationfor application of this styrylpyrazoles; kind of compound. thus, highlighting the interest and huge potential for application of this kind of compound. Keywords: pyrazoles; styrylpyrazoles; biological activity; organic synthesis; reactivity Keywords: pyrazoles; styrylpyrazoles; biological activity; organic synthesis; reactivity

1. Introduction 1. Introduction The pyrazole (1H-pyrazole, 1) (Figure 1) is an aromatic five-membered heterocyclic ring constitutedThe pyrazole by three (1H carbons-pyrazole, and1) (Figuretwo adjacent1) is an nitrogen aromatic atoms, five-membered located at heterocyclic 1- and 2-positions ring constituted [1]. N- byunsubstituted three carbons pyrazoles and two may adjacent present nitrogen three atoms, identi locatedcal and at non-separable 1- and 2-positions tautomers, [1]. N-unsubstituted due to rapid pyrazolesinterconversion may present in solution, three and identical it is usually and non-separable impossible to tautomers, unequivocally due assign to rapid the interconversion resonances of its in solution,proton-nuclear and it magnetic is usually resonance impossible (1H-NMR) to unequivocally spectrum. assign Three the partially resonances reduced of its forms proton-nuclear may also magneticexist: 1-pyrazolines resonance (12H-NMR), 2-pyrazolines spectrum. 3 and Three 3-pyrazolines partially reduced 4, and forms a fully may alsoreduced exist: form 1-pyrazolines known as2, 2-pyrazolinespyrazolidine 53 (Figureand 3-pyrazolines 1) [1,2]. 4, and a fully reduced form known as pyrazolidine 5 (Figure1)[ 1,2].

4 3 4 3 N N N N 5 2 N N 5 N2 H H N1 N N N N N N 1 H H H H 12345 Figure 1. Chemical structures and numbering of pyrazole 1,, dihydropyrazole dihydropyrazole (pyrazoline) tautomers 2–4 and pyrazolidine 5.

Pyrazole andand itsits derivatives derivatives occupy occupy a prime a prime place place in medicinal in medicinal chemistry chemistry because because they are they present are ® ® inpresent several in drugsseveral with drugs real with medicinal real medicinal applications, applications, such as celecoxib such as (Celebrexcelecoxib (Celebrex), sildenafil®), (Viagrasildenafil), rimonabant,(Viagra®), rimonabant, lonazolac, lonazolac, fomepizole, fomepizole, penthiopyrad, penthi doramapimod,opyrad, doramapimod, sulfaphenazole sulfaphenazole and in severaland in remarkableseveral remarkable compounds compounds with a wide with range a wide of pharmacological range of pharmacological activities, namely activities, anticancer namely [3], anticancer analgesic, anti-inflammatory[3], analgesic, anti-inflammatory and antioxidant and [4– antioxidant7], antibacterial [4–7], and antibacterial antifungal and [8,9 ]antifungal antipyretic, [8,9] antidepressant antipyretic, andantidepressant anticonvulsant and anticonvulsant [10,11], antidiabetic [10,11], [12 antidiabetic] and cannabinoid [12] and activities cannabinoid [13,14 activities], among [13,14], others [among15–21]. Along with the medicinal applications, pyrazoles are also useful as agrochemicals, such as herbicides, Molecules 2020, 25, x; doi: FOR PEER REVIEW www.mdpi.com/journal/molecules

Molecules 2020, 25, 5886; doi:10.3390/molecules25245886 www.mdpi.com/journal/molecules Molecules 2020, 25, 5886x FOR PEER REVIEW 2 of 34 32 others [15–21]. Along with the medicinal applications, pyrazoles are also useful as agrochemicals, fungicides,such as herbicides, and insecticides fungicides, [and22] insecticides and possess [22] other and applications,possess other applications, such as dyestu suchffs, as sunscreendyestuffs, materialssunscreen [materials23,24], analytical [23,24], analytical reagents andreagents pluripotent and pluripotent ligands inligands coordination in coordination chemistry chemistry [25,26]. For[25,26]. instance, For instance, polyaromatic polyaromatic pyrazoles pyrazoles possess important possess important biological, biological, photophysical, photophysical, optical and optical electronic and propertieselectronic properties [10,27–29]. [10,27–29]. This review review is isfocused focused on a on particular a particular type of type pyrazoles, of pyrazoles, the styrylpyrazoles the styrylpyrazoles (or styryl-1 (orH- styryl-1pyrazoles),H-pyrazoles), which present which a presentstyryl (2-arylvinyl) a styryl (2-arylvinyl) group at one group or atmore one positions or more positionsof the pyrazole of the pyrazolenucleus. It nucleus. is intended It is to intended give an tooverview give an of overview the styrylpyrazoles of the styrylpyrazoles chemistry chemistryreported in reported the literature, in the literature,including includingtheir properties their properties and biological and biological activity, activity, since the since 1970s the 1970sto the to present the present date. date. Despite Despite the thebiological biological activities activities of styrylpyrazoles of styrylpyrazoles [12,14], [12,14 their], their interesting interesting physicochemical physicochemical properties, properties, such such as tautomerism, isomerism [30,31] [30,31] and conjugation exte extension,nsion, due to the presence of the 2-arylvinyl group, as well as the rich chemistr chemistryy related to their synthesis synthesis and transformation, transformation, this type of pyrazole has rarely rarely been been studied, studied, as as can can be be seen seen from from the the low low number number of publications of publications in a very in a verylarge largetime span time spancovered covered by this by review. this review. In our In group, our group, we have we havebeen working been working with styrylpyrazoles with styrylpyrazoles for a long for a time. long time.Throughout Throughout this review, this review, we intend we intendto describe to describe the properties the properties and methods and methods of synthesis of synthesis of these of thesecompounds, compounds, and to and show to show their theirgreat great potential potential for a forpplication application in different in different fields, fields, from from medicine medicine to tomaterials materials chemistry, chemistry, including including their their use use as as key key te templatesmplates for for transformation transformation into into other valuable compounds. TheThe articlesarticles will will be be presented presented based based on the on molecules’ the molecules’ structure, structure, in particular, in particular, the position the ofposition the styryl of the group styryl in group the pyrazole in the pyrazole scaffold. scaffold.

2. Properties of Styrylpyrazoles The pharmacological activity activity of of styrylpyrazoles styrylpyrazoles and and related related compounds compounds has has been been known known for for a along long time. time. A study A study published published in 1970 in 1970described described the anti-inflammatory the anti-inflammatory activity activity of 1-phenyl-2-styryl- of 1-phenyl-2 1 2 3 -styryl-3,5-dioxopirazolidines3,5-dioxopirazolidines (6). Among (6). these Among compounds, these compounds, derivatives derivatives 6a (R1 = Me,6a R(R2 = =R3Me, = H, R R4 == nR-C=4HH,9) 4 1 2 3 4 Rand= 6bn-C (R41H =9 Cl,) and R2 6b= 4-OMe,(R = Cl, R3 = R H,= R4-OMe,4 = n-C4H R9)= (FigureH, R =2) nwere-C4H more9) (Figure active2) than were phenylbutazone more active than or phenylbutazoneoxyphenbutazone or in oxyphenbutazone the carrageenin-induced in the carrageenin-induced foot edema test in foot rats edema [32]. It test was in found rats [32 that]. It wasa p- foundmethylphenyl that a p -methylphenylring increased ringthe increasedintrinsic activity the intrinsic in general, activity while in general, a p-chlorophenyl while a p-chlorophenyl substituent substituentdecreases the decreases activity, theexcept activity, for compound except for 6b compound. The p-methoxy6b. The orp -methoxy3,4-methylenedioxy or 3,4-methylenedioxy substituents substituentsof the styryl ofgroup the styryltend to group increase tend both to increase toxicity bothand inhibitory toxicity and activity, inhibitory while activity, p-alkyl while substituentsp-alkyl substituents(Me or i-Pr) have (Me orthei-Pr) opposite have theeffect. opposite effect. Styrylpyrazoles were also found to act as dual inhibitors of 5-lipoxygenase5-lipoxygenase (5-LO) and cyclooxygenase (CO) in rat basophilic leukemia cells. In particular, compound 7 (Figure2 2)) exhibitedexhibited oral activity in various models of inflammationinflammation and, most importantly, is devoid of ulcerogenic potential [[33].33].

Figure 2. StyrylpyrazoleStyrylpyrazole derivatives 6 and 7 presenting anti-inflamma anti-inflammatorytory activity [[32,33].32,33].

Nauduri et et al. al. studied studied the theantibacterial antibacterial activity activity of 1,5-diphenyl-3 of 1,5-diphenyl-3-styryl-2-pyrazolines-styryl-2-pyrazolines 8, with8, withdifferent different substituents substituents (OMe, (OMe, NMe NMe2, NO22,, NOOH2 ,and OH isopropyl) and isopropyl) (Figure (Figure 3), towards3), towards Gram-positive Gram-positive and andGram-negative Gram-negative bacteria bacteria and and found found little little variation variation in inthe the geometric geometric means means of of minimum minimum inhibitory concentrations (MIC) (MIC) [34]. [34]. The The derivatives derivatives containing containing NMe NMe2, NO2,2 NO and2 OMeand OMein the in p-position the p-position of A and of B aromatic rings showed the highest activity (MIC = 3.55–6.56 μg/mL and 3.30–6.27 μg/mL against

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Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 3 of 34 A and B aromatic rings showed the highest activity (MIC = 3.55–6.56 µg/mL and 3.30–6.27 µg/mL againstGram-positive Gram-positive and Gram-negative and Gram-negative bacteria, bacteria, respective respectively).ly).ly). ThisThis This factfact fact waswas was attributedattributed attributed toto to thethe the strongstrong electronic-driving nature of thethe substituentssubstituents (either(either asas electron-donatingelectron-donating oror electron-withdrawingelectron-withdrawing substituents) andand due due to to a a more more lipophilic lipophiliclipophilic nature naturenature (for (for(for the thethe NMe NMeNMe2). Low22). Low substitution substitution in the in aromaticthe aromatic ring alsoring favoredalso favored the entry the ofentry the compoundof the compound in the bacteria in the bacteria through passivethrough di passiveffusion. diffusion. They have They compared have thecompared activity the of theseactivity compounds of these compounds with that of 1,3-diphenyl-5-styryl-2-pyrazolines,with that of 1,3-diphenyl-5-styryl-2-pyrazolines, which showed which lower activitiesshowed lower thanthe activities compounds than ofthe the compounds 3-styryl series. of th Moreover,e 3-styryl theseries. 1,5-diphenyl-3-styryl-2-pyrazolines Moreover, the 1,5-diphenyl-3- 8styryl-2-pyrazolinesbearing o- or p-hydroxyphenyl 8 bearingbearing o- rings or p-hydroxyphenyl showed superior rings antimycotic showed (antifungal)superior antimycotic activity relative (antifungal) to the otheractivity derivatives relative to (MIC the other= 11.3–24.8 derivativesµg/mL (MIC and = 12.16–13.6 11.3–24.8µ μgg/mL/mL against and 12.16–13.6 fungi and μg/mL yeast, against respectively). fungi Theand extendedyeast, respectively). electronic structureThe extended of the electronic 3-styryl compared structure of with the the 3-styryl 5-styryl compared derivatives with may the 5-styryl explain thederivatives lower MIC may values explain for the the lower compounds MIC values of the for 3-styryl the compounds series [34]. of the 3-styryl series [34].

Figure 3. 3-Styryl-2-pyrazolines3-Styryl-2-pyrazolines 8 presentingpresenting antibacterial antibacterial andanand antifungal activity [[34].34].

In the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and horseradish peroxidase (HRP)/luminol/H2O2 In the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and horseradish peroxidase (HRP)/luminol/H22O22 chemiluminescence assays, 5-aryl-3-styryl-1-carboxamidino-1H-pyrazole derivative 9 showed higher chemiluminescence assays, 5-aryl-3-styryl-1-carboxamidino-1H-pyrazole derivative 9 showedshowed higherhigher antioxidant activity (half maximal inhibitory concentration (IC50) 45.17–217.22 µg/mL, in DPPH assay) antioxidant activity (half maximal inhibitory concentration (IC5050) 45.17–217.22 μg/mL, in DPPH than 2-(5-aryl-3-styryl-1H-pyrazol-1-yl)-4-trifluoromethylpyrimidines 10 (Figure4). The antioxidant assay) than 2-(5-aryl-3-styryl-1H-pyrazol-1-yl)-4-trifluoromethylpyrimidines 10 (Figure(Figure 4).4). TheThe activity is dependent on the concentration and type of substituents in each compound, and resonance antioxidant activity is dependent on the concentrationion andand typetype ofof substituentssubstituents inin eacheach compound,compound, stabilization. For instance, the presence of SH at Y position strongly enhances antioxidant activity. and resonance stabilization. For instance, the presence of SH at Y position strongly enhances Some derivatives of compound 9 showed antimicrobial activity against bacteria Salmonella typhi, antioxidant activity. Some derivatives of compound 9 showedshowed antimicrobialantimicrobial activityactivity againstagainst bacteriabacteria Staphylococcus aureus and Streptococcus pneumoniae, with inhibition between 1.95 to 15.625 mg/mL. Salmonella typhi,, Staphylococcus aureus andand Streptococcus pneumoniae,, withwith inhibitioninhibition betweenbetween 1.951.95 toto The antimicrobial activity is also affected by the substituent [35]. 15.625 mg/mL. The antimicrobial activity is alsoalso affectedaffected byby thethe substituentsubstituent [35].[35].

Figure 4.4. 5-Aryl-3-styryl-1-carboxamidino-15-Aryl-3-styryl-1-carboxamidino-1HH-pyrazole-pyrazole-pyrazole derivativesderivatives derivatives prespres presentingenting antioxidant andand antimicrobial activityactivity 99 andand 1010 [[35].[35].35].

Furthermore, 3,5-bis(styryl)pyrazoles3,5-bis(styryl)pyrazoles12 12, curcumin,, curcumincurcumin (11 ((11) analogues) analogues (Figure (Figure5), are5), are well-known well-known for theirfor their antioxidant antioxidant activity. activity. Some Some derivatives derivatives showed showed superior superiorsuperior activity activityactivity to toto that thatthatof ofof curcumincurcumincurcumin inin DPPH,DPPH, β ferricferric reducingreducing antioxidantantioxidant powerpower (FRAP),(FRAP), andand β-carotene-carotene bleachingbleaching assaysassays [[36].36]. For For instance, curcumin (11)) showedshowed lowerlower inhibitioninhibition ofof DPPHDPPH•• (102(102 mmol), mmol), (half (half maximal maximal effective eeffectiveffective concentrationconcentration (EC ) = 40 0.06 µmol)) compared with 3,5-bis(4-hydroxy-3-methoxystyryl)pyrazole (12a) (EC5050) = 40 ± 0.06± μmol)) compared with 3,5-bis(4-hydroxy-3-methoxystyryl)pyrazole (12a) (EC5050 == 1414 ± 0.18 μmol). The presence of hydroxy and methoxy groups on the terminal phenyl rings is considered benefic for the antioxidant capacity. Moreover, the 3,5-bis(styryl)pyrazole CNB-001 hashas

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(EC = 14 0.18 µmol). The presence of hydroxy and methoxy groups on the terminal phenyl Molecules50 2020±, 25, x FOR PEER REVIEW 4 of 34 rings is considered benefic for the antioxidant capacity. Moreover, the 3,5-bis(styryl)pyrazole CNB-001 shownhas shown interesting interesting results results in studies in studies related related to neur to neuroprotectionoprotection and Alzheimer’s and Alzheimer’s disease, disease, and was and able was toable restore to restore membrane membrane homeostasis homeostasis disrupted disrupted afte afterr brain brain trauma, trauma, being being a apromising promising compound compound for for therapeutictherapeutic use use in in the the treatment treatment of Parkinson’s dise diseasease [37]. [37]. In In combination combination with with tissue tissue plasminogen plasminogen activator, CNB--001001 isis eefficientfficient ininthe the treatment treatment of of stroke stroke [38 [38].]. Compound Compound12a 12aalso also acted acted as as inhibitor inhibitor of ofβ-amyloid β-amyloid secretion secretion and and of protein of protein kinases kinases involved involved in neuronal in neuronal excitotoxicity excitotoxicity [39]. Some [39]. pyrazoles Some pyrazolesthat are analogues that are analogues of 12a displayed of 12a displayed good inhibition good inhibition of γ-secretase of γ-secretase activity, activity, tau aggregation, tau aggregation, and/or and/oraffinity affinity to fibrillar to fibrillar Aβ42 aggregates Aβ42 aggregates [40]. [40]. Other properties have been attributed to 3,5-bis(styryl)pyrazoles such such as as antimalarial, antimalarial, antimycobacterial, antiangiogenic, antiangiogenic, cytotoxic cytotoxic and and antiproliferative antiproliferative activities activities [39,41,42]. [39,41 As,42 an]. example, As an 3,5-bis(styryl)pyrazolesexample, 3,5-bis(styryl)pyrazoles 12a,b showed12a ,moreb showed effective more inhibition effective of inhibition chloroquine-sensitive of chloroquine-sensitive Plasmodium Plasmodium falciparum (IC = 0.48 0.04 µM and 0.87 0.07 µM) and chloroquine-resistant falciparum (IC50 = 0.48 ± 0.0450 μM and 0.87± ± 0.07 μM) and chloroquine-resistant± Plasmodium falciparum Plasmodium falciparum (IC = 0.45 0.07 µM and 0.89 0.10 µM), respectively, than curcumin (IC50 = 0.45 ± 0.07 μM and 0.8950 ± 0.10 ±μM), respectively, than± curcumin (IC50 = 3.25 ± 0.6 μM and 4.21 (IC = 3.25 0.6 µM and 4.21 0.8 µM) [41]. ± 0.850 μM) [41].± ± Several studies have have highlighted the the antiproliferative antiproliferative activity activity of of 12a12a inin PC3 PC3 cells, cells, with with growth µ inhibitoryinhibitory concentration (GI50)) values values of of 5.6 5.6 μMM[ [43]43] and and in in breast breast cancer cancer cell cell lines, lines, MCF-7 MCF-7 and and SKBR3, SKBR3, µ µ with GI GI5050 valuesvalues of of 4.19 4.19 μMM and and 0.25 0.25 μM,M, respectively respectively [42]. [42 Liao]. Liao and and coworkers coworkers have have also also shown shown the antiproliferativethe antiproliferative activity activity of 3,5-bis(styryl)pyrazoles of 3,5-bis(styryl)pyrazoles 12a12a andand 1313 inin the the androgen-independent androgen-independent PC3 PC3 prostate cancer cell line with GI50 valuesvalues in in the low micromolar range. In In particular, particular, compound 13 caused significant effects on the PC3 cell cycle, inducing cell death and binding to tubulin (Kd 0.4 caused significant effects on the PC3 cell cycle, inducing cell death and binding to tubulin (Kd 0.4 ± 0.1 μµM), inhibiting tubulin polymerization inin vitro, vitro, being competitive with paclitaxel for binding to tubulin,tubulin, and leading toto microtubulemicrotubule depolymerizationdepolymerization inin PC3 PC3 cells. cells. Therefore, Therefore,13 13was was considered considered as as a alead lead compound compound for for the the treatment treatment of of castration-resistant castration-resistant prostate prostate cancer cancer (CRPC) (CRPC) [44 [44].].

Figure 5. StructuresStructures of of curcumin curcumin ( (1111)) and and 3,5-bis(styryl)pyrazoles 3,5-bis(styryl)pyrazoles CNBCNB--001001,, 1212 andand 13,, presenting antioxidant, antimalarial, cytotoxic an andd antiproliferative activities [[36–44].36–44].

InIn additionaddition to pharmacologicalto pharmacological activities, activities, 4-styrylpyrazoles 4-styrylpyrazoles have shown have interesting shown photophysical interesting photophysicalproperties. In particular,properties. 1-(2-pyridyl)-4-styrylpyrazoles In particular, 1-(2-pyridyl)-4-styrylpyrazoles (PSPs) substituted (PSPs) at position substituted 3 with at donorposition or 3acceptor with donor aryl groupsor acceptor have aryl shown groups strong have blue-light shown emissionsstrong blue-light with high emi quantumssions with yields high (up quantum to 66%), yieldsdue to intramolecular(up to 66%), due charge to intramolecular transfer (ICT) phenomena charge transfer [45]. (ICT) The 3-phenyl-1-(2-pyridyl)-4-styrylpyrazole phenomena [45]. The 3-phenyl-1-(2- pyridyl)-4-styrylpyrazole14 (Figure6) was studied as a14 turn-off (Figure fluorescent 6) was studied probe in as metal a turn-off ion sensing, fluorescent showing probe a high in selectivity metal ion to sensing,Hg2+ (Limit showing of detection a high (LOD) selectivity= 3.1 to 10Hg72+M) (Limit in a processof detection thatcould (LOD) be = reversed 3.1 × 10− with7 M) in ethylenediamine. a process that × − couldAlthough be reversed pyrazoles with ethylenediamine. are rare in nature, due to the difficulty of living organisms to construct the N–NAlthough bond [46, 47pyrazoles], a styrylpyrazole are rare in naturalnature, derivative,due to the difficulty (E)-1,5-diphenyl-3-styryl-2-pyrazoline of living organisms to construct (DSDP) the N–N15 (also bond known [46,47], as (aE styrylpyrazole)-1,5-diphenyl-3-styryl-4,5-dihydro-1 natural derivative, (E)-1,5-diphenyl-3-styryl-2-pyrazolineH-pyrazole) (Figure6), was isolated from (DSDP) the 15 (also known as (E)-1,5-diphenyl-3-styryl-4,5-dihydro-1H-pyrazole) (Figure 6), was isolated from the aerial parts of Euphorbia guyoniana [48]. In 2017, Kundu et al. unveiled the binding interaction of DSDP 15 with the calf thymus DNA (ctDNA) [49]. By performing steady state and time resolved spectroscopic measurements, competitive binding studies, circular dichroism and a DNA helix melting study they unequivocally demonstrated that DSDP binds with the ctDNA through groove

Molecules 2020, 25, 5886 5 of 32 aerial parts of Euphorbia guyoniana [48]. In 2017, Kundu et al. unveiled the binding interaction of DSDP Molecules 2020, 25, x FOR PEER REVIEW 5 of 34 15 with the calf thymus DNA (ctDNA) [49]. By performing steady state and time resolved spectroscopic bindingmeasurements, mode with competitive no conformational binding studies, change. circular These dichroism findings andwere a DNAalso supported helix melting by studymolecular they dockingunequivocally simulation. demonstrated that DSDP binds with the ctDNA through groove binding mode with no conformationalLater, the same change. authors These reported findings werethe strong also supported binding byinteractions molecular of docking DSDP simulation.with two serum transportLater, proteins, the same human authors serum reported albumin the (HSA) strong an bindingd bovine interactions serum albumin of DSDP (BSA) with [50]. twoExploiting serum multi-spectroscopictransport proteins, human techniques serum together albumin with (HSA) in andsilico bovine molecular serum docking albumin simulation, (BSA) [50]. Exploitingthey have demonstratedmulti-spectroscopic that DSDP techniques is a potent together fluorophore. with in It silico binds molecular with both dockingproteins with simulation, the formation they have of a 1:2demonstrated protein–probe that complex DSDP is aat potent a lower fluorophore. protein concentration It binds with range both proteinsand a 1:1 with complex the formation at a higher of a 1:2protein protein–probe concentration complex range. at aThe lower calculated protein concentrationbinding constants range for and the a 1:1 2:1 complex DSDP-protein at a higher complexes protein wereconcentration found to range. be 1.37 The × 10 calculated10 M−2 and binding 1.47 × 10 constants10 M−2 for for HSA the 2:1and DSDP-protein BSA, respectively, complexes while were for the found 1:1 10 2 10 2 to be 1.37 10 M and 1.47 10 M for HSA and5 BSA,−1 respectively,5 while−1 for the 1:1 complexation complexation× process,− the constants× were− 1.85 × 10 M and 1.73 × 10 M for DSDP-HSA and DSDP- process, the constants were 1.85 105 M 1 and 1.73 105 M 1 for DSDP-HSA and DSDP-BSA systems, BSA systems, respectively. Moreover,× − they have× demonstrated− that hydrogen bonding and hydrophobicrespectively. Moreover,interactions they are have the demonstrated forces primarily that hydrogen responsible bonding for both and hydrophobictypes of binding. interactions The informationare the forces gathered primarily from responsible these studies for both may types be usef oful binding. for the Therational information design of gathered drugs looking from these at a greaterstudies clinical may be efficacy. useful for the rational design of drugs looking at a greater clinical efficacy. 1,3,5-Trisubstituted pyrazolines,pyrazolines, analogues analogues of DSDP,of DSDP, exhibited exhibited large large fluorescence fluorescence quantum quantum yields (yieldsΦf = 0.6–0.8),(Φf = 0.6–0.8), suited suited for thefor the design desi ofgn energy-transfer-basedof energy-transfer-based fluorescent fluorescent probes probes [51 [51].]. InIn DSDP’s structure, two of the aryl rings (phenyl and styryl)styryl) are interconnectedinterconnected electronically through the pyrazoline ππ-system-system while while the the 5-phenyl 5-phenyl ring ring is electronically is electronically decoupled decoupled and can and behave can behave as an electron as an electrondonating donating receptor receptor for cations for cations or electron or electron deficient deficient centers. centers. The loneThe lone pair pair of electrons of electrons on theon the N1 N1atom atom of theof the pyrazoline pyrazoline ring ring also also takes takes part part in in the the conjugation, conjugation, facilitating facilitating the the ICTICT process.process. Thus, DSDP acts as a D-π-A system and the introduction of an el electronectron withdrawing gr groupoup (such as as -CN, π -NO-NO22,, -COOEt)-COOEt) on on the the styryl styryl moiety moiety can enhancecan enhance the push–pull the push–pull D- -A capacityD-π-A capacity of DSDP-like of DSDP-like molecular molecularsystems [52 systems]. However, [52]. However, a drastic modification a drastic modificati of the photophysicalon of the photophysical properties properties of DSDP isof observed DSDP is observedupon dehydrogenation upon dehydrogenation of the pyrazoline of ringthe withpyrazo subsequentline ring formation with subsequent of the corresponding formation pyrazole of the (DSP)corresponding16 (Figure pyrazole6). While (DSP) DSDP 16gives (Figure dual 6).absorption While DSDP and gives dual dual emission absorption bands and corresponding dual emission to bandsthe locally corresponding excited (LE) to and the ICTlocally species, excited DSP (LE) yields and single ICT species, absorption DSP and yields emission single bands absorption for the and LE emissionspecies only. bands Comparative for the LE species steady stateonly. andComparativ time resolvede steady fluorometric state and time studies resolved have revealedfluorometric that studiesaromatization have revealed of the pyrazoline that aromatization ring completely of the pyrazoline inhibitsthe ring ICT completely process. inhibits These results the ICT were process. also Thesecorroborated results bywere quantum also corroborated chemical calculations by quantum [52 chemical]. calculations [52].

Figure 6. StyrylpyrazolesStyrylpyrazoles 1414–1616 presenting relevant photophysical properties [[45,48–52].45,48–52]. 3. Synthesis of Styrylpyrazoles 3. Synthesis of Styrylpyrazoles In this section, the methods for the synthesis of styrylpyrazoles are described in a systematic In this section, the methods for the synthesis of styrylpyrazoles are described in a systematic way, based on the compounds’ structure, considering the position of the styryl group in the pyrazole way, based on the compounds’ structure, considering the position of the styryl group in the pyrazole scaffold, starting from C-1 to C-5. Bis(styryl)pyrazoles, substituted at C-3 and C-5, are also considered. scaffold, starting from C-1 to C-5. Bis(styryl)pyrazoles, substituted at C-3 and C-5, are also Moreover, in each subheading, the methods will be presented by alphabetic order. Single examples of considered. Moreover, in each subheading, the methods will be presented by alphabetic order. Single a certain reaction will be considered at the end of each section in the miscellaneous subheading. examples of a certain reaction will be considered at the end of each section in the miscellaneous subheading.

3.1. Synthesis of 1-Styrylpyrazoles

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Molecules 2020, 25, x FOR PEER REVIEW 6 of 34 Molecules3.1. Synthesis 2020, 25 of, x1-Styrylpyrazoles FOR PEER REVIEW 6 of 34 3.1.1. N-Cross-Coupling Reaction of Pyrazoles with Styrylboronic Acid 3.1.1. NN-Cross-Coupling-Cross-Coupling Reaction Reaction of of Pyra Pyrazoleszoles with Styrylboronic Acid In 2010, Kantam et al. synthesized (E)-1-styrylpyrazoles in a simple and efficient way, by the cross-couplingIn 2010, Kantam reaction et of al. pyrazoles synthesized synthesized 17 with( (EE)-1-styrylpyrazoles)-1-styrylpyrazoles styrylboronic acid in in 18 a a usingsimple simple a andrecyclable and efficient efficient heterogeneous way, way, by the cross-couplingCu-exchanged reactionfluorapatite of pyrazoles (CuFAP) 17catalyst, with styrylboronic under base-free acid conditions 18 using a(Scheme recyclable 1) [53]. heterogeneous The lower Cu-exchangedyield (70%) for fluorapatite fluorapatitethe coupling (CuFAP) with 3,5-dimethyl-1 catalyst, unde underHr-pyrazole base-free 17 conditions (R1 = R2 = (Scheme Me) was 11))[ attributed [53].53]. The lower to the yieldsteric (70%)hindrance for thethe caused couplingcoupling by the withwith methyl 3,5-dimethyl-13,5-dimethyl-1 groups. WhHH-pyrazole-pyrazoleen the reaction 1717 (R(R11 was== R2 performed= Me)Me) was was inattributed the absence to the of stericair, no hindrance coupled product causedcaused bybywas thethe obtained, methyl methyl groups. sincegroups. O When2 Whis involveden the the reaction reaction in the was oxidation was performed performed of Cu(I) in thein to the absenceCu(II), absence which of air,of air,nois the coupledno active coupled product species product wasin the was obtained, reaction obtained, since mechanism since O2 is O involved2 [53].is involved in the in oxidation the oxidation of Cu(I) of Cu(I) to Cu(II), to Cu(II), which which is the isactive the active species species in the in reaction the reaction mechanism mechanism [53]. [53].

Scheme 1. Cross-coupling reactions of pyrazoles 17 with styrylboronic acid 18 to produce (E)-1- Schemestyrylpyrazoles 1. 1. Cross-couplingCross-coupling 19 [53]. reactions reactions of pyrazoles of pyrazoles 17 with17 with styrylboronic styrylboronic acid 18 acid to 18produceto produce (E)-1- styrylpyrazoles(E)-1-styrylpyrazoles 19 [53].19 [53]. 3.1.2. N-Styrylation of Pyrazoles with Activated and Non-Activated Alkynes 3.1.2. NN-Styrylation-Styrylation of of Pyrazoles Pyrazoles with with Ac Activatedtivated and and Non-Activated Non-Activated Alkynes In 1978, Burgeois et al. described a lithium-catalyzed stereospecific and stereoselective addition of theIn N–H1978, 1978, bondBurgeois Burgeois of pyrazole et etal. described al. 20 described to phenylacetylene, a lithium-catal a lithium-catalyzedyzed as astereospecific method stereospecific to prepare and stereoselective 1-styrylpyrazoles and stereoselective addition 21 ofaddition(Scheme the N–H 2) of [54].bond the Under of N–H pyrazole such bond conditions, 20 of to pyrazole phenylacetylene, (Z)-1-styryl-120 to phenylacetylene,Has-pyrazole a method (21a to) prepareand as (Z a)-5-amino-1-styryl-1 method1-styrylpyrazoles to prepare 21H- 1-styrylpyrazoles(Schemepyrazole 2)(21b [54].) were Under21 obtained(Scheme such conditions, 2in)[ 60%54]. and Under(Z 55%)-1-styryl-1 yield, such conditions,respectively.H-pyrazole ( (Z21a)-1-styryl-1) and (Z)-5-amino-1-styryl-1H-pyrazole (21a) andH- pyrazole(Z)-5-amino-1-styryl-1Tsuchimoto (21b) were et obtainedal.H -pyrazolereported in 60% (21ba andsimilar) were 55% obtained singleyield, respectively.addition in 60% andof 55%the yield,N–H respectively.bond of pyrazoles to Tsuchimoto et al. reported a similar single addition of the N–H bond of pyrazoles to phenylacetyleneTsuchimoto andet al.prop-1-yn-1-ylbenzene reported a similar insingle the presence addition of aof silver the catalystN–H bond (AgNO of 3 pyrazolesor AgOTf) toto phenylacetylene and prop-1-yn-1-ylbenzene in the presence of a silver catalyst (AgNO or AgOTf) phenylacetyleneproduce a regioisomeric and prop-1-yn-1-ylbenzene mixture of 1-substituted in the presencepyrazoles of 22a silver and 23catalyst (Scheme (AgNO 2) [55].3 or3 AgOTf)Complete to producetostereoselectivity produce a regioisomeric a regioisomeric was achieved, mixtur mixture sincee of of only1-substituted 1-substituted the (Z)-isomer pyrazoles pyrazoles of 1-styrylpyrazole 2222 andand 2323 (Scheme(Scheme was formed,22))[ [55].55]. indicating Complete stereoselectivitythat anti-addition, was via achieved, a concerted since mechanism, only the (Z in)-isomer which of pyrazole 1-styrylpyrazole nitrogen attackswas formed, the alkyne indicating from thatthe sideanti -addition,-addition,opposite to viavia a acoordinateda concerted concerted mechanism, mechanism,Lewis acid in(LA), in which which is involved pyrazole pyrazole as nitrogen anitrogen key step attacks attacks in the the thereaction alkyne alkyne from process from the theside[55]. side opposite opposite to a to coordinated a coordinated Lewis Lewis acid acid (LA), (LA), is involved is involved as a keyas a stepkey instep the in reaction the reaction process process [55]. [55].

Scheme 2. Addition of pyrazole 20 to alkynes to produce ((Z)-1-styrylpyrazoles)-1-styrylpyrazoles 2121––2323 [[54,55].54,55]. Scheme 2. Addition of pyrazole 20 to alkynes to produce (Z)-1-styrylpyrazoles 21–23 [54,55]. The role of two ruthenium complexes [Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4] (24) (dppe = diphenylphosphinoethThe role of two ane)ruthenium and complexes [Ru(dppp) [Ru(dppe)(PPh2(NCCH3)Cl][BPh3)(CH3CN)4] 2Cl][BPh(25) 4] (24(dppp) (dppe == diphenylphosphinoethdiphenylphosphinopropane)ane) as andeffi cient [Ru(dppp)catalysts in2(NCCH the regio-3)Cl][BPh and4] stereoselective(25) (dppp addition of= diphenylphosphinopropane) as efficient catalysts in the regio- and stereoselective addition of

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The role of two ruthenium complexes [Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4](24) (dppe = diphenylphosphinoethane) and [Ru(dppp)2(NCCH3)Cl][BPh4](25) (dppp = diphenylphosphinopropane)Molecules 2020, 25, x FOR PEER REVIEW as efficient catalysts in the regio- and stereoselective addition7 of 34 of pyrazoles 26 to alkynes was described by Das Kumar et al. (Scheme3)[ 56]. In general, the additionpyrazoles catalyzed 26 to alkynes by complexwas described24 aff byorded Das Kumar (E)-1-styrylpyrazoles et al. (Scheme 3)27 [56].while In general, complex the25 additionproduces catalyzed by complex 24 afforded (E)-1-styrylpyrazoles 27 while complex 25 produces (Z)-1- (Z)-1-styrylpyrazoles 28. Based on density functional theory calculations, the authors have shown that styrylpyrazoles 28. Based on density functional theory calculations, the authors have shown that stereoselectivity is dependent upon the ligand environment around the ruthenium center. stereoselectivity is dependent upon the ligand environment around the ruthenium center. Recently,Recently, Garg Garg et al. et reported al. reported a transition-metal-free a transition-metal-free chemo-, chemo-, regio-, regio- and stereoselective, and stereoselective synthesis of (Zsynthesis)- and (E )-1-styrylpyrazolesof (Z)- and (E)-1-styrylpyrazoles by the addition by of the pyrazoles addition26 ofonto pyrazoles functionalized 26 onto functionalized terminal alkynes usingterminal a super alkynes basicsolution using a super of KOH basic/dimethyl solution sulfoxideof KOH/dimethyl (DMSO) sulfoxide [31]. The (DMSO) nature [31]. of the The base nature seems to beof crucialthe base for seems the to reaction, be crucial which for the does reaction, not occurwhich indoes the not presence occur in ofthe an presence organic of base,an organic such as triethylaminebase, such as (Et triethylamine3N). The reaction (Et3N). stereoselectivityThe reaction stereoselectivity is governed is governed by time andby time amount and amount of the of base (Schemethe base3). Deuterium (Scheme 3). labeling Deuterium and labeling control experimentsand control experiments highlighted highlighted the role of the the role KOH of/ DMSOthe catalyticKOH/DMSO system in catalytic the cis systemtrans isomerization, in the cis→trans which isomerization, was further which supported was byfurther comparative supported1H-NMR by comparative 1H-NMR→ spectrum studies in DMSO/DMSO-d6. This method is of wide scope and spectrum studies in DMSO/DMSO-d6. This method is of wide scope and several functionalities, such as several functionalities, such as OH or Me, NH2, present both in the alkyne and pyrazole are well- OH or Me, NH2, present both in the alkyne and pyrazole are well-tolerated [31]. tolerated [31].

SchemeScheme 3. Stereoselective 3. Stereoselective additions additions of pyrazoles of pyrazoles26 to alkynes 26 to toalkynes produce to (Eproduce)- and (Z )-1-styrylpyrazoles(E)- and (Z)-1- 27 andstyrylpyrazoles28 [31,56]. 27 and 28 [31,56].

3.2. Synthesis3.2. Synthesis of 3(5)-Styrylpyrazoles of 3(5)-Styrylpyrazoles

3.2.1.3.2.1. Cyclocondensation Cyclocondensation Reactions Reactions TheThe cyclocondensation cyclocondensation of of (1 E(1,4E,4E)-1,5-diarylpenta-1,4-dien-3-oneE)-1,5-diarylpenta-1,4-dien-3-one 2929 withwith hydrazine hydrazine or phenyl or phenyl hydrazinehydrazine in glacialin glacial acetic acetic acid acid at at reflux reflux [ 57[57,58],,58], inin thethe presence of of sulfuric sulfuric acid acid [59], [59 or], orcellulose cellulose sulfonicsulfonic acid acid [60], [60], afforded afforded 5-aryl-3-styryl-4,5-dihydro-1 5-aryl-3-styryl-4,5-dihydro-1HH-pyrazoles-pyrazoles (pyrazolines)(pyrazolines) 15 oror 3030 (Scheme(Scheme 4). Following4). Following a similar a similar approach, approach, Nauduri Nauduri et al.et al. synthesized synthesized a series series of of 5-aryl-1-phenyl-3-styryl-4,5- 5-aryl-1-phenyl-3-styryl-4,5 dihydro-1H-pyrazoles by condensation of 29 analogues with phenyl hydrazine hydrochloride in a mixture of ethanol and chloroform, in the presence of a catalytic amount of concentrated HCl (70–

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-dihydro-1H-pyrazoles by condensation of 29 analogues with phenyl hydrazine hydrochloride in Molecules 20202020,, 2525,, xx FORFOR PEERPEER REVIEWREVIEW 88 ofof 3434 a mixture of ethanol and chloroform, in the presence of a catalytic amount of concentrated HCl (70–77%)77%)77%) [34].[34]. [34 ]. PathakPathak Pathak etet et al.al. al. studiedstudied studied thethe the reactionreaction reaction ofof of 292929 withwithwith hydrazinehydrazine hydrazine hydratehydrate hydrate inin inglacialglacial glacial aceticacetic acetic acidacid acid underunder under conventionalconventionalconventional reflux, reflux,reflux, ultrasound, ultrasound,ultrasound, microwave microwavemicrowave irradiation irrairradiation conditions conditions and usingand using mechanochemical mechanochemical mixing, andmixing, isolated and 1-acetyl-5-aryl-3-(substituted-styryl)pyrazolines isolated 1-acetyl-5-aryl-3-(substituted-styryl)pyrazolines30. In turn, 3030. pyrazolines. InIn turn,turn, pyrazolinespyrazolines15 were converted1515 werewere intoconvertedconverted the corresponding intointo thethe correspondingcorresponding pyrazoles by oxidationpyrazolespyrazoles (dehydrogenation)byby oxidationoxidation (dehydrogenation)(dehydrogenation) (Scheme4). Several (Scheme(Scheme oxidant 4).4). SeveralSeveral agents canoxidant be employed agents for can this be transformation; employed for this some tran commonsformation;sformation; examples somesome include commoncommon lead examplesexamples tetraacetate includeinclude [58], DMSOleadlead tetraacetate [58], DMSO in open air [61], MnO2 [62], p-chloranil [63], 2,3-dichloro-5,6-dicyano-1,4- in opentetraacetate air [61 [58],], MnO DMSO2 [62 ],inp -chloranilopen air [61], [63 ],MnO 2,3-dichloro-5,6-dicyano-1,4-benzoquinone2 [62], p-chloranil [63], 2,3-dichloro-5,6-dicyano-1,4- (DDQ) [64], Pdbenzoquinone/C[65]. In 2014, (DDQ) Ananthnag [64], Pd/C et al. [65]. developed In 2014, aAnanthnag simple and et high al. developed yielding methoda simple for and the high conversion yielding of method for the conversion of (E)-3- and 5-styrylpyrazolines into the corresponding pyrazoles via (E)-3-method and 5-styrylpyrazolinesfor the conversion of into (E the)-3- correspondingand 5-styrylpyrazolines pyrazoles into via iron(III)the corresponding catalyzed aerobic pyrazoles oxidative via iron(III)iron(III) catalyzedcatalyzed aerobicaerobic oxidativeoxidative aromatizationaromatization [65].[65]. TheThe useuse ofof FeClFeCl33 asas catalystcatalyst makesmakes thethe aromatization [65]. The use of FeCl3 as catalyst makes the reaction greener and more economical. reactionreaction greenergreener andand moremore economical.economical.

SchemeScheme 4. 4.Synthesis SynthesisSynthesis of ofof 3-styrylpyrazolines 3-styrylpyrazolines3-styrylpyrazolines 1515 andand 3030 andandand 3-styrylpyrazoles3-styrylpyrazoles 3-styrylpyrazoles 161616 [58].[58].[58 ].

GresslerGressler et et al. al. described described the the [3 [3+ + 2]2] cyclocondensationcyclocondensation of of 1,5-diarylpenta-1,4-dien-3-ones 1,5-diarylpenta-1,4-dien-3-ones 313131 withwithwith aminoguanidineaminoguanidineaminoguanidine hydrochloride hydrochloridehydrochloride32 3232in inin ethanol, ethanol,ethanol, in inin the thethe presencepresence ofof trtr triethylamine,iethylamine,iethylamine, asas as aa amethodmethod method toto to prepareprepare prepare 5-aryl-1-carboxamidino-3-styryl-4,5-dihydro-15-aryl-1-carboxamidino-35-aryl-1-carboxamidino-3-styryl-4,5-dihydro-1-styryl-4,5-dihydro-1HH-pyrazoles-pyrazoles-pyrazoles 99 (Scheme(Scheme 55)5))[ [35,66,67].[35,66,67].35,66,67].

SchemeScheme 5. 5.Synthesis SynthesisSynthesis of ofof 5-aryl-1-carboxamidino-3-styryl-4,5-dihydro-1 5-aryl-1-carboxa5-aryl-1-carboxamidino-3-styryl-4,5-dihydro-1HH-pyrazoles-pyrazoles-pyrazoles 99 9[35,66,67].[35,66,67].[35,66,67 ].

InInIn 1991, 1991,1991, PurkayasthaPurkayasthaPurkayastha etet et al.al. al. reportedreported reported thethe reactionreaction the reaction ofof α-oxoketene-oxoketene of α-oxoketene dithioacetaldithioacetal dithioacetal 3333 withwith hydrazinehydrazine33 with hydrazinehydrate in hydrate ethanol, in in ethanol, the presence in the presenceof acetic acid, of acetic as a acid,method as ato method exclusively to exclusively obtain (E)-3(5)-)-3(5)- obtain styrylpyrazolesstyrylpyrazoles ((3434 35 35)) (Scheme(Scheme 6).6). TheyThey havehave shownshown thatthat acidicacidic mediummedium isis requiredrequired forfor thethe

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(E)-3(5)-styrylpyrazoles (34 35) (Scheme6). They have shown that acidic medium is required for Molecules 2020, 25, x FOR PEER REVIEW 9 of 34 the regioselective formation of 34, otherwise, in neutral conditions, other products are formed [68]. Molecules 2020, 25, x FOR PEER REVIEW 9 of 34 The formationregioselective of formation styrylpyrazoles of 34, otherwise,34, in acidicin neutral conditions, conditions, was other explained products are through formed the[68]. attack The of β hydrazineformationregioselective on of protonated styrylpyrazoles formation 33of 34at 34, otherwise, the, in acidic-carbon conditions,in neutral with conditions, was a positive explained other charge, through products which the are attack isformed stabilized of hydrazine [68]. The by the two methylthioonformation protonated of styrylpyrazoles groups. 33 at the Inβ-carbon fact, 34, in thewith acidic( Ea )-3(5)-styrylpyrazole positiveconditions, charge, was whichexplained is34a stabilized through(Ar = thebyPh) theattack was two of isolatedmethylthio hydrazine as the sole productgroups.on protonated In (79%)fact, 33the whenat (E the)-3(5)-styrylpyrazole β33a-carbon(Ar with= Ph) a positive 34a reacted (Ar charge,= Ph) with was which hydrazine isolated is stabilized as hydratethe sole by product the in ethanol:acetictwo (79%) methylthio when acid (1:1)33agroups. mixture. (Ar =In Ph) fact, Other reacted the (E cinnamoyl )-3(5)-styrylpyrazolewith hydrazine oxoketene hydrate 34a (Ar dithioacetalsin ethanol:acetic = Ph) was isolated similarly acid (1:1)as the reactedmixture. sole product Other in these (79%) cinnamoyl conditions when affordingoxoketene33a (Ar a = series Ph) dithioacetals reacted of (E with)-3(5)-styrylpyrazoles. similarly hydrazine reacted hydrate in in these ethanol:acetic This conditions method acid isaffording (1:1) also mixture. suitable a series Other for of cinnamoyl the(E)-3(5)- synthesis styrylpyrazoles. This method is also suitable for the synthesis of 3-(4-arylbuta-1,3-dienyl)pyrazoles of 3-(4-arylbuta-1,3-dienyl)pyrazolesoxoketene dithioacetals similarly reacted and 3-(6-arylhexa-1,3,5-trienyl)pyrazoles in these conditions affording a series starting of (E)-3(5)- from the and 3-(6-arylhexa-1,3,5-trienyl)pyrazoles starting from the appropriate dienoyl- and trienoyl appropriatestyrylpyrazoles. dienoyl- This and method trienoyl is also oxoketene suitable dithioacetals,for the synthesis and of 3-(4-arylbuta-1,3-dienyl)pyrazoles has high practical utility, since the oxoketeneand 3-(6-arylhexa-1,3,5-trienyl)pyrazoles dithioacetals, and has high practical starting utility, from since the the introductionappropriate ofdienoyl- such enyl and side-chains trienoyl introduction of such enyl side-chains in the preformed pyrazole is not possible [68]. inoxoketene the preformed dithioacetals, pyrazole and is nothas possiblehigh practical [68]. utility, since the introduction of such enyl side-chains in the preformed pyrazole is not possible [68].

SchemeScheme 6. 6. ReactionReaction of of oxoketene oxoketene dithioacetals dithioacetals 33 with33 hydrazinewith hydrazine hydrate to hydratesynthesize to (E synthesize)-3(5)- styrylpyrazoles 34 [68]. (E)-3(5)-styrylpyrazolesScheme 6. Reaction 34of [oxoketene68]. dithioacetals 33 with hydrazine hydrate to synthesize (E)-3(5)- styrylpyrazoles 34 [68]. In 2001,In 2001, Pastine Pastine et al.et al. reported reported the the synthesis synthesis of ( (EE)-3-styrylpyrazoles)-3-styrylpyrazoles starting starting from from benzalacetone benzalacetone 36, which36, whichIn was 2001, convertedwas Pastine converted et into al. reported the into corresponding th thee corresponding synthesis hydrazones of (E )-3-styrylpyrazoleshydrazones37 by reaction37 by starting reaction with from hydrazine with benzalacetone hydrazine derivatives. derivatives. Then, compounds 37 were deprotonated with an excess of lithium diisopropylamide Then,36 compounds, which was37 convertedwere deprotonated into the corresponding with an excess hydrazones of lithium 37 diisopropylamide by reaction with (LDA),hydrazine and the (LDA), and the resulting dilithiated intermediates 38 were condensed at the carbanion center with a resultingderivatives. dilithiated Then, intermediatescompounds 37 38werewere deprotonated condensed with at an the ex carbanioncess of lithium center diisopropylamide with a variety of variety of substituted benzoate esters, such as methyl benzoate, methyl 4-t-butylbenzoate, (lithiated) substituted(LDA), and benzoate the resulting esters, dilithiated such as methyl intermediates benzoate, 38 were methyl condensed 4-t-butylbenzoate, at the carbanion (lithiated) center with methyl a methylvariety 4-hydroxybenzoate,of substituted benzoate or methylesters, such3,4,5-trimethoxybenzoate as methyl benzoate, methyl affording 4-t-butylbenzoate, 39. After acid cyclization (lithiated) 4-hydroxybenzoate, or methyl 3,4,5-trimethoxybenzoate affording 39. After acid cyclization of 39 with ofmethyl 39 with 4-hydroxybenzoate, 3 N hydrochloric acid,or methyl the 3-styrylpyrazoles 3,4,5-trimethoxybenzoate 40 were isolated affording (Scheme 39. After 7) [69]. acid cyclization 40 3 N hydrochloricof 39 with 3 N acid, hydrochloric the 3-styrylpyrazoles acid, the 3-styrylpyrazoleswere isolated 40 were (Scheme isolated 7(Scheme)[69]. 7) [69].

Scheme 7. Reaction of benzalacetone 36 with hydrazines to produce hydrazones 37 and their transformation into (E)-3-styrylpyrazoles 40 [69]. SchemeScheme 7. Reaction7. Reaction of of benzalacetone benzalacetone 3636 withwith hydrazines to to produce produce hydrazones hydrazones 37 and37 andtheir their transformationtransformation into into (E)-3-styrylpyrazoles (E)-3-styrylpyrazoles40 40[ 69[69].].

Molecules 2020, 25, 5886 10 of 32 Molecules 2020, 25, x FOR PEER REVIEW 10 of 34

MoleculesThe reaction2020, 25, x FOR ofof ( (PEEREE)-3-aryl-1-(3-phenyloxiran-2-yl)-prop-2-en-1-ones)-3-aryl-1-(3-phenyloxiran-2-yl)-prop-2-en-1-ones REVIEW ( (41)) with tosyl hydrazinehydrazine10 of 34 under acidacid catalysiscatalysis a ffaffordedorded (E ()-5-hydroxy-5-phenyl-3-styryl-1-tosyl-2-pyrazolinesE)-5-hydroxy-5-phenyl-3-styryl-1-tosyl-2-pyrazolines (42 )( (Scheme42) (Scheme8)[ 70 8)]. Then,[70]. Then, (TheE)-5-phenyl-3-styryl-1-tosyl-1 (reactionE)-5-phenyl-3-styryl-1-tosyl-1 of (E)-3-aryl-1-(3-phenyloxiran-2-yl)-prop-2-en-1-onesH-pyrazolesH-pyrazoles (43 ),(43 which), which are are formed formed (41) duewith due to tosylto dehydrationdehydration hydrazine of under acid catalysis afforded (E)-5-hydroxy-5-phenyl-3-styryl-1-tosyl-2-pyrazolines (42) (Scheme 8) 5-hydroxypyrazolines 42,, were also isolated, as as by-products, by-products, by by chromatography, chromatography, after crystallization [70]. Then, (E)-5-phenyl-3-styryl-1-tosyl-1H-pyrazoles (43), which are formed due to dehydration of of the major products. 5-hydroxypyrazolines 42, were also isolated, as by-products, by chromatography, after crystallization of the major products.

Scheme 8. 8.SynthesisSynthesis of (E)-5-hydroxy-5-phenyl-3-styryl-1-tosyl-2-pyrazolines of (E)-5-hydroxy-5-phenyl-3-styryl-1-tosyl-2-pyrazolines (42) and (E)-5-phenyl- (42) and (3-styryl-1-tosyl-1E)-5-phenyl-3-styryl-1-tosyl-1Scheme 8. SynthesisH-pyrazoles of (E)-5-hydroxy-5-phenyl-3-styryl-1-tosyl-2-pyrazolines (H43-pyrazoles) [70]. (43)[70]. (42) and (E)-5-phenyl- 3-styryl-1-tosyl-1H-pyrazoles (43) [70]. The formationformation of of pyrazolines pyrazolines42 occurred42 occurred through through oxirane oxirane ring-opening ring-opening at the α -carbon,at the α followed-carbon, byfollowed theThe rearrangement by formation the rearrangement of of pyrazolines the azadiene of the 42azadiene intermediateoccurred intermediate through (A) through oxirane (A) through aring-opening hydride a hydride [1,5 ]at sigmatropic [1,5]the sigmatropicα-carbon, shift toshiftfollowed 1,3-diketone to 1,3-diketone by the monohydrazone rearrangement monohydrazone of the (B, (azadiene SchemeB, Scheme9 intermediate). 9). Finally, Finally, ( the Athe) through intramolecularintramolecular a hydride cyclization cyclization [1,5] sigmatropic led led to to 5- shift to 1,3-diketone monohydrazone (B, Scheme 9). Finally, the intramolecular cyclization led to 5- 5-hydroxypyrazolineshydroxypyrazolines 4242. These. These compounds compounds are are only only stable stable if if they they have have an electron-withdrawingelectron-withdrawing hydroxypyrazolines 42. These compounds are only stable if they have an electron-withdrawing group, such as 1-acyl, or if a perfluoroalkylperfluoroalkyl groupgroup isis presentpresent atat thethe C-5C-5 ofof thethe pyrazolinepyrazoline ringring [[70].70]. group, such as 1-acyl, or if a perfluoroalkyl group is present at the C-5 of the pyrazoline ring [70].

SchemeScheme 9. 9.Mechanism Mechanism of of formation formation ofof ( (EE)-3-styrylpyrazolines)-3-styrylpyrazolines 42 42 and and ( E( E)-3-styrylpyrazoles)-3-styrylpyrazoles 43 43[70]. [[70].70 ].

The condensation of acetylenic ketones 44 with aryl hydrazines 45 produces TheThe condensation condensation ofof acetylenicacetylenic ketonesketones 44 withwith arylaryl hydrazineshydrazines 45 45 produces produces (E )-3(5)-(E)-3(5)- (E)-3(5)-styrylpyrazoles (46 and/or 47) in fair to good yield. The substitution pattern in these pyrazoles styrylpyrazolesstyrylpyrazoles ( 46(46 and/or and/or 4747) ) inin fairfair toto goodgood yield. TheThe subssubstitutiontitution pattern pattern in in these these pyrazoles pyrazoles dependsdepends on on the the nature nature of of the the substituentssubstituents and main mainlyly on on the the reaction reaction conditions conditions (Scheme (Scheme 10) 10 [71].)[71 ]. depends on the nature of the substituents and mainly on the reaction conditions (Scheme 10) [71]. WhenWhen methanol methanol is is used used as as solvent solvent andand thethe reaction is is stirred stirred at at room room temperature temperature for for a period a period prior prior When methanol is used as solvent and the reaction is stirred at room temperature for a period prior toto the the addition addition of of acid acid and and heating, heating, ((EE)-5-styrylpyrazoles)-5-styrylpyrazoles 4747 werewere obtained obtained as asthe the major major products. products. to the addition of acid and heating, (E)-5-styrylpyrazoles 47 were obtained as the major products. However,However, if acidif acid is is present present and and heat heat applied applied from from the the onset, onset, a a mixture mixture of of ( E(E)-3-)-3-and and 5-styrylpyrazoles5-styrylpyrazoles 46 However, if acid is present and heat applied from the onset, a mixture of (E)-3- and 5-styrylpyrazoles and4647 andis 47 obtained. is obtained. Regioselectivity, Regioselectivity, in this in this case, case, varies varies from from 39:61% 39:61% to to 83:17% 83:17% of of46 46:47:47,, depending depending on 46 and 47 is obtained. Regioselectivity, in this case, varies from 39:61% to 83:17% of 46:47, depending on the nature of the substituents. For instance, 1when R1 = 2MeO, R2 = 3H and R3 = MeSO2, the the nature of the substituents. For instance, when R = MeO, R = H and R = MeSO2, the regioisomer on the nature of the substituents. For instance, when R1 = MeO, R2 = H and R3 = MeSO2, the regioisomer 46 is obtained in higher amount. On contrary,1 when2 R1 = R2 = H3 and R3 = NO2, 46 is the 46 is obtained in higher amount. On contrary, when R = R = H and R = NO2, 46 is the minor regioisomer 46 is obtained in higher amount. On contrary, when R1 = R2 = H and R3 = NO2, 46 is the regioisomer.minor regioisomer. In the absence In the absence of acid, of the acid, initial the initia reactionl reaction step involvesstep involves Michael Michael addition addition of the of the more minormore regioisomer. basic terminal In nitrogenthe absence of the of hydrazine acid, the initiaderival reactiontive to the step terminal involves acetylenic Michael carbon addition to form of the basic terminal nitrogen of the hydrazine derivative to the terminal acetylenic carbon to form enamine, moreenamine, basic whichterminal exists nitrogen in tautomeric of the hydrazineequilibrium deriva with thetive isomeric to the terminal hydrazone. acetylenic The cyclization carbon ofto the form which exists in tautomeric equilibrium with the isomeric hydrazone. The cyclization of the hydrazone enamine,hydrazone which in the exists presence in tautomeric of added equilibrium acid subsequently with the afforded isomeric only hydrazone. (E)-5-styrylpyrazoles The cyclization 46. The of the hydrazone in the presence of added acid subsequently afforded only (E)-5-styrylpyrazoles 46. The

Molecules 2020, 25, 5886 11 of 32

Molecules 2020, 25, x FOR PEER REVIEW 11 of 34 in theMolecules presence 2020, 25 of, x addedFOR PEER acid REVIEW subsequently afforded only (E)-5-styrylpyrazoles 46. The formation11 of 34 of this isomer seems to be promoted by the strong electron-donating and electron-withdrawing effect of formationformation of ofthis this isomer isomer seems seems toto bebe promotedpromoted by thethe strongstrong electron-donatingelectron-donating and and electron- electron- the substituents. withdrawingwithdrawing effect effect of of the the substituents. substituents.

SchemeScheme 10. 10. CondensationCondensation of ofacetylenic acetylenic ketones ketones 44 with44 arylwith hydrazines aryl hydrazines 45 to produce45 to (E produce)-3(5)- Scheme 10. Condensation of acetylenic ketones 44 with aryl hydrazines 45 to produce (E)-3(5)- (E)-3(5)-styrylpyrazolesstyrylpyrazoles (46 and/or (46 and47) /[71].or 47 )[71]. styrylpyrazoles (46 and/or 47) [71].

TheThe microwave-assisted microwave-assistedN N-heterocyclization-heterocyclization ofof metal-diketonicmetal-diketonic complexes, complexes, Pd(dba) Pd(dba)2 or2 or Pd(dba) Pd(dba)3 3 The microwave-assisted N-heterocyclization of metal-diketonic complexes, Pd(dba)2 or Pd(dba)3 (dba(dba= dibenzylideneacetones) = dibenzylideneacetones) with with hydrochloride hydrochloride salts salts of various of various aryl hydrazines aryl hydrazines allows allows the synthesis the (dba = dibenzylideneacetones) with hydrochloride salts of various aryl hydrazines allows the ofsynthesis 1-aryl-5-phenyl-3-styryl-1 of 1-aryl-5-phenyl-3-styryl-1H-pyrazolesH-pyrazoles in a single in step a single and step with and very with good very yields good yields (Scheme (Scheme 11)[72 ]. synthesis of 1-aryl-5-phenyl-3-styryl-1H-pyrazoles in a single step and with very good yields (Scheme Metal-diketones11) [72]. Metal- actdiketones as both act catalyst as both and catalyst coupling and couplin partner.g partner. The hydrazine The hydrazine substrate substrate and the and solvent the 11) [72]. Metal-diketones act as both catalyst and coupling partner. The hydrazine substrate and the playsolvent an important play an important role in the role selectivity. in the selectivity. Reaction Reaction with phenyl with phenyl hydrazine hydrazine hydrochloride hydrochloride in water in solvent play an important role in the selectivity. Reaction with phenyl hydrazine hydrochloride in gavewater both gave (E)-3-styrylpyrazole both (E)-3-styrylpyrazole48 and (48E)-3-styrylpyrazoline and (E)-3-styrylpyrazoline49 in approximately 49 in approximately equal amounts. equal wateramounts. gave Ifboth the substrate (E)-3-styrylpyrazole is phenyl hydrazine 48 and (without (E)-3-styrylpyrazoline hydrochloride salt), 49 ( Ein)-3-styrylpyrazoline approximately equal 49 If the substrate is phenyl hydrazine (without hydrochloride salt), (E)-3-styrylpyrazoline 49 is the amounts.is the major If the reaction substrate product. is phenyl The usehydrazine of DMSO (without as a solvent hydrochloride instead of water salt), promotes(E)-3-styrylpyrazoline the formation 49 major reaction product. The use of DMSO as a solvent instead of water promotes the formation of is theof ( Emajor)-3-styrylpyrazole reaction product. 48 in highThe useyields. of DMSO as a solvent instead of water promotes the formation (E)-3-styrylpyrazole 48 in high yields. of (E)-3-styrylpyrazole 48 in high yields.

Scheme 11. Microwave-assisted synthesis of (E)-3-styrylpyrazoles 48 and (E)-3-styrylpyrazolines 49 [72]. Scheme 11. Microwave-assistedMicrowave-assisted synthesis synthesis of of (E ()-3-styrylpyrazolesE)-3-styrylpyrazoles 4848 andand (E)-3-styrylpyrazolines (E)-3-styrylpyrazolines 49 3.2.2.49[72].[ Intramolecular72 ]. Oxidative C–N Coupling of Hydrazones

3.2.2. IntramolecularThe ruthenium(II)-catalyzed Oxidative C–N oxidative Coupling C–N of co Hydrazonesupling of 2,4-dinitrophenylhydrazone of (1E,4E)- 3.2.2.1,5-diphenylpenta-1,4-dien-3-one Intramolecular Oxidative C–N 50 Coupling in the presence of Hydrazones of oxygen (1 atm) as the oxidant, afforded (E)-1- (2,4-dinitrophenyl)-5-phenyl-3-styryl-1The ruthenium(II)-catalyzed ruthenium(II)-catalyzed oxidative oxidativeH-pyrazole C–N C–N co (upling48). coupling [RuCl of 22,4-dinitrophenylhydrazone(p-cymene)] of 2,4-dinitrophenylhydrazone2 (5 mol%) was found of (1 toE be,4E of)- (11,5-diphenylpenta-1,4-dien-3-oneEthe,4E )-1,5-diphenylpenta-1,4-dien-3-onebest catalyst for this oxidative 50 C(spin the250)− presenceHin amination the presence of oxygen (Scheme of oxygen (1 12)atm) [73]. (1 as atm) theThis oxidant, as catalyst the oxidant, afforded allows a ffC–H orded(E)-1- (E)-1-(2,4-dinitrophenyl)-5-phenyl-3-styryl-1H-pyrazole (48). [RuCl (p-cymene)] (5 mol%) was found (2,4-dinitrophenyl)-5-phenyl-3-styryl-1bond cleavage via an o-metalation processH-pyrazole that involves (48). [RuClchelation2(p-cymene)] with2 the nitrogen2 (5 mol%)2 from was hydrazone. found to be to beConsequently, the best catalyst the formation for this oxidative of a C–N C(sp bond2) His aminationpossible via (Scheme reductive 12)[ elimination73]. This catalyst to generate allows the C–H the best catalyst for this oxidative C(sp2)−H− amination (Scheme 12) [73]. This catalyst allows C–H bondcorresponding cleavage via pyrazole. an o-metalation Finally, process processthe oxygen that that promotesinvolves involves chelat chelationoxidationion with withof the the the Ru(0) nitrogen nitrogen species from from to hydrazone. hydrazone.Ru(II) to complete the catalytic cycle. Consequently, the formation of a C–N bond is possiblepossible via reductivereductive elimination to generate the Other oxidative C(sp2)−H amination reactions have been reported using copper catalysts. By corresponding pyrazole. Finally, the oxygen promotes oxidation of the Ru(0) species to Ru(II) to using Cu(OAc)2 (10 mol%) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (30 mol%) in DMSO at 100 °C complete the catalytic cycle.

Other oxidative C(sp2)−H amination reactions have been reported using copper catalysts. By using Cu(OAc)2 (10 mol%) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (30 mol%) in DMSO at 100 °C

Molecules 2020, 25, 5886 12 of 32 corresponding pyrazole. Finally, the oxygen promotes oxidation of the Ru(0) species to Ru(II) to complete the catalytic cycle. Other oxidative C(sp2) H amination reactions have been reported using copper catalysts. By using Molecules 2020, 25, x FOR PEER REVIEW− 12 of 34 Cu(OAc)Molecules 20202 (10, 25 mol%), x FOR PEER and 1,4-diazabicyclo[2.2.2]octaneREVIEW (DABCO) (30 mol%) in DMSO at 100 ◦C12 in of the 34 Molecules 2020, 25, x FOR PEER REVIEW 12 of 34 presence of oxygen (1 atm) as the oxidant, (E)-1,5-diphenyl-3-styryl-1H-pyrazole (48,R1 = Ph) was 1 in the presence of oxygen (1 atm) as the oxidant, (E)-1,5-diphenyl-3-styryl-1H-pyrazole (48, R1 = Ph) obtainedin the presence (Scheme of 12oxygen)[74]. (1 atm) as the oxidant, (E)-1,5-diphenyl-3-styryl-1H-pyrazole (48, R1 = Ph) was obtained (Scheme 12) [74]. was obtained (Scheme 12) [74].

Scheme 12. E 48 Scheme 12. SynthesisSynthesis of of ( (E)-3-styrylpyrazoles)-3-styrylpyrazoles 48 by intramolecular oxidative C–N coupling of hydrazonesScheme 12.50 Synthesis[73,74]. of (E)-3-styrylpyrazoles 48 by intramolecular oxidative C–N coupling of hydrazones 50 [73,74]. hydrazones 50 [73,74]. 3.2.3. Miscellaneous 3.2.3. Miscellaneous 3.2.3.The Miscellaneous decarboxylative Knoevenagel reaction of aldehyde 51 with 3-methyl-5-pyrazoleacetic acid 52 The decarboxylative Knoevenagel reaction of aldehyde 51 with 3-methyl-5-pyrazoleacetic acid directlyThe a ffdecarboxylativeorded (E)-3-styrylpyrazole Knoevenagel7 (Schemereaction 13of)[ aldehyde33]. 51 with 3-methyl-5-pyrazoleacetic acid 52 directly afforded (E)-3-styrylpyrazole 7 (Scheme 13) [33]. 52 directly afforded (E)-3-styrylpyrazole 7 (Scheme 13) [33].

Scheme 13. Synthesis of (E)-3-styrylpyrazole 7 by Doebner modification of Knoevenagel Scheme 13.13. SynthesisSynthesis of of (E (E)-3-styrylpyrazole)-3-styrylpyrazole 77 byby Doebner Doebner modification modification of KnoevenagelKnoevenagel Scheme 13. Synthesis of (E)-3-styrylpyrazole 7 by Doebner modification of Knoevenagel condensation [[33].33]. condensation [33].

Hydrogenolysis of (E)-5-styrylisoxazole 53, using Mo(CO)6 in the presence of water (1.0 equiv), Hydrogenolysis of (E)-5-styrylisoxazole 53, using Mo(CO)6 inin the the presence presence of of water water (1.0 (1.0 equiv), Hydrogenolysis of (E)-5-styrylisoxazole 53, using Mo(CO)6 in the presence of water (1.0 equiv), followed by ring ring closure closure with with hydrazine hydrazine also also produced produced (E (E)-3-styrylpyrazole)-3-styrylpyrazole 7 7[33].[33]. In In a first a first step, step, a followed by ring closure with hydrazine also produced (E)-3-styrylpyrazole 7 [33]. In a first step, a aketone ketone is isobtained obtained (Scheme (Scheme 14, 14i),, which i), which after after reaction reaction with with 97% 97%hydrazine hydrazine in acetic in aceticacid gave acid ( gaveE)-3- ketone is obtained (Scheme 14, i), which after reaction with 97% hydrazine in acetic acid gave (E)-3- (styrylpyrazoleE)-3-styrylpyrazole 7 (Scheme7 (Scheme 14, ii). 14 , ii). styrylpyrazole 7 (Scheme 14, ii).

Scheme 14. Conversion of (E)-5-styrylisoxazole 53 into (E)-3-styrylpyrazole 7 by hydrogenolysis [33]. Scheme 14. Conversion of (E)-5-styrylisoxazole 53 into (E)-3-styrylpyrazole 7 by hydrogenolysis [[33].33]. Deshayes et al. reported the use of 3-bromomethylpyrazole 54 as template for the synthesis of Deshayes et al. reported the use of 3-bromomethylpyrazole 54 as template for the synthesis of (E)-3-styrylpyrazole 55. In a first step, this compound was treated with triethyl phosphite, in the (E)-3-styrylpyrazole 55. In a first step, this compound was treated with triethyl phosphite, in the Arbusov reaction, affording the corresponding diethylphosphonomethylpyrazole, which then Arbusov reaction, affording the corresponding diethylphosphonomethylpyrazole, which then reacted with benzaldehyde in the presence of sodium hydride to give the corresponding (E)-3- reacted with benzaldehyde in the presence of sodium hydride to give the corresponding (E)-3- styrylpyrazole 55 (Scheme 15) [75]. styrylpyrazole 55 (Scheme 15) [75].

Molecules 2020, 25, 5886 13 of 32

Deshayes et al. reported the use of 3-bromomethylpyrazole 54 as template for the synthesis of (E)-3-styrylpyrazole 55. In a first step, this compound was treated with triethyl phosphite, in the Arbusov reaction, affording the corresponding diethylphosphonomethylpyrazole, which then reacted with benzaldehyde in the presence of sodium hydride to give the corresponding (E)-3-styrylpyrazole 55Molecules(Scheme 2020 ,15 25)[, x75 FOR]. PEER REVIEW 13 of 34

Molecules 2020, 25, x FOR PEER REVIEW 13 of 34

Scheme 15. Synthesis of (E)-3-styrylpyrazole 55 [[75].75]. Scheme 15. Synthesis of (E)-3-styrylpyrazole 55 [75]. 3.3. Synthesis of 4-Styrylpyrazoles 3.3. Synthesis of 4-Styrylpyrazoles 3.3.1. Cross-Coupling Reactions 3.3.1. Cross-Coupling Reactions 3.3.1.(E)-(4-Styryl)aminopyrazoles Cross-Coupling Reactions can be accessed in a straightforward way by the Suzuki–Miyaura (E)-(4-Styryl)aminopyrazoles can be accessed in a straightforward way by the Suzuki–Miyaura cross-coupling reaction of 4-bromo aminopyrazoles 56 and their amides with styryl boronic acids cross-coupling(E)-(4-Styryl)aminopyrazoles reaction of 4-bromo canaminopyrazoles be accessed in 56 a andstraightforward their amides way with by styryl the Suzuki–Miyaura boronic acids 57 57 cross-coupling(Scheme 16). Usingreaction the of pre-catalyst4-bromo aminopyrazoles palladacycle 56 XPhos and their Pd G2amides and with XPhos, styryl in combinationboronic acids with57 (Scheme 16). Using the pre-catalyst palladacycle XPhos Pd G2 and XPhos, in combination with K2CO3 K2CO(Scheme3 in a 16). green Using solvent the pre-catalyst system (EtOH palladacycle/H2O), under XPhos microwave Pd G2 and irradiation, XPhos, in combination Jedináket al. with obtained K2CO the3 in a green solvent system (EtOH/H2O), under microwave irradiation, Jedináket al. obtained the (E)- (E)-(4-styryl)aminopyrazolesin a green solvent system (EtOH/H58 [76].2 DirectO), under comparison microwave of theirradiation, chloro, bromo,Jedináket and al. iodopyrazoles obtained the (E used)- (4-styryl)aminopyrazoles 58 [76]. Direct comparison of the chloro, bromo, and iodopyrazoles used as as substrate(4-styryl)aminopyrazoles in the Suzuki Miyaura 58 [76]. Direct reaction comparison revealed of that the bromo chloro, and bromo, chloro and derivatives iodopyrazoles were used superior as substrate in the Suzuki−Miyaura− reaction revealed that bromo and chloro derivatives were superior to iodopyrazoles,substrate in the Suzuki showing−Miyaura reduced reaction propensity revealed to dehalogenation that bromo and chloro [76]. Using derivatives the same were pre-catalyst superior to iodopyrazoles, showing reduced propensity to dehalogenation [76]. Using the same pre-catalyst (XPhosto iodopyrazoles, Pd G2), which showing enabled reduced the coupling propensity with to dehalogenation the electron deficient, [76]. Using electron-rich, the same pre-catalyst or sterically (XPhos Pd G2), which enabled the coupling with the electron deficient, electron-rich, or sterically demanding(XPhos Pd boronic G2), which acids, enabled Tomanov theá etcoupling al. coupled with thethe 4-bromopyrazoleselectron deficient, 59electron-rich,with styryl or boronic sterically acids demanding boronic acids, Tomanová et al. coupled the 4-bromopyrazoles 59 with styryl boronic acids 57 demandingto prepare theboronic (E)-3,5-dinitro-4-styryl-1 acids, Tomanová et al.H coupled-pyrazoles the 4-bromopyrazoles60 (Scheme 17)[ 7759 ].with The styryl introduction boronic acids of the 57 to prepare the (E)-3,5-dinitro-4-styryl-1H-pyrazoles 60 (Scheme 17) [77]. The introduction of the electron-deficient57 to prepare the nitro (E)-3,5-dinitro-4-styryl-1 groups as masked aminoH-pyrazoles functionalities 60 (Scheme improved 17) [77]. The the rateintroduction of the oxidative of the electron-deficient nitro groups as masked amino functionalities improved the rate of the oxidative additionelectron-deficient step and eliminated nitro groups the as Pd-independent masked amino functionalities side dehalogenation improved reaction. the rate Bothof the nitro oxidative groups additionaddition step step and and eliminated eliminated the the Pd-independent Pd-independent side dehalogenationdehalogenation reaction. reaction. Both Both nitro nitro groups groups were then converted into amine groups by iron-catalyzed reduction with hydrazine hydrate to give werewere then then converted converted into into amine amine groups groups byby iron-catalyzediron-catalyzed reductionreduction with with hydrazine hydrazine hydrate hydrate to togive give (E)-3,5-diamino-4-styryl-1H-pyrazoles (61). (E)-3,5-diamino-4-styryl-1(E)-3,5-diamino-4-styryl-1HH-pyrazoles-pyrazoles ( (6161).).

SchemeScheme 16. 16.Suzuki–Miyaura Suzuki–Miyaura coupling coupling ofof 4-bromo4-bromo aminopyrazoles 5656 andand their their amides amides with with styryl styryl Scheme 16. Suzuki–Miyaura coupling of 4-bromo aminopyrazoles 56 and their amides with styryl boronicboronic acids acids57 57to to prepare prepare (E ()-(4-styryl)aminopyrazolesE)-(4-styryl)aminopyrazoles 5858 [[76].76]. boronic acids 57 to prepare (E)-(4-styryl)aminopyrazoles 58 [76].

Molecules 2020, 25, 5886 14 of 32 Molecules 2020, 25, x FOR PEER REVIEW 14 of 34

Molecules 2020, 25, x FOR PEER REVIEW 14 of 34 Molecules 2020, 25, x FOR PEER REVIEW 14 of 34

SchemeScheme 17. 17.Synthesis Synthesis of of (E )-3,5-dinitro-4-styryl-1(E)-3,5-dinitro-4-styryl-1H-pyrazoles 6060 andand iron-catalyzed iron-catalyzed reduction reduction of the of the

nitronitro groups groups to produceto produce (E )-3,5-diamino-4-styryl-1(E)-3,5-diamino-4-styryl-1HH-pyrazoles-pyrazoles 6161 [77].[77]. Scheme 17. Synthesis of (E)-3,5-dinitro-4-styryl-1H-pyrazoles 60 and iron-catalyzed reduction of the nitro groups to produce (E)-3,5-diamino-4-styryl-1H-pyrazoles 61 [77]. StartingnitroStarting groups from from to 4-iodo-1-(4-nitrophenyl)-1 produce4-iodo-1-(4-nitrophenyl)-1 (E)-3,5-diamino-4-styryl-1HH-pyrazoleH-pyrazoles 6262 and 61and [77]. 4-methoxystyrene 4-methoxystyrene 63, 63Miller, Miller et al. et al. synthesized (E)-4-(4-methoxystyryl)-1-nitrophenyl-1H-pyrazole 64, using standard palladium- synthesizedStarting (E)-4-(4-methoxystyryl)-1-nitrophenyl-1 from 4-iodo-1-(4-nitrophenyl)-1H-pyrazoleH-pyrazole 62 and64 ,4-methoxystyrene using standard palladium-catalyzed 63, Miller et al. catalyzedStarting coupling from 4-iodo-1-(4-nitrophenyl)-1 conditions (Scheme 18). HFurthermore,-pyrazole 62 4-bromo-1-(4-nitrophenyl)-1and 4-methoxystyrene 63, MillerH-pyrazole et al. couplingsynthesized conditions (E)-4-(4-methoxystyryl (Scheme 18). Furthermore,)-1-nitrophenyl-1 4-bromoH-pyrazole-1-(4-nitrophenyl)-1 64, using Hstandard-pyrazole palladium- did not react synthesizeddid not react (underE)-4-(4-methoxystyryl the same conditions)-1-nitrophenyl-1 [71]. On theH -pyrazoleother hand, 64 the, using Mizoroki–Heck standard couplingpalladium- of undercatalyzed the same coupling conditions conditions [71]. On (Scheme the other 18). hand, Furthermore, the Mizoroki–Heck 4-bromo-1-(4-nitrophenyl)-1 coupling of previouslyH-pyrazole prepared catalyzedpreviously coupling prepared conditions 4-vinylpyrazole (Scheme 65 with 18). halobenzenes Furthermore, 66 4-bromo-1-(4-nitrophenyl)-1, using Pd(AcO)2 (10 mol%) asH -pyrazolea catalyst 4-vinylpyrazoledid not react65 underwith the halobenzenes same conditions66, using [71]. Pd(AcO)On the other2 (10 hand, mol%) the as Mizoroki–Heck a catalyst in the coupling presence of of a didin the not presence react under of a ligand the same (o-MePh) conditions3P (20 mol%),[71]. On afforded the other the hand, desired the ( EMizoroki–Heck)-1,3-disubstituted-4-styryl- coupling of previouslyo prepared 4-vinylpyrazole 65 with halobenzenesE 66, using Pd(AcO)2 (10 mol%)H as a catalyst67 ligandpreviously1H-pyrazoles ( -MePh) prepared3 P67 (20 [45] mol%), 4-vinylpyrazole (Scheme aff orded19). This 65 the with reaction desired halobenzenes (was)-1,3-disubstituted-4-styryl-1 performed 66, using under Pd(AcO) microwave2 (10 mol%)-pyrazoles irradiation as a catalyst to [45] in the presence of a ligand (o-MePh)3P (20 mol%), afforded the desired (E)-1,3-disubstituted-4-styryl- (Schemeinobtain the 19 presence the). Thiscompound reactionof a ligand in wasa shorter(o-MePh) performed reaction3P (20 undermol%), time. microwaveafforded the irradiation desired (E)-1,3-disubstituted-4-styryl- to obtain the compound in a shorter1H-pyrazoles reactiontime. 67 [45] (Scheme 19). This reaction was performed under microwave irradiation to obtain the compound in a shorter reaction time.

Scheme 18. Synthesis of (E)-4-(4-methoxystyryl)-1-nitrophenyl-1H-pyrazole 64 [71].

SchemeScheme 18. 18.Synthesis Synthesis of of ( E(E)-4-(4-methoxystyryl)-1-nitrophenyl-1)-4-(4-methoxystyryl)-1-nitrophenyl-1H-pyrazoleH-pyrazole 64 [71].64 [71 ].

Scheme 19. Mizoroki–Heck coupling of 4-vinylpyrazole 65 with halobenzenes 66 to prepare (E)-1,3-

disubstituted-4-styryl-1H-pyrazoles 67 [45]. Scheme 19. Mizoroki–Heck coupling of 4-vinylpyrazole 65 with halobenzenes 66 to prepare (E)-1,3- SchemeScheme 19. 19.Mizoroki–Heck Mizoroki–Heck coupling coupling of 4-vinylpyrazole of 4-vinylpyrazole 65 with65 halobenzeneswith halobenzenes 66 to prepare66 to(E)-1,3- prepare disubstituted-4-styryl-1H-pyrazoles 67 [45]. (E)-1,3-disubstituted-4-styryl-1disubstituted-4-styryl-1H-pyrazolesH-pyrazoles 67 [45].67 [45].

Molecules 2020, 25, 5886 15 of 32 Molecules 2020, 25, x FOR PEER REVIEW 15 of 34 3.3.2.Molecules Cyclocondensation 2020, 25, x FOR PEERReaction REVIEW 15 of 34 3.3.2. Cyclocondensation Reaction 3.3.2.Kim Cyclocondensation et al. described Reaction a convenient method to prepared (E)-4-styrylpyrazoles starting from Kim et al. described a convenient method to prepared (E)-4-styrylpyrazoles starting from α- α-alkenyl-α,β-enones 68, readily accessed from the Morita–Baylis–Hillman reaction. The reaction of 68 alkenyl-Kimα, βet-enones al. described 68, readily a convenient accessed frommethod the toMorita–Baylis–Hillman prepared (E)-4-styrylpyrazoles reaction. Thestarting reaction from of α 68- with aryl hydrazines in ethanol, in the presence of O2, afforded (E)-4-styrylpyrazoles 69 (Scheme 20), withalkenyl- arylα hydrazines,β-enones 68 in, ethanol,readily accessed in the presence from the of Morita–Baylis–Hillman O2, afforded (E)-4-styrylpyrazoles reaction. The 69 reaction (Scheme of 20),68 together with trace amounts of the corresponding 4-arylethylpyrazoles and pyridazine derivatives, togetherwith aryl with hydrazines trace amounts in ethanol, of the in thecorresponding presence of O4-arylethylpyrazoles2, afforded (E)-4-styrylpyrazoles and pyridazine 69 (Scheme derivatives, 20), which were identified but were not isolated [78]. whichtogether were with identified trace amounts but were of notthe isolatedcorresponding [78]. 4-arylethylpyrazoles and pyridazine derivatives, which were identified but were not isolated [78].

Scheme 20. ReactionReaction of of αα-alkenyl--alkenyl-αα,,ββ-enones-enones 6868 withwith arylhydrazines arylhydrazines to to produce produce ( (EE)-4-styrylpyrazoles)-4-styrylpyrazoles Scheme 20. Reaction of α-alkenyl-α,β-enones 68 with arylhydrazines to produce (E)-4-styrylpyrazoles 69 [78].[78]. 69 [78]. 3.3.3. 1,3-Dipolar 1,3-Dipolar Cycloaddition Cycloaddition Reaction 3.3.3. 1,3-Dipolar Cycloaddition Reaction 1,3-Dipolar cycloadditioncycloaddition reactionreaction of of ( E(E,E,E)-cinnamylideneacetophenones)-cinnamylideneacetophenones70 70and and diazomethane, diazomethane, at 1,3-Dipolar cycloaddition reaction of (E,E)-cinnamylideneacetophenones 70 and diazomethane, atroom room temperature temperature or or in in aa refrigerator, lead lead to to the the formation formation of of3-benzoyl-4-styryl-2-pyrazolines 3-benzoyl-4-styryl-2-pyrazolines 71. at room temperature or in a refrigerator, lead to the formation of 3-benzoyl-4-styryl-2-pyrazolines 71. By71. oxidation By oxidation with an with excess an of excess chloranil, of chloranil, in toluene, in pyrazolines toluene, pyrazolines 71 were converted71 were into converted 3(5)-benzoyl- into By oxidation with an excess of chloranil, in toluene, pyrazolines 71 were converted into 3(5)-benzoyl- 4-styrylpyrazoles3(5)-benzoyl-4-styrylpyrazoles 72 (Scheme 21)72 [79].(Scheme The 21regioselective)[79]. The regioselective formation of formation71 results offrom71 resultsthe reaction from 4-styrylpyrazoles 72 (Scheme 21) [79]. The regioselective formation of 71 results from the reaction betweenthe reaction the betweenCα=Cβ double the Cα bond=Cβ ofdouble 70 with bond diazomethane of 70 with diazomethanegiving rise to 1-pyrazolines giving rise to 73 1-pyrazolines, which then between the Cα=Cβ double bond of 70 with diazomethane giving rise to 1-pyrazolines 73, which then isomerize73, which theninto 2-pyrazoline isomerize into isomers 2-pyrazoline 71 (Scheme isomers 22).71 From(Scheme the reaction 22). From between the reaction the Cγ between=Cδ double the isomerize into 2-pyrazoline isomers 71 (Scheme 22). From the reaction between the Cγ=Cδ double bondCγ=C ofδ double70 with bonddiazomethane, of 70 with other diazomethane, cycloadducts other can cycloadductsbe formed; however, can be formed;their formation however, was their not bond of 70 with diazomethane, other cycloadducts can1 be formed;2 however,3 their formation was not reported.formation For was some not reported.derivatives For (R some1 = H, derivativesR2 = H and R (R3 = =H,H, Me), R small= H and amounts R = H, of Me),3-(2-benzofuranyl)- small amounts reported. For some derivatives (R1 = H, R2 = H and R3 = H, Me), small amounts of 3-(2-benzofuranyl)- 4-styryl-2-pyrazolinesof 3-(2-benzofuranyl)-4-styryl-2-pyrazolines were formed as by-products, were formed as a asresult by-products, of insertion as a of result a methylene of insertion group of a methylene4-styryl-2-pyrazolines group between were the formed carbonyl as by-products, and the 2-hydroxyphenyl as a result of group insertion leading of a tomethylene the formation group of betweenbetween the the carbonyl carbonyl andand thethe 2-hydroxyphenyl2-hydroxyphenyl group leading to thethe formationformation ofof compoundcompound 7474. . compound 74. Then, the intramolecular reaction of the hydroxy group with the carbonyl carbon and Then,Then, the the intramolecular intramolecular reactionreaction ofof thethe hydroxyhydroxy group with the carbonyl carboncarbon andand subsequentsubsequent subsequent water elimination from the obtained hemiacetal lead to the formation of the benzofuran waterwater elimination elimination fromfrom thethe obtainedobtained hemiacetalhemiacetal lead to the formation ofof thethe benzofuranbenzofuran ringring 7575 ring 75 (Scheme 22)[79]. (Scheme(Scheme 22) 22) [79]. [79]. 2 2 RR2 NH RR2 NH N NH N NH 2 N RR2 3 RR3 i ii i 1 ii 11 R O 3 RR OO 3 R3 RR3 1 RR1 OO 7070 1 RR1=H,OH=H,OH 71 7272 2 RR2=H,F,Me,OMe=H,F,Me,OMe 7examples 7examples7examples 3 40-58% 67-95% RR3=H,Me=H,Me 40-58% 67-95%

(i)(i) CH CH2N2N2,CH2,CH22ClCl22/diethyl/diethyl ether, ether, refrigerator, refrigerator, 48 48 h. h. (ii) Chloranil (3.0 equiv), toluene, reflux. (ii) Chloranil (3.0 equiv), toluene, reflux. SchemeScheme 21. 21. SynthesisSynthesis Synthesis of ofof ( ((EE)-3-benzoyl-4-styryl-2-pyrazolines)-3-benzoyl-4-styryl-2-pyrazolines)-3-benzoyl-4-styryl-2-pyrazolines 7171 andand 3-benzoyl-4-styryl-13-benzoyl-4-styryl-1 3-benzoyl-4-styryl-1HH-pyrazoles-pyrazoles-pyrazoles 7272 [79].[ 79[79].].

Molecules 2020, 25, 5886 16 of 32 Molecules 2020, 25, x FOR PEER REVIEW 16 of 34

2 R N R2 N N NH

CH N 2 2 R1 O 70 3 R1 O R R3

73 71 NH N N NH

O- OH O 3 OH CH2 R 3 N +-CH - + R 2 2 N2

-N2

N NH N NH O -H O 2 O R3 OH R3

75 74 Scheme 22. Mechanism of of formation formation of of 3-benzoyl-4-styryl-2-pyrazolines 3-benzoyl-4-styryl-2-pyrazolines 7171 andand 3-(2-benzofuranyl)- 3-(2-benzofuranyl) -4-styryl-2-pyrazolines4-styryl-2-pyrazolines 7575 [79].[79]. 3.3.4. Reaction of 3-Styrylchromones with Hydrazine Derivatives 3.3.4. Reaction of 3-Styrylchromones with Hydrazine Derivatives The reaction of (Z)- and (E)-3-styryl-4H-chromen-4-ones (76 and 78) (also known as 3-styrylchromones) The reaction of (Z)- and (E)-3-styryl-4H-chromen-4-ones (76 and 78) (also known as 3- with hydrazine hydrate in methanol, at room temperature, afforded the corresponding (Z)- and styrylchromones) with hydrazine hydrate in methanol, at room temperature, afforded the (E)-3(5)-(2-hydroxyphenyl)-4-styryl-1H-pyrazoles (77 and 79) in 70–94% and 32–98% yield, respectively corresponding (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styryl-1H-pyrazoles (77 and 79) in 70–94% and (Scheme 23) [80]. When the same method was followed to convert (Z)-3-(4-nitrostyryl)-4H-chromen-4-ones 32–98% yield, respectively (Scheme 23) [80]. When the same method was followed to convert (Z)-3- (76) into the corresponding pyrazoles, the (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)-1H-pyrazoles (4-nitrostyryl)-4H-chromen-4-ones (76) into the corresponding pyrazoles, the (E)-3(5)-(2- (79) were obtained in great yields (>73%) instead of the expected (Z)-isomer. These results indicate hydroxyphenyl)-4-(4-nitrostyryl)-1H-pyrazoles (79) were obtained in great yields (>73%) instead of that the strong electron-withdrawing effect of the p-nitro group has an important role in the (Z) (E) the expected (Z)-isomer. These results indicate that the strong electron-withdrawing effect of the→ p- isomerization during the transformation of (Z)-3-(4-nitrostyryl)-4H-chromen-4-ones into the corresponding nitro group has an important role in the (Z)→(E) isomerization during the transformation of (Z)-3-(4- (E)-4-(4-nitrostyryl)-1H-pyrazoles. Silva et al. have highlighted the role of the nitro group in the mechanism nitrostyryl)-4H-chromen-4-ones into the corresponding (E)-4-(4-nitrostyryl)-1H-pyrazoles. Silva et al. of formation of the (E)-4-styrylpyrazole isomer [81]. After the nucleophilic attack of hydrazine at C-2 of have highlighted the role of the nitro group in the mechanism of formation of the (E)-4-styrylpyrazole the chromone nucleus, the electronic conjugation moves towards the 4-nitro-3-styryl moiety, allowing isomer [81]. After the nucleophilic attack of hydrazine at C-2 of the chromone nucleus, the electronic the (Z) (E) isomerization of the vinylic double bond of the styryl group, to adopt the most stable conjugation→ moves towards the 4-nitro-3-styryl moiety, allowing the (Z)→(E) isomerization of the configuration, with consequent ring opening. Finally, an intramolecular reaction of the hydrazine and vinylic double bond of the styryl group, to adopt the most stable configuration, with consequent ring carbonyl group led to pyrazole ring formation (Scheme 24). opening. Finally, an intramolecular reaction of the hydrazine and carbonyl group led to pyrazole ring Although the biological activity of 4-styrylpyrazoles has rarely been studied, Silva et al. have formation (Scheme 24). shown that some derivatives of 4-styrylpyrazoles 77 and 79 with long alkyl chains of ten or twelve Although the biological activity of 4-styrylpyrazoles has rarely been studied, Silva et al. have carbons on the N-1 or linked at the oxygen of the 2 -hydroxyphenyl moiety present affinity for CB shown that some derivatives of 4-styrylpyrazoles 770 and 79 with long alkyl chains of ten or twelve1 type cannabinoid receptors in the micromolar range, or even in the nanomolar range, as observed for carbons on the N-1 or linked at the oxygen of the 2′-hydroxyphenyl moiety present affinity for CB1 the (E)-4-(4-chlorostyryl)-3(5)-(2-decyloxyphenyl)-1H-pyrazole (K = 53 33 nM) [14]. type cannabinoid receptors in the micromolar range, or even in thei nanomolar± range, as observed for the (E)-4-(4-chlorostyryl)-3(5)-(2-decyloxyphenyl)-1H-pyrazole (Ki = 53 ± 33 nM) [14].

Molecules 2020, 25, 5886 17 of 32 Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 17 of 34 Molecules 2020, 25, x FOR PEER REVIEW 17 of 34

SchemeScheme 23. 23.Synthesis Synthesis of of ( Z(Z)-)-)- and andand ( (E(E)-3(5)-(2-hydroxyphenyl)-4-styryl-1)-3(5)-(2-hydroxyphenyl)-4-styryl-1)-3(5)-(2-hydroxyphenyl)-4-styryl-1HH-pyrazoles-pyrazoles-pyrazoles 7777 andandand 7979 [80,81].[80,81].[80,81 ]. Scheme 23. Synthesis of (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styryl-1H-pyrazoles 77 and 79 [80,81].

SchemeScheme 24. 24.Mechanism Mechanism of the the transformation transformation of ( ofZ)-3-(4-nitrostyryl)-4)-3-(4-nitrostyryl)-4 (Z)-3-(4-nitrostyryl)-4H-chromen-4-ones-chromen-4-onesH-chromen-4-ones ((76)) intointo (76 (()E into)-)- Scheme 24. Mechanism of the transformation of (Z)-3-(4-nitrostyryl)-4H-chromen-4-ones (76) into (E)- (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)-13(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)-1H-pyrazoles-pyrazolesH-pyrazoles ((79)) ( [81].[81].79)[ 81]. 3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)-1H-pyrazoles (79) [81]. 3.3.5.3.3.5. Miscellaneous Miscellaneous 3.3.5. Miscellaneous TheThe Wittig Wittig reaction reaction ofof 4-formylpyrazole4-formylpyrazole 8080 withwithwith benzyltriphenylphosphoniumbenzyltriphenylphosphonium benzyltriphenylphosphonium bromidebromide bromide ((81)) inin (81 ) The Wittig reaction of 4-formylpyrazole 80 with benzyltriphenylphosphonium bromide (81) in inBuLi-THF BuLi-THF afforded afforded the the corresponding corresponding (E ()-)-E )-andand and ((Z ()-4-styrylpyrazoles)-4-styrylpyrazolesZ)-4-styrylpyrazoles 82 82withwithwith anan anE:ZE:Z ratioratioratio ofof of BuLi-THF afforded the corresponding (E)- and (Z)-4-styrylpyrazoles 82 with an E:Z ratio of approximatelyapproximately 1:3 1:3 (Scheme (Scheme 25 25))[ 45[45].]. approximately 1:3 (Scheme 25) [45].

Scheme 25. Wittig reaction of 4-formylpyrazole 80 withwith benzyltriphenylphosphoniumbenzyltriphenylphosphonium bromidebromide 81 toto SchemeScheme 25. 25.Wittig Wittig reaction reaction of of 4-formylpyrazole 4-formylpyrazole 80 with benzyltriphenylphosphonium bromide bromide 8181 to to prepare (E)-)- andand ((Z)-4-styrylpyrazoles)-4-styrylpyrazoles 82 [45].[45]. prepare (E)- and (Z)-4-styrylpyrazoles 82 [45]. prepare (E)- and (Z)-4-styrylpyrazoles 82 [45].

Molecules 2020, 25, 5886 18 of 32

Molecules 2020, 25, x FOR PEER REVIEW 18 of 34 Ahamad et al. described the synthesis of the (E)-4-styryl-5-vinylpyrazole 85 by a domino Ahamad et al. described the synthesis of the (E)-4-styryl-5-vinylpyrazole 85 by a domino reaction,Ahamad which et involvesal. described the 1,3-dipolarthe synthesis cycloaddition of the (E)-4-styryl-5-vinylpyrazole of Bestmann–Ohira reagent 85 by (BOR) a domino84 to reaction, which involves the 1,3-dipolar cycloaddition of Bestmann–Ohira reagent (BOR) 84 to reaction,(2E,4E)-5-phenylpenta-2,4-dienal which involves the 1,3-dipolar83, followed cycloaddition by a Horner–Wadsworth–Emmons of Bestmann–Ohira reagent reaction (BOR) of84 theto (2E,4E)-5-phenylpenta-2,4-dienal 83, followed by a Horner–Wadsworth–Emmons reaction of the (2resultingE,4E)-5-phenylpenta-2,4-dienal pyrazoline carboxaldehyde 83, andfollowed subsequent by a Horner–Wadsworth–Emmons 1,3-H shift to afford 85. This methodology reaction of hasthe resulting pyrazoline carboxaldehyde and subsequent 1,3-H shift to afford 85. This methodology has resultingrelevant applicationpyrazoline forcarboxaldehyde the synthesis and of 5-vinylpyrazoles subsequent 1,3-H (Scheme shift to 26 afford)[82]. 85. This methodology has relevant application for the synthesis of 5-vinylpyrazoles (Scheme 26) [82].

Scheme 26. SynthesisSynthesis of of the the ( EE)-4-styryl-5-vinylpyrazole)-4-styryl-5-vinylpyrazole 85 [82].[82]. 3.4. Synthesis of 5(3)-Styrylpyrazoles 3.4. Synthesis of 5(3)-Styrylpyrazoles 3.4.1. Cyclocondensation Reactions 3.4.1. Cyclocondensation Reactions One of the first reports about the synthesis of styrylpyrazoles dates back to 1978 [83]. At that One of the first reports about the synthesis of styrylpyrazoles dates back to 1978 [83]. At that time,One Soliman of the et first al. described reports about the reaction the synthesis of diketoester of styrylpyrazoles86 with aryl /dateshetaryl back hydrazines to 1978 in[83]. ethanol At that to time, Soliman et al. described the reaction of diketoester 86 with aryl/hetaryl hydrazines in ethanol time,prepare Soliman (E)-5-styrylpyrazoles et al. described87 the(Scheme reaction 27 of). diketoester 86 with aryl/hetaryl hydrazines in ethanol to prepare (E)-5-styrylpyrazoles 87 (Scheme 27).

Scheme 27. 27. CyclocondensationCyclocondensation of diketoester of diketoester 86 with86 witharyl/hetaryl aryl/hetaryl hydrazines hydrazines to prepare to prepare (E)-5- styrylpyrazoles(E)-5-styrylpyrazoles 87 [83].87 [83].

The first first approach to thethe synthesissynthesis ofof ((EE)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1HH-pyrazole-pyrazole ( (89a89a,, R1 == H)H )was was the the treatment treatment of 1-(2-hydroxy of 1-(2-hydroxyphenyl)-5-phenylpent-4-ene-1,3-dionephenyl)-5-phenylpent-4-ene-1,3-dione (88a, (R88a1 =,R H)1, which= H), existswhich in exists equilibrium in equilibrium with the with enolic the enolic form form(88a′ (),88a with0), with excess excess hydrazine hydrazine (formed (formed by bytreatment treatment of hydraziniumof hydrazinium sulfate sulfate with with potassium potassium carbonate), carbonate), added added gradually gradually (dropwise) (dropwise) and and using using a a 1:1 dichloromethane (DCM)(DCM)/methanol/methanol mixturemixture as as solvent solvent (Scheme (Scheme 28 28,, i) i) [84 [84].]. Using Using hydrazine hydrazine hydrate hydrate in inmethanol methanol at roomat room temperature, temperature, compounds compounds88 were88 were converted converted into into pyrazoles pyrazoles89 (Scheme 89 (Scheme 28, ii) 28, [84 ii)]. 1 1 2 2 [84].Furthermore, Furthermore, (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1 (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazolesH-pyrazoles89 (R 89 =(RH,1 = OMe,H, OMe, NO 2NO;R2; =R2H) = H)were were also also obtained obtained starting starting from from88 88by by reaction reaction with with hydrazine hydrazine hydrate, hydrate, inin aceticacetic acid (Scheme 28,28, iii) [84]. Treatment of acetic acid solutions of diketones 88 with an excess of phenyl hydrazine afforded a mixture of two 5-styrylpyrazole isomers 90 and 91, though pyrazoles 91 were obtained in a vestigial amount (Scheme 28, iv). In fact, the reaction of unsymmetrical diketones and

Molecules 2020, 25, 5886 19 of 32

Moleculesiii) [84]. 2020 Treatment, 25, x FOR of PEER acetic REVIEW acid solutions of diketones 88 with an excess of phenyl hydrazine aff19orded of 34 a mixture of two 5-styrylpyrazole isomers 90 and 91, though pyrazoles 91 were obtained in a vestigial monosubstituted hydrazines, such as phenyl hydrazine, although apparently simple, conceal a amountMolecules (Scheme 2020, 25, x FOR28, PEER iv). REVIEW In fact, the reaction of unsymmetrical diketones and monosubstituted19 of 34 complex mechanistic problem. Diketones 88 have two tautomeric forms (88 and 88′) and phenyl hydrazines, such as phenyl hydrazine, although apparently simple, conceal a complex mechanistic hydrazinemonosubstituted can react hydrazines, initially through such as NH phenyl or NH hydr2. Whenazine, the although reaction apparently is carried simple,out in methanolconceal a in problem. Diketones 88 have two tautomeric forms (88 and 880) and phenyl hydrazine can react initially neutralcomplex conditions, mechanistic a nucleophilic problem. Diketones attack of the 88 primaryhave two amine tautomeric (NH2) formsto the more(88 and electrophilic 88′) and phenyl position through NH or NH2. When the reaction is carried out in methanol in neutral conditions, a nucleophilic of hydrazinethe diketone can react(C-1) initially occurs throughand only NH pyrazoles or NH2. When91 were the reactionobtained is incarried low outyields. in methanol Using acidic in attack of the primary amine (NH2) to the more electrophilic position of the diketone (C-1) occurs and conditionsneutral conditions, (AcOH as a nucleophilicsolvent), the attack more of basic the primary amine amine(NH2) (NH was2 ) protonatedto the more electrophilicand subsequently position the only pyrazoles 91 were obtained in low yields. Using acidic conditions (AcOH as solvent), the more nucleophilicof the diketone attack (C-1) at the occurs more electrophilicand only pyrazoles position 91was were through obtained the NH in affordinglow yields. pyrazoles Using acidic 90 [84]. basic amine (NH2) was protonated and subsequently the nucleophilic attack at the more electrophilic conditions (AcOH as solvent), the more basic amine (NH2) was protonated and subsequently the positionnucleophilic was through attack at the the NHmore aff electrophilicording pyrazoles position90 was[84]. through the NH affording pyrazoles 90 [84].

SchemeScheme 28. SynthesisSynthesis of of ( (EE)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazoles-pyrazoles 89,, 90 and 91 [84].[84]. Scheme 28. Synthesis of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazoles 89, 90 and 91 [84]. Deshayes et et al. al. performed performed the reaction the reaction of enamine of enamine 92 with92 phenylwith hydrazine phenyl hydrazine in refluxing in Deshayes et al. performed the reaction of enamine 92 with phenyl hydrazine in refluxing ethanol,refluxing overnight, ethanol, overnight, to produce to produce4-ethoxycarbonyl-1-phenyl- 4-ethoxycarbonyl-1-phenyl-5-styrylpyrazole5-styrylpyrazole 93. In 93the. Insame the ethanol, overnight, to produce 4-ethoxycarbonyl-1-phenyl-5-styrylpyrazole 93. In the same conditions,same conditions, the reaction the reactionwith benzyl with hydrazine benzyl hydrazineafforded a 3:1 aff ordedmixture a of 3:1 two mixture pyrazole of isomers, two pyrazole the 1- conditions, the reaction with benzyl hydrazine afforded a 3:1 mixture of two pyrazole isomers, the 1- benzyl-4-ethoxycarbonyl-5-styrylpyrazoleisomers, the 1-benzyl-4-ethoxycarbonyl-5-styrylpyrazole 94 as the major94 asproduct the major together product with together 1-benzyl-4- with benzyl-4-ethoxycarbonyl-5-styrylpyrazole 94 as the major product together with 1-benzyl-4- ethoxycarbonyl-3-styrylpyrazole1-benzyl-4-ethoxycarbonyl-3-styrylpyrazole 95 (Scheme95 29)(Scheme [85]. 29)[85]. ethoxycarbonyl-3-styrylpyrazole 95 (Scheme 29) [85].

Scheme 29. Synthesis of 4-ethoxycarbonyl-5-/3-styrylpyrazoles 93, 94 and 95 [85]. SchemeScheme 29. SynthesisSynthesis of of 4-ethoxycarbonyl-5-/3-styrylpyrazoles 4-ethoxycarbonyl-5-/3-styrylpyrazoles 93,, 94 and 95 [85].[85]. 3.4.2. Reaction of α,β-Enones with Hydrazines 3.4.2. Reaction of α,β-Enones with Hydrazines The reaction of conjugated dienones (or α,β-enones) 96 with phenyl hydrazine hydrochloride in The reaction of conjugated dienones (or α,β-enones) 96 with phenyl hydrazine hydrochloride in a mixture of ethanol and chloroform, in the presence of a catalytic amount of concentrated HCl, a mixture of ethanol and chloroform, in the presence of a catalytic amount of concentrated HCl,

Molecules 2020, 25, 5886 20 of 32

3.4.2. Reaction of α,β-Enones with Hydrazines The reaction of conjugated dienones (or α,β-enones) 96 with phenyl hydrazine hydrochloride Moleculesin a mixture 2020, 25 of, xethanol FOR PEER and REVIEW chloroform, in the presence of a catalytic amount of concentrated20 HCl,of 34 afforded 1,3-diphenyl-5-styryl-4,5-dihydropyrazoles 97 (Ar = Ph) (Scheme 30, i) [34]. No expected afforded 1,3-diphenyl-5-styryl-4,5-dihydropyrazoles 97 (Ar = Ph) (Scheme 30, i) [34]. No expected dihydropyrazole was obtained in the reaction of 1,5-diphenylpenta-2,4-dien-1-one with phenyl dihydropyrazole was obtained in the reaction of 1,5-diphenylpenta-2,4-dien-1-one with phenyl hydrazine due to fast oxidation by atmospheric oxygen affording the corresponding pyrazole [34]. hydrazine due to fast oxidation by atmospheric oxygen affording the corresponding pyrazole [34]. Furthermore, 1-aryl-5-styrylpyrazoles 98 were synthetized by the one-pot reaction of conjugated Furthermore, 1-aryl-5-styrylpyrazoles 98 were synthetized by the one-pot reaction of conjugated dienones 96 with aryl hydrazine hydrochlorides in 1,2-dichlorobenzene at 130 ◦C, under O2 atmosphere dienones 96 with aryl hydrazine hydrochlorides in 1,2-dichlorobenzene at 130 °C, under O2 (Scheme 30, ii) [86,87]. Similar conditions for the reaction of Baylis–Hillman adduct 99 with phenyl atmosphere (Scheme 30, ii) [86,87]. Similar conditions for the reaction of Baylis–Hillman adduct 99 hydrazine afforded the styrylpyrazole 100 (Scheme 30)[87]. with phenyl hydrazine afforded the styrylpyrazole 100 (Scheme 30) [87].

Scheme 30. 30. ConversionConversion of ofα,βα-enones,β-enones 96 and96 andadduct adduct 99 into99 (intoE)-5-styrylpyrazolines (E)-5-styrylpyrazolines 97 and97 (Eand)-5- styrylpyrazoles(E)-5-styrylpyrazoles 98 and98 100and by100 reactionby reaction with phenyl/a with phenylryl hydrazine/aryl hydrazine hydrochlorides hydrochlorides [34,86,87]. [34,86 ,87].

3.4.3. Reaction Reaction of of 2-Styrylchromones 2-Styrylchromones with Hydrazines The reaction reaction of of 5-benzyloxy-2-styrylchromones 5-benzyloxy-2-styrylchromones 101101 withwith an an excess excess of ofhydrazine hydrazine hydrate hydrate in methanolin methanol at reflux at reflux yielded yielded (E)-3-(2-benzyloxy-6-hydroxyphenyl)-5-styryl-1 (E)-3-(2-benzyloxy-6-hydroxyphenyl)-5-styryl-1H-pyrazolesH-pyrazoles 102 (Scheme102 31).(Scheme Small 31 amounts). Small amountsof 3-(2-benzyloxy-6-hydroxyphenyl)-5-(2-phenylethyl)pyrazoles of 3-(2-benzyloxy-6-hydroxyphenyl)-5-(2-phenylethyl)pyrazoles 103a,d,e103a and,d 5-,e aryl-3-(2-benzyloxy-and 5-aryl-3-(2-benzyloxy-β,6-dihydroxystyryl)-2-pyrazolinesβ,6-dihydroxystyryl)-2-pyrazolines 104a–104ae were–e werealso formed, also formed, in addition in addition to the to pyrazolesthe pyrazoles 102a102a–e [88].–e [ Only88]. Only one isomer one isomer was obtained was obtained from fromthe reaction the reaction of 2-styrylchromones of 2-styrylchromones 101 with101 methylhydrazine.with methylhydrazine. Due to Due the to hydrogen the hydrogen bond bond between between 6′-OH 60 -OHand N and-2 inN -2each in each product, product, there there was wasthe formationthe formation of only of only one onetautomer, tautomer, the 3-(2-b the 3-(2-benzyloxy-6-hydroxyphenyl)-5-styrylpyrazolesenzyloxy-6-hydroxyphenyl)-5-styrylpyrazoles 102f–102fk and–k notand the not corresponding the corresponding 5-(2-benzyloxy-6-hydroxyphenyl)-3-styrylpyrazole 5-(2-benzyloxy-6-hydroxyphenyl)-3-styrylpyrazole [89]. [89].

MoleculesMolecules2020 2020, 25, ,25 5886, x FOR PEER REVIEW 21 21of 34 of 32 Molecules 2020, 25, x FOR PEER REVIEW 21 of 34

SchemeSchemeScheme 31. 31. Synthesis31. Synthesis Synthesis of of (ofE ()-3-(2-benzyloxy-6-hydroxyphenyl)-5-styryl-1 E(E)-3-(2-benzyloxy-6-hydroxyphenyl)-5-styryl-1)-3-(2-benzyloxy-6-hydroxyphenyl)-5-styryl-1HH-pyrazolesH-pyrazoles-pyrazoles 102 102 and102 and andsome some some derivativesderivativesderivatives of of pyrazoles of pyrazoles pyrazoles103 103 103and and and104 104 104isolated isolatedisolated as as by-productsby-products [88]. [88]. [88].

3.4.4.3.4.4.3.4.4. Wittig–Horner Wittig–Horner Wittig–Horner Reaction Reaction Reaction Deshayes et al. reported the reaction of phosponic esters, prepared from 1-substituted 5- DeshayesDeshayes et et al. al. reported the the reaction reaction of ofph phosponicosponic esters, esters, prepared prepared from from 1-substituted 1-substituted 5- bromomethylpyrazoles 105 and triethyl phosphite, with substituted benzaldehydes and furfural, in 5-bromomethylpyrazolesbromomethylpyrazoles 105105 andand triethyl triethyl phosphite, phosphite, with with substi substitutedtuted benzaldehydes benzaldehydes and furfural, and furfural, in dimethoxyethane, as a method to prepare (E)-4-ethoxycarbonyl-3-methyl-5-styryl-l-substituted indimethoxyethane, as as a methodmethod toto prepareprepare (E(E)-4-ethoxycarbonyl-3-methyl-5-styryl-l-substituted)-4-ethoxycarbonyl-3-methyl-5-styryl-l-substituted pyrazoles 106 (Scheme 32) [75,85]. pyrazolespyrazoles106 106(Scheme (Scheme 32 32))[75 [75,85].,85].

Scheme 32. Synthesis of (E)-4-ethoxycarbonyl-3-methyl-5-styry-l-substituted pyrazoles 106 [75,85]. SchemeScheme 32. 32.Synthesis Synthesis of of ( E(E)-4-ethoxycarbonyl-3-methyl-5-styry-l-substituted)-4-ethoxycarbonyl-3-methyl-5-styry-l-substituted pyrazoles pyrazoles 106106 [75,85].[75,85 ]. 3.5. Synthesis of Bis(Styryl)Pyrazoles 3.5.3.5. Synthesis Synthesis of of Bis(Styryl)Pyrazoles Bis(Styryl)Pyrazoles 3.5.1. Cyclocondensation Reaction

Cyclocondensation3.5.1. Cyclocondensation Reaction Reaction

Typically, 3,5-bis(styryl)pyrazole curcumin analogue 12a and N-aryl derivatives have been obtained by treatment of curcumin 11 with hydrazine hydrate or aryl hydrazines in ethanol [42] Molecules 2020, 25, 5886 22 of 32 or toluene [40] at reflux for a long reaction time of 24–40 h. Using glacial acetic acid at reflux, the reaction time can be reduced to 6–8 h [33,39,41]. Room temperature reactions have also been reported but required a longer reaction time [40]. In 2015, Sherin et al. reported a solvent-free, mechanochemical method for the synthesis of curcumin 11 derived 3,5-bis(styryl)pyrazoles 12a–f [36] (Scheme 33). The heterocyclization of 11 with hydrazine or hydrazine derivatives was performed with vigorous grinding, using an agate mortar and pestle, at room temperature, in the presence of a catalytic amount of acetic acid. A very short reaction time was necessary, in comparison with the previously referred methods that use conventional heating [39–42]. The reaction scope seems to be broad since phenyl hydrazine, p-methoxy, p-chloro, p-nitro, and p-carboxyphenyl hydrazines gave bis(styryl)pyrazoles 12b–f in good yields (79–84%). One year later, the same authors performed the mechanochemical synthesis of 1-phenyl-3,5-bis(styryl)pyrazoles 13a–f, varying the substituents present in the aromatic ring of both styryl groups [90]. Recently, Liao et al. described a rapid synthesis of similar 3,5-bis(styryl)pyrazole curcumin analogues 13 by using microwave irradiation conditions [44]. Molecules 2020, 25, x FOR PEER REVIEW 23 of 34

SchemeScheme 33. 33.Synthesis Synthesis of of 3,5-bis(styryl)pyrazoles 3,5-bis(styryl)pyrazoles 1212 andand 1313 [36,39–42,44,90].[36,39–42,44, 90].

4. Transformations of Styrylpyrazoles Styrylpyrazoles are interesting templates for synthetic manipulation towards new heterocycles. Nevertheless, to date, only a small number of transformations involving the 2-arylvinyl moiety of styrylpyrazoles have been reported in the literature. In this section, we describe the most common transformations of the 2-arylvinyl moiety of styrylpyrazoles.

4.1. Transformations of 4-Styrylpyrazoles

Diels–Alder Cycloadditions 4-Styrylpyrazoles (Z)-107 and (E)-108 can participate in Diels–Alder reactions, as dienophiles, involving the exocyclic (Cα = Cβ) double bond, or as dienes when this double bond is conjugated

Molecules 2020, 25, 5886 23 of 32

4. Transformations of Styrylpyrazoles Styrylpyrazoles are interesting templates for synthetic manipulation towards new heterocycles. Nevertheless, to date, only a small number of transformations involving the 2-arylvinyl moiety of styrylpyrazoles have been reported in the literature. In this section, we describe the most common transformations of the 2-arylvinyl moiety of styrylpyrazoles.

4.1. Transformations of 4-Styrylpyrazoles

Diels–Alder Cycloadditions 4-Styrylpyrazoles (Z)-107 and (E)-108 can participate in Diels–Alder reactions, as dienophiles, involving the exocyclic (Cα = Cβ) double bond, or as dienes when this double bond is conjugated withMolecules the C4 =2020C3(5), 25, x FOR double PEERbond REVIEW of the pyrazole moiety. Silva et al. obtained the tetrahydroindazoles24 of 34 109 and 110 in good yields and with high selectivities from the Diels–Alder reactions of (Z)- and with the C4 = C3(5) double bond of the pyrazole moiety. Silva et al. obtained the tetrahydroindazoles (E)-1-acetyl-4-styrylpyrazoles 107 and 108, which reacted as dienes, with both dienophiles, N-methyl- 109 and 110 in good yields and with high selectivities from the Diels–Alder reactions of (Z)- and (E)- or N-phenylmaleimide, using microwave irradiation (800 W) [91,92]. The expected indazoles 111 were 1-acetyl-4-styrylpyrazoles 107 and 108, which reacted as dienes, with both dienophiles, N-methyl- or obtainedN-phenylmaleimide, by dehydrogenation using microwave of the corresponding irradiation (800 adducts W) [91,92]. with The DDQ expected under microwaveindazoles 111 irradiation were or conventionalobtained by dehydrogenation heating conditions of the (Scheme correspondin 34)[g 91adducts]. They with have DDQ also under studied microwave the cycloadditionsirradiation 1 of (E)-1-acetyl-4-nitrostyrylpyrazoleor conventional heating conditions 108(Scheme(R =34)NO [91]2). They with haveN-phenylmaleimide also studied the cycloadditions and with dimethyl of acetylenedicarboxylate(E)-1-acetyl-4-nitrostyrylpyrazole (DMAD). In 108 the reaction(R1 = NO with2) withN-phenylmaleimide, N-phenylmaleimide theand cycloadduct with dimethyl112 was obtainedacetylenedicarboxylate in 49% yield together (DMAD). with theIn the indazole reaction113 with, obtained N-phenylmaleimide, as a by-product the cycloadduct (5% yield). 112 On thewas other hand,obtained in the reaction in 49% yield with together DMAD, with a conjugate the indazole addition 113, obtained of the pyrazole as a by-product nitrogen (5% to yield). DMAD On occurred the withother formation hand, ofin athe trace reaction amount with of DMAD, pyrazole a conjugat114 (Schemee addition 35)[ 91of ].the pyrazole nitrogen to DMAD occurred with formation of a trace amount of pyrazole 114 (Scheme 35) [91].

SchemeScheme 34. 34.Transformation Transformation of of 4-styrylpyrazoles 4-styrylpyrazoles 107107 andand 108108 intointo indazoles indazoles 111 111[91,92].[91 ,92].

Molecules 2020, 25, 5886 24 of 32

Molecules 2020, 25, x FOR PEER REVIEW 25 of 34

SchemeScheme 35. Transformation 35. Transformation of (E of)-4-styrylpyrazole (E)-4-styrylpyrazole108 108into into cycloadducts cycloadducts 112112, ,113113 andand pyrazole pyrazole 114114 [92]. [92]. 4.2. Transformations of 3(5)-Styrylpyrazoles 4.2. Transformations of 3(5)-Styrylpyrazoles 4.2.1. Diels–Alder Cycloadditions 4.2.1. Diels–Alder Cycloadditions StartingStarting from from 3- and 3- and 5-styrylpyrazoles 5-styrylpyrazoles115 115 andand 116116, ,Silva Silva et etal. al.developed developed a synthetic a synthetic route to route to prepareprepare naphthylpyrazoles naphthylpyrazoles [84 ].[84]. These These styrylpyrazoles, styrylpyrazoles, which which can canbehave behave as dienophiles, as dienophiles, undergo undergoa a Diels–AlderDiels–Alder cycloaddition cycloaddition with with o-benzoquinodimethane-benzoquinodimethane (117), ( 117the ),diene, the which diene, was which formed was in situ formed in situ byby the the thermal thermal extrusionextrusion of of sulfur sulfur dioxide dioxide from from 1,3-dihydrobenzo[ 1,3-dihydrobenzo[c]thiophenec]thiophene 2,2-dioxide. 2,2-dioxide. N- Substituted 3-styrylpyrazoles 115 reacted with diene 117 at 250 °C in 1,2,4-trichlorobenzene giving N-Substituted 3-styrylpyrazoles 115 reacted with diene 117 at 250 ◦C in 1,2,4-trichlorobenzene giving the corresponding 3-[2-(3-aryl-1,2,3,4-tetrahydronaphthyl)]-5-(2-hydroxyphenyl)-1-phenylpyrazoles the corresponding 3-[2-(3-aryl-1,2,3,4-tetrahydronaphthyl)]-5-(2-hydroxyphenyl)-1-phenylpyrazoles (118) in good yields (69–91%) (Scheme 36, i). The presence of an electron-withdrawing substituent on (118) inthe good p-position yields of (69–91%) the phenyl (Scheme ring increases 36, i). the The reactivi presencety of the of styryl an electron-withdrawing double bond [84]. These substituentauthors on the p-positionalso performed of the phenyl the Diels–Alder ring increases reaction the of reactivity (E)-3(5)-(2-hydroxyphenyl) of the styryl double-5(3)-styrylpyrazoles bond [84]. These (116) authors also performedwith diene the (117 Diels–Alder), but in this case reaction longer of reaction (E)-3(5)-(2-hydroxyphenyl)-5(3)-styrylpyrazoles times were necessary and the expected cycloadducts (116 ) with diene (117were), butobtained in this in lower case longeryields (24–48%). reaction The times efficiency were of necessary this Diels–Alder and the reaction expected increased cycloadducts by using were obtaineda LA, in loweraluminum(III) yields (24–48%).chloride, which The increased efficiency the ofreactivity this Diels–Alder of the styryl reactiondouble bond, increased probably by using through the formation of an aluminum(III) complex involving the oxygen of the 2′-hydroxy group a LA, aluminum(III)and the free nitrogen chloride, of the pyrazole which increasedmoiety. Under the these reactivity conditions, of thethe cycloadduct styryl double 119 containing bond, probably throughan the electron-donating formation of an substituent aluminum(III) at the p- complexposition of involving styryl moiety the oxygenwas obtained of the in 2better0-hydroxy yield. groupOn and the freethe nitrogen contrary, of the the cycloadduct pyrazole moiety.119 containing Under the these p-nitro conditions, group as substituent the cycloadduct was obtained119 incontaining better an electron-donatingyield without substituent addition of at thealuminum(III)p-position chlo of styrylride (Scheme moiety 36, was iii) obtained [84]. The in betterformation yield. of On the contrary,naphthylpyrazoles the cycloadduct 120119 andcontaining 121 occurred the byp-nitro dehydrogenation group as substituent of the corresponding was obtained cycloadducts in better yield with DDQ (2–6 days). The naphthylpyrazole 120 bearing an electron-donating substituent (R1 = OMe) without addition of aluminum(III) chloride (Scheme 36, iii) [84]. The formation of naphthylpyrazoles at the p-position of the phenyl group linked to the hydroaromatic ring was obtained in a shorter time 120 and 121 occurred by dehydrogenation of the corresponding cycloadducts with DDQ (2–6 days). (2 days) and with better yield (59%) than the other derivatives (R1 = H (25%) and R1 = NO2 (17%)). The 1 The naphthylpyrazolepresence of the p-methoxy120 bearing substituent an electron-donating stabilizes the carboc substituentation formed (R through= OMe) a hydride at the transferp-position of the phenylfrom group compound linked 118 to DDQ. the hydroaromatic To increase the yield ring of was this oxidation, obtained p-toluenesulfonic in a shorter time acid (2 was days) added and with and the products were obtained in a shorter 1time (2–7 h) and with1 better yields, especially for the better yield (59%) than the other derivatives (R = H (25%) and R = NO2 (17%)). The presence of the 1 p-methoxyderivative substituent containing stabilizes the nitro the group carbocation (R = NO2, formed36%) (Scheme through 36, ii). a hydrideThe oxidation transfer of cycloadducts from compound 118 to DDQ. To increase the yield of this oxidation, p-toluenesulfonic acid was added and the products were obtained in a shorter time (2–7 h) and with better yields, especially for the derivative containing 1 the nitro group (R = NO2, 36%) (Scheme 36, ii). The oxidation of cycloadducts 119 was also tried, using both methods (Scheme 36, ii) but only decomposition products were obtained, save the case of 3-(2-hydroxyphenyl)-5-{2-[3-(4-methoxyphenyl)]naphthyl}pyrazole 121 (R1 = OMe), which was obtained in low yield (13%, method B) [84]. Molecules 2020, 25, x FOR PEER REVIEW 26 of 34

119 was also tried, using both methods (Scheme 36, ii) but only decomposition products were Moleculesobtained,Molecules2020, save202025, 5886, 25 the, x FORcase PEER of 3-(2-hydroxyphenyl REVIEW )-5-{2-[3-(4-methoxyphenyl)]naphthyl}pyrazole26 121 of 3425 (R of1 32 = OMe), which was obtained in low yield (13%, method B) [84]. 119 was also tried, using both methods (Scheme 36, ii) but only decomposition products were obtained, save the case of 3-(2-hydroxyphenyl)-5-{2-[3-(4-methoxyphenyl)]naphthyl}pyrazole 121 (R1 = OMe), which was obtained in low yield (13%, method B) [84].

SchemeScheme 36. 36.Transformation Transformation of of styrylpyrazoles styrylpyrazoles 115115 and 116116 intointo tetrahydronaphthylpyrazoles tetrahydronaphthylpyrazoles 118 118 andand 119 and their oxidation to naphthylpyrazoles 120 and 121 [84]. 119 andScheme their 36. oxidation Transformation to naphthylpyrazoles of styrylpyrazoles120 115and and121 116 [into84]. tetrahydronaphthylpyrazoles 118 and 119 and their oxidation to naphthylpyrazoles 120 and 121 [84]. 4.2.2.4.2.2. Electrophilic Electrophilic Intramolecular Intramolecular Cyclization Cyclization C.4.2.2.C. Deshayes ElectrophilicDeshayes etet Intramolecularal. reported reported theCyclization electrophilic the electrophilic intramolecular intramolecular cyclization cyclization of 1-benzyl- of 1-benzyl-and 1- andphenyl-5-styrylpyrazoles 1-phenyl-5-styrylpyrazolesC. Deshayes et al. reported122, in122 thethe, in presenceelectrophilic the presence of polyphosphorintramolecular of polyphosphoric iccyclization acid (PPA), acidof 1-benzyl-which (PPA), led and which to 1- the led toformation thephenyl-5-styrylpyrazoles formation of 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo-type of 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo-type 122, in the presence of polyphosphor compoundsic acid (PPA), compounds 123 andwhich 124 led (Scheme123 to andthe 37) 124 (Scheme[85].formation Both 37)[ 85the of]. 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo-type Both5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo[1,5- the 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo[1,5- compoundsa]quinolines 123 and a(]quinolines123 124) (Schemeand 5-aryl-3- (123 37)) and 5-aryl-3-ethoxycarbonyl-4,5-dihydro-10ethoxycarbonyl-4,5-dihydro-10[85]. Both the 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo[1,5-H-pyrazolo[1,5-H-pyrazolo[1,5-b][2]benzazepinesb][2]benzazepines a]quinolines(124) were (124 (123obtained) were) and obtained 5-aryl-3-with very with ][2] verygood goodethoxycarbonyl-4,5-dihydro-10 yields, yields, save save for for124 124(R1 =(R R12H =-pyrazolo[1,5- H).R2 = H). b benzazepines (124) were obtained with very good yields, save for 124 (R1 = R2 = H).

SchemeSchemeScheme 37.37. 37. Transformation TransformationTransformation ofof 1-benzyl-1-benzyl- of 1-benzyl- and 1-phenyl-5-styrylpyrazoles and 1-phenyl-5-styrylpyrazoles 122122 into into 5-aryl-3- 5-aryl-3-122 into 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo-typeethoxycarbonyl-4,5-dihydrethoxycarbonyl-4,5-dihydropyrazolo-typeopyrazolo-type compoundscompounds compounds 123123 andand 124 124123 [85]. [85].and 124 [85].

In 2015, Moon et al. reported the acid-catalyzed intramolecular Friedel–Crafts (IMFC) reaction of several 1-aryl-5-styrylpyrazoles 125 in the presence of PPA to produce dihydropyrazolo[1,5-a]quinolines 126 (Scheme 38, i) [87]. It is worth mentioning that the corresponding five-membered ring product Molecules 2020, 25, x FOR PEER REVIEW 27 of 34

Molecules 2020, 25, 5886 26 of 32 In 2015, Moon et al. reported the acid-catalyzed intramolecular Friedel–Crafts (IMFC) reaction of several 1-aryl-5-styrylpyrazoles 125 in the presence of PPA to produce dihydropyrazolo[1,5- a]quinolines 126 (Scheme 38, i) [87]. It is worth mentioning that the corresponding five-membered was notring obtained. product Thiswas not fact obtained. can be explainedThis fact can by be the explained higher stabilityby the higher of benzylic stability carbocationof benzylic when comparedcarbocation to secondary when compared carbocation to secondary formed duringcarbocat theion reaction.formed during Moreover, the reaction. the obtained Moreover, yields the show that theobtained efficiency yields of theshow reaction that the is efficiency not significantly of the reaction affected is not by significantly the nature affected of the by substituents the nature of at the 1-, 3-, 4- andthe 5-positions substituents ofat pyrazolesthe 1-, 3-, 4-125 and. 5-positions The IMFC of reaction pyrazoles of 125 1-benzyl-5-styrylpyrazole. The IMFC reaction of 1-benzyl-5-125 (R1 = Bn) affordedstyrylpyrazole a 2,9-diphenyl-3,3a-diazabenzo[ 125 (R1 = Bn) afforded fa]azulene 2,9-diphenyl-3,3a-diazabenzo[ derivative [87]. Thef]azulene base-catalyzed derivative aerobic [87]. The oxidation base-catalyzed aerobic oxidation of dihydropyrazolo[1,5-a]quinolines 126 afforded the of dihydropyrazolo[1,5-a]quinolines 126 afforded the corresponding pyrazolo[1,5-a]quinolines 127 corresponding pyrazolo[1,5-a]quinolines 127 (Scheme 38, ii). However, the reaction only occurred 5 6 (Schemewhen 38, ii).R5 = However, Ph and R6 = the H [87]. reaction only occurred when R = Ph and R = H[87].

SchemeScheme 38. Transformation 38. Transformation of 1-aryl-5-styrylpyrazoles of 1-aryl-5-styrylpyrazoles 125125 intointo dihydropyrazolo[1,5- dihydropyrazolo[1,5-a]quinolinesa]quinolines 126 126 and theirand oxidation their oxidation to pyrazolo[1,5- to pyrazolo[1,5-a]quinolinesa]quinolines127 127 [87].[87].

4.2.3. Oxidative4.2.3. Oxidative Addition Addition Reactions Reactions In 2004, Ignatenko et al. converted several (E)-3- and 5-styrylpyrazoles 128 and 129 into In 2004, Ignatenko et al. converted several (E)-3- and 5-styrylpyrazoles 128 and 129 into phthalimidoaziridinylpyrazoles 131 and 132 by the oxidative addition of N-aminophthalimide phthalimidoaziridinylpyrazoles(NAPhth) (130) to the exocyclic131 and double132 bondby the in oxidative the presence addition of lead of tetraacetateN-aminophthalimide and potassium (NAPhth) (130) tocarbonate the exocyclic in dichloromethane double bond (Scheme in the 39). presence The reaction of lead with tetraacetate1,5-diphenylpyrazoles and potassium 128 afforded carbonate the in dichloromethanecorresponding (Scheme phthalimidoaziridinylpyrazoles 39). The reaction with 1,5-diphenylpyrazoles 131 with better yield128 athanfforded with the the corresponding 1,3- phthalimidoaziridinylpyrazolesdiphenylpyrazoles 129. Analogous131 with4,5-dihydropyr better yieldazoles thanwere withinert in the the 1,3-diphenylpyrazoles oxidative addition of 129. AnalogousNAPhth 4,5-dihydropyrazoles [57]. were inert in the oxidative addition of NAPhth [57]. Molecules 2020, 25, x FOR PEER REVIEW 28 of 34

Phth O N 1 1 R R2 R + N NH i R2 N N 2 N N Ph Ph 128 O 131 130 3examples (74-77%) O Phth Ph Ph N ii Ph N N + N NH2 24% Ph Ph N N 129 O Ph 130 132

O

1 2 R =R = Ph, 4-ClC6H4,4-MeOC6H4;Phth= N

O

(i) 130 (1.0 equiv), K2CO3 (5.0 equiv.), Pd(OAc)4 (1.0 equiv), CH2Cl2,-12ºC,30min. (ii) 130 (2.0 equiv), K2CO3 (10 equiv.), Pd(OAc)4 (2.0 equiv), CH2Cl2,-12ºC,30min. SchemeScheme 39. Transformation 39. Transformation of (E)-3- and of 5-styrylpyrazoles (E)-3- and 1285-styrylpyrazolesand 129 into phthalimidoaziridinylpyrazoles128 and 129 into 131 and phthalimidoaziridinylpyrazoles132 [57]. 131 and 132 [57]. 5. Conclusions Styrylpyrazoles have shown remarkable biological activities, namely as anti-inflammatory, antimicrobial (antibacterial and antifungal) and antioxidant agents. Among these compounds, the 3,5-bis(styryl)pyrazoles, curcumin analogues, should be highlighted herein due to their significant antioxidant, neuroprotective, antimalarial, antimycobacterial, antiangiogenic, cytotoxic and antiproliferative activities. Additionally, styrylpyrazoles present interesting photophysical properties suitable for metal ion sensing, for the design of energy-transfer-based fluorescent probes and are also good DNA groove binders. Although structure–activity relationship studies have been reported for some styrylpyrazole derivatives, there is a gap in the literature regarding a detailed investigation of the specific properties due to the presence of the styryl group, or the different properties that may appear by exchanging the styryl group position. As far as we know, there are no comparative data between styrylpyrazoles and analogous non-styrylpyrazoles, which are very important in order to understand the role of the styryl moiety in the pyrazoles’ properties. The synthesis of 1-styrylpyrazoles has been achieved starting from pyrazoles through N-cross- coupling reactions with styrylboronic acid or alternatively by the addition of N–H to activated and non-activated alkynes. In turn, the cyclocondensation reaction of different substrates, with hydrazine derivatives, is the most common strategy for the synthesis of 3-, 4-, and 5- styrylpyrazoles. Regarding the substrates, penta-1,4-dien-3-ones, α-oxoketene dithioacetals, benzalacetones, acetylenic ketones, 1,3-diketones and diketoesters are good substrates for the synthesis of 3- and 5- styrylpyrazoles while α-alkenyl-α,β-enones and diketones (curcumin analogues) are good synthons for the synthesis of 4- styrylpyrazoles and bis(styryl)pyrazoles, respectively. Moreover, reactions of 2- and 3- styrylchromones with hydrazine derivatives are often used to prepare 3(5)-styrylpyrazoles and 4- styrylpyrazoles, respectively. More recently, the cross-coupling reactions of halopyrazoles with styrylboronic acids gained relevance as a method to access 4-styrylpyrazoles in a straightforward way. Only a few examples of transformations of styrylpyrazoles involving the 2-arylvinyl moiety have been reported in the literature. These include Diels–Alder reactions, intramolecular cyclisation reactions and oxidative additions to the exocyclic double bond, and they allow the formation of more complex and very interesting heterocycles such as indazoles, naphthylpyrazoles, 4,5- dihydropyrazolo[1,5-a]quinolines, 4,5-dihydro-10H-pyrazolo[1,5-b][2]benzazepines, pyrazolo[1,5-

Molecules 2020, 25, 5886 27 of 32

5. Conclusions Styrylpyrazoles have shown remarkable biological activities, namely as anti-inflammatory, antimicrobial (antibacterial and antifungal) and antioxidant agents. Among these compounds, the 3,5-bis(styryl)pyrazoles, curcumin analogues, should be highlighted herein due to their significant antioxidant, neuroprotective, antimalarial, antimycobacterial, antiangiogenic, cytotoxic and antiproliferative activities. Additionally, styrylpyrazoles present interesting photophysical properties suitable for metal ion sensing, for the design of energy-transfer-based fluorescent probes and are also good DNA groove binders. Although structure–activity relationship studies have been reported for some styrylpyrazole derivatives, there is a gap in the literature regarding a detailed investigation of the specific properties due to the presence of the styryl group, or the different properties that may appear by exchanging the styryl group position. As far as we know, there are no comparative data between styrylpyrazoles and analogous non-styrylpyrazoles, which are very important in order to understand the role of the styryl moiety in the pyrazoles’ properties. The synthesis of 1-styrylpyrazoles has been achieved starting from pyrazoles through N-cross-coupling reactions with styrylboronic acid or alternatively by the addition of N–H to activated and non-activated alkynes. In turn, the cyclocondensation reaction of different substrates, with hydrazine derivatives, is the most common strategy for the synthesis of 3-, 4-, and 5- styrylpyrazoles. Regarding the substrates, penta-1,4-dien-3-ones, α-oxoketene dithioacetals, benzalacetones, acetylenic ketones, 1,3-diketones and diketoesters are good substrates for the synthesis of 3- and 5- styrylpyrazoles while α-alkenyl-α,β-enones and diketones (curcumin analogues) are good synthons for the synthesis of 4-styrylpyrazoles and bis(styryl)pyrazoles, respectively. Moreover, reactions of 2- and 3-styrylchromones with hydrazine derivatives are often used to prepare 3(5)-styrylpyrazoles and 4-styrylpyrazoles, respectively. More recently, the cross-coupling reactions of halopyrazoles with styrylboronic acids gained relevance as a method to access 4-styrylpyrazoles in a straightforward way. Only a few examples of transformations of styrylpyrazoles involving the 2-arylvinyl moiety have been reported in the literature. These include Diels–Alder reactions, intramolecular cyclisation reactions and oxidative additions to the exocyclic double bond, and they allow the formation of more complex and very interesting heterocycles such as indazoles, naphthylpyrazoles, 4,5-dihydropyrazolo[1,5-a] quinolines, 4,5-dihydro-10H-pyrazolo[1,5-b][2]benzazepines, pyrazolo[1,5-a]quinolines, 2,9-diphenyl-3,3a-diazabenzo [f ]azulene and phthalimidoaziridinylpyrazoles. Therefore, further studies towards the investigation of novel transformations of styrylpyrazoles are of high interest.

Author Contributions: Conceptualization, A.M.S.S. and V.L.M.S.; writing—original draft preparation, P.M.O.G. and P.M.S.O.; writing—review and editing, A.M.S.S. and V.L.M.S.; supervision, A.M.S.S. and V.L.M.S. All authors have read and agreed to the published version of the manuscript. Funding: The authors would like to thank the University of Aveiro and FCT/MEC for the financial support to the LAQV-REQUIMTE (UIDB/50006/2020) research project, financed by national funds and, when appropriate, co-financed by FEDER under the PT2020 Partnership Agreement of the Portuguese NMR network. Vera L. M. Silva thanks the assistant professor position (within CEE-CINST/2018; since 01/09/2019) and the integrated programme of SR&TD “pAGE—Protein Aggregation Across the Lifespan” (reference CENTRO-01-0145FEDER-000003), co-funded by the Centro 2020 program, Portugal 2020 and European Union through the European Regional Development Fund. Conflicts of Interest: The authors declare no conflict of interest.

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