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