Next Article in Journal
Can Natural Polyphenols Help in Reducing Cytokine Storm in COVID-19 Patients?
Next Article in Special Issue
Homocoupling Reactions of Azoles and Their Applications in Coordination Chemistry
Previous Article in Journal
Risk of Mercury Ingestion from Canned Fish in Poland
Previous Article in Special Issue
Fe(III) Complexes Based on Mono- and Bis-pyrazolyl-s-triazine Ligands: Synthesis, Molecular Structure, Hirshfeld, and Antimicrobial Evaluations
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Styrylpyrazoles: Properties, Synthesis and Transformations

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
*
Authors to whom correspondence should be addressed.
Submission received: 21 November 2020 / Revised: 6 December 2020 / Accepted: 9 December 2020 / Published: 12 December 2020

Abstract

:
The pyrazole nucleus and its reduced forms, pyrazolines and pyrazolidine, are privileged scaffolds in medicinal chemistry due to their remarkable biological activities. A huge number of pyrazole derivatives have been studied and reported over time. This review article gives an overview of pyrazole derivatives that contain a styryl (2-arylvinyl) group linked in different positions of the pyrazole backbone. Although there are studies on the synthesis of styrylpyrazoles dating back to the 1970s and even earlier, this type of compound has rarely been studied. This timely review intends to summarize the properties, biological activity, methods of synthesis and transformation of styrylpyrazoles; thus, highlighting the interest and huge potential for application of this kind of compound.

Graphical Abstract

1. Introduction

The pyrazole (1H-pyrazole, 1) (Figure 1) is an aromatic five-membered heterocyclic ring constituted by three carbons and two adjacent nitrogen atoms, located at 1- and 2-positions [1]. N-unsubstituted pyrazoles may present three identical and non-separable tautomers, due to rapid interconversion in solution, and it is usually impossible to unequivocally assign the resonances of its proton-nuclear magnetic resonance (1H-NMR) spectrum. Three partially reduced forms may also exist: 1-pyrazolines 2, 2-pyrazolines 3 and 3-pyrazolines 4, and a fully reduced form known as pyrazolidine 5 (Figure 1) [1,2].
Pyrazole and its derivatives occupy a prime place in medicinal chemistry because they are present in several drugs with real medicinal applications, such as celecoxib (Celebrex®), sildenafil (Viagra®), rimonabant, lonazolac, fomepizole, penthiopyrad, doramapimod, sulfaphenazole and in several remarkable compounds with a wide range of pharmacological activities, namely anticancer [3], analgesic, anti-inflammatory and antioxidant [4,5,6,7], antibacterial and antifungal [8,9] antipyretic, antidepressant and anticonvulsant [10,11], antidiabetic [12] and cannabinoid activities [13,14], among others [15,16,17,18,19,20,21]. Along with the medicinal applications, pyrazoles are also useful as agrochemicals, such as herbicides, fungicides, and insecticides [22] and possess other applications, such as dyestuffs, sunscreen materials [23,24], analytical reagents and pluripotent ligands in coordination chemistry [25,26]. For instance, polyaromatic pyrazoles possess important biological, photophysical, optical and electronic properties [10,27,28,29].
This review is focused on a particular type of pyrazoles, the styrylpyrazoles (or styryl-1H-pyrazoles), which present a styryl (2-arylvinyl) group at one or more positions of the pyrazole nucleus. It is intended to give an overview of the styrylpyrazoles chemistry reported in the literature, including their properties and biological activity, since the 1970s to the present date. Despite the biological activities of styrylpyrazoles [12,14], their interesting physicochemical properties, such as tautomerism, isomerism [30,31] and conjugation extension, due to the presence of the 2-arylvinyl group, as well as the rich chemistry related to their synthesis and transformation, this type of pyrazole has rarely been studied, as can be seen from the low number of publications in a very large time span covered by this review. In our group, we have been working with styrylpyrazoles for a long time. Throughout this review, we intend to describe the properties and methods of synthesis of these compounds, and to show their great potential for application in different fields, from medicine to materials chemistry, including their use as key templates for transformation into other valuable compounds. The articles will be presented based on the molecules’ structure, in particular, the position of the styryl group in the pyrazole scaffold.

2. Properties of Styrylpyrazoles

The pharmacological activity of styrylpyrazoles and related compounds has been known for a long time. A study published in 1970 described the anti-inflammatory activity of 1-phenyl-2-styryl-3,5-dioxopirazolidines (6). Among these compounds, derivatives 6a (R1 = Me, R2 = R3 = H, R4 = n-C4H9) and 6b (R1 = Cl, R2 = 4-OMe, R3 = H, R4 = n-C4H9) (Figure 2) were more active than phenylbutazone or oxyphenbutazone in the carrageenin-induced foot edema test in rats [32]. It was found that a p-methylphenyl ring increased the intrinsic activity in general, while a p-chlorophenyl substituent decreases the activity, except for compound 6b. The p-methoxy or 3,4-methylenedioxy substituents of the styryl group tend to increase both toxicity and inhibitory activity, while p-alkyl substituents (Me or i-Pr) have the opposite effect.
Styrylpyrazoles were also found to act as dual inhibitors of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) in rat basophilic leukemia cells. In particular, compound 7 (Figure 2) exhibited oral activity in various models of inflammation and, most importantly, is devoid of ulcerogenic potential [33].
Nauduri et al. studied the antibacterial activity of 1,5-diphenyl-3-styryl-2-pyrazolines 8, with different substituents (OMe, NMe2, NO2, OH and isopropyl) (Figure 3), towards Gram-positive and Gram-negative bacteria and found little variation in the geometric means of minimum inhibitory concentrations (MIC) [34]. The derivatives containing NMe2, NO2 and OMe in the p-position of A and B aromatic rings showed the highest activity (MIC = 3.55–6.56 μg/mL and 3.30–6.27 μg/mL against Gram-positive and Gram-negative bacteria, respectively). This fact was attributed to the strong electronic-driving nature of the substituents (either as electron-donating or electron-withdrawing substituents) and due to a more lipophilic nature (for the NMe2). Low substitution in the aromatic ring also favored the entry of the compound in the bacteria through passive diffusion. They have compared the activity of these compounds with that of 1,3-diphenyl-5-styryl-2-pyrazolines, which showed lower activities than the compounds of the 3-styryl series. Moreover, the 1,5-diphenyl-3-styryl-2-pyrazolines 8 bearing o- or p-hydroxyphenyl rings showed superior antimycotic (antifungal) activity relative to the other derivatives (MIC = 11.3–24.8 μg/mL and 12.16–13.6 μg/mL against fungi and yeast, respectively). The extended electronic structure of the 3-styryl compared with the 5-styryl derivatives may explain the lower MIC values for the compounds of the 3-styryl series [34].
In the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and horseradish peroxidase (HRP)/luminol/H2O2 chemiluminescence assays, 5-aryl-3-styryl-1-carboxamidino-1H-pyrazole derivative 9 showed higher antioxidant activity (half maximal inhibitory concentration (IC50) 45.17–217.22 μg/mL, in DPPH assay) than 2-(5-aryl-3-styryl-1H-pyrazol-1-yl)-4-trifluoromethylpyrimidines 10 (Figure 4). The antioxidant activity is dependent on the concentration and type of substituents in each compound, and resonance stabilization. For instance, the presence of SH at Y position strongly enhances antioxidant activity. Some derivatives of compound 9 showed antimicrobial activity against bacteria Salmonella typhi, Staphylococcus aureus and Streptococcus pneumoniae, with inhibition between 1.95 to 15.625 mg/mL. The antimicrobial activity is also affected by the substituent [35].
Furthermore, 3,5-bis(styryl)pyrazoles 12, curcumin (11) analogues (Figure 5), are well-known for their antioxidant activity. Some derivatives showed superior activity to that of curcumin in DPPH, ferric reducing antioxidant power (FRAP), and β-carotene bleaching assays [36]. For instance, curcumin (11) showed lower inhibition of DPPH (102 mmol), (half maximal effective concentration (EC50) = 40 ± 0.06 μmol)) compared with 3,5-bis(4-hydroxy-3-methoxystyryl)pyrazole (12a) (EC50 = 14 ± 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 has shown interesting results in studies related to neuroprotection and Alzheimer’s disease, and was able to restore membrane homeostasis disrupted after brain trauma, being a promising compound for therapeutic use in the treatment of Parkinson’s disease [37]. In combination with tissue plasminogen activator, CNB-001 is efficient in the treatment of stroke [38]. Compound 12a also acted as inhibitor of β-amyloid secretion and of protein kinases involved in neuronal excitotoxicity [39]. Some pyrazoles that are analogues of 12a displayed good inhibition of γ-secretase activity, tau aggregation, and/or affinity to fibrillar Aβ42 aggregates [40].
Other properties have been attributed to 3,5-bis(styryl)pyrazoles such as antimalarial, antimycobacterial, antiangiogenic, cytotoxic and antiproliferative activities [39,41,42]. As an example, 3,5-bis(styryl)pyrazoles 12a,b showed more effective inhibition of chloroquine-sensitive Plasmodium falciparum (IC50 = 0.48 ± 0.04 μM and 0.87 ± 0.07 μM) and chloroquine-resistant Plasmodium falciparum (IC50 = 0.45 ± 0.07 μM and 0.89 ± 0.10 μM), respectively, than curcumin (IC50 = 3.25 ± 0.6 μM and 4.21 ± 0.8 μM) [41].
Several studies have highlighted the antiproliferative activity of 12a in PC3 cells, with growth inhibitory concentration (GI50) values of 5.6 μM [43] and in breast cancer cell lines, MCF-7 and SKBR3, with GI50 values of 4.19 μM and 0.25 μM, respectively [42]. Liao and coworkers have also shown the antiproliferative activity of 3,5-bis(styryl)pyrazoles 12a and 13 in the androgen-independent PC3 prostate cancer cell line with GI50 values in the low micromolar range. In particular, compound 13 caused significant effects on the PC3 cell cycle, inducing cell death and binding to tubulin (Kd 0.4 ± 0.1 μM), inhibiting tubulin polymerization in vitro, being competitive with paclitaxel for binding to tubulin, and leading to microtubule depolymerization in PC3 cells. Therefore, 13 was considered as a lead compound for the treatment of castration-resistant prostate cancer (CRPC) [44].
In addition to pharmacological activities, 4-styrylpyrazoles have shown interesting photophysical properties. In particular, 1-(2-pyridyl)-4-styrylpyrazoles (PSPs) substituted at position 3 with donor or acceptor aryl groups have shown strong blue-light emissions with high quantum yields (up to 66%), due to intramolecular charge transfer (ICT) phenomena [45]. The 3-phenyl-1-(2-pyridyl)-4-styrylpyrazole 14 (Figure 6) was studied as a turn-off fluorescent probe in metal ion sensing, showing a high selectivity to Hg2+ (Limit of detection (LOD) = 3.1 × 10−7 M) in a process that could be reversed with ethylenediamine.
Although pyrazoles are rare in nature, due to the difficulty of living organisms to construct the N–N bond [46,47], a styrylpyrazole natural derivative, (E)-1,5-diphenyl-3-styryl-2-pyrazoline (DSDP) 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 binding mode with no conformational change. These findings were also supported by molecular docking simulation.
Later, the same authors reported the strong binding interactions of DSDP with two serum transport proteins, human serum albumin (HSA) and bovine serum albumin (BSA) [50]. Exploiting multi-spectroscopic techniques together with in silico molecular docking simulation, they have demonstrated that DSDP is a potent fluorophore. It binds with both proteins with the formation of a 1:2 protein–probe complex at a lower protein concentration range and a 1:1 complex at a higher protein concentration range. The calculated binding constants for the 2:1 DSDP-protein complexes were found to be 1.37 × 1010 M−2 and 1.47 × 1010 M−2 for HSA and BSA, respectively, while for the 1:1 complexation process, the constants were 1.85 × 105 M−1 and 1.73 × 105 M−1 for DSDP-HSA and DSDP-BSA systems, respectively. Moreover, they have demonstrated that hydrogen bonding and hydrophobic interactions are the forces primarily responsible for both types of binding. The information gathered from these studies may be useful for the rational design of drugs looking at a greater clinical efficacy.
1,3,5-Trisubstituted pyrazolines, analogues of DSDP, exhibited large fluorescence quantum yields (Φf = 0.6–0.8), suited for the design of energy-transfer-based fluorescent probes [51]. In DSDP’s structure, two of the aryl rings (phenyl and styryl) are interconnected electronically through the pyrazoline π-system while the 5-phenyl ring is electronically decoupled and can behave as an electron donating receptor for cations or electron deficient centers. The lone pair of electrons on the N1 atom of the pyrazoline ring also takes part in the conjugation, facilitating the ICT process. Thus, DSDP acts as a D-π-A system and the introduction of an electron withdrawing group (such as -CN, -NO2, -COOEt) on the styryl moiety can enhance the push–pull D-π-A capacity of DSDP-like molecular systems [52]. However, a drastic modification of the photophysical properties of DSDP is observed upon dehydrogenation of the pyrazoline ring with subsequent formation of the corresponding pyrazole (DSP) 16 (Figure 6). While DSDP gives dual absorption and dual emission bands corresponding to the locally excited (LE) and ICT species, DSP yields single absorption and emission bands for the LE species only. Comparative steady state and time resolved fluorometric studies have revealed that aromatization of the pyrazoline ring completely inhibits the ICT process. These results were also corroborated by quantum chemical calculations [52].

3. Synthesis of Styrylpyrazoles

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 scaffold, starting from C-1 to C-5. Bis(styryl)pyrazoles, substituted at C-3 and C-5, are also considered. Moreover, in each subheading, the methods will be presented by alphabetic order. Single examples of a certain reaction will be considered at the end of each section in the miscellaneous subheading.

3.1. Synthesis of 1-Styrylpyrazoles

3.1.1. N-Cross-Coupling Reaction of Pyrazoles with Styrylboronic Acid

In 2010, Kantam et al. synthesized (E)-1-styrylpyrazoles in a simple and efficient way, by the cross-coupling reaction of pyrazoles 17 with styrylboronic acid 18 using a recyclable heterogeneous Cu-exchanged fluorapatite (CuFAP) catalyst, under base-free conditions (Scheme 1) [53]. The lower yield (70%) for the coupling with 3,5-dimethyl-1H-pyrazole 17 (R1 = R2 = Me) was attributed to the steric hindrance caused by the methyl groups. When the reaction was performed in the absence of air, no coupled product was obtained, since O2 is involved in the oxidation of Cu(I) to Cu(II), which is the active species in the reaction mechanism [53].

3.1.2. N-Styrylation of Pyrazoles with Activated and Non-Activated Alkynes

In 1978, Burgeois et al. described a lithium-catalyzed stereospecific and stereoselective addition of the N–H bond of pyrazole 20 to phenylacetylene, as a method to prepare 1-styrylpyrazoles 21 (Scheme 2) [54]. Under such conditions, (Z)-1-styryl-1H-pyrazole (21a) and (Z)-5-amino-1-styryl-1H-pyrazole (21b) were obtained in 60% and 55% yield, respectively.
Tsuchimoto et al. reported a similar single addition of the N–H bond of pyrazoles to phenylacetylene and prop-1-yn-1-ylbenzene in the presence of a silver catalyst (AgNO3 or AgOTf) to produce a regioisomeric mixture of 1-substituted pyrazoles 22 and 23 (Scheme 2) [55]. Complete stereoselectivity was achieved, since only the (Z)-isomer of 1-styrylpyrazole was formed, indicating that anti-addition, via a concerted mechanism, in which pyrazole nitrogen attacks the alkyne from the side opposite to a coordinated Lewis acid (LA), is involved as a key step in the reaction process [55].
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) as efficient catalysts in the regio- and stereoselective addition of pyrazoles 26 to alkynes was described by Das Kumar et al. (Scheme 3) [56]. In general, the addition catalyzed by complex 24 afforded (E)-1-styrylpyrazoles 27 while complex 25 produces (Z)-1-styrylpyrazoles 28. Based on density functional theory calculations, the authors have shown that stereoselectivity is dependent upon the ligand environment around the ruthenium center.
Recently, Garg et al. reported a transition-metal-free chemo-, regio-, and stereoselective synthesis of (Z)- and (E)-1-styrylpyrazoles by the addition of pyrazoles 26 onto functionalized terminal alkynes using a super basic solution of KOH/dimethyl sulfoxide (DMSO) [31]. The nature of the base seems to be crucial for the reaction, which does not occur in the presence of an organic base, such as triethylamine (Et3N). The reaction stereoselectivity is governed by time and amount of the base (Scheme 3). Deuterium labeling and control experiments highlighted the role of the KOH/DMSO catalytic system in the cistrans isomerization, which was further supported by comparative 1H-NMR spectrum studies in DMSO/DMSO-d6. This method is of wide scope and several functionalities, such as OH or Me, NH2, present both in the alkyne and pyrazole are well-tolerated [31].

3.2. Synthesis of 3(5)-Styrylpyrazoles

3.2.1. Cyclocondensation Reactions

The cyclocondensation of (1E,4E)-1,5-diarylpenta-1,4-dien-3-one 29 with hydrazine or phenyl hydrazine in glacial acetic acid at reflux [57,58], in the presence of sulfuric acid [59], or cellulose sulfonic acid [60], afforded 5-aryl-3-styryl-4,5-dihydro-1H-pyrazoles (pyrazolines) 15 or 30 (Scheme 4). Following a similar approach, Nauduri et al. synthesized a series of 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 (70–77%) [34]. Pathak et al. studied the reaction of 29 with hydrazine hydrate in glacial acetic acid under conventional reflux, ultrasound, microwave irradiation conditions and using mechanochemical mixing, and isolated 1-acetyl-5-aryl-3-(substituted-styryl)pyrazolines 30. In turn, pyrazolines 15 were converted into the corresponding pyrazoles by oxidation (dehydrogenation) (Scheme 4). Several oxidant agents can be employed for this transformation; some common examples include lead tetraacetate [58], DMSO in open air [61], MnO2 [62], p-chloranil [63], 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) [64], Pd/C [65]. In 2014, Ananthnag et al. developed a simple and high yielding method for the conversion of (E)-3- and 5-styrylpyrazolines into the corresponding pyrazoles via iron(III) catalyzed aerobic oxidative aromatization [65]. The use of FeCl3 as catalyst makes the reaction greener and more economical.
Gressler et al. described the [3 + 2] cyclocondensation of 1,5-diarylpenta-1,4-dien-3-ones 31 with aminoguanidine hydrochloride 32 in ethanol, in the presence of triethylamine, as a method to prepare 5-aryl-1-carboxamidino-3-styryl-4,5-dihydro-1H-pyrazoles 9 (Scheme 5) [35,66,67].
In 1991, Purkayastha et al. reported the reaction of α-oxoketene dithioacetal 33 with hydrazine hydrate in ethanol, in the presence of acetic acid, as a method to exclusively obtain (E)-3(5)-styrylpyrazoles (34⇌35) (Scheme 6). They have shown that acidic medium is required for the regioselective formation of 34, otherwise, in neutral conditions, other products are formed [68]. The formation of styrylpyrazoles 34, in acidic conditions, was explained through the attack of hydrazine on protonated 33 at the β-carbon with a positive charge, which is stabilized by the two methylthio groups. In fact, the (E)-3(5)-styrylpyrazole 34a (Ar = Ph) was isolated as the sole product (79%) when 33a (Ar = Ph) reacted with hydrazine hydrate in ethanol:acetic acid (1:1) mixture. Other cinnamoyl oxoketene dithioacetals similarly reacted in these conditions affording a series of (E)-3(5)-styrylpyrazoles. This method is also suitable for the synthesis of 3-(4-arylbuta-1,3-dienyl)pyrazoles and 3-(6-arylhexa-1,3,5-trienyl)pyrazoles starting from the appropriate dienoyl- and trienoyl oxoketene dithioacetals, and has high practical utility, since the introduction of such enyl side-chains in the preformed pyrazole is not possible [68].
In 2001, Pastine et al. reported the synthesis of (E)-3-styrylpyrazoles starting from benzalacetone 36, which was converted into the corresponding hydrazones 37 by reaction with hydrazine derivatives. Then, compounds 37 were deprotonated with an excess of lithium diisopropylamide (LDA), and the resulting dilithiated intermediates 38 were condensed at the carbanion center with a variety of substituted benzoate esters, such as methyl benzoate, methyl 4-t-butylbenzoate, (lithiated) methyl 4-hydroxybenzoate, or methyl 3,4,5-trimethoxybenzoate affording 39. After acid cyclization of 39 with 3 N hydrochloric acid, the 3-styrylpyrazoles 40 were isolated (Scheme 7) [69].
The reaction of (E)-3-aryl-1-(3-phenyloxiran-2-yl)-prop-2-en-1-ones (41) with tosyl hydrazine under acid catalysis afforded (E)-5-hydroxy-5-phenyl-3-styryl-1-tosyl-2-pyrazolines (42) (Scheme 8) [70]. Then, (E)-5-phenyl-3-styryl-1-tosyl-1H-pyrazoles (43), which are formed due to dehydration of 5-hydroxypyrazolines 42, were also isolated, as by-products, by chromatography, after crystallization of the major products.
The formation of pyrazolines 42 occurred through oxirane ring-opening at the α-carbon, followed by the rearrangement of the azadiene intermediate (A) through a hydride [1,5] sigmatropic shift to 1,3-diketone monohydrazone (B, Scheme 9). Finally, the intramolecular cyclization led to 5-hydroxypyrazolines 42. These compounds are only stable if they have an electron-withdrawing group, such as 1-acyl, or if a perfluoroalkyl group is present at the C-5 of the pyrazoline ring [70].
The condensation of acetylenic ketones 44 with aryl hydrazines 45 produces (E)-3(5)-styrylpyrazoles (46 and/or 47) in fair to good yield. The substitution pattern in these pyrazoles depends on the nature of the substituents and mainly on the reaction conditions (Scheme 10) [71]. When methanol is used as solvent and the reaction is stirred at room temperature for a period prior to the addition of acid and heating, (E)-5-styrylpyrazoles 47 were obtained as the major products. However, if acid is present and heat applied from the onset, a mixture of (E)-3- and 5-styrylpyrazoles 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, when R1 = MeO, R2 = H and R3 = MeSO2, the regioisomer 46 is obtained in higher amount. On contrary, when R1 = R2 = H and R3 = NO2, 46 is the minor regioisomer. In the absence of acid, the initial reaction step involves Michael addition of the more basic terminal nitrogen of the hydrazine derivative to the terminal acetylenic carbon to form enamine, which exists in tautomeric equilibrium with the isomeric hydrazone. The cyclization of the hydrazone in the presence of added acid subsequently afforded only (E)-5-styrylpyrazoles 46. The formation of this isomer seems to be promoted by the strong electron-donating and electron-withdrawing effect of the substituents.
The microwave-assisted N-heterocyclization of metal-diketonic complexes, Pd(dba)2 or Pd(dba)3 (dba = dibenzylideneacetones) with hydrochloride salts of various aryl hydrazines allows the synthesis of 1-aryl-5-phenyl-3-styryl-1H-pyrazoles in a single step and with very good yields (Scheme 11) [72]. Metal-diketones act as both catalyst and coupling partner. The hydrazine substrate and the solvent play an important role in the selectivity. Reaction with phenyl hydrazine hydrochloride in water gave both (E)-3-styrylpyrazole 48 and (E)-3-styrylpyrazoline 49 in approximately equal amounts. If the substrate is phenyl hydrazine (without hydrochloride salt), (E)-3-styrylpyrazoline 49 is the major reaction product. The use of DMSO as a solvent instead of water promotes the formation of (E)-3-styrylpyrazole 48 in high yields.

3.2.2. Intramolecular Oxidative C–N Coupling of Hydrazones

The ruthenium(II)-catalyzed oxidative C–N coupling of 2,4-dinitrophenylhydrazone of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one 50 in the presence of oxygen (1 atm) as the oxidant, afforded (E)-1-(2,4-dinitrophenyl)-5-phenyl-3-styryl-1H-pyrazole (48). [RuCl2(p-cymene)]2 (5 mol%) was found to be the best catalyst for this oxidative C(sp2)−H amination (Scheme 12) [73]. This catalyst allows C–H bond cleavage via an o-metalation process that involves chelation with the nitrogen from hydrazone. Consequently, the formation of a C–N bond is possible via reductive elimination to generate the 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 Cu(OAc)2 (10 mol%) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (30 mol%) in DMSO at 100 °C in the presence of oxygen (1 atm) as the oxidant, (E)-1,5-diphenyl-3-styryl-1H-pyrazole (48, R1 = Ph) was obtained (Scheme 12) [74].

3.2.3. Miscellaneous

The decarboxylative Knoevenagel reaction of aldehyde 51 with 3-methyl-5-pyrazoleacetic acid 52 directly afforded (E)-3-styrylpyrazole 7 (Scheme 13) [33].
Hydrogenolysis of (E)-5-styrylisoxazole 53, using Mo(CO)6 in the presence of water (1.0 equiv), followed by ring closure with hydrazine also produced (E)-3-styrylpyrazole 7 [33]. In a first step, a ketone is obtained (Scheme 14, i), which after reaction with 97% hydrazine in acetic acid gave (E)-3-styrylpyrazole 7 (Scheme 14, ii).
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 55 (Scheme 15) [75].

3.3. Synthesis of 4-Styrylpyrazoles

3.3.1. Cross-Coupling Reactions

(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 57 (Scheme 16). Using the pre-catalyst palladacycle XPhos Pd G2 and XPhos, in combination with K2CO3 in a green solvent system (EtOH/H2O), under microwave irradiation, Jedináket al. obtained the (E)-(4-styryl)aminopyrazoles 58 [76]. Direct comparison of the chloro, bromo, and iodopyrazoles used as substrate in the Suzuki−Miyaura reaction revealed that bromo and chloro derivatives were superior to iodopyrazoles, showing reduced propensity to dehalogenation [76]. Using the same pre-catalyst (XPhos Pd G2), which enabled the coupling with the electron deficient, electron-rich, or sterically demanding boronic acids, Tomanová et al. coupled the 4-bromopyrazoles 59 with styryl boronic acids 57 to prepare the (E)-3,5-dinitro-4-styryl-1H-pyrazoles 60 (Scheme 17) [77]. The introduction of the electron-deficient nitro groups as masked amino functionalities improved the rate of the oxidative addition step and eliminated the Pd-independent side dehalogenation reaction. Both nitro groups were then converted into amine groups by iron-catalyzed reduction with hydrazine hydrate to give (E)-3,5-diamino-4-styryl-1H-pyrazoles (61).
Starting from 4-iodo-1-(4-nitrophenyl)-1H-pyrazole 62 and 4-methoxystyrene 63, Miller et al. synthesized (E)-4-(4-methoxystyryl)-1-nitrophenyl-1H-pyrazole 64, using standard palladium-catalyzed coupling conditions (Scheme 18). Furthermore, 4-bromo-1-(4-nitrophenyl)-1H-pyrazole did not react under the same conditions [71]. On the other hand, the Mizoroki–Heck coupling of previously prepared 4-vinylpyrazole 65 with halobenzenes 66, using Pd(AcO)2 (10 mol%) as a catalyst in the presence of a ligand (o-MePh)3P (20 mol%), afforded the desired (E)-1,3-disubstituted-4-styryl-1H-pyrazoles 67 [45] (Scheme 19). This reaction was performed under microwave irradiation to obtain the compound in a shorter reaction time.

3.3.2. Cyclocondensation Reaction

Kim et al. described a convenient method to prepared (E)-4-styrylpyrazoles starting from α-alkenyl-α,β-enones 68, readily accessed from the Morita–Baylis–Hillman reaction. The reaction of 68 with aryl hydrazines in ethanol, in the presence of O2, afforded (E)-4-styrylpyrazoles 69 (Scheme 20), together with trace amounts of the corresponding 4-arylethylpyrazoles and pyridazine derivatives, which were identified but were not isolated [78].

3.3.3. 1,3-Dipolar Cycloaddition Reaction

1,3-Dipolar cycloaddition reaction of (E,E)-cinnamylideneacetophenones 70 and diazomethane, at room temperature or in a refrigerator, lead to the formation of 3-benzoyl-4-styryl-2-pyrazolines 71. By oxidation with an excess of chloranil, in toluene, pyrazolines 71 were converted into 3(5)-benzoyl-4-styrylpyrazoles 72 (Scheme 21) [79]. The regioselective formation of 71 results from the reaction between the Cα=Cβ double bond of 70 with diazomethane giving rise to 1-pyrazolines 73, which then isomerize into 2-pyrazoline isomers 71 (Scheme 22). From the reaction between the Cγ=Cδ double bond of 70 with diazomethane, other cycloadducts can be formed; however, their formation was not reported. For some derivatives (R1 = H, R2 = H and R3 = H, Me), small amounts of 3-(2-benzofuranyl)-4-styryl-2-pyrazolines were formed as by-products, as a result of insertion of a methylene group between the carbonyl and the 2-hydroxyphenyl group leading to the formation of compound 74. Then, the intramolecular reaction of the hydroxy group with the carbonyl carbon and subsequent water elimination from the obtained hemiacetal lead to the formation of the benzofuran ring 75 (Scheme 22) [79].

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

3.3.5. Miscellaneous

The Wittig reaction of 4-formylpyrazole 80 with benzyltriphenylphosphonium bromide (81) in BuLi-THF afforded the corresponding (E)- and (Z)-4-styrylpyrazoles 82 with an E:Z ratio of approximately 1:3 (Scheme 25) [45].
Ahamad et al. described the synthesis of the (E)-4-styryl-5-vinylpyrazole 85 by a domino reaction, which involves the 1,3-dipolar cycloaddition of Bestmann–Ohira reagent (BOR) 84 to (2E,4E)-5-phenylpenta-2,4-dienal 83, followed by a Horner–Wadsworth–Emmons reaction of the resulting pyrazoline carboxaldehyde and subsequent 1,3-H shift to afford 85. This methodology has relevant application for the synthesis of 5-vinylpyrazoles (Scheme 26) [82].

3.4. Synthesis of 5(3)-Styrylpyrazoles

3.4.1. Cyclocondensation Reactions

One of the first reports about the synthesis of styrylpyrazoles dates back to 1978 [83]. At that time, Soliman et al. described the reaction of diketoester 86 with aryl/hetaryl hydrazines in ethanol to prepare (E)-5-styrylpyrazoles 87 (Scheme 27).
The first approach to the synthesis of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazole (89a, R1 = H) was the treatment of 1-(2-hydroxyphenyl)-5-phenylpent-4-ene-1,3-dione (88a, R1 = H), which exists in equilibrium with the enolic form (88a′), with excess hydrazine (formed by treatment of hydrazinium sulfate with potassium carbonate), added gradually (dropwise) and using a 1:1 dichloromethane (DCM)/methanol mixture as solvent (Scheme 28, i) [84]. Using hydrazine hydrate in methanol at room temperature, compounds 88 were converted into pyrazoles 89 (Scheme 28, ii) [84]. Furthermore, (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazoles 89 (R1 = H, OMe, NO2; R2 = H) were also obtained starting from 88 by reaction with hydrazine hydrate, in acetic acid (Scheme 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 monosubstituted hydrazines, such as phenyl hydrazine, although apparently simple, conceal a complex mechanistic problem. Diketones 88 have two tautomeric forms (88 and 88′) and phenyl hydrazine can react initially through NH or NH2. When the reaction is carried out in methanol in neutral conditions, a nucleophilic attack of the primary amine (NH2) to the more electrophilic position of the diketone (C-1) occurs and only pyrazoles 91 were obtained in low yields. Using acidic conditions (AcOH as solvent), the more basic amine (NH2) was protonated and subsequently the nucleophilic attack at the more electrophilic position was through the NH affording pyrazoles 90 [84].
Deshayes et al. performed the reaction of enamine 92 with phenyl hydrazine in refluxing ethanol, overnight, to produce 4-ethoxycarbonyl-1-phenyl-5-styrylpyrazole 93. In the same conditions, the reaction with benzyl hydrazine afforded a 3:1 mixture of two pyrazole isomers, the 1-benzyl-4-ethoxycarbonyl-5-styrylpyrazole 94 as the major product together with 1-benzyl-4-ethoxycarbonyl-3-styrylpyrazole 95 (Scheme 29) [85].

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 a mixture of ethanol and chloroform, in the presence of a catalytic amount of concentrated HCl, 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 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 dienones 96 with aryl hydrazine hydrochlorides in 1,2-dichlorobenzene at 130 °C, under O2 atmosphere (Scheme 30, ii) [86,87]. Similar conditions for the reaction of Baylis–Hillman adduct 99 with phenyl hydrazine afforded the styrylpyrazole 100 (Scheme 30) [87].

3.4.3. Reaction of 2-Styrylchromones with Hydrazines

The reaction of 5-benzyloxy-2-styrylchromones 101 with an excess of hydrazine hydrate in methanol at reflux yielded (E)-3-(2-benzyloxy-6-hydroxyphenyl)-5-styryl-1H-pyrazoles 102 (Scheme 31). Small amounts of 3-(2-benzyloxy-6-hydroxyphenyl)-5-(2-phenylethyl)pyrazoles 103a,d,e and 5-aryl-3-(2-benzyloxy-β,6-dihydroxystyryl)-2-pyrazolines 104ae were also formed, in addition to the pyrazoles 102ae [88]. Only one isomer was obtained from the reaction of 2-styrylchromones 101 with methylhydrazine. Due to the hydrogen bond between 6′-OH and N-2 in each product, there was the formation of only one tautomer, the 3-(2-benzyloxy-6-hydroxyphenyl)-5-styrylpyrazoles 102fk and not the corresponding 5-(2-benzyloxy-6-hydroxyphenyl)-3-styrylpyrazole [89].

3.4.4. Wittig–Horner Reaction

Deshayes et al. reported the reaction of phosponic esters, prepared from 1-substituted 5-bromomethylpyrazoles 105 and triethyl phosphite, with substituted benzaldehydes and furfural, in dimethoxyethane, as a method to prepare (E)-4-ethoxycarbonyl-3-methyl-5-styryl-l-substituted pyrazoles 106 (Scheme 32) [75,85].

3.5. Synthesis of Bis(Styryl)Pyrazoles

Cyclocondensation 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] 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 12af [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 [39,40,41,42]. The reaction scope seems to be broad since phenyl hydrazine, p-methoxy, p-chloro, p-nitro, and p-carboxyphenyl hydrazines gave bis(styryl)pyrazoles 12bf 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].

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 with the C4 = C3(5) double bond of the pyrazole moiety. Silva et al. obtained the tetrahydroindazoles 109 and 110 in good yields and with high selectivities from the Diels–Alder reactions of (Z)- and (E)-1-acetyl-4-styrylpyrazoles 107 and 108, which reacted as dienes, with both dienophiles, N-methyl- or N-phenylmaleimide, using microwave irradiation (800 W) [91,92]. The expected indazoles 111 were obtained by dehydrogenation of the corresponding adducts with DDQ under microwave irradiation or conventional heating conditions (Scheme 34) [91]. They have also studied the cycloadditions of (E)-1-acetyl-4-nitrostyrylpyrazole 108 (R1 = NO2) with N-phenylmaleimide and with dimethyl acetylenedicarboxylate (DMAD). In the reaction with N-phenylmaleimide, the cycloadduct 112 was obtained in 49% yield together with the indazole 113, obtained as a by-product (5% yield). On the other hand, in the reaction with DMAD, a conjugate addition of the pyrazole nitrogen to DMAD occurred with formation of a trace amount of pyrazole 114 (Scheme 35) [91].

4.2. Transformations of 3(5)-Styrylpyrazoles

4.2.1. Diels–Alder Cycloadditions

Starting from 3- and 5-styrylpyrazoles 115 and 116, Silva et al. developed a synthetic route to prepare naphthylpyrazoles [84]. These styrylpyrazoles, which can behave as dienophiles, undergo a Diels–Alder cycloaddition with o-benzoquinodimethane (117), the diene, which was formed in situ by the thermal extrusion of sulfur dioxide from 1,3-dihydrobenzo[c]thiophene 2,2-dioxide. 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 (118) in good yields (69–91%) (Scheme 36, i). The presence of an electron-withdrawing substituent on the p-position of the phenyl ring increases the reactivity of the styryl double bond [84]. These authors also performed the Diels–Alder reaction of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styrylpyrazoles (116) with diene (117), but in this case longer reaction times were necessary and the expected cycloadducts were obtained in lower yields (24–48%). The efficiency of this Diels–Alder reaction increased by using a LA, aluminum(III) chloride, which increased the reactivity of the styryl double bond, probably through the formation of an aluminum(III) complex involving the oxygen of the 2′-hydroxy group and the free nitrogen of the pyrazole moiety. Under these conditions, the cycloadduct 119 containing an electron-donating substituent at the p-position of styryl moiety was obtained in better yield. On the contrary, the cycloadduct 119 containing the p-nitro group as substituent was obtained in better yield without addition of aluminum(III) chloride (Scheme 36, iii) [84]. The formation of naphthylpyrazoles 120 and 121 occurred by dehydrogenation of the corresponding cycloadducts with DDQ (2–6 days). The naphthylpyrazole 120 bearing an electron-donating substituent (R1 = OMe) at the p-position of the phenyl group linked to the hydroaromatic ring was obtained in a shorter time (2 days) and with better yield (59%) than the other derivatives (R1 = H (25%) and R1 = NO2 (17%)). The presence of the p-methoxy substituent stabilizes the carbocation formed through a hydride transfer 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 the nitro group (R1 = 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].

4.2.2. Electrophilic Intramolecular Cyclization

C. Deshayes et al. reported the electrophilic intramolecular cyclization of 1-benzyl- and 1-phenyl-5-styrylpyrazoles 122, in the presence of polyphosphoric acid (PPA), which led to the formation of 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo-type compounds 123 and 124 (Scheme 37) [85]. Both the 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo[1,5-a]quinolines (123) and 5-aryl-3-ethoxycarbonyl-4,5-dihydro-10H-pyrazolo[1,5-b][2]benzazepines (124) were obtained with very good yields, save for 124 (R1 = R2 = H).
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 was not obtained. This fact can be explained by the higher stability of benzylic carbocation when compared to secondary carbocation formed during the reaction. Moreover, the obtained yields show that the efficiency of the reaction is not significantly affected by the nature of the substituents at the 1-, 3-, 4- and 5-positions of pyrazoles 125. The IMFC reaction of 1-benzyl-5-styrylpyrazole 125 (R1 = Bn) afforded a 2,9-diphenyl-3,3a-diazabenzo[f]azulene derivative [87]. The base-catalyzed aerobic oxidation of dihydropyrazolo[1,5-a]quinolines 126 afforded the corresponding pyrazolo[1,5-a]quinolines 127 (Scheme 38, ii). However, the reaction only occurred when R5 = Ph and R6 = H [87].

4.2.3. Oxidative Addition Reactions

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 (NAPhth) (130) to the exocyclic double bond in the presence of lead tetraacetate and potassium carbonate in dichloromethane (Scheme 39). The reaction with 1,5-diphenylpyrazoles 128 afforded the corresponding phthalimidoaziridinylpyrazoles 131 with better yield than with the 1,3-diphenylpyrazoles 129. Analogous 4,5-dihydropyrazoles were inert in the oxidative addition of NAPhth [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-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.

References

  1. Abrigach, F.; Touzani, R. Pyrazole derivatives with NCN junction and their biological activity: A review. Med. Chem. 2016, 6, 292–298. [Google Scholar] [CrossRef]
  2. Alam, M.J.; Alam, S.; Alam, P.; Naim, M.J. Green synthesis of pyrazole systems under solvent-free conditions. Int. J. Pharma Sci. Res. 2015, 6, 1433–1442. [Google Scholar] [CrossRef] [Green Version]
  3. Abdel-Maksoud, M.S.; El-Gamal, M.I.; Gamal El-Din, M.M.; Oh, C.H. Design, synthesis, in vitro anticancer evaluation, kinase inhibitory effects, and pharmacokinetic profile of new 1,3,4-triarylpyrazole derivatives possessing terminal sulfonamide moiety. J. Enz. Inhib. Med. Chem. 2019, 34, 97–109. [Google Scholar] [CrossRef] [Green Version]
  4. Amir, M.; Kumar, S. Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of 3,5-dimethyl pyrazoles, 3-methyl pyrazol-5-ones and 3,5-disubstituted pyrazolines. Indian J. Chem. 2005, 37, 2532–2537. [Google Scholar] [CrossRef]
  5. Achutha, D.K.; Kameshwar, V.H.; Ningappa, M.B.; Kariyappa, A.K. Synthesis and in vitro biological evaluation for antioxidant, anti-inflammatory activities and molecular docking studies of novel pyrazole derivatives. Biointerface Res. Appl. Chem. 2017, 7, 2040–2047. [Google Scholar]
  6. Prabhu, V.V.; Kannan, N.; Guruvayoorappan, C. 1,2-Diazole prevents cisplatin-induced nephrotoxicity in experimental rats. Pharmacol. Rep. 2013, 65, 980–990. [Google Scholar] [CrossRef]
  7. Silva, V.L.M.; Elguero, J.; Silva, A.M.S. Current progress on antioxidants incorporating the pyrazole core. Eur. J. Med. Chem. 2018, 156, 394–429. [Google Scholar] [CrossRef] [PubMed]
  8. Chowdary, B.N.; Umashankara, M.; Dinesh, B.; Girish, K.; Baba, A.R. Development of 5-(aryl)-3-phenyl-1H-pyrazole derivatives as potent antimicrobial compounds. Asian J. Chem. 2019, 31, 45–50. [Google Scholar] [CrossRef]
  9. Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Iwai, N.; Hiyama, Y.; Suzuki, K.; Ito, H.; Terauchi, H.; Kawasaki, M.; et al. Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives. J. Med. Chem. 2004, 47, 3693–3696. [Google Scholar] [CrossRef] [PubMed]
  10. Secci, D.; Bolasco, A.; Chimenti, P.; Carradori, S. The state of the art of pyrazole derivatives as monoamine oxidase inhibitors and antidepressant/anticonvulsant agents. Curr. Med. Chem. 2011, 18, 5114–5144. [Google Scholar] [CrossRef] [PubMed]
  11. Palaska, E.; Aytemir, M.; Uzbay, I.T.; Erol, D. Synthesis and antidepressant activities of some 3,5-diphenyl-2-pyrazolines. Eur. J. Med. Chem. 2001, 36, 539–543. [Google Scholar] [CrossRef]
  12. Datar, P.A.; Jadhav, S.R. Development of pyrazole compounds as antidiabetic agent: A review. Lett. Drug Des. Discov. 2014, 11, 686–703. [Google Scholar] [CrossRef]
  13. Silva, V.L.M.; Silva, A.M.S.; Pinto, D.C.G.A.; Jagerovic, N.; Callado, L.F.; Cavaleiro, J.A.S.; Elguero, J. Synthesis and pharmacological evaluation of chlorinated N-alkyl-3 and -5-(2-hydroxyphenyl)pyrazoles as CB1 cannabinoid ligands. Monatsh. Chem. 2007, 138, 797–811. [Google Scholar] [CrossRef]
  14. Silva, V.L.M.; Silva, A.M.S.; Pinto, D.C.G.A.; Rodríguez, P.; Gomez, M.; Jagerovic, N.; Callado, L.F.; Cavaleiro, J.A.S.; Elguero, J.; Fernandez-Ruiz, J. Synthesis and pharmacological evaluation of new (E)- and (Z)-3-aryl-4-styryl-1H-pyrazoles as potential cannabinoid ligands. Arkivoc 2010, 2010, 226–247. [Google Scholar] [CrossRef] [Green Version]
  15. Gomes, P.M.O.; Silva, A.M.S.; Silva, V.L.M. Pyrazoles as key scaffolds for the development of fluorine-18-labeled radiotracers for positron emission tomography (PET). Molecules 2020, 25, 1722. [Google Scholar] [CrossRef]
  16. Ansari, A.; Ali, A.; Asif, M. Biologically active pyrazole derivatives. New J. Chem. 2017, 41, 16–41. [Google Scholar] [CrossRef]
  17. Küçükgüzel, S.G.; Senkardes, S. Recent advances in bioactive pyrazoles. Eur. J. Med. Chem. 2015, 97, 786–815. [Google Scholar] [CrossRef]
  18. Santos, C.M.M.; Silva, V.L.M.; Silva, A.M.S. Synthesis of chromone-related pyrazole compounds. Molecules 2017, 22, 1665. [Google Scholar] [CrossRef] [Green Version]
  19. Faria, J.V.; Vegi, P.F.; Miguita, A.G.C.; dos Santos, M.S.; Boechat, N.; Bernardino, A.M.R. Recently reported biological activities of pyrazole compounds. Bioorg. Med. Chem. 2017, 25, 5891–5903. [Google Scholar] [CrossRef]
  20. Pérez-Fernández, R.; Goya, P.; Elguero, J. A review of recent progress (2002–2012) on the biological activities of pyrazoles. Arkivoc 2014, 2014, 233. [Google Scholar] [CrossRef]
  21. Marella, A.; Ali, M.R.; Alam, M.T.; Saha, R.; Tanwar, O.; Akhter, M.; Shaquiquzzaman, M.; Alam, M.M. Pyrazolines: A biological review. Mini Rev. Med. Chem. 2013, 13, 921–931. [Google Scholar] [CrossRef] [PubMed]
  22. Giornal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J.-P.; Leroux, F.R. Synthesis of diversely fluorinated pyrazoles as novel active agrochemical ingredients. J. Fluorine Chem. 2013, 152, 2–11. [Google Scholar] [CrossRef]
  23. Garcia, H.; Iborra, S.; Miranda, M.A.; Morera, I.M.; Primo, J. Pyrazoles and isoxazoles derived from 2-hydroxyaryl phenylethynyl ketones: Synthesis and spectrophotometric evaluation of their potential applicability as sunscreens. Heterocycles 1991, 32, 1745–1748. [Google Scholar] [CrossRef]
  24. Catalan, J.; Fabero, F.; Claramunt, R.M.; Santa Maria, M.D.; Foces-Foces, M.C.; Cano, F.H.; Martinez-Ripoll, M.; Elguero, J.; Sastre, R. New ultraviolet stabilizers: 3- and 5-(2′-hydroxyphenyl)pyrazoles. J. Am. Chem. Soc. 1992, 114, 5039–5048. [Google Scholar] [CrossRef]
  25. Trofimenko, S. Coordination chemistry of pyrazole-derived ligands. Chem. Rev. 1972, 72, 497–509. [Google Scholar] [CrossRef]
  26. Busev, A.I.; Akimov, V.K.; Gusev, S.I. Pyrazolone Derivatives as Analytical Reagents. Russ. Chem. Rev. 1965, 34, 237. [Google Scholar] [CrossRef]
  27. Meier, H.; Hormaza, A. Oligo(1,4-phenylenepyrazole-3,5-diyl)s. Eur. J. Org. Chem. 2003, 3372–3377. [Google Scholar] [CrossRef]
  28. Willy, B.; Müller, T.J.J. Rapid one-pot, four-step synthesis of highly fluorescent 1,3,4,5-tetrasubstituted pyrazoles. Org. Lett. 2011, 13, 2082–2085. [Google Scholar] [CrossRef]
  29. Dorlars, A.; Schellhammer, C.-W.; Schroeder, J. Heterocycles as Structural Units in New Optical Brighteners. Angew. Chem. Int. Ed. 1975, 14, 665–679. [Google Scholar] [CrossRef]
  30. Perevalov, V.P.; Baryshnenkova, L.I.; Sheban, G.V.; Karim, A.K.K.; Kramarenko, S.S.; Koldaeva, T.Y.; Stepanov, B.I. Spectral peculiarities of isomeric trans-styrylpyrazoles. Chem. Heterocycl. Compd. 1990, 26, 887–890. [Google Scholar] [CrossRef]
  31. Garg, V.; Kumar, P.; Verma, A.K. Chemo-, regio-, and stereoselective N-alkenylation of pyrazoles/benzpyrazoles using activated and unactivated alkynes. J. Org. Chem. 2017, 82, 10247–10262. [Google Scholar] [CrossRef] [PubMed]
  32. Yamamoto, H.; Kaneko, S.-I. Synthesis of 1-phenyl-2-styryl-3,5-dioxopyrazolidines as anti-inflammatory agents. J. Med. Chem. 1970, 13, 292–295. [Google Scholar] [CrossRef] [PubMed]
  33. Flynn, D.L.; Belliotti, T.R.; Boctor, A.M.; Connor, D.T.; Kostlan, C.R.; Nies, D.E.; Ortwine, D.F.; Schrier, D.J.; Sircar, J.C. Styrylpyrazoles, styrylisoxazoles and styrylisothiazoles. Novel 5-lipoxygenase and cyclooxygenase inhibitors. J. Med. Chem. 1991, 34, 518–525. [Google Scholar] [CrossRef] [PubMed]
  34. Nauduri, D.; Reddy, G.B.S. Antibacterials and antimycotics: Part 1: Synthesis and activity of 2-pyrazoline derivatives. Chem. Pharm. Bull. 1998, 46, 1254–1260. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Gressler, V.; Moura, S.; Flores, A.F.C.; Flores, D.C.; Colepicolo, P.; Pinto, E. Antioxidant and antimicrobial properties of 2-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidine and 1-carboxamidino-1H-pyrazole derivatives. J. Braz. Chem. Soc. 2010, 21, 1477–1483. [Google Scholar] [CrossRef]
  36. Sherin, D.R.; Rajasekharan, K.N. Mechanochemical synthesis and antioxidant activity of curcumin-templated azoles. Arch. Pharm. Chem. Life Sci. 2015, 348, 908–914. [Google Scholar] [CrossRef]
  37. Sharma, S.; Ying, Z.; Pinilla, F.G. A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma. Exp. Neurobiol. 2010, 226, 191–199. [Google Scholar] [CrossRef] [Green Version]
  38. Lapchak, P.A.; Boitano, P.D. Effect of the pleiotropic drug CNB-001 on tissue plasminogen activator (tPA) protease activity in vitro: Support for combination therapy to treat acute ischemic stroke. J. Neurol. Neurophysiol. 2014, 5, 214–219. [Google Scholar]
  39. Das, J.; Pany, S.; Panchal, S.; Majhi, A.; Rahman, G.M. Binding of isoxazole and pyrazole derivatives of curcumin with the activator binding domain of novel protein kinase C. Bioorg. Med. Chem. 2011, 19, 6196–6202. [Google Scholar] [CrossRef]
  40. Narlawar, R.; Pickhardt, M.; Leuchtenberger, S.; Baumann, K.; Krause, S.; Dyrks, T.; Weggen, S.; Mandelkow, E.; Schmidt, B. Curcumin-derived pyrazoles and isoxazoles: Swiss army knives or blunt tools for Alzheimer’s disease? ChemMedChem 2008, 3, 165–172. [Google Scholar] [CrossRef]
  41. Mishra, S.; Karmodiya, K.; Surolia, N.; Surolia, A. Synthesis and exploration of novel curcumin analogues as anti-malarial agents. Bioorg. Med. Chem. 2008, 16, 2894–2902. [Google Scholar] [CrossRef] [PubMed]
  42. Amolins, M.W.; Peterson, L.B.; Blagg, B.S.J. Synthesis and evaluation of electron-rich curcumin analogues. Bioorg. Med. Chem. 2009, 17, 360–367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Fuchs, J.R.; Pandit, B.; Bhasin, D.; Etter, J.P.; Regan, N.; Abdelhamid, D.; Li, C.; Lin, J.; Li, P.-K. Structure–activity relationship studies of curcumin analogues. Bioorg. Med. Chem. Lett. 2009, 19, 2065–2069. [Google Scholar] [CrossRef] [PubMed]
  44. Liao, V.W.Y.; Kumari, A.; Narlawar, R.; Vignarajan, S.; Hibbs, D.E.; Panda, D.; Groundwater, P.W. Tubulin-binding 3,5-bis(styryl)pyrazoles as lead compounds for the treatment of castration-resistant prostate cancer. Mol. Pharmacol. 2020, 97, 409–422. [Google Scholar] [CrossRef] [PubMed]
  45. Orrego-Hernández, J.; Cobo, J.; Portilla, J. Synthesis, photophysical properties, and metal-ion recognition studies of fluoroionophores based on 1-(2-pyridyl)-4-styrylpyrazoles. ACS Omega 2019, 4, 16689–16700. [Google Scholar] [CrossRef] [Green Version]
  46. Kumar, V.; Kaur, K.; Gupta, G.K.; Sharma, A.K. Pyrazole containing natural products: Synthetic preview and biological significance. Eur. J. Med. Chem. 2013, 69, 735–753. [Google Scholar] [CrossRef]
  47. Santos, N.E.; Carreira, A.R.F.; Silva, V.L.M.; Braga, S.S. Natural and biomimetic antitumor pyrazoles, A perspective. Molecules 2020, 25, 1364. [Google Scholar] [CrossRef] [Green Version]
  48. Boudiara, T.; Hichema, L.; Khalfallaha, A.; Kabouchea, A.; Kabouchea, Z.; Brouardb, I.; Jaime, B.; Bruneauc, C. A new alkaloid and flavonoids from the aerial parts of Euphorbia guyoniana. Nat. Prod. Commun. 2010, 5, 35–37. [Google Scholar] [CrossRef] [Green Version]
  49. Kundu, P.; Chattopadhyay, N. Interaction of a bioactive pyrazole derivative with calf thymus DNA: Deciphering the mode of binding by multi-spectroscopic and molecular docking investigations. J. Photochem. Photobiol. B Biol. 2017, 173, 485–492. [Google Scholar] [CrossRef]
  50. Kundu, P.; Chattopadhyay, N. Unraveling the binding interaction of a bioactive pyrazole-based probe with serum proteins: Relative concentration dependent 1:1 and 2:1 probe-protein stoichiometries. Biophys. Chem. 2018, 240, 70–81. [Google Scholar] [CrossRef]
  51. Cody, J.; Mandal, S.; Yang, L.; Fahrni, C.J. Differential tuning of the electron transfer parameters in 1,3,5-triarylpyrazolines: A rational design approach for optimizing the contrast ratio of fluorescent probes. J. Am. Chem. Soc. 2008, 130, 13023–13032. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Kundu, P.; Banerjee, D.; Maiti, G.; Chattopadhyay, N. Dehydrogenation induced inhibition of intramolecular charge transfer in substituted pyrazoline analogues. Phys. Chem. Chem. Phys. 2017, 19, 11937–11946. [Google Scholar] [CrossRef] [PubMed]
  53. Kantam, M.L.; Venkanna, G.T.; Kumar, K.B.S.; Subrahmanyam, V.B. An efficient N-arylation of heterocycles with aryl-, heteroaryl-, and vinylboronic acids catalyzed by copper fluorapatite. Helv. Chim. Acta 2010, 93, 974–979. [Google Scholar] [CrossRef]
  54. Bourgeois, P.; Lucrece, J.; Dunoguès, J. Addition d’hétérocycles azotés aux alcynes arylés; Synthèse de N-styrylazoles. J. Heterocycl. Chem. 1978, 15, 1543–1545. [Google Scholar] [CrossRef]
  55. Tsuchimoto, T.; Aoki, K.; Wagatsuma, T.; Suzuki, Y. Lewis Acid Catalyzed Addition of Pyrazoles to Alkynes: Selective Synthesis of Double and Single Addition Products. Eur. J. Org. Chem. 2008, 2008, 4035–4040. [Google Scholar] [CrossRef]
  56. Das, U.K.; Mandal, S.; Anoop, A.; Bhattacharjee, M. Structure−selectivity relationship in ruthenium-catalyzed regio- and stereoselective addition of alkynes to pyrazoles: An experimental and theoretical investigation. J. Org. Chem. 2014, 79, 9979–9991. [Google Scholar] [CrossRef]
  57. Ignatenko, O.A.; Blandov, A.N.; Kuznetsov, M.A. Oxidative addition of N-Aminophthalimide to alkenyl-4,5-dihydropyrazoles and alkenylpyrazoles. Synthesis of aziridinylpyrazoles. Russ. J. Org. Chem. 2005, 41, 1793–1801. [Google Scholar] [CrossRef]
  58. Pathak, V.N.; Joshi, R.; Sharma, J.; Gupta, N.; Rao, V.M. Mild and ecofriendly tandem synthesis, and spectral and antimicrobial studies of N1-acetyl-5-aryl-3-(substituted styryl)pyrazolines. Phosphorus Sulfur Silicon 2009, 184, 1854–1865. [Google Scholar] [CrossRef]
  59. Lakshmi, K.N.V.C.; Venkatesh, M.; Hareesh, J.; Raju, B.S.; Anupama, B. Synthesis, in silico and in vitro evaluation of some novel 5-[2-phenyl vinyl]-pyrazole and pyrazoline derivatives. Pharma Chem. 2016, 8, 122–128. [Google Scholar]
  60. Daneshfar, Z.; Rostami, A. Cellulose sulfonic acid as a green, efficient, and reusable catalyst for Nazarov cyclization of unactivated dienones and pyrazoline synthesis. RSC Adv. 2015, 5, 104695–104707. [Google Scholar] [CrossRef]
  61. Jenkins, R.N.; Hinnant, G.M.; Bean, A.C.; Stephens, C.E. Aerobic aromatization of 1,3,5-triarylpyrazolines in open air and without catalyst. Arkivoc 2015, 7, 347–353. [Google Scholar] [CrossRef] [Green Version]
  62. Huang, Y.R.; Katzenellenbogen, J.A. Regioselective synthesis of 1,3,5-triaryl-4-alkylpyrazoles:  Novel ligands for the estrogen receptor. Org. Lett. 2000, 2, 2833–2836. [Google Scholar] [CrossRef] [PubMed]
  63. Huisgen, R.; Seidel, M.; Wallbillich, G.; Knupfer, H. Diphenyl-nitrilimin und seine 1,3-dipolaren additionen an alkene und alkine. Tetrahedron 1962, 17, 3–29. [Google Scholar] [CrossRef]
  64. Walker, D.; Hiebert, J.D. 2,3-Dichloro-5,6-dicyanobenzoquinone and its reactions. Chem. Rev. 1967, 67, 153–195. [Google Scholar] [CrossRef]
  65. Ananthnag, G.S.; Adhikari, A.; Balakrishna, M.S. Iron-catalyzed aerobic oxidative aromatization of 1,3,5-trisubstituted pyrazolines. Catal. Commun. 2014, 43, 240–243. [Google Scholar] [CrossRef]
  66. Flores, D.C.; Fiss, G.F.; Wbatuba, L.S.; Martins, M.A.P.; Burrow, R.A.; Flores, A.F.C. Synthesis of new 2-(5-aryl-3-styryl-4,5-dihydro-1H-pyrazol-1-yl)-4-(trifluoromethyl)pyrimidines. Synthesis 2006, 14, 2349–2356. [Google Scholar] [CrossRef]
  67. Flores, A.F.C.; Flores, D.C.; Vicentia, J.R.M.; Campos, P.T. 2-[5-(2-Methylphenyl)-3-(2-methylstyryl)-4,5-dihydro-1H-pyrazol-1-yl]-6-(thiophen-2-yl)-4-(trifluoromethyl)-pyrimidine chloroform monosolvate. Acta Cryst. 2014, 70, 789–790. [Google Scholar] [CrossRef] [Green Version]
  68. Purkayastha, M.L.; Patro, B.; Ila, H.; Junjappa, H. Regioselective synthesis of 3 (or 5)-styryl-/(4-aryl-1,3-butadienyl)-/(6-aryl-1,3,5-hexatrienyl)-5 (or 3)-(methylthio)isoxazoles and pyrazoles via α-oxoketene dithioacetals. J. Heterocycl. Chem. 1991, 28, 1341–1349. [Google Scholar] [CrossRef]
  69. Pastine, S.J.; Kelly, W., Jr.; Bear, J.J.; Templeton III, J.N.; Beam, C.F. The preparation of 3-(2-phenylethenyl)-1H-pyrazoles from dilithiated (3E)-4-phenyl-3-buten-2-one hydrazones. Synth. Commun. 2001, 31, 539–548. [Google Scholar] [CrossRef]
  70. Kuz’menok, N.M.; Koval’chuk, T.A.; Zvonok, A.M. Synthesis of 5-hydroxy- and 5-amino-1-tosyl-5-phenyl-3-(2-arylvinyl)-4,5-dihydropyrazoles. Synlett 2005, 2005, 485–486. [Google Scholar] [CrossRef]
  71. Miller, R.D.; Reiser, O. The synthesis of electron donor-acceptor substituted pyrazoles. J. Heterocycl. Chem. 1993, 30, 755. [Google Scholar] [CrossRef]
  72. Venkateswarlu, V.; Kour, J.; Kumar, K.A.A.; Verma, P.K.; Reddy, G.L.; Hussain, Y.; Tabassum, A.; Balgotra, S.; Gupta, S.; Hudwekar, A.D.; et al. Direct N-heterocyclization of hydrazines to access styrylated pyrazoles: Synthesis of 1,3,5-trisubstituted pyrazoles and dihydropyrazoles. RSC Adv. 2018, 8, 26523–26527. [Google Scholar] [CrossRef] [Green Version]
  73. Hu, J.; Chen, S.; Sun, Y.; Yang, J.; Rao, Y. Synthesis of tri- and tetrasubstituted pyrazoles via Ru(II) catalysis: Intramolecular aerobic oxidative C-N coupling. Org. Lett. 2012, 14, 5030–5033. [Google Scholar] [CrossRef] [PubMed]
  74. Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H. Copper-catalyzed aerobic C(sp2)−H functionalization for C−N bond formation: Synthesis of pyrazoles and indazoles. J. Org. Chem. 2013, 78, 3636–3646. [Google Scholar] [CrossRef]
  75. Deshayes, C.; Chabannet, M.; Gelin, S. Synthesis of some 1-substituted-3-or-5-styrylpyrazoles. J. Heterocycl. Chem. 1981, 18, 1057–1059. [Google Scholar] [CrossRef]
  76. Jedinák, L.; Zátopková, R.; Zemánková, H.; Šustková, A.; Cankař, P. The Suzuki-Miyaura cross-coupling reaction of halogenated aminopyrazoles: Method development, scope, and mechanism of dehalogenation side reaction. J. Org. Chem. 2017, 82, 157–169. [Google Scholar] [CrossRef]
  77. Tomanová, M.; Jedinák, L.; Košař, J.; Kvapil, L.; Hradil, P.; Cankař, P. Synthesis of 4-substituted pyrazole-3,5-diamines via Suzuki–Miyaura coupling and iron-catalyzed reduction. Org. Biomol. Chem. 2017, 15, 10200–10211. [Google Scholar] [CrossRef]
  78. Kim, S.H.; Lim, J.W.; Yu, J.; Kim, J.N. Regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles from α-alkenyl-α,β-enones derived from Morita-Baylis-Hillman adducts. Bull. Korean Chem. Soc. 2013, 34, 2915–2920. [Google Scholar] [CrossRef] [Green Version]
  79. Pinto, D.C.G.A.; Silva, A.M.S.; Lévai, A.; Cavaleiro, J.A.S.; Patonay, T.; Elguero, J. Synthesis of 3-benzoyl-4-styryl-2-pyrazolines and their oxidation to the corresponding pyrazoles. Eur. J. Org. Chem. 2000, 2000, 2593–2599. [Google Scholar] [CrossRef]
  80. Silva, V.L.M.; Silva, A.M.S.; Pinto, D.C.G.A.; Cavaleiro, J.A.S.; Elguero, J. Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles. Monatsh. Chem. 2009, 140, 87–95. [Google Scholar] [CrossRef]
  81. Silva, V.L.M.; Silva, A.M.S.; Pinto, D.C.G.A.; Cavaleiro, J.A.S.; Elguero, J. Novel (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles from (E)- and (Z)-3-styrylchromones: The unexpected case of (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles. Tetrahedron Lett. 2007, 48, 3859–3862. [Google Scholar] [CrossRef]
  82. Ahamad, S.; Gupta, A.K.; Kantc, R.; Mohanan, K. Domino reaction involving the Bestmann–Ohira reagent and α,β-unsaturated aldehydes: Efficient synthesis of functionalized pyrazoles. Org. Biomol. Chem. 2015, 13, 1492–1499. [Google Scholar] [CrossRef] [PubMed]
  83. Soliman, R.; Mokhtar, H.; El Ashry, E.S.H. The scope of the reactions with hydrazines and hydrazones. Part 4. Trisubstituted pyrazoles of possible hypoglycemic and antibacterial activity. Pharmazie 1978, 33, 184–185. [Google Scholar] [CrossRef] [PubMed]
  84. Silva, V.L.M.; Silva, A.M.S.; Pinto, D.C.G.A.; Cavaleiro, J.A.S.; Elguero, J. 3(5)-(2-Hydroxyphenyl)-5(3)-styrylpyrazoles: Synthesis and Diels-Alder transformations. Eur. J. Org. Chem. 2004, 2004, 4348–4356. [Google Scholar] [CrossRef]
  85. Deshayes, C.; Chabannet, M.; Gelin, S. Synthesis of some 5-aryl-4,5-dihydropyrazolo[1,5-a]quinolines and 5-aryl-4,5-dihydro-10H-pyrazolo[1,5-b][2]benzazepines from 1-phenyl- or 1-benzyl-5-styrylpyrazoles. Synthesis 1982, 12, 1088–1089. [Google Scholar] [CrossRef]
  86. Yu, J.; Kim, K.H.; Moon, H.R.; Kim, J.N. Facile one-pot synthesis of 1,3,5-trisubstituted pyrazoles from α,β-enones. Bull. Korean Chem. Soc. 2014, 35, 1692–1696. [Google Scholar] [CrossRef] [Green Version]
  87. Moon, H.R.; Yu, J.; Kim, K.H.; Kim, J.N. Synthesis of pyrazolo[1,5-a]quinolines from 1-aryl-5-styrylpyrazoles via intramolecular Friedel-Crafts reaction/aerobic oxidation. Bull. Korean Chem. Soc. 2015, 36, 1189–1195. [Google Scholar] [CrossRef]
  88. Pinto, D.C.G.A.; Silva, A.M.S.; Cavaleiro, J.A.S.; Foces-Foces, C.; Llmas-Saiz, A.L.; Jagerovic, N.; Elguero, J. Synthesis and molecular structure of 3-(2-benzyloxy-6-hydroxyphenyl)-5-styrylpyrazoles. Reaction of 2-styrylchromones with hydrazine hydrate. Tetrahedron 1999, 55, 10187–10200. [Google Scholar] [CrossRef]
  89. Pinto, D.C.G.A.; Silva, A.M.S.; Cavaleiro, J.A.S. Novel (E)-3-(2′-benzyloxy-6′-hydroxyphenyl)-5-styrylpyrazoles from (E)-2-styrylchromones. J. Heterocycl. Chem. 1997, 3, 433–436. [Google Scholar] [CrossRef]
  90. Sherin, D.R.; Rajasekharan, K.N. Studies on the antioxidant activities of mechanochemically synthesized 1-aryl-3,5-bis(styryl)pyrazoles as curcuminoids derived CNB 001 analogs. Indian J. Heterocycl. Chem. 2016, 26, 81–86. [Google Scholar]
  91. Silva, V.L.M.; Silva, A.M.S.; Pinto, D.C.G.A.; Cavaleiro, J.A.S. Efficient microwave-assisted synthesis of tetrahydroindazoles and their oxidation to indazoles. Synlett 2006, 9, 1369–1373. [Google Scholar] [CrossRef]
  92. Silva, V.L.M.; Silva, A.M.S.; Pinto, D.C.G.A.; Elguero, J.; Cavaleiro, J.A.S. Synthesis of new 1H-indazoles through Diels-Alder transformations of 4-styrylpyrazoles under microwave irradiation conditions. Eur. J. Org. Chem. 2009, 4468–4479. [Google Scholar] [CrossRef]
Figure 1. Chemical structures and numbering of pyrazole 1, dihydropyrazole (pyrazoline) tautomers 24 and pyrazolidine 5.
Figure 1. Chemical structures and numbering of pyrazole 1, dihydropyrazole (pyrazoline) tautomers 24 and pyrazolidine 5.
Molecules 25 05886 g001
Figure 2. Styrylpyrazole derivatives 6 and 7 presenting anti-inflammatory activity [32,33].
Figure 2. Styrylpyrazole derivatives 6 and 7 presenting anti-inflammatory activity [32,33].
Molecules 25 05886 g002
Figure 3. 3-Styryl-2-pyrazolines 8 presenting antibacterial and antifungal activity [34].
Figure 3. 3-Styryl-2-pyrazolines 8 presenting antibacterial and antifungal activity [34].
Molecules 25 05886 g003
Figure 4. 5-Aryl-3-styryl-1-carboxamidino-1H-pyrazole derivatives presenting antioxidant and antimicrobial activity 9 and 10 [35].
Figure 4. 5-Aryl-3-styryl-1-carboxamidino-1H-pyrazole derivatives presenting antioxidant and antimicrobial activity 9 and 10 [35].
Molecules 25 05886 g004
Figure 5. Structures of curcumin (11) and 3,5-bis(styryl)pyrazoles CNB-001, 12 and 13, presenting antioxidant, antimalarial, cytotoxic and antiproliferative activities [36,37,38,39,40,41,42,43,44].
Figure 5. Structures of curcumin (11) and 3,5-bis(styryl)pyrazoles CNB-001, 12 and 13, presenting antioxidant, antimalarial, cytotoxic and antiproliferative activities [36,37,38,39,40,41,42,43,44].
Molecules 25 05886 g005
Figure 6. Styrylpyrazoles 1416 presenting relevant photophysical properties [45,48,49,50,51,52].
Figure 6. Styrylpyrazoles 1416 presenting relevant photophysical properties [45,48,49,50,51,52].
Molecules 25 05886 g006
Scheme 1. Cross-coupling reactions of pyrazoles 17 with styrylboronic acid 18 to produce (E)-1-styrylpyrazoles 19 [53].
Scheme 1. Cross-coupling reactions of pyrazoles 17 with styrylboronic acid 18 to produce (E)-1-styrylpyrazoles 19 [53].
Molecules 25 05886 sch001
Scheme 2. Addition of pyrazole 20 to alkynes to produce (Z)-1-styrylpyrazoles 2123 [54,55].
Scheme 2. Addition of pyrazole 20 to alkynes to produce (Z)-1-styrylpyrazoles 2123 [54,55].
Molecules 25 05886 sch002
Scheme 3. Stereoselective additions of pyrazoles 26 to alkynes to produce (E)- and (Z)-1-styrylpyrazoles 27 and 28 [31,56].
Scheme 3. Stereoselective additions of pyrazoles 26 to alkynes to produce (E)- and (Z)-1-styrylpyrazoles 27 and 28 [31,56].
Molecules 25 05886 sch003
Scheme 4. Synthesis of 3-styrylpyrazolines 15 and 30 and 3-styrylpyrazoles 16 [58].
Scheme 4. Synthesis of 3-styrylpyrazolines 15 and 30 and 3-styrylpyrazoles 16 [58].
Molecules 25 05886 sch004
Scheme 5. Synthesis of 5-aryl-1-carboxamidino-3-styryl-4,5-dihydro-1H-pyrazoles 9 [35,66,67].
Scheme 5. Synthesis of 5-aryl-1-carboxamidino-3-styryl-4,5-dihydro-1H-pyrazoles 9 [35,66,67].
Molecules 25 05886 sch005
Scheme 6. Reaction of oxoketene dithioacetals 33 with hydrazine hydrate to synthesize (E)-3(5)-styrylpyrazoles 34 [68].
Scheme 6. Reaction of oxoketene dithioacetals 33 with hydrazine hydrate to synthesize (E)-3(5)-styrylpyrazoles 34 [68].
Molecules 25 05886 sch006
Scheme 7. Reaction of benzalacetone 36 with hydrazines to produce hydrazones 37 and their transformation into (E)-3-styrylpyrazoles 40 [69].
Scheme 7. Reaction of benzalacetone 36 with hydrazines to produce hydrazones 37 and their transformation into (E)-3-styrylpyrazoles 40 [69].
Molecules 25 05886 sch007
Scheme 8. Synthesis of (E)-5-hydroxy-5-phenyl-3-styryl-1-tosyl-2-pyrazolines (42) and (E)-5-phenyl-3-styryl-1-tosyl-1H-pyrazoles (43) [70].
Scheme 8. Synthesis of (E)-5-hydroxy-5-phenyl-3-styryl-1-tosyl-2-pyrazolines (42) and (E)-5-phenyl-3-styryl-1-tosyl-1H-pyrazoles (43) [70].
Molecules 25 05886 sch008
Scheme 9. Mechanism of formation of (E)-3-styrylpyrazolines 42 and (E)-3-styrylpyrazoles 43 [70].
Scheme 9. Mechanism of formation of (E)-3-styrylpyrazolines 42 and (E)-3-styrylpyrazoles 43 [70].
Molecules 25 05886 sch009
Scheme 10. Condensation of acetylenic ketones 44 with aryl hydrazines 45 to produce (E)-3(5)-styrylpyrazoles (46 and/or 47) [71].
Scheme 10. Condensation of acetylenic ketones 44 with aryl hydrazines 45 to produce (E)-3(5)-styrylpyrazoles (46 and/or 47) [71].
Molecules 25 05886 sch010
Scheme 11. Microwave-assisted synthesis of (E)-3-styrylpyrazoles 48 and (E)-3-styrylpyrazolines 49 [72].
Scheme 11. Microwave-assisted synthesis of (E)-3-styrylpyrazoles 48 and (E)-3-styrylpyrazolines 49 [72].
Molecules 25 05886 sch011
Scheme 12. Synthesis of (E)-3-styrylpyrazoles 48 by intramolecular oxidative C–N coupling of hydrazones 50 [73,74].
Scheme 12. Synthesis of (E)-3-styrylpyrazoles 48 by intramolecular oxidative C–N coupling of hydrazones 50 [73,74].
Molecules 25 05886 sch012
Scheme 13. Synthesis of (E)-3-styrylpyrazole 7 by Doebner modification of Knoevenagel condensation [33].
Scheme 13. Synthesis of (E)-3-styrylpyrazole 7 by Doebner modification of Knoevenagel condensation [33].
Molecules 25 05886 sch013
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].
Molecules 25 05886 sch014
Scheme 15. Synthesis of (E)-3-styrylpyrazole 55 [75].
Scheme 15. Synthesis of (E)-3-styrylpyrazole 55 [75].
Molecules 25 05886 sch015
Scheme 16. Suzuki–Miyaura coupling of 4-bromo aminopyrazoles 56 and their amides with styryl boronic acids 57 to prepare (E)-(4-styryl)aminopyrazoles 58 [76].
Scheme 16. Suzuki–Miyaura coupling of 4-bromo aminopyrazoles 56 and their amides with styryl boronic acids 57 to prepare (E)-(4-styryl)aminopyrazoles 58 [76].
Molecules 25 05886 sch016
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].
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].
Molecules 25 05886 sch017
Scheme 18. Synthesis of (E)-4-(4-methoxystyryl)-1-nitrophenyl-1H-pyrazole 64 [71].
Scheme 18. Synthesis of (E)-4-(4-methoxystyryl)-1-nitrophenyl-1H-pyrazole 64 [71].
Molecules 25 05886 sch018
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-disubstituted-4-styryl-1H-pyrazoles 67 [45].
Molecules 25 05886 sch019
Scheme 20. Reaction of α-alkenyl-α,β-enones 68 with arylhydrazines to produce (E)-4-styrylpyrazoles 69 [78].
Scheme 20. Reaction of α-alkenyl-α,β-enones 68 with arylhydrazines to produce (E)-4-styrylpyrazoles 69 [78].
Molecules 25 05886 sch020
Scheme 21. Synthesis of (E)-3-benzoyl-4-styryl-2-pyrazolines 71 and 3-benzoyl-4-styryl-1H-pyrazoles 72 [79].
Scheme 21. Synthesis of (E)-3-benzoyl-4-styryl-2-pyrazolines 71 and 3-benzoyl-4-styryl-1H-pyrazoles 72 [79].
Molecules 25 05886 sch021
Scheme 22. Mechanism of formation of 3-benzoyl-4-styryl-2-pyrazolines 71 and 3-(2-benzofuranyl)-4-styryl-2-pyrazolines 75 [79].
Scheme 22. Mechanism of formation of 3-benzoyl-4-styryl-2-pyrazolines 71 and 3-(2-benzofuranyl)-4-styryl-2-pyrazolines 75 [79].
Molecules 25 05886 sch022
Scheme 23. Synthesis of (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styryl-1H-pyrazoles 77 and 79 [80,81].
Scheme 23. Synthesis of (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styryl-1H-pyrazoles 77 and 79 [80,81].
Molecules 25 05886 sch023
Scheme 24. Mechanism of the transformation of (Z)-3-(4-nitrostyryl)-4H-chromen-4-ones (76) into (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)-1H-pyrazoles (79) [81].
Scheme 24. Mechanism of the transformation of (Z)-3-(4-nitrostyryl)-4H-chromen-4-ones (76) into (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)-1H-pyrazoles (79) [81].
Molecules 25 05886 sch024
Scheme 25. Wittig reaction of 4-formylpyrazole 80 with benzyltriphenylphosphonium bromide 81 to prepare (E)- and (Z)-4-styrylpyrazoles 82 [45].
Scheme 25. Wittig reaction of 4-formylpyrazole 80 with benzyltriphenylphosphonium bromide 81 to prepare (E)- and (Z)-4-styrylpyrazoles 82 [45].
Molecules 25 05886 sch025
Scheme 26. Synthesis of the (E)-4-styryl-5-vinylpyrazole 85 [82].
Scheme 26. Synthesis of the (E)-4-styryl-5-vinylpyrazole 85 [82].
Molecules 25 05886 sch026
Scheme 27. Cyclocondensation of diketoester 86 with aryl/hetaryl hydrazines to prepare (E)-5-styrylpyrazoles 87 [83].
Scheme 27. Cyclocondensation of diketoester 86 with aryl/hetaryl hydrazines to prepare (E)-5-styrylpyrazoles 87 [83].
Molecules 25 05886 sch027
Scheme 28. Synthesis of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazoles 89, 90 and 91 [84].
Scheme 28. Synthesis of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazoles 89, 90 and 91 [84].
Molecules 25 05886 sch028
Scheme 29. Synthesis of 4-ethoxycarbonyl-5-/3-styrylpyrazoles 93, 94 and 95 [85].
Scheme 29. Synthesis of 4-ethoxycarbonyl-5-/3-styrylpyrazoles 93, 94 and 95 [85].
Molecules 25 05886 sch029
Scheme 30. Conversion of α,β-enones 96 and adduct 99 into (E)-5-styrylpyrazolines 97 and (E)-5-styrylpyrazoles 98 and 100 by reaction with phenyl/aryl hydrazine hydrochlorides [34,86,87].
Scheme 30. Conversion of α,β-enones 96 and adduct 99 into (E)-5-styrylpyrazolines 97 and (E)-5-styrylpyrazoles 98 and 100 by reaction with phenyl/aryl hydrazine hydrochlorides [34,86,87].
Molecules 25 05886 sch030
Scheme 31. Synthesis of (E)-3-(2-benzyloxy-6-hydroxyphenyl)-5-styryl-1H-pyrazoles 102 and some derivatives of pyrazoles 103 and 104 isolated as by-products [88].
Scheme 31. Synthesis of (E)-3-(2-benzyloxy-6-hydroxyphenyl)-5-styryl-1H-pyrazoles 102 and some derivatives of pyrazoles 103 and 104 isolated as by-products [88].
Molecules 25 05886 sch031
Scheme 32. Synthesis of (E)-4-ethoxycarbonyl-3-methyl-5-styry-l-substituted pyrazoles 106 [75,85].
Scheme 32. Synthesis of (E)-4-ethoxycarbonyl-3-methyl-5-styry-l-substituted pyrazoles 106 [75,85].
Molecules 25 05886 sch032
Scheme 33. Synthesis of 3,5-bis(styryl)pyrazoles 12 and 13 [36,39,40,41,42,44,90].
Scheme 33. Synthesis of 3,5-bis(styryl)pyrazoles 12 and 13 [36,39,40,41,42,44,90].
Molecules 25 05886 sch033
Scheme 34. Transformation of 4-styrylpyrazoles 107 and 108 into indazoles 111 [91,92].
Scheme 34. Transformation of 4-styrylpyrazoles 107 and 108 into indazoles 111 [91,92].
Molecules 25 05886 sch034
Scheme 35. Transformation of (E)-4-styrylpyrazole 108 into cycloadducts 112, 113 and pyrazole 114 [92].
Scheme 35. Transformation of (E)-4-styrylpyrazole 108 into cycloadducts 112, 113 and pyrazole 114 [92].
Molecules 25 05886 sch035
Scheme 36. Transformation of styrylpyrazoles 115 and 116 into tetrahydronaphthylpyrazoles 118 and 119 and their oxidation to naphthylpyrazoles 120 and 121 [84].
Scheme 36. Transformation of styrylpyrazoles 115 and 116 into tetrahydronaphthylpyrazoles 118 and 119 and their oxidation to naphthylpyrazoles 120 and 121 [84].
Molecules 25 05886 sch036
Scheme 37. Transformation of 1-benzyl- and 1-phenyl-5-styrylpyrazoles 122 into 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo-type compounds 123 and 124 [85].
Scheme 37. Transformation of 1-benzyl- and 1-phenyl-5-styrylpyrazoles 122 into 5-aryl-3-ethoxycarbonyl-4,5-dihydropyrazolo-type compounds 123 and 124 [85].
Molecules 25 05886 sch037
Scheme 38. Transformation of 1-aryl-5-styrylpyrazoles 125 into dihydropyrazolo[1,5-a]quinolines 126 and their oxidation to pyrazolo[1,5-a]quinolines 127 [87].
Scheme 38. Transformation of 1-aryl-5-styrylpyrazoles 125 into dihydropyrazolo[1,5-a]quinolines 126 and their oxidation to pyrazolo[1,5-a]quinolines 127 [87].
Molecules 25 05886 sch038
Scheme 39. Transformation of (E)-3- and 5-styrylpyrazoles 128 and 129 into phthalimidoaziridinylpyrazoles 131 and 132 [57].
Scheme 39. Transformation of (E)-3- and 5-styrylpyrazoles 128 and 129 into phthalimidoaziridinylpyrazoles 131 and 132 [57].
Molecules 25 05886 sch039
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Gomes, P.M.O.; Ouro, P.M.S.; Silva, A.M.S.; Silva, V.L.M. Styrylpyrazoles: Properties, Synthesis and Transformations. Molecules 2020, 25, 5886. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25245886

AMA Style

Gomes PMO, Ouro PMS, Silva AMS, Silva VLM. Styrylpyrazoles: Properties, Synthesis and Transformations. Molecules. 2020; 25(24):5886. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25245886

Chicago/Turabian Style

Gomes, Pedro M. O., Pedro M. S. Ouro, Artur M. S. Silva, and Vera L. M. Silva. 2020. "Styrylpyrazoles: Properties, Synthesis and Transformations" Molecules 25, no. 24: 5886. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25245886

Article Metrics

Back to TopTop