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Pyrazoles and thiazoles belong to 5-membered aromatic heterocycles called azoles. In addition to a nitrogen, pyrazoles contain an additional nitrogen in a 1,2 linkage and thiazoles contain a sulfur atom in a 1,3 linkage. These compounds are useful pharmacophores that offer a broad range of therapeutic applications. Pyrazoles can be synthesized by (i) the condensation of 1,3 dipolar compounds and alkenes/alkynes, (b) cyclocondensation of hydrazines and dicarbonyl reagents, and (c) multi-component reactions. Access to thiazoles is typically via (a) the condensation of α-haloketones with nucleophilic thioamides containing the N-C-S fragment, (b) a reaction between α-aminonitriles and various reactants containing an X-C-S fragment, and (c) a reaction of acylaminocarbonyls and phosphorus pentasulfide. This chapter will focus on the strategies and our perspectives on the synthesis of pyrazoles and thiazoles including derivatives at the 1,5 positions and 2, 4, 5 positions respectively, reported during 2015–2022. Additionally, their therapeutic and biological evaluations will be discussed.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
Krembil Research Institute, University Health Network, Toronto, Canada
Melissa M. Lewis-Bakker
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
Krembil Research Institute, University Health Network, Toronto, Canada
Lakshmi P. Kotra*
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
Krembil Research Institute, University Health Network, Toronto, Canada
*Address all correspondence to: p.kotra@utoronto.ca
1. Introduction
Heterocycles are cyclic compounds containing atoms other than carbons and hydrogens and may be synthesized or occur naturally in plants, animals and human beings. In particular, nitrogen-containing heterocycles are considered very important building blocks in the chemical and pharmaceutical industries (among others) since they can be used as catalysts, protecting groups, chiral auxiliaries and chemical intermediates.
Azoles are 5-membered nitrogen-containing aromatic heterocycles, to which thiazoles and pyrazoles belong. Pyrazoles contain two nitrogens in a 1,2 linkage while thiazoles contain nitrogen and sulfur in a 1,3 linkage. Pyrazoles and thiazoles are useful pharmacophores with a potential for various therapeutic applications.
This chapter will focus on the following as it relates to pyrazoles and thiazoles reported during 2015–2022: (i) strategies and perspectives on the synthesis of 1,5-disubstituted pyrazoles and 2,4,5-trisubstituted thiazoles derivatives and (ii) their therapeutic and biological evaluations.
The pyrazole structure exists as two tautomers due to the movement of the C-N double bond (Figure 1). When both nitrogens are unsubstituted, each has a similar reactivity. However, when any carbon or nitrogen atom is substituted, the substitution(s) influences the reactivity of the other positions of the ring. This in turn may lead to several regioisomers of the substitituted pyrazole.
Figure 1.
Tautomeric structures of an unsubstituted pyrazole.
2.2 Biological applications of Pyrazoles
Pyrazoles form core structures of many pharmaceutical products They have therapeutic properties such as antibacterial, anticancer, anti-inflammatory, anti-oxidant, anti-tuberculosis and anti-depressive agents [1, 2]. Examples of drugs containing the pyrazole moiety are Fomepizole for alcohol poisoning, Sildenafil or Viagra® for erectile dysfunction and Rimonabant for obesity treatment (Figure 2) [1].
Figure 2 .
Examples of drugs containing the pyrazole moiety.
2.3 Conventional synthesis of 1, 5-Pyrazoles
Pyrazoles are conventionally formed by (i) cycloadditions between 1,3 dipolar compounds and alkenes/alkynes and (ii) cyclocondensations of hydrazines and dicarbonyls (first reported in 1883 using dicarbonyls) as shown in Figure 3 [2]. Additionally, multi-component or one-pot reactions utilizing a combination of consisting of at least three of the afore-mentioned compounds can also generate various substituted pyrazoles. Disadvantages of these methods include the use of unstable reagents such as the diazo compounds in cycloadditions and product obtained as a mixture of regioisomers when substituted starting materials are used.
Figure 3.
Conventional reactions to form pyrazoles. A) Cycloadditions B) Cyclocondensations.
2.4 Recent synthetic routes towards 1, 5-Pyrazoles
2.4.1 Ruthenium-catalyzed Cyclocondensations of Propargyl alcohols and Hydrazines
Metal catalysts have proved to be quite efficient in organic chemistry as means of carrying out various and sometimes difficult transformations. In the synthesis of pyrazoles, the bifunctional ruthenium cyclopentadienone complex (Ru Catalyst) catalyzes the reaction between secondary propargyl alcohols and nucleophiles such as hydrazine giving 1,5-disubstituted pyrazoles along with byproducts [3]. This cascade conversion likely proceeds via cycloisomerization, Michael addition, cyclocondensation and dehydrogenation/oxidation) steps [3]. The reaction proceeds via microwave irradiation in toluene and when the nucleophile is phenyl hydrazine (2), both the 1,5- and 1,3-disubstituted regioisomers (a and b) are formed along with the 3-phenylbutene byproduct c (Figure 4) [3]. The trends in the yields indicates that when the R group of the propargyl alcohol 1 is bulky or has unsaturated side chains, the reaction favors the 1,5-disubstituted pyrazoles leading to higher yield of this regioisomer.
Figure 4.
Regioisomeric pyrazoles produced by the ruthenium catalyzed cascade conversions between secondary propargyl alcohols and phenyl hydrazine [3].
From a mechanistic perspective as shown in Figure 5, Kaufmann et al [3] reported that the propargyl alcohol is activated by the Ru catalyst to form the by the chelated π-complex I, which is then converted to the alkynyl species II. A 1,2-hydrogen shift forms the alkenyl complex III which then undergoes a regioselective nucleophilic attack by phenyl hydrazine to give complex IV. Cyclocondensation of complex IV gives the alkyl complex V which subsequently undergoes a β-hydride elimination to give the 1,5-pyrazole. The active catalyst is regenerated by the elimination of hydrogen from the hydride complex VI. The 1,3- regioisomer is formed from the hydrazone of intermediate III while the byproduct is formed when the internal carbon of the alkynyl complex II undergoes a nucleophilic attack, when non-bulky propargyl alcohols are used.
Figure 5.
Proposed mechanisms for the ruthenium catalyzed cascade conversions [3].
2.4.2 Ruthenium-catalyzed Cyclocondensation of Diazonium salts and Cyclopropanols
Another Ruthenium-catalyzed reaction to synthesize pyrazoles was reported by Cardinale et al [4]. The photocatalysis of arenediazoniums (10 and 12) and arylcyclopropanols (12 and 13) using [Ru(bpy)3]2+ under blue light irradiation in acetonitrile yielded 1, 5 -disubstituted pyrazoles 14–21 (Figure 6). This photocatalysis provides several advantages such mild reaction conditions (20 mins at room temperature), compatibility with functional groups such as I, SF5, SO2NH2, N3, CN and high regioselectivity and yields.
Figure 6.
Ruthenium-catalyzed synthesis of pyrazoles under blue light. Synthetic scope of (a) diazonium salts and (B) cyclopropanols [4].
The proposed mechanism of the photocatalysis is seen in Figure 7 [4]. The reaction is proposed to be initiated when the [Ru2+]* is the oxidatively quenched by the arenediazonium salt 10 (or 12) to give [Ru3+] which oxidizes the cyclopropanol 11 (or 13) to give VII•+. The radical cation VIII•+ is formed when VII•+ undergoes a fast ring-opening and trapping with the arenediazonium salt 10 (or 12). The newly formed VIII•+ can either (i) quench the excited catalyst thereby closing the photocatalytic cycle or (ii) become involved in a radical chain process by oxidizing another molecule of 11 (or 13). As a result of the dominance of the radical chain process, the arenediazonium 10 (or 12) is used in slight excess to activate the catalyst and produce the oxidant [Ru(bpy)33+] salt. The intermediate IX then undergoes cyclization followed by loss of water to produce the pyrazole.
Figure 7.
Proposed mechanism for the ruthenium photocatalysis of pyrazoles [4].
2.4.3 Copper-catalyzed reaction of α, β-Cyanoesters and Hydrazines
In another recent report, Cu(I) catalyst, Cu(PPh3)2NO3 was used to synthesize 1,5-disubstituted pyrazoles from hydrazines 22 and α,β-unsaturated cyanoester 23 under ultrasound irradiation (Figure 8) [5]. This efficient route uses short reaction times, moderate temperatures, facile work-ups, high regioselectivity and yields [5].
Figure 8.
Synthesis of the 1,5 pyrazoles using ultrasonication and a Cu(I) catalyst [5].
From a mechanistic perspective, the authors proposed that copper coordinates easily to π-bonds and heteroatoms. This would lead to the formation of the C-N bond via an oxidative addition followed by reductive elimination, similar to that observed in Pd(0) cross coupling reactions [5].
2.4.4 Reaction of Ferrocenes and Hydrazines
Ferrocene is an organometallic compound that has excellent redox properties and may be incorporated as part of a drug’s structural moiety, leading to additional therapeutic applications. Ferrocenyl compounds have shown potential as antimalarial, anticancer, cytotoxic and DNA-cleaving agents [6]. Ferrocenyl pyrazoles have also been shown to have potential therapeutic applications as well.
Recently, ferrocenyl pyrazoles 30 and 32 were prepared from ferrocenes 29 and 31, respectively, and hydrazines in a simple two-step procedure to regioselectively give the desired 1,5-pyrazoles in good yields (Figure 9A and 9B) [7].
Figure 9.
Synthesis of ferrocenyl pyrazoles [6].
The ferrocenyl pyrazoles 30 and 32 were then evaluated in four antimicrobial assays involving two strains each of fungi (Aspergillus niger, Trichophyton rubrum) and bacteria (Staphylococcus aureus, Klebsiella pneumoniae). Standard antimicrobial agents fluconazole and neomycin were used in the fungal and bacterial studies, respectively. In these assays, the zone of inhibition (Tables 1 and 2) was measured and the corresponding minimum inhibitory concentrations (MICs) were calculated. The MIC values ranged from 85 to 95 μg/mL indicating potential as antimicrobial agents.
DNA photo-cleavage activity of the ferrocenyl pyrazoles was also evaluated using super coiled plasmid DNA by gel electrophoresis [6]. When the faster super-coiled DNA (form I) was treated with the pyrazoles, it converted to the slower-moving nicked DNA (form II), in comparison to the untreated normal DNA. These results confirmed the DNA cleavage activity of both ferrocenyl pyrazoles.
2.4.5 C5-electrophilic fluorination of Pyrazoles
The 5-fluoropyrazole core is an important structural moiety in the agrochemical and pharmaceutical industries. Synthesis of 5-fluoropyrazoles typically occurs by reaction of (i) 1,3-dicarbonyl containing CF3/CF2 (fluorinated synthon) with hydrazines followed by HF-elimination [8]; (ii) copper-catalyzed click reaction of fluorosydnones with alkynes [9]; (iii) Selectfluor and pyrazoles containing carboxylic acids followed by decarboxylation [10] and (iv) KF with pyrazoles [11, 12]. The electrophilic fluorination of pyrazoles to give 5-fluoropyrazoles was recently described using N-fluorobenzenesulfonimide (NFSI) [13]. As shown in Figure 10 1-substituted pyrazoles were subjected to C5-deprotonation by lithium base, which was then fluorinated using NFSI to yield 1-substituted-5-fluoropyrazoles [13].
Figure 10.
Synthesis of 1-substituted-5-fluoropyrazoles [13].
Thiazoles are five-membered aromatic heterocycles belonging to the azole group. While azoles are generally characterized by the presence of a nitrogen atom, the thiazole ring features the N in a 1,3-linkage with sulfur. The sulfur atom bears a lone pair of electrons which are delocalized throughout the ring, while C2 bears an acidic proton allowing for a range of reactions to occur in this position (Figure 11) [14].
Figure 11.
Resonance of unsubstituted 1,3-thiazole.
3.2 Biological applications of Thiazoles
Thiazoles are noted for their utility in medicinal chemistry as an active and often potent pharmacophore [15] and are investigated for their therapeutical potential. Thiazoles are found in biologically relevant compounds such as the natural product Thiamin or Vitamin B1 and the first effective antibiotic drug series, Penicillin (Figure 12).
Figure 12.
Biologically relevant thiazole derivatives.
Additionally, there has been a growing interest in the synthesis of thiazole-containing compounds for applications as photosensitizers, sensors, catalysts, pigments, and more [16].
Certain biological applications of thiazoles were first identified in 1887 by Hantzsch and Weber. Since this discovery, thiazoles are a notable moiety present in several modern compounds of interest for their antitubercular [17], antidiabetic [18], antimalarial [19], antibacterial [19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31], antiviral [26, 32, 33, 34], antifungal [22, 24, 25, 26, 27, 29, 30, 33, 34], antioxidant [35], anti-inflammatory [30, 35], anti-cancer [36, 37], and anti-proliferative [27, 38, 39, 40], activities.
Figure 13 represents a few examples of approved drugs that contain a thiazole ring. Epothilones are a class of anti-neoplastic agents first identified in 1995, which act by stabilizing microtubules and inducing apoptosis [41, 42]. Ritonavir was discovered in 1998 as a potent and effective HIV protease inhibitor [43] and today, is used in combination with other antiretroviral agents in the treatment of HIV infection. More recently, it has been used in combination therapy with lopinavir to treat severe Covid-19 [44, 45]. The prodrug Cefpodoxime Proxetil was identified in 1993 as a safe and effective broad-spectrum antibiotic [46, 47, 48]. The thiazole moiety is unquestionably a vital functionality in the structure of many drugs.
Figure 13.
Approved drugs bearing thiazole moieties.
3.3 Conventional synthesis of 2, 4, 5-Thiazoles
The synthesis of thiazoles has been broadly described in literature over the years. The main methods used to prepare thiazoles are the Hantzsch, Cook-Heilbron and Gabriel’s syntheses as shown in Figure 14 [16].
Figure 14.
General synthetic scheme of 2,4,5-subsituted thiazoles by a) Hantzsch’s synthesis B) Cook-Heilbron’s synthesis and C) Gabriel’s synthesis [16].
Hantzsch’s synthesis of thiazole rings was first published in 1887 by Hantzsch and Weber [49]. Hantzsch’s synthesis involves the condensation and aromatization of α-haloketones with nucleophilic thioamides containing the N-C-S fragment, where cyclization yields the thiazole moiety [16].
The Cook-Heilbron reaction involves the interaction of aminonitrile derivatives with esters or various reactants containing a X-C-S fragment (such as dithioacids, carbon disulfide) under mild conditions to yield aminothiazoles [16, 50, 51, 52, 53]. This synthesis generally introduces different moieties to the 2-position of 4- or 5-aminothiazoles.
Gabriel’s synthesis was introduced in 1910 and describes the reaction between acylaminocarbonyls and phosphoruspentasulfide (such as Lawesson’s reagent) to yield a thiazole ring with phenyl and alkyl substitutions in the 2- and 5-positions [16, 54].
3.4 Recent synthetic routes towards 2,4,5-substituted thiazoles
3.4.1 Hantzsch’s synthesis from Thioamide andα-Halocarbonyls
Figure 15 describes the synthesis of MSI-1 (3-(5-isopropyl-4-(4-methylpyridin-3-yl) thiazol-2-yl) benzamide), a natural product monomer which acts as a SREBP-1 inhibitor in the treatment for lung squamous cell carcinoma (LUSC). It also enhances the sensitivity of these cancer cells to antitumor agents. Compound 40 was brominated to obtain 41 and in a parallel reaction, the thioamide derivative 43 was generated from 42. Subsequently, MSI-1 was obtained from the cyclocondensation reaction between α -halocarbonyl 41 and thioamide derivative 43 [55].
Figure 15.
Hantszch’s reaction between α-halocarbonyl 41 and thioamide 43 [55].
The reaction mechanism may proceed as shown in Figure 16 as described by Hantzsch A and Weber [49], where bromine of 45 acts as a leaving group of allowing the coupling of sulfur of 46 to the α-position of the carbonyl. Following a series of several proton transfers, cyclization occurs via the nucleophilic attack of nitrogen to the electron-deficient carbonyl carbon and the desired product 47 is obtained after elimination of water [55].
Figure 16.
Plausible mechanism of Hantzsch’s reaction [49].
Molecular docking studies show that MSI-1 enters the hydrophobic pocket of SREBP-1, binding through π-π conjugation. The complex is stabilized by further π-π interactions with three amino acid residues PHE271, TYR335, and PHE349. MSI-1 was shown to impedes the activation of SREBP-1 by inhibiting downstream genes of SREBP-1 associated to lipid metabolism in a dose dependent manner. Additionally, MSI-1 inhibits the Warburg Effect of cancerous and malignant cells and the Epithelial-Mesenchymal Transition process (indicative of chemo-resistance) in LUSC cell line NCI-H226. This effect was demonstrated by a decrease in glucose uptake and lactate production, as well as a reduction in ATP production and LDH activation [55].
3.4.2 Hantzsch’s synthesis from Thiourea andα-Halocarbonyls
Wang et al recently reported the synthesis of thiazole-naphthalene hybrids and their antiproliferative activities as tubulin polymerization inhibitors from thiourea and α-halocarbonyls (Figure 17) [56]. The condensation of 1-methoxynaphtalene 48 with phenylacetic acid 49 in presence of trifluoroacetic anhydride (TFAA) in trifluoroacetic acid (TFA) yielded deoxybenzoin 50. Compound 50 was then treated with pyridinium tribromide (PyBr3) in CH2Cl2 to brominate the α-position of the carbonyl. Finally, under reflux in ethanol, the cyclocondensation reaction of 51 and thiourea 52 produced desired compound 53. Three thiazole-naphthalene derivatives were prepared with this protocol. Moreover, fourteen compounds were generated by introducing substitutions to the amine in the presence of acid anhydride [56].
Figure 17.
Hantszch reaction between α-halocarbonyl 51 and thiourea 52 [56].
Compound 53 showed potent antiproliferative activity on the human breast cancer (MCF-7) and human lung adenocarcinoma (A549) cell lines when compared to standard treatments (cisplatin, 5-fluorouracil, tamoxifen, and CA-4). They determined that the 4-ethoxyphenyl substitution was more favorable than 4-methoxyphenyl. Additionally, replacement with 2-bromo-3,4,5-trimethoxyphenyl reduced the antiproliferative activity [56]. Compound 53 exhibited low toxicity in human normal cell line (IC50 = 16.37 ± 4.61 μM). Its in vitro tubulin polymerization inhibitory activity of was investigated and revealed that the compound acts as a tubulin destabilizing agent with an IC50 of 3.3 μM (compared to reference colchicine IC50 of 9.1 μM). Furthermore, it was demonstrated that compound 53 leads to cell cycle arrest at the metaphase in a dose-dependent manner, and an Annexin V-FITC/PI assay showed that it can effectively induce apoptosis in MCF-7 cells. Molecular docking studies revealed that 53 can bind with tubulin by adopting an “L-shaped” conformation. The naphthalene moiety can accommodate in the hydrophobic pocket of the protein, and it binds to the colchicine site of tubulin [56].
3.4.3 Holzapfel: Meyers: Nicolaou modification of Hantzsch’s synthesis
The Holzapfel-Meyers-Nicolaou modification is based on the Hantzsch reaction between thioamide and an α-halocarbonyl, however, it involves the generation of a hydroxythiazoline intermediate under basic conditions. This intermediate is then dehydrated in the presence of trifluoroacetic anhydride (TFAA) and pyridine, followed by the addition of triethylamine (TEA) to yield the desired thiazole [57].
Figure 18 shows a recent example of the Holzapfel-Meyers-Nicolau modification reported in the synthesis of 5-acylamino-1,3-thiazoles from α-chloroglycinates and thioamide derivatives [40]. ESI-MS monitoring revealed the presence of the hydroxy intermediate X. Dehydration of X results in the desired 5-acylaminothiazole derivative 56 in a high yield (87%). Phenylic substitutions were introduced successfully to the 2 and 4-positions using this approach [58].
Figure 18.
Holzapfel-Meyers-Nicolau reaction between α-chloroglycinate 54 and thioamide 55 [58].
3.4.4 Cook-Heilbron’s synthesis
Avadhani et al developed an efficient one-pot reaction for the preparation of 4-amino 2-aryl-5-substituted thiazoles. Figure 19 presents the reaction of cyanamide 57 with dithioester 58a or 58b with excess NaH, followed by the addition of halo-carbonyl derivative 59 to yield potent antiproliferative agents 4-amino-2-phenyl and 2-(thiophne-3-yl)- 5-(2,3,4-trimethoxybenzoyl)-thiazoles 60a and 60b in high yields (77% and 81% respectively). The Thorpe-Ziegler-type reaction proceeds via base-mediated intermolecular cyclization of N-cyanothioimidate intermediate XI [59].
Figure 19.
Cook-Heilbron’s reaction between cyanamide 57 and dithioate derivative 58 [59].
The 2-methylthio and arylamino substitutions can be introduced at the 2-position using this method, while the 5-position supports ester, nitrile, and carbonyl substituents. The latter can be utilized to introduce reactive functionalities, expanding the possible range of substitutions achieved by this protocol. The novel methodology was further validated by the synthesis of 26 4-amino-2-(het)aryl/alkyl 5-substituted thiazole derivatives [59]. It should be noted that this example introduces the amino moiety to the 4-position. The 5-aminothiazoles can be synthesized from the reaction with 2-aminoacetonitrile instead of cyanamide.
3.4.5 Lactic acid-mediated one-pot reaction
Figure 20 shows the one-pot Hantzsch synthesis of the 2-aminothiazole 63 using lactic acid as a green solvent and catalyst [60]. The ketone 61 was brominated in-situ followed by heterocyclization with thiourea 52 to produce the substituted aminothiazole 63. Lactic acid was selected as a solvent and catalyst due to its ability to solubilize all the reactants, its increased product yield and shorter reaction times in comparison to acetic acid. Maximum yields of 2-aminothiazoles (up to 96%) were obtained when the temperature was increased from room temperature (45% in 1.2 h) to 90–100°C [60]. Lower yields were reported yields when strong deactivating groups were introduced (such as -NO2), likely due to the reduced in-situ formation of the α-brominated ketone. Overall, this work developed an effective, rapid, and sustainable one-pot synthesis of 2-aminothiazoles in excellent yields [60].
Figure 20.
Lactic acid-mediated one-pot synthesis of 2-aminothiazoles [60].
The catalytic activity of hybrid PVA/Al2O3 nanofilms in the synthesis of thiazole derivatives was recently reported by Riyadh et al [61]. The reaction between the thiosemicarbazone 2-benzylidenehydrazine 64 and the α-haloester ethyl-2-chloro-3-oxobutanoate 65 in the presence of the PVA/Al2O3 nanocomposite as a basic catalyst is demonstrated in Figure 21. Under thermal conditions, the optimal loading catalyst was 10 wt% and the desired compounds were obtained after 180 min [61].
Figure 21.
Polyvinyl alcohol/aluminum oxide (PVA/Al2O3) thin film nanocomposite as a catalyst in the synthesis of 2,4,5-thiazoles [61].
Figure 22 describes a plausible reaction mechanism where the Al2O3 particles act as a base in the deprotonation of the thiol group from carbothioamide tautomeric intermediate XVIII. The thiolate anion XIX then attacks α-halocarbonyl 65, displacing -Cl and generating the intermediate XX. The cyclocondensation of XX yielded the desired thiazole derivatives. The catalyst was recycled three times and recovered in excellent yields (90%) [61].
Figure 22.
Proposed mechanism of PVA/Al2O3-catalyzed reaction [61].
This chapter reviewed novel synthetic methods involving the presence of catalysts, solvent-free conditions, and green chemistry approaches reported during 2015–2022, for the preparation of pyrazoles and thiazoles. Additionally, their therapeutic and biological evaluations were discussed. These structural moieties will continue to play an important role in therapeutic and other applications, therefore further development, versatility and diversification of their syntheses will continue to be of great interest to chemists worldwide.
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Written By
Erika Lozano, Melissa M. Lewis-Bakker and Lakshmi P. Kotra
Submitted: 30 October 2022Reviewed: 07 November 2022Published: 27 November 2022
Open access peer-reviewed chapter
