Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• compounds that generally enhance the bioactivity of agrochemical and pharmaceutical substrates. On the other hand, 5-aminopyrazole [11][12] is a nitrogen heterocycle that has attracted significant interest to pharmaceutical and medicinal chemists due to the presence of this nitrogen heterocycle in various

• , the reaction yielded compound 7 as the final product. Once the starting materials were synthesized, we focused our attention on the optimization of the reaction conditions. We chose the reaction between 4-cyclohexenyl-5-aminopyrazole (3aa) and methyl trifluoropyruvate (4a) for the optimization studies

• . Next, we evaluated the 5-aminopyrazole 3da prepared from tetrahydro-4H-pyran-4-one, and interestingly the corresponding trifluoromethyl carbinol 5daa was afforded, under both reaction conditions, in good yields (66% and 59% yield, respectively) but with a very low diastereoisomeric ratio (near to 1:1

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• catalyst was tested only with 5-aminopyrazole 4, and no comparison with a “classic” GBB reaction can be made, the authors compared HEDP with other catalysts on the same substrates, demonstrating that HEDP in MeOH/water was superior for yields, mildness, and less hazardous conditions (Scheme 3). Longo et al

New one-pot synthesis of 4-arylpyrazolo[3,4-b]pyridin-6-ones based on 5-aminopyrazoles and azlactones

• Vladislav Yu. Shuvalov,
• Ekaterina Yu. Vlasova,
• Tatyana Yu. Zheleznova and
• Alexander S. Fisyuk

Beilstein J. Org. Chem. 2023, 19, 1155–1160, doi:10.3762/bjoc.19.83

• when irradiated with UV light. Keywords: 5-aminopyrazole; azlactone; elimination; fluorescence; one-pot synthesis; pyrazolo[3,4-b]pyridin-6-one; Introduction The pyrazolo[3,4-b]pyridine scaffold is present in many biologically active compounds [1][2][3][4][5][6][7][8][9][10][11][12]. Among them, 4

• ]pyridones 3 obtained by this method vary widely [31][32][33]. Solvent-free reactions are convenient from both economic and environmental points of view. We obtained tetrahydro-1H-pyrazolo[3,4-b]pyridinone 3a by heating 5-aminopyrazole 1 with azlactone 2a in the absence of solvent at 150 °C in 62% yield

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• rigidity in the corresponding transition state (Scheme 23) [53]. In 2023, a chiral phosphoric acid ent-P17-mediated aza-Friedel–Crafts alkylation was reported between 5-aminopyrazole 92 as the π-nucleophile and 3H-indol-3-ones 69 as electrophilic reagents. The presence of an amino group in pyrazole 92 is

• . Atroposelective aza-Friedel–Crafts reaction. Coupling of 5-aminopyrazole and 3H-indol-3-ones. Pyrophosphoric acid-catalyzed aza-Friedel–Crafts reaction on phenols. Squaramide-assisted aza-Friedel–Crafts reaction. Thiourea-catalyzed aza-Friedel–Crafts reaction. Squaramide-catalyzed reaction between β-naphthols and

Ultrasonic-assisted unusual four-component synthesis of 7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines

• Yana I. Sakhno,
• Maryna V. Murlykina,
• Oleksandr I. Zbruyev,
• Anton V. Kozyryev,
• Svetlana V. Shishkina,
• Dmytro Sysoiev,
• Vladimir I. Musatov,
• Sergey M. Desenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2020, 16, 281–289, doi:10.3762/bjoc.16.27

• heterocycles of the types V–X (Scheme 2). It should be noted that such a type of MCR, giving previously undescribed 7-azolylamino-substituted tetrahydroazolopyrimidines, is reported for the first time herein. Thus, using 2 equivalents of 5-aminopyrazole-4-carbonitrile 1a/b in MCRs with aromatic aldehydes 2a–c

• a reactant in the reaction with 3-substituted-5-aminopyrazole-4-carbonitriles (R = H, CH3) 1a/b and aromatic aldehydes 2a–f (ultrasonication in acetic acid at room temperature for 120 min). In this case, the corresponding ethyl 3-cyano-7-((4-cyano-3-substituted-1H-pyrazol-5-yl)amino)-2-substituted-5

• 35%). The same carboxylic acid 7 was obtained by counter synthesis through a three-component reaction involving 5-aminopyrazole-4-carbonitrile (1a), 4-methoxybenzaldehyde (2b), and pyruvic acid (3a) under heating at reflux in acetic acid for 240 min (yield 28%) or through two-component

Molecular iodine-catalyzed one-pot multicomponent synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles

• Camila S. Pires,
• Daniela H. de Oliveira,
• Maria R. B. Pontel,
• Jean C. Kazmierczak,
• Roberta Cargnelutti,
• Diego Alves,
• Raquel G. Jacob and
• Ricardo F. Schumacher

Beilstein J. Org. Chem. 2018, 14, 2789–2798, doi:10.3762/bjoc.14.256

• non-separable mixture with the non-selenylated 5-aminopyrazole (Table 2, entry 6). Next we evaluated the reactivity of different functionalized arylhydrazines 2a–f using benzoylacetonitrile 1a and diphenyl diselenide 3a as standard reagents (Table 2, entries 7–11). Substituted arylhydrazines were

An unusual thionyl chloride-promoted C−C bond formation to obtain 4,4'-bipyrazolones

• Gernot A. Eller,
• Gytė Vilkauskaitė,
• Algirdas Šačkus,
• Vytas Martynaitis,
• Ashenafi Damtew Mamuye,
• Vittorio Pace and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2018, 14, 1287–1292, doi:10.3762/bjoc.14.110

• in a convenient access to 1-substituted or 1,3-disubstituted 5-chloropyrazole-4-carboxylates required as valuable precursors for further functionalizations. Such compounds have been mainly prepared from the corresponding 5-aminopyrazole-4-carboxylates via (non-aqueous) diazotation and subsequent

Synthesis of pyrazolopyrimidinones using a “one-pot” approach under microwave irradiation

• Mark Kelada,
• John M. D. Walsh,
• Robert W. Devine,
• Patrick McArdle and
• John C. Stephens

Beilstein J. Org. Chem. 2018, 14, 1222–1228, doi:10.3762/bjoc.14.104

• and reacted it with hydrazine, employing a constant temperature of 150 °C and a reaction time of 5 min. Results from the solvent screen can be found in Table 1, with high isolated yields of the product 5-aminopyrazole 2a in all cases. As expected, a significant improvement in reaction time was

• conventional heating. When a mixture of previously isolated 5-aminopyrazole 2a, β-ketoester, and acetic acid were heated under conventional refluxing conditions for 18 h, the product pyrazolo[1,5-a]pyrimidinone 3a could only be isolated in a 25% yield. As expected, heating the reaction mixture for 2 h at

• at reflux for 2 h. Solvent screen for the synthesis of 5-aminopyrazole 2a.a Temperature and time variations for the synthesis of 5-aminopyrazole 2a.a Supporting Information CCDC-1588686 contains the crystallographic data for 3m. The data can be obtained from The Cambridge Crystallographic Data

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• Ranjana Aggarwal Suresh Kumar Department of Chemistry, Kurukshetra University, Kurukshetra-136119, Haryana, India 10.3762/bjoc.14.15 Abstract The condensation of 5-aminopyrazole with various bielectrophilic moieties results in the formation of pyrazoloazines, an interesting array of fused

• substituted pyrazoloazines by a broad range of organic reactions by means of 5-aminopyrazole as a precursor. Keywords: 5-aminopyrazoles; fused pyrazole derivatives; pyrazolopyridines; pyrazolopyrimidines; pyrazolotriazines; Review Pyrazole and its derivatives are known to exhibit significant biological and

• ]pyridines and their applications brings great interest in this area. The most commonly applied method for the preparation of pyrazolo[3,4-b]pyridines uses 5-aminopyrazole as synthetic precursor [36][37][38][39]. Regardless to substantial studies in this field, researchers are still focused to provide

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• -oriented ester group. The only products obtained are 1,2-dihydropyrazole-3-carboxylates 62 in good yield. Interestingly, reactions with arylhydrazines afforded, in the presence of ammonium or sodium acetate, 5-aminopyrazole-3,4-dicarboxylates 63 [64] (Scheme 20). Apparently, in these cases, the

• dicyanofumarates E-1 with 1-azabicyclo[1.1.0]butanes 55. Formation of pyrazole derivatives in the reaction of hydrazines with E-1. Formation of 5-aminopyrazole-3,4-dicarboxylate 65 via heterocyclization reactions. Reactions of aryl- and hetarylcarbohydrazides 67 with E-1a. Multistep reaction leading to

New tricks of well-known aminoazoles in isocyanide-based multicomponent reactions and antibacterial activity of the compounds synthesized

• Maryna V. Murlykina,
• Maryna N. Kornet,
• Sergey M. Desenko,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Aleksander A. Brazhko,
• Vladimir I. Musatov,
• Erik V. Van der Eycken and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2017, 13, 1050–1063, doi:10.3762/bjoc.13.104

• with 2-amino-1,3,4-thiadiazoles [71][83][84][89][90], 2-aminoimidazoles [71][72][91][92], 2-aminoxazoles [71] and 1,2,5-oxadiazole-3,4-diamine [93] with the formation of imidazoazoles. Among the pyrazoles only 5-amino-3-methylpyrazole, 5-aminopyrazole-4-carbonitrile and ethyl 5-aminopyrazole-4

A convenient four-component one-pot strategy toward the synthesis of pyrazolo[3,4-d]pyrimidines

• Mingxing Liu,
• Jiarong Li,
• Hongxin Chai,
• Kai Zhang,
• Deli Yang,
• Qi Zhang and
• Daxin Shi

Beilstein J. Org. Chem. 2015, 11, 2125–2131, doi:10.3762/bjoc.11.229

• ]. For example, ibrutinib, sildenafil, allopurinol and zaleplon are famous pyrazolopyrimidine drugs. Because of the importance of pyrazolo[3,4-d]pyrimidines, many methods for the synthesis of pyrazolo[3,4-d]pyrimidines have been explored. Some examples include the condensation of 5-aminopyrazole-4

• -carbonitrile with amides [18][19][20][21], carboxylic acids [22][23][24], amidines [25][26], nitriles [27][28], ketones [29][30] and halohydrocarbon [31], the cyclization of 5-aminopyrazole-4-carboxamides with amides [32], ureas [33][34][35][36], esters [37][38][39] and acyl chloride [40], and the reaction of

• aminopyrazoles and amides [41][42]. In our previous studies, dihydropyrimidinone was synthesized through the condensation of 5-aminopyrazole-4-carbonitrile and ketones [29][30]. 5-Aminopyrazole-4-carbonitrile was prepared from the reaction of ethoxymethylenemalononitrile with phenylhydrazine in a step-wise

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach

• András Demjén,
• Márió Gyuris,
• János Wölfling,
• László G. Puskás and
• Iván Kanizsai

Beilstein J. Org. Chem. 2014, 10, 2338–2344, doi:10.3762/bjoc.10.243

• Abstract 5-Aminopyrazole-4-carbonitrile and ethyl 5-aminopyrazole-4-carboxylate, as potential trifunctional building blocks are introduced in a facile, chemo- and regioselective multicomponent assembly of imidazo[1,2-b]pyrazoles via the Groebke–Blackburn–Bienaymé reaction (GBB reaction). Besides the

• -aminopyrazole-4-carbonitrile (1a), p-tolualdehyde (2a) and tert-butyl isocyanide (3a) in order to elucidate the structure of the product and investigate the regioselectivity. The synthesis of 5-aminopyrazole-4-carbonitrile (1a) was based on a literature method [43][44]. A single product was observed in a yield

• and mode of isolation (Table 1, entries 7–15). The one-pot 3CR of 5-aminopyrazole-4-carbonitrile (1a), p-tolualdehyde (2a) and tert-butyl isocyanide (3a) catalysed by TFA (20 mol %) in water/EtOH 1:1 furnished 6 isolated by simple filtration in a yield of 79% during 15 min. These results led us to

Regioselectivity in the multicomponent reaction of 5-aminopyrazoles, cyclic 1,3-diketones and dimethylformamide dimethylacetal under controlled microwave heating

• Kamal Usef Sadek,
• Ramadan Ahmed Mekheimer,
• Tahany Mahmoud Mohamed,
• Moustafa Sherief Moustafa and
• Mohamed Hilmy Elnagdi

Beilstein J. Org. Chem. 2012, 8, 18–24, doi:10.3762/bjoc.8.3

• 50918, Jeddah 21533, Kingdom of Saudi Arabia Chemistry Department, Faculty of Science, Kuwait University, PO Box 5969, Safat, 13060 Kuwait 10.3762/bjoc.8.3 Abstract The multicomponent reaction of 5-aminopyrazole derivatives with cyclic 1,3-dicarbonyl compounds and dimethylformamide dimethylacetal

• reacting enaminone 7 with 5-aminopyrazole derivative 1f in DMF under microwave heating at 150 °C for 2 min (Table 1). When this compound was refluxed in DMF under microwave heating for 13 min it underwent cyclization to give 6g (Scheme 1). Moreover, the structure of compounds 6b–g was unequivocally

• subsequently reacted with 5-aminopyrazole 1 at the exocyclic amino function, followed by cyclization through water loss to give 6 (route A). Formation of isomeric product 4, which would be formed by route B, was ruled out based on spectral and X-ray diffraction data. From the data of the X-ray crystal

Approaches towards the synthesis of 5-aminopyrazoles

• Ranjana Aggarwal,
• Vinod Kumar,
• Rajiv Kumar and
• Shiv P. Singh

Beilstein J. Org. Chem. 2011, 7, 179–197, doi:10.3762/bjoc.7.25

• involve the reactions of β-ketonitriles, malononitrile, alkylidenemalononitriles and their derivatives with hydrazines, as well as some novel miscellaneous methods. Keywords: alkylidenemalononitriles; 5-aminopyrazoles; hydrazines; β-ketonitriles; malononitriles; Review The 5-aminopyrazole system

• trifluoromethylhydrazones appears at δ −64 to −66 ppm for Z-isomers and at δ −67 to −71 ppm for E-isomers. As expected, 5 underwent cyclization in refluxing ethanol to give the corresponding 5-aminopyrazole 6 [32]. α-Acetyl/formylbenzyl cyanide (R = H/CH3) 4 on reaction with heteroarylhydrazines in refluxing ethanol

• -aminopyrazoles 28. This new 5-aminopyrazole synthesis is more versatile and efficient than its predecessor as it avoids the use of troublesome β-ketonitrile functionality. This new route is also ideally suited for the synthesis of combinatorial libraries for drug target screening. In 2009, an efficient three