Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

One-pot activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion

• Christina Görgen,
• Katharina Boden,
• Guido J. Reiss,
• Walter Frank and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 1360–1370, doi:10.3762/bjoc.15.136

• , starting from phenylglyoxylic acid (1a), phenylacetylene (2a), and Boc-hydrazide (4a) through the formation of 1,4-diphenylbut-3-yne-1,2-dione (3a), with subsequent N-deacylation as the consequence of basic work-up (Scheme 2), furnished 5-benzoyl-3-phenyl-1H-pyrazole (6a) in 41% isolated yield. In addition

• to spectroscopic assignment the structure of 6a has now been corroborated by an X-ray structure analysis showing infinite chains of molecules 6a formed by intermolecular hydrogen bonding between the pyrazole N1 and the carbonyl O1 (Figure 3) [53]. The first assumption was that the tentative

• additionally corroborated by X-ray structure analysis showing that the assignment of intermediate 5a was not a fully unsaturated pyrazole (Figure 4) [53]. Therefore, we set out to optimize the one-pot synthesis of 1,5-diacyl-5-hydroxypyrazolines by choosing the model reaction of phenylglyoxylic acid (1a

Synthesis of 2H-furo[2,3-c]pyrazole ring systems through silver(I) ion-mediated ring-closure reaction

• Vaida Milišiūnaitė,
• Rūta Paulavičiūtė,
• Eglė Arbačiauskienė,
• Vytas Martynaitis,
• Wolfgang Holzer and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2019, 15, 679–684, doi:10.3762/bjoc.15.62

• g. 59, Kaunas LT-51423, Lithuania Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, Vienna 1090, Austria 10.3762/bjoc.15.62 Abstract Fused pyrazole ring systems are common structural motifs of numerous pharmaceutically important compounds. Nevertheless, access to

• derivatives of the aromatic 2H-furo[2,3-c]pyrazole ring system is still quite limited, and their chemistry and functional properties remain largely underexplored. The current study investigates routes to construct this system from easily accessible starting materials using metal-catalyzed reactions. A simple

• and efficient procedure to access the 2H-furo[2,3-c]pyrazole ring system was developed by employing the silver(I) ion-mediated ring-closure reaction of 4-alkynyl-3-hydroxy-1-phenyl-1H-pyrazoles as a key step. The required intermediate hydroxyalkynyl substrates for this reaction were prepared by a Pd

Mn-mediated sequential three-component domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction towards annulated imidazo[1,2-a]pyridines

• Olga A. Storozhenko,
• Alexey A. Festa,
• Delphine R. Bella Ndoutoume,
• Alexander V. Aksenov,
• Alexey V. Varlamov and
• Leonid G. Voskressensky

Beilstein J. Org. Chem. 2018, 14, 3078–3087, doi:10.3762/bjoc.14.287

• oxidative conditions has been developed. The employment of Mn(OAc)3·2H2O or KMnO4 as stoichiometric oxidants allowed the use of a wide range of nucleophiles, such as nitromethane, (aza)indoles, pyrroles, phenols, pyrazole, indazole and diethyl malonate. The formation of the target compounds presumably

• only one isomer, but the yields of the corresponding products 11c and 11d were low. Employed as N-nucleophiles, pyrazole and benzopyrazole successfully formed products 12 and 13, correspondingly, with moderate yields. The possibility to employ CH-acids as nucleophiles was finally demonstrated on

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

• -(phenylselanyl)-1H-pyrazol-5-amine was submitted to an oxidative dehydrogenative coupling to produce a diazo compound confirmed by X-ray analysis. Keywords: diaryl diselenide; diazo compound; 1H-pyrazole; molecular iodine; multicomponent reaction; Introduction Selenium-containing compounds are of great

• the 3-methyl-5-methylsulfanyl-4-phenylselanyl-1H-pyrazole [10]. Our research group described the multicomponent synthesis of 3,5-dimethyl-4-arylselanyl-1H-pyrazoles catalyzed by copper iodide using DMSO as solvent [4]. More recently, Zora and co-workers reported the one-pot preparation of 4

• -phenylselanyl-1H-pyrazoles through reaction of α,β-alkynic hydrazones with phenylselenyl chloride [11]. In this context, pyrazoles are one of the most important N-heterocycles found in natural products including formycin, pyrazofurin and withasomnine, for example. Still, pyrazole unities are present in several

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

• Gergő Mótyán,
• László Mérai,
• Márton Attila Kiss,
• Zsuzsanna Schelz,
• Izabella Sinka,
• István Zupkó and
• Éva Frank

Beilstein J. Org. Chem. 2018, 14, 2589–2596, doi:10.3762/bjoc.14.236

• action of these derivatives. Amongst steroidal 17-exo-heterocycles, those containing a pyrazole heteroaromatic ring are of special relevance with respect to the above-mentioned bioactivities [6][7][8][9]. Interestingly, so far only a few examples of compounds in which a pyrazolone moiety is attached to

• eight tautomeric forms [28], their N(1')-substituted derivatives, lacking a functionality on pyrazole C-4, can only exist in three equilibrating tautomers (OH, CH and NH) [18][29]. Therefore, further heterocyclizations of 4 were performed with monosubstituted hydrazine derivatives. The reaction with

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• developed a hydroarylation of alkynes with different arenes including phenylpyridines, pyrazole, and 6-arylpurines 17 using 5 mol % Cp*Co(CO)I2, 10 mol % AgSbF6, and 0.5 equiv PivOH in DCE (Scheme 13) [57]. The reaction proceeded efficiently with various alkynes to give alkenes 18, however, the reaction was

• *(C6H6)][B(C6F5)4]2 and LiOAc gave alcohol products 62 with high diastereoselectivity at ambient reaction conditions. The unique nature of cobalt was well presented by its superior reactivity and diastereoselectivity and it outmatched the rhodium catalyst. Different pyrazole derivatives with a wide range

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• carbamates, urea and non-basic heterocycles (Scheme 11) [54]. The scope covers a multitude of electron-poor and electron-rich arenes which can be reacted with carbamates, urea, pyrazole and triazole derivatives to furnish aminated products. The authors address the various reactivities observed with respect

Chiral bisoxazoline ligands designed to stabilize bimetallic complexes

• Deepankar Das,
• Rudrajit Mal,
• Nisha Mittal,
• Zhengbo Zhu,
• Thomas J. Emge and
• Daniel Seidel

Beilstein J. Org. Chem. 2018, 14, 2002–2011, doi:10.3762/bjoc.14.175

• , Florida 32611, USA 10.3762/bjoc.14.175 Abstract Chiral bisoxazoline ligands containing naphthyridine, pyridazine, pyrazole, and phenol bridging units were prepared and shown to form bimetallic complexes with various metal salts. X-ray crystal structures of bis-nickel naphthyridine-bridged, bis-zinc

• pyridazine-bridged, and bis-nickel as well as bis-palladium pyrazole-bridged complexes were obtained. Keywords: bimetallic complexes; bisoxazolines; chiral ligands; heterocycles; Introduction Metal-centered asymmetric catalysis most commonly relies on monometallic complexes of various chiral ligands, among

• available. This led to the selection of naphthyridine, pyridazine, pyrazole, and phenol building blocks. We opted to connect these linkers to oxazolines via amide bonds. The reasoning for this was twofold. Firstly, this should provide ligands with significantly improved stabilities over for instance imine

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• dissolved in a THF and hydrazine was dissolved in a mixture of solvents such as methanol, acetone, and water. The nitrile was pumped using pump P1 and hydrazine was pumped through P2 into the tubular reactor TR1 maintained at a temperature of 130 °C at residence time of 60 minutes to obtain the pyrazole

• . The impurities of the pyrazole were removed by passing it to the continuous countercurrent extraction E1. Here a solvent exchange process takes place between toluene and water. The pyrazole was then concentrated using automated rotary evaporator RE1. The concentrated product was diluted with DMSO

• using pump P13. Aromatic nucleophilic substitution: The nucleophilic substitution reaction takes place between the pyrazole and N-ethylmorpholine. Pyrazole of step 1 in the extractor was pumped through P13 and N-ethylmorpholine through P3 into the reactor TR2 to form the arylated product of the pyrazole

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• of aryl iodide. The latter is then used for a sequential ruthenium-catalyzed ortho-C–H functionalization directed by the pyrazole group (Scheme 37) [76]. Starting from non-symmetrical diaryl-λ3-iodanes, the electron-poorest or more sterically hindered aromatic group is first transferred to the 3,5

• -dimethylpyrazole. The reaction has been extended to 1,2,3-triazoles, benzotriazole, and pyrazole. In the latter case, the use of (styryl)(aryl)-λ3-iodanes has also proved to be possible, with the styryl moiety being selectively transferred in the first step. The following step of C–H activation then gives access

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• = COOEt); di-tert-butyl, R3 = COOt-Bu etc.) act as the most common dipolarophiles because of their high reactivity. Moreover, one or both carboxylate groups in position 3 and 4 in the final pyrazole are easily removable using a hydrolysis/decarboxylation protocol [5][16] thus giving pyrazole-4-carboxylic

• acids – potent xanthine oxidoreductase inhibitors [40] or even 3,4-unsubstituted pyrazoles [16]. Both pyrazole carboxylic groups can be also modified to hydrazides and oxazole rings [26] or a new condensed pyridazine ring [27]. Less reactive dipolarophiles such as dibenzoylacetylenes (1,4-diphenylbut-2

• (Scheme 3). It was also observed, that formation of isomeric pyrazole-4,5-dicarboxylates (B) can sometimes accompany the production of pyrazole-3,4-dicarboxylates (A) under thermal conditions [33] although their formation is not photoinduced (cf. next chapter) because the reaction also takes place in the

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

• , therein several drug molecules, agrochemicals, dyestuffs, compounds for optoelectronic purposes, complexing ligands and more contain a pyrazole nucleus [1][2][3][4][5][6][7][8]. Condensed pyrazoles are of special interest, as a commonly used example the phosphodiesterase 5 (PDE5) inhibitor sildenafil

• (Viagra®) can be mentioned [1]. In a series of former publications we described the synthesis of condensed pyrazole systems using various 4,5-disubstituted pyrazole derivatives as precursors for the annellation reaction [9][10][11][12][13][14][15][16]. Amongst these precursors 5-chloropyrazoles carrying C

• -substituents at the pyrazole C4 position, like 5-chloropyrazole-4-carbaldehydes or 4-esters, turned out to be particularly useful due to the easy conversion of the chloro substituent into other functional groups or its nature as a good leaving group in ring-closure reactions. In this respect we were interested

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• structure–activity relationship. It has been observed that the number and position of pyrrole rings are crucial for antileukemic activity. The presence of pyrrole rings close to the alkylating BAM moiety is responsible for better cytotoxic activity both in vitro and in vivo, whereas a pyrazole ring in close

Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

• Robby Vroemans,
• Fante Bamba,
• Jonas Winters,
• Joice Thomas,
• Jeroen Jacobs,
• Luc Van Meervelt,
• Jubi John and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 626–633, doi:10.3762/bjoc.14.49

• inseparable mixture of diastereomers. Various attempts were made with other azidobenzaldehydes (5-azido-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 2-azidoquinoline-3-carbaldehyde and 2-azido-5-nitrobenzaldehyde) and isocyanides (2-morpholinoethyl isocyanide) towards the synthesis of diketopiperazine-fused

• -methyl-1-phenyl-1H-pyrazole-4-carbaldehyde). The success in the synthesis of diketopiperazine-fused triazolobenzodiazepine prompted us to examine the possibility of making the sequential synthetic route in ‘one-pot’ starting from the Ugi 4-CR (Scheme 4). Thus we initiated the reaction sequence from the

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

• 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

• pyrazole is one of the most widely studied nitrogen-containing heterocyclic nuclei. Fused pyrazole derivatives are composed of the pyrazole nucleus attached to other heterocyclic moieties which enable them to exhibit improved pharmacological activities compared to the isolated fragments. These compounds

• are currently used in several marketed drugs like cartazolate (1), zaleplon (2), sildenafil (3), allopurinol (4), indiplon (5), etazolate (6) etc. (Figure 1). Fused pyrazole derivatives, especially pyrazoloazines have been reported to mimic purine bases, present in DNA and RNA, due to close structural

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• (Scheme 11) [30]. Amino- and azotrifluoromethylation of alkenes: Alkene trifluoromethylation was applied to the construction of indole, pyrazole and pyridazinone moieties via a multicomponent cascade reaction developed by Antonchick and Matcha in 2014 [31]. The method was based on the reaction between

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• efficient and regioselective synthesis of pyrazolo[1,5-a]pyrimidines and aryl[heteroaryl]pyrazolo[1,5-a]pyrimidines in acetic acid under reflux. The regioselectivity was attributed to the high nucleophilicity of the amino group in 3-amino-5-methyl-1H-pyrazole and the high electrophilicity of the β-carbon

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

• this series the experimental results were confirmed by computational methods. In the reaction of diazomethane with E-1b in THF at room temperature 4,5-dihydro-3H-pyrazole 35 was detected as the initial [3 + 2]-cycloadduct by 1H NMR spectroscopy [29] (Scheme 11). Fast tautomerization led to the

• corresponding 1H-pyrazole 36. The cycloaddition occurred with preservation of the configuration of the dipolarophile. In the presence of excess diazomethane the five-membered cycloadducts 35 and 36 were converted into a complex mixture of products. In a very recent study, we demonstrated that the reactions of

• . Stepwise [3 + 2]-cycloadditions of dimethyl dicyanofumarate (E-1b) and dimethyl dicyanomaleate (Z-1b) with the in situ generated azomethine ylides 32. [3 + 2]-Cycloaddition of diazomethane with dimethyl dicyanofumarate (E-1b) leading to 1H-pyrazole derivative 36. Reversible Diels–Alder reaction of fulvenes

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

• , Zhukovsky str., 66, 69600, Zaporizhzhya, Ukraine Faculty of Chemistry, V. N. Karazin Kharkiv National University, Svobody sq., 4, 61077, Kharkiv, Ukraine 10.3762/bjoc.13.104 Abstract The well-known aminoazoles, 3-amino-5-methylisoxazole and 5-amino-N-aryl-1H-pyrazole-4-carboxamides, were studied as an

• -aryl-1H-pyrazole-4-carboxamides; antibacterial activity; Groebke–Blackburn–Bienaymé reaction; isocyanide Ugi reaction; Introduction An intensive progress in pharmaceutical and medicinal chemistry, as well as in the generation and improvement of medicinal technologies has led to defeating a wide scope

• (anxiolytic) [27]. The activity of different imidazoheterocycles was also studied against migraine [30], gastric [31][32], heart [34][35][36], viral diseases [37][38][39][40][41] and an array of neurological syndromes [52]. The imidazo[1,2-b]pyrazole core shows also a pharmacological potential. Among others

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

Synthesis of tetrasubstituted pyrazoles containing pyridinyl substituents

• Josef Jansa,
• Ramona Schmidt,
• Ashenafi Damtew Mamuye,
• Laura Castoldi,
• Alexander Roller,
• Vittorio Pace and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2017, 13, 895–902, doi:10.3762/bjoc.13.90

• corresponding 1,3,5-trisubstituted pyrazoles. Iodination at the 4-position of the pyrazole nucleus by treatment with I2/HIO3 gives the appropriate 4-iodopyrazoles which served as starting materials for different cross-coupling reactions. Finally, Negishi cross-coupling employing organozinc halides and Pd

• condensation product was confirmed by crystal structure analysis. Keywords: Negishi coupling; NMR (1H; 13C; 15N); pyrazole; pyridine; X-ray structure analysis; Introduction The pyrazole nucleus is a frequently occurring motif in many pharmaceuticals [1][2] and biologically active compounds [3][4

• out to be superior to the reaction of compounds 2 with N-iodosuccinimide. Species 3a–d served as educts for the investigations concerning further functionalization at pyrazole C-4. Carboxylation of 4-iodopyrazoles 3a–d The lithium–iodine exchange proceeded quickly and quantitatively in case of 3,5-di

Derivatives of the triaminoguanidinium ion, 5. Acylation of triaminoguanidines leading to symmetrical tris(acylamino)guanidines and mesoionic 1,2,4-triazolium-3-aminides

• Jan Szabo,
• Julian Greiner and
• Gerhard Maas

Beilstein J. Org. Chem. 2017, 13, 579–588, doi:10.3762/bjoc.13.57

• , triaminoguanidinium salts or the neutral triaminoguanidine have been reacted with carbonyl compounds. Reactions with aldehydes [3][4][5][6][7] or ketones [8][9][10] yielded the corresponding tris(iminyl)guanidines; cyclocondensation of pentane-2,4-dione at one hydrazinyl branch of TAG-Cl afforded a pyrazole which

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• , pyrazole, and the Biginelli adduct as target ring systems with a view to discover new and greener strategies for their construction using multicomponent reactions. The application of the method is also extended to various heterocycles found in many natural products and pharmaceuticals. Keywords: atom

• pyrazole ring and compare them to what has been done in the literature. Finally, we apply all possible 3-partitions to the 6-membered Biginelli adduct to identify new assemblages for this structure that have potentially high probabilities of intrinsic greenness that exceed the material performance of the

• nucleophilic centre before bonding can take place. Such additional corrective operations reduce the overall material efficiencies of syntheses of odd-membered rings compared to even-membered rings. This point will be made more evident when we examine literature multicomponent syntheses of pyrazole, a five

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides

• Ilya V. Efimov,
• Marsel Z. Shafikov,
• Nikolai A. Beliaev,
• Natalia N. Volkova,
• Tetyana V. Beryozkina,
• Wim Dehaen,
• Zhijin Fan,
• Viktoria V. Grishko,
• Gert Lubec,
• Pavel A. Slepukhin and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2016, 12, 2390–2401, doi:10.3762/bjoc.12.233

• in the literature in comparison with monocyclic and fused derivatives [1][6]. Recently isoxazoles conjugated to pyrazole A [12], imidazole B [13] and tetrazole C [4] rings were found as promising candidates for anticancer and antidiabetic drugs and for the treatment of cognitive disorder (Figure 1