Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• alkylbiguanides with yields up to 97%, despite great variability in the case of alkylbiguanides (Scheme 8A) [24]. Recently, Zhou et al. reported similar conditions applied for the synthesis of anticancer biguanides [25]. The conditions chosen for the synthesis of a small library of pyrazole‐containing biguanide

• can act as a “bisamidine transfer agent” by the addition of an amine, and subsequent elimination of the leaving group. Two types of “biguanide transfer agents” have been developed so far. Depending on the nature of the leaving group they can be separated into either pyrazole or thiomethyl agents

• -amidinopyrazole hydrochloride from cyanoguanidine, by the addition of pyrazole hydrochloride in refluxing pyridine, refluxing 3 M aqueous HCl or by a direct fusion at 140–200 °C (no yields disclosed) [66]. Later in 1992, Bernatowicz et al., in an attempt to produce guanidine derivatives of ornithine-containing

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

Synthesis of bis(aryloxy)fluoromethanes using a heterodihalocarbene strategy

• Carl Recsei and
• Yaniv Barda

Beilstein J. Org. Chem. 2021, 17, 813–818, doi:10.3762/bjoc.17.70

• . Unfortunately, several methods of halodecarboxylation [11][12][13] failed to yield the desired product 10 (X = Cl, Br), likely due to the presence, in the pyrazole, of moieties sensitive to these conditions or to the instability of the product to the reaction conditions. Pursuing the heterodihalocarbene

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

• Maryna O. Mazur,
• Oleksii S. Zhelavskyi,
• Eugene M. Zviagin,
• Svitlana V. Shishkina,
• Vladimir I. Musatov,
• Maksim A. Kolosov,
• Elena H. Shvets,
• Anna Yu. Andryushchenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2021, 17, 678–687, doi:10.3762/bjoc.17.57

• molecular frameworks in medicinal chemistry. Of these, 1,4-benzodiazepines fused with pyrazole or triazole cycles are the base for many drugs (Figure 1) [1]. The spectrum of their biological activity includes tranquilizing, muscular relaxant, anticonvulsant, and sedative effects [2]. The general application

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• common nitrogen-containing compounds such as pyridine, pyrazine, 1H-pyrazole, 1H-indole, 1-methyl-1H-indole, piperidine, and piperazine were subjected to screening. Pyridine and piperidine slightly hamper the reaction of 1g (Table 2, entries 2 and 7, 80–82%). Other nitrogen-containing compounds have more

Selective and reversible 1,3-dipolar cycloaddition of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with 1,3-diphenylprop-2-en-1-ones under microwave irradiation

• Alexander P. Molchanov,
• Mariia M. Efremova,
• Mariya A. Kryukova and
• Mikhail A. Kuznetsov

Beilstein J. Org. Chem. 2020, 16, 2679–2686, doi:10.3762/bjoc.16.218

• the hexahydropyrazolo[1,2-a]pyrazole ring, respectively, apparently through zwitterionic intermediates [28][29]. At the same time, the cycloaddition of azomethine imine to 1,3-diphenylprop-2-en-1-ones (chalcones) in IL proceeds stereo- and regioselectively giving two diastereomeric bicyclic anti

Access to highly substituted oxazoles by the reaction of α-azidochalcone with potassium thiocyanate

• Mysore Bhyrappa Harisha,
• Pandi Dhanalakshmi,
• Rajendran Suresh,
• Raju Ranjith Kumar and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2020, 16, 2108–2118, doi:10.3762/bjoc.16.178

• synthesis of 2,4,5-trisubstituted oxazole from azirine. a) I2, PPh3; b) NaH, 1H-pyrazole; c) 2-bromoacetyl bromide, NaN3; d) heating; e) t-BuOK; f) Ph-CHO, visible light; g) KSCN, K2S2O8. Scope of the α-azidochalcones. The reactions were carried out at reflux temperature, using 1 (1 mmol), 2 (3 mmol

Anthelmintic drug discovery: target identification, screening methods and the role of open science

• Frederick A. Partridge,
• Ruth Forman,
• Carole J. R. Bataille,
• Graham M. Wynne,
• Marina Nick,
• Angela J. Russell,
• Kathryn J. Else and
• David B. Sattelle

Beilstein J. Org. Chem. 2020, 16, 1203–1224, doi:10.3762/bjoc.16.105

• . mansoni [161]) and the cestode E. multilocularis [162]. Perhaps the most promising lead from the Pathogen Box so far is tolfenpyrad, a pyrazole-5-carboxamide insecticide, which was first identified as an anthelmintic with activity against exsheathed L3 and L4 parasitic life stages of Haemonchus contortus

• follow-up study identified two additional pyrazole-5-carboxamide compounds with activity against H. contortus, although not improving on the potency of tolfenpyrad [166]. Tolfenpyrad acts in arthropods as an inhibitor of mitochondrial complex I [167]. It will be interesting if a tolfenpyrad derivative

• through systematic alteration of the pyrazole-5-carboxamide and phenoxybenzyloxy moieties within tolfenpyrad 19 (Table 4). The systematic variation of the p-methylphenyl ring within 19 gave rise to a number of aromatic and heteroaromatic analogues with similar levels of potency to tolfenpyrad (Table 4

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• avoided the presence of a Brønsted acid in the reaction media. As such, Collins and co-workers developed the catalyst [Cu(I)(pypzs)(BINAP)]BF4 where the ligand (5-(4-fluorosulfonyl)amino-3-(2pyridyl)pyrazole)) (pypzs) had an acidic proton prone to activate the carbonyl group during the pinacol coupling

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

• Tobias Lucas,
• Jule-Philipp Dietz and
• Till Opatz

Beilstein J. Org. Chem. 2020, 16, 445–450, doi:10.3762/bjoc.16.41

• -methylisourea hemisulfate. dReaction time of 24 h. eProduct detected by LC–MS. Cyclization with phenylhydrazine (12a) to obtain the desired pyrazole 13a and the byproducts 13b and 13c (detected via LC–MS). Testing of different counter ions. Synthesis of fluorinated pyrazoles. Supporting Information Supporting

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• selective metalation can be achieved by varying reaction conditions and reagents. α-Lithiation of the methylene bridge and pyrazole ring in compound 77 allows for the synthesis of tris- and bis(pyrazole)phosphines. Antiñollo et al. [80] and Otero et al. [81] (Scheme 15) demonstrated the effect of varying

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

• Republic 10.3762/bjoc.16.27 Abstract Four-component reactions of 3-amino-1,2,4-triazole or 5-amino-1H-pyrazole-4-carbonitrile with aromatic aldehydes and pyruvic acid or its esters under ultrasonication were studied. Unusual for such a reaction type, a cascade of elementary stages led to the formation of

• 7-azolylaminotetrahydroazolo[1,5-a]pyrimidines. Keywords: 5-amino-1H-pyrazole-4-carbonitrile; 3-amino-1,2,4-triazole; 7-azolylaminotetrahydroazolo[1,5-a]pyrimidines; heterocycle; multicomponent reaction; ultrasonication; Introduction Tetrahydropyrimidines are heterocycles of high pharmacological

• -pyrazole-4-carbonitrile with aromatic aldehydes and pyruvic acid or its esters under ultrasonication led to the formation of 4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines 4a–u (Scheme 4) containing an azolylamino substituent in the 7-position via an unusual pseudo four-component reaction, rather than two

Synthesis and herbicidal activities of aryloxyacetic acid derivatives as HPPD inhibitors

• Man-Man Wang,
• Hao Huang,
• Lei Shu,
• Jian-Min Liu,
• Jian-Qiu Zhang,
• Yi-Le Yan and
• Da-Yong Zhang

Beilstein J. Org. Chem. 2020, 16, 233–247, doi:10.3762/bjoc.16.25

• modifying pyrazole derivatives and the carbon−carbon bond between 1,3-dicarbonyl and aroyl moieties. Previously, a series of 2-(aryloxyacetyl)cyclohexane-1,3-diones was synthesized by Wang et al. [24]. We have been interested in inserting a carbon−oxygen bond between the triketone and aroyl moieties of HPPD

• of commercial mesotrione. Inspired by the above revelations, we synthesized a group of new HPPD inhibitors that contain pyrazole and triketone moieties to study their bioactivities; the design strategy is shown in Figure 2. By combining the two bioactive structures, namely the aromatic moieties of

• substituted 1,3-dimethyl-1H-pyrazole-5-ol, using DMAP as the catalyst. Subsequently, the key enol ester E and M were respectively obtained. Finally, Fries-type rearrangements were performed in anhydrous DCM at room temperature to afford the title compounds I and III [31]. As shown in Scheme 4, the title

A combinatorial approach to improving the performance of azoarene photoswitches

• Joaquin Calbo,
• Aditya R. Thawani,
• Rosina S. L. Gibson,
• Andrew J. P. White and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2019, 15, 2753–2764, doi:10.3762/bjoc.15.266

• azoarenes have been ortho-substitution of the benzene ring(s) or replacement of one of the benzenes for a pyrazole (to give arylazopyrazole switches). Here we study the combination of such high-performance features within a single switch architecture. Through computational analysis and experimental

• . An emerging alternative approach to tune the properties of azoarene photoswitches is to replace one or both of the benzene rings with a heteroaromatic ring [15][16]. While several useful heteroaromatic azo scaffolds have been reported, we previously identified such photoswitches containing a pyrazole

• study, was substitution on the benzene ring [18]. Since our work, Venkataramani and co-workers [28] have explored how substitution on the benzene ring of azopyrazoles can impact their properties. However, in their study they focused on dimethylpyrazoles not methylated on the pyrazole ring N–H; compounds

Photochromic diarylethene ligands featuring 2-(imidazol-2-yl)pyridine coordination site and their iron(II) complexes

• Andrey G. Lvov,
• Max Mörtel,
• Anton V. Yadykov,
• Frank W. Heinemann,
• Valerii Z. Shirinian and
• Marat M. Khusniyarov

Beilstein J. Org. Chem. 2019, 15, 2428–2437, doi:10.3762/bjoc.15.235

• bridging unit via its remaining methoxy group and the pyrazole moiety. The octahedral coordination environment is completed with the β-keto ester moiety of one ligand 6 and by the imidazole and pyridine groups of the second ligand 6. The Fe–O and Fe–N bond lengths to the bridging unit are 2.1687(15) Å and

• photodecomposition. Both 8 and 9 share a common structural motif that prevents photocyclization. Coordination of the β-keto ester moiety and the imidazole/pyrazole moiety to two different iron(II) ions puts the ligand under severe strain. Thus, the structural reorganization necessary to accommodate a new planar

Reversible switching of arylazopyrazole within a metal–organic cage

• Anton I. Hanopolskyi,
• Soumen De,
• Michał J. Białek,
• Yael Diskin-Posner,
• Liat Avram,
• Moran Feller and
• Rafal Klajn

Beilstein J. Org. Chem. 2019, 15, 2398–2407, doi:10.3762/bjoc.15.232

• (Figure 8c, step i). Coordination of Pd2+ to the azo moiety, combined with the strongly electron-donating pyrazole moiety, affords (Figure 8c, step ii) a system akin to push–pull azobenzenes, whose Z isomers can back-isomerize rapidly due to a reduced order of the N=N bond [52][53][54] (Figure 8c, step

Thermal stability of N-heterocycle-stabilized iodanes – a systematic investigation

• Andreas Boelke,
• Yulia A. Vlasenko,
• Mekhman S. Yusubov,
• Boris J. Nachtsheim and
• Pavel S. Postnikov

Beilstein J. Org. Chem. 2019, 15, 2311–2318, doi:10.3762/bjoc.15.223

• . However, even the triazoles 2, 3, and 5 can be considered as safe compounds, but still deserve a common precaution due to the narrow decomposition process. Pyrazoles 6 and 7 are thermally more stable (Tpeak = 168.9 and 196.5 °C) with a remarkably lower ΔHdec value. NH-pyrazole 6 shows the lowest ΔHdec

• model reaction, especially N-substituted triazoles 4 and 5. In contrast, the reactivity of triazole 3 is comparable to that of benzoxazoles 13 and 14 as well as pyrazole 7 and indazole 8. In our view thiazole 12 is the best compromise in this regard since it is thermally even more stable than 7 and 8

• with a significant higher reactivity. However, pyrazole 6 still shows a good reactivity in this model reaction with a concurrent outstanding thermal stability. If safety issues are a major concern, for example on a very large-scale synthesis, NHIs 6 or 12 should be the first choices. Except of 15 and 9

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