Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment

• Anas J. Rasras,
• Mohamed El-Naggar,
• Nesreen A. Safwat and
• Raed A. Al-Qawasmeh

Beilstein J. Org. Chem. 2022, 18, 631–638, doi:10.3762/bjoc.18.63

• exhibited selective activity against fungi only. Keywords: antibacterial; cholic acid; heterocyclic; Mannich reaction; oxadiazole; Introduction Microbial infections caused by Gram-negative and Gram-positive bacteria embarrass the health care system worldwide [1]. Pathogens such as Escherichia coli

• the development of multidrug resistant bacteria due to excessive use of antibiotics [2][4]. Heterocyclic compounds are the key components for drug design and synthesis. Among them, 1,3,4-oxadiazole derivatives are attractive and have been investigated for decades. This is due to their promising

• MCF7) [13]. In 2008, Muhi-eldeen et al, synthesized a hybrid compound with 1,3,4-oxadiazole moiety and pyrrolidine connected with propargylic moiety showed antibacterial activity against Staphylococcus aureus and E. coli [14]. On the other hand, the coupling of piperazine with heterocyclic compounds

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

• Md Imran Hossain,
• Md Imdadul H. Khan,
• Seong Jong Kim and
• Hoang V. Le

Beilstein J. Org. Chem. 2022, 18, 446–458, doi:10.3762/bjoc.18.47

• chlorides to form furoxans also known as 1,2,5-oxadiazole 2-oxides, a class of structures with important biological activities due to their unique electronic nature and coordination ability. Keywords: environmentally friendly; furoxans; 1,2,5-oxadiazole 2-oxides; trifluoromethyl-substituted isoxazoles

• expected 3,4,5-trisubstituted isoxazole 3a and 55% of a compound that we identified as furoxan 4 (a 1,2,5-oxadiazole 2-oxide) which formed through homo-coupling of substrate 1a (Table 1, entry 3). Na2CO3 in 98% water, 2% methanol produced 52% of the isoxazole 3a and 33% of compound 4 after 3 hours (Table 1

• with 95% yield (5% water, 95% methanol, room temperature, 2 hours; see Table 1, entry 15), which adds another method for the synthesis of furoxans to the current literature. The synthesis of furoxans or 1,2,5-oxadiazole-2-oxides was first reported by Kekulé in 1857 [36]. Since then, these nitric oxide

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

• Kian Donnelly and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

• an integrated quenching and extraction step. Lastly, the use of an automated in-line chromatography system was exploited to realise a powerful flow platform for the generation of the heterocyclic targets. Keywords: chromatography; flow synthesis; in-line purification; oxadiazole; reaction

• -oxadiazole unit [28][29][30][31][32][33]. In 2012, Guin and co-workers described the iodine-mediated cyclodesulphurisation of thiosemicarbazides, yielding the corresponding 1,3,4-oxadiazoles [32]. Subsequently, Yu and co-workers reported the iodine-mediated oxidative cyclisation of acyl hydrazones to form

• ]pentane (BCP) building blocks [36], we investigated their use in the oxadiazole-forming reaction. The BCP acid chloride 5 was synthesised from [1.1.1]propellane (3) via the photochemical reaction with isopropyl 2-chloro-2-oxoacetate (Scheme 4). The corresponding BCP acyl hydrazone was then obtained

Synthesis of 5-arylacetylenyl-1,2,4-oxadiazoles and their transformations under superelectrophilic activation conditions

• Andrey I. Puzanov,
• Dmitry S. Ryabukhin,
• Anna S. Zalivatskaya,
• Dmitriy N. Zakusilo,
• Darya S. Mikson,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2021, 17, 2417–2424, doi:10.3762/bjoc.17.158

• ; triflic acid; Introduction 1,2,4-Oxadiazoles have a great importance in chemistry, biology and medicine. Many drugs contain an 1,2,4-oxadiazole ring, such as butalamine [1], libexin [2], ataluren [3], oxolamine [4], and pleconaril [5]. Various oxadiazole derivatives show different kinds of activity

• against cancer [6][7], tuberculosis [8], Gram-positive bacteria [9], and they are used in treatment of epilepsy [10] and Alzheimer disease [11][12][13]. The synthesis of compounds of the 1,2,4-oxadiazole series is an actual task in organic and medicinal chemistry (see selected reviews on this topic [14

• ][15][16][17][18][19][20][21][22]). However, among all the varieties of 1,2,4-oxadiazoles, their acetylenic derivatives are quite rare. To the best of our knowledge, there is only one example of 1,2,4-oxadiazole conjugated with an acetylene bond, which is 3-phenylethynyl-1,2,4-oxadiazole [23]. Up to

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• ], 6,7-dihydro-6-oxo-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine [17], 1,2,4-triazino[5,6-b]indole [18], 1,3,4-thiadiazoline [19], 1,3,4-oxadiazoline [19], 1,2,4-triazoline [19], 3-mercapto-1H-1,2,4-triazole [20], 1,3,4-oxadiazole-2(3H)-thione [20], 4-amino-5-mercapto-4H-1,2,4-triazole [20], and 1,2,4

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

• addition of dimethylcyanoguanidine occurred in an acceptable 66% yield (Scheme 19, top) [49]. Interestingly, the addition of hydroxylamine hydrochloride under the same conditions led to the formation of unexpected 3,5-diamino-1,2,4-oxadiazole. This could be explained by the cyclization of the N5

• -hydroxybiguanide intermediate, and subsequent dimethylamine evolution. The synthesis of this oxadiazole was then optimized by using triethylamine and room temperature, which resulted in a 78% yield of the desired product (Scheme 19, bottom). Another interesting example of a ring closure by the intramolecular

• 90% yield. A Lewis acid-promoted cyclization (boron trifluoride etherate at 60 °C) avoided the use of high temperatures, while providing the products in comfortable yields. Dicyanamide has also been shown to react with hydroxylamine hydrochloride to form [1,2,4]oxadiazole-3,5-diamine (Scheme 29A) [49

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• either 1,2,4-oxadiazoles 72 or quinazolinones 73 (Scheme 26), depending on the reaction conditions. The 1,2,4-oxadiazole ring was selectively obtained in DMF at 60 °С under oxygen atmosphere (1 atm) in the presence of an excess of K3PO4, whereas in DMSO at 100 °С under air and in the presence of Cs2CO3

• intermediate, 4,5-dihydro-1,2,4-oxadiazole. An example of such intermediate 74 is shown in Scheme 27. Oxidative aromatization of 74 leads to 1,2,4-oxadiazole 72a (Scheme 26). The second pathway, hydrogen abstraction followed by β-scission presumably leads to iminyl radical, which forms the observed

Synthesis, liquid crystalline behaviour and structure–property relationships of 1,3-bis(5-substituted-1,3,4-oxadiazol-2-yl)benzenes

• Afef Mabrouki,
• Malek Fouzai,
• Armand Soldera,
• Abdelkader Kriaa and
• Ahmed Hedhli

Beilstein J. Org. Chem. 2020, 16, 149–158, doi:10.3762/bjoc.16.17

• moments were also investigated. Keywords: dipole moment; fluorine; liquid crystal; oxadiazole; Introduction Liquid-crystalline (LC) materials have been known for over a century [1]. It is clear that architecture and functionalization are essential aspects in molecular engineering of liquid crystals [2

• , while their hydrocarbon counterparts are non-mesomorphic [20]. On the other hand, many heterocyclic-based liquid crystals have been designed and then synthesised due to their large scope of applications [21]. In this context, the 1,3,4-oxadiazole group was of a particular interest from a synthetic

• viewpoint, considering the numerous ways to introduce this group into a molecule [22][23]. So, it was established that the introduction of a 1,3,4-oxadiazole ring as terminal group on a biphenyl provides liquid crystalline materials [24][25]. However, when the oxadiazole unit is incorporated in the aromatic

Synthesis of benzo[d]imidazo[2,1-b]benzoselenoazoles: Cs₂CO₃-mediated cyclization of 1-(2-bromoaryl)benzimidazoles with selenium

• Mio Matsumura,
• Yuki Kitamura,
• Arisa Yamauchi,
• Yoshitaka Kanazawa,
• Yuki Murata,
• Tadashi Hyodo,
• Kentaro Yamaguchi and
• Shuji Yasuike

Beilstein J. Org. Chem. 2019, 15, 2029–2035, doi:10.3762/bjoc.15.199

• Figure S2 in Supporting Information File 1). Cs2CO3-mediated C(Het)–S bond formations of a heteroazole such as imidazo[1,2-a]pyridine, oxadiazole, and benzimidazole with diaryl disulfides without a transition metal catalyst have previously been developed [18][19]. The key step in these reactions is

Reactions of 3-(p-substituted-phenyl)-5-chloromethyl-1,2,4-oxadiazoles with KCN leading to acetonitriles and alkanes via a non-reductive decyanation pathway

• Akın Sağırlı and
• Yaşar Dürüst

Beilstein J. Org. Chem. 2018, 14, 3011–3017, doi:10.3762/bjoc.14.280

• compounds were identified by means of IR, 1H NMR, 13C NMR, 2D NMR spectra, TOF–MS and X-ray measurements. Keywords: decyanation; KCN; 1,2,4-oxadiazole; Introduction Heterocyclic scaffolds bearing 1,2,4-oxadiazole rings have been the subject of an increasing and remarkable attention due to their various

• crystals, and solar cells [7][8][9][10]. Taking into account the above considerations, new synthetic protocols to develop 1,2,4-oxadiazole-based heterocycles have gained an increasing attention over the recent decades [11][12][13]. On the other hand, arylacetonitriles are known as valuable intermediates

• exploited by providing very limited structural data [19]. Interestingly, increasing the reaction temperature to 100 °C yielded 1,2,4-oxadiazole-substituted propanes 4 as the major products which can only be interpreted via a decyanation pathway of cyanated oxadiazoles 3 (Figure 2). Up to date, various

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

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

• the anti-configuration in all cases. In addition, the option for oxidation to the oxazole or thiazole is always enticing as a way of easily accessing a diverse set of molecules. Immediately akin to the oxazole moiety is the oxadiazole heterocycle, which exhibits similar properties. There are several

Recent advances in phosphorescent platinum complexes for organic light-emitting diodes

• Cristina Cebrián and
• Matteo Mauro

Beilstein J. Org. Chem. 2018, 14, 1459–1481, doi:10.3762/bjoc.14.124

• value dropping to 2% at a practical brightness of 500 cd m−2. Nevertheless, this work opens the door for a novel design of highly efficient deep-blue phosphors. More complex structures based on dinuclear platinum(II) complexes have also been recently described [20]. Upon using two 1,3,4-oxadiazole-2

• that leads to severe roll-off efficiency of OLEDs [64]. In particular, carbazole-based donor moieties and either phenylbenzimidazole (PBI) or oxadiazole (OXD) accepting units were selected as the hole-transporting and electron-transporting moiety, respectively. Two linkage fashions were explored

Recent advances on organic blue thermally activated delayed fluorescence (TADF) emitters for organic light-emitting diodes (OLEDs)

• Thanh-Tuân Bui,
• Fabrice Goubard,
• Malika Ibrahim-Ouali,
• Didier Gigmes and
• Frédéric Dumur

Beilstein J. Org. Chem. 2018, 14, 282–308, doi:10.3762/bjoc.14.18

One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates

• Jun Ki Kim,
• Hwan Jung Lim,
• Kyung Chae Jeong and
• Seong Jun Park

Beilstein J. Org. Chem. 2018, 14, 243–252, doi:10.3762/bjoc.14.16

• . Thiophene could not generate the desired intermediate because of the lower electronegativity and a weaker inductive effect of sulfur (Table 1, entry 8). Among 1,2,4-oxadiazole moieties, the 3-trifluoromethyloxadiazole group afforded the desired thiophene 8i (Table 1, entry 9), whereas the 5

• ]: among isomeric benzylpyridines, the 4-isomer is more acidic than the 2-isomer, and the 4- and 2-isomers are much more acidic than the 3-isomer. In the case of the oxadiazole-substituted compound 7i, inductive and mesomeric effects facilitated its sulfur ylide-like intermediate formation [71]. For

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

• ; cyclopropanations Dimethoxycarbene (6), generated in situ by thermal decomposition of 2,2-dimethoxy-2,5-dihydro-1,3,4-oxadiazole 7, reacts with E-1b yielding a mixture of the trans-configured tetramethoxycyclobutane 8 and 2,3-dihydrofuran 9 [21][22] (Scheme 3). The latter reacts further with dimethoxycarbene and

• , and in both cases pyrazol-3-ones 68 were obtained in ca. 35% yield (Scheme 22). The heterocyclization leading to 68 occurs in the intermediate enehydrazide 69 through the nucleophilic attack of the N-atom onto the ester group. The second product was postulated either as a 2,3-dihydro-1,3,4-oxadiazole

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

Metal-free hydroarylation of the side chain carbon–carbon double bond of 5-(2-arylethenyl)-3-aryl-1,2,4-oxadiazoles in triflic acid

• Anna S. Zalivatskaya,
• Dmitry S. Ryabukhin,
• Marina V. Tarasenko,
• Alexander Yu. Ivanov,
• Irina A. Boyarskaya,
• Elena V. Grinenko,
• Ludmila V. Osetrova,
• Eugeniy R. Kofanov and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2017, 13, 883–894, doi:10.3762/bjoc.13.89

• been paid to their synthesis and to the studies of their chemical, physical and biological properties (see numerous reviews [1][2][3][4][5][6][7][8]). The oxadiazole ring represents an essential part of the pharmacophore in many drugs. These compounds possess different kinds of biological activities

• , such as analgesic [9], anti-inflammatory [10], antimicrobial [11], antidiabetic [12], and anticancer [13] to name a few. Some representatives of 1,2,4-oxadiazole-based drugs are shown in Figure 1. Libexin and oxolamine are used as antitussive (cough) agents [14], butalamine is a coronary vasodilator

• and local anesthetic [15], and ataluren finds application for the treatment of fibrosis [16]. Often, oxadiazole derivatives act as inhibitors of bacterial phenylalanyl-tRNA-synthetase [17], phosphodiesterase 4B2 [18], y-secretase [19] and phenol-substituted 1,2,4-oxadiazoles exhibit powerful anti

Energy down converting organic fluorophore functionalized mesoporous silica hybrids for monolith-coated light emitting diodes

• Markus Börgardts and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2017, 13, 768–778, doi:10.3762/bjoc.13.76

• fluorophore derivatives 4 and 5 were accessible by Williamson ether synthesis [24]. The alkyne-functionalized green benzofurazane derivate 6 was obtained by nucleophilic aromatic substitution of 4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole (3) with propargylamine. The alkyne-functionalized derivatives 4, 5 and 6

Synthesis and optical properties of new 5'-aryl-substituted 2,5-bis(3-decyl-2,2'-bithiophen-5-yl)-1,3,4-oxadiazoles

• Anastasia S. Kostyuchenko,
• Tatyana Yu. Zheleznova,
• Anton J. Stasyuk,
• Aleksandra Kurowska,
• Wojciech Domagala,
• Adam Pron and
• Alexander S. Fisyuk

Beilstein J. Org. Chem. 2017, 13, 313–322, doi:10.3762/bjoc.13.34

• by quantum chemical DFT/TDDFT calculations carried out for these new molecules. Keywords: bithiophene; donor–acceptor; luminescence; 1,3,4-oxadiazole; palladium-catalyzed coupling; Introduction π-Conjugated donor–acceptor (D-A) compounds are of significant scientific interest because they

• enables the preparation of linear D–A–D compounds with one or two 1,3,4-oxadiazole [16][17][18][19], 1,3,4-thiadiazole [16][18][19][20][21][22] or 1,2,4-triazole [16][18] central rings symmetrically disubstituted with alkylbithiophene 1, 2 as well as star-shaped molecules with D–A arms 3 (Figure 1) [23

• oxadiazole central ring symmetrically functionalized with bithiophene end-capped with various aryl groups. Our preliminary studies show that these compounds can be used as electroluminophores in LEDs, which show superior performance as compared to the devices fabricated from 1 or 2 [18]. Results and

Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

• Ananda Herath and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2017, 13, 239–246, doi:10.3762/bjoc.13.26

• single-step liquid–liquid microextraction unit to remove high boiling point polar solvents and impurities and provides the target compounds in high purity with excellent overall yields. Keywords: imidazo[1,2-a]pyridine; imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazole; liquid–liquid extraction module

• ; microreactor; 1,2,4-oxadiazole; Introduction The design and execution of scalable and economically viable processes for the preparation of biologically active small molecules is a major hurdle in modern organic synthesis. The development of batch processes that combine multiple reactions into “one-pot” have

• , three-microreactor method for the highly efficient preparation of a diverse library of imidazo-oxadiazole derivatives. Moreover, this continuous-flow method was successfully combined with a single-step liquid–liquid microextraction unit to remove high boiling point polar solvents and impurities. Results

Sydnone C-4 heteroarylation with an indolizine ring via Chichibabin indolizine synthesis

• Florin Albota,
• Mino R. Caira,
• Constantin Draghici,
• Florea Dumitrascu and
• Denisa E. Dumitrescu

Beilstein J. Org. Chem. 2016, 12, 2503–2510, doi:10.3762/bjoc.12.245

• have been the subject of various reviews [6][7][8][9][10][11][12][13][14][15]. Sydnones 3 are mesoionic heterocyclic compounds with a 1,2,3-oxadiazole skeleton and their chemistry and biological properties are well represented and documented in the literature [20][21][22][23][24][25][26]. The most

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• -ethyl-2-oxazoline in methanol [69]. Additionally, acylnitroso compounds can be generated by the rearrangement of diazonitroalkanes 26 [70], the photochemical cleavage of 1,2,4-oxadiazole-4-oxides 25 [71] and the cycloreversion of 9,10-dimethylantracene adducts 27 (Scheme 7) [72][73]. Dienes: There is a

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• against a variety of bacterial strains, in line with a simulated enthalpic penalty of +8.8 kJ/mol. It has been suggested by Palumbo Piccionello et al., that, though the 1,2,4-oxadiazole ring is isosteric with the oxazolidinone ring and possesses similar hydrogen bond acceptors sites, the lack of

• contains a NH2 group that is able to form a weak H-bond, its amidic character and the lack of a chiral center leads to a side chain orientation parallel to the 1,2,4-oxadiazole ring, changing the overall binding mode in comparison with linezolid, and by this decreasing the overall binding affinity. Our

• 2 and 3, the morpholine ring was replaced by a 3-methyl-1,2,4-oxadiazole ring [44]. Whereas 2 maintains the linezolid C5 side chain, compound 3 is substituted by a imidazole-1-yl. With its MIC value of 2 mg/L compound 2 seems to be comparable (or even more effective against the MRSA 433 strain, see

C–H bond halogenation catalyzed or mediated by copper: an overview

• Wenyan Hao and
• Yunyun Liu

Beilstein J. Org. Chem. 2015, 11, 2132–2144, doi:10.3762/bjoc.11.230

• and 2-phenyl-1,3,4-oxadiazole were smoothly iodinated to provide iodoheteroarenes 18 (Scheme 10) [45]. As typical electron-enriched arenes, phenols and analogous arenes tend to undergo a single-electron transfer process [46], the property of these arenes also resulted in sound attention to their C–H