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

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

• 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

• except for one single use of silver dicyanamide [65]. Further investigations in this direction might help to soften the conditions and improve the yields. An interesting reactivity was reported with subsequent SEAr cyclization or 1,2,4-oxadiazole formation. However, these applications seem sparse with

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

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

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

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

• , 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

• activity. Thus, the synthesis of these particular 5-(2,2-diarylethyl)-substituted oxadiazoles 2 may be interesting for medicinal chemistry. Results and Discussion According to literature data [50][51] the protonation of a 1,2,4-oxadiazole ring takes place mainly at the N4 nitrogen. However, also the N2

• nitrogen may be protonated depending on the substituents attached to the heterocyclic system [50]. To investigate this issue in more detail we undertook a theoretical study on the protonation of 5-(2-phenylethenyl)-3-phenyl-1,2,4-oxadiazole (1a) by quantum-chemical calculations. Table 1 contains data

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

• and Discussion Historically the 1,2,4-oxadiazole scaffold has been used by medicinal chemists as a ubiquitous bioisosteric replacement of amide and ester functionalities in a wide variety of biologically active compounds [23][24]. This motif is found in several drugs and drug leads including

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

3-Glucosylated 5-amino-1,2,4-oxadiazoles: synthesis and evaluation as glycogen phosphorylase inhibitors

• Marion Donnier-Maréchal,
• David Goyard,
• Vincent Folliard,
• Tibor Docsa,
• Pal Gergely,
• Jean-Pierre Praly and
• Sébastien Vidal

Beilstein J. Org. Chem. 2015, 11, 499–503, doi:10.3762/bjoc.11.56

• structure–activity relationship study with several isomeric oxadiazoles. The regioisomeric substitution around the 1,2,4-oxadiazoles (F [22][23] vs G [23][24]) plays a role in the inhibition observed with the glucosyl group at the 5-position of the 1,2,4-oxadiazole ring being preferred. Isomeric 1,3,4

• -oxadiazole H [25] was practically inactive against GP in comparison to its 1,2,4-oxadiazole congeners (F and G). Nevertheless, inhibition could be restored by introducing a nitrogen atom (NH) between the glucosyl and aromatic aglycon (I [26]), while introduction on the other position (J [27]) did not help

Novel biphenyl-substituted 1,2,4-oxadiazole ferroelectric liquid crystals: synthesis and characterization

• Mahabaleshwara Subrao,
• Dakshina Murthy Potukuchi,
• Girish Sharada Ramachandra,
• Poornima Bhagavath,
• Sangeetha G. Bhat and
• Srinivasulu Maddasani

Beilstein J. Org. Chem. 2015, 11, 233–241, doi:10.3762/bjoc.11.26

• , Bangalore - 560 099, India Department of Physics, University College of Engineering, Jawaharlal Nehru Technological University: Kakinada, Kakinada - 533 003, India 10.3762/bjoc.11.26 Abstract Two novel series of unsymmetrically substituted 1,2,4-oxadiazole viz., R.Ox.C*Cn compounds are synthesized and

• ; SmC* phase; spontaneous polarization; Suzuki coupling; Introduction The 1,2,4-oxadiazole derivatives are prevalently reported compounds with promising biological [1][2][3][4][5] and physiological [6][7][8] activity such as antiinflammatory, antibacterial, antimicrobial, antifungal, anticancer

• -cyanobenzoate (2a) with hydroxylamine hydrochloride yielded the corresponding benzyl 4-(N'-hydroxycarbamimidoyl)benzoate (3a). This amidoxime (3a) is converted into benzyl 4-(5-(4-bromophenyl)-1,2,4-oxadiazole-3-yl)benzoate (5a) by treating it with 4-bromobenzoyl chloride in the presence of pyridine. Oxadiazole

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

• Catalin V. Maftei,
• Elena Fodor,
• Peter G. Jones,
• M. Heiko Franz,
• Gerhard Kelter,
• Heiner Fiebig and
• Ion Neda

Beilstein J. Org. Chem. 2013, 9, 2202–2215, doi:10.3762/bjoc.9.259

• natural products containing a 1,2,4-oxadiazole ring in their structure (quisqualic acid and phidianidines A and B), the natural product analogs 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-2,5-dione (4) and 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)-1H-pyrrole-2,5-dione (7) were

• heterocyclic 1,2,4-oxadiazole motif is of synthetic and pharmacological interest. It also forms an important constituent of biologically active compounds including natural products [1]. Sawyer et al. have described such compounds as bioisosteres for amides and esters [2], with the 1,2,4-oxadiazoles showing

• higher hydrolytic and metabolic stability. To the best of our knowledge, there are only a few examples of natural products with a 1,2,4-oxadiazole core or a structure based on it. The 3-substituted indole alkaloids, phidianidines A and B (Figure 1), have been isolated by Carbone et al. from the aeolid

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• resulted in a variety of radiolabeled molecular probes for in vivo PET/SPECT imaging. The scaffolds from which these newer radiolabeled probes are derived include chalcone (5) and its conformationally restricted analogues flavone (6) and aurone (7); stilbene (8) and its analogues diphenyl-1,2,4-oxadiazole

• -1,2,4-oxadiazole analogue 51c was more lipophilic than its 1,3,4 counterpart 50a (log P = 3.22 for 51c and 2.43 for 50a) [47]. In general, even though 3,5-diphenyl-1,2,4-oxadiazoles 51a–e show excellent affinity for Aβ aggregates in in vitro binding experiments (Ki = 4.3–47.1 nM), they show poorer brain

• by subsequent radioiodination of compound 53 (Scheme 5B) [47]. The 1,2,4-oxadiazole core of [125I]51c was obtained by DCC/HOBt-mediated condensation of 4-bromobenzamidoxime (54) and p-nitrobenzoic acid (55). Subsequent nitro reduction, reductive methylation, and radioiodination gave [125I]51c (Scheme

Liquid-crystalline heterodimesogens and ABA-heterotrimesogens comprising a bent 3,5-diphenyl-1,2,4-oxadiazole central unit

• Govindaswamy Shanker,
• Marko Prehm and
• Carsten Tschierske

Beilstein J. Org. Chem. 2012, 8, 472–485, doi:10.3762/bjoc.8.54

• terminally connected ABA-heterotrimesogens and heterodimesogens, composed of a bent 3,5-diphenyl-1,2,4-oxadiazole central unit and one or two rod-shaped 4-cyanobiphenyl cores or one 2-phenyl-1,3,4-thiadiazole core, connected by flexible spacers, have been synthesized, and their mesomorphic behavior was

• the 3,5-diphenyl-1,2,4-oxadiazole unit with one cyanobiphenyl core leads to the removal of tilted smectic and cybotactic nematic phases (SmC, NcybC), which are replaced by the nontilted CybA phases and nematic phases composed of SmA-type clusters (NcybA). The orthogonal cybotactic nematic phases of

• units led to a loss of LC properties [58]. The 3,5-diphenyl-1,2,4-oxadiazole segment has recently attracted significant attention as a central building block for bent-core LC molecules (angle ~140°) [59][60][61][62][63], due to the ferroelectric-like polar switching observed in the nematic phases of