Synthesis of 1,2,4-Oxadiazoles by Tandem Reaction of Nitroalkenes

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Synthesis of 1,2,4-Oxadiazoles by Tandem Reaction of Nitroalkenes with Arenes and Nitriles in the Superacid TfOH Andrei A. Golushko,† Olesya V. Khoroshilova,‡ and Aleksander V. Vasilyev*,†,§ †

Department of Organic Chemistry, Institute of Chemistry, Saint Petersburg State University, Universitetskaya nab., 7/9, Saint Petersburg 199034, Russia ‡ Center for X-ray Diffraction Studies, Research Park, Saint Petersburg State University, Universitetskiy pr., 26, Saint Petersburg, Petrodvoretz 198504, Russia § Department of Chemistry, Saint Petersburg State Forest Technical University, Institutsky per., 5, Saint Petersburg 194021, Russia

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S Supporting Information *

ABSTRACT: The tandem reaction of nitroalkenes with arenes and nitriles in the superacid CF3SO3H (TfOH) results in the formation of 1,2,4-oxadiazole derivatives in yields up to 96%. This reaction proceeds via the consequent interaction of arenes and nitriles, as nucleophiles, with intermediate cationic species derived by the protonation of nitroalkenes in TfOH. This is novel and general synthesis of 1,2,4-oxadiazoles, which are very important compounds for medicinal chemistry.

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INTRODUCTION 1,2,4-Oxadiazoles are important heterocyclic compounds due to their various kinds of biological activity. Several reviews on the syntheisis of 1,2,4-oxadiazole derivatives and study of their properties have been recently published.1−11 In medicinal chemistry oxadiazoles are considered as bioisosteric analogues of ester or amide groups.12 1,2,4-Oxadiazole ring is found in many drugs. For instance, Butalamine is a coronary vasodilator and local anesthetic,13 Libexin is a cough suppressant,14 and Ataluren is used for the treatment of fibrosis (Figure 1).15 Nowadays, further progress in the synthesis of oxadiazole derivatives and studies on their properties are actual goals in chemistry, biology, and medicine.

Scheme 1. Main Current Methods for the Synthesis of 1,2,4Oxadiazolesa

a

acid CF3SO3H (triflic acid, TfOH) affording the corresponding oximes of 3,3,3-trihalogeno-1,2-diarylpropan-1-ones II (Scheme 2).30 This reaction proceeds through the series of cationic intermediates A−E; some of them, A, C, E, were caught by NMR in TfOH to prove the reaction mechanism. In this reaction two arene molecules (π-nucleophiles) react consequently with cations A and then C leading to oximes II.30 One of the key intermediates of this transformation is cation C, which was specially generated at low temperature −40 °C in TfOH and studied by means of NMR.30 These species are stable under these conditions and react very slowly with second arene molecule at −40 °C in TfOH with the formation of structures D and then cations E. The main idea of the present study was to generate cations C from various nitroalkenes 1 under their reactions with arenes in TfOH and subject these species to consequent interaction with nitriles, as n-nucleophiles. In this case, one may expect an

Figure 1. Examples of drugs containing 1,2,4-oxadiazole structure.

There are two main methods for the construction of 1,2,4oxadiazole ring. The first one is O-acylation of amidoximes by carboxylic acids or their derivatives followed by cascade cyclization-dehydration leading to target oxadiazoles (see data in reviews3,6,9,11 and recent papers on similar procedures16−24) (amidoxime route in Scheme 1). Another approach is based on the [3 + 2] cycloaddition of nitriles with nitrile oxides25 or silyl nitronates26 (Scheme 1 and data in reviews6,9,11). One more method is based on the transformations of aldoximes.2,5,6,27 On the basis of our studies on electrophilic activation of organic compounds,28,29 we recently described reactions of 3,3,3-trihalogeno-1-nitropropenes I with arenes in the super© XXXX American Chemical Society

From literature data.

Received: March 22, 2019

A

DOI: 10.1021/acs.joc.9b00812 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 2. Reactions of CHaI3-Nitroethylenes I with Arenes in TfOH Leading to Oximes IIa

a

Data from ref 30.

Scheme 3. Main Idea of the Present Worka

a

Tandem reaction of arenes and nitriles with cations generated from nitroalkenes 1 in the superacid TfOH.

intermediate formation of species F and, then, compound G, which may finally lead to 1,2,4-oxadiazole 2 (Scheme 3). Thus, the main goal of this work was a study of tandem reaction of nitroalkenes with arenes and nitriles under the superelectrophilic activation conditions in TfOH.

Scheme 5. Reactions of Nitroalkene 1a with Various Arenes and Acetonitrile in TfOH Leading to Oxadiazoles 2f−2n

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RESULTS AND DISCUSSION We started with checking reactions of CCl3-nitroethylene 1a with benzene and various nitriles in TfOH (Scheme 4). The Scheme 4. Reactions of Nitroalkene 1a with Benzene and Various Nitriles in TfOH Leading to Oxadiazoles 2a−2e

reaction was performed in a one-pot, two-step procedure. First, nitroalkene 1a was added to a mixture of benzene (1.5 equiv) with TfOH and CH2Cl2 at −40 °C to generate species C during 1.5 h (see Schemes 2 and 3). It is critical for this step to keep temperatire at −40 °C, since at higher temperature cations C undergo consequent transformations.30 Then, the superacidic solution was quenched (for 10 min) with an excess of a nitrile or with a mixture of nitrile and pyridine (the last one was used to neutralize TfOH) and cooled to ca. −30 to −20 °C. Indeed, this method afforded the series of oxadiazoles 2a−2e (Scheme 4). It should be specially mentioned that addition of pyridine is crucial for quenching of superacidic solutions of cations C with benzonitrile and cyclopropylnitrile, since these particular nitriles are easily cyclized into the corresponding 1,3,5-triazines in TfOH. Addition of pyridine decreases significantly the amount of triazine byproducts. Then, the reaction scope with various arenes (1.5 equiv) was studied using 1a and acetonitrile, which gave oxadiazoles 2f− 2n in yields up to 94% (Scheme 5). Besides benzene, other

arenes, toluene, xylenes (dimethylbenzene), pseudocumene (1,2,4-trimethylbenzene), anisole (methoxybenzene), veratrole (1,2-dimethoxybenzene), and even sterically hindered substrates mesitylene (1,3,5-trimethylbenzene) and durene (1,2,4,5-tetramethylbenzene), were successfully involved in this reaction (Scheme 5). Note that the presence of the trichloromethyl substituent in oxadiazoles 2a−2n provides opportunities for further structural modification of these molecules by transformation of CCl3 group into, for instance, the carboxylic one and many others. Apart from compound 1a, different nitrostyrenes 1b−1f took part in the reaction affording oxadiazoles 2o−2zb in good yields, up to 96% (Scheme 6). In general, the yields of oxadiazoles 2o−2zb, prepared from aryl substituted nitroethylenes 1b−1f (Scheme 6), are higher compared to the yields of oxadiazoles 2a−2n, obtained from CCl3-substituted nitroethylene 1a (Schemes 4 and 5). It could be explained by higher stability of intermediate diaryl substituted cations C (R B

DOI: 10.1021/acs.joc.9b00812 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

minimization. Additional crystallographic information is available in the Supporting Information. Starting nitroalkenes were synthesized according to the literature procedures for 1a33 and for 1b−1f.34 General Procedure for the Synthesis of 1,2,4-Oxadiazoles 2. Nitroalkene 1 (0.16 mmol) was added to a mixture of TfOH (0.7 mL), CH2Cl2 (0.3 mL), and arene (0.24 mmol) at −40 °C. After it was stirred at −40 °C for 1.5 h, the reaction mixture was poured at once into nitrile (5 mL; in case of benzonitrile and cyclopropanecarbonitrile −2.00 mmol solution in 5 mL of CH2Cl2 and pyridine, 50 mg) cooled to −30 °C. The resulting solution was heated to −20 °C and stirred at this temperature for 10 min, then quenched with water (10 mL) and extracted with CHCl3 (3 × 10 mL). The combined organic phases were washed three times with water (20 mL), then dried with Na2SO4. Solvent was evaporated under the reduced pressure. In some cases, reaction products were additionally purified by preparative TLC on silica gel with elution by petroleum ether−ethyl acetate mixtures (v/v) (see an eluent mixture for each compound below). Large Scale Procedure for the Synthesis of Oxadiazole 2a. A solution of nitroalkene 1a (1.6 mmol) in CH2Cl2 (0.5 mL) was dropwise added to a mixture of TfOH (3 mL), CH2Cl2 (1 mL), and arene (2.4 mmol) at −40 °C. After it was stirred at −40 °C for 2 h, the reaction mixture was poured at once into acetonitrile (20 mL) cooled to −30 °C. The resulting solution was heated to room temperature, then quenched with water (10 mL) and extracted with CHCl3 (3 × 20 mL). The combined organic phases were washed with saturated aqueous solution of NaHCO3 (20 mL) and three times with water (20 mL), then dried with Na2SO4. Solvent was evaporated under the reduced pressure; purification was performed by column chromatography with a mixture of petroleum ether (40−70)−ethyl acetate, 9:1 (v/v). Yield 192 mg (41%). 5-Methyl-3-(2,2,2-trichloro-1-phenylethyl)-1,2,4-oxadiazole (2a). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), benzene (19 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 30 mg (65%). Transparent oil. 1H NMR, δ, ppm: 2.63 s (3H), 5.31 s (1H), 7.37− 7.41 m (3H), 7.76−7.79 m (2H). 13C{1H} NMR, δ, ppm: 12.6, 63.1, 98.8, 128.4, 129.4, 131.5, 133.2, 167.7, 176.8. IR (KBr, cm−1): 1580 (CN). HRMS (ESI-time-of-flight (TOF)) m/z: [M + H]+ Calcd for C11H10Cl3N2O 290.9854; Found 290.9858. 5-Ethyl-3-(2,2,2-trichloro-1-phenylethyl)-1,2,4-oxadiazole (2b). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), benzene (19 mg, 0.24 mmol), and propionitrile (5 mL). Yield 18 mg (38%). Transparent oil. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 1.41 t (3H, J 7.6 Hz), 2.95 q (2H, J 7.6 Hz), 5.32 s (1H), 7.34−7.50 m (3H), 7.75−7.82 m (2H). 13C{1H} NMR, δ, ppm: 10.8, 20.5, 63.3, 98.9, 128.4, 129.3, 131.6, 133.2, 167.5, 180.9. IR (KBr, cm−1): 1578 (C N). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for C12H11Cl3N2OAg 410.8997; Found 410.8982. 5-Chloromethyl-3-(2,2,2-trichloro-1-phenylethyl)-1,2,4-oxadiazole (2c). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), benzene (19 mg, 0.24 mmol), and chloroacetonitrile (5 mL). Transparent oil. 1H NMR, δ, ppm: 4.72 s (2H), 5.37 s (1H), 7.39−7.42 m (3H), 7.76−7.78 m (2H). 13C{1H} NMR, δ, ppm: 33.4, 63.1, 98.6, 128.5, 129.5, 131.5, 132.8, 168.2, 174.6. IR (KBr, cm−1): 1585 (CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H8Cl4N2ONa 348.9254; Found 348.9250. 5-Cyclopropyl-3-(2,2,2-trichloro-1-phenylethyl)-1,2,4-oxadiazole (2d). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), benzene (19 mg, 0.24 mmol), and cyclopropanecarbonitrile (172 mg, 2.56 mmol). Yield 18 mg (35%). Transparent oil. Purification by preparative TLC with a mixture of petroleum ether−ethyl acetate, 9:1. 1 H NMR, δ, ppm: 1.23−1.28 m (4H), 2.20−2.27 m (1H), 5.26 s (1H), 7.37−7.40 m (3H), 7.76−7.78 m (2H). 13C{1H} NMR, δ, ppm: 8.0, 10.58, 10.60, 63.2, 99.0, 128.3, 129.3, 131.6, 133.2, 167.5, 181.7. IR (KBr, cm−1): 1581(CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H11Cl3N2ONa 338.9830; Found 338.9830. 3-(2,2,2-Trichloro-1-phenylethyl)-5-phenyl-1,2,4-oxadiazole (2e). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), benzene

Scheme 6. Reactions of Nitrostyrenes 1b−1f with Arenes and Nitriles in TfOH Leading to Oxadiazoles 2o−2zb

= Ar′ in Scheme 3) and, therefore, higher selectivity of reactions of these species. Structures of compounds 2i, 2n, 2o, and 2x were additionally confirmed by X-ray analysis data (see Supporting Information).

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CONCLUSION We have developed a novel synthesis of 1,2,4-oxadiazoles based on the tandem reaction of nitroalkenes with arenes and nitriles in the superacid TfOH. This reaction is a general method for the synthesis of 1,2,4-oxadiazole derivatives. The method is tolerant to various substituents in starting compounds (nitroalkenes, arenes, and nitriles), at least, to groups, which are stable under superacidic solvation.

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EXPERIMENTAL SECTION

The NMR spectra of solutions of compounds in CDCl3 were recorded at 400, 376, and 100 MHz for 1H, 19F, and 13C NMR spectra, respectively, at 23 °C. The hydrogen residual signals of CDCl3 (δ 7.26 ppm) for 1H NMR spectra and the carbon signals of CDCl3 (δ 77.0 ppm) for 13C NMR were used as references. 19F NMR were indirectly referred to the signal of CFCl3 (δ 0.0 ppm). IR spectra of compounds were taken in KBr. High-resolution mass spectrometry (HRMS) was performed in electrospray ionization (ESI) mode. The preparative reactions were monitored by thin-layer chromatography (TLC) performed on silica gel plates using UV light for detection. Preparative TLC was performed on silica gel 5−40 μm. X-ray Diffraction Study. A suitable crystal was selected and studied on the diffractometer. The crystal was kept at 100(2) K during data collection. With Olex2,31 the structure was solved with the ShelXS32 structure solution program using Direct Methods and refined with the ShelXL refinement package using Least Squares C

DOI: 10.1021/acs.joc.9b00812 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry (19 mg, 0.24 mmol), and benzonitrile (230 mg, 2.24 mmol). Yield 16 mg (28%). Transparent oil. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 5.41 s (1H), 7.40−7.41 m (3H), 7.52−7.56 m (2H), 7.59−7.63 m (1H), 7.85−7.88 m (2H), 8.16−8.19 m (2H). 13C{1H} NMR, δ, ppm: 63.3, 99.0, 124.1, 128.4, 128.4, 129.3, 129.4, 131.7, 133.2, 133.2, 168.3, 175.9. IR (KBr, cm−1): 1562 (CN). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H12Cl3N2O 353.0010; Found 353.0007. 3-(2,2,2-Trichloro-1-(4-methylphenyl)ethyl)-5-methyl-1,2,4oxadiazole (2f). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), toluene (22 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 25 mg (53%). Transparent oil. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.36 s (3H), 2.62 s (3H), 5.28 s (1H), 7.20 d (2H, J 7.95 Hz), 7.64−7.66 m (2H). 13C{1H} NMR, δ, ppm: 12.6, 21.3, 62.9, 99.1, 129.1, 130.3, 131.4, 139.4, 167.8, 176.8. IR (KBr, cm−1): 1585 (CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H11Cl3N2ONa 326.9830; Found 326.9830. 3-(2,2,2-Trichloro-1-(3,4-dimethylphenyl)ethyl)-5-methyl1,2,4-oxadiazole (2g). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), 1,2-dimethylbenzene (25 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 48 mg (94%). Transparent oil. 1H NMR, δ, ppm: 2.27 s (3H), 2.29 s (3H), 2.63 s (3H), 5.26 s (1H), 7.14− 7.17 m (1H), 7.50−7.51 m (2H). 13C{1H} NMR, δ, ppm: 12.6, 19.7, 20.0, 63.0, 99.0, 128.8, 129.7, 130.6, 132.5, 136.7, 138.0, 167.8, 176.7. IR (KBr, cm−1): 1585 (CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H13Cl3N2ONa 340.9986; Found 340.9987. 3-(2,2,2-Trichloro-1-(2,4-dimethylphenyl)ethyl)-5-methyl1,2,4-oxadiazole (2h). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), 1,3-dimethylbenzene (25 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 45 mg (88%). Yellowish oil. 1H NMR, δ, ppm: 2.32 s (3H), 2.54 s (3H), 2.60 s (3H), 5.67 s (1H), 7.06−7.08 m (2H), 8.02−8.05 m (1H). 13C{1H} NMR, δ, ppm: 12.6, 20.7, 21.2, 57.2, 99.6, 126.9, 129.3, 130.3, 131.8, 138.0, 139.1, 168.0, 176.7. IR (KBr, cm−1): 1585 (CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H13Cl3N2ONa 340.9986; Found 340.9990. 3-(2,2,2-Trichloro-1-(2,5-dimethylphenyl)ethyl)-5-methyl1,2,4-oxadiazole (2i). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), 1,4-dimethylbenzene (25 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 30 mg (59%). Colorless solid, mp 97−97 °C. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.35 s (3H), 2.54 s (3H), 2.61 s (3H), 5.69 s (1H), 7.04−7.15 m (2H), 7.92 s (1H). 13C{1H} NMR, δ, ppm: 12.6, 20.3, 21.3, 57.5, 99.4, 130.0, 130.8, 130.9, 132.0, 135.0, 135.7, 167.9, 176.7. IR (KBr, cm−1): 1582 (CN). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for C13H13Cl3N2OAg 424.9153; Found 424.9139. 3-(2,2,2-Trichloro-1-(2,4,5-trimethylphenyl)ethyl)-5-methyl1,2,4-oxadiazole (2j). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), 1,2,4-trimethylbenzene (28 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 49 mg (92%). Transparent oil. 1H NMR, δ, ppm: 2.23 s (3H), 2.26 s (3H), 2.52 s (3H), 2.61 s (3H), 5.65 s (1H), 7.02 s (1H), 7.86 s (1H). 13C{1H} NMR, δ, ppm: 12.6, 19.5, 19.7, 20.1, 57.4, 99.6, 129.5, 131.3, 132.3, 134.3, 135.3, 137.8, 168.0, 176.6. IR (KBr, cm−1): 1586 (CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H15Cl3N2ONa 355.0143; Found 355.0146. 5-Methyl-3-(2,2,2-trichloro-1-(2,4,6-trimethylphenyl)ethyl)1,2,4-oxadiazole (2k). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), 1,3,5-trimethylbenzene (28 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 22 mg (42%). Yellowish oil. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.18 s (3H), 2.27 s (3H), 2.58 s (3H), 2.60 s (3H), 5.83 s (1H), 6.85 s (1H), 6.97 s (1H). 13C{1H} NMR, δ, ppm: 12.4, 21.0, 22.1, 22.8, 60.0, 98.8, 129.1, 130.1, 132.1, 138.3, 138.9, 139.9, 168.2, 176.3. IR (KBr): 1588 cm−1 (CN). HRMS (ESITOF) m/z: [M + H]+ Calcd for C14H16Cl3N2O 333.0323; Found 333.0320. 5-Methyl-3-(2,2,2-trichloro-1-(2,3,5,6-tetramethylphenyl)ethyl)-1,2,4-oxadiazole (2l). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), 1,2,4,5-tetramethylbenzene (25 mg, 0.19 mmol), and

acetonitrile (5 mL). Yield 19 mg (34%). Reddish solid, mp 139−140 °C. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.07 s (CH3), 2.16 s (CH3), 2.31 s (CH3), 2.48 s (CH3), 2.59 s (CH3), 6.04 s (1H), 7.05 s (1H). 13C{1H} NMR, δ, ppm: 12.4, 18.3, 19.1, 20.9, 21.8, 60.1, 98.9, 132.1, 133.3, 134.45, 134.51, 135.9, 136.1, 168.8, 176.3. IR (KBr): 1588 cm−1 (CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H17Cl3N2ONa 369.0299; Found 369.0299. 3-(2,2,2-Trichloro-1-(4-methoxyphenyl)ethyl)-5-methyl1,2,4-oxadiazole (2m). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), methoxybenzene (25 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 17 mg (33%). Transparent oil. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1 H NMR, δ, ppm: 2.63 s (3H), 3.81 s (3H), 5.25 s (1H), 6.88−6.92 m (2H), 7.67−7.70 m (2H). 113C{1H} NMR, δ, ppm: 12.6, 55.4, 62.5, 99.3, 113.8, 125.2, 132.8, 160.4, 167.8, 176.8. IR (KBr, cm−1): 1588 (CN). HRMS (ESI-TOF) m/z: [M + Na] + Calcd for C12H11Cl3N2O2Na 342.9779; Found 342.9775. 3-(2,2,2-Trichloro-1-(2,5-dimethoxylphenyl)ethyl)-5-methyl-1,2,4-oxadiazole (2n). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), 1,2-dimethoxybenzene (33 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 19 mg (34%). Yellowish solid, mp 144− 146 °C. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.63 s (3H), 3.88 s (3H), 3.90 s (3H), 5.24 s (1H), 6.86 d (1H, J 8.4 Hz), 7.28 dd (1H, J 8.4, 2.2 Hz), 7.34 d (1H, J 2.2 Hz). 13C{1H} NMR, δ, ppm: 12.6, 56.0, 56.2, 62.8, 99.2, 110.7, 114.6, 124.4, 125.4, 148.6, 145.0, 167.8, 176.7. IR (KBr, cm−1): 1578 (CN). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for C13H13Cl3N2O3Ag 456.9057; Found 456.9037. 5-Methyl-3-(diphenylmethyl)-1,2,4-oxadiazole (2o). Obtained from the β-nitrostyrene 1b (30 mg, 0.2 mmol), benzene (16 mg, 0.2 mmol), and acetonitrile (5 mL). Yield 19 mg (34%). Colorless solid, mp 75−76 °C. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.57 s (3H), 5.60 s (1H), 7.24−7.38 m (10H). 13C{1H} NMR, δ, ppm: 12.6, 48.8, 127.4, 128.8, 128.9, 139.7, 171.8, 176.8. IR (KBr, cm−1): 1586 (CN). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for C16H14N2OAg 357.0161; Found 357.0152. 3-(Diphenylmethyl)-5-phenyl-1,2,4-oxadiazole (2p). Obtained from the β-nitrostyrene 1b (30 mg, 0.2 mmol), benzene (16 mg, 0.2 mmol), and benzonitrile (200 mg, 2.0 mmol). Yield 50 mg (79%). Transparent oil. 1H NMR, δ, ppm: 5.72 s (1H), 7.28−7.31 m (2H), 7.35−7.39 m (4H), 7.44−7.45 m (4H), 7.49−7.53 m (2H), 7.56−7.60 m (1H), 8.15−8.17 m (2H). 13C{1H} NMR, δ, ppm: 49.0, 124.4, 127.3, 128.3, 128.7, 129.0, 129.1, 132.8, 139.9, 172.4, 175.9. IR (KBr, cm−1): 1561. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H16N2ONa 335.1155; Found 335.1162. 5-Cyclopropyl-3-(diphenylmethyl)-1,2,4-oxadiazole (2q). Obtained from the β-nitrostyrene 1b (30 mg, 0.2 mmol), benzene (16 mg, 0.2 mmol), and cyclopropanecarbonitrile (135 mg, 2.0 mmol). Yield 41 mg (74%). Transparent oil. 1H NMR, δ, ppm: 1.17− 1.24 m (4H), 2.17−2.23 m (1H), 5.56 s (1H), 7.24−7.28 m (2H), 7.31−7.35 m (8H). 13C{1H} NMR, δ, ppm: 8.0, 10.2, 48.9, 127.3, 128.7, 128.9, 139.9, 171.6, 181.6. IR (KBr, cm−1): 1581. HRMS (ESITOF) m/z: [M + Na]+ Calcd for C18H16N2ONa 299.1155; Found 299.1160. 3-((2,5-Dimethylphenyl)phenylmethyl)-5-methyl-1,2,4-oxadiazole (2r). Obtained from the β-nitrostyrene 1b (30 mg, 0.2 mmol), p-xylene (22 mg, 0.2 mmol), and acetonitrile (5 mL). Yield 52 mg (93%). Yellow solid, mp 102−104 °C. 1H NMR (CDCl3, 400 MHz) δ, ppm: 7.35−7.31 (m, 2H), 7.28−7.27 (m, 1H), 7.25−7.24 (m, 1H), 7.10−7.06 (m, 2H), 7.02−7.00 (m, 1H), 5.76 (s, 1H), 2.58 (s, 3H), 2.28 (s, 6H). 13C{1H} NMR (CDCl3, 101 MHz) δ, ppm: 176.6, 171.9, 139.1, 137.4, 135.6, 133.2, 130.6, 129.3, 128.9, 128.6, 128.1, 127.1, 45.3, 21.2, 19.3, 12.5. IR (KBr, cm−1): 1586 (CN). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O 279.1492; Found 279.1501. 3-((3,4-Dimethylphenyl)-phenylmethyl)-5-phenyl-1,2,4-oxadiazole (2s). Obtained from the β-nitrostyrene 1b (30 mg, 0.2 mmol), o-xylene (22 mg, 0.2 mmol), and benzonitrile (200 mg, 2.0 D

DOI: 10.1021/acs.joc.9b00812 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry mmol). Yield 47 mg (69%). Yellowish oil. 1H NMR, δ, ppm: 2.26 s (6H), 5.66 s (1H), 7.12−7.20 m (3H), 7.27−7.30 m (1H), 7.34−7.38 m (2H), 7.43−7.45 m (2H), 7.49−7.53 m (2H), 7.56−7.60 m (1H). 13 C{1H} NMR, δ, ppm: 19.5, 20.0, 48.7, 124.5, 126.4, 127.2, 128.3, 128.7, 129.0, 129.1, 130.0, 130.2, 132.7, 135.7, 136.9, 137.3, 140.1, 172.6, 175.8. IR (KBr, cm−1): 1562. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H21N2O 341.1649; Found 341.1656. 5-Methyl-3-((4-methylphenyl)phenylmethyl)-1,2,4-oxadiazole (2t). Obtained from the p-methyl-β-nitrostyrene 1c (30 mg, 0.18 mmol), benzene (22 mg, 0.28 mmol), and acetonitrile (5 mL). Yield 39 mg (81%). Yellowish oil. 1H NMR, δ, ppm: 2.34 s (3H), 2.57 s (3H), 5.57 s (1H), 7.15 d (2H, J 7.9), 7.24 d (2H, J 8.1 Hz), 7.26− 7.36 m (5H). 13C{1H} NMR, δ, ppm: 12.6, 21.1, 48.4, 127.3, 128.7, 128.78, 128.84, 129.4, 136.7, 137.0, 139.9, 172.0, 176.7. IR (KBr, cm−1): 1587 (CN). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for C17H16N2OAg 371.0320; Found 371.0308. 3-((2,5-Dimethylphenyl)-(4-methylphenyl)methyl)-5-methyl-1,2,4-oxadiazole (2u). Obtained from the p-methyl-β-nitrostyrene 1c (30 mg, 0.18 mmol), p-xylene (29 mg, 0.28 mmol), and acetonitrile (5 mL). Yield 34 mg (64%). Yellowish oil. 1H NMR, δ, ppm: 2.26 s (3H), 2.28 s (3H), 2.33 s (3H), 2.58 s (3H), 5.70 s (1H), 6.98−7.01 m (1H), 7.03−7.08 m (2H), 7.13 s (4H). 13C{1H} NMR, δ, ppm: 12.6, 19.4, 21.2, 21.3, 45.1, 128.1, 128.9, 129.3, 129.4, 130.7, 133.2, 135.7, 136.1, 136.8, 137.7, 172.2, 176.7. IR (KBr, cm−1): 1587 (CN). HRMS (ESI-TOF) m/z: [M + Na] + Calcd for C19H20N2ONa 315.1458; Found 315.1468. 3-((4-Methylphenyl)phenylmethyl)-5-phenyl-1,2,4-oxadiazole (2v). Obtained from the p-methyl-β-nitrostyrene 1c (30 mg, 0.18 mmol), benzene (22 mg, 0.28 mmol), and benzonitrile (98 mg, 0.93 mmol). Yield 19 mg (32%). Transparent oil. Purification by preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1. 1 H NMR, δ, ppm: 2.33 s (3H), 5.65 s (1H), 7.15 d (2H, J 8.0 Hz), 7.28−7.35 m (5H), 7.39−7.41 m (2H), 7.48−7.52 m (2H), 7.55− 7.59 m (1H), 8.12−8.15 m (2H). 13C{1H} NMR, δ, ppm: 21.2, 48.7, 124.5, 127.3, 128.4, 128.7, 128.9, 129.0, 129.1, 129.5, 132.8, 136.9, 137.0, 140.1, 172.6, 175.9. IR (KBr, cm−1): 1561. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H18N2ONa 349.1312; Found 349.1318. 3-((4-Fluorolphenyl)phenylmethyl)-5-methyl-1,2,4-oxadiazole (2w). Obtained from the p-fluoro-β-nitrostyrene 1d (30 mg, 0.18 mmol), benzene (21 mg, 0.27 mmol), and acetonitrile (5 mL). Yield 37 mg (77%). Transparent oil. 1H NMR, δ, ppm: 2.58 s (3H), 5.57 s (1H), 6.96−7.06 m (2H), 7.27−7.36 m (7H). 13C{1H} NMR, δ, ppm: 12.6, 48.0, 115.9 d (J 21.5 Hz), 127.5, 128.8, 128.9, 130.5 d (J 8.0 Hz), 135.5 d (J 3.4 Hz), 139.6, 162.1 d (J 247.1 Hz), 171.7, 176.9. 19 F NMR, δ, ppm: −115.39 s. IR (KBr, cm−1): 1587 (CN). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for C16H13FN2OAg 375.0070; Found 375.0070. 3-((4-Fluorophenyl)-(2,5-dimethylphenyl)methyl)-5-methyl-1,2,4-oxadiazole (2x). Obtained from the p-fluoro-β-nitrostyrene 1d (30 mg, 0.18 mmol), p-xylene (29 mg, 0.27 mmol), and acetonitrile (5 mL). Yield 48 mg (90%). Colorless solid, mp 93−94 °C. 1H NMR, δ, ppm: 2.26 s (3H), 2.28 s (3H), 2.59 s (3H), 5.22 s (1H), 6.99−7.03 m (4H), 7.08 d (1H, J 8.1 Hz), 7.19−7.23 m (2H). 13 C{1H} NMR, δ, ppm: 12.6, 19.3, 21.3, 44.7, 115.5 d (J 21.5 Hz), 128.3, 129.2, 130.6 d (J 8.1 Hz), 130.8, 133.2, 134.9 d (J 3.2 Hz), 135.8, 137.3, 162.0 d (J 245.9 Hz) 171.9, 176.9. 19F NMR, δ, ppm: −115.5 s. IR (KBr, cm−1): 1588 (CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H17FN2ONa 319.1203; Found 319.1217. 3-((4-Chlorophenyl)phenylmethyl)-5-methyl-1,2,4-oxadiazole (2y). Obtained from the p-chloro-β-nitrostyrene 1e (30 mg, 0.16 mmol), benzene (19 mg, 0.25 mmol), and acetonitrile (5 mL). Yield 45 mg (96%). Yellowish oil. 1H NMR, δ, ppm: 2.58 s (3H), 5.56 s (1H), 7.27−7.30 m (5H), 7.31−7.32 m (3H), 7.33−7.34 m (1H). 13 C{1H} NMR, δ, ppm: 12.6, 48.1, 127.6, 128.8, 128.87, 128.90, 130.3, 133.3, 138.2, 139.3, 171.5, 177.0. IR (KBr, cm−1): 1587 (C N). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for C16H13ClN2O 390.9766; Found 390.9762. 3-((4-Chlorophenyl)-(2,5-dimethylphenyl)methyl)-5-methyl-1,2,4-oxadiazole (2z). Obtained from the p-chloro-β-nitrostyrene 1e (30 mg, 0.16 mmol), p-xylene (26 mg, 0.25 mmol), and

acetonitrile (5 mL). Yield 46 mg (90%). Yellowish oil. 1H NMR, δ, ppm: 2.25 s (3H), 2.27 s (3H), 2.59 s (3H), 5.70 s (1H), 6.99−7.01 m (2H), 7.08 d (1H, J 7.5 Hz), 7.16−7.18 m (2H), 7.27−7.30 m (2H). 13C{1H} NMR, δ, ppm: 12.6, 19.4, 21.3, 44.8, 128.4, 128.9, 129.2, 130.4, 130.9, 133.19, 133.21, 135.9, 137.0, 137.8, 171.7, 176.9. IR (KBr, cm−1): 1587 (CN). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H18ClN2O 313.1101; Found 313.1102. 3-((4-Bromophenyl)phenylmethyl)-5-methyl-1,2,4-oxadiazole (2za). Obtained from the p-bromo-β-nitrostyrene 1f (30 mg, 0.13 mmol), bezene (15 mg, 0.2 mmol), and acetonitrile (5 mL). Yield 42 mg (93%). Yellowish oil. 1H NMR, δ, ppm: 2.58 s (3H), 5.44 s (1H), 7.20−7.22 m (2H), 7.27−7.35 m (5H), 7.44−7.46 m (2H). 13 C{1H} NMR, δ, ppm: 12.6, 48.2, 121.5, 127.6, 128.8, 128.9, 130.7, 131.9, 138.8, 139.2, 171.4, 177.0. IR (KBr, cm−1): 1585 (CN). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H14BrN2O 329.0294; Found 329.0284. 3-((4-Bromophenyl)-(2,5-dimethylphenyl)methyl)-5-methyl-1,2,4-oxadiazole (2zb). Obtained from the p-bromo-β-nitrostyrene 1f (30 mg, 0.13 mmol), p-xylene (21 mg, 0.2 mmol), and acetonitrile (5 mL). Yield 45 mg (96%). Yellowish oil. 1H NMR, δ, ppm: 2.25 s (3H), 2.27 s (3H), 2.60 s (3H), 5.68 s (1H), 7.00 d (2H, J 10.1 Hz) 7.07−7.12 m (3H), 7.44 d (2H, J 8.44 Hz). 13C{1H} NMR, δ, ppm: 12.6, 19.4, 21.3, 44.9, 121.3, 128.5, 129.2, 130.8, 130.9, 131.8, 133.2, 135.9, 137.0, 138.3, 171.6, 176.9. IR (KBr, cm−1): 1586 (CN). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H18BrN2O 357.0610; Found 357.0597.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00812. 1 H, 13C NMR and IR spectra of compounds (PDF) X-ray data (CIF) X-ray data (CIF) X-ray data (CIF) X-ray data (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected] ORCID

Aleksander V. Vasilyev: 0000-0003-3628-1492 Notes

The authors declare no competing financial interest. CCDC 1888351 (2i), CCDC 1894770 (2n), CCDC 1894769 (2o), and CCDC 1894768 (2x) contain the supplementary crystallographic data, which can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (internat.) + 44-1223-336033; E-mail: [email protected].

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ACKNOWLEDGMENTS This work was supported by Russian Scientific Foundation (Grant No. 18-13-00008). Spectral studies were performed at Center for Magnetic Resonance, Center for Chemical Analysis and Materials Research, and Research Center for X-ray Diffraction Studies of Saint Petersburg State University, Saint Petersburg, Russia. A.A.G. thanks O. Brunko for support of this work.

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REFERENCES

(1) Vivona, N.; Buscemi, S. An Assay for 1,2,4- and 1,2,5Oxadiazoles. Heterocycles 1995, 41, 2095−2116.

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DOI: 10.1021/acs.joc.9b00812 J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.9b00812 J. Org. Chem. XXXX, XXX, XXX−XXX