Note pubs.acs.org/joc
Application of N‑Acylbenzotriazoles in the Synthesis of 5‑Substituted 2‑Ethoxy-1,3,4-oxadiazoles as Building Blocks toward 3,5Disubstituted 1,3,4-Oxadiazol-2(3H)‑ones Sirawit Wet-osot,†,‡ Wong Phakhodee,†,§ and Mookda Pattarawarapan*,†,§ †
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, ‡Graduate School, and §Center of Excellence in Materials Science and Technology, Chiang Mai University, Chiang Mai 50200, Thailand S Supporting Information *
ABSTRACT: 5-Substituted-2-ethoxy-1,3,4-oxadiazoles were conveniently prepared through a one-pot sequential Nacylation/dehydrative cyclization between ethyl carbazate and N-acylbenzotriazoles in the presence of Ph3P−I2 as a dehydrating agent. Subsequent treatment with a stoichiometric amount of alkyl halides (X = Cl, Br, I) enables a rapid access to a variety of 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-ones in good to excellent yields.
R
reaction times, and requirement of linear assembly of reactants using multistep synthesis. Convergent approach toward the synthesis of 1,3,4-oxadiazol-2(3H)-one derivatives with the flexibility to incorporate various substituent groups at both 3and 5-positions is thus highly desirable. In this regard, we have developed a convenient one-pot twostep method for constructing ethoxy-substituted 1,3,4-oxadiazoles coupled with their conversion toward 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-ones (Scheme 1). Based on our previous experiences involving the synthetic application of N-acylbenzotriazoles and phosphine-mediated reactions,19 it was envisaged that a one-pot procedure through N-acylation of ethyl carbazate with N-acylbenzotriazoles 1, followed by Ph3P−I2-mediated dehydrative cyclization, should directly give rise to ethoxy-substituted 1,3,4-oxadiazoles 2. 3,5Disubstituted 1,3,4-oxadiazol-2(3H)-ones 3 could then be obtained through N-alkylation of 2 with inexpensive and readily available alkyl halides. It is important to note that unlike the previously described method requiring multistep preparation of the starting oxadiazoles and ineffective thermal alkylation with excess alkyl iodides,13,14 we have devised an improved protocol under milder conditions using stoichiometric amount of alkyl halides (X = Cl, Br, I). We set out to explore the one-pot procedure toward 2 using ethyl carbazate and N-benzoylbenzotriazole as the model substrates. Although the synthesis of acylhydrazines from Nacylbenzotriazoles has previously been reported in THF without any base or additives at room temperature,20 we decided to perform the first acylation step in dichloromethane in favor to the subsequent cyclization mediated by the Ph3P−I2 system. Unfortunately, it was found that ethyl 2-benzoylhydrazine-1-carboxylate was afforded in low amount when ethyl
ecently, there has been a growing interest in the synthesis and application of 2,5-disubstituted 1,3,4-oxadiazoles.1 Owing to their unique characteristics, including a broad range of biological activities2 as well as excellent electron-transporting properties,3 1,3,4-oxadiazoles are promising candidates in drug discovery, agrochemicals, and material development. Among the derivatives, 5-substituted 2-alkoxy-1,3,4-oxadiazole has received less attention4 despite the fact that compounds possessing this structural motif have been shown to exhibit kinase inhibition (I)5 as well as antifungal (II)4d and antibacterial (III)4d activities (Figure 1). Interestingly, it can also be used as a building block toward other valuable products such as 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-ones.6 The representative examples of bioactive oxadiazolones are IV (openers of large-conductance Ca2+-activated potassium (MaxiK) channels),7 V (selective inhibitor of monoamine oxidase type B),8 VI (potent human recombinant fatty acid amide hydrolase inhibitor),9 and VII (effective agent at stimulating neural stem cell maturation).10 According to Scheme 1, a number of methods have been introduced for the synthesis of 3,5-disubstituted 1,3,4oxadiazol-2(3H)-ones. The selected examples include (i) Nalkylation of alkoxy-substituted 1,3,4-oxadiazoles;6b,c (ii) Nalkylation of 1,3,4-oxadiazole-2-(3H)-ones using alkyl halides7,8a,11 or alcohol;12 (iii) decarboxylative cyclization of Nacylhydrazine-1,2-dicarboxylates derived from Mitsunobu reagents;13 (iv) oxidative cyclization and rearrangement of alkyl carbazates and aldehydes;14 (v) palladium-catalyzed oxidative carbonylation of hydrazides;15 (vi) one-pot reaction of acylhydrazines, carbon disulfide, propylene oxide, and organic halides under refluxing in water;16 (vii) cyclization of Nsubstituted acylhydrazines using phosgene;17 and (viii) 1,3dipolar cycloaddition of nitrile imine and carbon dioxide.18 Nevertheless, the existing procedures still involve the use of hazardous or expensive reagents, harsh conditions, long © 2017 American Chemical Society
Received: July 26, 2017 Published: September 1, 2017 9923
DOI: 10.1021/acs.joc.7b01863 J. Org. Chem. 2017, 82, 9923−9929
Note
The Journal of Organic Chemistry
Figure 1. Examples of bioactive compounds containing a 1,3,4-oxadiazole or 1,3,4-oxadiazol-2(3H)-one unit.
Scheme 1. Previously Reported Methods and Our Approach toward 3,5-Disubstituted 1,3,4-Oxadiazolones
carbazate was treated with N-benzoylbenzotriazole in the absence of base, even under ultrasonic irradiation (see Table S1). In the presence of triethylamine, N-acylation proceeded smoothly within 30 min. However, no oxadiazole formation was observed after subsequent treatment with Ph3P−I2, suggesting some interference of the remaining species from the first step. To our delight, when using potassium carbonate with the addition of a catalytic amount of DMAP (10 mol %), the time for the N-acylation step was reduced to ca. 10 min. Subsequent treatment with Ph3P−I2 and Et3N then gave rise to the desired product 2a in 86% yield within 5 min stirring at room temperature. Without necessity to further optimize the reaction conditions, we then focus on the synthesis of 2 through a one-pot sequential acylation−dehydrative cyclization between ethyl carbazate with N-acylbenzotriazoles (1). As summarized in Scheme 2, oxadiazoles 2 were afforded in good to excellent
yields within 5 min cyclization. The developed conditions were found to be compatible with substrates containing electrondonating as well as electron-withdrawing groups such as pOMe, p-Cl, p-Br, p-I, m-NMe2, or m-NO2, though the presence of a strong electron-withdrawing p-NO2 group lowered the yield of product 2e. Substrates bearing a sterically hindered o-I, o-OMe, or o-NPh group reacted smoothly to give good yields of 2f−2h. Additionally, other oxadiazoles having biphenyl (2k), naphthyl (2l), alkyl (2m), conjugated (2n), reactive hydroxy (2o), and heterocyclic (2p) functionalities could be prepared in satisfactory yields. With a series of 2 in hand, the N-alkylation conditions toward the synthesis of 3,5-disubstituted 1,3,4-oxadiazol-2(3H)ones 3 were optimized. Based on the previous studies, conversions of 2 into 3 require prolonged heating with an excess of alkyl halide at high temperatures (160−250 °C).6b,c To obtain the best conditions, we decided to carry out the 9924
DOI: 10.1021/acs.joc.7b01863 J. Org. Chem. 2017, 82, 9923−9929
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The Journal of Organic Chemistry Scheme 2. Synthesis of 5-Substituted 2-Ethoxy-1,3,4-oxadiazoles 2
reaction in a pressure tube under heating in a preset oil bath. By simply heating 2a with benzyl chloride (1.2 equiv) in DMF at 180 °C for 30 min, a complex mixture was obtained. Lowering the temperature to 120 °C gave no conversion. However, Nalkylation in the presence of Et3N (1.2 equiv) and a catalytic amount of KI (10 mol %) rapidly provided the desired oxadiazolone product 3a in 85% yield within 5 min (Scheme 3). The reaction was also found to proceed smoothly with other primary benzylic halides containing electron-withdrawing, electron-donating, as well as vinyl groups (see compounds 3b−3d). In the synthesis of 3d and 3e, the presence of a polymerizable styryl group could be tolerated. The substrates bearing electron-withdrawing or electron-donating groups reacted with benzyl chloride to afford the products 3f and 3g in satisfactory yields. It should be noted that, using the method in route iv (Scheme 1), the direct thermal rearrangement of the in situ generated 5-(4-nitrophenyl)-1,3,4-oxadiazoles bearing −OMe or −OBn groups only gave a decomposed mixture without the desired oxadiazolones.14 With the success in the synthesis of N-benzyl derivatives, substrate scope was further extended to other types of alkyl halides. Compared to primary benzyl halides, methyl iodide and isobutyl bromide were less effective, giving products 3h and 3i, respectively, in lower yields. Whereas the desired product 3j could be obtained in moderate yield using secondary allylic halide, an attempt to use secondary benzylic halides such as (1bromoethyl)benzene failed to give the desired product. Instead, the de-ethylated product, 5-phenyl-1,3,4-oxadiazole-2-(3H)-one (4), and the product derived from O- to N-ethyl migration (5) were obtained in 40 and 45%, respectively. It was initially believed that competing β-elimination of the halide substrate may liberate HBr to catalyze the de-ethylation process,6d
whereas the ethyl migration should be feasible in the absence of an alkyl halide. However, 1H NMR analysis of the crude products revealed no trace of styrene byproduct but the presence of 1-phenylethanol along with its corresponding formate ester derived from thermal reaction of (1-bromoethyl)benzene with DMF (see Figure S1 in the Supporting Information).21 Thus, the mechanism underlying the formation of 4 and 5 remains unclear and requires further investigation. It should be noted that the synthesis of 2 and 3 could be carried out in gram scale without complication, except that longer times are required for the reaction to complete. Starting with N-benzoylbenzotriazole (5.00 g, 22.2 mmol) and ethyl carbazate (2.54 g, 24.4 mmol), compound 2a was obtained in 84% yield (3.55 g) after ca. 1 h. Conversion of 2a into 3d, 3l, and 3m using 1.00 g (5.26 mmol) of 2a and the corresponding chlorides (6.312 mmol) for each reaction also gave high yields of the products after 15 min stirring at 120 °C in a pressure tube (Scheme 3). To gain a mechanistic insight, control experiments were further carried out. When 2a was subjected to the abovedescribed conditions in the absence of an alkyl halide, only the thermal rearrangement product 5 was formed in 37% without detectable de-ethylated product 4 (Scheme 4a). Whereas treatment of 5 with benzyl chloride led to no conversion to 3a, 4 underwent rapid benzylation to give 3a in high yield (Scheme 4b,c). These results suggested that 5 is not the reactive species. Although the formation of 3 through 4 is possible, it is highly unlikely that 4 is the key intermediate as it was not generally observed even in the absence of alkyl halide. Thus, the plausible mechanism for the Ph3P−I2-mediated formation of 2 and its conversion into 3 is shown in Scheme 5. N-Acylation of ethyl carbazate with N-acylbenzotriazole provides the corresponding hydrazide, which undergoes 9925
DOI: 10.1021/acs.joc.7b01863 J. Org. Chem. 2017, 82, 9923−9929
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The Journal of Organic Chemistry Scheme 3. Synthesis of 3,5-Disubstituted 1,3,4-Oxadiazol-2(3H)-ones 3
substitution of 2 with R2X, followed by de-ethylation of the Oethyl group with halide ions or possibly with triethylamine. In summary, we have developed a convenient one-pot approach for the preparation of 5-substituted 2-ethoxy-1,3,4oxadiazoles directly from N-acylbenzotriazoles. The reaction proceeded rapidly under mild conditions with functional group tolerance. These compounds served as versatile building blocks toward a variety of 3,5-disubstituted 1,3,4-oxadiazol-2(3H)ones, which may be difficult to obtain with previously reported procedures.
Scheme 4. Control Experiments
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EXPERIMENTAL SECTION
General Information. All reagents were purchased from SigmaAldrich Co., USA, and used without further purification. NAcylbenzotriazoles were synthesized according to our reported procedure.19a,d The acylation step was performed in an ultrasonic bath equipped with thermostat operating at 37 kHz (Elmasonic S30(H), Germany). The reaction was monitored by thin-layer chromatography carried out on silica gel plates (60F254, MERCK, Germany) and visualized under UV light (254 nm). Melting points were determined using Mettler Toledo DSC equipment at a heating
phosphorylation with phosphonium iodide before cyclization to give 2. N-Alkylation of 2 could proceed via nucleophilic 9926
DOI: 10.1021/acs.joc.7b01863 J. Org. Chem. 2017, 82, 9923−9929
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The Journal of Organic Chemistry Scheme 5. Plausible Mechanism for the Formation of 2 and 3
rate of 6 °C/min and are uncorrected. NMR spectra were determined using a Bruker AVANCE (400 MHz for 1H). Chemical shifts were reported in parts per million (ppm, δ) downfield from TMS. Highresolution mass spectra (HRMS) were recorded using the LC-DADESI-MS/MS system that consisted of a Waters Alliance 2695 LC-DAD and a Q-TOF 2 (quadrupole mass filter-time-of-flight) mass spectrometer with a Z-spray ES source. General Procedure for the Synthesis of 5-Substituted 2Ethoxy-1,3,4-oxadiazoles 2. A mixture of N-acylbenzotriazole 1 (0.54 mmol), ethyl carbazate (0.59 mmol), DMAP (6.6 mg, 0.054 mmol), and K2CO3 (0.0895 g, 0.648 mmol) in dry CH2Cl2 (2 mL) was sonicated in an ultrasonic bath for 10 min or until complete amide bond formation based on TLC. I2 (0.2056 g, 0.81 mmol) and Ph3P (0.2125 g, 0.81 mmol) were then added to the solution at 0 °C with stirring. After that, the mixture was treated with Et3N (0.164 g, 1.62 mmol) and stirred at room temperature for 5 min. The crude mixture was concentrated under reduced pressure and then purified by column chromatography using 5−20% ethyl acetate in hexane. 2-Ethoxy-5-phenyl-1,3,4-oxadiazole (2a): 6a white solid (0.0886 g, 86% yield); mp 119−120 °C; Rf 0.32 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.94−7.91 (m, 2H), 7.48−7.43 (m, 3H), 4.60 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 160.6, 131.3, 129.0, 126.2, 124.2, 69.3, 14.4. 2-Ethoxy-5-(4-methoxyphenyl)-1,3,4-oxadiazole (2b): 22 white solid (0.1073 g, 90% yield); mp 81−83 °C; Rf 0.31 (10% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 4.54 (q, J = 7.2 Hz, 1H), 3.80 (s, 3H), 1.47 (t, J = 7.2 Hz, 2H). 2-(4-Chlorophenyl)-5-ethoxy-1,3,4-oxadiazole (2c): 23 white solid (0.1071 g, 88% yield); mp 111−113 °C; Rf 0.33 (20% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 4.60 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H). 2-(4-Bromophenyl)-5-ethoxy-1,3,4-oxadiazole (2d): white solid (0.1296 g, 89% yield); mp 125−126 °C; Rf 0.39 (20% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 4.59 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 159.8, 132.3, 127.5, 125.8, 123.1, 69.5, 14.4; TOF-HRMS calcd for C10H1079BrN2O2 (M + H)+ 268.9926, found 268.9923; calcd for C10H1081BrN2O2 (M + H)+ 270.9906, found 270.9901. 2-Ethoxy-5-(4-nitrophenyl)-1,3,4-oxadiazole (2e): 23 white solid (0.0805 g, 63% yield); mp 156−157 °C; Rf 0.30 (15% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 4.65 (q, J = 7.2 Hz, 2H), 1.54 (t, J = 7.2 Hz, 3H). 2-Ethoxy-5-(2-iodophenyl)-1,3,4-oxadiazole (2f): white solid (0.1388 g, 81% yield); mp 52−53 °C; Rf 0.30 (10% EtOAc/hexanes); 1 H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 7.6, 1.6 Hz, 1H), 7.69 (dd, J = 7.6, 1.6 Hz, 1H), 7.41 (td, J = 7.6, 1.6 Hz, 1H), 7.13 (td, J = 7.6, 1.6 Hz, 1H), 4.59 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 165.9, 159.9, 141.2, 132.1,132.0, 130.9, 129.2, 128.2, 93.7, 69.4, 14.4; TOF-HRMS calcd for C10H10IN2O2 (M + H)+ 316.9787, found 316.9784.
2-Ethoxy-5-(2-methoxyphenyl)-1,3,4-oxadiazole (2g): colorless oil (0.0954 g, 80% yield); Rf 0.32 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 7.6, 1.6 Hz, 1H), 7.44 (td, J = 8.4, 1.6 Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 4.59 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 159.3, 157.7, 132.7, 130.0, 120.8, 113.4, 111.9, 69.1, 56.0, 14.4; TOF-HRMS calcd for C11H13N2O3 (M + H)+ 221.0926, found 221.0932. 2-(5-Ethoxy-1,3,4-oxadiazol-2-yl)-N-phenylaniline (2h): colorless oil (0.1142 g, 75% yield); Rf 0.53 (15% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H), 7.34−7.21 (m, 6H), 7.06 (t, J = 7.2 Hz, 1H), 6.79 (t, J = 8.0 Hz, 1H), 4.57 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.7, 160.7, 144.1, 140.8, 131.8, 129.3, 127.7, 123.5, 122.2, 117.8, 113.9, 107.7, 69.3, 14.3; TOF-HRMS calcd for C16H16N3O2 (M + H)+ 282.1243, found 282.1247. 3-(5-Ethoxy-1,3,4-oxadiazol-2-yl)-N,N-dimethylaniline (2i): yellow solid (0.1150 g, 91% yield); mp 91−92 °C; Rf 0.34 (20% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 7.30−7.22 (m, 3H), 6.80 (ddd, J = 8.2, 2.8, 1.2 Hz, 1H), 4.58 (q, J = 7.2 Hz, 1H), 2.97 (s, 6H), 1.50 (t, J = 7.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.5, 161.1, 150.5, 129.5, 124.6, 115.0, 113.9, 109.2, 69.0, 40.3, 14.3; TOFHRMS calcd for C12H16N3O2 (M + H)+ 234.1243, found 234.1243. 2-Ethoxy-5-(3-nitrophenyl)-1,3,4-oxadiazole (2j): 24 white solid (0.0995 g, 78% yield); mp 84−85 °C; Rf 0.30 (15% EtOAc/hexanes); 1 H NMR (400 MHz, CDCl3) δ 8.67 (t, J = 2.0 Hz, 1H), 8.29 (ddd, J = 8.0, 2.4, 1.2 Hz, 1H), 8.22 (dt, J = 8.0, 1.2 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 4.60 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). 2-([1,1′-Biphenyl]-4-yl)-5-ethoxy-1,3,4-oxadiazole (2k): white solid (0.1426 g, 99% yield); mp 115−117 °C; Rf 0.41 (20% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.44−7.33 (m, 3H), 4.57 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.6, 160.2, 143.7, 139.7, 128.9, 128.0, 127.4, 127.0, 126.4, 122.8, 69.2, 14.3; TOF-HRMS calcd for C16H15N2O2 (M + H)+ 267.1134, found 267.1136. 2-Ethoxy-5-(naphthalen-2-yl)-1,3,4-oxadiazole (2l): 4a white solid (0.0990 g, 76% yield); mp 95−96 °C; Rf 0.32 (15% EtOAc/hexanes); 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.03 (dd, J = 8.8, 1.6 Hz, 1H), 7.91−7.84 (m, 3H), 7.57−7.52 (m, 2H), 4.63 (q, J = 7.2 Hz, 2H), 1.54 (t, J = 7.2 Hz, 3H). 2-Ethoxy-5-(naphthalen-1-ylmethyl)-1,3,4-oxadiazole (2m): liquid (0.1157 g, 84% yield); Rf 0.34 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.83−7.79 (m, 1H), 7.57−7.42 (m, 4H), 4.49 (s, 2H), 4.45 (d, J = 7.2 Hz, 1H), 1.39 (t, J = 7.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) 165.9, 161.0, 133.9, 131.7, 129.9, 128.8, 128.6, 127.7, 126.7, 126.1, 125.5, 123.5, 68.9, 30.0, 14.3; TOF-HRMS calcd for C15H15N2O2 (M + H)+ 255.1134, found 255.1139. 2-Ethoxy-5-styryl-1,3,4-oxadiazole (2n): white solid (0.0926 g, 79% yield); mp 57−59 °C; Rf 0.42 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.50−7.48 (m, 2H), 7.40−7.31 (m, 4H), 6.87 (d, J = 16.4 Hz, 1H), 4.58 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 165.2, 160.5, 137.3, 134.9, 129.8, 9927
DOI: 10.1021/acs.joc.7b01863 J. Org. Chem. 2017, 82, 9923−9929
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The Journal of Organic Chemistry
(m, 6H), 7.02−6.96 (m, 2H), 4.97 (s, 2H), 3.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.8, 153.6, 152.2, 135.2, 132.9, 129.4, 128.8, 128.2, 120.6, 112.8, 111.9, 55.9, 49.7; TOF-HRMS calcd for C16H15N2O3 (M + H)+ 283.1083, found 283.1085. 3-Methyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3h): 25 white solid (0.0543 g, 75% yield); mp 105−106 °C; Rf 0.31 (10% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 7.81−7.78 (m, 2H), 7.50− 7.41 (m, 3H), 3.47 (s, 3H). 3-Isobutyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3i): 26 liquid (0.0476 g, 53% yield); Rf 0.54 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 8.0, 1.6 Hz, 2H), 7.52−7.43 (m, 3H), 3.60 (d, J = 6.8 Hz, 2H), 2.21 (m, 1H), 0.99 (d, J = 6.8 Hz, 6H). 3-(Cyclohex-2-en-1-yl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3j): liquid (0.0608 g, 61% yield); Rf 0.54 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.50−7.42 (m, 3H), 6.05−6.02 (m, 1H), 5.67−5.64 (m, 1H), 4.80−4.74 (m, 1H), 2.11−1.91 (m, 4H), 1.81−1.64 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.3, 153.2, 132.4, 131.4, 128.9, 125.7, 125.1, 124.1, 52.1, 28.0, 24.3, 20.3; TOF-HRMS calcd for C14H15N2O2 (M + H)+ 243.1134, found 243.1141. 3-(2-Methylbenzyl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3l): white solid (1.2723 g, 91% yield); mp = 94−96 °C; Rf 0.41 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.4, 1.6 Hz, 2H), 7.51−7.41 (m, 2H), 7.37−7.35 (m, 1H), 7.28−7.20 (m, 3H), 4.97 (s, 2H), 2.47 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.6, 153.4, 136.7, 133.0, 131.6, 130.7, 129.5, 128.9, 128.6, 126.4, 125.7, 123.9, 47.5, 19.4; TOF-HRMS calcd for C16H15N2O2 (M + H)+ 267.1134, found 267.1137. 3-(Naphthalen-1-ylmethyl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3m): yellow solid (1.3382 g, 84% yield); mp = 119−121 °C; Rf 0.42 (15% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ δ 8.29 (d, J = 8.8 Hz, 1H), 7.88 (t, J = 8.0 Hz, 2H), 7.78−7.75 (m, 2H), 7.65−7.60 (m, 2H), 7.56−7.47 (m, 2H), 7.43−7.36 (m, 3H), 5.38 (s, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 153.5, 153.4, 133.9, 131.5, 131.3, 130.5, 129.5, 128.9, 128.2, 127.0, 126.1, 125.7, 125.4, 123.8, 123.4, 47.7; TOF-HRMS calcd for C19H15N2O2 (M + H)+ 303.1134, found 303.1132. 5-Phenyl-1,3,4-oxadiazol-2(3H)-one (4): 27 yellow solid (0.0265 g, 40% yield); mp 133−135 °C; Rf 0.30 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.46−7.35 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 155.6, 155.1, 131.5, 128.9, 125.6, 123.9. 3-Ethyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (5): 13 liquid (0.0352 g, 45% yield); Rf 0.45 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 3H), 7.51−7.43 (m, 3H), 3.85 (d, J = 7.2 Hz, 2H), 1.40 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.5, 153.3, 145.4, 131.6, 129.1, 125.7, 124.1, 41.2, 13.6.
129.1, 127.4, 110.3, 69.3, 14.4; TOF-HRMS calcd for C12H13N2O2 (M + H)+ 217.0977, found 217.0971. 4-(5-Ethoxy-1,3,4-oxadiazol-2-yl)phenol (2o): white solid (0.0749 g, 67% yield); mp 201−202 °C; Rf 0.30 (40% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.2, 161.0, 160.2, 128.0, 116.0, 69.2, 14.3; TOF-HRMS calcd for C10H10N2NaO3 (M + Na)+ 229.0589, found 229.0585. 2-Ethoxy-5-(pyridin-3-yl)-1,3,4-oxadiazole (2p): liquid (0.0871 g, 84% yield); Rf 0.30 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.12 (dd, J = 8.0, 2.0 Hz, 1H), 7.35−7.31 (m, 1H), 4.53 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 158.2, 151.8, 146.9, 133.1, 123.6, 120.5, 69.5, 14.2; TOF-HRMS calcd for C9H10N3O2 (M + H)+ 192.0773, found 192.0776. General Procedure for the Synthesis of 3,5-Disubstituted 1,3,4-Oxadiazol-2(3H)-ones 3. In a 9 mL Ace pressure tube, oxadiazole 2 (0.41 mmol), alkyl halide (0.49 mmol), Et3N (0.0496 g, 0.49 mmol), KI (6.8 mg, 0.041 mmol) and DMF (1 mL) were added before the mixture was placed in a preset oil bath at 120 °C. After being stirred for 5 min, the crude mixture was purified by column chromatography using 5−15% ethyl acetate in hexane. 3-Benzyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3a): 25 white solid (0.0878 g, 85% yield); mp 112−115 °C; Rf 0.47 (10% EtOAc/hexanes 2 developed); 1H NMR (400 MHz, CDCl3 δ 7.85−7.80 (m, 2H), 7.49−7.31 (m, 8H), 4.95 (s, 2H). 3-(4-Bromobenzyl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3b): white solid (0.1247 g, 92% yield); mp 118−120 °C; Rf 0.50 (20% EtOAc/hexanes 2 developed); 1H NMR (400 MHz, CDCl3) δ 7.81 (dd, J = 8.4, 1.2 Hz, 2H), 7.52−7.42 (m, 5H), 7.29 (d, J = 8.4 Hz, 2H), 4.90 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.6, 153.5, 133.9, 132.1, 131.7, 130.1, 129.0, 125.8, 123.7, 122.6, 49.2; TOF-HRMS calcd for C15H1279BrN2O2 (M + H)+ 331.0082, found 331.0089; calcd for C15H1281BrN2O2 (M + H)+ 333.0062, found 333.0054. 3-(3-Methoxybenzyl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3c): white solid (0.1052 g, 91% yield); mp 78−80 °C; Rf 0.41 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.2 Hz, 2H), 7.52−7.43 (m, 3H), 7.31−7.24 (m, 3H), 7.17 (d, J = 7.2 Hz, 1H), 4.94 (s, 2H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.6, 153.3, 138.6, 134.9, 131.5, 129.2, 129.0, 128.9, 128.8, 125.7, 125.4, 123.9, 49.8, 21.4; TOF-HRMS calcd for C16H15N2O3 (M + H)+ 283.1083, found 283.1078. 5-Phenyl-3-(4-vinylbenzyl)-1,3,4-oxadiazol-2(3H)-one (3d): white solid (0.1027 g, 90% yield); mp 124−125 °C; Rf 0.47 (10% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.4, 1.6 Hz, 2H), 7.51−7.36 (m, 7H), 6.70 (dd, J = 17.6, 10.8 Hz, 1H), 5.75 (dd, J = 17.6, 0.8 Hz, 1H), 5.26 (dd, J = 10.8, 0.8 Hz, 1H), 4.94 (s, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 153.7, 153.5, 137.9, 136.3, 134.5, 131.7, 129.0, 128.7, 126.8, 125.8, 123.9, 114.6, 49.6; TOF-HRMS calcd for C17H15N2O2 (M + H)+ 279.1134, found 279.1131. 5-(4-Chlorophenyl)-3-(4-vinylbenzyl)-1,3,4-oxadiazol-2(3H)-one (3e): white solid (0.1100 g, 86% yield); mp 126−128 °C; Rf 0.45 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 2H), 7.43−7.36 (m, 6H), 6.70 (dd, J = 17.6, 10.8 Hz, 1H), 5.75 (d, J = 17.6 Hz, 1H), 5.26 (d, J = 10.8 Hz, 1H), 4.92 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.4, 152.7, 137.95, 137.89, 136.3, 134.3, 129.4, 128.7, 127.1, 126.8, 122.4, 114.7, 49.7; TOF-HRMS calcd for C17H1435ClN2O2 (M + H)+ 313.0744, found 313.0761; calcd for C17H1437ClN2O2 (M + H)+ 315.0714, found 315.0712. 3-Benzyl-5-(4-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one (3f): yellow solid (0.0901 g, 74% yield); mp 153−155 °C; Rf 0.30 (10% EtOAc/ hexanes 2 developed); 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 9.2 Hz, 2H), 8.00 (d, J = 9.2 Hz, 2H), 7.44−7.33 (m, 5H), 4.98 (s, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 153.1, 151.5, 149.4, 134.5, 129.4, 129.1, 128.7, 128.5, 126.6, 124.4, 50.2; TOF-HRMS calcd for C15H12N3O4 (M + H) + 298.0828, found 298.0834. 3-Benzyl-5-(2-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one (3g): liquid (0.0994 g, 86% yield); Rf 0.41 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 7.8, 1.6 Hz, 1H), 7.46−7.29
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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.7b01863.
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Copies of 1H NMR of all products and 13C NMR spectra for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Fax: (+) 66-53-892277. ORCID
Wong Phakhodee: 0000-0002-5489-9555 Mookda Pattarawarapan: 0000-0002-7484-122X Notes
The authors declare no competing financial interest. 9928
DOI: 10.1021/acs.joc.7b01863 J. Org. Chem. 2017, 82, 9923−9929
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The Journal of Organic Chemistry
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(18) Guo, C.-X.; Zhang, W.-Z.; Zhang, N.; Lu, X.-B. J. Org. Chem. 2017, 82, 7637. (19) (a) Wet-osot, S.; Phakhodee, W.; Pattarawarapan, M. Tetrahedron Lett. 2015, 56, 6998. (b) Duangkamol, C.; Wangngae, S.; Pattarawarapan, M.; Phakhodee, W. Eur. J. Org. Chem. 2014, 2014, 7109. (c) Wet-osot, S.; Duangkamol, C.; Phakhodee, W.; Pattarawarapan, M. ACS Comb. Sci. 2016, 18, 279. (d) Wet-osot, S.; Duangkamol, C.; Pattarawarapan, M.; Phakhodee, W. Monatsh. Chem. 2015, 146, 959. (20) Wang, X.; Yu, H.; Xu, P.; Zheng, R. J. Chem. Res. 2005, 2005, 595. (21) Abad, A.; Agullo, C.; Cunat, A. C.; Navarro, I. Synthesis 2005, 3355. (22) Dessolin, M.; Golfier, M. New J. Chem. 1993, 17, 823. (23) Huisgen, R.; Blaschke, H. Justus Liebigs Ann. Chem. 1965, 686, 145. (24) Sharnin, G. P.; Buzykin, B. I.; Fassakhov, R. K. Khim. Geterotsikl. Soedin. 1977, 741. (25) Bancerz, M.; Georges, M. K. J. Org. Chem. 2011, 76, 6377. (26) Golfier, M.; Guillerez, M. G.; Milcent, R. Tetrahedron Lett. 1974, 15, 3875. (27) Levins, C. G.; Wan, Z.-K. Org. Lett. 2008, 10, 1755.
ACKNOWLEDGMENTS Financial support from the Center of Excellence for Innovation in Chemistry (PERCH-CIC), Office of the Higher Education Commission, Ministry of Education, Thailand, and Center of Excellence in Materials Science and Technology under the administration of Materials Science Research Center, Faculty of Science, Chiang Mai University is gratefully acknowledged. Special appreciation to Chulabhorn Research Institute (CRI), Thailand, for the ESI-MS analysis.
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