Abstract
An efficient synthesis of a variety of 2,5-disubstituted 1,3,4-oxadiazole derivatives via a cyclization reaction by photoredox catalysis between aldehydes and hypervalent iodine(III) reagents is described. The reaction proceeds under mild conditions and affords various target compounds in excellent yields. The commercially available aldehydes without preactivation and a simple visible-light-promoted procedure without any catalysts make this strategy an alternative to the conventional methods.
Introduction
Oxadiazoles, especially 1,3,4-oxadiazoles, are a valuable structural motifs in natural products and biological compounds.1 They not only show a broad range of biological and pharmaceutical activities, such as endothelin (ET) A antagonists,2 HIV integrase inhibitors,3 and hepatitis C virus (HCV) inhibitors,4 but also serve as useful and significant fragments in functional materials.5 Due to the versatile applicability of 1,3,4-oxadiazoles, elegant efforts have been devoted to develop efficient methodologies for the synthesis of this scaffold.6 For instance, oxidative cyclization of N-acylhydrazones and dehydrative cyclization of 1,2-diacylhydrazines are general methods to synthesize of 1,3,4-oxadiazoles.7 However, most of these strategies rely on transition metal mediation or strong oxidation and suffer from certain limitations with respect to the substrate scope, diastereoselectivity, or apparative requirements and are not suitable for the collection of compound libraries. On the other hand, visible-light photoredox catalysis has served as an efficient strategy for the synthesis of organic motifs that are difficult to prepare by traditional methods.8 Recently, we have reported an efficient synthesis of a variety of 2,5-disubstituted 1,3,4-oxadiazole derivatives via a decarboxylative cyclization reaction by photoredox catalysis between commercially available α-oxocarboxylic acids and hypervalent iodine(III) reagents (Scheme 1a).9 Based on a series of mechanistic investigations, we proposed a mechanism involving acyl radicals generated from α-oxocarboxylic acids under white light-emitting diode (LED) irradiation. Acyl radicals, generated from various acyl precursors such as aldehydes, α-keto acids, carboxylic acids, and anhydrides, were easily accessible under mild reaction conditions.10 Aldehydes are one of the acyl radical sources,11 which have abundant, readily available, and versatile intermediates. During our investigation, one study on N-heterocyclic carbene-catalyzed cyclization of aldehydes with α-diazo iodonium triflate for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles was published (Scheme 1b).12 The process undergoes nucleophilic addition of NHC to the aldehyde, N-selective nucleophilic attack of α-diazo ammonium triflate, and cyclization to afford various 1,3,4-oxadiazole derivatives. In continuation of our interest in the field of hypervalent iodine chemistry, herein, we disclose a simple and efficient approach for the preparation of 2,5-disubstituted 1,3,4-oxadiazoles via catalyst-free visible-light-promoted cyclization of aldehydes with hypervalent iodine(III) reagents.
Scheme 1. Synthetic Strategies of 1,3,4-Oxadiazoles.
Results and Discussion
We chose hypervalent iodine reagent 1a and benzaldehyde 2a as model substrates (Table 1). Initially, Ru(bpy)3Cl2 was utilized as the catalyst and dichloromethane (DCM) as the solvent, and the reaction mixture was irradiated with white light at room temperature. Expectedly, the cyclization product ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate 3a was found in 61% yield after 12 h (Table 1, entry 1). Subsequently, some transition metal photocatalysts were screened for the cross-coupling of the hypervalent iodine reagent and benzaldehyde (Table 1, entries 2 and 3). However, no superior results were achieved when Ru(bpy)3(PF6)2 or Ir(ppy)3 was employed. Next, other organic photocatalysts were examined for this transformation, such as Eosin Y, Rhodamine B, 4CzPN, 4CzIPN, 4CzTPN, and DCA (entries 4–9). Among these catalysts, a relatively higher yield was acquired when DCA was utilized, delivering the product in 62% yield (entry 7). Although effective, the process usually involves high-value precious transition metals (Ir, Ru, etc.) or toxic organic dyes as photosensitizers, which can be a disadvantage in certain synthetic contexts. Then, a blank case was irradiated (entry 10). Unexpectedly, the yield of the target compound could reach 68% when no catalyst was involved.
Table 1. Optimization of the Reaction Conditionsa,b.
| entry | catalyst | light source | solvent | yield (%)b |
|---|---|---|---|---|
| 1 | Ru(bpy)3Cl2 | white | DCM | 65 |
| 2 | fac-Ir(ppy)3 | white | DCM | 13 |
| 3 | Ru(bpy)3(PF6)2 | white | DCM | 61 |
| 4 | 4CzPN | white | DCM | 28 |
| 5 | 4CzIPN | white | DCM | 21 |
| 6 | 4CzTPN | white | DCM | 11 |
| 7 | DCA | white | DCM | 62 |
| 8 | Rhodamine B | white | DCM | 30 |
| 9 | Eosin Y | white | DCM | 28 |
| 10 | white | DCM | 68 | |
| 11 | white | THF | ||
| 12 | white | CH3OH | ||
| 13 | white | DMSO | ||
| 14 | white | 1,4-dioxane | ||
| 15 | white | CH3CN | ||
| 16 | sunlight | DCM | 8 | |
| 17 | green | DCM | 35 | |
| 18 | blue | DCM | trace |
Reaction condition: 1a (0.5 mmol), 2a (0.75 mmol), and catalyst (5 mol %) in solvent (2.0 mL), r.t., 12 h, Ar.
Isolated yield. 4CzIPN: 2,4,5,6-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene, 4CzTPN: 1,2,4,5-tetrakis(car-bazol-9-yl)-3,6-dicyanobenzene, and 4CzPN: 1,2,3,4-tetrakis(carbazol-9-yl)-5,6-dicyanobenzene.
This result motivated us to further optimize the reaction conditions to obtain the required high yield of 1,3,4-oxadiazole. Several other solvents, such as CH3CN, THF, CH3OH, DMSO, DCE and 1,4-dioxane, and a light source were investigated (entries 11–18). Unfortunately, none of these conditions was found to be superior in comparison to the result obtained above.
With the above optimized conditions in hand, the versatility and limitations of the new protocol were investigated. Gratifyingly, through the observation of the reaction of various benzaldehydes, the corresponding 2,5-disubstituted 1,3,4-oxadiazole compounds were collected in moderate to good yields, and the result is summarized in Table 2. Generally, aldehyde-containing substituents of varying electronic characters (such as donating or withdrawing) and steric demand (such as para-, meta-, and ortho-) were satisfactorily compatible with the catalytic system to afford the desired oxadiazole derivatives 3a–3u in 48–89% yields. It was observed that the functional groups such as halogens (F, Cl, and Br) were suitable for this transformation, furnishing products 3b–3d in 80–84% yields. Notably, a range of benzaldehydes bearing various electron-donating groups (e.g., Me, MeO, and t-Bu) provide the desired products 3e–3g with yields in the range of 82–89%. Furthermore, the meta-substituted (3k–3n) and ortho-substituted (3o–3s) substrates worked well under the standard reaction conditions, converting to the oxadiazole products in decent yields. It was noteworthy to mention that the reaction was rather sensitive to the steric effect, and the reaction showed decreased reactivity (3o 50%, 3p 69%, 3q 50%, 3r 65%, 3s 55%, 3t 72%, and 3u 70%) when the ortho-position of the substrates was substituted.
Table 2. Scope of Aldehydes and the Hypervalent Iodine(III) Reagenta,b.
Reaction condition: 1 (0.5 mmol), 2 (0.75 mmol) in DCM (2.0 mL), r.t., 12 h, Ar.
Isolated yield.
Furthermore, the universality of this reaction by using disubstituted, trisubstituted, and various heterocyclic aldehyde compounds was evaluated. As shown in Table 2, the reactions of benzaldehyde with 2,3-, 2,4-, 2,6-, and 3,4-disubstituted phenyl rings also proceeded smoothly to give corresponding analogues 3v–3aa with satisfactory yields. Remarkably, this approach could be successfully explored to 2,4,6-trisubstituted and heterocyclic substrates, 2,4,6-trimethylbenzaldehyde, thiophene-2-carboxaldehyde, and N-containing heteroaromatic aldehydes participate in the reaction smoothly. In addition, hypervalent iodine(III) reagent benziodoxolone 1 with different substituents was tested, and the products 3A and 3B were obtained in 87 and 77% yields, respectively.
Finally, to clearly highlight the potential of our methodology, N-(4-(4-fluorophenyl)-5-formyl-6-isopropyl pyrimidin-2-yl)-N-methylmethanesulfinamide, the core structure of rosuvastatin, was investigated and transferred to the desired product 4a in 60% yield. To further define the scope of our protocol, the valuable l-tyrosine aldehyde was detected and the transformation proceeded smoothly to provide 4b with an acceptable yield (Scheme 2).
Scheme 2. Synthetic Application.
When the reaction of 1a and 2a was conducted under the standard condition in the presence of a radical trap, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), only a trace amount of 3a was isolated. According to the literature, the photochemical decomposition of the hypervalent iodine reagent is known to give two kinds of radicals.13 The calculations have shown that the hypervalent iodine reagent is an initiator of the free radical reaction. Based on the mechanistic investigations and related literature, a plausible mechanism is summarized in Scheme 3. Initially, radical B and D would be formed by homolysis from 1a under irradiation. Next, the hydrogen atom abstraction of the aldehyde hydrogen by B provides a carbonyl radical C(14) that reacts with the diazo radical D to form intermediate F, which could be transformed into the target compound 3a.
Scheme 3. Proposed Mechanism.
In conclusion, we have demonstrated a catalyst-free visible-light-promoted cyclization for the construction of 2,5-disubstituted 1,3,4-oxadiazole derivatives with aldehydes and hypervalent iodine(III) reagents. The developed methodology provides straightforward access to 2,5-disubstituted 1,3,4-oxadiazole derivatives in up to 89% yields. Remarkably, commercially available aldehydes without preactivation and a simple visible-light-promoted procedure make this strategy attractive and practical. Further applications of this cyclization are ongoing in our laboratory.
Experimental Section
General Information
All reactions were carried out under an Ar atmosphere condition. Aldehydes and various reagents were purchased from Sigma-Aldrich, Acros, or Alfa Aesar. The hypervalent iodine(III) reagents were prepared according to the literature. Flash column chromatography was performed using silica gel (200–300 mesh). Analytical thin-layer chromatography was performed using glass plates precoated with 200–300 mesh silica gel impregnated with a fluorescent indicator (254 nm). NMR spectra were recorded in CDCl3 on Bruker NMR-300 (300 MHz), NMR-400 (400 MHz), and NMR-500 (500 MHz) with TMS as an internal reference. HRMS were performed on an Agilent 6540 Q-TOF mass spectrometer (ESI). IR spectra were recorded on a Thermo Fisher IS50 FT-IR spectrometer. 4CzIPN, 4CzTPN, and CzPN were synthesized according to the previous literature.152af was synthesized according to the previous literature.16
General Procedure for Preparation of Hypervalent Iodine(III) Reagents
Hypervalent iodine(III) reagents 2a–2c were prepared according to the previously reported literature procedures.9
General Procedure for Preparation of Compounds 3 and 4
A solution of aldehyde 1 (0.5 mmol), hypervalent iodine reagents 2 (0.75 mmol), and DCM (2.0 mL) were added to a 10 mL Schlenk tube at r.t. The tube was filled with argon and then sealed and irradiated with a 40 W white LED (brand: Philips, approximately 4 cm away from the light source). After the complete conversion of the substrates (monitored by TLC), the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give the desired product. The obtained product was analyzed by 1H NMR, 13C NMR, and HRMS.
Ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (3a)
Column chromatography on silica gel (ethyl acetate/PE 1:8) afforded the title product 3a as a white crystalline solid (74.1 mg, 68%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 2H), 7.56–7.46 (m, 3H), 4.48 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.5, 156.5, 154.5, 132.9, 129.3, 127.7, 122.8, 63.6, 14.1.
Ethyl 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxylate (3b)
Column chromatography on silica gel (ethyl acetate/PE 1:8) afforded the title product 3b as a white crystalline solid (99.3 mg, 84%). The spectral data are in accordance with the literature.91H NMR (300 MHz, CDCl3) δ 8.14–8.09 (m, 2H), 7.20–7.17 (m, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.7, 165.4 (d, J = 253.7 Hz), 156.5, 154.4, 130.1 (d, J = 9.2 Hz), 119.1 (d, J = 3.8 Hz), 116.7 (d, J = 22.5 Hz), 14.1.
Ethyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate (3c)
Column chromatography on silica gel (ethyl acetate/PE 1:8) afforded the title product 3c as a white crystalline solid (105.6 mg, 84%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.7, 156.6, 154.3, 139.3, 129.7, 128.9, 121.2, 63.7, 14.1.
Ethyl 5-(4-bromophenyl)-1,3,4-oxadiazole-2-carboxylate (3d)
Column chromatography on silica gel (ethyl acetate/PE 1:8) afforded the title product 3d as a white crystalline solid (122.9 mg, 83%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 4.57 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.7, 156.6, 154.3, 132.6, 128.9, 127.7, 121.6, 63.6, 14.1.
Ethyl 5-p-tolyl-1,3,4-oxadiazole-2-carboxylate (3e)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3e as a white crystalline solid (99.6 mg, 86%). The spectral data are in accordance with the literature.91H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.55 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.5, 163.2, 156.1, 154.6, 129.5, 115.1, 114.7, 63.4, 55.6, 14.1.
Ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (3f)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3f as a white crystalline solid (101.8 mg, 82%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.55 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.5, 163.2, 156.1, 151.6, 129.6, 115.1, 114.7, 63.4, 55.6, 14.1.
Ethyl 5-(4-tert-butylphenyl)-1,3,4-oxadiazole-2-carboxylate (3g)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3g as a white crystalline solid (121.5 mg, 89%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 4.55 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H), 1.36 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 166.6, 156.6, 156.3, 154.5, 127.5, 126.3, 119.9, 63.5, 35.2, 31.1, 14.1. HRMS (ESI) m/z: [M + H]+ calcd for C15H19N2O3 275.1390; found 275.1391.
Ethyl 5-(biphenyl-4-yl)-1,3,4-oxadiazole-2-carboxylate (3h)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3h as a white crystalline solid (128.9 mg, 88%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.2 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 7.4 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.45–7.32 (m, 1H), 4.57 (q, J = 7.1 Hz, 2H), 1.51 (t, J = 7.1 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 166.4, 156.5, 154.5, 145.6, 139.5, 129.0, 128.5, 128.1, 127.8, 127.2, 121.4, 63.6, 14.1.
Ethyl 5-(3-phenoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (3i)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3i as a white crystalline solid (104.9 mg, 68%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.7 Hz, 1H), 7.78 (s, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.38 (t, J = 8.1 Hz, 2H), 7.24–7.15 (m, 2H), 7.05 (d, J = 8.1 Hz, 2H), 4.54 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.2, 161.8, 156.3, 155.2, 154.5, 130.1, 124.8, 120.3, 118.1, 111.9, 63.5, 14.2.
Ethyl 5-(4-acetamidophenyl)-1,3,4-oxadiazole-2-carboxylate (3j)
Column chromatography on silica gel (ethyl acetate/PE 1:10) afforded the title product 3j as a light-yellow solid (63.1 mg, 46%). MP: 210–211 °C. 1H NMR (400 MHz, DMDO) δ 10.35 (s, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.08 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, DMSO) δ 169.5, 165.7, 156.6, 154.5, 143.8, 128.6, 119.6, 117.0, 63.3, 24.6, 14.3. IR (KBr): ν = 3351, 2925, 1740, 1696, 1592, 1541, 1491, 1416, 1316, 1190, 1173, 1096, 1020, 855, 744. HRMS (ESI) m/z: [M + H]+ calcd for C13H14N3O4 276.0979; found 276.0980.
Ethyl 5-(3-fluorophenyl)-1,3,4-oxadiazole-2-carboxylate (3k)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3k as a white crystalline solid (89.8 mg, 76%). The spectral data are in accordance with the literature.171H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.56–7.53 (m, 1H), 7.31 (dt, J = 8.3, 1.9 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.4, 164.8 (d, J = 247.5 Hz), 156.6, 154.3, 131.2 (d, J = 8.0 Hz), 124.6, 123.1, 120.0 (d, J = 21.7 Hz), 114.6 (d, J = 24.3 Hz), 63.7, 14.1. 19F (470 MHz, CDCl3) δ −108.5.
Ethyl 5-(3-bromophenyl)-1,3,4-oxadiazole-2-carboxylate (3l)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3l as a white crystalline solid (115.3 mg, 78%). MP: 79–80 °C. 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 4.57 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.1, 156.6, 154.2, 135.8, 130.8, 130.4, 126.1, 124.6, 123.3, 63.7, 14.1. HRMS (ESI) [M + H]+ calcd for C11H10BrN2O3 296.9869; found 296.9870.
Ethyl 5-(3-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (3m)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3m as a white crystalline solid (98.6 mg, 79%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.15 (dd, J = 8.3, 2.5 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.4, 160.0, 156.5, 154.4, 130.4, 123.8, 120.0, 119.5, 63.5, 55.6, 14.1.
Ethyl 5-m-tolyl-1,3,4-oxadiazole-2-carboxylate (3n)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3n as a white crystalline solid (96.4 mg, 83%). The spectral data are in accordance with the literature.91H NMR (300 MHz, CDCl3) δ 7.90–7.84 (m, 2H), 7.34–7.32 (m, 2H), 4.47 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.6, 156.4, 154.5, 139.2, 133.6, 129.1, 128.1, 124.7, 122.6, 63.5, 21.3, 14.1.
Ethyl 5-(2-fluorophenyl)-1,3,4-oxadiazole-2-carboxylate (3o)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3o as a white crystalline solid (64.9 mg, 52%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.15 (t, J = 8.3 Hz, 1H), 7.64–7.59 (m, 1H), 7.36–7.31 (m, 2H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 162.4 (d, J = 234.7 Hz), 159.4, 156.7, 154.3, 134.6 (d, J = 8.6 Hz), 130.3, 124.8, 117.2 (d, J = 20.6 Hz), 111.4 (d, J = 11.6 Hz), 63.6, 14.1. 19F (470 MHz, CDCl3) δ −108.4.
Ethyl 5-(2-bromophenyl)-1,3,4-oxadiazole-2-carboxylate (3p)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3p as a white crystalline solid (102.4 mg, 69%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 7.7, 1.7 Hz, 1H), 7.80–7.78 (m, 1H), 7.51–7.43 (m, 2H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.4, 156.8, 154.3, 134.7, 133.3, 132.1, 127.7, 124.2, 122.1, 63.6, 14.1.
Ethyl 5-(2-iodophenyl)-1,3,4-oxadiazole-2-carboxylate (3q)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3q as a white crystalline solid (85.8 mg, 50%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 1H), 7.90–7.88 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.25–7.23 (m, 1H), 4.55 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.1, 156.8, 154.3, 141.6, 133.2, 131.8, 128.4, 128.1, 63.7, 14.1.
Ethyl 5-(2-cyanophenyl)-1,3,4-oxadiazole-2-carboxylate (3r)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3r as a white crystalline solid (79.0 mg, 65%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.82–7.80 (m, 1H), 7.76–7.74 (m, 1H), 4.57 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 163.6, 157.0, 153.9, 133.2, 132.6, 129.9, 124.8, 116.4, 111.3, 63.8, 14.1.
Ethyl 5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-carboxylate (3s)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3s as a white crystalline solid (78.6 mg, 55%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.08–8.06 (m, 1H), 7.92–7.89 (m, 1H), 7.77–7.75 (m, 2H), 4.56 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.7, 157.4, 154.1, 132.5, 132.2, 129.5, 129.3, 127.2 (q, J = 5.4 Hz), 124.1, 121.8, 121.2, 63.7, 14.0. 19F (470 MHz, CDCl3) δ – 63.3.
Ethyl 5-o-tolyl-1,3,4-oxadiazole-2-carboxylate (3t)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3t as a white crystalline solid (83.8 mg, 89%). The spectral data are in accordance with the literature.91H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.7 Hz, 1H), 7.28 (t, J = 8.1 Hz, 2H), 4.48 (q, J = 7.2 Hz, 2H), 2.67 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.8, 156.1, 154.6, 139.2, 132.2, 132.0, 129.6, 126.3, 121.9, 63.5, 22.1, 14.1.
Ethyl 5-(2-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (3u)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3u as a white crystalline solid (86.9 mg, 75%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.05–8.03 (m, 1H), 7.60–7.55 (m, 1H), 7.13–7.08 (m, 2H), 4.56 (q, J = 7.1 Hz, 2H), 4.01 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.4, 160.0, 156.5, 154.4, 130.4, 123.8, 120.0, 119.5, 111.9, 63.5, 55.6, 14.1.
Ethyl 5-(2,6-dichlorophenyl)-1,3,4-oxadiazole-2-carboxylate (3v)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3v as a white crystalline solid (93.3 mg, 65%). MP: 66–68 °C. 1H NMR (400 MHz, CDCl3) δ 7.49 (t, J = 4.1 Hz, 3H), 4.58 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 161.8, 157.5, 154.1, 136.5, 133.5, 128.4, 123.3, 63.8, 14.1. IR (KBr): ν = 3423, 3078, 1751, 1596, 1562, 1550, 1440, 1381, 1201, 1130, 1106, 1019, 843, 796. HRMS (ESI) m/z: [M + H]+ calcd for C11H9Cl2N2O3 286.9985; found 286.9986.
Ethyl 5-(2,4-dichlorophenyl)-1,3,4-oxadiazole-2-carboxylate (3w)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3w as a white crystalline solid (82.3 mg, 57%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.5, 1.5 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.1, 156.8, 154.2, 139.3, 134.6, 132.3, 131.5, 127.8, 120.6, 63.7, 14.1.
Ethyl 5-(2,3-dimethylphenyl)-1,3,4-oxadiazole-2-carboxylate (3x)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3x as a white crystalline solid (71.4 mg, 58%). MP: 49–51 °C. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 2.62 (s, 3H), 2.38 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 167.3, 156.2, 154.6, 138.6, 137.7, 133.8, 127.8, 125.9, 122.3, 63.4, 20.7, 17.2, 14.1. IR (KBr): ν = 3451, 2984, 1742, 1599, 1540, 1468, 1381, 1280, 1197, 1110, 1067, 1021, 842, 767. HRMS (ESI) m/z: [M + H]+ calcd for C13H15N2O3 247.1077; found 247.1079.
Ethyl 5-(3,4-dimethylphenyl)-1,3,4-oxadiazole-2-carboxylate (3y)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3y as a white crystalline solid (64.5 mg, 52%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.89–7.87 (m, 1H), 7.29 (d, J = 7.8 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 2.35 (s, 6H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.8, 156.3, 154.6, 142.4, 137.9, 130.5, 128.6, 125.2, 120.2, 63.5, 20.1.
Ethyl 5-(2,6-dimethylphenyl)-1,3,4-oxadiazole-2-carboxylate (3z)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3z as a white crystalline solid (96.6 mg, 79%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.1 Hz, 2H), 4.55 (q, J = 7.1 Hz, 2H), 2.29 (s, 6H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.0, 157.1, 154.5, 138.9, 131.5, 128.1, 122.8, 63.5, 20.4, 14.1.
Ethyl 5-(2,4-dimethoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (3aa)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3aa as a white crystalline solid (88.9 mg, 64%). The spectral data are in accordance with the literature.91H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 1H), 6.60 (dd, J = 8.8, 2.3 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 4.54 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.89 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.4, 164.6, 159.9, 155.8, 154.7, 132.2, 105.6, 104.6, 98.9, 63.2, 56.1, 55.6, 14.1.
Ethyl 5-mesityl-1,3,4-oxadiazole-2-carboxylate (3ab)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3ab as a white crystalline solid (62.5 mg, 48%). MP: 84–86 °C. 1H NMR (400 MHz, CDCl3) δ 6.97 (s, 2H), 4.54 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H), 2.27 (s, 6H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.3, 156.9, 154.5, 141.7, 138.8, 128.9, 119.8, 63.4, 21.3, 20.4, 14.1. IR (KBr): ν = 2920, 1742, 1613, 1540, 1471, 1379, 1272, 1197, 1168, 1071, 848. HRMS (ESI) m/z: [M + H]+ calcd for C14H17N2O3 261.1234; found 261.1236.
Ethyl 5-benzoyl-1,3,4-oxadiazole-2-carboxylate (3ac)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3ac as a white crystalline solid (126.8 mg, 89%). The spectral data are in accordance with the literature.17 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.3 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.4 Hz, 2H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.5, 156.5, 154.5, 132.8, 129.3, 127.6, 122.7, 63.6, 14.1.
Methyl 5-(thiophen-2-yl)-1,3,4-oxadiazole-2-carboxylate (3ad)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3ad as a white crystalline solid (53.5 mg, 51%). The spectral data are in accordance with the literature.91H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 3.7 Hz, 1H), 7.67 (d, J = 4.9 Hz, 1H), 7.22 (t, J = 4.2 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 162.7, 155.8, 154.3, 132.1, 131.7, 128.5, 123.8, 63.6, 14.1.
Ethyl 5-(6-bromopyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate (3ae)
Column chromatography on silica gel (ethyl acetate/PE 1:12) afforded the title product 3ae as a light-yellow solid (73.8 mg, 50%). MP: 90–91 °C. 1H NMR (300 MHz, CDCl3) δ 9.13–9.12 (m, 1H), 8.30 (dd, J = 8.4, 2.5 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 4.57 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 163.8, 156.9, 154.0, 148.7, 146.7, 136.7, 128.8, 118.7, 63.9, 14.1. IR (KBr): ν = 3463, 2981, 2923, 1751, 1596, 1534, 1410, 1294, 1196, 1103, 1011, 963, 843, 741. HRMS (ESI) m/z: [M + H]+ calcd for C10H9BrN3O3297.9822; found 297.9820.
Ethyl 5-(6-methoxypyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate (3af)
Column chromatography on silica gel (ethyl acetate/PE 1:12) afforded the title product 3af as a light-yellow solid (64.6 mg, 52%). MP: 96–97 °C. 1H NMR (300 MHz, CDCl3) δ 8.96 (d, J = 2.4 Hz, 1H), 8.28 (dd, J = 8.8, 2.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H), 4.03 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 166.7, 164.9, 156.3, 154.3, 47.4, 137.2, 112.7, 111.8, 63.6, 54.2, 14.1. IR (KBr): ν = 3463, 3005, 2963, 1741, 1613, 1537, 1489, 1405, 1097, 1013, 928, 758, 724. HRMS (ESI) m/z: [M + H]+ calcd for C11H12N3O4 250.0822; found 250.0823.
Methyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (3A)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3A as a white crystalline solid (202.1 mg, 90%). The spectral data are in accordance with the literature.181H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.06 (s, 3H), 3.86 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.5, 163.2, 155.9, 154.9, 129.5, 114.7, 55.5, 53.7.
Benzyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (3B)
Column chromatography on silica gel (ethyl acetate/PE 1:15) afforded the title product 3B as a white crystalline solid (73.8 mg, 48%). MP: 95–97 °C. 1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 6.9 Hz, 2H), 7.43–7.41 (m, 2H), 7.33–7.31 (m, 3H), 6.93 (d, J = 6.9 Hz, 2H), 5.42 (s, 2H), 3.81 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.7, 163.4, 156.1, 154.6, 134.3, 129.7, 129.1, 128.9, 115.2, 114.8, 68.9, 55.7. IR (KBr): ν = 3420, 2940, 2238, 1731, 1486, 1376, 1196, 1092, 843, 832, 748. HRMS (ESI) m/z: [M + H]+ calcd for C17H15N2O4 311.1026; found 311.1026.
4a
Column chromatography on silica gel (ethyl acetate/PE 1:10) afforded the title product 4a as a white crystalline solid (mg, 60%). MP: 175–177 °C. 1H NMR (400 MHz, CDCl3) δ 7.47–7.43 (m, 2H), 7.06 (t, J = 8.6 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 3.65 (s, 3H), 3.55 (s, 3H), 3.09–3.03 (m, 1H), 1.43 (t, J = 7.1 Hz, 3H), 1.30 (d, J = 6.7 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 177.8, 166.1, 164.1 (d, J = 250.4 Hz), 163.9, 159.9, 157.4, 153.8, 130.7 (d, J = 8.8 Hz), 116.9 (d, J = 21.8 Hz), 108.1, 63.7, 42.5, 33.5, 33.2, 21.7, 13.9. 19F (470 MHz, CDCl3) δ −108.9. IR (KBr): ν = 2950, 1743, 1599, 1509, 1442, 1382, 1372, 1320, 1259, 1226, 1150, 1072, 1055, 972, 907, 860, 781. HRMS (ESI) m/z: [M + H]+ calcd for C20H23FN5O5S 464.1398; found 464.1395.
4b
Column chromatography on silica gel (ethyl acetate/PE 1:10) afforded the title product 4b as a white crystalline solid (mg, 37%). MP: >250 °C. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.34 (dd, J = 10.6, 2.2 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 5.05 (d, J = 7.7 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 3.76 (s, 3H), 3.17–3.02 (m, 2H), 1.48 (t, J = 7.2 Hz, 3H), 1.41 (br, 9H). 13C NMR (125 MHz, CDCl3) δ 172.0, 165.2, 157.4, 156.3, 155.0, 154.6, 134.9, 131.6, 128.7, 112.3, 80.1, 63.4, 56.2, 54.4, 52.4, 37.3, 28.3, 14.1. IR (KBr): ν = 3416, 2922, 1743, 1685, 1637, 1618, 1571, 1534, 1439, 1438, 1383, 1153, 1024, 872. HRMS (ESI) m/z: [M + H]+ calcd for C21H28N3O8 450.1871; found 450.1869.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (21402013), Natural Science Foundation of Jiangsu Province (BK20140259), Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110), and Advanced Catalysis and Green Manufacturing Collaborative Innovation Center. We thank Du Xiaogang from Analysis and Testing Center, NERC Biomass of Changzhou University for analytical support.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c04098.
Characterization of products (copies of 1H, 13C, and 19F NMR spectra) (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
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