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. 2022 Aug 1;7(32):28148–28159. doi: 10.1021/acsomega.2c02323

Synthesis of 2-Imino-1,3,4-oxadiazolines from Acylhydrazides and Isothiocyanates via Aerobic Oxidation and a DMAP-Mediated Annulation Sequence

Jae Hyeok Lim 1, Sang Eun Baek 1, Bapurao Sudam Lad 1, Jinho Kim 1,*
PMCID: PMC9386851  PMID: 35990423

Abstract

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In this work, an efficient synthesis of 2-imino-1,3,4-oxadiazolines from acylhydrazides and isothiocyanates is described. In the presence of 4-dimethylaminopyridine (DMAP) and molecular oxygen, various 2-imino-1,3,4-oxadiazolines were produced in good to high yields. The developed method showed a broad substrate scope and was effective on the gram scale. On the basis of the mechanistic studies and previous literature, it was proposed that the mechanism consists of an aerobic oxidation of acylhydrazides facilitated by DMAP and isothiocyanates, followed by a DMAP-mediated annulation of the in situ generated acyldiazenes with isothiocyanates.

Introduction

The 1,3,4-oxadiazole skeleton is an interesting scaffold that plays a crucial role in multifarious areas. Various compounds bearing the 1,3,4-oxadiazole ring have emerged as potent candidates for the preparation of organic light-emitting diodes1 after the first utilization was reported in 1990.2 In organic synthesis, 1,3,4-oxadiazoles are useful building blocks for the stereoselective synthesis of natural products through an intramolecular [4 + 2]/[3 + 2] cycloaddition cascade.3 Moreover, 1,3,4-oxadiazole derivatives are important structural motifs used in the development of new drugs,4 with representative examples including raltegravir (antiretroviral drug for HIV),5 zibotentan (anticancer agent),6 and furamizole (hypnotic drug).7

A number of protocols to synthesize 1,3,4-oxadiazoles have been developed over the years.8 These protocols include the dehydrative cyclization of 1,2-diacylhydrazines,9 desulfurative cyclization of thiosemicarbazides,10 and oxidative cyclization of N-acylhydrazones or their analogues,11 among others.12 However, the construction of 2-imino-1,3,4-oxadiazolines, which can have potent biological activity,13 has been much less investigated.

The first syntheses of 2-imino-1,3,4-oxadiazolines were achieved by the cyclization of 1-aroyl-2,4-dimethylthiosemicarbazides using excess amounts of HgO, a highly toxic reagent (Scheme 1a).14 In 2014, palladium-catalyzed aerobic oxidative annulations of hydrazides with isocyanides were achieved by Xu and co-workers, but a precious metal was required, and only tert-butyl-substituted 2-imino-1,3,4-oxadiazolines were able to be synthesized (Scheme 1b).15 The Chang group revealed that 2-imino-1,3,4-oxadiazolines could also be generated by the I2-mediated oxidative annulation of acylhydrazides with isothiocyanates (Scheme 1c).16 However, the production of 2-imino-1,3,4-oxadiazolines having a halogenated phenyl ring at the R1 position or an aliphatic chain at the R3 position was problematic, presumably due to the excessively reactive iodine oxidant. Our group has studied aerobic oxidations of hydrazides and their utility in organic transformations.17 As our previous aerobic oxidations of acylhydrazides showed selective transformations with high functional group tolerance, we envisioned that aerobic oxidative annulation of acylhydrazides with isothiocyanates might provide a practical and efficient route to 2-imino-1,3,4-oxadiazolines with broad substrate scope. In this report, we describe a straightforward synthesis of 2-imino-1,3,4-oxadiazolines through aerobic oxidation of acylhydrazides followed by 4-dimethylaminopyridine (DMAP)-mediated annulation of the in situ generated acyldiazenes with isothiocyanates (Scheme 1d).

Scheme 1. Various Synthetic Methods for 2-Imino-1,3,4-oxadiazolines.

Scheme 1

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Results and Discussion

In order to realize our envisioned aerobic method, we initiated the optimization employing N′-phenylbenzohydrazide (1a) and phenyl isothiocyanate (2a) as model substrates (Table 1).18 Gratifyingly, our previously reported CuCl/DMAP system facilitated the aerobic oxidative annulation to produce 3a, albeit in a moderate yield (entry 1, Table 1).17b It is noteworthy that the use of DMAP alone can facilitate the aerobic oxidative annulation without Cu sources (entry 2). Good reactivity was observed using stoichiometric DMAP (entry 3); however, excess DMAP did not result in a higher yield (entry 4). Other bases such as pyridine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), Et3N (triethylamine), and K2CO3 were less reactive than DMAP (entries 5–8). A significant increase in yield was afforded when two equivalents of 2a were employed (entry 9). Reducing the temperature from 70 °C to room temperature resulted in decreased yield (entry 10). Among the solvents screened, only toluene showed similar reactivity to CH3CN,19 with other solvents, including DCE (dichloroethane) and DMF (N,N-dimethylformamide), showing inferior results (entries 11–13). Several control experiments were carried out. In the absence of DMAP, the reaction did not produce 3a with no conversion of 1a (entry 14). Under ambient atmosphere, a decreased yield of 3a was observed (entry 15). Unexpectedly, the desired product 3a was synthesized in 28% yield under anaerobic conditions (entry 16). However, the aerobic annulation proceeded ∼4.6-fold faster than the anaerobic annulation. This result indicates that the aerobic oxidative pathway is dominant in spite of the existence of the anaerobic pathway (Figure 1).

Table 1. Optimization of Aerobic Oxidative Annulationa.

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entry base (equiv) solvent yield (%)b
1c DMAP (0.2) CH3CN 60
2 DMAP (0.2) CH3CN 37
3 DMAP (1.0) CH3CN 75
4 DMAP (2.0) CH3CN 76
5 pyridine (1.0) CH3CN 5
6 DBU (1.0) CH3CN 25
7 Et3N (1.0) CH3CN 39
8 K2CO3 (2.0) CH3CN 50
9d DMAP (1.0) CH3CN 92
10d,e DMAP (1.0) CH3CN 35
11d DMAP (1.0) toluene 91
12d DMAP (1.0) DCE 73
13d DMAP (1.0) DMF 42
14d   CH3CN <1
15d,f DMAP (1.0) CH3CN 65
16d,g DMAP (1.0) CH3CN 28
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a

Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), and the base in the solvent (2.0 mL) under O2 at 70 °C for 15 h.

b

Yield of 3a was determined by 1H NMR spectroscopy with 1,1,2,2-tetrachloroethane as the internal standard.

c

In the presence of CuCl (10 mol %).

d

The use of 1.0 mmol 2a.

e

At room temperature.

f

Under air.

g

Under N2.

Figure 1.

Figure 1

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Reaction rates of the oxidative annulation of 1a with 2a under O2 and N2.

With the optimized conditions in hand (Table 1, entry 9), the reactivity of various hydrazides was investigated to gain insights into the substrate scope (Scheme 2). It was revealed that the reactivity for oxidative annulation was largely affected by the electronic nature of the phenyl ring at the R1 position. Relatively electron-rich acylhydrazides showed good yields under the optimized conditions (3a–3e and 3i–3n), while the annulation of electron-poor acylhydrazides was sluggish. However, longer reaction times led to acceptable yields for electron-poor acylhydrazides (3f–3h). No significant increase in conversion and yield was observed after 24 h. It is worth noting that halogenated substrates, which were problematic in previous I2-mediated oxidative annulation,16 were found to be compatible without significant drop in yield (3d, 3e, 3k, and 3n). The acylhydrazide 1o, which was synthesized by the reaction of tert-butyl hydrazine with benzoyl chloride, underwent the annulation in a moderate yield (3o); however, the reaction of N′-acetyl-N-benzoylhydrazide 1p generated neither the annulation product 3p nor the hydrolyzed product 3q.15 Electronic variations of the phenyl ring at the R2 position showed no critical influence on the reactivity of oxidative annulation regardless of ortho, meta, or para substitution (3r–3ac). The reactivity of other aromatic rings such as 2-naphthyl and 2-furyl was also investigated, and the corresponding 2-imino-1,3,4-oxadiazolines were produced in good yields (3ad–3ae). Acylhydrazides bearing cyclohexanecarbonyl or tert-butanecarbonyl were also well tolerated (3af and 3ag).

Scheme 2. Substrate Scope of Hydrazides,

Scheme 2

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Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), and DMAP (0.5 mmol) in CH3CN (2.0 mL) under an O2 balloon at 70 °C for 15 h.

Isolated yields.

For 24 h.

Various isothiocyanates were screened, and the results are delineated in Scheme 3. Phenyl isothiocyanates having electron-donating or electron-withdrawing substituents efficiently underwent the annulation to produce the corresponding 2-imino-1,3,4-oxadiazolines in good to high yields (4a–4o). The annulation was compatible with benzoyl isothiocyanate 2p to produce oxadiazoline 4p in a good yield. Lastly, the aliphatic isothiocyanate 2q could also be employed (4q).

Scheme 3. Substrate Scope of Isothiocyanates,

Scheme 3

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Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), and DMAP (0.5 mmol) in CH3CN (2.0 mL) under an O2 balloon at 70 °C for 15 h.

Isolated yields.

The developed annulation was also effective on a larger scale. We carried out the reaction of 1a with 2a on a 1.0 g scale, and the annulation product 3a was produced with no significant reduction in conversion or yield (Scheme 4).

Scheme 4. Gram-Scale Aerobic Oxidative Annulation.

Scheme 4

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In order to investigate the roles of reaction parameters and to study the reaction mechanism, several mechanistic experiments were carried out. When benzhydrazide 5 was used as a starting material instead of 1a under the optimized conditions, only benzoyl thiosemicarbazide 6 was produced in high yield with no production of 3q (Scheme 5a). The acyldiazene 7 was separately prepared by a known method17b,17d and then tested under the optimized conditions. Interestingly, the desired product 3a was produced in a quantitative yield under not only oxygen but also nitrogen (Scheme 5b). These results indicate that the plausible intermediate in the present protocol would not be the benzoyl thiosemicarbazide14 but the acyldiazene. Although the oxidative annulation of 1a with 2a showed a faster reaction rate under O2 than under N2 (Figure 1), no significant difference between the reaction rate under O2 and N2 was observed in the annulation of 7 with 2a (Figure 2).

Scheme 5. Control Experiments for Mechanistic Investigation.

Scheme 5

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Figure 2.

Figure 2

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Reaction rates of the annulation of 7 with 2a under O2 and N2.

This suggests that the molecular oxygen plays a role in the oxidation of 1a to 7 but not in the annulation. The oxidation of 1a to 7 was not observed, when the reaction was carried out without 2a (Scheme 5c). Therefore, we believe that 2a might be essential for the aerobic oxidation of 1a to 7. No annulation between 7 and 2a took place without DMAP (Scheme 5d); however, the use of catalytic amounts of DMAP produced 3a in 46% yield (Scheme 5e). These observations in combination with the optimization studies (Table 1, entry 14) suggest that DMAP facilitates not only the oxidation of hydrazine but also the annulation.

Based on our preliminary mechanistic studies and the previous literature, the proposed mechanism of the present protocol is shown in Figure 3. The aerobic oxidation of hydrazide facilitated by DMAP and isothiocyanate produces acyldiazene intermediate A, although at this stage, the detailed oxidation mechanism is not clear. The produced acyldiazene intermediate A reacts with zwitterionic intermediate B which is generated by the activation of isothiocyanate with DMAP,20 and the following cyclization and desulfurization16,21 produce the desired 2-imino-1,3,4-oxadiazoline product.

Figure 3.

Figure 3

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Proposed mechanism for aerobic oxidative annulation.

Conclusions

In conclusion, we have developed a novel synthetic method for 2-imino-1,3,4-oxadiazolines from acylhydrazides and isothiocyanates via an aerobic oxidation and DMAP-facilitated annulation sequence. In the presence of DMAP and molecular oxygen, a broad range of 2-imino-1,3,4-oxadiazolines were synthesized through the developed method. The present protocol was effective even on a large scale. Preliminary mechanistic studies revealed that the plausible mechanism consists of an aerobic oxidation of hydrazides into N-acyldiazenes, followed by a DMAP-mediated annulation between the generated N-acyldiazenes and isothiocyanates.

Experimental Section

General Considerations

All commercially available compounds and solvents were purchased and used as received, unless otherwise noted. Analytical thin layer chromatography (TLC) was performed on precoated silica gel 60 F254 plates. Visualization on TLC was achieved by the use of UV light (254 nm) and treatment with phosphomolybdic acid stain followed by heating. Flash chromatography was performed using silica gel (particle size 40–63 μm, 230–400 mesh). 1H and 13C NMR spectra were recorded on 400 MHz NMR (400 MHz for 1H, 101 MHz for 13C). Chemical shift values are given in parts per million relative to internal tetramethylsilane (0.00 ppm for 1H) or CDCl3 (77.06 ppm for 13C). The following abbreviations were used to describe peak splitting patterns when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, dd = double of doublet, dt = double of triplet, and td = triple of doublet. Coupling constants, J, were reported in the hertz unit (Hz). High-resolution mass spectra were obtained from the Korea Basic Science Institute (Daegu) by using the electron ionization method and magnetic sector mass analyzer.

General Procedure for Aerobic Oxidative Annulation of Acylhydrazides with Isothiocyanates

A 10 mL flame-dried test tube (O.D. 15 mm), which was equipped with a magnetic stir bar and charged with hydrazide 1 (0.5 mmol) and DMAP (1.0 equiv, 0.5 mmol), was evacuated and backfilled with oxygen (this process was repeated three times). After CH3CN (1.0 mL) was added, isothiocyanate 2 (2.0 equiv, 1.0 mmol) and CH3CN (1.0 mL) were added. Then, the reaction mixture was stirred at 70 °C for 15 h. The mixture was quenched with a saturated aqueous solution of NH4Cl at room temperature and diluted by adding dichloromethane (DCM). Two layers were separated, and the aqueous layer was extracted with DCM. The combined organic layer was dried over MgSO4, filtered, and concentrated on a rotary evaporator. The residue was purified by column chromatography to give 2-imino-1,3,4-oxadiazoline products.graphic file with name ao2c02323_0012.jpg

N,3,5-Triphenyl-1,3,4-oxadiazol-2(3H)-imine (3a)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 6.5 Hz, 2H), 7.43 (t, J = 7.2 Hz, 5H), 7.38–7.33 (m, 2H), 7.30 (d, J = 7.5 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 6.7 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 152.8, 145.6, 144.4, 137.6, 131.5, 129.1, 129.0, 128.9, 125.9, 124.9, 123.6, 123.3, 123.2, 118.5.graphic file with name ao2c02323_0013.jpg

3-(4-Methoxyphenyl)-N,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3b)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 9.1 Hz, 2H), 7.84 (d, J = 7.6 Hz, 2H), 7.42 (q, J = 5.8 Hz, 3H), 7.34 (t, J = 7.7 Hz, 2H), 7.29 (d, J = 7.4 Hz, 2H), 7.07 (t, J = 7.1 Hz, 1H), 6.95 (d, J = 9.1 Hz, 2H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 157.0, 152.5, 145.7, 144.7, 131.4, 130.9, 129.0, 128.9, 125.8, 123.6, 123.2, 123.0, 120.4, 114.1, 55.5; HRMS (EI) m/z: calcd for C21H17N3O2 [M]+, 343.1321; found, 343.1322.graphic file with name ao2c02323_0014.jpg

N,5-Diphenyl-3-(p-tolyl)-1,3,4-oxadiazol-2(3H)-imine (3c)16

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 7.46–7.38 (m, 3H), 7.34 (t, J = 7.7 Hz, 2H), 7.29 (d, J = 7.1 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.07 (t, J = 7.1 Hz, 1H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 152.5, 145.7, 144.4, 135.2, 134.5, 131.4, 129.4, 128.9, 125.8, 123.6, 123.3, 123.1, 118.5, 21.0.graphic file with name ao2c02323_0015.jpg

3-(4-Chlorophenyl)-N,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3d)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 7.0 Hz, 2H), 7.57–7.46 (m, 3H), 7.42 (d, J = 9.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.30 (d, J = 7.5 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 152.9, 145.2, 143.9, 136.1, 131.7, 129.9, 129.0, 128.9, 125.9, 123.4, 123.3, 123.2, 119.5.graphic file with name ao2c02323_0016.jpg

3-(4-Bromophenyl)-N,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3e)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.52–7.46 (m, 3H), 7.37 (t, J = 7.7 Hz, 2H), 7.30 (d, J = 7.4 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 152.9, 145.1, 143.9, 136.6, 131.8, 131.7, 129.0, 126.0, 123.4, 123.3, 123.1, 119.8, 117.7.graphic file with name ao2c02323_0017.jpg

N,5-Diphenyl-3-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-imine (3f)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 7.0 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.55–7.47 (m, 3H), 7.38 (t, J = 7.7 Hz, 2H), 7.31 (d, J = 7.4 Hz, 2H), 7.13 (t, J = 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 153.3, 144.9, 143.7, 140.2, 131.9, 129.0, 126.3 (q, J = 32.5 Hz), 126.08 (q, J = 3.8 Hz), 126.07, 126.06, 124.1 (q, J = 268.7 Hz), 123.6, 123.1, 117.8; 19F NMR (376 MHz, CDCl3): δ −62.09.graphic file with name ao2c02323_0018.jpg

4-[5-Phenyl-2-(phenylimino)-1,3,4-oxadiazol-3(2H)-yl]benzonitrile (3g)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 8.7 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.58–7.53 (m, 1H), 7.49 (t, J = 7.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 153.6, 144.6, 143.3, 140.8, 133.1, 132.2, 129.1, 129.0, 126.2, 123.9, 123.1, 122.9, 118.9, 118.0, 107.4.graphic file with name ao2c02323_0019.jpg

3-(4-Nitrophenyl)-N,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3h)16

Yellow solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.47 (d, J = 9.3 Hz, 2H), 8.33 (d, J = 9.3 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.60–7.54 (m, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.32 (d, J = 7.3 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 153.8, 144.4, 143.7, 143.1, 142.4, 132.3, 129.1, 126.2, 124.9, 124.0, 123.1, 122.8, 117.6.graphic file with name ao2c02323_0020.jpg

3-(3-Methoxyphenyl)-N,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3i)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 7.91 (s, 1H), 7.85 (d, J = 7.7 Hz, 2H), 7.79 (d, J = 9.1 Hz, 1H), 7.47–7.39 (m, 3H), 7.37–7.30 (m, 5H), 7.09 (t, J = 7.1 Hz, 1H), 6.73 (d, J = 9.5 Hz, 1H), 3.84 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 160.1, 152.6, 145.4, 144.2, 138.7, 131.5, 129.7, 128.9, 125.9, 123.5, 123.3, 123.2, 110.6, 104.2, 55.4; HRMS (EI) m/z: calcd for C21H17N3O2 [M]+, 343.1321; found, 343.1321.graphic file with name ao2c02323_0021.jpg

N,5-Diphenyl-3-(m-tolyl)-1,3,4-oxadiazol-2(3H)-imine (3j)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.2 Hz, 1H), 7.98 (s, 1H), 7.85 (d, J = 6.9 Hz, 2H), 7.47–7.39 (m, 3H), 7.37–7.28 (m, 5H), 7.08 (t, J = 7.1 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 152.6, 145.6, 144.4, 138.8, 137.5, 131.5, 129.0, 128.9, 128.8, 125.9, 125.7, 123.6, 123.3, 123.1, 119.1, 115.7, 21.8; HRMS (EI) m/z: calcd for C21H17N3O [M]+, 327.1372; found, 327.1368.graphic file with name ao2c02323_0022.jpg

3-(3-Chlorophenyl)-N,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3k)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.47–7.40 (m, 3H), 7.38–7.28 (m, 5H), 7.14–7.08 (m, 2H); 13C NMR (101 MHz, CDCl3): δ 153.0, 145.0, 143.7, 138.5, 134.6, 131.8, 129.9, 129.0, 126.0, 124.6, 123.5, 123.2, 118.2, 116.1.graphic file with name ao2c02323_0023.jpg

3-(2-Methoxyphenyl)-N,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3l)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 6.2 Hz, 1H), 7.47–7.40 (m, 3H), 7.38–7.33 (m, 1H), 7.30–7.14 (m, 4H), 7.02 (d, J = 8.0 Hz, 3H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 155.4, 153.3, 147.2, 131.3, 130.6, 129.1, 128.9, 128.7, 125.8, 125.2, 123.9, 123.2, 122.7, 120.9, 112.8, 56.0; HRMS (EI) m/z: calcd for C21H17N3O2 [M]+, 343.1321; found, 343.1319.graphic file with name ao2c02323_0024.jpg

N,5-Diphenyl-3-(o-tolyl)-1,3,4-oxadiazol-2(3H)-imine (3m)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 7.6 Hz, 2H), 7.53 (s, 1H), 7.49–7.44 (m, 3H), 7.35–7.28 (m, 5H), 7.24 (d, J = 6.8 Hz, 2H), 7.04 (t, J = 7.0 Hz, 1H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 153.3, 146.2, 145.7, 135.5, 135.3, 131.4, 131.3, 129.0, 128.9, 128.8, 127.0, 126.8, 125.7, 123.8, 123.2, 122.8, 18.5; HRMS (EI) m/z: calcd for C21H17N3O [M]+, 327.1372; found, 327.1373.graphic file with name ao2c02323_0025.jpg

3-(2-Chlorophenyl)-N,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3n)16

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 2H), 7.64 (s, 1H), 7.56–7.50 (m, 1H), 7.50–7.41 (m, 3H), 7.39–7.26 (m, 4H), 7.26–7.18 (m, 2H), 7.04 (t, J = 6.4 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 153.6, 146.0, 145.5, 134.1, 132.3, 131.5, 130.8, 130.2, 129.5, 128.9, 128.8, 127.7, 125.8, 123.7, 123.1, 123.0.graphic file with name ao2c02323_0026.jpg

3-(tert-Butyl)-N,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3o)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 3.8 Hz, 2H), 7.42 (s, 3H), 7.31 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 7.7 Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H), 1.68 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 150.6, 146.5, 146.4, 130.5, 128.7, 125.3, 124.4, 123.1, 122.1, 58.7, 27.6.graphic file with name ao2c02323_0027.jpg

5-(4-Methoxyphenyl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3r)16

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.7 Hz, 2H), 7.44 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 7.7 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 7.08 (t, J = 7.0 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 162.2, 152.8, 145.7, 144.5, 137.6, 128.9, 128.8, 127.7, 124.6, 123.2, 123.0, 118.3, 115.9, 114.4, 55.4.graphic file with name ao2c02323_0028.jpg

N,3-Diphenyl-5-(p-tolyl)-1,3,4-oxadiazol-2(3H)-imine (3s)16

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.9 Hz, 2H), 7.35 (dd, J = 10.8, 4.4 Hz, 2H), 7.30 (d, J = 7.4 Hz, 2H), 7.18 (dd, J = 14.6, 7.6 Hz, 3H), 7.08 (t, J = 7.0 Hz, 1H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 152.9, 145.6, 144.4, 142.1, 137.7, 129.7, 129.0, 128.9, 125.9, 124.7, 123.3, 120.7, 118.4, 21.7.graphic file with name ao2c02323_0029.jpg

5-(4-Chlorophenyl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3t)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.9 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.41 (m, 4H), 7.34 (d, J = 7.3 Hz, 2H), 7.27 (d, J = 7.4 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 151.9, 145.3, 144.0, 137.7, 137.5, 129.4, 129.0, 128.9, 127.2, 125.0, 123.3, 123.2, 122.0, 118.4.graphic file with name ao2c02323_0030.jpg

5-(4-Bromophenyl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3u)

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 7.9 Hz, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.47 (t, J = 7.9 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 152.0, 145.3, 144.0, 137.4, 132.3, 129.0, 128.9, 127.2, 126.1, 125.0, 123.3, 123.1, 122.4, 118.4; HRMS (EI) m/z: calcd for C20H14BrN3O [M]+, 393.0302; found, 393.0300.graphic file with name ao2c02323_0031.jpg

N,3-Diphenyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-imine (3v)

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 7.8 Hz, 2H), 7.99 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 7.4 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 151.4, 145.1, 143.8, 137.3, 132.9 (q, J = 33.3 Hz), 129.0, 128.9, 126.8, 126.1, 126.0 (q, J = 3.8 Hz), 125.2, 123.6 (q, J = 273.7 Hz), 123.4, 123.2, 118.5; 19F NMR (376 MHz, CDCl3): δ −63.01; HRMS (EI) m/z: calcd for C21H14F3N3O [M]+, 381.1089; found, 381.1090.graphic file with name ao2c02323_0032.jpg

4-[4-Phenyl-5-(phenylimino)-4,5-dihydro-1,3,4-oxadiazol-2-yl]benzonitrile (3w)

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.8 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.27 (d, J = 7.5 Hz, 2H), 7.23 (d, J = 7.5 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 151.0, 144.9, 143.6, 137.2, 132.7, 129.0, 128.9, 127.4, 126.2, 125.4, 123.6, 123.1, 118.5, 117.9, 114.7; HRMS (EI) m/z: calcd for C21H14N4O [M]+, 338.1168; found, 338.1165.graphic file with name ao2c02323_0033.jpg

5-(4-Nitrophenyl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3x)

Yellow solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 7.9 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H), 7.26 (d, J = 3.8 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 150.8, 149.1, 144.9, 143.6, 137.1, 129.0, 128.9, 126.6, 125.5, 124.3, 123.6, 123.0, 118.6; HRMS (EI) m/z: calcd for C20H14N4O3 [M]+, 358.1066; found, 358.1067.graphic file with name ao2c02323_0034.jpg

N,3-Diphenyl-5-(m-tolyl)-1,3,4-oxadiazol-2(3H)-imine (3y)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 12.8 Hz, 2H), 7.43 (t, J = 7.9 Hz, 2H), 7.35 (t, J = 6.8 Hz, 2H), 7.32–7.27 (m, 3H), 7.24 (d, J = 7.5 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.08 (t, J = 7.1 Hz, 1H), 2.35 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 152.9, 145.6, 144.3, 138.8, 137.6, 132.4, 129.0, 128.9, 128.8, 126.3, 124.8, 123.4, 123.3, 123.2, 118.4, 21.4; HRMS (EI) m/z: calcd for C21H17N3O [M]+, 327.1372; found, 327.1374.graphic file with name ao2c02323_0035.jpg

5-(3-Chlorophenyl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3z)

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.3 Hz, 2H), 7.83 (s, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 8.1 Hz, 3H), 7.35 (q, J = 7.3 Hz, 3H), 7.28 (d, J = 7.9 Hz, 2H), 7.19 (t, J = 7.1 Hz, 1H), 7.09 (t, J = 7.1 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 151.5, 145.2, 143.8, 137.4, 135.1, 131.5, 130.3, 129.0, 128.9, 125.7, 125.2, 125.0, 123.9, 123.4, 123.2, 118.4; HRMS (EI) m/z: calcd for C20H14ClN3O [M]+, 347.0825; found, 347.0827.graphic file with name ao2c02323_0036.jpg

5-(3-Nitrophenyl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3aa)

Yellow solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 7.21 (t, J = 7.0 Hz, 1H), 7.11 (t, J = 6.9 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 150.7, 148.5, 144.8, 143.4, 137.2, 131.1, 130.2, 129.1, 129.0, 125.7, 125.3, 125.2, 123.6, 123.1, 120.7, 118.4; HRMS (EI) m/z: calcd for C20H14N4O3 [M]+, 358.1066; found, 358.1063.graphic file with name ao2c02323_0037.jpg

N,3-Diphenyl-5-(o-tolyl)-1,3,4-oxadiazol-2(3H)-imine (3ab)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.35 (t, J = 7.6 Hz, 3H), 7.28 (dd, J = 19.4, 7.0 Hz, 4H), 7.22–7.17 (m, 1H), 7.08 (t, J = 7.0 Hz, 1H), 2.68 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 152.6, 145.4, 143.6, 137.6, 137.4, 131.5, 130.8, 128.6, 128.6, 127.6, 125.9, 124.4, 122.9, 122.8, 121.9, 117.9, 21.9; HRMS (EI) m/z: calcd for C21H17N3O [M]+, 327.1372; found, 327.1374.graphic file with name ao2c02323_0038.jpg

5-(2-Chlorophenyl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3ac)

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 7.9 Hz, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.40–7.36 (m, 1H), 7.34–7.31 (m, 5H), 7.21 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 6.4 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 150.9, 145.4, 143.9, 137.5, 132.8, 132.0, 131.5, 129.9, 128.9, 127.0, 125.0, 123.3, 122.4, 118.5; HRMS (EI) m/z: calcd for C20H14ClN3O [M]+, 347.0825; found, 347.0828.graphic file with name ao2c02323_0039.jpg

5-(Naphthalen-2-yl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3ad)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 8.21 (d, J = 5.4 Hz, 2H), 7.92 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 6.7 Hz, 1H), 7.52–7.42 (m, 4H), 7.40 (t, J = 7.8 Hz, 2H), 7.33 (d, J = 7.2 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 152.8, 145.5, 144.3, 137.6, 134.5, 132.7, 129.0, 128.9, 128.7, 128.0, 127.9, 127.1, 126.2, 124.8, 123.3, 123.2, 122.1, 120.7, 118.5.graphic file with name ao2c02323_0040.jpg

5-(Furan-2-yl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3ae)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 7.9 Hz, 2H), 7.59 (s, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.27 (d, J = 7.5 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 3.4 Hz, 1H), 6.58–6.51 (m, 1H); 13C NMR (101 MHz, CDCl3): δ 146.2, 145.6, 145.1, 143.3, 138.8, 137.3, 128.9, 128.8, 125.0, 123.3, 123.2, 118.5, 113.8, 112.0.graphic file with name ao2c02323_0041.jpg

5-Cyclohexyl-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3af)

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.1 Hz, 2H), 7.41 (t, J = 7.9 Hz, 2H), 7.31 (t, J = 7.7 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 2.63 (tt, J = 11.0, 3.4 Hz, 1H), 2.04 (d, J = 11.6 Hz, 2H), 1.82 (dd, J = 9.3, 3.2 Hz, 2H), 1.70 (d, J = 9.5 Hz, 1H), 1.61–1.49 (m, 2H), 1.41–1.25 (m, 3H); 13C NMR (101 MHz, CDCl3): δ 158.8, 145.8, 145.0, 137.6, 128.9, 128.8, 124.4, 123.2, 122.9, 118.1, 35.4, 29.3, 25.6, 25.2; HRMS (EI) m/z: calcd for C20H21N3O [M]+, 319.1685; found, 319.1688.graphic file with name ao2c02323_0042.jpg

5-(tert-Butyl)-N,3-diphenyl-1,3,4-oxadiazol-2(3H)-imine (3ag)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 7.8 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.26–7.21 (m, 2H), 7.16 (t, J = 7.4 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 1.37 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 161.7, 145.7, 145.1, 137.6, 128.8, 124.4, 123.2, 122.8, 118.2, 32.5, 27.3.graphic file with name ao2c02323_0043.jpg

N-(4-Methoxyphenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4a)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 6.2 Hz, 2H), 7.52–7.43 (m, 5H), 7.30–7.25 (m, 2H), 7.20 (t, J = 7.3 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 155.6, 152.6, 143.9, 138.6, 137.6, 131.4, 128.9, 128.8, 125.9, 124.7, 124.0, 123.6, 118.3, 114.1, 55.5.graphic file with name ao2c02323_0044.jpg

3,5-Diphenyl-N-(p-tolyl)-1,3,4-oxadiazol-2(3H)-imine (4b)16

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 7.7 Hz, 2H), 7.53–7.40 (m, 5H), 7.22 (d, J = 8.5 Hz, 3H), 7.16 (d, J = 8.2 Hz, 2H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 152.7, 144.1, 142.8, 137.6, 132.5, 131.4, 129.5, 128.9, 125.9, 124.7, 123.6, 123.0, 118.4, 20.9.graphic file with name ao2c02323_0045.jpg

N-(4-Fluorophenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4c)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 7.8 Hz, 2H), 7.92 (d, J = 7.7 Hz, 2H), 7.56–7.45 (m, 5H), 7.31–7.27 (m, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 8.7 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 159.0 (d, J = 230.3 Hz), 152.7, 144.5, 141.5, 137.5, 131.6, 129.0, 128.9, 125.9, 124.9, 124.2 (d, J = 8.0 Hz), 123.4, 118.5, 115.5 (d, J = 22.2 Hz); 19F NMR (376 MHz, CDCl3): δ −120.59; HRMS (EI) m/z: calcd for C20H14FN3O [M]+, 331.1121; found, 331.1121.graphic file with name ao2c02323_0046.jpg

N-(4-Chlorophenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4d)16

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 7.8 Hz, 2H), 7.54–7.42 (m, 5H), 7.31 (d, J = 8.7 Hz, 2H), 7.26–7.20 (m, 3H); 13C NMR (101 MHz, CDCl3): δ 152.8, 144.6, 144.1, 137.3, 131.6, 129.0, 128.9, 128.1, 125.9, 125.0, 124.5, 123.3, 118.5.graphic file with name ao2c02323_0047.jpg

N-(4-Bromophenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4e)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 6.6 Hz, 2H), 7.53–7.43 (m, 7H), 7.26–7.16 (m, 3H); 13C NMR (101 MHz, CDCl3): δ 152.8, 144.7, 144.6, 137.3, 131.9, 131.7, 129.0, 128.9, 125.9, 125.1, 124.9, 123.3, 118.6, 115.8; HRMS (EI) m/z: calcd for C20H14BrN3O [M]+, 391.0320; found, 391.0324.graphic file with name ao2c02323_0048.jpg

3,5-Diphenyl-N-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-imine (4f)16

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 7.1 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.55–7.45 (m, 5H), 7.38 (d, J = 8.2 Hz, 2H), 7.29–7.23 (m, 1H); 13C NMR (101 MHz, CDCl3): δ 153.0, 148.9, 145.2, 137.2, 131.8, 129.1, 129.0, 126.1 (q, J = 3.8 Hz), 126.0, 125.3, 123.3, 123.2, 118.7; 19F NMR (376 MHz, CDCl3): δ −61.76.graphic file with name ao2c02323_0049.jpg

4-{[3,5-Diphenyl-1,3,4-oxadiazol-2(3H)-ylidene]amino}benzonitrile (4g)16

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.8 Hz, 2H), 7.91 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.58–7.45 (m, 5H), 7.36 (d, J = 8.6 Hz, 2H), 7.29–7.24 (m, 1H); 13C NMR (101 MHz, CDCl3): δ 153.2, 150.0, 145.5, 136.9, 133.1, 131.9, 129.1, 129.0, 126.0, 125.6, 123.9, 123.0, 119.6, 118.9, 105.8.graphic file with name ao2c02323_0050.jpg

N-(4-Nitrophenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4h)16

Yellow solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 9.0 Hz, 2H), 8.18 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 7.5 Hz, 2H), 7.58–7.48 (m, 5H), 7.40 (d, J = 9.1 Hz, 2H), 7.30 (d, J = 7.0 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 153.3, 152.2, 145.9, 143.0, 136.8, 132.1, 129.1, 129.0, 126.0, 125.8, 125.0, 123.5, 122.9, 119.1.graphic file with name ao2c02323_0051.jpg

N-(3-Methoxyphenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4i)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 7.4 Hz, 2H), 7.55–7.43 (m, 5H), 7.28 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.87 (s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 3.85 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 160.2, 152.8, 146.8, 144.5, 137.5, 131.5, 129.5, 128.9, 128.9, 125.9, 124.9, 123.5, 118.5, 115.6, 109.1, 108.9, 55.3; HRMS (EI) m/z: calcd for C21H17N3O2 [M]+, 343.1321; found, 343.1319.graphic file with name ao2c02323_0052.jpg

N-(3-Chlorophenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4j)

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 7.8 Hz, 2H), 7.90 (d, J = 7.8 Hz, 2H), 7.52–7.43 (m, 5H), 7.34–7.30 (m, 1H), 7.29–7.24 (m, 1H), 7.24–7.16 (m, 2H), 7.06 (d, J = 7.8 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 152.9, 146.8, 144.9, 137.3, 134.3, 131.7, 129.8, 129.0, 128.9, 125.9, 125.1, 123.4, 123.3, 123.1, 121.4, 118.6; HRMS (EI) m/z: calcd for C20H14ClN3O [M]+, 347.0825; found, 347.0826.graphic file with name ao2c02323_0053.jpg

N-(3-Nitrophenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4k)

Yellow solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 7.8 Hz, 2H), 7.93 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.57–7.43 (m, 6H), 7.36 (d, J = 8.1 Hz, 1H), 7.28–7.24 (m, 1H), 7.16 (t, J = 7.8 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 153.0, 148.9, 146.7, 145.6, 137.0, 131.9, 129.8, 129.4, 129.1, 129.0, 125.9, 125.5, 123.0, 118.8, 118.0, 117.8; HRMS (EI) m/z: calcd for C20H14N4O3 [M]+, 358.1066; found, 358.1068.graphic file with name ao2c02323_0054.jpg

N-(2-Methoxyphenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4l)

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 7.9 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.50–7.41 (m, 5H), 7.24–7.16 (m, 2H), 7.09 (t, J = 7.7 Hz, 1H), 6.97 (t, J = 6.9 Hz, 2H), 3.85 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 152.8, 152.0, 144.9, 137.6, 131.4, 128.9, 128.8, 125.9, 124.7, 123.9, 123.6, 123.5, 120.8, 118.3, 111.7, 55.8; HRMS (EI) m/z: calcd for C21H17N3O2 [M]+, 343.1321; found, 343.1319.graphic file with name ao2c02323_0055.jpg

3,5-Diphenyl-N-(o-tolyl)-1,3,4-oxadiazol-2(3H)-imine (4m)16

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.50–7.41 (m, 5H), 7.31–7.18 (m, 4H), 7.01 (t, J = 7.4 Hz, 1H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 152.7, 144.3, 143.7, 137.7, 131.6, 131.5, 130.4, 128.9, 128.8, 126.3, 125.9, 124.7, 123.6, 123.2, 121.7, 118.2, 18.7.graphic file with name ao2c02323_0056.jpg

N-(2-Chlorophenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4n)

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.52–7.43 (m, 6H), 7.36 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 153.0, 144.9, 143.1, 137.3, 131.6, 129.8, 129.0, 128.9, 128.2, 127.1, 126.0, 125.1, 123.9, 123.5, 123.3, 118.5; HRMS (EI) m/z: calcd for C20H14ClN3O [M]+, 347.0825; found, 347.0825.graphic file with name ao2c02323_0057.jpg

N-(2-Nitrophenyl)-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4o)

Yellow solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 8.20 (d, J = 7.9 Hz, 2H), 7.94 (d, J = 6.6 Hz, 3H), 7.62 (d, J = 9.0 Hz, 1H), 7.57–7.46 (m, J = 15.0, 7.7 Hz, 6H), 7.31–7.26 (m, 1H); 13C NMR (101 MHz, CDCl3): δ 153.2, 145.8, 143.6, 140.6, 136.8, 133.3, 131.8, 129.0, 126.0, 125.6, 125.5, 125.0, 123.0, 122.9, 119.0; HRMS (EI) m/z: calcd for C20H14N4O3 [M]+, 358.1066; found, 358.1062.graphic file with name ao2c02323_0058.jpg

N-[3,5-Diphenyl-1,3,4-oxadiazol-2(3H)-ylidene]benzamide (4p)16

White solid, EtOAc/PE = 1:40, 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.3 Hz, 2H), 8.20 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.1 Hz, 2H), 7.60–7.50 (m, 6H), 7.47 (t, J = 7.2 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 173.4, 155.7, 151.6, 136.3, 136.2, 132.3, 132.2, 129.9, 129.1, 129.0, 128.2, 126.9, 126.6, 122.5, 120.5.graphic file with name ao2c02323_0059.jpg

N-Phenethyl-3,5-diphenyl-1,3,4-oxadiazol-2(3H)-imine (4q)

White solid, EtOAc/PE = 1:20, 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 7.5 Hz, 2H), 7.50–7.45 (m, 3H), 7.42 (t, J = 7.9 Hz, 2H), 7.36–7.28 (m, 4H), 7.22–7.12 (m, 2H), 3.76 (t, J = 7.5 Hz, 2H), 3.01 (t, J = 7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 152.3, 145.6, 140.7, 138.0, 131.1, 129.0, 128.9, 128.80, 128.3, 126.0, 125.7, 124.0, 117.6, 49.6, 38.1; HRMS (EI) m/z: calcd for C22H19N3O [M]+, 341.1528; found, 341.1525.

Procedure for Aerobic Oxidative Annulation on a Large Scale

A 250 mL round-bottom flask, which was equipped with a magnetic stir bar and charged with hydrazide 1a (4.7 mmol, 1.0 g) and DMAP (1.0 equiv, 4.7 mmol), was evacuated and backfilled with oxygen (this process was repeated three times). After 10 mL of CH3CN was added, 2a (2.0 equiv, 9.4 mmol) and CH3CN (5 mL) were added in sequence. The reaction mixture was stirred under an O2 balloon at 70 °C for 15 h. The mixture was quenched with a saturated aqueous solution of NH4Cl at room temperature and diluted by adding DCM. Two layers were separated, and the aqueous layer was extracted with DCM. The combined organic layer was dried over MgSO4, filtered, and concentrated on a rotary evaporator. The residue was purified by column chromatography to give 2-imino-1,3,4-oxadiazoline products (EtOAc/PE = 1:20).

Acknowledgments

This work is dedicated to Prof. Sukbok Chang on the occasion of his 60th birthday. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (no. 2021R1A2C4002062). This work was also supported by the Incheon National University RIBS Grant in 2019.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c02323.

  • Preparation of acylhydrazides, detail optimizations, and copies of 1H, 13C, and 19F NMR spectra (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao2c02323_si_001.pdf (3.5MB, pdf)

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Supplementary Materials

ao2c02323_si_001.pdf (3.5MB, pdf)

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