Abstract
A silver-assisted method for [3 + 2] annulation of nitrones with isocyanides has been developed. The developed protocol allows access to a variety of 2,3,4-trisubstituted 1,2,4-oxadiazolidin-5-one derivatives as single diastereomers in good to excellent yields using silver oxide as the catalyst and molecular oxygen as the terminal oxidant. A plausible mechanism involving a nucleophilic addition/cyclization/protodeargentation/oxidation pathway is proposed on the basis of experimental results.
Introduction
Nitrones and isocyanides constitute multifaceted building blocks in organic synthesis and have been extensively implemented in the construction of nitrogen-based heterocyclic compounds.1,2 Thus far, several remarkable reaction manifolds have been realized. Among these, the [3 + 2] dipolar cycloaddition reaction represents a powerful strategy to access five-membered heterocyclic compounds owing to its simplicity and atom efficiency.3,4 In contrast, [3 + 1] and [3 + 1 + 1] cycloaddition reactions of nitrones with isocyanides to assemble heterocycles have rarely been utilized.5−8
Only a handful of reports detailing the cycloaddition manifolds of nitrones with isocyanides have been disclosed (Figure 1a). For example, the Zhu, Zeeh, and Lorke groups have demonstrated that nitrones can undergo [3 + 1] cycloaddition with isocyanides to afford four-membered 4-imino-1,2-oxazetidine motifs.6 Furthermore, a proposed [3 + 3] cycloaddition process involving nitrones and α-metalated isocyanides to produce five-membered 2-imidazolidinones was recently reported.8 Also, Xu and co-workers realized that isocyanoacetates could react with nitrones to produce polysubstituted pyrroles in the presence of commercially available copper salts through a [3 + 1 + 1] cycloaddition manifold.7 Luzyanin and co-workers have also described a metal-mediated strategy in which nitrones react with palladium-bound isocyanides to provide carbene complexes (Figure 1b).9 Despite the number of synthetic methodologies that have been realized,10 the development of new and efficient methods that rely on easily available starting materials are of great value. As a continuation of the recently witnessed reports on isocyanide-involving reaction manifolds,11 we have explored silver-mediated manifolds involving isocyanides.12 Here, we disclose a silver-assisted [3 + 2] annulation reaction of nitrones with isocyanides for the assembly of 1,2,4-oxadiazolidin-5-ones and the subsequent decarboxylative process for accessing amidines, which are vital motifs in pharmaceuticals and natural products.13 The developed methods display broad substrate scope and are conducted under mild reaction conditions (Figure 1c).
Figure 1.
Annulation reactions of isocyanides with nitrones.
Results and Discussion
N-Benzylideneaniline oxide (1a) and 1-bromo-4-isocyanobenzene (2a) were selected as model substrates for the optimization of the [3 + 2] annulation reaction. To our delight, conducting the reaction in DMF at 80 °C in the presence of Ag2O (10 mol %) afforded the desired product 4-(4-bromophenyl)-2,3-diphenyl-1,2,4-oxadiazolidin-5-one (3a) in a 76% isolated yield after merely 4 h (Table 1, entry 1). Screening of other silver salts, including AgOAc, Ag2CO3, AgOTf, AgBF4, and other metal precursors, such as CuI and Pd(OAc)2, showed that Ag2CO3 and Ag2O displayed the best reactivity while AgOAc proved to be less efficient and the other metal catalysts were inactive (Table 1, entries 2–7). Next, switching to 1,4-dioxane greatly increased the yield of annulation adduct 3a to 91% (Table 1, entry 8). The use of aprotic or polar solvents, such as toluene and MeCN, had a negative effect on the reaction and delivered 3a in diminished yields (Table 1, entries 9 and 10) while employing the protic solvent EtOH nearly inhibited the reaction (Table 1, entry 11). Decreasing the reaction temperature from 80 to 40 °C led to a significantly diminished yield of the desired product (Table 1, entry 12). A control experiment established that a silver catalyst is required for the reaction to proceed (Table 1, entry 13). Furthermore, the annulation affords product 3a as a single diastereomer as confirmed by single-crystal X-ray diffraction analysis (CCDC 1915298, see Scheme 1).
Table 1. Optimization of the Reaction Conditionsa,b.
| entry | [M] | solvent | temp (°C) | yield (%)b |
|---|---|---|---|---|
| 1 | Ag2O | DMF | 80 | 76 |
| 2 | AgOAc | DMF | 80 | 42 |
| 3 | Ag2CO3 | DMF | 80 | 74 |
| 4 | AgOTf | DMF | 80 | <5c |
| 5 | AgBF4 | DMF | 80 | <5c |
| 6 | CuI | DMF | 80 | <5c |
| 7 | Pd(OAc)2 | DMF | 80 | <5c |
| 8 | Ag2O | 1,4-dioxane | 80 | 91 |
| 9 | Ag2O | toluene | 80 | 76 |
| 10 | Ag2O | CH3CN | 80 | 53 |
| 11 | Ag2O | EtOH | 80 | <10c |
| 12 | Ag2O | 1,4-dioxane | 40 | 38 |
| 13 | 1,4-dioxane | 80 | <5c |
Reaction conditions: all reactions were carried out with 1a (0.55 mmol), 2a (0.5 mmol), catalyst (10 mol %) in the solvent (2.0 mL) under air for 4 h.
Yield are of isolated 3a after purification by column chromatography.
Yield determined by 1H NMR analysis of the reaction mixture using CH2Br2 as the internal standard.
Scheme 1. Silver-Assisted Synthesis of Oxadiazolidinones.
All reactions were carried out with 1a (0.55 mmol), 2a (0.5 mmol), and Ag2O (10 mol %) in 1,4-dioxane (2.0 mL) at 80 °C under air for 4 h. Yields are of isolated products after purification by column chromatography. Products were isolated as single diastereomers.
Next, the optimal reaction conditions were adopted on a variety of nitrones and aryl isocyanides to investigate the generality of the protocol (Scheme 1). A collection of diversely functionalized nitrones underwent annulation with aryl isocyanides to deliver the corresponding product 3 in good to excellent yields. For example, para-substituted arene motifs bearing electron-donating or electron-withdrawing moieties were tolerated in the annulation with 1-bromo-4-isocyanobenzene (2a) to produce the corresponding products (3b–3g) in high yields. Similarly, ortho-, meta-, and disubstituted substrates were also well tolerated, affording products 3h–3n in good to high yields. Gratifyingly, common functional groups including alkyl, alkoxy, halogen, cyano, and trifluoromethyl were all effective. A more elaborate substrate (1p) with a potentially sensitive alkyne moiety could also be successfully converted to product 3p (72%), illustrating the compatibility of the developed method. Heteroaryl nitrones including 2-furyl and 2-thienyl were also evaluated, delivering the corresponding adducts 3t and 3u with high efficiency. Furthermore, subjecting the fused aromatic (1v) or alkyl (1w and 1x) nitrones to isocyanide 2a, afforded the desired products 3v–3x in good to excellent yields. The protocol also tolerated a wide variation of substituents on the arene ring on the isocyanides (2y–2ad), efficiently delivering a set of diverse oxadiazolidinones (3y–3ad) in high yields. The applicability of the annulation protocol was highlighted through a gram-scale reaction of N-benzylideneaniline oxide (1a) and 1-bromo-4-isocyanobenzene (2a). The reaction was performed on a 10 mmol scale and proceeded smoothly to give product 3a (3.26 g, 83%) even when decreasing the amount of the catalyst to 5 mol % (Scheme 1).
We further explored the application of the synthesized oxadiazolidinones. Intriguingly, subjecting 3a, 3y, 3z, 3ab, and 3ac to Cs2CO3 (2.0 equiv) triggered extrusion of CO2 to give amidines 4a–4e in up to 92% yield (Scheme 2). Compared to Anderson’s reaction conditions,10d no reaction occurred using compound 3 even when extending the reaction time to 24 h. Therefore, the developed protocol undoubtedly represents a more general and practical methodology to access amidines, complementing the existing ones.
Scheme 2. Application of Oxadiazolidinones to the Synthesis of Amidines through CO2 Extrusion.
A series of mechanistic experiments was performed to gain insights into the reaction mechanism (Scheme 3). The key step is clearly to derive the source of the carbonyl oxygen that is incorporated in oxadiazolidinone 3. Therefore, experiments were carried out with 1c and 2a under the optimized reaction conditions with the addition of 2.0 equiv of H218O (Scheme 3a). In the presence of H218O, the reaction between 1c and 2a only provides [16O]-3c; albeit with a decreased yield.14 This implies that O2 is the oxygen source in this reaction. Meanwhile, a decreased yield of product 3c was obtained when carrying out the reaction under N2, highlighting that O2 is necessary for the reaction to proceed efficiently (Scheme 3b).
Scheme 3. Mechanistic Investigations.
Based on the results from the described experiments and related literature precedents,2,15 a plausible mechanism was proposed (Scheme 4). Initially, isocyanide 2 coordinates to the silver center, generating silver intermediate A.16 Then, it is believed that nitrone 1 attacks complex A, producing intermediate B. This species presumably undergoes rapid intramolecular cyclization to generate the five-membered cyclized cationic intermediate C.17 Subsequent protodeargentation of intermediate C produces D, which is oxidized by O2,18 delivering product 3 with the regeneration of water and completing the catalytic cycle. Thus, the protodeargentation step can be initiated by residual water present in the solvent or air (cf. Scheme 1).
Scheme 4. Proposed Reaction Mechanism for the Formation of Oxadiazolidinone 3.
Conclusions
In summary, we have developed a silver-assisted protocol for [3 + 2] annulation between isocyanides and nitrones, providing a convenient approach for the construction of 2,3,4-trisubstituted 1,2,4-oxadiazolidin-5-ones in good to excellent yields. The reaction mechanism is proposed to proceed through a nucleophilic addition/cyclization/protodeargentation/oxidation pathway. Finally, base-promoted decarboxylation of the prepared oxadiazolidinones at ambient temperature is also described, providing a convenient protocol for the direct assembly of amidine compounds.
Experimental Section
General Information
All reagents were purchased from commercial suppliers and used without treatment, unless otherwise indicated. The products were purified by column chromatography on silica gel. 1H NMR and 13C NMR spectra were recorded on a Varian NMR spectrometer at 400 and 101 MHz, respectively. NMR spectra for compounds 3a–3ad were recorded in CDCl3, while compounds 4a–4e displayed spectra containing signals from multiple tautomeric forms and geometrical isomers; however, good quality NMR spectra for these compounds were obtained in CDCl3 upon the addition of a small amount of D2SO4. Mass spectra were recorded on a BRUKER Autoflex III Smartbeam MS-spectrometer. High-resolution mass spectra (HRMS) were recorded on a Bruker micrOTOF using atmospheric pressure chemical ionization (APCI) or electrospray ionization (ESI) methods.
General Procedure for Synthesis of 1,2,4-Oxadiazolidin-5-ones (with 3a as an Example)
A 10 mL Schlenk flask equipped with a magnetic stir bar was charged with a mixture of 1a (108 mg, 0.55 mmol), 2a (90 mg, 0.5 mmol), and 1,4-dioxane (2.0 mL). Then, Ag2O (12 mg, 10 mol %) was added and the mixture was stirred at 80 °C in an oil bath until substrate 2a was consumed as indicated by thin layer chromatography (TLC) (about 4 h). The resulting mixture was concentrated and the residue was taken up in CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated. Purification of the crude product by column chromatography (silica gel; petroleum ether/ethyl acetate 10:1) afforded 3a as a white solid (179 mg, 91%).
General Procedure for Synthesis of Amidines (with 4a as an Example)
A 10 mL Schlenk flask equipped with a magnetic stir bar was charged with a mixture of 3a (197 mg, 0.5 mmol) and Cs2CO3 (325 mg, 1 mmol, 2.0 equiv). Then, EtOH (2.0 mL) was added and the mixture was stirred at room temperature until substrate 3a was consumed as indicated by TLC (about 30 min). The resulting mixture was concentrated and the residue was taken up in CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated. Purification of the crude product by column chromatography (silica gel; petroleum ether/ethyl acetate 10:3) afforded 4a as a white solid (147 mg, 84%).
4-(4-Bromophenyl)-2,3-diphenyl-1,2,4-oxadiazolidin-5-one (3a)
The product was obtained in a 91% yield (179 mg). White solid; mp 139–140 °C; 1H NMR (400 MHz, CDCl3): δ 7.50–7.47 (m, 2H), 7.45–7.43 (m, 3H), 7.41–7.36 (m, 4H), 7.24–7.19 (m, 5H), 6.11 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.0, 149.1, 135.2, 134.7, 132.2, 130.2, 129.5, 129.4, 127.1, 125.9, 122.4, 118.8, 117.4, 86.3; HRMS (APCI) m/z: calcd for C20H16BrN2O2 [M + H]+, 395.0390; found, 395.0370.
4-(4-Bromophenyl)-2-phenyl-3-(p-tolyl)-1,2,4-oxadiazolidin-5-one (3b)
The product was obtained in a 92% yield (187 mg). White solid; mp 138–139 °C; 1H NMR (400 MHz, CDCl3): δ 7.41–7.36 (m, 6H), 7.25–7.19 (m, 7H), 6.07 (s, 1H), 2.37 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.0, 149.1, 140.4, 134.7, 132.2, 132.15, 130.0, 129.4, 127.1, 125.8, 122.5, 118.7, 117.4, 86.3, 21.3; HRMS (APCI) m/z: calcd for C21H18BrN2O2 [M + H]+, 409.0552; found, 409.0531.
4-(4-Bromophenyl)-3-(4-chlorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3c)
The product was obtained in a 87% yield (186 mg). White solid; mp 160–161 °C; 1H NMR (400 MHz, CDCl3): δ 7.42–7.38 (m, 8H), 7.26–7.16 (m, 5H), 6.08 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.8, 148.8, 136.3, 134.4, 133.7, 132.4, 129.6, 129.5, 128.6, 126.2, 122.6, 119.1, 117.5, 85.6; HRMS (APCI) m/z: calcd for C20H15BrClN2O2 [M + H]+, 429.0005; found, 429.0017.
3,4-Bis(4-bromophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3d)
The product was obtained in a 89% yield (209 mg). White solid; mp 168–169 °C; 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.4 Hz, 2H), 7.42–7.35 (m, 6H), 7.25–7.16 (m, 5H), 6.07 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.8, 148.8, 134.4, 134.2, 132.6, 132.4, 129.5, 128.9, 126.2, 124.6, 122.6, 119.2, 117.5, 85.7; HRMS (APCI) m/z: calcd for C20H15Br2N2O2 [M + H]+, 472.9500; found, 472.9471.
4-(4-Bromophenyl)-3-(4-fluorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3e)
The product was obtained in a 86% yield(177 mg). White solid; mp 150–151 °C; 1H NMR (400 MHz, CDCl3): δ 7.49–7.45 (m, 2H), 7.41–7.37 (m, 4H), 7.24–7.18 (m, 4H), 7.16–7.10 (m, 3H), 6.10 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 85.7, 116.5 (d, J(F–C) = 21.9 Hz), 117.5, 119.1, 122.7, 126.1, 129.2 (d, J(F–C) = 8.5 Hz), 129.5, 131.1 (d, J(F–C) = 3.2 Hz), 132.3, 134.4, 148.8, 153.8, 163.6 (d, J(F–C) = 248.9 Hz); HRMS (APCI) m/z: calcd for C20H15BrFN2O2 [M + H]+, 413.0301; found, 413.0300.
4-(4-Bromophenyl)-2-phenyl-3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazolidin-5-one (3f)
The product was obtained in a 79% yield (182 mg). White solid; mp 164–165 °C; 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.44–7.41 (m, 4H), 7.27–7.23 (m, 3H), 7.20–7.18 (m, 2H), 6.18 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.8, 148.9, 139.2, 134.4, 132.5, 132.2, 129.7, 127.6, 126.4, 124.9, 122.4, 122.2, 119.2, 117.5, 85.5; HRMS (APCI) m/z: calcd for C21H15BrF3N2O2 [M + H]+, 463.0269; found, 463.0276.
4-(4-(4-Bromophenyl)-5-oxo-2-phenyl-1,2,4-oxadiazolidin-3-yl)benzonitrile (3g)
The product was obtained in a 63% yield (132 mg). White solid; mp 144–145 °C; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.44–7.40 (m, 4H), 7.28–7.22 (m, 3H), 7.17 (d, J = 8.8 Hz, 2H), 6.17 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.6, 148.7, 140.2, 134.2, 133.1, 132.6, 129.7, 127.9, 126.5, 122.4, 119.4, 117.8, 117.5, 114.3, 85.2; HRMS (APCI) m/z: calcd for C21H15BrN3O2 [M + H]+, 420.0348; found, 420.0353.
4-(4-Bromophenyl)-3-(3-methoxyphenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3h)
The product was obtained in a 85% yield (180 mg). White solid; mp 124–125 °C; 1H NMR (400 MHz, CDCl3): δ 7.41–7.32 (m, 5H), 7.25–7.19 (m, 5H), 7.05–7.03 (m, 2H), 6.97–6.95 (m, 1H), 6.07 (s, 1H), 3.80 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 160.3, 153.9, 149.1, 136.7, 134.6, 132.2, 130.5, 129.4, 125.9, 122.4, 119.3, 118.8, 117.3, 115.5, 112.7, 86.2, 55.4; HRMS (APCI) m/z: calcd for C21H18BrN2O3 [M + H]+, 425.0501; found, 425.0509.
4-(4-Bromophenyl)-3-(3-chlorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3i)
The product was obtained in a 81% yield (173 mg). White solid; mp 161–163 °C; 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.43–7.39 (m, 5H), 7.38–7.33 (m, 2H), 7.25–7.18 (m, 5H), 6.08 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.8, 148.9, 137.4, 135.4, 134.4, 132.4, 130.7, 130.5, 129.6, 127.3, 126.2, 125.2, 122.4, 119.1, 117.4, 85.5; HRMS (APCI) m/z: calcd for C20H15BrClN2O2 [M + H]+, 429.0005; found, 429.0011.
4-(4-Bromophenyl)-3-(2-chlorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3j)
The product was obtained in a 84% yield (179 mg). White solid; mp 120–121 °C; 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 7.6 Hz, 2H), 7.44–7.33 (m, 8H), 7.24–7.21 (m, 3H), 6.70 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.4, 149.3, 134.5, 133.3, 132.4, 132.3, 131.5, 130.5, 129.5, 128.1, 127.9, 126.1, 121.3, 118.6, 117.5, 81.9; HRMS (APCI) m/z: calcd for C20H15BrClN2O2 [M + H]+, 429.0005; found, 429.0008.
3-(2-Bromophenyl)-4-(4-bromophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3k)
The product was obtained in a 85% yield (200 mg). Yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.42–7.39 (m, 7H), 7.33–7.29 (m, 1H), 7.25–7.21 (m, 3H), 6.69 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.4, 149.1, 134.4, 133.9, 133.8, 132.3, 131.7, 129.5, 128.8, 128.3, 126.2, 123.2, 121.6, 118.7, 117.9, 84.0; HRMS (APCI) m/z: calcd for C20H15Br2N2O2 [M + H]+, 472.9500; found, 472.9504.
4-(4-Bromophenyl)-3-(2-methoxyphenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3l)
The product was obtained in a 93% yield (197 mg). White solid; mp 128–129 °C; 1H NMR (400 MHz, CDCl3): δ 7.43–7.35 (m, 7H), 7.30–7.28 (m, 1H), 7.26–7.24 (m, 2H), 7.20–7.16 (m, 1H), 7.03–6.97 (m, 2H), 6.66 (s, 1H), 4.00 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 157.1, 154.6, 150.2, 135.1, 132.1, 131.4, 129.3, 126.8, 125.3, 122.8, 121.3, 120.8, 117.9, 116.6, 111.3, 80.7, 55.7; HRMS (APCI) m/z: calcd for C21H18BrN2O3 [M + H]+, 425.0501; found, 425.0470.
4-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3m)
The product was obtained in a 88% yield (195 mg). White solid; mp 109–110 °C; 1H NMR (400 MHz, CDCl3): δ 7.52–7.51 (m, 1H), 7.46–7.40 (m, 5H), 7.37–7.33 (m, 3H), 7.24–7.19 (m, 3H), 6.64 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.2, 149.0, 137.0, 134.2, 134.0, 132.5, 131.1, 130.4, 129.6, 129.0, 128.6, 126.3, 121.5, 118.9, 117.6, 81.5; HRMS (APCI) m/z: calcd for C20H14BrCl2N2O2 [M + H]+, 462.9616; found, 462.9622.
3-(2-Bromo-4-chlorophenyl)-4-(4-bromophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3n)
The product was obtained in a 94% yield (229 mg). White solid; mp 108–109 °C; 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 1.6 Hz, 1H), 7.48–7.37 (m, 8H), 7.27–7.23 (m, 1H), 7.21–7.19 (m, 2H), 6.64 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.2, 148.7, 137.0, 134.1, 133.4, 132.5, 132.4, 129.5, 129.2, 129.1, 126.4, 123.6, 121.7, 118.9, 117.9, 83.5; HRMS (APCI) m/z: calcd for C20H14Br2ClN2O2 [M + H]+, 506.9105; found, 506.9122.
3-(Benzo[d][1,3]dioxol-5-yl)-4-(4-bromophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3o)
The product was obtained in a 93% yield (203 mg). White solid; mp 141–142 °C; 1H NMR (400 MHz, CDCl3): δ 7.41–7.36 (m, 4H), 7.23–7.18 (m, 5H), 7.00 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.01–6.005 (m, 2H), 5.99 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.8, 149.3, 148.8, 134.6, 132.3, 129.4, 128.9, 126.0, 122.9, 121.7, 119.0, 117.6, 108.6, 107.2, 101.7, 86.3, 29.7; HRMS (APCI) m/z: calcd for C21H16BrN2O4 [M + H]+, 439.0293; found, 439.0297.
4-(4-Bromophenyl)-3-(2-((4-methoxyphenyl)ethynyl)-4-methylphenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3p)
The product was obtained in a 72% yield (193 mg). White solid; mp 168–169 °C; 1H NMR (400 MHz, CDCl3): δ 7.46 (s, 1H), 7.43–7.41 (m, 5H), 7.38–7.35 (m, 2H), 7.33–7.29 (m, 4H), 7.20–7.14 (m, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.82 (s, 1H), 3.85 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 160.2, 154.2, 149.6, 140.2, 134.8, 133.5, 133.1, 133.06, 132.2, 130.3, 129.3, 126.3, 125.6, 122.9, 121.3, 118.2, 117.3, 114.2, 96.0, 85.2, 83.3, 55.4, 21.1; HRMS (APCI) m/z: calcd for C30H24BrN2O3 [M + H]+, 539.0965; found, 539.0973.
4-(4-Bromophenyl)-3-phenyl-2-(m-tolyl)-1,2,4-oxadiazolidin-5-one (3q)
The product was obtained in a 85% yield (173 mg). White solid; mp 164–165 °C; 1H NMR (400 MHz, CDCl3): δ 7.50–7.43 (m, 5H), 7.38 (d, J = 8.8 Hz, 2H), 7.29–7.25 (m, 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 7.03–7.01 (m, 2H), 6.11 (s, 1H), 2.37 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.1, 149.3, 139.6, 135.3, 134.8, 132.2, 130.2, 129.3, 129.26, 127.1, 126.7, 122.3, 118.7, 117.9, 114.3, 86.3, 21.6; HRMS (APCI) m/z: calcd for C21H18BrN2O2 [M + H]+, 409.0552; found, 409.0563.
2,4-Bis(4-bromophenyl)-3-phenyl-1,2,4-oxadiazolidin-5-one (3r)
The product was obtained in a 89% yield (209 mg). White solid; mp 153–154 °C; 1H NMR (400 MHz, CDCl3): δ 7.51–7.49 (m, 2H), 7.47–7.43 (m, 5H), 7.40–7.38 (m, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.05 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.6, 148.0, 134.7, 134.4, 132.5, 132.3, 130.5, 129.4, 127.2, 122.7, 119.1, 119.0, 86.3; HRMS (APCI) m/z: calcd for C20H15Br2N2O2 [M + H]+, 472.9500; found, 472.9513.
4-(4-Bromophenyl)-3-phenyl-2-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazolidin-5-one (3s)
The product was obtained in a 77% yield (178 mg). White solid; mp 134–135 °C; 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.4 Hz, 2H), 7.51–7.46 (m, 5H), 7.40 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 6.15 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.2, 151.8, 134.7, 134.2, 132.4, 130.6, 129.5, 127.2, 126.8, 126.7, 122.9, 119.4, 116.6, 86.1; HRMS (APCI) m/z: calcd for C21H15BrF3N2O2 [M + H]+, 463.0269; found, 463.0271.
4-(4-Bromophenyl)-3-(furan-2-yl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3t)
The product was obtained in a 86% yield (165 mg), yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.44–7.39 (m, 4H), 7.28–7.20 (m, 5H), 6.54–6.53 (m, 1H), 6.42–6.41 (m, 1H), 6.21 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.7, 149.0, 147.9, 144.3, 134.6, 132.3, 129.5, 125.9, 121.9, 118.9, 117.1, 111.0, 110.6, 79.9; HRMS (APCI) m/z: calcd for C18H14BrN2O3 [M + H]+, 385.0188; found, 385.0197.
4-(4-Bromophenyl)-2-phenyl-3-(thiophen-2-yl)-1,2,4-oxadiazolidin-5-one (3u)
The product was obtained in a 81% yield (162 mg). Yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.45–7.38 (m, 5H), 7.25–7.21 (m, 5H), 7.15–7.14 (m, 1H), 7.01–6.99 (m, 1H), 6.38 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.4, 148.5, 138.6, 134.3, 132.4, 129.5, 128.3, 127.9, 127.1, 126.1, 123.2, 119.4, 117.5, 82.4; HRMS (APCI) m/z: calcd for C18H14BrN2O2S [M + H]+, 400.9959; found, 400.9967.
4-(4-Bromophenyl)-3-(naphthalen-1-yl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3v)
The product was obtained in a 90% yield (200 mg). White solid; mp 164–165 °C; 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.4 Hz, 1H), 7.97–7.93 (m, 2H), 7.65–7.55 (m, 3H), 7.49–7.45 (m, 1H), 7.42–7.38 (m, 2H), 7.34–7.24 (m, 5H), 7.20–7.16 (m, 2H), 6.88 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.5, 148.7, 134.8, 134.3, 132.2, 131.1, 130.6, 129.6, 129.5, 129.2, 127.3, 126.7, 126.3, 126.2, 125.3, 122.2, 122.1, 119.0, 118.7, 82.9; HRMS (APCI) m/z: calcd for C24H18BrN2O2 [M + H]+, 445.0546; found, 445.0558.
4-(4-Bromophenyl)-3-cyclohexyl-2-phenyl-1,2,4-oxadiazolidin-5-one (3w)
The product was obtained in a 62% yield (124 mg). White solid; mp 185–186 °C; 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 8.8 Hz, 2H), 7.40–7.36 (m, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.19–7.15 (m, 3H), 5.16 (d, J = 3.2 Hz, 1H), 1.85–1.82 (m, 4H), 1.76–1.70 (m, 2H), 1.54–1.39 (m, 2H), 1.33–1.22 (m, 2H), 1.19–1.16 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.3, 151.0, 135.0, 132.5, 129.4, 125.2, 122.3, 118.5, 116.3, 88.9, 40.6, 28.9, 26.0, 25.5; HRMS (APCI) m/z: calcd for C20H22BrN2O2 [M + H]+, 401.0859; found, 401.0866.
4-(4-Bromophenyl)-3-(cyclohex-3-en-1-yl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3x)
The product was obtained in a 71% yield (141 mg). White solid; mp 162–163 °C; 1H NMR (400 MHz, CDCl3): δ 7.48–7.46 (m, 2H), 7.41–7.37 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.21–7.17 (m, 3H), 5.70–5.69 (m, 2H), 5.28–5.25 (m, 1H), 2.37–1.93 (m, 6H), 1.81–1.62 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.3, 150.8, 134.9, 132.5, 129.5, 127.4, 126.5, 125.3, 125.1, 122.6, 116.4, 88.6, 37.1, 27.3, 24.7, 22.0; HRMS (APCI) m/z: calcd for C20H20BrN2O2 [M + H]+, 399.0703; found, 399.0709.
2,3,4-Triphenyl-1,2,4-oxadiazolidin-5-one (3y)
The product was obtained in a 90% yield (142 mg). White solid; mp 101–102 °C; 1H NMR (400 MHz, CDCl3): δ 7.70–7.08 (m, 15H), 6.21 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.3, 149.5, 135.8, 135.7, 130.1, 129.5, 129.31, 129.3, 127.2, 125.8, 125.7, 121.1, 117.3, 86.5; HRMS (APCI) m/z: calcd for C20H17N2O2 [M + H]+, 317.1285; found, 317.1293.
2,3-Diphenyl-4-(m-tolyl)-1,2,4-oxadiazolidin-5-one (3z)
The product was obtained in a 87% yield (143 mg). White solid; mp 108–109 °C; 1H NMR (400 MHz, CDCl3): δ 7.53–7.50 (m, 2H), 7.45–7.37 (m, 5H), 7.27–7.25 (m, 2H), 7.22–7.18 (m, 2H), 7.16–7.12 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.14 (s, 1H), 2.27 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.3, 149.5, 139.3, 135.9, 135.5, 130.0, 129.4, 129.2, 129.0, 127.1, 126.5, 125.7, 121.7, 118.0, 117.2, 86.5, 21.4; HRMS (APCI) m/z: calcd for C21H19N2O2 [M + H]+, 331.1441; found, 331.1449.
4-(4-Chlorophenyl)-2,3-diphenyl-1,2,4-oxadiazolidin-5-one (3aa)
The product was obtained in a 83% yield (145 mg). White solid; mp 110–111 °C; 1H NMR (400 MHz, CDCl3): δ 7.50–7.47 (m, 2H), 7.46–7.43 (m, 3H), 7.42–7.38 (m, 2H), 7.25–7.23 (m, 5H), 7.22–7.20 (m, 2H), 6.11 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.0, 149.2, 135.2, 134.1, 131.1, 130.3, 129.5, 129.4, 129.3, 127.2, 125.9, 122.3, 117.4, 86.4; HRMS (APCI) m/z: calcd for C20H16ClN2O2 [M + H]+, 351.0895; found, 351.0899.
2,3-Diphenyl-4-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazolidin-5-one (3ab)
The product was obtained in a 89% yield (171 mg). White solid; mp 111–112 °C; 1H NMR (400 MHz, CDCl3): δ 7.54–7.44 (m, 9H), 7.43–7.38 (m, 2H), 7.27–7.26 (m, 1H), 7.25–7.20 (m, 2H), 6.20 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.0, 149.1, 138.84, 138.8, 134.9, 130.3, 129.53, 129.5, 127.0, 126.4, 126.36, 126.1, 119.8, 117.4, 86.0; HRMS (APCI) m/z: calcd for C21H16F3N2O2 [M + H]+, 385.1158; found, 385.1161.
2,3-Diphenyl-4-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolidin-5-one (3ac)
The product was obtained in a 92% yield (186 mg). White solid; mp 93–94 °C; 1H NMR (400 MHz, CDCl3): δ 7.52–7.48 (m, 2H), 7.47–7.44 (m, 3H), 7.42–7.38 (m, 2H), 7.35–7.33 (m, 2H), 7.25–7.20 (m, 3H), 7.13–7.11 (m, 2H), 6.13 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 154.1, 149.1, 146.3, 146.2, 135.2, 134.2, 130.3, 129.5, 129.4, 127.1, 125.9, 122.1, 121.8, 117.3, 86.5; HRMS (APCI) m/z: calcd for C21H16F3N2O3 [M + H]+, 401.1108; found, 401.1112.
4-(2-Nitrophenyl)-2,3-diphenyl-1,2,4-oxadiazolidin-5-one (3ad)
The product was obtained in a 72% yield (129 mg). Yellow solid; mp 147–148 °C; 1H NMR (400 MHz, CDCl3): δ 8.03–7.97 (m, 1H), 7.57–7.51 (m, 2H), 7.48–7.29 (m, 7H), 7.23–7.12 (m, 3H), 7.91–6.86 (m, 1H), 6.09 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.6, 147.5, 145.9, 134.4, 133.8, 130.7, 130.4, 129.18, 129.17, 129.1, 128.8, 128.1, 126.2, 125.9, 118.6, 87.4; HRMS (APCI) m/z: calcd for C20H16N3O4 [M + H]+, 362.1135; found, 362.1139.
N′-(4-Bromophenyl)-N-phenylbenzimidamide (4a)
The product was obtained in a 84% yield (147 mg). White solid; mp 123–124 °C; 1H NMR (400 MHz, CDCl3 + D2SO4): δ 7.40–7.33 (m, 1H), 7.26–7.18 (m, 3H), 7.14 (d, J = 8.7 Hz, 1H), 7.09–7.03 (m, 4H), 6.98–6.89 (m, 3H), 6.87–6.77 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3 + D2SO4): δ 135.56, 134.96, 132.44, 132.08, 130.47, 129.20, 129.03, 127.10, 126.81, 125.29, 120.60; HRMS (ESI-TOF) m/z: calcd for C19H16BrN2 [M + H]+, 351.0491; found, 351.0507.
N′-(4-Chlorophenyl)-N-phenylbenzimidamide (4b)
The product was obtained in a 92% yield (140 mg). White solid; mp 120–121 °C; 1H NMR (400 MHz, CDCl3 + D2SO4): δ 14.16 (br s, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.8 Hz, 2H), 7.18 (d, J = 7.5 Hz, 2H), 7.13–7.01 (m, 5H), 6.90 (d, J = 6.8 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3 + D2SO4): δ 162.02, 136.41, 135.32, 132.17, 131.83, 130.11, 129.27, 128.92, 128.83, 126.42, 126.32, 126.03, 124.95; HRMS (ESI-TOF) m/z: calcd for C19H16ClN2 [M + H]+, 307.0997; found, 307.1003.
N-Phenyl-N′-(4-(trifluoromethyl)phenyl)benzimidamide (4c)
The product was obtained in a 87% yield (147 mg). White solid; mp 110–111 °C; 1H NMR (400 MHz, CDCl3 + D2SO4): δ 14.28 (br s, 1H), 7.52–7.45 (m, 1H), 7.40–7.30 (m, 5H), 7.24 (d, J = 7.6 Hz, 2H), 7.18–7.09 (m, 3H), 7.02 (d, J = 8.4 Hz, 2H), 6.98–6.92 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3 + D2SO4): δ 162.24, 139.94, 136.24, 132.50, 130.12, 129.45, 128.93, 128.08, 127.76, 126.68, 126.14, 126.00, 125.97, 125.00, 124.59, 122.36; HRMS (ESI-TOF) m/z: calcd for C20H16F3N2 [M + H]+, 341.1260; found, 341.1277.
N-Phenyl-N′-(4-(trifluoromethoxy)phenyl)benzimidamide (4d)
The product was obtained in a 88% yield (157 mg). White solid; mp 82–84 °C; 1H NMR (400 MHz, CDCl3 + D2SO4): δ 7.45 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.8 Hz, 2H), 7.20 (d, J = 7.6 Hz, 2H), 7.16–7.03 (m, 3H), 7.01–6.85 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3 + D2SO4): δ 162.05, 146.90, 136.44, 135.39, 132.26, 130.08, 129.32, 128.86, 126.44, 126.33, 126.04, 124.92, 121.56, 121.31, 119.00; HRMS (ESI-TOF) m/z: calcd for C20H16F3N2O [M + H]+, 357.1209; found, 357.1217.
N′-(4-Bromophenyl)-4-methyl-N-phenylbenzimidamide (4e)
The product was obtained in a 90% yield (163 mg). White solid; mp 121–122 °C; 1H NMR (400 MHz, CDCl3 + D2SO4): δ 7.27 (d, J = 8.6 Hz, 1H), 7.23–7.14 (m, 4H), 7.08 (d, J = 8.0 Hz, 2H), 7.05–6.94 (m, 2H), 6.87 (d, J = 8.6 Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3 + D2SO4): δ 163.51, 144.00, 132.34, 130.60, 130.11, 129.27, 127.41, 126.67, 126.63, 125.16, 125.12, 121.58, 120.98, 21.73; HRMS (ESI-TOF) m/z: calcd for C20H18BrN2 [M + H]+, 365.0648; found, 365.0657.
Acknowledgments
Financially supported by NSFC of China (no. 21702078), NSF of Jiangsu Province (no. BK20170231), and KTH Royal Institute of Technology. The Wenner-Gren Foundations and the Olle Engkvist Byggmästare Foundation are kindly acknowledged for postdoctoral fellowships to J.-Q.L. and A.S., respectively.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.9b03279.
The authors declare no competing financial interest.
Supplementary Material
References
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