Silver-Assisted [3 + 2] Annulation of Nitrones with Isocyanides: Synthesis of 2,3,4-Trisubstituted 1,2,4-Oxadiazolidin-5-ones

Article abstract of DOI:10.1021/acs.joc.9b03279

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.

Full text of DOI:10.1021/acs.joc.9b03279

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Article
Silver-Assisted [3 + 2] Annulation of Nitrones with Isocyanides:
Synthesis of 2,3,4-Trisubstituted 1,2,4-Oxadiazolidin-5-ones
Xuanyu Shen, Andrey Shatskiy, Yan Chen, Markus D. Kärkäs, Xiang-Shan Wang, and Jian-Quan Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03279 • Publication Date (Web): 04 Feb 2020
Downloaded from pubs.acs.org on February 4, 2020
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Silver-Assisted [3 + 2] Annulation of Nitrones with Isocyanides: Synthesis of
2,3,4-Trisubstituted 1,2,4-Oxadiazolidin-5-ones
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Xuanyu Shen,† Andrey Shatskiy,‡ Yan Chen,† Markus D. Kärkäs,*,‡ Xiang-Shan Wang,† Jian-Quan Liu*,†,‡
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†
School of Chemistry and Materials Science, Jiangsu Key Laboratory of Green Synthesis for
Functional Materials Jiangsu Normal University, Xuzhou, Jiangsu 221116, China
‡
Department of Chemistry, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden
* E-mail: karkas@kth.se (M.D.K.); liujq316@jsnu.edu.cn (J.-Q.L.)
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.
KEYWORDS: annulation; isocyanide; nitrone; oxadiazolidinone; silver
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INTRODUCTION
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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.5,6,7,8
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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 coworkers 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 coworkers 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 realized10 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-
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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).
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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 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 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
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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 °C to 40 °C led to significantly diminished yield of the desired product
(Table 1, entry 12). A control experiment established that the 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).
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Table 1. Optimization of the Reaction Conditions.a,b
entry
1
[M]
Ag2O
AgOAc
Ag2CO3
AgOTf
AgBF4
CuI
solvent
DMF
temp (°C)
80
yield (%)b
76
2
DMF
80
42
3
DMF
80
74
4
DMF
80
< 5c
< 5c
< 5c
< 5c
91
5
DMF
80
6
DMF
80
7
Pd(OAc)2
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
-
DMF
80
8
1,4-dioxane
toluene
CH3CN
EtOH
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9
80
76
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13
80
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< 10c
80
1,4-dioxane
1,4-dioxane
40
38
< 5c
80
a Reaction conditions: All reactions were carried out with 1a (0.55 mmol), 2a (0.5 mmol), catalyst (10
b
mol%) in solvent (2.0 mL) under air for 4 h. Yield are of isolated 3a after purification by column
c
1
chromatogrphy. Yield determined by H NMR analysis of the reaction mixture using CH2Br2 as
internal standard.
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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 yield. 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 yield. 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).
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Scheme 1. Silver-Assisted Synthesis of Oxadiazolidinones.a
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a
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 chromatogrphy. Products were isolated as single diastereomers.
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 amidines, complementing the
existing ones.
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Scheme 2. Application of Oxadiazolidinones to the Synthesis of Amidines through CO2 Extrusion.
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A series of mechanistic experiments was performed to gain insight 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
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reactions conditions with addition of 2.0 equiv. of H2 O (Scheme 3a). In the presence of H2 O, 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
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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).
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Scheme 4. Proposed Reaction Mechanism for 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.
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EXPERIMENTAL SECTION
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General Information. All reagents were purchased from commercial suppliers and used without
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treatment, unless otherwise indicated. The products were purified by column chromatography on
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silica gel. H NMR and C NMR spectra were recorded on a Varian NMR spectrometer at 400 MHz
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 addition of a small amount of D2SO4. Mass spectra were recorded on BRUKER AutoflexIII
Smartbeam MS-spectrometer. High-resolution mass spectra (HRMS) were recorded on Bruker
microTOF using APCI or ESI ionization 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 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
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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%).
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4-(4-Bromophenyl)-2,3-diphenyl-1,2,4-oxadiazolidin-5-one (3a). Yield: 91% (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),
13
7.24–7.19 (m, 5H), 6.11 (s, 1H); C{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 calculated for
C20H16BrN2O2 [M + H]+: 395.0390, found: 395.0370.
4-(4-Bromophenyl)-2-phenyl-3-(p-tolyl)-1,2,4-oxadiazolidin-5-one (3b). Yield: 92% (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 calculated for C21H18BrN2O2 [M + H]+:
409.0552, found: 409.0531.
4-(4-Bromophenyl)-3-(4-chlorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3c). Yield: 87% (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 calculated for C20H15BrClN2O2 [M + H]+: 429.0005,
found: 429.0017.
3,4-Bis(4-bromophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3d). Yield: 89% (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,
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5H), 6.07 (s, 1H); C{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 calculated for C20H15Br2N2O2 [M + H]+:
472.9500, found: 472.9471.
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4-(4-Bromophenyl)-3-(4-fluorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3e). Yield: 86% (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–
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7.18 (m, 4H), 7.16–7.10 (m, 3H), 6.10 (s, 1H); C{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 calculated 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). Yield: 79%
(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
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= 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); C{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 calculated 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). Yield: 63% (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 calculated for C21H15BrN3O2 [M + H]+: 420.0348, found:
420.0353.
4-(4-Bromophenyl)-3-(3-methoxyphenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3h). Yield: 85% (180
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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),
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7.05–7.03 (m, 2H), 6.97–6.95 (m, 1H), 6.07 (s, 1H), 3.80 (s, 3H); C{1H} NMR (101 MHz, CDCl3) δ
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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 calculated for C21H18BrN2O3 [M + H]+: 425.0501, found: 425.0509.
4-(4-Bromophenyl)-3-(3-chlorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3i). Yield: 81% (173 mg).
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White solid; mp 161–163 C; H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.43–7.39 (m, 5H), 7.38–7.33
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(m, 2H), 7.25–7.18 (m, 5H), 6.08 (s, 1H); C{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
calculated for C20H15BrClN2O2 [M + H]+: 429.0005, found: 429.0011.
4-(4-Bromophenyl)-3-(2-chlorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3j). Yield: 84% (179 mg).
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White solid; mp 120–121 C; H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 2H), 7.44–7.33 (m, 8H),
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7.24–7.21 (m, 3H), 6.70 (s, 1H); C{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
calculated for C20H15BrClN2O2 [M + H]+: 429.0005, found: 429.0008.
3-(2-Bromophenyl)-4-(4-bromophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3k). Yield: 85% (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
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(m, 7H), 7.33–7.29 (m, 1H), 7.25–7.21 (m, 3H), 6.69 (s, 1H); C{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 calculated for C20H15Br2N2O2 [M + H]+: 472.9500, found: 472.9504.
4-(4-Bromophenyl)-3-(2-methoxyphenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3l). Yield: 93% (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
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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 calculated for C21H18BrN2O3 [M + H]+: 425.0501,
found: 425.0470.
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4-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-2-phenyl-1,2,4-oxadiazolidin-5-one (3m). Yield: 88%
(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 calculated 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). Yield: 94%
(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
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(m, 8H), 7.27–7.23 (m, 1H), 7.21–7.19 (m, 2H), 6.64 (s, 1H); C{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 calculated 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). Yield: 93%
(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 calculated 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). Yield: 72% (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),
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6.82 (s, 1H), 3.85 (s, 3H), 2.36 (s, 3H); C{1H} NMR (101 MHz, CDCl3) δ 160.2, 154.2, 149.6, 140.2,
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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 calculated for C30H24BrN2O3 [M + H]+: 539.0965, found:
539.0973.
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4-(4-Bromophenyl)-3-phenyl-2-(m-tolyl)-1,2,4-oxadiazolidin-5-one (3q). Yield: 85% (173 mg). White
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solid; mp 164–165 C; H 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 calculated for C21H18BrN2O2 [M + H]+:
409.0552, found: 409.0563.
2,4-Bis(4-bromophenyl)-3-phenyl-1,2,4-oxadiazolidin-5-one (3r). Yield: 89% (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),
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7.17 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.05 (s, 1H); C{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
calculated 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). Yield: 77%
(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
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(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); C{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 calculated 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). Yield: 86% (165 mg),
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yellow oil; H 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
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(m, 1H), 6.42–6.41 (m, 1H), 6.21 (s, 1H); C{1H} NMR (101 MHz, CDCl3) δ 153.7, 149.0, 147.9, 144.3,
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134.6, 132.3, 129.5, 125.9, 121.9, 118.9, 117.1, 111.0, 110.6, 79.9; HRMS (APCI) m/z calculated for
C18H14BrN2O3 [M + H]+: 385.0188, found: 385.0197.
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4-(4-Bromophenyl)-2-phenyl-3-(thiophen-2-yl)-1,2,4-oxadiazolidin-5-one (3u). Yield: 81% (162 mg).
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Yellow oil; H NMR (400 MHz, CDCl3) δ 7.45–7.38 (m, 5H), 7.25–7.21 (m, 5H), 7.15–7.14 (m, 1H),
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7.01–6.99 (m, 1H), 6.38 (s, 1H); C{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 calculated 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). Yield: 90% (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),
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6.88 (s, 1H); C{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
calculated for C24H18BrN2O2 [M + H]+: 445.0546, found: 445.0558.
4-(4-Bromophenyl)-3-cyclohexyl-2-phenyl-1,2,4-oxadiazolidin-5-one (3w). Yield: 62% (124 mg).
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White solid; mp 185–186 C; H 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
calculated 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). Yield: 71% (141
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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),
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1.81–1.62 (m, 1H); C{1H} NMR (101 MHz, CDCl3) δ 154.3, 150.8, 134.9, 132.5, 129.5, 127.4, 126.5,
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125.3, 125.1, 122.6, 116.4, 88.6, 37.1, 27.3, 24.7, 22.0; HRMS (APCI) m/z calculated for C20H20BrN2O2
[M + H]+: 399.0703, found: 399.0709.
2,3,4-Triphenyl-1,2,4-oxadiazolidin-5-one (3y). Yield: 90% (142 mg). White solid; mp 101–102 C;
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1H NMR (400 MHz, CDCl3) δ 7.70–7.08 (m, 15H), 6.21 (s, 1H); C{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 calculated for C20H17N2O2 [M + H]+: 317.1285, found: 317.1293.
2,3-Diphenyl-4-(m-tolyl)-1,2,4-oxadiazolidin-5-one (3z). Yield: 87% (143 mg). White solid; mp 108–
1
109 C; H 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,
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3H); C{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 calculated for C21H19N2O2 [M +
H]+: 331.1441, found: 331.1449.
4-(4-Chlorophenyl)-2,3-diphenyl-1,2,4-oxadiazolidin-5-one (3aa). Yield: 83% (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),
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7.25–7.23 (m, 5H), 7.22–7.20 (m, 2H), 6.11 (s, 1H); C{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
calculated for C20H16ClN2O2 [M + H]+: 351.0895, found: 351.0899.
2,3-Diphenyl-4-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazolidin-5-one (3ab). Yield: 89% (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–
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7.26 (m, 1H), 7.25–7.20 (m, 2H), 6.20 (s, 1H); C{1H} NMR (101 MHz, CDCl3) δ 154.0, 149.1, 138.84,
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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
calculated for C21H16F3N2O2 [M + H]+: 385.1158, found: 385.1161.
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2,3-Diphenyl-4-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolidin-5-one (3ac). Yield: 92% (186 mg).
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White solid; mp 93–94 C; H 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 calculated for C21H16F3N2O3 [M + H]+: 401.1108, found:
401.1112.
4-(2-Nitrophenyl)-2,3-diphenyl-1,2,4-oxadiazolidin-5-one (3ad). Yield: 72% (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),
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7.23–7.12 (m, 3H), 7.91–6.86 (m, 1H), 6.09 (s, 1H); C{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 calculated for C20H16N3O4 [M + H]+: 362.1135, found: 362.1139.
N'-(4-Bromophenyl)-N-phenylbenzimidamide (4a). Yield: 84% (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 calculated for C19H16BrN2 [M + H]+: 351.0491, found: 351.0507.
N'-(4-Chlorophenyl)-N-phenylbenzimidamide (4b). Yield: 92% (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}
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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 calculated for C19H16ClN2 [M + H]+:
307.0997, found: 307.1003.
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N-Phenyl-N'-(4-(trifluoromethyl)phenyl)benzimidamide (4c). Yield: 87% (147 mg). White solid; mp
1
110–111 C; H NMR (400 MHz, CDCl3 + D2SO4) δ 14.28 (br s, 1H), 7.52–7.45 (m, 1H), 7.40–7.30 (m,
13
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); C{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 calculated for
C20H16F3N2 [M + H]+: 341.1260, found: 341.1277.
N-Phenyl-N'-(4-(trifluoromethoxy)phenyl)benzimidamide (4d). Yield: 88% (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
13
(d, J = 7.6 Hz, 2H), 7.16–7.03 (m, 3H), 7.01–6.85 (m, 6H); C{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 calculated for C20H16F3N2O [M + H]+: 357.1209, found:
357.1217.
N'-(4-Bromophenyl)-4-methyl-N-phenylbenzimidamide (4e). Yield: 90% (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 calculated for C20H18BrN2 [M + H]+: 365.0648, found:
365.0657.
ASSOCIATED CONTENT
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Supporting Information
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NMR spectra of compounds 3 and 4, and X-ray crystallographic data for compounds 3a and 4e. This
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material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: karkas@kth.se (M.D.K.)
*E-mail: liujq316@jsnu.edu.cn (J.-Q.L.)
ORCID
Jian-Quan Liu: 0000-0002-5533-2075
Andrey Shatskiy: 0000-0002-7249-7437
Markus D. Kärkäs: 0000-0002-6089-5454
Xiang-Shan Wang: 0000-0002-0077-7819
Notes
The authors declare no competing financial interest.
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.
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