NBS-mediated practical cyclization of N-acyl amidines to 1,2,4-oxadiazoles via oxidative N?O bond formation

Article abstract of DOI:10.1016/j.tet.2018.07.036

A reaction involving an efficient NBS-mediated oxidative N?O bond formation has been established for the synthesis of 1,2,4-oxadiazoles from readily accessible N-acyl amidines. The features of this synthetic method include simplicity of operation, mild re

Full text of DOI:10.1016/j.tet.2018.07.036

Accepted Manuscript
NBS-mediated practical cyclization of N-acyl amidines to 1,2,4-oxadiazoles via
oxidative N‒O bond formation
Ertong Li, Manman Wang, Zhen Wang, Wenquan Yu, Junbiao Chang
PII:
S0040-4020(18)30869-X
10.1016/j.tet.2018.07.036
TET 29696
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 May 2018
Revised Date: 5 July 2018
Accepted Date: 17 July 2018
Please cite this article as: Li E, Wang M, Wang Z, Yu W, Chang J, NBS-mediated practical cyclization
of N-acyl amidines to 1,2,4-oxadiazoles via oxidative N‒O bond formation, Tetrahedron (2018), doi:
10.1016/j.tet.2018.07.036.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
NBS-Mediated Practical Cyclization of N-Acyl Amidines to
1,2,4-Oxadiazoles via Oxidative N−O Bond Formation
Ertong Li, Manman Wang, Zhen Wang, Wenquan Yu,* and Junbiao Chang*
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan
Province 450001, China
Abstract: A reaction involving an efficient NBS-mediated oxidative N−O bond
formation has been established for the synthesis of 1,2,4-oxadiazoles from readily
accessible N-acyl amidines. The features of this synthetic method include simplicity
of operation, mild reaction conditions, short reaction times, high yields, and
eco-friendliness. The reaction also works well with crude N-acyl amidines obtained
by amidation of simple benzoic acids and amidines to produce biologically relevant
1,2,4-oxadiazoles in a scalable fashion.
Keywords: NBS; N−O bond formation; 1,2,4-oxadiazole; N-acyl amidine; ethyl
acetate
1

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ꢀ Introduction
1,2,4-Oxadiazole is an important heterocyclic scaffold in many important biological
and pharmaceutical compounds.1 Ataluren (3, Figure 1) for example, is an orally
available drug in Europe for the treatment of Duchenne muscular dystrophy caused by
a nonsense mutation in the dystrophin gene. As a Nrf2 activator, 1,2,4-oxadiazole
derivative 4 exhibits good efficacy in LPS-challenged mouse model.2 Compound 5
has been identified as a metabotropic glutamate subtype 5 (mGlu5) receptor
antagonist.3 Phidianidines A and B are two 1,2,4-oxadiazole-containing marine
natural products with potent antiproliferative activity.4 1,2,4-Oxadiazoles are also
useful synthons for construction of other heterocyclic systems and have extensive
applications in material science as components of polymers, liquid crystals, and
luminescent materials.1
Figure 1. Representative bioactive 1,2,4-oxadiazole-containing molecules.
The classical method for the construction of 1,2,4-oxadiazole frameworks involves
cyclodehydration of O-acylamidoximes or amidoximes with various carboxylic acid
derivatives.5 1,2,4-Oxadiazoles can also be synthesized via oxidative pathways from
amides with nitriles,6 N-benzyl amidoximes,7 aldoximes with nitriles,8 and amidines
with methylarenes.9 N-acyl amidines, also useful precursors in the synthesis of
1,2,4-oxadiazoles can be readily prepared by amidation of amidines with benzoic
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acids. Previously, oxidative cyclization of such substrates to form 1,2,4-oxadiazoles
was only achieved using hypochlorites.10 Recently, Hajela et al. reported a
non-oxidative annulation reaction of N-acyl amidines with hydroxylamine in acetic
acid,11 and later disclosed an I2-mediated oxidative cyclization method.12 There are
still certain limitations associated with existing methods including harsh reaction
conditions, limited substrate scope or scalability, and use of hazard materials.
Therefore, it is important to develop practical and environmentally benign approaches
to the synthesis of 1,2,4-oxadiazole derivatives under mild reaction conditions. Herein
we describe an NBS-promoted oxidative cyclization reaction of N-acyl amidines with
ethyl acetate as solvent, leading to 1,2,4-oxadiazoles.
ꢀ Results and Discussion
N-Bromosuccinimide (NBS) is a commercially available and inexpensive oxidant and
brominating reagent which enjoys a wide range of applications in organic synthesis.13
As an oxidant, NBS has been successfully employed in various annulation reactions
involving C‒C,14 C‒O,15 C‒N16 and C‒S17 bond formation. Yet, to the best of our
knowledge, applications of this reagent in heteroatom-heteroatom bond formation
have not been reported. Continuing our interest in heteroatom-heteroatom bond
construction,18 we investigated the use of NBS-mediated oxidative N−O bond
formation reactions in 1,2,4-oxadiazole synthesis. The necessary N-acyl amidine
substrate (2a) was readily obtained by the amidation of benzamidine with benzoic
acid.11 In the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base,
NBS-mediated cyclization of substrate 2a was complete within 10 min at room
temperature in most solvents (Table 1, entries 3−7), affording the expected product 1a
in excellent yields. This transformation requires a longer reaction time in EtOH (entry
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1) and toluene (entry 8) and resulted in decreased yields of 1a when the solvent was
DMF (entry 2) or toluene (entry 8). In view of the environmental impact of solvents,19
EtOAc was chosen for further optimization. Replacement of DBU with inorganic
bases (entries 9‒10) affected both the conversion rate and the yield of the product. No
desired product was formed when NEt3 was used as the base (entry 11) or no base was
used (entry 12). Complete consumption of substrate 2a required at least 1.2 equiv of
NBS (entry 5) and the yield was not affected by additional oxidant, NBS (entry 14).
Table 1. Optimization of reaction conditions for the synthesis of 1,2,4-oxadiazole 1a.a
Entry
1
NBS
1.2 eq
1.2 eq
1.2 eq
1.2 eq
1.2 eq
1.2 eq
1.2 eq
1.2 eq
1.2 eq
1.2 eq
1.2 eq
1.2 eq
Base
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
K2CO3
Cs2CO3
NEt3
‒
Solvent
EtOH
Time
3 h
Yieldb
96%
90%
95%
96%
99%
97%
95%
73%
85%
94%
trace
0%
2
DMF
10 min
10 min
10 min
10 min
10 min
10 min
12 h
3
DMSO
MeCN
EtOAc
1,4-dioxane
CH2Cl2
toluene
EtOAc
EtOAc
EtOAc
EtOAc
4
5
6
7
8
9
5 h
10
11
12
5 h
5 h
5 h
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13
14
1.0 eq
1.4 eq
DBU
DBU
EtOAc
EtOAc
0.5 h
82%
99%
10 min
aReaction conditions: 1) 2a (0.5 mmol), NBS (0.6 mmol), DBU (0.6 mmol ), solvent
(5 mL), rt. bIsolated yields.
With the optimal reaction conditions in hand, we explored the substrate scope and
generality of this synthetic method. As shown in Scheme 1, the reaction tolerates both
electron-donating and electron-withdrawing groups at the ortho-, meta- or para-
positions of the N-aroyl ring of substrates to produce 3,5-diaryl-1,2,4-oxadiazoles
(1b−i) in excellent yields. The 2-pyridyl (1j) and 2-furyl (1k) substituted products
could also be synthesized from corresponding precursors in good yields. N-acyl
benzamidines bearing alkenyl (1l−m) or alkyl substituents (1n−q) were also viable
substrates. Noticeably, ortho-substitution on the benzoyl moiety, R1 (1g−i) and a
bulky tert-butyl group (1q) had no effect on either the conversion rate or the yield.
Substrates bearing substituted phenyl (1r‒t), 2-pyridyl (1u) or aliphatic groups (1v‒w)
at the R2 position were all readily cyclized to form the desired 1,2,4-oxadiazole
(Scheme 2).
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Scheme 1. Substrate scope of the R1 group.
Scheme 2. Substrate scope of the R2 group.
To assess the practicality of this reaction, we probed the feasibility of direct
1,2,4-oxadiazole synthesis from simple benzoic acids and amidines without
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purification of the N-acyl amidine intermediates. The crude N-acyl amidines obtained
from the first step amidation were subjected directly to the NBS-mediated oxidative
cyclization conditions, and yielded 2-fluorophenyl-1,2,4-oxadiazole 1x and the
mGlu5 receptor antagonist 53 efficiently on a gram scale (Scheme 3). The former
product (1x) is an important intermediate in the synthesis of the Duchenne muscular
dystrophy drug Ataluren (3).11
Scheme 3. Gram-scale synthesis of biologically interesting 1,2,4-oxadiazoles (1x, 5)
omitting purification of the N-acyl amidine intermediates.
A tentative mechanism for this NBS-mediated cyclization of N-acyl amidines to
1,2,4-oxadiazoles is proposed in Scheme 4. In the formation of 1a for example,
bromination of substrate 2a by NBS under basic conditions generates a plausible
N-bromo species A.20 The carbonyl oxygen atom then attacks the bromo-substituted
nitrogen in compound A to form an intermediate (B) containing a new N−O bond.
Finally, the subsequent proton elimination by base produces the 1,2,4-oxadiazole
skeleton (1a). Owing to the halogen bond interaction between imines and NBS,21
DBU is preferable as the base (cf. entries 5, 9−11 in Table 1) in this transformation.
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Scheme 4. Proposed mechanism for the formation of 1,2,4-oxadiazole 1a.
ꢀ Conclusion
We have developed a first NBS-promoted oxidative N−O bond formation reaction in
the presence of DBU as base for 1,2,4-oxadiazole synthesis. This practical and
eco-friendly approach provides a facile and efficient access to 1,2,4-oxadiazole
derivatives from the corresponding N-acyl amidine precursors under mild reaction
conditions and with short reaction times. Moreover, sequential synthesis of
biologically interesting products from simple benzoic acids and amidines without
purification of N-acyl amidine intermediates can be conveniently carried out on a
gram scale.
ꢀ Experimental Section
1
13
General Information. H and C NMR spectra were recorded on a 400 MHz (100
13
MHz for C NMR) spectrometer. Chemical shift values are given in ppm (parts per
million) with reference to tetramethylsilane (TMS) as an internal standard. The peak
patterns are as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext,
sextet; m, multiplet; dd, doublet of doublets; dt, doublet of triplets. The coupling
constants (J) are reported in Hertz (Hz). Melting points were determined on a
micromelting point apparatus and are uncorrected. High-resolution mass spectra
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(HRMS) were obtained on a Q-TOF Mass Spectrometer equipped with an
electrospray ion source (ESI) and operated in the positive mode. Flash column
chromatography was performed over 200–300 mesh silica gel, and the eluent was a
mixture of EtOAc and petroleum ether (PE).
General procedure A for preparation of N-acyl amidine substrates 2.11 A mixture
of a carboxylic acid (2 mmol), the corresponding amidine salt (2 mmol), HBTU (834
mg, 2.2 mmol) and DIPEA (1.03 g, 8 mmol) in DMF (8 mL) was stirred at room
temperature for 3 h. It was then quenched with H2O (30 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic layer was washed with H2O (10 mL) and
brine (10 mL) successively, dried over anhydrous Na2SO4, concentrated, and purified
through silica gel column chromatography to give the substrate 2.
General procedure B for synthesis of 1,2,4-oxadiazoles 1. A solution of the N-acyl
amidine 2 (0.5 mmol) in EtOAc (5 mL) was treated with NBS (0.6 mmol) and DBU
(0.6 mmol) in sequence and then stirred at room temperature for 10 min when TLC
indicated the conversion was completed. The reaction was quenched with H2O (10
mL) and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed
with brine (10 mL), dried over anhydrous Na2SO4, concentrated, and then purified
through silica gel column chromatography to afford the product 1.
3,5-Diphenyl-1,2,4-oxadiazole (1a). Eluent: EtOAc/PE 10:90; yield: 111 mg, 99%;
1
white solid, mp 107-109 °C (lit.5j mp 106-108 °C); H NMR (400 MHz, CDCl3): δ
13
8.24-8.17 (m, 4H), 7.63-7.49 (m, 6H); C NMR (100 MHz, CDCl3): δ 175.7, 169.0,
132.8, 131.2, 129.1, 128.9, 128.2, 127.6, 127.0, 124.4; HRMS (m/z) [M + H]+ calcd
for C14H11N2O, 223.0866, found 223.0872.
3-Phenyl-5-(p-tolyl)-1,2,4-oxadiazole (1b). Eluent: EtOAc/PE 10:90; yield: 118 mg,
99%; white solid, mp 115-117 °C (lit.5f mp 114-116 °C); 1H NMR (400 MHz, CDCl3):
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δ 8.19-8.16 (m, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.52-7.49 (m, 3H), 7.35 (d, J = 8.0 Hz,
13
2H), 2.46 (s, 3H); C NMR (100 MHz, CDCl3): δ 175.9, 168.9, 143.5, 131.1, 129.8,
128.8, 128.1, 127.5, 127.1, 121.6, 21.8; HRMS (m/z) [M + H]+ calcd for C15H13N2O,
237.1022, found 237.1020.
5-(4-Methoxyphenyl)-3-phenyl-1,2,4-oxadiazole (1c). Eluent: EtOAc/PE 10:90;
yield: 142mg, 98%; white solid, mp 107-108 °C (lit.5c mp 107-108 °C); 1H NMR (400
MHz, CDCl3): δ 8.18-8.15 (m, 4H), 7.51-7.50 (m, 3H), 7.03 (d, J = 8.8 Hz, 2H), 3.89
13
(s, 3H); C NMR (100 MHz, CDCl3): δ 175.6, 168.8, 163.2, 131.1, 130.1, 128.8,
127.5, 127.2, 116.9, 114.5, 55.5; HRMS (m/z) [M + H]+ calcd for C15H13N2O2,
253.0972, found 253.0970.
5-(4-Fluorophenyl)-3-phenyl-1,2,4-oxadiazole (1d).22 Eluent: EtOAc/PE 10:90;
1
yield: 118 mg, 98%; white solid, mp 101-103 °C; H NMR (400 MHz, CDCl3): δ
13
8.25-8.21 (m, 2H), 8.17-8.15 (m, 2H), 7.53-7.49 (m, 3H), 7.26-7.21 (m, 2H); C
NMR (100 MHz, CDCl3): δ 174.8, 169.0, 165.5 (d, JC−F = 253.0 Hz), 131.3, 130.6 (d,
JC−F = 0.9 Hz), 128.9, 127.5, 126.9, 120.7 (d, JC−F = 3.0 Hz), 116.5 (d, JC−F = 22.0 Hz);
19F NMR (376 MHz, CDCl3) δ -105.1; HRMS (m/z) [M + H]+ calcd for C14H10FN2O,
241.0772, found 241.0774.
5-(4-Chlorophenyl)-3-phenyl-1,2,4-oxadiazole (1e). Eluent: EtOAc/PE 10:90; yield:
133 mg, 99%; white solid, mp 118-120 °C (lit.5j mp 118-119 °C); 1H NMR (400 MHz,
13
CDCl3): δ 8.17-8.14 (m, 4H), 7.54-7.50 (m, 5H); C NMR (100 MHz, CDCl3): δ
174.8, 169.1, 139.2, 131.3, 129.5 (2C), 128.9, 127.5, 126.8, 122.8; HRMS (m/z) [M +
H]+ calcd for C14H10ClN2O, 257.0476, found 257.0484.
3-Phenyl-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (1f). Eluent: EtOAc/PE
25:75; yield: 143 mg, 99%; white solid, mp 94-95 °C; 1H NMR (400 MHz, CDCl3): δ
8.52 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.22-8.19 (m, 2H), 7.89 (d, J = 8.0 Hz, 1H),
10

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13
7.73 (t, J = 8.0 Hz, 1H), 7.58-7.52 (m, 3H); C NMR (100 MHz, CDCl3): δ 174.3,
169.2, 131.9 (q, JC−F = 33.0 Hz), 131.4, 131.2 (d, JC−F = 0.9 Hz), 129.8, 129.2 (q, JC−F
= 3.0 Hz), 128.9, 127.6, 126.6, 125.1 (q, JC−F = 4.0 Hz), 125.1, 123.5 (q, JC−F = 271.0
19
Hz); F NMR (376 MHz, CDCl3) δ -62.9; HRMS (m/z) [M + H]+ calcd for
C15H10F3N2O, 291.0740, found 291.0740.
5-(2-Fluorophenyl)-3-phenyl-1,2,4-oxadiazole (1g). Eluent: EtOAc/PE 5:95; yield:
1
111 mg, 94%; white solid, mp 93-94 °C (lit.23 mp 94-95 °C); H NMR (400 MHz,
CDCl3): δ 8.24-8.16 (m, 3H), 7.63-7.57 (m, 1H), 7.55-7.49 (m, 3H), 7.36-7.26 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 172.7 (d, JC−F = 5.0 Hz), 168.8, 160.8 (d, JC−F
259.0 Hz), 134.6 (d, JC−F = 8.0 Hz), 131.3, 131.0, 128.9, 127.6, 126.8, 124.7 (d, JC−F
=
=
4.0 Hz), 117.2 (d, JC−F = 21.0 Hz), 112.9 (d, JC−F = 11.0 Hz); 19F NMR (376 MHz,
CDCl3) δ -108.3; HRMS (m/z) [M + H]+ calcd for C14H10FN2O, 241.0772, found
241.0771.
5-(2-Bromophenyl)-3-phenyl-1,2,4-oxadiazole (1h).9 Eluent: EtOAc/PE 20:80; yield:
149 mg, 99%; off-white solid, mp 57-58 °C; 1H NMR (400 MHz, CDCl3): δ 8.20-8.18
(m, 2H), 8.08 (dd, J = 8.0, 1.8 Hz, 1H), 7.80 (dd, J = 8.0, 1.2 Hz, 1H), 7.54-7.48 (m,
13
4H), 7.43 (td, J = 8.0, 1.6 Hz, 1H); C NMR (100 MHz, CDCl3): δ 174.9, 168.7,
143.8, 133.1, 132.2, 131.3, 128.9, 127.63, 127.61, 126.8, 125.8, 122.2; HRMS (m/z)
[M + H]+ calcd for C14H10BrN2O, 300.9971, found 300.9969.
5-Mesityl-3-phenyl-1,2,4-oxadiazole (1i). Eluent: EtOAc/PE 10:90; yield: 121 mg,
1
91%; white solid, mp 58-59 °C (lit.24 mp 56-57 °C); H NMR (400 MHz, CDCl3): δ
13
8.20-8.17 (m, 2H) 7.53-7.49 (m, 3H), 6.98 (s, 2H); C NMR (100 MHz, CDCl3): δ
176.7, 168.4, 141.3, 138.4, 131.2, 129.0, 128.9, 127.52, 127.1, 121.8, 21.3, 20.4;
HRMS (m/z) [M + H]+ calcd for C17H17N2O, 265.1335, found 265.1344.
3-Phenyl-5-(pyridin-3-yl)-1,2,4-oxadiazole (1j). Eluent: EtOAc/PE 10:90; yield: 107
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1
mg, 96%; white solid, mp 116-118 °C (lit.25 mp 117-118 °C); H NMR (400 MHz,
CDCl3): δ 9.46 (d, J = 1.6 Hz, 1H), 8.85 (dd, J = 4.8, 1.6 Hz, 1H), 8.48 (dt, J = 8.0,
13
2.0 Hz, 1H), 8.19-8.17 (m, 2H), 7.55-7.50 (m, 4H); C NMR (100 MHz, CDCl3): δ
173.7, 169.1, 153.3, 149.2, 135.3, 131.5, 129.0, 127.6, 126.5, 123.8, 120.8; HRMS
(m/z) [M + H]+ calcd for C13H10N3O, 224.0818, found 224.0821.
5-(Furan-2-yl)-3-phenyl-1,2,4-oxadiazole (1k).5g Eluent: EtOAc/PE 10:90; yield:
1
100 mg, 94%; light brown solid, mp 77-78 °C; H NMR (400 MHz, CDCl3): δ
8.18-8.16 (m, 2H), 7.73 (dd, J = 1.6, 0.8 Hz, 1H), 7.54-7.49 (m, 3H), 7.39 (dd, J = 3.6,
0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 168.7, 167.6, 146.7, 140.2, 131.4, 128.9,
127.6, 126.5, 116.6, 112.5; HRMS (m/z) [M + H]+ calcd for C12H9N2O2, 213.0659,
found 213.0660.
(E)-3-Phenyl-5-styryl-1,2,4-oxadiazole (1l). Eluent: EtOAc/PE 10:90; yield: 122 mg,
1
98%; white solid; mp 93-94 °C (lit.26 mp 95-97 °C); H NMR (400 MHz, CDCl3): δ
8.16-8.11 (m, 2H), 7.88 (d, J = 16.4 Hz, 1H), 7.62-7.57 (m, 2H), 7.52-7.47 (m, 3H),
13
7.46-7.42 (m, 3H), 7.07 (d, J = 16.4 Hz, 1H); C NMR (100 MHz, CDCl3): δ 176.3,
168.8, 131.1, 129.6, 128.8, 127.5, 127.0, 124.1, 19.0; HRMS (m/z) [M + H]+ calcd for
C16H13N2O, 249.1022, found 249.1024.
(E)-3-Phenyl-5-(prop-1-en-1-yl)-1,2,4-oxadiazole (1m).27 Eluent: EtOAc/PE 5:95;
1
yield: 90 mg, 97%; colorless oil; H NMR (400 MHz, CDCl3): δ 8.13-8.08 (m, 2H),
7.52-7.45 (m, 3H), 7.16 (dq, J = 16.0, 6.8 Hz, 1H), 6.48 (dd, J = 16.0, 1.6 Hz, 1H),
13
2.03 (dd, J = 7.2, 1.6 Hz, 3H); C NMR (100 MHz, CDCl3): δ 174.7, 168.4, 142.9,
131.1, 128.8, 127.4, 127.0, 115.0, 18.9; HRMS (m/z) [M + H]+ calcd for C11H11N2O,
187.0866, found 187.0869.
3-Phenyl-5-propyl-1,2,4-oxadiazole (1n).28 Eluent: EtOAc/PE 10:90; yield: 91 mg,
1
97%; colorless oil; H NMR (400 MHz, CDCl3): δ 8.09-8.07 (m, 2H), 7.50-7.45 (m,
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3H), 2.93 (t, J = 7.6 Hz, 2H), 1.91 (sext, J = 7.6 Hz, 2H), 1.06 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 179.9, 168.3, 131.1, 128.8, 127.4, 127.0, 28.5, 20.2, 13.7;
HRMS (m/z) [M + H]+ calcd for C11H13N2O, 189.1022, found 189.1023.
5-Isopropyl-3-phenyl-1,2,4-oxadiazole (1o). Eluent: EtOAc/PE 10:90; yield: 90 mg,
1
96%; colorless oil; H NMR (400 MHz, CDCl3): δ 8.09-8.07 (m, 2H), 7.50-7.45 (m,
13
3H), 3.29 (hept, J = 6.8 Hz, 1H), 1.46 (d, J = 7.2 Hz, 6H); C NMR (100 MHz,
CDCl3): δ 183.9, 168.2, 131.0, 128.8, 127.4, 127.1, 27.6, 20.2; HRMS (m/z) [M + H]+
calcd for C11H13N2O, 189.1022, found 189.1010.
5-Cyclohexyl-3-phenyl-1,2,4-oxadiazole (1p). Eluent: EtOAc/PE 10:90; yield: 108
1
mg, 95%; colorless oil; H NMR (400 MHz, CDCl3): δ 8.10-8.06 (m, 2H), 7.50-7.44
(m, 3H), 3.10 (tt, J = 11.6, 3.6 Hz, 1H), 2.16-2.11 (m, 2H), 1.90-1.84 (m, 2H),
13
1.76-1.66 (m, 3H), 1.48-1.28 (m, 3H); C NMR (100 MHz, CDCl3): δ 183.0, 168.1,
131.0, 128.8, 127.4, 127.1, 36.4, 30.3, 25.4; HRMS (m/z) [M + H]+ calcd for
C14H17N2O, 229.1335, found 229.1334.
5-(tert-Butyl)-3-phenyl-1,2,4-oxadiazole (1q). Eluent: EtOAc/PE 25:75; yield: 102
1
mg, 99%; colorless oil; H NMR (400 MHz, CDCl3): δ 8.11-8.06 (m, 2H), 7.50-7.44
13
(m, 3H), 1.50 (s, 9H); C NMR (100 MHz, CDCl3): δ 186.3, 168.2, 131.0, 128.8,
127.5, 127.2, 33.6, 28.5; HRMS (m/z) [M + H]+ calcd for C12H15N2O, 203.1179,
found 203.1183.
5-Phenyl-3-(p-tolyl)-1,2,4-oxadiazole (1r). Eluent: EtOAc/PE 10:90; yield: 123 mg,
99%; white solid, mp 105-106 °C (lit.29 mp 105-106 °C); 1H NMR (400 MHz, CDCl3):
δ 8.22-8.20 (m, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.62-7.52 (m, 3H), 7.31 (d, J = 8.0 Hz,
13
2H), 2.43 (s, 3H); C NMR (100 MHz, CDCl3): δ 175.6, 169.0, 141.5, 132.7, 129.6,
129.1, 128.2, 127.5, 124.4, 124.2, 21.6; HRMS (m/z) [M + H]+ calcd for C15H13N2O,
237.1022, found 237.1044.
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3-(4-Bromophenyl)-5-phenyl-1,2,4-oxadiazole (1s). Eluent: EtOAc/PE 10:90; yield:
149 mg, 99%; white solid, mp 108-109 °C (lit.5f mp 110-112 °C); 1H NMR (400 MHz,
CDCl3): δ 8.20 (d, J = 7.6 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H),
7.61-7.53 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 175.9, 168.3, 132.9, 132.2, 129.2,
129.0, 128.2, 125.9, 125.8, 124.2; HRMS (m/z) [M + H]+ calcd for C14H10BrN2O,
300.9971, found 300.9954.
5-Phenyl-3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (1t). Eluent: EtOAc/PE
10:90; yield: 145 mg, 99%; white solid, mp 91-92 °C; 1H NMR (400 MHz, CDCl3): δ
8.30 (d, J = 8.0 Hz, 2H), 8.23-8.21 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.65-7.55 (m,
13
3H); C NMR (100 MHz, CDCl3): δ 176.2, 168.0, 133.0, 132.9 (q, JC−F = 32.0 Hz),
130.4 (d, JC−F = 1.0 Hz), 129.2, 128.2, 127.9, 127.6, 125.9 (q, JC−F = 4.0 Hz), 124.0,
19
123.8 (q, JC−F = 270.0 Hz), 125.1, 123.5 (q, JC−F = 271.0 Hz); F NMR (376 MHz,
CDCl3) δ -63.0; HRMS (m/z) [M + H]+ calcd for C15H10F3N2O, 291.0740, found
291.0744.
5-Phenyl-3-(pyridin-4-yl)-1,2,4-oxadiazole (1u).6 Eluent: EtOAc; yield: 108 mg,
97%; white solid, mp 146-147 °C; 1H NMR (400 MHz, CDCl3): δ 8.82-8.80 (m, 2H),
13
8.23-8.21 (m, 2H), 8.04-8.03 (m, 2H), 7.66-7.62 (m, 1H), 7.59-7.55 (m, 2H); C
NMR (100 MHz, CDCl3): δ 176.5, 167.5, 150.7, 134.4, 133.2, 129.2, 128.2, 123.9,
121.3, 121.0; HRMS (m/z) [M + H]+ calcd for C13H10N3O, 224.0818, found 224.0807.
3-Isopropyl-5-phenyl-1,2,4-oxadiazole (1v). Eluent: EtOAc/PE 10:90; yield: 90 mg,
1
96%; colorless oil; H NMR (400 MHz, CDCl3): δ 8.15-8.13 (m, 2H), 7.59-7.49 (m,
13
3H), 3.17 (hept, J = 2.8 Hz, 1H), 1.41 (d, J = 2.8 Hz, 6H); C NMR (100 MHz,
CDCl3): δ 175.8, 175.3, 132.5, 129.0, 128.1, 124.5, 26.9, 20.6; HRMS (m/z) [M + H]+
calcd for C11H13N2O, 189.1022, found 189.1028.
3-Cyclopropyl-5-phenyl-1,2,4-oxadiazole (1w).5i Eluent: EtOAc/PE 10:90; yield: 91
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1
mg, 97%; colorless oil; H NMR (400 MHz, CDCl3): δ 8.01-7.99 (m, 2H), 7.50-7.47
13
(m, 1H), 7.46-7.39 (m, 2H), 2.10-2.03 (m, 1H), 1.08-0.98 (m, 4H); C NMR (100
MHz, CDCl3): δ 175.1, 173.1, 132.5, 129.0, 128.0, 124.4, 7.8, 7.0; HRMS (m/z) [M +
H]+ calcd for C11H11N2O, 187.0866, found 187.0867.
5-(2-Fluorophenyl)-3-(m-tolyl)-1,2,4-oxadiazole (1x). According to General
Procedures A and B, the reaction was carried out in a 5 mmol scale omitting the
purification of the N-acyl amidine intermediate with the second step cyclization for 30
min; eluent: EtOAc/PE 5:95; yield: 1155 mg, 91%; white solid, mp 93-94 °C (lit.11
1
mp 93 °C); H NMR (400 MHz, CDCl3): δ 8.22 (td, J = 7.6, 1.6 Hz, 1H), 8.00-7.97
(m, 2H), 7.62-7.57 (m, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.35-7.26 (m, 3H, overlapped
13
with chloroform), 2.45 (s, 3H); C NMR (100 MHz, CDCl3): δ 172.7 (d, JC−F = 5.0
Hz), 168.9, 160.8 (d, JC−F = 259.0 Hz), 138.7, 134.5 (d, JC−F = 9.0 Hz), 132.1, 131.0
(d, JC−F = 0.8 Hz), 128.8, 128.1, 126.6, 124.7, 124.7 (d, JC−F = 4.0 Hz), 117.2 (d, JC−F
19
= 21.0 Hz), 112.9 (d, JC−F = 12.0 Hz), 21.4; F NMR (376 MHz, CDCl3) δ -108.3;
HRMS (m/z) [M + H]+ calcd for C15H12FN2O, 255.0928, found 255.0927.
3-(3-(Pyridin-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (5). According to General
Procedures A and B, the reaction was carried out in a 5 mmol scale omitting the
purification of the N-acyl amidine intermediate with the second step cyclization for 30
min; eluent: EtOAc/PE 40:60; yield: 1178 mg, 95%; white solid, mp 149-150 °C (lit.5a
1
mp 148-149 °C); H NMR (400 MHz, CDCl3): δ 8.22 (td, J = 7.6, 1.6Hz, 1H),
8.00-7.97 (m, 2H), 7.62-7.60 (m, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.35-7.26 (m, 3H); 13C
NMR (100 MHz, CDCl3): δ 174.4, 169.1, 150.6, 145.9, 137.2, 135.9, 132.1, 131.8,
130.2, 125.9, 125.3, 123.4, 117.4, 113.9. HRMS (m/z) [M + H]+ calcd for C14H9N4O,
249.0771, found 249.0779.
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ꢀSupporting Information
Copies of NMR spectra of products 1.
ꢀ Author Information
Corresponding Authors
*E-mail: wenquan_yu@zzu.edu.cn
*E-mail: changjunbiao@zzu.edu.cn
Notes
The authors declare no competing financial interest.
ꢀ Acknowledgements
We thank the National Natural Science Foundation of China (No. 81773570 and
81330075), the Outstanding Young Talent Research Fund of Zhengzhou University
(No. 1521316004) for financial support.
ꢀ References
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20