Synthesis of 2-Amino-1,3,4-oxadiazoles through Elemental Sulfur Promoted Cyclization of Hydrazides with Isocyanides

Article abstract of DOI:10.1002/cjoc.201700188

A novel sulfur-promoted cyclization of hydrazides and isonitriles to produce 1,3,4-oxadiazole has been developed. The method is operationally simple and compatible with a wide scope of substrates and various 2-amino- 1,3,4-oxadiazoles are efficiently obtained in good yields.

Full text of DOI:10.1002/cjoc.201700188

FULL PAPER
DOI: 10.1002/cjoc.201700188
Synthesis of 2-Amino-1,3,4-oxadiazoles through Elemental
Sulfur Promoted Cyclization of Hydrazides with Isocyanides
Wenhu Bao, Chuang Chen, Niannian Yi, Jun Jiang, Zebing Zeng, Wei Deng,* Zhihong Peng,*
and Jiannan Xiang*
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering,
Hunan University, Changsha, Hunan 410082, China
A novel sulfur-promoted cyclization of hydrazides and isonitriles to produce 1,3,4-oxadiazole has been devel-
oped. The method is operationally simple and compatible with a wide scope of substrates and various 2-amino-
1,3,4-oxadiazoles are efficiently obtained in good yields.
Keywords novel, hydrazides, cyclization, isocyanides, 2-amino-1,3,4-oxadiazoles
Introduction
Scheme 1 Synthetic approaches to 1,3,4-oxadiazoles
Previous Works
Heterocyclic compounds are appealing to medicinal
chemists due to their unique chemical properties and a
wide range of biological activity.[1] As one of the basic
five-membered heterocycles, 1,3,4-oxadiazole com-
pounds have been studied extensively because of their
broad pharmaceutical, unique biological and optical
activities.[2] They are widely used in pesticides, medi-
cines and materials.[3] Some 1,3,4-oxadiazole deriva-
tives also have photosensitive properties,[4] which can
be used in the production of fluorescent agents and scin-
tillators, and can be used as photosensitive polymer ma-
terials for electroluminescent devices.[5] Moreover,
2-amino-1,3,4-oxadiazoles can serve as important in-
termediates in organic synthesis. For example, Boger
has used them to synthesize vindoline,[6] a major alka-
loid of Cantharanthus roseus.[7] Therefore, developing
simple and efficient methods for their synthesis is im-
portant and highly desirable.
N
N
O
[Cu]
(a)
R2
O
R2
base
R1
N
NH
R1
H
O
N
O
R2
[Pd]
(b)
NHAc
O
R1
R2NC
+
R1
N
H
N
N
O
DDQ, p-TsOH
NH2
+
Ar1
N
H
Ar2
H
O
Ar2
(c)
(d)
Ar1
N
N
N
N
O
O
O
R1
[Cu]
NH2
O
R1
N
H
R2
R2
O
+
base
N
NH2
H
O
R1
O
R2
POCl3
(e)
Many literatures have reported different approaches
to construct the oxadiazole skeleton.[8] For example, in
2011, Patel’s group reported Cu(II) catalyzed imine C-H
functionalization leading to 2,5-substituted-1,3,4-oxadi-
azoles (Scheme 1a).[9] Then, N-acylhydrazides and iso-
cyanides were used as the starting materials for the syn-
thesis of 2-amino-1,3,4-oxadiazoles by Xu’s group in
2014 (Scheme 1b).[10] In 2015, Kudelko’s group pre-
sented oxidative cyclization of N-aroylhydrazones to
2-(2-arylethenyl)-1,3,4-oxa-diazoles using DDQ as an
efficient oxidant (Scheme 1c).[11] Subsequently, Wu’s
group reported the synthesis of 1,3,4-oxadiazole via
copper-catalyzed coupling of isatins with hydrazides as
well (Scheme 1d).[12] Duan’ group developed a conven-
R1
NHNH2
+
R2
N
N
N
This Work
O
H
N
R2
S8
O
R2NC
NH2
R1
R1
N
DMSO,130 oC
N
H
N
R1 = aryl, alkyl, alkyne, heterocyclic
R2 = cyclohexyl, phenyl, tert-butyl
ient method for the synthesis of 2,5-disubstitut-
ed-1,3,4-oxadiazoles based on the reaction of N,N-di-
methyl amides with acid hydrazides (Scheme 1e).[13]
However, POCl3 is a dangerous reaction reagent. Even
*
E-mail: jnxiang@hnu.edu.cn
Received March 21, 2017; accepted May 9, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201700188 or from the author.
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1

Bao et al.
FULL PAPER
though these reactions are efficient, they tend to suffer
from problems such as using expensive palladium cata-
lyst, requiring the preparation of advanced intermediates
or limited scope. As a result, a simple and straightfor-
ward method for the preparation of 1,3,4-oxadiazoles
from simple starting materials remains elusive. In this
paper, we report a simple method to synthesize
1,3,4-oxadiazoles from hydrazides and isocyanides with
high yields, good functional group tolerance and opera-
tion simplicity.
(3a) Yield 87% (67.1 mg); white solid; m.p. 164－
166 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, J＝7.6
Hz, 2H), 7.22 (d, J＝7.6 Hz, 2H), 5.30 (d, J＝7.2 Hz,
1H), 3.71－3.49 (m, 1H), 2.37 (s, 3H), 2.18－2.00 (m,
2H), 1.83－1.66 (m, 2H), 1.62 (d, J＝13.2 Hz, 1H),
1.46－1.17 (m, 5H); 13C NMR (100 MHz, CDCl3) δ:
162.69, 158.78, 140.59, 129.41, 125.64, 121.8, 52.5,
33.2, 25.4, 24.6, 21.4; IR (KBr) ν: 3265, 3024, 2952,
2934, 2861, 1698, 1567, 1461, 1273, 1054, 827, 736
cm1. HRMS (ESI) calcd for C15H19N3O [M＋H]＋
257.1528, found 257.1525.
N-Cyclohexyl-5-phenyl-1,3,4-oxadiazol-2-amine
Experimental
(3b)[10] Yield 85% (62.0 mg); white solid; m.p. 157－
1
159 ℃ (Lit.[10] 156－158 ℃); H NMR (400 MHz,
Commercially available reagents were of reagent
grade (AR grade) and were used without further purifi-
cation. Reactions were monitored by thin layer chroma-
tography (TLC) using silicycle pre-coated silica gel
plates. Flash column chromatography was performed
CDCl3) δ: 7.90 (dd, J＝6.4, 3.2 Hz, 2H), 7.49－7.38 (m,
3H), 5.01 (d, J＝7.8 Hz, 1H), 3.64 (dt, J＝7.2, 3.2 Hz,
1H), 2.24－2.06 (m, 2H), 1.85－1.58 (m, 3H), 1.46－
1.19 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 162.8,
158.7, 130.4, 128.8, 125.7, 124.6, 52.6, 33.2, 25.4, 24.6;
IR (KBr) ν: 3261, 3024, 2925, 2854, 1621, 1523,
1451,1252, 1053, 686 cm1.
1
over silicycle silica gel (200－300 mesh). H NMR and
13C NMR spectra were recorded on 400 MHz NMR plus
spectrometer using residue solvent peaks as internal
standards. Infrared spectra were recorded with IR spec-
trometer and are reported in reciprocal centimeter
(cm1). High resolution mass spectra were obtained us-
ing GCT-TOF instrument with ESI source. Solvents
were purified by standard methods.
5-(4-(tert-Butyl)phenyl)-N-cyclohexyl-1,3,4-oxa-
diazol-2-amine (3c) Yield 84% (75.4 mg); white solid;
m.p. 162－163 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.81
(d, J＝8.0 Hz, 2H), 7.43 (d, J＝8.4 Hz, 2H), 5.34 (d,
J＝7.6 Hz, 1H), 3.69－3.48 (m, 1H), 2.11 (d, J＝11.2
Hz, 2H), 1.82－1.71 (m, 2H), 1.48－1.10 (m, 15H); 13C
NMR (100 MHz, CDCl3) δ: 162.7, 158.7, 153.7, 125.6,
121.8, 52.6, 34.8, 33.1, 31.1, 25.4, 24.6; IR (KBr) ν:
3273, 3017, 2952, 2937, 2856, 1681, 1554, 1452, 1364,
1046, 840, 752, 640, 557 cm1. HRMS (ESI) calcd for
C18H25N3O [M＋H]＋ 299.1998, found 299.1992.
N-Cyclohexyl-5-(4-methoxyphenyl)-1,3,4-oxadia-
zol-2-amine (3d)[15] Yield 86% (70.4 mg); yellow
General procedure of 3
To a sealed tube were added hydrazide (0.3 mmol),
sulphur (0.45 mmol, 14.4 mg), isonitriles (0.36 mmol,
39 mg) and DMSO (2 mL). Then the tube was stirred at
130 ℃ for 4 h. After completion of the reaction, the
resulting mixture was diluted with dichloromethane and
washed with water. The separated aqueous phase was
washed with CH2Cl2. The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under vacuo. The crude mix-
ture was purified by column chromatography on silica
gel with petroleum/ethyl acetate [V(EA)∶V(PE)＝1∶3]
to yield products 3a－3ac.
1
solid; m.p. 218－219 ℃ (Lit.[15] 221 ℃); H NMR
(400 MHz, CDCl3) δ: 7.78 (d, J＝8.4 Hz, 2H), 6.90 (d,
J＝8.4 Hz, 2H), 5.43 (d, J＝7.2 Hz, 1H), 3.80 (s, 3H),
3.58 (d, J＝7.2 Hz, 1H), 2.09 (d, J＝10.4 Hz, 2H), 1.73
(dd, J＝17.6, 8.4 Hz, 2H), 1.60 (d, J＝12.8 Hz, 1H),
1.40－1.15 (m, 5H); 13C NMR (100 MHz, CDCl3) δ:
162.6, 161.2, 158.5, 127.3, 117.2, 114.1, 55.2, 52.5, 33.1,
25.3, 24.6.
General procedure of 2ab[14]
To a round-bottom flask were added hydrazide (1b)
(1 equiv., 5 mmol, 0.68 g), isothiocyanate (2aa) (1.2
equiv., 6 mmol, 0.85 g) and ethanol (20 mL). The reac-
tion mixture was refluxed for 5 h. The progress of reac-
tion was monitored by TLC. After cooling, the precipi-
tate was collected, washed with distilled water, and re-
crystallized from ethanol to yield product 2ab (white
solid, 1.2 g, yield 85%). 1H NMR (400 MHz, DMSO-d6)
δ: 10.28 (s, 1H), 9.22 (s, 1H), 7.92 (d, J＝7.2 Hz, 2H),
7.73 (s, 1H), 7.51 (dt, J＝14.4, 6.9 Hz, 3H), 4.14 (s, 1H),
1.89－1.63 (m, 4H), 1.57 (d, J＝11.6 Hz, 1H), 1.35－
1.17 (m, 4H), 1.06 (d, J＝6.4 Hz, 1H); 13C NMR (100
MHz, DMSO-d6) δ: 181.0, 166.3, 133.1, 132.2, 128.7,
128.3, 53.5, 32.3, 25.7, 25.4; ESI-MS m/z: 278 [M＋
H]＋.
N-Cyclohexyl-5-(4-fluorophenyl)-1,3,4-oxadiazol-
2-amine (3e) Yield 84% (75.4 mg); yellow solid; m.p.
148－149 ℃; H NMR (400 MHz, CDCl3) δ: 8.00－
1
7.69 (m, 2H), 7.11 (t, J＝8.4 Hz, 2H), 5.51－5.05 (m,
1H), 3.60 (s, 1H), 2.10 (d, J＝10.8 Hz, 2H), 1.69 (dd,
J＝51.4, 10.8 Hz, 3H), 1.45－1.17 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ: 164.3, 161.8, 157.0, 126.9 (d, J＝
8.6 Hz), 120.1, 115.2, 115.0, 51.7, 32.3, 24.5, 23.7; 19F
NMR (376 MHz, CDCl3) δ: 109.1 (s); IR (KBr) ν:
3264, 3021, 2936, 2871, 1632, 1513, 1451, 1252, 1053,
830, 732 cm1. HRMS (ESI) calcd for C14H16FN3O [M
＋H]＋ 261.1277, found 261.1273.
5-(4-Chlorophenyl)-N-cyclohexyl-1,3,4-oxadiazol-
2-amine (3f)[15] Yield 91% (75.6 mg); white solid;
1
m.p. 285－287 ℃ (Lit.[15] 287 ℃); H NMR (400
N-Cyclohexyl-5-(p-tolyl)-1,3,4-oxadiazol-2-amine
MHz, CDCl3) δ: 7.80 (d, J＝8.4 Hz, 2H), 7.38 (d, J＝
2
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Synthesis of 2-Amino-1,3,4-oxadiazoles
8.4 Hz, 2H), 5.54 (d, J＝7.2 Hz, 1H), 3.72－3.45 (m,
1H), 2.09 (d, J＝10.4 Hz, 2H), 1.82－1.56 (m, 3H),
1.41－1.17 (m, 5H); 13C NMR (100 MHz, CDCl3) δ:
162.9, 157.8, 136.3, 129.1, 126.9, 123.0, 52.6, 33.1,
25.3, 24.6.
1455, 1048, 721 cm1. HRMS (ESI) calcd for
C14H18N4O [M＋H]＋ 258.1481, found 258.1472.
2-(5-(Cyclohexylamino)-1,3,4-oxadiazol-2-
yl)phenol (3l) Yield 81% (63.0 mg); white solid; m.p.
1
117－119 ℃; H NMR (400 MHz, CDCl3) δ: 10.03 (s,
5-(4-Bromophenyl)-N-cyclohexyl-1,3,4-oxadiazol-
2-amine (3g) Yield 82% (80.0 mg); white solid; m.p.
152－154 ℃; H NMR (400 MHz, CDCl3) δ: 7.67 (d,
1H), 7.47 (d, J＝7.6 Hz, 1H), 7.26 (t, J＝7.6 Hz, 1H),
6.99 (d, J＝8.4 Hz, 1H), 6.85 (t, J＝7.6 Hz, 1H), 5.39 (d,
J＝7.2 Hz, 1H), 3.63－3.48 (m, 1H), 2.05 (d, J＝10.4
Hz, 2H), 1.76－1.66 (m, 2H), 1.57 (d, J＝13.2 Hz, 1H),
1.37－1.14 (m, 5H); 13C NMR (100 MHz, CDCl3) δ:
160.7, 157.5, 155.7, 131.1, 124.3, 118.6, 116.1, 107.8,
51.8, 32.1, 24.4, 23.6; IR (KBr) ν: 3421, 3235, 3024,
2928, 2842, 1621, 1519, 1456, 1235, 1053, 732 cm1.
HRMS (ESI) calcd for C14H17N3O2 [M＋H]＋ 259.1321,
found 259.1318.
1
J＝8.4 Hz, 2H), 7.49 (d, J＝8.4 Hz, 2H), 5.35 (d, J＝
7.2 Hz, 1H), 3.64－3.43 (m, 1H), 2.11－1.99 (m, 2H),
1.77－1.51 (m, 3H), 1.37－1.12 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ: 162.1, 157.0, 131.2, 126.2, 123.8,
122.6, 51.8, 32.3, 24.5, 23.8; IR (KBr) ν: 3256, 3013,
2931, 2857, 1625, 1513, 1452, 1243, 1057, 826, 731
cm1. HRMS (ESI) calcd for C14H16BrN3O [M＋H]＋
321.0477, found 321.0475.
N-Cyclohexyl-5-(2-fluorophenyl)-1,3,4-oxadiazol-
2-amine (3m) Yield 83% (65.0 mg); yellow solid; m.p.
N-Cyclohexyl-5-(4-iodophenyl)-1,3,4-oxadiazol-2-
amine (3h) Yield 76% (84.1 mg); white solid; m.p.
1
116－118 ℃; H NMR (400 MHz, CDCl3) δ: 7.83 (t,
1
172－174 ℃; H NMR (400 MHz, CDCl3) δ: 7.70 (d,
J＝7.6 Hz, 1H), 7.34 (q, J＝7.2 Hz, 1H), 7.17－7.02 (m,
2H), 5.55 (d, J＝7.6 Hz, 1H), 3.64－3.47 (m, 1H), 2.04
(d, J＝10.0 Hz, 2H), 1.76－1.63 (m, 2H), 1.55 (d, J＝
12.8 Hz, 1H), 1.38－1.12 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ: 163.3, 160.6, 158.1, 155.2, 132.0 (d, J＝8.4
Hz), 128.9 (d, J＝1.6 Hz), 124.4 (d, J＝3.6 Hz), 116.8,
116.6, 113.1 (d, J＝12.0 Hz), 52.7, 33.2, 25.4, 24.7; 19F
NMR (376 MHz, CDCl3) δ: 111.4; IR (KBr) ν: 3262,
3017, 2931, 2851, 1643, 1532, 1456, 1276, 1054, 838,
737 cm1. HRMS (ESI) calcd for C14H16FN3O [M＋H]＋
261.1277, found 261.1269.
J＝8.4 Hz, 2H), 7.53 (d, J＝8.4 Hz, 2H), 5.26 (d, J＝
7.6 Hz, 1H), 3.66－3.45 (m, 1H), 2.03 (dd, J＝15.6, 9.2
Hz, 2H), 1.77－1.52 (m, 3H), 1.36－1.13 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ: 161.9, 157.1, 137.0, 126.1,
123.0, 95.6, 51.7, 32.2, 24.4, 23.6; IR (KBr) ν: 3253,
3008, 2934, 2861, 1631, 1504, 1453, 1238, 1053,835,
726 cm1. HRMS (ESI) calcd for C14H16IN3O [M＋H]＋
369.0338, found 369.0332.
4-(5-(Cyclohexylamino)-1,3,4-oxadiazol-2-yl)-
benzaldehyde (3i) Yield 81% (65.9 mg); white solid;
m.p. 172－173 ℃; 1H NMR (400 MHz, CDCl3) δ: 9.98
(s, 1H), 7.99 (d, J＝8.0 Hz, 2H), 7.89 (d, J＝8.0 Hz,
2H), 5.21 (d, J＝6.4 Hz, 1H), 3.65－3.53 (m, 1H), 2.11
－2.01 (m, 2H), 1.78－1.60 (m, 3H), 1.37－1.21 (m,
5H); 13C NMR (100 MHz, CDCl3) δ: 190.4, 162.3,
136.2, 129.2, 128.6, 125.1, 51.7, 32.2, 24.4, 23.6; IR
(KBr) ν: 3287, 3024, 2936, 2865, 2720, 1627, 1501,
1455, 1248, 1058, 742 cm1. HRMS (ESI) calcd for
C15H17N3O2 [M＋H]＋ 271.1321, found 271.1315.
4-(5-(Cyclohexylamino)-1,3,4-oxadiazol-2-yl)-
phenol (3j) Yield 87% (67.6 mg); white solid; m.p.
198－200 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.00
(s, 1H), 7.58 (d, J＝8.4 Hz, 2H), 7.48 (d, J＝7.6 Hz,
1H), 6.84 (d, J＝8.4 Hz, 2H), 2.03－1.80 (m, 2H), 1.65
(s, 2H), 1.50 (d, J＝11.6 Hz, 1H), 1.35－0.96 (m, 6H);
13C NMR (100 MHz, DMSO-d6) δ: 162.9, 159.9, 158.1,
127.5, 116.4, 115.8, 52.3, 32.8, 25.7, 24.9; IR (KBr) ν:
3426, 3247, 3016, 2931, 2867, 1617, 1512, 1457, 1224,
1064, 716 cm1. HRMS (ESI) calcd for C14H17N3O2
[M＋H]＋ 259.1321, found 259.1318.
5-(2-Chlorophenyl)-N-cyclohexyl-1,3,4-oxadiazol-
2-amine (3n) Yield 82% (68.2 mg); white solid; m.p.
1
156－158 ℃; H NMR (400 MHz, CDCl3) δ: 7.78 (d,
J＝7.2 Hz, 1H), 7.39 (d, J＝7.6 Hz, 1H), 7.34－7.20 (m,
2H), 5.78 (d, J＝5.2 Hz, 1H), 3.52 (s, 1H), 2.04 (s, 2H),
1.68 (s, 2H), 1.54 (d, J＝11.6 Hz, 1H), 1.35－1.13 (m,
5H); 13C NMR (100 MHz, CDCl3) δ: 162.5, 155.9,
131.4, 130.4, 130.1, 129.5, 126.0, 123,0, 51.8, 32.2,
24.5, 23.6; IR (KBr) ν: 3261, 3019, 2936, 2871, 1624,
1506, 1453, 1263, 1053, 826, 725 cm1. HRMS (ESI)
calcd for C14H16ClN3O [M ＋H]＋ 277.0982, found
277.0976.
5-(2-Bromophenyl)-N-cyclohexyl-1,3,4-oxadiazol-
2-amine (3o) Yield 78% (75.1 mg); white solid; m.p.
1
128－130 ℃; H NMR (400 MHz, CDCl3) δ: 7.75 (d,
J＝7.6 Hz, 1H), 7.60 (d, J＝8.0 Hz, 1H), 7.30 (t, J＝7.6
Hz, 1H), 7.21 (t, J＝7.6 Hz, 1H), 5.68 (d, J＝7.2 Hz,
1H), 3.61－3.46 (m, 1H), 2.04 (d, J＝8.4 Hz, 2H),
1.77－1.60 (m, 2H), 1.57 (t, J＝12.8 Hz, 1H), 1.35－
1.16 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 162.4,
156.3, 133.3, 130.4, 130.0, 126.4, 125.0, 119.9, 51.8,
32.2, 24.4, 23.6; IR (KBr) ν: 3267, 3025, 2934, 2862,
1643, 1521, 1462, 1263, 1064, 821, 732 cm1. HRMS
(ESI) calcd for C14H16BrN3O [M ＋ H] ＋ 321.0477,
found 321.0474.
5-(2-Aminophenyl)-N-cyclohexyl-1,3,4-oxadiazol-
2-amine (3k) Yield 84% (65.1 mg); yellow solid; m.p.
1
104－105 ℃; H NMR (400 MHz, CDCl3) δ: 7.47 (d,
J＝8.0 Hz, 1H), 7.11 (s, 1H), 6.77－6.54 (m, 2H), 5.28
(d, J＝200 Hz, 2H), 3.60－3.48 (m, 1H), 2.04 (d, J＝
11.6 Hz, 2H), 1.76－1.50 (m, 3H), 1.36－1.12 (m, 5H);
13C NMR (100 MHz, CDCl3) δ: 160.9, 158.3, 145.5,
130.4, 126.1, 115.9, 115.2, 106.1, 52.0, 32.5, 24.8, 24.0;
IR (KBr) ν: 3624, 3245, 3021, 2934, 2862, 1631, 1512,
N-Cyclohexyl-5-(2-iodophenyl)-1,3,4-oxadiazol-2-
amine (3p) Yield 74% (59.7 mg); yellow solid; m.p.
1
130－132 ℃; H NMR (400 MHz, CDCl3) δ: 7.93 (d,
J＝8.0 Hz, 1H), 7.68 (d, J＝7.6 Hz, 1H), 7.35 (t, J＝7.6
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Bao et al.
FULL PAPER
Hz, 1H), 7.05 (t, J＝7.6 Hz, 1H), 5.33 (d, J＝6.8 Hz,
1H), 3.62－3.49 (m, 1H), 2.06 (d, J＝10.0 Hz, 2H),
1.78－1.67 (m, 2H), 1.57 (d, J＝13.2 Hz, 1H), 1.37－
1.20 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 140.2,
130.6, 129.9, 128.9, 127.2, 92.7, 52.0, 32.4, 24.5, 23.8;
IR (KBr) ν: 3251, 3014, 2938, 2865, 1637, 1507, 1453,
1049, 832, 724 cm1. HRMS (ESI) calcd for
C14H16IN3O [M＋H]＋ 369.0338, found 369.0331.
amine (3v) Yield 76% (67.1 mg); yellow solid; m.p.
276－277 ℃; H NMR (400 MHz, CDCl3) δ: 8.87 (d,
1
J＝3.2 Hz, 1H), 8.34－7.97 (m, 4H), 7.37 (dd, J＝8.0,
4.4 Hz, 1H), 5.34 (d, J＝7.2 Hz, 1H), 3.69－3.54 (m,
1H), 2.09 (d, J＝10.8 Hz, 3H), 1.78－1.53 (m, 3H),
1.40－1.17 (m, 5H); 13C NMR (100 MHz, CDCl3) δ:
162.1, 157.3, 150.5, 147.8, 135.5, 129.3, 127.0, 125.4,
124.1, 121.7, 121.0, 51.7, 32.3, 24.4, 23.7; IR (KBr) ν:
3453, 3032, 2938, 2873, 1658, 1545,1505, 1453, 1195,
1103, 756 cm1. HRMS (ESI) calcd for C17H18N4O
[M＋H]＋ 294.1481, found 294.1483.
N-Cyclohexyl-5-(m-tolyl)-1,3,4-oxadiazol-2-amine
(3q) Yield 81% (62.5 mg); white solid; m.p. 124－
126 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.69－7.56 (m,
2H), 7.24－7.11 (m, 2H), 5.65－5.23 (m, 1H), 3.55 (d,
J＝7.2 Hz, 1H), 2.30 (s, 3H), 2.04 (d, J＝11.2 Hz, 2H),
1.76－1.51 (m, 3H), 1.37－1.13 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ: 161.8, 157.7, 137.5, 130.1, 127.6,
125.2, 123.4, 121.8, 51.5, 32.1, 24.3, 23.6, 20.2; IR
(KBr) ν: 3271, 3042, 2950, 2932, 2875, 1692, 1563,
1456, 1253, 1037, 841, 736 cm1. HRMS (ESI) calcd
for C15H19N3O [M＋H]＋ 257.1528, found 257.1522.
N-Cyclohexyl-5-(3-nitrophenyl)-1,3,4-oxadiazol-2-
amine (3r) Yield 73% (63.1 mg); yellow solid; m.p.
5-(3-Chloro-4-methylphenyl)-N-cyclohexyl-1,3,4-
oxadiazol-2-amine (3w) Yield 84% (73.3 mg); white
1
solid; m.p. 156－158 ℃; H NMR (400 MHz, CDCl3)
δ: 7.79 (s, 1H), 7.62 (d, J＝7.8 Hz, 1H), 7.23 (d, J＝7.8
Hz, 1H), 4.80 (d, J＝7.2 Hz, 1H), 3.57 (dd, J＝10.8, 6.8
Hz, 1H), 2.34 (s, 3H), 2.05 (d, J＝9.2 Hz, 2H), 1.75－
1.67 (m, 2H), 1.58 (d, J＝13.2 Hz, 1H), 1.39－1.18 (m,
5H); 13C NMR (100 MHz, CDCl3) δ: 161.7, 156.7,
137.6, 133.9, 130.4, 125.1, 122.9, 51.6, 32.2, 24.4, 23.6,
19.1; IR (KBr) ν: 3274, 3026, 2953, 2931, 2854, 1724,
1584, 1452, 1052, 736 cm1. HRMS (ESI) calcd for
C15H18ClN3O [M＋H]＋ 291.1138, found 291.1133.
5-(4-Bromo-3-methylphenyl)-N-cyclohexyl-1,3,4-
oxadiazol-2-amine (3x) Yield 82% (82.4 mg); white
1
188－190 ℃; H NMR (400 MHz, CDCl3) δ: 8.60 (s,
1H), 8.20 (t, J＝6.8 Hz, 2H), 7.58 (t, J＝8.0 Hz, 1H),
5.53 (d, J＝7.6 Hz, 1H), 3.67－3.53 (m, 1H), 2.07 (d,
J＝10.4 Hz, 2H), 1.80－1.52 (m, 3H), 1.39－1.11 (m,
5H); 13C NMR (100 MHz, CDCl3) δ: 162.4, 147.7,
130.3, 129.2, 125.4, 123.8, 119.5, 51.9, 32.3, 24.5, 23.7;
IR (KBr) ν: 3264, 3024, 2926, 2858, 1524, 1447, 1336,
1064, 954, 851, 742 cm1. HRMS (ESI) calcd for
C14H16N4O3 [M＋H]＋ 288.1222, found 288.1218.
1
solid; m.p. 167－169 ℃; H NMR (400 MHz, CDCl3)
δ: 7.69 (s, 1H), 7.54－7.41 (m, 2H), 5.29 (d, J＝6.8 Hz,
1H), 3.61－3.49 (m, 1H), 2.35 (s, 3H), 2.09－1.99 (m,
2H), 1.64 (dd, J＝52.4, 12.8 Hz, 3H), 1.38－1.16 (m,
5H); 13C NMR (100 MHz, CDCl3) δ: 161.9, 157.1,
137.7, 131.8, 126.7, 126.2, 123.4, 122.7, 51.6, 32.2,
24.4, 23.6, 21.9; IR (KBr) ν: 3286, 3031, 2945, 2931,
2865, 1703, 1578, 1464, 1246, 1037, 724 cm1. HRMS
(ESI) calcd for C15H18BrN3O [M ＋ H] ＋ 335.0633,
found 335.0630.
N-Phenyl-5-(o-tolyl)-1,3,4-oxadiazol-2-amine (3y)
Yield 64% (36.6 mg); yellow solid; m.p. 102－103 ℃;
1H NMR (400 MHz, CDCl3) δ: 8.50 (d, J＝2.4Hz, 1H),
7.89 (d, J＝8.4 Hz, 1H), 5.92 (t, J＝2.4 Hz, 1H), 4.27 (d,
J＝10.0 Hz, 1H), 2.09 (d, J＝13.0 Hz, 2H), 1.76 (dd,
J＝13.2, 4.8 Hz, 2H), 1.69－1.57 (m, 1H), 1.48－1.16
(m, 5H); 13C NMR (100 MHz, CDCl3) δ: 173.5, 163.7,
134.2, 97.9, 54.3, 31.7, 25.4, 24.6; IR (KBr) ν: 3272,
3018, 2927, 2867, 1632, 1521, 1463, 1247, 1053, 692
cm1. HRMS (ESI) calcd for C10H13N3O [M＋H]＋
191.1059, found 191.1053.
N-Cyclohexyl-5-(thiophen-2-yl)-1,3,4-oxadiazol-2-
amine (3s) Yield 75% (56.0 mg); yellow solid; m.p.
1
130－131 ℃; H NMR (400 MHz, CDCl3) δ: 7.44 (d,
J＝3.2 Hz, 1H), 7.32 (d, J＝4.8 Hz, 1H), 7.00 (t, J＝4.4
Hz, 1H), 5.55 (d, J＝7.2 Hz, 1H), 3.60－3.45 (m, 1H),
2.03 (d, J＝10.0 Hz, 2H), 1.74－1.50 (m, 3H), 1.34－
1.21 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 161.6,
154.1, 127.2, 126.8, 126.6, 125.2, 51.8, 32.3, 24.5, 23.8;
IR (KBr) ν: 3122, 2931, 2856, 1685, 1642, 1455, 1546,
1412, 1383, 817, 731 cm1. HRMS (ESI) calcd for
C12H15N3OS [M＋H]＋ 249.0936, found 249.0931.
N-Cyclohexyl-5-(furan-2-yl)-1,3,4-oxadiazol-2-
amine (3t)[10] Yield 72% (50.5 mg); white solid; m.p.
176－177 ℃ (Lit. 177－178 ℃); 1H NMR (400 MHz,
CDCl3) δ: 7.47 (s, 1H), 6.84 (d, J＝2.8 Hz, 1H), 6.45 (s,
1H), 5.62 (d, J＝7.2 Hz, 1H), 3.60－3.45 (m, 1H), 2.03
(d, J＝10.4 Hz, 2H), 1.77－1.50 (m, 3H), 1.36－1.15
(m, 5H); 13C NMR (100 MHz, CDCl3) δ: 161.6, 150.9,
143.5, 139.1, 110.8, 110.5, 51.8, 32.3, 24.5, 23.8.
5-(Furan-2-yl)-N-phenyl-1,3,4-oxadiazol-2-amine
(3z) Yield 83% (56.5 mg); brown solid; m.p. 201－
1
202 ℃; H NMR (400 MHz, DMSO-d6) δ: 10.74 (s,
N-Cyclohexyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-
amine (3u)[10] Yield 72% (50.5 mg); white solid; m.p.
175－176 ℃ (Lit. 175－176 ℃); 1H NMR (400 MHz,
CDCl3) δ: 8.65 (d, J＝3.2 Hz, 2H), 7.67 (d, J＝4.8 Hz,
2H), 5.78 (d, J＝7.2 Hz, 1H), 3.67－3.50 (m, 1H), 2.06
(d, J＝10.4 Hz, 2H), 1.78－1.53 (m, 3H), 1.38－1.15
(m, 5H); 13C NMR (100 MHz, CDCl3) δ: 162.8, 156.0,
149.8, 131.0, 118.6, 52.1, 32.5, 24.7, 23.9.
1H), 7.98 (s, 1H), 7.60 (d, J＝7.9 Hz, 2H), 7.36 (t, J＝
7.6 Hz, 2H), 7.13 (t, J＝2.8 Hz, 1H), 7.01 (s, 1H), 6.75
(d, J＝2.8 Hz, 1H); C NMR (100 MHz, DMSO-d6) δ:
159.7, 151.4, 146.4, 139.4, 138.9, 129.6, 122.5, 117.5,
112.8, 112.8; IR (KBr) ν: 3328, 3057, 2944, 1939, 1855,
1662, 1293, 1087, 960, 901, 841, 740 cm1. HRMS (ESI)
calcd for C12H9N3O2 [M ＋ H] ＋ 227.0695, found
227.0691.
13
N-Cyclohexyl-5-(quinolin-6-yl)-1,3,4-oxadiazol-2-
N-Phenyl-5-(o-tolyl)-1,3,4-oxadiazol-2-amine (3aa)
4
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© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—8

Synthesis of 2-Amino-1,3,4-oxadiazoles
Yield 81% (61.0 mg); white solid; m.p. 181－182 ℃;
1H NMR (400 MHz, DMSO-d6) δ: 10.64 (s, 1H), 7.80
(d, J＝7.6 Hz, 1H), 7.63 (d, J＝8.0 Hz, 2H), 7.48－7.33
(m, 5H), 7.01 (t, J＝7.4 Hz, 1H), 2.62 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ: 160.0, 158.3, 139.2, 137.4,
132.1, 131.0, 129.6, 128.3, 126.9, 123.6, 122.3, 117.5,
22.0. IR (KBr) ν: 3261, 3041, 2853, 1611, 1258, 1069,
913, 857, 735 cm1. HRMS (ESI) calcd for C15H13N3O
[M＋H]＋ 251.1059, found 251.1054.
tries 15, 16), suggesting that nitrogen or oxygen was not
crucial to this cyclization reaction. Based on the above
results, we concluded that the optimized conditions to
obtain the 2-amino-1,3,4-oxadiazoles were running the
reaction with 1a (1.0 equiv.), 2a (1.2 equiv.), and sulfur
(1.5 equiv.) in DMSO at 130 ℃ under air.
Table 1 Optimization of the reaction conditionsa
O
N-(tert-Butyl)-5-(p-tolyl)-1,3,4-oxadiazol-2-amine
NH2
NC
S8
(3ab)[10] Yield 76% (52.7 mg); white solid; m.p.
N
+
H
conditions
1
164－165 ℃ (Lit.[10] 168－169 ℃); H NMR (400
Me
1a
2a
MHz, CDCl3) δ: 7.71 (d, J＝7.6 Hz, 2H), 7.17 (d, J＝
8.0 Hz, 2H), 5.17 (d, J＝14.4 Hz, 1H), 2.32 (s, 3H),
1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 162.2,
158.9, 140.7, 129.5, 125.7, 121.8, 52.4, 29.1, 21.6.
H
N
O
N
Me
N
3a
N-Phenyl-5-propyl-1,3,4-oxadiazol-2-amine (3ac)
Yield 57% (34.7 mg); white solid; m.p. 113－114 ℃;
1H NMR (400 MHz, CDCl3) δ: 9.3 (s, 1H), 7.5 (d, J＝
8.0 Hz, 2H), 7.3 (t, J＝7.6 Hz, 2H), 7.1 (t, J＝7.6 Hz,
1H), 2.8 (t, J＝7.5 Hz, 2H), 1.86－1.75 (m, 2H), 1.1 (t,
Entry Sulfur/equiv.
Solvent
DMF
Temp./℃
120
Yieldb/%
0
1
0
2
0.5
1.2
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
DMF
120
40
13
3
DMF
120
73
J＝7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ: 160.8,
4
DMF
120
81
160.6, 138.3, 129.3, 122.7, 117.5, 27.3, 20.1, 13.6; IR
(KBr) ν: 3273, 3032, 2834, 1589, 1082, 924, 864, 802
cm1. HRMS (ESI) calcd for C11H13N3O [M＋H]＋
203.1059, found 203.1052.
5
DMF
120
82
6
CH3CN
120
40
7
1,4-Dioxane 120
25
8
DMSO
THF
120
120
120
120
120
100
130
130
130
85
Results and Discussion
9
trace
trace
trace
20
At the outset of our study, we chose to use 4-methyl-
benzohydrazide and isocyanocyclohexane as the sub-
strates to synthesize 1,3,4-oxadiazoles (Table 1, Entry 1).
After running the reaction in DMF under air at 120 ℃
for 4 h, the formation of the desired product 3a was not
observed. Then, 0.5 equiv. sulfur was added to the reac-
tion system, to our delight, the target product 3a was
obtained in 40% GC yield (Entry 2). Obviously, the el-
emental sulfur was essential for this cyclization reaction
to proceed. So the amount of elemental sulfur was fur-
ther tested (Entries 3－5). When the amount of sulfur
was increased from 1.2 equiv. to 2.0 equiv., the yield
was increased from 73% to 82%, and 1.5 equiv. of sul-
fur was found to be the best choice. Solvent also played
an important role in this reaction. When CH3CN and
1,4-dioxane were used as the solvent, 3a was obtained
in 40% and 25% yield respectively (Entries 6, 7). To our
surprise, when DMSO was used as the solvent, the de-
sired product 3a could be isolated in 85% yield (Entry
8). It was found that THF, CH3NO2, CH2Cl2 and toluene
all gave the product in much lower yields (Entries 9－
12). Next, we investigated the reaction temperature and
found that when the temperature was dropped to 100 ℃,
the yield went down to 70% (Entry 13). When the tem-
perature was raised to 130 ℃, the yield was increased
to 89% (Entry 14). The above results indicated that
130 ℃ was the optimal reaction temperature. The yield
did not change significantly when the reaction was
conducted under a nitrogen or oxygen atmosphere (En-
10
11
12
13
14
15c
16d
CH3NO2
CH2Cl2
Toluene
DMSO
DMSO
DMSO
DMSO
70
89 (87)
90
88
a Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), solvent (2
mL), air, 4 h. b The yield was determined by GC with biphenyl as
an internal standard. The number in parentheses was isolated
yield. c Under N2. d Under O2
With the optimized conditions in hand, the scope of
the hydrazides was explored. A variety of hydrazides
could efficiently react with three representative isoni-
triles to give the corresponding products in moderate to
good yields (Scheme 2). From the table, we can see that
all types of benzohydrazides can give the desired prod-
uct in good yields regardless of whether it has an elec-
tron-donating substituent (3d, 3j) or an electron-with-
drawing substituent on the phenyl ring (3e, 3f, 3i). To
our delight, 4-chlorobenzohydrazide gave a very high
yield up to 91%. However, the yield of 3p was only
74%, and this is likely due to the influence of steric
hindrance of the ortho-substiuent. We were pleased to
see that when heterocyclic hydrazides are used as the
substrates, the corresponding products can also be ob-
tained in good yields (3s－3v). Additionally hydrazide
Chin. J. Chem. 2017, XX, 1—X
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Bao et al.
FULL PAPER
substrates with disubstitution on the aryl ring (3w, 3x),
could also be used to obtain the corresponding oxadia-
zoles in excellent yields. We are glad to observe that
even hydrazide substituted with a sensitive terminal al-
kynyl group reacted smoothly to give the target product
3y in 64% yield. Since terminal alkynes can be used for
further transformations such as Sonogashira cross cou-
pling, the success of this substrate will significantly ex-
pand the scope of this reaction. For alkyl hydrazide, we
can also get the desired product 3ac. In addition to cy-
clohexyl isocyanide, other isocyanides such as
tert-butylisocyanide, phenyl isocyanide also worked
well and the desired products were produced in good
yields as well (3z, 3aa, 3ab).
sulfur powder as the reaction substrates under standard
conditions and the product 2aa was formed in 96%
yield by GC (Scheme 3b). Since we suspect that 2aa
was the actual intermediate in the reaction, we directly
used 2aa as the reaction substrate under standard condi-
tions and the desired product 3b was formed in 87%
yield by GC (Scheme 3c). Moreover, we believe that the
reaction of 1b with 2aa will generate 2ab, so we pre-
pared 2ab and subjected it to our reaction condition.
Under standard conditions, the desired product 3b was
formed in 92% yield by GC (Scheme 3d). These control
experiments showed that this reaction proceeds via the
formation of 2aa and 2ab intermediates to produce the
final product 3b.
In order to understand the mechanism of the reaction
better, we conducted a series of control experiments
(Scheme 3). First, without addition of sulfur powder, 1b
and 2a were added to the sealed tube under the standard
conditions for reaction. However, the desired product 3b
was not detected (Scheme 3a). Then we used 2a and
Based on our experimental results and previous lit-
erature reports, we propose a possible mechanism using
1b and 2a as examples (Scheme 4). Initially, isocyano-
cyclohexane reacts with elemental sulfur to form inter-
mediate 2aa, which can be detected by GC-MS. Then
2aa further reacts with benzoylhydrazide and undergoes
Scheme 2 Synthesis of 2-amino-1,3,4-oxadiazolesa,b
H
N
O
R2
O
S8
DMSO,130 °C
NH2
R2NC
R1
+
R1
N
N
H
N
3
1
2
R1 = aryl, alkyl, alkyne, heterocyclic
R2 = cyclohexyl, phenyl, t-butyl
H
R1 = p-Me, 3a, 87%
N
O
H,
3b, 85%
R1
S
N
N
p-t-Bu, 3c, 84%
p-OMe, 3d, 86%
p-F,
p-Cl,
p-Br,
3s, 75%
O
3e, 84%
3f, 91%
3g, 82%
3h, 76%
H
N
NH
N
O
N
O
N
N
p
-I,
p-CHO, 3i, 81%
3t, 72%
p-OH,
3j, 87%
H
N
o-NH2
o-OH,
o-F,
o-Cl,
o-Br,
o-I,
3k, 84%
O
3l, 81%
3m, 83%
3n, 82%
3o, 78%
3p, 74%
3q, 81%
N
N
N
H
N
O
3u, 72%
N
N
H
m-Me,
N
O
3ac, 57%
m-NO2,
3r, 73%
N
N
3y, 64%
H
H
H
N
N
N
O
N
O
O
Br
Me
N
N
N
N
N
N
Me
Cl
3v, 76%
3w, 84%
3x, 82%
H
H
H
O
N
N
O
O
N
O
N
N
N
N
N
N
Me
3ab, 76%
3z, 83%
3aa, 81%
a Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), sulfur (0.45 mmol), DMSO (2 mL), 130 oC, air, 4 h.
b Isolated yield.
6
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© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—8

Synthesis of 2-Amino-1,3,4-oxadiazoles
Scheme 3 Control experiments
O
H
N
NH2
N
O
N
NC
130 °C
DMSO
(a)
(b)
+
H
N
1b
3b
0%
2a
NC
130 °C
DMSO
N
C S
+
S8
2aa
96%
2a
O
H
NH2
N
N
130 °C
DMSO
O
S
C
N
H
+
(c)
(d)
N
N
1b
2aa
3b
87%
O
H
H
N
H
130°C
DMSO
N
N
O
N
H
N
S
N
2ab
3b
92%
Scheme 4 Proposed mechanism
Acknowledgement
intramolecular transformation to produce intermediate
2ab. It is clear that 2ab is one of thiourea derivatives
which can eliminate one molecule of H2S by heating.
Thus this step can provide the carbodiimide intermedi-
ate 2ac,[16] which is converted to 2ad by keto-enol tau-
tomerism. Finally, 2ad undergoes intramolecular nu-
cleophilic attack to produce produc 3b.
We are grateful for financial support from the Na-
tional Natural Science Foundation of China (Nos.
21502049 and 51573040), and the Planned Science and
Technology Project of Hunan Province, China (No.
2015WK3003).
References
Conclusions
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[2] (a) Khalilullah, H.; Ahsan, M. J.; Hedaitullah, M.; Khan, S.; Ahmed,
B. Mini-Rev. Med. Chem. 2012, 12, 789; (b) de Oliveira, C. S.; Lira,
B. F.; Barbosa-Filho, J. M.; Lorenzo, J. G.; de Athayde-Filho, P. F.
Molecules 2012, 17, 10192; (c) Yu, W.; Huang, G.; Zhang, Y.; Liu,
H.; Dong, L.; Yu, X.; Li, Y.; Chang, J. J. Org. Chem. 2013, 78,
10337; (d) Efimova, Y. A.; Karabanovich, G. G.; Artamonova, T. V.;
Koldobskii, G. I. Russ. J. Org. Chem. 2009, 45, 1241; (e) Niu, P.;
Kang, J.; Tian, X.; Song, L.; Liu, H.; Wu, J.; Yu, W.; Chang, J. J.
Org. Chem. 2015, 80, 1018; (f) Chen, L.; Wang, P.; Li, Z.; Zhou, L.;
Wu, Z.; Song, B.; Yang, S. Chin. J. Org. Chem. 2016, 34, 1236 (in
Chinese); (g) Lei, Q.; Qin, S. S.; Feng, C. C.; Li, P. P.; Zhang, Q. Q.;
In conclusion, we have developed an efficient ele-
mental sulfur-promoted cyclization reaction. This
method provides a simple route for the direct synthesis
of valuable 2-amino-1,3,4-oxadiazoles from easily
available hydrazides and isonitriles, with the advantages
of broad substrate range, and good functional group tol-
erance, which is of potential industrial significance.
Further studies of the synthetic compounds with biolog-
ical activities are ongoing in our laboratory.
Chin. J. Chem. 2017, XX, 1—X
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