Synthesis of 2-amino-1,3,4-oxadiazoles from isoselenocyanates via cyclodeselenization

Article abstract of DOI:10.1016/j.tet.2011.05.100

An efficient one-pot method to access 2-amino-1,3,4-oxadiazoles from isoselenocyanates and hydrazides or dihydrazides was developed via cyclodeselenization. Without any harsh reagents, various 2-amino-1,3,4- oxadiazoles were obtained in considerably high

Full text of DOI:10.1016/j.tet.2011.05.100

Tetrahedron 67 (2011) 5369e5374
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2-amino-1,3,4-oxadiazoles from isoselenocyanates via
cyclodeselenization
*
Yuanyuan Xie , Junli Liu, Ping Yang, Xiangjun Shi, Jianjun Li
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Chaowang Road,
Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot method to access 2-amino-1,3,4-oxadiazoles from isoselenocyanates and hydrazides
or dihydrazides was developed via cyclodeselenization. Without any harsh reagents, various 2-amino-
1,3,4-oxadiazoles were obtained in considerably high yields (82%e97%) and purities (>99%) directly with
simple crystallization in ethanol. And the formed precipitated Se powder during the reaction could be
recycled for preparation of isoselenocyanates efficiently. A plausible mechanism is proposed for the
formation of the target products.
Received 29 March 2011
Received in revised form 17 May 2011
Accepted 24 May 2011
Available online 30 May 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Isoselenocyanates
Cyclodeselenization
Selenium
Heterocycle
Oxadiazole
R1
R2
NH
O
X
R2
NH
1. Introduction
O
N
Coupling
Agent
R1
R1
X = O Method (i)
Method (ii)
N
Oxadiazoles are popular bioisosteres for the biologically active
amides, esters and ureas.1 In particular, 2-amino-1,3,4-oxadiazoles
are present in a wide range of pharmaceutically potent agents,2
generally including antimicrobial agents,3 anticancer agents,4
anti-inflammatory agents5 and anticonvulsant agents.6 In addi-
tion, they are utilized as intermediates to prepare various bi-
HN NH
O
S
Activate,
NHR2R3
R1
R2
R3
O
N
O
Method (iii)
N
N
N
H
N
ologically important compounds.7 As
a result, a variety of
Scheme 1. Literature methods for preparation of 2-amino-1,3,4-oxadiazoles.
approaches have been developed to obtain 2-amino-1,3,4-
oxadiazoles (Scheme 1).
method (iii) provides ready access to N,N-disubstituted 2-amino-
1,3,4-oxadiazoles, it only prepares 2-arylamino-1,3,4-oxadiazoles
in moderate yields.10
Generally, a large number of methods for the synthesis of 2-
amino-1,3,4-oxadiazoles are available in the literatures, which
could be broadly classified as, (i) cyclodehydration of semicarbazide
derivatives,8 (ii) cyclodesulfurization of thiosemicarbazide de-
rivatives,9 (iii) amination of oxadiazol-2-one at C2.10 However,
there are limitations to these methods, respectively. Method (i)
frequently causes significant byproduct formation and gives poor
yield, when POCl3,8a tosyl chloride,7 Burgess reagents8b,c and other
harsh conditions8dꢀg were employed. For method (ii), various
desulfurizing reagents have to be utilized, including I2/NaOH,9a
carbodiimides(DCC, EDC) or PS-carbodiimides,9bed tosyl chlor-
ide9e,f and stoichiometric mercury salts,9g,h which often lead to
inconvenient handling and undesirable byproducts. Although
Isoselenocyanates are widely employed in the synthesis of
selenium-containing heterocycles as a result of their convenient
preparation, low toxicity, relative stability and excellent reactivity.11
To the best of our knowledge, however, there are few studies on
synthesis of non-selenium-containing compounds from iso-
selenocyanates.11a Therefore, we were attracted to prepare non-
selenium-containing compounds from isoselenocyanates via
deselenization processes. Very recently, we have reported efficient
synthesis of 2-aminobenzimidazoles, 2-aminobenzoxazoles and 2-
aminobenzothiazoles from isoselenocyanates via cyclodeseleni-
zation.12 Herein, based on these results, we investigated the
cyclodeselenization of selenosemicarbazide derivatives, which
were obtained by the reaction of various isoselenocyanates with
hydrazides.
* Corresponding author. E-mail address: Pharmlab@zjut.edu.cn (Y. Xie).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.100

5370
Y. Xie et al. / Tetrahedron 67 (2011) 5369e5374
Table 2
2. Results and discussion
Preparation of 5-phenyl(alkyl)-2-arylamino-1,3,4-oxadiazoles
2
from iso-
Yieldc (%)
selenocyanates 3a
Initially selenosemicarbazide13 1Aa was selected to optimize the
reaction conditions. The effects of different solvents, reaction
temperatures and bases were investigated. The results were sum-
marized in Table 1. Among the solvents, DMF was proved to be the
optimal one, and the result might depend on the solubility of
selenosemicarbazide. A variation of the reaction temperature from
50 to 100 ꢁC causes positive effect on both reaction rate and yield. It
was noteworthy, the yield was not improved when the reaction was
carried out at 100 ꢁC, compared with 90 ꢁC. So the optimal reaction
conditions were established as using DMF as solvent, with the
temperature of 90 ꢁC without addition of any base.
Entry
R1
R2
Timesb (h)
Products
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
CH3
4.0
5.0
3.5
5.0
5.5
3.5
5.0
6.0
6.5
5.0
6.0
6.5
3.0
4.0
3.0
3.5
3.5
3.0
3.0
3.0
3.5
3.5
8.0
8.5
8.0
8.0
3.0
4.0
3.0
3.0
3.5
2Aa
2Ba
2Ca
2Da
2Ea
2Fa
2Ga
2Ab
2Bb
2Cb
2Db
2Gb
2Ac
2Bc
2Cc
2Dc
2Gc
2Ad
2Cd
2Dd
2Gd
2Hd
2Ae
2Be
2Ce
2De
2Af
2Bf
95, 91d
93, 93d
97, 96d
92
90
95
90
94
93
95
91
90
96
94
97
92
91
95
97
91
90
93
87
85
88
84
94
92
95
92
4-ClC6H4
4-MeOC6H4
2-MeC6H4
2-EtC6H4
3-MeC6H4
1-Naphthyl
C6H5
4-ClC6H4
4-MeOC6H4
2-MeC6H4
1-Naphthyl
C6H5
4-ClC6H4
4-MeOC6H4
2-MeC6H4
1-Naphthyl
C6H5
4eMeOC6H4
2-MeC6H4
1-Naphthyl
4-BrC6H4
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Table 1
Optimization of reaction conditions for the construction of 2-amino-1,3,4-
oxadiazoles via cyclodeselenization
N
O
O
N
H
N
H
N
N
H
N
H
Se
1Aa
2Aa
Entry
Solvents
Base
Temp (ꢁC)
Timesa (h)
Yieldb (%)
4-ClC6H4
4-MeOC6H4
2-MeC6H4
C6H5
4-ClC6H4
4-MeOC6H4
2-MeC6H4
1-Naphthyl
CH3
CH3
CH3
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
1
2
3
4
5
6
7
8
CH2Cl2
EtOAc
MeCN
EtOH
THF
TEA
TEA
TEA
TEA
TEA
d
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
90
50
70
90
100
48
48
48
48
10
48
3
24
10
4
None
None
15
<10
75
10
95
85
88
2Cf
2Df
2Gf
THF
91
DMF
DMF
DMF
DMF
DMF
TEA
d
a
Isoselenocyanates 3 (1 mmol) and hydrazides 4 (1 mmol) were heated at 90 ꢁ
C
9
10
11
d
in DMF.
d
95
95
b
c
Monitored by TLC, until isoselenocyanate 3 was fully consumed.
Isolated yield.
Using reproduced isoselenocyanates.
d
3
d
a
Monitored by TLC, until selenosemicarbazide 1Aa was fully consumed.
Isolated yield.
b
Electron-donating group (Table 2, entries 3 and 6) substituted
compounds showed slightly higher reactivity with slightly higher
yields than electron withdrawing group (Table 2, entry 2). However,
when the methyl or ethyl group attached to the ortho position of
the phenyl isoselenocyanate (Table 2, entries 4 and 5), the reaction
yields were decreased due to the steric effect. Moreover, naphthyl
isoselenocyanate was also an appropriate reactant for this reaction,
providing the desired product in 90% yield (Table 2, entry 7).
The applicability of hydrazides 4 was also studied. Firstly, dif-
ferent para-substituted benzoyl hydrazines were treated with iso-
Considering that selenosemicarbazide (1Aa) could be prepared
conveniently from isoselenocyanate 3A and hydrazide 4a, we
thought the procedure could be simplified. Then one-pot reaction
of isoselenocyanate 3A and hydrazide 4a was performed in DMF at
90 ꢁC (Scheme 2). The result was exciting, and 2-amino-1,3,4-
oxadiazole 2Aa was still obtained in 95% yield (Table 2, entry 1),
whereas the highest reported yield in the literature is 67%.9b,d,10 It
should be noted, the product could be conveniently afforded in high
purity after simple crystallization process, and the selenium pow-
der filtered off could be reused for preparing isoselenocyanates 3.11a
Subsequently, the scope of the reaction substrates was in-
vestigated under the optimized conditions. Various iso-
selenocyanates 3 and hydrazides 4 were conducted in DMF at 90 ꢁC,
and the results were summarized in Table 2. A variety of 5-phenyl-
2-arylamino-1,3,4-oxadiazoles 2 were obtained in excellent yields
ranging from 90 to 97% when substituted isoselenocyanates 3
reacted with hydrazide 4a. The nature of R1 group on the iso-
selenocyanates 3 affected the reaction rate and yields a little.
selenocyanates
3 under the optimized conditions, and the
corresponding products were obtained in excellent yields (Table 2,
entries 8e22). The yields could be affected slightly when the sub-
stituents were bonded to the para position of benzoyl hydrazine.
Then acetyl hydrazine and isonicotinohydrazide were also in-
vestigated.
5-Methyl-2-phenylamino-1,3,4-oxadiazoles
were
obtained in satisfactory yields (Table 2, entries 23e26), though
generally lower than those of 5-aryl-2-phenylamino-1,3,4-
oxadiazoles. Isonicotinohydrazide also provided the desired prod-
ucts with excellent yields comparable to benzoyl hydrazines (Table
2, entries 27e31).
To further examine the generality of this procedure, the reaction
of dihydrazides14 with isoselenocyanates was also studied. Grati-
fyingly, the desired products bis(1,3,4-oxadiazoles) were also
obtained in excellent yields under the standard reaction con-
ditions(Table 3).
A plausible mechanism is proposed for the formation of 2-
amino-1,3,4-oxadiazoles 2Aa (Scheme 3). Firstly, selenosemi-
carbazide 1Aa could be generated from isoselenocyanate 3A and
hydrazide 4a rapidly. Subsequently, the intramolecular cyclization
of 1Aa produced the intermediate 7 via attack of oxygen atom on
H
N
O
O
R1
N
R2
R1
C
DMF
90 o
R2
4a-4f
NHNH2
+
Se
3A-3H
N
N
C
2
3A: R1 = C6H5 ; 3B: R1 = 4-ClC6H4 ; 3C: R1 =4-MeOC6H4 ;
3D: R1 = 2-MeC6H4; 3E: R1 = 2-EtC6H4 ; 3F: R1 = 3-MeC6H4 ;
3G: R1 = 1-Naphthyl; 3H: R1=4-BrC6H4
4a: R2 = C6H5; 4b:R2 = 4-BrC6H4; 4c: R2 = 4-MeOC6H4;
4d: R2 = 4-MeC6H4; 4e: R2 = CH3; 4f: R2 = 4-Pyridyl
Scheme 2. Preparation of 5-phenyl(alkyl)-2-arylamino-1,3,4-oxadiazoles 2 from iso-
selenocyanates 3.

Y. Xie et al. / Tetrahedron 67 (2011) 5369e5374
5371
Table 3
4.2. General procedure for the synthesis of 2-amino-1,3,4-
oxadiazoles 2
Preparation of bis(1,3,4-oxadiazoles) from isoselenocyanates and dihydrazides via
cyclodeselenizationa
O
O
R
NH
HN
N
R
Phenyl isoselenocyanate 3A (0.182 g, 1 mmol) and benzoyl hy-
drazine 4a (0.136 g, 1 mmol) were added to DMF (10 mL) with
magnetic stirring. The mixture was heated to 90 ꢁC for 4 h. When the
reaction was completed as monitored by TLC, the mixture was
cooled to rt. The black selenium powder was filtered off and washed
with CH2Cl2 (10 mL). The recovery rate of black seleniumwas around
95%. The combined filtrate was concentrated in vacuo. The residue
was crystallized, filtered and washed by ethanol (10 mL) to give N,5-
diphenyl-1,3,4-oxadiazol-2-amine 2Aa (0.225 g, yield 95%, purity
99%) as white solid. Mp: 214.9e215.9 ꢁC; lit. mp:15 215 ꢁC; IR (KBr):
DMF
90oC
N
H2N
NH2
R
C
+
O
O
N
H
N
H
n
Se
N
N
N
n
6a-6e
5a-5c
5a, n = 0; 5b, n = 1; 5c, n = 4.
Entry
R
Compounds 5
Timesb (h)
Products
Yieldc (%)
1
2
3
4
5
4-ClC6H4
5a
5b
5c
5c
5c
4
10
6
5
4
6a
6b
6c
6d
6e
92
82
89
90
93
C6H5
C6H5
4-MeOC6H4
4-ClC6H4
nmax¼3262, 3053, 1620, 1604, 1579, 1501, 1243 cmꢀ1
;
1H NMR
a
(400 MHz, DMSO-d6): d 10.69 (br,1H, NH), 7.92e7.89 (m, 2H), 7.63 (d,
Isoselenocyanates 3 (1 mmol) and dihydrazides 5 (0.5 mmol) were heated at
90 ꢁC in DMF.
J¼8.4 Hz, 2H), 7.60e7.56 (m, 3H), 7.37 (t, J¼7.6 Hz, 2H), 7.02 (t,
b
c
J¼7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
d 159.9, 157.7, 138.6,
131.0, 129.4 (CHꢂ2), 129.1 (CHꢂ2), 125.5 (CHꢂ2), 123.9, 121.9, 117.1
Monitored by TLC, until isoselenocyanate 3 was fully consumed.
Isolated yield.
(CHꢂ2); MS (EI): m/z (%)¼237 (Mþ, 86), 77 (100).
O
O
N
Se
90 oC
4.2.1. N-(4-Chlorophenyl)-5-phenyl-1,3,4-oxadiazol-2-amine (2Ba,
Table 2)16. Light yellow solid; mp: 137.1e138.6 ꢁC; IR (KBr):
N
Ph
NHPh
NH2
Ph
C
Ph
N
H
Se
+
NH
nmax¼3274, 3067, 1642, 1587, 1488, 1227, 1045, 758 cmꢀ1
;
1H NMR
H
(400 MHz, DMSO-d6):
d
10.05 (br, 1H), 8.06 (d, J¼8.0 Hz, 1H),
3A
4a
1Aa
7.92e7.89 (m, 2H), 7.59e7.57 (m, 3H), 7.53 (dd, J1¼1.6 Hz, J2¼8.0 Hz,
1H), 7.41 (t, J¼8.0 Hz, 1H), 7.16 (t, J¼8.0 Hz, 1H); 13C NMR (100 MHz,
90 oC
DMSO-d6):
d
160.5, 158.5, 135.2, 131.1, 129.8, 129.3 (CHꢂ2), 127.9,
Ph
Se + H2O 1/2 O2
O
125.6 (CHꢂ2), 124.8, 123.9, 123.8, 122.1; MS (EI): m/z (%)¼273
Ph
NHPh
SeH
NHPh
O
(Mþþ2, 17), 271 (Mþ, 51), 77 (100).
N
N
N
N
2Aa
4.2.2. N-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazol-2-amine
H
(2Ca, Table 2)16. White solid; mp: 217.1e217.8 ꢁC; IR (KBr):
7
nmax¼3260, 3052, 1615, 1583, 1513, 1234, 1182, 1036, 827 cmꢀ1
;
1H
Scheme 3. Plausible mechanism for the formation of 2-amino-1,3,4-oxadiazoles 2.
NMR (400 MHz, DMSO-d6):
d 10.46 (s, 1H), 7.90e7.88 (m, 2H),
7.58e7.57 (m, 3H), 7.54 (d, J¼8.8 Hz, 2H), 6.96 (d, J¼8.8 Hz, 2H), 3.74
(s, 3H); 13C NMR (100 MHz, DMSO-d6):
d
160.2, 157.5, 154.5, 131.9,
carbonyl to selenocarbonyl. The intermediate 7 was then converted
to the 2-amino-1,3,4-oxadiazole 2Aa via cyclodeselenization with
the aid of oxygen. To confirm this process, the reaction was per-
formed in a nitrogen-protected vessel, no desired product and se-
lenium powder were detected. This result meant that oxygen was
crucial to this reaction. The detailed discussion was appeared in our
previous paper.12
130.8, 129.3 (CHꢂ2), 125.4 (CHꢂ2), 124.0, 118.6 (CHꢂ2), 114.3
(CHꢂ2), 55.2; MS (EI): m/z (%)¼267 (Mþ, 100).
4.2.3. N-(2-Methylphenyl)-5-phenyl-1,3,4-oxadiazol-2-amine (2Da,
Table 2). White solid; mp: 164.0e165.6 ꢁC; IR (KBr): nmax¼3284,
3060, 1646, 1601, 1585, 1491, 1245, 1051, 757 cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6):
d
9.67 (s, 1H), 7.88 (d, J¼3.6 Hz, 2H), 7.79 (d,
3. Conclusion
J¼8.4 Hz, 1H), 7.56e7.55 (m, 3H), 7.23 (d, J¼6.0 Hz, 2H), 7.04 (t,
J¼7.2 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d 161.1,
In conclusion, a facile and efficient approach to the synthesis of
2-amino-1,3,4-oxadiazoles was developed via a one-pot cyclo-
deselenization reaction of easily available isoselenocyanates and
hydrazides. Without using any deselenizing reagents, the desired
products could be obtained with excellent yields, compared with
the previous reported approaches. The products were purified
easily by crystallization in ethanol, and the complicated purifica-
tion procedures were avoided. In addition, the formed selenium
powder during the reaction could be recycled for preparation of
isoselenocyanates.
158.0, 136.7, 130.9, 130.7, 129.3 (CHꢂ2), 129.0, 126.6, 125.5 (CHꢂ2),
124.0, 123.9, 121.0, 18.0; MS (EI): m/z (%)¼251 (Mþ, 100); HRMS-ESI:
calcd for C15H14N3O (MþH)þ: 252.1137; found: 252.1147.
4.2.4. N-(2-Ethylphenyl)-5-phenyl-1,3,4-oxadiazol-2-amine (2Ea, Table
2). Light yellow solid; mp: 113.1e114.7 ꢁC; IR (KBr): nmax¼3273, 3054,
1638, 1597, 1585, 1478, 1251, 1045, 747 cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6):
d
9.63 (s, 1H), 7.87e7.84 (m, 2H), 7.73 (d, J¼7.6 Hz, 1H),
7.56e7.54 (m, 3H), 7.25e7.20 (m, 2H), 7.09 (td, J1¼7.6 Hz, J2¼1.2 Hz,
1H), 2.71 (q, J¼7.6 Hz, 2H), 1.16 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6):
d
161.2, 157.7, 135.7, 135.1, 130.6, 129.1 (CHꢂ2), 128.6,
4. Experimental
4.1. General
126.3, 125.2 (CHꢂ2), 124.2, 123.8, 121.8, 23.7, 14.3; MS (EI): m/z (%)¼
265 (Mþ, 99), 145 (96), 77 (100); HRMS-ESI: calcd for C16H16N3O
(MþH)þ: 266.1293; found: 266.1290.
€
Mp: Buchi B-540 apparatus; uncorrected. IR Spectra: Nicolet
4.2.5. N-(3-Methylphenyl)-5-phenyl-1,3,4-oxadiazol-2-amine (2Fa,
Table 2). Yellow solid; mp: 149.3e152.0 ꢁC; IR (KBr): nmax¼3166,
Avatar-370 spectrometer, in KBr; in cmꢀ1. 1H and 13C NMR Spectra:
Varian Mercury Plus-400 instrument, in (d6) DMSO at 400 and
3056, 1665, 1601, 1585, 1506, 1246, 1052, 775, 692 cmꢀ1 1H NMR
;
100 MHz, resp.;
d
in parts per million, J in hertz. ESI-MS: Thermo
(400 MHz, DMSO-d6):
(m, 3H), 7.43e7.40 (m, 2H), 7.23 (t, J¼7.6 Hz, 1H), 6.82 (d, J¼7.2 Hz,
1H), 2.32 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
159.6, 157.4,
d 10.59 (s, 1H), 7.89e7.87 (m, 2H), 7.58e7.54
Finnigan LCQ Advantage instrument; in m/z. HRMS: Agilent 6210 TOF
instrument.
d

5372
Y. Xie et al. / Tetrahedron 67 (2011) 5369e5374
138.3, 138.1, 130.7, 129.1 (CHꢂ2), 128.7, 125.3 (CHꢂ2), 123.7, 122.5,
117.4, 114.1, 21.4; MS (EI): m/z (%)¼251 (Mþ, 100); HRMS-ESI: calcd
for C15H14N3O (MþH)þ: 252.1137; found: 252.1134.
123 (100); HRMS-ESI: calcd for C18H13BrN3O (MþH)þ: 366.0242;
found: 366.0235.
4.2.12. 5-(4-Methoxyphenyl)-N-phenyl-1,3,4-oxadiazol-2-amine
(2Ac, Table 2). White solid; mp: 204.9e205.5 ꢁC; IR (KBr):
nmax¼3256, 3052, 1624, 1609, 1580, 1501, 1254, 1030, 833 cmꢀ1; 1H
4.2.6. N-(Naphthalen-1-yl)-5-phenyl-1,3,4-oxadiazol-2-amine (2Ga,
Table 2)17. Light yellow solid; mp: 192.0e193.0 ꢁC; IR (KBr):
nmax¼3146, 3057, 1648, 1621, 1597, 1577, 1491, 1242,1056, 776 cmꢀ1
;
NMR (400 MHz, DMSO-d6):
d
10.58 (s, 1H), 7.81 (d, J¼9.2 Hz, 2H),
1H NMR (400 MHz, DMSO-d6):
d
10.29 (br, 1H), 8.34 (d, J¼8.8 Hz,
7.60 (d, J¼8.8 Hz, 2H), 7.34 (dd, J1¼7.6 Hz, J2¼8.8 Hz, 2H), 7.10 (d,
1H), 8.08 (d, J¼7.6 Hz, 1H), 7.98e7.91 (m, 3H), 7.71 (d, J¼8.4 Hz, 1H),
J¼9.2 Hz, 2H), 6.99 (t, J¼7.6 Hz,1H), 3.82 (s, 3H); 13C NMR (100 MHz,
7.58e7.53 (m, 6H); 13C NMR (100 MHz, DMSO-d6):
d
161.3, 158.2,
DMSO-d6):
d
161.0, 159.2, 157.4, 138.5, 128.9 (CHꢂ2), 127.1 (CHꢂ2),
134.0, 133.9, 131.0, 129.4 (CHꢂ2), 128.3, 126.2, 125.9 (CHꢂ2), 125.8,
125.6 (CHꢂ2), 124.0, 123.7, 122.2, 116.6; MS (EI): m/z (%)¼287 (Mþ,
67), 77 (100).
121.5, 116.8 (CHꢂ2), 116.1, 114.6 (CHꢂ2), 55.4; MS (EI): m/z (%)¼267
(Mþ, 100); HRMS-ESI: calcd for C15H14N3O2 (MþH)þ: 268.1086;
found: 268.1082.
4.2.7. 5-(4-Bromophenyl)-N-phenyl-1,3,4-oxadiazol-2-amine (2Ab,
Table 2). White solid; mp: 260.5e261.9 ꢁC; IR (KBr): nmax¼3260,
3056, 1620, 1600, 1585, 1573, 1502, 1234, 1046, 830 cmꢀ1; 1H NMR
4.2.13. N-(4-Chlorophenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-
amine (2Bc, Table 2). Grey solid; mp: 277.1e278.9 ꢁC; IR (KBr):
nmax¼3266, 3072, 1626, 1610, 1576, 1487, 1243, 1025, 840 cmꢀ1; 1H
(400 MHz, DMSO-d6):
d
10.72 (br, 1H), 7.82 (d, J¼8.4 Hz, 2H), 7.77
NMR (400 MHz, DMSO-d6):
d
10.76 (s, 1H), 7.81 (d, J¼8.8 Hz, 2H),
(d, J¼8.4 Hz, 2H), 7.61 (d, J¼8.4 Hz, 2H), 7.36 (t, J¼7.6 Hz, 2H), 7.02
7.62 (d, J¼8.8 Hz, 2H), 7.40 (d, J¼8.8 Hz, 2H), 7.11 (d, J¼8.8 Hz, 2H),
(t, J¼7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
d
160.1, 157.1,
3.83 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d
161.0, 159.0, 157.6,
138.5, 132.4 (CHꢂ2), 129.1 (CHꢂ2), 127.4 (CHꢂ2), 124.3, 123.1,
122.0, 117.2 (CHꢂ2); MS (EI): m/z (%)¼317 (Mþþ2, 94), 315 (Mþ,
100).
137.5, 128.7 (CHꢂ2), 127.2 (CHꢂ2), 125.1, 118.3 (CHꢂ2), 116.0, 114.6
(CHꢂ2), 55.4; MS (EI): m/z (%)¼303 (Mþþ2, 24), 301 (Mþ, 72), 133
(100); HRMS-ESI: calcd for C15H13ClN3O2 (MþH)þ: 302.0696;
found: 302.0704.
4.2.8. 5-(4-Bromophenyl)-N-(4-chlorophenyl)-1,3,4-oxadiazol-2-
amine (2Bb, Table 2). White solid; mp: 257.1e257.8 ꢁC; IR (KBr):
nmax¼3258, 3057, 1620, 1600, 1585, 1571, 1496, 1237, 1049,
4.2.14. N,5-Bis(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine (2Cc,
Table 2). Grey solid; mp: 171.7e172.4 ꢁC; IR (KBr): nmax¼3255,
833 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6):
d
10.87 (s, 1H, NH), 7.80
3057, 1610, 1580, 1501, 1250, 1052, 833 cmꢀ1 1H NMR (400 MHz,
;
(d, J¼8.8 Hz, 2H), 7.77 (d, J¼8.8 Hz, 2H), 7.62 (d, J¼8.8 Hz, 2H), 7.41
DMSO-d6):
J¼8.8 Hz, 2H), 7.10 (d, J¼8.8 Hz, 2H), 6.93 (d, J¼8.8 Hz, 2H), 3.83
(s, 3H), 3.73 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
160.9,
159.5, 157.1, 154.1, 131.8, 127.0 (CHꢂ2), 118.2 (CHꢂ2), 116.2, 114.6
(CHꢂ2), 114.1 (CHꢂ2), 55.4, 55.2; MS (EI): m/z (%)¼297 (Mþ,
100); HRMS-ESI: calcd for C16H16N3O3 (MþH)þ: 298.1192; found:
298.1187.
d
10.34 (s, 1H), 7.80 (d, J¼8.8 Hz, 2H), 7.51 (d,
(d, J¼8.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6):
d 159.4, 156.9,
137.2, 132.1 (CHꢂ2), 128.7 (CHꢂ2), 127.2 (CHꢂ2), 125.3, 124.1, 122.7,
118.5 (CHꢂ2); MS (EI): m/z (%)¼353 (Mþþ4, 25), 351 (Mþþ2, 100),
349 (Mþ, 84); HRMS-ESI: calcd for C14H10BrClN3O (MþH)þ:
349.9696; found: 349.9693.
d
4.2.9. 5-(4-Bromophenyl)-N-(4-methoxyphenyl)-1,3,4-oxadiazol-2-
amine (2Cb, Table 2). White solid; mp: 262.0e263.2 ꢁC; IR (KBr):
nmax¼3264, 3060, 1617, 1600, 1588, 1573, 1513, 1235, 1068,
4.2.15. 5-(4-Methoxyphenyl)-N-(2-methylphenyl)-1,3,4-oxadiazol-2-
amine (2Dc, Table 2). Grey solid; mp: 153.8e154.4 ꢁC; IR (KBr):
nmax¼3289, 3044, 1658, 1616, 1602, 1504, 1253, 1045, 842 cmꢀ1; 1H
831 cmꢀ1 1H NMR (400 MHz, DMSO-d6):
; d 10.47 (s, 1H), 7.80 (d,
J¼9.2 Hz, 2H), 7.77 (d, J¼8.8 Hz, 2H), 7.51 (d, J¼9.2 Hz, 2H), 6.95 (d,
NMR (400 MHz, DMSO-d6): d 9.54 (s, 1H), 7.81e7.77 (m, 3H),
J¼8.8 Hz, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d
160.0,
7.23e7.20 (m, 2H), 7.10 (d, J¼9.2 Hz, 2H), 7.01 (td, J1¼7.2 Hz,
156.6, 154.2, 132.2 (CHꢂ2), 131.5, 127.1 (CHꢂ2), 124.0, 122.9, 118.5
(CHꢂ2), 114.2 (CHꢂ2), 55.2; MS (EI): m/z (%)¼347 (Mþþ2, 94), 345
(Mþ, 100); HRMS-ESI: calcd for C15H13BrN3O2 (MþH)þ: 346.0191;
found: 346.0184.
J2¼1.2 Hz, 1H), 3.83 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, DMSO-
d6):
d
160.9, 160.3, 157.6, 136.5, 130.4, 128.5, 127.0 (CHꢂ2), 126.3,
123.4, 120.5, 116.2, 114.6 (CHꢂ2), 55.4, 18.0; MS (EI): m/z (%)¼281
(Mþ, 69), 135 (100); HRMS-ESI: calcd for C16H16N3O2 (MþH)þ:
282.1243; found: 282.1239.
4.2.10. 5-(4-Bromophenyl)-N-(2-methylphenyl)-1,3,4-oxadiazol-2-
amine (2Db, Table 2). Grey solid; mp: 193.5e195.3 ꢁC; IR (KBr):
4.2.16. 5-(4-Methoxyphenyl)-N-(naphthalen-1-yl)-1,3,4-oxadiazol-
2-amine (2Gc, Table 2). White solid; mp: 231.9e232.8 ꢁC; IR (KBr):
nmax¼3223, 3052, 1633, 1611, 1578, 1503, 1256, 1032, 793 cmꢀ1; 1H
nmax¼3285, 1655, 1600, 1481, 1246, 1047, 835, 743 cmꢀ1
;
1H NMR
(400 MHz, DMSO-d6):
d 9.70 (s, 1H), 7.81e7.75 (m, 5H),
7.25e7.21 (m, 2H), 7.05 (td, J1¼7.6 Hz, J2¼1.2 Hz, 1H), 2.30 (s,
NMR (400 MHz, DMSO-d6): d 10.38 (br, 1H, NH), 8.33e8.30 (m, 1H),
3H); 13C NMR (100 MHz, DMSO-d6):
d
160.9, 157.0, 136.3, 132.2
8.06 (d, J¼7.6 Hz, 1H), 7.95e7.93 (m, 1H), 7.84 (d, J¼8.8 Hz, 2H), 7.68
(CHꢂ2), 130.4, 128.9, 127.1 (CHꢂ2), 126.3, 124.0, 123.8, 123.0,
120.9, 18.0; MS (EI): m/z (%)¼331 (Mþþ2, 63), 329 (Mþ, 66), 131
(100); HRMS-ESI: calcd for C15H13BrN3O (MþH)þ: 330.0242;
found: 330.0238.
(d, J¼8.0 Hz, 1H), 7.57e7.51 (m, 3H), 7.12 (d, J¼9.2 Hz, 2H), 3.84 (s,
3H, OCH3); 13C NMR (100 MHz, DMSO-d6):
d 161.0, 160.6, 157.9,
133.9, 133.6, 128.1, 127.2 (CHꢂ2), 126.0, 125.7, 125.6, 125.4, 123.3,
122.0, 116.2, 116.1, 114.6 (CHꢂ2), 55.4; MS (EI): m/z (%)¼317 (Mþ,
100); HRMS-ESI: calcd for C19H16N3O2 (MþH)þ: 318.1243; found:
318.1243.
4.2.11. 5-(4-Bromophenyl)-N-(naphthalen-1-yl)-1,3,4-oxadiazol-2-
amine (2Gb, Table 2). Red solid; mp: 223.7e225.1 ꢁC; IR (KBr):
nmax¼3198, 3010, 1636, 1602, 1573, 1481, 1270, 1068, 828 cmꢀ1; 1H
4.2.17. 5-(4-Methylphenyl)-N-phenyl-1,3,4-oxadiazol-2-amine (2Ad,
Table 2)18. Pink solid; mp: 224.8e225.2 ꢁC; lit. mp:5 226e227 ꢁC; IR
NMR (400 MHz, DMSO-d6):
d
10.53 (s, 1H), 8.32 (d, J¼7.6 Hz, 1H),
8.06 (d, J¼7.6 Hz, 1H), 7.96 (d, J¼8.4 Hz, 1H), 7.84 (d, J¼8.4 Hz, 2H),
(KBr): nmax¼3287, 1619, 1577, 1500, 1247, 1048, 821, 753 cmꢀ1
;
1H
7.79 (d, J¼8.4 Hz, 2H), 7.72 (d, J¼8.0 Hz, 1H), 7.59e7.53 (m, 3H); 13C
NMR (400 MHz, DMSO-d6):
d
10.60 (s, 1H); 7.76 (d, J¼8.4 Hz, 2H);
NMR (100 MHz, DMSO-d6):
d
161.5, 157.5, 133.8 (CHꢂ2), 132.4
7.59 (dd, J1¼8.8 Hz, J2¼1.2 Hz, 2H); 7.37e7.32 (m, 4H); 6.99 (t,
(CHꢂ2), 128.3, 127.4 (CHꢂ2), 126.3, 125.9 (CHꢂ3), 124.3, 123.9,
J¼7.6 Hz, 1H); 2.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d 159.4,
123.2, 122.2, 116.8; MS (EI): m/z (%)¼367 (Mþþ2, 92), 365 (Mþ, 98),
157.5, 140.7, 138.4, 129.6 (CHꢂ2), 128.8 (CHꢂ2), 125.3 (CHꢂ2), 121.6,

Y. Xie et al. / Tetrahedron 67 (2011) 5369e5374
5373
120.9, 116.8 (CHꢂ2), 21.1; MS (ESI): m/z (%)¼250 (Mꢀꢀ1, 100);
HRMS-ESI: calcd for C15H14N3O (MþH)þ 252.1137; found: 252.1131.
d6):
d
159.7,156.3,153.9,132.0,118.1 (CHꢂ2),114.1 (CHꢂ2), 55.2,10.5;
MS (EI): m/z (%)¼205 (Mþ, 100); HRMS-ESI: calcd for C10H12N3O2
(MþH)þ: 206.0930; found: 206.0932.
4.2.18. N-(4-Methoxyphenyl)-5-(4-methylphenyl)-1,3,4-oxadia-zol-
2-amine (2Cd, Table 2). White solid; mp: 213.2e213.9 ꢁC; IR (KBr):
nmax¼3259, 3063, 1613, 1578, 1501, 1232, 1040, 827 cmꢀ1; 1H NMR
4.2.25. 5-Methyl-N-(2-methylphenyl)-1,3,4-oxadiazol-2-amine (2De,
Table 2). Light yellow solid; mp: 179.0e179.9 ꢁC; IR (KBr):
nmax¼3241, 3034, 1659, 1594, 1482, 1233, 1065, 759 cmꢀ1; 1H NMR
(400 MHz, DMSO-d6):
d
10.39 (br,1H, NH), 7.75 (d, J¼8.0 Hz, 2H), 7.51
(400 MHz, DMSO-d6):
d
9.26 (br, 1H), 7.70 (dd, J1¼8.4 Hz, J2¼1.2 Hz,
(d, J¼9.2 Hz, 2H), 7.35 (d, J¼8.0 Hz, 2H), 6.94 (d, J¼9.2 Hz, 2H), 3.73 (s,
3H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d
159.7,157.3,154.1,
1H), 7.19e7.15 (m, 2H), 6.98 (td, J1¼7.2 Hz, J2¼1.2 Hz, 1H), 2.38 (s,
3H), 2.25 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d
160.5, 156.8,
140.6, 131.7, 129.6 (CHꢂ2), 125.2 (CHꢂ2), 121.0, 118.4 (CHꢂ2), 114.2
(CHꢂ2), 55.2, 21.1; MS (EI): m/z (%)¼281 (Mþ,100); HRMS-ESI: calcd
for C16H16N3O2 (MþH)þ: 282.1243; found: 282.1241.
136.7, 130.3, 128.2, 126.2, 123.1, 120.2, 17.9, 10.5; MS (EI): m/z (%)¼
189 (Mþ, 94), 131 (100); HRMS-ESI: calcd for C10H12N3O (MþH)þ:
190.0980; found: 190.0976.
4.2.19. N-(2-Methylphenyl)-5-(4-methylphenyl)-1,3,4-oxadiazol-2-
4.2.26. N-Phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amine (2Af, Table
2)20. White solid; mp: 217.6e218.8 ꢁC; lit. mp:5 216e218 ꢁC; IR
amine (2Dd, Table 2). Yellow solid; mp: 158.8e159.3 ꢁC; IR (KBr):
nmax¼3444, 3163,1655,1606,1584,1489, 1296,1048, 819, 741 cmꢀ1
;
(KBr): nmax¼3263, 3058, 1617, 1586, 1501, 1242, 1052, 750 cmꢀ1
;
1H
1H NMR (400 MHz, DMSO-d6):
d 9.59 (s, 1H), 7.78e7.75 (m, 3H),
NMR (400 MHz, DMSO-d6):
d
10.86 (s, 1H), 8.77 (d, J¼6.0 Hz, 2H), 7.79
7.36 (d, J¼8.0 Hz, 2H), 7.23e7.21 (m, 2H), 7.02 (t, J¼8.0 Hz, 1H), 2.38
(d, J¼6.0 Hz, 2H), 7.62 (d, J¼7.6 Hz, 2H), 7.37 (t, J¼7.6 Hz, 2H), 7.03 (t,
(s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d
160.6, 157.8,
J¼7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
d 160.2, 155.9, 150.4
140.5, 136.5, 130.4, 129.6 (CHꢂ2), 128.7, 126.3, 125.2 (CHꢂ2), 123.5,
121.0, 120.7, 21.1, 17.9; MS (ESI): m/z (%)¼264 (100, Mꢀꢀ1); HRMS-
ESI: calcd for C16H16N3O (MþH)þ 266.1293; found: 266.1288.
(CHꢂ2), 138.1, 130.5, 128.8 (CHꢂ2), 121.9, 118.9 (CHꢂ2), 117.1 (CHꢂ2);
MS (EI): m/z (%)¼238 (Mþ, 100).
4.2.27. N-(4-Chlorophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-
amine (2Bf, Table 2)21. White solid; mp: 292.8e293.8 ꢁC; lit. mp:7
291e292 ꢁC; IR (KBr): nmax¼3268, 3060, 1632, 1609, 1591, 1571,
4.2.20. N-(Naphthalen-1-yl)-5-(4-methylphenyl)-1,3,4-oxadiazol-2-
amine (2Gd, Table 2). White solid; mp: 184.3e183.9 ꢁC; IR (KBr):
nmax¼3445, 3044,1651,1623,1596,1578,1501,1313,1016, 821 cmꢀ1
;
1494,1253,1053, 817 cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d 11.04(br,
1H NMR (400 MHz, DMSO-d6):
d 10.43 (s, 1H), 8.33e8.30 (m, 1H),
1H), 8.78(d, J¼6.0Hz,2H),7.80(d,J¼6.0Hz, 2H), 7.64(d, J¼9.2Hz,2H),
8.06 (d, J¼7.6 Hz, 1H), 7.96e7.94 (m, 1H), 7.79 (d, J¼8.0 Hz, 2H), 7.69
7.43 (d, J¼9.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6):
d 160.3, 156.4,
(d, J¼8.0 Hz, 1H), 7.59e7.52 (m, 3H), 7.38 (d, J¼8.4 Hz, 2H), 2.39 (s,
150.8 (CHꢂ2), 137.3, 130.7, 129.0 (CHꢂ2), 125.9, 119.3 (CHꢂ2), 118.9
3H),13C NMR (100 MHz, DMSO-d6):
d 160.8,158.0,140.7,133.8,133.6,
(CHꢂ2); MS (EI): m/z (%)¼274 (Mþþ2, 33), 272 (Mþ, 100).
129.7 (CHꢂ2), 128.0, 126.0, 125.7, 125.6, 125.5, 125.3 (CHꢂ2), 123.4,
122.0,121.0,116.3, 21.1; MS (ESI): m/z (%)¼300 (100, Mꢀꢀ1); HRMS-
ESI: calcd for C19H16N3O (MþH)þ 302.1293; found: 302.1289.
4.2.28. N-(4-Methoxyphenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-
amine (2Cf, Table 2)21. Yellow solid; mp: 231.3e232.3 ꢁC; lit. mp:7
233e234 ꢁC; IR (KBr): nmax¼3282, 2963, 1645, 1600, 1574, 1511,
4.2.21. N-(4-Bromophenyl)-5-(4-methylphenyl)-1,3,4-oxadiazol-2-
amine (2Hd, Table 2). White solid; mp: 286.0e287.0 ꢁC; IR (KBr):
nmax¼3252, 3065, 1620, 1605, 1574, 1503, 1234, 1051, 826 cmꢀ1; 1H
1239,1038, 817 cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d 10.62 (s,1H),
8.76 (d, J¼6.0 Hz, 2H), 7.77 (d, J¼6.0 Hz, 2H), 7.53 (d, J¼9.2 Hz, 2H),
6.95 (d, J¼9.2 Hz, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
NMR (400 MHz, DMSO-d6):
d
10.81 (s, 1H), 7.77 (d, J¼8.0 Hz, 2H),
d
160.4, 155.6, 154.3, 150.4 (CHꢂ2), 131.3, 130.6, 118.9 (CHꢂ2), 118.6
7.57 (d, J¼9.2 Hz, 2H), 7.52 (d, J¼9.2 Hz, 2H), 7.37 (d, J¼8.0 Hz, 2H),
(CHꢂ2), 114.1 (CHꢂ2), 55.2; MS (EI): m/z (%)¼268 (Mþ, 100).
2.38 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6):
d
159.1, 157.7,
140.8, 137.8, 131.6 (CHꢂ2), 129.7 (CHꢂ2), 125.4, 120.8, 118.8 (CHꢂ2),
113.1, 21.1; MS (EI): m/z (%)¼331 (Mþþ2, 67), 329 (Mþ, 75), 159
(100); HRMS-ESI: calcd for C15H12BrN3NaO (MþNa)þ: 352.0061;
found: 352.0057.
4.2.29. N-(2-Methylphenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-
amine (2Df, Table 2)21. White solid; mp: 171.0e171.8 ꢁC; lit. mp:7
179e180 ꢁC; IR (KBr): nmax¼3226, 3052, 1620, 1588, 1488, 1254,
1050, 757 cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d 9.87 (br, 1H), 8.76
(d, J¼6.0 Hz, 2H), 7.77e7.73 (m, 3H), 7.25e7.22 (m, 2H), 7.06 (td,
4.2.22. 5-Methyl-N-phenyl-1,3,4-oxadiazol-2-amine (2Ae, Table
2)19. Light yellow solid; mp: 172.9e173.8 ꢁC; lit. mp:6
174e175 ꢁC; IR (KBr): nmax¼3252, 1638, 1579, 1500, 1242, 1058,
J1¼7.6 Hz, J2¼1.2 Hz,1H), 2.31 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d
161.5, 156.1, 150.5 (CHꢂ2), 136.0, 130.6, 130.4, 129.3, 126.3, 124.1,
121.4,118.8 (CHꢂ2),17.9; MS (EI): m/z (%)¼252 (Mþ,100); HRMS-ESI:
calcd for C14H13N4O (MþH)þ: 253.1089; found: 253.1085.
753 cmꢀ1 1H NMR (400 MHz, DMSO-d6):
; d 10.30 (s, 1H), 7.54 (d,
J¼8.4 Hz, 2H), 7.32 (t, J¼7.6 Hz, 2H), 6.97 (t, J¼7.2 Hz, 1H), 2.39 (s,
3H); 13C NMR (100 MHz, DMSO-d6):
d 159.4, 156.6, 138.7, 128.8
4.2.30. N-(Naphthalen-1-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-
amine (2Gf, Table 2). Yellow solid; mp: 207.9e208.5 ꢁC; IR (KBr):
nmax¼3222, 3044, 1631, 1605, 1594, 1582, 1502, 1238, 1076 cmꢀ1; 1H
(CHꢂ2), 121.3, 116.6 (CHꢂ2), 10.5; MS (EI): m/z (%)¼175 (Mþ, 100).
4.2.23. N-(4-Chlorophenyl)-5-methyl-1,3,4-oxadiazol-2-amine (2Be,
Table 2). White solid; mp: 195.1e196.2 ꢁC; IR (KBr): nmax¼3253,
NMR (400 MHz, DMSO-d6):
d
10.65 (s, 1H), 8.77 (d, J¼6.0 Hz, 2H),
8.30e8.27 (m, 1H), 8.02 (d, J¼7.2 Hz, 1H), 7.97e7.94 (m, 1H), 7.80 (d,
3054, 1644, 1612, 1581, 1572, 1496, 1245, 1093, 835 cmꢀ1 1H NMR
;
J¼6.0 Hz, 2H), 7.73 (d, J¼8.0 Hz, 1H), 7.58e7.53 (m, 3H); 13C NMR
(400 MHz, DMSO-d6):
d
10.47 (s, 1H), 7.54 (d, J¼8.8 Hz, 2H), 7.36 (d,
(100 MHz, DMSO-d6):
d
161.8, 156.4, 150.6 (CHꢂ2), 133.6, 133.4,
J¼8.8 Hz, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d 159.2,
130.7, 128.1, 126.1, 125.9, 125.8, 125.7, 124.0, 122.0, 119.0 (CHꢂ2),
156.9, 137.6, 128.7 (CHꢂ2), 124.9, 118.1 (CHꢂ2), 10.4; MS (EI): m/z
117.2; MS (EI): m/z (%)¼288 (Mþ, 100).
(%)¼211 (Mþþ2, 33), 209 (Mþ, 100).
4.2.24. N-(4-Methoxyphenyl)-5-methyl-1,3,4-oxadiazol-2-amine
4.3. General procedure for the synthesis of bis(1,3,4-
oxadiazoles) 6. (Take 6a, for example)
(2Ce, Table 2). Grey solid; mp: 135.9e136.5 ꢁC; IR (KBr): nmax¼3258,
3058, 1650, 1609, 1587, 1576, 1512, 1234, 1043, 825 cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6):
d
10.03 (s, 1H), 7.43 (d, J¼8.8 Hz, 2H), 6.89 (d,
Oxalyl dihydrazide 5a (0.059 g, 0.5 mmol) and 1-chloro-4-
isoselenocyanatobenzene 3B (0.217 g, 1.0 mmol) were added to
J¼8.8 Hz, 2H), 3.71 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-

5374
Y. Xie et al. / Tetrahedron 67 (2011) 5369e5374
DMF (10 mL) with magnetic stirring. The mixture was heated to 90 ꢁC
for 4 h. When the reaction was completed as monitored by TLC, the
mixture was cooled to rt. The black selenium powder was filtered off
and washed with ethanol (10 mL). The combined filtrate was con-
centrated in vacuo. The residue was crystallized, filtered and washed
Supplementary material
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.05.100.
5
5
0
by ethanol (10 mL) to give N ,N -bis(4-chlorophenyl)-2,20-bi(1,3,4-
oxadiazole)-5,50-diamine 6a (0.186 g, yield 96%) as a white solid.
References and notes
5
5
0
4.3.1. N ,N -Bis(4-chlorophenyl)-2,20-bi(1,3,4-oxadiazole)-5,50-di-
€
1. (a) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csoeregh, I.; Hesselink, W.;
Hacksell, U. J. Org. Chem. 1995, 60, 3112; (b) Poulain, R. F.; Tartar, A. L.; Deprez, B.
amine (6a, Table 3)22. White solid; mp: 326.1e327.0 ꢁC; IR (KBr):
ꢀ
nmax¼3268, 3074, 1619, 1578, 1546, 1490, 1242, 1050, 830 cmꢀ1
;
1H
P. Tetrahedron Lett. 2001, 42, 1495; (c) Poindexter, G. S.; Bruce, M. A.; Brei-
tenbucher, J. G.; Higgins, M. A.; Sit, S. Y.; Romine, J. L.; Martin, S. W.; Ward, S. A.;
McGovern, R. T.; Clarke, W.; Russell, J.; Antal-Zimanyi, I. Bioorg. Med. Chem.
2004, 12, 507; (d) Elzein, E.; Ibrahim, P.; Koltun, D. O.; Rehder, K.; Shenk, K. D.;
Marquart, T. A.; Jiang, B.; Li, X.; Natero, R.; Li, Y.; Nguyen, M.; Kerwar, S.; Chu, N.;
Soohoo, D.; Hao, J.; Maydanik, V. Y.; Lustig, D. A.; Zeng, D.; Leung, K.; Zablocki, J.
A. Bioorg. Med. Chem. Lett. 2004, 14, 6017.
2. (a) Blouin, M.; Grimm, E. L.; Gareau, Y.; Gagnon, M.; Juteau, H.; Laliberte, S.;
Mackay, B.; Friesen, R. WO 2006099735, 2006; (b) Zou, X. J.; Lai, L. H.; Jin, G. Y.;
Zhang, Z. X. J. Agric. Food Chem. 2002, 50, 3735; (c) Yale, H. L.; Lossee, K. J. Med.
Chem. 1966, 9, 478; (d) Rostom, S. A. F.; Shalaby, M. A.; EI-Demellawy, M. A. Eur.
J. Med. Chem. 2003, 38, 959; (e) Leber, J. D.; Li, M.; Lee, J.; Aubart, K. M.;
Christensen, S. B. WO 2005032550, 2005.
3. Nofal, Z. M.; Fahmy, H. H.; Mohamed, H. S. Arch. Pharm. Res. 2002, 25, 28.
4. (a) Ouyang, X.; Piatnitski, E. L.; Pattaropong, V.; Chen, X.; He, H. Y.; Kiselyov, A.
S.; Velankar, A.; Kawakami, J.; Labelle, M.; Smith, L.; Lohman, J.; Lee, S. P.;
Malikzay, A.; Fleming, J.; Gerlak, J.; Wang, Y.; Rosler, R. L.; Zhou, K.; Mitelman,
S.; Camara, M.; Surguladze, D.; Doody, J. F.; Tuma, M. C. Bioorg. Med. Chem. Lett.
2006, 16, 1191; (b) Kiselyov, A. S.; Semenova, M. N.; Chernyshova, N. B.; Leitao,
A.; Samet, A. V.; Kislyi, K. A.; Raihstat, M. M.; Oprea, T.; Lemcke, H.; Lantow, M.;
Weiss, D. G.; Ikizalp, N. N.; Kuznetsov, S. A.; Semenov, V. V. Eur. J. Med. Chem.
2010, 45, 1683; (c) Wrasidlo, W.; Dneprovskaia, E. WO 2006024034, 2006.
NMR (400 MHz, DMSO-d6):
d
11.24 (s, 2H), 7.62 (d, J¼8.8 Hz, 4H), 7.45
(d, J¼8.8Hz,4H);13CNMR(100MHz,DMSO-d6):
160.1 (CHꢂ2),146.9
d
(CHꢂ2),136.9 (CHꢂ2),129.0 (CHꢂ4),126.2 (CHꢂ2),119.0 (CHꢂ4); MS
(ESI): m/z (%)¼389 (Mꢀþ1, 65), 388 (Mꢀ, 25), 387 (Mꢀ-1,100); HRMS-
ESI: calcd for C16H9Cl2N6O2 (MꢀH)ꢀ: 387.0164; found: 387.0164.
4.3.2. 5,50-Methylenebis(N-phenyl-1,3,4-oxadiazol-2-amine) (6b, Table
3)23. White solid; mp: 250.1e250.7 ꢁC; lit. mp: 205 ꢁC; IR (KBr):
nmax¼3240, 3051, 1639, 1580, 1500, 1247, 1053, 752, 691 cmꢀ1
;
1H
NMR (400 MHz, DMSO-d6):
d
10.50 (s, 2H), 7.53 (d, J¼7.6 Hz, 4H),
7.34e7.30 (m, 4H), 6.98 (t, J¼7.6 Hz, 2H), 4.57 (s, 2H); 13C NMR
(100 MHz, DMSO-d6):
d
156.0 (CHꢂ2), 153.9 (CHꢂ2), 138.3 (CHꢂ2),
128.8 (CHꢂ4), 121.6 (CHꢂ2), 116.7 (CHꢂ4), 22.2; MS (ESI): m/z (%)¼
335 (Mþþ1, 100); HRMS-ESI: calcd for C17H13N6O2 (MꢀH)ꢀ:
333.1100; found: 333.1095.
_
4.3.3. 5,50-(1,4-Butanediyl)bis(N-phenyl-1,3,4-oxadiazol-2-amine)
(6c, Table 3)22. White solid; mp: 244.0e244.8 ꢁC; lit. mp: 230 ꢁC; IR
(KBr): nmax¼3289, 3059, 1630, 1607, 1573, 1551, 1504, 1242, 1055,
€ €
€
€ €
€
€ €
5. Kuc¸ ukguzel, S¸ . G.; Kuc¸ ukguzel, I; Tatar, E.; Rollas, S.; S¸ ahin, F.; Gulluce, M.;
Clercq, E. D.; Kabasakal, L. Eur. J. Med. Chem. 2007, 42, 893.
6. (a) Chaudhary, S. K.; Kumar, S.; Parmar, S. S.; Chaudhary, M. J. Pharm. Sci. 1978,
67, 987; (b) Siddiqui, N.; Alam, M. S.; Ahsan, W. Acta Pharm. 2008, 58, 445.
7. (a) Brown, P.; Best, D. J.; Broom, N. J. P.; Cassels, R.; O’Hanlon, P. J.; Mitchell, T. J.;
Osborne, N. F.; Wilson, J. M. J. Med. Chem. 1997, 40, 2563; (b) Choi, Y.; Ishikawa, H.;
Velcicky, J.;Elliott, G.I.;Miller, M.M.;Boger, D.L.Org. Lett.2005, 7, 4539;(c) Ishikawa,
H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10596.
8. (a) Shaker, R. M.; Mahmoud, A. F.; Abdel-Latif, F. F. Phosphorus, Sulfur and Silicon
2005, 180, 397; (b) Brain, C. T.; Paul, J. M.; Loong, Y.; Okaley, P. J. Tetrahedron Lett.
756, 690 cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d 10.34 (s, 2H), 7.52
(d, J¼7.6 Hz, 4H), 7.30 (t, J¼7.6 Hz, 4H), 6.95 (t, J¼7.6 Hz, 2H),
2.83e2.80 (m, 4H), 1.80e1.76 (m, 4H); 13C NMR (100 MHz, DMSO-
d6):
d
159.4 (CHꢂ2), 159.3 (CHꢂ2), 138.6 (CHꢂ2), 128.8 (CHꢂ4),
121.3 (CHꢂ2), 116.7 (CHꢂ4), 25.1 (CHꢂ2), 24.0 (CHꢂ2); MS (ESI): m/
z (%)¼377 (Mþþ1, 40); HRMS-ESI: calcd for C20H21N6O2 (MþH)þ:
377.1726; found: 377.1718.
ꢁ
1999, 40, 3275; (c) Brain, C. T.; Brunton, S. A. Synlett 2001, 382; (d) Kosmrlj, J.;
ꢁ
Kocevar, M.; Polanc, S. Synlett 1996, 652; (e) Mazurkiewicz, R.; Grymel, M. Pol. J.
Chem. 1997, 71, 77; (f) Baxendale, I. R.; Ley, S. V.; Martinelli, M. Tetrahedron
ꢁ ꢂ ꢀ
2005, 61, 5323; (g) Dumciute, J.; Martynaitis, V.; Holzer, W.; Mangelinckx, S.;
ꢁ
ꢁ
Kimpe, N. D.; Sackus, A. Tetrahedron 2006, 62, 3309.
4.3.4. 5,50-(1,4-Butanediyl)bis(N-(4-methoxyphenyl)-1,3,4-oxa-di-
azol-2-amine) (6d, Table 3). White solid; mp: 249.8e250.3 ꢁC; IR
(KBr): nmax¼3296, 3064, 1630, 1600, 1574, 1547, 1515, 1236, 1033,
9. (a) Zarghi, A.; Hajimahdi, Z.; Mohebbi, S.; Rashidi, H.; Mozaffari, S.; Sarraf, S.;
Faizi, M.; Tabatabaee, S. A.; Shafíee, A. Chem. Pharm. Bull. 2008, 56, 509; (b)
Coppo, F. T.; Evans, K. A.; Graybill, T. L.; Burton, G. Tetrahedron Lett. 2004, 45,
3257; (c) Severinsen, R.; Kilburn, J. P.; Lau, J. F. Tetrahedron 2005, 61, 5565; (d)
Piatnitski Chekler, E. L.; Elokdah, H. M.; Butera, J. Tetrahedron Lett. 2008, 49,
6709; (e) Hwang, J. Y.; Choi, H. S.; Lee, D. H.; Gong, Y. D. J. Comb. Chem. 2005, 7,
816; (f) Dolman, S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. W. J. Org. Chem. 2006,
71, 9548; (g) Atta, S. M. S.; Fawzy, N. M.; Ahmed, F. A.; Abdel-Rahman, A. H.
Phosphorus, Sulfur and Silicon 2002, 177, 863; (h) Wang, X. C.; Li, Z.; Wei, B. G.;
Yang, J. Y. Synth. Commun. 2002, 32, 1097.
829 cmꢀ1 1H NMR (400 MHz, DMSO-d6):
; d 10.10 (s, 2H), 7.43 (d,
J¼8.8 Hz, 4H), 6.89 (d, J¼8.8 Hz, 4H), 3.70 (s, 6H), 2.81e2.78 (m, 4H),
1.78e1.74 (m, 4H); 13C NMR (100 MHz, DMSO-d6):
d
159.6 (CHꢂ2),
159.1 (CHꢂ2), 153.9 (CHꢂ2), 131.9 (CHꢂ2), 118.1 (CHꢂ4), 114.1
(CHꢂ4), 55.3 (CHꢂ2), 25.2 (CHꢂ2), 24.1 (CHꢂ2); MS (ESI): m/z (%)¼
437 (Mþþ1, 100); HRMS-ESI: calcd for C22H25N6O4 (MþH)þ:
437.1937; found: 437.1932.
10. Levins, C. G.; Wan, Z. K. Org. Lett. 2008, 10, 1755.
ꢀ
ꢀ
~
ꢀ
11. (a) Fernandez-Bolanos, J. G.; Lopez, O; Ulgar, V.; Maya, I.; Fuentes, J. Tetrahedron
ꢀ
ꢀ
ꢀ
Lett. 2004, 45, 4081; (b) Lopez, O; Maza, S.; Ulgar, V.; Maya, I.; Fernandez-
Bolanos, J. G. Tetrahedron 2009, 65, 2556; (c) Sommen, G. L.; Linden, A.;
~
4.3.5. 5,50-(1,4-Butanediyl)bis(N-(4-chlorophenyl)-1,3,4-oxadia-zol-
2-amine) (6e, Table 3). White solid; mp: 272.1e273.0 ꢁC; IR (KBr):
nmax¼3268, 3210, 3011, 1632, 1601, 1570, 1494, 1246, 1093,
Heimgartner, H. Eur. J. Org. Chem. 2005, 3128; (d) Garud, D. R.; Makimura, M.;
Ando, H.; Ishihara, H.; Koketsu, M. Tetrahedron Lett. 2007, 48, 7764; (e) Garud,
D. R.; Koketsu, M. Org. Lett. 2008, 10, 3319; (f) Garud, D. R.; Toyoda, Y.; Koketsu,
M. Tetrahedron Lett. 2009, 50, 3035; (g) Sommen, G. L.; Linden, A.; Heimgartner,
H. Tetrahedron 2006, 62, 3344.
831 cmꢀ1 1H NMR (400 MHz, DMSO-d6):
; d 10.52 (s, 2H), 7.55 (d,
12. (a) Xie, Y. Y.; Zhang, F.; Li, J. J.; Shi, X. J. Synlett 2010, 901; (b) Xie, Y. Y.; Zhang, F.;
Cheng, X. D.; Li, J. J. Heterocycles 2010, 81, 2087.
13. Bilinski, S.; Bielak, L.; Chmielewski, J.; Marcewicz-Rojewska, B.; Musik, I. Acta
Pol. Pharm. 1989, 46, 343.
14. Avaji, P. G.; Kumar, C. H. V.; Patil, S. A.; Shivananda, K. N.; Nagaraju, C. Eur. J. Med.
Chem. 2009, 44, 3552.
J¼8.8 Hz, 4H), 7.36 (d, J¼8.8 Hz, 4H), 2.83e2.80 (m, 4H), 1.79e1.76
(m, 4H); 13C NMR (100 MHz, DMSO-d6):
d
159.6 (CHꢂ2), 159.1
(CHꢂ2), 137.6 (CHꢂ2), 128.7 (CHꢂ4), 124.9 (CHꢂ2), 118.1 (CHꢂ4),
25.1 (CHꢂ2), 24.0 (CHꢂ2); MS (ESI): m/z (%)¼445 (Mꢀþ1, 18),
444(Mꢀ, 7), 443 (Mꢀ-1, 30); HRMS-ESI: calcd for C20H17Cl2N6O2
(MꢀH)ꢀ: 443.0790; found: 443.0772.
15. Moeckel, K. Z. Chem. 1964, 4, 388.
ꢀ
16. Franski, R.; Gierczyk, B.; Schroeder, G. J. Mass Spectrom. 2006, 41, 312.
17. Froeyen, P. Phosphorus, Sulfur and Silicon 1991, 57, 11.
18. Simiti, I.; Ghiran, D. Farmacia 1971, 19, 199.
Acknowledgements
19. Herbst, R. M.; Klingbeil, J. K. J. Org. Chem. 1958, 23, 1912.
20. Efimova, Y. A.; Karabanovich, G. G.; Artamonova, T. V.; Koldobskii, G. I. Russ. J.
Org. Chem. 2009, 45, 1241.
21. Zhang, Z. Y.; Yang, K. X.; Zeng, F. L. Gaodeng Xuexiao Huaxue Xuebao 1988, 9, 239.
22. Kudari, S. M.; Sangapure, S. S. Curr. Sci. 1984, 53, 1086.
23. Behera, A. K.; Behera, R. K.; Pradhan, R.; Pati, A.; Patra, M. Indian. J. Heterocycl.
Chem. 2006, 16, 167.
We are grateful to the National Natural Science Foundation of
China (No 20906083) and Natural Science Foundation of Zhejiang
Province (No Y40900488) for financial support. We also thank
professors W.H. Zhong for helpful discussions.