A new and efficient method for the synthesis of 2-N-(aryl)-1,3,4-oxadiazole-2,5-diamine derivatives

Article abstract of DOI:10.1007/s11164-015-2128-9

We report a series of cyclic analogues of 2,5-diamino-1,3,4-oxadiazoles which were prepared in a simple and general protocol. This method involves easy cyclisation of N-(aryl)-1,2-hydrazinedicarboxamides and mediated by tosylchloride/pyridine in ethanol (

Full text of DOI:10.1007/s11164-015-2128-9

Res Chem Intermed
DOI 10.1007/s11164-015-2128-9
A new and efficient method for the synthesis of 2-N-
(aryl)-1,3,4-oxadiazole-2,5-diamine derivatives
Manuri Brahmayya1 Fan-Shuan Liu1
•
•
Shing-Yi Suen1 Chun-Chieh Huang1
Shenghong A. Dai1 Yi-Syuan Guo1
•
•
•
•
Yi-Fen Chen1
Received: 1 April 2015 / Accepted: 3 June 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract We report a series of cyclic analogues of 2,5-diamino-1,3,4-oxadiazoles
which were prepared in a simple and general protocol. This method involves easy
cyclisation of N-(aryl)-1,2-hydrazinedicarboxamides and mediated by tosylchloride/
pyridine in ethanol (solvent) under a reflux condition (79–80 °C), over a time period
of 20 h. We prepared different examples in a higher range of yields (80–98 %) by
using this protocol.
Keywords Cyclisation Á Heterocycles Á Heteroatom Á Synthesis Á Diamino
oxadiazoles Á Reaction mechanism
Introduction
Heterocyclic compounds represent a huge family of biologically active organic
molecules which have attracted the supreme attention of chemists throughout the
world [1–3]. A majority of marketed drugs have included heterocyclic entities,
highlighting their key roles in medicinal chemistry. In specific, the improvement of
an efficient and practical synthesis of 2,5-disubstituted-1,3,4-oxadiazoles is an
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2128-9)
contains supplementary material available to authorized users.
&
&
&
1
Manuri Brahmayya
manurichinna_07@yahoo.co.in
Shing-Yi Suen
sysuen@dragon.nchu.edu.tw
Shenghong A. Dai
shdai@dragon.nchu.edu.tw
Department of Chemical Engineering, National Chung Hsing University, Taichung 402,
Taiwan, ROC
123

M. Brahmayya et al.
active subject of current organic research. In the course of our research, we became
interested in 1,3,4-oxadiazoles as they are rousing and versatile building blocks with
a wide range of biological activities, including the following: antibacterial, antiviral,
anti-inflammatory, antitubercular, antipyretic, anticancer, central nervous system
depressant, antischistosomal, diuretic, analgesic, anticonvulsive and antiemetic
properties in the literature [4, 5]. The well-known use of 1,3,4-oxadiazole
derivatives as a scaffold in modern medicinal chemistry [6], as verified by these
specimens, establishes this moiety as a member of the prosperous structures course.
Nevertheless, apart from their common use, procedures based on dehydrative
cyclisation (Scheme 1) of semicarbazides are often used and remarkably involve
tough reagents such as concentrated sulfuric acid [7, 8] or phosphoryl chloride
(POCl3) [9]. On the other hand, reagents that primarily initiate one carbonyl group
for backing cyclization have been used. The outcomes of these particular reagents,
including Burgess-type [10, 11] reagents and phosphonium salts, in inflexible
byproduct materialization, conversely, have generally been limited to usage in solid-
phase synthetic strategies. Recently, the Boger group [12, 13] reported an exciting
method to synthesize 2-amino-[1,3,4]-oxadiazoles via the dehydrative cyclisation of
a semicarbazide substrates mediated by tosyl chloride and a base at conventional
room temperature [14, 15]. We have been paying attention to this methodology due
to the low price of reagents and mild reaction conditions. Typically, 2,5-diamino-
[1,3,4]oxadiazole derivatives are prepared by cyclization of the corresponding
acyclic hydrazine-1,2-dicarboxamide substrates, semicarbazides and thiosemicar-
bazides [16]. We have a current interest in the development of novel strategies to
access functionalized oxadiazoles. In an effort to chemically sew up these
biologically active heterocycles, we sought to develop a synthesis of 2,5-diamino
substituted-[1,3,4]-oxadiazoles as a major skeleton. Experimental charts for
cyclisation reactions are shown in the supporting information, S1–S11, and are
explained in the experimental section.
Previous
O
S
N
S
N
X
Desulfurative
or
dehydrative cyclisation
R2
R1
N
H
N
H
R1
R2
X
=
O,
2
1
Current
O
O
N
N
R1
R2
R1
Dehydrative cyclisation
R2
N
N
HN
NH
NH
HN
H
H
O
4
3
Scheme 1 Dithiocarbazate using for cyclisation of [1,3,4]-oxadiazole (1) and hydrazine-1,2-
dicarboxamide (3)
123

A new and efficient method for the synthesis of…
Experimental
All commercially available reagents and solvents were obtained from the
commercial suppliers and used without further purification. All these cyclization
reactions were conducted in a 50-mL round-bottomed Pyrex glass flask under N2
atmosphere with continuous and constant stirring speed at 900 rpm. Thin layer
chromatography (TLC) was implemented on silica gel plates. Flash column
chromatography was performed using 300–400 mesh silica gel. Visualization via
TLC was achieved by illumination under an ultraviolet (UV) lamp (254 nm).
Nuclear magnetic resonance (NMR) spectra were recorded on a 400-MHz
spectrometer for 1HNMR and 100 MHz for 13C NMR in deuterated dichloro
dimethyl silane (DMSO-d6) or deuterated chloroform (CDCl3) at room temperature;
tetramethylsilane (TMS) served as an internal standard. High-resolution mass
spectrometry (HRMS) was recorded. Some substrates were prepared according to
the known experimental procedures [17–32] with petty modification.
General procedure for intramolecular cyclisation
We mixed hydrazine-1,2-dicarboxamide (17.3 mmol, 2.045 equiv), 4-methylben-
zenesulfonyl chloride (10.7 mmol, 1.0 equiv), pyridine (36.45 mmol, 2.10 equiv) in
ethanol (20 mL) under a nitrogen atmosphere in a 50-mL round bottom flask which
was well purged by nitrogen with a neat and clean condenser and magnetic stir bar
(900 rpm). The reactor was well bottomed by oil bath. The reaction mixture was
then heated at the required reflux temperature (79–80 °C) until the required time
(20 h) to complete the reaction. TLC was checked until the absence of starting
substrates hydrazine-1 and 2-dicarboxamide derivatives in the product [TLC,
mobile phase ethyl acetate (EtOAc) (5): n-Hexane (5)], and also until the reaction
was adjudicated complete by liquid chromatography-mass spectrometry (LC–MS)
analysis, after which the reaction mixture was allowed to cool to room temperature.
EtOAc (10 mL) and brine solution (10 mL) were added to the mixture, which was
vigorously stirred for 5 min; then, the aqueous layer was removed. The removed
aqueous layer was again extracted with EtOAc (10 mL), and then the combined
organic layers were flushed with n-octane (2 9 25 mL) and the material was
concentrated to a yellowish slurry. The material was dissolved in 10 mL of ethanol
(EtOH) and filtered. We then added 15 mL of diethyl ether to this mixture and
stirred for 15 min at room temperature; a thin slurry was obtained. The slurry was
filtered to produce 1.75 g of glittery white powder (85.3 % yield). The products
1
were characterized by H, 13C NMR, and HRMS.
1H NMR, 13 C NMR, MASS (m/z) spectra data for some selected compounds
2-N-(4-Methoxyphenyl)-1,3,4-oxadiazole-2,5-diamine (4b): White semisolid,
m.p. 238-240 °C.1H NMR (400 MHz, DMSO-d6) d 3.7 (s, 3H, 1 9 OCH3), 5.2
(brs, 3H, 3 9 Ar–NH), 6.60-7.00 (m, 4H, 4 9 Ar–H); 13C NMR (100 MHz,
DMSO-d6) d 55.1,115.01, 115.03, 122.01, 122.03, 132.01, 153.30, 169.02, 169.04;
HRMS (ESI) calcd for [C9H11N4O2]?: 207.0877. Found: 207.0868.
123

M. Brahmayya et al.
2-N-(4-Methyphenyl)-1,3,4-oxadiazole-2,5-diamine (4c): Solid, m.p. 240-241 °C.
1H NMR (400 MHz, DMSO-d6) d 2.3 (s, 3H, 1 9 CH3), 5.0 (brs, 3H, 3 9 Ar–NH),
7.40 (m, 4H, 4 9 Ar–H); 13C NMR (100 MHz, DMSO-d6) d 21.02, 120.0, 120.01,
130.05, 131.00, 135.00, 153.3, 168.01, 169.03; HRMS (ESI) calcd for
[C9H11N4O]?: 191.0927. Found: 191.037.
2-N-(phenyl)-1,3,4-oxadiazole-2,5-diamine (4d): Yellow semisolid, m.p.
235–240 °C. 1H NMR (400 MHz, DMSO-d6) d 5.0 (brs, 3H, 3 9 Ar–NH),
7.0–7.5 (m, 5H, 5 9 ArH).13C NMR (100 MHz, DMSO-d6) d 116.01, 117.00,
129.0, 137.50, 168.0, 168.01; HRMS (ESI) calcd for [C8H9N4O]?: 177.0771.
Found: 177.0740.
2-N-(2-methoxyphenyl)-1,3,4-oxadiazole-2,5-diamine (4e): White solid, m.p.
1
270–272 °C. H NMR (400 MHz, DMSO-d6) d 3.8 (s, 3H, 1 9 OCH3), 5.45 (brs,
3H, 3 9 Ar–NH), 7.680 (m, 4H, 4 9 Ar–H); HRMS (ESI) calcd for [C9H11N4O2]?:
207.0859. Found: 207.0865.
2-N-(2,6-dimethoxyphenyl)-1,3,4-oxadiazole-2,5-diamine (4f): White, shiny
solid, m.p. 242 °C.1H NMR (400 MHz, DMSO-d6) d 3.8 (s, 3H, 1 9 OCH3),
3.90 (s, 3H, 1 9 OCH3), 5.50 (brs, 3H, 3 9 Ar–NH), 7.50 (m, 3H, 3 9 Ar–H); 13
C
NMR (100 MHz, DMSO-d6) d 55.01, 55.02, 105.01, 105.02, 130.05, 146.0, 146.01,
169.01, 169.03; HRMS (ESI) calcd for [C10H13N4O3]?: 237.091. Found: 237.100.
2-N-(3-chlorophenyl)-1, 3, 4-oxadiazole-2, 5-diamine (4g): Pale yellow solid,
m.p. 270–271 °C.1H NMR (400 MHz, DMSO-d6) d 5.00 (brs, 3H, 3 9 Ar–NH),
7.40 (m, 3H, 3 9 Ar–H); 13C NMR (100 MHz, DMSO-d6) d 115.70, 116.00,
121.90, 129.00, 135.00, 143.00,169.00, 169.02; HRMS (ESI) calcd for [C8H8ClN4-
O]?: 211.6209. Found: 211.6219.
2-N-(4-bromoophenyl)-1, 3, 4-oxadiazole-2, 5-diamine (4 h): White solid, m.p.
1
240-245 °C. H NMR (400 MHz, DMSO-d6) d 5.50 (brs, 3H, 3 9 Ar–NH), 7.40
(m, 4H, 4 9 Ar–H); 13C NMR (100 MHz, DMSO-d6) d 114.90, 117.80, 117.90,
129.00, 129.02, 143.01, 169.01, 169.02; HRMS (ESI) calcd for [C8H8BrN4O]?:
256.0711. Found: 256.0658.
2-N-(4-fluorophenyl)-1,3,4-oxadiazole-2,5-diamine (4i): Pale yellow solid, m.p.
265–269 °C.1H NMR (400 MHz, DMSO-d6) d 5.00 (brs, 3H, 3 9 Ar–NH),
7.70–7.80 (m, 3H, 3 9 Ar–H); 13C NMR (100 MHz, DMSO-d6) d 11,700,
118.00, 123.91, 124.00, 141.80, 155.00, 169.00, 169.01; HRMS (ESI) calcd for
[C8H8FN4O]?: 195.0456. Found: 195.0438.
2-N-(4-nitroophenyl)-1,3,4-oxadiazole-2,5-diamine (4j): Shiny white powder,
m.p. 276 °C. 1H NMR (400 MHz, DMSO-d6) d 5.40 (brs, 3H, 3 9 Ar–NH),
7.60–7.80 (m, 3H, 3 9 Ar–H); 13C NMR (100 MHz, DMSO-d6) d 119.01, 119.04,
124.40, 124.50, 137.00, 145.00, 170.00, 170.02; HRMS (ESI) calcd for
[C8H8N5O3]?: 222.0681. Found: 222.0701.
1
2-N-[4-(N,N-Dimethyl)phenyl]-1,3,4-oxadiazole-2,5-diamine (4k): Semisolid. H
NMR (400 MHz, DMSO-d6) d 2.8 (s, 6H, 2 9 NCH3), 5.40 (brs, 3H, 3 9 Ar–NH),
123

A new and efficient method for the synthesis of…
Table 1 Optimization of reaction conditions for the synthesis of 2,5-diamine-[1,3,4]-oxadiazole (4a–p)
Entry
Reagent (equiv)
Solvent
Temperature (°C)
Time (h)
Yield (%)a
4a
5
1
DCC
THF
70
70
70
70
79
80
60
80
110
70
60
60
80
80
80
80
80
80
80
140
12
12
24
24
20
24
24
20
20
20
20
20
20
20
20
20
20
20
20
5
15
20
70
50
98
60
80
23
12
65
70
10
19
10
0
[4
2
EDC.HCl
THF
[6
0
3
TsCl/pyridine
THF
4
TsCl/TEA
THF
[4
0
5
TsCl/pyridine (1.0/2.1)
TsCl/TEA (1.0/2.1)
TMSCl
EtOH
EtOH
DCE
6
[4
[5
5
7
8
TsCl
EtOH
Toluene
THF
9
TsCl/pyridine (1.0/2.1)
TsCl/pyridine (1.0/2.1)
TsCl/pyridine (1.0/2.1)
TsCl/K2CO3 (1.0/2.1)
DCC/pyridine (1.0/2.1)
TsCl/pyridine (1.0/2.1)
BF3.etherate
[5
[4
[5
[6
[5
[5
10
11
12
13
14
15
16
17
18
19
20
a
MeOH
DCE
DMSO
CHCl3
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
No Reagent
0
TsCl/pyridine (2.0/4.5)
TsCl/pyridine (2.3/5.0)
TsCl/pyridine (3.0/6.0)
TsCl/pyridine (4.0/7.0)
70
65
50
0
15
17
[20
75
Conversion rate and isolated yields were based on a GC monitoring
7.4 (d, J 8.1 2H, 2 9 Ar–H), 7.8 (d, J 8.3, 2H, 2 9 ArH); 13CNMR (100 MHz,
DMSO-d6) d 40.00,40.01,113.00, 113.03, 119.0, 119.04, 144.91, 145.70, 168.02,
168.04; HRMS (ESI) calcd for [C10H14N5O]?: 220.0203. Found: 220.0303.
2-N-[4-hydroxyphenyl]-1,3,4-oxadiazole-2,5-diamine (4 l): White powder, m.p.
278 °C. HRMS (ESI) calcd for [C8H9N4O2]?: 193.1430. Found: 193.1406.
2-N-[3,5-dimethylphenyl]-1,3,4-oxadiazole-2,5-diamine (4m): Semisolid. HRMS
(ESI) calcd for [C10H13N4O]?: 205.3016. Found: 204.3028.
2-N-(2-methylphenyl)-1,3,4-oxadiazole-2,5-diamine (4n):
White solid, m.p.
280–281 °C.1H NMR (400 MHz, DMSO-d6) d 2.3 (s, 3H, 1 9 ArCH3), 5.50 (brs,
3H, 3 9 Ar–NH), 7.4–7.6 (m, 4H, 4 9 Ar–H); HRMS (ESI) calcd for
[C9H11N4O]?: 191.0911. Found: 191.0919.
2-N-(2-chlorophenyl)-1,3,4-oxadiazole-2,5-diamine (4o):
White solid, m.p.
269–273 °C. HRMS (ESI) calcd for [C8H8ClN4O]?: 211.0124. Found: 211.0113.
123

M. Brahmayya et al.
2-N-(2-fluorophenyl)-1,3,4-oxadiazole-2,5-diamine (4p):
Semisolid. 1H NMR
(400 MHz, DMSO-d6) d 5.50 (brs, 3H, J 7.8, 3 9 Ar–NH), 7.25-7.75 (m, 4H,
4 9 Ar–H); HRMS (ESI) calcd for [C8H8FN4O]? 195.1703. Found: 195.1806.
Results and discussion
Initially N,N’-(aryl substituted)hydrazine-1,2-dicarboxamide (3a) was chosen as a
model substrate for the optimization of dehydrative-cyclisation environs. As depicted
in Table 1 (Scheme 2), a range of selected reagent systems were evaluated as careful
cyclisation conditions in the presence of different solvents. Our results indicate that the
catalyst systems, such as N,N’-dicyclohexylcarbodiimide (DCC), 3-(ethylimi-
nomethyleneamino)-N,N-dimethylpropan-1-amine (EDC.HCl), trimethylsilylchlo-
ride (TMSCl), boron trifluoride ethyl etherate (BF3.etherate) and p-toluenesulfonyl
chloride (TsCl) all have the capacity to catalyze the dehydrative cyclisation process
quite efficiently at 1.0 equivalents. Among the various dehydrating conditions, DCC
and EDC.HCl were found to be least effective for the cyclisation of hydrazodicabox-
amides under these conditions (Table 1, entries 1 and 2). It is worth mentioning that,
along with cyclized 1,3,4-oxadiazole (4a), the product 2,3-dihydro-[1,3,4]-oxadia-
zole-2,5-diamine (5) from 3a regularly looked as a side product in many of these
reactions. Reports in the literature suggest compound 4a is quite commonly the
preferred product in the presence of week basic conditions. Among these twenty
various (Table 1) selected reagent systems tested, TsCl-pyridine/EtOH appeared the
most effective in producing 4a in higher yields. Thus, we established TsCl as the
prominent reagent of choice based on its efficiency, cost effectiveness, and
environmentally benign nature. We then continued to further optimize the reagent
loading and solvent screening for the dehydrative cyclisation reaction. On increasing
the amount of TsCl-pyridine (in equivalents) from 2.0/4.5 to 4.0/7.0 led to a slight
decrease in the yield of 4a, and an increase in the yield of compound 5 (Table 1, entries
17-20, Scheme 2). On the other hand, when the amount of reagent system was reduced
to 1.0/2.1 (TsCl-pyridine), compound 4a formed exclusively (98 %) without any
discovery of compound 5 under these conditions (Table 1, entry 5). Moreover, in the
absence of tosylchloride-pyridine/EtOH, the formation of 4a did not take place at all
(Table 1, entry 15, Scheme 2). This suggests the presence of the basic condition such
as tosylchloride/pyridine was essential for the dehydrative cyclisation of 3a to takes
place.
With the superlative reagent system picked, we subsequently investigated the
effect of solvents on dehydrative cyclisation of 3a. It was discovered that a change in
solvent has an intensive impact on the reaction outcome. A cleaner conversion of 3a
to 4a was observed in ethanol, affording 4a at a 98-% yield, however, the required
reaction time took 20 h (Table 1, entry 5, Scheme 2). The desired cyclisation
reaction rate seems to be quite lethargic in nonpolar solvent, such as toluene. Use of
organic solvents (tetrahydrofuran, methanol and ethanol) mainly resulted in the
formation of compound 4a after a significantly longer time (Table 1, entries 5, 10
and 11). The commonly presented oxygen (the second most highly electronegative
element in the periodic table) in ethanol, methanol and tetrahydrofuran could
123

A new and efficient method for the synthesis of…
H
O
O
N
N
N
N
Reagent
Solvent
N
H
N
H
H2N
NH2
H2N
NH2
NH2
H2N
O
O
5
4a
3a
Scheme 2 Cyclization of hydrazine-1,2-dicarboxamide for various conditions
H
H
R
R
O
O
O
H
O
H
N
H
N
H
N
N
R1
R2
=
-
-
R
CH 3CH 2 CH
,
3
Fig. 1 Formation of cyclic, six-membered rings through intermolecular hydrogen bonding
increase the viscosity of the reaction mixture by forming strong interactions with the
terminal amines of substrates through intermolecular hydrogen bonds to avoid any
unwanted reaction centers, which results in the retention of terminal amino groups in
the final product (Fig. 1). Something interesting, an exclusive formation of 5 was
observed in DMF just after 5 h of reflux (Table 1, entry 20, Scheme 2). Reducing
the reaction temperature results in slowing of the reaction rate along with a
negotiated yield. Thus, after broad investigation, we concluded the best yield of 4a
(98 %) was obtained with TsCl-pyridine (1.0-2.1 equivalents)/ethanol 80 °C under
reflux (Table 1, entry 5, Scheme 2). These conditions were found to be superior
compared to conventional microwave irradiative cyclizations [33, 34]. Next, in order
to demonstrate the substrate choice and functional group acceptance, we selected
sixteen disubstituted-1,3,4-oxadiazoles (4a–p) in this present study (1-NMR and
13CNMR analyses were conducted for selected compounds and presented in the
supporting information S1–S11).
After possessing all the wanted hydrazodicaboxamides in our hands, we set out to
explore the opportunity of our cyclisation methodology in detail. A significant
substitution effect was observed on the reactivity of substrates towards the
cyclisation protocol (Table 2; Scheme 3). In general, the electron-donating groups
facilitated the reaction (80–90 %), while the electron-withdrawing [30–33]
substituents declined the reactivity of N-(ortho or meta or para substituted aryl
rings)-hydrazine-1, 2-dicarboxamide towards this reaction (10–20 %). Higher
temperatures (100–110 °C) and longer reaction times were required to promote
this cyclisation reaction of hydrazodicabonamides bearing electron-withdrawing
groups (Table 2, entries 3g-3k, 3o, and 3p). In the cases of aryl-hydrazodi-
cabonamides having electron-donating substituents [31–34], enhanced yields were
123

M. Brahmayya et al.
Table 2 Cyclisation of N-(aryl)-1, 2-hydrazinedicarboxamides to 2-N-(aryl)-1, 3, 4-oxadiazole-2,
5-diamine
Entry
3a
R1
R2
Product
Conversiona
(%)
Yield (%)b
N
N
H
H
93
99
97
90
H2N
NH2
O
4a
OCH3
CH3
OCH3
3b
N
N
H
H
98
91
N
H
H2N
O
4b
CH3
3c
N
N
O
H2N
N
H
O
N
4c
3d
3e
N
N
H
H
96
97
90
92
H2N
H2N
N
H
4d
H
H
H
N
3CO
3CO
N
H
O
4e
4f
H
N
3CO
3CO
3f
N
H
H
90
80
86
77
H2N
N
H
O
OCH3
OCH3
Cl
Cl
3g
N
N
N
N
H2N
H2N
H2N
N
O
H
4g
Br
F
Br
3h
3i
N
H
H
87
89
83
80
N
O
H
4h
4i
F
N
N
O
H
123

A new and efficient method for the synthesis of…
Table 2 continued
Entry
R1
R2
Product
Conversiona
(%)
Yield (%)b
NO2
NO2
3j
N
N
H
96
89
H2N
N
H
O
4j
CH3
N
CH3
3k
N
CH3
H
98
89
N
N
CH3
H2N
N
H
O
4k
OH
OH
3l
N
N
H
H
97
99
94
97
H2N
N
O
H
4l
CH3
CH3
3m
N
N
H2N
N
CH3
O
CH3
H
4m
3n
N
N
H
94
90
H2N
N
H
O
O
CH3
CH3
4n
4o
Cl
Cl
3o
3p
N
N
N
N
H
H
87
86
80
80
H2N
H2N
N
H
F
F
N
H
O
4p
a,b
Conversion rate and isolated yields were based on the GC monitoring
about 90–98 %, rather a loss in yield with the formation of minor amounts of
product 2, 3-dihydro-1, 3, 4-oxadiazole-2, 5-diamine (5) was observed.
Consistent with previous reports [35], we propose the mechanism (Scheme 4) for
the formation of 2,5-diamino-[1,3,4]-oxadiazole to be similar to the H.Gehlen
123

M. Brahmayya et al.
O
O
N
N
R1
R2
R1
TsCl
(1.0 equiv)
Pyridine (2.10 equiv )
R2
N
H
N
H
HN
NH
NH
O
HN
EtOH
20 hrs
80 0
C
(30 ml),
3a-p
4a-p
Scheme 3 Synthesis of 2-N-(aryl)-1,3,4-oxadiazole-2,5-diamine
B
N
H
c
NH
b
N
N
NH
a
d
NH 2
H2N
NH 2
H2N
1
2
O
O
N
O
O
.HCl
C
Ts
O
Cl
S
O
H
3C
H
A
N
N
NH 2
H2N
O
O
H
SO 3
O
S
O
N
N
H2N
NH 2
O
CH 3
CH 3
Transition state
Scheme 4 A plausible mechanism for the formation of 2,5-diamino-1,3,4-oxadiazole (4a)
cyclisation reaction [36]. Initially, pyridine (B) attacks one of the acidic protons of
nitrogen (b) in hydrazine-1,2-dicarboxamide (C) followed by a migration of double-
bond electrons of carbonyl oxygen (1) C (see Scheme 4) on to the tosyl cation
(A) resulting in the formation of tosylated-hydrazine-1,2-dicarboxamide and
pyridinium salt of hydrogen chloride (Scheme 4). This was further cyclised by
the removal of an acidic proton from nitrogen (c), an internal attack of double-
bonded electrons of a second carbonyl oxygen (2) in C (Scheme 4) onto the first
carbonyl carbon in C (Scheme 4) and thereafter the removal of p-toluenesulfonic
acid takes place, respectively, which resulted in the desired product 2, 5-diamino-
[1,3,4]-oxadiazole via a transition state (Scheme 4).
In summary, we reported one-pot synthesis of 2,5-disubstituted analogues to
cyclic 2,5-diamino-[1,3,4]-oxadiazoles from simple and readily available inputs
123

A new and efficient method for the synthesis of…
under mild reaction conditions. The flexibility of one-pot cyclic reactions provided a
series of new organic molecules in good yields, considering their molecular
difficulty, in approximately 20-24 h under smooth conditions. This procedure can
be extended to prepare other amines, making it a very useful methodology.
Acknowledgments The authors are thankful for funding support under the scheme of NSC 102-2811-E-
241-002, Taiwan, and ROC. One of the authors, MBY, conveys special thanks to S-Y.Suen and S.A.Dai.
References
1. M.R. Banday, R.H. Mattoo, A. Rauf, J. Chem. Sci. 122, 177 (2010)
2. C. Dobrot, C.C. Paraschivescu, I. Dumitru, M. Matache, I. Baciu, L.L. Rut, Tetrahedron Lett. 50,
1886 (2009)
3. M.B. Patel, N.R. Modi, J.P. Raval, S.K. Menon, Org. Bimol. Chem. 10, 1785 (2012)
4. R.R. Somani, P.Y. Shirodkar, V.J. Kadam, Chin. J. Chem. 26, 1727 (2008)
5. A. Hasan, M.R.K. Sheikh, S. Gapil, Asian J. Chem. 24, 2573 (2012)
6. P.H. Toy, Y. Lam, Solid-Phase Organic Synthesis: Concepts, Strategies, and Applications (Wiley,
London, 2012)
7. S. Sharma, V.K. Srivastava, A. Kumar, Eur. J. Med. Chem. 37, 689 (2002)
8. X. Zou, Z. Zhang, G. Jin, J. Chem. Res. 3, 228–230 (2002)
9. M. Demina, G. Sarapulova, A. Borisova, L. Larina, A. Medvedeva, Russ. J. Org. Chem. 39, 1522
(2003)
10. C.G. Levins, Z.K. Wan, Org. Lett. 10, 1755 (2008)
11. C.O. Kappe, Curr. Opin. Chem. Biol. 6, 314 (2002)
12. Y. Choi, H. Ishikawa, J. Velcicky, G.I. Elliott, M.M. Miller, D.L. Boger, Org. Lett. 7, 4539 (2005)
13. Z.Q. Yuan, H. Ishikawa, D.L. Boger, Org. Lett. 7, 741 (2005)
14. A.N. David, V. Anup, D.D. Carolyn, Bioorg. Med. Chem. Lett. 14, 5489 (2004)
15. D.A. Nugiel, A.M. Etzkorn, A. Vidwans, P.A. Benfield, M. Boisclair, C.R. Burton, S. Cox, P.M.
Czerniak, D. Doleniak, S.P. Seitz, J. Med. Chem. 44, 1334 (2001)
16. S.J. Dolman, F. Gosselin, P.D. Oshea, I.W. Davies, J. Org. Cehm. 71, 9548 (2006)
17. H.N. Dogan, A. Duran, S. Rollas, G. Sener, M.K. Uysal, D. Gulen, Bioorg. Med. Chem 10, 2893
(2002)
18. P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron 57, 9225 (2001)
19. A. Idesaki, M. Sugimoto, M. Yoshikawa, Ceramic Transactions. 243 (Wiley, New Jersey, 2014),
pp. 61–69
20. M. Saito, I. Osaka, T. Koganezawa, K. Takimiya, Heteroat. Chem. 25, 6 (2014)
21. Y. Wang, J. Wang, L. Xiang, C. Xi, D. Chen, T. Peng, G. Wang, Z. Mu Sepu. 32, 5 (2014)
22. P.C. de la Saulniere, Ann. Chim. Appl. 17, 353 (1942)
23. T. Tsuji, Pharm. Bull. 2, 22 (1954)
24. M.N. Egorova, I.M. Tereshin, G.K. Oliunina, Antibiotiki 22, 65 (1964)
25. Y.L. Wu, Yaoxue Xuebao 12, 8 (1965)
26. A.Y. Chervinskii, L.M. Kapkan, L.M. Litvinenko, T.M. Pekhtereva Dokl, Akad. Nauk SSSR 273, 6
(1983)
27. C.R. Kramer, L. Beck, Z. Chem. 20, 1 (1980)
28. H. Gehlen, W. Schade, Justus Liebigs Ann. Chem. 675, 180 (1964)
29. C.R. Kramer, L. Truemper, D. Herbert, Z. Chem. 22, 11 (1982)
30. N. Montazeri, K. Rad-Moghadam, Chin. Chem. Lett. 19, 1143 (2008)
31. D.A. Nugiel, A. Vidwans, C.D. Dzierba, Bioorg. Med. Chem. Lett. 14, 5489 (2004)
32. G. Zinner, M. Heitmann, Arch. Pharm. 314, 193 (1981)
33. R.A. Bunce, R.S. Childress, Synth. Commun. 26, 4081 (1996)
34. F.T. Coppo, K.A. Evans, T.L. Graybill, G. Burton, Tetrahedron Lett. 45, 3257 (2004)
35. J.G. Zeevaart, L. Wang, V.V. Thakur, C.S. Leung, J. Tirado-Rives, C.M. Bailey, R.A. Domaoal, K.S.
Anderson, W.L. Jorgensen, J. Am. Chem. Soc. 130, 9492 (2008)
36. H. Gehlen, K. Mockel, Justus Liebigs Annal. der Chemi. 685, 176 (1965)
123