One-pot synthesis of 2,5-disubstituted-1,3,4-oxadiazoles based on the reaction of N,N-dimethyl amides with acid hydrazides

Article abstract of DOI:10.1002/jccs.201300598

Convenient and efficient one pot method for the synthesis of 2,5-disubstituted-1,3,4-oxadiazoles based on the reaction of N,N-dimethyl amides with acid hydrazides has been developed. The methodology is applied to a wide range of difference aryl hydrazide and difference N,N-dimethyl amides to 2,5-disubstituted-1,3,4-oxadiazoles yield the in good to excellent yields. It will be possible wide useful application in synthesis. Synopsis Convenient and efficient one pot method for the synthesis of 2,5-disubstituted-1,3,4- oxadiazoles based on the reaction of N,N-dimethyl amides with acid hydrazides has been developed. The methodology is applied to a wide range of difference aryl hydrazide and difference N,N-dimethyl amides to 2,5-disubstituted- 1,3,4-oxadiazoles yield the in good to excellent yields. It will be possible wide useful application in synthesis. Copyright

Full text of DOI:10.1002/jccs.201300598

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
One-pot Synthesis of 2,5-Disubstituted-1,3,4-oxadiazoles Based on the Reaction of
N,N-Dimethyl Amides with Acid Hydrazides
Qiang Li,a,b Yi Tao,b Dongfang Xu,a* Haobing Zhangb and Liping Duanb*
aShanghai Normal University, Shanghai 200025, China
bNational Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, WHO Collaborating
Centre for Malaria, Schistosomiasis, and Filariasis, Key laboratory of Parasitology and Vector Biology at National
Institute of Parasitic Diseases, Shanghai 200005, China
(Received: Nov. 14, 2013; Accepted: Jan. 22, 2014; Published Online: ??; DOI: 10.1002/jccs.201300598)
Convenient and efficient one pot method for the synthesis of 2,5-disubstituted-1,3,4-oxadiazoles based on
the reaction of N,N-dimethyl amides with acid hydrazides has been developed. The methodology is ap-
plied to a wide range of difference aryl hydrazide and difference N,N-dimethyl amides to 2,5-disubsti-
tuted-1,3,4-oxadiazoles yield the in good to excellent yields. It will be possible wide useful application in
synthesis.
Keywords: One pot method; Synthesis; 1,3,4-Oxadiazoles derivatives.
INTRODUCTION
1,3,4-Oxadiazoles have been the subject of intensive
in good yield. The details for the syntheses are shown in
Scheme 1 and Table 1.
interest in medicinal chemistry, due to a wide variety of
their biological activities including antifungal, antimitio-
tic, antimycobacterial and antibacterial activities.1-3 Thus,
numerous methods have been explored for the synthesis of
this class of heterocycles. The commonly used synthetic
route for 1,3,4-oxadiazoles involves the cyclization of the
carboxylic acid hydrazides with a variety of dehydrating
reagents under harsh reaction conditions4-7 or the oxidation
of hydrazones using various oxidizing agents. The former
require long reaction times and high temperature.8 As to the
latter, these protocols use expensive catalysts.9-10 There are
a few reliable and operationally simple examples for the
one-step synthesis of 1,3,4-oxadiazoles using acid or or-
thoformate as raw materials.11-13 However, to the best of
our knowledge, preparation of 1,3,4-oxadiazoles utilizing
N,N-dimethyl amide as the reagent has not been reported
yet. Herein we reported in one pot synthesis of 2,5-disub-
stituted-1,3,4-oxadiazoles based on the reaction of N,N-di-
methyl amides with acid hydrazides by phosphorous oxy-
chloride as coupling reagent and cyclo-dehydration cata-
lyst in the absence of any solvent.
Scheme 1
The structures of (3) were characterized by mass
spectrometry and NMR. Elemental analyses of all com-
pounds were in agreement with the calculated values. The
molecular structure of 2-methyl-5-(4-nitrophenyl)-1,3,4-
oxadiazole (3g) was confirmed by X-ray analysis (Figure
1). From the crystal packing picture, a large variety of hy-
drogen-bonded networks was observed; a three-dimen-
sional network was formed by hydrogen bonding of the
benzene group with oxadiazole ring. Some selected bond
lengths and bond angles are listed in Table 2. The O(3)-
C(7) bond (1.3596(17) Å) and O(3)-C(8) bond (1.3663(18)
Å) are shorter than the typical C-O bond (1.43 Å)14 because
of the P-p conjugate effect, similarly, the N(2)-C(7) bond
(1.282(2) Å) and N(3)-C(8) bond (1.277(2) Å) is shorter
than the typical C=N bond (1.35 Å), respectively. The an-
gles containing unsaturated bond C(8)-N(3)-N(2), O(1)-
N(1)-O(2) and N(2)-C(7)-O(3) correspond to 106.24(13)°,
118.88(14)° and 112.38(13)° respectively. The torsion an-
gles of C(2)-C(3)-C(4)-C(7), C(9)-C(8)-O(3)-C(7) were
equal to -179.68(11)° and -179.48(15)°, respectively.
RESULTS AND DISCUSSION
Typically, compounds (3) were prepared by the reac-
tion of corresponding hydrazide (1) with difference N,N-
dimethyl amide (2) and phosphorus oxychloride in one pot
* Corresponding author. Tel: +021-64377008-2606; Email: lipingduan@yahoo.com
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Li et al.
Table 1. Synthesis of 1,3,4-oxadiazoles derivatives using N,N-
in Table 3, a variety of substituents such as F, Cl, Br, NO2,
CN, OMe, Me on the aromatic ring are compatible with this
reaction condition. Similarly the cyclization of hetercyclic
hydrazide such as 3-pyridyl led to the desired oxadizaole in
modest yield. Compared to substrates bearing electron–do-
nating groups, electron-withdrawing substrates gave better
yields. It appears that the electronic property of the acid
hydrazide plays certain roles in the cyclization.
dimethyl amides and acid hydrazides
Substrate
(2a-2c)
Entry Substrate (1a-1i)
Product (3a-3m)
O
O
N
1
N
2a
N
3a
O
O
O
2
NH NH
2
N
2b
N
3b
N
1a
O
Subsequently, we also reacted benzoic acid hydrazide
as well as 3-pyridyl acid hydrazide with several N,N-di-
methyl amides to give the corresponding oxadiazoles.
These results showed that the best substrates was N,N-di-
methyl acetamide, the reaction preceded smoothly in high
yield separately (92%; 83%). N,N-dimethyl benzamide
showed poor activity (79%; 72%) in one hour. In general,
when the N,N-dimethyl amides section contains a large
substituted group, the yields are lower than those of N,N-
dimethyl amides. It demonstrated that steric effect is also
an important influence on a reaction’s course or rate.
The possible mechanism of this reaction is shown in
O
N
3
N
N
3c
2c
O
F
O
NH NH
4
2
N
N
3d
3e
3f
F
1b
O
O
Cl
O
NHNH
5
6
7
8
2
N
N
Cl
1c
Br
O
NHNH
2
N
N
Br
1d
1e
1f
O
O N
2
O
O
NHNH
2
N
N
N
3g
O
N
2
2a
O
NC
O
NHNH
2
N
N
3h
3i
NC
O
H
CO
3
NHNH
2
O
9
H CO
3
N
N
1g
O
O
NHNH
2
10
N
N
3j
H C
3
1h
O
O
11
12
N
N
N
2a
N
3k
O
O
O
N
NHNH
N
2
2b
N
N
3l
N
1i
O
O
N
13
N
N
N
3m
2c
In order to further investigate the generality of this
methodology, the reaction of difference subsutited benzoic
acid hydrazide with difference N,N-dimethyl amides were
performed under similar condition (Table 3). Firstly, we
have tested variations of benzoic acid hydrazide moiety
participating in the formation of oxadiazoles, preserving
the same N,N-dimethyl acetyl amide. As the results shown
Fig. 1. (a) Molecular structure of (3g), (b) crystal
packing of compound (3g).
2
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One-pot Synthesis of 1,3,4-Oxadiazoles Derivatives
Table 2. Selected Bond Lengths (Å) and Bond Angles (°)
Bond
Dist.
Bond
C(7)-N(2)
C(8)-N(3)
Angle
Dist.
Bond
Dist.
C(7)-O(3)
C (8)-O(3)
Angle
1.3596(17)
1.3663(18)
(°)
1.282 (2)
1.277(2)
C(1)-N(1)
C(8)-C(9)
Angle
1.469(2)
1.478(2)
(°)
(°)
C(2)-C(1)-C(6)
C(2)-C(1)-N(1)
C(6)-C(1)-N(1)
C(1)-C(2)-C(3)
C(3)-C(4)-C(5)
C(3)-C(4)-C(7)
C(5)-C(4)-C(7)
122.95(14)
118.41(13)
118.64(13)
118.21(13)
120.42(14)
121.16(13)
118.42(13)
C(6)-C(5)-C(4)
N(2)-C(7)-O(3)
O(1)-N(1)-O(2)
O(3)-C(8)-C(9)
O(1)-N(1)-C(1)
C(7)-O(3)-C(8)
C(8)-N(3)-N(2)
119.95(13)
112.38(13)
122.93(16)
118.16(14)
118.88(14)
102.62(11)
106.24(13)
N(1)-C(1)-C(2)-C(3)
C(2)-C(3)-C(4)-C(7)
N(1)-C(1)-C(6)-C(5)
O(3)-C(7)-N(2)-N(3)
C(3)-C(4)-C(7)-O(3)
C(2)-C(1)-N(1)-O(1)
C(9)-C(8)-O(3)-C(7)
-179.75(12)
-179.68(11)
179.84(12)
-0.47(16)
6.78(19)
-0.8(2)
-179.48(15)
Symmetry transformation: a: x, y+1, z; b: –x, y, –z+1/2; c: –x, –y+1, –z
Scheme 2 The possible mechanism of this reaction
Table 3. Synthesis of 1,3,4-oxadiazoles (3a-3m)
Time
(min)
Yield
(%)
Entry
R1
R2
Product
1
2
3
4
5
6
7
8
Ph
Ph
Ph
CH3
CH3CH2
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
35
40
45
30
32
30
20
20
60
60
40
45
55
92
88
79
93
90
88
96
95
54
57
83
79
72
4-F-C6H4
4-Cl-C6H4
4-Br- C6H4
4-NO2- C6H4
4-CN- C6H4
4-MeO- C6H4
4-Me- C6H4
3-pyridyl
3-pyridyl
3-pyridyl
9
10
11
12
13
3j
3k
3l
3m
Scheme 2. We speculated that Schiff base formed first
through POCl3-assisted coupling, followed by elimination
of HN(CH3)2 and thus resulted in diaroyl hydrazines, fi-
nally the generated diaroyl hydrazines was dehydration
leading to formation of a stable oxadiazole ring. In the
present study intermediate was identified by LC/MS. Ac-
cording to the mass spectrum, it was identified as N¢-((di-
methylamino)(hydroxy)(phenyl)methyl)nicotinohydrazide
in 3-pyridyl acid hydrazide reaction of N,N-dimethyl benz-
amide (Figure 2). The molecular ion was m/z 289.25 [M +
H+]. The positively charged m/z = 244.20 of N¢-benzoyl-
nicotinohydrazide was also proved referring to Figure 2.
This agent POCl3 promotes coupling and cyclization at the
same time: firstly, the conversion of acid hydrazide into
Schiff base as coupling reagent, then as catalyst provide for
acidic environment, which helps Schiff base lead to oxa-
diazole derivatives. This reaction process might provide
the first example of using N,N-dimethyl amides to synthe-
size 1,3,4-oxadiazoles.15-19
In summary, a convenient and efficient one pot
method for the synthesis of 2,5-disubstituted-1,3,4-oxadi-
azoles based on the reaction of N,N-dimethyl amides with
acid hydrazides has been developed. The methodology is
applied to a wide range of difference aryl hydrazide and
difference N,N-dimethyl amides to 2,5-disubstituted-1,3,4-
oxadiazoles yield the in good to excellent yields.
EXPERIMENTAL
All solvents and other reagents were of high purity
(Aldrich and Sigma) and were used without further purification.
Elemental analysis was performed on a PE-2400 Elemental An-
1
alyzer, the C, H and N analysis were repeated twice. H-NMR
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2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) d 164.66, 163.43,
130.61, 127.18, 122.25, 120.45, 11.36; LC-MS [M+H+]: 161.14.
Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N, 17.49. Found: C,
67.40, H, 5.00; N, 17.51. 3b: White solid, m.p.105-107 oC IR
(KBr) v: 3443, 3330, 1639, 1632, 1512, 1423, 1299 cm-1. 1H NMR
(400 MHz, CDCl3) d: 7.71 (d, J = 7.2, 2H), 7.20 (t, J = 7.2, 2H),
7.19 (t, J = 7.2, 1H), 2.21 (m, 2H), 1.37 (t, 3H); 13C NMR (100
MHz, CDCl3) d 164.67, 163.46, 130.61, 127.18, 123.25, 121.45,
11.59, 9.18; LC-MS [M+H+]: 175.15. Anal. Calcd for C10H10N2O:
C, 68.95; H, 5.79; N, 16.08. Found: C, 68.91; H, 5.80; N, 16.09.
3c: White solid, m.p. 136-138 oC IR (KBr) v: 3441, 3328, 1636,
1628, 1501, 1421, 1308 cm-1. 1H NMR (400 MHz, CDCl3) d: 7.73
(d, J = 7.2, 4H), 7.18 (t, J = 7.2, 4H), 7.16 (t, J = 7.2, 2H); 13
C
NMR (100 MHz, CDCl3) d 164.69, 163.56, 129.67, 128.19,
123.27, 121.47; LC-MS [M+H+]: 223.16. Anal. Calcd for
C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.66; H, 4.52;
o
N, 12.53. 3d: White solid, m.p. 100-101 C IR (KBr) v: 3445,
1
3338, 1638, 1629, 1495, 1420, 1298 cm-1. H NMR (400 MHz,
CDCl3) d: 8.05-8.01 (d, J = 8.0, 2H), 7.26-7.22 (d, J = 8.0, 2H),
2.62 (s, 3H); 13C NMR (100 MHz, CDCl3) d 164.45, 163.59,
129.27, 129.18, 116.70, 116.48, 11.35; LC-MS [M+H+]: 179.16.
Anal. Calcd for C10H7FN2O: C, 60.67; H, 3.96; N, 15.72. Found:
C, 60.61; H, 4.00; N, 15.80. 3e: White solid, m.p. 109-110 oC IR
(KBr) v: 3440, 3335, 1640, 1630, 1498, 1422, 1307 cm-1. 1H NMR
(400 MHz, CDCl3) d: 7.98-7.94 (d, J = 8.0, 2H), 7.49-7.45 (d, J =
8.0, 2H), 2.63 (s, 3H); 13C NMR (100 MHz, CDCl3) d 164.00,
163.99, 138.03, 129.63, 128.22, 122.70, 11.32; LC-MS [M+H+]:
195.13. Anal. Calcd for C10H7ClN2O: C, 55.54; H, 3.63; N, 14.39.
Found: C, 55.50; H, 3.60; N, 14.41. 3f: Brown solid, m.p. 118-119
oC IR (KBr) v: 3442, 3337, 1643, 1638, 1503, 1423, 1301 cm-1. 1H
NMR (400 MHz, CDCl3) d: 7.90-7.86 (d, J = 8.0, 2H), 7.65-7.61
(d, J = 8.0, 2H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3) d:
164.66, 163.47, 130.61, 129.18, 120.25, 119.45, 11.38; LC-MS
[M+H+]: 239.10. Anal. Calcd for C10H7BrN2O: C, 45.22; H, 2.95;
N, 11.72. Found: C, 45.25; H, 3.00; N, 11.80. 3g: Brown solid,
m.p. 209.0-210.8 oC IR (KBr) v: 3441, 3338, 1642, 1623, 1498,
1427, 1291 cm-1. 1H NMR (400 MHz, CDCl3) d: 8.39-8.37 (d, J =
8.0, 2H), 8.25-8.23 (d, J = 8.0, 2H), 2.67 (s, 3H); 13C NMR (100
MHz, CDCl3) d 164.66, 163.43, 130.67, 127.87, 124.62, 11.40;
LC-MS [M+H+]: 206.12. Anal. Calcd for C9H7N3O3: C, 52.69; H,
3.44; N, 20.48. Found: C, 52.70; H, 3.44; N, 20.49. 3h: Brown
solid, m.p. 141.5-142.8 oC IR (KBr) v: 3440, 3335, 1640, 1630,
1500, 1422, 1300 cm-1. 1H NMR (400 MHz, CDCl3) d: 8.16-8.14
(d, J = 8.0, 2H), 7.81-7.79 (d, J = 8.0, 2H), 2.67 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 164.79, 163.65, 133.09, 128.04, 127.41,
118.13, 115.28, 114.26, 11.36; LC-MS [M+H+]: 186.15. Anal.
Fig. 2. (a) MS data of (3m) intermediate. (b) MS data
of (3m).
and 13C-NMR spectra were obtained in CDCl3 or DMSO-d6 with
TMS as internal standard on a Bruker AM-400 spectrometer.
Chemical shifts were reported as ppm. Mass spectra were mea-
sured on a LCQ LC-MS spectrometer. Melting points were deter-
mined by an BÜCHI melting point B-540 apparatus and were un-
corrected.
Typical experimental procedure: A solution of difference
acid hydrazide (1) (0.01 mol) was stirred in difference N,N-di-
methyl amide (2) (10 mL) solution. The reaction mixture was
o
heated up to 80 C, phosphorus oxychloride (0.011 mol) was
added into the reaction mixture. After the reaction was com-
pleted, the reaction mixture was added with cold water (50 mL)
and neutralized with Na2CO3 aqueous solution, the solution was
extracted with CH2Cl2. The organic layer was then dried over so-
dium sulfate and evaporated under vacuo. The crude material was
purified by chromatography on silica gel column using ethyl ace-
tate +petroleum ether (1+4 by volume) as eluent. The solvent was
removed under reduced pressure to give 2,5-disubstituted-1,3,4-
oxadiazoles.
o
3a: White solid, m.p. 67-68 C IR (KBr) v: 3440, 3335,
1640, 1630, 1500, 1422, 1300 cm-1. 1H NMR (400 MHz, CDCl3)
d: 7.70 (d, J = 7.0, 2H), 7.19 (t, J = 7.0, 2H), 7.18 (t, J = 7.0, 1H),
4
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One-pot Synthesis of 1,3,4-Oxadiazoles Derivatives
Calcd for C10H7N3O: C, 64.86; H, 3.81; N, 22.69. Found: C, 64.
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3444, 3338, 1648, 1631, 1509, 1425, 1308 cm-1. H NMR (400
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MHz, DMSO-d6) d: 9.30 (s, 1H), 8.80 (d, 1H), 8.47 (d, 1H), 8.23
(d, 2H), 7.70-7.65 (m, 4H), 2.70 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) d 164.67, 162.48, 151.98, 146.80, 143.81, 129.69,
127.18, 124.62, 123.75, 121.54, 11.78; LC-MS [M+H+]: 162.12.
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o
59. 66; H, 4.40; N, 26.10. 3l: White solid, m.p. 136-138 C IR
(KBr) v: 3441, 3335, 1645, 1628, 1500, 1420, 1303 cm-1. 1H NMR
(400 MHz, DMSO-d6) d: 9.28 (s, 1H), 8.89 (d, 1H), 8.43 (d, 1H),
8.17 (d, 2H), 7.73-7.69 (m, 4H), 2.72 (m, 2H), 1.63 (t, 3H); 13C
NMR (100 MHz, DMSO-d6) d: 164.67, 162.43, 152.65, 146.82,
142.67, 129.61, 127.18, 125.26, 122.35, 120.45, 20.14, 11.76;
LC-MS [M+H+]: 176.13. Anal. Calcd for C9H9N3O: C, 61.70; H,
5.18; N, 23.99. Found: C, 61.68; H, 5.20; N, 23.98. 3m: White
solid m.p. 107.7-109.9 oC IR (KBr) v: 3440, 3330, 1638, 1631,
1499, 1428, 1300 cm-1. 1H NMR (400 MHz, DMSO-d6) d: 9.31
(s, 1H), 8.82 (d, 1H, J = 4.5), 8.49 (d, J = 4.2, 1H), 8.15 (d, J = 4.1,
2H), 7.69-7.67 (m, 4H); 13C NMR (100 MHz, DMSO-d6) d:
164.66, 162.43, 151.78, 147.82, 142.67, 130.61, 127.18, 124.24,
122.25, 120.45; LC-MS [M+H+]: 224.14. Anal. Calcd for
C13H9N3O: C, 69.95; H, 4.06; N, 18.82. Found: C, 70.00; H, 4.08;
N, 18.98.
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ACKNOWLEDGEMENTS
The authors wish to acknowledge that this project is
supported by Shanghai Municipal Natural Science Founda-
tion (12ZR1434900), the Opening Project of Shanghai Key
Laboratory of New Drug Design (Grant No. 11DZ2260600).
The crystallographic data have been assigned the deposi-
tion numbers at the Cambridge crystallographic data center
(CCDC949962).
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