Synthesis of 3-(5-aryl-1,3,4-oxadiazol-2-yl)chromones

Article abstract of DOI:10.1023/B:COHC.0000003526.98678.6e

A general method was proposed for the synthesis of 3-(5-aryl-1,3,4-oxadiazol-2-yl)chromones starting from 3-formylchromone. This aldehyde yields acylhydrazones, from which the corresponding unstable nitrile imines are generated. These intermediates undergo intramolecular 1,3-dipolar cycloaddition.

Full text of DOI:10.1023/B:COHC.0000003526.98678.6e

Chemistry of Heterocyclic Compounds, Vol. 39, No. 8, 2003
SYNTHESIS OF 3-(5-ARYL-
1,3,4-OXADIAZOL-2-YL)CHROMONES
1,2
1
L. Cao and W. Wang
A general method was proposed for the synthesis of 3-(5-aryl-1,3,4-oxadiazol-2-yl)chromones starting
from 3-formylchromone. This aldehyde yields acylhydrazones, from which the corresponding unstable
nitrile imines are generated. These intermediates undergo intramolecular 1,3-dipolar cycloaddition.
Keywords: 3-hetarylchromones, 1,3,4-oxadiazoline, 3-formylchromone, synthesis.
3
-Hetarylchromones have a broad range of biological activity and display high anti-allergy, anti-
cholesterol, hypolipidemic, antimicrobial, fungicidal, and antiblastic activity. Some of these compounds are also
central nervous system stimulants [1]. Hence, considerable recent attention has been given to new compounds of
this series.
Frasinyuk and Khilya [1] have surveyed the methods for synthesizing 3-hetarylchromones and found
two major approaches: 1) construction of the chromone system from substituted α-hetaryl-2-
hydroxyacetophenones with participation of suitable reagents and 2) introduction of the heterocycle into a
prepared chromone system. In the present work, we selected the second approach for the synthesis of previously
unreported 3-(5-aryl-1,3,4-oxadiazol-2-yl)chromones starting from available 3-formylchromone (1) [2].
O
O
ArCONHNH2
CHO
CH=NNHCOAr
O
O
1
2a–i
O
O
Br /NaOAc
AcOH
2
N
N
O
Ar
3
a–i
2
, 3 a Ar = Ph, b Ar = o-ClC H , c Ar = o-(O N)C H , d Ar = p-(O N)C H ,
6
4
2
6
4
2
6 4
N
N
N
N
N
N
Ar =
CF3
g Ar =
e Ar =
f
,
,
,
N
CH2
N
CH2
CO–
N
N
h Ar =
, i Ar =
N
N
Me
_
_________________________________________________________________________________________
1
Chemistry Faculty, Sinsiang University, 830046 Urumchi, Chinese People's Republic; e-mail:
2
clhxj@xju.edu.cn. State Central Laboratory, Nankai University, 300070 Tientsin, Chinese People's Republic.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1227-1230, August, 2003. Original article
submitted October 21, 2002.
1
072
0009-3122/03/3908-1072$25.00©2003 Plenum Publishing Corporation

The reaction of 1 and aroylhydrazines gave the corresponding aroylhydrazones 2a-i. Then, the action of
bromine in the presence of sodium acetate on these hydrazones 2 gave intermediate nitrile imines [3], which
undergo intramolecular cycloaddition to give 3-(5-aryl-1,3,4-oxadiazol-2-yl)chromones 3.
-
1
The IR spectra of aroylhydrazones 2a-i have characteristic bands at 3200-3300 (NH) and 1630-1650 cm
1
(
(
C=O). The H NMR spectra of aroylhydrazones 2a-i show signals at 8.2-8.9 (pyrone 2-H) and 9.3-10.2 ppm
NH). The molecular ion peak in the mass spectra of these compounds has low intensity due to their instability.
+
The appearance of peaks with mass number 187 and ArCO peaks indicates that the C(O)–N bond is readily
+
+
cleaved and the major peak usually corresponds to the ArCO fragment except for 2g, for which the C
6
H peak
5
with mass number 77 predominates. The pyrone ring is split by a reverse Diels–Alder reaction, leading to a
fragment with m/z 120. The stepwise loss of one CO group and formation of fragments with m/z 92 and 64 is
then noted.
-1
The IR spectra of 3-(5-aryl-1,3,4-oxadiazol-2-yl)chromones 3a-i lack the band at 3200-3300 cm found
1
for hydrazones 2. The H NMR spectra of 3a-i lack signals at 9.3-10.2 ppm. Proton 2-H of the pyrone ring is
seen as a narrow signal at 5.8-6.1 ppm since it is affected by the unshared electron pair of the heteroatom of the
heterocyclic substituent at C-3 of the chromone.
Chromones 3a-a have a stable conjugation system. Thus, the molecular ion is the major peak in their
mass spectra. As a consequence, the oxadiazole ring is readily cleaved and a strong peak with m/z 173
+
(
[M - ArCN
2
]) ) is noted.
EXPERIMENTAL
GF-254 Plates were used for thin-layer chromatography. The melting points were determined using an
MP-S3 table manufactured in Japan. An MT-3 automatic analyzer was used for elemental analysis. The IR
1
spectra were taken on a Bruker EQUINOX-55 FT-IR spectrometer for KBr pellets. The H NMR spectra were
taken on a Bruker AX-200 spectrometer at 200 MHz in CDCl
3
or DMSO-d with TMS as the internal standard.
6
The mass spectra were taken on a HP 5988 automatic mass spectrometer.
General Method for the Preparation of Aroylhydrazones 2a-i. 3-Formylchromone 1 and
aroylhydrazones obtained taking account of the work of Chen [4] were mixed in equivalent amounts and then
dissolved in 95% aq. ethanol. A few drops of glacial acetic acid were added and the mixture was heated at
reflux for 5-6 h. After cooling, the crystalline precipitate was filtered off and recrystallized from abs. ethanol to
give aroylhydrazones 2a-i.
-1
Hydrazone 2a was obtained in 78% yield; mp 176-178°C. IR spectrum, ν, cm : 3280 (–NH–), 3076
1
(
Ar–H), 1679 (C=O), 1636 (C=N), 1070 (C–O–C). H NMR spectrum, δ, ppm: 10.21 (1H, br. s, NH); 8.87 (1H,
+
s, 2-H); 7.24-7.98 (10H, m, CH=N, Ar-H). Mass spectrum, m/z 292 [M] . Found, %: C 70.31; H 4.19; N 9.68.
C
H
17 12
N
2
O . Calculated, %: C 69.86; H 4.14; N 9.58.
3
-
1
Hydrazone 2b was obtained in 80% yield; mp 193-195°C. IR spectrum, ν, cm : 3230 (–NH–), 3059
1
(
Ar–H), 1674 (C=O), 1633 (C=N), 1059 (C–O–C), 656 (C–Cl). H NMR spectrum, δ, ppm: 10.15 (1H, br. s,
+
NH); 8.77 (1H, s, 2-H); 7.23-7.92 (9H, m, CH=N, Ar–H). Mass spectrum, m/z 328, 326 [M] . Found, %:
C 61.89; H 3.41; N 8.67. C17
H11ClN
2
O . Calculated, %: C 62.49; H 3.39; N 8.57.
3
-1
Hydrazone 2c was obtained in 95% yield; mp 206-207°C. IR spectrum, ν, cm : 3267 (–NH–), 3079
1
(
Ar–H), 1666 (C=O), 1633 (C=N), 1520, 1341 (–NO
2
), 1071 (C–O–C). H NMR spectrum, δ, ppm: 9.74 (1H,
+
br. s, NH); 8.70 (1H, s, 2-H); 8.42 (1H, d, CH=N); 7.23-7.92 (8H, m, Ar–H). Mass spectrum, m/z 337 [M] .
Found, %: C 60.63; H 3.31; N 12.40. C17
H
11
N
3
5
O . Calculated, %: C 60.54; H 3.29; N 12.46.
-1
Hydrazone 2d was obtained in 90% yield; mp 230-232°C. IR spectrum, ν, cm : 3260 (–NH–), 3071
1
(
(
Ar–H), 1670 (C=O), 1636 (C=N), 1498, 1319 (–NO
2
), 1518, 1338 (C–O–C). H NMR spectrum, δ, ppm: 9.72
+
1H, br. s, NH); 8.76 (1H, s, 2-H); 8.47 (1H, d, CH=N); 7.25-7.98 (8H, m, Ar–H). Mass spectrum, m/z 337 [M] .
. Calculated, %: C 60.54; H 3.29; N 12.45.
Found, %: C 60.32; H 3.21; N 12.58. C17
H
11
N
3
O
5
1
073

-1
Hydrazone 2e was obtained in 54% yield; mp 250-251.5°C. IR spectrum, ν, cm : 3251 (–NH–), 3043
1
(
Ar–H), 1636 (C=O), 1617 (C=N), 1097 (C–O–C). H NMR spectrum, δ, ppm: 9.83 (1H, br. s, NH); 8.35 (1H,
+
s, 2-H); 8.20 (1H, s, triazole H); 7.25-8.03 (10H, m, Ar–H). Mass spectrum, m/z 359 [M] . Found, %: C 64.19;
H 3.69; N 19.79. C19
H
13
N
5
O . Calculated, %: C 63.51; H 3.65; N 19.49.
3
-
1
Hydrazone 2f was obtained in 85% yield; mp 225-227°C. IR spectrum, ν, cm : 3220 (–NH–), 2994
1
(
Ar–H), 1698 (C=O), 1639 (C=N), 1119 (C–O–C). H NMR spectrum, δ, ppm: 9.32 (1H, br. s, NH); 8.58 (1H,
+
s, 2-H); 8.31 (1H, d, CH=N); 7.24-7.92 (8H, m, Ar–H); 5.94 (2H, s, CH
2
). Mass spectrum, m/z 414 [M] .
Found, %: C 57.95; H 3.20; N 13.63. C20
H
13
F N
3 4
3
O . Calculated, %: C 57.98; H 3.16; N 13.52.
-1
Hydrazone 2g was obtained in 61% yield; mp 240-241°C. IR spectrum, ν, cm : 3219 (–NH–), 2990
1
(
Ar–H), 1698 (C=O), 1640 (C=N), 1109 (C–O–C). H NMR spectrum, δ, ppm: 9.63 (1H, br. s, NH); 8.52 (1H,
+
s, 2-H); 8.30 (1H, d, CH=N); 7.23-7.86 (8H, m, Ar–H); 5.52 (2H, s, CH
2
). Mass spectrum, m/z 347 [M] .
Found, %: C 62.20; H 3.80; N 20.21. C18
H
13
N
5
3
O . Calculated, %: C 62.25; H 3.77; N 20.16.
-1
Hydrazone 2h was obtained in 90% yield; mp 214-216°C. IR spectrum, ν, cm : 3262 (–NH–), 3093
1
(
(
Ar–H), 1682 (C=O), 1648 (C=N), 1046 (C–O–C). H NMR spectrum, δ, ppm: 9.96 (1H, br. s, NH); 8.92, 8.81
+
2H, Py–H); 8.2 (1H, s, 2-H); 7.33-7.74 (7H, m, Ar–H, Py–H). Mass spectrum, m/z 293 [M] . Found, %:
C 66.04; H 3.83; N 14.53. C16
H
11
N
3
3
O . Calculated, %: C 65.53; H 3.78; N 14.33.
-
1
Hydrazone 2i was obtained in 92% yield; mp 223.5-225°C. IR spectrum, ν, cm : 3240 (–NH–), 3069
1
(
2
Ar–H), 1677 (C=O), 1641 (C=N), 1059 (C–O–C). H NMR spectrum, δ, ppm: 9.56 (1H, br. s, NH); 8.5 (1H, s,
+
-H); 8.25 (1H, d, CH=N); 7.56-7.26 (9H, m, Ar–H); 2.69 (3H, s, CH
3
). Mass spectrum, m/z 373 [M] .
Found, %: C 64.56; H 3.98; N 18.82. C20
H
15
N
5
3
O . Calculated, %: C 64.34; H 4.05; N 18.76.
General Method for the Preparation of 3-(5-Aryl-1,3,4-oxadiazol-2-yl)chromones 3a-i. A sample of
bromine (2.2 mmol) in glacial acetic (5 ml) was added dropwise to a solution of aroylhydrazone 2a-i (2 mmol)
and fused sodium acetate (10 mmol) in glacial acetic acid (10 ml) and stirred vigorously for 2-3 h at room
temperature. The reaction mixture was poured into chopped ice. The precipitate formed was recrystallized from
absolute ethanol to give chromones 3a-i.
3
-(5-Phenyl-1,3,4-oxadiazol-2-yl)chromone (3a) was obtained in 62% yield; mp 224-226°C. IR
-
1
1
spectrum, ν, cm : 3044 (Ar–H), 1683 (Ar–H), 1683 (C=O), 1629 (C=N), 1029 (C–O–C). H NMR spectrum,
+
δ, ppm: 7.24-7.99 (9H, m, Ar–H); 5.93 (1H, s, 2-H). Mass spectrum, m/z 290 [M] . Found, %: C 70.66; H 3.51;
N 9.73. C17
H
10
N
2
O . Calculated, %: C 70.34; H 3.47; N 9.65.
3
3
-[5-(o-Chlorophenyl)-1,3,4-oxadiazol-2-yl]chromone (3b) was obtained in 71% yield;
-
1
1
mp 202-205°C. IR spectrum, ν, cm : 3025 (Ar–H), 1690 (C=O), 1635 (C=N), 1044 (C–O–C). H NMR
+
spectrum, δ, ppm: 7.25-7.83 (8H, m, Ar–H); 6.01 (1H, s, 2-H). Mass spectrum, m/z 324 [M] . Found, %:
C 62.62; H 2.83; N 8.77. C17
H
9
ClN
2
3
O . Calculated, %: C 62.88; H 2.79; N 8.63.
3
-[5-(o-Nitrophenyl)-1,3,4-oxadiazol-2-yl]chromone (3c) was obtained in 68% yield; mp 222-224°C.
-1
1
IR spectrum, ν, cm : 3058 (Ar–H), 1672 (C=O), 1627 (C=N), 1520, 1341 (–NO
2
), 1088 (C–O–C). H NMR
+
spectrum, δ, ppm: 7.34-8.12 (8H, m, Ar–H); 5.82 (1H, s, 2-H). Mass spectrum, m/z 335 [M] . Found, %:
C 60.20; H 2.79; N 12.70. C17
H
9
N
3
5
O . Calculated, %: C 60.90; H 2.71; N 12.53.
3
-[5-(p-Nitrophenyl)-1,3,4-oxadiazol-2-yl]chromone (3d) was obtained in 61% yield; mp 258-260°C.
-1
1
IR spectrum, ν, cm : 3079 (Ar–H), 1681 (C=O), 1632 (C=N), 1498, 1319 (–NO
2
), 1060 (C–O–C). H NMR
+
spectrum, δ, ppm: 7.5-7.8 (8H, m, Ar–H); 5.84 (1H, s, 2-H). Mass spectrum, m/z 335 [M] . Found, %: C 61.08;
H 2.74; N 12.57. C17
H
9
N
3
5
O . Calculated, %: C 60.90; H 2.71; N 12.53.
3
-[5-(2-Phenyl-1,2,3-triazol-4-yl)-1,3,4-oxadiazol-2-yl]chromone (3e) was obtained in 50% yield;
-
1
1
mp >280°C. IR spectrum, ν, cm : 2980 (Ar–H), 1697 (C=O), 1653 (C=N), 1013 (C–O–C). H NMR spectrum,
+
δ, ppm: 7.40-8.14 (10H, m, triazole H, Ar–H); 5.95 (1H, s, 2-H). Mass spectrum, m/z 357 [M] . Found, %:
C 63.71; H 3.16; N 19.76. C19
H
11
N
5
3
O . Calculated, %: C 63.87; H 3.10; N 19.60.
1
074

3
-[5-(2-Trifluoromethylbenzimidazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]chromone (3f) was obtained
-1
in 80% yield; mp 236-238°C. IR spectrum, ν, cm : 3020 (Ar–H), 2994 (–CH
2
), 1688 (C=O), 1638 (C=N), 1114
). Mass
. Calculated, %: C 58.26; H 2.69;
1
(
C–O–C). H NMR spectrum, δ, ppm: 7.22-7.94 (8H, m, Ar–H); 5.80 (1H, s, 2-H); 5.52 (2H, s, CH
2
+
spectrum, m/z 412 [M] . Found, %: C 58.23; H 2.71; N 13.63. C20
H F
11 3
N O
4 3
N 13.59.
3
-[5-(Benzotriazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]chromone (3g) was obtained in 52% yield;
-1
mp 254-256°C. IR spectrum, ν, cm : 3089 (Ar–H), 2958 (–CH
2
), 1694 (C=O), 1646 (C=N), 1100 (C–O–C).
1
H NMR spectrum, δ, ppm: 7.24-7.76 (8H, m, Ar–H); 5.84 (1H, s, 2-H); 5.33 (2H, s, CH
2
). Mass spectrum,
+
m/z 345 [M] . Found, %: C 62.78; H 3.26; N 20.38. C18
H
11
N
5
O . Calculated, %: C 62.61; H 3.21; N 20.28.
3
3
-[5-(Pyridin-3-yl)-1,3,4-oxadiazol-2-yl]chromone (3h) was obtained in 55% yield; mp 199-201°C. IR
-
1
1
spectrum, ν, cm : 3046 (Ar–H), 1677 (C=O), 1620 (C=N), 1081 (C–O–C). H NMR spectrum, δ, ppm: 9.33,
+
8
.90, 8.71, 8.12 (4H, Py-H); 7.59-7.94 (4H, m, Ar–H); 5.90 (1H, s, 2-H). Mass spectrum, m/z [M] . Found, %:
C 65.90; H 3.01; N 14.48. C16
H
9
N
3
3
O . Calculated, %: C 65.98; H 3.11; N 14.43.
3
-[5-(5-Methyl-1-phenyl-1,2,3-triazol-4-yl)-1,3,4-oxadiazol-2-yl]chromone (3i) was obtained in 75%
-
1
1
yield; mp 218-220°C. IR spectrum, ν, cm : 3067 (Ar–H), 1669 (C=O), 1633 (C=N), 1056 (C–O–C). H NMR
+
spectrum, δ, ppm: 7.24-7.55 (9H, m, Ar–H); 6.05 (1H, s, 2-H); 2.65 (3H, s, CH
3
). Mass spectrum, m/z 371 [M] .
Found, %: C 64.71; H 3.57; N 18.91. C20
H
13
N
5
3
O . Calculated, %: C 64.69; H 13.53; N 18.86.
The authors express their gratitude for the financial support of the State Natural Sciences Fund of the
Chinese People's Republic (29962002) and State Central Heteroorganic Laboratory of Nankai University in the
Chinese People's Republic.
REFERENCES
1.
2.
3.
4.
M. S. Frasinyuk and V. P. Khilya, Khim. Geterotsikl. Soedin., 3 (1999).
A. Nohara, T. Umetani, and Y. Sanno, Tetrahedron Lett., 22, 1995 (1973).
M. S. Gibson, Tetrahedron, 18, 1377 (1962).
L. M. Chen, Z. Y. Zhang, X. Zhang, et al., Chem. J. Chin. Univ., 9, 283 (1988).
1
075