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

Article abstract of DOI:10.1023/B:COHC.0000027895.56561.7a

A method is proposed for the synthesis of 3-(3-acetyl-5-aryl-2,3-dihydro-1, 3,4-oxadiazol-2-yl)chromones which consists of the conversion of 3-formylchromones to aroylhydrazones and their subsequent heterocyclization using acetic anhydride.

Full text of DOI:10.1023/B:COHC.0000027895.56561.7a

Chemistry of Heterocyclic Compounds, Vol. 40, No. 2, 2004
SYNTHESIS OF 3-(3-ACETYL-
5-ARYL-2,3-DIHYDRO-1,3,4-
OXADIAZOL-2-YL)CHROMONES
L. Cao, L. Zhang, and J. J. Liu
A method is proposed for the synthesis of 3-(3-acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones
which consists of the conversion of 3-formylchromones to aroylhydrazones and their subsequent
heterocyclization using acetic anhydride.
Keywords: 3-hetarylchromones, 1,3,4-oxadiazolines.
3
-Hetarylchromones show a broad range of biological actions. They show high antiallergic,
anticholesteremic, hypolipidemic, antimicrobial, fungicidal, and antiblastic activity, as well they are stimulators
of the central nervous system [1]. For this reason much attention has been paid to the synthesis of novel
compounds in recent times.
Methods for the synthesis of 3-hetarylchromones has been collected in the review [1]. Two proposed
basic routes have been identified. The first is the construction of the chromone system from substituted
α-hetaryl-2-hydroxyacetophenones and the second is the introduction of the heterocycle into a prepared
chromone system.
In the present work we have selected the second approach to the synthesis of the previously unknown
3
-(3-acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones 1a-l using the available 3-formylchromones 2a-l
[2, 3].
R1
R1
O
O
O
O
ArCONHNH2
R2
R2
CHO
CH=NNHCOAr
2
a–l
3a–l
R1
O
COMe
(
MeCO) O
2
N
N
R2
reflux
O
O
Ar
1
a–l
, d Ar = p-O
, h Ar = p-O NC
i R = R = Cl, Ar = Ph; j Ar = o-ClC H , k Ar = p-MeOC H , l Ar = p-O NC H
1
2
1
–3 a R = H, R = Me, Ar = Ph; b Ar = o-ClC
6
H
4
, с Ar = p-MeOC
6
H
4
2 6 4
NC H ,
H ,
6 4
1
2
e R = H, R = Br, Ar = Ph; f Ar = o-ClC
6
H
4
, g Ar = p-MeOC
6
H
4
2
1
2
6
4
6
4
2
6
4
_
_________________________________________________________________________________________
Chemistry Faculty, Xinjiang University, Urumchi 830046, Peoples Republic of China; e-mail:
clhx@xju.edu.cn. State Central Laboratory, Nankai University, Tianjin 300070, Peoples Republic of China.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 252-256, February, 2004. Original article
submitted October 21, 2002.
2
14
0009-3122/04/4002-0214©2004 Plenum Publishing Corporation

Treatment of the 3-formylchromones with aroylhydrazines gave the corresponding aroylhydrazones 3a-l.
In the presence of acetic anhydride these undergo heterocyclization to give the 3-(3-acetyl-5-aryl-2,3-dihydro-
1
,3,4-oxadiazol-2-yl)chromones 1a-l.
The structures of compounds 1a-l and 3a-l were confirmed by elemental analytical data and from IR,
H NMR, and mass spectra. The characteristics of compounds 1a-l and 3a-l are given in Table 1 and the
H NMR and mass spectra in Tables 2 and 3.
1
1
TABLE 1. Characteristics of Compounds 1a-l and 3a-l
Found, %
Com-
pound
Empirical
formula
——————
Calculated, %
mp, °С
Yield, %
С
Н
N
1
1
1
1
1
1
1
1
1
1
1
1
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
20
20
21
20
19
19
20
19
19
19
20
19
18
18
19
18
17
17
18
17
17
17
18
17
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
16
N
2
O
4
68.91
4.65
4.63
3.96
3.95
4.81
4.79
3.86
3.84
3.19
3.17
2.72
2.70
3.43
3.41
2.65
2.64
3.02
3.00
2.56
2.53
3.24
3.26
2.48
2.47
4.64
4.61
3.87
3.85
4.77
4.79
3.71
3.73
2.97
2.99
2.49
2.48
3.28
3.27
2.44
2.42
2.80
2.79
2.30
2.29
3.07
3.09
2.24
2.23
8.07
8.04
7.35
7.32
7.36
7.40
10.71
10.68
6.81
6.78
6.29
6.26
6.35
6.32
9.19
9.17
6.92
6.95
6.44
6.40
6.49
6.47
9.39
9.37
9.13
9.15
8.24
8.22
8.40
8.33
12.04
11.96
7.58
7.55
6.94
6.91
7.01
6.98
10.08
10.10
7.70
7.76
7.11
7.08
7.18
7.16
10.39
10.35
173-174
187-188
248-249
222-224
215-216
206-207
233-234
228-229
136-137
204-205
239-241
212-214
209-210
234-235
214-216
235-236
217-218
197-198
207-208
195-196
211-213
176-177
188-190
283-284
80
52
47
43
79
51
47
42
83
52
44
54
85
75
60
57
88
72
62
70
82
60
55
51
6
8.96
15ClN
2
O
4
62.70
2.75
6
18
15
N
2
3
O
5
6
2
66.60
6.66
6
N
O
61.06
1.07
6
13BrN
O
4
55.20
5.23
5
12ClBrN
2
O
4
51.01
0.98
5
g
h
i
15BrN
12BrN
2
O
5
6
54.23
4.19
5
3
O
49.85
9.80
4
12Cl
11Cl
14Cl
11Cl
2
3
2
2
N
N
N
N
2
2
2
3
O
O
O
O
4
56.66
6.60
5
j
4
5
6
52.16
2.14
5
k
l
55.47
5.45
5
50.89
0.91
5
a
b
c
d
e
f
14
N
2
O
3
70.54
0.58
7
13ClN
2
O
3
63.40
3.44
6
16
13
N
2
3
O
4
67.90
7.85
6
N
O
5
61.60
1.54
6
11BrN
2
O
3
55.11
5.01
5
10ClBrN
2
O
3
50.40
0.34
5
g
h
i
13BrN
2
3
O
4
5
53.92
3.89
5
10BrN
O
49.09
9.06
4
10Cl
2
N
2
O
3
56.58
6.53
5
j
9
Cl
3
N
2
O
3
51.58
1.61
5
k
l
12Cl
2
N
2
O
4
55.30
5.26
5
9
Cl
2
N
3
O
5
50.24
0.27
5
2
15

1
TABLE 2. H NMR Spectra of Compounds 1a-l and 3a-l
Com-
pound
1
Н NMR spectrum, δ, ppm
1
1
1
1
1
1
1
1
1
1
1
1
3
3
3
a
b
c
d
e
f
8.83 (1H, s, 2-H); 8.39-7.28 (8H, m, 5, 7, 8-H, Ar–H); 7.01(1H, s, 2'-H);
.33 (3H, s, CH ); 2.37 (3H, s, COCH
8.89 (1H, s, 2-H); 8.29-7.25 (7H, m, 5, 7, 8-H, Ar–H); 7.07 (1H, s, 2'-H);
.30 (3H, s, CH ); 2.35 (3H, s, COCH
8.92 (1H, s, 2-H); 8.23-7.16 (7H, m, 5, 7, 8-H, Ar–H); 7.09 (1H, s, 2'-H);
.28 (3H, s, CH ); 2.37 (3H, s, COCH ); 3.59 (3H, s, OCH
8.81 (1H, s, 2-H); 8.39-7.28 (7H, m, 5, 7, 8-H, Ar–H); 7.12 (1H, s, 2'-H);
.28 (3H, s, COCH
8.87 (1H, s, 2-H); 8.31-7.22 (7H, m, 5, 7, 8-H, Ar–H); 7.07 (1H, s, 2'-H);
.37 (3H, s, COCH
8.79 (1H, s, 2-H); 8.35-7.18 (7H, m, 5, 7, 8-H, Ar–H); 7.12 (1H, s, 2'-H);
.28 (3H, s, COCH
8.95 (1H, s, 2-H); 8.28-7.12 (7H, m, 5, 7, 8-H, Ar–H); 7.09 (1H, s, 2'-H);
.28 (3H, s, COCH ); 3.62 (3H, s, OCH
8.91 (1H, s, 2-H); 8.25-7.10 (7H, m, 5, 7, 8-H, Ar–H); 7.03 (1H, s, 2'-H);
.39 (3H, s, COCH
8.88 (1H, s, 2-H); 8.13-7.22 (7H, m, 5, 7-H, Ar–H); 7.15 (1H, s, 2'-H);
.37 (3H, s, COCH
8.91 (1H, s, 2-H); 8.28-7.23 (6H, m, 5, 7-H, Ar–H); 7.09 (1H, s, 2'-H);
.28 (3H, s, COCH
8.91 (1H, s, 2-H); 8.19-7.18 (6H, m, 5, 7-H, Ar–H); 7.03 (1H, s, 2'-H);
.38 (3H, s, COCH ); 3.65 (3H, s, OCH
8.94 (1H, s, 2-H); 8.25-7.13 (6H, m, 5, 7-H, Ar–H); 7.00 (1H, s, 2'-H);
.31 (3H, s, COCH
12.21 (1H, br. s, NH); 8.87 (1H, s, 2-H); 7.24-7.98 (9H, m, CH=N, 5, 7, 8-H, Ar–H);
.31(3H, s, CH
12.15 (1H, br. s, NH); 8.77 (1H, s, 2-H); 7.23-7.92 (8H, m, CH=N, 5, 7, 8-H, Ar–H);
.31(3H, s, CH
12.08 (1H, br. s, NH); 8.70 (1H, s, 2-H); 7.28-8.10 (8H, m, CH=N, 5, 7, 8-H, Ar–H);
.31(3H, s, CH ); 3.56(3H, s, OCH
2
3
3
)
2
3
3
)
2
3
3
3
)
2
3
)
2
3
)
2
3
)
g
h
i
2
3
3
)
2
3
)
2
3
)
j
2
3
)
k
l
2
3
3
)
2
3
)
а
b
c
2
3
)
2
3
)
2
3
3
)
3
3
3
3
d
e
f
11.89 (1H, br. s, NH); 8.76 (1H, s, 2-H); 7.12-8.21 (8H, m, CH=N, 5, 7, 8-H, Ar–H)
11.98 (1H, br. s, NH); 8.79 (1H, s, 2-H); 7.22-8.19 (9H, m, CH=N, 5, 7, 8-H, Ar–H)
11.89 (1H, br. s, NH); 8.76 (1H, s, 2-H); 7.12-8.21 (8H, m, CH=N, 5, 7, 8-H, Ar–H)
12.00 (1H, br. s, NH); 8.52 (1H, s, 2-H); 7.23-8.25 (8H, m, CH=N, 5, 7, 8-H, Ar–H);
g
3
3
.66 (3H, s, OCH )
3
3
3
3
h
i
11,95 (1H, br. s, NH); 8.92 (1H, s, 2-H); 7.23-8.25 (8H, m, CH=N, 5, 7, 8-H, Ar–H)
12.02 (1H, br. s, NH); 8.58 (1H, s, 2-H); 7.23-8.33 (8H, m, CH=N, 5, 7-H, Ar–H)
11.83 (1H, br. s, N–H); 8.97 (1H, s, 2-H); 7.21-8.17 (7H, m, CH=N, 5, 7-H, Ar–H)
11.98 (1H, br. s, N–H); 8.97 (1H, s, 2-H); 7.13-8.32 (7H, m, CH=N, 5, 7-H, Ar–H);
j
k
3
.66 (3H, s, OCH
3
)
3
l
12.10 (1H, br. s, N–H); 8.95 (1H, s, 2-H); 7.22-8.38 (7H, m, CH=N, 5, 7-H, Ar–H)
The IR spectra of the aroylhydrazones 3a-l show characteristic absorption bands at 3100-3200 (NH),
-
1
1
1
660-1670 (C=O), 1620-1640 (C=N), and 1590-1610 cm . The H NMR spectra of aroylhydrazones 3a-l show
signals in the range 8.5-9.0 ppm for the 2-H of the pyrone ring and at 11.8-12.2 ppm for the NH group proton.
Due to the instability of the aroylhydrazones the molecular ion peak in their mass spectra was of low intensity.
+
The appearance of peaks for [M-ArCO] shows that the amide C–N bond undergoes fission readily. The
chromone ring is broken via a retro Diels–Alder reaction and is then stabilized by a stepwise fission at the single
CO group.
The IR spectra of the 3-(3-acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones 1a-l show the
-
1
absence of the absorption bands at 3100-3200 cm . Instead there are found bands characteristic of chromones
-
1
-1
(
1
1592-1620 and 1475-1510 cm ) and an acetyl group (1750-1760 cm ). The signal for the NH in the region
1
1.8-12.2 ppm is absent in the H NMR spectra.
16
2

TABLE 3. Mass Spectra of Compounds 1a-l and 3a-l
Com-
pound
Mass spectrum, m/z (%)
+
1
1
1
1
1
a
b
c
348 (M , 3), 305(100), 187, 160, 135, 91, 77, 51, 43(48)
+
+
384 ([M+2] , 1), 382 (M , 3), 341(33), 339(100), 187, 160, 135, 91, 77, 51, 43(52)
+
378 (M , 4), 335(100), 187, 160, 135, 91, 77, 51, 43(60)
+
d
e
393 ((M , 6), 350(100), 187, 173, 160, 135, 91, 77, 65, 43(50)
+
+
414 ([M+2] , 2), 412 (M , 2), 371, 369(100), 266, 264, 252, 250, 240, 238,
24, 215, 213, 121,119, 43(62)
2
+
+
+
1
f
450 ([M+4] , 1), 448 ([M+2] , 4), 446 (M , 3), 407, 405, 403(100), 253,
51, 226, 224, 201, 199, 121, 119, 43(38)
2
+
+
1
1
1
1
1
1
g
h
i
444 ([M+2] , 2), 442 (M , 2), 401(98), 399(100), 253, 251, 226, 224, 201, 199, 43(49)
+
+
459 ([M+2] , 3), 457 (M , 4), 416(97), 414(100), 253, 251, 226, 224, 201, 199, 43(60)
+
402 (M , 1), 363(12), 361(67), 359(100), 245, 243, 241, 218, 216, 214, 189, 43(49)
+
j
436 (M , 2), 397(10), 395(66), 393(100), 245, 243, 241, 218, 216, 214, 189, 43(51)
+
k
l
432 (M , 1), 393(11), 391(67), 389(100), 245, 243, 241, 218, 216, 214, 189, 43(46)
+
+
+
451 ([M+4] , 1), 449 ([M+2] , 5), 447 (M , 8), 408, 406, 404(100), 245, 243, 241,
2
18, 216, 214, 189, 43(53)
+
3
3
а
306 (M ,10), 278, 262, 260, 201, 173, 172, 160, 135, 105(100), 91, 77, 65
+
+
b
342 ([M+2] , 6), 340 (M ,19), 298, 296, 173, 172, 160, 141(30), 139(100),
1
35, 91, 77, 65
+
3
3
3
c
d
e
336 (M ,5), 292, 173, 172, 160, 135(100), 91, 77, 65
+
351 (M ,7), 323, 307, 305, 173, 172, 150(100), 135, 91, 77, 65
+
+
372 ([M+2] , 9), 370 (M , 10), 344, 342, 326, 324, 239, 237, 173, 172, 135(100),
7, 65
408 ([M+6] , 1), 406 ([M+4] , 4), 404 ([M+2] , 3), 360, 239, 237, 141(32), 139(100)
7
+
+
+
3
3
3
3
f
+
+
g
h
i
402 ([M+2] , 5), 400 (M , 6), 374, 372, 358, 356, 239, 237, 202, 135(100)
+
+
417 ([M+2] , 4), 415 (M , 5), 389, 387, 373, 371, 239, 237, 201, 199, 150(100)
+
+
+
364 ([M+4] , 0.7), 362 ([M+2] , 4), 360 (M , 6), 336, 334, 332, 227, 172, 135,
05(100)
400 ([M+6] , 0.1), 398 ([M+4] , 1), 396 ([M+2] , 3), 394(M , 3), 350, 229, 141(32),
39(100
394 ([M+4] , 0.5), 392 ([M+2] , 3), 390 (M , 4), 348, 231, 229, 227, 202, 135(100)
1
+
+
+
+
3
j
1
+
+
+
3
3
k
l
+
+
+
409 ([M+4] , 0.4), 407 ([M+2] , 3), 405 (M , 4), 381, 379, 377, 229, 227, 150(100)
The 2-H proton of the pyrone ring is seen as a sharp signal in the region 8.8-8.9 ppm [4] in the spectra of
the products 1a-l. The mass spectra of the products 1a-l show a low intensity peak for the molecular ion
+
(
generally less than 10%), the main peak being for [M-COCH ] . Subsequent fragmentation is similar to that
3
described above for the aroylhydrazones 3a-l.
EXPERIMENTAL
Thin-layer chromatographic analysis was carried out on GF-254 plates. Melting points were measured
on an MP-S3 heating table (Japan). Elemental analysis was carried out using an MT-3 automatic analyzer. IR
1
spectra were taken on a Bruker EQUINOX-55 FT-IR machine using KBr and H NMR spectra on a Bruker AX
8
0 (80 MHz) machine using CDCl or DMSO-d solvent and TMS internal standard. Mass spectra were recorded
3 6
on an HP 5988 AMS instrument.
General Method for Preparing the Aroylhydrazones (3a-l). Equal amounts of compounds 2a-l and
the aroylhydrazines (obtained as in [2, 5]) were mixed and dissolved in 95% alcohol. Several drops of glacial
acetic acid were added and the mixture was refluxed for 5-6 h with use of a reflux condenser. After cooling, the
crystals formed were filtered off and recrystallized from absolute alcohol to give the aroylhydrazones 3a-l.
2
17

General Method for Preparing 3-(3-Acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones (1a-
l). Acetic anhydride was added to the aroylhydrazone 3a-l (2 mmol) and refluxed for 2 h. After cooling, the
reaction mixture was poured into iced water. The precipitate was filtered off, washed with water, dried, and
recrystallized from DMF–EtOH–H O to give the products 1a-l.
2
The authors express their thanks for the financial support of the State Fund for Natural Science, Peoples
Republic of China (29962002) and to the Nankai University State Central Organoelemental Laboratory, Peoples
Republic of China.
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1
2
3
4
.
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.
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Isoflavonoids [in Russian], Rostov University Publishing House (1985) p. 129.
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.
2
18