Isomeric 3-isoxadiazolylcoumarins and their derivatives

Article abstract of DOI:10.1002/jhet.893

Here, we represent preparative methods of synthesis of isomeric 3-isoxadiazolylcoumarins and their derivatives. Two new synthetic methods have been developed for 3-[1,2,4-oxadiazol-5-yl]coumarins I. The first method is based on a three-component condensation of coumarin-;3-carboxylic acids, 1,1'-carbonyldiimidazole, and amidoximes. The second method essentially uses the interaction of 5-cyanomethyl-1,2,4-oxadiazoles with salicylic aldehydes. General approach for preparation of 3-[1,2,4-oxadiazol-3-yl]coumarins II has been worked out. Moreover, aforementioned synthetic ways open the way for the synthesis of 2-iminoderivatives III and IV not described before, those were diversified by reaction of nucleophilic substitution of 2-imino group with a numerous amino compounds.

Full text of DOI:10.1002/jhet.893

Month 2012
Isomeric 3‐Isoxadiazolylcoumarins and Their Derivatives
a
a
b
*
Oleksandr S. Detistov, Valeriy D. Orlov, and Irina O. Zhuravel’
aOrganic Chemical Department, V.N. Karazin Kharkiv National University,
4 Svoboda Sq., Kharkiv 61077, Ukraine
bNational Pharmaceutical University, 53 Pushkinska str., Kharkiv 61002, Ukraine
*
E-mail: deas@inbox.ru or o.s.detistov@gmail.com
Received November 22, 2010
DOI 10.1002/jhet.893
Published online 00 Month 2012 in Wiley Online Library (wileyonlinelibrary.com).
Here, we represent preparative methods of synthesis of isomeric 3-isoxadiazolylcoumarins and
their derivatives. Two new synthetic methods have been developed for 3-[1,2,4-oxadiazol-5-yl]coumarins
I. The first method is based on a three-component condensation of coumarin-;3-carboxylic acids, 1,10-
carbonyldiimidazole, and amidoximes. The second method essentially uses the interaction of 5-
cyanomethyl-1,2,4-oxadiazoles with salicylic aldehydes. General approach for preparation of 3-[1,2,
4-oxadiazol-3-yl]coumarins II has been worked out. Moreover, aforementioned synthetic ways open the
way for the synthesis of 2-iminoderivatives III and IV not described before, those were diversified by
reaction of nucleophilic substitution of 2-imino group with a numerous amino compounds.
J. Heterocyclic Chem., 00, 00 (2012).
INTRODUCTION
RESULTS AND DISCUSSION
The extensive use of 1,2,4-oxadiazoles (isoxadiazoles)
in medicinal chemistry [1-5] stimulates an elaboration
and an optimization of methods for their synthesis. In
general, structural combining of 1,2,4‐oxadiazole ring
with another heterocyclic moiety may lead to com-
pounds with broader spectrum of biological activity as
well as to the appearance of essentially new bioactiv-
ities. This article deals with heterocycles containing
1,2,4‐oxadiazole and coumarin cycles in the same
structure.
There are several synthetic ways for incorporation of 1,2,4‐
oxadiazole cycle with coumarin moiety described in the
literature. It is possible to obtain both 5‐coumarinyl substituted
isoxadiazoles and isomeric 3‐coumarinyl derivatives; in
addition, the isoxadiazole fragment can be in a different posi-
tion of coumarin cycle [6–9]. Also, some articles concern
heterocyclic structures, in which 1,2,4‐oxadiazole cycle is
not coupled directly with coumarin moiety [10–19].
The interest to those dinuclear systems depends much
on their pharmacological potential. Among their investigated
activities are antiproteolytic and antiinflammatory [15] and
the ability to inhibit β‐glucuronidase, 12‐lipoxygenase, and
monoamine oxidase [6,9]. That kind of compounds may
be useful as antimicrobial, antifungal, and antibacterial
agents [19].
Formerly described methods for synthesis of 3‐[1,2,4‐
oxadiazol‐5‐yl]coumarins are mainly based on the interaction
of functional derivatives of coumarin‐3‐carboxylic acids,
such as anhydrides, chlorinanhydrides, and esters, with
amidoximes [20–22]. However, those methods suffer from
grave shortcomings. There is an additional step for modifica-
tion of carboxylic group into more reactive derivative and the
necessity to separate out this product. It complicates synthetic
way and makes incompatible with several functional groups,
such as amino, hydroxy, etc. Indicated factors stimulate the
development of perfected synthetic methods. We chose
two tracks to solve this task.
The first way (method A) is based on the formation
1,2,4‐oxadiazole moiety on the basis of coumarin skele-
ton. It was implemented by in situ activation of coumarin‐
3‐carboxylic acid by 1,1′‐carbonyldiimidazole (CDI) with
further addition of amidoxime component to a reaction
mixture. This method affords a clean one‐pot approach by
consecutive addition of reagents, which is applicable to
parallel solution‐phase synthesis (Scheme 1).
Significantly, at the beginning, coumarin‐3‐carboxylic
acid forms reactive imidazole derivative V on treatment
with CDI. After addition of amidoxime at 70–80°C,
O‐heteroyl amidoxime VI is generated, which then
cyclizes at 110°C into ultimate product. Intermediates V
© 2012 HeteroCorporation

O. S. Detistov, V. D. Orlov, and I. O. Zhuravel’
Vol 000
Scheme 1
by spectral data. The position and multiplicity of signals
H‐4, H‐5, H‐6, H‐7, and H‐8 correspond to the substitu-
tion mode in the coumarin nucleus. The absence of signals of
and VI were not separated out in this case, but earlier
the same mechanism has been proved for one‐pot con-
densation of this type [23]. Coumarin‐3‐carboxylic acids
3a–f necessary for this reaction are easily obtained by
the reaction of salicylic aldehydes 1a–f with Meldrum’s
acid 2 according to the method described before [24].
Arylamidoximes 4a,b (N′‐hydroxybenzenecarboximida-
mides) synthesis was carried out from corresponding
benzonitriles and hydroxylamine [25]. 3‐[1,2,4‐Oxadiazol‐
5‐yl]coumarins 5a–l were synthesized by method A with
yields in the range 38–72% directly from coumarin‐3‐
carboxylic acids and arylamidoximes without the stage of
anhydrides, chlorinanhydrides, and esters preparation and
separation of intermediates.
1
proton of imino group in H NMR spectra of compounds
5m–o evidences that the transformation proceeds com-
pletely. In infrared (IR) spectra of samples from class 5
characteristic bands of lacton’s C¼O group valent oscillation
(1740–1772 cm−1) and low‐intensity bands of 1,2,4‐oxadia-
zole cycle C¼N bonds, which in most cases are overlapped
with bands of C¼O aromatic valent oscillation, are observed.
The integration of two heterocyclic fragments into one mol-
ecule is revealed by the “batochrom” shift of the long‐wave
band in ultraviolet (UV) spectra.
The Knoevenagel condensation of 5‐cyanomethyl‐
1,2,4‐oxadiazoles with salicylic aldehydes proceeding
in isopropanol allows to obtaine pure 2‐iminocoumarins
9a,b. Those compounds are characterized by singlet sig-
nal in the range 9.90–10.10 ppm in 1H NMR spectra
recorded in deuterated chloroform (CDCl3), whereas in
deuterated dimethyl sulfoxide (D6) (DMSO-d6) they
are unstable. Iminolactone fragment in the structure of
obtained compounds 9a,b is reactive toward nucleophilic
reagents; it enables to realize a number of substi-
tution reactions by 2‐imino group. Thereby, 2‐N‐
aryliminoderivatives 11a–c not described before were
obtained with 45–61% yields by the reaction of 2‐
iminocoumarin 9a with substituted anilines 10a–c. The
use of arylsulfonylhydrazides 12a–c in this reaction leads
to formation of new 2‐N‐arylsulfonylhydrazono‐3‐[3‐aryl‐
1,2,4‐oxadiazol‐5‐yl]coumarins 13a–c with 59–76%
yields. The signal of imino group proton is not observed in
1H NMR spectra of compounds 11a–c and 13a–c; this fact
indicates effective and complete reaction proceeding. NH
proton of arylsulfonylhydrazide fragment in 1H NMR spec-
tra of compounds 13a–c is observed as singlet signal in the
range 10.5–11.0 ppm. IR spectra of those substances show
bands of S¼O bonds valent oscillations in the range
1130–1170 cm−1.
The second approach (method B) for 3‐[1,2,4‐oxadia-
zol‐5‐yl]coumarins synthesis consists in the formation of
the coumarin cycle by Knoevenagel condensation of 5‐
cyanomethyl‐1,2,4‐oxadiazoles with salicylic aldehydes
(Scheme 2). If this reaction proceeds in anhydrous sol-
vent, such as isopropanol, 2‐imino derivatives form as
the final product. But these products are unstable in
aqueous mineral acid media, and therefore addition of
concentrated hydrochloric acid to the reaction mixture
in the end leads to formation of target coumarins.
5‐Cyanomethyl‐1,2,4‐oxadiazoles 7a,b, required for this
condensation, were prepared by reaction of amidoximes
4b,c with 1‐(cyanoacetyl)‐3,5‐dimethyl‐1H‐pyrazole 6
[26]. 3‐[1,2,4‐Oxadiazol‐5‐yl]coumarins 5m–o were
synthezised in this way with 58–67% yields.
Method B makes it possible to synthesize 3‐[1,2,4‐oxa-
diazol‐5‐yl]coumarins with hydroxyl group in a coumarin
moiety, for example, 8‐hydroxycoumarin 5o. To expand
synthetic availability of product class 5, coumarin 5o was
alkylated by benzylchlorides 8a–e and the series of
respective 8‐O‐benzyl derivatives 5p–t was obtained with
43–57% yields.
The structures of 3‐[1,2,4‐oxadiazol‐5‐yl]coumarins
5a–t synthesized by methods A and B were confirmed
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Isomeric 3‐Isoxadiazolylcoumarins and Their Derivatives
Scheme 2
It should be noted that 2‐imino group of compound 9b
was successfully substituted by hydroxylamine. For the
substitution reaction, base of hydroxylamine was used
and 2‐hydroxyiminocoumarin 14 was obtained with 45%
yield. Then compound 14 was introduced into the reaction
of acylation by various carboxylic acid anhydrides 15a–c.
The acylation reaction was carried out in acid anhydrides
media and 2‐acyloxyiminocoumarins 16a–c were synthesized
with 67–85% yields. 1H NMR spectrum of 2‐hydroxyimino-
coumarin 14 shows a signal of hydroxyimino group proton
In this work, the synthesis of 3‐[1,2,4‐oxadiazol‐3‐
yl]coumarins 22a–f isomeric to compounds 5 was realized.
Reports about syntheses of compounds from class 22 are
present in the literature, but they are separated and solitary
[21]. In this connection, we have developed a new prepara-
tive method permitting to synthesize a range of 3‐[1,2,
4‐oxadiazol‐3‐yl]coumarins 22 and go further to the synthe-
sis of related 2‐iminoderivatives 25. The method is based on
the condensation of 2‐(1,2,4‐oxadiazol‐3‐yl)‐acetamides
21a,b with salicylic aldehydes 1a,e,i (Scheme 3).
1
at 10.88 ppm. This signal disappears in H NMR spectra of
2‐acyloxyiminocoumarins 16a–c and signals of acylgroups
appear with corresponding multiplicity.
We chose 2‐cyanoacetamide 17 as initial compound
for modification of nitrile functionality. It makes
possible to obtain amidoxime 18 with good yields by a
Journal of Heterocyclic Chemistry
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O. S. Detistov, V. D. Orlov, and I. O. Zhuravel’
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Scheme 3
simple synthetic procedure, whereas the use of malono-
nitrile and ethyl cyanoacetate for the purpose of amid-
oxime preparation was not successful. Then amidoxime
18was introduced into the condensation reaction analo-
gous to that used for 3‐[1,2,4‐oxadiazol‐5‐yl]coumarins
5a–l preparation in method A. As a first step, O‐aroyl-
substituted amidoximes 20a,b were obtained by the reaction
of amidoxime 18 with aromatic acids 19a,b activated by
CDI in dioxane and separated out of the reaction mixture.
Next, compounds 20a,b were cyclized into 2‐(1,2,4‐oxadia-
zol‐3‐yl)‐acetamides 21a,b in dimethylformamide under
heating. Step‐by‐step approach in this case provides greater
yields of required synthons 21a,b.
corresponding 3‐cyanomethyl‐1,2,4‐oxadiazole 23. Product
23 forms 2‐imino‐3‐[1,2,4‐oxadiazol‐3‐yl]coumarin 24,
isomeric to compounds from class 9, by the reaction
with salicylic aldehyde 1d. Proceeding from iminocou-
marin 24, products of substitution at 2‐imino group
25a–c were obtained with 58–63% yields. Spectral char-
acteristics of 3‐[1,2,4‐oxadiazol‐3‐yl]coumarins 22a–f
and 2‐iminoderivatives 24 and 25a–c correspond to
structures shown in Scheme 3.
To summarize, new improved methods of synthesis
of 3‐[1,2,4‐oxadiazol‐5‐yl] and 3‐[1,2,4‐oxadiazol‐3‐
yl]coumarins have been elaborated. Furthermore, suggested
approaches open the way for the synthesis of related 2‐
iminoderivatives not described before. The presence in
structures given of several diversification points affords
ground for obtainment of considerable number of sub-
stances for screening of their biological activity.
The condencation of heterylacetamides 21 with sali-
cylic aldehydes 1a,e,i leads to the formation of target
compounds 22a–f with 31–52% yields. The treatment of
acetamide 21a with thionyl chloride results in the
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Isomeric 3‐Isoxadiazolylcoumarins and Their Derivatives
7‐N,N‐Diethylamino‐3‐(3‐phenyl‐1,2,4‐oxadiazol‐5‐yl)-
EXPERIMENTAL
coumarin (5f). This compound was obtained as light‐green fine‐
crystalline powder. Yield 38%, m.p. 205–206°C; 1H NMR
(DMSO‐d6): δ 1.12 (t, 6H, J = 7.2 Hz, 2CH2CH3), 3.47
(q, 4H, J = 6.8 Hz, 2CH2CH3), 6.08 (s, 1H, H‐8), 6.30 (d, 1H,
J = 8.7 Hz, H‐6), 7.24 (d, 1H, J = 8.9 Hz, H‐5), 7.55 (m,
3H), 8.07 (m, 2H), 8.82 (s, 1H, H‐4). Anal. Calcd. for
C21H19N3O3: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.83; H,
5.43; N, 11.88.
Melting points were measured with a Buchi B‐520 melting
point apparatus. NMR spectra were recorded on a Varian
Mercury 400 spectrometer in DMSO‐d6 and CDCl3 using
TMS as an internal standard (chemical shifts in ppm). Mass
spectral analysis was performed on a PE SCIEX API 150EX
mass spectrometer. IR spectra were recorded on Tensor 27
spectrometer in KBr. UV spectra were recorded on a “Specord
M40” spectrometer in ethanol.
General procedure for the preparation of 3‐(3‐aryl‐1,2,4‐
oxadiazol‐5‐yl)coumarins, 5a–l: Method A. A mixture of an
appropriate coumarin‐3‐carboxylic acid 3 (10 mmol) and CDI
(0.16 g, 10 mmol) in dry N,N‐dimethylformamide (2 mL) was
kept at 70–80°C for 20 min. Then corresponding amidoxime 4
(11 mmol) was added to a reaction mixture and temperature
was raised up to 110°C. At this temperature, solution was kept
for 3 h. Then solution was cooled, and the formed precipitate
of compound 5 was washed with isopropanol (2 × 5 mL). An
additional purification of compound 5 was performed by crys-
tallization from N,N‐dimethylformamide–isopropanol solvent
system at a suitable ratio.
3‐[3‐(4‐Methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarin (5g).
This compound was obtained as white fine‐crystalline powder.
Yield 72%, m.p. 207°C; IR: 1748, 1612, 1588, 1572, 1424,
1
1264 cm−1; H NMR (DMSO‐d6): δ 3.85 (s, 3H, OCH3), 7.13
(d, 2H, J = 8.1 Hz), 7.45 (t, 1H, J = 7.3 Hz, H‐6), 7.55
(d, 1H, J = 7.6 Hz, H‐8), 7.84 (t, 1H, J = 7.4 Hz, H‐7), 8.01
(d, 3H, J = 8.1 Hz, H‐5 + Ar‐H), 9.30 (s, 1H, H‐4); ms (m/z)
321(M+), 199, 150, 135. Anal. Calcd. for C18H12N2O4:
C, 67.50; H, 3.78; N, 8.75. Found: C, 67.64; H, 3.87; N, 8.97.
5,6‐Benzo‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl]-
coumarin (5h). This compound was obtained as yellow fine‐
crystalline powder. Yield 62%, m.p. 198°C; IR: 1772, 1624, 1608,
1584, 1548, 1476, 1264 cm−1; 1H NMR (DMSO‐d6): δ 3.86
(s, 3H, OCH3), 7.12 (d, 2H, J = 9.3 Hz), 7.63 (d, 1H, J = 8.7 Hz),
7.68 (t, 1H, J = 6.1 Hz), 7.80 (t, 1H, J = 7.2 Hz), 8.05 (d, 2H,
J = 9.3 Hz), 8.08 (d, 1H, J = 7.1 Hz), 8.36 (d, 1H, J = 9.8 Hz),
8.69 (d, 1H, J = 8.7 Hz), 9.67 (s, 1H, H‐4). Anal. Calcd. for
C22H14N2O4: C, 71.35; H, 3.81; N, 7.56. Found: C, 71.51; H,
3.98; N, 7.47.
3‐(3‐Phenyl‐1,2,4‐oxadiazol‐5‐yl)coumarin (5a). This com-
pound was obtained as white fine‐crystalline powder. Yield
45%, m.p. 170–171°C; IR: 1756, 1700, 1608, 1580, 1444,
1
1388, 1360, 1224 cm−1; H NMR: δ 7.46 (dt, 1H, J = 6.9 Hz,
J = 1.2 Hz, H‐6), 7.52 (d, 1H, J = 8.0 Hz, H‐8), 7.61 (m,
3H), 7.80 (dt, 1H, J = 8.2 Hz, J = 1.3 Hz, H‐7), 8.04 (dd,
1H, J = 8.1 Hz, J = 1.6 Hz, H‐5), 8.50 (m, 2H), 9.18 (s, 1H,
H‐4). Anal. Calcd. for C17H10N2O3: C, 70.34; H, 3.47; N,
9.65. Found: C, 70.39; H, 3.27; N, 9.67.
6‐Bromo‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl]-
coumarin (5i). This compound was obtained as white cotton‐like
1
solid. Yield 65%, m.p. 262–264°C; H NMR (DMSO‐d6): δ 3.84
5,6‐Benzo‐3‐(3‐phenyl‐1,2,4‐oxadiazol‐5‐yl)coumarin (5b).
This compound was obtained as yellow fine‐crystalline pow-
der. Yield 55%, m.p. 226–228°C; IR: 1744. 1564, 1552, 1444,
(s, 3H, OCH3), 7.14 (d, 2H, J = 9.4 Hz), 7.48 (d, 1H,
J = 9.3 Hz, H‐8), 7.92 (dd, 1H, J = 9.0 Hz, J = 2.5 Hz, H‐7),
8.00 (d, 2H, J = 9.4 Hz), 8.28 (d, 1H, J = 2.3 Hz, H‐5), 9.08
(s, 1H, H‐4). Anal. Calcd. for C18H11BrN2O4: C, 54.16; H,
2.78; N, 7.02. Found: C, 54.34; H, 2.99; N, 6.87.
7‐Methoxy‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl]-
coumarin (5j). This compound was obtained as yellow fine‐
crystalline powder. Yield 68%, m.p. 221–222°C; IR: 1744, 1602,
1568, 1372, 1284, 1260 cm−1; 1H NMR (DMSO‐d6): δ 3.81
(s, 3H, OCH3), 3.90 (s, 3H, OCH3), 7.12 (d, 2H, J = 9.0 Hz),
7.12 (m, 2H, H‐6,8), 7.94 (d, 1H, J = 9.0 Hz, H‐5), 8.00
(d, 2H, J = 9.7 Hz), 9.15 (s, 1H, H‐4). Anal. Calcd. for
C19H14N2O5: C, 65.14; H, 4.03; N, 8.00. Found: C, 65.35;
H, 4.13; N, 8.13.
1400, 1368, 1340, 1224 cm−1 1H NMR (DMSO‐d6): δ 7.63
;
(m, 5H), 7.81 (t, 1H, J = 6.9 Hz), 8.14 (m, 3H), 8.38 (d, 1H,
J = 8.3 Hz), 8.70 (d, 1H, J = 8.3 Hz), 9.69 (s, 1H, H‐4).
Anal. Calcd. for C21H12N2O3: C, 74.11; H, 3.55; N, 8.23.
Found: C, 74.23; H, 3.63; N, 8.41.
6‐Bromo‐3‐(3‐phenyl‐1,2,4‐oxadiazol‐5‐yl)coumarin (5c). This
compound was obtained as yellow fine‐crystalline powder.
1
Yield 40%, m.p. 222°C; H NMR (DMSO‐d6): δ 7.46 (d, 1H,
J = 9.5 Hz, H‐8), 7.60 (m, 3H), 7.91 (dd, 1H, J = 8.7 Hz,
J= 2.6 Hz, H‐7), 8.06 (m, 2H), 8.26 (d, 1H, J = 2.1 Hz,
H‐5), 9.15 (s, 1H, H‐4). Anal. Calcd. for C17H9BrN2O3:
C, 55.31; H, 2.46; N, 7.59. Found: C, 55.33; H, 2.39; N, 7.76.
7‐Methoxy‐3‐[3‐phenyl‐1,2,4‐oxadiazol‐5‐yl]coumarin (5d).
This compound was obtained as yellow fine‐crystalline pow-
der. Yield 59%, m.p. 207–208°C; IR: 1752, 1732, 1600, 1560,
8‐Methoxy‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl]-
coumarin (5k).
This compound was obtained as pale yellow
fine‐crystalline powder. Yield 53%, m.p. 224–225°C; IR: 1752,
1608, 1576, 1468, 1440, 1428, 1356, 1292 cm−1; 1H NMR
(DMSO‐d6): δ 3.84 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.15
(d, 2H, J = 9.5 Hz), 7.39 (t, 1H, J = 7.7 Hz, H‐6), 7.48 (dd,
1H, J = 9.2 Hz, J = 1.5 Hz, H‐7), 7.57 (dd, 1H, J = 7.3 Hz,
J = 1.8 Hz, H‐5), 8.02 (d, 2H, J = 9.5 Hz), 9.12 (s, 1H, H‐4).
Anal. Calcd. for C19H14N2O5: C, 65.14; H, 4.03; N, 8.00.
Found: C, 65.25; H, 4.13; N, 7.89.
1368, 1228 cm−1 1H NMR (DMSO‐d6): δ 3.90 (s, 3H,
;
OCH3), 7.08 (d, 1H, J = 9.4 Hz, H‐6), 7.08 (s, 1H, H‐8), 7.59
(m, 3H), 7.91 (d, 1H, J = 8.8 Hz, H‐5), 8.08 (m, 2H), 9.05 (s,
1H, H‐4). Anal. Calcd. for C18H12N2O4: C, 67.50; H, 3.78;
N, 8.75. Found: C, 67.43; H, 3.99; N, 8.78.
8‐Methoxy‐3‐(3‐phenyl‐1,2,4‐oxadiazol‐5‐yl)coumarin (5e).
This compound was obtained as yellow fine‐crystalline pow-
der. Yield 60%, m.p. 224–225°C; IR: 1760, 1608, 1576, 1468,
7‐N,N‐Diethylamino‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐
5‐yl]coumarin (5l). This compound was obtained as yellow
1
1444, 1356, 1252 cm−1; H NMR (DMSO‐d6): δ 3.92 (s, 3H,
1
fine‐crystalline powder. Yield 43%, m.p. 218–219°C; H NMR
OCH3), 7.40 (d, 1H, J = 8.0 Hz), 7.41 (t, 1H, J = 8.1 Hz,
H‐6), 7.60 (m, 4H), 8.08 (m, 2H), 9.02 (s, 1H, H‐4). Anal.
Calcd for C18H12N2O4: C, 67.50; H, 3.78; N, 8.75. Found: C,
67.64; H, 3.62; N, 8.56.
(DMSO‐d6): δ 1.14 (t, 6H, J = 8.4 Hz, 2CH2CH3), 3.49
(q, 4H, J = 6.7 Hz, 2CH2CH3), 3.83 (s, 3H, OCH3), 6.60
(s, 1H, H‐8), 6.83 (dd, 1H, J = 10.1 Hz, J = 2.5 Hz, H‐6),
7.11 (d, 2H, J = 11.7 Hz), 7.74 (d, 1H, J = 10.0 Hz, H‐5),
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O. S. Detistov, V. D. Orlov, and I. O. Zhuravel’
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7.98 (d, 2H, J = 11.7 Hz), 8.82 (s, 1H, H‐4). Anal. Calcd. for
C22H21N3O4: C, 67.51; H, 5.41; N, 10.74. Found: C, 67.63; H,
(3 mL) under heating. After the solution was formed, crumbled
potassium carbonate (0.39 g, 3 mmol) and corresponding ben-
zylchloride (1 mmol) were added under stirring. The reaction
was carried on at 70°C for 3 h under intensive stirring. Then
the reaction mixture was diluted with water (20 mL), the pre-
cipitate formed of compound 5 was filtered off, dried, and
recrystallized from isopropyl alcohol.
8‐(2‐Fluorobenzyl)oxy‐3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐
5‐yl]coumarin (5p). This compound was obtained as a white
powder. Yield 43%, m.p. 190–192°C; 1H NMR (DMSO‐d6):
δ2.28 (s, 3H, CH3), 5.30 (s, 2H, CH2), 7.25 (m, 3H), 7.37
(d, 2H, J = 11.8 Hz), 7.39 (m, 2H), 7.59 (d, 2H, J = 11.8
Hz), 7.95 (d, 2H, J = 10.4 Hz), 9.10 (s, 1H, H‐4). Anal. Calcd.
for C25H17FN2O4: C, 70.09; H, 4.00; N, 6.54. Found: C,
69.95; H, 4.12; N, 6.55.
8‐(3‐Fluorobenzyl)oxy‐3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐
5‐yl]coumarin (5q). This compound was obtained as a white
powder. Yield 48%, m.p. 187–188°C; 1H NMR (DMSO‐d6):
δ 2.37 (s, 3H, CH3), 5.30 (s, 2H, CH2), 7.18 (m, 1H), 7.33
(d, 2H, J = 9.0 Hz), 7.36 (m, 4H), 7.60 (m, 2H), 7.95 (d,
2H, J = 9.1 Hz), 9.13 (s, 1H, H‐4). Anal. Calcd. for
C25H17FN2O4: C, 70.09; H, 4.00; N, 6.54. Found: C, 69.97;
H, 4.03; N, 6.65.
8‐(4‐Fluorobenzyl)oxy‐3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐
5‐yl]coumarin (5r). This compound was obtained as a white
powder. Yield 52%, m.p. 201–203°C; 1H NMR (DMSO‐d6): δ
2.35 (s, 3H, CH3), 5.25 (s, 2H, CH2), 7.25 (m, 3H), 7.40 (d,
2H, J = 8.7 Hz), 7.53 (d, 2H, J = 9.7 Hz), 7.61 (d, 2H, J = 8.7 Hz),
7.97 (d, 2H, J = 9.8 Hz), 9.10 (s, 1H, H‐4). Anal. Calcd for
C25H17FN2O4: C, 70.09; H, 4.00; N, 6.54. Found: C, 70.12;
H, 4.05; N, 6.67.
5.36; N, 10.89.
General procedure for the preparation of 5‐cyanomethyl‐3‐
aryl‐1,2,4‐oxadiazoles, 7a,b. 1‐(Cyanoacetyl)‐3,5‐dimethyl‐1H‐
pyrazole 6 (6.5 g, 40 mmol) was dissolved in dioxane (25 mL) under
heating and then corresponding amidoxime 4 (40 mmol) was added.
The mixture was heated at reflux for 6 h. A solution was cooled and
was poured in glacial water (150 mL). Product 7 is precipitated as oil
that hardens on standing. The target compound 7 was purified by
flash chromatography (silica gel and ethyl acetate).
5‐Cyanomethyl‐3‐(4‐methylphenyl)‐1,2,4‐oxadiazole (7a).
1
Yield 79%, m.p. 76°C; H NMR (DMSO‐d6): δ 2.31 (s, 3H,
CH3), 4.73 (s, 2H, CH2), 7.32 (d, 2H, J = 9.3 Hz, H‐8), 7.90
(d, 2H, J = 9.3 Hz). Anal. Calcd. for C11H9N3O: C, 66.32; H,
4.55; N, 21.09. Found: C, 66.37; H, 4.63; N, 21.07.
5‐Cyanomethyl‐3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazole (7b).
Yield 85%, m.p. 66°C; 1H NMR (DMSO‐d6): δ 3.80 (s, 3H,
OCH3), 4.78 (s, 2H, CH2), 7.12 (d, 2H, J = 9.3 Hz, H‐8), 7.95
(d, 2H, J = 9.3 Hz). Anal. Calcd. for C11H9N3O2: C, 61.39;
H, 4.22; N, 19.52. Found: C, 61.43; H, 4.27; N, 19.57.
General procedure for the preparation of 3‐(3‐aryl‐1,2,4‐
oxadiazol‐5‐yl)coumarins, 5m–o: Method B. 5‐Cyanomethyl‐
3‐aryl‐1,2,4‐oxadiazole 7 (10 mmol) was dissolved in N,N‐
dimethylformamide (10 mL) under heating (50°C). Corresponding
salicylic aldehyde 1 (10 mmol) and a few drops of piperidine (in a
case of 3‐hydroxysalicylic aldehyde–20 mmol) were added. The
reaction mixture was kept at 80°C for 20 min. Then the aqueous
concentrated hydrochloric acid (3 mL) was added and a mixture
was kept at 100°C for 30 min. After the end of the reaction, hot
mixture was diluted with isopropanol (30 mL) and left cold for a
night. The precipitate formed of compound 5 was filtred off and
washed with ethanol (2 × 30 mL). An additional purification of
compound 5 was performed by crystallization from N,N‐dime-
thylformamide–isopropanol solvent mixture at a suitable ratio.
8‐Ethoxy‐3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarin
(5m). This compound was obtained as yellow fine‐crystalline
powder. Yield 67%, m.p. 203–204°C; 1H NMR (DMSO‐d6):
δ 1.40 (t, 3H, CH2CH3), 2.35 (s, 3H, CH3), 4.17 (q, 2H, CH2CH3),
7.30–7.51 (m, 3H), 7.35 (d, 2H, J = 9.4 Hz), 7.95 (d, 2H, J = 9.5
Hz), 9.06 (s, 1H, H‐4). Anal. Calcd. for C20H16N2O4: C, 68.96; H,
8‐(3‐Methylbenzyl)oxy‐3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐
5‐yl]coumarin (5s).
This compound was obtained as a white
powder. Yield 47%, m.p. 161–162°C; 1H NMR (DMSO‐d6): δ
2.31 (s, 3H, CH3), 2.36 (s, 3H, CH3), 5.23 (s, 2H, CH2), 7.18
(m, 1H), 7.32 (m, 4H), 7.41 (d, 2H, J = 7.7 Hz), 7.58 (t, 2H,
J = 6.7 Hz), 7.97 (d, 2H, J = 7.7 Hz), 9.11 (s, 1H, H‐4).
Anal. Calcd. for C26H20N2O4: C, 73.57; H, 4.75; N, 6.60.
Found: C, 73.49; H, 4.65; N, 6.62.
8‐(4‐Methylbenzyl)oxy‐3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐
5‐yl]coumarin (5t). This compound was obtained as a white
4.63; N, 8.04. Found: C, 69.02; H, 4.75; N, 8.15.
8‐Ethoxy‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl]-
1
powder. Yield 57%, m.p. 192°C; H NMR (DMSO‐d6): δ 2.27
coumarin (5n). This compound was obtained as yellow fine‐
crystalline powder. Yield 58%, m.p. 212–213°C; 1H NMR
(DMSO‐d6): δ 1.40 (t, 3H, CH2CH3), 3.82 (s, 3H, OCH3),
4.21 (q, 2H, CH2CH3), 7.13 (d, 2H, J = 10.3 Hz), 7.36 (t, 1H,
J = 8.0 Hz, H‐6), 7.45 (dd, 1H, J = 7.1 Hz, J = 1.4 Hz, H‐7),
7.55 (dd, 1H, J = 6.9 Hz, J = 1.8 Hz, H‐5), 8.02 (d, 2H,
J = 10.3 Hz), 9.10 (s, 1H, H‐4). Anal. Calcd. for C20H16N2O5:
(s, 3H, CH3), 2.40 (s, 3H, CH3), 5.24 (s, 2H, CH2), 7.21
(d, 2H, J = 9.4 Hz), 7.40 (d, 2H, J = 9.4 Hz), 7.42 (d, 2H,
J = 7.8 Hz), 7.54 (m, 3H), 7.96 (d, 2H, J = 7.8 Hz), 9.11
(s, 1H, H‐4). Anal. Calcd. for C26H20N2O4: C, 73.57;
H, 4.75; N, 6.60. Found: C, 73.65; H, 4.67; N, 6.60.
General procedure for the preparation of 2‐imino‐3‐[3‐aryl‐
1,2,4‐oxadiazol‐5‐yl]coumarins, 9a,b. All of these reactions
were carried out using anhydrous solvents and reagents.
C, 65.93; H, 4.43; N, 7.69. Found: C, 66.06; H, 4.50; N, 7.75.
8‐Hydroxy‐3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐5‐yl]-
Appropriate 5‐cyanomethyl‐3‐aryl‐1,2,4‐oxadiazole
7 (2.0 g,
coumarin (5o). This compound was obtained as yellow fine‐
1
10 mmol) was dissolved in isopropyl alcohol (20 mL) under
heating (30–40°C). Corresponding salicylic aldehyde 1 and 1–2
drops of piperidine were added to a warm solution. The reaction
mixture was heated at reflux for 20 min and then cooled to 0°C.
A formed precipitate of compound 9 was filtered off and washed
with isopropyl alcohol (2 × 20 mL).
2‐Imino‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl]-
coumarin (9a). This compound was obtained as yellow powder.
Yield 83%, m.p. 234–235°C; 1H NMR (CDCl3): δ 3.87 (s,
3H, OCH3), 7.03 (d, 2H, J = 8.1 Hz, Ar‐H), 7.12–7.60 (m,
crystalline powder. Yield 62%, m.p. 240°C; H NMR (DMSO‐d6):
δ 2.23 (s, 3H, CH3), 7.25 (d, 2H, J = 4.5 Hz, H‐5,7), 7.38
(d, 2H, J = 8.2 Hz), 7.43 (t, 1H, J = 5.4 Hz, H‐6), 7.95 (d,
2H, J = 8.2 Hz), 9.03 (s, 1H, H‐4), 10.49 (s, 1H, OH). Anal.
Calcd. for C18H12N2O4: C, 67.50; H, 3.78; N, 8.75. Found: C,
67.65; H, 3.66; N, 7.67.
General procedure for the preparation of 8‐benzyloxy‐
3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarins, 5p–t.
8‐Hydroxy‐3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarin
(5o; 0.3 g, 1 mmol) was dissolved in N,N‐dimethylformamide
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2012
Isomeric 3‐Isoxadiazolylcoumarins and Their Derivatives
4H, H‐5, H‐6, H‐7, H‐8), 8.12 (d, 2H, J = 8.1 Hz, Ar‐H),
8.22 (s, 1H, H‐4), 10.09 (s, 1H, NH). Anal. Calcd. for
C18H13N3O3: C, 67.71; H, 4.10; N, 13.16. Found: C, 67.68;
H, 4.12; N, 13.20.
8‐Ethoxy‐2‐imino‐3‐[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐
5‐yl]coumarin (9b). This compound was obtained as yellow
powder. Yield 78%, m.p. 207–208°C; 1H NMR (CDCl3):
δ 1.35 (t, 3H, CH3), 2.40 (s, 3H, CH3), 4.21 (q, 2H, ― CH2― ),
7.02–7.38 (m, 5H, Ar‐H, H‐5, H‐6, H‐7 ), 8.04 (d, 2H, Ar‐H),
8.22 (s, 1H, H‐4), 9.92 (s, 1H, NH). Anal. Calcd. for
C20H17N3O3: C, 69.15; H, 4.93; N, 12.10. Found: C, 69.23; H,
4.91; N, 12.14.
(d, 2H, J = 8.7 Hz), 8.02 (d, 2H, J = 9.3 Hz), 8.22 (s, 1H,
H‐4), 10.89 (s, 1H, NH). Anal. Calcd. for C25H20N4O5S: C,
61.47; H, 4.13; N, 11.47. Found: C, 61.25; H, 4.27; N, 12.45.
2‐N‐(3,4‐Dimethoxyphenyl)‐sylfonylhydrazono‐3‐[3‐(4‐methoxy-
phenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarin (13b). This compound was
obtained as orange powder. Yield 67%, m.p. 246–248°C; 1H
NMR (DMSO‐d6): δ 3.70 (s, 6H, 2OCH3), 3.84 (s, 3H,
OCH3), 7.08 (d, 1H, J = 8.8 Hz, H‐8), 7.15 (d, 2H, J = 9.8
Hz), 7.28 (m, 2H), 7.50 (m, 3H), 7.68 (d, 1H, J = 7.8 Hz,
H‐5), 8.00 (d, 2H, J = 9.8 Hz), 8.22 (s, 1H, H‐4), 10.76 (br.s,
1H, NH). Anal. Calcd. for C26H22N4O7S: C, 58.42; H, 4.15;
N, 10.48. Found: C, 58.55; H, 4.24; N, 10.53.
General procedure for the preparation of 2‐N‐arylimino‐3‐
[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarins, 11a–c.
Aromatic amine 10 (1.1 mmol) was dissolved in glacial acetic
acid (10 mL). 2‐Imino‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐
5‐yl]coumarin (8a; 0.3 g, 1 mmol) was added to the solution
under stirring. The temperature was raised to 70°C for 10 min.
Then the reaction mixture was cooled and left for 2 h at 0°C.
The formed precipitate of compound 11 was filtered off and
washed with acetic acid–water (3:1) mixture (2 × 10 mL).
2‐N‐(2,5‐Dimethoxyphenyl)‐sylfonylhydrazono‐3‐[3‐(4‐methoxy-
phenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarin (13c). This compound was
obtained as orange powder. Yield 59%, m.p. 285°C; H NMR
(DMSO‐d6): δ 3.70 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.84
(s, 3H, OCH3), 7.07 (d, 2H, J = 10.7 Hz), 7.12 (m, 2H), 7.33
(m, 2H), 7.54 (m, 2H), 7.68 (d, 1H, J = 7.5 Hz, H‐5), 7.92 (d,
2H, J = 10.7 Hz), 8.10 (s, 1H, H‐4), 10.59 (s, 1H, NH). Anal.
Calcd. for C26H22N4O7S: C, 58.42; H, 4.15; N, 10.48. Found:
C, 58.61; H, 4.09; N, 10.42.
1
Procedure for the preparation 8‐ethoxy‐2‐hydroxyimino‐3‐
[3‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarin (14). To a
solution of sodium acetate (0.09 g, 1.1 mmol) in glacial acetic
acid (3 mL), hydroxylamine hydrochloride (0.075 g, 1.1 mmol)
was added. Then the temperature of the reaction mixture was
raised up to 70°C and iminocoumarin 8b (1 mmol) was added
under stirring. The reaction mixture was left for 2 h at room
temperature. The formed precipitate of compound 14 was filtered
off and was washed with water (2 × 10 mL).
2‐N‐(4‐Methylphenyl)imino‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐
oxadiazol‐5‐yl]coumarin (11a). This compound was obtained as a
yellow powder. Yield 56%, m.p. 251–252°C; H NMR (DMSO‐
d6): δ 2.23 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 7.12 (m, 7H), 7.27
(t, 1H, J = 7.4 Hz, H‐6), 7.54 (t, 1H, J = 7.9 Hz, H‐7), 7.76 (d,
1H, J = 6.8 Hz, H‐5), 8.00 (d, 2H, J = 10.2 Hz), 8.23 (s, 1H,
H‐4). Anal. Calcd. for C25H19N3O3: C, 73.34; H, 4.68;
N, 10.26. Found: C, 73.38; H, 4.59; N, 10.33.
1
2‐N‐(4‐Acetylphenyl)imino‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐
oxadiazol‐5‐yl]coumarin (11b). This compound was obtained as a
This compound was obtained as a yellow powder. Yield
1
1
45%, m.p. 256°C, H NMR (DMSO‐d6): δ 1.35 (t, 3H, CH3),
yellow powder. Yield 45%, m.p. 231–232°C; H NMR (DMSO‐
2.40 (s, 3H, CH3), 4.14 (q, 2H, –CH–2 ), 7.11–7.24 (m, 3H),
7.38 (d, 2H, Ar‐H), 7.94 (d, 2H, Ar-H), 8.07 (s, 1H, H-4),
10.88 (s, 1H, OH). Anal. Calcd. for C20H17N3O4: C, 66.11,
H, 4.72, N, 11.56. Found: C, 66.21, H, 4.76, N, 11.61.
d6): δ 2.56 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 7.13 (d, 3H,
J = 7.4 Hz), 7.25 (d, 2H, J = 9.8 Hz), 7.32 (t, 1H, J = 8.2 Hz,
H‐6), 7.58 (t, 1H, J = 9.2 Hz, H‐7), 7.82 (d, 1H, J = 8.1 Hz,
H‐5), 7.94 (d, 2H, J = 9.8 Hz), 8.00 (d, 2H, J = 8.9 Hz),
8.64 (s, 1H, H‐4). Anal. Calcd. for C26H19N3O4: C, 71.39;
General procedure for the preparation of 8-ethoxy-2-
(acyloxy)imino-3-[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]
coumarins, 16a–c. 8-Ethoxy-2-hydroxyimino-3-[3-(4-methylphenyl)-
1,2,4-oxadiazol-5-yl]coumarin (1 mmol) was heated at reflux in a
corresponding anhydride (5 mmol) for 20–30 min. The hot reaction
mixture was diluted with isopropanol (7 mL) and left for a night in
a cool place. The formed precipitate of compound 16 was filtered
off and washed with cold isopropanol (2 × 5 mL) and then water
(2 × 10 mL). An additional purification of product 16 was
performed by crystallization from N,N‐dimethylformamide–
isopropanol solvent system at a suitable ratio.
H, 4.38; N, 9.61. Found: C, 71.48; H, 4.33; N, 9.57.
2‐N‐[4‐(N′‐Acetylamino)phenyl]imino‐3‐[3‐(4‐methoxyphenyl)‐
1,2,4‐oxadiazol‐5‐yl]coumarin (11c).
This compound was
obtained as a yellow powder. Yield 61%, m.p. 282–283°C; 1H
NMR (DMSO‐d6): δ 2.05 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.16
(d, 2H, J = 9.7 Hz), 7.24 (d, 2H, J = 8.0 Hz), 7.26 (m, 2H), 7.57
(s, 1H), 7.58 (d, 2H, J = 9.8 Hz), 7.78 (d, 1H, J = 8.1 Hz, H‐5),
8.03 (d, 2H, J = 9.7 Hz), 8.50 (s, 1H, H‐4), 9.93 (s, 1H, NH).
Anal. Calcd. for C26H20N4O4: C, 69.02; H, 4.46; N, 12.38. Found:
C, 69.05; H, 4.47; N, 12.43.
General procedure for the preparation of 2‐N‐
arylsulfonylhydrazono‐3‐[3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐
5‐yl] coumarins, 13a–c. Arylsulfonylhydrazide 12 (1.1 mmol) was
dissolved in glacial acetic acid (10 mL). 2‐Imino‐3‐[3‐(4‐
methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarin (8a; 0.3 g, 1 mmol)
was added to the solution under stirring and the temperature was
raised up to 70°C. The reaction mixture was left for 2 h at room
temperature. The formed precipitate of compound 13 was filtered
off and washed with water (2 × 10 mL).
8‐Ethoxy‐2‐(acetyloxy)imino‐3‐[3‐(4‐methylphenyl)‐1,2,4‐
oxadiazol‐5‐yl]coumarin (16a). This compound was obtained as a
yellow powder. Yield 78%, m.p. 208–209°C; 1H NMR (DMSO‐d6):
δ 1.38 (t, 3H, CH3), 2.25 (s, 3H, CH3), 2.36 (s, 3H, COCH3), 4.15
(q, 2H, ―CH2―), 7.30 (m, 3H), 7.40 (d, 2H, Ar‐H), 7.95 (d,
2H, Ar‐H), 8.55 (s, 1H, H‐4). Anal. Calcd. for C22H19N3O5: C,
65.18, H, 4.72, N, 10.36. Found: C, 64.98, H, 4.69, N, 10.43.
8‐Ethoxy‐2‐(propionyloxy)imino‐3‐[3‐(4‐methylphenyl)‐1,2,4‐
oxadiazol‐5‐yl]coumarin (16b). This compound was obtained as
a yellow powder. Yield 85%, m.p. 208–209°C; 1H NMR
(DMSO‐d6): δ 0.99 (t, 3H, CH3), 1.38 (t, 3H, CH3), 1.69 (q,
2H, ―CH2―), 2.39 (s, 3H, CH3), 4.16 (q, 2H, ―CH2― ),
7.26–7.36 (m, 3H), 7.39 (d, 2H, Ar‐H), 7.96 (d, 2H, Ar‐H),
8.54 (s, 1H, H‐4). Anal. Calcd. for C23H21N3O5: C, 65.86, H,
5.05, N, 10.02. Found: C, 65.89, H, 5.03, N, 10.07.
2‐N‐(4‐Methylphenyl)‐sylfonylhydrazono‐3‐[3‐(4‐methoxy‐
phenyl)‐1,2,4‐oxadiazol‐5‐yl]coumarin (13a). This compound
1
was obtained as orange powder. Yield 76%, m.p. 194–195°C; H
NMR (DMSO‐d6): δ 2.41 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 7.16
(d, 2H, J = 9.2 Hz), 7.28 (m, 2H), 7.36 (d, 2H, J = 8.8 Hz), 7.56
(t, 1H, J = 7.5 Hz, H‐7), 7.69 (d, 1H, J = 8.1 Hz, H‐5), 7.83
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

O. S. Detistov, V. D. Orlov, and I. O. Zhuravel’
Vol 000
8‐Ethoxy‐2‐(isobutyryloxy)imino‐3‐[3‐(4‐methylphenyl)‐1,2,4‐
oxadiazol‐5‐yl]coumarin (16c). This compound was obtained as a
yellow powder. Yield 67%, m.p. 170–171°C; H NMR (DMSO‐
2‐[5‐(4‐Methoxyphenyl)‐1,2,4‐oxadiazol‐3‐yl]acetamide (21b).
This compound was obtained as a white powder. Yield: 37%,
1
1
m.p. 173–174°C; H NMR (DMSO‐d6): δ 3.62 (s, 2H, CH2),
d6): δ 1.20 (d, 6H, 2CH3), 1.34 (t, 3H, CH3), 2.40 (s, 3H, CH3),
2.78 (m, 2H, ―CH2―), 4.16 (q, 2H, ―CH2―), 7.26–7.38 (m,
3H), 7.40 (d, 2H, Ar‐H), 7.96 (d, 2H, Ar‐H), 8.52 (s, 1H, H‐4).
Anal. Calcd. for C24H23N3O5: C, 66.50, H, 5.35, N, 9.69. Found:
C, 66.55, H, 5.39, N, 9,72.
3.82 (s, 3H, CH3), 7.16 (d, 2H, J = 7.3 Hz, Ar‐H), 7.19 (s,
1H, NH), 7.65 (s, 1H, NH), 8.06 (d, 2H, J = 7.3 Hz, Ar‐H).
Anal. Calcd. for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02.
Found: C, 56.7; H, 4.82; N, 18.03.
General procedure for the preparation of 3‐[5‐aryl‐1,2,4‐
oxadiazol‐3‐yl]coumarins, 22a–f. To a solution of 2‐[5‐aryl‐
1,2,4‐oxadiazol‐3‐yl]acetamide 21 (1 mmol) in isopropanol
(3 mL), salicylic aldehyde 1 (1.1 mmol) and catalytic amount of
piperidine (one to two drops) were added. The reaction mixture
was refluxed for 30 min. The solution was cooled to room
temperature. The formed precipitate was filtred off and washed
with isopropanol–water (4:1) mixture (2 × 5 mL).
Procedure for the preparation of 3-amino-3-(hydroxy-
(imino)propanamide)propanamide (18). To
a solution of
hydroxylamine hydrochloride (12.0 g, 0.17 mol) in 170 mL of
isopropyl alcohol, 25 mL (0.18 mol) of triethylamine was added.
After the addition was complete, the solution was stirred at 50°C
for 30 min. Then 2‐cyanoacetamide (12.0 g, 0.14 mol) was added.
The reaction mixture was refluxed for 30 min and cooled to 40°C.
The formed precipitate of compound 18 was filtred off and was
washed with warm isopropyl alcohol (2 × 30 mL).
This compound was obtained as a white fine‐crystalline powder.
Yield: 72%, m.p. 153–154°C; 1H NMR (DMSO‐d6): δ 2.72 (s, 2H,
CH2), 5.32 (s, 2H, NH2 amine), 6.93 (s, 1H, NH amide), 7.33 (s, 1H,
NH amide), 8.97 (s, 1H, OH). Anal. Calcd. for C3H7N3O2: C,
30.77; H, 6.03; N, 35.88. Found: C, 30.73; H, 6.09; N, 35.93.
General procedure for synthesis of 3‐amino‐3‐[(aroyloxy)-
imino]propanamides, 20a,b. To a solution of benzoic acid 19
(40 mmol) in dioxane (50 mL), CDI (5.67 g, 35 mmol) was
added. The solution was allowed to stay at 80°C for 20 min.
Then 3‐amino‐3‐(hydroxyimino)propanamide (18; 3.51 g, 30
mmol) was added. The reaction mixture was stirred at 80°C for
2 h and cooled to room temperature. The precipitate formed was
filtred off, washed with water (2 × 25 mL), and recrystallized
from methanol to provide pure desired compound 20.
3‐[5‐(4‐Methylphenyl)‐1,2,4‐oxadiazol‐3‐yl]coumarin (22a).
This compound was obtained as a brown fine‐crystalline pow-
der. Yield: 55%, m.p. 227–228°C; IR: 1740, 1728, 1612, 1572,
1560, 1504, 1400, 1276 cm−1 1H NMR (DMSO‐d6): δ 2.40
;
(s, 3H, CH3), 7.43 (d, 2H, J = 8.7 Hz), 7.45 (m, 2H), 7.73 (t,
1H, J = 4.3 Hz, H‐7), 7.97 (d, 1H, J = 7.5 Hz, H‐5), 8.06 (d,
2H, J = 8.7 Hz), 8.93 (s, 1H, H‐4). Anal. Calcd. for
C18H12N2O3: C, 71.05; H, 3.97; N, 9.21. Found: C, 71.12; H,
4.02; N, 9.22.
6‐Chloro‐3‐[5‐(4‐methylphenyl)‐1,2,4‐oxadiazol‐3‐yl]coumarin
(22b). This compound was obtained as a white powder. Yield:
28%, m.p. 234–235°C; 1H NMR (DMSO‐d6): δ 2.44 (c, 3H,
CH3), 7.46 (d, 2H, J = 7.1 Hz), 7.53 (d, 1H, J = 8.1 Hz, H‐8),
7.76 (dd, 1H, J = 8.9 Hz, J = 2.5 Hz, H‐7), 8.06 (d, 2H,
J = 7.6 Hz), 8.13 (d, 1H, J = 2.5 Hz, H‐5), 8.90 (s, 1H, H‐4).
Anal. Calcd. for C18H11ClN2O3: C, 63.82; H, 3.27; N, 8.27.
Found: C, 63.87; H, 3.31; N, 8.28.
3‐Amino‐3‐{[(4‐methylbenzoyl)oxy]imino}propanamide (20a).
This compound was obtained as a white powder. Yield: 75%, m.p.
8-Methoxy-3-[5-(4-methylphenyl)-1,2,4-oxadiazol-3-yl]-coumarin
1
192°C; H NMR (DMSO‐d6): δ 2.33 (s, 3H, CH3), 2.92 (s, 2H,
(22c). This compound was obtained as
a yellow pow-
CH2), 6.52 (s, 2H, NH2 amine), 7.09 (s, 1H, NH amide), 7.25 (d, 2H,
J = 7.3 Hz, Ar‐H), 7.51 (s, 1H, NH amide), 8.00 (d, 2H, J = 7.3
Hz, Ar‐H), 8.97 (s, 1H, OH). Anal. Calcd. for C11H13N3O3: C,
56.16; H, 5.57; N, 17.86. Found: C, 56.23; H, 5.54; N, 17.89.
3‐Amino‐3‐{[(4‐methoxybenzoyl)oxy]imino}propanamide (20b).
This compound was obtained as a white powder. Yield: 50%, m.
der. Yield: 34%, m.p. 225°C; IR: 1752, 1740, 1620, 1608, 1464,
1400, 1284cm−1; 1H NMR (DMSO‐d6): δ 2.39 (c, 3H, CH3), 3.93
(c, 3H, OCH3), 7.33 (t, 1H, J = 8.1 Hz, H‐6), 7.38 (d, 2H, J = 3.2
Hz, H‐7), 7.45 (d, 1H, J = 8.2 Hz), 7.49 (dd, 1H, J = 8.3 Hz,
J = 2.6 Hz, H‐5), 8.02 (d, 2H, J = 8.2 Hz), 8.85 (c, 1H, H‐4).
Anal. Calcd. for C19H14N2O4: C, 68.26; H, 4.22; N, 8.38.
Found: C, 68.37; H, 4.17; N, 8.42.
1
p. 189°C; H NMR (DMSO‐d6): δ 2.94 (s, 2H, CH2), 3.82 (s,
3H, OCH3), 6.54 (s, 2H, NH2 amine), 7.01 (d, 2H, J = 7.3 Hz,
Ar‐H), 7.12 (s, 1H, NH amide), 7.53 (s, 1H, NH amide), 8.07 (d,
2H, J = 7.3 Hz, Ar‐H). Anal. Calcd. for C11H13N3O4: C,
52.59; H, 5.22; N, 16.72. Found: C, 52.53; H, 5.28; N, 16.73.
General procedure for the preparation of 2‐[5‐aryl‐1,2,4‐
oxadiazol‐3‐yl]acetamides, 21a,b. 3-Amino‐3‐[(aroyloxy)imino]
propanamides 20 (10 mmol) was dissolved in N,N‐
dimethylformamide (10 mL). The temperature was raised up to
120°C and the reaction mixture was kept at this temperature for 2
h. Then the solution was deluted with water (50 mL) and extracted
with chloroform (3 × 20 mL). Chloroform extract was washed with
water (2 × 20 mL), dried (sodium sulfate), and concentrated in
vacuo. An oily residue was triturated under n‐hexane to form the
pure crystalline product 21.
3‐[5‐(4‐Methoxyphenyl)‐1,2,4‐oxadiazol‐3‐yl]coumarin (22d).
This compound was obtained as a brown powder. Yield: 52%, m.p.
253–254°C; IR: 1748, 1732, 1608, 1572, 1504, 1444, 1404, 1280
cm−1; 1H NMR (DMSO‐d6): δ 3.88 (c, 3H, OCH3), 7.19 (d, 2H,
J = 9.3 Hz), 7.42 (t, 1H, J = 7.5 Hz, H‐6), 7.49 (d, 1H, J = 7.6 Hz,
H‐8), 7.74 (td, 1H, J = 8.2 Hz, J = 1.9 Hz, H‐7), 7.99 (dd, 1H,
J = 8.0 Hz, J = 1.7 Hz, H‐5), 8.13 (d, 2H, J = 9.3 Hz), 8.92
(c, 1H, H‐4). Anal. Calcd. for C18H12N2O4: C, 67.50; H, 3.78;
N, 8.75. Found: C, 67.44; H, 3.79; N, 8.79.
6‐Chloro‐3‐[5‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐3‐yl]-
coumarin (22e). This compound was obtained as a white
1
powder. Yield: 31%, m.p. 238–239°C; H NMR (DMSO‐d6): δ
3.87 (c, 3H, OCH3), 7.22 (d, 2H, J = 9.7 Hz), 7.52 (d, 1H, J = 8.1
Hz, H‐8), 7.76 (dd, 1H, J = 9.6 Hz, J = 3.2 Hz, H‐7), 8.11
(d, 2H, J = 4.8 Hz), 8.12 (c, 1H, H‐5), 8.88 (c, 1H, H‐4).
Anal. Calcd. for C18H11ClN2O4: C, 60.94; H, 3.13; N, 7.90.
2‐[5‐(4‐Methylphenyl)‐1,2,4‐oxadiazol‐3‐yl]acetamide (21a).
This compound was obtained as a white powder. Yield: 30%,
1
m.p. 185–186°C; H NMR (DMSO‐d6): δ 2.35 (s, 3H, CH3),
Found: C, 60.88; H, 3.21; N, 7.94.
3.62 (s, 2H, CH2), 7.12 (s, 1H, NH), 7.40 (d, 2H, J = 7.3 Hz,
Ar‐H), 7.65 (s, 1H, NH), 7.97 (d, 2H, J = 7.3 Hz, Ar‐H).
Anal. Calcd. for C11H11N3O2: C, 60.82; H, 5.10; N, 19.34.
Found: C, 60.86; H, 5.12; N, 19.39.
8‐Methoxy‐3‐[5‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐3‐yl]-
coumarin (22f). This compound was obtained as a yellow powder.
Yield: 34%, m.p. 249°C; IR: 1732, 1612, 1508, 1460, 1404, 1260
1
cm−1; H NMR (DMSO‐d6): δ 3.86 (c, 3H, OCH3), 3.94 (c, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2012
Isomeric 3‐Isoxadiazolylcoumarins and Their Derivatives
OCH3), 7.18 (d, 2H, J = 9.1 Hz), 7.34 (t, 1H, J = 8.2 Hz, H‐6), 7.42
(m, 1H, H‐7), 7.52 (dd, 1H, J = 6.9 Hz, J = 2.5 Hz, H‐5), 8.12 (d,
2H, J = 9.1 Hz), 8.90 (c, 1H, H‐4). Anal. Calcd. for
C19H14N2O5: C, 65.14; H, 4.03; N, 8.00. Found: C, 64.95; H,
4.11; N, 8.05.
6.68 (m, 2H), 6.89 (m, 1H, H‐6), 7.11 (c, 1H, H‐8), 7.30 (d,
1H, J = 8.3 Hz), 7.47 (d, 2H, J = 9.6 Hz), 7.72 (d, 1H, J = 10.0
Hz), 7.93 (d, 1H, J = 8.6 Hz, H‐5), 8.04 (d, 2H, J = 9.4 Hz),
8.43 (c, 1H, H‐4). Anal. Calcd. for C25H18FN3O3: C, 70.25; H,
4.24; N, 9.83. Found: C, 70.27; H, 4.27; N, 9.91.
Procedure for the preparation of 3‐cyanomethyl‐5‐(4‐
methylphenyl)‐1,2,4‐oxadiazole (23). To a solution of 2‐[5‐(4‐
methylphenyl)‐1,2,4‐oxadiazol‐3‐yl]acetamide (18a; 1.8 g,
8 mmol) in N,N‐dimethylformamide (5 mL), thionyl chloride
(3.0 g, 25 mmol) was added. The reaction mixture was left for
overnight at room temperature. Then the reaction mixture was
poured out into ice water (25 mL), and a product was
extracted by chloroform (3 × 25 mL). Chloroform extracts
were combined, washed with water (2 × 50 mL), dried (sodium
sulfate), and concentrated in vacuo. Then crude product
was purified using column chromatography (silica gel and
2‐(4‐Ethoxyphenyl)imino‐7‐methoxy‐3‐[5‐(4‐methylphenyl)‐
1,2,4‐oxadiazol‐3‐yl]coumarin (25c).
This compound was
obtained as a yellow powder. Yield: 61%, m.p. 166°C; 1H
NMR (DMSO‐d6): δ 2.18 (c, 3H, CH3), 1.32 (t, 3H, CH2CH3),
2.40 (c, 3H, CH3), 3.83 (c, 3H, OCH3), 4.02 (KB, 2H,
CH2CH3), 6.87 (m, 2H), 7.18 (d, 2H, J = 8.7 Hz), 7.29 (m, 1H,
H‐6), 7.48 (d, 2H, J = 9.6 Hz), 7.68 (m, 1H), 7.94 (m, 1H,
H‐5), 8.02 (d, 2H, J = 9.7 Hz), 8.24 (c, 1H, H‐4). Anal.
Calcd. for C27H23N3O4: C, 71.51; H, 5.11; N, 9.27. Found:
C, 71.63; H, 5.19; N, 9.33.
chloroform).
This compound was obtained as a white powder. Yield:
33%, m.p. 94°C; 1H NMR (DMSO‐d6): δ 2.42 (c, 3H, CH3),
4.48 (c, 2H, CH2), 7.44 (d, 2H, J = 9.3 Hz, H‐8), 8.00 (d, 2H,
J = 9.3 Hz). Anal. Calcd. for C11H9N3O: C, 66.32; H, 4.55; N,
21.09. Found: C, 66.32; H, 4.59; N, 21.12.
Procedure for the preparation of 2-imino-7-methoxy-3-[5-
(4-methylphenyl)-1,2,4‐oxadiazol-3-yl]coumarin (24). 3-Cyano-
methyl-5-(4-methylphenyl)-1,2,4-oxadiazole (23; 0.5 g, 2.5
mmol) was dissolved in isopropanol (7 mL) under heating. To a
warm (30-40-C) solution, 2-hydroxy-4-methoxybenzaldehyde
(0.38 g, 2.5 mmol) and one to two drops of piperidine were
added. The reaction mixture was refluxed for 20 min and then
cooled up to 0ꢀC. After standing overnight at 0ꢀC a solid was
formed. It was filtred off and washed with isopropanol (2 × 5 mL)
to obtain the pure desired substance.
This compound was obtained as a yellow powder. Yield:
76%, m.p. 223–225ꢀC; 1H NMR (CDCl3): d 2.45 (c, 3H,
CH3), 3.84 (c, 3H, OCH3), 6.74 (m, 2H), 7.25 (c, 1H, H-8),
7.35 (d, 2H, J = 9.5 Hz), 8.08 (d, 2H, J = 9.3 Hz), 8.28 (c, 1c,
H‐4), 9.82 (c, 1H, NH). Anal. Calcd. for C19H15N3O3: C,
68.46, H, 4.54, N, 12.61. Found: C, 68.55, H, 4.65, N, 12.63.
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General procedure for the preparation of 2‐arylimino-7-
methoxy-3-[5-(4-methylphenyl)-1,2,4-oxadiazol-3-yl]coumarin
(25a–c). An aromatic amine (11 mmol) was dissolved in a
glacial acetic acid (3 mL). To a solution formed, 2-imino-7-
methoxy-3-[5‐(4‐methylphenyl)-1,2,4-oxadiazol-3-yl]coumarin
(24; 10 mmol) was added. The reaction mixture was heated up
to 70°C for 15 min and cooled to room temperature slowly.
The precipitate formed was filtred off and washed with acetic
acid–water (3:1) mixture (2 × 5 mL). Recrystallization from
N,N‐dimethylformamide–isopropanol solvent mixture at
a
suitable ratio affords pure compounds 25a–c.
2‐(3,4‐Demethylphenyl)imino-7-methoxy-3-[5-(4-methylphenyl)-
1,2,4‐oxadiazol‐3‐yl]coumarin (25a). This compound was obtained
as a yellow powder. Yield: 58%, m.p. 157°C; 1H NMR (DMSO-
d6): δ 2.18 (c, 3H, CH3), 2.28 (c, 3H, CH3), 2.40 (c, 3H, CH3),
3.78 (c, 3H, OCH3), 6.87 (m, 2H), 7.09 (m, 1H, H‐6), 7.32 (d,
1H, J = 8.7 Hz), 7.43 (d, 2H, J = 10.2 Hz), 7.50 (m, 1H), 7.93
(d, 1H, J = 8.8 Hz, H‐5), 8.03 (d, 2H, J = 10.3 Hz), 8.26 (c,
1H, H‐4). Anal. Calcd. for C27H23N3O3: C, 74.13; H, 5.30; N,
9.60. Found: C, 74.05; H, 5.27; N, 9.63.
2‐(2‐Fluorophenyl)imino‐7‐methoxy‐3‐[5‐(4‐methylphenyl)‐
1,2,4‐oxadiazol‐3‐yl]coumarin (25b). This compound was
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1
obtained as a yellow powder. Yield: 63%, m.p. 231–233°C; H
NMR (DMSO‐d6): δ 2.40 (c, 3H, CH3), 3.80 (c, 3H, OCH3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

O. S. Detistov, V. D. Orlov, and I. O. Zhuravel’
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet