Simple, efficient procedure for the synthesis of benzopyrano[2,3-c] isoxazoles

Article abstract of DOI:10.1080/00397911.2010.542863

Synthesis of 3-imino-benzopyrano[2,3-c]isoxazoles was successfully performed using heterorocyclization of 2-imino-2H-1-benzopyrano 3-carbonitrile derivatives with hydroxylamine. The synthesized compounds were characterized by infrared, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.542863

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Simple, Efficient Procedure for
the Synthesis of Benzopyrano[2,3-
c]isoxazoles
a
a
a
Myriam Kammoun , Hamida Turki , Houcine Ammar & Rachid El
a
Gharbi
a
Laboratoire de Chimie Appliquée: Hétérocycles, Corps Gras et
Polymères, Faculté des Sciences de Sfax, Université de Sfax, Sfax,
Tunisia
Accepted author version posted online: 17 Nov 2011.Published
online: 03 Feb 2012.
To cite this article: Myriam Kammoun , Hamida Turki , Houcine Ammar & Rachid El Gharbi
(
2012) Simple, Efficient Procedure for the Synthesis of Benzopyrano[2,3-c]isoxazoles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
2:11, 1677-1684, DOI: 10.1080/00397911.2010.542863
4
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Synthetic Communications , 42: 1677–1684, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.542863
SIMPLE, EFFICIENT PROCEDURE FOR THE SYNTHESIS
OF BENZOPYRANO[2,3-c]ISOXAZOLES
Myriam Kammoun, Hamida Turki, Houcine Ammar, and
Rachid El Gharbi
Laboratoire de Chimie Appliqu e´ e: H e´ t e´ rocycles, Corps Gras et Polym e` res,
Facult e´ des Sciences de Sfax, Universit e´ de Sfax, Sfax, Tunisia
GRAPHICAL ABSTRACT
Abstract Synthesis of 3-imino-benzopyrano[2,3-c]isoxazoles was successfully performed
using heterorocyclization of 2-imino-2H-1-benzopyrano 3-carbonitrile derivatives with
1
hydroxylamine. The synthesized compounds were characterized by infrared, H NMR,
13
C NMR, mass spectroscopy, and elemental analysis.
Keywords Benzopyrano isoxazole; hydroxylamine; iminocoumarin
INTRODUCTION
Benzopyrans have attracted much attention because of their useful applications
[
1–5]
in the field of medicinal pesticidal chemistry and their diverse biological activities.
For example, some benzopyrans have been reported to act as nervous system
[
depressants, as antibacterial agents, or as protein tyrosine kinase (PTK)
3]
[4]
[
inhibitors. Derivatives incorporating isoxazole heterocycle possess a broad spec-
5]
[
trum of pharmacological effectiveness such as antimicrobial, antifungal, and
6]
[7]
[8]
metastatic activities. These findings suggest that a satisfactory combination of ben-
zopyran and isoxazole moieties would constitutes an original way to develop organic
materials of special interest. It was reported that some benzopyrans fused with an
isoxazole ring revealed pronounced medicinal value because of the electronic
[
9,10]
relationship that exists between the two heterocyclic moieties.
some 3-piperazinyl benzopyranoisoxazoles have been proposed as antidepressant
For example,
[11]
and antagonist of a -adrenoceptor.
Andres et al. have showed that this family
2
Received October 13, 2010.
Address correspondence to Rachid El Gharbi, Laboratoire de Chimie Appliqu e´ e HCGP, Facult e´
des Sciences de Sfax, 3000 Sfax, Tunisia. E-mail: rachidelgharbi@yahoo.fr
1
677

1678
M. KAMMOUN ET AL.
of benzopyrano isoxazoles can be used in the treatment of major depression and
other mood disorders.
[12]
Thus far, however, the synthesis of heterocyclic compounds containing both
benzopyran and isoxazole moieties has stimulated few studies using the heterocycli-
[13,14]
[13,15,16]
[17,18]
zation of chromones,
coumarins,
or aldehydes
with hydroxylamine
and derivatives under acidic or basic catalyst conditions. All these routes led to simi-
lar structures where benzopyran and isoxazole groups are fused at the 3,4 positions
of the 1-benzopyran moiety, and only one report described the synthesis of structures
[19]
with a [3,2-d] junction.
The purpose of this study therefore was to widen the scope of these organic
materials by modifying the heterocyclic scaffold because their biological properties
would depend not only on the presence of benzopyran and isoxazole moieties but also
on their association mode. As a part of our research interest in the use of iminocou-
[20–22]
marins in heterocyclic synthesis,
the present article deals with the reaction of
cyano iminocoumarins with hydroxylamine as an original way to synthesize benzo-
pyrano [2,3-c]isoxazoles. To the best of our knowledge, no reports on this heterocyclic
scaffold have appeared in the literature.
RESULTS AND DISCUSSION
Scheme 1 illustrates the general reaction pathway used in this work, which
involves two steps: (i) the synthesis of 3-cyano iminocoumarins by Knoevenagel pro-
[20]
cedure as previously described and then (i) their conversion into the corresponding
benzopyrano[2,3-c]isoxazoles by heterocyclization with hydroxylamine (Table 1).
The treatment of iminocoumarins 1–7 with hydroxylamine (HA) was studied,
first focusing on a specific system, namely (1 þ HA). To optimize benzopyranoisox-
azole synthesis, a series of preliminary runs were conducted on this system in
homogenous or heterogeneous medium using various solvents ranging in polarity
and nucleophilic or electrophilic character (toluene, dichloromethane, chloroform,
Scheme 1.

SYNTHESIS OF BENZOPYRANO[2,3-c]ISOXAZOLES
1679
Table 1. Synthesis of iminocoumarins 1–7 and benzopyrano[2,3-c]isoxazoles 8–14
ꢀ
Iminocouarins
R
5
R
6
R
7
R
8
Compounds Time (days) Yields (%) Mp ( C)
1
2
—
—
N-(Et)
2
—
—
8
3
3
82
92
152
—
—
170
3
4
5
6
7
—
—
—
—
—
—
OCH
—
OH
—
—
—
10
11
12
13
14
3
4
3
9
9
93
58
72
67
55
155
148
139
145
147
3
—
OCH
—
3
—
Cl
OCH
—
3
—
ethanol, dimethylformamide, nitrobenzene, and acetic acid), and some acidic
catalysts (acetic acid, sulfuric acid, exchanger resin Amberlyst 15 and APTS) were
tested. When the reaction was carried out without catalyst, the interaction of HA
with 1 did not take place and no benzopyranoisoxazole was detected probably
because of the poor electrophilic reactivity of the imidic carbon toward nitrogen
of HA at ambient temperature. The use of acetic acid as appropriate catalyst
increased the electrophilic character of this carbon, resulting from protonation of
imidic nitrogen. The role of the reaction temperature was also inspected between 0
ꢀ
and 60 C. All reactions reached an asymptotic stillness, characterized by limiting
values of benzopyranoisoxazole yield. The best conditions related to the system
(
1 þ HA) can be summarized as follows: the best solvent and catalyst were found
ꢀ
to be chloroform and acetic acid, the optimum temperature was 25 C, and the
reaction time required to attain the asymptotic conditions was 72 h. With these con-
ditions, benzopyranoisoxazole 8 was isolated with good purity by simple filtration,
and yield was reproducibly close to 82%.
As shown in Scheme 2, tow possible distinct pathways can be envisaged for this
condensation involving in the first step aminolysis of 1 by Shmidt reaction (path A)
Scheme 2.

1680
M. KAMMOUN ET AL.
Scheme 3.
0
0
or Michael addition (path B) leading to the corresponding intermediates 8 or 8b
respectively. The spontaneous cyclization between the o-hydroxy group and the
cyano function gave benzopyrano[2,3-c]isoxazole 8 or benzopyrano[4,3-c]isoxazole
b. The elemental analysis and the spectral data showed that compound 8 was selec-
8
1
tively obtained without formation of any detectable 8b. In particular, the H NMR
spectrum of the obtained product indicated the presence of resonance of hydrogen
H at 8.27 ppm (CDCl =CF CO D) and the absence of signal arising from hydrogen
4
3
3
2
H9b in compound 8b.
The application of the optimized operating mode to iminocoumarins 2–7 gave
the corresponding benzopyrano[2,3-c]isoxazoles 9–14 in moderate to good yields
(55–93%) (Table 1). All the condensations showed a similar behavior but the specific
structure of iminocoumarins 1–7 affected the reaction time and the yield of the
corresponding benzopyranoisoxazoles. All these compounds exhibited Fourier
1
13
transform–infrared (FT-IR), H NMR, and C NMR spectra in good agreement
with their expected structures. Particularly, the absence in FT-IR spectra of the
ꢁ1
original absorption band at 2200–2300 cm characteristic of the CꢂN group and
ꢁ
1
ꢁ1
the appearance of absorption bands at 820–840 cm and 1240–1250 cm assigned
are a clear indication that
[
23,24]
respectively to N-O and C-O-N in the isoxazolic ring
the cyclocondensation reaction had gone to completion.
When benzopyranoisoxazole 9 was refluxed in acetic acid=ethanol=water
medium, the corresponding 3-oxo benzopyranoisoxazole 15 was obtained after
hydrolysis of the iminoester function (Scheme 3).
The progress of the reaction was followed by the changes in the FT-IR spectra
of samples withdrawn at regular intervals from the reaction media, which showed a
decrease of the absorption band characteristic of the imino function in the 3 position
ꢁ
1
and the appearance of an intense absorption band at 1702 cm assigned to the C=O
group resulting from the hydrolysis reaction.
CONCLUSION
We report in the present article, in full detail, a new synthetic method for
benzopyrano[2,3-c]isoxazoles based on the condensation of 3-cyano iminocoumarins
with hydroxylamine in the presence of acetic acid as catalyst. The mechanism of the
reaction involved the aminolysis of the imidic nitrogen by Schmidt reaction followed
by an intramolecular cyclization between O-hydroxyl group and cyano function.
Hydrolysis of compound 8 by refluxing in acetic acid=ethanol=water medium led
to the corresponding 3-oxo benzopyrano[2,3-c]isoxazole. All the structures of the

SYNTHESIS OF BENZOPYRANO[2,3-c]ISOXAZOLES
1681
1
13
obtained products have been elucidated by FT-IR, H NMR, C NMR, mass
spectroscopy, and elemental analysis.
EXPERIMENTAL
7
-Diethylamino-2-hydroxybenzaldehyde, malonitrile, and hydroxylamine were
commercially available from Aldrich. All melting points were determined on an
Electrothermal 9100 apparatus. Infrared (IR) spectra were registered on a Jasco
1
FT-IR 420 spectrophotometer apparatus using KBr pellets. H and C NMR spec-
13
tra were recorded on a Bruker WP 200 spectrometer at 300 MHz in CDCl and tri-
3
fluoro acetic acid-d with tetramethylsilane (TMS) as internal standard (chemical
shifts in ppm). Elemental microanalyses were preformed on a EA1112 analyzer from
CE Instruments at the Service Commun de Microanalyses de l’ENCIACET. Mass
spectra were recorded on a DSQII ThermoFisher spectrometer using chemical
ionization with ammoniac (positive mode) and chloroform as solvent. 3-Cyano
[
20]
iminocoumarins (1–7) were prepared as previously described.
General Procedure for the Synthesis of Benzopyranoisoxazoles 8–14
A mixture of hydroxylamine chlorohydrate (1 mmol) and triethylamine (1 mmol)
was stirred at room temperature in 30 ml of chloroform for 5 min and then 1 mmol of
3
-cyano iminocoumarin was added with a catalytic amount of acetic acid. The reaction
times and the yields are indicated in Table 1. The formed benzopyranoisoxazole was
collected by filtration, washed with chloroform, and then recrystallized from toluene.
Data
7
-Diethylamino-3-imino-3H-benzopyrano[2,3-c]isoxazole (8). Yellow-
ꢁ
1
brown solid. IR (KBr) (cm ): n ¼ 824 (N-O), 1248 (C-O-N), 1550 (C=C),
1
1
624=1647 (C=N), 3292 (NH). H NMR (CDCl =CF COOD) (ppm): d ¼ 1.33 (t,
3
3
J ¼ 7.0 Hz, 6H, CH ), 3.67 (q, J ¼ 7.0 Hz, 4H, CH N), 6.85 (s, 1H, H ), 7.08 (d,
3
2
8
1
3
J
¼ 9.0 Hz, 1H, H ), 7.64 (d, J ¼ 9.0 Hz, 1H, H ), 8.27(s, 1H, H ). C NMR
6 3 2 8
5
,6
6
5,6
5
4
(
(
(
DMSO-d ) (ppm): d ¼ 12.29 (2 CH ), 43.89 (2 CH N), 96.48 (C ), 107.12=107.24
C =C ), 113.88 (C ), 129.00 (C ), 129.13 (C ), 148.26 (C ), 149.51 (C ), 149.63
3a 4a 6 5 4 7 8a
C ), 153.05 (C ). Calculated for C H N O (%): C, 65.35; H, 5.88; N, 16.33.
9
a
3
14 15
3
2
þ
þ
Found: C, 65.41; H, 5.95; N, 16.39. MS (m=z) 276.1 [(M þ 1) ]; 291.1 [(M þ 18) ].
-Imino-3H-benzo[f]pyrano[2,3-c]isoxazole (9). Yellow solid. IR (KBr)
3
ꢁ
1
(
cm ): n ¼ 835 (N-O), 1243 (C-O-N), 1573 (C=C), 1647 (C=N), 3269 (NH).
1
H NMR (CDCl =CF COOD) (ppm): d ¼ 7.70 (d, J ¼ 9.0 Hz, 1H, H ), 7.88 (t,
3 3 7,8 8

1682
M. KAMMOUN ET AL.
J500 00 ¼ 7.0 Hz, 1H, H 00), 7.94 (t, J 00 00 ¼ 7.0 Hz, 1H, H 00), 8.14 (d, J
0 0
5 ,6
¼ 8.2 Hz, 1H,
4
, 6
6
5 ,6
5
H6
9
0
), 8.42 (d, J
0
0
¼ 8.2 Hz, 1H, H
0
), 8.53 (d, J ¼ 9.0 Hz, 1H, H ), 9.52 (s, 1H, H ),
5 ,6
5
7,8
7
1
3
.62 (s, 1H, NH). C NMR (CDCl =(ppm): d ¼ 113.11=114.39 (C =C ), 115.15
3
3a
4a
(
C ), 116.89 (C ), 121.95 (C
8
0
), 128.64 (C ), 129.78 (C 00), 130.40 (C 0), 131.97 (C 00),
5 5
6
6
5
6
1
C H N O (%): C, 71.18; H, 3.41; N, 11.86. Found: C, 71.22; H, 3.47; N, 11.85.
42.49 (C ), 148.50 (C ), 153.89 (C ), 160.75 (C ), 162.47 (C ). Calculated for
7 4 8a 9a 3
1
4
8
2
2
þ
MS (m=z) 254.0 [(M þ 18) )].
7
-Hydroxy-3-imino-3H-benzopyrano[2,3-c]isoxazole (10). Orange-brown
ꢁ
1
solid. IR (KBr) (cm ): n ¼ 844 (N-O), 1248 (C-O-N), 1562 (C=C), 1618=1658
1
(
(
1
(
(
C=N), 3258 (NH), 3470 (OH). H NMR (CDCl =CF COOD) (ppm): d ¼ 7.24
3
3
s, 1H, H ), 7.29 (d, J ¼ 9.0 Hz, 1H, H ), 7.81 (d, J ¼ 9.0 Hz, 1H, H ), 8.67 (s,
8
1
5,6
6
5,6
5
3
H, H4). C NMR (CDCl =CF COOD) (ppm): d ¼ 103.63 (C ), 109.09=112.87
3a 4a 6 5 4 8a 7
3
3
8
C =C ), 120.41 (C ), 133.49 (C ), 146.00 (C ), 147.02 (C ), 155.70 (C ), 159.95
C ), 161.66 (C ). Calculated for C H N O (%): C, 59.41; H, 2.99; N, 13.86.
9
a
3
10
6
2
3
Found: C, 59.46; H, 3.06; N, 13.93.
6
-Methoxy-3-imino-3H-benzopyrano[2,3-c]isoxazole (11). Yellow-brown
1
ꢁ
solid. IR (KBr) (cm ). n ¼ 830 (N-O), 1252 (C-O-N), 1572 (C=C), 1618=1644
1
(
7
C=N), 3258 (NH). H NMR (CDCl =CF COOD) (ppm): d ¼ 3.94 (s, 1H, OCH ),
3
3
3
1
3
.27 (s, 1H, H ), 7.66 (s, 1H, H ), 7.67 (s, 1H, H ), 8.82 (s, 1H, H ). C NMR
8 7 5 4
(
(
(
CDCl =CF COOD) (ppm): d ¼ 56.58 (OCH ), 96.05 (C ), 111.25 (C ), 118.59
3
3
3
3a
5
C ), 119.23 (C ), 129.42 (C ), 147.02 (C ), 156.45 (C ), 159.76 (C ), 161.10
4a 7 8 6 4 8a
C ), 164.21 (C ). Calculated for C H N O (%): C, 61.11; H, 3.73; N, 12.96.
3
9
a
3
11
8
2
Found: C, 61.16; H, 3.79; N, 13.00.
8
-Methoxy-3-imino-3H-benzopyrano[2,3-c]isoxazole (12). Yellow-brown
ꢁ
1
solid. IR (KBr) (cm ). n ¼ 844 (N-O), 1266 (C-O-N), 1564 (C=C), 1616=1648 (C=N),
1
3
(
232 (NH). H NMR (CDCl =CF COOD) (ppm): d ¼ 3.98 (s, 1H, OCH ), 7.3–7.8
3
3
3
1
3
m, 3H, H =H =H ), 8.72 (s, 1H, H ). C NMR (CDCl =CF COOD) (ppm):
5 6 7 4 3 3
d ¼ 59.90 (OCH ), 116.77=120.20 (C =C ), 121.91 (C ), 122.08 (C ), 129.58 (C ),
3
3a
4a
7
6
5
1
C H N O (%): C, 61.11; H, 3.73; N, 12.96. Found: C, 61.18; H, 3.76; N, 13.00.
45.00 (C ), 150.75 (C ), 151.22 (C ), 153.44 (C ), 162.91 (C ). Calculated for
8 4 8a 9a 3
1
1
8
2
3
7
-Methoxy-3-imino-3H-benzopyrano[2,3-c]isoxazole (13). Yellow-brown
1
ꢁ
solid. IR (KBr) (cm ). n ¼ 830 (N-O), 1268 (C-O-N), 1554 (C=C), 1652 (C=N),
1
3
366 (NH). H NMR (CDCl =CF COOD) (ppm): d ¼ 4.02 (s, 1H, OCH ), 7.10
3
3
3
(
s, 1H, H ), 7.30 (d, J ¼ 9.0 Hz, H ), 7.80 (d, J ¼ 9.0 Hz, H ), 8.61 (s, 1H, H ).
8
5,6
6
5,6
5
4
1
3
C NMR (CDCl =CF COOD) (ppm): d ¼ 56.30 (OCH ), 100.60=101.81 (C =C ),
3 3 3 3a 4a
1
11.67 (C ), 118.33 (C ), 129.42 (C ), 152.05 (C ), 153.47 (C ), 155.06 (C ), 163.68
8 6 5 4 7 8a
(C ), 169.93 (C ). Calculated for C H N O (%): C, 61.11; H, 3.73; N, 12.96.
Found: C, 61.18; H, 3.80; N, 13.01.
9a 3 11 8 2 3
6
-Chloro-3H-3-imino-3H-benzopyrano[2,3-c]isoxazole (14). Yellow-brown
ꢁ
1
solid. IR (KBr) (cm ). n ¼ 824 (N-O), 1250 (C-O-N), 1562 (C=C), 1612=1646
1
(
7
C=N), 3258 (NH). H NMR (CDCl =CF COOD) (ppm): d ¼ 7.44 (s, 1H, H ),
3
3
8
1
3
.73 (s, 1H, H ), 8.01 (s, 1H, H ), 8.75 (s, 1H, H ). C NMR (CDCl =CF COOD)
7 5 4 3 3
(
ppm): d ¼ 97.81=119.23 (C =C ), 119.39 (C ), 129.09 (C ), 129.73 (C ), 139.73 (C ),
3
a
4a
5
8
7
6

SYNTHESIS OF BENZOPYRANO[2,3-c]ISOXAZOLES
1683
1
50.07 (C ), 152.65 (C ), 154.89 (C ), 164.00 (C ). Calculated for C H ClN O
4 8a 9a 3 10 5 2 2
(%): C, 54.44, H, 2.28, N, 12.70. Found: C, 54.50; H, 2.33; N, 12.79.
3
-Oxo-3H-benzo[f]pyrano[2,3-c]isoxazole (15). Yellow solid. IR (KBr)
1
ꢁ
1
(
cm ). n ¼ 832 (N-O), 1247 (C-O-N), 1577 (C=C), 1702 (C=O). H NMR (CDCl =
3
CF COOD) (ppm): d ¼ 7.71 (d, J ¼ 9.0 Hz, 1H, H ), 7.90 (t, J 00 00 ¼ 6.9 Hz, 1H,
3
7,8
8
5 ,6
H
J5
00), 8.02 (t, J 00 00 ¼ 6.9 Hz, 1H, H 00), 8.20 (d, J
0
0
¼ 8.5 Hz, 1H, H
0
, 8.50 (d,
6
5 ,6
5
5 ,6
6 )
0
0
¼ 8.5 Hz, 1H, H ), 8.61 (d, J ¼ 9.0 Hz, 1H, H ), 9.63 (s, 1H, H ). Calculated
0
,6
5
7,8
7
4
for C H ClN O (%): C, 70.89; H, 2.97; N, 5.90. Found: C, 70.92; H, 2.99; N, 5.94.
1
0
5
2
2
ACKNOWLEDGMENT
The authors acknowledge the Ministry of Higher Education, Scientific
Research, and Technology in Tunisia for financial support.
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