Synthesis of novel isoxazole fused heterocycles

Article abstract of DOI:10.1080/00397911.2011.555051

Condensation of 3-aryl-4-formyl isoxazoles with 1,2-diamines led to the formation of 3-aryl-(6,7-benzo-1,5-heptadiazino)(3,2-d)-isoxazoles or isoxazolo-[5,4-b]-benzodiazepines and 3,10-diaryl-6,7,14,15-tetrhydro-13 H,16H-diisoxazole-(4,5-b;4,5-l)(1,4,8,11)-tetra-aza-cyclo-tetra-deca-4, 14-diones, the novel seven-and 14-membered heterocyclic systems. Similar compounds are of great importance in medicinal chemistry.

Full text of DOI:10.1080/00397911.2011.555051

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Synthesis of Novel Isoxazole Fused
Heterocycles
P. Sarita Rajender a , G. Sridevi b & K. Kondal Reddy c
a Department of Chemistry, Nizam College, Osmania University,
Basheerbagh, Hyderabad, India
b NB Science College P.G. Centre, Osmania University, Hyderabad,
India
c Department of Chemistry, University College of Science, Osmania
University, Hyderabad, India
Available online: 07 Dec 2011
To cite this article: P. Sarita Rajender, G. Sridevi & K. Kondal Reddy (2012): Synthesis of Novel
Isoxazole Fused Heterocycles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:15, 2191-2200
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Synthetic Communications1, 42: 2191–2200, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.555051
SYNTHESIS OF NOVEL ISOXAZOLE FUSED
HETEROCYCLES
P. Sarita Rajender,1 G. Sridevi,2 and K. Kondal Reddy3
1Department of Chemistry, Nizam College, Osmania University,
Basheerbagh, Hyderabad, India
2NB Science College P.G. Centre, Osmania University, Hyderabad, India
3Department of Chemistry, University College of Science, Osmania
University, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract Condensation of 3-aryl-4-formyl isoxazoles with 1,2-diamines led to the formation
of 3-aryl-(60,70-benzo-1,5-heptadiazino)(3,2-d)-isoxazoles or isoxazolo-[5,4-b]-benzo-
diazepines and 3,10-diaryl-6,7,14,15-tetrhydro-13H,16H-diisoxazole-(4,5-b;4,5-l)(1,4,8,11)-
tetra-aza-cyclo-tetra-deca-4,14-diones, the novel seven- and 14-membered heterocyclic
systems. Similar compounds are of great importance in medicinal chemistry.
Keywords 3-Aryl-4-formyl-5-chloro-isoxazoles; benzodiazepines; 1,2-diaminoethane;
orthophenylenediamine; tetra-aza-cyclo-tetra-deca-dienes
INTRODUCTION
In view of the reported importance[1] and our continued interest in isoxazole-
containing heterocycles,[2,3] we have prepared some novel isoxazole fused benzodia-
zepines, and the results are presented in this article. Benzodiazepines are important
heterocycles[4] with a wide range of applications and are used as anticonvulsant,
Received August 20, 2010.
Address correspondence to P. Sarita Rajender, Department of Chemistry, Nizam College, Osmania
University, Basheerbagh, Hyderabad 500 001, India. E-mail: saritarajender@gmail.com
2191

2192
P. S. RAJENDER, G. SRIDEVI, AND K. K. REDDY
anti-anxiety, sedative, antidepressive, hypnotic, and neuroleptic[5–8] agents. Hetero-
cyclic fused benzodiazapines have been reported to possess anti-inflamatory,[9] anti-
viral,[10] anti-HIV-1,[11] antimicrobial,[12] and antitumor[13] activity. It is well
established that many derivatives of both benzo fused and heterocyclic fused diaza-
pines are very important as drugs.[14] Therefore, it is anticipated that the isoxazole
fused benzodiazepines and tetra-aza macrocycles containing the isoxzole nucleus
in their skeleton possess interesting physiological and chemical properties. Tetra-aza
macrocyles have been found to be very good chelating agents.[15]
RESULTS AND DISCUSSION
Retrosynthetic analysis of isoxazole benzodiazepines and isoxzolo-tetra-aza
cyclo-tetra-decenes suggested that 3-aryl-5-chloro-4-formylisoxazole could be one
of the starting points. The formation of 5-chloro-4-formyl-3-phenyl isoxazole (2),
the only product obtained by the Vilsmier–Haack reaction of 3-phenyl-5-isoxazo-
lone (1), has been reported[16] by Anderson. However, Ashok and coworkers[17]
reported the formation of 2,4-dichloro-3-formyl-quinoline (3) under slightly differ-
ent experimental conditions. To further substantiate this reaction and to prepare
novel isoxazole fused diazepines and fused aza-macrocyclic systems, syntheses of
3-aryl-5-chloro-4-formylisoxazole and its reactions with various diamines have been
carried out.
=
Reaction of 3-phenyl-isoxazolone (1, R H), with dimethylformamide (DMF)–
=
POCl3 yielded both 5-chloro-4-formyl-3-phenyisoxazole (2, R H) and 3-formyl-2,4-
=
dichloro-quinoline (3, R H). Similarly, 3-p-toluyl-5-isoxazolone (1, R CH3) and
=
=
3-p-chlorophenyl-5-isoxazolone (1, R Cl) yielded corresponding compounds 2
=
=
(R CH3; Cl) and 3 (R CH3; Cl) respectively. However, in the case of 3-p-nitrophenyl-
=
=
5-isoxazolone (1, R NO2), corresponding quinoline derivative (3, R NO2) could
not be isolated. This may be attributed to the lesser migratory aptitude of p-nitro
phenyl group, inhibiting the rearrangement of the aryl moiety to nitrogen, which
could have resulted in ultimate formation of the quinoline skeleton and therefore
=
the formation of 3 (R NO2). This view is further supported by the reaction of
=
3-p-methoxyphenyl-5-isoxazolone (1, R OCH3) with DMF-POCl3, wherein the
[17]
=
formation of only the rearranged product (3, R OCH3) was observed
(Scheme 1). All these compounds were characterized based on the analytical and
spectral data. The infrared (IR) spectra of 2a to 2d exhibited absorptions at
Scheme 1. Preparation of 3-aryl-5-chloro-4-formyl-isoxazole (2) by Vilsmeir–Haack reaction of 3-aryl-
isoxazole-2-ene-5-ones (1).

ISOXAZOLE FUSED HETEROCYCLES
2193
Table 1. Melting points, yields, elemental analyses, and the spectral data of various 3-aryl-5-chloro-
4-formyl-isoxazoles 2a–d
Elemental analyses
found (calc.)
Molecalar
formula
Mp
(ꢁC)
Yield
(%)
Compound
m=z
C
H
N
1H NMR (CDCl3)
=
2a (R H)
C10H6NO2Cl 207 57.89
2.89
6.81
(6.84)
6.41
42–44
75–78
60 @ 7.4–7.6 (m, 3H), 7.8
(m, 2H) and 10 (s, 1H)
50 @ 2.5 (s, 3H), 7.3–7.5, (d,
J ¼ 8.1 Hz, 2H), 7.8
(d, J ¼ 8.1 Hz,2H) and
10 (s, 1H)
(57.83) (2.89)
2b (R CH3) C11H8NO2Cl 221 55.10 3.70
(55.07) (3.61)
=
(6.32)
=
2c (R Cl)
C10H5NO2Cl2 241 49.61 2.12
(49.59) (2.06)
5.81
(5.78)
48–50
65 @ 7.4–7.6 (d, J ¼ 8.0 Hz,
2H), 7.8–7.9 (d,
J ¼ 8.0 Hz, 2H) and 10
(s, 1H)
=
2d (R NO2) C10H5N2O4Cl 252 50.80
2.12
(50.73) (2.11) (11.93)
11.90 110–111 85 @ 8.0–8.2 (d, J ¼ 8.2 Hz,
2H), 8.3–8.4 (d,
J ¼ 8.1, 2H) and 10 (s,
1H)
ꢀ1
2800 cmꢀ1 (CH stretching); 1680 cmꢀ1 (C O) stretching; and 1560 cm
stretching). All the compounds gave satisfactory C, H, and N analyses (Table 1),
=
=
(C N
and the IR spectra of 3a to 3d exhibited aꢀb1sorptions at 2950 cmꢀ1 (CH stretching);
1700 cmꢀ1 (C O) stretching; and 1600 cm (C N stretching). All the compounds
gave satisfactory C, H, and N analyses (Table 2).
=
=
Table 2. Melting points, yields, elemental analyses, and the spectral data of various 2,4-dichloro-3-
formyl-6(un)-substituted quinolines (3)
Elemental analyses
found (calc.)
Molecular
formula
Mp Yield
(ꢁC) (%)
Compound
m=z
C
H
N
1H NMR (CDCl3)
=
3a (R H)
C10H5NOCl2 225 52.94
2.21
(53.00) (2.21) (6.18)
6.22
119
60
@ 7.5–8.0 (m, 3H), 8.4 (d,
J ¼ 2.1 Hz, 1H), and
10.5 (s, 1H, CHO)
=
3b (R CH3)
C11H7NOCl2 239 55.00
2.90
(55.00) (2.91) (5.83)
5.78
120
59
@ 2.40 (s, 3H, CH3),
7.5–7.9 (m, 2H), 8.0 (d,
J ¼ 2.1 Hz, 1H), and
10.48 (s, 1H, CHO)
@ 7.4–7.6 (m, 2H), 8.0 (d,
J ¼ 2.0 Hz, 1H) and
10.50 (s, 1H, CHO)
@ 4.00 (s, 3H, OCH3),
7.50–7.70 (m, 2H),
=
3c (R Cl)
C10H4NOCl3 260 45.90 5.50
(45.89) (1.58) (5.40)
1.61
130
152
65
60
=
3e (R OCH3) C10H7NO2Cl2 255 51.51
2.71 5.49
(51.56) (2.71) (5.46)
8.3–8.4 (d, J ¼ 2.2 Hz,
1H) and @ 10 (s, 1H)

2194
P. S. RAJENDER, G. SRIDEVI, AND K. K. REDDY
Reaction of 5-Chloro-4-formyl-3-phenyl-isoxazole with
Ortho-phenylenediamine
Reaction of 5-chloro-4-formyl-3-phenyisoxazole(s) (2) and orthophenylenedia-
mine (4) in equimolar proportions in hexane at room temperature followed by chro-
matographic separation gave two products (5 and 6), a novel protocol for the
synthesis of 1,5-dizepines. The compound with melting point 193 ꢁC showed IR
absorption bands at 2700–3200 cmꢀ1, indicating the presence of NH function and
=
a band at 1620 (C N) function. The molecular ion of this compound was observed
at m=z 295 (5). The relative intensities of peaks at m=z 295 (64%) and m=z 297 (22%)
indicated the presence of chlorine atoms. Further, its PMR in CDCl3 showed signals
at @ 7.3–7.9, m, 9H aromatic protons, 9.0 broad D2O exchangeable NH proton.
Based on spectral data and elemental analysis, the compound was identified as
3-phenyl-4-(benzimidazole-2-yl)-5-chloro-isoxazole (5). 13C NMR (CDCl3) recorded
peaks at @ 110–140 (9C, aromatic carbons). The compound with the melting pointꢀa1t
155–166 ꢁC indicated the presence of NH function in its IR spectrum at 3350 cm
.
Its PMR showed a broad signal at @ 1.5 (s, D2O exchangeable NH), 4.2 (s, 2H, -
CH2), and 7.7–6.9 (m, 9H, aromatic protons). 13C NMR (CDCl3) showed @ 44
(CH2, methylene protons), 120–164 (15 aromatic carbons). The molecular ion was
observed at m=z 263. Based on the given spectral data, the compound was identified
as isoxazolo-[5,4-b]-benzodiazepine (6) (Scheme 2). The formation of benzimidazolyl
isoxazoles and isoxazolobenzodiazipines in this reaction can be explained by the
intermediacy of the Schiff base (7). Nucleophilc attack of amino group on methylene
carbon followed by oxidation gives 5, whereas attack of NH2 on the isoxazole ring
followed by dehydrochlorination results in the formation of 6.[18] Similarly, the reac-
tion of other 3-aryl-5-chloroisoxazoles with other orthophenylenediamines resulted
in the formation of corresponding 5 and 6 (Scheme 3). The physical data and the
spectral analysis of these compounds is presented in the Tables 3 and 4. The IR spec-
tra of 5a–5d exhibited absorptions at 3200 cmꢀ1 (NH str.) and 1620 cmꢀ1 (C N
=
stretching); all the compounds gave satisfactory elemental analyses. The IR spectra
of 6a–6d exhibited absorptions at frequency 3500 cmꢀ1 (NH str.); all the compounds
gave satisfactory elemental analysis.
Reaction of 5-Chloro-4-formyl-3-phenylisoxazole with
1,2-Diamino-ethane (8)
Reaction of 5-chloro-4-formyl-3-phenyl isoxazole (2) with 1,2-diamino ethane
(8) in hexane at room temperature yielded a compound melting point of 188–190 ꢁC,
Scheme 2. Reaction of 3-aryl-5-chloro-4-formyl-isoxazole with orthophenylenediamine.

ISOXAZOLE FUSED HETEROCYCLES
2195
Scheme 3. Mechanism of formation of 3-aryl-4-(benzimidazol-2-yl)-5-chloro-isoxazole (5) and 3-aryl-
isoxazolo-[5,4-b]-benzodiazepines (6).
whose IR spectrum showed characteristic absorption due to NH function. Its PMR
(CDCl3) revealed signals at @ 1.5 (s, 2H, D2O exchangeable NH proton) centered at
3.6 (s, 4H, CH2 protons) and 3.8 (4H, s, CH2 protons) and peak at 7.5 to 7.9 (m,
10H, aromatic protons), 9.0 (s, 2H, methine protons). The 13C NMR (CDCl3)
showed peaks at @ 45 (2CH2), 53 (2CH2), 128–168 (20 C) in aromatic region. The
molecular ion was observed at m=z 426 in its mass spectrum. Based on its spectral
data and elemental analysis, the compound was assigned to be 3,10-diphenyl-6,7,14,
15-tetrahydro-13H,16H-diisoxazolo(4,5-f:4,5-l)1,4,8,11-tetra-aza-cyclo-tetra-deca-4,14-
diene (9) structure. Similarly, other 3-aryl-5-chloro-4-formyl analogs were treated
Table 3. Melting points, yields, elemental analyses, and the spectral data of various 3-aryl-4-
(benzimidazol-2-yl)-5-chloro-isoxazole 5a–d
Elemental analyses
found (calc.)
Molecular
formula
Mp Yield
(ꢁC) (%)
Compound
m=z
C
H
N
1H NMR
=
5a (R H)
C16H10N3OCl 295 66.10
3.41
14.18
193
198
62
65
@ 7.3–7.9 (m, 9H), 9.0 (s,
1H, D2O exchangeable)
@ 2.5 (s, 3H, CH3), 7.4–7.6
(m, 8H) and 9.0 (s, 1H,
D2O exchangeable)
(65.08) (3.38) (14.23)
5b (R CH3) C17H12N3OCl 309 65.89 3.80 13.10
(66.01) (3.88) (13.59)
=
=
5c (R Cl)
C16H9N3OCl2 329 58.40
(58.36) (2.73) (12.76)
5d (R NO2) C16H9N4O3Cl 340 56.51 2.71 16.39
(56.47) (2.64) (16.47)
2.80
12.68
202
216
57
52
@ 7.4–7.8 (m, 8H), 9.0 (s,
1H, D2O exchangeable)
@ 7.4–8.4 (m, 8H) and 9.0
(s, 1H, D2O
=
exchangeable)

2196
P. S. RAJENDER, G. SRIDEVI, AND K. K. REDDY
Table 4. Melting points, yields, elemental analyses, and the spectral data of various 3-aryl-isoxazolo-[5,
4-b]-benzodiazepines 6a–d
Elemental analyses
found (calc.)
Molecular
formula
Mp Yield
(ꢁC)
Compound
m=z
C
H
N
(%)
1H NMR
=
6a (R H)
C16H13N3O
263
72.89
(72.80)
4.89
(4.94)
16.01
(15.97)
156
34
@ 1.5 (D2O exchangeable),
4.2 (s, 2H), and 6.9–7.7
(m, 9H)
=
6b (R CH3) C17H15N3O
277
73.90
(73.64)
5.50
(5.42)
15.00
(15.16)
138
186
164
30
40
45
@ 1.5 (D2O exchangeable),
2.5 (s, 3H), 4.2 (s, 2H),
and 6.8–7.6, (m, 8H)
@ 1.5 (D2O exchangeable),
4.2 (s, 2H), and 6.9–7.3
(m, 8H)
=
6c (R Cl)
C16H12N3OCl 297
64.90
(64.64)
3.98
(4.04)
14.39
(14.47)
=
6d (R NO2) C16H12N4O3
308
62.39
(62.33)
3.78
(3.89)
18.21
(18.18)
@ 1.5 (D2O exchangeable),
4.2 (s, 2H), 6.8–8.5 (m,
8H)
Scheme 4. Reaction of of 3-aryl-5-chloro-4-formyl-isoxazole with 1,2-diaminoethane.
Scheme 5. Mechanism of formation of 3,10-diaryl-6,7,14,15-tetrahydro-13H,16H-diisoxazolo-(4,5-f:4,
5-l)1,4,8,11-tetra-aza-cyclo-tetra-deca-4,14-dienes.

ISOXAZOLE FUSED HETEROCYCLES
2197
Table 5. Melting points, yields, elemental analyses, and the spectral data of various 3,10-diaryl-6,7,14,15-
tetrahydro-13H,16H-diisoxazolo-(4,5-f:4,5-l)-1,4,8,11-tetra-aza-cyclo-tetra-deca-4,14-dienes 9a–d
Elemental analyses
found (calc.)
Molecular
formula
Mp Yield
(ꢁC) (%)
Compound
m=z
C
H
N
1H NMR
=
9a (R H)
C24H22N6O
426 68.01
5.21
(67.60) (5.16) (19.70)
19.71
188
194
206
212
80 @ 1.5 (s, 2H, D2O
exchangeable), 3.6 (s,
4H), 3.8 (s, 4H), and
7.5–7.9 (m, 10H), 9.0 (s,
2H)
=
9b (R CH3) C25H24N6O2
440 68.21 5.53
(68.18) (5.45) (19.00)
18.91
78 1.4 (s, 2H, D2O
exchangeable), 2.8 (s,
6H), 3.7 (s, 4H), 3.9 (s,
4H), and @ 7.4–7.7. (m,
8H), 8.8 (s, 2H)
=
9c (R Cl)
C24H21N6O2Cl 460 62.63
4.00
(62.60) (4.56) (18.26)
18.31
88 @ 1.5 (s, 2H, D2O
exchangeable), 3.7 (s,
4H), 3.8 (s, 4H), and
7.4–7.7. (m, 8H), 9.0 (s,
2H)
=
9d (R NO2) C24H21N7O4
489 61.21 20.91
(61.14) (4.45) (20.80)
4.39
85 @ 1.8 (s, 2H, D2O
exchangeable), 3.6 (s,
4H), 3.7 (s, 4H), and
7.5–7.9. (m, 8H), 9.2 (s,
2H)
with 1,2-diaminethane to yield corresponding 3,10-diarly-6,7,14,15-tetrahydro-13H,
16H-diisoxazolo(4,5-f:4,5-l)1,4,8,11-tetra-aza-cyclo-tetra-deca-4,14-dienes (Scheme 4).
These were characterized based on the spectral data given in Table 5. The IR spectra
of 9a–9d exhibited absorptions at 3335 cmꢀ1 (NH str.) and 1680 cmꢀ1 (C N) stretch-
=
ing; all the compounds gave satisfactory elemental analysis.
The mechanism of formation of 9 involves the formation of Schiffs base (10)
with 1 mol of ethylene diamine (8) reacting with 2 mol of (2). Nucleophilic displace-
ment of two chlorine atoms in 10 by two amino groups of 8 leads to 9 represented in
Scheme 5.
EXPERIMENTAL
Synthesis of 3-Aryl-isoxazol-2-ene-5-ones (1): General Procedure
Ethyl-p(un)-substituted benzoyl acetate6 and hydroxylamine hydrochloride
were taken in absolute ethanol and refluxed for 45 min. The reaction mixture was
cooled to room temperature, and 50% potassium hydroxide was added until the sol-
ution becomes alkaline and heating was continued for a further half an hour. The
reaction mixture was cooled and poured onto crushed ice with stirring and then
neutralized with diluted HCl. The solid thus separated was filtered to give corre-
spondingly substituted 3-aryl isoxazol-2-ene-5-ones, which were purified by recrys-
tallization from ethanol.

2198
P. S. RAJENDER, G. SRIDEVI, AND K. K. REDDY
Vilsmeir–Haack Reaction of 3-Aryl-isoxazol-2-ene-5-ones
Synthesis of 3-aryl-5-chloro-4-formyl-isoxazoles (2) and 2,4-dichloro-3-
formyl-6(un)-substituted quinolines (3): General procedure. Dimethyl forma-
mide (6.5 ml, 0.089 mmol) was added to phosphorus oxychloride (16 ml,
0.1045 mmol), with stirring at room temperature for 5 min. 3-Aryl isoxazol-2-ene-5-
one (1.61 g, 0.01 mmol) (1) was added, and stirring was continued for 1.5 h, main-
taining the temperature of the reaction at 70–80 ꢁC. The reaction at was brought
down to room temperature, poured onto crushed ice with vigorous stirring, and
extracted with dichloromethane, which on distillation yielded a red gummy material.
Chromotographic purification of the extract over a column of silica gel by eluting
with petroleum ether–benzene (4:1) mixture gave 3-aryl-5-chloro-4-formyl isoxazoles
(2). Further elution of the column with petroleum ether–benzene (1:1) mixture
yielded 2,4-dichloro-3-formyl-6(un)substituted quinolines (3).
Synthesis of 5-chloro-4-formyl-3-phenyl-isoxazole (2a) and 2,4-dichloro-
3-formyl quinoline (3a). Dimethyl formamide (6.5 ml, 0.089 mmol) was added to
phosphorus oxychloride (16.0 m, 0.1045 mmol) and stirred at room temperature
for 5 min. 3-Phenyl-isoxazole-2-ene-5-one (1.61 g, 0.01 mmol) was added to this
Vilsmeir-Haak reagent, and stirring continued for 1.5 h maintaining the tempera-
ture at 70–80 ꢁC. The reaction mixture was brought down to room temperature,
poured onto crushed ice, and then extracted with dichloromethane. Dichloro-
methane was distilled off, resulting in a red oily material, which was purified over
a column of silica gel. Elution of the column with hexane–ethyl acetate (4:1) mix-
ture yielded a colorless liquid, which was crystallized on standing overnight to give
5 chloro-4-formyl-3-phenyl isoxazole (2a) with mp 42–44 ꢁC. Further elution of the
column with petroleum ether–benzene (1:1) mixture yielded 2,4-dichloro-3-formyl
quinolines (3).
Reaction of 3-Aryl-5-chloro-4-formyl-isoxazole (2) with
Orthophenylenediamine (4)
Formation of 3-aryl-4-(benzimidazol-2-yl)-5-chloro-isoxazoles (5) and 3-
aryl-[6’,7’-b]-benzodiazepines (6). 3-Aryl-5-chloro-4-formyl isoxazole (2) and
orthophenylenediamine (4) were suspended in hexane in equimolar proportions.
The reaction mixture was stirred at room temperature for 2 h, and hexane was dis-
tilled off, resulting in a gummy mass. The crude solid was subjected to chromato-
graphy over a column of silica gel. Elution with petroleum ether–ethyl acetate
(9:1) mixture gave corresponding 3-aryl-4-(benzimidazol-2-yl)-5-chloro isoxazoles
(5) in good yields. Further elution of the column with hexane–ethyl acetate (7:3) mix-
ture gave correspondingly substituted 3-ary-[60,70-benzo-10,50-hepta-diazino] [3,
2-d]-isoxazole or isoxazolo [5,4-b]-benzodiazepines (6).
Synthesis of 3-phenyl-4-(benzimidazol-2-yl)-5-chloro-isoxazole (5a)
and 3-phenyl-[6’,7’-benzo-1’5’-heptadiazino]-[3,2-d]-isoxazole or isoxozolo-
[5,4-b]-benzodiazepines (6a). 5-Chloro-4-formyl-3-phenyl isoxazole (2) (207 mg,
1 mmol) was taken in hexane, and orthophenylenediamine (4) (108 mg, 1 mmol)
was added. The reaction mixture was stirred for 2 h. Hexane was distilled off, and

ISOXAZOLE FUSED HETEROCYCLES
2199
the chromatographic purification of the crude product over a column of silica gel by
eluting with hexane–ethyl acetate (9:1) mixture afforded pure 3-phenyl-
4-(benzimidazol-2-yl)-5-chloro isoxazole (5a), mp 193 ꢁC. Further elution with
benzene–ethyl acetate (7:3) mixture afforded 3-phenyl-[60,70-benzo-10,50-hepta-
diazine][3,2-d]-isoxazole or isoxazolo-[5,4-b]benzodiazepine) (6a), mp 156 ꢁC.
Reaction of 3-Aryl-4-formyl-5-chloro-isoxazole with
1,2-Di-aminoethane (8)
Formation of 3,10-Diaryl-6,7,14,15-tetra-hydro-13H,16H-diisoxazolo-[4,
5-f;4,5-1][1,4,8,11]-tetra-aza-cyclo-tetra-deca-4,14-diene (9). A mixture of
3-aryl-5-chloro-4-formyl isoxazole and ethylene diamine (8) were taken in equimolar
proportions in hexane and stirred for 2 h. The solid that resulted was purified over
a column of silica gel, eluting with hexane–ethyl acetate mixture to afford the corre-
sponding 3,10-diaryl-6,7,14,15-tetrahydro-13H,16H-diisoxazolo-[4,5-f;4,5-1][1,4,8,
11]-tetraazacyclotetradeca-4,14-diene (9).
Synthesis of 3,10-diphenyl-6,7,14,15-tetrahydro-13H,16H-di-isoxazolo-
[4,5-f;4,5-1][1,4,8,11]-tetra-aza-cyclo-tetra-deca-4,14-diene (9a). 5-Chloro-4-
formyl-3-phenyl isoxazole (207 mg, 1 mmol) and 1,2-diamino ethane (60 mg,
1.5 mmol) are taken in hexane and stirred at room temperature for 2 h. The resulted
solid was purified over a column of silica gel, and eluting with hexane–ethyl acetate
(9:1) mixture yielded a colorless crystalline solid (9a), mp 188 ꢁC.
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