1,3-Dipolar cycloaddition reaction: Synthesis of novel 5,6- dehydronorcantharidin derivatives of substituted aromatic amines with potential antitumor activities

Article abstract of DOI:10.1002/jhet.5570420103

Twelve novel compounds were synthesized by the [3+2] 1,3-dipolar cycloaddition reaction of 5,6-dehydronorcantharidin derivatives of substituted aromatic amines with nitrile oxides. The structure and the configuration of all compounds were confirmed by ¹H NMR, IR, MS, ¹H- ¹HCOSY, and NOESY spectral data. Their anti-tumor activities are under way.

Full text of DOI:10.1002/jhet.5570420103

Jan-Feb 2005
13
1,3-Dipolar Cycloaddition Reaction: Synthesis of Novel
5,6-Dehydronorcantharidin Derivatives of Substituted Aromatic
Amines with potential antitumor activities
b
a,
b
Li-Ping Deng, Fang-Ming Liu, * Hou-Yong Wang
a
Department of Chemistry, Hangzhou Teachers College, Hangzhou 310012;
Chemistry and Chemical Engineering Institute of Xinjiang University,
b
Ulumqi 830046
Received February 2, 2004
Twelve novel compounds were synthesized by the [3+2] 1,3-dipolar cycloaddition reaction of 5,6-dehy-
dronorcantharidin derivatives of substituted aromatic amines with nitrile oxides. The structure and the con-
1
1
1
figuration of all compounds were confirmed by H NMR, IR, MS, H- HCOSY, and NOESY spectral data.
Their anti-tumor activities are under way.
J. Heterocyclic Chem., 42, 13 (2005).
Cantharidin, is the major effective ingredient for the
Results and Discussion.
malignant tumor treatment among the people in China [1].
Recent study showes that cantharidin can treat liver can-
cer to some extent [2], and can also enhance white cell
without inhibiting the immune system [3]. So, cantharidin
is of great pharmacological interest and has gained great
attention. However, cantharidin is somewhat toxic and
difficult to synthesize. On the other hand, the derivatives
of the 5,6-dehydronorcantharidin show the same biologi-
cal activity, are less toxic and much easier to synthesize.
Furthermore, many compounds containing the 1,2,3-tri-
zolye ring have become a hot topic in heterocyclic chem-
istry because of their antitumor, anti-virus, analgesic,
sedative and fungicidal activities [4-6]. It has been shown
recently that the pharmacological activities of parent mol-
ecules will apparently be improved with the introduction
of 1,2,3-triazole to some active molecules, such as peni-
cillin, cephalesporins and so on. Tests with derivatives of
quinoxaline show them having anticancer, anti-HIV, anti-
fungal, antidepressant, anthelmintic and herbicidal prop-
erties [7-10]. Although 1,3-dipolar cycloaddition reac-
tions of nitrile oxides is the general method to synthesize
isoxazolines, there has been very little work on the 1,3-
dipolar cycloaddition reaction of 5,6-dehydronorcan-
The synthetic routes of the compounds mentioned
above are outlined in Scheme 1. The precursor 5,6-dehy-
dronorcantharidin derivatives 3a-3f were synthesized by
novel method in good yield, which was reported for the
first time.
Nitrile oxides are of great synthetic interest since the
product isoxazolines are versatile intermediates for the
synthesis of bifunctional compounds. However, nitrile
oxides are unstable and readily dimerize, hence we gener-
ate and react them in situ intermolecularly with 5,6-dehy-
dronorcantharidin, derivatives of substituted aromatic
amines, to produce isoxazoline adducts in excellent yield.
We have carried out the [4+2] cycloaddition of furan
with maleic anhydride to obtain 5,6-dehydronorcan-
tharidin 1, then by "one pot" method, 5,6-dehydronorcan-
tharidin 1 reacted with substituated phenylamine 2a-2f to
give compounds 3a-3f, after that, we carried out the [3+2]
cycloaddition of 3a-3f with two nitrile oxides, generated
(in situ) in the presence of triethylamine from α-chloro-2-
phenyl-2H-[1,2,3]triazole–4-formaldehyde oxime 4 and
α-chloro-quinoxaline-2-formaldehyde oxime 5 to obtain
the target compounds 6a-6f and 7a-7f respectively. The
reactions were monitored by thin-layer chromatography.
Complete information of the synthesis procedure will be
described in detail in experimental part.
The structure and configuration of the new compounds
(6a-6f and 7a-7f) were established by their elemental
microanalyses and spectral data. For example, the IR spec-
tra of compounds (6a-6f and 7a-7f) contain the character-
-1
istic C=N stretching frequencies at 1520-1560cm and the
carbonyl group C=O stretching frequency at 1779-1714
-1
-1
-1
tharidin derivatives. These observations prompted us to
study the synthesis of 5,6-dehydronorcantharidin deriva-
tives. We have successfully designed and efficiently syn-
thesized the 5,6-dehydronorcantharidin isoxazoline
adducts which possess a 1,2,3-triazole or quinoxaline ring
linked to 5,6-dehydronorcantharidin, with a view of com-
paring their biological properties.
cm , the absorption of Ar-H at 3066 cm and 3045 cm ,
-1
-1
and the appearance of C-O-C at 1289 cm and 1256 cm
respectively. The MS/EI spectra of (6a-6f and 7a-7f)
showed the characteristic molecular ion peaks. The m/z
and relative abundances of molecular ions and fragment
ions of the compounds are given in the experimental sec-
tion. They are also characterized by retro-dipolar cycload-

14
L.-P. Deng, F.-M. Liu, H.-Y. Wang
Vol. 42
Scheme
1
2a R =H; 2b R = Cl; 2c R =Br; 2d R =CH ; 2e R =OCH ; 2f R = NO ;
1
1
1
1
3
1
3
1
2
3a R =H; 3b R = Cl; 3c R =Br; 3d R =CH ; 3e R =OCH ; 3f R = NO ;
1
1
1
1
3
1
3
1
2
6a R =H; 6b R = Cl; 6c R =Br; 6d R =CH ; 6e R =OCH ; 6f R = NO ;
1
1
1
1
3
1
3
1
2
7a R =H; 7b R = Cl; 7c R =Br; 7d R =CH ; 7e R =OCH ; 7f R = NO ;
1
1
1
1
3
1
3
1
2
dition and retro Diels-Alder [4+2] cycloaddition frag-
ments.
The H nmr spectra of the new compounds measured in
structures. The Diels-Alder adduct 5,6-dehydronorcan-
tharidin 1 of furan with maleic anhydride has been shown
to have the exo configuration exclusively; the endo isomer
has never been reported [11-12]. For target compounds
6a–6f and 7a–7f, the presence of multiple signal at δ 8.39-
1
dimethyl sulfoxide-d (DMSO-d ) show the presence of
6
6
the expected protons, in agreement with the proposed
Figure 1. NOESY spectrum of 7a.

Jan-Feb 2005
1,3-Dipolar Cycloaddition Reaction
15
Figure 2. COSY spectrum of 6f.
7.48 was assigned to the aromatic protons, H and H
d
a
appeared as singlets, H , H , H , H appeared as doublets
e
f
c
b
due to the coupling between H and H , H and H .
e
f
c
b
1
Complete information of H nmr chemical shift and cou-
pling constants observed for compounds 6a-6f and 7a-7f
are presented in experimental part.
In order to identify the configuration of the isoxazoline
with 5,6-dehydronorcantharidin adducts (6a-6f and 7a-7f),
1
1
we have studied selective H- HCOSY spectra and
1
1
NOESY spectra of the compounds. H- HCOSY spectra
show the cross peaks between resonances for H and H ;
b
c
H and H ; NOESY spectra show that there are corre-
e
f
sponding peaks between resonances for H and H ; H and
a
b
a
H ; H and H ; H and H ; H and H ; H and H which
f
d
c
d
e
b
f
c
e
prove that the six protons are near in space and on the same
side. In order to rationalize the configuration of adducts,
we have also carried out theoretical calculation using
Figure 3. NOESY Spectrum of 6f.

16
L.-P. Deng, F.-M. Liu, H.-Y. Wang
Vol. 42
5,6-dehydronorcantharidin 1 with 4-methoxy- aniline 2e gave 4-
(4'-methoxyphenyl)-10-oxa-4-aza-tricyclo [5.2.1.0 ]dec-8-ene-
semi-empirical PM3 with the aid of TITAN software. The
result shows that the heat of formation of structure A is
201.9861 kcal/mole; the heat formation of structure B is
200.6798 kcal/mole; so structure B is theoretically the
more stable isomer. The calculation result combined with
2,6
3,5-dione 3e; the reaction of 5,6-dehydronorcantharidin 1 with 4-
nitro- aniline 2f gave 4-(4'-nitro-phenyl)-10- oxa-4-aza- tricyclo-
2,6
[5.2.1.0 ]dec-8-ene-3,5-dione 3f. 3a: yield 68.8%, m. p. 162-163
°C; 3b:yield 69.2%, m. p. 166-167 °C; 3c:yield 70.8%, m. p. 178-
179 °C 3d:yield 59.7%, m. p. 168-169 °C; 3e:yield 58.1%, m. p.
163-164 °C; 3f:yield 46.9%, m. p. 177-178 °C.
1
1
H- HCOSY and NOESY spectral data gives us a definite
configuration.
A heat of formation: 201.9861 kcal/mole
B heat of formation: 200.6798 kcal/mole
The compounds will be investigated for their antiviral
and antibacterial as well as antitumor activity and the
results will be reported when they become available.
General Procedure for the Preparation of the 5,6-Dehydronor-
cantharidinisoxazoline Adducts (6a-6f and 7a-7f).
To a solution of 3-acetyl-7-oxa-bicyclo[2.2.1]hept-5-
ene-2-carboxylic acid phenylamide 3a (1 mmole) and 4
(1 mmole) in dichloromethane (20 ml), add dried tri-
ethylamine (6 drops) and the reaction mixture was vig-
orously stirred at room temperature for 24 hours. Then
washed with water (30 ml) and extracted with
dichloromethane (30 ml). The extracts were washed
with water, dried over anhydrous sodium sulfate, con-
centrated in vacuum and the residue was recrystallized
from acetone to give the compound 6a. The synthesis of
compounds 6b-6f and 7a-7f was performed using the
same method.
EXPERIMENTAL
All melting points were determined on a mettler FP-5 capillary
1
melting point apparatus and are uncorrected. The H nmr, H-H
COSY and NOESY spectra were recorded on a Warlan Inova-400
(400MHz) spectrometer. The IR spectra were measured on a
Biorad FT-40 infrared spectrometer. The purity of all compounds
was checked by thin-layer chromatography (tlc) on silica gel 60-F-
254 precoated plates and the spots were located in using UV light
or by iodine vapor. Elemental microanalyses were done using
Perkin-Elmer 2400 CHNS Analyser, IR spectra were recorded
with a Biorad FT-40 spectrophotometer (KBr pellets), Mass spec-
tra were recorded on a VG ZAB-HS, spectrometer (EI, 70eV).
All solvents used were reagent grade except the dimethyl sul-
foxide used for spectroscopic measurements (spectrophotometric
grade). The preparation of 5,6-dehydronorcantharidin 1 was per-
formed according to the literature [13].
exo,exo-4,8-Epoxy-3a,4,4a,7a,8,8a-hexahydro-6-phenyl-3-(2-
phenyltriazolo-4-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole (6a).
Compound 6a was obtained as a colorless solid, yield 95%,
+
m.p. 277-278° C; MS (70eV) m/z (%) 427(M ), 286(3.2),
144(3.7), 119(42.5), 91(48.0), 77(53.8), 67(100); ir (KBr):
3066, 3045 (ArH), 1779, 1714 (C=O), 1530 (C=N), 1289,
-1
1
1256 (C-O) cm ; H nmr (DMSO-d , 400MHz): δ 8.55 (s,
6
"One-pot" Method for the Preparation of 3-Acetyl-7-oxa-bicy-
clo[2.2.1]hept-5-ene-2-carboxylic Acid Phenylamide 3a-3f.
1H, H-C=N), 8.07-7.19 (m, 10H, ArH), 5.30 (d, 1H, H ), 5.11
e
(s, 1H, H ), 5.04 (s, 1H, H ), 4.49 (d, 1H, H ), 3.59 (d, 1H,
d
a
f
H ), 3.40 (d, 1H, H ).
A mixture containing 10 mmol 5,6-dehydronorcantharidin 1 and
10 mmol amine 2a in 30 ml acetone was stirred at room tempera-
ture for about an hour. During which a large ammount of white pre-
c
b
Anal. Calcd. for C
H N O : C, 64.64; H , 3.98; N, 16.39.
23 17 5 4
Found: C, 64.42; H, 3.87; N, 16.22.
cipitate was formed. Then 0.1g Mn(Ac) , 7ml Et N and 60ml
2
3
exo,exo-6-(4-Chlorophenyl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahy-
dro-3-(2-phenyltriazolo-4-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole
(6b).
(AcO) O was added and the mixture was heated to 50-60 °C for
2
about two hours, during which the solvent again became clear. The
solution was then cooled, nonsoluble solids were filtered, and the
filtrate was poured into 50 ml ice–water. The precipitated solid was
collected by filtration and recrystalized from menthanol to give
compound 3a. Under similar experimental conditions the reaction
of 5,6-dehydronorcantharidin 1 with 4-chloro- aniline 2b gave 4-
Compound 6b was obtained as a colorless solid, yield 87%,
+
m.p. 289-291 °C; MS (70eV) m/z(%) 462(M ), 226(10.3), 166
(19), 131 (11.5), 127 (10.7), 118 (8.2), 91 (29.0), 77 (22.4), 66
(100) ; ir (KBr): 3103, 3040 (ArH), 1783, 1705 (C=O), 1594
-1
1
2,6
(C=N), 782 (C-Cl), 1270, 1243 (C-O-C) cm ; H nmr (DMSO-
(4-chlorophenyl)-10-oxa-4-aza-tricyclo[5.2.1.0 ]dec-8-ene-3,5-
d , 400MHz): δ 8.55 (s, 1H, H-C=N), 8.07-7.25 (m, 9H, ArH),
dione 3b; the reaction of 5,6-dehydronorcantharidin 1 with 4-bro-
moaniline 2c gave 4-(4'-bromophenyl)-10-oxa-4-aza-tricyclo
[5.2.1.0 ]dec-8-ene-3,5-dione 3c; the reaction of 5,6-dehydro-
6
5.30 (d, 1H, H ), 5.11 (s, 1H, H ), 5.03 (s, 1H, H ), 4.49(d, 1H,
e
d
a
2,6
H ), 3.59 (d 1H, H ), 3.40 (d, 1H, H ).
f
c
b
Anal. Calcd. for C
Found: C, 59.56; H, 3.39; N, 15.18.
H N O Cl: C, 59.74; H, 3.46; N, 15.15.
norcantharidin 1 with p-tolylamine 2d gave 4-p-tolyl-10-oxa-4-
aza-tricyclo[5.2.1.0 ]dec-8-ene-3,5-dione 3d; the reaction of
23 16 5 4
2,6

Jan-Feb 2005
1,3-Dipolar Cycloaddition Reaction
17
exo,exo-6-(4-Bromophenyl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(2-phenyltriazolo-4-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole (6c).
5.32 (s, 1H, H ), 5.17 (d, 1H, H ), 4.39 (d, 1H, H ), 3.41 (d, 1H,
a e f
H ), 3. 19 (d, 1H, H ).
c
b
Anal. Calcd. for C
Found: C, 66.67; H, 4.14; N, 13.48.
H N O : C, 66.83; H, 4.12; N, 13.56.
23 17 4 4
Compound 6c was obtained as a colorless solid, yield 91%,
+
m.p. 278-279 °C; MS (70eV) m/z(%) 506(M ), 239(14.5), 136
-1
(23.7) ,127 (7.2), 91 (43.8), 77 (45.4), 68 (100) cm ; IR (KBr):
exo,exo-6-(4-Chlorophenyl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahy-
dro-3-(quinoxaline-2-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole (7b).
3078, 3056 (ArH), 1785, 1722 (C=O) 1595 (C=N), 1256 , 1249
1
(C-O) ; H nmr (DMSO-d , 400MHz): δ 8.55 (s, 1H, H-C=N),
6
Compound 7b was obtained as a colorless solid, yield 70%,
m.p. 300 °C; MS (70eV) m/z(%) 448 (M ), 450 (M +2), 276
(23.1), 155 (49.4), 124 (11.6), 119 (43.2), 103 (33.8), 91 (18.2),
77 (35.5), 68 (100); IR (KBr) : 3080 3055 (ArH), 1782, 1743
(C=O), 1598 (C=N), 1257, 1264 (C-O) cm ; H nmr (DMSO-d ,
400MHz): δ 9.49 (s, 1H, H-C=N), 8.21-7.23 (m, 10H, ArH), 5.48
8.07-7.18 (m, 9H, ArH), 5.29 (d, J=8.40 Hz, 1H, H ), 5.11 (s, 1H,
e
+
+
H ), 5.04 (s, 1H, H ), 4.49 (d, J=8.40 Hz, 1H, H ), 3.59 (d, J=7.20
d
a
f
Hz, 1H, H ), 3.40 (d, J=7.20 Hz, 1H, H ).
c
b
Anal. Calcd. for C
H N O Br: C, 54.55; H, 3.16; N, 13.83.
23 16 5 4
-1 1
6
Found: C, 54.61; H ,3.21; N, 13.90.
exo,exo-4,8-Epoxy-3a,4,4a,7a,8,8a-hexahydro-3-(2-phenyltria-
zolo-4-yl)-6-(p-tolyl)-pyrrolo[3,4-f]-1,2-benzisoxazole (6d).
(s, 1H, H ), 5.32 (s, 1H, H ), 5.17(d, 1H, H ), 4.39(d, 1H, H ),
d
a
e
f
3.41(d, 1H, H ), 3.19 (d, 1H, H ).
c
b
Anal. Calcd. for C
Found: C, 61.48; H, 3.52; N, 14.35.
H N O Cl: C, 61.61; H, 3.57; N, 14.29.
23 16 4 4
Compound 6d was obtained as a colorless solid, yield 71%,
m.p. 275-276 °C; MS (70eV) m/z(%) 441 (M ), 368 (10.4),
+
223 (13.6), 104 (59.7) ,102 (21.3), 91 (32.8), 77 (36.0), 68 (100);
IR (KBr): 3082, 3056 (ArH), 1784, 1749 (C=O), 1596 (C=N),
exo,exo-6-(4-Bromophenyl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahy-
dro-3-(quinoxaline-2-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole (7c).
-1
1
1278, 1266 (C-O) cm ; H nmr (DMSO-d , 400MHz): δ 8.55 (s,
6
Compound 7c was obtained as a colorless solid, yield 78%,
1H, H-C=N), 8.07-7.07 (m, 9H, ArH), 5.29 (d, 1H, H ), 5.10 (s,
e
+
+
m.p. 300 °C; MS (70eV) m/z(%) 493 (M +2), 491(M ), 320
(11.7), 241 (11.0), 155 (49.5), 119 (43.3), 103 (28.2), 91 (34.7),
77 (22.8), 68 (100); IR (KBr) :3086 3059 (ArH), 1783,
1H, H ), 5.04 (s, 1H, H ), 4.48 (d, 1H, H ), 3.57(d,1H, H ), 3.38
d
a
f
c
(d, 1H, H ), 2.33 (-CH ).
b
3
Anal. Calcd. for C
H N O : C 65.31, H 4.31, N 15.87.
24 19 5 4
-1
1
1743(C=O), 1597(C=N), 1256, 1263(C-O) cm
, H nmr
Found: C 65.34, H 4.29, N 15.73.
(DMSO-d , 400MHz): δ 9.49 (s, 1H, H-C=N), 8.21-7.23 (m,
6
exo,exo-4,8-Epoxy-3a,4,4a,7a,8,8a-hexahydro-6-(4-
methoxyphenyl)-3-(2-phenyltriazolo-4-yl)-pyrrolo[3,4-f]-1,2-
benzisoxazole (6e).
10H, ArH), 5.47 (s, 1H, H ), 5.32 (s, 1H, H ), 5.17 (d,1H, H ), 4.
d
a
e
39(d, 1H, H ), 3.41(d, 1H, H ), 3.19 (d, 1H, H ).
f
c
b
Anal. Calcd. for C
H N O Br: C, 56.21; H, 3.26; N, 13.03.
23 16 4 4
Found: C, 56.23; H, 3.32; N, 13.04.
Compound 6e was obtained as a colorless solid, yield 68%,
m.p. 268-269 °C; MS (70ev) m/z(%) 457(M ), 359(11.7), 347
+
exo,exo-4,8-Epoxy-3a,4,4a,7a,8,8a-hexahydro-6-(4-p-tolyl)-3-
(quinoxaline-2-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole (7d).
(18.3), 148 (49.4), 123 (46.8) ,103 (30.6), 91 (15.5), 77 (38.2),
68(100); IR (KBr): 3080, 3055 (Ar-H), 1784, 1746 (C=O), 1596
-1
1
Compound 7d was obtained as a colorless solid, yield 69%,
m.p. 300 °C; MS (70eV) m/z (%) 427 (M ), 255 (13.4), 241
(13.6), 197 (18.8), 155 (44.7), 133 (23.1), 119 (46.7), 103 (35.4),
91 (14.1), 77 (38.5), 68 (100); IR (KBr) : 3081, 3056 (ArH),
(C=N), 1252, 1266 (C-O) cm ; H nmr (DMSO-d , 400MHz):
6
+
δ 8.55 (s, 1H, H-C=N), 8.07-7.06 (m, 9H, ArH), 5.29 (d, 1H, H ),
e
5.10 (s, 1H, H ), 5.02 (s, 1H, H ), 4.48 (d,1H, H ), 3.57 (d, 1H,
d
a
f
H ), 3.38 (d,1H, H ), 3.77(-OCH ).
v
c
b
3
-1
1
1783, 1747 (C=O), 1598 (C=N), 1252, 1265 (C-O) cm ; H nmr
Anal. Calcd. for C
H N O : C, 63.02; H,4.16; N ,15.32.
24 19 5 5
(DMSO-d , 400MHz): δ 9.49 (s, 1H, H-C=N), 8.21-7.26 (m,
Found: C, 63.14; H, 4.08; N,15.17.
6
10H, ArH), 5.47 (s, 1H, H ), 5.32 (s, 1H, H ), 5.17 (d,1H, H ),
d
a
e
exo,exo-4,8-Epoxy-3a,4,4a,7a,8,8a-hexahydro6-(4-nitrophenyl)-
3-(2-phenyltriazolo-4-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole (6f).
4.39 (d, 1H, H ), 3.41(d, 1H, H ), 3.19 (d, 1H, H ), 2.36 (-CH ).
f
c
b
3
Anal. Calcd. for C
H N O : C, 67.45; H, 4.45; N, 13.11.
24 19 4 4
Found: C, 67.40; H, 4.29; N, 13.04.
Compound 6f was obtained as a yellow solid, yield 62%, m.p.
266-268 °C; MS (70eV) m/z(%), 472 (M ), 221(34.4) 208(28.7),
+
exo,exo-4,8-Epoxy-3a,4,4a,7a,8,8a-hexahydro-6-(4-
methoxyphenyl)-3-(quinoxaline-2-yl)-pyrrolo[3,4-f]-1,2-ben-
zisoxazole (7e).
138(20.5), 127(7.3), 110(47.5), 91(36.6), 77(21.3), 68(100); IR
(KBr): 3089, 3055 (ArH), 1755, 1723(C=O), 1537(C=N), 1299,
-1
1
1240(C-O) cm ; H nmr (DMSO-d , 400MHz): δ 8.55 (s, 1H,
6
Compound 7e was obtained as a colorless solid, yield 66%,
m.p. 300 °C; MS (70eV) m/z(%) 443(M ), 270 (18.4), 241
H-C=N), 8.39-7.48 (m, 9H, ArH), 5.31 (d, 1H, H ), 5.15 (s, 1H,
e
+
H ), 5.07 (s, 1H, H ) 4.51(d, 1H, H ), 3.65(d, 1H, H ), 3.46 (d,
d
a
f
c
(13.5), 197 (18.0), 155 (47.2), 149 (21.8), 119 (46.2), 103 (37.3),
91 (16.7), 77 (33.6), 68 (100) ;IR (KBr) : 3081, 3056 (ArH),
1783, 1747 (C=O), 1598 (C=N) , 1252, 1265 (C-O) cm , H nmr
1H, H ).
Anal. Calcd. for C
Found: C, 54.39; H, 3.37; N, 17.64.
b
H N O : C, 58.47; H, 3.39; N,17.80.
23 16 6 6
-1 1
(DMSO-d , 400MHz): δ 9.50 (s, 1H, H-C=N), 8.21-7.23 (m,
6
exo,exo-4,8-Epoxy-3a,4,4a,7a,8,8a-hexahydro-6-phenyl-3-
(quinoxaline-2-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole (7a).
10H, ArH), 5.48 (s, 1H, H ), 5.32 (s, 1H, H ), 5.17(d, 1H, H ),
d
a
e
4.39(d, 1H, H ), 3.41(d, 1H, H ), 3.19(d, 1H, H ), 3.77 (-OCH ).
f
c
b
3
Compound 7a was obtained as a colorless solid, yield 68%,
m.p. 300 °C; MS (70eV) m/z(%) 413 (M ), 241 (11.3), 197
Anal. Calcd. for C
Found: C, 65.08; H, 4.29; N, 12.54.
H N O : C, 65.01; H, 4.30; N, 12.64.
24 19 4 5
+
(18.8), 155 (49.7), 129 (46.8), 103 (30.6), 91 (15.7), 77 (38.2), 68
(100); IR (KBr): 3081, 3056 (ArH) 1783, 1747(C=O), 1598
exo,exo-4,8-Epoxy-3a,4,4a,7a,8,8a-hexahydro-6-(4-nitrophenyl)-
3-(quinoxaline-2-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole (7f).
-1
1
(C=N), 1252, 1265 (C-O) cm ; H nmr (DMSO-d , 400MHz): δ
6
9.49 (s, 1H, H-C=N), 8.21-7.23 (m, 10H, ArH), 5.47 (s, 1H, H ),
Compound 7f was obtained as a yellow solid, yield 66%, m.p.
d

18
L.-P. Deng, F.-M. Liu, H.-Y. Wang
Vol. 42
Chem. Abstr., 94, 120481v (1981).
[4] O. Livi, P. L. Ferrarini and I. Tonetti, Farmaco, Ed. Sci., 31,
797 (1976).
+
300 °C; MS (70eV) m/z (%) 443 (M ), 270 (18.0), 241 (13.1),
197(18.2), 155 (47.7), 149 (21.3), 119 (46.2), 103 (37.5), 91
(16.4), 77 (33.2), 68 (100) IR (KBr): 3081, 3056 (ArH), 1783,
-1
1
[5] M. D. Alel, H. T Luu, R. G. Micetich, D. Q. Nguyen, A. B.
Oreski, M. L. Tempest, M. Daneshtalab J. Heterocyclic Chem., 33,
415 (1996).
[6] A. P. Oludotun, P. C. David, A. Kevin G. M. Ronald N. M.
Samarendra and K. A. H. Chieko Khim. Geterotsikl. Soedin., (Russ),
377 1536 (1998); Chem. Abstr., 131, 310469c (1999).
[7] M. Loriga, S. Piras, P. Sanna and G. Paglietti Farmaco, 52,
152 (1997).
[8] Y. Kurasawa and A. Takada Heterocycles, 24, 2321 (1986).
[9] Y. Kurasawa M. Muramatsu K. Yamazaki S. Tajima Y.
Okamoto and A. Takada J. Heterocyclic Chem., 23, 1379 (1986).
[10] H. S. Kim, J. Y. Chung, E. K. Kim, Y. T. Park, Y. S. Hong,
M. K. Lee, Y. Kurasawa and A. Takada, J. Heterocyclic Chem., 33,
1855 (1996).
[11] W. B. Ronfrow, and P. J. Hawkins, Organic Chemistry
Laboratory Operations, Macmillan, New York, P. 63 (1962).
[12] J. A. Berson, R. D. Reynolds and W. M. Jones, J. Am.
Chem. Soc., 78, 6049 (1956).
1747 (C=O), 1598 (C=N), 1252, 1265 (C-O) cm , H nmr
(DMSO-d , 400MHz): δ 9.51 (s, 1H, H-C=N), 8.26-7.28 (m,
10H, ArH), 5.48 (s, 1H, H ), 5.33 (s, 1H, H ), 5.1 8(d,1H, H ),
6
d
a
e
4.39 (d, 1H, H ), 3.41(d,1H, H ), 3.19 (d,1H, H ).
f
c
b
Anal. Calcd. for C
H N O : C, 60.39; H, 3.50; N, 15.32.
23 16 4 6
Found: C, 60.26; H, 3.58; N, 15.30.
Acknowledgement.
We are extremely grateful to the National Natural Science
Foundation of China for supporting this research (No 29702007,
20162004).
REFERENCES AND NOTES
[1] G. J. Wilbert Pharm.Sci., 56, 174 (1967).
[2] C.-H Wang, C - H Wu, K.-J Hsieh, K.-Y Yen and L.-L.
Yang, Toxicology, 147, 77 (2000).
[13] R. B. Woodward and B. Harold, J. Am. Chem. Soc., 70,
1161 (1948).
[3] G.-S. Wang, Acta Pharm. Sinica (Chinese) 15, 119 (1980);