Synthesis of Pyrazole-linked Norcantharidin Analogues of Substituted Chromones

Article abstract of DOI:10.1002/jhet.1665

Eighteen novel pyrazole-linked norcantharidin derivatives substituted by chromone ring were synthesized in a single step by the [3+2] 1,3-dipolar cycloaddition reaction of norcantharidin derivatives of substituted aromatic amines with hydrazone in the presence of chloramine-T as compared to the conventional method.

Full text of DOI:10.1002/jhet.1665

Month 2016
Synthesis of Pyrazole-linked Norcantharidin Analogues of Substituted
Chromones
1
a
a
a
Wei Wang,a,b Liping Deng, Shenlong Tang, and Qing Qian
*
aChemistry and Chemical Engineering Institute, Shaoxing University, Shaoxing, Zhejiang 312000, People’s Republic of China
bZhejiang Supor Pharmaceuticals, Shaoxing 312000, People’s Republic of China
*
E-mail: wwdlp@126.com
Received November 2, 2011
DOI 10.1002/jhet.1665
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Eighteen novel pyrazole-linked norcantharidin derivatives substituted by chromone ring were synthesized
in a single step by the [3+2] 1,3-dipolar cycloaddition reaction of norcantharidin derivatives of substituted
aromatic amines with hydrazone in the presence of chloramine-T as compared to the conventional method.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
(exo,exo-2,3-dimethyl-7-oxabicyclo[2.2.1]
japonicum Makino, Rhododendron ovatum, and Xantho-
ceras sorbifolia [14], and they have diverse activities. We
have synthesized series of norcantharidin analogues before
[15,16]. Pyrazoles possess extensive biological activities,
such as analgesic, anti-inflammatory, and leishmanicidal
[17–20]. Because of their unique structures and wide
biological activities [21,22], we combine chromones with pyr-
azoles as macromolecule substituted groups to explore the ac-
tivity. The main agent we used is chloramine-T (Fig. 1), which
has versatile properties and is easy to synthesize.
Cantharidin
heptane-2,3-dicarboxylic acid anhydride; Fig. 1) is isolated
from Chinese blister beetles Mylabris phalerata and Mylabris
cichorii [1,2]. As an antitumor agent, cantharidin is a strong
inhibitor of protein phosphatase types 1 (PP1), 2A (PP2A),
and PP5 [3–6]. It can act on a series of tumor cell types, such
as HeLa cells, murine ascites hepatoma, and reticulocell sar-
coma, the primary inhibition is to hepatoma. Despite so many
indications, its toxicity in the mucous membranes is unavoid-
able, mainly in the gastrointestinal tract, ureter, and kidney [1],
so naturally, the application is limited. Norcantharidin (Fig. 1),
the demethylated form of cantharidin, is also a strong inhibitor
of PP1 and PP2A. Likewise, it can inhibit tumor cell lines,
such as HeLa, glioblastoma, and HEP-2 [7–11]. What is more,
it comparatively has little cytotoxicity. McCluskey et al. and
Baba et al. [12,13] have carried out much work to explain
the structure–activity relationship. On the basis of the struc-
ture–activity relationship, structural modification is conducted
to explore the activity.
RESULTS AND DISCUSSION
The synthetic route is presented in Scheme 1, and the
physical data is listed in the Data section. Some features
can be found from the physical data. We used pyrazoles
to substitute at C5 and C6. Otherwise, chromones were
attached to them. Compound 1 was obtained by using the
[4 + 2] cycloaddition of furan with maleic anhydride. P-
substituted aniline and dehydronorcantharidin were used to
synthesize compounds 3a–3f. Lastly, chloramine-T was used
as a catalyst to catalyze the last equation to obtain 4a–4f,
5a–5f, and 6a–6f. The specific steps are listed in Scheme 1.
Chromone (Fig. 1) has a simple structure. It is a phenyl
that combines with g-pyrone. Chromone and its analogues
are widespread in various plants, such as Triadenum
© 2016 Wiley Periodicals, Inc.

2
W. Wang, L. Deng, S. Tang, and Q. Qian
Vol 000
1H NMR (DMSO) d: 9.030 (s, 1H, O–CH═), 8.130–6.968
(m 13H, Ar–H), 3.092 (s, 2H, 1-H, 4-H), 3.480 (s, 1H, 5-H),
2.336 (s, 1H, 6-H), 2.531,2 .514 (d, J = 6.8 Hz, 2H, 2-H, 3-H).
EXPERIMENTAL
Step A: Synthesis of compounds 3a–3f.
performed this work before [15].
We have
IR (KBr) n: 3095.26 (ArH), 1700.88 (C═O), 1652.91 (C═N),
1540.79 (C═C), 1458.02, 1387.12 (C–H in-plane), 1193.57
Step B: Synthesis of compounds 4a–4f, 5a–5f, and 6a–6f. To
a solution of 1 mmol compound 3a, which is obtained from step A,
and 1.1 mmol compound 10 in 20 mL alcohol, 1.2 mmol
chloramine-T is added, and the mixture is heated and refluxed
for 3–8 h which are monitored by thin-layer chromatography.
Then washed with 30 mL water and extracted with 30mL
dichloromethane. The extracts are dried over anhydrous sodium
sulfate, concentrated in vacuum and the residue is recrystallized
from methol to give the compound 4a. The compounds 4b–4f,
5a–5f, and 6a–6f can be obtained by using the same method.
(C–N), 911.13, 873.24, 657.91 (C–H out-plane) cmÀ1
.
Anal. Calcd for C30H20BrN3O5. C, 61.87; H, 3.46; N, 7.21.
Found: C, 61.86; H, 3.47; N, 7.21.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Hydroxyphenyl)-4,8-epoxy-
1-phenyl-3-(6-bromine-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,
8a-hexahydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (4b). This
compound was obtained as a yellow powder, mp 166.7–167.7ꢀC.
1H NMR (DMSO) d: 9.028 (s, 1H, O–CH═), 8.130–6.969 (m
12H, Ar–H), 3.096 (s, 2H, 1-H, 4-H), 3.498 (s, 1H, 5-H), 2.345
(s, 1H, 6-H), 2.532, 2.515 (d, J = 6.8 Hz, 2H, 2-H, 3-H), 7.177
(s, 1H, OH).
Data. rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(Phenyl)-4,8-epoxy1-
phenyl-3-(6-bromine-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,8a-
hexahydro- pyrrlol[3,4-f]indazole-5,7(1H,3aH)-dione (4a). This
compound was obtained as a yellow powder, mp 141.3–142.3ꢀC.
IR (KBr) n: 3415.60 (–OH), 3068.61 (ArH), 1716.53 (C═O),
1617.80 (C═N), 1541.36 (C═C), 1461.91, 1318.20 (C–H in-plane),
1218.39 (C–N), 953.73, 911.94, 815.98, 758.08 (C–H out-plane) cmÀ1
.
O
O
O
O
O
O2 Na
O
H3C
N
S
O
H
Cl
O
O
H
O
Cantharidin
Norcantharidin
Chloramine-T
Chromone
Figure 1. Chemical structures of cantharidin, norcantharidin, chloramine-T, and chromone.
Scheme 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis of Pyrazole-linked Norcantharidin Analogues of Substituted Chromones
3
Anal. Calcd for C30H20BrN3O6. C, 60.21; H, 3.37; N, 7.02.
Found: C, 60.20; H, 3.40; N, 7.04.
IR 3457 (N–C═O), 3088 (ArH), 1701 (C═O), 1565 (C═N),
1193 (C–O–C) cmÀ1
.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-p-Tolyl)-4,8-epoxy-1-phenyl-
3-(6-bromine-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,8a-hexahy-
dropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (4c). This compound
was obtained as a yellow powder, mp 129.8–130.8ꢀC.
1H NMR (DMSO) d: 9.028 (s, 1H, O–CH═), 8.130–6.970
(m, 12H, Ar–H), 3.088 (s, 2H, 1-H, 4-H), 3.497 (s, 1H, 5-H),
2.346 (s, 1H, 6-H), 2.523, 2.506 (d, J = 6.8 Hz, 2H, 2-H, 3-H),
5.239 (s, 3H, –CH3).
Anal. Calcd for C30H21N3O5. C, 71.56; H, 4.20; N, 8.35.
Found: C, 71.54; H, 4.20; N, 8.33.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Hydroxyphenyl)-4,8-epoxy-
1-phenyl-3-(4H-ch-romen-4-one-3-yl)-4,4a,6,7a,8,8a-hexahydro-
pyrrolo[3,4-f]indazole-5,7(1H,3aH)-d-ione (5b). This compound
was obtained as a red powder, mp 131.2–132.2ꢀC.
1H NMR (DMSO) d: 6.982–7.828 (m, 13H, Ar–H), 7.201
(s, 1H, C7–H), 3.117(s, 1H, C1–H), 2.519–2.524 (d, J = 2.0 Hz,
1H, C2–H), 2.529–2.526 (d, J = 1.2 Hz, 1H, C3–H), 3.517
(s, 1H, C4–H), 2.811 (s, 1H, C5–H), 2.704–2.715 (d, J = 4.4 Hz,
1H, C6–H), 5.141 (s, 1H, C8–H).
IR (KBr) n: 3091.38 (ArH), 1715.66 (C═O), 1617.53 (C═N),
1514.52 (C═C), 1458.73 (C–H in-plane), 1387.33 (–CH3),
1189.98 (C–N), 911.68, 832.76, 709.15 (C–H out-plane) cmÀ1
.
Anal. Calcd. for C31H22BrN3O5. C, 62.43; H, 3.72; N, 7.05.
Found: C, 62.43; H, 3.70; N, 7.02.
IR 3358 (N–C═O), 3047 (ArH), 1705 (C═O), 1537 (C═N),
1160 (C–O–C) cmÀ1
.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Nitrophenyl)-4,8-epoxy-1-
phenyl-3-(6-bromine-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,
8a-hexahydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (4d). This
compound was obtained as a yellow powder, mp 185.4–186.4ꢀC.
Anal. Calcd for C30H21N3O6. C, 69.36; H, 4.07; N, 8.09.
Found: C, 69.39; H, 4.05; N, 8.10.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-p-Tolyl)-4,8-epoxy-1-phenyl-
3-(4H-chromen-4-one-3-yl)-4,4a,6,7a,8,8a-hexahydropyrrolo[3,
4-f]indazole-5,7(1H,3aH)-dione (5c). This compound was
obtained as a red powder, mp 218.6–219.6ꢀC.
1H NMR (DMSO) d: 6.608–7.301 (m, 13H, Ar–H), 7.208
(s, 1H, C7–H), 3.149(s, 1H, C1–H), 2.514 (s, 1H, C2–H), 2.527
(s, 1H, C3–H), 3.487 (s, 1H, C4–H), 2.845 (s, 1H, C5–H),
2.743–2.769 (d, J = 1.6Hz, 1H, C6–H), 2.342 (s, 3H, C8–H)
1H NMR (DMSO) d: 9.027 (s, 1H, O–CH═), 8.358–6.983
(m, 12H, Ar–H), 3.156 (s, 2H, 1-H, 4-H), 3.487 (s, 1H, 5-H),
2.343 (s, 1H, 6-H), 2.534, 2.516 (d, J = 7.2 Hz, 2H, 2-H, 3-H).
IR (KBr) n: 3099.51 (ArH), 1725.43 (C═O), 1615.27 (C═N),
1596.54 (C═C), 1522.06, 1347.11 (–NO2), 1405.80 (C–H in-plane),
1217.87 (C–N), 911.78, 826.70, 699.28 (C–H out-plane) cmÀ1
.
Anal. Calcd for C30H19BrN4O7. C, 57.43; H, 3.05; N, 8.93.
Found: C, 57.40; H, 3.07; N, 8.92.
IR 3453 (N–C═O), 3069 (ArH), 1706 (C═O), 1558 (C═N),
1202 (C–O–C) cmÀ1
.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Chlorophenyl)-4,8-epoxy-
1-phenyl-3-(6-bromine-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,
8a-hexahydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (4e). This
compound was obtained as a yellow powder, mp 137.3–138.3ꢀC.
1H NMR (DMSO) d: 9.029 (s, 1H, O–CH═), 8.130–6.967
(m, 12H, Ar–H), 3.096 (s, 2H, 1-H, 4-H), 3.477 (s, 1H, 5-H),
2.338 (s, 1H, 6-H), 2.518, 2.509 (d, J = 3.6 Hz, 2H, 2-H, 3-H).
Anal. Calcd for C31H23N3O5. C, 71.94; H, 4.48; N, 8.12.
Found: C, 71.95; H, 4.50; N, 8.10.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Nitrophenyl)-4,8-epoxy-1-
phenyl-3-(4H-chrom-en-4-one-3-yl)-4,4a,6,7a,8,8a-hexahydro-
pyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (5d). This compound
was obtained as a red powder, mp> 241ꢀC.
1H NMR (DMSO) d: 7.314–7.939 (m, 13H, Ar–H), 7.318 (s, 1H,
C7–H), 3.094(s, 1H, C1–H), 2.512–2.519 (d, J = 2.8Hz, 1H, C2–H),
2.527–2.522 (d, J = 2.0Hz, 1H, C3–H), 3.478 (s, 1H, C4–H), 2.861
(s, 1H, C5–H), 2.728–2.733 (d, J =2.0Hz, 1H, C6–H).
IR (KBr) n: 3124.17 (ArH), 1716.96 (C═O), 1653.08 (C═N),
1541.11 (C═C), 1462.84, 1386.21 (C–H in-plane), 1186.72
(C–N), 911.69, 875.32, 723.97 (C–H out-plane) cmÀ1
.
Anal. Calcd for C30H19BrClN3O5. C, 58.41; H, 3.10; N, 6.81.
Found: C, 58.40; H, 3.11; N, 6.80.
IR 3448 (N–C═O), 3059 (ArH), 1716 (C═O), 1559 (C═N),
1142 (C–O–C) cmÀ1
.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Bromophenyl)-4,8-epoxy-
1-phenyl-3-(6-bromine-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,
8a-hexahydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (4f). This
compound was obtained as a yellow powder, mp 174.6–175.6ꢀC.
1H NMR (DMSO) d: 9.029 (s, 1H, O–CH═), 8.201–6.967
(m, 12H, Ar–H), 3.095 (s, 2H, 1-H, 4-H), 3.478 (s, 1H, 5-H),
2.340 (s, 1H, 6-H), 2.518, 2.509 (d, J = 3.6 Hz, 2H, 2-H, 3-H).
Anal. Calcd for C30H20N4O7 . C, 65.69; H, 3.68; N, 10.21.
Found: C, 65.70; H, 3.70; N, 10.20.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Chlorophenyl)-4,8-epoxy-
1-phenyl-3-(4H-chr omen-4-one-3-yl)-4,4a,6,7a,8,8a-hexahy-
dropyrrolo[3,4-f]indazole-5,7(1H,3aH)-di-one (5e). This compound
was obtained as a red powder, mp 218.6–219.6ꢀC.
1H NMR (DMSO) d: 6.876–7.519 (m, 13H, Ar–H), 7.310
(s, 1H, C7–H), 3.122(s, 1H, C1–H), 2.521–2.515 (d, J = 2.4 Hz,
1H, C2–H), 2.529–2.524 (d, J = 2.0 Hz, 1H, C3–H), 3.541
(s, 1H, C4–H), 2.792 (s, 1H, C5–H), 2.734 (s, 1H, C6–H).
IR (KBr) n: 3123.08 (ArH), 1716.85 (C═O), 1618.87(C═N),
1541.26 (C═C), 1462.13, 1408.67 (C–H in-plane), 1218.14
(C–N), 911.95, 816.19, 755.93 (C–H out-plane) cmÀ1
.
Anal. Calcd for C30H19Br2N3O5. C, 54.49; H, 2.90; N, 6.35.
Found: C, 54.50; H, 2.90; N, 6.35.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Penyl)-4,8-epoxy-1-phenyl-
3-(4H-chromen-4-one-3-yl)-4,4a,6,7a,8,8a-hexahydropyrrolo[3,
4-f]indazole-5,7(1H,3aH)-dione (5a). This compound was
obtained as a pink powder, mp 180.7–181.7ꢀC.
1H NMR (DMSO) d: 7.288–7.492 (m, 14H, Ar–H), 7.386
(s, 1H, C7–H), 3.118(s, 1H, C1–H), 2.520–2.524 (d, J = 1.6 Hz,
1H, C2–H), 2.527–2.538 (d, J = 4.4 Hz, 1H, C3–H), 3.499
(s, 1H, C4–H), 2.841 (s, 1H, C5–H), 2.740–2.749 (d, J = 3.6 Hz,
1H, C6–H).
IR 3473 (N–C═O), 3051 (ArH), 1715 (C═O), 1558 (C═N),
1132 (C–O–C) cmÀ1
.
Anal. Calcd for C30H20ClN3O5. C, 66.98; H, 3.75; N, 7.81.
Found: C, 66.95; H, 3.75; N, 7.80.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Bromophenyl)-4,8-epoxy-
1-phenyl-3-(4H-chr omen-4-one-3-yl)-4,4a,6,7a,8,8a-hexahy-
dropyrrolo[3,4-f]indazole-5,7(1H,3aH)-di-one (5f). This compound
was obtained as a red powder, mp 207.9–208.9ꢀC.
1H NMR (DMSO) d: 6.608–7.301 (m, 13H, Ar–H), 7.119
(s, 1H, C7–H), 3.142(s, 1H, C1–H), 2.512–2.517 (d, J = 2.0 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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W. Wang, L. Deng, S. Tang, and Q. Qian
Vol 000
1H, C2–H), 2.529–2.521 (d, J= 3.6 Hz, 1H, C3–H), 3.474 (s, 1H,
C4–H), 2.861 (s, 1H, C5–H), 2.748–2.740 (d, J=3.6 Hz, 1H, C6–H).
4.84 (s, 1H, C4–H), 4.28 (s, 1H, C3–H), 4.30 (s, 1H, C2–H), 4.33
(s, 1H, C1–H).
IR 3471 (N–C═O), 3084 (ArH), 1716 (C═O), 1581 (C═N),
IR 3358 (N–C═O), 3078 (ArH), 1598 (C═N), 1707 (C═O),
1159 (C–O–C) cmÀ1
.
1261 (C–O–C) cmÀ1
.
Anal. Calcd for C31H22ClN3O5. C, 67.45; H, 4.02; N, 7.61.
Found: C, 67.45; H, 4.04; N, 7.62.
Anal. Calcd for C30H20BrN3O5. C, 61.87; H, 3.46; N, 7.21.
Found: C, 61.90; H, 3.45; N, 7.22.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Bromophenyl)-4,8-epoxy-
1-phenyl-3-(6-methyl-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,8a-hexa-
hydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (6f). This compound
was obtained as a brown powder, mp 86.3–87.2ꢀC.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(Phenyl)-4,8-epoxy-1-phenyl-
3-(quinoxalin-2-yl)-4,4a,6,7a,8,8a-hexahydropyrrlol[3,4-f]indazole-
5,7(1H,3aH)-dione (6a). This compound was obtained as a red
powder, mp 91.8–92.6ꢀC.
1H NHR (DMSO) d: 2.44 (s, 3H, CH3), 7.26 (s, 1H, O═C–H),
7.29–7.83 (m, 13H, Ar–H), 2.10 (s, 1H, C6–H), 2.71 (s, 1H, C5–H),
4.27 (s, 1H, C4–H), 3.85 (s, 1H, C3–H), 3.02 (s, 1H, C2–H), 3.58
(s, 1H, C1–H).
1H NHR (DMSO) d: 2.44 (s, 3H, CH3), 7.23 (s, 1H, O═C–H),
6.38–7.82 (m, 13H, Ar–H), 2.11 (s, 1H, C6–H), 3.01 (s, 1H, C5–H),
4.84 (s, 1H, C4–H), 4.28 (s, 1H, C3–H), 4.30 (s, 1H, C2–H), 4.33
(s, 1H, C1–H).
IR 3442 (N–C═O), 1560 (C═N), 1706 (C═O), 1238 (C–O–C) cmÀ1
.
IR 3445 (N–C═O), 1714 (C═O), 1416 (C═N), 1159
(C–O–C) cmÀ1
.
Anal. Calcd for C31H22BrN3O5. C, 62.43; H, 3.72; N, 7.05.
Found: C, 62.44; H, 3.71; N, 7.03.
Anal. Calcd for C31H23N3O5. C, 71.79; H, 4.48; N, 8.12.
Found: C, 71.80; H, 4.45; N, 8.12.
Acknowledgments. This study was financially supported by
Zhejiang Provincial Natural Science Foundation of China under
Grant (No. LQ13H300001 and No. Y2100872), and supported
by the National Science Foundation for Young Scholars of
China under Grant (No. 81202411 and No.81502926).
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Hydroxyphenyl)-4,8-epoxy-
1-phenyl-3-(6-Met- hyl-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,8a-
hexahydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (6b). This
compound was obtained as a yellow powder, mp 107.2–108.2ꢀC.
1H NHR (DMSO) d: 2.44 (s, 3H, CH3), 7.57(s, 1H, O═C–H),
7.17–7.83 (m, 12H, Ar–H), 2.11 (s, 1H, C6–H), 3.02(s, 1H, C5–H),
4.27 (s, 1H, C4–H), 3.85 (s, 1H, C3–H), 3.02 (s, 1H, C2–H), 3.58
(s, 1H, C1–H), 5.40 (s, 1H, OH).
REFERENCES AND NOTES
IR3417(N–C═O),1558(C═N),1716(C═O),1249(C–O–C)cmÀ1
.
[1] Oaks, W. W.; Ditunno, J. F.; Magnani, T.; Levy, H. A.; Millsl,
C. Arch Int Med 1960, 105, 574.
Anal. Calcd for C31H23N3O6. C, 69.79; H, 4.35; N, 7.88.
[2] Wang, G. S. J Ethnopharmacol 1989, 26, 147.
[3] McCluskey, A.; Ackland, S. P.; Gardiner, E.; Walkom, C. C.;
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1966, 47, 606.
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E. J Med Chem 2009, 52, 4838.
[7] Wang, K. R.; Wang, Y. C.; Sun, Z. Q.; Xu, S. H.; Lian,
M. L.; Zen, C. C. 4th Int Congr Cell Biol 1988, 48, 76.
[8] Peng, F.; Wei, Y. Q.; Tian, L.; Yang, L.; Zhao, X.; Lu, Y.; Mao,
Y. Q.; Kan, B.; Lei, S.; Wang, G. S. J Cancer Res Clin Oncol 2002, 128, 223.
[9] Chen, Y. N.; Chen, J. C.; Yin, S. C.; Wang, G. S.; Tsauer,
W.; Hsu, S. F.; Hsu, S. Int J Cancer 2002, 100, 158.
[10] Sun, Z. X.; Ma, Q. W.; Zhao, T. D.; Wei, W. L.; Wang,
G. S.; Li, J. S. World J Gastroenterol 2000, 6, 263.
[11] Hong, C. Y.; Huang, S. C.; Lin, S. K.; Lee, J. J.; Chueh,
L. L.; Lee, C. H.; Lin, J. H.; Hsiao, M. Biochem Biophys Res Commun
2000, 276, 278.
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2002, 45, 1151.
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[14] Wang, X. X.; Wang, Z. Y.; Wang, B. Chin Pharm 2010, 13, 1725.
[15] Deng, L. P.; Liu, F. M.; Wang, H. Y. J Heterocycl Chem 2005, 42, 13.
[16] Deng, L. P.; Zhang, Y.; Tao, W. F.; Shen, J. F.; Wang, W. J
Heterocycl Chem 2011, 48, 158.
[17] Waldrep, T. W.; Beck, J. R.; Lynch, M. P.; Wright, F. L. J
Agric Food Chem 1990, 38, 541.
Found: C, 69.78; H, 4.36; N, 7.90.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-p-Tolyl)-4,8-epoxy-1-phenyl-
3-(6-methyl-4H- chromen-4-one-3-yl)-4,4a,6,7a,8,8a-hexahy-
dropyrrolo[3,4-f]indazole-5,7(1H,3aH)- dione (6c). This compound
was obtained as a gamboge powder, mp > 220ꢀC.
1H NHR (DMSO) d: 2.20 (s, 6H, CH3), 7.26 (s, 1H, O═C–H),
6.85–7.62 (m, 13H, Ar–H), 1.61 (s, 1H, C6–H), 3.03 (s, 1H, C5–H),
4.84 (s, 1H, C4–H), 4.28 (s, 1H, C3–H), 4.30 (s, 1H, C2–H), 4.33
(s, 1H, C1–H).
IR 3452 (N–C═O), 1705 (C═N), 1557 (C═O), 1242
(C–O–C) cmÀ1
.
Anal. Calcd for C32H25N3O5. C, 72.30; H, 4.74; N, 7.91.
Found: C, 72.30; H, 4.72; N, 7.92.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Nitrophenyl)-4,8-epoxy-1-
phenyl-3-(6-methyl-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,8a-hexahy-
dropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (6d). This compound
was obtained as a brown powder, mp 107.8–108.8ꢀC.
1H NHR (DMSO) d: 2.44 (s, 3H, CH3), 7.26(s, 1H, O═C–H),
6.62–8.09 (m, 7H, Ar–H), 2.10 (s, 1H, C6–H), 2.71 (s, 1H, C5–H),
4.27 (s, 1H, C4–H), 3.85 (s, 1H, C3–H), 3.02 (s, 1H, C2–H), 3.58
(s, 1H, C1–H).
IR 3260 (N–C═O), 3048 (ArH), 1597 (C═N), 1717 (C═O),
1270 (C–O–C) cmÀ1
.
Anal. Calcd for C31H22N4O7. C, 66.19; H, 3.94; N, 8.62.
Found: C, 66.20; H, 3.93; N, 8.60.
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25, 533.
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H. J Nat Prod 1988, 51, 1266.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(4-Chlorophenyl)-4,8-epoxy-
1-phenyl-3-(6-Meth-yl-4H-chromen-4-one-3-yl)-4,4a,6,7a,8,
8a-hexahydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (6e). This
compound was obtained as a brown powder, mp 105.7–106.7ꢀC.
1H NHR (DMSO) d: 2.44 (s, 3H, CH3), 7.26 (s, 1H, O═C–H),
6.41–7.82 (m, 13H,Ar–H), 2.10 (s, 1H, C6–H), 3.03 (s, 1H, C5–H),
[22] Vasilyev, S. A.; Boyarchuk, V. L.; Luykanchikov, M. S.;
Khilya, V. P. Khim Farm Zh 1991, 25, 34.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet