Synthesis of heterocyclic substituted norcantharidin derivatives

Article abstract of DOI:10.1002/jhet.596

Figure represented. Twenty novel norcantharidin derivatives, which were substituted by thiazole ring, were synthesized in a single step by the [3+2] 1,3-dipolar cycloaddition reaction with oxime or hydrazone in the presence of chloramine-T when compared with the conventional method.

Full text of DOI:10.1002/jhet.596

808
Synthesis of Heterocyclic Substituted Norcantharidin Derivatives
Liping Deng,a,b* Zhang Yong,a Weifeng Tao,b Jianfeng Shen,c
Vol 48
and Wei Wangb
aDepartment of Pharmacology, Chemistry and Chemical Engineering Institute, Shaoxing
University, Shaoxing 312000, Zhejiang, People’s Republic of China
bZhejiang Supor Pharmaceuticals, Shaoxing 312000, Zhejiang, People’s Republic of China
cZhejiang Zhenyuan Pharmaceuticals, Shaoxing 312000, Zhejiang, People’s Republic of China
*E-mail: wwdlp@126.com
Received February 2, 2010
DOI 10.1002/jhet.596
Published online 11 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
Twenty novel norcantharidin derivatives, which were substituted by thiazole ring, were synthesized in
a single step by the [3þ2] 1,3-dipolar cycloaddition reaction with oxime or hydrazone in the presence
of chloramine-T when compared with the conventional method.
J. Heterocyclic Chem., 48, 808 (2011).
INTRODUCTION
mucoepidermoid carcinoma, adenocystic carcinoma,
neuroblastoma, bone, leukaemia, ovarian, and colon
cancer cell lines [5].We have referred to all the known
cantharidin SAR data, briefly: no modification of the
bicycle [2.2.1] skeleton is permissible, the 7-oxa
bridge is required to maintain the activity, the pres-
ence of a double bond (5,6-ene) has little effect on the
activity. Replacement of the O-atom (anhydride) with
N (as N-H and N-R, where R¼ thiazolyl or aryl)
allows the development of a new series of anhydride
modified cantharidin analogues; some are more potent
than CAN or display potency similar to NCTD [6–10].
Isoxazoline and pyrazoline derivatives possess a wide
range of pharmacological activities [11]. Thus, it seemed
of interest to combine isoxazoline or pyrazoline with
Cantharidin (CAN, exo, exo-2,3-dimethyl-7-oxabicy-
clo [2.2.1] heptane-2,3-dicarboxylic acid anhydride,
Fig. 1) is an active ingredient of Chinese blister bee-
tles Mylabris [1], which has been used in China as a
medicinal agent for the treatment of cancer, in particu-
lar to hepatoma [2]. Recently, cantharidin has been
found active in cervical, tongue, ginival, bone, leukae-
mia, ovarian, and colon cancer cells [3]. However, the
renal toxicity of this drug has limited its application
[4]. Norcantharidin (NCTD, the demethylated canthari-
din derivative, Fig. 1) appeared to improve the awk-
ward side of cantharidin making the drug safer in
application. It was recently found to be capable of
inducing apoptosis in human cervical, tongue, ginival,
C
V
2011 HeteroCorporation

July 2011
Synthesis of Heterocyclic Substituted Norcantharidin Derivatives
809
with amino-substituted thiazole ring 2–3 to give compounds
4–5. After that, we reacted compounds 4–5 with DCC to get
compounds 6–7.At last, we carried out the [3þ2] cycloaddition
of 6–7 with oxime or hydrazone in the presence of chloram-
ine-T. Thus, we get compounds 6a–6j and 7a–7j [12,16].
General Procedure for the Preparation of the compounds
4–5. Compound 2 (10 mmol) was dissolved in acetone (10
mL). Then, this solution was added slowly to a solution of 1
(10 mmol) in acetone (20 mL). The reaction mixture reacted
in acetone for 8 h, then leached. The residue was dried, giving
the compound 4. The synthesis of compound 5 was performed
using the same method.
General Procedure for the Preparation of the compounds
6–7. Compound 4 (5 mmol) dissolved in DMF (10 mL), being
ice-bath. When the solution was down to 0ꢀC, DCC (5 mmol)
was added. The reaction mixture was refluxed in DMF for 10 h,
then leached. The extracts were poured into ice water (50 mL),
separating out crystal, then leached. The residue was dried, then
recrystallized from methanol to give the compound 6. The syn-
thesis of compound 7 was performed using the same method.
General Procedure for the Preparation of the 5,6-Dehy-
dronorcantharidin-isoxazoline and 5,6-Dehydronorcanthari-
din-pyrazoline Adducts (6a–6j and 7a–7j)data. Chloramine-
T (1.2 mmol) was added to a solution of 2 (1 mmol) and
4-fluorobenzaldehyde oxime (1 mmol) in ethanol (20 mL). The
reaction mixture was refluxed in ethanol for 12 h, then
leached. The residue was dried, then recrystallized from
Figure 1. Chemical structures of CAN, NCTD, and chloramine-T.
norcantharidin derivatives in a single molecule. We
have successfully synthesized some compounds before
[12], but the method is somewhat complex because we
have to synthesize nitrile oxide by the reaction of nitrile
oximes with tert-butyl hypochloride. With our sustained
interest in the synthesis of norcantharidin derivatives,
we have achieved a facile 1,3-dipolar cycloaddition
method by using chloramine-T (Fig. 1). Chloramine-T,
which is a versatile reagent in organic synthesis [13],
was used in this article for the in situ oxidation of
oximes and hydrazones of aldehydes to generate the
nitrile oxides; compared with the conventional method,
the synthetic route is more facile and the reaction rate is
enhanced tremendously.
In addition, thiazole derivatives are an important class
of heterocyclic derivatives containing N and S elements;
these compounds have a broad spectrum of biological
activity, showing a good anti-bacterial, anti-virus, anti-
tumor, weeding and regulation of plant growth, and
other bioactivity. They play an important regulatory role
in humans and other organisms’ metabolic process.
Therefore, the functional design of thiazole compounds
takes people’s attention [14]. So, we combine thiazole
with norcantharidin derivatives. Cooperating with isoxa-
zole or pyrazole, we look forward to the compounds
obtained having a good biological activity.
Scheme 1
RESULTS AND DISCUSSION
The synthetic route of the compounds mentioned is
outlined in Scheme 1. Such type of compounds (Table
1) with versatile activities may be of interest in chemis-
try, biochemistry, and pharmacology [15].
EXPERIMENTAL
Melting points were obtained on a B-540 Buchi melting
point apparatus and were uncorrected. 1H NMR spectra were
recorded on a Brucker AM-400 M Hz spectrometer with
SiMe4 as the internal standard in CDCl3. Element analyses
were performed on an EA-1110 instrument.
Nitrile oxides are of great synthetic interest because the
product, isoxazolines and pyrazolines, are versatile intermedi-
ates for the synthesis of bifunctional compounds. We have car-
ried out the [4þ2] cycloaddition of furan with maleic anhy-
dride to obtain 5,6-dehydronorcantharin 1, and then, reacted 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

810
L. Deng, Z. Yong, W. Tao, J. Shen, and W. Wang
Vol 48
Table 1
Physical data of compounds.
Analysis % calcd./found
Compound
R1
H
R2/R3
/
Time (h)
8
Mp (ꢀC)
Yield (%)
75.1
Molecular formula
C11H10N2O4S
C
H
N
4
163
49.62
49.65
51.42
51.40
53.22
53.23
54.95
54.97
56.10
56.08
53.80
53.81
53.14
53.11
55.20
55.18
55.47
55.44
57.14
57.15
54.88
54.86
54.12
54.09
56.20
56.17
56.47
56.50
65.14
65.12
60.44
60.43
56.37
56.35
63.15
63.17
61.27
61.26
65.77
65.79
61.16
61.14
57.15
57.17
63.77
63.78
61.94
61.92
3.79
3.76
4.32
4.33
3.25
3.24
3.84
3.85
3.14
3.15
3.01
3.04
3.52
3.55
3.66
3.64
3.19
3.17
3.53
3.51
3.39
3.41
3.86
3.88
4.01
3.98
3.55
3.53
4.10
4.11
3.59
3.61
3.15
3.14
3.67
3.66
3.76
3.74
4.42
4.44
3.90
3.93
3.45
3.43
3.96
3.99
4.04
4.01
10.52
10.51
9.99
5
CH3
H
/
/
8.5
10
11
12
11
11.5
12
6
158
145
59.7
15.8
76.8
27.8
22.5
24.3
31.2
40.6
54.7
35.4
27.4
33.4
53.7
26.3
22.9
20.4
43.0
35.7
32.8
41.1
29.7
48.8
38.6
C12H12N2O4S
C11H8N2O3S
10.02
11.28
11.30
10.68
10.65
10.90
10.87
10.46
10.42
9.78
6
7
CH3
H
/
136
C12H10N2O3S
C18H12N3O4FS
C18H12N3O4ClS
C19H15N3O5S2
C19H15N3O6S
C19H13N3O6S
C19H14N3O4FS
C19H14N3O4ClS
C20H17N3O5S2
C20H17N3O6S
C20H15N3O6S
C24H18N4O3S
C24H17N4O3SCl
C24H16N4O3Cl2S
C26H18N6O3S
C26H19N7O3S
C25H20N4O3S
C25H19N4O3SCl
C25H18N4O3Cl2S
C27H20N6O3S
C27H21N7O3S
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
6f
6g
6h
6i
C6H4F
>300
>300
>300
>300
>300
287
H
C6H4Cl
C6H4SOCH3
C6H3OCH3OH
C7H5O2
C6H4F
H
9.79
H
10.16
10.15
10.21
10.22
10.52
10.54
10.10
10.13
9.47
H
CH3
CH3
CH3
CH3
CH3
H
11.3
11
10.5
12
5
C6H4Cl
C6H4SOCH3
C6H3OCH3OH
C7H5O2
C6H5
268
>300
>300
282
9.50
9.83
9.85
9.88
10.01
12.66
12.64
11.75
11.72
10.96
10.97
16.99
16.96
19.24
19.22
12.27
12.25
11.41
11.39
10.66
10.63
16.53
16.50
18.73
18.75
10
11
10
7
>300
>300
>300
>300
218
H
C6H4Cl
C6H3Cl2
C8H5N2
C8H6N3
C6H5
H
H
6j
7f
7g
7h
7i
H
7
CH3
CH3
CH3
CH3
CH3
10.5
10
11
7
>300
>300
>300
>300
>300
C6H4Cl
C6H3Cl2
C8H5N2
C8H6N3
7j
6.5
methanol to give the compound 6a. The synthesis of com-
pounds 6b–6j and 7a–7j was performed using the same
method.
C4AH), 3.51 (s, 1H, C3-H), 3.11 (s, 1H, C2AH). Anal. Calcd.
for C11H10N2O4S: C, 49.62; H, 3.79; N, 10.52. Found: C,
49.65; H, 3.76; N, 10.51.
Data. (1S,2R,4R)-3-(Thiazol-2-ylcarbamoyl)-7-oxabicyclo
[2.2.1]hept-5-ene-2-carboxylic acid (4). This compound was
obtained as beige crystals, yield 75.1%, m.p.163ꢀC; 1H
NMR(DMSO-d6) d: 9.10 (s, 1H, ANH), 7.05–7.04 (d, J ¼ 3.6
Hz, 1H, NACH), 6.68–6.67 (d, J ¼ 4.0 Hz, 1H, S-CH), 6.20
(s, 2H, C5AH, C6AH), 4.87 (s, 1H, C1AH), 4.76 (s, 1H,
(1S,2R,4R)-3-(5-Methylthiazol-2-ylcarbamoyl)-7-oxabicyclo
[2.2.1]hept-5-ene-2-carboxylic acid (5). This compound was
obtained as brown crystals, yield 59.7%, m.p.158ꢀC; 1H
NMR(DMSO-d6) d: 9.15 (s, 1H, ANH), 7.25 (s, 1H, NACH),
5.91 (s, 2H, C5AH, C6AH), 4.91 (s, 1H, C1AH), 4.83 (s, 1H,
C4AH), 3.63 (s, 1H, C3AH), 3.14 (s, 1H, C2AH). 2.25 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Synthesis of Heterocyclic Substituted Norcantharidin Derivatives
811
CH3). Anal. Calcd. for C12H12N2O4S: C, 51.42; H, 4.32; N,
9.99. Found: C, 51.40; H, 4.33; N, 10.02.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(benzo[d][1,3]dioxol-5-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole-5,7
(1H,3aH)-dione (6e). This compound was obtained as beige
2-(Thiazol-2-yl)-4,7-epoxy-3a,4,7,7a-tetrahydro-1H-isoindole-
1,3(2H)-dione (6). This compound was obtained as beige crys-
tals, yield 15.8%, m.p.145ꢀC; 1H NMR(CDCl3) d: 7.80–7.79
(d, J ¼ 3.6 Hz, 1H, NACH), 7.34–7.33 (d, J ¼ 3.6, 1H, S-
CH), 6.59–6.57 (d, J ¼ 4.8, 2H, C5AH, C6AH), 5.44 (s, 2H,
C1AH, C4AH), 3.09 (s, 2H, C2AH, C3AH). Anal. Calcd. for
C11H8N2O3S: C, 53.22; H, 3.25; N, 11.28. Found: C, 53.23; H,
3.24; N, 11.30.
1
crystals, yield 40.6%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.47–
6.95 (m, 3H, Ar-H), 6.56–6.54 (d, J ¼ 12.38 Hz, 1H, NACH),
6.37–6.34 (d, J ¼ 12.77 Hz, 1H, S-CH), 6.07 (s, 2H, OCH2O),
5.27 (d, J ¼ 7.93 Hz, 1H, C5AH), 5.12 (s, 1H, C4AH), 4.81
(s, 1H, C1AH), 4.50 (d, J ¼ 7.92 Hz, 1H, C6AH), 3.56 (d, J
¼ 7.92 Hz, 1H, C3-H), 3.41 (d, J ¼ 7.91 Hz, 1H, C2-H). Anal.
Calcd. for C19H13N3O6S: C, 55.47; H, 3.19; N, 10.21. Found:
C, 55.44; H, 3.17; N, 10.22.
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(4-fluorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-
5,7(1H,3aH)-dione (7a). This compound was obtained as
beige crystals, yield 54.7%, m.p. 287ꢀC; 1H NMR(CDCl3) d:
7.70–7.22(m, 4H, Ar-H), 6.75 (s, 1H, NACH), 5.18 (d, J ¼
7.91 Hz, 1H, C5AH), 4.95(s, 1H, C4AH), 4.74(s, 1H, C1AH),
4.47(d, J ¼ 7.92 Hz, 1H, C6AH), 3.59(d, J ¼ 7.94 Hz, 1H,
C3AH), 3.37(d, J ¼ 7.93 Hz, 1H, C2AH), 2.50 (s, 3H, CH3).
Anal. Calcd. for C19H14N3O4FS: C, 57.14; H, 3.53; N, 10.52.
Found: C, 57.15; H, 3.51; N, 10.54.
2-(5-Methylthiazol-2-yl)-4,7-epoxy-3a,4,7,7a-tetrahydro-1H-
isoindole-1,3(2H)-dione (7). This compound was obtained as
beige crystals, yield 76.8%, m.p.136ꢀC; 1H NMR (CDCl3) d:
7.43–7.42 (d, J ¼ 1.2, 1H, NACH), 6.57 (s, 2H, C5AH,
C6AH), 5.42 (s, 2H, C1AH, C4AH), 3.05 (s, 2H, C2AH,
C3AH), 2.48 (s, 3H, CH3). Anal. Calcd. for C12H10N2O3S: C,
54.95; H, 3.84; N, 10.68. Found: C, 54.97; H, 3.85; N, 10.65.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(4-fluorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-5,7(1H,3aH)-
dione (6a). This compound was obtained as beige crystals,
1
yield 27.8%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.70–7.09 (m,
4H, Ar-H), 6.55–6.52 (d, J ¼ 12.41 Hz, 1H, NACH), 6.39–
6.36 (d, J ¼ 12.82 Hz, 1H, S-CH), 5.18 (d, J ¼ 7.92 Hz, 1H,
C5AH), 4.95(s, 1H, C4AH), 4.74(s, 1H, C1AH), 4.47(d, J ¼
7.92 Hz, 1H, C6AH), 3.59(d, J ¼ 7.94 Hz, 1H, C3AH),
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(4-chlorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-
5,7(1H,3aH)-dione (7b). This compound was obtained as beige
crystals, yield 35.4%, m.p. 268ꢀC; 1H NMR(CDCl3) d: 7.84–
7.46 (m, 4H, Ar-H), 6.74 (s, 1H, NACH), 5.18 (d, J ¼ 7.93
Hz, 1H, C5AH), 4.95 (s, 1H, C4AH), 4.73 (s, 1H, C1AH),
4.51 (d, J ¼ 7.92 Hz, 1H, C6AH), 3.60 (d, J ¼ 7.91 Hz, 1H,
C3AH), 3.36 (d, J ¼ 7.93 Hz, 1H, C2AH), 2.35 (s, 3H, CH3).
Anal. Calcd. for C19H14N3O4ClS: C, 54.88; H, 3.39; N, 10.10.
Found: C, 54.86; H, 3.41; N, 10.13.
3.37(d,
J
¼
7.93 Hz, 1H, C2AH). Anal. Calcd. for
C18H12N3O4FS: C, 56.10; H, 3.14; N, 10.90. Found: C, 56.08;
H, 3.15; N, 10.87.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(4-chlorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-5,7(1H,3aH)-
dione (6b). This compound was obtained as beige crystals,
1
yield 22.5%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.74–7.06 (m,
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(4-(methylsulfinyl)phenyl)-pyrrolo[3,4-f]-1,2-benzi-
soxazole-5,7(1H,3aH)-dione (7c). This compound was obtained
4H, Ar-H), 6.55–6.52 (d, J ¼ 12.42 Hz, 1H, NACH), 6.38–
6.36 (d, J ¼ 12.78 Hz, 1H, S-CH), 5.18 (d, J ¼ 7.93 Hz, 1H,
C5AH), 4.95 (s, 1H, C4AH), 4.73 (s, 1H, C1AH), 4.48 (d, J ¼
7.92 Hz, 1H, C6AH), 3.59 (d, J ¼ 7.92 Hz, 1H, C3AH), 3.36
1
as beige crystals, yield 27.4%, m.p. >300ꢀC; H NMR(CDCl3)
d: 8.05–7.74 (m, 4H, Ar-H), 6.74 (s, 1H, NACH), 5.24–5.22
(d, J ¼ 7.91 Hz, 1H, C5AH), 4.99 (s, 1H, C4AH), 4.76 (s, 1H,
C1AH), 4.51–4.49 (d, J ¼ 7.92 Hz, 1H, C6AH), 3.60–3.58 (d,
J ¼ 7.92 Hz, 1H, C3AH), 3.38–3.36 (d, J ¼ 7.90 Hz, 1H,
C2AH), 2.64 (s, 3H, CH3), 2.40 (s, 3H, CH3). Anal. Calcd. for
C20H17N3O5S2: C, 54.12; H, 3.86; N, 9.47. Found: C, 54.09;
H, 3.88; N, 9.50.
(d,
J
¼
7.93 Hz, 1H, C2AH). Anal. Calcd. for
C18H12N3O4ClS: C, 53.80; H, 3.01; N, 10.46. Found: C,
53.81; H, 3.04; N, 10.42.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(4-(methylsulfinyl)phenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-5,7
(1H,3aH)-dione (6c). This compound was obtained as beige
1
crystals, yield 24.3%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.81–
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(3-hydroxy-4-methoxyphenyl)-pyrrolo[3,4-f]-1,2-
benzisoxazole-5,7(1H,3aH)-dione (7d). This compound was
obtained as beige crystals, yield 33.4%, m.p. >300ꢀC; 1H
NMR(CDCl3) d: 7.47–6.89 (m, 3H, Ar-H), 6.47 (s, 1H, NACH),
5.24 (d, J ¼ 7.90 Hz, 1H, C5AH), 4.98 (s, 1H, C4AH), 4.75 (s,
1H, C1AH), 4.52 (d, J ¼ 7.93 Hz, 1H, C6AH), 3.83 (s, 3H,
OCH3), 3.59 (d, J ¼ 7.92 Hz, 1H, C3AH), 3.38 (d, J ¼ 7.92 Hz,
1H, C2AH), 2.30 (s, 3H, CH3). Anal. Calcd. for C20H17N3O6S:
C, 56.20; H, 4.01; N, 9.83. Found: C, 56.17; H, 3.98; N, 9.85.
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(benzo[d][1,3]dioxol-5-yl)-pyrrolo[3,4-f]-1,2-ben-
zisoxazole-5,7(1H,3aH)-dione (7e). This compound was
obtained as beige crystals, yield 53.7%, m.p. 282ꢀC; 1H
NMR(CDCl3) d: 7.47–6.95 (m, 3H, Ar-H), 6.70 (d, 1H,
NACH), 6.12 (s, 2H, OCH2O), 5.27 (d, J ¼ 7.93 Hz, 1H,
C5AH), 5.12 (s, 1H, C4AH), 4.81 (s, 1H, C1AH), 4.50 (d, J ¼
7.90 Hz, 1H, C6AH), 3.58 (d, J ¼ 7.92 Hz, 1H, C3AH), 3.41
(d, J ¼ 7.92 Hz, 1H, C2AH), 2.30 (s, 3H, CH3). Anal. Calcd.
6.96 (m, 4H, Ar-H), 6.55–6.52 (d, J ¼ 12.40 Hz, 1H, NACH),
6.38–6.35 (d, J ¼ 12.80 Hz, 1H, S-CH), 5.24–5.22 (d, J ¼
7.92 Hz, 1H, C5AH), 4.99 (s, 1H, C4AH), 4.76 (s, 1H,
C1AH), 4.51–4.49 (d, J ¼ 7.92 Hz, 1H, C6AH), 3.60–3.58 (d,
J ¼ 7.92 Hz, 1H, C3AH), 3.38–3.36 (d, J ¼ 7.92 Hz, 1H,
C2AH), 2.64 (s, 3H, CH3). Anal. Calcd. for C18H12N3O5S2: C,
53.14; H, 3.52; N, 9.78. Found: C, 53.11; H, 3.55; N, 9.79.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(3-hydroxy-4-methoxyphenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-
5,7(1H,3aH)-dione (6d). This compound was obtained as beige
1
crystals, yield 31.2%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.83–
7.19 (m, 3H, Ar-H), 6.55–6.52 (d, J ¼ 12.44 Hz, 1H, NACH),
6.38–6.36 (d, J ¼ 12.75 Hz, 1H, S-CH), 5.24 (d, J ¼ 7.90 Hz,
1H, C5AH), 4.98 (s, 1H, C4AH), 4.75 (s, 1H, C1AH), 4.52 (d,
J ¼ 7.93 Hz, 1H, C6AH), 3.77 (s, 3H, OCH3), 3.59 (d, J ¼
7.92 Hz, 1H, C3AH), 3.38 (d, J ¼ 7.92 Hz, 1H, C2AH). Anal.
Calcd. for C19H15N3O6S: C, 55.20; H, 3.66; N, 10.16. Found:
C, 55.18; H, 3.64; N, 10.15.
Journal of Heterocyclic Chemistry
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for C20H15N3O6S: C, 56.47; H, 3.55; N, 9.88. Found: C,
56.50; H, 3.53; N, 10.01.
C4AH), 5.26 (s, 1H, C1AH), 4.65–4.63 (d, J ¼ 9.20 Hz, 1H,
C5AH), 4.15–4.13 (d, J ¼ 9.20 Hz, 1H, C6AH), 3.38–3.36 (d,
J ¼ 7.20 Hz, 1H, C3AH), 3.33–3.31 (d, J ¼ 7.20 Hz, 1H,
C2AH), 2.37 (s, 3H, CH3). Anal. Calcd. for C25H20N4O3S: C,
65.77; H, 4.42; N, 12.27. Found: C, 65.79; H, 4.44; N, 12.25.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(5-Methylthiazol-2-yl)-4,8-
epoxy-1-phenyl-3-(2-chlorophenyl)-4,4a,6,7a,8,8a-hexahydropyr-
rolo[3,4-f]indazole-5,7(1H,3aH)-dione (7g). This compound
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(Thiazol-2-yl)-4,8-epoxy-1,3-
diphenyl-4,4a,6,7a,8,8a-hexahydropyrrolo[3,4-f]indazole-5,7
(1H,3aH)-dione (6f). This compound was obtained as beige
1
crystals, yield 26.3%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.76–
6.97 (m, 10H, Ar-H), 6.55–6.52 (d, J ¼ 12.41 Hz, 1H,
NACH), 6.39–6.36 (d, J ¼ 12.82 Hz, 1H, S-CH), 5.34 (s,
1H, C4AH), 5.27 (s, 1H, C1AH), 4.66–4.64 (d, J ¼ 9.60 Hz,
1H, C5AH), 4.16–4.14 (d, J ¼ 9.60 Hz, 1H, C6AH), 3.39–
3.37 (d, J ¼ 7.20 Hz, 1H, C3AH), 3.34–3.32 (d, J ¼ 7.20 Hz,
1H, C2AH). Anal. Calcd. for C24H18N4O3S: C, 65.14; H, 4.10;
N, 12.66. Found: C, 65.12; H, 4.11; N, 12.64.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(Thiazol-2-yl)-4,8-epoxy-1-
phenyl-3-(2-chlorophenyl)-4,4a,6,7a,8,8a-hexahydropyrrolo
[3,4-f]indazole-5,7(1H,3aH)-dione (6g). This compound was
obtained as beige crystals, yield 22.9%, m.p. >300ꢀC; 1H
NMR(CDCl3) d: 7.81–6.96 (m, 9H, Ar-H), 6.55–6.52 (d, J ¼ 12.43
Hz, 1H, NACH), 6.38–6.35 (d, J ¼ 12.79 Hz, 1H, S-CH), 5.31 (s,
1H, C4AH), 5.01 (s, 1H, C1AH), 4.65 (s, 2H, C5AH, C6AH), 3.30
(s, 2H, C3AH, C2AH). Anal. Calcd. for C24H17N4O3SCl: C, 60.44;
H, 3.59; N, 11.75. Found: C,60.43; H, 3.61; N, 11.72.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(Thiazol-2-yl)-4,8-epoxy-1-
phenyl-3-(2,3-dichlorophenyl)-4,4a,6,7a,8,8a-hexahydropyrrolo
[3,4-f]indazole-5,7(1H,3aH)-dione (6h). This compound was
obtained as beige crystals, yield 20.4%, m.p. >300ꢀC; 1H
NMR(CDCl3) d: 7.65–6.94 (m, 8H, Ar-H), 6.54–6.51 (d, J ¼
12.40 Hz, 1H, NACH), 6.38–6.35 (d, J ¼ 12.81 Hz, 1H, S-
CH), 5.31 (s, 1H, C4AH), 5.00 (s, 1H, C1AH), 4.67–4.65 (m,
2H, C5AH, C6AH), 3.31–3.29 (m, 2H, C3AH, C2AH). Anal.
Calcd. for C24H16N4O3Cl2S: C, 56.37; H, 3.15; N, 10.96.
Found: C, 56.35; H, 3.14; N, 10.97.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(Thiazol-2-yl)-4,8-epoxy-1-
phenyl-3-(quinoxalin-2-yl)-4,4a,6,7a,8,8a-hexahydropyrrolo
[3,4-f]indazole-5,7(1H,3aH)-dione (6i). This compound was
obtained as beige crystals, yield 43.0%, m.p. >300ꢀC; 1H
NMR(CDCl3) d: 9.54 (s, 1H, HC¼¼N), 8.14–7.00 (m, 9H, Ar-
H), 6.55–6.52 (d, J ¼ 12.40 Hz, 1H, NACH), 6.38–6.35 (d, J
¼ 12.80 Hz, 1H, S-CH), 5.58 (s, 1H, C4AH), 5.38 (s, 1H,
C1AH), 4.70–4.68 (d, J ¼ 9.20 Hz, 1H, C5AH), 4.26–4.24 (d,
J ¼ 9.20 Hz, 1H, C6AH), 3.49–3.47 (d, J ¼ 7.20 Hz, 1H,
C3AH), 3.38–3.36 (d, J ¼ 7.20 Hz, 1H, C2AH). Anal. Calcd.
for C26H18N6O3S: C, 63.15; H, 3.67; N, 16.99. Found: C,
63.17; H, 3.66; N, 16.96.
1
was obtained as beige crystals, yield 41.1%, m.p. >300ꢀC; H
NMR(CDCl3) d: 7.76–6.97 (m, 9H, Ar-H), 6.74 (s, 1H,
NACH), 5.29 (s, 1H, C4AH), 5.00 (s, 1H, C1AH), 4.64 (s, 2H,
C5AH, C6AH), 3.28 (s, 2H, C2AH, C3AH), 2.35 (s, 3H, CH3).
Anal. Calcd. for C25H19N4O3SCl: C, 61.16; H, 3.90; N, 11.41.
Found: C,61.14; H, 3.93; N, 11.39.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(5-Methylthiazol-2-yl)-4,8-
epoxy-1-phenyl-3-(2,3-dichlorophenyl)-4,4a,6,7a,8,8a-hexahy-
dropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (7h). This com-
pound was obtained as beige crystals, yield 29.7%, m.p.
1
>300ꢀC; H NMR(CDCl3) d: 7.65–6.92 (m, 8H, Ar-H), 6.75 (s,
1H, NACH), 5.30 (s, 1H, C4AH), 4.94 (s, 1H, C1AH), 4.68–
4.62 (m, 2H, C5AH, C6AH), 3.31–3.28 (m, 2H, C2AH, C3AH),
2.34 (s, 3H, CH3). Anal. Calcd. for C25H18N4O3Cl2S: C, 57.15;
H, 3.45; N, 10.66. Found: C, 57.17; H, 3.43; N, 10.63.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(5-Methylthiazol-2-yl)-4,8-
epoxy-1-phenyl-3-(quinoxalin-2-yl)-4,4a,6,7a,8,8a-hexahydropyr-
rolo[3,4-f]indazole-5,7(1H,3aH)-dione (7i). This compound was
obtained as beige crystals, yield 48.8%, m.p. >300ꢀC; 1H
NMR(CDCl3) d: 9.53 (s, 1H, HAC¼¼N), 8.12–6.99 (m, 9H,
Ar-H), 6.76 (s, 1H, NACH), 5.56 (s, 1H, C4AH), 5.37 (s, 1H,
C1AH), 4.74–4.72 (d, J ¼ 9.20 Hz, 1H, C5AH), 4.38–4.36 (d,
J ¼ 9.20 Hz, 1H, C6AH), 3.48–3.46 (d, J ¼ 7.20 Hz, 1H,
C3AH), 3.33–3.31 (d, J ¼ 7.20 Hz, 1H, C2AH), 2.37 (s, 3H,
CH3). Anal. Calcd. for C27H20N6O3S: C, 63.77; H, 3.96; N,
16.53. Found: C, 63.78; H, 3.99; N, 16.50.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(5-Methylthiazol-2-yl)-4,8-
epoxy-1-phenyl-3-(2-phenyl-2H-1,2,3-triazol-4-yl)-4,4a,6,7a,8,8a-
hexahydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (7j). This
compound was obtained as beige crystals, yield 38.6%, m.p.
>300ꢀC; 1H NMR(CDCl3) d: 8.51(s, 1H, HAC¼¼N), 8.20–
6.92 (M, 10H, Ar-H), 5.50 (s, 1H, C4AH), 5.33 (s, 1H,
C1AH), 4.65–4.63 (d, J ¼ 9.20 Hz, 1H, C5AH), 4.21–4.19 (d,
J ¼ 9.20 Hz, 1H, C6AH), 3.41–3.39 (d, J ¼ 7.20 Hz, 1H,
C3AH), 3.30–3.28 (d, J ¼ 7.20 Hz, 1H, C2AH), 2.35 (s, 3H,
CH3). Anal. Calcd. for C27H21N7O3S: C, 61.94; H, 4.04; N,
18.73. Found: C, 61.92; H, 4.01; N, 18.75.
rel-(3aR,4S,4aR,7aS,8S,8aR)-6-(Thiazol-2-yl)-4,8-epoxy-1-
phenyl-3-(2-phenyl-2H-1,2,3-triazol-4-yl)-4,4a,6,7a,8,8a-hex-
ahydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione (6j). This
compound was obtained as beige crystals, yield 35.7%, m.p.
218ꢀC; 1H NMR(CDCl3) d: 8.53(s, 1H, HAC¼¼N), 8.20–6.93
(m, 10H, Ar-H), 6.55–6.52 (d, J ¼ 12.40 Hz, 1H, NACH),
6.38–6.36 (d, J ¼ 12.76 Hz, 1H, S-CH), 5.51 (s, 1H, C4AH),
5.34 (s, 1H, C1AH), 4.65–4.62 (d, J ¼ 9.60 Hz, 1H, C5AH),
4.21–4.18 (d, J ¼ 9.60 Hz, 1H, C6AH), 3.41–3.39 (d, J ¼
7.20 Hz, 1H, C3AH), 3.30–3.28 (d, J ¼ 7.20 Hz, 1H, C2AH).
Anal. Calcd. for C26H19N7O3S: C, 61.27; H, 3.76; N, 19.24.
Found: C, 61.26; H, 3.74; N, 19.22.
Acknowledgment. The authors thank Zhejiang Provincial Natu-
ral Science Foundation, People’s Republic of China (Y2100872).
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Synthesis of Heterocyclic Substituted Norcantharidin Derivatives
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