Synthesis of Isoxazole-Linked Norcantharidin Analogues of Substituted Chromones

Article abstract of DOI:10.1002/jhet.2767

Eighteen novel norcantharidin derivatives, which were substituted by chromone ring, were synthesized in a single step by the [3 + 2] 1,3-dipolar cycloaddition reaction with three oximes in the presence of chloramine-T when compared with the conventional method.

Full text of DOI:10.1002/jhet.2767

Month 2016
Synthesis of Isoxazole-Linked Norcantharidin Analogues of
Substituted Chromones
a
a
a
a
Wei Wang,a,b Liping Deng,a,b Chunqi Hu, Yaohong Zhang, Yan Li, and Shufeng Zuo
*
aChemistry and Chemical Engineering Institute, Shaoxing University, Shaoxing 312000, People's Republic of China
bZhejiang Supor Pharmaceuticals, Shaoxing 312000, People's Republic of China
*E-mail: wwdlp@126.com
Received May 13, 2016
DOI 10.1002/jhet.2767
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Eighteen novel norcantharidin derivatives, which were substituted by chromone ring, were synthesized in
a single step by the [3 + 2] 1,3-dipolar cycloaddition reaction with three oximes in the presence of
chloramine-T when compared with the conventional method.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
McCluskey and Baba et al. [11,12] have done a variety of
researches to explain the relationship between structure and
activity. Bridging ether oxygen is crucial for activity. The
oxygen atom at five-membered ring can be replaced by
nitrogen atom. The C5/C6 positions can be replaced by many
substituent groups. Chromone and its analogues are
widespread in plants, such as Triadenum japonicum Makino,
Chuanminshen violaceum Sheh et Shan, Rhododendron
ovatum, Tuber Fleeceflower Root, peanut, and Xanthoceras
sorbifolia [13]. They possess simple structures and various
activities [14,15], as for isoxazoline analogues also own a
variety of pharmacological activities [16,17]; therefore, we
combine chromones with isoxazoles as a whole. We use
chloramine-T to synthesize the norcantharidin analogues
[18]. Chloramine-T (Fig. 1), which is a versatile reagent, is
widely used in chemical synthesis [19]. Chloramine-T was
used in this article to generate nitrile oxide in situ form
oximes. Such types of compounds 4a–4f, 5a–5f, and 6a–6f
with versatile activities may be of interest in chemistry,
biochemistry, and pharmacology.
Mylabris phalerata or Mylabris cichorii, the dried
bodies of blister beetles, as traditional Chinese medicine,
have been used to treat various cancers over 2000 years.
Cantharidin (exo, exo-2, 3-dimethyl-7-oxabicyclo [2.2.1]
heptane-2,3-dicarboxylic acid anhydride Fig. 1), which
can be isolated from the ancient medicines, is a natural
toxin to be applied to anticancer area for a long time [1].
It is a strong inhibitor to protein phosphatases type 1
(PP1), 2A (PP2A), and 5 (PP5) [2–4]. As the major
effective ingredient, cantharidin can act on various
tumors, such as HeLa cells, murine ascites hepatoma, or
reticulocell sarcoma, especially to hepatocarcinoma [1].
Nevertheless, because of its cytotoxicity to ureter and
kidney, the application to be chemotherapeutic agents
is limited [5]. For these reasons, exploring less
cytotoxicity analogues becomes desperate and necessary.
Norcantharidin (NCTD Fig. 1) is a better cantharidin
analogues. It is the demethylated form of cantharidin.
Similarly, NCTD is not only the PP1 and PP2A inhibitor,
but also PP2B inhibitor [6]. It can make some cancer lines
(human hepatoma, Hela cervical carcinoma, and some
leukemia cells) proliferate slowly [7,8]; furthermore,
RESULTS AND DISCUSSION
norcantharidin
hardly
causes
nephrotoxic
and
The synthetic route is presented in Scheme 1. The
physical data is presented in Table 1. [4 + 2] cycloaddition
of furan with maleic anhydride is the main method to
synthesize the analogues. Dehydronorcantharidin 1 is
inflammatory side effects [9,10]. Norcantharidin owns
excellent properties, so doing some modifications can
improve the activity and decrease cytotoxicity or ulteriorly.
© 2016 Wiley Periodicals, Inc.

W. Wang, L. Deng, C. Hu, Y. Zhang, Y. Li, and S. Zuo
Vol 000
Figure 1. Chemical structures of cantharidin, norcantharidin, chloramine-T, and chromone.
Scheme 1. Synthetic route of Isoxazole-linked Norcantharidin analogues.
obtained by this way. It is an intermediate. Then,
dehydronorcantharidin 1 reacted with p-substituted aniline
2a–2f to obtain compounds 3a–3f. In the last step,
compounds 3a–3f reacted, respectively, with three oximes
7–9 to get the product 4a–4f, 5a–5f, and 6a–6f. All
compounds were tested as racemic mixtures.
Synthesis of compound 4a–4f, 5a–5f, and 6a–6f. For the
conventional method (take 4a as an example) that we did
before, we carried out the [3+ 2] cycloaddition of 3a with
nitrile oxide, generated in situ in the presence of
triethylamine from α-chloro-6-bromo-4-oxo-4H-chromene-3-
carbaldehyde oxime to obtain the target compound 4a; the
reaction was monitored by thin-layer chromatography [18].
This conventional method requires the preparations of
tert-butyl hypochlorite first. Chloramine-T was used in this
article to generate nitrile oxide in situ form oximes.
To a solution of product 3a which is synthesized from
previous step (1mmol) and compound 7 (1.1mmol) in
ethanol (20mL), add chloramine-T (1.2mmol) and reflux for
3–8 h which are monitored by thin-layer chromatography.
Then, wash with 30 mL water and extract with 30 mL
dichloromethane. The extracts are dried over anhydrous
sodium sulfate and concentrated in vacuum, and the residue
is recrystallized from methol to give the compound 4a.The
same method to obtain compounds 4b–4f, 5a–5f, and 6a–6f.
Data
In order to identify the configuration of the norcantharidin
analogues (4a–4f, 5a–5f, 6a–6f), we have studied selective
1H–1HCOSY spectra and NOESY spectra of the
compounds. 1H–1HCOSY spectra showed cross peaks
between H-2 and H-3, H-5 and H-6. NOESY spectra
showed cross peaks between H-2 and H-6, H-3 and H-5.
The Diels–Alder adduct 5,6-dehydronorcantharidin of
furan with maleic anhydride has the exo configuration
exclusively; the endo isomer has never been reported
1
[20,21], which combined with H–1HCOSY and NOESY
spectra data, gives us
a
reasonable exo-adduct
configuration, as we have proved before similarly [18,22].
EXPERIMENTAL
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-phenyl)-3a,4,4a,7a,
8,8a-hexahydro-3-(6-bromine-4H-chromen-4-one-3-yl)-pyrrolo
Synthesis of compounds 3a–3f. We have synthesized
3a–3f before [18].
[3,4-f]-1,2-benzisoxazole (4a).
obtained as yellow powder, m.p. 182.4–183.3°C.
This compound was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Isoxazole-Linked Norcantharidin Analogues of
Substituted Chromones
Table 1
Physical data of compounds.
Analysis (%) calcd./found
H
Compound
R1/R3
m.p. (°C)
Molecular formula
C24H15BrN2O6
C24H15BrN2O7
C25H17BrN2O6
C24H14BrClN2O6
C24H14Br2N2O6
C24H16N2O6
C
N
4a
4b
4c
4e
4f
R2: Br, R1: H
182.4–183.3
210.8–211.8
167.9–170.0
173.4–174.4
202.7–203.7
98.7–100.5
131.8–133.2
104.2–106.1
114.7–115.6
143.7–145.0
140.2–141.7
104.8–105.3
110.4–111.5
108.9–110.0
98.5–99.5
56.82
56.80
55.09
55.07
57.60
57.60
53.21
53.22
49.17
49.16
67.29
67.30
64.87
64.90
67.87
67.88
60.89
60.88
62.28
62.27
56.82
56.81
67.87
67.86
65.50
65.50
68.42
68.40
61.60
61.60
62.97
62.95
57.60
57.60
2.98
2.95
2.89
2.90
3.29
3.27
2.60
2.58
2.41
2.43
3.76
3.74
3.63
3.60
4.10
4.12
3.19
3.18
3.27
3.28
2.98
2.99
4.10
4.12
3.96
3.94
4.42
4.43
3.52
3.54
3.59
3.60
3.29
3.27
5.52
5.51
5.35
5.35
5.37
5.35
5.17
5.16
4.78
4.79
6.54
6.55
6.30
6.30
6.33
6.32
8.88
8.87
6.05
6.02
5.52
5.54
6.33
6.33
6.11
6.12
6.14
6.14
8.62
8.61
5.87
5.90
5.37
5.36
R2: Br, R1: OH
R2: Br, R1: CH3
R2: Br, R1: Cl
R2: Br, R1: Br
R2: H, R1: H
5a
5b
5c
5d
5e
5f
R2: H, R1: OH
R2: H, R1: CH3
R2: H, R1: NO2
R2: H, R1: Cl
C24H16N2O7
C25H18N2O6
C24H15N3O8
C24H15ClN2O6
C24H15BrN2O6
C25H17N2O6
R2: H, R1: Br
6a
6b
6c
6d
6e
6f
R2: CH3, R1: H
R2: CH3, R1: OH
R2: CH3, R1: CH3
R2: CH3, R1: NO2
R2: CH3, R1: Cl
R2: CH3, R1: Br
C25H18N2O7
C26H20N2O6
C25H17N3O8
93.8–95.1
C25H17ClN2O6
C25H17BrN2O6
202.0–203.5
1HNMR (DMSO) δ: 5.255 (s, 1H, O—CH¼), 8.172–7.167
(m, 8H, Ar—H), 3.098 (s, 2H, 1-H, 4-H), 3.504 (s, 1H,
5-H), 2.377 (s, 1H, 6-H), 2.538, 2.516 (d, J=8.8Hz,
2H, 2-H, 3-H).
IR (KBr) ν: 3336.06 (—OH), 3094.92 (ArH), 1707.45
(C¼O), 1650.69 (C¼N), 1641.34 (C¼C), 1462.90, 1328.21
(C—H in-plane), 1153.59 (C—N), 809.29, 689.77, 665.86
(C—H out-plane) cmꢀ1
.
IR (KBr) ν: 3197.29 (ArH), 1701.27 (C¼O), 1653.28
(C¼N), 1558.35, 1507.01 (C¼C), 1457.90, 1387.13 (C—H
in-plane), 1193.78 (C—N), 873.32, 816.96, 711.20 (C—H
Anal. calcd. for C24H15BrN2O7. C, 55.09; H, 2.89; N,
5.35. Found: C, 55.07; H, 2.90; N, 5.35.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-p-tolyl)-3a,4,4a,7a,
8,8a-hexahydro-3-(6-bromine-4H-chromen-4-one-3-yl)-pyrrolo
[3,4-f]-1,2-benzisoxazole (4c). This compound was obtained
as yellow powder, m.p. 167.9–170.0°C.
out-plane) cmꢀ1
.
Anal. calcd. for C24H15BrN2O6. C, 56.82; H, 2.98; N,
5.52. Found: C, 56.80; H, 2.95; N, 5.51.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-hydroxyphenyl)-3a,
4,4a,7a,8,8a-hexahydro-3-(6-bromine-4H-chromen-4-one-3-yl)-
pyrrolo[3,4-f]-1,2-benzisoxazole (4b). This compound was
obtained as yellow powder, m.p. 210.8–211.8°C.
1H NMR (DMSO) δ: 5.243 (s, 1H, O—CH¼), 8.173–
7.066 (m, 7H, Ar—H), 3.073 (s, 2H, 1-H, 4-H), 3.528 (s,
1H, 5-H), 2.376 (s, 1H, 6-H), 2.534, 2.513 (d, J =8.4 Hz,
2H, 2-H, 3-H), 2.345 (s, 3H, —CH3).
1H NMR (DMSO) δ: 5.255 (s, 1H, O—CH¼),
8.178–7.184 (m, 7H, Ar—H), 3.098 (s, 2H, 1-H, 4-H),
3.504 (s, 1H, 5-H), 2.295 (s, 1H, 6-H), 2.519, 2.511(d,
J =3.2 Hz, 2H, 2-H, 3-H), 8.697 (s, 1H, OH).
IR (KBr) ν: 3093.03 (ArH), 1715.81 (C¼O), 1652.66
(C¼N), 1515.37 (C¼C), 1457.20 (C—H in-plane),
1387.62 (—CH3), 1189.90 (C—N), 876.10, 821.30,
709.01 (C—H out-plane) cmꢀ1
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W. Wang, L. Deng, C. Hu, Y. Zhang, Y. Li, and S. Zuo
Vol 000
Anal. calcd. for C25H17BrN2O6. C, 57.60; H, 3.29; N,
5.37. Found: C, 57.60; H, 3.27; N, 5.35.
Anal. calcd. for C24H16N2O7. C, 64.87; H, 3.63; N, 6.30.
Found: C, 64.90; H, 3.60; N, 6.30.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-chlorophenyl)-3a,4,
4a,7a,8,8a-hexahydro-3-(6-bromine-4H-chromen-4-one-3-yl)-py-
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-p-tolyl)-3a,4,4a,7a,
8,8a-hexahydro-3-(4H-chromen-4-one-3-yl)-pyrrolo[3,4-f]-1,2-
benzisoxazole (5c). This compound was obtained as red
powder, m.p. 104.2–106.1°C.
rrolo[3,4-f]-1,2-benzisoxazole (4e).
This compound was
obtained as yellow powder, m.p. 173.4–174.4°C.
1H NMR (DMSO) δ: 5.254 (s, 1H, O—CH¼), 8.080–
7.245 (m, 7H, Ar—H), 3.098 (s, 2H, 1-H, 4-H), 3.506 (s,
1H, 5-H), 2.380 (s, 1H, 6-H), 2.539, 2.517 (d, J= 8.8 Hz,
2H, 2-H, 3-H).
1H NMR (DMSO) δ: 6.608–7.301 (m, 8H, Ar—H),
7.144 (s, 1H, C7—H), 3.068 (s, 1H, C1—H), 2.509–2.512
(d, J= 1.2 Hz, 1H, C2—H), 2.527–2.518 (d, J =3.6Hz,
1H, C3—H), 3.492 (s, 1H, C4—H), 2.854 (s, 1H, C5—H),
2.743–2.749 (d, J = 2.4 Hz, 1H, C6—H), 2.343 (s, 3H,
C8—H).
IR (KBr) ν: 3092.71 (ArH), 1716.55 (C¼O), 1652.27
(C¼N), 1540.73 (C¼C), 1458.07, 1386.18 (C—H in-
plane), 1186.80 (C—N), 875.04, 807.80, 666.85 (C—H
IR 3091 (ArH), 1777 (C¼O), 1600 (C¼N), 1189
out-plane) cmꢀ1
.
(C—O) cmꢀ1
.
Anal. calcd. for C24H14BrClN2O6. C, 53.21; H, 2.60; N,
5.17. Found: C, 53.22; H, 2.58; N, 5.16.
Anal. calcd. for C25H18N2O6. C, 67.87; H, 4.10; N, 6.33.
Found: C, 67.88; H, 4.12; N, 6.32.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-bromophenyl)-3a,4,
4a,7a,8,8a-hexahydro-3-(6-bromine-4H-chromen-4-one-3-yl)-py
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-nitrophenyl)-3a,4,
4a,7a,8,8a-hexahydro-3-(4H-chromen-4-one-3-yl)-pyrrolo[3,4-
f]-1,2-benzisoxazole (5d). This compound was obtained as
yellow powder, m.p. 114.7–115.6°C.
-rrolo[3,4-f]-1,2-benzisoxazole (4f).
This compound was
obtained as yellow powder, m.p. 202.7–203.7°C.
1H NMR (DMSO) δ: 5.258 (s, 1H, O—CH¼), 8.079–
7.182 (m, 7H, Ar—H), 3.102 (s, 2H, 1-H, 4-H), 3.564 (s,
1H, 5-H), 2.378 (s, 1H, 6-H), 2.525, 2.517 (d, J= 3.2 Hz,
2H, 2-H, 3-H).
1H NMR (CDCl3) δ: 7.307–8.410 (m, 8H, Ar—H),
7.203 (s, 1H, C7—H), 3.418 (s, 1H, C1—H), 2.712–
2.719 (d, J= 2.8 Hz, 1H, C2—H), 2.651 (s, 1H, C3—H),
3.448 (s, 1H, C4—H), 2.720 (s, 1H, C5—H), 2.609 (s,
1H, C6—H).
IR (KBr) ν: 3093.74 (ArH), 1717.10 (C¼O), 1616.26
(C¼N), 1558.43 (C¼C), 1457.96, 1395.80, 1338.89
(C—H in-plane), 1161.97 (C—N), 815.54, 699.83,
IR 3083 (ArH), 1718 (C¼O), 1603 (C¼N), 1196
(C—O) cmꢀ1
.
603.14 (C—H out-plane) cmꢀ1
.
Anal. calcd. for C24H15N3O8. C, 60.89; H, 3.19; N, 8.88.
Found: C, 60.88; H, 3.18; N, 8.87.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-chlorophenyl)-3a,4,
4a,7a,8,8a-hexahyd-ro-3-(4H-chromen-4-one-3-yl)-pyrrolo[3,4-
f]-1,2-benzisoxazole (5e). This compound was obtained as
yellow powder, m.p. 143.7–145.0°C.
Anal. calcd. for C24H14Br2N2O6. C, 49.17; H, 2.41; N,
4.78. Found: C, 49.16; H, 2.43; N, 4.79.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-phenyl)-3a,4,4a,7a,
8,8a-hexahydro-3-(4H-chromen-4-one-3-yl)-pyrrolo[3,4-f]-1,2-
benzisoxazole (5a).
This compound was obtained as
yellow powder, m.p. 98.7–100.5°C.
1H NMR (CDCl3) δ: 7.307–8.410 (m, 8H, Ar—H),
7.203 (s, 1H, C7—H), 3.418 (s, 1H, C1—H), 2.706
(s, 1H, C2—H), 2.658 (s, 1H, C3—H), 3.457 (s, 1H,
C4—H), 2.711 (s, 1H, C5—H), 2.617 (s, 1H, C6—H).
IR 3045 (ArH), 1791 (C¼O), 1616 (C¼N), 1232
1H NMR (CDCl3) δ: 6.864–7.825 (m, 9H, Ar—H),
7.425 (s, 1H, C7—H), 3.127 (s, 1H, C1—H), 2.572 (s,
1H, C2—H), 2.679 (s, 1H, C3—H), 3.471 (s, 1H,
C4—H), 2.714 (s, 1H, C5—H), 2.627–2.638 (d,
J = 4.4 Hz, 1H, C6—H).
(C—O) cmꢀ1
.
IR 3064 (ArH), 1773 (C¼O), 1603 (C¼N), 1186
Anal. calcd. for C24H15ClN2O6. C, 62.28; H, 3.27; N,
6.05. Found: C, 62.27; H, 3.28; N, 6.02.
(C—O) cmꢀ1
.
Anal. calcd. for C24H14N2O6. C, 67.29; H, 3.76; N, 6.54.
Found: C, 67.30; H, 3.74; N, 6.55.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-hydroxyphenyl)-3a,
4,4a,7a,8,8a-hexahy-dro-3-(4H-chromen-4-one-3-yl)-pyrrolo[3,4-
f]-1,2-benzisoxazole (5b). This compound was obtained as
red powder, m.p. 131.8–133.2°C.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-bromophenyl)-3a,4,
4a,7a,8,8a-hexahyd-ro-3-(4H-chromen-4-one-3-yl)-pyrrolo[3,4-
f]-1,2-benzisoxazole (5f). This compound was obtained as
red powder, m.p. 140.2–141.7°C
1H NMR (CDCl3) δ: 6.892–7.947 (m, 8H, Ar—H),
7.219 (s, 1H, C7—H), 3.421 (s, 1H, C1—H), 2.717
(s, 1H, C2—H), 2.667 (s, 1H, C3—H), 3.462 (s, 1H,
C4—H), 2.701 (s, 1H, C5—H), 2.628 (s, 1H,
C6—H).
1H NMR (CDCl3) δ: 7.263–7.823 (m, 8H, Ar—H),
7.542–7.561 (d, J=7.6Hz, 1H, C7—H), 2.325 (s, 1H,
C1—H), 2.174 (s, 1H, C2—H), 2.246 (s, 1H, C3—H),
2.417 (s, 1H, C4—H), 2.401 (s, 1H, C5—H), 2.409 (s,
1H, C6—H), 6.860 (s, 1H, C8—H).
IR 3089 (ArH), 1716 (C¼O), 1558 (C¼N), 1186
(C—O—C), 1170 (C—N) cmꢀ1
.
IR 3076 (ArH), 1755 (C¼O), 1644 (C¼N), 1230
Anal. calcd. for C24H15BrN2O6. C, 56.82; H, 2.98; N,
5.52. Found: C, 56.81; H, 2.99; N, 5.54.
(C—O) cmꢀ1
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Isoxazole-Linked Norcantharidin Analogues of
Substituted Chromones
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-phenyl)-3a,4,4a,7a,
8,8a-hexahydro-3-(6-methyl-4H-chromen-4-one-3-yl)-pyrrolo[3,
4-f]-1,2-benzisoxazole (6a). This compound was obtained
as white powder, m.p. 104.8–105.3°C.
3.10 (s, 1H, C5—H), 3.46 (s, 2H, C4—H, C1—H), 2.52
(s, 2H, C2—H), 2.53 (s, 2H, C3—H).
IR 3227 (N—C¼O), 3086 (ArH), 1557 (C¼N), 1715
(C¼O), 1160 (C—O—C) cmꢀ1
.
1H NHR (DMSO) δ: 2.44 (s, 3H, CH3), 6.62–7.72
(m, 7H, Ar—H), 7.41 (s, 1H, O¼C—H), 3.55 (s, H,
C5—H), 2.38 (s, 1H, C6—H), 5.26 (s, 2H, C4—H),
4.83 (s, 1H, C1—H,), 3.10 (s, 2H, C2—H, C3—H).
IR 3420 (N—C¼O), 3258 (ArH), 1713 (C¼O), 1618
Anal. calcd. for C25H17ClN2O6. C, 62.97; H, 3.59; N,
5.87. Found: C, 62.95; H, 3.60; N, 5.90.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-bromophenyl)-3a,4,4a,
7a,8,8a-hexahyd-ro-3-(6-methyl-4H-chromen-4-one-3-yl)-pyrrolo[3,4-
f]-1,2-benzisoxazole (6f).
This compound was obtained as
(C¼N), 1287 (C—O—C) cmꢀ1
.
yellow powder, m.p. 202.0–203.5°C.
Anal. calcd. for C25H17N2O6. C, 67.87; H, 4.10; N, 6.33.
Found: C, 67.86; H, 4.12; N, 6.33.
1H NHR (DMSO) δ: 2.44 (s, 3H, CH3), 6.19–7.73 (m,
7H, Ar—H), 7.37 (s, 1H, O¼C—H), 3.55 (s, H, C5—H),
2.38 (s, 1H, C6—H), 5.26 (s, 1H, C4—H,), 4.83 (s, 1H,
C1—H,), 3.10 (s, 2H, C2—H, C3—H).
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-hydroxyphenyl)-3a,
4,4a,7a,8,8a-hexahy-dro-3-(6-methyl-4H-chromen-4-one-3-yl)-
pyrrolo[3,4-f]-1,2-benzisoxazole (6b). This compound was
obtained as yellow powder, m.p. 110.4–111.5°C.
IR 3461 (N—C¼O), 3089 (ArH), 1488 (C¼N), 1716
(C¼O), 1181 (C—O—C) cmꢀ1
.
1H NHR (DMSO) δ: 2.44 (s, 6H, CH3), 8.09–7.07 (m, 7H,
Ar—H), 7.14 (s, 1H, O¼C—H), 2.35–2.38 (d, J=12Hz, H,
C5—H), 2.54 (s, 1H, C6—H), 5.25 (s, 1H, O—H), 4.83 (s,
1H, C4—H), 3.07 (s, 1H, C1—H), 3.52 (s, 2H, C2—H, C3—H).
IR 3354 (N—C¼O), 3260 (ArH), 1557 (C¼N), 1715
Anal. calcd. for C25H17BrN2O6. C, 57.60; H, 3.29; N,
5.37. Found: C, 57.60; H, 3.27; N, 5.36.
Acknowledgments. This study was financially supported by
Zhejiang Provincial Natural Science Foundation of China under
Grant (No. LQ13H300001 and No. Y2100872) and the National
Science Foundation for Young Scholars of China under Grant
(No. 81202411 and No.81502926).
(C¼O), 1198 (C—O—C) cmꢀ1
.
Anal. calcd. for C25H18N2O7. C, 65.50; H, 3.96; N, 6.11.
Found: C, 65.50; H, 3.94; N, 6.12.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-p-tolyl)-3a,4,4a,7a,8,
\8a-hexahydro-3-(6-methyl-4H-chromen-4-one-3-yl)-pyrrolo[3,4-f]-
1,2-benzisoxazole (6c).
This compound was obtained as
REFERENCES AND NOTES
yellow powder, m.p. 108.9–110.0°C.
1H-NHR (DMSO) δ: 2.44(S, 6H, CH3), 8.09–7.07 (m, 7H,
Ar—H), 7.14 (s, 1H, O¼C—H), 2.35–2.38 (d, J=12Hz, H,
C5—H), 2.54 (s, 1H, C6—H), 5.25 (s, 1H, C4—H), 3.07
(s, 1H, C1—H), 3.52 (s, 2H, C2—H, C3—H).
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IR 3357 (N—C¼O), 3260 (ArH), 1714 (C¼N), 1567
(C¼O), 1189 (C—O—C) cmꢀ1
.
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exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-nitrophenyl)-3a,4,4a,
7a,8,8a-hexahydro-3-(6-methyl-4H-chromen-4-one-3-yl)-pyrrolo
[3,4-f]-1,2-benzisoxazole (6d).
obtained as yellow powder, m.p. 98.5–99.5°C.
This compound was
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1H-NHR (DMSO) δ: 2.44 (s, 3H, CH3), 6.63–8.39 (m,
7H, Ar—H), 8.08 (s, 1H, O¼C—H), 5.29 (s, H, C5—H),
2.38 (s, 1H, C6—H), 6.46 (s, 1H, C4—H), 3.15 (s, 1H,
C1—H), 3.52 (s, 2H, C2—H, C3—H).
IR 3413 (N—C¼O), 3230 (ArH), 1596 (C¼N), 1720
(C¼O), 1259 (C—O—C) cmꢀ1
.
Anal. calcd. for C25H17N3O8. C, 61.60; H, 3.52; N, 8.62.
Found: C, 61.60; H, 3.54; N, 8.61.
exo,exo-4,8-epoxy-5,7-(1h,6h)-dione-6-(4-chlorophenyl)-3a,4,
4a,7a,8,8a-hexahyd-ro-3-(6-methyl-4H-chromen-4-one-3-yl)-py-
rrolo[3,4-f]-1,2-benzisoxazole (6e).
This compound was
obtained as yellow powder, m.p. 93.8–95.1°C.
1H-NHR (DMSO) δ: 2.44 (s, 3H, CH3), 7.16–7.73 (m,
7H, Ar—H), 7.16 (s, 1H, O¼C—H), 2.38 (s, H, C6—H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W. Wang, L. Deng, C. Hu, Y. Zhang, Y. Li, and S. Zuo
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet