Heck-type hydroarylations and 1,3-dipolar cycloaddition reactions of new tricyclic hydrazones

Article abstract of DOI:10.1139/V09-179

The C-C coupling of the new tricyclic hydrazones 3-7 with aryl and heteroaryl halides gave under reductive Heck conditions the tricyclic 1-(arylideneamino)pyrolidine-2,5-diones 8-11a, 9-11b, 10c, and 12. The [3+2] cycloadditions of 3-7 with p-chlorophenyl

Full text of DOI:10.1139/V09-179

323
Heck-type hydroarylations and 1,3-dipolar
cycloaddition reactions of new tricyclic
hydrazones
Melek Gul and Nuket Ocal
Abstract: The C–C coupling of the new tricyclic hydrazones 3–7 with aryl and heteroaryl halides gave under reductive
Heck conditions the tricyclic 1-(arylideneamino)pyrolidine-2,5-diones 8–11a, 9–11b, 10c, and 12. The [3+2] cycloadditions
of 3–7 with p-chlorophenyl nitrile oxide (13) yielded the bridged isoxazoline derivatives 14–18 with potential biological
activity.
Key words: tricyclic hydrazone, reductive Heck reactions, C–C coupling, nitrile oxides, isoxazolines.
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Resume : Le couplage C–C des nouvelles hydrazones tricycliques 3–7 avec des halogenures d’aryles et d’heteroaryles,
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dans les conditions reductrices de Heck, conduisent a la formation des 1-(arylideneamino)pyrolidine-2,5-diones tricycles
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8–11a, 9–11b, 10c et 12. Les cycloadditions [3+2] des composes 3–7 avec l’oxyde du p-chlorophenylnitrile (13) condui-
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sent a la formation des derives isoxazolines pontees 14–18 qui peuvent presenter une activite biologique.
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Mots-cles : hydrazone tricyclique, reactions reductrices de Heck, couplage C–C, oxydes de nitriles, isoxazolines.
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[Traduit par la Redaction]
Introduction
Scheme 1. Preparation of compound 2.
In a collaborative effort with Kaufmann and co-workers,1–3
we reported palladium(II) acetate catalyzed asymmetric
Heck-type hydroarylations of bicyclic and tricyclic alkenes,
such as epibatidine analogs, and their domino–Heck applica-
tions by treating with aryl (or heteroaryl) iodides.4 We then
focused on reductive Heck reactions of tricyclic molecules
containing a strained C=C bond and an acylamino imide or
hydrazide group and possessing potential biological activ-
ity.5,6
Hydrazones are a versatile class of ligands that have ex-
tensive applications in various fields, possessing pronounced
biological and pharmaceutical activities as antitumor,7,8 anti-
microbial,9 antituberculosis,10 and antimalarial agents.11
These compounds play an important role in improving the
antitumor selectivity and toxicity profile of antitumor agents
by forming drug-carrier systems employing suitable carrier
proteins.12 Hydrazones, such as salicylaldeyde and hetero-
aryl substituted aldo hydrazones, act as orally effective
drugs for treatment of iron-overload diseases or genetic dis-
eases like b-thalassemia.13
Isoxazolines are generally synthesized by 1,3-dipolar cyclo-
additions of alkenes onto nitrile oxides. 1,3-Dipolar cycload-
dition reactions are useful tools for the construction of
biologically potent five-membered heterocycles.17
There are a few reports in the literature of the synthesis of
tricyclic hydrazones and practically no information on their
structure analyses.18,19 Therefore, we became interested in
the synthesis of possible bioactive aryl- and hetero-aryl sub-
stituted tricyclic hydrazones by reductive Heck reactions and
their isoxazoline derivatives via 1,3-dipolar cycloadditions.
Results and discussion
Our synthesis started with the reaction of endo-bicyclo[2.2.1]-
hept-5-ene-2,3-dicarboxylic anhydride (1) and hydrazine hy-
drate. The reaction occurred in benzene at room temperature
to give N-amino-bicyclo[2.2.1]hept-5-ene-2,endo-3-endo-di-
carboximide (2) as colorless crystals in a yield of 87%19
(Scheme 1).
In addition, five-membered heterocycles such as isoxazo-
lines represent a class of compounds of great biological im-
portance. For instance, isoxazolines possess
a broad
spectrum of biological activity, such as insecticidal, antibac-
terial, antibiotic, antitumor, and antifungal activities.14–16
Received 15 July 2009. Accepted 24 November 2009. Published on the NRC Research Press Web site at canjchem.nrc.ca on 4 March
2010.
This article is dedicated to Professor Dieter E. Kaufmann on the occasion of his 62nd birthday.
M. Gul and N. Ocal.1 Yildiz Technical University, Faculty of Art and Sciences, Department of Chemisty, Davutpasa Campus, Esenler,
Istanbul 34210, Turkey.
1Corresponding author (e-mail: nocal@yildiz.edu.tr).
Can. J. Chem. 88: 323–330 (2010)
doi:10.1139/V09-179
Published by NRC Research Press

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Can. J. Chem. Vol. 88, 2010
Scheme 3. Synthesis of reductive Heck compounds 8–12.
Scheme 2. Synthesis of compounds 3–7.
tions. (Table 2). The exo-position of the C–5 substituent
was confirmed by the fact that H5 showed no significant in-
teraction with H1. The geminal protons on C–6 were identi-
fied by vicinal coupling to H1.
1
Additionally, H–1H COSY spectra showed cross peaks
between H2 and H3 and between H5 and H6, respectively. In
addition to the 13C NMR, NOESY, HSQC, and FTIR spec-
tral data and elemental analyses which were in agreement
with the proposed structures, the mass spectra of all new
compounds showed the expected molecular ion peaks.
Norbornene and its derivatives have figured prominently
in organic chemistry. The presence of a rigid bicyclic skele-
ton gives rise to stereoisomers with fixed spatial orientation
of substitutents. The double bond in substituted norbornenes
is quite reactive toward cycloaadends, in particular toward
nitrile oxides in 1,3-dipolar additions. We carried out the
[3+2] cycloaddition of 3–7 with 4-chlorophenyl nitrile oxide
13 (generated in situ from 4-chlorobenzaldehyde with
NaOCl) to obtain the target compounds 14–18 (Scheme 4),
respectively.
We carried out the condensation of 2 with aryl- or hetero-
aryl-substituted aldeyhdes in dry ethanol to obtain new tricy-
clic hydrazones (3–7) (Scheme 2). The structures of these
synthesized compounds were elucidated using FTIR, 1H
NMR, 13C NMR, and mass spectroscopic methods as well
1
as elemental analysis. H NMR spectroscopy revealed that
in CDCl3 4–7 exist as an inseparable mixture of E and Z
isomers pertaining to the stereochemistry about the carbon=-
nitrogen double bond; the major isomers were tentatively as-
signed the E configuration. In compounds 4–7, varying
ratios of E/Z isomers (93:7, 92:8, 78:22, 52:48, respectively)
of the C=N bond were observed. The percentages of E and Z
isomers were determined by integration of the H8 protons.
Assignment of the stereochemistry was based upon the con-
sideration that in the E isomer, the proton attached to C=N
is in proximity to the imide nitrogen, resulting in an upfield
shift compared with the chemical shift of the Z isomer. Fur-
ther evidence for these structures were obtained from the
phase-sensitive NOESY measurements. The NOESY experi-
ment confirmed the assigned stereochemistries, showing an
interaction between H2 and H3 and the H8. In addition to
the 13C NMR and FTIR spectral data and elemental analyses
which were in agreement with the proposed structures, the
mass spectra of all new compounds showed the expected
molecular ion peaks.
Treatment of 3 with 4-chloro-1-iodobenzene and 4-me-
thoxy-1-iodobenzene under reductive Heck conditions and
subsequent column chromatography on silica gel gave 8a
and 8b as single diastereomers in isolated yields of 55%–
61%. The same reductive Heck arylation conditions were
successfully applied to the reaction of 4 with 4-methoxy-1-
iodobenzene and 2-chloro-5-iodopyridine to give the new
exo-arylated heterocycles 9a and 9b in good yields after
chromatographic separation. We also synthesized 10a, 10b,
and 10c from 5 with 2-iodothiophene, 4-chloro-1-iodobenzene,
and 2-chloro-1-iodobenzene and prepared 11a and 11b
from 6 with 1-iodobenzene and 2-iodothiophene (all
obtained as exo-isomers) under the same conditions. This
hydroarylation reaction was also applied successfully to 7
using 4-methoxy-1-iodobenzene to give 12 containing 4-
methoxyphenyl group (Table 1 and Scheme 3). All new
compounds were observed as E forms due to the isomerization
of Z forms during hydroarylation conditions.
1
The H NMR spectra of 14–18 are in accord with the pro-
posed structures. To identify the configuration of the isoxa-
zolines with tricyclic hydrazone adducts, we have studied
1
selective H–1H COSY and NOESY spectra obtained from
these compounds (Table 3).
1H–1H COSY spectra show the cross peaks between reso-
nances for H2 and H3; H5n and H6n. NOESY spectra show
that there are appropriate cross-peak resonances (H1 and H2;
H1 and H6n; H4 and H3; H4 and H5n; H2 and H6n; H3 and
H5n, respectively) verifying that the six protons are in close
spatial proximity and syn. The EI-MS spectra of cycload-
ducts 14–18 showed the characteristic molecular ion peaks.
In summary, palladium(II) acetate catalyzed hydroaryla-
tion of the readily accessible tricyclic hydrazones 3–7, in
the presence of triphenylarsine as ligand, was shown to be a
stereoselective, versatile, and high-yield approach to the
synthesis of aryl and heteroaryl derivatives of tricyclic hy-
drazones. Our results have also demonstrated that the 1,3-di-
polar cycloadditions of nitrile oxides onto bridged tricyclic
hydrazone derivatives prove useful for the construction of
novel heterocycles of potential pharmacological interest.
Experimental
All the reactions were carried out under nitrogen atmos-
phere unless otherwise indicated. Reactions were monitored
by thin-layer chromatography (TLC). Visualization of the
developed chromatograms was performed either with UV
light or KMnO4 stain. Products were purified by silica gel
chromatography with a solvent gradient of 2:1 (ethyl ace-
tate/n-hexane) to afford the title compounds. IR spectra
were obtained with a PerkinElmer FTIR instrument, and ab-
sorption frequencies are reported in cm–1. Melting points
The stereochemistry for each Heck product was inferred
from NMR spectra including diagnostic spin–spin interac-
Published by NRC Research Press

Gul and Ocal
325
Table 1. Hydroarylation reactions of tricyclic hydrazones, 3–7.
Published by NRC Research Press

326
Can. J. Chem. Vol. 88, 2010
1
Table 2. Selected H NMR data for compounds 8–12.
Entry
1
2
3
4
5
6
7
8
Compound
8a
8b
9a
9b
10a
10b
10c
11a
11b
12
H7a
1.63, d
1.51, d
1.60, d
1.62, d
1.66, d
1.68–1.62, m
1.68–1.60, m
1.62, d
H4
H5n
H8
3.02, brs
2.91, brs
2.95, brs
2.98, brs
2.98, brs
2.91, brs
2.91, brs
3.03, brs
3.01, brs
2.89, brs
2.97–2.89, m
2.85–2.79, m
2.88–2.84, m
2.83, dd
3.29–3.19, m
3.16, ddd
3.16, ddd
3.03, brs
3.33–3.21, m
2.85–2.82, m
9.68, s
9.59, s
9.43, s
9.35, s
9.34, s
9.27, s
9.21, s
9.37, s
9.35, s
9.24, s
9
10
1.67, d
1.49, d
1
Table 3. Selected H NMR data for compounds 14–18.
Scheme 4. Synthesis of compounds 14–18.
were determined with a Gallenkamp digital thermometer
equipment. All melting points are uncorrected. NMR spectra
were determined with a Bruker Ac-250 MHz NMR, Bruker
Ac-400 MHz NMR, or Varian-INOVA-500 MHz instru-
ment. 2D NMR experiments, such as COSY, 2D NOESY,
HMBC, and HSQC, were performed with a Bruker Ac-
400 MHz instrument. TMS (tetramethylsilane) was used as
an internal standard and CDCl3 was used as the solvent. Sig-
nal multiplicities in the NMR spectra are reported as fol-
lows: s, singlet; brs, broad singlet; d, doublet; dd, doublet
of doublets; and m, multiplet. Mass spectra were measured
either with Agillent LC–MSD Trap SL or MS-ESI. Elemen-
tal analyses were carried out with a Thermo Flash EA 1112
Series apparatus.
Entry
Compound
H3an
H8an
H9a
H10
1
2
3
4
5
14
15
16
17
18
3.61, dd
3.66, d
3.63, d
3.63, d
3.69, d
4.73, d
4.79, d
4.76, d
4.75, d
4.80, d
1.57, d
1.67, d
1.55, d
1.55, d
1.64, d
9.35, s
9.40, s
9.21, s
9.20, s
9.25, s
8.8, 1H, H7a). 13C NMR (100 MHz) d (ppm): 173.8 (2C,
C=O), 156.4 (N=CH), 138.3 (C–Cl), 136.4 (Csubst.), 134.7,
129.7 (C–Cl), 129.5, 128.9, 127.6, 51.8, 45.3, 44.0. MS-
ESI (EI, 70 eV): 336 [M+ + 1], 335 [M+], 270.96, 197.86,
166.08, 147.86, 119.95. Anal. calcd. for C16H12Cl2N2O2: C,
57.33; H, 3.61; N, 8.36. Found: C, 57.15; H, 3.44; N, 8.26.
Experimental procedure for the preparation of tricylic
hydrazones, 3–7
A mixture of 2 (178.85 mg, 1 mmol) and aromatic or het-
eroaromatic aldehyde (1.00 mmol) in ethanol (50–70 mL)
was heated at reflux for 10–12 h under nitrogen. The reac-
tion mixture was concentrated and the residue was chroma-
tographed on silica gel with ethyl acetate/n-hexane.
N-{[(5-bromo-2-hydroxyphenyl)methylene]amino}-
bicyclo[2.2.1]hept-5-ene-endo-2,endo-3-dicarboximide (4)
Colorless crystals, 52% yield. Mp 178 8C. Rf = 0.58 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3316, 3005, 2970,
1
1730, 1700, 1623, 1563, 1475, 1364, 1180, 745, 728. H
NMR (400 MHz) d (ppm): 11.12 (s, 1H, O–H, minor),
11.04 (s, 1H, O–H, major), 9.38 (s, 1H, H8, minor), 9.24 (s,
1H, H8, major), 7.46–7.40 (m, 2H, Haro.), 6.89 (d, J =
8.8 Hz, 1H, Haro.), 6.20 (s, 2H, H5–H6), 3.50 (s, 2H, H1–H4,
major), 3.37 (s, 2H, H2–H3, major), 3.18 (brs, 2H, H1–H4,
minor), 2.87 (brs, 2H, H2–H3, minor), 1.79 (d, J = 8.8 Hz,
1H, H7s, major), 1.58–1.67 (m, 2H, H7sminor – H7amajor),
1.36 (d, J = 8.8 Hz, 1H, H7a, minor) (E/Z, 93:7). 13C NMR
(100 MHz) d (ppm): 173.9 (2C, C=O, minor), 173.1 (2C,
C=O, major), 160.4 (C–OH, minor), 160.2 (C–OH, major),
158.6 (N=CH, minor), 158.7 (N=CH, major), 136.1 (C–Br,
N-{[(2,4-dichlorophenyl)methylene]amino}-
bicyclo[2.2.1]hept-5-ene-endo-2,endo-3-dicarboximide (3)
Colorless crystals, 65% yield. Mp 170 8C. Rf = 0.60 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3010, 2995, 2941,
1
1732, 1710, 1618, 1582, 1471, 1380, 1183, 745, 728. H
NMR (400 MHz) d (ppm): 9.50 (s, 1H, H8), 8.12 (d, J =
8.5 Hz, 1H, Haro.), 7.43 (s, 1H, Haro.), 7.30 (d, J = 7.2 Hz,
1H, Haro.), 6.23 (s, 2H, H5–H6) 3.54 (brs, 2H, H1–H4), 3.36
(s, 2H, H2–H3), 1.79 (d, J = 8.8 Hz, 1H, H7s), 1.61 (d, J =
Published by NRC Research Press

Gul and Ocal
327
minor), 136.0 (C–Br, major), 134.7 (Csubst.), 134.5 (minor),
ethyl acetate/n-hexane). FTIR (cm–1): 3104, 3011, 2972,
2935, 1764, 1738, 1696, 1589, 1427, 1373, 1180, 748, 719.
1H NMR (250 MHz) d (ppm): 9.12 (s, 1H, H8, minor), 9.07
(s, 1H, H8, major), 7.48–7.37 (m, 2H, Haro.), 7.05 (dd, J =
4.9 and 8.8 Hz, 1H, Haro.), 6.14 (s, 2H, H5–H6), 3.41 (brs,
H3, major–minor), 3.35 (brs, 2H, H2, major–minor), 3.06
(brs, 2H, H4, major–minor), 2.78 (brs, 2H, H1, major–mi-
nor), 1.71 (d, J = 7.8 Hz, 2H, H7s, major–minor), 1.34 (d, J =
7.8 Hz, 2H, H7a, major–minor) (E/Z, 52:48). 13C NMR
(62.5 MHz) d (ppm): 173.8 (2C, C=O, minor), 173.6 (2C,
C=O, major), 155.7 (N=CH, minor), 155.6 (N=CH, major),
134.6, 133.7 (minor), 133.6 (major), 131.3 (minor), 131.2
(major), 129.0 (Csubst., minor), 128.8 (Csubst., major), 127.7
(minor), 127.6 (major), 51.8, 46.8, 45.3, 45.2, 44.0. LC–
MSD: 295 [M+ + Na], 273 [M+ + 1], 272 [M+], 229, 163.
Anal. calcd. for C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29;
S, 11.77. Found: C, 61.69; H, 4.29; N, 10.19; S, 11.88.
134.5 (major), 119.6 (minor), 119.5 (major), 111.0 (Csubst.
,
minor), 110.9 (Csubst., major), 51.9, 46.9 (minor), 45.3
(major), 44.0 (major), 41.8 (minor). LC–MSD: 362 [M+ +
1], 361 [M+], 360 [M+ – 1], 296, 266, 195, 162. Anal. calcd.
for C16H13BrN2O3: C, 53.21; H, 3.63, N, 7.76. Found: C,
53.15; H, 3.49; N, 7.69.
N-{[(2,5-dimethoxyphenyl)methylene]amino}-
bicyclo[2.2.1]hept-5-ene-endo-2,endo-3-dicarboximide (5)
Colorless crystals, 45% yield. Mp 141 8C. Rf = 0.47 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3005, 2970, 2950,
1762, 1712, 1596, 1577 1495, 1463, 1180, 728, 716. 1H
NMR (400 MHz) d (ppm): 9.30 (s, 1H, H8, minor), 9.19 (s,
1H, H8, major), 7.64 (d, J = 3.1 Hz, 1H, Haro., minor), 7.58
(d, J = 3.1 Hz, Haro., major), 7.01 (dd, J = 3.1 and 7.7 Hz,
2H, Haro., major and minor), 6.86 (d, J = 8.8 Hz, 2H, Haro.
,
major–minor), 6.24 (s, 2H, H5–H6), 3.83 (s, 12H, –OCH3,
major–minor), 3.49 (s, 2H, H1–H4, major), 3.34 (s, 2H, H2–
H3, major), 3.16 (brs, 2H, H1–H4, minor), 2.86 (brs, 2H, H2–
H3, minor), 1.78 (d, J = 8.8 Hz, 1H, H7s, minor), 1.58 (m,
2H, H7a–H7s, major–minor), 1.46 (d, J = 8.8 Hz, 1H, H7a,
minor) (E/Z, 92:8). 13C NMR (100 MHz) d (ppm): 174.5
(2C, C=O, major), 173.8 (2C, C=O, minor), 159.6 (N=CH,
major), 159.4 (N=CH, minor), 154.1 (C–OCH3, major),
154.0 (C–OCH3, minor), 153.6 (C–OCH3, major), 153.5 (C–
OCH3, minor), 134.8 (minor), 134.7 (major), 121.6 (Csubst.),
121.2 (major), 121.1 (minor), 112.7 (major), 112.6 (minor),
110.0 (minor), 109.9 (major), 56.2 (minor), 55.9 (major),
51.8 (major), 51.5 (minor), 45.1 (major), 45.0 (minor), 44.5
(minor), 44.1 (major). LC–MSD: 327 [M+ + 1], 326 [M+],
325 [M+ – 1], 266, 242. Anal. calcd. for C18H18N2O4: C,
66.25; H, 5.56; N, 8.58. Found: C, 66.12; H, 5.54; N, 8.55.
Experimental procedure for the preparation of 8a–11a,
8b–11b, 10c, and 12
A solution of Pd(OAc)2 (5.6 mg, 0.025 mmol) and AsPh3
(33.7 mg, 0.11 mmol) in dry DMF (3 mL) was stirred in a
Schlenk flask under nitrogen at 65 8C for 15 min to form the
catalyst complex. Then, aryl iodide (306 mg, 1.5 mmol), hy-
drazone (3–7; 1.00 mmol), triethylamine (354 mg,
3.5 mmol), and formic acid (138 mg, 3.0 mmol) were added.
The mixture was heated to 65 8C for 24–48 h. After cooling
down to RT, brine (50 mL) was added, the reaction mixture
was extracted with ethyl acetate, and dried over MgSO4.
The solvent was evaporated, and the residue was purified
by chromatography.
5-(4-Chlorophenyl)-N-{[(2,4-dichlorophenyl)
methylene]amino}-bicyclo[2.2.1]heptane-endo-2,endo-3-
dicarboximide (8a)
N-{[2-naphthylmethylene]amino}-bicyclo [2.2.1]hept-5-ene-
endo-2,endo-3-dicarboximide (6)
Light yellow crystals, 55% yield. Mp 157 8C. Rf = 0.39
(2:1, ethyl acetate/n-hexane). FTIR (cm–1): 3068, 3025,
2963, 2875, 1789, 1714, 1616, 1582, 1491, 1469, 1416,
Colorless crystals, 72% yield. Mp 158 8C. Rf = 0.41 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 2967, 2963, 2860,
1734, 1710, 1603, 1568 1365, 1335, 1171, 756, 746. 1H
NMR (500 MHz) d (ppm): 9.24 (s, 1H, H8, minor), 9.11 (s,
1H, H8, major), 8.04 (d, J = 5.8 Hz, 1H, Haro.), 7.99 (d, J =
8.8 Hz, 1H, Haro.), 7.77–7.84 (m, 3H, Haro.), 7.43–7.50 (m,
2H, Haro.), 6.17 (s, 2H, H5–H6), 3.44 (s, 2H, H2–H3, major),
3.23 (s, 2H, H1–H4, major), 3.10 (brs, 2H, H2–H3, minor),
2.81 (brs, 2H, H1–H4, minor), 1.72 (d, J = 8.8 Hz, 1H H7s,
major), 1.56 (d, J = 8.8 Hz, 1H, H7s, minor), 1.52 (d, J =
8.8 Hz, 1H, H7a, major), 1.39 (d, J = 7.8 Hz, 1H, H7a, minor)
(E/Z, 78:22). 13C NMR (100 MHz) d (ppm): 174.3 (2C,
C=O, minor), 174.1 (2C, C=O, major), 161.9 (N=CH, mi-
nor), 161.7 (N=CH, major), 135.3 (minor), 135.2 (major),
134.7, 132.9 (minor), 132.8 (major), 131.6 (minor), 131.5
(major), 130.8 (minor), 130.7 (major), 128.9 (minor), 128.8
(major), 128.7 (minor), 128.6 (major), 127.9 (Csubst.), 127.8
(minor), 127.8 (major), 126.7, 123.4 (minor), 123.3 (major),
51.8, 41.8, 39.6. LC–MSD: 339 [M+ + Na], 317 [M+ + 1],
316 [M+], 282, 244. Anal. calcd. for C20H16N2O2: C, 75.93;
H, 5.10; N, 8.86. Found: C, 75.81; H, 4.98; N, 8.76.
1
1384, 1098, 866, 800. H NMR (400 MHz) d (ppm): 9.68
(s, 1H, H8), 8.20 (d, J = 8.5 Hz, 1H, Haro.), 7.47 (d, J =
1.9 Hz, 1H, Haro.), 7.34 (dd, J = 1.9 and 8.5 Hz, 1H, Haro.),
7.28 (d, J = 4.0 Hz, 2H, Haro.), 7.13 (d, J = 8.4 Hz, 2H,
Haro.) 3.33–3.23 (m, 2H, H2–H3), 3.02 (brs, 1H, H4), 2.97–
2.89 (m, 2H, H1–H5n), 1.96–1.88 (m, 3H, H7s, H6x ve H6n),
1.63 (d, J = 10.7, 1H, H7a). 13C NMR (100 MHz) d (ppm):
174.2–174.1 (2C, C=O), 156.9 (N=CH), 142.6 (Csubst.),
138.6 (Csubst.), 136.6 (C–Cl), 132.0 (C–Cl), 129.8, 129.4
(C–Cl), 128.9, 128.5, 128.3, 127.7, 46.8, 46.3, 46.0, 41.2,
40.0, 39.0, 32.6. LC–MS: 447 [M+], 412, 390, 258, 171.
Anal. calcd. for C22H17Cl3N2O2: C, 59.02; H, 3.83; N, 6.26.
Found: C, 58.91; H, 3.71; N, 6.16.
5-(4-Methoxyphenyl)-N-{[(2,4-dichlorophenyl)
methylene]amino}-bicyclo[2.2.1]heptane-endo-2,endo-3-
dicarboximide (8b)
Colorless crystals, 61% yield. Mp 184 8C. Rf = 0.39 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3037, 3015, 2975,
2960, 1771, 1711, 1596, 1582, 1499, 1471, 1454, 1377,
1
N-{[2-thienylmethylene]amino}-bicyclo[2.2.1]-hept-5-ene-
endo-2,endo-3-dicarboximide (7)
Colorless crystals, 59% yield. Mp 122 8C. Rf = 0.49 (2:1,
1275, 1260, 1174, 878, 867. H NMR (500 MHz) d (ppm):
9.59 (s, 1H, H8), 8.11 (d, J = 7.8 Hz, 1H, Haro.), 7.38–7.36
(m, 1H, Haro.), 7.26–7.24 (m, 1H, Haro.), 7.03 (d, J = 8.8 Hz,
Published by NRC Research Press

328
Can. J. Chem. Vol. 88, 2010
2H, Haro.), 6.75 (d, J = 8.8 Hz, 2H, Haro.), 3.73 (s, 3H,
OCH3), 3.19–3.13 (m, 2H, H2–H3), 2.91 (brs, 1H, H4),
2.85–2.79 (m, 2H, H1–H5n), 1.84–1.82 (m, 3H, H7s, H6n,
H6x), 1.51 (d, J = 10.7 Hz, 1H, H7a). 13C NMR (125 MHz)
d (ppm): 174.3–173.2 (2C, C=O), 155.6–154.8 (N=CH),
136.8 (Csubst.), 135.4 (Csubst.), 132.7 (C–Cl), 130.3 (C–Cl),
128.0, 127.9, 127.0, 126.7, 112.8, 54.2, 45.8, 40.8, 40.0,
39.0, 38.6, 38.0, 31.6. LC–MS: 443 [M+], 374, 322, 268.
Anal. calcd. for C23H20Cl2N2O3: C, 62.31; H, 4.55; N, 6.32.
Found: C, 62.18; H, 4.39; N, 6.37.
1421, 1384, 1224, 1195, 815, 733, 711. 1H NMR
(400 MHz) d (ppm): 9.34 (s, 1H, H8), 7.66 (d, J = 2.8 Hz,
1H, Haro.), 7.15 (d, J = 5.2 Hz, 1H, Haro.), 7.05 (dd, J = 3.2
and 9.2 Hz, 1H, Haro.), 6.94 (dd, J = 3.6 and 4.8 Hz, 1H,
Haro.), 6.88 (d, J = 9.2 Hz, 1H, Haro.), 6.83 (d, J = 3.2 Hz,
1H, Haro.), 3.85 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.29–
3.19 (m, 3H, H2–H3 and H5n), 2.98 (brs, 2H, H1–H4), 2.11–
2.01 (m, 2H, H6x–H6n), 1.94–1.89 (m, 1H, H7s), 1.66 (d, J =
10.7 Hz, 1H, H7a). 13C NMR (100 MHz) d (ppm): 174.0–
173.9 (2C, C=O), 159.8 (N=CH), 154.1 (C–OCH3), 153.6
(C–OCH3), 149.3 (Csubst.), 126.8, 123.5, 123.4 (Csubst.),
121.5, 121.4, 112.7, 110.0, 55.9–56.2 (2C, OCH3), 47.4,
46.6, 46.2, 39.6, 39.5, 37.9, 34.9. LC–MS: 433 [M + Na+],
410 [M+], 409 [M+ – 1], 274, 244, 218, 138. Anal. calcd. for
C22H22N2O4S: C, 64.37; H, 5.40; N, 6.82; S, 7.81. Found: C,
64.20; H, 5.29; N, 6.71; S, 7.99.
5-(4-Methoxyphenyl)-N-{[(5-bromo-2-hydroxyphenyl)
methylene]amino}-bicyclo[2.2.1]heptane-endo-2,endo-3-
dicarboximide (9a)
Light yellow crystals, 47% yield. Mp 187 8C. Rf = 0.60
(2:1, ethyl acetate/n-hexane). FTIR (cm–1): 3463, 3032,
3025, 2970, 2946, 1737, 1714, 1604, 1552, 1512, 1473,
1432, 1373, 1230, 1216, 1176, 822, 799, 777, 748. 1H
NMR (400 MHz) d (ppm): 11.14 (s, 1H, OH), 9.43 (s, 1H,
H8), 7.48–7.46 (m, 2H, Haro.), 7.12 (d, J = 8.6 Hz, 2H,
Haro.), 6.95 (d, J = 9.39 Hz, 1H, Haro.), 6.85 (d, J = 8.6 Hz,
2H, Haro.), 3.79 (s, 3H, OCH3), 3.32–3.19 (m, 2H, H2–H3),
2.95 (brs, 1H, H4), 2.88 (d, J = 6.8 Hz, 1H, H1), 2.88–2.84
(m, 1H, H5n), 1.95–1.89 (m, 3H, H7s, H6x ve H6n), 1.60 (d, J =
9.8 Hz, 1H, H7a). 13C NMR (100 MHz) d (ppm): 174.5–
174.4 (2C, C=O), 162.1 (N=CH), 144.3 (Csubst.), 135.3,
132.9, 131.8, 130.7 (Csubst.), 128.9, 128.7, 128.5, 127.9 (C–
OCH3), 127.1, 126.7 (C–Br), 126.2, 123.3, 47.0, 46.5, 46.0,
41.8, 40.0, 39.1, 32.5. LC–MS: 470 [M+ + 1], 469 [M+],
468 [M+ – 1], 390, 374, 344, 296, 220, 180. Anal. calcd.
for C23H21BrN2O4: C, 58.86; H, 4.51; N, 5.97. Found: C,
58.73; H, 4.40; N, 5.86.
5-(4-Chlorophenyl)-{[(2,5-dimethoxyphenyl)
methylene]amino}-bicyclo[2.2.1]heptane-endo-2,endo-3-
dicarboximide (10b)
Colorless crystals, 55% yield. Mp 185 8C. Rf = 0.45 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3058, 2969, 2947,
2878, 2839, 1737, 1706, 1614, 1598, 1493, 1462, 1423,
1
1376, 1217, 1189, 810, 792, 751. H NMR (500 MHz) d
(ppm): 9.27 (s, 1H, H8), 7.57 (d, J = 3.8 Hz, 1H, Haro.),
7.17 (d, J = 8.7 Hz, 2H, Haro.), 7.05 (d, J = 8.7 Hz, 2H,
Haro.), 6.96 (dd, J = 3.8 and 8.6 Hz, 1H, Haro.), 6.79 (d, J =
8.7 Hz, 1H, Haro.), 3.76 (s, 3H, OCH3), 3.75 (s, 3H, OCH3),
3.25–3.21 (m, 2H, H2–H3), 3.16 (ddd, J = 1.9, 8.8, and
11.7 Hz, 1H, H5n), 2.98 (d, J = 4.8 Hz, 1H, H1), 2.91 (brs,
1H, H4), 2.08 (ddd, J = 1.9, 8.8, and 11.7 Hz, 1H, H6n), 1.89
(d, J = 9.7 Hz, 1H, H6x), 1.68–1.62 (m, 2H, H7a ve H7s). 13C
NMR (100 MHz) d (ppm): 173.1–173.0 (2C, C=O), 158.6
(N=CH), 153.1 (C–OCH3), 152.7 (C–OCH3), 141.8 (C–Cl),
130.9 (Csubst.), 127.5, 127.4, 120.6 (Csubst.), 120.2, 111.8,
109.1, 55.3–54.9 (2C, OCH3), 45.9, 45.2, 44.9, 40.2, 38.9,
38.0, 31.6. LC–MS: 439 [M+ + 1], 438 [M+], 437 [M+ –
1], 378, 322, 268, 246, 139. Anal. calcd. for C24H23ClN2O4:
C, 65.68; H, 5.28; N, 6.38. Found: C, 65.53; H, 5.21; N,
6.43.
5-(6-Chloro-3-pyridyl)-N-{[(5-bromo-2-hydroxy-
phenyl)methylene]amino}-bicyclo[2.2.1]heptane-endo-
2,endo-3-dicarboximide (9b)
Colorless crystals, 60% yield. Mp 175 8C. Rf = 0.59 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3362, 3037, 2950,
2875, 1764, 1712, 1604, 1582, 1474, 1461, 1431, 1178,
1
825, 789, 740. H NMR (500 MHz) d (ppm): 10.96 (s, 1H,
OH), 9.35 (s, 1H, H8), 8.17 (d, J = 2.9 Hz, 1H, Haro.), 7.40–
7.38 (m, 3H, Haro.), 7.19 (d, J = 8.8 Hz, 1H, Haro.), 6.86 (d, J =
8.8 Hz, 1H, Haro.), 3.27 (dd, J = 5.8, 9.8 Hz, 1H, H3), 3.20
(ddd, J = 1.9, 4.8, and 6.8 Hz, 1H, H2), 2.98 (brs, 1H, H4),
2.92 (d, J = 4.8 Hz, 1H, H1), 2.83 (dd, J = 5.8 and 8.8 Hz,
1H, H5n), 1.90 (ddd, J = 1.9, 8.8, and 10.7 Hz, 1H, H6n),
1.82–1.76 (m, 2H, H7s, H6x), 1.62 (d, J = 10.7 Hz, 1H, H7a).
13C NMR (100 MHz) d (ppm): 172.2–172.1 (2C, C=O),
159.8 (N=CH), 157.8 (C–OH), 148.7 (Csubst.), 147.3, (Csubst.),
137.3 (C–Cl), 136.6 (C–Br), 135.4, 133.6, 123.0 118.6,
117.4, 110.1 45.7, 45.2, 44.5, 39.0, 38.2, 38.1, 31.6. LC–
MS: 475 [M+ + 1], 474 [M+], 473 [M+ – 1], 395, 345, 282,
180. Anal. calcd. for C21H17BrClN3O3: C, 53.13; H, 3.61; N,
8.85. Found: C, 53.03; H, 3.70; N, 8.79.
5-(2-Chlorophenyl)-{[(2,5-dimethoxyphenyl)
methylene]amino}-bicyclo[2.2.1]heptane-endo-2,endo-3-
dicarboximide (10c)
Colorless crystals, 59% yield. Mp 126 8C. Rf = 0.39 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3053, 2969, 2951,
2875, 1768, 1704, 1613, 1596, 1493, 1464, 1441, 1180,
1
837, 812, 792. H NMR (500 MHz) d (ppm): 9.21 (s, 1H,
H8), 7.59 (d, J = 3.9 Hz, 1H, Haro.), 7.29 (d, J = 7.8 Hz,
1H, Haro.), 7.18–7.13 (m, 2H, Haro.), 7.07 (ddd, J = 1.9, 8.8,
and 14.6 Hz, 1H, Haro.), 6.96 (dd, J = 2.9 and 8.8 Hz, 1H,
Haro.), 6.79 (d, J = 8.7 Hz, 1H, Haro.), 3.76 (s, 3H, OCH3),
3.75 (s, 3H, OCH3), 3.25–3.21 (m, 2H, H2–H3), 3.16 (ddd,
J = 1.9, 8.7, and 11.7 Hz, 1H, H5n), 2.98 (d, J = 4.8 Hz,
1H, H1), 2.91 (brs, 1H, H4), 2.08 (ddd, J = 1.9, 8.7, and
11.7 Hz, 1H, H6n), 1.89 (d, J = 9.7 Hz, 1H, H6x), 1.68–1.60
(m, 2H, H7a–H7s). 13C NMR (100 MHz) d (ppm): 173.1–
172.8 (2C, C=O), 154.5 (N=CH), 156.1 (C–Cl), 154.5
(Csubst.), 140.7 (C–OCH3), 138.1 (Csubst.), 128.8, 127.1,
120.2, 125.2, 120.6, 111.6, 110.2, 55.4–55.2 (2C, OCH3),
46.1, 45.2, 43.6, 40.0, 39.0, 38.0, 32.2. LC–MS: 439 [M+ +
5-(2-Thienyl)-N-{[(2,5-dimethoxyphenyl)
methylene]amino}-bicyclo[2.2.1]heptane-endo-2,endo-3-
dicarboximide (10a)
Colorless crystals, 65% yield. Mp 167 8C. Rf = 0.42 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3119, 3058, 2964,
2881, 2837, 1759, 1698, 1613, 1595, 1494, 1467, 1455,
Published by NRC Research Press

Gul and Ocal
329
1], 438 [M+], 437 [M+ – 1], 378, 322, 268, 246, 139. Anal.
calcd. for C24H23ClN2O4: C, 65.68; H, 5.28; N, 6.38. Found:
C, 65.59; H, 5.23; N, 6.45.
Experimental procedure for the preparation of 14–18
To a solution of 4-chlorobenzaldoxime (202.25 mg,
1.3 mmol) in dichloromethane was added tricyclic hydra-
zone 3–7 (1 mmol), and the solution was cooled to 0 8C.
Aqueous sodium hypochloride (5.25%, 3.5 g, 2.5 mmol)
was added dropwise over 30 min, and the reaction was
stirred overnight (0 8C – room temperature). The reaction
mixture was extracted with either dichloromethane (3 Â
10 mL) or diethyl ether and dried over MgSO4. The solvent
was evaporated, and the residue was purified by chromatog-
raphy.
5-(Phenyl)-N-{[2-napthylmethylene]amino}bicyclo
[2.2.1]heptane-endo-2,endo-3-dicarboximide (11a)
Light yellow crystals, 62% yield. Mp 132 8C. Rf = 0.57
(2:1, ethyl acetate/n-hexane). FTIR (cm–1): 3053, 3012,
2970, 2921, 2882, 1737, 1724, 1703, 1605, 1587, 1512,
1
1455, 1433, 1178, 761, 738. H NMR (400 MHz) d (ppm):
9.37 (s, 1H, H8), 8.20 (s, 1H, Haro.), 8.16 (d, J = 8.7 Hz,
1H, Haro.), 7.94–7.87 (m, 3H, Haro.), 7.53–7.60 (m, 2H,
4,8-Methano-3-(4-chlorophenyl)-6-(2,4-
H
aro.), 7.33–7.19 (m, 5H, Haro.), 3.34–3.24 (m, 2H, H2–H3),
dichloromethyleneamino)-4,4a,8,exo-8a-tetrahydro-exo-
3aH-isoxazolo[5,4-f]isoindole-5,7(6H,7aH)-endo-dione (14)
Colorless crystals, 80% yield. Mp 241 8C. Rf = 0.60 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3100, 3045, 2959,
2870, 1775, 1707, 1598, 1583, 1496, 1471, 1377, 1357,
3.03 (brs, 3H, H1–H4 and H5n), 2.05–1.94 (m, 3H, H7s, H6x
ve H6n), 1.62 (d, J = 9.0 Hz, 1H, H7a). 13C NMR
(100 MHz) d (ppm): 174.5–174.4 (2C, C=O), 162.1
(N=CH), 144.3 (Csubst.), 135.3, 132.9, 131.8, 130.7, 128.9,
128.7, 128.5, 127.9, 127.0, 126.7, 126.2, 123.3, 47.0, 46.5,
46.0, 41.8, 40.0, 39.1, 32.5. LC–MS: 395 [M+ + 1], 394
[M+], 393 [M+ – 1], 332, 234, 206, 194, 167. Anal. calcd.
for C26H22N2O2: C, 79.16; H, 5.62; N, 7.10. Found: C,
79.04; H, 5.70; N, 6.99.
1
1315, 1301, 1175, 900, 868, 827. H NMR (400 MHz) d
(ppm): 9.35 (s, 1H, H10), 8.10 (d, J = 8.8 Hz, 1H, Haro.),
7.55 (d, J = 8.8 Hz, 2H, Haro.), 7.39 (d, J = 1.95 Hz, 1H,
Haro.), 7.32 (d, J = 7.8 Hz, 2H, Haro.), 7.26 (dd, J = 1.9 and
7.8 Hz, 1H, Haro.), 4.73 (d, J = 7.8 Hz, 1H, H8an), 3.61 (dd,
J = 1.4 and 7.8 Hz, 1H, H3an), 3.26–3.23 (m, 2H, H4a–H7a),
3.22 (brs, 1H, H8), 3.02 (brs, 1H, H4), 1.82 (d, J = 10.7 Hz,
1H, H9s), 1.57 (d, J = 9.0 Hz, 1H, H9a). 13C NMR
(100 MHz) d (ppm): 172.0–171.1 (2C, C=O), 156.7 (Csubst.),
154.2 (N=CH), 137.9 (Csubst.), 135.7 (Csubst.), 135.4 (Csubst.),
128.9, 128.2, 128.0, 127.9, 127.0, 126.8, 125.5, 82.8, 51.4,
44.9, 43.8, 41.5, 41.2, 34.7. LC–MS: 491 [M+ + 1], 488.75
[M+], 487 [M+ – 1]. MS-ESI (EI, 70 eV): 490 [M+], 389.38,
363.31, 334.85, 317.14, 270.92, 220.07, 202.13, 167.23.
Anal. calcd. for C23H16Cl3N3O3: C, 56.52; H, 3.30; N, 8.60.
Found: C, 56.01; H, 3.33; N, 8.65.
5-(2-Thienyl)-N-{[2-naphthylmethylene]amino}bicyclo-
[2.2.1]heptane-endo-2,endo-3-dicarboximide (11b)
Light yellow crystals, 62% yield. Mp 145 8C. Rf = 0.57
(2:1, ethyl acetate/n-hexane). FTIR (cm–1): 3058, 3045,
2953, 2921, 2875, 1734, 1700, 1607, 1569, 1467, 1438,
1350, 1180, 773, 760, 741, 697. 1H NMR (400 MHz) d
(ppm): 9.35 (s, 1H, H8), 8.20 (brs, 1H, Haro.), 8.15 (d, J =
8.8 Hz, 1H, Haro.), 7.94–7.87 (m, 3H, Haro.), 7.53–7.60 (m,
2H, Haro.), 7.16 (d, J = 4.7 Hz, 1H, Haro.), 6.95–6.92 (m,
1H, Haro.), 6.84 (d, J = 3.4 Hz, 1H, Haro.), 3.33–3.21 (m,
3H, H2–H3 and H5n), 3.01 (brs, 2H, H1–H4), 2.18–2.03 (m,
2H, H6x–H6n), 1.95–1.90 (m, 1H, H7s), 1.67 (d, J = 10.2 Hz,
1H, H7a). 13C NMR (100 MHz) d (ppm): 174.2–174.1 (2C,
C=O), 162.2 (N=CH), 149.2 (Csubst.), 135.3, 132.9, 131.8,
130.6 (Csubst.), 128.9, 128.7, 127.9, 126.8, 126.7, 123.4,
123.3, 47.3, 46.6, 46.1, 39.6, 39.4, 38.0, 35.0. LC–MS: 400
[M+], 399 [M+ – 1], 370, 234, 206, 167. Anal. calcd. for
C24H20N2O2S: C, 71.98; H, 5.03; N, 6.99; S, 8.01. Found:
C, 71.81; H, 5.19; N, 6.81; S, 8.08.
4,8-Methano-3-(4-chlorophenyl)-6-(5-bromo-2-hydroxy-
phenylmethyleneamino)-4,4a,8,exo-8a-tetrahydro-exo-3aH-
isoxazolo[5,4-f]isoindole-5,7(6H,7aH)-endo-dione (15)
Colorless crystals, 78% yield. Mp 162 8C. Rf = 0.58 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3394, 3011, 2979,
2946, 1791, 1708, 1608, 1594, 1494, 1476, 1403, 1354,
1
1322, 1169, 741, 716. H NMR (400 MHz) d (ppm): 10.91
(s, 1H, O–H), 9.40 (s, 1H, H10), 7.62 (d, J = 8.5 Hz, 2H,
Haro.), 7.50 (d, J = 7.8 Hz, 2H, Haro.), 7.41 (d, J = 8.5 Hz,
2H, Haro.), 6.95 (d, J = 9.0 Hz, 1H, Haro.), 4.79 (d, J =
8.0 Hz, 1H, H8an), 3.66 (d, J = 8.0 Hz, 1H, H3an), 3.34 (d, J =
3.7 Hz, 2H, H4a–H7a), 3.30 (brs, 1H, H8), 3.11 (brs, 1H, H4),
1.92 (d, J = 11.3 Hz, 1H, H9s), 1.67 (d, J = 11.3 Hz, 1H,
H9a). 13C NMR (100 MHz) d (ppm): 172.3–171.7 (2C,
C=O), 161.5 (N=CH), 158.8 (Csubst.), 155.1 (Csubst.), 136.6
(Csubst.), 136.5 (Csubst.), 134.7, 129.3, 128.0, 126.3, 119.7,
118.1, 111.2, 83.2, 52.5, 45.8, 44.7, 42.5, 42.1, 35.7. LC–
MS: 516 [M+ + 1], 515 [M+], 513 [M+ – 1]. Anal. calcd.
for C23H17BrClN3O4: C, 53.67; H, 3.33; N, 8.16. Found: C,
53.48; H, 3.41; N, 8.19.
5-(4-Methoxyphenyl)-N-{[2-thienylmethylene] amino}-
bicyclo[2.2.1]heptane-endo-2,endo-3-dicarboximide (12)
Colorless crystals, 58% yield. Mp 177 8C. Rf= 0.49 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3082, 3032, 3068,
3053, 3012, 2955, 2886, 1764, 1713, 1609, 1581, 1511,
1
1464, 14434, 1373, 1247, 1170, 802, 744, 723. H NMR
(500 MHz) d (ppm): 9.24 (s, 1H, H8), 7.48 (d, J = 4.8 Hz,
1H, Haro.), 7.43 (d, J = 2.9 Hz, 1H, Haro.), 7.05–7.02 (m, 3H,
Haro.), 6.75 (d, J = 8.8 Hz, 2H, Haro.), 3.69 (s, 3H, OCH3),
3.18–3.09 (m, 2H, H2–H3), 2.89 (brs, 1H, H4), 2.85–2.82
(m, 2H, H1–H5n), 1.83–1.79 (m, 3H, H7s, H6n, H6x), 1.49 (d,
J = 10.7 Hz, 1H, H7a). 13C NMR (100 MHz) d (ppm):
173.3–173.2 (2C, C=O), 157.0 (N=CH), 154.8 (Csubst.),
136.8 (Csubst.), 135.4, 132.7, 130.3, 127.0, 126.7, 112.8, 54.2
(C–OCH3), 45.9, 45.4, 45.3, 40.0, 38.9, 38.0, 31.6. LC–MS:
381 [M+ + 1], 380 (M+), 379 [M+ – 1], 366, 232, 206, 167.
Anal. calcd. for C21H20N2O3S: C, 66.29; H, 5.30; N, 7.36; S,
8.43. Found: C, 66.08; H, 5.33; N, 7.23; S, 8.47.
4,8-Methano-3-(4-chlorophenyl)-6-(2,5-dimethoxy-
phenylmethyleneamino)-4,4a,8,exo-8a-tetrahydro-exo-3aH-
isoxazolo[5,4-f]isoindole-5,7(6H,7aH)-endo-dione (16)
Colorless crystals, 69% yield. Mp 211 8C. Rf = 0.49 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3053, 3009, 2970,
Published by NRC Research Press

330
Can. J. Chem. Vol. 88, 2010
2947, 1767, 1704, 1610, 1599, 1496, 1468, 1422, 1406,
1378, 1225, 1184, 920, 900, 822. H NMR (400 MHz) d
Acknowledgments
1
We gratefully acknowledge financial support of this work
by the Yildiz Technical University Scientific Research Proj-
ects Coordination Department (Project No. 28–01–02–04).
We thank Prof. Dr. I. Erden from San Francisco State Uni-
versity for fruitful discussions.
(ppm): 9.21 (s, 1H, H10), 7.57–7.56 (brs, 1H, Haro.), 7.54 (d,
J = 8.8 Hz, 2H, Haro.), 7.30 (d, J = 8.8 Hz, 2H, Haro.), 6.98
(dd, J = 2.9 and 8.8 Hz, 1H, Haro.), 6.80 (d, J = 9.7 Hz, 1H,
Haro.), 4.76 (d, J = 8.8 Hz, 1H, H8an), 3.77 (s, 3H, m-subst.,
OCH3), 3.74 (s, 3H, o-substituted, OCH3), 3.63 (d, J =
8.8 Hz, 1H, H3an), 3.21 (d, J = 3.9 Hz, 2H, H4a–H7a), 3.19
(brs, 1H, H8), 3.00 (brs, 1H, H4), 1.80 (d, J = 11.7 Hz, 1H,
H9s), 1.55 (d, J = 11.7 Hz, 1H, H9a). 13C NMR (100 MHz) d
(ppm): 172.0–171.1 (2C, C=O), 159.5 (N=CH), 154.3
(Csubst.), 153.2 (Csubst.), 152.7 (Csubst.), 135.3 (Csubst.), 128.2,
127.0, 125.5, 120.6, 120.1, 111.8, 109.0, 82.2, 55.2, 54.9,
51.5, 44.8, 43.9, 41.7, 41.1, 34.7. LC–MS: 481 [M+ + 1],
480 [M+]. Anal. calcd. for C25H22ClN3O5: C, 62.57; H,
4.62; N, 8.76. Found: C, 62.49; H, 4.59; N, 8.81.
References
(1) Namyslo, J. C.; Kaufmann, D. E. Chem. Ber. 1997, 130 (9),
1327. doi:10.1002/cber.19971300924.
(2) Namyslo, J. C.; Kaufmann, D. E. Synlett 1999, 1999 (6),
804. doi:10.1055/s-1999-2719.
(3) Storsberg, J.; Yao, M.-L.; Ocal, N.; de Meijere, A.; Adam,
A. E. W.; Kaufmann, D. E. Chem. Commun. (Camb.) 2005,
45 (45), 5665. doi:10.1039/b507732j. PMID:16292383.
(4) Yolacan, C.; Bagdatli, E.; Ocal, N.; Kaufmann, D. E. Mole-
cules 2006, 11 (8), 603. doi:10.3390/11080603. PMID:
17971733.
4,8-Methano-3-(4-chlorophenyl)-6-(2-napthyl-
methyleneamino)-4,4a,8,exo-8a-tetrahydro-exo-3aH-
isoxazolo[5,4-f]isoindole-5,7(6H,7aH)-endo-dione (17)
Colorless crystals, 85% yield. Mp 135 8C. Rf = 0.41 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3027, 3011, 2958,
2916, 2850, 1767, 1706, 1625, 1606, 1593, 1493, 1468,
¨
(5) Bagdatli, E.; Ocal, N.; Kaufmann, D. E. Helv. Chim. Acta
2007, 90 (12), 2380. doi:10.1002/hlca.200790244.
¨
¨
¨
(6) Goksu, G.; Gul, M.; Ocal, N.; Kaufmann, D. E. Tetrahedron
Lett. 2008, 49 (17), 2685. doi:10.1016/j.tetlet.2008.02.171.
(7) Terzioglu, N.; Gu¨rsoy, A. Eur. J. Med. Chem. 2003, 38 (7-8),
781. doi:10.1016/S0223-5234(03)00138-7. PMID:12932910.
(8) Cocco, M. T.; Congiu, C.; Lilliu, V.; Onnis, V. Bioorg. Med.
Chem. 2006, 14 (2), 366. doi:10.1016/j.bmc.2005.08.012.
PMID:16185883.
1
1366, 1346, 1178, 798, 738, 724. H NMR (400 MHz) d
(ppm): 9.20 (s, 1H, H10), 8.01 (dd, J = 1.4 and 8.8 Hz, 1H,
Haro.), 7.82–7.77 (m, 3H, Haro.), 7.53 (d, J = 8.8 Hz, 2H,
Haro.), 7.50–7.43 (m, 2H, Haro.), 7.28 (d, J = 8.8 Hz, 2H,
Haro.), 4.75 (d, J = 8.3 Hz, 1H, H8an), 3.63 (d, J = 8.3 Hz,
(9) Vicini, P.; Zani, F.; Cozzini, P.; Doytchinova, I. Eur. J. Med.
Chem. 2002, 37 (7), 553. doi:10.1016/S0223-5234(02)01378-
8. PMID:12126774.
1H, H3an), 3.23 (d, J = 4.8 Hz, 2H, H4a–H7a), 3.20 (brs, 1H,
H8), 2.99 (brs, 1H, H4), 1.80 (d, J = 11.2 Hz, 1H, H9s), 1.55
(d, J = 11.2 Hz, 1H, H9a). 13C NMR (100 MHz) d (ppm):
172.2–171.4 (2C, C=O), 161.8 (Csubst.), 154.3 (N=CH),
135.3 (Csubst.), 134.4 (Csubst.), 131.8 (Csubst.), 131.0, 129.3,
128.2, 127.9, 127.8, 127.1, 127.0, 125.8, 125.5, 122.0, 82.3,
52.4, 51.4, 44.8, 43.8, 41.6, 41.1. LC–MS: 471 [M+ + 1],
470 [M+], 469 [M+ – 1]. Anal. calcd. for C27H20ClN3O3: C,
69.01; H, 4.29; N, 8.94. Found: C, 69.19; H, 4.26; N, 8.78.
(10) Patole, J.; Sandbhor, U.; Padhye, S.; Deobagkar, D. N.; An-
son, C. E.; Powell, A. Bioorg. Med. Chem. Lett. 2003, 13 (1),
51. doi:10.1016/S0960-894X(02)00855-7. PMID:12467615.
(11) Walcourt, A.; Loyevsky, M.; Lovejoy, D. B.; Gordeuk, V. R.;
Richardson, D. R. Int. J. Biochem. Cell Biol. 2004, 36 (3),
401. doi:10.1016/S1357-2725(03)00248-6. PMID:14687919.
(12) Kratz, F.; Beyer, U.; Roth, T.; Tarasova, N.; Collery, P.; Le-
chenault, F.; Cazabat, A.; Schumacher, P.; Unger, C.;
Falken, U. J. Pharm. Sci. 1998, 87 (3), 338. doi:10.1021/
js970246a. PMID:9523988.
(13) Bernhardt, P. V.; Chin, P.; Sharpe, P. C.; Wang, J.-Y. C.; Ri-
chardson, D. R. J. Biol. Inorg. Chem. 2005, 10 (7), 761.
doi:10.1007/s00775-005-0018-0. PMID:16193304.
(14) Umesha, K. B.; Ajay Kumar, K.; Lokanatha Rai, K. M.
Synth. Commun. 2002, 32 (12), 1841. doi:10.1081/SCC-
120004066.
4,8-Methano-3-(4-chlorophenyl)-6-(2-thienylmethylene-
amino)-4,4a,8,exo-8a-tetrahydro-exo-3aH-isoxazolo[5,4-
f]isoindole-5,7(6H,7aH)-endo-dione (18)
Colorless crystals, 75% yield. Mp 169 8C. Rf = 0.47 (2:1,
ethyl acetate/n-hexane). FTIR (cm–1): 3088, 2976, 2921,
1769, 1701, 1592, 1514, 1494, 1343, 1319, 1184, 806, 728,
1
712. H NMR (400 MHz) d (ppm): 9.25 (s, 1H, H10), 7.62
(d, J = 8.3 Hz, 2H, Haro.), 7.59 (d, J = 5.0 Hz, 1H, Haro.),
7.53 (d, J = 3.6 Hz, 1H, Haro.), 7.38 (d, J = 8.2 Hz, 1H,
(15) Houari, G. A.; Kerbal, A.; Bennani, B.; Baba, M. F.; Daoudi,
M.; Hadda, T. B. Arkivoc 2008, xii, 42.
Haro.), 7.15 (d, J = 4.0 Hz, 2H, Haro.), 4.80 (d, J = 8.3 Hz,
(16) Jayashankara, B.; Rai, K. M. L. Arkivoc 2008, xi, 75.
(17) Caramella, P.; Gruenanger, P. In 1,3-Dipolar Cycloaddition
Chemsitry; Padwa, A., Ed.; Wiley Interscience: New York,
1984; Vol. 1.
(18) Verma, S. M.; Rao, C. K. Tetrahedron 1972, 28 (19), 5029.
doi:10.1016/0040-4020(72)88155-9.
(19) Kas’yan, L. I.; Tarabara, I. N.; Bondarenko, Ya. S.; Shish-
kina, S. V.; Shishkin, O. V.; Musatov, V. I. Russ. J. Org.
Chem. 2005, 41 (8), 1122. doi:10.1007/s11178-005-0305-9.
1H, H8an), 3.69 (d, J = 8.3 Hz, 1H, H3an), 3.32 (d, J =
3.7 Hz, 2H, H4a–H7a), 3.26 (brs, 1H, H8), 3.07 (brs, 1H, H4),
1.88 (d, J = 11.2 Hz, 1H, H9s), 1.64 (d, J = 11.2 Hz, 1H, H9a).
13C NMR (100 MHz) d (ppm): 173.0–171.3 (2C, C=O),
156.7 (Csubst.), 155.3 (N=CH), 137.2 (Csubst.), 136.3, 134.4,
131.9, 129.2, 128.1, 127.9, 126.4, 83.3, 52.4, 45.8, 44.7,
42.5, 42.1, 35.7. LC–MS: 427 [M+ + 1], 426 [M+], 425 [M+
– 1]. Anal. calcd. for C21H16ClN3O3S: C, 59.22; H, 3.79; N,
9.87; S, 7.53. Found: C, 59.01; H, 3.67; N, 9.75; S, 7.59.
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