Synthesis of new cantharimide analogues derived from 3-sulfolene

Article abstract of DOI:10.1055/s-0030-1258466

New types of norcantharimide analogues were prepared by three methods: epoxidation, photooxidation, and bromination. Epoxidation of deoxynorcantharimide with m-chloroperoxybenzoic acid gave an isomeric mixture. The selective formation of the syn-isomers was attributed to dipole-dipole interactions between the peracid and imide moiety. Photooxidation of deoxynorcanthamide gave syn-and anti-hydroperoxide analogues through ene addition of singlet oxygen; the anti-hydroperoxide was the major product in this case, as a result of the steric effect of the imide ring. Bromination of deoxynorcantharimide and subsequent transformations gave a pyrrolidine and the phthalimide core structure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258466

PAPER
1079
Synthesis of New Cantharimide Analogues Derived from 3-Sulfolene
C
antharimide Ana
y
logues se Tan, Birgul Koc, Ertan Sahin,1 Nurhan H. Kishali,* Yunus Kara*
Department of Chemistry, Faculty of Sciences, Atatürk University, 25240 Erzurum, Turkey
Fax +90(0442)2360948; E-mail: yukara@atauni.edu.tr; E-mail: nhorasan@atauni.edu.tr
Received 13 December 2010; revised 8 February 2011
agents. Cantharimides have been tested for various effects
and have been shown to inhibit xanthenes oxidase5 and to
have antiplatelet effects on thrombin, arachidonic acid,
collagen, and platelet-activating factor-induced aggrega-
Abstract: New types of norcantharimide analogues were prepared
by three methods: epoxidation, photooxidation, and bromination.
Epoxidation of deoxynorcantharimide with m-chloroperoxybenzoic
acid gave an isomeric mixture. The selective formation of the syn-
isomers was attributed to dipole–dipole interactions between the tion. N-Methylcantharimide (3, R = Me), for example,
peracid and imide moiety. Photooxidation of deoxynorcanthamide
shows tumor-inhibitory action in animals. McCluskey et
al.6 synthesized various norcantharimides through simple
gave syn- and anti- hydroperoxide analogues through ene addition
of singlet oxygen; the anti-hydroperoxide was the major product in
synthetic modifications of norcantharidin. This facilitated
this case, as a result of the steric effect of the imide ring. Bromina-
the development of a novel series of norcantharimides dis-
tion of deoxynorcantharimide and subsequent transformations gave
playing modest-to-good broad-spectrum cytotoxicity
against various carcinomas. Lin et al.7 reported that
cantharimide derivatives containing aliphatic, aryl, or py-
ridyl groups showed some effects in vitro against HepG2
and HL-60 cells, suggesting that they may have anticancer
activity. Chan and Tang8 studied the synthesis and cyto-
toxicity of some cantharimide derivatives, and they con-
cluded that cantharimide has shown relatively less
toxicity in treatment of nonmalignant hematological dis-
orders of bone marrow cells.
a pyrrolidine and the phthalimide core structure.
Key words: ene reactions, epoxidation, photooxidations, halogena-
tion, stereoselective synthesis, heterocycles
Cantharidin (1; Figure 1) is a naturally occurring cyclic
anhydride found in many species of blister beetles, most
notably Lytta vesicatoria, widely known as Spanish fly.2
Spanish fly induces the formation of blisters upon contact
with skin, and its ingestion produces dose-dependent
physiological symptoms, including abdominal pain and
gastrointestinal hemorrhage. Although it is highly toxic,
dried Spanish fly has been used as an aphrodisiac since the
time of the ancient Greeks and Romans. Spanish fly has
also been used as a natural remedy in China for the past
2000 years, and it has been used worldwide as an antican-
cer agent since 1264, particularly in the treatment of
hepatoma and oesophageal carcinoma.3 Cantharide and its
analogues are of considerable interest as potential inhibi-
tors of the serine/threonine protein phosphates 1 and 2A
(PP1 and PP2A).4
Here, we report a synthesis of a series of new norcantha-
rimide analogues, including 4–6 (Figure 2), from 3-sul-
folene (7; 2,5-dihydrothiophene 1,1-dioxide) and the
characterization of the products.
O
O
O
R
R
NEt
NEt
NEt
O
RO
O
O
O
4a (syn)
4b (anti)
5a (anti) R = OH
5b (syn) R = OH
6a R = OAc
6b R = Br
Figure 2
O
O
O
O
O
O
O
Our approach involved assembling the cyclic scaffold by
Diels–Alder cycloaddition of maleic anhydride (8) to 3-
sulfolene (7) to give the dione 9, as reported in the litera-
ture.9 Condensation of ethylamine with dione 9 in the
presence of a 3:1 mixture of toluene and triethylamine
gave the imide 10 in 80% yield (Scheme 1).6
O
O
O
NR
O
cantharidine (1)
norcantharidine (2)
norcantharimide (3)
Figure 1
Imide 10 is a deoxy derivative of N-ethylnorcantharimide
(3, R = Et). We used three methods to prepare synthetic
analogues of 3: epoxidation, an ene reaction involving
singlet oxygen, and bromination. Epoxidation of imide 10
with m-chloroperoxybenzoic acid at room temperature
gave an isomeric mixture of epoxides syn-4a and anti-4b
in a ratio of 4:1 (determined from the 1H NMR spectrum
of the crude reaction product mixture) (Scheme 2). The
isomeric mixture of epoxides 4a and 4b was separated by
column chromatography, and the structures of 4a and 4b
Norcantharidin, the demethylated analogue of canthari-
din, also shows anticancer activity and stimulates bone
marrow, while showing no nephrotoxicity. Derivatives of
modified synthetic norcantharidin (2) and N-substituted
norcantharimides (3) are potentially useful as anticancer
SYNTHESIS 2011, No. 7, pp 1079–1084
x
x
.
x
x
.2
0
1
1
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1258466; Art ID: Z52110SS
© Georg Thieme Verlag Stuttgart · New York

1080
A. Tan et al.
PAPER
O
O
O
O
4-positions. Acid-catalyzed ring cleavage of syn-epoxide
4a, followed by acetylation, gave imide 6a in 70% yield
xylene
reflux
SO2
+
1
O
(Scheme 3). The structure of 6a was assigned by H and
13C NMR spectroscopy. There are two distinct AB-sys-
O
8
1
7
tems in the H NMR spectrum, corresponding to six
9
NH2Et
toluene
Et3N
methylene protons. The methyl protons resonate at d = 2.0
and 1.9 ppm. The structure was confirmed by double res-
onance experiments and by the presence of 14 lines in the
13C NMR.
reflux
O
NEt
O
O
AcO
AcO
H+/H2O
AcCl
10
O
NEt
O
NEt
Scheme 1
O
O
4a
6a
O
Scheme 3
NEt
O
O
To synthesize other derivative of 3, imide 10 was subject-
ed to a singlet oxygen ene reaction.11 Tetraphenylporphy-
rin-sensitized photooxygenation of 10 in dichloromethane
at room temperature gave two isomeric products anti-5a
and syn-5b in a ratio of 5.25:1 (determined by H NMR
spectroscopy of the crude product) (Scheme 4).
O
O
4a 80%
4b 20%
MCPBA
NEt
CH2Cl2
r.t.
O
1
10
NEt
O
O
O
O
O
Scheme 2
1O2
NEt
+
NEt
NEt
CH2Cl2–hexane
r.t.
HOO
HOO
O
O
O
10
5a (anti) 84%
5b (syn) 16%
Scheme 4
Compound anti-5a was isolated by fractional crystalliza-
tion from the mixture and its structure was assigned by 1H
and 13C NMR spectroscopy. The configuration of the hy-
droperoxide was confirmed by single-crystal analysis
(Figure 4).
Figure 3 Molecular structure of compound 4a
were assigned by 1H and 13C NMR spectrocopy and con-
firmed by single-crystal X-ray analysis (Figure 3).
The two faces of the double bond in 10 are not symmetric,
and syn- or anti- product may form with respect to the im-
ide ring. Attack on the double bond was expected to occur
predominantly from the more-open face opposite the imi-
de ring. However, contrary to expectations, the syn-iso-
mer was obtained as the major product of the reaction,
showing that electronic effects dominate steric effects.
Similar results, in which electronic effects overshadow
steric effects, have been observed in the stereoselective
oxidation of 5,6-dimethyl-2-phenyl-3a,4,7,7a-tetrahydro-
1H-isoindole-1,3(2H)-diones by m-chloroperoxybenzoic
acid.10 The predominance of the syn-isomer over the anti-
isomer can be explained in terms of the dipole–dipole in-
teraction between the peracid and imide moieties of 10. In
the epoxy derivative 4, the epoxy oxygen atom is attached
to the carbon atoms in the 2- and 3-positions unlike nor-
cantharimide (3, R = H), where it is attached at the 1- and
Figure 4 Molecular structure of hydroperoxide 5a
The syn-5b isomer could not be purified by crystallization
or by the usual chromatographic techniques, so its struc-
ture was elucidated by comparison of the 1H NMR spec-
trum of the isomeric anti-5a with that of the isomeric
mixture. The predominant formation of anti-hydroperox-
ide 5a cannot be explained solely in terms of steric effects
of the imide group. The oxygen molecule is nonpolar and
cannot therefore interact with the amide or carbonyl
group, whereas oxidation by m-chloroperoxybenzoic acid
Synthesis 2011, No. 7, 1079–1084 © Thieme Stuttgart · New York

PAPER
Cantharimide Analogues
1081
proceeds predominantly in favor of the syn-product 4a as NMR spectrum of compound 15, there are three distinct
a result of a dipole–dipole interaction.
AB-systems corresponding to two olefinic protons, two
methine (CH) protons, and two methylene protons. These
protons resonated at d = 6.88–6.19, 3.75–3.54, and 3.05–
2.69 ppm respectively. The CH2 protons of ethyl groups
appears as quartet at 3.56 ppm and methyl protons reso-
nates at 1.15 ppm. The 13C NMR spectrum was also con-
sistent with structure 15.
When the ethyl group in 10 was replaced by a phenyl
group, the epoxidation and ene reactions of compound 11
proceeded in a similar manner to those of compound 10
(Scheme 5).
O
Imide 10 was smoothly brominated in dichloromethane to
give the expected trans-dibromo compound 6b in high
yield (Scheme 7). Attempts to synthesize the correspond-
ing diene by elimination of hydrogen bromide from dibro-
mide 6b were unsuccessful; treatment of 6b with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) resulted in con-
version of the dibromide into the aromatic phthalimide de-
rivative 16,13 instead of the expected diene (Scheme 7).
syn-12a (80%)
O
O
NPh
O
O
MCPBA
NPh
+
CH2Cl2
r.t.
O
O
anti-12b (20%)
anti-13a (85%)
11
NPh
O
O
1
The structure of 16 was assigned by H and 13C NMR
spectroscopy.
NPh
O
O
Br
Br
O
HOO
HOO
LiAlH4
Br2
O
O
NEt
NEt
NEt
1O2
CH2Cl2
THF
reflux
+
NPh
O
O
CH2Cl2–
hexane
r.t.
17
6b
10
O
syn-13b (15%)
NPh
11
DBU
CH2Cl2
O
O
Scheme 5
NEt
The peroxide group in anti-5a was selectively reduced by
using dimethyl sulfide as a reducing agent,12 to give the
desired hydroxy derivative 14 (Scheme 6). The structure
of 14 was assigned by 1H and 13C NMR spectroscopy. In
the 1H NMR spectrum of compound 14, there are two dis-
tinct AB-systems corresponding to two olefinic protons
and two methylene protons. Although the hydroperoxide
proton of anti-5a appeared at d = 8.59 ppm, the hydroxy
proton of 14 moved to d = 4.12 ppm and appeared as a
broad singlet after cleavage of the hydroperoxide bond.
O
16
Scheme 7
We decided to carry out a reduction reaction to prepare
derivatives from 6b. Surprisingly, reduction of dibromide
6b with lithium aluminum hydride gave the hexahydroin-
dole 17 exclusively.14 The formation of compound 17 can
be explained by reductive elimination of bromine atoms.
The hydride reacts in a similar manner to zinc metal atoms
in the dibromide elimination reaction. To the best of our
knowledge, this is a unique example of a reaction that
gives a pyrrolidine by lithium aluminum hydride induced
elimination and reduction. The inversion of the ethyl
group in 17 was deduced from the duplication of six over-
lapping lines in the 13C NMR spectrum. Product 17 was
also obtained directly by reduction of imide 10 with lithi-
um aluminum hydride.
Treatment of compound 14 with pyridinium dichromate
gave ketone 15 as the sole product. The structure of 15
was assigned by 1H and 13C NMR spectroscopy. In the 1H
O
NEt
O
NEt
Me2S
CH2Cl2
HOO
HO
O
O
5a
14
PCC
To summarize, we have developed novel and efficient
routes for the synthesis of new classes of norcantharimide
analogues 4, 5, 6, 12, and 13, starting from readily avail-
able 3-sulfolene. The methods should be applicable to the
synthesis of a large number of new norcantharimide ana-
logues. Furthermore, the difference in the distributions of
the products obtained from 10 and 11 by oxidation with
m-chloroperoxybenzoic acid and by photooxygenation
was rationalized in terms of dipole–dipole interactions
and steric effects that direct the stereochemical outcome
CH2Cl2
O
NEt
O
O
15
Scheme 6
Synthesis 2011, No. 7, 1079–1084 © Thieme Stuttgart · New York

1082
A. Tan et al.
PAPER
(first isomer, 15:85; second isomer, 40:60)] then crystallized
(CH2Cl2–hexanes).
of the reaction. Note that the synthesis the cantharimide
derivatives is versatile and has further applications. We
obtained a key compound for the preparation of pyrro-
lidines that may be useful in preparing biologically active
compounds. We are currently working on extending this
method to permit studies on biological properties of
cantharimide analogues.
4a
Colorless crystals; mp 75–76 °C.
1H NMR (400 MHz, CDCl3): d = 3.45 (qd, J = 7.1, 1.0 Hz, 2 H),
3.19 (m, 2 H), 2.85 (m, 2 H), 2.54 (m, 2 H), 1.83 (m, 2 H), 1.07 (td,
J = 7.1, 1.3 Hz, 3 H).
13C NMR (100 MHz, CHCl3): d = 179.6, 49.3, 35.4, 33.7, 23.2, 13.1.
Column chromatography: silica gel 60 (70–230 mesh) and neutral
Al2O3 (III activated) were used. Solvents were purified and dried by
standard procedures before use. Melting points were determined on
a Büchi-539 apparatus and are uncorrected. 1H and 13C NMR spec-
tra were recorded on a Varian 400 MHz spectrometer. Elemental
analyses were carried out with a Leco CHNS-932 instrument.
4b
Colorless crystals; mp 79–80 °C.
1H NMR (400 MHz, CDCl3): d = 3.53 (q, J = 7.3 Hz, 2 H), 3.13 (m,
2 H), 2.71 (m, 3 H), 2.68 (m, 1 H), 2.13 (dd, J = 15, 2 Hz, 2 H), 1.15
(t, J = 7 Hz, 3 H).
13C NMR (100 MHz, CHCl3): d = 180.5, 50.9, 35.6, 34.3, 22.6,
3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione (9)
12.5.
Maleic anhydride (6.23 g, 63.3 mmol) was added over 5 h to a mag-
netically stirred soln of 3-sulfolene (7; 10.0 g, 84.6 mmol) in xylene
(10 mL) at 150 °C. The mixture was then cooled to r.t. The solvents
were removed by rotary evaporation the product was crystallized
(CH2Cl2–hexane) as white crystals; yield: 6.85 g (93–97%); mp 99–
102 °C.
Anal. Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.18. Found: C,
61.91; H, 7.16; N, 6.81.
(syn)-4-Phenyltetrahydro-1aH-oxireno[f]isoindole-3,5(2H,4H)-
dione (12a) and (anti)-4-Phenyltetrahydro-1aH-oxireno[f]isoin-
dole-3,5(2H,4H)-dione (12b)
2-Ethyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (10)
EtNH2 (18 mmol, 1 equiv) was added to a magnetically stirred soln
of dione 9 (18 mmol, 1 equiv) and Et3N (1.5 mL) in toluene (15
mL), and the mixture was refluxed for 36 h. The soln was cooled,
diluted with EtOAc (45 mL), washed with sat. aq NaHCO3 (25 mL),
dried (MgSO4), filtered, and concentrated under reduced pressure.
The resulting crude product was recrystallized (EtOAc–hexanes) to
give colorless crystals; yield: 73%; mp 43–45 °C.
1H NMR (400 MHz, CDCl3): d = 5.87 (m, 2 H), 3.50 (q, J = 7 Hz,
2 H), 3.05 (m, 2 H), 2.60 (dm, J = 16 Hz, A part of AB system, 2
H), 2.20 (dm, J = 16 Hz, B part of AB system, 2 H), 1.00 (t, J = 7
Hz, 3 H).
These were prepared in a similar manner to 4a and 4b described
above.
12a
Colorless crystals; mp 217–218 °C.
1H NMR (400 MHz, CDCl3): d = 7.37 (m, 5 H), 3.25 (m, 2 H), 2.95
(dm, J = 4.3 Hz, 2 H), 2.82 (dm, J = 15.4 Hz, A part of AB system,
2 H), 2.25 (ddd, J = 15.4, 5.1, 2.4 Hz, B part of AB system, 2 H).
13C NMR (100 MHz, CHCl3): d = 179.9, 132.9, 129.4, 128.8, 127.0,
51.0, 35.9, 23.0.
12b
13C NMR (100 MHz, CHCl3): d = 180.0, 127.9, 39.3, 34.1, 23.7,
13.2.
Colorless crystals; mp 209–210 °C.
1H NMR (400 MHz, CDCl3): d = 7.37 (m, 5 H), 3.24 (m, 2 H), 2.95
(m, 2 H), 2.82 (dm, J = 15.3 Hz, A part of AB system, 2 H), 2.25
(dm, J = 15.3 Hz, A part of AB system, 2 H).
Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,
66.02; H, 7.31; N, 7.73.
13C NMR (100 MHz, CHCl3): d = 179.9, 132.8, 129.4, 128.8, 126.9,
2-Phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (11)
Prepared from 9 (18 mmol, 1 equiv) and PhNH2 (18 mmol, 1 equiv)
by using the above procedure for 10. Colorless crystals; yield: 78%;
mp 114–115 °C.
51.0, 35.9, 23.0.
Singlet Oxygen Ene Reactions of 10 and 11
Tetraphenylporphyrin (20 mg) was added to a stirred soln of dione
10 or 11 (5.5 mmol, 1 equiv) in CH2Cl2 (150 mL). The mixture was
irradiated with a tungsten–halogen projection lamp (500 W) while
oxygen was passed through the soln and the mixture was stirred at
r.t. The solvent was then evaporated at 30 °C under reduced pres-
sure. The major products (5a or 13a) were separated by fractional
crystallization in CH2Cl2–hexanes.
1H NMR (400 MHz, CDCl3): d = 7.31 (m, 5 H), 5.98 (m, 2 H), 3.26
(m, 2 H), 2.72 (dm, J = 15.5 Hz, A part of AB system; 2 H), 2.31
(dm, J = 15.5 Hz, B part of AB system, 2 H).
13C NMR (100 MHz, CHCl3): d = 179.4, 132.3, 129.0, 128.8, 128.1,
126.7, 39.5, 24.0.
Anal. Calcd for C10H13NO2: C, 73.99, H, 5.77; N, 6.16. Found: C,
73.99; H, 5.77; N, 6.16.
(anti)-2-Ethyl-5-hydroperoxy-3a,4,5,7a-tetrahydro-1H-isoin-
dole-1,3(2H)-dione (5a)
Mp 101–102 °C.
1H NMR (400 MHz, CDCl3): d = 8.3 (s, 1 H, OOH), 6.1 (m, 2 H),
4.46 (m, 1 H), 3.53 (q, J = 7 Hz, 2 H), 3.46 (dm, J = 8 Hz, A part of
AB system, 1 H), 3.23 (q, J = 8 Hz, B part of AB system, 1 H), 2.18
(t, J = 6 Hz, 2 H), 1.14 (t, J = 7 Hz, 3 H).
(syn)-4-Ethyltetrahydro-1aH-oxireno[f]isoindole-3,5(2H,4H)-
dione (4a) and (anti)-4-Ethyltetrahydro-1aH-oxireno[f]isoin-
dole-3,5(2H,4H)-dione (4b)
The imide 10 (13.3 mmol, 1 equiv), 70–80% MCPBA (20 mmol,
1.5 equiv), and excess NaHCO3 were magnetically stirred in
CH2Cl2 (120 mL) for 6 h. The resulting slurry was transferred to a
separatory funnel and treated with 15% aq Na2S2O3 (50 mL) to
eliminate unreacted peracid. The soln was then washed successively
with 10% aq NaHCO3 (50 mL) and brine, dried (MgSO4), and con-
centrated to give a crude product; yield: 91%. The isomeric prod-
ucts were separated by column chromatography [EtOAc–hexane
13C NMR (100 MHz, CDCl3): d = 178.7, 176.2, 129.1, 126.2, 75.5,
41.3, 36.3, 34.0, 25.5, 13.1.
Anal. Calcd for C10H13NO4: C, 56.86; H, 6.20; N, 6.63. Found: C,
56.92; H, 6.38; N, 6.61.
Synthesis 2011, No. 7, 1079–1084 © Thieme Stuttgart · New York

PAPER
Cantharimide Analogues
1083
(anti)-2-Phenyl-5-hydroperoxy-3a,4,5,7a-tetrahydro-1H-isoin-
dole-1,3(2H)-dione (13a)
13C NMR (100 MHz, CDCl3): d = 178.6, 178.1, 169.7 (2C), 69.4,
69.0, 36.9, 36.3, 33.8, 25.8, 24.4, 21.1, 21.0, 13.1.
1H NMR (400 MHz, CDCl3): d = 8.19 (s, 1 H, OOH), 7.47 (m, 5 H),
6.17 (m, 2 H), 6.29 (m, 1 H), 3.66 (dm, J = 8 Hz, A part of AB sys-
tem, 1 H), 3.23 (q, J = 8 Hz, B part of AB system, 1 H), 2.29 (m, 2
H).
Anal. Calcd for C14H19NO6: C, 56.56; H, 6.44; N, 4.71. Found: C,
56.65; H, 6.52; N, 4.82.
5,6-Dibromo-2-ethylhexahydro-1H-isoindole-1,3(2H)-dione
(6b)
13C NMR (100 MHz, CDCl3): d = 177.8, 175.3, 131.8, 129.4, 129.3,
128.9, 126.5, 126.1, 75.4, 41.5, 36.5, 25.6.
A soln of Br2 (0.89 g, 5.6 mmol) in CH2Cl2 (5 mL) was added drop-
wise over 10 min to a magnetically stirred soln of epoxide 10 (1.0
g, 5.6 mmol) in anhyd CH2Cl2 (30 mL) at 0 °C. The mixture was
stirred for an additional 30 min at r.t. Evaporation of the solvent and
crystallization of the residue from CH2Cl2–hexanes at 0 °C gave
white crystals; yield: 1.86 g (98%); mp 133–134 °C.
1H NMR (400 MHz, CDCl3): d = 4.49 (m, 2 H), 3.53 (q, J = 7.1 Hz,
2 H), 3.13 (q, J = 10.3 Hz, 1 H), 2.86 (dt, J = 8.1, 2.6 Hz, 1 H), 2.78
(ddd, A part of AB system, J = 15.8, 8.1, 4.0 Hz, 1 H), 2.65 (dt, B
part of AB system, J = 15.8, 2.6 Hz, 1 H), 2.48 (ddd, A part of AB
system, J = 15.4, 10.3, 2.9 Hz, 1 H) 2.40 (dddd, B part of AB sys-
tem, J = 15.4, 7.6, 4.0, 1.1 Hz, 1 H), 1.12 (t, J = 7.1 Hz, 3 H).
(3aS*,5S*,7aR*)-2-Ethyl-5-hydroxy-3a,4,5,7a-tetrahydro-1H-
isoindole-1,3(2H)-dione (14)
A soln of peroxide 5a (300 mg, 1.42 mmol) in CH2Cl2 (25 mL) was
added to magnetically stirred slurry of Me2S (176 mg, 2.84 mmol)
in CH2Cl2 (25 mL) at r.t. After the addition was complete (~10 min),
the mixture was stirred for 6 h. The solvent was then removed by
rotary evaporation, and the residue was extracted with CH2Cl2
(3 × 30 mL). The extracts were dried (Na2SO4) and the soln was
concentrated to give a residue that was crystallized (CH2Cl2–hex-
anes) to give colorless crystals; yield: 200 mg (72%); mp 93–94 °C.
1H NMR (400 MHz, CDCl3): d = 6.00 (dtd, J = 10.1, 2.2, 0.7 Hz, A
part of AB system, 1 H), 5.85 (ddd, J = 10.1, 4.2, 1.8 Hz, B part of
AB system, 1 H), 4.11 (m, 1 H, OH), 3.49 (q, J = 7.3 Hz, 2 H), 3.44
(tt, J = 6.4, 1.8 Hz, 1 H), 3.18 (dt, J = 5.5, 1.1 Hz, 1 H), 2.43 (dtd,
A part of AB system J = 13, 4.9, 0.7 Hz, 1 H), 1.73 (ddd, B part of
AB system J = 13, 9.2, 6.2 Hz, 1 H), 1.09 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.5, 177.4, 49.3, 48.6, 36.3,
35.9, 33.9, 29.0, 26.5, 12.9.
Anal. Calcd for C10H13Br2NO2: C, 35.43; H, 3.86; N, 4.13. Found:
C, 35.40; H, 3.77; N, 4.11.
2-Ethyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole (17)
13C NMR (100 MHz, CDCl3): d = 178.8, 176.8, 135.2, 122.9, 62.6,
41.1, 37.0, 34.0, 30.2, 13.1.
A soln of dibromide 6b (1 g, 2.9 mmol) in THF (20 mL) was added
over 0.5 h to a magnetically stirred slurry of LiAlH4 (0.67 g, 17.7
mmol) in anhyd THF (50 mL) under N2 at 0 °C, and the mixture was
then stirred at 60 °C for 4 h. The mixture was cooled to r.t., EtOAc
(5 mL) was added, and the mixture was washed with sat. aq NH4Cl
(10 mL). The solid was filtered off and extracted with EtOAc (3 ×
20 mL). The combined organic phase was washed with sat. aq
NH4Cl (20 mL) then dried (Na2SO4) and concentrated to give the
crude amine that was purified by column chromatography [Al2O3
(20 g), EtOAc–hexanes (20:80)] to give a pale-yellow liquid; yield:
0.3 g (68%).
1H NMR (400 MHz, CDCl3): d = 5.42 (m, 2 H), 2.56 (m, 2 H), 2.10
(m, 2 H), 2.02 (m, 2 H), 1.79 (m, 4 H), 1.52 (m, 2 H), 0.72 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 127.46 (127.37), 60.49 (60.42),
50.54 (50.46), 35.51 (35.46), 26.35 (26.31), 13.89 (13.83).
Anal. Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.18. Found: C,
61.53; H, 6.78; N, 7.15.
(3aS*,7aR*)-2-Ethyl-3a,7a-dihydro-1H-isoindole-1,3,5(2H,4H)-
trione (15)
Hydroxy derivative 14 (103 mmol, 1 equiv) at 0 °C was added to a
mixture of PCC (228 mmol, 2 equiv) and powdered MS (3 Å, half
the weight of PCC) in anhyd CH2Cl2 (25 mL). The mixture was
stirred 4 h at r.t., then CH2Cl2 was evaporated and to the residue was
slurried in Et2O (50 mL). The slurry was stirred and filtered through
a pad of Celite. The residue was washed with Et2O (3 or 4 × 25 mL)
and filtered. The filtrate was concentrated to give virtually pure ke-
tone; yield: 73 mg (72%).
1H NMR (400 MHz, CDCl3): d = 6.87 (dd, A part of AB system,
J = 10.3, 4.4 Hz, 1 H), 6.18 (dd, B part of AB system, J = 10.3, 2.6
Hz, 1 H), 3.75 (m, A part of AB system, 1 H), 3.56 (q, J = 7.3 Hz,
2 H), 3.44 (m, B part of AB system, 1 H), 3.05 (dd, A part of AB
system, J = 17.6, 3.3 Hz, 1 H), 2.69 (dd, B part of AB system,
J = 17.6, 9.2 Hz, 1 H), 1.15 (t, J = 7.3 Hz, 3 H)
Anal. Calcd for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C,
68.21; H, 5.21; N, 7.95.
2-Ethyl-1H-isoindole-1,3(2H)-dione (16)
A solution of DBU (0.24 g, 1.62 mmol) in CH2Cl2 (10 mL) was add-
ed to a soln of dibromide 6b (0.25 g, 0.73 mmol) in CH2Cl2 (10 mL)
at r.t., and the mixture was stirred for 12 h at r.t. The solid was fil-
tered off and the organic phase was poured into H2O (20 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic phase
was washed with sat. aq NH4Cl (20 mL), dried (Na2SO4), and evap-
orated under reduced pressure to give a colorless liquid;14 yield:
0.09 g (70%).
1H NMR (400 MHz, CDCl3): d = 7.74 (m, 4 H), 3.72 (q, J = 7.1 Hz,
2 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.4, 134.0, 132.5, 123.3, 33.1,
14.1.
13C NMR (100 MHz, CDCl3): d = 193.6, 177.0 (2C), 141.9, 131.6,
41.8, 37.7, 34.5, 33.5, 13.0.
2-Ethyl-1,3-dioxooctahydro-1H-isoindole-5,6-diyl Diacetate
(6a)
A catalytic amount of concd H2SO4 was added to stirred soln of ep-
oxide 4a (200 mg, 0.77 mmol) in Ac2O (2 mL), and the mixture was
stirred for 3 h at r.t. The mixture was cooled to 0 °C, H2O (20 mL)
was added, and the mixture stirred for 1 h. The mixture was extract-
ed with Et2O (3 × 50 mL), and the combined organic extracts were
washed with sat. aq NaHCO3 (15 mL) and H2O (15 mL), then dried
(MgSO4). Removal of the solvent under reduced pressure gave a
colorless liquid; yield: 118 mg (70%).
1H NMR (400 MHz, CDCl3): d = 4.91 (m, 2 H), 3.53 (q, J = 7.1 Hz,
2 H), 2.99 (m, A part of AB system, 1 H), 2.91 (m, B part of AB sys-
tem, 1 H), 2.15–2.06 (m, 4 H), 2.05 (s, 3 H), 1.96 (s, 3 H), 1.14 (t,
J = 7.1 Hz, 3 H).
Anal. Calcd for C10H9NO2: C, 68.56; H, 5.18; N, 8.0. Found: C,
68.21; H, 5.21; N, 7.95.
Crystallography
Crystals of 4a and 4b were obtained from CH2Cl2–hexane.
Crystal data for 4a: C10H13NO3, crystal system, space group: triclin-
ic, P1 (no. 2); unit cell dimensions: a = 5.0310(2), b = 7.7379(3),
Synthesis 2011, No. 7, 1079–1084 © Thieme Stuttgart · New York

1084
A. Tan et al.
PAPER
c = 12.9939(4) Å, a = 83.90(2), b = 82.63(3), g = 77.65(2)°; vol-
ume: 488.46(9) Å3; Z = 2; calculated density: 1.33 g/cm3; absorp-
tion coefficient: 1.33 mm–1; F(000): 208; q-range for data collection
2.7 –26.4°; refinement method: full-matrix least-square on F2; data/
parameters: 1992/128; goodness-of-fit on F2: 1.053; final R indices
[I > 2s(I)]: R1 = 0.051, wR2 = 0.130; R indices (all data):
R1 = 0.073, wR2 = 0.144.
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T. W. T.; Yu, M. W. Y.; Tanga, J. C. O.; Chan, A. S. C.
Bioorg. Med. Chem. Lett. 2007, 17, 1155.
Crystal data for 5a: C10H13NO, crystal system, space group: mono-
clinic, P21/n; unit cell dimensions: a = 7.5245(2), b = 8.8253(3),
c = 15.8110(6) Å, a = 90, b = 103.16(3), g = 90°; volume:
1022.35(5) Å3; Z = 4; calculated density: 1.37 g/cm3; absorption
coefficient: 0.107 mm–1; F(000): 448; q-range for data collection
2.7–26.5°; refinement method: full-matrix least-square on F2; data/
parameters: 2097/138; goodness-of-fit on F2: 1.046; final R indices
[I > 2s(I)]: R1 = 0.063, wR2 = 0.144; R indices (all data):
R1 = 0.104, wR2 = 0.167; largest diff. peak and hole: 0.180 and -
0.192 e Å–3; largest diff. peak and hole: 0.136 and –0.142 e Å–3
Crystallographic data, excluding structure factors, for compounds
4a and 5a have been deposited with the Cambridge Crystallograph-
ic Data Centre as supplementary publication numbers CCDC
789887 and 789999, respectively. Copies can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK or e-mail: deposit@ccdc. cam.ac.uk.
(9) Cope, A. C.; Herrick, E. C. Org. Synth., Coll. Vol. IV; John
Wiley & Sons: London, 1963, 890.
(10) Kishikawa, K.; Naruse, M.; Kohmoto, S.; Yamamoto, M.;
Yamaguchi, K. J. Chem. Soc., Perkin Trans. 1 2001, 462.
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(b) Kara, Y.; Balci, M. Tetrahedron Lett. 1994, 35, 3349.
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8, 1791. (b) Horasan Kishali, N.; Kara, Y. Tetrahedron
2008, 64, 7956. (c) Amels, P.; Elias, H.; Wannowius, K.-J.
J. Chem. Soc., Faraday Trans. 1997, 93, 2537.
Acknowledgment
The authors are indebted to the Department of Chemistry and to the
Atatürk University for financial support and for purchasing the 400-
MHz NMR. We also thank Dr Fraser Fleming, Dr Hasan Seçen, and
Dr Ramazan Altundas for helpful discussions.
(13) (a) Wanga, J.; Yanga, F.; Shena, J.; Wanga, W.; Wang, L.
Lett. Org. Chem. 2008, 5, 26. (b) Liang, Z.-P.; Li, J. Acta
Crystallogr. 2006, 62, 5439.
References
(14) (a) Schmidt, R. A. Arch. Biochem. Biophys. 1959, 83, 233.
(1) Author to whom inquires concerning the X-ray structure
should be directed. E-mail: ertan@atauni.edu.tr.
(b) Rolf, H.; Erich, L. Chem. Ber. 1960, 93, 65.
Synthesis 2011, No. 7, 1079–1084 © Thieme Stuttgart · New York