Synthesis of new hexahydro-1H-isoindole-1,3(2H)-dione derivatives from 2-ethyl / phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3-(2H)-dione

Abstract

A new and appropriate synthesis for hexahydro-1H-isoindole-1,3(2H)-dione derivatives has been developed
starting from 3-sulfolene. The epoxidation of 2-ethyl/phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3-(2H)-dione and then the opening of the epoxide with nucleophiles gave hexahydro-1H-isoindole-1,3(2H)-dione derivatives. Amino and triazole derivatives of hexahydro-1H-isoindole-1,3(2H)-dione were synthesized from the formed product by the opening reaction of the epoxide with sodium azide. Hydroxyl analogues were obtained from cis-hydroxylation of 2-ethyl/phenyl-3a,4,7,7atetrahydro-1H-isoindole-1,3-(2H)-dione. The hydroxyl groups were converted to acetate.

Full text

Turk J Chem
(2016) 40: 830 – 840
c
⃝T¨
UB˙
ITAK
doi:10.3906/kim-1511-66
Turkish Journal of Chemistry
http://journals.tubitak.gov.tr/chem/
Researc h Article
Synthesis of new hexahydro-1H-isoindole-1,3(2H)-dione derivatives from
2-ethyl/phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3-(2H)-dione
Ay¸se TAN1, Birg¨ul KOC¸ 2, Nurhan K˙
ISHALI2,∗, Ertan S¸ AH˙
IN2,∗∗, Yunus KARA2,∗
1Department of Food Business, Vocational School of Technical Sciences, Mu¸s Alparslan University, Mu¸s, Turkey
2Department of Chemistry, Faculty of Sciences, Atat¨urk University, Erzurum, Turkey
Received: 23.11.2015 •Accepted/Published Online: 20.04.2016 •Final Version: 02.11.2016
Abstract: A new and appropriate synthesis for hexahydro-1H-isoindole-1,3(2H)-dione derivatives has been developed
starting from 3-sulfolene. The epoxidation of 2-ethyl/phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3-(2H)-dione and then
the opening of the epoxide with nucleophiles gave hexahydro-1H-isoindole-1,3(2H)-dione derivatives. Amino and triazole
derivatives of hexahydro-1H-isoindole-1,3(2H)-dione were synthesized from the formed product by the opening reaction
of the epoxide with sodium azide. Hydroxyl analogues were obtained from cis-hydroxylation of 2-ethyl/phenyl-3a,4,7,7a-
tetrahydro-1H-isoindole-1,3-(2H)-dione. The hydroxyl groups were converted to acetate.
Key words: Norcantharimide, cis-hydroxylation, epoxidation, ring opening epoxide, reduction of azide
1. Introduction
Norcantharimides, which are derivatives of cantharidine (1), are composed of a tricyclic imide skeleton. Can-
tharidine (1) and norcantharimide (3) derivatives are important potential anticancer agents.1−3The effect of
norcantharimide (3) derivatives was observed in a large number of cancer types.4For this reason, in recent
years much effort has been devoted to the synthesis of N-derivatives of norcantharimide (3).4Norcantharimide
(3) derivatives can be obtained by attaching different functional groups to the imide nitrogen or cyclohexane
ring.5,6Some of the synthesized derivatives have been investigated for their effects on different carcinomas. For
example, McCluskey et al. investigated the anticancer activity of norcantharimide derivatives of different groups
attached to the imide nitrogen.5,6Lin et al. have also studied the N-substituted cantharimides (aliphatic, aryl,
and pyridyl groups) in vitro against HepG2 and HL-60 cells.7,8Chan and Tang reported the synthesis and cy-
totoxicity of some cantharimide derivatives.9More recently, we have reported the first ever successful synthesis
of a new type of norcantharimide derivative10,11 containing a substituted group on the cyclohexane ring. We
also explored the fluorescence properties of isoindole derivatives of norcantharimide.12
Hexahydro-1H-isoindole-1,3(2H)-dione’s structure was similar to that of norcantharimide. Therefore, in
this study, our objective was to synthesize different norcantharimide derivatives via functionalization of the
cyclohexane ring. Two methods, based on epoxidation and cis−hydroxylation, were used for the preparation
of synthetic derivatives of norcantharimide (3).
∗Correspondence: nhorasan@atauni.edu.tr, yukara@atauni.edu.tr
∗∗ To whom inquiries concerning the X-ray structure should be directed.
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2. Results and discussion
The key compound in this study was 3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione, which was prepared via
cycloaddition of 3-sulfolene and maleic anhydride. The reaction of the primary amine with 3a,4,7,7a-tetrahydro-
isobenzofuran-1,3-dione in the presence of a toluene and triethylamine mixture gave the corresponding hexahydro-
1H-isoindole-1,3(2H)-dione 4in 80% yield (Figure 2).13
Figure 1. Structure of cantharidine (1), norcantharidine (2), and norcantharimide (3).
Figure 2. 2-Alkyl/aryl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3-(2H)-dione (4).
In this research, we initially investigated the hydroxylation reaction of hexahydro-1H-isoindole-1,3(2H)-
dione 4.4KMnO4was used for the synthesis of cis-diol. Therefore, compounds 4a and 4b were treated with
KMnO4at room temperature, followed by acetylation to give 5a in 56% and 5b 60% yield (Scheme 1). The
1H NMR spectrum analysis of the crude product revealed the formation of a single isomer. As seen, the two
faces of the double bond in 4(a, b) are not symmetrical and so the double bond could be attacked from both
sides. NMR experiments showed that the anti-isomer is formed in this reaction.
Scheme 1. Synthesis of cis-diacetate 5a and 5b.
The structure of the product formed in this reaction was determined by NMR spectrum analysis and it
was anti-isomer. Here, the formation of anti-isomers 5a and 5b may be explained by considering the steric
effects of the imide group. Therefore, KMnO 4approached compound 4a and 4b exclusively from the sterically
less crowded face of the molecule.
The hydroxylation of hexahydro-1H-isoindole-1,3(2H)-dione 4a with OsO4gave a very interesting sole
product. 1H and 13 C NMR spectroscopic data confirmed the hydroxylation of the double bond. In fact, we
supposed that the OsO 4would add to the double bond to give a cis−diol. However, 1H NMR spectrum analysis
showed no hydroxyl groups. In addition, two methyl peaks were observed in this spectrum. In addition, in the
DEPT spectrum of the molecule 6, 26.0 and 23.6 ppm signals of the methyl carbon and 107.5 ppm signal of the
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quaternary carbon were determined. In this case we assumed that ketal was formed in this reaction. This can
be explained by the fact that the resulting diols were converted to ketal, depending on the reaction conditions
(Scheme 2).
Scheme 2. Synthesis of ketal 6.
Further structure analysis of 6was achieved by single crystal analysis (Figures 3a and 3b). Furthermore,
the single crystal analysis of ketal 6showed that an anti-product formed with respect to the imide ring. Thus,
the X-ray of structure 6can inform us about the approach of OsO4. As in the KMnO4reaction, it approached
compound 4a exclusively from the sterically less crowded face of the molecule.
a) b)
Figure 3. a) ORTEP diagram of 6. Thermal ellipsoids are shown at 50% probability level. b) Stacking geometry of
the compound 6along the a-axis in the unit cell.
On the other hand, in our previous studies, the epoxidation of hexahydro-1H-isoindole-1,3(2H)-diones
4a and 4b was carried out with m-CPBA. A mixture of syn−and anti-isomers in a ratio of 4:1 was obtained
from this reaction.10,11 In addition, we also studied the epoxidation reaction of 4c with m-CPBA and achieved
similar results (Scheme 3). These results showed that the rates of product formation are not affected by the
groups attached to the nitrogen atom in the imide ring. In these reactions, the greater formation of syn-isomer
than of anti-isomer is explained by the dipole–dipole interaction between the RCO3H and the imide moieties
of the compounds by comparison with similar studies.10,14
Scheme 3. Synthesis of epoxide isomers.
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For further functionalization of the hexahydro-1H-isoindole-1,3(2H)-dione 4, the epoxide syn-7a was
converted to trans-diacetate derivatives 8, by using acetic anhydride in concentrated H2SO 4(Scheme 4). The
exact structure was determined by 1H and 13 C NMR experiments.10,11
Scheme 4. Synthesis of trans-diacetate 8.
The epoxide ring opening of syn −7a was achieved with MeOH in the presence of H2SO 4(Scheme 5),
followed by the acetylation of the hydroxyl group with acetyl chloride. The structure of 9was elucidated
according to the 1H NMR spectrum.
Scheme 5. Synthesis of trans-methoxy acetate 9.
Epoxide syn−7a was opened with NaN15
3in CH3OH to give azido-alcohol 10a (R = –Et), as a single
stereoisomer in a yield of 80%. The sharp signal belonged to the azide group at 2109 cm −1and the broad
hydroxyl group signal was observed to be 3454 cm−1in the IR spectrum.
The resulting azido-alcohol derivative was converted to corresponding acetate 11 (Scheme 6). Then
compound 11a was converted to its amine derivative 12 with Pd/C catalyzed hydrogenation in the presence of
CHCl3(Scheme 7). 1H NMR and IR spectrum data confirmed the reduction of the azide group. However, 1H
NMR and 13 C NMR spectral analyses showed no acetyl group. The 1H NMR and 13 C NMR spectra showed
that other reactions occurred in the course of reduction of the azide group. Thus the exact structure of 12 was
determined by X-ray crystal analysis (Figure 4).
Scheme 6. Synthesis of azido-alcohol 10 and azido-acetate 11.
Scheme 7. Synthesis of amine 12.
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a) b)
Figure 4. a) ORTEP diagram of 12. Thermal ellipsoids are shown at 50% probability level; b) H-bonding pattern
(dashed lines) along the a-axis in the unit cell. O 4–H · · · Cld = 3.159(5)˚
A, <(O4–H· · ·Cld ) = 160◦; O3–H· · · Clf =
3.243(5)˚
A, <(O2–H· · · O1f ) = 174◦; N2–H· · · Cl = 3.113(5)˚
A, <(N2–H···Cl) = 173◦; O 4–H ···O3= 2.728(7)˚
A,
<(O4–H···O3) = 141◦. (Symmetry code: δ=−1 + x, y, z;f=x, y, 1 + z) .
The acetyl group is removed during hydrogenation of 11a according to the crystal structure of 12, and
H-bonding was observed between the –OH group and the H2O molecule. Moreover, the amine group (–NH2)
resulting from reduction of the azide group transforms into its amine salt following hydrogenation (Figures 4a
and 4b).
Triazoles can act as the functional group and as attractive linker units, and are important in constructing
bioactive and functional molecules.16−19 Triazole and its derivatives have been synthesized by various groups
and used in different areas.20 1,2,3-Triazoles are commonly prepared by the Huisgen 1, 3-dipolar cycloaddition
of azides with alkynes. Therefore, as a part of our study we synthesized triazoles from azides 10a and 10b.
Compounds 10a and 10b were reacted with acetylene dicarboxylate cycloaddition in a solution of sodium
ascorbate and CuSO4.5H2O. Consequently, the norcantharimide derivatives 14a and 14b containing a triazole
skeleton were synthesized (Scheme 8). The structure of product 14a was elucidated by using NMR and X-ray
analysis (Figures 5a and 5b).
Scheme 8. The synthesis of triazole derivatives 14.
3. Conclusions
We have accomplished the synthesis of modified hexahydro-1H-isoindole-1,3(2H)-dione derivatives. These
derivatives comprise hydroxyl, acetate, amino, azido, and triazole groups. We think that while the dipole–
dipole interaction plays a role in m-CPBA oxidation, in the case of oxidation with OsO4or KMnO4the steric
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effects are directing the derivative outcome of the products. Thus, the configuration of the other carbon atoms,
C-5 and C-6, was controlled by epoxidation and cis-hydroxylation reactions. Application of this methodology
may provide opportunities for the synthesis of other hexahydro-1H-isoindole-1,3(2H)-dione derivatives.
a) b)
Figure 5. a) ORTEP diagram of compound 14a. Thermal ellipsoids are shown at 50% probability level; b) Dimeric
structure of 14a with O–H · · · N bonding O7–H · · · N2a= 2.828(2)˚
A, <(O7–H· · ·N2a) = 169◦. (Symmetry code:
α= 3 −x, 1−y , −z).
4. Experimental
4.1. General
Column chromatography (CC): silica-gel 60 (70–230 mesh) and AlOx(neutral Al 2O3, type-III). Solvents were
purified and dried by standard procedures before use. Mp: B¨uchi-539 cap. Melting point apparatus; uncorrected.
1H and 13 C NMR spectra: Varian spectrometer; δgin ppm, Jin Hz. Elemental analyses: Leco CHNS-932
instrument.
4.2. Synthesis of 5,6-diacetoxy-2-ethyl-1,3-dioxo-octahydro-isoindole (5a)
To a magnetically stirred acetone solution (25 mL) of 2-ethyl-3a,4,7,7a-tetrahydro-isoindole-1,3-dione (4a) (0.27
g, 1.5 mmol) was added a solution of KMnO4(0.48 g, 3.00 mmol) and MgSO4(0.36 g, 3.00 mmol) in water (25
mL) at –5 ◦C over 30 min. After the addition was complete, the reaction mixture was stirred for an additional
36 h at the given temperature and then filtered. The precipitate was washed several times with hot water. The
combined filtrates were concentrated to 20 mL by rotoevaporation. The aqueous solution was extracted with
ethyl acetate (3 ×30 mL) and the extracts were dried (Na2SO 4) . Evaporation of the solvent gave 2-ethyl-5,6-
dihydroxy-hexahydro-isoindole-1,3-dione. The crude product was dissolved in DCM (25 mL) and acetyl chloride
(1.2 g, 15 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The mixture was
cooled to 0 ◦C and then water (100 mL) and DCM (50 mL) were added. The organic phase was separated,
washed with saturated NaHCO3and water (2 ×50 mL), and dried (Na 2SO 4) . Removal of the solvent under
reduced pressure gave 6a,5,6-diacetoxy-2-ethyl-1,3-dioxo-octahydro-isoindole. Recrystallization of the residue
from EtOAc/hexane gave 0.25 g, 56%, pale yellow liquid. 1H NMR (400 MHz, CDCl3) : 5.05 (m, 2H), 3.54 (q,
2H, J= 7.1 Hz), 3.03 (m, 2H), 2.25 (m, 2H), 2.07 (s, 6H), 1.95 (m, 2H), 1.16 (t, 3H, J= 7.1 Hz). 13 C NMR
(100 MHz, CDCl3): 178.0, 170.2, 67.9, 37.8, 33.9, 25.7, 21.1, 13.2. Anal. calc. for. C 14 H19 NO 6, (297.30), C
56.56; H 6.44; N 4.71. Found: C 56.65; H 6.53; N 4.83.
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4.3. Synthesis of 5,6-diacetoxy-2-phenyl-1,3-dioxo-octahydro-isoindole (5b)
To a magnetically stirred acetone solution (25 mL) of 2-phenyl-3a,4,7,7a-tetrahydro-isoindole-1,3-dione (4b)
(0.27 g, 1.2 mmol) was added a solution of KMnO4(0.38 g, 2.4 mmol) and MgSO4(0.29 g, 2.4 mmol) in
water (25 mL) at –5 ◦C for 30 min. After the addition was complete, the reaction mixture was stirred for
additional 36 h at the given temperature and then filtered. The precipitate was washed several times with
hot water. The combined filtrates were concentrated to 20 mL by rotoevaporation. The aqueous solution was
extracted with ethyl acetate (3 ×30 mL), and the extracts were dried (Na 2SO 4) . Evaporation of the solvent
gave 2-phenyl-5,6-dihydroxy-hexahydro-isoindole-1,3-dione. The crude product was dissolved in DCM (25 mL).
Then acetyl chloride (1.2 g, 15 mmol) was added to the solution. The reaction mixture was stirred at room
temperature for 12 h. The mixture was cooled to 0 ◦C and then water (100 mL) and DCM (50 mL) were
added. The organic phase was separated, washed with saturated NaHCO3and water (2 ×50 mL), and dried
(Na2SO4). Removal of the solvent under reduced pressure gave 6a,5,6-diacetoxy-2-phenyl-1,3-dioxo-octahydro-
isoindole (5b). Recrystallization of the residue from EtOAc/hexane gave 0.25 g, 60%, colorless crystal, mp:
291–292 ◦C. 1H NMR (400 MHz, CDCl3): 7.50–7.26 (m, 5H), 5.09 (m, 2H), 3.24 (m, 2H), 2.33 (m, 2H), 2.12
(m, 2H), 2.09 (s, 3H), 2.08 (s, 3H). 13 C NMR (100 MHz, CDCl 3): 177.2, 170.2, 131.8, 129.5, 128.9, 126.4, 67.8,
38.2, 25.8, 21.2. Anal. calc. for. C18 H19 NO6, (297.30), C 62.60; H 5.55; N 4.06. Found: C 61.59; H 5.77; N
4.01.
4.4. Synthesis of 6-ethyl-2,2-dimethyl-hexahydro-[1,3]dioxolo[4,5-f]isoindole -5,7-dione (6)
To a stirred solution of syn-2-ethyl-3a,4,7,7a-tetrahydro-isoindole-1,3-dione (4a) (280 mg, 1.56 mmol) in
(CH3)2CO/H2O (2 mL, 1:1) were added NMO (189 mg, 1.87 mmol) and OsO4(4.0 mg, 0.016 mmol) at
0◦C. The resulting mixture was stirred vigorously under nitrogen at room temperature for 12 h. During the
stirring the reaction mixture became homogeneous. Sodium hydrogensulfide (0.2 g) and florisil (0.5 g) slurried in
water (2 mL) were added, the slurry was stirred for 10 min and the mixture was filtered through a pad of Celite
(0.5 g) in a 50-mL sintered-glass funnel. The Celite cake was washed with acetone (3 ×10 mL). The filtrate
was neutralized to pH 7 with H2SO 4. The organic layer was removed in vacuo. The resulting aqueous solution
was adjusted to pH 5 with sulfuric acid. Then the crude product was separated from N-methylmorpholine
hydrosulfate by extraction with ethyl acetate (4 ×20 mL). The combined ethyl acetate extracts were washed
with 5 mL of 25% NaCl solution and three times with water and dried (Na2SO 4) . Evaporation of the solvent
and crystallization of the residue from EtOAc/n-hexane gave 6-ethyl-2,2-dimethyl-hexahydro-[1,3]dioxolo[4,5-
f]isoindole-5,7-dione (6) (0.277 g, 70%). Colorless crystal, mp: 111–112 ◦C. 1H NMR (400 MHz, CDCl3): 4.33
(s, 2H), 3.40 (q, 2H, J= 7.3 Hz), 2.91 (m, 2H), 2.21 (dd, 2H, J= 14.5, 3.5 Hz), 1.32 (s, 3H), 1.2 (s, 3H), 1.02
(t, 3H, J= 7.3 Hz). 13 C NMR (100 MHz, CDCl 3) : 179.8, 71.3, 34.1, 33.5, 26.0, 26.0, 23.6, 13.1. Anal. calc.
for. (C13 H19 NO4), (253.13), C 61.64; H 7.56; N 5.53. Found: C 61.51; H 7.46; N 5.63. IR (KBr, cm −1) : 3453,
3054, 2982, 2938, 1772, 1705, 1444, 1405, 1378, 1352, 1296, 1260, 1228, 1164, 1137, 1076, 1040.
4.5. Synthesis of 5-acetoxy-2-ethyl-6-methoxy-1,3-dioxo-octahydro-isoindole (9)
To a solution of syn-4-ethyl-tetrahydro-1aH-oxireno[f]isoindole-3,5(2H,4H)-dione (7a) (2.2 mmol, 0.42 g) in
DCM (15 mL) were added methanol (5 mL) and a catalytic amount H2SO 4. The mixture was stirred at room
temperature and the reaction’s progress was monitored until it was completed. After 18 h, 2 g of NaHCO 3was
added to the reaction mixture, followed by stirring at 40 min. Then the mixture was filtered for removal of the
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solid phase. The solvent was removed under reduced pressure. The residue was solved with ethyl acetate (50
mL). The organic phase was washed with NaHCO3solution (50 mL) and water (3 ×50 mL), and then dried
over MgSO4, and ethyl acetate was removed under reduced pressure. The residue was purified by thin layer
chromatography (TLC) eluting with AcOEt/hexane (3:7) (Rf= 0.57) to give 9(390 mg, 67%) as a pale yellow
liquid. 1H NMR (400 MHz, CDCl34.95 (m, 1H), 3.49 (q, 2H, J= 7.1 Hz), 3.37 (m, 1H), 3.35 (s, 3H), 2.86
(m, 1H), 2.81 (m, 1H), 2.06 (m, 3H), 1.92 (s, 3H), 1.80 (m, 1H), 1.11 (t, 3H, J= 7.3 Hz). 13 C NMR (100
MHz, CDCl3): δ179.7, 178.7, 169.9, 75.5, 69.5, 57.1, 36.5, 36.1, 33.7, 25.2, 23.3, 21.3, 13.2. Anal. calc. for.
C13 H19 NO5(269.13): C 57.98; H 7.11; N 5.20. Found: C 57.70; H 7.23; N 4.83.
4.6. Synthesis of 5-acetoxy-6-azido-2-ethyl-1,3-dioxo-octahydro-isoindole (11a)
To a stirred solution of syn-4-ethyl-tetrahydro-1aH-oxireno-[f]isoindole-3,5(2H,4H)-dion (7a) (1.3 g, 6.65 mmol)
in 20 mL of methyl alcohol was added a solution of NH4Cl (0.72 g, 13.2 mmol) and NaN 3(1.73 g, 26.6 mmol)
in water (10 mL) dropwise at 0 ◦C over 15 min. The mixture was stirred at 90 ◦C for 26 h. After the filtration
of the reaction mixture, the solvent was removed. The reaction mixture was cooled to room temperature and
methanol was evaporated. Then H 2O (10 mL) and ether (60 mL) were added. The organic layer was separated
and washed with H2O (3 ×50 mL). The organic layer was dried over Na2SO4and ether was evaporated.
Removal of the solvent under reduced pressure gave azido-alcohol derivative isoindoline (5-azido-6-hydoxy-2-
ethyl-1,3-dioxo-octahydro-isoindole) (10a) (1.4 g, 87%, yellow liquid). 1H NMR (400 MHz, CDCl3): 3.68 (m,
1H), 3.54 (q, 2H, J= 7.3 Hz), 3.41 (m, 1H), 2.97 (td, 1H, A part of AB 1system, J= 7.6, 2.2 Hz), 2.91 (q,
1H, B part of AB1system, J= 7.6 Hz), 2.45 (dt, 1H, A part of AB2system, J= 14.6, 4.8 Hz), 2.37 (bs, 1H,
OH), 2.29 (ddd, 1H, A part of AB3system, J= 14.6, 7.3, 3.7 Hz), 1.80 (ddd, 1H, B part of AB2system, J=
14.6, 8.5, 7.3 Hz), 1.64 (dt, 1H, B part of AB3system, J= 14.6, 8.5 Hz), 1.15 (t, 3H, J= 7.3 Hz). 13 C NMR
(100 MHz, CDCl3): 178.6, 178.1, 69.4, 61.9, 38.2, 38.1, 33.9, 30.3, 25.4, 13.0. Anal. calc. for. C10 H14 N4O3
(238.11): C 50.41; H 5.92; N 23.52. Found: C 50.53; H 6.03; N 21.61. IR (KBr, cm −1) : 3454, 2928, 2109, 1774,
1697, 1445, 1404, 1378, 1350, 1360, 1221. Next the azido-alcohol 10a was dissolved in DCM (25 mL) and acetyl
chloride (1.2 g, 15 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The
mixture was cooled to 0 ◦C. Then water (100 mL) and DCM (50 mL) were added successively. The organic
phase was separated, washed with saturated NaHCO3and water (2 ×50 mL), and dried (Na2SO4). Removal
of the solvent under reduced pressure gave acetoxy-azide derivative isoindoline 5-acetoxy-6-azido-2-ethyl-1,3-
dioxo-octahydro-isoindole (11a) (1.26 g, 90%). 1H NMR (400 MHz, CDCl3) : 4.80 (m, 1H), 3.57 (m, 1H), 3.53
(m, 2H), 2.94 (dm, J= 14.0, Hz, 2H), 2.22 (m, 2H), 2.06 (m, 1H), 1.99 (s, 3H), 1.86 (m, 1H) 1.12 (t, J= 7.2
Hz, 3H). 13 C NMR (100 MHz, CDCl3): 178.1, 177.9, 169.8, 70.8, 70.2, 58.6, 37.4, 37.2, 26.3, 25.8, 21.1, 13.1.
4.7. Synthesis of 5-acetoxy-6-azido-2-phenyl-1,3-dioxo-octahydro-isoindole (11b)
To a stirred solution of syn-4-phenyl-tetrahydro-1aH-oxireno-[f]isoindole-3,5(2H,4H)-dion (7b) (1.35 g, 5.56
mmol) in 20 mL of methyl alcohol was added a solution of NH4Cl (0.595 g, 11.12 mmol) and NaN3(1.45
g, 22.24 mmol) in water (10 mL) dropwise at 0 ◦C over 15 min. The mixture was stirred at 90 ◦C for 26
h. After the filtration of the reaction mixture, the solvent was removed. The reaction mixture was cooled to
room temperature and methanol was evaporated. Then H2O (10 mL) and ether (60 mL) were added. The
organic layer was separated and washed with H2O (3 ×50 mL). The organic layer was dried over Na2SO4and
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ether was evaporated. Removal of the solvent under reduced pressure gave azido-alcohol derivative isoindoline
(5-azido-6-hydoxy-2-phenyl-1,3-dioxo-octahydro-isoindole) (10b) (1.08 g, 68%, yellow liquid). 1H NMR (400
MHz, CDCl3): 7.50–7.26 (m, 5H), 3.73 (m, 1H), 3.52 (m, 1H), 3.18 (m, 1H), 3.07 (m, 1H), 2.56 (dt, J= 9.4,
4.3 Hz, 1H), 2.51 (bs, 1H, OH), 2.38–2.26 (m, 1H), 1.88 (m, 2H). 13 C NMR (100 MHz, CDCl 3) : 178.8, 178.2,
129.4, 129.3, 128.9, 126.4, 69.3, 61.7, 38.4, 38.3, 30.1, 25.4. IR (KBr, cm−1) : 3457, 2930, 2115, 1772, 1693,
1444, 1400, 1377, 1352, 1225. Anal. calc. for. C14 H14 N4O3(286.11): C, 58.74; H, 4.93; N, 19.57; Found: C
58.63; H 4.52; N 19.61. Then the azido-alcohol 10b was dissolved in DCM (25 mL) and acetyl chloride (0.86
g, 11 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The mixture was
cooled to 0 ◦C. Then water (100 mL) and DCM (50 mL) were added successively. The organic phase was
separated, washed with saturated NaHCO3and water (2 ×50 mL), and dried (Na 2SO4). Removal of the
solvent under reduced pressure gave acetoxy-azide derivative isoindoline 5-acetoxy-6-azido-2-phenyl-1,3-dioxo-
octahydro-isoindole (11b) (1.1 g, 90%). 1H NMR (400 MHz, CDCl3): 7.39 (m, 5H), 5.10 (m, 1H), 3.55 (m,
1H), 3.18 (td, J= 8.1, 2.0 Hz, 1H), 3.06 (dd, J= 9.9, 8.1, 2H), 2.50 (ddd, J= 13.6, 5.5, 2.0 Hz, 1H), 2.32 (m,
1H), 2.12 (m, 1H) 2.08 (s, 3H). 13 C NMR (100 MHz, CDCl 3) : 179.5, 179.0, 168.7, 134.4, 129.2, 128.7, 126.7,
69.5, 62.0, 38.7, 38.3, 30.1, 25.4, 20.1.
4.8. Synthesis of 5-amino-2-ethyl-6-hydroxy-hexahydro-isoindole-1,3-dione HCl salt (12)
Into a 50-mL flask were placed Pd/C (20 mg) and 5-acetoxy-6-azido-2-ethyl-1,3-dioxo-octahydro-isoindole (11a)
(0.2 g, 0.78 mmol) in MeOH (6 mL) and CHCl3(1 mL). A balloon filled with H 2gas (3 L) was fitted to the
flask. The mixture was deoxygenated by flushing with H2and then hydrogenated at room temperature for 26
h. The catalyst was removed by filtration. Recrystallization of the residue from EtOAc/n-hexane gave 5-amino-
2-ethyl-6-hydroxy-hexahydro-isoindole-1,3-dione HCl salt (12) (0.14 g, 83%). Colorless crystal, mp: 85–87 ◦C.
1H NMR (400 MHz, D2O): 3.62 (td, 1H, J= 10.3, 4.0 Hz), 3.34 (q, 2H, J= 7.3 Hz), 3.14 (td, 1H, J= 7.3,
1.8 Hz), 3.04 (dt, 1H, J= 10.3, 7.7 Hz), 2.84 (m, 1H), 2.48 (dm, 1H), 2.21 (m, 1H), 1.71 (ddd, 1H, J= 19.6,
12.5, 7.4 Hz), 1.31 (dt, 1H, J= 13.8, 10.3 Hz), 0.93 (t, 3H, J= 7.3 Hz). 13 C NMR (100 MHz, D 2O): 181.6,
180.4, 67.7, 52.2, 38.6, 38.4, 34.1, 32.5, 24.0, 11.8. IR (KBr, cm −1) : 3501, 3161, 2955, 2926, 2854, 1697, 1462,
1405, 1349, 1261, 1224, 1090, 1017.
4.9. Synthesis of triazole derivative 14a
To a stirred solution of 10a (0.42 g, 1.76 mmol) in 20 mL of methyl alcohol were added consecutively a solution
of sodium ascorbate [ascorbic acid (0.3 g, 1.7 mmol), 4 mL of H 2O + NaHCO 3(0.1 g, 1.2 mmol), 4 mL H 2O)],
CuSO4.5H2O [0.04 g, 0.16 mmol + 1 ml H 2O], and dimethyl-acetylene dicarboxylate (0.46 g, 3.52 mol) in
DCM (2 mL) at room temperature. The mixture was stirred at room temperature for 12 h and monitored by
TLC. Then the reaction mixture was solved with DCM (50 mL). The organic layer was separated and washed
with H2O (3 ×50 mL). The organic layer was dried over Na2SO 4. Evaporation of the solvent followed by
crystallization of the residue from DCM/hexane (1:1) gave 14a. Colorless crystal, 0.6 g, 91%, mp: 155–156 ◦C.
1H NMR (400 MHz, CDCl3): 4.62 (m, 1H), 4.23 (m, 1H) 3.99 (s, 3H), 3.94 (s, 3H), 3.56 (q, 2H, J= 7.3 Hz),
3.20 (m, 1H), 3.19 (bs, 1H, OH), 3.12 (td, 1H, J= 9.2, 7.0 Hz), 2.77 (ddd, 1H, J= 14.3, 5.1, 3.3 Hz), 2.50 (m,
2H), 1.67 (dt, 1H, J= 14.3, 9.5 Hz), 1.18 (t, 3H, J= 7.3 Hz). 13 C NMR (100 MHz, CDCl3): 178.5, 177.5,
160.5, 159.2, 139.9, 131.4, 70.0, 62.6, 54.0, 53.0, 38.9, 38.6, 34.1, 32.7, 26.4, 13.0. Anal. calc. for. C 16 H20 N4O7
(380.35), C 50.52; H 5.30; N 14.73; found: C 49.59; H 5.187; N 14.28.
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TAN et al./Turk J Chem
4.10. Synthesis of triazole derivative 14b
To a stirred solution of 10b (0.5 g, 1.75 mmol) in 20 mL of t-BuOH-H2O (1:1) were added consecutively a
solution of sodium ascorbate [ascorbic acid (0.3 g, 1.7 mmol), 4 mL of H 2O + NaHCO 3(0.1 g, 1.2 mmol), 4
mL of H2O)], CuSO4.5H2O [0.04 g, 0.17 mmol + 1 mL of H2O], and dimethyl-acetylene dicarboxylate (0.5
g, 3.52 mol) at room temperature. The mixture was stirred at room temperature for 12 h and monitored by
TLC. Then the reaction mixture was solved with DCM (50 mL). The organic layer was separated and washed
with H2O (3 ×50 mL). The organic layer was dried over Na2SO 4. Evaporation of the solvent followed by
crystallization of the residue from DCM/hexane (1:1) gave 14b. Colorless crystal, 0.67 g, 89%, mp: 129–131
◦C. 1H NMR (400 MHz, CDCl3): 7.50–7.26 (m, 5H), 4.74 (m, 1H), 4.26 (bs, 1H) 3.98 (s, 3H), 3.95 (s, 3H),
3.41 (m, 1H), 3.27 (q, 1H, J= 8.4 Hz), 3.20 (bs, 1H, OH), 2.85 (dd, 1H, J= 14.3, 5.3 Hz), 2.57 (m, 2H),
1.93 (dt, 1H, J= 14.3, 8.4 Hz). 13 C NMR (100 MHz, CDCl3): 177.4, 176.6, 160.3, 159.0, 139.8, 131.8, 131.1,
129.2, 128.7, 126.3, 69.8, 62.2, 53.8, 52.8, 38.8, 38.3, 32.1, 25.9. HRMS: (ESI/[M +/Na]) m/z found: 429.1421,
requires: 428.13.
4.11. Crystallography
For the crystal structure determination, the single crystals of the compounds 6,12, and 14a were used for data
collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-dimensional area IP
detector). The graphite-monochromatized Mo Kαradiation (λ= 0.71073 ˚
A) and oscillation scans technique
with ∆w = 5◦for each image were used for data collection. The lattice parameters were determined by the least-
squares methods on the basis of all reflections with F2>2σg (F 2) . Integration of the intensities, correction
for Lorentz and polarization effects, and cell refinement were performed using Crystal Clear (Rigaku/MSC Inc.,
2005) software.21 The structures were solved by direct methods using the program SHELXS-9722 and refined
by a full-matrix least-squares procedure using the same program.22 Hydroxyl and water H molecules were
positioned from the difference Fourier map, all other H atoms were positioned geometrically and refined using
a riding model. The final difference Fourier maps showed no peaks of chemical significance. Crystal data for 6:
C13 H19 NO4, crystal system, space group: monoclinic, P21/n; (no: 14); unit cell dimensions: α= 7.6753(3), β
= 9.1962(3), γ= 19.6112(8) ˚
A, β= 98.00(2); volume: 1370.73(9) ˚
A3; Z = 4; calculated density: 1.227 g/cm3;
absorption coefficient: 0.091 mm −1; F(000): 544; θ-range for data collection 2.1–26.5 ◦; refinement method:
full-matrix least-square on F2; data/parameters: 2813/165; goodness-of-fit on F2: 1.043; final R indices [I >2
σg(I)]: R1= 0.065, wR2= 0.152; R indices (all data): R 1= 0.142, wR 2= 0.190; largest diff. peak and hole:
0.317 and –0.185 e ˚
A3; Crystal data for 12: C10 H17 N2O3·Cl·H2O, crystal system, space group: monoclinic,
Pc; (no: 7); unit cell dimensions: α= 6.7478(2), β= 15.0516(3), γ= 6.8591(2) ˚
A, β= 108.13(2); volume:
662.04(3) ˚
A3; Z = 2; calculated density: 1.338 g/cm 3; absorption coefficient: 0.294 mm −1; F(000): 284;
θ-range for data collection 2.7–26.4◦; refinement method: full-matrix least-square on F2; data/parameters:
2030/166; goodness-of-fit on F 2: 1.04; final R indices [I >2σg(I)]: R 1= 0.065, wR 2= 0.182; R indices (all
data): R1= 0.079, wR2= 0.210; largest diff. peak and hole: 0.421 and –0.264 e ˚
A3; Crystal data for 14a:
C16 H20 N4O7, crystal system, space group: monoclinic, P-1; (no: 2); unit cell dimensions: α= 8.4612(2), β
= 9.7794(3), γ= 11.6188(3) ˚
A, α= 100.42(2) β= 93.72(2), γ= 109.34(2); volume: 884.10(4) ˚
A3; Z = 2;
calculated density: 1.429 g/cm3; absorption coefficient: 0.114 mm −1; F(000): 400; θ-range for data collection
1.8–26.4◦; refinement method: full-matrix least-square on F2; data/parameters: 3165/248; goodness-of-fit on
839

TAN et al./Turk J Chem
F2: 1.044; final R indices [I >2σg (I)]: R 1= 0.036, wR2= 0.096; R indices (all data): R1= 0.042, wR 2=
0.101; largest diff. peak and hole: 0.258 and –0.166 e ˚
A3; CCDC-973056 (6), CCDC-973328 (12), and CCDC-
972561 (14a) contain the supplementary crystallographic data for this paper. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: + 44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgments
We would like to thank Atat¨urk University (Pro ject number: 2012/470) for its financial support of this work.
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