Synthesis of substituted pyrrolo[3,4-a]carbazoles

Article abstract of DOI:10.1002/hlca.200590231

The cycloaddition between W-protected 3-{1-[(trimethylsilyl)oxy]ethenyl}- 1H-indoles and substituted maleimides (=1H-pyrrole-2,5-diones) yielded substituted pyrrolo[3,4-a]carbazole derivatives bearing an additional succinimide (=pyrrolidine-2,5-dione) moi

Full text of DOI:10.1002/hlca.200590231

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Synthesis of Substituted Pyrrolo[3,4-a]carbazoles
by Michaela Bleile, Trixie Wagnera), and Hans-Hartwig Otto*b)
a) Novartis Institutes for BioMedical Research, Lichtstr. 35, WSJ-503.12.08, CH-4056 Basel
b) Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald,
Friedrich-Ludwig-Jahn-Strasse 17, D-17487 Greifswald
(phone: +49-3834-864875; fax: +49-3834-864874; e-mail: ottohh@pharmazie.uni-greifswald.de)
The cycloaddition between N-protected 3-{1-[(trimethylsilyl)oxy]ethenyl}-1H-indoles and substituted
maleimides (=1H-pyrrole-2,5-diones) yielded substituted pyrrolo[3,4-a]carbazole derivatives bearing an addi-
tional succinimide (=pyrrolidine-2,5-dione) moiety either at C(5a) or C(10b) depending on the type of the pro-
tection group at the indole N-atom. Derivatives substituted at C(10b) were isolated when the protection group,
Me3Si or Boc (tBuOCO), was eliminated during the reaction (Schemes 2 and 3), whereas a substitution at C(5a)
was observed when an electron-withdrawing group, Tos (4-MeC6H4SO2) or pivaloyl (Me3CCO), was not
eliminated (Scheme 1). Complex results were found in reactions between 1-(trimethylsilyl)-3-{1-
[(trimethylsilyl)oxy]ethenyl}-1H-indole, in contrast to formerly reported results (Scheme 3). Some derivatives
of 1H,5H-[1,2,4]triazolo[1’,2 :1,2]pyridazino[3,4-b]indole-1,3(2H)-dione were obtained from reactions with 4-
phenyl-3H-1,2,4-triazole-3,5(4H)-dione (Scheme 2). All structures were established by spectroscopic data, by
calculations, and one representative structure was confirmed by an X-ray crystallographic analysis (Fig.).
Finally, the formation of the different structure types was discussed, and compared with similar reactions
reported in the literature.
Introduction. – Fused indole derivatives like carbazoles were found in a large num-
ber of highly potent natural products like ellipticine, a drug used in tumor therapy, vinc-
amine, used against Alzheimer disease, or the large group of secale alkaloids [1]. Dur-
ing the last decade, camptothecine and some synthetic derivatives like topotecane and
irinotecane gained great importance as inhibitors of topoisomerase I and are today
used against different types of cancer. The cycloaddition of appropriate dienophiles
to 2- or 3-ethenyl-1H-indoles is used as a standard procedure for the synthesis of
those fused indoles [2]. As we have studied reactions between cyclopentadiene and
1-[(1-silyloxy)ethenyl]naphthalene derivatives and maleimides (=1H-pyrrole-2,5-dio-
nes) [3], we continue here with the report on the cycloaddition between N-substituted
3-[(1-silyloxy)ethenyl]-1H-indoles and maleimides and on some reactions of the cyclo-
adducts.
Results. – Although a protecting group at the indole N-atom was described as not
being necessary for some reactions [4], we noticed that in most cycloadditions, a pro-
tecting group at the N-atom supported the reactions and increased the yields. There-
fore, we used the N-protected compounds 1a–c, 9, and 14 as starting materials. Com-
pound 14 was prepared according to a known procedure [5], the other compounds
were synthesized from the parent acetyl derivatives following a standard procedure
[6] in nearly quantitative yields. All compounds were obtained as sensitive liquids
© 2005 Verlag Helvetica Chimica Acta AG, Zürich

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Scheme 1
which tend to polymerize and were, therefore, used as crude products without further
purification.
When the reactions between the 1-[(4-methylphenyl)sulfonyl]-3-{1-[(trimethyl-
silyl)oxy]ethenyl}-1H-indole (1a) and the N-substituted maleimides 2a, 2b, or 2c
were carried out in a reactant ratio of 1:1, a mixture of starting materials, degradation
products, and small amounts of 1:2 adducts but no 1:1 adduct were obtained after
workup. But when 1:2 mixtures of the reactants were stirred in toluene at room tem-
perature for some hours, the crystalline compounds 3a–c were isolated after evapora-
tion of the solvent and purification by crystallization or CC (Scheme 1).
Inspection of the elemental analyses and of the spectroscopic data immediately
revealed that 3a–c are not, as first expected, 1:1 adducts, but were formed by a 1:2
addition. The IR spectra showed strong bands of the imide CO groups at ca. 1780
and 1720 cmꢀ1, another carbonyl band at 1702–1712 cmꢀ1 (saturated cyclic ketone),
and the bands of the protecting sulfonamide group at ca. 1350 and 1170 cmꢀ1. Further-
more, the 1H-NMR spectra of 3b showed two signals for the MeN group, and that of 3c

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gave two sets of signals for the EtN group. NMR Spectroscopy and X-ray crystallo-
graphic analysis (see below) finally established the proposed structures.
The analogous reaction between the N-pivaloyl derivative 1b (Piv=Me3CCO) and
the maleimides 2a–c yielded the analogous structures 3d–f. The carbonyl group in
position 5 of the products 3 can react with MeOH/MeONa yielding the hemiketal, as
was demonstrated in the case of 3d by the formation of 4 (Scheme 1). During chromato-
graphic workup of 3f, the substituent at C(5a) was eliminated, and we isolated 5. As
demonstrated by other experiments, this elimination can occur either during chroma-
tography on silica gel or during prolonged heating for recrystallization.
The elimination of the substituent at C(5a) is in agreement with the observations we
made in reactions with the Boc-protected 1c (Boc=(tert-butoxy)carbonyl=tBuOCO).
The reaction with 2a at room temperature yielded the expected product 3g. But from
the reaction between 1c and 2b at room temperature, we obtained the addition product
3h and the elimination product 7. When 3g was heated to the melting point, we
observed cleavage of the Boc group but no elimination of the substituent at C(5a),
and we isolated 6.
As the spectroscopic data of compounds 3a–h showed analogous patterns, the
structure elucidation is discussed by means of the data of compound 3c. The identifica-
1
1
tion of the signals was possible from H,13C-HETCOR (300 MHz), H,1H-COSY (300
MHz), and NOE experiments. The 13C-NMR data (75.43 MHz) were compared with
those obtained by SPECINFO [7] and showed satisfactory agreement (Table).
Table. Experimental and Calculated (SPECINFO) 13C-NMR Shift Data of 3c
C(1)
C(3)
C(3a)
C(4)
C(5)
C(5a)
C(5b)
C(9a)
C(10a)
C(10b)
Exper.
Calc.
172.72
175.16
175.9
177.40
38.21
40.04
38.7
46.73
204.71
208.17
58.20
54.98
128.72
129.6
141.41
143.6
65.39
71.87
39.93
50.14
The 1H-NMR signal of HꢀC(3a) of 3c at d 3.32 showed a coupling constant J=9.8 (9.5) Hz with the signal
of HꢀC(10b) at d 3.66, and a coupling constant J=5.9 Hz with both HꢀC(4) at d 2.83, whereas the signal of Hꢀ
C(10b) coupled with the signal of HꢀC(10a) (J=8.5 (8.3) Hz) at d 5.89. This signal did not exhibit any other
coupling, and thereby demonstrated that the additional substituent should be located at C(5a). The signals of
the protons of the succinimide (=pyrrolidine-2,5-dione) moiety at C(5a) were found as an ABX system.
Finally, the structure deduced from spectroscopic data was confirmed by an X-ray
crystallographic analysis of 3c (Fig. 1,a) clearly showing that the succinimide moiety is
attached at C(5a), that the succinimide moiety and HꢀC(10a) are cis oriented with a
torsion angle HꢀC(10a)ꢀC(10a)ꢀC(5a)ꢀC(13)=33.1(1.2)8, that HꢀC(10a) and Hꢀ
C(10b) are also cis oriented, and finally that even HꢀC(10b) and HꢀC(3a) are cis ori-
ented. A PM3 calculation (HYPERCHEM) [8] gave a similar structure (Fig. 1,b).
A surprising result was obtained from the reaction between the Boc-protected
derivative 1c and 2c in refluxing toluene. After evaporation of the solvent and crystal-
lization, a compound was obtained whose elemental analysis and MS showed a 1:2
1
ratio of the reaction partners, but the H-NMR data exhibited significant differences
when compared with the data of compounds like 3a or 3c. The Boc group was lost prob-
1
ably by a thermal decomposition, and in the H-NMR spectrum, a broad s at d 11.7
caused by HꢀN(10) was detected. Further spectroscopic data established the proposed

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Figure. a) Structure of 3c in the crystal [9] (ellipsoids drawn at 50% probability, radii of H-atoms arbitrary;
arbitrary atom numbering). b) Structure of 3c obtained by a PM3 calculation.
structure 8 (Scheme 2) in which the additional succinimide moiety is not fixed at C(5a)
but at C(10b). Calculations of the distances for the favored conformation of 8 (MM2,
SYBYL [9]) resulted in the following values: HꢀC(3a)/HtransꢀC(4’) 2.497 Å, Hꢀ
C(3’)/HcisꢀC(4’) 2.364 Å, and HꢀC(3’)/HꢀN(10) 2.596 Å, in agreement with the
observed NOEs.
Analyzing the data of the COSYand NOE experiments performed with 8 revealed two groups of 3 protons
each from which one was caused by the H-atoms of the succinimide moiety and the other one belonged to the

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Scheme 2
pyrrolocarbazole system indicating that neither at C(5a) nor at C(10a) a proton was located. Irradiation at d 4.06
(HꢀC(3’)) simplified both signals at d 2.05 and 2.28 to d with J=18 Hz, which therefore could be caused solely
by the two HꢀC(4’) of the succinimide moiety. The second 3-H system, an ABC system, showed signals at d 2.50,
2.80, and 2.86 with Jgem =18.0, Jcis =8.6, and Jtrans =1.4 Hz and was caused by the pyrrolocarbazole part. NOEs
were found between HꢀC(3a) and HtransꢀC(4’), HꢀC(3’) and HꢀC(4’), and HꢀC(3’) and HꢀN(10).
Compounds 1a–c reacted as 1,3-dienes substituted in position 2 by a Me3SiO group,
in position 3 by an aryl group, and in position 4 by an N-atom which is substituted by an
electron-withdrawing group. In contrast, the benzyl substituent at the N-atom of diene
9 is not an electron-withdrawing substituent. This 1,3-diene did not react with male-
imides in toluene at room temperature, and when the mixtures were refluxed for sev-

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eral hours or days, only decomposition occurred. A successful reaction, but with lower
yields, was observed when we performed the reaction in CH2Cl2 at ꢀ788 in the presence
of EtAlCl2. The products 10a and 10b were isolated after hydrolytic (HCl) workup
(Scheme 2). Interestingly, this reaction did not result in the addition of a second male-
imide molecule. Probably, the re-aromatization after hydrolysis of the Me3SiO group is
favored compared to a further addition. All analytical data were in agreement with the
structures 10a and 10b.
The IR spectra of 10a,b were characterized by the strong C=O absorptions at 1783 and 1720 cmꢀ1 of the
imide part, and at 1650 cmꢀ1 of the a,b-unsaturated ketone moiety. The 1H-NMR spectra contained a 4-H system
caused by HꢀC(10b), HꢀC(3a), and the two HꢀC(4) at d 2.99, 3.15, 3.82, and 4.46, and Jgem =17.1 Hz,
J(3a,4)=6.6, and 8.2 Hz, and J(3a,10b)=8.1 Hz (values from 10a) establishing the cis configuration.
In contrast to the less reactive maleimides, the highly reactive 4-phenyl-3H-1,2,4-
triazole-3,5(4H)-dione reacted at ꢀ788 in THF nearly quantitative with 9 yielding 11
after hydrolytic workup with MeOH, without addition of a second molecule of the
dienophile (Scheme 2). The IR spectrum (KBr) of 11 showed a strong absorption at
1
3445 cmꢀ1; in the H-NMR spectrum in CDCl3, (D6)DMSO, or (D6)acetone, a broad
s at d ca. 10, and the signal at d 154 in the 13C-NMR spectrum indicated that 11 prefer-
red the enol structure in the solid state and in solution. The attempt to cleave the Nꢀ
benzyl bond by catalytic hydrogenation (Pd/C) was not successful, but the spectra of
the isolated product were consistent with the proposed structure of isomer 12. Reac-
tions of 11 with H2NOH·HCl and H2NOMe·HCl following standard procedures
yielded 13a and 13b, respectively, which exist, according to spectroscopic data, in solu-
tion as an equilibrium between the imine and the enamine structure.
A very complex behavior was observed in the reactions of the bis-silylated 1H-in-
dole derivative 14. Its synthesis and reaction with N-phenylmaleimide is described in
[5]. According to this report, the normal addition product I should be obtained
which by dehydrogenation should be transformed into the more stable structure II
(Scheme 3). Repeating the reaction, we could not verify these reported results. Follow-
ing exactly the reported procedure, we isolated from the reaction between 14 and 2a
always two products. According to the NMR data, the first one, 15a, was a mixture
of two diastereoisomers, which differ only in the configuration at C(3’) of the succin-
imide moiety attached at C(10b), and which were deprotected at N(10). The second
product, 16, was not deprotected at N(10) and bore the additional succinimide moiety
at C(5a). The analogous reaction between 14 and 2b yielded 15b and 19, whereas the
reaction with 2c only yielded 8 (Scheme 3).
The reaction of 14 with N-phenylcitraconimide (17) was very slow, the yield was
poor, and in the isolated product 18, the additional Me group was found at C(3a) [3].
The 1H-NMR spectrum of 18 showed 1 s at d 1.50 (Me), an AB system at d 2.55 and 3.00 with Jgem =16.8 Hz
for the two HꢀC(4), and a s at d 4.10 caused by HꢀC(10b), indicating the cis orientation between HꢀC(10b)
and MeꢀC(3a).
Discussion. – The reaction between N-substituted maleimides and N-protected 3-
[(1-trimethylsilyl)oxy]ethenyl]-1H-indoles did not end up with the expected 1:1
adduct, the silylated enol. This structure was not detected in any reaction. Instead,

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Scheme 3
the cycloaddition was followed by the addition of a second maleimide molecule. This
addition occurred either at C(5a) or at C(10b) of the pyrrolocarbazole, and depended
on the protecting group at the indole N-atom. Pindur and Rogge [10] described reac-
tions between 2a and unprotected 3-{1-[(trimethylsilyl)oxy]ethenyl}-1-H-indole, and
isolated, as a by-product, a 1:2 adduct, but the second addition – the authors discussed
a hetero-ene or a conjugate addition reaction for its formation – occurred at C(4). In
our experiments, the protecting group was a relatively bulky electron-withdrawing
group, Tos, pivaloyl, or Boc (see 1a–c), which could not be deleted during the reaction
at room temperature. The addition of a second maleimide molecule to C(5a) and the
formation of 3a–h, therefore, might be explained as a sequence of a 1:1 cycloaddition

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between the 1,3-diene 1 and the maleimide (2), followed by an ene addition of a second
maleimide molecule to the (silyloxy)ene moiety at C(5a) of the first adduct, and fol-
lowed finally by the hydrolysis of the silyloxy group to the C(5) ketone. Structures
like 5 and 7 could be formed either by a thermal elimination from the 1:2 adduct or,
if they were found together with the addition product, by a partial re-aromatization
of the indole moiety before the second addition ocurred. If the N-atom in the starting
material was protected by a benzyl group (see 9), a cycloadduct was found only from
reactions in the presence of a Lewis acid (EtAlCl2), and stabilization of the adduct
was faster than the addition of a second molecule. If the protecting group was easily
deleted like the Me3Si or the Boc group, the formation of a reactive center at C(10b)
and the addition of the second maleimide molecule at this position was favored (!
8, 15a, 15b). This addition possibly might be understood either as a Michael-type addi-
tion of an anion intermediate at C(10b) to the second maleimide molecule, or as an ene
reaction between an intermediately formed enamine structure (indol N-atom, C(10a),
C(10b)) and the second maleimide molecule. All additions occurred as ‘syn’ additions,
and thereby led to products with all-cis configurations.
We wish to thank Novartis, Basel, for support and biological tests, Degussa AG, for generous support with
chemicals, E. Merck KGaG, Darmstadt, for extended support with chemicals, with chromatography materials,
and for HPLC experiments, the Fonds der Chemischen Industrie, Frankfurt a. Main, for continuous financial sup-
port, and Volker Brecht, Freiburg, for excellent NMR spectroscopy.
Experimental Part
General. Abbreviations: HMPA, hexamethylphosphoric triamide; LDA, lithium diisopropylamide. The fol-
lowing compounds were prepared according to known procedures: 3-Acetyl-1-[(4-methylphenyl)sulfonyl]-1H-
indole [11], 3-acetyl-1-(2,2-dimethylpropanoyl)-1H-indole [12], 3-acetyl-1-benzyl-1H-indole [13], 3-acetyl-1-
[(tert-butoxy)carbonyl]-1H-indole [14], and 1-(trimethylsilyl)-3-{1-[(trimethylsilyl)oxy]ethenyl}-1H-indole (14)
[5]. THF was stored under CaCl2 protection, and distilled from Na and benzophenone prior to use. Other sol-
vents were dried/purified according to literature procedures. LDA was prepared by mixing equivalent amounts
of iPr2NH and BuLi (15% in hexane). All reactions at ꢀ788 were done under N2. Column chromatography (CC):
silica gel 60, Merck 7734. TLC precoated silica-gel 60 F254 plates Merck 5549. M.p.: Mel-Temp-II apparatus; not
corrected. IR Spectra (KBr, cmꢀ1): Perkin-Elmer IR 841. NMR Spectra: Varian T 60, Bruker WP 80, Varian
1
Unity 300 for H; Varian Unity 300 (75.43 MHz) for 13C; d in ppm rel. to SiMe4 as internal standard, J in Hz;
d(H) from spectra in CDCl3, if not otherwise noted. MS: Finnigan MAT 312, MAT 44 S; EI spectra at 2008
and 70 eV; CI spectra with CH4 or NH3 at ca. 300 mbar. Elemental analyses: Institute of Pharmacy, University
of Greifswald, or Chemisches Laboratorium, University of Freiburg.
1-[(4-Methylphenyl)sulfonyl]-3-{1-[(trimethylsilyl)oxy]ethenyl}-1H-indole (1a). A soln. of 3-acetyl-1-[(4-
methylphenyl)sulfonyl]-1H-indole (3.12 g, 10 mmol) in THF (20 ml) was added dropwise at ꢀ788 to a LDA
soln. in THF (20 ml), and after stirring for 10 min, Me3SiCl (2.5 ml, 20 mmol) was added in one portion.
When the mixture was warmed to r.t. (ca. 2 h), pentane (50 ml) was added. The org. layer was washed with
an aq. sat. NaHCO3 soln. (100 ml), dried (MgSO4), and evaporated: 3.8 g (99%; not purified) of 1a which
was immediately used for further reactions. IR (film): 2959 (CH), 1670 (C=C), 1596 (arom. CꢀC), 1377,
1174 (SO2), 1252 (Me-Si), 1090 (SiꢀO), 961 (=CH), 848, 750 (SiMe3). 1H-NMR (60 MHz): 0.26 (s, Me3Si);
2.30 (s, Me); 4.54, 4.88 (d, J=1.7, C=CH2); 7.00–8.00 (m, 9 arom. H). MS: 385 (45, M+·, C20H23NO3SSi+),
313 (6, [acetyltosylindole]+·).
1-(2,2-Dimethylpropanoyl)-3-{1-[(trimethylsilyl)oxy]ethenyl}-1H-indole (1b). From 3-acetyl-1-(2,2-dime-
thylpropanoyl)-1H-indole (2.43 g, 10 mmol), as described for 1a: 3 g (95%; not purified) of 1b which was imme-
diately used for further reactions. IR (film): 2959 (CH), 1696 (C=C), 1622, 1549 (CO), 1253 (SiꢀMe), 958
(=CH), 1074 (SiꢀO), 845, 753 (SiMe3).
1-[(tert-Butoxy)carbonyl]-3-{1-[(trimethylsilyl)oxy]ethenyl}-1H-indole (1c). From 3-acetyl-1-[(tert-
butoxy)carbonyl]-1H-indole (2.59 g, 10 mmol), as described for 1a: 3.2 g (95%; not purified) of 1c which was

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immediately used for further reactions. IR (film): 3053 (=CH2), 2978 (CH), 1630 (C=C, CO), 1451 (Me), 1065,
1013 (SiꢀO), 845, 748 (SiMe3).
5a-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-3a,4,5a,10,10a,10b-hexahydro-10-[(4-methylphenyl)sulfonyl]-2-phen-
ylpyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (3a). Under N2 and at r.t., a soln. of 1a (3.86 g, 10 mmol) and 2a (3.46
g, 20 mmol) in toluene (100 ml) was stirred until the precipitation was complete. Then, the solvent was evapo-
rated and the residue in MeOH (100 ml) refluxed for 1 h. After cooling to r.t., the precipitate was collected: 2.04
g (31%) of 3a. Rf (cyclohexane/AcOEt 1:1) 0.53. Colorless crystals. M.p. 2808 (AcOEt). IR: 2926 (CH), 1781,
1712 (CO), 1597 (CꢀC), 1382, 1170 (SO2), 755, 696 (arom.). 1H-NMR (300 MHz): 1.94 (dd, J(3’,4’; trans)=6.1,
J(3’,4’; cis)=9.3, HꢀC(3’)); 2.05 (dd, J(4’,3’; cis)=9.3, J(4’,4’)=17.5, HcisꢀC(4’)); 2.38 (s, Me); 2.85 (dd, J(4A,
3a)=9.0, J(4A,4B)=15.3, HAꢀC(4)); 2.97 (dd, J(4B,3a)=3.7, J(4B,4A)=15.4, HBꢀC(4)); 3.02 (dd, J(4’,3’;
trans)=6.1, J(4’,4’)=17.5, HtransꢀC(4’)); 3.50 (ddd, J(3a,4B)=3.7, J(3a,4A)=9.3, J(3a,10b)=9.3, HꢀC(3a));
3.82 (dd, J(10b,10a)=8.5, J(10b,3a)=9.3, HꢀC(10b)); 5.95 (d, J(10a,10b)=8.3, HꢀC(10a)); 6.84 (dd, J=2.0,
J=7.8, 2 arom. H); 7.11–7.53 (m, 13 arom. H); 7.7 (d, J=8.1, HꢀC(9)); 7.81 (d, J=8.3, 2 arom. H). Anal.
calc. for C37H29N3O7S (659.72): C 67.36, H 4.43, N 6.37; found: C 66.87, H 4.44, N 6.07.
3a,4,5a,10,10a,10b-Hexahydro-2-methyl-5a-(1-methyl-2,5-dioxopyrrolidin-3-yl)-10-[(4-methylphenyl)sulfo-
nyl]-pyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (3b). From 1a (3.86 g, 10 mmol) and 2b (2.2 g, 20 mmol), as descri-
bed for 3a (72 h) at r.t., 1.9 g (36%) of 3b. Colorless crystals. M.p. 2268 (cyclohexane/AcOEt 1:1). IR: 2949
1
(CH), 1781, 1702 (CO), 1598 (CꢀC), 1461, 1435 (CH), 1364, 1168 (SO2). H-NMR (300 MHz): 1.80–1.90 (m,
HꢀC(3’), HcisꢀC(4’)); 2.34, 2.58 (2s, 2 Me); 2.80 (m, HAꢀC(4), HBꢀC(4), HtransꢀC(4’)); 2.90 (s, Me); 3.32 (dt,
J(3a,4)=5.9, J(3a,10b)=9.3, HꢀC(3a)); 3.67 (dd, J(10b,3a)=9.1, J(10b,10a)=8.6, HꢀC(10b)); 5.86 (d,
J(10a,10b)=8.6, HꢀC(10a)); 7.00 (ddd, J(7,9)=1, J(7,6)=7.6, J(7,8)=7.6, HꢀC(7)); 7.18 (dd, J(6,8)=0.7,
J(6,7)=7.6, HꢀC(6)); 7.23 (d, J=7.8, 2 arom. H); 7.32 (ddd, J(8,6)=1.2, J(8,7)=7.6, J(8,9)=8.1, HꢀC(8));
7.64 (d, J(9,8)=8.1, HꢀC(9)); 7.80 (d, J=8.3, 2 arom. H). 13C-NMR (75.43 MHz): 21.46 (Me); 24.70 (MeN);
24.81 (MeN); 31.27 (CH2); 38.27 (C(3a)); 38.42 (CH2); 40.31 (C(10b)); 45.17 (C(3’)); 58.27 (C(5a)); 65.76
(C(10a)); 117.05 (C(9)); 124.58 (C(7)); 124.66 (C(6)); 127.00 (arom. C); 128.63 (C(5b)); 129.81 (arom. C);
130.64 (C(8)); 136.02 (arom. C); 141.34 (C(9a)); 144.80 (arom. C); 173.10, 174.28, 176.06, 176.67, 204.86
(CO). MS: 535 (100, M+.). Anal. calc. for C27H25N3O7S (535.58): C 60.55, H 4.71, N 7.85; found: C 60.94, H
4.79, N 7.23.
2-Ethyl-5a-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-3a,4,5a,10,10a,10b-hexahydro-10-[(4-methylphenyl)sulfonyl]-
pyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (3c). From 1a (3.86 g, 10 mmol) and 2c (2.5 g, 20 mmol), as described
for 3a. CC (cyclohexane/AcOEt 1:1; Rf 0.38) gave 1.45 g (26%) of 3c. Colorless crystals. M.p. 2088 (MeOH). IR:
2980 (CH), 1777, 1704 (CO), 1597 (arom. CꢀC), 1461, 1402 (CH), 1350, 1169 (SO2), 1225 (CꢀC), 815, 797
(arom.). 1H-NMR (300 MHz): 0.60 (t, J=7.3, Me); 1.07 (t, J=7.3, Me); 1.68 (dd, J(3’,4’; trans)=5.6, J(3’,4’;
cis)=9.0, HꢀC(3’)); 1.81 (dd, J(4’,3’; cis)=9.0, J(4’,4’)=17.8, HcisꢀC(4’)); 2.32 (s, Me); 2.80 (dd, J(4’,3’;
trans)=5.6, J(4’,4’)=17.6, HtransꢀC(4’)); 2.83 (d, J(4,3a)=5.9, HAꢀC(4), HBꢀC(4)); 3.19 (q, J=7.3, CH2);
3.32 (dt, J(3a,4)=5.9, J(3a,10b)=9.8, HꢀC(3a)); 3.43 (q, J=7.3, CH2); 3.66 (dd, J(10b,10a)=8.5, J(10b,
3a)=9.5, HꢀC(10b)); 5.89 (d, J(10a,10b)=8.3, HꢀC(10a)); 6.98 (ddd, J(7,9)=1, J(7,6)=7.6, J(7,8)=7.6, Hꢀ
C(7)); 7.21 (d, J=8.1, 2 arom. H); 7.23 (d, J(6,7)=7.3, HꢀC(6)); 7.32 (ddd, J(8,6)=1.2, J(8,7)=7.8, J(8,
9)=8.1, HꢀC(8)); 7.67 (d, J(9,8)=8.1, HꢀC(9)); 7.80 (d, J=8.3, 2 arom. H). 13C-NMR (75.43 MHz): 12.33
(Me); 12.77(Me); 21.50 (Me); 31.16 (C(4’)); 33.74 (CH2); 33.87 (CH2); 38.21 (C(3a)); 38.70 (C(4)); 39.93
(C(10b)); 45.20 (C(3’)); 58.20 (C(5a)); 65.39 (C(10a)); 117.09 (C(9)); 124.52 (C(7)); 124.92 (C(6)); 126.99
(arom. C); 128.72 (C(5b)); 129.86 (arom. C); 130.72 (C(8)); 136.22 (arom. C); 141.41 (C(9a)); 144.73 (arom.
C); 172.72 (C(1)); 173.99 (C(2’)); 175.90 (C(3)); 176.35 (C(5’)); 204.71 (C(5)). FAB-MS (FAB gun, Xe, 6 kV,
2 mA): 564 (M+.), 437 ([Mꢀethylsuccinimide]+), 409 ([M+1ꢀTos]+), 283 ([M+1ꢀTos-ethylsuccinimide]+).
Anal. calc. for C29H29N3O7S (563.63): C 61.80, H 5.19, N 7.46; found: C 61.59, H 4.98, N 7.23.
Crystal-Structure Analysis of 3c. Crystals suitable for diffraction experiments were grown from EtOH.
C29H29N3O7S, Mr 563.61, monoclinic, space group P21/c with a=8.738(2), b=16.516(3), c=18.913(3) Å,
b=101.613(9)8, V=2673.6(9) Å3, Z=4, Dc =1.400 g·cmꢀ3, 34253 reflections measured, 4877 independent
(Rint =0.0455), 3.598<q<69.238, 379 parameters, no restraints, R1 =0.0369, wR2 =0.0911 for 4057 reflections
with I>2s(I), R1 =0.0482, wR2 =0.0996 for all 4877 data, goodness-of-fit=1.039, res. electron den-
sity=+0.37/ꢀ0.34 e·Å3. Diffraction data were collected at 100 K with a Bruker AXS-SMART-6000-CCD detec-
tor on a three-circle platform goniometer with CuKa radiation from a fine-focus sealed tube generator equipped
with a graphite monochromator. A semi-empirical absorption correction was applied, based on the intensities of
symmetry-related reflections measured at different angular settings [15]. The structure was solved and refined
on F2 with the SHELXTL suite of programs [16]. Non-H-atoms were refined with anisotropic displacement
parameters, H-atoms at tertiary C-atoms were located in difference Fourier maps and refined isotropically,

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HELVETICA CHIMICA ACTA – Vol. 88 (2005)
all other H-atoms were calculated in idealized positions and refined using a riding model. Displacement param-
eters and bond lengths of the ethyl side chain at N(2) indicate disorder. The disorder was not modeled. CCDC-
261131 contains the supplementary crystallographic data (excluding structure factors) for this paper. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
10-(2,2-Dimethylpropanoyl)-5a-(2,5-dioxo-1-phenylpyrrolidin-3-yl)-3a,4,5a,10,10a,10b-hexahydro-2-phe-
nylpyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (3d). From 1b (3.15 g, 10 mmol) and 2a (1.73 g, 10 mmol), as de-
scribed for 3a (96 h) at r.t.: 1.04 g (35%) of 3d. Colorless crystals. TLC (cyclohexane/AcOEt 1 :1): Rf 0.53.
1
M.p. 288–2928 (AcOEt). IR: 1778, 1719 (CO), 1660, 1595 (CO, amide). H-NMR (300 MHz): 1.53 (s, Me3C);
2.42 (dd, J(4’,3’; cis)=11.8, J(4’,4’)=20.5, HcisꢀC(4’)); 2.90 (dd, J(4A,3a)=7.8, J(4A,4B)=16.4, HAꢀC(4));
3.23 (dd, J(4B,3a)=2.9, J(4B,4A)=16.4, HBꢀC(4)); 3.23 (dd, J(3’,4’; trans)=5.6, J(3’,4’; cis)=11.9, HꢀC(3’));
3.26 (dd, J(4’,3’; trans) = 5.6, J(4’,4’) = 20.1, HtransꢀC(4’)); 3.47 (ddd, J(3a,4B) = 2.9, J(3a,4A) = 7.8, J(3a,
10b)=10.3, HꢀC(3a)); 3.99 (dd, J(10b,10a)=9.8, J(10b,3a)=9.9, HꢀC(10b)); 6.25 (d, J(10a,10b)=9.8, Hꢀ
C(10a)); 6,54–8,00 (m, 14 arom. H). MS: 589 (6, M+.), 505 (8, [MꢀC5H9O]+), 331 (45), 174, 85, 57 (100, C4Hþ9 ).
EI-HR-MS: 589.221287 (calc. 589.221171). Anal. calc. for C35H31N3O6 (589.64): C 71.29, H 5.30, N 7.13; found: C
68.88, H 5.31, N 6.84.
10-(2,2-Dimethylpropanoyl)-3a,4,5a,10,10a,10b-hexahydro-2-methyl-5a-(1-methyl-2,5-dioxopyrrolidin-3-
yl)pyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (3e). From 1b (3.15 g, 10 mmol) and 2b (1.1 g, 10 mmol), as descri-
bed for 3a (3 weeks at r.t.). Then the solvent was evaporated, the residue stirred with MeOH (a few ml) for 2–5
h, and the solvent evaporated: 710 mg (30%) of 3e. Colorless crystals. M.p. 2268 (AcOEt). IR: 2971 (CH), 1769,
1702 (CO), 1649 (CO amide), 1466, 1439 (Me), 1381, 1354, 1209 (Me3C). 1H-NMR (300 MHz): 1.53 (s, Me3C);
2.24 (dd, J(4’,3’; cis)=10.7, J(4’,4’)=19.5, HcisꢀC(4’)); 2.80 (dd, J(4A,4B)=16.6, J(4A,3a)=7.6, HAꢀC(4)); 3.06
(dd, J(3’,4’; trans)=5.6, J(3’,4’; cis)=11, HꢀC(3’)); 3.08 (dd, J(4’,4’)=19.4, J(4’,3’; trans)=5.6, HtransꢀC(4’)); 3.13
(dd, J(4B,4A)=16.5, J(4B,3a)=2.7, HBꢀC(4)); 3.26 (ddd, J(3a,4B)=2.7, J(3a,4A)=7.5, J(3a,10b)=9.7, Hꢀ
C(3a)); 3.82 (dd, J(10b,10a)=9.5, J(10b,3a)=9.5, HꢀC(10b)); 6.09 (d, J(10a,10b)=9.5, HꢀC(10a)); 7.01
(ddd, J(7,9)=1.2, J(7,6)=7.6, J(7,8)=7.6, HꢀC(7)); 7.11 (dd, J(6,8)=1.5, J(6,7)=7.6, HꢀC(6)); 7.28 (ddd,
J(8,6)=1.2, J(8,7)=7.3, J(8,9)=8.1, HꢀC(8)); 7.99 (d, J(9,8)=8.1, HꢀC(9)). Anal. calc. for C25H27N3O6
(465.50): C 64.50, H 5.85, N 9.03; found: C 64.25, H 5.74, N 8.97.
10-[(tert-Butoxy)carbonyl]-5a-(2,5-dioxo-1-phenylpyrrolidin-3-yl)-3a,4,5a,10,10a,10b-hexahydro-2-phenyl-
pyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (3g). A soln. of 1c (3.31 g, 10 mmol) and 2a (1.73 g, 10 mmol) in tolu-
ene (30–50 ml) was stirred at r.t. for 4 d. Then the solvent was evaporated: 1.5 g (50%) of 3g. Colorless crystals.
M.p. 240–2438 (AcOEt). IR: 2980 (CH), 1783, 1720 (CO), 1598 (arom. CꢀC), 1390, 1256 (Me3C). 1H-NMR (300
MHz, (D6)DMSO): 1.60 (s, Me3C); 2.60 (dd, J(4’,3’; cis)=9.3, J(4’,4’)=18.1, HcisꢀC(4’)); 2.82 (m, HAꢀC(4));
2.82 (dd, J(4’,3’; trans)=4.6, J(4’,4’)=18.2, HtransꢀC(4’)); 3.1 (m, HBꢀC(4)), 3.60 (dd, J(3’,4’; trans)=4.6, J(3’,
4’; cis)=9.4, HꢀC(3’)); 3.80 (ddd, J(3a,10b)=9.0, J(3a,4B)=2.4, J(3a,4A)=9.0, HꢀC(3a)); 4.02 (dd, J(10b,
10a)=9.3, J(10b,3a)=9.3, HꢀC(10b)); 5.75 (d, J(10a,10b)=8.8, HꢀC(10a)); 6.50–7.70 (m, 14 arom. H).
FAB-MS (FAB gun, Xe, 8 kV, 1 mV): 605 (1.14, M+.). MS: 605 (0.29, M+.), 505 (10.11, [M+1ꢀBoc]+), 331
(75.55, [M+1ꢀBoc-phenylmaleimide]+). Anal. calc. for C35H31N3O7 (605.64): C 69.41, H 5.16, N 6.94; found:
C 68.92, H 5.16, N 6.79.
10-[(tert-Butoxy)carbonyl]-3a,4,5a,10,10a,10b-hexahydro-2-methyl-5a-(1-methyl-2,5-dioxopyrrolidin-3-yl)-
pyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (3h). As described for 3g, from 1c (3.31 g, 10 mmol) and 2b (1.1 g, 10
mmol). MeOH (a few ml) was added to the residue, the mixture was filtered, and from the filtrate, 3h/7 (520 mg,
14%) was isolated. The insoluble residue was separated by filtration: 500 mg (20%) of 3h. Colorless crystals.
M.p. 245–2488 (AcOEt). IR: 2977 (CH), 1777, 1703 (CO), 1480, 1385, 1244 (Me). 1H-NMR (300 MHz,
CDCl3/(D6)DMSO): 1.48 (s, Me3C); 2.3 (m, HcisꢀC(4’), HtransꢀC(4’)); 2.40, 2.44 (2s, 2 MeN); 2.75 (dd, J(4B,
3a)=3.7, J(4B,4A)=14.5, HBꢀC(4)); 3.07 (dd, J(4A,3a)=8.3, J(4A,4B)=14.5, HAꢀC(4)); 3.26 (ddd, J(3a,
4B)=3.7, J(3a,4A)=8.3, J(3a,10b)=8.7, HꢀC(3a)); 3.50 (dd, J(3’,4’; trans)=5.6, J(3’,4’; cis)=8.8, HꢀC(3’));
3.64 (dd, J(10b,3a)=8.8, J(10b,10a)=8.6, HꢀC(10b)); 4.99 (d, J(10a,10b)=8.3, HꢀC(10a)); 6.78 (ddd, J(7,
9)=1, J(7,8)=7.6, J(7,6)=7.6, HꢀC(7)); 7.10 (ddd, J(8,6)=1.5, J(8,7)=7.6, J(8,9)=7.8, HꢀC(8)); 7.18 (dd,
J(9,7)=1, J(9,8)=7.7, HꢀC(9)); 7.44 (d, J(6,7)=8.1, HꢀC(6)). Anal. calc. for C25H26N3O7 (480.49): C 62.49,
H 5.45, N 8.75; found: C 61.49, H 5.52, N 8.53.
10-(2,2-Dimethylpropanoyl)-5a-(2,5-dioxo-1-phenylpyrrolidin-3-yl)-4,5,5a,10,10a,10b-hexahydro-5-hy-
droxy-5-methoxy-2-phenylpyrrolo[3,4-a]carbazole-1,3(2H,3a,H)-dione (4). A soln. of 3d (400 mg, 0.68 mmol) in
MeOH (20 ml) and 0.1N MeONa/MeOH (1 ml) was stirred for 30 min. Then H2O (50 ml) and AcOEt (50 ml)
were added. The aq. layer was twice extracted with AcOEt, the combined org. layer washed with an aq. sat.
NaCl soln., dried (MgSO4), and evaporated: 240 mg (38%) of 4. Colorless crystals. M.p. 2708 (MeOH). IR:

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3431 (OH), 2956 (CH), 1712, 1632 (CO), 1597 (arom. CꢀC), 1475, 1437, 1387 (Me). 1H-NMR (300 MHz): 1.46
(s, Me3C); 1.82 (dd, J(4’,4’)=17.7, J(4’,3’; cis)=8.1, HcisꢀC(4’)); 2.35 (ddd, J(4A,4B)=14.3, J(4A,3a)=8.3, J(4A,
OH)=2.4, HAꢀC(4)); 2.77(dd, J(4B,4A)=14.5, J(4B,3a)=0.9, HBꢀC(4)); 2.80 (dd, J(4’,4’)=17.7, J(4’,3’;
trans)=4.6, HtransꢀC(4’)); 2.95 (d, J(OH,4A)=2.4, OH); 3.34 (m, HꢀC(3a)); 3.58 (dd, J(3’,4’; trans)=4.6,
J(3’,4’; cis)=8.0, HꢀC(3’)); 3.62 (s, MeO); 4.26 (dd, J(10b,10a)=7.8, J(10b,3a)=10.1, HꢀC(10b)); 5.42 (d,
J(10a,10b)=7.9, HꢀC(10a)); 6.90–7.65 (m, 14 arom. H). MS: 621 (12, M+.), 590 (1.4, [MꢀMeO]+), 505 (1.1,
[MꢀOMeꢀC4H9O]+), 174 (1.3, [N-phenylsuccinimide]+), 130 (4), 57 (100, C4Hþ9 ). EI-HR-MS: 621.247502 (C36-
H35N3Oþ7 ); calc. 621.247508, 0.0 ppm).
10-(2,2-Dimethylpropanoyl)-2-ethyl-3a,4,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3,5(2H)-trione
(5).
From 1b (3.15 g, 10 mmol) and 2c, as described for 3e. CC (cyclohexane/AcOEt 1:1) gave 340 mg (9.3%) of
5. Colorless crystals. M.p. 197–2008. IR: 2973, 2917 (CH), 1778, 1708 (CO), 1671, 1569 (CO, amide), 1449
(Me), 1397, 1378, 1222 (Me3C). 1H-NMR (300 MHz): 1.15 (t, J=7.3, Me); 3.00 (d, J(4,3a)=7.1, HAꢀC(4),
HBꢀC(4)); 3.55 (q, J=7.3, CH2); 3.71 (dt, J(3a,4)=7.1, J(3a,10b)=8.6, HꢀC(3a)); 5.0 (d, J(10b,3a)=8.6, Hꢀ
C(10b)); 7.37 (m, 2 arom. H); 7.67 (d, 1 arom. H); 8.32 (dd, 1 arom. H). MS: 366 (16, M+.), 282 (61,
[M+1ꢀpivaloyl]+), 57(100). Anal. calc. for C21H22N2O4 (366.41): C 68.84, H 6.05, N 7.65; found: C 68.67, H
5.99, N 7.59.
3a,4,5a,10,10a,10b-Hexahydro-2-phenyl-5a-(1-phenyl-2,5-dioxopyrrolidin-3-yl)pyrrolo[3,4-a]carbazole-1,3,5-
(2H)-trione (6). Dry 3g was heated until melting occurred. M.p. ca. 3008. IR: 3354 (NH), 1778, 1708 (CO), 1597,
1500 (arom. CꢀC), 1261, 1187 (CH). 1H-NMR (300 MHz): 2.71 (dd, J(4B,3a)=7.9, J(4B,4A)=12.5, HBꢀC(4));
2.84 (dd, J(4A,3a)=12.4, J(4A,4B)=12.4, HAꢀC(4)); 3.08 (dd, J(4’,3’; cis)=9.0, J(4’,4’)=17.1, HcisꢀC(4’)); 3.43
(dd, J(3’,4’; trans)=7.3, J(3’,4’; cis)=9.0, HꢀC(3’)); 3.50 (ddd, J(3a,4B)=7.9, J(3a,4A)=12.2, J(3a,10b)=10.0,
HꢀC(3a)); 3.66 (dd, J(4’,3’; trans)=7.3, J(4’,4’)=17.3, HtransꢀC(4’)); 4.24 (dd, J(10b,3a)=10.0, J(10b,10a)=5.3,
HꢀC(10b)); 4.51 (d, J(NH,10a)=5.5, NH); 5.1 (dd, J(10a,NH)=5.3, J(10a,10b)=5.3, HꢀC(10a)); 6.70–7.50
(m, 14 arom. H). EI-HR-MS: 505.163772 (C30H23N3Oþ5 ; calc. 505.163603; ꢀ0.3 ppm).
10-[(tert-Butoxy)carbonyl]-3a,4,10,10b-tetrahydro-2-methylpyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (7).
As a by-product from the synthesis of 3h. Colorless crystals. M.p. 1768. IR: 2982 (CH), 1745, 1697, 1666
1
(CO), 1454, 1375 (Me). H-NMR (300 MHz): 1.8 (s, Me3C); 2.98 (s, MeN); 2.99 (d, J(4A,3a)=8.1, HAꢀC(4));
3.01 (d, J(4B,3a)=5.6, HBꢀC(4)); 3.70 (ddd, J(3a,4B)=6.1, J(3a,4A)=8.3, J(3a,10b)=8.3, HꢀC(3a)); 5.32
(d, J(10b,3a)=8.3, HꢀC(10b)); 7.7–8.25 (m, 4 arom. H). Anal. calc. for C20H20N2O5 (368.39): C 65.21, H
5.47, N 7.60; found: C 64.87, H 5.39, N 7.58.
2-Ethyl-10b-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-3a,4,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3,5(2H)-tri-
one (8). a) From 1c (3.31 g, 10 mmol) and 2c (1.25 g, 10 mmol), as described for 3g (3 d under reflux, then evap-
oration): 960 mg (47%) of 8. b) From 14 (3.0 g, 10 mmol) and 2c (1.3 g, 10 mmol) as described for 15b: 980 mg
(48%) of 8. Colorless crystals. M.p. 241–2438 (AcOEt). IR: 3181 (NH), 2982 (CH), 1778, 1701, 1619 (CO), 1584
(arom. CꢀC), 1460, 1380 (Me). 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 0.7 (2t, J=7.3, 2 Me); 2.05 (dd, J(4’,3’;
trans)=6.7, J(4’,4’)=18.1, HtransꢀC(4’)); 2.28 (dd, J(4’,3’; cis)=9.5, J(4’,4’)=18.2, HcisꢀC(4’)); 2.50 (dd, J(4B,
3a)=8.7, J(4B,4A)=18.0, HBꢀC(4)); 2.80 (dd, J(4A,3a)=1.4, J(4A,4B)=18.1, HAꢀC(4)); 2.86 (dd, J(3a,
4A)=1.4, J(3a,4B)=8.6, HꢀC(3a)); 3.10 (m, 2 CH2); 4.06 (dd, J(3’,4’; trans)=6.7, J(3’,4’; cis)=9.4, Hꢀ
C(3’)); 6.80 (ddd, J(7,9)=1.4, J(7,6)=7.3, J(7,8)=7.5, HꢀC(7)); 6.86 (ddd, J(8,6)=1.5, J(8,7)=7.5, J(8,
9)=7.5, HꢀC(8)); 7.08 (dd, J(9,6)=0.9, J(9,7)=1.4, J(9,8)=7.5, HꢀC(9)); 7.71(ddd, J(6,9)=0.6, J(6,8)=1.5,
J(6,7)=7, HꢀC(6)). Anal. calc. for C22H21N3O5 (407.42): C 64.86, H 5.20, N 10.31; found: C 64.08, H 5.23, N 9.91.
1-Benzyl-3-{1-[(trimethylsilyl)oxy]ethenyl}-1H-indole (9). From 3-acetyl-1-benzyl-1H-indole (2.5 g, 10
mmol), LDA (20 mmol), and Me3SiCl (2.5 ml, 20 mmol), as described for 1a. After stirring for 90 min at
ꢀ788, the mixture was poured into Et2O (100 ml), the org. layer washed with aq. sat. NH4Cl soln. (3×100
ml), dried (MgSO4), and evaporated: 3.0 g (93%; not purified) of 9 which was immediately used for further reac-
tions. IR (film): 2958 (CH), 1636 (C=C), 1528 (arom. CꢀC), 1252 (SiꢀMe), 1090 (SiꢀO), 845 (Me3Si). 1H-NMR
(60 MHz): 0.2 (s, Me3Si); 4.48, 4.90 (2d, J=1.2, =CH2); 5.04, 5.31 (2s, CH2); 7.00–7.92 (m, 9 arom. H).
10-Benzyl-3a,4,10,10b-tetrahydro-2-phenylpyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (10a). At ꢀ788,
1M
EtAlCl2 in hexane (10 ml) was injected via a septum into a vigorously stirred soln. of 2a (1.73 g, 10 mmol) in
CH2Cl2 (40 ml), and after 30 min a soln. of 9 (3.2 g, 10 mmol) in CH2Cl2 (20 ml) was added. Stirring was contin-
ued for 2 h at ꢀ788, then the mixture allowed to warm to r.t., and stirring continued for 2 d. After hydrolysis with
dil. HCl soln. (caution!), the mixture was extracted with CH2Cl2 and the org. layer dried (MgSO4) and evapo-
rated. A few ml MeOH and dil. HCl soln. were added to the residue, and the mixture was refluxed for 2 h. After
evaporation, the residue was purified by CC (AcOEt/cyclohexane 1 :1): 80 mg (2%) of 10a. Colorless crystals.
M.p. 2448 (MeOH). IR: 1783, 1720, 1649 (CO), 1528, 1495 (arom. CꢀC). 1H-NMR (300 MHz): 2.99 (dd, J(4B,
3a)=8.1, J(4B,4A)=17.1, HBꢀC(4)); 3.15 (dd, J(4A,3a)=6.6, J(4A,4B)=17.1, HAꢀC(4)); 3.82 (ddd, J(3a,

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HELVETICA CHIMICA ACTA – Vol. 88 (2005)
4A)=6.6, J(3a,4B)=8.2, J(3a,10b)=8.2, HꢀC(3a)); 4.46 (d, J(10b,3a)=8.1, HꢀC(10b)); 5.66, 6.13 (2d, J=17.1,
CH2); 6.98–8.36 (m, 14 arom. H). Anal. calc. for C27H20N2O3 (420.47): C 77.13, H 4.79, N 6.66; found: C 76.07, H
4.86, N 6.47.
10-Benzyl-2-ethyl-3a,4,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (10b). From 2c (1.25 g,
10 mmol) and 9 (3.21 g, 10 mmol), as described for 10a, but after warming to r.t., the mixture was refluxed
for 72 h and then cooled to r.t.: 84 mg (2.3%) of 10b. Colorless crystals. M.p. 1908 (MeOH). IR: 1779, 1708,
1642 (CO), 1529, 1497 (arom. CꢀC). 1H-NMR (300 MHz): 1.16 (t, J=7.3, Me); 2.91 (dd, J(4B,4A)=17.2,
J(4B,3a)=8.2, HBꢀC(4)); 3.04 (dd, J(4A,4B)=17.1, J(4A,3a)=6.1, HAꢀC(4)); 3.58 (q, J=7.3, CH2); 3.64
(ddd, J(3a,4A)=6.1, J(3a,4B)=8.2, J(3a,10b)=8.2, HꢀC(3a)); 4.29 (d, J(10b,3a)=8.1, HꢀC(10b)); 5.66, 6.14
(2d, J=16.9, CH2); 6.99–8.31 (m, 9 arom. H). Anal. calc. for C23H20N2O3 (372.42): C 74.18, H 5.41, N 7.52;
found: C 73.98, H 5.43, N 7.44.
11-Benzyl-11,11a-dihydro-6-hydroxy-2-phenyl-1H,5H-[1,2,4]triazolo[1’,2’:1,2]pyridazino[3,4-b]indole-1,3-
(2H)-dione (11). At ꢀ788, a soln. of 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (1.16 g, 6 mmol) in THF (10 ml)
was dropwise added with stirring to a soln. of 9 (3.2 g, 10 mmol) in THF (50 ml). After 2 h at ꢀ788, the mixture
was allowed to warm to r.t., the solvent evaporated, and the residue stirred with MeOH (a few ml) for 5–6 h. The
solvent was evaporated, and after addition of toluene (a few ml), the insoluble part was separated: 2.4 g (92%)
of 11. Colorless crystals. M.p. 2128. IR: 3445 (OH), 1706 (CO), 1187 (arom. CꢀOH). 1H-NMR (CDCl3/
(D6)DMSO 5 :1): 4.72 (s, HAꢀC(5), HBꢀC(5)); 5.2 (s, CH2); 6.99–8.15 (m, 15 arom. H); 9.9 (br. s, OH).
Anal. calc. for C25H20N4O3 (424.46): C 70.74, H 4.75, N 13.20; found: C 70.53, H 4.82, N 13.12.
11-Benzyl-6,11-dihydro-6-hydroxy-2-phenyl-1H,5H-[1,2,4]triazolo[1’,2’:1,2]pyridazino[3,4-b]indole-1,3-
(2H)-dione (12). From 11 (400 mg, 0.9 mmol) by hydrogenation with H2 (Pd/C) in MeOH/CH2Cl2 1:1 at r. t. for
72 h: 280 mg (70%) of 12. Colorless crystals. 1H-NMR (300 MHz): 3.90 (dd, J(5,6)=9.4, J(5,5)=14.5, HAꢀC(5));
4.20 (dd, J(5,6)=3.5, J(5,5)=14.5, HBꢀC(5)); 4.84 (dd, J(6,5)=3.4, J(6,5)=9.5, HꢀC(6)); 5.30 (s, CH2); 7.0–7.8
(m, 15 arom. H); 8.05 (br. s, OH).
11-Benzyl-6,6a,11,11a-tetrahydro-6-(hydroxyimino)-2-phenyl-1H,5H-[1,2,4]triazolo[1’,2’:1,2]pyridazino-
[3,4-b]indole-1,3(2H)-dione (13a). A mixture of AcONa (5.0 g, 60 mmol), and H2NOH·HCl (4.2 g, 60 mmol) in
EtOH (50 ml) was refluxed for some min and then filtered. To the filtrate, 11 (1.0 g, 2.35 mmol) was added and
the mixture was then refluxed for 3 h. After evaporation, EtOH (20 ml) was added to the residue, followed by
H2O until the mixture was cloudy: 840 mg (81%) of 13a. Colorless needles. M.p. 1668 (EtOH). IR: 3385 (OH),
1691 (CO). 1H-NMR ((D6)DMSO): 4.82 (s, HAꢀC(5), HBꢀC(5)); 5.40 (s, CH2); 7.07–8.16 (m, 15 arom. H, OH);
11.9 (br. s, NH). Anal. calc. for C25H21N5O3 (439.47): C 68.33, H 4.82, N 15.94; found: C 68.67, H 5.01, N 15.44.
11-Benzyl-6,6a,11,11a-tetrahydro-6-(methoxyimino)-2-phenyl-1H,5H[1,2,4]triazolo[1’,2’:1,2]pyridazino-
[3,4-b]indole-1,3(2H)-dione (13b). As described for 13a, from AcONa (2.0 g, 24 mmol), H2NOMe·HCl (2.0 g,
24 mmol), and 11 (0.43 g, 1 mmol): 385 mg (85%) of 13b. Colorless needles. M.p. 221–2238 (EtOH). IR: 3434
1
(NH), 1703 (CO), 1600 (arom. CꢀC). H-NMR ((D6)DMSO): 3.95 (s, MeO); 4.8 (s, HAꢀC(5), HBꢀC(5)); 5.4
(s, CH2); 7–8.2 (m, 15 arom. H); 10.6 (br. s, NH). MS: 453 (16.8, M+), 91 (100, PhC2þ), 77 (6.5, Ph). EI-HR-
MS: 453.1801 (C26H23N5Oþ3 ; calc. 453.1810, 2.0 ppm).
10b-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-3a,4,10,10b-tetrahydro-2-phenylpyrrolo[3,4-a]carbazole-1,3,5(2H)-
trione (15a). A soln. of 2a (1.73 g, 10 mmol) and 14 (3 g, 10 mmol) in toluene was stirred for 24 h. After evap-
oration, the residue was stirred with MeOH (a few ml) at r.t., the solvent evaporated, and the residue purified by
CC (cyclohexane/AcOEt 1:1): 1.2 g (48%) of isomers 15aa/15ab 4 :1. Colorless crystals. M.p. 2728. IR: 3411
(NH), 1782, 1712, 1650 (CO), 1597 (arom. CꢀC). 15aa: 1H-NMR (300 MHz): 2.43 (dd, J(4’,3’; trans)=7.5,
J(4’,4’)=17.9, HtransꢀC(4’)); 2.57 (dd, J(4’,3’; cis)=9.4, J(4’,4’)=17.9, HcisꢀC(4’)); 2.80 (dd, J(4B,3a)=8.8,
J(4B,4A)=18.1, HBꢀC(4)); 3.04 (dd, J(4A,3a)=1.5, J(4A,4B)=18.2, HAꢀC(4)); 3.45 (dd, J(3a,4A)=1.5,
J(3a,4B)=8.8, HꢀC(3a)); 4.47 (dd, J(3’,4’; trans)=7.5, J(3’,4’; cis)=8.9, HꢀC(3’)); 6.80–7.90 (m, 14 arom.
H); 11.80 (s, NH). MS: 503 (79, M+.), 330 (71, [M+1ꢀphenylmaleimide]+), 329 (40, [Mꢀphenylmaleimide]+),
174 (14, [phenylmaleimide]+), 130 (4), 77(4). EI-HR-MS: 503.1481 (C30H21N3Oþ5 ; calc. 503.1483, 0.4 ppm).
3a,4,10,10b-Tetrahydro-2-methyl-10b-(1-methyl-2,5-dioxopyrrolidin-3-yl)-pyrrolo[3,4-a]carbazole-1,3,5-
(2H)-trione (15b). As described for 15a, with 14 (3.0 g, 10 mmol), 2b (1.1 g, 10 mmol), and toluene (30 ml) (3 d at
r.t.; stirring of MeOH soln. for 1 h): 135 mg (7%) of 15b/19. 15b: Colorless crystals. M.p. 2758 (AcOEt). IR: 3333
(NH), 1778, 1704, 1636 (CO), 1583 (arom. CꢀC). 1H-NMR (300 MHz): 2.46 (dd, J(4’,3’; trans)=6.7, J(4’,
4’)=18.4, HtransꢀC(4’)); 2.75 (dd, J(4’,3’; cis)=9.5, J(4’,4’)=18.4, HcisꢀC(4’)); 2.88 (dd, J(4B,3a)=8.7, J(4B,
4A)=18.4, HBꢀC(4)); 3.14 (dd, J(3a,4A)=1.2, J(3a,4B)=8.7, HꢀC(3)); 3.43 (dd, J(4A,3a)=1.2, J(4A,
4B)=18.4, HAꢀC(4)); 4.18 (dd, J(3’,4’; trans)=6.7, J(3’,4’; cis)=9.4, HꢀC(3’)); 7.26–8.26 (m, 4 arom. H); 9.7
(br. s, NH). MS: 379 (96, M+.), 268 (90.11, [Mꢀmaleimide]+). EI-HR-MS: 379.1168 (C20H17N3Oþ5 calc.;
379.1169, 0.2 ppm).

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5a-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-3a,4,5a,10,10a,10b-hexahydro-2-phenyl-10-(trimethylsilyl)pyrrolo-
[3,4-a]carbazole-1,3,5(2H)-trione (16). As described 15a, from 14 (3 g, 10 mmol) and 2a (1.73 g, 10 mmol) (30
min at r.t., stirring of MeOH soln. for only 1 h): 850 mg (30%) of 16. Colorless crystals. M.p. 3008. IR: 1777,
1714 (CO), 1596 (arom. CꢀC), 1187, 1110, 1068, 1026, 983 (SiꢀN), 842, 757 (SiMe3). 1H-NMR (300 MHz):
0.40 (s, Me3Si); 2.47 (dd, J(4’,3’; cis)=9, J(4’,4’)=18.1, HcisꢀC(4’)); 2.83 (dd, J(4A,3a)=8.54, J(4A,4B)=15.9,
HAꢀC(4)); 3.06 (dd, J(3’,4’; trans)=5.6, J(3’,4’; cis)=9, HꢀC(3’)); 3.16 (dd, J(4’,3’; trans)=5.6, J(4’,4’)=18.1,
HtransꢀC(4’)); 3.21 (dd, J(4B,3a)=2.7, J(4B,4A)=15.8, HBꢀC(4)); 3.42 (dd, J(10b,10a)=8.6, J(10b,3a)=9.5,
HꢀC(10b)); 3.48 (ddd, J(3a,4B)=2.7, J(3a,4A)=9.2, J(3a,10b)=9.2, HꢀC(3a)); 5.52 (d, J(10a,10b)=8.5, Hꢀ
C(10a)); 6.70–7.55 (m, 14 arom. H). Anal. calc. for C33H31N3O5Si (577.71): C 68.61, H 5.41, N 7.27; found: C
68.75, H 5.49, N 7.16.
3a,4,10,10b-Tetrahydro-3a-methyl-2-phenylpyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (18). As described for
15b, from 14 (3.0 g, 10 mmol) and N-phenylcitraconimide (=3-methyl-1-phenyl-1H-pyrrole-2,5-dione; 17;
1.87 g, 10 mmol): 70 mg (2%) of 18. Colorless crystals. M.p. 272–2758 (MeOH). IR: 3185 (NH), 1719 1633
(CO). 1H-NMR (300 MHz): 1.5 (s, Me); 2.55 (d, J=16.1, HBꢀC(4)); 3.0 (d, J=16.8, HAꢀC(4)); 4.1 (s, Hꢀ
C(10b)); 7.0–8.0 (m, 9 arom. H); 11.6 (br. s, NH). MS: 344 (100, M+.). EI-HR-MS: 344.1161 (C21H16N2O3þ ;
calc. 344.1162).
3a,4,10,10b-Tetrahydro-2-methylpyrrolo[3,4-a]carbazole-1,3,5(2H)-trione (19). From the mixture 15b/19 by
crystallization from AcOEt, or by heating of 7 (368 mg, 1 mmol) until the product was melting (ca. 3008), and
crystallization of the residue from MeOH: 242 mg (90%) of 19. Colorless crystals. M.p. 2828. IR: 3227 (NH),
1779, 1703 (C=O), 1626 (a,b-unsatd. C=O). 1H-NMR (300 MHz): 2.59 (dd, J(4A,3a)=8.8, J(4A,4B)=17.6,
HAꢀC(4)); 2.68 (s, Me); 2.88 (dd, J(4B,3a)=2.7, J(4B,4A)=17.3, HBꢀC(4)); 3.45 (ddd, J(3a,4B)=2.7, J(3a,
4A)=8.6, J(3a,10b)=8.6, HꢀC(3a)); 4.19 (d, J(10b,3a)=8.3, HꢀC(10b)); 6.93 (m, 2 arom. H); 7.22 (m, 1
arom. H); 7.84 (m, 1 arom. H); 11.4 (br. s, NH). MS: 268 (24, M+.). EI-HR-MS: 268.0848 (C15H12N2O3þ ; calc.
268.0849). Anal. calc. for C15H12N2O3 (268.27): C 67.16, H 4.51, N 10.44; found: C 66.52, H 4.47, N 10.29.
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Received June 28, 2005