Stereochemistry of 1,3-dipolar-cycloaddition of 3,4-dihydroisoquinoline- and 3,4-dihydro-carboline-N-methoxycarbonyl- and N-phenacyl-methylides with maleic and fumaric nitrile

Article abstract of DOI:10.1002/jhet.5570440621

(Chemical Equation Presented) The 1,3-dipolar-cycloadditions of two kind of isoquinolinium and carbolinium ylides with fumaric and maleic nitrile resulted in pyrroloisoquinoline and indolizino[8,7-b]indole derivatives, respectively, which are analogues of biologically active alkaloids. The cycloadditions were performed in good yield and proved to be stereoselective. The structure elucidation and complete ¹H and ¹³C assignments have been achieved by a combination of various one- and two-dimensional NMR experiments.

Full text of DOI:10.1002/jhet.5570440621

Nov-Dec 2007
1373
Stereochemistry of 1,3-Dipolar-cycloaddition of 3,4-Dihydro-
isoquinoline- and 3,4-Dihydro-carboline-N-methoxycarbonyl- and
N-Phenacyl-methylides with Maleic and Fumaric Nitrile
István Kádas,ꢀ a Gábor Szántó, b László Tꢀke, b András Simon, c and Gábor Tóthꢀc
aResearch Group of Organic Chemical Technology, Hungarian Academy of Sciences, Budapest University of
Technology and Economics, H-1521 Budapest, Hungary; bInstitute of Organic Chemical Technology, Budapest
University of Technology and Economics, H-1521 Budapest, Hungary; cDepartment of General and Analytical
Chemistry, Budapest University of Technology and Economics, H-1111 Budapest, Szent Gellért tér 4, Hungary
Fax: +36-1/4633408, Email: gabor.toth@mail.bme.hu
Received January 2, 2007
Dedicated to Professor Albert Lévai (University of Debrecen, Hungary) on the ocassion of his
65th birthday
MeO
MeO
MeO
+
N
COR
CN
N
COR
CN
MeO
H
H
CN
NC
NC
MeO
MeO
MeO
MeO
NC
CN
NC
N
COR
N
COR
ꢀ
ꢀ
H
NC
CN
MeO
MeO
R = OMe, Ph
N
COR
CN
H
NC
N
COR
N
H
H
N
COR
CN
COR
N
+
N
H
N
H
NC
CN
+
H
H
CN
NC
NC
CN
N
COR
NC
CN
N
H
NC
H
N
COR
N
H
ꢀ
ꢀ
NC
CN
R = OMe, Ph
N
COR
CN
N
COR
CN
N
H
N
H
H
H
NC
NC
The 1,3-dipolar-cycloadditions of two kind of isoquinolinium and carbolinium ylides with fumaric and
maleic nitrile resulted in pyrroloisoquinoline and indolizino[8,7-b]indole derivatives, respectively, which
are analogues of biologically active alkaloids. The cycloadditions were performed in good yield and
1
proved to be stereoselective. The structure elucidation and complete H and 13C assignments have been
achieved by a combination of various one- and two-dimensional NMR experiments.
J. Heterocyclic Chem., 44, 1373 (2007).
Earlier we reported the 1,3-cycloaddition of azo-
methine-ylide 3a, obtained with the deprotonation method
[4] from the quaternary isoquinoline salt 2a in the
presence of organic base, with several dipolarophiles and
studied the stereochemistry of the cycloadducts [5-15]. In
most cases the deprotonation method proved to be the best
preparative way to obtain cyclic azomethine ylides,
therefore we decided to continue these studies utilising
this method. In our present report, the 1,3-dipolar-
cycloaddition of ylide 2a with both stereoisomers of the
powerful dipolarophile 1,2-dicyano-ethylene: the maleic
INTRODUCTION
In the last decade new pyrroloisoquinoline and
indolizino[8,7-b]indole alkaloids, having cytotoxic and
other biologic activity, were isolated from Carduus
crispus and Kopsia griffithii, respectively, by Chinese [1]
and Malaysian [2] groups. At the same time Poissonnet et
al. reported on 1,2-dicyano substituted analogues of the
latter alkaloids with considerable anti-leukemic activity
[3]. Considering these effects this class of compounds
seems to be promising also from biological aspects.

1374
I. Kádas, G. Szántó, L. Tꢀke, A. Simon, and G. Tóth
Vol 44
(4) and fumaric nitrile (5) have been investigated resulting
the isomers 6a and 7a, and in the frame of our ongoing
program to synthesize biologically active alkaloid
analogues, we aimed at extending the cycloaddition
studies to other quaternization agents and other cyclic
azomethines (Scheme 1).
most cases the investigations were not extended to
thorough stereochemical studies applying one- and two
dimensional NMR methodes.
As it was outlined in the introduction first we extended
our quaternization-deprotonation sequence to a quat-
ernization reagent, the phenacyl bromide, which was not
applied by us earlier. Thus, we quaternized 3,4-dihydro-
6,7-dimethoxy-isoquinoline (1) with phenacyl-bromide to
2b from which ylide 3b could be prepared in situ with
triethylamine and latter was reacted immediately with the
desired dipolarophiles 4 and 5. The obtained cycloadducts
were 6b, 8b and 9b, respectively. The reactions resulted
racemates but for the sake of clarity only one enantiomer
with H-10b in ‘ꢀ’ position is shown.
RESULTS AND DISCUSSION
The deprotonation method for the preparation of
stabilized cyclic azomethine ylides is one of the most
direct routes of generating 1,3-dipoles. At first Huisgen
[16] applied this approach in the study of 1,3-dipolar
cycloaddition of N-phenacyl-3,4-dihydro-isoquinolinium
ylides. Despite the considerable advantages of this
Scheme 1
7
MeO
MeO
MeO
6a
10a
5
N
10b
COOMe
CN
N
COPh
CN
MeO
3
10
H
H
1
NC
NC
NC
CN
4
6a
6b
a) BrCH2COOMe
b) BrCH2COPh
MeO
MeO
MeO
MeO
MeO
Et3N
Br
N
R
N
N
R
MeO
ꢀ
ꢀ
3a R = COOMe
3b R = COPh
2a R = COOMe
2b R = COPh
1
CN
NC
5
MeO
MeO
MeO
MeO
MeO
N
COOMe
CN
N
COPh
+
N
COPh
or
MeO
H
H
H
NC
NC
NC
CN
CN
7a
8b
9b
Synthesis of pyrroloisoquinoline derivatives 6-9 (racemate).
As a further extension of our studies to 3,4-dihydro-
carboline ylides, we used the dehydrogenation method
[21] for the preparation of the methoxycarbonyl-derivera-
tive because in this case the use of the deprotonation
method failed. The starting material for the dehydro-
genation method, tetrahydro-carboline derivative 11 could
be synthesized from tetrahydro-ß-carboline 10 and methyl
bromoacetate in dimethyl-formamide. The ylide 14a
could be obtained in situ in dimethyl-formamide in the
presence of Pd-black at 110 °C. Dipolarophiles 4 and 5
were added at the beginning of the reaction which was
continued for 48 hours at 110 °C and the reaction yielded
isomers 17a, 18a and 19a, respectively (Scheme 2).
method in the next years it was relatively sparsely
applied: only Tsuge et al. used it also for the preparation
of isoquinolinium ylides [17], then Potaꢁek [18] and
Sꢂiwa [19] applied it for the synthesis of phenantridinium
and benzo[h]napthyridinium ylides, respectively. It is
worth mentioning some other less direct synthetic routes,
which were also applied for the preparation of non-
stabilized cyclic azomethine ylides by Poissonnet
(desylilation route [3]), and Novikov (difluoro-carbene
addition route [20]) and for stabilized cyclic ylides by
Grigg (dehydrogenation route [21]). The cited authors
[3,16-21] studied the 1,3-dipolar cycloaddition reactions
of the so prepared cyclic azomethine ylides with activated
olefines e.g. maleic imides, fumaric and maleic esters and
even with fumaric nitrile [18], but none of them examined
the cycloadditions of stabilized dihydro-isoquinoline and
carboline ylides with maleic and fumaric nitriles and in
Finally the 3,4-dihydro-ß-carboline (12) was easily
quaternized with phenacyl-bromide to 13, which was then
deprotonated with triethylamine in situ to the ylide 14b in
the presence of the desired dipolarophiles 4 and 5. These
reactions gave the isomers 16b, 15b, 17b and 18b, 20b,

Nov-Dec 2007
Stereochemistry of 1,3-Dipolar-cycloaddition of Cyclic Azomethine Ylides
with Maleic and Fumaric Nitrile
1375
respectively. It should be mentioned that for these
compounds we applied a special not IUPAC numbering to
allow the easy comparison of the NMR data of pyrrolo-
isoquinoline and indolizino[8,7-b]indole derivatives.
equilibrium should be taken into account as it is shown on the
example of indolizino[8,7-b]indole (15b-20b) derivatives
(Figure 1). We accomplished a conformational examination
with the help of the program HyperChem 7.0.
Scheme 2
7
6a
5
6b
10a
10'
N
COPh
N
COOMe
CN
N
COPh
CN
N
COPh
CN
N
N
N
N
H
10b
1
3
10
+
+
H
H
H
H
H
H
H
NC
CN
NC
NC
NC
17a
17b
16b
15b
NC
CN
4
BrCH2 COOMe
Pd-black
NH
N
COOMe
DMF, 110 C
o
N
H
N
H
48 hours
11
10
N
R
N
ꢀ
ꢀ
H
BrCH2COPh
Et3N
Br
14a R = COOMe
14b R = COPh
N
N
COPh
CN
N
H
N
H
NC
12
5
13
N
COOMe
COPh
N
COOMe
CN
COPh
N
N
N
N
N
N
H
H
H
H
H
H
H
+
H
+
NC
CN
NC
CN
NC
NC
CN
18a
19a
18b
20b
Synthesis of indolizino[8,7-b]indole derivatives 15-20 (racemate).
When only one isomer was formed during the reaction, it
was isolated by extraction with benzene, in other cases
column chromatography was used to separate and isolate the
products. At any time, when dehydrogenation method was
used to perform the cycloaddition, the yields always
surpassed that of the deprotonation method, a plausible
reason could be that the latter way utilizes milder conditions.
In the trans conformation the lone electron pair of the
nitrogen atom between the six- and five-membered rings is
in an antiperiplanar position to the 10b-hydrogen, whereas its
arrangement is gauche in cis-1 and cis-2. Inversion of the
pyramidal nitrogen atom in the trans conformer leads to the
cis-1 conformer in which the C-3 atom is axial with respect
to the six-membered ring resulting the characteristic ~5 ppm
ꢁ-gauche upfield shift at C-6. Ring inversion of the cis-1
conformer results in formation of cis-2. The pseudorotation
of the five-membered ring renders possible the coexistence
of several conformations at this ring. Differentiation of the
trans and cis-2 conformers can be achieved utilizing the Hꢀ-
10b/Hꢀ-5 steric proximity detected by NOE response in
conformer trans. Detection of Hꢂ-5/Hꢂ-1 or Hꢂ-5/Hꢂ-2 NOE
cross-peaks prove the cis-2 conformation, but it should be
mentioned, that in several cases the absence of these cross-
peaks can be explained with pseudorotation of the five-
membered ring of the cis-2 conformer. The Hꢀ-5 and Hꢂ-6
hydrogen atoms are diaxial in the trans and cis-1 conformers
STRUCTURE ELUCIDATION
The structures of products were determined with compre-
hensive one- and two-dimensional NMR methods using
widely accepted strategies [22, 23]. To alleviate the character-
ization of diastereomers we introduced the abbreviation
including the ꢀ or ꢀ position of the hydrogen atoms H-10b, H-
1
1, H-2, H-3. Characteristic H and 13C NMR data were
collected in Tables 1-3. The structure elucidation was particu-
larly challenging since the resulting pyrroloisoquinoline (6a-
9b) and indolizino[8,7-b]indole (15b-20b) derivatives besides
four stereogenic centres, also incorporate a bridgehead
nitrogen in a relatively flexible skeleton. Thus as we discussed
previously [7,9,11] due to nitrogen and ring inversions for the
junctions of the six-membered and five-membered rings the
existence of a triple trans ꢀ cis-1 ꢀ cis-2 type conformational
3
and the corresponding JH,H coupling is about 10-11 Hz,
whereas these hydrogens are diequatorial arranged in cis-2
3
resulting a ~ 3 Hz coupling. Detection of an averaged JH,H
value of the trans arranged H-5 and H-6 atoms indicates a
conformation equilibrium with a considerable appearance of

1376
I. Kádas, G. Szántó, L. Tꢀke, A. Simon, and G. Tóth
Vol 44
cis-2 conformer, as it was observed in case of compounds 6a,
7a and 9b (Table 1). According to our investigations
compounds 6b and 8b appeared predominantly in cis-2
conformer. It is worth mentioning that the chemical shifts of
C-6 in 7a (26.7 ppm) is ca. 1.5 ppm smaller than in
compounds 6a, 6b, 8b and 9b, may be indicative of the
participation of cis-1 in the equilibrium.
It was found that the characteristic 13C chemical shift of
C-6 in the indolizino[8,7-b]indole derivatives is 21.5 ppm
(Table 2) for the trans and cis-2 conformers (15b, 16b),
whereas in case of cis-1 it is only 16.5 ppm (19a). These
chemical shifts are in good agreement with the data
obtained for indolo[2,3-a]quinolizine derivatives [24].
The ꢀC-6: 19.5 ppm in compound 18a proves the
existence of cis-1 in the conformational equilibrium with
cis-2 and trans. Compound 17a should exist in an
equilibrium of cis-1/trans, in accordance with the value of
ꢀC-6: 18.2 ppm and with the strong NOE response of Hꢀ-
5/Hꢀ-10b. We were prompted to investigate the
temperature dependence of this equilibrium.
Lowering the temperature from 300K till 215K we
didn’t observed a coalescence, but the equilibrium shifted
strongly to the site of cis-1 as it follows from the value of
ꢀC-6: 16.4 ppm, which is in good agreement with the
value measured for 19a.
The characteristic NMR data of the indolizino[8,7-b]-
indole derivatives with R = COPh substituent are
summarized in Table 3.
trans
cis-1
cis-2
Figure 1. Conformational equilibrium of the indolizino[8,7-b]indole skeleton.

Nov-Dec 2007
Stereochemistry of 1,3-Dipolar-cycloaddition of Cyclic Azomethine Ylides
with Maleic and Fumaric Nitrile
1377

1378
I. Kádas, G. Szántó, L. Tꢀke, A. Simon, and G. Tóth
Vol 44

Nov-Dec 2007
Stereochemistry of 1,3-Dipolar-cycloaddition of Cyclic Azomethine Ylides
with Maleic and Fumaric Nitrile
1379

1380
I. Kádas, G. Szántó, L. Tꢀke, A. Simon, and G. Tóth
Vol 44
for 6 hours, and the precipitated material was collected by
filtration. Yield: 1.05 g (51 %), yellow solid, mp.: 191-198 °C.
Anal. Calcd. for C19H20BrNO3: C, 58.47; H, 5.17; N, 3.59;
found: C, 58.53; H, 5.20; N, 3.52.
The only derivative with the relative configuration at C-
10b/C-1/C-2/C-3 atoms, containing the hydrogen atoms in
ꢀꢀꢀꢀ positions is 16b, and it exhibits trans conformation
most probably due to sterical reason. In the case of the
cycloadducts 15b, 16b, and 17b the following statements can
be settled: the cis-1 conformer can be excluded because of the
value of the chemical shift of the C-6 atom; the characteristic
shift of the C-6 atom in case of the cis-1 conformer is between
15-16 ppm, but in contrast, the chemical shifts for the
cycloadducts are about 21 ppm. The missing spatial proximity
between the H-10b and Hax-5 nuclei and the steric proximity
between the H-1 and Hax-5 nuclei – which is characteristic for
cis-2 – prove the fact that the compounds 15b and 17b are
mainly in the cis-2 conformer.
Preparation of cycloadducts 6a and 7a. A mixture of 3,4-
dihydro-6,7-dimethoxy-N-(carbomethoxymethyl)-isoquinolin-
ium bromide (2a) (0.3000 g, 0.872 mmol) and maleic nitrile (4)
or fumaric nitrile (5) (0.0681 g, 0.872 mmol) were dissolved in
chloroform (10 mL), and triethylamine (0.25 mL, 1.83 mmol)
was added to the mixture, which was stirred then for 24 hours at
room temperature, the solvents were removed in vacuo. In case
of both reactions only one isomer was formed, which was
isolated then by extracting the reaction mixture residue with
benzene. The yield was 77 % in case of maleic nitrile and 79 %
in case of fumaric nitrile.
6a: pale yellow solid, mp.: 160-162 °C. Anal. Calcd. for
C18H19N3O4: C, 63.33; H, 5.61; N, 12.31; found: C, 63.22; H,
5.71; N, 12.36.
It is known that the trans orientation of the lone pair of
1
the nitrogen atom has a specific influence on the JC,H
7a: yellow solid mp.: 140-142 °C. Anal. Calcd. for
C18H19N3O4: C, 63.33; H, 5.61; N, 12.31; found: C, 63.23; H,
5.65; N, 12.33.
coupling constants and this can be utilized for the
determination of the relative configuration of the NC-H
hydrogens and of the lone pair [25]. For the analogous
1
Preparation of cycloadducts 6b and 8b, 9b: A mixture of
3,4-dihydro-6,7-dimethoxy-N-(benzoylmethyl)-isoquinolinium
bromide (2b) (0.3000 g, 0.872 mmol) and maleic nitrile (4) or
fumaric nitrile (5) (0.0681 g, 0.872 mmol) were dissolved in
chloroform (10 mL), and triethylamine (0.25 mL, 1.83 mmol)
was added to the mixture, which was stirred then for 24 hours at
room temperature, the solvents were removed in vacuo. In case
of the reaction between 2a and 4, only one isomer was formed,
which was isolated then by extracting the reaction mixture
residue with benzene. When fumaric nitrile (5) was used as a
dipolarophile, the products were separated by column
chromatography on silica eluting with the 1:1 mixture of hexane
and ethyl acetate. The combined yield was 76 % in case of
maleic nitrile and 82 % in case of fumaric nitrile.
6b: pale yellow solid, mp.: 198-200 °C. Anal. Calcd. for
C23H21N3O3: C, 71.30; H, 5.46; N, 10.85; found: C, 71.31; H,
5.31; N, 10.99.
8b (major compound): yellow solid mp.: 92-94 °C. Anal.
Calcd. for C23H21N3O3: C, 71.30; H, 5.46; N, 10.85; found: C,
71.31; H, 5.31; N, 10.99.
pyrroloisoquinolines we detected values of JC,H = 135-
138 Hz in the trans, whereas 147-149 Hz couplings
appeared for cis-1 and cis-2 conformers [10,11]. We
1
measured JC-10b,H-10b = 138 Hz, which gives further
support to the trans conformation of compound 16b.
EXPERIMENTAL
We have reacted two kinds of isoquinolinium and carbolinium
ylides with fumaric and maleic nitrile. The reactions were
performed in a good (ca. 75-80 %) yield, which makes this
method a competent way to synthesize such compounds in mild
conditions. The cycloadditions were proved to be stereoselective
according to the Woodward-Hoffmann rules. The product ratios
of the reaction 14b with 4 were determined by HPLC and also
1
by H NMR methods resulting in good agreement 4:1:1 for
compounds 16b, 15b, 17b. The product ratios of the other
cycloadditions were evaluated by 1H NMR method. Melting
points were determined with a Büchi 510-apparatus and are
uncorrected. The IR spectra were measured on a Perkin Elmer
1600 FT-IR. The tlc performed on Kieselgel 60 F254 (Merck)
layer using 1:1 mixture of hexane and ethyl acetate.
9b (minor compound): yellow solid, mp.: becomes black at
196-200 °C, and does not melt till 240 °C. Anal. Calcd. for
C23H21N3O3: C, 71.30; H, 5.46; N, 10.85; found: C, 71.31; H,
5.31; N, 10.99.
The NMR spectra were recorded on BRUKER Avance DRX-
500 and Bruker Avance 500 MHz spectrometers. Chemical
shifts were determined on ꢁ-scale. For structure elucidation and
Methyl 1,2,3,4-tetrahydrocarboline-2-ylacetate (11). Tetra-
hydro-ß-carboline (10) (1.72 g, 10 mmol) was dissolved in dry
dimethyl formamide (30 mL), freshly dried potassium-carbonate
(0.83 g, 6 mmol) was added and the mixture was heated to 80 °C.
Then methyl bromoacetate (1.03 mL, 11 mmol) in dry dimethyl
formamide (10 mL) was added to the reaction mixture within 30
minutes. The reaction mixture was kept at 80 °C for 4 hours,
cooled and poured on ice. After 10 minutes precipitation began to
appear, which was then filtered, washed with water and dried in
desiccator. Yield: 1.73 g (71 %), yellow solid. mp.: 141-4 °C. mp
1
1H/13C NMR signal assignment one-dimensional H, 13C, APT,
DEPT-135, selective 1D-NOESY, selective 1D-ROESY and
1
1
two-dimensional gradient selected H,1H-COSY, H,13C-HSQC,
1H,13C-HMQC, 1H,13C-HMBC, 1H,1H-NOESY and 1H,1H-
1
ROESY spectra were run. The JC,H couplings were obtained
1
from the H coupled HSQC or HMQC experiments. In case of
some selective 1D-NOESY and -ROESY measurements a few
drops of benzene-d6 were added to achieve an appropriate signal
dispersion of the hydrogen signals of the five membered ring.
3,4-dihydro-6,7-dimetoxy-N-(benzoylmethyl)-isoquinolin-
ium bromide (2b). 3,4-Dihydro-6,7-dimethoxy-isoquinoline (1)
(1.00 g, 5.23 mmol) was dissolved in acetonitrile (5 mL), and
phenacyl-bromide (1.04 g, 5.23 mmol) was added to the
solution. The reaction mixture was stirred at room temperature
1
(recrystallized from methanol): 142-4 °C. H-NMR (CDCl3, 500
MHz) ꢁ: 2.82 (m, 2H), 3.00 (m, 2H), 3.45 (s, 2H), 3.75 (s, 3H),
7.06-7.13 (m, 2H), 7.24 (m, 1H), 7.45 (d, 1H), 7.87 (s, 1H) ppm;
13C-NMR (CDCl3, 125 MHz) ꢁ: 21.1, 49.9, 50.9, 52.0, 58.1,
108.2, 111.0, 118.1, 119.5, 121.6, 127.4, 131.3, 136.3, 171.4 ppm.
Anal. Calcd. for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47; found:
C, 68.84; H, 6.52; N, 11.52.

Nov-Dec 2007
Stereochemistry of 1,3-Dipolar-cycloaddition of Cyclic Azomethine Ylides
with Maleic and Fumaric Nitrile
1381
Preparation of the 3,4-dihydro-2-(benzoylmethyl)-ß-
carbolinium bromide (13). 3,4-Dihydro-ß-carboline (12) (0.5
g, 0.294 mmol) was dissolved in acetonitrile (10 mL), and
phenacyl bromide (0,6 g, 0.300 mmol) was added to the
solution. The reaction mixture was stirred at room temperature
for 2 hours, and the precipitated material was filtered off. Yield:
0.6 g (55 %), yellow solid, mp.: 228-232 °C. 1H-NMR (DMSO-
d6, 500 MHz, ꢀ): 3.16 (t, 2H), 4.15 (t, 2H), 5.88 (s, 2H), 7.21-
8.06 (m, 9H), 9.13 (s, 1H), 12.50 (s, 1H) ppm. 13C-NMR
(DMSO-d6, 125 MHz): 19.3, 50.7, 64.7, 113.7, 121.8, 122.2,
123.7, 124.5, 125.7, 128.3, 129.1, 129.4, 133.9, 134.6, 141.9,
157.4, 191.8 ppm. IR (KBr): ꢁNH: 3408; ꢁCH: 2833, 2924 and
3050; ꢁCO: 1702 cm-1. Anal. Calcd. for C19H17BrNO2: C, 61.80;
H, 4.64; N, 7.59; found: C, 61.83; H, 4.56; N, 7.65.
20b (minor compound): yellow solid, mp.: 162-164 °C. Anal.
Calcd. for C23H18N4O: C, 75.39; H, 4.95; N, 15.29; found: C,
75.52; H, 4.93; N, 15.26.
Acknowledgement. This study was sponsored by the
Hungarian Scientific Research Fund (Grant No. OTKA T046127
and T034772). A. S. is grateful for the Varga/Rohr fellowship,
G. Sz. thanks to BUTE for a PhD fellowship. The assistance of
G. Seress in the HPLC experiments is highly appreciated.
REFERENCES
[1] Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002,
58, 6795.
[2] Kam, T. S.; Sim, K. M. Phytochemistry 1998, 47, 145.
[3] Poissonnet, G.; Théret-Bettiol, M.-H.; Dodd, R. H. J. Org.
Chem. 1996, 61, 2273.; Bertrand, M.; Poissonnet, G.; Théret-Bettiol, M.-
H.; Gaspard, C.; Werner, G. H.; Pfeiffer, B.; Renard, P.; Leonce, S.;
Dodd, R. H. Biorg. Med. Chem. 2001, 9, 2155.
[4] Tsuge, O.; Kanemasa, S. In Adv. Het. Chem. 1989, 45, 231.
[5] Bende, Z.; Simon, K.; Tóth, G.; Tꢀke, L.; Weber, L. Liebigs
Ann. Chem. 1982, 924.
[6] Bende, Z.; Bitter, I.; Tꢀke, L.; Weber, L.; Tóth, G.; Janke, F.
Liebigs Ann. Chem. 1982, 2146.
[7] Tóth, G.; Janke, F.; Bende, Z.; Weber, L.; Simon, K. J.
Chem. Soc. Perkin Trans. 1. 1983, 1961.
[8] Bende, Z.; Tꢀke, L.; Weber, L.; Tóth, G.; Janke, F.; Csonka,
G. Tetrahedron 1984, 40, 369.
[9] Tóth, G.; Tischer, T.; Bende, Z.; Szejtli, G.; Tꢀke, L.
Monatsh. Chem. 1990, 121, 529.
[10] Tischer, T.; Tꢀke, L.; Tóth, G. Acta Chim. Hung. 1990, 127, 171.
[11] Janke, F.; Himmelreich, U.; Tóth, G.; Tischer, T.; Kádas, I.;
Bende, Z.; Tꢀke, L. J. Het. Chem. 1991, 28, 867.
[12] Szöllꢀsy, Á.; Tischer, T.; Kádas, I.; Tꢀke, L.; Tóth, G.
Tetrahedron 1999, 55, 7279.
Preparation of cycloadducts 17a, 18a and 19a. A mixture of
methyl 1,2,3,4-tetrahydrocarbolin-2-yl acetate (11) (0.30 g, 1.23
mmol), maleic nitrile (4) or fumaric nitrile (5) (0.10 g, 1.28
mmol) and palladium black (24.6 mg, 0.246 mmol) in dry
dimethyl formamide (10 mL) was stirred and heated at 110 °C
for 48 hours. The reaction mixture was cooled, diluted with
chloroform (10 mL), and filtered. The solvent was removed
under reduced pressure to leave a dark brown viscous oil. The
products were purified then by column chromatography on silica
eluting with the 1:1 mixture of hexane and ethyl acetate. The
combined yield was 55 % in case of maleic nitrile and 49 % in
case of fumaric nitrile.
17a: yellow solid, mp.: 192-195 °C. Anal. Calcd. for
C18H16N4O2: C, 67.49; H, 5.03; N, 17.49; found: C, 67.55; H,
5.06; N, 17.45.
18a: yellow solid, mp.: 156-158 °C. Anal. Calcd. for
C18H16N4O2: C, 67.49; H, 5.03; N, 17.49; found: C, 67.52; H,
5.07; N, 17.52.
19a: yellow solid, mp.: 125-127 °C. Anal. Calcd. for
C18H16N4O2: C, 67.49; H, 5.03; N, 17.49; found: C, 67.52; H,
5.12; N, 17.54.
[13] Nyerges, M.; Gajdics, L.; Szöllꢀsy, Á.; Tꢀke, L. Synlett 1999,
111.
[14] Fejes, I.; Tꢀke, L.; Nyerges, M.; Pak, C. S. Tetrahedron
2000, 56, 639.
[15] Fejes, I.; Nyerges, M.; Szöllꢀsy, Á.; Blaskó, G.; Tꢀke, L.
Tetrahedron 2001, 57, 1129.
[16] Huisgen, R.; Grashey, R.; Steingruber, R. Tetrahedron
Letters 1963, 1441.
Preparation of cycloadducts 16b, 15b, 17b and 18b, 20b:
A mixture of 3,4-dihydro-2-(benzoylmethyl)-ß-carbolinium
bromide (13) (0.3379 g, 0.916 mmol) and maleic nitrile (4) or
fumaric nitrile (5) (0.0715 g, 0.916 mmol) were dissolved in
chloroform (15 mL), and triethylamine (0.25 mL, 1.83 mmol)
was added to the mixture, which was stirred then for 24 hours at
room temperature. During that time, in case of maleic nitrile,
16b began to precipitate. After filtering it, chloroform was
removed from the reaction mixture in vacuo leaving a dark
viscous oil. The products were separated then by column
chromatography on silica eluting with the 1:1 mixture of hexane
and ethyl acetate. The combined yield was 80 % in case of
maleic nitrile and 85 % in case of fumaric nitrile.
[17] Tsuge, O.; Kanemasa, S.; Takenaka, S. Bull. Chem. Soc.
Japan 1985, 58, 3320.
[18] Potaꢁek, M.; Topinka, T.; Dostal, J.; Marek, J. Coll. Czech.
Chem. Commun. 1994, 58, 3320.; Dostal, J.; Potaꢁek, M.; Humpa, O.;
Marek, J. Bull. Soc. Chim. Belg. 1994, 103, 343.; Potaꢁek, M.; Topinka,
T.; Dostal, J.; Humpa, O. Coll. Czech. Chem. Commun. 1995, 60, 1199.
[19] Bachowska, B.; Sꢂiwa, W. Monatsch. Chem. 1984, 115, 1101.
[20] Novikov, M. S.; Khlebnikov, A. F.; Shevchenko, M. V. J.
Fluorine Chem. 2003, 123, 177.
16b (precipitated compound): pale yellow solid, mp.: 222-225
°C. Anal. Calcd. for C23H18N4O: C, 75.39; H, 4.95; N, 15.29;
found: C, 75.35; H, 4.87; N, 15.35.
[21] Grigg, R.; Heaney, F. J. Chem. Soc. Perkin Trans. 1. 1989, 198.
[22] Pretsch, E.; Tóth, G.; Munk, M. E.; Badertscher, M.
Computer-Aided Structures Elucidation. Spectra Interpretation and
Structure Generation, Wiley-VCH Verlag GmbH
Weinheim, 2002.
& Co. KgaA,
15b (major compound): yellow oil (can be crystallized with
chloroform), mp.: 80-83 °C. Anal. Calcd. for C23H18N4O: C,
75.39; H, 4.95; N, 15.29; found: C, 75.45; H, 4.89; N, 15.31.
17b (minor compound): yellow solid, mp.: 207-209 °C. Anal.
Calcd. for C23H18N4O: C, 75.39; H, 4.95; N, 15.29; found: C,
75.49; H, 5.05; N, 15.34.
18b (major compound): yellow solid mp.: 124-127 °C. Anal.
Calcd. for C23H18N4O: C, 75.39; H, 4.95; N, 15.29; found: C,
75.25; H, 4.99; N, 15.39.
[23] Duddeck, H.; Dietrich, W.; Tóth, G. Structure Elucidation by
Modern NMR. A Workbook, Springer-Steinkopff, Darmstadt, 1998.
[24] Shamma, M.; Hindenlang, D. M. Carbon-13 NMR Shift
Assignments of Amines and Alkaloids Plenum Press, London, 1979, pp
208-209.; Szántay, C. jr., Tóth, G.; Márványos, E.; Thaler, Gy.;
Duddeck, H. J. Chem. Soc. Perkin Trans. 2. 1988, 537.
[25] Gil, V. M. S.; von Philipsborn, W. Magn. Reson. Chem.
1989, 27, 409.