Unexpected recyclization of 1H-δ-carbolines to pyrrolo[1,2-a]indoles

Article abstract of DOI:10.1023/A:1025110602750

When 1H-2-methyl-1-p-nitrophenyl-3-ethoxycarbonylpyrido[3,2-b]indole (1) is heated in alcoholic solutions of ammonia, we observe a previously unknown recyclization leading to formation of 2-alkoxycarbonyl-3-methyl-9-p-nitrophenylimino-9H-pyrrolo[1,2-a]indoles (3,6).

Full text of DOI:10.1023/A:1025110602750

Chemistry of Heterocyclic Compounds, Vol. 39, No. 5, 2003
UNEXPECTED RECYCLIZATION
OF 1H-δ-CARBOLINES TO
a
PYRROLO[1,2- ]INDOLES
S. Yu. Ryabova1, L. M. Alekseeva1, A. S. Shashkov2, and V. G. Granik1
1
When 1H-2-methyl-1-p-nitrophenyl-3-ethoxycarbonylpyrido[3,2-b]indole ( ) is heated in alcoholic
solutions of ammonia, we observe a previously unknown recyclization leading to formation of
3,6
2-alkoxycarbonyl-3-methyl-9-p-nitrophenylimino-9H-pyrrolo[1,2-a]indoles ( ).
Keywords: δ-carboline, pyrido[3,2-b]indole, pyrrolo[1,2-a]indole, hydrolysis, transesterification,
recyclization.
As a continuation of research on synthesis and properties of pyrido[3,2-b]indole derivatives obtained on
the basis of 1-acetylindoxyl, in this work we have studied the reaction of 1H-2-methyl-1-p-nitrophenyl-3-
ethoxycarbonylpyrido[3,2-b]indole (1) [1] with ammonia, with the aim of obtaining the corresponding
carbamide 2. However, we found that when compound 1 is heated in an ethanolic solution of ammonia at 100°C
in an autoclave for 8 h, the process occurs in a different direction and unexpectedly leads to formation of
2-ethoxycarbonyl-3-methyl-9-p-nitrophenylimino-9H-pyrrolo[1,2-a]indole (3) in 75% yield. Considering that
derivatives of 2-amino-δ-carboline can add nucleophilic reagents at the 4 position [2,3], we can give the scheme
for this unusual reaction (Scheme 1).
In the first step, addition of ammonia occurs to form the 4-amino-1,4-dihydro-δ-carboline derivative A.
This process is possible due to rearrangement of the double bonds to form the aromatic indole ring. The
1,4-dihydropyridine moiety, which is a cyclic enamine, can open up when treated with nucleophilic reagents (in
this case, opening occurs during a transamination reaction [4]), to form an enamine of the indole series B, which
then undergoes ring closure to form the pyrrolo[1,2-a]indole derivative C and then is converted to the end
product 3.
We should note that opening of 1,4-dihydropyridines when treated with acids is described in the
literature [5].
As we see from the suggested scheme, as a result of this unusual recyclization, the pyridine moiety of
compound 1 is converted to a pyrrole with formation of the isomeric pyrrolo[1,2-a]indole 3. Evidence for the
occurrence of such isomerization comes from the fact that the molecular weights of the starting compound and
the compound obtained are identical (mass spectra: [M]+· 375), although fragmentation by electron impact gives
1
different results. The structure of compound 3 unambiguously follows from comparison of its H NMR
__________________________________________________________________________________________
1
State Science Center of the Russian Federation "NIOPIK", Moscow 103787, Russia; e-mail:
2
makar-cl@ropnet.ru. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow
117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 754-760, May, 2003. Original article
submitted November 28, 2000.
654
0009-3122/03/3905-0654$25.00©2003 Plenum Publishing Corporation

Scheme 1
C6H4–NO2-p
C6H4–NO2-p
9
6
N1
Me
N
Me
NH3/EtOH
8
7
2
3
N
CONH2
N
COOEt
4
5
2
1
NH3/EtOH
C6H4–NO2-p
C H –NO -p
NH
6
4
2
Me
N
NH2
H
– NH3
N
N
H
COOEt
H
COOEt
NH2
H2N
A
B
Me
3'
2'
1'
4'
5
8
C H –NO -p
N
6
4
2
NO2
N
4
4a
8a
6
7
5'
6'
3a
NH2
N
– NH3
3
9N
H
COOEt
1
2
Me
COOEt
Me
C
3
spectrum with the spectrum of the starting δ-carboline 1 and with the spectrum of 4-ethoxycarbonyl-1-methyl-4-
oxo-4H-pyrrolo[1,2-a]indole (4) described previously in the literature [6] and isolated as a result of hydrolysis
of the tricyclic derivative 3 in acid medium.
O
HCl/H2O
3
EtOH
N
COOEt
Me
4
1
In the H NMR spectrum of compound 3, we observe the following signals (DMSO-d6), δ, ppm: 1.17
(3H, t, 2-COOCH2CH3); 4.08 (2H, q, 2-COOCH2CH3); 2.74 (3H, s, 1-CH3); 7.06, 8.20 (4H, A2B2-system,
1-p-nitrophenyl); 7.20 (1H, t, 6-H); 7.40 (1H, d, 8-H); 7.42 (1H, t, 7-H); 7.75 (1H, d, 5-H) and 5.93 (1H, s, 3-H).
In comparing this spectrum with the spectrum of the starting δ-carboline 1 [1], it is established that both spectra
have the same set of signals which however have markedly different chemical shifts. This is especially so for
the chemical shifts of the 3-H and 4-H protons and the 5-H and 9-H protons in compounds 3 and 1 respectively.
The signal from the proton in the 3 position (~5.93 ppm) of tricycle 3 is upfield from the signal from the proton
in the 4 position (~8.9 ppm) of δ-carboline 1 for two reasons: first of all, because the 3-H proton in compound 3
belongs to the electron-rich pyrrole ring (in contrast to the 4-H proton in compound 1, which is found on the
electron-poor pyridine ring), and secondly because of the shielding effect of the p-nitrophenyl substituent on the
proton in the 3 position (in pyrroloindole 3). The latter circumstance explains why the 3-H signal in compound 3
is found upfield not only from the 4-H signal in δ-carboline 1 but also from signals from analogous protons in
655

other pyrrolo[1,2-a]indole derivatives (~7.0-7.5 ppm) that do not have such a substituent in the 4 position [7, 8].
Of course such an effect of the p-nitrophenylimine substituent on the proton in the 3 position can occur only if
the p-nitrophenyl substituent is turned toward the pyrrole (rather than the benzene) moiety of the molecule. In
fact, the NOE difference spectrum supports such a configuration: when the proton in the 3 position is
presaturated, we observe a response from the protons of the p-nitrophenyl substituent (7.06 ppm and 8.20 ppm)
indicating their spatial proximity. At the same time, in the 1H NMR spectrum of tricycle 3, the signal from the
proton in the 3 position is shifted upfield, the signal from the aromatic 5-H proton is shifted downfield
compared with the signal from the 9-H proton in compound 2, which is also consistent with the structural
changes on going from δ-carboline to pyrroloindole. In the latter compound, the 5-H proton (in contrast to 9-H
in δ-carboline) does not experience an anisotropic effect from the p-nitrophenyl substituent and probably is in
the deshielding region of the double bond.
If we compare the 1H NMR spectra of tricycle 3 and its hydrolysis product 4 (the full spectrum is given
in the experimental section), we see that the chemical shifts of the aromatic protons and also the protons of the
COOCH2CH3 and CH3 groups as we go from 3 to 4 do not undergo any substantial changes, while the signal
from the proton in the 1 position in compound 4, which not does experience the shielding effect of the
p-nitrophenyl substituent, is shifted downfield and is observed at 7.02 ppm (which is typical for pyrroloindole
compounds with such a structure [7, 8]).
Additional support for compound 1 undergoing significant structural changes come from NOE
difference spectral data: when the protons of the methyl group in compound 3 are presaturated, we observe a
response from the proton in the 8 position which confirms the steric proximity of the 1-CH3 group and the 8-H
proton and is evidence in favor of an angular structure for tricycle 3.
We also recorded and compared the HMBC [heteronuclear multiple bond correlation] NMR spectra of
compounds 3 and 4 (and also 6, see below) (Table 1). The chemical shifts of like carbon atoms are close and
have identical correlation peaks. An exception is the chemical shift of the C(4) atom: on going from 3 to 4, it
changes from 152.0 to 178.8 ppm. In the same region (178.1 ppm) we observe a signal from the carbonyl carbon
atom C(4) in 2-piperidinomethylene-2H-pyrrolo[1,2-a]indole-1,4-dione [9].
Then we studied the reaction of δ-carboline 1 with ammonia at lower temperature. We established that
the recyclization 1 → 3 does not occur at 20°C (δ-carboline 1 is isolated), while at 50°C the conversion is only
20%.
An important role is also played by the polarity of the solvent. For example, in dioxane with an 85-fold
excess of ammonia and after holding for 8 h at 100°C in an autoclave, we could detect the presence of tricycle 3
in the reaction mixture only by chromatography.
Based on the reaction scheme given above, it follows that the indicated recyclization can occur not only
when treated with ammonia but also when treated with other amines. When compound 1 is reacted with a
25-fold excess of piperidine under similar conditions, δ-carboline 1 is completely converted; but we could
isolate pyrroloindole 3 and also its hydrolysis product 4 in slight amounts by column chromatography from the
reaction mass, which is a complex mixture of compounds. The hydrolysis 3 → 4 probably occurs during
prolonged heating of the reaction mass.
Under other conditions, and specifically when δ-carboline 1 is refluxed with a 25-fold excess of
piperidine in alcohol, tricycle 3 is formed in 10% yield, while we recovered a mixture of compounds 3, 4 and
p-nitroaniline from the mother liquor by column chromatography.
The reaction of δ-carboline 1 with methanol, due to the weak nucleophilicity of the latter, does not lead
to formation of a dihydropyridine ring and then pyrroloindole, but transesterification occurs quite rapidly and
the corresponding methyl ester 5 is formed. When compound 1 is treated with methanolic ammonia, the
recyclization product 6 is formed, which contains a methoxycarbonyl group in the 2 position.
656

TABLE 1. 13C NMR Spectra of Compounds 3, 6, 4 and Proton–Carbon
Correlations in the HMBC Spectrum (1H–13C correlation through 2 and 3
bonds)*
13С Chemical shifts, δ, ppm*2
Carbon
Compound
atoms
3
6
4
3
2
1
8а
8
7
6
5
4а
4
4а
1'
114.0 (no corr.)
118.8 (1-CH3)
135.3 (3-H, 1-CH3)
141.0 (5-, 7-H)
112.1 (6-H)
132.5 (5-H)
125.3 (8-H)
123.6 (7-H)
131.5 (6-, 8-H)
152.3 (5-H)
125.3 (3-H)
157.6 (3'-, 5'-H)
119.5 (6'-, 2'-H)
124.9 (5'-, 3'-H)
143.6 (2'-, 6'-,3'-, 5'-Н)
163.5 (OCH2CH3)
11.8 (no corr.)
114.5 (no corr.)
118.3 (1-CH3)
136.2 (3-H, 1-CH3)
141.7 (5-, 7-H)
112.3 (6-H)
132.8 (5-H)
125.9 (8-H)
124.3 (7-H)
132.1 (6-, 8-H)
153.1 (5-H)
125.9 (3-H)
158.1 (3'-, 5'-H)
119.9 (6'-, 2'-H)
125.7 (5'-, 3'-H)
144.5 (2'-, 6'-,3'-, 5'-Н)
164.5 (OCH3)
12.2 (no corr.)
115.0 (no corr.)
119.5 (1-CH3)
138.4 (3-H, 1-CH3)
143.3 (5-, 7-H)
112.3 (6-H)
134.3 (8-, 5-H)
126.1 (8-H)
124.7 (7-H)
130.7 (6-, 8-H)
178.8 (5-H)
129.7 (3-H)
—
2', 6'
3', 5'
4'
—
—
—
2-СOOR*3
1-СН3
164.0 (OCH2CH3)
12.4 (no corr.)
_______
* Solvent, CDCl3 (for 4 and 6), CDCl3 + DMSO-d6 (for 3).
*2 Protons with which the correlation is observed are indicated within
parentheses.
*3 Chemical shifts, δ, ppm: 3 R = CH2CH3 59.3, 13.8, 6 R = CH3 51.1, 4 R =
CH2CH3 60.0, 14.3.
C6H4–NO2-p
N
–C6H4–NO2-p
Me
N
NH3/MeOH
MeOH
1
N
N
COOMe
COOMe
Me
5
6
From this it follows that in conversion of δ-carboline 1 to pyrroloindole 6, transesterification occurs in
the first step followed by recyclization. It has been shown experimentally that neither transesterification nor
amidation of the recyclized product 3 occur under the selected conditions.
EXPERIMENTAL
The IR spectra of the compounds were obtained on a Perkin-Elmer 457. The mass spectra were taken on
1
a Finnigan SSQ-710 mass spectrometer with direct injection of the sample into the ion source. The H NMR
spectra were recorded on a Bruker AC-200 spectrometer (200 MHz), the two-dimensional HMBC NMR spectra
were taken on a Bruker DRX-500 spectrometer using Bruker standard procedures. The reactions and purity of
657

TABLE 2. Characteristics of Synthesized Compounds
Found, %
Calculated, %
H
IR spectrum
(thin film),
ν, cm-1
mp, °C,
Mass
——————
Com-
pound
Empirical
formula
Yield,
%
(solvent for
spectrum,
recrystallization)
m/z, M+
С
N
С21H17N3O4 67.28 4.34 11.43
253-253.5
173-173.5
1700, 1649,
1611, 1597,
1585, 1548,
1508, 1460,
1420, 1370,
1340
1696, 1612,
1548, 1514,
1474, 1427,
1391, 1277,
1230, 1209,
1100
375
255
75
3
67.19 4.57 11.20
4*
C15H13NO3 70.55 5.38
70.58 5.13
5.40
5.49
70
C20H15N3O4 66.53 4.17 11.48
66.48 4.18 11.63
252 dec.
1713, 1624,
1526, 1494,
1460, 1380,
1320, 1300,
1270, 1220
1700, 1649,
1611, 1598,
1585, 1548,
1508, 1460,
1420, 1370,
1340
361
361
69
44
5
6
(methanol)
C20H15N3O4 66.51 4.38 11.26
66.48 4.18 11.63
259-259.5
(acetone)
_______
* IR spectrum in KBr disk.
the substances were monitored on Silufol UV-254 plates in chloroform (for compounds 3, 4, 6, visualization in
UV light) and in the system ethylacetate–isopropanol–ammonia, 5:3:1 (for compounds 1 and 5).
The physicochemical characteristics of the synthesized substances are given in Table 2.
p
a
2-Ethoxycarbonyl-1-methyl-4- -nitrophenylimino-4H-pyrrolo[1,2- ]indole (3).
A. A mixture of
δ-carboline 1 (1.2 g, 3.2 mmol) and an ethanol solution of ammonia (15% solution) (60 ml) was held for 8 h at
100°C in an autoclave. This was cooled down, the precipitate was filtered out and washed with ethanol. The
substance was purified by column chromatography (SiO2, 1×40, chloroform as eluent). The yellow band was
collected. Pyrroloindole 3 (0.9 g) was obtained.
B. A mixture of δ-carboline 1 (0.2 g, 0.53 mmol), absolute ethanol (15 ml), and piperidine (1.3 ml,
13 mmol) was held for 9 h at 100°C in an autoclave. The mixture was cooled and the solution was evaporated
down. The oily residue was mixed with ether, the precipitate (0.15 g) was filtered out and dissolved in
chloroform. The solution was applied to a SiO2 column and eluted with chloroform. The yellow band was
collected and combined with the wash ether solution and evaporated down. The residue was triturated with
ethanol, the precipitate was filtered out and washed with ethanol. Obtained 0.02 g of precipitate "a", which
according to TLC data is compound 3 with compound 4 as an impurity. The ethanol mother liquor was
evaporated down. The residue was dissolved in chloroform and filtered through a bed of SiO2. The chloroform
was evaporated off and 0.02 g of precipitate "b" was obtained: a mixture of compounds 3 and 4 (1:1 according
to TLC). Precipitate "b" was recrystallized from methanol (2 ml). Obtained 0.01 g of a substance which was
added to precipitate "a". A total of 0.03 g (precipitate "a") was recrystallized from methanol (25 ml). Obtained
0.01 g (5%) of pyrroloindole 3; there was no depression of the melting point for a mixed sample with a sample
of this compound obtained by method A. The methanolic mother liquors from recrystallization of precipitates
"a" and "b" were combined and evaporated down, and the precipitate (0.03 g) was recrystallized from
658

isopropanol. Obtained 0.01 g (7%) of pyrroloindole 4; there was no depression of the melting point for a mixed
sample of this with a sample of this compound obtained by hydrolysis of compound 3.
C. A mixture of δ-carboline 1 (0.3 g, 0.8 mmol), absolute ethanol (20 ml), and piperidine (0.9 ml,
9 mmol) was refluxed for 17 h, piperidine (1 ml, 10 mmol) was added and it was refluxed for another 2 h. After
16 h, the precipitate was filtered out and washed with alcohol. Obtained 0.02 g of pyrroloindole 3. Another 1 ml
of piperidine was added to the mother liquor and it was refluxed for 6 h. After 16 h, the precipitate was filtered
out and washed with ethanol. An additional 0.01 g of pyrroloindole 3 was obtained. Total yield 0.03 g (10%).
There was no depression of the melting point for a mixed sample of the substance with a sample of this
compound obtained by method A.
p
a
2-Methoxycarbonyl-1-methyl-4- -nitrophenylimino-4H-pyrrolo[1,2- ]indole (6).
A mixture of
δ-carboline 1 (0.4 g, 1.1 mmol) and methanolic ammonia (19% solution) (20 ml) was held for 5.5 h at 100°C in
an autoclave. The substance was isolated and purified as for compound 3. Obtained 0.17 g of pyrroloindole 6.
1H NMR spectrum (DMSO-d6), δ, ppm: 3.66 (3H, s, 2-COOCH3); 2.83 (3H, s, 1-CH3); 7.27, 8.34 (4H, A2B2
system, 1-p-nitrophenyl); 7.38 (1H, t, 6-H); 7.67 (2H, m, 7-H, 8-H); 7.87 (1H, d, 5-H), and 5.92 (1H, s, 3-H).
a
10% HCl (20 ml) was added to a
2-Ethoxycarbonyl-1-methyl-4-oxo-4H-pyrrolo[1,2- ]indole (4).
suspension of imine 3 (0.4 g, 1.1 mmol) in ethanol (20 ml), heated up to 70°C; this was stirred while refluxing
for 0.5 h. The solution obtained was cooled. The precipitate was filtered out and washed with 50% ethanol. The
1
substance (0.23 g) was purified as for compound 3. Obtained 0.19 g pyrroloindole 4. H NMR spectrum
(DMSO-d6), δ, ppm: 1.28 (3H, t, 2-COOCH2CH3); 4.21 (2H, q, 2-COOCH2CH3); 2.78 (3H, s, 1-CH3), 7.28, 7.59
(4H, m, benzene ring protons), and 7.02 (1H, s, 3-H).
p
b
1H-3-Methoxycarbonyl-2-methyl-1- -nitrophenylpyrido[3,2- ]indole (5).
A mixture of δ-carboline
1 (0.3 g, 0.8 mmol) and methanol (10 ml) was held for 8 h at 100°C in an autoclave. This was cooled down and
the solution was evaporated. The residue was stirred with methanol (1-2 ml), the precipitate was filtered out.
Obtained 0.11 g of δ-carboline 5. The methanolic mother liquor was evaporated off, the residue was suspended
in water (20 ml) and a few drops of conc. HCl (pH 3) were added and it was heated to boiling. The solution of
the chloride of δ-carboline 5 was filtered, cooled, and alkalinized with a 40% NaOH solution (pH 9). The
precipitate was filtered out, washed with water, methanol (0.5 ml) and ether. An additional 0.09 g of δ-carboline
1
5 was obtained. Total yield 0.2 g. H NMR spectrum (DMSO-d6), δ, ppm: 2.71 (3H, s, 2-CH3); 3.99 (3H, s,
COOCH3); 8.11, 8.70 (4H, A2B2 system, 1-p-nitrophenyl), 6.02 (1H, d, 9-H); 6.70 (1H, t, 8-H); 7.33 (1H, t,
7-H); 7.64 (1H, d, 6-H), and 8.87 (1H, s, 4-H).
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik, Khim. Geterotsikl. Soedin., 1086 (2001).
S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik, Mendeleev Commun., No. 3, 107 (1995).
S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik, Khim.-Farm. Zh., No. 9, 29 (1996).
V. G. Granik, Usp. Khim., 53, 651 (1984).
A. Sausin'sh and G. Dubur, Khim. Geterotsikl. Soedin., 579 (1993).
W. K. Anderson and P. F. Corey, J. Org. Chem., 43, 559 (1977).
S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik, Khim. Geterotsikl. Soedin., 1991 (1991).
S. Yu. Ryabova, N. Z. Tugusheva, N. P. Solov'eva, S. D. Yuzhakov, A. V. Denisov, and V. G. Granik,
Khim.-Farm. Zh., No. 11, 21 (1993).
N. Z. Tugusheva, S. Yu. Ryabova, N. P. Solov'eva, and V. G. Granik, Khim. Geterotsikl. Soedin., 781
(1994).
9.
659