A versatile one-pot synthesis of β-carbolines by reaction of pyranoindolones with phenyl- and benzoylhydrazine

Article abstract of DOI:10.1055/s-0028-1083152

The synthesis of a number of 2-anilino- and 2-(benzoyl-amino)-β- carbolin-3-ones in good yields by a one-step sequence from the reaction of pyranoindolones with phenylhydrazine or benzoylhydrazine is described; the observed good regioselectivity of the reaction is discussed. Full assignment of all ¹H and ¹³C NMR chemical shifts has been unambiguously achieved.

Full text of DOI:10.1055/s-0028-1083152

PAPER
3273
A Versatile One-Pot Synthesis of b-Carbolines by Reaction of Pyranoindolones
with Phenyl- and Benzoylhydrazine
O
ne-PotSynthesis
e
of
b
-Carbo
s
line
s
pina Livadiotou, Dimitra Hatzimimikou, Constantinos Neochoritis, Michael A. Terzidis,
Constantinos A. Tsoleridis,* Julia Stephanidou-Stephanatou*
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece
Fax +30(2310)997679; E-mail: tsolerid@chem.auth.gr; E-mail: ioulia@chem.auth.gr
Received 13 June 2008; revised 3 July 2008
no- and 2-(benzoylamino)-b-carbolin-3-ones in good
Abstract: The synthesis of a number of 2-anilino- and 2-(benzoyl-
yields.
amino)-b-carbolin-3-ones in good yields by a one-step sequence
from the reaction of pyranoindolones with phenylhydrazine or ben-
zoylhydrazine is described; the observed good regioselectivity of
Sometime ago we studied the reaction between 1-meth-
ylpyranoindolone using aromatic amines as nucleophiles
in boiling bromobenzene, whereupon Schiff bases 1 were
isolated as the sole reaction product.16 More recently, the
same reaction was repeated under reflux in isopropyl al-
cohol and, in this case, 2-acetylindolo-3-acetic acid
amides 2 were isolated14 (Scheme 1). Amides were also
isolated from the reaction of 1-methylpyranoindolone
with methanolic dimethylamine.17 In addition, very re-
cently, we studied the reaction of pyranoindolones with
the bisnucleophile, methylhydrazine, whereupon diazepi-
noindole derivatives were isolated.18 These results are in
agreement with the presence of two electrophilic centers
at C1 and C3 of the indolones and a strong solvent effect.
In the light of the above results and in continuation of our
research into the synthesis of compounds containing the
indole ring, we studied the reaction of pyranoindolones
with the bisnucleophiles phenyl- and benzoylhydrazine.
1
the reaction is discussed. Full assignment of all H and 13C NMR
chemical shifts has been unambiguously achieved.
Key words: benzoylhydrazine, p-benzylic coupling, bisnucleo-
philes, one-pot reaction, phenylhydrazine, pyranoindoles
Pyrido[3,4-b]indoles, commonly known as b-carbolines,
are a widely distributed family of indole alkaloids and are
found in several plant families such as Apocynaceae,
Elaeagnaceae, Leguminosae, Passifloraceae, and Zygo-
phyllaceae.1 Moreover, b-carbolines possess a wide diver-
sity of important biological activity, particular concerning
the muscular, cardiovascular, and central nervous sys-
tems.2,3 Due to their unique rigid heterocyclic skeleton,
many b-carbolines are known to bind with high affinity to
benzodiazepine, serotonin, and dopamine receptor sites.
They are also DNA intercalating agents4 and inhibit en-
zymes,5 such as monoamine oxidase A.6 In addition, they
show convulsive and anticonvulsive actions, anxiolytic,
tremorogenic, and immunomodulatory effects.7–9 1-Oxo-
b-carbolines are of interest in medicine,10 as many of them
have been patented11 and described as useful central ner-
vous system depressants. In contrast, few examples of 3-
oxo-b-carbolines are known, mainly synthesized by the
reaction of 2-acylindole-3-acetic acid esters with primary
amines.12 A four-step synthesis of 1-methylcarbolin-3-
one starting from indoleacetic acid has also been report-
ed.13 More recently, a two-step sequence was used for the
synthesis of 1-methyl-2-phenyl or benzyl derivatives
starting from the reaction of pyranoindolones with prima-
ry amines followed by ring closure of the isolated 2-
acetylindole-3-acetic acid amides with triethylamine.14
Formation of 1-phenyl-3-benzyl-substituted derivatives
in low yield through the transformation of 5-benzotriaz-
olyl-3,4-dihydropyridin-2-ones has also been reported.15
Me
Ar
N
N
a
O
Me
O
H
1
O
Ar
N
N
H
b
H
Me
O
N
H
Me
2
Scheme 1 Reagents and conditions: (a) ArNH2, PhBr, reflux, 2 h;
(b) ArNH2, i-PrOH, reflux, 0.5–2 h.
When pyranoindolones 3 were allowed to react with two
molar equivalents of phenylhydrazine in refluxing bro-
mobenzene for two hours, the b-carbolinones 4 were iso-
lated in good yields (65–69%, Table 1). Analogous was
the reaction with benzoylhydrazine, whereupon com-
pounds 5 were formed also in good yields (67–74%,
Scheme 2). By lowering the reaction temperature, namely
by using boiling xylene, no reaction was observed. In or-
der to examine the solvent effect, the reaction was also
carried out in protic solvents, such as boiling propanol and
butanol, whereupon several unidentified decomposition
products were isolated, as a result of the pyranone ring
opening.
In the present work we wish to describe a one-pot synthet-
ic methodology for the preparation of a series of 2-anili-
SYNTHESIS 2008, No. 20, pp 3273–3278
x
x.
x
x
.
2
0
0
8
Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083152; Art ID: P06308SS
© Georg Thieme Verlag Stuttgart · New York

3274
D. Livadiotou et al.
PAPER
O
O
5
4
6
6'
2'
5'
3'
1'
N
1
4'
7
NH
R1
R2
a
8
9
N
O
R2
R1
a
b
c
d
e
f
H
H
H
Me
Me
Me
Et
n-Pr
Me
Et
O
4
b
N
R1
R2
N
NHCO
3
Me n-Pr
N
R2
R1
5
Scheme 2 Reagents and conditions: (a) PhNHNH2, PhBr, reflux, 2 h; (b) BzNHNH2, PhBr, reflux, 2 h.
Concerning the reaction mechanism, attack of the less
hindered NH2 group of phenylhydrazine11 to the carbonyl
carbon of pyranoindolones, being the more reactive elec-
trophilic center, would be expected (Scheme 3, path a).
This attack would lead to the formation of the 2-acyl de-
rivatives 6, from which, by recyclization and dehydration,
carbolines 4 could be formed. However, this path can be
excluded since it is known that 2-acetylindoles do not re-
act with nitrogen nucleophiles in bromobenzene even on
prolonged heating,16 and that protic solvents and acidic
conditions are required for this reaction.19 On the other
hand, the formation of carbolines 4 is also possible by at-
tack to the less electrophilic center, namely C1, leading to
the acid 7 (path b), from which, by dehydration, 4 can be
formed. Dehydration is facilitated by the ability of aprotic
solvents, in contrast to protic solvents, to carry away the
water formed during the reaction.
Table 1 Reaction Conditions and Products
Substrate Hydrazine Solvent Temp Time Product Yield
(°C)
156
156
156
156
156
156
97
(h)
2
2
2
2
2
2
4
6
2
2
2
2
2
2
(%)
67
69
65
67
69
68
–
3a
3b
3c
3d
3e
3f
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
BzNHNH2
BzNHNH2
BzNHNH2
BzNHNH2
BzNHNH2
BzNHNH2
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PrOH
4a
4b
4c
4d
4e
4f
–
3a
3a
3a
3b
3c
3d
3e
3f
BuOH 118
–
–
The isolation of products 4 through path b is also in agree-
ment with the results previously obtained from the reac-
tion of pyranoindolones with aromatic amines,16 where in
aprotic solvents the nucleophilic aromatic amine attacks
the less electrophilic center C1 of the pyranoindolone.
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
156
156
156
156
156
156
5a
5b
5c
5d
5e
5f
74
72
68
73
71
67
The assigned molecular structures of all new compounds
4 and 5 are based on rigorous spectroscopic analysis in-
cluding IR, NMR (1H, 13C, COSY, NOESY, HETCOR,
and COLOC), MS and elemental analysis data.
Regarding the structure of the isolated b-carbolines 4 and
5 the assignment of 4d is described. The elemental analy-
sis and mass spectra unequivocally established the reac-
O
a
O
O
O
Path a
••
NHNHPh
H2NNHPh
••
NNHPh
OH
+
O
N
R1
N
R1
N
R1
3
b
R2
R2
R2
Path b
6
– H2O
OH
O
O
e
NNHPh
••
NHNHPh
– H2O
N
R1
N
R1
R2
R2
7
4
Scheme 3 Plausible mechanism for the formation of 4
Synthesis 2008, No. 20, 3273–3278 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of b-Carbolines
3275
tion of one molecule of pyranoindolone 3d with one d = 120.7 (C4b). Concerning the indole ring sequence it is
molecule of hydrazine with the loss of a water molecule, characterized by the COLOC correlations of the C5 pro-
a fact that was also confirmed from the 13C NMR spec- ton with C7 protonated carbon (d =130.7) and with the
trum, where 17 different signals were observed. More- C8a quaternary carbon at d = 147.7, of the C6 proton
over, in the IR spectra (see Experimental Section) in (d = 7.14) with the C8 protonated carbon (d = 109.0) and
addition to the carbonyl (1658 cm–1), an NH absorption at of the C8 proton (d = 7.22) with the C6 protonated carbon
1
3219 cm–1 was identified. From the H–H COSY spectrum (d = 119.4). Moreover, the NH proton appears in the H
two distinguishable proton multiplet groups were defined NMR as a singlet at d = 8.01 correlating with the quater-
corresponding to indole and NH-aromatic rings.
nary carbon at d = 130.4 (C1) and also with the protonated
carbon at d = 115.0 (C2¢) indicating thus the position of
the anilino group. Finally, characteristic COLOC correla-
tions for the phenyl ring are also observed. In Figure 1 all
the observed COLOC correlations in compounds 4d and
5e are depicted.
H
H
O
H
H
H
N
H
H
N
N
Me
H
1
H
It is also noteworthy that H NMR of the propyl deriva-
H
Me
tives 4c, 4f, and 5f show two distinct multiplets for the
middle b-methylene protons, whereas the a-methylene
protons show two distinct multiplets as clean ddd with
couplings, in the case of 4f, J = 5.6, 7.5, and 14.5 Hz. This
multiplicity is attributed to the difficulty in spinning of the
group. Methylene protons in 1-ethyl-9-methyl derivative
4e follow the same trend.
H
4d
H
H
O
H
H
H
H
N
N
H
C
H
N
O
CH2
Me
H
NOESY
H
H
Me
In conclusion, we have developed a direct method for the
synthesis of a series of 2-anilino - and 2-(benzoylamino)-
b-carbolin-3-ones in good yields by a one-step sequence
from the reaction of pyranoindolones with phenylhydra-
zine or benzoylhydrazine. In addition, the observed good
regioselectivity of the reaction is discussed. Moreover,
this high yielding reaction constitutes one of few exam-
ples of a reaction of pyranoindolones with bisnucleo-
5e
Figure 1 COLOC correlations between protons and carbons (via
2JC-H and JC-H) in compounds 4d and 5e. In 5e, NOESY correlation
3
has observed between H8 and 9-Me protons.
In the 1H NMR of 4d the presence of the four indole aro-
matic protons resonating as a doublet of doublet of dou-
blets at d = 7.92 (J = 0.7, 1.3, 7.8 Hz, H5),20 a double
doublet of doublets at d = 7.14 (J = 0.8, 7.1, 7.8 Hz, H6),
a double doublet of doublets at d = 7.56 (J = 1.3, 7.1, 8.4
Hz, H7), and as a doublet of broad signals at d = 7.22
(J = 8.4 Hz, H8), partially overlapped by N-Ph protons,
with their carbons resonating at d = 122.8, 119.4, 130.7,
and 109.0, respectively, was identified. Moreover, the 4-
position proton appears as a quartet at d = 7.12 (6J = 0.75
Hz) coupled with 1-methyl protons (analogous to p-ben-
zylic coupling) resonating at d = 2.88 (C at d = 14.7), ver-
ified also from their proton COSY correlation. The
presence of the phenyl moiety is identified from the three
characteristic proton multiplets at d = 6.66–6.70 (H2¢,
H6¢), 7.21–7.26 (H3¢, H5¢), and 6.98 (H4¢) with their car-
bons resonating at d = 115.0, 129.4, and 122.7, respec-
tively. Finally, the 9-methyl group appears as a singlet at
d = 3.85 with carbon resonating at d = 33.3. Long range
C–H correlation (COLOC) spectra were optimized for
J = 10 Hz, so aromatic protons show COLOC correlations
via 3J, whereas protons on saturated carbons show
COLOC via 2J and 3J couplings. Consequently, the 1-me-
thyl group protons gave COLOC correlations with the car-
bon at d = 130.4 (C1) and with the quaternary carbon at
d = 126.9 (C9a). The N-methyl protons correlated with
the same quaternary carbon (C9a) and with the quaternary
carbon at d = 147.7 (C8a). The C4 proton gave COLOC
correlations with (C9a) and with the quaternary carbon at
1
13
philes. Full assignment of all H and C NMR chemical
shifts has been unambiguously achieved.
Work is continuing in our laboratory in this area and we
will report on further studies in the future using other bis-
nucleophiles.
Melting points were measured on a Kofler hot-stage and are uncor-
rected. Column chromatography was carried out using Merck silica
gel. TLC was performed using precoated silica gel glass plates 0.25
mm containing fluorescent indicator UV254 purchased from Mach-
erey–Nagel using a 3:1 mixture of petroleum ether–EtOAc. Petro-
leum ether (PE) refers to bp 60–80 °C. NMR spectra were recorded
at r.t. on a Bruker AM 300 spectrometer at 300 MHz for 1H and 75
MHz for 13C, respectively, using CDCl3 as solvent, unless otherwise
indicated. In the case of insoluble substances 5–20% of DMSO-d6
was added, whereas in one case only DMSO-d6 was used, as indi-
cated. TMS was used as internal standard for 1H and TMS (d = 0.00)
or to CDCl3 (d = 77.05) for 13C NMR spectra; in the case of DMSO-
d6 solns the signal of the solvent at d = 39.7 was used for calibration.
1
Second order H NMR spectra were analyzed by simulation.20 IR
spectra were recorded on a Perkin-Elmer 297 spectrophotometer or
on a Perkin-Elmer 1600 series FTIR spectrophotometer. LR-MS
(EI) were recorded on a 6890N GC/MS system (Agilent Technolo-
gy); in some cases LC-MS (ESI, 1.65 eV) spectra were recorded on
an LCMS-2010 EV system (Shimadzu). Elemental analyses per-
formed with a Perkin-Elmer 2400-II CHN analyzer. Structural as-
signments of the derived compounds were established by analysis
of their IR, MS, and NMR spectra (1H, 13C, DEPT, COSY, NOESY,
HETCOR, and COLOC).
Synthesis 2008, No. 20, 3273–3278 © Thieme Stuttgart · New York

3276
D. Livadiotou et al.
PAPER
2-Anilino-2,9-dihydro-3H-b-carbolin-3-ones 4a–f and 2-(Ben-
zoylamino)-2,9-dihydro-3H-b-carbolin-3-ones 5a–f; General
Procedure
(C2¢, C6¢), 118.3 (C6), 120.1 (C4b), 120.7 (C5), 122.5 (C4¢), 126.9
(C9a), 128.7 (C3¢, C5¢), 130.0 (C7), 130.1 (C1), 138.1 (C4a), 145.7
(C1¢), 148.0 (C8a), 159.6 (C3).
To a refluxing soln of pyranoindolone 3 (1.5 mmol) in PhBr (15
mL), PhNHNH2 (3.0 mmol) or BzNHNH2 (2.0 mmol) was added
and refluxing was continued for 2 h. The mixture was cooled down
(5–10 °C), whereupon the precipitated product was filtered out,
washed with Et2O, and recrystallized (EtOH). In the cases where
crystallization was not possible the solvent was distilled off and the
resulting residue was subjected to column chromatography (silica
gel, PE–EtOAc, 5:1, slowly increasing the polarity up to 3:1) to give
4a–f or 5a–f.
MS (EI, 70 eV): m/z (%) = 317 (5) [M+], 296 (42), 198 (100).
Anal. Calcd for C20H19N3O (317.38): C, 75.69; H, 6.03; N, 13.24.
Found: C, 75.81; H, 6.12, N, 13.58.
2-Anilino-1,9-dimethyl-2,9-dihydro-3H-b-carbolin-3-one (4d)
Yellow crystals; yield: 0.304 g (67%); mp 218–221 °C (EtOH).
IR (Nujol): 3219 (NH), 1658 cm–1 (NC=O).
1H NMR: d = 2.88 (d, J = 0.75 Hz, 3 H, 1-Me), 3.85 (s, 3 H, 9-Me),
6.68 (AA¢, J = 1.1, 2.0, 8.2 Hz, 2 H, H2¢, H6¢), 6.98 (tt, J = 1.1, 7.3
Hz, 1 H, H4¢), 7.12 (q, J = 0.75 Hz, 1 H, H4), 7.14 (ddd, J = 0.8, 7.1,
7.8 Hz, 1 H, H6), 7.22 (br d, J = 8.4 Hz, 1 H, H8), 7.23 (BB¢, J =
2.0, 7.3, 8.2 Hz, 2 H, H3¢, H5¢), 7.56 (ddd, J = 1.3, 7.1, 8.4 Hz, 1 H,
H7), 7.92 (ddd, J = 0.7, 1.3, 7.8 Hz, 1 H, H5), 8.01 (br s, 1 H, 2-NH).
13C NMR: d = 14.7 (1-Me), 33.3 (9-Me), 102.6 (C4), 109.0 (C8),
115.0 (C2¢, C6¢), 119.4 (C6), 120.7 (C4b), 122.7 (C4¢), 122.8 (C5),
126.9 (C9a), 129.4 (C3¢, C5¢), 130.4 (C1), 130.7 (C7), 138.8 (C4a),
147.0 (C1¢), 147.7 (C8a), 159.7 (C3).
2-Anilino-1-methyl-2,9-dihydro-3H-b-carbolin-3-one (4a)
Yellow crystals; yield: 0.290 g (67%); mp 256–258 °C (EtOH).
IR (Nujol): 3228 (NH), 1667 cm–1 (NC=O).
1H NMR (CDCl3, DMSO-d6): d = 2.65 (s, 3 H, 1-Me), 6.65 (d,
J = 8.0 Hz, 2 H, H2¢, H6¢),20 6.93 (t, J = 7.1 Hz, 1 H, H4¢), 7.01 (s,
1 H, H4), 7.08 (dd, J = 7.1, 7.9 Hz, 1 H, H6), 7.20 (dd, J = 7.1, 8.0
Hz, 2 H, H3¢, H5¢), 7.31 (d, J = 8.4 Hz, 1 H, H8), 7.46 (dd, J = 7.1,
8.4 Hz, 1 H, H7), 7.89 (d, J = 7.9 Hz, 1 H, H5), 8.15 (br s, 1 H, 2-
NH), 9.93 (br s, 1 H, H9).
13C NMR (CDCl3, DMSO-d6): d = 14.1 (1-Me), 101.3 (C4), 111.1
(C8), 113.4 (C2¢, C6¢), 118.4 (C6), 120.2 (C5), 120.8 (C4b), 122.5
(C4¢), 124.7 (C9a), 128.8 (C3¢, C5¢), 130.0 (C7), 130.5 (C1), 137.8
(C4a), 145.6 (C8a), 147.4 (C1¢), 159.4 (C3).
MS (EI, 70 eV): m/z (%) = 303 (30) [M+], 212 (100) [M+ – N-Ph],
197 (38), 183 (40), 169 (25).
Anal. Calcd for C19H17N3O (303.36): C, 75.23; H, 5.65; N, 13.85.
Found: C, 75.54; H, 5.73; N, 13.68.
MS (EI, 70 eV): m/z (%) = 289 (45) [M+], 281 (46), 260 (85), 198
(100), 169 (85), 154 (20), 128 (30).
2-Anilino-1-ethyl-9-methyl-2,9-dihydro-3H-b-carbolin-3-one
(4e)
Yellow crystals; yield: 0.328 g (69%); mp 199–200 °C (EtOH).
IR (Nujol): 3240 (NH), 1659 cm–1 (NC=O).
Anal. Calcd for C18H15N3O (289.33): C, 74.72; H, 5.23; N, 14.52.
Found: C, 74.76; H, 5.03; N, 14.68.
1H NMR: d = 1.35 (t, J = 7.5 Hz, 3 H, 1-CH2CH3), 3.08 (dq, J = 7.5,
14.5 Hz, 1 H, 1-CH2CH3), 3.32 (dq, J = 7.5, 14.5 Hz, 1 H, 1-
CH2CH3), 3.84 (s, 3 H, 9-Me), 6.63 (d, J = 8.0 Hz, 2 H, H2¢, H6¢),
6.94 (t, J = 7.3 Hz, 1 H, H4¢), 7.10 (s, 1 H, H4), 7.12 (dd, J = 7.1,
7.6 Hz, 1 H, H6), 7.20 (dd, J = 7.3, 8.2 Hz, 2 H, H3¢, H5¢), 7.22 (d,
J = 8.4 Hz, 1 H, H8), 7.55 (ddd, J = 1.1, 7.1, 8.4 Hz, 1 H, H7), 7.83
(br s, 1 H, NH), 7.89 (dd, J = 1.0, 7.6 Hz, 1 H, H5).
13C NMR: d = 15.1 (1-CH2CH3), 21.6 (1-CH2CH3), 32.7 (9-Me),
103.2 (C4), 109.0 (C8), 114.5 (C2¢, C6¢), 119.3 (C6), 120.5 (C4b),
122.3 (C4¢), 122.8 (C5), 126.1 (C9a), 129.3 (C3¢, C5¢), 130.8 (C7),
136.2 (C1), 139.4 (C4a), 147.5 (C1¢), 147.5 (C8a), 159.9 (C3).
2-Anilino-1-ethyl-2,9-dihydro-3H-b-carbolin-3-one (4b)
Yellow crystals; yield: 0.314 g (69%); mp 243–245 °C (EtOH).
IR (Nujol): 3306 (NH), 1671 cm–1 (NC=O).
1H NMR (CDCl3): d = 1.31 (t, J = 7.5 Hz, 3 H, CH2CH3), 2.96 (q,
J = 7.5 Hz, 2 H, CH2CH3), 6.64 (d, J = 8.0 Hz, 2 H, H2¢, H6¢), 6.96
(t, J = 7.2 Hz, 1 H, H4¢), 7.10 (s, 1 H, H4), 7.15 (dd, J = 7.0, 7.5 Hz,
1 H, H6), 7.21 (dd, J = 7.2, 8.0 Hz, 2 H, H3¢, H5¢), 7.29 (d, J = 8.4
Hz, 1 H, H8), 7.50 (dd, J = 7.0, 8.4 Hz, 1 H, H7), 7.52 (br s, 1 H, 2-
NH), 7.76 (br s, 1 H, H9), 7.92 (d, J = 7.5 Hz, 1 H, H5).
13C NMR (CDCl3, DMSO-d6): d = 13.2 (CH2CH3), 21.8 (CH2CH3),
101.7 (C4), 111.3 (C8), 113.6 (C2¢, C6¢), 118.4 (C6), 120.1 (C4b),
120.9 (C5), 122.5 (C4¢), 124.4 (C9a), 128.8 (C3¢, C5¢), 130.1 (C7),
136.1 (C1), 138.2 (C4a), 145.7 (C1¢), 147.8 (C8a), 159.6 (C3).
MS (EI, 70 eV): m/z (%) = 317 (28) [M+], 288 (100), 272 (8), 225
(10), 168 (15).
Anal. Calcd for C20H19N3O (317.38): C, 75.69; H, 6.03; N, 13.24.
Found: C, 75.68; H, 6.16; N, 13.38.
MS (EI, 70 eV): m/z (%) = 303 (56) [M+], 274 (100), 258 (10), 211
(40), 183 (20), 154 (15), 128 (12).
2-Anilino-9-methyl-1-propyl-2,9-dihydro-3H-b-carbolin-3-one
(4f)
Yellow crystals; yield: 0.337 g (68%); mp 242–243 °C (EtOH).
Anal. Calcd for C19H17N3O (303.36): C, 75.23; H, 5.65; N, 13.85.
Found: C, 75.05; H, 5.43, N, 13.67.
IR (Nujol): 3218 (NH), 1649 cm–1 (NC=O).
2-Anilino-1-propyl-2,9-dihydro-3H-b-carbolin-3-one (4c)
Yellow crystals; yield: 0.308 g (65%); mp 252–253 °C (EtOH).
1H NMR: d = 1.01 (t, J = 7.5 Hz, 3 H, 1-CH2CH2CH3), 1.57–1.75
(m, 1 H, 1-CH2CH2CH3), 1.80–1.98 (m, 1 H, 1-CH2CH2CH3), 3.05
(ddd, J = 5.6, 7.5, 14.5 Hz, 1 H, 1-CH2CH2CH3),20 3.24 (ddd,
J = 5.5, 7.5, 14.5 Hz, 1 H, 1-CH2CH2CH3), 3.84 (s, 3 H, 9-Me), 6.65
(d, J = 7.7 Hz, 2 H, H2¢, H6¢), 6.96 (t, J = 7.3 Hz, 1 H, H4¢), 7.11 (s,
1 H, H4), 7.13 (dd, J = 7.2, 7.7 Hz, 1 H, H6), 7.22 (dd, J = 7.3, 7.7
Hz, 2 H, H3¢, H5¢), 7.23 (d, J = 8.3 Hz, 1 H, H8), 7.56 (dd, J = 7.2,
8.3 Hz, 1 H, H7), 7.83 (s, 1 H, 2-NH), 7.90 (d, J = 7.7 Hz, 1 H, H5).
13C NMR: d = 14.0 (1-CH2CH2CH3), 24.1 (1-CH2CH2CH3), 30.0
(1-CH2CH2CH3), 32.7 (9-Me), 103.2 (C4), 109.00 (C8), 114.5 (C2¢,
C6¢), 119.3 (C6), 120.5 (C4b), 122.3 (C4¢), 122.8 (C5), 126.3 (C9a),
129.3 (C3¢, C5¢), 130.8 (C7), 135.1 (C1), 139.3 (C4a), 147.5 and
147.6 (C1¢ and C8a), 159.9 (C3).
IR (Nujol): 3186 (NH), 1663 cm–1 (NC=O).
1H NMR: d = 0.97 (t, J = 7.5 Hz, 3 H, CH2CH2CH3), 1.69 and 1.82
(two multiplets of AB system, 2 H, CH2CH2CH3), 2.90 and 3.01
(two multiplets of AB system, 2 H, CH2CH2CH3), 6.62 (d, J = 7.8
Hz, 2 H, H2¢, H6¢), 6.90 (t, J = 7.5 Hz, 1 H, H4¢), 7.01 (s, 1 H, H4),
7.06 (ddd, J = 0.8, 7.25, 7.75 Hz, 1 H, H6), 7.18 (dd, J = 7.5, 7.8 Hz,
2 H, H3¢, H5¢), 7.30 (dd, J = 0.8, 8.4 Hz, 1 H, H8), 7.46 (ddd,
J = 1.0, 7.25, 8.4 Hz, 1 H, H7), 7.88 (dd, J = 1.0, 7.75 Hz, 1 H, H5),
8.65 (br s, 1 H, 2-NH), 10.48 (br s, 1 H, 9-NH).
13C NMR (CDCl3, DMSO-d6): d = 13.8 (CH2CH2CH3), 22.1
(CH2CH2CH3), 30.1 (CH2CH2CH3), 101.8 (C4), 111.1 (C8), 113.4
Synthesis 2008, No. 20, 3273–3278 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of b-Carbolines
3277
MS (EI, 70 eV): m/z (%) = 332 (100) [M+ + 1], 302 (63), 254 (40),
241 (65), 213 (90).
Anal. Calcd for C21H19N3O2 (345.39): C, 73.03; H, 5.54; N, 12.17.
Found: C, 73.26; H, 5.67; N, 12.00.
Anal. Calcd for C21H21N3O (331.41): C, 76.11; H, 6.39; N, 12.68.
Found: C, 75.98; H, 6.26; N, 12.78.
2-(Benzoylamino)-1,9-dimethyl-2,9-dihydro-3H-b-carbolin-3-
one (5d)
Yellow crystals; yield: 0.362 g (73%); mp 96–98 °C (EtOH).
IR (Nujol): 3300 (NH), 1687 and 1659 cm–1 (C=O).
2-(Benzoylamino)-1-methyl-2,9-dihydro-3H-b-carbolin-3-one
(5a)
Yellow crystals; yield: 0.352 g (74%); mp 195–197 °C (EtOH).
IR (Nujol): 3299 (NH), 1681 cm–1 (NC=O).
1H NMR (CDCl3, DMSO-d6): d = 2.85 (s, 3 H, 1-Me), 3.77 (s, 3 H,
9-Me), 7.01 (s, 1 H, H4), 7.10 (dd, J = 7.2, 7.7 Hz, 1 H, H6), 7.15
(d, J = 8.1 Hz, 1 H, H8), 7.40–7.50 (m, 2 H, H3¢, H5¢), 7.50–7.58
(m, 2 H, H7, H4¢), 7.87 (d, J = 7.7 Hz, 1 H, H5), 8.05 (d, J = 7.7 Hz,
2 H, H2¢, H6¢), 10.20 (br s, 1 H, 2-NH).
13C NMR (CDCl3, DMSO-d6): d = 14.4 (1-Me), 33.1 (9-Me), 102.1
(C4), 108.9 (C8), 119.0 (C6), 120.7 (C4b), 122.7 (C4¢), 122.8 (C5),
126.9 (C9a), 128.0 (C2¢, C6¢), 128.3 (C3¢, C5¢), 130.4 (C1), 130.7
(C7), 138.8 (C4a), 147.0 (C1¢), 147.7 (C8a), 159.7 (C3), 167.2 (2-
C=O).
1H NMR (DMSO-d6): d = 2.52 (s, 3 H, 1-Me), 6.97 (s, 1 H, H4),
7.05 (dd, J = 7.2, 7.7 Hz, 1 H, H6), 7.31 (d, J = 8.1 Hz, 1 H, H8),
7.49 (dd, J = 7.2, 8.1 Hz, 1 H, H7), 7.58 (dd, J = 7.1, 7.5 Hz, 2 H,
H3¢, H5¢), 7.67 (t, J = 7.5 Hz, 1 H, H4¢), 8.02 (d, J = 7.7 Hz, 1 H,
H5), 8.04 (d, J = 7.6 Hz, 2 H, H2¢, H6¢), 10.6 (s, 1 H, 2-NH), 11.4
(s, 1 H, H9).
13C NMR (DMSO-d6): d = 14.3 (1-Me), 101.6 (C4), 111.2 (C8),
118.6 (C6), 120.4 (C4b), 122.7 (C5), 125.1 (C9a), 128.1 (C2¢, C6¢),
128.4 (C3¢, C5¢), 130.3 (C1), 130.4 (C7), 131.9 (C1¢), 132.3 (C4¢),
139.1 (C4a), 146.0 (C8a), 159.3 (C3), 167.4 (2-C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 332 (100), [M+ + 1].
Anal. Calcd for C20H17N3O2 (331.37): C, 72.49; H, 5.17; N, 12.68.
Found: C, 72.34; H, 5.28; N, 12.50.
LC-MS (ESI, 1.65 eV): m/z (%) = 318 (100), [M+ + 1].
Anal. Calcd for C19H15N3O2 (317.34): C, 71.91; H, 4.76; N, 13.24.
Found: C, 71.74; H, 4.53; N, 13.08.
2-(Benzoylamino)-1-ethyl-9-methyl-2,9-dihydro-3H-b-carbo-
lin-3-one (5e)
Yellow crystals; yield: 0.367 g (71%); mp 146–148 °C (EtOH).
IR (Nujol): 3250 (NH), 1660 cm–1 (C=O).
2-(Benzoylamino)-1-ethyl-2,9-dihydro-3H-b-carbolin-3-one
(5b)
Yellow crystals; yield: 0.357 g (72%); mp 274–275 °C (EtOH).
IR (Nujol): 3235 (NH), 1671 cm–1 (NC=O).
1H NMR: d = 1.37 (br t, J = 7.4 Hz, 3 H, 1-CH2CH3), 3.09 (br q,
J = 7.4 Hz, 2 H, 1-CH2CH3), 3.63 (s, 3 H, 9-Me), 6.75 (s, 1 H, H4),
6.99 (ddd, J = 1.0, 7.4, 7.7 Hz, 1 H, H6), 7.02 (dd, J = 1.0, 8.2 Hz,
1 H, H8), 7.20 (t, 7.5 Hz, 2 H, H3¢, H5¢), 7.33 (t, J = 7.5 Hz, 1 H,
H4¢), 7.44 (ddd, J = 1.2, 7.4, 8.2 Hz, 1 H, H7), 7.66 (dd, J = 1.2, 7.7
Hz, 1 H, H5), 8.05 (d, J = 7.5 Hz, 2 H, H2¢, H6¢), 10.60 (br s, 1 H,
2-NH).
13C NMR: d = 14.6 (1-CH2CH3), 21.7 (1-CH2CH3), 32.4 (9-Me),
102.6 (C4), 108.8 (C8), 119.0 (C6), 120.0 (C4b), 122.4 (C5), 126.4
(C9a), 128.1 (C2¢, C6¢), 128.4 (C3¢, C5¢), 130.9 (C7), 131.2 (C1¢),
132.2 (C4¢), 136.4 (C1), 140.0 (C4a), 147.3 (C8a), 159.7 (C3),
167.9 (2-C=O).
1H NMR (CDCl3, DMSO-d6): d = 1.40 (t, J = 7.5 Hz, 3 H,
CH2CH3), 3.07 (q, J = 7.5 Hz, 2 H, CH2CH3), 7.00 (s, 1 H, H4), 7.12
(dd, J = 7.1, 7.9 Hz, 1 H, H6), 7.39 (d, J = 8.3 Hz, 1 H, H8), 7.54
(dd, J = 7.1, 8.3 Hz, 1 H, H7), 7.61 (dd, J = 7.1, 7.5 Hz, 2 H, H3¢,
H5¢), 7.67 (t, J = 7.5 Hz, 1 H, H4), 7.97 (d, J = 8.0 Hz, 1 H, H5),
8.17 (d, J = 7.1 Hz, 2 H, H2¢, H6¢), 10.58 (s, 1 H, 2-NH), 11.50 (br
s, 1 H, H9).
13C NMR (CDCl3, DMSO-d6): d = 12.9 (CH2CH3), 21.8 (CH2CH3),
101.6 (C4), 111.2 (C8), 118.4 (C6), 120.1 (C4b), 122.7 (C5), 124.1
(C9a), 127.6 (C2¢, C6¢), 128.3 (C3¢, C5¢), 130.4 (C1¢), 132.0 (C1),
132.2 (C7), 135.4 (C4¢), 139.1 (C4a), 145.9 (C8a), 159.0 (C3),
167.3 (2-C=O).
MS (EI, 70 eV): m/z (%) = 327 (100) [M+ – 18], 312 (78), 207 (5),
195 (10), 181 (13), 163 (10), 105 (30).
LC-MS (ESI, 1.65 eV): m/z (%) = 332 (100), [M+ + 1].
Anal. Calcd for C21H19N3O2 (345.39): C, 73.03; H, 5.54; N, 12.17.
Found: C, 72.89; H, 5.43; N, 12.25.
Anal. Calcd for C20H17N3O2 (331.37): C, 72.49; H, 5.17; N, 12.68.
Found: C, 72.74; H, 5.03; N, 12.78.
2-(Benzoylamino)-9-methyl-1-propyl-2,9-dihydro-3H-b-carbo-
lin-3-one (5f)
Yellow crystals; yield: 0.361 g (67%); mp 124–126 °C (EtOH).
IR (Nujol): 3268 (NH), 1685, 1651 cm–1 (C=O).
2-(Benzoylamino)-1-propyl-2,9-dihydro-3H-b-carbolin-3-one
(5c)
Yellow crystals; yield: 0.352 g (68%); mp 252–253 °C (EtOH).
IR (Nujol): 3218 (NH), 1664 cm–1 (NC=O).
1H NMR: d = 1.01 (t, J = 7.3 Hz, 3 H, 1-CH2CH2CH3), 1.82 (m, 2
H, 1-CH2CH2CH3), 3.06 (dt, J = 7.5, 7.5 Hz, 2 H, 1-CH2CH2CH3),
3.70 (s, 3 H, 9-Me), 6.88 (s, 1 H, H4), 7.04 (dd, J = 7.2, 7.6 Hz, 1
H, H6), 7.09 (d, J = 8.4 Hz, 1 H, H8), 7.27 (t, J = 7.6 Hz, 2 H, H3¢,
H5¢), 7.40 (t, J = 7.6 Hz, 1 H, H4¢), 7.48 (dd, J = 7.2, 8.4 Hz, 1 H,
H7), 7.75 (d, J = 7.6 Hz, 1 H, H5), 8.02 (d, J = 7.6 Hz, 2 H, H2¢,
H6¢), 11.2 (br s, 1 H, 2-NH).
13C NMR: d = 14.1 (1-CH2CH2CH3), 23.6 (1-CH2CH2CH3), 30.1
(1-CH2CH2CH3), 32.4 (9-Me), 102.7 (C4), 108.9 (C8), 119.2 (C6),
120.0 (C4b), 122.5 (C5), 126.8 (C9a), 128.0 (C2¢, C6¢), 128.5 (C3¢,
C5¢), 130.9 (C7), 131.3 (C1¢), 132.3 (C4¢), 135.3 (C1), 140.0 (C4a),
147.4 (C8a), 159.7 (C3), 168.1 (2-C=O).
1H NMR: d = 0.96 (t, J = 7.4 Hz, 3 H, CH2CH2CH3), 1.78 (sext,
J = 7.4 Hz, 2 H, CH2CH2CH3), 2.88 (t, J = 7.4 Hz, 2 H,
CH2CH2CH3), 6.74 (s, 1 H, H4), 6.98 (dd, J = 7.7, 7.2 Hz, 1 H, H6),
7.20 (d, J = 7.7 Hz, 1 H, H8), 7.35–7.45 (m, 3 H, H3¢, H4¢, H5¢),
7.45–7.50 (m, 1 H, H7), 7.69 (d, J = 7.7 Hz, 1 H, H5), 8.06 (d,
J = 7.3 Hz, 2 H, H2¢, H6¢), 9.78 (s, 1 H, 2-NH), 11.48 (br s, 1 H, H9).
13C NMR (CDCl3, DMSO-d6): d = 13.9 (CH2CH2CH3), 21.5
(CH2CH2CH3), 30.1 (CH2CH2CH3), 101.6 (C4), 111.2 (C8), 118.4
(C6), 120.1 (C4b), 122.8 (C5), 127.1 (C9a), 127.9 (C2¢, C6¢), 128.4
(C3¢, C5¢), 130.4 (C1), 131.2 (C7), 132.2 (C4¢), 134.1 (C1¢), 138.9
(C4a), 145.9 (C8a), 159.0 (C3), 167.1 (2-C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 360 (100), [M+ + 1].
LC-MS (ESI, 1.65 eV: m/z (%) = 346 (100) [M+ + 1].
Anal. Calcd for C22H21N3O2 (359.42): C, 73.52; H, 5.89; N, 11.69.
Found: C, 73.40; H, 5.63; N, 11.92.
Synthesis 2008, No. 20, 3273–3278 © Thieme Stuttgart · New York

3278
D. Livadiotou et al.
PAPER
(9) Fuller, R. W.; Wong, C. J.; Hemrick-Luecke, S. K. Life Sci.
1986, 38, 409.
(10) (a) Pohl, B.; Luchterhandt, T.; Bracher, F. Synth. Commun.
2007, 37, 1273. (b) Lingam, Y.; Rao, D. M.; Bhowmik,
D. R.; Islam, A. Synth. Commun. 2007, 37, 4313.
(11) Teshigawara, T. JP42008628, 1967; Chem. Abstr. 1968, 68,
49580g.
(12) Plieninger, H.; Müller, W.; Weinerth, K. Chem. Ber. 1964,
97, 667.
(13) Dorofeenko, G. N.; Korobkova, V. G.; Guzhina, E. A. Chem.
Heterocycl. Compd. 1971, 7, 319.
References and notes
(1) Allen, J. R. F.; Holmstedt, B. Phytochemistry 1980, 19,
1573.
(2) (a) Love, B. E. Org. Prep. Proced. Int. 1996, 28, 3.
(b) Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 6201.
(c) Nakagawa, M. J. Heterocycl. Chem. 2000, 37, 567.
(d) Cox, E. D.; Diaz-Arauzo, H.; Huang, Q.; Reddy, M. S.;
Ma, C.; Harris, B.; McKernan, R.; Skolnick, P.; Cook, J. M.
J. Med. Chem. 1998, 41, 2537. (e) Batch, A.; Dodd, R. H.
J. Org. Chem. 1998, 63, 872.
(3) (a) Rommelspacher, H.; May, T.; Salewsky, B. Eur. J.
Pharmacol. 1994, 252, 51. (b) Kim, H.; Sablin, S. O.;
Ramsay, R. R. Arch. Biochem. Biophys. 1997, 337, 137.
(c) Herraiz, T.; Chaparro, C. Biochem. Biophys. Res.
Commun. 2005, 326, 378. (d) Evans, A. K.; Lowry, C. A.
CNS Drug Rev. 2007, 13, 475.
(4) (a) Taira, Z.; Kanzawa, S.; Dohara, C.; Ishida, S.;
Matsumoto, M.; Sakiya, Y. Jpn. J. Toxicol. Environ. Health
1997, 43, 83. (b) Balón, M.; Muñoz, M. A.; Carmora, C.;
Guardado, P.; Galán, M. Biophys. Chem. 1999, 80, 41.
(5) Funayama, Y.; Nishio, K.; Wakabayashi, K.; Nagao, M.;
Shimoi, K.; Ohira, T.; Hasegawa, S.; Saijo, N. Mutat. Res.
1996, 349, 183.
(14) (a) Tolkunov, S. V.; Tolkunov, V. S.; Dulenko, V. I. Chem.
Heterocycl. Compd. 2004, 40, 481. (b) Tolkunov, V. S.;
Vysotsky, Y. B.; Gorban, O. A.; Shishkina, S. V.; Shishkin,
O. V.; Dulenko, V. I. Chem. Heterocycl. Compd. 2005, 41,
515.
(15) Katritzky, A. R.; Shcherbakova, I. V. J. Heterocycl. Chem.
1996, 33, 2031.
(16) Doitsides, N.; Mentzafos, D.; Mitkidou, S.; Terzis, A.;
Stephanidou-Stephanatou, J. Synth. Commun. 1995, 25,
1411.
(17) Modi, S. P.; Archer, S. J. Org. Chem. 1989, 54, 5189.
(18) Hatzimimikou, D.; Livadiotou, D.; Tsoleridis, C. A.;
Stephanidou-Stephanatou, J. Synlett 2008, 1773.
(19) (a) Diels, O.; Köllisch, A. Chem. Ber. 1911, 44, 266.
(b) Bennasar, M.-L.; Juan, C.; Roca, T.; Monerris, M.;
Bosch, J. Tetrahedron 2001, 57, 10125.
(6) (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
(b) Yu, S.; Berner, O. M.; Cook, J. M. J. Am. Chem. Soc.
2000, 122, 7827. (c) Danieli, B.; Giovanelli, P.; Lesma, G.;
Passarella, D.; Saccetti, A.; Silvani, A. J. Comb. Chem.
2005, 7, 458.
(20) The multiplicities and chemical shifts of the aromatic
protons and of some second-order spectra of R2 substituent
have been confirmed after simulation with program
SpinWorks, version 2.5, available from ftp://
davinci.chem.umanitoba.ca.
(7) Loew, G. H.; Nienow, J.; Lawson, J. A.; Toll, L.; Uyeno,
E. T. Mol. Pharmacol. 1985, 28, 17.
(8) Barbaccia, M. L.; Ravizza, L.; Costa, E. J. Pharmacol. Exp.
Ther. 1986, 236, 307.
Synthesis 2008, No. 20, 3273–3278 © Thieme Stuttgart · New York