A facile synthesis of 3-substituted 9H-pyrido[3,4-b]indol- 1(2H)-one derivatives from 3-substituted β-carbolines

Article abstract of DOI:10.3390/molecules15085680

A mild and efficient two-step synthesis of 3-substituted β-carbolinone derivatives from 3-substituted β-carboline in good yields is described. A possible reaction mechanism for the formation of the skeleton of β-carbolin-1-one is proposed. The structures of these compounds were established by IR, ₁H-NMR, ¹³C-NMR, mass spectrometry and elemental analysis, as well as X-ray crystallographic analysis of 4-2 and 6-2.

Full text of DOI:10.3390/molecules15085680

Molecules 2010, 15, 5680-5691; doi:10.3390/molecules15085680
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Facile Synthesis of 3-Substituted 9H-Pyrido[3,4-b]indol-
(2H)-one Derivatives from 3-Substituted β-Carbolines
1
1
1,
1
1
1
1,2,
Guowu Lin , Yue Wang *, Qingfa Zhou , Weifang Tang , Jian Wang and Tao Lu
*
1
College of Basic Science, China Pharmaceutical University, Nanjing 210009, China
2
Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China
Pharmaceutical University, Nanjing 210009, China
*
Author to whom correspondence should be addressed; E-Mail: lutao@cpu.edu.cn;
zwy_1115@cpu.edu.cn.
Received: 2 August 2010; in revised form: 10 August 2010 / Accepted: 11 August 2010 /
Published: 17 August 2010
Abstract: A mild and efficient two-step synthesis of 3-substituted β-carbolinone
derivatives from 3-substituted β-carboline in good yields is described. A possible reaction
mechanism for the formation of the skeleton of β-carbolin-1-one is proposed. The
1
13
structures of these compounds were established by IR, H-NMR, C-NMR, mass
spectrometry and elemental analysis, as well as X-ray crystallographic analysis of 4-2 and
6
-2.
Keywords: β-carboline, β-carbolinone, rearrangement, electron-withdrawing, X-ray
crystal structure.
Introduction
Natural products have a profound impact on both chemical biology and drug discovery, and the
substituted β-carboline moiety is an example. β-Carboline is a key pharmacophore present in a large
number of natural tricyclic alkaloids, which can be found in numerous plants and animals, exhibiting
potent biological activities [1-10]. As a key member of the β-carboline family, its structural variant
tricyclic β-carbolinone (9H-pyrido[3,4-b]indol-1(2H)-one derivative or β-carbolin-1-one, Figure 1) has
served as an important intermediate for the preparation of complex alkaloids [11-19] and has been
found to possess potent bioactivities. The natural and synthetic β-carbolinones are reported to have

Molecules 2008, 13
5681
pharmacological effects in several aspects, such as the anticancer activity against colon and lung
cancers, central nervous system activity in mammals, and also as the biological control agent for
receptor research on bio-enzyme inhibitors, such as the inhibition of HLE (Human leukocyte elastase)
[20-23]. In continuation of our work on biologically active β-carbolinone alkaloids [24], we focused
our interest on the synthesis of 3-disubstituted β-carbolinones.
Figure 1. The structure of tricyclic β-carbolinones.
R1
NH
A
C
O
B
N
H
The total synthesis of these substituted tricyclic β-carbolinones has attracted great attention,
however, few facile synthetic approaches to β-carbolinones have been published over the years. A
majority of alkaloids are substituted at the 3-position of β-carbolinones, and two major synthetic
strategies have been adopted for this purpose: one approach starting from tryptamine which offers an
easy access to β-carbolinone (9H-pyrido[3,4-b]indol-1(2H)-one, Scheme 1) [25], and another three step
route to synthesize 3-aryl-β-carbolinone by reaction of chalcone derivatives with N-acetyl-2-
cyanoglycine ethyl ester (Scheme 2) [26]. Nevertheless, it is still difficult to introduce other groups
directly at the 3-position of the β-carbolinone by these methodologies, especially for the synthesis of
electron-withdrawing substituents at the 3-position of β-carbolinone. So it is urgent and significant to
find a new and effective way to synthesize a large number of 3-substituted (electron-withdrawing) β-
carbolinones. Herein, we report a novel synthetic route for the preparation of 3-substituted (electron-
withdrawing substituents) β-carbolinones.
Scheme 1. A conventional route to synthesize of 9H-pyrido[3,4-b]indol-1(2H)-one.
Cl CO-CO-OCCl
HBr
Pd/C
3
3
NH2
NH
NH
(C H ) N
2
5 3
N
N
N
H
H
H
O
O
4
-2
Scheme 2. A route to synthesize 3-aryl-9H-pyrido[3,4-b]indol-1(2H)-one.
CO Et
2
O
AcHN
CN
O
CO Et
2
Ar
10%mol t-BuONa
THF, r.t., 2 hr
R
Ar
AcHN
O
CN
R
X
X
EtO C
2
Ar
NH
aq. HCl-HOAc
r.t., 7 hr
AcHN
NH
Ar
CuI, NaH, DEM
reflux, 7-10 hr
R
N
R
H
O
X

Molecules 2008, 13
5682
Results and Discussion
In this paper, we describe a two-step preparation of 3-substituted β-carbolinones using 3-substituted
β-carbolines as the starting materials (Scheme 3).
Scheme 3. A route to synthesize 3-substituted β-carbolinones.
R1
R1
R1
NH
m-CPBA, EtOH
CHCl , reflux
Ac O, reflux
2
N
N
3
N
H
N
NaOH, EtOH, r.t.
N
O
H
H
O
X
X-1
X-2
X = 4, 5, 6, 7, 8, 9, 12, 13, 14, 15
For the first step, in a mixed and refluxing 1:1 chloroform/ethanol solution, β-carboline derivatives
X were treated with 3-chloro-peroxybenzoic acid (m-CPBA) yielding the corresponding N-oxides X-1
in excellent yields, which then were purified by flash column chromatography; in the second step, the
β-carbolinones were obtained through the regioselective rearrangement of the β-carboline-N-oxides in
acetic anhydride at refluxing and subsequently hydrolysis in a solution of EtOH/aqueous 2 M NaOH
(
1:1) at room temperature. The 3-substituted β-carboline substrates were synthesized according to the
literature procedure [27-31], which is summarized in Scheme 4.
Scheme 4. Synthesis of 3-substituted β-carbolines.
CO H
CO H
CO Et
2
2
2
(
a)
(b)
(
c)
NH2
NH
NH
N
N
N
N
H
3
N
H
4
H
H
1
2
CON3
i)
(d)
CONHNH2
COOEt
e)
CH OH
2
(
(h)
(
N
N
N
N
N
N
N
N
H
H
H
H
1
0
9
6
5
(j)
(
f)
(m)
NH2
Br
CHO
CONHCH3
(
l)
N
N
N
N
H
11
N
N
N
H
N
H
H
1
4
7
1
5
(
k)
(
g)
O
CN
R
N
N
N
N
H
H
1
2;13
8
Reagents and Conditions: (a) HCHO, NaOH; (b) C
2 5 2 2
H OH, SOCl ; (c) SeO , AcOH, reflux; (d)
.
KMnO , DMF, r.t.; (e) LiAlH , THF, 10 °C; (f) MnO , CH Cl , reflux; (g) I , NH H O, THF, r.t.;
4
4
2
2
2
2
3
2
(
h) NH NH , MeOH, reflux; (i) NaNO , HCl; (j) reflux, NaOH; (k) ROH (anhydrous), isoamyl
2 2 2
nitrite, concentrated H SO ; (l) NaNO , HBr, Br ; (m) CH NH , MeOH, reflux.
2
4
2
2
3
2

Molecules 2008, 13
5683
Based on our experimental results and other similar reactions [32-37], the reaction mechanism of β-
carboline N-oxides with glacial acetic acid and sodium hydroxide was presumed to be as shown in
Scheme 5. The overall process may be summarized as follows: i) β-carboline-N-oxide X-1 was
refluxed with excess acetic anhydride to yield light brown syrup from which intermediate I (2-acetoxy-
-
β-carboline derivative) was formed; ii) another acetyl oxygen anion (CH COO ) attacks the carbon
3
1 2
atom at 1-position of 2-acetoxy-β-carboline, and meanwhile the (C = N ) double bond was broken to
give ntermediate II (1,2-diacetoxy-1,2-dihydro-β-carboline); iii) elimination of one molecule of acetic
acid, and regeneration of the (C = N ) double bond to give intermediate III (1-acetoxy-β-carboline
1
2
derivative)’ iv) by the hydrolysis of 1-acetoxy-β-carbolines III in sodium hydroxide solution, the
target compounds were obtained via intermediate IV.
Scheme 5. The possible mechanism for the synthesis of 3-substituted 9H-pyrido[3,4-
b]indol-1(2H)-one derivatives.
R1
R1
R1
O
m-CPBA
Ac O
2
N
N
N
N
H
N
O
N
H
H
I
X
X-1
O
CH3
AcO
R1
R1
-
AcOH
OH
2
OAc
2
N
N
N
N
H
1
1
OAc
H
OAc
R1
II
III
R1
NH
N
N
H
N
H
X-2
OH
O
IV
The various β-carbolines were used as substrates, and the results are summarized in Table 1. Under
identical reaction conditions, using 3-ethoxycarbonyl-β-carboline, 3-hydroxymethyl-β-carboline,
3
-cyano-β-carboline, β-carboline-3-carbohydrazide, or 3-(N-methylcarbamoyl)-β-carboline as starting
materials, we obtained good yields (about 67-85%) of corresponding products (entries 2, 3, 5, 6 and 10
in Table 1). However, other β-carboline derivatives gave moderate yields (about 30-50%) of the
corresponding β-carbolinones (entries 4, 7, 8 and 9). This discrepancy may be attributed to the
different groups at the 3-position, because electron withdrawing substituents at the 3-position can
enhance the electronic stability of intermediate I, and therefore, a relatively higher yield of product
could be obtained. However, an electron-rich substituent is not beneficial for the electronic stability of
intermediate I, so poor yield were observed in our experiments. All products were fully characterized
by spectroscopic means.

Molecules 2008, 13
5684
Table 1. Yields and times for the synthesis of 9H-pyrido[3,4-b]indol-1(2H)-one derivative.
1
a
b, c
Entry
R
Product (X-2)
(4-2)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
H
6
4
8
6
4
65
85
75
52
72
67
45
53
30
82
COOCH
2
CH
3
(5-2)
(6-2)
(7-2)
(8-2)
CH
2
OH
CHO
CN
CONHNH2
(9-2)
4
OCH
OCH CH
Br
CONHCH
3
(12-2)
(13-2)
(14-2)
(15-2)
b
10
10
12
4
2
3
10
3
a
c
Monitored by TLC until N-oxidation is complete. Isolated yield by column chromatography.
The yields of conversion of the N-oxides X-1 into 3-substituted -carbolinones X-2.
2
At the same time, we obtained colorless platelet crystals of 4-2 from 80% (v/v) MeOH/H O solution
and 6-2 from 50% (v/v) MeOH/DMF (dimethylformamide) at room temperature
(Figures 2-3) [38] for X-ray analysis.
Figure 2. ORTEP drawing of the X-ray crystal structure of compound 4-2. Displacement
ellipsoids were drawn at 50% probability level.
Figure 3. ORTEP drawing of the X-ray crystal structure of compound 6-2. Displacement
ellipsoids were drawn at 50% probability level.

Molecules 2008, 13
5685
Conclusions
We have developed a simple and efficient two-step synthetic route for the synthesis in moderate to
good yields of 3-substituted β-carbolinone derivatives from 3-substituted β-carbolines, and the
reagents used are not hazardous and are easy to handle. This method offered a facile way to introduce
various electron-withdrawing or electron-rich substituents into β-carbolinone derivatives at 3-position,
which should broaden the application scope of the β-carbolinone skeleton. This type of reaction has
been widely applied in our laboratory for the preparation of 3-substituted β-carbolinone derivatives. In
addition, a plausible reaction mechanism has been proposed.
Experimental
General
Unless otherwise specified, reagents were purchased from commercial suppliers and used without
further purification. Reaction progress was monitored using analytical thin layer chromatography
(TLC) on percolated Merck silica gel Kiesegel 60 F254 plates, and the spots were detected under UV
light (254 nm). Melting points were determined with a digital melting point apparatus and are reported
1
13
1
13
uncorrected. H-NMR and C-NMR spectra were recorded at 300 MHz ( H) or 75 MHz ( C) on a
Bruker ARX 300 spectrometer. IR spectra were measured on a Jasco FT/IR-430 spectrophotometer.
Mass spectra were recorded on an a Quattro microMS Micromass UK mass spectrometer, and was
recorded on an electrospray ionization mass spectrometer as the value m/z. The X-ray measurements
were made on a Rigaku RAXIS RAPID diffractometer with a graphite monochromatised Mo Kα
radiation (λ= 0.71069 Å) using ω scan mode.
General Procedure for the synthesis of N-oxidation
In a 100 mL single-necked, round-bottomed flask equipped with a magnetic stirrer, β-carboline
3
derivative (1 mmol), 3-chloroperoxybenzoic acid (670 mg, 3 mmol), CHCl (5 mL) and EtOH (5 mL)
were added. The reaction mixture was refluxed until there were no starting materials left (TLC
monitoring), then cooled to room temperature. NaOH (3 mL, 0.1 M) were added and stirring was
continued for 30 min. The aqueous phase was extracted with CHCl (2 × 25 mL), and the combined
3
2 4
organic phases were dried with Mg SO and concentrated in vacuo. The residues were purified by
flash column chromatography using an eluent MeOH-CHCl to give the title compound as a pale
3
yellow solid. Other compounds were synthesized similarly and the yields and spectroscopic data of 4-
1
, 5-1, 6-1, 7-1, 8-1, 9-1, 12-1, 13-1, 14-1 and 15-1 were as follows.
β-Carboline-N-oxide (4-1). Yield: 175 mg (95%), pale yellow solid. ESI-MS m/z 185.10 (M + 1).
3
-Ethoxycarbonyl-β-carboline-N-oxide (5-1). Yield: 238 mg (93%), pale yellow solid. ESI-MS m/z
257.45 (M + 1).
3
-Hydroxymethyl-β-carboline-N-oxide (6-1). Yield: 190 mg (89%), pale yellow solid. ESI-MS m/z
215.20 (M + 1).

Molecules 2008, 13
5686
3
-Formyl-β-carboline-N-oxide (7-1). Yield: 127 mg (60%), pale yellow solid. ESI-MS m/z 213.10
(M + 1).
3
-Cyano-β-carboline-N-oxide (8-1). Yield: 188 mg (90%), pale yellow solid. ESI-MS m/z 210.05
(M + 1).
β-Carboline-3-carbohydrazide-N-oxide (9-1). Yield: 198 mg (82%), pale yellow solid. ESI-MS m/z
243.12 (M + 1).
3
-Methoxyl-β-carboline-N-oxide (12-1). Yield: 160 mg (75%), pale yellow solid. ESI-MS m/z 215.05
(M + 1).
3-Ethoxy-β-carboline-N-oxide (13-1). Yield: 183 mg (80%), pale yellow solid. ESI-MS m/z 229.10
(M + 1).
3
-Bromo-β-carboline-N-oxide (14-1). Yield: 174 mg (66%), pale yellow solid. ESI-MS m/z 264.15
(M + 1).
3
-(N-Methylcarbamoyl)-β-carboline-N-oxide (15-1). Yield: 186 mg (87%), pale yellow solid. ESI-MS
m/z 242.20 (M + 1)
General Procedure for the synthesis of 9H-pyrido[3,4-b]indol-1(2H)-one derivatives
A β-carboline N-oxide derivative (1 mmol) were dissolved in acetic anhydride (10 mL), and the
mixture was heated under reflux for 6 hours until there were no starting materials left (TLC control).
After being cooled to ambient temperature, the reaction mixture was concentrated under reduced
pressure. The intermediate 2-acetoxy-β-carboline derivative was dissolved in EtOH/aqueous 2 M
NaOH (1:1), and stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the
residue was purified by column chromatography using MeOH/CHCl as an eluent to give the title
3
pyridoindolone.
9
H-Pyrido[3,4-b]indol-1(2H)-one (4-2): Prepared from 4-1, yield 120 mg (65%), white solid, m.p.
-1
1
2
53-255 °C. IR (KBr): 3261, 3112, 2966, 2840, 1645, 1446, 738 cm . ESI-MS m/z 185.05 (M + 1). H
): δ = 11.91 (1H, s, indole), 11.35 (1H, s, -NHCO-), 8.03 (1H, d, J = 8.0 Hz, ArH),
.50 (1H, d, J = 7.8 Hz, ArH), 7.39 (1H, t, J = 7.2 Hz, ArH), 7.17(1H, t, J = 8.0 Hz, ArH), 7.07 (1H, t,
-NMR (DMSO-d
6
7
1
3
J = 7.3 Hz, ArH), 6.96 (1H, d, J = 7.0 Hz, ArH). C-NMR (DMSO-d
24.6, 124.4, 122.1, 121.4, 119.6, 112.6, 99.8. Anal. Calcd for C11
Found: C, 71.70; H, 4.37; N, 15.23.
6
): δ = 155.8, 139.1, 128.2, 126.3,
1
8 2
H N O: C, 71.73; H, 4.38; N, 15.21.
3
-Ethoxycarbonyl-9H-pyrido[3,4-b]indol-1(2H)-one (5-2): Prepared from 5-1, yield 217 mg (85%),
-1
white solid. m.p. 257-259 °C. IR (KBr): 3380, 3128, 2985, 1701, 1652, 1298, 1249 cm . ESI-MS m/z
1
257.00 (M + 1). H -NMR (DMSO-d ): δ = 12.49 (1H, s, indole), 11.31 (1H, s, -NHCO-), 8.20 (1H, d,
6

Molecules 2008, 13
5687
J = 8.3 Hz, ArH), 7.92 (1H, s, ArH), 7.55 (1H, d, J = 7.2 Hz, ArH), 7.46 (1H, t, J = 7.6 Hz, ArH), 7.26
13
(
1H, t, J = 8.0 Hz, ArH), 4.30 (2H, q, J = 6.5 Hz,-OCH
DMSO-d ): δ = 161.6, 154.8, 139.5, 131.2, 126.8, 125.0, 122.7, 122.2, 121.7, 120.7, 112.9, 106.2,
1.5, 14.3. Anal. Calcd for C H N O : C, 65.62; H, 4.72; N, 10.93. Found: C, 65.60; H, 4.75;
2 3
), 1.30 (3H, t, J = 4.3 Hz, -CH ). C-NMR
(
6
6
1
4
12
2
3
N, 10.94
3
-Hydroxymethyl-9H-pyrido[3,4-b]indol-1(2H)-one (6-2): Prepared from 6-1, yield 160 mg (75%),
-1
white solid. m.p. 283-285 °C. IR (KBr): 3382, 3182, 3137, 2997, 1639, 1431, 1328, 744 cm ; ESI-MS
1
m/z 215.05 (M + 1). H-NMR (DMSO-d
6
): δ = 11.84 (1H, s, indole), 11.18 (1H, s, -NHCO-), 8.01
(1H, d, J = 7.9 Hz, ArH), 7.50 (1H, d, J = 7.2 Hz, ArH), 7.41 (1H, t, J = 8.0 Hz, ArH), 7.18 (1H, t,
J = 7.3 Hz, ArH), 6.92 (1H, s, ArH), 5.30 (H, t, J = 6.1 Hz, -OH), 4.40 (2H, t, J = 3.5 Hz, -CH O-).
2
1
3
C-NMR (DMSO-d
6
) : δ = 155.9, 139.4, 138.5, 126.9, 126.2, 124.4, 122.1, 121.3, 119.5, 112.6, 96.8,
6
0.3. Anal. Calcd for C H N O : C, 67.28; H, 4.71; N, 13.08. Found: C, 67.31; H, 4.65; N, 13.06.
1
2
10
2
2
3
-Formyl-9H-pyrido[3,4-b]indol-1(2H)-one (7-2): Prepared from 7-1, yield 110 mg (52%), white
-1
solid. m.p. 276-277 °C. IR (KBr): 3350, 3120, 2990, 1705, 1669, 1300 cm . ESI-MS m/z 213.10 (M +
1
1
). H-NMR (300MHz, DMSO-d
6
): δ = 11.73 (1H, s, indole), 11.23 (1H, s, -NHCO-), 9.50 (2H, t,
J = 7.8 Hz, -CHO), δ8.0 (1H, d, J = 8.0 Hz, ArH), 7.60 (1H, d, J = 7.2 Hz, ArH), 7.52 (1H, t,
1
3
J = 7.0 Hz, ArH), 7.12 (1H, t, J = 8.1 Hz, ArH), 6.95 (1H, s, ArH). C-NMR (300MHz, DMSO-d
δ = 165.1, 152.1, 142.9, 140.1, 125.6, 124.6, 121.5, 120.6, 119.9, 119.3, 115.7, 114.2. Anal. Calcd for
: C, 67.92; H, 3.80; N, 13.20. Found: C, 67.90; H, 3.83; N, 13.21.
6
):
12 8 2 2
C H N O
3
-Cyano-9H-pyrido[3,4-b]indol-1(2H)-one (8-2): Prepared from 8-1, yield 150 mg (72%), white solid.
-1
m.p. 259-261 °C. IR (KBr): 3290, 3106, 2987, 2230, 1650, 1228 cm . ESI-MS m/z 210.30 (M + 1).
1
H-NMR (DMSO-d
6
): δ = 12.05 (1H, s, indole), 11.31 (1H, s, -NHCO-), 8.11 (1H, d, J = 8.0 Hz, ArH),
7
.69 (1H, d, J = 7.8 Hz, ArH), 7.45 (1H, t, J = 7.6 Hz, ArH), 7.20 (1H, t, J = 8.2 Hz, ArH), 6.93 (1H, s,
1
3
ArH). C-NMR (DMSO-d
6
): δ = 155.3, 145.2, 138.1, 126.9, 125.8, 124.4, 122.9, 121.6, 119.6, 119.0,
1
2
15.7, 115.2. Anal. Calcd for C H N O: C, 68.89; H, 3.37; N, 20.09. Found: C, 68.90; H, 3.33; N,
1
2
7
3
0.11.
9
H-Pyrido[3,4-b]indol-1(2H)-one-3-carbohydrazide (9-2): Prepared from 9-1, yield 190 mg (67%),
-1
white solid. m.p. 303-305 °C. IR (KBr): 3386, 3251, 3053, 2979, 2935, 1718, 1629, 1245, 738 cm .
1
ESI-MS m/z 243.30 (M + 1). H-NMR (DMSO-d
6
): δ = 12.13 (1H, s, indole), 11.70 (1H, s, -NHCO-),
9
.01(1H, s, -NH), 8.05 (1H, d, J = 7.9 Hz, ArH), 7.45 (1H, d, J = 7.0 Hz, ArH), 7.39 (1H, t, J = 8.0 Hz,
1
3
ArH), 7.10 (1H, t, J = 7.9 Hz, ArH), 6.90 (1H, s, ArH), 4.50(2H, s, -NH ). C-NMR (DMSO-d ):
2
6
δ = 167.2, 153.2, 142.8, 139.5, 126.5, 122.4, 121.9, 121.3, 119.9, 119.6, 114.7, 111.4. Anal. Calcd for
: C, 59.50; H, 4.16; N, 23.13. Found: C, 59.48; H, 4.19; N, 23.12.
12 10 4 2
C H N O
3
-Methoxy-9H-pyrido[3,4-b]indol-1(2H)-one (12-2): Prepared from 12-1, yield 96 mg (45%), white
-1
solid. m.p. 180-181 °C. IR (KBr): 3360, 3120, 2860, 1665, 1290, 1050 cm . ESI-MS m/z 215.00 (M +
1
1
). H-NMR (DMSO-d
6
): δ = 11.62 (1H, s, indole), 11.50 (1H, s, -NHCO-), 7.98 (1H, d, J = 7.8 Hz,
ArH), 7.42 (1H, d, J = 8.1 Hz, ArH), 7.35 (1H, t, J = 7.2 Hz, ArH), 7.10 (1H, t, J = 8.1 Hz, ArH), 6.33

Molecules 2008, 13
1H, s, ArH), 3.80 (3H, s, -OCH
5688
1
3
(
3
). C-NMR (DMSO-d
6
): δ = 156.5, 152.0, 142.1, 139.5, 124.5, 122.4,
1
21.9, 120.6, 119.6, 114.7, 104.1, 60.5. Anal. Calcd for C12
10 2 2
H N O : C, 67.28; H, 4.71; N, 13.08.
Found: C, 67.30; H, 4.70; N, 13.07.
3
-Ethoxy-9H-pyrido[3,4-b]indol-1(2H)-one (13-2): Prepared from 13-1, yield 120 mg (53%), white
-1
solid. m.p. 183-184 °C. IR (KBr): 3365, 3250, 2900, 1640, 1300, 1100 cm . ESI-MS m/z 229.00 (M +
1
1
). H-NMR (DMSO-d ): δ = 11.71 (1H, s, indole), 11.43 (1H, s, -NHCO-), 8.05 (1H, d, J = 8.0 Hz,
6
ArH), 7.45 (1H, d, J = 7.3 Hz, ArH), 7.37 (1H, t, J = 7.9 Hz, ArH), 7.10 (1H, t, J = 8.0 Hz, ArH), 6.55
1
3
(
2 3 6
1H, s, ArH), 4.0 (2H, q, J = 4.6 Hz, -OCH ) , 1.3 (3H, t, J = 5.1 Hz, -CH ). C-NMR (DMSO-d ):
δ = 156.7, 152.2, 142.5, 139.3, 125.0, 122.3, 121.7, 120.8, 119.6, 115.3, 103.6, 69.0, 19.7. Anal. Calcd
for C H N O : C, 68.41; H, 5.30; N, 12.27. Found: C, 68.20; H, 5.55; N, 12.23.
1
3
12
2
2
3
-Bromo-9H-pyrido[3,4-b]indol-1(2H)-one (14-2): Prepared from 14-1, yield 80 mg (30%), pale
-1
yellow solid. m.p. 270-271 °C. IR (KBr): 3382, 3207, 2921, 1660, 1299 cm ; ESI-MS m/z 264.50 (M
1
+
1). H-NMR (DMSO-d ): δ = 12.13 (1H, s, indole), 11.45 (1H, s, -NHCO-), 8.00 (1H, d, J = 7.7 Hz,
6
ArH), 7.54 (1H, d, J = 8.0 Hz, ArH), 7.41 (1H, t, J = 8.7 Hz, ArH), 7.05 (1H, t, J = 7.2 Hz, ArH), 6.67
1
3
(
1H, s, ArH). C-NMR (DMSO-d
14.5, 109.3. Anal. Calcd for C11
N, 10.67.
6
): δ = 155.7, 141.9, 139.6, 126.3, 122.0, 121.8 120.4, 119.7, 116.7,
BrN O: C, 50.22; H, 2.68; N, 10.65. Found: C, 50.20; H, 2.69;
1
H
7
2
3
-(N-Methylcarbamoyl)-9H-pyrido[3,4-b]indol-1(2H)-one (15-2): Prepared from 15-1, yield 197 mg
-1
(
82%), white solid. m.p. 282-283 °C. IR (KBr) 3360, 3320, 3280, 2990, 1710, 1660, 1314 cm ; ESI-
1
MS m/z 242.20 (M + 1). H-NMR (DMSO-d
6
): δ = 11.70 (1H, s, indole), 11.25 (1H, s, -NHCO-), 8.88
(
1H, s, -CONHCH
J = 7.2 Hz, ArH), 7.20 (1H, t, J = 7.6 Hz, ArH), 6.85 (1H, s, ArH), 2.80 (3H, d, J = 4.3 Hz, -CH
NMR (DMSO-d ): δ = 162.7, 155.3, 141.9, 127.7, 123.2, 121.8, 121.5,121.1, 119.9, 118.8, 114.3,
12.7, 36.2. Anal. Calcd for C13 : C, 64.72; H, 4.60; N, 17.42. Found: C, C, 64.75; H, 4.58; N,
7.40.
3
), 8.05 (1H, d, J = 8.0 Hz, ArH), 7.55 (1H, d, J = 7.9 Hz, ArH), 7.45 (1H, t,
13
3
). C-
6
1
1
11 3 2
H N O
Acknowledgements
We are grateful to the National Natural Science Foundation of China (No. 30973609) and the
Fundamental Research Funds for the Central Universities（Program No. 2J10004) for financial
support.
References and Notes
1
2
3
4
5
. Abramovitch, R. A.; Spenser, I. D. The carbolines. Adv. Het. Chem. 1964, 3, 79-207.
. Stuart, K.; Woo-Ming, R. β-Carboline alkaloids. Heterocycles 1975, 3, 223-264.
. Smith, T. A. Tryptamine and related compounds in plants. Phytochemistry 1977, 16, 171-175.
. Allen, J. R. The simple β-carboline alkaloids. Phytochemistry 1980, 19, 1573-1582.
. Braestrup, C.; Nielsen, M.; Olsen, C. E. Urinary and brain β-carboline-3-carboxylates as potent
inhibitors of brain benzodiazepine receptors. Proc. Natl. Acad. Sci. USA 1980, 77, 2288-2292.

Molecules 2008, 13
5689
6
7
. Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J. Regioselective metalation of 9-methoxymethyl-β-
carboline-3-carboxamides with amidomagnesium chlorides. Synthesis 1995, 1225-1227.
. Molina, P.; Fresneda, P. M. Iminophosphorane-mediated annelation of a pyridine or pyrimidine
ring into an indole ring: Synthesis of β-, r-carbolines and pyrimido[4,5-b]indole derivatives. J.
Chem. Soc., Perkin Trans. 1988, 7, 1819-1822.
8
. Molina, P.; Fresneda, P. M.; Zafra, G. S.; Almendros, P. Iminophosphorane-mediated syntheses of
the fascaplysin alkaloid of marine origin and nitramarine. Tetrahedron Lett. 1994, 35, 8851-8854.
. Dodd, H. R.; Ovannes, C.; Robert, G.; Potier, P. Hybrid molecules: Growth inhibition of
leishmania donovani promastigotes by thiosemicarbazones of 3-carboxy-.beta.- carbolines. J.
Med. Chem. 1989, 32, 1272-1276.
9
1
0. Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.; Agarwal, S. K.; Bhaduri, A. P.; Singh, S. N.;
Fatima, N.; Chatterjee, R. K. Potent 1,3-disubstituted-9H-pyrido[3,4-b]indoles as new lead
compounds in antifilarial chemotherapy. J. Med. Chem. 1999, 42, 1667-1672.
1
1
1
1
1
1. Reinecke, M. G.; Newsom, J. G.; Almqvist, K. A., An Improved Synthesis of Thiophene-2,3-
dicarboxylic Acid by Sequential Carboxylation Synthesis 1980, 1980, 327-328.
2. Bracher, F.; Hildebrand, D., 1,9-Dimetalated β-carbolines. Versatile building blocks for the total
synthesis of Alkaloids. Tetrahedron 1994, 50, 12329-12336.
3. Franz, B.; Dirk, H.; Ludger, E., beta-Carboline Alkaloids .5. Total Synthesis of the Antimicrobial
Marine Alkaloid Eudistomin T. Archiv der Pharmazie 1994, 327, 121-122.
4. Choshi, T.; Matsuya, Y.; Okita, M.; Inada, K.; Sugino, E.; Hibino, S., The first total synthesis of
the novel [beta]-carboline alkaloid oxopropaline G.. Tetrahedron Lett. 1998, 39, 2341-2344.
5. Campos, J.; Núñez, M. d. C.; Rodríguez, V.; Gallo, M. A.; Espinosa, A., QSAR of 1,1'-(1,2-
ethylenebisbenzyl)bis(4-substitutedpyridinium) dibromides as choline kinase inhibitors: a different
approach for antiproliferative drug design. Bioorg. Med. Chem. Lett. 2000, 10, 767-770.
6. Kanekiyo, N.; Choshi, T.; Kuwada, T.; Sugino, E.; Hibino, S., The First Total Synthesis of (R )-(-)-
Pyridindolol K2 and Its Enantiomer. Heterocycles 2000, 53, 1877-1880.
1
1
7. Choshi, T.; Kuwada, T.; Fukui, M.; Matsuya, Y.; Sugino, E.; Hibino, S., Total syntheses of novel
cytocidal beta-carboline alkaloids, oxopropalines D and G. Chem Pharm Bull (Tokyo) 2000, 48,
108-113.
1
1
8. Kanekiyo, N.; Kuwada, T.; Choshi, T.; Nobuhiro, J.; Hibino, S., Total Syntheses of beta-Carboline
Alkaloids, (R)-(-)-Pyridindolol K1, (R)-(-)-Pyridindolol K2, and (R)-(-)-Pyridindolol. J. Org.
Chem. 2001, 66, 8793-8798.
9. Sherif, A. F. R.; Ahmed, M. F.; Farid, S. G. S.; Mona, M. E.-S.; Sigurd, E.; Jochen, L., Synthesis
and 5-HT2A Antagonist Activity of Derivatives of the Novel Heterocycles Indolo[3,2-
d]pyrrolo[3,2-g]azecine and Benzo[d]pyrrolo[3,2-g]azecine compared to the Benz[d]indolo[2,3-
g]azecine Derivative LE 300. Arch. Pharm. 2001, 334, 241-247.
2
0. Veale, C. A.; Damewood, J. R.; Steelman, G. B.; Bryant, C.; Gomes, B.; Williams, J., Non-
peptidic inhibitors of human leukocyte elastase .4. design, synthesis, and in vitro and in vivo
activity of a series of .beta.-carbolinone-containing trifluoromethyl ketones. J. Med. Chem. 1995,
3
8, 86-97.
2
1. Ritzeler, O., Dr; Castro, A., Dr; Grenler, L.; Soucy, F. Substituted beta-carbolines as lkB kinase
inhibitors. EP Pat.1134221 (A1), 2001.

Molecules 2008, 13
5690
2
2. Nielsch, U.; Sperzel, M.; Bethe, B.; Junge, B.; Lieb, F.; Velten, R. Treating tumor necrosis factor
mediated inflammatory disease, e.g. arteriosclerosis, using new or known beta-carboline
derivatives. DE Pat. 19807993 (A1), 1999.
2
2
2
3. Menta, E.; Pescalli, N.; Spinelli, S. 1H-pirido[3, 4-b]indol-1-one derivavives. WO Pat.
2
001/009129, 2001.
4. Lu, T.; Lin, G. W.; Chen, Y. D.; Wang, Y.; Zhang, L. Y.; Sun, N. Y.; Hao, L. H.; Zhu, Y.
Preparation of β-carbolines as cyclin-dependent kinase 2 inhibitors. CN Patent 101475571 A, 2009.
5. Bracher F., Hildebrand D. β-carboline-Alkaloide, Synthese von 1-Aryl- and 1-Alkenyl-β-
carbolinen durch Palladium-katalysierte Kupplungsreak tionen. Liebigs Ann. Chem. 1992,
1
315-1319.
2
6. Hu, Y. F.; Wang, S. Z.; Ge, Z. M.; Shi, H. J.; Lu, J. Preparation method and application of 3-aryl-
β-carboline-ones. CN. Patent 1611500A, 2003.
2
7. Eric, D. C.; Hernando, D. A.; Qi, H.; Mundla, S. R.; Chunrong, M.; Brad, H.; Ruth, M.; Phil, S.
Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-β-
carboline-3-carboxylic acid ethyl ester (6-PBC) and the full agonist 6-(benzyloxy)-4-
(
methoxymethyl)-β-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and
recombinant GABAA receptors. J. Med. Chem. 1998, 41, 2537-2552.
2
2
3
3
8. Sanjay, K. S.; Alka, A.; Prem, M. S. C.; Shiv, K. A.; Amiya, P. B.; Som, N. S.; Nigar, F.; Ranjit,
K. C. Potent 1,3-disubstituted-9H-pyrido[3,4-b]indoles as new lead compounds in antifilarial
chemotherapy. J. Med. Chem. 1999, 42, 1667-1672.
9. Michael, C.; Robert, W. W.; Fil G.; James, M. C.; Steven, A. B.; Kenner, C. R.; Jacqueline, N. C.;
Steven, M. P.; Phil, S. β-Carbolines: Synthesis and neurochemical and pharmacological actions on
brain benzodiazepine receptors. J. Med. Chem. 1982, 25, 1081-1091.
0. Klaus, P. L.; Walter, G. S.; Wolfgang, W.; Walter, E. M. β-Carbolines as benzodiazepine receptor
ligands. 1. Synthesis and benzodiazepine receptor interaction of esters of β-carboline-3-carboxylic
acid. J. Med. Chem. 1983, 26, 499-503.
1. Robert, H. D.; Catherine, O.; Lia, P. C.; Anne, V.; Patrice, V.; Georges, C.; Jean, R.; Pierre, P. 3-
Amino-β-carboline derivatives and the benzodiazepine receptor. Synthesis of a selective
antagonist of the sedative action of diazepam. J. Med. Chem. 1985, 28, 824-828.
3
2. Shunsaku, S.; Katsunori, T. Furopyridines. XIX[1]. Reaction of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]-
and -[3,2-c]pyridine with acetic anhydride. J. Heterocyclic Chem. 1996, 33, 647-654.
3. Seiji, Y.; Masahide, K.; Keiko, O.; Hajime, Y.; Yoshiro, H.; Shunsaku, S. Furopyridines.
XXVII[1]. Reaction of 2-methyl and 2-cyano derivatives of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -
3
[3,2-c]pyridine. J. Heterocyclic Chem. 1998, 33, 1237-1247.
3
3
3
4. Choshi, T.; Matsuya, Y.; Okita, M.; Inada, K.; Sugino, E.; Hibino, S., The first total synthesis of
the novel [beta]-carboline alkaloid oxopropaline G. Tetrahedron Lett. 1998, 39, 2341-2344.
5. Kanekiyo, N.; Choshi, T.; Kuwada, T.; Sugino, E.; Hibino, S., The First Total Synthesis of (R )-(-)-
Pyridindolol K2 and Its Enantiomer. Heterocycles 2000, 53, 1877-1880.
6. Kanekiyo, N.; Kuwada, T.; Choshi, T.; Nobuhiro, J.; Hibino, S., Total Syntheses of beta-Carboline
Alkaloids, (R)-(-)-Pyridindolol K1, (R)-(-)-Pyridindolol K2, and (R)-(-)-Pyridindolol. J. Org.
Chem. 2001, 66, 8793-8798.

Molecules 2008, 13
5691
3
3
7. Engler, T. A.; Wanner, J., Lewis Acid-Directed Cyclocondensation of Piperidone Enol Ethers with
-Methoxy-4-(N-phenylsulfonyl)-1,4-benzoquinoneimine: A New Regioselective Synthesis of
2
Oxygenated Carbolines. J. Org. Chem. 2000, 65, 2444-2457.
8. CCDC 749299 and 771291 contains the supplementary crystallographic data of compounds 4-2
and 6-2. These data can be obtained free of charge from the Cambridge Crystallographic Data
Centre Via www.ccdc.cam.ac.uk/data_request/cif/, accessed on 17 August 2010.
Sample Availability: Not available.
©
2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an Open Access article
distributed under the terms and conditions of the Creative Commons Attribution license
http://creativecommons.org/licenses/by/3.0/).
(