A new, simple, and high-yielding synthesis of 2,9-Dihydro-1 H- pyrido[3,4- b ]indol-1-ones

Article abstract of DOI:10.1055/s-0033-1339155

A new, simple, and high-yielding method was developed to prepare 2,9-dihydro-1H-pyrido[3,4-b]indol-1-ones by selective cyclization of the appropriate N-(2,2-dimethoxyethyl)-1H-indole-2-carboxamide in polyphosphoric acid at 110 °C for 30 minutes. The reaction yield was strongly dependent on the acid used. The method was less affected by the presence of electron-donating and -withdrawing substituents at 5-position of the indole nucleus. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339155

PAPER
▌2093
paper
A New, Simple, and High-Yielding Synthesis of 2,9-Dihydro-1H-pyrido[3,4-
b]indol-1-ones
2,9-Dihydro-1H-pyrido[3,4-b]indol-1-ones
Giuseppe La Regina,*a Valeria Famiglini,a Sara Passacantilli,a Sveva Pelliccia,b Pasqualina Punzi,c Romano Silvestria
a
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma,
Piazzale Aldo Moro 5, 00185 Rome, Italy
Fax +39(06)49913993; E-mail: giuseppe.laregina@uniroma1.it
b
Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
c
Dipartimento di Chimica, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Rome, Italy
Received: 29.11.2013; Accepted after revision: 10.05.2014
O
Abstract: A new, simple, and high-yielding method was developed
NH
O
NH
O
MeO
MeO
to prepare 2,9-dihydro-1H-pyrido[3,4-b]indol-1-ones by selective
cyclization of the appropriate N-(2,2-dimethoxyethyl)-1H-indole-
2-carboxamide in polyphosphoric acid at 110 °C for 30 minutes.
The reaction yield was strongly dependent on the acid used. The
method was less affected by the presence of electron-donating and
-withdrawing substituents at 5-position of the indole nucleus.
N
N
H
H
2
1
R
H
N
Key words: β-carbolinones, β-carboline, polyphosphoric acid, cy-
clization, heterocycles
NC
NH
O
MeO
MeO
NH
O
N
N
Natural and synthetic 2,9-dihydro-1H-pyrido[3,4-b]indol-
1-ones (β-carbolinones) were reported to exhibit impor-
tant biological effects. For example, natural oppositinine
A (1, Figure 1), extracted from the bark of Neisosperma
oppositifolia, showed potent vasorelaxant effects on the
rat aorta.1 In addition, synthetic β-carbolinone 2 displayed
a potent activity against colon and lung cancer cells,2
while compounds 3 and 4 were potent kinase inhibitors
(Figure 1).3,4 β-Carbolinones were useful to prepare some
alkaloids, such as shishijimicin A,5 manzamine A,6 pau-
ridianthine,7 pauridianthinine,7 and nitramarine,7 by
means of transformation into the corresponding 1-halo-β-
carbolines and β-carbolines endowed with interesting
biological activities.8–14
Cl
R
Me
Cl
3
4
Figure 1 β-Carbolinone derivatives of biological interest
with Dess–Martin reagent and subsequent heating in for-
mic acid10 or the reaction of indole-3-propionic acid with
diphenylphosphoryl azide and triethylamine and subse-
quent cyclization in the presence of boron trifluoride in a
one-pot procedure.17 Usually, the final aromatization to
the corresponding β-carbolinones was mediated by palla-
dium catalyst5,10,14,15 or 2,3-dichloro-5,6-dicyano-p-ben-
zoquinone.13,14
The synthesis of β-carbolinones involves the preparation
of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one as the
key intermediate. The latter is usually prepared by treating
tryptamine (or its derivative) with triphosgene followed
by hydrobromic acid-mediated ring closure.5,14,15 An im-
proved approach consisted of carbamoylation of trypt-
amine and subsequent treatment with boron trifluoride.14
According to the approach reported by Abramovitch and
Shapiro,16 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-
one derivative was obtained by treating ethyl 2-oxopiper-
idine-3-carboxylate with a base and then with the diazoni-
um salt of the appropriate aniline to provide the
corresponding 3-(2-phenylhydrazono)piperidin-2-one,
which was cyclized in the presence of formic acid.13 Other
methods included treatment of 3-hydroxy-2-piperidone
β-Carbolinones were also prepared by acetylation of 1-
methyl-4,9-dihydro-3H-pyrido[3,4-b]indole with acetic
anhydride/sodium acetate, permanganate oxidation of the
N-acetyl derivative and final hydrolysis with aqueous eth-
anolic potassium hydroxide or with boron trifluoride.18
An alternative synthesis of β-carbolinones was achieved
via intramolecular Diels–Alder reaction in tetrahydro-
naphthalene of 3-(2-ethynylamino)-2(1H)-pyrazinones,
obtained by treating 3,5-dichloro-2(1H)-pyrazinones with
2-iodoaniline in the presence of sodium hydride and sub-
sequent bis(triphenylphosphine)palladium dichloride/
cuprous iodide-assisted coupling with terminal alkynes.19
A two-step method, including 3-chloroperoxybenzoic
acid oxidation of β-carboline, treatment with acetic anhy-
dride at reflux temperature, and final sodium hydroxide
hydrolysis, was also developed.20 A further procedure in-
cluded the intramolecular Friedel–Crafts reaction of in-
dole-2-carboxylic acid β-oxoamides in the presence of
trifluoroacetic acid or indium(III) chloride.21
SYNTHESIS 2014, 46, 2093–2097
Advanced online publication: 02.06.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339155; Art ID: ss-2013-n0771-op
© Georg Thieme Verlag Stuttgart · New York

2094
G. La Regina et al.
PAPER
The above discussed synthetic routes to β-carbolinones
suffer from several disadvantages, such as high toxicity of
some reagents,5,14,15,17,21 complex reaction scheme includ-
R
R
OH
O
HN
O
AADMA
OMe
Et3N, BOP
anhyd DMF
25 °C, 2 h
N
N
OMe
H
H
ing more than
3
steps,13,19,20 prolonged reaction
12–18
times,10,13,14,17,19–21 and limited commercial availability of
starting materials.5,14,15,18–20
NH
R
PPA
The use of 2-aminoacetaldehyde acetals as C–C–N syn-
thons in heterocyclic synthesis is well known.22 In partic-
ular, Pomeranz–Fritsch reaction provides an efficient
method for the preparation of isoquinolines, by the acid-
catalyzed cyclization of benzalamino acetals prepared
from aromatic aldehydes and aminoacetal.
O
110 °C
30 min
N
H
5–11
R = H, Me, F, Cl, Br, OMe, NO2
Scheme 1 Synthesis of 2,9-dihydro-1H-pyrido[3,4-b]indol-1-ones
5–11
Here, we wish to report a new, simple, and high-yielding
method to prepare 2,9-dihydro-1H-pyrido[3,4-b]indol-1-
ones 5–11 by treating N-(2,2-dimethoxyethyl)-1H-indole-
2-carboxamides 12–18 with polyphosphoric acid (PPA) at
110 °C for 30 minutes (Scheme 1).
Reaction of compound 12 with hydrogen chloride in 1,4-
dioxane at 50 °C for 30 minutes furnished β-carbolinone
5 in low yield (17%, Table 1, entry 1). A similar result was
obtained when derivative 12 was treated with sulfuric acid
at 25 °C for 24 hours (20%, entry 2). In both cases, pyr-
azino[1,2-a]indol-1(2H)-one 19 was isolated as the main
reaction product (83% and 80%, respectively). This result
was in agreement with that reported by Johnson and co-
workers.22
As a model study, the cyclization of N-(2,2-dimethoxy-
ethyl)-1H-indole-2-carboxamide (12) was investigated
(Table 1). This reaction could furnish two distinct prod-
ucts, depending on if the ring closure proceeded from po-
sition 1 (route B) or position 3 (route A) of the indole
nucleus (Table 1). Carboxamide 12 was prepared by cou-
pling 1H-indole-2-carboxylic acid with aminoacetalde-
hyde dimethyl acetal (AADMA) in the presence of
triethylamine and (benzotriazol-1-yloxy)tris(dimethyl-
amino)phosphonium hexafluorophosphate (BOP) in an-
hydrous DMF at 25 °C for 2 hours (Scheme 1).
Trifluoroacetic acetic-mediated ring closure furnished
compound 5 in moderate yield (45%, entry 3). An im-
proved reaction yield (86%, entry 4) was obtained by re-
acting carboxamide 12 with boron trifluoride diethyl
Table 1 Optimization of Reaction Conditions for Compound 5
MeO
NH
O
NH
O
A
A
N
H
N
H
3
O
I
5
NH 1
HN
OMe
O
O
B
MeO
N
N
NH
NH
B
12
MeO
II
19
Yield (%)a
Entry
Reaction conditions
5
19
1
HCl saturated in 1,4-dioxane, 50 °C, 30 min
H2SO4 in Et2O (1:5 v/v), 25 °C, 24 h
CF3CO2H, CH2Cl2, 25 °C, 4 h
17
20
45
86
98
55
56
83
80
55
14
2
2
3
4
Et2O·BF3, benzene, 50 °C, 2 h
5
polyphosphoric acid, 110 °C, 30 min
AcOH, 80 °C, 12 h
6
45
44
7
NH4Cl, EtOH–H2O (1:1 v/v), 80 °C, 12 h
a Isolated yield.
Synthesis 2014, 46, 2093–2097
© Georg Thieme Verlag Stuttgart · New York

PAPER
2,9-Dihydro-1H-pyrido[3,4-b]indol-1-ones
2095
etherate in benzene at 50 °C for 2 hours. The best result Reaction of 5-Me (13), 5-F (14), 5-Cl (15), 5-Br (16), 5-
(98%, entry 5) was reached when the starting compound OMe (17), and 5-NO2 (18) substituted N-(2,2-dimethoxy-
12 was treated with polyphosphoric acid at 110 °C for 30 ethyl)-1H-indole-2-carboxamides with PPA at 110 °C for
minutes. No yield improvement for compound 5 was ob- 30 minutes furnished the corresponding 2,9-dihydro-1H-
tained by heating the reaction mixture at 80 °C for 12 pyrido-[3,4-b]indol-1-ones 6–11 in very high yields,
hours in the presence of acetic acid (55%, entry 6) or am- ranging from 88% to 98% (Table 2). The obtained yields
monium chloride (56%, entry 7).
highlight that the method was less affected by the pres-
ence of an electron-donating or -withdrawing group at 5-
postion of the indole nucleus.
It is important to note that, compared with already report-
ed methods involving the use of hydrogen chloride or sul-
furic acid,23–25 PPA ensured that the cyclization reaction In conclusion, we have synthesized 2,9-dihydro-1H-pyri-
of compound 12 gave derivative 5 in high yield, even do-[3,4-b]indol-1-ones 5–11 in high yields. Compared
when the nitrogen atom of aminoacetal was not alkylated. with previously reported approaches, the new method: (a)
A similar result was found by Herz and Tsai in a related is very simple, including the coupling of the appropriate
cyclization leading to thienopyridines.26
1H-indole-2-carboxylic acid with AADMA and subse-
quent cyclization in PPA; (b) is highly selective, leading
only to β-carbolinones, even when the nitrogen atom of
aminoacetal is not alkylated; (c) does not involve the use
of highly toxic reagents and/or drastic reaction conditions;
(d) requires very short reaction times; and (e) uses easily
accessible starting materials.
Although we were not able to deeply investigate the reac-
tion mechanism, it could be hypothesized that route A has
species I as the key intermediate, which after aromatiza-
tion of the piperidinone ring, furnishes compound 5 (Ta-
ble 1). In the case of route B, the reaction could produce
species II, which after aromatization of the piperazinone
nucleus, provides derivative 19 (Table 1). Our experi-
ments suggested that the reaction pathway is strongly de-
pendent on the pKa of the acid used. In fact, when a strong
acid (negative pKa values), such as HCl or H2SO4 was
used, the reaction furnished product 19. On the contrary,
a less strong acid (positive pKa values), such as PPA, or a
Lewis acid, such as BF3, promoted the formation of deriv-
ative 5.
All reagents and solvents were handled according to material safety
data sheet of the supplier and were used as purchased, without fur-
ther purification. Organic solutions were dried over anhydrous
Na2SO4. Evaporation of the solvents was carried out on Büchi Ro-
tavapor R-210 equipped with Büchi V-855 vacuum controller and
Büchi V-700 and V-710 vacuum pumps. Flash chromatography was
carried out on Interchim Spot II Flash, using Merck SuperVario-
Flash D26 cartridges packed with Merck Geduran 60 (0.040–0.063
mm) silica gel. Silica gel TLC cards from Macherey-Nagel (silica
gel precoated aluminum cards with fluorescent indicator visualiz-
able at 254 nm) were used for TLC. Developed plates were visual-
ized by a Spectroline ENF 260C/FE UV apparatus. Melting points
(mp) were determined on Stuart Scientific SMP1 apparatus and are
uncorrected. IR spectra were run on PerkinElmer SpectrumOne FT-
ATR spectrophotometer. Band position and absorption ranges are
given in cm–1. 1H (400.13 MHz) and 13C (100.6 MHz) NMR spectra
were recorded on Bruker Avance 400 spectrometer in the indicated
solvent and the corresponding fid files were processed by Mes-
treLab Research S.L. MestreReNova 6.2.1-769 software. Chemical
shifts are expressed in δ units (ppm) from TMS. Mass spectrometric
analysis was recorded on a Micromass Q-TOF MICRO and Orbi-
trap Exactive spectrometers equipped with an ESI source (positive
or negative ion mode); data were analyzed using the MassLynx
software developed by Waters. Elemental analyses of the com-
pounds were found within ± 0.4% of the theoretical values.
Encouraged by these promising results, the validity of the
new method was tested by treating N-(2,2-dimethoxyeth-
yl)-1H-indole-2-carboxamides 13–18, bearing both elec-
tron-donating (5-Me, 5-OMe) and -withdrawing groups
(5-F, 5-Cl, 5-Br, 5-NO2), with PPA at 110 °C for 30 min-
utes (Table 2). Starting compounds were prepared in high
yields (90–98%) similar to compound 12 (Scheme 1).
Table 2 Synthesis of 2,9-Dihydro-1H-pyrido[3,4-b]indol-1-ones 5–
11
R1
R1
NH
O
HN
O
PPA
OMe
110 °C
30 min
N
H
OMe
N
H
N-(2,2-Dimethoxyethyl)-1H-indole-2-carboxamides; General
Procedure 1 (GP1)
12–18
5–11
To a solution of the appropriate 1H-indole-2-carboxylic acid (1
mmol), aminoacetaldehyde dimethyl acetal (180.2 mg, 0.21 mL, 2
mmol), and Et3N (303.6 mg, 0.42 mL, 3 mmol) in anhydrous DMF
(2.5 mL) was added BOP (442.3 mg, 1 mmol). The reaction mixture
was stirred at 25 °C for 2 h, then diluted with H2O (10 mL), and ex-
tracted with EtOAc (3 × 10 mL). The combined organic layers were
washed with brine (3 × 10 mL), dried, and filtered. Removal of the
solvent gave a residue, which was purified by flash chromatography
(EtOAc–n-hexane as eluent) to furnish the title compound.
Entry
R1
Carboxamide β-Carbolinone
Yield (%)a
1
2
3
4
5
6
7
H
12
13
14
15
16
5
98%
95%
97%
98%
96%
88%
93%
Me
F
6
7
Cl
Br
8
9
N-(2,2-Dimethoxyethyl)-1H-indole-2-carboxamide (12)
Synthesized according to GP1, starting from 1H-indole-2-carboxyl-
ic acid and aminoacetaldehyde dimethyl acetal; yield: 243.3 mg
(98%); yellow solid; mp 110–115 °C (EtOH).
IR (ATR): 1632, 3239, 3306 cm–1.
1H NMR (CDCl3): δ = 3.39 (s, 6 H), 3.58 (t, J = 5.3 Hz, 2 H), 4.44
(t, J = 5.3 Hz, 1 H), 6.33 (br s, exchangeable with D2O, 1 H), 6.81–
OMe 17
NO2 18
10
11
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2093–2097

2096
G. La Regina et al.
PAPER
6.82 (m, 1 H), 7.06–7.10 (m, 1 H), 7.21–7.25 (m, 1 H), 7.36–7.38
IR (ATR): 1624, 2959, 3253 cm–1.
(m, 1 H), 7.58–7.60 (m, 1 H), 9.26 (br s, exchangeable with D2O, 1
H).
1H NMR (DMSO-d6): δ = 3.31 (s, 6 H), 3.38 (t, J = 5.6 Hz, 2 H),
3.76 (s, 3 H), 4.52 (t, J = 5.5 Hz, 1 H), 6.83 (dd, J = 2.4, 8.8 Hz, 1
H), 7.06–7.08 (m, 2 H), 7.31 (d, J = 8.9 Hz, 1 H), 8.50 (br s, ex-
changeable with D2O, 1 H), 11.43 (br s, exchangeable with D2O, 1
H).
Anal. Calcd for C13H16N2O3 (248.28): C, 62.89; H, 6.50; N, 11.28.
Found: C, 62.90; H, 6.52; N, 11.29.
N-(2,2-Dimethoxyethyl)-5-methyl-1H-indole-2-carboxamide
(13)
Synthesized according to GP1, starting from 5-methyl-1H-indole-
2-carboxylic acid and aminoacetaldehyde dimethyl acetal; yield:
254.4 mg (97%); white solid; mp 130–135 °C (EtOH).
Anal. Cald for C14H18N2O4 (278.30): C, 60.42; H, 6.52; N, 10.07.
Found: C, 60.44; H, 6.53; N, 10.08.
N-(2,2-Dimethoxyethyl)-5-nitro-1H-indole-2-carboxamide (18)
Synthesized according to GP1, starting from 5-nitro-1H-indole-2-
carboxylic acid and aminoacetaldehyde dimethyl acetal; yield:
263.9 mg (90%); yellow solid; mp 218–223 °C (EtOH).
IR (ATR): 1616, 2931, 3267 cm–1.
1H NMR (DMSO-d6): δ = 2.37 (s, 3 H), 3.31 (s, 6 H), 3.38 (t, J = 5.7
Hz, 2 H), 4.52 (t, J = 5.4 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 7.05 (s,
1 H), 7.31 (d, J = 8.3 Hz, 1 H), 7.38 (s, 1 H), 8.48 (br s, exchange-
able with D2O, 1 H), 11.43 (br s, exchangeable with D2O, 1 H).
IR (ATR): 1635, 2946, 3251 cm–1.
1H NMR (DMSO-d6): δ = 3.31 (s, 6 H), 3.41 (t, J = 5.7 Hz, 2 H),
4.53 (t, J = 5.5 Hz, 1 H), 7.44 (s, 1 H), 7.58 (d, J = 9.1 Hz, 1 H), 8.07
(dd, J = 2.2, 9.04 Hz, 1 H), 8.71 (d, J = 2.2 Hz, 1 H), 8.84 (br s, ex-
changeable with D2O, 1 H), 12.35 (br s, exchangeable with D2O, 1
H).
Anal. Calcd for C14H18N2O3 (262.30): C, 64.10; H, 6.92; N, 10.68.
Found: C, 64.11; H, 6.90; N, 10.67.
N-(2,2-Dimethoxyethyl)-5-fluoro-1H-indole-2-carboxamide
(14)
Synthesized according to GP1, starting from 5-fluoro-1H-indole-2-
carboxylic acid and aminoacetaldehyde dimethyl acetal; yield:
258.3 mg (97%); white solid; mp 107–112 °C (EtOH).
Anal. Calcd for C13H15N3O5 (293.28): C, 53.24; H, 5.16; N, 14.33.
Found: C, 53.22; H, 5.15; N, 14.34.
2,9-Dihydro-1H-pyrido[3,4-b]indol-1-ones; General Procedure
2 (GP2)
IR (ATR): 1560, 1630, 1941, 3257 cm–1.
A mixture of the appropriate N-(2,2-dimethoxyethyl)-1H-indole-2-
carboxamide 12–18 (1 mmol) and polyphosphoric acid (2 g) was
heated at 110 °C for 30 min. After cooling, the reaction mixture was
treated with sat. aq NaHCO3 until pH 7 and extracted with EtOAc
(3 × 10 mL). The combined organic layers were washed with brine
(3 × 10 mL), dried, and filtered. Removal of the solvent gave a res-
idue, which was purified by flash chromatography (CH2Cl2–EtOH
as eluent) to furnish the title compound.
1H NMR (DMSO-d6): δ = 3.30 (s, 6 H), 3.38 (t, J = 5.5 Hz, 2 H),
4.51 (t, J = 5.5 Hz, 1 H), 7.00–7.04 (m, 1 H), 7.13 (s, 1 H), 7.37–
7.42 (m, 2 H), 8.58 (br s, exchangeable with D2O, 1 H), 11.67 (br s,
exchangeable with D2O, 1 H).
Anal. Calcd for C13H15FN2O3 (266.27): C, 58.64; H, 5.68; F, 7.14;
N, 10.52. Found: C, 58.61; H, 5.66; F, 7.12; N, 10.51.
N-(2,2-Dimethoxyethyl)-5-chloro-1H-indole-2-carboxamide
(15)
Synthesized according to GP1, starting from 5-chloro-1H-indole-2-
carboxylic acid and aminoacetaldehyde dimethyl acetal; yield:
268.6 mg (95%); yellow solid; mp 168–170 °C (EtOH).
2,9-Dihydro-1H-pyrido[3,4-b]indol-1-one (5)
Synthesized according to GP2, starting from 12; yield: 180.5 mg
(98%); yellow solid; mp 251–252 °C (EtOH) (Lit.20 mp 253–
255 °C).
1H and 13C spectra were identical to those reported in literature.20
HRMS (ESI): m/z [2 M + Na]+ calcd for C22H17N4O2 + Na:
IR (ATR): 1625, 2940, 3201, 3357 cm–1.
1H NMR (DMSO-d6): δ = 3.31 (s, 6 H), 3.38 (t, J = 5.7 Hz, 2 H),
4.51 (t, J = 5.5 Hz, 1 H), 7.12 (s, 1 H), 7.16 (dd, J = 2.0, 8.7 Hz, 1
H), 7.42 (d, J = 8.7 Hz, 1 H), 7.66–7.68 (m, 1 H), 8.61 (br s, ex-
changeable with D2O, 1 H), 11.78 (br s, exchangeable with D2O, 1
H).
391.1097; found: 391.1017.
6-Methyl-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (6)
Synthesized according to GP2, starting from 13; yield: 188.3 mg
(95%); green solid; mp >280 °C (EtOH).
IR (ATR): 1644, 2918, 3185, 3410 cm–1.
Anal. Calcd for C13H15ClN2O3 (282.72): C, 52.23; H, 5.35; Cl,
12.54; N, 9.91. Found: C, 52.21; H, 5.33; Cl, 12.54; N, 9.92.
1H NMR (DMSO-d6): δ = 2.49 (s, 3 H), 6.92 (d, J = 6.4 Hz, 1 H),
7.02–7.04 (m, 1 H), 7.22 (d, J = 8.6 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1
H), 7.79 (s, 1 H), 11.32 (br s, exchangeable with D2O, 1 H), 11.78
(br s, exchangeable with D2O, 1 H).
13C NMR (DMSO-d6): δ = 21.48, 100.48, 112.69, 121.02, 122.53,
124.61, 124.71, 128.39, 128.59, 128.93, 137.87, 156.18.
N-(2,2-Dimethoxyethyl)-5-bromo-1H-indole-2-carboxamide
(16)
Synthesized according to GP1, starting from 5-bromo-1H-indole-2-
carboxylic acid and aminoacetaldehyde dimethyl acetal; yield:
314.1 mg (96%); white solid; mp 122–124 °C (EtOH).
IR (ATR): 1623, 2947, 3202, 3348 cm–1.
HRMS (ESI): m/z [2 M + Na]+ calcd for C24H20N4O2 + Na:
1H NMR (DMSO-d6): δ = 3.31 (s, 6 H), 3.39 (t, J = 5.8 Hz, 2 H),
4.52 (t, J = 5.5 Hz, 1 H), 7.14 (s, 1 H), 7.29 (dd, J = 2.0, 8.7 Hz, 1
H), 7.39 (d, J = 8.7 Hz, 1 H), 7.84–7.86 (m, 1 H), 8.64 (br s, ex-
changeable with D2O, 1 H), 11.80 (br s, exchangeable with D2O, 1
H).
419.1484; found: 419.1502.
Anal. Calcd for C12H10N2O (198.22): C, 72.71; H, 5.08; N, 14.13.
Found: C, 72.10; H, 5.10; N, 15.11.
6-Fluoro-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (7)
Synthesized according to GP2, starting from 14; yield: 196.1 mg
Anal. Calcd for C13H15BrN2O3 (327.17): C, 47.72; H, 4.62; Br,
24.42; N, 8.56. Found: C, 47.73; H, 4.60; Br, 24.43; N, 8.57.
(97%); green solid; mp >280 °C (EtOH) (Lit.14 mp 314–317 °C).
1H and 13C spectra were identical to those reported in literature.14
HRMS (ESI): m/z [M – H]– calcd for C11H6FN2O: 201.0464; found:
N-(2,2-Dimethoxyethyl)-5-methoxy-1H-indole-2-carboxamide
(17)
Synthesized according to GP1, starting from 5-methoxy-1H-indole-
2-carboxylic acid and aminoacetaldehyde dimethyl acetal; yield:
256.0 mg (92%); white solid; mp 143–148 °C (EtOH).
201.0465.
Synthesis 2014, 46, 2093–2097
© Georg Thieme Verlag Stuttgart · New York

PAPER
2,9-Dihydro-1H-pyrido[3,4-b]indol-1-ones
2097
6-Chloro-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (8)
Synthesized according to GP2, starting from 15; yield: 196.1 mg
(98%); light brown solid; mp >280 °C (EtOH) (Lit.14 mp 284–
285 °C).
1H and 13C spectra were identical to those reported in literature.11
HRMS (ESI): m/z [M + H]+ calcd for C11H8ClN2O: 219.0325;
References
(1) Ahmad, K.; Thomas, N. F.; Hadi, A. H. A.; Mukhtar, M. R.;
Mohamad, K.; Nafiah, M. A.; Takeya, K.; Morita, H.;
Litaudon, M.; Arai, H.; Awang, K. Chem. Pharm. Bull.
2010, 58, 1085.
(2) Menta, E.; Pescalli, N.; Spinelli, S. Patent PCT Int. Appl.
WO 2001009129 A2, 2001; Chem. Abstr. 2001, 134,
162922.
(3) Cincinelli, R.; Cassinelli, G.; Dallavalle, S.; Lanzi, C.;
Merlini, L.; Botta, B.; Tuccinardi, T.; Martinelli, A.; Penco,
S.; Zunino, F. J. Med. Chem. 2008, 51, 7777.
(4) Huber, K.; Brault, L.; Fedorov, O.; Gasser, C.;
Filippakopoulos, P.; Bullock, A. N.; Fabbro, D.; Trappe, J.;
Schwaller, J.; Knapp, S.; Bracher, F. J. Med. Chem. 2012,
55, 403.
found: 219.0312.
6-Bromo-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (9)
Synthesized according to GP2, starting from 16; yield: 252.6 mg
(96%); white solid; mp >280 °C (EtOH).
IR (ATR): 1664, 2944, 3360 cm–1.
1H NMR (DMSO-d6): δ = 7.02–7.03 (m, 1 H), 7.09–7.12 (m, 1 H),
7.46–7.53 (m, 2 H), 8.30–8.32 (m, 1 H), 11.45 (br s, exchangeable
with D2O, 1 H), 12.13 (br s, exchangeable with D2O, 1 H).
(5) Nicolaou, K. C.; Kiappes, J. L.; Tian, W.; Gondi, V. B.;
Becker, J. Org. Lett. 2011, 13, 3924.
(6) Hawkins, A.; Jakubec, P.; Ironmonger, A.; Dixon, D. J.
Tetrahedron Lett. 2013, 54, 365.
(7) Bracher, F.; Hildebrand, D. Tetrahedron 1994, 50, 12329.
(8) Barker, M. D.; Woodward, P. R.; Lewis, J. R. British Patent
Appl. GB 2155462 A, 1985; Chem. Abstr. 1986, 104,
207245.
13C NMR (DMSO-d6): δ = 100.15, 112.14, 114.94, 124.02, 124.25,
124.29, 125.39, 129.20, 129.31, 138.06, 156.04.
HRMS (ESI): m/z [M – H]– calcd for C11H6BrN2O: 260.9669;
found: 260.9670.
Anal. Calcd for C11H7BrN2O (263.09): C, 50.22; H, 2.68; Br, 30.37;
N, 10.65. Found: C, 50.23; H, 2.66; Br, 30.35; N, 10.67.
6-Methoxy-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (10)
Synthesized according to GP2, starting from 17; yield: 188.5 mg
(88%); grey solid; mp >280 °C (EtOH) (Lit.3 mp >250 °C).
1H and 13C spectra were identical to those reported in literature.5
HRMS (ESI): m/z [M + Na]+ calcd for C12H10N2O2 + Na: 237.0640;
found: 237.0648.
(9) Csanyi, D.; Hajos, G.; Riedl, Z.; Timari, G.; Bajor, Z.;
Cochard, F.; Sapi, J.; Laronze, J.-Y. Bioorg. Med. Chem.
Lett. 2000, 10, 1767.
(10) Ritzeler, O.; Castro, A.; Grenier, L.; Soucy, F. European
Patent Appl. EP 1134221 A1, 2001; Chem. Abstr. 2011, 135,
242149.
(11) Ritzeler, O.; Castro, A.; Grenier, L.; Soucy, F.; Hancock, W.
W.; Mazdiyasni, H.; Palombella, V.; Adams, J. European
Patent Appl. EP 1209158 A1, 2002; Chem. Abstr. 2002, 137,
6093.
6-Nitro-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (11)
Synthesized according to GP2, starting from 18; yield: 213.1 mg
(93%); yellow solid; mp >300 °C (EtOH).
(12) Meyers, M. J.; Trujillo, J. I.; Vernier, W. F.; Anderson, D.
R.; Reitz, D. B.; Buchler, I. P.; Hegde, S. G.; Mahoney, M.
W.; Wu, K. K. Patent PCT Int. Appl. WO 2005009370 A2,
2005; Chem. Abstr. 2005, 142, 198047.
(13) Goldberg, D.; Abeywardane, A.; Miller, C.; Morwick, T.;
Netherton, M.; Snow, R.; Wang, J.; Wu, J.-P.; Xiong, Z. US
Patent Appl. Publ. US 20060276496 A1, 2006; Chem. Abstr.
2006, 146, 45497.
IR (ATR): 1678, 2851, 2922, 3277 cm–1.
1H NMR (DMSO-d6): δ = 7.21–7.22 (m, 2 H), 7.64 (d, J = 9.1 Hz,
1 H), 8.26 (d, J = 8.6 Hz, 1 H), 9.12–9.15 (m, 1 H), 11.62 (br s, ex-
changeable with D2O, 1 H), 12.70 (br s, exchangeable with D2O, 1
H).
13C NMR (DMSO-d6): δ = 100.18, 113.40, 119.69, 121.71, 122.00,
126.46, 126.82, 130.74, 141.23, 142.30, 155.88.
(14) Thompson, M. J.; Louth, J. C.; Little, S. M.; Jackson, M. P.;
Boursereau, Y.; Chen, B.; Coldham, I. ChemMedChem
2012, 7, 578.
(15) Bracher, F.; Hildebrand, D. Liebigs Ann. Chem. 1992, 1315.
(16) Abramovitch, R. A.; Shapiro, D. J. Chem. Soc. 1956, 4589.
(17) Judd, K. E.; Mahon, M. F.; Caggiano, L. Synthesis 2009,
2809.
(18) Atta-ur-Rahman; Ghazala, M. Synthesis 1980, 372.
(19) Tahri, A.; Buysens, K. J.; Van der Eycken, E. V.;
Vandenberghe, D. M.; Hoornaert, G. J. Tetrahedron 1998,
54, 13211.
(20) Lin, G.; Wang, Y.; Zhou, Q.; Tang, W.; Wang, J.; Lu, T.
Molecules 2010, 15, 5680.
HRMS (ESI): m/z [M – H]– calcd for C11H6N3O3: 228.0409; found:
228.0403.
Anal. Calcd for C11H7N3O3 (229.19): C, 57.65; H, 3.08; N, 18.33.
Found: C, 57.63; H, 3.10; N, 18.32.
Acknowledgment
This research was supported by Bando Futuro in Ricerca 2010
(grant No. RBFR10ZJQT), PRIN 2010-2011 (grant No.
2010W7YRLZ), and Sapienza Università di Roma grant year 2012
(grant No. C26A12K7F2) and 2013 (grant No. C26H135FL5). The
authors thank Giancarlo Fabrizi for helpful suggestions, and Anto-
nella Goggiamani and Alessia Ciogli for 13C NMR and HRMS spec-
tra, respectively.
(21) Cincinelli, R.; Dallavalle, S.; Merlini, L. Synlett 2008, 1309.
(22) Bobbitt, J. M.; Bourque, A. J. Heterocycles 1987, 25, 601.
(23) Johnson, J. R.; Larsen, A. A.; Holley, A. D.; Gerzon, K.
J. Am. Chem. Soc. 1947, 69, 2364.
Supporting Information for this article is available online
(24) Menta, E.; Nicotra, F.; Pescalli, N.; Spinelli, S. Patent PCT
Int. Appl. WO 0109136 A1, 2001; Chem. Abstr. 2001, 134,
163063.
at http://www.thieme-connect.com/products/ejournals/journal/
1
10.1055/s-00000084. Included are copies of H NMR, 13C NMR
and HRMS spectra of compounds 5–11.SnoIufproi
m
tgioSratnungIifo
maoirt
r
p
t
(25) Lindwall, H. G.; Mantell, G. J. J. Org. Chem. 1953, 18, 345.
(26) Herz, W.; Tsai, L. J. Am. Chem. Soc. 1953, 75, 5122.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2093–2097