Synthesis of carbolines by photostimulated cyclization of anilinohalopyridines

Article abstract of DOI:10.1021/jo200923n

A general synthetic route to prepare all four carboline regioisomers by photostimulated cyclization of anilinohalopyridines is described. The methodology affords various substituted carbolines in good to excellent yields. In the case of α-carbolines, the S_RN1 methodology complements previously reported palladium-catalyzed cyclization approaches.

Full text of DOI:10.1021/jo200923n

NOTE
pubs.acs.org/joc
Synthesis of Carbolines by Photostimulated Cyclization of
Anilinohalopyridines
Joydev K. Laha,† Silvia M. Barolo,‡ Roberto A. Rossi,*,‡ and Gregory D. Cuny*,†
†Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women’s Hospital and
Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
‡INFIQC, Departamento de Química Orgꢀanica, Facultad de Ciencias Químicas, Universidad Nacional de Cꢀordoba,
Ciudad Universitaria, 5000 Cꢀordoba, Argentina
S Supporting Information
b
ABSTRACT: A general synthetic route to prepare all four carboline regioisomers
by photostimulated cyclization of anilinohalopyridines is described. The meth-
odology affords various substituted carbolines in good to excellent yields. In the
case of R-carbolines, the SRN1 methodology complements previously reported
palladium-catalyzed cyclization approaches.
arbolines (pyrido[x,y-b]indoles), 1 (Figure 1), are a promi-
nent class of nitrogen-containing heterocycles that comprise
four carboline regioisomers have been limited. Clark et al.
reported the photocyclization of anilinopyridines to give carbo-
lines, often as a mixture of regioisomers (eq 1).16 Quꢀeguiner et al.
employed a combination of palladium-catalyzed cross-couplings
of iodofluoropyridines with aminophenylboronic acids followed
by intramolecular nucleophilic substitutions.17 Sakamoto et al.
reported a two-step approach that consists of palladium-cata-
lyzed amination followed by intramolecular arylation of anilino-
bromopyridines, which allowed access to the four parent
carboline regioisomers in 31À61% yield.18
C
many natural products and bioactive compounds.1À5 Depending
upon the position of the nitrogen present in the fused pyridine
ring, four regioisomers of carbolines are known. From among
them, β-carbolines (pyrido[3,4-b]indoles) are most widely dis-
tributed in nature. Compounds containing β-carbolines have
been found to exhibit a wide range of biological activities, such as
central nervous system (CNS) and antitumor properties (e.g.,
IKB kinase and PDE5 inhibition).1 γ-Carbolines (pyrido[4,3-b]-
indoles) can also be found in various natural products and in a
number of antitumor agents.2 The natural abundance of R- and
δ-carbolines (pyrido[2,3-b]indoles and pyrido[3,2-b]indoles,
respectively) has so far been more limited, however, to only a
few sources. For example, the R-carboline natural product
mescengricin has been isolated from Streptomyces griseoflavus
and reported to inhibit L-glutamate excitotoxicity in neurons.3
Figure 1. General structure of carbolines.
Recently, we described a one-pot synthesis of R-carbolines via
palladium-catalyzed sequential aryl amination of anilines and 2,3-
dihalopyridines followed by intramolecular arylation of the
2-anilino-3-halopyridine intermediates.6b Although a variety of
R-carbolines were obtained in moderate to excellent yields
using this methodology, some limitations were encountered.
Several synthetic R-carbolines have also been shown to have
an array of biological properties, such as anxiolytic, anti-
inflammatory, and CNS-stimulating activities.4 δ-Carbolines
have been studied extensively for antitumor and antibiotic
properties.5
Although various synthetic strategies to one1,2,6À9 or more
carboline regioisomers10À15 have been previously reported,
general approaches that allowed access to the synthesis of all
Received: May 13, 2011
Published: July 08, 2011
r
2011 American Chemical Society
6421
dx.doi.org/10.1021/jo200923n J. Org. Chem. 2011, 76, 6421–6425
|

The Journal of Organic Chemistry
NOTE
Table 1. Synthesis of Substituted r-Carbolines by
For example, poor yields of R-carbolines were observed with 4-,
5-, or 6-substituted 2,3-dihalopyridines. Similar results were obtained
with anilines containing electron-donating substituents in the 2,5- or
3,5-positions. In many instances, these one-pot reactions did produce
the 2-anilino-3-halopyridine intermediates in good yields but failed to
cyclize to R-carbolines. On the basis of these limitations, an alternate
method was sought for the synthesis of R-carbolines that would also
be applicable to β-, γ-, and δ-carbolines.
Photostimulated SRN1 Reactiona
The unimolecular radical nucleophilic substitution (SRN1)
reaction is a synthetically useful process to mediate aromatic
nucleophilic substitutions for the preparation of carbocycles and
heterocycles.19,20 For example, Rossi et al. has recently demon-
strated the application of SRN1 reactions in the synthesis of
substituted carbazoles in excellent yields (81À99%).21 Herein is
described a general method for the synthesis of all four carboline
regioisomers from anilinohalopyridines using photostimulated
SRN1 reactions.
entry substrate
X
R1
R2
product yieldb (%)
1
2c
3
4
5
6
7
2b
2c
2d
2e
2f
Cl
Br
Br
Cl
H
H
H
H
H
3a
3b
3c
3d
3e
3f
75
63
90
84
79
51
37
19
54
21
90
67
2-OEt
3-Me
4-Me
H
Br 6-CO2Bu-t
Cl 6-CN
Cl 7-OBn
5-OBn
2g
2h
H
H
3g
3h
3i
H
8
2i
Cl 5-OMe
7-OMe
4-Me
4-Me
H
3j
9
2j
Cl 5,7-di-OMe
3k
3l
10
2k
Cl 5,8-di-Me
H
The application of SRN1 reactions to the synthesis of
R-carbolines was initially studied with 3-bromo-N-phenylpyridin-
a Condition A: liquid NH3, hν, 60 min. b Isolated yield. c 120 min.
Table 2. Synthesis of β-, γ-, and δ-Carbolines by Photostimulated SRN1 Reactiona
c
e
a Condition A: liquid NH3, hν, 60 min. Condition B: DMSO, hν, 60 min. b Position of nitrogen. Isolated yields. d 180 min. Determined by gas
chromatography. 4c:4d ≈ 1:1.
f
6422
dx.doi.org/10.1021/jo200923n |J. Org. Chem. 2011, 76, 6421–6425

The Journal of Organic Chemistry
NOTE
2-amine, 2a (λmax 269 nm in DMSO).18 Photostimulation for
60 min in the presence of KOBu-t (2 equiv) in liquid ammonia
under a nitrogen atmosphere (condition A) afforded 88% yield of
R-carboline, 3a17 (eq 2). A modestly lower yield of 3a (67%) was
obtained when DMSO was used as solvent (condition B). In
THF, however, no reaction was observed. As anticipated, no
reaction was detected in the absence of light or in the presence of
the radical initiator FeCl2, and the photostimulated reaction was
partially inhibited by 1,4-dinitrobenzene.19
yield (entry 5). A similar result (76% yield) was obtained using
condition B (entry 6).
In summary, a general high yielding method for the synthesis of
all four carboline regioisomers by photostimulated SRN1 cyclization
of anilinohalopyridines has been developed. This process also
provides a complementary approach to metal-catalyzed methods
for the synthesis of R-carbolines. In some cases, the SRN1 reaction
was successful when palladium-mediated methods were not.
Further exploration of photostimulated SRN1 reactions should
prove useful for extending this methodology to the synthesis of
other heterocyclic systems.
In order to prepare various substituted carbolines, the 2-ani-
lino-3-halopyridines 2cÀk were generated from anilines and 2,3-
dihalopyridines using a palladium-catalyzed coupling reaction
previously described.6b Similarly, the substrates 2l and 2m were
synthesized in 42À45% yield from the corresponding anilines and
3,4-dichloropyridine using a higher catalyst loading. All anilines
and dihalopyridines were commercially available, except 4-meth-
yl-2,3-dichloropyridine22 that was synthesized from 2,3-dichlor-
opyridine using regioselective lithiation chemistry.
’ EXPERIMENTAL SECTION
General Methods. Unless otherwise noted, all reagents and
solvents were purchased from commercial sources and used without
purification. All palladium-coupling reactions were degassed with argon.
The proton and carbon NMR spectra were obtained in CDCl3 or
DMSO-d6 using a 400 or 500 MHz spectrometer and are reported in δ
units ppm. Coupling constants (J values) are reported in Hz. Column
chromatography was performed on silica gel (grade 60, 230À400 mesh)
or utilizing a CombiFlash Sg 100c separation system with disposable
silica gel columns. Mass spectra (MS) were recorded with an ESI source.
High-resolution mass spectra were obtained by using a Tesla FTMS. All
melting points were taken in glass capillary tubes and are uncorrected.
Gas chromatographic (GC) analyses were performed on an instrument
with a flame ionization detector equipped with a VF-5 ms column (15 m Â
0.25 mm  0.25 μm). Quantification by GC was performed by the
internal standard method. GC-MS analyses were carried out on a
spectrometer equipped with a quadrupole detector and a VF-5 ms
column (30 m  0.25 mm  0.25 μm). The photochemical reactor
consists of an oval mirror-type wall of ca. 30 cm maximum radius
equipped with two Philips HPI-T 400 W lamps of metallic iodide
inserted into a water-refrigerated Pyrex flask placed ca. 20 cm from the
reaction vessel. The spectrum of the light source showed five broad
emission maxima at about 380, 410, 440, 530, and 570 nm. Potentio-
metric titrations of halide ions were performed in a pH meter with an
Ag/Ag+ electrode.
Next, the scope of the SRN1 reaction for the synthesis of
various substituted R-carbolines using condition A was explored.
For example, with 3-chloro-N-phenylpyridin-2-amine, 2b,6b
R-carboline, 3a, was obtained in 75% yield (Table 1, entry 1),
demonstrating that the reaction was useful for both chlorine- and
bromine-containing substrates. Next, the method was applied to
the synthesis of R-carbolines containing a substituent on either
the pyridine or benzene rings. When the photostimulated reac-
tions were carried out with substrates 2c,6b 2d,23 or 2e having a
substitution at the 2-, 3-, or 4-positions on the pyridine ring, the
corresponding R-carbolines 3b,6b 3c,24 and 3d25 were obtained
in 63À90% yields (entries 2À4). Similarly, substrates 2f,6b 2g, or
2h having monosubstitution on the benzene ring also afforded
the R-carbolines 3e,6b 3f,25 and a separable mixture of 3g6b
and 3h6b in moderate yields (entries 5À7). In the case of 2h, the
two regioisomers 3g and 3h were generated in a ∼2:1 ratio as
1
determined by H NMR. Good yields of R-carbolines were
also obtained for a variety of disubstituted anilinohalopyridines
(entries 8À10). Substrate 2i afforded two regioisomeric R-carbo-
lines 3i and 3j in 54% and 21% isolated yields (entry 8). The
photostimulation of 5,7-dimethoxy- 2j6b or 5,8-dimethylanilino-
chloropyridines 2k6b produced R-carbolines 3k and 3l6b in 90%
and 67% yields, respectively (entries 9 and 10). In several
instances, the SRN1 methodology proved more efficient than
the previously reported palladium-catalyzed one-pot process.
For example, the R-carbolines 3b, 3e, and 3l were obtained in
only poor yields (19%, 37%, and 25%, respectively) using the
palladium-mediated process, while 3d and 3k could not be
generated.6b
All anilines and dihalopyridines except 4-methyl-2,3-dichloropyridine
were purchased from commercial vendors.
Synthesis of 4-Methyl 2,3-dichloropyridine (for the pre-
paration of 2e).22 A solution of 2,3-dichloropyridine (740 mg, 5.00
mmol) in anhydrous THF (10 mL) was treated dropwise with LDA
(3 mL, 6.00 mmol, 2 M in THF) at À78 °C for 10 min. After the mixture
was stirred for 1 h at À78 °C, CH3I (850 mg, 6.00 mmol) was added
dropwise, and the reaction mixture was allowed to warm to À20 °C over
1 h. At this temperature, the reaction was quenched by adding aqueous
NH4Cl. Excess ethyl acetate was added to the reaction mixture, the
organic layer was then washed with brine, dried over anhydrous Na2SO4,
filtered, and then concentrated. Chromatography [silica, hexane/ethyl
acetate (9:1)] of the crude mixture afforded a viscous liquid (665 mg,
82% yield): 1H NMR (500 MHz, CDCl3) δ 2.40 (s, 3H), 7.08 (d, J = 8.0
Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8,
124.9, 130.7, 146.3, 148.6, 149.6.
General Procedure for Aryl Amination. A mixture of 2,3-
dihalopyridine (1 mmol), aniline (1.1 mmol), Pd(OAc)2 (5À10 mol %),
PPh3 (10À20 mol %), and NaOBu-t (1.2 mmol) in 2.5 mL toluene (or
o-xylene) was degassed with argon for about 5 min and then heated at
120 °C (140 °C in the case of o-xylene) for 3À18 h in a screw-capped
sample vial. The reaction mixture was concentrated under reduced
pressure. The residue was dissolved in ethyl acetate (10 mL), and the
solution was washed several times with water and then brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was purified
The photostimulated SRN1 methodology was further ex-
tended to the synthesis of β-, γ-, and δ-carbolines. The photo-
stimulation of 4-bromo-N-phenylpyridin-3-amine, 2n,18 gave ss-
carboline 4a17 in 70% and 54% yields under conditions A and B,
respectively (Table 2, entry 1). A significant amount (12%) of
unreacted 2n was recovered when condition B was used. How-
ever, longer photostimulation time (180 min) in DMSO im-
proved the yield of 4a to 70% (entry 2). γ-Carboline 4b17 was
obtained from 3-chloro-N-phenylpyridin-4-amine, 2l, in 72%
yield using condition A (entry 3). Substrate 2m similarly under-
went photostimulated cyclization resulting in an inseparable
mixture of regioisomers 4c and 4d produced in nearly equal
amounts (entry 4). Finally, 2-bromo-N-phenylpyridin-3-amine,
2o,18 under condition A gave δ-carboline 4e17 in 80% isolated
6423
dx.doi.org/10.1021/jo200923n |J. Org. Chem. 2011, 76, 6421–6425

The Journal of Organic Chemistry
NOTE
by column chromatography on silica gel using hexane/ethyl acetate as
eluent (9:1 to 7:3) to give the anilinohalopyridines.
and deoxygenated, KOBu-t (45 mg, 0.40 mmol) was added, 2n (50 mg,
0.20 mmol) was added, and the reaction mixture was irradiated for
180 min. The reaction was quenched with water and excess solid ammonium
nitrate. The residue was extracted with dichloromethane (3 Â 30 mL),
and the organic extracted was washed with water, dried over anhydrous
MgSO4, filtered, and concentrated to give the crude products. The
bromide ions in theaqueoussolution were determinedpotentiometrically.
3-Methyl-9H-pyrido[2,3-b]indole (3c).24 Compound 3c was
purified by column chromatography on silica gel eluting with dichlor-
omethane: ethanol (98:2) and then recrystallized from dichloromethane
to give white needles: mp 276À277 °C; 1H NMR (400.16 MHz,
DMSO-d6) δ 2.44 (s, 3H), 7.18 (ddd, J = 8.0, 7.0 Hz, 1.2, 1H),
7.40À7.48 (m, 2H), 8.10 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 8.29 (s,
1H), 11.61 (s, 1H); 13C NMR (100.62 MHz, DMSO-d6) δ 18.00,
111.12, 114.90, 119.08, 120.13, 121.00, 123.46, 126.36, 128.40, 139.23,
3-Chloro-4-methyl-N-phenylpyridin-2-amine (2e): 66% yield;
colorless viscous liquid;1H NMR (500 MHz, CDCl3) δ2.37 (s, 3H), 6.64 (d,
J = 4.5 Hz, 1H), 7.02À7.06 (m, 2H), 7.32À7.36 (m, 2H), 7.62 (d, J = 7.5
Hz, 2H), 7.99 (d, J = 5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.2,
115.3, 116.2, 117.4, 120.1, 122.7, 129.0, 140.1, 144.8, 145.5, 145.9, 151.4;
HRMS obsd 219.0683, calcd 219.0681 for C12H12N2Cl (M + H).
3-Chloro-N-(4-cyano)-phenylpyridin-2-amine (2g): 67%
yield; white solid; mp 162À164 °C; 1H NMR (400 MHz, CDCl3) δ
6.85 (dd, J = 7.5, 5.0 Hz, 1H), 7.23 (br, 1H), 7.60À7.63 (m, 2H),
7.65 (dd, J = 7.5, 2.0 Hz, 1H), 7.80À7.84 (m, 2H), 8.20 (dd, J = 5.0,
1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 104.8, 117.0, 117.1,
118.8, 119.6, 133.3, 137.3, 144.0, 145.8, 150.2; HRMS obsd
230.0479, calcd 230.0477 for C12H9N3Cl (M + H).
3-Chloro-N-(3-benzyloxy)phenylpyridin-2-amine (2h): 69%
yield; white solid; mp 60À62 °C; 1H NMR (400 MHz, CDCl3) δ 5.12
(s, 2H), 6.69À6.75 (m, 2H), 7.01 (br, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.24
(d, J = 8.0 Hz, 1H), 7.33À7.37 (m, 1H), 7.39À7.43 (m, 2H), 7.49 (d, J =
8.0 Hz, 1H), 7.54À7.60 (m, 3H), 8.15 (d, J = 4.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 70.2, 106.8, 109.2, 112.6, 115.4, 116.3, 127.7,
128.1, 128.7, 129.7, 136.8, 137.3, 141.1, 146.0, 151.3, 159.6; HRMS obsd
311.0962, calcd 311.0946 for C18H16ClN2O (M + H).
3-Chloro-4-methyl-N-(3-methoxy)phenylpyridin-2-amine
(2i): 65% yield; colorless viscous liquid; 1H NMR (500 MHz, CDCl3) δ
2.37 (s, 3H), 3.82 (s, 3H), 6.60 (dd, J = 7.5, 2.0 Hz, 1H), 6.65 (d, J = 4.5
Hz, 1H), 7.04 (br, 1H), 7.11 (dd, J = 7.5, 2.0 Hz, 1H), 7.23 (t, J = 8.5 Hz,
1H), 7.40 (dd, J = 2.5, 2.0 Hz, 1H), 8.00 (d, J = 5.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.2, 55.4, 105.9, 108.1, 112.4, 116.3, 117.4, 129.7,
141.4, 144.8, 145.5, 151.4, 160.4; HRMS obsd 249.0789, calcd 249.0786
for C13H14ClN2O (M + H).
3-Chloro-N-phenylpyridin-4-amine (2l): 42% yield; white
solid; mp 90À92 °C; 1H NMR (500 MHz, DMSO-d6) δ 6.91 (d, J =
6.0 Hz, 1H), 7.15À7.18 (m, 1H), 7.29 (d, J = 7.5 Hz, 2H), 7.38À7.42 m,
2H), 8.08 (d, J = 5.5 Hz, 1H), 8.33 (s. 1H), 8.35 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 107.5, 117.7, 123.4, 125.6, 129.9, 138.6, 147.1,
148.6, 149.2; HRMS obsd 205.0527, calcd 205.0527 for C11H10ClN2
(M + H).
3-Chloro-N-(3-methoxy)phenylpyridin-4-amine (2m): 45%
yield; white solid; mp 105À107 °C; 1H NMR (500 MHz, CDCl3) δ 3.82
(s, 3H), 6.46 (br, 1H), 6.74À6.78 (m, 2H), 6.83 (dd, J = 8.0, 2.0 Hz,
1H), 7.00 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 8.15 (dd, J = 5.5,
1.5 Hz, 1H), 8.38 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.5, 107.9,
109.1, 110.8, 115.4, 117.8, 130.6, 139.8, 147.0, 148.5, 149.2, 160.9;
HRMS obsd 235.0632, calcd 235.0628 for C12H12ClN2O (M + H).
General Procedure for the Synthesis of Carbolines in
Liquid Ammonia Exemplified in the Synthesis of 9H-Pyrido-
[2,3-b]indole (3a). Liquid ammonia (150 mL), previously dried over
Na metal, was distilled into a 250 mL three-necked, round-bottomed
flask equipped with a coldfinger condenser and a magnetic stirrer under
a nitrogen atmosphere. KOBu-t (45 mg, 0.40 mmol) and 2a (50 mg,
0.20 mmol) were added to the liquid ammonia and the solution was
irradiated for 60 min. The reaction was quenched by addition of excess
solid NH4NO3, and the ammonia was allowed to evaporate. Water
(50 mL) was added to the residue, and the mixture was extracted with
dichloromethane (3 Â 30 mL). The organic extract was washed with
water (2 Â 20 mL), dried over anhydrous MgSO4, and then filtered. The
solvent was removed under reduced pressure to obtain the crude
product. The bromide ions in the aqueous solution were determined
potentiometrically.
13
146.47, 150.48; 1HÀ C HSQC NMR (DMSO-d6) δH/δC 2.44/18.00,
7.18/119.08, 7.40À7.48/111.12, 7.40À7.48/126.36, 8.10/121.00, 8.26/
146.47, 8.29/128.40; GC/MS EI m/z 182 (M+, 100).
4-Methyl-9H-pyrido[2,3-b]indole (3d).25 Compound 3d was
purified by recrystallization from dichloromethane to give white crystals:
mp 211À212 °C; 1H NMR (400.16 MHz, DMSO-d6) δ 2.80 (s, 3H),
7.00 (d, J = 4.8 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H); 7.45 (t, J = 8.0 Hz, 1H),
7.52 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 4.8 Hz, 1H),
11.78 (s, 1H); 13C NMR (100.62 MHz, DMSO-d6) δ 19.53, 111.06,
113.96, 116.74, 119.40, 120.82, 122.72, 125.93, 138.58, 141.62, 145.80,
1
13
151.82; HÀ C HSQC NMR (DMSO-d6) δC/δH 2.80/19.53, 7.00/
116.74, 7.23/119.40, 7.45/125.93, 7.52/111.06, 8.11/122.72, 8.28/
145.80; GC/MS EI m/z 182 (M+, 100).
5-Methoxy-4-methyl-9H-pyrido[2,3-b]indole (3i). Compound
3i was purified by column chromatography on silica gel eluting with
petroleum ether/ ethyl acetate gradient (75:25 f 30:70) to give white
crystals: mp 252À253 °C; 1H NMR (400.16 MHz, DMSO-d6) δ 2.90 (s,
3H), 3.95 (s, 3H), 6.73 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 4.8 Hz, 1H), 7.08
(d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 8.20 (d, J = 4.8 Hz, 1H), 11.80
(br, 1H); 13C NMR (100.62 MHz, DMSO-d6) δ 22.57, 55.14, 100.89,
104.15, 109.97, 113.83, 117.79, 127.35, 140.15, 141.61, 145.05, 151.43,
1
13
154.68; HÀ C HSQC NMR (DMSO-d6) δH/δC 2.90/22.57, 3.95/
55.14, 6.73/100.89, 6.96/117.79, 7.08/104.15, 7.36/127.35, 8.20/145.05.
1
1HÀ H COSY NMR (DMSO-d6) δH/δH 2.90/2.90, 3.95/3.95, 7.36/
6.73, 7.36/7.08, 8.20/6.96, 11.80/11.80; GC/MS EI m/z 212 (M+, 100);
HRMS(ESI) m/zobsd 213.1025, calcd 213.1022 for C13H13N2O(M+H+).
7-Methoxy-4-methyl-9H-pyrido[2,3-b]indole (3j). Compound
3j was purified by column chromatography on silica gel eluting with
petroleum ether: ethyl acetate gradient (75:25 f 30:70) to give light
yellow crystals: mp 212À213 °C; 1H NMR (400.16 MHz, DMSO-d6) δ
2.75 (s, 3H), 3.85 (s, 3H), 6.84 (dd, J = 8.4, 2.0 Hz, 1H), 6.96À6.98 (m,
2H), 7.97 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 4.8 Hz, 1H), 11.64 (s, 1H); 13C
NMR (100.62 MHz, DMSO-d6) δ 19.36, 55.24, 94.63, 108.42, 114,28,
13
114.46, 116.75, 123.52, 140.04, 140.10, 144.25, 151.96, 158.52; 1HÀ C
HSQC NMR (DMSO-d6) δH/δC 2.75/19.36, 3.85/55.24, 7.97/123.52,
6.84/108.42, 6.96À6.98/94.63, 6.96À6.98/116.75, 7.97/123.52, 8.18/
1
144.25; 1HÀ H COSY NMR (DMSO-d6) δH/δH 2.75/2.75, 3.85/3.85,
6.84/6.96À6.98, 6.84/7.97, 6.96À6.98/8.17, 11.64/11.64; GC/MS EI
m/z 212 (M+, 100). HRMS (ESI) m/z obsd 213.1040, calcd 213.1022
for C13H13N2O (M + H+).
5,7-Dimethoxy-9H-pyrido[2,3-b]indole (3k). Compound 3k
was purified by chromatography on silica gel eluting with dichloro-
methane: ethanol (98:2) and then recrystallized from dichloromethane
1
to give colorless crystals: mp 247À249 °C; H NMR (400.16 MHz,
DMSO-d6) δ 3.85 (s, 3H), 3.98 (s, 3H), 6.38 (s, 1H), 6.60 (s, 1H),
7.12 (dd, J = 7.6, 4.8 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 4.8 Hz,
1H), 11.69 (s, 1H); 13C NMR (100.62 MHz, DMSO-d6) δ 55.44, 55.50,
87.32, 91.29, 103.40, 114.80, 115.12, 128.05, 140.86, 143.34, 151.31,
General Procedureforthe Synthesis ofCarbolines inDMSO
Exemplified in the Synthesis of 9H-Pyrido[3,4-b]indole (4a).
The reaction was carried out in a Schlenk tube equipped with a nitrogen
inlet and magnetic stirrer at room temperature. DMSO (5 mL) was dried
13
156.52, 160.46; 1HÀ C HSQC NMR (DMSO-d6) δH/δC 3.85/55.44,
6424
dx.doi.org/10.1021/jo200923n |J. Org. Chem. 2011, 76, 6421–6425

The Journal of Organic Chemistry
NOTE
3.98/55.50, 6.38/91.29, 6.60/87.32, 7.12/115.12, 8.22/128.05, 8.25/
(8) For examples of synthetic approaches to γ-carbolines, see ref 2;
also see: (a) Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2010, 12, 1540–1543. (b)
Chiba, S.; Xu, Y-J; Wang, Y.-F. J. Am. Chem. Soc. 2009, 131, 12886–12887.
(9) For examples of synthetic approaches to δ-carbolines, see: (a)
Papamicael, C.; Queguiner, G.; Bourguignon, J.; Dupas, G. Tetrahedron
2001, 57, 5385–5391. (b) Rao, M. V. B.; Kumar, U. K. S.; Ila, H.;
Junjappa, H. Tetrahedron 1999, 55, 11563–11578. (c) Arzel, E.; Rocca,
P.; Marsais, F.; Godard, A.; Queguiner, G. Heterocycles 1999, 50,
215–226. (d) Trudell, M. L.; Fukada, N.; Cook, J. M. J. Org. Chem.
1987, 52, 4293–4296. (e) Velezheva, V. S.; Nevskii, K. V.; Suvorov, N. N.
Khim. Geterotsikl. Soedinenii 1985, 230–235. (f) Velezheva, V. S.; Yarosh,
A. V.; Kozik, T. A.; Suvorov, N. N. Zh. Org. Khim. 1978, 14, 1712–1723.
(10) Molina, P.; Fresneda, P. M. J. Chem. Soc., Perkin Trans. 1 1988,
1819–1822.
(11) Mehta, L. K.; Parrick, J.; Payne, F. J. Chem. Soc., Perkin Trans. 1
1993, 1261–1267.
(12) Sakamoto, T.; Numata, A.; Saitoh, H.; Kondo, Y. Chem. Pharm.
Bull. 1999, 47, 1740–1743.
(13) Kanekiyo, N.; Kuwada, T.; Choshi, T.; Nobuhiro, J.; Hibiho, S.
J. Org. Chem. 2001, 66, 8793–8798.
1
143.34; 1HÀ H COSY NMR (DMSO-d6) δH/δH 3.85/3.85, 3.98/3.98,
6.38/6.60, 6.73/7.36, 7.08/7.36, 6.96/8.20, 11.69/11.69; GC/MS EI
m/z 228 (M+, 100). HRMS (ESI) m/z obsd 229.0977, calcd 229.0972
for C13H13N2O2 (M + H+).
7-Methoxy-5H-pyrido[4,3-b]indole (4c). Compound 4c could
not be separated from the mixture of 4c and 4d: 1H NMR (400.16 MHz,
CDCl3) δ 3.73 (s, 3H), 6.81 (dd, J = 8.4, 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz,
1H), 7.25 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 6.0 Hz,
1H), 9.16 (s, 1H); 13C NMR (100.62 MHz, CDCl3) δ 55.61, 95.40,
106.44, 109.48, 115.04, 120.64, 121.32, 141.06, 141.66, 142.92, 144.78,
13
156.16; 1HÀ C HSQC NMR (CDCl3) δH/δC 6.87/95.40, 6.81/
1
1
109.48, 7.25/106.44, 7.88/121.32, 8.36/142.92, 9.16/141.06; HÀ H
COSY NMR (CDCl3) δH/δH 3.73/3.73, 6.81/7.88, 6.87/6.87, 7.25/
8.36, 9.16/9.16; HRMS obsd 199.0892, calcd for 199.0866 C12H11N2O
(M + H).
5-Methoxy-5H-pyrido[4,3-b]indole (4d). Compound 4d could
not be separated from the mixture of 4c and 4d: 1H NMR (400.16 MHz,
CDCl3) δ 3.96 (s, 3H), 6.63 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H),
7.28À7.32 (m, 2H), 8.41 (d, J = 5.6 Hz, 1H), 9.46 (s, 1H); 13C NMR
(100.62 MHz, CDCl3) δ 55.52, 101.30, 104.37, 106.24, 111.01, 120.02,
(14) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 9318–9330.
(15) Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2010, 12, 1540–1543.
(16) Clark, V. M.; Cox, A.; Herbert, E. J. J. Chem. Soc. C 1968,
831–833.
(17) Rocca, P.; Marsais, F.; Godard, A.; Quꢀeguiner, G. Tetrahedron
1993, 49, 49–64.
1
13
127.98, 141.59, 142.97, 143.94, 144.08, 159.80; HÀ C HSQC NMR
(CDCl3) δH/δC 6.63/101.30, 7.05/104.37, 7.28À7.32/106.24, 7.28À
1
7.32/127.98, 8.41/142.97, 9.46/144.08; 1HÀ H COSY NMR (CDCl3)
δH/δH 3.96/3.96, 6.63/7.28À7.32, 7.05/7.28À7.32, 7.28À7.32/8.41, 9.46/
(18) Iwaki, T; Yashuara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
1999, 1505–1510.
9.46; HRMS obsd 199.0892, calcd for 199.0866 C12H11N2O (M + H).
(19) Rossi, R. A.; Pierini, A. B.; Pe~nꢀe~nory, A. B. Chem. Rev. 2003,
103, 71–167.
’ ASSOCIATED CONTENT
(20) In the initiation step of the SRN1 mechanism (schematic
presentation shown below), the radical anion of substrate RX•À can
be formed by an electron transfer (ET) from the nucleophile or from a
suitable electron source. In some systems the ET step is spontaneous;
however, in others, light is required to catalyze the reaction. The RX•À
fragments to afford the radical R• and the anion of the leaving group. The
radical then reacts with the nucleophile to give a radical anion of the
substitution product RNu•À, which by ET to the substrate forms the
intermediates required to continue the propagation cycle.
S
Supporting Information. Spectraforall compounds. This
b
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rossi@fcq.unc.edu.ar; gcuny@rics.bwh.harvard.edu.
’ ACKNOWLEDGMENT
We greatly appreciate financial support from the Harvard
NeuroDiscovery Center and Consejo Nacional de Investigaciones
Científicas y Tꢀecnicas, FONCYT and SECYT, Universidad Na-
cional de Cꢀordoba.
(21) Budꢀen, M. E.; Vaillard, V. A.; Martín, S. E.; Rossi, R. A. J. Org.
Chem. 2009, 74, 4490–4498.
(22) Smith, N.; Bonnefous, C.; Govek, S. P.; Wu, D.; Pinkerton,
A. B.; Kahraman, M.; Cook, T.; Noble, S. A.; Borchardt, A. J.; Prins, T.
PCT Int. Appl. WO 2009117421, September 2009.
(23) Adam, M. S. S.; Kindermann, M. K.; Koeckerling, M.; Heinicke,
J. W. Eur. J. Org. Chem. 2009, 4655–4665.
(24) Sharbatyan, P. A.; Kost, A. N.; Men’shikov, V. V.; Yudin, L. G.;
Chernyshova, N. B. Khim. Geterotsikl. Soedinenii 1980, 1227–1234.
(25) Stephenson, L.; Warburton, W. K. J. Chem. Soc. C 1970, 1355–
1364.
’ REFERENCES
(1) (a) Rosillo, M.; Gonzalez-Gomez, A.; Dominguez, G.; Perez-
Castells, J. Targets Heterocycl. Syst. 2008, 12, 212–257. (b) Cao, R.; Peng,
W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14, 479–500.
(2) Alekseyev, R. S.; Kurkin, A. V.; Yurovskaya, M. A. Chem.
Heterocycl. Compd. 2009, 45, 889–925.
(3) Kim, J.-S.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1997, 38, 3431–3434.
(4) Semenov, A. A.; Tolstikhina, V. V. Chem. Heterocycl. Compd.
1984, 345–356.
(5) Kumar, E. V. K. Suresh; Etukala, J. R.; Ablordeppey, S. Y. Mini
Rev. Med. Chem. 2008, 8, 538–554.
(6) For examples of synthetic approaches to R-carbolines, see ref 4;
also see: (a) Chavan, N. L.; Nayak, S. K.; Kusurkar, R. S. Tetrahedron
2010, 66, 1827–1831. (b) Laha, J. K.; Petrou, P.; Cuny, G. D. J. Org.
Chem. 2009, 74, 3152–3155 and references cited therein.
(7) For examples of synthetic approaches to β-carbolines, see ref 1;
also see: Wu, M.; Wang, S. Synthesis 2010, 587–592.
6425
dx.doi.org/10.1021/jo200923n |J. Org. Chem. 2011, 76, 6421–6425