Rapid access to diverse α-carbolines through sequential transition metal catalyzed amination and direct C-H arylation

Article abstract of DOI:10.1016/j.tet.2014.06.100

An efficient sequence of Pd catalyzed amination and direct C-H arylation for a synthesis of pharmacologically important α-carbolines is described. The outstanding feature in the synthetic sequence is that a combination of DBU and 2-(dicyclohexylphosphino)

Full text of DOI:10.1016/j.tet.2014.06.100

Tetrahedron 70 (2014) 5550e5557
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Rapid access to diverse a-carbolines through sequential transition
metal catalyzed amination and direct CeH arylation
*
Masahiro Mineno , Misayo Sera, Tsuyoshi Ueda, Masahiro Mizuno, Mitsuhisa Yamano,
*
Hideya Mizufune , Atsuhiko Zanka
Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi 2-chome, Yodogawa-ku,
Osaka 532-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 April 2014
Received in revised form 24 June 2014
Accepted 25 June 2014
Available online 28 June 2014
An efficient sequence of Pd catalyzed amination and direct CeH arylation for a synthesis of pharma-
cologically important a-carbolines is described. The outstanding feature in the synthetic sequence is that
a combination of DBU and 2-(dicyclohexylphosphino)biphenyl (DCHPB) plays a critical role to not only
enhance the reactivity but also suppress hydrodehalogenation in the direct CeH arylation step. The
reaction protocol provides
ketone moieties in moderate to excellent yields. Moreover, combination with Cu catalyzed amination
further enhanced the versatility of the -carboline synthesis.
a-carbolines with various substituents including base-sensitive ester and
Keywords:
a
a
-Carbolines
Ó 2014 Elsevier Ltd. All rights reserved.
BuchwaldeHartwig amination
Direct CeH arylation
DBU
1. Introduction
a-Carbolines (pyrido[2,3-b]indoles) (1) have recently received
much interest since the discovery of various biologically active
natural products, such as mescengricin (2),1 neocryptolepine (3),2
grossularine-1 (4a) and grossularine-2 (4b)3 (Fig. 1). Additionally,
synthetic a-carbolines have been found to exhibit a wide variety of
biological properties, such as anxiolytic,1,4 anti-inflammatory5 and
CNS-stimulating activities.6 Furthermore, the tricyclic ring system
has recently attracted increasing attention as a pharmacophore for
kinase inhibitors, such as cyclin-dependent kinase (CDK) in-
hibitors,7 glycogen synthetase kinase (GSK) inhibitors,8 and ana-
plastic lymphoma kinase (ALK) inhibitors,9 which are being
explored as various anticancer and antidiabetic agents. These at-
tractive biological properties have intrigued the synthetic chemists
and encouraged them to develop new synthetic pathways to these
ring systems.
Fig. 1. Chemical structures of
ologically active natural products.
a-carboline (1) and a-carboline structure based bi-
For the preparation of this ring system, various synthetic
methods have been developed and they can be classified into the
following four strategies; (i) intramolecular biaryl coupling re-
action of N-arylaminopyridine derivatives,10,11 (ii) intramolecular
amination reaction to form the pyrrole CeN bond,12e14 (iii)
benzannulation,15e17 and (iv) pyridine ring formation
(Scheme 1).16c,18e21
Among these synthetic methods, the GraebeeUllmann reaction,
classified as an intramolecular biaryl coupling strategy (i), has been
most often employed, due to the easy access to the penultimate
precursors.9e11 However, the reaction requires a benzotriazole in-
termediate, which is considered a significant drawback because of
the high temperature conditions needed for cyclization with
* Corresponding authors. Tel.: þ81 6 6300 6784; fax: þ81 6 6300 6251; e-mail
addresses: masahiro.mineno@takeda.com (M. Mineno), hideya.mizufune@takeda.
com (H. Mizufune).
http://dx.doi.org/10.1016/j.tet.2014.06.100
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

M. Mineno et al. / Tetrahedron 70 (2014) 5550e5557
5551
Scheme 2. Synthetic strategy toward a-carboline.
identified the ligand XANTPHOS (4,5-bis(diphenylphosphino)-9,9-
dimethyl xanthene) in the presence of Pd(OAc)2 and Cs2CO3 as
the most active catalyst system for the amination.
Scheme 1. Common a-carboline syntheses.
Next, our efforts were turned toward the Pd catalyzed direct
CeH arylation. Direct CeH arylation of 3-bromo-5-methyl-N-phe-
nylpyridine-2-amine (7a) was examined under the original condi-
tions reported by Sakamoto group20 (Table 1, run 1), and it was
a potential risk of explosion. Even in the case of the modified reaction
employing UV light, or microwave irradiation, the protocol is still not
practical.11d,e Likewise, other protocols have drawbacks from a prac-
tical perspective, particularly for the preparation of complex sub-
strates. For example, the intramolecular amination strategy (ii)
requires the preparation of 3-(2-aminophenyl)-2-fluoropyridine,12
3-(2-nitrophenyl)pyridine,13 or 3-(2-azidophenyl)pyridine,14 which
are prepared by a combination of biaryl coupling and functionali-
zation at the ortho position of the phenyl ring. Regarding the ben-
zannulation strategy (iii), the complicated 7-aza-indole derivatives
are prepared for aromatization reaction after a Fisher’s indole syn-
thesis15 or a DielseAlder reaction,8b,16 and an intramolecular Frie-
deleCrafts type acylation.17 As for the pyridine ring formation
strategy (iv), multi-step syntheses are also required for the substrate,
such as N-phenyl-aminopyrazine derivatives for the DielseAlder
reaction,16c 2-aminoindole derivatives7a,18 and 3-substituted in-
doles19 for cyclization. Thus, while those strategies provide regio-
found that only a small amount of the desired a-carboline (1a) was
obtained with undesired 8a arising from hydrodebromination of
7a, as expected.22
Table 1
Base effect on direct CeH arylation of 7aa
Run
Base
Conversion (%)b
1a
8a
1
2
3
4
5
6
7
8
9
K2CO3
Cs2CO3
NaOAc
K3PO4
i-Pr2NEt
NEt3
Cy2NMe
DABCO
DBU
2
7
1
3
1
10
13
11
11
6
20
32
50
3
specific syntheses of substituted a-carbolines, they require complex
substrates as the precursors, which cause multi-step syntheses for
their preparation and limits both the availability of the starting
16
22
16
<1
<1
<1
materials and the scope for further functionalization on the a-car-
boline. Additionally, substituent diversity on the benzene ring has
not been systematically studied to date, in comparison with that on
the pyridine ring.
Sakamoto and co-workers have reported an intramolecular
biaryl coupling strategy, utilizing a sequential Pd catalyzed cross
coupling method employing amination and direct CeH arylation.20
10
DBN
a
Reaction condition: 7a (1.0 mmol), Pd(OAc)2 (5 mol %), Base (2 equiv), DMAc
(1 mL), 130 ꢀC, 5 h.
b
Determined by HPLC analysis.
The method offered an effective and convenient access to
a
-car-
The result led us to further investigate how to enhance the re-
activity and suppress the side reaction. First, a series of bases were
examined in the presence of Pd(OAc)2 in DMAc (Table 1).
bolines, particularly from the viewpoint of substrate preparations,
but it needs harsh conditions (reflux in DMF for 67 h) and gave the
product in low yield (31%) for the direct CeH arylation, and was
Although some prior literature suggested that inorganic bases
are effective to enhance the reaction rate and suppress the hydro-
debromination,23 several inorganic bases (Cs2CO3, NaOAc and
K3PO4) were found to be ineffective in this reaction, giving low
conversions and a considerable amount of 8a (runs 2e4). Next,
organic amines were examined, and it was found that although
alkyl acyclic amines (i-Pr2NEt, Et3N,24 and Cy2NMe)25 gave a large
amount of 8a (runs 5e7), satisfactory results could be obtained
with cyclic tertiary amines DABCO (1,4-diazabicyclo[2.2.2]oc-
tane),26 DBU (1,8-diazabicyclo [5.4.0]undec-7-ene) and DBN (1,5-
diazabicyclo [4.3.0]non-5-ene), which exclusively provided 1a in
moderate yield (runs 8e10). While DBN displays the highest con-
version among cyclic tertiary amines, DBU was finally selected as
the optimal base for the reaction, on consideration of its wide ap-
plicability even for base-sensitive substituents.27
only applied to one example of a non-substituted
a-carboline.
Therefore, a mild and efficient protocol for direct CeH arylation is
still desired, which would contribute to the easy and rapid accesses
to various
In the course of our drug research and development, an efficient
synthetic strategy for -carbolines with various substituents on the
a-carbolines.
a
benzene ring was required, and we developed several Pd catalyzed
syntheses, which we disclosed in a patent.21 Herein, we describe in
more detail our studies on a versatile and practical synthetic pro-
tocol for a-carbolines through a sequence of transition metal cat-
alyzed amination and direct CeH arylation (Scheme 2).
2. Results and discussions
Our initial studies were commenced by establishing an efficient
catalyst system for Pd catalyzed amination of 2-amino-3-
bromopyridine (5) with aryl iodide (6). To identify the optimal re-
action condition for this reaction, an extensive screening of catalyst
systems, including ligands and bases, was performed, which
With DBU as the base, the influence of ligand on the reactivity
was examined. A screening of different ligands was performed at
130 ꢀC for 1 h in the presence of 5 mol % of Pd(OAc)2 and 2.0 equiv of
DBU (Table 2). A large number of ligands including monodentate
triarylphosphines (PPh3, P(o-Tolyl)3), trialkylphosphines (P(t-Bu)3,

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M. Mineno et al. / Tetrahedron 70 (2014) 5550e5557
Table 2
P(t-Bu)2Me, PCy3), dialkylbiphenylphosphines (2-dicyclo hex-
Ligand effect on direct CeH arylation of 7aa
ylphosphino-20,40,60-triisopropyl biphenyl (XPhos), 2-dicyclohexyl
phosphino-20-(N,N-dimethylamino)biphenyl (DavePhos), 2-(di-
tert-butylphosphino)biphenyl (DTBPB), 2-(dicyclohexylphosphino)
biphenyl (DCHPB)), bidentate phosphines, (dppp, dppf, rac-BINAP,
XANTPHOS)
and
N-heterocyclic
carbene
(1,3-bis(2,6-
diisopropylphenyl) imidazolium chloride ([IPr]HCl)) were
screened. As shown in Table 2, the DCHPB-based catalyst system
gave fast reaction that reached full conversion within 1 h (run 9),
though P(t-Bu)2Me (run 4) gave moderate conversion among
monodentate triarylphosphines and bulky trialkylphosphines,
standard ligands for intramolecular direct CeH arylations.28 To our
knowledge, it is uncommon that dialkylbiphenylphosphines, such
as DCHPB is effective in this kind of intramolecular CeH arylation.29
Furthermore, since DCHPB was quite effective for the reaction,
compared with other dialkylbiphenylphosphines (X-Phos,
DavePhos and DTBPB) (runs 6e8), we consider a balance of bulki-
ness between dialkyl and biphenyl group on the phosphine might
be a key to accelerate the reaction.30
Run
Ligand
Conversion (%)b
1a
8a
1
2
3
4
5
6
7
8
PPh3
19
6
d
d
d
d
d
d
d
d
d
d
d
3
P(o-Tolyl)3
P(t-Bu)3
P(t-Bu)2Me
PCy3
17
73
42
56
4
12
99
26
27
6
X-Phosc
DavePhosd
DTBPBe
DCHPBf
DPPE
9
10
11
12
13
14
DPPF
rac-BINAP
XANTPHOS
[iPr]HCl
Having established the optimal catalyst systems for both the Pd
catalyzed amination and direct CeH arylation, a versatile synthesis
13
4
d
2
of a
-carbolines was addressed (Table 3).31 Gratifyingly, it was found
a
Reaction conditions: 7a (1.0 mmol), Pd(OAc)2 (5 mol %), Ligand (10 mol %), DBU
(2 equiv), DMAc (1 mL), 130 ꢀC, 1 h.
that various electronically and structurally diverse substrates could
be applied in this sequence. As can be seen in the synthesis of 1g,1h,
1j and 1k, a variety of base-sensitive functional groups including
ester, ketone, nitrile and amide were tolerant. Additionally, the
catalyst system also worked even in the presence of bromide and
b
Determined by HPLC analysis.
c
2-Dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
d
2-Dicyclohexylphosphino-20-(N,N-dimethyl amino)biphenyl.
e
2-(Di-tert-butylphosphino)biphenyl.
2-(Dicyclo hexylphosphino)biphenyl.
f
chloride substituents on the a-carbolines, allowing the opportunity
Table 3
Synthesis of a
-carboline 1 by a sequence of Pd catalyzed amination and direct CeH arylationa

M. Mineno et al. / Tetrahedron 70 (2014) 5550e5557
5553
for further other transition metal catalyzed functionalizations (1m
and 1n). It is noteworthy from practical perspectives that this re-
action system was successfully performed on multigram scales and
arylpyridin-2-amines (7) successfully underwent the Pd catalyzed
direct CeH arylation to provide the corresponding series of -car-
a
bolines (1). It is noteworthy that the aryl iodide with a hydroxy
methyl group (6q), which was considered difficult to be applied to
the Pd catalyzed amination, could be successfully converted to 7q
without involvingintermolecularO-arylation, andthe subsequent Pd
catalyzed CeH arylation was carried out with no intramolecular O-
arylation.
allowed isolation of the desired a-carboline products as nearly pure
materials by just adding water to the resulting reaction mixture.
Moreover, to confirm the regioselectivity of the Pd catalyzed
cyclization, the reaction starting from 3-substituted aryl iodide (6p)
was attempted, and it was found that the 7-substituted a-carboline
(1p) was exclusively obtained, with no 5-substituted compound
(1p0) detected (Scheme 3). Thus, we achieved selective function-
3. Summary
alization at the 6-, 7- and 8-positions of the
a-carbolines. As for the
preparation of 5-substituted -carbolines, the 8-substituent ap-
a
We have developed a versatile and practical synthetic protocol
pears to be essential, as shown in the synthesis for 1n.
for pharmacologically important a-carbolines, through a sequence
of Pd catalyzed amination and direct CeH arylation. The outstanding
feature in the direct CeH arylation is that a combination of DBU and
DCHPB plays a critical role to not onlyenhance the reactivity but also
suppress hydrodehalogenation. The reaction system enables the
versatile synthesis of
Moreover, the combination with Cu catalyzed amination afforded
a wide diversity of -carbolines. The protocol readily affords various
-carbolines that could be useful for new drug development.
a-carbolines in moderate to excellent yields.
a
a
4. Experimental section
4.1. General
All materials were purchased from commercial suppliers and
Scheme 3. Regioselective direct CeH arylation.
used without further purification. Melting points were recorded on
€
a Buchi B-540 micromelting apparatus and were uncorrected. NMR
spectra were run at either 300 MHz (1H)/75 MHz (13C) (Bruker
DPX-300) or 500 MHz (1H)/125 MHz (13C) (Bruker UltraShield-500
Thus, having established a versatile and practical
a-carboline
synthesis employing sequential Pd catalyzed amination and direct
CeH arylation, our interests were then directed toward extending
the application to include Cu catalyzed amination. Copper is con-
sidered a more attractive catalyst than palladium due to its relative
inexpensiveness, ready availability, lower toxicity and robustness
even under atmospheric condition.32 Also, Cu catalyzed amination
could be expected to broaden the range of the applicable substrates
for the system.33
PLUS). Chemical shifts are reported as
d values using tetrame-
thylsilane as an internal standard and coupling constants (J) are
given in hertz (Hertz).
4.2. General procedure for 7 (Pd catalyzed procedure)
Under N2 atmosphere, to a solution of palladium acetate
(120 mg, 0.53 mmol, 5 mol %) and XANTPHOS (309 mg, 0.53 mmol,
5 mol %) in anisole (30 mL) was added 3-bromo-5-methyl-pyridin-
2-ylamine (5) (2.0 g, 10.7 mmol, 1.0 equiv), aryl iodides (6)
(10.7 mmol) and cesium carbonate (4.9 g, 15.0 mmol,1.4 equiv), and
the mixture was stirred at 130 ꢀC for 1e13 h. After cooling to room
temperature, water (40 mL) was added to the mixture. The mixture
was concentrated in vacuo and ethyl acetate (100 mL) was added to
the residue. The organic layer was washed with water (20 mL) and
concentrated in vacuo to give the crude product, which was puri-
fied by flash chromatography to give 7.
Foroptimizationof the reaction, thecouplingreaction of5 with 6e
was investigated. Initially, several different ligands (N,N0-dimethy-
laminocyclohexane, 1,10-phenathroline, 2-acetylcyclohexanone,34
ethylene glycol, L-proline, ethanolamine) were screened in the
presence of CuI, and K2CO3. Consequently, ethanolamine was found
as the best ligand for the reaction (Scheme 4). The reaction system
was then successfully applied to other aryl iodides (6a, 6g and 6q),
providing desired products in moderate yield. The obtained N-
4.2.1. 3-Bromo-5-methyl-N-phenylpyridine-2-amine (7a). The title
compound was prepared from 5 (9.4 g) and iodobenzene (6a)
(10.2 g), according to the general procedure using t-BuOH as a sol-
vent under reflux conditions. Yield: 87% (11.5 g). White solid. Mp
62.5e64.5 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼2.24 (s, 3H), 6.89 (br s,
1H), 7.01e7.06 (m, 1H), 7.31e7.36 (m, 2H), 7.58e7.61 (m, 3H), 7.80
(s, 1H). 13C NMR (75 MHz, CDCl3):
d
¼17.1, 106.1, 119.4, 122.3, 125.1,
128.9, 140.2, 140.9, 146.1, 149.8. HRMS (FAB): m/z [MꢁH]þ (calcd for
C12H11BrN2: 261.0027; found: 261.0027.).
4.2.2. 3-Bromo-5-methyl-N-1-naphtylpyridine-2-amine (7b). The
title compound was prepared according to the general procedure.
Yield: 63% (2.1 g), Brown solid. Mp 127.7e132.6 ꢀC. 1H NMR
(500 MHz, DMSO-d6):
(m, 1H), 7.71e7.78 (m, 2H), 7.80e7.87 (m, 2H), 7.90e7.96 (m, 1H),
8.16 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
¼16.4, 105.5, 121.5,
122.9, 124.4, 124.8, 125.6, 125.7, 125.8, 128.1, 129.1, 134.0, 136.7,
d
¼2.15 (s, 3H), 7.41e7.53 (m, 3H), 7.55e7.61
d
Scheme 4.
direct CeH arylation.
a-Carboline synthesis through Cu catalyzed amination and Pd catalyzed

5554
M. Mineno et al. / Tetrahedron 70 (2014) 5550e5557
141.2, 146.1, 152.0. HRMS (FAB): m/z [MꢁH]þ (calcd for C16H13BrN2:
149.1, 196.0. HRMS (FAB): m/z [MꢁH]þ (calcd for C14H13BrN2O:
311.0184; found: 311.0179).
303.0133; found: 303.0132).
4.2.9. 4-[(3-Bromo-5-methylpyridin-2-yl)amino]benzonitrile
(7j). The title compound was prepared from 5 (2.0 g) and 4-
iodobenzonitrile (6j) (2.5 g), according to the general procedure.
Yield: 68% (2.1 g). Off-white solid. Mp 163.4e165.3 ꢀC. 1H NMR
4.2.3. N-([1,10-Biphenyl]-4-yl)-3-bromo-5-methylpyridin-2-amine
(7c). The title compound was prepared according to the general
procedure. Yield: 24% (860 mg), Yellow solid. Mp 90.0e91.3 ꢀC. 1H
NMR (500 MHz, DMSO-d6):
d
¼2.21 (s, 3H), 7.28e7.34 (m, 1H), 7.44
(500 MHz, DMSO-d6):
d
¼2.24 (s, 3H), 7.67 (dd, J¼7.0, 1.9 Hz, 2H),
(t, J¼7.7 Hz, 2H), 7.59 (m, 2H), 7.62e7.68 (m, 2H), 7.73 (m, 2H),
7.77 (dd, J¼7.0, 1.9 Hz, 2H), 7.92 (s, 1H), 8.10 (s, 1H), 8.64 (s, 1H). 13
C
7.80e7.89 (m, 1H), 8.00e8.07 (m, 1H), 8.10 (s, 1H). 13C NMR
NMR (125 MHz, DMSO-d6):
d¼16.6, 101.8, 107.6, 118.3, 119.6, 127.9,
(125 MHz, DMSO-d6):
d
¼16.5, 106.1, 120.0, 125.7, 126.0, 126.5, 126.6,
132.7, 142.1, 145.7, 146.0, 148.8. HRMS (FAB): m/z [MꢁH]þ (calcd for
128.8, 133.1, 140.0, 140.5, 141.6, 145.9, 149.9. HRMS (EI): m/z [M]þ
C13H10BrN3: 285.9980; found: 285.9972).
(calcd for C18H15BrN2: 337.0340; found: 337.0341).
4.2.10. 3-[3-Bromo-5-methylpyridin-2-yl)amino]-2-methyl-N-(1-
methylpiperidin-4-yl)benzamide (7k). The title compound was pre-
pared from 5 (350 mg) and 3-iodo-2-methyl-N-(1-methylpiperidin-
4-yl)benzamide (6k) (670 mg), according to the general procedure.
Yield: 38% (295 mg). Reddish white solid. Mp 262.1e266.5 ꢀC. 1H
4.2.4. N-([1,10-Biphenyl]-2-yl)-3-bromo-5-methylpyridin-2-amine
(7d). The title compound was prepared under the following con-
ditions; catalyst: Pd2(dba)3, ligand: dppf, solvent: toluene, base:
NaOt-Bu, temperature: 100 ꢀC. Yield: 2.9 g (81%). Off-white solid.
Mp 229.2e231.2 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d¼2.14 (s, 3H),
NMR (500 MHz, DMSO-d6):
d
¼1.46e1.59 (m, 2H),1.72e1.81 (m, 2H),
7.14 (td, J¼7.5, 1.4 Hz, 1H), 7.26 (dd, J¼7.6, 1.9 Hz, 1H), 7.31e7.49 (m,
8H), 7.72 (d, J¼2.2 Hz, 1H), 7.92 (dd, J¼1.7, 0.8 Hz, 1H), 8.15 (dd,
1.90e1.99 (m, 2H), 2.12 (s, 3H), 2.15 (s, 3H), 2.16 (s, 3H), 2.66e2.80
(m, 2H), 3.59e3.79 (m, 1H), 6.98e7.11 (m, 1H), 7.19 (t, J¼7.7 Hz, 1H),
7.52 (d, J¼7.3 Hz, 1H), 7.60 (s, 1H), 7.74e7.82 (m, 1H), 7.82e7.90 (m,
J¼8.2, 1.3 Hz, 1H). 13C NMR (125 MHz, DMSO-d6):
¼16.4, 105.6,
d
1H), 8.21 (d, J¼7.9 Hz, 1H). 13C NMR (125 MHz, DMSO-d6):
¼14.4,
d
121.6, 122.8,125.1,127.6,127.9, 128.8,128.9,129.9,133.1,137.3, 138.5,
141.0, 145.8, 149.8. HRMS (EI): m/z [MꢁH]þ (calcd for C18H15BrN2:
337.0340; found: 337.0337).
16.4, 31.4, 45.96, 46.04, 54.3, 105.3, 122.7, 124.6, 125.4, 129.3, 133.5,
138.9, 139.5,141.2, 126.0, 151.1, 168.6. HRMS (EI): m/z [M]þ (calcd for
C20H25BrN4O: 416.1212; found: 416.1202).
4.2.5. 3-Bromo-N-(2-methoxyphenyl)-5-methylpyridine-2-amine
(7e). The title compound was prepared from 5 (10.0 g) and 2-
iodoanisole (6e) (12.5 g), according to the general procedure
under the following conditions; catalyst: Pd2(dba)3, ligand: dppf,
solvent: toluene, base: NaOt-Bu, temperature: 100 ꢀC. Yield: 91%
(14.8 g), White solid. Mp 111.8e114.4 ꢀC. 1H NMR (500 MHz,
4.2.11. 3-Bromo-N-(2-bromophenyl)-5-methylpyridine-2-amine
(7m). The title compound was prepared according to the general
procedure. Yield: 67% (2.5 g); Off-white solid. Mp 54.7e56.5 ꢀC. 1H
NMR (500 MHz, DMSO-d6):
d
¼2.21 (s, 3H), 6.90e7.06 (m, 1H),
7.35e7.42 (m, 1H), 7.65 (dd, J¼8.0, 1.7 Hz, 1H), 7.73 (s, 1H), 7.81e7.96
(m, 1H), 7.97e8.09 (m, 1H), 8.27 (dd, J¼8.4, 1.7 Hz, 1H). 13C NMR
DMSO-d6):
7.01e7.12 (m, 1H), 7.71 (s, 1H), 7.80e7.90 (m, 1H), 7.99e8.11 (m,
1H), 8.39e8.50 (m, 1H). 13C NMR (125 MHz, DMSO-d6):
d
¼2.20 (s, 3H), 3.91 (s, 3H), 6.87e7.00 (m, 2H),
(125 MHz, DMSO-d6):
d
¼16.5, 106.2, 114.6, 121.6, 123.8, 126.2, 128.2,
132.4, 138.1, 141.4, 145.9, 149.3. HRMS (EI): m/z [M]þ (calcd for
12H10Br2N2: 339.9211; found: 339.9211).
d
¼16.5,
C
56.0, 106.1, 110.5, 117.5, 120.5, 121.4, 125.2, 129.5, 141.1, 145.9, 147.7,
149.2. HRMS (EI): m/z [M]þ (calcd for C13H13BrN2O: 292.0211;
found: 292.0205).
4.2.12. 3-Bromo-N-(5-chloro-2-methoxyphenyl)-5-methyl pyridine-
2-amine (7n). The title compound was prepared from 5 (9.8 g) and
4-chloro-2-iodo-1-methoxybenzene (6n) (13.4 g), according to the
general procedure under the following conditions; catalyst:
Pd2(dba)3, ligand: dppf, solvent: toluene, base: NaOt-Bu, tempera-
ture: 100 ꢀC. Yield: 79% (12.9 g). White solid. Mp 139.2e141.2 ꢀC. 1H
4.2.6. 3-Bromo-5-methyl-N-[4-(methylthio)phenylpyridine-2-amine
(7f). The title compound was prepared according to the general
procedure. Yield: 20% (500 mg); White solid. Mp 54.5e57.3 ꢀC. 1H
NMR (500 MHz, DMSO-d6):
d
¼2.19 (s, 3H), 2.44 (s, 3H), 7.16e7.25
NMR (300 MHz, CDCl3):
d
¼2.23 (s, 3H), 3.92 (s, 3H), 6.77 (d,
(m, 2H), 7.54e7.63 (m, 2H), 7.81 (d, J¼2.5 Hz, 1H), 7.92e8.03 (m,
J¼8.6 Hz, 1H), 6.87 (dd, J¼8.6, 2.5 Hz,1H), 7.59 (d, J¼1.5 Hz,1H), 7.75
2H). 13C NMR (125 MHz, DMSO-d6):
d¼16.2, 16.4, 105.8,120.6,125.4,
(br s, 1H), 8.05 (d, J¼1.0 Hz, 1H), 8.69 (d, J¼2.5 Hz, 1H). 13C NMR
127.5, 129.5, 138.7, 141.5, 145.8, 149.9. HRMS (FAB): m/z [MꢁH]þ
(75 MHz, CDCl3)
d
¼17.1, 56.2, 106.8, 110.4, 117.1, 120.1, 125.4, 126.0,
(calcd for C13H13BrN2S: 306.9905; found: 306.9904).
131.2, 140.9, 146.0, 146.3, 149.3. MS: m/z¼327 [MþH]þ. Anal. Calcd
for C13H12N2OBrCl: C, 47.66; H, 3.69; N, 8.55; Br 24.39; Cl 10.82.
found: C, 47.94; H, 3.62; N, 8.68; Br, 24.36; Cl, 10.86.
4.2.7. Methyl 3-[(3-bromo-5-methylpyridin-2-yl)amino]-2-
methylbenzoate (7g). The title compound was prepared from 5
(6.2 g) and methyl 3-iodo-2-methylbenzoate (6g) (9.2 g), according
to the general procedure using toluene as a solvent at 100 ꢀC. Yield:
43% (4.8 g). White solid. Mp 63.9e64.7 ꢀC. 1H NMR (500 MHz,
4.2.13. Ethyl
3-((3-bromo-5-methylpyridin-2-yl)amino)-benzoate
(7p). The title compound was prepared from 5 (10.0 g) and ethyl 2-
iodobenzoate (6p) (14.8 g), according to the general procedure. 7p
was telescoped to the subsequent step. White solid. Mp
DMSO-d6):
1H), 7.51e7.56 (m, 1H), 7.56e7.61 (m, 1H), 7.75e7.79 (m, 2H),
7.81e7.87 (m, 1H). 13C NMR (125 MHz, DMSO-d6):
d¼2.15 (s, 3H), 2.26 (s, 3H), 3.83 (s, 3H), 7.27 (t, J¼7.9 Hz,
50.8e52.8 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼1.33 (t, J¼7.1 Hz,
d¼15.1, 16.4, 52.0,
3H), 2.21 (s, 3H), 4.32 (q, J¼7.3 Hz, 2H), 7.40 (t, J¼7.9 Hz, 1H), 7.54
(dt, J¼7.7, 1.3 Hz, 1H), 7.85 (d, J¼2.2 Hz, 1H), 7.89 (ddd, J¼8.2, 2.2,
1.0 Hz, 1H), 8.01 (dd, J¼1.9, 0.6 Hz, 1H), 8.23 (t, J¼2.1 Hz, 1H), 8.31 (s,
105.2, 124.6, 125.6, 129.0, 131.4, 133.5, 140.3, 141.2, 146.0, 148.0,
151.3, 168.0. HRMS (EI): m/z [M]þ (calcd for C15H15BrN2O2:
334.0317; found: 334.0313).
1H). 13C NMR (125 MHz, DMSO-d6):
121.9, 124.1, 126.2, 128.5, 130.1, 141.4, 141.7, 145.8, 149.8, 165.9. MS
(ESI): m/z¼335 [MþH]þ. Anal. Calcd for C15H15BrN2O2; C,53.75; H,
4.41; N, 8.36; Br, 23.84. found: C, 53.88; H, 4.43; N, 8.18; Br, 23.49.
d
¼14.2, 16.5, 60.6, 106.2, 120.2,
4.2.8. 1-{4-[(3-Bromo-5-methylpyridin-2-yl)amino]
phenyl}etha-
none (7h). The title compound was prepared according to the
general procedure. Yield: 1.5 g (45%); White solid. Mp 91.9e93.0 ꢀC.
1H NMR (500 MHz, DMSO-d6):
d
¼2.23 (s, 3H), 2.50 (s, 3H),
4.3. General procedure for 7 (Cu catalyzed procedure)
7.67e7.74 (m, 2H), 7.83e7.89 (m, 2H), 7.91 (d, J¼2.2 Hz, 1H),
8.06e8.11 (m, 1H), 8.50 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
Under N2 atmosphere, to a solution of copper iodide (204 mg,
0.11 mmol, 10 mol %) and ethanolamine (131 mg, 0.22 mmol,
d¼16.5, 26.2, 107.3, 117.6, 127.4, 129.2, 129.3, 141.9, 145.9, 146.0,

M. Mineno et al. / Tetrahedron 70 (2014) 5550e5557
5555
20 mol %) in anisole (30 mL) was added aryl iodides (6)
(10.7 mmol), 3-bromo-5-methyl-pyridin-2-ylamine (5)
141.2, 145.9, 149.7. HRMS (EI): m/z [M]þ (calcd for C16H12N2:
232.1000; found: 232.0996).
(10.7 mmol) and potassium carbonate (2.2 g, 16.0 mmol, 1.5 equiv),
and the mixture was stirred at 130 ꢀC for 4e18 h. After cooling to
room temperature, water (30 mL) was added to the mixture. The
mixture was concentrated in vacuo and ethyl acetate (50 mL) was
added to the residue. The organic layer was washed with water
(20 mL) and concentrated in vacuo to give the crude product. The
crude product was purified by flash chromatography to give the
title compound.
4.4.3. 3-Methyl-6-phenyl-9H-pyrido[2,3-b]indole (1c). The title
compound was prepared from 7c (500 mg), according to the gen-
eral procedure. Yield: 99% (375 mg). Pale yellow solid. Mp
300.1e302.8 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼2.47 (s, 3H),
7.31e7.38 (m, 1H), 7.49 (t, J¼7.9 Hz, 2H), 7.57 (d, J¼8.5 Hz, 1H),
7.69e7.92 (m, 3H), 8.17e8.36 (m, 1H), 8.46 (dt, J¼8.1, 1.1 Hz, 2H),
11.78 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
d
¼18.0, 111.6, 115.6,
119.2, 120.8, 123.7, 125.6, 126.5, 126.6, 128.9, 129.3, 131.8, 138.7,
141.0, 146.0, 150.4. HRMS (EI): m/z [M]þ (calcd for C18H14N2:
258.1157; found: 258.1157).
4.3.1. 3-Bromo-N-(2-methoxyphenyl)-5-methylpyridine-2-amine
(7e). The title compound was prepared from 5 (1.0 g) and 6e (1.3 g),
according to the general procedure. Yield: 46% (720 mg).
4.4.4. 3-Methyl-8-phenyl-9H-pyrido[2,3-b]indole (1d). The title
compound was prepared from 7d (500 mg), according to the gen-
eral procedure. Yield: 97% (370 mg). White solid. Mp
4.3.2. 3-Bromo-5-methyl-N-phenylpyridine-2-amine (7a). The title
compound was prepared according to the general procedure. Yield:
25% (700 mg).
229.2e231.2 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d 2.47 (s, 3H), 7.31 (t,
J¼7.6 Hz, 1H), 7.41e7.48 (m, 2H), 7.55 (t, J¼7.7 Hz, 2H), 7.71 (dd,
J¼8.2, 1.3 Hz, 2H), 8.14 (dd, J¼7.6, 1.3 Hz, 1H), 8.28 (d, J¼2.5 Hz, 2H),
8.34e8.39 (m, 1H), 11.51 (s, 1H). 13C NMR (125 MHz, DMSO-d 6):
4.3.3. Methyl 3-[(3-bromo-5-methylpyridin-2-yl)amino]-2-methyl-
benzoate (7g). The title compound was prepared according to the
general procedure. Yield: 32% (1.1 g).
d
18.0,115.1,119.8,120.1,121.2,123.8,125.2,126.7,127.3,128.4,128.5,
128.9, 136.4, 138.2, 146.8, 151.1. HRMS (EI): m/z [M]þ (calcd for
C18H14N2: 258.1157; found: 258.1154).
4.3.4. {2-[(3-Bromo-5-methylpyridin-2-yl)amine]phenyl} methanol
(7q). The title compound was prepared from 5 (1.5 g) and (2-
iodophenyl)methanol (6q) (1.9 g), according to the general pro-
cedure. Yield: 20% (470 mg); Off-white solid. Mp 129.3e131.8 ꢀC. 1H
4.4.5. 8-Methoxy-3-methyl-9H-pyrido[2,3-b]indole (1e). The title
compound was prepared from 7e (32.0 g), according to the general
procedure. Yield: 95% (22.1 g). Brown solid. Mp 215.9e220.2 ꢀC. 1H
NMR (500 MHz, DMSO-d6):
d
¼2.20 (s, 3H), 4.56 (d, J¼5.0 Hz, 2H),
5.67 (t, J¼5.0 Hz, 1H), 6.96 (td, J¼7.4, 1.3 Hz, 1H), 7.25 (d, J¼7.3 Hz,
NMR (500 MHz, DMSO-d6):
d
¼2.44 (s, 3H), 3.97 (s, 3H), 7.03 (d,
2H), 7.84 (d, J¼2.2 Hz, 1H), 7.93e8.00 (m, 1H), 8.09 (dd, J¼8.7, 1.1 Hz,
J¼7.9 Hz, 1H), 7.13 (t, J¼7.7 Hz, 1H), 7.69 (d, J¼7.9 Hz, 1H), 8.27 (q,
1H), 8.66 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
d
¼16.5, 62.5, 105.7,
J¼2.6 Hz, 2H), 11.72 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
¼18.0,
d
120.2, 121.5, 125.1, 127.5, 128.3, 130.5, 139.7, 141.3, 145.8, 150.0.
HRMS (EI): m/z [M]þ (calcd for C13H13BrN2O: 292.0211; found:
292.0208).
55.5, 107.3, 113.3, 115.1, 119.7, 121.2, 123.5, 128.4, 129.1, 145.7, 146.5,
150.3. HRMS (EI): m/z [M]þ (calcd for C13H12N2O: 212.0950; found:
212.0946).
4.4. General procedure for 1
4.4.6. 3-Methyl-6-(methylthio)-9H-pyrido[2,3-b]indole (1f). The ti-
tle compound was prepared from 7f (400 mg), according to the
general procedure. Yield: 86% (253 mg). Orange solid. Mp 155 ꢀC dec.
Under N2 atmosphere, to a solution of palladium acetate (21 mg,
0.09 mmol, 5 mol %) and 2-(di-cyclohexylphosphino)biphenyl
(DCHPB) (65 mg, 0.19 mmol, 10 mol %) in N,N-dimethylacetamide
(3 mL) was added N-arylpyridin-2-amines (7) (3.09 mmol) and DBU
(942 mg, 6.19 mmol, 2.0 equiv), and the mixture was stirred at
130 ꢀC for 1e8 h. After cooling to room temperature, water (6 mL)
was added to the mixture. The mixture was then stirred at ambient
temperature for 0.5 h before the precipitate was filtered and
washed with methanol (4 mL) and water (2 mL) to give the title
compound.
1H NMR (500 MHz, DMSO-d6):
d
¼2.46 (s, 3H), 2.55 (s, 3H), 7.42e7.49
(m, 2H), 8.13e8.18 (m, 1H), 8.27e8.34 (m, 1H), 8.41e8.49 (m, 1H),
11.88 (s,1H).13C NMR (125 MHz, DMSO-d6):
d
¼17.2,17.9,112.0,115.3,
120.7, 120.9, 123.8, 127.4, 127.6, 129.9, 137.5, 145.1, 149.5. HRMS (EI):
m/z [M]þ (calcd for C13H12N2S: 288.0721; found: 288.0711).
4.4.7. Methyl 3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylate
(1g). The title compound was prepared from 7g (4.8 g), according
to the general procedure. Yield: 59% (2.1 g). Off-white solid. Mp
296.6e298.7 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼2.46 (s, 3H), 2.77
4.4.1. 3-Methyl-9H-pyrido[2,3-b]indole (1a). The title compound
was prepared from 7a (10.5 g), according to the general procedure.
Yield: 97% (7.5 g). Off-white solid. Mp 269.4e271.4 ꢀC. 1H NMR
(s, 3H), 3.87 (s, 3H), 7.67 (d, J¼8.2 Hz, 1H), 8.04 (d, J¼8.5 Hz, 1H),
8.37 (dd, J¼9.9, 2.4 Hz, 2H), 11.90 (s, 1H). 13C NMR (125 MHz, DMSO-
d6):
d
¼14.9, 18.0, 51.8, 114.6, 118.1, 120.9, 122.4, 123.0, 124.2, 126.6,
(300 MHz, DMSO-d6):
(m, 2H), 8.11 (d, J¼7.8 Hz, 1H), 8.26 (d, J¼1.5 Hz, 1H), 8.30 (s, 1H),
11.59 (br s, 1H). 13C NMR (75 MHz, DMSO-d6):
d¼2.45 (s, 3H), 7.16e7.21 (m, 1H), 7.39e7.48
129.3, 138.9, 148.0, 151.4, 168.0. HRMS (EI): m/z [M]þ (calcd for
15H14N2O2: 254.1055; found: 254.1056).
C
d
¼18.2, 111.3, 115.1,
119.3, 120.3, 121.2, 123.6, 126.5, 128.6, 139.3, 146.7, 150.7. HRMS (EI):
4.4.8. 1-(3-Methyl-9H-pyrido[2,3-b]indol-6-yl)ethanone (1h). The
title compound was prepared from 7h (1.0 g), according to the
general procedure. Yield: 84% (0.6 g). Off-white solid. Mp
m/z [M]þ (calcd for C12H10N2: 182.0841; found: 182.0844.).
4.4.2. 8-Methyl-11H-benzo[g]pyrido[2,3-b]indole (1b). The title
compound was prepared from 7b (500 mg), according to the gen-
eral procedure. Yield: 87% (322 mg). Yellow solid. Mp
287.6e290.6 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼2.48 (s, 3H), 2.67
(s, 3H), 7.55 (d, J¼8.5 Hz, 1H), 8.07 (dd, J¼8.5, 1.9 Hz, 1H), 8.22e8.42
(m, 1H), 8.51 (dd, J¼1.9, 0.6 Hz, 1H), 8.86 (d, J¼1.9 Hz, 1H), 12.14 (s,
301.1e303.5 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d¼2.50 (s, 3H), 7.58
1H). 13C NMR (125 MHz, DMSO-d6):
d
¼18.0, 26.5, 111.0, 115.7, 120.0,
(ddd, J¼8.2, 6.8, 1.4 Hz, 1H), 7.64 (td, J¼7.5, 1.4 Hz, 1h), 7.67 (d,
J¼8.5 Hz, 1H), 8.04 (d, J¼7.9 Hz, 1H), 8.19 (d, J¼8.5 Hz, 1H), 8.33 (d,
J¼2.2 Hz, 1H), 8.38 (dd, J¼1.9, 0.6 Hz, 1H), 8.60 (d, J¼7.6 Hz, 1H),
122.9, 124.6, 126.7, 129.0, 129.6, 142.1, 146.5, 150.6,196.9. HRMS (EI):
m/z [M]þ (calcd for C14H12N2O: 224.0950; found: 224.0948).
12.64 (br s, 1H). 13C NMR (125 MHz, DMSO-d6):
d
¼18.1, 114.9, 115.6,
4.4.9. 3-Methyl-9H-pyrido[2,3-b]indole-6-carbonitrile (1j). The title
compound was prepared from 7j (1.0 g), according to the general
119.66, 119.69, 121.2, 122.2, 124.1, 125.6, 127.9, 128.5, 132.2, 135.0,

5556
M. Mineno et al. / Tetrahedron 70 (2014) 5550e5557
procedure. Yield: 99% (0.7 g). Pale yellow solid. Mp 285.6e288.6 ꢀC.
1H NMR (500 MHz, DMSO-d6):
References and notes
d¼2.47 (s, 3H), 7.62 (d, J¼8.5 Hz, 1H),
1. Kim, J.-S.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron Lett. 1997,
38, 3431.
7.80 (dd, J¼8.4, 1.7 Hz, 1H), 8.37e8.40 (m, 1H), 8.41e8.48 (m, 1H),
8.69 (d, J¼1.9 Hz, 1H), 12.27 (br s, 1H). 13C NMR (125 MHz, DMSO-
2. (a) Sharaf, M. H. M.; Schiff, P. L., Jr.; Tackie, A. N.; Phoebe, C. H., Jr.; Martin, G. E. J.
Heterocycl. Chem. 1996, 33, 239; (b) Cimanga, K.; De Bruyne, T.; Pieters, L.;
Claeys, M.; Vlietinck, A. Tetrahedron Lett. 1989, 37, 1703.
3. Moquin-Patey, C.; Guyot, M. Tetrahedron 1989, 45, 3445.
4. (a) Stolc, S. Life Sci. 1999, 65, 1943; (b) Bolton, D.; Forbes, I. T.; Hayward, C. J.;
Piper, D. C.; Thomas, D. R.; Thompson, M.; Upton, N. Bioorg. Med. Chem. Lett.
1993, 3, 1941.
5. Okamoto, T.; Akase, T.; Izumi, S.; Inaba, S.; Yamamoto, H. Japanese Patent
7,220,196; Chem. Abstr. 1972, 77, 152142.
6. Winters, J.; Di Mola, N. West German Patent 2,442,513; Chem. Abstr. 1975, 82,
156255.
7. (a) Sennhenn, P.; Mantoulidis, A.; Treu, M.; Tontsch-Grunt, U.; Spevak, W.;
d6):
d
¼18.0, 101.0, 112.2, 114.2, 120.2, 120.4, 125.0, 126.3, 129.4,
129.5, 141.2, 148.0, 150.8. HRMS (EI): m/z [M]þ (calcd for C13H9N3:
207.0796; found: 207.0789).
4.4.10. 3,8-Dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]
indole-7-carboxamide (1k). The title compound was prepared from
7k (250 mg), according to the general procedure. Yield: 65%
(130 mg). White solid. Mp 335.8e336.8 ꢀC. 1H NMR (500 MHz,
DMSO-d6):
d
¼1.58 (d, J¼8.8 Hz, 2H), 1.84 (d, J¼11.3 Hz, 2H), 2.00 (t,
€
McConnell, D.; Schoop, A.; Bruckner, R.; Jacobi, A.; Guertler, U.; Schnapp, G.;
J¼10.9 Hz, 2H), 2.20 (s, 3H), 2.49 (s, 3H), 2.58 (s, 3H), 2.79 (d,
J¼11.0 Hz, 2H), 3.77 (br s, 1H), 7.17 (d, J¼7.6 Hz, 1H), 8.00 (d,
J¼7.9 Hz, 1H), 8.20 (d, J¼7.8 Hz, 1H), 8.35 (d, J¼9.7 Hz, 1H), 11.7 (s,
Klein, C.; Himmelsbach, F.; Pautsch, A.; Betzemeier, B.; Herfurth, L.; Mack, J.;
Wiedenmayer, D.; Bader, G.; Reiser, U. WO 2,006,131,552; Chem. Abstr. 2006,
146, 62695. (b) Hudkins, R. L. WO 2,001,014,380.
8. (a) Joseph, B.; Meijer, L.; Liger, F. WO 2,006,040,451; Chem. Abstr. 2006, 144,
390900. (b) Joseph, J.; Laurent, M.; Liger, F. French Patent 2,876,377, 2006.
9. Ganmbacortipasserini, C.; Mologni, L.; Scapozza, L.; Ahmed, S.; Goekjian, P. G.;
Gueyrard, D.; Popowycz, F.; Joseph, B.; Schneider, C.; Garcia, P. WO
2,010,025,872.
1H). 13C NMR (125 MHz, DMSO-d6):
d
¼14.0, 17.8, 28.8, 31.3, 45.8,
54.2, 113.7, 117.7, 118.0, 118.3, 121.0, 123.6, 124.1, 125.1, 128.6, 140.2,
151.0, 167.8. HRMS (EI): m/z [M]þ (calcd for C20H24N4O: 336.1950;
found: 336.1954).
10. (a) Laha, J. K.; Barolo, S. M.; Rossi, R. A.; Cuny, G. D. J. Org. Chem. 2011, 76, 6421;
(b) Clark, V. M.; Cox, A.; Herbert, E. J. J. Chem. Soc. C 1968, 831.
11. Selected recent works: (a) Schneider, C.; Gueyrard, D.; Popowycz, F.; Joseph, B.;
Goekjian, P. G. Synlett 2007, 2237; (b) Vera-Luque, P.; Alajarín, R.; Alvarez-Builla,
4.4.11. 8-Bromo-3-methyl-9H-pyrido[2,3-b]indole (1m). The title
compound was prepared from 7m (500 mg), according to the
general procedure. Yield: 15% (90 mg). Yellow solid. Mp 389.0 ꢀC
ꢀ
J.; Vaquero, J. J. Org. Lett. 2006, 8, 415; (c) Kaczmarek, L.; Preczynska-Czoch, W.;
ꢀ
Osaidacz, J.; Mordarski, M.; Sokalski, W. A.; Boratynski, J.; Marcinkowska, E.;
dec. 1H NMR (500 MHz, DMSO-d6):
d
¼2.47 (s, 3H), 7.16 (t, J¼7.7 Hz,
1H), 7.65 (d, J¼6.9 Hz, 1H), 8.15 (d, J¼7.3 Hz, 1H), 8.32e8.40 (m, 2H),
11.93 (br s, 1H). 13C NMR (125 MHz, DMSO-d6):
ꢀ
Glazman-Kusnierczyk, H.; Radzikowski, C. Bioorg. Med. Chem. 1999, 7, 2457; (d)
ꢀ
ꢀ
Peczynska-Czoch, W.; Pognan, F.; Kaczmarek, q.; Boratynski, J. J. Med. Chem.
1994, 37, 3503; (e) Mahta, L. K.; Parrick, J.; Payne, F. J. Chem. Soc., Perkin Trans. 1
1993, 1261.
d
¼18.0, 103.7, 115.1,
12. (a) Aubriot, S.; Nicolle, E.; Lattier, M.; Morel, C.; Cao, W.; Daniel, K. W.; Collins,
S.; Leclerc, G.; Faure, P. Bioorg. Med. Chem. Lett. 2002, 12, 209; (b) Rocca, P.;
Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron 1993, 49, 49; (c) Achab, S.;
Guyot, M.; Potier, P. Tetrahedron Lett. 1993, 54, 2127.
120.3, 120.6, 122.0, 124.5, 128.9, 129.1, 137.7, 147.5, 150.6. HRMS (EI):
m/z [M]þ (calcd for C12H9BrN2: 259.9949; found: 259.9940).
ꢀ
ꢀ
13. (a) Pudlo, M.; Csanyi, D.; Moreau, F.; Hajos, G.; Riedl, Z.; Sapi, J. Tetrahedron
2007, 63, 10320; (b) Smith, P. A. S.; Boyer, J. H. J. Am. Chem. Soc. 1951, 73, 2626.
14. (a) Smitrovich, J. H.; Davies, I. W. Org. Lett. 2004, 6, 533; (b) Bunyan, P. J.; Ca-
dogan, J. I. G. J. Chem. Soc. 1963, 42.
4.4.12. 5-Chloro-8-methoxy-3-methyl-9H-pyrido[2,3-b]
indole
(1n). The title compound was prepared from 7n (3.0 g), accord-
ing to the general procedure. Yield: 55% (1.25 g). White solid. Mp
299.5e301.5 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
¼2.48 (s, 3H),
15. Okuda, S.; Robinson, M. M. J. Am. Chem. Soc. 1959, 81, 740.
16. (a) Chavan, N. L.; Nayak, S. K.; Kusurkar, R. S. Tetrahedron 2010, 66, 1827; (b)
3.98 (s, 3H), 7.05 (d, J¼8.5 Hz, 1H), 7.17 (d, J¼8.5 Hz, 1H), 8.35 (d,
^
^
Joseph, B.; Costa, H. D.; MeAroura, J. Y.; LeAonceb, S. Tetrahedron 2000, 56, 3189;
(c) Tahri, A.; Buysens, K. J.; Van der Eycken, E. V.; Vandenberghe, D. M.;
Hoornaert, G. J. Tetrahedron 1998, 54, 13211; (d) Bonser, R. W.; Slater, M. J.;
Cockerill, G. S.; WO 96,004,906; Chem. Abstr. 1996, 125, 19022. (e) Slater, M. J.;
Cockerill, G. S.; Robinson, J. E. WO 95,007,910; Chem. Abstr. 1995, 123, 256682.
17. Liger, F.; Popowycz, F.; Besson, T.; Picot, L.; Galmarini, C. M.; Joseph, B. Bioorg.
Med. Chem. 2007, 15, 5615.
J¼1.7 Hz, 1H), 8.50 (d, J¼1.7 Hz, 1H), 12.11 (br s, 1H). 13C NMR
(75 MHz, DMSO-d6):
d
¼18.2, 56.1, 108.1, 114.1, 117.9, 119.2, 119.6,
124.3, 129.9, 130.2, 144.9, 147.5, 150.1. MS: m/z¼247 [MþH]þ.
Anal. Calcd for C13H11N2OCl: C, 63.29; H, 4.49; N, 11.36; Cl, 14.37.
found: C, 63.21; H, 4.26; N, 11.44; Cl, 14.37.
18. (a) Kumar, A. S.; Rao, P. V. A.; Nagarajan, R. Org. Biomol. Chem. 2012, 10, 5084; (b)
Gupta, S.; Kumar, B.; Kundu, B. J. Org. Chem. 2011, 76, 10154; (c) Sharma, S. K.;
Gupta, S.; Saifuddin, M.; Mandadapu, A. K.; Agarwal, P. K.; Gauniyal, H. M.;
Kundu, B. Tetrahedron Lett. 2011, 52, 65; (d) Kumar, A. S.; Nagarajan, R. Org. Lett.
2011, 13, 1398; (e) Iaroshenko, V. O.; Groth, U.; Kryvokhyzha, N. V.; Obeid, S.;
Tolmachev, A. A. Synlett 2008, 343; (f) Borini, C.; Funicello, M.; Spagnolo, P.
Synlett 2006, 1574; (g) Erba, E.; Gelmi, M. L.; Pocar, D. Tetrahedron 2000, 56,
9991; (h) Choshi, T.; Yamada, S.; Sugino, E.; Kuwada, T.; Hibino, S. Synlett 1995,
147; (i) Choshi, T.; Yamada, S.; Sugino, E.; Kuwada, T.; Hibino, S. J. Org. Chem.
1995, 60, 5899; (j) Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1995, 36,
2615; (k) Levacber, V.; Bowsad, N.; Dupas, G.; Bourguignon, J.; Queguiner, G.
Tetrahedron 1992, 831; (l) Morina, P.; Alajarın, M.; Vidal, A.; Sanchez-Andrada, P.
J. Org. Chem. 1992, 57, 929; (m) Morina, P.; Fresneda, P. M. Synthesis 1989, 878.
19. (a) Markey, S. J.; Lewis, W.; Moody, C. J. Org. Lett. 2013, 15, 6306; (b) Portela-
Cubillo, F.; Surgenor, B. A.; Aitken, R. A.; Walton, J. C. J. Org. Chem. 2008, 73,
8124; (c) Portella-Cubillo, F.; Scott, J. S.; Walton, J. C. Chem. Commun. 2007,
4041; (d) Tanaka, K.; Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2005, 78,
1659; (e) Ono, A.; Narasaka, K. Chem. Lett. 2001, 146; (f) Beccalli, E. M.; Clerici, F.;
Marchesini, A. Tetrahedron 2001, 57, 4787; (g) Braun, O.; Patra, P. K.; Junjappa, H.
Tetrahedron Lett. 1999, 40, 3797; (h) Abouabdellah, A.; Dodd, R. H. Tetrahedron
Lett. 1998, 39, 2119.
4.4.13. Ethyl 3-methyl-9H-pyrido[2,3-b]indole-7-carboxylate
(1p). The title compound was prepared from telescoped 7p,
according to the general procedure (6.4 g, two steps total: 47%).
Yellow solid. Mp 304.2e306.0 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼1.37 (t, J¼7.1 Hz, 3H), 2.47 (s, 3H), 4.37 (q, J¼6.9 Hz, 2H), 7.81 (dd,
J¼8.2, 1.6 Hz, 1H), 8.10 (d, J¼1.0 Hz, 1H), 8.23 (d, J¼8.2 Hz, 1H), 8.37
(s, 1H), 8.41 (s, 1H), 11.92 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
d
¼14.2, 18.0, 60.7, 112.3, 114.2, 119.7, 121.0, 123.9, 124.3, 127.3, 129.5,
138.4, 148.3, 151.4, 166.1. HRMS (EI): m/z [M]þ (calcd for
15H14N2O2: 254.1055; found: 254.1054).
ꢁ
ꢀ
C
4.4.14. (3-Methyl-9H-pyrido[2,3-b]indol-8-yl)methanol
(1q). The
title compound was prepared from 7q (300 mg), according to the
general procedure. Yield: 88% (192 mg). Yellow solid. Mp
226.1e229.8 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼2.46 (s, 3H), 4.86
20. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 1505.
21. Mizuno, M.; Mizufune, H.; Sera, M.; Mineno, M.; Ueda, T. WO 2,008,016,184;
Chem. Abstr. 2008, 148, 239178.
(d, J¼5.7 Hz, 2H), 5.23 (t, J¼5.8 Hz, 1H), 7.19 (d, J¼7.6 Hz, 1H),
7.33e7.54 (m, 1H), 8.01 (d, J¼7.6 Hz, 1H), 8.28 (d, J¼2.5 Hz, 1H), 8.31
(d, J¼2.5 Hz, 1H), 11.48 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
ꢀ
22. (a) Baelen, G. V.; Meyers, C.; Lemiere, G. L. F.; Hostyn, S.; Dommisse, R.; Maes,
L.; Augustyns, K.; Haemers, A.; Pieters, L.; Maes, B. U. W. Tetrahedron 2008, 64,
11802; (b) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 581.
d
¼18.0, 59.6, 115.0, 119.0, 119.4, 120.0, 123.5, 124.3, 125.5, 128.3,
136.6, 146.4, 150.7. HRMS (EI): m/z [M]þ (calcd for C13H12N2O:
212.0950; found: 212.0947).
23. (a) Ackermann, L.; Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1; (b) Parisien,
M.; Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578; (c) Zhang, Y.-M.; Razler,
T.; Jackson, P. F. Tetrahedron Lett. 2002, 43, 8235; (d) Hennings, D. D.; Iwasa, S.;
Rawal, V. H. J. Org. Chem. 1997, 2, 2.
Acknowledgements
24. Hennessy, E.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084.
25. Littke, A.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
We thank Dr. David Cork for helpful discussions.

M. Mineno et al. / Tetrahedron 70 (2014) 5550e5557
5557
26. Lautens, M.; Fang, Y. B. Org. Lett. 2003, 5, 3679.
27. After our patent publication (Ref. 21), some examples of Pd mediated direct
CeH arylation with DBU have been reported. (a) Laha, J. K.; Petrou, P.; Cuny, G.
30. A combination effect between the other base and DCHBP has not been evalu-
ated, and is considered to be a next research area.
31. Application of one-pot procedure and employment of arylbromide as a sub-
strate for the sequence have not been investigated yet, which could be a next
target.
ꢀ
D. J. Org. Chem. 2009, 74, 3152; (b) Hostyn, S.; Baelen, G. V.; Lemiere, G. L. F.;
Maes, B. U. W. Adv. Synth. Catal. 2008, 350, 2653.
28. For the review see: Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,107,174.
29. Some examples using o-biphenyl-based triarylphosphines in intramolecular
direct CeH arylation have been reported: (a) Garcia-Cudrado, D.; de Mendoza,
P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129,
6880; (b) Lafrance, M.; Blaquiere, N.; Fagnou, K. Eur. J. Org. Chem. 2007, 81; (c)
Garcia-Cudrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem.
Soc. 2006, 128, 1066; (d) Campeau, L.-C.; Parisien, M.; Fagnou, K. J. Am. Chem.
Soc. 2004, 126, 9186.
32. Selected reviews see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400; (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
33. Filipski, K. J.; Kohrt, J. T.; Casimiro-Garcia, A.; Huis, C. A.; Dudley, D. A.; Cody, W.
L.; Bigge, C. F.; Desiraju, S.; Sun, S.; Maiti, S. N.; Jaber, M. R.; Edmunds, J. J.
Tetrahedron Lett. 2006, 47, 7677.
34. For a pioneering work: Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8742.