Efficient access to β- and γ-carbolines from a common starting material by sequential site-selective Pd-catalyzed C–C, C–N coupling reactions

Article abstract of DOI:10.1016/j.tet.2019.130569

Two efficient and practical approaches are reported for the synthesis of β- and γ-carboline derivatives from 3,4-dibromopyridine as a common starting material. The β-carbolines were prepared by site-selective Pd-catalyzed C–C coupling with o-bromophenylboronic acid and subsequent cyclization by double C–N coupling with amines. γ-Carbolines were prepared from the same starting material by C–N coupling with anilines and subsequent annulation by domino C–C/C–N coupling with o-bromophenylboronic acid.

Full text of DOI:10.1016/j.tet.2019.130569

Tetrahedron 75 (2019) 130569
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Tetrahedron
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Efficient access to b- and g-carbolines from a common starting
material by sequential site-selective Pd-catalyzed CeC, CeN coupling
reactions
Tran Quang Hung a **, Do Trung Hieu c, Dinh Van Tinh d, Ha Nam Do c,
, b,
,
, f
Tuan Anh Nguyen Tien c h, Dang Van Do c, Le Thanh Son c, Ngoc Han Tran e
,
,
, ***
Nguyen Van Tuyen a b, Vu Minh Tan g, Peter Ehlers h, Tuan Thanh Dang c
,
, i, *
Peter Langer h
a Institute of Chemistry Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet Str., Nghia Do, Cau Giay, Hanoi, Vietnam
b Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet Str., Nghia Do, Cau Giay, Hanoi, Vietnam
c Faculty of Chemistry, VNU-University of Science, 19 Le Thanh Tong, Hanoi, Vietnam
d University of Languages and International Studies, Vietnam National University, 1-Pham Van Dong Str., Cau Giay, Ha Noi, Vietnam
e Institute of Research and Development, Duy Tan University, Da Nang 550000, Vietnam
f NUS Environmental Research Institute, National University of Singapore, 5A Engineering Drive 1, T-Lab Building, Singapore, 117411, Singapore
g Hanoi University of Industry, 298 Cau Dien Street, Bac Tu Liem District, Hanoi, Vietnam
h
€
Institut für Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059, Rostock, Germany
i
€
Leibniz Institut für Katalyse an der Universitat Rostock (e.V.), Albert-Einstein-Str. 29a, 18059, Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Two efficient and practical approaches are reported for the synthesis of b- and g-carboline derivatives
Received 21 June 2019
Received in revised form
23 August 2019
Accepted 25 August 2019
Available online 29 August 2019
from 3,4-dibromopyridine as a common starting material. The
selective Pd-catalyzed CeC coupling with o-bromophenylboronic acid and subsequent cyclization by
double CeN coupling with amines. -Carbolines were prepared from the same starting material by CeN
coupling with anilines and subsequent annulation by domino CeC/CeN coupling with o-bromophe-
nylboronic acid.
b-carbolines were prepared by site-
g
© 2019 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Catalysis
Palladium
Cyclizations
Regioselectivity
Carbolines
1. Introduction
molecules [1]. Among the four different carboline derivatives,
especially b-carbolines are popularly present in nature [2]. Since
Carbolines (pyridoindoles) are present in the core structure of
many important natural products and pharmaceutically active
the first isolation of Eudistomin A from Eudistoma olivaceum in
1984, a variety of related Eudistomin alkaloids (BeW) have been
isolated (Fig. 1) [2,3]. In 1986, Manzamine A, an interesting natural
alkaloid containing a b-carboline structure, was isolated from the
€
* Corresponding author. Institut für Chemie, Universitat Rostock, Albert-Einstein-
Str. 3a, 18059, Rostock, Germany.
Okinawa sponge genus Haliclona [4]. Until now, more than 80
Manzamine alkaloids were obtained from other marine sponge
species [2].
Especially, the well-known canthine alkaloids containing a b-
carboline core structure were isolated from various plants (Ruta-
ceae, Simaroubaceae, Amaranthaceae, Caryophyllaceae families)
** Corresponding author. Institute of Chemistry Vietnam Academy of Science and
Technology, 18-Hoang Quoc Viet Str., Nghia Do, Cau Giay, Hanoi, Vietnam.
*** Corresponding author. Faculty of Chemistry, VNU University of Science, 19 Le
Thanh Tong, Hanoi, Vietnam.
E-mail addresses: hungtq@gmail.com (T.Q. Hung), thanhtuandang@hotmail.com
(T.T. Dang), peter.langer@uni-rostock.de (P. Langer).
and marine organisms [2]. Natural
b-carbolines showed a wide
URL: http://www.vast.ac.vn/, http://hus.vnu.edu.vn/en
https://doi.org/10.1016/j.tet.2019.130569
0040-4020/© 2019 Elsevier Ltd. All rights reserved.

2
T.Q. Hung et al. / Tetrahedron 75 (2019) 130569
Fig. 1. Natural alkaloids and bioactive compounds containing b-carboline and g-carboline cores.
range of pharmacological properties as, for example, anti-cancer,
anti-inflammatory, anti-Alzheimer, antimalarial, anti-HIV, and
proceed under mild conditions. In 2015, Shu et al. described an
elegant Au-catalyzed synthesis of 3-amino-
-carbolines via [4 þ 2]
cycloaddition of azides and ynamides [16]. In 2017, Ye and co-
workers also developed a similar synthesis of 3-amino- -carbo-
lines by gold-catalyzed intermolecular reaction of ynamides with
3-indolyl azides [17]. Both - and -carbolines could also be pre-
b
antibacterial activities [1,2]. On the other hand, the
b-carboline
moiety is also present in many important synthetic drugs, such as
ZK91296 and ZK93426 (anxiogenic drug candidates) or Abecamil
(anxiolytic drug) (Fig. 1) [5].
b
b
g
In comparison to
b
-carbolines, the
g
-carboline core structure is
pared by Ru and Rh-catalyzed [2þ2þ2] cycloadditions [18].
Recently, an interesting synthesis of carboline derivatives by Cu-
catalyzed arene-ynamide cyclization has been developed [19].
Numerous efforts have been made to use palladium catalysts for the
less abundant in natural products [6]. A typical natural alkaloid,
Ingenine B, was isolated from an indonesian sponge which showed
high cytotoxicity against the murine lymphoma cancer cell [7].
Isocanthine and its derivatives are another family of alkaloids
synthesis of b- and g-carbolines. Since the first research on the
possessing interesting bioactivities [8]. The
also appears in synthetic compounds which exhibit a wide range of
biological properties, such as activity as anti-Alzheimer agents, BET
g
-carboline structure
synthesis of carboline derivatives by combination of Pd-catalyzed
amination and intramolecular arylation reactions [20], a series of
Pd-catalyzed syntheses of carbolines have been developed. Repre-
sentative examples include Pd-catalyzed iminoannulations of al-
kynes [21], Pd-catalyzed CeN coupling/CeH activation reactions of
anilines and halopyridines [22], the Pd-catalyzed imidoylative
cyclization of tryptophan-derived isocyanides with aryl iodides
inhibitors, and DNA intercalators [9]. b-Carbolines and g-carbolines
have also found many applications in the field of material sciences
[10]. For example, carbolines CzCb1-3 show interesting photo-
physical properties, as well as device performances (Fig. 2) [11].
Among them, CzCb2 exhibited both high quantum efficiency of
deep blue PHOLEDs. Recently, a series of potential organic materials
with interesting physical properties (P1eP144) were prepared and
evaluated by HOMO-LUMO calculations [10].
Due to the importance of b- and g-carboline derivatives, the
development of new synthetic methods to access these structures
has gained increasing attention [12]. Classic methods for the syn-
[23], Pd-catalyzed synthesis of b-carbolines based on a-arylation of
ketones with 3-bromoindoles [24], Pd-catalyzed ring expansion of
azidoalcohols [25], and Pd-catalyzed cyclization of vinylindoles
[26]. In 2016, the Ramasastry group reported unprecedented ex-
amples of relay catalysis through the sequential use of silver, bis-
muth, and palladium catalysts to prepare a series of functionalized
b-carbolines [27]. Recently, Liao et al. developed an interesting
thesis of
Bischler-Napieralski [14], and Pictet-Spengler [15] reactions.
Recently, efficient syntheses of functionalized - and -carbolines
by transition metal catalyzed reactions have been developed which
b
-,
g
-carbolines are based on the Graebe-Ullmann [13],
process for the efficient synthesis of both - and -carbolines via
b
g
redox-free Pd-catalyzed CeH addition of indoles to nitriles/cycli-
zation sequences [28]. Interestingly, Verma et al. described a metal-
free regioselective hydration of o-alkynylaldehydes, then the
b
g
Fig. 2. Organic materials containing b- and g-carbolines.

T.Q. Hung et al. / Tetrahedron 75 (2019) 130569
3
second cyclocondensation with ammonium acetate to form
g
-car-
by single-crystal X-ray diffraction (Fig. 4) [32].
bolines in very good yields [29]. Previous carboline syntheses often
give regioisomeric mixtures or require many synthetic steps for the
preparation of the starting materials. In fact, g-carbolines are not
readily available and only a few methods for their synthesis have
been reported so far. In recent years, we and others reported the
Double Pd-catalyzed cyclizations of 3a with diamines 6a and 6b
were next studied. The desired dicarbolines 7a and 7b were ob-
tained in 45% and 43% yields, respectively. It is worth to mention,
that product 7b represents a novel aza-analogue of PHOLED ma-
terial CxCb2.
synthesis of various heterocycles, including
a- and
d-carbolines,
The application of our methodology to the synthesis of g-car-
based on site-selective Suzuki and Buchwald-Hartwig reactions
[30,31].
bolines was studied next. We predicted that the CeN coupling of
3,4-dibromopyridine (1a) with amines may occur regioselectively
at the 4-position of pyridine ring due to the lower electron density.
In fact, the reaction of 1a with aniline successfully gave product 8a
in 72% yield using Pd(OAc)2/PPh3. The reaction of 8a with o-
Herein, we report two new strategies for the synthesis of
b- and
g
-carbolines. -Carbolines were prepared by regioselective Suzuki
b
reactions of 3,4-dibromopyridine with o-bromophenylboronic acid
and subsequent cyclization by double Buchwald-Hartwig reaction
(bromo)phenylboronic acid (2) directly afforded the desired g-
with amines.
g
-Carbolines were prepared from the same starting
carboline 9a in 57% yield. The reaction was carried out in the
presence of Pd(PPh3)4 (5%), Pd2dba3 (5%) and SPhos (10 mol%). The
formation of the product presumably proceeds by initial Suzuki
reaction to give intermediate A and subsequent Pd-catalyzed
material, 3,4-dibromopyridine, by a reversed order of coupling re-
actions, i.e. first CeN coupling with anilines and subsequent cycli-
zation by domino CeC/CeN coupling with o-bromophenylboronic
acid. Therefore, from a methodology viewpoint, we believe that the
present work represents a significant extension of our previous
work in this field. In addition, we believe that, from a preparative
intramolecular cyclization. Other
g-carboline derivatives (9b-e)
were successfully prepared using our developed procedure.
viewpoint, the approach to b- and g-carbolines reported herein is
more convenient and efficient in comparison to other methods in
3. Conclusions
terms of yield, selectivity and availability of starting materials.
In conclusion, we have developed a practical two-step synthesis
of b- and g-carbolines from commercially available chemicals. The
2. Results and discussion
two developed strategies are based on sequential Pd-catalyzed site-
selective SuzukieMiyaura and CeN coupling reactions of 3,4-
dibromopyridine with o-bromophenylboronic acid and amines.
The site-selective Suzuki-Miyaura reaction of commercially
available 3,4-dibromopyridine 1a with 1.2 equivalents of o-(bromo)
phenylboronic acid 2 in the use of 5 mol-% of Pd(PPh3)4 resulted in
formation of intermediate 3a in 89% yield. The subsequent two-fold
Buchwald-Hartwig reaction of 3a with a series of amines 4 gave the
4. Experimental section
desired
Scheme 2).
Our initial optimizations started with Pd-catalyzed cyclization
b
-carbolines 5 in good to excellent yields (Scheme 1) (see
4.1. Procedure for the synthesis of 3-bromo-4-(2-bromophenyl)
pyridine
of 3a with 3,5-dimethoxyaniline 5c (Table 1). Several parameters,
including the palladium source, ligand, solvent and temperature,
were examined in detail. The screening of different monodentate
phosphine ligands, for example, Xphos, SPhos, PCy3, and P(t-Bu)3
gave 5c, albeit, in only moderate yields (entries 6e11). In order to
examine the effect of bidentate ligands in this cyclization, we
studied BINAP, XantPhos, DpePhos, Dppf, and Dppe. Indeed, the
yield of the desired product was improved. Up to 97% were ach-
ieved when Dppf was used as the ligand in combination with
Pd2(dba)3. The use of Pd(OAc)2 as the palladium source resulted in a
lower yield (55%). During the screening of the conditions, we also
figured out that toluene proved to be the most suitable solvent for
the success of this cyclization (see Fig. 3).
Pd(PPh3)4 (244 mg, 0.211 mmol, 0.05 equiv.), was added to a
pressure tube containing 3,4-dibromopyridine (1 g, 4.22 mmol, 1
equiv.) and o-bromophenylboronic acid (848 mg, 4.22 mmol, 1
equiv.) under argon. The tube was backfilled with argon several
times. The degassed THF (35 mL), 1 M aqueous K2CO3 (25 mL) and
10% aqueous KOH (5 drops) was added under argon. The reaction
mixture was backfilled with argon several times, then refluxed for
24 h. After cooling, the reaction mixture was diluted with
dichloromethane (60 mL), and the resulting mixture was filtered
through a pad of Celite, which was washed three times with
dichloromethane (40 mL). The filtrate was concentrated in vacuo.
The crude product was purified by flash chromatography (silica gel;
hexane/ethyl acetate, 5:1) to yield 3 (1.176 g, 89%) as colorless oil. 1H
With our optimized conditions in hand, we explored the sub-
strate scope of this cyclization using different amines (Table 2). The
desired b-carboline derivatives were isolated in 62e95% yields (5a-
NMR (500 MHz, Chloroform-d)
d
8.84 (s,1H), 8.59 (d, J ¼ 4.9 Hz,1H),
7.68 (dd, J ¼ 8.1, 1.2 Hz, 1H), 7.44e7.37 (m, 1H), 7.30 (td, J ¼ 7.8,
1.8 Hz, 1H), 7.22e7.17 (m, 2H); 13C NMR (126 MHz, Chloroform-d)
o). Both aromatic and aliphatic amines could be successfully
employed (5h-o). The structure of 5c was independently confirmed
d
152.20, 149.49, 148.14, 139.33, 132.93, 130.25, 130.19, 127.42,
125.64, 122.20, 121.97.
Scheme 1. Synthesis of b-carbolines. Conditions: i) 2 (1.2 equiv.), Pd(PPh3)4 (5 mol-%), 1 M K2CO3 (25 mL), 10% KOH (5 drops), tetrahydrofuran (THF) (35 mL), reflux, 24 h; ii) 4 (3
equiv.), NaOtBu (6 equiv.), Pd2(dba)3 (5 mol-%; dba ¼ dibenzylideneacetone), ligand 10% of 1,1-bis(diphenylphosphino)ferrocene (dppf); toluene, 110 ꢀC, 7 h.

4
T.Q. Hung et al. / Tetrahedron 75 (2019) 130569
Scheme 2. Synthesis of bis-b-carbolines.
Table 1
Optimization for the synthesis of 9-(3,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indole.
Entry
Catalyst
Ligand
Base
Solvent
Yield (%)a
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
BINAP
BINAP
XantPhos
DpePhos
Dppf
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
55
75
85
78
97
26
43
24
11
46
31
dppe
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
CsCO3
9
10
11
NaOtBu
NaOtBu
NaOtBu
1,4-dioxane
DMF
a
Yields were calculated based on 1H NMR using 1,4-dioxane as internal standard.
4.2. General procedure A for the synthesis of N-substituted 9H-
pyrido [3,4-b]indole as exemplified by the preparation of 5-phenyl-
9H-pyrido [3,4-b]indole
hexane/ethyl acetate, 5:1) to yield 5a (72 mg, 92%) as a white solid;
m.p. 127e129 ꢀC. 1H NMR (500 MHz, Chloroform-d)
8.85 (s, 1H),
d
8.52 (d, J ¼ 5.3 Hz, 1H), 8.20 (dt, J ¼ 7.9, 1.0 Hz, 1H), 8.02 (dd, J ¼ 5.3,
1.1 Hz,1H), 7.67e7.62 (m, 2H), 7.62e7.57 (m, 2H), 7.57e7.45 (m, 3H),
7.35 (ddd, J ¼ 7.9, 7.0, 1.0 Hz, 1H); 13C NMR (126 MHz, Chloroform-d)
Aniline (89 mg, 0.958 mmol, 3 equiv.) was added to a pressure
tube that was charged with 3-bromo-4-(2-bromophenyl)pyridine 3
d 141.65, 139.92, 136.84, 133.22, 130.13, 128.96, 128.60, 128.04,
(100 mg, 0.319
equiv.), dppf (18 mg, 32
m
mol, 1 equiv.), Pd2(dba)3 (15 mg, 16
m
mol, 0.05
126.88, 121.80, 121.59, 120.63, 114.49, 110.56; GCeMS (EI, 70 eV): m/
z (%) ¼ 244 (100), 216 (4), 122 (9); HRMS (EI): calcd. for C17H12N2
[M]þ 244.09950, found 244.09915.
mmol, 0.1 equiv.) and sodium tert-butoxide
(184 mg, 1.917 mmol, 6 equiv.) under argon. The tube was backfilled
with argon several times. The degassed anhydrous toluene (5 mL)
was added under argon. The reaction mixture then heated at 110 ꢀC
for 12 h. After cooling, the reaction mixture was diluted with
dichloromethane (10 mL), and the resulting mixture was filtered
through a pad of Celite, which was washed three times with
dichloromethane (30 mL). The filtrate was concentrated in vacuo.
The crude product was purified by flash chromatography (silica gel;
4.2.1. 9-(4-butylphenyl)-9H-pyrido[3,4-b]indole 5b
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 4-n-butylaniline (143 mg, 0.958 mmol) gave a
crude product, which was purified by flash chromatography (silica
gel; heptanes/ethyl acetate, 5:1) to yield 5b (68 mg, 71%) as a white
solid; m.p. 112e114 ꢀC; 1H NMR (500 MHz, Chloroform-d)
d 8.82 (s,

T.Q. Hung et al. / Tetrahedron 75 (2019) 130569
5
Table 2
Synthesis of b-carbolines (5 a-o).
5
R
Time (hours)
Yield (%)a
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Ph
14
14
14
14
14
14
14
8
8
8
8
8
92
71
95
93
88
60
63
88
85
87
82
76
83
92
62
4-nBuC6H4
3,5-(MeO)2C6H3
3,4-(MeO)2C6H3
2,4-(MeO)2C6H3
4-FC6H4
4-CF3C6H4
Bn
4-Me(C6H4)CH2
4-(MeO)C6H4CH2
4-F(C6H4)CH2
3,4-F2(C6H3)CH2
3-F3C(C6H4)CH2
PhCH2CH2
8
8
8
Cyclopentyl
a
Yields of the isolated products.
Table 3
Synthesis of g
-carbolines (9 a-e), Conditions: i) 3a (1 equiv.), 4 (1 equiv.), Pd(OAc)2 (5%), PPh3 (10%), NaOtBu (3 equiv.), Toluene,110 ꢀC, 5h; ii) Pd(PPh3)4 (5%), Pd2dba3 (5%), SPhos
(10 mol%), K3PO4 (3 equiv.), 1,4-dioxane/H2O (5/1 vol).
4
R
8 (%)a
9 (%)a
a
b
c
d
e
Ph
72
65
74
68
67
57
52
55
57
51
4-nBuC6H4
4-(MeO)C6H4
4-FC6H4
4-(F3C)C6H4
a
Yields of isolated products.

6
T.Q. Hung et al. / Tetrahedron 75 (2019) 130569
Fig. 3. Structure of bidentate ligands.
137.37, 133.17, 129.48, 128.70, 128.60, 121.79, 121.32, 120.46, 119.41,
114.50, 111.94, 110.55, 110.47, 56.21, 56.18; GCeMS (EI, 70 eV): m/z
(%) ¼ 304 (100), 261 (28), 164 (14); HRMS (ESI): calcd. for
C19H16O2N2 [Mþ1]þ 305.12845, found 305.1271.
4.2.4. 9-(2,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indole 5e
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 2,4-dimethoxyaniline (147 mg, 0.958 mmol) gave
a crude product, which was purified by flash chromatography
(silica gel; heptanes/ethyl acetate, 2:1) to yield 5e (86 mg, 88%) as a
white solid; m.p. 193e195 ꢀC; 1H NMR (500 MHz, Chloroform-d)
d
8.55 (d, J ¼ 1.1 Hz, 1H), 8.47 (d, J ¼ 5.2 Hz, 1H), 8.16 (dt, J ¼ 7.8,
1.0 Hz, 1H), 7.98 (dd, J ¼ 5.3, 1.1 Hz, 1H), 7.49 (ddd, J ¼ 8.3, 7.1, 1.2 Hz,
1H), 7.35 (d, J ¼ 8.5 Hz, 1H), 7.32e7.23 (m, 1H), 7.20 (dt, J ¼ 8.3,
0.9 Hz, 1H), 6.71 (d, J ¼ 2.6 Hz, 1H), 6.66 (dd, J ¼ 8.6, 2.7 Hz, 1H), 3.91
(s, 3H), 3.66 (s, 3H); 13C NMR (126 MHz, Chloroform-d)
d 161.12,
Fig. 4. X-ray single-crystal structure of compound 5c.
156.79, 142.38, 139.30, 137.54, 133.66, 130.12, 128.56, 128.26, 121.60,
121.31, 120.08, 117.78, 114.42, 110.80, 105.02, 100.11, 55.70, 55.68;
GCeMS (EI, 70 eV): m/z (%) ¼ 304 (100), 289 (16), 274 (10); HRMS
(EI): calcd. for C19H16O2N2 [M]þ 304.12063, found 304.12040.
1H), 8.50 (d, J ¼ 5.2 Hz, 1H), 8.18 (d, J ¼ 7.9 Hz, 1H), 8.00 (d,
J ¼ 5.2 Hz, 1H), 7.56e7.49 (m, 1H), 7.49e7.43 (m, 3H), 7.41 (d,
J ¼ 8.3 Hz, 2H), 7.32 (t, J ¼ 7.4 Hz, 1H), 2.74 (t, J ¼ 7.8 Hz, 2H),
1.76e1.66 (m, 2H), 1.44 (dt, J ¼ 14.7, 7.4 Hz, 2H), 0.99 (t, J ¼ 7.4 Hz,
4.2.5. 9-(4-fluorophenyl)-9H-pyrido[3,4-b]indole 5f
3H); 13C NMR (126 MHz, Chloroform-d)
d 143.04, 141.82, 139.63,
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 4-fluoroaniline (107 mg, 0.958 mmol) gave a
crude product, which was purified by flash chromatography (silica
gel; heptanes/ethyl acetate, 5:1) to yield 5f (69 mg, 82%) as a white
solid; m.p. 127e129 ꢀC; 1H NMR (500 MHz, Chloroform-d)
137.13, 134.23, 133.24, 130.01, 128.86, 128.53, 126.65, 121.76, 121.45,
120.47,114.48,110.65, 35.39, 33.55, 22.43, 13.98; GCeMS (EI, 70 eV):
m/z (%) ¼ 300 (92), 257 (100), 242 (5); HRMS (EI): calcd. for
C
21H20N2 [M]þ 300.16210, found 300.16171.
d
8.78e8.75 (m, 1H), 8.51 (d, J ¼ 5.3 Hz, 1H), 8.17 (dt, J ¼ 7.9, 1.0 Hz,
1H), 7.98 (dd, J ¼ 5.2, 1.1 Hz, 1H), 7.57e7.49 (m, 3H), 7.41e7.35 (m,
1H), 7.35e7.27 (m, 3H); 13C NMR (126 MHz, Chloroform-d)
161.94
4.2.2. 9-(3,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indole 5c
d
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 3,5-dimethoxyaniline (147 mg, 0.958 mmol) gave
a crude product, which was purified by flash chromatography
(silica gel; heptanes/ethyl acetate, 2:1) to yield 5c (92 mg, 95%) as a
white solid; m.p. 160e161 ꢀC; 1H NMR (500 MHz, Chloroform-d)
(d, J ¼ 248.4 Hz), 141.77, 140.08, 137.14, 132.96, 132.73, 128.92,
128.82, 128.74 (d, J ¼ 4.3 Hz), 121.87, 121.54, 120.75, 117.16 (d,
J ¼ 22.9 Hz), 114.53, 110.30; GCeMS (EI, 70 eV): m/z (%) ¼ 262 (100),
234 (4), 131 (10); HRMS (EI): calcd. for C17H11N2F1 [M]þ 262.09008,
found 262.08976.
d
8.92 (s,1H), 8.51 (d, J ¼ 5.3 Hz,1H), 8.16 (d, J ¼ 7.9 Hz,1H), 7.98 (dd,
J ¼ 5.2, 1.1 Hz, 1H), 7.57e7.49 (m, 2H), 7.32 (ddd, J ¼ 7.9, 5.9, 2.1 Hz,
1H), 6.72 (d, J ¼ 2.3 Hz, 2H), 6.58 (t, J ¼ 2.3 Hz, 1H), 3.83 (s, 6H); 13
C
4.2.6. 9-(4-(trifluoromethyl)phenyl)-9H-pyrido [3,4-b]indole 5g
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 4-(trifluoromethyl)aniline (154 mg, 0.958 mmol)
gave a crude product, which was purified by flash chromatography
(silica gel; heptanes/ethyl acetate, 5:1) to yield 5g (63 mg, 63%) as a
white solid; m.p. 135e138 ꢀC; 1H NMR (500 MHz, Chloroform-d)
NMR (126 MHz, Chloroform-d)
d 161.89, 141.46, 139.88, 138.43,
136.84, 133.44, 128.98, 128.64, 121.77, 121.58, 120.65, 114.48, 110.86,
105.00, 100.17, 55.65; GCeMS (EI, 70 eV): m/z (%) ¼ 304 (100), 261
(5), 245 (7); HRMS (EI): calcd. for C19H16O2N2 [M]þ 304.12063,
found 304.12152.
d
8.88 (s, 1H), 8.56 (d, J ¼ 5.2 Hz, 1H), 8.21 (dt, J ¼ 8.0, 1.0 Hz, 1H),
8.02 (dd, J ¼ 5.2, 1.1 Hz, 1H), 7.94e7.89 (m, 2H), 7.75 (d, J ¼ 8.2 Hz,
2H), 7.58 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H), 7.51 (dt, J ¼ 8.4, 1.0 Hz, 1H),
7.39 (ddd, J ¼ 7.9, 7.0, 1.0 Hz, 1H); 13C NMR (126 MHz, Chloroform-d)
4.2.3. 9-(3,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indole 5d
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 3,4-dimethoxyaniline (147 mg, 0.958 mmol) gave
a crude product, which was purified by flash chromatography
(silica gel; heptanes/ethyl acetate, 2:1) to yield 5d (90 mg, 93%) as a
white solid; m.p. 116e117 ꢀC; 1H NMR (500 MHz, Chloroform-d)
d
141.09, 140.61, 140.21, 132.89, 129.90 (d, J ¼ 32.9 Hz), 129.49,
128.95, 127.41 (q, J ¼ 3.7 Hz), 126.88, 123.79 (d, J ¼ 272.3 Hz), 122.01,
121.98, 121.30, 114.65, 110.33; GCeMS (EI, 70 eV): m/z (%) ¼ 312
(100), 189 (14), 69 (20); HRMS (ESI): calcd. for C18H11F3N2 [Mþ1]þ
313.09471, found 313.0927.
d
8.82e8.78 (m, 1H), 8.50 (d, J ¼ 5.3 Hz, 1H), 8.17 (dt, J ¼ 7.9, 1.0 Hz,
1H), 7.98 (dd, J ¼ 5.2, 1.1 Hz, 1H), 7.53 (ddd, J ¼ 8.3, 7.0, 1.2 Hz, 1H),
7.42 (d, J ¼ 8.2 Hz, 1H), 7.32 (td, J ¼ 7.5, 7.0, 1.0 Hz, 1H), 7.11 (dd,
J ¼ 8.4, 2.3 Hz, 1H), 7.09e7.01 (m, 2H), 3.98 (s, 3H), 3.88 (s, 3H); 13
C
4.2.7. 9-Benzyl-9H-pyrido[3,4-b]indole 5h
NMR (126 MHz, Chloroform-d)
d
150.11, 148.95, 142.07, 139.64,
Following general procedure A and using compound 3 (100 mg,

T.Q. Hung et al. / Tetrahedron 75 (2019) 130569
7
0.319 mmol) and benzylamine (103 mg, 0.958 mmol) gave a crude
product, which was purified by flash chromatography (silica gel;
heptanes/ethyl acetate, 4:1) to yield 5h (73 mg, 88%) as a white
white solid; m.p. 113e115 ꢀC; 1H NMR (500 MHz, Chloroform-d)
d
8.80 (d, J ¼ 1.1 Hz, 1H), 8.50 (d, J ¼ 5.2 Hz, 1H), 8.17 (dt, J ¼ 7.9,
1.0 Hz, 1H), 7.98 (dd, J ¼ 5.3, 1.1 Hz, 1H), 7.57 (ddd, J ¼ 8.3, 7.1, 1.2 Hz,
1H), 7.38 (dd, J ¼ 8.4, 1.0 Hz, 1H), 7.32 (ddd, J ¼ 7.9, 7.1, 0.9 Hz, 1H),
7.06 (dt, J ¼ 10.0, 8.2 Hz, 1H), 6.96e6.84 (m, 2H), 5.50 (d, J ¼ 1.2 Hz,
solid; m.p. 129e131 ꢀC; 1H NMR (500 MHz, Chloroform-d)
d 8.83 (d,
J ¼ 1.1 Hz, 1H), 8.47 (d, J ¼ 5.2 Hz, 1H), 8.14 (dt, J ¼ 7.8, 0.9 Hz, 1H),
7.95 (dd, J ¼ 5.2, 1.1 Hz, 1H), 7.53 (ddd, J ¼ 8.3, 7.1, 1.2 Hz, 1H), 7.41 (d,
J ¼ 8.3 Hz, 1H), 7.31e7.25 (m, 1H), 7.23 (td, J ¼ 5.7, 2.8 Hz, 3H),
7.15e7.10 (m, 2H), 5.51 (s, 2H); 13C NMR (126 MHz, Chloroform-d)
2H); 13C NMR (126 MHz, Chloroform-d)
d
151.29 (dd, J ¼ 93.0,
12.8 Hz), 149.30 (dd, J ¼ 91.8, 12.7 Hz), 141.15, 139.71, 136.48,
133.52e133.33 (m), 132.03, 128.79, 128.77, 122.43 (dd, J ¼ 6.6,
3.7 Hz), 122.11, 121.43, 120.33, 117.86 (d, J ¼ 17.5 Hz), 115.55 (d,
J ¼ 17.8 Hz), 114.71, 109.44, 45.97; GCeMS (EI, 70 eV): m/z (%) ¼ 294
(71), 127 (100), 101 (6); HRMS (EI): calcd. for C18H12N2F2 [M]þ
294.09631, found 294.09604.
d
141.44, 139.35, 136.73, 136.46, 132.38, 128.95, 128.60, 128.56,
127.85, 126.51, 121.95, 121.32, 119.98, 114.59, 109.74, 46.94; GCeMS
(EI, 70 eV): m/z (%) ¼ 258 (79), 91 (100), 65 (10); HRMS (EI): calcd.
for C18H14N2 [M]þ 258.11515, found 258.11508.
4.2.8. 9-(4-methylbenzyl)-9H-pyrido[3,4-b]indole 5i
4.2.12. 9-(3-(trifluoromethyl)benzyl)-9H-pyrido[3,4-b]indole 5n
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 4-(trifluoromethyl)benzylamine (168 mg,
0.958 mmol) gave a crude product, which was purified by flash
chromatography (silica gel; heptanes/ethyl acetate, 4:1) to yield 5n
(87 mg, 83%) as a white solid; m.p. 123e125 ꢀC; 1H NMR (500 MHz,
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 4-methylbenzylamine (116 mg, 0.958 mmol) gave
a crude product, which was purified by flash chromatography
(silica gel; heptanes/ethyl acetate, 4:1) to yield 5i (74 mg, 85%) as a
white solid; m.p. 128e129 ꢀC; 1H NMR (500 MHz, Chloroform-d)
d
8.85 (s, 1H), 8.48 (s, 1H), 8.17 (dt, J ¼ 7.9, 1.0 Hz, 1H), 7.98 (d,
Chloroform-d)
d
8.82 (s, 1H), 8.51 (d, J ¼ 5.2 Hz, 1H), 8.20 (dt, J ¼ 7.8,
J ¼ 5.1 Hz, 1H), 7.56 (ddd, J ¼ 8.3, 7.1, 1.2 Hz, 1H), 7.48e7.42 (m, 1H),
7.30 (ddd, J ¼ 8.0, 7.1, 0.9 Hz, 1H), 7.10e7.03 (m, 4H), 5.54 (s, 2H),
1.0 Hz, 1H), 8.03e7.99 (m, 1H), 7.59 (ddd, J ¼ 8.3, 7.1, 1.2 Hz, 1H), 7.53
(d, J ¼ 8.6 Hz, 2H), 7.44e7.30 (m, 2H), 7.26 (s, 1H), 7.24e7.19 (m, 1H),
2.29 (s, 3H); 13C NMR (126 MHz, Chloroform-d)
d
141.46, 139.22,
5.63 (s, 2H); 13C NMR (126 MHz, Chloroform-d)
d 141.28, 139.70,
137.59, 133.39, 132.39, 129.60, 128.58, 128.51, 126.50, 121.91, 121.30,
119.89, 109.77, 46.79, 21.04; GCeMS (EI, 70 eV): m/z (%) ¼ 272 (65),
105 (100), 77 (10); HRMS (EI): calcd. for C19H16N2 [M]þ 272.13080,
found 272.13101.
137.54, 132.03, 129.61, 128.85, 128.80, 124.87, 124.84, 123.32, 123.29,
122.12, 121.46, 120.34, 114.74, 109.47, 46.60; GCeMS (EI, 70 eV): m/z
(%) ¼ 326 (100), 167 (14), 159 (72), 140 (14), 109 (11); HRMS (EI):
calcd. for C19H13N2F3 [M]þ 326.10253, found 326.10178.
4.2.9. 9-(4-methoxybenzyl)-9H-pyrido[3,4-b]indole 5j
4.2.13. 9-Phenethyl-9H-pyrido[3,4-b]indole 5ꢀ
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 4-methoxybenzylamine (131 mg, 0.958 mmol)
gave a crude product, which was purified by flash chromatography
(silica gel; heptanes/ethyl acetate, 4:1) to yield 5j (80 mg, 87%) as a
white solid; m.p. 152e155 ꢀC; 1H NMR (500 MHz, Chloroform-d)
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and phenylethylenamine (116 mg, 0.958 mmol) gave a
crude product, which was purified by flash chromatography (silica
gel; heptanes/ethyl acetate, 4:1) to yield 5o (80 mg, 92%) as a white
solid; m.p. 80e83 ꢀC; 1H NMR (500 MHz, Chloroform-d)
d 8.72 (d,
d
8.83 (d, J ¼ 1.0 Hz, 1H), 8.45 (d, J ¼ 5.3 Hz, 1H), 8.12 (dt, J ¼ 7.9,
J ¼ 2.4 Hz, 1H), 8.41 (dd, J ¼ 5.2, 2.6 Hz, 1H), 8.12 (dd, J ¼ 7.8, 2.5 Hz,
1H), 7.92 (dd, J ¼ 5.2, 2.3 Hz, 1H), 7.53 (tdd, J ¼ 7.0, 2.9, 1.5 Hz, 1H),
7.36 (dd, J ¼ 8.5, 2.6 Hz, 1H), 7.29e7.14 (m, 4H), 7.11e7.05 (m, 2H),
4.60 (td, J ¼ 7.3, 2.6 Hz, 2H), 3.16 (td, J ¼ 7.3, 2.6 Hz, 2H); 13C NMR
1.0 Hz, 1H), 7.93 (dd, J ¼ 5.2, 1.1 Hz, 1H), 7.53 (ddd, J ¼ 8.4, 7.2, 1.2 Hz,
1H), 7.42 (d, J ¼ 8.3 Hz, 1H), 7.27 (dd, J ¼ 15.0, 0.9 Hz, 1H), 7.09e7.04
(m, 2H), 6.79e6.73 (m, 2H), 5.44 (s, 2H), 3.69 (s, 3H); 13C NMR
(126 MHz, Chloroform-d)
d
159.15, 141.28, 139.12, 136.57, 132.31,
(126 MHz, Chloroform-d) d 140.86, 138.74, 138.03, 136.24, 131.88,
128.46, 128.40, 128.37, 127.76, 121.81, 121.19, 119.79, 114.46, 114.23,
109.66, 55.15, 46.34; GCeMS (EI, 70 eV): m/z (%) ¼ 288 (26), 121
(100), 77 (6); HRMS (EI): calcd. for C19H16O1N2 [M]þ 288.12571,
found 288.12538.
128.45, 128.42, 128.10, 128.03, 126.59, 121.56, 121.00, 119.44, 114.11,
109.22, 44.98, 35.17; GCeMS (EI, 70 eV): m/z (%) ¼ 272 (24), 181
(100), 127 (12); HRMS (EI): calcd. for C19H16N2 [M]þ 272.13080,
found 272.13112.
4.2.10. 9-(4-fluorobenzyl)-9H-pyrido[3,4-b]indole 5k
4.2.14. 9-Cyclopentyl-9H-pyrido [3,4-b]indole 5p
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 4-fluorobenzylamine (120 mg, 0.958 mmol)gave a
crude product, which was purified by flash chromatography (silica
gel; heptanes/ethyl acetate, 4:1) to yield 5k (72 mg, 82%) as a white
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and cyclopentylamine (82 mg, 0.958 mmol) gave a
crude product, which was purified by flash chromatography (silica
gel; heptanes/ethyl acetate, 4:1) to yield 5p (47 mg, 62%) as a
solid; m.p. 110e112 ꢀC; 1H NMR (500 MHz, Chloroform-d)
d
8.83 (s,
colorless oil; 1H NMR (500 MHz, Chloroform-d)
d 8.99e8.95 (m,
1H), 8.48 (d, J ¼ 5.2 Hz, 1H), 8.18 (d, J ¼ 7.8 Hz, 1H), 7.99 (d,
J ¼ 5.2 Hz, 1H), 7.57 (ddd, J ¼ 8.3, 7.0, 1.2 Hz, 1H), 7.43 (d, J ¼ 8.3 Hz,
1H), 7.32 (t, J ¼ 7.5 Hz, 1H), 7.13 (dd, J ¼ 8.6, 5.3 Hz, 2H), 7.00e6.93
1H), 8.44 (d, J ¼ 5.2 Hz, 1H), 8.15 (dt, J ¼ 7.9, 1.0 Hz, 1H), 7.97 (dd,
J ¼ 5.2, 1.1 Hz, 1H), 7.58 (dd, J ¼ 8.4, 1.3 Hz, 1H), 7.56e7.51 (m, 1H),
7.30e7.24 (m, 1H), 5.19 (p, J ¼ 9.0 Hz, 1H), 2.35 (qd, J ¼ 8.5, 3.9 Hz,
2H), 2.24e2.17 (m, 2H), 2.12 (tq, J ¼ 6.5, 1.9 Hz, 2H), 1.91e1.84 (m,
(m, 2H), 5.54 (s, 2H); 13C NMR (126 MHz, Chloroform-d)
d 162.35 (d,
J ¼ 246.5 Hz), 141.31, 139.39, 132.14, 132.12, 128.74, 128.66, 128.17 (d,
J ¼ 8.1 Hz), 122.03, 121.36, 120.13, 115.91 (d, J ¼ 21.8 Hz), 114.69,
109.61, 46.32; GCeMS (EI, 70 eV): m/z (%) ¼ 276 (53), 109 (100), 83
(9); HRMS (EI): calcd. for C18H13N2F1 [M]þ 276.10573, found
276.10573.
2H); 13C NMR (126 MHz, Chloroform-d)
d 140.70, 138.48, 135.74,
133.00, 128.91, 128.05, 121.87, 121.45, 119.37, 114.60, 110.48, 56.17,
29.68, 25.24; GCeMS (EI, 70 eV): m/z (%) ¼ 236 (59), 207 (22), 168
(100), 140 (12); HRMS (EI): calcd. for C16H16N2 [M]þ 236.13080,
found 236.13071.
4.2.11. 9-(3,4-difluorobenzyl)-9H-pyrido[3,4-b]indole 5l
4.3. Procedure B for the synthesis of dicarboline substituted product
as exemplified by the preparation of 4,40-bis(9H-pyrido [3,4-b]indol-
9-yl)-1,10-biphenyl
Following general procedure A and using compound 3 (100 mg,
0.319 mmol) and 3,4-difluorobenzylamine (137 mg, 0.958 mmol)
gave a crude product, which was purified by flash chromatography
(silica gel; heptanes/ethyl acetate, 4:1) to yield 5l (67 mg, 76%) as a
Benzidine (53.5 mg, 0.290 mmol, 1 equiv.) was added to a

8
T.Q. Hung et al. / Tetrahedron 75 (2019) 130569
pressure tube that was charged with 3-bromo-4-(2-bromophenyl)
pyridine 3 (200 mg, 0.639 mol, 2.2 equiv.), Pd2(dba)3 (13 mg,
15 mol, 0.05 equiv.), dppf (16 mg, 29 mol, 0.1 equiv.) and sodium
Chloroform-d) d 151.46, 148.77, 148.50, 140.58, 135.93, 129.63,
123.83, 108.09, 107.67, 35.11, 33.58, 22.31, 13.94.
m
m
m
tert-butoxide (279 mg, 2.900 mmol, 10 equiv.) under argon. The
tube was backfilled with argon several times. The degassed anhy-
drous toluene (10 mL) was added under argon. The reaction
mixture then heated at 110 ꢀC for 24 h. After cooling, the reaction
mixture was diluted with dichloromethane (10 mL), and the
resulting mixture was filtered through a pad of Celite, which was
washed three times with dichloromethane (30 mL). The filtrate was
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel; hexane/ethyl acetate, 3:1) to yield 7a
(64 mg, 45%) as a white solid; m.p. 214-126 ꢀC. 1H NMR (500 MHz,
4.4.2. 3-Bromo-N-(4-methoxyphenyl)pyridin-4-amine 8c
Following general procedure C and using compound 1 (200 mg,
0.844 mmol) and p-anisidine (114 mg, 0.929 mmol) gave a crude
product, which was purified by flash chromatography (silica gel;
heptanes/ethyl acetate, 4:1) to yield 8c (174 mg, 74%) as a colorless
oil; 1H NMR (500 MHz, Chloroform-d)
d 8.17e8.12 (m, 1H),
7.77e7.71 (m, 2H), 7.51e7.45 (m, 1H), 7.33e7.31 (m, 1H), 7.26 (s, 1H),
7.10 (ddd, J ¼ 9.4, 6.6, 1.3 Hz, 1H), 6.70 (td, J ¼ 6.8, 1.0 Hz, 1H), 1.00 (s,
3H); 13C NMR (126 MHz, Chloroform-d)
d 134.11, 129.90, 126.43,
123.78, 122.41, 120.95, 119.66, 118.46, 110.87, 35.36.
Chloroform-d)
d
8.95 (s, 2H), 8.56 (d, J ¼ 5.3 Hz, 2H), 8.26e8.20 (m,
2H), 8.04 (dd, J ¼ 5.2, 1.1 Hz, 2H), 7.98e7.93 (m, 4H), 7.77e7.71 (m,
4.4.3. 5-(4-fluorophenyl)-5H-pyrido [4,3-b]indole 8d
4H), 7.62e7.57 (m, 4H), 7.42e7.36 (m, 2H); 13C NMR (126 MHz,
Following general procedure C and using compound 1 (200 mg,
0.844 mmol) and 4-fluoroaniline (103 mg, 0.929 mmol) gave a
crude product, which was purified by flash chromatography (silica
gel; heptanes/ethyl acetate, 5:1) to yield 8d (153 mg, 68%) as a
Chloroform-d)
d 141.58, 140.06, 139.71, 136.95, 136.50, 133.17,
129.20, 128.83, 128.76, 127.28, 121.92, 121.74, 120.85, 114.60, 110.62;
HRMS (ESI): calcd. for C34H22N4 [Mþ1]þ 487.19172, found 487.1894.
colorless oil; 1H NMR (500 MHz, Chloroform-d)
d
8.52 (s, 1H), 8.17
(s, 1H), 7.24e7.18 (m, 2H), 7.14e7.08 (m, 2H), 6.74 (s, 1H), 6.44 (s,
1H); 13C NMR (126 MHz, Chloroform-d)
4.3.1. 2,6-bis(9H-pyrido [3,4-b]indol-9-yl)pyridine 7b
Following general procedure B and using 2,6-diaminopyridine
(47 mg, 0.426 mmol) and 3-bromo-4-(2-bromophenyl)pyridine 3
d
160.58 (d, J ¼ 246.1 Hz),
151.48, 148.81, 148.59, 134.28, 129.78, 126.26 (d, J ¼ 8.1 Hz), 116.66
(200 mg, 0.639 mmol, 2.2 equiv.), gave a crude product, which was
(d, J ¼ 22.8 Hz).
purified by flash chromatography (silica gel; heptanes/ethyl ace-
tate, 2:1) to yield 7b (75 mg, 43%) as a white solid; m.p.
4.4.4. 3-Bromo-N-(4-(trifluoromethyl)phenyl)pyridin-4-amine 8e
Following general procedure C and using compound 1 (200 mg,
0.844 mmol) and 4-(trifluoromethyl)aniline (150 mg, 0.929 mmol)
gave a crude product, which was purified by flash chromatography
(silica gel; heptanes/ethyl acetate, 5:1) to yield 8e (179 mg, 6867%)
254e256 ꢀC; 1H NMR (500 MHz, Chloroform-d)
d 8.95 (s, 2H), 8.56
(d, J ¼ 5.3 Hz, 2H), 8.26e8.20 (m, 2H), 8.04 (dd, J ¼ 5.2, 1.1 Hz, 2H),
7.97e7.94 (m, 3H), 7.75e7.73 (m, 2H), 7.60e7.59 (m, 2H), 7.38 (td,
J ¼ 5.3, 2.8 Hz, 2H); 13C NMR (126 MHz, Chloroform-d)
d 141.58,
140.06, 139.71, 136.95, 136.50, 133.17, 129.20, 128.83, 127.28, 121.92,
121.74, 120.85, 114.60, 110.62; HRMS (ESI): calcd. for C27H17N5
[Mþ1]þ 412.15567, found 412.1543.
as a colorless oil; 1H NMR (500 MHz, Chloroform-d)
d 8.56 (s, 1H),
8.23 (d, J ¼ 5.7 Hz, 1H), 7.66 (d, J ¼ 8.4 Hz, 2H), 7.33 (d, J ¼ 8.3 Hz,
2H), 7.07 (d, J ¼ 5.6 Hz, 1H), 6.64 (s, 1H); 13C NMR (126 MHz, Chlo-
roform-d)
d
165.03, 152.01, 149.01, 131.24, 127.02 (d, J ¼ 3.8 Hz),
4.4. General procedure C for the synthesis of N-substituted 3-
bromo-pyridin-4-amine as exemplified by the preparation of 3-
bromo-N-phenylpyridin-4-amine
126.68 (d, J ¼ 33.1 Hz), 123.96 (d, J ¼ 271.7 Hz), 121.60, 120.74, 28.22.
4.5. General procedure D for the synthesis of N-substituted 5H-
pyrido [4,3-b]indoles as exemplified by the preparation of 5-phenyl-
5H-pyrido [4,3-b]indole
Aniline (86 mg, 0.929 mmol, 1.1 equiv.) was added to a pressure
tube that was charged with 3,4-dibromopyridine 1 (200 mg,
0.844 mmol, 1 equiv.), Pd(OAc)2 (9 mg, 42
m
mol, 0.05 equiv.), PPh3
3-bromo-N-phenylpyridin-4-amine 8a (124 mg, 0.498 mmol, 1
equiv.) was added to a pressure tube that was charged with o-
(22 mg, 84 mol, 0.1 equiv.) and sodium tert-butoxide (243 mg,
m
2.53 mmol, 3 equiv.) under argon. The tube was backfilled with
argon several times. The degassed anhydrous toluene (7 mL) was
added under argon. The reaction mixture then heated at 110 ꢀC for
5 h. After cooling, the reaction mixture was diluted with dichloro-
methane (10 mL), and the resulting mixture was filtered through a
pad of Celite, which was washed three times with dichloromethane
(30 mL). The filtrate was concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel; hexane/ethyl ac-
etate, 10:1) to yield 8a (151 mg, 72%) as a colorless oil; 1H NMR
bromophenylboronic acid (100 mg, 0.498 mmol,
Pd(PPh3)4 (29 mg, 25 mol, 0.05 equiv.), Pd2(dba)3 (23 mg, 25
0.05 equiv.), SPhos (20 mg, 50 mol, 0.1 equiv.) and Tripotassium
1
equiv.),
m
mmol,
m
phosphate (317 mg, 1.494 mmol, 3 equiv.) under argon. The tube
was backfilled with argon several times. The degassed 1,4-dioxane
(5 mL) and distilled water (1 mL) was added under argon. The re-
action mixture then heated at 110 ꢀC overnight. After cooling, the
reaction mixture was diluted with dichloromethane (10 mL), and
the resulting mixture was filtered through a pad of Celite, which
was washed three times with dichloromethane (30 mL). The filtrate
was concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel; hexane/ethyl acetate, 5:1) to yield 9a
(69 mg, 57%) as a white solid; m.p. 131e134 ꢀC; 1H NMR (500 MHz,
(500 MHz, Chloroform-d)
7.44e7.37 (m, 2H), 7.28e7.19 (m, 3H), 6.91 (d, J ¼ 5.7 Hz,1H), 6.52 (s,
1H); 13C NMR (126 MHz, Chloroform-d)
151.54, 148.79, 148.11,
138.47, 129.76, 125.54, 123.44, 108.39, 107.78.
d
8.48 (s, 1H), 8.13 (d, J ¼ 5.7 Hz, 1H),
d
Chloroform-d)
d
9.38 (d, J ¼ 1.1 Hz, 1H), 8.51 (d, J ¼ 5.8 Hz, 1H), 8.21
4.4.1. 3-Bromo-N-(4-butylphenyl)pyridin-4-amine 8b
(dt, J ¼ 7.8, 1.0 Hz, 1H), 7.67e7.60 (m, 2H), 7.55e7.51 (m, 3H),
7.48e7.46 (m, 1H), 7.43 (dt, J ¼ 8.3, 1.0 Hz, 1H), 7.38 (ddd, J ¼ 8.1, 7.0,
1.2 Hz, 1H), 7.29 (dd, J ¼ 5.8, 1.0 Hz, 1H); 13C NMR (126 MHz, Chlo-
Following general procedure C and using compound 1 (200 mg,
0.844 mmol) and n-butylaniline (139 mg, 0.929 mmol) gave a crude
product, which was purified by flash chromatography (silica gel;
heptanes/ethyl acetate, 4:1) to yield 8b (168 mg, 65%) as a colorless
roform-d)
d 145.22, 142.85, 141.01, 136.49, 130.13, 129.46, 128.28,
127.06, 126.86, 121.75, 121.44, 120.71, 120.15, 110.30, 105.06; HRMS
(ESI): calcd. for C17H12O1N2 [Mþ1]þ 245.10732, found 245.1065.
oil; 1H NMR (500 MHz, Chloroform-d)
d
8.44 (s, 1H), 8.09 (d,
J ¼ 5.7 Hz, 1H), 7.23e7.18 (m, 2H), 7.15e7.09 (m, 2H), 6.82 (d,
J ¼ 5.7 Hz, 1H), 6.48 (s, 1H), 2.65e2.58 (m, 2H), 1.65e1.58 (m, 2H),
1.41e1.33 (m, 2H), 0.94 (t, J ¼ 7.4 Hz, 3H); 13C NMR (126 MHz,
4.5.1. 5-(4-butylphenyl)-5H-pyrido[4,3-b]indole 9b
Following general procedure
D and using compound 8b

T.Q. Hung et al. / Tetrahedron 75 (2019) 130569
9
(152 mg, 0.498 mmol) and o-bromophenylboronic acid (100 mg,
Appendix A. Supplementary data
0.498 mmol) gave a crude product, which was purified by flash
chromatography (silica gel; heptanes/ethyl acetate, 5:1) to yield 9b
(78 mg, 52%) as a white solid; m.p. 111e113 ꢀC; 1H NMR (500 MHz,
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.130569.
Chloroform-d)
d
9.30 (s, 1H), 8.48e8.39 (m, 1H), 8.12 (dt, J ¼ 7.8,
1.0 Hz, 1H), 7.44e7.37 (m, 2H), 7.34 (s, 4H), 7.29 (ddd, J ¼ 8.0, 6.9,
1.2 Hz, 1H), 7.20 (d, J ¼ 5.7 Hz, 1H), 2.71e2.64 (m, 2H), 1.64 (tt,
J ¼ 9.1, 6.8 Hz, 2H), 1.41e1.33 (m, 2H), 0.92 (t, J ¼ 7.4 Hz, 3H); 13C
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4.5.2. 5-(4-methoxyphenyl)-5H-pyrido [4,3-b]indole 9c
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Chloroform-d)
d 9.30 (s, 1H), 8.43 (s, 1H), 8.13e8.08 (m, 1H), 7.37
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Chloroform-d)
d 159.43, 145.38, 141.44, 128.96, 128.24, 126.98,
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calcd. for C18H14O1N2 [Mþ1]þ 275.11789, found 275.0595.
4.5.3. 5-(4-fluorophenyl)-5H-pyrido[4,3-b]indole 9d
Following general procedure
D and using compound 8d
(133 mg, 0.498 mmol, 1 equiv.) and o-bromophenylboronic acid
(100 mg, 0.498 mmol) gave a crude product, which was purified by
flash chromatography (silica gel; heptanes/ethyl acetate, 5:1) to
yield 9d (74 mg, 57%) as a white solid; m.p. 135e138 ꢀC; 1H NMR
(500 MHz, Chloroform-d)
d
9.39 (s, 1H), 8.54 (d, J ¼ 5.8 Hz, 1H), 8.22
(dt, J ¼ 7.6,1.0 Hz,1H), 7.92 (d, J ¼ 8.3 Hz, 2H), 7.70 (d, J ¼ 8.2 Hz, 2H),
7.52e7.48 (m, 1H), 7.47e7.40 (m, 2H), 7.31 (dd, J ¼ 5.8, 1.0 Hz, 1H);
13C NMR (126 MHz, Chloroform-d)
d
149.98 (d, J ¼ 159.1 Hz),145.46,
144.61, 142.96, 140.44, 139.80, 129.47 (d, J ¼ 14.8 Hz), 127.41 (d,
J ¼ 3.9 Hz), 126.97, 122.06, 122.03, 120.95, 120.36 (d, J ¼ 17.4 Hz),
110.08, 104.88; HRMS (ESI): calcd. for
263.09790, found 263.0438.
C
17H11F1N2 [Mþ1]þ
4.5.4. 5-(4-(trifluoromethyl)phenyl)-5H-pyrido [4,3-b]indole 9e
Following general procedure and using compound 8e
D
(158 mg, 0.498 mmol, 1 equiv.) and o-bromophenylboronic acid
(100 mg, 0.498 mmol) gave a crude product, which was purified by
flash chromatography (silica gel; heptanes/ethyl acetate, 5:1) to
yield 9e (79 mg, 51%) as a white solid; m.p. 136e138 ꢀC; 1H NMR
(500 MHz, Chloroform-d)
d
9.40e9.37 (m, 1H), 8.52 (d, J ¼ 5.8 Hz,
1H), 8.22 (dt, J ¼ 7.8, 1.0 Hz, 1H), 7.54e7.47 (m, 3H), 7.42e7.39 (m,
1H), 7.39e7.36 (m, 1H), 7.36e7.31 (m, 2H), 7.24 (dd, J ¼ 5.8, 0.9 Hz,
1H); 13C NMR (126 MHz, Chloroform-d)
d
162.16 (d, J ¼ 249.0 Hz),
(b) T.Q. Hung, D.H. Hoang, N.N. Thang, T.T. Dang, K. Ayub, A. Villinger,
S. Lochbrunner, G.-U. Flechsig, P. Langer, Org. Biomol. Chem. 12 (2014) 6151;
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W. Breitsprecher, P. Langer, Org. Biomol. Chem. 13 (2015) 583;
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370;
145.23, 144.92, 142.55, 141.19, 132.30, 128.83 (d, J ¼ 8.6 Hz), 127.30,
121.68, 121.63, 120.84, 117.32, 117.14, 110.11, 104.92; HRMS (ESI):
calcd. for C18H11F3N2 [Mþ1]þ 313.09471, found 313.0281.
(e) I. Malik, Z. Ahmad, S. Reimann, M. Nawaz, T. Patonay, P. Langer, Synlett
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Biomol. Chem. 13 (2015) 1375;
Acknowledgments
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[32] CCDC 1908210, Contain supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via. www.ccdc.cam.ac.uk/data_request/cif.
Financial support by the Vietnam National Foundation for Sci-
ence and Technology Development (NAFOSTED, grant number
104.01-2015.81) is gratefully acknowledged.