Efficient synthesis of α- and δ-carbolines by sequential Pd-catalyzed site-selective C-C and twofold C-N coupling reactions

Article abstract of DOI:10.1039/c4ob02226b

Two concise and efficient approaches were developed for the synthesis of α- and δ-carboline derivatives. The success of the synthesis relies on site-selective Suzuki-Miyaura reactions of 1-chloro-2-bromopyridine or 2,3-dibromopyridine with 2-bromophenylbo

Full text of DOI:10.1039/c4ob02226b

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Efficient Synthesis of αꢀ and δꢀCarbolines by Sequential Pdꢀ
Catalyzed SiteꢀSelective CꢀC and Twofold CꢀN Coupling Reactions
Tran Quang Hung,a Tuan Thanh Dang,a,b* Julia Janke,a Alexander Villinger,a Peter Langera,c*
a Institut für Chemie, Universität Rostock, AlbertꢀEinsteinꢀStr. 3a, 18059 Rostock, Germany.
Fax: +49 381 4986412; Tel: +49 381 4986410
b Organic Chemistry. Institute of Chemical and Engineering Sciences, 8 Biomedical Grove, #07ꢀ
01 Neuros, Singapore 138665.
Eꢀmail: peter.langer@uniꢀrostock.de; eꢀmail: dang_tuan@ices.aꢀstar.edu.sg
c
Leibniz Institut für Katalyse an der Universität Rostock e. V. (LIKAT), AlbertꢀEinsteinꢀStr.
29a, 18059 Rostock, Germany.
ABSTRACT
Two concise and efficient approaches were developed for the synthesis of αꢀ and δꢀcarboline
derivatives. The success of the synthesis relies on siteꢀselective SuzukiꢀMiyaura reaction of 1ꢀ
chloroꢀ2ꢀbromopyridine or 2,3ꢀdibromopyridine with 2ꢀbromophenylboronic acid and
subsequent cyclization with amines which proceeds by twofold Pdꢀcatalyzed CꢀN coupling.
Graphical abstract:

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INTRODUCTION
Carbolines (pyridoindoles) are present in many natural products and synthetic bioactive
molecules.1 Among the class of carbolines, especially βꢀcarbolines and γꢀcarbolines are widely
spread in nature. A smaller number of αꢀcarbolines were also isolated as natural alkaloids.
Examples include the αꢀcarbolines grossularine 1 and 2, anticancer compounds isolated from
Dendrodoa grossularia,2 and mescengricin which represents an inhibitor of Lꢀglutamate
excitotoxicity isolated from Streptomyces griseoflavu.3 A few δꢀcarbolines have also been
isolated, for example, quindoline, cryptolepine, cryptoquindoline, cryptomisrine, and
jusbetonin.4 All of these alkaloids were isolated from Cryptolepis sanguinolenta and Justica
bentonica, which have been traditionally used for the treatment of malaria and several infectious
diseases in Central and West Africa.5 In the light of recent research in medicinal chemistry, αꢀ
and δꢀcarboline derivatives have shown important biological properties, such as antitumor,6
antimalarial,7 antimicrobial,8 antiviral,9 and antiꢀinflammatory10 activities. In the context of drug
discovery, implitapide, a potential drug containing an αꢀcarboline moiety, was used in clinical
trials for the treatment of atherosclerosis.11
Figure 1. Some bioactive compounds containing αꢀ and δꢀcarboline substructures.

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Carbolines not only find many important applications in medicinal chemistry, but also in
material sciences. For example, carbolines and their derivatives were commonly used as electron
transport unit in bipolar host materials.12 The replacement of the carbazole by a carboline unit
improved the electron carrier mobility.12 In 2013, Lee et al. synthesized CzBPCb and CbBPCb
which showed above 30% external quantum efficiency in blue phosphorescence organic light
emitting diodes.13 The trimer TATA showed a 200 times longer lifeꢀtime than the analogue
carrying three carbazole units.14
Figure 2. Some organic materials contain αꢀcarbolines structure.
Because of the importance of carbolines in both medicinal chemistry and material sciences,
many synthetic methods have been developed for the synthesis of carbolines. Classic methods to
prepare αꢀcarbolines have been reported, for examples, intramolecular DielsꢀAlder reactions,15
GraebeꢀUllmann reactions of triazoles,16 annulations of azaindoles17 and multiꢀcomponent
reactions.18 In 2011, Kumar and Nagarajan reported a twoꢀstep synthesis of αꢀcarbolines based
on the Pdꢀcatalyzed amidation of 3ꢀacetylꢀ2ꢀchloroindoles followed by a VilsmeierꢀHaack
reaction.19 Recently, some oneꢀpot syntheses based on Pdꢀcatalyzed aryl aminations and
subsequent intramolecular arylations were reported.20 In 2013, Moody et al. described a new
method for the synthesis of αꢀcarbolines by 6πꢀelectrocyclizations of indoleꢀ3ꢀalkenyl oximes.21

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Very recently, Yang et al. developed a convenient approach to αꢀcarbolines by a oneꢀpot tandem
reaction of α,βꢀunsaturated ketones with 2ꢀnitrophenylacetonitriles in the presence of zinc dust.22
In contrast to αꢀ, βꢀ, and γꢀcarbolines, only a few methods have been developed so far for the
synthesis of δꢀcarbolines. In 1997, Yang et al. converted αꢀ(oꢀbromoanilino)alkenenitriles to δꢀ
carboline derivatives by domino Pdꢀcatalyzed cyclizations.23 In their effort to access
functionalized δꢀcarbolines, Dupas et al. carried out cyclizations of indole amines with 1,3ꢀ
dicarbonyl compounds to afford 3,4ꢀdisubtituted δꢀcarbolines.24 During the synthesis of bioactive
analogues of Eudistomin D, Kobayashi and coworkers reported photocyclizations of Nꢀ(4ꢀ
methoxyꢀ3,5ꢀdimethylphenyl)pyridinꢀ3ꢀamine which gave mixtures of regioisomeric βꢀ and δ–
carbolines.25 In 2011, Ablordeppey et al. developed a short method for the formation of δꢀ
carboline derivatives in moderate yields by another Pdꢀcatalyzed intramolecular arylation of Nꢀ
arylꢀ3ꢀaminopyridine.26 Recently, Kundu et al. reported an efficient oneꢀpot multicomponent
reation using NꢀBocꢀ3ꢀamido indoles, aryl aldehydes and terminal alkynes under microwave
conditions which gave δꢀcarbolines in good yields.27 δꢀCarbolines could also be synthesized by
intramolecular reductive ring closure of 3ꢀnitroꢀ2ꢀphenylpyridines using phosphine reagents.28 In
2012, Detert’s group prepared δꢀcarboline in 6 steps starting from 2ꢀchloroꢀ3ꢀnitropyridine.29
Very recently, Cao et al. described an interesting synthesis of δꢀcarbolines by a Pdꢀcatalyzed
cascade reaction of 2ꢀiodoanilines and Nꢀtosylꢀenynamines.30 General methods, which allow to
access all four types of carbolines, have been reported, but still have limitations. Sakamoto and
coworkers developed the first Pdꢀcatalyzed intramolecular arylation of orthoꢀbromoꢀsubstituted
anilinopyridines which provided a very convenient and general method to prepare all four
regioisomeric carbolines in 31ꢀ61% yield.31 Recently, Cuny and coworkers reported a general
pathway to prepare selectively αꢀ, βꢀ, γꢀ, and δ–carbolines in good yields by photostimulated
cyclization of anilinohalopyridines.32
In fact, the reported synthetic methods are often complicated, low yielding or require many
synthetic steps to prepare the starting materials. Baumgartner and Lammertsma and their
coworkers reported the synthesis of phospholes by reaction of 2,3ꢀdibromobenzothiophene with
oꢀbromophenylboronic
acid
and
subsequent
base
mediated
cyclization
with
dichlorophosphanes.33a,b Nozaki and Chida and their coworkers reported the cyclization of

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dibromobiphenyls and related compounds with amines.33c,d Related transformations have also
been reported.33eꢀh We have previously reported the synthesis of diindolo[3,2ꢀb:4,5ꢀ
b’]thiophenes,33i indolo[2,3ꢀb]quinoxalines,33j and 5ꢀmethylꢀ5,10ꢀdihydroindolo[3,2ꢀb]indoles33k
based on the cyclization of oꢀbromophenylboronic acid with tetrabromothiophene and 2,3ꢀ
dibromoquinoxaline, and 2,3ꢀdibromoꢀ1ꢀmethylꢀ1Hꢀindole, respectively. Herein, we wish to
report a new and efficient twoꢀstep strategy for the chemoselective synthesis of αꢀ and δꢀ
carbolines from readily available starting materials. Our synthesis is based on what are, to the
best of our knowledge, the first siteꢀselective Suzuki reactions of oꢀbromophenylboronic acid
with 2,3ꢀdihalopyridines (1ꢀchloroꢀ2ꢀbromopyridine or 2,3ꢀdibromopyridine) and subsequent
twoꢀfold CꢀN coupling reactions.
RESULTS AND DISCUSSION
The chemoselective SuzukiꢀMiyaura reaction of commercially available 2ꢀchloroꢀ3ꢀ
bromopyridine (1a) with 1.2 equivalents of oꢀbromophenylboronic acid (2) in the presence of 5%
mol of Pd(PPh3)4 gave product 3a in 85% isolated yield. The reaction proceeded
chemoselectively at position 3 which is attached to the bromide atom which is a better leaving
group than chloride. The subsequent cyclization of 3a with various amines 4, by twoꢀfold Pdꢀ
catalyzed CꢀN coupling, resulted in formation of the desired αꢀcarbolines 5 (Scheme 1).
Scheme 1. Synthesis of of αꢀcarbolines. Conditions: (i) 1.2 equiv. of 2, 5.0 mol% of Pd(PPh3)4
catalyst, 3 equiv. of NaOH, THF, H2O, 70 ºC, 4h. (ii) 1.5 equiv. of 4, 3 equiv. of NaOtꢀBu, 5
mol% of Pd2(dba)3, ligand (method A: 10% of dppf, method B: 10% of dpePhos), toluene, 100
ºC, 7h.

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Our initial optimizations started with Pdꢀcatalyzed cyclization of 3a with tertꢀbutylaniline 5c
using 4ꢀnitroacetophenone as an internal standard (Table 1). Important factors including
palladium source, ligand, solvent and temperature were examined in detail. The screening of
different monodentate phosphine ligands, for example, Xphos, Xphos(tBu)2, SPhos, DavePhos,
PCy3, P(tBu)3 gave 5c in up to 93% yield (Entries 6ꢀ11). In order to investigate the effect of
bidentate ligands in this cyclization, we carried out some further optimizations using bidentate
phosphine ligands, such as XantPhos, DpePhos, Dppf. In fact, the yield was improved to up to
97% using the dppf ligand in combination with Pd2dba3 (method A). The use of Pd(OAc)2 as
palladium resulted in lower yield (85%). During the optimizations, we also realized that toluene
was the most suitable solvent for this cyclization.
Table 1. Optimizations for the synthesis of 5c
Entry Catalyst Ligand
Solvent
Tol
Time (h) Temperature (ºC) Yield (%)a
Pd2(dba)3 BINAP
Pd2(dba)3 XantPhos
Pd2(dba)3 DpePhos
Pd2(dba)3 Dppe
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
100
100
100
100
100
100
100
100
100
100
100
100
100
100
110
56
93
95
81
97
64
79
87
35
93
88
85b
87
53
82
1
Tol
2
Tol
3
Tol
4
Pd2(dba)3 Dppf
Tol
5
Pd2(dba)3 PCy3·HBF4
Tol
6
Pd2(dba)3 P(tꢀBu)3·HBF4 Tol
7
Pd2(dba)3 XPhos
Pd2(dba)3 XPhos·tBu2
Pd2(dba)3 SPhos
Pd2(dba)3 DavePhos
Pd(OAc)2 Dppf
Tol
8
Tol
9
Tol
10
11
12
13
14
15
Tol
Tol
Pd2(dba)3 Dppf
Dioxane
DMF
Tol
Pd2(dba)3 Dppf
Pd2(dba)3 Dppf

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Pd2(dba)3 Dppf
Tol
7
80
77
16
a
1
Yield was calculated by HꢀNMR of crude product using 4ꢀnitroacetophenone as an internal
standard. b 10 mol% of Pd(OAc)2 was used.
P(Cy)2
P(t-Bu)2
P
P
HBF4
P(t-Bu)3
P(Cy)3
XPhos
XPhos(t-Bu)2
PCy2
PCy2
OMe
PPh2
PPh2
N
MeO
DavePhos
SPhos
BINAP
PPh2
PPh2
PPh2
Fe
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
Xantphos
Dppf
DPEPhos
Dppe
Figure 3. Struture of monodentate and bidentate ligands.
With our optimized conditions in hand (method A), we were interested to explore the substrate
scope of the cyclization of 3a with a series of different amines. The cyclization products 5aꢀh,
which are depicted in Table 2, were isolated in 83ꢀ98% yields. The reaction was compatible with
a variety of functional groups. The structure of 5d was independently confirmed by singleꢀcrystal
Xꢀray diffraction (Figure 4). Unfortunately, the Pdꢀcatalyzed cyclization of 3a with aliphatic
amines using method A did not result in satisfactory yields, due to the formation of side
products. After some optimization studies using different conditions, we found that employment

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of dpePhos as the ligand (method B) allowed to improve the yield of the reaction. Up to 90%
isolated yields of the cyclization products were achieved (products 5iꢀl).
Figure 4. Xꢀray structure of 5d
Table 2. Synthesis of αꢀcarbolines 5aꢀl
5
a
b
c
d
e
f
R
Method a
Yield (%)b
Ph
A
A
A
A
A
A
A
A
B
92
95
94
89
88
98
92
83
88
4ꢀMeC6H4
4ꢀ(tꢀBu)C6H4
4ꢀFC6H4
3ꢀ(CF3)C6H4
4ꢀ(MeO)C6H4
4ꢀ(MeS)C6H4
4ꢀ(CN)C6H4
Bn
g
h
i

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(4ꢀFC6H4)CH2
B
B
B
87
90
91
j
k
l
3ꢀ(CF3)C6H4CH2
nꢀC3H7
a
Conditions: 3 equiv. of 4, 6 equiv. of NaOtBu, 5% mol of Pd2(dba)3, ligand (method A: 10
mol% of Dppf, method B: 10 mol% of DpePhos), toluene, 100 ºC, 7 h. b Isolated yields
We were interested to extend to the synthesis of bis(carbolines). The Pdꢀcatalyzed cyclization of
3a with diamines 6a and 6b afforded, following our optimized procedure, products 7a and 7b in
46 and 50% yields, respectively. It is worth to mention that product 7b represents an analogue of
the recently developed ligand dNinp ligand.34 This, our methodology allows for a convenient
access to this type of molecule.
Scheme 2. Synthesis of bis(carbolines) 7a,b. Conditions: 2.2 equiv. of 3a, 1 equiv. of 6a,b, 6
equiv. of NaOtBu, 5% mol of Pd2(dba)3, 10% of dppf, toluene, 110 ºC, 10 h.

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Our next goal was to apply our methodology to the synthesis of δꢀcarbolines. The Suzukiꢀ
Miyaura coupling of oꢀbromophenylboronic acid (2) with 2,3ꢀdibromopyridine (1b) proceeded,
following our optimized procedure, with very good regioselectivity at the more electronꢀdeficient
2ꢀposition of the pyridine ring and afforded product 3b in 96% isolated yield. With intermediate
3b in hand, we prepared a series of δꢀcarbolines 8aꢀj, using either method A or method B, in
moderate to excellent yields. The yields were moderate in case of less nucleophilic amines
carrying an electron withdrawing substituent located at the aryl group. The structure of 8b was
independently confirmed by Xꢀray crystal structure analysis (Figure 5).35
Scheme 3. Synthesis of δꢀcarbolines 8aꢀi
Conditions: (i) 1.2 equiv. of 2, 5% of Pd(Ph3)4 catalyst, 3 equiv. of NaOH, THF, H2O, 70 ºC, 4 h.
(ii) 3 equiv. of 4, 6 equiv. of NaOtBu, 5% mol of Pd2(dba)3, ligand (method A: 10 mol% of
Dppf, method B: 10 mol% of DpePhos), toluene, 100 ºC, 7 h.
Table 3. Synthesis of δꢀcarbolines 8aꢀi
8
a
b
c
d
e
f
R
Conditions Yield (%)
Ph
A
A
A
A
A
B
83
73
64
94
75
42
4ꢀFC6H4
3ꢀ(F3C)C6H4
4ꢀ(MeO)C6H4
3,5ꢀ(MeO)2C6H4
4ꢀ(NC)C6H4

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Bn
4ꢀ(MeO)C6H4CH2
PhCH2CH2
B
92
65
77
g
h
i
B
B
Conditions: 3 equiv. of 4, 6 equiv. of NaOtBu, 5% mol of Pd2(dba)3, ligand (method A: 10 mol%
of Dppf, method B: 10 mol% of DpePhos), toluene, 100 ºC, 7 h.
Figure 5. Xꢀray structure of 8b.
The cyclization of 3b with diamine 6a afforded bis(carboline) 9 in 40% isolated yield (Scheme
4).
NH2
Br
N
6a
H2N
N
N
N
N
ii
Br
3b
9
(40%)

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Scheme 4. Synthesis of bis(carboline) 9. Conditions: 2.5 equiv. of 3, 1 equiv. of 6a, 6 equiv. of
NaOtBu, 5% mol of Pd2(dba)3, 10% of dppf, toluene, 100 ºC, 10 h.
CONCLUSION
In conclusion, we have successfully developed an efficient twoꢀstep synthesis of αꢀ and δꢀ
carbolines from readily available chemicals. The reactions rely on siteꢀselective SuzukiꢀMiyaura
reaction and subsequent twoꢀfold CꢀN coupling reactions. The synthesis of βꢀ and γꢀcarbolines
are currently carrying out in our laboratory. Our results reported herein would be interesting for
further applications in both medicinal chemistry and materials science.
Experimental Section
General. Chemicals were purchased from alfa aesar, sigma Aldrich and were used without
further purification. NMR spectra were recorded on a Brucker AV 300 and 250 MHz
instruments. IR spectra were recorded on a Perkin Elmer FT IR 1600 spectrometer (ATR). Mass
spectra were obtained on a HewlettꢀPackard HPGC/MS 5890/5972 instrument (EI, 70 eV) by GC
inlet or on an MXꢀ1321 instrument (EI, 70 eV) by direct inlet. Column chromatography was
performed on silica gel (63e200 mesh, Merck) and silica gel Merck 60F254 plates were used for
TLC. Commercially available solvents were distilled for column chromatography. All other
solvents were purified and dried by standard methods.

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General procedure for prepared of 3-(2-bromophenyl)-2-chloropyridine
3a. 3ꢀbromoꢀ2ꢀ
chloropyridine 1a (1 g, 5.2 mmol), 2ꢀbromophenyl boronic acid 2 (1.25 g, 6.2 mmol), Pd(PPh3)4
(300 mg, 260 µmol) and sodium hydroxide (624 mg, 15.6 mmol) were added to 500 mL Schlenk
flask. The mixture was backꢀfilled several times with argon. To the mixture 70 mL THF and 10
mL distilled water were added, then, backꢀfilled several times. The reaction was heated at 70 ºC
for 4h. The solvent was evaporated in vacuo. The residue was extracted with dichloromethane
and water. The organic layer was dried over MgSO4, filtered and the solvent was evaporated in
vacuo. The yellow residue was purified by column chromatography (silica gel,
heptane/ethylacetate 4:1) to yield 3ꢀ(2ꢀbromophenyl)ꢀ2ꢀchloropyridine 3a (1.19 g, 85 %) as
1
colorless syrup; H NMR (300 MHz, CDCl3) δ 8.38 (dd, J = 4.8, 1.9 Hz, 1H), 7.66 – 7.59 (m,
1H), 7.54 (dd, J = 7.5, 2.0 Hz, 1H), 7.33 (td, J = 7.6, 1.3 Hz, 1H), 7.29 – 7.13 (m, 3H); 13C NMR
(75 MHz, CDCl3) δ 150.36, 149.18, 139.84, 138.41, 136.39, 132.88, 130.95, 130.07, 127.42,
123.40, 122.16; IR (ATR, cmꢀ1): ν = 3051 (w), 1576 (m), 1558 (m), 1479 (w), 1441 (m), 1427
(m), 1390 (vs), 1300 (w), 1255 (w), 1242 (w), 1207 (m), 1122 (m), 1103 (s), 1063 (s), 1053 (m),
1026 (m), 997 (s), 945 (w), 802 (m), 781 (m), 748 (vs), 723 (s), 694 (s), 654 (s), 615 (m), 569
(m), 553 (m); GCꢀMS (EI, 70 eV): m/z (%) = 269 (59), 188 (100), 153 (58), 126(29); HRMS
81
(EI): calcd. for C11H7N1Br1Cl1 ([M]+): 266.94449; found: 266.94495; calcd. for C11H7N1 Br1Cl1
37
([M]+): 268.94244; found: 268.94288; calcd. for C11H7N1Br1 Cl1 ([M]+): 270.93949; found:
270.94012.
General procedure A for double CꢀN coupling with aniline derivatives, exemplified by: 9-
phenyl-9H-pyrido[2,3-b]indole 8a. Aniline (52 µL, 0.56 mmol) was added to pressure tube
charged with 3a (100 mg, 0.37 mmol), Pd2(dba)3 (17 mg, 19 µmol), ligand dppf (21 mg, 37

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µmol) and sodium tertꢀbutoxide (107 mg, 1.12 mmol) under argon. The mixture was backꢀfilled
with argon several times. The mixture was dissolved in anhydrous toluene (10 mL) and heated at
110 ºC for 7 h. After cooling, the reaction mixture was diluted with dichloromethane (20 mL)
and filtered through a celite pad, washing with dichloromethane (40 mL). The filtrate was
reduced in vacuo. The product was separated via flash chromatography (silica gel,
heptanes/ethylacetate 3:1) to yield 9ꢀphenylꢀ9Hꢀpyrido[2,3ꢀb]indole 5a (84 mg, 92%) as a white
solid; m.p. 110ꢀ111 ºC; 1H NMR (250 MHz, CDCl3) δ 8.42 (dd, J = 4.9, 1.6 Hz, 1H), 8.31 (dd, J
= 7.7, 1.6 Hz, 1H), 8.05 (dt, J = 7.7, 0.9 Hz, 1H), 7.63 – 7.48 (m, 4H), 7.47 – 7.33 (m, 3H), 7.33
– 7.22 (m, 1H), 7.20 – 7.10 (m, 1H); 13C NMR (63 MHz, CDCl3) δ 151.93, 146.47, 140.11,
136.26, 129.65, 128.28, 127.64, 127.38, 126.93, 120.91, 120.81, 120.71, 116.36, 116.04, 110.41;
IR (ATR, cmꢀ1): ν = 3037 (m), 1591 (s), 1568 (m), 1504 (s), 1473 (s), 1452 (s), 1414 (vs), 1377
(m), 1354 (m), 1335 (s), 1309 (m), 1290 (s), 1228 (s), 1176 (m), 1167 (m), 1115 (s), 1074 (m),
1051 (m), 1026 (m), 997 (m), 970 (m), 958 (m), 951 (m), 937 (m), 766 (s), 756 (s), 748 (s), 735
(vs), 715 (m), 692 (vs), 636 (s), 617 (s), 579 (s), 569 (m); GCꢀMS (EI, 70 eV): m/z (%) = 243
(100), 122 (17); HRMS (ESI): calcd. for C17H12N2 ([M + H]+): 245.10732; found: 245.10756.
9-(p-Tolyl)-9H-pyrido[2,3-b]indole 5b was prepared following general procedure A using 3a
(100 mg, 0.37 mmol) and 4ꢀtoluidine (60 mg, 0.56 mmol). The product was purified by flash
chromatography (silica gel, heptanes/ethylacetate 3:1) to yield 5b (91 mg, 95 %) as a white solid;
m.p. 102ꢀ103 ºC; 1H NMR (250 MHz, CDCl3) δ 8.40 (dd, J = 4.9, 1.6 Hz, 1H), 8.29 (dd, J = 7.7,
1.6 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.48 – 7.29 (m, 6H), 7.28 – 7.19 (m, 1H), 7.18 – 7.09 (m,
1H), 2.39 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 152.10, 146.50, 140.28, 137.60, 133.56, 130.30,
128.21, 127.25, 126.85, 120.87, 120.71, 120.54, 116.24, 115.87, 110.39, 21.26; IR (ATR, cmꢀ1):

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ν = 3039 (w), 2920 (w), 1589 (m), 1568 (m), 1514 (s), 1475 (m), 1456 (s), 1412 (vs), 1377 (m),
1354 (m), 1336 (s), 1311 (m), 1290 (s), 1228 (s), 1219 (s), 1200 (m), 1182 (m), 1169 (m), 1155
(w), 1120 (m), 1109 (m), 1051 (w), 1038 (w), 1018 (m), 997 (m), 966 (w), 951 (w), 941 (w), 924
(m), 841 (w), 812 (s), 798 (m), 771 (vs), 744 (s), 735 (vs), 714 (s), 702 (s), 646 (m), 633 (s), 617
(m), 577 (s), 571 (s); GCꢀMS (EI, 70 eV): m/z (%) = 258 (100), 242 (17), 128 (9); HRMS
(ESI): calcd. for C18H14N2 ([M + H]+): 259.12297; found: 259.12331.
9-(4-(tert-Butyl)phenyl)-9H-pyrido[2,3-b]indole 5c was prepared following general procedure A
using 3a (100 mg, 0.37 mmol) and 4ꢀtertꢀbutylaniline (83 mg, 0.56 mmol). The product was
purified by flash chromatography (silica gel, heptanes/ethylacetate 3:1) to yield 5c (105 mg, 94
1
%) as a white solid; m.p. 147ꢀ148 ºC; H NMR (250 MHz, CDCl3) δ 8.41 (dd, J = 4.9, 1.6 Hz,
1H), 8.29 (dd, J = 7.7, 1.6 Hz, 1H), 8.06 – 7.99 (m, 1H), 7.58 – 7.32 (m, 6H), 7.23 (ddd, J = 8.1,
6.7, 1.6 Hz, 1H), 7.19 – 7.08 (m, 1H), 1.32 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 152.01,
150.43, 146.50, 140.26, 133.51, 128.22, 126.84, 126.77, 126.63, 120.84, 120.72, 120.56, 116.31,
115.87, 110.55, 34.76, 31.42; IR (ATR, cmꢀ1): ν = 2960 (m), 2902 (w), 2868 (w), 1587 (m), 1568
(m), 1520 (s), 1475 (m), 1454 (s), 1414 (vs), 1360 (m), 1335 (s), 1288 (s), 1269 (m), 1228 (s),
1186 (m), 1169 (m), 1153 (w), 1119 (m), 1097 (w), 1018 (m), 997 (m), 930 (m), 833 (m), 825
(m), 800 (w), 769 (vs), 748 (s), 739 (vs), 687 (m), 638 (s), 617 (m), 580 (m), 569 (m), 552 (s);
GCꢀMS (EI, 70 eV): m/z (%) = 300 (45), 285 (100), 128 (13); HRMS (EI): calcd. for C21H20N2
([M]+): 300.16210; found: 300.16183.
9-(4-Fluorophenyl)-9H-pyrido[2,3-b]indole 5d was prepared following general procedure A
using 3a (100 mg, 0.37 mmol) and 4ꢀfluoroaniline (53 µL, 0.56 mmol). The product was purified

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by flash chromatography (silica gel, heptanes/ethylacetate 3:1) to yield 5d (87 mg, 89 %) as a
white solid; m.p. 156ꢀ157 ºC; 1H NMR (300 MHz, CDCl3) δ 8.38 (dd, J = 4.9, 1.6 Hz, 1H), 8.27
(dt, J = 5.0, 2.5 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.55 – 7.46 (m, 2H), 7.42 – 7.29 (m, 2H), 7.28
– 7.10 (m, 4H) ; 19F NMR (282 MHz, CDCl3) δ ꢀ112.83 (s); 13C NMR (75 MHz, CDCl3) δ
161.79 (d, J = 247.2 Hz), 152.02, 146.54, 140.17, 132.23 (d, J = 3.1 Hz), 129.23 (d, J = 8.6 Hz),
128.39, 127.08, 121.04, 120.89, 120.83, 116.66 (d, J = 22.8 Hz), 116.35, 116.22, 110.19; IR
(ATR, cmꢀ1): ν = 3061 (w), 1589 (m), 1570 (m), 1510 (s), 1475 (s), 1456 (s), 1416 (s), 1356 (m),
1336 (s), 1294 (s), 1228 (s), 1213 (s), 1173 (s), 1151 (s), 1119 (s), 1092 (s), 1053 (m), 1020 (m),
1012 (m), 997 (m), 964 (m), 953 (m), 941 (m), 931 (m), 924 (m), 899 (w), 870 (w), 856 (w), 833
(s), 816 (s), 798 (m), 769 (vs), 762 (s), 746 (s), 737 (vs), 715 (s), 704 (s), 665 (m), 644 (m), 629
(m), 617 (m), 579 (s), 569 (s); GCꢀMS (EI, 70 eV): m/z (%) = 261 (100), 131 (9); HRMS (ESI):
calcd. for C17H11F1N2 ([M + H]+): 263.0979; found: 263.09813.
9-(3-(Trifluoromethyl)phenyl)-9H-pyrido[2,3-b]indole 5e was prepared following general
procedure A using 3a (100 mg, 0.37 mmol) and 4ꢀfluoroaniline (53 µL, 0.56 mmol). The product
was purified by flash chromatography (silica gel, heptanes/ethylacetate 3:1) to yield 5e (87 mg,
1
89 %) as a white solid; m.p. 71ꢀ72 ºC; H NMR (300 MHz, CDCl3) δ 8.38 (dd, J = 4.9, 1.6 Hz,
1H), 8.28 (dd, J = 7.7, 1.6 Hz, 1H), 8.02 (dt, J = 7.8, 0.9 Hz, 1H), 7.87 (s, 1H), 7.84 – 7.76 (m,
1H), 7.68 – 7.59 (m, 2H), 7.41 – 7.35 (m, 2H), 7.26 (ddd, J = 8.2, 5.4, 2.9 Hz, 1H), 7.20 – 7.13
(m, 1H) ; 19F NMR (282 MHz, CDCl3) δ ꢀ62.70 (s); 13C NMR (75 MHz, CDCl3) δ 151.71,
146.56, 139.59, 136.99, 132.14 (q, J = 32.8 Hz), 130.73 (d, J = 1.0 Hz), 130.25, 128.49, 127.28,
124.47 – 123.68 (m, 2xC), 123.83 (q, J = 272.6 Hz), 121.31, 121.17, 121.14, 116.66, 116.57,
110.10; IR (ATR, cmꢀ1): ν = 3051 (w), 1612 (w), 1591 (m), 1574 (m), 1497 (m), 1477 (m), 1458

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(s), 1410 (s), 1358 (m), 1338 (m), 1321 (s), 1306 (s), 1290 (s), 1275 (s), 1228 (s), 1178 (m), 1167
(s), 1155 (s), 1119 (vs), 1103 (s), 1093 (s), 1068 (s), 1020 (m), 999 (m), 972 (s), 937 (m), 931
(m), 914 (m), 889 (m), 852 (m), 810 (s), 796 (s), 771 (s), 760 (m), 744 (s), 737 (vs), 715 (m), 694
(vs), 661 (s), 642 (s), 619 (s), 582 (m), 565 (m), 528 (s); GCꢀMS (EI, 70 eV): m/z (%) = 311
(100), 243 (11); HRMS (ESI): calcd. for C18H11F3N2 ([M + H]+): 313.09471; found: 313.09460.
9-(4-Methoxyphenyl)-9H-pyrido[2,3-b]indole 5f was prepared following general procedure A
using 3a (100 mg, 0.37 mmol) and pꢀanisidine (69 mg, 0.56 mmol). The product was purified by
flash chromatography (silica gel, heptanes/ethylacetate 2:1) to yield 5f (100 mg, 98 %) as a white
solid; m.p. 137ꢀ138 ºC; 1H NMR (250 MHz, CDCl3) δ 8.40 (dd, J = 4.9, 1.6 Hz, 1H), 8.30 (dd, J
= 7.7, 1.6 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.51 – 7.41 (m, 2H), 7.40 – 7.30 (m, 2H), 7.29 –
7.19 (m, 1H), 7.18 – 7.09 (m, 1H), 7.09 – 7.01 (m, 2H), 3.82 (s, 3H); 13C NMR (63 MHz,
CDCl3) δ 159.00, 152.24, 146.51, 140.55, 128.90, 128.73, 128.22, 126.86, 120.86, 120.60,
120.49, 116.17, 115.81, 115.00, 110.30, 55.58; IR (ATR, cmꢀ1): ν = 3057 (w), 2960 (w), 2935
(w), 2908 (w), 2835 (w), 1589 (m), 1570 (m), 1512 (s), 1477 (m), 1456 (s), 1441 (m), 1416 (s),
1358 (m), 1336 (m), 1298 (m), 1288 (s), 1230 (vs), 1190 (m), 1174 (s), 1149 (m), 1117 (s), 1103
(s), 1053 (w), 1028 (s), 999 (m), 962 (m), 951 (m), 939 (m), 930 (m), 918 (m), 847 (w), 827 (s),
814 (m), 798 (m), 769 (vs), 744 (s), 735 (vs), 721 (s), 702 (m), 646 (s), 631 (s), 617 (m), 586 (s),
579 (s), 571 (m), 530 (vs); GCꢀMS (EI, 70 eV): m/z (%) = 274 (100), 259 (55), 231 (25), 168
(10), 115 (9); HRMS (EI): calcd. for C18H14O1N2 ([M]+): 274.11006; found: 274.10996.
9-(4-(Methylthio)phenyl)-9H-pyrido[2,3-b]indole 5g was prepared following general procedure
A using 3a (100 mg, 0.37 mmol) and 4ꢀ(methylthio)aniline (69 µL, 0.56 mmol). The product

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was purified by flash chromatography (silica gel, heptanes/ethylacetate 2:1) to yield 5g (99 mg,
92 %) as a white solid; m.p. 136ꢀ137 ºC; 1H NMR (250 MHz, CDCl3) δ 8.40 (dd, J = 4.9, 1.6 Hz,
1H), 8.30 (dd, J = 7.7, 1.6 Hz, 1H), 8.04 (dt, J = 7.7, 1.0 Hz, 1H), 7.52 – 7.36 (m, 6H), 7.31 –
7.21 (m, 1H), 7.15 (dd, J = 7.6, 4.8 Hz, 1H), 2.48 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 150.92,
145.46, 139.03, 137.06, 132.25, 127.27, 126.70, 125.94, 119.92, 119.78, 119.73, 115.32, 115.05,
109.30, 15.00; IR (ATR, cmꢀ1): ν = 3039 (w), 2960 (m), 2920 (m), 1626 (w), 1589 (m), 1568
(m), 1500 (s), 1475 (m), 1452 (m), 1437 (m), 1414 (s), 1356 (m), 1335 (m), 1309 (m), 1300 (m),
1290 (s), 1259 (m), 1228 (s), 1182 (m), 1169 (m), 1151 (m), 1117 (m), 1103 (m), 1090 (s), 1049
(m), 1014 (s), 997 (s), 980 (m), 970 (m), 953 (m), 933 (m), 924 (m), 858 (m), 814 (s), 798 (s),
769 (vs), 735 (vs), 714 (s), 679 (m), 642 (s), 629 (s), 617 (m), 580 (m), 569 (m); GCꢀMS (EI, 70
eV): m/z (%) = 290 (100), 275 (50), 243 (24); HRMS (EI): calcd. for C18H14N2S1 ([M]+):
290.08722; found: 290.08702.
9-(4-Cyanophenyl)-9H-pyrido[2,3-b]indole 5h was prepared following general procedure A
using 3a (100 mg, 0.37 mmol) and 4ꢀaminobenzonitrile (66 mg, 0.56 mmol). The product was
purified by flash chromatography (silica gel, heptanes/ethylacetate 1.5:1) to yield 5h (83 mg, 83
1
%) as a white solid; m.p. 179ꢀ180 ºC; H NMR (250 MHz, CDCl3) δ 8.38 (dd, J = 4.9, 1.6 Hz,
1H), 8.29 (dd, J = 7.7, 1.6 Hz, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.51 – 7.36 (m, 2H), 7.33 – 7.24 (m,
1H), 7.19 (dd, J = 7.8, 4.9 Hz, 1H) ; 13C NMR (63 MHz, CDCl3) δ 151.32, 146.45, 140.52,
138.85, 133.45, 128.58, 127.37, 127.28, 121.74, 121.45, 121.28, 118.52, 117.11, 116.85, 110.41,
110.23; IR (ATR, cmꢀ1): ν = 3057 (w), 2227 (m), 1603 (m), 1591 (m), 1574 (m), 1512 (m), 1487
(w), 1475 (w), 1450 (m), 1410 (s), 1356 (m), 1336 (m), 1311 (w), 1286 (m), 1228 (m), 1217 (m),
1184 (w), 1169 (m), 1155 (w), 1119 (m), 1103 (w), 1057 (w), 1020 (w), 1001 (w), 960 (w), 953

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(w), 945 (w), 928 (w), 856 (m), 833 (m), 823 (m), 800 (w), 789 (w), 773 (m), 766 (s), 744 (m),
735 (vs), 694 (m), 656 (w), 631 (m), 619 (w), 577 (m), 569 (m), 550 (s), 532 (m); GCꢀMS (EI,
70 eV): m/z (%) = 268 (100), 134 (7); HRMS (EI): calcd. for C18H10N3 ([M]+): 268.08692;
found: 268.08700.
General procedure B for double CꢀN coupling with chain amine derivatives, exemplified
by: 5-benzyl-5H-pyrido[3,2-b]indole 5i. To pressure tube charged with 3a (100 mg, 0.37 mmol),
Pd2(dba)3 (17 mg, 19 µmol), ligand DPEPhos (21 mg, 37 µmol) and sodium tertꢀbutoxide (107
mg, 0.12 mmol) under argon. The mixture was backꢀfilled with argon several times. The mixture
was dissolved in anhydrous toluene (10 mL). benzylamine (61 µL, 0.56 mmol) was added to the
mixture and heated at 100 ºC for 7 h. After cooling, the reaction mixture was diluted with
dichloromethane (20 mL) and filtered through a celite pad, washing with dichloromethane (40
mL). The filtrate was reduced in vacuo. The product was separated via flash chromatography
(silica gel, heptanes/ethylacetate 3:1) to yield 5i (85 mg, 88 %) as a white solid; m.p. 98ꢀ99 ºC;
1H NMR (250 MHz, CDCl3) δ 8.41 (dd, J = 4.9, 1.6 Hz, 1H), 8.20 (dd, J = 7.7, 1.6 Hz, 1H), 7.99
13
– 7.92 (m, 1H), 7.36 – 7.20 (m, 2H), 7.19 – 7.01 (m, 7H), 5.58 (s, 2H) ; C NMR (63 MHz,
CDCl3) δ 150.65, 145.10, 138.49, 136.25, 127.55, 127.08, 126.26, 125.88, 125.68, 119.92,
119.56, 118.93, 114.79, 114.24, 108.80, 43.87; IR (ATR, cmꢀ1): ν = 3028 (w), 2960 (w), 2918
(w), 1626 (w), 1589 (m), 1568 (m), 1483 (s), 1466 (s), 1452 (m), 1431 (s), 1412 (s), 1356 (m),
1348 (m), 1333 (m), 1315 (w), 1292 (m), 1259 (s), 1211 (s), 1194 (m), 1155 (m), 1128 (m), 1119
(m), 1092 (m), 1078 (m), 1065 (m), 1053 (m), 1030 (s), 1020 (s), 995 (s), 970 (m), 947 (m), 928
(w), 906 (w), 870 (w), 850 (m), 839 (m), 800 (s), 791 (s), 773 (vs), 748 (s), 729 (vs), 694 (s), 652
(s), 619 (m), 606 (m), 582 (m), 569 (m), 555 (s), 528 (s); GCꢀMS (EI, 70 eV): m/z (%) = 257

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(100), 181 (34), 91 (45); HRMS (ESI): calcd. for C18H14N2 ([M + H]+): 259.12297; found:
259.12298.
5-(4-Fluorobenzyl)-5H-pyrido[3,2-b]indole 5j was prepared following general procedure A
using 3a (100 mg, 0.37 mmol) and 4ꢀfluorobenzylamine (61 µL, 0.56 mmol). The product was
purified by flash chromatography (silica gel, heptanes/ethylacetate 3:1) to yield 5j (90 mg, 87 %)
1
as a white solid; m.p. 103ꢀ104 ºC; H NMR (300 MHz, CDCl3) δ 8.43 (dd, J = 4.9, 1.6 Hz, 1H),
8.25 (dd, J = 7.7, 1.6 Hz, 1H), 8.02 – 7.96 (m, 1H), 7.36 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.28 –
7.07 (m, 5H), 6.89 – 6.79 (m, 2H), 5.57 (s, 2H) ; 19F NMR (282 MHz, CDCl3) δ ꢀ115.23 (s); 13C
NMR (75 MHz, CDCl3) δ 161.07 (d, J = 245.4 Hz), 150.56, 145.15, 138.33, 132.02 (d, J = 3.2
Hz), 127.62 (d, J = 8.1 Hz), 127.20, 125.77, 120.05, 119.63, 119.09, 114.85, 114.47 (d, J = 21.6
Hz), 114.39, 108.65, 43.24; IR (ATR, cmꢀ1): ν = 3053 (w), 3034 (w), 2935 (w), 1624 (w), 1587
(m), 1572 (m), 1508 (s), 1481 (m), 1464 (s), 1439 (m), 1416 (s), 1383 (w), 1354 (m), 1335 (m),
1294 (m), 1252 (m), 1217 (s), 1207 (s), 1163 (m), 1128 (m), 1119 (m), 1101 (m), 1061 (m), 1049
(m), 1030 (w), 1020 (m), 1001 (w), 987 (m), 966 (w), 928 (w), 862 (m), 849 (m), 823 (m), 800
(m), 791 (m), 777 (vs), 762 (s), 746 (s), 735 (vs), 704 (m), 665 (w), 638 (m), 629 (s), 619 (m),
609 (m), 580 (m), 565 (m); GCꢀMS (EI, 70 eV): m/z (%) = 276 (100), 181 (30), 109 (73);
HRMS (ESI): calcd. for C18H13F1N2 ([M + H]+): 277.11355; found: 277.11394.
5-(3-(Trifluoromethyl)benzyl)-5H-pyrido[3,2-b]indole 5k was prepared following general
procedure A using 3a (100 mg, 0.37 mmol) and 3ꢀ(trifluoromethyl)benzylamine (80 µL, 0.56
mmol). The product was purified by flash chromatography (silica gel, heptanes/ethylacetate 3:1)
1
to yield 5k (109 mg, 90 %) as a white solid; m.p. 81ꢀ82 ºC; H NMR (300 MHz, CDCl3) δ 8.39

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(dd, J = 4.9, 1.6 Hz, 1H), 8.21 (dd, J = 7.7, 1.6 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H),
7.39 – 7.30 (m, 2H), 7.17 (ddd, J = 11.9, 6.6, 0.9 Hz, 4H), 7.12 – 7.03 (m, 1H), 5.60 (s, 2H); 19F
NMR (282 MHz, CDCl3) δ ꢀ62.51 (s); 13C NMR (75 MHz, CDCl3) δ 151.65, 146.29, 139.36,
138.47, 131.04 (q, J = 32.3 Hz), 130.30, 129.26, 128.36, 126.99, 124.38 (q, J = 3.8 Hz), 124.06
(q, J = 272.4 Hz), 123.89 (q, J = 3.8 Hz), 121.23, 120.81, 120.37, 115.99, 115.68, 109.55, 44.61;
IR (ATR, cmꢀ1): ν = 3053 (w), 1628 (w), 1591 (m), 1572 (m), 1483 (m), 1466 (m), 1450 (w),
1433 (m), 1416 (s), 1325 (vs), 1296 (m), 1281 (m), 1261 (m), 1217 (m), 1205 (m), 1186 (m),
1157 (s), 1117 (vs), 1097 (s), 1072 (vs), 1022 (m), 1011 (m), 993 (m), 966 (m), 937 (m), 922
(m), 903 (m), 868 (m), 852 (m), 800 (s), 791 (s), 771 (s), 744 (s), 735 (s), 702 (vs), 671 (m), 646
(s), 619 (m), 600 (m), 575 (m), 559 (m); GCꢀMS (EI, 70 eV): m/z (%) = 326 (100), 181 (62),
159 (20), 140 (13), 109 (13); HRMS (ESI): calcd. for C19H13F3N2 ([M + H]+): 327.11036; found:
327.11066.
5-Propyl-5H-pyrido[3,2-b]indole 5l was prepared following general procedure A using 3a (100
mg, 0.37 mmol) and nꢀpropylamine (46 µL, 0.56 mmol). The product was purified by flash
chromatography (silica gel, heptanes/ethylacetate 3:1) to yield 5l (71 mg, 91 %) as a white
1
liquid; H NMR (300 MHz, CDCl3) δ 8.38 (dd, J = 4.9, 1.6 Hz, 1H), 8.16 (dd, J = 7.6, 1.6 Hz,
1H), 7.97 – 7.89 (m, 1H), 7.43 – 7.29 (m, 2H), 7.14 (ddd, J = 8.0, 6.9, 1.4 Hz, 1H), 7.01 (dd, J =
13
7.6, 4.9 Hz, 1H), 4.37 – 4.26 (m, 2H), 1.90 – 1.73 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); C NMR
(75 MHz, CDCl3) δ 151.61, 145.94, 139.71, 128.03, 126.61, 121.03, 120.44, 119.62, 115.83,
114.86, 109.38, 43.16, 22.32, 11.65; IR (ATR, cmꢀ1): ν = 3049 (w), 2962 (m), 2929 (m), 2874
(w), 1626 (w), 1589 (m), 1570 (m), 1481 (s), 1466 (s), 1443 (m), 1414 (vs), 1381 (m), 1371 (m),
1360 (m), 1342 (s), 1333 (s), 1313 (w), 1290 (s), 1255 (m), 1219 (s), 1157 (m), 1138 (m), 1128

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(m), 1119 (s), 1090 (w), 1068 (m), 1049 (w), 1018 (w), 997 (m), 960 (w), 926 (w), 893 (w), 845
(w), 800 (w), 771 (vs), 748 (s), 733 (vs), 712 (m), 633 (m), 619 (m), 580 (m), 561 (m); GCꢀMS
(EI, 70 eV): m/z (%) = 210 (32), 181 (100), 168 (82), 140 (12), 127 (14); HRMS (EI): calcd. for
C14H14N2 ([M]+): 210.11515; found: 210.11500.
General procedure C for double CꢀN coupling with diamine derivatives, exemplified by:
1,4-bis(9H-pyrido[2,3-b]indol-9-yl)benzene 7a. To pressure tube was charged with 3a (200 mg,
0.75 mmol), 1,4ꢀdiaminobenzen (37 mg, 0.34 mmol), Pd2(dba)3 (15 mg, 17 µmol), ligand dppf
(19 mg, 34 µmol) and sodium tertꢀbutoxide (195 mg, 2.0 mmol) under argon. The mixture was
backꢀfilled with argon several times. The mixture was dissolved in anhydrous toluene (10 mL)
and heated at 110 ºC for 10 h. After cooling, the reaction mixture was diluted with
dichloromethane (20 mL) and filtered through a celite pad, washing with dichloromethane (40
mL). The filtrate was reduced in vacuo. The product was separated via flash chromatography
(silica gel, heptanes/dichloromethane/ethylacetate 1:1:1) to yield 1,4ꢀbis(9Hꢀpyrido[2,3ꢀb]indolꢀ
9ꢀyl)benzene 7a (64 mg, 46 %) as a white solid; m.p. 307ꢀ308 ºC; 1H NMR (300 MHz, CDCl3) δ
8.46 (dd, J = 4.8, 1.4 Hz, 2H), 8.34 (dt, J = 9.4, 4.7 Hz, 2H), 8.09 (d, J = 7.7 Hz, 2H), 7.87 (s,
4H), 7.62 (d, J = 8.2 Hz, 2H), 7.50 – 7.37 (m, 3H), 7.30 (t, J = 7.5 Hz, 2H), 7.25 – 7.16 (m, 3H).
13C NMR (75 MHz, CDCl3) δ 151.90, 146.48, 139.94, 135.34, 128.42, 128.32, 127.14, 121.02,
116.61, 116.37, 110.73; IR (ATR, cmꢀ1): ν = 3045 (m), 2922 (m), 1591 (m), 1572 (m), 1518 (s),
1481 (m), 1450 (s), 1406 (s), 1356 (m), 1338 (s), 1317 (m), 1290 (s), 1228 (s), 1173 (m), 1128
(m), 1120 (m), 1111 (m), 1051 (m), 1018 (m), 999 (m), 928 (m), 918 (m), 827 (m), 762 (s), 742
(s), 727 (vs), 700 (s), 642 (s), 619 (m), 579 (m), 567 (m), 534 (s); GCꢀMS (EI, 70 eV): m/z (%) =

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410 (100), 242 (24), 205 (23), 191 (12); HRMS (EI): calcd. for C28H18N4 ([M]+): 410.15260;
found: 410.15147.
9-(6-(9H-Indeno[2,1-b]pyridin-9-yl)pyridin-2-yl)-9H-pyrido[2,3-b]indole 7b was prepared
following general procedure C using 3a (200 mg, 0.75 mmol) and 2,6ꢀdiaminopyridine (37 mg,
0.34 mmol). The product was purified by flash chromatography (silica gel,
heptanes/dichloromethane/ethylacetate 1:1:1) to yield 7b (70 mg, 50 %) as a white solid; m.p.
1
236ꢀ237 ºC; H NMR (300 MHz, CDCl3) δ 8.51 (dd, J = 4.8, 1.5 Hz, 2H), 8.43 – 8.29 (m, 4H),
8.29 – 8.21 (m, 2H), 8.13 (dd, J = 8.8, 7.1 Hz, 1H), 8.00 (t, J = 9.9 Hz, 2H), 7.38 – 7.14 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 151.36, 149.76, 146.01, 140.02, 139.02, 128.26, 127.54, 121.79,
121.57, 120.37, 117.76, 117.15, 116.61, 114.34; IR (ATR, cmꢀ1): ν = 3047 (w), 2922 (w), 1599
(m), 1591 (s), 1570 (m), 1485 (w), 1450 (vs), 1414 (m), 1400 (vs), 1362 (m), 1340 (m), 1331 (s),
1286 (s), 1242 (m), 1223 (m), 1209 (m), 1180 (s), 1165 (m), 1155 (m), 1120 (m), 1105 (m), 1095
(m), 1057 (m), 1039 (m), 1026 (m), 999 (m), 985 (w), 974 (w), 968 (w), 957 (w), 943 (m), 933
(m), 922 (m), 849 (w), 796 (m), 764 (vs), 744 (s), 727 (vs), 700 (m), 683 (m), 658 (m), 634 (m),
619 (m), 611 (m), 579 (m), 567 (w), 559 (m); GCꢀMS (EI, 70 eV): m/z (%) = 410 (100), 244
(28), 206 (89); HRMS (EI): calcd. for C27H16N5 ([M]+): 410.14002; found: 410.13958.
General procedure for prepared of 3-bromo-2-(2-bromophenyl)pyridine 3b. 2,3ꢀ
dibromopyridine 1b (1 g, 4.2 mmol), 2ꢀbromophenyl boronic acid 2 (1.0 g, 5.1 mmol), Pd(PPh3)4
(244 mg, 211 µmol) and sodium hydroxide (507 mg, 12.7 mmol) were added to 500 mL Schlenk
flask. The mixture was backꢀfilled several times with argon. To the mixture 70 mL THF and 10
mL distilled water were added, then, backꢀfilled several times. The reaction was heated at 70 ºC

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for 4h. The solvent was evaporated in vacuo. The residue was extracted with dichloromethane
and water. The organic layer was dried over MgSO4, filtered and the solvent was evaporated in
vacuo. The yellow residue was purified by column chromatography (silica gel,
Heptane/dichloromethane/ethylacetate 4:1:1) to yield 3ꢀbromoꢀ2ꢀ(2ꢀbromophenyl)pyridine 3b
1
(1.27 g, 96 %) as colorless syrup; H NMR (300 MHz, CDCl3) δ 8.57 (dd, J = 4.7, 1.5 Hz, 1H),
7.93 (dd, J = 8.1, 1.5 Hz, 1H), 7.63 – 7.58 (m, 1H), 7.39 – 7.32 (m, 1H), 7.29 – 7.13 (m, 7H); 13C
NMR (75 MHz, CDCl3) δ 147.84, 140.99, 140.46, 132.69, 130.23, 130.08, 127.34, 124.13,
122.46, 121.35; IR (ATR, cmꢀ1): ν = 3053 (w), 2920 (w), 2850 (w), 1593 (m), 1568 (m), 1549
(m), 1479 (m), 1437 (m), 1412 (s), 1298 (w), 1269 (w), 1252 (m), 1230 (w), 1211 (w), 1201 (w),
1159 (w), 1124 (m), 1093 (m), 1055 (m), 1024 (s), 1011 (vs), 943 (m), 793 (s), 777 (m), 748
(vs), 723 (s), 694 (m), 681 (s), 650 (m), 615 (s), 561 (m); GCꢀMS (EI, 70 eV): m/z (%) = 313
(37), 234 (99), 233 (100), 153 (82), 126 (28), 99 (10), 75 (14), 63 (10), 50 (12); HRMS (EI):
81
calcd. for C11H7N1Br2 ([M]+): 310.89398; found: 310.89479; calcd. for C11H7N1Br1 Br1 ([M]+):
312.89193; found: 312.89233; calcd. for C11H7N1 Br2 ([M]+): 314.88988; found: 314.89073.
81
General procedure D for double CꢀN coupling with aniline derivatives, exemplified by: 5-
phenyl-5H-pyrido[3,2-b]indole 8a. Aniline (44 µL, 479 µmol) was added to pressure tube
charged with 3b (100 mg, 0.32 mmol), Pd2(dba)3 (15 mg, 16 µmol), ligand dppf (18 mg, 32
µmol) and sodium tertꢀbutoxide (92 mg, 0.96 mmol) under argon. The mixture was backꢀfilled
with argon several times. The mixture was dissolved in anhydrous toluene (10 mL) and heated at
100 ºC for 4 h. After cooling, the reaction mixture was diluted with dichloromethane (20 mL)
and filtered through a celite pad, washing with dichloromethane (40 mL). The filtrate was
reduced in vacuo. The product was separated via flash chromatography (silica gel,

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heptanes/dichloromethane/ethylacetate 10:1:1) to yield 5ꢀphenylꢀ5Hꢀpyrido[3,2ꢀb]indole 8a (65
1
mg, 83%) as a white solid; m.p. 99ꢀ101 ºC; H NMR (250 MHz, CDCl3) δ 8.50 (dd, J = 4.7, 1.3
Hz, 1H), 8.40 – 8.30 (m, 1H), 7.60 – 7.12 (m, 11H); 13C NMR (63 MHz, CDCl3) δ 142.54,
142.26, 141.54, 136.84, 134.31, 130.04, 127.95, 127.80, 126.79, 122.45, 120.87, 120.83, 120.18,
116.72, 110.04; IR (ATR, cmꢀ1): ν = 3053 (m), 1622 (m), 1593 (s), 1574 (m), 1502 (s), 1481 (s),
1452 (s), 1412 (vs), 1371 (m), 1340 (m), 1315 (m), 1304 (s), 1282 (m), 1234 (m), 1209 (s), 1178
(m), 1167 (m), 1147 (m), 1119 (m), 1107 (m), 1072 (m), 1026 (m), 1011 (m), 931 (m), 906 (m),
787 (m), 777 (s), 762 (s), 744 (vs), 727 (vs), 698 (vs), 665 (m), 642 (m), 633 (s), 615 (s), 582
(m), 567 (m), 534 (m); GCꢀMS (EI, 70 eV): m/z (%) = 244 (100), 216 (4), 189 (3), 167 (3), 152
(3), 140 (4), 122 (9), 88 (3), 77 (4), 63 (3), 51 (5), 39 (4); HRMS (EI): calcd. for C17H12N2
([M]+): 244.09950; found: 244.09922;
5-(4-Fluorophenyl)-5H-pyrido[3,2-b]indole 8b was prepared following general procedure D
using 3b (100 mg, 0.32 mmol) and 4ꢀfluoroaniline (45 µL, 0.48 mmol). The product was purified
by flash chromatography (silica gel, heptanes/dichloromethane/ethylacetate 8:1:1) to yield 8b
1
(61 mg, 73 %) as a white solid; m.p. 115ꢀ117 ºC; H NMR (250 MHz, CDCl3) δ 8.49 (dd, J =
4.7, 1.3 Hz, 1H), 8.39 – 8.29 (m, 1H), 7.53 – 7.32 (m, 4H), 7.31 – 7.11 (m, 3H), 6.78 – 6.65 (m,
19
13
1H), 6.48 (ddd, J = 6.7, 5.2, 2.9 Hz, 1H); F NMR (282 MHz, CDCl3) δ ꢀ112.83 (s); C NMR
(63 MHz, CDCl3) δ 161.79 (d, J = 248.2 Hz), 142.62, 141.69, 134.45, 132.77, 128.73 (d, J = 8.6
Hz), 128.06, 122.38, 120.94, 120.27, 117.24, 116.88, 116.50, 115.61 (d, J = 22.4 Hz), 109.80; IR
(ATR, cmꢀ1): ν = 3055 (m), 3037 (m), 1620 (m), 1587 (m), 1506 (vs), 1477 (s), 1452 (s), 1412
(s), 1354 (m), 1342 (m), 1311 (s), 1294 (m), 1281 (m), 1215 (s), 1207 (s), 1169 (s), 1151 (s),
1119 (m), 1105 (m), 1093 (s), 1049 (m), 1034 (m), 1028 (m), 1011 (m), 937 (m), 912 (s), 845

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(s), 833 (s), 816 (s), 781 (s), 764 (m), 742 (vs), 727 (vs), 715 (s), 700 (s), 646 (m), 627 (m), 617
(s), 575 (s), 534 (s); GCꢀMS (EI, 70 eV): m/z (%) = 262 (100), 261 (29), 131 (10); HRMS (EI):
calcd. for C17H11F1N2 ([M]+): 262.09008; found: 262.08948.
5-(3-(Trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole 8c was prepared following general
procedure D using 3b (100 mg, 0.32 mmol) and 3ꢀ(trifluoromethyl)aniline (60 µL, 0.48 mmol).
The
product
was
purified
by
flash
chromatography
(silica
gel,
heptanes/dichloromethane/ethylacetate 8:1:1) to yield 8c (64 mg, 64 %) as a white solid; m.p.
1
144ꢀ146 ºC; H NMR (250 MHz, CDCl3) δ 8.54 (dd, J = 4.7, 1.3 Hz, 1H), 8.47 – 8.29 (m, 1H),
19
13
7.84 – 7.53 (m, 4H), 7.52 – 7.14 (m, 4H); F NMR (282 MHz, CDCl3) δ ꢀ62.70 (s); C NMR
(63 MHz, CDCl3) δ 143.08, 142.52, 141.17, 137.65, 133.96, 132.76 (q, J = 33.2 Hz), 130.80,
130.03, 128.26, 124.44 (q, J = 3.6 Hz), 123.61 (q, J = 3.6 Hz), 122.75, 121.41, 121.09, 120.39,
116.43, 109.66; IR (ATR, cmꢀ1): ν = 3055 (w), 3041 (w), 1622 (m), 1606 (w), 1595 (m), 1579
(w), 1498 (m), 1481 (m), 1456 (s), 1412 (s), 1362 (m), 1356 (m), 1333 (m), 1309 (s), 1292 (m),
1275 (m), 1232 (m), 1217 (m), 1207 (m), 1182 (s), 1163 (s), 1155 (s), 1117 (vs), 1095 (s), 1074
(s), 1028 (m), 1014 (m), 1001 (m), 966 (m), 945 (m), 935 (m), 928 (m), 918 (m), 906 (m), 854
(w), 810 (m), 802 (s), 791 (m), 781 (s), 760 (w), 744 (vs), 727 (s), 715 (s), 706 (vs), 673 (m), 663
(s), 638 (m), 621 (m), 607 (m), 582 (w), 563 (w), 536 (m); GCꢀMS (EI, 70 eV): m/z (%) = 312
(100), 242 (8); HRMS (EI): calcd. for C18H11F3N2 ([M]+): 312.08688; found: 312.08662.
5-(4-Methoxyphenyl)-5H-pyrido[3,2-b]indole 8d was prepared following general procedure D
using 3b (100 mg, 0.32 mmol) and pꢀanisidine (59 mg, 0.48 mmol). The product was purified by
flash chromatography (silica gel, heptanes/dichloromethane/ethylacetate 5:1:1) to yield 8d (88

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1
mg, 94 %) as a white solid; m.p. 128ꢀ130 ºC; H NMR (250 MHz, CDCl3) δ 8.53 (dd, J = 4.7,
1.3 Hz, 1H), 8.43 – 8.30 (m, 1H), 7.55 (dd, J = 8.3, 1.4 Hz, 1H), 7.50 – 7.21 (m, 6H), 7.11 – 6.99
(m, 2H), 3.85 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 159.13, 142.22, 142.06, 134.81, 129.36,
128.30, 127.90, 122.13, 120.85, 120.59, 120.12, 116.68, 115.22, 109.97, 55.62; IR (ATR, cmꢀ1):
ν = 2955 (w), 2929 (w), 2837 (w), 1620 (m), 1510 (vs), 1479 (m), 1454 (s), 1441 (m), 1414 (s),
1385 (w), 1342 (m), 1313 (s), 1300 (m), 1286 (m), 1242 (s), 1209 (s), 1176 (s), 1149 (m), 1120
(m), 1107 (s), 1066 (m), 1028 (s), 1012 (m), 937 (m), 912 (m), 860 (w), 829 (s), 812 (m), 791
(s), 748 (vs), 729 (vs), 700 (s), 667 (m), 646 (m), 629 (m), 617 (s), 584 (s), 536 (s); GCꢀMS (EI,
70 eV): m/z (%) = 274 (100), 259 (55), 231 (13), 230 (15), 229 (14), 115 (9); HRMS (EI): calcd.
for C18H14O1N2 ([M]+): 274.11006; found: 274.11009.
5-(3,5-Dimethoxyphenyl)-5H-pyrido[3,2-b]indole 8e was prepared following general procedure
D using 3b (100 mg, 0.32 mmol) and 3,5ꢀdimethoxyaniline (73 mg, 0.48 mmol). The product
was purified by flash chromatography (silica gel, heptanes/dichloromethane/ethylacetate 3:1:1)
to yield 8d (88 mg, 94 %) as a white solid; m.p. 150ꢀ152 ºC; 1H NMR (250 MHz, CDCl3) δ 8.58
– 8.41 (m, 1H), 8.33 (dd, J = 7.7, 0.7 Hz, 1H), 7.64 (dd, J = 8.3, 1.3 Hz, 1H), 7.53 – 7.12 (m,
13
4H), 6.57 (d, J = 2.2 Hz, 2H), 6.45 (t, J = 2.2 Hz, 1H), 3.71 (s, J = 9.9 Hz, 6H); C NMR (63
MHz, CDCl3) δ 161.82, 142.55, 142.26, 141.37, 138.46, 134.17, 127.95, 122.48, 120.82, 120.20,
116.99, 110.33, 104.96, 99.76, 93.72, 55.59; IR (ATR, cmꢀ1): ν = 3051 (m), 3007 (m), 2970 (m),
2945 (m), 2916 (m), 2841 (m), 1620 (m), 1605 (s), 1583 (s), 1495 (m), 1475 (m), 1452 (s), 1425
(s), 1416 (s), 1367 (m), 1342 (m), 1331 (m), 1313 (s), 1296 (s), 1282 (s), 1252 (m), 1223 (m),
1194 (s), 1147 (vs), 1057 (s), 1009 (s), 991 (m), 928 (m), 906 (m), 868 (m), 852 (m), 833 (s), 823
(s), 783 (s), 773 (s), 741 (s), 723 (vs), 696 (s), 690 (s), 675 (s), 660 (s), 621 (s), 607 (s), 573 (s),

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557 (m), 532 (m); GCꢀMS (EI, 70 eV): m/z (%) = 304 (100), 261 (8), 245 (10), 218 (7); HRMS
(EI): calcd. for C19H16O2N2 ([M]+): 304.12063; found: 304.12015.
5-(4-Cyanophenyl)-5H-pyrido[3,2-b]indole 8f was prepared following general procedure D
using 3b (100 mg, 0.32 mmol) and 4ꢀaminobenzonitrile (56 mg, 0.48 mmol). The product was
purified by flash chromatography (silica gel, heptanes/dichloromethane/ethylacetate 4:1:1) to
1
yield 8f (36 mg, 42 %) as a white solid; m.p. 162ꢀ164 ºC; H NMR (250 MHz, CDCl3) δ 8.57
(dd, J = 4.7, 1.3 Hz, 1H), 8.41 – 8.33 (m, 1H), 7.90 – 7.81 (m, 2H), 7.71 – 7.60 (m, 3H), 7.52 –
7.23 (m, 4H), 13C NMR (63 MHz, CDCl3) δ 143.51, 141.21, 134.10, 133.45, 128.42, 126.86,
123.12, 121.88, 121.23, 120.49, 116.59, 111.02, 109.77; IR (ATR, cmꢀ1): ν = 3051 (w), 3007
(w), 2226 (m), 1616 (w), 1601 (s), 1587 (m), 1558 (w), 1506 (s), 1489 (w), 1479 (m), 1454 (m),
1412 (s), 1373 (w), 1354 (m), 1340 (m), 1315 (s), 1290 (m), 1246 (w), 1234 (m), 1221 (m), 1207
(s), 1182 (m), 1169 (m), 1153 (m), 1136 (m), 1128 (m), 1117 (m), 1107 (m), 1053 (w), 1028 (w),
1014 (m), 978 (w), 968 (w), 953 (w), 935 (w), 916 (m), 885 (w), 841 (s), 783 (s), 748 (vs), 731
(vs), 723 (s), 667 (m), 656 (m), 631 (m), 619 (s), 582 (w), 567 (m), 552 (s), 528 (m); GCꢀMS
(EI, 70 eV): m/z (%) = 269 (100), 270 (25), 75 (7), 39 (7); HRMS (EI): calcd. for C18H11N3
([M]+): 269.09475; found: 269.09432.
General procedure E for double CꢀN coupling with chain amine derivatives, exemplified
by: 5-benzyl-5H-pyrido[3,2-b]indole 8g. To pressure tube charged with 3b (100 mg, 0.32
mmol), Pd2(dba)3 (15 mg, 16 µmol), ligand DPEPhos (17 mg, 32 µmol) and sodium tertꢀ
butoxide (92 mg, 0.96 mmol) under argon. The mixture was backꢀfilled with argon several times.
The mixture was dissolved in anhydrous toluene (10 mL). benzylamine 4i (52 µL, 0.48 mmol)

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was added to the mixture and heated at 100 ºC for 7 h. After cooling, the reaction mixture was
diluted with dichloromethane (20 mL) and filtered through a celite pad, washing with
dichloromethane (40 mL). The filtrate was reduced in vacuo. The product was separated via flash
chromatography (silica gel, heptanes/dichloromethane/ethylacetate 5:1:1) to yield 8g (76 mg, 92
1
%) as a white solid; m.p. 137ꢀ139 ºC; H NMR (250 MHz, CDCl3) δ 8.43 (dd, J = 4.7, 1.2 Hz,
1H), 8.32 (d, J = 7.7 Hz, 1H), 7.45 – 7.30 (m, 2H), 7.28 – 7.01 (m, 6H), 6.93 (dd, J = 6.7, 2.6 Hz,
2H), 5.26 (s, 2H); 13C NMR (63 MHz, CDCl3) δ 140.82, 140.75, 140.27, 135.40, 132.91, 127.78,
126.80, 126.62, 125.25, 121.08, 119.82, 119.07, 118.93, 114.75, 108.14, 45.35; IR (ATR, cmꢀ1):
ν = 3051 (w), 3028 (w), 2926 (w), 1622 (m), 1603 (w), 1589 (m), 1576 (w), 1558 (w), 1495 (m),
1483 (m), 1458 (s), 1450 (s), 1414 (s), 1373 (m), 1356 (w), 1335 (s), 1319 (s), 1281 (w), 1263
(w), 1242 (m), 1211 (m), 1194 (s), 1178 (m), 1149 (m), 1132 (m), 1117 (m), 1080 (m), 1057 (w),
1047 (w), 1028 (m), 1012 (m), 999 (w), 972 (w), 962 (w), 937 (w), 912 (w), 845 (m), 802 (w),
789 (m), 781 (s), 742 (vs), 731 (vs), 721 (vs), 694 (s), 644 (m), 621 (m), 600 (m), 584 (m), 567
(m), 557 (m), 536 (m); GCꢀMS (EI, 70 eV): m/z (%) = 258 (88), 181 (5), 167 (8), 91 (100), 39
(9); HRMS (EI): calcd. for C18H14N2 ([M]+): 258.11515; found: 258.11534.
5-(4-Methoxybenzyl)-5H-pyrido[3,2-b]indole 8h was prepared following general procedure E
using compound 3b (100 mg, 0.32 mmol) and 4ꢀmethoxybenzylamine (63 µL, 0.48 mmol). The
product was purified by flash chromatography (silica gel, heptanes/dichloromethane/ethylacetate
3:1:1) to yield 8h (60 mg, 65 %) as a white solid; m.p. 124ꢀ126 ºC; 1H NMR (300 MHz, CDCl3)
δ 8.42 (dt, J = 5.7, 2.9 Hz, 1H), 8.36 – 8.28 (m, 1H), 7.48 – 7.31 (m, 2H), 7.30 – 7.07 (m, 3H),
6.88 (t, J = 5.8 Hz, 2H), 6.68 – 6.58 (m, 2H), 5.22 (s, 2H), 3.57 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.15, 141.92, 141.77, 141.37, 134.01, 128.51, 127.90, 127.71, 122.17, 120.94,