Copper-Catalyzed Synthesis of β- And δ-Carbolines by Double N-Arylation of Primary Amines

Article abstract of DOI:10.1055/s-0040-1720461

Two efficient and practical approaches are reported for the synthesis of β- and δ-carbolines from 3,4-dibromopyridine. The synthesis is based on site-selective Cu-catalyzed double C-N coupling reactions and subsequent annulations by twofold Pd-catalyzed C-N coupling with amines.

Full text of DOI:10.1055/s-0040-1720461

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–E
letter
A
en
B. Van Phuc et al.
Letter
Synlett
Copper-Catalyzed Synthesis of - and -Carbolines by Double
N-Arylation of Primary Amines
Ban Van Phuca
Ha Nam Dob
d
Br
g
0
0
0
0-0
0
0
1
-6
9
6
9
-
4
6
6
X
CuI/L-proline
Nguyen Minh Quanc
Nguyen Ngoc Tuana
Nguyen Quang Ana
Nguyen Van Tuyena,c
Hoang Le Tuan Anhd
Tran Quang Hung*a,c
Tuan Thanh Dang*b
N
b
+ RNH2
K2CO3, DMSO
120 °C, 24 h
N
a
N
R
Br
b
-carbolines (8 examples)
Up to 84% yield
d
Up to 95% yield
-carbolines (15 examples)
0
0
0
0
-
0
0
0
1
-
9
8
6
7
-
9
2
0
7
Peter Langer*e,f
0
0
0
0-0
0
0
2
-7
6
6
5
-
8
9
1
2
a Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Ho-
ang Quoc Viet, Hanoi, Vietnam
hungtq@gmail.com
b Faculty of Chemistry, Hanoi University of Science, Vietnam National University
(VNU), 19-Le Thanh Tong, Hanoi, Vietnam
dangthanhtuan@hus.edu.vn
c Graduate University of Science and Technology, Vietnam Academy of Science
and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
hungtq@gmail.com
d Center for Research and Technology Transfer, Vietnam Academy of Science and
Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
hoangletuananh@uni-rostock.de
e Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock,
Germany
peter.langer@uni-rostock.de
Leibniz Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str.
f
3a, 18059 Rostock, Germany
peter.langer@uni-rostock.de
Corresponding Authors
Received: 02.02.2021
Accepted after revision: 21.03.2021
Published online: 31.03.2021
kaloids which were isolated from several marine sponge
species.2 Canthine alkaloids, containing the core of -carbo-
lines, were isolated from several plant families (Rutaceae,
Simaroubaceae, Amaranthaceae, Caryophyllaceae) and from
marine organisms.2 Natural -carbolines exhibit a wide
range of important medicinal activities, for example, anti-
Alzheimer, anti-cancer, anti-inflammatory, anti-HIV, and
antimalarial activities.1,2 In addition, the -carboline struc-
ture is present in many synthetic drugs, such as in
ZK91296, ZK93426 (anxiogenic agents) or Abecamil (an
anxiolytic drug) (Figure 1).5 In comparison to -carbolines,
only a few -carbolines were isolated as natural products.
Examples include cryptolepine, cryptoquindoline, crypto-
misrine, jusbetonin, and quindoline.6 These natural alka-
loids were isolated from Cryptolepis sanguinolenta and Jus-
ticia bentonica, which have been known as traditional med-
icines for the treatment of malaria and of other infectious
diseases in Central and West Africa.6 In recent studies it has
been shown that -carboline derivatives exhibit important
bioactivities, such as anti-inflammatory,7 antitumor,8 anti-
malarial,9 antimicrobial,10 and antiviral11 activities.
DOI: 10.1055/s-0040-1720461; Art ID: st-2021-b0040-l
Abstract Two efficient and practical approaches are reported for the
synthesis of - and -carbolines from 3,4-dibromopyridine. The synthe-
sis is based on site-selective Cu-catalyzed double C–N coupling reac-
tions and subsequent annulations by twofold Pd-catalyzed C–N cou-
pling with amines.
Key words catalysis, heterocycles, cross-coupling, cyclizations, cop-
per
Carbolines (pyridoindoles) are important compounds,
due to their presence in many alkaloids and pharmaceuti-
cals.1 There are four different carboline regioisomers and
especially -carbolines appear frequently in natural prod-
ucts.2 In 1984, eudistomin A was isolated from Eudistoma
olivaceum. Later, a big family of eudistomin derivatives (B–
W) was isolated from nature (Figure 1).3 In 1986, man-
zamine A was isolated from the Okinawa sponge genus Hal-
iclona.4 Up to now, there are more than 80 manzamine al-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
B. Van Phuc et al.
Letter
Synlett
the synthesis of -carboline derivatives by application of
domino Pd-catalyzed cyclizations of -(o-bromoanilino)-
alkenenitriles.17n In order to prepare 3,4-disubstituted -
carbolines, the Dupas group developed cyclization reac-
tions of indole amines with 1,3-dicarbonyl compounds.17o
In 2011, Ablordeppey et al. reported a practical method for
the preparation of -carboline derivatives in moderate
yields by intramolecular Pd-catalyzed arylation of N-aryl-3-
aminopyridine.17p In 2012, Detert et al. reported a six-step
synthesis of -carbolines starting from 2-chloro-3-nitropy-
ridine.17q In the same year, the Cao group developed a
method for the preparation of -carbolines using a Pd-cata-
lyzed cyclization of 2-iodoanilines with N-tosyl-
enynamines.17r In 2015, we reported a convenient synthesis
of -carboline derivatives from 1,2-dibromopyridine via se-
quential site-selective Pd-catalyzed C–C/C–N coupling reac-
tions.17s
Known methods often result in the formation of regio-
isomeric products or require the use of expensive transi-
tion-metal catalysts (Au, Rh, Ru, Pd). In our previous work
related to the chemoselective synthesis of carbolines,17m,s
we studied twofold Pd-catalyzed C–N coupling reactions as
the key steps for the formation of the carboline rings. The
application of inexpensive, stable, and readily available cop-
per salts instead of expensive transition-metal catalysts in
combination with often expensive ligands is of considerable
current interest in the field of organic synthesis. Recently,
we have reported a practical method using Cu catalyst for
the synthesis of carbazole derivatives.18 In exploration of
further applications in Cu-catalyzed double C–N coupling
reactions, herein, we wish to report a convenient, inexpen-
sive, and practical method for the Cu-catalyzed synthesis of
- and -carboline derivatives from readily available start-
ing materials (Scheme 1). Our methodology shows toler-
ance of many functional groups and proceeds in good yields
and with high selectivity.
HOOC
O
N
BnO
MeO
O
N
N
H
H
O
NH
NH2
O
N
H
OH
N
H
N
Lavendamycin
Abecamil
N
H
N
N
OH
N
H
HO
Manzamine A
N
N
O
Quindoline
HO
N
δ
γ
O
HO
N
N
β
HN
Me
α
N
H
Structure of carbolines
Cryptoquindoline
Jusbetonin
Figure 1 Several natural alkaloids containing the carbazole core
Carboline derivatives also play a role in the develop-
ment of novel light-emitting devices (hole-transporting, lu-
minescent, and host materials).12 In order to improve elec-
tron-carrier mobility, quantum yield efficiency, and stabili-
ty of organic materials, the carbazole moiety of such
materials was successfully replaced by - and -carboline
structures.12
Due to their importance, a variety of classical and mod-
ern methods have been developed for the synthesis of car-
boline derivatives. Classical methods for the synthesis of -
carbolines rely on the Cadogan,13 Bischler–Napieralski,14
and Pictet–Spengler15 reactions. In 2011, Cuny et al. devel-
oped a metal-free synthesis of four types of carbolines
based on photostimulated cyclization of anilinohalopyri-
dines via the SRN1 mechanism.16 Efficient catalytic ap-
proaches to -carbolines have also been reported.17 For ex-
ample, Shu et al. demonstrated an Au-catalyzed synthesis of
3-amino--carbolines via [4+2] cycloaddition of azides and
ynamides.17a In addition, - and -carbolines were prepared
by Ru- and Rh-catalyzed [2+2+2] cycloadditions.17b Recent-
ly, a Cu-catalyzed arene–ynamide cyclization has been de-
scribed.17c Several syntheses of -carbolines by using palla-
dium catalysts have been reported. The first study on the
synthesis of four types of carbolines via a tandem process of
Pd-catalyzed amination and intramolecular arylation reac-
tions has been reported in 1999.17d Typical reports on the
Pd-catalyzed synthesis of -carbolines involve iminoannu-
lation reactions of alkynes,17e,f,h tandem C–N coupling/C–H
activation reactions of anilines with halopyridines,17i cy-
clizations of tryptophan-derived isocyanides and aryl io-
dides,17j -arylations of ketones with 3-bromoindoles,17k
and cyclizations of vinylindoles.17l Recently, we described
an efficient synthesis of -carboline derivatives from 3,4-
dibromopyridine via site-selective Pd-catalyzed C–C cou-
pling reactions with o-bromophenyl boronic acid, followed
by twofold cyclizations with amines.17m
X
X
+ RNH2
+ RNH2
N
[Pd] cat.
[Cu] cat.
N
N
R
N
X
X
(X = Br, Cl)
Our previous reports
(X = Br) This work
Scheme 1 Synthesis of carbolines by double N-arylation reactions
The starting material 3-bromo-2-(2-bromophenyl)pyri-
dine (1a) was prepared following our previously reported
procedure.17s The twofold C–N coupling reaction of 1a with
benzyl amine (2a, 1.5 equiv), using 20 mol% of Cu catalyst in
combination with 24 mol% of ligand at 120 °C resulted in
the formation of the desired carboline 3a (Table 1). Several
key reaction factors which may influence this transforma-
tion, including copper source, ligand, and solvent, were
screened to optimize the yield. In order to find a suitable li-
In contrast to -, -, and -carbolines, several synthetic
methods using Pd catalysis have been also reported for the
synthesis of -carbolines.17n–s In 1997, Yang et al. developed
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

C
B. Van Phuc et al.
Letter
Synlett
Table 1 Optimization of the Synthesis of -Carbolinea
ployed. Finally, a control experiment without using CuI cat-
alyst was performed which did not give even trace amounts
of -carboline product (entry 16). In contrast, employment
of PdCl2 instead of CuI provided the product, albeit in only
15% yield. It seems unlikely to us that the reaction might be
catalyzed by Pd impurities present in the copper iodide as
the purity of CuI was relatively high (Aldrich, 99%). In addi-
tion, phosphane ligands as typical for Pd(0)-catalyzed
Buchwald–Hartwig reactions were not present in the reac-
tion mixture.
N
Br
N
[Cu] (20 mol%), ligand
H2N
+
Ph
N
base, 120 °C
solvent, 24 h
Br
Ph
1a
2a
3a
Entry Catalyst Ligand
Base
Solvent
Yield (%)b
1
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
CuI
CuI
CuI
–
BINAP
dppe
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
45
36
52
42
40
90
79
82
47
72
85
83
82
85
–
With our optimized conditions in hand,20,21 we studied
the substrate scope of this transformation using several dif-
ferent amines, and indeed, a series of products could be
successfully prepared (Scheme 2). -Carboline derivatives
bearing with a variety of functional groups were obtained
in 60–95% yields (3a–o). The use of both benzylic and ali-
phatic amines resulted in high yields. In fact, with benzyl
amine derivatives containing electron-donating groups
(methyl and methoxy), up to 95% yield of the desired carbo-
line was isolated (3b). In contrast, lower yields were ob-
tained in the presence of electron-withdrawing groups, due
to the weaker nucleophilic properties of these amines (3d–
3
IPr·HCl
4
1,10-phenanthroline
bipyridine
L-proline
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
KOtBu
KOH
5
6
7
L-proline
8
L-proline
9
L-proline
10
11
12
13
14
15
16
L-proline
L-proline
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
L-proline
L-proline
Br
N
L-proline
NMP
CuI/L-proline
N
R-NH2
N
R
+
L-proline
dioxane
DMSO
120 °C, DMSO, 24 h
Br
1a
L-proline
–
3a–o
2a–o
a Reaction conditions: 1a (1.3 mmol), 2a (2.0 equiv), base (3 equiv), [Cu]
catalyst (20 mol%), ligand (20 mol%), 120 °C, 24 h.
b Yields of isolated products.
N
N
N
N
N
N
N
N
gand, we initially chose K2CO3 as the base and DMSO as the
solvent. Our initial optimizations started with employment
of phosphine and carbene ligands, for example, BINAP,
dppe, IPr which, however, gave carboline 3a in only low
yields (entries 1–3). Then, bipyridine ligands were exam-
ined which also did not result in satisfactory results (en-
tries 4, 5). Recently, amino acids and their derivatives were
shown to be efficient bidentate ligands in combination with
copper sources for C–N coupling reactions.19 We employed
simple L-proline as the ligand which gave the desired prod-
uct in 90% yield (entry 6). Then, a quick examination using
different bases was carried out. However, other bases did
not give better yields of the carboline product (entries 7–
10). In order to understand the influence of the copper
sources in this reaction, we carried out some further opti-
mizations using other common copper salts, such as CuBr
and CuCl (entries 11, 12). Indeed, an 85% yield of carboline
product was observed using CuBr as the catalyst. Subse-
quently, we tried to evaluate the role of the solvent and
used, for example, NMP, DMF, and dioxane under the stan-
dard conditions described above (entries 13–15). Still, an
85% yield of -carboline product was obtained when the re-
action was carried out in NMP. However, only trace
amounts of product were observed when dioxane was em-
OMe
F
Me
3c, 90%
3b, 95%
3d, 93%
3a, 90%
N
N
N
N
N
N
N
N
2
CF3
F
F
Me
3g, 91%
3f, 70%
3h, 86%
3e, 80%
N
N
N
N
N
N
N
N
MeO
3k, 88%
OMe
SMe
OMe
3l, 91%
3i, 80%
3j, 85%
N
N
N
N
N
N
F
F
F
Me
3m, 92%
3o, 60%
3n, 90%
Scheme 2 Synthesis of -carboline derivatives 3a–o. Reagents and con-
ditions: 2a–o (2.0 equiv), K2CO3 (3 equiv), [Cu] catalyst (20 mol%), li-
gand (20 mol%), 120 °C, 24 h; yields of isolated products are given.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

D
B. Van Phuc et al.
Letter
Synlett
f). Subsequently, anilines were employed, and the desired
carboline products could again be isolated in good yields
(3i–o).
Finally, we applied our procedure to the synthesis of -
carboline derivatives (4a–h) by double Cu-catalyzed cy-
clization of intermediate 1b with amines 2a–h. The desired
-carbolines 4a–h could be prepared in 38–84% yields.22,23
While the reactions of benzylic and aliphatic amines with
1b proceeded in good yields (4a–f, Scheme 3), employment
of anilines resulted only in moderate yields.
References and Notes
(1) (a) Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14,
479. (b) Alekseyev, R. S.; Kurkin, A. V.; Yurovskaya, M. A. Chem.
Heterocycl. Compd. 2009, 45, 889. (c) Kumar, E. V.; Etukala, J. R.;
Ablordeppey, S. Y. Mini.-Rev. Med. Chem. 2008, 8, 538.
(d) Smirnova, O. B.; Golovko, T. V.; Granik, V. G. Pharm. Chem. J.
2011, 45, 389.
(2) Dai, J.; Dan, W.; Schneider, U.; Wang, J. Eur. J. Med. Chem. 2018,
157, 622.
(3) (a) Kobayashi, J.; Harbour, G. C.; Gilmore, J.; Rinehart, K. L. J. Am.
Chem. Soc. 1984, 106, 1526. (b) Rinehart, K. L.; Kobayashi, J.;
Harbour, G. C.; Hughes, R. G.; Mizsak, S. A.; Scahill, T. A. J. Am.
Chem. Soc. 1984, 106, 1524.
(4) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am. Chem.
Soc. 1986, 108, 6404.
(5) (a) Uredi, D.; Motati, D. R.; Watkins, E. B. Org. Lett. 2018, 20,
6336. (b) Kumar, S.; Singh, A.; Kumar, K.; Kumar, V. Eur. J. Med.
Chem. 2017, 142, 48.
Br
N
N
CuI/L-proline
RNH2
N
R
+
120 °C, DMSO, 24 h
Br
1b
4a–h
2a–h
N
N
N
N
(6) (a) Subbaraju, G. V.; Kavitha, J.; Rajasekhar, D.; Jimenez, J. I.
J. Nat. Prod. 2004, 67, 461. (b) Paulo, A.; Gomes, E. T.; Steele, J.;
Warhurst, D. C.; Houghton, P. J. Planta Med. 2000, 66, 30.
(c) Sharaf, M. H. M.; Schiff, P. L.; Tackie, A. N.; Phoebe, C. H.;
Johnson, R. L.; Minick, D.; Andrews, C. W.; Crouch, R. C.; Martin,
G. E. J. Heterocycl. Chem. 1996, 33, 789. (d) Yang, S.-W.; Abdel-
Kader, M.; Malone, S.; Werkhoven, M. C. M.; Wisse, J. H.;
Bursuker, I.; Neddermann, K.; Fairchild, C.; Raventos-Suarez, C.;
Menendez, A. T.; Lane, K.; Kingston, D. G. I. J. Nat. Prod. 1999, 62,
976.
N
N
N
N
OMe
N
F
4c, 61%
4d, 68%
4b, 69%
4a, 67%
N
N
N
N
N
N
2
N
Me
OMe
4h, 38%
(7) (a) Okamoto, T.; Akase, T.; Izumi, S.; Inaba, S.; Yamamoto, H. JP
7220196, 1972; Chem. Abstr. 1972, 152142 (b) Winters, J.; Di
Mola, N. West German Patent 2442513, 1975, Chem. Abstr. 1975,
156255
4e, 70%
4f, 84%
4g, 44%
Scheme 3 Synthesis of -carboline derivatives 4a–h. Reagents and con-
ditions: 2a–h (2.0 equiv), K2CO3 (3 equiv), [Cu] catalyst (20 mol%), li-
gand (20 mol%), 120 °C, 24 h; yields of isolated products are given.
(8) (a) Seville, S.; Phillips, R. M.; Shnyder, S. D.; Wright, C. W. Bioorg.
Med. Chem. 2007, 15, 6353. (b) Riechert-Krause, F.; Eick, A.;
Grunert, R.; Bednarski, P. J.; Weisz, K. Bioorg. Med. Chem. Lett.
2011, 21, 2380. (c) Li, B.; Yue, Z.-Z.; Feng, J.-M.; He, Q.; Miao, Z.-
H.; Yang, C.-H. Eur. J. Med. Chem. 2013, 66, 531.
(d) Rajanarendar, E.; Govardhan Reddy, K.; Ramakrishna, S.;
Nagi Reddy, M.; Shireesha, B.; Durgaiah, G.; Reddy, Y. N. Bioorg.
Med. Chem. Lett. 2012, 22, 6677. (e) Yin, R.; Zhang, M.; Hao, C.;
Wang, W.; Qiu, P.; Wan, S.; Zhang, L.; Jiang, T. Chem. Commun.
2013, 49, 8516. (f) Boddupally, P. V. L.; Hahn, S.; Beman, C.; De,
B.; Brooks, T. A.; Gokhale, V.; Hurley, L. H. J. Med. Chem. 2012,
55, 6076. (g) Beauchard, A.; Jaunet, A.; Murillo, L.; Baldeyrou, B.;
Lansiaux, A.; Chérouvrier, J.-R.; Domon, L.; Picot, L.; Bailly, C.;
Besson, T.; Thiéry, V. Eur. J. Med. Chem. 2009, 44, 3858.
(9) (a) Rocha e Silva, L. F.; Montoia, A.; Amorim, R. C. N.; Melo, M. R.;
Henrique, M. C.; Nunomura, S. M.; Costa, M. R. F.; Andrade Neto,
V. F.; Costa, D. S.; Dantas, G.; Lavrado, J.; Moreira, R.; Paulo, A.;
Pinto, A. C.; Tadei, W. P.; Zacardi, R. S.; Eberlin, M. N.; Pohlit, A.
M. Phytomedicine 2012, 20, 71. (b) Van Baelen, G.; Hostyn, S.;
Dhooghe, L.; Tapolcsányi, P.; Mátyus, P.; Lemière, G.;
Dommisse, R.; Kaiser, M.; Brun, R.; Cos, P.; Maes, L.; Hajós, G.;
Riedl, Z.; Nagy, I.; Maes, B. U. W.; Pieters, L. Bioorg. Med. Chem.
2009, 17, 7209.
In conclusion, we have reported a practical, inexpensive,
and efficient one-pot synthesis of - and -carboline deriv-
atives. The reactions rely on twofold Cu-catalyzed C–N cou-
pling reactions of 2,2′-dibromobiaryl compounds with
amines with tolerance of many functional groups. Our pro-
cedure could be advantageous for applications in both me-
dicinal chemistry and materials science.
Conflict of Interest
The authors declare no conflict of interest.
Funding Information
This research is funded by the Vietnam National Foundation for Sci-
ence and Technology Development (NAFOSTED, Grant Number
104.01-2020.35).
V
ietnamNatio
n
al
F
o
u
n
datio
n
forScie
n
cean
d
T
e
ch
n
o
lo
g
y
D
ev
e
lo
p
m
ent(1
0
4
.
0
1-2
0
2
0
.
3
5)
(10) Queiroz, M.-J. R. P.; Ferreira, I. C. F. R.; Gaetano, Y. D.; Kirsch, G.;
Calhelha, R. C.; Estevinho, L. M. Bioorg. Med. Chem. 2006, 14,
6827.
Supporting Information
(11) (a) Sako, K.; Aoyama, H.; Sato, S.; Hashimoto, Y.; Baba, M. Bioorg.
Med. Chem. 2008, 16, 3780. (b) Peczynska-Czoch, W.; Pognan,
F.; Kaczmarek, L.; Boratynski, J. J. Med. Chem. 1994, 37, 3503.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1720461. Su
p
p
ortingInformationS
u
p
p
ortingI
n
formatio
n
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

E
B. Van Phuc et al.
Letter
Synlett
(12) (a) Moon, J. S.; Ahn, D. H.; Kim, S. W.; Lee, S. Y.; Lee, J. Y.; Kwon,
J. H. RSC Adv. 2018, 8, 17025. (b) Im, Y.; Lee, J. Y. Chem. Commun.
2013, 49, 5948. (c) Junyou, P.; Hong, H. WO2018095396A1,
2017.
(13) Peng, H.; Chen, X.; Chen, Y.; He, Q.; Xie, Y.; Yang, C. Tetrahedron
2011, 67, 5725.
(14) Movassaghi, M.; Hill, M. D. Org. Lett. 2008, 10, 3485.
(15) Audia, J. E.; Droste, J. J.; Nissen, J. S.; Murdoch, G. L.; Evrard, D. A.
J. Org. Chem. 1996, 61, 7937.
(16) Laha, J. K.; Barolo, S. M.; Rossi, R. A.; Cuny, G. D. J. Org. Chem.
2011, 76, 6421.
(17) (a) Shu, C.; Wang, Y.-H.; Zhou, B.; Li, X.-L.; Ping, Y.-F.; Lu, X.; Ye,
L.-W. J. Am. Chem. Soc. 2015, 137, 9567. (b) Nissen, F.; Richard,
V.; Alayrac, C.; Witulski, B. Chem. Commun. 2011, 47, 6656.
(c) Li, L.; Chen, X.-M.; Wang, Z.-S.; Zhou, B.; Liu, X.; Lu, X.; Ye, L.-
W. ACS Catal. 2017, 7, 4004. (d) Iwaki, T.; Yasuhara, A.;
Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 1505. (e) Zhang,
H.; Larock, R. C. J. Org. Chem. 2002, 67, 9318. (f) Zhang, H.;
Larock, R. C. Org. Lett. 2001, 3, 3083. (g) Too, P. C.; Chua, S. H.;
Wong, S. H.; Chiba, S. J. Org. Chem. 2011, 76, 6159. (h) Ding, S.;
Shi, Z.; Jiao, N. Org. Lett. 2010, 12, 1540. (i) Namjoshi, O. A.;
Gryboski, A.; Fonseca, G. O.; Van Linn, M. L.; Wang, Z.-j.;
Deschamps, J. R.; Cook, J. M. J. Org. Chem. 2011, 76, 4721.
(j) Tang, S.; Wang, J.; Xiong, Z.; Xie, Z.; Li, D.; Huang, J.; Zhu, Q.
Org. Lett. 2017, 19, 5577. (k) Alves Esteves, C. H.; Smith, P. D.;
Donohoe, T. J. J. Org. Chem. 2017, 82, 4435. (l) Kamlah, A.; Lirk,
F.; Bracher, F. Tetrahedron 2016, 72, 837. (m) Hung, T. Q.; Hieu,
D. T.; Van Tinh, D.; Do, H. N.; Nguyen Tien, T. A.; Van Do, D.; Son,
L. T.; Tran, N. H.; Van Tuyen, N.; Tan, V. M.; Ehlers, P.; Dang, T. T.;
Langer, P. Tetrahedron 2019, 75, 130569. (n) Yang, C.-C.; Tai, H.-
column chromatography (silica gel, hexane/ethyl acetate = 20:1)
to yield 3-bromo-2-(2-bromophenyl)pyridine (1a)17s (2.20 g,
85%) as a colorless oil.
(21) General Procedure for the Synthesis of 5H-Pyrido[3,2-
b]indoles 3a–o
3-Bromo-2-(2-bromophenyl)pyridine (1a, 100 mg, 0.32 mmol),
4-fluoroaniline (116 mg, 0.958 mmol), copper(I) iodide (12 mg,
0.064 mmol, Aldrich, 99%), L-proline (11 mg, 0.096 mmol), and
K2CO3 (132 mg, 0.958 mmol) were dissolved in DMSO (1.5 mL)
and heated at 120 °C for 24 h. After cooling, the reaction
mixture was poured into water (50 mL) and extracted with
ethyl acetate (3 × 50 mL). The organic layer was dried over
MgSO4, filtered, and the solvent was evaporated in vacuo. The
residue was purified by column chromatography (silica gel, hex-
ane/ethyl acetate = 5:1) to yield 5-(4-methylbenzyl)-5H-pyr-
ido[3,2-b]indole (3b, 85 mg, 95%) as a white solid. 1H NMR (500
MHz, CDCl3):  = 8.57 (s, 1 H), 8.46 (s, 1 H), 7.65 (s, 1 H), 7.56–
7.50 (m, 1 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.35 (d, J = 6.8 Hz, 2 H),
7.07 (d, J = 7.9 Hz, 2 H), 7.01 (d, J = 7.9 Hz, 2 H), 5.47 (s, 2 H), 2.29
(s, 3 H). 13C NMR (126 MHz, CDCl3):  = 141.4, 137.5, 133.5,
129.6, 127.9, 126.4, 120.2, 109.3, 21.1. HRMS (ESI): m/z calcd for
C19H16N2 [M + 1]+: 273.1386; found: 273.1401.
(22) Preparation of 3-Bromo-4-(2-bromophenyl)pyridine (1b)
3,4-Dibromopyridine (2.00 g, 8.44 mmol), 2-bromophenylbo-
ronic acid (1.70 g, 8.44 mmol), and Pd(PPh3)4 (488 mg, 0.422
mmol) were added to a 250 mL Schlenk flask. The mixture was
backfilled several times with argon. To the mixture were added
K2CO3 (1 M, 25 mL), 5 drops of aqueous KOH (10%), and 35 mL of
THF, then backfilled several times with argon. The reaction was
heated at 70 °C for 18 h. The solvent was evaporated in vacuo.
The residue was extracted with ethyl acetate and water. The
organic layer was dried over MgSO4, filtered, and the solvent
was evaporated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/ethyl acetate = 20:1) to yield
3-bromo-4-(2-bromophenyl)pyridine (1b)17m (2.30 g, 80%) as a
colorless syrup.
M.; Sun, P.-J. J. Chem. Soc., Perkin Trans.
1 1997, 2843.
(o) Papamicaël, C.; Quéguiner, G.; Bourguignon, J.; Dupas, G.
Tetrahedron 2001, 57, 5385. (p) Mazu, T. K.; Etukala, J. R.; Jacob,
M. R.; Khan, S. I.; Walker, L. A.; Ablordeppey, S. Y. Eur. J. Med.
Chem. 2011, 46, 2378. (q) Detert, H.; Letessier, J. Synthesis 2011,
290. (r) Cao, J.; Xu, Y.; Kong, Y.; Cui, Y.; Hu, Z.; Wang, G.; Deng,
Y.; Lai, G. Org. Lett. 2012, 14, 38. (s) Hung, T. Q.; Dang, T. T.;
Janke, J.; Villinger, A.; Langer, P. Org. Biomol. Chem. 2015, 13,
1375.
(23) General Procedure for the Synthesis of 9H-pyrido[3,4-
b]indoles 4a–h
3-Bromo-2-(2-bromophenyl)pyridine (1a, 100 mg, 0.32 mmol),
4-fluoroaniline (116 mg, 0.958 mmol), copper(I) iodide (15.4
mg, 0.08 mmol), L-proline (11 mg, 0.096 mmol), and K2CO3 (132
mg, 0.958 mmol) were dissolved in DMSO (1.5 mL) and heated
at 160 °C for 24 h. After cooling, the reaction mixture was
poured into water (50 mL) and extracted with ethyl acetate (3 ×
50 mL). The organic layer was dried over MgSO4, filtered, and
the solvent was evaporated in vacuo. The residue was purified
by column chromatography (silica gel, hexane/ethyl acetate =
5:1) to yield 9-phenethyl-9H-pyrido[3,4-b]indole (4e, 61 mg,
(18) Do, H. N.; Quan, N. M.; Van Phuc, B.; Van Tinh, D.; Tien, N. Q.;
Nga, T. T. T.; Nguyen, V. T.; Hung, T. Q.; Dang, T. T.; Langer, P.
Synlett 2021, 32, 611.
(19) (a) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (b) Zhang, H.;
Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
(20) Preparation of 3-Bromo-2-(2-bromophenyl)pyridine (1a)
2,3-Dibromopyridine (2.00 g, 8.44 mmol), 2-bromophenyl
boronic acid (1.70 g, 8.44 mmol), and Pd(PPh3)4 (488 mg, 0.422
mmol) were added to a 250 mL Schlenk flask. The mixture was
backfilled several times with argon. To the mixture were added
K2CO3 (1 M, 25 mL), 5 drops of aqueous KOH (10%) and 35 mL of
THF, then backfilled several times with argon. The reaction was
heated at 70 °C for 18 h. The solvent was evaporated in vacuo.
The residue was extracted with ethyl acetate and water. The
organic layer was dried over MgSO4, filtered, and the solvent
was evaporated in vacuo. The yellow residue was purified by
1
70%) as a white solid. H NMR (500 MHz, CDCl3):  = 8.72 (s, 1
H), 8.43 (d, J = 4.9 Hz, 1 H), 8.14 (dt, J = 7.9, 1.0 Hz, 1 H), 7.95 (d,
J = 5.2 Hz, 1 H), 7.56 (ddd, J = 8.4, 7.1, 1.2 Hz, 1 H), 7.39–7.33 (m,
1 H), 7.32–7.23 (m, 2 H), 7.25–7.20 (m, 1 H), 7.23–7.17 (m, 2 H),
7.17 (ddt, J = 7.7, 5.7, 1.6 Hz, 1 H), 7.11–7.05 (m, 2 H), 4.59 (t, J =
7.4 Hz, 2 H), 3.15 (t, J = 7.4 Hz, 2 H). 13C NMR (126 MHz, CDCl3):
 = 141.1, 138.5, 138.2, 131.7, 128.8, 128.7, 128.7, 128.6, 128.5,
126.9, 126.4, 122.0, 121.1, 119.8, 109.4, 45.3, 35.5. HRMS (ESI):
m/z calcd for C19H16N2 [M + 1]+: 273.1386; found: 273.1400.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E