Chemoselective functionalization of α-carbolines at the C-2, C-3, C-4, and C-6 positions using Suzuki-Miyaura reactions

Article abstract of DOI:10.1016/j.tet.2009.04.032

The synthesis of 2-, 3-, 4-, and 6-substituted pyrido[2,3-b]indoles (α-carbolines) by palladium-catalyzed cross-coupling reactions from the corresponding halopyrido[2,3-b]indoles is described. A sequential and a one-pot chemoselective double Suzuki-Miyaur

Full text of DOI:10.1016/j.tet.2009.04.032

Tetrahedron 65 (2009) 5427–5437
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemoselective functionalization of
a
-carbolines at the C-2, C-3, C-4,
and C-6 positions using Suzuki–Miyaura reactions
a
a
b
a,
*
´
ˆ
Cedric Schneider , David Gueyrard , Benoıt Joseph , Peter G. Goekjian
a Universite´ de Lyon, Laboratoire Chimie Organique 2dGlycochimie, ICBMS, CNRS, UMR-5246, Universite´ Claude BernarddLyon 1,
ˆ
Batiment CuriendCPE Lyon, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
b
´
´
Universite de Lyon, Laboratoire Chimie Organique 1, ICBMS, CNRS, UMR-5246, Universite Claude BernarddLyon 1,
ˆ
Batiment CuriendCPE Lyon, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 2-, 3-, 4-, and 6-substituted pyrido[2,3-b]indoles (a-carbolines) by palladium-catalyzed
Received 25 February 2009
Received in revised form 3 April 2009
Accepted 9 April 2009
cross-coupling reactions from the corresponding halopyrido[2,3-b]indoles is described. A sequential and
a one-pot chemoselective double Suzuki–Miyaura coupling route is presented for the synthesis of
symmetrically and unsymmetrically disubstituted pyrido[2,3-b]indoles.
Available online 17 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
(
a
-carbolines) through Suzuki–Miyaura cross-coupling reactions
(Scheme 1). The -carboline skeleton is encountered in a variety of
biologically active natural products,11 yet the functionalization of
the
-carboline ring system itself remains largely underexploited.12
a
The Suzuki–Miyaura cross-coupling reaction is among the most
widely used Csp2–Csp2 bond-forming reactions in organic synthe-
sis.1 Much recent work has been directed toward the development
of new catalysts in order to extend the scope of the reaction to aryl
chlorides as coupling partners.2 The properties of the palladium
ligands have a significant impact on the outcome of the coupling
reaction, as palladium complexes derived from sterically hindered
and electron-rich phosphines were found to be effective catalysts
for the coupling of aryl chlorides.3 Some notable examples include
the use of bulky trialkylphosphines such as P(tBu3) by Fu,4 or di-
alkylbiphenylphosphines such as S-Phos by Buchwald.5
a
In particular, reports of Pd-catalyzed cross-coupling reactions of
pyrido[2,3-b]indoles are very limited in the literature.13 We there-
fore decided to investigate this question, with an eye toward de-
veloping chemoselective cross-coupling strategies in order to allow
rapid and convenient functionalization of C-2, C-3 or C-4-chlorine-
substituted 6-bromopyrido[2,3-b]indoles.
2. Results and discussion
Chlorine-substituted heterocycles have been employed less
commonly than aryl chlorides as substrates for Suzuki–Miyaura
cross-coupling reactions.6 Reports of Csp2–Csp2 bond formation on
chloro-substituted nitrogen heterocycles, such as chloropyr-
We selected the readily accessible chloropyrido[2,3-b]indoles
as initial starting materials for the study of Suzuki–Miyaura
coupling reactions for introducing carbon side chains onto the a-
carboline ring system. Thus, 2- and 3-chloropyrido[2,3-b]indoles 1
and 2 were synthesized by a Graebe–Ullmann reaction from
chloropyridines in two steps.14 The 4-chloropyrido[2,3-b]indole 3
was prepared by Reissert-Henze reaction on pyrido[2,3-b]indole
N-oxide.15
idines,6a–c,7 azaindoles,8 quinolines,9 and
b
-carbolines,10 have
been described in the presence of different Pd–L catalysts. In
particular, the catalytic Pd/S-Phos system was described for ami-
noheteroaryl chlorides in several articles.5a–c,6b Extending the
cross-coupling reaction to other heteroaryl substrates, in partic-
ular for sequential double coupling reactions, remains of current
interest.
R2
Cl
N
Ar
N
X
Pd0, ArB(OH)2
We report herein the functionalization of the C-2, C-3, C-4, and
C-6 positions of mono- and dihalogenated pyrido[2,3-b]indoles
symmetrical
or unsymmetrical
substitution
N
N
R1
R1
R1 = H, SO2Ph; X = H, Br
R1 = H, SO2Ph; R2 = H, Ar'
* Corresponding author. Fax: þ33 (0)4 78 89 89 14.
E-mail address: goekjian@univ-lyon1.fr (P.G. Goekjian).
Scheme 1. Functionalization of
Suzuki–Miyaura reactions.
a-carbolines at the 2-, 3-, 4-, and 6-positions using
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.032

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C. Schneider et al. / Tetrahedron 65 (2009) 5427–5437
Table 1
Suzuki–Miyaura reactions on chloropyrido[2,3-b]indoles 1–3
Cl
i) or ii)
8-19
ArB(OH)2
+
N
N
H
4-7
1: 2-Cl, 2: 3-Cl, 3: 4-Cl
Entry
1
Catalytic systema
Pd(PPh3)4
Pyridoindoles
ArB(OH)2
Products
Yield (%)
70
B(OH)2
B(OH)2
MeO
1
8
9
N
MeO
N
H
4
2
3
Pd(OAc)2/S-Phos
Pd(OAc)2/S-Phos
68
68
Ph
1
1
N
N
H
5
4
5
Pd(OAc)2/S-Phos
10
81
83
B(OH)2
N
O
N
O
H
6
O2N
Pd(PPh3)4
1
2
11
12
O2N
B(OH)2
N
N
7
H
MeO
6
7
8
Pd(OAc)2/S-Phos
Pd(OAc)2/S-Phos
Pd(OAc)2/S-Phos
4
73
68
65
N
N
H
Ph
2
2
2
5
6
7
13
14
15
N
N
H
O
N
N
H
O2N
9
Pd(OAc)2/S-Phos
70
N
N
H
10
11
Pd(PPh3)4
70
71
OMe
Pd(OAc)2/S-Phos
3
4
16
N
N
N
H
Ph
12
Pd(OAc)2/S-Phos
3
5
17
72
N
H

C. Schneider et al. / Tetrahedron 65 (2009) 5427–5437
5429
Table 1 (continued )
Entry
Catalytic systema
Pyridoindoles
ArB(OH)2
Products
Yield (%)
76
O
13
Pd(OAc)2/S-Phos
3
6
18
N
N
H
NO2
14
Pd(PPh3)4
3
7
19
77
N
N
H
a
Reaction conditions: (i) Pd(OAc)2 (8 mol %), S-Phos (16 mol %), K3PO4 (2 equiv), 1,4-dioxane (2.5 mL/mmol), ArB(OH)2 (1.1 equiv), 100 ꢀC, overnight or (ii) Pd(PPh3)4
(8 mol %), K2CO3 (3 equiv), ArB(OH)2 (1.2 equiv), 1,4-dioxane/H2O, 100 ꢀC, 12 h.
2.1. Suzuki–Miyaura reactions of 2-, 3-, and 4-
chloropyrido[2,3-b]indoles
Pd(OAc)2/S-Phos nor Pd(PPh3)4, allowed us to obtain a coupling
product directly from 6-bromo-3-chloropyrido[2,3-b]indole 21,
presumably due to the poor solubility of this substrate under the
reaction conditions. In order to overcome this problem, the nitro-
gen atom was protected using NaH and benzenesulfonyl chloride in
THF to give 23–25. The 3-chloro derivative 24 undergoes palla-
dium-catalyzed cross-coupling reaction with Pd(PPh3)4 and 4-
methoxyphenyl- or (E)-phenylvinylboronic acids 4 and 5 to afford
Our initial studies focused on the straightforward functionali-
zation of the a-carboline using palladium-catalyzed coupling re-
actions on chloropyrido[2,3-b]indoles. Two catalytic systems were
investigated, the Buchwald (Pd/S-Phos) and a traditional palladium
catalyst, Pd(PPh3)4 (Table 1). The 2-, 3-, and 4-chloro-substituted a-
carbolines 1–3 each undergoes clean cross-coupling reactions us-
ing the Buchwald catalytic system in 65–81% yields. This method
allowed the coupling of each substrate with 4-methoxyphenyl-,
(E)-styryl-, furan-2-yl- or 3-nitrophenylboronic acid 4–7 in good
yields (entries 2–4, 6–9, and 7–9, Table 1). However, Pd(PPh3)4 was
found to be equally effective for the coupling of 2- and 4-chloro-
pyrido[2,3-b]indoles 1 and 3 with the two arylboronic acids tested
(entries 1, 5, 10, and 14, Table 1). The cross-coupling reaction of 3-
chloropyrido[2,3-b]indole 2 using Pd(PPh3)4 as catalyst failed, as
only the Pd(OAc)2/S-Phos catalyst system under non-aqueous
conditions was able to produce the 3-substituted compounds in
good yield. These results are consistent with literature studies of
the reactivity of 2-, 3-, and 4-chloropyridines.1d
3-chloro-6-substituted-a-carbolines 27 and 30 in good yields (en-
tries 4 and 5, Table 2). Given the lower reactivity of the C-3-chlorine
bond of 24, the coupling reactions could be performed successfully
at 100 ꢀC in 1,4-dioxane/H2O (Scheme 2).
Inthe case of the 2-and4-chloro derivatives, the 6-substituted-a-
carbolines were obtained in lower yields at high temperature, due to
a poor chemoselectivity between the more reactive carbon–chlorine
bonds and the carbon–bromine bond. For example at 100 ꢀC (entries
1 and 2, Table 2), compound 26 was obtained in only 37% yield, along
with 41% of the disubstituted compound 37 and 20% of unreacted
starting material. Therefore, milder conditions at 70 ꢀC in THF/H2O
were tested, which allowed for the chemoselective Suzuki–Miyaura
reaction at the C-6 position of the 2- and 4-chloro compounds 23 and
25. These conditions afforded the corresponding mono-coupled
products 26, 28, 29, and 31 (entries 1, 3, 6, and 7, Table 2) in good
yields with little or none of the disubstituted products or unreacted
starting material.
2.2. Chemoselective Suzuki–Miyaura reactions of 2-, 3-, and
4-chloropyrido[2,3-b]indoles bearing a bromine at the C-6
position
Cl
Br
Chemoselective cross-coupling reactions of bromine-
substituted a-carbolines in the presence of a chlorine substituent
i)
1-3
on the pyrido ring were investigated, with an eye toward de-
veloping a sequential double coupling strategy. Regioselective
electrophilic bromination of pyrido[2,3-b]indoles 1–3 was achieved
in the presence of bromine in CH2Cl2 to afford the corresponding
6-bromo compounds 20–22 in fair yields.12a
N
OMe
N
R
Cl
20-22: R = H
ii)
iii) or iv)
23-25: R = SO2Ph
N
The cross-coupling reaction was first investigated using the less
reactive 3-chloro isomer 21. Unfortunately, neither catalytic system,
N
iii) or iv)
Ph
SO2Ph
26: 2-Cl, 27: 3-Cl, 28: 4-Cl
Table 2
Chemoselective Suzuki–Miyaura reactionsa
Cl
Entry
Pyridoindoles
ArB(OH)2
Temperature (ꢀC)
Products
Yield (%)
N
1
2
3
4
5
6
7
23
23
23
24
24
25
25
4
4
5
4
5
4
5
70
100
70
100
100
70
26
26
29
27
30
28
31
58
37
64
83
71
70
68
N
SO2Ph
29: 2-Cl, 30: 3-Cl, 31: 4-Cl
Scheme 2. (i) Br2 (1.2 equiv), CH2Cl2, rt, 90 min, 20¼75%, 21¼78%, 22¼76%. (ii) 60%
NaH (1.1 equiv), PhSO2Cl (1.2 equiv) THF, 0 ꢀC to rt, 12 h, 23¼90%, 24¼91%, 25¼85%. (iii)
Pd(PPh3)4 (8 mol %), K2CO3 (3 equiv), ArB(OH)2 (1.1 equiv), H2O/THF, 70 ꢀC, 12 h. (iv)
Pd(PPh3)4 (8 mol %), K2CO3 (3 equiv), ArB(OH)2 (1.1 equiv), 1,4-dioxane/H2O, 100 ꢀC,
12 h.
70
a
Pd(PPh3)4 (8 mol %), K2CO3 (3 equiv), ArB(OH)2 (1.1 equiv), H2O/THF or 1,4-di-
oxane, 12 h.

5430
C. Schneider et al. / Tetrahedron 65 (2009) 5427–5437
OMe
one-pot double Suzuki–Miyaura reaction conditions. Thus, we ap-
OMe
plied such conditions to 6-bromo-chloropyrido[2,3-b]indoles
23–25 (Scheme 4).
The use of 4-methoxyphenylboronic acid (4) (2.2 equiv) in the
presence Pd(PPh3)4 in 1,4-dioxane/H2O at 100 C according to Mer-
R3
R2
R1
i) or ii)
Cl
ꢀ
´
N
our’s procedure16 allowed us to obtain the desired symmetrically
2,6- and 4,6-disubstituted compounds 37 and 39 in 90% and 89%
yields, respectively. One-pot coupling conditions for the preparation
N
N
N
SO2Ph
32: R1 = (E)-styryl, R2 = R3 = H
33: R2 = (E)-styryl, R1 = R3 = H
34: R1 = R2 = H, R3 = (E)-styryl
SO2Ph
26- 28
of 3,6-diaryl-a-carbolines using 4-methoxyphenylboronic acid (4)
(3 equiv) in the presence of Pd(OAc)2/S-Phos in 1,4-dioxane at 100 ꢀC
provided the symmetrically disubstituted compound 38 in 81% yield.
We then sought to develop conditions for a regioselective
double coupling reaction in one pot to produce unsymmetrically
disubstituted compounds. Treatment of the 2,6- or 4,6-dihalo-
genated starting material 23 or 25 with 4-methoxyphenylboronic
acid (4) (1.1 equiv) and a catalytic amount of Pd(PPh3)4 in 1,4-di-
oxane/H2O at 70 ꢀC, followed by addition of the second boronic acid
5 at 100 ꢀC afforded products 32 and 34 in 54% and 71% yield,
respectively. We further developed a one-pot Suzuki–Miyaura
reaction with the Buchwald catalytic system (Pd/S-Phos) for the
preparation of unsymmetrically disubstituted 3,6-diaryl com-
pounds. Thus, treatment of the protected 6-bromo-3-chloropyr-
ido[2,3-b]indole 24 with 4-methoxyphenylboronic acid (4)
(1.2 equiv) and a catalytic amount of Pd(OAc)2/S-Phos, K3PO4, in
1,4-dioxane at 50 ꢀC, followed after 5 h by addition of the second
boronic acid 5 (2.5 equiv) at 100 ꢀC afforded the product 33 in 65%
yield. Such conditions can readily be applied to any combination of
boronic acids, and thus provides a convenient method for pro-
ducing a wide range of 2,6-, 3,6-, or 4,6-disubstituted pyrido[2,3-
b]indoles.
OMe
OMe
Cl
Ph
iv)
N
N
R
N
N
H
36
27: R = SO2Ph
35: R = H
iii)
Scheme 3. (i) Pd(PPh3)4 (8 mol %), K2CO3 (3 equiv), (E)-phenylvinylboronic acid (5)
(1.1 equiv), 1,4-dioxane/H2O, 100 ꢀC, 12 h, 32¼84%, 34¼87%. (ii) Pd(OAc)2 (8 mol %), S-
Phos (16 mol %), K3PO4 (3 equiv), (E)-phenylvinylboronic acid (5) (2.5 equiv), 1,4-di-
oxane (2.5 mL/mmol), 100 ꢀC, 12 h, 33¼79%. (iii) 1.0 M TBAF in THF (5 equiv), THF,
reflux, 4 h, 35¼84%. (iv) Pd(OAc)2 (8 mol %), S-Phos (16 mol %), K3PO4 (2.5 equiv), (E)-
phenylvinylboronic acid (5) (1.5 equiv), 1,4-dioxane/H2O (2.5 mL/mmol), 100 ꢀC, 12 h,
36¼65%.
2.3. Sequential double Suzuki–Miyaura coupling reactions of
2-, 3-, and 4-chloro-6-(4-methoxyphenyl)pyrido[2,3-b]indoles
The ability to substitute halogens sequentially by cross-coupling
reactions opens a simple route to diaryl-, aryl-, vinyl-, and
divinylsubstituted a-carbolines. Such an approach further allows
In conclusion, we have developed new routes to functionalize a-
carbolines through palladium-catalyzed Suzuki–Miyaura reactions.
This methodology provides a powerful tool for the preparation of
a wide range of 2-, 3-, 4-, and 6-substituted pyrido[2,3-b]indoles
and allows a rapid increase in molecular complexity. The sequential
or one-pot Suzuki–Miyaura synthetic routes thus provide access to
unsymmetrically disubstituted products such as 32, 33, 34, and 36
in 33–47% overall yield in 3–5 steps from the readily available
mono-substituted chloro-9H-pyrido[2,3-b]indoles 1–3.
for a variety of substitution patterns on the aryl and vinyl groups.
The unsymmetrically disubstituted pyrido[2,3-b]indoles 32–34
were therefore synthesized by performing a second palladium
coupling reaction at position C-2, C-3, and C-4 (Scheme 3) of the
products of the Suzuki–Miyaura reactions at C-6 described above.
Thus, treatment of the 6-aryl-2-chloro product 26 and the 6-
aryl-4-chloro coupling product 28 with Pd(PPh3)4, K2CO3, and (E)-
phenylvinylboronic acid (5) (1.1 equiv) in 1,4-dioxane/H2O at 100 ꢀC
afforded 6-(4-methoxyphenyl)-2-styryl-9H-pyrido[2,3-b]indole 32
and 6-(4-methoxyphenyl)-4-styryl-9H-pyrido[2,3-b]indole 34, re-
spectively, in excellent yields. The corresponding 9-benzene-
sulfonyl-6-(4-methoxyphenyl)-3-styryl-9H-pyrido[2,3-b]indole (33)
was synthesized from the less reactive 3-chloro compound 27 in
1,4-dioxane at 100 ꢀC in 79% yield using the Pd(OAc)2/S-Phos cat-
alyst system and a slightly larger excess of (E)-phenylvinylboronic
acid (5) (2.5 equiv). Alternatively, the 3-chloro product 27 was
deprotected with 1.0 M TBAF in THF at reflux to furnish 3-chloro-6-
(4-methoxyphenyl)-9H-pyrido[2,3-b]indole (35) in 84% yield
(Scheme 3); cross-coupling reaction at the C-3 position was then
OMe
R3
R2
R1
Cl
Br
i) or ii)
N
N
N
N
SO2Ph
SO2Ph
37: R1 = 4-MeOPh, R2 = R3 = H
38: R2 = 4-MeOPh, R1 = R3 = H
39: R1 = R2 = H, R3 = 4-MeOPh
23 - 25
iii) or iv)
performed on the unprotected
a-carboline 35, using a catalytic
OMe
amount of Pd(OAc)2/S-Phos, K3PO4, and (E)-phenylvinylboronic
acid (5) (1.5 equiv) in 1,4-dioxane at 100 ꢀC, to provide the desired
product 36 in 65% yield. The benzenesulfonyl-protected compound
27 gave a lower 48% yield with the same number of equivalents
showing that the protecting group interferes somewhat with the
coupling reaction.
R3
R2
R1
32: R1 = (E)-styryl, R2 = R3 = H
33: R2 = (E)-styryl, R1 = R3 = H
34: R1 = R2 = H, R3 = (E)-styryl
N
N
SO2Ph
Scheme 4. (i) Pd(PPh3)4 (8 mol %), K2CO3 (3 equiv), 4-methoxyphenylboronic acid (4)
(2.2 equiv), 1,4-dioxane/H2O, 100 ꢀC, 12 h, 37¼90%, 39¼89%. (ii) Pd(OAc)2 (8 mol %), S-
Phos (16 mol %), K3PO4 (3.0 equiv), 4-methoxyphenylboronic acid (4) (3 equiv), 1,4-
dioxane (2.5 mL/mmol), 100 ꢀC, 12 h, 38¼81%. (iii) Pd(PPh3)4 (8 mol %), K2CO3
(3 equiv), 4-methoxyphenylboronic acid (4) (1.1 equiv), 1,4-dioxane/H2O, 70 ꢀC, 4 h
then (E)-phenylvinylboronic acid (5) (1.1 equiv), 100 ꢀC, 2 h, 32¼54%, 34¼71%. (iv)
Pd(OAc)2 (8 mol %), S-Phos (16 mol %), K3PO4 (3.5 equiv), 4-methoxyphenylboronic
acid (4) (1.2 equiv), 1,4-dioxane (2.5 mL/mmol), 50 ꢀC, 5 h, then (E)-phenylvinylboronic
acid (5) (2.5 equiv), 100 ꢀC, 12 h, 33¼65%.
2.3.1. One-pot double Suzuki–Miyaura coupling
Finally, we investigated the possibility of developing more effi-
cient, one-pot sequential coupling conditions for preparation of
2,6-, 3,6-, and 4,6-diaryl-a-carbolines. Indeed, C–C bond formation
on two positions is usually realized in two steps, both in the liter-
ature and in the route described above (Scheme 3). However,
16
Beletskaya et al.9a,d and Merour et al. have recently developed
´

C. Schneider et al. / Tetrahedron 65 (2009) 5427–5437
5431
3. Experimental
3.1. General
3.2.2. 2-(Styryl)-9H-pyrido[2,3-b]indole (9)
Procedure A. The product was purified by flash chromatography
(CH2Cl2/EtOAc 9:1) to afford 9 (92 mg, 0.340 mmol) in 68% yield as
a white solid; mp>220 ꢀC; IR 3159, 3089, 3041, 2888, 1601, 1579,
1458, 1413, 1227, 954, 726, 685 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
All reactions were carried out under an argon atmosphere.
Solvents (THF, 1,4-dioxane) were distilled and dried by standard
methods 4-Methoxyphenylboronic acid (4) was purchased from
Maybridge. Pd(OAc)2 and furan-2-ylboronic acid (6) were pur-
chased from Acros. Pd(PPh3)4, S-Phos, (E)-phenylvinylboronic acid
(5), and 3-nitrophenylboronic acid (7) were purchased from
Aldrich. Reactions were routinely monitored by thin-layer chro-
matography (TLC) on silica gel 60 F254. Purifications on flash silica
gel column chromatography were performed with GeduranÒ silica
d
11.75 (br s, 1H), 8.48 (d, 1H, J¼7.9 Hz), 8.12 (d, 1H, J¼7.9 Hz), 7.72
(d, 1H, J¼16.0 Hz), 7.69 (d, 2H, J¼7.2 Hz), 7.46–7.40 (m, 6H), 7.34–
7.29 (m, 1H), 7.21 (td, 1H, J¼1.3 and 8.1 Hz); 13C NMR (75 MHz,
DMSO-d6) d 152.0 (C), 151.8 (C), 139.4 (C), 136.5 (C), 131.0 (CH), 128.9
(CH), 128.8 (2 CH), 128.8 (CH), 128.1 (CH), 126.9 (2 CH), 126.5 (CH),
120.9 (CH), 120.5 (C), 119.5 (CH), 114.9 (CH), 114.6 (C), 111.1 (CH); MS
(ESI) m/z 271.2 [MþH]þ; HRMS (ESI): Calcd for C19H15N2 [MþH]þ:
271.1235. Found: 271.1236.
gel Si 60 (40–63 m
m). 1H and 13C NMR spectra were recorded at
23 ꢀC. The following abbreviations are used to describe the ob-
served multiplicities: s, singlet; d, doublet; dd, doublet of doublets;
ddd, doublet of doublet of doublets; t, triplet; td, triplet of doublets;
m, multiplet; br s, broad singlet. 13C NMR multiplicities are based
on DEPT experiments. MS (EI, ESI and CI) and HRMS were recorded
in positive ion mode. Unless otherwise indicated, peaks corre-
sponding only to the major 35Cl isotope are given in the LRMS and
the HRMS, while the bromine isotopes are indicated in the LRMS (in
the case of HRMS, only 79Br isotope is given). Melting points are
uncorrected. IR spectra were recorded by attenuated-total-re-
flection (ATR) spectroscopy using a ZnSe crystal.
3.2.3. 2-(Furan-2-yl)-9H-pyrido[2,3-b]indole (10)
Procedure A. The product was purified by flash chromatography
(CH2Cl2) to afford 10 (95 mg, 0.405 mmol) in 81% yield as a brown
solid; mp 208–210 ꢀC; IR 3235, 2923, 1626, 1593, 1490, 1458, 1412,
1229, 1087, 884, 734 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
; d 11.85
(br s, 1H), 8.54 (d, 1H, J¼7.8 Hz), 8.13 (d, 1H, J¼7.8 Hz), 7.85 (d, 1H,
J¼1.7 Hz), 7.62 (d, 1H, J¼8.1 Hz), 7.48–7.41 (m, 2H), 7.22 (ddd, 1H,
J¼1.9, 6.8, and 8.1 Hz), 7.13 (d, 1H, J¼3.4 Hz), 6.68 (dd, 1H, J¼1.7 and
3.4 Hz); 13C NMR (75 MHz, DMSO-d6)
d 154.0 (C), 151.8 (C), 145.3
(CH), 143.8 (C), 139.3 (C), 129.1 (CH), 126.5 (CH), 120.9 (CH), 120.4
(C), 119.6 (CH), 114.3 (C), 112.3 (CH), 111.2 (CH), 110.2 (CH), 108.3
(CH); MS (CI isobutane) m/z 235 [MþH]þ; HRMS (CI isobutane):
Calcd for C15H11N2O [MþH]þ: 235.0871. Found: 235.0873.
3.2. General procedure for Suzuki reactions
Procedure A for Suzuki–Miyaura coupling with Pd(OAc)2/S-Phos. A
3.2.4. 2-(3-Nitrophenyl)-9H-pyrido[2,3-b]indole (11)
sealed pressure tube with a stir bar was charged with Pd(OAc)2
Procedure B. The product was purified by flash chromatography
(CH2Cl2/PE 9:1) to afford 11 (120 mg, 0.415 mmol) in 83% yield as
a yellow solid; mp 185–187 ꢀC; IR 3165, 3091, 1625, 1596, 1585,
(8 mol %), S-Phos (16 mol %),
a-carboline (100 mg, 0.498 mmol),
boronic acid (1.2 equiv), and K3PO4 (2 equiv). The tube was evacu-
ated and back-filled with argon (this was repeated three additional
times). Freshly degassed 1,4-dioxane (2.5 mL/mmol) was added
and the reaction mixture was stirred at 100 ꢀC overnight. After
cooling to rt, the solution was diluted with H2O and extracted with
EtOAc (3ꢁ20 mL). The combined organic layers were dried over
MgSO4, then filtered through Celite, and the solvent was removed
under reduced pressure. The product was purified as described
below and an analytical sample for mp was obtained by trituration
with MeOH.
Procedure B for Suzuki–Miyaura coupling with Pd(PPh3)4. At rt
under an inert atmosphere, Pd(PPh3)4 (8 mol %), boronic acid
(1.1 equiv), and 0.3 M aqueous K2CO3 solution (3 equiv) in H2O
were added to a 0.1 M solution of 1 or 3 (100 mg, 0.498 mmol) in
1,4-dioxane. This solution was stirred at 100 ꢀC for 12 h. After
cooling to rt, the solution was filtered through Celite and solvents
were removed under reduced pressure. The product was purified as
described below and an analytical sample for mp was obtained by
trituration with MeOH.
1518, 1455, 1414, 1346, 1286, 789, 755, 684 cmꢂ1
;
1H NMR
(300 MHz, DMSO-d6)
d
12.01 (br s, 1H), 9.03 (t, 1H, J¼1.7 Hz), 8.62
(d, 1H, J¼8.0 Hz), 8.60 (d, 1H J¼8.1 Hz), 8.25 (dd, 1H, J¼1.7 and
8.1 Hz), 8.19 (d, 1H, J¼7.7 Hz), 7.96 (d, 1H, J¼8.0 Hz), 7.79 (t, 1H,
J¼8.1 Hz), 7.51 (d, 1H, J¼8.9 Hz), 7.47 (td, 1H, J¼0.8 and 8.9 Hz), 7.25
(td, 1H, J¼1.5 and 7.9 Hz); 13C NMR (75 MHz, DMSO-d6)
d 152.0 (C),
150.0 (C), 148.5 (C), 141.0 (C), 139.6 (C), 132.7 (CH), 130.3 (CH), 129.5
(CH), 127.0 (CH), 123.1 (CH), 121.4 (CH), 120.9 (CH), 120.1 (C), 119.7
(CH), 115.4 (C), 112.2 (C), 111.3 (CH); MS (ESI) m/z 290.2 [MþH]þ,
244.3 [MꢂNO2þH]þ; HRMS (ESI): Calcd for C17H12N3O2 [MþH]þ:
290.0930. Found: 290.0931.
3.2.5. 3-(4-Methoxyphenyl)-9H-pyrido[2,3-b]indole (12)
Procedure A. The product was purified by flash chromatography
(CH2Cl2/EtOAc 9:1) to afford 12 (99 mg, 0.363 mmol) in 73% yield as
a yellow solid; mp>220 ꢀC (lit. mp 265–266 ꢀC (EtOH)17); IR 3125,
2979, 1607, 1587, 1570, 1519, 1455, 1244, 1231, 1034, 742 cmꢂ1 1H
;
NMR (300 MHz, DMSO-d6)
d
11.80 (br s, 1H), 8.75 (d, 1H, J¼2.1 Hz),
8.67 (d, 1H, J¼2.1 Hz), 8.23 (d, 1H, J¼7.9 Hz), 7.72 (d, 2H, J¼8.6 Hz),
3.2.1. 2-(4-Methoxyphenyl)-9H-pyrido[2,3-b]indole (8)
7.51–7.43 (m, 2H), 7.23 (td, 1H, J¼1.5 and 8.1 Hz), 7.07 (d, 2H,
Procedure A or B. The product was purified by flash chroma-
tography (CH2Cl2) to afford 8 as a white solid (procedure A: 93 mg,
0.339 mmol, 68% yield; procedure B: 96 mg, 0.350 mmol, 70%
yield); mp>220 ꢀC; IR 3136, 3083, 2958, 1596, 1583, 1572, 1457,
J¼8.6 Hz), 3.82 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d 158.6 (C),
151.1 (C), 144.4 (CH), 139.4 (C), 130.9 (C), 127.9 (2 CH), 127.4
(C),126.7 (CH),126.0 (CH),121.4 (CH),120.5 (C),119.3 (CH),115.3 (C),
114.5 (2 CH), 111.3 (CH), 55.2 (CH3); MS (ESI) m/z 275.2 [MþH]þ;
Anal. Calcd for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C,
78.46; H, 4.98; N, 10.44.
1415, 1028, 818 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
; d 11.80 (br s,
1H), 8.52 (d, 1H, J¼8.1 Hz), 8.14 (d, 2H, J¼8.9 Hz), 8.13 (br d, 1H,
J¼6.8 Hz), 7.74 (d, 1H, J¼8.1 Hz), 7.48 (br d, 1H, J¼7.3 Hz), 7.42 (td,
1H, J¼1.0 and 6.8 Hz), 7.21 (td, 1H, J¼1.3 and 7.9 Hz), 7.07 (d, 2H,
3.2.6. 3-(Styryl)-9H-pyrido[2,3-b]indole (13)
J¼8.9 Hz), 3.83 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
159.8 (C),
Procedure A. The product was purified by flash chromatography
(CH2Cl2/EtOAc 9:1) to afford 13 (91 mg, 0.338 mmol) in 68% yield as
a white solid; mp>220 ꢀC; IR 2973, 1604, 1496, 1456, 1403, 1243,
152.8 (C), 152.0 (C), 139.1 (C), 131.9 (C), 129.1 (CH), 128.0 (2 CH),
126.2 (CH), 120.9 (CH), 120.5 (C), 119.4 (CH), 114.1 (2 CH), 113.5 (C),
111.2 (CH), 111.1 (CH), 55.2 (CH3); MS (ESI) m/z 275.2 [MþH]þ;
HRMS (ESI): Calcd for C18H15N2O [MþH]þ: 275.1184. Found:
275.1186.
1109, 961, 741, 685 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
d 11.85 (br
s, 1H), 8.84 (d, 1H, J¼2.1 Hz), 8.62 (d, 1H, J¼2.1 Hz), 8.19 (d, 1H,
J¼7.7 Hz), 7.63 (d, 2H, J¼7.4 Hz), 7.51–7.34 (m, 6H), 7.30–7.22 (m,

5432
C. Schneider et al. / Tetrahedron 65 (2009) 5427–5437
2H); 13C NMR (75 MHz, DMSO-d6)
d
151.6 (C), 146.2 (CH), 139.4 (C),
3.2.11. 4-(Furan-2-yl)-9H-pyrido[2,3-b]indole (18)
137.4 (C),128.7 (2 CH),127.3 (CH),126.9 (CH),126.8 (CH),126.4 (CH),
126.2 (2 CH), 124.8 (CH), 124.7 (C), 121.3 (CH), 120.4 (C), 119.7 (CH),
115.5 (C), 111.4 (CH); MS (ESI) m/z 271.2 [MþH]þ; HRMS (ESI): Calcd
for C19H15N2 [MþH]þ: 271.1235. Found: 271.1236.
Procedure A. The product was purified by flash chromatography
(CH2Cl2/EtOAc 8:2) to afford 18 (88 mg, 0.376 mmol) in 76% yield as
a green solid; mp>220 ꢀC; IR 3135, 3062, 1617, 1590, 1546, 1454,
1264, 1026, 996, 733, 670 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
;
d
12.00 (br s, 1H), 8.50 (d, 1H, J¼8.5 Hz), 8.42 (d, 1H, J¼5.3 Hz), 8.13
3.2.7. 3-(Furan-2-yl)-9H-pyrido[2,3-b]indole (14)
(dd, 1H, J¼0.7 and 1.7 Hz), 7.54–7.51 (m, 1H), 7.48 (td, 1H, J¼1.1 and
6.9 Hz), 7.43 (d, 1H, J¼5.1 Hz), 7.31 (dd, 1H, J¼0.7 and 3.4 Hz), 7.21
(ddd, 1H, J¼1.5, 6.8, and 8.2 Hz), 6.82 (dd, 1H, J¼1.7 and 3.4 Hz); 13C
Procedure A. The product was purified by flash chromatogra-
phy (CH2Cl2/EtOAc 9:1) to afford 14 (75 mg, 0.320 mmol) in 65%
yield as a yellow solid; mp>220 ꢀC; IR 3124, 3079, 1628, 1604,
NMR (75 MHz, DMSO-d6)
d 153.0 (C), 151.7 (C), 145.8 (CH), 144.5
1445, 1234, 1005, 731, 722 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6)
(CH),139.2 (C),131.7 (C),126.7 (CH),123.7 (CH),119.7 (C),119.5 (CH),
112.5 (2 CH), 111.2 (CH), 111.1 (CH), 109.8 (C); MS (CI, isobutane) m/z
235 [MþH]þ; HRMS (CI isobutane): Calcd for C15H11N2O [MþH]þ:
235.0871. Found: 235.0872.
d
11.91 (br s, 1H), 8.80 (s, 2H), 8.23 (d, 1H, J¼7.9 Hz), 7.79 (dd, 1H,
J¼0.8 and 1.8 Hz), 7.51 (d, 1H, J¼8.1 Hz), 7.47 (td, 1H, J¼1.1 and
8.1 Hz), 7.24 (ddd, 1H, J¼1.9 and 7.2 Hz), 6.99 (dd, 1H, J¼0.7 and
3.4 Hz), 6.64 (dd, 1H, J¼1.8 and 3.4 Hz); 13C NMR (75 MHz, DMSO-
d6)
d
152.2 (C), 151.1 (C), 142.5 (CH), 142.4 (CH), 139.4 (C), 126.9
3.2.12. 4-(3-Nitrophenyl)-9H-pyrido[2,3-b]indole (19)
(CH), 123.3 (CH), 121.5 (CH), 120.4 (C), 119.7 (CH), 118.7 (C), 115.1
Procedure B. The product was purified by chromatography
(CH2Cl2/EtOAc 8:2) to afford 19 (110 mg, 0.380 mmol) in 77% yield
as a yellow solid; mp>220 ꢀC; IR 3063, 1622, 1599, 1561, 1523, 1456,
ꢃ
(C), 112.0 (CH), 111.4 (CH), 104.6 (CH); MS (EI) m/z 234.0 [M]þ
;
ꢃ
HRMS (EI): Calcd for C15H10N2O [M]þ
234.0792.
: 234.0793. Found:
1344, 1292, 815, 734 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
; d 12.11
(br s, 1H), 8.52 (d, 1H, J¼5.0 Hz), 8.48 (t, 1H, J¼1.8 Hz), 8.43 (ddd, 1H,
J¼1.0, 1.8, and 8.0 Hz), 8.18 (ddd, 1H, J¼1.0, 1.8, and 8.0 Hz), 7.93 (t,
1H, J¼8.0 Hz), 7.55 (d, 1H, J¼7.9 Hz), 7.46 (d, 1H, J¼7.9 Hz), 7.45 (td,
1H, J¼1.0 and 7.9 Hz), 7.21 (d, 1H, J¼5.0 Hz), 7.04 (td, 1H, J¼1.0 and
3.2.8. 3-(3-Nitrophenyl)-9H-pyrido[2,3-b]indole (15)
Procedure A. The product was purified by flash chromatography
(CH2Cl2/EtOAc 8:2) to afford 15 (100 mg, 0.346 mmol) in 70% yield
as a yellow solid; mp>220 ꢀC; IR 3127, 3069, 1606, 1523, 1343, 1231,
7.9 Hz); 13C NMR (75 MHz, DMSO-d6)
d 152.3 (C), 148.1 (C), 146.2
871, 733, 674 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
d
11.99 (br s, 1H),
(CH), 141.6 (C), 139.9 (C), 139.2 (C), 135.2 (CH), 130.6 (CH), 126.8
(CH), 123.5 (CH), 123.1 (CH), 121.7 (CH), 119.4 (CH), 119.2 (C), 115.8
(CH), 111.9 (C), 111.6 (CH); MS (ESI) m/z 290.2 [MþH]þ, 244.3
[MꢂNO2þH]þ; HRMS (ESI): Calcd for C17H12N3O2 [MþH]þ:
290.0930. Found: 290.0925; Anal. Calcd for C17H11N3O2: C, 70.58; H,
3.83; N, 14.52. Found: C, 70.30; H, 3.85; N, 14.20.
9.02 (d, 1H, J¼2.3 Hz), 8.85 (d, 1H, J¼2.3 Hz), 8.62 (t, 1H, J¼2.1 Hz),
8.32–8.27 (m, 2H), 8.23 (ddd, 1H, J¼1.0, 2.1, and 8.2 Hz), 7.81 (t, 1H,
J¼8.2 Hz), 7.55–7.46 (m, 2H), 7.27 (td, 1H, J¼1.5 and 7.2 Hz); 13C
NMR (75 MHz, DMSO-d6) d 152.2 (C),148.8 (C),145.3 (CH),140.7 (C),
139.8 (C), 133.6 (CH), 130.8 (CH), 127.3 (2 CH), 125.6 (C), 122.0 (CH),
121.9 (CH), 121.4 (CH), 120.8 (C), 120.1 (CH), 115.8 (C), 111.8 (CH); MS
(ESI) m/z 290.1 [MþH]þ; HRMS (ESI): Calcd for C17H12N3O2
[MþH]þ: 290.0930. Found: 290.0934.
3.3. General procedure for the bromation reaction
At rt and under an inert atmosphere, a solution of bromine
(1.2 equiv, 0.7 M) in CH2Cl2 was added to a 0.45 M suspension of 1
or 2 or 3 (1 equiv) in anhydrous CH2Cl2. The mixture was stirred for
1 h at rt. Excess bromine was reduced by addition of saturated
aqueous Na2S2O3 solution. The resulting mixture was extracted
with EtOAc/DMF (99:1). The combined organic phases were
washed with brine, dried over MgSO4, filtered, and evaporated
under reduced pressure. The product was purified by trituration
with MeOH.
3.2.9. 4-(4-Methoxyphenyl)-9H-pyrido[2,3-b]indole (16)
Procedure A or B. The product was purified by flash chroma-
tography (CH2Cl2/EtOAc 9:1) to afford 16 as a yellow solid (pro-
cedure A: 97 mg, 0.350 mmol, 71% yield, procedure B: 96 mg,
0.350 mmol, 70% yield); mp 208–210 ꢀC; IR 3062, 2968, 2835, 1599,
1560, 1515, 1456, 1252, 1176, 1029, 809, 745, 724 cmꢂ1 1H NMR
;
(300 MHz, DMSO-d6)
d
11.93 (br s, 1H), 8.41 (d, 1H, J¼5.0 Hz), 7.63
(d, 2H, J¼8.7 Hz), 7.60 (d, 1H, J¼9.0 Hz), 7.50 (d, 1H, J¼8.1 Hz), 7.40
(td, 1H, J¼0.9 and 7.2 Hz), 7.17 (d, 2H, J¼8.7 Hz), 7.06 (d, 1H,
J¼5.0 Hz), 7.04 (td, 1H, J¼1.1 and 7.5 Hz), 3.88 (s, 3H); 13C NMR
3.3.1. 6-Bromo-2-chloro-9H-pyrido[2,3-b]indole (20)
(75 MHz, DMSO-d6)
d
159.6 (C), 149.2 (C), 145.9 (CH), 144.1 (C),
Starting material 1: 500 mg, 2.49 mmol. Compound 20 was
obtained by trituration with MeOH (522 mg, 1.87 mmol, 75%
yield); mp>220 ꢀC; IR 3135, 3053, 2956, 1626, 1597, 1574, 1404,
138.9 (C), 130.6 (C), 129.8 (2 CH), 126.4 (CH), 121.9 (CH), 119.9 (C),
119.0 (CH), 115.9 (CH), 114.2 (2 CH), 112.1 (C), 111.3 (CH), 55.3 (CH3);
ꢃ
MS (ESI) m/z 275.2 [MþH]þ; HRMS (EI): Calcd for C18H14N2O [M]þ
:
1273, 1202, 1128, 794, 771 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
;
274.1106. Found: 274.1105.
d
12.21 (br s, 1H), 8.62 (d, 1H, J¼8.1 Hz), 8.46 (d, 1H, J¼1.7 Hz), 7.61
(dd, 1H, J¼1.7 and 8.7 Hz), 7.48 (d, 1H, J¼8.7 Hz), 7.31 (d, 1H,
3.2.10. 4-(Styryl)-9H-pyrido[2,3-b]indole (17)
J¼8.1 Hz); 13C NMR (75 MHz, DMSO-d6)
d 151.2 (C), 147.1 (C), 137.5
Procedure A. The product was purified by flash chroma-
tography (CH2Cl2/EtOAc 9:1) to afford 17 (96 mg, 0.355 mmol)
in 72% yield as a yellow solid; mp>220 ꢀC; IR 3059, 2972,
(C), 132.2 (CH), 129.3 (CH), 123.9 (CH), 121.8 (C), 115.0 (CH), 113.6
ꢃ
(CH), 113.4 (C), 112.1 (C); MS (ESI) m/z 279 [MꢂH, 79Br]ꢂ , 281
ꢃ
ꢃ
[MꢂH, 81Br]ꢂ ; HRMS (EI): Calcd for C11H6BrClN2 [M]þ : 279.9403.
1633, 1599, 1580, 1561, 1455, 1397, 1255, 957, 730, 690 cmꢂ1
;
Found: 279.9405.
1H NMR (300 MHz, DMSO-d6)
d 11.87 (br s, 1H), 8.39 (d, 1H,
J¼5.3 Hz), 8.32 (d, 1H, J¼8.0 Hz), 8.07 (d, 1H, J¼16.3 Hz), 7.85
(d, 2H, J¼7.2 Hz), 7.65 (d, 1H, J¼16.3 Hz), 7.53 (d, 1H, J¼5.3 Hz),
7.51–7.45 (m, 4H), 7.41–7.36 (m, 1H), 7.27 (td, 1H, J¼1.5 and
3.3.2. 6-Bromo-3-chloro-9H-pyrido[2,3-b]indole (21)
Starting material 2: 200 mg, 0.990 mmol. The compound 21
was obtained by trituration with MeOH (217 mg, 0.775 mmol, 78%
yield); mp>220 ꢀC; IR 3031, 3005, 2957, 1577, 1604, 1486, 1269,
8.0 Hz); 13C NMR (75 MHz, DMSO-d6)
d 152.7 (C), 145.9 (CH),
139.8 (C), 139.0 (C), 136.3 (C), 134.5 (CH), 128.9 (2 CH), 128.8
(CH), 127.4 (2 CH), 126.3 (CH), 123.7 (CH), 123.4 (CH), 120.4 (C),
119.7 (CH), 112.3 (C), 111.2 (CH), 110.9 (CH); MS (EI) m/z 270
[M]þ; HRMS (ESI): Calcd for C19H15N2 [MþH]þ: 271.1235.
Found: 271.1235.
1232, 1089, 803, 700 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
; d 12.19
(br s, 1H), 8.75 (d, 1H, J¼2.5 Hz), 8.48 (d, 1H, J¼1.9 Hz), 8.46 (d, 1H,
J¼2.5 Hz), 7.62 (dd, 1H, J¼1.9 and 8.6 Hz), 7.48 (d, 1H, J¼8.6 Hz);
13C NMR (75 MHz, DMSO-d6)
d 150.3 (C), 145.0 (CH), 138.4 (C),
129.9 (CH), 128.8 (CH), 124.4 (CH), 122.1 (C), 121.5 (C), 115.4 (C),

C. Schneider et al. / Tetrahedron 65 (2009) 5427–5437
5433
ꢃ
113.6 (CH), 111.8 (C); MS (ESI) m/z 281 [MþH, 79Br]þ , 283 [MþH,
(571 mg, 1.35 mmol) in 85% yield as a white solid; mp 212–214 ꢀC
(CH2Cl2/PE); IR 3122, 3059, 1607, 1579, 1558, 1432, 1384, 1349, 1193,
ꢃ
ꢃ
81Br]þ ; HRMS (EI): Calcd for C11H6BrClN2 [M]þ : 279.9403. Found:
279.9405.
1183, 995, 806, 722 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 8.50 (d, 1H,
J¼2.1 Hz), 8.45 (d,1H, J¼5.3 Hz), 8.40 (d,1H, J¼8.9 Hz), 8.14–8.11 (m,
2H), 7.71 (dd, 1H, J¼2.1 and 8.9 Hz), 7.55 (tt, 1H, J¼1.3 and 7.3 Hz),
7.45–7.40 (m, 2H), 7.29 (d, 1H, J¼5.3 Hz); 13C NMR (75 MHz, CDCl3)
3.3.3. 6-Bromo-4-chloro-9H-pyrido[2,3-b]indole (22)
Starting material 3: 500 mg, 2.49 mmol. Compound 22 was
obtained by trituration with MeOH (530 mg, 1.89 mmol, 76%
yield); mp>220 ꢀC; IR 3123, 2950, 1603, 1569, 1442, 1276, 870,
d
151.6 (C), 147.5 (CH),138.8 (C),138.3 (C), 136.4 (C),134.5 (CH),131.9
(CH), 129.2 (2 CH), 127.8 (2 CH), 125.9 (CH), 123.4 (C), 120.5 (CH),
117.4 (C), 116.4 (CH); 115.6 (C); MS (ESI) m/z 420.9 [MþH, 79Br]þ,
422.9 [MþH, 81Br]þ, 442.9 [MþNa, 79Br]þ, 444.9 [MþNa, 81Br]þ;
Anal. Calcd for C17H10BrClN2O2S: C, 48.42; H, 2.39; N, 6.64. Found:
C, 48.43; H, 2.29; N, 7.07.
795 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
d 12.40 (br s, 1H), 8.43 (d,
1H, J¼1.5 Hz), 8.42 (d, 1H, J¼5.3 Hz), 7.69 (dd, 1H, J¼1.5 and
8.6 Hz), 7.54 (d, 1H, J¼8.6 Hz), 7.38 (d, 1H, J¼5.3 Hz); 13C NMR
(75 MHz, DMSO-d6)
d 152.8 (C), 147.6 (CH), 137.6 (C), 136.9 (C),
129.9 (CH), 124.4 (CH), 120.7 (C), 115.9 (CH), 113.7 (CH), 111.9 (C),
ꢃ
ꢃ
111.7 (C); MS (ESI) m/z 281.1 [MþH, 79Br]þ , 283.1 [MþH, 81Br]þ
;
3.5. Typical procedure for Suzuki coupling at C-6
HRMS (ESI): Calcd for C11H7BrClN2 [MþH]þ: 280.9481. Found:
280.9485.
At rt and under inert atmosphere, a solution of Pd(PPh3)4
(0.08 equiv), boronic acid (1.1 equiv), and 0.3 M aqueous K2CO3
(3 equiv) was added to a 0.1 M suspension of 24 in 1,4-dioxane (or
23, or 25 in THF). This solution was stirred at 100 ꢀC or 70 ꢀC, re-
spectively, for 12 h. After cooling to rt, the solution was filtered
through Celite and solvents were removed under reduced pressure.
The product was purified as described below and an analytical
sample for mp was obtained by trituration with MeOH.
3.4. General procedure for the benzenesulfonyl protection
To a 0.15 M suspension of 20 or 21 or 22 in THF at 0 ꢀC was added
NaH (60% in oil, 1.1 equiv) in small portions and the resulting so-
lution mixture was stirred at 0 ꢀC for 20 min. A solution of benze-
nesulfonyl chloride (1.2 equiv) was added dropwise at 0 ꢀC. The
final solution was stirred for 12 h and was slowly quenched with
a
5% aqueous NaHCO3 solution and extracted with EtOAc
3.5.1. 9-Benzenesulfonyl-2-chloro-6-(4-methoxyphenyl)-9H-
pyrido[2,3-b]indole (26)
(3ꢁ20 mL). The combined organic layers were dried over MgSO4,
then filtered, and the solvent was removed under reduced pressure.
The product was purified as described below and an analytical
sample for mp was obtained by trituration with MeOH.
Starting material 23: 100 mg, 0.237 mmol. The crude product
was purified by flash chromatography (CH2Cl2/PE 3:7) to afford 26
(62 mg, 0.138 mmol) in 58% yield as a white solid; mp 176–178 ꢀC
(CH2Cl2/PE); IR 2932, 1606, 1587, 1567, 1519, 1465, 1450, 1369, 1172,
3.4.1. 9-Benzenesulfonyl-6-bromo-2-chloro-9H-pyrido[2,3-b]-
indole (23)
1039, 813, 732, 683 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 8.48 (d, 1H,
J¼8.7 Hz), 8.24–8.21 (m, 2H), 8.14 (d, 1H, J¼8.1 Hz), 8.01 (d, 1H,
J¼1.5 Hz), 7.74 (dd, 1H, J¼1.5 and 8.7 Hz), 7.57 (d, 2H, J¼8.7 Hz), 7.56
(td, 1H, J¼1.1 and 8.1 Hz), 7.48–7.43 (m, 2H), 7.28 (d, 1H, J¼8.1 Hz),
Starting material 20: 200 mg, 0.716 mmol. The crude product
was purified by flash chromatography (CH2Cl2) to afford 23
(272 mg, 0.647 mmol) in 90% yield as a white solid; mp 204–
206 ꢀC (CH2Cl2/PE); IR 3060, 1614, 1573, 1448, 1380, 1371, 1187,
6.98 (d, 2H, J¼8.7 Hz), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 162.4
(C), 159.4 (C), 148.4 (C), 138.4 (C), 137.3 (C), 136.7 (C), 134.3 (CH),
133.0 (C), 130.5 (CH), 129.1 (2 CH), 128.4 (2 CH), 128.1 (2 CH), 127.6
(CH), 122.7 (C), 119.5 (CH), 118.5 (CH), 117.3 (C), 115.3 (CH), 114.5 (2
CH), 55.5 (CH3); MS (ESI) m/z 448.9 [MþH]þ, 471 [MþNa]þ; Anal.
Calcd for C24H17ClN2O3S: C, 64.21; H, 3.82; N, 6.24. Found: C, 64.25;
H, 3.95; N, 6.55.
1173, 1128, 1088, 979, 813, 727, 682 cmꢂ1
CDCl3)
;
1H NMR (300 MHz,
d
8.37 (d, 1H, J¼8.9 Hz), 8.21–8.18 (m, 2H), 8.08 (d, 1H,
J¼8.1 Hz), 8.02 (d, 1H, J¼1.8 Hz), 7.68 (dd, 1H, J¼1.8 and 8.9 Hz),
7.58–7.56 (m, 1H), 7.50–7.45 (m, 2H), 7.31 (d, 1H, J¼8.1 Hz); 13C
NMR (75 MHz, CDCl3)
d 149.6 (C), 149.2 (C), 138.1 (C), 136.5 (C),
134.5 (CH), 131.4 (CH), 130.7 (CH), 129.1 (2 CH), 128.2 (2 CH), 123.8
(C), 123.6 (CH), 119.8 (CH), 117.5 (C), 116.6 (CH), 115.9 (C); MS (ESI)
m/z 421.0 [MþH, 79Br]þ, 422.9 [MþH, 81Br]þ; HRMS (ESI): Calcd for
C17H10BrClN2O2SNa [MþNa]þ: 442.9233. Found: 442.9229.
3.5.2. 9-Benzenesulfonyl-3-chloro-6-(4-methoxyphenyl)-9H-
pyrido[2,3-b]indole (27)
Starting material 24: 150 mg, 0.355 mmol. The crude product
was purified by flash chromatography (CH2Cl2/PE 7:3) to afford 27
(132 mg, 0.294 mmol) in 83% yield as a yellow solid; mp>220 ꢀC
(CH2Cl2/PE); IR 3016, 1607, 1683, 1520, 1473, 1361, 1216, 1182, 1091,
3.4.2. 9-Benzenesulfonyl-6-bromo-3-chloro-9H-pyrido[2,3-b]-
indole (24)
Starting material 21: 400 mg, 1.42 mmol. The crude product was
purified by flash chromatography (CH2Cl2/PE 1:1) to afford 24
(543 mg, 1.29 mmol) in 91% yield as a white solid; mp>220 ꢀC; IR
3061, 1584, 1569, 1447, 1384, 1356, 1184, 1091, 970, 847, 815,
978, 822, 725 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 8.50 (d, 1H,
J¼8.9 Hz), 8.50 (d,1H, J¼2.3 Hz), 8.19 (d,1H, J¼2.3 Hz), 8.15–8.12 (m,
2H), 8.02 (d, 1H, J¼1.5 Hz), 7.78 (dd, 1H, J¼1.5 and 8.9 Hz), 7.57 (d,
2H, J¼8.8 Hz), 7.55–7.51 (m, 1H), 7.45–7.40 (td, 2H, J¼2.8 and
8.9 Hz), 7.01 (d, 2H, J¼8.8 Hz), 3.87 (s, 3H); 13C NMR (75 MHz,
724 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6)
d
8.86 (d, 1H, J¼2.5 Hz),
8.62 (d, 1H, J¼2.5 Hz), 8.56 (d, 1H, J¼2.1 Hz), 8.30 (d, 1H, J¼9.0 Hz),
8.05–8.02 (m, 2H), 7.85 (dd, 1H, J¼2.1 and 9.0 Hz), 7.70 (tt, 1H, J¼1.1
CDCl3) d 162.6 (C), 159.5 (C), 159.0 (C), 149.2 (C), 145.7 (CH), 138.6
(C), 137.5 (C), 134.3 (CH), 132.9 (C) 129.2 (2 CH), 128.4 (2 CH), 128.3
(CH), 128.1 (CH), 127.6 (2 CH), 122.4 (C), 120.1 (C), 118.8 (CH), 115.5
(CH), 114.6 (2 CH), 54.5 (CH3); MS (ESI) m/z 449.0 [MþH]þ, 471.0
[MþNa]þ, 918.8 [2MþNa]þ; Anal. Calcd for C24H17ClN2O3S: C, 64.21;
H, 3.82; N, 6.24. Found: C, 64.77; H, 3.87; N, 6.63.
and 7.4 Hz), 7.59–7.54 (m, 2H); 13C NMR (75 MHz, DMSO-d6)
d 148.2
(C),145.6 (CH),137.2 (C),136.3 (C),134.6 (CH),131.8 (CH),129.6 (CH),
129.3 (2 CH), 126.9 (C), 126.7 (2 CH), 124.6 (CH), 123.3 (C), 116.1 (C);
116.5 (C) 116.2 (CH); MS (ESI) m/z 421.0 [MþH, 79Br]þ, 443.1 [MþNa,
79Br]þ; HRMS (ESI): Calcd for C17H10BrClN2O2SNa [MþNa]þ:
442.9233. Found: 442.9229.
3.5.3. 9-Benzenesulfonyl-4-chloro-6-(4-methoxyphenyl)-9H-
pyrido[2,3-b]indole (28)
3.4.3. 9-Benzenesulfonyl-6-bromo-4-chloro-9H-pyrido[2,3-
b]indole (25)
Starting material 22: 445 mg, 1.59 mmol. The crude product was
purified by flash chromatography (CH2Cl2/PE 1:1) to afford 25
Starting material 25: 100 mg, 0.237 mmol. The crude product
was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 28
(75 mg, 0.167 mmol) in 70% yield as a white solid; mp 209–211 ꢀC
(CH2Cl2/PE); IR 3020, 2835, 1607, 1583, 1521, 1467, 1441, 1375, 1234,

5434
C. Schneider et al. / Tetrahedron 65 (2009) 5427–5437
1172,1020, 834, 770, 690 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
8.56 (d,
3.6. Typical procedure Suzuki–Miyaura on 2- and 4-chloro-6-
1H, J¼1.8 Hz), 8.55 (d, 1H, J¼8.8 Hz), 8.43 (d, 1H, J¼5.5 Hz), 8.18–
8.15 (m, 2H), 7.80 (dd, 1H, J¼1.8 and 8.8 Hz), 7.61 (d, 2H, J¼8.7 Hz),
7.54 (tt, 1H, J¼1.3 and 7.4 Hz), 7.45–7.40 (m, 2H), 7.29 (d, 1H,
J¼5.5 Hz), 7.03 (d, 2H, J¼8.7 Hz), 3.87 (s, 3H); 13C NMR (75 MHz,
substituted pyrido[2,3-b]indoles
At rt and under an inert atmosphere, a solution of Pd(PPh3)4,
(0.08 equiv), (E)-phenylvinylboronic acid (5) (1.1 equiv), and 0.3 M
K2CO3 (3 equiv) in H2O was added to a 0.1 M solution of 26 or 28 in
1,4-dioxane. This solution was stirred at 100 ꢀC for 12 h. After
cooling to rt, solution was filtered through Celite and solvents were
removed under reduced pressure.
CDCl3) d 159.4 (C),151.9 (C),146.8 (CH),138.6 (C), 138.5 (C),137.3 (C),
136.7 (C), 134.3 (CH), 133.2 (C), 129.1 (2 CH), 128.5 (2 CH), 128.0
(CH), 127.8 (2 CH), 122.5 (C), 121.2 (CH), 120.4 (CH), 116.8 (C), 115.0
(CH), 114.5 (2 CH); 55.5 (CH3); MS (ESI) m/z 449.0 [MþH]þ, 471.0
[MþNa]þ, 918.8 [2MþNa]þ; HRMS (ESI): Calcd for C24H17ClN2O3SNa
[MþNa]þ: 471.0546. Found: 471.0545.
3.6.1. 9-Benzenesulfonyl-6-(4-methoxyphenyl)-2-(styryl)-9H-
pyrido[2,3-b]indole (32)
3.5.4. 9-Benzenesulfonyl-2-chloro-6-(styryl)-9H-pyrido[2,3-b]-
indole (29)
Starting material 26: 104 mg, 0.231 mmol. The crude product
was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 32
(100 mg, 0.194 mmol), in 84% yield as a yellow solid; mp 193–
195 ꢀC (CH2Cl2/PE); IR 2926,1607,1586,1518,1465,1382,1172,1090,
Starting material 23: 200 mg, 0.476 mmol. The crude product
was purified by flash chromatography (CH2Cl2/PE 3:7) to afford 29
(134 mg, 0.301 mmol) in 64% yield as a white solid; mp 180–
182 ꢀC (CH2Cl2/PE); IR 3022, 1587, 1571, 1470, 1447, 1380, 1172, 980,
967, 812 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
8.58 (d, 1H, J¼8.9 Hz),
8.34–8.31 (m, 2H), 8.14 (d, 1H, J¼7.9 Hz), 8.06 (d, 1H, J¼1.8 Hz), 7.91
(d, 1H, J¼16.0 Hz), 7.78 (dd, 1H, J¼1.8 and 8.6 Hz), 7.71 (d, 2H,
J¼7.4 Hz), 7.66 (d, 2H, J¼8.6 Hz), 7.60–7.36 (m, 6H), 7.34 (d, 1H,
J¼2.6 Hz), 7.28 (d, 1H, J¼16.0 Hz), 7.09 (d, 2H, J¼8.6 Hz), 3.94 (s,
807, 753, 728, 682 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 8.46 (d, 1H,
J¼8.9 Hz), 8.23–8.20 (m, 2H), 8.11 (d, 1H, J¼8.1 Hz), 8.00 (d, 1H,
J¼1.8 Hz), 7.75 (dd, 1H, J¼1.8 and 9.0 Hz), 7.57–7.54 (m, 3H), 7.49–
7.47 (m, 2H), 7.39 (t, 2H, J¼7.1 Hz), 7.31 (d, 1H, J¼8.1 Hz), 7.31 (td,
1H, J¼1.1 and 7.2 Hz), 7.23 (d, 1H, J¼16.3 Hz), 7.17 (d, 1H,
3H); 13C NMR (75 MHz, CDCl3)
d 159.3 (C), 153.5 (C), 151.2 (C), 139.0
(C), 137.1 (C), 136.9 (C), 136.8 (C), 134.0 (CH), 133.4 (CH), 133.2 (C),
128.9 (4 CH),128.6 (CH),128.5 (CH); 128.3 (2 CH),127.9 (3 CH),127.3
(2 CH), 127.0 (CH), 123.6 (C), 118.5 (CH), 118.3 (CH), 117.4 (C), 115.2
(CH), 114.4 (2 CH); 55.4 (CH3); MS (ESI) m/z 517.1 [MþH]þ, 539
[MþNa]þ; Anal. Calcd for C32H24N2O3S: C, 74.40; H, 4.68; N, 5.42.
Found: C, 74.58; H, 4.82; N, 5.45.
J¼16.3 Hz); 13C NMR (75 MHz, CDCl3)
d 162.4 (C), 148.5 (C), 138.3
(C), 137.2 (C), 137.1 (C), 134.3 (CH), 133.8 (C), 130.5 (CH), 129.2 (CH),
129.1 (2 CH), 128.9 (2 CH), 128.2 (2 CH), 127.9 (CH), 127.8 (CH),
127.1 (CH), 126.6 (2 CH), 122.6 (C), 119.6 (CH), 118.4 (CH), 117.1 (C),
115.3 (CH); MS (ESI) m/z 445.0 [MþH]þ, 467.0 [MþNa]þ, 910.6
[2MþNa]þ; HRMS (ESI): Calcd for C25H17ClN2O2SNa [MþNa]þ:
467.0597. Found: 467.0597.
3.6.2. 9-Benzenesulfonyl-6-(4-methoxyphenyl)-4-(styryl)-9H-
pyrido[2,3-b]indole (34)
3.5.5. 9-Benzenesulfonyl-3-chloro-6-(styryl)-9H-pyrido[2,3-b]-
indole (30)
Starting material 24: 100 mg, 0.237 mmol. The crude product
was purified by flash chromatography (CH2Cl2/PE 6:4) to afford 30
in (75 mg, 0.168 mmol) 71% yield as a yellow solid; mp 190–192 ꢀC
(MeOH); IR 3025, 1568, 1474, 1433, 1366, 1176, 1090, 972, 727,
Starting material 28: 60 mg, 0.134 mmol. The crude product was
purified by flash chromatography (CH2Cl2/PE 7:3) to afford 34
(61 mg, 0.118 mmol) in 87% yield as a yellow solid; mp 190–192 ꢀC
(CH2Cl2/PE); IR 3073, 2838, 1633, 1607, 1587, 1517, 1462, 1443, 1377,
1179, 1047, 810, 728, 688 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 8.59 (d,
1H, J¼8.7 Hz), 8.52 (d, 1H, J¼5.1 Hz), 8.23 (d, 1H, J¼1.8 Hz), 8.20–
8.17 (m, 2H), 7.84 (d, 1H, J¼16.2 Hz), 7.75 (dd, 1H, J¼1.8 and 8.7 Hz),
7.62–7.58 (m, 2H), 7.58 (d, 2H, J¼8.8 Hz), 7.52–7.50 (m, 1H), 7.45 (d,
1H, J¼5.1 Hz), 7.43–7.36 (m, 5H), 7.35 (d, 1H, J¼16.2 Hz), 7.02 (d, 2H,
683 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
8.50 (d, 1H, J¼2.4 Hz), 8.45
(d, 1H, J¼8.9 Hz), 8.18 (d, 1H, J¼2.4 Hz), 8.14–8.11 (m, 2H), 8.00 (d,
1H, J¼1.7 Hz), 7.76 (dd, 1H, J¼1.7 and 8.9 Hz), 7.57–7.52 (m, 3H),
7.45–7.36 (m, 4H), 7.29 (tt, 1H, J¼1.2 and 7.4 Hz), 7.23 (d, 1H,
J¼16.4 Hz), 7.16 (d, 1H, J¼16.4 Hz); 13C NMR (75 MHz, CDCl3)
J¼8.8 Hz), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 159.4 (C), 146.7
(CH), 141.6 (C), 138.9 (C), 137.1 (C), 136.8 (C), 136.2 (C), 135.8 (CH),
134.0 (CH), 133.5 (C), 129.2 (3 CH), 129.0 (2 CH), 128.4 (2 CH), 127.7
(2 CH), 127.3 (2 CH), 127.1 (CH), 124.0 (C), 123.4 (CH), 121.2 (CH),
116.0 (CH), 115.9 (C), 115.3 (CH), 114.6 (2 CH), 55.5 (CH3); MS (ESI)
m/z 517.1 [MþH]þ, 1055.0 [2MþNa]þ; Anal. Calcd C32H24N2O3S: C,
74.40; H, 4.68; N, 5.42. Found: C, 74.39; H, 4.68; N, 5.62.
d
162.4 (C), 145.7 (CH), 138.5 (C), 137.8 (C), 137.1 (C), 134.3 (CH),
133.9 (C), 129.3 (CH), 129.2 (2 CH), 128.9 (2 CH), 128.1 (CH), 128.0
(CH), 127.8 (CH), 127.7 (CH), 127.6 (C), 127.6 (2 CH), 126.7 (2 CH),
122.4 (C), 119.9 (C), 118.6 (CH), 115.5 (CH); MS (ESI) m/z 445.0
[MþH]þ, 466.9 [MþNa]þ, 910.9 [2MþNa]þ; HRMS (ESI): Calcd for
C25H17ClN2O2SNa [MþNa]þ: 467.0597. Found: 467.0598.
3.7. 9-Benzenesulfonyl-6-(4-methoxyphenyl)-3-(styryl)-9H-
pyrido[2,3-b]indole (33)
3.5.6. 9-Benzenesulfonyl-4-chloro-6-(styryl)-9H-pyrido[2,3-b]-
indole (31)
Starting material 25: 100 mg, 0.237 mmol. The crude product
was purified by flash chromatography (CH2Cl2/PE 6:4) to afford 31
(72 mg, 0.161 mmol) in 68% yield as a white solid; mp 216–218 ꢀC
(CH2Cl2/PE); IR 3063, 2924, 1614, 1583, 1562, 1442, 1371, 1170, 1006,
A sealed pressure tube with a stir bar was charged with
Pd(OAc)2 (4 mg, 0.018 mmol, 0.04 equiv), S-Phos (15 mg,
0.036 mmol, 0.08 equiv), a-carboline 27 (100 mg, 0.222 mmol), (E)-
phenylvinylboronic acid (5) (82 mg, 0.556 mmol, 2.5 equiv), and
K3PO4 (141 mg, 0.666 mmol, 3 equiv). The tube was evacuated and
back-filled with argon (this was repeated three additional times).
995, 814, 684 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 8.51 (d, 1H,
J¼8.6 Hz), 8.51 (d,1H, J¼1.5 Hz), 8.43 (d,1H, J¼5.5 Hz), 8.16–8.15 (m,
2H), 7.81 (dd,1H, J¼1.5 and 8.6 Hz), 7.58–7.52 (m, 3H), 7.45–7.36 (m,
4H), 7.31–7.28 (m,1H), 7.30 (d, 1H, J¼5.5 Hz), 7.27 (d,1H, J¼16.4 Hz),
Freshly degassed 1,4-dioxane (600 mL) was added and the reaction
mixture was stirred at 100 ꢀC overnight. After cooling to rt, the
solution was diluted with H2O and extracted with EtOAc
(3ꢁ20 mL). The combined organic layers were dried over MgSO4,
then filtered through Celite, and the solvent was removed under
reduced pressure. The crude product was purified by flash chro-
matography (CH2Cl2/PE 3:1) to afford 33 (90 mg, 0.174 mmol) in
79% yield as a yellow solid; mp 176–178 ꢀC (CH2Cl2/PE); IR 3036,
7.18 (d, 1H, J¼16.4 Hz); 13C NMR (75 MHz, CDCl3)
d 162.4 (C), 149.8
(C), 146.9 (CH), 138.5 (C), 137.2 (C), 137.1 (C), 134.3 (CH), 133.8 (C),
129.2 (CH),129.1 (2 CH),128.9 (2 CH),128.1 (CH),127.9 (CH),127.8 (2
CH), 127.3 (CH), 126.7 (2 CH), 122.4 (C), 121.2 (CH), 120.4 (CH), 116.7
(C), 115.0 (CH); MS (ESI) m/z 445.0 [MþH]þ, 466.9 [MþNa]þ, 910.8
[2MþNa]þ; HRMS (ESI): Calcd for C25H17ClN2O2SNa [MþNa]þ:
467.0597. Found: 467.0598.
2934, 1609, 1481, 1462, 1442, 1369, 1255, 1178, 1038, 980, 810 cmꢂ1
;

C. Schneider et al. / Tetrahedron 65 (2009) 5427–5437
5435
1H NMR (300 MHz, CDCl3)
d
8.67 (d, 1H, J¼2.1 Hz), 8.50 (d, 1H,
3.10. Typical procedure for Suzuki reactions with 2 equiv of
boronic acid from compounds 23 and 25
J¼8.6 Hz), 8.39 (d, 1H, J¼2.1 Hz), 8.18–8.15 (m, 2H), 8.11 (d, 1H,
J¼1.8 Hz), 7.76 (dd, 1H, J¼1.8 and 8.6 Hz), 7.61 (d, 2H, J¼8.7 Hz),
7.56–7.50 (m, 3H), 7.43 (d, 2H, J¼7.9 Hz), 7.38 (d, 2H, J¼7.9 Hz), 7.31
(d, 1H, J¼7.4 Hz), 7.24 (s, 2H), 7.03 (d, 2H, J¼8.7 Hz), 3.88 (s, 3H); 13C
At rt and under inert atmosphere, a solution of Pd(PPh3)4
(0.08 equiv), 4-methoxyphenylboronic acid (4) (2.2 equiv), and
a 0.3 M K2CO3 solution (3 equiv) was added to 0.1 M solution of 23
or 25 in 1,4-dioxane. This solution was stirred at reflux for 12 h.
After cooling to rt, solution was filtered through Celite and solvents
were removed under reduced pressure.
NMR (75 MHz, CDCl3)
d 159.4 (C), 150.5 (C), 146.6 (CH), 138.7 (C),
137.2 (C), 137.1 (C), 136.8 (C), 134.0 (CH), 133.1 (C), 130.1 (CH), 129.3
(C), 129.0 (2 CH), 128.9 (2 CH), 128.3 (2 CH), 128.2 (CH), 127.6 (3 CH),
126.6 (2 CH), 124.8 (CH), 124.7 (CH), 123.4 (C), 119.2 (C), 118.7 (CH),
115.4 (CH), 114.5 (2 CH), 55.5 (CH3); MS (ESI) m/z 517.0 [MþH]þ,
539.0 [MþNa]þ, 1054.8 [2MþNa]þ; HRMS (ESI): Calcd for
C32H25N2O3S [MþH]þ: 517.1586. Found: 517.1587.
3.10.1. 9-Benzenesulfonyl-2,6-di-(4-methoxyphenyl)-9H-
pyrido[2,3-b]indole (37)
Starting material 23: 100 mg, 0.237 mmol. The crude product
was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 37
(112 mg, 0.215 mmol) in 90% yield as white solid; mp 206–208 ꢀC
(CH2Cl2/PE); IR 2993, 1607, 1591, 1518, 1464, 1167, 1039, 978,
3.8. 3-Chloro-6-(4-methoxyphenyl)-9H-pyrido[2,3-b]-
indole (35)
807 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
8.51 (d, 1H, J¼8.7 Hz), 8.23–
At rt and under inert atmosphere, a 1.0 M TBAF solution in THF
(1.8 mL, 1.88 mmol, 5 equiv) was added to a solution of 27 (169 mg,
0.376 mmol) in THF (17 mL). The solution was refluxed for 2 h. The
resulting mixture was then cautiously quenched at 0 ꢀC with H2O.
The mixture was extracted with EtOAc (3ꢁ10 mL). The resulting
organic layers were dried over MgSO4, then filtered, and the solvent
was removed under reduced pressure. The crude product was pu-
rified by flash chromatography (CH2Cl2/EtOAc 9:1 to EtOAc) to af-
ford 35 (97 mg, 0.313 mmol) in 84% yield as a yellow solid;
mp>220 ꢀC (MeOH); IR 3109, 3035, 2935, 2848, 1630, 1603, 1578,
8.20 (m, 2H), 8.16 (d, 1H, J¼7.7 Hz), 8.15 (d, 2H, J¼8.79 Hz), 8.02 (d,
1H, J¼1.5 Hz), 7.72 (dd, 1H, J¼1.5 and 8.7 Hz), 7.66 (d, 1H, J¼8.1 Hz),
7.60 (d, 2H, J¼8.7 Hz), 7.50–7.46 (m, 1H), 7.41–7.36 (m, 2H), 7.04 (d,
2H, J¼8.7 Hz), 7.02 (d, 2H, J¼8.7 Hz), 3.89 (s, 3H), 3.87 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 160.8 (C),159.3 (C),154.6 (C),151.3 (C),139.9
(C), 136.9 (2 C), 133.9 (CH), 133.4 (C), 131.6 (C), 128.9 (2 CH), 128.5 (2
CH), 128.4 (2 CH), 127.8 (2 CH), 126.9 (CH), 123.7 (C), 118.4 (CH),
116.6 (C), 115.2 (CH), 115.1 (CH), 114.5 (3 CH), 114.3 (2 CH); 55.5 (2
CH3); MS (ESI) m/z 521.1 [MþH]þ, 543.0 [MþNa]þ; HRMS (ESI):
Calcd for C31H24N2O4SNa [MþNa]þ: 543.1354. Found: 543.1355.
1483, 1232, 1090, 1033, 800, 778, 700 cmꢂ1
DMSO-d6)
;
1H NMR (300 MHz,
d
12.02 (br s, 1H), 8.74 (d, 1H, J¼2.4 Hz), 8.49 (d, 1H,
3.10.2. 9-Benzenesulfonyl-4,6-di-(4-methoxyphenyl)-9H-
pyrido[2,3-b]indole (39)
J¼1.8 Hz), 8.42 (d, 1H, J¼2.4 Hz), 7.76 (dd, 1H, J¼1.8 and 8.6 Hz), 7.67
(d, 2H, J¼8.6 Hz), 7.55 (d, 1H, J¼8.6 Hz), 7.06 (d, 2H, J¼8.6 Hz), 3.81
Starting material 25: 100 mg, 0.237 mmol. The crude product
was purified by flash chromatography (CH2Cl2/PE 1:1) to afford 39
(110 mg, 0.211 mmol) in 89% yield as a white solid; mp 162–164 ꢀC
(s, 3H); 13C NMR (75 MHz, DMSO-d6)
d 158.4 (C), 150.7 (C), 144.1
(CH), 138.8 (C), 133.2 (C), 132.1 (C), 128.3 (CH), 127.7 (2 CH), 126.2
(CH), 121.7 (C), 120.2 (C), 119.3 (CH), 126.6 (C), 114.4 (2 CH), 111.8
(CH), 55.2 (CH3); MS (ESI) m/z 309.1 [MþH]þ; HRMS (EI): Calcd for
(CH2Cl2/PE); IR 3010, 2965, 1608, 1515, 1464, 1232, 1170, 822 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
8.55 (d, 1H, J¼5.0 Hz), 8.53 (dd, 1H,
ꢃ
C18H13ClN2O [M]þ : 308.0716. Found: 308.0714.
J¼0.8 and 8.5 Hz), 8.22–8.20 (m, 2H), 7.72 (d, 1H, J¼1.9 Hz), 7.70 (dd
1H, J¼1.9 and 8.5 Hz), 7.54–7.41 (m, 3H), 7.51 (d, 2H, J¼8.7 Hz), 7.38
(d, 2H, J¼8.7 Hz), 7.14 (d, 1H, J¼5.0 Hz), 7.07 (d, 2H, J¼8.7 Hz), 6.94
(d, 2H, J¼8.7 Hz), 3.90 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3)
3.9. 6-(4-Methoxyphenyl)-3-(styryl)-9H-pyrido[2,3-b]-
indole (36)
d
160.5 (C), 159.2 (C), 151.7 (C), 149.5 (2 C), 146.6 (CH), 145.7 (C),
A sealed pressure tube with a stir bar was charged with
Pd(OAc)2 (5 mg, 0.02 mmol, 0.08 equiv), S-Phos (18 mg, 0.04 mmol,
138.9 (C), 136.7 (C), 136.3 (C), 134.0 (CH), 133.2 (C), 130.0 (2 CH),
129.0 (2 CH), 128.1 (2 CH), 127.8 (2 CH), 126.9 (CH), 123.5 (C), 120.7
(CH), 120.5 (CH), 115.0 (CH), 114.5 (2 CH), 114.3 (2 CH), 55.6 (CH3),
55.5 (CH3); MS (ESI) m/z 521.1 [MþH]þ, 1062.9 [2MþNa]þ; Anal.
Calcd C31H24N2O4S: C, 71.52; H, 4.65; N, 5.38. Found: C, 71.12; H,
4.70; N, 5.52.
0.16 equiv),
a-carboline 35 (83 mg, 0.267 mmol), (E)-phenyl-
vinylboronic acid (5) (59 mg, 0.400 mmol, 1.5 equiv), and K3PO4
(142 mg, 0.667 mmol, 2.5 equiv). The tube was evacuated and back-
filled with argon (this was repeated three additional times). Freshly
degassed 1,4-dioxane (700 mL) was added and the reaction mixture
was stirred at 100 ꢀC overnight. After cooling to rt, the solution was
diluted with H2O and extracted with EtOAc (3ꢁ20 mL). The com-
bined organic layers were dried over MgSO4, then filtered through
Celite, and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography (CH2Cl2/EtOAc
9:1) to afford 36 (65 mg, 0.172 mmol) in 65% yield as a white solid;
mp>220 ꢀC (MeOH); IR 3060, 2994, 2833, 1606, 1517, 1485, 1460,
3.10.3. 9-Benzenesulfonyl-3,6-di-(4-methoxyphenyl)-9H-
pyrido[2,3-b]indole (38)
A sealed pressure tube with a stir bar was charged with Pd(OAc)2
(5 mg, 0.02 mmol, 0.08 equiv), S-Phos (17 mg, 0.04 mmol, 0.16 equiv),
6-bromo-3-chloropyrido[2,3-b]indole 24 (100 mg, 0.238 mmol),
4-methoxyphenylboronic acid (4) (109 mg, 0.71 mmol, 3 equiv),
and K3PO4 (177 mg, 0.833 mmol, 3.5 equiv). The tube was evacu-
ated and back-filled with argon (this was repeated three additional
1232, 957, 813, 740, 692 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
;
d
11.86 (br s, 1H), 8.95 (d, 1H, J¼2.1 Hz), 8.61 (d, 1H, J¼2.1 Hz), 8.47
times). Freshly degassed 1,4-dioxane (650 mL) was added and the
(d, 1H, J¼1.6 Hz), 7.74 (dd, 1H, J¼1.6 and 8.5 Hz), 7.71 (d, 2H,
J¼8.9 Hz), 7.63 (d, 2H, J¼7.3 Hz), 7.54 (d, 1H, J¼8.5 Hz), 7.46 (d, 1H,
J¼16.4 Hz), 7.43–7.39 (m, 2H), 7.37 (d, 1H, J¼16.4 Hz), 7.27 (t, 1H,
J¼7.4 Hz), 7.07 (d, 2H, J¼8.9 Hz), 3.82 (s, 3H); 13C NMR (75 MHz,
reaction mixture was stirred at 100 ꢀC overnight. After cooling to rt,
the solution was diluted with H2O and extracted with EtOAc
(3ꢁ30 mL). The combined organic layers were dried over MgSO4,
then filtered through Celite, and the solvent was removed under
reduced pressure. The crude product was purified by flash chro-
matography (CH2Cl2) to afford 38 in 81% yield as a white solid; mp
110–112 ꢀC (CH2Cl2/PE); IR 2933, 1608, 1518, 1475, 1438, 1362, 1362,
DMSO-d6) d 158.4 (C),152.0 (C),146.5 (CH),138.5 (C),137.4 (C),133.4
(C), 131.9 (C), 128.8 (2 CH), 127.7 (2 CH), 127.4 (CH), 126.8 (CH), 126.3
(CH), 126.2 (2 CH), 125.6 (CH), 124.9 (CH), 127.8 (C), 121.1 (C), 118.9
(CH), 115.8 (C), 114.4 (2 CH), 111.7 (CH), 55.2 (CH3); MS (ESI) m/z
377.3 [MþH]þ; HRMS (ESI): Calcd for C26H21N2O [MþH]þ: 377.1654.
Found: 377.1653.
1174, 1245, 1089, 1038, 976, 816 cmꢂ1
8.77 (d, 1H, J¼2.1 Hz), 8.51 (d, 1H, J¼8.8 Hz), 8.34 (d, 1H, J¼2.1 Hz),
8.20–8.17 (m, 2H), 8.11 (d, 1H, J¼1.7 Hz), 7.76 (dd, 1H, J¼1.7 and
;
1H NMR (300 MHz, CDCl3)
d

5436
C. Schneider et al. / Tetrahedron 65 (2009) 5427–5437
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8.8 Hz), 7.60 (d, 2H, J¼8.9 Hz), 7.56 (d, 2H, J¼8.9 Hz), 7.52 (tt, 1H,
J¼1.3 and 6.0 Hz), 7.45–7.39 (m, 2H), 7.02 (d, 2H, J¼8.9 Hz), 7.03 (d,
2H, J¼8.9 Hz), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
159.7 (C), 159.3 (C), 150.2 (C), 145.8 (CH), 138.8 (C), 137.1 (2 C),
2. (a) Diebolt, O.; Braunstein, P.; Nolan, S. P.; Cazin, C. S. J. Chem. Commun. 2008,
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Liu, D.; Kapes, L. M.; Zhang, X. J. Org. Chem. 2006, 71, 3928–3934; (k) Acker-
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Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722–9723.
134.0 (CH), 133.1 (C), 132.7 (C), 130.3 (C), 129.0 (2 CH), 128.4 (2 CH),
128.3 (2 CH), 127.5 (2 CH),127.4 (CH),126.3 (CH), 123.5 (C), 119.0 (C),
118.6 (CH), 115.3 (CH), 114.7 (2 CH), 114.4 (2 CH), 55.4 (2 CH3); MS
(ESI) m/z 521.0 [MþH]þ, 543.0 [MþNa]þ, 1062.8 [2MþNa]þ; HRMS
(ESI): Calcd for C31H25N2O4S [MþH]þ: 521.1535. Found: 521.1534.
3.11. Typical procedure for Suzuki reactions with two
different boronic acids from 2-chloro or 4-chloro 6-
bromopyrido[2,3-b]indole
At rt and under an inert atmosphere, a solution of Pd(PPh3)4
(22 mg, 0.019 mmol, 0.08 equiv), 4-methoxyphenylboronic acid (4)
(40 mg, 0.261 mmol, 1.1 equiv), and K2CO3 (99 mg, 0.714 mmol,
3 equiv) in H2O (2.5 mL) was added to a solution of 23 or 25
(100 mg, 0.238 mmol) in 1,4-dioxane (10 mL). This solution was
stirred at 70 ꢀC for 4 h. After cooling to rt, (E)-phenylvinylboronic
acid (5) (39 mg, 0.262 mmol, 1.1 equiv) was added to the solution.
This solution was stirred at 100 ꢀC for 2 h. After cooling to rt, the
solution was diluted with H2O and extracted with EtOAc
(3ꢁ20 mL). The combined organic layers were dried over MgSO4,
then filtered through Celite, and the solvents were removed under
reduced pressure. The crude product was purified by flash chro-
matography (CH2Cl2/PE 1:1 or CH2Cl2/PE 7:3) to afford 32 or 34 in
54% or 71% yield.
6. (a) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358–3366; (b)
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King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.;
Larsen, R. D.; Martinelli, M. J.; Reider, P. J. Org. Lett. 2006, 8,1787–1789; (e) Kudo, N.;
Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282–1284; (f) Cooke, G.;
Augier de Cremiers, H.; Rotello, V. M.; Tarbit, B.; Vanderstraeten, P. E. Tetrahedron
2001, 57, 2787–2789.
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G. A.; Yun, C. S. Tetrahedron 2002, 58, 1465–1470; (d) Lohse, O.; Thevenin, P.;
Waldvogel, E. Synlett 1999, 45–48; (e) Cruskie, M. P.; Zoltewicz, J. A., Jr.; Abboud,
K. A. J. Org. Chem. 1995, 60, 7491–7495; (f) Rocca, P.; Marsais, F.; Godard, A.;
Queguiner, G. Tetrahedron 1993, 49, 3325–3342.
3.12. Typical procedure for Suzuki reactions with two
different boronic acids from 6-bromo-3-chloropyrido[2,3-
b]indole
A sealed pressure tube with a stir bar was charged with Pd(OAc)2
(5 mg, 0.02 mmol, 0.08 equiv), S-Phos (17 mg, 0.04 mmol, 0.16 equiv),
6-bromo-3-chloropyrido[2,3-b]indole 24 (100 mg, 0.238 mmol), 4-
methoxyphenylboronic acid (4) (44 mg, 0.286 mmol, 1.2 equiv),
and K3PO4 (151 mg, 0.71 mmol, 3 equiv). The tube was evacuated
and back-filled with argon (this was repeated three additional
times). Freshly degassed 1,4-dioxane (650 mL) was added and the
8. (a) Schirok, H. J. Org. Chem. 2006, 71, 5538–5545; (b) Allegretti, M.; Arcadi, A.;
Marinelli, F.; Nicolini, L. Synlett 2001, 609–612.
reaction mixture was stirred at 50 ꢀC for 5 h. After cooling to rt, (E)-
phenylvinylboronic acid (5) (88 mg, 0.595 mmol, 2.5 equiv) was
added to the solution. This solution was stirred at 100 ꢀC for 12 h.
After cooling to rt, the solution was diluted with H2O and extracted
with EtOAc (3ꢁ20 mL). The combined organic layers were dried
over MgSO4, then filtered through Celite, and the solvents were
removed under reduced pressure. The crude product was purified
by flash chromatography (CH2Cl2/PE 3:1) to afford 33 in 65% yield.
9. (a) Beletskaya, I. P.; Tsvetkov, A. V.; Tsvetkov, P. V.; Latyshev, G. V.; Lukashev, N.
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P. J. Tetrahedron 1992, 48, 8117–8126.
10. (a) Bracher, F.; Hildebrand, D. Liebigs Ann. Chem. 1992, 1315–1319; (b) Bracher,
F.; Hildebrand, D. Liebigs Ann. Chem. 1993, 1335–1337.
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Heterocycl. Chem. 2006, 2, 93–128; (c) Moquin-Pattey, C.; Guyot, M. Tetrahedron
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H. Tetrahedron Lett. 1997, 38, 3431–3434.
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Acknowledgements
`
The authors thank the ‘Ministere de la Recherche et de l’En-
´
seignement Superieur’ for a Graduate Fellowship (C.S.). Financial
support from the European Union (Contract Nꢀ LSHB-CT-2004-
503467) is also gratefully acknowledged.
13. (a) Das, S.; Brown, J. W.; Dong, Q.; Gong, X.; Kaldor, S. W.; Liu, Y.; Paraselli, B. R.;
Scorah, N.; Stafford, J. A.; Wallace, M. B. Appl. Int. WO 2007/044779; Chem.
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Grunt, U.; Spevak, W.; McConnell, D.; Schoop, A.; Brueckner, R.; Jacobi, A.;
Guertler, U.; Schnapp, G.; Klein, C.; Himmelsbach, F.; Pautsch, A.; Betzemeier, B.;
Herfurth, L.; Mack, J.; Wiedenmayer, D.; Bader, G.; Reiser, U. Appl. Int. WO 2006/
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R.; Stafford, J. A.; Wallace, M. B.; Wijesekera, H. Appl. Int. WO 2008/054956;
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.04.032.
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