Synthesis of 2-, 3-, and 4-substituted pyrido[2,3-b]indoles by C-N, C-O, and C-C(sp) bond formation

Article abstract of DOI:10.1002/ejoc.201000795

The synthesis of 2-, 3-, and 4-substituted α-carbolines is described starting from the corresponding chloropyrido[2,3-b]indoles by Buchwald-Hartwig and Sonogashira cross-coupling reactions. Regioselective Sonogashira reactions on 2,4-dichloropyrido[2,3-b]

Full text of DOI:10.1002/ejoc.201000795

FULL PAPER
DOI: 10.1002/ejoc.201000795
Synthesis of 2-, 3-, and 4-Substituted Pyrido[2,3-b]indoles by C–N, C–O, and
C–C(sp) Bond Formation
Cédric Schneider,[a] David Goyard,[a] David Gueyrard,[a] Benoît Joseph,[b] and
Peter G. Goekjian*[a]
Keywords: Natural products / Nitrogen heterocycles / Palladium / Polycycles / Cross-coupling
The synthesis of 2-, 3-, and 4-substituted α-carbolines is de- dichloropyrido[2,3-b]indoles are also presented as an ef-
scribed starting from the corresponding chloropyrido[2,3-b]-
indoles by Buchwald–Hartwig and Sonogashira cross-cou-
pling reactions. Regioselective Sonogashira reactions on 2,4-
ficient route to unsymmetrically 2,4-disubstituted α-carbol-
ines.
Introduction
α-Carbolines (pyrido[2,3-b]indoles) display a variety of
biological properties.[1] Among them, natural products such
as Grossularine-1 and -2 (Figure 1), which are marine alk-
aloids isolated from Dendrodoa grossularia in 1989, have at-
tracted interest for their antiproliferative activity.[2] Simi-
larly, Mescengricin, which was isolated from Streptomyces
griseoflavus, was found to protect neuronal cells by sup-
pressing the excitotoxicity induced by l-glutamate (Fig-
ure 1).[3] At the same time, a rapidly increasing number of
synthetic pyrido[2,3-b]indoles have appeared in the patent
literature for a range of potential applications.[4] Thus,
much effort has been devoted to the synthesis and function-
alization of pyrido[2,3-b]indoles.[5]
The synthesis of heteroatom-substituted α-carbolines,
such as the grossularines or compounds I and II, having
potent cyclin-dependent kinase (CDK) inhibitory activi-
Figure 1. α-Carboline natural products.
ties[4a,4b] (Figure 2), has attracted our attention in particu- philic substitution.[4a,4b,7] The introduction of alkylamines
lar. Relatively few methods are available for preparing by palladium-catalyzed coupling reaction has been reported
heteroatom-substituted α-carbolines. For the most part, briefly by Panunzio et al.[5h] Similarly, we became interested
heteroatoms have been introduced either prior to formation in alkynyl-substituted pyrido[2,3-b]indoles, which have re-
of the α-carboline skeletons,[6] starting from 2-acetamidino-
3-cyanoindoles, 2-amidinylindole-3-carbaldehyde, or 4-
amino-2-(benzotriazol-1-yl)quinolines, or by functionaliza-
tion of halo- or O-triflate-substituted pyridines by nucleo-
[a] Université de Lyon, Laboratoire de Chimie Organique
2-Glycochimie, Institut de Chimie et Biochimie Moléculaires et
Supramoléculaires, UMR 5246 CNRS – Université Claude
Bernard Lyon 1, Bât. Curien CPE-Lyon,
43 bd du 11 novembre 1918, 69622 Villeurbanne, France
Fax: +33-4-72448349
E-mail: goekjian@univ-lyon1.fr
[b] Université de Lyon, Université Claude Bernard – Lyon 1,
Institut de Chimie et Biochimie Moléculaires et
Supramoléculaires UMR-CNRS 5246, Bât. Curien CPE-Lyon,
43 bd du 11 novembre 1918, 69622 Villeurbanne, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000795.
Figure 2. α-Carboline CDK inhibitors.
Eur. J. Org. Chem. 2010, 6665–6677
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Scheme 1. Functionalization of α-carbolines at positions 2, 3, and 4.
ceived scant attention, with only an isolated example of the reaction on pyrido[2,3-b]indole N-oxide.[12] The ethoxy-
Sonogashira coupling on 3-bromo-α-carbolines being de- methyl-protected forms 4–6 (Figure 3) were prepared by
scribed by Sennhenn et al. in the patent literature.[4b] We N-alkylation with ethoxymethyl chloride (EOMCl) in the
therefore decided to study the preparation of heteroatom- presence of sodium hydride in N,N-dimethylformamide
and alkynyl-substituted α-carbolines from chlorine-substi- (DMF).
tuted precursors using palladium chemistry.
Palladium-catalyzed Buchwald–Hartwig,[8] and Sonoga-
shira coupling reactions[9] and, in particular, sequential
double coupling reactions on readily available chloro- or
dichloro-α-carbolines would provide a particularly efficient
approach to a wide range of heteroatom-substituted com-
pounds, especially those involving relatively less nucleo-
philic substituents, such as arylamino and aryloxy groups.
We also noted that the preparation of alkynyl-substituted
α-carbolines from the corresponding chloropyrido[2,3-b]-
indoles had not been reported and we thus investigated
Figure 3. Chloropyrido[2,3-b]indole starting materials.
Sonogashira coupling reactions on this system. Whereas
such reactions can now be considered as classical organic
reactions, many different experimental conditions have been
reported, thus the most appropriate conditions must be
identified for each particular heterocycle (Scheme 1).
Furthermore, sequential double-coupling reactions provide
a particularly efficient approach to more highly substituted
compounds, and we recently reported a sequential double
Suzuki coupling reaction on 2,6-, 3,6-, and 4,6-bromo,chlo-
ropyrido[2,3-b]indoles.[10] We report here the results of our
investigations into the sequential double Sonogashira cou-
pling reaction on the more challenging case, 2,4-dichloro-
pyrido[2,3-b]indole.
Various parameters were investigated with 2-chloropyr-
ido[2,3-b]indole (1) as substrate (Table 1, entries 1–6). Buch-
wald[13] and Thutewohl[14] demonstrated recently that C–N
and C–O coupling reactions can be performed on chloro-
substituted pyridines and 7-azaindoles using [Pd2(dba)3]
Table 1. Buchwald–Hartwig coupling reactions on 2-, 3-, and 4-
chloropyrido[2,3-b]indoles with arylamines.
Entry Starting material
Ar
Conditions[a] Product Yield [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2
2
2
3
3
3
Ph
Ph
A
B
B
7
7
8
8
9
10
11
11
12
13
14
15
0
62
0
3-NO2C6H4
3-NO2C6H4
3-MeOC6H4
2-NO2C6H4
Ph
C
C
C
C
D
D
C
C
C
61
70
53
0
78
80
79
70
80
Results and Discussion
Ph
3-MeOC6H4
3-NO2C6H4
3-MeOC6H4
2-NO2C6H4
Synthesis of Monosubstituted α-Carbolines
10
11
12
The readily accessible chloropyrido[2,3-b]indoles 1–3
were selected as initial starting materials for the study of
palladium-catalyzed C–N, C–O, and C–C(sp) bond forma-
tion on the α-carboline ring system. The 2- and 3-chloro-
pyrido[2,3-b]indoles 1 and 2 were prepared in two steps
using a Graebe–Ullmann reaction starting from the corre-
sponding dichloropyridines,[5e,11] and the 4-chloropyrido-
[a] Method A: [Pd2(dba)3] (0.08 equiv.), X-Phos (0.16 equiv.),
NaOtBu (3 equiv.), amine (1.3 equiv.), toluene, 110 °C, 12 h;
Method B: [Pd2(dba)3] (0.08 equiv.), X-Phos (0.16 equiv.),
LiHMDS (3 equiv.), arylamine (1.3 equiv.), THF, 70 °C, 12 h;
Method C: [Pd2(dba)3] (0.08 equiv.), X-Phos (0.16 equiv.), K2CO3
(3 equiv.), arylamine (1.3 equiv.), tBuOH, 100 °C, 12 h; Method D:
[Pd2(dba)3] (0.08 equiv.), X-Phos (0.16 equiv.), NaOtBu (3 equiv.),
[2,3-b]indole 3 was synthesized through a Reissert–Henze arylamine (1.3 equiv.), tBuOH, 100 °C, 12 h.
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Substituted Pyrido[2,3-b]indoles
and X-Phos. Using this catalytic system, the influence of
the solvent [toluene, tetrahydrofuran (THF) or tert-butyl
alcohol (tBuOH)] and the base (LiHMDS, K2CO3 or Na-
OtBu) was studied to optimize the reaction on the α-carb-
oline substrate. The Buchwald [Pd2(dba)3]/X-Phos catalytic
system was found to be effective, however, the solvent and
base still needed to be adapted to the particular nucleophile.
The conditions described by Thutewohl were found to be
the most general. The moderate yields reflect, in part, diffi-
culties in the isolation and purification of the poorly soluble
products.
2- and 4-chloro-substituted α-carbolines 1 and 3 were
thus coupled cleanly with aniline, 3-nitroaniline, 3-meth-
oxyaniline, and 2-nitroaniline in 53–80% yields using Thu-
tewohl’s conditions (Table 1, entries 2–6 and 10–12). It
should be noted that no coupling was observed in these
cases under basic conditions in the absence of palladium
catalyst. However, the conditions proved unsuccessful for
the less reactive 3-chloro-isomer 2 (Table 1, entry 7). Use
of the stronger base, NaOtBu in tBuOH, proved to be far
superior. This method allowed clean coupling of aniline and
3-methoxyaniline in 78 and 80% yield, respectively (Table 1,
entries 8 and 9). However, electron-deficient anilines, such
as 3-nitroaniline, failed to provide the desired 3-substituted
products under any of the conditions tested (Scheme 2).
Scheme 3. Synthesis of 2- and 4-aryloxy-α-carbolines.
Table 2. Buchwald–Hartwig coupling reactions of 2- and 4-chlo-
ropyrido[2,3-b]indoles with phenols.[a]
Entry Starting material
Ar
Product
Yield [%]
1
2
3
4
4
4
6
6
3-NO2C6H4
3-MeOC6H4
3-NO2C6H4
3-MeOC6H4
16
17
18
19
62
67
86
78
[a] Reagents and conditions: [Pd2(dba)3] (0.08 equiv.), X-Phos
(0.16 equiv.), NaOtBu (3 equiv.), phenol (1.3 equiv.), toluene,
110 °C, 12 h.
Having performed the Buchwald–Hartwig coupling reac-
tions on either protected or unprotected α-carbolines, we
next turned our attention to the Sonogashira reaction
(Table 3 and Scheme 4). The coupling reaction to be proved
effective with the unprotected 2-chloropyrido[2,3-b]indole
(1), using either aryl- or alkyl-substituted acetylenes, and
gave the desired products in moderate 61–64% yields
(Table 3, entries 1 and 2). The copper-free conditions used
by Buchwald in the pyridine cases, in aprotic solvents (diox-
ane or acetonitrile) with an inorganic base (Cs2CO3) proved
to be the most effective.[16] However, the poor solubility of
the substrates 1–3 in these solvents limited the applicability
of these conditions. The reaction was therefore investigated
using the EOM-protected chloropyrido[2,3-b]indoles 4–6.
The coupling reaction proceeded in high yields on the 2-,
3-, and 4-chloropyrido[2,3-b]indoles (Table 3, entries 3–11),
Scheme 2. Synthesis of 2-, 3-, and 4-arylamino-α-carbolines.
Having successfully achieved the coupling of arylamines
to the α-carboline ring system, we investigated the Buch-
wald–Hartwig coupling of the corresponding phenols. Ini-
tial attempts with the unprotected chloropyrido[2,3-b]-
indoles 1–3 proved unsuccessful. However, it has previously
been shown that protection of the nitrogen is important to
avoid deactivation of the aryl chlorides under basic condi-
tions.[14,15] Therefore, coupling of the EOM-protected chlo-
ropyrido[2,3-b]indoles 4–6 were investigated (Scheme 3).
The coupling of both electron-rich and -deficient phenols
proceeded smoothly with the protected 2- and 4-chloropyr-
ido[2,3-b]indoles 4 and 6 under Buchwald’s conditions in
toluene in the presence of NaOtBu (Table 2). The yields
were acceptable, ranging from 62 to 86%. However, we were
unable to couple the protected 3-chloropyrido[2,3-b]indole
5 under any of the conditions investigated.
Table 3. Sonogashira coupling reactions of 2-, 3-, and 4-chloropyr-
ido[2,3-b]indoles with acetylenes.[a]
Entry Starting material
R
T [°C] t [h]
Product Yield [%]
1
2
3
4
5
6
7
8
9
1
1
4
4
4
5
5
5
6
6
6
Ph
nPr
Ph
nPr
cHex
Ph
nPr
cHex
Ph
nPr
cHex
70
70
90
70
70
90
70
90
90
70
90
12
12
12
12
12
12
12
24
12
12
12
20
21
22
23
24
25
26
27
28
29
30
64
61
80
85
87
95
81
63
95
90
80
10
11
[a] Reagents and conditions: [PdCl2(MeCN)2] (0.08 equiv.), X-Phos
(0.16 equiv.), Cs2CO3 (2.6 equiv.), acetylene (1.3 equiv.), MeCN.
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although slightly higher temperatures and longer reaction
times were required with the less reactive acetylenes (e.g.,
Table 3, entry 8).
Scheme 4. Synthesis of 2-, 3-, and 4-ethynyl-α-carbolines.
Scheme 5. Sequential palladium-catalyzed coupling reactions of 6-
bromo-3-chloropyrido[2,3-b]indole 31.
Synthesis of Disubstituted α-Carbolines by Simultaneous or
Sequential Double Coupling Reactions
The ability to perform either one-pot, double-coupling
reactions, or regioselective sequential bis-coupling reactions
provides extremely rapid and efficient access to a large vari-
ety of structurally diverse heterocyclic compounds. The se-
quential double substitution reaction of 6-bromo-3-chlo-
ropyrido[2,3-b]indole (31), as demonstrated previously with
the Suzuki coupling,[10] unsurprisingly, also worked in the
case of a sequential Sonogashira–Buchwald–Hartwig cou-
pling (Scheme 5). However, it was preferable to reduce the
acetylene before performing the Buchwald–Hartwig cou-
pling. Similarly, the more closely matched 6-bromo-2-chlo-
ropyrido[2,3-b]indole can be functionalized through a re-
gioselective, sequential Suzuki–Buchwald–Hartwig cou-
pling to furnish the compound 36.
Scheme 6. Synthesis of 2,4-dichloropyrido[2,3-b]indoles.
We therefore investigated the most challenging case, the of the two activated chlorides would provide particularly
bis-coupling reactions of 2,4-dichloropyrido[2,3-b]indoles efficient access to more complex α-carbolines. The Sonoga-
38 and 39 bearing two activated chlorine atoms of similar shira reaction was used to test this hypothesis.[17] Using
reactivity. These compounds were prepared through a sec- copper in the presence of [PdCl2(PPh3)2] and triethylamine,
ond Reissert–Henze reaction on 4-chloropyrido[2,3-b]ind- in a method first reported by Rault et al.,[18] proved effec-
ole N-oxide (37; Scheme 6).
tive, but the poor solubility of the starting material required
We first investigated the double coupling reaction as a the use of DMF as a co-solvent in our case. The reaction
route to symmetrically 2,4-disubstituted α-carbolines provided the monosubstituted acetylenes 43 and 44 with
(Table 4, entries 1–3). The double Buchwald coupling with 3- very good regiocontrol, although competing homodimeri-
methoxyaniline proceeded smoothly by using the unprotected zation of the acetylene required an optimization of the
starting material 38 to provide the disubstituted product 40 number of equivalents of acetylene in each case (Table 4,
in 90% yield. As in the monosubstituted cases, substitution entries 4 and 5).
with phenols and acetylenes was more effective on the EOM-
Having accessed the key monosubstituted α-carbolines
protected 2,4-dichloropyrido[2,3-b]indole 39, providing the 43 and 44, a second substitution could be performed by
2,4-bis(methoxyphenyloxy)- and 2,4-bis(phenylethynyl)-sub- applying subsequent Suzuki coupling (Table 4, entry 6), mi-
stituted α-carbolines 41 and 42, respectively (Table 4, entries crowave-induced nucleophilic substitution (Table 4, entry
2 and 3) in acceptable yields (Scheme 7).
7), or Sonogashira coupling (Table 4, entry 8). As shown
The regioselective monosubstitution of the 2,4-dichlo- above, the Buchwald couplings could be used after re-
ropyrido[2,3-b]indole (39) based on a differential reactivity duction of the triple bond.
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Substituted Pyrido[2,3-b]indoles
Table 4. Buchwald–Hartwig and Sonogashira coupling reactions of 2,4-dichloropyrido[2,3-b]indoles.
Entry SM
X
Y
Method[a]
Cat.
(equiv.)
Phosphane
(equiv.)
Base
(equiv.)
Solvent
T
t
Product Yield
[%]
[°C] [h]
1
2
3
4
38 3-MeOPhNH 3-MeOPhNH
A
B
C
D
Pd2(dba)3 (0.08)
Pd2(dba)3 (0.08)
Pd(Cl)2(MeCN)2 (0.08) X-Phos (0.16)
Pd(Cl)2(PPh3)2 (0.1)
CuI (0.2)
X-Phos (0.16)
X-Phos (0.16)
K2CO3 (3)
K2CO3 (3)
Cs2CO3 (5.2)
tBuOH
toluene
MeCN
100 12
100 12
90 12
80 12
40
41
42
43
90
80
62
73
39 3-MeOPhO
3-MeOPhO
Ph-CϵC
Cl
39
39
Ph-CϵC
cHexCϵC
PPh3 (0.1)
Et3N/DMF (2:1)
5
39
Ph-CϵC
Cl
D
Pd(Cl)2(PPh3)2 (0.1)
CuI (0.2)
PPh3 (0.1)
Et3N/DMF (2:1)
100 12
44
65
6
7
8
43
44
44
cHexCϵC
Ph-CϵC
Ph-CϵC
4-MeOPh
N-Me-piperazinyl
cHex-CϵC
E
F
G
Pd(PPh3)4 (0.08)
K2CO3 (3)
H2O/1,4-dioxane 100 12
200
Et3N/DMF (2:1) 80 12
45
46
47
71
84
76
1
Pd(Cl)2(PPh3)2 (0.1)
CuI (0.2)
PPh3 (0.1)
[a] Method A: 3-methoxyaniline (2.6 equiv.); Method B: 3-methoxyphenol (2.6 equiv.); Method C: phenylacetylene (2.6 equiv.); Method
D: acetylene (2.5–3 equiv.); Method E: 4-methoxyphenylboronic acid (1.3 equiv.); Method F: microwaves, N-methylpiperazine; Method
G: cyclohexylacetylene (3 equiv.).
Scheme 7. Sequential Sonogashira and Buchwald–Hartwig reactions of 2,4-dichloropyrido[2,3-b]indoles.
Conclusions
Experimental Section
General: All reactions were carried out under an argon atmosphere.
Solvents (THF, tBuOH, toluene, acetonitrile, and DMF) and tri-
ethylamine were distilled and dried by standard methods. [Pd2-
(dba)3] was purchased from Strem chemicals, X-Phos [2-(dicyclo-
hexylphosphanyl)-2Ј,4Ј,6Ј-triisopropylbiphenyl] and [PdCl2(PPh3)2]
were purchased from Aldrich. Reactions were routinely monitored
by thin-layer chromatography (TLC) on silica gel 60 F254. Purifica-
tions on flash silica gel column chromatography were performed
with Geduran silica gel Si 60 (40–63 μm). 1H and 13C NMR spectra
were recorded with a Bruker Avance DRX300 spectrometer at
Palladium-catalyzed Buchwald–Hartwig and Sonoga-
shira coupling reactions on readily accessible chloropyr-
ido[2,3-b]indoles provide efficient and general access to ni-
trogen-, oxygen-, and carbon-substituted α-carbolines. In
addition, the selective monosubstitution of 2,4-dichloropyr-
ido[2,3-b]indoles followed by a second substitution reaction
provides a particularly efficient route to complex com-
pounds that may serve, for example, in the context of the
parallel synthesis of biologically relevant molecules.
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P. G. Goekjian et al.
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25 °C. The following abbreviations are used to describe the ob-
served multiplicities: singlet (s), doublet (d), doublet of doublets
(dd), doublet of doublet of doublets (ddd), triplet (t), triplet of
doublets (td), multiplet (m), broad singlet (br. s), sextuplet (sext).
13C NMR multiplicities were assigned on the basis of DEPT experi-
ments. MS (EI, ESI, SIMS, LSIMS, and CI) and HRMS were re-
corded in positive ion mode with a Thermofinnigan apparatus. In
the case of chlorine-containing compounds, the 35Cl and 37Cl iso-
tope peaks are reported. IR spectra were recorded by attenuated-
total-reflection (ATR) spectroscopy using a ZnSe crystal.
261, 263 [M + H+]. HRMS (CI): calcd. for C14H14ClN2O 261.0795;
found 261.0795.
Phenyl-(9H-pyrido[2,3-b]indol-2-yl)amine (7):[19] A sealed pressure
tube with stir bar was charged with 2-chloro-9H-pyrido[2,3-b]-
indole (1; 100 mg, 0.498 mmol), [Pd2(dba)3] (37.0 mg, 0.04 mmol),
and X-Phos (37.0 mg, 0.08 mmol). The tube was evacuated and
back-filled with argon (repeated for three additional times). Aniline
(60 μL, 0.65 mmol) and LiHMDS (1.0 m in THF, 1.5 mL,
3.00 mmol) were added and the reaction mixture was stirred at
65 °C overnight. After cooling to r.t., the solution was quenched
with H2O and extracted with EtOAc (3ϫ20 mL). The combined
organic layers were dried with MgSO4, then filtered through Celite
and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (CH2Cl2) to afford
compound 7 (80 mg, 62% yield) as a white solid. 1H NMR
(300 MHz, [D6]acetone): δ = 10.56 (br. s, 1 H), 8.40 (br. s, 1 H),
8.20 (d, J = 8.5 Hz, 1 H), 7.91 (d, J = 7.7 Hz, 1 H), 7.85 (d, J =
7.7 Hz, 2 H), 7.48 (d, J = 8.1 Hz, 1 H), 7.31–7.25 (m, 3 H), 7.15
(t, J = 7.5 Hz, 1 H), 6.92 (t, J = 7.2 Hz, 1 H), 6.73 (d, J = 8.5 Hz,
1 H) ppm. MS (ESI): m/z = 258 [M + H+].
General Procedure for EOM Protection: NaH (60% in oil, 3 equiv.)
was added to a stirred suspension of chloro-9H-pyrido[2,3-b]indole
(1 equiv., 0.4 m in DMF) at 0 °C. After stirring at 0 °C for 20 min,
EOM-Cl (2.5 equiv.) was added dropwise. The reaction mixture was
stirred for 12 h and then poured into 5% aqueous saturated
NaHCO3 solution and extracted with EtOAc (3ϫ20 mL). The
combined organic layers were dried with MgSO4 and the solvent
was removed under reduced pressure.
2-Chloro-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole (4): The product
was purified by column chromatography on silica gel (CH2Cl2/
petroleum ether, 1:1) to afford compound 4 (255 mg, 99% yield) as
a white solid; m.p. 70–72 °C (CH2Cl2/petroleum ether). IR (neat
General Procedure for C–N Bond Formation with 2- or 4-Chloro
Derivatives: A sealed pressure tube with stir bar was charged with
2-chloro-9H-pyrido[2,3-b]indole (1) or 4-chloro-9H-pyrido[2,3-b]-
indole (3) (100 mg, 0.498 mmol), [Pd2(dba)3] (37 mg, 0.04 mmol),
X-Phos (38 mg, 0.08 mmol), and K2CO3 (190 mg, 1.37 mmol). The
tube was evacuated and back-filled with argon (repeated for three
additional times). Degassed tBuOH (1 mL) and the selected aryl-
amine (1.3 equiv.) were added and the reaction mixture was stirred
at 100 °C overnight. After cooling to r.t., the solution was
quenched with H2O and extracted with EtOAc (3ϫ20 mL). The
combined organic layers were dried with MgSO4, then filtered
through Celite and the solvent was removed under reduced pres-
sure.
powder): ν = 3055, 2979, 2930, 2890, 1587, 1560, 1470, 1418, 1388,
˜
1122, 1092, 1070, 1050, 911, 804, 773 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.17 (d, J = 7.9 Hz, 1 H), 7.99 (d, J = 7.7 Hz, 1 H),
7.64 (d, J = 8.3 Hz, 1 H), 7.53 (td, J = 8.3, 7.3, 1.0 Hz, 1 H), 7.33
(td, J = 7.7, 1.0 Hz, 1 H), 7.18 (d, J = 7.9 Hz, 1 H), 5.92 (s, 2 H),
3.54 (q, J = 6.9 Hz, 2 H), 1.15 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 151.2 (C), 147.6 (C), 139.4 (C), 130.4 (CH),
127.2 (CH), 121.3 (CH), 120.8 (CH), 120.4 (C), 115.8 (CH), 114.6
(C), 110.8 (CH), 71.1 (CH2), 64.4 (CH2), 15.0 (CH3) ppm. MS (CI):
m/z = 261, 263 [M + H+]. HRMS (CI): calcd. for C14H14ClN2O
261.0795; found 261.0793.
(3-Nitrophenyl)-(9H-pyrido[2,3-b]indol-2-yl)amine (8): The crude
product was purified by flash chromatography (CH2Cl2/petroleum
ether, 9:1) to afford compound 8 (93 mg, 61% yield) as a red solid;
3-Chloro-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole (5): The product
was purified by column chromatography on silica gel (CH2Cl2) to
afford compound 5 (650 mg, 82% yield) as a white solid; m.p. 88–
m.p. Ͼ220 °C (MeOH). IR (neat powder): ν = 3373, 3128, 1575,
˜
1599, 1527, 1505, 1413, 1334, 1253, 1205, 1129, 800, 779, 756 cm–1.
1H NMR (300 MHz, [D6]DMSO): δ = 11.62 (br. s, 1 H), 9.76 (br.
s, 1 H), 8.93 (t, J = 2.3 Hz, 1 H), 8.31 (d, J = 8.3 Hz, 1 H), 8.15
(ddd, J = 8.2, 2.3, 0.8 Hz, 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.73
(ddd, J = 8.2, 2.3, 0.8 Hz, 1 H), 7.56 (t, J = 8.2 Hz, 1 H), 7.43 (d,
J = 7.8 Hz, 1 H), 7.30 (td, J = 7.5, 1.0 Hz, 1 H), 7.15 (td, J = 7.8,
1.0 Hz, 1 H), 6.74 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 153.3 (C), 150.4 (C), 148.3 (C), 143.1 (C), 137.7
(C), 130.4 (CH), 129.7 (CH), 124.2 (CH), 123.5 (CH), 121.3 (C),
119.3 (2ϫCH), 114.2 (CH), 111.2 (CH), 111.0 (CH), 107.5 (C),
103.8 (CH) ppm. MS (CI, 100 °C): m/z = 305 [M + H+]. HRMS
(CI): calcd. for C17H13N4O2 305.1039; found 305.1039.
90 °C (CH Cl /petroleum ether). IR (neat powder): ν = 3056, 2978,
˜
2
2
2878, 1588, 1565, 1489, 1466, 1455, 1372, 1267, 1092, 1055, 1012,
1
902, 829, 781 cm–1. H NMR (300 MHz, CDCl3): δ = 8.42 (d, J =
2.3 Hz, 1 H), 8.28 (d, J = 2.3 Hz, 1 H), 8.03 (d, J = 7.7 Hz, 1 H),
7.62 (d, J = 8.3 Hz, 1 H), 7.56 (td, J = 7.5, 7.1, 1.1 Hz, 1 H), 7.34
(td, J = 8.1, 1.1 Hz, 1 H), 5.90 (s, 2 H), 3.54 (q, J = 6.9 Hz, 2 H),
1.15 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
150.1 (C), 144.5 (CH), 140.2 (C), 127.8 (CH), 127.8 (CH), 123.8
(C), 121.2 (CH), 121.1 (CH), 119.9 (C), 117.0 (C), 110.7 (CH), 71.1
(CH2), 64.4 (CH2), 15.0 (CH3) ppm. MS (ESI): m/z = 261, 263
[M + H+]. HRMS (CI): calcd. for C14H13ClN2O 261.0795; found
261.0794.
4-Chloro-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole (6): The product
was purified by column chromatography on silica gel (CH2Cl2/
petroleum ether, 9:1) to afford compound 6 (631 mg, 85% yield) as
a white solid; m.p. 68–70 °C (CH2Cl2/petroleum ether). IR (neat
(3-Methoxyphenyl)-(9H-pyrido[2,3-b]indol-2-yl)amine
crude product was purified by flash chromatography (CH2Cl2/pe-
troleum ether, 9:1) to afford compound 9 (100 mg, 70% yield) as a
brown solid; m.p. 206–208 °C (MeOH). IR (neat powder): ν =
(9):
The
˜
powder): ν = 3084, 2971, 2938, 2903, 1588, 1556, 1459, 1357, 1132,
3385, 3053, 1595, 1579, 1492, 1416, 1212, 1129, 1036, 776,
˜
1100, 1070, 1061, 813, 784 cm–1. 1H NMR (300 MHz, CDCl3): δ = 736 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 11.50 (br. s, 1 H),
8.47 (d, J = 8.0 Hz, 1 H), 8.34 (d, J = 5.3 Hz, 1 H), 7.67 (d, J = 9.20 (br. s, 1 H), 8.21 (d, J = 8.4 Hz, 1 H), 7.90 (d, J = 7.4 Hz, 1
8.3 Hz, 1 H), 7.57 (td, J = 8.3, 7.1, 1.3 Hz, 1 H), 7.37 (td, J = 8.0, H),7.70 (t, J = 2.3 Hz, 1 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.27 (d, J
1.1 Hz, 1 H), 7.19 (d, J = 5.3 Hz, 1 H), 5.87 (s, 2 H), 3.54 (q, J =
= 8.0 Hz, 1 H), 7.25 (td, J = 8.4, 1.1 Hz, 1 H), 7.17 (t, J = 8.0 Hz,
6.9 Hz, 2 H), 1.15 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, 1 H), 7.12 (td, J = 8.4, 1.1 Hz, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 6.48
CDCl3): δ = 152.8 (C), 146.0 (C), 139.5 (C), 138.2 (C), 127.7 (CH), (ddd, J = 8.0, 2.3, 0.8 Hz, 1 H), 3.78 (s, 3 H) ppm. 13C NMR
123.4 (CH), 121.3 (CH), 120.0 (C), 116.9 (CH), 114.2 (CH), 110.4
(75 MHz, [D6]DMSO): δ = 159.7 (C), 154.1 (C), 150.8 (C), 143.1
(CH), 71.3 (CH2), 64.5 (CH2), 15.1 (CH3) ppm. MS (CI): m/z = (C), 137.4 (C), 129.9 (CH), 129.2 (CH), 1237 (CH), 121.5 (C), 119.1
6670
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6665–6677

Substituted Pyrido[2,3-b]indoles
(CH), 119.0 (CH), 110.7 (CH), 110.4 (CH), 106.4 (C), 105.4 (CH), 136.6 (C), 135.8 (CH), 126.3 (CH), 125.9 (CH), 121.8 (CH), 121.0
103.8 (CH), 103.6 (CH), 54.8 (CH3) ppm. MS (ESI): m/z = 290
(CH), 119.9 (CH), 119.5 (CH), 119.2 (C), 111.1 (CH), 106.1 (C),
[M + H+]. HRMS (ESI): calcd. for C18H16N3O 290.1293; found 105.8 (CH) ppm. MS (ESI): m/z = 305 [M + H+]. HRMS (ESI):
290.1291.
calcd. for C17H13N4O2 305.1039; found 305.1036.
(2-Nitrophenyl)-(9H-pyrido[2,3-b]indol-2-yl)amine (10): The crude
General Procedure for C–N Bond Formation on 3-Chloro Deriva-
product was purified by flash chromatography (CH2Cl2/petroleum
tives: A sealed pressure tube with a stir bar was charged with 3-
ether, 9:1) to afford compound 10 (80 mg, 53% yield) as a red solid; chloro-9H-pyrido[2,3-b]indole (2; 100 mg, 0.498 mmol), [Pd2-
m.p. 204–206 °C (MeOH). IR (neat powder): ν = 3390, 3297, 3057,
(dba)3] (37 mg, 0.04 mmol), X-Phos (38 mg, 0.08 mmol), and Na-
OtBu (132 mg, 1.37 mmol). The tube was evacuated and back-filled
with argon (repeated for three additional times). Degassed tBuOH
˜
1569, 1595, 1458, 1496, 1414, 1318, 1254, 1202, 1133, 1077, 826,
733 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 10.38 (br. s, 1 H),
8.87 (d, J = 8.7 Hz, 1 H), 8.53 (br. s, 1 H), 8.25 (d, J = 8.5 Hz, 2 (1 mL) and aniline (1.3 equiv.) were added and the reaction mixture
H), 7.96 (d, J = 7.9 Hz, 1 H), 7.57 (td, J = 8.9, 1.5 Hz, 1 H), 7.42–
7.37 (m, 3 H), 6.95 (td, J = 7.9, 1.1 Hz, 1 H), 6.87 (d, J = 8.7 Hz,
1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 151.7 (C), 150.4
was stirred at 100 °C overnight. After cooling to r.t., the solution
was quenched with H2O and extracted with EtOAc (3ϫ30 mL).
The combined organic layers were dried with MgSO4, then filtered
(C), 137.9 (C), 137.4 (C), 136.8 (C), 134.8 (CH), 130.6 (CH), 125.6 through Celite and the solvent was removed under reduced pres-
(CH), 124.7 (CH), 121.7 (CH), 121.0 (C), 120.7 (CH), 119.7 (CH), sure.
119.4 (CH), 111.0 (CH), 109.2 (C), 105.0 (CH) ppm. MS (CI,
Phenyl-(9H-pyrido[2,3-b]indol-3-yl)amine (11): The crude product
150 °C): m/z = 305 [M + H+]. HRMS (ESI): calcd. for C17H13N4O2
was purified by column chromatography on silica gel (CH2Cl2/
305.1039; found 305.1038.
EtOAc, 8:2) to afford compound 11 (100 mg, 78% yield) as a
(3-Nitrophenyl)-(9H-pyrido[2,3-b]indol-4-yl)amine (13): The crude
product was purified by flash chromatography (CH2Cl2/petroleum
ether, 9:1) to afford compound 13 (110 mg, 79% yield) as a yellow
brown solid; m.p. Ͼ220 °C (MeOH). IR (neat powder): ν = 3362,
˜
1
3140, 1600, 1494, 1454, 1387, 1301, 1268, 1227, 783, 738 cm–1. H
NMR (300 MHz, [D6]DMSO): δ = 11.61 (br. s, 1 H), 8.29 (d, J =
2.3 Hz, 1 H), 8.24 (d, J = 2.3 Hz, 1 H), 8.13 (d, J = 7.7 Hz, 1 H),
8.01 (br. s, 1 H), 7.46 (d, J = 7.3 Hz, 1 H), 7.41 (td, J = 8.3, 8.1,
1.1 Hz, 1 H), 7.21–7.13 (m, 3 H), 6.93 (d, J = 7.7 Hz, 2 H), 6.72
(t, J = 7.1 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
solid; m.p. Ͼ220 °C (MeOH). IR (neat powder): ν = 3411, 3058,
˜
1
1594, 1574, 1504, 1334, 1259, 1065, 999, 880, 794 cm–1. H NMR
(300 MHz, [D6]DMSO): δ = 11.80 (br. s, 1 H), 9.10 (br. s, 1 H),
8.22 (d, J = 5.6 Hz, 1 H), 8.06 (t, J = 2.3 Hz, 1 H), 8.00 (d, J =
7.2 Hz, 1 H), 7.82 (ddd, J = 8.3, 2.3, 0.9 Hz, 1 H), 7.67 (ddd, J = 148.1 (C), 146.1 (C), 141.1 (CH), 139.5 (C), 131.9 (C), 129.2
8.3, 2.3, 0.9 Hz, 1 H), 7.58 (t, J = 8.3 Hz, 1 H), 7.48 (d, J = 8.0 Hz, (2ϫCH), 126.5 (CH), 121.4 (CH), 120.6 (CH), 120.2 (C), 118.9
1 H), 7.39 (td, J = 7.2, 1.1 Hz, 1 H), 7.15 (td, J = 8.0, 1.1 Hz, 1 H),
6.98 (d, J = 5.6 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 153.8 (C), 148.6 (C), 146.9 (CH), 144.2 (C), 143.4 (C), 137.9 (C),
130.4 (CH), 125.3 (CH), 124.9 (CH), 122.9 (CH), 119.6 (C), 118.9
(CH), 115.8 (CH), 113.1 (CH), 110.7 (CH), 104.9 (C), 103.4
(CH) ppm. MS (ESI): m/z = 305 [M + H+]. HRMS (ESI): calcd.
for C17H13N4O2 305.1039; found 305.1041.
(CH), 118.2 (CH), 115.2 (C), 114.1 (2ϫCH), 111.1 (CH) ppm. MS
(ESI): m/z = 260 [M + H+]. HRMS (ESI): calcd. for C17H14N3
260.1188; found 260.1189.
(3-Methoxyphenyl)-(9H-pyrido[2,3-b]indol-3-yl)amine (12): The
product was purified by column chromatography on silica gel
(CH2Cl2/EtOAc, 8:2) to afford compound 12 (116 mg, 80% yield)
as a yellow solid; m.p. 163–165 °C (MeOH). IR (neat powder): ν =
˜
(3-Methoxyphenyl)-(9H-pyrido[2,3-b]indol-4-yl)amine (14): The
crude product was purified by flash chromatography (CH2Cl2/
EtOAc, 6:4) to afford compound 14 (100 mg, 70% yield) as a white
3391, 3145, 3059, 1609, 1590, 1522, 1457, 1387, 1277, 1217, 1153,
1
1046, 750, 734 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 11.62
(br. s, 1 H), 8.31 (d, J = 2.3 Hz, 1 H), 8.24 (d, J = 2.3 Hz, 1 H),
8.14 (d, J = 7.7 Hz, 1 H), 8.01 (br. s, 1 H), 7.46 (d, J = 7.5 Hz, 1
H), 7.42 (td, J = 8.1, 0.8 Hz, 1 H), 7.16 (td, J = 7.9, 1.3 Hz, 1 H),
7.08 (t, J = 7.9 Hz, 1 H), 6.50 (dd, J = 8.1, 2.2 Hz, 1 H), 6.45 (t, J
solid; m.p. Ͼ220 °C (MeOH). IR (neat powder): ν = 3440, 3051,
˜
1615, 1594, 1577, 1490, 1455, 1341, 1262, 1158, 1042, 854, 762,
728 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 11.64 (br. s, 1 H),
8.50 (br. s, 1 H), 8.10 (d, J = 5.6 Hz, 1 H), 8.08 (d, J = 7.2 Hz, 1 = 2.2 Hz, 1 H), 8.31 (dd, J = 8.1, 2.2 Hz, 1 H), 3.68 (s, 3 H) ppm.
H), 7.44 (d, J = 7.7 Hz, 1 H), 7.36 (td, J = 7.5, 0.9 Hz, 1 H), 7.25
(t, J = 8.4 Hz, 1 H), 7.14 (td, J = 7.5, 0.9 Hz, 1 H), 6.89–6.86 (m,
2 H), 6.85 (d, J = 5.6 Hz, 1 H), 6.63 (dt, J = 8.4, 1.7 Hz, 1 H), 3.73
13C NMR (75 MHz, [D6]DMSO): δ = 160.4 (C), 148.3 (C), 147.6
(C), 141.4 (CH), 139.5 (C), 131.7 (C), 130.3 (CH), 126.5 (CH),
121.4 (CH), 121.1 (CH), 120.2 (C), 119.0 (CH), 115.2 (C), 111.2
(s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.1 (C), (CH), 106.8 (CH), 103.7 (CH), 99.8 (CH), 54.7 (CH3) ppm. MS
153.7 (C), 146.8 (CH), 145.9 (C), 142.7 (C), 137.6 (C), 129.9 (CH), (ESI): m/z = 290.2 [M + H+]. HRMS (ESI): calcd. for C18H16N3O:
124.9 (CH), 122.7 (CH), 120.0 (C), 118.8 (CH), 112.9 (CH), 110.5
(CH), 108.1 (CH), 106.4 (CH), 103.6 (C), 102.3 (CH), 54.9
(CH3) ppm. MS (ESI): m/z = 290 [M + H+]. HRMS (ESI): calcd.
for C18H16N3O 290.1293; found 290.1288.
290.1293; found 290.1293.
N,NЈ-Bis(3-methoxyphenyl)-9H-pyrido[2,3-b]indole-2,4-diamine (40):
A sealed pressure tube with a stir bar was charged with 2,4-
dichloro-9H-pyrido[2,3-b]indole (38; 100 mg, 0.424 mmol),
[Pd2(dba)3] (32 mg, 0.034 mmol), X-Phos (34 mg, 0.07 mmol), and
K2CO3 (180 mg, 1.3 mmol). The tube was evacuated and back-
filled with argon (repeated for three additional times). Degassed
tBuOH (850 μL) and 3-methoxyaniline (148 μL, 1.1 mmol) were
added and the reaction mixture was stirred at 100 °C overnight.
After cooling to r.t., the solution was quenched with H2O and ex-
tracted with EtOAc (3ϫ30 mL). The combined organic layers were
(2-Nitrophenyl)-(9H-pyrido[2,3-b]indol-4-yl)amine (15): The crude
product was purified by flash chromatography (CH2Cl2/petroleum
ether, 1:1) to afford compound 15 (121 mg, 80% yield) as a red
solid; m.p. Ͼ220 °C (MeOH). IR (neat powder): ν = 3330, 3037,
˜
1
1615, 1588, 1498, 1458, 1347, 1256, 1153, 866, 776 cm–1. H NMR
(300 MHz, [D6]DMSO): δ = 11.93 (br. s, 1 H), 9.71 (br. s, 1 H),
8.31 (d, J = 5.5 Hz, 1 H), 8.24 (dd, J = 8.0, 1.3 Hz, 1 H), 7.86 (d,
J = 7.9 Hz, 1 H), 7.61 (td, J = 7.9, 1.5 Hz, 1 H), 7.52 (d, J = 8.1 Hz, dried with MgSO4, then filtered through Celite and the solvent was
1 H), 7.48–7.40 (m, 1 H), 7.43 (td, J = 8.1, 1.1 Hz, 1 H), 7.19–7.12 removed under reduced pressure. The product was purified by col-
(m, 2 H), 7.11 (d, J = 5.5 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]- umn chromatography on silica gel (CH2Cl2 to CH2Cl2/EtOAc, 9:1)
DMSO): δ = 153.6 (C), 147.0 (CH), 142.2 (C), 138.3 (C), 138.2 (C), to afford compound 40 (157 mg, 90% yield) as a white solid; m.p.
Eur. J. Org. Chem. 2010, 6665–6677
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6671

P. G. Goekjian et al.
FULL PAPER
148–150 °C (MeOH). IR (neat powder): ν = 3419, 3396, 1610, 1501,
116.3 (CH), 112.2 (C), 110.6 (CH), 104.0 (CH), 70.9 (CH2), 64.4
(CH2), 14.9 (CH3) ppm. MS (SIMS): m/z = 363 [M]+. HRMS
(LSIMS): calcd. for C20H17N3O4 363.1219; found 363.1218.
˜
1
1579, 1516, 1456, 1411, 1205, 1160, 807, 763, 736 cm–1. H NMR
(300 MHz, [D6]DMSO): δ = 11.44 (br. s, 1 H), 8.96 (br. s, 1 H),
8.28 (br. s, 1 H), 7.98 (d, J = 8.3 Hz, 1 H), 7.63 (t, J = 2.3 Hz, 1
H), 7.37 (d, J = 7.9 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 1 H), 7.24–7.19
(m, 2 H), 7.13 (t, J = 8.1 Hz, 1 H), 7.08 (t, J = 7.1 Hz, 1 H), 6.95–
9.93 (m, 2 H), 6.63 (dd, J = 7.7, 1.9 Hz, 1 H), 6.46 (s, 1 H), 6.44
(dd, J = 8.9, 2.6 Hz, 1 H), 3.77 (s, 3 H), 3.76 (s, 3 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 160.0 (C), 159.7 (C), 155.1 (C),
152.6 (C), 147.2 (C), 143.5 (C), 143.0 (C), 136.6 (C), 129.8 (CH),
129.0 (CH), 122.6 (CH), 121.0 (C), 120.8 (CH), 118.7 (CH), 113.3
(CH), 110.4 (CH), 110.1 (CH), 107.8 (CH), 106.6 (CH), 105.1
(CH), 103.7 (CH), 97.4 (C), 88.6 (CH), 54.9 (CH3), 54.8
(CH3) ppm. MS (ESI): m/z = 411 [M + H+]. HRMS (ESI): calcd.
for C25H23N4O2 411.1821; found 411.1821.
9-(Ethoxymethyl)-2-(3-methoxyphenoxy)-9H-pyrido[2,3-b]indole (17):
The product was purified by column chromatography on silica gel
(CH2Cl2/petroleum ether, 7:3) to afford compound 17 (90 mg, 67%
yield) as a brown oil. IR (NaCl): ν = 2959, 2918, 1592, 1574, 1421,
˜
1340, 1212, 1137, 1042, 985, 778, 748, 735 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.25 (d, J = 8.3 Hz, 1 H), 7.96 (d, J =
8.4 Hz, 1 H), 7.61 (d, J = 8.3 Hz, 1 H), 7.45 (td, J = 8.3, 7.4,
1.1 Hz, 1 H), 7.31 (td, J = 7.9, 1.1 Hz, 1 H), 7.28 (d, J = 7.5 Hz, 1
H), 6.81–6.74 (m, 4 H), 5.76 (s, 2 H), 3.81 (s, 3 H), 3.47 (q, J =
7.0 Hz, 2 H), 1.09 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 162.0 (C), 160.9 (C), 156.0 (C), 150.6 (C), 139.1 (C),
131.7 (CH), 129.9 (CH), 125.8 (CH), 121.3 (C), 121.0 (CH), 120.0
(CH), 113.3 (CH), 111.4 (C), 110.5 (CH), 110.2 (CH), 107.0 (CH),
103.5 (CH), 70.9 (CH2), 64.4 (CH2), 55.5 (CH3), 14.9 (CH3) ppm.
MS (CI): m/z = 349 [M + H+]. HRMS (CI): calcd. for C21H21N2O3
349.1552; found 349.1554.
Phenyl(6-styryl-9H-pyrido[2,3-b]indol-2-yl)amine (36):
A sealed
pressure tube with a stir bar was charged with 2-chloro-6-styryl-
9H-pyrido[2,3-b]indole[10] (54 mg, 0.178 mmol), [Pd2(dba)3] (13 mg,
0.014 mmol), X-Phos (13 mg, 0.029 mmol), and K2CO3 (74 mg,
0.53 mmol). The tube was evacuated and back-filled with argon
(repeated for three additional times). Degassed tBuOH (1 mL) and
aniline (1.3 equiv.) were added and the reaction mixture was stirred
at 100 °C overnight. After cooling to r.t., the solution was
quenched with H2O and extracted with EtOAc (3ϫ30 mL). The
crude material was purified by flash chromatography (EtOAc/
petroleum ether, 15:85) to afford compound 36 (40 mg, 62% yield)
9-(Ethoxymethyl)-4-(3-nitrophenoxy)-9H-pyrido[2,3-b]indole (18):
The product was purified by column chromatography on silica gel
(CH2Cl2/petroleum ether, 9:1) to afford compound 18 (120 mg,
86% yield) as a brown solid; m.p. 85–90 °C (EtOH). IR (neat pow-
der): ν = 3047, 2977, 2882, 1601, 1568, 1524, 1460, 1347, 1258,
˜
1
1080, 801, 790 cm–1. H NMR (300 MHz, CDCl3): δ = 8.37 (d, J
= 5.6 Hz, 1 H), 8.15–8.11 (m, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 8.08
(t, J = 2.1 Hz, 1 H), 7.68 (dd, J = 8.3, 8.1 Hz, 1 H), 7.67 (d, J =
7.9 Hz, 1 H), 7.58–7.55 (m, 1 H), 7.55 (td, J = 8.2, 1.1 Hz, 1 H),
7.31 (td, J = 8.2, 1.1 Hz, 1 H), 6.59 (d, J = 5.6 Hz, 1 H), 5.97 (s, 2
H), 3.59 (q, J = 6.9 Hz, 2 H), 1.17 (t, J = 6.9 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 158.7 (C), 155.6 (C), 154.4 (C), 149.5
(C), 147.4 (CH), 139.0 (C), 130.9 (CH), 127.0 (CH), 126.2 (CH),
123.4 (CH), 121.4 (CH), 119.8 (CH), 119.4 (C), 115.4 (CH), 110.4
(CH), 106.7 (C), 104.0 (CH), 71.4 (CH2), 64.5 (CH2), 15.1
(CH3) ppm. MS (SIMS): m/z = 363 [M+]. HRMS (LSIMS): calcd.
for C20H17N3O4 363.1219; found 363.1219.
as a solid; m.p. Ͼ220 °C. IR (neat powder): ν = 3405, 3384, 3017,
˜
2970, 1594, 1469, 1436, 1365, 1228, 1216, 1206, 961, 802, 748 cm–1.
1H NMR (300 MHz, [D6]DMSO): δ = 11.59 (br. s, 1 H), 9.23 (br.
s, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 8.15 (d, J = 0.8 Hz, 1 H), 7.84
(d, J = 7.5 Hz, 2 H), 7.60 (d, J = 7.3 Hz, 2 H), 7.55 (d, J = 8.3 Hz,
1 H), 7.40–7.18 (m, 8 H), 6.93–6.88 (m, 1 H), 6.71 (d, J = 8.5 Hz,
1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 154.4 (C), 151.4
(C), 141.8 (C), 137.6 (C), 137.3 (C), 130.1 (CH), 129.7 (CH), 128.7
(2ϫCH), 128.6 (2ϫCH), 128.5 (C), 126.9 (CH), 126.0 (2ϫCH),
125.3 (CH), 122.8 (CH), 122.0 (C), 120.3 (CH), 118.0 (2ϫCH),
117.3 (CH), 110.9 (CH), 106.5 (C), 103.7 (CH) ppm. MS (ESI): m/z
= 362 [M + H+]. HRMS (ESI): calcd. for C25H20N3 362.1657;
found 362.1653.
9-(Ethoxymethyl)-4-(3-methoxyphenoxy)-9H-pyrido[2,3-b]indole (19):
The product was purified by column chromatography on silica gel
(CH2Cl2) to afford compound 19 (105 mg, 78% yield) as a yellow
General Procedure for C–O Bond Formation: A solution of 2-
chloro-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole (4) or 4-chloro-9-
(ethoxymethyl)-9H-pyrido[2,3-b]indole (6) (100 mg, 0.386 mmol),
phenol (1.3 equiv.), [Pd2(dba)3] (28 mg, 0.03 mmol), X-Phos
(26 mg, 0.06 mmol), and K2CO3 (160 mg, 1.15 mmol) in degassed
toluene (1.5 mL/mmol) was stirred overnight at 110 °C in a sealed
tube. After cooling to r.t., the products were extracted from the
water layer with EtOAc, dried with MgSO4, filtered through Celite
and the solvents were removed under reduced pressure.
oil. IR (NaCl): ν = 3053, 1590, 1565, 1483, 1459, 1262, 1170, 1137,
˜
1081, 751 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.29 (d, J =
5.8 Hz, 1 H), 8.26 (d, J = 7.7 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 1 H),
7.52 (td, J = 8.3, 7.3, 1.4 Hz, 1 H), 7.36 (d, J = 8.3 Hz, 1 H), 7.32
(td, J = 7.7, 1.4 Hz, 1 H), 6.85–6.79 (m, 3 H), 6.55 (d, J = 5.8 Hz,
1 H), 5.95 (s, 2 H), 3.83 (s, 3 H), 3.58 (q, J = 6.9 Hz, 2 H), 1.16 (t,
J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.2 (C),
160.3 (C), 155.6 (C), 154.3 (C), 147.4 (CH), 138.7 (C), 130.6 (CH),
126.4 (CH), 123.5 (CH), 121.1 (CH), 119.9 (C), 112.8 (CH), 111.1
(CH), 110.0 (CH), 106.7 (CH), 106.0 (C), 103.4 (CH), 71.3 (CH2),
64.3 (CH2), 55.5 (CH3), 15.1 (CH3) ppm. MS (CI): m/z = 349 [M
+ H+]. HRMS (CI): calcd. for C21H21N2O3 349.1552; found
349.1553.
9-(Ethoxymethyl)-2-(3-nitrophenoxy)-9H-pyrido[2,3-b]indole (16):
The product was purified by column chromatography on silica gel
(CH2Cl2/petroleum ether, 1:1) and recrystallization from EtOH to
afford 16 (86 mg, 62% yield) as a yellow solid; m.p. 98–100 °C
(EtOH). IR (neat powder): ν = 3118, 3101, 1596, 1574, 1523, 1467,
9-(Ethoxymethyl)-2,4-bis(3-methoxyphenoxy)-9H-pyrido[2,3-b]-
indole (41): A solution of 2,4-dichloro-9-(ethoxymethyl)-9H-pyr-
ido[2,3-b]indole (39; 50 mg, 0.17 mmol), 3-methoxyphenol (41 μL,
0.391 mmol), [Pd2(dba)3] (12 mg, 0.013 mmol), X-Phos (13 mg,
0.032 mmol), and K2CO3 (71 mg, 0.51 mmol) in degassed toluene
(390 μL) was stirred overnight at 110 °C in a sealed tube. After
˜
1
1424, 1345, 1313, 1274, 1221, 1071, 981, 822, 736 cm–1. H NMR
(300 MHz, CDCl3): δ = 8.35 (d, J = 8.2 Hz, 1 H), 8.16–8.15 (m, 1
H), 8.08 (ddd, J = 5.8, 3.2, 2.1 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H),
7.62 (d, J = 8.2 Hz, 1 H), 7.58–7.55 (m, 2 H), 7.48 (td, J = 7.5,
1.1 Hz, 1 H), 7.32 (td, J = 8.2, 1.1 Hz, 1 H), 6.90 (d, J = 8.2 Hz, 1
H), 5.68 (s, 2 H), 3.41 (q, J = 6.9 Hz, 2 H), 1.06 (t, J = 6.9 Hz, 3 cooling to r.t., the products were extracted from the water layer
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.6 (C), 155.3 (C),
with EtOAc, dried with MgSO4, filtered through Celite and the
150.1 (C), 149.0 (C), 139.2 (C), 132.1 (CH), 130.0 (CH), 127.3 solvents were removed under reduced pressure. The product was
(CH), 126.2 (CH), 121.2 (CH), 121.0 (C), 120.2 (CH), 119.1 (CH), purified by column chromatography on silica gel (CH2Cl2/petro-
6672
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6665–6677

Substituted Pyrido[2,3-b]indoles
leum ether, 1:1) to afford compound 41 (64 mg, 80% yield) as a
brown solid; m.p. 96–98 °C (CH2Cl2/petroleum ether). IR (neat
additional times). Acetonitrile (0.6 mmol/mL) was added (when de-
gassed solvent was used), the alkyne (1.3 equiv.) was injected and
the reaction mixture was stirred at 70 °C or 90 °C (see Table 3)
overnight. After cooling to r.t., the resulting mixture was then
quenched with H2O and extracted with EtOAc. The combined or-
ganic layers were dried (MgSO4), filtered through Celite and the
powder): ν = 3070, 2974, 2939, 2839, 1588, 1568, 1463, 1342, 1190,
˜
1152, 1034, 1024, 834, 755 cm–1. 1H NMR (300 MHz, [D6]DMSO):
δ = 8.01 (d, J = 7.5 Hz, 1 H), 7.68 (d, J = 8.3 Hz, 1 H), 7.44 (td,
J = 8.1, 1.0 Hz, 1 H), 7.42 (t, J = 8.1 Hz, 1 H), 7.30 (t, J = 8.9 Hz,
2 H), 6.96 (t, J = 2.2 Hz, 1 H), 6.91 (t, J = 8.1 Hz, 2 H), 6.80–6.73 solvents were removed under reduced pressure.
(m, 2 H), 6.76 (s, 1 H), 6.04 (s, 1 H), 5.66 (s, 2 H), 3.78 (s, 3 H),
9-(Ethoxymethyl)-2-(phenyleth-1-ynyl)-9H-pyrido[2,3-b]indole (22):
3.73 (s, 3 H), 3.38 (q, J = 7.0 Hz, 2 H), 0.98 (t, J = 7.0 Hz, 3
H) ppm. 13C NMR (75 MHz, [D6]acetone): δ = 163.9 (C), 163.6
(C), 162.3 (C), 161.7 (C), 156.6 (C), 156.2 (C), 152.8 (C), 139.1 (C),
131.6 (CH), 130.5 (CH), 126.0 (CH), 122.8 (CH), 121.9 (CH), 120.9
(C), 113.7 (CH), 113.5 (CH), 112.3 (CH), 111.0 (CH), 110.9 (CH),
107.6 (CH), 107.5 (CH), 102.1 (C), 91.3 (CH), 71.4 (CH2), 64.8
(CH2), 55.9 (CH3), 55.7 (CH3), 15.1 (CH3) ppm. MS (CI, 200 °C):
m/z = 471 [M + H+]. HRMS (CI): calcd. for C28H27N2O5 471.1920;
found 471.1920.
The product was purified by column chromatography on silica gel
(CH2Cl2/petroleum ether, 7:3) to afford compound 22 (101 mg,
80% yield) as a yellow solid; m.p. 88–90 °C (CH2Cl2/petroleum
ether). IR (neat powder): ν = 3052, 2211, 1587, 1565, 1469, 1422,
˜
139, 1345, 1122, 1075, 1055, 1008, 784, 750 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.28 (d, J = 7.9 Hz, 1 H), 8.05 (d, J =
7.5 Hz, 1 H), 7.67 (d, J = 8.2 Hz, 1 H), 7.67–7.64 (m, 2 H), 7.54
(td, J = 8.2, 7.5, 1.1 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.39–7.37
(m, 3 H), 7.33 (td, J = 7.1, 1.0 Hz, 1 H), 5.97 (s, 2 H), 3.57 (q, J
= 6.9 Hz, 2 H), 1.16 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 151.8 (C), 140.1 (C), 139.0 (C), 132.1 (2ϫCH), 128.9
(CH), 128.5 (2ϫCH), 128.2 (CH), 127.5 (CH), 122.7 (C), 121.1
(2ϫCH), 120.7 (C), 120.3 (CH), 115.8 (C), 110.8 (CH), 90.1 (C),
89.1 (C), 71.1 (CH2), 64.3 (CH2), 15.1 (CH3) ppm. MS (CI): m/z =
283 [M + H+].
General Procedure for the Sonogashira Reaction on Compound 1: A
Schlenk tube with a stir bar was charged with [PdCl2(CH3CN)2]
(11 mg, 0.04 mmol), X-Phos (39 mg, 0.08 mmol), 2-chloro-9H-pyr-
ido[2,3-b]indole (1; 100 mg, 0.499 mmol), and Cs2CO3 (424 mg,
1.3 mmol). The tube was evacuated and back-filled with argon (re-
peated for three additional times). Acetonitrile (900 μL, 0.6 mmol/
mL) was added (when degassed solvent was used) and then the
alkyne (1.3 equiv.) was injected. The reaction mixture was stirred
overnight at 70 °C, then, after cooling to r.t., the resulting mixture
was then quenched with H2O and extracted with EtOAc. The com-
bined organic layers were dried (MgSO4), filtered through Celite
and the solvents were removed under reduced pressure.
9-(Ethoxymethyl)-2-(pent-1-ynyl)-9H-pyrido[2,3-b]indole (23): The
product was purified by column chromatography on silica gel
(CH2Cl2/petroleum ether, 6:4) to afford compound 23 (96 mg, 85%
yield) as a yellow solid; m.p. 73–75 °C (CH2Cl2/petroleum ether).
IR (neat powder): ν = 3010, 2968, 2930, 2870, 2219, 1584, 1565,
˜
1463, 1421, 1388, 1340, 1230, 1055, 784, 750 cm–1. 1H NMR
2-(Phenyleth-1-ynyl)-9H-pyrido[2,3-b]indole (20): The product was (300 MHz, CDCl3): δ = 8.21 (d, J = 7.9 Hz, 1 H), 8.02 (d, J =
purified by column chromatography on silica gel (CH2Cl2) to af-
ford compound 20 (85 mg, 64% yield) as a yellow solid; m.p.
7.6 Hz, 1 H), 7.65 (d, J = 8.2 Hz, 1 H), 7.51 (td, J = 8.2, 7.6,
1.3 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 1 H), 7.31 (td, J = 8.3, 1.0 Hz, 1
H), 5.94 (s, 2 H), 3.53 (q, J = 7.0 Hz, 2 H), 2.48 (t, J = 7.3 Hz, 2
H), 1.71 (sext, J = 7.3 Hz, 2 H), 1.13 (t, J = 7.0 Hz, 3 H), 1.09 (t,
J = 7.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 151.7 (C),
Ͼ220 °C. IR (neat powder): ν = 3144, 3084, 3054, 2202, 1599, 1490,
˜
1460, 1411, 1283, 997, 826 cm–1. 1H NMR (300 MHz, [D6]DMSO):
δ = 11.87 (br. s, 1 H), 8.54 (d, J = 7.9 Hz, 1 H), 8.19 (d, J = 7.7 Hz,
1 H), 7.66–7.62 (m, 2 H), 7.53 (d, J = 7.1 Hz, 1 H), 7.50–7.47 (m, 139.9 (C), 139.7 (C), 128.1 (CH), 127.2 (CH), 120.9 (CH), 120.9
4 H), 7.48 (ddd, J = 8.1, 7.1, 1.1 Hz, 1 H), 7.25 (ddd, J = 8.1, 7.1,
1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 151.6 (C),
139.6 (C), 137.8 (C), 131.6 (2ϫCH), 129.2 (CH), 128.8 (2ϫCH),
128.6 (CH), 127.3 (C), 121.7 (CH), 121.5 (CH), 120.1 (C), 119.8
(CH), 118.9 (CH), 115.2 (C), 111.4 (CH), 90.3 (C), 87.8 (C) ppm.
MS (EI): m/z = 268 [M]+. HRMS (CI): calcd. for C14H13N2
268.1000; found 268.1002.
(CH), 120.7 (C), 119.9 (CH), 115.2 (C), 110.7 (CH), 90.6 (C), 81.7
(C), 71.0 (CH2), 64.1 (CH2), 22.0 (CH2), 21.6 (CH2), 15.0 (CH3),
13.7 (CH3) ppm. MS (ESI): m/z = 247 [M + H+ – EtOH+], 293 [M
+ H+].
2-(Cyclohexyleth-1-ynyl)-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole
(24): The product was purified by column chromatography on silica
gel (CH2Cl2/petroleum ether, 4:6) to afford compound 24 (111 mg,
2-(Pent-1-ynyl)-9H-pyrido[2,3-b]indole (21): The product was puri-
fied by column chromatography on silica gel (CH2Cl2/EtOAc, 9:1)
to afford compound 21 (71 mg, 61% yield) as a yellow solid; m.p.
87% yield) as a brown oil. IR (NaCl): ν = 2048, 2927, 2852, 1564,
˜
1587, 1468, 1419, 1385, 1338, 1217, 1095, 1078, 1052, 787,
1
736 cm–1. H NMR (300 MHz, CDCl3): δ = 8.20 (d, J = 7.9 Hz, 1
158–160 °C (MeOH). IR (neat powder): ν = 3156, 3056, 2951, 2926,
H), 8.01 (d, J = 7.9 Hz, 1 H), 7.64 (d, J = 8.3 Hz, 1 H), 7.51 (td,
J = 8.3, 7.2, 1.3 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 1 H), 7.31 (td, J =
7.9, 0.8 Hz, 1 H), 5.93 (s, 2 H), 3.53 (q, J = 7.0 Hz, 2 H), 2.68 (m,
˜
2854, 2223, 1602, 1575, 1457, 1413, 1229, 1119, 998, 816, 784,
733 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 11.75 (br. s, 1 H),
8.45 (d, J = 7.8 Hz, 1 H), 8.14 (d, J = 7.6 Hz, 1 H), 7.50 (d, J = 1 H), 1.97 (br. s, 2 H), 1.80 (br. s, 2 H), 1.62 (br. s, 3 H), 1.40 (br.
7.6 Hz, 1 H), 7.45 (td, J = 8.1, 6.8, 1.1 Hz, 1 H), 7.27 (d, J = s, 3 H), 1.13 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
7.8 Hz, 1 H), 7.22 (ddd, J = 8.1, 6.8, 1.7 Hz, 1 H), 2.51–2.44 (m, 2
δ = 151.7 (C), 140.0 (C), 139.9 (C), 128.1 (CH), 127.2 (CH), 120.9
H), 1.61 (q, J = 7.0 Hz, 2 H), 1.04 (t, J = 7.0 Hz, 3 H) ppm. 13C (CH), 120.9 (CH), 120.8 (C), 120.1 (CH), 115.2 (C), 110.7 (CH),
NMR (75 MHz, [D6]DMSO): δ = 151.6 (C), 139.4 (C), 138.7 (C),
128.5 (CH), 126.9 (CH), 121.3 (CH), 120.1 (C), 119.6 (CH), 118.3
(CH), 114.5 (C), 111.3 (CH), 89.6 (C), 81.9 (C), 21.5 (CH2), 20.5
(CH2), 13.3 (CH3) ppm. MS (EI): m/z = 234 [M]+.
94.7 (C), 81.5 (C), 71.1 (CH2), 64.2 (CH2), 32.2 (2ϫCH2), 29.9
(CH), 26.0 (CH2), 25.1 (2ϫCH2), 13.7 (CH3) ppm. MS (ESI): m/z
= 333 [M + H+]. HRMS (CI): calcd. for C22H25N2O 333.1967;
found 333.1967.
Procedure for the Sonogashira Reaction on Compounds 4–6: A
Schlenk tube with stir bar was charged with [PdCl2(CH3CN)2]
(0.08 equiv.), X-Phos (0.16 equiv.), chloro-9-(ethoxymethyl)-9H-
pyrido[2,3-b]indole (4–6) (1 equiv.), and Cs2CO3 (2.6 equiv.). The
tube was evacuated and back-filled with argon (repeated for three
9-(Ethoxymethyl)-3-(phenyleth-1-ynyl)-9H-pyrido[2,3-b]indole (25):
The product was purified by column chromatography on silica gel
(CH2Cl2/petroleum ether, 8:2) to afford compound 25 (120 mg,
95% yield) as a yellow solid; m.p. 68–70 °C (CH2Cl2/petroleum
ether). IR (neat powder): ν = 3029, 2211, 1738, 1592, 1493, 1461,
˜
Eur. J. Org. Chem. 2010, 6665–6677
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6673

P. G. Goekjian et al.
FULL PAPER
1374, 1229, 1068, 1057, 895, 782, 750 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.66 (d, J = 1.9 Hz, 1 H), 8.45 (d, J = 1.9 Hz, 1 H),
solid; m.p. 72–74 °C (EtOH). IR (NaCl): ν = 3057, 2966, 2928,
˜
1
2223, 1582, 1560, 1462, 1413, 1287, 1078, 1063, 814, 739 cm–1. H
8.06 (d, J = 7.7 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 7.60–7.53 (m, NMR (300 MHz, CDCl3): δ = 8.52 (d, J = 7.5 Hz, 1 H), 8.38 (d,
3 H), 7.41–7.32 (m, 4 H), 5.93 (s, 2 H), 3.57 (q, J = 6.9 Hz, 2 H),
1.16 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
150.8 (C), 149.2 (CH), 139.9 (C), 131.6 (2ϫCH), 130.9 (CH), 128.5
(2ϫCH), 128.3 (CH), 127.6 (CH), 123.3 (C), 121.3 (CH), 121.1
J = 5.2 Hz, 1 H), 7.65 (d, J = 8.3 Hz, 1 H), 7.54 (td, J = 8.3, 7.5,
1.1 Hz, 1 H), 7.33 (td, J = 8.3, 1.1 Hz, 1 H), 7.17 (d, J = 5.2 Hz, 1
H), 5.92 (s, 2 H), 3.54 (q, J = 7.0 Hz, 2 H), 2.63 (t, J = 7.3 Hz, 2
H), 1.81 (m, J = 7.3 Hz, 2 H), 1.16 (t, J = 7.3 Hz, 3 H), 1.14 (t, J
(CH), 120.5 (C), 115.7 (C), 112.2 (C), 110.7 (CH), 90.4 (C), 87.6 = 7.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 145.0 (CH),
(C), 71.1 (CH2), 64.4 (CH2), 15.0 (CH3) ppm. MS (ESI): m/z = 281 139.5 (C), 127.4 (CH), 125.7 (C), 122.5 (CH), 121.1 (2 C), 120.9
[M + H+ – EtOH+], 327 [M + H+].
(CH), 118.9 (CH), 116.1 (C), 110.3 (CH), 99.8 (C), 78.3 (C), 71.1
(CH2), 64.4 (CH2), 22.3 (CH2), 22.0 (CH2), 15.1 (CH3), 13.8
(CH3) ppm. MS (CI): m/z = 293 [M + H+]. HRMS (CI): calcd. for
C19H21N2O 293.1654; found 293.1654.
9-(Ethoxymethyl)-3-(pent-1-ynyl)-9H-pyrido[2,3-b]indole (26): The
product was purified by column chromatography on silica gel
(CH2Cl2/petroleum ether, 8:2) to afford compound 26 (91 mg, 81%
yield) as a yellow solid; m.p. 58–60 °C (CH2Cl2/petroleum ether).
4-(Cyclohexyleth-1-ynyl)-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole
(30): The product was purified by column chromatography on silica
gel (CH2Cl2/petroleum ether, 7:3) to afford compound 30 (102 mg,
IR (neat powder): ν = 3056, 2967, 2930, 2100, 1596, 1476, 1463,
˜
1
1388, 1372, 1238, 1061, 1005, 902, 740 cm–1. H NMR (300 MHz,
CDCl3): δ = 8.52 (d, J = 1.9 Hz, 1 H), 8.32 (d, J = 1.9 Hz, 1 H),
8.02 (d, J = 7.7 Hz, 1 H), 7.64 (d, J = 8.3 Hz, 1 H), 7.53 (td, J =
8.1, 7.1, 1.1 Hz, 1 H), 7.32 (td, J = 7.7, 7.1, 1.0 Hz, 1 H), 5.77 (s,
1 H), 3.43 (q, J = 7.0 Hz, 2 H), 2.35 (t, J = 7.0 Hz, 2 H), 1.58 (q,
J = 7.0 Hz, 2 H), 1.03 (t, J = 7.0 Hz, 3 H), 0.99 (t, J = 7.0 Hz, 3
H), 1.09 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 150.5 (C), 149.2 (CH), 139.8 (C), 130.9 (CH), 127.4 (CH), 121.0
(2 CH), 120.5 (C), 115.6 (C), 113.0 (C), 110.6 (CH), 91.1 (C), 78.6
(C), 71.1 (CH2), 64.3 (CH2), 22.3 (CH2), 21.6 (CH2), 15.0 (CH3),
13.7 (CH3) ppm. MS (CI): m/z = 293 [M + H+]. HRMS (CI): calcd.
for C19H21N2O 293.1654; found 293.1654.
80% yield) as a brown oil. IR (NaCl): ν = 2927, 2852, 2221, 1583,
˜
1560, 1485, 1461, 1360, 1285, 1083, 819, 792 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 8.54 (d, J = 7.9 Hz, 1 H), 8.38 (d, J =
5.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.53 (t, J = 7.7 Hz, 1 H),
7.34 (t, J = 7.7 Hz, 1 H), 7.17 (d, J = 5.2 Hz, 1 H), 5.92 (s, 2 H),
3.54 (q, J = 7.0 Hz, 2 H), 2.82 (m, 1 H), 2.06 (br. s, 2 H), 1.84 (br.
s, 2 H), 1.69 (br. s, 3 H), 1.45 (br. s, 3 H), 1.14 (t, J = 7.0 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.0 (C), 145.3 (CH),
139.4 (C), 127.2 (CH), 125.5 (C), 122.4 (CH), 121.0 (C), 120.7
(CH), 118.9 (CH), 115.8 (C), 110.1 (CH), 103.5 (C), 78.0 (C), 71.0
(CH2), 64.2 (CH2), 32.6 (2ϫCH2), 30.3 (CH), 25.9 (CH2), 25.1
(2ϫCH2), 15.0 (CH3) ppm. MS (CI): m/z = 333 [M + H+]. HRMS
(CI): calcd. for C22H25N2O 333.1966; found 333.1968.
3-(Cyclohexyleth-1-ynyl)-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole
(27): The product was purified by column chromatography on silica
gel (CH2Cl2/petroleum ether, 7:3) to afford compound 27 (81 mg,
3-Chloro-6-(2-phenyleth-1-ynyl)-9-(phenylsulfonyl)-9H-pyrido[2,3-b]-
indole (32): To a solution of 6-bromo-3-chloro-9-(phenylsulfonyl)-
9H-pyrido[2,3-b]indole (31)[10] (100 mg, 0.24 mmol, 1 equiv.) in an-
hydrous DMF (1.5 mL) under argon, [Pd(Cl)2(PPh3)2] (17 mg,
0.024 mmol, 0.1 equiv.), CuI (9 mg, 0.048 mmol, 0.2 equiv.), PPh3
(6 mg, 0.024 mmol, 0.1 equiv.), 1-ethynylbenzene (0.079 mL,
0.72 mmol, 3 equiv.), and Et3N (3 mL) were added. The mixture
was stirred at 80 °C overnight and then poured into water (5 mL)
and extracted with CH2Cl2 (3ϫ10 mL). The combined organic lay-
ers were washed with brine (3ϫ10 mL) and concentrated under
reduced pressure. The crude residue was purified over silica gel col-
umn (CH2Cl2/petroleum ether, 1:1) to afford the product 32 (98 mg,
63% yield) as a brown oil. IR (NaCl): ν = 3048, 2926, 2852, 1596,
˜
1
1480, 1448, 1231, 1094, 1073, 752, 738 cm–1. H NMR (300 MHz,
CDCl3): δ = 8.51 (d, J = 1.9 Hz, 1 H), 8.32 (d, J = 1.9 Hz, 1 H),
8.02 (d, J = 7.5 Hz, 1 H), 7.64 (d, J = 8.2 Hz, 1 H), 7.53 (td, J =
8.2, 7.5, 1.0 Hz, 1 H), 7.32 (td, J = 7.5, 1.0 Hz, 1 H), 5.90 (s, 2 H),
3.53 (q, J = 6.9 Hz, 2 H), 2.65 (m, 1 H), 1.89 (br. s, 2 H), 1.79 (br.
s, 2 H), 1.39 (br. s, 4 H), 1.27 (br. s, 2 H), 1.13 (t, J = 6.9 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.6 (C), 149.2 (CH),
139.9 (C), 131.0 (CH), 127.4 (CH), 121.1 (2ϫCH), 120.6 (C), 115.6
(C), 113.1 (C), 110.6 (CH), 95.3 (C), 78.4 (C), 71.1 (CH2), 64.3
(CH2), 32.9 (3ϫCH2), 29.9 (CH), 26.0 (CH2), 25.0 (CH2), 15.0
(CH3) ppm. MS (CI): m/z = 333 [M + H+]. HRMS (CI): calcd. for
C22H25N2O: 333.1966; found 333.1966.
92% yield) as a white solid; m.p. 190–194 °C. IR (neat powder): ν
˜
= 3135, 3061, 1494, 1468, 1434, 1380, 1360, 1264, 1211, 1183, 1090,
973, 830, 727, 700 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.51 (d,
J = 2.3 Hz, 1 H), 8.46 (d, J = 8.9 Hz, 1 H), 8.15 (d, J = 2.3 Hz, 2
H), 8.10 (m, 2 H), 7.76 (dd, J = 8.9, 1.7 Hz, 1 H), 7.58–7.54 (m, 3
H), 7.47–7.36 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
149.2 (C), 146.1 (CH), 138.4 (C), 137.9 (C), 134.4 (CH), 132.6
(CH), 131.8 (2ϫCH), 129.2 (2ϫCH), 128.6 (CH), 128.6 (2ϫCH),
128.3 (CH), 127.8 (C), 127.7 (2ϫCH), 124.2 (CH), 123.1 (C), 122.0
(C), 119.5 (C), 119.3 (C), 115.4 (CH), 90.0 (C), 88.7 (C) ppm. MS
(ESI): m/z = 443, 445 [M + H+].
9-(Ethoxymethyl)-4-(phenyleth-1-ynyl)-9H-pyrido[2,3-b]indole (28):
The product was purified by column chromatography on silica gel
(CH2Cl2/petroleum ether, 9:1) to afford compound 28 (136 mg,
95% yield) as a yellow solid; m.p. 89–91 °C (CH2Cl2/petroleum
ether). IR (neat powder): ν = 3052, 2212, 1738, 1581, 1482, 1558,
˜
1460, 1374, 1211, 1078, 819, 749, 733 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.61 (d, J = 7.7 Hz, 1 H), 8.45 (d, J = 5.2 Hz, 1 H),
7.72 (dd, J = 7.5, 3.8 Hz, 2 H), 7.68 (d, J = 8.1 Hz, 1 H), 7.57 (td,
J = 8.2, 7.1, 1.0 Hz, 1 H), 7.48–7.43 (m, 3 H), 7.37 (td, J = 8.1,
1.0 Hz, 1 H), 7.30 (d, J = 5.2 Hz, 1 H), 5.95 (s, 2 H), 3.52 (q, J =
6.9 Hz, 2 H), 1.16 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.0 (C), 145.4 (CH), 139.7 (C), 132.0 (2ϫCH), 129.3
(CH), 128.7 (2ϫCH), 127.5 (CH), 124.3 (C), 122.7 (CH), 122.6
(C), 121.0, (CH), 120.9 (C), 118.6 (CH), 115.8 (C), 110.3 (CH),
97.3 (C), 86.6 (C), 71.1 (CH2), 64.4 (CH2), 15.1 (CH3) ppm. MS
(ESI): m/z = 281.3 [M + H+ – EtOH+], 327.0 [M + H+].
3-Chloro-6-(2-phenylethyl)-9-(phenylsulfonyl)-9H-pyrido[2,3-b]-
indole (33): A solution of 3-chloro-6-(2-phenylethynyl)-9-(phenyl-
sulfonyl)-9H-pyrido[2,3-b]indole (32; 200 mg, 0.45 mmol, 1 equiv.)
in anhydrous ethanol (25 mL) was treated with 10% Pd/C (50 mg,
0.047 mmol, 0.1 equiv.) and then stirred at r.t. under an atmosphere
of H2 overnight. The reaction mixture was filtered through Celite
and then concentrated under reduced pressure. The crude product
(pale-yellow solid) was purified over silica gel chromatography
(CH2Cl2/petroleum ether, 7:3) to afford compound 33 (183 mg,
9-(Ethoxymethyl)-4-(pent-1-ynyl)-9H-pyrido[2,3-b]indole (29): The
product was purified by column chromatography on silica gel
(CH2Cl2) to afford compound 29 (101 mg, 90% yield) as a yellow
91% yield) as a white solid; m.p. 158–162 °C. IR (neat powder): ν
˜
6674
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6665–6677

Substituted Pyrido[2,3-b]indoles
= 3057, 3023, 2926, 1494, 1475, 1432, 1376, 1366, 1255, 1182, 1712,
pyrido[2,3-b]indole N-oxide (37) (1 equiv.) in DMF. The reaction
1090, 977, 908, 713, 683 cm–1. 1H NMR (300 MHz, CDCl3): δ = mixture was heated at 100 °C for 12 h, then cooled to r.t. and the
8.48 (d, J = 2.3 Hz, 1 H), 8.36 (d, J = 8.7 Hz, 1 H), 8.12 (m, 3 H),
resulting mixture was cautiously quenched at 0 °C with H2O and
extracted with EtOAc. The combined organic layers were dried
7.67 (s, 1 H), 7.56–7.52 (m, 1 H), 7.45–7.38 (m, 3 H), 7.32–7.18 (m,
5 H), 3.12–2.97 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = with MgSO4, filtered and the solvents were removed under reduced
149.2 (C), 145.4 (CH), 141.4 (C), 138.7 (C), 138.1 (C), 137.0 (C),
pressure. Trituration of the crude residue from MeOH then fil-
134.2 (CH), 130.0 (CH), 129.1 (2ϫCH), 128.6 (2ϫCH), 128.6 tration afforded compound 38 (600 mg, 74% yield) as a white solid;
(2ϫCH), 128.9 (2ϫCH), 127.6 (CH), 127.5 (C), 126.3 (CH), 122.0
(C), 120.6 (CH), 120.0 (C), 115.1 (CH), 38.2 (CH2), 38.8
(CH2) ppm. MS (ESI): m/z = 447.1 [M + H+].
m.p. Ͼ220 °C (MeOH). IR (neat powder): ν = 3139, 3062, 1598,
˜
1560, 1452, 1401, 1314, 1201, 1118, 868, 728 cm–1. 1H NMR
(300 MHz, [D6]DMSO): δ = 12.43 (br. s, 1 H), 8.35 (d, J = 7.9 Hz,
1 H), 7.58–7.56 (m, 2 H), 7.48 (s, 1 H), 7.34 (td, J = 8.1, 2.5 Hz, 1
H) ppm. MS (CI): m/z = 237 [M + H+] at 200 °C. HRMS (CI):
calcd. for C11H7Cl2N2 236.9986; found 236.9980.
3-Chloro-6-(2-phenylethyl)-9H-pyrido[2,3-b]indole (34): To a solu-
tion
of
3-chloro-6-(2-phenylethyl)-9-(phenylsulfonyl)-9H-pyr-
ido[2,3-b]indole (33; 170 mg, 0.38 mmol, 1 equiv.) in THF (18 mL)
under argon, TBAF (1 m in THF, 1.91 mL, 1.91 mmol, 5 equiv.)
was added dropwise. The reaction was heated to reflux for 4 h and
then evaporated. The crude product was purified by silica gel
chromatography (EtOAc/petroleum ether, 1:1) to afford compound
34 (108 mg, 91% yield) as a white solid; m.p. 216–220 °C. IR (neat
2,4-Dichloro-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole (39): NaH
(60% in oil, 2.1 mmol) was added to a stirred 0.4 m suspension of
2,4-dichloro-9H-pyrido[2,3-b]indole (38) (1 equiv.) in DMF at 0 °C.
After stirring at 0 °C for 20 min, EOMCl (2 equiv.) was added
dropwise. The reaction mixture was stirred for 12 h and then
poured into a 5% aqueous saturated NaHCO3 solution and ex-
tracted with EtOAc (3ϫ20 mL). The combined organic layers were
dried (MgSO4), the solvent was removed under reduced pressure,
and the residue was purified by column chromatography on silica
gel (CH2Cl2/petroleum ether, 4:6) to afford compound 39 (246 mg,
80% yield) as a white solid; m.p. 111–113 °C (CH2Cl2/petroleum
powder): ν = 3111, 3028, 2921, 2851, 1600, 1490, 1453, 1389, 1271,
˜
1236, 1087, 1030, 931, 732, 682 cm–1. 1H NMR (300 MHz, [D6]-
DMSO): δ = 11.88 (br. s, 1 H), 8.60 (d, J = 2.5 Hz, 1 H), 8.39 (d,
J = 2.4 Hz, 1 H), 8.06 (s, 1 H), 7.43–7.35 (m, 3 H), 7.25 (m, 3 H),
7.18 (m, 1 H), 3.06–2.92 (m, 4 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 150.3 (C), 143.8 (CH), 141.6 (C), 138.2 (C), 133.0
(C), 128.4 (2ϫCH), 128.3 (CH), 128.2 (2ϫCH), 127.8 (CH), 125.8
(CH), 121.5 (C), 120.9 (CH), 119.6 (C), 116.3 (C), 111.2 (CH), 37.7
(CH2), 37.3 (CH2) ppm. MS (ESI): m/z = 307.2 [M + H+].
ether). IR (neat powder): ν = 3107, 2980, 2911, 1574, 1549, 1468,
˜
1388, 1311, 1119, 1076, 1062, 836, 750, 736 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.36 (d, J = 7.9 Hz, 1 H), 7.63 (d, J =
8.1 Hz, 1 H), 7.56 (td, J = 8.2, 7.2, 1.1 Hz, 1 H), 7.36 (td, J = 8.2,
7.2, 1.1 Hz, 1 H), 7.18 (s, 1 H), 5.83 (s, 2 H), 3.52 (q, J = 6.9 Hz,
2 H), 1.15 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 151.5 (C), 147.3 (C), 139.2 (2ϫC), 127.7 (CH), 122.9 (CH),
121.8 (CH), 119.6 (C), 116.2 (CH), 112.6 (C), 110.7 (CH), 71.3
(CH2), 64.5 (CH2), 15.0 (CH3) ppm. MS (CI): m/z = 295 [M + H+].
HRMS (CI): calcd. for C14H12Cl2N2O 295.0402; found 295.0402.
N-(3-Methoxyphenyl)-6-(2-phenylethyl)-9H-pyrido[2,3-b]indol-3-
amine (35): 3-Chloro-6-(2-phenylethyl)-9H-pyrido[2,3-b]indole (34;
50 mg, 0.16 mmol, 1 equiv.), [Pd2(dba)3] (8.2 mg, 0.008 mmol,
0.05 equiv.), X-Phos (8.1 mg, 0.016 mmol, 0.1 equiv.), and NaOtBu
(36 mg, 0.37 mmol, 2.2 equiv.) were introduced into a Schlenk tube
and flushed with N2. tBuOH (0.255 mL) and m-anisidine (25 mg,
0.20 mmol, 1.2 equiv.) were then added and the reaction was heated
to 100 °C overnight. After cooling, the mixture was filtered through
Celite and evaporated under reduced pressure. The crude product
(yellow oil) was purified by silica gel chromatography (EtOAc/pe-
troleum ether, 4:6 to 6:4) to afford compound 35 (18 mg, 29%
9-(Ethoxymethyl)-2,4-bis(phenylethynyl)-9H-pyrido[2,3-b]indole (42):
A Schlenk tube with stir bar was charged with [Pd(Cl)2(CH3CN)2]
(8 mg, 0.03 mmol, 0.08 equiv.), X-Phos (29 mg, 0.06 mmol,
0.16 equiv.), 2,4-dichloro-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole
(39; 100 mg, 0.34 mmol, 1 equiv.), and Cs2CO3 (577 mg,
1.77 mmol, 5.2 equiv.). The tube was evacuated and back-filled
with argon (repeated for three additional times). Anhydrous aceto-
nitrile (620 μL, 0.6 mmol/mL) was added (when degassed solvent
was used) and then phenylacetylene (91 mg, 100 μL, 0.884 mmol,
2.6 equiv.) was injected and the reaction mixture was stirred over-
night at 90 °C. After cooling to r.t., the products were extracted
from the water layer with ethyl acetate, dried with MgSO4, filtered
through Celite and the solvents were removed under reduced pres-
sure. The product was purified by column chromatography on silica
gel (CH2Cl2/petroleum ether, 4:6) to afford 42 (91 mg, 62% yield)
yield) as a green solid; m.p. 161–165 °C. IR (neat powder): ν =
˜
3359, 3145, 3022, 1595, 1494, 1467, 1383, 1218, 1151, 1038, 968,
891, 809, 771, 685 cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.94 (br.
s, 1 H), 8.36 (br. s, 1 H), 8.18 (s, 1 H), 7.78 (s, 1 H), 7.41 (d, J =
8.3 Hz, 1 H), 7.32–7.14 (m, 7 H), 6.52 (d, J = 8.1 Hz, 1 H), 6.47–
6.44 (m, 2 H), 3.77 (s, 3 H), 3.12–2.97 (m, 4 H) ppm. MS (ESI):
m/z = 394.3 [M + H+].
4-Chloro-9H-pyrido[2,3-b]indole N-Oxide (37): m-Chloroperbenzoic
acid 70% (1.50 g, 8.6 mmol) was added to a 0.06 m stirred solution
of 4-chloro-9H-pyrido[2,3-b]indole (3; 1.05 g, 5.2 mmol) at r.t. in
CHCl3. The reaction mixture was stirred for 12 h at r.t., then the
solution was neutralized with saturated aqueous solution of K2CO3
and the layers were separated. The organic layer was washed with
brine and dried with MgSO4, filtered, and concentrated in vacuo.
Trituration of the crude residue from Et2O then filtration afforded
compound 37 (786 mg, 64% yield) as a brown solid; m.p. Ͼ220 °C
as a yellow solid; m.p. 65–67 °C (EtOH). IR (neat powder): ν =
˜
3016, 2970, 2211, 1571, 1559, 1442, 1365, 1216, 1083, 750 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 8.59 (d, J = 7.7 Hz, 1 H), 7.73–7.64
(m, 5 H), 7.61 (s, 1 H), 7.58 (app. td, J = 1.1, 7.3, 8.1 Hz, 1 H),
7.48–7.45 (m, 3 H), 7.40–7.35 (m, 4 H), 5.93 (s, 2 H), 3.58 (q, J =
6.9 Hz, 2 H), 1.16 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 151.9 (C), 140.3 (C), 138.5 (C), 132.2 (2ϫCH), 132.0
(2ϫCH), 129.5 (CH), 129.0 (CH), 128.8 (2ϫCH), 128.5 (2ϫCH),
127.9 (CH), 124.6 (C), 122.8 (CH), 122.7 (CH), 122.6 (C), 122.4
(C), 121.4 (CH), 120.8 (C), 115.4 (C), 110.6 (CH), 97.8 (C), 89.6
(C), 89.5 (C), 86.0 (C), 71.2 (CH2), 64.4 (CH2), 15.1 (CH3) ppm.
MS (ESI): m/z = 382 [M + H+ – EtOH]+, 427 [M + H+].
(MeOH). IR (neat powder): ν = 3052, 2980, 1602, 1571, 1469, 1458,
˜
1434, 1292, 1195, 1085, 932 cm–1. 1H NMR (300 MHz, [D6]-
DMSO): δ = 12.93 (br. s, 1 H), 8.38 (d, J = 7.9 Hz, 1 H), 8.36 (d,
J = 6.8 Hz, 1 H), 7.62–7.60 (m, 2 H), 7.38 (ddd, J = 8.1, 5.1, 2.8 Hz,
1 H), 7.33 (d, J = 6.8 Hz, 1 H) ppm. MS (CI): m/z = 186 [M +
H+].
2,4-Dichloro-9H-pyrido[2,3-b]indole (38): Methanesulfonyl chloride
(2 equiv.) was added to a 0.4 m stirred suspension of 4-chloro-9H-
4-Chloro-2-(2-cyclohexyleth-1-ynyl)-9-(ethoxymethyl)-9H-pyrido-
[2,3-b]indole (43): Into a Schlenk tube with a screw cap, were intro-
Eur. J. Org. Chem. 2010, 6665–6677
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6675

P. G. Goekjian et al.
FULL PAPER
ducedunderargon,2,4-dichloro-9-(ethoxymethyl)-9H-pyrido[2,3-b]-
indole (39; 120 mg, 0.408 mmol, 1 equiv.), cyclohexylacetylene
(135 μL, 1.02 mmol, 2.5 equiv.), [PdCl2(PPh3)2] (29 mg, 0.04 mmol,
0.1 equiv.), CuI (16 mg, 0.08 mmol, 0.2 equiv.), and PPh3 (11 mg,
0.04 mmol, 0.1 equiv.), followed by addition of Et3N (1.2 mL) and
DMF (720 μL). The reaction mixture was stirred at 80 °C (the reac-
tion was monitored by TLC). After 12 h of heating, the reaction
mixture was poured into water and extracted with EtOAc. The
ether, 4:6) to afford 45 (54 mg, 71 % yield) as a yellow oil. IR
(NaCl): ν = 3068, 2927, 2852, 2226, 1609, 1577, 1558, 1510, 1465,
˜
1
1293, 1246, 1174, 1082, 1029, 832, 751 cm–1. H NMR (300 MHz,
CDCl3): δ = 7.67 (d, J = 7.7 Hz, 1 H), 7.64 (d, J = 8.2 Hz, 1 H),
7.59 (d, J = 8.9 Hz, 2 H), 7.45 (ddd, J = 8.2, 7.1, 1.1 Hz, 1 H), 7.24
(s, 1 H), 7.09 (td, J = 7.1, 1.1 Hz, 1 H), 7.08 (d, J = 8.9 Hz, 2 H),
5.98 (s, 2 H), 3.92 (s, 3 H), 3.57 (q, J = 7.0 Hz, 2 H), 2.68 (m, 1
H), 1.96 (br. s, 2 H), 1.79 (br. s, 2 H), 1.60 (br. s, 4 H), 1.37 (br. s,
combined organic layers were washed with brine, dried with 2 H), 1.16 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
MgSO4, filtered through Celite and the solvents were evaporated
to dryness. The crude product was purified by column chromatog-
raphy on silica gel (CH2Cl2/petroleum ether, 2:8) to afford com-
pound 43 (109 mg, 73% yield) as a brown solid; m.p. 84–86 °C
δ = 160.1 (C), 152.3 (C), 145.0 (C), 140.0 (C), 139.6 (C), 130.7 (C),
130.0 (2ϫCH), 126.9 (CH), 122.5 (CH), 121.4 (CH), 120.7 (C),
120.5 (CH), 114.2 (2ϫCH), 112.7 (C), 110.5 (CH), 94.7 (C), 81.5
(C), 71.1 (CH2), 64.2 (CH2), 55.4 (CH3), 32.5 (2ϫCH2), 29.9 (CH),
25.9 (CH2), 25.0 (2ϫCH2), 15.1 (CH3) ppm. MS (ESI): m/z = 439.1
[M + H+]. HRMS (ESI, 100 °C): calcd. for C29H30N2O2 439.2389;
found 439.2384.
(CH Cl /petroleum ether). IR (neat powder): ν = 3078, 2928, 2853,
˜
2
2
1
2224, 1587, 1572, 1469, 1387, 1081, 1065, 831, 749 cm–1. H NMR
(300 MHz, CDCl3): δ = 8.34 (d, J = 7.8 Hz, 1 H), 7.58 (d, J =
8.2 Hz, 1 H), 7.48 (td, J = 8.2, 7.2, 1.1 Hz, 1 H), 7.28 (td, J = 7.8,
1.1 Hz, 1 H), 7.18 (s, 1 H), 5.85 (s, 2 H), 3.44 (q, J = 6.9 Hz, 2 H),
2.60 (m, 1 H), 1.87 (br. s, 2 H), 1.72 (br. s, 2 H), 1.55 (br. s, 3 H),
1.33 (br. s, 3 H), 1.06 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.3 (C), 139.9 (C), 139.8 (C), 137.8 (C), 127.8 (CH),
123.2 (CH), 121.5 (CH), 120.6 (CH), 120.0 (C), 113.3 (C), 110.7
(CH), 95.9 (C), 80.4 (C), 71.4 (CH2), 64.4 (CH2), 32.4 (2ϫCH2),
29.9 (CH), 25.9 (CH2), 25.1 (2ϫCH2), 15.1 (CH3) ppm. MS (CI):
m/z = 367 [M + H+]. HRMS (CI): calcd. for C22H24ClN2O
367.1577; found 367.1577.
9-(Ethoxymethyl)-4-(4-methylpiperazin-1-yl)-2-(phenyleth-1-ynyl)-
9H-pyrido[2,3-b]indole (46): At r.t., 4-chloro-9-(ethoxymethyl)-2-
(phenyleth-1-ynyl)-9H-pyrido[2,3-b]indole (44; 30 mg, 0.083 mmol,
1 equiv.) was dissolved in N-methylpiperazine (4 mL) in a micro-
wave vial. The solution was stirred at 200 °C for 1 h under micro-
wave irradiation (Biotage Initiator). The resulting mixture was
quenched with water and then extracted with EtOAc. The resulting
organic layers were dried with MgSO4, filtered, and the solvents
were removed under reduced pressure. The product was purified by
column chromatography on alumina (EtOAc) to afford compound
46 (30 mg, 84% yield) as a yellow solid; m.p. 55–58 °C (EtOH). IR
4-Chloro-9-(ethoxymethyl)-2-(phenyleth-1-ynyl)-9H-pyrido[2,3-b]-
indole (44): Into a Schlenk tube with a screw cap, were introduced
under argon, 2,4-dichloro-9-(ethoxymethyl)-9H-pyrido[2,3-b]indole
(39; 50 mg, 0.17 mmol, 1 equiv.), phenylacetylene (66 μL,
0.51 mmol, 3 equiv.), [PdCl2(PPh3)2] (12 mg, 0.017 mmol,
0.1 equiv.), CuI (7 mg, 0.034 mmol, 0.2 equiv.), and PPh3 (5 mg,
0.017 mmol, 0.1 equiv.), followed by Et3N (600 μL) and DMF
(300 μL). The reaction mixture was stirred at 80 °C (the reaction
was monitored by TLC) and, after 12 h of heating, the reaction
mixture was poured into water and extracted with EtOAc. The
(neat powder): ν = 3068, 2923, 2850, 1562, 1453, 1472, 1092, 1002,
˜
736, 752 cm–1 1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J =
.
7.7 Hz, 1 H), 7.68–7.64 (m, 3 H), 7.50 (td, J = 8.3, 1.1 Hz, 1 H),
7.40–7.35 (m, 3 H), 7.34 (td, J = 8.1, 1.1 Hz, 1 H), 7.06 (s, 1 H),
5.97 (s, 2 H), 3.56 (q, J = 6.9 Hz, 2 H), 3.42 (br. s, 4 H), 2.83 (br.
s, 4 H), 2.50 (s, 3 H), 1.14 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 154.8 (C), 153.5 (C), 140.1 (C), 139.2 (C),
132.2 (2 ϫCH), 128.9 (CH), 128.4 (2 ϫCH), 126.1 (CH), 123.0
(CH), 122.7 (C), 120.9 (CH), 120.2 (C), 110.4 (CH), 109.6 (CH),
combined organic layers were washed with brine, dried with 107.3 (C), 90.3 (C), 88.5 (C), 71.2 (CH2), 64.2 (CH2), 55.2
MgSO4, filtered through Celite and the solvents were evaporated
to dryness. The residue was purified by column chromatography
on silica gel (CH2Cl2/petroleum ether, 3:7) to afford compound 44
(40 mg, 65% yield) as a brown solid; m.p. 162–164 °C (CH2Cl2/
(2ϫCH2), 50.4 (2ϫCH2), 46.3 (CH3), 15.1 (CH3) ppm. MS (CI,
200 °C): m/z = 425 [M + H+]. HRMS (CI): calcd. for C27H28N4O
425.2341; found 425.2341.
2-(2-Cyclohexyleth-1-ynyl)-9-(ethoxymethyl)-2-(phenyleth-1-ynyl)-
9H-pyrido[2,3-b]indole (47): Into a Schlenk tube fitted with a screw
cap, were introduced under argon, 4-chloro-9-(ethoxymethyl)-2-
(phenyleth-1-ynyl)-9H-pyrido[2,3-b]indole (44; 67 mg, 0.186 mmol,
1 equiv.), cyclohexylacetylene (60 mg, 0.558 mmol, 3 equiv.),
[PdCl2(PPh3)2] (14 mg, 0.02 mmol, 0.1 equiv.), CuI (8 mg,
0.04 mmol, 0.2 equiv.), PPh3 (2 mg, 0.02 mmol, 0.1 equiv.), then an-
hydrous Et3N (600 μL) and anhydrous DMF (300 μL). The reac-
tion mixture was stirred at 80 °C (the reaction was monitored by
TLC) for 12 h, then poured into water and extracted with EtOAc.
The combined organic layers were washed with brine, dried with
MgSO4, filtered through Celite and the solvents were evaporated
to dryness. The residue was purified by column chromatography
petroleum ether). IR (neat powder): ν = 3107, 2207, 1589, 1548,
˜
1
1467, 1387, 1310, 1076, 1063, 837, 751 cm–1. H NMR (300 MHz,
CDCl3): δ = 8.47 (d, J = 7.9 Hz, 1 H), 7.68 (d, J = 8.3 Hz, 1 H),
7.66–7.63 (m, 2 H), 7.59 (td, J = 8.3, 7.2, 1.1 Hz, 1 H), 7.48 (s, 1
H), 7.41–7.38 (m, 4 H), 5.96 (s, 2 H), 3.56 (q, J = 6.9 Hz, 2 H),
1.16 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
152.4 (C), 140.0 (C), 139.2 (C), 137.8 (C), 132.2 (2ϫCH), 129.2
(CH), 128.5 (2ϫCH), 128.0 (CH), 123.3 (CH), 122.3 (C), 121.6
(CH), 120.7 (CH), 119.9 (C), 113.8 (C), 110.7 (CH), 89.8 (C), 89.1
(C), 71.4 (CH2), 64.5 (CH2), 15.1 (CH3) ppm. MS (CI): m/z = 361
[M + H+]. HRMS (CI): calcd. for C22H18ClN2O 361.1108; found
361.1108.
2-(2-Cyclohexyleth-1-ynyl)-9-(ethoxymethyl)-4-(4-methoxyphenyl)- on silica gel (CH2Cl2/petroleum ether, 3:7) to afford compound 47
9H-pyrido[2,3-b]indole (45): At r.t., under an inert atmosphere, a
solution of [Pd(PPh3)4] (31 mg, 0.026 mmol, 0.15 equiv.), 4-meth-
oxyphenylboronic acid (40 mg, 0.26 mmol, 1.5 equiv.), and 0.3 m
aqueous K2CO3 (72 mg, 0.52 mmol, 3 equiv.) were added to a sus-
(61 mg, 76% yield) as a brown oil. IR (NaCl): ν = 3056, 2927, 2852,
˜
2218, 1573, 1559, 1466, 1447, 1348, 1291, 1217, 1092, 750 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 8.52 (d, J = 7.7 Hz, 1 H), 7.66 (d,
J = 7.6 Hz, 1 H), 7.64–7.62 (m, 2 H), 7.55 (td, J = 7.3, 1.1 Hz, 1
pension of 43 (50 mg, 0.172 mmol, 1 equiv.) in 1,4-dioxane H), 7.48 (s, 1 H), 7.39–7.32 (m, 4 H), 5.95 (s, 2 H), 3.54 (q, J =
(7.2 mL). The solution was stirred at 100 °C for 12 h then, after
cooling to r.t., the solution was filtered through Celite and the sol-
vents were removed under reduced pressure. The product was puri-
fied by column chromatography on silica gel (CH2Cl2/petroleum
6.9 Hz, 2 H), 2.83 (m, 1 H), 2.05 (br. s, 2 H), 1.85 (br. s, 2 H), 1.68
(br. s, 4 H), 1.44 (br. s, 2 H), 1.14 (t, J = 6.9 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 152.1 (C), 140.1 (C), 138.6 (C), 132.1
(2ϫCH), 128.9 (CH), 128.5 (2ϫCH), 127.7 (CH), 125.6 (C), 123.2
6676
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6665–6677

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Received: June 2, 2010
Published Online: October 20, 2010
Eur. J. Org. Chem. 2010, 6665–6677
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6677