Three-component tandem reaction involving acid chlorides, terminal alkynes, and 2-aminoindole hydrochlorides: Synthesis of α-carboline derivatives in aqueous conditions via regioselective [3 + 3] cyclocondensation

Article abstract of DOI:10.1021/jo201994v

An efficient synthesis toward highly diversified α-carboline derivatives via a three-component tandem reaction using acid chlorides, terminal alkynes, and 2-aminoindole hydrochlorides has been described. The salient feature of the one-pot strategy involve

Full text of DOI:10.1021/jo201994v

Article
pubs.acs.org/joc
Three-Component Tandem Reaction Involving Acid Chlorides,
Terminal Alkynes, and 2-Aminoindole Hydrochlorides: Synthesis of
α-Carboline Derivatives in Aqueous Conditions via Regioselective
[3 + 3] Cyclocondensation
Sahaj Gupta,† Brijesh Kumar,‡ and Bijoy Kundu*,†
‡
†Medicinal & Process Chemistry Division and Sophisticated and Analytical Instrument Facility, Central Drug Research Institute,
CSIR, Lucknow 226001, India
S
* Supporting Information
ABSTRACT: An efficient synthesis toward highly diversified α-carboline derivatives via a three-component tandem reaction
using acid chlorides, terminal alkynes, and 2-aminoindole hydrochlorides has been described. The salient feature of the one-pot
strategy involves regioselective [3 + 3]-cyclocondensation and the presence of water in the reaction medium to facilitate
cyclization. Nonaqueous conditions furnished products in poor yields.
reported in the literature for this tricyclic template.
Retrosynthetic analysis (Figure 1) of the α-carboline, among
many possible routes, suggests that the 2-aminoindole (1)
could be an important component for the straightforward
synthesis of α-carboline derivatives in one pot. The reason for
its poor exploration to the synthesis of α-carboline may be
attributed to its association with extremely poor stability as a
free base.18 Recently, we addressed the stability issues by
employing bis-carbamate-protected 2-aminoindole and subject-
ing it to a three-component tandem format by treatment with
disubstituted propargyl alcohols and I2/ICl.19 Although by
using the protected 2-aminoindoles we were able to prevent
degradation of 2-aminoindole, the strategy furnished Na-
derivatized-α-carbolines via iodocycloelimination with an
alkyloxy carbonyl group anchored to the NaH of the indole.
Since further attempts to remove the Na-protecting group were
not successful, this prompted us to develop an alternative
strategy for the synthesis of 9H-pyrido[2,3-b]indole derivatives
directly from the unprotected 2-aminoindole hydrochloride. In
this paper, we report a three-component tandem reaction
involving acid chlorides, terminal aromatic/aliphatic alkynes,
and 2-aminoindole hydrochlorides that allows direct access to
the highly substituted α-carbolines.
INTRODUCTION
■
The search for a one-pot, three-component tandem process1
with multiple bond-forming abilities to furnish natural product
based polyheterocycles has become one of the major challenges
for synthetic chemists in both academia and industry. As part of
our continuing effort toward the development of new routes
involving multistep/one-pot reactions2 for the synthesis of
indole-based natural products3 as well as polyheterocycles,4 we
embarked with a search for a one-pot, three-component
tandem format for the synthesis of naturally occurring α-
carboline (9H-pyrido[2,3-b]indole) derivatives. The α-carbo-
lines are structural templates found in an array of natural
products: dendrodoine A, grossularines-1 and -2, metabolites
isolated from the tunicate Dendrodoa grossularia,5 indoloquino-
line alkaloid cryptotackiene from Cryptolepis sanguinolenta,6
kapakahines from the marine sponge Cribrochalina olemda,7 and
mescengricin, isolated from Streptomyces griseoflavus.8 These
naturally derived α-carboline derivatives as well as synthetic α-
carbolines are associated with pharmacological activities ranging
from anticancer9 to antiviral.10 Thus, as an attractive naturally
occurring synthetic target, several multistep methodologies
involving Diels−Alder reaction,11 annulation of azaindoles,12
modified Graebe−Ullman reaction of triazoles,13 annulation of
indole ring onto pyridine,14 generation of the pyrrole ring by
annulating appropriately tethered phenyl and pyridine rings,15
nucleophilic arylfluorine displacement reactions,16 and more
recently,17 one-pot synthesis involving Pd-catalyzed aryl
amination followed by intramolecular arylation have been
Received: September 30, 2011
Published: November 15, 2011
© 2011 American Chemical Society
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Figure 1. Retrosynthetic strategies for the α-carboline depicting involvement of the 2-aminoindole as one of the common reactants for the synthesis
of 9H-pyrido[2,3-b]indole in two different formats.
Scheme 1. Three-Component Reaction Involving 1a, 2, and 3a Furnishing an Unusual Pentacyclic Ring20 with No Participation
of the Alkyne Moiety
presence of a series of bases such as TEA, DABCO, Cs2CO3,
Na2CO3, t-BuOK, and KOH using acetonitrile and DMSO as
solvents, and the results are summarized in Table 1 (entries 1−
14). Among the bases used, t-BuOK (entry 4) and KOH (entry
5) in ACN at 80 °C afforded products in 44% and 65% isolated
yield, respectively, whereas others failed to afford the title
compound (entries 1−3). Switching solvent from acetonitrile
to DMSO under heating at 120 °C for 1 h in the presence of
Cs2CO3 (2.5 equiv), t-BuOK (2.5 equiv), and KOH (2.5 equiv)
furnished 6a in 56% (entry 6), 41% (entry 8), and 16% (entry
10) isolated yields, respectively. Use of DABCO (entry 7) and
Na2CO3 (entry 9) completely failed to afford the title
compounds. It is interesting to note from these findings that
although addition of solid KOH promoted cyclization in the
acetonitrile (entry 5) in 65% yield, use of DMSO as solvent was
found to be detrimental (entries 10 and 11). We attributed this
to an incomplete deprotonation of the 2-aminoindole hydro-
chloride in DMSO in comparison to the acetonitrile. This then
prompted us to use 10% aqueous KOH (1.3 equiv) as a base in
DMSO with the view to facilitate deprotonation, and pleasingly,
we observed formation of the title compound 6a in 81%
isolated yield within 2 min at rt (entry 12). Nonetheless,
application of 10% aqueous KOH as a base in acetonitrile or
water either reduced the yield of 6a to 10% (entry 13) or failed
to promote cyclocondensation (entry 14).
RESULTS AND DISCUSSION
■
As depicted in route A of Figure 1, we envisaged that owing to
the activated nature of the indole ring, it may be possible to
construct α-carbolines in one pot by treating 1 with an
aldehyde (2) and a terminal aromatic alkyne (3) as this may
initiate heteroannulation via 6-endo cyclization by involving the
C-3 nucleophilic carbon of the indole. Our studies thus
commenced with a CuI-catalyzed three-component reaction
(Scheme 1) involving 5-methyl-2-aminoindole hydrochloride
(1a), 4-bromobenzaldehyde (2), and phenylacetylene (3a).
However, after completion of the reaction, instead of isolating
the desired α-carboline derivative, we obtained a pentacyclic
compound (4) in 46% yield with no participation of the alkyne
moiety. Indeed, a literature survey revealed the synthesis of a
compound based on 4 by simply heating 1-methyl-1H-indol-2-
ylamine hydrochloride and benzaldehyde in ethanol.20
This prompted us to examine the second retrosynthetic route
B as depicted in Figure 1 for the α-carboline, which suggests its
accessibility via [3 + 3]-cyclocondensation of the 2-aminoindole
hydrochloride 1 with an alkynone21 5 by employing an
appropriate base for in situ generation of 2-aminoindole.
Accordingly, we screened a variety of bases for developing a
rapid [3 + 3]-cyclocondensation protocol in a manner that will
prevent degradation of the 2-aminoindole following an
autoxidation22 pathway (Table 1).
We were intrigued by these findings because it is apparent
that the presence of water/KOH/DMSO in the reaction
mixture facilitates the rapid [3 + 3]-cyclocondensation between
the alkynone 5a and 5-methyl-2-aminoindole hydrochloride 1a
The optimization studies were carried out by using 5-methyl-
2-aminoindole hydrochloride 1a and 1-(4-methoxyphenyl)-3-
phenylpropynone 5a as model substrates. Initially, we carried
out [3 + 3]-cyclocondensation by treating 1a with 5a in the
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Table 1. Optimization of Reaction Conditions for the Regioselective [3 + 3] Cyclocondensation Involving 1-(4-
Methoxyphenyl)-3-phenylpropynone 5a and 5-Methyl-2-aminoindole Hydrochloride 1a To Afford 6a
entry
solvent
T (°C)/time
base
yield (%)
1
2
ACN
80/5 h
80/12 h
80/6 h
80/1 h
80/1 h
120/1 h
120/1 h
120/1 h
120/1 h
120/1 h
rt/12 h
rt/2 min
rt/1 h
TEA
0
0
ACN
DABCO (2.5 equiv)
Na2CO3 (2.5 equiv)
t-BuOK (2.5 equiv)
KOH (2.5 equiv)
3
ACN
0
4
ACN
44
65
56
0
5
ACN
6
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
ACN
Cs2CO3 (2.5 equiv)
DABCO (2.5 equiv)
t-BuOK (2.5 equiv)
Na2CO3 (2.5 equiv)
KOH (2.5 equiv)
7
8
41
0
9
10
11
12
13
14
16
0
KOH (2.5 equiv)
10% aq KOH (1.3 equiv)
10% aq KOH (1.3 equiv)
KOH (2.5 equiv)
81
10
0
H2O
rt/16 h
to afford α-carboline derivative 6a. Nevertheless, it is also
interesting to note that during [3 + 3]-cyclocondensation we
observed complete regioselectivity despite availability of two
nucleophilic centers NaH and C-3 in the indole ring, and
indeed, the more nucleophilic C-3 was preferred over Na for the
cyclocondensation (Table 1). Recently, we reported involve-
ment of NaH in the 2-amino-1H-indole-3-carboxylic acid ethyl
ester during the [3 + 3]-cyclocondensation with an alkynone by
keeping the C-3 of the indole blocked with a COOEt group to
give pyrimido[1,2-a]indoles.23
Once the conditions for the regioselective [3 + 3]-
cyclocondensation between 5-methyl-2-aminoindole hydro-
chloride 1a and the alkynone 5a were optimized, we next
proceeded with the development of a one-pot, three-
component tandem strategy for the synthesis of α-carboline
derivatives by carrying out both reactions in a sequential
format. Indeed, the challenging task for us was to combine the
two organic reaction conditions involving Sonogashira coupling
and [3 + 3]-cyclocondensation in a manner that will lead to the
formation of several bonds resulting in α-carboline derivatives
without the isolation of the intermediate(s).
For combining the two reactions in a sequential format in
one pot, we carried out optimization studies using 4-
methoxybenzoyl chloride 7a, phenylacetylene 3a, and 5-
methyl-2-aminoindole hydrochloride 1a as model substrates,
and results have been summarized in Table 2 (entry 1−15).
The progress of the reaction after each step was monitored by
TLC/HPLC. We initiated our investigation by treating 7a and
3a in the presence of PdCl2(PPh3)2/CuI and TEA in THF at rt
for 1 h followed by the addition of 1a in the presence of 10% aq
KOH. Under these conditions, although the alkynone
formation was complete, its conversion to 6a was not observed
even after the solvent was changed from THF to acetonitrile
and DMSO (entries 1−3). Next, we decided to carry out
Sonogashira couplings under aqueous conditions and accord-
ingly treated 7a with 3a in the presence of PdCl2(PPh3)2, CuI,
K2CO3, and SDS in H2O using the literature procedure24
followed by the addition of 1a in the presence of t-BuOK (2.5
equiv) in DMSO at rt. Under these conditions, although
formation of the alkynone 5a occurred in 90% yield (based on
HPLC), the title compound was obtained in traces (entry 4);
however, increasing the temperature led to a meager enhance-
ment in the yield to 15% (entry 5). Attempts to further
improve the yield were then made by replacing t-BuOK with
Cs2CO3 and KOH. Carrying out reaction in the presence of
Cs2CO3 (2.5 equiv) at rt furnished 6a in traces (entry 6),
whereas increasing the temperature or concentration of the
Cs2CO3 to 4 equiv raised the yield of the final product to 24%
(entry 7) and 56% (entry 8), respectively. Replacing Cs2CO3
with 10% aq KOH in DMSO was found to be ineffective when
added to the alkynone generated in situ under aqueous
conditions (entry 9). This can be attributed to the overall
dilution in the concentration of KOH in the reaction mixture
following its addition as 10% aqueous solution to the alkynone
5a synthesized in neat water (used as a medium for
Sonogashira coupling). This prompted us to add solid KOH
in DMSO and as anticipated, in the initial experiments.
Addition of 2 equiv of solid KOH at rt afforded α-carboline
derivative 6a in 57% isolated yield; however, increasing the
concentration of solid KOH from 2.0 equiv to 3.0 and 4.0 equiv
in DMSO at rt raised the isolated yield of 6a to 65% (entry 11)
and 76% (entry 12), respectively. Notably, under the increased
concentrations of KOH, the time taken for the completion of
cyclocondensation was significantly reduced from 6 to 2 h. In
the next set of experiments, we established the role of water for
the three-component tandem reaction by carrying out
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Table 2. Optimization of reaction Conditions for the Three-Component Tandem Protocol in One Pot Involving 4-Methoxy
Acid Chloride 7a, Phenylacetylene 3a, and 5-Methyl-2-aminoindole Hydrochloride 1a
a
tandem reaction conditions in one-pot (i) Sonogashira coupling and (ii) [3 + 3]
cyclocondensation
reaction time for steps
i/ii
% yields of alkynones /products
entry
1
5a/6a
(i) PdCl2(PPh3)2/CuI, TEA, THF, rt
1 h/16 h
1 h/16 h
1 h/16 h
3 h/16 h
3 h/16 h
3 h/16 h
3 h/16 h
3 h/16 h
3 h/6 h
89/0
83/0
90/0
(i) 10% aq KOH, THF, rt
2
3
(ii) PdCl2(PPh3)2, CuI, TEA, ACN, rt
(ii) 10% aq KOH, ACN, rt
(i) Pd/C, PdCl2(PPh3)2, CuI, TEA, THF, rt
(ii) 10% aq KOH, DMSO, rt
b
4
(i) PdCl2(PPh3)2, CuI, K2CO3, SDS, H2O, 0 to 65 °C
(ii) t-BuOK (2.5 equiv), DMSO, rt
90/trace
b
5
(i) PdCl2(PPh3)2, CuI, K2CO3, SDS, H2O, 0 to 65 °C
(ii) t-BuOK (2.5 equiv), DMSO, 65 °C
(i) PdCl2(PPh3)2, CuI, K2CO3, SDS, H2O, 0 to 65 °C
(ii) Cs2CO3 (2.5 equiv), DMSO, rt
91/15
b
6
92/trace
b
7
(i) PdCl2(PPh3)2, CuI, K2CO3, SDS, H2O, 0 to 65 °C
(ii) Cs2CO3 (2.5 equiv), DMSO, 65 °C
(i) PdCl2(PPh3)2, CuI, K2CO3, SDS, H2O, 0 to 65 °C
(ii) Cs2CO3 (4 equiv), DMSO, 65 °C
(i) PdCl2 (PPh3)2/CuI, K2CO3, SDS, H2O, 0 to 65 °C
(ii) 10% KOH (1.3 equiv), DMSO, rt
(i) PdCl2 (PPh3)2/CuI, K2CO3, SDS, H2O, 0 to 65 °C
(ii) KOH (2.0 equiv), DMSO, rt
88/24
b
8
87/56
b
9
89/<10
b
10
11
12
13
14
15
3 h/16 h
3 h/2 h
91/57
b
(i) PdCl2 (PPh3)2/CuI, K2CO3, SDS, H2O, 0 to 65 °C
(ii) KOH (3.0 equiv), DMSO, rt
88/65
b
(i) PdCl2 (PPh3)2/CuI, K2CO3, SDS, H2O, 0 to 65 °C
(ii) KOH (4.0 equiv), DMSO, rt
3 h/2 h
91/76
(i) PdCl2(PPh3)2/CuI, TEA, THF, rt
1 h/12 h
1 h/15 min
1 h/1 h
90/0
(ii) KOH (4.0 equiv), DMSO, rt
b
(i) PdCl2(PPh3)2/CuI, TEA, THF, rt
90/79
(ii) KOH (4.0 equiv), DMSO−H2O, rt
(i) PdCl2(PPh3)2/CuI, TEA, ACN, rt
b
90/61
(ii) KOH (4.0 equiv), DMSO−H2O, rt
a
b
Yield of alkynone is based on HPLC. Isolated yields; SDS = sodium dodecyl sulfate.
formation of the alkynone 5a via Sonogashira couplings in THF
and followed it up by adding solid KOH (4 equiv) and 2-
aminoindole hydrochloride either in DMSO or in DMSO−
water mixture. As envisaged, use of DMSO alone completely
failed to furnish the desired compound (entry 13), whereas use
of a DMSO−water mixture afforded the title compound in 79%
isolated yield (entry 14) with the time for cyclocondensation
being reduced to 15 min. Switching solvent from THF to
acetonitrile for the Sonogashira reaction coupled with the use
of DMSO−water mixture for cyclocondensation afforded the
title compound in reduced yield (entry 15). Thus, nonaqueous
conditions in general failed to promote formation of the title
compounds, whereas the two optimized aqueous conditions
that were found to be suitable included method A, involving
water/KOH in DMSO, and method B, involving THF/KOH in
DMSO−water.
Following the optimization of reaction conditions in one pot,
we next examined the scope and limitation of our strategy by
treating a variety of 2-aminoindole hydrochlorides with a range
of acid chlorides and terminal alkynes using the optimized
conditions. The R1 in the acid chlorides has been exclusively
restricted to aromatic rings, whereas R2 in the terminal alkynes
include both aliphatic and aromatic moieties. The R3 in the
phenyl ring of the indole moiety has been substituted by
introducing electron-donating CH3 at position 5 and electron-
withdrawing groups (F, CF3) at position 6. The 2-aminoindole
hydrochloride derivatives (1a−d) were obtained using a
literature procedure25 and characterized by NMR in their
respective ring-protonated tautomeric forms, 1,3-dihydro-2H-
indol-2-imine hydrochloride derivatives.26 The latter in the
presence of base gets transformed into 2-aminoindole as a free
amine. The reactants 1a−d, 7a−e, and 3a−f were then
subjected to three-component tandem reactions to furnish 25
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Table 3. Three-Component Tandem Reactions Involving Acid Chlorides 7a−e, Terminal Alkynes 3a−f, and 2-Aminoindole
Hydrochlorides 1a−d To Afford α-Carboline Derivatives 6a−z
a
entry
R1 (7)
R2 (3)
C6H5
R3 (1)
method
compd
yield (%)
1
2
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
C6H5
5-CH3
H
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
6a
6b
6c
6d
6e
6f
76
58
74
46
75
71
77
72
73
56
44
70
75
71
70
69
74
76
69
58
64
70
66
52
10
42
C6H9
3
4-CH3C6H4
(CH2)5CH3
C6H5
6-CF3
6-CF3
6-F
4
5
6
4-C(CH3)3C6H4
4-CH3C6H5
C6H5
H
7
C6H5
H
6g
6h
6i
8
C6H5
5-CH3
5-CH3
5-CH3
6-F
9
C6H5
4-C(CH3)3C6H4
C6H9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
C6H5
6j
C6H5
(CH2)5CH3
4-C(CH3)3C6H4
C6H5
6k
6l
C6H5
6-CF3
6-CF3
6-F
C6H5
6m
6n
6o
6p
6q
6r
C6H5
4-CH3C6H4
4-CH3C6H4
4-C(CH3)3C6H4
C6H5
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
3,4-di-CH3OC6H3
3,4-di-CH3OC6H3
3,4-di-CH3OC6H3
3,4-di-CH3O−C6H3
C(CH3)3
H
H
5-CH3
6-F
C6H5
4-C(CH3)3C6H4
C6H9
6-F
6s
6t
6-CF3
H
C6H5
6u
6v
6w
6x
6y
4-CH3C6H4
C6H5
5-CH3
6-CF3
6-F
C6H9
C6H5
H
b
C6H5
(CH3)3Si
H
6z
a
Method A: (i) alkyne (1.0 equiv), acid chloride (2.0 equiv), PdCl2(PPh3)2 (2 mol %), CuI (5 mol %), SDS (7 mol %), K2CO3 (3 equiv), H2O, 0−
65 °C, 3 h; (ii) KOH (4.0 equiv), 2-amino indole hydrochloride (1.0 equiv) DMSO (1 mL). Method B: (i) alkyne (1.0 equiv), acid chloride (1.0
equiv), PdCl2(PPh3)2 (2 mol %), CuI (4 mol %), TEA (1.25 equiv), THF (2 mL), rt, 1 h; (ii) KOH (4.0 equiv), 2-aminoindole hydrochloride (1.0
b
equiv), DMSO−H2O (1:1; 4 mL);. The product was obtained with R2 = H.
new compounds 6a−y and one known compound 6z27 in
moderate to good yields (Table 3). As is evident from Table 3,
the electronic properties of the substituent on the phenyl ring
of the indole moiety had no effect on the yields of the final
compounds (entries 1, 5, and 13). Similarly, introducing a
substituent on the phenyl ring of the aromatic acid chlorides
had a negligible effect on the reactions, offering products with
minimal variation in yields (entries 3, 15 and 22). An attempt
to employ aliphatic acid chlorides such as propanoyl- and p-
tolylacetyl chlorides failed to yield the desired compounds
except for pivaloyl chloride, which furnished 6y in poor
(∼10%) yield using method B (entry 25). Among terminal
alkynes, substitution on the aromatic ring had no effect on the
isolated yields of the title compounds (entries 6−8); however,
replacement of the aromatic ring with an aliphatic moiety
reduced the yields of the final compounds (entries 2, 4, 10, 11,
20, and 24). The use of ethynyltrimethylsilane 3f afforded final
product 6z (R2 = H; without the trimethylsilyl group) in 42%
isolated yield (entry 26). Thus, among the effects of the three
substituents R1, R2, and R3 examined on the reaction yields,
substitution on the terminal alkynes represented by R2 had a
major impact. In general, terminal alkynes with R2 as the
aromatic ring furnished products in 10−77% isolated yield,
whereas R2 having an aliphatic moiety furnished products in
42−58% isolated yield.
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110.9 (d, J = 22.5 Hz), 100.2(d, J = 27.8 Hz), 35.4; HRMS (ESI) calcd
for C8H8FN2 [M − Cl] 151.0672, found 151.0672.
CONCLUSION
■
In conclusion, we have developed an efficient, three-component
tandem reaction for the synthesis of highly substituted naturally
occurring α-carbolines derivatives. The strategy involves
condensation of acid chlorides with terminal alkynes under
Sonogashira conditions both in aqueous and nonaqueous
medium followed by in situ [3 + 3] cyclocondensation of the
resulting alkynones with 2-aminoindole hydrochlorides in the
presence of KOH in DMSO/DMSO−H2O. Further studies
with the application of a one-pot, three-component tandem
process to other functionalized indoles as one of the reactants is
in progress.
III. Procedure for the synthesis of pentacyclic system 4 via
three component reaction following route A (Figure 1). To a
stirred solution of 5-methyl-1H-indol-2-amine hydrochloride salt 1a
(1.0 mmol), 4-bromobenzaldehyde 2 (1.0 mmol) and phenyl
acetylene 3a (1.0 mmol) in DMSO was added CuI (20 mol %).
The resulting solution was heated at 100 °C for 6 h and the crude
reaction mixture was filtered through a Celite bed; followed by
washing of the Celite bed with EtOAc (2 × 10 mL). The filtrate was
diluted with water (10 mL) and extracted with EtOAc (3 × 15 mL).
The combined organic extracts was washed with brine, dried over
anhydrous sodium sulfate and evaporated under reduced pressure in
vacuo. The crude reaction mixture was purified by column
chromatography on 60−120 mesh silica using EtOAc/hexane as
eluent to afford the title compound (4) as white solid; yield =46%; mp
EXPERIMENTAL SECTION
1
>250 °C; FT-IR (KBr) νmax 3150, 3033, 2934, 1594, 1262 cm−1; H
■
I. General Information and Methods. All reagents and solvents
were purchased from commercial sources and used without
purification. NMR spectra were recorded with 200, 300, and 400
NMR (300 MHz, CDCl3): δ 9.65 (s, 2H), 7.65 (d, J = 8.4 Hz, 2H),
7.15−7.08 (m, 6H), 6.75 (s, 2H), 2.34 (s, 6 H); 13C NMR (75 MHz,
CDCl3): δ 150.9, 139.1, 136.6, 136.0, 132.2, 130.6, 129.1, 126.2, 122.7,
122.0, 121.2, 110.5, 108.7, 21.8 ppm. HRMS (ESI) calcd for
C25H19BrN3 [M + H] 440.0762, found 440.0738.
1
MHz spectrometers for H NMR and 50, 75, 100, and 150 MHz for
13C NMR. Chemical shifts (δ) are given in ppm relative to the residual
signals of tetramethylsilane in CDCl3 or deuterated solvent CDCl3/
DMSO-d6 for 1H and 13C NMR. Multiplicities are reported as follows:
singlet (s), doublet (d), doublet of doublets (dd), doublet of triplets
(dt), triplet (t), quartet (q), multiplet (m). High-resolution mass
spectra were taken with a mass spectrometer. Column chromatog-
raphy was performed using silica gel (100−200 mesh) as the stationary
phase. All reactions were monitored by thin-layer chromatography
(TLC). The purity and characterization of these compounds were
further established using HR/EI mass spectroscopy. Melting points
were measured on a capillary melting point apparatus and are
uncorrected.
IV. Procedure for the Synthesis of 2-(4-Methoxyphenyl)-6-
methyl-4-phenyl-9H-pyrido[2,3-b]indole 6a from 1a and 5a.
To a stirred solution of 1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-
one (100 mg, 0.424 mmol) 5 and 1H-indol-2-amine hydrochloride salt
(77 mg, 0.424 mmol) 1a in DMSO (5 mL) was added 10% aqueous
KOH (31 mg, 0.551 mmol), and the reaction mixture was stirred at rt
for 2 min. The reaction mixture was diluted with water and extracted
with EtOAc (3 × 10 mL). The combined organic extracts were washed
with brine, dried over anhydrous sodium sulfate, and evaporated under
reduced pressure in vacuo. The crude reaction mixture was purified by
column chromatography on 60−120 mesh silica using EtOAc/hexane
as eluent to afford the title compound as white solid (125 mg, 81%).
V. General Procedure for the Synthesis of 9H-Pyrido[2,3-
b]indole Derivatives 6a−z from 1a−d, 3a−f, and 7a−
e. Method A. Terminal alkynes 3a−e (1 mmol), acid chlorides
7a−d (2 mmol), sodium dodecyl sulfate (7 mol %), PdCl2(PPh3)2 (2
mol %), and CuI (5 mol %) were added in a small test tube cooled by
ice−water bath. To this reaction mixture was added in small portions
K2CO3 (3 mmol) in 1 mL of water with stirring. After the addition was
completed, the vial was capped and heated at 65 °C for 3 h. After the
formation of alkynone as monitored by TLC, the reaction mixture was
diluted with DMSO (1 mL) at rt followed by addition of 1H-indol-2-
amine hydrochloride derivatives (1.0 mmol, 1a−d) and KOH (4.0
mmol). The reaction mixture was stirred for 2 h at rt, and the crude
reaction mixture was filtered through a Celite bed followed by washing
of the Celite bed with EtOAc (2 × 10 mL). The filtrate was diluted
with water (10 mL) and extracted with EtOAc (3 × 25 mL). The
combined organic extracts was washed with brine, dried over
anhydrous sodium sulfate, and evaporated under reduced pressure in
vacuo. The crude reaction mixture was purified by column
chromatography on 60−120 mesh silica using EtOAc/hexane as
eluent to afford the final compounds (6a−t).
Method B. To a solution of Pd(PPh3)2Cl2 (2 mol %), CuI (4 mol
%), and TEA (1.25 mmol) in THF (5.0 mL) were added acid chloride
(1.0 mmol, 7a−e) and terminal alkyne (1.0 mmol, 3a−f) under N2
atmosphere. The reaction was stirred at rt for 1 h, the formation of
alkynone was monitored by TLC, and the reaction mixture was diluted
with DMSO−H2O (1:1; 10 mL) followed by addition of 1H-indol-2-
amine hydrochloride derivatives (1.0 mmol, 1a−d) and KOH (4.0
mmol). The reaction mixture was stirred for 15 min at rt, and the
crude reaction mixture was filtered through a Celite bed followed by
washing of the Celite bed with EtOAc (2 × 10 mL). The filtrate was
diluted with water (10 mL) and extracted with EtOAc (3 × 25 mL).
The combined organic extracts were washed with brine, dried over
anhydrous sodium sulfate, and evaporated under reduced pressure in
vacuo. The crude reaction mixture was purified by column
chromatography on 60−120 mesh silica using EtOAc/hexane as
eluent to afford the final compounds (6u−z).
II. Synthesis of 1H-Indol-2-amine Hydrochloride Salt
Derivatives 1a−d. These compounds were synthesized using
methods reported in the literature.14d,23
5-Methyl-1H-indol-2-amine Hydrochloride Salt 1a. Characterized
as the tautomeric form 5-methyl-1,3-dihydro-2H-indol-2-imine hydro-
chloride:24 white solid; yield = 79%; mp 233−235 °C; FT-IR (KBr)
1
νmax 3390, 3253, 3174, 2975, 1488, 1216 cm−1; H NMR (300 MHz,
DMSO-d6) δ 12.41 (s, 1H), 10.25 (s, 1H), 9.95 (s, 1H), 7.19 (s, 1H),
7.08 (s, 2H), 4.12 (s, 2H), 2.27 (s, 3H); 13C NMR (75 MHz, DMSO-
d6) δ 170.7, 140.4, 132.8, 128.2, 126.5, 125.2, 111.5, 35.8, 20.7; HRMS
(ESI) calcd for C9H11N2 [M − Cl] 147.0922, found 147.0922.
1H-Indol-2-amine Hydrochloride Salt 1b. Characterized as the
tautomeric form 1,3-dihydro-2H-indol-2-imine hydrochloride:24 white
solid; yield = 75%; mp 225−227 °C; FT-IR (KBr) νmax 3473, 3233,
1
3073, 2947, 1469, 1221 cm−1; H NMR (300 MHz, DMSO-d6): δ
12.49 (s, 1H), 10.31 (s, 1H), 10.03 (s, 1H), 7.39 (d, J = 7.2 Hz, 1H),
7.28 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 7.13−7.08 (m, 1H),
4.18 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 171.0, 142.8, 128.0,
126.5, 124.7, 123.7, 111.8, 36.0; HRMS (ESI) calcd for C8H9N2 [M −
Cl] 133.0766, found 133.0766.
6-(Trifluoromethyl)-1H-indol-2-amine Hydrochloride Salt 1c.
Characterized as the tautomeric form 6-(trifluoromethyl)-1,3-dihy-
dro-2H-indol-2-imine hydrochloride:24 white solid; yield = 77%; mp
>250 °C; FT-IR (KBr) νmax 3330, 3222, 3184, 3072, 1451, 1220 cm−1
;
1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.36 (s, 1H), 10.20
(s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.51 (s, 2H), 4.29 (s, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 171.4, 143.8, 131.6, 128.7 (q, J = 32 Hz),
125.5, 122.7, 120.5, 36.2; HRMS (ESI) calcd for C9H8F3N2 [M − Cl]
201.0640, found 201.0640.
6-Fluoro-1H-indol-2-amine Hydrochloride Salt 1d. Characterized
as the tautomeric form 6-fluoro-1,3-dihydro-2H-indol-2-imine hydro-
chloride:24 brown solid; yield = 81%; mp 245−247 °C; FT-IR (KBr)
1
νmax 3466, 3253, 3137, 2945, 1501, 1220 cm−1; H NMR (300 MHz,
DMSO-d6) δ 12.53 (s, 1H), 10.46 (s, 1H), 10.27 (s, 1H), 7.43−7.39
(m, 1H), 7.08 (dd, J = 2.0, 9.0 Hz, 1H), 6.96−6.93 (m, 1H), 4.16 (s,
2H); 13C NMR (75 MHz, DMSO-d6) δ 172.0, 161.9 (d, J = 240 Hz),
144.2 (d, J = 12.75 Hz), 125.8 (d, J = 9.8 Hz), 122.5 (d, J = 2.3 Hz),
10159
dx.doi.org/10.1021/jo201994v | J. Org. Chem. 2011, 76, 10154−10162

The Journal of Organic Chemistry
Article
2-(4-Methoxyphenyl)-6-methyl-4-phenyl-9H-pyrido[2,3-b]indole
6-Methyl-2,4-diphenyl-9H-pyrido[2,3-b]indole (6h): white solid;
yield = 72%; mp 248−249 °C; FT-IR (KBr) νmax 3064, 1584, 1219
(6a): white solid; yield = 76%; mp 240−242 °C; FT-IR (KBr) νmax
1
3058, 2939, 1586, 1240 cm−1; H NMR (400 MHz, DMSO-d6) δ
1
cm−1; H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.21 (d, J =
11.71 (s, 1H), 8.16 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 7.1 Hz, 2H), 7.65−
7.56 (m, 3H), 7.53 (s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.20
(d, J = 8.1 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H), 2.27 (s,
3H); 13C NMR (100 MHz, DMSO-d6) δ 160.0, 152.8, 152.8, 145.0,
138.8, 137.6, 131.8, 128.7, 128.6, 128.2, 127.7, 127.5, 121.5, 120.1,
114.1, 112.0, 111.0, 110.5, 55.2, 21.3; HRMS (ESI) calcd for
C25H21N2O [M + H] 365.1654, found 365.1662.
7.2 Hz, 2H), 7.77 (d, J = 6.5 Hz, 2H), 7.67−7.59 (m, 4H), 7.54−7.49
(m, 2H), 7.46−7.40 (m, 2H), 7.33 (s, 1H), 7.24 (d, J = 7.3 Hz, 1H),
2.28 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 152.9, 152.8, 145.0,
139.3, 138.7, 137.8, 129.1, 128.8, 128.7, 127.8, 126.9, 126.8, 121.7,
121.6, 120.0, 112.8, 112.7, 111.2, 111.1, 21.3; HRMS (ESI) calcd for
C24H19N2 [M + H] 335.1548, found 335.1557.
4-(4-tert-Butylphenyl)-6-methyl-2-phenyl-9H-pyrido[2,3-b]indole
(6i): white solid; yield = 73%; mp 229−231 °C; FT-IR (KBr) νmax
4-Cyclohex-1-en-1-yl-2-(4-methoxyphenyl)-9H-pyrido[2,3-b]-
1
3128, 2944, 1464, 1217 cm−1; H NMR (300 MHz, DMSO-d6) δ
indole (6b): white solid; yield = 58%; mp 248−250 °C; FT-IR (KBr)
1
νmax 3150, 2949, 1457, 1252 cm−1; H NMR (300 MHz, CDCl3) δ
11.92 (s, 1H), 8.21 (d, J = 7.2 Hz, 2H), 7.72−7.62 (m, 5H), 7.53−7.37
(m, 5H), 7.24 (d, J = 8.0 Hz, 1H), 2.28 (s, 3H), 1.40 (s, 9H); 13C
NMR (150 MHz, DMSO-d6) δ 153.3, 153.2, 151.8, 145.4, 139.8,
138.2, 136.3, 129.1, 129.1, 128.8, 128.2, 128.1, 127.3, 125.9, 122.2,
120.5, 113.2, 111.7, 111.5, 34.9, 31.6, 21.8; HRMS (ESI) calcd for
C28H27N2 [M + H] 391.2174, found 391.2187.
11.13 (s, 1H), 8.10 (d, J = 8.7 Hz, 2H), 8.0 (d, J = 7.8 Hz, 1H), 7.36
(s, 1H), 7.28−7.23 (m, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 8.7
Hz, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.1 (s, 1H), 3.88 (s, 3H), 2.53−2.34
(m, 4H), 1.96−1.86 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 159.9,
152.8, 152.6, 147.7, 139.2, 136.1, 131.9, 128.1, 127.0, 125.8, 121.9,
120.2, 119.3, 114.0, 111.1, 110.4, 55.2, 28.1, 24.9, 22.5, 21.7; HRMS
(ESI) calcd for C24H23N2O [M + H] 355.1811, found 355.1825.
2-(4-Methoxyphenyl)-4-(4-methylphenyl)-7-(trifluoromethyl)-9H-
pyrido[2,3-b]indole (6c): white solid; yield = 74%; mp >250 °C; FT-
4-Cyclohex-1-en-1-yl-6-methyl-2-phenyl-9H-pyrido[2,3-b]indole
(6j): white solid; yield = 56%; mp 206−208 °C; FT-IR (KBr) νmax
1
2931, 1634, 1218 cm−1; H NMR (300 MHz, DMSO-d6) δ 11.71 (s,
1H), 8.10 (d, J = 7.2 Hz, 2H), 7.68 (s, 1H), 7.47−7.32 (m, 5H), 7.19
(d, J = 7.4 Hz, 1H), 5.98 (s, 1H), 2.45−2.44 (m, 2H), 2.39 (s, 3H),
2.25 (s, 2H), 1.85−1.75 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ
152.9, 152.8, 147.8, 139.5, 137.6, 136.2, 128.7, 128.6, 128.0, 127.4,
127.2, 126.8, 122.1, 120.3, 111.1, 111.0, 28.2, 24.9, 22.6, 21.8, 21.4;
HRMS (ESI) calcd for C24H23N2 [M + H] 339.1861, found 339.1873.
7-Fluoro-4-hexyl-2-phenyl-9H-pyrido[2,3-b]indole (6k): white
solid; yield = 44%; mp 150−152 °C; FT-IR (KBr) νmax 3157, 2946,
1450, 1222 cm−1; 1H NMR (300 MHz, CDCl3) δ 12.30 (s, 1H), 8.13
(d, J = 5.1 Hz, 2H), 7.86−7.88 (m, 1H), 7.55 (s, 3H), 7.42 (s, 1H),
6.92−6.90 (m, 1H), 5.95 (d, J = 8.9 Hz, 1H), 3.20 (s, 2H), 1.87−1.81
(m, 3H), 1.52−1.26 (s, 5H), 0.90 (s, 3H); 13C NMR (50 MHz,
CDCl3) δ 164.1, 153.9 (d, J = 15 Hz), 147.8, 140.6, 140.2 (d, J = 13
Hz), 129.4, 128.9, 128.1, 123.3 (d, J = 10 Hz), 117.3, 114.4, 113.7,
107.9 (d, J = 24 Hz), 98.4 (d, J = 27 Hz), 34.1, 31.8, 29.6, 29.2, 22.7,
14.2; HRMS (ESI) calcd for C23H24FN2 [M + H] 347.1923, found
347.1928.
4-(4-tert-Butylphenyl)-7-(trifluoromethyl)-2-phenyl-9H-pyrido-
[2,3-b]indole (6l): white solid; yield = 70%; mp 243−244 °C; FT-IR
(KBr) νmax 3044, 2957, 1522, 1249 cm−1; 1H NMR (300 MHz,
DMSO-d6) δ 12.43 (s, 1H), 8.25 (d, J = 7.0 Hz, 2H), 7.80−7.72 (m,
5H), 7.65 (d, J = 8.3 Hz, 2H), 7.55−7.44 (m, 3H), 7.39 (d, J = 8.6 Hz,
1H), 1.40 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 154.6, 153.4,
151.7, 146.2, 138.9, 138.7, 135.2, 129.1, 128.8, 128.3, 127.1, 126.5,
126.0, 125.7, 122.9, 122.5, 115.6, 113.7, 110.5, 108.1, 34.5, 31.1;
HRMS (ESI) calcd for C28H24F3N2 [M + H] 445.1891, found
445.1890.
1
IR (KBr) νmax 3245, 1522, 1249 cm−1; H NMR (300 MHz, DMSO-
d6) δ 12.36 (s, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.77−7.65 (m, 5H), 7.45
(d, J = 7.8 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H),
3.84 (s, 3H), 2.47 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 160.3,
154.5, 153.4, 146.2, 138.4, 135.3, 131.3, 129.4, 128.4, 128.4, 126.1 (t, J
= 32.3 Hz), 123.1,123.1, 122.9, 122.2, 115.5, 114.1, 112.9, 109.8, 108.0,
55.2, 20.9; HRMS (ESI) calcd for C26H20F3N2O [M + H] 433.1527,
found 433.1531.
4-Hexyl-2-(4-methoxyphenyl)-7-(trifluoromethyl)-9H-pyrido[2,3-
b]indole (6d): white solid; yield = 46%; mp 177−178 °C; FT-IR
(KBr) νmax 3051, 2948, 1574, 1218 cm−1; 1H NMR (300 MHz,
CDCl3) δ = 12.80 (s, 1H), 8.12 (d, J = 8.6 Hz, 2H), 8.04 (d, J = 8.1
Hz, 1H), 7.43−7.40 (m, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.59 (s, 1H),
3.90 (s, 3H), 3.25 (t, J = 7.5 Hz, 2H), 1.90−1.83 (m, 2H), 1.56−1.54
(m, 2H), 1.37−1.36 (m, 4H), 0.93−0.91 (m, 3H); 13C NMR (75
MHz, CDCl3) δ 161.0, 155.7, 154.0, 149.5, 138.3, 132.6, 129.5, 127.0
(t, J = 33 Hz), 123.5, 122.9, 122.4, 116.2, 114.8, 114.2, 112.6, 109.0,
55.4, 34.3, 31.9, 29.6, 29.3, 22.7, 14.2; HRMS (ESI) calcd for
C25H26F3N2O [M + H] 427.1998, found 427.1975.
7-Fluoro-2-(4-methoxyphenyl)-4-phenyl-9H-pyrido[2,3-b]indole
(6e): white solid; yield = 75%; mp >250 °C; FT-IR (KBr) νmax 3061,
1
2941, 1112 cm−1; H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H),
8.18 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 6.5 Hz, 2H), 7.66−7.58 (m, 4H),
7.49−7.44 (m, 1H), 7.25 (dd, J = 2.1, 9.6 Hz, 1H), 7.07 (d, J = 8.7 Hz,
2H), 6.92−6.85 (m, 1H), 3.83 (s, 3H); 13C NMR (150 MHz, DMSO-
d6) δ 162.4, 160.8, 160.5, 153.4 (d, J = 53 Hz), 145.1, 140.6 (d, J = 13
Hz), 138.9, 131.9, 129.3, 129.2, 128.9, 128.6, 123.3 (d, J = 10 Hz),
117.2, 114.5, 112.9, 110.9, 107.7 (d, J = 24 Hz), 98.2 (d, J = 26 Hz),
55.6; HRMS (ESI) calcd for C24H18FN2O [M + H] 369.1404, found
369.1415.
2,4-Diphenyl-7-(trifluoromethyl)-9H-pyrido[2,3-b]indole (6m):
white solid; yield = 75%; mp 238−240 °C; FT-IR (KBr) νmax 3034,
1
2868, 1593, 1232 cm−1; H NMR (300 MHz, DMSO-d6) δ 12.46 (s,
1H), 8.26 (d, J = 7.0 Hz, 2H), 7.80−7.76 (m, 4H), 7.71−7.45 (m,
7H), 7.38 (d, J = 8.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ
154.7, 153.4, 146.3, 138.9, 138.7, 138.1, 129.2, 129.1, 129.0, 128.8,
128.6, 127.1, 126.5, 126.1, 122.9, 122.4, 115.6, 113.6, 110.5, 108.2;
HRMS (ESI) calcd for C24H16F3N2 [M + H] 389.1265, found
389.1265.
4-(4-tert-Butylphenyl)-2-phenyl-9H-pyrido[2,3-b]indole (6f):
white solid; yield = 71%; mp 248−250 °C; FT-IR (KBr) νmax 3073,
1
2965, 1591, 1293 cm−1; H NMR (300 MHz, DMSO-d6) δ 12.04 (s,
1H), 8.22 (d, J = 7.2 Hz, 2H), 7.73 (d, J = 8.25 Hz, 2H), 7.66−7.62
(m, 4H), 7.53−7.49 (m, 3H), 7.46−7.39 (m, 2H), 7.04 (t, J = 7.2 Hz,
1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.4, 153.5,
152.0, 146.4, 140.4, 139.5, 136.4, 129.2, 128.9, 128.6, 127.9, 126.4,
125.8, 122.6, 120.9, 119.6, 114.7, 113.0, 111.4, 34.9, 31.6; HRMS
(ESI) calcd for C27H25N2 [M + H] 377.2017, found 377.2024.
4-(4-Methylphenyl)-2-phenyl-9H-pyrido[2,3-b]indole (6g): white
solid; yield = 77%; mp 221−223 °C; FT-IR (KBr) νmax 3087, 2953,
1458, 1217 cm−1; 1H NMR (300 MHz, CDCl3) δ 11.31 (s, 1H), 8.19
(d, J = 6.8 Hz, 2H), 7.70−7.64 (m, 3H), 7.56−7.45 (m, 4H), 7.39 (d, J
= 7.7 Hz, 2H), 7.21 (d, J = 7.3 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 6.72
(d, J = 8.0 Hz, 1H), 2.51 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
153.0, 152.7, 145.1, 139.5, 139.3, 138.2, 135.7, 129.3, 128.7, 128.5,
126.9, 126.4, 121.8, 119.9, 119.2, 112.9, 111.4, 111.3, 111.3, 20.9;
HRMS (ESI) calcd for C24H19N2 [M + H] 335.1548, found 335.1564.
7-Fluoro-4-(4-methylphenyl)-2-phenyl-9H-pyrido[2,3-b]indole
(6n): white solid; yield = 71%; mp >250 °C; FT-IR (KBr) νmax 3092,
1
2940, 1509, 1212 cm−1; H NMR (300 MHz, DMSO-d6) δ 12.17 (s,
1H), 8.20 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 8.0 Hz, 3H), 7.58−7.49 (m,
3H), 7.46−7.43 (m, 3H), 7.25 (dd, J = 2.3, 9.6 Hz, 1H), 6.90 (td, J =
2.3, 9.6 Hz, 1H), 2.46 (s, 3H); 13C NMR (50 MHz, DMSO-d6) δ
163.7, 158.9, 153.2, 152.8, 144.8, 140.4 (d, J = 13 Hz), 139.2, 138.4,
135.5, 129.5, 128.8, 128.5, 126.9, 123.2 (d, J = 10 Hz), 116.7, 113.3,
111.2, 107.3 (d, J = 24 Hz), 97.9 (d, J = 32 Hz), 20.9; HRMS (ESI)
calcd for C24H18FN2 [M + H] 353.1454, found 353.1442.
2,4-Bis(4-methylphenyl)-9H-pyrido[2,3-b]indole (6o): white solid;
yield = 70%; mp 245−247 °C; FT-IR (KBr) νmax 3057, 2973, 1588,
1298 cm−1; 1H NMR (300 MHz, CDCl3) δ 10.94 (s, 1H), 8.1 (d, J =
10160
dx.doi.org/10.1021/jo201994v | J. Org. Chem. 2011, 76, 10154−10162

The Journal of Organic Chemistry
Article
8.0 Hz, 2H), 7.69−7.63 (m, 3H), 7.53 (s, 1H), 7.41−7.32 (m, 4H),
7.25−7.22 (m, 1H), 7.03−6.98 (m, 1H), 6.84 (d, J = 8.1 Hz, 1H), 2.51
(s, 3H), 2.44 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 153.6, 153.1,
145.6, 139.9, 138.7, 138.6, 136.9, 136.2, 129.8, 129.7, 128.9, 127.2,
126.8, 122.1, 120.4, 119.6, 113.0, 111.8, 111.6, 21.4, 21.3; HRMS
(ESI) calcd for C25H21N2 [M + H] 349.1704, found 349.1690.
4-(4-tert-Butylphenyl)-2-(4-methylphenyl)-9H-pyrido[2,3-b]indole
(6p): white solid; yield = 69%; mp >250 °C; FT-IR (KBr) νmax 3047,
(d, J = 8.3 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.82 (s,
3H), 2.47 (s, 3H), 2.28 (s, 3H); 13C NMR (50 MHz, DMSO-d6) δ
152.9, 149.7, 149.0, 145.1, 138.3, 137.7, 136.0, 132.2, 129.4, 128.6,
127.7, 127.6, 121.6, 120.2, 119.6, 112.4, 111.8, 111.1, 110.7, 110.2,
55.6, 21.4, 21.0; HRMS (ESI) calcd for C27H25N2O2 [M + H]
409.1916, found 409.1898.
2-(3,4-Dimethoxyphenyl)-4-phenyl-7-(trifluoromethyl)-9H-
pyrido[2,3-b]indole (6w): white solid; yield = 66%; mp 158−160 °C;
FT-IR (KBr) νmax 2946, 2836, 1449, 1221 cm−1; 1H NMR (300 MHz,
DMSO-d6) δ 12.45 (s, 1H), 7.85 (d, J = 7.0 Hz, 2H), 7.79−7.74 (m,
4H), 7.66−7.64 (m, 4H), 7.36 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.9 Hz,
1H), 3.90 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ
154.6, 153.3, 150.1, 149.0, 146.2, 138.5, 138.3, 131.6, 129.0, 128.6,
126.6, 126.2, 125.8, 123.0, 122.2, 119.9, 115.6, 113.1, 111.7, 110.3,
110.0, 108.1, 55.6; HRMS (ESI) calcd for C26H20F3N2O2 [M + H]
449.1477, found 449.1477.
1
2955, 1450, 1025 cm−1; H NMR (300 MHz, DMSO-d6) δ 12.00 (s,
1H), 8.13 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.66−7.61 (m,
4H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.0
Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H), 2.38 (s, 3H), 1.40 (s, 9H); 13C
NMR (50 MHz, DMSO-d6) δ 153.1, 152.7, 151.4, 145.0, 139.5, 138.3,
136.5, 135.8, 129.4, 128.4, 126.8, 126.3, 125.6, 121.7, 120.0, 119.2,
112.7, 111.3, 111.1, 34.6, 31.2, 20.8; HRMS (ESI) calcd for C28H27N2
[M + H] 391.2174, found 391.2161.
4-Cyclohex-1-en-1-yl-7-fluoro-2-(3,4-dimethoxyphenyl)-9H-
6-Methyl-2-(4-methylphenyl)-4-phenyl-9H-pyrido[2,3-b]indole
pyrido[2,3-b]indole (6x): pale yellow solid; yield = 52%; mp 222−224
(6q): white solid; yield = 74%; mp 224−226 °C; FT-IR (KBr) νmax
1
°C; FT-IR (KBr) νmax 3097, 2958, 1509, 1259 cm−1; H NMR (300
1
3063, 2995, 1587, 1217 cm−1; H NMR (300 MHz, DMSO-d6) δ
MHz, DMSO-d6) δ 12.02 (s, 1H), 7.96−7.91 (m, 1H), 7.75 (d, J = 9.0
Hz, 2H), 7.50 (s, 1H), 7.22 (dd, J = 2.1, 9.6 Hz, 1H), 7.08−7.00 (m,
2H), 6.04 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 2.50 (s, 2H), 2.30 (s,
2H), 1.90−1.81 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 161.0 (d,
J = 239 Hz), 152.4 (d, J = 32 Hz), 149.7, 148.9, 147.4, 140.1 (d, J = 12
Hz), 135.9, 132.0, 127.3, 123.4 (d, J = 11 Hz), 119.5, 117.0, 111.7,
110.9, 110.2, 110.1, 107.3 (d, J = 24 Hz), 97.7 (d, J = 27 Hz), 55.6,
28.1, 24.9, 22.6, 21.7; HRMS (ESI) calcd for C25H24FN2O2 [M + H]
403.1822, found 403.1819.
11.88 (s, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.77−7.74 (m, 2H), 7.66−7.58
(m, 4H), 7.40 (d, J = 8.2 Hz, 1H), 7.32−7.30 (m, 3H), 7.22 (d, J = 8.2
Hz, 1H), 2.37 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
δ 152.9, 152.8, 144.9, 138.8, 138.2, 137.7, 136.6, 129.3, 128.7, 128.6,
127.7, 127.6, 126.7, 121.5, 120.0, 112.4, 112.4, 111.1, 110.9, 21.2, 20.8;
HRMS (ESI) calcd for C25H21N2 [M + H] 349.1704, found 349.1704.
7-Fluoro-2-(4-methylphenyl)-4-phenyl-9H-pyrido[2,3-b]indole
(6r): white solid; yield = 76%; mp >250 °C; FT-IR (KBr) νmax 3088,
1
2922, 1590, 1210 cm−1; H NMR (300 MHz, DMSO-d6) δ 12.17 (s,
2-tert-Butyl-4-phenyl-9H-pyrido[2,3-b]indole (6y): pale yellow
1H), 8.12 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 6.4 Hz, 2H), 7.64−7.59 (m,
4H), 7.51−7.46 (m, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.27−7.24 (m,
1H), 6.92−6.87 (m, 1H), 2.38 (s, 3H); 13C NMR (50 MHz, DMSO-
d6) δ 153.1, 153.0, 144.7, 140.5, 138.5, 136.4, 129.4, 128.9, 128.6,
126.8, 123.1, 123.0, 116.7, 112.9, 110.9, 107.5, 107.1, 98.1, 97.6, 20.8
ppm; HRMS (ESI) calcd for C24H18FN2 [M + H] 353.1454, found
353.1459.
4-(4-tert-Butylphenyl)-7-fluoro-2-(4-methylphenyl)-9H-pyrido-
[2,3-b]indole (6s): white solid; yield = 69%; mp >250 °C; FT-IR
(KBr) νmax 3004, 2965, 1599, 1216 cm−1; 1H NMR (300 MHz,
DMSO-d6) δ 12.15 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.79−7.53 (m,
6H), 7.30−7.21 (m, 3H), 6.93−6.86 (m, 1H), 2.35 (s, 3H), 1.37 (s,
9H); 13C NMR (100 MHz, DMSO-d6) δ 162.4, 160.0, 153.1 (d, J = 30
Hz), 151.5, 144.7, 140.3 (d, J = 13 Hz), 138.3, 136.4, 135.6, 129.4,
128.3, 126.8, 125.7, 123.1 (d, J = 10 Hz), 116.8, 113.1, 110.8, 107.3 (d,
J = 24 Hz), 97.8 (d, J = 26 Hz), 34.6, 31.2, 20.8; HRMS (ESI) calcd
for C28H26FN2 [M + H] 409.2080, found 409.2084.
solid; yield = 10%; mp 202−204 °C; FT-IR (KBr) νmax 3154, 2942,
1
1513, 1256 cm−1; H NMR (300 MHz, CDCl3) δ 9.68 (s, 1H), 7.69
(d, J = 6.5 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.56−7.46 (m, 3H),
7.37−7.29 (m, 2H), 7.18 (s, 1H), 7.02−6.97 (m, 1H), 1.50 (s, 9H)
13C NMR (75 MHz, CDCl3) δ 166.8, 152.3, 145.6, 139.8, 138.8, 128.9,
128.8, 128.6, 126.2, 122.5, 121.2, 119.6, 112.8, 111.4, 111.0, 37.9, 30.8;
HRMS (ESI) calcd for C21H21N2 [M + H] 301.1705, found 301.1706.
2-Phenyl-9H-pyrido[2,3-b]indole (6z): pale yellow solid; yield =
42%; mp 242−244 °C (lit.27 mp 245−246); FT-IR (KBr) νmax 3134,
1
2931, 1601, 1449 cm−1; H NMR (400 MHz, DMSO-d6) δ 11.87 (s,
1H), 8.53 (d, J = 8.1 Hz, 1H), 8.18−8.14 (m, 3H), 7.77 (d, J = 8.1 Hz,
1H), 7.53−7.40 (m, 5H), 7.22 (t, J = 7.4 Hz, 1H); 13C NMR (100
MHz, DMSO-d6) δ 152.9, 152.1, 139.5, 139.4, 129.2, 128.7, 128.6,
126.7, 126.6, 121.1, 120.4, 119.5, 114.3, 111.9, 111.3; HRMS (ESI)
calcd for C17H13N2 [M + H] 245.1079, found 245.1065.
ASSOCIATED CONTENT
4-Cyclohex-1-en-1-yl-7-(trifluoromethyl)-2-(4-methylphenyl)-9H-
■
pyrido[2,3-b]indole (6t): white solid; yield = 58%; mp >250 °C; FT-
S
* Supporting Information
1
IR (KBr) νmax 3099, 2917, 1595, 1232 cm−1; H NMR (300 MHz,
1
Copies of H and 13C NMR, HRMS spectra of all obtained
DMSO-d6) δ 12.27 (s, 1H), 8.17−8.10 (m, 3H), 7.77 (s,1H), 7.59 (s,
1H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 6.09 (s, 1H),
2.50 (s, 2H), 2.38 (s, 3H), 2.32 (s, 2H), 1.91−1.82 (m, 4H); 13C NMR
(50 MHz, DMSO-d6) δ 154.6, 153.4, 149.0, 138.6, 135.9 (d, J = 27
Hz), 129.4, 128.6 (d, J = 22 Hz), 127.8, 127.1, 126.9, 125.7, 123.2,
122.8, 122.5, 115.7, 111.5, 109.9, 108.0, 28.1, 24.9, 22.5, 21.6, 20.8;
HRMS (ESI) calcd for C25H22F3N2 [M + H] 407.1735, found
407.1740.
compounds, and 2D spectra of 6a. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +91 522 2612411-18. Fax: +91 522 2623405. E-mail:
bijoy_kundu@yahoo.com, b_kundu@cdri.res.in.
■
2-(3,4-Dimethoxyphenyl)-4-phenyl-9H-pyrido[2,3-b]indole (6u):
pale yellow solid; yield = 64%; mp 211−213 °C; FT-IR (KBr) νmax
1
2953, 1452, 1261 cm−1; H NMR (300 MHz, DMSO-d6) δ 12.04 (s,
ACKNOWLEDGMENTS
■
1H), 7.83−7.75 (m, 4H), 7.66−7.58 (m, 4H), 7.49 (d, J = 5.7 Hz,
2H), 7.38 (t, J = 7.7 Hz, 1H), 7.09−6.99 (m, 2H), 3.89 (s, 3H), 3.83
(s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 153.1, 152.6, 149.7, 149.0,
145.1, 139.5, 138.8, 132.0, 128.8, 128.7, 128.7, 126.3, 121.6, 120.0,
119.7, 119.2, 112.4, 111.8, 111.4, 110.9, 110.2, 55.6; HRMS (ESI)
calcd for C25H21N2O2 [M + H] 381.1603, found 381.1602.
2-(3,4-Dimethoxyphenyl)-6-methyl-4-(4-methylphenyl)-9H-
pyrido[2,3-b]indole (6v): orange solid; yield = 70%; mp 211−212 °C;
FT-IR (KBr) νmax 3194, 2952, 1514, 1259 cm−1; 1H NMR (300 MHz,
DMSO-d6) δ 11.87 (s, 1H), 7.79−7.75 (m, 2H), 7.65 (d, J = 7.9 Hz,
2H), 7.55 (s, 1H), 7.44 (d, J = 7.8 Hz, 2H), 7.39−7.37 (m, 2H), 7.21
S.G. is thankful to CSIR, New Delhi, India, for fellowships. We
thank SAIF and Dr. Ashish Arora, Division of Molecular and
Structural Biology, CSIR-CDRI, India for providing NMR data.
CDRI Communication No. 8156.
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