Syntheses of 4-indolylquinoline derivatives via reductive cyclization of indolylnitrochalcone derivatives by Fe/HCl

Article abstract of DOI:10.3390/molecules201219862

An easy and efficient procedure for the synthesis of 4-indolylquinoline derivatives is described. This process involves two steps, the first of which is the Michael addition of indole to nitrochalcones promoted by sulfamic acid under solvent free conditions and the second step is a reductive cyclization of the indolylnitrochalcone intermediates to 4-indolylquinoline derivatives by Fe/HCl in ethanol. In both steps, the reactions are clean and the yields of products are high.

Full text of DOI:10.3390/molecules201219862

Article
Syntheses of 4-Indolylquinoline Derivatives via
Reductive Cyclization of Indolylnitrochalcone
Derivatives by Fe/HCl
†
†
Wen-Chang Chen , Chan-Chieh Lin , Veerababurao Kavala, Chun-Wei Kuo, Chia-Yu Huang and
Ching-Fa Yao *
Received: 23 November 2015 ; Accepted: 8 December 2015 ; Published: 15 December 2015
Academic Editor: Wim Dehaen
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Ting-Chow Road, Taipei 116,
Taiwan; wcchen@taigenbiotech.com (W.-C.C.); ntnu21236@gmail.com (C.-C.L.);
kavalaveeru@gmail.com (V.K.); cwkuo.water@gmail.com (C.-W.K.); tlotras@gmail.com (C.-Y.H.)
*
†
Correspondence: cheyaocf@ntnu.edu.tw or cheyaocf@yahoo.com.tw; Tel.: +886-2-29309092
These authors contributed equally to this work.
Abstract: An easy and efficient procedure for the synthesis of 4-indolylquinoline derivatives is
described. This process involves two steps, the first of which is the Michael addition of indole
to nitrochalcones promoted by sulfamic acid under solvent free conditions and the second step is a
reductive cyclization of the indolylnitrochalcone intermediates to 4-indolylquinoline derivatives by
Fe/HCl in ethanol. In both steps, the reactions are clean and the yields of products are high.
Keywords: Fe/HCl; reductive cyclization; 4-indolylquinoline; indolylchalcone
1
. Introduction
Indole and quinoline are two important class of structural scaffolds that are found in a vast
number of natural products and pharmaceutically active compounds [1–6]. Compounds containing
both indole and quinoline rings are called as indolylquinolines and are known to exhibit a wide
variety of biological activities, including antibiotic, antimicrobial and antifungal activities [7–12].
Although different kinds of indolylquinoline derivatives are known in the literature, three types of
indolylquinoline derivatives such as 2-indolylquinoline, 3-indolylquinoline, and 4-indolylquinoline
are frequently found in many bioactive compounds. For example, 2-indolylquinoline [13,14]
exhibit antistaphylococcal activities, 3-indolylquinolines [15–18] inhibit the activity of PDGF-RTK,
4
-indolylquinolines [19–22] have been known for potential treatments for allergic rhinitis, asthma
and other inflammatory diseases (Figure 1) [13,14].
Figure 1. Bioactive indolylquinolines derivatives.
Molecules 2015, 20, 22499–22519; doi:10.3390/molecules201219862
www.mdpi.com/journal/molecules

Molecules 2015, 20, 22499–22519
A vast number of protocols are available for the synthesis of 2-indolylquinoline and
3
4
-indolyl-quinoline derivatives [15–18], however, methods which describe the synthesis of
-indolylquinoline derivatives are limited [19–22]. Marinelli and coworkers described a one-pot
synthesis of 4-indolyl-quinoline derivatives from β-(2-aminophenyl)-α,β-ynones [23]. Recently, we
reported a method for accessing 4-indolylquinoline derivatives through an inverse electron-demand
aza-Diels-Alder reaction [24]. Some of these reported procedures required functionalized quinoline
derivatives such as haloquinolines or indolylboronic acid derivatives and a few methods are
associated with the use of expensive metal catalysts and starting materials. Hence, a simple and
handy method for the synthesis of 4-indolylquinoline derivatives from easily available starting
materials is desirable.
For the past decade, we have been working on the use of reductive cyclization reactions [25–32]
to generate a wide variety of nitrogen heterocycles, including indolylquinoline derivatives,
1
3
,3 -biindoles, quinoline derivatives, 2H-1,4-benzoxazin-3-(4H)-ones, carbazolone derivatives,
2
,3-disubstituted indole derivatives, acridinones and phenathridine derivatives by using Fe/AcOH
as a reagent [33–36]. In continuation to our interest on reductive cyclization reactions, we proposed to
synthesize 4-indolylquinoline derivatives in two steps starting from 2-nitrochalcone derivatives and
indoles. The proposed strategy for the synthesis of 4-indolyl quinoline derivatives is shown in the
Scheme 1. This strategy involves two steps: a Michael addition of indole to 2-nitrochalcone followed
by the reductive cyclization.
Scheme 1. The proposed strategy for the synthesis of 4-indolyl quinoline derivatives.
2
. Results and Discussion
To execute our strategy, we need to synthesize the Michael adducts of indoles and various
-nitrochalcone derivatives. Although, several procedures describe the Michael addition reactions
2
of indoles to chalcones [37–42], to our knowledge there is no procedure available for the Michael
addition of 2-nitrochalcone with indole derivatives. On the other hand, we have reported Michael
addition reactions of various 2-nitroalkenes and indoles using sulfamic acid as a catalyst under
solvent free conditions to obtain the corresponding indolylnitroalkane derivatives in good to excellent
yields [30]. We wished to adopt similar conditions to synthesize our starting materials, thus
˝
we tested the reaction of indole, 2-nitrochalcone, and sulfamic acid at the temperature of 90 C
under solvent free conditions. To our delight, the reaction was complete in 4 h and provided the
corresponding 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one derivative was obtained in
good yield (Table 1, Entry 1).
Encouraged by this result, we applied these reaction conditions to synthesize various substituted
indolylnitrochalcones. The reactions of indole with nitrochalcone derivatives with halogen group (F,
Cl and Br) containing 2-nitrobenzalehydes and acetophenone proceeded quickly and afforded the
desired products in good to excellent yields (Table 1, Entries 2–4). On the other hand, the reactions of
indole with nitrochalcone derivatives derived from 2-nitrobenzaldehyde and ortho halogen group (Cl
or Br) substituted acetophenones took place smoothly to provide the corresponding Michael adducts
in quantitative yields.
22500

Molecules 2015, 20, 22499–22519
Table 1. Michael addition of various 2-nitrochalcones and indole.
Entry a
Nitrochalcone
Indole
2a
Product
Time (h)
Yield % b
O
NH
O
1
4.0
83
NO
2
1
a
NO23a
NH
O
F
O
2
3
4
2a
2a
2a
0.5
1.0
2.5
76
89
99
F
NO
2
1
b
NO23b
NH
O
O
Cl
Br
Cl
Br
NO2
1
c
NO23c
NH
O
O
NO
2
1
d
NO23d
O
Cl
5
2a
2.5
99
NO2
1
e
O
Br
6
7
8
9
2a
2a
2a
2a
2.5
2.0
2.5
2.5
99
99
99
93
NO
2
1
f
NH
O
O
NO
2
1
g
NO
2
3g
NH
O
O
NO
2
O
1
h
NO
2
3h
O
NH
O
O
O
O
O
O
NO
2
1
i
NO
2
3i
NH
O
O
1
1
0
1
2a
2a
3
98
93
NO
2
1
j
NO
2
3j
NH
O
S
O
10
S
NO
2
1
k
NO
2
3k
a
All reactions were carried out by using 1.0 equiv. of 1 and 1.2 equiv. of 2a in the presence of 50 mol % of
b
sulfamic acid; Isolated yields.
22501

Molecules 2015, 20, 22499–22519
Next, we investigated the reactions of unsubstituted nitrochalcone and various substituted
indoles (Table 2).
Table 2. Michael addition of 2-nitrochalcone (1a) and various indoles.
NH
O
H
O
N
sulfamic acid
neat, 90 o
C
NO2
R1
NO2
R2
1a
2a
3
Entry a
Nitrochalcone
Indole
2b
Product
Time (h)
Yield % b
NH
H
N
F
O
1
2.0
1.5
81
1
a
F
NO2 3l
NH
O
Cl
H
N
2
2c
85
1
a
Cl
NO2 3m
NH
O
Br
H
N
3
4
2d
2e
3.0
1.0
89
99
1
a
Br
NO2
3n
NH
H
MeO
N
O
1
a
MeO
2
NO 3o
NH
H
N
O
5
2f
1.0
1.0
90
97
1
a
NO
2
3
p
N
N
O
6
7
2g
1
a
NO
2
3q
NH
H
N
O
2h
2i
2.0
72
70
65
1a
NO2
3r
NH
Ph
O
H
N
8
1a
Ph
3
2
s
NO
a
All reactions were carried out by using 1.0 equiv. of 1 and 1.2 equiv. of 2a in the presence of 50 mol % of
b
sulfamic acid; Isolated yields.
When nitrochalcone was treated with electron-withdrawing group containing indoles such as
-fluoroindole, 5-chloroindole and 5-bromoindole, the reactions produced the corresponding Michael
5
adducts in good yields. On the other hand, the reactions of nitrochalcone and electron-donating
indoles such as 5-methoxyindole and 6-methylindole provided its corresponding Michael adducts
in excellent yields. Next, the reaction of N-methylindole and 2-nitrochalcone afford the desired
Michael adduct in excellent yield. Further, the reaction of 2-nitrochalcone with 2-phenylindole
22502

Molecules 2015, 20, 22499–22519
or 2-methylindole afforded the corresponding Michael adducts in moderate yields. Moreover, the
reactions of 2-nitrochalcone with 2-phenylindole or 2-methylindole took longer to go to completion
(
Table 2).
After the preparation of various substituted 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenyl-
propan-1-one derivatives, we then focused on the reductive cyclization of these compounds to
-indolylquinoline derivatives. Initially, we treated 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenyl-
propan-1-one with the standard reductive cyclization agent Fe/AcOH [9] (Table 3, entry 1). Under
4
1
13
these conditions the reaction afforded two compounds. From the H- and C-NMR spectral data and
mass spectral analysis, it was revealed that the major product was the 4-indolylquinoline derivative
and the minor product was the indole-eliminated 2-phenylquinoline derivative.
Then, we tried Zn as reducing reagent (Table 3, entries 2 and 3), but the results were not
encouraging. As it is reported in the literature [43,44] that Fe/HCl is an efficient reductive cyclizing
agent, next, we used Fe/HCl in EtOH (Table 3, entry 4) for this transformation. To our delight,
the reaction produced the indolylquinoline derivative in excellent yield without any of the minor
product. Further, when the reaction was performed using a mixed solvent such as ethanol and water
(1:1), the reaction afforded an excellent yield of the 4-indolylquinoline derivative (Table 3, entry 5).
However, the reaction time was longer in this case. Furthermore, when the reaction was performed
in methanol it resulted in a decreased yield of the desired product (Table 3, entry 6). From the
optimization results, the reaction condition using Fe/HCl in ethanol at reflux temperature (Table 3,
entry 5) were found to be the best condition for the synthesis of 4-indolylquinoline derivatives from
the corresponding 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one derivatives (Table 3).
Table 3. Optimization studies for reductive cyclization of 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-
phenylpropan-1-one (3a)
.
Entry a
Reductant
Solvent
Time (h)
Yield of 4a (%) b
Yield of 5a (%) b
1
2
3
4
5
Fe
Zn
AcOH
AcOH
0.5
10
2.0
1.0
4.0
10
72
16
0
90
88
57
24
21
0
0
0
c
d
Zn
Fe
Fe
Fe
THF–H O
2
e
EtOH
e
f
EtOH–H O
2
e
6
MeOH
0
a
a (1.0 equiv.), metal (6.0 equiv.), solvent (10 mL); b Isolated yields; c NH4Cl (1.1 equiv.); d THF–H2O (2:1);
3
e
HCl (1.0 equiv.); f EtOH–H2O (4:1).
Having the optimized reaction conditions in hand, we then investigated the scope and
limitations of this protocol. As shown in Table 4, 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-
1
-one (3a) reacted under optimized reaction conditions to produce the 4-indolyl-quinoline derivatives
in excellent yield.
Under the present reaction conditions, the substrates containing electron-withdrawing groups
F, Cl and Br) in the nitrochalcone part of 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one
(
reacted well and afforded the corresponding 4-indolyl-quinoline derivatives in good yields,
while the reactions of the substrates possessing electron-donating groups provided the
desired 4-indolylquinoline derivatives in excellent yields. Moreover, the substrate bearing a
naphthalene ring also provided the corresponding product in 93% yield under the present
reaction conditions. Next, the 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one derivative
containing a thiophene group was also reacted under the present reaction conditions to obtain the
corresponding indolylquinoline derivative in excellent yield (Table 4).
22503

Molecules 2015, 20, 22499–22519
Table 4. Reductive cyclization of substituted 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one
derivatives derived from various 2-nitrochalcone and indoles.
Entry a
Indolylnitrochalcone
Product
Time (h)
Yield (%) b,c
NH
O
1
4.0
83
NO
2
3a
NH
O
2
3
4
0.5
1.0
2.5
76
89
99
F
NO2 3b
H
N
NH
O
Cl
Cl
N
NO
2
3
c
4c
H
N
NH
O
Br
Br
N
NO
NH
2
3d
4
d
H
N
Cl
O
Cl
5
6
2.5
2.5
99
99
N
NO
2
3
e
4e
H
NH
N
O
Br
Br
NO
2
N
3f
4f
H
N
NH
O
7
8
9
2.0
2.5
2.5
99
99
93
N
NO
2
4g
H
N
NH
O
OMe
N
NO
2
O
3h
4h
NH
O
O
O
NO
2
3
i
H
N
NH
O
1
1
0
1
3
93
93
NO
2
N
4j
3
j
H
NH
N
O
S
S
10
N
NO
2
3
k
4k
a
Condition: 3 (1.0 equiv.), Fe (6.0 equiv.), HCl (1.0 equiv.), EtOH (10 mL); b Isolated yields; c no trace of 5
was observed.
22504

Molecules 2015, 20, 22499–22519
Next, we investigated the reactions of Michael adducts derived from nitrochalcone and various
indoles. As shown in the Table 5, the 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one
derivatives derived from electron poor indoles (fluoro-, chloro-, and bromoindoles) underwent
a smooth reductive cyclization to afford the desired 4-indolylquinoline derivatives in excellent
yield, whereas, the substrates derived from the electron rich indoles produced the corresponding
indolylquinoline derivatives in slightly lower yields than those of electron poor indoles. It is
notable that the reactions of the substrate obtained from 2-phenyl or 2-methylindole provided the
corresponding 4-indolylquinoline derivative in moderate yield along with a substantial amount of
the indole cleaved product as byproduct. These results show that steric hindrance influences the
elimination of indole to produce the indole-cleaved product (Table 5).
To further examine the influence of steric hindrance, we investigated the reactions of
the 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one substrates containing a methyl group
adjacent to the nitro group as well the substrates derived from 2,5-dimethylindoles. As shown in the
Table 6, steric hindrance adjacent to the nitro group has less influence on the reaction outcome, as the
substrate 3t gave the corresponding indolylquinoline in good yield along with traces of the indole
cleaved product. However, when the substrate 3u derived from 2,5-dimethylindole was treated
under the present reaction conditions, we obtained 66% of indolylquinoline derivative and 30% of
indole-cleaved product. Furthermore, we obtained only indole-cleaved product, when the substrate
3
v containing a methyl group adjacent to the nitro as well as the second indole position was used.
It is important to note that the reactions took longer when the methyl group was adjacent to the nitro
group as in case of entries 2, 3 in Table 6.
Table 5. Reductive cyclization of 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one derivatives
derived from various indoles and 2-nitrochalcone.
Entry a
Indolylnitrochalcone
Product
Time (h)
Yield % b
H
N
NH
O
F
1
1.5
99
F
N
4l
NO2 3l
H
N
NH
Cl
O
2
1.5
99
Cl
N
NO2 3m
4m
H
N
NH
O
Br
3
4
1.5
1.0
99
82
Br
N
NO2
4n
3n
H
NH
O
N
MeO
MeO
N
NO2 3o
4o
22505

Molecules 2015, 20, 22499–22519
Table 5. Cont.
Entry a
Indolylnitrochalcone
Product
Time (h)
Yield % b
H
N
5
1.0
85
N
4
p
N
O
N
6
7
1.0
3.0
6.0
83
NO
2
N
3
q
4q
H
N
NH
O
66 c
N
4r
NO
2
3r
H
N
NH
Ph
O
Ph
57 d
8
N
NO2 3s
4s
a
Condition: 3 (1.0 equiv.), Fe (6.0 equiv.), HCl (1.0 equiv.), EtOH (10 mL); b Isolated yields; c 17% of product 5
formed along with 4r (66%); d 30% of 5 formed along with 4s (57%)
Table 6. Reductive cyclization of sterically hindered 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-
1
-one derivatives.
Entry a
Substrate
Solvent
Time (h)
Yield of 4 (%) b
Yield of 5 (%) b
NH
1
24
85
8
N
4t
NH
O
2
1.0
66
30
70
NO
2
3
u
3
24
0
a
Condition: 3 (1.0 equiv.), Fe (6.0 equiv.), HCl (1.0 equiv.), EtOH (10 mL); b Isolated yields.
22506

Molecules 2015, 20, 22499–22519
A reaction mechanism for the formation of the indolylquinoline as well as the indole-cleaved
product from 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3a) is proposed based
on our previous work (Scheme 2). Initially, the nitro group of the 3-(1H-indol-3-yl)-3-(2-
nitrophenyl)-1-phenylpropan-1-one (3a) is reduced to an amino group by Fe/HCl, then it attacks the
carbonyl group in the presence of FeCl in the solvent, forming a dihydroquinoline intermediate. The
3
dihydroquinoline intermediate compound is unstable, and undergoes aromatization by the loss of
hydrogen or the indole moiety to give either 4a or 5a. Besides, we also anticipate that indolylquinoline
derivative 4a may also undergo a slow decomposition to indole-cleaved product 5a through reductive
elimination. To explore this reductive elimination possibility, the indolylquinoline 4a was treated with
Fe/AcOH under the identical conditions used in the preparation of indolylquinoline derivatives. We
obtained around 14% of indole-cleaved product along with 82% of the unchanged indolylquinoline
4
a after 24 h. The result was similar even when reaction was conducted with Fe/HCl used as
reagent in ethanol. However, when the reaction was performed with FeCl , the indolylquinoline
3
was unchanged. From these experiments, we cannot exclude this route for the formation of the
indole-cleaved product.
Scheme 2. Mechanistic route for the reductive cyclization of 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-
1
-phenylpropan-1-one derivatives.
3
. Experimental Section
3
.1. General Information
All chemicals were purchased from various commercial sources and used directly without
further purification. Analytical thin-layer chromatography was performed using E. Merck (New York,
NY, USA) silica gel 60F glass plates and E. Merck silica gel 60 (230–400 mesh) was used in flash
chromatography separations. MS were measured by a JMS-HX110 spectrometer (JEOL, Hsinchu,
1
Japan). HRMS spectra were recorded using ESI-TOF or EI+ mode or FAB+. H- (400 MHz) and
13
C-NMR (100 MHz) spectra were recorded with an Advance EX 400 MHz spectrometer (Bruker, San
Francisco, CA, USA). Chemical shifts are reported in parts per million (δ) using TMS as an internal
standard and coupling constant were expressed in hertz. IR spectra were performed on a 100 series
FT-IR instrument (Perkin Elmer, Waltham, MA, USA). Melting points were recorded using a capillary
melting point apparatus (Electrothermal, Staffordshire, UK) and are uncorrected. All substrates were
prepared using literature procedures.
22507

Molecules 2015, 20, 22499–22519
3
.2. General Procedure for the Reaction of Indoles with Nitrochalcones to give Products 3a–3v
The mixture of nitrochalcone (2.0 mmol), indole (2.2 mmol), and sulfamic acid (1 mmol,
˝
0
.5 eq.) was heated at 90 C until the complete consumption of starting materials, which was
monitored by TLC. Then, the reaction mixture was allowed to cool to room temperature, diluted
with ethyl acetate (20 mL) and washed with water, followed by brine. The organic layer was
separated, dried over anhydrous MgSO , and concentrated in vacuum to obtain the crude product.
4
The residue was purified by flash column chromatography (petroleum ether/ethyl acetate) to obtain
1
13
the desired products 3a–3v. (The H-, C-NMR spectra of the compounds (3a–3v) was showed
in Supplementary).
3
-(1H-Indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3a): Pale crystalline yellow solid (crystallized
˝
from ethyl acetate and hexane) with a melting point of 176–178 C; IR (KBr): 3320, 3050, 1684, 1525,
´
1 1
1
7
1
7
1
354, 741 cm . H-NMR (DMSO-d ) δ 10.99 (s, 1H), 8.00 (d, J = 7.5 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H),
6
.61 (d, J = 6.3 Hz, 2H), 7.54–7.48 (m, 3H), 7.42–7.36 (m, 2H), 7.38–7.33 (m, 2H), 7.04 (t, J = 7.3 Hz,
H), 6.90 (t, J = 4.7 Hz, 1H), 5.45 (t, J = 6.8 Hz, 1H), 4.04 (dd, J = 18.0, 6.4 Hz, 1H), 3.88 (dd, J = 18.0,
.6 Hz, 1H); 13C-NMR (DMSO-d ) δ 197.8, 149.7, 138.0, 136.4, 136.4, 133.3, 132.6, 130.1, 128.6, 128.0,
6
27.2, 126.2, 123.7, 123.1, 121.2, 118.6, 118.4, 116.2, 111.5, 44.5, 31.5; MS (EI) m/z (relative intensity) 370
+
+
(M , 36), 353 (47), 251 (100), 231 (59), 204 (65), 105 (87); HRMS (EI) m/z calcd for C H N O (M )
23 18 2 3
3
70.1317, found 370.1310.
3-(5-Fluoro-2-nitrophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (3b): Purified by column chromatography
using 1:5 ethyl acetate and hexane. After concentration in vacuo it give a brown oil; IR (KBr): 3340,
´
1
1
3
056, 1670, 1601, 1520, 1474, 1347, 1287, 974, 623 cm
.
H-NMR (CDCl ) δ 8.16 (s, 1H), 7.97–7.95
3
(m, 2H), 7.90 (dd, J = 9.0, 5.2 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.47–7.43 (m, 3H), 7.32 (d, J = 8.2 Hz,
1
6
1
H), 7.16 (dt, J = 7.6, 0.7 Hz, 1H), 7.12–7.09 (m, 2H), 7.03 (dt, J = 7.1, 0.4 Hz, 1H), 6.95 (ddd, J = 9.2,
.5, 2.7 Hz, 1H), 5.79 (t, J = 7.1 Hz, 1H), 3.86 (dd, J = 17.3, 7.4 Hz, 1H), 3.76 (dd, J = 17.3, 7.4 Hz,
13
H); C-NMR (CDCl ) δ 197.4, 164.7 (d, JC–F = 254 Hz), 146.1 (d, JC–F = 3 Hz), 143.2, 143.1, 136.7
3
(d, JC–F = 10 Hz), 133.6, 128.9, 128.3, 127.5 (d, JC–F = 10 Hz), 126.5, 122.8, 122.2, 120.1, 119.4, 117.0 (d,
JC–F = 24 Hz), 116.9, 114.6 (d, J
= 23 Hz), 111.5, 44.9, 33.2; HRMS (EI) m/z calcd for C H N O F
23 18 2 3
C–F
+
([M + H] ) 389.1301, found 389.1318.
3
-(5-Chloro-2-nitrophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (3c): Purified by column chromatography
using 1:4 ethyl acetate and hexane. After concentration in vacuo a pale brown solid with a melting
˝
1
point of 151–153 C was obtained; H-NMR (CDCl ) δ 8.09 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.78 (d,
3
J = 8.7, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.46–7.42 (m, 3H), 7.38 (d, J = 2.0, 1H), 7.33 (d, J = 8.1, 1H), 7.25 (s,
1
1
1
H), 7.16 (t, J = 7.4, 1H), 7.12 (s, 1H), 7.03 (t, J = 7.6, 1H), 5.73 (t, J = 7.2, 1H), 3.87 (dd, J = 17.4, 6.8 Hz,
H), 3.75 (dd, J = 17.2, 7.7 Hz, 1H); 13C-NMR (CDCl ) δ 197.3, 148.4, 141.4, 139.1, 136.8, 136.7, 133.6,
3
30.2, 128.9, 128.3, 127.6, 126.5, 126.1, 122.8, 122.2, 120.1, 119.4, 116.8, 111.5, 44.9, 32.9; MS (EI) m/z
+
+
(relative intensity) 406 ([M + 2] , 8), 404 (M , 25), 387 (29), 285 (85), 265 (41), 253 (33), 204 (26), 203
+
(11), 132 (11), 105 (100); HRMS (EI) m/z calcd. for C H N O Cl (M ) 404.0928, found 404.0926.
23
17
2
3
3
-(5-Bromo-2-nitrophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (3d): Purified by column chromatography
using 1:4 ethyl acetate and hexane. Concentration in vacuo give a pale brown solid with a melting
˝
1
point of 166–168 C; H-NMR (CDCl ) δ 8.14 (s, 1H), 7.93 (d, J = 7.4 Hz, 2H), 7.66 (d, J = 8.6, 1H),
3
7
.55–7.52 (m, 2H), 7.46–7.40 (m, 3H), 7.37 (dd, J = 8.6, 2.0 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.14 (t,
J = 7.3 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 5.70 (t, J = 7.1 Hz, 1H), 3.85 (dd,
J = 17.3, 6.8 Hz, 1H), 3.72 (dd, J = 17.2, 7.6 Hz, 1H); 13C-NMR (CDCl ) δ 197.3, 149.0, 141.4, 136.8,
3
1
3
36.7, 133.6, 133.2, 130.6, 128.9, 128.3, 127.5, 126.5, 126.1, 122.8, 122.2, 120.1, 119.4, 116.8, 111.5, 44.9,
+
+
2.8; MS (EI) m/z (relative intensity) 450 ([M + 2] , 23), 448 (M , 23), 431 (26), 329 (100), 311 (63), 285
+
(30), 217 (30), 206 (54), 176 (16), 132 (27), 105 (95); HRMS (EI) m/z calcd. for C H N O Br (M )
23
17
2
3
4
48.0423, found 448.0432.
22508

Molecules 2015, 20, 22499–22519
1
-(2-Chlorophenyl)-3-(1H-indol-3-yl)-3-(2-nitrophenyl)propan-1-one (3e): Yellow crystalline solid (crystallized
˝
1
from ethyl acetate and hexane) with a melting point of 114–116 C; H-NMR (CDCl ) δ 8.07 (s, 1H),
3
7
3
1
1
.80 (d, J = 8.1 Hz, 1H), 7.43–7.21 (m, 9H), 7.14 (m, 2H), 6.98 (t, J = 7.5 Hz, 1H), 5.55 (t, J = 7.4 Hz, 1H),
13
.84 (dd, J = 17.0, 7.0 Hz, 1H), 3.77 (dd, J = 17.0, 8.1 Hz, 1H); C-NMR (CDCl ) δ 201.3, 149.8, 138.9,
3
38.4, 136.7, 132.8, 131.9, 130.8, 130.6, 130.2, 129.0, 127.4, 127.1, 126.5, 124.5, 122.6, 122.5, 119.8, 119.3,
+
+
16.7, 111.4, 49.3, 33.3; MS (EI) m/z (relative intensity) 406 ([M + 2] , 6), 404 (M , 18), 354 (24), 269
+
(44), 251 (74), 207 (46), 204 (42), 139 (100), 105 (76); HRMS (EI) m/z calcd for C H N O Cl (M )
2
3
17
2
3
4
04.0928, found 404.0929.
1-(2-Bromophenyl)-3-(1H-indol-3-yl)-3-(2-nitrophenyl)propan-1-one (3f): Purified by column chromatography
using 1:5 ethyl acetate and hexane. After concentration in vacuo a yellow crystalline solid (from ethyl
˝
1
acetate and hexane) with a melting point of 132–134 C was obtained; H-NMR (CDCl ) δ 8.08 (s,
3
1
H), 7.81 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.44–7.38 (m, 2H), 7.33–7.30 (m, 3H), 7.26–7.19
(
1
1
m, 3H), 7.15–7.12 (m, 2H), 6.98 (t, J = 7.7 Hz, 1H), 5.54 (t, J = 7.4 Hz, 1H), 3.83 (dd, J = 16.9, 6.8 Hz,
H), 3.74 (dd, J = 16.9, 8.0 Hz, 1H); 13C-NMR (CDCl ) δ 202.0, 149.9, 141.1, 138.3, 136.7, 133.8, 132.9,
3
31.8, 130.3, 128.7, 127.6, 127.5, 126.5, 124.5, 122.7, 122.5, 119.8, 119.3, 118.7, 116.6, 111.4, 49.0, 33.4; MS
+
+
(EI) m/z (relative intensity) 450 ([M + 2] , 10), 448 (M , 10), 354 (27), 251 (60), 204 (50), 183 (100), 155
+
(16), 132 (14), 105 (13); HRMS (EI) m/z calcd. for C H N O Br (M ) 448.0423, found 448.0420.
23
17
2
3
3
-(1H-Indol-3-yl)-3-(2-nitrophenyl)-1-p-tolylpropan-1-one (3g): Purified by column chromatography
1
using 1:5 ethyl acetate and hexane. After concentration in vacuo an orange oil was obtained; H-NMR
(
CDCl ) δ 8.01 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.46–7.38 (m, 3H), 7.31 (t,
3
J = 8.2 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 7.11 (s, 1H), 7.00 (t, J = 7.6 Hz, 1H),
5
.68 (t, J = 7.2 Hz, 1H), 3.84 (dd, J = 16.8, 7.4 Hz, 1H), 3.77 (dd, J = 17.2, 7.8 Hz, 1H), 2.39 (s, 3H);
13
C-NMR (CDCl ) δ 197.4, 150.1, 144.3, 139.0, 136.8, 134.4, 132.7, 130.1, 129.5, 128.4, 127.3, 126.6, 124.4,
3
+
1
22.5, 122.3, 119.8, 119.4, 117.4, 111.4, 44.9, 33.2, 21.8; MS (EI) m/z (relative intensity) 384 (M , 46),
+
3
50 (39), 251 (100), 232 (40), 206 (38), 119 (63); HRMS (EI) m/z calcd for C H N O (M ) 384.1474,
24
20
2
3
found 384.1473.
3-(1H-Indol-3-yl)-1-(4-methoxyphenyl)-3-(2-nitrophenyl)propan-1-one (3h): Purified by column chromatography
using 1:5 ethyl acetate and hexane. After concentration in vacuo a yellow solid with a melting point
˝
1
of 207–209 C was obtained; H-NMR (400 MHz,DMSO-d ) δ 10.96 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H),
6
7
.81 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.39–7.31 (m, 4H), 7.05–7.00
(
(
m, 3H), 6.89 (t, J = 7.4 Hz, 1H), 5.41 (t, J = 7.2 Hz, 1H), 3.95 (dd, J = 17.7, 6.6 Hz, 1H), 3.83 (s, 3H), 3.77
dd, J = 17.7, 8.0 Hz, 1H); 13C-NMR (DMSO-d ) δ 196.1, 163.2, 149.7, 138.8, 136.3, 132.6, 130.4, 130.0,
6
1
29.5, 127.1, 126.2, 123.7, 123.0, 121.2, 118.5, 118.4, 116.3, 113.8, 111.4, 55.5, 44.0, 31.6; MS (EI) m/z
+
(relative intensity) 400 (M , 25), 366 (29), 250 (63), 222 (29), 206 (22), 135 (100); HRMS (EI) m/z calcd
+
for C H N O (M ) 400.1423, found 400.1428.
24
20
2
4
1
-(Benzo[d][1,3]dioxol-5-yl)-3-(1H-indol-3-yl)-3-(2-nitrophenyl)propan-1-one (3i): Purified by column
chromatography using 1:5 ethyl acetate and hexane. After concentration in vacuo a pale yellow solid
˝
1
with a melting point of 150–152 C was obtained; H-NMR (CDCl ) δ 8.05 (s, 1H), 7.78 (dd, J = 8.0,
3
0
1
.8 Hz, 1H), 7.58 (dd, J = 8.2, 1.7 Hz, 1H), 7.44–7.37 (m, 4H), 7.30–7.26 (m, 2H), 7.13 (dt, J = 7.2, 0.5 Hz,
H), 7.08 (d, J = 2.0 Hz, 1H), 6.99 (dt, J = 7.5, 0.5 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.01 (s, 2H), 5.65
13
(t, J = 7.2 Hz, 1H), 3.77 (dd, J = 16.8, 7.2 Hz, 1H), 3.70 (dd, J = 17.0, 7.5 Hz, 1H); C-NMR (CDCl ) δ
3
1
1
2
95.8, 152.1, 150.2, 148.4, 138.9, 136.8, 132.7, 131.8, 130.2, 127.3, 126.6, 124.6, 124.5, 122.5, 122.3, 119.9,
+
19.5, 117.4, 111.4, 108.2, 108.1, 102.0, 44.8, 33.4; MS (EI) m/z (relative intensity) 414 (M , 18), 380 (17),
+
51 (65), 207 (20), 148 (100); HRMS (EI) m/z calcd for C H N O (M ) 414.1216, found 414.1209.
24
18
2
5
3-(1H-Indol-3-yl)-1-(naphthalen-2-yl)-3-(2-nitrophenyl)propan-1-one (3j): Purified by column chromatography
using 1:5 ethyl acetate and hexane. After concentration in vacuo a yellow solid with a melting point
˝
1
of 185–187 C was isolated; H-NMR (DMSO-d ) δ 10.98 (s, 1H), 8.79 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H),
6
7
.99–7.96 (m, 3H), 7.84 (dd, J = 8.1, 1.1 Hz, 1H), 7.67–7.62 (m, 3H), 7.54 (dt, J = 7.7, 1.1 Hz, 1H), 7.44
22509

Molecules 2015, 20, 22499–22519
(d, J = 2.2 Hz, 1H), 7.42–7.38 (m, 2H), 7.33 (d, J = 8.1 Hz, 1H), 7.04 (dt, J = 7.1, 0.8 Hz, 1H), 6.90 (dt,
J = 7.4, 0.6 Hz, 1H), 5.49 (t, J = 7.2 Hz, 1H), 4.19 (dd, J = 17.9, 6.8 Hz, 1H), 3.99 (dd, J = 17.8, 7.7 Hz,
13
1
H); C-NMR (DMSO-d ) δ 197.7, 149.7, 138.8, 136.4, 135.1, 133.7, 132.7, 132.2, 130.1, 130.1, 129.6,
6
1
28.7, 128.2, 127.6, 127.2, 126.9, 126.2, 123.8, 123.5, 123.1, 121.2, 118.6, 118.4, 116.2, 111.5, 44.5, 31.7;
+
MS (EI) m/z (relative intensity) 420 (M , 5), 251 (19), 155 (100), 127 (36); HRMS (EI) m/z calcd for
C H N O (M ) 420.1474, found 420.1465.
+
27
20
2
3
3
-(1H-Indol-3-yl)-3-(2-nitrophenyl)-1-(thiophen-2-yl)propan-1-one (3k): Purified by column chromatography
using 1:5 ethyl acetate and hexane. After concentration in vacuo a pale brown solid with a melting
point of 146–148 C was obtained; 1H-NMR (CDCl ) δ 8.04 (s, 1H), 7.81–7.79 (m, 2H), 7.61 (d,
˝
3
J =4.7 Hz, 1H), 7.47–7.40 (m, 2H), 7.36–7.28 (m, 3H), 7.17–7.10 (m, 3H), 7.00 (t, J = 7.5 Hz, 1H), 5.67
13
(
t, J = 7.4 Hz, 1H), 3.79 (dd, J = 14.5, 5.8 Hz, 1H), 3.74 (dd, J = 14.6, 5.6 Hz, 1H); C-NMR (CDCl ) δ
3
1
1
90.7, 150.0, 144.1, 138.6, 136.7, 134.1, 132.8, 132.3, 130.3, 128.4, 127.5, 126.6, 124.5, 122.5, 119.8, 119.3,
16.9, 111.5, 45.6, 33.6; MS (EI) m/z (relative intensity) 251 (22), 204 (25), 111 (100); HRMS (EI) m/z
+
calcd for C H N O S (M ) 376.0882, found 376.0880.
21
26
2
3
3
-(5-Fluoro-1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3l): Purified by column chromatography
using 1:4 ethyl acetate and hexane. After concentration in vacuo a yellow solid with a melting point
˝
1
of 192–194 C was obtained; H-NMR (DMSO-d ) δ 11.10 (s, 1H), 7.99 (d, J = 7.7 Hz, 2H), 7.83
6
(d, J = 8.1 Hz, 1H), 7.63–7.61 (m, 2H), 7.56–7.48 (m, 4H), 7.38 (t, J = 7.8 Hz, 1H), 7.33 (dd, J = 8.8,
4
.6 Hz, 1H), 7.15 (dd, J = 10.2, 2.0 Hz, 1H), 6.88 (dt, J = 9.2, 2.2 Hz, 1H), 5.37 (t, J = 7.3 Hz, 1H), 4.00
13
(dd, J = 18.1, 6.2 Hz, 1H), 3.92 (dd, J = 18.1, 8.1 Hz, 1H); C-NMR (DMSO-d ) δ 197.8, 156.7 (d,
6
JC–F = 230 Hz), 149.8, 138.5, 136.4, 133.3, 133.1, 132.7, 129.9, 128.6, 128.0, 127.2, 126.4 (d, JC–F = 10 Hz),
1
2
25.3, 123.8, 116.6 (d, JC–F = 5 Hz), 112.5 (d, J
= 10 Hz), 109.4 (d, JC–F = 26 Hz), 103.2 (d, JC–F =
C–F
+
3 Hz); MS (EI) m/z (relative intensity) 388 (M , 29), 371 (25), 269 (92), 222 (56); HRMS (EI) m/z calcd
+
for C H N O F (M ) 388.1223, found 388.1227.
23
17
2
3
3-(5-Chloro-1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3m): Purified by column chromatography
using 1:4 ethyl acetate and hexane. After concentration in vacuo a pale yellow solid with a melting
˝
1
point of 198–200 C was obtained; H-NMR (DMSO-d ) δ 11.22 (s, 1H), 7.99 (d, J = 7.4 Hz, 2H), 7.84
6
(d, J = 8.0 Hz, 1H), 7.64–7.61 (m, 2H), 7.56–7.48 (m, 4H), 7.46 (d, J = 1.5 Hz, 1H), 7.40–7.34 (m, 2H),
7
8
1
.04 (dd, J = 8.6, 1.8 Hz, 1H), 5.38 (t, J = 7.2 Hz, 1H), 4.00 (dd, J = 18.2, 6.4 Hz, 1H), 3.92 (dd, J = 18.2,
.4 Hz, 1H); 13C-NMR (DMSO-d ) δ 197.7, 149.8, 138.5, 136.4, 134.8, 133.3, 132.8, 130.0, 128.6, 127.3,
6
27.3, 125.1, 123.9, 123.3, 121.2, 117.7, 116.2, 113.1, 44.5, 31.3; MS (EI) m/z (relative intensity) 406
+
+
([M + 2] , 10), 404 (M , 31), 387 (25), 285 (92), 265 (30), 253 (29), 205 (32), 204 (19), 105 (94), 84 (100);
+
HRMS (EI) m/z calcd for C H N O Cl (M ) 404.0928, found 404.0930.
23
17
2
3
3
-(5-Bromo-1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3n): Purified by column chromatography
using 1:5 ethyl acetate and hexane. Concentration in vacuo gave a brown solid with a melting point
˝
1
of 152–154 C; H-NMR (DMSO-d ) δ 11.25 (s, 1H), 8.00 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 8.1 Hz, 1H),
6
7
1
8
1
4
.63–7.60 (m, 3H), 7.56–7.52 (m, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 8.6 Hz,
H), 7.16 (d, J = 8.6 Hz, 1H), 5.40 (t, J = 7.2, 1H), 4.01 (dd, J = 18.2, 6.0 Hz, 1H), 3.92 (dd, J = 18.2,
.4 Hz, 1H); 13C-NMR (DMSO-d ) δ 197.7, 149.7, 138.4, 136.4, 135.0, 133.3, 132.8, 129.9, 128.6, 128.0,
6
28.0, 127.3, 124.9, 123.8, 123.7, 120.7, 116.1, 113.5, 111.2, 44.5, 31.2; MS (EI) m/z (relative intensity)
+
+
50 ([M + 2] , 7), 448 (M , 7), 431 (7), 329 (26), 311 (23), 284 (16), 217 (13), 205 (23), 105 (100); HRMS
+
(EI) m/z calcd for C H N O Br (M ) 448.0423, found 448.0414.
23
17
2
3
3
-(5-Methoxy-1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3o): Purified by column chromatography
1
using 1:5 ethyl acetate and hexane. After concentration in vacuo a green oil was obtained; H-NMR
(
CDCl ) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.89 (d, J = 1.3 Hz, 1H), 7.71 (dd, J = 8.0, 1.1 Hz, 1H), 7.49 (t, J = 7.5
3
Hz, 1H), 7.37 (m, 3H), 7.31 (dt, J = 7.7, 1.0 Hz, 1H), 7.19 (dt, J = 7.5, 1.2 Hz, 1H), 7.08 (d, J = 8.8 Hz,
1
1
H), 6.98 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 8.8, 2.4 Hz, 1H), 5.61 (t, J = 7.2 Hz,
13
H), 3.79 (dd, J = 17.2, 6.9 Hz, 1H), 3.72 (dd, J = 17.2, 7.5 Hz, 1H), 3.66 (s, 3H); C-NMR (CDCl ) δ
3
22510

Molecules 2015, 20, 22499–22519
1
1
2
97.7, 154.3, 150.4, 138.8, 136.8, 133.5, 132.7, 131.8, 130.2, 128.9, 128.3, 127.4, 127.1, 124.4, 122.7, 117.4,
+
12.9, 112.1, 101.2, 55.9, 45.0, 33.0, MS (EI) m/z (relative intensity) 400 (M , 32), 383 (25), 281 (68),
+
61 (39), 249 (24), 204 (16), 162 (12), 105 (100); HRMS (EI) m/z calcd for C H N O (M ) 400.1423,
24
20
2
4
found 400.1431.
3-(7-Methyl-1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3p): Purified by column chromatography
using 1:5 ethyl acetate and hexane. After concentration in vacuo a pale green solid with a melting
˝
1
point of 139–141 C was obtained; H-NMR (CDCl ) δ 7.97–7.95 (m, 3H), 7.80 (d, J = 8.1 Hz, 1H),
3
7
2
.55 (t, J = 7.36 Hz, 1H), 7.46–7.39 (m, 4H), 7.31–7.23 (m, 2H), 7.11 (d, J = 1.8 Hz, 1H), 6.96–6.91 (m,
H), 5.67 (t, J = 7.2 Hz, 1H), 3.87 (dd, J = 16.7, 7.2 Hz, 1H), 3.80 (dd, J = 16.7, 6.6 Hz, 1H), 2.45 (s, 3H);
1
3
C-NMR (CDCl ) δ 197.8, 150.1, 138.9, 136.8, 136.3, 133.4, 132.8, 130.1, 128.8, 128.3, 127.3, 126.1, 124.5,
3
+
1
23.1, 122.0, 120.6, 120.1, 117.8, 117.2, 45.0, 33.3, 16.7; MS (EI) m/z (relative intensity) 384 (M , 23), 367
(
28), 265 (60), 245 (41), 219 (32), 204 (12), 146 (10), 105 (100); HRMS (EI) m/z calcd for C H N O
24 20 2 3
+
(
M ) 384.1474, found 384.1476.
-(1-Methyl-1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3q): Purified by column chromatography
using 1:5 ethyl acetate and hexane. After concentration in vacuo a yellow solid with a melting point
3
˝
1
of 166–168 C was obtained; H-NMR (CDCl ) δ 7.96 (d, J = 7.7 Hz, 2H), 7.80 (d, J = 8.1 Hz, 1H), 7.55
3
(
6
(
t, J = 7.2 Hz, 1H), 7.47–7.39 (m, 5H), 7.30–7.24 (m, 2H), 7.18 (t, J = 7.2 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H),
.95 (s, 1H), 5.67 (t, J = 7.2 Hz, 1H), 3.86 (dd, J = 16.9, 7.2 Hz, 1H), 3.80 (dd, J = 16.8, 6.8 Hz, 1H), 3.74
s, 3H); 13C-NMR (CDCl ) δ 197.6, 150.1, 139.1, 137.5, 136.9, 133.4, 132.7, 130.1, 128.8, 128.3, 127.3,
3
1
27.0, 127.0, 124.5, 122.2, 119.6, 119.4, 115.9, 109.5, 45.2, 33.1, 33.0; MS (EI) m/z (relative intensity) 384
+
(M , 24), 367 (55), 265 (100), 248 (45), 218 (58), 217 (23), 146 (20), 105 (58); HRMS (EI) m/z calcd for
+
C H N O (M ) 384.1474, found 384.1478.
24
20
2
3
3-(2-Methyl-1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3r): Purified by column chromatography
using 1:5 ethyl acetate and hexane. Concentration in vacuo gave a yellow solid with a melting point
˝
1
of 129–131 C; H-NMR (CDCl ) δ 7.88 (s, 1H), 7.86 (d, J = 1.0 Hz, 1H), 7.77 (s, 1H), 7.72 (d, J = 7.9 Hz,
3
1
H), 7.68 (d, J = 8.0 Hz, 1H), 7.53–7.47 (m, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.20 (d,
J = 80 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 7.3 Hz, 1H), 5.71 (t, J = 7.2 Hz, 1H), 3.95 (dd, J = 16.9,
13
7
.8 Hz, 1H), 3.84 (dd, J = 16.9, 6.7 Hz, 1H); C-NMR (CDCl ) δ 198.0, 150.4, 138.6, 137.0, 135.7, 133.3,
3
1
33.1, 132.3, 129.3, 128.8, 128.2, 127.6, 127.3, 124.9, 121.1, 119.7, 118.6, 111.5, 110.8, 43.3, 33.1, 12.2; MS
+
(EI) m/z (relative intensity) 384 (M , 53), 367 (17), 265(100), 247 (92), 218 (60), 217 (46), 146 (67), 105
+
(55); HRMS (EI) m/z calcd for C H N O (M ) 384.1474, found 384.1481.
24
20
2
3
3
-(2-Nitrophenyl)-1-phenyl-3-(2-phenyl-1H-indol-3-yl)propan-1-one (3s): Purified by column chromatography
using 1:5 ethyl acetate and hexane. After concentration in vacuo a deep brown oil was obtained; IR
´
KBr): 3390, 3059, 1682, 1601, 1526, 1451, 1351, 741, 698 cm . H-NMR (CDCl ) δ 8.15 (s,1H), 7.74 (d,
3
1 1
(
J = 7.4 Hz, 2H), 7.67 (t, J = 7.1 Hz, 2H), 7.60 (d, J = 7.9 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.36–7.20 (m,
1
1
1
4
0H), 7.11 (t, J = 7.2 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 5.80 (t, J = 7.3 Hz, 1H), 4.05 (dd, J = 17.4, 8.5 Hz,
H), 3.78 (dd, J = 17.3, 6.1 Hz, 1H); 13C-NMR (CDCl ) δ 197.6, 149.2, 139.0, 136.6, 136.5, 136.0, 132.9,
3
32.5, 132.5, 130.1, 128.6, 128.5, 128.4, 128.1, 127.9, 127.8, 127.2, 124.5, 121.9, 119.9, 119.8, 111.8, 111.7,
+
4.1, 33.8; HRMS (ESI) m/z calcd for C H N O Na ([M + Na] ) 469.1528, found 469.1519.
29
22
2
3
3
-(1H-Indol-3-yl)-3-(3-methyl-2-nitrophenyl)-1-phenylpropan-1-one (3t): Purified by column chromatography
using 1:5 ethyl acetate and hexane. After concentration in vacuo a pale pink solid with a melting
˝
1
point of 191–193 C was obtained; H-NMR (CDCl ) δ 8.00 (s, 1H), 7.93 (d, J = 7.6 Hz, 2H), 7.54 (t, J =
3
7
.3 Hz, 1H), 7.45–7.38 (m, 3H), 7.26 (t, J = 8.1 Hz, 1H), 7.21–7.20 (m, 2H), 7.14–7.10 (m, 2H), 7.02–6.98
(
(
m, 2H), 5.07 (t, J = 6.8 Hz, 1H), 3.81 (dd, J = 16.8, 8.5 Hz, 1H), 3.69 (dd, J = 16.8, 6.0 Hz, 1H), 2.31
s, 3H); 13C-NMR (CDCl ) δ 197.6, 151.5, 136.9, 136.8, 135.9, 133.4, 130.2, 129.7, 129.6, 128.9, 128.4,
3
1
27.0, 126.6, 122.6, 122.3, 119.9, 119.5, 117.0, 111.3, 45.1, 34.0, 17.7; MS (EI) m/z (relative intensity) 384
+
+
(M , 22), 367 (25), 265 (23), 247 (60), 221 (42), 204 (18); HRMS (EI) m/z calcd for C H N O (M )
24 20 2 3
3
84.1474, found 384.1476.
22511

Molecules 2015, 20, 22499–22519
3
-(2,5-Dimethyl-1H-indol-3-yl)-3-(2-nitrophenyl)-1-phenylpropan-1-one (3u): Purified by column
chromatography using 1:4 ethyl acetate and hexane. After concentration in vacuo a green solid
˝
1
with a melting point of 119–121 C was obtained; H-NMR (CDCl ) δ 7.88 (dd, J = 7.8, 1.3 Hz, 2H),
3
7
2
6
1
.71–7.67 (m, 3H), 7.54–7.48 (m, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.32 (dt, J = 8.4, 1.2 Hz, 1H), 7.11–7.09 (m,
H), 6.87 (d, J = 8.1 Hz, 1H), 5.69 (t, J = 7.1 Hz, 1H), 3.94 (dd, J = 17.0, 7.6 Hz, 1H), 3.84 (dd, J = 17.0,
.8 Hz, 1H), 2.34 (s, 3H), 2.33 (s, 3H); 13C-NMR (CDCl ) δ 198.0, 150.3, 138.7, 137.1, 133.9, 133.2, 133.2,
3
32.3, 129.5, 128.7, 128.7, 128.2, 127.9, 127.2, 124.8, 122.6, 118.5, 111.0, 110.5, 43.4, 33.1, 21.9, 12.3; MS
+
(EI) m/z (relative intensity) 398 (M , 25), 262 (53), 261 (36), 207 (33), 160 (48), 105 (100); HRMS (EI)
+
m/z calcd for C H N O (M ) 398.1630, found 398.1629.
25
22
2
3
3
-(2,5-Dimethyl-1H-indol-3-yl)-3-(3-methyl-2-nitrophenyl)-1-phenylpropan-1-one (3v): Purified by column
chromatography using 1:4 ethyl acetate and hexane. After concentration in vacuo a pale yellow solid
˝
1
with a melting point of 173–175 C was obtained; H-NMR (CDCl ) δ 77.88–7.86 (m, 2H), 7.63 (s, 1H),
3
7
7
1
1
1
2
.55–7.50 (m, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.31 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H),
.09 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 5.18 (dd, J = 8.2, 6.2 Hz, 1H), 3.96 (dd, J = 16.9, 8.4 Hz,
13
H), 3.80 (dd, J = 16.9, 6.2 Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 2.23 (s, 3H); C-NMR (CDCl ) δ 197.9,
3
51.8, 137.1, 135.7, 133.9, 133.2, 133.0, 130.0, 129.9, 129.4, 128.7, 128.5, 128.2, 127.6, 126.2, 122.5, 118.5,
+
10.7, 110.4 ,43.2, 33.0, 21.9, 17.6, 12.1; MS (EI) m/z (relative intensity) 412 (M , 25), 275 (39), 247 (16),
+
21 (50), 160 (37), 105 (100); HRMS (EI) m/z calcd for C H N O (M ) 412.1787, found 412.1780.
26
24
2
3
3
.3. General Procedure for Reductive Cyclization (Synthesis of 4a–4u)
To a stirred solution of 3a (1 mmol) in ethanol (10 mL), powdered Fe (6 mmol) and HCl
1 mmol) were added and the reaction mixture was kept stirring at reflux until TLC analysis showed
(
complete consumption of 3a. Then, the reaction mixture was quenched by saturated aq. NaHCO3,
filtered by celite and concentrated, then the residue was extracted with ethyl acetate three times
(10 mL each time). The combined organic layers were dried over magnesium sulfate, filtered and
concentrated. The residue was purified by recrystallization or flash chromatography (EtOAc/hexane)
1
13
to afford the final product 4a. (The H-, C-NMR spectra of the compounds (4a–4u) was showed
in Supplementary).
4
-(1H-Indol-3-yl)-2-phenylquinoline (4a): Pale yellow crystalline solid (crystallized from ethyl acetate
˝
and hexane) with a melting point of 229–231 C; IR (KBr): 3200, 3050, 1591, 1546, 1498, 1237, 828,
7
´
. H-NMR (DMSO-d ) δ 11.78 (s, 1H), 8.31 (d, J = 7.2 Hz, 2H), 8.17–8.13 (m, 3H), 7.90 (d,
6
1
1
41 cm
J = 1.8 Hz, 1H), 7.79 (t, J = 7.3 Hz, 1H), 7.59–7.48 (m, 6H), 7.23 (t, J = 7.3 Hz, 1H), 7.11 (t, J = 7.5 Hz,
13
1
H); C-NMR (DMSO-d ) δ 155.9, 148.5, 142.9, 139.0, 136.6, 129.7, 129.6, 129.4, 128.8, 127.3, 126.6,
6
1
26.2, 126.1, 126.0, 125.7, 121.9, 120.0, 119.1, 118.5, 112.2, 112.0; MS (EI) m/z (relative intensity) 320
+
+
(M , 100); HRMS (EI) m/z calcd for C H N (M ) 320.1313, found 320.1307.
23 16 2
6
-Fluoro-4-(1H-indol-3-yl)-2-phenylquinoline (4b): Purified by column chromatography using 1:4 ethyl
˝
acetate and hexane. After concentration in vacuo a pale brown solid with a melting point of 154–156 C
was obtained; IR (KBr): 3320, 3048, 1588, 1545, 1494,1240, 830, 750 cm . H-NMR (DMSO-d ) δ 11.81
´
1 1
6
(
(
(
(
s, 1H), 8.31–8.28 (m, 2H), 8.21 (dd, J = 17.4, 5.7 Hz, 1H), 8.16 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.79
dd, J = 10.5, 2.6 Hz, 1H), 7.70 (dt, J = 8.4, 2.7 Hz, 1H), 7.60–7.48 (m, 5H), 7.24 (t, J = 7.6 Hz, 1H), 7.13
t, J = 7.8 Hz, 1H); 13C-NMR (DMSO-d ) δ 159.3 (d, J
= 244 Hz), 155.5 (d, JC–F = 3 Hz), 145.7, 142.5
C–F
6
d, JC–F = 3 Hz), 138.7, 136.6, 132.5 (d, JC–F = 5 Hz), 129.5, 128.8, 127.2, 126.7, 126.4 (d, JC–F = 9 Hz),
1
26.0, 122.0, 120.1, 119.6 (d, J
= 25 Hz), 119.1, 118.9, 112.3, 111.5, 109.3 (d, JC–F = 23 Hz); MS (EI)
C–F
+
m/z (relative intensity) 338 (M , 100), 337 (65), 285 (24), 149 (87), 105 (30); HRMS (EI) m/z calcd for
C H N F (M ) 338.1219, found 338.1213.
+
23
15
2
6
-Chloro-4-(1H-indol-3-yl)-2-phenylquinoline (4c): Purified by column chromatography using 1:4 ethyl
acetate and hexane. After concentration in vacuo a pale yellow solid with a melting point of
˝
09–211 C was obtained; H-NMR (DMSO-d ) δ 11.83 (s, 1H), 8.29 (d, J = 8.6 Hz, 2H), 8.16–8.13
6
1
2
22512

Molecules 2015, 20, 22499–22519
(
m, 2H), 8.10 (d, J = 1.8 Hz, 1H), 7.94 (s, 1H), 7.77 (dd, J = 8.9, 2.1 Hz, 1H), 7.60–7.48 (m, 5H), 7.24 (t,
13
J = 7.3 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H); C-NMR (DMSO-d ) δ 156.4, 147.0, 142.4, 138.6, 136.6, 131.8,
6
1
30.6, 130.2, 129.7, 128.8, 127.3, 126.9, 126.5, 126.1, 124.8, 122.1, 120.2, 119.4, 118.9, 112.3, 111.4; MS (EI)
+
+
m/z (relative intensity) 356 ([M + 2] , 8), 354 (M , 24), 353 (12), 149 (100); HRMS (EI) m/z calcd for
C H N Cl (M ) 354.0924, found 354.0919.
+
23
15
2
6
-Bromo-4-(1H-indol-3-yl)-2-phenylquinoline (4d): Purified by column chromatography using 1:4 ethyl
˝
acetate and hexane. After concentration in vacuo a yellow solid with a melting point of 214–216 C
was obtained; H-NMR (DMSO-d ) δ 11.83 (s, 1H), 8.28 (d, J = 7.4 Hz, 2H), 8.26 (d, J = 1.8 Hz, 1H),
1
6
8
.15 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 8.9, 1.8 Hz, 1H), 7.60 (d,
13
J = 8.1 Hz, 1H), 7.54–7.46 (m, 4H), 7.24 (t, J = 7.3 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H); C-NMR (DMSO-d6)
δ 156.5, 147.2, 142.3, 138.6, 136.6, 132.7, 131.9, 129.7, 128.8, 128.1, 127.4, 127.0, 126.9, 126.1, 122.1, 120.2,
1
+
+
19.4, 119.2, 118.9, 112.3, 111.4; MS (EI) m/z (relative intensity) 400 ([M + 2] , 100), 398 (M , 98), 319
+
(34), 318 (27); HRMS (EI) m/z calcd for C H N Br (M ) 398.0419, found 398.0417.
23
15
2
2
-(2-Chlorophenyl)-4-(1H-indol-3-yl)quinoline (4e): Purified by column chromatography using 1:4 ethyl
acetate and hexane. After concentration in vacuo a pale yellow solid with a melting point of
˝
42–244 C was obtained; H-NMR (DMSO-d ) δ 11.78 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.13 (d,
6
1
2
J = 8.2 Hz, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.85- 7.77 (m, 3H), 7.65–7.51 (m, 6H), 7.22 (t, J = 7.3 Hz,
1
1
H), 7.12 (t, J = 7.5 Hz, 1H); 13C-NMR (DMSO-d ) δ 156.3, 148.4, 141.7, 139.3, 136.6, 131.8, 131.3, 130.2,
6
29.8, 129.6, 129.6, 127.4, 126.8, 126.6, 126.1, 126.0, 125.4, 122.0, 122.0, 120.1, 118.8, 112.2, 111.4; MS (EI)
+
+
+
m/z (relative intensity) 356 ([M + 2] , 42), 354 (M , 100); HRMS (EI) m/z calcd for C H N Cl (M )
23
15
2
3
54.0924, found 354.0924.
2
-(2-Bromophenyl)-4-(1H-indol-3-yl)quinoline (4f): Purified by column chromatography using 1:4 ethyl
acetate and hexane). After concentration in vacuo a pale yellow solid with a melting point of
˝
36–238 C was obtained; H-NMR (DMSO-d ) δ 11.80 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.13 (d,
6
1
2
J = 8.1 Hz, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.83–7.78 (m, 3H), 7.73 (dd, J = 7.6, 1.6 Hz, 1H), 7.65–7.62
m, 2H), 7.58–7.52 (m, 2H), 7.41 (dt, J = 7.8, 1.8 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H);
(
1
3
C-NMR (DMSO-d ) δ 157.8, 148.3, 141.7, 141.3, 136.6, 132.9, 131.7, 130.3, 129.6, 129.6, 127.8, 126.8,
6
1
4
26.6, 126.1, 126.0, 125.4, 122.0, 122.0, 121.1, 120.1, 118.9, 112.2, 111.4; MS (EI) m/z (relative intensity)
+
+
+
00 ([M + 2] , 100), 399 ([M + 1] , 95), 398 (M , 90), 338 (13), 319 (34), 204 (22), 159 (12); HRMS (EI)
+
m/z calcd for C H N Br (M ) 398.0419, found 398.0412.
23
15
2
4
-(1H-Indol-3-yl)-2-p-tolylquinoline (4g): Purified by column chromatography using 1:4 ethyl acetate
˝
and hexane. After concentration in vacuo an orange solid with s melting point of 277–279 C was
obtained; IR (KBr): 3300, 3040, 1585, 1439, 1364, 1240, 814, 734 cm
´
1
1
. H-NMR (DMSO-d ) δ 11.74
6
(s, 1H), 8.21 (d, J = 8.1 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H), 8.09 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.78 (t,
J = 6.8 Hz, 1H), 7.57–7.51 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.11 (t, J = 7.4 Hz,
1
1
H), 2.40 (s, 3H); 13C-NMR (DMSO-d ) δ 155.8, 148.5, 142.8, 139.0, 136.5, 136.2, 129.6, 129.6, 129.4,
6
27.1, 126.5, 126.2, 126.0, 125.9, 125.6, 121.9, 120.0, 119.1, 118.3, 112.2, 112.0, 20.9; MS (EI) m/z (relative
+
+
intensity) 334 (M , 100); HRMS (EI) m/z calcd for C H N (M ) 334.1470, found 334.1469.
24
18
2
4
-(1H-Indol-3-yl)-2-(4-methoxyphenyl)quinoline (4h): Purified by column chromatography using 1:4
ethyl acetate and hexane. After concentration in vacuo a pale yellow solid with a melting point of
˝
31–233 C was obtained; H-NMR (DMSO-d ) δ 11.74 (s, 1H), 8.28 (td, J = 8.8, 2.8 Hz, 2H), 8.11 (ddd,
6
1
2
J = 8.6, 2.3, 1.0 Hz, 2H), 8.08 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.77 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.57 (d,
J = 8.1 Hz, 1H), 7.53–7.50 (m, 2H), 7.23 (ddd, J = 7.8, 7.2, 0.6 Hz, 1H), 7.13–7.09 (m, 3H), 3.85 (s, 3H);
1
3
C-NMR (DMSO-d ) δ 160.5, 155.5, 148.5, 142.6, 136.5, 131.4, 129.5, 129.5, 128.6, 126.4, 126.3, 125.9,
6
+
1
1
25.6, 125.4, 121.8, 119.9, 119.1, 118.1, 114.1, 112.1, 112.1, 55.2; MS (EI) m/z (relative intensity) 350 (M ,
00), 349 (64); HRMS (EI) m/z calcd for C H N O (M ) 350.1419, found 350.1412.
+
24
18
2
2
-(Benzo[d][1,3]dioxol-5-yl)-4-(1H-indol-3-yl)quinoline (4i): Purified by column chromatography using
1
:3 ethyl acetate and hexane. After concentration in vacuo a yellow solid with a melting point of
22513

Molecules 2015, 20, 22499–22519
˝
1
2
7
2
1
37–239 C was obtained; H-NMR (DMSO-d ) δ 11.74 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.06 (s, 1H),
6
.89–7.85 (m, 3H), 7.77 (t, J = 7.2 Hz, 1H), 7.57–7.50 (m, 3H), 7.22 (t, J = 7.4 Hz, 1H), 7.13–7.07 (m,
H), 6.12 (s, 2H); 13C-NMR (DMSO-d ) δ 155.3, 148.6, 148.4, 148.1, 142.8, 136.6, 133.4, 129.6, 129.6,
6
26.6, 126.3, 126.0, 125.8, 125.6, 121.9, 121.7, 120.0, 119.2, 118.3, 112.2, 112.1, 108.5, 107.3, 101.4; MS
EI) m/z (relative intensity) 364 (M , 100); HRMS (EI) m/z calcd for C H N O (M ) 364.1212,
+
+
(
26 14 2 2
found 364.1218.
4
-(1H-Indol-3-yl)-2-(naphthalen-2-yl)quinoline (4j): Purified by column chromatography using 1:4 ethyl
˝
acetate and hexane. After concentration in vacuo an orange solid with a melting point > 300 C was
obtained; H-NMR (DMSO-d ) δ 11.77 (s, 1H), 8.87 (s, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H),
1
6
8
7
.21 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 8.13–8.09 (m, 2H), 8.01–7.99 (m, 1H), 7.93 (s, 1H),
.83 (t, J = 7.2 Hz, 1H), 7.59–7.55 (m, 5H), 7.24 (t, J = 7.4 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H); C-NMR
13
(
DMSO-d ) δ 155.7, 148.5, 143.0, 136.6, 136.3, 133.4, 133.1, 129.7, 129.7, 128.8, 128.3, 127.5, 126.9, 126.8,
6
1
26.6, 126.5, 126.3, 126.2, 126.1, 125.8, 124.8, 121.9, 120.0, 119.1, 118.8, 112.2, 112.0; HRMS (ESI) m/z
+
calcd for C H N ([M + H] ) 371.1548, found 371.1554.
27
19
2
4
-(1H-Indol-3-yl)-2-(thiophen-2-yl)quinoline (4k): Purified by column chromatography using 1:4 ethyl
˝
acetate and hexane. After concentration in vacuo a yellow solid with a melting point of 201–203 C
was obtained; IR (KBr): 3300, 3054, 1587, 1545, 1425, 1370, 1240, 811, 744 cm . H-NMR (DMSO-d )
´
1 1
6
δ 11.75 (s, 1H), 8.11 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 3.7 Hz, 1H), 7.87
(
(
d, J = 2.5 Hz, 1H), 7.78–7.73 (m, 2H), 7.57 (d, J = 8.2 Hz, 1H), 7.53–7.50 (m, 2H), 7.25–7.20 (m, 2H), 7.11
t, J = 7.8 Hz, 1H); 13C-NMR (DMSO-d ) δ 151.6, 148.2, 145.0, 142.8, 136.5, 129.8, 129.3, 129.0, 128.5,
6
1
26.8, 126.6, 126.3, 126.1, 125.8, 125.8, 121.9, 120.0, 119.1, 117.4, 112.2, 111.7; MS (EI) m/z (relative
+
+
intensity) 326 (M , 100), 163 (10), 84 (13), 66 (15); HRMS (EI) m/z calcd for C H N S (M ) 326.0878,
21
14
2
found 326.0883.
4
-(5-Fluoro-1H-indol-3-yl)-2-phenylquinoline (4l): Pale yellow crystalline solid (crystallized from ethyl
˝
1
acetate and hexane) with a melting point of 236–238 C; H-NMR (DMSO-d ) δ 11.87 (s, 1H), 8.32 (d,
6
J = 7.4 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.11–8.10 (m, 2H), 7.97 (d, J = 2.3 Hz, 1H), 7.80 (t, J = 7.6 Hz,
13
1
H), 7.84–7.59 (m, 5H), 7.22 (dd, J = 9.9, 1.8 Hz, 1H), 7.08 (dt, J = 9.1, 2.1 Hz, 1H); C-NMR (DMSO-d6)
δ 157.6 (d, J = 232 Hz), 155.9, 128.5, 142.4, 139.0, 133.3, 129.8, 129.7, 129.4, 128.8, 128.6, 127.3,
C´´F
1
26.6 (d, JC–F = 10 Hz), 126.2, 125.9, 125.6, 118.6, 113.3 (d, JC–F = 10 Hz), 112.3 (d, J
= 4 Hz), 110.3 (d,
C–F
+
JC–F = 26 Hz), 103.9 (d, J
= 23 Hz); MS (EI) m/z (relative intensity) 338 (M , 100); HRMS (EI) m/z
C–F
+
calcd for C H N F (M ) 338.1219, found 338.1210.
2
3
15
2
4
-(5-Chloro-1H-indol-3-yl)-2-phenylquinoline (4m): Yellow crystalline solid (crystallized from ethyl
˝
1
acetate and hexane) with a melting point of 204–206 C; H-NMR (DMSO-d ) δ 11.97 (s, 1H), 8.32
6
(
d, J = 7.4 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.98 (s, 1H), 7.80 (t,
13
J = 7.7 Hz, 1H), 7.60–7.48 (m, 5H), 7.46 (d J = 1.0 Hz, 1H), 7.20 (dd, J = 8.6, 1.4 Hz, 1H); C-NMR
(
1
DMSO-d ) δ 155.9, 148.5, 142.2, 139.0, 135.1, 129.8, 129.7, 129.4, 128.7, 128.2, 127.5, 127.3, 126.2, 125.8,
6
+
25.7, 124.7, 122.0, 118.8, 118.3, 113.8, 111.9; MS (EI) m/z (relative intensity) 356 ([M + 2] , 33), 354
+
+
(M , 100); HRMS (EI) m/z calcd for C H N Cl (M ) 354.0924, found 354.0924.
23 15 2
4
-(5-Bromo-1H-indol-3-yl)-2-phenylquinoline (4n): Purified by column chromatography using 1:4 ethyl
˝
acetate and hexane). After concentration in vacuo a pale green solid with a melting point of 255–257 C
was obtained; H-NMR (DMSO-d ) δ 12.00 (s, 1H), 8.32 (d, J = 7.3 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H),
1
6
8
.12 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.97 (s, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.61–7.46 (m, 6H), 7.34 (d,
13
J = 8.6 Hz, 1H); C-NMR (DMSO-d ) δ 155.9, 148.4, 142.1, 138.9, 135.3, 129.8, 129.7, 129.4, 128.8, 128.1,
6
1
4
28.0, 127.3, 126.2, 125.8, 125.7, 124.5, 121.2, 118.8, 114.2, 112.5, 111.7; MS (EI) m/z (relative intensity)
+
+
+
00 ([M + 2] , 85), 398 (M , 100); HRMS (EI) m/z calcd for C H N Br (M ) 398.0419, found 398.0425.
23
15
2
4
-(5-Methoxy-1H-indol-3-yl)-2-phenylquinoline (4o): White crystalline solid (crystallized from ethyl
˝
1
acetate and hexane) with a melting point of 183–185 C; H-NMR (DMSO-d ) δ 11.63 (s, 1H), 8.31
6
(dd, J = 7.2 Hz, 2H), 8.15 (d, J = 8.7 Hz, 2H), 8.13 (s, 1H), 7.85 (d, J = 2.6 Hz, 1H), 7.79 (dt, J = 7.0,
22514

Molecules 2015, 20, 22499–22519
1
1
1
.8 Hz, 1H), 7.59–7.54 (m, 3H), 7.52–7.46 (m, 2H), 6.96 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz,
H), 3.67 (s, 3H); 13C-NMR (DMSO-d ) δ 155.9, 154.1, 148.6, 143.1, 139.0, 131.7, 129.8, 129.7, 129.4,
6
28.8, 127.3, 127.2, 126.6, 126.2, 126.0 125.7, 118.4, 113.0,112.1, 112.0, 100.9, 55.3; MS (EI) m/z (relative
+
+
intensity) 350 (M , 100), 349 (18); HRMS (EI) m/z calcd for C H N O (M ) 350.1419, found 350.1422.
24
18
2
4
-(7-Methyl-1H-indol-3-yl)-2-phenylquinoline (4p): Purified by column chromatography using 1:4 ethyl
acetate and hexane. After concentration in vacuo a pale yellow solid with a melting point of
˝
63–165 C was obtained; H-NMR (DMSO-d ) δ 11.74 (s, 1H), 8.30 (d, J = 7.3 Hz, 2H), 8.15 (d,
6
1
1
J = 8.7 Hz, 2H), 8.12 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.58–7.48 (m, 4H), 7.37–7.34
13
(
m, 1H), 7.03–7.00 (m, 2H), 2.58 (s, 3H); C-NMR (DMSO-d ) δ 155.8, 148.5, 143.1, 139.0, 136.1, 129.7,
6
1
29.6, 129.4, 128.8, 127.3, 126.3, 126.1, 126.0, 126.0, 125.7, 122.4, 121.4, 120.2, 118.6, 116.7, 112.5, 16.8; MS
+
+
(EI) m/z (relative intensity) 334 (M , 100), 333 (68); HRMS (EI) m/z calcd for C H N (M ) 334.1470
24 18 2
found 334.1477.
4
-(1-Methyl-1H-indol-3-yl)-2-phenylquinoline (4q): White crystalline solid (from ethyl acetate and
˝
1
hexane) with a melting point of 138–140 C; H-NMR (DMSO-d ) δ 8.30 (d, J = 8.0 Hz, 2H), 8.17
6
(
dd, J = 10.9, 8.8 Hz, 2H), 8.11 (s, 1H), 7.91 (s, 1H), 7.80 (dd, J = 8.0, 7.1 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H),
13
7
1
1
.59–7.49 (m, 5H), 7.30 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 3.96 (s, 3H); C-NMR (DMSO-d ) δ
6
55.8, 148.5, 142.4, 139.0, 137.0, 130.7, 129.7, 129.7, 129.4, 128.8, 127.2, 126.5, 126.1, 125.9, 125.6, 122.0,
+
20.3, 119.3, 118.4, 111.0, 110.5, 32.8; MS (EI) m/z (relative intensity) 334 (M , 100), 333 (61); HRMS
+
(EI) m/z calcd for C H N (M ) 334.1470, found 334.1469.
24
18
2
4
-(2-Methyl-1H-indol-3-yl)-2-phenylquinoline (4r): Purified by column chromatography using 1:4 ethyl
˝
acetate and hexane. After concentration in vacuo a brown solid with a melting point of 98–100 C was
obtained; H-NMR (DMSO-d ) δ 8.73 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 7.6 Hz, 2H), 7.87 (s,
1
6
1
H), 7.81 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H), 7.42–7.29 (m, 4H), 7.17 (t,
13
J = 7.3 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 2.21 (s, 3H); C-NMR (DMSO-d ) δ 157.4, 149.1, 143.5, 140.0,
6
1
1
35.6, 133.8, 129.9, 129.8, 129.4, 129.0, 128.7, 127.9, 127.2, 126.8, 126.0, 121.9, 121.2, 120.3, 119.1, 110.9,
+
10.8, 12.7; MS (EI) m/z (relative intensity) 334 (M , 100), 333 (55), HRMS (EI) m/z calcd for C H N
24
18
2
+
(M ) 334.1470, found 334.1464.
2
-Phenyl-4-(2-phenyl-1H-indol-3-yl)quinoline (4s): Purified by column chromatography using 1:4 ethyl
˝
acetate and hexane. After concentration in vacuo an orange solid with a melting point of 282–284 C
was obtained; H-NMR (DMSO-d ) δ 12.00 (s, 1H), 8.21 (d, J = 7.3 Hz, 2H), 8.15 (d, J = 8.4 Hz, 1H), 8.04
1
6
(
(
s, 1H), 7.72–7.65 (m, 2H), 7.60 (d, J = 8.1 Hz, 1H), 7.50–7.42 (m, 5H), 7.22 (t, J = 7.7 Hz, 1H), 7.26–7.16
13
m, 5H), 7.01 (t, J = 7.5 Hz, 1H); C-NMR (DMSO-d ) δ 155.9, 148.4, 143.6, 138.7, 136.3, 135.9, 131.9,
6
1
1
29.7, 129.7, 129.5, 128.9, 128.8, 128.6, 127.7, 127.5, 127.2, 126.4, 126.1, 126.0, 122.4, 120.6, 120.1, 118.7,
+
11.7, 109.1; MS (EI) m/z (relative intensity) 396 (M , 100), 395 (36), 193 (14); HRMS (EI) m/z calcd for
+
C H N (M ) 396.1626, found 396.1634.
29
20
2
4
-(1H-Indol-3-yl)-8-methyl-2-phenylquinoline (4t): Purified by column chromatography using 1:4 ethyl
acetate and hexane. After concentration in vacuo a pale orange solid with a melting point of
˝
02–104 C was obtained; H-NMR (CDCl ) δ 11.75 (s, 1H), 8.35 (d, J = 7.5 Hz, 2H), 8.13 (s, 1H), 7.99
3
1
1
(
1
1
d, J = 8.3 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.63–7.46 (m, 6H), 7.40 (t, J = 8.1 Hz, 1H), 7.22 (t, J = 7.2 Hz,
13
H), 7.10 (t, J = 7.4 Hz, 1H), 2.87 (s, 3H); C-NMR (CDCl ) δ 154.4, 147.3, 143.2, 139.3, 137.0, 136.6,
3
29.6, 129.3, 128.8, 127.2, 126.5, 126.4, 125.7, 124.0, 121.9, 120.0, 119.1, 118.3, 112.4, 112.2, 18.2; MS (EI)
+
+
m/z (relative intensity) 334 (M , 100), 333 (30), 219 (30); HRMS (EI) m/z calcd for C H N (M )
24
18
2
3
34.1470, found 334.1471.
4
-(2,5-Dimethyl-1H-indol-3-yl)-2-phenylquinoline (4u): Purified by column chromatography using 1:4
ethyl acetate and hexane. After concentration in vacuo an orange solid with a melting point of
˝
1
1
1
2
81–183 C was obtained; H-NMR (CDCl ) δ 8.27 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 7.4 Hz, 3H), 7.90 (s,
3
H), 7.84 (d, J = 8.3 Hz, 1H), 7.73 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 7.54 (t, J = 7.2 Hz, 2H), 7.49–7.41 (m,
13
H), 7.31 (d, J = 8.2 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 2.38 (s, 3H), 2.37 (s, 3H); C-NMR
2515
2

Molecules 2015, 20, 22499–22519
(
1
3
CDCl ) δ 157.3, 149.2, 143.4, 140.3, 133.9, 133.6, 130.3, 129.9, 129.7, 129.4, 129.1, 129.0, 127.9, 127.3,
3
+
26.8, 126.1, 123.7, 121.2, 119.0, 110.9, 110.4, 21.7, 13.0; MS (EI) m/z (relative intensity) 348 (M , 100),
+
47 (35), 166 (11); HRMS (EI) m/z calcd for C H N (M ) 348.1626, found 348.1632.
25
20
2
2
-Phenylquinoline (5a): Purified by column chromatography using 1:6 ethyl acetate and hexane. After
˝
1
concentration in vacuo a white solid with a melting point of 84–86 C was obtained; H-NMR (CDCl )
3
δ 8.46 (d, J = 8.7 Hz, 1H), 8.28 (d, J = 7.1 Hz, 2H), 8.15 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 8.00 (d,
J = 7.8 Hz, 1H), 7.79 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.62–7.45 (m, 4H); 13C-NMR (CDCl ) δ 156.1, 147.6,
3
1
2
38.7, 137.2, 130.0, 129.6, 129.1, 128.9, 127.8, 127.2, 127.0, 126.5, 118.8; MS (EI) m/z (relative intensity)
+
+
05 (M , 100), 204 (78); HRMS (EI) m/z calcd for C H N (M ) 205.0891, found 205.0889.
15
11
8
-Methyl-2-phenylquinoline (5v): Purified by column chromatography using 1:6 ethyl acetate and
1
hexane. After concentration in vacuo an orange oil was obtained; H-NMR (CDCl ) δ 8.30 (d,
3
J = 7.5 Hz, 2H), 8.18 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.61–7.54
13
(
m, 3H), 7.49 (t, J = 7.1 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 2.94 (s, 3H); C-NMR (CDCl ) δ 155.7,
3
1
47.4, 140.1, 137.9, 137.1, 129.9, 129.4, 129.0, 127.7, 127.3, 126.2, 125.6, 118.4, 18.1; MS (EI) m/z (relative
+
+
intensity) 219 (M , 100); HRMS (EI) m/z calcd for C H N (M ) 219.1048, found 219.1044.
16
13
4
. Conclusions
In summary, we have successfully developed a strategy for the synthesis of 4-indolylquinoline
derivatives from 2-nitrochalcone derivatives in two steps. The process involves as a first step the
Michael addition of indole to nitrochalcones under solvent free conditions catalyzed by sulfamic
acid and the second step is a reductive cyclization of the 3-(1H-indol-3-yl)-3-(2-nitrophenyl)-1-
phenylpropan-1-one derivatives to 4-indolylquinoline derivatives via reductive cyclization by
Fe/HCl in ethanol. A wide substrate scope, clean reactions and high yields of the products are the
main merits of this strategy. This procedure offers an easy, convenient and alternative method to
existing methodologies for the synthesis of indolylquinoline derivatives.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/
1
2/19862/s1.
Acknowledgments: Financial support for this work by the Ministry of Science and Technology of China
MOST 103-2113-M-003-008-MY3), National Taiwan Normal University (103-07-C) and Instrumentation Centre
(
at National Taiwan Normal University is gratefully acknowledged. The authors are grateful to Hsiu-Ni Huan
and Chiu-Hui He for providing mass and NMR spectral data presented in this paper.
Author Contributions: Ching-Fa Yao, Wen-Chang Chen, Chan-Chieh Lin, conceived and designed the
experiments; Wen-Chang Chen, Chan-Chieh Lin, Chun-Wei Kuo, and Chia-Yu Huang performed the
experiments; Chia-Yu Huang, Chun-Wei Kuo analyzed the data; Veerababurao Kavala and Ching-Fa Yao wrote
the paper.
Conflicts of Interest: The authors declare no conflicts of interest.
References
1
2
.
.
Van Order, R.B.; Lindwall, H.G. Indole. Chem. Rev. 1942, 30, 69–96.
Finlayson, R.; Pearce, A.N.; Page, M.J.; Kaiser, M.; Bourguet-Kondracki, M.L.; Harper, J.L.; Webb, V.L.;
Copp, B.R. Didemnidines A and B, Indole Spermidine Alkaloids from the New Zealand Ascidian Didemnum
sp. J. Nat. Prod. 2011, 74, 888–892. [CrossRef] [PubMed]
3
.
Koyama, K.; Hirasawa, Y.; Nugroho, A.E.; Hosoya, T.; Hoe, T.C.; Chan, K.L.; Morita, H. Alsmaphorazines
A and B, Novel Indole Alkaloids from Alstonia pneumatophore. Org. Lett. 2010, 12, 4188–4191. [CrossRef]
[PubMed]
4
.
.
Afzal, O.; Kumar, S.; Haider, M.R.; Ali, M.R.; Kumar, R.; Jaggi, M.; Bawa, S. A review on anticancer potential
of bioactive heterocycle quinoline. Eur. J. Med. Chem. 2015, 97, 871–910. [CrossRef] [PubMed]
Chung, P.Y.; Bian, Z.X.; Pun, H.Y.; Chan, D.; Chan, A.S.C.; Chui, C.H.; Tang, J.C.O.; Lam, K.H. Recent
advances in research of natural and synthetic bioactive quinolones. Future Med. Chem. 2014, 7, 947–967.
5
22516

Molecules 2015, 20, 22499–22519
6
.
.
Michael, J.P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2005, 22, 627–646. [CrossRef]
PubMed]
Liu, C.Y.; Wu, P.T.; Wang, J.P.; Fan, P.W.; Hsieh, C.H.; Su, C.L.; Chiu, C.C.; Yao, C.F.; Fang, K. An
indolylquinoline derivative promotes apoptosis in human lung cancer cells by impairing mitochondrial
functions. Apoptosis 2015, 20, 1471–1482. [CrossRef] [PubMed]
[
7
8
.
.
Bhowal, S.K.; Lala, S.; Hazra, A.; Paira, P.; Banerjee, S.; Mondal, N.B.; Chakraborty, S. Synthesis and
2
1
assessment of fertility-regulating potential of 2-(2 -chloroacetamidobenzyl)-3-(3 -indolyl) quinoline in
adult rats as a male contraceptive agent. Contraception 2008, 77, 214–222. [CrossRef] [PubMed]
Kuethe, J.T.; Wong, A.; Qu, C.; Smitrovich, J.; Davies, I.W.; Hughes, D.L. Synthesis of 5-Substituted-1H-
indol-2-yl-1H-quinolin-2-ones: A Novel Class of KDR Kinase Inhibitors. J. Org. Chem. 2005, 70, 2555–2567.
9
[CrossRef] [PubMed]
1
0. Payack, J.F.; Vazquez, E.; Matty, L.; Kress, M.H.; McNamara, J. A Concise Synthesis of a Novel
Antiangiogenic Tyrosine Kinase Inhibitor. J. Org. Chem. 2005, 70, 175–178. [CrossRef] [PubMed]
1
1. Maguire, M.P.; Sheets, K.R.; McVety, K.; Spada, A.P.; Zilbersteint, A. A New Series of PDGF Receptor
Tyrosine Kinase Inhibitors: 3-Substituted Quinoline Derivatives. J. Med. Chem. 1994, 37, 2129–2137.
[CrossRef]
1
1
1
1
1
2. Oliva, B.; Miller, K.; Caggiano, N.; O’Neill, A.J.; Cuny, G.D.; Hoemann, M.Z.; Hauske, J.R.; Chopra, I.
Biological Properties of Novel Antistaphylococcal Quinoline-Indole Agents. Antimicrob. Agents Chemother.
2
003, 47, 458–466. [CrossRef] [PubMed]
3. Hoemam, M.Z.; Kumaravel, G.; Xie, R.L.; Rossi, R.F.; Meyer, S.; Sidhu, A.; Cunny, G.D.; Hauske, J.R.
Potent In vitro methicillin-resistant Staphylococcus aureus activity of 2-(1H-indol-3-yl)quinoline derivatives.
Bioorg. Med. Chem. Lett. 2000, 10, 2675–2678. [CrossRef]
4. Birkinshaw, T.N.; Teague, S.J.; Beech, C.; Bonnert, R.V.; Hill, S.; Patel, A.; Reakes, S.; Sanganee, H.;
Dougall, I.G.; Phillips, T.T.; et al. Discovery of potent CRTh2 (DP ) receptor antagonists. Bioorg. Med.
2
Chem. Lett. 2006, 16, 4287–4290. [CrossRef] [PubMed]
5. Kuriyama, M.; Matsuo, S.; Shinozawa, M.; Onomura, O. Ether-Imidazolium Carbenes for Suzuki–Miyaura
Cross-Coupling of Heteroaryl Chlorides with Aryl/Heteroarylboron Reagents. Org. Lett. 2013, 15,
2
716–2719. [CrossRef] [PubMed]
6. Kumar, K.S.; Kumar, S.K.; Sreenivas, B.Y.; Gorja, D.R.; Kapavarapu, R.; Rambabu, D.; Krishna, G.R.;
Reddy, C.M.; Rao, M.V.B.; Parsa, K.V.L.; Pal, M. C–C bond formation at C-2 of a quinoline ring: Synthesis of
2
-(1H-indol-3-yl)quinoline-3-carbonitrile derivatives as a new class of PDE4 inhibitors. Bioorg. Med. Chem.
2
012, 20, 2199–2207. [CrossRef] [PubMed]
1
1
1
7. Brasse, M.; Ellman, J.A.; Bergman, R.G. A facile, metal- and solvent-free, autoxidative coupling of
quinolones with indoles and pyrroles. Chem. Commun. 2011, 5019–5021. [CrossRef] [PubMed]
8. Mahato, S.B.; Mandal, N.B.; Chattopadhyay, S.; Nandia, G.; Luger, P.; Weber, M. Synthesis of
indolylquinolines under Friedel-Crafts reaction conditions. Tetrahedron 1994, 50, 10803–10812. [CrossRef]
9. Khalafi-Nezhad, A.; Sarikhani, S.; Shahidzadeh, E.S.; Panahi, F. L-Proline-promoted three-component
reaction of anilines, aldehydes and barbituric acids/malononitrile: Regioselective synthesis of
5
2
-arylpyrimido[4,5-b]quinoline-diones and 2-amino-4-arylquinoline-3-carbonitriles in water. Green Chem.
012, 14, 2876–2884. [CrossRef]
2
2
0. Kumar, S.; Sahu, D.P. Friedel-Crafts heteroarylation of (hetero)arenes: A facile entry to 4-(hetero)aryl
quinazolines and quinolones. J. Hetero. Chem. 2009, 46, 748–755. [CrossRef]
1. Nishida, A.; Miyashita, N.; Fuwa, M.; Nakagawa, M. Synthesis of (3-indolyl)heteroaromatics by
suzuki-miyaura coupling and their inhibitory activity in lipid peroxidation. Heterocycles 2003, 59, 473–476.
[CrossRef]
2
2. Ciattini, P.G.; Morera, E.; Ortar, G. An efficient synthesis of 3-substituted indoles by palladium-catalyzed
coupling reaction of 3-tributylstannylindoles with organic triflates and halides. Tetrahedron Lett. 1994, 35,
2
405–2408. [CrossRef]
3. Arcadi, A.; Chiarini, M.; Marinelli, F.; Picchini, S. A Concise One-Pot Approach to the Synthesis of
-(1H-Indol-3-yl)quinolones. Synthesis 2011, 4084–4090.
4. Zanwar, M.R.; Gawande, S.D.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Iron(III) Chloride Catalyzed Synthesis of
Highly Substituted Indolyl-Tetrahydroquinoline Derivatives by Using Indolylnitroalkene as Dienophiles
2
2
4
22517

Molecules 2015, 20, 22499–22519
and Its Application to the Synthesis of Indolo-Benzonaphthyridine Derivatives. Adv. Synth. Catal. 2014,
3
56, 3849–3860. [CrossRef]
2
2
2
5. Rajawinslin, R.R.; Ichake, S.S.; Kavala, V.; Gawande, S.D.; Huang, Y.-H.; Kuo, C.-W.; Yao, C.-F. Iron/acetic
acid mediated synthesis of 6, 7-dihydrodibenzo [b, j][1,7] phenanthroline derivatives via intramolecular
reductive cyclization. RSC Adv. 2015, 5, 52141–52153. [CrossRef]
6. Rajawinslin, R.R.; Gawande, S.D.; Kavala, V.; Huang, Y.-H.; Kuo, C.-W.; Kuo, T.-S.; Chen, M.-L.; He, C.-H.;
Yao, C.-F. Iron/acetic acid mediated intermolecular tandem C–C and C–N bond formation: an easy access
to acridinone and quinoline derivatives. RSC Adv. 2014, 4, 37806–37811. [CrossRef]
7. Ramesh, C.; Lei, P.M.; Janreddy, D.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Synthesis of Indolylquinolines,
Indolylacridines, and Indolylcyclopenta[b]quinolines from the Baylis–Hillman Adducts:
An
in Situ [1,3]-Sigmatropic Rearrangement of an Indole Nucleus to Access Indolylacridines and
Indolylcyclopenta[b]quinolones. J. Org. Chem. 2012, 77, 8451–8464. [CrossRef] [PubMed]
2
8. Janreddy, D.; Kavala, V.; Bosco, J.W.; Kuo, C.-W.; Yao, C.-F. An Easy Access to Carbazolones and
2
,3-Disubstituted Indoles. Eur. J. Org. Chem. 2011, 2360–2365. [CrossRef]
9. Ramesh, C.; Raju, B.R.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. A simple and facile route for the synthesis of
H-1,4-benzoxazin-3-(4H)-ones via reductive cyclization of 2-(2-nitrophenoxy) acetonitrile adducts in the
2
2
presence of Fe/acetic acid. Tetrahedron 2011, 67, 1187–1192. [CrossRef]
3
3
0. Ramesh, C.; Kavala, V.; Kuo, C.-W.; Raju, B.R.; Yao, C.-F. An Unprecedented Route for the Synthesis
1
of 3, 3 -Biindoles by Reductive Cyclization of 3-[2-Nitro-1-(2-nitrophenyl)ethyl]-1H-indoles Mediated by
Iron/Acetic Acid. Eur. J. Org. Chem. 2010, 3796–3801. [CrossRef]
1. Ramesh, C.; Kavala, V.; Raju, B.R.; Kuo, C.-W.; Yao, C.-F. A simple and facile route for the synthesis of
2
H-1, 4-benzoxazin-3-(4H)-ones via reductive cyclization of 2-(2-nitrophenoxy) acetonitrile adducts in the
presence of Fe/acetic acid. Tetrahedron Lett. 2010, 51, 5234–5237. [CrossRef]
3
3
3
2. Ramesh, C.; Kavala, V.; Raju, B.R.; Kuo, C.-W.; Yao, C.-F. Novel synthesis of indolylquinoline derivatives
via the C-alkylation of Baylis–Hillman adducts. Tetrahedron Lett. 2009, 50, 4037–4041. [CrossRef]
3. Lee, K.Y.; Lee, Y.; Kim, J.N. Synthesis of β,γ-Disubstituted α-Methylene-γ-butyrolactams Starting from the
Baylis-Hillman Adducts. Bull. Korean Chem. Soc. 2007, 28, 143–146. [CrossRef]
4. Basavaiah, D.; Rao, J.S.; Raju, J. Simple, Facile, and One-Pot Conversion of the Baylis´Hillman Adducts
into Functionalized 1,2,3,4-Tetrahydroacridines and Cyclopenta[b]quinolones. J. Org. Chem. 2004, 69,
7
379–7382. [CrossRef] [PubMed]
3
5. Jonsson, S.; Arribas, C.S.; Wendt, O.F.; Siegel, J.S.; Warnmark, K. Synthesis of 2-pyridone-fused
1
,2 -bipyridine derivatives. An unexpectedly complex solid state structure of 3,6-dimethyl-9H-4,5,9-
2
triazaphenanthren-10-one. Org. Biomol. Chem. 2005, 3, 996–1001. [CrossRef] [PubMed]
6. Basavaiah, D.; Raju, J.; Rao, J.S. Applications of Baylis–Hillman adducts: a simple, convenient, and one-pot
synthesis of 3-benzoylquinolines. Tetrahedron Lett. 2006, 47, 73–77. [CrossRef]
7. Mahmoudi, A.; Jafari, A.S.; Saeedi, H. Firouzabadi Sulfonic acid-functionalized magnetic nanoparticles
as a recyclable and eco-friendly catalyst for atom economical Michael addition reactions and bis indolyl
methane synthesis. RSC Adv. 2015, 5, 3023–3030. [CrossRef]
3
3
3
8. Li, S.-S.; Lin, H.; Zhanga, X.-M.; Dong, L. Ruthenium-catalyzed direct C3 alkylation of indoles with
α,β-unsaturated ketones. Org. Biomol. Chem. 2015, 13, 1254–1263. [CrossRef] [PubMed]
9. Veisi, H.; Maleki, B.; Eshbala, H.; Veisi, H.; Masti, R.; Ashrafi, S.S.; Baghayeri, M. In situ generation
of Iron(III) dodecyl sulfate as Lewis acid-surfactant catalyst for synthesis of bis-indolyl, tris-indolyl,
Di(bis-indolyl), Tri(bis-indolyl), tetra(bis-indolyl)methanes and 3-alkylated indole compounds in water.
RSC Adv. 2014, 4, 30683–30688. [CrossRef]
3
4
0. Gohain, M.; Jacobs, J.; Marais, C.; Bezuidenhoudt, B.C.B. Al(OTf) Catalysed Friedel-Crafts Michael Type
3
Addition of Indoles to α,β-Unsaturated Ketones with PEG-200 as Recyclable Solvent. Aust. J. Chem. 2013,
6
6, 1594–1599. [CrossRef]
4
1. Zhan, Z.-P.; Yang, R.-F.; Lang, K. Samarium triiodide-catalyzed conjugate addition of indoles with
electron-deficient olefins. Tetrahedron Lett. 2005, 46, 3859–3862. [CrossRef]
4
2. Kumar, V.; Kaur, S.; Kumar, S. ZrCl catalyzed highly selective and efficient Michael addition of heterocyclic
4
enamines with α,β-unsaturated olefins. Tetrahedron Lett. 2006, 47, 7001–7005. [CrossRef]
22518

Molecules 2015, 20, 22499–22519
4
4
3. Yin, P.; Liu, N.; Deng, Y.-X.; Chen, Y.; Deng, Y.; He, L. Synthesis of 2,4-Diaminoquinazolines and Tricyclic
Quinazolines by Cascade Reductive Cyclization of Methyl N-Cyano-2-nitrobenzimidates. J. Org. Chem.
2
012, 77, 2649–2658. [CrossRef] [PubMed]
4. Sandelier, M.J.; Shong, P.D. Reductive Cyclization of O-Nitrophenyl Propargyl Alcohols: Facile Synthesis
of Substituted Quinolines. Org. Lett. 2007, 9, 3209–3212. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds 3a–3v, 4a–4u are available from the authors.
©
2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open
access article distributed under the terms and conditions of the Creative Commons by
Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
22519