Synthesis of novel indolo[2,3-c]quinolinones via Ugi-4CR/palladium- catalyzed arylation

Article abstract of DOI:10.1016/j.tet.2014.03.079

In this letter, an expedient method was developed for the construction of novel indolo[2,3-c]quinolinone derivatives via palladium-catalyzed arylation of Ugi adducts obtained from the reaction of indole-2-carboxylic acid, various aromatic aldehydes, 2-bro

Full text of DOI:10.1016/j.tet.2014.03.079

Tetrahedron 70 (2014) 3931e3934
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Synthesis of novel indolo[2,3-c]quinolinones via Ugi-4CR/
palladium-catalyzed arylation
Mohammad Ali Rasouli a, Mohammad Mahdavi b, Loghman Firoozpour c,
,c,
Abbas Shafiee b, Alireza Foroumadi b
*
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
b Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medicinal Sciences,
Tehran, Iran
c Drug Design & Development Research Center, Tehran University of Medicinal Sciences, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
In this letter, an expedient method was developed for the construction of novel indolo[2,3-c]quinolinone
derivatives via palladium-catalyzed arylation of Ugi adducts obtained from the reaction of indole-2-
carboxylic acid, various aromatic aldehydes, 2-bromoanilines, and isocyanides. The reaction proceeded
efficiently with various starting materials to produce the indoloquinolinone scaffolds in good yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 22 January 2014
Received in revised form 12 March 2014
Accepted 24 March 2014
Available online 13 April 2014
Keywords:
Indolo[2,3-c]quinolinone
Ugi reactions
Pd-catalyzed
Heterocycles
1. Introduction
(Fig. 1, B), and 5,10-dihydro-11H-indolo[3,2-b]quinolin-11-one
(Fig. 1, C) extracted from the roots of Cryptolepis sanguinolenta1,2
Fused indole-quinoline derivatives are significant heterocyclic
compounds due to their abundance in a wide spectrum of phar-
maceuticals and natural products. For instance, naturally occurring
indoloquinoline alkaloids; cryptolepine (Fig. 1, A), neocryptolepine
have shown various biological properties, such as antimalarial,3,4
antibacterial, and antifungal,5,6 cytotoxicity, and antiplasmodial
activities.7 On the other hand, studying this class of heterocyclic
rings elucidated the importance and necessity of indoloquinolines
in drug discovery8 and among them indolo[2,3-c]quinolinone de-
rivatives (Fig. 1, D) attracted our attention because they possess
remarkable properties. Some derivatives prepared by Fryer et al.9
exhibited anti-tumor activity by suppressing the growth of trans-
plantable tumors. Also antitumor activity of these heterocycles has
been separately proved by Fukushima et al.10 and Grunberg et al.11
In addition, indolo[2,3-c]quinolinone derivatives have shown good
inhibition towards tubulin polymerization.12
In spite of the fact that indolo[2,3-c]quinolinones are very im-
portant, few efficient synthetic methods have been reported. Some
of them are based on photochemical reactions;13 oxidative photo-
chemical cyclization of amides by Kanaoka et al.,13a photo-
stimulated intramolecular S1RN reactions with N-(2-chlorophenyl)-
1H-indole-2-carboxamides by Vaillard et al.,13b and recently, se-
quential photocyclizations of 3-(2-azidophenyl)-N-phenyl-
acrylamides by Li et al.13c 5,7-Dihydro-6H-indolo[2,3-c]quinolin-6-
one derivatives were synthesized through the reaction of 1-methyl-
3-formyloxindole with phenylhydrazines by Tokmakov et al.14
Apart from these methods, Hostyn et al.15 described a procedure
Fig. 1. Cryptolepine A, neocryptolepine B, 10-dihydro-11H-indolo[3,2-b]quinolin-11-
one C, and indolo[2,3-c]quinolinone derivatives D.
* Corresponding author. Tel.: þ98 21 66954708; fax: þ98 21 66461178; e-mail
addresses: aforoumadi@yahoo.com, aforoumadi@tums.ac.ir (A. Foroumadi).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.079

3932
M.A. Rasouli et al. / Tetrahedron 70 (2014) 3931e3934
based on Pd-catalyzed intramolecular arylation of 3-(2-
bromophenylamino)quinolones under microwave irradiation.
Focusing on the above mentioned properties of indolo[2,3-c]
quinolinones9e12 and also lack of diverse reports in the literature
reveals that they are still highly desired. Therefore, following our
previous works on the multicomponent reactions and synthesis of
new N-heterocyclic compounds,16 a two-step approach toward the
synthesis of novel indolo[2,3-c]quinolinone derivatives 6 is re-
ported via palladium-catalyzed arylation of Ugi adducts obtained
from the reaction of indole-2-carboxylic acid 1, aromatic aldehydes
2, 2-bromoanilines 3, and isocyanides 4 (Scheme 1).
this regard, a wide range of metal-catalyzed procedures have been
developed.17 Considering our previous experience in Pd-catalyzed
intramolecular preparation of novel quinolinones;16b herein, we
investigated Pd-catalyzed synthesis of indolo[2,3-c]quinolinone
derivatives 6aej from versatile starting materials bearing indole
moiety 5aej (Table 1).
In the search for optimized conditions, we selected N-(2-
bromophenyl)-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-1H-
indole-2-carboxamide (5a) as a model substrate and the C-aryla-
tion reaction was conducted in the presence of different palladium
sources, such as palladium acetate Pd(OAc)2, palladium(II) chloride
Scheme 1. Synthesis of indolo[2,3-c]quinolinone derivatives 6.
2. Results and discussion
PdCl2, and tetrakis(triphenylphosphine)palladium(0) Pd[(PPh)3]4
in various solvents as summarized in Table 2. Our studies demon-
strated that using triphenyl phosphine (PPh3) and potassium car-
bonate (K2CO3) is essential for the desired C3-arylation of indole
ring to proceed. As can be seen in Table 2, it was perceived that
Pd(OAc)2 catalyzed the reaction much better than PdCl2 and Pd
[(PPh)3]4 and 5 mol % of catalyst was enough for the above men-
tioned reaction.
To obtain the title compounds 6, we began our studies by the
preparation of several Ugi adducts 5. It was found that all com-
pounds 5 were easily prepared by the reaction of indole-2-
carboxylic acid 1, various aromatic aldehydes 2, 2-bromoanilines
3, and isocyanides 4 in methanol at ambient temperature in the
absence of any catalysts or additives within 24 h (Scheme 1). It is
worthy to mention that after completion of the reaction, the pre-
cipitated products 5 were filtered off and used for further reaction
without any purification (Table 1, 5aej).
Our solvent screening indicated the significance of solvent and
its effect on the yield of reaction. Among tested solvents; dime-
thylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile
Table 1
Synthesis of indolo[2,3-c]quinolinone derivatives 6aej
Entry
R1
Ar
R2
Ugi adduct 5
Yield (%)a
Product 6
Yield (%)a
Mp (ꢀC)
1
2
3
4
5
7
8
8
9
H
H
C6H5e
Cyclohexyl
Cyclohexyl
1,1,3,3-Tetramethylbutyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
1,1,3,3-Tetramethylbutyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
5a
5b
5c
5d
5e
5f
5g
5h
5i
92
95
83
93
86
88
66
90
94
83
6a
6b
6c
6d
6e
6f
6g
6h
6i
85
67
65
52
55
82
51
76
55
69
205e206
233e235
249e250
243e245
202e203
>250
>250
>250
>250
208e210
3-OMeeC6H4e
3,4-diOMeeC6H3e
3,5-diOMeeC6H3e
4-MeeC6H4e
4-BreC6H4e
4-BreC6H4e
4-CleC6H4e
3-CleC6H4e
1-Naphthyl
Me
Me
H
Me
Me
H
H
H
10
5j
6j
a
Isolated yields.
In the next step, we investigated the further C-3 arylation re-
action of compounds 5. Selective C-2 and C-3 arylation of indoles is
one of the most significant and attractive tools for carbonecarbon
bond formation. At this juncture, direct C-arylation of free indoles
have led to many pioneering advances and is a fundamental ob-
jective for the advancement of substituted indole synthesis.17 In
(CH3CN), and toluene (PhCH3); toluene was the best choice. It is
worth mentioning that in all cases, temperature had a key role and
the reaction needed to be heated at reflux. In this manner, carrying
out the model reaction in the presence of 5 mol % of Pd(OAc)2 in
toluene under reflux conditions led to the formation of 6a within
24 h in 85% yield. The structure of 6a was confirmed by analytical

M.A. Rasouli et al. / Tetrahedron 70 (2014) 3931e3934
3933
Table 2
24e48 h. After that the mixture was filtered off and the solvent was
removed under reduced pressure. The resulting residue was
extracted with ethyl acetate and purified by column chromatog-
raphy (ethyl acetate/petroleum ether¼1/3 as eluent and silica gel as
stationary phase).
Optimization of reaction conditions to synthesize compound 6a
Entry
Solvent
Pd sourcea
Yield (%)b
1
2
3
4
5
6
7
DMSO
DMF
DMF
CH3CN
PhCH3
PhCH3
PhCH3
Pd(OAc)2
Pd(OAc)2
Pd[(PPh)3]4
Pd(OAc)2
Pd(OAc)2
PdCl2
12
62
43
42
85
22
47
4.2.1.1. N-Cyclohexyl-2-(6-oxo-6,7-dihydro-5H-indolo[2,3-c]qui-
nolin-5-yl)-2-phenylacetamide 6a. Yield: 85%; mp 205e206 ꢀC; IR
(KBr, cmꢁ1
CDCl3)
) n
: 3406, 3254 (NH), 1662, 1634 (CO). 1H NMR (500 MHz,
ppm: 1.21e1.96 (m, 10H, cyclohexyl), 4.07 (m, 1H, NCH,
Pd[(PPh3)]4
d
a
The model reaction was carried out in the presence of Pd catalyst (5 mol %), PPh3
cyclohexyl), 5.95 (s, 1H, CH), 6.76e7.63 (m, 13H, ArH), 7.96 (br s, 1H,
(15 mol %), and K2CO3 (3 mmol) under reflux.
NH), 10.90e11.00 (br s, 1H, NH). 13C NMR (125 MHz, DMSO-d6)
b
Isolated yields.
d
ppm: 24.6, 24.8, 25.1, 31.8, 32.1, 48.2, 57.1, 105.5, 111.8, 113.7, 118.4,
information obtained from mass spectrometry, IR, and NMR
spectroscopies.
120.8, 121.2, 121.7, 122.5, 124.2, 124.8, 126.9, 127.8, 128.0, 128.8,
136.3, 137.7, 137.8, 140.3, 159.6, 166.8. MS (m/z): 449 (Mþ, 9), 350
(100), 324 (83), 293 (32), 217 (93), 205 (16), 190 (47), 83 (27), 55
(38). Anal. Calcd for C29H27N3O2: C, 77.51; H, 6.06; N, 9.35. Found: C,
77.57; H, 6.03; N, 9.32.
Then, in order to show the generality and scope of this effective
protocol, we utilized various Ugi adducts 5 and achieved the C-3
arylation reaction under the optimized conditions to obtain dif-
ferent indolo[2,3-c]quinolinones 6 (Table 1, Scheme 1). As can be
seen in Table 1, all derivatives underwent facile C-arylation and
electronic effects of substituents attached to the aromatic rings did
not influence the arylation reaction significantly.
4.2.1.2. N-Cyclohexyl-2-(3-methoxyphenyl)-2-(6-oxo-6,7-
dihydro-5H-indolo[2,3-c]quinolin-5-yl)acetamide 6b. Yield: 67%;
mp 235e236 ꢀC; IR (KBr, cmꢁ1
)
n
: 3421, 3275 (NH), 1631, 1620 (CO).
1H NMR (500 MHz, DMSO-d6)
d ppm: 0.98e1.81 (m, 10H, cyclo-
3. Conclusion
hexyl), 3.68 (s, 3H, OMe), 3.68 (m, 1H, NCH, cyclohexyl), 6.72 (d,
J¼8.0 Hz, 1H, ArH), 6.82 (d, J¼7.3 Hz, 1H, ArH), 6.86 (s, 1H, CH), 7.18
(t, J¼8.0 Hz, 1H, ArH), 7.29e7.35 (m, 5H, ArH), 7.40 (t, J¼8.0 Hz, 1H,
ArH), 7.66 (d, J¼8.0 Hz, 1H, ArH), 7.94 (1H, NH), 8.24 (d, J¼8.0 Hz,
1H), 8.28 (s, 1H, ArH), 12.67 (s, 1H, NH). 13C NMR (125 MHz, DMSO-
In conclusion, we have described a facile, efficient, and user-
friendly method for the synthesis of indolo[2,3-c]quinolinone de-
rivatives. At first, various Ugi adducts were prepared by the 4-CR of
indole-2-carboxylic acid, aromatic aldehydes, 2-bromoanilines, and
isocyanides. Then, palladium-catalyzed C-3 arylation of indole
moiety led to the formation of corresponding products in good
yields. It should be noted that all reactions showed a good tolerance
toward various starting materials having electron-donating and
electron-withdrawing substituents. Also it is worth mentioning
that C-3 arylation of indole derivatives was successfully achieved
without disturbance and protection of the NeH function.
d6)
d ppm: 24.8, 24.9, 25.7, 30.0, 32.6, 51.7, 56.1, 71.1, 106.2, 112.6,
113.0,113.5,114.3,119.4,120.5,121.4, 122.6,123.1,125.0,125.9,130.0,
130.1, 131.4, 136.7, 139.1, 141.0, 144.8, 149.4, 161.5, 168.8. MS (m/z):
479 (Mþ, 3), 380 (39), 354 (13), 323 (9), 217 (66), 205 (12), 190 (40),
135 (25), 121 (42), 83 (89), 55 (100). Anal. Calcd for C30H29N3O3: C,
75.16; H, 6.10; N, 8.77. Found: C, 75.26; H, 6.19; N, 8.72.
4.2.1.3. 2-(3,4-Dimethoxyphenyl)-2-(2-methyl-6-oxo-6,7-
dihydro-5H-indolo[2,3-c]quinolin-5-yl)-N-(2,4,4-trimethylpentꢁa1n-2-
yl)acetamide 6c. Yield: 65%; mp 249e250 ꢀC; IR (KBr, cm
) n:
4. Experimental section
4.1. General
3435, 3277 (NH), 1629, 1619 (CO). 1H NMR (400 MHz, DMSO-d6)
d
ppm: 0.85 (s, 9H, 3ꢂMe), 1.34 (s, 6H, 2ꢂMe), 1.68 (d, J¼1e2 Hz,
CH), 1.72 (d, J¼1e2 Hz, CH), 2.40 (s, 3H, Me), 3.65 (s, 3H, OMe), 3.69
(s, 3H, OMe), 6.67 (d, J¼5.7 Hz, 1H, ArH), 6.85 (d, J¼6.3 Hz, 1H, ArH),
6.97 (s, 1H, CH), 7.13e7.19 (m, 3H, ArH), 7.29 (d, J¼5.7, 1H, ArH), 7.39
(d, J¼6.3 Hz, 1H, ArH), 7.63 (d, J¼6.3 Hz, 1H, ArH), 8.06 (s, 1H, NH),
8.23 (d, J¼5.7 Hz, 1H, ArH), 12.59 (s, 1H, NH). 13C NMR (100 MHz,
Melting points were taken on a Kofler hot stage apparatus and
are uncorrected. 1H and 13C NMR spectra were recorded on Bruker
FT-500 and FT-400, using TMS as an internal standard. The IR
spectra were obtained on a Nicolet Magna FTIR 550 spectropho-
tometer (in KBr). Mass spectra were determined on an Agilent
Technology (HP) mass spectrometer operating at an ionization po-
tential of 70 eV. The elemental analysis was performed with an
Elementar Analysensystem GmbH VarioEL CHNS mode. All reagents
and solvents were obtained from Merck and Aldrich and used
without any purification. Silica gel 60 (0.040e0.063 mm) were used
for column chromatography. Thin layer chromatography (TLC) was
performed using silica gel 60/Kieselguhr F254 precoated on Alumi-
num sheets (thickness 0.2 mm), commercially available from
Merck.
DMSO-d6)
d ppm: 20.8, 29.0, 29.1, 31.6, 31.7, 51.6, 55.1, 55.9, 56.0,
105.9, 112.1, 112.3, 112.6, 113.9, 119.3, 120.4, 121.3, 121.6, 122.6, 124.6,
125.2, 129.5, 129.8, 131.2, 136.5, 138.3, 140.6, 148.3, 148.8, 160.0,
167.6. MS (m/z): 553 (Mþ, 7), 424 (100), 398 (24), 367 (14), 248 (13),
231 (60), 219 (16), 204 (16), 166 (15), 151 (37), 57 (65). Anal. Calcd
for C34H39N3O4: C, 73.78; H, 7.11; N, 7.59. Found: C, 73.82; H, 7.15; N,
7.53.
4.2.1.4. N-Cyclohexyl-2-(3,5-dimethoxyphenyl)-2-(2-methyl-6-
oxo-6,7-dihydro-5H-indolo[2,3-c]quinolin-5-yl)acetamide 6d. Yield:
52%; mp 243e245 ꢀC; IR (KBr, cmꢁ1
)
n
: 3446, 3272 (NH), 1626, 1595
4.2. Synthesis of indolo[2,3-c]quinolinone derivatives 6
(CO). 1H NMR (500 MHz, CDCl3)
d ppm: 1.01e1.61 (m, 10H, cyclo-
hexyl), 2.57 (s, 3H, Me), 3.55 (m, 1H, NCH, cyclohexyl), 3.92 (s, 3H,
OMe), 3.97 (s, 3H, OMe), 5.85 (s, 1H, CH), 6.58e6.65 (m, 3H, ArH),
7.38 (t, J¼7.5 Hz, 1H, ArH), 7.53 (t, J¼7.5 Hz, 1H, ArH), 7.65 (s, 1H,
ArH), 7.91 (d, J¼7.5 Hz, 1H, ArH), 8.08 (s, 1H, ArH), 8.27 (s, 1H, ArH),
4.2.1. General procedure. A mixture of indole-2-carboxylic acid 1
(1 mmol), 2-bromo aniline 2 (1 mmol), aromatic aldehyde 3
(1 mmol), and isocyanide 4 (1.2 mmol) were dissolved in methanol
(10 mL) and stirred at room temperature for 24 h. After completion
of reaction, the precipitated Ugi product 5 was filtered off, washed
with petroleum ether, and used for further reactions. Then, a mix-
ture of Ugi product 5 (1 mmol), Pd(OAc)2 (5 mol %), PPh3 (15 mol %),
and K2CO3 (3 mmol) in toluene (10 mL) was heated at reflux for
8.33 (d, J¼8.0 Hz, 1H, ArH). 13C NMR (125 MHz, DMSO-d6)
d ppm:
20.9, 24.8, 25.3, 25.6, 31.4, 32.8, 48.7, 55.6, 55.6, 95.9, 104.9, 106.8,
107.1, 113.2, 118.1, 120.2, 122.8, 123.5, 126.4, 126.7, 129.3, 132.1, 138.5,
144.4, 156.5, 160.4, 160.6, 160.9, 162.6, 166.7. MS (m/z): 523 (Mþ, 4),
501 (5), 424 (67), 398 (43), 325 (37), 299 (100), 284 (20), 192 (15),

3934
M.A. Rasouli et al. / Tetrahedron 70 (2014) 3931e3934
165 (28), 152 (13), 91 (39), 83 (15), 55 (32). Anal. Calcd for
32H33N3O4: C, 73.42; H, 6.36; N, 8.03. Found: C, 73.49; H, 6.27; N,
7.99.
ArH), 7.12 (t, J¼7.2 Hz, ArH), 7.20e7.48 (m, 10H), 11.68 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6)
ppm: 24.6, 25.3, 25.4, 31.6, 32.7,
C
d
48.8, 86.3, 105.8, 108.3, 114.3, 115.3, 115.8, 117.2, 122.7, 123.0, 123.4,
124.1, 124.2, 124.7, 125.8, 127.2, 128.7, 129.7, 130.5, 133.0, 148.1, 151.9,
165.6, 169.7. MS (m/z): 485 (Mþ, 3), 483 (9), 386 (33), 384 (100), 360
(10), 358 (29), 327 (14), 234 (21), 217 (99), 205 (28), 190 (45), 83
(61), 55 (92). Anal. Calcd for C29H26N3O2Cl: C, 71.97; H, 5.42; N, 8.69.
Found: C, 72.03; H, 5.37; N, 8.64.
4.2.1.5. N-Cyclohexyl-2-(6-oxo-6,7-dihydro-5H-indolo[2,3-c]qui-
nolin-5-yl)-2-(p-tolyl)acetamide 6e. Yield: 55%; mp 202e203 ꢀC; IR
(KBr, cmꢁ1
DMSO-d6)
)
n
: 3406, 3253 (NH), 1660, 1633 (CO). 1H NMR (500 MHz,
d ppm: 0.87e2.0 (m, 10H, cyclohexyl), 2.37 (s, 3H, Me),
3.97 (m, 1H, NCH, cyclohexyl), 5.91 (s, 1H, CH), 7.31e7.56 (m, 12H,
ArH), 11.60 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6)
d
ppm: 21.9,
4.2.1.10. N-Cyclohexyl-2-(naphthalen-1-yl)-2-(6-oxo-6,7-dihydro-
24.8, 24.9, 26.6, 31.7, 32.1, 48.1, 57.8, 104.6, 112.1, 120.0, 122.0, 123.4,
125.5, 126.7, 127.2, 128.0, 129.5, 130.4, 132.6, 133.0, 133.6, 134.4,
137.7, 139.0, 159.0, 164.3. MS (m/z): 461 (Mþ, 2), 395 (5), 387 (15),
384 (8), 368 (16), 362 (25), 353 (9), 339 (14), 336 (28). Anal. Calcd
for C30H29N3O2: C, 78.01; H, 6.34; N, 9.11. Found: C, 77.91; H, 6.45;
N, 9.05.
5H-indolo[2,3-c]quinolin-5-yl)acetamide
208e210 ꢀC; IR (KBr, cmꢁ1 : 3427, 3226 (NH), 1647, 1572 (C]O). 1H
NMR (400 MHz, CDCl3) ppm: 1.13e1.75 (m, 10H, cyclohexyl), 4.09
6j. Yield:
69%;
mp
)
n
d
(m, 1H, NCH, cyclohexyl), 5.72 (s, 1H, CH), 6.27 (s, 1H, ArH), 7.10 (t,
J¼5.7 Hz, 1H, ArH), 7.18e7.60 (m, 8H, ArH), 7.67 (t, J¼5.7 Hz, 1H,
ArH), 7.81e8.02 (m, 4H, ArH), 8.24 (d, J¼6.5 Hz, 1H, NH), 11.91 (br s,
1H, NH). 13C NMR (100 MHz, CDCl3)
d ppm: 24.7, 25.5, 29.7, 30.9,
4.2.1.6. 2-(4-Bromophenyl)-N-cyclohexyl-2-(2-methyl-6-oxo-6,7-
32.3, 49.7, 71.6, 110.2, 111.0, 113.1, 115.0, 120.6, 121.5, 122.4, 123.5,
124.2, 124.9, 126.1, 126.3, 127.1, 128.3, 128.8, 129.0, 129.6, 130.9, 131.4,
132.8, 133.9, 135.7, 138.0, 140.4, 160.2, 168.1. MS (m/z): 499 (Mþ, 2),
414 (33), 400 (74), 387 (11), 374 (82), 357 (6), 248 (7), 231 (24), 218
(13), 204 (13),141 (24), 83 (88), 55 (100). Anal. Calcd for C33H29N3O2:
C, 79.36; H, 5.86; N, 8.42. Found: C, 79.74; H, 5.91; N, 8.34.
dihydro-5H-indolo[2,3-c]quinolin-5-yl)acetamide 6f. Yield: 82%;
mp>250 ꢀC; IR (KBr, cmꢁ1 : 3408, 3249 (NH), 1643, 1560. 1H NMR
) n
(500 MHz, DMSO-d6)
d ppm: 0.96e1.82 (m, 10H, cyclohexyl), 2.28
(s, 3H, Me), 3.58 (m, 1H, NCH, cyclohexyl), 6.15 (s, 1H, CH), 6.90 (t,
J¼7.5 Hz, 1H, ArH), 7.11e7.40 (m, 10H, ArH), 11.66 (s, 1H, NH). 13C
NMR (100 MHz, DMSO-d6)
d ppm: 20.8, 24.8, 25.0, 25.6, 32.6, 32.7,
48.4, 64.8, 105.0, 112.6, 120.1, 122.0, 122.1, 124.3, 126.1, 127.3, 129.5,
130.5, 130.9, 133.1, 133.4, 133.5, 133.8, 136.1, 141.1, 161.7, 168.9; MS
(m/z): 543 (2), 541 (Mþ, 2), 498 (27), 444 (7), 442 (7), 418 (80), 416
(80), 354 (85), 286 (26), 284 (26), 262 (34), 248 (26), 172 (38), 170
(38), 144 (100), 116 (51), 89 (92), 55 (55). Anal. Calcd for
Acknowledgements
This research was supported by grants from the Research
Council of Tehran University of Medical Sciences and Iranian Na-
tional Science Foundation (INSF).
C
30H28N3O2Br: C, 66.42; H, 5.21; N, 7.75. Found: C, 66.46, H, 5.18; N,
7.66.
Supplementary data
4.2.1.7. 2-(4-Bromophenyl)-2-(2-methyl-6-oxo-6,7-dihydro-5H-
indolo[2,3-c]quinolin-5-yl)-N-(2,4,4-trimethylpentan-2-yl)acetamide
6g. Yield: 51%, mp>250 ꢀC; IR (KBr, cmꢁ1
: 3407, 3242 (NH), 1641,
1575 (CO). 1H NMR (400 MHz, DMSO-d6)
ppm: 0.89 (s, 9H, 3ꢂMe),
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.079.
)
d
n
References and notes
1.31 (s, 6H, 2ꢂMe), 1.69 (d, J¼1e2 Hz, CH), 1.73 (d, J¼1e2 Hz, CH),
2.30 (s, 3H, Me), 6.19 (s, 1H, CH), 6.90 (t, J¼7.5 Hz, 1H, ArH),
7.13e7.47 (m, 10H, ArH), 11.69 (s, 1H, NH). 13C NMR (100 MHz,
1. Alajarin, M.; Molina, P.; Vidal, A. J. Nat. Prod. 1997, 60, 747.
2. Crouch, R. C.; Davis, A. O.; Spitzer, T. D.; Martin, G. E.; Sharaf, M. M. H.; Schiff, P.
L., Jr.; Phoebe, C. H., Jr.; Tackie, A. N. J. Heterocycl. Chem. 1995, 32, 1077.
3. (a) Cimanga, K.; De Bruyne, T.; Lasure, A.; Van Poel, B.; Pieters, L.; Claeys, M.;
Berghe, D. V.; Kambu, K.; Tona, L.; Vlietinck, A. J. Planta Med. 1996, 62, 22; (b)
Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlietinck, A. Tetrahedron Lett.
1996, 37, 1703; (c) Cimanga, K.; De Bruyne, T.; Pieters, L.; Vlietinck, A. J.; Turger,
C. A. J. Nat. Prod. 1997, 60, 688.
4. Lu, W.-J.; Wicht, K. J.; Wang, L.; Imai, K.; Mei, Z.-W.; Kaiser, M.; El Sayed, I. E. T.;
Egan, T. J.; Inokuchi, T. Eur. J. Med. Chem. 2013, 64, 498.
5. Cimanga, K.; De Bruyne, T.; Pieters, L.; Totte, J.; Tona, L.; Kambu, K.; Berghe, D.
V.; Vlietinck, A. J. Phytomedicine 1998, 5, 209.
DMSO-d6)
d ppm: 20.8, 29.0, 29.1, 31.5, 31.7, 48.9, 51.9, 104.9, 112.6,
120.1, 122.0,122.1, 124.3, 126.1, 127.2,129.5,130.4,130.9,133.1,133.4,
133.5, 133.8, 136.1, 141.0, 161.3, 168.6. MS (m/z): 573 (17), 571 (Mþ,
17), 444 (32), 442 (34), 418 (15), 416 (15), 314 (13), 270 (26), 236
(74), 205 (36), 175 (100), 57 (8). Anal. Calcd for C32H34N3O2Br: C,
67.13; H, 5.99; N, 7.34. Found: C, 67.20; H, 6.07; N, 7.27.
6. Boakye-Yiadom, K.; Heman-Ackah, S. M. J. Pharm. Sci. 1979, 68, 1510.
7. Van Miert, S.; Jonckers, T.; Maes, L.; Vlietinck, A.; Dommisse, R.; Lemiere, G.;
Pieters, L. Acta Hortic. 2005, 677, 91.
8. Lavrado, J.; Moreira, R.; Paulo, A. Curr. Med. Chem. 2010, 17, 2348.
9. Fryer, R. I.; Ning, R. Y.-F.; Sternbach, L. H.; Walser, A. U.S. Patent 4,014,883, 1977;
Chem. Abstr. 1977, 39450s.
4.2.1.8. 2-(4-Chlorophenyl)-N-cyclohexyl-2-(6-oxo-6,7-dihydro-
ꢀ
5H-indolo[2,3-c]quinolin-5-yl)acetamide
6h. Yield:
76%;
mp>250 ꢀC; IR (KBr, cmꢁ1
NMR (500 MHz, DMSO-d6)
)
n
: 3421, 3231 (NH), 1623, 1612 (CO). 1H
d
ppm: 0.99e1.83 (m, 10H, cyclohexyl),
3.60 (m, 1H, NCH, cyclohexyl), 6.19 (s, 1H, CH), 6.90 (t, J¼5.7 Hz, 1H,
10. Fukushima, K.; Teller, M. N.; Mountain, I. M.; Tarnowski, G. S.; Stock, C. C. J.
ArH), 7.13 (t, J¼5.7 Hz, 1H, ArH), 7.19e7.27 (m, 6H, ArH), 7.39 (d,
Reticuloendothel. Soc. 1979, 26, 187.
J¼6.3 Hz, 2H, ArH), 7.45 (d, J¼6.3 Hz, 2H, ArH), 11.69 (s, 1H, NH). 13
C
11. Grunberg, E.; Kramer, M. J.; Buck, M.; Trown, P. W. Chemotherapy 1978, 24, 77.
12. Putey, A.; Popowycz, F.; Do, Q.-T.; Bernard, P.; Talapatra, S. K.; Kozielski, F.;
Galmarini, C. M.; Joseph, B. J. Med. Chem. 2009, 52, 5916.
NMR (100 MHz, DMSO-d6)
d ppm: 24.8, 25.0, 25.6, 32.6, 32.7, 48.4,
64.7, 105.0, 112.6, 120.2, 122.1, 124.3, 126.5, 127.2, 128.0, 128.9, 130.4,
131.2, 132.6, 133.0, 133.3, 134.4, 136.1, 138.8, 161.5, 168.9. MS (m/z):
485 (0.7), 483 (Mþ, 2), 386 (3), 384 (8), 360 (14), 358 (40), 294 (28),
240 (17), 144 (100), 125 (51), 115 (42), 89 (91), 55 (91). Anal. Calcd
for C29H26N3O2Cl: C, 71.97; H, 5.42; N, 8.69. Found: C, 72.06; H,
5.49; N, 8.73.
ꢁ
13. (a) Kanaoka, Y.; Itoh, K. Synthesis 1972, 36; (b) Vaillard, V. A.; Buden, M. E.;
Martín, S. E.; Rossi, R. A. Tetrahedron Lett. 2009, 50, 3829; (c) Li, Z.; Wang, W.;
Zhang, X.; Hu, C.; Zhang, W. Synlett 2013, 73.
14. Tokmakov, G. P.; Zemlyanova, T. G.; Grandberg, I. I. Chem. Heterocycl. Compd.
1994, 30, 434.
15. Hostyn, S.; Maes, B. U. W.; Baelen, G. V.; Gulevskaya, A.; Meyers, C.; Smits, K.
Tetrahedron 2006, 62, 4676.
16. (a) Rasouli, M. A.; Mahdavi, M.; Ranjbar, P. R.; Saeedi, M.; Shafiee, A.; For-
oumadi, A. Tetrahedron Lett. 2012, 53, 7088; (b) Rasouli, M. A.; Mahdavi, M.;
Saeedi, M.; Ranjbar, P. R.; Shafiee, A.; Foroumadi, A. J. Heterocycl. Chem. http://
dx.doi.org/10.1002/jhet.2053. (c) Saeedi, M.; Mahdavi, M.; Foroumadi, A.; Sha-
fiee, A. Tetrahedron 2013, 69, 3506.
17. (a) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996; (b) Wang,
X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476; (c) Lane, B. S.; Brown,
M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050.
4.2.1.9. 2-(3-Chlorophenyl)-N-cyclohexyl-2-(6-oxo-6,7-dihydro-
5H-indolo[2,3-c]quinolin-5-yl)acetamide
6i. Yield:
55%;
mp>250 ꢀC; IR (KBr, cmꢁ1
NMR (500 MHz, DMSO-d6)
)
n
: 3411, 3257 (NH), 1634, 1572 (CO). 1H
d
ppm: 1.00e1.82 (m, 10H, cyclohexyl),
3.60 (m, 1H, NCH, cyclohexyl), 6.20 (s, 1H, CH), 6.91 (t, J¼7.2 Hz, 1H,