Synthesis of indolo[3,2-c]quinoline and pyrido[3',2':4,5][3,2- c]quinoline derivatives

Article abstract of DOI:10.1055/s-2000-6374

Potential antitumoral scaffold indolo[3,2-c]quinoline 5a was obtained by an intramolecular Heck cyclisation from the corresponding 2-iodophenyl-3- indolecarboxamide 4a. The 7-azaindole analogue 5b was prepared by the same approach. Triflate displacement o

Full text of DOI:10.1055/s-2000-6374

PAPER
549
Synthesis of Indolo[3,2-c]quinoline and Pyrido[3’,2’:4,5][3,2-c]quinoline
Derivatives
Abderrahim Mouaddib,a-c Benoît Joseph,a Aissa Hasnaoui,c Jean-Yves Méroura*
a Institut de Chimie Organique et Analytique Associé au CNRS, Université d’Orléans, BP 6759, 45067 Orléans Cedex 2, France
b Faculté des Sciences et Techniques, Béni Mellal, Université Cadi Ayyad, Morocco
c Faculté des Sciences Semlalia, Marrakech, Université Cadi Ayyad, Morocco
Fax (33) 238417281; E-mail: jean-yves.merour@univ-orleans.fr
Received 30 September 1999; revised 11 November 1999
Abstract: Potential antitumoral scaffold indolo[3,2-c]quinoline 5a
was obtained by an intramolecular Heck cyclisation from the corre-
sponding 2-iodophenyl-3-indolecarboxamide 4a. The 7-azaindole
analogue 5b was prepared by the same approach. Triflate displace-
ment of compounds 6 according to Suzuki and Stille reactions gave
the 6-substituted derivatives 7-10.
Key words: indole, 7-azaindole, palladium, cyclisation, quinoline
15% yield.23 Alkylation of oxindole with 2-nitrobenzyl
chloride after rearrangement produces three products, two
of which possess the same 11H-indolo[3,2-c]quinoline
structure.24 Cyclisation of 2-(2-aminophenyl)indole oc-
curred with phosgene25 or in a carefully controlled acidic
medium in the presence of benzoyl cyanide or acetyl
cyanide26 to give 5 or 6-phenyl or 6-methyl-11H-indo-
lo[3,2-c]quinoline. None of these methods were consid-
ered satisfactory because of the moderate yields observed.
Ellipticine1 has generated considerable interest because of
its potent antitumoral activity in animals and humans. Nu-
merous derivatives have been prepared and their biologi-
cal activities described.2,3 Among the structural
variations4 the pyridocarbazole backbone has been inves-
tigated. Thus, active 7H and 11H-pyridocarbazoles5,6 de-
rivatives I or benzocarbazoles7 have been prepared.
Recently compounds II have been reported8 to show anti-
HIV and antitumor activities.
In addition, the recent publication of two papers concern-
ing: (a) the carbonylative cyclisation of (o-aminophe-
nyl)ethynyl derivatives27 which afforded indolo[3,2-
c]quinoline compounds of type 9a in a two step procedure
and (b) the synthetic utility of triflate derivatives of b-car-
bolines,28 prompted us to report our own results.
We planned to generate the six-membered ring of the
quinoline system by an intramolecular Heck reaction29-32
of N-2-iodophenyl-3-indolecarboxamide 3a and N-2-
iodophenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide
3b prepared in two steps from easily available compounds
1a-b.33,34
As a part of our program is devoted to the search of new
anticancer agents,9-12 we became interested in the prepara-
tion of 6-substituted indolo[3,2-c]quinoline III and 6-sub-
stituted pyrido[3’,2’:4,5][3,2-c]quinoline IV derivatives
through triflates 6. The latter were obtained from the cor-
responding amides 5, which permitted us to introduce a
wide range of substituents in position-6 via well-docu-
mented palladium-mediated cross-coupling reactions. We
included the synthesis of aza-analogue IV since the 7-aza-
indole framework had not been studied as much as its in-
dolic counterpart, despite its promising biological
properties.13-22
Compound 2a was obtained from 1-phenylsulfonyl-3-
formylindole 1a by NaClO2 oxidation in dioxane/water in
82% yield. Similarly, 2b was prepared from 1-phenylsul-
fonyl-3-formylpyrido[2,3-b]pyridine 1b in 95% yield.
Amidification of 2a-b with 2-iodoaniline in the presence
of
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide
(EDCI)/ 4-dimethylaminopyridine
hydrochloride
(DMAP) afforded the corresponding amides 3a-b in 82%
and 79% yield, respectively.
In order to prevent deiodination on the phenyl during the
Heck reaction, amides 3a-b were protected35 with the
Boc group to give 4a-b, respectively. It was reported36
that secondary amides react sluggishly compared to tertia-
ry amides in Heck-type cyclisation. After much experi-
mentation (amount of catalyst, base, ligand, reaction
time), optimal cyclisation reactions were carried out on
compounds 4a-b with Pd(OAc)2 (20%), triphenylphos-
Three general approaches to the synthesis of 11H-indo-
lo[3,2-c]quinolin-6-one moiety 5 have been described in
the literature so far. Photochemical cyclo-deshydrogena-
tion of phenyl 1H-3-indolecarboxamide have been report-
ed to generate 11H-indolo[3,2-c]quinolin-6-one in only
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550
A. Mouaddib et al.
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Scheme 1
Table 1 Palladium-Catalysed Coupling Reactions of 6
phine (40%) and silver carbonate (2 equivalents) in DMF
at 100 °C for 24 hours to give tetracyclic derivatives 5a-
b in 75% and 72% yield, respectively. It should be noted
that the use of less than 20% of Pd(OAc)2 decreased the
reaction yield and initial attempts to accomplish Heck re-
action of 4 with triethylamine as base were completely un-
successful. Loss of the Boc group was observed in this
synthetic step (since the IR spectrum of 5a did not show
the NH vibration). Thus, 5a was reacted with Boc2O/
DMAP/CH3CN to obtain the N-Boc derivative 5c which
allowed to establish the presence of the NH bond. Cycli-
sation on position-2 of the indole ring and not on position-
4 was confirmed by 2D-NMR experiments. It should be
noted that no 3-spiro-2-oxindoles were formed as reported
for palladium-catalysed intramolecular alkene arylation.37
Method
1
A
Compound
Yielda
7a; X = CH
77%
76%
1
8a; X = CH
1
2
8b; X = N
72%
81%
9a; X = CH
2
2
9b; X = N
82%
96%
10a; X = CH
2
10b; X = N
89%
a Isolated yield of purified product.
Introduction of the triflate group on compounds 5a-b was
accomplished using trifluoromethanesulfonic anhydride
in dichloromethane in the presence of pyridine at room
temperature to afford 6a-b in good yields (88% and 79%,
respectively). A range of palladium-catalysed couplings
to 6 was examined to easily introduce various groups on
position-6 of the tetracyclic structure (Scheme 2).
nyl)tributyltin (1.5 equivalents) in the presence of
Pd(PPh3)4 (6%), LiCl (2.8 equivalents) in DMF at 90 °C
for 1.5 hours gave compound 7a. Similarly, coupling re-
actions between 6 and (2-furanyl)tributyltin afforded
compounds 8a-b. Suzuki reactions of 6 with 4-methox-
yphenylboronic acid (1.5 equivalents) or 2-ben-
zo[b]thiophene-2-boronic acid (1.5 equivalents) in the
presence of Pd(PPh3)4 (6%) and 2 M aqueous NaHCO3 as
base, in a mixture of toluene/ethanol (5:1) at 90 °C for 2
hours afforded compounds 9 and 10, respectively.
Heck reaction between compound 6b and methyl acrylate
(1.5 equivalents) in the presence of Pd(OAc)2 (20%),
triphenylphosphine (40%) and silver carbonate (2 equiva-
lents) was also performed in DMF at 100 °C for 3 hours to
afford azadiene 11b in 51% yield.
Scheme 2
Finally, we tried to prepare potential anticancer agents
through the introduction of an aminoalkyl chain on posi-
tion-6, which is very often encountered in anticancer
agents. Thus, 6-chloro derivative 12, obtained after treat-
Suzuki and Stille reactions afforded products 7-10 in
good yields. Stille reaction of 6a with (1-ethoxyvi-
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Synthesis of Indolo[3,2-c]quinoline and Pyrido[3’,2’:4,5][3,2-c]quinoline Derivatives
551
of 4000-600 cm-1 on a Perkin-Elmer spectrometer FT PARAGON
1000 PC. MS spectra were recorded under ion spray conditions on
a Perkin-Elmer mass spectrometer SCIEX API 300. Column chro-
matographic separations were performed on Merck silica gel 60
(0.040-0.063 mm) using petroleum ether (40-60°C). Compounds
1a32 and 1b33 were prepared according to the reported methods. Mp,
IR, MS, 1H NMR and 13C NMR data of prepared compounds 2-12
are reported in Tables 2-7.
ment of 5a with POCl3, was tentatively condensed with 2-
(diethylamino)ethylamine to afford only unprotected
compound 13.24 Palladium-catalysed aminations using
Buchwald38 or Hartwig39 conditions are under progress to
obtain the desired derivatives.
1-Phenylsulfonylindole-3-carboxylic Acid (2a)
To a solution of 1-phenylsulfonyl-3-formylindole 1a (400 mg, 1.4
mmol) in dioxane (15 mL)/ H2O (5 mL) was added NaClO2
(164 mg, 1.8 mmol) followed by sulfamic acid (774 mg, 8.0 mmol)
at r.t. The reaction was almost instantaneous and was monitored by
TLC. Saturated NaHCO3 was added, with precaution, to the solu-
tion and then the reaction was stirred for a few minutes. The solu-
tion was concentrated and the residue was dissolved in EtOAc and
washed with 10% HCl and H2O. The organic layer was dried
(MgSO4) and evaporated in vacuo to give the crude product. Re-
crystallisation gave 2a (345 mg, 82%) as white crystals.
To sum up, we have established a convenient method to
obtain indolo[3,2-c]quinoline 5a or pyrido[3’2’:4,5][3,2-
c]quinoline 5b structures through an intramolecular Heck
reaction. The 6-substituted derivatives were obtained
from the corresponding triflates 6 via Stille or Suzuki re-
action.
1-Phenylsulfonylpyrrolo[2,3-b]pyridine-3-carboxylic Acid (2b)
The same procedure applied to 1b gave 2b in 95% yield.
Mps were determined on a Buchi SMP-20 melting point apparatus
and are uncorrected. 1H NMR and 13C NMR spectra were recorded
in the indicated solvent on a Brüker Avance DPX250 (250 MHz for
proton and 62.9 MHz for carbon). Chemical shifts for 1H are given
relative to internal TMS, while the 13C chemical shifts were ob-
tained with the solvent signal set to d (CDCl3) = 77.16 ppm and
d (DMSO-d6) = 39.52 ppm. IR spectra were recorded in the range
N-(2-Iodophenyl)-1-(phenylsulfonyl)-1H-indole-3-carboxam-
ide (3a)
To a suspension of acid 2a (200 mg, 0.7 mmol) in anhyd CH2Cl2
(10 mL) were added, successively, DMAP (161 mg, 1.3 mmol), 2-
iodoaniline (219 mg, 1.0 mmol) dissolved in CH2Cl2 (2 mL), and
EDCI∑HCl (151 mg, 0.8 mmol) at 0 °C. The final solution was
stirred overnight at r.t. After hydrolysis, the organic layer was dried
Table 2 Mp, IR and MS Data of Compounds 2−6
Compound
Mp (°C)
IR (cm–1)
MS
Formula
m/z (M++1)
2a
2b
3a
3b
4a
4b
5a
5b
5c
6a
6b
232
(MeOH/PE)
3200−2500 (OH), 1675 (CO)
3200−2500 (OH), 1686 (CO)
3241 (NH), 1640 (CO)
3252 (NH), 1637 (CO)
1736 (CO), 1680 (CO)
1737 (CO), 1683 (CO)
1667 (CO)
302
303
503
504
603
604
375
376
475
507
508
C15H11NO4S
(301.3)
224
(MeOH/PE)
C14H10N2O4S
(302.3)
192
(Et2O/PE)
C21H15IN2O3S
(502.3)
216
(CH2Cl2/PE)
C20H14IN3O3S
(503.3)
84
C26H23IN2O5S
(602.4)
(Et2O/PE)
96
C25H22IN3O5S
(603.4)
(Et2O/PE)
256
(MeOH/PE)
C21H14N2O3S
(374.4)
252
(MeOH/PE)
1667 (CO)
C20H13N3O3S
(375.4)
oil
1769 (CO), 1667 (CO)
C26H22N2O5S
(474.5)
134
(Et2O/PE)
1598, 1564, 1515, 1448, 1424,
1380, 1212
C22H13F3N2O5S2
(506.5)
144
(Et2O/PE)
1612, 1589, 1557, 1511, 1405,
1370, 1345, 1223
C21H12F3N3O5S2
(507.5)
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Table 3 Yield, Mp, IR and MS Data of Compounds 7−12
Compound
Yield
77%
76%
72%
81%
82%
96%
89%
51%
96%
Mp (°C)
IR (cm−1)
MS
Formula
m/z (M++1)
7a
120
(Et2O/PE)
2957, 2925, 2854, 1654, 1560,
1447, 1378, 1311
429
C25H20N2O3S
(428.5)
8a
198
(CH2Cl2/Et2O)
1586, 1563, 1550, 1500,
1446, 1376, 1188
425
C25H16N2O3S
(424.5)
8b
202
(CH2Cl2/PE)
1583, 1560, 1548, 1498,
1376, 1187
426
C24H15N3O3S
(425.5)
9a
201
(Et2O/PE)
1608, 1499, 1448, 1440, 1362,
1247, 1187, 1172
465
C28H20N2O3S
(464.5)
9b
212
(Et2O/PE)
1606, 1494, 1393, 1380, 1251,
1190, 1171
466
C27H19N3O3S
(465.5)
10a
10b
11b
12
224
(CH2Cl2/PE)
1574, 1552, 1501, 1449, 1370,
1345, 1189, 1178
491
C29H18N2O2S2
(490.6)
212
(CH2Cl2/PE)
1565, 1550, 1497, 1393, 1359,
1336, 1186
492
C28H17N3O2S2
(491.6)
202
(CH2Cl2/PE)
1717 (CO), 1551, 1448, 1433,
1379, 1262, 1187
444
C24H17N3O4S
(443.5)
152
(CH2Cl2/PE)
1562, 1503, 1443, 1374, 1347,
1185, 1176
393, 395
C21H13ClN2O2S
(392.9)
Table 4 1H NMR Data of Compounds 1-6
Compound
2aa
1H NMR (ppm) d, J (Hz)
7.34-7.46 (m, 2 H, HAr), 7.60-7.77 (m, 3 H, HAr), 7.97-8.16 (m, 4 H, HAr), 8.38 (s, 1 H, H2), 13.02 (br s, 1 H, OH)
2ba
7.41 (dd, 1 H, J = 4.8, 7.8, HPyr), 7.61-7.78 (m, 3 H, HAr), 8.23 (br d, 2 H, J = 8.2, HAr), 8.36 (d, 1 H, J = 7.8, HPyr), 8.42
(s, 1 H, H2), 8.44 (d, 1 H, J = 4.8, HPyr), 13.14 (br s, 1 H, OH)
3ab
3bb
6.90 (t, 1 H, J = 7.5, HAr), 7.35-7.63 (m, 6 H, HAr), 7.83 (dd, 1 H, J = 1.3, 7.8, HAr), 7.95-8.04 (m, 3 H, HAr), 8.08 (br s,
1 H, NH), 8.21 (dd, 1 H, J = 1.9, 7.0, HAr), 8.24 (s, 1 H, H2), 8.38 (dd, 1 H, J = 1.3, 8.2, HAr)
6.62 (t, 1 H, J = 7.5, HAr), 6.99-7.14 (m, 2 H, HAr + HPyr), 7.23-7.39 (m, 3 H, HAr), 7.55 (dd, 1 H, J = 1.0, 7.8, HAr), 7.77
(br s, 1 H, NH), 7.99-8.07 (m, 3 H, HAr), 8.09 (s, 1 H, H2), 8.23-8.28 (m, 2 H, HPyr
)
4ab
4bb
1.26 (s, 9 H, CH3), 7.06-7.13 (m, 1 H, HAr), 7.30-7.60 (m, 7 H, HAr), 7.88-8.02 (m, 5 H, HAr), 8.05 (s, 1 H, H2)
1.34 (s, 9 H, CH3), 7.12 (br t, 1 H, J = 7.2, HAr), 7.25-7.34 (m, 2 H, HAr), 7.41-7.64 (m, 4 H, HAr + HPyr), 7.95 (br d,
1 H, J = 7.8, HAr), 8.15 (s, 1 H, H2), 8.20 (br d, 2 H, J = 8.1, HAr), 8.36 (dd, 1 H, J = 1.6, 7.8, HPyr), 8.44 (dd, 1 H, J = 1.6,
4.7, HPyr
)
5aa
5ba
5cb
6ab
7.29-7.62 (m, 10 H, HAr), 8.19 (d, 2 H, J = 8.2, HAr), 8.55 (d, 1 H, J = 8.2, HAr), 12.16 (s, 1 H, NH)
7.32-7.71 (m, 7 H, HAr + HPyr), 7.90 (d, 2 H, J = 7.8 Hz, HAr), 8.42-8.51 (m, 3 H, HAr + HPyr), 12.26 (br s, 1 H, NH)
1.73 (s, 9 H, CH3), 7.12-7.50 (m, 9 H, HAr), 7.26-7.56 (m, 1 H, HAr), 8.22-8.27 (m, 2 H, HAr), 8.81 (d, 1 H, J = 8.8, HAr)
7.08-7.19 (m, 4 H, HAr), 7.33-7.40 (m, 1 H, HAr), 7.45-7.62 (m, 2 H, HAr), 7.71-7.86 (m, 2 H, HAr), 7.99 (br d, 1 H,
J = 7.9, HAr), 8.13 (br d, 1 H, J = 8.1, HAr), 8.41 (br d, 1 H, J = 8.1, HAr), 9.08 (br d, 1 H, J = 8.5, HAr)
6bb
7.37-7.44 (m, 3 H, HAr + HPyr), 7.51-7.58 (m, 1 H, HAr), 7.71-7.87 (m, 2 H, HAr), 7.91-7.96 (m, 2 H, HAr), 8.15 (dd,
1 H, J = 1.0, 8.2, HAr), 8.36 (dd, 1 H, J = 1.6, 7.9, HPyr), 8.60 (dd, 1 H, J = 1.6, 5.4, HPyr), 8.95 (dd, 1 H, J = 1.3, 8.5, HAr)
a In DMSO-d6.
b In CDCl3.
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Synthesis of Indolo[3,2-c]quinoline and Pyrido[3’,2’:4,5][3,2-c]quinoline Derivatives
553
(MgSO4) and evaporated. The crude residue was purified by flash
chromatography on silica gel (CH2Cl2) to give 3a (228 mg, 82%) as
crystals.
(84 mg, 0.3 mmol) and silver carbonate (419 mg, 1.5 mmol). The
mixture was then stirred at 100 °C for 1 day. After cooling, the sol-
vent was evaporated. The residue was dissolved in CH2Cl2 and
washed 3 times with water. The organic layer was dried (MgSO4)
and evaporated in vacuo. The crude product was purified by flash
chromatography on silica gel (PE/EtOAc, 1:1) to afford 5a (213 mg,
75%) as crystals.
N-(2-Iodophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carboxamide (3b)
The same procedure applied to 2b afforded 3b in 79% yield.
11-(Phenylsulfonyl)-6,11-dihydro-5H-pyrido[3’,2’:4,5]pyrrolo-
[3,2-c]quinolin-6-one (5b)
The same procedure applied to 4b afforded 5b in 72% yield.
tert-Butyl N-(2-Iodophenyl)-N-4{[1-(phenylsulfonyl)-1H-3-in-
dolyl]carbonyl}carbamate (4a)
A solution of amide 3a (480 mg, 1.0 mmol), DMAP (117 mg,
1.0 mmol), Et3N (0.14 mL, 1.0 mmol) and Boc2O (251 mg, 1.2
mmol) in CH3CN (15 mL) was stirred at r.t. for 16 h. The solvent
was removed in vacuo. The crude residue was purified by flash
chromatography on silica gel (PE/EtOAc, 1:3) to afford 4a (560 mg,
97%) as crystals.
tert-Butyl 11-(Phenylsulfonyl)-6-oxo-6,11-dihydro-5H-indolo-
[3,2-c]quinoline-5-carboxylate (5c)
Same procedure as for compound 4a starting from compound 5a,
afforded 5c in 96% yield.
tert-Butyl N-(2-Iodophenyl)-N-4{[1-(phenylsulfonyl)-1H-pyrro-
lo[2,3-b]pyridin-3-yl]carbonyl}carbamate (4b)
11-(Phenylsulfonyl)-11H-indolo[3,2-c]quinolin-6-yl trifluoro-
methanesulfonate (6a)
The same procedure applied to 3b afforded 4b in 97% yield.
To a stirred solution of 5a (200 mg, 0.5 mmol) in CH2Cl2 (20 mL)
under Ar at 0 °C was added pyridine (0.5 mL, 6.2 mmol) followed
by trifluoromethanesulfonic anhydride (0.18 mL, 1.1 mmol). The
solution was stirred at r.t. for 3 h., then washed with sat. NaHCO3
(30 mL) and H2O (20 mL), dried (MgSO4) and evaporated in vacuo.
11-(Phenylsulfonyl)-6,11-dihydro-5H-indolo[3,2-c]quinolin-6-
one (5a)
To a solution of indole 4a (460 mg, 0.76 mmol) in DMF (10 mL)
was added Pd(OAc)2 (34 mg, 0.15 mmol), triphenylphosphine
Table 5 13C NMR Data of Compounds 1–6
Compound
13C NMR (ppm) d, J (Hz)
2aa
113.2 (CH), 114.1 (C), 121.8 (CH), 124.5 (CH), 125.5 (CH), 127.2 (2CH), 127.5 (C), 130.1 (2CH), 131.9 (CH), 134.1
(C), 135.2 (CH), 136.4 (C), 164.3 (CO)
2ba
3ab
3bb
4ab
111.2 (C), 120.1 (CH), 120.5 (C), 128.1 (2CH), 129.7 (2 CH), 130.6 (CH), 131.5 (CH), 135.3 (CH), 136.7 (C), 145.6
(CH), 146.3 (C), 163.9 (CO)
90.3 (C), 113.7 (CH), 118.0 (C), 121.8 (CH), 122.2 (CH), 124.7 (CH), 126.0 (CH), 126.3 (CH), 127.2 (2CH), 127.5 (C),
128.3 (CH), 129.5 (CH), 129.8 (2CH), 134.7 (CH), 135.1 (C), 137.6 (C), 138.2 (C), 139.0 (CH), 161.5 (CO)
90.5 (C), 114.6 (C), 120.2 (CH), 120.5 (C), 122.3 (CH), 126.4 (CH), 127.4 (CH), 128.6 (2CH), 129.3 (2CH), 129.5 (CH),
130.8 (CH), 134.8 (CH), 137.6 (C), 138.0 (C), 139.0 (CH), 146.3 (CH), 147.1 (C), 160.9 (CO)
28.0 (3CH3), 84.1 (C), 99.8 (C), 113.5 (CH), 118.2 (C), 122.1 (CH), 124.5 (CH), 125.6 (CH), 127.2 (2CH), 128.3 (C),
129.4 (CH), 129.6 (2CH), 129.9 (CH), 130.0 (CH), 131.1 (CH), 134.4 (C), 134.5 (CH), 137.7 (C), 139.9 (CH), 142.0 (C),
152.0 (CO), 165.1 (CO)
4bb
27.8 (3CH3), 84.3 (C), 99.8 (C), 114.7 (C), 120.1 (CH), 121.2 (C), 128.5 (2CH), 129.3 (2CH), 129.5 (CH), 130.0 (CH),
130.1 (CH), 130.9 (CH), 131.2 (CH), 134.7 (CH), 137.7 (C), 140.0 (CH), 141.8 (C), 146.0 (CH), 146.6 (C), 151.9 (CO),
164.6 (CO)
5aa
5ba
5cb
112.7 (C), 116.2 (CH), 117.2 (C), 117.4 (CH), 121.5 (CH), 121.6 (CH), 126.0 (CH), 126.3 (2CH), 126.8 (CH), 126.9
(CH), 127.3 (C), 129.3 (2CH), 130.2 (CH), 134.8 (CH), 134.9 (C), 138.6 (C), 139.4 (C), 142.9 (C), 158.5 (CO)
112.3 (C), 113.7 (C), 116.3 (CH), 119.3 (C), 121.3 (CH), 121.4 (CH), 127.3 (3CH), 129.4 (2CH), 130.0 (CH), 130.5
(CH), 134.8 (CH), 137.3 (C), 139.0 (C), 142.5 (C), 145.9 (CH), 151.8 (C), 158.4 (CO)
28.0 (3CH3), 87.6 (C), 114.1 (C), 114.3 (CH+C), 117.9 (CH), 122.6 (CH), 122.9 (CH), 126.3 (CH), 126.8 (2CH), 127.1
(CH), 127.7 (C), 128.9 (3CH), 130.5 (CH), 134.3 (CH), 135.5 (C), 136.2 (C), 140.4 (C), 143.8 (C), 150.9 (CO), 157.3
(CO)
6aa
6ba
113.3 (C), 118.7 (CH), 118.7 (q, CF3, J = 320), 120.2 (C), 121.7 (CH), 123.8 (C), 126.5 (2CH), 126.6 (CH), 126.8 (CH),
127.4 (CH), 128.3 (CH), 128.8 (2CH), 129.2 (CH), 130.4 (CH), 134.4 (CH), 135.2 (C), 140.9 (C), 144.9 (C), 146.3 (C),
148.5 (C)
109.3 (C), 115.9 (C), 118.7 (q, CF3, J = 320), 119.4 (C), 121.3 (CH), 127.3 (2CH), 128.0 (2CH), 129.1 (2CH), 129.5
(CH), 130.3 (CH), 130.8 (CH), 134.7 (CH), 137.8 (C), 145.1 (C), 145.4 (C), 147.8 (CH), 148.7 (C), 152.7 (C)
a In DMSO-d6.
b In CDCl3.
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A. Mouaddib et al.
PAPER
The crude residue was purified by flash chromatography on silica
gel (PE/EtOAc, 8:2) to give 6a (236 mg, 88%) as crystals.
Methyl (E)-3-[11-Phenylsulfonyl-11H-pyrido[3’,2’:4,5]pyrro-
lo[3,2-c]quinolin-6-yl]prop-2-enoate (11b)
Triflate 6b (100 mg, 0.2 mmol), Pd(OAc)2 (9 mg, 0.04 mmol),
triphenylphosphine (21 mg, 0.08 mmol), silver carbonate (110 mg,
0.4 mmol) and methyl acrylate (26 mg, 0.3 mmol) were stirred in
DMF (10 mL) at 100 °C for 3 h. After filtration, the mixture was
evaporated in vacuo, then the crude oil was diluted in CH2Cl2 (30
mL). The organic layer was washed with H2O, dried (MgSO4) and
evaporated. The crude residue was purified by flash column chro-
matography (PE/EtOAc, 8:2) to afford 11b (45 mg, 51%) as a solid.
11-(Phenylsulfonyl)-11H-pyrido[3’,2’:4,5]pyrrolo[3,2-c]quino-
lin-6-yl Trifluoromethanesulfonate (6b)
The same procedure applied to 5b afforded 6b in 79% yield.
Stille Reactions of 6a-b with Tin Derivatives; Method 1
To a mixture of LiCl (19 mg, 0.45 mmol) and freshly prepared
Pd(PPh3)4 (11 mg, 0.01 mmol) in DMF (10 mL) under Ar, triflate 6
(0.16 mmol), (1-ethoxyvinyl)tributyltin (0.24 mmol) or (2-fura-
nyl)tributyltin (0.24 mmol) in DMF (5 mL) were added. The stirred
solution was heated at 90 °C for 2 h. The solvent was then removed
in vacuo and the crude residue was purified by flash chromatogra-
phy on silica gel (PE/EtOAc, 1:3) to give 7-8.
6-Chloro-11-(phenylsulfonyl)-11H-indolo[3,2-c]quinoline (12)24
Compound 5a (120 mg, 0.32 mmol) was dissolved in toluene
(10 mL) / DMF (1 mL), phosphorus oxychloride (53 mg, 0.38
mmol) was added at 0 °C and then the mixture was stirred at r.t. for
4 h. Evaporation of the mixture in vacuo followed by hydrolysis,
neutralisation with sat. NaHCO3, extraction with EtOAc and drying
(MgSO4) afforded a solid; The crude solid was quickly purified by
flash column chromatography (PE/EtOAc, 8:2) to afford 12 (120
mg, 96%) as a solid.
Suzuki Reactions of 6a-b with Boronic Acids; Method 2
To a stirred solution of triflate 6 (0.2 mmol) in toluene (5 mL) under
Ar was added freshly prepared Pd(PPh3)4 (14 mg, 0.012 mmol). The
mixture was allowed to stir for 30 min r.t. Boronic acid
(0.3 mmol) (4-methoxyphenylboronic acid or benzo[b]thiophene-2-
boronic acid) in ethanol (2 mL) was then added, followed immedi-
ately by sat. NaHCO3 (2 mL). The heterogeneous solution was
stirred at 90 °C for 2 h. Brine solution was then added, the two lay-
ers were separated and the aqueous phase was extracted with
CH2Cl2 (3 x 30 mL). The combined organic extracts were dried
(MgSO4) and evaporated in vacuo. The crude residue was purified
by flash chromatography on silica gel (PE/EtOAc, 8:2) to give com-
pounds 9-10.
References
(1) Woodward, R. B.; Iacobucci, G. A.; Hochtein, F. A. J. Am.
Chem. Soc. 1959, 81, 4434.
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Med. Chem. 1999, 42, 2191.
Table 6 1H NMR (CDCl3) Data of Compounds 7–12
Compound
1H NMR (ppm) δ, J (Hz)
7a
0.92 (t, 3H, J = 7.5, CH3), 4.01 (q, 2 H, J = 7.5, CH2), 4.61 (d, 1 H, J = 2.5, =CH2), 4.64 (d, 1 H, J = 2.5, =CH2), 7.04-
7.7 (m, 4 H, HAr), 7.25-7.40 (m, 2 H, HAr), 7.45-7.52 (td, 1 H, J = 2.8, HAr), 7.71-7.86 (m, 3 H, HAr), 8.24 (br d, 1 H, J
= 8.1, HAr), 8.33 (br d, 1 H, J = 8.1, HAr), 8.95 (br d, 1 H, J = 8.5, HAr)
8a
8b
9a
6.63-6.67 (m, 1 H, HAr), 7.08-7.15 (m, 5 H, HAr), 7.25-7.35 (m, 2 H, HAr), 7.45-7.52 (m, 2 H, HAr), 7.65-7.76 (m, 2 H,
HAr), 7.78 (br d, 1H, J = 7.9, HAr), 8.23 (br d, 1H, J = 8.1, HAr), 8.36 (br d, 1H, J = 8.1, HAr), 8.95 (br d, 1H, J = 8.5, HAr)
6.70-6.72 (m, 1 H, HAr), 7.23-7.51 (m, 5 H, HAr + HPyr), 7.63-7.75 (m, 3 H, HAr), 7.80 (br d, 2 H, J = 7.5, HAr), 8.22 (d,
1 H, J = 8.2, HAr), 8.42 (dd, 1 H, J = 1.2, 8.0, HPyr), 8.51 (dd, 1 H, J = 1.2, 4.7, HPyr), 8.79 (d, 1 H, J = 7.9, HAr)
3.90 (s, 3 H, CH3), 7.03 (br d, 2 H, J = 8.8, HAr), 7.08-7.19 (m, 7 H, HAr), 7.33-7.40 (m, 1 H, HAr), 7.45 (br d, 2 H, J =
8.8, HAr), 7.69 (t, 1 H, J = 6.9, HAr), 7.78 (t, 1 H, J = 6.9, HAr), 8.24 (d, 1 H, J = 8.5, HAr), 8.34 (d, 1 H, J = 8.2, HAr), 8.97
(d, 1 H, J = 8.5, HAr)
9b
3.92 (s, 3 H, CH3), 7.05-7.12 (m, 3 H, HAr + HPyr), 7.34-7.40 (m, 2 H, HAr), 7.48-7.55 (m, 1 H, HAr), 7.61-7.70 (m, 4
H, HAr+HPyr), 7.75-7.88 (m, 3 H, HAr), 8.25 (dd, 1 H, J = 1.0, 8.2, HAr), 8.49 (dd, 1 H, J = 1.6, 5.0, HPyr), 8.83 (dd, 1 H,
J = 1.0, 8.5, HAr)
10a
10b
11b
7.08-7.25 (m, 5 H, HAr), 7.35-7.46 (m, 4 H, HAr), 7.50 (br s, 1 H, HAr), 7.66 (d, 1 H, J = 8.1, HAr), 7.70-7.84 (m, 3 H,
HAr), 7.92-7.96 (m, 1 H, HAr), 8.25 (d, 1 H, J = 8.5, HAr), 8.36 (d, 1 H, J = 8.5, HAr), 8.98 (d, 1 H, J = 8.5, HAr)
7.15 (dd, 1 H, J = 5.0, 8.0, HPyr), 7.31-7.58 (m, 5 H, HAr), 7.66-8.00 (m, 7 H, HAr), 8.10 (dd, 1 H, J = 1.9, 8.0, HPyr), 8.28
(dd, 1 H, J = 1.0, 8.4, HAr), 8.52 (dd, 1 H, J = 1.9, 5.0, HPyr), 8.83 (dd, 1 H, J = 1.0, 8.4, HAr)
3.89 (s, 3 H, OCH3), 7.29-7.52 (m, 5 H, HAr+ HPyr + CH=), 7.66-7.84 (m, 4 H, HAr), 8.23 (dd, 1 H, J = 1.0, 8.5, HAr),
8.38 (dd, 1 H, J = 1.6, 7.9, HPyr), 8.43 (d, 1 H, J = 15.3, CH=), 8.56 (dd, 1 H, J = 1.6, 4.7, HPyr), 8.83 (dd, 1 H, J = 1.0,
8.5, HAr)
12
7.05-7.15 (m, 4 H, HAr), 7.25-7.35 (m, 1 H, HAr), 7.40-7.58 (m, 2 H, HAr), 7.65-7.80 (m, 2 H, HAr), 8.10 (d, 1 H, J =
1.3, 8.2, HAr), 8.36 (t, 2 H, J = 8.2, HAr), 8.97 (dd, 1 H, J = 1.3, 8.2, HAr)
Synthesis 2000, No. 4, 549–556 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Indolo[3,2-c]quinoline and Pyrido[3’,2’:4,5][3,2-c]quinoline Derivatives
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Table 7 13C NMR (CDCl3) Data of Compounds 7–12
Compound
13C NMR (ppm) d
7a
14.3 (CH3), 63.8 (CH2), 87.9 (CH2=), 119.0 (CH), 120.6 (C), 120.9 (C), 122.5 (CH), 125.8 (CH), 126.7 (CH), 126.8
(3CH), 126.8 (CH), 127.3 (C), 128.3 (2CH), 129.3 (CH), 130.0 (CH), 133.8 (CH), 134.7 (C), 141.4 (C), 143.9 (C), 147.2
(C), 150.6 (C), 159.9 (C)
8a
8b
112.2 (CH), 112.4 (CH), 119.2 (CH), 120.4 (C), 120.9 (C), 122.7 (CH), 125.7 (CH), 125.9 (CH), 126.7 (CH), 126.9
(2CH), 127.0 (CH), 127.5 (CH), 128.4 (2CH), 129.6 (CH), 129.7 (CH), 134.0 (CH), 134.5 (C), 141.4 (C), 143.7 (2C),
144.4 (C), 144.7 (C), 152.8 (C)
112.6 (CH), 112.7 (CH), 116.4 (C), 119.2 (C), 119.4 (C), 120.6 (CH), 126.4 (CH), 127.3 (CH), 127.9 (2CH), 128.9
(2CH), 129.7 (CH), 130.0 (CH), 131.8 (CH), 134.2 (CH), 137.6 (C), 143.4 (C), 143.7 (CH), 144.2 (C), 146.8 (CH), 147.8
(C), 153.2 (C), 153.5 (C)
9a
55.5 (CH3), 114.2 (2CH), 119.4 (CH), 120.2 (C), 121.3 (C), 121.9 (CH), 125.7 (CH), 126.4 (CH), 126.8 (CH), 127.0
(2CH), 127.3 (CH), 128.1 (C), 128.3 (2CH), 129.5 (CH), 129.6 (CH), 130.5 (2CH), 132.1 (C), 133.9 (CH), 134.5 (C),
141.5 (C), 144.4 (C), 147.7 (C), 154.9 (C), 160.7 (C)
9b
55.6 (CH3), 114.4 (2CH), 117.1 (C), 119.1 (C), 119.7 (C), 120.3 (CH), 126.2 (CH), 127.0 (CH), 127.8 (2CH), 128.8
(2CH), 129.8 (CH), 129.9 (CH), 130.3 (CH), 130.5 (2CH), 131.9 (C), 134.2 (CH), 137.7 (C), 142.8 (C), 146.8 (CH),
148.1 (C), 153.6 (C), 155.0 (C), 160.8 (C)
10a
10b
11b
12
119.5 (CH), 120.5 (C), 121.2 (C), 121.8 (CH), 122.6 (CH), 124.4 (CH), 124.7 (CH), 125.2 (CH), 125.4 (CH), 125.9 (CH),
126.8 (CH), 126.9 (2CH), 127.0 (2CH), 127.5 (C), 127.7 (CH), 128.4 (2CH), 129.8 (CH), 134.0 (CH), 134.5 (C), 139.7
(C), 141.0 (C), 141.5 (C), 142.0 (C), 144.5 (C), 147.5 (C), 148.4 (C)
119.1 (C), 119.5 (C), 120.4 (CH), 122.7 (CH), 124.5 (CH), 124.9 (CH), 125.2 (CH), 125.6 (CH), 126.9 (CH), 127.1 (CH),
128.0 (2CH), 128.9 (3CH), 130.1 (C), 130.2 (CH), 130.3 (CH), 134.3 (CH), 137.8 (C), 139.7 (C), 141.1 (C), 142.0 (C),
143.0 (C), 147.1 (CH), 147.9 (C), 148.8 (C), 153.5 (C)
52.3 (CH3), 117.6 (C), 118.6 (C), 119.8 (C), 120.9 (CH), 125.9 (CH), 127.0 (CH), 127.3 (CH), 127.9 (2CH), 128.9 (2CH),
130.2 (CH), 130.3 (CH), 130.8 (CH), 134.3 (CH), 137.7 (C), 139.6 (CH), 142.6 (C), 147.0 (CH), 147.9 (C), 148.1 (C),
153.4 (C), 167.1 (CO)
118.7 (CH), 119.8 (C), 120.4 (C), 122.4 (CH), 125.9 (C), 126.2 (CH), 126.7 (2CH), 126.8 (CH), 127.0 (CH), 127.9 (CH),
128.6 (2CH), 128.8 (CH), 130.1 (CH), 134.2 (CH), 135.1 (C), 140.1 (C), 144.5 (2C), 147.0 (C)
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PAPER
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Article Identifier:
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6488 and references therein.
Synthesis 2000, No. 4, 549–556 ISSN 0039-7881 © Thieme Stuttgart · New York