6-Aryl-11H-indolo[3,2-c]quinolines through the palladium-catalyzed carbonylative cyclization of o-(o-aminophenyl)trifluoroacetanilide with aryl iodides

Article abstract of DOI:10.1055/s-1999-2659

6-Aryl-11H-indolo[3,2-c]quinolines are prepared through a straightforward palladium-catalyzed carbonylative cyclization of o-(o'- aminophenylethynyl)trifluoroacetanilide with aryl iodides followed by the cyclization of the resultant 3-acylindole derivativ

Full text of DOI:10.1055/s-1999-2659

620
LETTER
6-Aryl-11H-indolo[3,2-c]quinolines through the Palladium-Catalyzed
Carbonylative Cyclization of o-(o-Aminophenyl)trifluoroacetanilide with Aryl
Iodides
Sandro Cacchi,*a Giancarlo Fabrizi,a Paola Pace,a Fabio Marinellib*
a Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università “La Sapienza”, P.le A. Moro 5,
00185 Roma, Italy
b Dipartimento di Chimica, Ing. Chimica e Materiali, Via Vetoio, 67100 L’Aquila, Italy
Fax+39 (6) 4991.2780; E-mail: cacchi@uniroma1.it
Received 14 January 1999
Abstract: 6-Aryl-11H-indolo[3,2-c]quinolines are prepared
through a straightforward palladium-catalyzed carbonylative cy-
clization of o-(o’-aminophenylethynyl)trifluoroacetanilide with
aryl iodides followed by the cyclization of the resultant 3-acylindole
derivatives. The reaction is best carried out as a one-pot process.
Key words: indoloquinolines, cyclization, palladium catalysis, car-
bonylation, alkynes
Our aminopalladation/reductive elimination tandem reac-
tion of functionalized alkynes with organopalladium com-
plexes has been proved to be a versatile approach to the
construction of the indole ring. 2-Unsubstituted-3-aryl-,1
2,3-disubstituted-,2 2-substituted-3-acyl-,3 and 2-substi-
tuted-3-allylindoles4 have been prepared from readily
Scheme 1
available o-alkynyltrifluoroacetanilides. Application of
the methodology to the preparation of biologically active
Table 1. Palladium-Catalyzed Reaction of o-(o-Amino phenyl)eth-
molecules3,5 and its adaptation to a solid-supported
ynyltrifluoroacetanilide 1 and Bis(o-amino phenyl)acetylene 7 with
synthesis6 have also been reported.
p-Iodoanisole under an Atmosphere of Carbon Monoxidea
Our continuing interest in the synthesis of indole deriva-
tives by this chemistry as well as the valuable biological
activity7 exhibited by some indolo[3,2-c]quinolines (they
may also be useful intermediates in the synthesis of com-
plex molecules)8 led us to investigate the extension of the
methodology to the synthesis of the indolo[3,2-c]quino-
lines 4 from o-(o’-aminophenylethynyl)trifluoroacetanil-
ide 1 and aryl iodides, according to the basic sequence
outlined in Scheme 1. Here we wish to report the result of
this study.
The starting alkyne 1 was prepared through the palladium-
catalyzed coupling of o-trifluoroacetamidophenyl iodide
with o-ethynylaniline.9
a Unless otherwise stated, reactions were carried out in anhydrous
MeCN, using the following molar ratios: 1(or 7):p-iodoanisole:
Pd(PPh3)4:K2CO3 = 1:1:0.05:5. b Yields refer to single runs and are gi-
ven for isolated products. c Carried out in analytical grade MeCN. d 6-
(p-Methoxyphenyl)-11H-indolo[3,2-c]quinoline was isolated in 15%
yield. e Bis(o-aminophenyl)acetylene was recovered in 73% yield.
First attempts of carbonylative cyclization to give the 3-
acylindole product 3 were made employing p-iodoanisole
as the aryl iodide in MeCN at 50 °C under a balloon of
carbon monoxide and some of our results are summarized
in Table 1. Interestingly, instead of the expected 2-(o-ami-
nophenyl)-3-acylindole, the reaction produced the corre-
sponding 2-(o-trifluoroacetamidophenyl)- derivative 5a11
(Scheme 2). The combined utilization of anhydrous sol-
vent and higher pressure of carbon monoxide slightly in-
creased the yield of 5a (Table 1, entry 3).
Exposure of 5a to MeOH/H2O 95/5 in the presence of
K2CO3 at 80 °C for 1 h allowed us to isolate the indolo-
quinoline product 4a in 86% yield12 (44% overall yield).
Best results were obtained when the preparation of the in-
doloquinoline was carried out as a one-pot process, omit-
ting the isolation of the acylindole intermediate: 4a was in
Synlett 1999, No. 5, 620–622 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
6-Aryl-11H-indolo[3,2-c]quinolines through the Palladium-Catalyzed Carbonylative Cyclization
621
this case isolated in 70% overall yield. Therefore, the one- As to the mechanism of cyclization of 1 to 5, a reasonable
pot protocol13 was employed when the reaction was ex- working hypothesis based on our previous work on this
tended to include other aryl iodides. Our preparative re- type of reaction3 considers the pathway illustrated in
sults are listed in Table 2.
Scheme 3. Nucleophilic attack of the nitrogen atom of the
trifluoroacetamido group across the carbon-carbon triple
bond activated by coordination to an acylpalladium com-
plex generates 6, which subsequently undergoes the re-
ductive elimination of palladium(0) species and a
transamidation reaction, not necessarily in this order. The
view that the nucleophilic attack of trifluoroacetamido ni-
trogen is favored over that of the free amino group is sup-
ported by our previous studies2 and by the observation
that none of the indole derivative was formed when bis(o-
aminophenyl)acetylene 7, containing two free amino
groups, was subjected to cyclization conditions (Table 1,
entry 4). Clearly, the acidity of the nitrogen-hydrogen
bond plays an important role in the cyclization step.
Table 2. One-Pot Synthesis of 6-Aryl-11H-indolo[3,2-c]quinolines 4
aCarbonylations were carried out in a 50 mL stainless steel vessel, on
a 0.5 mmol scale in anhydrous MeCN (3 mL) at 50 °C, using the fol-
lowing molar ratios:1:2:K2CO3:Pd(PPh3)4 = 1:1:5:0.05. Hydrolyses
were carried out at 80 °C in 11 mL of MeOH/H2O (95/5 v/v) in the
presence of 6 equiv of K2CO3. bYields refer to single runs and are gi-
ven for isolated products. c In analytical grade MeCN.
Scheme 3
To sum up, we have developed an efficient, straightfor-
ward procedure for the preparation of functionalized indo-
lo[3,2-c]quinoline derivatives that may provide new
strategies in the design of synthetic protocols to this class
of compounds.
Acknowledgement
Work carried out in the framework of the National Project "Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni" sup-
ported by the Ministero dell'Università e della Ricerca Scientifica e
Tecnologica, Rome. Financial support of this research by the Uni-
versity “La Sapienza”, Rome, and by the Consiglio Nazionale delle
Ricerche (CNR) is also gratefully acknowledged. The authors are
also greatly indebted to Dr. Luciana Turchetto of the Istituto Supe-
riore di Sanità for obtaining the mass spectra of new products.
Scheme 2
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622
S. Cacchi et al.
LETTER
(DMSO) d 190.4, 161.9, 154.7 (q, J = 36.8 Hz, COCF3),
139.6, 136.1, 133.3, 132.1, 131.8, 131.5, 129.1, 127.7, 127.1,
126.2, 125.1, 122.6, 121.1, 120.7, 118.7 (q, J = 286.5 Hz,
CF3), 113.4, 112.9, 111.8, 55.3; MS m/z (relative intensity)
438 (M+, 31), 368 (100). Anal. Calcd. for C24H17F3N2O3: C,
65.75; H, 3.91. Found: C, 65.68; H, 3.84.
References and Notes
(1) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P.
Synlett 1997, 1363.
(2) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992,
33, 3915.
(3) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F.
Tetrahedron 1994, 50, 437.
(4) Cacchi, S.; Fabrizi, G. Pace, P. J. Org. Chem. 1998, 63, 1001.
(5) Saulnier, M.G.; Frennesson, D.B.; Deshpande, M.S.; Vyas,
D.M. Tetrahedron Lett. 1995, 36, 7841.
(12) Hydrolysis and cyclization of 5a to 4a: to a solution of 5a
(0.150 g, 0.34 mmol) in MeOH/H2O 95/5 v/v (11 mL) was
added K2CO3 (0.284 g, 2.1 mmol) and the mixture was stirred
at 80 °C for 2 h. After cooling, the mixture was diluted with
ethyl acetate, washed with water, dried (Na2SO4) and
(6) Collini, M.D.; Ellingboe, J.W. Tetrahedron Lett. 1997, 38,
7963.
concentrated under vacuum. The residue was purified by
chromatography on silica gel eluting with a n-hexane/EtOAc
50/50 (v/v) mixture to give 0.095 g of 4a (86% yield).
(13) General procedure for the one-pot synthesis of 6-
arylindolo[3,2-c]quinolines 4: in a stainless steel vessel, to a
solution of o-(o’-aminophenylethynyl)trifluoroacetanilide
(0.150 g, 0.49 mmol) and p-iodoanisole (0.115 g, 0.49 mmol)
in 3 mL of anhydrous MeCN, K2CO3 (0.340 g, 2.47 mmol)
and Pd(Ph3P)4 (0.028 g, 0.025 mmol) were added. The flask
was purged with carbon monoxide for a few seconds. Then,
the carbon monoxide pressure was increased up to 3 atm and
the mixture was stirred at 50 °C for 24 h. After cooling, the
reaction mixture was diluted with ethyl acetate, washed with
water, dried over Na2SO4 and concentrated under reduced
pressure. The crude mixture was dissolved in MeOH/H2O 95/
5 v/v (11 mL) and K2CO3 (0.408 g, 2.94 mmol) was added.
The solution was stirred at 80 °C for 2 h. After the usual work
up, the reaction mixture was purified by chromatography on
silica gel eluting with a n-hexane/EtOAc 55/45 (v/v) mixture
to give 0.112 g of 4a (70% yield): mp 269-70 °C; IR (KBr)
3200, 1612, 836, 749 cm-1; 1H NMR (DMSO) d 12.87 (s, 1 H),
8.56 (d, J = 7.5 Hz, 1 H), 8.11 (d, J = 7.6 Hz, 1 H), 7.83-7.63
(m, 6 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.20-7.11 (m, 3 H), 3.90 (s,
3 H); 13C NMR (DMSO) d 159.8, 155.2, 145.0, 141.0, 139.0,
133.0, 130.3, 129.2, 128.4, 125.4, 125.3, 121.9, 121.8, 121.1,
120.2, 120.1, 116.1, 113.7, 111.9, 55.3; MS m/z (relative
intensity) 324 (M+, 73), 323 (100), 280 (44). Anal. Calcd. for
C22H16N2O: C, 81.46; H, 4.97. Found: C, 81.40; H, 4.93.
(7) For a recent reference, see: Helissey, P.; Giorgi-Renault, S.;
Renault, J.; Cros, S. Chem. Pharm. Bull. 1989, 37, 675;
Werbel L.M.; Kesten, S.J.; Turner, W.R. Eur. J. Med. Chem.
1993, 28, 837; Koh, H.L.; Go, M.L.; Ngiam, T.L.; Mak, J.W.
Eur. J. Med. Chem. 1994, 29 107;
(8) See for example: Molina, A.; Vaquero, J.J.; Garcia-Navio,
J.L.; Alvarez-Builla, J. Tetrahedron Lett. 1993, 34, 2673;
Molina, A.; Vaquero, J.J.; Garcia-Navio, J.L.; Alvarez-Builla,
J.; de Pascual-Teresa, B.; Gago, F.; Rodrigo, M.M.;
Ballesteros, M. J. Org. Chem. 1996, 61, 5587.
(9) o-(o’-Aminophenylethynyl)trifluoroacetanilide1was isolated
in 70% yield upon treatment of o-trifluoroacetamidophenyl
iodide (1.88 g, 5.98 mmol) with o-ethynylaniline10 (0.70 g,
5.98 mmol) in the presence of CuI (0.046 g, 0.24 mmol),
PdCl2(Ph3P)2 (0.084 g, 0.12 mmol) in DMF (3 mL) and Et2NH
(5 mL) at room temperature for 3 h: mp 92-3 °C; IR (KBr)
3400, 1715, 750 cm-1; 1H NMR (CDCl3) d 8.84 (bs, 1 H), 8.34
(d, J = 8.3 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.51-7.14 (m, 4
H), 6.79-6.70 (m, 2 H), 4.27 (bs, 2 H); 13C NMR (CDCl3) d
154.7 (q, J = 37.9 Hz, COCF3), 148.1, 135.9, 132.36, 131.8,
131.0, 130.0, 125.8, 120.0, 118.5, 115.6 (q, J = 288.5 Hz,
CF3), 114.9, 113.9, 106.4, 94.9, 88.3.
(10) o-Ethynylaniline was prepared according to: Arcadi, A.;
Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581.
(11) 3-(p-Methoxybenzoyl)-2-(o-trifluoroacetamidophenyl)indole
5a was isolated in 51% yield upon treatment of o-(o’-
aminophenyl ethynyl)trifluoroacetanilide with p-iodoanisole
according to the procedure described in ref. 3: mp 205-7 °C;
IR (KBr) 3272, 1736, 760, 751, 715 cm-1; 1H NMR (DMSO)
d 12.17 (s, 1 H), 10.91 (s, 1 H), 7.68-7.35 (m, 7 H), 7.28-7.08
(m, 3 H), 6.75 (d, J = 8.6 Hz, 2 H), 3.73 (s, 3 H); 13C NMR
Article Identifier:
1437-2096,E;1999,0,05,0620,0622,ftx,en;G01599ST.pdf
Synlett 1999, No. 5, 620–622 ISSN 0936-5214 © Thieme Stuttgart · New York