12-Acylindolo[1,2-c]quinazolines by palladium-catalyzed cyclocarbonylation of o-alkynyltrifluoroacetanilides.

Article abstract of DOI:10.1021/ol0256769

6-Trifluoromethyl-12-acylindolo[1,2-c]quinazolines are prepared in high yield through the palladium-catalyzed reaction of bis(o-trifluoroacetamidophenyl)acetylene with aryl or vinyl halides and triflates. The reaction, which tolerates a variety of importa

Full text of DOI:10.1021/ol0256769

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1355-1358
12-Acylindolo[1,2-c]quinazolines by
Palladium-Catalyzed Cyclocarbonylation
of o-Alkynyltrifluoroacetanilides
,†
Gianfranco Battistuzzi,† Sandro Cacchi,* Giancarlo Fabrizi,† Fabio Marinelli,‡ and
Luca M. Parisi†
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersita` degli Studi “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy, and
Dipartimento di Chimica Ingegneria Chimica e Materiali della Facolta` di Scienze,
UniVersita` de L’Aquila, Via Vetoio, Coppito Due, I-67100 L’Aquila, Italy
sandro.cacchi@uniroma1.it
Received February 6, 2002
ABSTRACT
6-Trifluoromethyl-12-acylindolo[1,2-c]quinazolines are prepared in high yield through the palladium-catalyzed reaction of bis(o-trifluoroaceta-
midophenyl)acetylene with aryl or vinyl halides and triflates. The reaction, which tolerates a variety of important functional groups, probably
involves the formation of a 3-acyl-2-(o-trifluoroacetamidophenyl)indole intermediate, followed by its cyclization to the indoloquinazoline product.
We have recently reported that o-(o-aminophenylethynyl)-
trifluoroacetanilide 1 reacts with aryl iodides in the presence
of carbon monoxide to give 2-(o-trifluoroacetamidophenyl)-
3-acylindole 3 derivatives that, in turn, cyclize to indolo-
[3,2-c]quinolines 41 (Scheme 1). During this study, formation
of 6-trifluoromethyl-12-acylindolo[1,2-c]quinazolines2,3 as
byproducts was observed in some cases. For example, the
reaction of 1 with m-trifluoromethylphenyl iodide under our
standard conditions [Pd(PPh3)4, K2CO3, MeCN, 50 °C]
afforded the expected 3-acylindole derivative 3a in 66% yield
along with a 17% yield of the indoloquinazoline product 5a
(Scheme 2).
The presence of the indolo[1,2-c]quinazoline skeleton in
natural substances such as Hinckdentine A,4 an unusual
marine alkaloid that has been isolated from the bryozoan
Scheme 1
† Universita` degli Studi “La Sapienza”.
‡ Universita` de L’Aquila.
(1) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett 1999, 620-
622.
(2) For a recent reference on the chemistry of indolo[1,2-c]quinazolines,
see: Billimoria, A. D.; Cava, M. P. J. Org. Chem. 1994, 59, 6777-6782.
Merour, J.-Y.; Savelon, L. Heterocycles 1991, 32, 849-853. Molina, P.;
Alajarin, M.; Vidal, A. Tetrahedron 1990, 46, 1063-1078.
(3) For a review on indolo[1, 2-c]quinazolines, see: Billimoria, A. D.;
Cava, M. P. Heterocycles 1996, 42, 453-473.
10.1021/ol0256769 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/20/2002

Scheme 2
Scheme 3
Hincksinoflustra denticulata, as well as the biological activity
exhibited by certain derivatives of indolo[1,2-c]quinazoline,5,6
prompted us to investigate further the cyclization of 1 to
indolo[1,2-c]quinazoline products and, possibly, the synthetic
scope of the reaction.
indoloquinazoline product 5a was obtained in 70% yield.
Employment of anhydrous MeCN and K2CO3 was suggested
by the observation that early hydrolysis of the trifluoroac-
etamido group could otherwise take place, thus preventing
cyclization. The acidity of the -NHCOR group in compound
6 was also found to play an important role in the formation
of the indoloquinazoline skeleton. Indeed, the reaction of
6b (R ) CH3-) with m-trifluoromethylphenyl iodide, under
the same reaction conditions, afforded 5a in only 44% yield.
Consequently, we decided to employ the readily available9
bis(o-trifluoroacetamidophenyl)acetylene 9 (Scheme 4) as the
building block for such a transformation.
Our initial studies focused on understanding the mecha-
nism of formation of the indoloquinazoline skeleton and
showed that 5a, under reaction conditions, is not generated
from 3a through the nucleophilic attack of the indole nitrogen
to the carbonyl of the ortho trifluoroacetamido group. We
therefore reasoned that formation of the indoloquinazoline
skeleton would involve the following key steps: (1) conver-
sion of the free amino group of 1 into the amide derivative
6 via acylation with an acylpalladium complex formed in
situ, (2) aminopalladation-reductive elimination domino
reaction to afford the 3-acylindole derivative 7,1,7,8 (3)
formation of the tetracyclic intermediate 8 via intramolecular
nucleophilic attack of the ortho nitrogen to the carbonyl of
the trifluoroacetyl group, and (4) subsequent elimination of
a carboxylic acid (Scheme 3).
Scheme 4
On the basis of this assumption, we prepared the amide
6a (R ) m-CF3-C6H4-; the possible intermediate in the
formation of 5a from 1 and 2a) and subjected it to
m-trifluoromethylphenyl iodide in the presence of Pd(PPh3)4,
carbon monoxide (3 bar), and anhydrous K2CO3 in anhydrous
MeCN at 50 °C for 24 h. We were pleased to find that the
(4) Blackman, A. J.; Hamley, T. W.; Picker, R.; Taylor, W. C.; Thirasana,
N. Tetrahedron Lett. 1987, 28, 5561-5562.
(5) Duncan, R. L. Ger. Offen. 2,051,961, April 29, 1971.
(6) Grinev, A. N.; Kurilo, G. N.; Cherkasova, A. A.; Mashkovskii, M.
D.; Andreeva, N. I.; Sokolov, I. K. Khim.-Farm. Zh. 1978, 12, 97-101.
(7) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron 1994,
50, 437-452.
(8) For other examples of preparation of indole derivatives via the
aminopalladation-reductive elimination domino methodology, see: (a)
Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2000, 394-396.
(b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2000, 647-
649. (c) Cacchi, S.; Fabrizi, G. Pace, P. J. Org. Chem. 1998, 63, 1001-
1011. (d) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett
1997, 1363-1366. (e) Collini, M. D.; Ellingboe, J. W. Tetrahedron Lett.
1997, 38, 7963-7966. (f) Saulnier, M. G.; Frennesson, D. B.; Deshpande,
M. S.; Vyas, D. M. Tetrahedron Lett. 1995, 36, 7841-7844. (g) Arcadi,
A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992, 33, 3915-3918.
The development of an optimum set of reaction conditions
was briefly investigated. Solvents, the pressure of carbon
(9) Arcadi, A.; Cacchi, S.; Cassetta, A.; Fabrizi, G.; Parisi, L. M. Synlett
2001, 1605.
1356
Org. Lett., Vol. 4, No. 8, 2002

monoxide, and the nature of the organic halide or triflate
were found to influence the reaction outcome, particularly
the selectivity between the 12-acylindoloquinazoline product
5 and the 12-arylindoloquinazoline product 10. For example,
the reaction of 9 with p-iodoanisole under a balloon of carbon
monoxide [Pd(PPh3)4, K2CO3, 50 °C, 24 h] gave the expected
5m in 88% yield in MeCN, while in DMSO, the 12-aryl-
derivative 10m, not incorporating a molecule of carbon
monoxide, was isolated in 78% yield. With aryl iodides
bearing electron-withdrawing substituents, a higher pressure
of carbon monoxide was found necessary to increase the ratio
of 5 to 10. However, the use of an excessive pressure of
carbon monoxide gave lower yields of 5. In practice, it
appears that an optimum pressure of carbon monoxide has
to be used to get the best results. For example, when the
reaction was carried out in MeCN under a balloon of carbon
monoxide with a moderate electron-poor aryl iodide such
as m-trifluoromethylphenyl iodide, 5a was isolated in 69%
yield along with a 21% yield of 10a. Raising the pressure
of carbon monoxide up to 5 bar led to the isolation of 5a in
89% yield (10a was obtained in 9% yield). A further increase
in the pressure of carbon monoxide (10 bar), however,
produced 5a in lower yield (70%), though 10a was isolated
in only 4% yield.
Table 1. Palladium-Catalyzed Synthesis of
6-Trifluoromethyl-12-acylindolo[1,2-c]quinazolines 5 from
Bis(o-trifluoroacetamidophenyl)acetylene 9, Organic Halides or
Triflates 2, and Carbon Monoxidea
In summary, the best standard reaction conditions thus far
developed employ 1 equiv of 9 (0.25 mmol), 1 equiv of the
organic halide or triflate 2, 0.05 equiv of Pd(PPh3)4, and 5
equiv of anhydrous K2CO3 in anhydrous MeCN (2 mL) at
50 °C under 5 bar of carbon monoxide.
Under these conditions, a high 5 to 10 selectivity was
usually observed and a variety of aryl iodides afforded the
desired indoloquinazoline derivatives in good to high yields
(Table). Among the aryl iodides investigated, only with 3,5-
di(trifluoromethyl)phenyl iodide and p-nitrophenyl iodide
were the two indoloquinazoline products isolated in almost
equimolar amounts (entries 2 and 8). The presence of ortho
substituents in the aryl iodide does not seem to hamper the
reaction (cf. entry 10 with entry 11).
With vinylic triflates, the addition of n-Bu4NBr or n-Bu4-
NI was found to show a remarkably beneficial effect on the
ratio of 5 to 10. The best results were observed in the
presence of n-Bu4NI (cf. entry 14 with entries 15 and 16).
In conclusion, this palladium-catalyzed reaction provides
a straightforward route to 12-acylindolo[1,2-c]quinazolines
from readily available bis(o-trifluoroacetamidophenyl)acet-
ylene and a variety of aryl iodides and vinyl triflates. The
methodology can tolerate many important functional groups
and should allow for easy access to substituted derivatives
of this class of compounds.
a Unless otherwise stated, reactions were conducted at 1.25 × 10-2
concentrations of starting substrates in anhydrous MeCN (2 mL) at 50 °C
under 5 bar of carbon monoxide, for 24 h, using the following molar ratio:
9:2:Pd(PPh3)4:K2CO3 ) 1:1:0.05:5. b Yields refer to single runs and are
given for isolated products. All new products had satisfactory elemental
analyses, and their spectra were consistent with the postulated structures.
c Numbers in parentheses represent the yields of side products 10. d Under
10 bar of carbon monoxide, 5b and 10b were isolated in 24 and 54% yields,
respectively. e Employed as a commercially available E/Z mixture. However,
only the 12-acylindolo[1,2-c]quinazoline derivative containing the (E)-styryl
fragment was isolated. f In the presence of 1.1 equiv of n-Bu4NBr. g In the
presence of 1.1 equiv of n-Bu4NI.
M
Acknowledgment. Work carried out in the framework
of the National Project “Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni” was supported by the Min-
istero dell’Universita` e della Ricerca Scientifica e Tecno-
logica, Rome. The authors are also greatly indebted to
Consiglio Nazionale delle Ricerche (CNR) and the University
“La Sapienza”, Rome, for financial support of this research.
Org. Lett., Vol. 4, No. 8, 2002
1357

Supporting Information Available: Preparation of bis-
(o-trifluoroacetamidophenyl)acetylene 9, a typical experi-
mental procedure for the preparation of 12-acylindolo[1,2-
c]quinazolines 5, and characterization data for all the
compounds listed in Table. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0256769
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Org. Lett., Vol. 4, No. 8, 2002