Palladium-catalyzed domino C,N-coupling/carbonylation/suzuki coupling reaction: An efficient synthesis of 2-aroyl-/heteroaroylindoles

Article abstract of DOI:10.1021/ol901875z

A convenient one-pot synthesis of 2-aroylindoles using a domino palladium-catalyzed C,N-coupllng/carbonylatlon/C,C-coupling sequence Is described. The reaction Involved easily prepared 2-gem-dibromovinylanilines and boronic acids under carbon monoxide. Op

Full text of DOI:10.1021/ol901875z

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4608-4611
Palladium-Catalyzed Domino
C,N-Coupling/Carbonylation/Suzuki
Coupling Reaction: An Efficient
Synthesis of 2-Aroyl-/Heteroaroylindoles
Martin Arthuis, Rene´e Pontikis,* and Jean-Claude Florent*
Institut Curie, Centre de Recherche, 26 rue d’Ulm, Paris F-75248 cedex 05, France,
and CNRS, UMR 176, 26 rue d’Ulm, Paris F-75248 cedex 05, France
renee.pontikis@curie.fr; jean-claude.florent@curie.fr
Received August 12, 2009
ABSTRACT
A convenient one-pot synthesis of 2-aroylindoles using a domino palladium-catalyzed C,N-coupling/carbonylation/C,C-coupling sequence
is described. The reaction involved easily prepared 2-gem-dibromovinylanilines and boronic acids under carbon monoxide. Optimized
reaction conditions allowed the construction of a wide variety of highly functionalized 2-aroyl-/heteroaroylindoles in satisfactory yields.
The indole scaffold is prevalent in a plethora of natural
and synthetic compounds characterized by a variety of
biological and pharmacological activities.1 In particular,
the 2-aroylindole moiety is presented in several potent
tubulin polymerization inhibitors.2 In connection with our
ongoing studies3 on the synthesis of new vascular disrupt-
ing agents,4 we were especially interested in the construc-
tion of polysubstituted indoles bearing a 2-aroyl or
2-heteroaroyl group.
synthetic route involves regioselective addition of a variety
of acyl electrophiles on an N-protected 2-lithioindole spe-
cies.5 Other synthetic pathways include (a) cyclization of
chalcones bearing a 2-nitrogen group,6 (b) palladium-
catalyzed coupling reactions with an acid chloride,7 and (c)
palladium carbonylative cross-coupling with indoylborate.8
Moreover, these methodologies require the “de novo”
construction of conveniently N-protected indoles or highly
functionalized precursors.
Relatively few methods for the synthesis of the 2-aroylin-
dole skeleton have been reported. The most common
In this context, we became interested in the development
of a reliable approach for the synthesis of polysubstituted
2-aroylindoles. The palladium-catalyzed domino reaction
appears as an attractive synthetic route that prevents the
tedious construction of elaborated precursors and enhances
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893. (b) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843. (c)
Humphrey, G. R.; Kuethe, J. T. Chem. ReV 2006, 106, 2875.
(2) (a) Romagnoli, R.; Baraldi, P. G.; Sarkar, T.; Carrion, M. D.; Cara,
C. L.; Cruz-Lopez, O.; Preti, D.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo,
S.; Di Cristina, A.; Zonta, N.; Balzarini, J.; Brancale, A.; Hsieh, H.-P.;
Hamel, E. J. Med. Chem. 2008, 51, 1464. (b) Mahboobi, S.; Pongratz, H.;
Hufsky, H.; Hockemeyer, J.; Frieser, M.; Lyssenko, A.; Paper, D. H.;
Burgermeister, J.; Bohmer, F.-D.; Fiebig, H.-H.; Burger, A. M.; Baasner,
S.; Beckers, T. J. Med. Chem. 2001, 44, 4535.
(5) For some examples, see: (a) Shirley, D. A.; Roussel, P. A. J. Am.
Chem. Soc. 1953, 75, 375. (b) Sundberg, R. J.; Russel, H. F. J. Org. Chem.
1973, 38, 3324. (c) Saulnier, M.; Gribble, G. J. Org. Chem. 1982, 47, 757.
(d) Gharpure, M.; Stoller, A.; Bellamy, F.; Firnau, G.; Snieckus, V. Synthesis
1991, 1079, and references cited therein.
(6) (a) Mali, R.; Tllve, S.; Desai, V. J. Chem. Res., Miniprint 1999,
150. (b) Akazome, M.; Kondo, T.; Watanabe, Y. Chem. Lett. 1992, 21,
769.
(3) (a) Arthuis, M.; Pontikis, R.; Florent, J. C. Tetrahedron Lett. 2007,
48, 6397. (b) Arthuis, M.; Pontikis, R.; Florent, J.-C. J. Org. Chem. 2009,
74, 2234. (c) Ty, N.; Kaffy, J.; Arrault, A.; Thoret, S.; Pontikis, R.; Dubois,
J.; Morin-Allory, L.; Florent, J.-C. Bioorg. Med. Chem. Lett. 2009, 19, 1405.
(4) (a) Lippert, J. W., III Bioorg. Med. Chem. 2007, 15, 605. (b) Hinnen,
P.; Esken, F. Br. J. Cancer 2007, 96, 1159.
(7) (a) Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59, 4250. (b)
Abbiati, G.; Casoni, A.; Canevari, V.; Nava, D.; Rossi, E. Org. Lett. 2006,
8, 4839.
(8) Ishikura, M.; Terashima, M. J. Org. Chem. 1994, 59, 2634.
10.1021/ol901875z CCC: $40.75
Published on Web 09/18/2009
 2009 American Chemical Society

the efficiency of reaching the target molecules. Recently,
some interesting syntheses of 2-substituted indoles via
palladium-catalyzed tandem reactions, starting from 2-gem-
dibromovinylanilines, have emerged in the literature.9
Lautens and co-workers reported several C,N/C,C se-
quences providing 2-aryl,10 2-heteroaryl,11 2-alkenyl,12 or
2-alkynyl13 indoles. Interestingly, a tandem C,N/carbo-
nylation reaction published by Alper and co-workers
allowed access to various methyl-2-indolecarboxylates.14
Accordingly, we envisioned that 2-bromoindolesreported
as a potential intermediate in these tandem reactionsscould
generate, by the migratory insertion of carbon monoxide,
an acylpalladium species which could undergo transmeta-
lation with a boronic acid.15,16
Table 1. Optimization of the Reaction Conditionsa
temp
yield
entry solvent basea
CO
catalyst (°C)/time (h) 2a/4 (%)b
1
2
3
4
5
6
7
toluene K3PO4 balloon Pd(PPh3)4
toluene K2CO3 balloon Pd(PPh3)4
toluene Cs2CO3 balloon Pd(PPh3)4
90/6
29/15
45/7
25/2
90/24
90/24
90/48
90/2
toluene CsF
balloon Pd(PPh3)4
trace
45/25
28/8
c
toluene K2CO3 balloon Pd(PPh3)4
toluene K2CO3 balloon PdCl2dppfc
toluene K2CO3 balloon Pd2dba3/
Xantphosc
90/18
90/18
12/6
Herein, we report an effective domino C,N-coupling/
carbonylation/C,C-coupling sequence as a new route to
2-aroyl-/heteroaroylindoles bearing a variety of functional
groups. The reaction involves 2-gem-dibromovinylanilines,17
carbon monoxide, and boronic acids using palladium ca-
talysis (Scheme 1).
8
9
toluene K2CO3 12 bar Pd(PPh3)4
dioxane K2CO3 12 bar Pd(PPh3)4
110/16
100/16
85/24
85/48
85/60
44/0
61/0
54/0
62/0
70/0
10 dioxane K2CO3 12 bar Pd(PPh3)4
11 dioxane K2CO3 12 bar Pd(PPh3)4
12 dioxane K2CO3 12 bar Pd(PPh3)4
a All reactions were performed on a 1 mmol scale using 5 mol % of
catalyst, 5 equiv of base, and 1.1 equiv of phenylboronic acid. b Isolated
yield after column chromatography. c 3 equiv of KI was added.
Scheme 1. Strategic Approach to the Synthesis of 2-Acylindoles
K2CO3 proved to be the most efficient (entries 2s45%
yieldsvs 1, 3, and 4).
Other catalyst systems did not favor the expected three-
step tandem process (entries 5-7).19 To promote the car-
bonylation step, the domino reaction was performed under
12 bar of CO (entries 8-12). Using this relatively low
pressure, the sequence provided exclusively 2-benzoylindole
2a (entry 8, 44% yield). Exchanging toluene to dioxane at
100 °C resulted in a higher yield of 2a (entry 9, 61%), but
a longer heating time did not improve the coupling efficiency
(data not shown). Reducing the temperature to 85 °C resulted
in a slight diminution of the yield (entry 10, 54%), while
heating for a longer time (48 or 60 h) allowed recovery of
up to 70% yield for product 2a (entries 11 and 12).
Modification of the catalytic system also failed to improve
the yield (data not shown).
The 2-gem-dibromovinylaniline 1a and phenylboronic acid
3a were chosen to investigate the feasibility of the projected
reaction (Table 1). Thus, using Pd(PPh3)4, K3PO4 as a base,
and toluene as the solvent under 1 atm of CO at 90 °C until
consumption of the starting aniline, the desired aroylindole
2a5b could be isolated in 29% yield, but along with the
2-phenylindole18 4 (15% yield) arising from a C,N/Suzuki
reaction (entry 1). Several bases were next examined, and
(9) Thiegles, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett.
2004, 45, 907.
(10) Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008, 73, 538.
(11) Fang, Y.-Q.; Karish, R.; Lautens, M. J. Org. Chem. 2007, 72, 1341.
(12) Fayol, A.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203.
(13) Nagamochi, M.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955.
(14) Viera, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett. 2008,
10, 4899.
To examine the scope of this one-pot protocol, we selected
the optimized reaction conditions (K2CO3, Pd(PPh3)4, CO
12 bar, dioxane) and chose the temperature/time parameters
with respect to the nature of the engaged substrates.
For substituted anilines 1b-1g,20 which are prone to
degradation, domino reactions were conducted at 85 °C
for 24 h. As highlighted in Table 2, several functional
groups are tolerated including chlorine (entry 1, 68%),
the electron-withdrawing methoxycarbonyl group (entry
2, 50%), or electron-releasing groups (entries 4-6) to
produce benzoylindoles 2b-2f2b,6a in good yields. The
reaction can also be conducted with the polysubstituted
aniline 1g to provide 2-benzoyl-4,5,6-trimethoxindole 2g in
(15) Carbonylative cross-coupling reactions had proved to be an efficient
tool for the preparation of unsymmetrical ketones. See: (a) Brunet, J.-J.;
Chauvin, R. Chem. Soc. ReV 1995, 24, 89. (b) Neigishi, E.-i. Handbook of
Organopalladium Chemistry for Organic Synthesis; Ed.;Wiley-Interscience:
New York, 2002; Part IV, p 2309. (c) O’Keefe, B. M.; Simmons, N.; Martin,
S. F. Org. Lett. 2008, 10, 5301. (d) Brennfu¨hrer, A.; Neumann, H.; Beller,
M. Angew. Chem., Int. Ed. 2009, 48, 4114
.
(16) For recent examples of carbonylation used in combination with
alternative palladium-catalyzed reactions, see: (a) Awuah, E.; Capretta, A.
Org. Lett. 2009, 11, 3210. (b) Tadd, A. C.; Matsuno, A.; Fielding, M. R.;
Willis, M. C. Org. Lett. 2009, 11, 583. (c) Chouhan, G.; Alper, H. Org.
Lett. 2008, 10, 4987. (d) Martinelli, J. R.; Watson, D. A.; Freckmann,
D. M. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102,
and references cited therein. (e) Worlikar, S. A.; Larock, R. C. J. Org.
Chem. 2008, 73, 7175. (f) Grigg, R.; Sridharan, V.; Saha, M.; Mutton, S.;
(19) KI and dppf complex were reported to enhance the carbon monoxide
insertion vs the transmetalation of boronic acids, see: Ishiyama, T.; Kizaki,
H.; Hayashi, T.; Suzuki, A.; Miyaura, N. J. Org. Chem. 1998, 63, 4726.
(20) gem-Dibromovinylanilines 1b-1g were prepared in a two-step
sequence (Ramirez olefination, reduction using SnCl2·2H2O) from o-
nitrobenzaldehyde derivatives according to Fang and Lautens (see ref 10).
Kilner, C.; Macpherson, D.; Milner, P. J. Org. Chem. 2008, 73, 8352
.
(17) For a recent review on the site-selective cross-coupling of dihalo-
genated compounds, see: Wang, J. R.; Manabe, K. Synthesis 2009, 1405.
(18) Augustine, R. L.; Gustavsen, A. J.; Wanat, S. F.; Pattison, I. C.;
Houghton, K. S.; Koletar, G. J. Org. Chem. 1973, 38, 3004.
Org. Lett., Vol. 11, No. 20, 2009
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Table 2. Variation of the 2-gem-Dibromovinylanilinesa
Table 3. Scope of Aryl Boronic Acidsa
a All reactions were performed on a 1 mmol scale using 5 mol % of
Pd(PPh3)4, 5 equiv of K2CO3, and 1.1 equiv of phenyl boronic acid under
an atmosphere of CO (12 bar). b Isolated yield after column chromatography.
c Reaction run at 100 °C for 16 h.
good yield (entry 6, 65%). It is noteworthy that yields could
be further enhanced by increasing the reaction time. We then
turned our attention to the scope of aryl boronic acids. Since
the starting aniline 1a was robust enough, these reactions
were conducted at higher temperature (100 °C) for 16 h
using several commercially available boronic acids 3h-3o
(Table 3).
a All reactions were performed on a 1 mmol scale using 5 mol % of
Pd(PPh3)4, 5 equiv of K2CO3, and 1.1 equiv of boronic acid under an
atmosphere of CO (12 bar). b Isolated yield after column chromatography.
Electron-rich partners, such as 4-methoxyphenyl or
3,4,5-trimethoxyphenyl boronic acids, performed well
under the optimized conditions (entries 1 and 2).2b,21 The
reaction seems to be sensitive to steric hindrance imposed
by the o-substitution of the boronic acid. For example,
2-methoxyphenylboronic acid 3j furnished the aroylindole
2j21 in modest yield (entry 3, 40%), whereas with the 2,6-
dimethylphenylboronic acid, an attempt to isolated indole
2k was unsuccessful despite complete consumption of aniline
1a (entry 4). Electron-deficient substrates, such as 4-triflu-
oromethyl or 4-chlorophenylboronic acids, react smoothly
(entries 5-6, 73 and 70%, respectively).22 Boronic acid 3n,
bearing an amido group, participates in the reaction albeit
in a lower yield (entry 7, 29%). Phenylvinylboronic acid also
proved to be an efficient partner of the domino reaction
providing indol-2-ylchalcone 2o in good yield (entry 8, 67%).
Finally, we explored the application of the domino reaction
to heteroarylboronic acids (Table 4). The reaction proved to
be compatible with various substrates such as thiophen-3-,
benzofuran-2-, or dibenzofuran-4-boronic acids providing
2-heteroaroylindoles 2p-2s2b,23 in fair to good yields (entries
1-3, 58-71%). Reaction with isoquinolin-3-boronic acid
was less efficient providing indole 2s in low yield, probably
due to the nitrogen of the boronic acid (entry 4, 21%).
(22) Takeda, Y.; Kikuchi, A.; Terashima, M. Heterocycles 1993, 35,
573.
(21) Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985, 26, 5935
.
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Org. Lett., Vol. 11, No. 20, 2009

2-Naphthylboronic acid also participated in the domino
process leading to polycyclic compound 2t24 in good yield
(entry 5, 70%).
Table 4. Scope of Heteroaryl Boronic Acidsa
In summary, we have established a novel and efficient
protocol for the preparation of 2-aroylindoles in moderate
to good yields, through a one-pot palladium-catalyzed
C,N-coupling/carbonylation/Suzuki coupling sequence.
The reaction tolerates various functional groups, thus
providing a practical access to a wide range of 2-aroyl-
or 2-heteroaroylindoles from readily accessible starting
materials. The application of this methodology to the
synthesis of bioactive compounds is underway in our
laboratory.
Acknowledgment. This work was financially supported
by the Centre National de la Recherche Scientifique, the
Institut Curie, and INCa. M.A. thanks the Ministe`re de
l’Enseignement Supe´rieur et de la Recherche for a Ph.D.
Fellowship Grant.
Supporting Information Available: Synthetic procedures,
1
characterization data, and copies of the H NMR and 13C
NMR experiments. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL901875Z
a All reactions were performed on a 1 mmol scale using 5 mol % of
Pd(PPh3)4, 5 equiv of K2CO3, and 1.1 equiv of boronic acid under an
atmosphere of CO (12 bar). b Isolated yield after column chromatography.
(23) Mahboobi, S.; Uecker, A.; Cenac, C.; Sellmer, A.; Eichhorn, E.;
Elz, S.; Bo¨hmer, F.-D.; Dove, S. Bioorg. Med. Chem. 2007, 15, 2187.
(24) Kar, S.; Lahiri, S. J. Indian. Chem. Soc. 1999, 76, 607.
Org. Lett., Vol. 11, No. 20, 2009
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