Palladium-catalyzed synthesis of 2-(aminomethyl)indoles from ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonate

Article abstract of DOI:10.1021/ol060499n

The palladium-catalyzed reaction of ethyl 3-(o-trifluoroacetamidophenyl)-1- propargyl carbonate with piperazines in the presence of Pd(PPh₃) ₄ in THF at 80 °C affords 2-(piperazin-1-ylmethyl)indoles in excellent yields. Good to excellent yields are also obtained with other secondary amines.

Full text of DOI:10.1021/ol060499n

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2083-2086
Palladium-Catalyzed Synthesis of
2-(Aminomethyl)indoles from Ethyl
3-(o-Trifluoroacetamidophenyl)-1-propargyl
Carbonate
Ilaria Ambrogio, Sandro Cacchi,* and Giancarlo Fabrizi
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersita` degli Studi “La Sapienza”, Piazzale Aldo Moro 5, 00185 Roma, Italy
sandro.cacchi@uniroma1.it
Received February 28, 2006
ABSTRACT
The palladium-catalyzed reaction of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonate with piperazines in the presence of Pd(PPh3)4
in THF at 80
amines.
°C affords 2-(piperazin-1-ylmethyl)indoles in excellent yields. Good to excellent yields are also obtained with other secondary
Our palladium-catalyzed hydroarylation/cyclization of alkynes
bearing nucleophilic and electrophilic centers close to the
carbon-carbon triple bond was proved to be a useful tool
for the construction of heterocyclic rings.1 Using this
procedure, we prepared butenolides,2 quinolines,3 chromenes,4
coumarins, and chromanols.5 During our continuing studies
on this research area, we had the occasion to examine the
reaction of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl
carbonate 1a with p-iodoanisole under the hydroarylation
conditions shown in Scheme 1. 2-Methyl indole 3 was
isolated in 78% yield, and 2-(piperidin-1-ylmethyl)indole 4
in was isolated in 4% yield; none of the hydroarylation
product 2 was observed.
Scheme 1
(1) Cacchi, S.; Fabrizi, G. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York,
2002; Vol 1, 1335.
(2) (a) Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Marinelli, F.;
Pietroni, B. Tetrahedron 1988, 44, 481. (b) Arcadi, A.; Bernocchi, E.; Burini,
A.; Cacchi, S.; Marinellli, F.; Pietroni, B. Tetrahedron Lett. 1989, 30, 3465.
(c) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P. Eur. J. Org.
Chem. 1999, 3305.
(3) (a) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P.
Tetrahedron 1996, 52, 10225. (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A.;
Moreno-Man˜as, M.; Vallribera, A. Tetrahedron Lett. 2002, 43, 5537.
(4) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P. Eur. J.
Org. Chem. 2000, 4099. (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A. J. Mol.
Catal. A 2004, 214, 57. (c) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli,
F.; Verdecchia, M. Synlett, in press.
Though we did not obtain the desired product, the reaction
provided us with some data which attracted our attention.
Indeed, this is an example of a new palladium-catalyzed
cyclization of an acyclic alkyne to free N-H functionalized
(5) Cacchi, S.; Fabrizi, G.; Moro, L.; Pace, P. Synlett 1997, 1367
10.1021/ol060499n CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/15/2006

indoles. In particular, of great interest to us was the formation
of 4a (albeit in very poor yield), in which two carbon-
nitrogen bonds are formed in a single operative step. The
conversion of this side reaction into a synthetically useful
process would add to known procedures based on the
cyclization of o-alkynylanilines and o-alkynylanilides6 a new
useful approach for the assembly of the functionalized pyrrole
nucleus incorporated into the indole system (Scheme 2) and
Scheme 3
Scheme 2. Retrosynthetic Representation of the
Palladium-Catalyzed Assembly of the Pyrrole Nucleus from
Ethyl 3-(o-Trifluoroacetamidophenyl)-1-propargyl Carbonate 1a
Part of our optimization work using different catalyst
systems and solvents is summarized in Table 1. p-Iodoanisole
Table 1. Examination of the Reaction of Ethyl
3-(o-Trifluoroacetamidophenyl)-1-propargyl Carbonate 1a with
N-Ethylpiperazine 5aa
entry
catalyst system
solvent
time (h)
yield % of 6ab
open a straightforward route to an important class of indole
derivatives. Indeed, the 2-(aminomethyl)indole motif is a key
structural feature present in several biologically active
compounds.7 In particular, 2-(piperazin-1-ylmethyl)indoles,
containing two privileged substructures (the indole and
piperazine nuclei),8 exhibit important biological activities and
have attracted considerable attention in organic, medical, and
pharmaceutical chemistry.9
Therefore, the development of a protocol for the prepara-
tion of 2-(piperazin-1-ylmethyl)indoles 6 from 1a and
piperazines 5 (Scheme 3) was initially explored when we
started this research project.
Compound 1a was prepared through a four-step process
from o-iodoaniline via Sonogashira cross-coupling with the
tetrahydropyranyl derivative of propargyl alcohol followed
by trifluoroacetylation, deprotection, and esterification steps
in 80% overall isolated yield, omitting isolation and char-
acterization of reaction intermediates.
1
2
3
4
5
6
7
8
Pd(OAc)2, PPh3
Pd2(dba)3, PPh3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3, dppf
Pd2(dba)3, dppe
PdCl2(2-furyl)2
THF
THF
MeCN
DMF
THF
THF
THF
THF
6
6
6
6
1.5
6
52
58
57c
54c
91
85
50
33
24
24
a Unless otherwise stated, reactions were carried out on a 0.159 mmol
scale in 1 mL of solvent under argon at 80 °C by using 1 equiv of 1a, 3
equiv of 5a, 0.05 equiv of [Pd], 0.1 equiv of PPh3, or 0.05 equiv of bidentate
phosphine ligand. b Yields are given for isolated products. c With 0.05 equiv
of Pd(PPh3)4.
(which did not enter the catalytic cycle affording isolated
products) and formic acid (very likely involved in the
formation of 3) were omitted. Moderate yields were obtained
under a variety of reaction conditions (Table 1, entries 1-4).
The best result in terms of yield and reaction time was
obtained in the presence of Pd(PPh3)4 in THF (Table 1, entry
5). Longer reaction times and lower yields were observed
with Pd2(dba)3 and bidentate ligands such as dppf and dppe
(Table 1, entries 6 and 7). A longer reaction time and lower
yield were also observed using the less reactive propargyl
acetate10 1b as the starting alkyne (50% yield; Pd(PPh3)4,
THF, 80 °C, 24 h). A slight increase of the yield (67%) was
observed with 1b at 100 °C after 9 h, but the yield was still
significantly lower than that with 1a.
The best conditions found for 1a [Pd(PPh3)4, THF, 80 °C]
proved to be very efficient for a number of related cycliza-
tions to 2-(piperazin-1-ylmethyl)indoles as indicated in Table
2. Only with 5j (Table 2, entry 10), the desired indole product
was isolated in moderate yield, very likely because of the
low nucleophilicity of the nitrogen derivative due to steric
effects.
(6) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873.
(7) See, for example: (a) Moro´n, J. A.; Campillo, M.; Perez, V.; Unzeta,
M.; Pardo, L. J. Med. Chem. 2000, 43, 1684. See also: (b) Spadoni, G.;
Balsamini, C.; Diamantini, G.; Tontini, A.; Tarzia, G.; Mor, M.; Rivara,
S.; Plazzi, P. V.; Nonno, R.; Lucini, V.; Pannacci, M.; Fraschini, F.; Stankov,
B. M. J. Med. Chem. 2001, 44, 2900. (c) Spadoni, G.; Balsamini, C.; Bedini,
A.; Diamantini, G.; Di Giacomo, B.; Tontini, A.; Tarzia, G.; Mor, M.; Plazzi,
P. V.; Rivara, S.; Nonno, R.; Pannacci, M.; Lucini, V.; Fraschini, F.;
Stankov, B. M. J. Med. Chem. 1998, 41, 3624.
(8) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893.
(9) For some recent references, see: (a) Hu¨bner, H.; Gmeiner, P.;
Kraxner, J. J. Med. Chem. 2000, 43, 4563. (b) Clifford, J. J.; Waddington,
J. L. Neuropsychopharmacol. 2000, 22, 538. Ortner, B.; Waibel, R.;
Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40, 1283. (c) Moll, A.; Hu¨bner,
H.; Gmeiner, P.; Troschutz, R. Bioorg. Med. Chem. 2002, 10, 1671. (d)
Brioni, J. D.; Kolasa, T.; Hsieh, G. C.; Donnelly-Roberts, D. L. WO
2002041894, 2002; Chem. Abstr. 2002, 136, 395987. (e) Fliri, A. F. J.;
Sanner, M. A.; Seymour, P. A.; Zorn, S. H. Eur. Patent 1177792, 2002;
Chem. Abstr. 2002, 136, 145264. (f) Fliri, A. F. J.; Majchrzak, M. J.;
Seymour, P. A.; Zorn, S. H.; Rollema, H. U.S. Patent 842,569, 2003; Chem.
Abstr. 2003, 138, 401610. (g) Cowart, M.; Latshaw, S. P.; Bhatia, P.;
Daanen, J. F.; Rohde, J.; Nelson, S. L.; Patel, M.; Kolasa, T.; Nakane, M.;
Uchic, M. E.; Miller, L. N.; Terranova, M. A.; Chang, R.; Donnelly-Roberts,
D. L.; Namovic, M. T.; Hollingsworth, P. R.; Martino, B. R.; Lynch, J. J.,
III.; Sullivan, J. P.; Hsieh, G. C.; Moreland, R. B.; Brioni, J. D. S.; Andrew,
O. J. Med. Chem. 2004, 47, 3853. (h) Stewart, A. O.; Cowart, M. D.;
Moreland, R. B.; Latshaw, S. P.; Matulenko, M. A.; Bhatia, P. A.; Wang,
X.; Daanen, J. F.; Nelson, S. L.; Terranova, M. A.; Namovic, M. T.;
Donnelly-Roberts, D. L.; Miller, L. N.; Nakane, M.; Sullivan, J. P.; Brioni,
J. D. J. Med. Chem. 2004, 47, 2348.
Then, the extension of the reaction to other secondary
amines and even to primary amines was briefly investigated
(10) For a review on the palladium-catalyzed reactions of propargyl
esters, see: (a) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl. 1995,
34, 2589.
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Org. Lett., Vol. 8, No. 10, 2006

(Table 3). Yields are usually good to high with secondary
amines (Table 3, entries 1-3). The moderate yield obtained
Table 2. Palladium-Catalyzed Synthesis of 2-(Piperazin-1-
ylmethyl)indoles 6 from Ethyl 3-(o-Trifluoroacetamidophenyl)-
1-propargyl Carbonate 1a and Piperazines 5a
Table 3. Palladium-Catalyzed Reaction of Ethyl
3-(o-Trifluoroacetamidophenyl)-1-propargyl Carbonate 1a with
Secondary Aminesa
a Unless otherwise stated, reactions were carried out on a 0.159 mmol
scale in 1 mL of THF under argon at 80 °C by using 1 equiv of 1a, 3 equiv
of secondary amine, and 0.05 equiv of Pd(PPh3)4. b Yields are given for
isolated products. c The indole product 4a was isolated in 84% yield in the
presence of 0.0125 equiv of Pd2(dba)3 and 0.05 equiv of PPh3 after 6 h and
in 73% yield with 0.025 equiv of Pd2(dba)3, omitting PPh3, after 24 h. d With
5 equiv of amine.
with diisopropylamine (Table 3, entry 4) was attributed again
to the involvement of steric effects. With primary amines,
the efficiency of the reaction is flawed by the occurrence of
side reactions. For example, with benzylamine and butyl-
amine, complex reaction mixtures were obtained that we have
not thoroughly investigated.
Although the precise mechanism for this indole synthesis
is not clear, a possible rationale considers the following basic
steps: (a) initial formation of the σ-allenylpalladium complex
7 (via a SN2′ reaction of the palladium complex with 1a)
which would be in equilibrium with the π-propargylpalla-
dium intermediate 8,11 (b) intramolecular nucleophilic attack
of the nitrogen at the central carbon of the allenyl/propar-
gylpalladium complex,10,12,13 (c) protonation of the resultant
carbene 9 to give the π-allylpalladium complex 10, (d)
regioselective intermolecular nucleophilic attack of the
nitrogen nucleophile at the less hindered allylic terminus of
10 (Scheme 4).
As observed in our previous studies on the aminopalla-
dation-reductive elimination route to indoles,14 the acidity
of the nitrogen-hydrogen bond was found to play a crucial
role. When ethyl 3-(o-acetamidophenyl)-1-propargyl carbon-
ate 11, containing a less acidic nitrogen-hydrogen bond,
was subjected to 4-ethylpiperazine under our standard
(11) Tsutsumi, K.; Ogoshi, S.; Nishiguchi, S.; Kurosawa, H. J. Am. Chem.
Soc. 1998, 120, 1938.
(12) Baize, M. W.; Blosser, P. W.; Plantevin, V.; Schimpff, D. G.;
Gallucci, J. C.; Wojcicki, A. Organometallics 1996, 15, 164.
(13) For some examples of reactions involving a nucleophilic attack at
the central sp carbon of a σ-propargylpalladium complex to give a
π-allylpalladium complex which is further attacked by a second nucleophile,
see: (a) Fournier-Nguefack, C.; Lhoste, P.; Sinou, D. Synlett 1996, 553.
(b) Labrosse, J.-R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1999, 40, 9025.
(c) Labrosse, J.-R.; Lhoste, P.; Sinou, D. Org. Lett. 2000, 2, 527. (d)
Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem. Soc. 2003, 125,
4874. (e) Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron
2005, 61, 4381.
a Reactions were carried out on a 0.159 mmol scale in 1 mL of THF
under argon at 80 °C by using 1 equiv of 1a, 3 equiv of 5, and 0.05 equiv
of Pd(PPh3)4. b Yields are given for isolated products.
Org. Lett., Vol. 8, No. 10, 2006
2085

Scheme 4
ligands15 and that the best ligands for the palladium-catalyzed
reaction of propargyl halides16 and carbonates10 with soft
nucleophiles are the bidentate ligands.
In conclusion, we have developed a straightforward, very
useful new approach to 2-(aminomethyl)indoles, including
the important class of 2-(piperazin-1-ylmethyl)indoles. The
procedure is simple. The reaction proceeds under mild
conditions, and indole products are formed in good to
excellent yields. Further investigations, directed toward the
utilization of this strategy to the assembly of other func-
tionalized indole products, are currently in progress.
Acknowledgment. Work was carried out in the frame-
work of the National Project “Stereoselezione in Sintesi
Organica: Metodologie ed Applicazioni” by the Ministero
dell’Universita` e della Ricerca Scientifica e Tecnologica,
Rome, and by the University “La Sapienza”, Rome.
conditions, a complex reaction mixture was obtained and the
indole product was formed only in trace amounts, if any.
Interestingly, the present indole synthesis gives excellent
results using a monodentate phosphine ligand, though it has
been reported that π-propargylpalladium complexes are
formed in a more stable manner in the presence of bidentate
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060499N
(14) (a) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002,
2671. (b) Cacchi, S.; Fabrizi, G.; Lamba, D.; Marinelli, F.; Parisi, L. M.
Synthesis 2003, 728. (c) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Parisi, L. M.
Tetrahedron Lett. 2004, 45, 2431. (d) Cacchi, S.; Fabrizi, G.; Parisi, L. M.
Synthesis 2004, 1889. (e) Cacchi, S.; Fabrizi, G.; Parisi, L. M. J. Comb.
Chem. 2005, 7, 510. (f) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.;
Parisi, L. M. J. Org. Chem. 2005, 70, 6213
(15) (a) Tsutsumi, K.; Kawase, T.; Kakiuchi, K.; Ogoshi, S.; Okada, Y.;
Kurosawa, H. Bull. Chem. Soc. Jpn. 1999, 72, 2687. (b) Korawa, Y.; Mori,
M. J. Org. Chem. 2003, 68, 8068.
(16) Tsutsumi, K.; Yabukami, T.; Fujimoto, K.; Kawase, T.; Morimoto,
T.; Kakiuchi, K. Organometallics 2003, 22, 2996.
2086
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