Palladium-catalyzed reaction of o-alkynyltrifluoroacetanilides with 1-bromoalkynes. An approach to 2-substituted 3-alkynylindoles and 2-substituted 3-acylindoles

Article abstract of DOI:10.1021/jo050517z

The palladium-catalyzed reaction of o-alkynyltrifluoroacetanilides with 1-bromoalkynes affords free N-H 2-substituted 3-alkynylindoles in satisfactory to high yield. 2-Substituted 3-alkynylindoles revealed useful intermediates for the regioselective synthesis of 2-substituted 3-acylindoles. The latter can be prepared from o-alkynyltrifluoroacetanilides and 1-bromoalkynes via a one-pot cyclization-hydration protocol, omitting the isolation of 2-substituted 3-alkynylindoles.

Full text of DOI:10.1021/jo050517z

Palladium-Catalyzed Reaction of o-Alkynyltrifluoroacetanilides
with 1-Bromoalkynes. An Approach to 2-Substituted
3-Alkynylindoles and 2-Substituted 3-Acylindoles
Antonio Arcadi,† Sandro Cacchi,*,‡ Giancarlo Fabrizi,‡ Fabio Marinelli,† and Luca M. Parisi‡
Dipartimento di Chimica Ingegneria Chimica e Materiali della Facolta` di Scienze, Universita` di
L’Aquila, Via Vetoio, Coppito Due, I-67100 L’Aquila, Italy, and Dipartimento di Studi di Chimica e
Tecnologia delle Sostanze Biologicamente Attive, Universita` degli Studi “La Sapienza”, P. le A. Moro 5,
00185 Rome, Italy
sandro.cacchi@uniroma1.it
Received March 15, 2005
The palladium-catalyzed reaction of o-alkynyltrifluoroacetanilides with 1-bromoalkynes affords free
N-H 2-substituted 3-alkynylindoles in satisfactory to high yield. 2-Substituted 3-alkynylindoles
revealed useful intermediates for the regioselective synthesis of 2-substituted 3-acylindoles. The
latter can be prepared from o-alkynyltrifluoroacetanilides and 1-bromoalkynes via a one-pot
cyclization-hydration protocol, omitting the isolation of 2-substituted 3-alkynylindoles.
SCHEME 1
Introduction
The construction of the functionalized pyrrole ring
incorporated into the indole system through our amino-
palladation-reductive elimination reaction has been
shown to be a simple and versatile tool for a rapid assem-
bly of indole derivatives with a high level of molecular
complexity from acyclic precursors.1 The reaction toler-
ates a wide range of functional groups amenable to
further functionalization, so that even higher structural
complexity can be readily achieved.2 In connection with
our current research interests in this area and in order
to widen the scope and generality of the methodology,
we decided to develop a procedure for the preparation of
2-substituted 3-alkynylindoles through the palladium-
catalyzed reaction of readily available o-alkynyltrifluo-
roacetanilides with 1-haloalkynes (Scheme 1).
1-Halo-1-alkynes have never been used in this indole
chemistry. In general, they have been rarely used in the
functionalization of alkynes through reactions involving
intramolecular nucleophilic attack across the carbon-
carbon triple bond activated by coordination to an orga-
nopalladium complex.3 To the best of our knowledge, only
a couple of examples of this type of reaction have been
reported. One of them is due to Balme et al. who first
described the utilization of 1-halo-1-alkynes in the syn-
thesis of 5-(E)-alkylidene tetrahydro-2-furanones from
† Universita` di L’Aquila.
‡ Universita` degli Studi “La Sapienza”.
(1) For a review, see: (a) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur.
J. Org. Chem. 2002, 2671. See also: (b) Cacchi, S.; Fabrizi, G.; Parisi,
L. M. Synthesis 2004, 1889. (c) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Parisi,
L. M. Tetrahedron Lett. 2004, 45, 2431 (d) Cacchi, S.; Fabrizi, G.;
Lamba, D.; Marinelli, F.; Parisi, L. M. Synthesis 2003, 728. (e) Flynn,
B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670.
(2) (a) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett 1999,
620. (b) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron
1994, 50, 437.
10.1021/jo050517z CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/07/2005
J. Org. Chem. 2005, 70, 6213-6217
6213

Arcadi et al.
pentynoic acids.4 The other one was recently reported by
Larock and co-workers, who described the preparation
of 3,4-disubstituted isoquinolines via intramolecular cy-
clization of N-tert-butyl-o-(1-alkynyl)benzaldimines pro-
moted by a variety of organopalladium complexes, in-
cluding σ-alkynylpalladium complexes.5 On the other
hand, some indole derivatives containing 3-alkynyl sub-
stituents have been shown to exhibit interesting biologi-
cal activities.6 Furthermore, the introduction of the
alkyne functionalilty into the indole system appears
particularly suited for further elaboration of indoles. For
example, alkynylindoles have been reported to be useful
intermediates for the synthesis of carbolines.7 Particu-
larly, in connection with our interest in the synthesis of
3-acylindoles,1b,2,8 we envisaged that 3-alkynylindoles
could be useful precursors of this important class of indole
derivatives9,10 through the regioselective11,12 addition of
water.
SCHEME 2
Results and Discussion
Initial attempts focused on exploring the feasibility of
the transformation. o-(Phenylethynyl)trifluoroacetanilide
1a and 1-iodo-phenylacetylene 2a were used as the model
system (Scheme 2), and the following reaction variables
were examined: the nature of the phosphine ligand, the
base, the solvent, and the reaction temperature. All
reactions were conducted on a 0.35 mmol scale in 2 mL
of solvent under argon, using 1.2 equiv of 2a, 5 mol % of
palladium, 10 mol % of phosphine ligand, and 3 equiv of
base. Compound 1a was prepared from o-iodoaniline via
Sonogashira coupling with phenylacetylene, followed by
the reaction of the resulting coupling product with
trifluoroacetic anhydride according to the previously
described procedure.13 1-Iodophenylacetylene was pre-
pared from the reaction of phenylacetylene with ethyl-
magnesium bromide followed by treatment with iodine.14
Some results from that study are summarized in Table
1.
Under a variety of reaction conditions, the desired
indole derivative 3a was isolated in low yields, the main
reaction product being 2-phenylindole 5a (Table 1, entries
2-4) or the biindole 6a (Table 1, entries 5-7). Appar-
ently, in analogy to previous findings,4 1-iodophenyl-
acetylene is not a good partner for aminopalladation-
reductive elimination reactions, most probably because
of its tendency to undergo side reactions we have not
investigated (for example, 1-iodoalkynes have been re-
cently shown to undergo palladium-catalyzed homocou-
pling to give 1,3-diynes).15
Hereafter we wish to report the results of this study.
(3) For recent reviews on this type of chemistry, see the following.
Cyclization with nitrogen nucleophiles: (a) Cacchi, S.; Marinelli, F.
In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; John Wiley & Sons: New York, 2002; Vol. 2, p 2227.
(b) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Heterocycles 2002, 58, 667.
Cyclization with oxygen nucleophiles: (c) Cacchi, S.; Arcadi, A. In
Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; John Wiley & Sons: New York, 2002; Vol. 2, p 2193.
(d) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Heterocycles 2002, 56, 613.
Cyclization with carbon nucleophiles: (e) Balme, G.; Bouyssi, D.;
Monteiro, N. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York, 2002; Vol.
2, p 2245. See also: (f) Balme, G. Bossharth, E. Monteiro, N. Eur. J.
Org. Chem. 2003, 4101. (g) Balme, G.; Bouyssi, D.; Lomberget, T.
Monteiro, N. Synthesis 2003, 2115.
(4) Bouyssi, D.; Gore, J.; Balme, G. Tetrahedron Lett. 1992, 33, 2811.
(5) Dai, G.; Larock, R. C. J. Org. Chem. 2003, 68, 920.
(6) (a) Hewkin, C. T.; Fabio, R.; Conti, N.; Cugola, A.; Gastaldi, P.;
Micheli, F.; Quaglia, A. M. Arch. Pharm. Pharm. Med. Chem. 1999,
332, 55. (b) Cugola, A.; Gaviraghi, G.; Micheli, F. Patent WO 9420465,
1994; Chem. Abstr. 1994, 121, 300763.
(7) (a) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 7048. (b)
Kanekiyo, N.; Kuwada, T.; Choshi, T.; Nobuhiro, J.; Hibino, S. J. Org.
Chem. 2001, 66, 8793. (c) Abbiati, G.; Beccalli, E. M.; Marchesini, A.;
Rossi, E. Synthesis 2001, 2477.
(8) Battistuzzi, G.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L.
M. Org. Lett. 2002, 4, 1355.
(9) For some recent utilizations of 3-acylindoles as intermediates,
see: (a) Hendrickson, J. B.; Wang, J. Org. Lett. 2004, 6, 3. (b) Na,
Y.-M.; Le Borgne, M.; Pagniez, F.; Le Baut, G.; Le Pape, P. Eur. J.
Med. Chem. 2003, 75. (c) Fresneda, P. M.; Molina, P.; Delgado, S.;
Bleda, J. A. Tetrahedron Lett. 2000, 41, 4777. (d) Fresneda, P. M.;
Molina, P.; Saez, M. A. Synlett 1999, 1651. (e) Faul, M. M.; Winneroski,
L. L.; Krumrich, C. A. J. Org. Chem. 1998, 63, 6053. (f) Wang, S.-P.
Heterocycles 1997, 45, 347.
We have since explored the utilization of 1-bromophen-
ylacetylene 2b, prepared by reaction of phenylacetylene
with silver nitrate and N-bromosuccinimide,16 and have
found that the reaction of 2b with 1a in the presence of
Pd(PPh3)4 as the palladium(0) source and K2CO3 as the
base, in DMSO, DMF, or MeCN at 60 °C affords the
corresponding 3-alkynyl derivative in good yields (Table
1, entries 8-10) with a higher reaction rate in DMF.
Similar yield and reaction rate as high as in DMF was
observed with Cs2CO3 in MeCN (Table 1, compare entry
9 with entry 11). The use of Pd(OAc)2 and PPh3 was also
(10) For some references on biological activities of 3-acylindoles,
see: (a) Curtin, M. L.; Davidsen, S. K.; Heyman, H. R.; Garland, R.
B.; Sheppard, G. S.; Florjancic, A. S.; Xu, L.; Carrera, G. M., Jr.;
Steinman, D. H.; Trautmann, J. A.; Albert, D. H.; Magoc, T. J.; Tapang,
P.; Rhein, D. A.; Conway, R. G.; Luo, G.; Denissen, J. F.; Marsh, K. C.;
Morgan, D. W.; Summers, J. B. J. Med. Chem. 1998, 41, 74. (b) Lehr,
M. J. Med. Chem. 1997, 40, 2694. (c) Eissenstat, M. A.; Bell, M. R.;
D’Ambra, T. E.; Alexander, E. J.; Daum, S. J.; Ackerman, J. H.; Gruett,
M. D.; Kumar, V.; Estep, K. G.; Olefirowicz, E. M.; Wetzel, J. R.;
Alexander, M. D.; Weaver, J. D.; Haycock, D. A.; Luttinger, D. A.;
Casiano, F. M.; Chippari, S. M.; Kuster, J. E.; Stevenson, J. I.; Ward,
S. J. J. Med. Chem. 1995, 38, 3094. (d) D’Ambra, T. E.; Estep, K. G.;
Bell, M. R.; Eissenstat, M. A.; Josef, K. L.; Ward, S. J.; Haycock, D.
A.; Baizman, E. R.; Casiano, F. M.; Beglin, N. C.; Chippari, S. M.;
Grego, J. D.; Kullnig, R. K.; Daley, G. T. J. Med. Chem. 1992, 35, 124.
(e) Bell, M. R.; D’Ambra, T. E.; Kumar, V.; Eissenstat, M. A.;
Herrmann, J. L., Jr.; Wetzel, J. R.; Rosi, D.; Philion, R. E.; Daum, S.
J.; Hlasta, D. J.; Kullnig, R. K.; Ackerman, J. H.; Haubrich, D. R.;
Luttinger, D. A.; Baizman, E. R.; Miller, M. S.; Ward, S. J. J. Med.
Chem. 1991, 34, 1099.
(12) Quantum mechanical calculations (PC Spartan Pro 1.0) indi-
cated that the addition of water to acetylenic moiety of 3 should occur
with high regioselectivity to give 3-acylindole derivatives.
(13) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron
1994, 50, 437.
(14) Rao, M. L. N.; Periasamy, M. Synth. Commun. 1995, 25, 2295.
(15) Damle, S. V.; Seomoon, D.; Lee, P. H. J. Org. Chem. 2003, 68,
7085.
(11) For a kinetic study on the substituent effects on the acid
hydration of alkynes, see: Allen, A. D.; Chiang, Y.; Kresge, A. J.;
Tidwell, T. T. J. Org. Chem. 1982, 47, 775.
(16) Li, L.-S.; Wu, Y.-L. Tetrahedron Lett. 2002, 43, 2427.
6214 J. Org. Chem., Vol. 70, No. 16, 2005

2-Substituted 3-Alkynyl- and 3-Acylindoles
TABLE 1. Ligands, Bases, Solvents, and Temperature in the Palladium-Catalyzed Reaction of
o-(Phenylethynyl)trifluoroacetanilide 1a with 1-Iodophenylacetylene 2a and 1-Bromophenylacetylene 2ba
time
(h)
yield %
yield %
yield %
entry
2
Pd(0)
ligand
base
solvent
T (°C)
of 3ab
of 5ab
of 6ab
1
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
P(o-tol)3
P(o-tol)3
P(2-furyl)3
P(o-tol)3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
MeCN
MeCN
MeCN
DMSO
DMF
40
60
60
80
80
80
100
60
60
60
60
60
40
21
2
19
28
20
24
26
18
24
76
78
78
76
63c
tr
50
60
71
18
30
19
2
3
4
2
5
1
45
31
40
6
1
7
1
8
9
9
6
10
11
12
MeCN
MeCN
MeCN
16
6
tr
8
10
PPh3
23
a Reactions were carried out on a 0.346 mmol scale, in 2 mL of solvent, under an argon atmosphere, using 1 equiv of 1, 1.2 equiv of 2,
0.05 equiv of [Pd], and 3 equiv of base. b Yields refer to isolated products. c Pd(OAc)2/PPh3 ) 1:4.
SCHEME 3
attempted. Indeed, the mixture of PPh3 and Pd(OAc)2 is
known to generate spontaneously a zerovalent palladium
complex that gives rise to oxidative addition reactions.17
However, under these conditions the desired 3a was
isolated in lower yield (Table 1, entry 12) than with Pd-
(PPh3)4. Therefore, we initially selected Pd(PPh3)4 and
Cs2CO3 in MeCN at 60 °C as satisfactory reaction
conditions when we set out to explore the scope and
limitations of this route to 3-alkynylindoles (see Table
2). However, Cs2CO3 did not provide as high reaction rate
and comparable or better yields on a number of starting
materials as with our model system. In some cases, K2-
CO3 provided better results (Table 2, compare entries 8
and 23 with, respectively, entries 7 and 22). In practice,
the effectiveness of each base is to be evaluated each
time.
SCHEME 4
Good to high yields of indole products have been
usually obtained with 1-bromoarylalkynes bearing elec-
tron-donating or electron-withdrawing substituents. Alkyl
groups bound to the alkyne fragment showed a tendency
to give lower yields. In these cases, the use of Pd2(dba)3
and P(Bu-t)3 as the ligand (added to the reaction mixture
as the tetrafluoroborate salt)18 can produce a significant
increase of the yield (Table 2, compare entry 20 with
entry 21). An interesting feature of the reaction is the
formation of indoles containing free N-H pyrrole nuclei
(the amide bond is broken during the reaction or/and the
workup), avoiding troublesome and time-consuming depro-
tecting steps.
As to the mechanism, most probably the reaction
proceeds through the basic steps of the aminopallada-
tion-reductive elimination reaction:1a (a) reaction of 1
with a σ-alkynylpalladium intermediate [generated in
situ via oxidative addition of the bromoalkyne to Pd(0)]
to give a π-alkyne-σ-alkynylpalladium complex, (b) in-
tramolecular nucleophilic attack of the nitrogen nucleo-
phile across the activated carbon-carbon triple bond, and
(c) reductive elimination of the resultant σ-indolyl-σ-
alkynylpalladium intermediate that furnishes the indole
product 3 and regenerates the active palladium catalyst.
With a satisfactory procedure in hand for the prepara-
tion of 3-alkynylindoles 3, we next attempted their
conversion into 3-acylindoles 4. We were pleased to find
that the reaction proceeded with very high regioselectiv-
ity and that 4 could be readily obtained from 3 in high
yield at room temperature in the presence of catalytic
amounts of TsOH19 (Scheme 3). Our preparative results
are summarized in Table 3. The presence of electron-
withdrawing or electron-donating substituents in the C2-
position (R1) or in the alkyne moiety (R2) does not
influence the regioselectivity of the acid hydration. All
of the substrates that we have investigated gave always
3-acylindoles as the sole reaction products.
We have also developed a one-pot protocol for the
preparation of 2-substituted 3-acylindoles from 1-bromo-
alkynes and o-alkynyltrifluoroacetanilides that omits the
isolation of the alkynylindole intermediate. As an ex-
ample, 4g was obtained from 1a and 2j in 57% overall
yield (Scheme 4).
Notably, the whole process mimics the formation of
3-acylindoles via the reaction of alkyl halides with
o-alkynyltrifluoroacetanilides in the presence of carbon
monoxide. Such a reaction was attempted by us with
benzyl bromide and o-hexynyltrifluoroacetanilide, but the
corresponding 3-acylindole was isolated in only 32% yield,
the main product being the N-benzyl derivative of the
starting alkyne generated via the competitive SN reaction.
In conclusion, we have developed straightforward new
routes for the preparation of 2-substituted 3-alkynylin-
(17) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992,
11, 3009.
(18) Netherton, M.; Fu, G. C, Org. Lett. 2001, 3, 4295.
(19) For a masterful review on the transition-metal-catalyzed ad-
dition of heteroatom-hydrogen bonds to alkynes, see: Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
J. Org. Chem, Vol. 70, No. 16, 2005 6215

Arcadi et al.
TABLE 2. 2-Substituted 3-Alkynylindoles 3 via the Palladium-Catalyzed Reaction of o-Alkynyltrifluoroacetanilides 1
with 1-Bromoalkynes 2a
a Reactions were carried out at 60 °C on a 0.346 mmol scale, in 2 mL of MeCN, under an argon atmosphere, using 1 equiv of 1, 1.2
equiv of 2, 0.05 equiv of Pd(PPh)4, and 3 equiv of Cs2CO3 or K2CO3. b Yields refer to isolated products. c Cs2CO3. d K2CO3. e In the presence
of 0.025 equiv of Pd2(dba)3 and 0.1 equiv of HP(Bu-t)3BF4.
6216 J. Org. Chem., Vol. 70, No. 16, 2005

2-Substituted 3-Alkynyl- and 3-Acylindoles
TABLE 3. Conversion of 2-Substituted 3-Alkynylindoles
3 into 2-Substituted 3-Acylindoles 4a
important class of indole derivatives and a convenient
alternative to classical methods based on the acylation
of indoles such as the Friedel-Craft acylations,20
Vilsmeier-Haack acylations,21 and the reactions of indole
salts with acyl chlorides.22
entry
R1, 1
R2, 2
t (h) yield % of 4b
1
2
3
4
5
6
p-MeOC6H4
p-MeOC6H4
Ph
Ph
3i
6
70
95
89
68
98
90
4a
4b
4c
4d
4e
4f
m-NO2-p-MeC6H3 3k 16
p-MeOC6H4
p-MeCOC6H4 Ph
3b
3l
3t 16
3o
5
7
Acknowledgment. Work carried out in the frame-
work of the National Project “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” supported by the
Ministero dell’Istruzione, dell’Universita` e della Ricerca
and by the University “La Sapienza”. We also thank Mr.
Gilles Lemiere for his dedication and contribution to this
project within the Erasmus program.
p-MeOC6H4
CH2OTHP
n-C8H17
p-MeCOC6H4
9
a Reactions were carried out at room temperature on a 0,15
mmol scale, in 2 mL of a 2:1 MeOH/Me2CO mixture using 0.2 equiv
of TsOH. b Yields refer to isolated products.
doles and 2-substituted 3-acylindoles containing a free
N-H pyrrole nucleus from readily available acyclic
precursors. The process occurs under mild conditions and
tolerates many important functional groups. As to 2-sub-
stituted 3-acylindoles, the present cyclization-hydration
methodology can provide a useful approach to this
Supporting Information Available: Experimental pro-
cedure and complete description of product characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO050517Z
(20) For some recent references, see: (a) Okauchi, T.; Itonaga, M.;
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(c) Nakatsuka, S.; Teranishi, K.; Goto, T. Tetrahedron Lett. 1994, 35,
2699. (d) Tani, M.; Aoki, T.; Ito, S.; Matsumoto, S.; Hideshima, M.;
Fukushima, K.; Nozawa, R.; Maeda, T.; Tashiro, M.; Yokoyama, Y.;
Murakami, Y. Chem. Pharm. Bull. 1990, 38, 3261.
(22) For some recent references, see: (a) Yang, C. X.; Patel, H. H.;
Ku, Y.-Y.; Shah, R.; Sawick, D. Synth. Commun. 1997, 27, 2125. (b)
Faul, M. M.; Winneroski, L. L. Tetrahedron Lett. 1997, 38, 4749. (c)
Davidsen, S. K.; Summers, J. B.; Albert, D. H.; Holms, J. H.; Heyman,
H. R.; Magoc, T. J.; Conway, R. G.; Rhein, D. A.; Carter, G. W. J. Med.
Chem. 1994, 37, 4423. (d) Macor, J. E.; Blank, D. H.; Fox, C. B.; Lebel,
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(21) For a recent reference, see: Allen, M. S.; Hamaker, L. K..;
LaLoggia, A. J.; Cook, J. M. Synth. Commun. 1992, 22, 2077.
J. Org. Chem, Vol. 70, No. 16, 2005 6217