2-Aryl and 2-Heteroaryl Indoles from 1-Alkynes and o- lodotrifluoroacetanilide through a Domino Copper-Catalyzed Coupling-Cyclization Process

Article abstract of DOI:10.1021/ol035378r

(Matrix presented) A general method for the synthesis of 2-aryl and 2-heteroaryl indoles from aryl iodides and 1-alkynes through a domino copper-catalyzed process is reported. The best results have been obtained with [Cu(phen)(PPh₃)₂]NO₃ in the presence of K ₃PO₄ in toluene or dioxane at 110°C. 2-Aryl and 2-heteroaryl indoles can also be isolated in good yields by using catalysts derived from Cul and PPh₃ in dioxane at 110°C.

Full text of DOI:10.1021/ol035378r

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3843-3846
2-Aryl and 2-Heteroaryl Indoles from
1-Alkynes and o-Iodotrifluoroacetanilide
through a Domino Copper-Catalyzed
Coupling−Cyclization Process†
Sandro Cacchi,* Giancarlo Fabrizi, 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 Roma, Italy
sandro.cacchi@uniroma1.it
Received July 23, 2003
ABSTRACT
A general method for the synthesis of 2-aryl and 2-heteroaryl indoles from aryl iodides and 1-alkynes through a domino copper-catalyzed
process is reported. The best results have been obtained with [Cu(phen)(PPh3)2]NO in the presence of K3PO in toluene or dioxane at 110 °C.
3
4
2-Aryl and 2-heteroaryl indoles can also be isolated in good yields by using catalysts derived from CuI and PPh3 in dioxane at 110 °C.
The indole nucleus is present in a number of bioactive
molecules,1 and this, undoubtedly, plays a key role in the
continued search for the development of new, efficient, and
selective protocols for its construction. Classical methods
include (to name a few) the Fischer indole synthesis, the
Batcho-Limgruber synthesis from o-nitrotoluenes and dim-
ethylformamide acetals, the Gassman synthesis from N-
haloanilines, the reductive cyclization of o-nitrobenzyl
ketones, and the Madelung cyclization of N-acyl-o-tolu-
idines.2 More recently, transition-metal-based reactions,
particularly palladium-catalyzed protocols3 (some of them
developed in our laboratories),3° have been widely employed
providing increased functional group tolerance and improved
yields. Surprisingly, little attention has been paid to copper-
based protocols. A copper-assisted synthesis has been
described in which indoles are prepared upon treatment of
o-(trimethylsilylethynyl)anilines with 2 equiv of CuI.4 For-
mation of indole in moderate yield was observed in the
reaction of o-ethynyltrifluoroacetanilide with 3.2 equiv of
(3) Cyclization of N-allyl-o-haloanilines: (a) Mori, M.; Chiba, K.; Ban,
Y.; Tetrahedron Lett. 1977, 1037. (b) Odle, R.; Blevins, B.; Ratcliff, M.;
Hegedus, L. S. J. Org. Chem. 1980, 45, 2709. (c) Larock, R. C.; Babu, S.
Tetrahedron Lett. 1987, 28, 5291. Cyclization of o-halo-N-propargylanil-
ides: (d) Brown, D.; Grigg, R.; Sridharan, V.; Tambyrajah, V.; Thorntorn-
Pett, M. Tetrahedron 1998, 54, 2595. Cyclization of o-vinylanilines and
o-vinylnitroarenes: (e) Harrington, P. J.; Hegedus, L. S. J. Org. Chem.
1984, 49, 2657. (f) Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille,
J. K. J. Org. Chem. 1988, 53, 1170. (g) Kasahara, A.; Izumi, T.; Murakami,
S.; Miyamoto, K.; Hino, T. J. Heterocycl. Chem. 1989, 26, 1405. Cyclization
of o-allylanilines: (h) Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am.
Chem. Soc. 1980, 102, 3583. Cyclization of o-haloanilino enamine: (i)
Kasahara, A.; Izumi, T.; Murakami, S.; Yanai, H.; Takatori, M. Bull. Chem.
Soc. Jpn. 1986, 59, 927. (j) Sakamoto, T.; Nagano, T.; Kondo, Y.;
Yamanaka, H. Synthesis 1990, 215. Cyclization of o-alkynyl anilines: (k)
Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H. Tetrahedron Lett. 1985,
26, 5963. (l) Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988,
29, 1799. Annulation of internal alkynes: (m) Larock, R. C.; Yum, E. K.
J. Am. Chem. Soc. 1991, 113, 6689. (n) Larock, R. C.; Yum, E. K.; Refvik,
M. D. J. Org. Chem. 1998, 63, 7652. Aminopalladation-reductive
elimination domino reaction review: (o) Battistuzzi, G.; Cacchi, S.; Fabrizi,
G. Eur. J. Org. Chem. 2002, 2671. Cyclization of o-(1-alkynyl)-N-alkylidene
anilines: (p) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc.
2000, 122, 5662.
† Dedicated to Professor Luciano Caglioti on the occasion of his 70th
birthday.
(1) For a recent review of indole containing natural products, see: (a)
Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155. (b) Lounasmaa, M.; Tolvanen,
A. Nat. Prod. Rep. 2000, 17, 175.
(2) For reviews on indole syntheses, see: (a) Indoles; Sundberg, R. J.,
Ed.; Academic: London, 1996. (b) Sundberg, R. J. Pyrroles and their Benzo
Derivatives: Synthesis and Applications. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984;
Vol. 4, pp 313-376.
(4) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Pe´rez, M.;
Garc´ıa-Martin, M. A.; Gonza´lez, J. M. J. Org. Chem. 1996, 61, 5804.
10.1021/ol035378r CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003

Cu(OAc)2.5 N-Methanesulfonyl and N-ethoxycarbonyl de-
rivatives of o-alkynylanilines were converted into the cor-
responding protected indoles through a copper-catalyzed
cyclization in the presence of Cu(OAc)2 and Cu(OTf)2.6 An
example of cyclization of o-alkynylaniline to prepare a free
N-H indole was described, but the target compound was
obtained in good yield only in the presence of the moisture-
sensitive Cu(OTf)2.6
Because of the economic attractiveness of copper-based
methods (and hence of their potential in large-scale reactions)
and stimulated by the growing interest in copper-catalyzed
procedures,7 we became interested in the development of a
copper-catalyzed synthesis of indoles. In particular, we
focused our attention on the preparation of 2-substituted free
N-H indoles from aryl iodides containing an ortho nitrogen
nucleophile and 1-alkynes through an integrated process
involving two basic steps: coupling of o-iodoaniline (or a
suitable derivative) with 1-alkynes followed by a cyclization
step (Scheme 1).
the copper-catalyzed cyclization of o-(phenylethynyl)aniline
3a (R ) Ph, E ) H). Treatment of 1 equiv of 3a [prepared
from 1a (E ) H) and phenylacetylene via Sonogashira
coupling]8 with 5% of CuI, 2 equiv of K3PO4 in dioxane at
110 °C for 24 h gave only trace amounts, if any, of the
desired 2-phenylindole 4a. The addition of a chelating ligand
for copper such as (()-1,2-trans-cyclohexanediamine (CHDA),
which has been reported by Buchwald and co-workers7l to
provide more active catalysts, led to the isolation of 4a in
50% yield (24 h; 3a was recovered in 45% yield).
Surmising that a more acidic N-H bond might favor the
cyclization reaction generating, under basic conditions, a
stronger anionic nitrogen nucleophile (or that the nucleophilic
attack of nitrogen could be assisted by proton removal in
the transition state leading to the cyclization adduct), we
attempted the use of the acetamido derivative 3b (R ) Ph;
E ) COMe). However, despite a higher conversion, es-
sentially the same yield of 4a (52%) was attained. In fact,
its formation was paralleled by the formation of a 20% yield
of the alkylidenebenzoxazine 5 (its stereochemistry was not
established) derived from a competing O-cyclization process
(Scheme 2).
Scheme 1
Scheme 2
Here, we report the results of this study.
Since it is known that aryl iodides and 1-alkynes can
readily give coupling products through copper-catalyzed
reactions,7a,b preliminary studies explored the feasibility of
Only upon going to the trifluoroacetamido derivative 3c
(R ) Ph, E ) COCF3)9 did the reaction afford 4a in high
yield (83%) after 1.5 h. No evidence of the O-cyclization
byproduct was attained in this case.
To check the role of copper in this cyclization reaction,
3c was reacted under the above conditions omitting CuI and
the ligand. The indole product was isolated in 13% yield
after 1.5 h (3c was recovered in 57% yield) and only a
moderate increase in the yield was obtained by prolonging
the reaction time to 24 h (4a was isolated in 30% yield and
3c was recovered in 42% yield), thus emphasizing the
remarkable role of copper in the cyclization step.
(5) Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Vyas, D. M.
Tetrahedron Lett. 1995, 36, 7841.
(6) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T.
Tetrahedron Lett. 2002, 43, 1277.
(7) For recent references on Cu-catalyzed reaction, see the following.
Formation of C-C bonds: (a) Okuro, K.; Furuune, M.; Enna, M.; Miura,
M.; Nomura, M. J. Org. Chem. 1993, 58, 4716. (b) Gujadhur, R. K.; Bates,
C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315. (c) Bates, C. G.; Saejueng,
P.; Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4, 4727. (d) Hennessy,
E.; Buchwald, S. L. Org. Lett. 2002, 4, 269. Formation of C-N bonds: ref
6b. (e) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727. (f) Wolter, M.; Klapars, A.; Buchwald, S. L. Org.
Lett. 2001, 3, 3803. (g) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3,
2077. (h) Lang, F.; Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron
Lett. 2001, 42, 3251. (i) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T.
Tetrahedron Lett. 2001, 42, 4791. (j) Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 3703. (k) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org.
Lett. 2002, 4, 581. (l) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 11684. (m) Evindadr, G.; Batey, R. A. Org. Lett.
2003, 5, 133. (n) Mallesham, B.; Rajesh, B. M.; Reddy, R.; Srinivas, D.;
Trhan, S. Org. Lett. 2003, 5, 963. (o) Frederick, M. O.; Mulder, J. A.;
Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas,
C. J. J. Am. Chem. Soc. 2003, 125, 2368. Formation of C-O bonds: ref
7b; (p) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973, ref 7j. Formation of C-P bonds: (q) Gelman, D.; Jiang, L.;
Buchwald, S. L. Org. Lett. 2003, 5, 2315. Formation of C-S bonds: (r)
Baskin, J. M.; Wang, Z. Org. Lett. 2002, 4, 4423. (s) Bates, C. G.; Gujadhur,
R. K.; Venkataraman, D. Org. Lett. 2002, 4. 2803. Conjugate reduction:
(t) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J. Am.
Che. Soc. 2000, 122, 6797.
Other o-alkynyltrifluoroacetanilides, containing a variety
of aryl and alkyl substituents, were then converted into the
corresponding indole products in good to high yields (Table
1) in the presence of CuI, (()-1,2-trans-cyclohexanediamine,
(8) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-WCH: Weinheim, 1998; p 203. (b)
Sonogashira, K. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York, 2002; Vol. 1,
p 493.
(9) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581.
3844
Org. Lett., Vol. 5, No. 21, 2003

cedure A) was largely employed when the process was
extended to include other 1-alkynes, though the use of readily
available CuI and PPh3 (procedure B) was also explored.
Our preparative results are summarized in Table 2.
Table 1. Copper-Catalyzed Cyclization of
o-Alkynyltrifluoroacetanilides 3 to 2-Substituted Indoles 4a
entry o-alkynyltrifluoroacetanilide 3, R ligand yield (%) of 4b
1
2
3
4
5
6
Ph
Ph
CHDAc
PPh3
CHDAc
CHDAc
CHDAc
CHDAc
83
82d
49
60
88
84
Table 2. Copper-Catalyzed Synthesis of 2-Substituted Indoles
from o-Iodotrifluoroacetanilide 1b and 1-Alkynes 2a
CH2NHCOEt
p-NO2-C6H4
o-Br-C6H4
n-C5H11
a Unless otherwise stated, reactions were carried out on a 0.5 mmol scale
in 2 mL of dioxane by using 1 equiv of o-alkynyltrifluoroacetanilide 3, 5
mol % of CuI, 10 mol % of (()-1,2-trans-cyclohexanediamine, and 2 equiv
of K3PO4 at 110 °C for 1.5 h. b Yields are given for isolated products.
c CHDA) (()-1,2-trans-cyclohexanediamine. d In the presence of 10 mol
% of PPh3.
and K3PO4. The use of PPh3 as the ligand proved equally
effective (Table 1, entry 2).
With an efficient protocol for the copper-catalyzed cy-
clization of o-alkynyltrifluoroacetanilides to free N-H
indoles in hand, we next set out to develop appropriate
conditions to allow for their preparation from o-iodotrifluo-
roacetanilide 1b (E ) COCF3) and 1-alkynes in a single
operative step.
In our first attempt, 1b was reacted with phenylacetylene
in the presence of CuI, (()-1,2-trans-cyclohexanediamine,
and K3PO4 in dioxane at 110 °C for 24 h. However, 2-phenyl
indole was isolated in only 30% yield. The use of PPh3 as
the ligand provided a slightly better result (34% yield).
Therefore, we decided to examine some additional variables.
It was then observed that high yields of 2-phenyl indole could
be obtained by using 15 mol % of CuI in the presence of
30% PPh3 in dioxane (2-phenyl indole was isolated in 88%
yield). Replacement of dioxane by more polar solvents such
as DMSO or DMA was found to be detrimental (43 and 31%
yields, respectively) while a good yield (71%) was obtained
in toluene.
We extended our optimization studies to other copper
catalysts. In particular, we explored the use of some of the
catalysts recently developed by Venkataraman and co-
workers7c and found that high yields could be obtained with
10 mol % of [Cu(phen](PPh3)2]NO3 and K3PO4 in toluene
or dioxane at 110 °C (78 and 75% yields, respectively). The
use of Cs2CO3 as the base produced lower yields (49% in
toluene; 41% in dioxane).
After observing that [Cu(phen)(PPh3)2]NO3 is superior to
the CuI/(()-1,2-trans-cyclohexanediamine catalyst system
in the domino process with o-iodotrifluoroacetanilide 1b, we
went back and examined its utilization in the cyclization of
o-(phenylethynyl)aniline 3a. In case of success, the develop-
ment of a domino process using o-iodoaniline would be
feasible. Notably, it afforded 4a in only 30% yield (3a was
recovered in 45% yield; toluene, 100 °C, 24 hswith CuI/
(()-1,2-trans-cyclohexanediamine 4a was isolated in 50%
yield).
a Reactions were carried out on a 0.5 mmol scale in 2 mL of solvent at
110 °C. b Procedure A: 1 equiv of o-iodotrifluoroacetanilide 1b, 1 equiv
of 1-alkyne 2, 10 mol % of [Cu(phen](PPh3)2]NO3, 2 equiv of K3PO4.
Procedure B: 1 equiv of o-iodotrifluoroacetanilide 1b, 1 equiv of 1-alkyne
2, 15 mol % of CuI, 30 mol % of PPh3, 2 equiv of K3PO4. c Yields are
given for isolated products. d 1b was recovered in 13% yield.
Under these conditions, the reaction proceeds very smoothly
and appears to tolerate a wide range of functionalized
1-alkynes, including those containing ether, amide, aldehyde,
ester, nitro, and heterocyclic groups. Only 1-hexyne, among
the alkynes that we have investigated, produced the desired
indole product in low yield (Table 2, entry 18). As the
cyclization of the corresponding preformed coupling deriva-
tive affords 2-butyl indole in high yield (Table 1, entry 6),
it seems that in this case the efficiency of the domino process
Therefore, 1b was selected as the building block and the
procedure based on the use of [Cu(phen](PPh3)2]NO3 (pro-
Org. Lett., Vol. 5, No. 21, 2003
3845

is primarily limited by a sluggish coupling step. No attempts
have been made to optimize the copper-catalyzed reaction
of 1-hexyne with 1b.
cleophile across the carbon-carbon triple bond activated by
the formation of an η2-alkyne-copper complex.11 The tri-
fluoroacetyl group plays an important role in favoring the
cyclization step but, unlike the acetyl group, does not afford
O-cyclization products (at least with the examples that we
have investigated). It is also readily removed from indole
derivatives under reaction conditions and/or during workup
so that the procedure affords free N-H indoles avoiding
cumbersome deprotecting protocols.
In conclusion, we have established that [Cu(phen](PPh3)2]-
NO3 and CuI/PPh3 serve as efficient catalysts for the
preparation of 2-aryl and 2-heteroaryl indoles from o-
iodotrifluoroacetanilide and 1-alkynes. Our method compares
very favorably to the known palladium- and copper-based
processes for the preparation of this class of compounds.
When o-ethynyltrifluoroacetanilide was reacted with p-
iodoanisole (procedure A) to evaluate the feasibility of a
method in which 2-substituted indoles could be prepared
from the same acetylenic building block and various aryl
and vinyl halides or triflates,10 the cyclization of o-ethynyl-
trifluoroacetanilide to indole (isolated in 87% yield) was
found to be faster than its coupling with p-iodoanisole and
no 2-substituted indole was formed (Scheme 3).
Scheme 3
Acknowledgment. Work carried out in the framework
of the National Project “Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni” supported by the Ministero
dell’Universita` e della Ricerca Scientifica e Tecnologica,
Rome, and by the University “La Sapienza”, Rome.
Supporting Information Available: A complete descrip-
tion of experimental details, table with data for optimizing
conditions for the preparation of 2-phenyl indole from
o-iodotrifluoroacetanilide 1b and phenylacetylene, and prod-
uct characterization. This material is available free of charge
via the Internet at http://pubs.acs.org.
As for the mechanism, the coupling step should proceed
according to the proposal of Miura and co-workers for the
CuI-catalyzed reaction of 1-alkynes with aryl and vinyl
iodides.8 The cyclization reaction most probably involves
the intramolecular nucleophilic attack of the nitrogen nu-
OL035378R
(10) Cacchi, S.; Carnicelli, V.; Marinelli, F. J. Organomet. Chem. 1994,
475, 289.
(11) The formation of an η2-alkyne-Cu(I) complex has been reported:
Macomber, D. W.; Rausch, M. D. J. Am. Chem. Soc. 1983, 105, 5325.
3846
Org. Lett., Vol. 5, No. 21, 2003