Gold(III)-catalyzed double hydroamination of o-alkynylaniline with terminal alkynes leading to N-vinylindoles

Article abstract of DOI:10.1021/ol062918m

A highly efficient double-hydroamination reaction of o-alkynylanilines with terminal alkynes leading to N-alkenylindoles was developed by using gold(III) as a catalyst under neat conditions.

Full text of DOI:10.1021/ol062918m

ORGANIC
LETTERS
2
007
Vol. 9, No. 4
27-630
Gold(III)-Catalyzed Double
Hydroamination of o-Alkynylaniline with
Terminal Alkynes Leading to
N-Vinylindoles
6
Yuhua Zhang, James P. Donahue,†,‡ and Chao-Jun Li*,†,§
†
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118, and
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West,
Montreal QC, Canada H3A 2K6
cj.li@mcgill.ca
Received December 2, 2006
ABSTRACT
A highly efficient double-hydroamination reaction of o-alkynylanilines with terminal alkynes leading to N-alkenylindoles was developed by
using gold(III) as a catalyst under neat conditions.
Indoles are important chemicals that exhibit a wide range
of biological activities. Many naturally occurring compounds
Stille reported the palladium(II)-catalyzed intramolecular
cyclization of 2-alkynylanilines to produce 2-substituted
1
3
d
contain indole as a key structural motif. Because of the wide
application of indoles in pharmaceutical research, the de-
velopment of efficient methods for their synthesis has
continuously attracted the attentions of many chemists.
Among the various synthetic strategies, catalytic transfor-
mations by using transition-metal catalysts is one of the
modern approaches for forming indoles.1,2 In particular, the
use of functionalized o-alkynylaniline derivatives as the
indoles in high yield. Cacchi and co-workers reported a
regioselective synthesis of 3-allylindoles via the palladium-
catalyzed cyclization of o-alkynyltrifluoroacetanilides with
4
allyl esters. Knochel reported the synthesis of polyfunc-
tionalized indoles mediated by 1-4 equiv of cesium and
potassium bases (such as CsO-t-Bu, KO-t-Bu, and KH) in
5
N-methylpyrrolidinone. Hiroya and co-workers developed
an efficient Cu(II)-catalyzed indole formation and applied
3
6
starting materials are some of the most efficient approaches.
the method to natural product syntheses. Arcadi and co-
workers reported a synthesis via a reaction of o-alkynyl-
†
Tulane University.
To whom crystallography inquiries should be addressed.
McGill University.
aniline and R,â-enones to form C-3-alkylindoles catalyzed
‡
7
§
by gold catalyst. Yamamoto and co-workers reported that
(
1) For reviews on indole chemistry, see: (a) Sundberg, R. L. Indoles;
Academic: London, 1996. (b) Katritzky, A. R.; Pozharskii, A. F. Handbook
of Heterocyclic Chemistry; Pergamon: Oxford, 2000; Chapter 4. (c) Joule,
J. A. In Science of Synthesis (Houben-Weyl Methods of Molecular
Transformations); Thomas, E. J., Ed.; Georg Thieme: Stuttgart, 2000; Vol.
0, pp 361-652. (d) Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic
Chemistry; Pergamon: Oxford, 2000; Chapter 3. For other references, see:
e) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045; (f) Gribble,
(3) (a) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62,
6507. (b) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; P e´ rez, M.;
Garc ´ı a-Mart ´ı n, M. A.; Gonz a´ lez, J. M. J. Org. Chem. 1996, 61, 5804. (c)-
Kondo, Y.; Kojima, S.; Sakamoto, T. Heterocycles 1996, 43, 2741. (d)
Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856. (e) Arcadi, A.;
Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581.
(4) Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001.
(5) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.
Tetrahedron 2003, 59, 1571.
1
(
G. W. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, UK, 1996; Vol.
2
, p 207.
2) (a) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113. (b)
Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988, 27, 2225.
(6) (a) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126.
(b) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T.
Tetrahedron Lett. 2002, 43, 1277.
(
1
0.1021/ol062918m CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/18/2007

in the presence of certain nucleophiles, such as allyl
carbonate and alcohol, tandem cyclization of 2-alkynylaniline
proceeded successfully to give the nucleophile incorporated
Table 2. Gold(III)-Catalyzed Double-Hydroamination of
o-Alkynylaniline and Terminal Alkynesa
8
indoles.
On the other hand, N-vinylindole compounds have been
shown to serve as monomers for the synthesis of poly(N-
9
vinylindoles), which can be used as semiconductors and pho-
tosensitives materials. However, so far, only a few methods
1
0
for the synthesis of N-vinylindoles have been described.
These procedures are rather limited in scope and selectivity.
Recently, we reported a domino reaction of unactivated
alkyne and aniline to generate 1,2-dihydroquinolines ef-
11
4
ficiently catalzyed by AgBF . In addition, we also found
that o-alkynylaryl aldehyde reacted with terminal alkynes
to form 1-alkynyl-1H-isochromenes in water catalyzed by
1
2
3
Me PAuCl. Herein, we wish to report an efficient double
hydroamination of o-alkynylaniline with terminal alkynes to
form N-vinylindole compounds catalyzed by gold(III) under
neat conditions.
At the beginning of this study, we found that the double-
hydroamination product can be formed in 40% yield by using
2
Cu(OTf) as a catalyst under microwave conditions at 100
°C for 20 min (Table 1, entry 1). Subsequently, it was found
Table 1. Lewis Acid Catalyzed Hydroamination of
2
-(Phenylethynyl)aniline and Phenylacetylenea
b
entry
cat.
T (°C)
yield (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)
AgOTf
AgBF4
AuCl3
AuCl3/AgOTf
In(OTf)3
Y(OTf)3
Sn(OTf)2
100
60
60
60
60
60
rt
rt
rt
rt
40
53
63
62
59
73
88
no convn
no convn
no convn
1
0
a
Conditions: 1a (0.2 mmol), 1b (0.4 mmol), rt, N2. Reaction time was
1
2
h unless otherwise noted. b Yields were determined by H NMR with 0.2
mmol of nitromethane as an internal standard (no convn ) no conversion).
c
Reaction time was 20 min under microwave conditions.
that the best conditions for copper and silver catalysts are at
6
0 °C (entries 2-5). After further optimizations, the desired
product can be obtained in 88% yield at room temperature
without any solvent in the presence of AuCl /AgOTf (5 mol
3
a
Reaction conditions: 2-alkynylaniline (0.2 mmol), terminal alkyne (0.4
(
7) Alfonsi, M; Arcadi, A.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org.
Chem. 2005, 70, 2265.
8) (a) Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 11940.
b) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122,
mmol), AuCl3 (5 mol %), AgOTf (15 mol %), rt, 3 h, N2. b Isolated yield.
(
(
5662. (c) Kamijo, S.; Sasaki, Y.; Yamamoto, Y. Tetrahedron Lett. 2004,
45, 35. (d) Kamijo, S. Yamamoto, Y. Angew. Chem., Int. Ed. 2002, 41,
3230. (e) Kamijo, S.; Yamamoto, Y. J. Org. Chem. 2003, 68, 4764.
%
/15 mol %) (entry 7). Other catalysts such as In(OTf)
3
,
Y(OTf) , and Sn(OTf) were found to be ineffective in this
3
2
628
Org. Lett., Vol. 9, No. 4, 2007

reaction (entries 8-10). Different solvents were also exam-
ined, and the best results were obtained without using any
solvent.
Subsequently, various o-alkynylanilines were reacted with
terminal alkynes under the standard reaction conditions
(Table 2). With 2-(phenylethynyl)aniline, both electron-rich
and electron-poor arylacetylenes provided excellent yields
of the desired products (entries 1-5). Aliphatic alkyl- and
alkenylalkynes appeared less reactive (entries 6-8). On the
other hand, the reactivities of alkyl- and alkenyl-substituted
acetylenic anilines were similar (entries 9-17) and were
lower than those of phenyl-substituted acetylenic anilines.
The molecular structure of 4c was confirmed by its X-ray
single-crystal diffraction (Figure 1). The presence of a bulky
Figure 3. Gold(III)-catalyzed hydroamination of aniline with
arylacetylene.
To understand the mechanism of the reaction, we exam-
ined two other reactions (Figure 4). The desired product (1c)
Figure 4. Gold(III)-catalyzed hydroamination.
Figure 1. ORTEP diagram of 4c. Important bond distances
include: C(1)-C(2) 1.3694; N(2)-C(1) 1.3975; N(2)-C(4) 1.3887;
N(2)-C(15) 1.4368; C(15)-C(16) 1.3264.
was not observed after 2-phenyl-1H-indole (7a) and phenyl-
acetylene were stirred together at room temperature in the
3
presence of AuCl /AgOTf for 12 h, and 90% of 7a re-
mained unreacted. However, the reaction of 2-(phenylethy-
nyl)aniline with acetophenone gave compound 1c in 11%
NMR yield after being stirred at rt for 3 h. This result
suggests that the first step of this reaction is the intermo-
lecular hydroamination, which is followed by the intramo-
trimethylsilyl group prevented the second hydroamination
reaction completely (Figure 2). When aniline was reacted
1
3
lecular hydroamination.
Therefore, a tentative mechanism for the gold (III)-
catalyzed double hydroamination is proposed in Scheme 1.
Terminal alkyne 1 is activated by Au(OTf) to generate the
3
intermediate A. A further reacts with 2 to yield the first-
hydroamination product 3. Then the carbon-carbon triple
3
bond of 3 is activated by Au(OTf) again and produces the
intermediate B via nucleophilic addition of the imine
nitrogen. Finally, the C-3-position of indole is protonated to
give the final product 4 and the catalyst is regenerated.
Figure 2. Gold(III)-catalyzed hydroamination of 2-[(trimethylsilyl)-
ethynyl]aniline with 1-ethynyl-4-methoxybenzene.
(10) (a) Movassaghi, M.; Ondrus, A. E. J. Org. Chem. 2005, 70, 8638.
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Polyakova, M. N.; Suvorov, N. N. Zh. Org. Khim. 1983, 19, 206.
with arylacetylene, only phenylimine was obtained as the
final product (Figure 3).
(11) (a) Luo, Y.; Li, Z.; Li, C. J. Org. Lett. 2005, 7, 2675. For other
examples of silver-catalyzed hydroaminations, see: (b) Lingaiah, N.; Babu,
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(
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Org. Lett., Vol. 9, No. 4, 2007
629

Acknowledgment. We are grateful to Canada Research
Chair (Tier I) foundation (to C.-J.L.) and the US Environ-
mental Protection Agency for support of our research. Y.Z.
thanks Liang Zhao at McGill for the help with HRMS.
Scheme 1. Tentative Mechanism for the Gold(III)-Catalyzed
Double Hydroamination
Supporting Information Available: Representative ex-
perimental procedure and characterization of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062918M
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In conclusion, a highly efficient double-hydroamination
of o-alkynylanilines with terminal alkynes leading to N-
vinylindoles was developed. This approach is simple, and
double-hydroamination could be accomplished in a one-pot
process, under mild conditions without solvent. The detailed
mechanism and the scope of the reaction, especially the
reason for the intermolecular hydroamination prior to the
direct intramolecular indole formation, are currently under
investigation.
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