AuCl3-catalyzed tandem reaction of N-(o-alkynylphenyl)imines: A modular entry to polycyclic frameworks containing an indole unit

Article abstract of DOI:10.1055/s-0028-1087938

A highly efficient tandem cyclization reaction of N-(o-alkynylphenyl) imines leading to ring-fused indoles was developed by using gold(III) as a catalyst under extremely mild reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087938

LETTER
763
AuCl3-Catalyzed Tandem Reaction of N-(o-Alkynylphenyl)imines:
A Modular Entry to Polycyclic Frameworks Containing an Indole Unit
A
uC
l
-CatalyzedTande
e
m
Reaction
i
of
N
-(
o
j
-Alky
u
n
ines Fu,a Chen Xu,a Guanglong Zou,b Dongfeng Hong,a Dongsheng Deng,a Zhiqiang Wang,a Baoming Ji*a
3
a
College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022, P. R. of China
Fax +86(379)655821; E-mail: lyhxxjbm@lynu.edu.cn
b
School of Chemistry and Environmental Science, Guizhou University for Nationalities, Guiyang 550025, P. R. of China
Received 3 October 2008
iminium ion, which is trapped by a tethered nucleophile to
afford ring-fused indoles in a novel tandem reaction pro-
cess (Scheme 1). Herein, we present a convenient and ef-
ficient method for the synthesis of ring-fused indoles
starting from compounds of type 1 catalyzed by gold(III)
under mild conditions.
Abstract: A highly efficient tandem cyclization reaction of N-(o-
alkynylphenyl)imines leading to ring-fused indoles was developed
by using gold(III) as a catalyst under extremely mild reaction con-
ditions.
Key words: cyclization, gold, indoles, N-(o-alkynylphenyl)imines
R3
n
Indoles are important chemicals that exhibit a wide range
of biological activities. They are found as key structural
elements in many naturally occurring compounds.1 As a
consequence, much attention has been paid to the synthe-
sis of indole derivatives. In addition to classical methods
(e.g., the Fischer synthesis,2 the Reissert synthesis,3 the
Madelung synthesis4), numerous transition-metal-cata-
lyzed heteroannulation reactions have been developed
with remarkable improvements in terms of efficiency and
wide scope of application.5 A particularly attractive meth-
odology is based on transition-metal-catalyzed cycliza-
tion of o-alkynylaniline derivatives.6 Hiroya developed an
efficient Cu(II)-catalyzed indoles formation by cycliza-
tion of 2-ethynyl aniline derivatives.7 Yamamoto and co-
workers reported that tandem cyclization of 2-alkynyla-
niline proceeded successfully to give the nucleophile in-
corporated indoles in the presence of certain nucleophiles,
such as allyl carbonate and alcohol.8 Nevertheless, the de-
velopment of synthetic routes that allow the facile assem-
bly of indole derivatives under mild conditions still
remains an important objective.
OH
R3
On
N
N
R1
R2
R1
R2
Scheme 1
We initially examined the reaction of 3-[2-(diphenyl-me-
thyleneamino)phenyl]prop-2-yn-1-ol (1a) using different
metal catalysts in CH2Cl2 at room temperature (Table 1).
To our delight, the ring-fused indole 2a was formed in all
cases as the only major product. Lewis acids such as
Cu(OTf)2, AgO2CCF3, Hg(O2CCF3)2, and AgBF4 were
active, but only modest yields were obtained after long re-
action time. In contrast, employment of Pd(OAc)2,
PdCl2(PPh3)2, Cu(OAc)2, and CuI catalysts under these
conditions resulted in low yields, and the reactions were
generally much more sluggish. Significantly, we found
that AuCl3 was a particularly efficient catalyst for this
reaction. With only 3 mol% of this catalyst, the ring-fused
indole formation was complete after less than 30 minutes
at room temperature to afford 2a in 90% yield (Table 1,
entry 4). It was found that decreasing the catalyst load to
1 mol% of AuCl3 had virtually no effect on the reaction
course, producing 2a in 84% yield (Table 1, entry 5),
though the reaction was slower. The molecular structure
of 2a was confirmed by single-crystal X-ray diffraction
analysis (Figure 1).13
Previous investigations have shown that Au(III) salts and
Au(I) complexes display considerable catalytic activity
under moderate conditions.9 The activation of alkynes or
allenes with carbophilic, Lewis acidic gold salts is the
most widespread application of homogeneous gold catal-
ysis, and it is also utilized for the construction of carbocy-
clic or heterocyclic compounds.10 Recently, the design of
gold-catalyzed tandem nucleophilic additions that pre-
serve atom economy in a one-pot reaction has attracted at-
tention because of the application to efficient construction
of molecular structures.11 As a continuation of our interest
in the design and discovery of new reactions for the syn-
thesis of heterocycles,12 we envisioned that N-(o-alky-
nylphenyl)imines 1 might cyclize via the formation of an
Next we investigated the annulation reaction of various N-
(o-propynolphenyl)imines 1. The results summarized in
Table 2 proved that this sequential reaction indeed provid-
ed a straightforward entry to a variety of fused tricyclic
compounds with an indole unit in good to high yields. The
substituent on the aromatic ring of R1 and R2 did not affect
the efficiency of the reaction. For imines 1 having an elec-
tron-withdrawing or an electron-donating group on the
benzene ring, these reactions proceeded smoothly to give
the corresponding cyclization products. Employing N-(o-
propynolphenyl)phenylimine as a substrate, the annula-
SYNLETT 2009, No. 5, pp 0763–0766
x
x.
x
x.
2
0
0
9
Advanced online publication: 24.02.2009
DOI: 10.1055/s-0028-1087938; Art ID: W15608ST
© Georg Thieme Verlag Stuttgart · New York

764
W. Fu et al.
LETTER
Table 2 Gold(III)-Catalyzed Tandem Cyclization of 1a
n
R3
OH
R3
AuCl3
O n
R2
N
N
CH2Cl2, r.t.
R1
R1
R2
1
2
Entry
1
R1
Ph
R2
R3
H
n
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
Yields (%)b
2a, 90
2b, 88
2c, 91
complexc
2d, 79
2e, 83
2f, 94
Ph
2
4-FC6H4
Ph
4-FC6H4
4-ClC6H4
H
H
3
H
Figure 1
4
Ph
H
Table 1 Effect of Catalyst on the Reaction of 1a To Give 2aa
5
Ph
3-MeOC6H4
4-MeOC6H4
Ph
H
OH
6
Ph
H
catalyst
N
CH2Cl2, r.t.
7
Ph
Me
Me
Me
Me
H
N
O
8
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
Ph
2g, 80
2h, 89
2i, 90
Ph
Ph
Ph
Ph
9
Ph
Entry
Catalyst
Amount Time (h)
Yields (%)b
(mol%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-FC6H4
1
2
–
–
24
3
0
Ph
2j, 92
Cu(OTf)2
AgO2CCF3
AuCl3
3
76
4-FC6H4
4-FC6H4
4-ClC6H4
3-MeOC6H4
H
H
2k, 89
2l, 87
3
3
3
81
Ph
H
4
3
0.5
2
90
Ph
H
2m, 84
2n, 58
2o, 93
2p, 78
2q, 91
2r, 90
2s, 88
5
AuCl3
1
84
Ph
H
6
Pd(OAc)2
PdCl2(PPh3)2
Hg(O2CCF3)2
AgBF4
5
24
24
10
3
45 (43)c
48 (38)c
57
Ph
Ph
Me
Me
Me
Me
H
7
5
4-MeOC6H4
Ph
4-MeOC6H4
4-ClC6H4
4-FC6H4
Ph
8
10
3
9
82
4-FC6H4
Ph
10
11
CuI
10
10
24
24
37 (50)c
21 (71)c
Cu(OAc)2
4-FC6H4
Ph
4-FC6H4
4-ClC6H4
Ph
H
2t, 92
a All of the reactions were carried out on a 0.5 mmol scale.
b Isolated yields.
H
2u, 87
2v, 90
2w, 91
2x, 88
2y, 89
c Starting material was recovered in parentheses.
Ph
Me
Me
Me
Me
4-MeOC6H4
Ph
4-MeOC6H4
4-ClC6H4
4-FC6H4
tion failed, and a complex mixture of unidentified prod-
ucts was obtained under the reaction conditions (Table 2,
entry 4). This transformation can be successfully extended
to a variety of N-(o-hydroxyalkynylphenyl)imines 1 lead-
ing to the generation of the corresponding ring-fused in-
doles in 58–93% yield (Table 2, entries 11–26).14 Their
4-FC6H4
a Unless noted, all of the reaction was carried out using 1 (0.5 mmol)
and AuCl3 (3 mol%) at r.t. for 30 min.
b Isolated yields.
1
structures were assigned on the basis of H NMR, 13C
c Decomposition of starting material was observed.
NMR, IR spectra, and MS data.
3, which enhances the electrophilicity of the alkyne. The
subsequent domino nucleophilic attack/anti-endo-dig cy-
clization affords organogold intermediate 6. Protonolysis
of the resulting organogold intermediate 6 gives product 2
On the basis of the above observations, a plausible mech-
anisms is proposed for this novel Au(III)-catalyzed trans-
formation (Scheme 2). A cationic Au(III) species first
coordinates to the triple bond to generate an intermediate
Synlett 2009, No. 5, 763–766 © Thieme Stuttgart · New York

LETTER
AuCl3-Catalyzed Tandem Reaction of N-(o-Alkynylphenyl)imines
765
AuCl3
R3
OH
N
n
R1
R2
OH
coordination
R3
3
N
–AuCl3
[Au]
N
R1
R2
R3
R3
1
n
or
n
OH
N
OH
AuCl3
R1
R2
R1
R2
R3
4
5
protonolysis
H+
AuCl2
n
N
R3
O
HCl
R1
R2
n
N
2
O
R1
R2
6
Scheme 2
G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
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and regenerates the gold catalyst. Alternatively, the reac-
tion may involve the intermediate iminium ion 5,15 which
is formed by the intramolecular addition of the nitrogen
atom of the imine to the gold-coordinated alkynes. The
iminium ion 5 undergoes the subsequent reaction with a
tethered nucleophile followed by protonation to regener-
ate the Au(III) catalyst and afford the final product 2.
E. F. V., Eds.; Pergamon Press: Oxford, 1996.
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In conclusion, we have developed a gold-catalyzed domi-
no reaction of N-(o-alkynylphenyl)imines that provides
an efficient route to ring-fused indoles under mild condi-
tions. The substrates can be readily prepared from the cor-
responding o-iodoanilines, ketones, and alkynes. Further
studies to elucidate the precise mechanism of this reaction
and to extend the scope of synthetic utility are in progress
in our laboratory.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful to the National Natural Science Foundation of
China (No. 20872057) and the Natural Science Foundation of Hen-
an Province, China (No. 082300420040) for financial support of
this work.
References and Notes
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766
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LETTER
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a = 10.5127 (12) Å, b = 11.3097 (13) Å, c = 14.1538 (16)
Å, a = 85.2950 (10)°, b = 81.3660 (10)°, g = 78.5540 (10)°,
V = 1628.3 (3) Å3; Dcalc = 1.270 g/cm3; F000 = 656;
residuals: R; Rw: 0.0578, 0.1065.
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(14) General Procedure
To a solution of N-(o-alkynylphenyl) imines 1 (0.5 mmol) in
dry CH2Cl2 (5 mL) was added a solution of AuCl3 (3 mol%)
in MeCN (0.05 M). The mixture was stirred for 30 min at r.t.
After evaporation of the solvent, the residue was purified by
column chromatography on SiO2 (PE–EtOAc, 25:1) to
afford 2.
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