Flexible and practical synthesis of 3-oxyindoles through gold-catalyzed intermolecular oxidation of o-ethynylanilines

Article abstract of DOI:10.1039/c4cc03565h

A novel gold-catalyzed intermolecular oxidation of o-ethynylanilines has been developed. A range of functionalized 3-oxyindoles are readily accessed by utilizing this strategy. Importantly, this gold-catalyzed oxidative process outcompetes the typical ind

Full text of DOI:10.1039/c4cc03565h

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Flexible and practical synthesis of 3-oxyindoles
through gold-catalyzed intermolecular oxidation
of o-ethynylanilines†
Cite this: Chem. Commun., 2014,
50, 8689
Received 12th May 2014,
Accepted 6th June 2014
Chao Shu, Long Li, Xin-Yu Xiao, Yong-Fei Yu, Yi-Fan Ping, Jin-Mei Zhou and
Long-Wu Ye*
DOI: 10.1039/c4cc03565h
www.rsc.org/chemcomm
A novel gold-catalyzed intermolecular oxidation of o-ethynylanilines
has been developed. A range of functionalized 3-oxyindoles are readily
accessed by utilizing this strategy. Importantly, this gold-catalyzed
oxidative process outcompetes the typical indole formation.
Functionalized 3-oxyindoles are privileged heterocyclic structural
motifs because of their frequent occurrence in the structures of a
great number of biologically active natural and non-natural pro-
ducts (Fig. 1).1 In addition, they can also serve as valuable building
blocks for the synthesis of complex molecules due to their latent
reactivity and highly selective transformations they can undergo.2
It is surprising, however, that only a few preparative methods have
been reported.3 Consequently, the development of novel methods
for the synthesis of 3-oxyindoles is highly desirable, especially
those with high efficiency, flexibility, and good modularity.
Fig. 1 Selected examples of naturally occurring 3-oxyindoles.
Over the past decade, transition metal-catalyzed intramolecular
cyclization of o-alkynyl anilines has regained considerable attention,
providing concise routes to prepare azaheterocycles, especially the
indole compounds (eqn (1), Scheme 1).4–6 Typically, for internal
alkynes, cycloisomerization is initiated by coordination of transition
metals to alkynes to induce nucleophilic attack.5 However, in the
case of terminal alkynes, such a heterocyclization proceeds most
likely through a metal vinylidene intermediate.6 Substantial pro-
gress has also been made in the last few years in gold-catalyzed
cyclization of o-alkynyl anilines to construct indoles.7 In our recent
study on gold-catalyzed cyclization reactions,8 we have reported an
oxidative cyclization of homopropargyl alcohols and homopropargyl
amides to form the corresponding g-lactones8c and g-lactams,8b
respectively, through gold catalysis. When the reaction scope was
extended to aromatic substrate 1, an indole compound was formed
in high efficiency and no trace of the desired 2-oxyindole product
could be observed.8b Inspired by recent significant advances in
Scheme 1 Formation of 3-oxyindoles through gold-catalyzed inter-
molecular alkyne oxidation.
State Key Laboratory for Physical Chemistry of Solid Surfaces, The Key Laboratory
for Chemical Biology of Fujian Province and Department of Chemistry, College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, Fujian,
P. R. China. E-mail: longwuye@xmu.edu.cn; Fax: +86-592-218-5833
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc03565h
gold-catalyzed intermolecular oxidation of alkynes via an a-carbonyl
carbenoid route9,10 and our recent work on this oxidative cyclization
(eqn (2), Scheme 1),8a we seek to use N-oxides as the oxidants to
investigate the oxidative cyclization,8a,11 hoping to circumvent this
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Table 1 Optimization of reaction conditionsa
formation of 3-oxyindole. While the exact reason for this fine
control of the reactivity remains unclear, we suspect that the bulky
gold complex prefers promoting the exo attack, which is the case
with oxidation; as a result, the endo attack in the indole formation
is comparatively slow because of the apparent steric issue by
putting the bulky gold moiety toward the internal side of the
alkyne. Further studies, including the theoretical calculations, are
needed to elucidate it. Here, it should be mentioned that the
treatment of indole 2a with BrettPhosAuNTf2 (5 mol%), 5b
(2.0 equiv.) and MsOH (1.1 equiv.) in DCE could not afford the
3-oxyindole 3a and only 2a was recovered, indicating that 3a
should be formed directly from the o-ethynylaniline substrate 1a
but not indole 2a. In addition, lowering the amount of N-oxide
gave a slightly improved yield (Table 1, entry 14). However, only
75% conversion was observed in 5 h when the amount of MsOH
was reduced to 0.2 equiv. (Table 1, entry 15). Notably, without a
gold catalyst, the reaction failed to give even a trace of 3-oxyindole
3a under the acidic reaction conditions, and PtCl2 and AgNTf2
could not catalyze this reaction.
With this significantly improved protocol in hand, we then
examined the scope of this gold-catalyzed oxidative cyclization
reaction. Various o-ethynylaniline derivatives 1 were suitable
substrates for this cyclization to furnish the corresponding
3-oxyindoles 3 with mostly good to excellent yields. Except for
substrate 1i, which also afforded indole 2i in 34% yield
(Table 2, entry 8), only 3-oxyindole formation was observed in
all cases. Notably, for the substrates bearing an electron-
withdrawing group, the reaction resulted in the formation of
a complex product mixture under the optimal conditions.
However, we were delighted to find that the reduced amounts
of MsOH could give a much improved yield (Table 2, entries
4–8, 10 and 11). In the case of disubstituted substrates 1m–1n,
without using any acid is preferred (Table 2, entries 12 and 13).
Yieldb (%)
3a 2a
87
Entry
L
Oxidant (R)
Acid
1
2
3
Et3P
Ipr
PPh3
4a (2-Br)
4a (2-Br)
4a (2-Br)
1.1 equiv. MsOH 12
1.1 equiv. MsOH 32c
1.1 equiv. MsOH 11
30
88
90
28
43
10
10
45
6
4
5
6
7
8
9
10
11
12
13
14 f
15 f
P(4-CF3C6H4)3 4a (2-Br)
1.1 equiv. MsOH
9
Cy-JohnPhos
XPhos
4a (2-Br)
4a (2-Br)
4a (2-Br)
1.1 equiv. MsOH 56
1.1 equiv. MsOH 45
1.1 equiv. MsOH 50d
1.1 equiv. MsOH 36e
1.1 equiv. MsOH 32
BrettPhos
BrettPhos
BrettPhos
BrettPhos
BrettPhos
Et3P
4b (3,5-Cl2)
4c (2,6-Br2)
5a (R0 = Me) 1.1 equiv. MsOH 82
i
5b (R0 = Pr) 1.1 equiv. MsOH 89
o1
82
86
o1
i
5b (R0 = Pr) 1.1 equiv. MsOH 16
i
PPh3
5b (R0 = Pr) 1.1 equiv. MsOH 13
i
BrettPhos
BrettPhos
5b (R0 = Pr) 1.1 equiv. MsOH 92g
5b (R0 = Pr) 0.2 equiv. MsOH 70h o1
i
a
Reaction conditions: [1a] = 0.05 M, oxidant (2.0 equiv.); DCE:
1,2-dichloroethane. Estimated by 1H NMR using diethylphthalate as
internal reference. 25% of 1a remained unreacted. 30% of 1a remained
b
c
d
e
f
unreacted. 40% of 1a remained unreacted. 1.3 equiv. of 5b was used.
g
h
Yield of isolated 3a was 91%. 25% of 1a remained unreacted.
typical indole formation (eqn (3), Scheme 1). Herein, we wish to In addition, o-ethynylanilines containing
a Bs (4-bromo-
report the realization of such a gold-catalyzed oxidative protocol and benzenesulfonyl), a Ns (2-nitrobenzenesulfonyl) or a Ms group
the development of a very practical solution to 3-oxyindole synthesis, also reacted to give the corresponding 3o–3q in excellent yields
which outcompetes the occurrence of indoles.
(Table 2, entries 14–16). To test the practicality of the current
We used o-ethynylaniline 1a as the model substrate for our catalytic system, the reaction was carried out in a 10 mmol scale
initial study and some of the results are summarized in Table 1. in the presence of 2.5 mol% gold catalyst and the desired
The influence of different gold catalysts was first examined 3-oxyindole 3a was afforded in 87% yield, highlighting the
(Table 1, entries 1–7). Using 2-bromopyridine N-oxide as the value of this new catalysis (Table 2, entry 17).
oxidant and Et3PAuNTf2 as the gold catalyst, we were pleased to
We then considered the possibility of extending the reaction to
observe the desired 3-oxyindole 3a formation albeit in a low yield internal alkynes. However, only indole formation could be observed
(12%) other than indole 2a (87%) (Table 1, entry 1). Further studies under the above optimized reaction conditions (eqn (4)), and further
revealed that 3-oxyindole 3a formation could become dominant studies in this direction are currently ongoing.
when using the bulkier gold catalysts and BrettPhosAuNTf2
gave the best results (Table 1, entry 7). To our delight, it was found
that the reaction yield could be substantially improved by varying
the oxidants from the pyridine N-oxides to quinoline N-oxides.
Strikingly, the use of 8-isopropylquinoline N-oxide 5b as the
oxidant completely suppressed the formation of indole 2a and
the desired 3-oxyindole 3a could be furnished in 89% yield
(Table 1, entry 11). However, the combination of 5b with the
(4)
Et3PAuNTf2 or Ph3PAuNTf2 still led to the formation of indole as
These 3-oxyindoles are potentially useful in organic synth-
the main product (Table 1, entries 12 and 13). This suggests that esis and will constitute valuable precursors especially for the
the use of the bulky BrettPhosAuNTf2 is more crucial for the construction of the corresponding azaaurones, which exist in a
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Table 2 Reaction scope for the formation of indolin-3-onesa
3p with benzaldehyde under acidic conditions, followed by
deprotection with PhSH, provided the final azaaurone 6.
In summary, we have developed a flexible and general
solution for the synthesis of various 3-oxyindoles through a
gold-catalyzed intermolecular alkyne oxidation. Most impor-
tantly, this gold-catalyzed oxidative process outcompetes the
typical indole formation. The use of readily available substrates,
a simple procedure, and mild reaction conditions and, in
particular, no need to exclude moisture or air (‘‘open flask’’)
render these methods potentially useful in organic synthesis.
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21102119 and
21272191), and the Program for Changjiang Scholars and
Innovative Research Team in University (PCSIRT) and NFFTBS
(No. J1310024).
Entry Product
1
3
Yield (%) Entry Product
3
Yield (%)
3b 87
3c 84
3d 85
10b
11b
12d
3k 90
3l 79
3m 74
2
3
Notes and references
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