Gold-catalyzed annulations of allenes with N-hydroxyanilines to form indole derivatives with benzaldehyde as a promoter

Article abstract of DOI:10.1039/c3ob42131g

Gold-catalyzed syntheses of 2,3-disubstituted indole derivatives from N-hydroxyanilines and allenes are described; these reactions require benzaldehyde as an additive to generate nitrones in situ. Our control experiments indicate that nitrones and water were indispensable in the reactions whereas N-hydroxyanilines alone were inactive nucleophiles. This synthetic method is compatible with allenes and N-hydroxyanilines with a reasonable range, further highlighting its synthetic utility.

Full text of DOI:10.1039/c3ob42131g

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Gold-catalyzed annulations of allenes with
N-hydroxyanilines to form indole derivatives with
benzaldehyde as a promoter†
Cite this: Org. Biomol. Chem., 2014,
12, 737
Received 25th October 2013,
Accepted 9th December 2013
Rahul Kisan Kawade, Po-Han Huang, Somnath Narayan Karad and Rai-Shung Liu*
DOI: 10.1039/c3ob42131g
www.rsc.org/obc
Gold-catalyzed syntheses of 2,3-disubstituted indole derivatives
from N-hydroxyanilines and allenes are described; these reactions
require benzaldehyde as an additive to generate nitrones in situ.
Our control experiments indicate that nitrones and water were
indispensable in the reactions whereas N-hydroxyanilines alone
were inactive nucleophiles. This synthetic method is compatible
with allenes and N-hydroxyanilines with
a reasonable range,
further highlighting its synthetic utility.
Indole derivatives are important and valuable intermediates
for the synthesis of numerous bioactive molecules and natu-
rally occurring alkaloids.1 Besides Fisher-indole syntheses,2,3
there is considerable interest in the development of new
indole syntheses through metal-catalyzed reactions under mild
conditions.1,4,5 Gold-catalyzed electrophilic activations of
alkynes are powerful tools to access various indole skeletons.5
Zhang and coworkers reported5a,b gold-catalyzed annulations
between terminal alkynes with N-hydroxyaniline species under
room temperature (Scheme 1, eqn (1)), giving good yields of
indole products via a key 3,3-sigmatropic shift of O-alkenyl-
N-aryl-hydroxyaniline intermediates II. We are aware of no
examples of the use of allene substrates to prepare indole
derivatives in gold-catalyzed reactions. We envisage that indole
formation would be feasible if allenes replace alkynes in the
reactions with N-hydroxyanilines, according to the protocol in
eqn (2). Nucleophilic attack of an oxygen-based nucleophile at
gold-π-allenes is reported to be feasible with gold catalysts.6
We report herein a new synthesis of indole derivatives accord-
ing to this protocol (eqn (2)), but with benzaldehyde as a pro-
moter. In other words, N-hydroxyanilines react with
benzaldehyde to form nitrones initially, which are active
nucleophiles to attack gold-π-allene species effectively. This
report is in sharp contrast with metal-catalyzed or thermal
reactions between nitrones and allenes, which typically afford
Scheme 1 Indole syntheses from alkynes and allenes.
stable [3 + 2]-cycloadducts.7 Allene substrates employed in this
work bear no activating groups, thus eluding this cyclo-
addition path.
Table 1 shows the realization of a new indole synthesis
using an allene substrate 1a. In our initial test, the reaction of
this allene with N-hydroxyaniline 3a (1.1 equiv.) with P(t-Bu)2-
(o-biphenyl)AuCl/AgNTf2 (10 mol%) in hot dichloroethane
(DCE, 60 °C, 12 h) gave complicated mixtures of products
(entry 1). With benzaldehyde as an additive, its increasing
amount (0.1, 1.0 and 1.5 equiv.) gave the desired indole 2a
with enhanced yields, from 12% to 60% as depicted in entries
2–4. An optimized yield of 78% was obtained for indole 2a
with an equal loading (2.0 equiv.) of N-hydroxyaniline and
benzaldehyde (entry 5). A variation of the counter anion as in
P(t-Bu)2(o-biphenyl)AuCl/AgSbF6 gave the desired 2a in 72%
yield (entry 6). Less acidic IPrAuCl/AgNTf2 (IPr = 1,3-bis(di-
isopropylphenyl)-imidazol-2-ylidene) was rather inactive to give
2a in only 22% yield, with unreacted 1a in a 62% recovery
(entry 7). In contrast, PPh3AuCl/AgNTf2 gave indole product 2a
in 64% yield, but with unreacted 1a in minor proportion (18%)
(entry 8). In the absence of a metal catalyst, we observed no
reaction between these reactants in hot DCE (60 °C, 12 h). The
effects of solvents and catalyst loadings are provided in ESI.†
Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan,
Republic of China. E-mail: rsliu@mx.nthu.edu.tw
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ob42131g
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Table 1 Catalyst screening over various gold catalysts
Compoundsb (%)
Entry
Catalyst
n
m
t (hour)
1a
2a
c
1
2
3
4
5
6
7
8
9
LAuCl/AgNTf2
LAuCl/AgNTf2
LAuCl/AgNTf2
LAuCl/AgNTf2
LAuCl/AgNTf2
LAuCl/AgSbF6
IPrAuCl/AgNTf2
PPh3AuCl/AgNTf2
—
1.1
1.1
1.1
1.1
2.0
2.0
2.0
2.0
2.0
0
12
6
6
6
6
—
16
—
—
—
—
62
18
58
—
12
48
60
78
72
22
64
—
0.1
1.1
1.5
2.0
2.0
2.0
2.0
2.0
8
10
10
12
L = P(t-Bu)2(o-biphenyl), IPr = 1,3-bis(2,6-diisopropylphenyl-imidazol-2-ylidene). a [1a] = 0.156 M. b Product yields are reported after separation
from a silica column. c Complex mixtures of products.
We postulate that N-hydroxyaniline 3a likely reacts with
benzaldehyde to form nitrone 4a, which is an active nucleo-
phile. Accordingly, we performed control experiments to test
the reaction of allene 1a with nitrone 4a (2.0 equiv.) using the
same gold catalyst (10 mol%); the result is depicted in eqn (3).
In dry and hot dichloroethane (60 °C, 6 h), the yield of the
desired indole 2a was somewhat low, ca. 35% yield; the reason
might be due to the lack of one extra water as compared to the
N-hydroxyanilines/benzaldehyde system. With added water
(2.0 equiv.), the yield of indole compound 2a was increased
to 71%. Water appears to be indispensable in this indole
synthesis, and its role is rationalized in a discussion of its
mechanism (vide infra).
Table 2 The reactions of various allene substrates
ð3Þ
We prepared additional allenes 1b–1m to generalize the
reaction scope. In a standard procedure, N-hydroxyaniline 3a
(2.0 equiv.) was first stirred with benzaldehyde (2.0 equiv.) in
dry DCE at 28 °C for 2 h to generate nitrone 4a and water to
reach an equilibrium condition. To this mixture was added
allene 1a and a gold catalyst (10 mol%), and the resulting solu-
tion was heated to 60 °C for 1–6 h. In all cases, indole products
2b–2m were produced exclusively with no tractable amount of
[3 + 2]-cycloadducts (Table 2). As shown in entries 1–5, these
gold-catalyzed reactions were effective in producing indole
derivatives 2b–2f bearing various arylethyl substituents (aryl =
4-XC6H4, X = H, Me, OMe, F and Cl); their corresponding
yields were 72–85% yields. For their 2- and 3-thienyl analogues
2g and 2h, their resulting yields were 79–80% (entries 6–7).
L = P(t-Bu)2(o-biphenyl). a [1b–m] = 0.231 M. b Product yields are
reported after separation from a silica column.
Entries 8–12 show the compatibility of these annulations with
allenes 1i–1m bearing benzyl ether, dioxalane, nitro, ester and
siloxy moieties, to afford the desired products 2i–2m in satis-
factory yields (61–85%).
We also examined the reactions of N-hydroxylanilines 3a–3e
with allene 1b to assess the reaction scope. For electron-rich
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Table 3 The reactions with various N-hydroxyanilines
Conclusions
Before this work, gold-catalyzed syntheses of indole derivatives
relied heavily on the electrophilic activations of alkynes.5 We
sought to achieve indole synthesis with allene substrates.9
With benzaldehyde as an additive,
a
gold complex
implemented catalytic annulations of N-hydroxyanilines with
allenes to form indole products in satisfactory yields. This
indole synthesis was compatible with allene substrates and
N-hydroxyanilines over a reasonable range. Our control experi-
ments indicate that N-hydroxyanilines reacted with benz-
aldehyde to form nitrones that were active nucleophiles. Water
was indispensable because a hydrolysis step was involved for
key iminium intermediates. In contrast, an N-hydroxyaniline
proved to be inactive as a nucleophilic reagent.
L = P(t-Bu)2(o-biphenyl). a [1b] = 0.231 M. b Product yields are reported
after separation from a silica column.
Acknowledgements
The authors wish to thank the National Science Council,
Taiwan, and the Ministry of Education for supporting this
work.
Notes and references
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Scheme 2 A plausible reaction mechanism.
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N-hydroxylanilines species 3a–3b, their gold-catalyzed annula-
tions with allene 1b gave the desired indole products 5a–5b in
70–71% yields (entries 1–2). The reactions were extended to
the production of indole products 5c–5e bearing 4-fluoro,
4-bromo and 4-ethoxycarbonyl groups; their resulting yields
were satisfactory (63–74%, entries 3–5) (Table 3).
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important roles in this indole synthesis whereas N-hydroxy-
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N–O bond cleavage of [3 + 2]-cycloadducts from nitrones
and allenes, but such reactions were only operable with
those allenes bearing an ester group; see ref. 7f. Different
products would form from those cycloadducts bearing no
functional groups. This pathway is inapplicable to our
system because we obtained no tractable amount of [3 + 2]-
cycloadduct that should be stable in the presence of gold
catalysts (see ref. 7c).
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bearing no activation group, but its reaction with N-hydro-
xyaniline and benzaldehyde failed to give indole product; we
recovered starting 1n in 76% yield.
7 For such [3
+ 2]-cycloadditions, allene substrates are
required to bear either an electron-withdrawing or -donating
group; see selected examples: (a) W. R. Dolbier, Jr.,
G. E. Wicks and C. R. Burholder, J. Org. Chem., 1987, 52,
740 | Org. Biomol. Chem., 2014, 12, 737–740
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