Gold-catalyzed intermolecular reactions of (Z)-enynols with indoles for the construction of dihydroeyelohepta [b]indole skeletons through a cascade friedel-crafts/hydroarylation sequence

Article abstract of DOI:10.1002/adsc.200900068

An efficient domino approach for the synthesis of indole-fused carbocycles and their analogues from the reactions of suitably substituted (Z)-enynols with indoles or pyrroles under mild reaction conditions was developed. This methodology is realized by a

Full text of DOI:10.1002/adsc.200900068

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DOI: 10.1002/adsc.200900068
Gold-Catalyzed Intermolecular Reactions of (Z)-Enynols with
Indoles for the Construction of Dihydrocyclohepta[b]indole
Skeletons through a Cascade Friedel–Crafts/Hydroarylation
Sequence
Yuhua Lu,a,b Xiangwei Du,a Xueshun Jia,b and Yuanhong Liua,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: yhliu@mail.sioc.ac.cn
Department of Chemistry, Shanghai University, Shangda Rd. 99, Shanghai 200444, Peopleꢀs Republic of China
b
Received: February 2, 2009; Published online: June 16, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900068.
Abstract: An efficient domino approach for the
synthesis of indole-fused carbocycles and their ana-
logues from the reactions of suitably substituted
(Z)-enynols with indoles or pyrroles under mild re-
action conditions was developed. This methodology
is realized by a tandem reaction using Au/Ag cata-
lysts, which could catalyze both of the Friedel–
Crafts and the hydroarylation reaction in the same
vessel.
philes, leading to a diverse range of functionalized
carbo- or heterocycles. However, there are only limit-
ed reports for the intermolecular cyclization or cyclo-
AHCTUNGTRENNUNG
isomerization of alkynes.[2] Recently, we have report-
ed[3] a general synthetic approach to furans and ster-
eodefined dihydrofurans via the gold-catalyzed cycli-
zation of (Z)-2-en-4-yn-1-ols.[3a] We have also devel-
oped a straightforward synthesis of allylic amines
from allylic alcohols through direct amination by uti-
lization of gold as catalysts.[3b] The reactions were sug-
gested to be initiated through the facile formation of
an allylic cation intermediate.[4] On the other hand,
gold complexes are also particularly active catalysts
for the hydroarylation of alkynes[5] and allenes[6]. For
example, the Echavarren group has reported that in-
doles react intramolecularly with alkynes to generate
Keywords: enynols; Friedel–Crafts reaction; gold
catalysis; hydroarylation; indoles
In recent years, goldACTHNUGRTNEUNG(III) salts and gold(I) complexes six- to eight membered-ring annulated com-
have been shown to display considerable catalytic ac- pounds.[5b–c,7] Encouraged by these results, we envi-
tivity under moderate conditions, rendering them at- sioned that a tandem process might be achieved
tractive reagents in organic synthesis.[1] Especially, which could couple the Friedel–Crafts reaction via an
gold catalysts have been proved to be powerful allylic cation intermediate with a subsequent hydroar-
alkynophilic Lewis acids to activate the p-systems ylation directly through the reactions of (Z)-enynols
toward nucleophilic attack. The majority of studies with indoles mediated by
a single-pot catalyst
have then concentrated on the intramolecular cycliza- (Scheme 1). This process would also enable the new
À
tion of alkynes bearing proximate C, O, N nucleo- C C bond formations to occur at both the C-2 and C-
Scheme 1.
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3 positions of indoles in one operation, and there is temperature in THF for 5 h using 5% (PPh3)AuCl
no need to isolate the intermediate arylated enynes. and 5% AgSbF6 as catalysts (entry 2). Reactions in
The resulting products are of considerable interest CH2Cl2 only led to low conversions (entry 3). Chang-
as they are present as key structural subunits in ing the counteranion by activating (PPh3)AuCl with
indole alkaloids such as ambiguine,[8] silicine[9] and AgOTf afforded a lower yield of the desired product
caulersin[10] (Scheme 2).
(entry 4). However, the use of cationic gold(I) com-
plex PPh3AuNTf2 cleanly converted 1a to 2a at room
temperature (entry 5). AgSbF6 alone did not promote
any transformation (entry 6). Interestingly, only the
seven-membered ring derivative 2 was formed by a 7-
endo-dig pathway during the cyclization, while the re-
gioisomer derived from a 6-exo-dig reaction was not
observed. It is noteworthy that this gold(I)-catalyzed
À
domino reaction entails one C O bond cleavage and
À
two C C bond formations in a single operation.
With this result in hand, we next examined the sub-
strate scope with a range of trisubstituted (Z)-enynols
(Table 2). We first examined the electronic effects of
the substituents on the aromatic ring of R1 at the C-1
position. It was found that an electron-withdrawing
(Cl) substituent on the aryl group afforded the corre-
sponding product 2b in 92% yield (Table 2, entry 2).
However, an electron-donating (OMe) substituent on
the aryl group only resulted in a moderate yield
(51%) of the product (entry 3). This might be due to
Scheme 2.
To probe the feasibility of the proposed transforma- the decreased electrophilicity of the allylic cation in-
tions, we initially investigated the reactions of the termediate in the latter case. A thienyl group at C-1
readily available (Z)-1,3,5-triphenylpent-2-en-4-yn-1- was compatible under the reaction conditions with a
ol 1a with indole (Table 1). On the basis of our previ- higher catalysts loading of 10%, furnishing 2d in 49%
ous observations, we first examined the reactions in yield (entry 4). The structure of 2d was confirmed by
the presence of AuCl3, however, product formation X-ray crystallography.[11] However, when the alkyl
was not observed (Table 1, entry 1). After many ef- group was introduced at the C-1 position, the corre-
forts, we were pleased to find that the reaction pro- sponding 2e was formed only in 27% yield, moreover,
ceed smoothly, and the desired dihydrocyclohep- a furan derivative was isolated as a major product.
ACHTUNGTRENNUNGta[b]indole 2a was obtained in 85% yield at room The results indicated that the reaction rate of the
Table 1. Optimization studies for the formation of dihydrocyclohepta[b]indole.
[a]
Isolated yields.
Trace amounts of by-products were formed.
NR=no reaction.
[b]
[c]
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Gold-Catalyzed Intermolecular Reactions of (Z)-Enynols with Indoles
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Table 2. One-pot synthesis of indole-fused carbocycles through the reactions of (Z)-
enynols with indole.
[a]
Isolated yields.
10% (PPh3)AuCl/10% AgSbF6 was used.
1 equiv. BF3·Et2O, 50 8C, 6 h, then 5% (PPh3)AuCl/5% AgSbF6, room temperature,
[b]
[c]
7 h.
[d]
The TBS group was removed during the reaction.
Friedel–Crafts arylation in this case is much slower tected alcohol 1j gave rise to a desilylated product 2j
than that of cycloisomerization through an oxygen nu- in 54% yield, indicating that the TBS group was
cleophile. Remarkably, it was found that BF3·Et2O easily removed during the reaction (entry 10).
could effectively promote[3c] the first step of arylation
The cycliztions have also been successfully extend-
reaction. Thus, by first stirring the reaction mixture in ed to various substituted indoles with X, OMe, or
the presence of 1 equivalent of BF3·Et2O for 6 h at NO2 functionalities, and moderate to good yields
508C, and then adding the Au/Ag catalysts at room were realized for all cases (Table 3).
temperature, the desired indole derivative 2e could be
Interestingly, when terminal alkyne 1l was used, 1-
obtained in 66% yield (entry 5). The above results in- methyl-2,4-diphenyl-9H-carbazole 3 was obtained in
dicated that the nature of the substituent on C-1 76% yield [Scheme 3, Eq. (1)]. The results indicated
played an important role in this reaction. The sub- that a 6-exo-dig cyclization followed by double bond
stituent effects on C-3 and C-5 were also examined. A isomerization took place in the step of hydroarylation.
broad variety of (Z)-enynols bearing alkyl or aryl The cyclization of enynol 1a with pyrrole was also ex-
groups on C-3 and/or alkyne terminus C-5 were plored. In this case, however, a 1,8-dihydrocyclohep-
smoothly converted into the indole derivatives to ta[b]pyrrole 4 was formed in 68% yield, in which a
yield 2f–2k in 52–87% yields (entries 6–11). It is inter- sp3 carbon center is located on the C-2 position of
esting to note that the reaction has also been accom- pyrrole [Scheme 3, Eq. (2)]. The structure of 4 has
plished starting from 1i having a methoxy functionali- been verified by X-ray crystallography.[11]
ty, leading to 2i in 66% yield (entry 9). A TBS-pro-
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Table 3. Formation of various dihydrocyclohepta[b]indoles.
process. The results strongly supported our assump-
tion that 2 was formed through Au(I)-catalyzed hy-
droarylation of enyne 5 in the one-pot procedure.
We propose the following reaction mechanism for
this tandem sequence (Scheme 5). The reaction is ini-
+
À
tiated by Au -assisted C O bond cleavage of enynol
1, resulting in the formation of an allylic cation inter-
mediate 7, 7 undergoes the Friedel–Crafts reaction
with indole through the electrophilic attack of the
indole 3-position to afford the indolyl enyne 5 and re-
generate the Au+ catalyst. At this point, the inter-
mediate 5 enters into the hydroarylation sequence.
Then at first, coordination of the gold complex to the
triple bond of 5 to form intermediate 8 occurs, which
is followed by the intramolecular nucleophilic attack
of the indole ring at the triple bond, presumably via a
spirocyclic intermediate 9,[4d,5b,c] to give a seven-mem-
bered carbocation 10 via a 1,2-migration process.[12]
Alternatively, intermediate 10 might be formed di-
rectly from 8. Elimination of a proton followed by
protodemetalation of the resulting organogold inter-
mediate affords the product 2 with regeneration of
[a]
Isolated yields.
Reaction was carried out at room temperature for 1 h,
and then at refluxing temperature for 6 h.
[b]
To understand the reaction mechanism, the arylated the catalyst.
product 5 has been isolated by stopping the reaction
In summary, we have developed an efficient
at 10 min (Scheme 4). The structure of 5b has also domino approach for the synthesis of indole-fused
been confirmed by single-crystal analysis.[11] The re- carbocycles including dihydrocyclohepta[b]indoles or
sults clearly showed that the Friedel–Crafts reaction -pyrroles and 9H-carbazoles via the cationic gold(I)
selectively occurred at the C-3 position of the indole complex catalyzed Friedel–Crafts/hydroarylation reac-
ring. The intramolecular cyclization of 5a catalyzed by tions. The Lewis acid BF3·Et2O was required in some
(PPh3)AuCl/AgSbF6 proceeded smoothly to provide cases to realize a successful domino process, depend-
the same product of 2m as observed in the tandem ing on the substitution pattern on the enynols. Further
Scheme 3.
Scheme 4.
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Gold-Catalyzed Intermolecular Reactions of (Z)-Enynols with Indoles
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Scheme 5.
studies to extend the scope and synthetic utility for State Basic Research Development Program (Grant No.
2006CB806105) for financial support.
this Au/Ag-catalyzed cascade reaction are in progress
in our laboratory.
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General Procedure: Au/Ag-Catalyzed One-Pot
SynACHTUNGTRENNUNGthesis of Dihydrocyclohepta[b]indole from the
Reaction of a (Z)-2-En-4-yn-1-ol with Indole
Under argon atmosphere, to a solution of (Z)-enynol 1
(0.3 mmol) in 5 mL THF was added indole or its derivative
(0.45 mmol). After indole was dissolved, Ph3PAuCl (5
mol%) and AgSbF6 (5 mol%, used as a 0.05M solution in
MeCN) were added successively. The resulting solution was
stirred at room temperature until the reaction was complete
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new compounds and X-ray crystallography of compounds
2d, 4 and 5b are given in the Supporting Information file.
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