Gold-catalyzed Bicyclization of Diaryl Alkynes: Synthesis of Polycyclic Fused Indole and Spirooxindole Derivatives

Article abstract of DOI:10.1021/acs.orglett.8b00939

An unprecedented gold-catalyzed bicyclization reaction of diaryl alkynes has been developed for the synthesis of indoles in good to high yields. Mechanistically, this alkyne bifunctionalization transformation was terminated by a stepwise formal X-H insert

Full text of DOI:10.1021/acs.orglett.8b00939

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold-catalyzed Bicyclization of Diaryl Alkynes: Synthesis of Polycyclic
Fused Indole and Spirooxindole Derivatives
Ju Cai,† Bing Wu,† Guangwei Rong,† Cheng Zhang,† Lihua Qiu,*,† and Xinfang Xu*,†,‡
†College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
‡School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
S
* Supporting Information
ABSTRACT: An unprecedented gold-catalyzed bicyclization reaction
of diaryl alkynes has been developed for the synthesis of indoles in
good to high yields. Mechanistically, this alkyne bifunctionalization
transformation was terminated by a stepwise formal X−H insertion
reaction to furnish the corresponding polycyclic-frameworks with
structural diversity, and the key intermediate 3H-indole was isolated
and characterized for the first time. In addition, further transformation
of these generated tetracyclic-indoles with PCC as the oxidant
provided straightforward access to the spirooxindoles in high yields.
Scheme 1. Gold-catalyzed Alkyne Cyclization with Azide
he indole nucleus is a very important element of many
T
natural and synthetic useful molecules with significant
biological activities.1 Thus, the synthesis of indole has been
drawing considerable attention since its first discovery by Baeyer
in 1866.2 Classic approaches have been extensively studied and
proven to be extremely useful, such as Fischer indole synthesis,3
Bartoli indole synthesis,4 and Leimgruber−Batcho indole
synthesis.5 Recently, catalytic aromatic ring modifications have
shown broad applications for the diversity synthesis of
multifunctionalized indoles.6 However, examples for the syn-
thesis of indoles with polycyclic fused rings7 or spiro structures,8
which are the key structural motifs in many pharmacologically
important compounds, are quite limited with these classical
approaches.9 Thus, the development of efficient methods for the
synthesis of structural appealing indole molecules is highly
desired.
In recent decades, the gold-catalyzed alkyne transformations
have shown broad applications in synthetic organic chemistry for
the construction of carbon−carbon and carbon−heteroatom
bonds.10 Since the pioneering example reported by Teles,11
numerous exciting research works have been disclosed based on
the electrophilic activation of the π-systems via homogeneous
gold catalysis.12 It is noteworthy that Toste realized the first gold-
catalyzed intramolecular Schmidt reaction of an alkyne with a
tethered azide moiety, affording multisubstituted pyrroles under
mild conditions (Scheme 1a).13 This strategy was further
investigated by Zhang,14 Gagosz,15 Ohno,16 and Ye17 through
the interception of corresponding intermediates with various
nucleophiles to build indole skeletons in the presence of a gold
catalyst (Scheme 1b). Although an α-imino carbenoid
intermediate was proposed and recognized as the key
intermediate in these transformations, the mechanism for the
subsequent carbenoid reaction step, whether concerted or
stepwise, was not disclosed. In addition, anthranils,18 indazoles,19
isoxazoles,20 nitrosobenzenes,21 amines,22 nitriles,23 isocyanoa-
cetates,24 imines,25 and others26 have also been used as nitrogen
sources for the annulation with alkynes to offer the
corresponding N-heterocycles with structural diversity. Inspired
by those advances and as the continuation of our interest in
alkyne bifunctionalization for the synthesis of heterocycles,27 we
envisioned that a general approach for the construction of
polycyclic frameworks could be realized via intramolecular
Received: March 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00939
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
interception of an in situ formed carbenoid intermediate. Herein,
we present our recent results in this context; a gold-catalyzed
intramolecular bicyclization of diaryl alkynes 1 in which the α-
imino carbenoid intermediate was terminated with O−H/N−H
insertion, and electrophilic aromatic substitution to yield to the
corresponding polycyclic N-heterocycles with structural diversity
(Scheme 1c). Moreover, a stepwise H-shift mechanism for the
final carbenoid reaction step was proposed and verified for the
first time in this work.
Scheme 2. Substrate Scope
Initially, we employed the diaryl alkyne 1a, easily synthesized
from corresponding ortho-alkyl aniline and aryl halide via
coupling reaction followed azidation as the model substrate
(Table 1). Various transition metal catalysts were screened, such
a
Table 1. Optimization of the Reaction Conditions
b
entry
cat. (mol %)
Cu(hfacac)2 (2.0)
yield (%)
c
1
2
3
4
5
6
7
8
ND
d
AgSbF6 (20)
<5%
c
Pd(dba)3 (5.0)
ND
c
Rh2(OAc)4 (1.0)
ND
a
Reactions were carried out on a 0.2 mmol scale with JohnphosAu-
PPh3AuNTf2 (5.0)
57
36
84
88
85
46
(CH3CN)SbF6 (4.6 mg, 3.0 mol %) in DCE (4.0 mL) at 60 °C under
JohnphosAuCl (5)/AgSbF6 (5.0)
JohnphosAu(CH3CN)SbF6 (5.0)
JohnphosAu(CH3CN)SbF6 (3.0)
JohnphosAu(CH3CN)SbF6 (3.0)
JohnphosAu(CH3CN)SbF6 (3.0)
b
argon atmosphere for 12 h. The reaction was carried out on a 5.0
mmol scale with 2.0 mol % gold catalyst.
e
9
f
arenes (2b and 2i). Functional groups, such as alkynyl (2j) and
naphthyl (2k), were well tolerated. Two isomers were obtained
in the case of reaction with 1k, which may be due to the inherent
thermostability of these products, and slow conversion of 3H-
isomer 2k′ to the 1H-product 2k was observed with proton
NMR by monitoring the reaction mixture at different periods of
reaction time in CD2Cl2 (see Figure S1).28 In addition, the
secondary alcohols were also viable and led to the tetracyclic
products 2m and 2n in synthetically useful yields. It is
noteworthy that the high yield was retained, and even the
reaction was carried out on gram scale (2g, 74% yield, note b).
To demonstrate the practicality and synthetic utility of the
current method, a further transformation with these fused indole
products was conducted (Scheme 3). Although the direct
10
a
Reactions were carried out on a 0.2 mmol scale in 4.0 mL of solvent
with corresponding catalyst at 60 °C under argon atmosphere for 12 h.
b
c
Isolated yields. Low conversion (<10%) was observed, and most of
d
e
the material 1a was recovered. 60% conversions. The reaction was
carried out in dichloromethane under reflux. The reaction was carried
out in toluene.
f
as copper-, silver-, palladium-, and rhodium-complexes, which
have been reported for the activation of alkynes (entries 1−4).
However, no reaction occurred in most of these cases, and 1a was
decomposed into a complex mixture slowly in the presence of
AgSbF6 (entry 2). To our delight, the desired tetra-cyclic product
2a was obtained in moderate to high yields when the reaction was
catalyzed by gold-catalysts (entries 5−7). Although the
combination of JohnphosAuCl and AgSbF6 turned out to be
less efficient, affording 2a in only 36% yield (entry 6), the use of
commercially available JohnphosAu(CH3CN)SbF6 showed
much better results (entry 7, 84% yield), and the catalyst loading
could be reduced to 3.0 mol % without decreasing the high yield
(entry 8). In addition, both dichloromethane (DCM) and
toluene were found to be compatible with this reaction, and the
product 2a was formed in high and moderate yields under these
conditions, respectively (entries 9 and 10). The molecular
structure of 2a was inferred from X-ray diffraction analysis of its
analogue 2d.
Scheme 3. Synthesis of Spirooxindole 3
With the optimal reaction conditions established, the substrate
scope with respect to the various substitutions on the diaryl
alkynes was investigated. As shown in Scheme 2, both electron-
donating and electron-withdrawing groups were well tolerated
with good to excellent yields (2a−2l). It was found that the
reaction showed no obvious effect to the steric demand of the
oxidation of the methylene part to the carbonyl group had failed,
the spirooxindoles 3 were obtained in good to high yields from
the Boc-protected substrates with PCC as the oxidant.29 The
molecular structure of 3g was confirmed by X-ray diffraction. It is
worth noting that polycyclic spirooxindoles are important
scaffolds in natural products and pharmaceutical molecules,
B
DOI: 10.1021/acs.orglett.8b00939
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Letter
which have shown potential anticancer and cytotoxic activities.30
This protocol provided straightforward access to these motifs
from readily available materials under mild conditions.
Control experiments were conducted to explore the
mechanism of this reaction. In order to rule out the possibility
of the initial hydroxyl group addition with the activated alkyne
moiety, substrate 4 without the azide group was prepared and
applied to the reaction conditions. It turned out that no reaction
occurred under the standard conditions with most of the starting
material recovered (eq 1). Evidence for the existence of an α-
α-imino gold carbenoid species B after extrusion of N2.
Subsequently, the gold carbenoid intermediate was captured by
the nucleophilic hydroxyl group through a stepwise formal O−H
insertion reaction to generate the corresponding polycyclic
product 2 via C after 1,3-H. It is worth noting that the 1,3-H shift
transformation to thermodynamically more stable 1H-indole was
observed by the proton NMR for the first time and that one of
the key intermediates, 3H-isomer 2k′, was isolated and
characterized (see Figure S1 for details).28
In summary, we have developed an atom-economical
approach to the fused indoles in good to high yields under
mild reaction conditions. The reaction was initiated via a gold-
catalyzed 5-endo-dig cyclization to form the α-imino carbenoid,
followed by O−H/N−H insertion, and electrophilic aromatic
substitution to yield the corresponding polycyclic N-heterocycles
with structural diversity, including fused tetracyclic indoles and
π-conjugated polycyclic hydrocabons (CPHs). Moreover, these
tetracyclic-indole products could be further transformed into
spirooxindoles with PCC as oxidant in high yields, which are
privileged motifs in bioactive molecules, pharmaceuticals, and
natural products.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00939.
Experimental procedure and spectroscopic data for all
compounds (PDF)
Accession Codes
imino carbenoid intermediate could be anticipated by the
formation of products 6 and 8 from corresponding materials
through electrophilic aromatic substitution and N−H insertion
reaction as terminating reactions, respectively (eqs 2 and 3). In
addition, this protocol could also be used for the preparation of
seven-membered heterocycle 10 in 71% yield (eq 4). All these
results not only well rationalized the reaction mechanism, but
also underlined the synthetic advantages of our method in
diversity oriented synthesis.
CCDC 1587682 and 1832661 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Based on these results and the reported literature,13−17
a
tentative mechanism was proposed for the generation of
polycyclic indoles, which is shown in Scheme 4. Initial 5-endo-
dig nucleophilic cyclization of the gold(I) activated alkyne moiety
with tethered azide formed intermediate A, which further led to
*E-mail: qiulihua@suda.edu.cn.
*E-mail: xinfangxu@suda.edu.cn.
ORCID
Xinfang Xu: 0000-0002-8706-5151
Notes
Scheme 4. Proposed Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this research from the National Natural Science
Foundation of China and the NSFC of Jiangsu (NSFC21602148
and BK20150315) is gratefully acknowledged.
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