Multicomponent cascade cycloaddition involving tropone, allenoate, and isocyanide: A rapid access to a 7,6,5-fused tricyclic skeleton

Article abstract of DOI:10.1021/ol502656g

Multicomponent cascade cycloaddition of tropone, allenoate, and isocyanide has been disclosed. This method allows for the rapid construction of a highly unusual tricyclic skeleton in an efficient manner. The proposed transformation proceeds through [8 + 2 + 1] cycloaddition, [1,5]-H shift, and cyclization followed by an alkoxy group migration process.

Full text of DOI:10.1021/ol502656g

Letter
pubs.acs.org/OrgLett
Multicomponent Cascade Cycloaddition Involving Tropone,
Allenoate, and Isocyanide: A Rapid Access to a 7,6,5-Fused Tricyclic
Skeleton
Shuanglong Jia,† Shikuan Su,† Chunju Li,† Xueshun Jia,*,†,‡ and Jian Li*,†
†Department of Chemistry, Innovative Drug Research Center, Shanghai University, 99 Shangda Road, Shanghai 200444, P. R. China
‡Key Laboratory of Synthetic Organic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 345 Lingling Road, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: Multicomponent cascade cycloaddition of tropone, allenoate, and isocyanide has been disclosed. This method
allows for the rapid construction of a highly unusual tricyclic skeleton in an efficient manner. The proposed transformation
proceeds through [8 + 2 + 1] cycloaddition, [1,5]-H shift, and cyclization followed by an alkoxy group migration process.
Scheme 1. Selective Cycloaddition Involving Tropone and
Allenoate
ropone and its derivatives represent highly valuable
Tbuilding blocks and have been extensively used in organic
synthesis and mechanistic studies.1 Moreover, troponoids have
also found application in syntheses of natural products2 since
the tropolone moieties are frequently present in some
alkaloids.3 In particular, they are proven to be a versatile
cycloaddition partner in a variety of high-order cycloadditions.
It is therefore not surprising that many impressive cyclo-
additions have been extensively reported using tropone as
four-,4 six-,5 and eight-membered6 building blocks, respectively.
Recently, reactions involving tropone and 1,3-dipoles have
attracted much attention from organic chemists. Early works
include the reactions of tropone and 1,3-dipoles derivated from
allenoate and modified allylic compounds in the presence of a
phosphine catalyst (Scheme 1).7 The palladium-complex-
catalyzed [6 + 3] cycloaddition constitutes another representa-
tive example.8 Following these pioneering works, Ni- and
SnCl4-catalyzed [8 + 3] cycloadditions of tropone and dipoles
in situ generated from 1,1-cyclopropane derivatives have also
been achieved.9 More recently, the metal-catalyzed [6 + 3]
cycloaddition of tropone with azomethine ylide has been
reported to approach bicyclic heterocycles.10 Yet, to our
knowledge, whereas the traditional cycloadditions involving
tropone can serve as highly efficient protocols for the syntheses
of bicyclic frameworks, examples in the construction of a more
complex tricyclic skeleton are still very rare.
and diversity.11,12 Remarkably, IMCRs enjoy unique superiority
over traditional methods for the rapid and efficient generation
of structurally complex molecules.13 As a result, the past
decades have witnessed a rapid increase in the application of
isocyanide-based multicomponent reactions.14 In 2011, we
developed the first example of a multicomponent reaction
involving isocyanide and allenoate, thus providing a quick
access to spirooxindole.15 The system was subsequently proven
to be an efficient strategy to construct other five-membered
carbocycles and heterocycles.16a,b More recently, we have also
Isocyanide-based multicomponent reactions (IMCRs) have
been widely investigated in organic synthesis owing to their
inherent features such as atom and step economy, convergence,
Received: September 8, 2014
© XXXX American Chemical Society
A
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Letter
found that this MCR method can also be used to synthesize
more complex fused derivatives by using substituted
allenoate.16d Taking the high reactivity of tropone into
consideration, we assume that the tropone may react with
isocyanide and allenoate to give new results. As a continuation
of our previous research,16 herein we wish to report the
multicomponent cascade cycloaddition from readily available
isocyanide, allenoate, and tropone (Scheme 1).
In order to test our hypothesis, we initially selected tert-butyl
isocyanide 1a, allenoate 2a, and tropone 3 as model substrates.
Upon heating the mixture in toluene for 20 h, the reaction gave
rise to 7,6,5-fused tricyclic adduct 4a in 61% yield (Table 1,
Table 1. Multicomponent Cascade Cycloaddition to
Synthesize 7,6,5-Fused Tricyclic Derivatives with Isocyanide
1a, Allenoate 2, and Tropone 3
Figure 1. Single crystal X-ray structure for 4a.
a
X-ray analysis.18 These results also implied that varying the
substituents on the aromatic rings did not have any major
impact on the yield of product 4. Remarkably, the nature of the
substituent R1 in allenoate 2 played an important role in the
present transformation. As shown in Table 1, a complex
mixture was observed when allenoate with a methyl
substitution was used (Table 1, entry 13), whereas substrates
2 bearing the CN and CO2Me group proceeded smoothly to
produce the products 4m and 4n (Table 1, entries 14−15).
These results might indicate that the presence of an anion-
stabilizing group such as an aryl, CN group is indispensible. It
was also worthy to note that the allenoates 2 were used as four
carbon (C4) building blocks to form the rings, which is less
common.19 In our previous works, the multicomponent
reactions involving isocyanide and allenoate were usually used
for the syntheses of five-membered rings.15,16 In contrast, the
first step in the present IMCRs essentially involved the
formation of a six-membered ring, thus offering a new
opportunity for the construction of structurally unusual
skeletons with diversity.
To further demonstrate the scope and limitation of the
present reaction, a series of aliphatic and aromatic isocyanides
were used to undergo the standard conditions. To our delight,
all isocyanides used worked well to give the products 5. For
instance, the employment of cyclohexyl isocyanide essentially
led to the formation of 5d in 80% yield (Table 2, entry 4).
Sterically hindered admantyl isocyanide 1f was also found to be
compatible with the present cascade cycloaddition protocol
(Table 2, entry 6). To our surprise, the less reactive 4-
bromophenyl isocyanide also showed high performance to
afford 5g in good yield (Table 2, entry 7).
a
Reaction conditions: isocyanide 1a (0.5 mmol), allenoate 2 (0.6
mmol), and tropone 3 (0.5 mmol) in 5 mL of toluene and heated
under reflux. Yield of product after silica gel chromatography. In this
case, a very complex mixture was observed.
b
c
Based on the experimental results, a mechanistic proposal is
outlined in Scheme 2. The beginning of the cascade
cycloaddition involves the formation of resonance-stabilized
species, which are very reactive and exist as form A↔B. Then,
nucleophilic attack takes place to produce intermediate C. The
following [1,5]-H shift20 step is believed to be the key step in
the whole transformation, which is facilitated by the presence of
a functional group such as an aryl or another electron-
withdrawing group. Further cyclization and the second [1,5]-H
shift essentially result in the formation of intermediate G. The
last step comprises the elimination of the ethoxy group and
nucleophilic addition, thus furnishing a formal ethoxy group
migration.
entry 1). The structure of compound 4a was unambiguously
confirmed by single-crystal X-ray analysis (Figure 1).17 In this
process, reactions to see the effect of different solvents and
temperature were also conducted. However, only toluene under
reflux was found to be the best conditions. Encouraged by this
result, we then turned our attention to investigate the scope of
allenoate with different substitution patterns. Pleasingly,
allenoate bearing electron-deficient (Table 1, entries 2−7)
and electron-rich substituents (Table 1, entries 8−11) on the
aromatic ring all worked well under the standard conditions to
afford the desired compounds 4. All new compounds were
characterized by 1H NMR, 13C NMR, and HRMS. Notably, the
structure of compound 4d was also confirmed by single-crystal
Subsequently, experiments varying the alkyl group in
allenoate were also conducted (Scheme 3). In this stage,
B
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Letter
Table 2. Multicomponent Cascade Cycloaddition To
Scheme 3. Expanded Reactions by Changing the Alkoxy
Group in Allenoate
Synthesize 7,6,5-Fused Tricyclic Derivatives with Isocyanide
a
1, Allenoate 2a, and Tropone 3
a
All reactions were carried out with 0.5 mmol of isocyanide 1, 0.6
mmol of allenoate 2a, and 0.5 mmol of tropone 3 in 5 mL of toluene
b
under reflux unless otherwise noted. Yield of product after silica gel
chromatography.
experience unusual [8 + 2 + 1] cycloaddition, sequential [1,5]-
H shift, cyclization, and group migration. Remarkably, the
present reaction also demonstrates very high synthetic
efficiency since the allenoate is used as a C4 component to
form the rings. This protocol is also featured by excellent atom
economy and mild conditions. As a result, the present reaction
has potential to be further applied in organic synthesis.
Scheme 2. Proposed Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
Experiment procedures and full characterization of all
1
compounds, spectral data, H and 13C NMR spectra for all
products, and X-ray crystal structure data (CIF) for compounds
4a and 4d. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xsjia@mail.shu.edu.cn.
*E-mail: lijian@shu.edu.cn.
Notes
allenoate bearing both linear groups and alkyl substitution with
a side chain proceeded readily to yield the corresponding
adducts 6a, 6b, and 6c. In addition, experiments with
isocyanides other than tert-butyl ones were also tested. In this
case, 2,6-dimethoxyphenyl isocyanide gave a good yield of
product 6e.
In conclusion, we have disclosed an unprecedented multi-
component cascade cycloaddition reaction from readily
available isocyanide, allenoate, and tropone. The present
strategy provides a new opportunity to access 7,6,5-fused
tricyclic skeletons, which are difficult to synthesize with
traditional methods. The reaction mechanism is believed to
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21272148, 21472121, and 21272147) and the Key
Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Science, for financial support. We also thank Dr. H. Deng and
M. Shao (Laboratory for Microstructures, Shanghai University)
for NMR spectroscopy and X-ray measurements.
C
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Ji, S.-J. Org. Lett. 2013, 15, 1954.
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