A thermally-induced, tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition approach to carbocyclic spirooxindoles

Article abstract of DOI:10.3762/bjoc.6.33

The synthesis of C3-carbocyclic spirooxindoles was realized by way of an intramolecular [2 + 2] cycloaddition reaction between a vinylidene indolin-2-one and an alkyne. The cycloaddition reaction occurs selectively with the distal double bond of the allene, is tolerant of a phenyl and trimethylsilyl group on the terminus of the alkyne, and can be used to access bicyclo[4.2.0]octadienes and bicyclo[5.2.0]nonadienes. The allene precursors are not observed, but are likely intermediates of an infrequently encountered thermal [3,3]-sigmatropic rearrangement of a propargylic acetate.

Full text of DOI:10.3762/bjoc.6.33

A thermally-induced, tandem [3,3]-sigmatropic
rearrangement/[2 + 2] cycloaddition approach
to carbocyclic spirooxindoles
Kay M. Brummond* and Joshua M. Osbourn
Preliminary Communication
Open Access
Address:
Beilstein Journal of Organic Chemistry 2010, 6, No. 33.
Department of Chemistry, University of Pittsburgh, Pittsburgh,
Pennsylvania 15260, U.S.A
doi:10.3762/bjoc.6.33
Received: 19 February 2010
Accepted: 31 March 2010
Published: 08 April 2010
Email:
Kay M. Brummond* - kbrummon@pitt.edu
* Corresponding author
Associate Editor: J. Aubé
Keywords:
© 2010 Brummond and Osbourn; licensee Beilstein-Institut.
License and terms: see end of document.
allene; propargylic acetate; spirooxindole; thermal [2 + 2]
cycloaddition; thermal [3,3]-sigmatropic rearrangement; vinylidene
indolin-2-one
Abstract
The synthesis of C3-carbocyclic spirooxindoles was realized by way of an intramolecular [2 + 2] cycloaddition reaction between a
vinylidene indolin-2-one and an alkyne. The cycloaddition reaction occurs selectively with the distal double bond of the allene, is
tolerant of a phenyl and trimethylsilyl group on the terminus of the alkyne, and can be used to access bicyclo[4.2.0]octadienes and
bicyclo[5.2.0]nonadienes. The allene precursors are not observed, but are likely intermediates of an infrequently encountered
thermal [3,3]-sigmatropic rearrangement of a propargylic acetate.
Introduction
Spirooxindoles are structural motifs containing a heterocycle or containing this basic skeleton is welwitindolinone A isonitrile
carbocycle at the C3 position of an oxindole. Particularly well (4); a compound that has recently captured the attention of the
known are the pyrrolidinyl-spirooxindoles 1 which have been synthetic community [3,4].
classified as a privileged motif due to their presence in a large
number of heterocyclic alkaloids (Figure 1) [1]. Spirotrypro- Spiro[cyclobutane-1,3'-indolin]-2'-ones (3, n = 0) have previ-
statin B (2) is just one example of many natural products from ously been prepared but the synthetic approach is mostly
this class exhibiting interesting biological activity [2]. Com- limited to simple spirocyclobutanes that are accessed via alkyl-
pounds possessing a carbocycle at the C3 position of the oxin- ation chemistry [5]. Alternatively, more structurally complex
dole, such as 3, are less common and spirooxindoles containing spirocyclobutanes have been obtained from homodimerization
a four carbon spirocycle are rare. One notable natural product reactions of allenes or alkenes [6,7]. However, neither of these
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Beilstein Journal of Organic Chemistry 2010, 6, No. 33.
Figure 1: Heterocyclic and carbocyclic spirooxindoles.
approaches provides an enabling strategy for accessing the Results and Discussion
densely functionalized and unsymmetrical molecular architec- To begin the investigation, the first challenge was the prepar-
tures of many of the natural products possessing this oxindoline ation of a functionalized vinylidene indolin-2-one 5 (Figure 2).
core. We anticipated that access to this class of compounds util- There is only one report of this allene substructure in the litera-
izing chemistry developed in our laboratories would provide an ture and it was not particularly well suited for the incorporation
expansion of substructures within this chemical space, thus of additional functionality [6]. Scattered reports of propargylic
enhancing the discovery of new biological probes and pharma- acetates thermally rearranging to allenyl acetates exist, thus, it
ceuticals [8].
was reasoned that the allene moiety of 5 could be obtained by
way of a thermal [3,3]-sigmatropic rearrangement of the
We recently disclosed a thermal [2 + 2] cycloaddition reaction propargylic acetate 6 to give compound 5 where R2 = OAc
of allene-ynes to provide a variety of alkylidene cyclobutenes in (Figure 2) [27].
good yields [9-18]. Notable features of this reaction were the
stability of the resulting alkylidene cyclobutenes, the regiose-
lectivity for reaction of the distal double bond of the allene, and
ready cyclization of substrates possessing heteroatom tethers to
give heterocyclic structures (Scheme 1) [19-26]. Inspired by the
unique skeleton of welwitindolinone A, the feasibility of this
method for the preparation of spirooxindole alkaloids was in-
vestigated. The preliminary results of this study are reported
herein.
Figure 2: Access to vinylidene indolin-2-ones.
Preparation of propargylic acetate 9a was accomplished by the
addition of the lithium acetylide of 8 to N-methyl isatin (7)
followed by acetylation of the resulting propargyl alcohol.
Heating propargylic acetate 9a to 225 °C in 1,2-dichloroben-
zene in the microwave for 30 min gave the spirooxindole 10a in
Scheme 1: A thermal [2 + 2] cycloaddition reaction.
60% yield (Scheme 2). Structural confirmation of 10a was
Scheme 2: A tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 33.
achieved using COSY, HMQC and HMBC. Attempts to effect material was observed (entry 3, Table 1). When N-methyl-
the [3,3]-sigmatropic rearrangement of the propargyl acetate 9a pyrrolidinone (NMP) was used as a solvent the reaction mix-
using transition metal catalysis (AuCl3 10 mol %, toluene, 1 h, ture could be heated to higher temperatures (250 °C vs. 225 °C
rt) led to hydrolysis of the allenyl acetate functionality.
in 1,2-dichlorobenzene) and the reaction times were shorter
which had a marginal affect on the yield of the reaction
This densely functionalized alkylidene cyclobutene 10a is (compare entries 5 and 6). A further advantage of NMP over
postulated to arise via the [2 + 2] cycloaddition reaction 1,2-dichorobenzene was the ease of isolation of the products
between the alkyne and the allenyl acetate in intermediate 11 since the solvent could be removed with aqueous washings
which in turn arises from the thermal [3,3]-sigmatropic instead of column chromatography. To investigate the yield of
rearrangement of 9a (Figure 3).
this reaction the transformation of propargyl acetate 9f to
spirooxindole 10f was monitored by proton NMR. We found
that the NMR yield is consistent with the isolated yield and the
source of lost mass is attributed to decomposition during the
course of the reaction as evidenced by baseline impurities on
the TLC. However, the only discernable product in the NMR
spectrum is the desired spirooxindole 10f.
Conclusion
Figure 3: A tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloadd-
We have developed a concise synthesis to C3-carbocyclic
spirooxindoles. One important feature of this thermal tandem
[3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition reaction
ition.
We have briefly investigated the scope and limitations of this is that the reaction remains selective for the distal double bond
tandem cycloaddition reaction by varying the protecting group of the allene even with densely functionalized allenes [29]. In
on the oxindole nitrogen, altering the substitution on the alkyne addition, conversion of the propargylic acetate to the spirooxin-
terminus and increasing the number of carbon atoms in the dole in one step provides a rapid and potentially stereoselective
tether. Groups such as methyl (Me), methoxymethyl (MOM), increase in molecular complexity. Furthermore, this approach
and 2-(trimethylsilyl)ethoxymethyl (SEM) were found to be includes a rare example of a thermal [3,3]-sigmatropic
well tolerated. Substrates possessing either a phenyl or a silyl rearrangement of a propargylic acetate while metal catalyzed
group on the alkyne terminus also gave good yields of the rearrangements of the propargyl acetates are common. Work is
spirooxindoles. However, when a terminal alkyne was subjected currently underway to expand the synthetic utility of this reac-
to the reaction conditions, only decomposition of the starting tion.
Table 1: Synthesis of spirooxindoles.
Entry
R1
R2
n
Solventa
Temp
Time
Product
Yield
1
2
3
4
5
6
7
Me
Ph
TMS
H
1
1
1
1
1
1
2
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
N-methylpyrrolidinone
N-methylpyrrolidinone
225 °C
225 °C
225 °C
225 °C
225 °C
250 °C
250 °C
30 min
50 min
50 min
60 min
60 min
10 min
5 min
10a
10b
10c
10d
10e
10e
10f
60%
50%
0%
Me
Me
SEM
MOM
MOM
MOM
Ph
Ph
Ph
Ph
61%
57%
61%
48%
aIn our original report, the most successful solvent system for the cycloaddition was toluene doped with an ionic liquid (0.3 M). However we have moved
away from this solvent system because subsequent to that study, two sample solutions (out of hundreds), that were allowed to age for an hour prior to
microwave irradiation, immediately exploded upon irradiation. Oliver Kappe has made similar observations when using ionic liquids in the presence of
ethylene gas in the microwave. Kappe demonstrated that the explosion is due to the ionic liquid initiating an exothermic polymerization reaction [28]. We
suspect that the ionic liquid initiated a polymerization reaction of the allene-ynes when allowed to stand prior to irradiation.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 33.
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Spirooxindole (10a) Propargyl acetate 9 (30 mg, 0.081 mmol)
was dissolved in 1,2-dichlorobenzene (1.62 mL) in a 0.5–2 mL
Biotage™ microwave vial. The vial was capped and the solu-
tion irradiated in the microwave for 30 min at 225 °C. The reac-
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silica gel column. The column was eluted with hexanes (100
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containing the desired product were concentrated under reduced
pressure to provide 18 mg of spirooxindole 10a as a brown oil
in 60% yield.
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Supporting Information
General methods, experimental and spectral data are
provided for all new compounds in the Supporting
Information.
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[http://www.beilstein-journals.org/bjoc/content/
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