Cyclooctatetraenes through Valence Isomerization of Cubanes: Scope and Limitations

Article abstract of DOI:10.1002/chem.201805124

The scope and limitations of Eaton's rhodium(I)-catalyzed valence isomerization of cubane to cyclooctatetraene (COT) were investigated in the context of functional group tolerability, multiple substitution modes and the ability of cubane-alcohols to undergo one-pot tandem Ley–Griffith Wittig reactions in the absence of a transition metal catalyst.

Full text of DOI:10.1002/chem.201805124

DOI: 10.1002/chem.201805124
Communication
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Hydrocarbons
Cyclooctatetraenes through Valence Isomerization of Cubanes:
Scope and Limitations
Sevan D. Houston+,[a] Hui Xing+,[a] Paul V. Bernhardt,[a] Timothy J. Vanden Berg,[a]
John Tsanaktsidis,[b] G. Paul Savage,[b] and Craig M. Williams*[a]
Dedicated to Professor Philip Eaton
Abstract: The scope and limitations of Eaton’s rhodium(I)-
catalyzed valence isomerization of cubane to cycloocta-
tetraene (COT) were investigated in the context of func-
tional group tolerability, multiple substitution modes and
the ability of cubane-alcohols to undergo one-pot tandem
Ley–Griffith Wittig reactions in the absence of a transition
metal catalyst.
Since the discovery of 1,3,5,7-cyclooctatetraene (COT, 1) in
1911 by the German Nobel laureate Willstꢀtter and his co-
worker Waser,[1] COT and its derivatives have found increasing
application in diverse areas of synthetic chemistry.[2] Some im-
portant examples include the total synthesis of natural prod-
Scheme 1. Cyclooctatetraene (COT, 1) and applications thereof in natural
product total synthesis, organometallics, materials chemistry, and drug lead.
ucts (e.g., pentacycloanammoxic acid (2) by Corey and Mascit-
ti),[3] use in organometallic chemistry (e.g., as a versatile ligand
either in its neutral or anionic form[4] such as the bis-COT palla-
dium sandwich complex 3),[5] materials chemistry (e.g., 4 as a
acetylene using a nickel cyanide/calcium carbide catalyst, effec-
useful OLED emitter of blue light),[6] in polymer chemistry as a
swelling agent[7] and more recently to access the archetypal
fluxional hydrocarbon bullvalene on a practical scale.[8] Beyond
these broad applications, our group recently identified COT as
a (bio)motif (i.e., bioactive complement to cubane (bio)isoster-
ism), which enhanced biological activity in select pharmaceuti-
cal templates, for example, the warfarin analogue 5[9]
(Scheme 1). That said, methods to access COT derivatives are
limited.
tively making COT a readily available commodity chemical;[10]
although, this method has limited scope with substituted ace-
tylenes.[11] Monobromo-COT (6), reported by Huisgen et al.,[12]
provided a platform for functionalizing the COT core (e.g.,
access to COT-carboxylic acid 7 via Grignard formation).[13] 1,2-
Disubstituted COTs (e.g., 8) can be reached by photolytic addi-
tion of substituted acetylenes to benzene, via [2+2] photocy-
clization followed by valence tautomerization (i.e., 9),[14] which
our group utilized previously to access bicyclo[4.2.0]octa-2,4-
dienes.[15] Protocols for arriving at 1,4-disubstituted COT deriva-
tives (e.g., 10) are quite limited and have restricted synthetic
utility, but the key advances in this area were made by Huis-
gen, through alkylation (e.g., 11) of the sulfur dioxide cycload-
duct of COT (i.e., 12) (Scheme 2),[16] with further developments
provided by Paquette and Streitwieser.[17] In addition, 1,4-di-
metalation of COT has also been reported.[18] However, all
these methods suffer from either multistep procedures, low
yields, long reaction times, laborious purification protocols,
and/or limited scope. Furthermore, although other poly-substi-
tution patterns are available, including benzo and annulated
derivatives,[19] rapid and routine access to mono and disubsti-
tuted COT systems are not available.
The first preparation of COT (1) by Willstꢀtter and Waser was
by means of a low-yielding ten-step sequence starting from a
tropinone derivative obtained from a pomegranate tree root
bark.[1] In 1948, Reppe identified a one-step tetramerization of
[a] Dr. S. D. Houston,+ Dr. H. Xing,+ Prof. P. V. Bernhardt, T. J. Vanden Berg,
Prof. C. M. Williams
School of Chemistry and Molecular Biosciences
University of Queensland, Brisbane, 4072, Queensland (Australia)
E-mail: c.williams3@uq.edu.au
[b] Dr. J. Tsanaktsidis, Dr. G. P. Savage
CSIRO Manufacturing, Ian Wark Laboratory
Melbourne, 3168, Victoria (Australia)
[+] These authors contributed equally to this work.
In a continuing effort to explore the fundamental reactivity
of cubane (13),[20] Eaton discovered that the strained hydrocar-
bon underwent valence isomerization to COT on treatment
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201805124.
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Scheme 2. Reported synthetic methods to access functionalized COT sys-
tems, including Eaton’s valence isomerization of cubane (13) to COT (1).
with rhodium(I) norbornadiene chloride dimer (i.e.,
[Rh(nbd)Cl]2) and subsequent exposure of the intermediate tri-
cyclo[4.2.0.02,5]octa-3,7-diene (14) to thermal conditions
(Scheme 2).[21] Interestingly, only the rearrangement of a few
esoteric cubanes was reported,[22] but functional examples
were never published, apart from examples in the polymer
field[7,23] and supramolecular chemistry.[24] Understandably, the
lack of interest in this methodological approach likely originat-
ed from the scarcity of starting cubane substrates.
Scheme 3. Synthesis of the mono- and disubstituted cubane library.
[DMAP=N,N-(dimethylamino)pyridine, DMF=N,N-dimethylformamide,
DPPA=diphenylphosphorylazide, TEA=triethylamine, LDA=lithium N,N-di-
isopropylamide, DCM=dichloromethane, THF=tetrahydrofuran,
DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, TMS=trimethylsilyl,
DMDO=dimethyldioxirane, DIPA=N,N-diisopropylamine].
However, with the advent of our improved process scale
synthesis of dimethyl cubane-1,4-dicarboxylate (15),[25] experi-
ence in manipulating cubane drug and agrichemical candi-
dates,[26] and the recent development of aryl coupling to
cubane reported by Senge et al.,[27] Eaton’s method has poten-
tial to evolve from physical organic chemistry observation to
widely deployable synthetic methodology. Herein reported is a
wide scope and limitations study utilizing numerous mono-
and disubstituted cubane derivatives in the context of their
ability to undergo valence isomerization to the corresponding
COT derivatives.
ing 4-chloro acid 22, whilst hydrolysis of mono-ester 19 gave
acid 23, which acted as a key platform for accessing a wide
range of monosubstituted cubane derivatives. Initially, valuable
amides were targeted, for example, the Weinreb amide[29] 24
and the N,N-diisopropylamide 25, which can be used for ortho-
lithiation of the cubane ring system.[20] The Weinreb amide 24
was then taken through to the methyl ketone 26 and the cy-
clopentyl ketone 27. Ketone 27 was further transformed, via
Rubottom oxidation[30] of the TMS enol ether 28, to the hy-
droxy ketone 29 (confirmed by X-ray crystal-structure analysis),
in the view that this is a sensitive functional group to be ex-
plored in the valence isomerization process. Borane reduction
of 23 gave cubylmethanol 30 in excellent yield. Considering
that most examples thus far have a carbonyl directly attached
to the cubane core, 23 was subjected to a single unit homolo-
gation to give 31 (which also underwent borane reduction to
give 32), using the Arndt–Eistert protocol,[31] which involves
the Wolff rearrangement[32] as the key step. Lastly, an example
with nitrogen directly attached to the cubane core was re-
quired, and thus the t-Boc amide 33 was prepared according
to our previously reported synthesis.[26] Briefly, the synthesis of
33 involved transesterification of 15 followed by half hydroly-
The general approach taken to build a library of candidates
for performing this study focused on functionalization and de-
rivatization of cubane diester (15) (Scheme 3), which is now
readily available from commercial sources. Half hydrolysis of
15 proceeded smoothly and reliably to give the acid-ester 16
in 95% yield, which also underwent borane reduction to give
alcohol 17. Barton decarboxylation of 16 using our chloroform
hydrogen atom donor methodology[28] in combination with
the sodium salt of 1-hydroxypyridine-2(1H)-thione (18) gave
the mono-ester 19 (90% yield). Substitution of chloroform
with either carbon tetrachloride or 1,1,1-trifluoro-2-iodoethane
when running the Barton reaction gave the 4-chloro (20) and
4-iodo-cubane-1-methoxycarbonyl (21) in good to excellent
yields. Hydrolysis of the 4-chloro ester 20 gave the correspond-
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sis to give acid-ester 34, and diphenylphosphoryl azide (DPPA)
mediated Curtius rearrangement[33] in t-butanol (Scheme 3).
With a range of mono- and 1,4-disubstituted cubane deriva-
tives (i.e., 15–33) in hand the valence isomerization to COT de-
rivatives could be explored. [Note: There are at least 20 va-
lence isomers with the general formula (CH)8;[34] however, the
only interconversion of cubane as reported by Eaton was
COT].[22] Treatment of the mono-substituted cubanes with the
commercially available rhodium(I) catalyst [Rh(nbd)Cl]2 in tolu-
ene at temperatures between 60 and 1108C afforded COT de-
rivatives 35–46 in yields ranging from 53–88% (Scheme 4).
mediate tricyclo[4.2.0.02,5]octa-3,7-diene (47), which was isolat-
ed in 52% yield and found to be reasonably stable (i.e., when
stored at 88C, only slight degradation was observed over a
period of three weeks). Although stable, 47 underwent thermal
rearrangement at 1108C (in the absence of rhodium catalyst)
giving the COT derivative 48 in 56% yield. Unfortunately,
higher substituted cubanes, such as the 1,2,3,4-tetrasubstituted
example 49[35] led only to a complex COT product distribution
(Scheme 5).
Scheme 5. Observation of the tricyclo[4.2.0.02,5]octa-3,7-diene (47) intermedi-
ate and tetrasubstituted cubane analogue 49; [nbd=norbornadiene].
Encouraged by the broad substrate compatibility of Eaton’s
valence isomerization, a catalyst-free variant was developed.
The rearrangement of 4-iodo-1-vinyl cubane to 4-iodo-1-vinyl
COT (and subsequently to the corresponding trans-b-halo sty-
rene) has been reported under thermally promoted conditions
in the absence of [Rh(nbd)Cl]2.[36] Notably, the transformation
was greatly accelerated by the addition of a Lewis acid
(BCl3).[36c] Given that the valence isomerization can be per-
formed without a rhodium catalyst and best proceeds with an
electron deficient moiety appended directly to the cubane
framework, an opportunity to incorporate both precepts into
one contiguous methodology was envisaged. Our recent work
extending the Ley–Griffith oxidation[37] [that is, tetrapropylam-
monium perruthenate (TPAP) oxidation][38] in the context of
tandem Wittig reactions[39] was applied to cubane-alcohols 50
(see the Supporting Information for synthetic methods) to
expand the mono- and 1,2-disubstituted COT derivative library.
A range of mono- and 1,4-disubstituted COT derivatives were
obtained (i.e., 55–65) in yields ranging from 15–57%, which,
considering three reactions are occurring in the one pot, was
deemed satisfactory (Scheme 6). A general trend of E stereose-
lectivity was observed, based on the measurement of a large
vinyl coupling constant (J=ca. 16 Hz) where possible, although
Scheme 4. Functionalized cubane conversion to mono- and disubstituted
COTs, through valence isomerization. [nbd=norbornadiene].
Even the tertiary free hydroxyl group present in 29 was well
tolerated, giving COT 42 in 56% yield. COT alcohol 39 was
only obtained after heating at 1108C (see below). The 1,4-di-
substituted cubane derivatives were generally better tolerated,
giving higher yields of the 1,4-disusubstituted COT derivatives
44–46, ranging from 77–88%. Difficulty was encountered iso-
lating a pure sample of the chloro substituted system 43
either as the methyl ester (R=Me) or the carboxylic acid (R=
H) from the corresponding cubanes 20 and 22 (Scheme 4).
To confirm whether [Rh(nbd)Cl]2 was the optimum catalyst,
a number of different rhodium based catalysts were screened
using cubanes 15 and 25 as the test substrates. [Rh(nbd)Cl]2
was found to be superior for both cases. However, [Rh(COD)-
(MeCN)2]BF4 and [Rh(nbd)(MeCN)2]SbF6 afforded COT 45 in 63
and 30% respectively, whereas for COT 37 yields were very
similar, that is, 61 and 63%, respectively. The polymer-bound
[Rh(nbd)(PPh3)]BF4 Fibre-catꢂ, and the rhodium(II) catalyst
Rh2(OAc)4 gave no product.
1
the complex H-NMR olefinic regions of 55–65 precluded mea-
surement of one or both signals in some cases. An X-ray crystal
structure for diester 64 was obtained unambiguously confer-
ring E stereochemistry (see the Supporting Information). A no-
table exception was that of COT derivative 58, which was ob-
served as a 2:1 E:Z mixture. Reactions with the cyano phos-
phorane (52, R2 =CN) were generally low yielding and difficult
to push to completion (i.e., 58, 62). Reaction of (4-iodocuban-
1-yl)methanol (50, R1 =I, see the Supporting Information) gave
the corresponding trans-b-halo styrene 66.[36]
In the case of cubane 31 (Scheme 3), which does not con-
tain an electron-withdrawing carbonyl group, treatment with
the rhodium catalyst at 608C gave for the first time the inter-
Promotion of the valence isomerization by the perruthenate
catalyst was ruled out based on a series of control experi-
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Scheme 8. Observed basic chemistry of the COT system.
Acknowledgements
The authors thank the University of Queensland (UQ) and the
CSIRO (Melbourne) for financial support, Queensland University
of Technology (QUT) for assistance with mass spectrometry
(Prof. Stephen Blanksby and Mrs. Silvia Gemme), the Australian
Synchrotron (Melbourne, Australia) for access to beamtime and
Dr Aiden Brock for the collection of synchrotron data. The Aus-
tralian Research Council for a Future Fellowship award (grant
number FT110100851) to C.M.W. is also gratefully acknowl-
edged. S.D.H. gratefully acknowledges the Northcote Trust and
Britain–Australia Society for their award of the Northcote Grad-
uate Scholarship. H.X. gratefully acknowledges the UQ Gradu-
ate School and the School of Chemistry and Molecular Biosci-
ences for a graduate scholarship. T.J.V. gratefully acknowledges
the Australian Government for a Research Training Program
Scholarship. C.M.W. gratefully acknowledges financial support
from the Department of Agriculture and Water Resources.
Scheme 6. One-pot tandem Ley–Griffith Wittig reactions in the absence of a
transition metal catalyst. [nbd=norbornadiene, TPAP=tetrapropylammoni-
um perruthenate, NMO=N-methyl morpholine N-oxide].
ments: 1) heating an isolated sample of 53 (R1 =CO2Me, R2 =
CO2Et) in toluene at 1108C for 6 h gave 60 in 90% yield and
2) heating cubane diester 15 to 1108C in the presence of TPAP
did not give any of the corresponding COT derivative 45 (see
the Supporting Information). Electron deficient functionality di-
rectly appended to the cubane framework was found to be es-
sential for the progress of the tandem reaction: when homolo-
gated cubane-alcohol 32 was subjected to the tandem condi-
tions only cubane 67 was recovered (Scheme 7).
Conflict of interest
CSIRO (J.T. and G.P.S.) and UQ (C.M.W.) have a formal relation-
ship with Boron Molecular Pty Ltd. who supply cubane inter-
mediates.
Scheme 7. Failed tandem valence isomerization reaction. [DCM=dichloro-
methane, TPAP=tetrapropylammonium perruthenate, NMO=N-methyl mor-
pholine N-oxide, MS=molecular sieve].
Keywords: cubanes · cyclooctatetraenes · rhodium · tandem ·
valence isomerization
Lastly, some basic chemistry of the COT system was ex-
plored. Hydrogenation of COT 56 was investigated.[40] The reac-
tion proceeded in a straightforward fashion using Adams’s cat-
alyst (platinum oxide) in glacial acetic acid, giving the reduced
product, ethyl 3-cyclooctylpropanoate (68) in moderate yield
(43%). Hydrolysis of 1,4-disubstituted COT derivative 45 pro-
ceeded smoothly, giving the corresponding dicarboxylic acid
(69) in 47% yield (Scheme 8).
In conclusion, Eaton’s observation of rhodium(I)-catalyzed
valence isomerization of cubane to COT has been validated,
and the scope greatly extended, such that it can be used as a
synthetic protocol to access a wide range of mono- and 1,4-
disubstituted COT derivatives. Furthermore, a catalyst-free
tandem Wittig sequence was devised based on an in situ one-
step oxidation of cubane-alcohols, which further broadens the
scope of the methodology. Hydrogenation of COT derivatives
can provide access to substituted cyclooctyl derivatives, and
generally it is possible to hydrolyze COT esters.
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Manuscript received: October 11, 2018
[26] a) B. A. Chalmers, H. Xing, S. Houston, C. Clark, S. Ghassabian, A. Kuo, B.
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Version of record online: && &&, 0000
Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
5
ꢁ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Hydrocarbons
S. D. Houston, H. Xing, P. V. Bernhardt,
T. J. Vanden Berg, J. Tsanaktsidis,
G. P. Savage, C. M. Williams*
&& – &&
Releasing the strain! This work aims to
take Eaton’s rhodium(I)-catalyzed va-
lence isomerization of cubane to cyclo-
octatetraene (COT) to the next level.
Functional group tolerability, scope, and
limitations of this reaction were investi-
gated in the context of developing de-
ployable methodology for the increas-
ing number of applications involving
the COT ring system.
Cyclooctatetraenes through Valence
Isomerization of Cubanes: Scope and
Limitations
&
&
Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
6
ꢁ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!