Synthesis of 5-alkylidene-1,3-dioxane-4,6-diones, an easily accessible family of axially chiral alkenes: Preparation in non-racemic form and platinum binding studies

Article abstract of DOI:10.1039/b608785j

A general synthetic route to 5-alkylidene-1,3-dioxane-4,6-diones, which are a family of axially chiral alkenes, is described. Conformational issues are explored and the platinum-binding properties of these species are discussed. That these alkenes exist as stable enantiomers is established by their partial kinetic resolution upon reaction with cysteine. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b608785j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of 5-alkylidene-1,3-dioxane-4,6-diones, an easily accessible family
of axially chiral alkenes: preparation in non-racemic form and platinum
binding studies
Meritxell Casadesus, Michael P. Coogan* and Li-Ling Ooi
Received 21st June 2006, Accepted 18th August 2006
First published as an Advance Article on the web 14th September 2006
DOI: 10.1039/b608785j
A general synthetic route to 5-alkylidene-1,3-dioxane-4,6-diones, which are a family of axially chiral
alkenes, is described. Conformational issues are explored and the platinum-binding properties of these
species are discussed. That these alkenes exist as stable enantiomers is established by their partial
kinetic resolution upon reaction with cysteine.
primordial Earth experienced non-racemic irradiation prior to the
Introduction
development of biological chirality.1
Molecules in which one of the elements of chirality involves a
The classic example of a molecule which is chiral by virtue
of a double bond configuration is trans-cyclooctene, and this
of enantiomers may be achieved by alkene isomerisation. Alkenes
material has been shown to be capable of deracemisation by
carbon–carbon double bond are interesting in that interconversion
intense irradiation with circularly polarised u. v. (Scheme 1).2
This is an unusual example, however, in that irradiation can cause
not only interconversion of enantiomers, but also produces the
(achiral) cis-isomer. More recently alkylidene cyclohexanes have
emerged as one of the more interesting families of chiral molecules
which can be racemised by photochemical isomerisation of an
alkene,3 and indeed, these species have also been deracemised by
irradiation with circularly polarised light (Scheme 2). Amongst
other prominent molecules which have been photochemically
deracemised with circularly polarised light are the crowded helical
tetraaryls such as the 9,9ꢀ-oxo and thioxanthenylidenes which have
been studied by Feringa et al. (Scheme 3).4 The aim of the present
work was to develop routes which would allow rapid access to a
large and varied series of molecules which would both be capable
of photochemical racemisation (and potentially deracemisation)
via double bond isomerisation, and be crystalline, in order
to allow any enantiomeric excess obtained to be enhanced by
may be isomerised through many processes including irradiation
with the correct frequency of electromagnetic radiation (usually
u. v.) to induce diradical formation and thus lower the barrier to
rotation around the carbon–carbon bond, which upon relaxation
and reformation of the alkene results in isomerisation. In many
cases, instead of direct excitation of the alkene, irradiation excites
another group, often a carbonyl, which then transfers excitation to
the alkene, generating a species in which, again, the carbon–carbon
bond is formally single, allowing rotation and thus isomerisation.
In chiral molecules in which interconversion of enantiomers is
achieved by double bond isomerisation, this provides a path
for photochemical racemisation, or, in certain cases the use of
circular polarised light allows photochemical deracemisation.
Circularly polarised light is intrinsically chiral, and as such the
interaction with chiral molecules is diastereoisomeric, with each
enantiomeric form of circularly polarised light being absorbed
to a different extent by each enantiomer of the sample, with the
difference being referred to as the anisotropy factor De. Thus, when
irradiation of a racemic sample of substrate is carried out with a
single enantiomer of circularly polarised light, the enantiomer of
sample which has the highest extinction coefficient is racemised
faster than its enantiomer, which leads to an excess of the lower
absorbing enantiomer. As the De values for simple molecules are
small, typically ≤1% of the absolute extinction coefficients, the
enantiomeric excesses obtained in such experiments are usually
very small, but they are important examples of absolute asym-
metric induction, that is the induction of enantiomeric excesses by
reactions of racemic mixtures or achiral molecules, using only the
chirality of physical forces rather than chiral chemicals, and as
such have implications for the origins of biological homochirality,
as it has been observed that cosmic background radiation is
significantly circularly polarised at many wavelengths, and thus
Scheme 1
Department of Chemistry, Cardiff University, Park Place, Cardiff,
Wales/Cymru, UK CF10 3TB. E-mail: cooganmp@cf.ac.uk; Fax: + 44
02920 874030; Tel: +44 02920 874066
Scheme 2
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5-Alkylidene-1,3-dioxane-4,6-diones
There are a small range of examples of non-symmetrical examples
of 5-alkylidene-1,3-dioxane-4,6-diones known5 (there are many
examples of the symmetrical materials derived from Meldrum’s
acid), but there is no general method for their synthesis and
a literature search found no mention of their chirality. Thus it
was decided that a small range of alkylidene substituted non-
symmetrical analogues of Meldrum’s acid should be synthesised
in order to assess the ease of synthesis, stability and crystallinity
of these species and to allow their chirality to be confirmed.
There are two obvious routes to such materials: A) the synthesis
of alkylidene malonic acid derivatives, followed by cyclisation to
the non-symmetrical acetals; and B) the synthesis first of cyclic
malonate acetals, followed by their condensation with carbonyl
compounds (Scheme 4).
The first of these routes was attempted with condensation of
malonic acid with a variety of aromatic aldehydes giving the
alkylidene malonic acids 1a–c in acceptable to good yields (given
the availability of the starting materials no optimisation was
considered). These alkylidene malonic acids proved, however, to be
reluctant to condense with aldehydes or ketones to give the desired
products. A variety of reaction conditions, reagents and catalysts
were screened in an attempt to obtain cyclisation, concentrating
on Brønsted acids (TsOH, H2SO4, TFA) and standard dehydrating
reagents/conditions (Dean–Stark or acetic anhydride), but in
all cases the major products were either starting materials or
decomposition products, with no evidence of successful cyclisation
(we were able to compare crude spectra with the spectra of
the desired materials obtained later to confirm this conclusion)
(Scheme 5). It is possible that the lack of conformational freedom
in the alkylidene malonic acids is responsible for this reluctance
to cyclise. It is assumed that the ring-closing step would involve
generation of an oxonium ion by acid catalysed dehydration of
an intermediate hemiacetal, followed by nucleophilic attack at
the sp2 carbon. Although by the Baldwin-style analysis this is a
6-endo-trig cyclisation which is formally favoured, there may be
insufficient conformational flexibility in the highly unsaturated
backbone which would form the ring to allow the carboxylate to
approach the sp2 carbon at the Burgi–Dunitz angle.
Scheme 3
in situ crystallisation. A survey of the literature was made to find
the simplest routes to such species, and to find which families
were typically crystalline. Substituted cyclooctenes and methylene
cyclohexanes both suffer from low melting points (many are
liquid at ambient temperature), and the bixanthenylidenes, while
typically high melting solids, are not accessible by the simple one or
two step reactions which are useful if a large series of compounds
is sought, therefore attention turned to developing new families of
axially chiral alkenes.
Results and discussion
A consideration of the structural features required suggested
that a potentially viable route to double-bond chiral compounds
amenable to rapid analogue collection was the condensation of
aldehydes with an activated methylene group in a prochiral ring.
The direct analogues of the alkylidene cyclohexanes accessible
by this route would be the condensation products of simple
analogues of dimedone, which are available via condensations
of Michael acceptors with malonate esters, however a survey of
the literature in this area suggested that the precursors for the
condensations (5-monosubstituted cyclohexane-1,3-diones) were
best approached by routes which varied depending upon the nature
of the substituent, and in many cases would require 2 or more step
syntheses of the Michael acceptors, which while trivial moved
away from the desired rapid access to a range of analogues. The
dioxoanalogue of dimedone, Meldrum’s acid, however, seemed a
good candidate for studies as condensation of Meldrum’s acid
with aldehydes is known and high yielding and the substitution of
acetone for non-symmetrical ketones in the synthesis of Meldrum’s
acid analogues should allow for chirality. As two of the three
components in the synthesis are carbonyl compounds, a one-pot
synthesis is conceivable in which malonic acid is cyclised, then
condensed with the same carbonyl compound. In order to validate
this approach, therefore, and to demonstrate their chirality, a study
has been undertaken of 5-alkylidene-1,3-dioxane-4,6-diones.
In the light of the failure to obtain the desired species from this
approach, attention turned to the initial condensation to the un-
symmetrical Meldrum’s acid derivatives, followed by condensation
to the alkylidene species, which should suffer from no untoward
stereoelectronic effects. The condensation of Meldrum’s acid itself
with aldehydes and ketones is well known and a huge range of
Scheme 4
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Table 1 Yields of 5-alkylidene-1,3-dioxane-4,6-diones
R
Rꢀ
Rꢀꢀ
Yield (%)
Mpt/◦C
3a
3b
3c
3d
3e
4
Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
Ph
H
H
H
H
H
H
43
37
66
66
33
21
107–108
146–149
89–91
91–93
79–81
4-NO2–C6H4
2-NO2–C6H4
4-MeO–C6H4
CH(CH3)2
Ph
Scheme 5 (i) NH4OAc, EtOH; (ii) various conditions.
146–148
such derivatives is known, however substituting the gem-dimethyl
group of Meldrum’s acid with a non-symmetrical substitution
pattern was necessary for chiral products. The condensation
of malonic acid with aromatic aldehydes has been reported
to give the cyclic acetals6 however in the present study the
reaction of equimolar ratios of aromatic aldehydes with malonic
acid never gave this desired product cleanly, although a double
condensation did give useful materials (see below). The major
product from the reactions of aromatic aldehydes with malonic
acid under the high temperature conditions recommended for the
cycloacetalisation, in fact was in most cases the relevant cinnamic
acid derivative. These materials are formed from the condensation
used previously to give the alkylidene malonic acids, followed
by thermal decarboxylation. In order to retard the Knoevenagel
condensation to the alkylidene species, attention turned to the
use of ketones. In order to maintain crystallinity it was felt that
an aromatic substituent was desirable, and a methylene group
was also likely to be useful in order that diastereotopicity could
With a robust route to a crystalline non-symmetrical Meldrum’s
acid derivative, 2 the Knoevenagel condensations of this material
with a variety of ketones were studied. These reactions proceeded
smoothly with benzaldehyde, a variety of substituted benzalde-
hydes (2-nitro, 4-nitro, 4-methoxy) and with isobutyraldehyde.
All these products were highly crystalline and while the yields
were generally better with the substituted aromatic aldehydes,
even with benzaldehyde and isobutyraldehyde yields of around
50% were obtained after crystallisation of the products from
the reaction mixtures (Scheme 6; Table 1). Given the few steps
involved in the preparation of these species no attempt was made
to optimise the yields, or even to recover more of the product than
was simply delivered by crystallisation. To demonstrate that this
approach could provide a one-pot route to alkylidene malonates,
malonic acid and an excess of benzaldehyde were reacted under
the conditions used for the synthesis of 1, and the derived
alkylidene malonate was recovered by crystallisation, albeit in a
low yield (Scheme 7; Table 1). Although all of the ketone-derived
species were synthesised from benzyl acetone, as these synthetic
approaches work equally well for the chiral materials derived from
benzyl acetone and the acetone derivatives, it seems likely that this
chemistry would be applicable to derivatives of a wide range of
aliphatic ketones, giving a vast scope to the species available.
1
be observed in the H NMR, which could confirm the chirality
of the products. The attempted condensation of malonic acid
with acetophenone following the literature method which had
proven to be the highest yielding route to Meldrum’s acid7 gave
none of the desired product (from NMR and mass spectroscopy
of the crude reaction mixtures). The literature8 suggested that
the condensation of malonic acid with aromatic ketones gives
not the 1,3-dioxane-4,6-diones but instead tends to condense via
nucleophilic attack at the ketone, often followed by dehydration
and decarboxylation to the unsaturated acid. Therefore, benzyl
acetone was selected as an aliphatic ketone which has both an
aromatic substituent and methylene groups, while the carbonyl
group is more similar to acetone than the carbonyl of an aromatic
ketone. (A range of alkylidene malonates derived from benzyl
acetone have been prepared on solid supports as intermediates in
solid-phase synthesis9 however they were not liberated from the
support in this form and no comment was made on chirality.) The
condensation of benzyl acetone with malonic acid was investigated
under a variety of conditions, with the product mixtures varying
greatly with temperature, pH and reagents. Eventually it was found
that a variation of a literature7 procedure for Meldrum’s acid
provided the most reliable route to 2-methyl-2-(2-phenylethyl)-
1,3-dioxane-4,5-dione 2, whereby excess malonic acid was reacted
with benzyl acetone in the presence of acetic anhydride and sulfuric
acid. The excess malonic acid is easily removed by filtration of
a solution of the crude reaction product in dichloromethane,
and after evaporation the cyclic acetal slowly crystallises from
the by-products in good yield. Interestingly this material is very
susceptible to hydrolysis and must be stored under anhydrous
conditions, in stark contrast to Meldrum’s acid itself, which while
having some hydrolytic instability is much more robust than the
benzyl derivative considered here.
Scheme 6 (i) H2SO4, Ac2O; (ii) NH4OAc.
Scheme 7 (i) H2SO4, Ac2O
These species proved to be considerably less susceptible to
hydrolysis than the parent compound, in fact surviving prolonged
exposure to water in a 2-phase system (see below). This hydrolytic
stability is, presumably, the reversal of the Burgi–Dunitz angle
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argument which precluded the formation of these species by
cyclocondensation. In the same way that although malonic acid
easily cyclo-condenses with ketones, alkylidene malonic acids seem
to have insufficient conformational flexibility to allow the ring
closure step to take place. It is likely that, while the methylene
species is susceptible to hydrolysis, the alkylidene analogues are
too rigid to allow an oxygen lone pair to align anti periplanar to
the carbon–oxygen bond (i.e. syn periplanar with the r* orbital)
which must be broken in hydrolysis.
and only benzyl acetone is observed as a discrete product of the
fragmentation (Scheme 8).
With a range of 5-alkylidene-1,3-dioxane-4,6-diones in hand
which had been designed to show chirality, their 1H NMRs were
examined for evidence of diastereotopicity in the signals from
the methylene groups. Rather than the simple pairs of triplets
predicted by first-order coupling for the methylene groups of
the 2-phenylethyl substituent, a pair of complex multiplets were
observed. However, this could not be attributed to molecular
chirality as the same phenomenon is observed in these signals
in the precursor 2 which formally has a plane of symmetry and is
thus necessarily achiral. The non-first order nature of this region of
the spectrum was unexpected, and could reflect a preferred twisted
conformation of the six-membered ring with a trans arrangement
of carbonyls in which the plane of symmetry associated with the
cis form is lost (Fig. 1). In the solid state at least, however, many
analogues, and indeed Meldrum’s acid itself exist in the cis form10
and thus the complex NMR is more likely to be the result of
anisogamy, i.e. magnetic nonequivalence due to different coupling
constants to the vicinal proton barriers in the chain.
Scheme 8 (i) Xylene reflux.
As chiral stationary phase chromatography seemed unsuitable
for establishing the stability of the enantiomers, attention turned
to NMR chiral shift reagents. As it was expected that the esters
of the alkylidene malonates would have a reasonable negative
character and thus hydrogen-bonding ability, attempts were made
to resolve the enantiomers with the use of the Eu-based shift
reagent Eu(HFC)3. Although at certain ratios of shift reagent to
substrate there was evidence that single peaks were becoming
split, it was impossible to achieve separation between peaks
which would allow a determination of the kinetic parameters for
racemisation, and thus establish the stability of the new chiral
system. As these chiral shift reagents seemed to be unsuitable for
the molecules in question, attention turned to a different kind of
chiral metal complex which has been used in e. e. determinations
of unsaturated systems. Parker et al. showed11 that it is possible
to use the phosphorus NMR signals of homochiral platinum
DIOP complexes to determine the e. e. of coordinated alkenes.
Ethylene(DIOP)Pt0 reacts with a wide range of alkenes with
displacement of ethylene to give the alkene Pt complex. In the
case of chiral alkenes, the resultant complexes exist as mixtures
of diastereoisomers, which are seen as inequivalent in the 31P
NMR allowing the determination of the e. e. of the alkenes.
The 31P spectra are often complex, as unsymmetrically substituted
alkenes lead to the 31P nuclei in each molecule being inequivalent
and coupling to each other, in addition to the Pt–P coupling in
that fraction of the sample containing the spin-active Pt nucleus,
thus giving 12 signals per diastereoisomer. Fortunately the large
spectral range of 31P NMR usually leads to well separated signals
allowing determination of e. e. In the case of 5-alkylidene-1,3-
dioxane-4,6-diones, the case is further complicated by the existence
of two inequivalent faces of the alkene, doubling the number of
isomers which can result from the complexation (Scheme 9).
Fig. 1 Conformers of 1,3-dioxane-1,6-diones.
As this complex system is observed even in the achiral unsub-
stituted species, the use of NMR measurements to characterise
molecular chirality was inappropriate. Although the molecules
must necessarily exist as a pair of enantiomers, it was thought
possible that they may be unstable to racemisation through an
addition–elimination mechanism. The extremely polarised nature
of the alkene, due to its conjugation with two carbonyls could lower
the barrier to rotation, or a mechanism for racemisation could
operate whereby polar solvents, or lone pairs of other molecules,
act as nucleophiles in a Michael-addition–retro-Michael sequence,
allowing racemisation. Given the possibility therefore that these
species may not exist as stable enantiomers it was essential to
investigate their stability, and as NMR was unsuitable, other
methods were examined. None of the chiral HPLC columns tested
(Chirocel OD, OJ) gave any separation between enantiomers, and
it became apparent that GC was leading to decomposition. Mass
spectra recorded at temperatures similar to the GC conditions
showed that a fragmentation had occurred at high temperature
(this was also observed in refluxing xylene) whereby the parent
ketone (benzyl acetone) is eliminated from the ring. In the mass
spectrum cationic fragments are observed correlating to the mass
of the remaining portion of the molecule. In experiments, however,
these fragments are lost as a mixture of decomposition products,
Scheme 9
The reaction of 5-(4-nitrobenzylidene)-2-methyl-2-(phenyl-
ethyl)-1,3-dioxane-4,6-dione 3b with Pt0 (DIOP)ethylene in d6-
benzene gave a spectrum with 32 peaks, 16 centred around 7.5 ppm
and 16 symmetrically separated around the central peaks at
−8 ppm and 23 ppm, assigned to the 195Pt satellites (Fig. 2). By a
consideration of the ratios of signal intensities, a certain degree of
assignment of the signals was possible. As the sample was racemic,
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Fig. 2 31P NMR spectrum of 3b coordinated to Pt–DIOP.
Table 2 31P NMR data for the main facial isomer (minor facial isomer
and it is common for little kinetic resolution to be observed in these
complexations, it was expected that the ratio of diastereoisomers
resulting from the reaction of the enantiomerically pure DIOP
complex with the racemic alkene would be close to unity. However,
it was expected that there could be a large degree of selectivity
of which face of the alkene is complexed, as one face will
experience more steric strain as a result of the conformation of
the six-membered ring being distorted by the non-symmetrical
substitution in the 5-position. The typical configuration of these
rings is largely planar with the 5-carbon out of the plane of the
ring in an envelope-type conformation.12 One of the substituents
is in a pseudo-equatorial position, far from the ring and with no
role in blocking the coordination of the alkene, while the other
is in a pseudoaxial position which will experience diaxial type
interactions with the lone-pairs of the 1,3 oxygens, and will interact
with incoming complexes to retard coordination of that face of the
alkene. It is reasonable to suppose that the favoured conformation
will have the larger group in the pseudoequatorial position, and
thus it is likely to be the face of the alkene which is syn to the
smaller substituent (in this case the methyl group) which is more
hindered, and therefore coordination of Pt occurs predominantly
on the same face as the phenethyl group. As each of the isomers
thus formed should give two doublets, correlated pairs of peaks
were easily assigned by their mutual JPP. The remaining sets of
peaks were assigned as pairs of diastereoisomers on the basis of
intensities, with the isomers resulting from facial differentiation in
complexation being in an approximate 10 : 1 ratio, and with these
sets, the pairs of diastereoisomers reflecting the racemic nature
of the sample apparently being in a 10 : 11 ratio. The assumption
behind these assignations is that the relaxation times of the isomers
will be similar and thus the 31P line intensities can be taken as
almost quantitative. In this context it would appear that there has
been some slight kinetic resolution in the complex formation to
give the 10 : 11 ratio, however this could be calculated for in e. e.
determination on a non-racemic sample. A tentative assignment
of individual 31P nuclei in each complex can be made from the
sidebands are too weak to accurately measure Pt–P data)
Diastereoisomer dp/ppm dpꢀ/ppm
J
J
Pt,P/Hz
JPt,P /Hz
ꢀ
P,P /Hz
ꢀ
Major
Minor
7.12
8.28
7.62
6.77
27
27
4326
4326
3228
3231
magnitude of the value of JPt,P in each case. The magnitude of JM,P
in complexes is highly dependent on the trans influence, with p
acidic ligands leading to low values.13 This effect is particularly
pronounced in square planar complexes and given that one of the
carbon atoms in the complex has two ester groups, it is likely to
be highly p acidic and thus gives very low values for JP,P . These
assignments are summarised in Table 2.
P and Pꢀ have been determined from the magnitude of JPt–P
as the 31P nuclei trans to the benzylidene carbon and C5 of the
ring respectively. The low value of JPP (27 Hz compared to 59 to
72 Hz in similar complexes) is again considered more likely to be
a result of the extremely electron deficient system lowering Fermi
contact through the P–Pt–P system, rather than the variation in
bond angles which usually explains variations in P–M–P coupling.
In this case the fact that in comparison with literature examples12
the P–M–P system is unaltered, and only the trans ligand varies
between our systems and the literature examples militates against
this line of reasoning. Other spectra were less clearly resolved than
this example, with apparently only one isomer being observed
in the case of 3d and 4. These complexes were of very low
solubility and it is more likely that preferential crystallisation
of one isomer led to this observation than kinetic resolution in
complex formation. Conformational isomerism (hindered rotation
around the C–C bond between the alkene and the 2-nitrophenyl
group) is assumed to lead to the doubling of the peaks for 3c.
In order to justify our conclusion that the phenethyl group
would take up the pseudoequatorial position, thus rendering
the face of the double bond syn to the methyl group more
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Fig. 3 ORTEP14 views (50%) of 3d showing molecular structure, and how the methyl group sterically hinders the C12 C14 double bond.
=
hindered, the X-ray crystal structure of one of the compounds,
2d the methoxyphenyl substituted example, was determined. The
structure (Fig. 3) clearly shows the carbonyls in a cis conformation,
with the envelope formed by the C-5 having the phenethyl group
in a pseudoequatorial position and thus the methyl group causes
severe hindrance of the syn face of the double bond.
alkylidene malonates. Although these results were disappointing
in that reproducible kinetic resolution was not achieved (thus no
data for optical rotations are given in the experimental section),
samples of optically enriched alkylidene malonates were in fact
obtained for all of the species examined (Scheme 10).
Although there was now crystallographic evidence that the
alkylidene malonate esters adopted necessarily chiral confor-
mations, and the Pt0 complexes appeared to be capable of
allowing differentiation of enantiomers by the formation of
diastereoisomers in the 31P NMR, this is not evidence of the
existence of stable enantiomers which do not easily interconvert,
which would render the new family of chiral species useless.
In order to investigate the stability of the enantiomers towards
interconversion, a partial kinetic resolution was attempted. As
the alkene of the alkylidene malonates is conjugated with two
ester groups, it seemed likely to be reactive towards the addition
of nucleophiles. A series of chiral nuclophiles was screened for
reaction with alkylidene malonates. The only one which gave
an irreversible reaction appeared to be L-cysteine. The adducts
formed upon reaction of L-cysteine with a series of alkylidene
malonates were insoluble in all but the most polar of organic
solvents and were hydroscopic and unstable, however they were
shown to be the required Michael addition products in the more
easily handleable cases by NMR and mass spectrometry, although
full characterisation was not achieved. A series of attempts was
made to achieve kinetic resolution of the alkylidene malonates by
simply reacting half an equivalent of L-cysteine in ethanol with
the alkylidene malonates, then purifying the unreacted alkylidene
malonate using the extreme insolubility of these compounds by
evaporation of the reaction mixture followed by dissolution in
chlorinated solvents and filtering off both the adducts, and any
unreacted amino acid. The results of these attempts were mixed,
with in some cases optical activity being observed in the alkylidene
malonates, and in other cases racemic material being recovered.
Attempts to standardise the procedures failed to give reproducible
results, and this was assigned to the low solubility of both the
reactants in ethanol, which leads to irreproducibility in the ratios
of each reactant in solution due to difficult-to-control variables
such as rate of stirring and particle size. Varying the solvent
from alcohols gave no reaction at all, presumably as in non-polar
organics the amino acid is completely insoluble. In highly polar
organics the nucleophilicity of the L-cysteine may be moderated (or
retro-Michael promoted) and when the reaction was attempted in a
two phase system with the alkylidene malonate in an organic phase,
rapidly stirred with a solution of cysteine, very little or no reaction
was observed and no optical activity was observed in the unreacted
Scheme 10
The optical activity could be incontrovertibly assigned to the
alkylidene malonates as, along with them showing perfect spectral
purity, in all cases the sign of the optical rotation observed was neg-
ative, while both L-cysteine and the adducts have positive optical
rotations. The stability of these species towards racemisation was
established by following the optical activity over long periods of
time, at elevated temperatures and in a variety of solvents. Along
with the possibility that the high degree of polarisation of the
alkene could render its natural barrier to rotation (racemisation)
low, the possibility exists that polar solvents may catalyse the
racemisation. It was possible to demonstrate that the natural
barrier to rotation is high enough for these to be considered as true
atropisomers, fulfilling the Oki criteria,15 and going much further
in that no loss of optical rotation was observed over many days
in solution at ambient temperature. In order to demonstrate that
polar solvents do not racemise these compounds by a Michael-
addition–retro-Michael sequence, they were heated in acetone and
ethanol with no loss of optical rotation being observed. Attempts
to determine the e. e.s of the optically enriched samples using the
Pt0 method failed, with apparently racemic spectra being recorded,
presumably an indication of a very low degree of enantiomeric
excess resulting from poor kinetic resolution.
Conclusion
It has been demonstrated that 5-alkylidene-1,3-dioxane-4,6-diones
are an easily accessible family of axially chiral alkenes which show
barriers to racemisation which allow them to be considered as
stable enantiomers.
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malonic acid (26.62 g, 256 mmol) and ammonium acetate (0.10 g,
1.3 mmol) in ethanol (40 mL) was stirred under nitrogen at
room temperature for 5 days. The solvent was evaporated until
dryness and the solid residue was dissolved in ethyl acetate. The
product was extracted then with sodium hydroxide, precipitated
with hydrochloric acid and collected by filtration to give 1.35 g
(42.6%) of 1c.17 dH (400 MHz, CD3OD) 7.80 (d, 1H, 3J = 8.0 Hz,
ArH-6), 7.90 (dd, 1H, 3J = 8.0 Hz, 3J = 7.0 Hz, ArH-5), 8.00 (dd,
Experimental
General experimental
All starting materials and reagents were purchased from commer-
cial suppliers and used as supplied unless otherwise stated. H
1
and 13C NMR spectra were recorded on a Bruker DPX 400 MHz
at 400 MHz (proton) and 160 MHz (carbon), or an APX 250 at
250 MHz and 100 MHz respectively. 31P NMR were recorded on a
Jeol at 121 MHz. IR spectra were recorded on a Perkin Elmer 1600
FT IR as thin films or nujol mulls; mass spectra were recorded
on a VG Fisons Platform II or at the EPSRC national mass
spectrometry service in Swansea (HRMS). Elemental analyses
were performed by Warwick Analytical Services (University of
Warwick).
3
3
=
1H, J = 8.0 Hz, J = 7.0 Hz, Ar H-4), 8.40 (s, 1H, CH C), 8.50
(d, 1H, 3J = 8.0 Hz, ArH-3). Mp 151–154 ◦C.
2-Methyl-2-(2-phenylethyl)-1,3-dioxane-4,6-dione
(2). The
synthesis of 2-methyl-2-(2-phenylethyl)-1,3-dioxane-4,6-dione (2)
was performed following a similar procedure to that described
in the literature.7 A mixture of 4-phenyl-2-butanone (45 mL,
300 mmol), malonic acid (20.8 g, 200 mmol) and sulfuric acid
(0.6 mL, 12 mmol) was added to a Schlenk, under nitrogen. It
was stirred for 15 min at room temperature and acetic anhydride
(24 mL, 250 mmol) was then added very slowly. The mixture
was stirred at room temperature for 18 hours. The solvent was
evaporated until dryness, and the remaining solid was dissolved
in dichloromethane, filtered, and recrystallised from ethyl acetate
and petrol to give 5.39 g (11.5%) of 2. dH (400 MHz, CDCl3)
1.75 (s, 3H, CH3), 2.29 (m, 2H, CH2–CH2–Ph), 2.86 (m, 2H,
CH2–CH2–Ph), 3.60 (s, 2H, CH2(CO)2), 7.10 (m, 3H, PhH-3,4,5),
7.25 (m, 2H, Ph-2,6). dC (101 MHz, CDCl3): d 26.53, 29.46,
Crystallographic data for 3d: C21H20O5, crystal system mon-
oclinic; space group P21/a; a = 9.6549(2), b = 12.9703(3), c =
˚
14.7696(4) A, a = 90, b = 108.6430(10), c = 90; Z = 4; T = 150(2)
−1
˚
K; l = 0.095 mm ; k = 0.71069 A (MoKa); F(000) 744; 3.14 <
h < 27.48; 20365 reflections, 3980 unique [R(int) = 0.0826]; R1 =
0.0524, wR2 = 0.1052 [I > 2r(I)]; R1 = 0.0899, wR2 = 0.1171 (all
data).†
3-(4-Methoxyphenyl)-2-carboxy-2-propenoic acid (1a). The
synthesis of 3-(4-methoxyphenyl)-2-carboxy-2-propenoic acid (1)
was performed following a procedure described in the literature.16
A mixture of p-anisaldehyde (9.0 mL, 55 mmol), malonic acid
(11.44 g, 110 mmol) and ammonium acetate (0.04 g, 0.52 mmol) in
ethanol (25 mL) was stirred under nitrogen at room temperature
for 7 days. The solvent was then evaporated until dryness, the
solid residue was dissolved in ethyl acetate, extracted then with
sodium hydroxide, precipitated with hydrochloric acid and finally
a solid was collected by filtration to give 5.46 g (44.7%) of 1a.17
36.64, 42.59, 107.64, 126.91, 128.69, 129.13, 140.12, 163.27. mmax
:
1781, 1744 cm−1. Mp 85–87 ◦C. C13H14O4 requires C 66.66 H 6.02
found C 65.99 H 6.04%.
5-Benzylidene-2-methyl-2-phenylethyl-1,3-dioxane-4,6-dione (3a).
A mixture of 4 (0.47 g, 2 mmol), benzaldehyde (0.24 mL, 2.4 mmol)
and ammonium acetate (1.5 mg, 0.002 mmol) in ethanol (10 mL)
was stirred at room temperature for 18 h. A white solid was
collected by filtration and washed with cold ethanol, to afford
0.276 g (43%) of 3a. dH (400 MHz, CDCl3) 1.75 (s, 3H, CH3),
2.23 (m, 2H, CH2–CH2–Ph), 2.82 (m, 2H, CH2–CH2–Ph), 7.15
(m, 3H, CH2PhH-3,4,5), 7.23 (app. t, 2H, 3J = 6.5 Hz), 7.42 (m,
3
dH (400 MHz, CD3OD) 3.75 (s, 3H, CH3O), 6.85 (dd, 2H, J =
4
3
4
7.1 Hz, J = 1.7 Hz, Ar-H2,6), 7.45 (dd, 2H, J = 7.1 Hz, J =
◦
1.7 Hz, Ar-H3,5), 7.55 (s, 1H, CH C). Mp 207–209 C (lit.17
=
204–205 ◦C).
3-(4-Nitrophenyl)-2-carboxy-2-propenoic acid (1b). The syn-
thesis of 3-(4-nitrophenyl)-2-carboxy-2-propenoic (2) acid was
performed following a procedure similar to the one described
in the literature.17 A mixture of p-nitrobenzaldehyde (2.02 g,
13.37 mmol), malonic acid (2.87 g, 27.57 mmol) and ammonium
acetate (0.01 g, 0.13 mmol) in ethanol (25 mL) was stirred under
nitrogen at room temperature for 14 days. The solvent was then
evaporated until dryness, and the solid residue was dissolved in
ethyl acetate. The product was extracted with sodium hydroxide,
precipitated with hydrochloric acid and collected by filtration to
give 1.35 g (42.6%) of 1b.17 dH (400 MHz, CD3OD) 7.65 (s, 1H,
2H, CHPhH-3,5), 7.51 (app. t, 1H, 3J = 7.0 Hz, CHPhH-4), 7.99
3
=
(app. d, 2H, J = 7.72 Hz, CHPhH-2,6), 8.39 (s, 1H, CH C). dC
(101 MHz, CDCl3): d 26.68, 29.61, 42.57, 105.97, 115.06, 126.78,
128.75, 129.08, 129.18, 132.06, 134.13, 134.22, 140.52, 158.83,
160.13, 163.72. Mp 107 ◦C. m/z (EI/CI MS) 173.9, 91.1, 43.2.
C20H18O4 requires C 74.52, H 5.63, N 0.00; found C 74.31, H 5.69,
N 0.07%.
5-(4-Nitrobenzylidene)-2-methyl-2-(phenylethyl)-1,3-dioxane-4,6-
dione (3b). A mixture of p-nitrobenzaldehyde (0.75 g, 5 mmol),
2 (1 g, 4.3 mmol) and ammonium acetate (0.003 g, 0.004 mmol) in
ethanol (10 mL) was stirred under nitrogen at room temperature
for 3 hours. A yellow solid was then collected by filtration and
recrystallised from ethanol, to afford 0.59 g (37%) of 3b. dH
(400 MHz, CDCl3) 1.75 (s, 3H, CH3), 2.20 (m, 2H, CH2–CH2–
Ph), 2.75 (m, 2H, CH2–CH2–Ph), 7.15 (m, 3H, PhH-3,4,5), 7.20
3
3
=
CH C), 7.70 (d, 2H, J = 8.7 Hz, Ar-H2,6), 8.2 (d, 2H, J =
8.8 Hz, Ar-H3,5). Mp 242–244 ◦C.
3-(2-Nitrophenyl)-2-carboxy-2-propenoic acid (1c). The syn-
thesis of 3-(2-nitrophenyl)-2-carboxy-2-propenoic acid (3) was
performed following a procedure similar to that described in the
literature.17 A mixture of o-nitrobenzaldehyde (14.70 g, 128 mmol),
3
(m, 2H, Ph-H2,6), 8.00 (d, 2H, J = 7.0 Hz, ArH-2,6), 8.25 (dd,
3
4
=
2H, J = 7.0 Hz, J = 1.8 Hz, Ar-H3,5), 8.40 (s, 1H, CH C). dC
(101 MHz, CDCl3) 26.97, 29.59, 42.66, 106.69, 118.78, 123.98,
126.91, 128.72, 129.14, 133.52, 137.80, 140.21, 149.92, 155.13,
† CCDC reference number 611771. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b608785j
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159.29, 162.55. Mp 146–149 ◦C. mmax: 1729, 1529, 1350 cm−1.
C20H17NO6 requires C 65.39, H 4.66, N 3.81; found C 65.22, H
4.64, H 3.78%. m/z (EI) 367.
added very slowly and the mixture was stirred at room temperature
for 18 h. A white solid was collected by filtration and it was
recrystallised from ethyl acetate and petrol to obtain 2.26 g (21%)
of 4.17 dH (400 MHz, CDCl3) 6.70 (s, 1H, sp3CHPh), 7.40 (m, 5H,
3
=
5-(2-Nitrobenzylidene)-2-methyl-2-(phenylethyl)-1,3-dioxane-4,6-
dione (3c). A mixture of o-nitrobenzaldehyde (0.76 g, 5 mmol),
2 (1.0 g, 4.3 mmol) and ammonium acetate (0.003 g, 0.004 mmol)
in ethanol (6 mL) was stirred under nitrogen at room temperature
for 18 hours. A yellow solid was then collected by filtration
and recrystallised from ethanol, to give 1.03 g (66%) of 3c. dH
(400 MHz, CDCl3) 1.75 (s, 3H, CH3), 2.22 (m, 2H, CH2–CH2–
Ph), 2.83 (m, 2H, CH2–CH2–Ph), 7.15 (m, 3H, PhH-3,4,5), 7.24
sp CHPhH-2–6), 7.50 (m, 3H, C CHPhH-3,4,5), 7.95 (dd, 2H,
3
4
=
=
J = 8.0 Hz, J = 1.4 Hz, C CHPhH-2,6), 8.30 (s, 1H, C CH).
dC(101 MHz) 97.11, 116.1, 126.85, 129.30, 131.16, 131.85, 133.26,
134.11, 134.56, 159.58, 161.25, 164.55. Mp 146–148 ◦C. m/z (ES)
280.2 (M+).
General procedure for deracemisation of benzylidene malonates.
A mixture of the benzylidene malonate (2.18 mmol) and L-cysteine
(0.132 g, 1.09 mmol) in 20 mL of ethanol was stirred at room
temperature for 18 h. The solvent was then evaporated and the
solid residue was dissolved in 200 mL of CH2Cl2. The product
was collected in the filtrate, by evaporation of the DCM, and
3
4
3
(dd, 2H, J = 7.1 Hz, J = 1.8 Hz, PhH-2,6), 7.42 (d, 1H, J =
7.7 Hz, ArH-6), 7.60 (m, 1H, ArH-5), 7.68 (m, 1H, ArH-4), 8.24
3
4
=
(dd, 1H, J = 8.2 Hz, J = 1.1 Hz), 8.76 (s, 1H, CH C). dC
(101 MHz, CDCl3): d 27.02, 29.57, 42.63, 106.83, 118.04, 125.28,
126.82, 128.74, 129.08, 130.27, 130.67, 131.34, 134.25, 140.35,
146.69, 156.46, 159.36, 161.919. Mp 89–91 ◦C. mmax 1777, 1743,
1531, 1336 cm−1. C20H17NO6 requires C 65.39, H 4.66, N 3.81;
found C 65.12, H 4.64, N 3.72%. m/z (APCI) 368 (M + 1), 266
(M − 102), 220 (M − 148).
1
its purity was confirmed by H NMR and the optical rotation
recorded in dichloromethane solution. The observed rotations
were inconsistent, but when non-zero were always negative. The
adducts were insoluble in dichloromethane. Examination of the
insoluble fraction by NMR showed mixtures of adducts, the acids
derived from hydrolysis of the dioxane ring, and other unidentified
materials. Homogeneous products were never isolated and partial
characterisation is listed below.
5-(4-Methoxybenzylidene)-2-methyl-2-(phenylethyl)-1,3-dioxane-
4,6-dione (3d). A mixture of p-anisaldehyde (1.12 mL, 10 mmol),
2 (2 g, 8.6 mmol) and ammonium acetate (0.006 g, 0.008 mmol) in
ethanol (10 mL) was stirred under nitrogen at room temperature
for 24 h. A bright yellow solid was then collected by filtration
and recrystallised from ethanol, to give 2.00 g (66%) of 3d. dH
(400 MHz, CDCl3) 1.68 (s, 3H, CH3), 2.22 (m, 2H, CH2–CH2–
Ph), 2.80 (m, 2H, CH2–CH2–Ph), 3.83 (s, 3H, OCH3), 6.93 (dd,
2H, 3J = 7.1 Hz, 4J = 1.8 Hz, ArH-3,5), 7.18 (m, 3H, PhH-3,4,5),
Deracemisation of 5-(4-nitrobenzylidene)-2-methyl-2-(phenyl-
ethyl)-1,3-dioxane-4,6-dione (3b). Adduct: HRMS calculated
mass for C23H24N2O8S [M + H]+ 489.1326; measured mass [M +
H]+ 489.1324.
Deracemisation of 5-benzylidene-2-phenyl-1,3-dioxane-4,6-dione
(4). Following the above procedure for deracemisation, a sec-
ond reasonably homogeneous product was observed in the
dichloromethane-insoluble material, apparently a mixture of two
diastereoisomeric acids derived from hydrolysis of the adducts.
Diastereoisomer A (55%): dH (400 MHz, CDCl3) 3.20 (dd, 1H,
2J = 10.2 Hz, 3J = 4.5 Hz, CHHS), 3.36 (dd, 1H, 2J = 10.2 Hz,
3
4
7.22 (m, 2H, PhH-2,6), 8.17 (dd, 2H, J = 7.1 Hz, J = 1.8 Hz,
=
ArH-2,6), 8.35 (s, 1H, CH C). dC (101 MHz, CDCl3) 26.52,
29.62, 42.51, 56.13, 105.54, 111.04, 114.81, 125.13, 126.70,
128.76, 129.04, 138.20, 140.69, 158.61, 160.88, 164.53, 165.14.
Mp 91–93 ◦C. mmax: 1722 cm−1. C21H20O5 requires C 71.58, H 5.72;
found C 71.41, H 5.61%. m/z (EI) 352.2.
3J = 7.1 Hz CHHS), 4.30 (dd, 1H, J = 4.5 Hz, J = 7.0 Hz,
CHCH2S), 7.39 (m, 3H, PhH-3,4,5), 7.51 (app. d, 2H,3J = 7.3 Hz,
Ph-H2,6). Diastereoisomer B (45%): dH (400 MHz, CDCl3) 3.13
3
3
5-Isobutylidene-2-methyl-2-(2-phenylethyl)-1,3-dioxane-4,6-dione
(3e). A mixture of isobutanone (0.91 mL, 10 mmol), 2 (0.94 g,
4.00 mmol) and ammonium acetate (0.003 g, 0.004 mmol)
dissolved in 10 mL of ethanol was stirred under nitrogen at
room temperature for 18 hours. A white solid was collected by
filtration and recrystallised from ethanol to give 0.46 g (33%)
2
3
(dd, 1H, J = 9.9 Hz, J = 9.0 Hz), 3.42 (dd, 1H, 2J = 10.0 Hz,
3J = 7.1 Hz), 3.96 (dd, 1H, J = 8.7 Hz, J = 7.2 Hz), 7.39 (m,
3H), 7.58 (d, 2H, 3J = 8.2 Hz). HRMS calculated for C20H19NO6S
(adduct) [M − H] 400.0860; measured mass [M − H] 400.0864.
3
3
3
of 3e. dH (250 MHz, CDCl3) 1.08 (d, 3H, J = 6.6 Hz, 1/2 ×
General procedure for coordination of Pt(0)–(S)–DIOP ethene
to benzylidene malonates. Pt(0)–(S)–DIOP ethene (40 mg,
0.055 mmol) was dissolved in C6D6 (0.7 mL). To the solution
was then added an excess of benzylidene malonate and the
mixture was shaken well for 2 min and the 31P NMR recorded
immediately. Low solubility of complexes derived from 3d, 4 led
to lack of observation of 195Pt satellites. Conformational isomerism
(hindered rotation around the C–C bond between the alkene and
the 2-nitrophenyl group) is assumed to lead to the doubling of the
peaks for 3c.
CH(CH3)2), 1.11 (d, 3H, 3J = 6.6 Hz, 1/2 × CH(CH3)2), 1.67 (s,
3H, C(CH3)(2-Ph–Et)), 2.15 (m, 2H, CH2–CH2–Ph), 2.78 (m, 2H,
CH2–CH2–Ph), 3.71 (dh, 1H, J = 10.6 Hz, 6.6 Hz, CH(CH3)2),
7.10 (m, 3H, PhH-3,4,5), 7.20 (m, 2H, PhH-2,6), 7.65 (d, 1H,
=
J = 10.6 Hz, CH C). dC (101 MHz, CDCl3) 21.54, 21.86, 26.78,
29.52, 30.01, 42.57, 106.19, 116.55, 126.77, 128.71, 129.06, 140.50,
◦
160.03, 162.55, 174.38. Mp 79–81 C. mmax: 1731 cm−1. m/z (ES)
288.2 (M). C17H20O4 requires C 70.83, H 6.91, N 0.00; found C
70.29, H 6.97, N 0.09%.
5-Benzylidene-2-phenyl-1,3-dioxane-4,6-dione (4). A mixture
of benzaldehyde (11.4 mL, 112.5 mmol), malonic acid (10.4 g,
100 mmol) and sulfuric acid (0.30 mL, 6 mmol) was stirred at
5-Benzylidene-2-methyl-2-phenylethyl-1,3-dioxane-4,6-dione (3a).
dP (121 MHz, C6D6) 10.22 (J = 35.5 Hz), 9.32 (J = 35.5 Hz), 8.39
(J = 35.5 Hz), 7.99 (J = 32.5 Hz), 7.24 (J = 35.5 Hz), 5.29 (J =
35.5 Hz).
◦
0 C for 15 min. Acetic anhydride (12 mL, 125 mmol) was then
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5-(4-Nitrobenzylidene)-2-methyl-2-(phenylethyl)-1,3-dioxane-4,6-
dione (3b). dP (121 MHz, C6D6) 7.12 (JPP = 27 Hz, JPtP
References
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JPtP = 4326 Hz), 6.77 (JPP = 27 Hz, JPtP = 3231 Hz). m/z (ES).
Theoretical isotope model [M + H]+ 1060.3 (62%), 1061.3 (100%),
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data 1060.3 (30%), 1061.3 (73%), 1062.4 (100%), 1063.5 (27%),
1064.5 (10%). Theoretical isotope model [M + Na]+ 1082.2 (62%),
1083.2 (100%), 1084.2 (98%), 1085.3 (41%), 1086.3 (25%), 1087.3
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5-(2-Nitrobenzylidene)-2-methyl-2-(phenylethyl)-1,3-dioxane-4,6-
dione (3c). dP (121 MHz, C6D6) 8.52 (J = 29.6 Hz), 8.05 (J =
29.6 Hz), 7.50 (J = 26.7 Hz), 7.05 (J = 29.6 Hz), 6.80 (J =
29.6 Hz), 5.24 (J = 29.6 Hz).
5-(4-Methoxybenzylidene)-2-methyl-2-(phenylethyl)-1,3-dioxane-
4,6-dione (3d). dP (121 MHz, C6D6) 9.72 (J = 35.5 Hz), 8.42
(J = 35.5 Hz).
5-Benzylidene-2-phenyl-1,3-dioxane-4,6-dione (4). dP (121 MHz,
C6D6) 10.89 (J = 32.6 Hz), 6.84 (J = 32.6 Hz).
13 Joan Mason, Multinuclear NMR, Plenum Press, New York,
1987.
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Meritxell Casadesus. We thank Robert L. Jenkins and Robin Hicks
(Cardiff University) for mass spectra and NMR assistance.
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3830 | Org. Biomol. Chem., 2006, 4, 3822–3830
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The Royal Society of Chemistry 2006
©