The azomethine ylide strategy for β-lactam synthesis. A comprehensive mechanistic evaluation

Article abstract of DOI:10.1039/b010046n

The release of azomethine ylide reactivity from oxazolidinones such as 4a/b and 7 is proposed to involve a stepwise fragmentation via 12 and 13 followed by cycloaddition (to an alkene) leading to adduct 14, which then undergoes decarboxylation under the reaction conditions to give the observed product 15. In the case of C=C-based dipolaro-philes, the cycloaddition is concerted and stereospecific, and the cycloaddition step is rate determining. Extensive experimental, together with computational data, including racemisation and kinetic studies, as well as the changes in reactivity associated with varying key structural features associated with the β-lactam based oxazolidinones is presented in support of the favoured mechanistic postulate. The fragmentation-cycloaddition-decarboxylation sequence is an alternative pathway for the release of an azomethine ylide from an oxazolidinone to that process already well established for N-alkyl oxazolidinones (concerted decarboxylation before cycloaddition). The N-acyl component associated with 4 may influence this change in mechanism, but specific structural features associated with the β-lactam system (ring strain and the presence of a malonyl moiety) are most likely responsible for the mechanistic divergence that is observed.

Full text of DOI:10.1039/b010046n

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The azomethine ylide strategy for ꢀ-lactam synthesis.
A comprehensive mechanistic evaluation
David Brown,a Giles A. Brown,a Sarah R. Martel,a Denis Planchenault,a Evelyn Turmes,a
Kenneth E. Walsh,a Richard Wisedale,a Neil J. Hales,b Colin W. G. Fishwickc and
Timothy Gallagher*a
1
a School of Chemistry, University of Bristol, Bristol, UK BS8 1TS
b AstraZeneca, Mereside, Alderley Park, Macclesfield, UK SK10 4TG
c School of Chemistry, University of Leeds, Leeds, UK LS2 9JT
Received (in Cambridge, UK) 18th December 2000, Accepted 1st March 2001
First published as an Advance Article on the web 16th May 2001
The release of azomethine ylide reactivity from oxazolidinones such as 4a/b and 7 is proposed to involve a stepwise
fragmentation via 12 and 13 followed by cycloaddition (to an alkene) leading to adduct 14, which then undergoes
decarboxylation under the reaction conditions to give the observed product 15. In the case of C᎐C-based dipolaro-
᎐
philes, the cycloaddition is concerted and stereospecific, and the cycloaddition step is rate determining. Extensive
experimental, together with computational data, including racemisation and kinetic studies, as well as the changes
in reactivity associated with varying key structural features associated with the β-lactam based oxazolidinones is
presented in support of the favoured mechanistic postulate. The fragmentation–cycloaddition–decarboxylation
sequence is an alternative pathway for the release of an azomethine ylide from an oxazolidinone to that process
already well established for N-alkyl oxazolidinones (concerted decarboxylation before cycloaddition). The N-acyl
component associated with 4 may influence this change in mechanism, but specific structural features associated with
the β-lactam system (ring strain and the presence of a malonyl moiety) are most likely responsible for the mechanistic
divergence that is observed.
and carbapenem ring systems respectively).3 Based on this
precedent, it is possible to formulate an approach to general
structure 1 that is based on the azomethine ylide 2, where the
1,3-dipole is contained within the skeleton of the β-lactam
component. Dipole 2 not only provides the reactivity that is
needed to construct the five-membered ring present in 1, but
also carries within it those structural features (the β-lactam unit
itself and the C(2) carboxy function) that are recognized as key
Introduction
The bicyclic heterocyclic unit 1 represents a generic framework
comprising the core of a diverse and commercially important
group of β-lactam antibiotics. This group includes carbapenams
and carbapenems, and heteroatom substituted variants, most
notably the sulfur-based penams and penems. Such molecules
have been the subject of intense synthetic interest and, given
their clinical significance, new and particularly flexible entries
requirements for viable antibacterial activity. Furthermore, this
cycloaddition process is necessarily a two component process,
to these targets remain important synthetic objectives.1
and the dipolarophile 3 employed offers a powerful means of
introducing additional flexibility and, above all, structural
diversity. Azomethine ylides not only react well with a variety
of alkenes and alkynes, but also with other 2π-components
based on C᎐O,4a C᎐N5 and C᎐S6 containing dipolarophiles.
᎐
᎐
᎐
With the ability to vary the nature of the dipolarophile (and
thereby X and R1), this approach offers the potential of a
comprehensive entry into general structure 1. A combination
of this flexibility with the direct and highly convergent nature
of the overall process represents a powerful tool that has par-
ticular attractions in the drug discovery process.
Our studies in this area focussed on the five-membered
ring azacycle that is present within general structure 1, which
suggested a synthetic approach based on establishing this
moiety using a 1,3-dipolar cycloaddition.2 The ability of
1,3-dipolar cycloadditions to provide access to a variety of
heterocyclic frameworks is already very well established, and
azomethine ylides constitute an important class of dipole for
constructing pyrrolidines and pyrrolines (cf. the carbapenam
Despite these apparent advantages, the successful imple-
mentation of a 1,3-dipolar cycloaddition based strategy for
the construction of bicyclic β-lactams has only recently been
achieved.2a The key to this success lies in an ability to generate
the requisite azomethine ylide reactivity—the ester-stabilized
1,3-dipole 2 or its equivalent. We have developed a solution to
this central issue whereby the necessary 1,3-dipolar reactivity
1270
J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b010046n

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Scheme 1
equivalent but not identical to 2—is available from an oxazo-
determining step.‡ In any event, oxazolidinones 5 and related
lidinone precursor 4. Thermolysis of 4 in the presence of a
suitable dipolarophile provides an efficient route to racemic
carbapenams and carbapenems, and to the thia analogues,
penams and penems respectively (Scheme 1). Details of the
synthetic aspects of this chemistry have been published2a,b but
more recently, C᎐O,2c C᎐Se,2e and C᎐N2f based dipolarophiles
derivatives are thermally unstable, and we have found that these
derivatives undergo ready decomposition when heated in the
absence of a dipolarophile. It is also pertinent to note that
the systems studied by Grigg (such as 5) incorporate an
N-alkyl substituent, while the 1,3-dipole precursors used in the
β-lactam series constitute N-acyl oxazolidinone derivatives.
Nevertheless, our initial expectation was that the presence
of an N-acyl, rather than N-alkyl moiety, would not have an
overriding influence on the basic reaction mechanism involved,
and that the β-lactam containing oxazolidinones e.g. 4 and
7 would follow a similar pathway.§ We expected to see a rate
determining—and probably concerted—decarboxylation step,
followed by a fast cycloaddition event.
᎐
᎐
᎐
have also been found to successfully partner the azomethine
ylide generated from 4 to afford the corresponding heteroatom-
containing bicyclic β-lactams.
Oxazolidinones as a source of azomethine ylides
The formation of azomethine ylides by thermal decarboxyl-
ation of oxazolidinones is, in a more general sense, well estab-
lished having been known for 30 years.4a,7–10 Oxazolidinones 5,
which can be generated by condensation of an α-amino acid
with an aldehyde, provide a versatile entry into azomethine
ylide derived cycloadducts, illustrated for example in Scheme 2.
The following paper11 describes work directed towards the
generation of the “parent” β-lactam-based azomethine ylide 2,
and a number of avenues that were explored in order to achieve
this objective. These results, as well as those derived from a
series of related studies, have also contributed towards our
appreciation of the scope and limitations of the cycloaddition
chemistry associated with the oxazolidinone-derived pathways
outlined in Scheme 1.
In this paper we deal with key aspects of the β-lactam based
azomethine ylide cycloaddition strategy, focussing on the suc-
cessful process for the synthesis of bicyclic β-lactams based on
thermolysis of 4 in the presence of a dipolarophile. As this
synthetic programme evolved, it became evident that the mech-
anism by which azomethine ylide reactivity was released from 4
did not conform to our initial expectations.12 As a consequence,
a more extensive mechanistic investigation has now been under-
taken and the full results of this study are presented here.
Scheme 2
Extensive studies, most significantly by Grigg,10 have not
only demonstrated the synthetic value of this process, but also
established a number of important mechanistic characteristics.
Stereochemical correlations between the starting oxazolidinone
5 and the final cycloadduct established that dipole formation
involves a concerted decarboxylation (a 1,3-dipolar cyclo-
reversion). For cyclic α-amino acids (lacking a benzylic
carboxylic acid function) this leads stereospecifically to the
anti azomethine ylide 6, which is captured by cycloaddition to
give mixtures of endo and exo cycloadducts.†
‡ The work of Tsuge and co-workers9b showed that different dipolaro-
philes react with the same azomethine ylide (derived from an amino acid
and an aldehyde) and lead to similar yields of cycloadducts after
comparable reaction times. This can be interpreted (albeit tentatively)
to suggest that the rate of reaction is independent of the dipolarophile.
§ The pyrrolidinone-based N-acyloxazolidinone i has been reported
(D. K. Dikshit, A. Maheshwari and S. K. Panday, Tetrahedron Lett.,
1995, 36, 6131). No cycloaddition chemistry has been reported for this
system.
Quantitative kinetic information for the chemistry shown
in Scheme 2 has not been reported, but it is reasonable that
decarboxylation (azomethine ylide formation) is the rate-
† The stereospecificity of the decarboxylation step with respect to
the geometry of the azomethine ylide does depend on the structure
of the α-amino acid. Complete stereoselectivity (stereospecificity) is
associated with cyclic amino acids but decreased stereoselectivity is
observed with acyclic amino acids and for systems where the carboxylic
acid resides at a benzylic centre.10
J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280
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Scheme 3
was re-isolated (after ca. 17 h) in essentially quantitative yield
but this recovered material was shown to be racemic. This
Results and discussion
ꢀ-Lactam containing oxazolidinones
observation was verified by using optical rotation measure-
1
ments and chiral shift H NMR experiments using Eu(hfc)3
To date, we have utilized two β-lactam based oxazolidinones
4a/b13 and 714 as sources of azomethine ylide reactivity for the
synthesis of carbapenams, carbapenems, penams, penems, and
oxapenams.2d The chemistry described in this paper will focus
on the more readily available derivatives 4a/b, which are pre-
pared on a multigram scale starting from natural clavulanic
acid. Oxazolidinones 4a/b are readily purified by crystallization
but are sensitive to moisture and are not readily amenable to
chromatography. Almost all of the chemistry described in this
paper was carried out using the 4-nitrobenzyl ester derivative
4a, although it should be appreciated that the corresponding
benzyl ester 4b behaves in an essentially identical fashion.
The enantiomerically pure oxazolidinone 4 gives racemic
cycloadducts. In contrast, with the C(6) substituted variant 7,
the O-silyl protected (6S)-(1-hydroxyethyl) side chain is
retained throughout the cycloaddition process, and this feature
serves to maintain overall stereochemical integrity leading
ultimately to enantiomerically pure cycloadducts. Neverthe-
less, the way in which oxazolidinones 4a/b formed racemic
products proved to be highly significant in our mechanistic
investigations.
(hfc = heptafluoropropylhydroxymethylenecamphorate).
A
more controlled kinetic study, again using both αD and 1H
NMR to follow the course of racemisation of 4a, showed that
this was a first order process with t1/2 = ca. 2.5 h (in MeCN at
80 ЊC). Observation of this racemisation process was crucial
to the development of an alternative mechanistic rationale to
account for the reactivity of the β-lactam based oxazolidinones
4a/b (and by inference the C(6) substituted variant 7).
Precedent for this type of racemisation process does exist within
the β-lactam area,15 and this is more appropriately discussed
in detail in the accompanying paper.11
We have also probed the kinetic properties of two cycloaddi-
tion reactions using MeCN as solvent. The first involved a
reactive dipolarophile (NPM) and the other using a signifi-
cantly less reactive trap (methyl dithiobenzoate) (Scheme 3). In
the case of NPM, the isolation method16 was used in order to
establish that the reaction leading to the racemic cycloadduct 8
was second order overall (k = 17.8 × 10Ϫ3 mol dmϪ1 sϪ1 at
98 ЊC), and first order in each of oxazolidinone 4a and NPM.
We were also able to determine the thermodynamic parameters
for this cycloaddition reaction and these are shown in Table 1.
Data from two related reactions (those shown in Equations 1
and 2)17 are provided for purposes of comparison, and the
values we have obtained, especially in respect of the strongly
negative entropy of activation, are similar to these more typical
1,3-dipolar cycloaddition processes. There is a caveat that must
be placed on the thermodynamic data obtained from 4a. The
fragmentation–cycloaddition reaction does not take place to
a significant extent below 80 ЊC, at which temperature oxazo-
lidinone 4a is relatively stable. However, at higher temperatures
(>110 ЊC), the rate of decomposition of 4a complicated the
kinetic analysis and, as a consequence, we were limited to
using a narrow temperature range (85 to 98 ЊC) to obtain the
parameters shown in Table 1.
Synthetic and mechanistic experiments
It became clear that the reactivity of 4a (and also 7) was not
consistent with the general mechanistic pathway established
by Grigg10 for N-alkyloxazolidinone derivatives (as outlined
in Scheme 2). In particular, 4a was relatively stable towards
thermolysis and when unreactive (usually electron rich) di-
polarophiles were employed, 4a was recovered even after pro-
longed reaction times. Furthermore, when dipolarophiles of
᎐
different reactivity e.g. N-phenylmaleimide (NPM) vs. PhC᎐CH
᎐
were used, a significantly longer reaction time was required for
᎐
the less reactive PhC᎐CH to achieve (i) a comparable con-
᎐
version of 4a and (ii) a similar yield of cycloadduct.¶ This
suggested that it was the reactivity rather than the actual
generation of the dipolarophile that was important and,
in turn, raised the possibility of cycloaddition as the rate-
(1)
1
determining step. We never observed (e.g. by H NMR) the
build-up of any intermediate dipolar species in reactions
involving less reactive dipolarophiles and these results
prompted a series of more detailed experiments designed to
probe this mechanistic enigma.
(2)
A critical observation was made when thermolysis of 4a was
carried out in the absence of a dipolarophile trap: the anticipated
decomposition of the oxazolidinone did not occur.|| Instead 4a
᎐
Table 1
¶ The higher reactivity of NPM as compared to PhC᎐CH was easily
᎐
demonstrated by a direct competition experiment. Also, a number of
solvents have been successfully employed in the β-lactam cycloaddition
process, including MeCN, PhMe, EtOAc, a range of chlorinated and
ether solvents, DMF, DMSO, and CF3CH2OH. Acetonitrile proved to
give consistently cleaner and faster reactions and higher yields.
|| Oxazolidinone 4a does decompose slowly on prolonged heating at
80 ЊC and more rapidly at temperatures in excess of 110 ЊC. Extended
heating of 4a (MeCN, >30 h) in the absence of a dipolarophile led to
complete decomposition, and we have not been able to characterize any
products (such as azomethine ylide dimer derived from the “parent”
1,3-dipole 2) from this experiment.
4a ϩ NPM→8
Equation 1a
Equation 2b
∆HЊ‡
∆SЊ‡
∆GЊ‡
EACT
76.8 kJ molϪ1
76.6 kJ molϪ1
65.7 kJ molϪ1
Ϫ76.8 J molϪ1 KϪ1 Ϫ121.4 J molϪ1 KϪ1 Ϫ133.9 J molϪ1 KϪ1
107.6 kJ molϪ1
79.9 kJ molϪ1
112.7 kJ molϪ1
79.1 kJ molϪ1 c
105.6 kJ molϪ1
68.2 kJ molϪ1 c
a Ref. 17a and 17b. b Ref. 17b and 17c. c Calculated based on reported
data.
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J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280

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Scheme 4
Similar results and limitations were associated with the reac-
is released from 4 differs fundamentally from that associated
tion between 4a and methyl dithiobenzoate to give the penem
precursor 9, again using MeCN as solvent. The reaction was
with better known N-alkyloxazolidinones. 1. The simple β-
lactam based oxazolidinone 4a does not undergo spontaneous
decarboxylation when heated—in the presence of an effective
dipolarophile, 4a is consumed but when heated for a similar
period of time either alone or with an unreactive trap, 4a
is recovered. 2. Oxazolidinone 4a does, however, undergo
first order with respect to both 4a and the C᎐S based dipo-
᎐
larophile (second order overall; k = 1.1 × 10Ϫ3 mol dmϪ1 sϪ1
at 80 ЊC). In this slower reaction, partial decomposition of
both reactants over the prolonged reaction time required made
more detailed analysis of this process impractical. Additionally,
the computational studies described below point to a possible
complication associated with the kinetic analysis of the NPM
reaction (see Scheme 9).
a
first order racemisation under thermal conditions. 3.
Kinetic analysis of the reaction of 4a with N-phenylmaleimide
has shown that this cycloaddition is a second order process
overall, with a negative entropy of activation and we con-
clude that it is likely that the cycloaddition step is rate
determining. 4. The stereochemistry of the dipolarophile is
retained and we conclude from this that the cycloaddition
Useful conclusions can also be drawn from the stereo-
chemical outcome of the cycloaddition process. Firstly, using
dimethyl fumarate and dimethyl maleate with the benzyl ester
derivative 4b, we have demonstrated that the cycloaddition
step is stereospecific (Scheme 4). A single cycloadduct 10 was
isolated in 74% yield from dimethyl maleate, and dimethyl
fumarate led to a major product 11 in 42% yield. A minor
isomeric product (which was not 10) was detected by NMR in
this latter reaction but could not be isolated or further charac-
terized. The relative stereochemistry of 10 has been determined
by NOE experiments. We were not able to unambiguously
involving alkenes is
a concerted process. However, the
(C2) carboxy stereochemistry is thermodynamically controlled
and contains no information about the structure of reaction
intermediates.
The mechanism already established for the fragmentation
of N-alkyloxazolidinones, which would require the direct (con-
certed) decarboxylation of 4 to give azomethine ylide 2, is
not consistent with these observations, and an alternative
explanation for the fate of the β-lactam-based oxazolidinones
is required. Our proposal, shown in Scheme 5, has two key
features: (i) the nature of the azomethine ylide species 13
involved and (ii) the suggestion that the (concerted and stereo-
specific) cycloaddition step precedes decarboxylation. The first
phase of this process requires ring opening of oxazolidinone
4 to give 12, followed by proton transfer to generate 13, and
it is this ‘carboxylated’ azomethine ylide intermediate—the
carboxylated variant of our initial target 1,3-dipole 2—that is
postulated to participate in the crucial cycloaddition reaction.
The ring strain associated with 4 is a likely contributor to the
ease of ring opening and, based on related structures reported
by Bordwell,19 the malonyl proton present in 12 is anticipated to
be of comparable acidity to that of a carboxylic acid.**
assign the structure of 11 (the major adduct derived from fuma-
3
rate) using NOE, and coupling constants (3JH(2)–H(3), JH(3)–H(4)
)
do not, in our experience, provide a reliable means for establish-
ing relative stereochemistry in this type of β-lactam derivative.
The structure shown for 11 is consistent with that observed in
most cases examined, i.e. a trans relationship between the ring
substituents at C(2) and C(3), but this assignment must be
regarded as provisional.
Importantly, the lack of any crossover products from
these two reactions supports the participation of an azomethine
ylide intermediate in an otherwise conventional and concerted
[4π ϩ 2π] cycloaddition step leading to the cycloadducts that
we have observed. This statement can, of course, apply only to
C᎐C-based dipolarophiles, since it is conceivable that cyclo-
᎐
additions involving highly polarized dipolarophiles, such as
To account for the racemisation of 4, formation of the
‘carboxylated’ azomethine ylide 13 must be reversible. In the
absence of an effective dipolarophile, this equilibrium would
result in the observed racemisation, but in the presence of a
suitable trap, the azomethine ylide 13 is intercepted and under-
those incorporating C᎐X (where X = NR, O, S, Se), could
᎐
proceed via a stepwise pathway.
More significantly for our mechanistic proposals, we have
only isolated products corresponding to the thermodynamically
more stable stereochemical trans relationship18 between C(2)
and C(5)—see 8–11. This places the C(2) carboxy moiety on
the exo face of the 1-azabicyclo[3.2.0]heptane framework, an
observation that not only applies to these examples but to all
of the cycloadducts we have isolated to date. This particular
stereochemical outcome does not conflict with the Grigg10
mechanism (cf. Scheme 2) since a similar outcome would be
expected if an anti dipole was involved in the cycloaddition
step (see Computational studies described below). However,
the stereochemical outcome in the β-lactam series may also be
interpreted in another way that is consistent with the other
observations that we have made.
** Bordwell19 has measured the acidity of both iii (pKHA 11.8) and
ii (pKHA5.6). These measurements were made in DMSO (a non-
hydrogen bond donor solvent), and it is of interest to compare these
values to those obtained for carboxylic acids e.g. PhCO2H: pKHA 11.1
(in DMSO). The zwitterions iv derived from iii contain structural
features—enolate of a β-dicarbonyl adjacent to an iminium moiety
(albeit not N-acyl)—similar to those found in 13.
Clearly, the experimental results described above indicate
that the mechanism by which azomethine ylide reactivity
J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280
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Scheme 5
goes a cycloaddition reaction. The final transformation would
associated with this type of substrate is dealt with in the
then require decarboxylation of the initially formed adduct 14.
If this pathway is followed, then decarboxylation must take
place under the reaction conditions since we have been unable
to detect adducts retaining the carboxylic acid function. This
final step is also expected to give the (observed) thermo-
dynamically more stable trans relationship between C(2) and
C(5) in the final product 15. Based on the kinetic data pre-
sented above, we suggest that the cycloaddition step is rate
determining, i.e. k3 is slow. An alternative scenario would
involve decarboxylation of 14 to give 15 as the rate-limiting
event (k3 > k4), but we regard this as less likely. We also consider
decarboxylation of 12 to give 2 as unlikely (see Scheme 8).
Under specific circumstances, this pathway can operate (see
Scheme 7) but only when proton tautomerisation is unavailable.
In order to probe further the proposal outlined in Scheme 5,
two additional substrates have been investigated. We evaluated
the thio analogue 18 as a precursor to an azomethine ylide,
and the preparation of racemic 18 is outlined in Scheme 6,
computational section of this paper.
The second substrate examined was the α-methylated oxazo-
lidinone 19. This substrate, which has proven to be particularly
useful, lacks the acidic malonyl proton but otherwise closely
mimics oxazolidinone 4. The α-methylated variant 19 was
prepared by direct alkylation of 4a and isolated, albeit in low
yield, as a 2 : 1 mixture of diastereoisomers; the sensitivity of
19 precluded separation of these isomers by chromatography
and the mixture was used in subsequent experiments (Scheme
7). Thermolysis of 19 (MeCN, 100 ЊC, sealed tube) was then
Scheme 7 Reagents and conditions: i, NaHMDS, Ϫ78 ЊC, MeI, THF
(29% as a 2 : 1 mixture of isomers); ii, MeCN, 100 ЊC (sealed tube) 2 h;
iii, N-phenylmaleimide, MeCN, 100 ЊC (sealed tube), 15 h (20: 78%
yield).
studied. After 2 hours, the 2 : 1 mixture of isomers of 19 had
1
undergone clean conversion to a 5 : 95 mixture (by H NMR),
favouring what had originally been the minor diastereomer.
Heating 19 in the presence of N-phenylmaleimide (MeCN,
100 ЊC, sealed tube, 15 h) gave a single cycloadduct 20 in
78% isolated yield, and while the gross structure of 20 has been
established, the detailed stereochemistry of this adduct was not
pursued.††
Thermolysis of the α-methylated oxazolidinone 19 (MeCN,
100 ЊC, sealed tube, 15 h) but in the absence of NPM did result
in significant decomposition, and we have correlated the path-
ways associated with decomposition and cycloaddition (leading
to 20). Solutions of 19 (in MeCN containing a small quantity
of DMSO as an internal standard) were heated with and
without NPM. After 14 hours, the extent of decay of 19 (as
Scheme 6 Reagents and conditions: i, K2CO3, BrCH2CO2Me, DMF
(68%); ii, AgNO3, py, MeOH, EtOAc, then 4-NO2C6H4OCOCl,
i-Pr2NEt, DMAP, THF (83% overall); LiHMDS, THF (46%).
starting from the known S-protected 4-tritylthioazetidin-2-one
16.19 N-Alkylation of racemic 16, followed by trityl cleavage
and S-acylation gave the thiocarbonate 17, which underwent
base-mediated cyclization to give the thiazolidinone 18 as a
crystalline solid. Thermolysis of 18 (MeCN, 100 ЊC, 23 h or 1,2-
dichlorobenzene, 150 ЊC, 20 h) in the presence of NPM failed
to produce a cycloadduct, and 18 was recovered unchanged.
Subsequent heating of 18 and NPM in 1,2-dichlorobenzene
at 200 ЊC (in a sealed tube) resulted in decomposition—no
evidence for cycloaddition was detected. Loss of COS (vs. CO2)
does (ultimately) represent a thermodynamically less favourable
process (see below) and the involvement of a more acidic thiol
acid (the S-analogue of 12) may also influence (disfavourably)
the key proton transfer step [cf. 12 to 13]. However, a significant
factor accounting for the reduced reactivity of 18 is the com-
parative lack of strain associated with a sulfur (as opposed
an oxygen) containing five-membered ring; the ring strain
†† Thermal epimerisation of 19 is presumed to involve C(5) rather
than C(2) via 21. We have not determined that the mixture correspond-
ing to 19 is composed of enantiomerically pure isomers, and the
structure of 19 (as shown in Scheme 7) is not intended to imply an
absolute stereochemistry. Although the stereochemistry of cycloadduct
1
20 has not been pursued, it is noteworthy that the H NMR spectrum
of 20 is virtually superimposable (chemical shifts and J values) on the
1
similar regions of the H NMR spectrum of cycloadduct 8, which has
already been assigned as the endo adduct.2a
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J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280

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Scheme 8
Table 2 Heats of formation and transition state imaginary frequencies
judged by the amount of 19 remaining—ca. 20%) correlated
almost exactly to the amount of cycloadduct 20 produced in the
parallel experiment. This result indicates that the thermal
decomposition of 19 and the subsequent cycloaddition reaction
with NPM are both efficient processes.
for Scheme 8
Structure
Hf a X = O
Hf a X = S
νi b X = O
νi b X = S
23
Ϫ163.05
Ϫ144.83
Ϫ141.82d
Ϫ149.93
Ϫ136.87
(Ϫ129.49)c
Ϫ128.67
Ϫ136.36
Ϫ103.30
Ϫ76.68d
Ϫ106.50
Ϫ89.47
—
—
—
—
—
—
—
—
Based on these observations, the mechanism associated with
conversion of 19 to 20 most reasonably involves a stepwise
(reversible) fragmentation via 21 and irreversible decarboxyl-
ation to yield azomethine ylide 22. Isomerization of 19 (from
a 2 : 1 mixture to a 5 : 95 mixture of isomers) under the con-
ditions used provides support for this pathway.
24
25
26
TS1
TS2
TS3
Ϫ355.93
(Ϫ330.23)c
Ϫ568.50
Ϫ146.04
(Ϫ472.94)c
Ϫ572.22
(Ϫ80.68)c
Ϫ85.28
a Heats of formation in kcal molϪ1, obtained using AM1 (X = O) or
PM3 (X = S) Hamiltonians and the COSMO20 model to simulate a
solvent field equivalent to that of acetonitrile. b All transition structures
were characterized by observing them to have a single negative vibra-
tional frequency corresponding to the reaction coordinate following
a normal mode analysis (expressed in cmϪ1). c Transition state could
not be located in acetonitrile and energy is a single-point estimate
(COSMO) on a gas-phase derived transition structure. d Energies are
those of 1,3-dipole plus calculated heats of formation (COSMO) of
CO2 (Hf(MeCN) = Ϫ88.89 kcal molϪ1) and COS (Hf(MeCN) = Ϫ23.75
kcal molϪ1) respectively.
This result does raise the possibility that a similar noncon-
certed path is available to oxazolidinone 4 leading to azo-
methine ylide 2, and these two processes have been compared
computationally (see Scheme 8). However, given that we
observe both racemisation of 4 (where both the C(2) and C(5)
stereocentres have to be involved) and cycloadduct formation
under conditions that otherwise do not lead to decomposition
of 4, this alternative stepwise decarboxylation can only play at
best a minor role.
Computational studies
Table 3 Activation energies for Scheme 8
In order to gain further insight into the mechanistic possibilities
outlined above, semi-empirical calculations were performed in
order to estimate the relative energies of the intermediates and
transition states involved in the generation of the two possible
dipoles 2 and 13 as shown in Scheme 5. For simplicity, the
calculations were carried out on the methyl (rather than
PNB) ester 23, but using a simulated solvent dielectric in order
to closely match the calculation results to the actual reaction
conditions used. Both the oxazolidinone (X = O) and thiazo-
lidinone (X = S) series have been compared, and the results are
summarised below (Scheme 8 and Tables 2 and 3).
Three discrete fragmentation pathways have been considered.
1. Stepwise fragmentation followed by decarboxylation to give
azomethine ylide 25 (via TS1 and TS3) (cf. 19→22). 2. Stepwise
fragmentation followed by tautomerisation (via TS1 and TS4)
to give carboxylated azomethine ylide 26 (which represents our
favoured mechanistic pathway). 3. Concerted decarboxylation
(via TS2) also to give azomethine ylide 25 which corresponds to
the established10 mechanism for the formation of azomethine
ylides from N-alkyloxazolidinones.
valuea X = O
valuea X = S
∆E1
∆E2
∆E3
∆E4
∆E5
∆E6
26.18
(33.56)b
(Ϫ12.33)b
Ϫ7.96
16.16
Ϫ12.33
46.89
(55.68)b
(Ϫ4.00)b
Ϫ13.83
18.02
8.60
a Heats of formation in kcal molϪ1, obtained using AM1 (X = O) or
PM3 (X = S) Hamiltonians and the COSMO20 model to simulate a
solvent field equivalent to that of acetonitrile. b Transition state could
not be located in acetonitrile and energy is a single-point estimate
(COSMO) on a gas-phase derived transition structure. d Energies are
those of 1,3-dipole plus calculated heats of formation (COSMO) of
CO2 (Hf(MeCN) = Ϫ88.89 kcal molϪ1) and COS (Hf(MeCN) = Ϫ23.75
kcal molϪ1) respectively.
cleavage of the C–O bond in oxazolidinone 23 (X = O) to
yield zwitterion 24 (X = O) via transition state TS1 (X = O)
is favoured and reversible (∆E4 < ∆E1) compared to concerted
loss of carbon dioxide from 23 (X = O) via transition state TS2
Clearly, the data shown in Tables 2 and 3 indicate that
J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280
1275

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(X = O) to yield anti dipole 25 (∆E1 < ∆E2). Indeed, transition
state TS2 (X = O) was not stable in a simulated acetonitrile
environment when attempts at optimisation were made using
the COSMO20 model, and all measurements are single-point
estimates on a transition structure optimised in vacuo.
Decarboxylation of zwitterion 24 (X = O) to yield anti-dipole
25 (X = O) via transition state TS3 (X = O) is, however, pre-
dicted to be energetically reasonable. However, an alternative
pathway involving formal (but stepwise) proton tautomerism of
zwitterion 24 (X = O) via transition states approximated via
TS4 (X = O) to yield dipole 26 (X = O) would appear particu-
larly favourable. Although the energetics and the structure(s) of
TS4 (X = O) have not been calculated in the present study, a
number of previous reports19,21 strongly indicate the extremely
favourable nature of the transformation of zwitterion 24
(X = O) into dipole 26 (X = O). As mentioned above, Bordwell
and co-workers19 have found that malonyl-based systems which
contain an iminium moiety attached to the malonyl carbon as
present in zwitterion 24 (X = O) show the expected enhanced
degrees of acidity when compared to simpler malonate-derived
carbon acids.
Additionally for weak acids, including malonate derivatives,
Dillon21 has demonstrated an approximately linear relation-
ship between measured pKa’s and measured rates (and thus
activation energies) of ionisation. A weak carbon acid, such as
1-chloronitroethane, has a pKa of around 7 with an activation
energy for ionisation of 20 kcal molϪ1. Substituting the
inductively anion-stabilising chlorine atom for a conjugating
substituent (as in ethyl nitroacetate) decreases the pKa to
approx. 6 with a corresponding decrease in activation energy
required for ionisation to 16 kcal molϪ1. It would be expected
that C–H cleavage in zwitterion 24 (X = O) would be particu-
larly favourable and this species is likely to have a pKa of
5.6 or lower. This would require an energy barrier probably
appreciably lower than 16 kcal molϪ1 to induce C–H bond
cleavage and carboxylate protonation to yield dipole 26
(X = O).
Fig. 1
than those determined for 23 (X = O). Additionally, as with the
oxazolidinone, the concerted fragmentation pathway could
not be established in a simulated acetonitrile environment.
As indicated previously, although a number of factors could
contribute to the higher energies involved in the sulfur-
containing substrates, the relative strain energies of oxygen
versus sulfur ring systems appears to be an important factor.
Comparison of the calculated heats of formation (H) and
differences associated with ring size (∆H) for a series of simple
bicyclic O- and S-based heterocycles is shown in Fig. 1. As can
be seen, decreasing ring size in the oxygen-containing ring
system results in a considerable increase in energy compared
to that for the thia analogues.
The viability of both 1,3-dipoles of the types 25 and 26
(Scheme 8) to undergo cycloaddition has also been investigated
using a semi-empirical approach (Scheme 9 and Tables 4–6).
Due to computational limitations, initial studies were per-
formed in the gas phase as summarised below. These cal-
culations were also extended to include solvent-based studies
on the simplified (methyl ester containing) dipole species
(see Table 5).
The energetics of these cycloaddition processes are shown
in Table 6, and as can be seen, both the ‘decarboxylated’
1,3-dipoles 27 (X = H), and the ‘carboxylated’ systems 27
(X = CO2H) are predicted to undergo efficient cycloadditions
to maleimide derivatives, cycloadditions in vacuo generally
possessing activation energies in the range 7–14 kcal molϪ1
(entries 1–4) and 12–24 kcal molϪ1 for the solution-phase
reactions (entries 5 and 6) respectively.
These calculations indicate that generation of anti dipole
25 via concerted thermal loss of carbon dioxide from oxa-
zolidinone 23 (X = O) does not occur in acetonitrile. As
suggested by the α-methylated variant 19, formation of
azomethine ylide 25 in acetonitrile is possible via stepwise
decarboxylation with the intermediacy of zwitterion 24
(X = O).‡‡ However, tautomerism in zwitterion 24 (X = O)
to yield dipole 26 (X = O) is even more favourable and, for
this and the other reasons discussed above, remains the pre-
ferred reaction pathway for fragmentation of oxazolidinone 23
(X = O) to give an azomethine ylide.
All cycloadditions favour formation of the endo adducts 29
(i.e. ∆E9 < ∆E10) with those resulting from cycloadditions of the
‘non-carboxylated’ dipoles (entries 1, 3, and 5) having around
half the activation energy of the corresponding ‘carboxylated’
systems (entries 2, 4, and 6). In the ‘carboxylated’ series
(X = CO2H), however, the calculated preference associated
with the endo pathway is marginal. It is particularly noteworthy
The data in Tables 2 and 3 also shed light on the observed
lack of reactivity of the thio variant 23 (X = S). The activation
energies for both C–S cleavage of this substrate and the con-
certed loss of COS are in excess of 20 kcal molϪ1 higher
that the value of the activation energy (∆E9 = 24.11 kcal molϪ1
)
for cycloaddition of the ‘carboxylated’ dipole model 27
(X = CO2H, R = H) in acetonitrile is comparable with the
largest of the calculated activation energies in the oxazol-
idinone fragmentation sequence (that of ∆E1 = 26.18 kcal
molϪ1, corresponding to C–O cleavage) which suggests that the
rates of both steps may influence the overall reaction kinetics.
The heats of formation of the cycloadducts 29 and 30 are
generally much lower than those for the corresponding trans-
ition states TS5 and TS6, such that the cycloadditions are
essentially irreversible under these conditions (i.e., ∆E11 ӷ ∆E9,
and ∆E12 ӷ ∆E10).
‡‡ A parallel series of calculations relating to the transformations
shown in Scheme 8 (X = O throughout) were performed based on the
one diastereomer (of the possible two) of the α-methylated oxa-
zolidinone v, and results are summarized here. Heats of formation and
transition state imaginary frequencies for the methyl ester analogues
of 23 Ϫ161.84; 24 Ϫ142.02; 25 Ϫ144.78; TS1 Ϫ135.12 [Ϫ321.65];
TS2 (Ϫ129.50)a [(Ϫ337.71)a]; TS3 Ϫ128.52 [Ϫ535.36].
Effect of Lewis acids
The mechanistic proposals presented here raise a number
of other interesting issues. While we cannot determine experi-
mentally the relative positions of the equilibria linking 12 and
13 (Scheme 5) or rates of these interconversions (k1/kϪ1, k2/kϪ2),
increasing the concentration of the azomethine ylide 13 should
accelerate the rate of formation of the final cycloadduct 15.
Activation energies for equivalent transformations involving v as
shown in Scheme 8: ∆E1 26.72; ∆E2 (32.34)a; ∆E3 (Ϫ15.28)a; ∆E4 Ϫ6.9;
∆E5 13.5; ∆E6 Ϫ16.26. (a Transition state could not be located in
acetonitrile and the energy is a single-point estimate (COSMO) on a
gas-phase derived transition structure.)
1276
J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280

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Scheme 9
Table 4 Heats of formation, transition state imaginary frequencies and dipole moments for Scheme 9
Structure
No.
Structure
No.
R
RЈ
X
Hf a (νi)b [Dipole]c
R
RЈ
X
Hf a (νi)b [Dipole]c
27
PNB
—
PNB
PNB
PNB
—
H
—
H
H
H
Ϫ2.38
5.83
Ϫ66.72
Ϫ63.87
10.79
(Ϫ334.5)
[5.29]
27
Me
—
Me
Me
Me
—
H
—
H
H
H
Ϫ33.47
Ϫ28.88
Ϫ134.61
Ϫ131.97
Ϫ55.88
(Ϫ319.67)
[2.45]
28
Ph
Ph
Ph
Ph
28
Me
Me
Me
Me
29
30
TS5
29
30
TS5
TS6
PNB
Ph
H
14.45
(Ϫ385.66)
[6.63]
TS6
Me
Me
H
Ϫ52.64
(Ϫ381.95)
[3.31]
27
PNB
PNB
PNB
PNB
—
CO2H
CO2H
CO2H
CO2H
Ϫ88.18
Ϫ137.06
Ϫ137.83
Ϫ68.70
(Ϫ506.43)
[6.33]
27
Me
Me
Me
Me
—
CO2H
CO2H
CO2H
CO2H
Ϫ119.42
Ϫ205.01
Ϫ206.85
Ϫ134.82
(Ϫ499.24)
[2.86]
29
Ph
Ph
Ph
29
Me
Me
Me
30
TS5
30
TS5
TS6
PNB
Ph
CO2H
Ϫ67.38
(Ϫ503.28)
[3.99]
TS6
Me
Me
CO2H
Ϫ134.72
(Ϫ463.69)
[3.58]
a Heats of formation (Hf) and energy differences (∆H) in kcal molϪ1, obtained using AM1 Hamiltonian. b All transition structures were characterized
by observing them to have a single negative vibrational frequency corresponding to the reaction coordinate following a normal mode analysis
(expressed in cmϪ1). c Expressed in Debyes.
One approach to this would be use of an oxaphilic Lewis acid
that might serve to lower the barrier to the initial fragmentation
of 4 (which corresponds to ∆E1 in Scheme 8 and is the highest
barrier in the formation of the carboxylated dipole) and also
enhance the C–H acidity associated with 12. Such interactions
might then increase the effective concentration of the key
azomethine ylide intermediate, and with this in mind a wide
range of Lewis acids have been evaluated using the reaction
between 4a and NPM as a model system.§§
time for a comparable level of conversion of 4a and isolated
yield of adduct ( )-8. A similar acceleration has also been
observed when thiobenzophenone was employed, a process that
leads directly to the diphenylpenam derivative ( )-31. In this
case, however, use of the Lewis acid catalyst did cause some
reduction in yield.¶¶
Conclusions
The general sensitivity of oxazolidinone 4a precluded use of
many of the more conventional Lewis acids, but LiBr did show
a significant effect (Scheme 10). Using the same concentrations
of reactants and the same reaction temperature, addition of 1.1
equivalents of LiBr resulted in a significant decrease in reaction
Evidence has been obtained pointing towards an alternative
mechanism for the fragmentation of oxazolidinones to give
azomethine ylides to that previously elucidated by Grigg.10 In
the β-lactam based derivatives exemplified by 4, and based on
the weight of evidence, we favour formation and participation
of the carboxylated azomethine ylide 13. This species can
undergo concerted and stereospecific cycloaddition reactions,
followed by decarboxylation of the initial adduct 14 to give
§§ A variety of Lewis acids were screened without success: Ti(Oi-Pr)4,
AgX (X = OAc, NO3), MgBr2, ZnBr2, CeBr3, Sc(OTf)3. Lithium salts
(LiClO4, LiBr, LiI) led to some acceleration, but LiBr was clearly
superior. LiBr is similarly effective at accelerating the rate of reaction
between the more substituted oxazolidinone 7 and NPM. We have also
studied, without success, a range of acidic and basic catalysts with the
aim of promoting, for example, the proton transfer step associated with
the conversion of 12 to 13. We have not attempted to promote ring
opening–fragmentation of the thia analogue 18 or the α-methylated
oxazolidinone 19 using a Lewis acid.
¶¶ The possibility that the carbonyl group of NPM or the thiocarbonyl
moiety of thiobenzophenone interacts with LiBr and that this provides
a mechanism for activation cannot be ignored. Attempts to catalyze the
᎐
reaction of 4a with PhC᎐CH using LiBr as additive failed because the
᎐
resulting cycloadduct underwent rapid decomposition in the presence
of LiBr, a fact that was supported by a control experiment.
J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280
1277

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is a slower and (at best) minor pathway when compared to
4 → 12 → 13 (Scheme 5).
The observations presented in this paper do not invalidate
the earlier mechanistic proposals developed for the N-alkyl-
oxazolidinones such as 5. In fact, it is more reasonable to sug-
gest that it is the β-lactam series that shows the “anomalous”
reactivity profile. This is a consequence of the particular
and somewhat unusual structural features present in 4—a very
strained five-membered ring (which facilitates ring opening to
give 12) and the presence of an acidic proton associated with
the malonyl moiety, which is activated by the adjacent iminium
moiety. A combination of these features provides the means
of generating the key 1,3-dipole critical to the success of the
azomethine ylide strategy for β-lactam synthesis.
The following paper describes a series of related studies
that were directed towards alternative methods and substrates
for generating β-lactam-based azomethine ylides. These
include efforts to generate the “parent” 1,3-dipole 2 by
eliminating those structural features that appear to bias the
fragmentation–cycloaddition–decarboxylation pathway which
is favoured for 4.
Scheme 10
the observed product 15. A stepwise alternative operates in the
case of the α-methylated oxazolidinone 19, which undergoes
a stepwise fragmentation and decarboxylation prior to cyclo-
addition. This system does, however, lack an acidic malonyl
proton, which is a key feature of oxazolidinone 4. If 4 does
undergo a similar stepwise fragmentation to that proposed
for the α-methylated oxazolidinone 19, we suggest that this
Experimental
General
Infrared spectra (νmax) were recorded using a Perkin-Elmer 1715
FTIR spectrometer, in the range of 4000–600 cmϪ1 either as a
neat film on NaCl plates or as a solution in CH2Cl2, using NaCl
solution cells. Mass spectra m/z (E.I., C.I., FAB) were obtained
using a Fisons/VG Analytical Autospec System. Nuclear
magnetic resonance (NMR) spectra were recorded at the field
strength shown and in CDCl3, unless otherwise indicated using
standard pulse sequences on an Alpha 500, JEOL GX400,
Lambda 300, or Delta 270 with proton and carbon assignments
made using a combination of 1H/1H and 1H/13C correlation
spectroscopy. Flash column chromatography was carried out
on either Silica Gel (Merck 1.09385) or 60H Silica Gel (Merck
TLC, Merck 1.11695) and all commercially available reagents
and solvents were purified and dried according to standard
procedures.
Table 5 Heats of formation, transition state imaginary frequencies
and dipole moments for Scheme 9 in MeCN
Structurea
No.
R
RЈ
X
Hf a,b (νi)c [Dipole]d
27
Me
—
Me
Me
Me
—
H
—
H
H
H
Ϫ52.93
Ϫ42.85
Ϫ163.39
Ϫ161.69
Ϫ83.03
(Ϫ387.55)
[4.46]
28
Me
Me
Me
Me
29
30
TS5
TS6
Me
Me
H
Ϫ80.16
(Ϫ375.07)
[5.63]
Kinetic study
General procedures. A solution of oxazolidinone 4a13b (60
mg, 0.196 mmol), 1,4-dibromobenzene (46.2 mg, 0.196 mmol)
(which served as an internal standard) and NPM (33.9 mg,
0.159 mmol) in MeCN (6 cm3) was divided into 6 × 1 cm3
portions, and 5 × 1 cm3 portions were placed in identical reseal-
able tubes. The remaining portion provided the data point t = 0.
The five tubes were heated in a temperature-controlled oil bath
at the desired temperature (initial kinetic data was obtained at
98 ЊC) and tubes were removed at hourly intervals.
With each sample, the bulk of the solvent was removed
carefully in vacuo and the residue was analysed by 1H
NMR (300 MHz). Using distinct signals associated with the
individual components enabled the ratio of 4a and 82a to be
determined for each time point. The internal standard showed
that negligible decomposition of 4a occurred under the con-
ditions employed. This reaction was also run under pseudo-first
27
H
H
H
H
—
CO2H
CO2H
CO2H
CO2H
Ϫ159.05
Ϫ246.97
Ϫ247.55
Ϫ177.79
(Ϫ575.07)
[6.12]
Ϫ176.83
(Ϫ566.82)
[4.52]
297
30
Me
Me
Me
TS5
TS6
H
Me
CO2H
a These entries refer to calculations of reactions in acetonitrile using the
COSMO20 algorithm. b Heats of formation (Hf) and energy differences
(∆H) in kcal molϪ1, obtained using AM1 Hamiltonian. c All transition
structures were characterized by observing them to have a single nega-
tive vibrational frequency corresponding to the reaction coordinate
following a normal mode analysis (expressed in cmϪ1). d Expressed
in Debyes.
Table 6 Energies of cycloadditions in Scheme 9
Entry
R
RЈ
X
∆E9
7.34
13.65
6.47
13.48
12.75
24.11
∆E10
∆E11
∆E12
1
2
3
4
5
6
PNB
PNB
Me
Me
Me
H
Ph
Ph
Me
Me
Me
Me
H
CO2H
H
CO2H
H
CO2H
11.00
14.97
9.71
13.58
15.62
25.07
Ϫ77.51
Ϫ68.36
Ϫ78.73
Ϫ70.19
Ϫ80.36
Ϫ69.18
Ϫ78.32
Ϫ70.45
Ϫ79.33
Ϫ72.13
Ϫ81.53
Ϫ70.72
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J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280

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order conditions (i.e. 10 fold excess of NPM) and a plot of
ln [4a] against time was linear (R2 = 0.99).
lisation from petroleum ether, afforded the title compound
(4.14 g, 68%) as a colourless crystalline solid, mp 120–122 ЊC
(MeOH) (Found: C, 71.65; H, 5.63; N, 3.44. C25H23NO3S
requires C, 71.92; H, 5.55; N, 3.35%); νmax (CH2Cl2)/cmϪ1 1768
and 1748; δH (270 MHz) 3.05 (1 H, dd, J 15.1, 2.2, 3β-H), 3.26
(1 H, d, J 18.3), 3.31 (1 H, dd, J 15.1, 5.0, 3α-H), 3.64 (3 H, s,
OMe), 3.91 (1 H, d, J 18.3), 4.51 (1 H, dd, J 5.0, 2.2, 4-H) and
7.20–7.39 (15 H, m, Ar); δC (75.5 MHz) 40.5 (CH2), 48.0 (CH2),
52.0 (OMe), 57.4 (CH), 67.7 (C), 127.3 (CH), 128.3 (CH), 129.6
Analysis of the alternative pseudo-first order plot (using
an excess of 4a) was complicated by slow but competitive
decomposition of 4a. The isolation method16 was used to
establish the overall second order of the reaction. This involved
doubling the excess of NPM, which resulted in a doubling
of the pseudo-first order rate constant. Thermodynamic
parameters (Table 1) were obtained by determining second
order rate constants at 358.2, 361.2, 363.9, 368.2 and 370.2 K,
and a plot of ln kr vs. 1/T (R2 = 0.954) was used to obtained
EACT and ln kr/T (R2 = 0.951) provided ∆HЊ‡, and ∆SЊ‡, and
∆GЊ‡.
(CH), 144.1 (Cipso), 165.7 (C᎐O) and 167.9 (C᎐O); m/z (C.I.)
᎐
᎐
275 (Ph3CSϩ, 1%), 243 (Ph3Cϩ, 100) and 142 (Mϩ Ϫ SCPh3, 9).
( )-Methyl 4-(p-nitrophenoxycarbonylthio)-2-oxoazetidin-1-
A similar procedure was followed to determine the order and
rate constant for the reaction of 4a with methyl dithiobenzoate,
which was conducted at 80 ЊC. Further analysis of this reaction
was complicated by decomposition of both reactants (and
possibly the products) during the long reaction times that were
required.
ylacetate 17
To an ice-cold solution of methyl 4-(triphenylmethylthio)-2-
oxoazetidin-1-ylacetate (0.90 g, 2.2 mmol) in MeOH (10 cm3)
and EtOAc (10 cm3) was added pyridine (0.3 cm3) followed by a
solution of AgNO3 in methanol (0.12 mol dmϪ3, 24 cm3,
2.9 mmol), whereupon a colourless precipitate resulted. After
stirring for a further 1 h at 0 ЊC, hydrogen sulfide was passed
through the mixture at 0 ЊC until deposition of a dense black
solid (Ag2S) was complete, leaving a colourless solution. The
solution was flushed with nitrogen, filtered, and concentrated
under reduced pressure. The residue was partitioned between
CH2Cl2 (40 cm3) and aqueous HCl (1 mol dmϪ3, 10 cm3). The
organic solution was washed with brine, dried (Na2SO4) and
evaporated in vacuo to give a colourless solid. 1H NMR analysis
showed a 6.5 : 1 mixture of the desired methyl 4-mercapto-2-
oxoazetidin-1-ylacetate with starting material, which was used
without further purification.
A solution of the crude thiol (prepared above) in THF
(5 cm3) was added to a solution of p-nitrophenyl chloroformate
(0.43 g, 2.1 mmol), N,N-diisopropylethylamine (280 mg,
2.2 mmol) and catalytic DMAP in THF (5 cm3) at 0 ЊC under
an atmosphere of nitrogen. A colourless precipitate soon
resulted and, after stirring for 40 min, the reaction mixture was
partitioned between EtOAc (20 cm3) and water (5 cm3). The
organic solution was washed with brine, dried (Na2SO4)
and concentrated in vacuo. Purification of the residue by flash
chromatography (10–50% EtOAc–petroleum ether) afforded
the thioacylated azetidinone 17 (338 mg, 83%) as a colourless
solid, mp 119.5–120.5 ЊC (CCl4) (Found: C, 45.52; H, 3.71;
N, 8.55. C13H12N2O7S requires C, 45.88; H, 3.55; N, 8.23%);
νmax (CH2Cl2)/cmϪ1 1779, 1750 and 1727; δH (270 MHz) 3.15 (1
H, dd, J 15.2, 2.5, 3-H), 3.65 (1 H, dd, J 15.2, 5.5, 3-H), 3.75 (3
H, s, OMe), 3.80 (1 H, d, J 18.2), 4.28 (1 H, d, J 18.2), 5.57 (1 H,
dd, J 5.5, 2.5, 4-H), 7.37 (2 H, part of AAЈBBЈ, J 9.3, Ar)
and 8.30 (2 H, part of AAЈBBЈ, J 9.3, Ar); δC (75.5 MHz) 42.1
(CH2), 44.2 (CH2), 52.5 (CH3), 56.5 (CH), 121.9 (CH), 125.4
( ) Benzyl (2R*,3R*,4S*,5S*)-3,4-bis(methoxycarbonyl)-7-oxo-
1-azabicyclo[3.2.0]heptane-2-carboxylate 10
A solution of oxazolidinone 4b13b (100 mg, 0.38 mmol) and
dimethyl maleate (66 mg, 0.46 mmol) in MeCN (2 cm3) was
heated under reflux for 60 h. Removal of solvent and purifica-
tion of the residue by flash chromatography (40% EtOAc–60%
petroleum ether 40–60 ЊC) gave cycloadduct 10 (102 mg, 74%)
as a colourless oil. (Found: M ϩ Hϩ, 362.1237. C18H20NO7
requires M, 362.1240); νmax (film)/cmϪ1 2956, 1781 and 1742;
δH (270 MHz) 2.71 (1 H, dd, J 16.3, 2.2, 6β-H), 3.25 (1 H, dd,
J 16.3, 5.1, 6α-H), 3.60 (1 H, t, J 7, 4-H), 3.65 (3 H, s, CO2Me),
3.71 (3 H, s, CO2Me), 4.04 (1 H, dd, J 7.5, 7, 3-H), 4.12 (1 H, m,
5-H), 4.92 (1 H, d, J 7.5, 2-H), 5.18 (1 H, d, J 12.4, ArCH2), 5.23
(1 H, d, J 12.4, ArCH2), 7.36 (5 H, br s, Ar); m/z (C.I.) 362
(M ϩ Hϩ, 2%).
NOE data for 10: Irradiation of H(2) showed no enhance-
ment of H(3). Irradiation of H(3) showed enhancement of
H(4) and irradiation of H(4) showed enhancement of both
H(3) and H(5). Irradiation of H(5) showed enhancements of
both H(6α) and H(6β) and H(4).
( ) Benzyl (2R*,3R*,4R*,5S*)- (or 2R*,3S*,4R*,5S*)-3,4-bis-
(methoxycarbonyl)-7-oxo-1-azabicyclo[3.2.0]heptane-2-carb-
oxylate 11
A solution of the oxazolidinone 4b (100 mg, 0.38 mmol) and
dimethyl fumarate (67 mg, 0.47 mmol) in MeCN (2 cm3) was
heated under reflux for 60 h. Removal of solvent and purifica-
tion of the residue by flash chromatography (20–40% EtOAc–
petroleum ether 40–60 ЊC) gave 11 (58 mg, 42%) as a colourless
oil. (Found: M ϩ Hϩ, 362.1231. C18H20NO7 requires M,
362.1240); νmax(film)/cmϪ1 2956, 1780 and 1740 (br); δH (270
MHz) 2.97 (1 H, dd, J 16.1, 2.0, 6β-H), 3.22 (1 H, dd, J 9.2, 7.7,
4-H), 3.40 (1 H, dd, J 16.1, 4.8, 6α-H), 3.69 (3 H, s, CO2Me),
3.73 (3 H, s, CO2Me), 4.05 (1 H, dd, J 9.2, 7.3, 3-H), 4.06 (1 H,
m, 5-H), 4.70 (1 H, d, J 7.3, 2-H), 5.14 (1 H, d, J 12.3, ArCH2),
5.24 (1 H, d, J 12.3, ArCH2), 7.35 (5 H, m, Ar); m/z (C.I.) 362
(M ϩ Hϩ, 1%).
(CH), 145.7 (Cipso), 155.0 (Cipso), 164.5 (C᎐O), 167.8 (C᎐O),
᎐
᎐
168.0 (C᎐O); m/z (E.I.) 281 (Mϩ Ϫ CO Me, 15%).
᎐
2
( )-Methyl (2S*,5R*)-3,7-dioxo-4-thia-1-azabicyclo[3.2.0]-
heptane-2-carboxylate 18
To a solution of LiHMDS (1.0 mol dmϪ3 in THF; 6.0 cm3,
6.0 mmol) at Ϫ78 ЊC under a nitrogen atmosphere was added a
solution of the 4-thioacylated azetidinone 17 (1.00 g, 2.9 mmol)
in THF (10 cm3). After stirring at Ϫ78 ЊC for 75 min, further
LiHMDS solution (1.0 mol dmϪ3 in THF, 1 cm3) was added and
stirring continued for 15 min. The reaction mixture was diluted
with EtOAc (30 cm3) and quenched with aqueous HCl (1 mol
dmϪ3, 10 cm3). The aqueous solution was further extracted with
EtOAc (10 cm3) and the combined organic solutions washed
with brine, dried (Na2SO4) and concentrated in vacuo. Purifi-
cation by flash chromatography (50% EtOAc–50% petroleum
ether) gave thiazolidinone (18) (270 mg, 46%) as a colourless oil
(Found: M ϩ Hϩ, 202.0174. C7H8NO4S requires M, 202.0174);
νmax (CH2Cl2)/cmϪ1 1797, 1756 and 1726; δH (270 MHz) 3.43
(1 H, dd, J 16.4, 1.7, 6β-H), 3.84 (3 H, s, OMe), 3.94 (1 H, dd,
( )-Methyl 4-(triphenylmethylthio)-2-oxoazetidin-1-ylacetate
To a solution of 4-(triphenylmethylthioazetidin-2-one 1622
(5.03 g, 14.6 mmol) in DMF (25 cm3) was added methyl
bromoacetate (1.5 cm3, 15.8 mmol) and K2CO3 (4.39 g, 31.8
mmol). The mixture was stirred at room temperature for
17.5 h and then partitioned between Et2O (150 cm3) and water
(100 cm3). The aqueous solution was further extracted with
Et2O (50 cm3) and the combined ethereal solutions washed with
brine, dried (Na2SO4) and concentrated in vacuo to a yellow
oil. Purification by flash chromatography (10–40% EtOAc–
petroleum ether) yielded a pale yellow oil, which, upon crystal-
J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280
1279

View Article Online
W. D ürckheimer, J. Blumbach, R. Lattrell and K. H. Scheunemann,
J 16.4, 4.2, 6α-H), 5.08 (1 H, s, 2-H) and 5.59 (1 H, dd, J 4.2,
1.7, 5-H); δC (75.5 MHz) 49.4 (CH2), 53.5 (OCH3), 60.6 (CH),
Angew. Chem., Int. Ed. Engl., 1985, 24, 180; (c) G. I. Georg, The
Organic Chemistry of β-Lactams, VCH, New York, 1992; (d) G. I.
Georg, in Recent Advances in the Chemistry and Biology of β-Lactam
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in-Print no. 8), 1993, 3, 2159–2313; (e) M. Gomez-Gallego,
M. J. Macheno and M. A. Sierra, Tetrahedron, 2000, 56, 5743; ( f )
M. J. Miller, in Recent Aspects of the Chemistry of β-Lactams—II,
Tetrahedron (Symposia-in-Print no. 80), 2000, 56, 5553–5742.
2 (a) S. R. Martel, R. Wisedale, T. Gallagher, L. D. Hall, M. F.
Mahon, R. H. Bradbury and N. J. Hales, J. Am. Chem. Soc., 1997,
119, 2309; (b) D. Planchenault, R. Wisedale, T. Gallagher and
N. J. Hales, J. Org. Chem., 1997, 62, 3438; (c) M. D. Andrews,
G. A. Brown, J. P. H. Charmant, T. M. Peakman, A. Rebello,
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(e) G. A. Brown, K. M. Anderson, M. Murray, T. Gallagher and
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Thesis, University of Bristol, 2000.
3 (a) J. W. Lown, in 1,3-Dipolar Cycloaddition Chemistry, ed.
A. Padwa, Wiley, New York, 1984; (b) R. Grigg, Chem. Soc. Rev.,
1987, 16, 89; (c) W. H. Pearson, Studies in Natural Products
Chemisty, ed. Atta-ur-Rahman, Elsevier, Amsterdam, 1988;
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4 (a) G. P. Rizzi, J. Org. Chem., 1970, 35, 2069; (b) M. Joucla and
J. Mortier, Tetrahedron Lett., 1987, 28, 2973; (c) H. Ardill, R. Grigg,
V. Sridharan, S. Surendrakumar, S. Thianpatanagul and S.
Kanajun, J. Chem. Soc., Chem. Commun., 1986, 602.
66.4 (CH), 164.1 (C᎐O), 168.6 (C᎐O) and 198.8 (C᎐O);
᎐
᎐
᎐
m/z (C.I.) 202 (M ϩ Hϩ, 1%).
4-Nitrobenzyl (2S*,5R*)-3,7-dioxo-2-methyl-4-oxa-1-azabi-
cyclo[3.2.0]heptane-2-carboxylate 19
To a stirred solution of oxazolidinone 4a (606 mg, 1.98 mmol)
in THF (20 cm3) at Ϫ78 ЊC under N2 was added dropwise over
15 min a solution of NaHMDS (1.0 mol dmϪ3 in THF; 2.0 cm3,
2.0 mmol). After stirring at Ϫ78 ЊC for 10 min, iodomethane
(0.65 cm3, 1.5 g, 10.4 mmol, 5 eq.) was added. Stirring was
continued and the mixture was allowed to slowly warm to room
temperature. After 3 h, AcOH (0.1 mol dmϪ3 in THF, 10 cm3)
was added and the solvent removed in vacuo. The residue was
treated with CH2Cl2 (10 cm3) and the resulting slurry was
purified rapidly by filtration through a short column of silica
(eluting with CH2Cl2) to give the α-methylated oxazolidinone
19 (185 mg, 29%) as a pale yellow oil as a 2 : 1 mixture of
diastereoisomers (Found: M ϩ Hϩ, 321.0737. C14H13N2O7
requires M, 321.0723); νmax/cmϪ1 1795 and 1760; δH (270 MHz,
d3-MeCN) 1.60 (3 H, s, Me, major isomer), 1.86 (3 H, s, Me,
minor isomer), 3.32 (1 H, dd, J 17.5, 1, H(6), major isomer),
3.35 (1 H, dd, J 17.5, 3, H(6), minor isomer), 3.57 (1 H, dd,
J 17.5, 3, H(6), major isomer), 5.21 (1 H, d, J 13.2, CH2Ar,
major isomer), 5.32 (2 H, s CH2Ar, minor isomer), 5.42 ( 1 H, d,
J 13.2, CH2Ar, major isomer), 5.75 (1 H, dd, J 3.0, 1.0, H(5)
minor isomer), 5.79 (1 H, dd, J 3.0, 1.0, H(5) major isomer),
7.60–7.54 (2 H, m, ArH both isomers) and 8.25–8.20 (2 H,
m, ArH both isomers); δC (75.5 MHz) 16.6 (CH3 minor), 18.9
(CH3 major), 47.2 (C(6) major), 47.7 (C(6) minor), 66.9 (CH2Ar
minor), 67.1 (CH2Ar major), 82.5 (C(5) major), 83.4 (C(5)
minor), 123.9 (CH major), 124.1 (CH minor), 128.4 (CH
minor), 128.7 (CH major), 141.3 (Cipso major), 148.0
(Cipso minor), 164.1 (CO major), 165.4 (CO minor), 169.9 (CO
minor), 170.1 (CO major), 171.7 (CO minor), 172.3 (CO
major); m/z (E.I.ϩ) 321 ([M ϩ H]ϩ, 2.5%), 292 (30), 248 (35),
140 (80), 136 ([O2NC6H4CH2]ϩ, 100).
5 (a) R. Huisgen, W. Scheer, G. Szcimies and H. Huber, Tetrahedron
Lett., 1966, 397; (b) R. Huisgen, R. Grashey and E. Steingruber,
Tetrahedron Lett., 1963, 1441; (c) Z. Bende, I. Bitter, L. Toke,
L. Weber, G. Toth and F. Janke, Liebigs Ann. Chem., 1982, 2146;
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6 A. Padwa and W. Dent, J. Org. Chem., 1987, 52, 235.
7 A. Eschenmoser, Chem. Soc. Rev., 1976, 5, 377.
8 K. Burger, A. Meffert and S. Bauer, J. Fluorine Chem., 1977,
10, 57.
9 (a) O. Tsuge, S. Kanemasa, M. Ohe, K. Yorozu, S. Takenaka and
K. Ueno, Bull. Chem. Soc. Jpn., 1987, 60, 4067; (b) O. Tsuge,
S. Kanemasa, M. Ohe and S. Takenaka, Bull. Chem. Soc. Jpn., 1987,
60, 4079; (c) S. Kanemasa, K. Sakamoto and O. Tsuge, Bull. Chem.
Soc. Jpn., 1989, 62, 1960.
10 (a) R. Grigg, S. Surendrakumar, S. Thianpatanagul and D. Vipond,
J. Chem. Soc., Perkin Trans. 1, 1988, 2693; (b) R. Grigg, J. Idle,
P. McMeekin, S. Surendrakumar and D. Vipond, J. Chem. Soc.,
Perkin Trans. 1, 1988, 2703.
11 G. A. Brown, S. R. Martel, R. Wisedale, J. P. A. Charmant,
T. Gallagher, N. J. Hales and C. W. G. Fishwick, J. Chem. Soc.,
Perkin Trans. 1, 2001, following paper (DOI: 10.1039/b010050l).
12 S. R. Martel, D. Planchenault, R. Wisedale, T. Gallagher and
N. J. Hales, Chem. Commun., 1997, 1897.
13 (a) T. T. Howarth and I. Stirling, Ger. Offen. 2,655,675, (Chem.
Abstr., 1977, 87, 102313); (b) A. G. Brown, D. F. Corbett,
J. Goodacre, J. B. Harbridge, T. T. Howarth, R. J. Ponsford,
I. Stirling and T. J. King, J. Chem. Soc., Perkin Trans. 1, 1984, 635.
14 E. J. J. Grabowski and P. J. Reider, European Patent 78 026 (Chem.
Abstr., 1983, 99, 122171).
15 P. C. Cherry, C. E. Newall and N. S. Watson, J. Chem. Soc., Chem.
Commun., 1978, 469.
16 H. E. Avery, Basic Reaction Kinetics and Mechanisms, Macmillan,
London, 1974.
17 (a) R. Huisgen, R. Grashey, H. Gotthardt and R. Schmidt, Angew.
Chem., Int. Ed. Engl., 1962, 1, 48; (b) R. Huisgen, Angew. Chem., Int.
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18 (a) A. G. Brown, D. F. Corbett and T. T. Howarth, J. Chem. Soc.,
Chem. Commun., 1977, 359; (b) S. M. Schmitt, D. B. R. Johnston
and B. G. Christensen, J. Org. Chem., 1980, 45, 1135; (c) T. C. Smale
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4-Nitrobenzyl 2-methyl-9-phenyl-4,8,10-trioxo-3,9-diazatricyclo-
[5.3.0.03,6]decane-2-carboxylate 20
To a solution of α-methylated oxazolidinone 19 (31 mg,
0.10 mmol) in degassed MeCN (2 cm3) under N2 was added
N-phenylmaleimide (19 mg, 0.11 mmol, 1.1 eq.). The mixture
was heated at 100 ЊC in a sealed tube for 15 h, before concen-
trating directly onto silica gel. Purification by flash column
chromatography (98 : 2 CH2Cl2–Et2O) gave cycloadduct 20
(34 mg, 78%) as a colourless oil and as a single diastereo-
isomer (Found: M ϩ Hϩ, 450.1307. C23H20N3O7 requires M,
450.1301); νmax/cmϪ1 1770 and 1720; δH (270 MHz) 1.99 (3 H, s,
Me), 3.12 (1 H, dd, J 2.3 and 16.5, H(5)), 3.36 (1 H, dd, J 5.0,
16.5, H(5)), 3.76 (1 H, t, J 8.3, C(7)), 4.11 (1 H, d, J 8.3, H(11)),
4.22 (1 H, ddd, J 2.3, 5.0, 8.3, H(6)), 5.32 (2 H, s, CH2Ar), 7.22–
7.18 (2 H, m, ArH), 7.57–7.44 (5 H, m, ArH), 8.29–8.25 (2 H,
m, ArH); δC (75.5 MHz) 16.6 (Me), 40.9 (C(6)), 47.9, 54.1,
58.0, 66.5, 71.0 (C(2)), 124.1, 126.4, 128.5, 129.4, 129.45, 131.0,
141.75, 169.8, 170.4, 172.6, 174.0; m/z (C.I.ϩ) 450 ([M ϩ H]ϩ,
1%), 408 (7), 138 (100).
Acknowledgements
We thank AstraZeneca, EPSRC and the Royal Society for
financial support, and SB Pharmaceuticals for a generous and
continuing supply of clavulanic acid.
20 A. Klant and G. Schuurman, J. Chem. Soc., Perkin Trans. 2, 1993,
799.
21 W. J. Leanza, F. DiNinno, D. A. Muthard, R. R. Wilkening, K. J.
Wildonger, R. W. Ratcliffe and B. G. Christensen, Tetrahedron,
1983, 39, 2505.
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1280
J. Chem. Soc., Perkin Trans. 1, 2001, 1270–1280