Nitrogen-containing heterocycles: 1,3-dipolar cycloaddition of stabilized nitrones with alkynes; Primary cycloadducts, first and second generation rearrangement processes

Article abstract of DOI:10.1039/b106832f

[4.3.0]- and [5.3.0]Bicyclic ring systems containing a nitrogen atom at the bridgehead position were prepared by a [3+2] addition of acetylenic dipolarophiles to the conformationally locked cyclic α-alkoxycarbonylnitrones 1a-c and 18. Reaction proceeded w

Full text of DOI:10.1039/b106832f

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Nitrogen-containing heterocycles: 1,3-dipolar cycloaddition of
stabilized nitrones with alkynes; primary cycloadducts, first and
second generation rearrangement processes
1
Frances Heaney,*a Julie Fenlon,b Colm O’Mahony,b Patrick McArdleb and
Desmond Cunninghamb
a Department of Chemistry, National University of Ireland, Maynooth, Ireland
b Department of Chemistry, National University of Ireland, Galway, Ireland
Received (in Cambridge, UK) 27th July 2001, Accepted 10th September 2001
First published as an Advance Article on the web 28th November 2001
[4.3.0]- and [5.3.0]Bicyclic ring systems containing a nitrogen atom at the bridgehead position were prepared by a
[3ϩ2] addition of acetylenic dipolarophiles to the conformationally locked cyclic α-alkoxycarbonylnitrones 1a–c and
18. Reaction proceeded with a high degree of diastereofacial selectivity with cycloaddition taking place to the face of
the dipole opposite the C-5 methyl group. Reaction with the C-phenyl nitrones, 1b and 1c, was straightforward and
the structure of 12b, arising from reaction of 1b with dimethyl acetylenedicarboxylate has been determined by single
crystal X-ray diffraction. The identity of the product(s) from reaction of C-methyl nitrones, 1a or 18, with dimethyl
acetylenedicarboxylate varies with reaction duration; 12a and 20 are the primary cycloaddition products and the
pyrrolooxazinones 14 and 22 appear after prolonged reaction duration. A similar pattern of reactivity is observed
when the same dipoles react with methyl propiolate. The structure of 14 has been confirmed following X-ray
crystallographic analysis. The primary cycloadducts, 12a, 20, 24a and 30, bearing a C3a-methyl group had poor
thermal stability and rearranged to the pyrrolooxazinones 13, 21, 25 and 31 respectively. A mechanistic proposal for
the origin of the fused pyrroles is included. A C-6 methyl substituent on the dipole 18 had no determining influence
on the stereochemical course or the rate of the cycloaddition reaction established by its unsubstituted analogues 1a
and 1b. In addition to its mechanistic findings, this paper reports two significant synthetic advances: access to a range
of unusually substituted hetero-fused pyrroles and to isoxazolooxazepinones, a rare bicyclic ring system.
γ-heteroatom, as in 11b, appears to have little influence on reac-
Introduction
tivity.10b,c The influence of the lactone/lactam moiety on the
The 1,3-dipolar cycloaddition reaction of nitrones and nitrile
cycloadditive potential of the dipoles 4, 6, 7 and 8 has been to
reduce their reactivity and high pressure, long reaction times or
Lewis acid catalysts have generally been employed to promote
oxides is amongst the most important methodologies for the
construction of N-containing heterocycles.1 We have recently
reported the ready preparation of the E-geometry fixed cyclic
reaction. The nitrones 1 and 18, unlike their sister dipoles 2, 4, 6
dipoles 1 by thermal cyclization of the corresponding E-alkenyl
and 7, are C-substituted and consequently cycloaddition could
oximes.2 “Lactone” containing nitrones like 1 are relatively rare,
however synthesis of their 5-membered analogues has been
be slow, but it should lead to highly substituted isoxazolo-
oxazinones. We now report our findings on the reaction
of 1 and 18 with electron poor acetylenes and the tendency
of the primary cycloadducts to participate in rearrangement
reported; reaction of isonitroso Meldrum’s acid with ketones
forms 2 in moderate yield.3 Tamura’s group have prepared
the C-5 phenyloxazinone N-oxide 4 by indirect oxidation of
reactions.
R-phenylglycinol followed by condensation with methyl glyoxy-
late,4 whilst Baldwin and co-workers report formation of the
same dipole by direct oxidation (dimethyldioxirane, 3–4 equiv-
alents) of oxazinone 3.5a Looper and Williams report the
success of Davis’ oxaziridine for oxidation of analogues of 3,5b
and finally, 6, the lactam analogue of 1 has been accessed by
oxidation (H2O2, Na2WO4) of the pyrazinone 5.6 Related
dipoles, the azomethine ylides 7 have been extensively studied
by Harwood et al.7 and preparation and cycloaddition of the
azomethine imine 8 has recently been reported.8 Ali and Wazeer
have shown earlier that the introduction of an α-keto substitu-
ent lowers the reactivity of the cyclic nitrone 9 compared to the
parent 10,9 † whilst the presence of a β-heteroatom makes 11a
more reactive than the carbocyclic analogue.10a ‡ Finally, a
† It is reported that bond opposition strain in the transition state lead-
ing to cycloaddition and a lower dipole moment combine to render the
α-keto dipole a less reactive species.
‡ It is proposed that the skeletal oxygen atom may have a defining
influence on the conformation of the heterocyclic dipole and that the
torsional strain relieved when it undergoes cycloaddition will be greater
than that associated with addition to the carbocyclic analogue.
Results and discussion
Following stirring in boiling CHCl3 (30 h) the dipole 1a reacts
with dimethyl acetylenedicarboxylate (1.5 eq.) in a diastereo-
facially specific manner furnishing 12a as the only reaction
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J. Chem. Soc., Perkin Trans. 1, 2001, 3382–3392
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106832f

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1
Table 1 Selected H NMR spectral data for the isoxazolooxazinones
an additional methoxy resonance signal. To the new adduct we
12, 15, 23, 24 and 23c
assigned structure 14. A crystal of 14 suitable for X-ray analysis
was obtained following slow evaporation of C6H6 and confirm-
ation that it has a 1-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]-
oxazinone framework rests with this structure determination.
The ORTEX drawing of 14 is shown in Fig. 1. The pyrrole ring,
1H NMR position (ppm) [3J6,7, 3J6,6/Hz]
Adduct
6a-H
6b-H
7-H
2-H/3-H
12a
12b
15
23a
24a
23b
24b
23c
4.30 [2.93, 12.02]
4.14 [3.17, 11.96]
4.33 [3.17, 11.72]
4.46 [2.69, 12.02]
4.25 [2.93, 11.96]
4.05 [3.17, 11.96]
4.20 [2.93, 11.96]
4.24 [3.05, 11.60]
4.10 [9.40, 12.02]
3.85 [10.99, 11.96]
4.68 [9.52, 11.72]
4.16 [6.84, 12.02]
4.05 [11.96, 11.96]
3.73 [11.23, 11.96]
4.04 [10.74, 11.96]
4.57 [9.77, 11.60]
3.45
3.62
3.72
3.48
3.32
3.57
3.54
3.65
—
—
—
7.38
6.00
7.48
6.26
7.19
Fig. 1 ORTEX drawing of compound 14.
as expected, is planar (mean deviation from planarity 0.04 Å),
and 4-C and 2-C (crystal numbering system) are on opposite
sides of the plane by just 0.9 Å. The estimated dihedral angles
3aH–C–C–4H, Ϫ63.32Њ (0.32) and 3bH–C–C–4H, 54.73Њ (0.32)
are not as would be expected from analysis of the vicinal coup-
ling constants 3J3,4 of 14. The apparent failure of the NMR and
crystallographic data to correlate simply means that the six-
membered ring adopts a different conformation in solution
than in the solid state. The 1-oxo-3,4-dihydro-1H-pyrrolo-
[2,1-c][1,4]oxazinone framework of 14 has previously been
accessed by Harwood and Lilly following aromatisation of the
reaction product of azomethine ylide 7 (R = CO2Et) with
methyl propiolate.7b
Initially, it seemed likely that 14 may arise via 13 by way of a
direct cycloaddition–cycloreversion sequence involving a [4ϩ2]
addition of the pyrrole nucleus to a second equivalent of
dimethyl acetylenedicarboxylate, followed by elimination of a
molecule of methyl propiolate (Scheme 2, path A). Dimethyl
product. Nuclear Overhauser enhancement difference spec-
troscopy (NOEDS) experiments gave only a weak indication as
to the relative stereochemistry of 12a, which, following com-
acetylenedicarboxylate is
a reactive dienophile and the
involvement of 13 in a Diels–Alder reaction could be con-
sidered to be facilitated by the following structural features. The
2- and 5-positions of the pyrrole ring are already substituted,
therefore, Michael type addition is not an attractive option. The
pyrrole nitrogen atom is substituted thus lowering the acti-
vation energy for the [4ϩ2] cycloaddition. Finally the conjugat-
ing substituents in 13 lower the aromaticity of the pyrrole
nucleus further permitting it to function as a diene in a Diels–
Alder reaction.12 Despite these characteristics it was discovered
that independent heating of 13 with dimethyl acetylenedicarbo-
xylate failed to furnish any 14. This result suggests a critical role
for unreacted nitrone in the formation of 14 and our revised
mechanism (Scheme 2, path B) follows from a series of reac-
tions with 21, the 3-methyl analogue of 13; these observations
will be discussed below.
The reaction of C-phenyl dipole 1b with dimethyl acetylene-
dicarboxylate progressed more slowly than its methyl analogue
and some unreacted nitrone (26%) was present even after 40 h
heating. The diastereomeric products 12b and 15 were obtained
in a ratio of 10 : 1. The C-3a position carries a phenyl substitu-
ent and hence there exists no opportunity for 12b or 15 to form
pyrrolo-fused adducts in an analogous fashion to 13 or 14. As
1
parison with H NMR spectral data of the analogous adducts
12b and 15 (Table 1), is tentatively assigned as shown in the
drawing. Although 12a is stable either as a solid or in solution
at rt, efforts to recrystallise it [from CHCl3 (wet or dry) or C6H6]
alerted us to its very limited thermal stability. It was sub-
sequently found that following heating alone in boiling CHCl3
(25 h) 12a completely disappeared and the pyrrolo-fused bicycle
13 was isolated in 80% yield. ∆4-Isoxazolines are well recog-
nised as labile heterocycles11a and their ring opening reactions
have been synthetically exploited.11b Recent experiments sup-
port the involvement of acylaziridines and azomethine ylides as
intermediates in the ring transformation of isoxazolines,11c,d
and one possible route to the pyrrole nucleus from the aziridine
is detailed in Scheme 1. In an effort to obtain 13 directly
from reaction of 1a with dimethyl acetylenedicarboxylate, the
original reaction was repeated extending the time to 48 h.
Following purification of the product mixture two adducts were
isolated: the primary cycloadduct 12a (25%) and a second com-
1
pound (31%), not 13, but rather a new product with H NMR
spectral data similar to 13 with two exceptions—the loss of the
“aromatic” pyrrole H signal (δH 7.29 ppm) and the presence of
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Scheme 1
Scheme 2
X-ray analysis. A crystal suitable for structure determination
was obtained following slow solvent evaporation (CHCl3–
hexane) and the ORTEX drawing of 12b is shown in Fig. 2. The
isoxazoline ring is quite flat with a mean deviation from
planarity of 0.1 Å and the angle this ring makes with the plane
defined by C(10)–N(1)–C(1)–C(8) (crystal numbering system) is
63.0Њ. The dihedral angles 9bH–C–C–10H and 9aH–C–C–10H
are estimated as Ϫ69.53Њ (0.53) and 172.95Њ (0.41), respectively.
These angles correlate well with the observed vicinal coupling
3
3
in 12b J6a,7 (3.17 Hz) and J6b,7 (10.99 Hz) suggesting that in
this adduct the oxazinone ring adopts a similar conformation
in the solid and the solution state. From the product structure it
is clear that 12b arises via addition of the dipolarophile to the
least hindered (α) face of the dipole. The same facial specificity
has previously been observed in the addition of olefinic sub-
strates to the chiral dipoles 4 and 7. In the reported cases the
C-5 “directing” group is a bulky phenyl substituent,4,5a,7c–e,13 but
in the current example the smaller methyl substituent is quite
effective in shielding one π-face of the dipole. NOEDS results
on the minor diastereomer 15 were also inconclusive, however,
it must, by default, have the C-3a and the C-7 substituents on
was observed for 12a, NOEDS results were inconclusive (0.8%
NOE between 7-Me and the 3a-ArH). However, the relative
stereochemistry of 12b was confirmed following a single crystal
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dicarboxylate gave 20 in 74% yield after 7.5 h heating in boiling
CHCl3. As expected, reaction at rt was much slower, however,
almost quantitative yield resulted after 7 d. Analysis of the
NOEDS results for 20 clearly indicates that the dipolarophile
added to the face of the dipole opposite the C-5 substituent.
The rate and diastereoselectivity of reaction of 18 with
dimethyl acetylenedicarboxylate compare favourably with those
observed for the C-6 unsubstituted analogues 1a and 1b. In
contrast, Baldwin et al.5a note a much reduced reaction rate and
almost complete loss of stereoselectivity when cycloaddition to
the diphenyl nitrone 4b is compared to reaction with the
monosubstituted dipole 4a.
The primary adduct 20 has limited thermal stability and
heating in the minimum amount of boiling CHCl3 effects
rearrangement to the pyrrolo-fused oxazinone 21 (76%). If
reaction between nitrone 18 and dimethyl acetylenedicarboxyl-
ate is allowed to continue for 24 h at reflux or 10 d at rt the
pyrrolo-fused adduct 22 accompanies the primary cycloadduct
20. We believe that 20 relates to 21 and 22 in the same way as
12a relates to 13 and 14. It is our proposal that 21, the initial
product of a thermal rearrangement of the primary cyclo-
adduct 20, subsequently serves as a precursor to 22. The
original proposal that 21 would lead directly to 22 (Scheme 2,
path A) was revised when simple heating of 21 with dimethyl
acetylenedicarboxylate failed to give any new product. It was
only when free nitrone 18 (10 mol%) was added to an equimolar
mixture of 21 and dimethyl acetylenedicarboxylate that any
trace of the pyrrole 22 became evident. After heating for 28 h in
Fig. 2 ORTEX drawing of compound 12b.
opposite faces. The change in relative stereochemistry between
12b and 15 is reflected in the resonance position of the 6b-
proton; in 12b this proton is shielded by the phenyl ring (δ 3.85
ppm) whilst in 15 it resonates further downfield (δ 4.68 ppm)
(Table 1).
The 7-membered cyclic nitrone 1c reacted with dimethyl
acetylenedicarboxylate (1.3 eq.) in a diastereofacially specific
manner and the isoxazolooxazepinone 16 was isolated in 87%
yield (CHCl3, 32 h). Apart from our previous report, the 7,5-
bicyclic skeleton of 16 remains unknown.2
1
boiling CHCl3 the H NMR spectrum of the crude reaction
mixture shows signals characteristic of the tris(methoxycarbo-
nyl)pyrrole 22 (5.03 ppm, m, 3-H and 3.91, s, OMe); the relative
intensities of the diagnostic signals for 21 and 22 suggest they
are present in a ∼7 : 1 ratio. These experimental results suggest
that, despite the structural attributes listed above, the pyrrole
nucleus of 21 (or 13) is too unreactive to form a Diels–Alder
adduct with dimethyl acetylenedicarboxylate and the first step
in the generation of 22 (or 14) is likely the quaternisation of the
pyrrole nitrogen atom by nucleophilic attack on the nitrone.
The N-protonated species is more susceptible to a cyclo-
addition–cycloreversion process, which ultimately leads to 22
(Scheme 2, path B). The origin of 14 likely mirrors that of
22 and the prolonged reaction of dipoles like 1a and 18 with
dimethyl acetylenedicarboxylate may represent a useful route to
unusually substituted hetero-fused pyrroles.
One interesting feature of the 1H NMR spectrum (CDCl3) of
21 is the appearance of the signals for 3-H and 4-H as quartets
rather than the expected doublet of quartets. The implication is
that each of these protons is spin coupled only to the adjacent
Me group with there being zero coupling between 3-H and 4-H
and indeed decoupling experiments are in complete agreement
with this conclusion. Clearly when in solution in CDCl3 21 must
adopt a conformation where the dihedral angle 3-H–C–C–4-H
would result in J = 0. Interestingly, no changes were observed in
the general appearance of the spectrum upon changing the
NMR solvent to C6D6.
The dipoles 1a, 1b and 1c all reacted with methyl propiolate
in boiling CHCl3 giving regioisomeric 4- and 5-substituted
∆4-isoxazolines. For all of the dipoles reaction with methyl
propiolate was more sluggish than with dimethyl acetylene-
The nitrone 18 was prepared in order to observe the influence
of a C-6 dipole substituent on the diastereoselectivity of the
cycloaddition reaction. Pyruvic acid was allowed to react with
but-3-en-2-ol and the resulting ester 17a upon treatment with
NH2OH afforded the oxime 17b. Thermal cyclisation (xylene,
140 ЊC, 51 h) of 17b proceeded with a moderate degree of facial
selectivity, generating the diastereomeric dipoles 18 and 19 in
the ratio 10 : 3. The major nitrone, 18, has the C-5 methyl group
shielding one face of the dipole and the C-6 substituent shield-
ing the opposite face (NOEDS results are summarised in the
drawings). The cycloaddition of 18 with dimethyl acetylene-
dicarboxylate and a larger excess of dipolarophile was
employed to promote cycloaddition. In the case of 1a reaction
was complete after heating for 32 h and the adducts 23a (56%)
and 24a (23%) were obtained. Their regiochemical assignment
is obvious from the resonance position of the isoxazoline pro-
ton, 2-H/3-H (Table 1). Cycloaddition took place in a facially
specific manner and only one diastereomer of each regioisomer
is found. For this series of compounds the stereochemical
relationship between 6a/6b-H and 7-H is based on the magni-
14
tude of the vicinal coupling constants J6,7 where Jax,eq < Jax,ax
(Table 1). That this generalisation holds for the current
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structures is supported by comparison between the crystallo-
graphic and the NMR spectral measurements for 12b. NOEDS
experiments on 23a indicate a small enhancement (∼0.5%) on
6b-H following irradiation of 3a-Me, and as 6b-H is cis to 7-Me
it follows that the 3a- and 7-methyl groups lie on the same face
of the molecule. Regioselective formation of the 4-substituted
adduct (isoxazolidine numbering) is in keeping with literature
precedent for the addition of acetylenes to C-substituted
nitrones.15 The relative stereochemistry of the minor adduct 24a
remains unknown as NOEDS results were inconclusive.
cycloadduct 23a has its 2-H signal at 7.48 ppm in the 1H NMR
spectrum and this signal has all but disappeared from the spec-
trum of the crude reaction mixture (82 h) and a new signal
presented at 7.36 ppm. Following flash chromatography it
became evident that the aforementioned signal was represent-
ative of an inseparable mixture of isomeric pyrroles identified
as 13 and 13i. Integration of signals characteristic of each com-
pound suggests the components to be present in the following
approximate ratios 24a : 23a : 25 : 25i : 13 plus 13i 3 : trace : 15 :
4 : 25.
The pyrrole 25 could have its origins in a straightforward
thermal rearrangement of 24a, akin to the observed transform-
ation of 12a to 13. However, this is probably not the case since
the corresponding reaction of dipoles 1a and 18 with dimethyl
acetylenedicarboxylate did not stop with the products of a
simple thermal reaction (13 and 21), but rather continued in a
more complex process furnishing instead 14 and 22. This appar-
ent anomaly is satisfied by considering that if pyrrole 25 were to
participate in an activation–addition–elimination sequence of
the type proposed for 13 and 21 (Scheme 2, path B), the
unsymmetrical nature of methyl propiolate should result in the
formation of two regioisomeric Diels–Alder cycloadducts A
and B. Elimination from A would return 25 and therefore the
process would be degenerate. However, elimination from B
would afford the isomeric compound 25i. Evidence to support
The adduct 24a, by virtue of the direction of polarisation of
the conjugated “double bond” of its isoxazoline ring, is acti-
vated to acylaziridine formation, and on thermal activation it
converts to the pyrrolooxazinone 25. The rate and extent of the
transformation are significantly reduced (40%, 56 h), but it
most likely proceeds by a mechanism parallel to that outlined
for 12a (80%, 25 h) in Scheme 1. The adduct 23a is not activated
toward acylaziridine formation in the same way as its regio-
isomer and it is thermally stable after 24 h heating in boiling
CHCl3. However, inspection of the crude 1H NMR spectrum of
the mixture after 82 h heating it is clear that very little of 23a
remains intact and whilst much decomposition has occurred
one new compound can be seen. This material, present in a 5 : 1
ratio with 23a has been isolated and characterised as the pyrrole
26a. The pyrrolooxazinone 26a likely arises from 23a as shown
in Scheme 3, a homolytic cleavage of the isoxazoline N–O bond
1
the structure of 25i lies with the crude H NMR spectral data
which clearly show a pair of doublets, 7.05 and 6.96 ppm with
J 4.4 Hz, typical of ortho-related protons on a pyrrole ring.
The pyrrolooxazinones 13 and 13i likely arise from 23a in a
parallel fashion i.e. an initial thermal rearrangement of 23a to
the pyrrolo-fused adduct 26a followed by an activation, Diels–
Alder cycloaddition sequence generating regioisomeric inter-
mediates C and D, methyl propiolate elimination affords 13 and
13i respectively.
As observed with dimethyl acetylenedicarboxylate the phenyl
substituted dipole 1b reacts more slowly with methyl propiolate
than its counterpart and 43% nitrone remained after a reaction
time of 40 h. Further 1b does not exhibit high diastereoselectiv-
ity in reaction with methyl propiolate and the diastereomeric
4-substituted isoxazolines 23b (31%) and 23c (13%) are isolated
with the 5-substituted adduct 24b (17%). For each of 23b
and 24b an ∼3% enhancement was observed on Ar-H upon
irradiation of 6b-H, and taken together with the coupling con-
stant data for J6,7 the relative stereochemistry of 23b and 24b is
thus assigned as shown in the diagrams. The relative stereo-
chemistry of 23c must be opposite to that of 23b and it is
assigned by default. Again it is worth noting the deshielding
experienced by 6b-H when the relative configuration at the
stereogenic centres is changed: thus, for 23b and 24b 6b-H
resonates at ∼δ 4.0 ppm whilst the same proton in 23c appears at
δ 4.57 ppm (Table 1).
To encourage reaction of 1c with methyl propiolate it
was necessary to employ a great excess of dipolarophile and
accordingly methyl propiolate was used as both reactant and
solvent. After 36 h the regioisomeric 4- and 5-substituted
∆4-isoxazolines 27 and 28 were formed in 24 and 60% yield
respectively. The similarity between the 1H NMR spectral data
of the three [5.3.0]bicyclic adducts 16, 27 and 28 suggests that
all the cycloadditions took place with the same stereochemical
sense (Table 2).
Scheme 3
of 23a generates a diradical species which is a precursor to the
acylaziridine, the mechanism for formation of the pyrrole ring
from the acylaziridine intermediate is as delinated for 13 in
Scheme 1.
As previously observed in the reaction of C-methyl dipoles
with dimethyl acetylenedicarboxylate, the composition of the
products of reaction between 1a and methyl propiolate is
1
Table 2 Selected H NMR spectral data for the isoxazolooxazepin-
ones 16, 27 and 28
δH (ppm)
1
dependent on reaction duration. After 82 h at reflux the H
NMR spectrum of the crude mixture clearly shows signals
characteristic of the primary adduct 24a (6.00 ppm, s, 3-H) as
well as a pair of doublets, 7.49 and 7.52 ppm each with a small
J value (∼1.5 Hz) characteristic of the meta-coupled aromatic
protons of 25. A second pair of doublets in the Ar–H region of
the spectrum points to the presence of a further reaction
product which we propose to have structure 25i. The primary
Adduct
6a-H and 6b-H
7a-H
7b-H
8-H
16
27
28
3.88 (2H)
3.86 (2H)
4.10 (1H) and 3.90 (1H)
2.24
2.21
2.23
1.67
1.64
1.75
3.60
3.50
3.52
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reactivity of its sister compounds 12a, 20 and 24a, it rearranges
to the pyrrole 31 (67%) following heating in boiling CHCl3. The
isomeric adduct 29, like its sister compound 23a, is less prone to
thermal rearrangement, remaining intact after 24 h (CHCl3, 63
ЊC). Following heating for 82 h some decomposition became
evident, however a single new compound, the pyrrolooxazinone
26b was isolated from the reaction mixture. A proposed mech-
anistic origin of 26b is outlined in Scheme 3. When reaction
between 18 and methyl propiolate was extended to 84 h and the
products were analysed by 1H NMR spectroscopy, it was found
that the regioisomeric primary cycloadducts 29 and 30 were
accompanied by the pyrrole 31 and what is believed to be its
isomer 31i. The pyrroles 31 and 31i are analogous with 25 and
25i and presumably share the same mechanistic origin.
It is clear from the reaction of the 3,5,6-trimethyl nitrone 18
with dimethyl acetylenedicarboxylate and with methyl propi-
olate that the stereochemical mode of reaction is the same as
that observed with the less substituted nitrones 1. The C-6
substituent on 18 is more remote from the dipole reacting site
and it is apparent that if it is to have a chance to invert the
diastereoselectivity of the cycloaddition reaction it needs to
be much larger than the C-5 group. Work is progressing in this
direction.
To promote reaction between the fully substituted nitrone 18
and methyl propiolate, the reactants were heated in refluxing
CHCl3 (30 h). As with 1a, the 4-substituted isoxazoline is the
major regioisomer and 29 and 30 were isolated in the ratio 3 : 2.
NOEDS results indicate that the new adducts have the same
relative stereochemistry and that in each case cycloaddition
proceeded through a transition state involving the dipolarophile
approaching the dipole on the face opposite the C-5 methyl
group. The direction of polarisation of the isoxazoline C᎐C
bond makes regioisomer 30 a good candidate for thermally
᎐
Conclusion
induced acylaziridine formation and in keeping with the
In conclusion, 1,3-dipolar cycloaddition of the oxazinone
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N-oxides 1a,b to acetylenic dipolarophiles proceeded to afford
cycloadducts predominately through addition to the less substi-
tuted face of the dipole. The phenyl substituted dipole 1b with
its enhanced conjugation is a more sluggish reactant than its
methyl analogue 1a; this was reflected in longer reaction times
and incomplete conversion to cycloadducts. Adducts arising
from reaction of 1a, with a C-3a methyl substituent are prone
to primary and secondary rearrangement processes opening a
route to highly substituted pyrrolo-fused oxazinones. The
seven-membered dipole 1c on trapping with the acetylenes
furnished novel isoxazolooxazepinones: examples of a rare
bicyclic ring system. The trapping of the trisubstituted nitrone
18 with acetylenic dipolarophiles indicates that the additional
C-6 substituent had no role to play in influencing the stereo-
chemical course of the cycloaddition. It remains to be seen if a
group larger than methyl is able to override the control of the
C-5 substituent. The high regio- and diastereoselectivities of
the cycloaddition chemistry of 1 and 18 encourage us in future
investigations of their chiral, non-racemic derivatives in search
of enantiopure products.
(10 cm3) at reflux under a nitrogen atmosphere for 25 h. The
mixture was allowed to cool to rt and the solvent removed
under reduced pressure. The crude product was purified by flash
chromatography (Et2O–petroleum spirit, 1 : 2) yielding 13, col-
ourless needles (75 mg, 80%), mp 116–119 ЊC (from Et2O–
petroleum spirit) (Found: C, 53.88; H, 4.94; N, 4.74. C12H13NO6
requires: C, 53.93; H, 4.87; N, 5.24%); δH (400 MHz) 1.56 (3H,
d, J 6.59, Me), 3.87 and 3.94 (2 × 3H, 2 × s, 2 × OMe), 4.44 (1H,
d, J 11.96, 3b-H), 4.66 (1H, dd, J 11.96 and 3.17, 3a-H), 5.06
(1H, m, 4-H), 7.36 (1H, s, Ar-H); δC (100 MHz) 18.83 (Me),
49.15 (4-C), 52.20 and 52.71 (OMe), 70.76 (3-C), 118.35 (8-C),
118.52 (7-C), 120.90, 121.54 (8a-C, 6-C), 157.42, 160.43 and
163.62 (2 × CO Me and C᎐O); DEPT 135 (400 MHz) 18.83
᎐
2
(Me), 49.15 (4-C), 52.20 and 52.71 (OMe), 70.76 (Ϫve, 3-C),
118.35 (8-C), νmax/cmϪ1 3138, 2359, 2340 (Ar-CH), 1732, 1714,
1706 (3 × C᎐O), 1463 (Ar C᎐C), 1226 (C–O).
᎐
᎐
Trimethyl 4-methyl-1-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]-
oxazine-6,7,8-tricarboxylate 14
The nitrone 1a (0.30 g, 2.1 mmol) and dimethyl acetylene-
dicarboxylate (0.40 g, 2.8 mmol) were stirred in CHCl3 (40 cm3)
at reflux under a nitrogen atmosphere for 48 h. The reaction
mixture was allowed to cool to rt and the solvent was removed
under reduced pressure. The yellow oily residue was purified by
flash chromatography (Et2O–petroleum spirit, 1 : 1) yielding
12a (148 mg, 25%, spectral data as previously reported), 14 (209
mg, 31%) and unreacted nitrone (32 mg, 11%). Compound 14:
colourless needles, mp 99–101 ЊC (from C6H6) (Found: C, 51.62;
H, 4.40; N, 4.22. C14H15NO8 requires: C, 51.69; H, 4.62; N,
4.31%); δH (400 MHz) 1.59 (3H, d, J 6.83, 4-Me), 3.90 (6H, s,
2 × OMe), 3.91 (3H, s, OMe), 4.43 (1H, d, J 10.99, 3b-H), 4.65
(1H, br dd, 3a-H), 5.20 (1H, m, 4-H); δH (400 MHz, d6-acetone)
1.78 (3H, d, J 6.59, Me), 3.98, 3.99 and 4.07 (3 × 3H, 3 × s,
3 × OMe), 4.75 (1H, dd, J 11.99 and 1.10, 3b-H), 5.05 (1H, dd,
J 11.99 and 2.75, 3a-H), 5.36 (1H, m, 4-H); δC (C6D6, 100 MHz)
17.23 (Me), 49.46 (4-C), 51.88 (OMe), 52.09 (OMe), 52.22
(OMe), 69.41 (3-C), 120.71 (7-C), 121.98 (8-C), 122.87 (6-C),
123.63 (8a-C), 155.10, 159.39, 162.99, 163.46 (3 × CO2Me
and C᎐O), νmax/cmϪ1 1716, 1721, 1737, 1755, (4 × C᎐O), 1554
Experimental
Mps were determined on an Electrothermal melting point
apparatus and are uncorrected. Elemental analyses were per-
formed on a Perkin-Elmer model 240 CHN analyser. IR spectra
(Nujol mull and liquid film) were measured on a Perkin
Elmer 1600 series (FT) or a Perkin Elmer 983G spectrometer.
1H and 13C NMR spectra were recorded using a JEOL
EX270 FT NMR spectrometer and a JEOL JNM-LA400 FT
NMR spectrometer at probe temperatures with tetramethyl-
silane as internal reference and deuteriochloroform as solvent;
J values are given in hertz. Flash column chromatography
was carried out on silica gel 60 (Merck 9385, 70–230
mesh) and analytical TLC plates were purchased from Merck.
Samples were located by UV illumination using a portable
Spectroline Hanovia lamp (λ = 254 nm) or by the use of iodine
staining. Mass spectra were recorded on a Profile Kratos
Analytical Instrument.
᎐
᎐
(C᎐N); m/z 325 (M ϩ), 294 (base), 236.
ؒ
᎐
Dimethyl 3a,7-dimethyl-4-oxo-3a,4,6,7-tetrahydroisoxazolo-
[3,2-c][1,4]oxazine-2,3-dicarboxylate 12a
X-Ray crystal structure determination of 14.§ The structure
was solved by direct methods, SHELXS-97,16 and refined by
full matrix least squares using SHELXL-97.17 SHELX oper-
ations were rendered paperless using ORTEX which was also
used to obtain the drawings.18 Data were corrected for Lorentz
and polarization effects but not for absorption. Hydrogen
atoms were included in calculated positions with thermal
parameters 30% larger than the atom to which they were
attached. The non-hydrogen atoms were refined anisotropically.
All calculations were performed on a Pentium PC. Crystal data
for 14 are given in Table 3.
The nitrone 1a (0.11 g, 0.78 mmol) and dimethyl acetylene-
dicarboxylate (0.16 g, 1.2 mmol) were stirred in CHCl3 (24 cm3)
at reflux under a nitrogen atmosphere for 30 h. The reaction
mixture was cooled to rt and the solvent removed under
reduced pressure. The yellow oily residue was purified by flash
chromatography (Et2O–petroleum spirit 40–60 ЊC, 2 : 1) giving
12a, colourless needles (0.18 g, 81%), mp 99–101 ЊC (from
CHCl3–petroleum spirit) (Found: C, 50.45; H, 5.16; N, 4.78.
C12H15NO7 requires: C, 50.53; H, 5.26; N, 4.91%); δH (400
MHz) 1.29 (3H, d, J 6.35, 7-Me), 1.83 (3H, s, 3a-Me), 3.45 (1H,
m, 7-H), 3.83 and 3.87 (2 × 3H, 2 × s, 2 × OMe), 4.10 (1H, dd,
J 12.02 and 9.40, 6b-H), 4.30 (1H, dd, J 12.02 and 2.93, 6a-H);
δC (100 MHz) 14.84 (7-Me), 27.03 (3a-Me), 52.63 and 53.14
(OMe), 55.73 (7-C), 67.96 (6-C), 74.49 (3a-C), 114.66 (3-C),
Dimethyl 7-methyl-4-oxo-3a-phenyl-3a,4,6,7-tetrahydro-
isoxazolo[3,2-c][1,4]oxazine-2,3-dicarboxylates 12b and 15
Freshly recrystallised nitrone 1b (0.19 g, 0.93 mmol) and
dimethyl acetylenedicarboxylate (0.18 g, 1.27 mmol) were
stirred in CHCl3 (23 cm3) at reflux under a nitrogen atmosphere
for 40 h. The reaction mixture was allowed to cool to rt and the
solvent was removed under reduced pressure. The yellow oily
residue was purified by flash chromatography (Et2O–petroleum
spirit, 1 : 1), yielding 12b (178 mg, 56%), 15 (17.5 mg, 6%) and
unreacted nitrone (0.05 g, 26%). Compound 12b: colourless
cubic crystals, mp 159–162 ЊC (from CHCl3–hexane) (Found: C,
58.82; H, 4.99; N, 4.40. C17H17NO7 requires: C, 58.79; H, 4.90;
146.34 (2-C), 158.01, 161.92 and 167.27 (C᎐O and 2 × CO Me);
᎐
2
DEPT 135 (400 MHz) 14.83 (7-Me), 27.02 (3a-Me), 52.64
(OMe), 53.17 (OMe), 55.73 (7-C), 67.67 (6-C) and unreacted
nitrone (0.025 g, 11%).
NOEDS results: irradiation of 6b-H caused a 19% enhance-
ment on its partner 6a-H, 2% enhancement on 7-Me and 0.8%
on 3a-Me. Back irradiation of 3a-Me caused a 0.6% enhance-
ment on 6b-H. Irradiation of 6a-H caused an enhancement of
5.8% on 7-H and 23% on its partner 6b-H.
Dimethyl 4-methyl-1-oxo-3,4,6,7-tetrahydro-1H-pyrrolo[2,1-c]-
[1,4]oxazine-6,7-dicarboxylate 13
§ CCDC reference numbers 168302 and 168303. See http://
www.rsc.org/suppdata/p1/b1/b106832f/ for crystallographic files in .cif
or other electronic format.
The adduct 12a (100 mg, 0.35 mmol) was stirred in CHCl3
3388
J. Chem. Soc., Perkin Trans. 1, 2001, 3382–3392

View Article Online
Table 3 Crystal data and structure refinementa for 14
2,3-Dimethoxycarbonyl-8-methyl-3a-phenyl-7,8-dihydro-6H-
isoxazolo[3,2-c][1,4]oxazepin-4(3aH)-one 16
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
Unit cell dimensions
C14H15NO8
325.27
293(2)
Monoclinic
P21/a
The nitrone 1c (0.55 g, 2.50 mmol) and dimethyl acetylenedi-
carboxylate (0.46 g, 3,25 mmol) were stirred in CHCl3 (20 cm3)
at reflux under a nitrogen atmosphere for 32 h. The reaction
mixture was allowed to cool to rt and the reaction solvent
removed under reduced pressure. The yellow oily residue was
purified by flash chromatography (Et2O–petroleum spirit, 1.5 :
1.0) to give 16 (0.79 g, 87%) and unchanged nitrone (0.07 g,
12%). Compound 16: colourless cubic crystals (from C6H6–
petroleum spirit), mp 145–146 ЊC (Found: C, 60.08; H, 7.12; N,
5.22%. C18H19NO7 requires: C, 59.83; H, 7.28; N, 5.36%);
δH (270 MHz) 1.42 (3H, d, J 5.87, Me), 2.24 and 1.67 (2 × 1H,
2 × m, 7a-H and 7b-H), 3.60 (1H, m, 8-H), 3.85 and 3.67
(2 × 3H, 2 × s, 2 × OMe), 3.88 (2H, m, 6a-H and 6b-H), 7.40
(3H, m, m- and p-Ar-H), 7.62 (2H, m, o-Ar-H); δC (67.5 MHz)
19.6 (Me), 36.6 (7-C), 51.9 and 53.2 (2 × OMe), 57.2 (8-C), 64.0
(6-C), 86.7 (3a-C), 113.1 (3-C), 126.3–134.8 (Ar-C), 138.0 (2-C),
a = 9.917(2) Å
b = 11.620(3) Å
c = 13.983(4) Å
β = 107.40(2)Њ
1537.4(7) Å3
4
Volume
Z
Density (calculated)
Absorption coefficient
Independent reflections
Final R indices [I > 2σ(I )]
1.405 Mg mϪ3
0.117 mmϪ1
1880 [R(int) = 0.0150]
R1 = 0.0365, wR2 = 0.0934
a R indices: R1 = [Σ||Fo| Ϫ |Fc||]/Σ|Fo| (based on F), wR2 = [[Σw(|Fo
Ϫ
2
2
½
F2-C|)2]/[Σw(Fo )2]] (based on F 2). w = 1/[(σFo)2 ϩ (0.0569P)2]. Goodness-
of-fit = [Σw(Fo2 Ϫ F2-C)2/(Nobs Ϫ Nparameters)] .
½
159.7, 164.3 and 168.6 (2 × CO Me and C᎐O).
᎐
2
Table 4 Crystal data and structure refinementa for 12b
1-Methylprop-2-enyl 2-oxopropanoate 17a
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
Unit cell dimensions
C17H17NO7
347.32
293(2)
Orthorhombic
P21
Pyruvic acid (5.07 g, 57.6 mmol) and but-3-en-2-ol (4.98 g, 69.2
mmol) were heated for 5 h at reflux in C6H6 (200 cm3) in the
presence of a catalytic amount of p-TsOH (0.55 g, 2.89 mmol)
using a Dean–Stark apparatus. The reaction was allowed to
cool to rt and was washed with sat. NaHCO3 (2 × 150 cm3) and
then with water (2 × 150 cm3). The organic layers were collected
and dried (anhydrous Na2SO4), filtered and concentrated to
yield the crude product as a yellow, pungent, mobile oil (6.56 g,
80.2%) which was not purified further. δH (400 MHz) 1.35 (3H,
dd, J 6.21 and 2.01, OCMe), 2.39 (3H, s, Me), 5.14 (1H, dd,
a = 9.023(3) Å
b = 11.0408(16) Å
c = 16.112(3) Å
β = 89.976(19)Њ
1605.1(6) Å3
4
Volume
Z
Density (calculated)
Absorption coefficient
Independent reflections
Final R indices [I > 2σ(I )]
1.437 Mg mϪ3
0.113 mmϪ1
1823 [R(int) = 0.0583]
R1 = 0.0501, wR2 = 0.1127
J 1.10 and 10.62, ᎐CH ), 5.25 (1H, dd, J 1.10 and 17.21, ᎐CH ),
᎐
᎐
2
2
5.37 (1H, M, CH᎐), 5.81 (1H, m, OCH).
᎐
a R indices: R1 = [Σ||Fo| Ϫ |Fc||]/Σ|Fo| (based on F), wR2 = [[Σw(|Fo
Ϫ
2
2
½
F2-C|)2]/[Σw(Fo )2]] (based on F 2). w = 1/[(σFo)2 ϩ (0.0569P)2]. Goodness-
1-Methylprop-2-enyl 2-(hydroxyimino)propanoate 17b
of-fit = [Σw(Fo2 Ϫ F2-C)2/(Nobs Ϫ Nparameters)] .
½
The α-keto ester 17a (6 g, 42.2 mmol), pyridine (5.01 g, 63.4
mmol) and NH2OHؒHCl (4.40 g, 63.3 mmol) were stirred in
EtOH (600 cm3) at rt for 15 h. The mixture was concentrated
and taken up in CH2Cl2 (300 cm3) and washed with water
(2 × 150 cm3). The organic layers were collected, dried
(anhydrous Na2SO4), filtered and concentrated to yield the
product, colourless plates (5.97 g, 90%), mp 56.5–58.5 ЊC (from
C6H6–hexane) (Found: C, 53.72; H, 6.79; N, 8.69. C7H11NO3
requires: C, 53.50; H, 7.01; N, 8.92%); δH (400 MHz) 1.38 (3H,
d, J 6.22, OCMe), 2.09 (3H, s, Me), 5.16 (1H, dd, J 10.62 and
N, 4.04%); δH (400 MHz) 1.32 (3H, d, J 6.35, Me), 3.62 (1H, m,
7-H), 3.66 (3H, s, OMe), 3.85 (1H, dd, J 11.96 and 10.99, 6b-H),
3.89 (3H, s, OMe), 4.14 (1H, dd, J 11.96 and 3.17, 6a-H), 7.42
(3H, m, m- and p-Ar-H), 7.60 (2H, m, o-Ar-H); δC (100 MHz)
15.73 (Me), 52.16 and 53.27 (2 × OMe), 58.62 (7-C), 67.40
(6-C), 79.59 (3a-C), 111.86 (3-C), 127.10, 128.63, 128.97
(Ar-C), 137.84 (quaternary n-Ar-C), 149.18 (2-C), 158.39,
161.66 and 167.82 (2 × CO Me and C᎐O).
᎐
2
NOEDS results for 12b: irradiation of 7-Me caused a 4.9%
enhancement on 7-H and 1.2% on 6a-H and 0.8% on each of
the Ar-H signals.
0.91, ᎐CH ), 5.28 (1H, dd, J 17.21 and 0.91, ᎐CH ), 5.47 (1H,
᎐
᎐
2
2
m, OCH), 5.87 (1H, m, CH᎐), 10.64 (1H, br s, OH); δ (100
᎐
C
MHz) 10.42 (OCMe), 19.81 (Me), 72.75 (OC), 116.57 (᎐CH ),
᎐
2
136.91 (CH᎐), 149.18 (C᎐N), 162.85 (C᎐O).
᎐
᎐
᎐
X-Ray crystal structure determination of 12b.§ As for
compound 14. Crystal data for 12b are given in Table 4.
2,3,5-Trimethyl-6-oxo-3,6-dihydro-2H-1,4-oxazin-4-ium-4-
Compound 15: a brown–orange gum which solidified on
standing (decomposed 118 ЊC) (combustion analysis is
obtained as an enriched mixture of 12b with 15. Found: C,
58.80; H, 4.64; N, 3.84. C16H17NO7 requires: C, 58.78; H, 4.89;
N, 4.03%); δH (400 MHz) 1.31 (3H, d, J 6.60, 7-Me), 3.63 (3H, s,
OMe), 3.72 (1H, m, 7-H), 3.93 (3H, s, OMe), 4.33 (1H, dd,
J 11.90 and 3.30, 6a-H), 4.68 (1H, dd, J 11.90 and 9.52, 6b-H),
7.37 (3H, m, m- and p-Ar-H), 7.54 (2H, m, o-Ar-H); δC (100
MHz, obtained for an enriched mixture of 12b with 15) 13.40
(7-Me), 52.98 and 53.74 (2 × OMe), 58.96 (7-C), 68.90 (6-C),
79.77 (3a-C), 111.65 (3-C), 128.13, 128.21, 128.81 (Ar-C),
137.09 (quaternary n-Ar-C), 153.09 (2-C), 158.61, 162.01 and
olates 18 and 19
Oxime 17b (1.2 g, 7.64 mmol) was heated at reflux in xylene
(410 cm3) in the presence of hydroquinone (1% w/v, 4.1 g) under
a nitrogen atmosphere for 51 h. The reaction mixture was
allowed to cool to rt and the precipitated hydroquinone was
filtered off. The filtrate was concentrated and taken up in
CHCI3 (10 cm3), and further hydroquinone precipitated, which
was again removed by filtration. The filtrate was concentrated
to yield the crude product, a black viscous oil. Purification by
flash chromatography (Et2O–petroleum spirit, 4 : 1) afforded 18
(624 mg, 52%), 19 (190 mg, 16%) and unreacted oxime 17b
(260 mg, 22%).
166.64 (2 × CO Me and C᎐O).
᎐
2
NOEDS results for 15: irradiation of 7-H gave an enhance-
ment of 8.10% onto 7-Me and 2.17% onto 6a-H. Irradiation
of 6a-H gave an enhancement of 26.76% onto its partner
6b-H.
Compound 18: colourless cubic crystals, mp 82–84 ЊC (from
CHCl3–hexane) (Found: C, 53.76; H, 7.01; N, 8.59. C7H11NO3
requires: C, 53.50; H, 7.01; N, 8.92%); δH (400 MHz) 1.51 (3H,
d, J 6.59, 6-Me), 1.53 (3H, d, J 6.60, 5-Me), 2.22 (3H, s, 3-Me),
J. Chem. Soc., Perkin Trans. 1, 2001, 3382–3392
3389

View Article Online
3.91 (1H, m, 5-H), 4.45 (1H, m, 6-H); δC (100 MHz) 11.95
Dimethyl 3,4-dimethyl-1-oxo-3,4-dihydro-1H-pyrrolo[2,1-c]-
(6-Me), 14.29 (5-Me), 18.41 (3-Me), 67.74 (5-C), 75.05 (6-C),
[1,4]oxazine-6,7-dicarboxylate 21
134.83 (3-C), 159.03 (C᎐O).
᎐
The adduct 20 (50 mg, 0.167 mmol) was stirred with heating
under vigorous reflux in the minimum amount of CHCl3
(1 cm3) for 48 h. The reaction was allowed to cool to rt and the
solvent removed under reduced pressure. The crude product
was purified by flash chromatography (Et2O–petroleum spirit;
1 : 2) yielding 21 (35.5 mg, 76%), which crystallised as colour-
less needles, mp 118–120 ЊC (from Et2O–petroleum spirit)
(Found: C, 55.84; H, 5.26; N, 4.81. C13H15NO6 requires: C,
55.52; H, 5.34; N, 4.98%); δH (400 MHz) 1.38 (3H, d, J 6.87,
4-Me), 1.56 (3H, d, J 6.78, 3-Me), 3.87 (3H, s, OMe), 3.95 (3H,
s, OMe), 4.71 (1H, q, J 6.87, 4-H), 4.86 (1H, q, J 6.78, 3-H),
7.35 (1H, s, 8-H); δC (100 MHz) 19.34 (4-Me), 20.61 (3-Me),
52.20 (4-C), 52.71 (OMe), 53.18 (OMe), 78.10 (3-C), 117.97
(8-C), 120.65, 121.79 and 125.75 (7-C, 6-C and 8a-C), 156.87,
NOEDS results for 18: irradiation of 5-H caused a 0.68%
enhancement on 6-H and 5.14% enhancement on the signal
representing 5-Me and 6-Me. m/z 57 (base), 68, 85, 113, 157
(Mϩ).
Compound 19: a brown mobile oil which solidified on stand-
ing (Found: C, 53.55; H, 6.83; N, 8.67. C7H11NO3 requires: C,
53.50; H, 7.01; N, 8.92%); δH (400 MHz) 1.42 (3H, d, J 6.59,
6-Me), 1.47 (3H, d, J 6.96, 5-Me), 2.20 (3H, s, 3-Me), 3.97 (1H,
m, 5-H), 4.82 (1H, m, 6-H); δC (100 MHz) 11.61 (6-Me), 11.83
(5-Me), 15.69 (3-Me), 68.30 (5-C), 72.37 (6-C), 134.23 (3-C),
159.62 (C᎐O).
᎐
NOEDS results for 19: irradiation of 5-H caused a 3.93%
enhancement on 6-H and irradiation of 6-H caused a 4.11%
enhancement on the signal representing 5-H.
159.67 and 163.66 (2 × CO Me and C᎐O); m/z 281 (M ϩ), 250.
ؒ
᎐
2
Dimethyl 3a,6,7-trimethyl-4-oxo-3a,4,6,7-tetrahydroisoxazolo-
[3,2-c][1,4]oxazine-2,3-dicarboxylate 20 and trimethyl 3,4-
dimethyl-1-oxo-3,4,6,7-tetrahydro-1H-pyrrolo[2,1-c][1,4]-
oxazine-6,7,8-tricarboxylate 22
Methyl 3a,7-dimethyl-4-oxo-3a,4,6,7-tetrahydroisoxazolo[3,2-
c][1,4]oxazine-3-carboxylate 23a and methyl 3a,7-dimethyl-4-
oxo-3a,4,6,7-tetrahydroisoxazolo[3,2-c][1,4]oxazine-2-
carboxylate 24a
(i) Nitrone 18 (0.050 g, 0.318 mmol) and dimethyl acetylenedi-
carboxylate (0.090 g, 0.63 mmol) were stirred in CHCl3 (5 cm3)
at reflux under a nitrogen atmosphere for 7.5 h. The reaction
mixture was allowed to cool to rt, was concentrated under
reduced pressure and purified by flash chromatography (Et2O–
petroleum spirit, 1 : 2) yielding 20 (134 mg, 74%). Compound
20: colourless needle-like crystals, mp 157–159.5 ЊC (from
CHCl3–hexane) (Found: C, 51.81; H, 5.53; N, 4.23. C13H17NO7
requires: C, 52.17; H, 5.68; N, 4.68%); δH (400 MHz) 1.28 (3H,
d, J 5.86, 7-Me), 1.40 (3H, d, J 6.59, 6-Me), 1.82 (3H, s, 3a-Me),
3.07 (1H, m, 7-H), 3.83 (3H, s, OMe), 3.85 (3H, s, OMe), 4.21
(1H, m, 6-H); δC (100 MHz) 15.14 (7-Me), 17.47 (6-Me), 26.94
(3a-Me), 52.71 (OMe), 53.10 (OMe), 61.21 (7-C), 74.71 (3a-C),
75.26 (6-C), 115.55 (3-C), 145.32 (2-C), 158.01, 162.13 and
The nitrone 1a (0.10 g, 0.69 mmol) and methyl propiolate
(0.29 g, 3.49 mmol) were stirred in CHCl3 (10 cm3) at reflux
under a nitrogen atmosphere for 25 h. The reaction mixture was
allowed to cool to rt and the reaction solvent and unreacted
dipolarophile were removed under reduced pressure, yielding
the crude product as an orange–brown oil. The residue was
purified by flash chromatography (Et2O–petroleum spirit, 1 : 2),
yielding 24a (36.5 mg, 23%), 23a (88.5 mg, 56%) and unreacted
dipole (19 mg, 19%).
Compound 24a: colourless cubic crystals, mp 88–90 ЊC (from
CHCl3–hexane) (Found: C, 52.57; H, 5.96; N, 6.09. C10H13NO5
requires: C, 52.86; H, 5.73; N, 6.16%); δH (400 MHz) 1.28 (3H,
d, J 6.35, 7-Me), 1.66 (3H, s, 3a-Me), 3.32 (1H, m, 7-H), 3.85
(3H, s, OMe), 4.05 (1H, dd, J 11.96 and 2.93, 6a-H), 4.25 (1H,
dd, J 11.96 and 2.93, 6a-H), 6.00 (1H, s, 3-H); δC (100 MHz)
14.93 (7-Me), 27.58 (3a-Me), 52.54 (OMe), 54.96 (7-C), 68.21
(6-C), 73.82 (3a-C), 112.67 (3-C), 144.89 (2-C), 158.73 and
167.65 (2 × CO Me and C᎐O).
᎐
2
NOEDS results for 20: irradiation of 3a-Me caused a 1.27%
enhancement of 6-H and 0.2 on 7-H. Irradiation of 6-H caused
the following enhancements 4.30% on 6-Me, 2.73 on 7-Me, 2.07
on 3a-Me and 1.63 on 7-H. Irradiation of the signal for 7-H
caused the following enhancements 1.95% on 6-Me, 4.53 on
7-Me and 1.60 on 6-H.
168.84 (CO Me and C᎐O); DEPT 135 (400 MHz) 14.93 (7-Me),
᎐
2
27.58 (3a-Me), 52.54 (OMe), 54.96 (7-C), 68.21 (6-C), 112.67
(3-C).
NOEDS results for 24a: irradiation of 6a-H caused an
enhancement of 4.1% on 7-H, 2.9% onto 7-Me and 22.5% on its
partner 6b-H. Irradiation of 6b-H caused an 18.8% enhance-
ment on its partner 6a-H, 2% enhancement on 7-H and no
enhancement on either 7-Me or 3a-Me.
Compound 23a: a viscous yellow oil (Found: C, 52.74; H,
5.68; N, 6.34. C10H13NO5 requires: C, 52.86; H, 5.73; N, 6.16%);
δH (400 MHz) 1.29 (3H, d, J 6.84, 7-Me), 1.82 (3H, s, 3a-Me),
3.48 (1H, m, 7-H), 3.75 (3H, s, OMe), 4.16 (1H, dd, J 12.02 and
6.71, 6b-H), 4.46 (1H, dd, J 12.02 and 2.69, 6a-H), 7.48 (1H, s,
2-H); δC (100 MHz) 15.18 (7-Me), 26.86 (3a-Me), 51.40 (OMe),
57.68 (7-C), 67.15 (6-C), 70.12 (3a-C), 109.31 (3-C), 154.53
(ii) When the reaction was repeated, on twice the scale of
(i) above, and extending the reaction time to 24 h, adduct 20
(134 mg, 72%) and trimethyl 3,4-dimethyl-1-oxo-3,4,6,7-tetra-
hydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,7,8-tricarboxylate 22 (27
mg, 15%) were obtained; data for 20 as reported above.
Compound 22: a yellow amorphous solid, mp 103–108 ЊC
(CHCl3–hexane) (Found: C, 52.74; H, 5.37; N, 3.57. C15H17NO8
requires: C, 53.10; H, 5.01; N, 4.13%); δH (400 MHz) 1.39
(3H, d, J 6.96, 4-Me), 1.58 (3H, d, J 6.59, 3-Me), 3.91 (9H, s,
3 × OMe), 4.72 (1H, m, 4-H), 5.03 (1H, m, 3-H); δC (100 MHz)
19.21 (4-Me), 20.32 (3-Me), 52.71 (4-C), 52.80 and 53.69
(OMe), 76.70 (3-C), 120.27, 121.45, 122.03, 124.17, (6-C, 7-C,
8-C, 8a-C), 154.38, 159.41, 162.43 and 164.00 (3 × CO2Me and
(2-C), 162.47 and 167.86 (CO Me and C᎐O); DEPT 135
᎐
2
(400 MHz) 15.18 (7-Me), 26.86 (3a-Me), 51.40 (OMe), 57.68
(7-C), 67.15 (6-C), 154.53 (2-C).
C᎐O); m/z 55, 236, 308 (base), 339 (Mϩ).
᎐
(iii) Nitrone 18 (0.05 g, 0.318 mmol) and dimethyl acetylene-
dicarboxylate (0.09 g, 0.64 mmol) were stirred in CHCl3 (5 cm3)
at rt under a nitrogen atmosphere for 7 d. The reaction mixture
was concentrated and purified by flash chromatography (Et2O–
petroleum spirit, 1 : 2) yielding 20 (90.3 mg, 95%) which crystal-
lised as colourless needle-like crystals, data agree with those
reported above.
(iv) When the reaction was repeated, at rt, on twice the scale
of (iii) above, extending the reaction time to 10 d, adduct 20
(157.5 mg, 83%) and trimethyl 3,4-dimethyl-1-oxo-3,4,6,7-
tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,7,8-tricarboxylate
22 (15.3 mg, 8%) were obtained; data as reported above.
NOEDS results for 23a: irradiation of 6b-H caused a 19%
enhancement on its partner 6a-H, and a 1.8% enhancement on
7-Me. Irradiation of 3a-Me caused a 0.55% enhancement on
6b-H. Irradiation of 6a-H caused an enhancement of 4%
on 7-H and 20% on its partner 6b-H.
(ii)When the above reaction was repeated extending the
duration to 82 h heating crude 1H NMR spectral analysis
showed 24a, 23a, 25, 25i, 13 plus 13i present in a 3 : trace : 15 :
4 : 25 ratio. 25 is characterised by a separate experiment (see
below) and 25i is proposed on the basis of a pair of doublets,
6.96 and 7.05 ppm each with J value (~4.4 Hz) characteristic of
the ortho-coupled aromatic protons. Adducts 13 and 13i are
3390
J. Chem. Soc., Perkin Trans. 1, 2001, 3382–3392

View Article Online
characterised as a mixture δH (400 MHz) 1.56 (6H, 2 × over-
lapping d, Me [13 and 13i]), 3.87 & 3.94 (2 × 3H, 2 × s, 2 × OMe
[13]), 3.89 & 3.90 (2 × 3H, 2 × s, 2 × OMe [13i]), 4.44 (1H,
2 × overlapping d, 3b-H [13 and 13i]), 4.65 (2H, m, 3a-H [13
and 13i]), 5.05 (1H, m, 4-H [13]), 5.35 (1H, m, 4-H [13]), 7.36
(2H, s, Ar-H [13 and 13i]).
6a-H caused an enhancement of 3.9% on 7-H and 11% on its
partner 6b-H.
Compound 23b: a colourless viscous oil (Found: C, 61.92; H,
5.09; N, 4.84. C15H15NO5 requires: C, 62.28; H, 5.19; N, 4.84%);
δH (400 MHz) 1.30 (3H, d, J 6.35, 7-Me), 3.57 (1H, m, 7-H),
3.59 (3H, s, OMe), 3.73 (1H, dd, J 11.96 and 11.23, 6b-H),
4.05 (1H, dd, 11.96 and 3.17, 6a-H), 7.40 (3H, m, o- and
p-Ar-H), 7.48 (1H, s, 2-H), 7.60 (2H, m, m-Ar-H); δC (67.5
MHz) 16.26 (7-Me), 51.19 (OMe), 59.85 (7-C), 66.94
(6-C), 76.87 (3a-C), 110.47 (quaternary n-Ar-C), 127.30–128.63
(5 × Ar-C), 138.31 (3-C), 152.86 (2-C), 162.41 and 168.48
Methyl 4-methyl-1-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]-
oxazine-7-carboxylate 25
The adduct 24a (59 mg, 0.26 mmol) in CHCl3 (1 cm3) was held
at vigorous reflux under a nitrogen atmosphere for 56 h. The
resulting mixture was concentrated under reduced pressure and
purification by flash chromatography (Et2O–petroleum spirit,
1 : 1) yielded 25 as fine colourless needles (21.6 mg, 40%), mp
127.5–128.0 ЊC (from C6H6–petroleum spirit) (Found: C, 57.42;
H, 5.55; N, 6.38. C10H11NO4 requires: C, 57.42; H, 5.26; N,
6.70%); δH (400 MHz) 1.59 (3H, d, J 6.59, Me), 3.84 (3H, s,
OMe), 4.29 (1H, dd, J 11.53 and 7.87, 3b-H), 4.42 (1H, m, 4-H),
4.55 (1H, dd, J 11.53 and 3.48, 3a-H), 7.49 and 7.52 (2 × 1H,
2 × d, J 1.46, 6-H and 8-H); δC (100 MHz) 15.94 (Me), 49.23
(4-C), 51.52 (OMe), 71.01 (3-C), 118.06 (7-C), 118.69 (8-C),
119.76 (8a-C), 126.00 (6-C), 157.88 and 163.83 (CO2Me and
(CO Me and C᎐O).
᎐
2
NOEDS results for 23b: irradiation of 6b-H caused a 3%
enhancement on the Ar-H signal and 20% enhancement on its
partner 6a-H.
Compound 23c: a brown–orange viscous oil (Found: C,
62.20; H, 5.06; N, 4.61. C15H15NO5 requires: C, 62.28; H, 5.19;
N, 4.84%); δH (400 MHz) 1.22 (3H, d, J 6.71, 7-Me), 3.57 (3H, s,
OMe), 3.65 (1H, m, 7-H), 4.24 (1H, dd, J 11.60 and 3.05, 6a-H),
4.57 (1H, dd, J 9.77 and 11.60, 6b-H), 7.19 (1H, s, 2-H), 7.34
(3H, m, o- and p-Ar-H), 7.42 (2H, d, J 1.22, m-Ar-H); δC (100
MHz) 13.52 (7-Me), 51.48 (7-C), 52.84 (OMe), 68.51 (6-C),
75.64 (3a-C), 110.75 (3-C), 127.78–128.67 (Ar-C), 137.38
(quaternary n-Ar-C), 155.89 (2-C), 162.21 and 166.67 (CO2Me
C᎐O).
᎐
and C᎐O).
᎐
Methyl 4-methyl-1-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]-
oxazine-6-carboxylate 26a
3-Methoxycarbonyl-8-methyl-3a-phenyl-7,8-dihydro-6H-
isoxazolo[3,2-c][1,4]oxazepin-4(3aH)-one 27 and 2-methoxy-
carbonyl-8-methyl-3a-phenyl-7,8-dihydro-6H-isoxazolo[3,2-c]-
[1,4]oxazepin-4(3aH)-one 28
The adduct 23a (63 mg, 0.28 mmol) was stirred in CHCl3 (3
cm3) with heating at reflux under a N2 atm for 82 h. The mixture
was allowed to cool to rt and the solvent removed under
reduced pressure. Purification of the crude mixture by flash
chromatography (petroleum spirit–Et2O, 2 : 1) afforded the title
compound 26a (14 mg, 24%) and returned 23a (8 mg, 12%).
26a, colourless cubic crystals, mp 138–140 ЊC (from CHCl3).
(Rf 0.676, Et2O); δH (400 MHz) 1.54 (3H, d, J 6.83, 4-Me),
3.89 (3H, s, OMe), 4.43 (1H, d, J 11.71, 3a-H), 4.65 (1H, dd,
J 11.71 and 3.90, 3b-H), 5.29 (1H, m, 4-H), 6.95 (1H, d, J 3.90,
8-H), 7.05 (1H, d, J 3.90, 7-H); δC(100 MHz) 18.79 (4-Me),
48.64 (4-C), 51.86 (OMe), 71.01 (3-C), 116.57 (7-C), 117.46
(8-C), 123.20 (8a-C), 124.30 (6-C), 158.27 (1-C), 160.69
(CO2Me).
Freshly recrystallised nitrone 1c (0.46 g, 2.10 mmol) was stirred
in neat methyl propiolate (5 cm3, 4.73 g, 56.0 mmol) under a
nitrogen atmosphere at 65 ЊC for 36 h. Unreacted dipolarophile
was removed under reduced pressure (100 ЊC, 15 mmHg) to
leave a viscous yellow oil. The crude products were separated by
flash chromatography (Et2O–petroleum spirit, 1.0 : 1.8) yielding
28 (0.38 g, 60%), 27 (0.15 g, 24%) and unreacted dipole (0.06 g,
13%).
Compound 28: colourless prisms, mp 133–134 ЊC (from
C6H6–petroleum spirit) (Found: C, 63.09; H, 5.76; N, 4.48.
C16H17NO5 requires: C, 63.37; H, 5.61; N, 4.62%); δH (270
MHz) 1.44 (3H, d, J 5.86, Me), 1.75 (1H, m, 7b-H), 2.23 (1H,
m, 7a-H), 3.52 (1H, m, 8-H), 3.78 (3H, s, OMe), 3.90 (1H, m,
J 12.45 and 6.60, 6b-H), 4.10 (1H, m, 6a-H), 6.19 (1H, s, 3-H),
7.38 (3H, m, m- and p-Ar-H), 7.62 (2H, m, o-Ar-H); δC (67.5
MHz) 19.8 (Me), 36.8 (7-C), 52.6 (OMe), 55.9 (8-C), 63.9 (6-C),
86.5 (3a-C), 113.6 (3-C), 125.0–138.5 (Ar-C), 142.5 (2-C), 159.0
Methyl 7-methyl-4-oxo-3a-phenyl-3a,4,6,7-tetrahydroisoxazolo-
[3,2-c][1,4]oxazine-2-carboxylate 24b and methyl 7-methyl-4-
oxo-3a-phenyl-3a,4,6,7-tetrahydroisoxazolo[3,2-c][1,4]oxazine-
3-carboxylates 23b and 23c
Freshly recrystallised nitrone 1b (0.11 g, 0.54 mmol) and methyl
propiolate (0.25 g, 3.02 mmol) were stirred in CHCl3 (15 cm3) at
reflux under a nitrogen atmosphere for 40 h. The reaction
mixture was allowed to cool to rt and the solvent removed
under reduced pressure yielding the crude product, a viscous
yellow oil which was purified by flash chromatography (Et2O–
petroleum spirit, 1 : 2), yielding 24b (26.1 mg, 17%), 23b (48.8
mg, 31%) and 23c (19.2 mg, 13%) and unreacted nitrone
(47 mg, 43%).
Compound 24b: colourless cubic crystals, mp 122–125 ЊC
(from CHCl3–hexane) (Found: C, 62.08; H, 4.94; N, 4.96.
C15H15NO5 requires: C, 62.28; H, 5.19; N, 4.84%); δH (400
MHz) 1.40 (3H, d, J 6.35, 7-Me), 3.54 (1H, m, 7-H), 3.82 (3H, s,
OMe), 4.04 (1H, dd, J 11.96 and 10.74, 6b-H), 4.20 (1H, dd,
J 11.96 and 2.93, 6a-H), 6.26 (1H, s, 3-H), 7.34–7.42 (3H, m,
o- and p-Ar-H), 7.67 (2H, m, m-Ar-H); δC (100 MHz) 15.67
(7-Me), 52.65 (OMe), 57.06 (7-C), 67.98 (6-C), 79.6 (3a-C),
111.75 (3-C), 126.27, 128.35, 128.78 and 129.03 (Ar-C), 144.61
(2-C), 158.75 and 167.50 (CO Me and C᎐O).
and 169.7 (CO Me and C᎐O).
᎐
2
Compound 27: colourless rods, mp 130–131 ЊC (from C6H6–
petroleum spirit) (Found: C, 63.20; H, 5.49; N, 4.49. C16H17NO5
requires: C, 63.37; H, 5.61; N, 4.62%); δH (270 MHz) 1.44 (3H,
d, J 5.86, Me), 1.64 (1H, m, 7b-H), 2.21 (1H, m, 7a-H), 3.50
(1H, m, 8-H), 3.60 (3H, s, OMe), 3.86 (2H, m, 6b-H, 6a-H),
7.35 (4H, m, m- and p-Ar-H and 2-H), 7.65 (2H, m, o-Ar-H);
δC (67.5 MHz) 18.9 (Me), 36.4 (7-C), 53.3 (OMe), 55.6 (8-C),
64.1 (6-C), 86.9 (3a-C), 110.4 (3-C), 125.9–138.5 (Ar-C), 152.9
(2-C), 158.6 and 168.6 (CO Me and C᎐O).
᎐
2
Methyl 3a,6,7-trimethyl-4-oxo-3a,4,6,7-tetrahydroisoxazolo-
[3,2-c][1,4]oxazine-3-carboxylate 29 and methyl 3a,6,7-tri-
methyl-4-oxo-3a,4,6,7-tetrahydroisoxazolo[3,2-c][1,4]oxazine-
2-carboxylate 30
Nitrone 18 (0.2 g, 1.27 mmol) and methyl propiolate (0.535 g,
6.37 mmol) were heated at reflux in CHCl3 (20 cm3) under a
nitrogen atmosphere for 30 h. The reaction was allowed to cool
to rt and the solvent and excess dipolarophile were removed
under reduced pressure. The resulting mixture was purified by
flash chromatography (Et2O–petroleum spirit, 1 : 2) yielding
᎐
2
NOEDS results for 24b: irradiation of 6b-H caused a 3.5%
enhancement on the Ar-H signal, 21% enhancement on its
partner 6a-H and 2% enhancement on 7-Me. Irradiation
of 7-Me caused a 0.6% enhancement on Ar-H. Irradiation of
J. Chem. Soc., Perkin Trans. 1, 2001, 3382–3392
3391

View Article Online
30 (60.7 mg, 20%), 29 (117.7 mg, 38%) and unreacted nitrone
(57.9 mg, 29%).
58.90; H, 6.06; N, 5.98. C11H13NO4 requires: C, 59.19; H, 5.87;
N, 6.27%); δH (400 MHz) 1.36 (3H, d, J 6.35, 4-Me), 1.53 (3H,
d, J 6.35, 3-Me), 3.89 (3H, s, OMe), 4.70 (1H, quartet, J 6.67,
4-H), 5.12 (1H, quartet, J 6.67, 3-H), 6.95 (1H, d, J 4.39, 8-H),
7.03 (1H, d, J 4.39, 7-H); δC (100 MHz) 19.43 (4-Me), 20.57
(3-Me), 51.82 (4-C), 52.59 (OMe), 78.27 (3-C), 116.10 (7-C),
117.42 (8-C), 122.94 (8a-C), 124.64 (6-C), 157.42 (1-C), 161.37
(CO2Me).
Compound 30: a colourless oil which solidified in the cold,
mp 89–92 ЊC (Found: C, 54.96; H, 6.13; N, 5.65. C11H15NO5
requires: C, 54.77; H, 6.22; N, 5.81%); δH (400 MHz) 1.28 (3H,
d, J 6.22, 7-Me), 1.38 (3H, d, J 6.59, 6-Me), 1.64 (3H, s, 3a-Me),
2.97 (1H, m, 7-H), 3.83 (3H, s, OMe), 4.17 (1H, m, 6-H),
6.01 (1H, s, 3-H); δH (400 MHz) (C6D6) 0.73 (3H, d, J 6.39,
7-Me), 0.83 (3H, d, J 6.39, 6-Me), 1.45 (3H, s, 3a-Me), 2.41
(1H, m, 7-H), 3.25 (3H, s, OMe), 3.45 (1H, m, 6-H), 6.00
(1H, s, 3-H); δC (100 MHz) 15.31 (7-Me), 17.47 (6-Me), 27.45
(3a-Me), 52.54 (OMe), 60.65 (7-C), 73.65 (3a-C), 75.51
(6-C), 112.92 (3-C), 144.59 (2-C), 158.86 and 169.26 (CO2Me
Acknowledgements
This work has been supported by an Enterprise Ireland Post-
graduate Award (JF), and the Chemistry Departments of
the National University of Ireland Galway and the National
University of Ireland, Maynooth.
and C᎐O); m/z 110, 142 (base), 154, 170, 182, 198, 241 (Mϩ),
᎐
242 (M ϩ 1).
NOEDS results for 30 (recorded in C6D6): irradiation of
3a-Me caused a 1.14% enhancement on 6-H and 0.9 on 3-H.
Irradiation of 7-H caused the following enhancements 3.39%
on 6-Me and 4.06 on 7-Me. Irradiation of the signal for 6-H
caused the following enhancements 3.26% on 7-Me, 1.05 on
3a-Me and 1.27 on 7-H.
Compound 29: brown needles, mp 98–102 ЊC (from CHCl3–
hexane) (Found: C, 54.82; H, 6.18; N, 5.55. C11H15NO5
requires: C, 54.77; H, 6.22; N, 5.81%); δH (400 MHz) 1.25 (3H,
d, J 6.22, 7-Me), 1.38 (3H, d, J 6.22, 6-Me), 1.83 (3H, s, 3a-Me),
3.01 (1H, m, 7-H), 3.75 (3H, s, OMe), 4.24 (1H, m, 6-H), 7.34
(1H, s, 2-H); δC (100 MHz) 15.99 (7-Me), 17.56 (6-Me), 26.86
(3a-Me), 51.40 (OMe), 63.97 (7-C), 71.06 (3a-C), 73.69 (6-C),
109.57 (3-C), 152.96 (2-C), 162.89 and 169.39 (CO2Me and
References
1 For general reviews on nitrone cycloaddition chemistry, see: J. J.
Tufariello, in 1,3-Dipolar Cycloaddition Reactions, ed. A. Padwa,
Wiley, New York, 1984, vol. 2, p. 83; P. N. Confalone and E. M.
Huie, Org. React. (N. Y.), 1988, 36, 1; W. Carruthers, in
Cycloaddition Reactions in Organic Synthesis, Pergamon, Oxford,
1990, p. 269.
2 C. O’Mahony and F. Heaney, Chem. Commun., 1996, 167; F. Heaney
and C. O’Mahony, J. Chem. Soc., Perkin Trans. 1, 1998, 341.
3 N. Katagiri, A. Kurimoto, A. Yamada, H. Sato, T. Katsuhara,
K. Takagi and C. Kaneko, J. Chem. Soc., Chem. Commun., 1994,
281; N. Katagiri, M. Okada, Y. Morishita and C. Kaneko,
Tetrahedron, 1997, 53, 5725; S. Ham and D. Birney, Tetrahedron
Lett., 1994, 35, 8113.
4 O. Tamura, K. Gotanda, R. Terashima, M. Kikuchi, T. Miyawaki
and M. Sakamoto, Chem. Commun., 1996, 1861; O. Tamura,
K. Gotanda, J. Yoshino, Y. Morita, R. Terashima, M. Kikuchi,
T. Miyawaki, N. Mita, M. Yamashita, H. Ishibashi and M.
Sakamoto, J. Org. Chem., 2000, 65, 8544.
5 (a) S. W. Baldwin, B. G. Young and A. T. McPhail, Tetrahedron
Lett., 1998, 39, 6819; (b) R. E. Looper and R. M. Williams,
Tetrahedron Lett., 2001, 42, 769.
6 R. C. Bernotas and G. Adams, Tetrahedron Lett., 1996, 37, 7339.
7 (a) L. M. Harwood, A. C. Manage, S. Robin, S. F. G. Hopes,
D. Watkin and C. E. Williams, Synlett, 1993, 777; (b) L. M.
Harwood and I. A. Lilly, Tetrahedron: Asymmetry, 1995, 6, 1557;
(c) D. Alker, L. M. Harwood and C. E. Williams, Tetrahedron, 1997,
53, 12671; (d ) D. Alker, G. Hamblett, L. M. Harwood, S. M.
Robertson, D. J. Watkin and C. E. Williams, Tetrahedron, 1998, 54,
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Lett., 1998, 39, 475; ( f ) M. G. B. Drew, L. M. Harwood, D. W. Price,
M.-S. Choi and G. Park, Tetrahedron Lett., 2000, 41, 5077.
8 F. Roussi, M. Bonin, A. Chiaroni, L. Micouin, C. Riche and
H.-P. Husson, Tetrahedron Lett., 1999, 40, 3727.
C᎐O).
᎐
NOEDS results for 29: irradiation of 3a-Me caused a 2.54%
enhancement on 6-H and 0.2% on 7-H. Irradiation of 7-H
caused the following % enhancements: 2.42 on 6-Me, 5.23 on
7-Me and 1.18 on 6-H. Irradiation of the signal for 6-H caused
the following % enhancements: 3.55 on 7-Me, 4.79 on 6-Me,
5.17 on 3a-Me and 0.73 on 7-H.
(ii) When the above reaction was repeated, extending the dur-
ation to 84 h crude 1H NMR spectral analysis showed 29, 30, 31
and 31i present in the ratio 10 : 6 : 2.6 : 2.
Methyl 3,4-dimethyl-1-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]-
oxazine-8-carboxylate 31
The adduct 30 (58 mg, 0.24 mmol) was stirred with heating at
vigorous reflux in CHCl3 (1 cm3) for 80 h. The reaction was
allowed to cool to rt and the solvent removed under reduced
pressure. The crude mixture was purified by flash chromato-
graphy (Et2O–petroleum spirit, 1 : 1) yielding 31 (36 mg, 67%)
and unreacted 30 (9.6 mg, 17%). Compound 31 crystallised to
yellow cubic crystals, mp 129–132 ЊC (from C6H6–petroleum
spirit) (Found: C, 58.82; H, 5.79; N, 5.65. C11H13NO4 requires:
C, 59.19; H, 5.83; N, 6.28%); δH (400 MHz) 1.52 (3H, d, J 6.59,
4-Me), 1.60 (3H, d, J 6.59, 3-Me), 3.84 (3H, s, OMe), 4.07 (1H,
dq, J 8.24 and 6.59, 4-H), 4.46 (1H, dq, J 8.24 and 6.59, 3-H),
7.48 (1H, d, J 1.46, 6-H), 7.53 (1H, d, J 1.46, 8-H); δC (100
MHz) 15.77 (4-Me), 17.77 (3-Me), 51.22 (OMe), 54.50 (4-C),
78.70 (3-C), 118.06 (7-C), 118.44 (8-C), 120.05 (8a-C), 125.79
9 S. A. Ali and M. I. M. Wazeer, J. Chem. Soc., Perkin Trans. 2, 1986,
1789; S. A. Ali and M. I. M. Wazeer, Tetrahedron, 1988, 44, 187.
10 (a) S. A. Ali and H. A. Almuallem, Tetrahedron, 1992, 48, 5273;
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1998, 2699; (c) M. I. M. Wazeer, H. P. Perzanowski, S. I. Qureshi,
M. B. Al-Murad and S. A. Ali, Tetrahedron, 2000, 56, 7229.
11 (a) J. P. Freeman, Chem. Rev., 1983, 83, 241; (b) for a recent example,
see: N. Coskun, F. T. Tat and Ö. Ö. Güven, Tetrahedron, 2001, 57,
¸
3413; (c) W. Friebolin and W. Eberbach, Tetrahedron, 2001, 57, 4349;
(d ) B.-X. Zhao, Y. Yu and S. Eguchi, Tetrahedron, 1996, 52, 12049.
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13 O. Tamura, T. Kuroki, Y. Sakai, J.-I. Takizawa, J. Yoshino,
Y. Morita, N. Mita, K. Gotanda and M. Sakamoto, Tetrahedron
Lett., 1999, 40, 895.
(6-C), 157.73 and 163.91 (CO Me and C᎐O).
᎐
2
Methyl 3,4-dimethyl-1-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]-
oxazine-6-carboxylate 26b
14 H. Günther, NMR Spectroscopy. Basic principles, concepts and
applications in chemistry, 2nd edn., 1994, Wiley, New York, pp. 114–
117.
15 K. N. Houk, A. Bimanand, D. Mukherjee, J. Sims, Y.-M. Chang,
D. C. Kaufman and L. N. Domelsmith, Heterocycles, 1977, 7, 293;
A. Liguori, R. Ottana, G. Romeo, G. Sindona and N. Uccella,
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16 G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467.
17 G. M. Sheldrick, SHELXL-97 a computer program for crystal
structure determination, University of Göttingen, 1997.
18 P. McArdle, J. Appl. Crystallogr., 1995, 28, 65.
The adduct 29 (0.12 g, 0.49 mmol) was stirred in CHCl3 (4 cm3)
with heating at reflux under a N2 atm for 84 h. The mixture was
allowed to cool to rt and the solvent removed under reduced
pressure. Purification of the crude mixture by flash chromato-
graphy (petroleum spirit–Et2O, 2 : 1) afforded title compound
(14 mg, 12.8%) and returned 29 (38 mg, 32%). 26b, colourless
cubic crystals, mp 155–156 ЊC (from CHCl3–hexane) (Found: C,
3392
J. Chem. Soc., Perkin Trans. 1, 2001, 3382–3392