Chemistry of pyrrolizinones. Part 1. Reactions of pyrrolizin-3-ones with electrophiles: Synthesis of 3,8-didehydroheliotridin-5-one

Article abstract of DOI:10.1039/b005620k

The reaction of pyrrolizin-3-one 1 with dry hydrogen chloride gives the 1-chloro-1,2-dihydro derivative 8 (93%) by electrophilic addition. The halogen of 8 is readily displaced by O-nucleophiles to give 6, 9 or 10 in 87-100% yield, and this strategy has been employed in a short synthesis of the necine base didehydroheliotridin-5-one 4. Pyrrolizinone 1 can be brominated by N-bromosuccinimide in the presence of nucleophiles to give 20 or 21, or under free radical conditions to give the 2-bromopyrrolizinone 22 (55%). Vilsmeier formylation of 1 gave a variety of products including the 5-formylpyrrolizinone 26 (16%), but azo-coupling could only be observed under basic conditions to give the coupled propenoate 31 (46%) via the anion of the ring-opened species 30. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b005620k

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Chemistry of pyrrolizinones. Part 1. Reactions of pyrrolizin-3-ones
with electrophiles: synthesis of 3,8-didehydroheliotridin-5-one1
Hamish McNab* and (the late) Craig Thornley
1
Department of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh,
UK EH9 3JJ
Received (in Cambridge, UK) 12th July 2000, Accepted 17th August 2000
First published as an Advance Article on the web 10th October 2000
The reaction of pyrrolizin-3-one 1 with dry hydrogen chloride gives the 1-chloro-1,2-dihydro derivative 8 (93%)
by electrophilic addition. The halogen of 8 is readily displaced by O-nucleophiles to give 6, 9 or 10 in 87–100%
yield, and this strategy has been employed in a short synthesis of the necine base didehydroheliotridin-5-one 4.
Pyrrolizinone 1 can be brominated by N-bromosuccinimide in the presence of nucleophiles to give 20 or 21, or
under free radical conditions to give the 2-bromopyrrolizinone 22 (55%). Vilsmeier formylation of 1 gave a variety
of products including the 5-formylpyrrolizinone 26 (16%), but azo-coupling could only be observed under basic
conditions to give the coupled propenoate 31 (46%) via the anion of the ring-opened species 30.
In this paper, we report the results of a systematic study of
3J 6.8 Hz, and 2.95, 2J 18.6, 3J 2.0 Hz], showing a large geminal
the reactions of pyrrolizin-3-one 1 with simple electrophiles.1
coupling constant relating the two protons at position 2, and
two vicinal 3J1,2 couplings relating protons syn (6.8 Hz) and anti
(2.0 Hz) to the proton at position 1. The regiochemistry was
4
confirmed by the presence of a minor coupling J1,7 of 0.9 Hz,
which is characteristic of ortho-benzylic interactions.8,9
Pyrrolizinone 1 is known to be stable in neutral methanol,
and so the most likely mechanism for the formation of 6 is
electrophilic attack of Hϩ at the 2-position to give the reson-
ance stabilised carbocation 7, followed by quenching by either
methanol (to give 6) or initially by chloride ion (to give 8)
(Scheme 1). In the latter case, an SN1 process could regenerate
the carbocation 7 leading to 6 in the presence of an excess of
Though there have been no authentic previous reports of such
reactions in the literature,2 we were encouraged by an earlier
observation3 that in the preparation of the 6-bromo compound
2 by flash vacuum pyrolysis (FVP) a small quantity of a
dibromo impurity was obtained. We speculated at the time3
that this might have been formed by adventitious addition of
HBr across the 1,2-double bond to give 3. This mode of
behaviour is now confirmed, and the synthetic potential of such
1-halogeno-1,2-dihydropyrrolizin-3-ones leading to 1-hydroxy-
1,2-dihydropyrrolizinones is now explored. The introduction of
such functionality is an important step in the development
of simple routes from pyrrolizinones4,5 to pyrrolizine natural
products, and we illustrate our methodology with details of a
concise synthesis of the Senecio alkaloid 3,8-didehydro-
heliotridin-5-one 4.1
Results and discussion
In view of the presence of the lactam function in pyrrolizin-3-
one 1, we expected that treatment of this compound with
methanolic hydrogen chloride would lead to ring opening to the
propenoate 5 as found under basic conditions.2 Indeed, N-acyl-
pyrroles and -indoles are known to be cleaved under the influ-
ence of acid catalysis.6 In the event, the only product which
could be isolated when 1 was heated under reflux for 2 h with
methanolic HCl was the methyl ether 6. Its structure followed
by analogy of its spectra with those of other 1-functionalised-
1,2-dihydropyrrolizinones;1,7 in particular the ABX pattern of
1
the 1- and 2-proton resonances in the H NMR spectrum was
characteristic [δH(1) 4.83, 3J 6.8 and 2.0 Hz; δH(2) 3.33, 2J 18.6,
Scheme 1
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This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005620k

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methanol. Although the yield of 6 was low (22%), this experi-
ment nevertheless demonstrated the rather surprising reactivity
of the enone moiety of 1 towards electrophiles (due to the
stability of the cation 7), together with the equally surprising
stability of both 1 and its 1,2-dihydro derivatives towards ring
opening under acidic conditions.
These observations were further confirmed by the reaction of
1 with dry hydrogen chloride in dichloromethane solution (i.e.
in the absence of a competing nucleophilic solvent). After only
30 min at room temperature, a 93% yield of the 1-chloro com-
pound 8 was obtained. This compound was characterised by its
1
mass spectrum [m/z 157 and 155 (Mϩ)], by its H NMR spec-
trum (which shows a closely similar coupling pattern to that of
6—see Experimental) and by the further reactions described
below.
In the presence of a non-nucleophilic base such as triethyl-
amine, clean dehydrochlorination of 8 took place at room tem-
perature to regenerate pyrrolizin-3-one 1 in 70% yield. More
usefully, 8 proved to be an exceptional alkylating agent in reac-
tions with O-nucleophiles. Thus treatment with an excess of
methanol at room temperature (30 min) gave the ether 6 in
quantitative yield (identical with that obtained from 1 and
methanolic HCl), aqueous acetone gave the alcohol 9 (93%)
and a solution of sodium acetate in glacial acetic acid gave the
acetoxy derivative 10 (87%) (Scheme 2). This strategy therefore
Scheme 3 Reagents and conditions: (i) hν CuSO4; (ii)
;
(iii) FVP (600 ЊC); (iv) K2CO3, MeOH; (v) FVP (650 ЊC); (vi) HCl, then
H2O.
15 was isolated in 60% yield. FVP of 15 at 600 ЊC produced the
protected pyrrolizin-3-one 16 in 90% yield after distillation.
Removal of the acetate protecting group was achieved with
anhydrous potassium carbonate in methanol (20 ЊC, 1 h), but
even under these mild basic conditions quantitative ring
opening to the (Z)-propenoate 17 (99%) took place. However,
regeneration of the lactam ring was conveniently achieved by
FVP of the crude propenoate 17 at 650 ЊC (cf. ref. 5), and by
this means the deprotected pyrrolizinone 18 was obtained in
59% overall yield from 16. (An alternative strategy, involving
direct Wittig olefination of the protected aldehyde 11 did not
give significant amounts of propenoate 17, as either E- or
Z-isomer.) Treatment of the pyrrolizinone 18 with gaseous
hydrogen chloride in dichloromethane followed immediately by
addition of water gave a product (63%) whose mass spectrum
Scheme 2 Reagents and conditions: (i) HCl, CH2Cl2; (ii) Et3N;
(iii) MeOH; (iv) H2O; (v) NaOAc–HOAc.
allows a two-step O-functionalisation of the 1-position of
pyrrolizin-3-ones and hence a means of incorporating a key
structural feature of most pyrrolizidine alkaloids into the
bicyclic framework. This transformation was not possible by
conjugate addition of O-nucleophiles owing to preferential
reaction of hard nucleophiles at the carbonyl group.1,3 However,
these compounds contain features of the toxic pyrrolic metabol-
ites of pyrrolizidine alkaloids, and were always handled with
extreme care; the labile chloro compound 8 in particular
was generally not isolated but was transformed to the other
derivatives in situ.
1
showed the correct molecular ion and whose H NMR spec-
trum was identical with that of 4 previously reported (see
Experimental).13 The feasibility of this final transformation was
previously established by corresponding reaction of the pro-
tected pyrrolizinone 16 to give 19 (also 63%). In summary, the
With these—and earlier5—results in place, we embarked on a
preparation of the dihydropyrrolizin-3-one base 3,8-didehydro-
heliotridin-5-one 4 (originally named 5,7a-didehydrohelio-
tridin-3-one) which is the base portion of a number of alkaloids
isolated from various Senecio species of Chile, Australia and
South Africa10,11 and has been the subject of two earlier syn-
theses.12,13 In our route (Scheme 3), the carbon skeleton of 4 was
assembled from Meldrum’s acid and the protected pyrrole 11,
which was obtained in 27% yield by photolytic ring contraction
of the pyridine N-oxide 12 in aqueous copper() sulfate
solution (cf. ref. 5 and references therein). Initial attempts to
prepare the hydroxymethyl pyrrole 13 directly from the
unprotected N-oxide 14 by this route were unsuccessful.
Knoevenagel condensation of Meldrum’s acid and 11 required
rather more vigorous conditions than usual5 (100 ЊC, 2 h), pre-
sumably owing to steric effects, but the condensation product
base 4 has been prepared in 5 manipulative steps from the
simple pyrrole 11, in 20% overall (unoptimised) yield, and has
established that the methods we have developed here, and in
previous work1,5 give viable routes to compounds of biological
interest.
The reactivity of 1 towards electrophiles was further demon-
strated by its reaction with brominating agents under a variety
of conditions. Although treatment with molecular bromine
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Table 1 Selected 1H NMR parameters of 20 and 21
δH(1)
δH(2)
δH(5)
δH(6)
δH(7)
Compound
(nJ/Hz)
(nJ/Hz)
(nJ/Hz)
(nJ/Hz)
(nJ/Hz)
20
21
4.94 (1.9)
6.05 (1.7, 1.0)
4.70 (1.9)
4.80 (1.7)
7.10 (3.2, 0.9)
7.13 (3.2, 1.0)
6.55 (3.2, 3.2)
6.57 (3.2, 3.2)
6.31 (3.2, 0.9)
6.32 (3.2, 1.0)
was unsuccessful, the use of N-bromosuccinimide (NBS) in
methanol or acetic acid at room temperature gave the 1-
methoxy-2-bromo and 1-acetoxy-2-bromo compounds 20 and
21 respectively in up to 82% yield. In practice, even these reac-
tions could be irreproducible and on occasions the NMR spec-
trum of the crude product obtained after the starting material
had been completely consumed (TLC) showed no pyrrole
resonances whatsoever. In the successful bromination of 1 in
glacial acetic acid, an inseparable mixture of products was
obtained comprising the acetate 21 together with some of the
elimination product 22 and a trace of the dibromo compound
23 (MS evidence only). However, complete elimination of acetic
acid from 21 could be effected by FVP of the crude reaction
mixture at 600 ЊC, and in this way the 2-bromopyrrolizinone 22
could be obtained as the sole product in 35% overall yield from
1 (Scheme 4).
Fig. 1 NOE data for 20.
irradiated in the NOE experiment (1.5%) is probably due to a
slight twist in the 5-membered ring so that these protons are
relatively close in space even though they are anti to one
another.]
Bromination of 1 under free radical conditions was also
investigated using NBS in carbon tetrachloride solution using
dibenzoyl peroxide as initiator. It was anticipated that the 1,2-
dibromopyrrolizinone 23 would be the major product under
such conditions, but only a trace of this material could be iden-
tified from the H and 13C NMR spectra of the crude reaction
1
mixture, and it could not be isolated. Instead, the major
product after 2 h under reflux was found to be 2-bromo-
pyrrolizin-3-one 22 (55%), and this is the method of choice for
its preparation. Since it is unlikely that 22 can be formed by a
genuine free radical substitution mechanism, it is more prob-
able that it arises by initial formation of the dibromo derivative
23 followed by elimination in situ. Unfortunately, attempts to
functionalise the 5-methyl group of 5-methylpyrrolizinone 25
by free radical bromination were unsuccessful.
We have also studied the reaction of 1 with electrophiles
which might be expected to attack the pyrrole ring of 1 under
aromatic substitution conditions. Although both starting
materials were recovered unchanged when 1 was treated with
methoxymethylene Meldrum’s acid,14 products were obtained
by formylation under Vilsmeier conditions and by diazo-
coupling. However, electrophilic attack of pyrrolizinone itself
may not be involved in the mechanism of either of these reac-
tions. Thus seven compounds were isolated when 1 was treated
with DMF–POCl3 in dichloroethane (15 min under reflux)
followed by work-up in the presence of sodium acetate and
dry-flash chromatography (Scheme 5). These include recovered
starting material 1 (9%), and the hydroxy compound 9 (6%) and
Scheme 4 Reagents and conditions: (i) NBS, MeOH; (ii) NBS, HOAc;
(iii) FVP (600 ЊC); (iv) NBS, PhCOO2COPh.
Pyrolytic eliminations of ester groups are invariably syn
retro-ene-type processes, which suggests that the two substitu-
ents adopt the anti configuration, as expected from the most
likely bromination mechanism via the bromonium ion 24
(Scheme 4). The regio- and stereo-chemistry of the alkoxy-
bromination of 1 to give 20 were established unambiguously by
a series of NOE experiments (Fig. 1 and Table 1). The methoxy
resonance of 20 was obvious by inspection (δH 3.52), and
irradiation at this position caused enhancement of one of
the pyrrole signals (which identifies the latter signal as due to
H-7, and confirms the location of the methoxy group at the
1-position). In addition, both aliphatic resonances are enhanced
(which confirms that the methoxy group is on the same side of
the molecule as H-2, and hence that anti addition has taken
place). This assignment is further confirmed by the size of the
3
vicinal coupling J1,2 (1.9 Hz) consistent with an anti relation-
ship (see above), and the corresponding coupling constant in
the acetoxy compound 21 (1.7 Hz) indicated that the same
stereochemistry of addition had been maintained (Table 1). [In
the spectrum of 20, a small enhancement of H-2 when H-1 is
Scheme 5 Reagents and conditions: (i) DMF/POCl3.
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fully applied to the synthesis of the dihydropyrrolizin-3-one
base 3,8-didehydroheliotridin-5-one 4. Further application of
these reactions as routes to pyrrolizidine alkaloids will be the
subjects of future papers in this series.
Experimental
Unless otherwise stated, 1H and 13C NMR spectra were
recorded at 200 and 50 MHz respectively for solutions in
[2H]chloroform. Coupling constants are quoted in Hz. IR spec-
tra were recorded for liquid films or Nujol mulls, and absorp-
Fig. 2 NOE data for 31.
tion maxima are given in cmϪ1
.
acetate 10 (9%), which are probably formed during work-up via
the chloro compound 8. Four formylated derivatives were also
isolated, viz. just one formylated pyrrolizinone identified as 26
(16%) (see below), formed with complete regiocontrol, together
with its 1-chloro-, 1-acetoxy- and 1-hydroxy-1,2-dihydro deriva-
tives 27 (trace), 28 (2%) and 29 (1.2%) respectively. Although
28 and 29 are clearly formed in work-up in the same manner as
9 and 10, it is not clear whether the hydrochlorination to give
27 also takes place in work-up, or by fortuitous reaction of 1
with HCl present in the excess of phosphoryl chloride prior to
the actual formylation step (Scheme 5). According to this
mechanism, 26 would arise by formylation of 8 to give 27,
followed by elimination of HCl during work-up. Clearly more
work will be required to clarify the mechanism and optimise
this process from a preparative point of view, but nevertheless
we have shown that the pyrrole ring of pyrrolizinones can be
functionalised by substitution processes.
The regiochemistry of the formylation follows from the
NMR spectra of 26, which show two ‘pyrrole’ doublets with
3JHH 3.5 Hz, showing that the reaction must have taken place
at either the 5- or 7-positions, and the presence of a methine
signal at ca. δC 110 is consistent with the 7-position being
unsubstituted.5,15
When 1 was treated with benzenediazonium tetrafluoro-
borate under neutral conditions, or with benzenediazonium
chloride under mildly acidic conditions, no reaction took place.
If the solution was basified, the conditions resulted in the cleav-
age of the amide linkage to give the propenoate 30 (25%) and
its azo-coupled derivative 31 (46%) (see below). Coupling of
Reaction of pyrrolizin-3-one 1 with methanolic hydrogen chloride
Pyrrolizin-3-one 14 (0.123 g, 1 mmol) was dissolved in meth-
anol (8 cm3) and treated with a solution of hydrogen chloride in
methanol (39% w/v, 2 cm3). The solution was heated at reflux
for 2 h and was then allowed to cool to room temperature.
Dichloromethane (25 cm3) was added and the solution was
washed with water (25 cm3). Solid sodium bicarbonate was
added to the aqueous layer until no further evolution of carbon
dioxide was observed. The aqueous layer was extracted with
additional dichloromethane (25 cm3). The combined organic
layers were washed with water (3 × 25 cm3), dried (MgSO4) and
concentrated to give a brown oil. Trituration of the oil with
ether gave a polymeric brown solid which was removed by fil-
tration. Concentration of the filtrate gave after bulb-to-bulb
(Kugelrohr) distillation 1,2-dihydro-1-methoxy-3H-pyrrolizin-3-
one 6 (0.035 g, 22%), bp 62–65 ЊC (0.5 Torr) (Found: Mϩ,
151.0632. C8H9NO2 requires M, 151.0633); νmax 2932, 2824,
1758 and 1565; δH 7.07 (1H, dd, 3J 3.1 and 4J 0.9), 6.48 (1H, t,
3J 3.1), 6.26 (1H, dt, 3J 3.1 and 4J 0.9), 4.83 (1H, ddd, 3J 6.8, 2.0
4
2
3
and J 0.9), 3.41 (3H, s), 3.33 (1H, dd, J 18.6 and J 6.8) and
2.95 (1H, dd, 2J 18.6 and 3J 2.0); δC 169.23 (quat), 138.72 (quat),
118.78, 111.96, 107.43, 70.22, 55.92 and 42.65; m/z 151 (Mϩ,
60%), 120 (100), 92 (54), 80 (53), 79 (42), 65 (35), 52 (18) and
39 (41).
1-Chloro-1,2-dihydro-3H-pyrrolizin-3-one 8
Dry hydrogen chloride gas, generated by the action of concen-
trated sulfuric acid on solid ammonium chloride, was bubbled
through a stirred solution of pyrrolizin-3-one 1 (0.597 g, 5
mmol) in dichloromethane (50 cm3) until the solution became
black (ca. 30–60 min). Potassium carbonate (5 g) was added
and the solution was stirred for a further 1 h. Solids were
removed by filtration through Celite and the solution was evap-
orated with minimum heating to give, as a free flowing orange
liquid which became brown on standing, 1-chloro-1,2-dihydro-
3H-pyrrolizin-3-one 8 (0.724 g, 93%) (Found: Mϩ, 155.0144.
C7H635ClNO requires M, 155.0138); δH (360 MHz) 7.05 (1H,
benzenediazonium chloride with 30 under acidic conditions
again led to recovered starting material, but basification caused
some degree of coupling to occur to give 31 (43%) together with
some recovered starting material. These results suggest that the
azo-coupling in fact proceeds via the anion derived from 30
which is strongly activated towards electrophilic substitution; it
is interesting to note that the Z-double bond of 30 is configur-
ationally stable under these conditions. An attempt to effect
ring closure to the pyrrolizinone by FVP5 of the propenoate 31
at 650 ЊC proved unsuccessful.
3
4
3
3
dd, J 3.1 and J 0.9), 6.50 (1H, t, J 3.1), 6.26 (1H, dt, J 3.1
4
3
4
and J 0.9), 5.37 (1H, ddd, J 7.4, 2.1 and J 0.9), 3.63 (1H,
2
3
2
3
dd, J 19.2 and J 7.4) and 3.21 (1H, dd, J 19.2 and J 2.1);
δC 167.64 (quat), 138.36 (quat), 119.74, 112.48, 107.83, 46.57
and 45.72; m/z 157 (Mϩ, 7%), 155 (Mϩ, 22%), 120 (79), 119
(100), 92 (35), 91 (51), 65 (18), 64 (36), 63 (32) and 40 (31).
The regiochemistry of the coupling reaction was established
by the NOE data of 31 summarised in Fig. 2. The alkene reson-
ances were readily identified by inspection, and irradiation of
the enoate β-proton caused enhancement of one of the pyrrole
signals, which was also enhanced by irradiation of the other
pyrrole signal. Hence, substitution must have taken place at the
vacant pyrrole α-position—C5.
In summary, we have demonstrated that reactions of the
pyrrolizin-3-one system with electrophiles afford useful means
of functionalising the 1-position (via the chloro compound 8),
the 2-position (via bromination) and in principle the 5-position
(via Vilsmeier formylation). The reactions have been success-
Reactions of 1-chloro-1,2-dihydro-3H-pyrrolizin-3-one 8
(i) With triethylamine. A solution of the title compound 8
(0.155 g, 1 mmol) in sodium-dried ether (10 cm3) was treated
with triethylamine (0.17 cm3, 1.2 mmol) and the solution was
stirred at room temperature for 3 h. Dichloromethane (15 cm3)
was added and the solution was washed with aqueous hydro-
chloric acid (0.2 M, 15 cm3) and water (15 cm3). The residue
obtained after drying of the extracts (Mg2SO4) and removal of
the solvent was subjected to bulb-to-bulb (Kugelrohr) distil-
lation to give pyrrolizin-3-one 1 (0.083 g, 70%), bp 93–95 ЊC (14
Torr) [lit.,4 130 ЊC (16 Torr)]; δH (80 MHz) 7.06 (1H, dd, 3J 5.9
J. Chem. Soc., Perkin Trans. 1, 2000, 3584–3591
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and 6J 0.6), 6.87 (1H, m), 5.97 (2H, m) and 5.64 (1H, dd,
3J 5.9 and 6J 0.6) (in agreement with published data4).
g, 60%), bp 168–173 ЊC (1.5 Torr) (Found: Mϩ, 167.0575.
C8H9NO3 requires M, 167.0582); νmax 1739 and 1225; δH 8.00
(2H, d, J 7.0), 7.10 (2H, d, J 7.0), 4.88 (2H, s) and 1.93 (3H, s);
δC 169.81 (quat), 138.57, 134.45 (quat), 124.69, 63.98 and 20.19;
m/z 167 (Mϩ, 34%), 109 (25), 108 (75), 96 (43), 52 (27), 51 (28),
43 (100) and 39 (36). This compound has been previously
reported without characterisation.18 It is highly hygroscopic
and requires to be stored at Ϫ20 ЊC.
(ii) With O-nucleophiles. 1-Chloro-1,2-dihydro-3H-pyrrol-
izin-3-one 8 (1 mmol) was treated directly with the nucleophile
source indicated. [Prior to treatment with water as the nucleo-
phile, 8 was dissolved in acetone (2 cm3).] The mixture was set
aside or stirred at room temperature for the time stated. Water
(15 cm3) was added and the solution was extracted thoroughly
with dichloromethane (3 × 15 cm3). The combined extracts
were washed with water (20 cm3) and dried (Na2SO4). In the
work-up of the reaction with glacial acetic acid–sodium acetate,
additional washes with saturated aqueous sodium bicarbonate
(2 × 25 cm3) and water again (25 cm3) were carried out.
Removal of the solvent under vacuum gave the following com-
pounds. The nucleophile source, its quantity and the reaction
time are quoted. 1,2-Dihydro-1-hydroxy-3H-pyrrolizin-3-one 9
[water (5 cm3), 30 min] (0.127 g, 93%), bp 118–122 ЊC (0.8 Torr)
(decomp.) (Found: Mϩ, 137.0481. C7H7NO2 requires M,
137.0477); νmax 3400, 2920, 1740 and 1570; δH 6.99 (1H, dd,
3-(Acetoxymethyl)pyrrole-2-carbaldehyde 11
The pyridine N-oxide 12 (1.66 g, 3 mmol) was dissolved in
aqueous copper() sulfate solution (0.2 M, 670 cm3). The solu-
tion was photolysed according to the method described in refs.
5 and 19. After work-up by continuous extraction, dry flash
chromatography (ethyl acetate, n-hexane) gave as the first
fraction 3-(acetoxymethyl)pyrrole-2-carbaldehyde 11 (0.456 g,
27%), mp 59–61 ЊC {after distillation [bp 98–100 ЊC (0.15
Torr)]} (Found: Mϩ, 167.0582. C8H9NO3 requires M,
167.0582); νmax 3250, 1736, 1644 and 1619; δH 10.2 (1H, br s),
9.73 (1H, d, 5J 1.0), 7.08 (1H, td, 3J 2.6 and 5J 1.0), 6.34 (1H, t,
3J 2.6), 5.28 (2H, s) and 2.08 (3H, s); δC 178.32, 170.65 (quat),
129.59 (two quat), 125.66, 112.26, 57.60 and 20.81; m/z 167
(Mϩ, 15%), 125 (27), 108 (26), 107 (50), 105 (26), 79 (36), 53 (23)
and 43 (100).
4
3
3
3J 3.1 and J 0.9), 6.45 (1H, t, J 3.1), 6.20 (1H, dt, J 3.1
and 4J 0.9), 5.23 (1H, ddd, 3J 7.0, 2.2 and 4J 0.9), 3.35 (1H, dd,
2J 18.8 and 3J 7.0), 3.2–3.3 (1H, br s) and 2.87 (1H, dd, 2J 18.8
3
and J 2.2); δC 169.57 (quat), 141.63 (quat), 119.15, 111.65,
106.35, 62.01 and 45.54; m/z 137 (Mϩ, 39%), 120 (14), 95 (27),
94 (42), 71 (35), 58 (29) and 43 (100). 1,2-Dihydro-1-methoxy-
3H-pyrrolizin-3-one 6 [methanol (7 cm3), 30 min] (0.212 g,
100%), bp 60–63 ЊC (0.2 Torr) (decomp.) (spectra identical with
those of the authentic sample reported above). 1-Acetoxy-
1,2-dihydro-3H-pyrrolizin-3-one 10 [sodium acetate (0.087 g,
1.1 mmol) in glacial acetic acid (10 cm3), 20 min] (0.157 g, 87%),
bp 121–122 ЊC (0.8 Torr) (decomp.) [lit.,16 180 ЊC (decomp.)];
2,2-Dimethyl-5-[3-(acetoxymethyl)pyrrol-2-ylmethylidene]-1,3-
dioxane-4,6-dione 15
The pyrrole-2-carbaldehyde 11 (0.334 g, 2 mmol) was dissolved
in toluene (5 cm3) and treated with piperidine (2 drops), glacial
acetic acid (2 drops) and Meldrum’s acid (0.29 g, 2 mmol). The
solution was stirred at room temperature overnight and then
heated on a steam bath for 2 h. The solvent was removed and
the residue was recrystallised from ethanol to give 2,2-dimethyl-
5-[3-(acetoxymethyl)pyrrol-2-ylmethylidene]-1,3-dioxane-4,6-
dione 15 (0.353 g, 60%), mp 136–138 ЊC (from ethanol) (Found:
C, 57.3; H, 5.1; N, 4.6. C14H15NO6 requires C, 57.35; H, 5.1; N,
4.5); νmax 3243, 1731, 1682 and 1556; δH 8.39 (1H, s), 7.36 (1H, t,
3J 2.7), 6.55 (1H, t, J 2.7), 5.23 (2H, s), 2.08 (3H, s) and 1.74
(6H, s); δC 170.45 (quat), 164.31 (quat), 163.88 (quat), 139.90,
136.27 (quat), 130.47, 126.20 (quat), 115.24, 104.23 (quat),
100.70 (quat), 57.65, 27.10 and 20.76; m/z 293 (Mϩ, 34%), 235
(18), 149 (100), 148 (21), 121 (92), 120 (20), 104 (24), 93 (29),
and 43 (54).
3
4
νmax 3130, 1760, 1745 and 1575; δH 7.04 (1H, dd, J 3.1 and J
3
3
4
1.0), 6.44 (1H, t, J 3.1), 6.23 (1H, dt, J 3.1 and J 1.0), 5.96
3
4
2
3
(1H, ddd, J 7.2, 2.0 and J 1.0), 3.42 (1H, dd, J 18.9 and J
7.2), 2.97 (1H, dd, 2J 18.9 and 3J 2.0) and 2.03 (3H, s); δC 170.40
(quat), 168.24 (quat), 137.47 (quat), 119.21, 112.31, 108.85,
63.80, 42.01 and 20.66 (νmax and δH in agreement with published
data16).
4-(Acetoxymethyl)pyridine
Acetic anhydride (12.46 g, 0.12 mol) was added dropwise
over 20 min to 4-(hydroxymethyl)pyridine (4-pyridylmethanol)
(11.23 g, 0.1 mol). The resulting solution was stirred at room
temperature for 90 min at which point aqueous sodium hydrox-
ide (2 M, 80 cm3) was added carefully with cooling. The solu-
tion was extracted with dichloromethane (3 × 150 cm3). The
combined extracts were washed with water (150 cm3), dried
(MgSO4) and evaporated. Distillation of the residue gave
4-(acetoxymethyl)pyridine (14.34 g, 92%), bp 130–132 ЊC (20
Torr) [lit.,17 126 ЊC (20 Torr)]; νmax 3020, 1745, 1610 and 1565;
δH 8.48 (2H, br d, J 5.7), 7.15 (2H, dd, J 4.5 and 1.5), 5.01 (2H,
s) and 2.05 (3H, s); δC 170.27 (quat), 149.69, 144.75 (quat),
121.68, 63.98 and 20.54.
7-(Acetoxymethyl)-3H-pyrrolizin-3-one 16
2,2-Dimethyl-5-[3-(acetoxymethyl)pyrrol-2-ylmethylidene]-1,3-
dioxane-4,6-dione 15 (0.173 g, 0.6 mmol) was subjected to FVP
by sublimation through a horizontal silica furnace tube using
our standard apparatus.5 The following parameters were used:
furnace temperature 600 ЊC, inlet temperature 140–160 ЊC,
pressure 0.005 Torr, pyrolysis time 75 min. The product
obtained from the trap was 7-(acetoxymethyl)-3H-pyrrolizin-3-
one 16 (0.114 g, 90%), bp 104–107 ЊC (2.5 Torr) (Found: Mϩ,
191.0589. C10H9NO3 requires M, 191.0582); νmax 1743 (br), 1607
and 1525; δH 7.18 (1H, d, 3J 5.9), 6.87 (1H, d, 3J 3.2), 5.98 (1H,
4-(Acetoxymethyl)pyridine N-oxide 12
3
3
d, J 3.2), 5.67 (1H, d, J 5.9), 4.89 (2H, s) and 2.08 (3H, s);
δC (one quaternary missing) 170.47 (quat), 137.41, 135.09
(quat), 121.88, 121.37 (quat), 119.11, 115.54, 58.08, and 20.77;
m/z 191 (Mϩ, 94%), 149 (100), 132 (74), 131 (36), 120 (33), 104
(74), 103 (31), 91 (56), 51 (38), 44 (27), 43 (80) and 40 (31).
A solution of 4-(acetoxymethyl)pyridine (15.16 g, 0.1 mol) in
glacial acetic acid (60 cm3) was treated with aqueous hydrogen
peroxide solution (28%, 10 cm3) and the solution was heated at
80–90 ЊC for 3 h. Further hydrogen peroxide solution (7.5 cm3)
was added and the reaction mixture was heated at 80–90 ЊC for
an additional 9 h. The solution was next cooled and concen-
trated to 20–30 cm3 by rotary evaporation. Water (20 cm3) was
added and the solution was again concentrated, to approxi-
mately 20 cm3. The concentrate was taken up in chloroform (50
cm3) and the solution was poured onto a paste of potassium
carbonate (10 g) and water and shaken. The organic layer was
separated, dried (MgSO4) and evaporated to give, after bulb-to-
bulb distillation, 4-(acetoxymethyl)pyridine N-oxide 12 (10.03
7-(Hydroxymethyl)-3H-pyrrolizin-3-one 18
A solution of the (acetoxymethyl)pyrrolizin-3-one 16 (0.192 g,
1 mmol) in methanol (5 cm3) was treated with potassium
carbonate (0.068 g, 0.5 mmol) and the mixture was stirred at
room temperature over a period of 1 h. Water (10 cm3) was
added and the solution was extracted with dichloromethane
(3 × 20 cm3). The combined extracts were dried (MgSO4) and
3588
J. Chem. Soc., Perkin Trans. 1, 2000, 3584–3591

View Article Online
evaporated to give methyl (Z)-3-[3-(hydroxymethyl)pyrrol-2-
yl]propenoate 17 (0.179 g, 99%) (Found: Mϩ, 181.0739. C9H11-
NO3 requires M, 181.0739); δH 12.31 (1H, br s), 6.95 (1H, d,
mmol). After the solution had been stirred at room temperature
for 3 days, it was added to dichloromethane (25 cm3) and
washed successively with saturated aqueous sodium bicarbon-
ate solution (20 cm3) and water (20 cm3). The organic solution
was dried (MgSO4) and the solvent was removed thoroughly in
vacuo to give trans-2-bromo-1,2-dihydro-1-methoxy-3H-pyrrol-
izin-3-one 20 (0.202 g, 82%) which underwent partial decom-
position upon distillation (0.086 g, 36%), bp 122–124 ЊC (0.1
Torr) (Found: Mϩ, 230.9719 and 228.9736. C8H881BrNO2
requires M, 230.9719 and C8H879BrNO2 requires M, 228.9739);
νmax 3140, 2940, 2830, 1765, 1720 and 1580; δH 7.10 (1H, dd,
3J 12.6), 6.94 (1H, t, J 2.6), 6.29 (1H, t, J 2.6), 5.68 (1H,
d, 3J 12.6), 4.66 (2H, s), 3.76 (3H, s) and 1.69 (1H, br s);
δC 169.56 (quat), 131.57, 130.05 (quat), 125.97 (quat), 121.73,
110.44, 107.45, 57.16 and 51.57; m/z 181 (Mϩ, 84%), 148 (20),
132 (28), 122 (56), 121 (100), 120 (67), 94 (44), 93 (50), 92 (33)
and 65 (25). This compound was used immediately for flash
vacuum pyrolysis under the following conditions: furnace
temperature 650 ЊC, inlet temperature 80–100 ЊC, pressure
range 0.002–0.005 Torr, pyrolysis time 1 h. 7-(Hydroxymethyl)-
3H-pyrrolizin-3-one 18 (0.089 g, 60%) was thus obtained, bp
85–88 ЊC (0.4 Torr), mp 86–87 ЊC (Found: Mϩ, 149.0469.
C8H7NO2 requires M, 149.0477); νmax 1721; δH 7.19 (1H, d,
3
3
4
3
3
3J 3.2 and J 0.9), 6.55 (1H, t, J 3.2), 6.31 (1H, dd, J 3.2 and
4J 0.9), 4.94 (1H, d, 3J 1.9), 4.70 (1H, d, 3J 1.9) and 3.52 (3H, s);
δC (one quaternary missing) 135.27 (quat), 120.16, 113.00,
108.46, 80.20, 57.05 and 47.34; m/z 231 (Mϩ, 65%), 229 (Mϩ,
62%), 200 (63), 198 (56), 150 (44), 119 (100), 110 (29), 91 (31),
80 (72), 79 (52), 63 (24) and 43 (29).
3
3
3J 5.8), 6.85 (1H, d, J 3.2), 5.93 (1H, d, J 3.2), 5.62 (1H, d,
3J 5.8), 4.52 (2H, s) and 2.04 (1H, br s); δC (one quaternary
missing) 137.89, 133.85 (quat), 127.33 (quat), 121.24, 119.36,
114.43 and 57.93; m/z 149 (Mϩ, 100%), 148 (31), 132 (59), 120
(48), 104 (34), 92 (32), 65 (28), 52 (24), 51 (24) and 39 (46).
(ii) 1-Acetoxy-2-bromo-1,2-dihydro-3H-pyrrolizin-3-one 21.
Pyrrolizin-3-one 1 (0.245 g, 2 mmol) was dissolved in glacial
acetic acid (6 cm3) and treated with N-bromosuccinimide (0.72
g, 4 mmol). The solution was stirred at room temperature and
the reaction was monitored by TLC (silica, 30% ethyl acetate in
n-hexane). Reaction was complete after 75 min at which point
the solution was added to water (30 cm3) and extracted thor-
oughly with dichloromethane (3 × 40 cm3). The combined
organic extracts were washed with saturated aqueous sodium
bicarbonate solution (3 × 50 cm3) and water (50 cm3), dried
(MgSO4) and the solvent was removed thoroughly in vacuo to
give impure trans-2-bromo-1-acetoxy-1,2-dihydro-3H-pyrrolizin-
3-one, 21 bp 102–104 ЊC (0.3 Torr) (decomp.) [Found (FAB):
Mϩ, 258.9668 and 256.9668. C9H881BrNO3 requires M,
258.9668 and C9H879BrNO3 requires M, 256.9668]; δH 7.13 (1H,
dd, 3J 3.2 and 4J 1.0), 6.57 (1H, t, 3J 3.2), 6.32 (1H, dt, 3J 3.2 and
4J 1.0), 6.05 (1H, dd, 3J 1.7 and 4J 1.0), 4.80 (1H, d, 3J 1.7) and
2.11 (3H, s); δC (one quaternary missing) 169.78 (quat), 164.57
(quat), 120.59, 113.54, 110.34, 72.60, 46.31 and 20.56; m/z
(FAB) 260 [(M ϩ H)ϩ, 20%], 258 [(M ϩ H)ϩ, 33], 257 (40), 237
(41), 215 (59) and 200 (34); additional peaks were identified
at m/z 280 (69%), 278 (100) and 276 (79) [corresponding to
(C7H5Br2NO Ϫ H)ϩ], probably due to the dibromo compound
23. Purification of the product could not be achieved by
chromatography nor by distillation. The major contaminant
was identified as 2-bromo-3H-pyrrolizin-3-one 22.
1,2-Dihydro-1-hydroxy-7-(hydroxymethyl)-3H-pyrrolizin-3-one
(3,8-didehydroheliotridin-5-one) 4
Dry hydrogen chloride gas generated from the action of con-
centrated sulfuric acid (3.2 cm3) on ammonium chloride (2.31
g) was passed through a stirred solution of 7-(hydroxymethyl)-
pyrrolizin-3-one 18 (0.076 g, 0.51 mmol) in dichloromethane
(10 cm3) over a period of 10 min during which time there was a
loss of the characteristic colour of the pyrrolizin-3-one. The
solution was stirred at room temperature for a further 15 min
at which point potassium carbonate (1 g) was added. After a
further 1 h at room temperature, the solids were removed by
filtration and the filtrate was evaporated. The residue (0.113 g)
was taken up in acetone (2 cm3). Water (8 cm3) was added and
the solution was set aside for 30 min. The aqueous solution was
extracted with dichloromethane (3 × 15 cm3) and the combined
extracts were dried (Na2SO4) and evaporated to give 1,2-
dihydro-1-hydroxy-7-(hydroxymethyl)-3H-pyrrolizin-3-one
4
(3,8-didehydroheliotridin-5-one) (0.054 g, 63%) (Found: Mϩ,
167.0568. C8H9NO3 requires Mϩ 167.0582); δH 6.95 (1H, d,
3
3
3J 3.1), 6.32 (1H, d, J 3.1), 5.27 (1H, dd, J 7.2 and 2.5), 4.70
(1H, d, 2J 13.1), 4.59 (1H, d, 2J 13.1), 3.31 (1H, dd, 2J 18.7 and
3J 7.2) and 2.88 (1H, dd, J 18.7 and J 2.5) (identical with
literature data13); m/z 167 (Mϩ, 74%), 150 (50), 149 (100), 121
(32), 108 (46), 104 (33), 79 (47), 71 (33), 57 (49), 52 (31), 45 (75),
43 (79) and 41 (42). Attempted purification by distillation led to
decomposition.
2
3
Complete elimination of acetic acid from 21 could be effected
by flash vacuum pyrolysis of the crude product under the fol-
lowing conditions (furnace temperature 600 ЊC, inlet temper-
ature 120 ЊC, pressure 0.005 Torr, pyrolysis time 30 min). The
dark red pyrolysate was washed from the trap with dichloro-
methane (10 cm3). The solution was washed with aqueous
sodium bicarbonate solution (1 M, 10 cm3) and water (10 cm3),
dried (MgSO4) and concentrated to give 2-bromo-3H-pyrrolizin-
3-one 22 (0.141 g, 35%), bp 68–70 ЊC (0.3 Torr) (Found: Mϩ,
198.9459 and 196.9477. C7H481BrNO requires M, 198.9457 and
C7H479BrNO requires M, 196.9477); νmax 3140, 1750, 1675
7-(Acetoxymethyl)-1,2-dihydro-1-hydroxy-3H-pyrrolizin-3-one
19
In a pilot reaction, treatment of a solution of 7-(acetoxy-
methyl)-3H-pyrrolizin-3-one 16 (0.016 g, 0.08 mmol) in
dichloromethane (2 cm3) with hydrogen chloride, followed by
treatment of the initial product in acetone (2 cm3) with water
(3 cm3) over 20 min, as described above, gave, after the usual
work-up, a lightly coloured oil (0.011 g, 63%) which was identi-
fied as 7-(acetoxymethyl)-1,2-dihydro-1-hydroxy-3H-pyrrolizin-
3-one 19 on the basis of its 1H NMR and mass spectra; δH 7.00
(1H, d, 3J 3.2), 6.45 (1H, d, 3J 3.2), 5.35 (1H, dd, 3J 6.9 and 2.0),
5.22 (1H, d, 2J 12.4), 4.81 (1H, d, 2J 12.4), 3.34 (1H, dd, 2J 18.7
6
3
4
and 1560; δH 7.16 (1H, d, J 0.5), 6.95 (1H, ddd, J 2.9, J 1.3
6
and J 0.5) and 6.01 (2H, m); δC 160.22 (quat), 135.72, 135.53
(quat), 120.41, 115.53, 112.86 (quat) and 111.94; m/z 199 (Mϩ,
50%), 197 (Mϩ, 44), 90 (100), 63 (74) and 39 (30).
(iii) Reaction with bromine. A solution of pyrrolizin-3-one 1
(0.1 mmol) in [2H]chloroform (0.5 cm3) was treated with brom-
ine (0.1, 0.2 and 0.3 mmol). In each case, there were no identifi-
3
2
3
and J 6.9), 2.94 (1H, dd, J 18.7 and J 2.0) and 2.05 (3H, s);
m/z 209 (Mϩ, 7%), 191 (3), 149 (34), 86 (68), 84 (100) and 70
(19). This product was not characterised further.
1
able resonances present in the H NMR spectrum (60 MHz)
after 15 min.
Reactions of pyrrolizin-3-one 1 with brominating agents
(iv) Reactions with NBS in the presence of radical initiator. A
solution of pyrrolizin-3-one 1 (0.119 g, 1 mmol) in carbon
tetrachloride (3 cm3) was treated with N-bromosuccinimide
(0.218 g, 1.2 mmol) and a few crystals of benzoyl peroxide. The
(i) 2-Bromo-1,2-dihydro-1-methoxy-3H-pyrrolizin-3-one 20. A
solution of pyrrolizin-3-one 1 (0.125 g, 1.0 mmol) in methanol
(3 cm3) was treated with N-bromosuccinimide (0.230 g, 1.3
J. Chem. Soc., Perkin Trans. 1, 2000, 3584–3591
3589

View Article Online
solution was heated at reflux for 2 h. When the solution had
cooled, the insoluble succinimide was removed by filtration
and washed with a little fresh carbon tetrachloride. The
combined filtrate and washings were evaporated. Dry flash
chromatography of the residue (ethyl acetate–n-hexane) gave
2-bromopyrrolizin-3-one 22, bp 68–70 ЊC (0.03 Torr) (0.109 g,
55% after distillation) (spectra identical with sample reported
above).
(identical with sample reported above): 1,2-dihydro-1-hydroxy-
3-oxo-3H-pyrrolizine-5-carbaldehyde 29 (0.015 g, 2%) (Found:
Mϩ 165.0428. C8H7NO3 requires Mϩ 165.0426); δH 10.14
3
3
(1H, s), 7.32 (1H, d, J 3.7), 6.38 (1H, d, J 3.7), 5.36 (1H, dd,
3J 7.3 and 2.4), 3.49 (1H, dd, 2J 18.9 and 3J 7.3) and 3.04 (1H,
2
3
dd, J 18.9 and J 2.4); m/z 165 (Mϩ, 60%), 123 (20), 122 (64),
94 (22), 84 (35), 57 (25), 45 (30) and 43 (100).
1
The H NMR spectrum of the crude reaction mixture indi-
Azo-coupling reactions of pyrrolizin-3-one
cated the presence of a second product which could be isolated
neither by chromatography nor by distillation. The compound
was tentatively identified as trans-1,2-dibromo-1,2-dihydro-
3H-pyrrolizin-3-one 23; δH (one resonance hidden) 6.60 (1H,
t, J 3.2), 6.37 (1H, dt, J 3.2 and J 1.0), 5.49 (1H, dd, J 1.4
and 4J 1.0) and 5.03 (1H, d, 3J 1.4); δC (two quaternaries
missing) 121.08, 114.28, 109.86, 49.83 and 40.34.
A solution of benzenediazonium chloride (1 mmol) in water
(5 cm3) was added to a stirred solution of pyrrolizin-3-one 1
(0.125 g, 1 mmol) in methanol (5 cm3) at room temperature.
After stirring the solution for 20 min, aqueous sodium hydrox-
ide (2 M, 2 cm3) was added and the solution was stirred for
a further 30 min. The reaction mixture was extracted with
dichloromethane (3 × 15 cm3). The combined extracts were
dried (MgSO4) and evaporated. Bulb-to-bulb distillation of the
residue gave as the first fraction methyl (Z)-3-(pyrrol-2-yl)-
propenoate 30 (0.040 g, 25%), bp 59–62 ЊC (0.5 Torr); δH 7.01
(1H, m), 6.78 (1H, d, 3J 12.5), 6.51 (1H, m), 6.27 (1H, dt, 3J 3.6
and 4J 2.5), 5.53 (1H, d, 3J 12.5) and 3.77 (3H, s) (identical with
authentic sample5); the second fraction was methyl (Z)-3-(2-
phenylazopyrrol-5-yl)propenoate 31 (0.123 g, 46%), bp 175–
177 ЊC (0.5 Torr) (Found: Mϩ 255.1025. C14H13N3O2 requires
M, 255.1008); νmax 3260 (br), 1700, 1600 and 1450; λmax/MeOH
(ε) 247 (9400), 286 (10200) and 425 (22800); δH 12.69 (1H, br s),
7.92 (2H, m), 7.54–7.40 (3H, m), 7.00 (1H, dd, 3J 3.9 and
3
3
4
3
The reaction was also carried out with 2 mmol of N-bromo-
succinimide. 1H NMR spectroscopy (80 MHz) showed no
difference in the composition of the crude reaction mixture.
5-Methyl-3H-pyrrolizin-3-one 255 (0.068 g, 0.5 mmol) was
treated with N-bromosuccinimide (0.102 g, 0.57 mmol) over
90 min under the conditions described above. No discernible
1
products could be identified from the H NMR spectrum (60
MHz) of the crude reaction mixture, after filtration and
removal of the solvent from the filtrate.
Vilsmeier–Haack formylation of pyrrolizinone 1
3
3
4
4J 1.9), 6.76 (1H, d, J 12.5), 6.60 (1H, dd, J 3.9 and J 1.9),
N,N-Dimethylformamide (1.25 cm3) was added with stirring to
phosphoryl chloride (2.5 cm3) and the temperature was kept
within the range 10–20 ЊC. 1,2-Dichloroethane (10 cm3) was
added and the solution was cooled to 5 ЊC, and maintained at
this temperature during the gradual addition, with stirring, of a
solution of pyrrolizin-3-one (0.600 g, 5 mmol) in 1,2-dichloro-
ethane (15 cm3). The solution was heated at reflux for 15 min
and then allowed to cool to room temperature. The solution
was cooled in an ice bath during the careful addition of sodium
acetate trihydrate (18.75 g) in water (25 cm3). Further water (25
cm3) was added and the reaction mixture was extracted with
ether (4 × 100 cm3). The combined extracts were washed with
water (2 × 100 cm3), dried (MgSO4) and the solvents were evap-
orated. Dry flash chromatography (ethyl acetate–n-hexane) of
the residue gave the following products which were character-
3
5.75 (1H, d, J 12.5) and 3.83 (3H, s); δC 168.48 (quat), 152.82
(quat), 147.41 (quat), 133.93, 130.58 (quat), 130.15, 128.88,
122.52, 119.89, 113.89, 112.28 and 51.90; m/z 255 (Mϩ, 100%),
240 (18), 195 (11), 167 (10), 150 (27), 135 (10), 90 (23), 77
(78), 65 (14) and 51 (16). Without the addition of aqueous
sodium hydroxide solution, there was no evidence of any
reaction after 45 min.
Methyl (Z)-3-(pyrrol-2-yl)propenoate 30 (0.150 g, 1 mmol)
was reacted with benzenediazonium chloride (1.25 mmol) by
the method described above to give unreacted propenoate 30
(0.057 g, 36%), bp 65–68 ЊC (0.003 Torr) and the phenylazo-
pyrrole 31 (0.112 g, 43%), bp 138–140 ЊC (0.005 Torr), identical
with that obtained previously.
Pyrrolizin-3-one 1 (0.031 g, 0.26 mmol) was dissolved in
[2H3]acetonitrile (0.5 cm3) and the solution was cooled to 0 ЊC.
Benzenediazonium tetrafluoroborate (0.053 g, 0.28 mmol) was
added and the solution was allowed to warm to room temper-
1
ised by their H NMR and mass spectra. Pyrrolizin-3-one 1
(0.054 g, 9%); 1-acetoxy-1,2-dihydropyrrolizin-3-one 10 (0.079
g, 9%) (identical with sample reported above); 1-chloro-1,2-
dihydro-3-oxo-3H-pyrrolizine-5-carbaldehyde 27 (trace) (Found:
Mϩ, 185.0066 and 183.0085. C8H637ClNO2 requires M,
185.0058 and C8H635ClNO2 requires M, 183.0087); δH 10.26
1
ature. The reaction was monitored by H NMR spectroscopy
(60 MHz). After setting the sample aside overnight at room
temperature no identifiable resonances could be observed.
3
3
(1H, s), 7.36 (1H, d, J 3.7), 6.43 (1H, d, J 3.7), 5.43 (1H, dd,
3J 7.5 and 2.4), 3.77 (1H, dd, 2J 19.3 and 3J 7.5) and 3.34 (1H,
Acknowledgements
2
3
dd, J 19.3 and J 2.4); m/z 185 (Mϩ, 3%), 183 (Mϩ, 9%), 148
(37), 147 (100), 146 (33), 119 (34), 91 (41), 64 (29) and 63 (25);
3-oxo-3H-pyrrolizine-5-carbaldehyde 26 (0.121 g, 16%) (Found:
Mϩ 147.0416. C8H5NO2 requires M, 147.0320); δH 9.97 (1H, s),
7.20 (1H, d, 3J 6.0), 6.89 (1H, d, 3J 3.5), 6.14 (1H, d, 3J 3.5) and
We are grateful to The University of Edinburgh for a Research
Studentship (to C. T.) and to Lonza Ltd. for a generous gift
of Meldrum’s acid. This series of papers is dedicated to the
memory of Dr Craig Thornley.
3
5.89 (1H, d, J 6.0); δC 178.98, 164.67 (quat), 141.76 (quat),
137.75, 134.17 (quat), 124.62, 123.89 and 110.79; m/z 147
(Mϩ, 100%), 146 (29), 119 (44), 91 (88), 90 (23), 85 (21), 71 (31),
64 (45), 63 (40), 57 (49), 55 (22), 43 (41) and 41 (30); 1-acetoxy-
1,2-dihydro-3-oxo-3H-pyrrolizine-5-carbaldehyde 28 (0.012 g,
1.2%) (Found: Mϩ 207.0536. C10H9NO4 requires M, 207.0532);
δH 10.27 (1H, d, 5J 0.5), 7.33 (1H, d, 3J 3.7), 6.41 (1H, dt, 3J 3.7
References
1 Preliminary communication, H. McNab and C. Thornley, J. Chem.
Soc., Chem. Commun., 1993, 1570.
2 For a review, see H. McNab and C. Thornley, Heterocycles, 1994,
37, 1977.
3 A. J. Blake, H. McNab and R. Morrison, J. Chem. Soc., Perkin
Trans. 1, 1988, 2145.
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3
4
and J 0.8), 6.06 (1H, ddd, J 7.4, 2.2 and J 0.8), 3.56 (1H,
2
3
2
3
dd, J 19.1 and J 7.4), 3.12 (1H, dd, J 19.1 and J 2.2) and
2.16 (3H, s); δC 179.27, 170.21 (quat), 168.57 (quat), 143.64
(quat), 130.19 (quat), 125.52, 110.00, 63.69, 41.52 and 30.76;
m/z 207 (Mϩ, 46%), 165 (30), 148 (62), 147 (49), 120 (25), 119
(49), 92 (27), 91 (49), 71 (26), 65 (31), 64 (22), 57 (42) and 43
(100); 1,2-dihydro-1-hydroxypyrrolizin-3-one 9 (0.038 g, 6%)
3590
J. Chem. Soc., Perkin Trans. 1, 2000, 3584–3591

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