Synthesis of pyrrolizin-3-ones by flash vacuum pyrolysis of pyrrol-2-ylmethylidene Meldrum's acid derivatives and 3-(pyrrol-2-yl)propenoic esters

Article abstract of DOI:10.1039/a701749i

Monosubstituted pyrrolizin-3-ones 1 with substituants at the 1-, 5-, 6- or 7-positions are prepared in excellent yield by flash vacuum pyrolysis (FVP) of appropriate Meldrum's acid derivatives 2. The mechanism involves formation of the pyrrol-2-ylmethylideneketene 29, which can also be generated thermally from 3-(pyrrol-2-yl)propenoate esters (e.g. 30). This alternative route has been used to make a range of 2-substituted pyrrolizin-3-ones, again in excellent yield. The 3-oxo-3H-pyrrolizine-2-carboxylic acid 42 could not be made in this way owing to facile decarboxylation to pyrrolizinone 1, and extension to the formation of the azaazulenone 48 was again unsuccessful.

Full text of DOI:10.1039/a701749i

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Synthesis of pyrrolizin-3-ones by flash vacuum pyrolysis of
pyrrol-2-ylmethylidene Meldrum’s acid derivatives and
3-(pyrrol-2-yl)propenoic esters
Shirley E. Campbell, Murray C. Comer, Paul A. Derbyshire,
Xavier L. M. Despinoy, Hamish McNab,* Roderick Morrison,
Craig C. Sommerville and (the late) Craig Thornley
Department of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh,
UK EH9 3JJ
M onosubstituted pyrrolizin-3-ones 1 with substituents at the 1-, 5-, 6- or 7-positions are prepared in
excellent yield by flash vacuum pyrolysis (F VP) of appropriate M eldrum’s acid derivatives 2. The
mechanism involves formation of the pyrrol-2-ylmethylideneketene 29, which can also be generated
thermally from 3-(pyrrol-2-yl)propenoate esters (e.g. 30). This alternative route has been used to make a
range of 2-substituted pyrrolizin-3-ones, again in excellent yield. The 3-oxo-3H -pyrrolizine-2-carboxylic
acid 42 could not be made in this way owing to facile decarboxylation to pyrrolizinone 1, and extension to
the formation of the azaazulenone 48 was again unsuccessful.
Some years ago we reported a simple and efficient synthesis of
pyrrolizin-3-one 1 by flash vacuum pyrolysis (FVP) of the con-
densation product 2 of pyrrole-2-carbaldehyde and Meldrum’s
acid.1 Later, we applied this methodology to the crystalline
6-bromo derivative 3,2 and obtained the first X-ray crystallo-
using piperidinium acetate catalyst 8 in toluene at room tem-
perature (Scheme 1, route a) works well if the appropriate
pyrrole-2-carbaldehyde is readily available. Thus, we have used
the photochemical ring contraction of 4-substituted pyridine
N-oxides9–11 to prepare a range of 3-substituted pyrrole-2-
carbaldehydes 5–7 containing electron donating and electron
R3
O
O
Me
R6
EtO2C
CHO
O
O
CHO
H
N
H
N
H
8
N
H
N
O
N
O
5 R3 = Me
6 R3 = OMe
2
9
1 R6 = H
3 R6 = Br
7 R3 = CO2Me
graphic data for this ring system.2 The Meldrum’s acid route
was also used to make certain azapyrrolizinone ring systems for
the first time,3 and their NMR spectra have been discussed in
detail.4 Since pyrrolizinones remain relatively unexplored in the
literature,5 we now report a more extensive study of the scope
and mechanism of this synthetic route from which a comple-
mentary pyrolytic synthesis via pyrrolylpropenoic esters has
evolved.6 Our corresponding work on the azapyrrolizinones is
discussed in the accompanying paper.7
O
O
O
O
O
O
N
O
O
N
H
H
Me
R5
R3
R4
10 R3 = Me, R4 = R5 = H
11 R3 = OMe, R4 = R5 = H
12 R3 = CO2Me, R4 = R5 = H
13 R3 = R4 = H, R5 = CO2Et
14 R3 = R4 = H, R5 = Me
15 R3 = R4 = H, R5 = Ph
16 R3 = Ph, R4 = R5 = H
17 R3 = R5 = H, R4 = Ph
Two routes to the key Meldrum’s acid precursors were
employed (Scheme 1). The classic Knoevenagel condensation
18
R
O
O
+
CHO
N
H
O
O
Route a
i
O
O
O
O
N
H
withdrawing groups, and we prepared ethyl 5-formylpyrrole-2-
carboxylate 8 by Vilsmeier formylation of the ester using a
literature method.12 Yields for the Meldrum’s acid conden-
sation to give the derivatives 10–13 were in the range 62–98%.
Condensation of Meldrum’s acid with 2-acetylpyrrole 9 was
achieved by the titanium tetrachloride method 13 though the
yield of 18 obtained in this way was consistently lower than for
the aldehyde reactions (57%).
Route b
O
O
R
R
+
ii
N
O
O
H
OMe
4
Scheme 1 Reagents and conditions: i, piperidinium acetate, toluene,
20 ЊC; ii, acetonitrile, 20 ЊC
We have also reported a direct route to 2 by reaction of
J. Chem. Soc., Perkin Trans. 1, 1997
2195

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4
pyrrole itself with methoxymethylidene Meldrum’s acid 4,14
which should in effect bypass a formylation step if the simple
pyrrole is available (Scheme 1, route b). Indeed 2-methyl-
pyrrole15 and 2-phenylpyrrole16 gave the 5-substituted pyrrol-2-
yl derivatives 14 and 15 respectively under mild conditions in
60–70% yield with total regioselectivity. Surprisingly, 3-phenyl-
pyrrole16 gave the 3-phenyl- and 4-phenyl-pyrrol-2-yl deriv-
atives 16 and 17 respectively in almost equal amount. Presum-
ably any acceleration due to the electronic stabilisation of the
intermediate en route to 16 afforded by the phenyl group is
balanced by retardation due to its steric effect. Compounds 16
and 17 were only partially separable by crystallisation, though
the pyrrolizinones derived therefrom could be more readily
purified (see below).
The Meldrum’s acid derivatives showed characteristic
features in their spectra. Where present, the N᎐H signal in the
1H NMR spectra in [2H]chloroform occurred at particularly
high frequency (δH 12–13), consistent with strong hydrogen
bonding to one of the carbonyl groups (see below). The 5-
methylidene proton resonates at δH 8.0–8.3, except in the case of
the 3-carboxylic ester 12 where the adjacent substituent causes
a further deshielding of ca. 1 ppm. The 13C NMR spectra show
quaternary signals in the range δC 103–105 due to C(2) of the
Meldrum’s acid ring, but the corresponding signal for C(5)
occurs over a much wider range (δC 95–106). As expected, elec-
tron donating groups (e.g. 3-methoxy) on the pyrrole cause this
peak to shift to the low frequency part of the range, and elec-
tron withdrawing groups (e.g. 3- or 5-carboxylic esters) have the
opposite effect. The carbonyl signals due to C(4) and C(6)
would be expected to occur at different chemical shifts owing to
the hydrogen bonding mentioned above but if [2H]chloroform is
used as the solvent only one signal is normally present at room
temperature. The expected two signals are often observed in
hydrogen bond acceptor solvents such as [2H6]acetone or
DMSO. The 5-methylidene carbon signal is found over a wide
range, centred around δC 140. In some examples this peak is
broad, indicating that exchange processes may be operating
such as those found in dialkylaminomethylidene Meldrum’s
acid derivatives.17
the basis of the small coupling constant J5,7 (0.8 Hz) linking
the two protons in the ‘left-hand’ ring. The coupling constant
relating the protons in the corresponding ring of the 7-phenyl
isomer 27 (3J5,6) is 3.3 Hz. All of the pyrrolizin-3-ones have
intense orange–red colours and were characterised by their
NMR spectra (see below). This methodology can therefore be
applied to 1-substituted (23), 5-substituted (22, 24 and 25),
6-substituted (3 and 26) and 7-substituted (19–21 and 27)
pyrrolizinones with equal efficiency.
The most likely mechanism for the thermolysis is shown in
Scheme 3 (route a). Methylideneketenes (e.g. 28) are well char-
O
O
O
•
•
Route a
O
O
N
H
H
N
H
O
O
H
•
28
N
N
O
MeO2C
OMe
29
Route b
H
H
N
N
30
Scheme 3
acterised as the key intermediates in the pyrolysis of Meldrum’s
acid derivatives,18 and a [1,7] hydrogen shift involving the pyr-
role NH generates the pyrrol-2-ylmethylideneketene 29 which is
the immediate precursor of the pyrrolizinone by an electro-
cyclic ring closure. This mechanism is supported by a deuterium
labelling experiment which confirms that the NH of the pre-
cursor appears exclusively at the 2-position of the pyrrolizinone
product (Scheme 3, H = 2H). Due to the high efficiency of the
hydrogen atom as a migrating group in sigmatropic shifts it is
unlikely that this route will be applicable in general for the
preparation of 2-substituted pyrrolizin-3-ones. Indeed, we
have shown in the corresponding indole series that N-alkylated
precursors lead to quite different products.19
Flash vacuum pyrolysis of the Meldrum’s acid derivatives
10–15 and 18 at ca. 600 ЊC (10Ϫ2–10Ϫ3 Torr) gave the pyrrolizin-
3-ones 19–25 in excellent yield (typically 70–90%) and in high
purity (Scheme 2). The thermolysis conditions are therefore tol-
Nevertheless, it is clear from the mechanism (Scheme 3, route
a) that the methylideneketene merely serves as a route to the
ketene 29, and so we explored more direct routes to this inter-
mediate. Chuche and co-workers have shown that related
iminoketenes e.g. 31 can be generated by thermal elimination of
R7
R1
O
O
i
R6
O
O
N
H
N
R5
19 R7 = Me
O
O
•
Rn
20 R7 = OMe
21 R7 = CO2Me
22 R5 = CO2Et
23 R1 = Me
24 R5 = Me
25 R5 = Ph
Me
N
R
(Where unspecified, Rn = H)
31
alcohols from enamino esters,20 and, in a straightforward exten-
sion of this methodology it was easy to show that pyrrolizin-3-
one 1 itself was readily formed (87%) by pyrolysis of the (E)-
propenoate ester 3021,22 at 850 ЊC (Scheme 3, route b). We have
demonstrated in a related example that the particularly high
furnace temperature is required for E–Z isomerisation 23 of the
propenoate precursor prior to the elimination step,7 but the
stability of the pyrrolizin-3-one system is noteworthy and these
extreme conditions do not detract from the synthetic utility of
the method. Indeed the ability to utilise either (E)- or (Z)-
propenoates or a mixture of these isomers is a particularly
attractive feature of the route.
26 R6 = Ph
27 R7 = Ph
Scheme 2 Reagents and conditions: i, FVP (600 ЊC, 0.001 Torr)
erant to the presence of electron withdrawing or electron donat-
ing groups at various positions in the pyrrole ring, or the pres-
ence of an alkyl group in the exocyclic methylidene position.
Pyrolysis of the mixture 16 and 17 gave a mixture of 6- and 7-
phenylpyrrolizin-3-ones 26 and 27 respectively (84% in total)
which were separated by recrystallisation from n-hexane. The
less soluble fraction was identified as the 6-phenyl isomer 26 on
The synthetic potential of this new method is demonstrated
2196
J. Chem. Soc., Perkin Trans. 1, 1997

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by synthesis and pyrolysis of a range of 2-substituted 3-(pyrrol-
2-yl)propenoates to give pyrrolizinones, many of which cannot
be made by the Meldrum’s acid route. Thus pyrrole-2-
carbaldehyde was transformed into the parent propenoate 30
and its 2-methyl derivative 32 by the Wittig reaction,21,22 and
H
O
O
CO2Et
N
N
•
O
O
43
R2
N
N
O
CO2R1
O
H
R2
O
32 R1 = Et, R2 = Me
37 R2 = Me
N
OH
H
N
•
33 R1 = Me, R2 = CO2Me
34 R1 = Et, R2 = CO2Et
35 R1 = Me, R2 = COMe
36 R1 = Me, R2 = CN
38 R2 = CO2Me
39 R2 = CO2Et
40 R2 = COMe
41 R2 = CN
O
H
42 R2 = CO2H
N
N
•
O
O
into the 2-functionalised derivatives 33–36 by Knoevenagel
condensation under similar conditions to those employed for
the Meldrum’s acid derivatives. Pyrolysis of these propenoates
all gave the expected pyrrolizinones 37–41 in ca. 80% yield,
though the furnace temperature had to be carefully optimised
for the best results. Thus the 2-methyl derivative 32 and the
cyano compound 36 required furnace temperatures of 800 ЊC
or above for complete conversion to the products 37 and 41
respectively. No deleterious results were observed by the use of
the ethyl ester 32 which might be expected to eliminate ethene
under these pyrolysis conditions. In contrast, pyrolysis of the
malonate derivatives 33 and 34 requires furnace temperatures
of only 600–650 ЊC to generate the pyrrolizinones 38 and 39,
since one of the ester groups is necessarily in the correct con-
figuration for the alcohol elimination. Surprisingly, the acetyl
compound 35, which is obtained as a mixture of isomers in 5:2
ratio, was transformed to the product 40 in 76% yield at just
650 ЊC, which suggests that E–Z isomerisation is particularly
facile for this compound.
Further insight into the pyrolizin-3-one–pyrrol-2-ylmethyl-
ideneketene equilibrium is provided by an analysis of the results
of the pyrolysis of the diethyl malonate derivative 34 at various
temperatures. Even at 600 ЊC, a small amount (6%) of
pyrrolizin-3-one 1 was detected along with the 2-carboxylic
ester 39 as major product, whereas at 750 ЊC the level of 1 had
increased to 91%. No other pyrrolizinones could be detected at
these, or at intermediate temperatures, and in particular the
known carboxylic acid 4224 was absent. Repyrolysis of the iso-
lated 3-oxo-3H-pyrrolizine-2-carboxylic ester 39 at temper-
atures in the range 650–750 ЊC gave similar results. Although
the thermal cis elimination of ethene from ethyl esters is expected
at such pyrolysis temperatures, the quantitative decarboxylation
of an apparently unactivated carboxylic acid function does not
normally occur under our conditions at temperatures below
850 ЊC. The most reasonable explanation is that the pyrroliz-
Scheme 4
6
teristic J2,6 of ca. 0.8 Hz was often useful in assigning reson-
ances. The majority of the spectra could therefore be assigned
by inspection, though the 1-methyl compound 23 required a
high field instrument (at least 360 MHz) for a first order spec-
trum to be obtained. Methyl substitution in general induces a
1
small shielding effect at the adjacent position in both H and
31C NMR spectra, but has relatively little effect at other sites of
the molecule. A 4J of ca. 1.7 Hz is observed between protons on
a 1- or 2-methyl group and the proton at the adjacent site, but
such coupling is much smaller in magnitude when the substit-
uent is at the 5- or 7-positions. The 7-methoxy substituent in 20
also has only a small influence on most 1H and 13C NMR chem-
ical shifts, though C(7a) is shielded by ca. 19 ppm by com-
parison with the parent compound 1.
A 5-, 6- or 7-phenyl substituent deshields adjacent protons by
up to 0.4 ppm (compounds 25–27); this is almost certainly a
ring current effect since these substituents have very little influ-
ence on the 13C NMR spectra. The chemical shifts of the para
carbon atoms of the phenyl rings are sensitive probes of the
electronic nature of the pyrrolizinone ring. Those of the 6-
phenyl (δC 126.90) and 7-phenyl (δC 127.99) are both at a lower
frequency than the corresponding meta carbon signal, indicat-
ing that the pyrrolizinone ring acts as a net electron donating
group at these sites. In contrast, the signal for the para carbon
atom of the 5-phenyl compound 25 (δC 128.60) is slightly
deshielded relative to the meta carbon signal which suggests
that the pyrrolizinone ring is a net electron withdrawing group
at the 5-position. The effect is, however, much smaller than for
the corresponding phenyl group of the azapyrrolizinone 447
and may be too insignificant to be relevant to chemical reactiv-
ity (e.g. electrophilic substitution reactions).
inone is in equilibrium with
a corresponding pyrrol-2-
ylmethylideneketene 43 and this function can participate in a
concerted CO2 elimination sequence as soon as the carboxylic
acid is generated (Scheme 4). The surprising observation—
particularly in view of the high thermal stability of the
pyrrolizinones—is that this equilibrium must be already in
place at temperatures of 650 ЊC and below for the decarboxyl-
ation to take place. We have reached similar conclusions in
work on the decarboxylation of α-pyrone derivatives such as
coumalic acid.25
Me
O
O
N
H
O
O
N
N
H
N
Ph
44
O
CO2Me
46
45
The NMR spectra of pyrrolizin-3-one itself has been studied
previously,4 but with the availability of the range of derivatives
reported here the effects of substituents can now be investi-
N
H
N
1
gated. If the H NMR spectra are recorded with good reso-
CHO
O
lution, the minor long range coupling constants expected from
those of 1 could usually be identified and in particular a charac-
47
48
J. Chem. Soc., Perkin Trans. 1, 1997
2197

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1
Table 1 JCH Values for representative pyrrolizin-3-ones
1JCH /Hz
Pyrrolizinone
Substituent
1
2
5
6
7
Alkyl
1
23
37
24
19
41
22
—
176.3
—
181.8
179.2
—
181.6
179.4
—
192.1
192.4
192.2
—
191.8
194.9
—
174.8
173.8
173.6
172.1
172.1
179.7
177.0
175.0
174.3
174.8
174.4
—
—
1-Me
2-Me
5-Me
7-Me
2-CN
5-CO2Et
128.9
128.5
129.4
128.0
—
174.6
175.2
174.9
181.5
178.7
177.2
177.7
182.8
147.8, 127.4
n
Table 2 JCH Values for representative pyrrolizin-3-ones
nJCH a/Hz
Substituent
1,2
2,1
3,2
3,1
5,6
5,7
6,5
6,7
7,6
7,5
1
23
37
24
19
41
22
—
3.0
6.4
6.1
—
—
—
—
7.6
8.3
—
—
—
11.8
—
—
—
—
7.6
7.7
7.7
—
8.2
7.8
7.8
7.6
7.7
7.7
7.8
—
7.8
8.0
7.9
—
4.5
4.3
5.1
4.5
—
4.7
4.8
7.5
4.5
—
7.6
7.6
7.5
—
—
7.6
—
1-Me
2-Me
5-Me
7-Me
2-CN
5-CO2Et
5.5
7.8
—
—
4.1
—
<5b
—
7.6
10.6
13.0
7.8
7.8
6.7
—
3.6
4.2
4.1
4.0
—
a
Couplings of bridgehead quaternary carbon C(7a) are not readily identified. b Resonance complicated by coupling of C nucleus to methyl carbon.
An ester substituent at positions 2, 5 or 7 (in 38, 22 and 21
at 700 ЊC a complex mixture was obtained from which only
pyrrole itself could be identified from its characteristic 1H
NMR spectrum (δH 6.24 and 6.81). Apparently no trace of 48
was formed under these conditions.
respectively) causes a general deshielding effect on the proton
resonances of the other sites; 2-acetyl or 2-cyano groups (in 40
and 41) have very similar effects. The situation in the 13C NMR
spectra of these compounds is more complex. For the com-
pounds containing electron withdrawing groups at the 2-
position (38, 40 and 41) signals due to positions 1, 5, 6 and 7 are
deshielded as expected, but the quaternaries at C3 and C7a are
both shielded by 3–6 ppm.
Experimental
1H and 13C NMR spectra were recorded at 200 (or 250) and 50
(or 63) MHz respectively for solutions in deuteriochloroform
unless otherwise stated; coupling constants (J) are given in Hz.
Infrared parameters (νmax) are quoted in cmϪ1 for Nujol mulls
or liquid films.
Proton–carbon coupling constants nJCH have been measured
for a representative series of substituted pyrrolizinones and are
1
reported in Tables 1 and 2. Increases in JCH relative to the
parent system 1 of up to 7 Hz are observed when the pyrroliz-
inone contains an electron withdrawing group. The effect is
usually greatest at the adjacent position, though the significant
increases at all sites of the cyano compound 41 is noteworthy.
The networks of long range couplings reported in Table 2 vary
little from those of the parent compound; no cross-ring inter-
actions are observed. In systems containing a methyl group, the
two-bond coupling of the ipso carbon atom to the methyl
protons is of the order of 7.5 Hz.
The mass spectrum of 1 is dominated by ring cleavage due to
loss of CO from the molecular ion, and this pattern is main-
tained for the simple alkyl, aryl and cyano derivatives reported
here. For those compounds containing an additional carbonyl
group (21–22 and 38–40) ionisation at this site followed by
α-cleavage leads to (M Ϫ OR) peaks (from the esters) or an
(M Ϫ Me) peak (from the methyl ketone) which are usually
more intense than those due to ring cleavage. Loss of a methyl
group under electron impact is also found for the methoxy
compound 20, but this breakdown is only about half as intense
as the standard ring cleavage.
Synthesis of pyrrole precursors
2-Methylpyrrole was obtained in 72% yield by Wolff–Kishner
reduction of pyrrole-2-carbaldehyde.15 2-Phenylpyrrole and
3-phenylpyrrole were obtained in 25 and 26% yield respectively
by flash vacuum pyrolysis of 1-phenylpyrrole,16 and were separ-
ated by dry flash chromatography on silica.
3-Substituted pyrrole-2-carbaldehydes were made by photo-
lytic ring contraction of 4-substituted pyridine N-oxides in the
presence of copper() ions. The following procedure for 3-
methylpyrrole-2-carbaldehyde10 5 is typical. A degassed solution
of 4-picoline N-oxide (4-methylpyridine N-oxide) (1.89 g, 17
mmol) and copper() sulfate pentahydrate (39.10 g, 0.16 mol) in
deionised water (670 cm3) was irradiated by a 400 W mercury
vapour lamp for 6 h. A gentle stream of nitrogen through the
solution was maintained during the photolysis. The reaction
mixture was saturated with sodium chloride and continuously
extracted with methylene chloride (250 cm3). The combined
extracts were dried (MgSO4) and evaporated. Flash chrom-
atography (25% ethyl acetate–n-hexane) of the dark brown
residue gave 3-methylpyrrole-2-carbaldehyde 5 (0.620 g, 33%)
as a light brown solid, mp 92–94 ЊC (from n-hexane) (lit.,10 90–
Finally, the possible extension of the pyrolytic methods to
cyclisation of the vinylogous species 45 and 46 was briefly
investigated. The Meldrum’s acid derivative 45 was prepared by
Knoevenagel condensation of the aldehyde 47, whereas the
pentadienoate 46 was obtained from pyrrole-2-carbaldehyde
and the appropriate Wittig reagent.26 However, pyrolysis of 45
3
4
92 ЊC); δH 10.39 (1H, br s), 9.59 (1H, s), 7.04 (1H, t, J and J
3
4
2.4), 6.11 (1H, t, J and J 2.4) and 2.37 (3H, s) (in agreement
with published data 28); δC 177.49, 133.11 (q), 129.35 (q), 126.39,
112.56 and 10.48. Also made by this method were 3-methoxy-
pyrrole-2-carbaldehyde 6 (23%), mp 131–132 ЊC (lit.,9 135–
136 ЊC) δH (360 MHz) 9.80 (1H, br s), 9.50 (1H, apparent s),
6.95 (1H, td, 3J and 4J 2.9, 5J 1.0), 5.87 (1H, t, 3J and 4J 2.8) and
3.77 (3H, s) (in agreement with published data 9); δC 175.24,
158.98 (q), 127.07, 118.70 (q), 95.20 and 57.76; m/z 125 (Mϩ,
1
at 600 ЊC gave a material whose H NMR spectrum was com-
plex with only small peaks attributable to the expected aza-
azulenone 4827 (ca. 13%), partly owing to the poor volatility of
the precursor. Unfortunately, FVP of the volatile ester 46 at
600 ЊC gave only recovered starting material (TLC) whereas
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J. Chem. Soc., Perkin Trans. 1, 1997

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100%), 124 (17), 82 (18) and 79 (12); and methyl 2-formyl-
pyrrole-3-carboxylate 7 (24%), mp 129–130 ЊC (from ethyl
acetate) (lit.,29 129 ЊC), δH 10.20 (1H, s), 10.00 (1H, br s), 7.02
(1H, dd, J 2.8 and J 2.7), 6.75 (1H, dd, J 2.8 and J 2.7) and
3.89 (3H, s); δC 181.92, 163.95 (q), 132.64 (q), 124.32, 122.51
(q), 113.50 and 51.68.
H, 5.15; N, 4.8%); νmax 3200, 1715, 1695 and 1560; δH 12.89 (1H,
3
br s), 8.27 (1H, s), 7.01 (2H, apparent d), 4.40 (2H, q, J 7.2),
3
1.77 (6H, s) and 1.40 (3H, t, J 7.2); δC 163.31 (q), 163.14 (q),
3
4
3
4
159.39 (q), 143.78, 131.98 (q), 129.61 (q), 128.18, 116.78, 105.18
(q), 104.67 (q), 61.47, 27.27 and 14.09; m/z 293 (Mϩ, 90%), 235
(83), 191 (89), 163 (50), 146 (90), 119 (100), 91 (31), 63 (26) and
43 (38).
Ethyl 5-formylpyrrole-2-carboxylate 8
Dimethyl 2-[(pyrrol-2-yl)methylidene]malonate 33. Com-
pound 33 (from dimethyl malonate and pyrrole-2-carb-
aldehyde) (96%) had bp 169–174 ЊC (1.5 Torr) (Found: C, 57.4;
H, 5.3; N, 6.9. C10H11NO4 requires C, 57.4; H, 5.3; N, 6.7%); δH
11.31 (1H, br s), 7.61 (1H, s), 6.98 (1H, m), 6.61 (1H, m), 6.21
(1H, m), 3.72 (3H, s) and 3.68 (3H, s); δC 168.00 (q), 166.55 (q),
137.36, 126.72 (q), 126.17, 122.75, 112.77 (q), 111.24, 51.95 and
51.79; m/z 209 (Mϩ, 40%), 208 (80), 177 (62), 146 (35), 119
(100), 90 (69) and 63 (94).
Ethyl pyrrole-2-carboxylate was prepared by the Organic
Syntheses method 30 and was subjected to Vilsmeier formyl-
ation.31 Distillation of the dark red residue obtained after
workup gave as the first fraction, bp 130–132 ЊC (2 Torr) [lit.,31
82–86 ЊC (0.05 Torr)], ethyl 5-formylpyrrole-2-carboxylate 8
(9.67 g, 58%), mp 71–73 ЊC (lit.,31 75 ЊC); δH 10.28 (1H, br s),
9.65 (1H, s), 6.91 (2H, s), 4.36 (2H, q, 3J 7.1) and 1.35 (3H, t, 3J
7.1) (in agreement with published data 32); δC 180.30, 160.30 (q),
134.35 (q), 128.50 (q), 119.55, 115.41, 61.99 and 14.09. The
residue remaining after collection of the required fraction had
1H NMR spectrum (60 MHz) consistent with ethyl 4-formyl-
pyrrole-2-carboxylate.
Diethyl 2-[(pyrrol-2-yl)methylidene]malonate 34. Compound
34 (from diethyl malonate and pyrrole-2-carbaldehyde) (78%)
had bp 100–105 ЊC (0.1 Torr) (Found: C, 61.8; H, 6.8; N, 6.95;
Mϩ, 237.0991. C12H15NO4 requires C, 60.8; H, 6.3; N, 5.95%;
M, 237.1001); δH 11.31 (1H, br s), 7.63 (1H, s), 7.02 (1H, m),
6.68 (1H, m), 6.26 (1H, m), 4.28 (2H, q, 3J 7.2), 4.23 (2H, q, 3J
Condensation of pyrrole-2-carbaldehydes with active methylene
compounds8
3
3
7.2), 1.29 (3H, t, J 7.2) and 1.28 (3H, t, J 7.2); δC 167.92 (q),
166.47 (q), 136.99, 127.00 (q), 125.68, 122.64, 113.48 (q),
111.13, 61.17, 60.81, 14.01 and 13.86; m/z 237 (Mϩ, 37%), 146
(35), 119 (27), 75 (39), 65 (100) and 53 (65).
The active methylene compound (5 mmol), piperidine (5 drops)
and glacial acetic acid (5 drops) were added to the pyrrole-
carbaldehyde (5 mmol) in the minimum amount of toluene. The
solution was stirred overnight at room temperature, unless
otherwise stated. The solvent was removed under vacuum and
the orange or yellow product was conveniently purified by bulb-
to-bulb distillation or by recrystallisation.
The following derivatives were prepared by this method. The
active methylene compound and aldehyde used are indicated.
5-[(3-Methylpyrrol-2-yl)methylidene]-2,2-dimethyl-1,3-
dioxane-4,6-dione 10. Compound 10 (from Meldrum’s acid and
3-methylpyrrole-2-carbaldehyde 5) (77%) had mp 170.5–172 ЊC
(from ethanol) (Found: C, 61.05; H, 5.7; N, 6.10. C12H13NO4
requires C, 61.3; H, 5.55; N, 5.95%); νmax 3289, 1722, 1681 and
1559; δH 12.70 (1H, br s), 8.27 (1H, s), 7.33 (1H, apparent t, 3J
and 4J 2.9), 6.33 (1H, apparent t, 3J and 4J 2.9), 2.37 (3H, s) and
1.73 (6H, s); δC 164.61 (q), 141.07 (q), 139.41, 131.75, 127.18
(q), 115.10, 103.87 (q), 97.86 (q), 29.51 and 26.97; m/z 235 (Mϩ,
42%), 177 (19), 133 (56), 105 (100), 104 (46), 78 (15), 51 (13) and
43 (15).
Methyl (E)- and (Z)-2-acetyl-3-(pyrrol-2-yl)propenoate 35.
Compound 35 (from methyl acetoacetate and pyrrole-2-
carbaldehyde, 48 h) (72% in total) had bp 130–150 ЊC (1 Torr)
(Found: C, 62.5; H, 6.25;. N, 7.3; Mϩ, 193.0737. C10H11NO3
requires C, 62.2; H, 5.7; N, 7.25%; M, 197.0739); δH (major and
minor isomers present in a ratio of 5:2; distinguishable minor
isomer signals reported in parentheses) 12.12 (11.51) (1H, br
s), 7.21 (7.62) (1H, s), 7.09 (1H, m), 6.77 (1H, m), 6.33 (1H,
m), 3.79 (3.83) (3H, s) and 2.50 (2.38) (3H, s); δC (minor
isomer in parentheses) 199.97 (197.11) (q), 168.14 (168.84)
(q), 138.25 (137.72), 128.30 (127.22) (q), 126.77, 125.36
(124.74), 119.03 (120.60) (q), 112.48 (111.75), 51.81 (51.88)
and 31.46 (29.36); m/z 193 (Mϩ, 50%), 146 (100), 91 (22), 65
(13) and 43 (47).
Methyl 2-cyano-3-(pyrrol-2-yl)propenoate 36. Compound 36
(from methyl cyanoacetate and pyrrole-2-carbaldehyde) (67%)
had mp 112–114 ЊC (from ethanol) (Found: C, 61.0; H, 4.6; N,
15.9. C9H8NO2 requires C, 61.35; H, 4.55; N, 15.9%); δH 9.94
(1H, br s), 8.01 (1H, s), 7.24 (1H, m), 6.98 (1H, m), 6.42 (1H, m)
and 3.86 (3H, s); δC 163.81 (q), 142.53, 128.44, 126.58 (q),
124.27, 118.20 (q), 112.36, 91.16 (q) and 52.66; m/z 176 (Mϩ,
100%), 145 (76), 144 (84), 116 (81) and 90 (25).
2,2-Dimethyl-5-[3-(pyrrol-2-yl)prop-2-enylidene]-1,3-dioxane-
4,6-dione 45. In a similar procedure, 3-(pyrrol-2-yl)propenal
4733 (0.36 g, 3 mmol) was reacted with Meldrum’s acid (0.43 g,
3 mmol) to give compound 45 (0.68 g, 92%), mp 190–192 ЊC
(decomp.) (from ethanol) (Found: C, 63.45; H, 5.3; N, 5.7.
C13H13NO4 requires C, 63.15; H, 5.25; N, 5.65%); δH 10.55 (1H,
br s), 8.21 (1H, d, 3J 12.5), 7.96 (1H, t, 3J 12.5), 7.34 (1H, d, 3J
12.5), 7.23 (1H, m), 6.80 (1H, m), 6.38 (1H, m) and 1.74 (6H, s);
δC 163.59 (q), 162.90 (q), 159.80, 145.24, 130.51 (q), 128.39,
121.80, 118.18, 112.69, 104.71 (q), 104.27 (q) and 27.36; m/z
247 (Mϩ, 60%), 189 (65), 121 (75), 117 (100) and 90 (38).
5-[(3-Methoxypyrrol-2-yl)methylidene]-2,2-dimethyl-1,3-
dioxane-4,6-dione 11. Compound 11 (from Meldrum’s acid and
3-methoxypyrrole-2-carbaldehyde 6) (72%) had mp 190–191 ЊC
(from ethanol) (Found: C, 57.2; N, 5.25; N, 5.5. C12H13NO5
requires C, 57.35; H, 5.2; N, 5.6%); δH ([2H6]DMSO) 11.85 (1H,
5
3
5
br s), 7.99 (1H, d, J 0.8), 7.66 (1H, dd, J 2.8 and J 0.8), 6.18
3
(1H, d, J 2.8), 3.93 (3H, s) and 1.65 (6H, s); δC([2H6]DMSO)
164.02 (q), 162.78 (q), 136.52, 134.01, 116.61 (q), 103.47 (q),
96.30, 94.25 (q), 58.83 and 26.62; m/z 251 (Mϩ, 43%), 250 (68),
194 (38), 193 (30), 192 (41), 176 (28), 149 (70), 134 (48), 121
(59), 120 (100), 106 (52) and 93 (51).
2,2-Dimethyl-5-[(3-methoxycarbonylpyrrol-2-yl)methylidene]-
1,3-dioxane-4,6-dione 12. Compound 12 (from Meldrum’s acid
and methyl 2-formylpyrrole-3-carboxylate 7) (86%) had mp
191 ЊC (from isopropyl alcohol) (Found: C, 55.65; H, 4.85; N,
4.9. C13H13NO6 requires C, 55.9; H, 4.7; N, 5.0%); νmax 1744,
1712 and 1687; δH 13.08 (1H, br s), 9.34 (1H, s), 7.28 (1H, t, 3J
and 4J 2.5), 6.96 (1H, t, 3J and 4J 2.5), 3.89 (3H, s) and 1.75 (6H,
s); δC 163.58 (q), 142.39, 127.99 (q), 127.69, 126.51 (q), 116.69,
104.96 (q), 104.55 (q), 51.88 (q) and 27.19 (one quaternary
signal missing); m/z 279 (Mϩ, 53%), 222 (20), 221 (51), 190 (20),
177 (65), 149 (97), 146 (41), 134 (100) and 118 (55).
5-[(5-Ethoxycarbonylpyrrol-2-yl)methylidene]-2,2-dimethyl-
1,3-dioxane-4,6-dione 13. Compound 13 (from Meldrum’s acid
and ethyl 5-formylpyrrole-2-carboxylate 8) (98% after tri-
turation with n-hexane) had mp 166–168 ЊC (from ethanol)
(Found: C, 57.1; H, 5.2; N, 4.65. C14H15NO6 requires C, 57.35;
2,2-Dimethyl-5-[1-(pyrrol-2-yl)ethylidene]-1,3-dioxane-4,6-
dione 18
A solution of titanium tetrachloride (9 cm3, 82 mmol) in carbon
tetrachloride (20 cm3) was added dropwise under an atmos-
phere of nitrogen to ice-cold tetrahydrofuran (160 cm3). The
resulting mixture was treated with a solution of Meldrum’s acid
(5.96 g, 41 mmol) and 2-acetylpyrrole 9 (4.45 g, 41 mmol) in
tetrahydrofuran (40 cm3), followed by a solution of pyridine (13
cm3) in tetrahydrofuran (20 cm3). The mixture was stirred at
0 ЊC for 3.5 h and then at room temperature overnight, after
J. Chem. Soc., Perkin Trans. 1, 1997
2199

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which water (40 cm3) was added, the resulting mixture was
filtered through Celite, concentrated and extracted with diethyl
ether (6 × 100 cm3). The combined organic layers were washed
with brine (20 cm3), saturated aqueous sodium hydrogen car-
bonate (20 cm3) and dried (MgSO4). The solvents were removed
under reduced pressure to give a crop of yellow crystals of 2,2-
dimethyl-5-[1-(pyrrol-2-yl)ethylidene]-1,3-dioxane-4,6-dione 18
(5.48 g, 57%) after recrystallisation from ethanol, mp 127–
129 ЊC (from ethanol) (Found: C, 61.3; H, 5.6; N, 5.95.
C12H13NO4 requires C, 61.3; H, 5.55; N, 5.95%); νmax 3260, 1780
and 1740; δH ([2H6]DMSO) 12.10 (1H, br s), 7.39 (1H, m), 7.18
(1H, m), 6.37 (1H, m), 2.70 (3H, s) and 1.72 (6H, s);
δC([2H6]DMSO) 162.38 (q), 157.77 (q), 130.10 (q), 128.83,
122.24, 111.74, 105.58 (q), 102.61 (q), 26.89 and 22.97; m/z 235
(Mϩ, 13%), 177 (39), 133 (100) and 104 (47).
phosphoranylidene)acetate (0.813 g, 2.4 mmol), 20 cm3, 1 h,
sublimation] (0.236 g, 78%, ratio E :Z = 90:10) had mp 93.5–
94.5 ЊC [from toluene–light petroleum (bp 60–80 ЊC)] (lit.,21
103 ЊC); λmax(EtOH) (ε/dm3 molϪ1 cmϪ1) 260–265 (6760) and
330 (22 900); δH (minor stereoisomer in square brackets) 8.81
(1H, br s) [12.22 (1H, br s)], 7.56 (1H, d, 3J 15.9) [6.77 (1H, d, 3J
12.5)], 6.93 (1H, m) [7.01 (1H, br d)], 6.56 (1H, m) [6.52 (1H,
m)], 6.27 (1H, m) [6.27 (1H, m)], 6.00 (1H, d, 3J 15.9) [5.53 (1H,
3
d, J 12.5)] and 3.77 (3H, s) [3.77 (3H, s)] (in agreement with
literature data);21,22 δC(minor stereoisomer in square brackets)
168.01 (q) [169.50 (q)], 134.30 [134.77], 128.20 (q) [128.94 (q)],
122.30 [122.90], 114.32 [118.62], 110.83 [110.05], 110.61 [106.98]
and 51.39 [51.47].
Ethyl (E)-2-methyl-3-(pyrrol-2-yl)propenoate 32. Compound
32 [from pyrrole-2-carbaldehyde (0.201 g, 2.1 mmol), ethyl 2-
(triphenylphosphoranylidene)propanoate (1.01 g, 3.0 mmol),
25 cm3, 4 h, ethyl acetate–n-hexane] (0.366 g, 97%) had mp 78–
79 ЊC [from light petroleum (bp 60–80 ЊC)] (lit.,22 79–80 ЊC);
νmax 3290, 1680 and 1630; δH 8.78 (1H, br s), 7.57 (1H, s), 6.94
(1H, m), 6.54 (1H, br s), 6.34 (1H, m), 4.25 (2H, q, 3J 7.1), 2.16
(3H, d, 4J 1.3) and 1.33 (3H, t, 3J 7.1); δC 168.97 (q), 128.87 (q),
128.50, 121.03 (q), 120.82, 113.55, 110.76, 60.54, 14.20 and
13.89 (all spectroscopic data in agreement with published
data 22). Another fraction was identified as ethyl (Z)-2-methyl-3-
(pyrrol-2-yl)propenoate (9 mg, 2%), oil; δH 11.99 (1H, br s), 6.92
(1H, m), 6.73 (1H, br s), 6.39 (1H, m), 6.24 (1H, m), 4.25 (2H, q,
Reactions of pyrroles with methoxymethylidene Meldrum’s
acid14
The appropriate pyrrole (11 mmol) was added to a solution of
methoxymethylidene Meldrum’s acid 4 (1.86 g, 10 mmol) in the
minimum volume of acetonitrile (8 cm3), and the mixture was
stirred at room temperature for the stated length of time. Con-
centration of the solution under vacuum yielded a crop of yel-
low crystals which were washed with hexane. The following
derivatives were made by this method.
2,2-Dimethyl-5-[(5-methylpyrrol-2-yl)methylidene]-1,3-
dioxane-4,6-dione 14. Compound 14 (1.43 g, 61%) (from 2-
methylpyrrole, stirred at room temperature for 40 h) had mp
136–137 ЊC (from ethanol) (Found: C, 61.6; H, 5.55; N, 6.0.
C12H13NO4 requires C, 61.3; H, 5.55; N, 5.95%); νmax 3250, 1735
and 1680; δH 8.04 (1H, s), 7.37 (1H, br s), 6.38 (1H, m), 2.43
(3H, s) and 1.67 (6H, s); δC([2H6]DMSO) 163.65 (q), 145.90 (q),
140.66, 132.07 (br), 127.92 (q), 114.94, 103.30 (q), 97.31 (q),
4
3
3J 7.1), 2.06 (3H, d, J 1.2) and 1.33 (3H, t, J 7.1); δC (three
quaternaries missing) 132.33, 121.30, 117.09, 109.44, 60.47,
21.74 and 14.08 (all spectroscopic data in agreement with pub-
lished data.22
Methyl (E,E)-5-(pyrrol-2-yl)penta-2,4-dienoate 46. Com-
pound 46 [from pyrrole-2-carbaldehyde (0.420 g, 4.4 mmol),
3-methoxycarbonylprop-2-enylidenetriphenylphosphorane26
(1.902 g, 5.4 mmol) in toluene (50 cm3), 17 h, ethyl acetate,
n-hexane] (0.400 g, 51%) was the major fraction, mp 131–
132 ЊC (from hexane) (lit.,21 130 ЊC) δH 8.70 (1H, br s), 7.39 (1H,
ddd, 3J 15.2 and 11.1, nJ 0.6), 6.86 (1H, m), 6.75 (1H, d, 3J 15.6),
6.40–6.50 (2H, m), 5.86 (1, d, 3J 15.2) and 3.74 (3H, s); δC
167.88 (q), 145.38, 130.32, 129.74 (q), 121.13, 120.48, 117.79,
111.94, 110.58 and 51.37.
1
26.53 and 13.70 (both H and 13C NMR spectra show evidence
of exchange processes at room temperature); m/z 235 (Mϩ,
24%), 177 (12), 133 (100) and 104 (40).
2,2-Dimethyl-5-[(2-phenylpyrrol-2-yl)methylidene]-1,3-
dioxane-4,6-dione 15. Compound 15 (65%) (from 2-phenyl-
pyrrole, stirred at room temperature overnight) had mp 139–
141 ЊC (from ethanol) (Found: C, 68.4; H, 5.1; N, 4.7.
C17H15NO4 requires C, 68.4; H, 5.1; N, 4.7%); δH 8.20 (1H, s),
3
4
7.74 (2H, m), 7.4–7.5 (3H, m), 7.18 (1H, dd, J 4.2 and J 2.1),
Pyrrolizinones
3
4
6.89 (1H, dd, J 4.2 and J 2.3) and 1.78 (6H, s); δC 164.68 (q),
163.97 (q), 144.98 (q), 141.40, 131.46, 129.68, 129.41 (q),
129.14, 125.47, 112.38, 103.91 (q), 99.04 (q) and 26.98 (one
quaternary signal missing); m/z 297 (Mϩ, 13%), 195 (85), 143
(100) and 115 (43).
2,2-Dimethyl-5-[(3-phenylpyrrol-2-yl)methylidene]-1,3-
dioxane-4,6-dione 16 and 2,2-dimethyl-5-[(4-phenylpyrrol-2-
yl)methylidene]-1,3-dioxane-4,6-dione 17. Reaction of 3-phenyl-
pyrrole under similar conditions gave an equimolar mixture of
compounds 16 and 17 (78%), mp 180–182 ЊC (from ethanol)
which could only be partially separated into a major and minor
isomer (17 and 16 respectively) by recrystallisation (Found: C,
68.4; H, 5.1; N, 4.8. C17H15NO4 requires C, 68.4; H, 5.1; N,
4.7%); δH (major isomer) 8.29 (1H, s), 7.71 (1H, m), 7.2–7.6
(6H, m) and 1.77 (6H, s); δH (minor isomer) 8.34 (1H, s), 7.2–
7.6 (6H, m), 6.62 (1H, t, J 2.4) and 1.76 (6H, s).
Pyrolysis of Meldrum’s acid derivatives. The Meldrum’s acid
derivative was sublimed at low pressure into a horizontal quartz
pyrolysis tube (35 × 2.5 cm) which was maintained at the
appropriate temperature by an electrically heated furnace. The
products were collected in a U-tube cooled by liquid nitrogen
situated at the exit point of the furnace.
The following pyrrolizinones were obtained by pyrolysis of
Meldrum’s acid derivatives. The 2,2-dimethyl-5-[(pyrrol-2-
yl)methylidene]-1,3-dioxane-4,6-dione substrate and pyrolysis
parameters [furnace temperature (Tf), inlet temperature (Ti),
pressure (P) and pyrolysis time (t)] are quoted.
7-Methylpyrrolizin-3-one 19. Compound 19 {from 2,2-
dimethyl-5-[(3-methylpyrrol-2-yl)methylidene]-1,3-dioxane-4,6-
dione 10 (2.20 g, 9 mmol)} (Tf 650 ЊC, Ti 120–130 ЊC, P 0.005
Torr, t 4 h) (1.20 g, 96%) had bp 64–66 ЊC (0.4 Torr) (Found:
Mϩ, 133.0533. C8H7NO requires M, 133.0528); νmax 1738 and
1526; δH 7.05 (1H, d, 3J 5.8), 6.81 (1H, m, 3J 3.2 and 5J 0.5), 5.80
3
3
5
Wittig reactions of pyrrole-2-carbaldehydes
(1H, d, J 3.2), 5.56 (1H, d, J 5.8) and 1.98 (3H, d, J 0.5); δC
165.66 (q), 136.69, 134.08 (q), 123.98 (q), 120.54, 119.18, 117.62
and 11.03; m/z 133 (Mϩ, 100%), 105 (32), 104 (71), 79 (12), 78
(18), 52 (15) and 51 (20).
A solution of the appropriate pyrrole-2-carbaldehyde and ylide
in dry benzene was heated at reflux under nitrogen for the time
stated. The solvent was removed and, unless otherwise stated,
the products were obtained by dry flash chromatography of
the residue. The following 3-(pyrrol-2-yl)propenoates were
obtained by this means. The aldehyde and ylide, volume of
solvent, reaction time and the eluent used in the chromato-
graphic separation (or other workup method) are quoted.
Methyl 3-(pyrrol-2-yl)propenoate 30. Compound 30 [from
pyrrole-2-carbaldehyde (0.213 g, 2.2 mmol), methyl (triphenyl-
7-Methoxypyrrolizin-3-one 20. Compound 20 {from 2,2-
dimethyl-5-[(3-methoxypyrrol-2-yl)methylidene]-1,3-dioxane-
4,6-dione 11 (0.260 g, 1.0 mmol)} (Tf 600 ЊC, Ti 150–180 ЊC, P
0.03 Torr, t 35 min) (0.058 g, 37%) had bp 90–95 ЊC (0.2 Torr)
(Found: Mϩ, 149.0476. C8H7NO2 requires M, 149.0477); δH
3
3
3
7.11 (1H, d, J 5.8), 6.84 (1H, d, J 3.3), 5.67 (1H, d, J 3.3),
3
5.52 (1H, d, J 5.8) and 3.82 (3H, s); δC 164.91 (q), 149.42 (q),
2200
J. Chem. Soc., Perkin Trans. 1, 1997

View Online
137.18, 120.37, 117.91, 116.88 (q), 107.53 and 58.95; m/z 149
(Mϩ, 100%), 134 (20), 120 (40), 106 (65), 80 (32) and 52 (49).
Methyl 3-oxo-3H-pyrrolizine-7-carboxylate 21. Compound
21 {from 2,2-dimethyl-5-[(3-methoxycarbonylpyrrol-2-yl)-
methylidene]-1,3-dioxane-4,6-dione 12 (1.75 g, 6 mmol)} (Tf
620 ЊC, Ti 160–180 ЊC, P 0.01 Torr, t 1 h) (0.90 g, 81%) had mp
70–71 ЊC (from n-hexane) (Found: C, 61.1; H, 4.0; N, 7.75.
C9H7NO3 requires C, 61.0; H, 3.95; N, 7.9%); νmax 1742, 1720,
1586 and 1524; δH 7.38 (1H, dd, 3J 5.9 and 5J 0.5), 6.84 (1H, dd,
5.72 (1H, dd, 3J 5.8 and 6J 0.8); δC 168.32 (q), 137.87, 132.81 (q),
128.87, 127.99, 126.70, 121.02, 119.83 and 114.32 (two quater-
naries not apparent).
[2-2H]Pyrrolizin-3-one. Deuterium exchange of the NH of
the Meldrum’s acid derivative 2 was accomplished by dissolving
the substrate (0.22 g, 2 mmol) in [2H]chloroform (1.5 cm3) fol-
lowed by addition of [2H]methanol (2 cm3) within the inlet tube
of the FVP apparatus.35 The solvents were removed at the oil
pump, and the residue was sublimed into the pyrolysis tube at
5
6
1
3J 3.3 and J 0.5), 6.34 (1H, dd, 3J 3.3 and J 0.9), 5.80 (1H, dd,
600 ЊC (0.002 Torr). The H NMR spectrum of the product
6
3J 5.9 and J 0.9) and 3.80 (3H, s); δC 165.12 (q), 163.14 (q),
showed no signal at δH 5.62 corresponding to H(2); the level
of deuterium incorporation at this position was ca. 96%, and
there was no significant incorporation at other sites in the
product.
139.76 (q), 138.24, 123.61, 118.21, 115.84 (q), 115.08 and 51.60;
m/z 177 (Mϩ, 100%), 146 (76), 134 (37), 118 (42), 90 (16) and 63
(33).
Ethyl 3-oxo-3H-pyrrolizine-5-carboxylate 22. Compound
Pyrolysis of 3-(pyrrol-2-yl)propenoic ester derivatives.
Pyrolysis of the 3-(pyrrol-2-yl)propenoic ester derivatives was
carried out as described above for the Meldrum’s acid deriv-
atives. However, upon completion of the pyrolysis the volatile
alcohol generated in the reaction was removed into the pump
trap by allowing the product trap to warm up partially while the
system was still under vacuum. When no more alcohol
remained, the product trap was allowed to warm to room tem-
perature under an atmosphere of dry nitrogen. The product was
removed from the trap by dissolving in acetone. After removal
of the solvent, the pyrrolizinone was subjected to bulb to bulb
(Kugelrohr) distillation where appropriate. The following
pyrrolizin-3-ones were prepared by this means. The substrate
and pyrolysis parameters are quoted as above.
22
{from
2,2-dimethyl-5-[(2-ethoxycarbonylpyrrol-5-yl)-
methylidene]-1,3-dioxane-4,6-dione 13 (0.293 g, 1.0 mmol)} (Tf
550 ЊC, Ti 150–170 ЊC, P 0.002 Torr, t 1 h 40 min) (0.132 g, 69%)
had bp 65–67 ЊC (0.2 Torr) (Found: Mϩ, 191.0579. C10H9NO3
3
requires M, 191.0582); νmax 1750 and 1710; δH 7.12 (1H, d, J
3
6
3
6.0), 6.78 (1H, dd, J 3.4 and J 0.7), 6.01 (1H, d, J 3.4), 5.80
6
(1H, dd, 3J 6.0 and J 0.7), 4.30 (2H, q, 3J 7.1) and 1.33 (3H, t,
3J 7.1); δC 163.43 (q), 158.72 (q), 141.68 (q), 136.70, 126.15 (q),
124.10, 123.84, 109.45, 60.84 and 14.08; m/z 191 (Mϩ, 100%),
163 (18), 146 (75), 119 (35), 91 (13) and 63 (10).
1-Methylpyrrolizin-3-one 23. Compound 23 {from 2,2-
dimethyl-5-[1-(pyrrol-2-yl)ethylidene]-1,3-dioxane-4,6-dione 18
(0.58 g, 2.5 mmol)} (Tf 600 ЊC, Ti 130–140 ЊC, P 0.002 Torr, t 1
h) (0.24 g, 73%) had bp 112 ЊC (4 Torr) [lit.,34 110–130 ЊC (17
Pyrrolizin-3-one 1. Compound 1 [from methyl 3-(pyrrol-2-
yl)propenoate 30 (0.095 g, 0.63 mmol)] (Tf 850 ЊC, Ti 50 ЊC, P
0.025 Torr, t 15 min) (0.065 g, 87%) had bp 95–100 ЊC (17 Torr)
4
Torr)]; νmax 1725; δH (360 MHz) 6.87 (1H, dd, 3J 3.0 and J 1.0),
4
6
6.00 (1H, dd, 3J 3.0 and J 1.0), 5.98 (1H, td, 3J 3.0 and J 0.7),
4
6
4
6
5.39 (1H, qd, J 1.7 and J 0.6) and 2.07 (3H, d, J 1.7); δC
165.66 (q), 151.83 (q), 138.63 (q), 118.22, 117.52, 114.67,
109.09, and 13.08; m/z 133 (Mϩ, 100%), 118 (14), 104 (96), 94
(11), and 78 (29).
[lit.,1 130 ЊC (16 Torr)]; δH 7.04 (1H, dd, 3J 5.9 and J 0.5), 6.86
3
3
(1H, t, J 2.0), 5.96 (2H, m) and 5.62 (1H, d, J 5.9) (in agree-
ment with published data 1).
2-Methylpyrrolizin-3-one 37. Compound 37 [from ethyl 3-
(pyrrol-2-yl)-2-methylpropenoate 32 (0.177 g, 1.0 mmol)] (Tf
800 ЊC, Ti 90 ЊC, P 0.008 Torr, t 20 min) (0.115 g, 87%) had bp
45–50 ЊC (0.2 Torr) (Found: Mϩ, 133.0525. C8H7NO requires
5-Methylpyrrolizin-3-one 24. Compound 24 {from 2,2-
dimethyl-5-[(5-methylpyrrol-2-yl)methylidene]-1,3-dioxane-4,6-
dione 14 (0.578 g, 2.5 mmol)} (Tf 600 ЊC, Ti 130–140 ЊC, P 0.005
Torr, t 45 min) (0.285 g, 87%) had bp 91–95 ЊC (21 Torr)
(Found: C, 73.4; H, 5.4; N, 10.8; Mϩ, 133.0523. C8H7NO
requires C, 72.2; H, 5.25; N, 10.55%; M, 133.0528); νmax 1730
and 1585; δH 7.03 (1H, d, 3J 5.9), 5.89 (1H, d, 3J 2.9), 5.64 (1H,
3
M, 133.0528); νmax 1735 and 1475; δH 6.83 (1H, br d, J 3.2),
6.68 (1H, qd, 4J 1.7 and 5J 0.6), 5.93 (1H, t, 3J 3.1), 5.82 (1H, d,
n
of apparent t, 3J 3.2, 4J 0.7 and J 0.7) and 1.86 (3H, d, 4J 1.7);
δC 166.54 (q), 136.48 (q), 132.14 (q), 131.38, 118.23, 114.98,
109.29 and 10.63; m/z 133 (Mϩ, 100%), 105 (29), 104 (61), 78
(15), 57 (15), 51 (15) and 39 (11).
3
m), 5.60 (1H, d, J 5.9) and 2.29 (3H, s); δC 166.50 (q), 137.36,
135.76 (q), 134.23 (q), 120.60, 112.89, 111.64 and 11.91; m/z 133
(Mϩ, 100%), 104 (57), 78 (19) and 63 (24).
Methyl 3-oxo-3H-pyrrolizine-2-carboxylate 38. Compound
38 {from dimethyl 2-[(pyrrol-2-yl)methylidene]malonate 33
(0.33 g, 1.6 mmol)} (Tf 650 ЊC, Ti 100–120 ЊC, P 0.002 Torr, t 20
min) (0.25 g, 84%) had mp 105 ЊC (from cyclohexane) (Found:
C, 61.25; H, 4.05; N, 7.8. C9H7NO3 requires C, 61.0; H, 3.95; N,
5-Phenylpyrrolizin-3-one 25. Compound 25 {from 2,2-
dimethyl-5-[(5-phenylpyrrol-2-yl)methylidene]-1,3-dioxane-4,6-
dione 15 (0.54 g, 1.8 mmol)} (Tf 600 ЊC, Ti 160–180 ЊC, P 0.002
Torr, t 1 h) (0.31 g, 88%) had bp 97–98 ЊC (0.2 Torr) (Found:
Mϩ, 195.0686. C13H9NO requires M, 195.0684); δH 7.2–7.9 (5H,
3
3
7.9%); δH 7.85 (1H, s), 7.03 (1H, d, J 3.3), 6.33 (1H, d, J 3.3),
3
3
6
3
m), 7.10 (1H, d, J 5.9), 6.19 (1H, dd, J 3.3 and J 0.7), 6.07
(1H, d, 3J 3.3) and 5.09 (1H, dd, 3J 5.8 and 6J 0.7); δC 166.21 (q),
138.49 (q), 137.55, 129.60 (q), 128.60, 128.12, 126.72, 121.70,
114.67 and 112.20 (one quaternary obscured); m/z 195 (Mϩ,
100%), 167 (32), 166 (31), 140 (11), 139 (13) and 63 (14).
6.13 (1H, t, J 3.3) and 3.83 (3H, s); δC 161.30 (q), 160.72 (q),
145.16, 133.19 (q), 122.98 (q), 121.32, 117.14, 116.77 and 51.79;
m/z 177 (Mϩ, 74%), 146 (100), 119 (29), 90 (39), 63 (38) and 59
(20).
Ethyl 3-oxo-3H-pyrrolizine-2-carboxylate 39. Compound 39
{from diethyl 2-[(pyrrol-2-yl)methylidene]malonate 34 (0.059 g,
0.25 mmol)} (Tf 600 ЊC, Ti 120 ЊC, P 0.008 Torr, t 20 min) [0.015
g, 30%; this represents a minimum yield since the (solid) prod-
uct was simply scraped from the trap] had mp 59–63 ЊC (lit.,24
60–61 ЊC) (Found: C, 62.4; H, 4.8; N, 7.4. C10H9NO3 requires C,
62.8; H, 4.7; N, 7.35%); δH 7.82 (1H, s), 7.03 (1H, d, 3J 3.1), 6.31
(1H, d, 3J 3.1), 6.12 (1H, t, 3J 3.1), 4.28 (2H, q, 3J 7.1) and 1.33
6-Phenylpyrrolizin-3-one 26 and 7-phenylpyrrolizin-3-one 27.
Compounds 26 and 27 {from 2,2-dimethyl-5-[(3- and 4-
phenylpyrrol-2-yl)methylidene]-1,3-dioxane-4,6-dione 16 and
17 (0.37 g, 1.25 mmol)] (Tf 600 ЊC, Ti 160–180 ЊC, P 0.002 Torr,
t 1.25 h) (0.204 g, 84%) were characterised as the mixture
(Found: Mϩ, 195.0691. C13H9NO requires M, 195.0684); m/z
195 (Mϩ, 100%), 167 (29), 140 (16), 139 (37), 94 (18) and 63
(11); recrystallisation from n-hexane gave a fraction which was
almost pure 6-phenylpyrrolizin-3-one 26 (21%), δH 7.2–7.5 (6H,
m), 7.13 (1H, d, 3J 6.0), 6.35 (1H, d, 4J 0.8) and 5.73 (1H, d, 3J
6.0); δC 165.57 (q), 139.90, 137.48 (q), 133.22 (q), 131.63 (q),
128.66, 126.90, 124.91, 122.47, 114.15 and 110.03; the residue
after recrystallisation was predominantly 7-phenylpyrrolizin-3-
one 27, δH 7.3–7.5 (5H, m), 7.32 (1H, dd, 3J 5.8 and 5J 0.4), 6.97
3
(3H, t, J 7.1); δC 160.80 (2q), 144.70, 133.19 (q), 123.30 (q),
121.17, 116.85, 116.66, 60.71 and 14.08; m/z 191 (Mϩ, 68%), 161
(13), 146 (100), 119 (52), 91 (23), 90 (26) and 63 (18); a small
amount (6%) of pyrrolizin-3-one was also detected at this
temperature and was left as a liquid residue in the trap; the
percentage in the pyrolysate of this product increased at higher
temperatures as follows: 650 ЊC, 21%; 700 ЊC, 35%; 750 ЊC,
91%.
3
5
3
6
(1H, dd, J 3.3 and J 0.4) 6.27 (1H, dd, J 3.3 and J 0.8) and
J. Chem. Soc., Perkin Trans. 1, 1997
2201

View Online
5 H. McNab and C. Thornley, Heterocycles, 1994, 37, 1977.
6 H. McNab and C. Thornley, J. Chem. Soc., Chem. Commun., 1993,
1570.
7 H. McNab and C. Thornley, J. Chem. Soc., Perkin Trans. 1, 1997,
following paper.
8 H. McNab and I. Stobie, J. Chem. Soc., Perkin Trans. 1, 1982, 1845
and references cited therein.
9 F. Bellamy, P. Martz and J. Streith, Heterocycles, 1975, 3, 295.
10 F. Bellamy and J. Streith, J. Chem. Res., (S), 1979, 18; (M), 1979,
0101.
11 F. Bellamy, J. Streith and H. Fritz, Nouv. J. Chim., 1979, 3, 115.
12 W. A. M. Davies, A. R. Pinder and I. G. Morris, Tetrahedron, 1962,
18, 405.
13 G. J. Baxter and R. F. C. Brown, Aust. J. Chem., 1975, 28, 1551.
14 P. A. Derbyshire, G. A. Hunter, H. McNab and L. C. Monahan,
J. Chem. Soc., Perkin Trans. 1, 1993, 2017.
15 J. W. Cornforth and M. E. Forth, J. Chem. Soc., 1958, 1091.
16 C. L. Hickson and H. McNab, J. Chem. Soc., Perkin Trans. 1, 1988,
339.
17 A. J. Blake, H. McNab and L. C. Monahan, J. Chem. Soc., Perkin
Trans. 2, 1991, 2003.
18 R. F. C. Brown and F. W. Eastwood, in Chemistry of Ketenes,
Allenes and Related Compounds, Part 2, ed. S. Patai, Wiley-
Interscience, Chichester, 1980, p. 757.
19 D. W. M. Benzies, P. M. Fresneda, R. A. Jones and H. McNab,
J. Chem. Soc., Perkin Trans. 1, 1986, 1651.
20 For example, A. Maujean, G. Marcy and J. Chuche, J. Chem. Soc.,
Chem. Commun., 1980, 92.
Repyrolysis of ethyl 3-oxopyrrolizine-2-carboxylate 39 as
above showed clean conversion to pyrrolizin-3-one 1 with no
evidence for any stable intermediates. The amounts of conver-
sion were as follows: 650 ЊC, 47%; 700 ЊC, 53%; 750 ЊC, 89%.
2-Acetylpyrrolizin-3-one 40. Compound 40 [from methyl 2-
acetyl-3-(pyrrol-2-yl)propenoate 35 (0.21 g, 1.1 mmol)] (Tf
650 ЊC, Ti 120 ЊC, P 0.003 Torr, t 10 min) (0.14 g, 76%) had mp
103 ЊC (Found: C, 66.9; H, 4.4; N, 8.6. C9H7NO2 requires C,
67.1; H, 4.3; N, 8.7%); δH 7.82 (1H, d, 5J 0.8), 7.01 (1H, appar-
ent dt, 3J 3.2, 4J and 5J 0.8), 6.37 (1H, dd, 3J 3.2 and 4J 0.8), 6.15
(1H, t, 3J 3.2) and 2.46 (3H, s); δC 162.58 (q), 145.55, 133.53 (q),
130.55 (q), 121.00, 118.10, 117.02 and 26.90 (one quaternary
signal missing); m/z 161 (Mϩ, 54%), 146 (100), 91 (21), 90 (24),
63 (24) and 43 (43).
2-Cyanopyrrolizin-3-one 41. Compound 41 [from methyl 2-
cyano-3-(pyrrol-2-yl)propenoate 36 (1.02 g, 5.8 mmol)] (Tf
800 ЊC, Ti 120–130 ЊC, P 0.002 Torr, t 1 h) (0.68 g, 81%) had mp
137–138 ЊC (from ethyl acetate–cyclohexane) (Found: C, 67.0;
H, 2.95; N, 19.4. C8H4N2O requires C, 66.65; H, 2.8; N,
19.45%); δH 7.67 (1H, s), 7.05 (1H, d, 3J 3.2), 6.42 (1H, d, 3J 3.2)
and 6.20 (1H, t, 3J 3.2); δC 159.46 (q), 147.47, 133.72 (q), 122.86,
118.75, 118.12, 111.65 (q) and 105.68 (q); m/z 144 (Mϩ, 100%),
116 (63), 89 (57), 88 (18), 63 (32) and 62 (28).
21 Y. Badar, W. J. S. Lockley, T. P. Toube, B. C. L. Weedon and
L. R. G. Valadon, J. Chem. Soc., Perkin Trans. 1, 1973, 1416.
22 F. R. Ahmed and T. P Toube, J. Chem. Res., (S), 1986, 440; (M),
1986, 3601.
23 C. L. Hickson and H. McNab, J. Chem. Res., (S), 1989, 176.
24 R. Neidlein and G. Jeromin, J. Chem. Res., (S), 1980, 223; (M),
1980, 3090.
25 G. A. Cartwright and H. McNab, unpublished work.
26 E. Buchta and F. Andrée, Chem. Ber., 1959, 92, 3111.
27 W. Flitsch, B. Müter and U. Wolf, Chem. Ber., 1973, 106, 1993.
28 G. S. Coumbarides, J. M. Mercy and T. P. Toube, J. Chem. Res., (S),
1990, 151.
Pyrolysis of compounds 45 and 46
The Meldrum’s acid derivative 45 (0.09 g, 0.35 mmol) was sub-
limed at 100–150 ЊC (0.003 Torr) during 3 h into the furnace
tube which was held at 600 ЊC. There was considerable decom-
position in the inlet and much of the pyrolysate was insoluble in
[2H]chloroform. However, a small amount of the azaazulenone
48 (ca. 13%) was present in the soluble fraction and was identi-
fied by its characteristic resonance at δH 8.20 (1H, m).27
The pyrolysate from FVP of 46 (0.027 g, 700 ЊC, 100 ЊC,
1
0.001 Torr, 20 min) was examined by H NMR spectroscopy.
No trace of the azaazulenone 48 was obtained and the only
identifiable product was pyrrole (see Discussion section).
29 E. Bisagni, J. P. Marquet and J. Andre-Louisfert, Bull. Soc. Chim.
Fr., 1968, 637.
30 D. M. Bailey, R. E. Johnson and N. F. Albertson, Org. Synth., Coll.
Vol. 6, 1988, 618.
31 W. A. M. Davies, A. R. Pinder and I. G. Morris, Tetrahedron, 1962,
18, 405.
32 P. Fournari, M. Farnier and C. Fournier, Bull. Soc. Chim. Fr., 1972,
283.
33 For example, W. Hinz, R. A. Jones, S. U. Patel and M.-H. Karatza,
Tetrahedron, 1986, 42, 3753.
Acknowledgements
We are grateful to The University of Edinburgh for a Research
Studentship (to C. T.), to Lonza Ltd. for a generous gift of
Meldrum’s acid and to Glaxo Wellcome for financial support.
34 W. Flitsch and U. Neumann, Chem. Ber., 1971, 104, 2170.
35 H. McNab, J. Chem. Soc., Perkin Trans. 1, 1983, 1203.
References
1 H. McNab, J. Org. Chem., 1981, 46, 2809.
2 A. J. Blake, H. McNab and R. Morrison, J. Chem. Soc., Perkin
Trans. 1, 1988, 2145.
3 H. McNab, J. Chem. Soc., Perkin Trans. 1, 1987, 653.
4 H. McNab, J. Chem. Soc., Perkin Trans. 1, 1987, 657.
Paper 7/01749I
Received 12th March 1997
Accepted 11th April 1997
2202
J. Chem. Soc., Perkin Trans. 1, 1997