1-Methoxycarbonylpyrrolizin-3-one and related compounds

Article abstract of DOI:10.1039/b901961h

Flash vacuum pyrolysis (FVP) of dimethyl E- or Z-pyrrol-2-ylbut-2-enedioate 5 at 700 °C gave 1-methoxycarbonylpyrrolizin-3-one 1. The sequence involves E- to Z-isomerisation (if necessary), elimination of methanol and cyclisation; the elimination step is

Full text of DOI:10.1039/b901961h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
1
-Methoxycarbonylpyrrolizin-3-one and related compounds†
Xavier L. M. Despinoy and Hamish McNab*
Received 29th January 2009, Accepted 6th March 2009
First published as an Advance Article on the web 2nd April 2009
DOI: 10.1039/b901961h
◦
Flash vacuum pyrolysis (FVP) of dimethyl E- or Z-pyrrol-2-ylbut-2-enedioate 5 at 700 C gave
1
-methoxycarbonylpyrrolizin-3-one 1. The sequence involves E- to Z-isomerisation (if necessary),
elimination of methanol and cyclisation; the elimination step is rate determining. The pyrrolizinone 1 is
stable at low temperatures, but at room temperature dimerises spontaneously across the 1,2-bond to
give a mixture of trans- and cis- cyclobutanes 2 and 3, respectively. In this process 1 behaves as a
◦
captodative alkene. The dimerisation can be reversed at >100 C. Related pyrrolizinones such as the
esters 14 and 22 and the amide 15 are stable to dimerisation. The diacid 12 and the amide 10 do not
cyclise to pyrrolizinones under FVP conditions, but instead give the anhydride 19 and the maleimide 18,
respectively; at high furnace temperatures, 2-ethynylpyrrole 17 is obtained from 12 and from 19.
Introduction
In this paper we present full details of results published
1
in a preliminary communication where we showed that
1
-methoxycarbonylpyrrolizin-3-one 1, synthesised in the gas-
phase by flash vacuum pyrolysis (FVP), spontaneously dimerises
at room temperature to the cyclobutanes 2 and 3. We discuss
the mechanism of formation of 1, which differs in some details
from the ‘normal’ pyrolytic formation of pyrrolizinones and
2
related compounds from acrylate esters. We report the syntheses
of several analogues of 1, and complete the series of possible
pyrrolizin-3-one monocarboxylic esters. Compound 1 is the
only pyrrolizinone we have discovered which shows spontaneous
dimerisation behaviour (though pyrrolizinone itself has been
Scheme 1
3
shown to dimerise under photochemical conditions ).
Results and discussion
Thermal formation and subsequent collapse of pyrrolylketenes
4
from pyrrolylacrylate esters provides a general route to the
5
pyrrolizin-3-one ring system. Equilibration of the E- and
Z-isomers of the precursor takes place under the FVP conditions,
prior to ketene generation. In order to generate the ketene 4 en
route to methoxycarbonylpyrrolizin-3-ones such as 1, the diesters
◦
Scheme 2 Reagents and conditions: (i) DMAD, 4 days, 20 C; (ii) (COCl)
2
,
◦
◦
-
Ph
78 C, then NaOMe; (iii) (COCl)
2
, -78 C, then NH
3
or Me
2
NH; (iv)
5
were required (Scheme 1) and two routes were used for their
P=C(R)CO
2
R¢, toluene or xylene, reflux; (v) NaOH, MeOH/H O,
3
2
synthesis (Scheme 2).
reflux.
6
First, the known treatment of pyrrole with DMAD gave 5 as
a mixture of E- and Z-isomers (36 and 28%, respectively) which
could be separated by chromatography. The configuration of the
alkene was best assigned by the chemical shift of the NH proton.
When the pyrrole and the ester group are on the same side of the
School of Chemistry, The University of Edinburgh, West Mains Road,
Edinburgh, UK EH9 3JJ. E-mail: H.McNab@ed.ac.uk; Fax: +44 131 650
4
743; Tel: +44 131 650 4718
†
Electronic supplementary information (ESI) available: Experimental and
spectra. See DOI: 10.1039/b901961h
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molecule (the E-isomers‡ ), hydrogen bonding causes substantial
deshielding of the NH (d >12 p.p.m.). In the Z-isomer of 5, the
NH resonates at ca. 9 p.p.m.
H
The diesters 5 can also be made by Wittig reactions of methyl
pyrrol-2-ylglyoxylate 6, itself readily formed by reaction of pyrrole
◦
7
with oxalyl chloride at -78 C, followed by quenching with
sodium methoxide (Scheme 2). In practice, this second route
had few advantages over the DMAD method for the preparation
of 5 itself, but the use of different Wittig reagents allowed the
introduction of substituents into the acrylate chain (e.g. 7). In
addition, application of different quenching reagents provided a
route to the amides 10 and 11 (via 8 and 9, respectively) which
could not be accessed by the DMAD method. The diacid Z-12
was obtained by hydrolysis of the diester Z-5.
◦
Small-scale FVP of 5, at 700 C in the absence of special
precautions at the liquid nitrogen trap and with rapid analysis of
the pyrolysate, gave a mixture of three compounds. The first was
readily identified as the pyrrolizinone 1 by NMR spectroscopic
5
Fig. 2 X-Ray crystal structure of 3 showing crystallographic numbering
scheme. See ref. 1 for details.
comparison with other pyrrolizinones. The other two products,
which were obtained exclusively if a solution of the pyrolysate
was allowed to stand at room temperature for ca. 24 h, could
be separated by chromatography; they were identified by mass
spectrometry as dimers of 1. Their constitutions as the trans-
and cis- isomers, 2 and 3, respectively, formed in 2:1 ratio
in 66% overall yield, were best determined unambiguously by
1
X-ray crystallography (Fig. 1 and 2). The pyrrolizinone 1 can
be obtained in reasonable purity on a preparative scale by
modification of the FVP trap design to keep the pyrolysate as
cold as possible during work-up (see Experimental section); under
these conditions the dimerisation process is slow.
Fig. 3 X-Ray crystal structure of 13 showing crystallographic numbering
scheme. See ref. 8 for details.
is a [4+2] cycloadduct of 1 (acting as the dienophile) and 5 (acting
as the diene) (Scheme 3). It is known that 2-vinylpyrroles can
9
behave as dienes in appropriate circumstances. Initial attempts to
replicate this reaction preparatively were unsuccessful.
Fig. 1 X-Ray crystal structure of 2 showing crystallographic numbering
scheme. See ref. 1 for details.
Initially, it proved difficult to obtain a crystal of the cis-isomer
3
and, on one occasion a single crystal of trimethyl 6-oxo-
5
,5a,10b,10c-tetrahydro-3H-pyrrolizino[1,2-e]indole-4,5,10b-tri-
8
carboxylate 13 was selected (Fig. 3). In principle, this compound
‡
Note that due to the Cahn–Ingold–Prelog priority rules, the Z-isomers
of the acrylates that lack an ester group in the 3-position, have the same
relative configuration to the pyrrole moiety as the E-isomer of 5.
Scheme 3
2
188 | Org. Biomol. Chem., 2009, 7, 2187–2194
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◦
Formation of 2 and 3 clearly takes place by head-to-head
dimerisation across the 1,2-bond of two pyrrolizinone moieties.
The reaction rate is qualitatively independent of solvent, exposure
to light and of the presence of a radical inhibitor. The mecha-
nism must therefore be quite different from the photochemical
is stable for up to 15 min at 91 C, but the trans-dimer to monomer
◦
equilibrium is established after ca. 25 min at 101 C (36% 1). The
ratio of monomer 1 : trans-dimer 2 : cis-dimer 3 after 15 min at
106 C was found to be 48 : 49 : 3 though it is not clear whether the
equilibrium position of 3 has been established after this period.
The monomer 1 is therefore kinetically stable to dimerisation only
below room temperature (see above) but is thermodynamically
stable at high temperatures.
◦
3
dimerisation of pyrrolizin-3-one itself. Spontaneous dimerisation
of alkenes in the absence of light usually takes place only when the
double bond contains both a powerful electron withdrawing group
and a powerful electron donating group attached to the same
10
carbon atom (a so-called captodative olefin ). These requirements
are met by 1, in which the pyrrole unit is able to act as the donating
group.
We have previously found that FVP conditions for the trans-
formation of 3-(azol-2-yl)acrylate esters into pyrrolizin-3-ones
and their analogues are dependent on the configuration of the
The dimerisation process was surprisingly sensitive to minor
structural modifications in the region of the ester group. Thus, the
2
alkene. Transformation of Z-isomers‡ is complete at around
◦
◦
7
00 C, whereas the E isomers require ca. 850 C for to-
1
-carbomethoxy-2-methylpyrrolizinone 14 was obtained in 73%
◦
tal conversion to products. This shows that formation of the
Z-isomers is needed for reaction, consistent with the intramolecu-
lar nature of the elimination step. E- to Z-isomerisation is clearly
the rate determining step for these transformations, followed by
rapid elimination and cyclisation. The cyclisation step is likely to
yield by FVP of 7 at 625 C and was stable as the monomer.
FVP of the amide 11 proved more complex, but under optimised
conditions (650 C) a 17% yield of the pure pyrrolizinone 15
◦
could be obtained by Kugelrohr distillation and it was also
stable for weeks at room temperature. Minor products included
pyrrolizinone itself 16 and 2-ethynylpyrrole 17 (see below). Their
proportions increased at higher furnace temperatures and they are
11
be a pseudopericyclic process with a low (or non-existent) barrier.
However, the temperature profiles for the FVP reactions of both
E- and Z-isomers of 5 are identical within experimental error
probably formed by retro-ene elimination of MeN CH
=
2
followed
(
7
Fig. 4) with complete transformation to cyclised products at
00 C.
by sequential loss of CO (Scheme 4). Similar retro-ene processes
◦
12
have been previously reported.
Fig. 4 Temperature–conversion plot for the formation of 1 by FVP of
E-5 (squares) and Z-5 (circles).
◦
Scheme 4 Reagents and conditions: (i) FVP 600–700 C; (ii) –MeN=CH
iii) –CO and H-shift; (iv) –2CO and H-shift.
;
2
(
This result suggests that the presence of the second ester group
facilitates the E- to Z-isomerisation process so that the elimination
becomes the rate determining step. However, equilibration of
Both 14 and 15 are, in principle, captodative alkenes, yet neither
has any tendency to dimerise. In the first case, dimerisation may
be hindered by the presence of the methyl substituent and in the
second, the electron withdrawing effect of the amide function is
apparently insufficient to cause the reaction.
dimethyl fumarate and dimethyl maleate is incomplete below
◦
8
00 C in our apparatus (see ESI†), so the pyrrole unit and the ester
group in 5 must have a synergistic effect in lowering the barrier for
◦
the interconversion. The captodative alkene concept may again be
FVP of the N-unsubstituted amide 10 (700 C) or of the
10
◦
relevant here. This result nevertheless has the synthetic advantage
that either the E- or the Z-isomer of 5, or a mixture of both, can be
used to prepare the pyrrolizinone 1 under identical FVP conditions
diacid 12 (400 C) caused the formation of the maleimide 18
and the maleic anhydride 19 respectively rather than cyclisation
◦
to the pyrrolizinones. At higher temperatures (700 C), both the
◦
at the relatively low furnace temperature of 700 C.
diacid 12 and an authentic sample of the maleic anhydride 19
gave 2-ethynylpyrrole 17 as the only product (Scheme 5). FVP of
phenylmaleic anhydride similarly provided phenylacetylene. The
The position of the equilibrium of monomer 1 with dimers 2 and
3, was studied by heating the trans dimer 2 in solution. Structure 2
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mechanism of these reactions involves concomitant decarbonyla-
tion and decarboxylation of the anhydride moiety.
pyrrolizidine alkaloids. This approach has been successful and
will be reported in a future paper.
Experimental
1
13
H and C NMR spectra were recorded at 200 (or 250) and 50
2
(
or 63) MHz respectively for solutions in [ H]chloroform unless
otherwise stated. Coupling constants are quoted in Hz. Mass
spectra were recorded under electron impact conditions.
Methyl pyrrol-2-ylglyoxylate 6
3
A solution of pyrrole (3.35 g, 50 mmol) in dry ether (20 cm ) was
added over 1 h to a stirred solution of oxalyl chloride (7.40 g,
3
◦
5
8 mmol) in ether (50 cm ) kept at -78 C. The solution became
◦
◦
Scheme 5 Reagents and conditions: (i) FVP 700 C; (ii) FVP 400 C.
◦
yellow. Stirring was continued for 1 h at -78 C and the cold
reaction mixture was then poured slowly onto a vigorously stirred
solution of sodium methoxide [from sodium (1.55 g, 67 mmol)] in
methanol (100 cm ) at -78 C. The resulting white suspension was
warmed up to 0 C and a solution of sodium hydrogen carbonate
10 g, 120 mmol) in water (150 cm ) was added. The solution
was then concentrated and extracted with dichloromethane (3 ¥
100 cm ). The combined organic layers were dried (MgSO )
and the solvents were removed to yield, after recrystallisation
from chloroform, methyl pyrrol-2-ylglyoxylate 6 (4.38 g, 57%) as
colourless crystals, mp 66–67 C (from chloroform) (lit., 69–
0 C); nmax (nujol) 3297, 1724 and 1636; d
.37 (1H, m), 7.19 (1H, m), 6.30 (1H, m) and 3.89 (3H, s); d
71.33 (quat), 162.41 (quat), 129.03 (quat), 128.75, 122.78, 112.07
Pyrrolizin-3-ones with methyl or ethyl carboxylic ester sub-
3
◦
1
4
4
4
stituents in the 1-, 2-, 5- and 7-positions are now known and all
except the 1-isomer are stable. In order to complete the series of
possible pyrrolizinone monocarboxylic esters, the 6-substituted-
derivative 22 was made by the standard Meldrum’s acid route
using the known 4-methoxycarbonylpyrrole-2-carboxaldehyde
0 as starting material (Scheme 6 and Experimental section).
The FVP step gave 6-methoxycarbonylpyrrolizin-3-one 22 (88%)
as a stable solid which, as expected, showed no tendency to
dimerise.
◦
3
(
4
,5
3
13
4
2
◦
14
◦
7
7
1
H
10.41 (1H, br, NH),
C
and 52.71.
Pyrrol-2-ylglyoxylamide 8
3
A solution of pyrrole (3.05 g, 45 mmol) in dry ether (50 cm ) was
added over 1 h to a stirred solution of oxalyl chloride (6.31 g,
3
◦
5
0 mmol) in ether (40 cm ) kept at -78 C. Stirring was continued
◦
for 1 h at -78 C and the cold reaction mixture was then poured
slowly onto a vigorously stirred solution of liquid ammonia (ca.
Scheme 6 Reagents and conditions: (i) Meldrum’s acid, piperidinium
acetate, 24 h, 20 C; (ii) FVP 650 C.
◦
3
3
20 cm ) in ether (100 cm ), kept at -78 C in a flask equipped
◦
◦
with a dry ice condenser and a calcium chloride trap. The trap was
then replaced by a tube connected to an inverted funnel placed in a
water bath, and the system was allowed to reach room temperature
overnight. Water was added, the ether layer was separated and the
aqueous layer was continuously extracted with dichloromethane
over 3 days. The combined ether and dichloromethane fractions
were concentrated to give pyrrol-2-ylglyoxylamide 8 (4.41 g, 70%)
Conclusions
1
-Methoxycarbonylpyrrolizin-3-one 1 has been prepared under
◦
FVP conditions and is kinetically stable at -20 C. Unlike
the formation of pyrrolizinones by FVP of other 3-(pyrrol-2-
yl)acrylate esters, the alcohol elimination stage of the mechanism is
rate determining. At room temperature 1 behaves as a captodative
olefin and dimerises spontaneously in head-to-head fashion to
provide the cyclobutanes 2 and 3. No dimers are formed under
these conditions from 1-dimethylaminocarbonylpyrrolizin-3-one
◦
15
◦
as a white solid, mp 125 C (from chloroform) (lit., 126–127 C);
2
n
max (nujol) 3452, 3295, 1705 and 1622; d
H
([ H ]acetone) 11.47
6
(
(
1H, br, NH), 7.78 (1H, br, NH), 7.49 (1H, m), 7.31 (1H, m), 7.20
1H, br, NH) and 6.33 (1H, m). The C spectrum was complicated
13
by exchange processes but the following peaks were resolved at
2
6
3 MHz (297 K): d
C
([ H ]acetone) 164.10 (quat), 164.05 (quat),
6
15 or from 1-methoxycarbonyl-2-methylpyrrolizin-3-one 14, or
1
28.20 (quat), 128.04 (quat), 127.13, 126.96 (quat), 120.76 (br CH)
from any other carboxylic ester derivatives of pyrrolizinone, so the
structural and electronic requirements for the dimerisation process
and 110.22.
are stringent. The dimerisation reaction of 1 can be reversed at
N,N -Dimethyl-pyrrol-2-ylglyoxylamide 9
◦
>100 C. The methods described here provide the pyrrolizinone
3
skeleton with carbon-based functionality in the 1-position which
creates the possibility of a pyrrolizinone approach to simple
A solution of pyrrole (1.52 g, 23 mmol) in dry ether (10 cm )
was added over 1 h to a stirred solution of oxalyl chloride
2
190 | Org. Biomol. Chem., 2009, 7, 2187–2194
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3
◦
3
(
3.13 g, 25 mmol) in ether (25 cm ) kept at -78 C. Stirring was
130 cm , 3.5 h, 0 mg recovered starting material] methyl
◦
continued for 1 h at -78 C and the cold reaction mixture was
then poured slowly onto a vigorously stirred solution of anhydrous
dimethylamine (25 cm ) in ether (50 cm ) at -78 C. After warming
to room temperature, the white precipitate which had formed was
filtered off and washed thoroughly with dichloromethane. The
(E)-3-aminocarbonyl-3-(pyrrol-2-yl)propenoate E-10 (687 mg,
33%) yellow crystals, mp 152–153 C (from chloroform/hexane)
◦
3
3
◦
(Found: C, 55.65, H, 5.15, N, 14.3. C
9
H
10
N
2
O
3
requires C, 55.65,
]acetone) 12.44 (1H, br, NH), 7.30
(1H, br, NH), 7.21 (1H, m), 6.98 (1H, br, NH), 6.70 (1H, m),
2
H, 5.15, N, 14.45%); d
H
([ H
6
2
filtrate was concentrated, dried (MgSO
4
) and purified by dry flash
6.26 (1H, m), 5.68 (1H, s) and 3.78 (3H, s); d
C
([ H ]acetone)
6
chromatography to give N,N -dimethyl-pyrrol-2-ylglyoxylamide 9
169.06 (quat), 168.34 (quat), 143.80 (quat), 125.41 (quat), 122.97,
117.05, 109.11, 105.23 and 50.62; m/z 194 (M , 81%), 177 (32),
◦
+
(
2.64 g, 70%) as white crystals, mp 110 C (from ethyl acetate)
(
6
Found: C, 57.9; H, 6.05; N, 16.8. C
.05; N, 16.85%); nmax (nujol) 1639 and 1627; d
NH), 7.11 (1H, m), 6.98 (1H, m), 6.26 (1H, m) 3.02 (3H, s) and
8
H
5
NO
3
requires C, 57.8; H,
118 (31) and 91 (100). A very minor fraction, strongly fluorescent,
was isolated from the column and characterised as methyl
H
10.62 (1H, br,
[5-oxo-4-(pyrrol-2-yl)-1H-pyrrole-2(5H)-ylidene]acetate (5 mg,
+
2
1
.97 (3H, s); d
C
179.73 (quat), 166.51 (quat), 128.96 (quat), 127.75,
0.2%), (Found: M 218.0690. C11
H
10
N
2
3
O requires M 218.0691);
+
20.87, 111.53, 37.25 and 34.18; m/z 166 (M , 15%), 109 (21), 94
d
H
10.39 (1H, br, NH), 9.23 (1H, br, NH), 6.95 (1H, m), 6.73
n
(
100), 72 (46) and 66 (21).
(1H, m), 6.71 (1H, d, J 1.5), 6.31 (1H, m), 5.38 (1H, s) and 3.77
3H, s); d 171.38 (quat), 167.51 (quat), 149.69 (quat), 128.48
(quat), 123.61 (quat), 121.88, 119.86, 111.73, 110.80, 98.96 and
(
C
Propenoic acid ester derivatives
+
5
1
4
1.61; m/z 218 (M , 58%), 187 (31), 186 (26), 125 (20), 119 (22),
11 (38), 97 (66), 95 (44), 91 (26), 85 (40), 83 (65), 55 (89) and
3 (100).
A solution of the appropriate pyrrol-2-ylglyoxylic acid derivative
and ylide was heated at reflux in the solvent reported (unless
otherwise stated) for the time stated. The solvent was removed
and the products were separated from residual starting material
and triphenylphosphine oxide by careful dry flash chromatogra-
phy, using hexane and ethyl acetate as eluents. The carbonylic
compound, ylide, solvent, volume of solvent, reaction time and
recovered starting material are quoted.
Methyl (E)- and (Z)-3-(N,N -dimethylaminocarbonyl)-3-(pyrrol-
-yl)propenoate 11. [from N,N -dimethyl-pyrrol-2-yl-glyoxy-
2
lamide 9 (610 mg, 3.7 mmol) and methyl (triphenylphospho-
3
ranylidene)acetate (1.64 g, 4.9 mmol), p-xylene, 55 cm , 44 h,
94 mg recovered starting material] methyl (E)-3-(N,N -dimethyl-
Dimethyl (E)- and (Z)-pyrrol-2-ylbut-2-enedioate 5. [from
methyl pyrrol-2-yl glyoxylate 6 (72 mg, 0.5 mmol) and methyl
aminocarbonyl)-3-(pyrrol-2-yl)propenoate E-11 (360 mg, 44%)
◦
+
yellow oil, bp 95–100 C (0.3 Torr) (Found: M 222.1000.
requires M 222.1004); d 12.49 (1H, br, NH), 7.03
(1H, m), 6.40 (1H, m), 6.26 (1H, m) 5.49 (1H, s), 3.75 (3H, s),
3.08 (3H, s) and 2.94 (3H, s); d 168.93 (quat), 168.89 (quat),
(
3
triphenylphosphoranylidene)acetate (186 mg, 0.6 mmol), toluene,
cm , 3.5 h, 0 mg recovered starting material]; dimethyl
C
11
H
14
N
2
O
3
H
3
(E)-pyrrol-2-ylbut-2-enedioate E-5 (54 mg, 49%) and dimethyl
C
(
Z)-pyrrol-2-ylbut-2-enedioate Z-5 (16 mg, 15%) (data identical
143.41 (quat), 125.60 (quat), 123.66, 117.00, 110.44, 105.28,
51.71, 38.46 and 34.38; m/z 222 (M , 92%), 190 (19), 178
+
to those reported above).
(
23), 151 (81), 150 (78), 119 (33), 118 (28), 116 (50), 92 (30)
Ethyl (E)- and (Z)-3-methoxycarbonyl-2-methyl-3-(pyrrol-2-
yl)propenoate 7. [from methyl pyrrol-2-yl-glyoxylate 6 (630 mg,
and 91 (100). A second column (alumina, using hexane/ethyl
acetate as eluant) was necessary to separate the (Z)-isomer from
triphenylphosphine; methyl (Z)-3-(N,N -dimethylaminocarbonyl)-
4
.1 mmol) and ethyl 2-(triphenylphosphoranylidene)propionate
3
(
1.78 g, 4.9 mmol), p-xylene, 30 cm , 36 h, 186 mg recovered start-
3
-(pyrrol-2-yl)propenoate Z-11 (126 mg, 15%) yellow crystals,
ing material] ethyl (E)-3-methoxycarbonyl-2-methyl-3-(pyrrol-2-
◦
mp 147–149 C (from ethyl acetate) (Found: C, 59.35; H, 6.45;
◦
yl)propenoate E-7 (35 mg, 4%), bp 105–110 C (0.3 Torr) (Found:
N, 12.2. C11
.44 (1H, br, NH), 6.83 (1H, m), 6.48 (1H, m), 6.20 (1H, m), 6.00
1H, s), 3.68 (3H, s), 3.11 (3H, s) and 2.88 (3H, s); d 168.80
quat), 166.25 (quat), 142.96 (quat), 126.23 (quat), 123.84, 113.48,
H
14
N
2
O
3
requires C, 59.45; H, 6.35; N, 12.6%); d
H
+
M 237.1001. C12
H
15NO
4
requires M 237.1001); d 11.95 (1H, br,
H
9
(
(
1
(
3
NH), 6.90 (1H, m), 6.22 (2H, m), 4.24 (2H, q, J 7.1), 3.89 (3H,
s), 1.99 (3H, s) and 1.30 (3H, t, J 7.1); d
C
3
C
169.48 (quat), 169.02
(
1
quat), 135.88 (quat), 125.30 (quat), 121.65, 116.38 (quat), 115.14,
09.75, 61.23, 52.22, 18.14 and 13.87; m/z 237 (M , 40%), 205
+
10.26, 106.51, 51.24, 37.57 and 34.33; m/z 222 (M , 100%), 178
22), 151 (90), 150 (85), 119 (29), 118 (25), 116 (50), 92 (29) and
1 (92).
+
(
(
(
22), 191 (53), 177 (54), 176 (55), 155 (66), 154 (64), 128 (56), 127
100), 126 (80), 105 (70), 104 (71), 99 (67), 83 (68), 77 (62), 55
9
80), 43 (83) and 39 (66); ethyl (Z)-3-methoxycarbonyl-2-methyl-
◦
FVP experiments
3
-(pyrrol-2-yl)propenoate Z-7 (382 mg, 39%), bp 145–150 C (1
+
Torr) (Found: M 237.0999. C12
H
15NO
4
requires M 237.1001); d
H
The precursors were distilled under vacuum through a silica
pyrolysis tube (35 ¥ 2.5 cm), which was heated by a laboratory
tube furnace. Unless otherwise stated, products were collected
in a U-tube trap cooled by liquid nitrogen and situated at the
exit point of the furnace. Upon completion of the pyrolysis
the trap was allowed to warm up to room temperature under
nitrogen and the product was generally removed from the trap by
dissolution in acetone. Removal of the solvent(s) followed by bulb-
to-bulb distillation, sublimation or recrystallisation afforded the
pure pyrrolizin-3-ones. Pyrolysis parameters are quoted as follows:
8
.96 (1H, br, NH), 6.87 (1H, m), 6.43 (1H, m), 6.28 (1H, m), 4.21
3
3
(
2H, q, J 7.1), 3.80 (3H, s), 2.15 (3H, s) and 1.29 (3H, t, J 7.1); d
C
1
69.62 (quat), 167.74 (quat), 132.66 (quat), 124.57 (quat), 124.41
(
2
quat), 120.64, 113.44, 110.10, 61.11, 52.51, 15.71 and 13.92; m/z
37 (M , 77%), 205 (49), 191 (60), 177 (87), 176 (78), 163 (37), 105
+
(
100), 104 (84) and 94 (30).
Methyl (E)-3-aminocarbonyl-3-(pyrrol-2-yl)propenoate 10.
[
(
from pyrrol-2-yl-glyoxylamide 8 (1.48 g, 11 mmol) and methyl
triphenylphosphoranylidene)acetate (4.81 g, 14 mmol), toluene,
This journal is © The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 2187–2194 | 2191

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furnace temperature (T
appropriate) (P) and reaction time (t).
f
), inlet temperature (T
i
), pressure (range if
qualitatively identical, the reaction being complete in just over
1 day.
FVP of dimethyl E- and Z-pyrrol-2-ylbut-2-enedioate 5
Formation of trimethyl 6-oxo-5,5a,10b,10c-tetrahydro-3H-
pyrrolizino[1,2-e]indole-4,5,10b-tricarboxylate 13
E-5 or Z-5 or a mixture of both, were used interchangeably (see
below for justification).
During recrystallisation trials of a fraction which was pre-
dominantly the cis-dimer 3, a single crystal of trimethyl 6-oxo-
Method 1—isolation of 1. Upon completion of the FVP of
◦
◦
dimethyl pyrrol-2-ylbut-2-enedioate 5 [70 mg, T
f
700 C, T 80 C,
i
5,5a,10b,10c-tetrahydro-3H-pyrrolizino[1,2-e]indole-4,5,10b-tri-
P 0.005 Torr, t 15 min], the trap was kept cold and slowly warmed
◦
◦
2
carboxylate 13 was selected for X-ray crystallography after slow
to -30 C/-20 C (bath of dry ice/acetone) and [ H]chloroform
8
+
1
13
recrystallisation from isopropyl alcohol. (Found: M 386.1136.
was added. H and C NMR spectra were recorded immediately
+
C
19
H
18
N
2
O requires M 386.1114); m/z 386 (M , 1.6%), 354 (11),
7
at 253 K and were characteristic of 1-methoxycarbonylpyrrolizin-
3
3
322 (8), 290 (10), 178 (13), 177 (100), 149 (11), 118 (42) and
91 (20).
3
(
(
-one 1; d
1H, s), 6.02 (1H, t, J 3.1) and 3.87 (3H, s); d
quat), 161.40 (quat), 140.88 (quat), 133.93 (quat), 126.34, 119.82,
H
(253 K) 6.91 (1H, d, J 3.1), 6.29 (1H, d, J 3.1), 6.21
3
C
(253 K) 163.77
1
4
16.28, 114.11 and 52.77; lmax (methanol) 313 (loge ≥ 3.51) and
38 (loge ≥ 2.72).
2
-Methyl-1-methoxycarbonylpyrrolizin-3-one 14
In order to obtain 1 for further reactions, a cold-finger
The pyrolysate from FVP of ethyl (Z)-3-methoxycarbonyl-2-
trap was situated as close as possible to the exit point of the
furnace. The connection between the furnace silica tube and
the cold finger trap was wrapped in aluminium foil so that 1-
methoxycarbonylpyrrolizin-3-one 1 condensed almost exclusively
on the cold finger. Under nitrogen, it was washed from the trap,
methyl-3-(pyrrol-2-yl)propenoate 7 [(141 mg, 0.6 mmol), T
f
◦
◦
6
25 C, T 120–150 C, P 0.02–0.05 Torr, t 20 min] was dissolved
i
in dichloromethane. Removal of the solvents and bulb-to-bulb
distillation afforded 2-methyl-1-methoxycarbonylpyrrolizin-3-one
◦
1
4 (83 mg, 73%) as the major product, bp 110–120 C (0.3 Torr)
◦
using ice-cold acetone and kept below 0 C before use.
+
(
(
Found: M 191.0574. C10
H
9
6
NO
3
requires M 191.0582); d
H
4
6.86
Method 2—isolation of 2 and 3. Using a U-tube trap, the
3
4
3
1H, ddq, J 3.1, J 0.8 and J 0.5), 6.14 (1H, ddq, J 3.1, J 0.8
products of pyrolysis [from dimethyl pyrrol-2-ylbut-2-enedioate
6
3
6
and J 0.5), 5.99 (1H, t, J 3.1), 3.87 (3H, s) and 2.15 (3H, t, J
◦
◦
(
231 mg, 1.1 mmol), T
f
700 C, T 60 C, P 0.0005 Torr, t 15 min]
i
3
0.5); d
C
164.90 (quat), 162.43 (quat), 139.63 (quat), 132.56 (quat),
were dissolved in acetone (50 cm ). The solution was filtered and
set aside for 4 days. The solvent was then removed to give a mixture
of trans- and cis- dimethyl 7,8-dioxo-7,7a,7b,8-tetrahydro-6a,8a-
1
24.53 (quat), 118.77, 116.06, 111.76, 52.01 and 10.32; m/z 191
+
(
M , 55%), 176 (50), 132 (19), 105 (84), 104 (100), 77 (41) and
51 (63).
diaza-cyclobuta[1,2-a;4,3-a¢]dipentalene-3b,3c dicarboxylate
and 3 (129 mg, 66%), respectively in a 2:1 ratio (determined by H
2
1
NMR spectroscopy). Dry flash column chromatography on silica
1
-(N,N -Dimethylaminocarbonyl)pyrrolizin-3-one 15
(
using ethyl acetate and hexane as eluants) allowed the separation
of the two dimers. The first to elute was the major trans-isomer
The pyrolysate from FVP of methyl (E)-3-(N,N -dimethyl-
aminocarbonyl)-3-(pyrrol-2-yl) propenoate 11 [(190 mg,
◦
2
6
7
d
as colourless crystals, mp 178 C (from toluene) (Found: C,
◦
◦
1.15; H, 3.95; N, 7.85. C18
H
14
N
2
O
6
requires C, 61.0; H, 3.95; N,
requires M 354.0851);
0.8 mmol), T
f
650 C, T 100–120 C, P 0.01–0.05 Torr,
i
+
.9%) (Found: M 354.0846. C18
H
14
N
2
O
6
t 35 min] was rinsed with dichloromethane and the solvents were
removed under vacuum to yield a dark liquid (101 mg) containing
3 products: 1-(N,N -dimethylaminocarbonyl)pyrrolizin-3-one 15
3
4
3
H
7.17 (2H, dd, J 3.2 and J 1.1), 6.54 (2H, t, J 3.2), 6.37 (2H,
3
4
dd, J 3.2 and J 1.1), 4.03 (2H, s) and 3.57 (6H, s); d 167.30
C
◦
+
(
(
(
quat), 166.48 (quat), 133.09 (quat), 120.11, 113.71, 109.00, 55.02
quat), 52.96 and 47.52; m/z 354 (M , 8%), 322 (12), 290 (9), 178
(46%), bp 180–185 C (0.6 Torr) (partial decomp.) (Found: M
+
3
190.0744. C10
H
10
N
2
O
2
requires M 190.0742); d
H
6.93 (1H, dd, J
4
3
4
3
12), 177 (100), 118 (33) and 91 (20): followed by the cis-isomer
3.1 and J 0.8), 6.10 (1H, dd, J 3.1 and J 0.8), 6.04 (1H, td, J 3.1
and J 0.7), 5.67 (1H, d, J 0.7), 3.11 (3H, s) and 3.06 (3H, s); d
◦
6
6
3
as colourless crystals mp 160–162 C (from hexane) (Found:
C
+
M 354.0871. C18
H
14
3
N
2
O
6
requires M 354.0851); d
H
6.90 (2H, d,
164.11 (quat), 162.75 (quat), 145.47 (quat), 134.95 (quat), 119.37,
3
3
+
J 3.1), 6.33 (2H, t, J 3.1), 6.13 (2H, d, J 3.1), 4.36 (2H, s) and
119.28, 115.85, 112.54, 38.27 and 34.78; m/z 190 (M , 100%), 147
3
1
3
.80 (6H, s); d
C
168.07 (quat), 165.85 (quat), 133.09 (quat), 119.77,
(42), 119 (38), 118 (32), 91 (93), 90 (44), 72 (44), 63 (24), 44 (12),
+
3
13.30, 108.99, 53.40 (quat), 53.18 and 47.12; m/z 354 (M , 4%),
22 (8), 290 (7), 178 (11), 177 (100), 118 (54), 91 (42), 90 (20), 63
42 (19) and 39 (22), pyrrolizin-3-one 16 (8%); d
H
7.05 (1H, d, J
3
3
5.9), 6.87 (1H, d, J 3.1), 5.97 (2H, m) and 5.64 (1H, d, J 5.9)
and 2-ethynylpyrrole 17 (11%); d 6.73 (1H, m), 6.49 (1H, m),
.14 (1H, m) and 3.16 (1H, s) (data compatible with the spectrum
(
13) and 39 (13).
H
6
16
of an authentic sample ). Distillation of the entire fraction gave
pure 1-(N,N -dimethylaminocarbonyl)pyrrolizin-3-one 15 (28 mg,
17%) which is stable in solution for weeks at room temperature.
Dimerisation of 1-methoxycarbonylpyrrolizin-3-one 1
Various solutions of 1-methoxycarbonylpyrrolizin-3-one 1 were
monitored by H NMR spectroscopy. The solvent and particular
1
◦
◦
At 600 C, 20% of the starting material was recovered.
2
2
conditions included the following: [ H]chloroform; [ H
6
]acetone;
At 700 C, 1-(N,N -dimethylaminocarbonyl)pyrrolizin-3-one 15,
2
2
2
[
H
4
]methanol; [ H]chloroform in the dark; [ H]chloroform with
pyrrolizin-3-one 16 and 2-ethynylpyrrole 17 were formed in the
2
,4,6-tri-tert-butylphenol (15 eq). The rates of dimerisation were
ratio 38 : 31 : 31.
2
192 | Org. Biomol. Chem., 2009, 7, 2187–2194
This journal is © The Royal Society of Chemistry 2009

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◦
FVP of methyl (E)-3-aminocarbonyl-3-(pyrrol-2-yl)propenoate 10
FVP of methyl (E)-3-aminocarbonyl-3-(pyrrol-2-yl)propenoate 10
FVP of 3-(pyrrol-2-yl)furan-2,5-dione 19 (20 mg, T
f
700 C,
◦
T
i
105 C, P 0.005 Torr, t 5 min) gave 2-ethynylpyrrole 17,
16
characterised as above.
◦
◦
[
(56 mg, 0.3 mmol), T
f
700 C, T
i
120 C, P 0.02 Torr, t 35 min]
◦
Similarly pyrolysis of phenylmaleic anhydride (25 mg, T
f
750 C,
gave a red pyrolysate which was washed with acetone. Removal of
the solvents yielded 3-(pyrrol-2-yl)-pyrrole-2,5-dione 18 (30 mg,
◦
T
(
i
135 C, P 0.005 Torr, t 10 min) gave ethynylbenzene; d
H
7.3–7.5
17
5H, m) and 3.02 (1H, s) (compatible with literature data ).
+
6
1
1
4%) which decomposed on attempted distillation. (Found: M
2
62.0430. C
8
H
6
N
2
O
2
requires M 162.0429); d
H
([ H ]acetone)
6
2
4
,2-Dimethyl-5-(4-methoxycarbonylpyrrol-2-ylidene)-1,3-dioxan-
,6-dione 21
1.17 (1H, br, NH), 9.93 (1H, br, NH), 7.24 (1H, m), 7.14
n
n
(
1H, m), 6.49 (1H, s) and 6.32 (1H, dt, J 3.8 and J 2.4); d
C
2
12
(
1
[ H
21.22 (quat), 114.63, 112.69 and 109.96; m/z 162 (M , 4%)
and 91 (100). A trace of a minor by-product was identified as
6
]acetone) 171.00 (quat), 170.80 (quat), 135.09 (quat), 124.06,
Reaction of 4-methoxycarbonylpyrrole-2-carboxaldehyde 20
(0.55 g, 4 mmol) with Meldrum’s acid (0.58 g, 4 mmol) in toluene
(8 cm ) containing glacial acetic acid (4 drops) and piperidine
(4 drops) gave, after 24 h at room temperature 2,2-dimethyl-5-(4-
methoxycarbonylpyrrol-2-ylidene)-1,3-dioxan-4,6-dione 21 (0.68
g, 68%) as yellow crystals, mp 239–241 C (dec.) (from methanol)
(Found: C, 55.85; H, 4.5; N, 5.1. C H NO requires C, 55.9; H,
+
3
1
1
-aminocarbonylpyrrolizin-3-one on the basis of its H NMR
]acetone) 7.76 (1H, br, NH), 7.37 (1H, br, NH),
.09 (1H, d, J 3.2), 6.38 (1H, d, J 3.2), 6.22 (1H, s) and 6.14 (1H,
2
spectrum; d
7
t, J 3.2).
H
3
([ H
6
3
◦
3
1
3
13
6
5
4
.65; N, 5.0%); d
H
12.76 (1H, br, NH), 8.26 (1H, d, J 0.7), 7.84
(1H, br s), 7.45 (1H, d, J 0.7), 3.84 (3H, s) and 1.76 (6H, s); dC
5
Synthesis and pyrolysis of (Z)-(pyrrol-2-yl)but-2-enedioic acid 12
1
1
63.89 (quat), 163.22 (quat), 143.91, 133.07, 129.39, 128.46 (quat),
To a solution of dimethyl (Z)-(pyrrol-2-yl)but-2-enedioate Z-5
20.71 (quat), 104.68 (quat), 103.53 (quat), 51.59 and 27.24 (one
3
(
1.94 g, 9 mmol) in methanol (100 cm ) was added a solution of
+
quaternary signal not apparent); m/z 279 (M , 17%), 248 (2), 221
3
aqueous sodium hydroxide (5 M, 20 cm ) and the reaction mixture
was heated under reflux for 5 h. Methanol was removed under
vacuum leaving a light brown residue to which was added water
(20), 177 (48), 146 (100), 118 (20), 90 (14), 63 (16), 44 (25) and
4
3 (27).
3
3
(
60 cm ) and hydrochloric acid (5%, 60 cm ). After extraction
6
-Methoxycarbonylpyrrolizin-3-one 22
3
with ether (3 ¥ 100 cm ), the combined organic layers were dried
MgSO ) and concentrated to give (Z)-pyrrol-2-ylbut-2-enedioic
(
4
FVP of 2,2-dimethyl-5-(4-methoxycarbonylpyrrol-2-ylidene)-1,3-
dioxan-4,6-dione 21 (236 mg, 0.8 mmol) (T
P 0.01 Torr, t 25 min) gave 6-methoxycarbonylpyrrolizin-3-one
◦
◦
acid 12 (1.28 g, 76%) as a yellow solid which quickly becomes
brown-black at room temperature. (Found: C, 52.4; H, 4.2; N, 7.2.
f
650 C, T 180–200 C,
i
+
◦
C
1
8
H
7
NO
81.0361. C
and 1664; d
4
, 0.2 H
2
O requires C, 52.0; H, 4.0; N, 7.6%) (Found: M
22 (131 mg, 88%), mp 111–112 C (from ethyl acetate/hexane)
8
H
7
NO
4
requires M 181.0375); nmax (nujol) 3373, 1715
]acetone) 10.80 (1H, br, NH), 5.6–8.4 (2H, br,
H), 7.06 (1H, m), 6.49 (1H, m), 6.23 (1H, m) and 6.14 (1H,
(Found: C, 61.05; H, 3.85; N, 7.9. C
H
NO requires C, 61.0; H,
9
7
3
2
H
([ H
6
3
.95; N, 7.9%); d 7.49 (1H, t, J and J 0.7), 7.18 (1H, dd, J 6.0
4
5
3
H
2CO
2
5
4
3
n
and J 0.7), 6.39 (1H, d, J 0.7), 5.77 (1H, dd, J 6.0 and J 0.3)
and 3.78 (3H, s); d 165.05 (quat), 163.62 (quat), 138.90, 136.29
quat), 123.11, 122.84 (quat), 122.50, 110.74 and 51.42; m/z 177
2
s); d
1
C
([ H ]acetone) 166.76 (quat), 165.23 (quat), 140.90 (quat),
6
C
+
25.71 (quat), 122.68, 113.09, 109.34 and 106.06; m/z 181 (M ,
(
(
1
%), 164 (16), 163 (81), 137 (3), 119 (9), 92 (23) and 91 (100).
+
M , 98%), 146 (100), 134 (48), 118 (51), 90 (24) and 63 (66).
◦
FVP of (Z)-pyrrol-2-ylbut-2-enedioic acid 12 (50 mg, T
f
400 C,
◦
T
2
i
135–150 C, P 0.0006 Torr, t 25 min) gave exclusively 3-(pyrrol-
1
Acknowledgements
-yl)furan-2,5-dione 19 characterised by its H NMR spectrum,
identical with that of an authentic sample (see below).
We are grateful to The University of Edinburgh for support and
to Dr R. O. Gould and Professor S. Parsons for the X-ray crystal
structures.
◦
FVP of (Z)-pyrrol-2-ylbut-2-enedioic acid 12 at 700 C (24 mg,
◦
◦
T
2
f
700 C, T
i
120–150 C, P 0.005–0.01 Torr, t 10 min) gave
1,8
16
-ethynylpyrrole 17, characterised as above.
Notes and references
Synthesis and pyrolysis of 3-(pyrrol-2-yl)furan-2,5-dione 19
1
M. C. Comer, X. L. M. Despinoy, R. O. Gould, H. McNab and S.
Parsons, Chem. Commun., 1996, 1083–1084.
A solution of (Z)-(pyrrol-2-yl)but-2-enedioic acid 12 (240 mg,
3
1
.3 mmol) and acetic anhydride (3 cm ) was heated at reflux
2 H. McNab and C. Thornley, J. Chem. Soc., Perkin Trans. 1, 1997,
2
203–2209.
for 1.5 h. Acetic acid and acetic anhydride were then removed
under vacuum to leave a black residue, which was dissolved
in dichloromethane and heated under reflux with decolourising
charcoal for 0.5 h. Filtration through Celite and removal of the
solvent gave 3-(pyrrol-2-yl)furan-2,5-dione 19 (89 mg, 41%) as
3
4
X. L. M. Despinoy and H. McNab, Arkivoc, 2000, 1, 252–258.
S. E. Campbell, M. C. Comer, P. A. Derbyshire, X. L. M. Despinoy, H.
McNab, R. Morrison, C. C. Sommerville and C. Thornley, J. Chem.
Soc., Perkin Trans. 1, 1997, 2195–2202.
5
6
Review H. McNab and C. Thornley, Heterocycles, 1994, 37, 1977–2008.
C. K. Lee, C. S. Hahn and W. E. Noland, J. Org. Chem., 1978, 43,
◦
a yellow oil which slowly solidified, mp 110–112 C (from ethyl
3
727–3729.
+
acetate) (Found: M 163.0267. C
8
H
5
NO
3
requires M 163.0269);
7 R. Greenhouse, C. Ramirez and J. M. Muchowski, J. Org. Chem., 1985,
d
H
10.02 (1H, br, NH), 7.18 (1H, m), 7.04 (1H, m), 6.45 (1H, s)
50, 2961–2965.
8
9
X. L. M. Despinoy, H. McNab and S. Parsons, Acta Crystallogr., Sect.
C, 1996, 52, 3064–3067.
and 6.42 (1H, m); d 166.95 (quat), 164.43 (quat), 136.97 (quat),
1
3
C
+
26.50, 120.95 (quat), 117.94, 113.00 and 112.12; m/z 163 (M ,
0%), 92 (8), 91 (100), 64 (15) and 63 (17).
W. E. Noland, C. K. Lee, S. K. Bae, B. Y. Chung, C. S. Hahn and K. J.
Kim, J. Org. Chem., 1983, 48, 2488–2491.
This journal is © The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 2187–2194 | 2193

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1
0 H. G. Viehe, Z. Janousek, R. Mer e´ nyi and L. Stella, Acc. Chem. Res.,
14 A. Treibs and F.-H. Kreuzer, Liebigs Ann. Chem., 1969, 721, 105–
1
985, 18, 148–154.
115.
1
1
1 cf. D. M. Birney, J. Org. Chem., 1996, 61, 243–251.
15 J. L. Archibald and M. E. Freed, J. Heterocycl. Chem., 1967, 4, 335–338.
16 C. Wentrup and H.-W. Winter, Angew. Chem., Int. Ed. Engl., 1978, 17,
609–610.
2 H. Bibas, R. Koch and C. Wentrup, J. Org. Chem., 1998, 63, 2619–
2
626.
13
1
1
3 H. J. Anderson, C. E. Loader and A. Foster, Can. J. Chem., 1980, 58,
17 J. Pouchert and J. Behnke, The Aldrich library of C and H NMR
2
527–2530.
spectra, Edition 1, Aldrich Chemical Company Inc., 1993.
2
194 | Org. Biomol. Chem., 2009, 7, 2187–2194
This journal is © The Royal Society of Chemistry 2009