Facile entry to ethyl tetrahydro-1H-pyrrolizin-7a(5H)-ylacetate: A versatile pharmaceutical intermediate

Article abstract of DOI:10.3987/COM-08-11369

An improved synthesis of ethyl tetrahydro-1H-pyrrolizin-7a(5H)-ylacetate is reported. This valuable pharmaceutical intermediate was easily obtained from 1,7-diiodo-4-heptanone in 46% yield, thus improving the procedure reported in the literature (23% yield) which starts from 1,7-dichloro-4-heptanone. Moreover, 1,7-diiodo-4-heptanone was obtained as an easily manageable solid, in this being preferable to its 1,7-dichloro isologue, which is a quite unstable oil. The former was synthesized in high overall yield (75%) starting from the commercially available diethyl 4-oxoheptanedioate, thus overtaking the well-known problems related to the use of γ-butyrolactone. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11369

HETEROCYCLES, Vol. 75, No. 9, 2008
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HETEROCYCLES, Vol. 75, No. 9, 2008, pp. 2193 - 2200. © The Japan Institute of Heterocyclic Chemistry
Received, 15th February, 2008, Accepted, 16th April, 2008, Published online, 21st April, 2008. COM-08-11369
FACILE ENTRY TO ETHYL TETRAHYDRO-1H-PYRROLIZIN-
7
a(5H)-YLACETATE: A VERSATILE PHARMACEUTICAL
INTERMEDIATE
Claudio Bruno, Alessia Catalano, Giovanni Lentini,* Alessia Carocci,
Carlo Franchini, and Vincenzo Tortorella
Medicinal Chemistry Department – Campus, University of Studies – Faculty of
Pharmacy, via E. Orabona n. 4, 70125 Bari, Italy
glentini@farmchim.uniba.it
Abstract – An improved synthesis of ethyl tetrahydro-1H-pyrrolizin-
7
a(5H)-ylacetate is reported. This valuable pharmaceutical intermediate was
easily obtained from 1,7-diiodo-4-heptanone in 46% yield, thus improving the
procedure reported in the literature (23% yield) which starts from
1
,7-dichloro-4-heptanone. Moreover, 1,7-diiodo-4-heptanone was obtained as an
easily manageable solid, in this being preferable to its 1,7-dichloro isologue,
which is a quite unstable oil. The former was synthesized in high overall yield
(
75%) starting from the commercially available diethyl 4-oxoheptanedioate, thus
overtaking the well-known problems related to the use of γ-butyrolactone.
INTRODUCTION
The pyrrolizidine ring system – 1-azabicyclo[3.3.0]octane or perhydropyrrolizine – represents a part of
the structure of several drugs with different pharmacological properties. A series of compounds bearing
7
a-substituted pyrrolizidine ring are shown in Figure 1. Pilsicainide (1) is an antiarrhythmic belonging to
1
,2
class I currently used in therapy in Japan, while its oxymethylene analogue 2 proved to be a 4-fold
c
3
more potent use-dependent blocking agent on human skeletal muscle voltage-gated sodium channels.
4
5,6
Piracetam analogs 3 and SK-946 have been proposed as nootropic agents acting through the activation
6
,7
of the muscarinic M
1
receptor. Affinity for M
1
receptors was also found in the heterocyclic derivatives
8
7
9
10
4
and 5, while SK-951 has been proposed as a prokinetic agent acting as a 5-HT receptor agonist.
4

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HETEROCYCLES, Vol. 75, No. 9, 2008
O
R
H
N
NO2
H
N
X
N
N
(
)n
N
N
O
3
1
: X = NHCO; Pilsicainide
: X = OCH2
SK-946
2
n = 1, 2
R = H, Et, Ph
Cl
H N
2
N
H
N
N
N
O
N
N
H
N
N N
H N
O
O
2
4
5
SK-951
Figure 1. Pharmacological relevant compounds containing the 1-azabicyclo[3.3.0]octane moiety
There are two possible conformers for the pyrrolizidine ring, i.e. the trans- and cis-fused form, the latter
being favoured in that it is free from strong angular strains; in aqueous solution, unstrained pyrrolizidines
show high basicity and are apparently the strongest bases among saturated tertiary amines, being the
unshared electron pair of the nitrogen more accessible for protonation in the cis-fused geometry than in
1
1
the trans-fused one. 7a-Substitution is generally preferred when complex stereochemical items are to be
1
2
avoided ― that is a golden rule in drug research.
Some of the methods reported so far for the synthesis of perhydropyrrolizine-7a-derivatives present
1
3
13
disadvantages such as a high number of steps and the use of either electrogenerated reactants or high
1
4
pressure hydrogenation devices. More conveniently, perhydropyrrolizine-7a-derivatives are generally
15–17
18,19
obtained by either the use of 1,7-dichloro-4-heptanone
or 4-(2-oxopyrrolidin-1-yl)butanoic acid,
1
8,20–22
both obtained starting from γ-butyrolactone.
sodium salt of 2-pyrrolidinone at high temperature and pass through unstable pyrrolizine
However, some of the reported procedures use the
1
8
1
8,19
intermediates
which have to be purified as the corresponding perchlorates. Both the above procedures
2
3,24
are tainted by the hazard of explosions.
A recently reported synthesis of both pilsicainide and its
3
bioisostere (1, and 2, respectively, Figure 1) passes through ethyl tetrahydro-1H-pyrrolizin-
7
a(5H)-ylacetate, which was obtained from 4-(2-oxopyrrolidin-1-yl)butanoic acid, in turn prepared
starting from alternative commercially available compounds which are not included in the regulated
substance list. However, the routes reported passed through several steps and gave the key intermediate in
overall moderate yields. Moreover, they did not overtake the use of perchloric acid to convert an unstable
pyrrolizine intermediate into the corresponding perchlorate. In this paper, we propose the use of

HETEROCYCLES, Vol. 75, No. 9, 2008
2195
1,7-diiodo-4-heptanone, in lieu of 1,7-dichloro-4-heptanone, as a reagent for the synthesis of ethyl
tetrahydro-1H-pyrrolizin-7a(5H)-ylacetate. Unlike its dichloro analogue, 1,7-diiodo-4-heptanone is a
solid that can be easily weighed and stored for some days in the refrigerator. It is mentioned in the Patent
2
5
literature, but the only preparation we could find was unpractical and inefficient in that it gave the
desired intermediate in low yield (29%) as a by-product of an attempt of deprotection run on
26
7
,7-dimethoxy[3]triangulane. Herein, we report a simple synthetic route to 1,7-diiodo-4-heptanone (9,
Scheme 1) which starts from commercially available diethyl 4-oxoheptanedioate (6). Ethyl
tetrahydro-1H-pyrrolizin-7a(5H)-ylacetate (15) was obtained starting from 9, as shown in Scheme 2.
RESULTS AND DISCUSSION
Protection of the carbonyl group of the commercially available diethyl 4-oxoheptanedioate (6) with
®
27
triethyl orthoformate in the presence of Amberlyst 15 gave the ketal 7, which was submitted to
reduction with LiAlH to give the diol 8. Finally, the hydroxy groups of 8 were replaced by iodine in the
4
28
presence of triphenylphosphine. The conditions of this reaction were able to remove the protection of
the carbonyl group to give 9 in 75% overall yield from 6. An alternative route to 9 envisaged the
4
spirolactone 10, which underwent reduction with LiAlH to give dihydroxyketone 11. Unfortunately, 11
was only obtained in a complex mixture in very low yield (EIMS) and this route was abandoned.
O
O
O
O
O
a
O
O
8
6%
O
O
O
O
6
7
8
b
97%
O
O
O
c
I
I
HO
OH
9
0%
9
O
O
O
b
HO
OH
<
10%
O
O
1
1
10
Scheme 1. Reagents and conditions: (a) triethyl orthoformate, Amberlyst 15, 0 °C, 12 h; (b) LiAlH4,
anhyd. THF, 0 °C, 1 h; (c) I , triphenylphosphine, anhyd. toluene, 130 °C, 1 h.
2

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HETEROCYCLES, Vol. 75, No. 9, 2008
The diiodoketone 9 represents the key intermediate for the synthesis of methyl and ethyl
1
tetrahydro-1H-pyrrolizin-7a(5H)-ylacetates (14 and 15, respectively, Scheme 2). Reaction of 9 with ethyl
potassium malonate in MeOH in the presence of an excess of gaseous ammonia gave a mixture of 15 and
its inferior homologue 14 in 40% and 10% yield, respectively, as assessed by GC/MS analysis. Possible
intermediates 13 and 12, respectively, are reported in square brackets. The same reaction carried out
using methyl potassium malonate in MeOH gave pure 14 in 45% yield. Pure 15 was obtained in 46%
yield by reacting 9 with ethyl potassium malonate in absolute EtOH in the presence of an excess of
gaseous ammonia.
O
O
O
O
O
O
OMe
OEt
HO
OMe HO
OEt
b
+
+
a
N
N
N
N
1
4
15
1
2
13
O
O
O
O
OMe
HO
OMe
d
I
I
c
N
N
1
4
9
12
O
e
O
O
OEt
HO
OEt
b
N
N
1
5
1
3
Scheme 2. Reagents and conditions: (a) gaseous NH , ethyl potassium malonate, MeOH, rt, 24 h; (b) EtOH, 70
3
°
C, 2 h; (c) gaseous NH , methyl potassium malonate, MeOH, rt, 24 h; (d) MeOH, 70 °C, 2 h; (e) gaseous NH ,
3
3
ethyl potassium malonate, abs. EtOH, rt, 24 h.
CONCLUSIONS
A facile synthesis of ethyl tetrahydro-1H-pyrrolizin-7a(5H)-ylacetate (15) is reported. It consists of only
four steps, gave 15 in acceptable (35%) overall yield, and uses compounds that are not included in the
2
3,24
regulated substance lists. Furthermore, the route proposed herein avoids the risk of explosions
that
less attractive. The conversion of 9 into 15 (46% yield)
was performed more efficiently than the previously reported reaction carried out on
3
,18,19
makes some of the early proposed methods
1
5
1
,7-dichloro-4-heptanone (23% yield). Moreover, 1,7-diiodo-4-heptanone is a solid, easy to handle and
store, that can be prepared starting from the commercially available diethyl 4-oxoheptanedioate (6). The

HETEROCYCLES, Vol. 75, No. 9, 2008
2197
ester 15 represents the intermediate for the synthesis of a large variety of drugs bearing the
4
1
-azabicyclo[3.3.0]octane moiety, such as nootropic agents, drugs effective against Alzheimer disease,
9,10
1–3
prokinetics,
antiarrhythmics, and skeletal muscle sodium channel blockers. The facile route to 15
proposed herein might facilitate the access to further analogues.
EXPERIMENTAL
General. All chemicals were purchased from Sigma-Aldrich or Lancaster in the highest quality
commercially available. Solvents were RP grade unless otherwise indicated. Yields refer to purified
products and were not optimized. The structures of the compounds were confirmed by routine
spectrometric analyses. Only spectra for compounds not previously described are given. Melting points
were determined on a Gallenkamp apparatus in open glass capillary tubes and are uncorrected. Infrared
spectra were recorded on a Perkin-Elmer (Norwalk, CT) Spectrum One FT spectrophotometer and band
−
1
1
13
positions are given in reciprocal centimeters (cm ). H NMR and C NMR spectra were recorded on a
1
13
Varian Mercury-VX spectrometer operating at 300 and 75 MHz for H and C, respectively, using CDCl
3
as a solvent. Chemical shifts are reported in parts per million (ppm) relative to solvent resonance: δ 7.26
1
13
(
H NMR) and δ 77.3 ( C NMR). J values are given in Hz. EIMS spectra were recorded on a
Hewlett-Packard 6890-5973 MSD gas chromatograph/mass spectrometer at low resolution.
+
/–
ESI /MS/MS analyses were performed with an Agilent 1100 series LC-MSD trap system VL
Workstation. GC was performed on a Varian 3800 gas chromatograph equipped with a flame ionization
detector and a Jew Scientific DB-5 capillary column (30 m, 0.25 mm i. d., 0.25 µm film thickness).
Chromatographic separations were performed on silica gel columns by flash chromatography (Kieselgel
29
6
0, 0.040−0.063 mm, Merck, Darmstadt, Germany) as described by Still et al. TLC analyses were
performed on precoated silica gel on aluminium sheets (Kieselgel 60 F254, Merck).
®
Diethyl 4,4-diethoxyheptanedioate (7). 0.25 g of Amberlyst 15 were added to 6 (1.00 g, 4.34 mmol).
The suspension was cooled to 0 °C, then triethyl orthoformate (3.61 mL, 21.7 mmol) was added. The
mixture was stirred for 12 h, then it was filtered and purified by silica-gel flash chromatography
1
(
petroleum ether/EtOAc = 9:1) to give 7 (1.09 g, 86%) as a colorless oil: IR (neat) 1740 (C=O); H NMR:
δ 1.14 (t, J = 7.1 Hz, 6H, CH
3
CH
2
O), 1.24 (t, J = 7.1 Hz, 6H, CH
CO), 3.41 (q, J = 7.1 Hz, 4H, CH
OCO); C NMR: δ 14.5 (2C), 15.6 (2C), 29.0 (2C), 29.5 (2C), 55.8 (2C), 60.7 (2C), 101.9 (1C),
3
CH
2
OCO), 1.87–1.92 (m, 4H,
CH
2
2
CH
2
CO), 2.26−2.32 (m, 4H, CH
2
2
O), 4.10 (q, J = 7.1 Hz, 4H,
1
3
CH
+
+
+
1
73.5 (2C); MS (70 eV) m/z (%) 185 (M – 119, 21), 101 (100); ESI /MS m/z: 327 (M+Na) ;
+
ESI /MS/MS m/z: 281 (100).

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HETEROCYCLES, Vol. 75, No. 9, 2008
4
,4-Diethoxyheptanediol (8). To a stirred solution of 7 (0.96 g, 3.16 mmol) in dry THF (20 mL), LiAlH
0.36 g, 9.48 mmol) under N atmosphere was added. The mixture was stirred at 0 °C for 1 h. The
reaction was quenched by careful addition of few drops of water until the end of gas evolution. The
4
(
2
residue was removed by filtration and the filtrate was dried over anhydrous Na
2
SO
4
and concentrated
1
under vacuum to give 8 (0.67 g, 97%) as a white solid: mp 94–95 °C; IR (KBr): 3284, 3157 (OH); H
NMR: δ 1.23 (t, J = 7.1 Hz, 6H, CH
Hz, 4H, CH CH ), 3.81–3.97 (m, 4H, CH
7.4 (2C), 115.0 (1C); MS (70 eV) m/z (%) 128 (M – 92, 8), 87 (100); ESI /MS m/z: 243 (M+Na) ;
3
), 1.55 (bs, 2H, OH), 1.85–2.09 (m, 8H, CH
2
2
CH ), 3.71 (q, J = 7.1
1
3
2
3
2
OH); C NMR: δ 18.6 (2C), 24.9 (2C), 35.0 (2C), 58.6 (2C),
+
+
+
6
+
–
–
–
ESI /MS/MS m/z (%): 197 (100); ESI /MS m/z: 219 (M–H) ; ESI /MS/MS m/z (%): 173 (100); Anal.
Calcd for C11 (220.30): C, 59.97; H, 10.98. Found C, 59.59; H, 10.81.
24 4
H O
1
,7-Diiodoheptan-4-one (9). To a stirred solution of 8 (0.30 g, 1.36 mmol) in dry toluene (15 mL) under
2
N atmosphere, triphenylphosphine (0.93 g, 3.54 mmol) was added. The reaction mixture was brought to
1
30 °C and then iodine (0.90 g, 3.54 mmol) was added portionwise. The mixture was refluxed for 1 h,
then absolute EtOH (0.3 mL) was added in two portions at ca. 30 min intervals. After evaporation of the
solvent, the residue was taken up with CHCl and washed twice with saturated Na aqueous solution
and then twice with H O. The organic layer was dried (Na SO ) and concentrated under vacuum, then
3
2 2 3
S O
2
2
4
EtOAc was added and the precipitate formed was filtered off. The filtrate was evaporated and the residue
was purified by silica-gel flash chromatography (petroleum ether/ EtOAc = 9:1) to give 9 (0.45 g, 90%)
2
6
2 2
as a yellowish solid, which was recrystallized from Et O: mp 47–48 °C (lit., 43–45 °C, Et O); IR (KBr):
+
1
706 (C=O) 565 (C-I); MS (70 eV) m/z (%) 238 (M – 128, 22), 84 (100). Other spectroscopic data were
26
in agreement with the literature.
Ethyl tetrahydro-1H-pyrrolizin-7a(5H)-ylacetate (15). Method A. Gaseous ammonia (7 g) was added
to 40 mL of MeOH at 0 °C. To this solution compound 9 (2.20 g, 6.01 mmol) and ethyl potassium
malonate (5.11 g, 30.0 mmol) were added. The mixture was stirred for 24 h at rt, then it was concentrated
under vacuum and the residue was taken up with absolute EtOH. This mixture was heated at 70 °C for 2 h.
The solvent was evaporated and the residue was submitted to distillation (70 °C, 2 mmHg) to give a
colorless oil consisting of a mixture of 15 (40%) and 14 (10%) as assessed by GC/MS analysis. Method
B. Gaseous ammonia (2.5 g) was added to 20 mL of absolute EtOH at 0 °C. To this solution compound 9
(0.50 g, 1.37 mmol) and ethyl potassium malonate (1.16 g, 6.83 mmol) were added. The mixture was
stirred for 24 h at rt, then it was concentrated under vacuum and the residue was taken up with absolute
EtOH. This mixture was heated at 70 °C for 2 h. The solvent was evaporated and the residue was
submitted to distillation (70 °C, 2 mmHg) to give 15 (0.12 g, 46%) as a colorless oil. Spectroscopic data
1
were in agreement with the literature.

HETEROCYCLES, Vol. 75, No. 9, 2008
2199
Methyl tetrahydro-1H-pyrrolizin-7a(5H)-ylacetate (14). Gaseous ammonia (3 g) was added to 20 mL
of MeOH at 0 °C. To this solution compound 9 (1.60 g, 4.37 mmol) and methyl potassium malonate (3.1
g, 21.8 mmol) were added. The mixture was stirred for 24 h at rt, then it was concentrated under vacuum
and the residue was taken up with methanol. This mixture was heated at 70 °C for 2 h. The solvent was
evaporated and the residue was submitted to distillation (70 °C, 2 mmHg) to give 14 (0.36 g, 45%) as a
1
colorless oil. IR (neat): 1736 (C=O); H NMR: δ 1.59–1.68 (m, 2H, CHHC), 1.77 (apparent octet, J = 6.3
3
0
Hz, 4H, CH
2
CH
2
CH
2
), 1.93–2.01 (m, 2H, CHHC), 2.48 (s, 2H, CH
2
CO)(lit., 2.44, s, 2H, CH
2
CO), 2.56
3
0
(
d t, J = 10.4, 6.5 Hz, 2H, CHHN), 3.07 (d t, J = 10.4, 5.9 Hz, 2H, CHHN), 3.63 (s, 3H, CH
3
) (lit., 3.60,
1
3
s, 3H, COOMe); C NMR: δ 25.2 (2C), 37.7 (2C), 45.8 (1C), 51.5 (1C), 55.4 (2C), 72.3 (1C), 172.4
+
(
1C); MS (70 eV) m/z (%) 183 (M , 1), 110 (100).
ACKNOWLEDGEMENTS
This work was accomplished thanks to financial support of the Ministero dell’Istruzione, dell’Università e
della Ricerca (MIUR 2003033405).
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