Pyrrolizine and indolizine derivatives from 1,6-dioxo-2,4-diene by inter- and intramolecular ring closure

Article abstract of DOI:10.3987/COM-02-9494

A variety of 1-amino-alkyl esters and nitriles react with 1,6-dioxo-2,4-diene to give pyrrole derivatives in good yield. Mild basic conditions facilitate the further intramoleular Dieckmann or Thorpe like condensation giving pyrrolizine and indolizine derivatives. These reactions provide simple, two step sequence to pyrrolizine and indolizine derivatives with control of product dictated by the base used for the condensation reaction.

Full text of DOI:10.3987/COM-02-9494

HETEROCYCLES, Vol 57, No. 7, 2002, pp.1303 - 1311, Received, 19th April, 2002
PYRROLIZINE AND INDOLIZINE DERIVATIVES FROM 1,6-DIOXO-
2,4-DIENE BY INTER- AND INTRAMOLECULAR RING CLOSURE
Chi Wi Ong,a* Ming Chih Lai,a Jing Jyh Jan,a and Yu An Changb
cong@mail.nsysu.edu.tw
aDepartment of Chemistry, National Sun Yat Sen University, Kaoshiung, Taiwan 804
bChung Chou Institute of Technology, Yuan-Lin Town, Chang-Hwa, Taiwan
Abstract – A variety of 1-amino-alkyl esters and nitriles react with
1,6-dioxo-2,4-diene to give pyrrole derivatives in good yield. Mild basic
conditions facilitate the further intramoleular Dieckmann or Thorpe like
condensation giving pyrrolizine and indolizine derivatives. These reactions
provide simple, two step sequence to pyrrolizine and indolizine derivatives with
control of product dictated by the base used for the condensation reaction.
INTRODUCTION
The pyrrolizine and indolizine alkaloids constitute a very large family of natural product having a wide
range of potent biological activities that are widely isolated from plants, insects, animals, oceanic lives
and secondary metabolites of microbes. 1-3 In view of the intense interest in the pyrrolizine and indolizine
alkaloids and the scarcity of natural samples, many new methodologies and strategies have been
developed towards their synthesis.4-12 We have recently reported the synthesis of 1,2,5-trisubstituted
pyrrole derivatives from the reaction of 1,6-dioxo-2,4-diene with a variety of primary amines.13 This
prompt us to extend the synthetic potentiality of this method for the synthesis of pyrrolizine and

indolizine derivatives by synthesizing pyrrole derivatives with an appropriate N-substitution that can
further undergo the second intramolecular condensation reaction to give fused[1,2-a]pyrroles.
RESULT AND DISCUSSIONS
13
In our previous studies, we have demonstrated that 1,6-dioxo-2,4-diene (1) react with ethyl glycinate
to give pyrrole derivative (2a) in good yield, and this intermediate was used to test the practicality of the
second intramolecular Dieckmann type cyclization14 to synthesize pyrrolizine derivative. The treatment
of 2a with 1 equiv. of potassium butoxide (tert-BuOK) underwent cyclization to give 3a in moderate
yield (Scheme 1). It was found that under this reaction condition, the cyclization took place regio- and
chemoselectively to give a single product. An interesting observation during the cyclization reaction was
the expulsions of a hydroxy group rather than the usual ethoxy group to give the vinyl ether (3a), a
diversion from the normal Dieckmann-type cyclization. The presence of an ethoxy group in 3a was
obvious by inspection of the 1H NMR spectrum that showed a quartet and triplet at δ 4.30 (J = 4.6 Hz)
and 1.32(J = 4.8 Hz) respectively. Apparently, the transient alkoxide anion formed was protonated
readily under this reaction condition to form a hemiacetal, whereby in this case the hydroxy group
became more susceptible to elimination as compared with the ethoxy group. The availability of a proton
O
O
( )
n X
H2N
Ph
Ph
N
( )n
EtOH
O
1
X
2a : X= COOEt, n=1
2b : X= COOEt, n=2
2c : X= CN, n=2
2d : X= COOEt, n=3
O
t-BuOK
(or NaH)
N
N
+
Ph
THF
( )n
O
Ph
OR
OEt
4a
3a : R= Et, n=1
3b : R= Et, n=2
3c : R= H, n=2
3d : R= Et, n=3
H+ / H2O
Scheme 1. Synthesis of pyrrolizines and indolizines.

source for the instantaneous protonation of the transient alkoxide intermediate was attributed to the
following sequence of events: (i) the enolization of the pyrrole-2-methylene carbonyl to the enol form,
(ii) the transfer of a proton from the enol to the transient alkoxide anion via a six-member transitional
state to form the requisite hemiacetal, and (iii) the expulsion of hydroxy group to give the vinyl ether
(Scheme 2). In general, irrespectively of the base used, the cyclization reactions must proceed with the
unusual elimination of the hydroxy group to give the vinyl ether.
We next study the judicious choice of base on the cyclization reaction. When 2a was treated with 1 equiv.
of sodium hydride (NaH) in THF, this afforded two products in a 1 : 2 ratio, one being the cyclized
products (3a) (18%) and a new compound that was assigned 4a (36%). Deprotonation by NaH can take
placed at the two α-methylene ester groups in 2a and these can undergo an intramolecular condensation
to form 3a and 4a. The two regiosiomeric products (3a) and (4a) can be differentiated by their NMR
spectra. The 13C NMR spectrum with a chemical shift at δ 193 was in agreement for the presence of the
13
ketogroup in 3a. In contrast, the C NMR spectrum of compound (4a) showed a typical ester chemical
1
shift at δ 163. Furthermore, the H NMR spectrum for the ring methylene protons in 3a appears as a
singlet at δ 5.19, consistent to that of pyrrolo[1,2-a]pyrrole reported,11 and also indicative of the same
regiochemistry at the double bond. On the other hand the ring methylene proton in 4a showed germinal
Ph
O
N
N
O
H
2a
Ph
O
O
OEt
OEt
Ph
N
O
3a
OH
EtO
Scheme 2. Formation of vinyl ether during cyclization reaction
1
coupling in the H NMR spectrum. The 2D NMR (1H and 13C NMR) experiment for 3a showed the

methylene proton resonance at δH 5.19 correlated with the carbon signal at δC 47.17; and for 4a the
methylene proton resonance at δH 5.18 and 4.91 correlated with the carbon signal at δC 47.31. The close
proximity of the 13C NMR for the methylene carbon in 3a and 4a can be accounted for from the fact that
the ϒ−carbon for enolketone (3a) resonance at a higher field as compared to the ϒ-carbon of
α,β-unsatutrated compound (4a), whereas conversely the α-carbon to nitrogen (3a) resonances at a
lower field as compared to the α-carbon of a double bond (4a). These two opposing phenomenon
accounts for the close proximity of the13C NMR spectrum for 3a and 4a. Importantly, we have shown
that the use of sodium hydride and potassium tert-butoxide as bases in the cyclization of 2a occurred
with different regiospecificity at the α-methylene ester groups. For the purpose of obtaining a single
product, we therefore chose to use tert-BuOK for further studies.
The synthesis of the indolizine system requires the preparation of ethyl 1-pyrrolylpropionate (2b).
Treatment of 1 with β-alanine ethyl ester underwent the requisite intermoleuclar cylization smoothly to
give 1-pyrrolepropionate (2b) in high yield. Indeed, the reaction of 2b with 1 equivalent of tert-BuOK
also underwent regioselective Dieckmann-type cyclization to give indolizidine derivative (3b) in
moderate yield (60%). Importantly, this reaction also gave rise to the vinyl ether (3b), thus implying the
generality for the elimination of the hydroxy group in this class of compounds. We next extend the scope
of our study to the base catalyzed condensation of the enolate with an N-tethered cyano group, an
intramolecular version of the Thrope-type cyclization. The reaction of 1 with 1-aminopropionitrile
gave good yield of 1-pyrrolylpropionitrile (2c). The reaction of 2c with 1 equivalent of tert-BuOK was
found to undergo regioselective Thrope-like cyclization to give indolizidines ring system (3c) (in the
enol form) in moderate yield (55%).
Attempt hydrolysis of the vinyl ether in 3b to the enol (3c) was carried out. When 3b was refluxed in
water under acid catalysis (HCl) for a prolonged period, it was converted successfully to the enol (3c),
and this rigorously proved their structures.
The scope of this new methodology can be extended for the synthesis of N-fused pyrrolo-ring system of
larger ring size. The reaction of 1 with ethyl 4-aminobutanoate gave the pyrrole derivatives (2d) in

moderate yield (64%). Cyclization of 2d with tert-BuOK gave 3d in a lower yield (25%) The size of the
ring being formed was found to have an influence on the yield of the cyclized product.
CONCLUSIONS
In conclusion, a rapid synthesis of pyrrolizine and indolizine ring system in two steps starting from
1,6-dioxo-2,4-diene has been achieved. This approach starts with the construction of an appropriately
functionalized pyrrole ring from the reaction of 1,6-dioxo-2,4-diene with commercially available amines,
followed by a subsequent intramolecular cyclization via Dieckmann or Thrope-like reaction. Moreover,
the usual expulsion of an ethoxide to give the carbonyl group during Dieckmann type cyclization was
not observed, but rather the hydroxy group was eliminated to give the vinyl ether.
ACKNOWLEDGEMENT
We will like to thank National Science Council of Taiwan for financial support.
EXPERIMENTAL
Melting points reported were uncorrected. IR spectra were recorded by dissolving the compound in
1
CHCl3 and absorption maxima are given in cm-1. H NMR were recorded on a 200 MHz spectrometer
using TMS as the internal standard and CDCl3 as the solvent. MS spectral measurement and elemental
analyses were carried out using the instrumentation center of NSC, Taiwan.
Compounds (1) and (2a)13 were previously prepared in our laboratory.
General Procedure for the Preparation of Pyrrole Derivatives from 1,6-Dioxo-2,4-dienes and
Amine. The appropriate amine hydrochloride salt (1.1 mmol) in ethanol (10 mL) was neutralized with
sodium carbonate (116.6 mg, 1.1 mmol) at rt. A solution of the appropriate 1,6-dioxo-2,4-diene in
ethanol (5 mL) was added and the reaction was stirred at rt for approximately 6 h (The reaction was
monitor using TLC and terminated when other spots started to appear. Prolong reaction time led to a

lower yield of the product and many side products). The ethanol was first removed in vacuo, water
added, and extracted with chloroform. The organic phase was washed with brine solution, dried (Na2SO4)
and solvent removed on a rotatory evaporator. The crude product was purified by preparative thin layer
chromatography (silica gel).
Ethyl 2-(2-Oxophenylethyl)-5-methyl(pyrrol-1-yl)propionate (2b). (EtOAc/ hexane, 1 : 5 as the
1
eluent, yellow solid, mp 69-71oC, 95%). IR νmax 1723 and 1690 cm-1. H NMR δ 8.05 (d, J = 7.7 Hz,
2H), 7.57 (m, 1H), 7.50 (m, 2H), 5.89 (d, J = 3.4 Hz, 1H), 5.84 (d, J = 3.4 Hz, 1H), 4.29 (s, 2H), 4.14 (q,
J = 6.7 Hz, 2H), 4.10 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.24 (s, 3H), 1.23 (t, J = 7.3 Hz, 3H).
MS m/z 299. Anal. Calcd for C18H21NO3: C, 72.20; H, 7.07; N, 4.68. Found: C, 72.50; H, 7.10; N, 4.70.
2-(2-Oxophenylethyl)-5-methyl(pyrrol-1-yl)propionitrile (2c). (EtOAc/ hexane, 1 : 5 as the eluent,
yellow solid, mp 95-96oC, 90%). IR νmax 2015 and 1690 cm-1. 1H NMR δ 8.05 (d, J = 7.7 Hz, 2H), 7.59
(m, 1H), 7.47 (m, 2H), 5.93 (d, J = 3.6 Hz, 1H), 5.87 (d, J = 3.6 Hz, 1H), 4.29 (s, 2H), 4.12 (t, J = 7.5 Hz,
2H), 2.69 (t, J = 7.5 Hz, 2H), 2.25 (s, 3H). MS m/z 252. Anal. Calcd for C16H16N2O: C, 76.15; H, 6.04;
N, 11.11. Found: C, 76.18; H, 6.37; N, 11.07.
Ethyl 2-(2-Oxophenylethyl)-5-methyl(pyrrol-1-yl)butyrate (2d). (EtOAc/ hexane, 1 : 5 as the eluent,
yellow solid, mp 82-83oC, 64%). IR νmax 1723 and 1690 cm-1. 1H NMR δ 8.04 (d, J = 7.8 Hz, 2H), 7.55
(m, 1H), 7.48 (m, 2H), 5.89 (d, J = 3.4 Hz, 1H), 5.82 (d, J = 3.4 Hz, 1H), 4.25 (s, 2H), 4.11 (q, J = 7.2
Hz, 2H), 3.82 (t, J = 8.1 Hz, 2H), 2.32 (t, J = 6.9 Hz, 2H), 2.24 (s, 3H), 1.91 (m, 1H), 1.23 (t, J = 7.0Hz,
3H). MS m/z 313. Anal. Calcd for C19H23NO3: 72.82; H, 7.40; N, 4.47. Found: C, 72.50; H, 7.25; N,
4.42.
General Procedure for the Preparation of Pyrrolizine and Indolizine Derivatives. To a solution of
the appropriate N-tethered pyrrole (0.5 mmol) in THF (20 mL) was added tert-BuOK (56 mg, 0.5 mmol)
at rt. The reaction was stirred for approximately 6 h. The THF was removed in vacuo, water added,
extracted with chloroform, and extract was washed with brine, and dried (Na2SO4). The crude product
was purified by preparative thin layer chromatography (silica gel).

The reaction with NaH was carried out using similar method whereby tert-BuOK is replaced with NaH.
(2-Ethoxy-5-methyl-3H-pyrrolizin-1-ly)-phenylmethanone (3a). (Ether/ hexane, 1 : 3 as the eluent,
yellow liquid, 45%). IR νmax 1670 cm-1. 1H NMR δ 7.98 (d, J = 7.3 Hz, 2H), 7.50 (m, 3H), 6.89 (d, J =
3.8 Hz, 1H), 6.09 (d, J = 3.8 Hz, 1H), 5.19 (s, 2H), 4.30 (q, J = 4.6 Hz, 2H), 2.28 (s, 3H), 1.32 (t, J = 4.8
13
Hz, 3H). C NMR δ 193.11 (C), 182.90 (C), 168.31 (C), 142.08 (C), 134.23 (CH), 133.45 (C), 130.11
(CH), 128.71 (CH), 127.51 (C), 125.20 (CH), 110.93 (CH), 61.76 (CH2), 47.17 (CH2), 14.17 (CH3),
12.17 (CH3). MS m/z 267. Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.68; H,
6.45; N, 5.26.
Ethyl 5-Methyl-2-phenyl-1H-pyrrolizine-3-carboxylate (4a). The cyclization was carried out using
NaH. This give rise to a mixture of 3a (18%) and 4a (35%) (Ether/ hexane, 1 : 3 as the eluent). IR νmax
1
1675 cm-1. H NMR δ 8.12 (d, J = 8.0 Hz, 2H), 7.52 (m, 1H), 7.41 (m, 2H), 7.17 (d, J = 4.0 Hz, 1H),
6.02 (d, J = 4.0 Hz, 1H), 5.18 (d, J = 10.5 Hz, 1H), 4.91 (d, J = 10.5 Hz, 1H), 4.14 (q, J = 2.4 Hz, 2H),
2.19 (s, 3H), 1.20 (t, J = 4.5 Hz, 3H). 13C NMR δ 183.12 (C), 168.31 (C), 165.77 (C), 139.91 (C),
135.59 (C), 133.18 (CH), 129.96 (CH), 129.63 (CH), 128.76 (C), 120.85 (CH), 109.59 (CH), 61.45
(CH2), 47.31 (CH2), 13.99 (CH3), 12.19 (CH3). MS m/z 267. Anal. Calcd for C17H17NO2: C, 76.38; H,
6.41; N, 5.24. Found: C, 76.54; H, 6.42; N, 5.25.
(7-Ethoxy-3-methyl-5,6-dihydroindolizin-8-yl)phenylmethanone (3b). (Ether/ hexane, 1 : 3 as the
eluent, yellow liquid, 60%). IR νmax 1665 cm-1. 1H NMR δ 8.00 (d, J = 7.4 Hz, 2H), 7.60 (m, 1H), 7.50
(m, 2H), 6.85 (d, J = 4.2 Hz, 1H), 6.01 (d, J = 4.2 Hz, 1H), 4.60 (t, J = 7.2 Hz, 2H), 4.15 (q, J = 7.2 Hz,
2H), 2.89 (t, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.24 (t, J = 6.9 Hz, 3H). 13C NMR δ 193.34 (C), 182.09 (C),
171.18 (C), 142.21 (C), 134.17 (C), 133.49 (CH), 129.99 (CH), 128.32 (CH), 126.88 (C), 125.61 (CH),
110.85 (CH), 60.77 (CH2), 41.55 (CH2), 35.26 (CH2), 14.09 (CH3), 12.35 (CH3). MS m/z 281. Anal.
Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.58; H, 6.80; N, 4.86.
(7-Hydroxy-3-methyl-5,6-dihydroindolizin-8-yl)phenylmethanone (3c). (Ether/ hexane, 1 : 3 as the
eluent, yellow liquid, 55%). IR νmax 3457 and 1660 cm-1. 1H NMR δ 7.99 (d, J = 7.6, 2H), 7.62 (m,
1H), 7.52 (m, 2H), 6.89 (d, J = 4.4 Hz, 1H), 6.09 (d, J = 4.4 Hz, 1H), 4.64 (t, J = 4.2 Hz, 2H), 2.98 (t, J =

4.2 Hz, 2H), 2.24 (s, 3H). 13C NMR δ 192.88 (C), 182.41 (C), 142.41 (C), 134.35 (C), 133.24 (C),
129.96 (CH), 128.88 (CH), 126.91 (CH), 126.21 (C), 117.47 (CH), 111.56 (CH), 41.56 (CH2), 19.46
(CH2), 12.58 (CH3). MS m/z 253. Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.68; H, 5.93; N, 5.48.
{8-Ethoxy-3-methyl-5,6-dihydro-5H-pyrrolo[1,2-a]azepin-9-yl}phenylmethanone (3d). (Ether/ hexane,
1 : 3 as the eluent, yellow liquid, 25%). IR νmax 1668 cm-1. 1H NMR δ 8.00 (d, J = 7.2 Hz, 2H), 7.61 (m,
1H), 7.47 (m, 2H), 6.83 (d, J = 4.2 Hz, 1H), 6.02 (d, J = 4.2 Hz, 1H), 4.47 (t, J = 5.0 Hz, 2H), 4.16 (q, J
= 5.0 Hz, 2H), 2.45 (t, J = 4.8 Hz, 2H), 2.35 (s, 3H), 2.12 (m, 2H), 1.26 (t, J = 5.0 Hz, 3H). 13C NMR δ
193.39 (C), 182.24 (C), 172.89 (C), 142.04 (C), 134.12 (C), 133.60 (CH), 130.01 (CH), 128.69 (C),
126.89 (C), 125.40 (CH), 110.78 (CH), 60.55 (CH2), 44.89 (CH2), 31.04 (CH2), 25.85 (CH2), 14.22
(CH3), 12.28 (CH3). MS m/z 295. Anal. Calcd for C19H21NO2: C, 77.76; H, 7.17; N, 4.74. Found: C,
77.58; H, 7.13; N, 4.67.
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