An expedient synthesis of diversified pyrrolizines and indolizines

Article abstract of DOI:10.1016/j.tetlet.2003.11.146

A general and rapid synthesis of new families of pyrrolizines and indolizines in good overall yields via an intramolecular [3+2] cycloaddition reaction is described. Diversity of substitutions can be achieved by the appropriate choice of readily available starting materials. The experimental procedures are straightforward and are performed under neutral conditions. New syntheses are also described for the preparation of N-propargylic 2-amino-benzaldehydes and S-propargylic 2-thiobenzaldehydes.

Full text of DOI:10.1016/j.tetlet.2003.11.146

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1567–1570
An expedient synthesis of diversified pyrrolizines and indolizines
George Bashiardes,* Imad Safir, Francis Barbot and Joelle Laduranty
Dꢀepartement de Chimie, SFA-UMR 6514, Universitꢀe de Poitiers, 40 avenue du Recteur Pineau, 86022 Poitiers, France
Received 14 October 2003; revised 7 November 2003; accepted 18 November 2003
Abstract—A general and rapid synthesis of new families of pyrrolizines and indolizines in good overall yields via an intramolecular
[3+2] cycloaddition reaction is described. Diversity of substitutions can be achieved by the appropriate choice of readily available
starting materials. The experimental procedures are straightforward and are performed under neutral conditions. New syntheses are
also described for the preparation of N-propargylic 2-amino-benzaldehydes and S-propargylic 2-thiobenzaldehydes.
Ó 2003 Elsevier Ltd. All rights reserved.
Indolizines and pyrrolizines are compounds generally
associated with pharmaceutical activities1 such as anti-
inflammatory (oxygenase inhibitors), anti-tumour
(alkylating) agents or even CNS activity (Fig. 1).
Amongst these important properties, however, selectiv-
ity in biological activity cannot be modulated in order to
allow improvement in their activity or toxicity. Access to
structural analogues and new classes of compounds by
methods allowing the synthesis of diversely substituted
derivatives would be an important target for research in
medicinal chemistry. Although some methods2 have
been reported describing the preparation of such com-
pounds, often they are limited to the synthesis of specific
examples. We report here the synthesis of variously
substituted tetracyclic (hydro)-pyrrolizines and indoli-
zines (Fig. 1) by choice, using a general method. The
process makes use of commercial or readily available
starting materials, which allow the introduction of
diversity and the parallel preparation of numerous
derivatives. The capacity for diversity by this method is
illustrated by the synthesis of compounds belonging to
new structural families. The added functionalities and
rigidification of the structure could modulate bioavail-
ability or activity.
The [3+2] dipolar cycloaddition reaction involving
azomethine ylides is a useful tool for the synthesis of aza
heterocycles. These ylides are 1,3-dipolar species, which
can be either stabilized or non-stabilized and can
undergo cycloadditions with a variety of alkynes,
including non-activated examples to provide pyrrolines
and pyrroles efficiently3 (Scheme 1).
AcO
Ph
Ph
NH
HO
H2N
Cl
N
N
N
We applied an intramolecular [3+2] cycloaddition
wherein the azomethine ylides were generated in the
presence of the required alkyne moiety. In this manner,
contrary to intermolecular cycloadditions, the regio-
chemistry and substitution pattern is totally controlled.
Both types of ylides were prepared in situ, the non-sta-
bilized examples being derived from the condensation of
a-amino acids with aldehydes, while the stabilized
examples are obtained by condensation with a-amino
esters.
Ph
HOOC
OH
5-HT2 candidate
COOR
Licofelone
Active mitomycin C
derivative
R
R
R
R
X
(
)n n=1,2
(
)n n=1,2
N
N
O
H
New tetracyclic derivatives
Figure 1. Pyrrolizines and indolizines with potential biological activity.
The O-propargylic salicylaldehydes 1a–d were prepared
by conventional methods, usually in quantitative yields,
from salicylaldehyde and a propargylic halide in di-
methylformamide (DMF) in the presence of potassium
carbonate. The condensation and intramolecular
Keywords: Pyrrolizines indolizines diversity.
* Corresponding author. Tel.: +33-5494-53966; fax: +33-5494-54588;
e-mail: georges.bashiardes@univ-poitiers.fr
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.146

1568
G. Bashiardes et al. / Tetrahedron Letters 45 (2004) 1567–1570
R1
1
1
R1
R
R2
2
toluene
reflux,
(
) n=1,2
CO2H
R
O
R
O
(
) n=1,2
CO2Me
CO2Me
H
toluene
reflux
+
O
O
+
N
H
( )n=1,2
then
sulphur
N
H
( ) n=1,2
CHO
2
N
CHO
N
R
H
1
H
1a-d
2a,b
R2
1a-d
5a,b
6a-d, n=1
7a-d, n=2
1a R1 = H, R2 = H
1a R1 = H, R2 = H
1b R1 = H, R2 = Ph
1c R1 = Me, R2 = H
CO2H
2a
2b
N
H
1b R1 = H, R2 = Ph
1c R1 = Me, R2 = H
1d R1 = H, R2 = Me
2
R
R
O
(
) n=1,2
N
H
CO2H
N
Me
3a-c, n=1
4a-c, n=2
CO2Me
Pyrrolizines
O
Pyrrolizines
CO2Me
CO2Me
N
O
5
O
4
4a
6
H
O
3a
6d
N
O
N
6a
3
2
O
H
1,2,3a,10b -Tetrahydro-4-methyl-
H
β
7
8
N
10b
O
10a
β
3a -methoxycarbonyl-5H-
11
6a
N
1
chromeno[3',4'-b]pyrrolizine
10
N
6b
3a
9
Me
Me
1,2-Dihydro-5H-
chromeno[3',4'-b]pyrrolizine
CO2Me
3c
CO2Me
3b
O
+
N
H
N
Indolizines
H
O
O
O
6c'
6c
N
N
N
Me
Indolizines
CO2Me
O
4c
CO2Me
CO2Me
4a
4b
O
O
N
H
7d
N
N
Scheme 1. Cycloaddition with a-amino acids––one-pot synthesis of
dihydropyrrolizines and tetrahydroindolizines.
H
H
β
1,2,3,4,4a,11b -hexahydro-
5-methyl-4aβ-methoxycarbonyl-
6H-chromeno[3',4'-b]indolizine
7a
7b
Me
O
Me
cycloaddition of these salicylaldehyde derivatives with
a-amino acids 2a,b gave the expected pyrroline inter-
mediates (Scheme 1). The diastereoisomers (ratio 1/1)
were not systematically isolated, although it is indeed
possible to do so for structural characterization, and the
crude reaction mixture was treated with sulfur4 in tol-
uene at reflux to give new tetracyclic pyrroles 3a–c and
4a–c. This one-pot procedure provided the required di-
hydropyrrolizines and tetrahydroindolizines in good
overall yields (Table 1).
CO2Me
CO2Me
O
+
N
N
H
H
7c'
7c
Scheme 2. Cycloaddition with a-amino esters––carbomethoxy pyr-
rolizines and indolizines. (For reasons of clarity, only one of the cis
enantiomers is depicted.)
Table 2. Oxa-pyrrolizines and -indolizines
The cycloaddition of stabilized azomethine ylides gen-
erated from aldehydes 1a–d and methyl prolinate 5a or
methyl pipecolinate 5b (Scheme 2, Table 2) on heating in
refluxing toluene provided cycloadducts derived from
the anti-dipole6 in good yields. These new tetrahydro-
pyrrolizines 6a–d and hexahydroindolizines 7a–d pos-
sessing a quaternary carboxylic group all had the same
stereochemistry in which the angular (10b or 11b) pro-
ton and the quaternary carboxylic group are cis to one
another. In the case of the secondary O-(1-methyl-
propargyl)salicylaldehyde 1c (entries 3 and 7), cycload-
Entry
Aldehyde/
amino ester
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
1a/5a
1b/5a
1c/5a
1d/5a
1a/5b
1b/5b
1c/5b
1d/5b
2
6a
6b
77
91
82
74
76
94
70
80
2
3.5
4
6c/6c0
6d
3
7a2d
7b
3
4
7c/7c0
6
7d
Table 1. One-pot synthesis of pyrrolizines and indolizines
dition with the two amino esters led to two
diastereoisomeric adducts 6c/6c0 and 7c/7c0, each in a 1:1
ratio in which only the methyl substituents (C-5 or C-6)
are of opposite configuration.
Entry
Aldehyde/
amino acid
Timea
Product5
Yield (%)
1
2
3
4
5
6
1a/2a
1b/2a
1c/2a
1a/2b
1b/2b
1c/2b
2 h+4 h
2 h+3 h
3 h+4 h
4 h+4 h
4 h+4 h
4 h+4 h
3a
3b
3c
4a
4b
4c
71
69
66
75
73
64
As an extension to this work, we wished to study the
condensations using other heteroatom-containing
propargylic derivatives for which we describe new
syntheses (Scheme 3). We thus prepared N-propargylic
2-aminobenzaldehydes 12a,b and S-propargylic thio-
a Heat 1 and 2 in toluene, then add sulfur and heat.

G. Bashiardes et al. / Tetrahedron Letters 45 (2004) 1567–1570
Table 3. Aza- and thia-pyrrolizines and -indolizines
1569
H
N
H, Ph
H
N
Br
10a,b
LiAlH4
N
H, Ph
Entry
Aldehyde/
amino ester
X
Time (h)
Product Yield
(%)
O
Et2O,
0°C, 4hr
11a,b
79%, 98%
K2CO3/MeCN
40°C, 48h
O
OH
OH
1
2
3
4
5
6
7
8
12a/5a
12b/5a
15a/5a
15b/5a
12a/5b
12b/5b
15a/5b
15b/5b
NMe
NMe
S
2
16a
16b
17a
17b
18a
18b
19a
19b
68
76
68
75
81
83
65
74
9
8
98%
2
Swern
2
H, Ph
S
2
N
NMe
NMe
S
4
12a,b
4
81%, 82%
4.5
4
O
S
H, Ph
H, Ph
Br
SH
OH
K2CO3
S
The S-propargylic 2-thiobenzaldehydes 15a,b were pre-
pared in a similar manner from 2-mercaptobenzyl
alcohol 13 by S-alkylation then Swern oxidation. The
overall yields of 15a and 15b were 67% and 54%,
respectively.
S
+
acetone,
heat
Swern
15a,b
69%, 62%
H, Ph
10a,b
OH
O
13
14a,b
95%, 87%
Scheme 3. Preparation of propargylic benzaldehydes.
The 2-N- and 2-S-propargylic benzaldehydes 12 and 15
thus obtained were treated with methyl prolinate or
methyl pipecolinate in toluene at reflux for 2–4 h. With
no other workup other than cooling and evaporation of
the solvent, the crude mixtures were purified by column
chromatography to provide single diastereomeric aza-
and thia-compounds in good yields ranging from 65% to
83% (Table 3).
salicylaldehydes 15a,b, which then underwent the same
condensations as described above with a-amino esters 5a
and 5b. These examples led to the stereoselective syn-
thesis of a new series of aza- and thia-tetrahydro-
pyrrolizines 16a,b and -hexahydroindolizines 18a,b
possessing a chiral quaternary carboxylic moiety.
(Scheme 4).
The added physical and electronic effects of the different
heteroatoms in the compounds described in this work
can have varying effects on possible biological activities
in these series. Most importantly, though, we are cur-
rently taking advantage of the chemical properties of
these compounds.
The N-propargylic 2-aminobenzaldehydes 12a,b were
prepared from methyl anthranilate7 in a three-step
sequence, starting with lithium aluminium hydride
(LiAlH4) reduction to the benzylic alcohol 9 followed by
N-alkylation with the appropriate propargylic halide
10a,b, then Swern oxidation to the required benzalde-
hyde. The two compounds 12a and 12b were obtained in
overall yields of 63% and 79%, respectively.
In conclusion, we report a rapid synthesis of new fam-
ilies of pyrrolizines and indolizines in good overall yields
via an intramolecular [3+2] cycloaddition reaction. The
method is general and diversity of substitutions can be
achieved by the appropriate choice of readily available
starting materials. The experimental procedures are
straightforward and are performed under neutral con-
ditions. New syntheses are also described for the prep-
aration of N-propargylic 2-amino-benzaldehydes and
S-propargylic 2-thiobenzaldehydes.
R
X
CO2Me
) n=1,2
(
) n=1,2
CO2Me
toluene
reflux
X
+
(
N
H
R
N
CHO
H
5a, n=1, prolinate
12a R = H, X = NMe
12b R = Ph, X = NMe
5b, n=2, pipecolinate
16a,b n=1 R = H, Ph
18a,b n=2 R = H, Ph
X=NMe
15c R = H, X = S
15d R = Ph, X = S
17a,b n=1 R = H, Ph
19a,b n=2 R = H, Ph
X=S
Acknowledgements
G.B. wishes to thank the Centre National pour la
Recherche Scientifique (CNRS) for a grant (‘‘Aide Jeune
Equipe’’).
Pyrrolizines
CO2Me
S
CO2Me
CO2Me
N
CO2Me
N
S
N
H
N
N
H
N
H
H
16a
16b
17a
17b
References and notes
Indolizines
CO2Me
N
CO2Me
CO2Me
CO2Me
N
S
S
1. Examples: (a) Ulbrich, H.; Fiebich, B.; Dannhardt, G. Eur.
J. Med. Chem. 2002, 37, 953–959; (b) Rajaraman, S.;
Jimenez, L. S. Tetrahedron 2002, 58, 10407–10412; (c)
Portevin, B.; Torjman, C.; Pastoureau, P.; Bonnet, J.; De
Nanteuil, G. J. Med. Chem. 2000, 43, 4582–4593, and
references cited therein.
N
H
N
N
H
N
H
H
18a
18b
19a
19b
Scheme 4. Aza- and thia-pyrrolizines and indolizines.

1570
G. Bashiardes et al. / Tetrahedron Letters 45 (2004) 1567–1570
2. Examples: (a) Dalla Croce, P.; La Rosa, C. Heterocycles
2001, 55, 1843–1857; (b) Basavaiah, D.; Rao, A. J.
Tetrahedron Lett. 2003, 44, 4365–4368; (c) Okano, T.;
Sakaida, T.; Eguchi, S. J. Org. Chem. 1996, 61, 8826–8830;
(d) Grigg, R.; Duffy, L. M.; Dorrity, M. J.; Malone, J. F.;
Rajviroongit, S.; Thornton-Pett, M. Tetrahedron 1990, 46,
2213–2230.
3. Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J. Tetra-
hedron Lett. 2003, 44, 8417–8420.
4. Rhee, M.-H.; Vogel, Z.; Barg, J.; Bayewitch, M.; Levy, R.;
approximately 1 h or until completion (TLC). After cooling,
the crude mixture was filtered and the solvent removed
under reduced pressure. The expected pyrrolizine or
indolizine was purified by column chromatography on
silica gel (dichloromethane/pentane 1:1): Example com-
pound 3a (1,2-dihydro-5H-chromeno[30,40-b]pyrrolizine):
1H NMR (300 MHz, CDCl3): 7.21 (dd, 1H, H-10, J 7.4
and 1.6 Hz); 6.98 (dd, 1H, H-8, J 7.1 and 1.7 Hz); 6.92–6.84
(m, 2H, H-7 and H-9); 5.63 (s, 1H, H-4); 5.25 (s, 2H, 2H-5);
4.13 (m, 2H); 2.82 (m, 2H); 2.54 (quint, 2H, 2H-2, J 7.2 Hz);
13C NMR 75 MHz (CDCl3): 152.0 (C6a); 139.5 (C3a); 125.8
(C8); 121.2 (C9); 119.5, 118.9 and 118.8 (C10a, C4a and C10b);
118.8 (C10); 116.6 (C7); 95.4 (C4); 66.4 (C5); 46.3 (C1); 28.0
(C2); 23.7 (C3).
ꢁ
Hanus, L.; Beruer, A.; Mechoulam, R. J. Med. Chem. 1997,
40, 3228–3233.
5. Typical experimental procedure: Secondary-amino acid
(5 mmol) and O-propargylic salicylaldehyde (2.5 mmol)
were stirred and heated in toluene (15 mL) at reflux. When
carbon dioxide gas evolution had ceased and starting
aldehyde had been consumed (TLC), sulfur powder
(12.5 mmol) was added and heating was continued for
6. Tsuge, O.; Kanemasa, S.; Ohe, M.; Yorozu, K.; Takenaka,
S.; Ueno, K. Chem. Lett. 1986, 1, 1271–1274.
7. Mahmud, H.; Lovely, C. J.; Rasika-Dias, H. V. Tetrahe-
dron 2001, 57, 4095–4105.