Easy one-pot access to substituted 2-phenylpyrrolines from 2-pyrrolidinone

Article abstract of DOI:10.1016/S0040-4039(01)01192-3

An easy access to 2-aryl pyrrolidines is the reduction, stereospecific or not, of the corresponding 2-aryl-pyrroline (5-aryl-3,4-dihydro-2H-pyrrole). Preparation of the latter has been carried out from 2-pyrrolidinone using an easy one-pot two-step method

Full text of DOI:10.1016/S0040-4039(01)01192-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6101–6104
Easy one-pot access to substituted 2-phenylpyrrolines
from 2-pyrrolidinone
Ce´cile Coindet, Alain Comel and Gilbert Kirsch*
Laboratoire d’Inge´nierie Mole´culaire et Biochimie Pharmacologique, Faculte´ des Sciences, Universite´ de Metz, Ile du saulcy,
57045 Metz Cedex 1, France
Received 5 June 2001; revised 2 July 2001; accepted 4 July 2001
Abstract—An easy access to 2-aryl pyrrolidines is the reduction, stereospecific or not, of the corresponding 2-aryl-pyrroline
(5-aryl-3,4-dihydro-2H-pyrrole). Preparation of the latter has been carried out from 2-pyrrolidinone using an easy one-pot
two-step method for the first time. © 2001 Elsevier Science Ltd. All rights reserved.
Substituted 2-phenylpyrrolidines are key intermediates
for the preparation of tricyclic systems such as
pyrrolo[2,1-a]isoquinolines which exhibit significant
pharmacological activities.1
A second approach consists of the addition of aryl
lithium or magnesium bromide on 2-pyrrolidinones
which necessitates the protection of the nitrogen atom.
Generally, the addition leads to the opening of the ring7
and a second deprotection–cyclization step in basic
media was required.
Several synthetic ways, proposed in the literature, allow
these compounds to be obtained and can be classified in
two groups: multi-steps stereoselective methods2 and
shorter racemic ways.1,3,4 Generally, the desired enan-
tiomer, sometimes present in moderate ee, has to be
isolated from the mixture of isomers.
Fowler et al.8 proposed the reduction of the addition
products with LiAlH4 which leads directly to the
expected pyrrolidine. In our case, a deprotection step
has to be added to this method in order to obtain later
the N-unsubstituted pyrrolidine (Scheme 2).
Buchwald’s method,5 based on a stereospecific catalytic
hydrogenation of a 2-aryl-pyrroline (5-aryl-3,4-dihydro-
2H-pyrrole) 1, appeared to be the most accurate for the
preparation of pure (R)- or (S)-2-aryl-pyrrolidine 2.
The ee values reported are so high (generally equal to
99%) that the mixture of enantiomers obtained may be
used without further separation (Scheme 1).
Our strategy is based on the transformation of the
starting lactam into a pyrroline bearing a leaving group
which acts as a protecting group in a first step, but
allows the formation of the double bond by sponta-
neous deprotection.
A first attempt had been described by Etienne and
Correia.3 The pyrrolidinone was O-methylated with
moderate yields using dimethyl sulfate in refluxing ben-
zene and reacted, after purification, with phenylmagne-
sium bromide in order to obtain 2-phenyl-pyrroline.
Therefore, we decided to investigate the general prepa-
ration of substituted 2-phenyl pyrrolines 1, starting
material for Buchwald’s reduction to the pyrrolidines 2.
One method starting from N-vinyl-pyrrolidinone has
been described to obtain a pyrroline substituted either
with a phenyl1 or a 3-pyridyl6 group, but we were not
able to reproduce the results published.1
We decided to improve this method and, at the same
time, to avoid the use of dimethyl sulfate and benzene.
Buchwald’s
Ar
Multi steps
" Chiral pool "
reactions
Ar
reduction
N
N
H
2 (R or S)
1
Scheme 1.
* Corresponding author. E-mail: kirsch@bridoux.sciences.univ-metz.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01192-3

6102
C. Coindet et al. / Tetrahedron Letters 42 (2001) 6101–6104
ClSiMe3
ArLi or
O
O
OSiMe3
Ar
N
N
H
N
N
ArMgBr
1
SiMe3
i) ArLi
ii) deprotection
iii) H+
protection
O
N
PG
Scheme 2.
We needed a reagent able to react specifically with the
oxygen atom leading to an intermediate compatible with
the use of an organometallic reagent in a second step.
cannot be used for the preparation of bromo- or
iodophenyl pyrrolines. Only substituted biphenyls have
been observed in appreciable amounts.
Blocking the lactam with a trimethylsilyl group, predom-
inantly located on the nitrogen atom, allows us to have
a better leaving group than the methoxy group and also
a group compatible with the use of organometallic
reagents. The reaction can be run as a one-pot procedure
since the silylated intermediate can be added without
purification to the organometallic derivative. The results
are given in Table 1. Silylation of pyrrolidinone leads to
two different isomers probably in equilibrium (see
This easy one-pot procedure provides other advantages.
The pyrrolines 2 obtained do not need to be further
purified and are easily collected, after the hydrolysis of
the crude reaction mixture with 1N HCl, by filtration or
by extraction with ether from the aqueous basified phase.
Of course, we do not need to follow a protection–depro-
tection procedure and all the reagents used are readily
accessible and easy to handle. On the other hand, the
great number of bromobenzene derivatives commercially
available makes the method really attractive.
1
Scheme 2) and H NMR confirms that this step was
quantitative. The purification of this intermediate can be
achieved by distillation but does not improve signifi-
cantly the yields of pyrroline 1, although only the
N-substituted pyrrolidinone has been detected and iden-
We must underline the fact that, to the best of our
knowledge, no substituted 2-aryl-pyrrolines are
described in the literature following a related method
since generally only the phenyl group is required.
1
tified by H NMR (data identical to those described in
Ref. 11) and NOESY experiments, which is in agreement
with previous 13C and 15N NMR9,10 studies.
In summary, we described here an alternative, easy to
handle one-pot method to prepare substituted 2-
arylpyrrolines. These compounds are easily obtained as
pure solids (or oils for 2-phenyl and 2-(4-trimethylsilyl)-
phenyl-pyrrolines) and can be directly reduced to the
expected pyrrolidines either in a racemic mixture or with
high ee using Buchwald’s method.
We must note that during our investigations we realized
that this strategy had been previously used but exclu-
sively for the preparation of 2-alkyl-pyrrolines and
analogues.11,12 The authors11 claimed that the use of
Grignard reagents could lead to the expected pyrroline
in poor yields due to a side reaction (apparently Grignard
reagent attacks the silyllactam at silicon) which is not in
agreement with our results. Nevertheless, we observed
that the results obtained with Grignard reagents were
much less reproducible than those using substituted
phenyl lithium ones. This may be an explanation for our
divergences. On the other hand, Grignard reagents
Experimental
Typical procedure for the preparation of 2-aryl-pyrrolines
1a–i. To a mixture of 2-pyrrolidinone (42.4 mmol) and
triethylamine (44.5 mmol) in diethyl ether was added
trimethylsilyl chloride (44.5 mmol) at 0°C under argon.
Table 1. Yields of pyrrolines 1 from 2-pyrrolidinone
1) (Me)3SiCl
2) ArLi or ArMgX
O
Ar
N
N
1
H
Structure of Ar
1 equiv. of ArMgBr (%)
1 equiv. of ArLi (%)
34
1a
1b
1c
1d
1e
1f
1g
1h
1i
Phenyl
90
35
45
47
3-Chloro-phenyl
4-Chloro-phenyl
4-Methoxy-phenyl
3-Bromo-phenyl
4-Bromo-phenyl
4-Iodo-phenyl
4-Trimethylsilyl-phenyl
2-Thienyl
24
45
50
41
25

C. Coindet et al. / Tetrahedron Letters 42 (2001) 6101–6104
6103
The reaction mixture was refluxed for 30 min, cooled at
room temperature, and filtrated. A solution of Grignard
reagent or aryl lithium (42.4 mmol) was added to the
filtrate at room temperature or at −30°C for aryl lithium
and allowed to warm to room temperature. The reaction
mixture was refluxed for 3 h and then quenched with 1N
hydrochloric acid. The aqueous solution was extracted
with diethyl ether and then made basic with 10% sodium
hydroxide. The basic phase was filtered off in order to
collect the pure pyrroline or extracted with diethyl ether,
dried over magnesium sulfate and concentrated under
vacuum when a Grignard reagent is used.
Product
Name
Physical data
1H NMR (250 MHz, CDCl3) 13C NMR (62.5 MHz, CDCl3)
1a
IR: wCN=1615 cm−1 7.82 (m, 2H)
173.08, 134.44,
130.10, 128.22,
127.42, 61.32, 34.73,
22.48
2-Phenylpyrroline
7.37 (m, 3H)
Oil
4.09 (m, 2H)
2.93 (m, 2H)
2.04 (m, 2H)
1b
IR: wCN=1619 cm−1 7.83 (s, 1H)
172.09, 136.32,
134.48, 130.21,
129.63, 127.69,
125.67, 61.55, 34.88,
22.62
2-(3-Chloro)phenylpyrroline
7.70 (d, 1H, J=7.4)
7.37 (m, 1H)
Mp 54°C
7.34 (d, 1H, J=7.4)
4.09 (m, 2H)
2.91 (m, 2H)
2.04 (m, 2H)
1c
IR: wCN=1622 cm−1 7.78 (d, 2H, J=8.5)
7.38 (d, 2H, J=8.5)
172.06, 136.22,
132.99, 128.81,
2-(4-2-(4-Chloro)-
phenylpyrroline
Mp 65–66°C
4.07 (m, 2H)
2.93 (m, 2H)
2.06 (t, 2H)
128.52, 61.49, 34.78,
22.61
1d
IR: wCN=1603 cm−1 7.78 (d, 2H, J=8.7)
6.91 (d, 2H, J=8.7)
Mp 74°C
172.44, 161.17,
129.05, 127.37,
113.59, 61.19, 55.16,
34.71, 22.60
2-(4-Methoxy)phenylpyrroline
4.02 (m, 2H)
3.83 (s, 3H)
2.90 (m, 2H)
2.01 (m, 2H)
1e
IR: wCN=1618 cm−1 8.00 (s, 1H)
171.98, 136.62,
133.13, 130.61,
129.91, 126.11,
2-(3-Bromo)phenylpyrroline
7.75 (d, 1H, J=8.0)
7.55 (d, 1H, J=7.8)
Mp 49–50°C
7.27 (dd, 1H, J=7.8, J=7.9) 122.64, 61.59, 34.86, 22.66
4.05 (m, 2H)
2.91 (m, 2H)
2.05 (m, 2H)
1f
IR: wCN=1623 cm−1 7.71 (d, 2H, J=8.5)
7.54 (d, 2H, J=8.5)
172.04, 135.51,
131.55, 129.08,
124.69, 61.61, 34.79,
22.67
2-(4-Bromo)phenylpyrroline
Mp 87°C
4.05 (m, 2H)
2.92 (m, 2H)
2.05 (m, 2H)
1g
IR: wCN=1608 cm−1 7.75 (d, 2H, J=8.4)
7.56 (d, 2H, J=8.4)
172.40, 137.56,
134.04, 129.17, 96.85,
61.62, 34.74, 22.66
2-(4-Iodo)phenylpyrroline
Mp 99°C
4.05 (m, 2H)
2.91 (m, 2H)
2.04 (m, 2H)
1h
IR: wCN=1614 cm−1 7.81 (d, 2H, J=7.9)
7.56 (d, 2H, J=7.9)
173.36, 143.35,
133.37, 126.90,
2-(4-Trimethylsilyl)-
phenylpyrroline
Oil
4.07 (m, 2H)
2.95 (m, 2H)
2.03 (m, 2H)
0.28 (s, 9H)
126.72, 61.53, 34.89,
22.63, −1.24
1i
IR: wCN=1609 cm−1 7.40 (d, 1H, J=5.0)
7.31 (d, 1H, J=3.7)
167.87, 139.64,
128.98, 128.90,
2-(2-Thienyl)pyrroline
Mp 52°C
7.06 (dd, 1H, J=3.7, J=5.0) 127.37, 61.28, 35.59, 23.01
4.03 (m, 2H)
2.93 (m, 2H)
2.04 (m, 2H)

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C. Coindet et al. / Tetrahedron Letters 42 (2001) 6101–6104
6. (a) Peyton, III, J. J. Org. Chem. 1982, 47, 4165;
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