A new method for the synthesis of plurisubstituted pyrroles

Article abstract of DOI:10.1016/j.tetlet.2003.09.099

A versatile method for the synthesis of pyrroles is described using an intramolecular [3+2] cycloaddition reaction. This method allows the expedient preparation of 'plurisubstituted' compounds in which functionality is incorporated by choice, using appropriate readily available starting materials. Polycyclic pyrrole derivatives as well as 2-aryl monocyclic analogues are described. Several families of compounds are synthesized by sequential transformations. The method is designed to allow the creation of libraries with increased diversity of functionality by combinatorial or parallel synthesis.

Full text of DOI:10.1016/j.tetlet.2003.09.099

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8417–8420
A new method for the synthesis of plurisubstituted pyrroles
George Bashiardes,* Imad Safir, Francis Barbot and Joelle Laduranty
De´partement de Chimie, SFA-UMR 6514, Universite´ de Poitiers, 40 avenue du Recteur Pineau, 86022 Poitiers, France
Received 19 August 2003; revised 4 September 2003; accepted 12 September 2003
Abstract—A versatile method for the synthesis of pyrroles is described using an intramolecular [3+2] cycloaddition reaction. This
method allows the expedient preparation of ‘plurisubstituted’ compounds in which functionality is incorporated by choice, using
appropriate readily available starting materials. Polycyclic pyrrole derivatives as well as 2-aryl monocyclic analogues are described.
Several families of compounds are synthesized by sequential transformations. The method is designed to allow the creation of
libraries with increased diversity of functionality by combinatorial or parallel synthesis.
© 2003 Elsevier Ltd. All rights reserved.
Pyrroles are important substructures of pharmaceuti-
cally important compounds and also of numerous natu-
ral products.1 The synthesis of pyrroles containing
various substituents with specifically required regio-
chemistry is a subject of continued research.2 In this
paper we describe a general synthesis for the prepara-
tion of pyrroles by use of the versatile [3+2] cycloaddi-
tion reaction.3 Our method is complementary to
existing procedures and overall yields are satisfactory.
Moreover the synthetic approach is particularly conve-
nient in that it was designed to accommodate parallel
synthetic or combinatorial preparations of diversified
libraries of pyrroles amenable to pharmaceutical
research and for new lead generation or lead optimiza-
tion. The approach we employed makes use of low cost,
easily available starting materials and mild experimen-
tal conditions, allowing for a large variety of sub-
hyde is readily alkylated using a propargylic halide in
DMF in the presence of potassium carbonate. Indeed, a
number of O-propargylic salicylaldehydes were pre-
pared in yields generally almost quantitative (Table 1).
The required compounds were extracted from the reac-
tion medium in excellent purity and required no further
purification. The choice of the propargylic reagents was
such that the resulting substituted salicylaldehydes had
diverse degrees of functionality in order to explore the
relative reactivity in the subsequent cycloaddition
reaction.
stituents.
In
our
approach,
O-propargylic
salicylaldehydes4 are treated with N-alkylglycinate
derivatives in a neutral solvent such as toluene at reflux,
then the reaction mixture is treated with manganese
dioxide at room temperature to provide directly the
required pyrroles (Scheme 1).
Scheme 1. Overall one-pot regioselective synthesis of
pyrroles.
Table 1. Preparation of O-propargylic salicylaldehydes
The initial, expected product which is a pyrroline is not
isolated by this procedure, although it is possible to
arrest the reaction at that stage. A variety of substituted
amino esters were used, either commercial or readily
available, alongside a number of different propargylic
derivatives of salicylic aldehyde containing varying
degrees of substitution and functionality. Salicylalde-
Entry
Halide
Product
Yield (%)
1
2
3
4
1a 3-bromopropyne
2a
2b
2c
2d
94
94
79
95
1b 3-bromo-1-phenylpropyne
1c 4-bromobut-2-yne
1d 3-bromobutyne
* Corresponding author. E-mail: georges.bashiardes@univ-poitiers.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.099

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G. Bashiardes et al. / Tetrahedron Letters 44 (2003) 8417–8420
were followed by thin layer chromatography (TLC) as
well as gas liquid chromatography (GLC). The interme-
diate D3-pyrrolines 4a–g were indeed formed and were
monitored by GLC during the course of the reaction
(Scheme 2). In some cases the D2-isomer and the corre-
sponding pyrrole were also observed. In order to char-
acterize all products formed, in some of the examples,
the three components were isolated by flash column
chromatography on silica gel and fully characterized.
However, this isolation step was not necessary and, in
fact, the crude reaction mixture was subsequently sim-
ply cooled to room temperature and treated directly
with manganese dioxide (MnO2).5 The overall yields of
tricyclic pyrroles were good, ranging from 50 to 96%
(Table 2). Such yields compare very favourably with
other methods.1
Figure 1. O-Propargylic salicylaldehydes 2a–d.
Table 2. Synthesis of pyrroles from O-propargylic salicyl-
aldehydes
Table 2 illustrates the reactants, the times of reaction
and the overall yields of pyrroles, starting from O-
propargylic salicylaldehydes (see Fig. 2 for structures).
Entry
Aldehyde/
aminoester
Time (h)
Product
Yield (%)
As a further investigation of the extent of the cycload-
dition reaction on O-propargylic salicylaldehydes with
amino acid derivatives, the reaction was investigated
using amino acids instead of amino esters. Thus, sar-
1
2
3
4
5
6
7
8
2a/3a
2a/3b
2b/3a
2b/3c
2c/3a
2c/3c
2d/3a
2d/3c
1.5
1.5
2.5
4.5
5
8
2
4.5
5a
5b
5c
5d
5e
5f
65
69
71
96
50
68
54
60
cosine 6a and N-methyl- -alanine 6b were employed.
L
We were hoping to observe in situ aromatizing decar-
boxylation, which would lead directly to pyrroles, ana-
logues to the examples above. However the products
obtained were the D3-pyrroline derivatives 4i–m, which
had not aromatized during the course of the reaction
(Table 3, below). Attempts to oxidize pyrrolines 4i–m
as described above were fruitless, probably due to the
lack of activating carboxylic substituents. Decarboxyla-
tion probably occurs during the reaction to provide the
azomethine ylide by a mechanism different to that with
the ester analogues.4 Nethertheless the oxidation of the
pyrrolines 4i–m was performed using Pd/C in refluxing
ethyl acetate3 giving pyrroles 7i–m in moderate to good
yields (Table 3, Fig. 3).
5g
5h
The chemistry of our pyrrole synthesis was further
extended by an interesting sequence of modifications, to
furnish monocyclic pyrroles 9 (Scheme 3). Thus, tri-
Scheme 2. Cycloaddition reactions of O-propargylic salicyl-
aldehydes and N-substituted glycinate esters, followed by
oxidation.
Starting secondary halide 3-bromobutyne 1d (entry 4)
and primary halide 4-bromobut-2-yne 1c (entry 3) were
prepared from the corresponding propargylic alcohol
by treatment with phosphorus tribromide (PBr3), in
67% and 89% yields, respectively (Fig. 1).
Compounds 2a–d were then treated with 2 equivalents
of N-alkylglycinate derivatives 3a–d in anhydrous tolu-
ene at reflux for varying times (Table 2). The reactions
Figure 2. Pyrroles synthesized by cycloaddition.

G. Bashiardes et al. / Tetrahedron Letters 44 (2003) 8417–8420
8419
Table 3. Cycloaddition in presence of sarcosine and N-
methyl- -alanine and aromatization giving the correspond-
ing pyrroles
new lactonic compounds are now susceptible to attack
and ring-opening by nucleophiles leading to ‘function-
alising simplification’. We have currently only exploited
this possibility using potassium hydroxide7 in alcoholic
solvents, but further work is underway to employ other
heteroatomic or carbon-based nucleophiles.
L
Following nucleophilic attack and ring-opening by
alkoxide anion, the monocyclic pyrroles below were
obtained (Table 5 and Figs. 4 and 5).
Typical experimental procedure for cycloaddition and
typical spectral data: To a solution of 6.25 mmol of
O-propargylic salicylaldehyde 2 in toluene or xylene
were added 12.5 mmol of amino ester 3. The resulting
solution was heated to reflux, preferably using a Dean-
Entry
Aldehyde/amino Pyrrolines/yield
Pyrroles/yield
(%)
acid
(%)
1
2
3
4
5
2a/6a
2b/6a
2d/6a
2a/6b
2b/6b
4i/87
4j/72
4k/69
4l/64
4m/68
7i/57
7j/54
7k/56
7l/72
7m/57
Table 5. Nucleophilic ring-opening of coumarin com-
pounds (step 2)
Entry
Coumarin
Time (h)
Product
Yield (%)
1
2
3
4
8a
8d
8e
8f
2
2
2
2
9a
9d
9e
9f
62
54
62
68
Figure 3. Pyrroles synthesized by cycloaddition of amino
acids followed by oxidation with Pd/C.
Figure 4. Coumarin compounds obtained by oxidation with
PCC.
Scheme 3. Modification and ‘functionalising simplification’ of
tricyclic pyrroles.
cyclic pyrroles 5a–f were first transformed to their
corresponding coumarin analogues by oxidation using
pyridinium chlorochromate (PCC) (Table 4).6 These
Table 4. PCC oxidation to coumarin compounds (step 1)
Entry
Pyrrole
Time (h)
Product
Yield (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
22
20
17
20
24
16.5
8a
8b
8c
8d
8e
8f
65
69
71
96
50
68
Figure 5. Monocyclic pyrroles. * The letters in the numbering
are maintained so as to coincide with substituent patterns in
all series.

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G. Bashiardes et al. / Tetrahedron Letters 44 (2003) 8417–8420
Acknowledgements
Stark apparatus, and the reaction was monitored by
thin layer chromatography (TLC) or gas chromato-
graphy (GC) until total consumption of the aldehyde.
We wish to thank Professors J. P. Gesson and J. C.
Jacquesy.
After cooling to room temperature, an excess (156
mmol) of activated manganese dioxide was added and
the mixture was stirred for 20 h. The mixture is then
filtered on celite to remove the oxidant and the
resulting solution was evaporated to dryness. The
crude mixture was then purified by column chro-
matography on silica gel to provide pyrrole 5. Exam-
ple 5d: NMR 1H (CDCl3): 7.50–7.10 (m, 12H); 6.70
(dd, 1H, J 1.2 and 8.1 Hz); 6.82 (td, 1H, J 1.2 and
7.6 Hz); 5.90 (s, 2H); 5.04 (s, 2H); 3.96 (q, 2H, J 7.1
Hz); 0.86 (t, 3H, J 7.1 Hz).
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In conclusion, this paper describes the use of a ver-
satile [3+2] cycloaddition reaction for the synthesis of
a variety of pyrroles. Regiochemically-controlled for-
mation of tricyclic pyrroles proceeded in high yields.
These compounds were then sequentially transformed
into coumarins, then to monocyclic 2-arylpyrroles by
nucleophilic ring-opening. The reaction was explored
using various substitutions in order to study the con-
sequences of increased steric or activating effects, and
provides diversity of molecular structures. The
method is complementary to other syntheses of
pyrroles with overall yields that compare favourably.
Moreover, this approach allows the creation of diver-
sity by simple choice of readily-available starting
materials.
1983, 165–180.