Facile synthesis of N-substituted pyrroles via microwave-induced bismuth nitrate-catalyzed reaction

Article abstract of DOI:10.1016/j.tetlet.2009.06.002

Simple synthesis of N-substituted pyrroles using microwave-induced bismuth nitrate-catalyzed reaction has been accomplished with an excellent yield. A plausible mechanism has been advanced. This reaction also provides a simple method to prepare diverse varieties of N-substituted pyrrole derivatives with less nucleophilic polyaromatic amines.

Full text of DOI:10.1016/j.tetlet.2009.06.002

Tetrahedron Letters 50 (2009) 5445–5448
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of N-substituted pyrroles via microwave-induced bismuth
nitrate-catalyzed reaction
*
Sonya Rivera , Debasish Bandyopadhyay, Bimal K. Banik
The University of Texas Pan American, Department of Chemistry, 1201 West University Drive, Edinburg, TX 78539, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple synthesis of N-substituted pyrroles using microwave-induced bismuth nitrate-catalyzed reaction
has been accomplished with an excellent yield. A plausible mechanism has been advanced. This reaction
also provides a simple method to prepare diverse varieties of N-substituted pyrrole derivatives with less
nucleophilic polyaromatic amines.
Received 13 April 2009
Revised 25 May 2009
Accepted 1 June 2009
Available online 6 June 2009
Ó 2009 Published by Elsevier Ltd.
Keywords:
Pyrrole synthesis
Bismuth nitrate
Microwave irradiation
Polyaromatic compounds
1. Introduction
ical activity of these compounds. Because of the biological
activities of these derivatives, we became interested in the synthe-
Pyrroles are an important class of compounds with different
biological activities.1 Many methods for the synthesis of diversely
substituted pyrroles have been developed.2 Conjugate addition
reactions,3 transition metal-mediated reactions,4 reductive cou-
plings,5 aza-Wittig reactions,6 and other multistep operations7
have been performed for the synthesis of pyrroles. Despite these
huge developments, the Paal-Knorr8 reaction is considered to be
the most attractive method for the synthesis of pyrroles. In this
Letter, we describe a simple method for synthesis of N-substituted
pyrroles starting from commercially available 2, 5-dimethoxytet-
rahydrofuran and various (aliphatic, aromatic, heteroaromatic,
and polyaromatic) amines by bismuth nitrate-catalyzed reaction
in a microwave oven. This reaction is extremely rapid and pro-
duces products in excellent yields.
sis of pyrroles bound to the amines of different structures. Since
Paal–Knorr method requires a 1,4-dicarbonyl compound and Lewis
acids as catalysts, we envision that our work on bismuth nitrate-
catalyzed10 reactions on acetal and glycosylation may prove useful
for the facile synthesis of pyrroles under mild conditions if we se-
lect 2, 5-dimethoxytetrahydrofuran (1) as one of the reactants. Our
hypothesis has been tested by reacting different types of amines
(2) and 2,5-dimethoxytetrahydrofuran in a microwave oven in
the presence of bismuth nitrate as a catalyst. It is remarkable to
note that the reaction proceeded extremely well in the absence
of any solvent.11 However, solvent can also be used. Reactions per-
formed without solvent (Table 1, entries 1, 4, and 7) are faster and
high yielding than those performed in THF and water (Table 1, en-
tries 2, 3, 5, 6, 8, and 9). Most of the reactions are completed within
5–15 min of irradiation at 75 °C and at 300 W power level. The
yields of the products are also shown in Table 1. Aliphatic and aro-
matic amines produce pyrroles in very high yields. Importantly, the
reaction with naphthylamine proceeded faster than that with
monocyclic aromatic amino compounds (Scheme 1 and Table 1).
This method has been applied with other bismuth-based reagents
in catalytic proportion (5–10 mol %; bismuth chloride, bismuth
subnitrate, bismuth oxide, and bismuth bromide). Stannic chloride,
zinc chloride, and boron trifluoride etherate failed to improve the
yield of the products. The best results have been observed with bis-
muth nitrate as the catalyst.
2. Results and discussion
Our research group demonstrated several studies directed
toward the synthesis of b-lactams and polycyclic aromatic com-
pounds. We9 performed a structure–activity relationship study of
various polyaromatic compounds toward the development of no-
vel anticancer agents. It was reported that the modification of
the terminal heterocyclic ring is crucial in determining the biolog-
* Corresponding author.
E-mail addresses: bkbanik04@yahoo.com, banik@panam.edu (B.K. Banik).
Undergraduate research participant.
The methoxy groups in 1 can be deprotected under acidic con-
ditions and microwave irradiation. The intermediate can easily
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.06.002

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S. Rivera et al. / Tetrahedron Letters 50 (2009) 5445–5448
Bi(NO3)3.5H2O
R
NH2
N
R
MWI
2
3
O
MeO
OMe
1
Scheme 1.
Table 1
Bismuth nitrate pentahydrate-catalyzed microwave-assisted synthesis of pyrroles from the reaction between amine (1 mmol) and 2,5-dimethoxytetrahydrofuran (1 mmol)
Entry
1
RNH2
Solvent
Bi(NO3)3Á5H2O (mg)
MWI (temp/time/pressure)
Yielda (%)
Neat
20
300 W 90 °C 5 min
100
NH2
2
3
THF
H2O
50
20
300 W 75 °C 15 min
300 W 90 °C 5 min
90
95
NH2
NH2
OCH3
4
5
Neat
THF
30
40
300 W 90 °C 10 min
300 W 90 °C 10 min
95
85
NH2
OCH3
NH2
OCH3
6
7
H2O
Neat
THF
H2O
Neat
THF
Neat
30
20
20
20
20
30
20
300 W 90 °C 10 min
300 W 75 °C 5 min
300 W 90 °C 10 min
300 W 90 °C 10 min
300 W 90 °C 10 min
300 W 140 °C 40 min
300 W 110 °C 40 min
85
100
90
95
85
74
92
NH2
NH2
NH2
NH2
8
9
NH2
10
11
NH2
NO2
NH2
12
O2N
a
NMR indicated the formation of the product without any side reactions. Starting materials were consumed completely.
form the reactive dialdehyde 2. The reactive dialdehyde 2 on reac-
tion with amines can lead to pyrroles 3 following a nucleophilic
addition and subsequent dehydration-aromatization route. This
reaction suggests the capability of bismuth nitrate to serve as a
Lewis activator (Scheme 2).
Proton NMR spectroscopy has been used to strengthen the
proposed mechanism as shown in Scheme 2. 1H NMR has been
taken upon irradiation of a CDCl3 solution of 1 for 5 min. A down-
field signal due to the –CHO group is observed. The intensity of the
–CHO group becomes more predominant in the 1H NMR when 1 is

S. Rivera et al. / Tetrahedron Letters 50 (2009) 5445–5448
5447
Bi(NO3)3.5H2O
MWI
O
1
O
O
MeO
OMe
O
H
O
O
H
5
4
R
NH2
N
R
3
Scheme 2. Bismuth nitrate-catalyzed pyrrole synthesis: plausible mechanism of the reaction.
Table 2
Microwave-induced synthesis of pyrroles attached with polyaromatic/heteroaromatic systems
Entry
Anime
Solvent
Bi(NO3)3Á5H2O (mg)
MWI (power/temp/time)
Product
Yielda (%)
85
NH2
N
1
THF
20
300 W 120 °C 5 min
NH2
N
2
3
4
THF
THF
THF
20
20
20
300 W 110 °C 15 min
300 W 120 °C 5 min
300 W 150 °C 35 min
82
89
80
NH2
N
NH2
NH2
N
N
NH2
N
N
5
6
THF
THF
Neat
20
20
20
300 W 150 °C 50 min
300 W 110 °C 30 min
300 W 90 °C 5 min
77
82
95
N
N
N
NH2
N
N
N
N
7
N
NH2
N
a
NMR indicated the formation of the product without any side reactions. Starting materials were consumed completely.
irradiated in CDCl3 in the presence of catalytic amounts of bismuth
nitrate. This suggests the formation of 5 in the reaction media in
the presence of bismuth nitrate and microwave irradiation.
The reaction between 1 and 2 can give pyrrole (about 60%) in
the absence of bismuth nitrate on irradiation of the reaction mix-
ture for a long time. However, in the presence of bismuth nitrate,

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S. Rivera et al. / Tetrahedron Letters 50 (2009) 5445–5448
in most of the cases, the reaction gives products within 5–15 min
(Table 1). The presence of small amounts of bismuth nitrate
(ꢀ5 mol %) is necessary for the success of the reaction. The reaction
fails to produce the product in satisfactory yields at room temper-
ature (without microwave irradiation), the reaction produces the
product in a low yield at a high temperature (150 °C, 1 h, without
microwave irradiation) along with uncharacterized materials.
As part of our continuous research9 in the field of polyaromatic
anticancer drug development, we have applied our newly devel-
oped procedure in the synthesis of polyaromatic and heteroaro-
matic pyrrole derivatives. It has been found that the method is
equally effective with much less nucleophilic amines. However,
for polyaromatic amines, THF is the solvent of choice for the prep-
aration of N-substituted pyrroles. Polyaromatic amines are not sol-
uble in water. It has also been found that these types of compounds
give poor yields of products in the absence of a solvent. The results
are summarized in Table 2.
In conclusion, the present bismuth nitrate-catalyzed micro-
wave-induced method is superior to the other Lewis acid-mediated
syntheses of N-substituted pyrroles in terms of yield of the prod-
ucts (more than 85–100% yields) and time of the reaction. The de-
scribed synthetic protocol allows for the preparation of a variety of
pyrroles without the use of expensive or sensitive reagents. Based
on the simplicity of the procedure, products can be isolated very
easily. The method as reported herein may find applications in
other areas of research.
Acknowledgment
We gratefully acknowledge the funding support from the NIH-
SCORE (Grant # 2S06M008038-37).
References and notes
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3. Experimental
General procedure for the synthesis of pyrroles (3): Amine 1
(1.0 mmol),2,5-dimethoxytetrahydrofuran(1.2 mmol),andbismuth
nitrate pentahydrate (10–30 mg) were irradiated in a CEM auto-
mated microwave oven as specified in Table 1. Ether (10 mL) was
added to the reaction mixture and it was then filtered. Pure product
was isolated from the reaction mixture after evaporation of ether.