An expeditious synthesis of n-substituted pyrroles via microwave-induced iodine-catalyzed reactions under solventless conditions

Article abstract of DOI:10.3390/molecules15042520

An expeditious synthesis of N-substituted pyrroles has been developed by reacting 2,5-dimethoxy tetrahydrofuran and several amines using a microwave-induced molecular iodine-catalyzed reaction under solventless conditions. Copyright

Full text of DOI:10.3390/molecules15042520

Molecules 2010, 15, 2520-2525; doi:10.3390/molecules15042520
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
An Expeditious Synthesis of N-substituted Pyrroles via
Microwave-Induced Iodine-Catalyzed Reactions under
Solventless Conditions
Debasish Bandyopadhyay, Sanghamitra Mukherjee and Bimal K. Banik*
Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive,
Edinburg, TX 78541, USA
*
Author to whom correspondence should be addressed; E-Mail: banik@panam.edu;
Tel.: +956-380 8741; Fax: +956-384-5006.
Received: 20 January 2010; in revised form: 1 March 2010 / Accepted: 2 April 2010 /
Published: 9 April 2010
Abstract: An expeditious synthesis of N-substituted pyrroles has been developed by
reacting 2,5-dimethoxy tetrahydrofuran and several amines using a microwave-induced
molecular iodine-catalyzed reaction under solventless conditions.
Keywords: pyrrole; molecular iodine; microwave irradiation; solventless reaction
1
. Introduction
Pyrroles are an important class of organic compounds with different types of medicinal
activities [1,2], consequently, many methods for the synthesis of diversely substituted pyrroles have
been developed [3]. However, the most reliable method for the synthesis of pyrroles is the Paal-Knorr
reaction [4,5]. Because of the biological activities of our polyaromatic compounds [6–10], we became
interested in the synthesis of pyrroles bound to the amines of different structures. We describe here a
simple method of synthesis of N-substituted pyrroles by reacting 2,5-dimethoxytetrahydrofuran (1) and
various amines in the absence of any solvent in a microwave oven in the presence of catalytic amounts
(
~5 mol%) of molecular iodine. This reaction produces pyrroles in excellent yield and within a short
time under (Scheme 1).

Molecules 2010, 15
Scheme 1. Iodine-catalyzed microwave-induced synthesis of N-substituted pyrroles.
2521
I2/MWI
R
NH2
N
R
2
O
MeO
OMe
1
3
2
. Results and Discussion
This reaction has been tested by reacting different types of amines 2 and 2,5-dimethoxy-
tetrahydrofuran in a microwave oven in the presence of molecular iodine as a catalyst. The reaction
yields the products extremely well in the absence of any solvent. Reaction conditions and the yields of
the products are shown in Table 1. Both aliphatic and aromatic amines produce pyrroles in very high
yield. Importantly, the reaction produces product with multicyclic aromatic amines. A diamine (entry
9
) and a heteropolyaromatic amine (entry 10) required higher temperature and longer reaction times,
probably due to the diminished availability of the nitrogen (amine) lone pair.
We hypothesized that our work on iodine-catalyzed [11–16] reactions on acetal and glycosylation
might prove useful for the facile synthesis of pyrroles under mild conditions. The methoxy groups in
2
,5-dimethoxytetrahydrofuran (1) can be deprotected under mild acidic conditions and microwave
irradiation. The intermediate can easily form the dialdehyde 5. On reaction with amines and the
dialdehyde, pyrroles 3 can be prepared following a nucleophilic addition and subsequent dehydration-
1
aromatization route (Scheme 2). After irradiating a CDCl solution of 1 for 5 minutes, H-NMR has
3
been taken. A downfield signal due to the –CHO group is observed. The intensity of the –CHO group
1
becomes more predominant in the H-NMR when 1 was irradiated in CDCl
3
in the presence of
catalytic amounts of iodine. This suggests the facile formation of dialdehyde 5 in the reaction media in
the presence of iodine and microwave irradiation.
Scheme 2. Iodine-catalyzed pyrrole synthesis: plausible mechanism of the reaction.
The presence of small amount of iodine (~5 mol %) is essential for the success of the reaction.

Molecules 2010, 15
Table 1. Microwave-induced iodine-catalyzed synthesis of pyrroles.
2522
3. Experimental
3.1. General
Melting points were determined in a Fisher Scientific electrochemical Mel-Temp* manual melting
point apparatus (Model 1001) equipped with a 300 °C thermometer. Elemental analyses (C, H, N)

Molecules 2010, 15
2523
were conducted using the Perkin-Elmer 2400 series II elemental analyzer, their results were found to
be in good agreement (± 0.2%) with the calculated values for C, H, N. FT-IR spectra were registered
1
13
on a Bruker IFS 55 Equinox FTIR spectrophotometer as KBr discs. H-NMR (300 MHz) and C-
NMR (75.4 MHz) spectra were obtained at room temperature with JEOL Eclipse-300 equipment using
TMS as internal standard and CDCl as solvent. Analytical grade chemicals (Sigma-Aldrich
3
Corporation) were used throughout the project. Deionized water was used for the preparation of all
aqueous solutions.
3
.2. General procedure for the synthesis of pyrroles (3)
Amine 2 (1.0 mmol), 2,5-dimethoxytetrahydrofuran (1, 1.2 mmol) and iodine (5 mol%) was
irradiated in a CEM automated microwave oven, as specified in Table 1. After completion of the
reaction (monitored by TLC) diethyl ether (10 mL) was added to the reaction mixture which was then
filtered. Pure product was isolated from the reaction mixture after evaporation of ether. Spectroscopic
data for representative compounds, e.g. monoaromatic (entries 1 and 2), alicyclic (entry 5),
polyaromatic (entries 6 and 7) as well as heteropolyaromatic (entry 10) are as follows:
-
1 1
1
-Phenyl-1H-pyrrole (3a, entry 1). Brown sticky oil. IR: 2923, 1312, 1106, 782, 611 cm ; H-NMR δ
13
(
ppm): 6.39 (m, 2H, pyrrole), 7.24 (d, 2H, J = 3.12, pyrrole), 7.42–7.53 (m, 5H, Ar-H); C-NMR δ
ppm): 109.07 (2C), 115.51 (2C), 122.96 (2C), 124.57, 128.62 (2C), 137.08. Anal. Calcd. for C10 N:
(
H
9
C, 83.88; H, 6.34; N, 9.78. Experimental: C, 83.79; H, 6.31; N, 8.72.
1
-(4-Methoxyphenyl)-1H-pyrrole (3b, entry 2). Black amorphous solid. Solidified from
-1 1
dichloromethane/hexane mixture; Mp: 89 °C; IR: 2954, 1301, 1191, 850, 748 cm ; H-NMR δ (ppm):
1
3
3
.87 (s, 3H, OCH
δ (ppm): 55.66 (OCH
Calcd for C11 11NO: C, 76.28; H, 6.40; N, 8.09. Experimental: C, 76.20; H, 6.27; N, 7.97.
3
), 6.33 (m, 2H, pyrrole), 6.67 (d, 2H, J = 3.30), 6.96–7.73(m, 4H, Ar-H); C-NMR
3
), 109.93 (2C), 114.71 (2C), 120.15 (2C), 126.07 (2C), 132.56, 158.21. Anal.
H
1
-(Adamntan-1-yl)-1H-pyrrole (3e, entry 5). Yellow crystals. Crystallized from diethyl ether/hexane
-1 1
mixture; Mp: 71 °C; IR: 2923, 2855, 1479, 1450, 1219, 713, 619 cm ; H-NMR δ (ppm): 1.77 (m,
1
3
3
H), 2.12 (d, 6H, J = 3.00), 2.23 (m, 6H), 6.19 (t, 2H, J = 2.19, pyrrole), 6.91(m, 2H, pyrrole); C-
NMR δ (ppm): 29.79 (3C), 36.35 (3C), 44.04 (3C), 55.00, 107.24 (2C), 116.55 (2C). Anal. Calcd for
19N: C, 83.53; H, 9.51; N, 6.96. Experimental: C, 83.41; H, 9.50; N, 6.89.
14
C H
1
-(Chrysen-6-yl)-1H-pyrrole (3f, entry 6). Brown crystals. Crystallized from ethyl acetate/hexane
-1 1
mixture; Mp: 139 °C; IR: 2947, 2924, 1513, 1461, 1071, 812 cm ; H-NMR δ (ppm): 6.49 (t, 2H,
13
J = 2.21, pyrrole), 7.12 (m, 2H, pyrrole), 7.70–8.72 (m, 11H, Ar-H); C-NMR δ (ppm): 109.27 (2C),
20.98, 121.29 (2C), 123.23, 123.49 (2C), 123.64 (2C), 124.05, 126.45 (2C), 126.75 (2C), 126.88
2C), 127.42, 128.64 (2C), 132.26, 137.94. Anal. Calcd for C H N: C, 90.08; H, 5.15; N, 4.77.
1
(
2
2
15
Experimental: C, 89.91; H, 5.04; N, 4.76.
1
-(Pyren-1-yl)-1H-pyrrole (3g, entry 7). Pale yellow crystals. Crystallized from diethyl ether/hexane
-1
1
mixture; Mp: 78 °C; IR: 2956, 2927,1598, 1511, 1304, 1072, 848 cm ; H-NMR δ (ppm): 6.53
13
(
m, 2H, pyrrole), 7.15 (m, 2H, pyrrole), 8.01–8.19 (m, 9H, Ar-H); C-NMR δ (ppm): 109.45 (2C),

Molecules 2010, 15
2524
122.36, 123.83 (2C), 124.89, 125.42, 126.51, 126.72, 127.19, 127.89 (2C), 128.63 (2C), 128.92,
1
30.62, 131.01, 131.39, 133.43, 135.97. Anal. Calcd for C H N: C, 89.86; H, 4.90; N, 5.24.
2
0
13
Experimental: C, 89.77; H, 4.81; N, 5.17.
5
-(1H-Pyrrol-1-yl)-1,10-phenanthroline (3j, entry 10). Yellowish brown amorphous solid. Solidified
-1 1
from methanol/hexane mixture; Mp: 192 °C; IR: 3186, 2362, 2336, 1591, 1539, 1074, 739 cm ; H-
1
3
NMR δ (ppm): 6.44 (broad s, 2H, pyrrole), 7.02 (broad s, 2H, pyrrole), 7.62–9.20 (m, 7H, Ar-H); C-
NMR δ (ppm): 110.14 (2C), 122.79, 123.24 (2C), 123.55 (2C), 123.74 (2C), 129.04, 132.26, 136.17,
1
43.91, 144.09, 150.80, 150.91. Anal. Calcd for C H N : C, 78.35; H, 4.52; N, 17.13. Experimental:
16 11 3
C, 78.23; H, 4.43; N, 17.02.
4
. Conclusions
In summary, the present iodine-catalyzed microwave-induced method in the absence of any solvent
is excellent for the preparation of N-substituted pyrroles (75–98% yields). Because of the simplicity of
the procedure, products can be isolated very easily. The compounds reported herein will be tested
against a number of cancer cells in vitro.
Acknowledgements
We gratefully acknowledge the funding support from National Cancer Institute (NIH/NCI-P20,
Grant# 5P20CA138022-02).
References and Notes
1
2
3
4
. Lainton, J.A.H.; Hoffman, J.W.; Martin, D.R.; Compton, D.R. 1-Alkyl-3-(1-naphthoyl)pyrroles: a
new class of cannabinoid. Tetrahedron Lett. 1995, 36, 1401–1404.
. de Leon, C.Y.; Ganem, B. A new approach to porphobilinogen and its analogs. Tetrahedron 1997,
5
3, 7731–7752.
. Gilchrist, T.L. Synthesis of aromatic heterocycles. J. Chem. Soc., Perkin Trans 1 1998, 615–628
and references cited therein.
. Ruault, P.; Pilard, J-F.; Touaux, B.; Boullet, F.T.; Hamelin, J. Rapid generation of amines by
microwave irradiation of ureas dispersed on clay. Synlett 1994, 935–936.
5
. Danks, T.N. Microwave assisted synthesis of pyrroles. Tetrahedron Lett. 1999, 40, 3957–3960.
. Becker, F.F.; Banik, B.K. Polycyclic aromatic compounds as anticancer agents: synthesis and
biological evaluation of some chrysene derivatives. Bioorg. Med. Chem. Lett. 1998,
6
8
, 2877–2880.
7
. Becker, F.F.; Mukhopadhyay, C.; Hackfeld, L.; Banik, I.; Banik, B.K. Polycyclic aromatic
compounds as anticancer agents: synthesis and biological evaluation of dibenzofluorene
derivatives. Bioorg. Med. Chem. 2000, 8, 2693–2699.
8
. Banik, B.K.; Becker, F.F. Polycyclic aromatic compounds as anticancer agents. 4. Structure-
activity relationships of chrysene and pyrene derivatives. Bioorg. Med. Chem. 2001, 9, 593–605.

Molecules 2010, 15
2525
9
. Banik, B.K.; Becker, F.F. Synthesis, electrophilic substitution and structure-activity relationship
studies of polycyclic aromatic compounds towards the development of anticancer agents. Curr.
Med. Chem. 2001, 8, 1513–1533.
1
1
1
1
0. Banik, I.; Becker, F.F.; Banik, B.K. Stereoselective Synthesis of β-Lactams with Polyaromatic
Imines: Entry to New and Novel Anticancer Agents. J. Med. Chem. 2003, 46, 12–15.
1. Banik, B.K.; Manhas, M.S.; Bose, A.K. Stereospecific Glycosylation via Ferrier Rearrangement
for Optical Resolution. J. Org. Chem. 1994, 59, 4714–4716.
2. Banik, B.K.; Manhas, M.S.; Bose, A.K. Studies on lactams. 103. Enantiopure α-hydroxy-β-
lactams via stereoselective glycosylation. Tetrahedron Lett. 1997, 38, 5077–5080.
3. Banik, B.K.; Zegrocka, O. Manhas, M.S.; Bose, A.K. Studies on lactams. 104. Enantiomerically
pure β-lactams with the thienamycin side chain via glycosylation. Heterocycles 1997,
2
7, 173–176.
14. Banik, B.K.; Fernandez, M.; Alvarez, C. Iodine-catalyzed highly efficient Michael reaction of
indoles under solvent-free condition. Tetrahedron Lett. 2005, 46, 2479–2482.
15. Banik, B.K.; Garcia, I.; Morales, F.; Aguilar, C. Novel synthesis of substituted pyrrole bound to
indolinone via molecular iodine-catalyzed reaction. Heterocycl. Commun. 2007, 13, 109–112.
16. Banik, B.K.; Garza, R. Molecular iodine-catalyzed deprotection of acetals and ketals in acetone.
Chem. Edu. 2007, 12, 75–76.
Sample Availability: Samples of the compounds are available from the authors.
2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
©
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).