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An Expeditious Synthesis of N-substituted Pyrroles via Microwave-Induced Iodine-Catalyzed Reactions under Solventless Conditions

Debasish Bandyopadhyay
Sanghamitra Mukherjee
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.
Molecules 2010, 15(4), 2520-2525;
Submission received: 20 January 2010 / Revised: 1 March 2010 / Accepted: 2 April 2010 / Published: 9 April 2010
(This article belongs to the Special Issue Organic Iodine Chemistry)


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.

Graphical Abstract

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 [6,7,8,9,10], 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).
Scheme 1. Iodine-catalyzed microwave-induced synthesis of N-substituted pyrroles.
Scheme 1. Iodine-catalyzed microwave-induced synthesis of N-substituted pyrroles.
Molecules 15 02520 g001

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 [11,12,13,14,15,16] 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-aromatization route (Scheme 2). After irradiating a CDCl3 solution of 1 for 5 minutes, 1H-NMR has been taken. A downfield signal due to the –CHO group is observed. The intensity of the –CHO group becomes more predominant in the 1H-NMR when 1 was irradiated in CDCl3 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.
Scheme 2. Iodine-catalyzed pyrrole synthesis: plausible mechanism of the reaction.
Molecules 15 02520 g002
The presence of small amount of iodine (~5 mol %) is essential for the success of the reaction.
Table 1. Microwave-induced iodine-catalyzed synthesis of pyrroles.
Table 1. Microwave-induced iodine-catalyzed synthesis of pyrroles.
Molecules 15 02520 i001

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) 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 on a Bruker IFS 55 Equinox FTIR spectrophotometer as KBr discs. 1H-NMR (300 MHz) and 13C-NMR (75.4 MHz) spectra were obtained at room temperature with JEOL Eclipse-300 equipment using TMS as internal standard and CDCl3 as solvent. Analytical grade chemicals (Sigma-Aldrich 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-Phenyl-1H-pyrrole (3a, entry 1). Brown sticky oil. IR: 2923, 1312, 1106, 782, 611 cm-1; 1H-NMR δ (ppm): 6.39 (m, 2H, pyrrole), 7.24 (d, 2H, J = 3.12, pyrrole), 7.42–7.53 (m, 5H, Ar-H); 13C-NMR δ (ppm): 109.07 (2C), 115.51 (2C), 122.96 (2C), 124.57, 128.62 (2C), 137.08. Anal. Calcd. for C10H9N: 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 dichloromethane/hexane mixture; Mp: 89 °C; IR: 2954, 1301, 1191, 850, 748 cm-1; 1H-NMR δ (ppm): 3.87 (s, 3H, OCH3), 6.33 (m, 2H, pyrrole), 6.67 (d, 2H, J = 3.30), 6.96–7.73(m, 4H, Ar-H); 13C-NMR δ (ppm): 55.66 (OCH3), 109.93 (2C), 114.71 (2C), 120.15 (2C), 126.07 (2C), 132.56, 158.21. Anal. Calcd for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Experimental: C, 76.20; H, 6.27; N, 7.97.
1-(Adamntan-1-yl)-1H-pyrrole (3e, entry 5). Yellow crystals. Crystallized from diethyl ether/hexane mixture; Mp: 71 °C; IR: 2923, 2855, 1479, 1450, 1219, 713, 619 cm-1; 1H-NMR δ (ppm): 1.77 (m, 3H), 2.12 (d, 6H, J = 3.00), 2.23 (m, 6H), 6.19 (t, 2H, J = 2.19, pyrrole), 6.91(m, 2H, pyrrole); 13C-NMR δ (ppm): 29.79 (3C), 36.35 (3C), 44.04 (3C), 55.00, 107.24 (2C), 116.55 (2C). Anal. Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Experimental: C, 83.41; H, 9.50; N, 6.89.
1-(Chrysen-6-yl)-1H-pyrrole (3f, entry 6). Brown crystals. Crystallized from ethyl acetate/hexane mixture; Mp: 139 °C; IR: 2947, 2924, 1513, 1461, 1071, 812 cm-1; 1H-NMR δ (ppm): 6.49 (t, 2H, J = 2.21, pyrrole), 7.12 (m, 2H, pyrrole), 7.70–8.72 (m, 11H, Ar-H); 13C-NMR δ (ppm): 109.27 (2C), 120.98, 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 C22H15N: C, 90.08; H, 5.15; N, 4.77. 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 mixture; Mp: 78 °C; IR: 2956, 2927,1598, 1511, 1304, 1072, 848 cm-1; 1H-NMR δ (ppm): 6.53 (m, 2H, pyrrole), 7.15 (m, 2H, pyrrole), 8.01–8.19 (m, 9H, Ar-H); 13C-NMR δ (ppm): 109.45 (2C), 122.36, 123.83 (2C), 124.89, 125.42, 126.51, 126.72, 127.19, 127.89 (2C), 128.63 (2C), 128.92, 130.62, 131.01, 131.39, 133.43, 135.97. Anal. Calcd for C20H13N: C, 89.86; H, 4.90; N, 5.24. 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 from methanol/hexane mixture; Mp: 192 °C; IR: 3186, 2362, 2336, 1591, 1539, 1074, 739 cm-1; 1H-NMR δ (ppm): 6.44 (broad s, 2H, pyrrole), 7.02 (broad s, 2H, pyrrole), 7.62–9.20 (m, 7H, Ar-H); 13C-NMR δ (ppm): 110.14 (2C), 122.79, 123.24 (2C), 123.55 (2C), 123.74 (2C), 129.04, 132.26, 136.17, 143.91, 144.09, 150.80, 150.91. Anal. Calcd for C16H11N3: C, 78.35; H, 4.52; N, 17.13. Experimental: 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.


We gratefully acknowledge the funding support from National Cancer Institute (NIH/NCI-P20, Grant# 5P20CA138022-02).
  • Sample Availability: Samples of the compounds are available from the authors.

References and Notes

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MDPI and ACS Style

Bandyopadhyay, D.; Mukherjee, S.; Banik, B.K. An Expeditious Synthesis of N-substituted Pyrroles via Microwave-Induced Iodine-Catalyzed Reactions under Solventless Conditions. Molecules 2010, 15, 2520-2525.

AMA Style

Bandyopadhyay D, Mukherjee S, Banik BK. An Expeditious Synthesis of N-substituted Pyrroles via Microwave-Induced Iodine-Catalyzed Reactions under Solventless Conditions. Molecules. 2010; 15(4):2520-2525.

Chicago/Turabian Style

Bandyopadhyay, Debasish, Sanghamitra Mukherjee, and Bimal K. Banik. 2010. "An Expeditious Synthesis of N-substituted Pyrroles via Microwave-Induced Iodine-Catalyzed Reactions under Solventless Conditions" Molecules 15, no. 4: 2520-2525.

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