Open Access

Polystyrenesulfonate-catalyzed synthesis of novel pyrroles through Paal-Knorr reaction

  • Mandira Banik1,
  • Bianca Ramirez1,
  • Ashwini Reddy1,
  • Debasish Bandyopadhyay1 and
  • Bimal K Banik1Email author
Organic and Medicinal Chemistry Letters20122:11

https://doi.org/10.1186/2191-2858-2-11

Received: 22 November 2011

Accepted: 27 March 2012

Published: 27 March 2012

Abstract

Background

The classical Paal-Knorr reaction is one of the simplest and most economical methods for the synthesis of biologically important and pharmacologically useful pyrrole derivatives.

Results

Polystyrenesulfonate-catalyzed simple synthesis of substituted pyrroles following Paal-Knorr reaction has been accomplished with an excellent yield in aqueous solution. This method also produces pyrroles with multicyclic polyaromatic amines.

Conclusions

The present procedure for the synthesis of N-polyaromatic substituted pyrroles will find application in the synthesis of potent biologically active molecules.

Keywords

pyrrole polystyrene sulfonate Paal-Knorr reaction catalysis.

Background

Pyrroles have demonstrated important different biological activities in several areas [1]. On this basis, diverse methods for the synthesis of substituted pyrroles are known [2]. For example, Conjugate addition reaction has been developed for the preparation of pyrroles [3]. Pyrroles can also be prepared from transition metals [4], reductive coupling reaction [5], aza-Wittig reaction [6], and other multi-step reactions [7]. However, Paal-Knorr reaction is the most reliable methods for the synthesis of pyrroles [8]. Clay-induced [9] reaction and microwave irradiation method [10] have been used for the synthesis of pyrroles. Several synthetic procedures from our laboratory have also been reported [1116]. In this article, we report simple synthesis of substituted pyrroles using an aqueous solution of polystyrenesulfonate in ethanol. Unlike many methods, synthesis of pyrroles in aqueous solution is new and challenging (Figure 1).
Figure 1

Polystyrene sulfonate-catalyzed simple synthesis of N -substituted pyrroles.

Results and discussion

Synthesis of pyrroles with polyaromatic amines has not been reported. High-power microwave irradiation or considerable amounts of acids under anhydrous conditions are always necessary in the Paal-Knorr reaction. Therefore, mild reaction conditions that can overcome some of the shortcomings of previous methods are necessary. In continuation of our research on environmentally benign reaction and biological evaluation of various polyaromatic compounds as novel anticancer agents [1722], we have investigated Paal-Knorr reaction using aqueous polystyrenesulfonate. After various experimentations, we have identified polystyrenesulfonate as a good catalyst for the preparation of pyrroles starting from amines and 1,4-diketo compound. Several amines including monocyclic, bicyclic, tricyclic, and tetracyclic aromatic amines were used. The other starting material was commercially available 2,5-hexanone (acetonylacetone) (Figure 1). At the beginning of the procedure, the diketo compound (2), the amine (1) and polystyrenesulfonate were added in ethanol. The mixture was then stirred at room temperature for 2 h-overnight depending upon the nature of the aromatic amines. The reaction mixture was basified with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was then washed with brine, dried with sodium sulphate and evaporated. The yields of the products are shown in the Table 1. The less basic aromatic amines needed longer reaction time although the yields are comparable to the more basic amino compounds.
Table 1

Polystyrene sulfonate-catalyzed simple synthesis of N-substituted pyrroles following Figure 1

Entry

Amine

Product

Time (h)

Yield (%)a

1

10

96

2

15

81

3

11

83

4

19

98

5

18

94

6

20

88

7

22

85

aisolated yield

Conclusions

In conclusion, a new procedure for the synthesis of N-substituted pyrroles has been developed. 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. This reaction will be applicable to the synthesis of various organic compounds of medicinal interests.

Methods

General

FT-IR spectra were registered on a Bruker IFS 55 Equinox FTIR spectrophotometer as KBr discs. 1H NMR (600 MHz) and 13C-NMR (150 MHz) spectra were obtained at room temperature with Bruker-600 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.

General procedure for the synthesis of pyrroles (3)

Amine (1.0 mmol), 2,5-hexanedione (1.2 mmol) and polystyrene sulfonate (18 wt. % solution in water) in water/ethanol (1:1) mixture was stirred at room temperature as specified in Table 1 and the progress of the reaction was monitored by TLC every 30 min. After completion of the reaction (Table 1) the reaction mixture was basified with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was then washed with brine, dried with sodium sulphate and evaporated to isolate the pure product.

Authors' information

MB is a high school research participant; BM is an undergraduate research participant and AR is a graduate student.

Declarations

Acknowledgements

We gratefully acknowledged the funding support from the Kleberg Foundation, Texas.

Authors’ Affiliations

(1)
Department of Chemistry, The University of Texas-Pan American

References

  1. De Leon CY, Ganem B: A new approach to porphobilinogen and its analogs. Tetrahedron 1997, 53: 7731–7752. 10.1016/S0040-4020(97)00469-9View ArticleGoogle Scholar
  2. Gilchrist TL: Synthesis of aromatic heterocycles. J Chem Soc Perkin Trans 1998, 1: 615–628.View ArticleGoogle Scholar
  3. Dieter RK, Yu H: A facile synthesis of polysubstituted pyrroles. Org Lett 2000, 2: 2283–2286. 10.1021/ol006050qView ArticleGoogle Scholar
  4. Iwasawa N, Maeyama K, Saitou M: Reactions of propargyl metallic species generated by the addition of alkynyllithiums to fischer-type carbene complexes. J Am Chem Soc 1997, 119: 1486–1487. 10.1021/ja962173nView ArticleGoogle Scholar
  5. Furstner A, Weintritt H, Hupperts A: A new titanium-mediated approach to pyrroles: First synthesis of lukianol a and lamellarin- o -dimethyl ether. J Org Chem 1995, 60: 6637–6641. 10.1021/jo00125a068View ArticleGoogle Scholar
  6. Katritzky A, Jiang J, Steel PJ: 1-Aza-1,3-bis(triphenylphosphor- ranylidene)propane: A novel: CHCH 2 N: Synthon. J Org Chem 1994, 59: 4551–4555. 10.1021/jo00095a034View ArticleGoogle Scholar
  7. Arcadi A, Rossi E: Synthesis of functionalized furans and pyrroles through annulation reactions of 4-pentynones. Tetrahedron 1998, 54: 15253–15272. 10.1016/S0040-4020(98)00953-3View ArticleGoogle Scholar
  8. Cooney JV, McEwen WE: Synthesis of substituted pyrroles by intramolecular condensation of a Wittig reagent with the carbonyl group of a tertiary amide. J Org Chem 1981, 46: 2570–2573. 10.1021/jo00325a027View ArticleGoogle Scholar
  9. Ruault P, Pilard J-F, Touaux B, Boullet FT, Hamelin J: Rapid generation of amines by microwave irradiation of ureas dispersed on clay. Synlett 1994, 6: 935–936.View ArticleGoogle Scholar
  10. Danks TN: Microwave assisted synthesis of pyrroles. Tetrahedron Lett 1999, 40: 3957–3960. 10.1016/S0040-4039(99)00620-6View ArticleGoogle Scholar
  11. Banik BK, Samajdar S, Banik I: Simple synthesis of substituted pyrroles. J Org Chem 2004, 69: 213–216. 10.1021/jo035200iView ArticleGoogle Scholar
  12. Banik BK, Banik I, Renteria M, Dasgupta SK: A straightforward highly efficient Paal-Knorr synthesis of pyrroles. Tetrahedron Lett 2005, 46: 2643–2645. 10.1016/j.tetlet.2005.02.103View ArticleGoogle Scholar
  13. Bandyopadhyay D, Mukherjee S, Banik BK: An expeditious synthesis of N -substituted pyrroles via microwave-induced iodine-catalyzed reaction under solventless conditions. Molecules 2010, 15: 2520–2525. 10.3390/molecules15042520View ArticleGoogle Scholar
  14. Andoh-Baidoo R, Danso R, Mukherjee S, Bandyopadhyay D, Banik BK: Microwave-induced N -bromosuccinimide-mediated novel synthesis of pyrroles via Paal-Knorr reaction. Heterocycl Lett 2011,1(special, July):107–109.Google Scholar
  15. Abrego D, Bandyopadhyay D, Banik BK: Microwave-induced indium-catalyzed synthesis of pyrrole fused with indolinone in water. Heterocycl Lett 2011, 1: 94–95.Google Scholar
  16. Rivera S, Bandyopadhyay D, Banik BK: Facile synthesis of N -substituted pyrroles via microwave-induced bismuth nitrate-catalyzed reaction under solventless conditions. Tetrahedron Lett 2009, 50: 5445–5448. 10.1016/j.tetlet.2009.06.002View ArticleGoogle Scholar
  17. Banik I, Becker FF, Banik BK: Stereoselective synthesis of β-Lactams with Polyaromatic Imines: entry to new and novel anticancer agents. J Med Chem 2003, 46: 12–15. 10.1021/jm0255825View ArticleGoogle Scholar
  18. Becker FF, Banik BK: Polycyclic aromatic compounds as anticancer agents: synthesis and biological evaluation of some chrysene derivatives. Bioorg Med Chem Lett 1998, 8: 2877–2880. 10.1016/S0960-894X(98)00520-4View ArticleGoogle Scholar
  19. Becker FF, Mukhopadhyay C, Hackfeld L, Banik I, Banik BK: Polycyclic aromatic compounds as anticancer agents: synthesis and biological evaluation of dibenzofluorene derivatives. Bioorg Med Chem 2000, 8: 2693–2699. 10.1016/S0968-0896(00)00213-3View ArticleGoogle Scholar
  20. Banik BK, Becker FF: Polycyclic aromatic compounds as anticancer agents. 4. Structure-activity relationships of chrysene and pyrene derivatives. Bioorg Med Chem 2001, 9: 593–605. 10.1016/S0968-0896(00)00297-2View ArticleGoogle Scholar
  21. Banik BK, Becker FF: 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.View ArticleGoogle Scholar
  22. Banik BK, Becker FF, Banik I: Synthesis of anticancer β-lactams: Mechanism of action. Bioorg Med Chem 2004, 12: 2523–2528. 10.1016/j.bmc.2004.03.033View ArticleGoogle Scholar

Copyright

© Banik et al; licensee Springer. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.