A straightforward highly efficient Paal-Knorr synthesis of pyrroles

Article abstract of DOI:10.1016/j.tetlet.2005.02.103

A straightforward simple synthesis of substituted pyrroles using bismuth nitrate-catalyzed modified Paal-Knorr method has been accomplished with an excellent yield. This method produces pyrroles with multicyclic aromatic amines.

Full text of DOI:10.1016/j.tetlet.2005.02.103

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2643–2645
A straightforward highly efficient Paal–Knorr synthesis of pyrroles
Bimal K. Banik,a,* Indrani Banik,b Mercy Renteriaa,ꢀ and Swapan K. Dasguptab
aDepartment of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78541, USA
bThe University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
Received 24 January 2005; revised 11 February 2005; accepted 14 February 2005
Abstract—A straightforward simple synthesis of substituted pyrroles using bismuth nitrate-catalyzed modified Paal–Knorr method
has been accomplished with an excellent yield. This method produces pyrroles with multicyclic aromatic amines.
Ó 2005 Elsevier Ltd. All rights reserved.
From the extensive work on the synthesis of pyrroles,
the Paal–Knorr method has received increasing atten-
tion from synthetic perspectives.1 These techniques
clearly extend the scope of this objective, but success
with less nucleophilic aromatic amines has not been re-
Scheme 1.
ported. Moreover, microwave irradiation or consider-
able amounts of acids are always necessary in the
Paal–Knorr reaction.2–4 Therefore, mild reaction condi-
tions that can overcome the shortcomings of the previ-
ous methods are necessary. In this letter, we describe
a straightforward synthesis of substituted pyrroles by
at room temperature for the specified time. Several
amines 1 were used for this study. The other starting
material was 2,5-diketone 2 (Scheme 1). The less basic
aromatic amines needed longer reaction time for the
generation of the products although the yields are com-
parable to the more basic amino compounds. If one of
bismuth nitrate-catalyzed modified Paal–Knorr reac-
tions.
In our earlier paper, we5 performed a structure–activity
the reactants is a liquid, the reaction can proceed with-
relationship study of various polyaromatic compounds
out solvent. If the reaction mixture is very thick slurry,
prepared from their corresponding amines toward the
a small amount of solvent (1 g of the substrate/1 mL sol-
development of novel anticancer agents. Based on the
vent) is necessary for better yield of the product.
promising biological activity of these compounds, we
became interested in the synthesis of pyrroles bound to
This method of pyrrole formation proceeds exceedingly
the polyaromatic amines. It was realized that our own
well with multicyclic aromatic amines (Table 1, entries
work on bismuth nitrate-catalyzed6 organic transform-
3–7) without the need for strong Lewis acids or other
strong acids. In addition, all of the reactions were suc-
ations could be very fruitful for the facile synthesis of
pyrroles under very mild conditions.
cessful at room temperature. In contrast, previously
even with simple aniline derivatives, high temperature
In our procedure, the starting materials (amines and ke-
and/or microwave irradiation were required.
tones) are mixed with bismuth nitrate (5 mol %) in the
presence of dichloromethane and the solution is kept
To improve the scope of this bismuth nitrate-catalyzed
method of pyrrole formation, substituted diketones 2b
and 2c were used. Under identical conditions, a clean
formation of pyrrole 3k was observed with 2b and
1,2,5-trisubstituted pyrroles were accessible. However,
the yield of the product 3l was low when 2c was used
as the ketone component (Scheme 2).
Keywords: Pyrroles; Bismuth nitrate; Paal–Knorr reaction.
*
Corresponding author. Tel.: +1 956 380 8741; fax: +1 956 384
5006; e-mail: banik@panam.edu
ꢀ Undergraduate research participant.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.103

2644
B. K. Banik et al. / Tetrahedron Letters 46 (2005) 2643–2645
Table 1. Bismuth nitrate-catalyzed synthesis of pyrrole 3
Entry Amine Product Time Yield
(h)
(%)
1
2
3
PhÆNH2
10
96
15
11
81
83
Scheme 2.
zinc sulfate proved to be ineffective. Bismuth chloride
produced low yield of the products with more nucleo-
philic amines (Table 1, aniline and p-anisidine, entries
1 and 2). However, with polyaromatic amines (Table
1, 6-aminochrysene, entry 7), the reaction failed to pro-
duce pyrrole. The failure of these salts to promote a
Paal–Knorr reaction indicates the importance of bis-
muth nitrate in this reaction. The present bismuth
nitrate-catalyzed reaction is much superior over the
Lewis acid-mediated synthesis of pyrroles in terms of
yield of the products. The reaction proceeds in the pres-
ence of small amount of nitric acid, although the iso-
lated yields of the products are not comparable with
those of bismuth nitrate-catalyzed process. Therefore,
the use of commercially available nontoxic bismuth
nitrate as the catalyst seems to be very convenient for
Paal–Knorr reaction. Notably, this method has been
proved to be highly effective for the synthesis of pyrroles
with several less nucleophilic polyaromatic aromatic
amines.8 In addition, unlike many other procedures,
no extra energy source, like microwave irradiation or
ultrasound is needed for the success of the reaction. This
method has great potential for future application.
4
5
6
19
18
20
98
94
88
7
22
85
Acknowledgements
8
9
NH2(CH2)2NH2
10
10
85
95
We gratefully acknowledge the funding support from
the University of Texas, MD Anderson Cancer Center
and the Robert Welch Foundation departmental grant
(BG-0017).
PhCH2NH2
References and notes
1. (a) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1998, 615;
(b) Dieter, R. K.; Yu, H. Org. Lett. 2000, 2, 2283; (c)
Iwasawa, N.; Maeyama, K.; Saitou, M. J. Am. Chem. Soc.
1997, 119, 1486; (d) Furstner, A.; Weintritt, H.; Hupperts,
A. J. Org. Chem. 1995, 60, 6637; (e) Katritzky, A.; Jiang, J.;
Steel, P. J. J. Org. Chem. 1994, 59, 4551; (f) Arcadi, A.;
Rossi, E. Tetrahedron 1998, 54, 15253; (f) Periasamy, M.;
Srinivas, G.; Bharati, P. J. Org. Chem. 1999, 64, 4204, and
references cited therein.
2. Cooney, J. V.; McEwen, W. E. J. Org. Chem. 1981, 46,
2570.
3. Ruault, P.; Pilard, J.-F.; Touaux, B.; Boullet, F. T.;
Hamelin, J. Synlett 1994, 935.
4. Danks, T. N. Tetrahedron Lett. 1999, 40, 3957.
10
25
70
The reaction between 1 and 2 does not proceed without
bismuth nitrate.7 The presence of small amounts of bis-
muth nitrate (1–0.05 mmol) is essential for the success of
the reaction. To confirm the role of bismuth nitrate, a
few other salts were investigated. Ferric nitrate, sodium
nitrate, zinc nitrate, copper nitrate, copper sulfate and

B. K. Banik et al. / Tetrahedron Letters 46 (2005) 2643–2645
2645
5. Banik, B. K.; Becker, F. F. Bioorg. Med. Chem. 2001, 9,
593, and references cited therein.
(1.1 mmol) in dichloromethane (2 mL) at room tempera-
ture, bismuth nitrate pentahydrate (1–0.5 mmol) was
added. The mixture was allowed to stir at this temperature
for a period specified in Table 1. This resulting mixture was
washed successively with saturated NaHCO3 solution
(2 mL) and brine (2 mL). The organic layer was dried with
sodium sulfate and concentrated. The residue was purified
by filtration through a short column of florisil using ethyl
acetate–hexanes (30:70) as the solvent system to afford the
pyrroles (70–98% yield).
6. We have devised several bismuth nitrate-induced methods.
For example, see: (a) Samajdar, S.; Becker, F. F.; Banik, B.
K. Tetrahedron Lett. 2000, 41, 8017; (b) Srivastava, N.;
Banik, B. K. J. Org. Chem. 2003, 68, 2109; (c) Banik, B. K.;
Samajdar, S.; Banik, I.; Ng, S.; Hann, J. Heterocycles 2003,
61, 97; (d) Banik, B. K.; Adler, D.; Nguyen, P.; Srivastava,
N. Heterocycles 2003, 61, 101; (e) Srivastava, N.; Das-
gupta, S. K.; Banik, B. K. Tetrahedron Lett. 2003, 44,
1191.
7. The application of bismuth salts-mediated reaction is
gaining attention in synthetic chemistry. For some exam-
ples, see: (a) Carrigan, M. D.; Sarapa, D.; Smith, R. C.;
Wieland, L. C.; Mohan, R. S. J. Org. Chem. 2002, 67, 1027;
(b) Eash, K. J.; Paulia, M. S.; Wieland, L. C.; Mohan, R. S.
J. Org. Chem. 2000, 65, 8399.
1-(1-Naphthalenyl)-2,5-dimethylpyrrole: mp 118 °C; IR
(CH2Cl2) 3062, 1595, 1578, 1522, 1506, 1468 cmÀ1 1H
;
NMR (300 MHz) d 1.89 (6H, s), 6.00 (2H, s), 7.13 (1H, d,
J = 8.34 Hz), 7.39–7.57 (4H, m), 7.91 (2H, d, J = 8.25 Hz)
1
1-(6-Chrysenyl)-2,5-dimethylpyrrole: mp 225 °C; H NMR
(300 MHz) d 1.97 (6H, s), 5.99 (2H, s), 7.25 (1H, m), 7.58–
7.74 (4H, m), 8.03 (1H, m), 8.08 (1H, d, J = 9.09 Hz), 8.69
(2H, m), 8.76 (1H, d, J = 9.10 Hz), 8.84 (1H, d,
J = 8.20 Hz).
8. General procedure for the synthesis of pyrroles (3): To a
solution of the amine 1 (1 mmol) and hexane-2,4-dione 2