Synthesis of 1,2′- and 1,3′-bipyrroles from 2- and 3-nitropyrroles

Article abstract of DOI:10.1016/j.tetlet.2008.04.025

1,2′- and 1,3′-Bipyrroles, which are attractive precursors for the synthesis of bipyrrole-based natural products, are synthesized in one-pot from 2- and 3-nitropyrroles by a sequential nitro group reduction-Paal-Knorr pyrrole synthesis.

Full text of DOI:10.1016/j.tetlet.2008.04.025

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3545–3548
Synthesis of 1,20- and 1,30-bipyrroles from 2- and 3-nitropyrroles
Liangfeng Fu, Gordon W. Gribble *
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
Received 29 February 2008; revised 3 April 2008; accepted 3 April 2008
Available online 6 April 2008
Abstract
1,20- and 1,30-Bipyrroles, which are attractive precursors for the synthesis of bipyrrole-based natural products, are synthesized in
one-pot from 2- and 3-nitropyrroles by a sequential nitro group reduction—Paal–Knorr pyrrole synthesis.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Bipyrroles; Nitropyrroles; Reduction; Paal–Knorr pyrrole synthesis
Bipyrroles are attractive precursors for the synthesis of
the various polyhalogenated 2,20- and 1,20-bipyrroles found
in marine organisms (Fig. 1), which are ubiquitous in the
marine environment.1,2 Previous syntheses of 2,20-bipyr-
roles include coupling of 2-halopyrroles;3 for example,
phenyliodine bis(trifluoroacetate),4 palladium,5 nickel,6
and other methods.7 However, no general method is avail-
able for the preparation of 1,20- and 1,30-bipyrroles and
only a few syntheses are known.8,9
of 2- and 3-nitropyrroles as a simple route to 1,20- and
1,30-bipyrroles. We now describe the results of this study.
We selected the readily available10b 1-methyl-3-nitropyr-
role (1a), 3-nitro-1-(phenylsulfonyl)pyrrole (1b), 1-methyl-
2-nitropyrrole (1c), and 2-nitro-1-(phenylsulfonyl)pyrrole
(1d) as substrates (Scheme 1).
Thus, 3-nitro-1-(phenylsulfonyl)pyrrole (1b) was treated
with indium or tin and 2,5-dimethoxy-2,5-dihydrofuran in
acetic acid at 60 °C under nitrogen to afford a low yield
(22%) of the desired bipyrrole 2b. No improvement was
seen when the solvent was changed to toluene, benzene,
dichloroethane, or methanol. Similarly, 2-nitro-1-(phenyl-
sulfonyl)pyrrole (1d) gave bipyrrole 2d in only 20% yield
(Scheme 2).
Our recent reductive acylation of 3-nitroindoles10a and
2- and 3-nitropyrroles10b prompted us to explore the use
Me Me
Me Me
However, the use of 1,4-dicarbonyl compounds, which
are widely employed in thePaal–Knorr synthesis of pyrroles
from primary amines,11 was more productive (Scheme 3).
Thus, exposing 1-methyl-3-nitropyrrole (1a) to a mixture
of tin, acetonylacetone, and acetic acid in methanol,
Br
Br
Br
Br
Cl
Br
Cl
Br
N
N
N
N
Br Br
Me Cl
Br Br
Me Br
Cl
Cl
Cl
Br
Br
Br
Br
N
N
N
N
NO2
NO2
Cl
Cl Cl
Br Br
NO2
NO2
N
N
N
N
Fig. 1. Representative marine bipyrrole natural products.
SO2Ph
SO2Ph
Me
Me
1a
1b
1c
1d
*
Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946.
Scheme 1.
E-mail address: ggribble@dartmouth.edu (G. W. Gribble).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.025

3546
L. Fu, G. W. Gribble / Tetrahedron Letters 49 (2008) 3545–3548
respectively (Table 1, entries 9 and 10). Similarly, bipyrrole
5a14 is isolated in 62% yield from the reaction of 3-nitro-
pyrrole 1a and dibenzoylethane (Table 1, entry 11). How-
ever, bipyrrole 5b could not be isolated in several
attempts (entry 12).
NO2
N
OMe
MeO
O
N
N
Sn or In, AcOH, 60 oC
SO2Ph
SO2Ph
22% for 3-nitro
20% for 2-nitro
1b, 1d
2b, 2d
We also explored catalytic reduction in place of the tin
conditions in this sequence (Scheme 4). In the event, the
treatment of 3-nitropyrrole 1a with H2, Pd/C, and aceto-
nylacetone in methanol gives the desired bipyrrole 3a13 in
91% yield following column chromatography (Table 2,
Scheme 2.
provides the desired bipyrrole 3a12 in 86% yield after col-
umn chromatography (Table 1, entry 1). Similarly, an
87% yield of 3b14 was obtained from nitropyrrole 1b (Table
1, entry 2). In contrast, 2-nitropyrrole 1d affords 3d14 in
only 45% yield.
Me
H2, Pd/C,
solvent, 60-70 oC
NO2
N
Likewise, 2-nitropyrrole 1c gives 3c14 in 42% yield in a
solvent mixture of methanol and dichloroethane.
To possibly circumvent the low yield observed with 2,5-
dimethoxy-2,5-dihydrofuran, we prepared and utilized in
its place, succindialdehyde, readily available from 2,5-
dimethoxy-2,5-dihydrofuran.15 To our delight, under these
conditions 3-nitro-1-(phenylsulfonyl)pyrrole (1b) gives the
desired bipyrrole 2b14 in 91% yield after column chroma-
tography (Table 1, entry 6). The use of succindialdehyde
also affords bipyrroles 2a, 2c, and 2d14 but in 35–65%
yields.
N
Me
O
N
PG
PG
O
1a-d
3a-d
6
Scheme 4.
Table 2
Catalytic reductive pyrrolylation of nitropyrroles with acetonylacetone (6)
Entry
Nitropyrrole
Solvent
Product
Yielda (%)
1
2
3
4
a
1a
1b
1c
1d
MeOH
MeOH
3a
3b
3c
3d
91
92
15
43
Acetonylacetophenone and dibenzoylethane also
undergo this sequential reduction—Paal–Knorr sequence.
Thus, 3-nitropyrroles 1a and 1b with acetylacetophenone
furnish bipyrroles 4a14 and 4b14 in 91% and 70% yields,
AcOH (CH2Cl)2
AcOH (CH2Cl)2
Yield after column chromatography.
R1
R1
Sn, AcOH,
NO2
N
solvent, 60-70 oC
R2
N
R2
+
N
N
O
N
PG
R1
PG
R2
PG
O
1a-1d
2c,2d,3c,3d
2a,2b,3a,3b
4a,4b,5a,5b
Scheme 3.
Table 1
Sn-mediated reductive pyrrolylation of nitropyrroles with dicarbonyl compounds
Entry
Nitropyrrole
PG
R1 & R2
Solvent
Product
Yielda (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1a
1b
Me
SO2Ph
Me
SO2Ph
Me
SO2Ph
Me
SO2Ph
Me
SO2Ph
Me
R1 = R2 = Me
R1 = R2 = Me
R1 = R2 = Me
R1 = R2 = Me
R1 = R2 = H
MeOH
MeOH
MeOH, (ClCH2)2
MeOH
MeOH
MeOH
MeOH, (ClCH2)2
MeOH
MeOH
MeOH
MeOH
3a
3b
3c
3d
2a
2b
2c
2d
4a
4b
5a
5b
86
87
42
45
39
91
35
65
91
70
62
0
R1 = R2 = H
R1 = R2 = H
R1 = R2 = H
R1 = Me, R2 = Ph
R1 = Me, R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
9
10
11
12
a
SO2Ph
MeOH
Yield after column chromatography.

L. Fu, G. W. Gribble / Tetrahedron Letters 49 (2008) 3545–3548
3547
entry 1). Similarly, 3b14 is obtained in 92% yield from 3-
nitropyrrole 1b (Table 2, entry 2). Whereas neither 2-nitro-
pyrrole 1c or 1d leads to their corresponding bipyrroles in
methanol, a mixture of acetic acid and dichloroethane pro-
vides a low yield of bipyrrole 3c14 and a 43% yield of bipyr-
role 3d,14 respectively (entries 3 and 4).
In summary, we describe the first general synthesis of N-
protected 1,20- and 1,30-bipyrroles from 2- and 3-nitropyr-
roles that features a simple in situ reduction—Paal–Knorr
pyrrole annulation sequence. The application of this
method to naturally occurring bipyrroles is underway.
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Acknowledgments
This work was supported by the Donors of the Petro-
leum Research Fund (PRF), administrated by the Ameri-
can Chemical Society, and by Wyeth.
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12. Representative procedure (3a) (Procedure I): 1-Methyl-3-nitropyrrole
(1a) (100 mg, 0.80mmol) and tin (470 mg, 4.0 mmol) in MeOH (5 mL)
were added to acetic acid (1 mL) and acetonylacetone (271 mg,
2.4 mmol). The resulting mixture was heated to 70 °C under nitrogen
for 0.5 h. The reaction mixture was cooled to room temperature and
transferred into a beaker. Saturated NaHCO3 was added carefully
until the solution was no longer acidic. The organic layer was
separated, and the aqueous layer was extracted with EtOAc
(3 ꢀ 15 mL). The combined organic layer was washed with saturated
NaHCO3 (20 mL), brine (20 mL), and dried over Na2SO4. The
removal of solvent and column chromatography over hexane–EtOAc
(16:1 and 4:1) gave product 3a (120 mg, 0.69 mmol) as a white solid in
87% yield: mp 46–47 °C; 1H NMR (CDCl3): d = 6.62–6.65 (m, 2H),
6.13 (dd, 1H), 5.93 (s, 2H), 3.76 (s, 3H), 2.17 (s, 6H); 13C NMR
(CDCl3): d = 130.0, 123.0, 121.0, 118.7, 108.1, 105.0, 37.0, 13.3; MS
(EI): m/z (%) = 174 ([M+], 100), 159, 132, 118, 94, 81; HRMS (EI):
m/z calcd for C11H14N2: 174.1157. Found: 174.1156.
4. (a) Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006,
8, 2007–2010; (b) Moreno, I.; Tellitu, I.; Dominguez, E.; SanMartin,
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SanMartin, R.; Dominguez, E. Synlett 2001, 1161–1163.
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2007, 44, 739–743; (b) Decreau, R. A.; Collman, J. P. Tetrahedron

3548
L. Fu, G. W. Gribble / Tetrahedron Letters 49 (2008) 3545–3548
13. Representative procedure (3a) (Procedure II) : To a solution of 1-
methyl-3-nitropyrrole (1a) (59 mg, 0.47 mmol) and acetonylacetone
(160 mg, 1.4 mmol) in anhydrous methanol (3 mL) was added 10%
palladium on carbon (12 mg). The atmosphere of the flask was
replaced by hydrogen gas and the reaction was cooled to ꢁ78 °C.
After three vacuum/hydrogen cycles to remove air from the reaction
flask, the reaction mixture was heated to 70 °C under atmospheric
pressure for 1.5 h, having the hydrogen atmosphere maintained by a
balloon. The catalyst was removed by filtration through Celite. The
filtrate was evaporated and the crude product was purified by column
chromatography (hexane–EtOAc = 16:1) to give the desired product
(3a) (73 mg, 90%) as a white solid which was identical with the sample
prepared above by 1H NMR, 13C NMR, and TLC.
14. Compound 3b: white solid; mp 91–92 °C; 1H NMR (CDCl3): d = 7.89
(m, 2H), 7.64–7.67 (m, 1H), 7.54–7.57 (m, 2H), 7.21 (dd, 1H), 7.14 (t,
1H), 6.27 (dd, 1H), 5.85 (s, 2H), 2.00 (s, 6H); 13C NMR (CDCl3):
d = 138.8, 134.5, 129.8, 129.3, 128.0, 127.0, 120.7, 117.3, 114.0, 106.2,
13.1; MS (EI): m/z (%) = 300 ([M+]), 272, 257, 242, 229, 206, 191, 159
(100), 143, 125, 111, 97, 71; HRMS (EI): m/z calcd for C16H16N2O2S:
300.0933. Found: 300.0929. Compound 3c: yellow oil; 1H NMR
(CDCl3): d = 6.67 (dd, 1H), 6.20 (dd, 1H), 6.12 (dd, 1H), 5.92 (s, 2H),
3.23 (s, 3H), 2.01 (s, 6H); 13C NMR (CDCl3): d = 130.7, 126.9, 120.4,
106.9, 106.4, 106.0, 32.4, 12.7; MS (EI): m/z (%) = 174 ([M+], 100),
159, 132, 118, 94, 81; HRMS (EI): m/z calcd for C11H14N2: 174.1157.
Found: 174.1156. Compound 3d: white solid; mp 105–106 °C; 1H
NMR (CDCl3): d = 7.60–7.63 (m, 1H), 7.56 (m, 2H), 7.41–7.45 (m,
3H), 6.32 (t, 1H), 6.15 (dd, 1H), 5.80 (s, 2H), 1.57 (s, 6H); 13C NMR
(CDCl3): d = 138.0, 134.4, 131.7, 129.3, 128.5, 127.3, 121.8, 113.7,
110.1, 106.6, 12.3; MS (EI): m/z (%) = 300 ([M+]), 272, 257, 229, 191,
175, 159 (100), 131, 117, 91, 77; HRMS (EI): m/z calcd for
C16H16N2O2S: 300.0933. Found: 300.0933. Compound 2a: column
chromatography over Al2O3; yellowish oil (solid upon standing); 1H
NMR (CDCl3): d = 6.90 (dd, 2H), 6.67 (m, 1H), 6.53 (dd, 1H), 6.25
(dd, 2H), 6.20 (dd, 1H), 3.67 (s, 3H); 13C NMR (CDCl3): d = 128.0,
121.2, 120.4, 112.1, 108.8, 102.2, 36.9; MS (EI): m/z (%) = 146 ([M+],
100), 131, 118, 104, 91, 78; HRMS (EI): m/z calcd for C9H10N2:
146.0844. Found: 146.0844. Compound 2b: white solid; mp 77–78 °C;
1H NMR (CDCl3): d = 7.89 (m, 2H), 7.62–7.65 (m, 1H), 7.52–7.55
(m, 2H), 7.17 (m, 2H), 6.89 (m, 2H), 6.43 (dd, 1H), 6.27 (m, 2H); 13C
NMR (CDCl3): d = 138.8, 134.4, 131.9, 129.8, 127.1, 121.3, 119.6,
110.3, 108.5, 108.1; MS (EI):m/z (%) = 272 ([M+]), 236, 207, 191, 177,
149, 131 (100), 104, 87, 77; HRMS (EI): m/z calcd for C14H12N2O2S:
272.0620. Found: 272.0622. Compound 2c: column chromatography
over Al2O3; yellow oil; 1H NMR (CDCl3): d = 6.78 (t, 2H), 6.59 (t,
1H), 6.32 (t, 2H), 6.14 (m, 2H), 3.39 (s, 3H); 13C NMR (CDCl3):
d = 123.4, 119.8, 109.1, 106.4, 104.1, 103.7, 27.5; HRMS (EI): m/z
calcd for C9H10N2: 146.0844. Found: 146.0842. Compound 2d:
yellowish oil; 1H NMR (CDCl3): d = 7.57 (m, 1H), 7.47 (m, 2H),
7.38–7.42 (m, 2H), 7.35 (dd, 1H), 6.49 (t, 2H), 6.28 (t, 1H), 6.17 (m,
3H); 13C NMR (CDCl3): d = 137.8, 134.2, 130.4, 129.4, 127.8, 125.2,
121.3, 111.4, 110.3, 109.3; MS (EI): m/z (%) = 272 ([M+]), 207, 191,
149, 131 (100), 104, 77; HRMS (EI): m/z calcd for C14H12N2O2S:
272.0620. Found: 272.0622. Compound 4a: yellow oil; 1H NMR
(CDCl3): d = 7.35 (m, 2H), 7.25–7.29 (m, 2H), 7.17–7.20 (m, 1H), 6.59
(t, 1H), 6.49 (m, 1H), 6.41 (d, 1H), 6.14 (d, 1H), 6.12 (dd, 1H), 3.64 (s,
3H), 2.28 (s, 3H); 13C NMR (CDCl3): d = 134.8, 134.4, 132.9, 128.1,
127.9, 125.8, 123.5, 121.0, 118.9, 108.6, 108.1, 106.9, 36.9, 13.6; MS
(EI): m/z (%) = 236 ([M+], 100), 221, 194, 180, 159, 132, 118, 81;
HRMS (EI): m/z calcd for C16H16N2: 236.1314. Found: 236.1313.
Compound 4b: white solid; mp 109–110 °C; 1H NMR (CDCl3): d =
7.75–7.77 (m, 2H), 7.67 (m, 1H), 7.50–7.53 (m, 2H), 6.99–7.13 (m,
7H), 6.28 (d, 1H), 6.19 (dd, 1H), 6.05 (dd, 1H), 2.13 (s, 3H); 13C NMR
(CDCl3): d = 139.0, 134.6, 134.3, 133.4, 132.1, 129.7, 128.5, 128.1,
128.0, 127.0, 126.1, 120.6, 117.5, 114.3, 109.0, 107.9, 13.3; MS (EI):
m/z (%) = 362 ([M+]), 260, 238, 219, 206, 191, 169, 155, 141, 125, 105,
71; HRMS (EI): m/z calcd for C21H18O2N2S: 362.1089. Found:
362.1088. Compound 5a: white solid; mp 175–176 °C; 1H NMR
(CDCl3): d = 7.19–7.34 (m, 10H), 6.49 (m, 3H), 6.35 (t, 1H), 5.95
(dd, 1H), 3.58 (s, 3H); 13C NMR (CDCl3): d = 136.7, 134.0, 128.7,
127.9, 126.3, 123.4, 120.8, 119.3, 109.3, 109.2, 36.9; MS (EI): m/z
(%) = 298 ([M+], 100), 283, 254, 243, 220, 194, 178, 167, 149, 115,
105, 77; HRMS (EI): m/z calcd for C21H18N2: 298.1470. Found:
298.1469.
15. (a) House, H. O.; Cronin, T. H. J. Org. Chem. 1965, 30, 1061–1070;
(b) Mueller, R.; Yang, J.; Duan, C.; Pop, E.; Zhang, L. H.; Huang, T.;
Denisenko, A.; Denisko, O. V.; Oniciu, D. C.; Bisgaier, C. L.; Pape,
M. E.; Freiman, C. D.; Goetz, B.; Cramer, C. T.; Hopson, K. L.;
Dasseux, J. H. J. Med. Chem. 2004, 47, 5183–5197.