Novel approach for the synthesis of N-Substituted pyrroles starting directly from nitro compounds in water

Article abstract of DOI:10.1080/00397911.2010.526748

A novel approach for a facile high-yielding synthesis of N-substituted pyrroles has been discovered by the treatment of nitroarenes with 2,5-dimethoxytetrahydrofuran using indium in dilute aqueous HCl at room temperature. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.526748

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Novel Approach for the Synthesis of N-
Substituted Pyrroles Starting Directly
from Nitro Compounds in Water
Biswanath Das a , Digambar Balaji Shinde a , Boddu Shashi Kanth a &
Jayprakash Narayan Kumar a
a Organic Chemistry Division I, Indian Institute of Chemical
Technology, Hyderabad, India
Accepted author version posted online: 04 Aug 2011.Version of
record first published: 17 Oct 2011.
To cite this article: Biswanath Das , Digambar Balaji Shinde , Boddu Shashi Kanth & Jayprakash
Narayan Kumar (2012): Novel Approach for the Synthesis of N-Substituted Pyrroles Starting Directly
from Nitro Compounds in Water, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:4, 548-553
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Synthetic Communications1, 42: 548–553, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.526748
NOVEL APPROACH FOR THE SYNTHESIS OF
N-SUBSTITUTED PYRROLES STARTING DIRECTLY
FROM NITRO COMPOUNDS IN WATER
Biswanath Das, Digambar Balaji Shinde, Boddu Shashi Kanth,
and Jayprakash Narayan Kumar
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A novel approach for a facile high-yielding synthesis of N-substituted pyrroles has
been discovered by the treatment of nitroarenes with 2,5-dimethoxytetrahydrofuran using
indium in dilute aqueous HCl at room temperature.
Keywords Aqueous HCl; indium; nitro compound; N-substituted pyrroles; Paal–Knorr
reaction
INTRODUCTION
Pyrroles represent an important class of heterocycles whose structural
motifs are present in various bioactive natural molecules such as chlorophyll and
hemoglobin.[1] They are useful precursors in the synthesis of these natural products
and related compounds. Bioactive indolizidine alkaloids and different lactam
derivatives are also prepared using pyrroles as the intermediates.[2] Pyrrole deriva-
tives exhibit various pharmacological activities including antitumoral, antiviral,
and antibacterial properties.[3] Several valuable drugs such as Cloripac (anti-
inflammatory agent) and Lipitor (cholesterol-lowering agent) contain pyrrole
units.[4] Pyrroles are also applied in materials science.[5] Thus, the synthesis of pyrrole
derivatives is an important task in organic chemistry. A most attractive method for
the synthesis of these compounds in the Paal–Knorr reaction in which amines are
converted into pyrroles.[6] Herein we report a distinct approach for the preparation
of N-substituted pyrroles starting from nitro compounds.
Received July 8, 2010.
Part 201 in the series, ‘‘Studies on novel synthetic methodologies.’’
Address correspondence to Biswanath Das, Organic Chemistry Division I, Indian Institute of
Chemical Technology, Hyderabad 500 007, India. E-mail: biswanathdas@yahoo.com
548

SYNTHESIS OF N-SUBSTITUTED PYRROLES
549
Scheme 1. Synthesis of N-substituted pyrroles from nitroarenes.
RESULTS AND DISCUSSION
In continuation of our work[7] on the development of useful synthetic methodol-
ogies in aqueous medium, we have discovered that N-substituted pyrroles can be
synthesized efficiently by the reaction of nitro compounds with 2,5-dimethoxytetrahy-
drofuran using indium in dilute aqueous HCl at room temperature (Scheme 1).
Initially, the reaction of nitrobenzene and 2,5-dimethoxytetrahydrofuran was
carried out using various metals such as Fe, Zn, In, and Sn in aqueous HCl at room
temperature (Table 1). Considering the reaction time and yield, In was found to be
most effective. Subsequently, an In = aqueous HCl system was used to prepare a series
of N-substituted pyrroles from different nitro arenes (Table 2). The products were
formed within 50–70 min in good yields (71–84%). The nitrobenzenes containing
electron-donating as well as electron-withdrawing groups underwent the conversion
smoothly. Different functionalities including hydroxyl, ether, and halogen remained
unchanged. Even nitrile and acyl groups were not reduced under the present reaction
conditions (Table 2, entries j and k). The reaction with a dinitrobenzene afforded only
an N-substituted pyrrole containing an intact nitro group (Table 2, entries h and n). A
sterically hindered nitrocompound such as 1-nitronaphthalene furnished the desired
pyrrole in good yield (Table 2, entry r). However, with a nitroalkane, a mixture of
products was obtained. The structures of the pyrroles were settled from their spectral
1
[infrared (IR), H NMR, 13C NMR and, mass (MS)] and analytical data.
In the present conversion, initially nitro compounds on treatment with
In=aqueous HCl reduced to amines,[8] which then react with 2,5-dimethoxytetrahy-
drofuran to form the corresponding N-substituted pyrroles (Scheme 2).[9]
In recent years, organic reactions in water have attracted much attention
because of economic and environmental benefits. The present synthesis of pyrroles
is an important addition to these reactions.
Table 1. Synthesis of an N-phenyl pyrrole using different metalsa
Entry
Metal
Time
Yield (%)b
1
2
3
4
Sn
Zn
In
8 h
5 h
45
55
79
20
55 min
12 h
Fe
aReaction conditions: Nitrobenzene (1.0 mmol), 2,5-dimethoxytetrahydro-
furan (1.2 mmol), metal (2.0 mmol), and 1N HCl (1 mL) at room temperature.
bIsolated yields of pure compound after column chromatography.

550
B. DAS ET AL.
Table 2. Synthesis of N-substituted pyrrolesa,b
Entry
Ar
Product
Time (min)
Yieldc (%)
Ref.
[10a,c]
[10a]
a
b
c
d
e
f
C6H5
3a
3b
3c
3d
3e
3f
55
50
50
50
65
55
65
65
60
65
70
60
65
65
60
70
70
70
79
82
81
80
76
84
79
75
79
80
73
78
71
74
75
78
72
77
4-MeC6H4
4-MeOC6H4
4-ClC6H4
[10a,c]
[10a,c]
[10a]
4-BrC6H4
4-FC6H4
[10e]
[10f]
g
h
i
4-HOC6H4
4-NO2C6H4
4-CF3C6H4
4-CNC6H4
4-MeCOC6H4
3-MeC6H4
3-MeOC6H4
3-NO2C6H4
3-ClC6H4
3g
3h
3i
[10a,c]
[10c]
[10f]
j
3j
[10d]
k
l
3k
3l
[10a,d]
[10a,d]
[10a,d]
[10a,d]
[10d]
m
n
o
p
q
r
3m
3n
3o
3p
3q
3r
2-ClC6H4
2,3-Cl2C6H3
[10b,c]
C
10H7
aReaction conditions: Nitroarene (1.0 mmol), 2,5-dimethoxytetrahydrofuran
(1.2 mmol), indium metal (2.0 mmol), and 1N HCl (1 mL) at room temperature.
bAll products were fully characterized by the usual spectroscopic techniques.
cYields of pure isolated products after column chromatography.
Scheme 2. Mechanism of the synthesis of N-substituted pyrroles.
CONCLUSION
In conclusion, we have developed a novel, efficient method for the synthesis of
N-substituted pyrroles by the treatment of nitro compounds with 2,5-dimethoxyte-
trahydrofuran using indium in dilute aqueous HCl at room temperature. The direct
application of nitro compounds, conversion in water, mild reaction conditions, and
good yields are the notable advantages of the present method.
EXPERIMENTAL
General Procedure for the Synthesis N-Substituted Pyrrole
To a mixture of nitro compound (1.0 mmol) and indium (325 mesh, 2.0 mmol),
1N aqueous HCl (1 mL) and water (2 mL) were added. The mixture was stirred at
room temperature for 10 min, followed by addition of 2,5-dimethoxytetrahydrofuran

SYNTHESIS OF N-SUBSTITUTED PYRROLES
551
(1.2 mmol), and the stirring was continued. The reaction was monitored by thin-layer
chromatography (TLC). After completion, the reaction mixture was washed with
saturated NaHCO3 solution (3 ꢀ 5 mL) and water (3 ꢀ 5 mL) and subsequently
extracted with EtOAc (3 ꢀ 5 mL). The extract was concentrated, and the residue
was subjected to column chromatography (silica gel, hexane–EtOAc) to obtain pure
N-substituted pyrrole.
1
The spectral (IR, H and 13C NMR and MS) data of the known compounds
(references in Table 2) agreed well with those reported earlier. However, for the com-
pounds whose spectral data are incomplete as well as for the unknown compound
(3q), the relevant spectral and analytical data are given here.
Selected Data
Compound 3f: 1-(4-Fluorophenyl)-1H-pyrrole. IR tmax (KBr): 1617, 1525,
1
1345, 1254 cmꢁ1; H NMR (200 MHz, CDCl3) d ppm 7.29–7.03 (4H, m), 6.91 (2H,
brs), 6.28 (2H, brs); 13C NMR (50 MHz, CDCl3) d ppm 158.7, 136.1, 122.2, 120.2,
116.4, 110.2; ESIMS m=z 162 [M þ H]þ. Anal. calcd. for C10H8FN: C, 74.53; H,
4.94; N, 8.70%. Found: C, 74.62; H, 4.88; N, 8.76%.
Compound 3g: 1-(4-Hydroxyphenyl)-1H-pyrrole. IR tmax (KBr): 3385,
1638, 1524, 1384, 1254 cmꢁ1 1H NMR (200 MHz, CDCl3) d ppm 7.24 (2H, d,
;
J ¼ 8.0 Hz), 6.91 (2H, brs), 6.82 (2H, d, J ¼ 8.0 Hz), 6.24 (2H, brs), 4.81 (1H, brs);
13C NMR (50 MHz, CDCl3) d ppm 153.9, 133.0, 122.3, 120.2, 116.4, 110.1; ESIMS
m=z 160 [M þ H]þ. Anal. calcd. for C10H8NO: C, 74.47; H, 5.66; N, 8.81%. Found:
C, 75.38; H, 5.62; N, 8.86%.
Compound 3j: 4-(1H-Pyrrol-1-yl) benzonitrile. IR tmax (KBr) 2223, 1603,
1515, 1455, 1332 cmꢁ1; 1H NMR (200 MHz, CDCl3) d ppm 7.70 (2H, d, J ¼ 8.0 Hz),
7.46 (2H, d, J ¼ 8.0 Hz), 7.09 (2H, brs), 6.36 (2H, brs); 13C NMR (50 MHz, CDCl3) d
ppm 143.8, 133.9, 120.1, 118.9, 118.1, 112.5, 109.0; ESIMS m=z 169 [M þ H]þ. Anal.
calcd. for C11H8N2: C, 78.57; H, 4.76; N, 16.67%. Found: C, 78.63; H, 4.82; N,
16.73%.
Compound 3p: 1-(2-Chlorophenyl)-1H-pyrrole. IR tmax (KBr) 1608, 1532,
1
1465, 1343, 1267 cmꢁ1; H NMR (200 MHz, CDCl3) d ppm 7.52-7.19 (4H, m), 6.84
(2H, brs), 6.28 (2H, brs); 13C NMR (50 MHz, CDCl3) d ppm 136.6, 131.3, 131.0,
128.1, 127.8, 12.0, 109.8; ESIMS m=z 178, 180 [M þ H]þ. Anal. calcd. for C10H8ClN:
C, 67.61; H, 4.51; N, 7.89%. Found: C, 67.69; H, 4.56; N, 7.81%.
Compound 3q: 1-(2,3-Dichlorophenyl)-1H-pyrrole. IR tmax (KBr) 1579,
1490, 1425, 1334 cmꢁ1; 1H NMR (200 MHz, CDCl3) d ppm 7.41 (1H, t, J ¼ 8.0 Hz),
7.24–7.11 (2H, m), 6.90 (2H, brs), 6.62 (2H, brs); 13C NMR (50 MHz, CDCl3) d ppm
140.8, 134.7, 129.2, 127.4, 126.2, 122.1, 110.0, 96.2; ESIMS m=z 212, 214, 216
[M þ H]þ. Anal. calcd. for C10H7 Cl2N: C, 55.60; H, 3.30; N, 6.60%. Found: C,
56.68; H, 3.25; N, 6.54%.

552
B. DAS ET AL.
ACKNOWLEDGMENT
The authors thank the Council for Scientific and Industrial Research and the
University Grants Commission, New Delhi, for financial assistance.
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