Sulfamic acid as a novel, efficient, cost-effective, and reusable solid acid catalyst for the synthesis of pyrroles under solvent-free conditions

Article abstract of DOI:10.1080/00397910701821051

Paal-Knorr condensation of 2,5-hexadione with primary amines in the presence of a catalytic amount of sulfamic acid under solvent-free conditions has been accomplished with an excellent yield. This is a very easy, rapid, and high-yielding reaction for the synthesis N-substituted pyrrole derivatives. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701821051

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Sulfamic Acid as a Novel, Efficient,
Cost‐Effective, and Reusable Solid Acid
Catalyst for the Synthesis of Pyrroles under
Solvent‐Free Conditions
a
Surya K. De
a
Burnham Institute for Medical Research, La Jolla, California, USA
Published online: 15 Feb 2008.
To cite this article: Surya K. De (2008): Sulfamic Acid as a Novel, Efficient, Cost‐Effective, and Reusable
Solid Acid Catalyst for the Synthesis of Pyrroles under Solvent‐Free Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:5, 803-809
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Synthetic Communications , 38: 803–809, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701821051
Sulfamic Acid as a Novel, Efficient,
Cost-Effective, and Reusable Solid Acid
Catalyst for the Synthesis of Pyrroles under
Solvent-Free Conditions
Surya K. De
Burnham Institute for Medical Research, La Jolla, California, USA
Abstract: Paal–Knorr condensation of 2,5-hexadione with primary amines in the
presence of a catalytic amount of sulfamic acid under solvent-free conditions has
been accomplished with an excellent yield. This is a very easy, rapid, and
high-yielding reaction for the synthesis N-substituted pyrrole derivatives.
Keywords: Paal–Knorr reaction, pyrroles, solvent-free conditions, sulfamic acid
INTRODUCTION
Pyrroles are an important class of heterocyclic compounds with different bio-
[
1]
logical activities. Members of this family have wide applications in
medicinal chemistry and are used as antimalarial, anti-inflammatory antiastha-
[2]
matic, antibacterial, antihypertensive, and tyrosine kinase inhibiting agents.
In addition, pyrroles are found in many naturally occurring compounds such as
[3]
heme, chlorophyll, and vitamin B . Despite their importance from a
1
2
pharmacological, industrial, and synthetic point of view, relatively few
[4]
methods for their preparation have been reported. Of the current methods
[
5]
[6]
[7]
such as Hantzsch,
8]
Knorr,
reaction is one of the most simple and straightforward
and aza-Witting reactions,
the
[
Paal–Knorr
methods for the synthesis of N-substituted pyrroles. Many catalysts have
Received in the USA September 13, 2007
Address correspondence to Surya K. De, Burnham Institute for Medical Research,
10901 North Torrey Pines Road, La Jolla, California 92037, USA. E-mail: skd125@
yahoo.com
8
03

8
04
S. K. De
[
9]
[10]
been used to promote the Paal–Knorr reaction such as Ti(OiPr) , Al O ,
4
2 3
[
11]
[12]
[13]
[14]
Bi(NO ) ,
3
Bi(OTf)3,
Sc(OTf)3
montmorillonite-KSF,
and
3
15]
[
others. No reaction is observed in the absence of catalyst. However,
many of these methods have some drawbacks such as low yields of the
[
11]
[11]
[10]
products,
workup leading to the generation of large amounts of toxic-metal-containing
long reaction times,
harsh reactions conditions,
tedious
[
9]
[12]
waste, the requirement for an inert atmosphere or high temperatures, and
[
11]
[9,13]
the use of stoichiometric
or relatively expensive reagents.
This
reaction is usually carried in polar and toxic solvents such as DMSO and
DMF. Moreover, the main disadvantage of almost all existing methods is
that the catalysts are destroyed in the workup procedure and cannot be
recovered or reused. Therefore, the search continues for a better catalyst for
the synthesis of pyrroles in terms of operational simplicity, reusability,
economic viability, and greater selectivity.
RESULTS AND DISCUSSION
Recently, there has been considerable interest in the use of solid acids as het-
Heterogeneous solid acids are
[16]
erogeneous catalysts in organic synthesis.
more advantageous than conventional homogeneous acid catalysts because
they can be easily recovered from the reaction mixture by simple filtration
and reused. Sulfamic acid (H NSO H) is a common inorganic acid with
2
3
mild acidity that is nonvolatile, noncorrosive, and utilized as a stable, low-
cost, highly efficient green catalyst in organic synthesis.
[17]
It is insoluble in
common organic solvents and is a commercially available, cheap reagent.
In recent years, sulfamic acid has been used in many organic reactions as
[
17]
an efficient heterogeneous catalyst.
use of sulfamic acid as a catalyst for the synthesis of pyrroles.
However, there are no reports of the
[18]
In continuation of our work to develop new synthetic methodologies, we
report herein a facile method for the synthesis of pyrroles by the condensation of
1,4-diketones with primary amines in the presence of a catalytic amount of
sulfamic acid under solvent-free conditions. Accordingly, treatment of 1,4-
diketone with aniline in the presence of a catalytic amount of sulfamic acid
afforded 2,5-dimethyl-N-phenylpyrrole in 92% yield (Scheme 1). In the same
manner, a variety of a amines were coupled with a 1,4-diketone in the
Scheme 1.

Sulfamic Acid–Catalyst Pyrrole Synthesis
805
Table 1. Synthesis of pyrroles using sulfamic acid as a catalyst
a
Time
(min)
Yield
(%)
Entry
Amine
Product
1
2
3
4
5
6
7
8
9
C
6
H
5
NH
4-NO
Furfurylamine
4-CH OC H NH
2
2
2a
2b
2c
2d
2e
2f
30
60
35
25
40
75
60
40
90
90
92
81
89
93
87
82
82
91
85
88
2 6 4 2
C H NH
3
6
4
Benzyl amine
n-Butyl amine
2-Aminopyridine
4-ClC NH
2g
2h
2i
6
H
4
2
1-Aminonaphthalene
1-Aminoanthracene
1
0
2j
a
Yields refer to pure products and were characterized by comparison of
[9–14]
1
their mp, IR, and H NMR spectra with those of authentic samples.
presence of a catalytic amount of sulfamic acid at room temperature to give
the corresponding pyrroles in good to excellent yields (Table 1). We also
observed that the reaction in DCM, methanol, or THF takes longer times than
in the neat conditions. This acceleration is probably attributable to the concen-
tration effect.
To extend the scope of this reaction, other substituted diketones such as 1,4-
diphenylbutane-1,4-dione and 1-phenylpentane-1,4-dione were used. Clean
formation of pyrroles was observed under solvent-free conditions (Scheme 2).
This method does not require any other additives to promote the reaction. The
reaction is fairly general, clean, and efficient. The experimental procedure is
very simple. The high-yield transformation did not lead to any significant
amounts of undesirable side products. Unlike previously reported methods, the
present method does not require high temperatures to produce pyrrole
Scheme 2.

8
06
S. K. De
derivatives. Theresultsshown inTable1clearly indicatethescope andgenerality
of the reactions with respect to various aromatic, aliphatic, and heterocyclic
primary amines.
EXPERIMENTAL
NMR spectra were recorded on a Bruker ARX 300 (330-MHz) instrument.
Low-resolution mass spectra (EI, CI) were recorded on a Finnigan 4000 mass
spectrometer. High-resolution mass spectra were recorded (HRMS, ESI)
were recorded on Finnigan Mat XL 95 mass spectrometer. Melting points
were recorded on Buchi R-535 apparatus and are uncorrected. All solvents
and reagents were purchased from Aldrich with high quality and were used
without any further purification. All yields refer to isolated products.
Typical Procedure
A mixture of hexane-2,5-dione (684 mg, 6 mmol), aniline (465 mg, 5 mmol),
and sulfamic acid (25 mg, 5 mol%) was stirred at room temperature under
solvent-free conditions for 30 min. After completion of the reaction, as
indicated by thin-layer chromatography (TLC), the reaction mixture was
diluted with diethyl ether and filtered to recover the catalyst. The ether layer
was washed with brine, dried (MgSO ), and concentrated in vacuo. The
4
residue was purified by silica-gel column chromatography (20% ethyl acetate
in hexane) to afford the pure product (786 mg) in 92% yield. The recovered
catalyst was washed with diethyl ether and activated at 708C prior to reuse.
The IR spectrum of the recovered catalyst was identical to that of the commer-
cially available catalyst (Aldrich), which could be reused for the next reaction
without losing any significant activity. The catalyst was recovered and reused
three times (reaction yields: 82%, 76%, and 62%). All compounds are known
[9–15]
and were identified by comparison with those of the authentic samples.
Product Characterization Data
1
,5-Dimethyl-1-pheny-1H-pyrrole (2a, entry 1): Oil; H NMR (300 MHz,
2
CDCl ) d 2.06 (s, 6H), 5.94 (s, 2H), 7.20–7.28 (m, 2H), 7.42–7.54
3
(
for C H N: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.19; H, 7.71; N, 8.21.
m, 3H). HRMS calcd. for C H N 171.1048; found 171.1049. Anal. calcd.
12 13
1
2 13
1
-(4-Methoxyphenyl)-2,5-dimethyl-1-H-pyrrole (2d, entry 4): Mp 60–618C;
1
H NMR (300 MHz, CDCl ) d 2.04 (s, 6H), 3.88 (s, 3H), 5.89 (s, 2H), 6.92
m, 2H), 7.16 (m, 2H). HRMS calcd. for C H NO 201.1154; found
3
(
1
3 15
2
7
01.1156. Anal. calcd. for C H NO: C, 77.58; H, 7.15; N, 6.95. Found: C,
13 15
7.52; H, 7.18; N, 6.99.

Sulfamic Acid–Catalyst Pyrrole Synthesis
807
1
1
-Benzyl-2,5-dimethyl-1H-pyrrole (2e, entry 5): Mp 43–458C; H NMR
(
300 MHz, CDCl ) d 2.18 (s, 6H), 5.04 (s, 2H), 5.89 (s, 2H), 6.90–6.95
3
(
m, 2H), 7.20–7.41 (m, 3H). HRMS calcd. for C H N 185.1205; found
1
3 15
1
8
85.1204. Anal. calcd. for C H N: C, 84.28; H, 8.16; N, 7.56. Found: C,
13 15
4.32; H, 8.21; N, 7.61.
1
-Butyl-2,5-dimethyl-1H-pyrrole (2f, entry 6): Oil; H NMR (300 MHz,
1
CDCl ) d 0.94 (t, J ¼ 7.2 Hz, 3H), 1.38 (m, 2H), 1.61 (m, 2H), 2.17
3
(
s, 6H), 3.71 (t, J ¼ 7.2 Hz, 2H), 5.79 (s, 2H). HRMS calcd. for C H N
1
0 17
1
N, 9.26. Found: C, 76.43; H, 11.38; N, 9.30.
51.1361; found 151.1360. Anal. calcd. for C H N: C, 76.41; H, 11.33;
10 17
1
-(2,5-Dimethyl-1H-pyrrol-1yl)-pyridine (2g, entry 7): H NMR (300 MHz,
2
CDCl ) d 2.10 (s, 6H), 5.92 (s, 2H), 7.27 (m, 2H), 7.81 (m, 1H), 8.61 (m, 1H).
3
HRMS calcd. for C H N 172.1000; found 172.10002. Anal. calcd. for
11 12 2
C H N: C, 76.71; H, 7.02; N, 16.27. Found: C, 76.76; H, 7.05; N, 16.30.
11 12
2
,5-Dimethy-1-(naphthalene-1-yl)-1H-pyrrole (2i, entry 9): Mp 120–1218C;
1
H NMR (300 MHz, CDCl ) d 1.91 (s, 6H), 6.01 (s, 2H), 7.15
3
(
d, J ¼ 8.2 Hz, 1H), 7.36–7.59 (m, 4H), 7.94 (d, J ¼ 8.2 Hz, 2H). HRMS
calcd. for C H N 221.1204; found 221.1206. Anal. calcd. for C H N: C,
15
1
6
16 15
8
6.84; H, 6.83; N, 6.33. Found: C, 86.88; H, 6.85; N, 6.31.
1
-(Anthracen-1-yl)-2,5-dimethyl-1H-pyrrole (2j, entry 10): Mp 183–1848C;
1
H NMR (300 MHz, CDCl ) d 1.95 (s, 6H), 6.04 (s, 2H), 7.35–7.59
3
(
m, 4H), 7.71 (s, 1H), 7.92 (d, J ¼ 8 Hz, 1H), 8.02 (d, J ¼ 7.9 Hz, 1H),
8
found 271.1362. Anal. calcd. for C H N: C, 88.52; H, 6.31; N, 5.16.
.10 (d, J ¼ 8.4 Hz, 1H), 8.52 (s, 1H). HRMS calcd. for C H N 271.1361;
20 17
2
0 17
Found: C, 88.58; H, 6.37; N, 5.20.
1
-Methyl-1,5-dipheny-1H-pyrrole (Scheme 2): H NMR (300-MHz, CDCl ) d
2
2
3
.15 (s, 3H), 6.09 (d, J ¼ 3.6 Hz, 1H), 6.32 (d, J ¼ 3.5 Hz, 1H), 7.02–7.40
(m, 10 H). HRMS calcd. for C H N 233.1204; found 233.1206. Anal. calcd.
for C H N: C, 87.52; H, 6.48; N, 6.00. Found: C, 87.58; H, 6.54; N, 6.04.
17 15
1
7 17
CONCLUSION
In conclusion, we have demonstrated a mild and efficient procedure for the
synthesis of pyrrole derivatives using a catalytic amount of sulfamic acid.
The significant features of this method include (a) operational simplicity,
(b) the use of an inexpensive and reusable catalyst, (c) high yields, and (d)
short reaction times. In addition, unlike many other methods, no extra energy
source such as microwave irradiation or ultrasound is needed for the success
of the reaction. This procedure has a great potential for future application.

8
08
S. K. De
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