A facile synthesis of N-substituted 2,5-dimethylpyrroles with saccharin as a green catalyst

Article abstract of DOI:10.1007/s10593-015-1701-x

[MediaObject not available: see fulltext.]The paper describes a convenient method for the preparation of N-substituted 2,5-dimethylpyrroles using edible sweetener saccharin. Various heterocyclic and aromatic hydrazides have been converted to their corresp

Full text of DOI:10.1007/s10593-015-1701-x

DOI 10.1007/s10593-015-1701-x
Chemistry of Heterocyclic Compounds 2015, 51(4), 320–323
A facile synthesis of N-substituted 2,5-dimethylpyrroles
with saccharin as a green catalyst
Namratha Bhandari1, Santosh L. Gaonkar1*
1 Department of Chemistry, Manipal Institute of Technology, Manipal University,
Manipal 576104, India; е-mail: gaonkarslg@rediffmail.com
Submitted March 7, 2015
Accepted March 25, 2015
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(4), 320–323
Me
O
O
H
N
Saccharin
Me
+
NH2
N
Me
R
N
MeOH
rt, 30 min
O
H
O
R
Me
The paper describes a convenient method for the preparation of N-substituted 2,5-dimethylpyrroles using edible sweetener saccharin.
Various heterocyclic and aromatic hydrazides have been converted to their corresponding Paal–Knorr pyrroles at room temperature in
methanol with saccharin as a green catalyst. Saccharin can be recycled for the next two runs without apparent loss in its activity. Here we
propose a method which is speedy, proficient, and ecologically safe.
Keywords: pyrrole, saccharin, cyclocondensation, Paal–Knorr reaction.
The ring closure reaction between amines or hydrazides
and open chain carbonyl compounds forms compounds of a
class called Paal–Knorr pyrroles. Pyrroles are the synthons
of quite a few unnatural heterocyclic derivatives that
demonstrate properties like antimicrobial,1–3 antitubercular,4–6
analgesic,7–9 anti-inflammatory,10–12 and antitumor activi-
ties.13–15 Pyrrole ring is the key structural unit of important
naturally occurring compounds, such as vitamin B12,
heme, and chlorophyll.
Natural sugars and unnatural sweeteners are becoming
employed as reagents and catalysts in organic functional
group transformations. Recently, β-cyclodextrin,37 a cyclic
oligosaccharide containing seven glucose units in the
molecule has been introduced as a catalyst for the Paal–
Knorr reaction. In search of a green catalyst, we have come
across the artificial sweetener saccharin. Saccharin
(1,2-benzisothiazol-3(2H)-one 1,1-dioxide) is a Brønsted
acid with moderate acidity (pKa 2.32). This inexpensive,
edible, and benign chemical has been used as a catalyst for
some organic functional group transformations.38,39 To the
best of our knowledge, a saccharin-mediated Paal–Knorr
reaction has not been demonstrated yet. In continuance to
our work on development of new reagents in organic
synthesis,40,41 we herewith report a simple method to
produce pyrroles using saccharin as an interesting catalyst.
The purpose of the present work was to obtain 1-(4-fluoro-
phenyl)-N-(2,5-dimethyl-1H-pyrrol-1-yl)-1,3-dihydro-2-benzo-
furan-5-carboxamide (3a) from 1-(4-fluorophenyl)-1,3-di-
hydro-2-benzofuran-5-carbohydrazide (2a). To develop an
easily adaptable catalytic version of the Paal–Knorr pyrrole
synthesis was another objective of the investigation. Firstly, the
solubility of compound 2a was tested in a variety of solvents.
Compound 2a was soluble in methanol, but only sparingly
soluble in other polar solvents like water, ethanol, and iso-
propanol. Similarly, it was soluble in diethyl ether, but hardly
soluble in toluene, ethyl acetate, hexane, and dichloromethane.
As diethyl ether is a highly volatile flammable liquid, methanol
was chosen as the reaction medium.
The popular Paal–Knorr pyrrole synthesis has been
originally carried out by boiling amines in acetic acid for
an elongated period.16 There are different promoting agents
in use like Sc(OTf)3,17 xanthan sulfuric acid,18 silica
sulfuric acid,19 p-toluenesulfonic acid, 20 amberlite IR 120
acidic resin,21 polystyrene-supported GaCl3,22 silica-
23
supported SbCl3, PEG-bound sulfonic acid,24 mont-
morillonite.25 Although there are a number of catalysts and
different synthetic strategies26–28 the application of the Paal–
Knorr synthesis is limited by the harsh reaction conditions
and wearying work-up.
Most of the methods are particular to certain types of
starting materials. Thus, we faced a difficulty in the
reaction of hexane-2,5-dione (1) with 1-(4-fluorophenyl)-
1,3-dihydro-2-benzofuran-5-carbohydrazide (2a).29 Gentle
reaction conditions were required to obtain the desired
1-(4-fluorophenyl)-N-(2,5-dimethyl-1H-pyrrol-1-yl)-1,3-di-
hydro-2-benzofuran-5-carboxamide (3a) (Scheme 1).
Compounds 2a and 3a can be regarded as derivatives of
1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile29
which has been used as an intermediate in the synthesis of
citalopram,30 a well-known antidepressant.31–36
We carried out the reaction of compounds 1 and 2a in
methanol at various temperatures. Without the use of any
0009-3122/15/5104-0320©2015 Springer Science+Business Media New York
320

Chemistry of Heterocyclic Compounds 2015, 51(4), 320–323
Scheme 1
Me
O
O
Saccharin
H
Me
+
NH2
N N
Me
R
N
H
MeOH
rt, 30 min
O
O
R
Me
3a–l
1
2a–l
Cl
O
S
Me
O
S
NH
2, 3 a R =
, b R =
, c R =
, d R =
, e R =
, f R =
,
N
Cl
O
F
g R =
, h R =
, i R =
, j R =
, k R =
, l R =
MeO
Br
Cl
F
Me
catalyst, the reaction did not go to completion. The use of a
catalyst was, therefore, an obvious necessity. In order to
find the best conditions for the reaction under investigation,
we tried to prepare compound 3a using several Brønsted
acids acting as catalysts. The results are summarized in
Table 1. The Paal–Knorr reaction with p-TsOH,
benzenesulfonic acid, and methanesulfonic acid with the
similar acidity yielded a complex mixture as was evident by
NMR analysis. Different Brønsted acids with pKa 1.2–3.8
afforded good to moderate yields. Saccharin with pKa 2.3
showed the best result, and was thus chosen for further study.
The impact of the relative saccharin concentration on the
model reaction was also investigated. The best catalyst load
was turned out to be 25 mol % (Table 2). Lower amount of
saccharin afforded lower yields while higher amounts did
not cause an increase of the yield. Meanwhile, no
substantial loss of the product yield was observed when the
catalyst contained in the filtrate from the reaction mixture
was reused twice.
To appreciate the scope of the saccharin-mediated Paal–
Knorr reaction, different hydrazides 2b–l were condensed
with hexane-2,5-dione (1) under the optimized conditions
(Scheme 1). The yields of the corresponding products 3b–l
are shown in Table 3. A close inspection of the yields
shows that heterocyclic, as well as aromatic hydrazides
react equally well with hexane-2,5-dione (1) under the
described conditions forming stable products.
Table 1. Effect of different catalysts on the synthesis
of compound 3a*
Entry
Catalyst
pKa
Yield, %
1
2
3
4
5
6
7
8
9
p-Toluenesulfonic acid
Benzenesulfonic acid
Methanesulfonic acid
Sulfamic acid
Oxalic acid
–2.8
–2.8
–1.9
1.0
0
0
0
29
51
86
71
63
36
1.2
Saccharin
2.3
Citric acid
3.1
Glycolic acid
3.8
Acetic acid
4.7
* Reaction conditions: compound 1 (6.0 mmol), compound 2a (4.0 mmol),
catalyst (1.0 mmol), MeOH (6 ml), room temperature, 30 min.
Table 2. Effect of the relative amount of saccharin
on the yield of compound 3a*
Entry
Amount of saccharin, mol %
Yield, %
1
2
3
4
12.5
25
53
86
86
86
37.5
50
In conclusion, there are several reports in literature
describing the use of catalysts for the Paal–Knorr conden-
sation. In the present work, saccharin exhibited a promising
applicability owing to its non-toxic nature, low cost,
ecological safety, product yield, easy isolation procedures,
and reusability.
* Reaction conditions as specified in Table 1.
Table 3. Melting points and yields of synthesized compounds 3a–l
Compound Mp, °C
Yield, % Compound Mp, °C
Yield, %
182–184
86
82
89
91
80
84
3g42
3h42
3i
164–166
200–202
208–210
196–200
190–192
174–176
84
92
85
87
90
90
3a
Experimental
186–188
3b
Fourier transform IR spectra in KBr pellets were
1
recorded on a Shimadzu 8300 FT-IR spectrometer. H and
194–196
214–216
210–212
218–220
3c
3d
3e
3f
13C NMR spectra (400 and 100 MHz) were recorded on a
Bruker AM spectrometer in DMSO-d6 solution with TMS
as internal standard. ESI mass spectra were recorded on an
Agilent 6520 ESIQTOF instrument at ionization potential
of 110 V and acetonitrile as solvent. Elemental analyses
3j
3k
3l
321

Chemistry of Heterocyclic Compounds 2015, 51(4), 320–323
were performed on a Vario-EL instrument. The melting
N-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-methyl-1,3-thiazole-
4-carboxamide (3e). IR spectrum, ν, cm–1: 3241 (NH),
2955 (Ar CH), 1612 (C=O), 1537 (CH3). 1H NMR
spectrum, δ, ppm: 11.18 (1H, s, NH); 7.12 (1H, s,
H thiazole); 5.61 (2H, s, H pyrrole); 2.05 (6H, s, 2CH3);
1.21 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 158.3;
138.3; 137.2; 135.6; 128.7 (C9); 104.1; 21.4; 11.2. Found,
%: C 56.19; H 5.50; N 17.88. C11H13N3OS. Calculated, %:
C 56.15; H 5.57; N 17.86.
points were determined on a Thomas Hoover apparatus and
remain uncorrected. Reactions were monitored by thin-
layer chromatography using 0.25 mm silica gel plates
(60F254, Merck) and PhMe–EtOAc, 2:1, as the mobile
phase. Visualization was made with ultraviolet light. Rea-
gents were obtained commercially and used as received.
Saccharin-mediated Paal–Knorr pyrrole cyclocon-
densation (General method). Saccharin (0.183 g, 1.0 mmol)
was added to a solution of hexane-2,5-dione (1) (0.684 g,
6.0 mmol) and hydrazide 2a–l (4.0 mmol) in methanol
(6 ml). The mixture was stirred at room temperature for
30 min. After the completion of the reaction, the mixture
was cooled in an ice bath. The brown solid product was
filtered off and recrystallized from MeOH. The filtrate
could be used for the next two runs with fresh reactants 1
and 2a–l without any sign of decreased catalytic activity.
1-(4-Fluorophenyl)-N-(2,5-dimethyl-1H-pyrrol-1-yl)-
1,3-dihydro-2-benzofuran-5-carboxamide (3a). IR spectrum,
ν, cm–1: 3251 (NH), 2356 (Ar CH), 1662 (C=O), 1512
(CH3), 1330 (COC), 1226 (CF). 1H NMR spectrum, δ, ppm
(J, Hz): 11.25 (1H, s, NH); 7.94 (1H, s, H Ar); 7.84 (1H, d,
J = 7.6, H Ar); 7.42 (2H, t, J = 6.8, H Ar); 7.21 (3H, t,
J = 8.8, H Ar); 6.26 (1H, s, CH); 5.70 (2H, s, H pyrrole);
5.36 (1H, d, J = 12.8, CH); 5.18 (1H, d, J = 12.8, CH); 2.20
(6H, s, 2CH3). 13C NMR spectrum, δ, ppm: 166.2; 163.4;
146.4; 139.9; 138.8; 132.2; 129.1; 129.0; 127.4; 122.8;
121.3; 115.7; 103.6; 84.5; 72.8; 11.4. Mass spectrum, m/z
(Irel, %): 351 [M+H]+ (100), 241 (2), 214 (10), 165 (11), 94
(20), 67 (7). Found, %: C 71.92; H 5.40; N 8.05.
C21H19FN2O2. Calculated, %: C 71.98; H 5.47; N 8.00.
2-{2-[(2,6-Dichlorophenyl)amino]phenyl}-N-(2,5-dimethyl-
1H-pyrrol-1-yl)acetamide (3f). IR spectrum, ν, cm–1:
3328 (NH), 2360 (Ar CH), 1674 (C=O), 1450 (CH3), 775
1
(CCl). H NMR spectrum, δ, ppm (J, Hz): 11.09 (1H, s,
NH); 7.71 (1H, s, H Ar); 7.52 (2H, d, J = 7.6, H Ar); 7.31
(1H, d, J = 6.0, H Ar); 7.18 (1H, t, J = 7.2, H Ar); 7.08
(1H, d, J = 6.8, H Ar); 6.92 (1H, d, J = 6.4, H Ar); 6.32
(1H, d, J = 7.2, H Ar); 5.63 (2H, s, H pyrrole); 3.78 (2H, s,
CH2); 2.06 (6H, s, 2CH3). 13C NMR spectrum, δ, ppm:
171.5; 143.2; 137.4; 130.8; 130.0; 129.6; 128.1; 127.9;
127.1; 125.8; 124.9; 121.5; 116.7; 104.7; 103.5; 37.5; 11.6.
Found, %: C 61.8; H 4.99; N 10.80. C20H19Cl2N3O.
Calculated, %: C 61.86; H 4.93; N 10.82.
N-(2,5-Dimethyl-1H-pyrrol-1-yl)benzamide
(3g).
IR spectrum, ν, cm–1: 3148 (NH), 2576 (Ar CH), 1681
1
(C=O), 1511 (CH3). H NMR spectrum, δ, ppm (J, Hz):
11.41 (1H, s, NH); 8.18 (2H, d, J = 7.5, H Ar); 7.61 (1H, t,
J = 7.2, H Ar); 7.56 (2H, t, J = 7.6, H Ar); 5.21 (2H, s,
H Pyrrole); 2.04 (6H, s, 2CH3). 13C NMR spectrum,
δ, ppm: 167.8; 136.4; 133.9; 131.0; 130.2; 128.6; 102.8;
11.1. Found, %: C 72.81; H 6.57; N 13.05. C13H14N2O.
Calculated, %: C 72.87; H 6.59; N 13.07.
N-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-benzofuran-2-carb-
4-Methoxy-N-(2,5-dimethyl-1H-pyrrol-1-yl)benzamide
(3h). IR spectrum, ν, cm–1: 3232 (NH), 2846 (Ar CH), 1644
(C=O), 1564 (CH3), 1248 (COC). 1H NMR spectrum,
δ, ppm (J, Hz): 11.06 (1H, s, NH); 7.20 (2H, d, J = 8.0,
H Ar); 6.92 (2H, d, J = 8.0, H Ar); 5.70 (2H, s, H pyrrole);
3.21 (3H, s, OCH3); 2.03 (6H, s, 2CH3). 13C NMR
spectrum, δ, ppm: 171.4; 166.2; 134.2; 131.3; 130.1; 129.5;
103.7; 55.6; 11.1. Found, %: C 68.78; H 6.66; N 11.42.
C14H16N2O2. Calculated, %: C 68.83; H 6.60; N 11.47.
4-Bromo-N-(2,5-dimethyl-1H-pyrrol-1-yl)benzamide (3i).
IR spectrum, ν, cm–1: 3144 (NH), 2972 (Ar CH), 1654
(C=O), 1502 (CH3), 511 (CBr). 1H NMR spectrum, δ, ppm
(J, Hz): 11.02 (1H, s, NH); 7.86 (2H, d, J = 7.5, H Ar); 7.72
(2H, d, J = 7.5, H Ar); 5.61 (2H, s, H pyrrole); 2.02 (6H, s,
2CH3). 13C NMR spectrum, δ, ppm: 160.4; 134.9; 133.2;
129.1; 127.7; 124.2; 102.8; 11.2. Found, %: C 53.20; H 4.42;
N 9.58. C13H13BrN2O. Calculated, %: C 53.26; H 4.47; N 9.56.
4-Chloro-N-(2,5-dimethyl-1H-pyrrol-1-yl)benzamide
(3j). IR spectrum, ν, cm–1: 3227 (NH), 2891 (Ar CH), 1605
(C=O), 1556 (CH3), 747 (CCl). 1H NMR spectrum, δ, ppm:
11.35 (1H, s, NH); 7.89 (2H, s, H Ar); 7.89–7.79 (2H, m,
H Ar); 5.71 (2H, s, H pyrrole); 2.03 (6H, s, 2CH3).
13C NMR spectrum, δ, ppm: 165.4; 132.2; 131.4; 130.0;
127.4; 126.6; 103.7; 11.4. Found, %: C 62.77; H 5.25; N 11.21.
C13H13ClN2O. Calculated, %: C 62.78; H 5.27; N 11.26.
4-Fluoro-N-(2,5-dimethyl-1H-pyrrol-1-yl)benzamide
(3k). IR spectrum, ν, cm–1: 3319 (NH), 2462 (Ar CH),
oxamide (3b). IR spectrum, ν, cm–1: 3232 (NH), 2993 (Ar
1
CH), 1674 (C=O), 1589 (CH3), 1222 (COC). H NMR
spectrum, δ, ppm (J, Hz): 11.60 (1H, s, NH); 7.84 (1H, d,
J = 7.6, H benzofuran); 7.78 (1H, s, H benzofuran); 7.73
(1H, d, J = 8.0, H benzofuran); 7.56–7.52 (1H, t, J = 7.6,
H benzofuran); 7.41–7.37 (1H, t, J = 7.6, H benzofuran); 5.72
(2H, s, H pyrrole); 2.05 (6H, s, 2CH3).13C NMR spectrum,
δ, ppm: 158.1; 155.0; 147.1; 128.0; 127.5; 127.2; 124.5; 123.5;
112.4; 111.8; 103.8; 11.5. Found, %: C 70.88; H 5.51; N 11.09.
C15H14N2O2. Calculated, %: C 70.85; H 5.55; N 11.02.
N-(2,5-Dimethyl-1H-pyrrol-1-yl)furan-2-carboxamide (3c).
IR spectrum, ν, cm–1: 3217 (NH), 2354 (Ar CH), 1650
1
(C=O), 1522 (CH3). H NMR spectrum, δ, ppm (J, Hz):
11.28 (1H, s, NH); 7.79 (2H, d, J = 4.6, H furan); 7.17 (1H, t,
J = 4.0, H furan); 5.72 (2H, s, H pyrrole); 2.07 (6H, s, 2CH3).
13C NMR spectrum, δ, ppm: 162.1; 140.2; 136.8; 135.6; 112.7;
106.2; 103.5; 11.4. Found, %: C 64.62; H 5.75; N 13.77.
C11H12N2O2. Calculated, %: C 64.69; H 5.92; N 13.72.
N-(2,5-Dimethyl-1H-pyrrol-1-yl)thiophene-2-carboxamide
(3d). IR spectrum, ν, cm–1: 3236 (NH), 2360 (Ar CH), 1674
(C=O), 1539 (CH3). 1H NMR spectrum, δ, ppm (J, Hz): 11.30
(1H, s, NH); 7.92 (2H, d, J = 4.8, H thiophene); 7.25 (1H, t,
J = 4.0, H thiophene); 5.70 (2H, s, H pyrrole); 2.00 (6H, s,
2CH3). 13C NMR spectrum, δ, ppm: 161.0; 132.8; 129.9;
128.7; 127.6; 127.5; 103.7; 11.5. Found, %: C 59.93;
H 5.40; N 12.76. C11H12N2OS. Calculated, %: C 59.97;
H 5.49; N 12.72.
1
1615 (C=O), 1528 (CH3), 1177 (CF). H NMR spectrum,
322

Chemistry of Heterocyclic Compounds 2015, 51(4), 320–323
Saparpakorn, P.; Hannongbua, S.; Wolschann, P.; Pungpo, P.
δ, ppm (J, Hz): 11.11 (1H, s, NH); 8.02 (2H, d, J = 7.5,
Mol. Inf. 2013, 32, 541.
H Ar); 7.31 (2H, d, J = 7.5, H Ar); 5.25 (2H, s, H pyrrole);
2.10 (6H, s, 2CH3). 13C NMR spectrum, δ, ppm: 168.9;
161.5; 134.0; 131.4; 128.7; 112.6; 103.7; 11.3. Found:
C 67.21; H 5.70; N 12.03. C13H13FN2O. Calculated, %:
C 67.23; H 5.64; N 12.06.
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Roxas, A.; Caruso, A.; Trombadone, S. Eur. J. Med. Chem.
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N-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methylbenzamide (3l).
IR spectrum, ν, cm–1: 3014 (NH), 2781 (Ar CH), 1623
1
(C=O), 1552 (CH3). H NMR spectrum, δ, ppm (J, Hz):
11.32 (1H, s, NH); 7.85 (2H, d, J = 7.6, H Ar); 7.32 (2H, d,
J = 7.5, H Ar); 5.72 (2H, s, H pyrrole); 2.00 (6H, s, 2CH3);
1.24 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 168.5; 140.7;
136.0; 132.6; 129.4; 128.4; 103.4; 21.2; 11.1. Found, %:
C 73.61; H 7.10; N 12.24. C14H16N2O. Calculated, %: C 73.66;
H 7.06; N 12.27.
We gratefully acknowledge the access to laboratory
facilities of Manipal Institute of Technology, Manipal.
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The Supplementary material is available for authorized
users.
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