Novel synthetic route to pyrano[2,3-b]pyrrole derivatives

Article abstract of DOI:10.1080/15533174.2011.614313

Synthesis of a new series of 2-amino-4,7-dihydro-4-arylpyrano[2,3-b] pyrrole-3-carbonitrile has been reported. The acid-catalyzed cyclocondensation synthesis proceeded by the one-pot reaction of 2-hydroxypyrrole, malononitrile, and various aromatic aldehydes in the presence of silica-supported ionic liquid of [pmim]HSO_{4 SiO2} (silica-supported 1-methyl-3- (triethoxysilylpropyl)imidazolium hydrogensulfate) as an efficient catalyst. The electronic nature of the substitution attached to the aldehyde affected the reaction efficiency profoundly.

Full text of DOI:10.1080/15533174.2011.614313

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Novel Synthetic Route to Pyrano[2,3-b]pyrrole
Derivatives
Saman Damavandi a & Reza Sandaroos b
a Department of Chemistry, Islamic Azad University, Sarvestan Branch, Sarvestan, I. R. Iran
b Department of Chemistry, Faculty of Science, University of Birjand, Birjand, I. R. Iran
Available online: 03 Apr 2012
To cite this article: Saman Damavandi & Reza Sandaroos (2012): Novel Synthetic Route to Pyrano[2,3-b]pyrrole Derivatives,
Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 42:5, 621-627
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 42:621–627, 2012
Copyright ꢀ Taylor & Francis Group, LLC
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ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2011.614313
Novel Synthetic Route to Pyrano[2,3-b]pyrrole Derivatives
Saman Damavandi1 and Reza Sandaroos2
1Department of Chemistry, Islamic Azad University, Sarvestan Branch, Sarvestan, I. R. Iran
2Department of Chemistry, Faculty of Science, University of Birjand, Birjand, I. R. Iran
tivity.[23] Some of these compounds are widely employed as
cosmetics and pigments and as potential biodegradable agro-
chemicals.[24] Accordingly, the synthesis of such compounds is
an interesting challenge.
Synthesis of
a
new series of 2-amino-4,7-dihydro-4-
arylpyrano[2,3-b]pyrrole-3-carbonitrile has been reported. The
acid-catalyzed cyclocondensation synthesis proceeded by the
one-pot reaction of 2-hydroxypyrrole, malononitrile, and var-
ious aromatic aldehydes in the presence of silica-supported
ionic liquid of [pmim]HSO4 SiO2 (silica-supported 1-methyl-3-
(triethoxysilylpropyl)imidazolium hydrogensulfate) as an efficient
catalyst. The electronic nature of the substitution attached to the
aldehyde affected the reaction efficiency profoundly.
Many researches have been devoted to the synthesis of var-
ious pyran derivatives such as benzopyrans,[25,26] naphtopy-
rans,[27–29] and 4-substitueted pyrans[30] in order to the ob-
tain more biologically potent heterocyclic systems. However,
to the best of our knowledge, synthesis of 2-amino-4,7-dihydro-
4-arylpyrano[2,3-b]pyrrole-3-carbonitrile derivatives has never
been reported up to now. In the present study, we have re-
ported the synthesis of 2-amino-4,7-dihydro-4-arylpyrano[2,3-
b]pyrrole-3-carbonitrile by one-pot cyclocondensation of 3-
hydroxypyrrole, aromatic aldehydes, and malononitrile in
the presence of [pmim]HSO4SiO2 being a silica-supported
Keywords 2-amino-4,
7-dihydro-4-arylpyrano[2,3-b]pyrrole-3-
carbonitrile, hydrogensulfate ionic liquid, one-pot
INTRODUCTION
Recently, ionic liquids have become a powerful alternative
to conventional molecular organic solvents due to their partic-
ular properties, such as undetectable vapor pressure and the
ability to dissolve many organic and inorganic substances.[1]
In addition, the ionic liquids are readily recycled and tunable
to specific chemical tasks. One type is Brønsted acidic task-
specific ionic liquids (BAILs). Among these ionic liquids pos-
sessing HSO4 as a counteranion they find a broad application
in organic synthesis, acting as both solvents and catalysts. Re-
cently, immobilization processes involving acidic ionic liquids
on solids supports have been designed.[2–8] The heterogeniza-
tion of catalysts and reagents can offer important advantages in
handling, separation, and reuse procedures. Based on economic
criteria, it is desirable to minimize the amount of ionic liquid
utilized in a potential process. Immobilized acidic ionic liquids
have been used as novel solid catalysts for a wide spectrum of
reactions.[9–13]
−
ionic liquid with acidic counteranion of HSO4 (Figures 1
and 2).
EXPERIMENTAL
General
All chemicals and accessible ionic liquids were purchased
from Merck, Fluka, and Aldrich Chemical Companies. All
yields refer to isolated products. The products were charac-
terized by their spectral data. IR spectra were recorded on a
1
Shimadzu-IR 470 spectrophotometer. H NMR spectra were
recorded on a Bruker. 100-MHz spectrometer in chloroform as
the solvent and TMS as internal standard. Elemental analysis (C,
H, N%) was carried out by Perkin-Elmer 2400 series-II elemen-
tal analyzer. [pmim]HSO4 SiO2 (extent of labeling 0.25 mmol/gr
loading) was prepared according to the literature.[31]
The 4H-pyran derivatives are of the immense interests in the
area of synthesizing veracious drugs due to their various phar-
macological and biological activities, such as antimicrobial,[14]
mutagenicity,[15,16] antiproliferative,[17] sex pheromone,[18] anti-
tumor,[19] cancer therapy,[20–22] and central nervous system ac-
General Procedure for Synthesis of Pyranopyrrole
Derivatives 5a-l
A mixture of aldehyde (1 mmol), 2-hydroxypyrrole (1
mmol), malononitrile (1.1 mmol), and ionic liquid catalyst (0.1
mmol) in CH3CN (4 mml) was stirred at 60◦C for the appropriate
time. The reaction was monitored by TLC and after completion
of the reaction, the catalyst was simply recovered by filtration
and washed by dichloromethane. The residue was concentrated
in vacuo and the crude product was purified by column chro-
matography on silica gel.
Received 10 July 2011; accepted 9 August 2011.
Address correspondence to Saman Damavandi, Department of
Chemistry, Islamic Azad University, Sarvestan Branch, Sarvestan, I.
R. Iran. E-mail: Saman damavandi@yahoo.com
621

622
S. DAMAVANDI AND R. SANDAROOS
TABLE 1
Comparing the catalytic efficiency of various ionic liquidsa
Entry
Catalyst
Time (h)
Yield (%)b
1
2
3
4
5
—
24
5
8
7.5
10
0
FIG. 1. One-pot synthesis of pyranopyrroles.
[pmim]HSO4 SiO2
[pmim]HSO4
[pmim]BF4
[pmim]Cl
90
63
15
7
2-amino-4,7-dihydro-4-(4-methoxyphenyl)pyrano[2,3-
b]pyrrole-3-carbonitrile (5a)
aReaction conditions: 1.0 equiv. of 2-hydroxypyrrole, 1.0 equiv. of
benzaldehyde, 1.0 equiv. of malononitrile, 10 mol% of catalyst, 4 mL
of CH3CN as solvent and at 60◦C.
Anal. Calcd. for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72%.
Found: C, 66.31; H, 4.81; N, 15.63%. IR (KBr, νmax, cm−1):
3410 & 3255 (asym. & sym. str. of -NH2), 3400 (NH), 2120
(-CN str.), 1265 (asym. str. of cyclic ArC-O-C ether). 1H NMR
(400 MHz, CD3Cl3) δH (ppm): 3.55 (s, 3H, OCH3), 5.58 (s, 1H,
CH), 6.17 (d, 1H, pyrr), 6.55 (d, 2H, Ar-H), 6.65 (d, 1H, pyrr),
6.97 (s, 2H, D2O exch., NH2), 7.12 (d, 2H, Ar-H), 7.64 (s, 1H,
pyrrole NH). 13C NMR (250 MHz, CD3Cl3) δC (ppm): 28.2,
61.11, 63.15, 101.7, 106.9, 119.9, 122.5, 126.7, 120.2, 127.7,
129.9, 154.1, 167.4.
bIsolated yields.
2-amino-4-(4-bromophenyl)-4,7-dihydropyrano[2,3-b]pyrrole-
3-carbonitrile (5e)
Anal. Calcd. for C14H10BrN3O: C, 53.19; H, 3.19; N,
13.29%. Found: C, 52.66; H, 3.15; N, 13.22%. IR (KBr, νmax
,
cm−1): 3410 & 3295 (asym. & sym. str. of -NH2), 3405 (NH),
2175 (-CN str.), 1251 (asym. str. of cyclic ArC-O-C ether). 1H
NMR (400 MHz, CD3Cl3) δH (ppm): 5.55 (s, 1H, pyrr), 6.27
(d, 1H, pyrr), 6.65 (d, 1H, pyrr), 6.85 (s, 2H, D2O exch., NH2),
6.95–7.20 (m, 4H, Ar-H), 7.75 (brs, 1H, pyrr NH). 13C NMR
(250 MHz, CD3Cl3) δC (ppm): 28.7, 56.2, 110.1, 111.9, 118.6,
124.5, 126.7, 128.8, 129.7, 132.5, 133.4, 142.4, 173.4.
2-amino-4,7-dihydro-4-p-tolylpyrano[2,3-b]pyrrole-3-
carbonitrile (5c)
Anal. Calcd. for C15H13N3O: C, 71.70; H, 5.21; N, 16.72%.
Found: C, 70.86; H, 5.11; N, 16.55%. IR (KBr, νmax, cm−1):
3411 & 3265 (asym. & sym. str. of -NH2), 3427 (NH), 2205
(-CN str.), 1275 (asym. str. of cyclic ArC-O-C ether). 1H NMR
(400 MHz, CD3Cl3) δH (ppm): 2.34 (s, 3H, Ar-CH3), 5.66 (s,
1H, CH), 6.20 (d, 1H, pyrr), 6.84 (s, 2H, D2O exch., NH2), 6.92
(d, 1H, pyrr), 7.03–7.12 (m, 4H, Ar-H), 7.40 (s, 1H, pyrr NH).
13C NMR (250 MHz, CD3Cl3) δC (ppm): 24.2, 29.10, 57.25,
102.4, 105.8, 117.4, 126.1, 133.3, 129.2, 129.7, 132.2, 141.1,
167.1.
2-amino-4-(4-cyanophenyl)-4,7-dihydropyrano[2,3-b]pyrrole-
3-carbonitrile (5h)
Anal. Calcd. for C15H10N4O: C, 68.69; H, 3.84; N, 21.36%.
Found: C, 67.95; H, 3.76; N, 20.98%. IR (KBr, νmax, cm−1):
3417 & 3235 (asym. & sym. str. of -NH2), 3440 (NH), 2165
(-CN str.), 1245 (asym. str. of cyclic ArC-O-C ether). 1H NMR
(400 MHz, CD3Cl3) δH (ppm): 5.55 (s, 1H, pyrr), 6.14 (d, 1H,
pyrr), 6.53 (s, 2H, D2O exch., NH2), 6.71 (d, 1H, pyrr), 7.15
(s, 1H, pyrr NH), 7.22 (d, 2H, Ar-H), 7.35 (d, 2H, Ar-H). 13C
NMR (250 MHz, CD3Cl3) δC (ppm): 32.4, 62.72, 110.1, 114.4,
121.9, 122.6, 124.8, 125.5, 129.7, 129.9, 133.5, 138.3, 172.7.
TABLE 2
Reusability of [pmim] HSO4 SiO2
a
No. of run
Time (h)
Yield (%)b
1
2
3
4
3
3
3
3
90
88
87
84
aReaction conditions: 1.0 equiv. of 2-hydroxypyrrole, 1.0 equiv.
of benzaldehyde, 1.0 equiv. of malonoitrile, 10 mol% of [pmim]
HSO4 SiO2, 4 mL of solvent and at 60◦C.
FIG. 2. Structures of silica-supported (a) and unsupported ionic liquid cata-
lysts (b).
bIsolated yields.

NOVEL SYNTHETIC ROUTE TO PYRANO[2,3-b]
623
TABLE 3
2-amino-4,7-dihydro-4-(4-nitrophenyl)pyrano[2,3-b]pyrrole-
Effect of solvents on the catalytic efficiency of [pmim]
3-carbonitrile (5j)
a
HSO4 SiO2
Anal. Calcd. for C14H10N4O3: C, 59.57; H, 3.57; N, 19.85%.
Found: C, 59.33; H, 3.51; N, 19.74%. IR (KBr, νmax, cm−1):
3412 & 3225 (asym. & sym. str. of -NH2), 3435 (NH), 2190 (-
CN str.), 1355 & 1554 (asym. & sym. str. of -NO2), 1241 (asym.
str. of cyclic ArC-O-C ether). 1H NMR (400 MHz, CD3Cl3) δH
(ppm): 5.50 (s, 1H, pyrr), 6.24 (d, 1H, pyrr), 6.43 (s, 2H, D2O
exch., NH2), 6.65 (d, 1H, pyrr), 7.35 (s, 1H, pyrr), 7.41 (d, 2H,
Ar-H), 8.10 (d, 2H, Ar-H),. 13C NMR (250 MHz, CD3Cl3) δC
(ppm): 28.8, 55.33, 105.5, 107.9, 118.3, 126.7, 128.7, 129.4,
129.6, 136.7, 143.3, 169.2.
Entry
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
Benzene
CH3CN
MeOH
EtOH
6
5
7
6.5
7.5
60
90
34
55
67
Toluene
aReaction conditions: 1.0 equiv. of 2-hydroxypyrrole, 1.0 equiv.
of benzaldehyde, 1.0 equiv. of malonoitrile, 10 mol% of [pmim]
HSO4 SiO2, 4 mL of solvent and at 60◦C.
bIsolated yields.
FIG. 3. Proposed mechanism for one-pot three-component synthesis of pyrano[3,2-b]pyrrole derivatives catalyzed by [pmim] HSO4 SiO2
.

624
S. DAMAVANDI AND R. SANDAROOS
TABLE 4
One-pot three-component synthesis of 5-amino-7-aryl-6-cyano-4H-pyrano[3,2-b]pyrrolesa
Entry
1
Aldehyde
Productb
Time (h)
Yield (%)c
5
76
2
3
4
90
82
4.5
4
5
2.5
90
88
3
6
2
90
(continued on next page)

NOVEL SYNTHETIC ROUTE TO PYRANO[2,3-b]
625
TABLE 4
One-pot three-component synthesis of 5-amino-7-aryl-6-cyano-4H-pyrano[3,2-b]pyrrolesa (continued)
Entry
7
Aldehyde
Productb
Time (h)
Yield (%)c
2
86
8
9
4.5
5.5
73
70
10
11
8
8
64
62
12
7
40
aReaction conditions: 1.0 equiv. of 3-hydroxypyrrole, 1.0 equiv. of aldehyde, 1.0 equiv. of malonoitrile, 10 mol% of [pmim] HSO4 SiO2, 4 mL
of CH3CN as solvent and at 60◦C.
bThe products were identified by 1HNMR and IR spectrometer.
cIsolated yields.

626
S. DAMAVANDI AND R. SANDAROOS
2-amino-4-(furan-2-yl)-4,7-dihydropyrano[2,3-b]pyrrole-
3-carbonitrile (5l)
by attack of hydroxyl group on one of two nitrile groups.
Cyclization and subsequently tatumerization affords the target
product.
Anal. Calcd. for C12H9N3O2: C, 63.43; H, 3.99; N, 18.49%.
Found: C, 63.13; H, 3.89; N, 18.33%. IR (KBr, ν, cm−1): 3415
& 3232 (asym. & sym. str. of -NH2), 3425 (NH), 2166 (-CN
str.), 1255 (asym. str. of cyclic ArC-O-C ether). 1H NMR (400
MHz, CD3Cl3) δH (ppm): 5.43 (s, 1H, CH), 5.85 (dd, 1H, furan),
6.27 (m, 2 H, pyrr & furan), 6.55 (d, 1H, pyrr), 6.65 (s, 2H, D2O
exch., NH2), 7.33 (d, 1H, furan), 7.50 (s, 1H, pyrr NH). 13C
NMR (250 MHz, CD3Cl3) δC (ppm): 29.5, 56.7, 105.4, 107.3,
111.1, 112.9, 121.5, 126.6, 138.8, 144.3, 150.7, 163.6.
We extended the model reaction using different derivatives of
benzaldehyde. It was revealed that the electronic nature of sub-
stituted groups on benzealdehyde could intensely affect reaction
times and chemical yields. Reaction efficiencies were improved
by changing the substituent groups from methoxy to Br and
then Cl. Surprisingly, the presence of more strong electron-
withdrawing groups, such as NO2 and CN, altered the results
(Table 4). This contradictory behavior could be the consequence
of a change in the rate-determining step. It is conceivable that
the first step, nucleophilic attack of pyrrole to the aldehyde,
might be the rate-determining step, which can be accelerated by
electron-withdrawing groups. However, the second step (dehy-
droxylation step) could probably become rate-determining step
as the substituents become more electron-withdrawing. Because
the second step proceeds better with electron-releasing group,
the presence of CN and NO2 groups prolongs the reaction time
and decreases chemical yield.
RESULTS AND DISCUSSIONS
Initially,
a mixture of benzaldehyde (1 mmol), 3-
hydroxypyrrole (1 mmol), and malononitrile (1 mmol), and
10% mol of different ionic liquid catalysts, was chosen as the
model reaction. To find out the most effective catalyst, three
ionic liquids of [pmim]HSO4 (1-propyl-3-methylimidazolium-
HSO4), [pmim]BF4 (1-propyl-3-methylimidazolium-BF4), and
[pmim]Cl (1-propyl-3-methylimidazolium-Cl), possessing dif-
ferent counteranions (Figure 2), were comparatively used for
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