Ethylenediammonium diformate (EDDF) in PEG600: An efficient ambiphilic novel catalytic system for the one-pot synthesis of 4H-pyrans via Knoevenagel condensation

Article abstract of DOI:10.1039/c3ra42410c

A novel ethylenediammonium diformate-polyethylene glycol (EDDF-PEG ₆₀₀) system was developed as a catalyst for the Knoevenagel condensation and Knoevenagel initiated three-component one-pot synthesis of 4H-pyrans at room temperature with high yields and in short reaction times. Further, the EDDF-PEG₆₀₀ catalytic system was recycled six times without any appreciable loss in its activity and hence can be termed as a green, environmentally benign catalytic system. A plausible mechanism depicting the ambiphilic nature of EDDF (catalyst) and PEG (promoting medium) acting in synergy has been proposed. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ra42410c

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Ethylenediammonium diformate (EDDF) in PEG600: an
efficient ambiphilic novel catalytic system for the one-
pot synthesis of 4H-pyrans via Knoevenagel
condensation3
Cite this: DOI: 10.1039/c3ra42410c
Anuj Thakur, Mohit Tripathi, U. Chinna Rajesh and Diwan S. Rawat*
A novel ethylenediammonium diformate–polyethylene glycol (EDDF-PEG600) system was developed as a
catalyst for the Knoevenagel condensation and Knoevenagel initiated three-component one-pot synthesis
of 4H-pyrans at room temperature with high yields and in short reaction times. Further, the EDDF-PEG600
catalytic system was recycled six times without any appreciable loss in its activity and hence can be termed
as a green, environmentally benign catalytic system. A plausible mechanism depicting the ambiphilic
nature of EDDF (catalyst) and PEG (promoting medium) acting in synergy has been proposed.
Received 15th May 2013,
Accepted 2nd August 2013
DOI: 10.1039/c3ra42410c
www.rsc.org/advances
We thought that replacement of the acetate counterion of
EDDA by the formate ion might improve the acidic nature and
Introduction
In the context of green chemistry and due to increasing
regulatory and economic pressures, there is always a need for
generating catalytic systems and processes that are environ-
mentally benign, have high atom-economies and are high-
yielding.1 Many recent discoveries in the field of synthetic
organic chemistry are centred on these issues and these are
ever-increasing. One such finding is the effect of ionic
environment on the outcome of a reaction as exemplified by
the use of ionic liquids (ILs, weakly co-ordinated salts).2 ILs
have found numerous applications, the most prominent being
their use as alternate reaction media and as catalysts for
important organic transformations.2 Recently, it has been
proposed that the cation and anion of an IL may act
cooperatively as nucleophilic and electrophilic catalysts
(ambiphilic dual activation) thereby catalysing various organic
reactions more efficiently.3 However, there are still some
issues associated with the use of ionic liquids such as toxicity,
biodegradability and many of the processes to produce ILs are
themselves not green.4,5 Hence, it would be beneficial to
combine the best of ionic catalysis and the use of greener
environmentally-friendly solvents.
also the catalytic activity of the resulting ethylenediammo-
nium diformate (EDDF). EDDF is a salt (m.p. 132 uC), and was
reported as a precursor for the synthesis of various mono- and
di-N-substituted ethylenediamines in 1954.7 To the best of our
knowledge there are no scientific reports on its catalytic
activity. Encouraged by recent reports on the catalytic potential
of ammonium based salts such as EDDA,6 2-hydroxyethylam-
monium formate (HEAF),8,9 together with the concept of
ambiphilic dual activation,3,9,10 and as a part of our ongoing
work towards the synthesis of biologically relevant mole-
cules,11 we explored EDDF’s catalytic potential and report
herein EDDF-PEG600 as an efficient novel catalytic system for
the Knoevenagel condensation and subsequent one-pot
synthesis of various 4H-pyrans.
Pyrans are important heterocycles found in various natural
products and many compounds possessing the 4H-pyran ring
system, including chromenes and spirooxindoles, have shown
a wide range of biological activities.12–14 4H-Pyrans are
synthesised easily through a one-pot domino Knoevenagel–
Michael–Thorpe–Ziegler reaction sequence,15 which is
a
Knoevenagel initiated domino reaction. Recently many green
approaches for the Knoevenagel reaction have been reported
using catalysts such as ionic liquids ([bmim]OH,
[MMIm][MSO4]), enzymes (BLAP, baker’s yeast), clays and
heterogeneous catalysts etc.16-18 However, these methods still
pose problems such as long reaction times, low yields, tedious
work-ups, expensive catalysts, recyclability issues, and some
processes may not be feasible from an industrial point of view.
To this end, we studied a model Knoevenagel reaction between
benzaldehyde and malononitrile and tested EDDF for its
Ethylenediammonium diacetate (EDDA), a salt (m.p. 120
uC), has been reported as an efficient catalyst for limited
organic reactions such as Knoevenagel condensations, intra-
molecular hetero-Diels–Alder and some domino reactions.6
Department of Chemistry, University of Delhi, Delhi-110007, India.
E-mail: dsrawat@chemistry.du.ac.in; Fax: +91-11-27667501; Tel: 91-11-27662683
Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
3
of EDDF, 4H-pyrans 7i, 7u, 7v, 8a, 9a and spirooxindoles 11a, 12a, 13a. See DOI:
10.1039/c3ra42410c
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Scheme 1 EDDF catalysed Knoevenagel condensation of benzaldehyde (1a)
with malononitrile/ethyl cyanoacetate (2a or 2b).
catalytic activity. Based on our initial results, EDDF was
dispersed in PEG600 by ultrasonication and then examined as a
novel catalytic system for synthesizing an array of 4H-pyrans
via Knoevenagel-initiated domino reactions.
Scheme 2 Synthesis of 4H-pyran derivatives.
Results and discussion
The initial studies were carried out on the model Knoevenagel
condensation of benzaldehyde with malononitrile using 20
mol% EDDF as catalyst with various solvents at ambient
temperature (Scheme 1, Table 1). Good yields (79–86%) were
obtained in almost all polar solvents and with the combina-
tion of PEG the reaction completed within a minute and
furnished more than 90% isolated yield (Table 1, entries 6 and
7). The efficacy of the catalytic system was also studied with
ethyl cyanoacetate as active methylene substrate.
Next, the amount of EDDF was decreased and it was
observed that 5 mol% of EDDF in PEG600 would suffice. PEG600
was preferred over PEG400 since the latter is more hygro-
scopic19 and the higher weight PEGs are solids. The model
reaction was also performed in either PEG600 or EDDF, but the
progress of the reaction was slow (Table 1, entries 9 and 10).
Thus, it was concluded that the combination of EDDF and
PEG600 was the best catalytic system for the Knoevenagel
condensation.
PEG600 (promoting medium/solvent) that is easy to handle and
also recyclable. For this purpose, an EDDF-PEG600 system was
prepared by dispersing EDDF (150 mg) in 10 mL of PEG600 by
ultrasonic irradiation for 7 h. This catalytic system was
subsequently applied for the synthesis of various 4H-pyrans
via a one-pot three-component reaction. First, we performed
the one-pot reaction between various aromatic/aliphatic
aldehydes, malononitrile/ethyl cyanoacetate and dimedone/
1,3-cyclohexadione with the EDDF-PEG600 catalytic system at
ambient temperature to form 4H-pyrans (Scheme 2). All the
reactions with malononitrile showed good to excellent yields
in relatively short reaction times without any side reactions
(Table 2). The work-up procedure was quite simple and
involved addition of a small amount of water to afford the
product as a precipitate which was filtered and dried under
vacuum. When ethyl cyanoacetate was used (Table 2, entry 7b),
the progress of the reaction was slow and furnished moderate
yield even after 30 min, which was attributed to the competing
formation of the Knoevenagel adduct of benzaldehyde with the
1,3-dicarbonyl owing to the strong catalytic activity of the
EDDF-PEG600 system. Aromatic aldehydes with electron with-
drawing substituents (NO2, CF3, F, Cl, Br) at ortho, para and
meta positions showed the best reactivity with 85–98% yields.
Whereas, aromatic aldehydes with electron donating substi-
tuents (p-methoxy, p-methyl) and aliphatic aldehydes showed
less reactivity with moderate to good yields (65–75%) (Table 2,
entries 7g, 7h, 7n and 7o). To study the versatility of the EDDF-
PEG600 catalytic system, the reaction was performed by
replacing dimedone/1,3-cyclohexadione with other carbonyl
compounds possessing reactive an a-methylene group such as
pyrazolone (5) and 4-hydroxycoumarin (6) to yield the
dihydropyrano[2,3-c]pyrazoles (8a, 8b) and dihydropyrano[2,
3-c]chromenes (9a, 9b) (Scheme 2).
With these initial encouraging results in hand, we wished
to develop a catalytic system involving EDDF (catalyst) and
Table 1 Optimisation conditions for EDDF catalysed Knoevenagel condensation
reaction in various solvents at room temperaturea
Entry
R
Catalyst (mol%) Solvent Time [min] Yield [%]b
1
2
3
4
5
6
7
8
CN
CN
CN
CN
CN
CN
CN
EDDF (20)
EDDF (20)
EDDF (20)
EDDF (20)
EDDF (20)
EDDF (20)
EDDF (20)
MeOH
Toluene 60
EtOH
ACN
H2O
PEG400
PEG600
PEG600
PEG600
—
PEG600
PEG600
PEG600
2
81
50
86
80
79
92
96
87
82
70
95
95
81
2
2
2
1
1
25
15
2
1
1
COOEt EDDF (20)
9
CN
CN
CN
CN
CN
—
10
11
12
13
EDDF (20)
EDDF (10)
EDDF (5)
EDDF (1)
Next, in order to further examine the efficacy of the catalytic
system, aldehydes were replaced with isatins to form diverse
spirooxindole derivatives via the one-pot reaction of isatin,
malononitrile/ethyl cyanoacetate and various carbonyl sub-
strates with an active a-methylene group (1,3-cyclohexadione/
4
a
Benzaldehyde 1a (1 mmol), malononitrile/ethyl cyanoacetate 2 (1
b
mmol), EDDF (1–20 mol%), solvent (0.5 mL). Isolated yield.
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Table 2 EDDF-PEG600 catalysed one-pot three-component synthesis of various
4H-pyrans via Knoevenagel reaction at room temperaturea
Table 3 EDDF-PEG600 catalysed one-pot synthesis of various spirooxindoles at
room temperaturea
m.p. [uC]
m.p. [uC]
Time Yield
Entry Sub.
R
R1
[min] [%]b Observed Literature
Entry Sub. R R1
Time [min] Yield [%]b Observed Literature
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4a
4a
4a
4a
5
Ph
Ph
CN
COOEt 40
CN
CN
CN
5
89
63
92
89
88
88
75
70
91
85
87
94
98
65
72
61
89
91
86
96
87
88
89
93
91
88
230–231 [229–231]20
181–183 [180–181]24
224–226 [220–224]26
226–228 [225–227]20
221–223 Unknown
233–235 [235–237]20
215–217 [216–218]23
193–194 [190–192]20
210–212 Unknown
236–238 Unknown
242–244 Unknown
204–207 [201–203]20
198–200 [196–198]21
208–210 Unknown
190–192 [188–190]21
223–225 [224–225]21
205–207 [203–205]25
226–227 [224–226]21
218–220 [221–223]20
250–252 Unknown
236–238 Unknown
234–236 Unknown
246–247 [244]22
11a 4a
11b 4b
11c 4a
11d 4b Br CN
11e 4a
H
H
Br CN
CN
CN
7
12
7
87
91
79
87
59
87
83
89
92
300–301 [298–299]28
293–295 [290–292]28
292–294 [290–292]28
4-Br-Ph
4-Cl-Ph
4-F-Ph
4-NO2-Ph CN
4-Me-Ph CN
4-OMe-Ph CN
4-CF3-Ph
3-F-Ph
2-F-Ph
3-NO2-Ph CN
2-NO2-Ph CN
Cyclohexyl CN
Propyl
Ph
4-Br-Ph
2-NO2-Ph CN
2,4-Cl-Ph CN
8
8
7
16
11
13
7
8
5
7
5
20
25
6
6
7
7
8
8
9
.300
[.300]28
H
H
COOEt 60
CN
252–254 [253–255]28
284–286 [285–286]29
290–292 [282–283]29
12a
12b
13a
13b
5
5
6
6
5
6
12
11
Br CN
CN
Br CN
H
.300
.300
[.300]28
[.300]28
CN
CN
CN
a
Isatin 10 (1 mmol), malononitrile or ethyl cyanoacetate 2 (1 mmol),
b
compound 4, 5 or 6 (1 mmol), EDDF-PEG600 (0.5 mL). Isolated
yield.
CN
CN
CN
with ethyl cyanoacetate was not so encouraging due to the
aforementioned reason, but all the reactions with malononi-
trile gave high yields.
7s
7t
3,5-F-Ph
CN
CN
CN
CN
c
7u
7v
8a
8b
9a
9b
c
Scheme 4 depicts a plausible mechanism for the EDDF-
PEG600 catalysed one-pot synthesis of 4H-pyrans. Probably, the
ethylenediammonium part (acidic) induces the electrophilicity
of the carbonyl group via protonation and hence aids in the
attack of malonate carbanion III. A similar mechanism
showing the ambiphilic dual activation role of HEAF in the
Henry reaction has been reported.9 The resulting intermediate
V is stabilised by PEG600 via H-bonding and EDDF acts as an
ambiphile in the rest of the steps to form Knoevenagel product
3a. On the other hand, the role of EDDF in aiding keto–enol
tautomerism in the dicarbonyl (4a to VII) is also envisioned,
which undergoes Michael-addition with the Knoevenagel
product 3a to give intermediate VIII, which is protonated (IX)
followed by tautomerisation to give intermediate X (assisted
again by EDDF) and finally undergoes cyclisation and imine–
amine tautomerism to yield the 4H-pyran 7a. PEG600 plays a
significant role as a polarizing and stabilizing medium in the
overall sequence of the mechanism (intermediates V, X and XI)
and acts synergistically. Hence, by using such a hybrid
catalytic system that includes the catalyst and the promoter,
better catalytic activity can be anticipated.
25
10
9
12
9
Ph
5
6
6
2-NO2-Ph CN
Ph CN
3-NO2-Ph CN
240–242 [241]22
257–259 [256–258]27
260–262 [262–264]27
a
Aldehyde 1 (1 mmol), malononitrile or ethyl cyanoacetate 2 (1
mmol), compound 4, 5 or 6 (1 mmol), EDDF-PEG600 (0.5 mL).
b
c
Isolated yield. For 7u and 7v the aldehydes used were 4-((2-
chloropyrimidin-4-yl)oxy)benzaldehyde and 1-tosyl-1H-indole-3-
carbaldehyde respectively (Scheme 2).
dimedone or pyrazolone or 4-hydroxycoumarin) (Scheme 3).
The reactions proceeded smoothly and gave high yields in
short reaction times at room temperature (Table 3). The yield
The reusability of the EDDF-PEG600 catalytic system was
also examined on a model one-pot reaction between benzal-
dehyde, malononitrile and 1,3-cyclohexadione under the
optimised conditions (Table 2, entry 7a). After completion of
the reaction, water was added and the resultant solid product
was filtered, washed with water and the combined filtrate
containing the catalyst was concentrated under reduced
pressure to remove water. The recovered EDDF-PEG600 was
re-used at least six times without any appreciable loss in its
catalytic activity (Fig. 1).
The FT-IR spectrum of EDDF was recorded before and after
dispersion in PEG600 (Fig. 2a and 2c). The broad band with
weak intensity in the range of 3400–2350 cm21 exhibits a
characteristic ammonium structure and the band at 1600
Scheme 3 Synthesis of spirooxindole derivatives.
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Scheme 4 Plausible mechanism of the EDDF-PEG600 catalysed one-pot three-component synthesis of 4H-pyran 7a.
cm21 represents the carbonyl stretching (formate) and N–H
plane bending vibrations of the ammonium ion (Fig. 2a).30
After dispersion of EDDF in PEG600, the broad band appearing
at y3400 cm21 indicated that the ammonium of EDDF is
embedded with the O–H stretching vibration of PEG600 with
absorbed moisture and the band appearing at 2935 cm21
indicates the C–H stretching of the ethylene groups of both
EDDF and PEG as shown in Fig. 2c. The IR spectrum of EDDF-
PEG600 was recorded after six cycles for the synthesis of
4H-pyran (7a) and no appreciable changes were observed
(Fig. 2d). Further, to check the applicability of the developed
catalytic system at large scales, model reactions between
different substrates were performed at the 100 mmol scale and
the results are summarised in Table 4.
Experimental
All reagents were purchased from Merck and Aldrich and were
used as such. Reaction progress was monitored using pre-
coated TLC plates (E. Merck Kieselgel 60 F254) and spots were
visualised under UV light and also by exposing TLC plates to
1
iodine vapour. H NMR and 13C NMR spectra were taken on a
Jeol Spectrospin spectrometer at 400 MHz and 100 MHz
respectively using TMS as an internal standard. Melting points
Fig. 1 Comparative recycling study of the EDDF-PEG600 catalyst for the synthesis
of 4H-pyran (7a).
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homogeneous and well dispersed mixture was collected and
characterised by IR.
Procedure for Knoevenagel condensation reaction
A mixture of benzaldehyde (1 mmol), malononitrile/ethyl
cyanoacetate (1 mmol) and EDDF (1–20 mol%) in appropriate
solvent (0.5 mL) was stirred for an appropriate time at room
temperature. After completion of reaction as monitored by
TLC, water (2 mL) was added and the reaction mixture was
extracted with ethyl acetate (3 6 5 mL). The combined organic
layer was evaporated under reduced pressure and the resulting
solid was recrystallised from ethanol to give pure product.
General procedure for the synthesis of 4H-pyrans
To a mixture of aldehyde 1 (1 mmol), malononitrile or ethyl
cyanoacetate 2a or 2b (1 mmol), and carbonyl compound
possessing a reactive a-methylene group 4, 5 or 6 (1 mmol) was
added 0.5 mL of EDDF-PEG600 and the mixture was stirred at
room temperature for the respective time as mentioned in
Table 2. After completion of the reaction (monitored by TLC),
water (5 mL) was added and the resulting precipitate was
filtered, washed with water (20 mL) and recrystallised from
ethanol. The filtrate containing catalyst was extracted with
diethyl ether (3 6 5 mL), the aqueous layer was separated and
water was evaporated under reduced pressure at 50 uC to give
pure catalyst which can be used for the next run under the
same conditions.
Fig. 2 FT-IR spectra of (a) EDDF, (b) PEG600, (c) fresh EDDF-PEG600 and (d) sixth
time recycled EDDF-PEG600
.
were recorded in open capillary tubes on an ERS automated
melting point apparatus and are uncorrected. IR spectra were
recorded using Perkin-Elmer and Bruker FT-IR in the range of
4000–100 cm21 and only characteristic frequencies are
expressed.
General procedure for the synthesis of spirooxindoles
Preparation and characterisation of the catalyst
To a mixture of isatin 10 (1 mmol), malononitrile or ethyl
cyanoacetate 2a or 2b (1 mmol), and carbonyl compound
possessing a reactive a-methylene group 4, 5 or 6 (1 mmol) was
added 0.5 mL of EDDF-PEG600 and the mixture was stirred at
room temperature for the respective time as mentioned in
Table 3. After completion of the reaction (monitored by TLC),
water (5 mL) was added and the resulting precipitate was
filtered, washed with water followed by cold ethanol and dried
under vacuum at 50 uC resulting in the desired product.
Procedure for the preparation of EDDF. Ethylenediamine (10
mL, 0.15 mol) was diluted with 15 mL of acetone and was
added dropwise to a previously cooled and stirred mixture of
90% formic acid (aq.) (12.5 mL, 0.30 mol) and 15 mL of
acetone. The reaction mixture was maintained at 0 uC under
continuous stirring for 2 h. The precipitated ethylenediammo-
nium diformate (EDDF) as a white solid was filtered, washed
with acetone and dried at 50 uC under vacuum. Yield: 98%; mp
130–132 uC (Lit 132 uC);7 IR (nmax/cm21, KBr): 3410, 3162, 2927,
2817, 2121, 1600, 1511, 1375, 1095, 1062, 789, 765; 1H NMR
(400 MHz, DMSO): dH 2.82 (s, 4H), 8.37 (s, 2H); 13C NMR (100
MHz, D2O): dC 37.64, 171.07.
Spectral data of selected compounds
2-Amino-5-oxo-4-(4-trifluoromethylphenyl)-5,6,7,8-tetrahy-
dro-4H-chromene-3-carbonitrile (7i). White solid, mp 210–212
uC; IR (nmax/cm21, KBr): 3430, 3335, 2972, 2197, 1682, 1659,
1597, 1422, 1365, 1260, 1161, 1105, 1004, 846, 509; 1H NMR
(400 MHz; CDCl3; Me4Si): dH 1.88–1.97 (m, 2H), 2.24–2.31 (m,
2H), 2.58–2.67 (m, 2H), 4.29 (s, 1H), 7.10 (br s, 2H), 7.38 (d, 2H,
J = 8.05 Hz), 7.64 (d, 2H, J = 8.05 Hz); 13C NMR (100 MHz;
CDCl3; Me4Si): dC 19.74, 26.48, 35.50, 36.23, 57.31, 113.02,
119.40, 122.91, 125.31, 127.24, 128.07, 149.35, 158.49, 164.93,
195.90; ESI-MS (m/z): 335.13 (M + H)+; Anal. Calcd for
Procedure for the preparation of EDDF-PEG600. EDDDF-
PEG600 was prepared by dispersing 150 mg of EDDF in 10 mL
of PEG600 using ultrasonic irradiation for 7 h. The resulting
Table 4 Comparison of the EDDF-PEG600 catalysed one-pot synthesis of
4H-pyrans and spirooxindoles on 1 mmol and 100 mmol reaction scales
1 mmol scaleb
Time [min]
100 mmol scale
Time [min]
C
17H13F3N2O2: C, 61.08; H, 3.92; N, 8.38; found: C, 61.13; H,
Entry
Yield [%]a
Yield [%]a
3.90; N, 8.41%.
2-Amino-4-(3,5-difluorophenyl)-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (7t). White solid, mp 250–252 uC;
IR (nmax/cm21, KBr): 3335, 3327, 3179, 2927, 2192, 1684, 1647,
1459, 1369, 1216, 1119, 1003, 859, 696; 1H NMR (400 MHz;
CDCl3; Me4Si): dH 1.82–1.85 (m, 2H), 2.17–2.21 (m, 2H), 2.41–
2.61 (m, 2H), 4.16 (s, 1H), 6.78 (dd, 2H, J = 2.2 Hz, J = 8.79 Hz),
6.93–6.96 (m, 1H), 7.02 (br s, 2H); 13C NMR (100 MHz; CDCl3;
7a
8a
9a
11a
12a
13a
5
10
12
7
5
12
89
89
91
87
87
89
6
11
13
7
5
13
94
92
95
94
93
95
a
b
Isolated yield. From Table 2 and Table 3.
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Me4Si): dC 19.73, 26.55, 35.31, 36.27, 57.11, 102.15, 110.46,
112.53, 119.46, 149.55, 158.55, 161.13, 163.58, 165.35, 196.05;
ESI-MS (m/z): 303.10 (M + H)+; Anal. Calcd for C16H12F2N2O2:
C, 63.57; H, 4.00; N, 9.27; found: C, 63.67; H, 4.04; N, 9.25%.
2-Amino-4-[4-(2-chloropyrimidin-4-yloxy)phenyl]-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (7u). White
solid, mp 236–238 uC; IR (nmax/cm21, KBr): 3337, 3321, 3183,
2922, 2189, 1677, 1646, 1607, 1562, 1458, 1332, 1191, 953, 844,
284–286 uC; IR (nmax/cm21, KBr): 3421, 3389, 3339, 3138, 2685,
2184, 1711, 1650, 1582, 1516, 1411, 1322, 1209, 1157, 1053,
1
933, 698; H NMR (400 MHz; CDCl3; Me4Si): dH 1.51 (s, 3H),
6.89 (d, 1H, J = 8.05 Hz), 6.95–7.07 (m, 2H), 7.17–7.27 (m, 3H),
10.58 (br s, 1H), 12.27 (br s, 1H, NH); 13C NMR (100 MHz;
CDCl3; Me4Si): dC 9.00, 47.33, 55.20, 95.43, 109.73, 118.79,
122.57, 124.56, 128.96, 132.71, 134.78, 141.54, 155.30, 162.52,
178.08; ESI-MS (m/z): 294.11 (M + H)+; Anal. Calcd for
1
C
15H11N5O2: C, 61.43; H, 3.78; N, 23.88; found: C, 61.46; H,
532; H NMR (400 MHz; CDCl3; Me4Si): dH 1.88–1.98 (m, 2H),
3.75; N, 23.91%.
2.24–2.38 (m, 2H), 2.58–2.68 (m, 2H), 4.25 (s, 1H), 7.05 (br s,
2H), 7.11 (d, 1H, J = 5.13 Hz), 7.18 (d, 2H, J = 8.05 Hz), 7.25 (d,
2H, J = 8.05 Hz), 8.60 (d, 1H, J = 5.13 Hz); 13C NMR (100 MHz;
CDCl3; Me4Si): dC 19.77, 26.51, 34.91, 36.31, 57.96, 107.64,
113.60, 119.77, 121.26, 128.65, 142.66, 150.12, 158.59, 159.00,
161.47, 164.81, 169.99, 196.02; ESI-MS (m/z): 395.09 (M + H)+,
396.09 (M + 2)+; Anal. Calcd for C20H15ClN4O3: C, 60.84; H,
3.83; N, 14.19; found: C, 60.81; H, 3.85; N, 14.20%.
2-Amino-5-oxo-4-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (7v). White
solid, mp 234–236 uC; IR (nmax/cm21, KBr): 3435, 3422, 3198,
2944, 2194, 1678, 1655, 1364, 1173, 975, 740, 674, 568; 1H NMR
(400 MHz; CDCl3; Me4Si): dH 1.69–1.71 (m, 1H), 1.79–1.85 (m,
1H), 2.07–2.24 (m, 5H), 2.42–2.59 (m, 2H), 4.43 (s, 1H), 6.94 (br
s, 2H), 7.09–7.12 (m, 1H), 7.15–7.17 (m, 1H), 7.19–7.22 (m, 2H),
7.29–7.31 (m, 1H), 7.47 (s, 1H), 7.65 (d, 2H, J = 8.05 Hz), 7.73
(d, 1H, J = 8.05 Hz); 13C NMR (100 MHz; CDCl3; Me4Si): dC
19.86, 21.00, 26.48, 27.08, 36.29, 56.52, 112.05, 113.44, 119.57,
119.65, 123.39, 124.39, 124.59, 125.27, 126.59, 128.88, 130.13,
134.01, 134.83, 145.31, 158.73, 164.72, 195.83; ESI-MS (m/z):
460.09 (M + H)+; Anal. Calcd for C25H21N3O4S: C, 65.34; H,
4.61; N, 9.14; S, 6.98; found: C, 65.37; H, 4.65; N, 9.12; S,
6.95%.
29-Amino-2,59-dioxo-59H-spiro[indoline-3,49-pyrano[3,2-
c]chromene]-39-carbonitrile (13a). Off-white solid, mp >300 uC;
IR (nmax/cm21, KBr): 3475, 3356, 3119, 2197, 1736, 1679, 1623,
1
1474, 1365, 1073; H NMR (400 MHz; CDCl3; Me4Si): dH 6.84
(d, 1H, J = 7.32 Hz), 6.91–6.94 (m, 1H), 7.20 (d, 2H, J = 7.32 Hz),
7.48 (d, 1H, J = 8.05 Hz), 7.51–7.55 (m, 1H), 7.65 (s, 2H), 7.74–
7.78 (m, 1H), 7.93 (dd, 1H, J = 1.46 Hz, J = 7.32 Hz), 10.66 (br s,
1H); 13C NMR (100 MHz; CDCl3; Me4Si): dC 47.60, 57.03,
101.43, 109.52, 112.37, 116.68, 116.97, 122.07, 122.68, 124.13,
125.03, 128.93, 133.03, 133.69, 142.19, 152.03, 155.07, 158.27,
158.45, 177.13; ESI-MS (m/z): 358.09 (M + H)+; Anal. Calcd for
C
20H11N3O4: C, 67.23; H, 3.10; N, 11.76; found: C, 67.21; H,
3.15; N, 11.79%.
Conclusions
To conclude, a highly efficient catalytic system combining
EDDF (catalyst) and PEG600 (promoting medium) was devel-
oped for the first time and applied as a novel catalyst for the
Knoevenagel condensation and Knoevenagel initiated one-pot
synthesis of various 4H-pyrans including chromenes and
spirooxindoles. EDDF can act as a cooperative ambiphilic
catalyst in the reaction sequence, while PEG may provide a
polarising medium and assist in stabilising the reaction
intermediates. The developed catalytic system was easy to
handle, green, non-toxic, inexpensive and gave high yields at
shorter reaction times. The main advantage of the EDDF-
PEG600 catalytic system was that the reactions could be
performed at room temperature and showed excellent toler-
ance towards a wide range of substrates. Further, it was
recycled and showed no appreciable loss in reaction yields.
Moreover, owing to its simplicity and amenability to large
scale operation, it can be termed as a useful and effective way
to synthesise such an important class of compounds. Further
investigation into the ability of the EDDF-PEG600 system to
catalyse a number of reactions of synthetic importance is
underway.
6-Amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyra-
1
zole-5-carbonitrile (8a). White solid; mp 246–247 uC; H NMR
(400 MHz; CDCl3; Me4Si): dH 1.76 (s, 3H, CH3), 4.58 (s, 1H),
6.86 (br s, 2H, NH2), 7.15 (d, 2H, J = 7.32 Hz), 7.19–7.22 (m,
1H), 7.28–7.32 (m, 2H), 12.08 (s, 1H, NH); 13C NMR (100 MHz;
CDCl3; Me4Si): dC 9.7, 36.22, 57.16, 97.64, 120.82, 126.73,
127.46, 128.43, 135.57, 144.44, 154.76, 160.86.
2-Amino-5-oxo-4-phenyl-4H,5H-pyrano[3,2-c]chromene-3-
carbonitrile (9a). White solid, mp 257–259 uC; 1H NMR (400
MHz; CDCl3; Me4Si) dH 4.40 (s, 1H), 7.19–7.21 (m, 3H), 7.25–
7.29 (m, 2H), 7.36 (br s, 2H, NH2), 7.39–7.48 (m, 2H), 7.66 (t,
1H, J = 7.25 Hz), 7.86 (d, 1H, J = 8.05 Hz).
2-Amino-29,5-dioxo-5,7-dihydrospiro[furo[3,4-b]pyran-
4,39-indoline]-3-carbonitrile (11a). Off-white solid; mp 300–301
uC; IR (nmax/cm21, KBr): 3375, 3287, 3136, 2190, 1713, 1682,
1
1650, 1602, 1469, 1355, 1210, 1078, 1009; H NMR (400 MHz;
CDCl3; Me4Si) dH 1.85–1.96 (m, 2H), 2.15–2.28 (m, 2H), 2.64 (t,
2H, J = 5.86 Hz), 6.76 (d, 1H, J = 8.05 Hz), 6.84–6.91 (m, 1H),
6.98 (d, 1H, J = 7.32 Hz), 7.10–7.15 (m, 1H), 7.20 (bs s, 2H),
10.37 (bs s, 1H); 13C NMR (100 MHz; CDCl3; Me4Si): dC 19.81,
26.76, 36.40, 46.89, 57.54, 109.16, 111.88, 117.38, 121.66,
123.21, 128.16, 134.55, 142.00, 158.66, 166.80, 178.17, 195.05;
ESI-MS (m/z): 308.11 (M + H)+; Anal. Calcd for C17H13N3O3: C,
66.44; H, 4.26; N, 13.67; found: C, 66.47; H, 4.28; N, 13.68%.
69-Amino-39-methyl-2-oxo-19H-spiro[indoline-3,49-pyr-
ano[2,3-c]pyrazole]-59-carbonitrile (12a). Off-white solid, mp
Acknowledgements
DSR thanks the Council of Scientific and Industrial Research
(02(0049)/12/EMR-II), New Delhi, India and the University of
Delhi, Delhi, India for financial support. AT, MT and UCR are
thankful to CSIR, DST and UGC for the award of a senior
research fellowship, INSPIRE junior research fellowship and
RSC Adv.
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