Borax catalyzed domino reactions: Synthesis of highly functionalised pyridines, dienes, anilines and dihydropyrano[3,2-c]chromenes

Article abstract of DOI:10.1039/c4ra03627a

Borax, an innocuous, inexpensive, and a naturally occurring material, very efficiently catalyzes the Knoevenagel condensation and Michael addition in domino fashion for the construction of highly functionalised pyridines, dienes, anilines and dihydropyran

Full text of DOI:10.1039/c4ra03627a

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Borax catalyzed domino reactions: synthesis of
highly functionalised pyridines, dienes, anilines and
dihydropyrano[3,2-c]chromenes†
Cite this: RSC Adv., 2014, 4, 29750
*
Aniruddha Molla and Sahid Hussain
Borax, an innocuous, inexpensive, and a naturally occurring material, very efficiently catalyzes the
Knoevenagel condensation and Michael addition in domino fashion for the construction of highly
functionalised pyridines, dienes, anilines and dihydropyrano[3,2-c]chromenes. The present protocol
offers advantages in terms of higher yields, wide scope of substrates, operational simplicity, short
reaction time, no requirement of workup or column chromatography, and easy access to a wide range
of structurally diverse functionalized molecules of biological importance. Recycling of the catalyst and
scaling up of the reactions are important attributes of this catalytic process.
Received 21st April 2014
Accepted 6th June 2014
DOI: 10.1039/c4ra03627a
www.rsc.org/advances
fruitful. These compounds nd applications as antibacterial,5
anticancer,6 antiprion,7 and anti HBV infection8 compounds.
Introduction
Moreover, these compounds have also been used as non-
nucleoside agonist of the human adenosine A19 receptor and as
anti HIV-1 agents.10 Consequently, researchers have made
considerable effort towards their synthesis. Traditionally,
highly functionalized pyridine derivatives are prepared by
reuxing active methylene compounds (malononitrile) with an
aldehyde and thiols using Et3N or DABCO as a catalyst.11 Low
yields (20–48%) and byproduct (enaminonitriles) formation are
the main limitations of this method. In order to overcome these
limitations, a few new methods have been developed using
different catalysts such as nanocrystalline magnesium oxide,12
silica nanoparticles,13 KF/alumina,14 basic ionic liquid
[bmIm]OH,15 ZnCl2,16 piperidine/microwave,17 DBU,18 Zn(II) and
Cd(II) metal–organic frameworks (MOFs).19 Recently, KOH has
also been employed for the synthesis of highly functionalized
pyridine derivatives.20 Each methodology has some advantages
over the others; however, the search still continues for better
catalysts which bring about the Knoevenagel condensation and
The construction of several bonds in a one-step operation has
become one of the most important tools for organic synthesis.1
It has gradually gained interest because of its remarkable
advantages such as high bond forming efficiency, molecular
diversity, a reduction of work-up, extraction, and purication
processes, and hence minimizing waste generation making the
process green.2 Therefore, researchers are endeavouring
towards the construction of C–C, C–N and C–S bonds in one pot
process either using one type of reaction with several reaction
sites or combining more than one reaction. One of the most
utilized reactions in this fashion is Knoevenagel condensation
whose products (i.e. a,b-unsaturated compounds) are useful
intermediates for other reactions. For instance, Knoevenagel
condensation has been successfully used in the synthesis of
highly functionalised molecules in combination with Michael
addition, Robinson annulations, Diels–Alder and ene reactions.3
The synthesis of highly functionalized pyridines, dienes,
anilines and dihydropyrano[3,2-c]chromene is important as
these compounds are constructed through the Knoevenagel
condensation and Michael addition reactions. The adduct 3,5-
dicyanopyridines are privileged heterocyclic scaffolds (Fig. 1).
Modication of the substituent at C2, C4, and C6 of the pyridine
core produces libraries of compounds with diverse biological
activities.4 Assessment of the literature has revealed that the
highly substituted pyridines and chromenes, such as those
involving the 2-amino-4-aryl-6-sulfanyl substitution pattern and
substituted pyrano[3,2-c]chromenes, have been particularly
Department of Chemistry, Indian Institute of Technology Patna, Patna 800 013, India.
E-mail: sahid@iitp.ac.in; Fax: +91-612-227-7383; Tel: +91-612-255-2022
† Electronic supplementary information (ESI) available: Spectral data of all
compounds are available. See DOI: 10.1039/c4ra03627a
Fig. 1 Potent biologically active highly substituted pyridines(1–4) and
naturally occurring pyranocoumarins(5).
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Michael addition simultaneously. Notably, most of the methods 20 mol% to check the alacrity in both cases. A higher catalyst
recently developed have involved catalysts which are air/mois- percentage did not have much effect towards decreasing the
ture sensitive, toxic, expensive, require special effort for their reaction time and increasing product formation. The best result
preparation and special work-up and separation techniques for was obtained with 10 mol% of catalyst in EtOH under reux
their recovery and recycling. Considering all these and being conditions (Table 2).
intrigued by the fact that the pH of an aqueous solution of borax
The reaction strategy worked well. Structurally diverse
is 9.5 and the properties of borax to produce a hydroxyl anion aromatic aldehydes bearing substituents such as Me, NO2,
(Brønsted base) and boric acid (Lewis acid) upon hydrolysis that OMe, Cl and Br were examined with malononitrile and thiols
are conducive for both the Knoevenagel and Michael addition (aliphatic and aromatic) under the optimized reaction condi-
reactions,21a–d we thought it worthwhile to extend the use of tions and the results presented in Table 2 (entries 1–19). The
borax as a potential catalyst21 to carry out the above mentioned reactions with benzyl thiol went on well affording the products
transformations. We decided to investigate the efficacy of borax in high yields (Table 2, entries 6–11). Aromatic aldehydes
as catalyst for the synthesis of 2-amino-4-(aryl)-6-(alkyl or aryl)- bearing electron-withdrawing groups afforded the correspond-
3,5-pyridinedicarbonitriles, highly substituted dienes and dihy- ing product with slightly longer reaction times (Table 2, entries
dropyrano[3,2-c]chromene derivatives. Herein we report our 5 and 10). Under similar experimental conditions, aliphatic and
results of borax catalyzed one-pot condensation of aldehydes, aromatic dithiols underwent the reaction giving good yields
alkyl nitriles (malononitrile) and thiols (aromatic and aliphatic) (Table 2, entries 18 and 19). These reactions were nearly as facile
for the synthesis of pyridine derivatives, cyclic monoketones for as observed with the monothiols. Incidentally, reactions
the synthesis of 1,3 diene derivatives and nally 4-hydrox- involving dithiols appear to be quite scarce.11b Such reactions
ycoumarin, for the synthesis of dihydropyrano[3,2-c]chromene may be highly useful in the designed synthesis of supramolec-
heterocycles.
ular architectures, organosulfur polymers and macromolecules.
Moreover, the reactions of 2,6-dichlorobenzaldehyde afforded
dihydropyridine (Table 2, entry 15). This may be due to the
steric effect of two –Cl substituents in the ortho position, which
prevents aromatization. We have also tried reactions with ethyl
2-cyanoacetate and 2-cyanoacetamide; only the Knoevenagel
condensation product was observed with the corresponding
aldehyde.
Results and discussion
In search of better catalytic systems for this domino reaction,
optimization of the reaction conditions was carried out taking
benzaldehyde (1.0 mmol), malononitrile (2.1 mmol) and thio-
phenol (1.0 mmol) as model substrates. The results of the
optimization are summarized in Table 1. To initiate our study,
the model reaction was performed at room temperature in the
absence of catalyst; no desired product was formed both in
ethanol and water. Then we studied the reaction under reux
conditions with 1 mol% of catalyst; 40% of the product was
obtained in 2 hours. We increased the amount of catalyst to 5
mol% and 64% of the product was observed under the reux
conditions. We further increased the catalyst loading to 10 and
Interestingly, when we performed the reaction of 2-amino-
thiophenol with malononitrile and 4-cholorobenzaldehyde, we
isolated
only
2-amino-6-(2-aminophenylthio)-4-(4-chlor-
ophenyl) pyridine-3,5-dicarbonitrile as the product in good yield
(Table 2, entry 16). For the same set of reactions, 2-amino-4-(4-
chlorophenyl)-6-(2-mercaptophenylamino) pyridine-3,5 dicar-
bonitrile was also reported,20 which clearly indicates the selec-
tivity of this protocol only with thiols over amines.
In order to extend the scope of this methodology, we carried
out reactions of an aldehyde, malononitrile and enolizable
ketones. It is anticipated and is evident from the literature that
the combination of the above reactants in a ratio of 1 : 2 : 1
usually provides 2,6-dicyanoaniline derivatives. However, we
could isolate diene intermediates in the case of cyclohexanone
and cyclododecanone. Recently, Mukhopadhyay et al. have
shown that the formation of 2,6-dicyanoaniline (i.e. aromati-
zation) from the intermediate diene is temperature depen-
dent.22 The synthesis of cyclohexa-1,3-diene is relatively rare22
and such wide range of functionalized dienes may nd use as
intermediates for the construction of larger molecules or as a
relatively non-toxic precursor of HCN. Interestingly, our
preliminary investigation on the above reaction produces the
diene as the sole product in one hour under reux conditions.
No change in the product was observed on prolonging the
reaction time (6 h). This may be due to the mild basicity of the
catalyst. The reactions of other substituted aromatic aldehydes
(such as Cl, Me, Br, and OMe) with cyclohexanone and malo-
nonitrile afforded the desired products in good yields (Table 3,
entries 1–4). It is interesting to note that the reaction of
Table 1 Optimization of the reaction conditions
Run Catalyst (mol%) Solvent Condition Time (h) Yielda (%)
01
02
03
04
05
06
07
08
09
10
—
—
—
1
H2O
R.T
R.T
10
10
10
—
—
Trace
40
64
69
65
83
88
EtOH
EtOH
EtOH
EtOH
H2O
Reux
Reux
Reux
Reux
Reux
R.T
2.0
5
2.0
2.0
1.5
2.0
1.0
1.0
10
10
10
10
20
H2O
EtOH
EtOH
EtOH
Reux
Reux
88
a
Isolated yield.
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Table 2 Synthesis of 2-amino pyridine-3,5-dicarbonitrile derivatives
Run
01
Aldehyde
Thiol
Product
Time (h)
1.0
Yielda (%)
88
02
03
04
1.0
1.0
1.0
92, 87b, 96c
90
88
05
06
1.5
1.5
82
86
07
08
09
1.0
1.0
1.0
84
83
84
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Table 2 (Contd.)
Run
10
Aldehyde
Thiol
Product
Time (h)
2.5
Yielda (%)
81
11
12
13
1.0
0.5
0.5
86
91
90
14
15
2.0
2.0
80
78
16
1.5
82
17
18
1.5
1.0
85
83
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Table 2 (Contd.)
Run
Aldehyde
Thiol
Product
Time (h)
Yielda (%)
19
1.0
75
a
Isolated yield. b Yield aer 5th run. c Yield on a 10 mmol scale.
cycloheptanone under similar reaction conditions with some operational simplicity, high yields of the products and the
selected aldehydes and malononitrile yielded aniline (and not avoidance of column chromatography. Moreover, borax, being a
the diene) as the sole product (Table 3, entries 5 and 6) whereas naturally occurring material, soluble and capable of func-
cyclododecanone produces the diene product only (Table 3, tioning efficiently in ethanol/water, satises some the tenets of
entry 7). When we tried the reaction with an acyclic ketone “green chemistry.” The reactions are thus more conducive to
(butan-2-one) it failed to produce the desired product and the the environment and provide scope for further study.
product of the Knoevenagel condensation was isolated. Simi-
larly, when we changed malononitrile with ethyl 2-cyanoacetate
or 2-cyanoacetamide, keeping the other reactants the same, the
protocol did not work.
Synthesis of 2-amino-4-(aryl)-6-(alkyl or aryl)-3,5-
pyridinedicarbonitriles
In continuation of our sustained interest in exploring the
catalytic activity of borax for diverse reactions, we turned our
attention towards the synthesis of dihydropyrano[3,2-c]chro-
mene derivatives. In order to test the efficacy, we carried out
reactions of equimolar amounts of 4-hydroxycoumarin, dime-
thylacetylenedicarboxylate (DMAD) and malononitrile in pres-
ence of 10 mol% of borax in water. Interestingly, we get 87%
yield of our expected product in 1.5 h. To generalize the scope of
the reaction, a series of compound (3a–f) were synthesized
varying the three reactants. It was observed that the desired
product was obtained in each case with 83–87% yield (Table 4,
entries 1–6). It is important to note that in all the reactions the
products precipitate out as a solid, making the separation of
catalyst and purication of product very simple.
Recyclability of the catalyst was examined through a series of
reactions with 4-chlorobenzaldehyde, malononitrile and thio-
phenol by using the ethanolic phase containing borax, obtained
aer ltration of the reaction mixture. The catalyst could be
reused for at least ve reaction cycles with consistent activity
(Table 2, entry 2). Importantly, the reaction can be performed
on a relatively large scale (10 mmol) to give good yields (Table 2,
entry 2), which shows its potential for scale-up applications.
In conclusion, we have developed a facile, convenient and
efficient one-pot domino reaction for the synthesis of highly
substituted pyridines, dienes and chromenes of potential
synthetic and pharmacological interest. This protocol offers
multifarious advantages such as lower cost, a ready available
and relatively non-toxic catalyst, wide scope of substrates,
To a solution of aldehyde (1.0 mmol), malononitrile (2.1 mmol)
and borax (0.1 mmol) in 3 mL of ethanol was added thiols (1.0
mmol) at room temperature in a round bottom ask equipped
with a condenser. The reaction mixture was stirred under reux
conditions for the required time (Table 2) and then allowed to
cool to room temperature. The progress of the reaction was
monitored by TLC, and aer completion of the reaction, the
reaction mixture was gradually cooled to room temperature.
The solid product was ltered off, washed with ethanol and
dried to obtain the corresponding product.
2-Amino-6-(benzylthio)-4-(4-bromophenyl)pyridine-3,5-
ꢀ
dicarbonitrile (1h). Yield 83%. Solid, m.p. 202–204 C. IR nmax
(KBr): 3438, 3328, 3220, 2211, 1630, 1542, 1520, 1321, 1263, 1040
cmꢁ1. 1H NMR (400 MHz, DMSO-d6): d ¼ 4.49 (s, 2H), 7.22–7.26
(m, 1H), 7.28–7.32 (m, 2H), 7.41–7.45 (m, 2H), 7.47–7.49 (m,
2H), 7.69–7.72 (m, 2H), 7.90 (br s, 2H) ppm. 13C NMR (125 MHz,
DMSO-d6 + CDCl3): 33.4, 85.6, 93.1, 114.8, 114.9, 124.1, 127.1,
128.2, 129.1, 130.2, 131.6, 132.8, 137.0, 156.7, 159.5, 166.6. Anal.
calcd for C20H13BrN4S: C, 57.02; H, 3.11; N, 13.30; obtained C,
56.95; H, 3.09; N, 13.34%.
2-Amino-6-(benzylthio)-4-(4-nitrophenyl)pyridine-3,5-dicar-
bonitrile (1j). Yield 81%. Solid, m.p. 210–212 ꢀC. IR nmax (KBr):
3435, 3329, 3219, 2215, 1630, 1548, 1349, 1263, 1105, 1041
cmꢁ1. 1H NMR (500 MHz, CDCl3 + DMSO-d6): d ¼ 4.45 (s, 2H),
6.12 (br s, 2H), 7.25–7.34 (m, 5H), 7.37 (d, J ¼ 7.2, 2H), 7.65 (d, J
¼ 7.8, 2H) ppm. 13C NMR (125 MHz, DMSO-d6 + CDCl3): 35.0,
86.3, 95.7, 114.3, 114.8, 124.4, 127.9, 128.8, 129.2, 129.9, 135.9,
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Table 3 Borax catalysed synthesis of dienes and anilines
3480, 3345, 3220, 2955, 2214, 1630, 1573, 1543, 1493, 1417,
1264, 1014 cmꢁ1. 1H NMR (400 MHz, CDCl3): d ¼ 0.97 (t, J ¼ 7.2,
3H), 1.43–1.51 (m, 2H), 1.69–1.74 (m, 2H), 3.21 (t, J ¼ 7.2, 2H),
5.67 (br s, 2H), 7.46 (d, J ¼ 8.4, 2H), 7.51 (d, J ¼ 8.4, 2H) ppm. 13
C
NMR (100 MHz, CDCl3): 13.6, 21.9, 30.4, 30.8, 86.1, 96.6, 114.8,
115.3, 129.4, 129.9, 131.6, 137.3, 156.7, 159.2, 169.9. Anal. calcd
for C17H15ClN4S: C, 59.56; H, 4.41; N, 16.34; obtained C, 59.52;
H, 4.38; N, 16.37%.
Run Aldehyde Ketone
Product
Time (h) Yielda (%)
6,60-(Propane-1,3-diylbis(sulfanediyl))bis(2-amino-4-phenyl-
pyridine-3,5-dicarbonitrile) (1r). Yield 83%. Solid, m.p. 255–257
ꢀC. IR nmax (KBr): 3463, 3329, 3214, 2212, 2186, 1618, 1548, 1524,
01
1.0
1.0
89
88
1
1441, 1266, 1042 cmꢁ1. H NMR (400 MHz, CDCl3): d ¼ 1.99–
2.02 (m, 3H), 3.22–3.26 (m, 6H), 6.54 (br s, 4H), 7.31–7.37 (m,
10H) ppm. 13C NMR (100 MHz, CDCl3): 28.0, 28.9, 86.5, 95.5,
115.2, 115.3, 128.3, 128.8, 130.6, 133.6, 158.1, 159.7, 160.0. Anal.
calcd for C29H20N8S2: C, 63.95; H, 3.70; N, 20.57; obtained C,
63.89; H, 3.68; N, 20.60%.
02
03
04
05
06
6,60-(4,40-Thiobis(4,1-phenylene)bis(sulfanediyl))bis(2-
amino-4-(4-chlorophenyl)pyridine-3,5-dicarbonitrile) (1s). Yield
ꢀ
75%. Solid, m.p. 188–190 C. IR nmax (KBr): 3477, 3336, 3223,
1.0
1.0
1.5
1.5
85
87
83
82
2222, 1630, 1547, 1499, 1255, 1096, 1003 cmꢁ1 1H NMR
.
(400 MHz, DMSO-d6): d ¼ 7.26–7.50 (m, 8H), 7.51–7.69 (m, 8H),
7.94 (br s, 4H) ppm. 13C NMR (100 MHz, DMSO-d6): 87.2, 93.3,
114.9, 115.1, 126.4, 128.6, 128.9, 130.4, 131.3, 131.7, 132.7,
135.4, 135.8, 136.0, 157.5, 159.6. Anal. calcd for C38H20Cl2N8S3:
C, 60.39; H, 2.67; N, 14.83; obtained C, 60.35; H, 2.66; N,
14.85%.
Synthesis of dienes and aniline derivatives
To a solution of aldehyde (1.0 mmol), malononitrile (2.1
mmol) and borax (0.1 mmol) in 3 mL of ethanol was added the
cyclic ketone (1.0 mmol) at room temperature in a round
bottom ask equipped with a condenser. The reaction mixture
was stirred under reux conditions for the required time
(Table 3) and then allowed to cool to room temperature. The
progress of the reaction was monitored by TLC, and aer
completion of the reaction, the reaction mixture was gradually
cooled to room temperature. The solid product was ltered off,
washed with ethanol and dried to obtain the corresponding
product.
07
2.0
76
a
Isolated yield.
2-Amino-4-(4-chlorophenyl)-4a,5,6,7-tetrahydronaphthalene-
1,3,3(4H)-tricarbonitrile (2a). Yield 89%. Solid, m.p. 232–234 ꢀC.
IR nmax (KBr): 3421, 3344, 3252, 3227, 2944, 2908, 2864, 2832,
2212, 1646, 1603, 1567, 1494, 1447, 1413, 1392, 1278, 1093, 1015
cmꢁ1. 1H NMR (400 MHz, CDCl3): d ¼ 0.86–0.95 (m, 1H), 1.44–
1.54 (m, 2H), 1.71–1.74 (m, 1H), 2.04–2.23 (m, 2H), 2.74–2.80 (m,
1H), 3.45–3.48 (m, 1H), 5.77–5.78 (m, 1H), 7.25 (br s, 2H), 7.44–
7.61 (m, 4H) ppm.
139.5, 149.2, 155.8, 159.3, 169.1. Anal. calcd for C20H13N5O2S: C,
62.00; H, 3.38; N, 18.08; obtained C, 61.88; H, 3.36; N, 18.11%.
2-Amino-4-(4-chlorophenyl)-6-(4-methoxyphenylthio)pyri-
ꢀ
dine-3,5-dicarbonitrile (1l). Yield 91%. Solid, m.p. 220–222 C.
IR nmax (KBr): 3467, 3345, 3222, 2212, 1633, 1546, 1525, 1494,
1253, 1179, 1024 cmꢁ1. 1H NMR (500 MHz, CDCl3): d ¼ 3.85 (s,
3H), 5.56 (br s, 2H), 6.96 (d, J ¼ 9.0, 2H), 7.43–7.53 (m, 6H) ppm.
13C NMR (125 MHz, CDCl3): 55.5, 87.0, 95.4, 114.8, 115.1, 115.2,
117.4, 129.5, 129.9, 131.6, 137.5(2C), 157.1, 159.4, 161.2, 170.3.
Anal. calcd for C20H13ClN4OS: C, 61.14; H, 3.34; N, 14.26;
obtained C, 61.09; H, 3.31; N, 14.30%.
2-Amino-4-(4-bromophenyl)-6,7,8,9-tetrahydro-5H-benzo[7]
annulene-1,3-dicarbonitrile (2f). Yield 82%. Solid, m.p. 250–252
ꢀC. IR nmax (KBr): 3467, 3341, 3320, 2935, 2857, 2200, 1646, 1603,
1
1569, 1491, 1405, 1223, 1076, 1006 cmꢁ1. H NMR (400 MHz,
CDCl3): d ¼ 1.16–1.48 (m, 4H), 1.67–1.81 (m, 2H), 2.12–2.18 (m,
2H), 2.50–2.57 (m, 1H), 2.93–2.95 (m, 1H), 7.09 (br s, 2H), 7.19–
7.21 (m, 2H), 7.59–7.61 (m, 2H) ppm.
2-Amino-6-(butylthio)-4-(4-chlorophenyl)pyridine-3,5-dicar-
bonitrile (1n). Yield 80%. Solid, m.p. 108–110 ꢀC. IR nmax (KBr):
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Table 4 Borax catalysed synthesis of dihydropyrano[3,2-c]chromene derivatives
Run
01
Hydroxy compound
R1
R2
Product
Time (h)
1.5
Yielda (%)
Me
CN
87
02
03
Et
CN
1.5
1.5
83
85
Me
CO2Et
04
05
Me
Me
Et
CN
CN
CN
2.0
2.0
2.0
86
84
83
06
a
Isolated yield.
(E)-2-Amino-4-(4-chlorophenyl)-4a,5,6,7,8,9,10,11-
octahydrobenzo[10]annulene-1,3,3(4H)-tricarbonitrile (2g)
Synthesis of dihydropyrano[3,2-c]chromene derivatives
To a solution of 4-hydroxy derivative (1.0 mmol), malononitrile
Yield 76%. Solid, m.p. 230–232 ꢀC. IR nmax (KBr): 3350, 3229, (1.1 mmol) and borax (0.1 mmol) in 3 mL of water was added
1
3099, 2926, 2857, 2200, 1672, 1586, 1421, 1093 cmꢁ1. H NMR dimethyl/diethyl acetylenedicarboxylate (1.0 mmol) at room
(400 MHz, DMSO-d6): d ¼ 1.29–1.45 (m, 7H), 1.57–1.63 (m, 2H), temperature in
a round bottom ask equipped with a
2.15–2.20 (m, 2H), 2.51–2.53 (m, 2H), 2.79–2.83 (m, 2H), 6.23– condenser. The reaction mixture was stirred under reux
6.37 (m, 2H), 7.28–7.30 (m, 2H), 7.34–7.36 (m, 2H), 8.17 (br s, conditions for the required time (Table 4) and then allowed to
2H) ppm. 13C NMR (100 MHz, DMSO-d6 + CDCl3): 28.5, 28.6, cool to room temperature. The progress of the reaction was
28.7, 28.8, 28.9 (2C), 32.4, 32.9, 42.0, 76.9, 99.5, 112.7, 113.0, monitored by TLC, and aer completion of the reaction, the
127.2, 128.2, 128.3, 131.2, 131.7, 136.2, 157.6, 163.4 ppm. Anal. reaction mixture was gradually cooled to room temperature.
calcd for C20H13N5O2S: C, 62.00; H, 3.38; N, 18.08; obtained C, The solid product was ltered off, washed with ethanol and
61.96; H, 3.36; N, 18.11%.
dried to obtain the corresponding product.
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Methyl 3-amino-2-cyano-4-(2-methoxy-2-oxoethyl)-7-methyl-
RSC Advances
¨
A. Domling, Multicomponent Reactions, in Green
Techniques for Organic Synthesis and Medicinal Chemistry,
ed. W. Zhang and B. W. Cue, John Wiley & Sons, Ltd,
Chichester, UK, 2012; (g) A. Doling, Chem. Rev., 2006, 106,
17–89; (h) J. Yu, F. Shi and L.-Z. Gong, Acc. Chem. Res.,
2011, 44, 1156–1171; (i) A. Domling, W. Wang and
K. Wang, Chem. Rev., 2012, 112, 3083–3135.
5-oxo-4,5-dihydropyrano[4,3-b]pyran-4-carboxylate (3e). Yield
ꢀ
86%. Solid, m.p. 154–156 C. IR nmax (KBr): 3475, 3361, 3185,
1
2956, 2193, 1731, 1609, 1431, 1357, 1204, 985 cmꢁ1. H NMR
(400 MHz, DMSO-d6): d ¼ 2.05 (s, 3H), 2.67–2.71 (m, 1H), 2.87–
2.91 (m, 1H), 3.44 (s, 3H), 3.59 (s, 3H), 6.08 (s, 1H), 7.31 (br s,
2H) ppm. 13C NMR (100 MHz, DMSO-d6): 19.4, 37.2, 42.8, 52.4,
53.0, 55.2, 88.1, 97.9, 98.7, 112.0, 117.1, 159.1, 161.2, 163.8,
166.5, 170.6 ppm. Anal. calcd for C15H14N2O7: C, 53.89; H, 4.22;
N, 8.38 obtained C, 53.84; H, 4.20; N, 8.41%.
3 (a) D. B. Ramachary and M. J. Kishor, J. Org. Chem., 2007,
72, 5056–5068; (b) D. B. Ramachary, K. Ramakumar and
V. V. Narayana, J. Org. Chem., 2007, 72, 14581; (c)
A. Kumar and R. A. Maurya, Tetrahedron, 2007, 63, 1946–
1952; (d) G. Sabitha, N. Fatima, E. V. Reddy and
J. S. Yadav, Adv. Synth. Catal., 2005, 347, 1353–1355; (e)
D. B. Ramachary, K. Anebouselvy, N. S. Chowdari and
C. F. Barbas, III, J. Org. Chem., 2004, 69, 5838–5849; (f)
G. Sabitha, G. S. K. K. Reddy, M. Rajkumar, J. S. Yadav,
K. V. S. Ramakrishna and A. C. Kunwar, Tetrahedron Lett.,
2003, 44, 7455–7457; (g) P. A. Clarke and W. H. C. Martin,
Org. Lett., 2002, 4, 4527–4529; (h) C. Tratrat, S. Giorgi-
Renault and H.-P. Husson, Org. Lett., 2002, 4, 3187–3189;
(i) S. Marchalin, K. Cvopova, D. P. Pham-Huu,
M. Chudik, J. Kozisek, I. Svoboda and A. Daeich,
Tetrahedron Lett., 2001, 42, 5663–5667; (j) J. M. Betancort,
K. Sakthivel, R. Thayumanavan and C. F. Barbas, III,
Tetrahedron Lett., 2001, 42, 4441–4444; (k) L. F. Tietze
and Y. Zhou, Angew. Chem., Int. Ed., 1999, 38, 2045–2047;
(l) M. Miyano and M. A. Stealey, J. Org. Chem., 1982, 47,
3184–3186.
Methyl
3-amino-2-cyano-4-(2-methoxy-2-oxoethyl)-5,10-
dioxo-5,10-dihydro-4H-benzo[g]chromene-4-carboxylate
(3f).
Yield 84%. Solid, m.p. 142–144 ꢀC. IR nmax (KBr): 3337, 3200,
1
2956, 2210, 1731, 1633, 1431, 1357, 1058 cmꢁ1. H NMR (400
MHz, DMSO-d6): d ¼ 3.51 (s, 3H), 3.68 (s, 3H), 3.85–3.86 (m, 1H),
3.91–3.92 (m, 1H), 7.53 (br s, 2H), 7.64–7.78 (m, 2H), 7.80–7.85
(m, 1H), 7.86–7.87 (m, 1H) ppm. 13C NMR (100 MHz, DMSO-d6 +
CDCl3): 36.9, 45.8, 51.9, 52.5, 53.0, 89.1, 106.6, 112.84, 117.7,
124.7, 124.9, 129.9, 131.6, 133.2, 135.8, 161.2, 163.8, 172.1,
180.1, 186.2 ppm. Anal. calcd for C19H14N2O7: C, 59.69; H, 3.69;
N, 7.33 obtained C, 59.65; H, 3.67; N, 7.35%.
Ethyl
3-amino-2-cyano-4-(2-ethoxy-2-oxoethyl)-5,10-dioxo-
5,10-dihydro-4H-benzo[g]chromene-4-carboxylate (3g). Yield
ꢀ
83%. Solid, m.p. 136–138 C. IR nmax (KBr): 3321, 3200, 2980,
1
2201, 1722, 1633, 1446, 1366, 1195, 1017 cmꢁ1. H NMR (400
MHz, DMSO-d6): d ¼ 1.04 (t, J ¼ 7.04, 3H), 1.17 (t, J ¼ 7.08, 3H),
3.00–3.04 (m, 1H), 3.18–3.22 (m, 1H), 3.90–3.95 (m, 2H), 4.12–
4.19 (m, 2H), 7.62–7.85 (m, 4H), 7.87–7.88 (m, 2H) ppm. 13C
NMR (100 MHz, DMSO-d6 + CDCl3): 14.3, 14.7, 44.7, 58.9, 60.5,
62.0, 76.5, 106.5, 112.8, 117.7, 124.9, 125.1, 129.9, 131.6, 133.2,
135.6, 170.4, 172.9, 174.1, 180.2, 186.3 ppm. Anal. calcd for
4 M. T. Cocco, C. Congiu, V. Lilliu and V. Onnis, Eur. J. Med.
Chem., 2005, 40, 1365–1372 and references cited therein.
5 (a) S. K. Srivastava, R. P. Tripathi and R. Ramachandran, J.
¨
Biol. Chem., 2005, 280, 30273–30281; (b) H. Brotz-
C
21H18N2O7: C, 61.46; H, 4.42; N, 6.83 obtained C, 61.42; H,
Oesterhelt, I. Knezevic, S. Bartel, T. Lampe, U. Warnecke-
4.40; N, 6.86%.
¨
Eberz, K. Ziegelbauer, D. Habich and H. Labischinski, J.
Biol. Chem., 2003, 278, 39435–39442.
Acknowledgements
6 M. A. Azuine, H. Tokuda, J. Takayasu, F. Enjyo,
T. Mukainaka, T. Konoshima, H. Nishino and
G. J. Kapadia, Pharmacol. Res., 2004, 49, 161–169.
7 T. R. K. Reddy, R. Mutter, W. Heal, K. Guo, V. J. Gillet, S. Pratt
and B. Chen, J. Med. Chem., 2006, 46, 607–615.
A.M. is thankful to IIT Patna for his research fellowship. The
authors are thankful to SAIF (Panjab University, Chandigarh)
and IIT Kanpur for NMR facility. The authors are also thankful
to the Department of Science and Technology for research grant
no. SR/FT/CS-093/2009.
8 H. Chen, W. Zhang, R. Tam and A. K. Raney, PCT Int. Appl.
WO 2005058315 A1 20050630, 2005.
9 L. H. Heitman, T. Mulder-Krieger, R. F. Spanjersberg,
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