Imidazole as organocatalyst for multicomponent reactions: Diversity oriented synthesis of functionalized hetero- and carbocycles using in situ-generated benzylidenemalononitrile derivatives

Article abstract of DOI:10.1039/c3ra45252b

The multicomponent reaction of malononitrile, aldehyde and a third reaction partner such as naphthol/4-hydroxycoumarine/2-hydroxynaphthoquinone/kojic acid/enolizable ketone or thiol in the presence of imidazole as an organocatalyst provides very interesti

Full text of DOI:10.1039/c3ra45252b

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Imidazole as organocatalyst for multicomponent
reactions: diversity oriented synthesis of
functionalized hetero- and carbocycles using
in situ-generated benzylidenemalononitrile
derivatives†
Cite this: RSC Adv., 2014, 4, 3732
*
Md. Nasim Khan, Suman Pal, Shaik Karamthulla and Lokman H. Choudhury
The multicomponent reaction of malononitrile, aldehyde and a third reaction partner such as naphthol/4-
hydroxycoumarine/2-hydroxynaphthoquinone/kojic acid/enolizable ketone or thiol in the presence of
imidazole as an organocatalyst provides very interesting molecular diversity. In an almost neutral reaction
medium, this protocol provides easy access to highly functionalized 2-amino-4H-chromenes, dienes
and 2-amino pyridines using in situ-generated aryl/alkylylidenemalononitrile derivatives obtained from
the reaction of aldehydes and malononitrile along with various nucleophiles under reflux conditions in
ethanol. This methodology is useful for the easy access of a wide range of structurally diverse
functionalized molecules having potential application in biological systems.
Received 20th September 2013
Accepted 23rd October 2013
DOI: 10.1039/c3ra45252b
www.rsc.org/advances
cyclohexene,6 3,4-dihydropyridi-2-one derivatives by three
component reactions7 etc.
Introduction
In continuation of our research work on multicomponent
reactions,8 we were interested to explore the catalytic potential
of imidazole in our multicomponent reactions for easy access
to diverse and highly substituted hetero- and carbocycles.
From the literature studies we realized that highly substituted
pyrans/chromenes and pyridines tethered with –NH2 and –CN
functionality in the 2,3-position, as shown as in Fig. 1,
possesses diverse pharmacological properties.9 Considering
their importance, a considerable number of methods are
found in the literature for the synthesis of these molecules.10
Most of the reported methods are based on three component
reactions (3CR), using aldehyde, malononitrile and various
nucleophiles in the presence of a wide range of catalysts.
Although a wide range of methods exist in the literature, still
better and more efficient methods that provide easy access to
these functionalized molecules are sought aer due to the
diverse biological applications of these molecules. As an
Organocatalysis is one of the most promising areas in organic
synthesis and it has gained considerable attention in recent
times.1 Similarly, multicomponent reactions are a popular and
greener synthetic tool to access diverse molecular scaffolds.2
Combining both concepts, organocatalysis in multicomponent
reactions (MCRs) has emerged as a very useful strategy in
organic synthesis.3 The application of small organic molecules
as organocatalysts in MCRs for diversity-oriented synthesis
offers many advantages, i.e. it avoids the use of toxic metals as
well as the need to maintain an inert atmosphere during the
reactions, in addition to pot, step and atom economy.
Imidazole is a versatile reagent in organic synthesis. Because
of its unique reactivity pattern, it is widely used in organic
synthesis. The presence of aza (–N]) and amine (–NH–) func-
tionalities in the ring makes it amphoteric and the basicity is
mild due to the presence of a pyridine-like nitrogen atom in the
imidazole ring. The mild catalytic nature of imidazole mini-
mizes side product formation and improves the yield of prod-
ucts. The catalytic activity of this reagent has been explored by
various groups. Recently, it has been used for the mono-
acylation of symmetrical diamines,4 synthesis of multi-
substituted 2-aminothiophenes,5 synthesis of polysubstituted
Department of Chemistry, Indian Institute of Technology Patna, Patna-800013, India.
E-mail: lokman@iitp.ac.in; Fax: +91 612 227 7383; Tel: +91 612 255 2038
† Electronic supplementary information (ESI) available: 1H, 13C-NMR spectra of
all the synthesized compounds. See DOI: 10.1039/c3ra45252b
Fig. 1 Core of highly substituted 4H-pyran and pyridines with amino
and nitrile functionality in the adjacent position having diverse phar-
macological properties.
3732 | RSC Adv., 2014, 4, 3732–3741
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example, recently Wang and coworkers11 have reported the
With the optimized conditions in hand, we turned our
synthesis of various optically pure pyranocoumarins and 2- attention to investigate the scope and general applicability of
amino-4H-chromenes catalyzed by a thiourea based organo- this procedure by varying the aldehyde and naphthol deriva-
catalyst. They also investigated the antimicrobial properties of tives. Aromatic aldehydes tethered with both electron donating
the synthesized optically pure compounds. In addition to and withdrawing groups underwent this three component
these, some of the methods reported suffer from one drawback reaction smoothly under the optimized reaction conditions to
or another, such as the use of expensive catalysts, the need to afford the desired products in very good yields. Aliphatic
prepare the catalyst prior to use, long reaction times, low yields aldehydes such as cyclohexane carboxaldehyde also underwent
and tedious procedures, or the method is limited to substrates a similar three component reaction to provide the corre-
that synthesise only one type of molecule. The necessity for the sponding 2-amino-4H-chromene derivative 1bc in good yield.
development of new methods can also be realized from the Both a and b-naphthols are suitable for this multicomponent
recently developed methods such as the use of potassium reaction. The results are summarized in Table 1. It is worth
phthalimide-N-oxyl,12 CaCl2 with ultrasonic irradiation,13 mentioning that, considering the importance of the 2-amino-
DMAP14 etc.
chromenes, a wide range of methodologies for the synthesis of
Considering the importance of these molecules, and in these compounds are being reported in the literature using
continuation of our efforts towards the synthesis of function- various homogeneous catalysts such as DBU,15 NaOH,16
19
alized heterocycles by MCRs, we wanted to explore imidazole in I2/K2CO3,17 InCl3,18 TiCl4 etc. In addition to these, hetero-
our MCRs, for easy access to a wide range of structurally diverse geneous catalysts have also been used for the synthesis of 2-
functionalized molecules using in situ-generated alkyl/benzyli- amino-chromenes such as nano-sized MgO,20 nano-structured
denemalononitrile derivatives and various nucleophiles, as diphosphate (Na2CaP2O7),21 Mg/Al hydrotalcite,22 triazine
shown in Scheme 1.
functionalized ordered mesoporous organo silica,23 Tungstic
acid functionalized mesoporous SBA-15 (ref. 24) and phos-
phates25 etc. The present method offers a lot of advantages over
most of the reported methods, such as ready availability, low
cost, mild nature of the imidazole and good yields. In addition
to these, the method is metal free and works under mild
conditions.
Encouraged by the results of imidazole catalysis for the
synthesis of 2-amino-4H-chromene derivatives we wanted to
check whether it will also exhibit similar results in the case of
other three component reactions involving the in situ-generated
benzylidene malononitrile derivative and a nucleophile such as
2-hydroxynaphthalene-1,4-dione. Keeping the amount of imid-
azole 20 mol% as previously and ethanol as the solvent, the
Result and discussion
For our initial study, the reaction of 4-methoxybenzaldehyde
(1.0 mmol), malononitrile (1.0 mmol) and a-naphthol (1.0
mmol) was chosen. In the absence of any catalyst and at room
temperature the above reaction in ethanol provided only traces
of the desired three component product 1ab aer 12 hours.
Interestingly, when the same reaction was tested in the pres-
ence of 10 mol% imidazole at room temperature, the desired
product was obtained in 45% yield within 12 hours. Encouraged
by this result we tried to optimize the reaction conditions by
varying the amount of imidazole and reaction temperature. The
best result was obtained in the presence of 20 mol% of imid-
azole in ethanol under reux conditions. Under these optimum
reaction conditions 1ab was obtained in 92% yield within
30 min.
Table 1 Imidazole mediated synthesis of 2-amino-4H-chromene
derivativesa
a/b
Entry
R
naphthol Productb Time (h) Yieldc (%)
1
2
3
4
5
6
7
C6H5
a
a
a
a
b
b
b
1aa
1ab
1ac
1ad
1ba
1bb
1bc
0.5
0.5
0.7
0.7
1.0
1.0
1.0
88
92
90
89
86
93
87
4-OMe–C6H4
4-Cl–C6H4
4-Br–C6H4
C6H5
4-CN–C6H4
C6H11
a
Reaction conditions: aldehyde (1.0 mmol), malononitrile (1.0 mmol), a/
b-naphthol (1.0 mmol), imidazole (0.2 mmol) in 5 ml ethanol under
reux conditions. All products were fully characterized by IR, 1H
b
Scheme 1 Imidazole mediated MCRs for the synthesis of structurally
diverse molecules.
NMR, 13C NMR and elemental analysis. c Isolated yield.
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Table
3
Synthesis of 2-amino-6-(hydroxymethyl)-4-aryl/alkyl-8-
reaction of benzaldehyde, malononitrile and 2-hydroxynaph-
thalene-1,4-dione was tested under reux conditions.
oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrilea
Interestingly, within 30 minutes the expected corresponding
three component product 2a was obtained in 93% yield. Similar
to 2a, 2b–2d were also synthesized by varying the aldehydes
under similar reaction conditions and the results are summa-
rized in Table 2. It is important to mention that the purication
process of all these products is very simple, as on completion of
the reaction the products come out as a solid precipitate, which
is ltered from the reaction mixture and the resultant solids are Entry
puried by recrystallization from ethanol.
R
Productb
Time (h)
Yieldc (%)
1
C6H5
3a
3b
3c
3d
3e
1.5
1.0
1.0
1.5
1.5
88
85
89
83
86
Encouraged by these results, we attempted the present
2
4-Me–C6H4
3-NO2–C6H4
4-Br–C6H4
2,4-Cl–C6H3
protocol for the three component reaction of kojic acid with
3
4
5
benzylidenemalononitrile obtained from the in situ condensa-
tion of aromatic aldehydes and malononitrile. In this case also
the reaction worked smoothly and the corresponding three
component products (Table 3, entries 1–5) were obtained in
good yields. Benzaldehyde derivatives such as 4-CH3, 3-NO2, 4-
Br and 2,4-Cl-benzaldehyde underwent this three component
reaction under the optimized reaction conditions and afforded
the desired products (3b–3e) in very good yields (Table 3).
Further, to show the generality and versatility of imidazole as
an organocatalyst, this protocol was extended to the synthesis of
2-amino-4-aryl/alkyl-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-
carbonitrile derivatives by a one-pot reaction of 4-hydroxy-
coumarin, aldehyde and malononitrile in the presence of
20 mol% imidazole and in ethanol as a solvent under reux
conditions.
Aromatic as well as aliphatic aldehydes provide the corre-
sponding three component products in good yields (Table 4,
entries 1–4).
Next we wanted to see the outcome of imidazole-mediated
four component reactions of aldehyde, malononitrile and eno-
lizable ketones. From the literature we realized that this
combination (1 : 2 : 1; aldehyde : malononitrile : enolizable
ketone) usually provides 2,6-dicyanoaniline derivatives in the
a
Reaction conditions: aldehyde (1.0 mmol), malononitrile (1.0 mmol),
kojic acid (1.0 mmol), imidazole (0.2 mmol) in 5 ml ethanol under
reux conditions. All products were fully characterized by IR, 1H
b
NMR, 13C NMR and elemental analysis. c Isolated yield.
presence of various catalysts and the substituted cyclohexa-1,3-
diene intermediates are not usually isolated, due to their
tendency for aromatization.26 Recently, a few methods have
been reported in the literature for the synthesis of the important
diene intermediate as an exclusive product instead of 2,6-
dicyano aniline. Mukhopadhyay and coworkers27 have shown
that the synthesis of 2,6-dicyanoaniline and the intermediate
diene are temperature dependent. In their studies, when the
reactions were performed at room temperature in water, cyclo-
hexa-1,3-dienes were the major products, and under reux
conditions the observed products were 2,6-dicyanoanilines.
Synthesis of cyclohexa-1,3-diene as a single product have also
been reported using 1,2-diamine28 at room temperature and
using the ionic liquid [BMIm][BF4]29 with reux at 90 C.
Interestingly, in our preliminary studies on the reaction of
acetophenone (1.0 mmol) with 4-Cl-benzaldehyde (1.0 mmol)
ꢀ
Table 2 Synthesis of 2-amino-5,10-dioxo-4-aryl/alkyl-5,10-dihydro-
4H-benzo[g]chromene-3-carbonitrilesa
Table 4 Synthesis of 2-amino-4-aryl/alkyl-5-oxo-4,5-dihydropyrano
[3,2-c]chromene-3-carbonitrilea
Entry
R
Productb
Time (h)
Yieldc (%)
Entry
R
Productb
Time (h)
Yieldc (%)
1
2
3
4
5
C6H5
2a
2b
2c
2d
2e
0.5
0.5
0.5
0.5
1.0
93
92
91
94
89
4-OMe–C6H4
4-NO2–C6H4
4-CN–C6H4
C6H11
1
2
3
4
4-MeS–C6H4
2-Naphthyl
C6H5CH2
C6H13
4a
4b
4c
4d
1.5
1.0
1.0
1.5
89
94
90
92
a
a
Reaction conditions: aldehyde (1.0 mmol), malononitrile (1.0 mmol), 2-
Reaction conditions: aldehyde (1.0 mmol), malononitrile (1.0 mmol), 4-
hydroxynaphthalene-1,4-dione (1.0 mmol), imidazole (0.2 mmol) in 5 ml hydroxycoumarin (1.0 mmol), imidazole (0.2 mmol) in 5 ml ethanol
b
ethanol under reux conditions. b All products were fully characterized under reux conditions. All products were fully characterized by IR,
1
c
by IR, H NMR, 13C NMR and elemental analysis. c Isolated yield.
1H NMR, 13C NMR and elemental analysis. Isolated yield.
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and malononitrile (2.0 mmol) in the presence of 20 mol% aldehydes bearing electron donating groups such as –OMe
imidazole and ethanol as a solvent under reux conditions, and electron withdrawing groups such as –CN were also found
we ended up with diene 5a as the sole product. Even aer to be suitable in this process, with the isolated yields 91% and
continuing the reaction for longer we did not observe any 90% for 6b and 6c, respectively. 2-Naphthaldehyde, a bulky
change in the reaction outcome. In a similar manner, by aldehyde, showed a very good yield of 92%. An aliphatic
varying the aldehyde and ketone under the optimized reac- aldehyde such as cyclohexanecarboxaldehyde was also found
tion conditions, compound 5b was also synthesized in good to be applicable in this process and gave the corresponding
yields. Mechanistically, 5a is the intermediate to access the pyridine product 6e with 85% isolated yield. To see the scope
corresponding 2,6-dicyano aniline derivatives. We believe of the process, an aliphatic thiol such as cyclohexanethiol was
that, due to the mild basicity of imidazole, the nal stage also tested but in this case the reaction took a little more time
elimination of HCN was not possible in this case. Thus, we as compared to the other thiols. From all these studies we
realized that this imidazole mediated process may serve as an have found that imidazole is a versatile organocatalyst for one
efficient tool for easy access to a wide range of functionalized pot multicomponent reactions employing in situ-generated
dienes (carbocycles) in good yields. Interestingly, under alkyl/benzylidene malononitrile with various nucleophiles
similar reaction conditions, a cyclic ketone such as cyclo- (Table 6).
hexanone provided the corresponding exo-cyclic diene 5c in
81% yield instead of the endo-cyclic diene. Using the same
procedure, 5d was also synthesized in one pot from the
reaction of cyclohexanone, malononitrile and 2-naph-
Table 6 Synthesis of 2-amino pyridine-3,5-dicarbonitrile derivativesa
thaldehyde, a bulky aldehyde (Table 5).
These positive results prompted us to explore the full
potential of imidazole in other MCRs involving in situ benzy-
lidenemalononitrile derivatives. In continuation of our explo-
ration of organocatalytic activity of imidazole in
multicomponent reactions we turned our attention to
Entry
R
R1
Productb Time (h) Yieldc (%)
synthesize highly substituted pyridines from the reaction of
one equivalent aldehyde, two equivalents malononitrile and
one equivalent thiol. Recently, we have reported a base cata-
lyzed synthesis of highly substituted pyridines and their photo
physical studies.30 To check the suitability of imidazole for
this MCR, initially the reaction of one equivalent benzalde-
hyde, one equivalent thiophenol and two equivalents malo-
nonitrile was tested in presence of 20 mol% imidazole under
reux conditions. Interestingly, in this case we also achieved a
good result of 86% yield of 6a within 1.0 h. Aromatic
1
2
3
4
5
6
C6H5
C6H5
6a
6b
1.0
0.5
0.5
0.5
1.0
2.0
86
91
90
92
85
81
4-OMe–C6H4 C6H5
4-CN–C6H4
2-Naphthyl
C6H11
2-Me–C6H4 6c
2-Me–C6H4 6d
C6H5
6e
6f
4-Cl–C6H4
C6H11
a
Reaction conditions: aldehyde (1.0 mmol), malononitrile (2.0 mmol),
thiol (1.0 mmol), imidazole (0.2 mmol) in 5 ml ethanol under reux
conditions. All products were fully characterized by IR, 1H NMR, 13C
b
NMR and elemental analysis. c Isolated yield.
Table 5 Synthesis of tetrahydronaphthalene/cyclohexa-1,3-dienea
Entry
Ketone
R
Productb
Time (h)
Yieldc (%)
1
2
3
4
Acetophenone
4-Bromo acetophenone
Cyclohexanone
4-Cl–C6H4
5a
5b
5c
5d
9
12
4
86
88
81
90
4-OMe–C6H4
3-NO2–C6H4
2-Naphthyl
Cyclohexanone
6
a
Reaction conditions: aldehyde (1.0 mmol), malononitrile (2.0 mmol), enolizable ketone (1.0 mmol), imidazole (0.2 mmol) in 5 ml ethanol under
reux conditions. All products were fully characterized by IR, H NMR, 13C NMR and elemental analysis. c Isolated yield.
b
1
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3.77 (s, 3H) ppm; 13C NMR (CDCl3 + DMSO-d6, 100 MHz):
d ¼ 159.6, 158.5, 143.1, 137.2, 133.0, 129.0, 127.5, 126.5, 126.4,
126.1, 124.1, 123.2, 120.9, 120.4, 117.5, 114.0, 59.3, 55.1, 40.7
ppm; elemental analysis calc. for C21H16N2O2 (328.36): C, 76.81;
H, 4.91; N, 8.53; found: C, 76.78; H, 4.94; N, 8.58%.
Conclusion
In summary, the present work describes imidazole-mediated
multicomponent reactions involving in situ-generated alkyl/
benzylidine malononitrile as intermediates for easy access to a
wide range of highly substituted annulated pyrans, cyclohexa-
1,3-dienes and 2-amino pyridines. This protocol has the
advantages of a wide scope of substrates, ready availability,
lower cost of the catalyst, operational simplicity, and no need
for column chromatographic separation, with good to high
isolated yields.
2-Amino-4-(4-chlorophenyl)-4H-benzo[h]chromene-3-carbo
ꢀ
nitrile (1ac). White solid; 90% yield; mp 200–202 C; IR (KBr):
3439, 3348, 3244, 2963, 2861, 2219, 1646, 1591, 1521, 1461,
1392, 1278, 1183, 1033, 883, 847, 763 cmꢁ1; 1H NMR (CDCl3, 400
MHz): d ¼ 8.17 (d, J ¼ 8.0 Hz, 1H), 7.79 (d, J ¼ 8.0 Hz, 1H), 7.60–
7.51 (m, 3H), 7.28 (d, J ¼ 8.4 Hz, 2H), 7.17 (d, J ¼ 8.4 Hz, 2H),
6.98 (d, J ¼ 8.4 Hz, 1H), 4.86 (s, 1H), 4.79 (bs, 2H) ppm; 13C NMR
(CDCl3 + DMSO-d6, 100 MHz): d ¼ 159.7, 143.4, 143.3, 133.2,
132.8, 129.4, 128.8, 127.6, 126.8, 126.6, 125.9, 124.4, 123.2,
120.9, 120.2, 116.7, 58.9, 40.9 ppm; elemental analysis calc. for
Experimental
General
C
20H13ClN2O (332.78): C, 72.18; H, 3.94; N, 8.42; found: C, 72.21;
All reagents were used without further purication and were
H, 3.96; N, 8.45%.
procured from commercial sources. A Shimadzu FTIR spectro-
photometer was used for recording IR spectra. 1H NMR and 13
C
2-Amino-4-(4-bromophenyl)-4H-benzo[h]chromene-3-carbo
ꢀ
nitrile (1ad). Light yellow solid; 89% yield; mp 252–254 C; IR
NMR spectra were recorded on Jeol 500, Varian 400 and Bruker
300/400/500 MHz spectrometers in CDCl3 and DMSO-d6 using
TMS as an internal reference. Elemental analyses were carried
out in a Perkin Elmer 2400 automatic CHN analyzer or Ele-
menter Vario EL III. All compounds were characterized by their
(KBr): 3438, 3329, 3241, 2953, 2861, 2223, 1651, 1587, 1522,
1463, 1390, 1274, 1187, 1031, 886, 843, 767 cmꢁ1 1H NMR
;
(CDCl3, 400 MHz): d ¼ 8.17 (d, J ¼ 8.0 Hz, 1H), 7.80 (d, J ¼ 8.0
Hz, 1H), 7.60–7.51 (m, 3H), 7.44 (d, J ¼ 8.0 Hz, 2H), 7.11 (d, J ¼
8.4 Hz, 2H), 6.98 (d, J ¼ 8.4 Hz, 1H), 4.85 (s, 1H), 4.77 (bs, 2H)
ppm; 13C NMR (CDCl3 + DMSO-d6, 100 MHz): d ¼ 159.9, 144.1,
143.1, 132.9, 131.4, 129.6, 127.3, 126.5, 126.3, 125.7, 123.9,
123.0, 120.9, 120.5, 120.2, 116.5, 57.4, 40.9 ppm; elemental
analysis calc. for C20H13BrN2O (377.23): C, 63.68; H, 3.47; N,
7.43; found: C, 63.64; H, 3.50; N, 7.49%.
1
melting points, H NMR and 13C NMR spectra and elemental
analysis.
General procedure for the synthesis of 2-amino-4-(aryl/alkyl)-
4H-benzo[h]chromene-3-carbonitrile (1aa–1ad and 1ba–1bc)
A mixture of aldehyde (1.0 mmol), malononitrile (1.0 mmol),
3-Amino-1-phenyl-1H-benzo[f]chromene-2-carbonitrile (1ba).
imidazole (0.2 mmol) and a/b-naphthol (1.0 mmol) in 5 ml White solid; 86% yield; mp 297–299 ꢀC; IR (KBr): 3441, 3347,
ethanol was taken in a 25 ml round bottomed ask tted with a 3248, 2953, 2861, 2211, 1643, 1583, 1509, 1464, 1392, 1276,
reux condenser. The reaction mixture was stirred under reux 1178, 1028, 876, 847, 773 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz): d
conditions. The progress of the reaction was monitored by TLC. ¼ 7.92 (d, J ¼ 9.0 Hz, 1H), 7.90–7.88 (m, 1H), 7.82 (d, J ¼ 9.0 Hz,
Aer completion of the reaction, the reaction mixture was 1H), 7.43–7.37 (m, 2H), 7.32 (d, J ¼ 9.0 Hz, 1H), 7.25–7.21 (m,
gradually cooled to room temperature. The solid product was 2H), 7.18–7.16 (m, 2H), 7.12 (tt, J ¼ 7.5, 1.5 Hz, 1H), 6.97 (bs,
collected by simple ltration and washed with ethanol and 2H), 5.28 (s, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz): d ¼ 160.2,
dried. The obtained solid was found to be pure enough for 147.3, 146.2, 131.3, 130.6, 129.9, 129.2, 128.9, 127.5, 127.5,
further characterization.
127.1, 125.4, 124.1, 120.9, 117.3, 116.5, 58.4, 38.5 ppm;
2-Amino-4-phenyl-4H-benzo[h]chromene-3-carbonitrile elemental analysis calc. for C20H14N2O (298.34): C, 80.52; H,
ꢀ
(1aa). White solid; 88% yield; mp 222–224 C; IR (KBr): 3446, 4.73; N, 9.39; found: C, 80.56; H, 4.78; N, 9.34%.
3349, 3252, 2963, 2854, 2214, 1649, 1597, 1519, 1468, 1391,
3-Amino-1-(4-cyanophenyl)-1H-benzo[f]chromene-2-carbo
1270, 1184, 1031, 885, 841, 763 cmꢁ1 1H NMR (CDCl3, 400 nitrile (1bb). Yellow-brown solid; 93% yield; mp 280–282 ꢀC; IR
;
MHz): d ¼ 8.17 (d, J ¼ 8.4 Hz, 1H), 7.78 (d, J ¼ 8.0 Hz, 1H), 7.59– (KBr): 3447, 3304, 3168, 3065, 2873, 2226, 2184, 1650, 1587,
7.49 (m, 3H), 7.33–7.29 (m, 2H), 7.26–7.22 (m, 3H), 7.02 (d, J ¼ 1518, 1406, 1291, 1238, 1181, 1084, 845, 808, 735, 662, 559 cmꢁ1
;
8.4 Hz, 1H), 4.87 (s, 1H), 4.76 (bs, 2H) ppm; 13C NMR (DMSO-d6, 1H NMR (CDCl3 + DMSO-d6, 400 MHz): d ¼ 7.84 (d, J ¼ 9.0 Hz,
100 MHz): d ¼ 160.6, 146.2, 143.2, 133.2, 129.2, 128.1, 127.4, 1H), 7.82–7.79 (m, 1H), 7.63–7.61 (m, 1H), 7.57 (d, J ¼ 8.2 Hz,
127.2, 127.1, 126.7, 124.4, 123.2, 121.2, 121.0, 118.4, 56.8, 41.4 2H), 7.36–7.34 (m, 2H), 7.30 (d, J ¼ 8.1 Hz, 2H), 7.29 (d, J ¼ 9.3
ppm; elemental analysis calc. for C20H14N2O (298.34): C, 80.52; Hz, 1H), 6.89 (bs, 2H), 5.29 (s, 1H) ppm; 13C NMR (CDCl3
+
H, 4.73; N, 9.39; found: C, 80.49; H, 4.71; N, 9.45%.
DMSO-d6, 100 MHz): d ¼ 160.0, 150.7, 147.1, 132.7, 130.9, 130.1,
2-Amino-4-(4-methoxyphenyl)-4H-benzo[h]chromene-3-carbo 129.9, 128.6, 128.0, 127.3, 125.0, 123.3, 120.4, 118.6, 116.9,
ꢀ
nitrile (1ab). Light yellow solid; 92% yield; mp 191–193 C; IR 114.1, 109.9, 57.0, 38.5 ppm; elemental analysis calc. for
(KBr): 3428, 3339, 3246, 2957, 2868, 2213, 1641, 1592, 1521,
C21H13N3O (323.35): C, 78.00; H, 4.05; N, 13.00; found: C, 78.04;
1460, 1393, 1268, 1181, 1032, 887, 842, 761 cmꢁ1 1H NMR H, 4.08; N, 13.05%.
;
(CDCl3, 400 MHz): d ¼ 8.17 (d, J ¼ 8.4 Hz, 1H), 7.78 (d, J ¼ 7.6
3-Amino-1-cyclohexyl-1H-benzo[f]chromꢀene-2-carbonitrile
Hz, 1H), 7.59–7.49 (m, 3H), 7.15 (d, J ¼ 8.8 Hz, 2H), 7.01 (d, J ¼ (1bc). White solid; 87% yield; mp 245–247 C; IR (KBr): 3437,
8.8 Hz, 1H), 6.84 (d, J ¼ 8.4 Hz, 2H), 4.83 (s, 1H), 4.75 (bs, 2H), 3335, 3209, 3056, 2924, 2852, 2185, 1643, 1586, 1517, 1418,
3736 | RSC Adv., 2014, 4, 3732–3741
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1240, 1182, 1082, 967, 816, 749 cmꢁ1; 1H NMR (CDCl3 + DMSO- 280–282 ꢀC; IR (KBr): 3438, 3333, 3222, 3123, 3097, 3060, 2234,
d6, 400 MHz): d ¼ 7.87 (d, J ¼ 8.5 Hz, 1H), 7.83 (d, J ¼ 8.1 Hz, 2197, 1688, 1671, 1629, 1598, 1403, 1358, 1240, 1206, 1073,
1H), 7.74 (d, J ¼ 8.8 Hz, 1H), 7.54–7.51 (m, 1H), 7.42–7.39 (m, 1021, 945, 852, 779, 715, 615, 568 cmꢁ1; 1H NMR (DMSO-d6, 500
1H), 7.16 (d, J ¼ 8.9 Hz, 1H), 6.75 (bs, 2H), 3.98 (s, 1H), 1.82–1.56 MHz): d ¼ 8.04–8.02 (m, 1H), 7.85–7.81 (m, 3H), 7.76 (d, J ¼ 8.5
(m, 3H), 1.54–1.38 (m, 3H), 1.17–0.94 (m, 4H), 0.90–0.78 (m, 1H) Hz, 2H), 7.55 (d, J ¼ 8.5 Hz, 2H), 7.43 (bs, 2H), 4.72 (s, 1H) ppm;
ppm; 13C NMR (CDCl3 + DMSO-d6, 100 MHz): d ¼ 162.7, 147.6, 13C NMR (DMSO-d6, 125 MHz): d ¼ 183.0, 177.2, 158.8, 149.9,
130.7, 129.8, 128.4, 128.1, 126.8, 124.5, 122.7, 122.1, 117.3, 149.5, 135.0, 134.7, 133.0, 131.4, 131.2, 129.3, 126.5, 126.3,
116.3, 51.4, 45.2, 37.7, 30.7, 26.4, 26.2, 25.8, 25.4 ppm; 121.1, 119.5, 119.2, 110.4, 57.0, 37.1 ppm; elemental analysis
elemental analysis calc. for C20H20N2O (304.39): C, 78.92; H, calc. for C20H11N3O3 (341.32): C, 70.38; H, 3.25; N, 12.31; found:
6.62; N, 9.20; found: C, 78.97; H, 6.64; N, 9.23%.
C, 70.35; H, 3.28; N, 12.36%.
2-Amino-4-cyclohexyl-5,10-dioxo-5,10-dihydro-4H-benzo[g]-
chromene-3-carbonitrile (2e). Orange solid; 89% yield; mp 248–
250 ꢀC; IR (KBr): 3465, 3380, 3306, 3244, 3191, 2923, 2848, 2194,
1684, 1660, 1601, 1412, 1376, 1329, 1300, 1249, 1209, 1047, 944,
891, 716, 532 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz): d ¼ 8.01–7.98
General procedure for the synthesis of 2-amino-5,10-dioxo-4-
aryl/alkyl-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile
(2a–2e)
The procedure for the synthesis of 2a–2e is the same as that (m, 2H), 7.87–7.82 (m, 2H), 7.26 (bs, 2H), 3.37 (d, J ¼ 3.0 Hz, 1H),
used for above. In this case instead of naphthol 1.0 mmol of 2- 1.69 (d, J ¼ 12.5 Hz, 1H), 1.62–1.54 (m, 3H), 1.49–1.42 (m, 2H),
hydroxy naphthaquinone was used.
1.32–1.25 (m, 1H), 1.16–0.99 (m, 3H), 0.92–0.81 (m, 1H) ppm;
2-Amino-5,10-dioxo-4-phenyl-5,10-dihydro-4H-benzo[g]- 13C NMR (DMSO-d6, 125 MHz): d ¼ 183.4, 177.1, 161.6, 150.5,
chromene-3-carbonitrile (2a). Orange solid; 93% yield; mp 269– 134.9, 134.5, 131.7, 131.1, 126.5, 126.4, 124.2, 121.3, 52.3, 44.6,
271 ꢀC; IR (KBr): 3405, 3325, 3192, 3021, 2199, 1701, 1688, 1674, 36.4, 30.8, 27.6, 26.6, 26.3, 26.0 ppm; elemental analysis calc. for
1602, 1405, 1367, 1302, 1245, 1206, 1071, 1016, 948, 755, 717,
C20H18N2O3 (334.37): C, 71.84; H, 5.43; N, 8.38; found: C, 71.86;
525 cmꢁ1; 1H NMR (CDCl3 + DMSO-d6, 400 MHz): d ¼ 8.09–8.07 H, 5.46; N, 8.43%.
(m, 1H), 7.94–7.92 (m, 1H), 7.82–7.79 (m, 2H), 7.34–7.29 (m,
4H), 7.26–7.21 (m, 1H), 7.15 (bs, 2H), 4.67 (s, 1H) ppm; 13C NMR
(CDCl3 + DMSO-d6, 100 MHz): d ¼ 182.4, 176.9, 158.6, 148.5,
143.1, 134.6, 134.0, 131.0, 130.3, 128.6, 127.6, 127.2, 126.2,
126.1, 122.8, 119.3, 57.6, 36.5 ppm; elemental analysis calc. for
General procedure for the synthesis of 2-amino-6-
(hydroxymethyl)-4-aryl/alkyl-8-oxo-4,8-dihydropyrano [3,2-b]-
pyran-3-carbonitrile (3a–3e)
C
20H12N2O3 (328.32): C, 73.16; H, 3.68; N, 8.53; found: C, 73.19; A mixture of aldehyde (1.0 mmol), malononitrile (1.0 mmol),
H, 3.70; N, 8.58%.
imidazole (0.2 mmol), kojic acid (1.0 mmol) and ethanol (5 ml) at
2-Amino-4-(4-methoxyphenyl)-5,10-dioxo-5,10-dihydro-4H- room temperature was taken in a 25 ml round bottomed ask
benzo[g]chromene-3-carbonitrile (2b). Red-brown solid; 92% tted with a reux condenser. The reaction mixture was stirred
yield; mp 243–245 ꢀC; IR (KBr): 3406, 3327, 3193, 3067, 2834, under reux conditions in open air. Aer some time the reaction
2196, 1705, 1691, 1683, 1604, 1512, 1410, 1366, 1302, 1243, mixture gave rise to a clear solution. The progress of the reaction
1
1201, 1072, 1022, 949, 835, 717, 616, 567, 530 cmꢁ1; H NMR was monitored with TLC (hexane–ethyl acetate, 7 : 3). Aer
(CDCl3 + DMSO-d6, 400 MHz): d ¼ 8.11–8.05 (m, 1H), 7.94–7.90 completion of the reaction, the reaction mixture was gradually
(m, 1H), 7.82–7.73 (m, 2H), 7.23 (d, J ¼ 8.0 Hz, 2H), 6.93 (bs, 2H), cooled to room temperature. The solid product was collected by
6.83 (d, J ¼ 8.0 Hz, 2H), 4.65 (s, 1H), 3.75 (s, 3H) ppm; 13C NMR simple ltration, washed with ethanol and dried. The obtained
(CDCl3 + DMSO-d6, 100 MHz): d ¼ 182.4, 176.9, 158.6, 158.4, solid was pure enough for further characterization.
148.0, 134.9, 134.4, 133.8, 131.0, 130.1, 128.8, 126.1, 126.0,
2-Amino-6-(hydroxymethyl)-8-oxo-4-phenyl-4,8-dihydropyrano
123.1, 119.3, 113.8, 58.0, 54.9, 35.6 ppm; elemental analysis [3,2-b]pyran-3-carbonitrile (3a). White solid; 88% yield; 237–239
calc. for C21H14N2O4 (358.35): C, 70.39; H, 3.94; N, 7.82; found: ꢀC; IR (KBr): 3373, 3305, 3189, 3085, 3028, 2191, 1670, 1635,
C, 70.41; H, 3.97; N, 7.85%.
1595, 1446, 1411, 1206, 1058, 1013, 852, 710, 629, 588, 528 cmꢁ1
;
2-Amino-4-(4-nitrophenyl)-5,10-dioxo-5,10-dihydro-4H-benzo- 1H NMR (CDCl3 + DMSO-d6, 400 MHz): d ¼ 7.40–7.36 (m, 2H),
[g]chromene-3-carbonitrile (2c). Orange solid; 91% yield; mp 7.32–7.28 (m, 3H), 7.16 (bs, 2H), 6.34 (s, 1H), 5.67 (bs, 1H), 4.72
262–264 ꢀC; IR (KBr): 3457, 3355, 3254, 3190, 3110, 3067, 2199, (s, 1H), 4.23 (d, J ¼ 15.9 Hz, 1H), 4.13 (d, J ¼ 15.9 Hz, 1H) ppm;
1685, 1674, 1632, 1600, 1516, 1402, 1354, 1243, 1206, 1074, 948, 13C NMR (CDCl3 + DMSO-d6, 100 MHz): d ¼ 169.6, 168.1, 159.3,
862, 830, 714, 613, 532 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz): d ¼ 148.7, 140.5, 136.3, 128.7, 127.7, 127.6, 119.1, 111.2, 59.1, 55.4,
8.15 (d, J ¼ 9.0 Hz, 2H), 8.05–8.03 (m, 1H), 7.86–7.79 (m, 3H), 40.5 ppm; elemental analysis calc. for C16H12N2O4 (296.28): C,
7.63 (d, J ¼ 9.0 Hz, 2H), 7.46 (bs, 2H), 4.80 (s, 1H) ppm; 13C NMR 64.86; H, 4.08; N, 9.46; found: C, 64.89; H, 4.11; N, 9.48%.
(DMSO-d6, 125 MHz): d ¼ 183.0, 177.2, 158.8, 151.5, 149.9,
2-Amino-6-(hydroxymethyl)-4-(4-methylphenyl)-8-oxo-4,8-
147.0, 135.0, 134.7, 131.4, 131.2, 129.6, 126.6, 126.3, 124.2, dihydropyrano[3,2-b]pyran-3-carbonitrile (3b). Light yellow
121.1, 119.5, 56.8, 36.9 ppm; elemental analysis calc. for solid; 85% yield; mp 224–226 ꢀC; IR (KBr): 3397, 3303, 3189,
C
20H11N3O5 (373.32): C, 64.35; H, 2.97; N, 11.26; found: C, 64.38; 3084, 3048, 2921, 2861, 2192, 1635, 1598, 1510, 1208, 1098,
H, 3.00; N, 11.30%.
1059, 1007, 861, 817, 750, 614, 521 cmꢁ1 1H NMR (CDCl3
;
+
2-Amino-4-(4-cyanophenyl)-5,10-dioxo-5,10-dihydro-4H-benzo- DMSO-d6, 400 MHz): d ¼ 7.17 (bs, 4H), 6.80 (bs, 2H), 6.40 (s, 1H),
[g]chromene-3-dicarbonitrile (2d). Orange solid; 94% yield; mp 5.80 (t, J ¼ 6.0 Hz, 1H), 4.63 (s, 1H), 4.29 (dd, J ¼ 16.1, 5.8 Hz,
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1H), 4.19 (dd, J ¼ 16.1, 5.8 Hz, 1H), 2.33 (s, 3H) ppm; 13C NMR (DMSO-d6, 125 MHz): d ¼ 160.0, 158.4, 153.8, 152.6, 140.5,
(CDCl3 + DMSO-d6, 100 MHz): d ¼ 170.3, 168.4, 159.5, 149.1, 137.3, 133.4, 128.8, 126.5, 125.2, 122.9, 119.7, 117.0, 113.4,
137.4, 137.2, 136.3, 129.4, 127.5, 119.2, 111.2, 59.4, 56.0, 40.3, 104.3, 58.3, 36.9, 15.1 ppm; elemental analysis calc. for
20.8 ppm; elemental analysis calc. for C17H14N2O4 (310.30): C,
65.80; H, 4.55; N, 9.03; found: C, 65.84; H, 4.57; N, 9.08%.
2-Amino-6-(hydroxymethyl)-4-(3-nitrophenyl)-8-oxo-4,8-dihy-
C20H14N2O3S (362.40): C, 66.28; H, 3.89; N, 7.73; found: C, 66.25;
H, 3.91; N, 7.78%.
2-Amino-4-(naphthalen-2-yl)-5-oxo-4H,5H-pyrano[3,2-c]-
dropyrano[3,2-b]pyran-3-carbonitrile (3c). White solid; 89% chromene-3-carbonitrile (4b). White solid; 94% yield; mp 241–
yield; mp 236–238 ꢀC; IR (KBr): 3524, 3384, 3319, 3210, 3082, 243 ꢀC; IR (KBr): 3400, 3319, 3254, 3191, 3050, 2199, 1711, 1671,
2868, 2189, 1672, 1640, 1595, 1532, 1440, 1413, 1315, 1219, 1606, 1455, 1387, 1254, 1053, 954, 905, 759 cmꢁ1
;
1H NMR
1067, 869, 722, 551 cmꢁ1; H NMR (DMSO-d6, 500 MHz): d ¼ (DMSO-d6, 500 MHz): d ¼ 7.94–7.89 (m, 2H), 7.86–7.84 (m, 2H),
8.18 (ddd, J ¼ 8.0, 2.5, 1.0 Hz, 1H), 8.16 (t, J ¼ 2.0 Hz, 1H), 7.80 7.80 (s, 1H), 7.70 (td, J ¼ 7.7, 1.5 Hz, 1H), 7.51–7.45 (m, 4H), 7.43
(td, J ¼ 8.0, 1.5 Hz, 1H), 7.70 (t, J ¼ 8.0 Hz, 1H), 7.36 (bs, 2H), (bs, 2H), 7.39 (dd, J ¼ 8.5, 1.5 Hz, 1H), 4.62 (s, 1H) ppm; 13C
6.33 (s, 1H), 5.65 (t, J ¼ 6.0 Hz, 1H), 5.12 (s, 1H), 4.18 (dd, J ¼ NMR (DMSO-d6, 125 MHz): d ¼ 160.1, 158.4, 154.0, 152.7, 141.2,
15.5, 6.0 Hz, 1H), 4.11 (dd, J ¼ 15.5, 6.0 Hz, 1H) ppm; 13C NMR 133.4, 133.3, 132.7, 128.7, 128.3, 127.9, 126.7, 126.4, 126.3,
(DMSO-d6, 125 MHz): d ¼ 170.0, 168.8, 159.9, 148.5, 148.2, 125.2, 123.0, 119.7, 117.1, 113.5, 104.2, 58.4, 37.7 ppm;
143.3, 137.1, 135.2, 131.1, 123.5, 123.0, 119.5, 112.0, 59.5, 55.2 elemental analysis calc. for C24H14N2O3 (378.38): C, 76.18; H,
ppm; elemental analysis calc. for C16H11N3O6 (341.28): C, 56.31; 3.73; N, 7.40; found: C, 76.21; H, 3.77; N, 7.44%.
1
H, 3.25; N, 12.31; found: C, 56.33; H, 3.27; N, 12.36%.
2-Amino-4-benzyl-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-car-
2-Amino-4-(4-bromophenyl)-6-(hydroxymethyl)-8-oxo-4,8- bonitrile (4c). Light yellow solid; 90% yield; mp 223–225 ꢀC; IR
dihydropyrano[3,2-b]pyran-3-carbonitrile (3d). White solid; (KBr): 3407, 3303, 3190, 3084, 3028, 3007, 2935, 2884, 2192,
83% yield; mp 228–230 ꢀC; IR (KBr): 3461, 3336, 3174, 2977, 1724, 1665, 1603, 1493, 1446, 1393, 1308, 1275, 1193, 1051, 965,
2892, 2865, 2191, 1675, 1647, 1593, 1489, 1444, 1422, 1260, 753, 713, 600, 543, 517 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz): d ¼
1207, 1162, 1070, 1042, 1011, 964, 877, 833, 764, 717, 689, 554, 7.66–7.62 (m, 1H), 7.54 (d, J ¼ 7.5 Hz, 1H), 7.45 (t, J ¼ 8.5 Hz,
502 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz): d ¼ 7.57 (d, J ¼ 8.5 Hz, 1H), 7.37–7.33 (m, 1H), 7.16 (bs, 2H), 7.14–7.08 (m, 3H), 6.91 (d,
2H), 7.26 (bs, 2H), 7.25 (d, J ¼ 8.0 Hz, 2H), 6.32 (s, 1H), 5.66 (t, J ¼ 7.0 Hz, 2H), 3.72 (dd, J ¼ 8.5, 4.5 Hz, 1H), 3.05 (dd, J ¼ 13.0,
J ¼ 6.0 Hz, 1H), 4.83 (s, 1H), 4.19 (dd, J ¼ 16.0, 6.0 Hz, 1H), 4.11 4.5 Hz, 1H), 2.81 (dd, J ¼ 13.0, 3.5 Hz, 1H) ppm; 13C NMR
(dd, J ¼ 16.0, 6.0 Hz, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz): d (DMSO-d6, 125 MHz): d ¼ 160.5, 159.9, 154.7, 152.4, 137.3,
¼ 170.0, 168.7, 159.7, 148.9, 140.7, 136.9, 132.3, 130.5, 121.6, 133.3, 130.0, 128.3, 126.9, 125.1, 122.4, 119.9, 117.0, 113.0,
119.6, 111.9, 59.6, 55.7, 40.5 ppm; elemental analysis calc. for 103.4, 54.8, 38.8, 33.2 ppm; elemental analysis calc. for
C
16H11BrN2O4 (375.17): C, 51.22; H, 2.96; N, 7.47; found: C,
C20H14N2O3 (330.34): C, 72.72; H, 4.27; N, 8.48; found: C, 72.77;
51.25; H, 2.94; N, 7.52%.
H, 4.25; N, 8.52%.
2-Amino-4-(2,4-dichlorophenyl)-6-(hydroxymethyl)-8-oxo-4,8-
2-Amino-4-hexyl-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbo
ꢀ
dihydropyrano[3,2-b]pyran-3-carbonitrile (3e). White solid; 86% nitrile (4d). White solid; 92% yield; mp 228–230 C; IR (KBr):
yield; mp 258–260 ꢀC; IR (KBr): 3446, 3342, 3196, 3067, 3026, 3403, 3326, 3253, 3195, 3060, 2915, 2869, 2854, 2204, 1713, 1678,
2974, 2889, 2190, 1676, 1641, 1595, 1562, 1474, 1441, 1412, 1609, 1455, 1394, 1315, 1208, 1185, 1108, 1042, 956, 903, 754, 526
1
1384, 1316, 1208, 1164, 1049, 966, 858, 778, 682, 565 cmꢁ1; H cmꢁ1; 1H NMR (DMSO-d6, 500 MHz): d ¼ 7.79 (dd, J ¼ 8.0, 1.5 Hz,
NMR (DMSO-d6, 500 MHz): d ¼ 7.65 (d, J ¼ 2.0 Hz, 1H), 7.46 (dd, 1H), 7.67 (dt, J ¼ 8.5, 1.5 Hz, 1H), 7.45–7.42 (m, 2H), 7.27 (bs, 2H),
J ¼ 8.0, 1.5 Hz, 1H), 7.65 (t, J ¼ 6.0 Hz, 1H), 7.30 (bs, 2H), 6.32 (s, 3.40 (dd, J ¼ 5.5, 4.0 Hz, 1H), 1.73–1.67 (m, 1H), 1.56–1.51 (m,
1H), 5.65 (t, J ¼ 6.0 Hz, 1H), 5.26 (s, 1H), 4.17 (dd, J ¼ 16.5, 6.0 1H), 1.24–1.11 (m, 8H), 0.78 (t, J ¼ 7.0 Hz, 3H) ppm; 13C NMR
Hz, 1H), 4.09 (dd, J ¼ 15.5, 5.5 Hz, 1H) ppm; 13C NMR (DMSO- (DMSO-d6, 125 MHz): d ¼ 160.4, 159.9, 154.6, 152.5, 133.2, 125.1,
d6, 125 MHz): d ¼ 169.9, 168.8, 160.0, 147.9, 137.5, 137.0, 134.1, 122.6, 120.1, 117.0, 113.4, 104.7, 55.6, 34.1, 31.6, 31.3, 29.0, 24.6,
133.9, 132.9, 129.9, 128.8, 119.3, 111.9, 59.5, 56.5, 38.2 ppm; 22.4, 14.3 ppm; elemental analysis calc. for C19H20N2O3 (324.37):
elemental analysis calc. for C16H10Cl2N2O4 (365.17): C, 52.63; H, C, 70.35; H, 6.21; N, 8.64; found: C, 70.39.; H, 6.25; N, 8.68%.
2.76; N, 7.67; found: C, 52.65; H, 2.74; N, 7.69%.
General procedure for the synthesis of
General procedure for the synthesis of 2-amino-4-aryl/alkyl-5-
tetrahydronaphthaalene/cyclohexa-1,3-diene (5a–5d)
oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (4a–4d)
A mixture of aldehyde (1.0 mmol), malononitrile (2.0 mmol),
Procedure for 4a–4d is similar to 1aa. In these cases 4- imidazole (0.2 mmol), enolizable ketone (1.0 mmol) and
hydroxycoumarin (1.0 mmol) was used instead of naphthol. ethanol (5 ml) at room temperature was taken in a 25 ml round
2-Amino-4-[4-(methylsulfanyl)phenyl]-5-oxo-4H,5H-pyrano- bottomed ask tted with a reux condenser. The reaction
[3,2-c]chromene-3-carbonitrile (4a). White solid; 89% yield; mp mixture was stirred under reux conditions in open air. The
242–244 ꢀC; IR (KBr): 3446, 3326, 3289, 3252, 3212, 3184, 2198, progress of the reaction was monitored by TLC. On completion
1721, 1679, 1594, 1492, 1455, 1408, 1375, 1172, 1113, 1046, 954, of the reaction, the reaction mixture was gradually cooled to
843, 766, 561 cmꢁ1; 1H NMR (DMSO-d6, 500 MHz): d ¼ 7.88 (d, J room temperature. The solid product was collected by simple
¼ 7.5 Hz, 1H), 7.69 (t, J ¼ 7.5 Hz, 1H), 7.49–7.43 (m, 2H), 7.38 ltration and washed with ethanol and dried. The solid was
(bs, 2H), 7.18 (bs, 4H), 4.40 (s, 1H), 2.42 (s, 3H) ppm; 13C NMR further crystallized in acetonitrile to obtain pure solid.
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2-Amino-6-(4-chlorophenyl)-4-phenylcyclohexa-2,4-diene-1,
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taken in a 25 ml round bottom ask tted with a reux
condenser. The reaction mixture was stirred under reux
conditions in open air. Aer some time the reaction mixture
gave rise to a clear solution. The progress of the reaction was
monitored by TLC. Aer completion of the reaction, the reac-
tion mixture was gradually cooled to room temperature. The
solid product was collected by simple ltration, washed with
ethanol and dried to obtain a pure solid. The obtained solid was
pure enough for further characterization.
1,3-tricarbonitrile (5a). Yellow solid; 86% yield; mp 246–248 ꢀC;
IR (KBr): 3363, 3344, 3226, 3070, 3052, 2224, 2213, 1663, 1610,
1554, 1530, 1491, 1444, 1405, 1311, 1209, 1091, 1011, 975, 827,
1
772, 705, 571 cmꢁ1; H NMR (DMSO-d6, 300 MHz): d ¼ 9.13 (s,
1H), 8.97 (s, 1H), 7.67 (d, J ¼ 8.4 Hz, 2H), 7.56–7.46 (m, 5H + 1H),
7.31 (d, J ¼ 5.1 Hz, 2H), 6.69 (d, J ¼ 15.9 Hz, 1H) ppm; 13C NMR
(DMSO-d6, 75 MHz): d ¼ 164.2, 160.7, 143.2, 135.1, 133.3, 132.7,
130.2, 129.9, 129.1, 128.5, 128.4, 125.9, 115.4, 114.70, 113.7, 102.6,
51.6 ppm; elemental analysis calc. for C21H13ClN4 (356.81): C,
70.69; H, 3.67; N, 15.70; found: C, 70.67; H, 3.68; N, 15.67%.
2-Amino-4-(4-bromophenyl)-6-(4-methoxyphenyl) cyclohexa-
2,4-diene-1,1,3-tricarbonitrile (5b). Yellow solid; 88% yield; mp
253–255 ꢀC; IR (KBr): 3391, 3301, 3203, 3067, 3016, 2968, 2935,
2837, 2224, 2214, 1641, 1596, 1565, 1552, 1533, 1508, 1461,
2-Amino-4-phenyl-6-(phenylsulfanyl)pyridine-3,5-dicarboni-
trile (6a). White solid; 86% yield; mp 214–216 ꢀC. IR (KBr): 3485,
1
3361, 3211, 3053, 2218, 1618, 1546, 1263, 753 cmꢁ1; H NMR
(CDCl3, 400 MHz): d ¼ 7.57–7.50 (m, 7H), 7.49–7.48 (m, 3H),
5.53 (bs, 2H) ppm; 13C NMR (CDCl3, 125 MHz): d ¼ 169.1, 159.3,
158.4, 135.8, 133.2, 131.0, 130.0, 129.3, 129.0, 128.5, 127.2,
115.2, 114.8, 95.9, 87.4 ppm; elemental analysis calc. for
1324, 1283, 1257, 1175, 1097, 1011, 976, 829, 778, 594, 539 cmꢁ1
;
1H NMR (DMSO-d6, 300 MHz): d ¼ 9.31 (s, 1H), 9.15 (s, 1H), 7.81
(d, J ¼ 8.4 Hz, 2H), 7.60 (d, J ¼ 8.7 Hz, 2H), 7.31 (d, J ¼ 8.4 Hz,
2H), 7.10 (d, J ¼ 15.6 Hz, 1H), 6.97 (d, J ¼ 8.7 Hz, 2H), 6.59 (d, J ¼
15.6 Hz, 1H), 3.79 (s, 3H) ppm; 13C NMR (DMSO-d6, 75 MHz): d
¼ 163.3, 161.3, 160.1, 144.5, 134.2, 132.0, 130.8, 130.3, 127.4,
123.5, 121.1, 115.8, 115.3, 114.5, 114.1, 101.5, 55.3, 52.2 ppm;
elemental analysis calc. for C22H15BrN4O (431.28): C, 61.27; H,
3.51; N, 12.99; found: C, 61.22; H, 3.55; N, 13.04%.
2-Amino-4-(3-nitrophenyl)-5,6,7,8-tetrahydro naphthalene-
1,3,3(4H)-tricarbonitrile (5c). White solid; 81% yield; mp 196–
198 ꢀC; IR (KBr): 3425, 3331, 3227, 3089, 3037, 3010, 2958, 2925,
2863, 2843, 2214, 1650, 1600, 1531, 1481, 1435, 1391, 1349,
1270, 1165, 1104, 910, 854, 825, 736, 723, 638, 599, 455 cmꢁ1; 1H
NMR (DMSO-d6, 300 MHz): d ¼ 8.41 (s, 1H), 8.31 (d, J ¼ 7.5 Hz,
1H), 8.09–7.81 (m, 2H), 7.39 (s, 2H), 5.76 (s, 1H), 3.94 (d, J ¼ 12.3
Hz, 1H), 2.91 (bs, 1H), 2.23–2.07 (m, 2H), 1.67–1.46 (m, 3H), 0.89
(d, J ¼ 12.3 Hz, 1H) ppm; 13C NMR (DMSO-d6, 75 MHz): d ¼
143.0, 138.8, 136.8, 134.1, 130.3, 128.3, 126.7, 124.0, 120.7,
116.0, 112.2, 112.0, 81.7, 49.6, 42.4, 33.5, 26.9, 24.8, 20.8 ppm;
elemental analysis calc. for C19H15N5O2 (345.35): C, 66.08; H,
4.38; N, 20.28; found: C, 66.12; H, 4.33; N, 20.24%.
3-Amino-5,6,7,8-tetrahydro-1,20-binaphthyl-2,2,4(1H)-tri-
carbonitrile (5d). White solid; 90% yield; mp 297–299 ꢀC; IR
(KBr): 3417, 3341, 3253, 3060, 2937, 2910, 2872, 2832, 2212,
1650, 1601, 1508, 1429, 1394, 1339, 1275, 1209, 1156, 1020, 899,
863, 825, 774, 762, 592, 481 cmꢁ1; 1H NMR (CDCl3 + DMSO-d6,
400 MHz): d ¼ 8.14 (s, 1H), 8.01 (d, J ¼ 8.6 Hz, 1H), 7.94 (m, 2H),
7.72 (d, J ¼ 8.5 Hz, 1H), 7.56–7.52 (m, 2H), 7.30 (s, 2H), 5.78 (s,
1H), 3.60 (t, 1H), 2.93 (s, 1H), 2.20 (m, 1H), 2.10–2.03 (m, 1H),
1.65–1.47 (m, 3H), 0.95–0.89 (m, 1H) ppm; 13C NMR (CDCl3 +
DMSO-d6, 100 MHz): d ¼ 143.4, 132.6, 132.2, 131.8, 130.0, 128.6,
128.3, 128.1, 127.8, 127.5, 126.7, 126.6, 123.8, 120.6, 116.0,
112.4, 81.5, 51.3, 42.7, 33.8, 26.9, 24.9, 21.0 ppm; elemental
analysis calc. for C23H18N4 (350.42): C, 78.83; H, 5.18; N, 15.99;
found: C, 78.88; H, 5.13; N, 15.93%.
C
19H12N4S (328.39): C, 69.49; H, 3.68; N, 17.06; found: C, 69.54;
H, 3.70; N, 17.11%.
2-Amino-4-(4-methoxyphenyl)-6-(phenylsulfanyl) pyridine-
3,5-dicarbonitrile (6b). White solid; 91% yield; mp 235–237 ꢀC;
IR (KBr): 3441, 3332, 3227, 3056, 2983, 2846, 2227, 2215, 1641,
1606, 1512, 1463, 1290, 1259, 1190, 1019, 837, 756 cmꢁ1 1H
;
NMR (CDCl3, 500 MHz): d ¼ 7.55 (dd, J ¼ 7.4, 2.3 Hz, 2H), 7.51
(d, J ¼ 8.4 Hz, 2H), 7.48–7.45 (m, 3H), 7.05 (d, J ¼ 8.6 Hz, 2H),
5.43 (bs, 2H), 3.87 (s, 3H) ppm; 13C NMR (DMSO-d6, 125 MHz): d
¼ 166.6, 161.3, 160.2, 158.8, 135.3, 130.7, 130.1, 129.9, 127.7,
126.3, 116.0, 115.8, 114.6, 93.9, 87.5, 55.8 ppm; elemental
analysis calc. for C20H14N4OS (358.42): C, 67.02; H, 3.94; N,
15.63%. Found: C, 67.06; H, 3.99; N, 15.68%.
2-Amino-4-(4-cyanophenyl)-6-[(2-methylphenyl)sulfanyl]-
pyridine-3,5-dicarbonitrile (6c). White solid; 90% yield; mp 268–
270 ꢀC; IR (KBr): 3432, 3323, 3227, 3091, 3057, 2985, 2930, 2236,
2212, 1637, 1542, 1464, 1263, 1028, 846, 814, 755, 708 cmꢁ1; 1H
NMR (DMSO-d6, 500 MHz): d ¼ 8.04–8.02 (d, J ¼ 8.3 Hz, 2H),
7.76–7.74 (d, J ¼ 8.3 Hz, 2H), 7.76 (bs, 2H), 7.55–7.53 (d, J ¼ 7.56
Hz, 1H), 7.42–7.40 (m, 2H), 7.30–7.25 (m, 1H), 2.38 (s, 3H) ppm;
13C NMR (DMSO-d6, 125 MHz): d ¼ 166.5, 159.5, 156.6, 142.8,
138.3, 136.1, 132.5, 130.8, 130.4, 129.5, 126.7, 126.2, 117.9,
114.6, 113.3, 92.8, 86.4, 20.5 ppm; elemental analysis calc. for
C
21H13N5S (367.43): C, 68.65; H, 3.57; N, 19.06%. Found: C,
68.60; H, 3.53; N, 19.03%.
2-Amino-6-[(2-methylphenyl)sulfanyl]-4-(naphthalen-2-yl)-
pyridine-3,5-dicarbonitrile (6d). White solid; 92% yield; mp
229–231 ꢀC; IR (KBr): 3328, 3223, 3051, 2924, 2854, 2214, 1627,
1550, 1264, 1032, 761 cmꢁ1; H NMR (CDCl3 + DMSO-d6, 400
1
MHz): d ¼ 8.06–8.03 (m, 2H), 8.00–7.95 (m, 2H), 7.63–7.57 (m,
3H), 7.54 (d, J ¼ 7.5 Hz, 1H), 7.41–7.37 (m, 4H), 7.28–7.24 (m,
1H), 2.42 (s, 3H) ppm; 13C NMR (CDCl3 + DMSO-d6, 100 MHz): d
¼ 166.7, 159.6, 158.0, 142.9, 136.1, 133.3, 132.2, 131.1, 130.6,
130.2, 128.3, 128.2, 127.5, 127.4, 126.8, 126.5, 126.4, 125.1,
115.1, 115.0, 93.6, 86.8, 20.5 ppm; elemental analysis calc. for
C
24H16N4S (392.48): C, 73.45; H, 4.11; N, 14.28%. Found: C,
73.41; H, 4.08; N, 14.24%.
2-Amino-4-cyclohexyl-6-(phenylsulfanyl)pyridine-3,5-dicarbo-
nitrile (6e). White solid; 85% yield; mp 202–204 ꢀC; IR (KBr):
General procedure for the synthesis of 2-amino-4-(aryl/alkyl)-
6-(aryl/alkylsulfanyl)-pyridine-3,5-dicarbonitrile (6a–6f)
A mixture of aldehyde (1.0 mmol), malononitrile (2.0 mmol), 3478, 3348, 3216, 3064, 2934, 2855, 2219, 1625, 1555, 1524,
imidazole (0.2 mmol), thiol (1.0 mmol) and ethanol (5 ml) was 1442, 1255, 1108, 936, 754, 706 cmꢁ1 1H NMR (CDCl3, 300
;
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MHz): d ¼ 7.53–7.50 (m, 2H), 7.45–7.39 (m, 3H), 5.41 (bs, 2H),
3.10–3.01 (m, 1H), 2.18–2.02 (m, 2H), 1.97–1.85 (m, 2H), 1.82–
1.72 (m, 3H), 1.49–1.33 (m, 3H) ppm; 13C NMR (CDCl3, 100
MHz): d ¼ 169.4, 164.7, 160.1, 135.9, 123.0, 129.43, 127.5, 115.7,
115.2, 95.5, 86.6, 44.8, 30.1, 26.5, 25.4 ppm; elemental analysis
calc. for C19H18N4S (334.44): C, 68.23; H, 5.42; N, 16.75; found:
C, 68.26; H, 5.47; N, 16.80%.
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2-Amino-4-(4-chlorophenyl)-6-(cyclohexylsulfanyl) pyridine-
ꢀ
3,5-dicarbonitrile (6f). White solid; 81% yield; mp 222–224 C;
IR (KBr): 3497, 3392, 3063, 2933, 2853, 2217, 1605, 1544, 1494,
1449, 1267, 1093, 835, 803, 779 cmꢁ1 1H NMR (CDCl3, 300
;
MHz): d ¼ 7.52 (d, J ¼ 8.4 Hz, 2H), 7.45 (d, J ¼ 8.6 Hz, 2H), 5.67
(bs, 2H), 3.97–3.89 (m, 1H), 2.08–2.04 (m, 2H), 1.82–1.78 (m,
2H), 1.66–1.25 (m, 6H); 13C NMR (CDCl3, 100 MHz): d ¼ 169.9,
159.4, 156.9, 137.4, 131.9, 130.0, 129.6, 115.5, 115.0, 96.7, 86.2,
44.2, 32.8, 26.0, 25.7 ppm; elemental analysis calc. for
C
19H17ClN4S (368.88): C, 61.86; H, 4.65; N, 15.19%. Found: C,
61.81; H, 4.68; N, 15.23%.
Acknowledgements
Authors are grateful to the Department of Science and Tech-
nology, India for the nancial support with Sanction no. SR/FT/
CS-042/2009 and IIT Patna for carrying out this work. M. N. K.
and S. K. are thankful to CSIR for their research fellowship. S. P.
is grateful to UGC for his research fellowship. We are also
grateful to SAIF CDRI Lucknow, Bose Institute, Kolkata, IIT
Guwahati, IIT Kanpur and SAIF Panjab University for providing
analytical facilities.
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