A one-pot three-component domino protocol for the synthesis of penta-substituted 4H-pyrans

Article abstract of DOI:10.1039/c3ra41510d

A library of novel 2-(1H-indol-3-yl)-6-(methylamino)-5-nitro-4-aryl-4H- pyran-3-carbonitriles and 6-(methylamino)-4-(aryl)-5-nitro-2-phenyl-4H-pyran-3- carbonitriles were synthesized in excellent yields via domino one-pot three-component reactions of 3-(1H-indol-3-yl)-3-oxopropanenitrile or benzoylacetonitrile, aromatic aldehydes and (E)-N-methyl-1-(methylthio)-2- nitroethenamine respectively. This reaction presumably occurs via domino Knoevenagel condensation-Michael addition-intramolecular O-cyclization sequence of reactions. The significant advantages of this reaction include one-pot process, simple work-up procedure, excellent yields and no column chromatographic purification.

Full text of DOI:10.1039/c3ra41510d

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A one-pot three-component domino protocol for the
synthesis of penta-substituted 4H-pyrans3
Cite this: DOI: 10.1039/c3ra41510d
Sathiyamoorthi Sivakumar, Selvaraj Kanchithalaivan and Raju Ranjith Kumar*
A library of novel 2-(1H-indol-3-yl)-6-(methylamino)-5-nitro-4-aryl-4H-pyran-3-carbonitriles and 6-(methy-
lamino)-4-(aryl)-5-nitro-2-phenyl-4H-pyran-3-carbonitriles were synthesized in excellent yields via domino
one-pot three-component reactions of 3-(1H-indol-3-yl)-3-oxopropanenitrile or benzoylacetonitrile,
aromatic aldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethenamine respectively. This reaction pre-
sumably occurs via domino Knoevenagel condensation–Michael addition–intramolecular O-cyclization
sequence of reactions. The significant advantages of this reaction include one-pot process, simple work-up
procedure, excellent yields and no column chromatographic purification.
Received 27th March 2013,
Accepted 14th May 2013
DOI: 10.1039/c3ra41510d
www.rsc.org/advances
the synthesis of 2-amino-4H-pyran-3-carbonitrile derivatives
from the three-component reactions of malononitrile, aro-
Introduction
Domino reactions are multi-step processes which allow several
bond forming transformations to occur under the same
reaction conditions, without the addition of other reagents
and catalysts. The subsequent reaction occurs as a result of the
functionality formed in the previous step.1 As these reactions
involve multiple processes in one-pot, the need to isolate and
purify the intermediates in each step is avoided thereby
eliminating the use of large quantity of toxic solvents. Domino
reactions are widely accepted by organic chemists world-wide
as they increase the synthetic efficiency by reducing the
number of laboratory procedures, quantity of chemical and
solvents. Incidentally, domino reactions are considered
‘‘Green protocols’’ with respect to atom economy, prevention
of waste and avoiding time-consuming purification or protec-
tion/de-protection steps.2 In recent years, investigations
pertaining to domino protocols which offer an expedient
access to novel heterocycles starting from readily available
substrates have gained much of the attention of synthetic
organic chemists.3
Highly functionalized 4H-pyrans constitute a versatile class
of organic heterocycles4 with wide range of biological and
chemical applications. These compounds are significant
precursors towards the construction of more complex hetero-
cycles and natural products.5 In this context, a number of
methods have been developed for their synthesis, which
include step-wise as well as one-pot multi-component reac-
tions. It is pertinent to note that investigations pertaining to
matic aldehydes and carbonyl compounds have received much
attention.6
Other reports for the synthesis of 4H-pyrans include the
DABCO-catalyzed [4 + 2] cycloaddition of b,c-unsaturated
a-ketoesters with allenic esters,7 nucleophilic addition to
electron-deficient 1,3-conjugated enynes in the presence of
phase-transfer catalyst,8 DBU catalyzed reaction of 1-(1-
alkynyl)-2-alken-1-ones with 1,3-dicarbonyl compounds,9 reac-
tions of 1,5-dicarbonyl compounds with Vilsmeier–Haack
reagent10 and Zn(OAc)2-mediated condensation of 1,3-dicar-
bonyl compounds with aromatic aldehydes.11
In the present work, we report the first domino one-pot
three-component reactions of 3-(1H-indol-3-yl)-3-oxopropane-
nitrile 1 or benzoylacetonitrile 2, aromatic aldehydes 3 and (E)-
N-methyl-1-(methylthio)-2-nitroethenamine 4 to afford novel 2-
(1H-indol-3-yl)-6-(methylamino)-5-nitro-4-aryl-4H-pyran-3-car-
bonitriles
5 and 6-(methylamino)-4-(aryl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitriles 6 respectively (Scheme 1).
Incidentally, the acetonitriles 1 and 2 are reactive com-
pounds extensively used in domino reactions for the synthesis
of divergent heterocycles. For example, 3-pyranyl indoles,12a
indolyl-pyridines,12b two-carbon-tethered 1,3-oxathiazole-indo-
les,12c indolyl-spirooxindoles,12d furanylindoles,12e naphtho-
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai-625021, Tamil Nadu, India.
E-mail: raju.ranjithkumar@gmail.com
Electronic supplementary information (ESI) available: CCDC 911400. For ESI
3
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3ra41510d
Scheme 1 Synthesis of penta-substituted 4H-pyrans 5 and 6.
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DBU and DMAP in refluxing ethanol (Table 1, entries 2–8) but
these bases could not promote the reaction efficiently even at
prolonged reaction times and poor yields of 5b were observed
(,40%). However, when Et3N was used as base in refluxing
ethanol the reaction completed within 1.5 h with almost
quantitative yield of 5b (95%, Table 1, entry 9). Further, in this
case the product is precipitated in the reaction vessel and
hence no column chromatographic purification is required.
After completion of the reaction the product is filtered and
washed with ethanol to obtain pure 5b. In the presence of
potassium carbonate or sodium hydroxide, 5b was obtained in
traces at longer reaction time (Table 1, entries 10 and 11).
Then, the test reaction was carried out with common base-
solvent pair conditions which are frequently reported in the
literature. For example, L-proline-methanol combination
afforded a moderate yield of 55% of 5b, whereas other
conditions failed to induce much effect on the reaction and
consequently poor yields were observed (Table 1, entries 12–
16). From the above results, Et3N emerged as the ideal choice
of base for these domino reactions. Having determined the
optimum base for the reaction, investigation pertaining to the
choice of an appropriate solvent was performed. The above
test reaction was investigated with different solvents such as
THF, CH3CN, MeOH and 2-propanol (Table 1, entries 17–20).
From the data in Table 1, ethanol was found to be the ideal
solvent for this domino reaction which afforded maximum
yield of 5b (Table 1, entry 9).
Table 1 Optimization of reaction conditions
Entry Base
Solvent
Time (h) Yield of 5ba%
1
2
3
4
5
6
7
8
9
10
11
12
—
EtOH
EtOH
EtOH
8
0b
Pyridine (1.0)
Piperidine (1.0)
Pyrrolidine (1.0) EtOH
L-Proline (1.0)
DABCO (1.0)
DBU (1.0)
DMAP
Et3N (1.0)
K2CO3 (1.0)
NaOH (1.0)
L-Proline (1.0)
4.5
6.5
6
15
25
25
40
EtOH
6
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
10
10
7
32
30
20
1.5
95
12
12
6
trace
trace
55
13
14
15
16
17
18
19
20
Pyrrolidine (1.0) THF
6
6.5
5.5
6
8
30
25
36
27
50
42
40
60
DMAP (1.0)
DABCO (1.0)
DBU (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
neat
neat
CH3CN
MeOH
2-Propanol 10
THF
CH3CN
8
8
a
b
The optimal conditions thus established were then applied
to the synthesis of a library of novel 2-(1H-indol-3-yl)-6-
Isolated yield. Product not formed.
(methylamino)-5-nitro-4-aryl-4H-pyran-3-carbonitriles
5a–q
and 6-(methylamino)-4-(aryl)-5-nitro-2-phenyl-4H-pyran-3-car-
bonitriles 6a–p via the one-pot three-component domino
reactions of 3-(1H-indol-3-yl)-3-oxopropanenitrile 1 or benzoy-
lacetonitrile 2, aromatic aldehydes 3 and (E)-N-methyl-1-
(methylthio)-2-nitroethenamine 4 respectively (Table 2). A total
of thirty three novel 4H-pyran-3-carbonitriles 5 and 6 were
synthesized in excellent yields apart from 3-pyridine-carbox-
aldehyde (6q) wherein the reaction failed to occur.
The structure of all the 4H-pyran-3-carbonitriles 5 and 6
were elucidated with the help of 1H, 13C and 2D NMR
spectroscopy as described for 5f. In the 1H NMR spectra of
5f the singlet at 4.90 ppm can be assigned to H-4 on the basis
of its multiplicity. Further, H-4 shows (i) C,H-COSY correlation
with carbon signal at 39.7 ppm due to C-4 and (ii) HMBC
correlation with carbon signals at 88.9, 106.1, 117.7, 128.6,
133.3, 153.4 and 156.9 ppm which can be assigned to C-3, C-5,
nitrile carbon, C-299, C-199, C-2 and C-6 respectively. From the
C,H-COSY spectra H-299 appears as a doublet at 7.30 ppm (J =
8.7 Hz) and shows a H,H-COSY correlation with adjacent H-399
at 6.87 ppm (J = 8.7 Hz). The methoxy protons appear as a
singlet at 3.79 ppm and show a HMBC correlation with C-499 at
158.8 ppm. The N-CH3 protons appears as a doublet at 3.31
ppm (J = 4.8 Hz) and show HMBC correlation with C-6 at 156.9
ppm. The H-29 of indole ring gives a singlet at 7.97 ppm and
shows (i) C,H-COSY at 129.5 ppm due to C-29 and (ii) HMBC
correlation with C-39 at 104.6 ppm, C-3a9 at 124.0 ppm and
pyrans,13a fused pyrazolo[3,4-b]pyridines, pyrido[2,3-d] pyrimi-
dines,13b and thiochromeno[2,3-b]pyridines.13c Further, it is
noteworthy that (E)-N-methyl-1-(methylthio)-2-nitroethena-
mine 4 has received much attention recently as versatile
intermediate in organic synthesis.14 It is a crucial intermediate
in the synthesis of ranitidine and nizatidine.15 Moreover, the
present work is the first report on the use of 4 in the synthesis
of penta-substituted 4H-pyran derivatives.
Results and discussion
Initially, 3-(1H-indol-3-yl)-3-oxopropanenitrile 1, p-chloro-ben-
zaldehyde 3b and (E)-N-methyl-1-(methylthio)-2-nitro-ethena-
mine
4 leading to the formation of 2-(1H-indol-3-yl)-6-
(methylamino)-5-nitro-4-(4-chlorophenyl)-4H-pyran-3-carboni-
trile 5b was chosen as a model substrate to investigate the
feasibility of the strategy and to optimize the reaction
conditions (Table 1).
To begin with the reaction was performed in the absence of
base in ethanol which failed to yield the product even after 8 h
either at ambient temperature or reflux conditions (Table 1,
entry 1). This reaction was then tested in the presence of bases
such as pyridine, piperidine, pyrrolidine, L-Proline, DABCO,
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Table 2 Three component domino synthesis of 5 and 6
Yield (%)a
m.p. (uC)
Comp 5 and 6 Ar
5
6
5
6
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
C6H5
4-ClC6H4
4-FC6H4
93
95
94
93
91
92
92
93
91
92
91
92
93
93
93
94
95
92
92
93
92
92
91
91
92
91
93
93
92
275–276 240–241
293–294 208–209
286–287 210–211
295–296 198–199
289–290 206–207
270–271 204–205
277–278 260–261
289–290 254–255
278–279 263–264
275–276 237–238
273–274 190–191
270–271 237–238
256–257 241–242
261–262 260–261
299–300 252–253
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4
2-ClC6H4
2-BrC6H4
2-CH3C6H4
2-CH3OC6H4
3-FC6H4
3-BrC6H4
3-O2NC6H4
2,5-(CH3O)2C6H3 93
2,4-Cl2C6H3
Naphthyl
C5H4N
Fig. 2 ORTEP diagram of 6d.16
92
91
91
260–261 258–259
b
b
—
250–251
—
a
b
Isolated yield. Product not formed.
C-7a9 at 135.8 ppm. The other protons of indole ring appear as
multiplet at 7.22–7.82 ppm whereas the two NH protons
appear as broad singlets at 10.34 ppm and 11.75 ppm. The
1
HMBC correlations, H and 13C NMR chemical shifts of 5f are
shown in Fig. 1.
Similarly, the structure of 6 was also elucidated unambigu-
Scheme 2 Plausible mechanism for the formation of 5 and 6.
1
ously using H, 13C and 2D NMR spectroscopy. The structure
of 6 assigned from NMR spectroscopy was further confirmed
from the single crystal X-ray studies.16 The ORTEP diagram of
6d is shown in Fig. 2. The structure of 6 assigned from NMR
spectroscopy and X-ray studies agree well.
(methylthio)-2-nitroethenamine 4 to give 9. The intermediate
9 is susceptible to either an intramolecular O- or N-cyclization
which can afford 5/6 or the dihydropyridines 12 respectively.
However, in the present investigation, 2-(1H-indol-3-yl)-6-
A plausible mechanistic pathway for the formation of 5 and
6
is outlined in Scheme 2. Initially, the Knoevenagel
(methylamino)-5-nitro-4-aryl-4H-pyran-3-carbonitriles
5a–q
condensation between 3-(1H-indol-3-yl)-3-oxopropanenitrile 1
or benzoylacetonitrile 2 and aromatic aldehyde 3 affords 8,17
which undergoes Michael addition with (E)-N-methyl-1-
and 6-(methylamino)-4-(aryl)-5-nitro-2-phenyl-4H-pyran-3-car-
bonitriles 6a–p were obtained as the sole product, whereas
the N-cyclized product 12 was not formed even in traces in the
course of the reaction. Thus the intermediate 9 undergoes
tautomerisation to form 10 followed by O-cyclization to form 5
or 6 via the elimination of MeSH thereby attributing to the
regioselectivity involved in this domino reaction.
Conclusions
The present work reports the one-pot three-component
domino reactions for the expedient synthesis of penta-
substituted novel 4H-pyrans regioselectively in almost quanti-
tative yields. It is noteworthy that this domino reaction results
Fig. 1 HMBC’s, 1H and 13C NMR chemical shifts of 5f.
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117.1, 119.6, 120.4, 122.0, 123.7, 127.9, 128.9, 129.2, 131.8,
135.6, 139.8, 153.6, 156.6: Anal. Calcd for C21H15ClN4O3: C,
62.00; H, 3.72; N, 13.77%. Found C, 62.07; H, 3.65; N, 13.69%.
in the formation of three new bonds (two C–C and one C–O) in
a single operation. The important advantages of this metho-
dology include simple and readily available reagents, simple
practical work-up and no column chromatographic purifica-
tion as the product is obtained in pure form just by filtration.
Further investigations pertaining to the synthesis of several
novel heterocycles using (E)-N-methyl-1-(methylthio)-2-
nitroethenamine are presently under progress.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(4-fluorophenyl)-
4H-pyran-3-carbonitrile 5c
1
Yellow solid; Yield 94%; mp 286–287 uC; H NMR (300 MHz,
DMSO-D6/CDCl3) dH: 3.25 (d, 3H, J = 4.5 Hz, NH–CH3), 4.91 (s,
1H, Ar–CH), 7.11 (t, 2H, J = 8.4 Hz, Ar–H), 7.17–7.27 (m, 2H, Ar–
H), 7.41 (dd, 2H, J = 8.4, 5.4 Hz, Ar–H), 7.53 (d, 1H, J = 7.8 Hz,
Ar–H), 7.80 (d, 1H, J = 7.5 Hz, Ar–H), 8.02 (d, 1H, J = 8.1 Hz, Ar–
H), 10.40 (d, 1H, J = 4.8 Hz, N–H), 12.00 (brs, N–H); 13C NMR
(75 MHz, DMSO-D6/CDCl3) dC: 28.1, 39.7, 87.8, 104.3, 105.7,
112.1, 114.6, 114.9, 117.2, 119.6, 120.5, 122.2, 123.8, 128.9,
129.1, 135.7, 136.7, 153.7, 156.8, 162.8: Anal. Calcd for
Experimental section
Melting points were measured in open capillary tubes and are
uncorrected. The 1H-NMR, 13C-NMR, DEPT, H,H-COSY, C,H-
COSY and HMBC spectra were recorded on a Bruker (Avance)
300 MHz NMR instrument using TMS as an internal standard
and CDCl3 and DMSO-D6 as a solvents. Standard Bruker
software was used throughout the spectral analysis. Chemical
shifts are given in parts per million (d-scale) and the coupling
constants are given in Hertz. Elemental analyses were
performed on a Perkin Elmer 2400 Series II Elemental CHNS
analyzer. Silica gel-G plates (Merck) were used for TLC analysis
with a mixture of petroleum ether (60–80 uC) and ethyl acetate
as the eluent.
C
21H15FN4O3: C, 64.61; H, 3.87; N, 14.35%. Found C, 64.56;
H, 3.94; N, 14.23%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(4-bromophenyl)-
4H-pyran-3-carbonitrile 5d
Pale yellow solid; Yield 93%; mp 295–296 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.25 (d, 3H, J = 3.6 Hz, NH–CH3),
4.88 (s, 1H, Ar–CH), 7.16–7.26 (m, 2H, Ar–H), 7.31 (d, 2H, J =
7.2 Hz, Ar–H), 7.48–7.52 (m, 3H, Ar–H), 7.80 (d, 1H, J = 7.5 Hz,
Ar–H), 7.99 (s, 1H, Ar–H), 10.39 (brs, N–H), 11.92 (brs, N–H);
13C NMR (75 MHz, DMSO-D6/CDCl3) dC: 27.9, 39.8, 87.3, 104.0,
105.1, 111.8, 116.8, 119.5, 120.0, 120.2, 121.9, 123.6, 129.1,
130.7, 135.5, 140.1, 153.5, 156.5: Anal. Calcd for C21H15BrN4O3:
C, 55.89; H, 3.35; N, 12.42% . Found C, 55.84; H, 3.44; N,
12.45%.
General procedure for the synthesis of 5 and 6
A mixture of 3-(1H-indol-3-yl)-3-oxopropanenitrile 1 (1.0 mmol)
or benzoylacetonitrile 2 (1.0 mmol), aromatic aldehyde 3 (1.0
mmol) and (E)-N-methyl-1-(methylthio)-2-nitroethenamine 4
(1.0 mmol) were dissolved in EtOH (10 mL) in a 50 ml round
bottom flask. Then Et3N (1.0 mmol) was added slowly and the
reaction mixture was refluxed on a water bath. The consump-
tion of starting material was monitored by TLC. After 90 min
the precipitated solid was filtered and washed with cold EtOH
(5–7 mL) and dried under vacuum to obtain pure 5 or 6. The
spectroscopic data for compounds 5 and 6 are given below.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(4-methylphenyl)-
4H-pyran-3-carbonitrile 5e
Light yellow solid; Yield 91%; mp 289–290 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 2.33 (s, 3H, Ar–CH3), 3.25 (d, 3H, J
= 4.8 Hz, NH–CH3), 4.85 (s, 1H, Ar–CH), 7.15–7.27 (m, 6H, Ar–
H), 7.53 (d, 1H, J = 7.2 Hz, Ar–H), 7.79 (d, 1H, J = 7.8 Hz, Ar–H),
7.99 (s, 1H, Ar–H), 10.40 (brs, N–H), 11.93 (brs, N–H); 13C NMR
(75 MHz, DMSO-D6/CDCl3) dC: 20.3, 28.1, 40.0, 88.3, 104.3,
105.9, 112.1, 117.3, 119.6, 120.5, 122.2, 123.8, 126.9, 128.6,
128.9, 135.7, 136.4, 137.7, 153.5, 156.8: Anal. Calcd for
2-(1H-Indol-3yl)-6-(methylamino)-5-nitro-4-phenyl-4H-pyran-3-
carbonitrile 5a
Light yellow solid; Yield 93%; mp 275–276 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.24 (s, 3H, NH–CH3), 4.90 (s, 1H,
Ar–CH), 7.18–7.26 (m, 2H, Ar–H), 7.30–7.32 (m, 1H, Ar–H),
7.36–7.39 (m, 4H, Ar–H), 7.53 (d, 1H, J = 7.5 Hz, Ar–H), 7.79 (d,
1H, J = 7.5 Hz, Ar–H), 8.02 (s, 1H, Ar–H), 10.41 (brs, N–H),
12.02 (brs, N–H); 13C NMR (75 MHz, DMSO-D6/CDCl3) dC: 28.1,
40.4, 88.1, 104.3, 105.7, 112.0, 117.2, 119.6, 120.4, 122.1, 123.8,
126.9, 127.1, 128.0, 129.1, 135.6, 140.8, 153.5, 156.8: Anal.
Calcd for C21H16N4O3: C, 67.73; H, 4.33; N, 15.05%. Found C,
67.67; H, 4.40; N, 15.12%.
C
22H18N4O3: C, 68.38; H, 4.70; N, 14.50%. Found C, 68.45; H,
4.62; N, 14.45%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(4-
methoxyphenyl)-4H-pyran-3-carbonitrile 5f
1
Yellow solid; Yield 92%; mp 270–271 uC; H NMR (300 MHz,
DMSO-D6/CDCl3) dH: 3.31 (d, 3H, J = 4.8 Hz, NH–CH3), 3.79 (s,
3H, Ar–OCH3), 4.90 (s, 1H, Ar–CH), 6.88 (d, 2H, J = 8.7 Hz, Ar–
H), 7.22–7.27 (m, 2H, Ar–H), 7.30 (d, 2H, J = 8.7 Hz, Ar–H),
7.50–7.53 (m, 1H, Ar–H),7.82 (d, 1H, J = 7.2 Hz, Ar–H), 7.97 (d,
1H, J = 2.7 Hz, Ar–H), 10.37 (brs, N–H), 11.78 (brs, N–H); 13C
NMR (75 MHz, DMSO-D6/CDCl3) dC: 28.3, 39.7, 54.8, 88.9,
104.6 106.1, 112.3, 113.7, 117.7, 119.9, 120.7, 122.5, 124.0,
128.6, 129.5, 133.3, 135.8, 153.4, 156.9, 158.4: Anal. Calcd for
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(4-chlorophenyl)-
4H-pyran-3-carbonitrile 5b
Pale yellow solid; Yield 95%; mp 293–294 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.22 (s, 3H, NH–CH3), 4.91 (s, 1H,
Ar–CH), 7.19–7.24 (m, 2H, Ar–H), 7.41–7.52 (m, 4H, Ar–H), 7.53
(d, 1H, J = 6.9 Hz, Ar–H), 7.81 (d, 1H, J = 6.6 Hz, Ar–H), 8.10 (s,
1H, Ar–H), 10.41 (brs, N–H), 12.03 (brs, N–H); 13C NMR (75
MHz, DMSO-D6/CDCl3) dC: 28.1, 39.8, 87.4, 104.2, 105.2, 111.9,
C
22H18N4O4: C, 65.66; H, 4.51; N, 13.92%. Found C, 65.74; H,
4.45; N, 13.87%.
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Ar–CH), 7.43–7.59 (m, 5H, Ar–H), 7.71–7.79 (m, 1H, Ar–H), 7.87
(d, 1H, J = 7.2 Hz, Ar–H), 8.14 (d, 1H, J = 7.5 Hz, Ar–H), 8.42 (s,
1H, Ar–H), 10.78 (brs, N–H), 12.42 (brs, N–H); 13C NMR (75
MHz, DMSO-D6/CDCl3) dC: 28.4, 40.2, 87.7, 104.4, 105.3, 112.3,
113.9, 114.1, 114.2, 114.4, 117.5, 120.0, 120.7, 122.5, 123.6,
123.9, 129.7, 130.2, 130.3, 135.8, 144.2, 144.3, 153.7, 156.9,
160.4, 163.6: Anal. Calcd for C21H15FN4O3: C, 64.61; H, 3.87; N,
14.35% . Found C, 64.57; H, 3.81; N, 14.30%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(2-chlorophenyl)-
4H-pyran-3-carbonitrile 5g
Light yellow solid; Yield 92%; mp 277–278 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.18 (s, 3H, NH–CH3), 5.37 (s, 1H,
Ar–CH), 7.17–7.27 (m, 2H, Ar–H), 7.30–7.39 (m, 2H, Ar–H), 7.46
(dd, 1H, J = 7.2, 1.8 Hz, Ar–H), 7.50–7.55 (m, 2H, Ar–H), 7.79 (d,
1H, J = 7.2 Hz, Ar–H), 8.09 (s, 1H, Ar–H), 10.47 (brs, N–H),
12.08 (brs, N–H); 13C NMR (75 MHz, DMSO-D6/CDCl3) dC: 28.1,
38.3, 86.4, 104.2, 104.9, 112.1, 116.9, 119.8, 120.6, 122.3, 123.9,
127.1, 128.8, 129.3, 129.4, 130.5, 132.3, 135.6, 137.7, 153.9,
157.0: Anal. Calcd for C21H15ClN4O3: C, 62.00; H, 3.72; N,
13.77%. Found C, 61.91; H, 3.61; N, 13.70%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(3-bromophenyl)-
4H-pyran-3-carbonitrile 5l
Pale yellow solid; Yield 92%; mp 270–271 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.51 (s, 3H, NH–CH3), 5.26 (s, 1H,
Ar–CH), 7.50–7.60 (m, 2H, Ar–H), 7.68 (d, 1H, J = 7.8 Hz, Ar–H),
7.75 (d, 1H, J = 7.8 Hz, Ar–H), 7.83 (d, 1H, J = 7.8 Hz, Ar–H),
7.87 (d, 1H, J = 7.2 Hz, Ar–H), 7.94 (s, 1H, Ar–H), 8.15 (d, 1H, J =
7.2 Hz, Ar–H), 8.43 (s, 1H, Ar–H), 10.78 (brs, N–H), 12.43 (brs,
N–H); 13C NMR (75 MHz, DMSO-D6/CDCl3) dC: 28.4, 40.2, 87.5,
104.4, 105.2, 112.3, 117.4, 120.0, 120.7, 121.5, 122.4, 123.9,
126.6, 129.7, 130.1, 130.5, 135.8, 143.9, 153.8, 156.9: Anal.
Calcd for C21H15BrN4O3: C, 55.89; H, 3.35; N, 12.42%. Found
C, 55.82; H, 3.29; N, 12.37%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(2-bromophenyl)-
4H-pyran-3-carbonitrile 5h
Pale yellow solid; Yield 93%; mp 289–290 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.27 (d, 3H, J = 4.8 Hz, NH–CH3),
5.38 (s, 1H, Ar–CH), 7.14–7.25 (m, 3H, Ar–H), 7.31–7.40 (m, 2H,
Ar–H), 7.50 (d, 1H, J = 7.8 Hz, Ar–H), 7.56 (d, 1H, J = 7.8 Hz, Ar–
H), 7.78 (d, 1H, J = 8.1 Hz, Ar–H), 7.96 (d, 1H, J = 2.7 Hz), 10.44
(d, 1H, J = 4.8 Hz, N–H), 11.87 (brs, N–H); 13C NMR (75 MHz,
DMSO-D6/CDCl3) dC: 27.9, 40.2, 86.3, 104.1, 105.0, 111.9, 116.5,
119.5, 120.3, 122.0, 122.5, 123.8, 127.4, 128.6, 129.0, 130.2,
132.5, 135.6, 139.1, 153.8, 156.9: Anal. Calcd for C21H15BrN4O3:
C, 55.89; H, 3.35; N, 12.42%. Found C, 56.01; H, 3.41; N,
12.49%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(3-nitrophenyl)-
4H-pyran-3-carbonitrile 5m
1
Bright yellow solid; Yield 93%; mp 256–257 uC; H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.32 (d, 3H, J = 4.8 Hz, NH–CH3),
5.09 (s, 1H, Ar–CH), 7.19–7.29 (m, 2H, Ar–H), 7.52 (d, 1H, J =
7.8 Hz, Ar–H), 7.60 (t, 1H, J = 8.1 Hz, Ar–H), 7.82 (t, 2H, J = 7.2
Hz, Ar–H), 8.00 (d, 1H, J = 1.8 Hz, Ar–H), 8.15 (d, 1H, J = 8.1 Hz,
Ar–H), 8.23 (s, 1H, Ar–H), 10.43 (d, 1H, J = 4.8 Hz, N–H), 11.80
(brs, N–H); 13C NMR (75 MHz, DMSO-D6/CDCl3) dC: 27.9, 39.9,
86.1, 103.9, 104.7, 111.8, 116.6, 119.3, 120.3, 121.6, 121.7,
121.9, 123.5, 128.9, 133.3, 135.4, 142.5, 147.3, 154.1, 156.4:
Anal. Calcd for C21H15N5O5: C, 60.43; H, 3.62; N, 16.78%.
Found C, 60.51; H, 3.70; N, 16.70%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(2-methylphenyl)-
4H-pyran-3-carbonitrile 5i
Pale yellow solid; Yield 91%; mp 278–279 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 2.59 (s, 3H, Ar–CH3), 3.24 (s, 3H,
NH–CH3), 5.20 (s, 1H, Ar–CH), 7.18–7.25 (m, 6H, Ar–H), 7.52
(d, 1H, J = 7.8, Ar–H), 7.79 (d, 1H, J = 7.5 Hz, Ar–H), 8.0 (s, 1H,
Ar–H), 10.43 (br s, N–H), 11.99 (br s, N–H); 13C NMR (75 MHz,
DMSO-D6/CDCl3) dC: 18.3, 27.9, 35.9, 87.9, 104.2, 106.2, 111.8,
116.9, 119.3, 120.3, 121.9, 123.7, 125.9, 126.5, 126.7, 128.6,
129.5, 135.4, 135.6, 139.3, 153.1, 156.8: Anal. Calcd for
C22H18N4O3: C, 68.38; H, 4.70; N, 14.50%. Found C, 68.47; H,
4.64; N, 14.43%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(2,5-
dimethoxyphenyl)-4H-pyran-3-carbonitrile 5n
Light yellow solid; Yield 93%; mp 261–262 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.31 (d, 3H, J = 5.1 Hz, NH–CH3),
3.74 (s, 3H, Ar–OCH3), 3.78 (s, 3H, Ar–OCH3), 5.00 (s, 1H, Ar–
CH), 6.80–6.87 (m, 2H, Ar–H), 6.91 (d, 1H, J = 2.7, Ar–H), 7.20–
7.28 (m, 1H, Ar–H), 7.51 (d, 1H, J = 7.2, Ar–H), 7.62 (s, 1H, Ar–
H), 7.81 (d, 1H, J = 7.2, Ar–H), 7.93 (d, 1H, J = 3.0 Hz, Ar–H),
10.48 (d, 1H, J = 4.8 Hz, N–H), 11.57 (brs, N–H); 13C NMR (75
MHz, DMSO-D6/CDCl3) dC: 27.7, 37.4, 54.6, 55.4, 86.0, 104.3,
104.8, 111.7, 111.9, 116.2, 117.1, 119.2, 120.1, 121.8, 123.7,
128.2, 128.4, 135.4, 151.1, 152.3, 153.8, 157.3: Anal. Calcd for
C23H20N4O5: C, 63.88; H, 4.66; N, 12.96%. Found C, 63.95; H,
4.59; N, 12.90%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(2-
methoxyphenyl)-4H-pyran-3-carbonitrile 5j
Light yellow solid; Yield 92%; mp 275–276 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.20 (s, 3H, NH–CH3), 3.75 (s, 3H,
Ar–OCH3), 5.04 (s, 1H, Ar–CH), 6.97 (d, 1H, J = 7.2, Ar–H), 7.04
(d, 1H, J = 8.1, Ar–H), 7.20–7.34 (m, 4H, Ar–H), 7.54 (d, 1H, J =
7.2, Ar–H), 7.80 (d, 1H, J = 7.2 Hz, Ar–H), 8.08 (s, 1H, Ar–H),
10.47 (brs, N–H), 12.04 (brs, N–H); 13C NMR (75 MHz, DMSO-
D6/CDCl3) dC: 28.0, 37.2, 55.2, 86.7, 104.5, 104.9, 111.5, 112.1,
117.5, 119.6, 119.9, 120.5, 122.2, 123.9, 127.5, 128.6, 129.1,
129.9, 135.6, 153.9, 157.1, 157.5: Anal. Calcd for C22H18N4O4:
C, 65.66; H, 4.51; N, 13.92%. Found C, 65.74; H, 4.60; N,
13.88%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(2,4-
dichlorophenyl)-4H-pyran-3-carbonitrile 5o
1
Yellow solid; Yield 92%; mp 299–300 uC; H NMR (300 MHz,
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(3-fluorophenyl)-
4H-pyran-3-carbonitrile 5k
Light yellow solid; Yield 91%; mp 273–274 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.50 (s, 3H, NH–CH3), 5.27 (s, 1H,
DMSO-D6/CDCl3) dH: 3.23 (s, 3H, NH–CH3), 5.36 (s, 1H, Ar–
CH), 7.17–7.27 (m, 2H, Ar–H), 7.38 (dd, 1H, J = 8.4, 2.1 Hz, Ar–
H), 7.50–7.55 (m, 3H, Ar–H), 7.79 (d, 1H, J = 7.5 Hz, Ar–H), 8.04
(s, 1H, Ar–H), 10.47 (brs, N–H), 11.81 (brs, N–H); 13C NMR (75
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MHz, DMSO-D6/CDCl3) dC: 28.3, 37.9, 85.7, 104.2, 104.6, 112.2,
116.8, 119.8, 120.6, 122.3, 123.9, 127.2, 128.8, 129.5, 131.7,
132.6, 133.4, 135.7, 136.8, 154.3, 156.9: Anal. Calcd for
C21H14Cl2N4O3: C, 57.16; H, 3.20; N, 12.70%. Found C, 57.07;
H, 3.12; N, 12.65%.
6-(Methylamino)-4-(4-fluorophenyl)-5-nitro-2-phenyl-4H-pyran-
3-carbonitrile 6c
Light yellow solid; Yield 94%; mp 210–211 uC; 1H NMR (300
MHz, CDCl3) dH: 3.23 (d, 3H, J = 5.1 Hz, NH–CH3), 4.96 (s, 1H,
Ar–CH), 7.04 (t, 2H, J = 8.1 Hz, Ar–H), 7.34 (dd, 2H, J = 8.1, 5.4
Hz, Ar–H), 7.48–7.60 (m, 3H, Ar–H), 7.80 (d, 2H, J = 8.1 Hz, Ar–
H), 10.09 (d, 1H, J = 4.8 Hz, N–H); 13C NMR (75 MHz, CDCl3)
dC: 28.2, 40.9, 93.9, 106.8, 115.7, 115.9, 116.2, 127.7, 129.0,
129.4, 129.6, 132.2, 135.5, 156.2, 157.4. Anal. Calcd for
C19H14FN3O3: C, 64.95; H, 4.02; N, 11.96%. Found C, 64.86;
H, 4.09; N, 11.91%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(1-naphthyl)-
4H-pyran-3-carbonitrile 5p
Light yellow solid; Yield 91%; mp 260–261 uC; 1H NMR (300
MHz, DMSO-D6/CDCl3) dH: 3.31 (d, 3H, J = 4.5 Hz, NH–CH3),
5.89 (s, 1H, Ar–CH), 7.15–7.26 (m, 2H, Ar–H), 7.48–7.52 (m, 3H,
Ar–H), 7.56 (d, 1H, J = 7.5 Hz, Ar–H), 7.59–7.65 (m, 1H, Ar–H),
7.78–7.84 (m, 2H, Ar–H), 7.91–7.94 (m, 2H, Ar–H), 8.52 (d, 1H, J
= 8.4 Hz, Ar–H), 10.45 (d, 1H, J = 4.5 Hz, N–H), 11.90 (brs, N–
H); 13C NMR (75 MHz, DMSO-D6/CDCl3) dC: 27.9, 34.9, 88.3,
104.1, 106.2, 111.7, 116.8, 119.4, 120.1, 121.8, 122.4, 123.7,
124.7, 124.8, 124.9, 125.4, 127.2, 127.7, 128.7, 130.5, 132.6,
135.5, 138.2, 153.2, 156.8: Anal. Calcd for C25H18N4O3: C,
71.08; H, 4.29; N, 13.26%. Found C, 71.01; H, 4.32; N, 13.21%.
6-(Methylamino)-4-(4-bromophenyl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitrile 6d
1
Light brown solid; Yield 95%; mp 198–199 uC; H NMR (300
MHz, CDCl3) dH: 3.23 (s, 3H, NH–CH3), 4.94 (s, 1H, Ar–CH),
7.24 (dd, 2H, J = 6.9, 1.8 Hz, Ar–H), 7.47–7.59 (m, 5H, Ar–H),
7.77–7.80 (m, 2H, Ar–H), 10.08 (brs, N–H); 13C NMR (75 MHz,
CDCl3) dC: 28.2, 41.1, 93.2, 106.3, 116.2, 122.1, 127.6, 128.8,
128.9, 129.5, 131.9, 132.2, 138.7, 156.2, 157.3. Anal. Calcd for
C19H14BrN3O3: C, 55.36; H, 3.42; N, 10.19%. Found C, 55.43; H,
3.35; N, 10.25%.
2-(1H-Indol-3-yl)-6-(methylamino)-5-nitro-4-(pyridin-3-yl)-
4H-pyran-3-carbonitrile 5q
1
Yellow solid; Yield 91%; mp 250–251 uC; H NMR (300 MHz,
6-(Methylamino)-4-(4-methylphenyl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitrile 6e
DMSO-D6/CDCl3) dH: 3.25 (d, 3H, J = 4.8 Hz, NH–CH3), 4.95 (s,
1H, Ar–CH), 7.17–7.27 (m, 2H, Ar–H), 7.34 (dd, 1H, J = 7.5, 4.5
Hz, Ar–H), 7.51 (d, 1H, J = 7.2 Hz, Ar–H), 7.75 (dd, 1H, J = 7.8,
1.5 Hz, Ar–H), 7.82 (d, 1H, J = 7.2 Hz, Ar–H), 8.02 (d, 1H, J = 2.7
Hz, Ar–H), 8.50 (d, 1H, J = 4.5 Hz, Ar–H), 8.66 (s, 1H, Ar–H),
10.41 (d, 1H, J = 4.5 Hz, N–H), 11.92 (brs, N–H); 13C NMR (75
MHz, DMSO-D6/CDCl3) dC: 27.9, 37.9, 86.5, 103.9, 104.8, 111.7,
116.7, 119.3, 120.3, 121.9, 122.8, 123.5, 128.8, 134.4, 135.5,
135.8, 147.8, 148.4, 156.5: Anal. Calcd for C20H15N5O3: C,
64.34; H, 4.05; N, 18.76%. Found C, 64.41; H, 3.97; N, 18.70%.
1
White solid; Yield 92%; mp 206–207 uC; H NMR (300 MHz,
CDCl3) dH: 2.33 (s, 3H, Ar–CH3), 3.21 (d, 3H, J = 5.1 Hz, NH–
CH3), 4.95 (s, 1H, Ar–CH), 7.16 (d, 2H, J = 7.8 Hz, Ar–H), 7.24
(d, 2H, J = 7.8 Hz, Ar–H), 7.47–7.55 (m, 3H, Ar–H), 7.79 (d, 2H, J
= 7.5 Hz, Ar–H), 10.10 (brs, N–H); 13C NMR (75 MHz, CDCl3)
dC: 21.1, 28.2, 41.1, 94.2, 106.9, 116.4, 127.6, 127.7, 128.9,
129.2, 129.6, 131.9, 136.7, 137.8, 155.9, 157.5. Anal. Calcd for
C20H17N3O3: C, 69.15; H, 4.93, N, 12.10%. Found C, 69.21; H,
4.86; N, 12.04%.
6-(Methylamino)-2,4-diphenyl-5-nitro-4H-pyran-3-carbonitrile
6a
6-(Methylamino)-4-(4-methoxyphenyl)-5-nitro-2-phenyl-
White solid; Yield 93%; mp 240–241 uC; 1H NMR (300 MHz,
CDCl3) dH: 3.24 (d, 3H, J = 5.1 Hz, NH–CH3), 4.98 (s, 1H, Ar–
CH), 7.26–7.37 (m, 5H, Ar–H), 7.47–7.58 (m, 3H, Ar–H), 7.80 (d,
2H, J = 7.8 Hz, Ar–H), 10.08 (brs, N–H); 13C NMR (75 MHz,
CDCl3/DMSO-D6) dC: 27.5, 40.6, 92.7, 105.4, 115.4, 126.7, 126.8,
127.0, 127.8, 127.9, 128.2, 131.1, 139.2, 155.2, 156.3. Anal.
Calcd for C19H15N3O3: C, 68.46; H, 4.54; N, 12.61% . Found C,
68.39; H, 4.61; N, 12.54%.
4H-pyran-3-carbonitrile 6f
1
Brown solid; Yield 92%; mp 204–205 uC; H NMR (300 MHz,
CDCl3) dH: 3.22 (d, 3H, J = 5.1 Hz, NH–CH3), 3.78 (s, 3H, Ar–
OCH3), 4.92 (s, 1H, Ar–CH), 6.88 (d, 2H, J = 7.5 Hz, Ar–H), 7.27
(d, 2H, J = 7.5 Hz, Ar–H), 7.47–7.57 (m, 3H, Ar–H), 7.79 (d, 2H, J
= 6.0 Hz, Ar–H), 10.08 (brs, N–H); 13C NMR (75 MHz, CDCl3)
dC: 28.2, 40.7, 55.2, 94.1, 106.9, 114.2, 116.5, 127.6, 128.8,
128.9, 129.1, 131.7, 131.9, 155.7, 157.4, 159.3. Anal. Calcd for
C20H17N3O4: C, 66.11; H, 4.72; N, 11.56%. Found C, 66.19; H,
4.64; N, 11.51%.
6-(Methylamino)-4-(4-chlorophenyl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitrile 6b
1
6-(Methylamino)-4-(2-chlorophenyl)-5-nitro-2-phenyl-
Light brown solid; Yield 93%; mp 208–209 uC; H NMR (300
4H-pyran-3-carbonitrile 6g
MHz, CDCl3) dH: 3.23 (d, 3H, J = 5.1 Hz, NH–CH3), 4.95 (s, 1H,
Ar–CH), 7.26–7.35 (m, 4H, Ar–H), 7.47–7.60 (m, 3H, Ar–H), 7.79
(d, 2H, J = 7.8 Hz, Ar–H), 10.09 (brs, N–H); 13C NMR (75 MHz,
CDCl3) dC: 28.3, 41.1, 93.6, 106.5, 116.2, 127.7, 129.01, 129.04,
129.1, 129.2, 132.2, 132.3, 134.0, 138.2, 138.3, 156.3, 157.4.
Anal. Calcd for C19H14ClN3O3: C, 62.05; H, 3.84; N, 11.43%.
Found C, 62.10; H, 3.79; N, 11.34%.
1
White solid; Yield 93%; mp 260–261 uC; H NMR (300 MHz,
CDCl3) dH: 3.24 (d, 3H, J = 5.1 Hz, NH–CH3), 5.34 (s, 1H, Ar–
CH), 7.25–7.32 (m, 2H, Ar–H), 7.38 (dd, 1H, J = 7.5, 2.1 Hz, Ar–
H), 7.43 (dd, 1H, J = 6.9, 2.7 Hz, Ar–H), 7.47–7.59 (m, 3H, Ar–
H), 7.78 (dd, 2H, J = 7.8, 1.8 Hz, Ar–H), 10.23 (brs, N–H); 13C
NMR (75 MHz, CDCl3) dC: 28.2, 40.7, 91.9, 105.8, 115.8, 127.3,
127.8, 129.0, 129.2, 129.5, 130.7, 131.9, 132.1, 133.6, 135.8,
156.7, 157.8. Anal. Calcd for C19H14ClN3O3: C, 62.05; H, 3.84;
N, 11.43%. Found C, 62.11; H, 3.76; N, 11.39%.
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128.9, 129.0, 130.4, 131.4, 132.3, 141.9, 156.4, 157.3: Anal.
Calcd for C19H14BrN3O3: C, 55.36; H, 3.42; N, 10.19%. Found
C, 55.45; H, 3.37; N, 10.11%.
6-(Methylamino)-4-(2-bromophenyl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitrile 6h
White solid; Yield 92%; mp 254–255 uC; 1H NMR (300 MHz,
CDCl3) dH: 3.24 (d, 3H, J = 5.1 Hz, NH–CH3), 5.40 (s, 1H, Ar–
CH), 7.17 (t, 1H, J = 7.5 Hz, Ar–H), 7.33 (t, 1H, J = 7.5 Hz, Ar–H),
7.40 (d, 1H, J = 7.5 Hz, Ar–H), 7.48–7.59 (m, 4H, Ar–H), 7.79 (d,
2H, J = 7.8 Hz, Ar–H), 10.23 (brs, N–H); 13C NMR (75 MHz,
CDCl3/DMSO-D6) dC: 27.6, 40.7, 90.8, 104.7, 115.0, 122.5, 126.9,
127.1, 128.0, 128.2, 128.7, 130.3, 131.2, 132.6, 137.5, 155.7,
156.5. Anal. Calcd for C19H14BrN3O3: C, 55.36; H, 3.42; N,
10.19%. Found C, 55.43; H, 3.36; N, 10.27%.
6-(Methylamino)-4-(3-nitrophenyl)-5-nitro-2-phenyl-4H-pyran-
3-carbonitrile 6m
1
Bright yellow solid; Yield 93%; mp 241–242 uC; H NMR (300
MHz, CDCl3) dH: 3.29 (s, 3H, NH–CH3), 5.13 (s, 1H, Ar–CH),
7.43–7.56 (m, 4H, Ar–H), 7.80–7.82 (m, 3H, Ar–H), 8.16–8.18
(m, 2H, Ar–H), 10.22 (brs, N–H); 13C NMR (75 MHz, CDCl3/
DMSO-D6) dC: 27.7, 40.4, 91.2, 104.3, 115.2, 121.7, 121.9, 126.9,
127.9, 129.0, 131.3, 133.4, 141.6, 147.3, 155.8, 155.9: Anal.
Calcd for C19H14N4O5: C, 60.32; H, 3.73; N, 14.81%. Found C,
60.37; H, 3.67; N, 14.78%.
6-(Methylamino)-4-(2-methylphenyl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitrile 6i
Light yellow solid; Yield 92%; mp 263–264 uC; 1H NMR (300
MHz, CDCl3) dH: 2.67 (s, 3H, Ar–CH3), 3.25 (d, 3H, J = 5.1 Hz,
NH–CH3), 5.30 (s, 1H, Ar–CH), 7.06–7.09 (m, 1H, Ar–H), 7.15–
7.19 (m, 3H, Ar–H), 7.47–7.58 (m, 3H, Ar–H), 7.78 (d, 2H, J = 7.8
Hz, Ar–H), 10.13 (brs, N–H); 13C NMR (75 MHz, CDCl3/DMSO-
D6) dC: 18.5, 27.7, 36.4, 92.9, 106.3, 115.7, 126.1, 126.7, 127.0,
128.2, 128.5, 129.9, 131.3, 135.9, 138.3, 155.1, 156.7. Anal.
Calcd for C20H17N3O3: C, 69.15; H, 4.93; N, 12.10%. Found C,
69.22; H, 4.85; N, 12.05%.
6-(Methylamino)-4-(2,5-dimethoxyphenyl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitrile 6n
Light yellow solid; Yield 93%; mp 260–261 uC; 1H NMR (300
MHz, CDCl3) dH: 3.24 (d, 3H, J = 5.4 Hz, NH–CH3), 3.74 (s, 3H,
Ar–OCH3), 3.78 (s, 3H, Ar–OCH3), 5.05 (s, 1H, Ar–CH), 6.81–
6.86 (m, 2H, Ar–H), 6.92 (d, 1H, J = 2.4 Hz, Ar–H), 7.48–7.56 (m,
3H, Ar–H), 7.77 (dd, 2H, J = 8.4, 2.1 Hz, Ar–H), 10.27 (d, 1H, J =
5.1 Hz, N–H): 13C NMR (75 MHz, CDCl3/DMSO-D6) dC: 27.4,
37.8, 54.6, 55.2, 90.4, 104.4, 111.6, 112.2, 115.6, 116.3, 126.8,
127.1, 127.9, 128.6, 130.8, 151.1, 152.4, 155.7, 156.9: Anal.
Calcd for C21H19N3O5: C, 64.12; H, 4.87; N, 10.68%. Found C,
64.19; H, 4.80; N, 10.62%.
6-(Methylamino)-4-(2-methoxyphenyl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitrile 6j
1
Light brown solid; Yield 91%; mp 237–238 uC; H NMR (300
6-(Methylamino)-4-(2,4-dichlorophenyl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitrile 6o
MHz, CDCl3) dH: 3.22 (d, 3H, J = 5.1 Hz, NH–CH3), 3.77 (s, 3H,
Ar–OCH3), 5.11 (s, 1H, Ar–CH), 6.89 (d, 1H, J = 8.4 Hz, Ar–H),
6.96 (td, 1H, J = 7.5, 0.9 Hz, Ar–H), 7.25–7.30 (m, 1H, Ar–H),
7.36 (dd, 1H, J = 7.5, 1.5 Hz, Ar–H), 7.46–7.57 (m, 3H, Ar–H),
7.76 (dd, 2H, J = 8.4, 1.8 Hz, Ar–H), 10.26 (brs, N–H); 13C NMR
(75 MHz, CDCl3) dC: 28.1, 38.7, 55.5, 92.2, 106.2, 111.4, 116.5,
120.9, 126.3, 127.6, 128.9, 129.6, 131.1, 131.8, 156.5, 157.8,
158.3: Anal. Calcd for C20H17N3O4: C, 66.11; H, 4.72; N,
11.56%. Found C, 66.19; H, 4.64; N, 11.50%.
1
White solid; Yield 93%; mp 252–253 uC; H NMR (300 MHz,
CDCl3) dH: 3.25 (d, 3H, J = 4.8 Hz, NH–CH3), 5.30 (s, 1H, Ar–
CH), 7.26–7.29 (m, 1H, Ar–H), 7.36–7.40 (m, 2H, Ar–H), 7.52–
7.54 (m, 3H, Ar–H), 7.78 (d, 2H, J = 6.3 Hz, Ar–H), 10.19 (brs, N–
H);13C NMR (75 MHz, CDCl3) dC: 28.3, 40.3, 91.2, 91.4, 105.4,
115.7, 127.6, 127.8, 129.0, 130.5, 132.3, 132.8, 134.3, 134.4,
134.8, 156.9, 157.7: Anal. Calcd for C19H13Cl2N3O3: C, 56.73; H,
3.26; N, 10.45%. Found C, 56.67; H, 3.21; N, 10.49%.
6-(Methylamino)-4-(3-fluorophenyl)-5-nitro-2-phenyl-4H-pyran-
3-carbonitrile 6k
6-(Methylamino)-4-(1-naphthyl)-5-nitro-2-phenyl-4H-pyran-3-
1
carbonitrile 6p
Light brown solid; Yield 91%; mp 190–191 uC; H NMR (300
1
MHz, DMSO-D6) dH: 3.13 (s, 3H, NH–CH3), 4.98 (s, 1H, Ar–CH),
7.15 (t, 1H, J = 8.1 Hz, Ar–H), 7.25–7.30 (m, 2H, Ar–H), 7.42 (dd,
1H, J = 14.4, 8.1 Hz, Ar–H), 7.53–7.64 (m, 3H, Ar–H), 7.84 (d,
2H, J = 7.8 Hz, Ar–H), 10.36 (brs, N–H); 13C NMR (75 MHz,
DMSO-D6) dC: 28.2, 40.5, 92.0, 105.0, 114.2, 114.3, 114.4, 114.6,
116.3, 123.8, 127.7, 128.6, 128.8, 130.3, 130.4, 131.7, 143.4,
143.5, 155.9, 156.5, 160.4, 163.6. Anal. Calcd for C19H14FN3O3:
C, 64.95; H, 4.02; N, 11.96%. Found C, 64.87; H, 4.07; N,
11.89%.
Bright yellow solid; Yield 92%; mp 258–259 uC; H NMR (300
MHz, CDCl3) dH: 3.30 (d, 3H, J = 5.1 Hz, NH–CH3), 5.91 (s, 1H,
Ar–CH), 7.38 (t, 2H, J = 7.2 Hz, Ar–H), 7.43–7.55 (m, 4H, Ar–H),
7.62 (t, 1H, J = 7.5 Hz, Ar–H), 7.76–7.83 (m, 3H, Ar–H), 7.88 (d,
1H, J = 8.4 Hz, Ar–H), 8.45 (d, 1H, J = 8.4 Hz, Ar–H), 10.14 (brs,
N–H); 13C NMR (75 MHz, CDCl3/DMSO-D6) dC: 27.7, 35.1, 92.7,
105.9, 115.6, 122.3, 124.8, 125.1, 125.6, 127.0, 127.5, 127.8,
127.9, 128.4, 130.5, 131.0, 132.6, 137.4, 155.1, 156.4. Anal.
Calcd for C23H17N3O3: C, 72.05; H, 4.47; N, 10.96%. Found C,
72.14; H, 4.57; N, 10.87%.
6-(Methylamino)-4-(3-bromophenyl)-5-nitro-2-phenyl-
4H-pyran-3-carbonitrile 6l
White solid; Yield 92%; mp 237–238 uC; 1H NMR (300 MHz,
CDCl3) dH: 3.25 (d, 3H, J = 5.1 Hz, NH–CH3), 4.95 (s, 1H, Ar–
CH), 7.21–7.27 (m, 1H, Ar–H), 7.35 (dd, 1H, J = 6.9, 1.5 Hz, Ar–
H), 7.43–7.45 (m, 2H, Ar–H), 7.48–7.60 (m, 3H, Ar–H), 7.80 (dd,
2H, J = 8.4, 1.8 Hz, Ar–H), 10.10 (brs, N–H); 13C NMR (75 MHz,
CDCl3) dC: 28.3, 41.3, 93.3, 106.2, 116.1, 123.0, 126.9, 127.7,
Acknowledgements
RRK thanks the Department of Science and Technology, New
Delhi for the funds under (i) DST-SERC Fast Track scheme no.
SR/FT/CS-073/2009 and (ii) IRHPA programme for providing
high resolution NMR facility. RRK and SS thank the
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RSC Advances
7 C. K. Pei, L. Wu, Z. Lian and M. Shi, Org. Biomol. Chem.,
2012, 10, 171.
8 J. Hu, L. Liu, S. Yang and Y. M. Liang, Org. Biomol. Chem.,
2011, 9, 3375.
Sophisticated Analytical Instrument Facility, Indian Institute
of Technology Madras for single crystal X-ray diffraction
studies. SS thanks the University Grants Commission, New
Delhi for the fellowship under UGC-BSR meritorious scheme.
9 Y. Xiao and J. Zhang, Chem. Commun., 2009, 3594.
10 M. Venugopal, R. Umarani, P. T. Perumal and S. Rajadurai,
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16 Crystallographic data (excluding structure factors) for
compound 6d has been deposited with the Cambridge
Crystallographic Data Center as supplementary publication
number CCDC 911400. Copy of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0) 1223 762911 or
e-mail: deposit@ccdc.cam.ac.uk].
17 That the domino process involves the formation of
intermediate 8 is supported by the isolation of 8 in a
separate reaction of 1 or 2 with aromatic aldehyde in the
presence of triethylamine under similar reaction condi-
tions. The NMR spectral data of 8 are included in the
Electronic Supplementary Information .
3
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