A catalyst- A nd solvent-free protocol for the sustainable synthesis of fused 4: H-pyran derivatives

Article abstract of DOI:10.1039/c9ra04370e

An efficient and cost-effective method was developed for the synthesis of two kinds of fused 4H-pyran derivatives, namely, dihydropyrano[2,3-c]pyrazole 4 and pyrano[3,2-c]chromenone 6. The reactions of 3-methyl-1-phenyl-5-pyrazolone/4-hydroxycoumarin with

Full text of DOI:10.1039/c9ra04370e

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A catalyst- and solvent-free protocol for the
sustainable synthesis of fused 4H-pyran
derivatives†
Cite this: RSC Adv., 2019, 9, 26393
a
a
a
b
Md. Musawwer Khan, * Sumbulunnisan Shareef, Saigal and Subash C. Sahoo
An efficient and cost-effective method was developed for the synthesis of two kinds of fused 4H-pyran
derivatives, namely, dihydropyrano[2,3-c]pyrazole 4 and pyrano[3,2-c]chromenone 6. The reactions of
3
-methyl-1-phenyl-5-pyrazolone/4-hydroxycoumarin with aromatic aldehydes and (E)-N-methyl-1-
(methylthio)-2-nitroethenamine (NMSM), involving the Knoevenagel, Michael-addition, O-cyclization and
elimination reactions under thermal heating, afforded the desired products. The synthesized compounds
were characterized by standard spectroscopic techniques. Further, the structures of pyrazole-fused 4H-
pyran 4a and coumarin-fused 4H-pyran 6b were confirmed by single-crystal XRD analysis. The short
reaction time, good-to-excellent yields, elimination of the use of expensive, metallic and toxic catalysts
or hazardous organic solvents and high atom-economy are some noteworthy features of this protocol.
Received 11th June 2019
Accepted 2nd August 2019
DOI: 10.1039/c9ra04370e
rsc.li/rsc-advances
6
properties. Among the fused heterocycles, pyrazole- and
coumarin-fused oxygen-containing heterocyclic systems,
Introduction
Recent advances in science and technology are focusing on the particularly 4H-pyran derivatives, are omnipresent in several
development of approaches that prevent pollution and mini- natural and unnatural bioactive molecules with promising
7
mize the usage of non-renewable resources. Recently, green properties both in pharmacological and materials sciences.
techniques and processes, which obey green chemistry princi- Pyrazole-fused 4H-pyran derivatives have shown several bio-
1
8
9
ples have gained signicant ecological and economic interest.
Green chemistry not only deals with processes that reduce the crobial, anti-inammatory, anti-tubercular, hypoglycemic
logical activities such as antimalarial, antibacterial, antimi-
10
11
12
13
generation of hazardous chemicals but also introduces modern and vasodilator activities. On the other hand, coumarin-fused
synthetic approaches, wherein synthetic chemists construct 4H-pyrans also exhibit several activities like antioxidant,
14
2
15
16
compounds more ecologically and prociently.
antifungal and anticancer. Fig. 1 provides a glimpse of fused
In this context, catalyst- and solvent-free multi-component 4H-pyran-based biologically and medicinally active compounds.
syntheses have appeared as the most powerful strategy in For example, compounds I and II have antibacterial character-
17
contemporary situations, as they fulll maximum principles of istics, whereas, compounds III and IV possess antifungal
3
18
green chemistry. Multicomponent domino reactions (MDRs) activity.
are convergent organic reactions, in which three or more reac-
Recently,
tant molecules with multiple bond-forming tendencies and (NMSM) was explored as a fascinating building block for the
(E)-N-methyl-1-(methylthio)-2-nitroethenamine
19
high atom-economy combine in one pot without the isolation of construction of diverse heterocyclic compounds. The starting
4
undesirable intermediates. Therefore, MDR strategies have material NMSM has a polarizable ethylene skeleton, bearing
been explored to access functionalized organic compounds electrophilic and nucleophilic centers at the two ends, as well as
under green-chemistry conditions and are preferred over step- electron-withdrawing (–NO
), electron-donating (CH NH–) and
2
3
5
wise synthetic strategies.
good leaving groups (methylsulfanyl), where each of them plays
Fused heterocycles represent a dynamic class of organic an important role in the formation of products.
compounds with notable medicinal and agrochemical
A literature scan revealed that the synthesis of pyrazole-fused
H-pyran was performed previously using InCl (ref. 20) and
piperidine, whereas coumarin-fused 4H-pyran scaffolds were
4
3
21
a
22
0
Department of Chemistry, Aligarh Muslim University, Aligarh, 202002, India. E-mail: prepared using catalysts such as STA, 6,6 -thiobis(methylene)-
musawwer@gmail.com
23
24
b-cyclodextrin dimer and piperidine. Regardless of the
b
Department of Chemistry, Center of Advanced Studies in Chemistry, Panjab
adequacy of these reported methods, each exhibits one or more
University, Chandigarh-160014, India
2
0–24
shortcomings, such as the required usage of catalysts
or
†
Electronic supplementary information (ESI) available. CCDC 1901104 and
901105. For ESI and crystallographic data in CIF or other electronic format see
20,24
20,24
solvents
and prolonged reaction time.
Therefore, there
1
still remains a scope of improvement of the synthetic strategy to
DOI: 10.1039/c9ra04370e
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Fig. 1 Some representative examples of biologically active fused 4H-pyrans.
access such important fused 4H-pyrans. In continuation of our Amusingly, the reaction afforded better results in terms of
effort to develop green and sustainable methodologies for the reaction time and yield.
synthesis of heterocycles by using NMSM and other building
In addition, the above reaction was executed at different
25,26
ꢀ
blocks,
we herein intended to utilize the distinctive reactivity temperatures ranging from 90 to 130 C under catalyst- and
of NMSM and aromatic aldehydes with 3-methyl-1-phenyl-5- solvent-free conditions (Table 1, entries 8–12) to assess the
pyrazolone/4-hydroxycoumarin for the synthesis of fused 4H- effect of temperature. We observed that maximum yields were
ꢀ
pyran, as depicted in Scheme 1.
obtained at 110 C within a short time period, and no further
increase in the yield occurred with an increase in the temper-
ꢀ
ature. Thus, the solvent-free and catalyst-free reaction at 110 C
emerged as the optimized condition for the present protocol for
Results and discussion
For the present study, a model reaction was initially conducted the synthesis of compound 4a.
between NMSM 1 (1.0 mmol), benzaldehyde 2 (1.0 mmol) and 3-
Similar optimal conditions were found for the synthesis of
methyl-1-phenyl-5-pyrazolone 3 (1.0 mmol) in the presence of compound 6a by performing a series of reactions between 4-
1
0 mol% of ZnO nano-catalyst under reuxing ethanol (4 mL) hydroxycoumarine, benzaldehyde and NMSM, which are also
Table 1, entry 1). The progress of the reaction was monitored by summarized in Table 1.
thin layer chromatography (TLC). Aer the completion of the
Aer determining the optimized conditions, we focused on
reaction, the product 4a was isolated in 60% yield by simple establishing the substrate scope. A reaction was performed
ltration. The structure of the compound 4a was conrmed by between compound 3, 4-chlorobenzaldehyde and NMSM under
(

1
13
its melting point, IR, H and C NMR spectroscopies, and the the optimized reaction conditions, which gave the desired
2
0–24
data matched well with the reported data.
these results, we proceeded to optimize the reaction conditions.
For this process, the model reaction was executed in the pres- were performed with other aromatic aldehydes having substit-
ence of different acid and base catalysts (10 mol%) in EtOH (4 uents such as 4-Br, 4-F, 4-Me, 4-Et, 4-NO , 4-OMe, 3-Cl, 2-Cl, 3-
mL) as well as without catalyst in EtOH with reux (Table 1, Br, 3-NO , 3,4-(OMe) , and 3,4,5-(OMe) with 3-methyl-1-phenyl-
Encouraged by product 4b with 85% yield (Table 2).
Next, using the optimized reaction conditions, reactions
2
2
2
3
entries 2–6). Unfortunately, we did not observe any improve- 5-pyrazolone and NMSM. The reactions afforded corresponding
ment in the results. Therefore, the original reaction was per- products 4c–4n with good-to-excellent yields. Similarly, this
ꢀ
formed without any catalyst or solvent at 80 C (Table 1, entry 7). reaction was also performed with a hetero-aromatic aldehyde,
Scheme 1 Synthesis of pyrazole- and coumarin-fused 4H-pyrans under neat conditions.
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a
Table 1 Optimization of reaction conditions for the synthesis of compounds 4a and 6a
4a
6a
b
b
Entry
Catalyst (mol%)
Solvent
Temp.
Time
Yield (%)
Time
Yield (%)
1
2
3
4
5
6
7
8
Nano ZnO (10 mol%)
DMAP (10 mol%)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Neat
Neat
Neat
Neat
Neat
Neat
Reux
Reux
Reux
Reux
Reux
Reux
7 h
60
49
43
55
50
34
63
70
78
87
87
84
5 h
9 h
12 h
4 h
3 h
2 h
1 h
55 min
40 min
30 min
30 min
30 min
65
51
40
61
53
55
66
73
82
91
91
89
10 h
11 h
6 h
5 h
4 h
2 h
1 h
50 min
45 min
45 min
40 min
Et
3
N (10 mol%)
(10 mol%)
I
2
AcOH (10 mol%)
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
ꢀ
80 C
ꢀ
90 C
ꢀ
9
100 C
c
ꢀ
1
1
1
0
1
2
110 C
ꢀ
120 C
ꢀ
130 C
a
b
Reaction conditions: 3-methyl-1-phenyl-5-pyrazolone/4-hydroxy coumarin (1 mmol), benzaldehyde (1 mmol) and NMSM (1 mmol). Isolated
c
yields. Optimized reaction conditions.
i.e. pyridine-3-carbaldehyde, which afforded the expected yellow and white-colored crystals of compounds 4a and 6b,
product 4o in 83% yield.
3
respectively, were grown by the slow evaporation of CH CN
Further, to investigate the generality and applicability of the solvent for X-ray analysis. The data were obtained from a Super
above protocol, we executed the reaction by replacing reactant 3 Nova, single source at offset/far and HyPix3000 diffractometer
with 4-hydroxycoumarin and 5 using aromatic aldehydes teth- using graphite-monochromated Mo(Ka) radiation (l ¼ 0.71073
˚
ered to substituents like 4-Cl, 4-Br, 4-F, 4-Me, 4-OMe, 4-NO
2
, 4- A) at 293 K.
Et, 3,4-diOMe, 3,4,5-triOMe, 3-NO
2
, 3-Cl, 2-NO
2
and NMSM
The crystallized compound of 4a has a monoclinic crystal
1
under similar optimized conditions, which afforded the desired system, with the space group P2 /c and the unit cell dimensions
˚
˚
˚
coumarin-fused 4H-pyrans 6b–m in good yields, as shown in a ¼ 10.7875(3) A, b ¼ 20.8262(4) A, c ¼ 8.0335(2) A. On the other
Table 3. Aldehydes possessing both electron-withdrawing hand, the crystallized compound of 6b also has a monoclinic
groups as well as electron-donating groups afforded products crystal system with the space group P2
1
/c and unit cell dimen-
˚
˚
˚
smoothly. The reaction of 4-hydroxycoumarin was also per- sions a ¼ 8.5412(2) A, b ¼ 13.1791(3) A, c ¼ 14.8906(3) A.
formed with thiophene-2-carbaldehyde and NMSM, which fur-
Finally, the formation of the products can be rationalized via
nished the product 6n in good yield.
a
domino reaction involving Knoevenagel condensation,
All the synthesized compounds were characterized by spec- Michael-addition, O-cyclization and elimination mechanisms,
1
13
troscopic techniques including IR, H and C NMR spectros- as illustrated in Scheme 2.
copies and elemental analysis; the resulting data for several of
The rst step is a simple Knoevenagel condensation of an
the reported compounds are well-matched with the litera- aromatic aldehyde with a 1,3-dinuleophilic oxygen-containing
20–24
ture.
Further, the structure and stereochemistry of the compound (4-hydroxycoumarin or 3-methyl-1-phenyl-5-
compounds 4a (CCDC 1901104) and 6b (CCDC 1901105) were pyrazolone) to generate an intermediate I. The intermediate I
unambiguously conrmed by single-crystal X-ray diffraction undergoes a Michael-addition reaction with NMSM to form
analysis, and the ORTEP diagrams are shown in Fig. 2 and 3, species II. Then, species II affords the desired product 4/6 by an
respectively.
intra-molecular O-cyclization followed by the elimination of
Single crystals of the compounds 4a and 6b were mounted –MeSH via species III.
on a glass ber and utilized for XRD data collection. Light
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a
Table 2 Substrate scope for the synthesis of 4a–4o
Reported
mp ( C)
b
ꢀ
ꢀ
Entry
Ar
Time (min)
Yield (%)
Product
mp ( C)
Ref.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
C
6
H
5
45
40
45
40
50
50
40
45
50
55
55
45
40
45
50
87
85
86
86
81
79
89
87
85
83
83
86
90
91
83
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
206–208
206–208
208–209
202–204
216–218
210–212
217–218
210–212
254–256
244–245
238–240
227–228
216–217
218–220
220–221
208–209
210–211
228–229
223–224
219–220
—
217–218
220–221
256–258
244–245
238–239
228–229
—
21
20
20
20
21
—
21
20
20
21
20
20
—
20
—
4-Cl-C
4-Br-C
4-F-C
4-Me-C
4-Et-C
4-NO -C
4-OMe-C
3-Cl-C
2-Cl-C
3-Br-C
3-NO -C
3,4-OMe-C
6 5
H
6 5
H
6
H
5
6
H
5
6
H
5
2
6
H
5
6
H
5
6
H
H
5
5
0
1
2
3
4
5
6
6
H
5
2
6 5
H
6
H
5
3,4,5-OMe-C
Pyrid-3-yl
6
H
5
218–219
—
a
b
ꢀ
Reaction conditions: 3-methyl-1-phenyl-5-pyrazolone (1 mmol), aryl aldehydes (1 mmol), NMSM (1 mmol) under neat conditions at 110 C.
Isolated yields.
Varian-AS400 NMR, and Bruker Bio Spin GmbH spectrometers
Conclusion
using tetramethylsilane (TMS) as the internal standard and
In summary, we have successfully developed a practical and DMSO-d or CDCl as the solvent. Crystal data were collected with
6
3
green method for the synthesis of highly functionalized pyr- a Super Nova, single source at offset/far and HyPix3000 diffrac-
azole- and coumarin-fused 4H-pyrans by the reaction of NMSM tometer (CCD) using graphite monochromated MoKa radiation
˚
or aryl aldehydes with 3-methyl-1-phenyl-5-pyrazolone or 4- (l ¼ 0.71073 A) at 296 K. HRMS spectra were recorded on a high-
hydroxycoumarin, respectively, under thermal heating and neat resolution mass spectrometer XEVO G2-XS QTOF.
conditions. The presented protocol is characterized by impor-
tant features such as a short reaction time, good-to-excellent Typical procedure for the preparation of functionalized fused
yields, elimination of the use of toxic catalysts or solvents, 4H-pyrans (4 and 6)
easy isolation of compounds without traditional column puri-
A dried 5 mL round-bottom ask was equipped with a Teon-

cation and applicability to a broad range of substrates.
coated magnet and charged with a combination of 3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one/4-hydroxycoumarin (1 mmol),
aromatic aldehyde (1 mmol), and NMSM (1 mmol). The mixture
Experimental
ꢀ
of all the reagents was heated at 110 C with stirring for
a specied time under neat conditions. The progress of the
reactions was monitored by TLC. Aer completion of the reac-
tion as indicated by TLC, the resulting precipitate was cooled,
and 2 mL of ethanol was added and stirred for 5 min. Next, the
precipitate was ltered and washed with 3 mL cold ethanol.
Purication of the crude product was done by recrystallization
from hot acetonitrile to yield the pure products.
General
4-Hydroxycoumarin, 3-methyl-1-phenyl-5-pyrazolone, NMSM and
all the aldehydes were procured from Sigma-Aldrich. All the
solvents were obtained from Merck and Otto Chemie. All the
reactions were completed in a REMI 2MLH thermo-mechanical
stirrer. TLC analysis was carried out using silica gel GF-254
from SRL (Alfa Aesar). Melting points were obtained on a Stuart
digital melting point apparatus (SMP10) and are uncorrected. IR
spectra were performed with potassium bromide (KBr) pellets on
Characterization data of selected compounds
1
13
a PerkinElmer 10.4.00 IR spectrophotometer. H and C NMR
4a:
N,3-Dimethyl-5-nitro-1,4-diphenyl-1,4-dihydropyrano
spectral analyses were performed on Bruker (Avance-II 400 MHz), [2,3-c]pyrazol-6-amine. Isolated as yellow solid; yield: 87%; mp
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a
Table 3 Substrate scope for the synthesis of 6a–6n
a
ꢀ
Reaction conditions: 3-methyl-1-phenyl-5-pyrazolone (1 mmol), aromatic aldehydes (1 mmol), NMSM (1 mmol) under neat conditions at 110 C.
Isolated yields.
b
ꢀ
ꢁ1
2
1
06–208 C; IR (KBr, cm ): 3173, 3067, 3026, 2943, 2920, 1868, ArH), 7.49 (t, J ¼ 7.0 Hz, 2H, ArH), 7.69 (d, J ¼ 7.5 Hz, 2H, ArH),
1
1
3
3
655, 1519, 1449, 1390, 1265, 1126, 969, 864, 753; H NMR (500 10.55 (s, 1H, NH); C NMR (125 MHz, CDCl ) d 12.7, 28.4, 38.4,
MHz, CDCl ) d 2.00 (s, 3H, CH ), 3.22 (d, J ¼ 4.0 Hz, 3H, NCH ), 101.1, 110.1, 120.7, 126.8, 126.9, 128.0, 128.2, 129.3, 137.4,
3
3
3
5
.25 (s, 1H, CH), 7.20 (d, J ¼ 5.5 Hz, 1H, ArH), 7.28–7.35 (m, 5H, 141.9, 146.4, 159.2; anal. calcd for C H N O : C, 66.29; H,
2
0
18 4 3
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Fig. 2 ORTEP representation of compound 4a (CCDC 1901104).
1
3
5
.01; N, 15.46%. Found: C, 66.19; H, 5.05; N, 15.39%. EI-HRMS: 4.4 Hz, 1H, NH); C NMR (100 MHz, CDCl
3
) d 12.7, 28.5, 37.6,
+
anal. calcd for [C20
H
18
N
4
O
3
+ H ]: anal. calcd: 363.1412, found: 100.8, 110.3, 115.0, 115.2, 120.7, 126.9, 129.4, 129.8, 137.3,
141.9, 146.3, 154.5, 159.0, 160.5, 163.6; anal. calcd for
3
63.1452.
b:
dihydropyrano[2,3-c]pyrazol-6-amine. Isolated as white solid; 4.36; N, 14.10%.
4
4-(4-Chlorophenyl)-N,3-dimethyl-5-nitro-1-phenyl-1,4-
C
20
H17ClN
4
O
3
: C, 60.53; H, 4.32; N, 14.12%. Found: C, 60.50; H,
ꢀ
ꢁ1
yield: 85%; mp 206–208 C; IR (KBr, cm ): 3411, 3184, 3073,
2
4c:
4-(4-Bromophenyl)-N,3-dimethyl-5-nitro-1-phenyl-1,4-
946, 2887, 1656, 1617, 1514, 1430, 1296, 1266, 1158, 1016, H dihydropyrano[2,3-c]pyrazol-6-amine. Isolated as white solid;
1
ꢀ
ꢁ1
NMR (400 MHz, CDCl ) d 1.98 (s, 3H, CH ), 3.23 (d, J ¼ 5.16 Hz, yield: 86%; mp 208–209 C; IR (KBr, cm ): 3433, 3185, 3068,
3
3
1
3
7
2
H, NCH
.27 (m, 2H, ArH), 7.34 (t, J ¼ 8 Hz, 1H, ArH), 7.49 (t, J ¼ 7.2 Hz, (400 MHz, DMSO-d
H, ArH), 7.68 (dd, J ¼ 8.8 Hz, 1.0 Hz, 2H, ArH), 10.56 (d, J ¼ NCH ), 5.20 (s, 1H, CH), 7.16–7.20 (m, 2H, ArH), 7.34 (m, 1H,
3
), 5.23 (s, 1H, CH), 6.95 (t, J ¼ 8.0 Hz, 2H, ArH), 7.25– 2923, 2368, 1654, 1518, 1388, 1232, 1125, 1012, 904; H NMR
6
) d 1.98 (s, 3H, CH
3
), 3.23 (d, J ¼ 5.0 Hz, 3H,
3
ArH), 7.40 (d, J ¼ 8.0 Hz, 2H, ArH), 7.49 (t, J ¼ 7.9 Hz, 2H, ArH),
7
.67 (dd, J ¼ 8.6, 1.1 Hz, 2H, ArH), 10.55 (d, J ¼ 5.5 Hz, 1H, NH);
1
3
C NMR (100 MHz, DMSO-d ) d 12.7, 28.5, 37.9, 100.4, 110.0,
6
1
1
1
20.7, 120.8, 126.9, 129.4, 129.9, 131.3, 137.3, 140.9, 141.8,
46.3, 159.0; anal. calcd for C H BrN O : C, 54.44; H, 3.88; N,
2
0
17
4 3
2.70. Found: C, 54.34; H, 3.85; N, 12.73%.
d: 4-(4-Fluorophenyl)-N,3-dimethyl-5-nitro-1-phenyl-1,4-
dihydropyrano[2,3-c]pyrazol-6-amine. Isolated as white solid;
4
ꢀ
ꢁ1
yield: 86%; mp: 202–204 C; IR (KBr, cm ): 3435, 2924, 2855,
1
1656.7, 1513.4, 1466.6, 1364, 1231, 1048, 753, 664, 530; H NMR
(
400 MHz, CDCl ) d 1.98 (s, 3H, CH ), 3.23 (d, J ¼ 5.2 Hz, 3H,
3
3
NCH ), 5.22 (s, 1H, CH), 7.24 (s, 4H, ArH), 7.34 (t, J ¼ 7.52 Hz,
3
1
H, ArH), 7.49 (t, J ¼ 7.6 Hz, 2H, ArH), 7.67 (d, J ¼ 8.8 Hz, 2H,
13
ArH), 10.56 (d, J ¼ 4.8 Hz, 1H, NH); C NMR (100 MHz, CDCl
d 12.8, 28.5, 37.8, 100.5, 110.1, 120.8, 127.0, 128.4, 129.4, 129.5,
32.7, 137.3, 140.4, 141.9, 146.3, 159.0; anal. calcd for
: C, 63.15; H, 4.50; N, 14.73%. Found: C, 63.10; H,
.47; N, 14.75%.
f: 4-(4-Ethylphenyl)-N,3-dimethyl-5-nitro-1-phenyl-1,4-dihy-
dropyrano[2,3-c]pyrazol-6-amine. Isolated as white solid; yield:
3
)
1
20 4 3
C H17FN O
4
4
ꢀ
ꢁ1
7
9%; mp 210–212 C; IR (KBr, cm ): 3435, 3177, 3048, 3021,
2
962, 2929, 2875, 1654, 1519, 1474, 1392, 1267, 1195, 1050, 963;
1
H NMR (400 MHz, CDCl
3
) d 1.19 (t, J ¼ 7.6 Hz, 3H, CH
3
), 2.0 (s,
Fig. 3 ORTEP representation of compound 6b (CCDC 1901105).
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Scheme 2 Plausible mechanism for the synthesis of the pyrazole- and coumarin-fused 4H-pyrans.
ꢀ
ꢁ1
3
H, CH
3
), 2.59 (q, J ¼ 7.6 Hz, 2H, CH ), 3.19 (d, J ¼ 5.2 Hz, 3H, yield: 85%; mp 244–245 C; IR (KBr, cm ): 3177, 3064, 2946,
2
1
NCH ), 5.22 (s, 1H, CH), 7.10 (d, J ¼ 8.0 Hz, 2H, ArH), 7.20 (d, J ¼ 2486, 2275, 1661, 1520, 1361, 1267, 1131, 908; H NMR (400
3
8
.0 Hz, 2H, ArH), 7.30–7.34 (m, 1H, ArH), 7.46–7.50 (m, 2H, MHz, DMSO-d ) d 1.91 (s, 3H, CH ), 3.20 (d, J ¼ 4.8 Hz, 3H,
6
3
13
ArH), 7.61–7.68 (m, 2H, ArH), 10.55 (d, J ¼ 5.2 Hz, 1H, NH);
C
NCH ), 5.60 (s, 1H, CH), 7.17–7.22 (m, 2H, ArH), 7.32 (d, J ¼
3
NMR (100 MHz, CDCl
3
) d 12.8, 15.4, 28.4, 28.4, 37.9, 101.2, 7.6 Hz, 2H, ArH), 7.49 (t, J ¼ 8.0 Hz, 2H, ArH), 7.68–7.71 (m, 3H,
13
1
1
5
10.6, 120.6, 126.7, 127.7, 127.9, 129.4, 137.4, 139.0, 141.8, ArH), 10.62 (d, J ¼ 5.2 Hz, 1H, NH); C NMR (100 MHz, DMSO-
42.8, 146.4, 159.1; anal. calcd for C22 : C, 67.68; H, ) d 12.4, 28.5, 38.8, 108.1, 120.2, 120.5, 126.4, 126.9, 128.0,
.68; N, 14.35%. Found: C, 67.60; H, 5.65; N, 14.40%. 129.1, 132.5, 137.0, 141.8, 145.1, 158.7; anal. calcd for
g: N,3-Dimethyl-5-nitro-4-(4-nitrophenyl)-1-phenyl-1,4-
dihydropyrano[2,3-c]pyrazol-6-amine. Isolated as white solid; 4.37; N, 14.10%.
H
22
N
4
O
3
d
6
4
C
20
H17ClN
4
O
3
: C, 60.53; H, 4.32; N, 14.12%. Found: C, 60.45; H,
ꢀ
ꢁ1
yield: 89%; mp: 217–218 C; IR (KBr, cm ): 3439, 2927, 1653,
4l: N,3-Dimethyl-5-nitro-4-(3-nitrophenyl)-1-phenyl-1,4-dihy-
1
6
4
7
8
458, 1558, 1391, 1350, 1235, 1270, 1127, 1058, 821, 754, 714, dropyrano[2,3-c]pyrazol-6-amine. Isolated as white solid; yield:
1
ꢀ
ꢁ1
91; H NMR (500 MHz, CDCl
.0 Hz, 3H, NCH
), 5.36 (s, 1H, CH), 7.37 (t, J ¼ 7.5 Hz, 1H, ArH), 1870, 1794, 1656, 1527, 1457, 1349, 1266, 1128, 1053, 927; H
.49–7.53 (m, 4H), 7.69 (d, J ¼ 7.5 Hz, 2H, ArH), 8.16 (d, J ¼ NMR (400 MHz, DMSO-d ) d 1.90 (s, 3H, CH ), 3.19 (d, J ¼
), 5.46 (s, 1H, CH), 7.37 (t, J ¼ 7.6 Hz, 1H, ArH),
) d 12.7, 28.6, 38.4, 99.6, 109.4, 120.8, 123.5, 127.1, 7.53–7.62 (m, 3H, ArH), 7.77 (d, J ¼ 7.6 Hz, 2H, ArH), 7.88 (d, J ¼
29.1, 129.4, 137.2, 141.9, 146.0, 146.9, 149.3, 159.0; anal. calcd 8.0 Hz, 1H, ArH), 8.09 (dd, J ¼ 8.4, 1.2 Hz, 1H, ArH), 8.27 (s, 1H,
3
) d 1.98 (s, 3H, CH
3
), 3.28 (d, J ¼ 86%; mp 227–228 C; IR (KBr, cm ): 3615, 3178, 3078, 2924,
1
3
6
3
1
3
.0 Hz, 2H, ArH), 10.57 (d, J ¼ 2.0 Hz, 1H, NH); C NMR (125 5.2 Hz, 3H, NCH
3
MHz, CDCl
1
3
1
3
for C H N O : C, 58.97; H, 4.21; N, 17.19%. Found: C, 58.90; ArH), 10.67 (d, J ¼ 4.8 Hz, 1H, NH); C NMR (100 MHz, DMSO-
2
0
17 5 5
H, 4.25; N, 17.25%.
h: 4-(4-Methoxyphenyl)-N,3-dimethyl-5-nitro-1-phenyl-1,4- 129.4, 134.8, 137.0, 141.8, 145.3, 147.6, 158.6; anal. calcd for
dihydropyrano[2,3-c]pyrazol-6-amine. Isolated as white solid; : C, 58.97; H, 4.21; N, 17.19%. Found: C, 58.90; H,
yield: 87%; mp: 210–212 C; IR (KBr, cm ): 3430, 3185, 1654, 4.25; N, 17.20%.
d ) d 12.5, 28.7, 37.6, 99.4, 108.1, 120.4, 121.7, 122.4, 126.7,
6
4
20 17 5 5
C H N O
ꢀ
ꢁ1
1
1
611, 1515, 1494, 1448, 1386, 1355, 1260, 1128, 756, H NMR
500 MHz, CDCl ) d 2.01 (s, 3H, CH
), 3.23 (d, J ¼ 4.9 Hz, 3H, yphenyl)-1,4-dihydropyrano[2,3-c]pyrazol-6-amine. Isolated as
NCH ), 3.78 (s, 3H, OCH ), 5.22 (s, 1H, CH), 6.82 (d, J ¼ 8.0 Hz, white solid; yield: 89%; mp 218–220 C; IR (KBr, cm ): 3436,
4n:
N,3-Dimethyl-5-nitro-1-phenyl-4-(3,4,5-trimethox-
(
3
3
ꢀ
ꢁ1
3
3
1
2
H, ArH), 7.22 (d, J ¼ 8.0 Hz, 2H, ArH), 7.34 (t, J ¼ 7.3 Hz, 1H, 2947, 1655, 1620, 1595, 1495, 1355, 1234, 1127, 1054, 923; H
ArH), 7.50 (t, J ¼ 7.5 Hz, 2H, ArH), 7.70 (d, J ¼ 7.8 Hz, 2H, ArH), NMR (400 MHz, DMSO-d ) d 2.08 (s, 3H, CH ), 3.28 (d, J ¼
6
3
1
3
1
5
1
0.56 (s, 1H, NH); C NMR (125 MHz, CDCl
3
) d 12.7, 28.4, 37.5, 5.2 Hz, 3H, NCH
3
), 3.82 (s, 3H, OCH
3
3
), 3.84 (s, 6H, OCH ), 5.24
5.2, 101.3, 110.7, 113.6, 114.9, 120.7, 126.7, 129.3, 134.0, 137.5, (s, 1H, CH), 6.51 (s, 2H, ArH), 7.34–7.38 (m, 1H, ArH), 7.52 (t, J ¼
41.9, 146.4, 158.5, 159.1; anal. calcd for C21
20 4 4
H N O
: C, 64.28; 16.0, 8.0 Hz, 2H, ArH), 7.70 (dd, J ¼ 8.6 Hz, 1.0 Hz, 2H, ArH),
1
3
H, 5.14; N, 14.28%. Found: C, 64.32; H, 5.17; N, 14.30%.
j: 4-(2-Chlorophenyl)-N,3-dimethyl-5-nitro-1-phenyl-1,4- d 13.0, 28.6, 38.7, 56.2, 60.8, 100.8, 105.5, 110.2, 120.7, 126.9,
dihydropyrano[2,3-c]pyrazol-6-amine. Isolated as white solid; 129.4, 137.1, 137.5, 141.8, 142.4, 146.5, 153.0, 159.1; anal. calcd
10.60 (d, J ¼ 5.2 Hz, 1H, NH); C NMR (100 MHz, DMSO-d
6
)
4
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RSC Adv., 2019, 9, 26393–26401 | 26399

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for C23
H, 5.37, N, 12.40%.
H
24
N
4
O
6
: C, 61.05; H, 5.35; N, 12.38%. Found: C, 61.10; 3.32 (d, J ¼ 5 Hz, 3H, NCH
3
), 5.0 (s, 1H, CH), 7.0 (d, J ¼ 8.2 Hz,
2H, ArH), 7.23 (d, J ¼ 8.2 Hz, 2H, ArH), 7.49 (m, 2H, ArH), 7.73
4
o: N,3-Dimethyl-5-nitro-1-phenyl-4-(pyridin-3-yl)-1,4-dihy- (m, 1H, ArH), 8.0 (dd, J ¼ 7.9, 1.5 Hz, 1H, ArH), 10.39 (d, J ¼
13
dropyrano[2,3-c]pyrazol-6-amine. Isolated as white solid; yield: 4.8 Hz, 1H); C (100 MHz, CDCl ) d 15.5, 27.7, 28.6, 103.6,
3
ꢀ
ꢁ1
83%; mp 220–221 C; IR (KBr, cm ): 3399, 3184, 3060, 2993, 106.7, 107.8, 112.5, 115.5, 116.5, 122.7, 125.0, 127.1, 127.4,
1
2920, 1654, 1620, 1595, 1520, 1490, 1388, 1265, 925; H NMR 128.3, 133.1, 138.5, 142.5, 151.7, 151.9, 152.3, 156.7, 159.2. Anal.
(
500 MHz, CDCl
3
) d 1.98 (s, 3H, CH
), 5.26 (s, 1H, CH), 7.21 (d, J ¼ 5.5 Hz, 1H, ArH), 7.35 (t, J ¼ 66.18; H, 4.77; N, 7.35%.
6j: 2-(Methylamino)-3-nitro-4-(3-nitrophenyl)pyrano[3,2-c]
3
), 3.24 (d, J ¼ 4.0 Hz, 3H, calcd for C21
18 2 5
H N O : C, 66.66; H, 4.79; N, 7.40%. Found: C,
NCH
7
1
3
.0 Hz, 1H, ArH), 7.50 (t, J ¼ 7.2 Hz, 2H, ArH), 7.62 (d, J ¼ 6.5 Hz,
H, ArH), 7.68 (d, J ¼ 7.5 Hz, 2H, ArH), 8.45 (d, J ¼ 3.5 Hz), 8.58 chromen-5(4H)-one. Isolated as light yellow solid; yield: 81%;
1
3
ꢀ
ꢁ1
(
s, 1H, ArH), 10.55 (s, 1H, NH); C NMR (125 MHz, CDCl ) mp 258–260 C; IR (KBr, cm ): 2927, 1726, 1674, 1631, 1460,
3
1
d 12.7, 28.5, 36.5, 99.9, 109.6, 114.9, 120.8, 123.2, 127.0, 129.4, 1272, 1163, 1105, 1072; H NMR (400 MHz, DMSO-d ) d 3.32 (d, J
6
1
35.6, 137.3, 137.4, 142.0, 146.1, 148.3, 149.8, 159.0; anal. calcd ¼ 5.0, 3H, NCH
for C19
: C, 62.80; H, 4.72; N, 19.27%. Found: C, 62.85; (m, 1H, ArH), 7.90–7.93, (dd, J ¼ 8.2, 2.3, Hz, 1H, ArH), 8.03 (dd,
H, 4.75; N, 19.30%.
a: 2-(Methylamino)-3-nitro-4-phenylpyrano[3,2-c]chromen- (100 MHz, DMSO-d
(4H)-one (6a). Isolated as yellow solid; yield: 91%; mp: 278– 123.0, 123.3, 125.0, 129.4, 133.4, 135.4, 143.3, 147.3, 152.2,
3
), 6.07 (s, 1H, CH), 7.47–7.59 (m, 5H, ArH), 7.74
17 5 3
H N O
1
3
J ¼ 8.0, 1.6 Hz, 1H, ArH), 10.51 (d, J ¼ 5.2 Hz, 1H, NH); C NMR
) d 28.7, 105.2, 107.0, 116.6, 118.2, 122.1,
6
6
5
2
1
ꢀ
ꢁ1
80 C; IR (KBr, cm ): 3438, 3200, 3061, 2927, 1727, 1672, 1629, 156.6, 159.4; anal. calcd for C H N O : C, 57.73; H, 3.31; N,
1
9
13 3 7
1
455, 1358, 1268, 1154, 1013, 949; H NMR (500 MHz, DMSO-d ) 10.63%. Found: C, 57.77; H, 3.28; N, 10.60%.
6
d 3.69 (s, 3H, NCH ), 5.04 (s, 1H, CH), 6.820 (d, J ¼ 7.0 Hz, 2H,
6l: 4-(3-Chlorophenyl)-2-(methylamino)-3-nitropyrano[3,2-c]
3
ArH), 7.24 (d, J ¼ 7.0 Hz, 2H, ArH), 7.48–7.52 (m, 3H, ArH), 7.73 chromen-5(4H)-one. Isolated as yellow solid; yield: 85%; mp:
ꢀ
ꢁ1
(
t, J ¼ 7.0 Hz, 1H, ArH), 8.01 (d, J ¼ 7.0 Hz, 1H, ArH), 10.36 (s, 270–272 C; IR (KBr, cm ): 3206, 2926, 2855, 1729, 1610, 1435,
1
3
1
1
1
1
6
H, NH); C NMR (125 MHz, DMSO-d
08.4, 113.1, 113.9, 114.9, 117.0, 123.2, 125.4, 129.9, 133.5, NCH
52.1, 152.4, 157.2, 158.7, 159.6; anal. calcd for C19
: C, 7.47–7.53 (m, 2H, ArH), 7.72–7.76 (m, 1H), 8.0 (dd, J ¼ 7.6,
6
) d 29.1, 36.7, 55.5, 107.3, 1015; H NMR (400 MHz, DMSO-d
6
), d 3.33 (d, J ¼ 4.8 Hz, 3H,
3
), 5.06 (s, 1H, CH), 7.25–7.34 (m, 3H, ArH), 7.41 (s, 1H),
14 2 5
H N O
1
3
5.14; H, 4.03; N, 8.00%. Found: C, 65.85; H, 4.07; N, 8.03%. EI- 1.2 Hz, 1H), 10.44 (d, J ¼ 4.8 Hz, 1H); C NMR (100 MHz,
+
HRMS: anal. calcd for [C H N O + H ]: cacld: 351.0936, DMSO-d ) d 28.7, 37.4, 105.7, 107.2, 112.5, 116.5, 122.9, 124.9,
1
9
14
2
5
6
found: 351.0979.
127.0, 127.3, 128.4, 129.8, 132.5, 133.2, 143.5, 152.0, 156.5,
2 5
6b: 4-(4-Chlorophenyl)-2-(methylamino)-3-nitropyrano[3,2-c] 159.1; anal. calcd for C19H13ClN O : C, 59.31; H, 3.41; N, 7.28%.
chromen-5(4H)-one. Isolated as white solid; yield: 92%; mp: Found: C, 59.27; H, 3.39; N, 7.35%.
ꢀ
ꢁ1
2
1
3
56–258 C; IR (KBr, cm ) 3188, 2978, 2834, 1731, 1242, 1125,
1
606, 1426; H NMR (400 MHz, DMSO-d
H, NCH
6
) d 3.32 (d, J ¼ 4.0 Hz,
Conflicts of interest
3
), 5.15 (s, 1H, CH), 7.45 (d, J ¼ 5.6 Hz, 1H, ArH), 7.50 (t,
J ¼ 5.2 Hz, 1H, ArH), 7.65 (d, J ¼ 6.0, 2H, ArH), 7.62–7.77 (m, 1H,
There are no conicts to declare.
ArH), 8.0 (d, J ¼ 5.2 Hz, ArH), 8.10 (d, J ¼ 6.0 Hz, 2H, ArH), 10.5
1
3
(
d, J ¼ 3.2 Hz, 1H, NH); C NMR (100 MHz, DMSO-d ) d 29.1,
6
3
1
C
8.1, 105.6, 107.4, 112.8, 117.0, 123.4, 123.5, 125.6, 127.1, 130.5, Acknowledgements
33.9, 146.9, 149.1, 152.5, 152.7, 157.0, 159.7. Anal. calcd for
S. Shareef and Saigal are grateful to CSIR, New Delhi for their
research fellowship. The authors would like to thanks SAIF-PU,
Panjab University, Chandigarh and SAIF, IIT Roorkee, IIT Ropar
for providing the spectral data such as H and C NMR, HRMS,
elemental analysis and SC Sahoo thanks DST-FIST for the single
crystal XRD facility at Panjab University Chandigarh. We are
also obliged to the Chairman, Department of Chemistry, AMU,
Aligarh for providing general facility to execute this task.
19 2 5
H13ClN O : C, 59.31; H, 3.41; N, 7.28%. Found: C, 59.35; H,
3
.43; N, 7.31%.
d: 4-(4-Fluorophenyl)-2-(methylamino)-3-nitropyrano[3,2-c]
chromen-5(4H)-one. Isolated as yellow solid; yield: 86%; mp:
6
1
13
ꢀ
ꢁ1
2
1
62–264 C; IR (KBr, cm ): 3421, 3066, 2942, 1722, 1672, 1505,
1
384, 1271, 1158, 1069, 908; H NMR (400 MHz, DMSO-d6)
d 3.33 (d, J ¼ 5.04 Hz, 3H, NCH
3
), 5.07 (s, 1H, CH), 7.08 (t, J ¼
.8 Hz, 2H, ArH), 7.38 (dd, J ¼ 5.3 Hz, 2H, ArH), 7.51 (q, J ¼
.6 Hz, 2H, ArH), 7.74 (m, 1H, ArH), 8.0 (dd, J ¼ 8.0, 1.6 Hz, 1H,
8
7
1
3
ArH), 10.4 (d, J ¼ 4.72, 1H, NH); C NMR (100 MHz, DMSO-d
6
)
Notes and references
d 28.6, 36.8, 106.3, 107.6, 112.5, 114.6, 114.8, 116.5, 122.8, 125.0,
1
1
30.4, 130.5, 133.1, 137.3, 151.8, 151.9, 156.6, 159.1, 159.9,
62.3; anal. calcd for C H FN O : C, 61.96; H, 3.56; N, 7.61%.
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9
13
2 5
Found: C, 61.91; H, 3.51; N, 7.60%.
h: 4-(4-Ethylphenyl)-2-(methylamino)-3-nitropyrano[3,2-c]
chromen-5(4H)-one. Isolated as yellow solid; yield: 83%; mp:
2
1
6
ꢀ
ꢁ1
56–258 C; IR (KBr, cm ): 3213, 3022, 2961, 2932, 2871, 1734,
1
674, 1630, 1460, 1569, 1360, 1268, 1106, 948, 839; H NMR (400
MHz, DMSO-d
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) d 1.12 (t, J ¼ 7.7 Hz, 3H), 2.53 (t, J ¼ 7.6 Hz, 2H),
26400 | RSC Adv., 2019, 9, 26393–26401
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