An efficient five-component synthesis of thioether containing dihydropyrano[2,3-c]pyrazoles: a green domino strategy

Article abstract of DOI:10.1039/C6NJ02313D

An efficient route for the synthesis of novel thioether containing dihydropyrano[2,3-c]pyrazoles has been accomplished via a solvent-free, catalyst-free, one-pot, five component domino strategy. This synthetic approach offers several advantages such as an easy work-up, no need for purification techniques and a short reaction time with good atom economy and high yields of the products (81-86%).

Full text of DOI:10.1039/C6NJ02313D

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An efficient five-component synthesis of thio ether containing
dihydropyrano[2,3-c]pyrazoles : A green domino strategy†
Vediyappan Ramesha,b, Sivakumar Shanmugamb, Natarajan Savitha Devi,a,*
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient route to the synthesis of novel thio ether containing dihydropyrano[2,3-c]pyrazoles have been accomplished
via a solvent-free, catalyst-free via one-pot, five component domino strategy. This synthetic approach offers several
advantages such as easy work-up, no need of purification techniques, short reaction time with good atom economy and
high yields of products (81-86%).
DOI: 10.1039/x0xx00000x
www.rsc.org/
methodology for the synthesis of heterocycles,18 here in, we
present an efficient five component synthesis of thio ether
Introduction
Multi component reactions (MCRs) are powerful tools to
synthesis of libraries of complex molecules especially in
modern organic synthesis and drug discovery in medicinal
chemistry.1 The main advantages of MCRs compared with
traditional multistep procedures are high efficiency, mild
reaction conditions, experimental simplicity, low cost,
avoidance of large quantities of waste, ready availability of
reagents/starting materials and the ability to generate a
significant variety of products.2 Dihydropyrano[2,3-c]pyrazole
derivatives in organic synthesis as essential intermediates3
and have vital role in medicinal chemistry as it has broad
spectrum of biological activities such as antimicrobial,4
antiinflammatory,5 anticancer,6,7 and analgesic.8 Some of its
derivatives acted against vasodilator and hypotensive,9
containing dihydropyrano[2,3-c]pyrazoles under solvent free
condition.
hypoglycemic,5a
insecticidal.5a,10
Biologically
active
dihydropyrano[2,3-c]-pyrazoles are represented in fig 1.
Compound A is having molluscicidal11,12 activitity. Compound B
is a potential inhibitor of human Chk1 kinase.13 Compound C &
D exhibit fungicidal activity14 and antibacterial activity13a,15
respectively. In 2002, Shestopalov et al., 16 reported the two or
three component synthesis of some sulfur containing
dihydropyrano[2,3-c]pyrazoles. Since sulfur containing
scaffold17 is expected to have an excellent biological activity,
Figure 1. Biologically active dihydropyrano[2,3-c]-pyrazoles
thio
ether
containing
dihydropyrano[2,3-c]pyrazoles
(TEDHPPs) is also expected to have a better activity than the
simple dihydropyrano[2,3-c]pyrazoles. Solvent and catalyst
free methods are more desirable for making such biologically
important scaffolds as they offer a greener synthetic protocol.
In continuation of our efforts in the useful synthetic
Scheme 1. Synthesis of functionalized pyrano[2,3-c]pyrazoles via a five-component
reaction
a.Department of Chemistry, Arul Anandar College (Autonomous), Madurai –
625 514, India. E-mail: savitha.devi@gmail.com
b.Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai - 625 021, India. E-mail: shivazzen@gmail.com
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, characterization data and copies of 1H, 13C NMR & Mass spectra of
all the synthesized compounds.
To the best of our knowledge through careful literature
survey, this is the first report for the synthesis of thio ether
containing dihydropyrano[2,3-c]pyrazoles using
a
five
component domino strategy. The advantages of this reaction is
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IPA, ACN, water, toluene, xylene, CHCl3, THF and DCE under
refluxing conditions was unsuccessful (Table 1, Entry 4-12). On
the other hand, the reaction performance was drastically
enhanced under solvent-free conditions at 80°C. (Table 1,
entry 13).
solvent and catalyst free methodology in a short reaction time
with no column purification in excellent yields.
Results and discussion
Figure 2. Isolated impurities A1 and B from the reaction mixture
When the temperature was raised to 120°C (Table 1, Entry 14),
the results are in agreement with the expectation. Increasing
the reaction time and temperature did not have any impact on
the product yield (Table 1, Entry 15 & Entry 16).
Scheme 2. Synthesis of functionalized pyrano[2,3-c]pyrazoles via
component reaction
a four-
Table 1 Optimization of the five component reaction conditionsa
In our initial study, we started with a four component reaction
of ethyl 4-((4-chlorophenyl)thio)-3-oxobutanoate phenyl
hydrazine , 4-cyanobenzaldehyde 4e and malononitrile
taken as a model reaction for the synthesis of 6-amino-3-
methyl-4-phenyl1,4-dihydropyrano [2,3-c]pyrazole-5-
I,
3
5
carbonitrile 6n. When the reaction was carried out in ethanol
at reflux temperature, 6n was obtained in 86% yield (Table 1,
1
Entry 1) in 180 minutes. The H NMR spectrum of 6n in which
the methylene protons appears as two doublets clearly shows
the presence of chiral centre in the pyrano-pyrazole system.
The presence of methylene group was confirmed with DEPT-
135 and the remaining pyrano-pyrazole part was confirmed
with the 1H and 13C NMR of the plenty of reported pyrano-
pyrazole19 systems. From the ESI-MS m/z analysis the mass for
the compound 6n was found to be 494. Encouraged by this
initial success, in our own concern, we have attempted a five
Entry
Base
Solvent Temperature
(°C)
Time (min)
Yieldb
Ig
IIh
6n
of 6n
1c
2d
TEA
TEA
--
EtOH
EtOH
EtOH
MeOH
IPA
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
80
--
120 180
86
30f
60
62
56
57
60
40
45
40
43
48
70
83
84
83
--
--
240
20
20
20
15
20
10
10
10
10
10
10
5
3e
120
90
300
240
420
360
300
240
200
360
300
320
10
4e
--
component reaction of ethyl 4-chloro-3-oxobutanoate
benzenethiol 2a, phenyl hydrazine , 4-cyanobenzaldehyde 4e
and malononitrile in the presence of a base TEA. After the
1,
5e
--
140
140
90
3
,
6e
--
ACN
H2O
5
7e
--
8e
--
Toluene
Xylene
CHCl3
THF
240
240
240
180
260
60
completion of the reaction we have isolated two impurities
namely, diethyl 2,5-dioxocyclohexane-1,4-dicarboxylate20 A1
and hydrazone21 B impurity at this stage which suppressed the
9e
--
10e
11e
12e
13e
14e
15e
16e
--
--
product formation, furnishing low yield (Table 1, Entry 2). The
1
(Fig. 2) were confirmed by H, 13C, DEPT-135
--
DCE
--
impurity A1
&
B
--
and HRMS spectroscopic techniques (see ESI†). Impurity A1 is
--
--
120
10
5
obtained due to the self-condensation of ethyl 4-chloro-3-
--
--
120
30
30
30
5
oxobutanoate
due to the condensation of aldehyde 4e and phenyl hydrazine
. It was found that in the absence of TEA, the formation of A1
was drastically decreased. In order to decrease the formation
of the hydrazone impurity, the reaction was carried out
through sequential addition of and at reflux temperature
followed by then reflux, subsequent addition of and
1 in the presence of base. Impurity B is formed
--
--
150
5
5
aReaction conditions: conventional heating under solvent free condition at 120°C with 1
b
(1.0 equiv.), 2b (1.1 equiv.), 3 (1.1 equiv.), 4e (1.1 equiv.), 5 (1.1 equiv.) for 20 min;
3
Isolated yield; c four component reaction of I, 3, followed by 4e and 5; d five component
one pot reaction; e1 and 2b was heated and maintained appropriate temperature
followed by addition of 3 and maintained same fixed temperature consequent addition
B
of 4e,
5
and maintained same temperature; fpurified by column; gethyl 4-((4-
1
2
chlorophenyl)thio)-3-oxobutanoate (I); h5-(((4-chlorophenyl)thio)methyl)-2-phenyl-2,4-
3
4
3
dihydro-3H-pyrazol-3-one (II);
without base. The product was obtained in good yield (60 %)
(Table 1, Entry 3). An effort of gaining the yield by varying the
solvents ranging from polar ones to non-polar, such as MeOH,
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Table 2 Synthesis of dihydropyrano[2,3-c]pyrazoles 6a-ad
NR – No Reaction
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Thus the optimized condition for this reaction was found to be The formation of the pyrano[2,3-c]pyrazole derivative, namely,
heating the reactants at 120°C under without solvent. (Table 1, 6-amino-1,4-diphenyl-3-((phenylthio)methyl)-1,4
Entry 14).
To explore the scope and generality of this domino MCR, we simultaneous formation of three intermediates, 3-oxo-4-
extended the same to construct a library of thio ether (arylthio)butanoate via SN2 reaction, pyrazolone II via cyclo
containing pyrano[2,3-c]pyrazole derivatives 6a-z under the condensation and arylidenemalononitrile III by Knoevenagel
optimized reaction conditions and it was successful with condensation reaction. Intermediate formation the liberated
dihydropyrano[2,3-c]pyrazole-5-carbonitrile, proceeds via the
I
I
various aromatic aldehydes and thiophenol (Table 2). A variety hydrochloride, followed by cyclo condensation with
of aryl aldehydes (e.g. –NO2, –CN, –F, –Cl, –Br, –OMe, –OEt, – phenylhydrazine to produced intermediate II. After which the
Me) and thiophenols (e.g. –H, –Cl, –Br, –Me) containing intermediate II undergoes Michael addition with III followed
different substituents both electron withdrawing and electron by enolization afforded intermediate
donating afforded in good to excellent yields. The electronic undergoes intramolecular electrophilic O-cyclization via
effects of the substituent were not observed much in the Thorpe-Ziegler reaction to form VI Finally, after the
yields of the products. Furthermore, all the compounds were tautomeric proton shift and affording the desired product thio
V. Intermediate V then
6
.
1
characterized by H & 13C NMR and ESI-MS spectral analysis. ether containing pyrano[2,3-c]pyrazole derivative
One of the synthesized compound 6q structure was confirmed
further using 1D, 2D and ESI-Mass spectral techniques (see
ESI†). However, no desired products 6aa-ad was obtained
from the aliphatic aldehydes such as acetaldehyde and
isobutyraldehyde and heterocyclic aldehydes such as pyridine-
2-carbaldehyde and pyrrole-2-carbaldehyde.
6 is formed.
Figure 3. Reaction was done at 1 g scale level; (a) ethyl 4-chloro-3-oxobutanoate (1)
and 4-chlorobenzenethiol (2b) at room temperature; (b) after 10 minutes heat at 120
°C; (c) after phenylhydrazine (3) addition maintained 5 minutes at 120 °C; (d) after 4-
cyanobenzaldehyde (4e) , malononitrile (5) was added and heated to 120 °C for 5
minutes; (e) after ethanol addition
Figure 4. UV-vis spectra of intermediates (I, II and III) were compared with
isolated from reaction and synthesized under optimized condition
The plausible mechanism for the formation of 6-amino-4-(4-
aryl)-1-phenyl-3-((phenylthio) methyl)-1,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile 6 is described (Scheme 3).
Figure 5. UV-vis spectra of intermediates I, II and III.
To establish the proposed mechanism, we have performed the
Scheme 3. Plausible reaction mechanism for the functionalized pyrano[2,3-
c]pyrazoles
6
synthesis of pyrano[2,3-c]pyrazole step by step under
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optimized reaction condition. We have synthesized three General procedure for the synthesis of 6-amino-1,4-diphenyl-
intermediates I, II and III separately from the respective 3-((phenylthio)methyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-
starting materials under optimized condition. Also all three carbonitrile (6)
intermediates were isolated and purified by column
chromatography.
A
mixture of commercially available ethyl 4-chloro-3-
oxobutanoate 1 (1.0 equiv.), substituted benzenethiol 2 (1.1
Finally, intermediates
condition affording pyrano[2,3-c]pyrazole derivative. The condition. TLC was checked followed by addition of
intermediates were confirmed by melting point determination phenylhydrazine (1.1 equiv.) at 120°C and maintained same
and UV-vis spectroscopic studies. The melting point values are temperature for minutes. After monitored by TLC,
in agreement with synthesized compounds. The formation of subsequent addition of aldehyde (1.1 equiv.) and
(1.1 equiv.) were done under solvent free
condition. The completion of the reaction was monitored by
I, II and III were mixed under optimized equiv.), was heated to 120°C for 10 minutes under solvent free
3
5
4
1
these intermediates were further confirmed by H, 13C, DEPT- malononitrile
5
135 and HRMS spectroscopic techniques (see ESI†).
The UV- Vis spectroscopy of all thee (I, II and III) synthesized TLC. The reaction mixture was cooled to room temperature
intermediate and isolated from reaction mixture were in followed by addition of ethanol (5 mL). The product appeared
perfect alignment with (Fig. 4) respective intermediate. The as a solid, by trituration with ethanol, was filtered and washed
UV-vis spectra of the three different intermediates are shown with another 2 mL of EtOH to remove the other impurities.
in Fig. 5. The observed λmax value ethyl 4-((4- Finally, the product
chlorophenyl)thio)-3-oxobutanoate ( ) of 256 nm, pyrazolone was pure enough for the spectral investigations.
II) of 253 and 2-(4-cyanobenzylidene)malononitrile (III) of 253 6-amino-4-(2-ethoxyphenyl)-1-phenyl-3-
6 was dried under reduced pressure and
I
(
was observed.
((phenylthio)methyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (6a). Isolated as white solid; Rf = 0.41 (3:7
o
1
EtOAc/pet-ether); mp 180–182 C; H NMR (300 MHz, DMSO-
d6) δ: 7.72 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 15.6 Hz, 2H), 7.34 –
7.12 (m, 10H), 6.94 – 6.84 (m, 2H), 4.87 (s, 1H), 3.91 – 3.84 (m,
3H), 3.47 (d, J = 13.8 Hz, 1H), 1.14 (t, J = 13.5 Hz, 3H); 13C NMR
(75 MHz, DMSO-d6) δ: 160.4, 157.0, 145.1, 145.0, 137.9, 136.2,
130.9, 129.8, 129.3, 129.3, 129.1, 126.9, 126.6, 120.8, 120.6,
112.9, 99.2, 63.8, 57.9, 33.0, 30.1, 14.9; ESI Calcd m/z 480,
Found 479 [(M-1)]+; Anal. Calcd for: C28H24N4O2S: C, 69.98; H,
5.03; N, 11.66; O, 6.66%; Found C, 69.95; H, 5.06; N, 11.69%; *
One of the –SCH2 proton was merged with –CH2 as –OEt peak.
6-amino-4-(4-chlorophenyl)-1-phenyl-3-((phenylthio)methyl)-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6b). Isolated
as white solid; Rf = 0.42 (3:7 EtOAc/pet-ether); mp 200–202 °C;
1H NMR (300 MHz, DMSO-d6) δ: 7.73 (d, J = 7.5 Hz, 2H), 7.49 (t,
J = 15.9 Hz, 2H), 7.38 – 7.34 (m, 3H), 7.29 – 7.16 (m, 9H), 4.68
(s, 1H), 3.91 (d, J = 13.8 Hz, 1H), 3.42 (d, J = 14.1 Hz, 1H); 13C
NMR (75 MHz, DMSO-d6) δ: 160.2, 145.7, 145.0, 143.1, 138.1,
136.3, 132.7, 130.6, 130.2, 129.8, 129.4, 127.5, 127.1, 121.2,
120.6, 99.0, 58.6, 37.2, 30.7; Anal. Calcd for: C26H19ClN4OS: C,
66.31; H, 4.07; N, 11.90%; Found C, 66.34; H, 4.04; N, 11.93%.
6-amino-4-(4-methoxyphenyl)-1-phenyl-3-
Conclusions
In conclusion, we have developed a simple and efficient five
component domino synthesis of thio ether containing
dihydropyrano[2,3-c]pyrazoles
6 under solvent free, catalyst
free condition using commercially available starting materials
in a short reaction time. The significant features of this
methodology are short reaction time, an excellent yield with
good atom economy (80.56%), no column purification, low-
cost, operational simplicity, vast structural diversity and
minimal environmental waste. The biological studies for the
library of compounds synthesized are underway.
Experimental Section
General remarks
The melting points were measured in open capillary tubes and
are uncorrected. The reaction was monitored by TLC on Merck
GF 254 with detection by UV light for visualization using a
mixture of petroleum ether (60-80 ˚C) and ethyl acetate (7:3)
as the eluent. Nuclear Magnetic Resonance (1H and 13C NMR)
spectra were recorded on a Bruker (Advance) 300 MHz
spectrometer in DMSO-d6 using TMS as an internal standard.
((phenylthio)methyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (6c). Isolated as white solid; Rf = 0.37 (3:7
EtOAc/pet-ether); mp 196–198 oC; 1H NMR (300 MHz, DMSO-
d6) δ: 7.73 (d, J = 8.1 Hz, 2H), 7.49 (t, J = 15.3 Hz, 2H), 7.36 –
7.13 (m, 12H), 6.86 (d, J = 8.4 Hz, 2H), 4.60 (s, 1H), 3.90 (d, J =
14.1 Hz, 1H), 3.72 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ:
160.0, 159.2, 145.8, 144.9, 138.1, 136.3, 136.0, 130.2, 129.8,
127.5, 127.1, 121.2, 120.7, 114.8, 99.7, 59.4, 55.9, 37.0, 30.7;
ESI Calcd m/z 466, found 465 [(M-1)]+; Anal. Calcd for:
C27H22N4O2S: C, 69.51; H, 4.75; N, 12.01%; Found C, 69.54; H,
4.73; N, 12.04%; * One of the –SCH2 proton was merged with
water peak.
Chemical shifts are reported in parts per million (
constants (J values) are reported in Hertz (Hz) and spin
multiplicities are indicated by the following symbols:
δ), coupling
s
(singlet), d (doublet), t (triplet), (multiplet). 13C NMR spectra
were routinely run with broadband decoupling. Absorption
spectra studies of all samples were recorded on Agilent
Technologies 8453 spectrophotometer by taking the solution
in a 1 cm path length quartz cell in the wavelength range of
200-1100 nm. Elemental analyses were carried out with
Perkin-Elmer 2400 series II analyzer. Electrospray ionization
mass spectrometry (ESI-MS) was recorded in LCQ Fleet,
Thermo Fisher Instruments Limited, US and High resolution
mass spectra were recorded on a Water Q-TOF micro mass
spectrometer using ESI mode.
6-amino-1-phenyl-3-((phenylthio)methyl)-4-(p-tolyl)-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6d). Isolated as
white solid; Rf = 0.46 (3:7 EtOAc/pet-ether); mp 178–180 oC;
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1H NMR (300 MHz, DMSO-d6) δ: 7.73 (d, J = 8.1 Hz, 2H), 7.49 (t, 6-amino-4-(2,4-dichlorophenyl)-1-phenyl-3-
J = 15.0 Hz, 2H), 7.36 – 7.21 (m, 10H), 7.11 (s, 2H), 4.60 (s, 1H), ((phenylthio)methyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-
3.90 (d, J = 13.8 Hz, 1H), 2.27 (s, 3H); 13C NMR (75 MHz, DMSO- carbonitrile (6i). Isolated as white solid; Rf = 0.40 (3:7
1
d6) δ: 160.0, 145.7, 144.9, 141.0, 138.1, 137.2, 136.3, 130.2, EtOAc/pet-ether); mp 204–206 °C; H NMR (300 MHz, DMSO-
130.0, 129.8, 128.6, 127.4, 127.1, 121.2, 120.7, 99.6, 59.2, d6) δ: 7.72 (d, J = 8.0 Hz, 2H), 7.51 (m, 4H), 7.36 (s, 4H), 7.28 –
37.4, 30.7, 21.6; ESI Calcd m/z 450, found 451 [(M+1)]+; Anal. 7.16 (m, 5H), 5.20 (s, 1H), 3.90 (d, J = 13.8 Hz, 1H); 13C NMR (75
Calcd for: C27H22N4OS: C, 71.98; H, 4.92; N, 12.44%; Found: C, MHz, DMSO-d6) δ: 164.7, 149.5, 149.4, 143.9, 142.1, 140.3,
71.95; H, 4.95; N, 12.47%; * One of the –SCH2 proton was 138.3, 137.5, 137.4, 134.3, 133.7, 133.6, 132.9, 131.7, 131.4,
merged with water peak.
125.3, 124.3, 102.1, 61.2, 38.7, 34.7; Anal. Calcd for:
C26H18Cl2N4OS: C, 61.79; H, 3.59; N, 11.09%; Found C, 61.82; H,
6-amino-4-(4-cyanophenyl)-1-phenyl-3-((phenylthio)methyl)-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6e). Isolated 3.62; N, 11.13%; * One of the –SCH2 proton was merged with
as white solid; Rf = 0.30 (3:7 EtOAc/pet-ether); mp 194–196 oC; water peak.
1H NMR (300 MHz, DMSO-d6) δ: 7.79 – 7.72 (m, 4H), 7.52 – 6-amino-1-phenyl-3-((phenylthio)methyl)-4-(o-tolyl)-1,4-
7.45 (m, 4H), 7.40 – 7.18 (m, 8H), 4.80 (s, 1H), 3.91 (d, J = 13.8 dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6j). Isolated as
Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 160.4, 149.6, 145.6, white solid; Rf = 0.40 (3:7 EtOAc/pet-ether); mp 170–172 oC; 1H
145.2, 138.0, 136.2, 133.5, 130.2, 129.9, 129.8, 127.6, 127.1, NMR (300 MHz, DMSO-d6) δ: 7.76 (d, J = 7.5 Hz, 2H), 7.55 –
121.3, 120.5, 119.6, 110.9, 98.5, 58.0, 37.8, 30.7; ESI Calcd m/z 7.47 (m, 2H), 7.39 – 7.10 (m, 12H), 5.02 (s, 1H), 3.90 (d, J = 13.5
461, found 460 [(M-1)]+; Anal. Calcd for: C27H19N5OS: C, 70.26; Hz, 1H), 2.37 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ: 159.3,
H, 4.15; N, 15.17%; Found C, 70.28; H, 4.19; N, 15.20%; * One 144.8, 140.9, 137.4, 135.5, 129.5, 123.0, 128.8, 127.2, 126.9,
of the –SCH2 proton was merged with water peak.
6-amino-4-(4-ethoxyphenyl)-1-phenyl-3-
126.8, 126.3, 120.5, 120.0, 98.7, 58.0, 33.4, 30.0, 19.1; Anal.
Calcd for: C27H22N4OS: C, 71.98; H, 4.92; N, 12.44%; Found C,
71.96; H, 4.95; N, 12.47%; * One of the –SCH2 proton was
((phenylthio)methyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (6f). Isolated as white solid; Rf = 0.44 (3:7 merged with water peak.
o
EtOAc/pet-ether); mp 188–190 C; 1H NMR (300 MHz, DMSO- 6-amino-4-(4-nitrophenyl)-1-phenyl-3-((phenylthio)methyl)-
d6) δ: 7.72 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 15.3 Hz, 2H), 7.36 – 1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6k). Isolated
7.11 (m, 10H), 6.84 (d, J = 8.1 Hz, 2H), 4.58 (s, 1H), 3.98 – 3.87 as white solid; Rf = 0.32 (3:7 EtOAc/pet-ether); mp 208–210 oC;
(m, 3H), 1.29 (t, J = 13.8 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) 1H NMR (300 MHz, DMSO-d6) δ: 8.16 (d, J = 8.4 Hz, 2H), 7.74
δ: 160.0, 158.5, 145.8, 144.9, 138.1, 136.3, 135.9, 130.3, 129.8, (d, J = 8.4 Hz, 2H), 7.56 – 7.48 (m, 5H), 7.41 – 7.34 (m, 2H), 7.28
127.5, 127.1, 121.2, 115.2, 99.7, 39.5, 37.0, 30.7, 15.5; Anal. – 7.16 (m, 5H), 4.88 (s, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.50 (d, J =
Calcd for: C28H24N4O2S: C, 69.98; H, 5.03; N, 11.66%; Found C, 13.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 159.7, 151.0,
69.95; H, 5.06; N, 11.69%; * One of the ethyl –SCH2 proton was 146.9, 145.0, 144.5, 137.4, 135.6, 129.5, 129.1, 126.9, 129.1,
merged with ethyl –CH2 and another one –SCH2 proton was 124.0, 120.7, 119.7, 97.7, 57.4, 36.9, 30.1; Anal. Calcd for:
merged with water peak.
C26H19N5O3S: C, 64.85; H, 3.98; N, 14.54%; Found C, 64.88; H,
3.96; N, 14.57%.
6-amino-4-(3-nitrophenyl)-1-phenyl-3-((phenylthio)methyl)-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6g). Isolated 6-amino-4-(4-fluorophenyl)-1-phenyl-3-((phenylthio)methyl)-
as white solid; Rf = 0.32 (3:7 EtOAc/pet-ether); mp 192–194 oC; 1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6l). Isolated
1H NMR (300 MHz, DMSO-d6) δ: 8.12 (d, J = 9.6 Hz, 2H), 7.72 as white solid; Rf = 0.43 (3:7 EtOAc/pet-ether); mp 180–182 oC;
(d, J = 9.3 Hz, 3H), 7.56 (t, J = 15.6 Hz, 1H), 7.50 (t, J = 15.3 Hz, 1H NMR (300 MHz, DMSO-d6) δ: 7.73 (d, J = 7.8 Hz, 2H), 7.50 (t,
2H), 7.40 – 7.32 (m, 3H), 7.26 – 7.15 (m, 5H), 4.93 (s, 1H), 3.92 J = 15.9 Hz, 2H), 7.37 – 7.24 (m, 10H), 7.21 – 7.10 (m, 3H), 4.69
(d, J = 13.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 160.4, (s, 1H), 3.91 (d, J = 13.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
148.8, 146.4, 145.6, 145.2, 138.0, 136.2, 135.8, 131.1, 130.2, δ: 159.4, 145.0, 144.3, 139.6, 137.4, 135.6, 130.0, 129.9, 129.5,
129.7, 127.6, 127.0, 123.3, 121.3, 120.5, 98.5, 58.1, 37.4, 30.7; 129.1, 126.8, 126.4, 120.5, 119.9, 115.6, 15.3, 98.6, 58.2, 36.4,
Anal. Calcd for: C26H19N5O3S: C, 64.85; H, 3.98; N, 14.54%; 30.0; ESI Calcd m/z 454, Found 453 [(M-1)]+; Anal. Calcd for:
Found C, 64.89; H, 4.01; N, 14.56%; * One of the –SCH2 proton C26H19FN4OS: C, 68.71; H, 4.21; N, 12.33%; Found C, 68.75; H,
was merged with water peak.
4.24; N, 12.36%;* One of the –SCH2 proton was merged with
6-amino-4-(3-chlorophenyl)-1-phenyl-3-((phenylthio)methyl)- water peak.
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6h). Isolated 6-amino-4-(4-bromophenyl)-1-phenyl-3-((phenylthio)methyl)-
as white solid; Rf = 0.37 (3:7 EtOAc/pet-ether); mp 178–180 oC; 1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
(6m).
1H NMR (300 MHz, DMSO-d6) δ: 7.72 (d, J = 7.8 Hz, 2H), 7.50 (t, Isolated as white solid; Rf = 0.43 (3:7 EtOAc/pet-ether); mp
J = 7.7 Hz, 2H), 7.43 – 7.40 (m, 1H), 7.37 – 7.16 (m, 11H), 5.19 196–198 oC; 1H NMR (300 MHz, DMSO-d6) δ: 7.73 (d, J = 8.1 Hz,
(s, 1H), 3.90 (d, J = 13.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) 2H), 7.49 (t, J = 13.5 Hz, 3H), 7.37 – 7.20 (m, 10H), 4.67 (s, 1H),
δ: 164.6, 149.5, 144.6, 142.1, 140.3, 137.4, 136.0, 134.7, 134.3, 3.91 (d, J = 13.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 159.5,
133.9, 133.8, 132.7, 131.6, 131.1, 125.3, 124.4, 102.5, 61.6, 145.0, 144.3, 142.8, 137.4, 135.6, 131.7, 130.3, 129.5, 129.1,
39.1, 34.7; ESI Calcd m/z 470, Found 471 [(M+1)]+; Anal. Calcd 126.8, 126.4, 120.6, 119.9, 98.3, 57.9, 36.6, 30.1; Anal. Calcd
for: C26H19ClN4OS: C, 66.31; H, 4.07; Cl, 7.53; N, 11.90%; Found for: C26H19BrN4OS: C, 60.59; H, 3.72; N, 10.87%; Found C,
C, 66.35; H, 4.10; N, 11.89%; * One of the –SCH2 proton was 60.62; H, 3.75; N, 10.85%; * One of the –SCH2 proton was
merged with water peak.
merged with water peak.
6 | J. Name., 2012, 00, 1-3
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Journal Name
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DOI: 10.1039/C6NJ02313D
ARTICLE
6-amino-3-(((4-chlorophenyl)thio)methyl)-4-(4-cyanophenyl)- (d, J = 14.4 Hz, 1H); 13C NMR (75 MHz, DMSO- d6) δ: 160.2,
1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 145.4, 145.1, 143.5, 132.4, 131.8, 131.4, 131.0, 130.2, 129.7,
(6n). Isolated as white solid; Rf = 0.31 (3:7 EtOAc/pet-ether); 127.6, 121.3, 120.6, 99.0, 58.6, 37.3, 30.7; ESI Calcd m/z 548,
o
mp 200–202 C; 1H NMR (300 MHz, DMSO-d6) δ: 7.79 (d, J = found 549 [(M+1)]+; Anal. Calcd for: C26H18BrClN4OS: C, 56.79;
7.8 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 – 7.47 (m, 4H), 7.38 – H, 3.30; N, 10.19%; Found C, 56.82; H, 3.34; N, 10.21%.
7.32 (m, 5H), 7.25 (d, J = 8.1 Hz, 2H), 4.85 (s, 1H), 3.92 (d, J = 6-amino-3-(((2-bromophenyl)thio)methyl)-4-(2-
14.1 Hz, 1H), 3.51 (d, J = 14.1 Hz, 1H); 13C NMR (75 MHz, ethoxyphenyl)-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
DMSO-d6) δ: 159.6, 149.0, 144.5, 137.3, 134.6, 132.8, 131.1, carbonitrile (6s). Isolated as white solid; Rf = 0.38 (3:7
1
130.6, 129.5, 129.2, 128.9, 126.9, 120.7, 119.8, 118.9, 110.2, EtOAc/pet-ether); mp 184–186 °C; H NMR (300 MHz, DMSO-
97.7, 57.3, 37.0, 29.9; ESI Calcd m/z 495, Found 494 [(M-1)]+; d6) δ: 7.75 (d, J = 7.2 Hz, 2H), 7.59 – 7.48 (m, 4H), 7.35 – 7.08
Anal. Calcd for: C27H18ClN5OS: C, 65.38; H, 3.66; N, 14.12%; (m, 8H), 6.94 – 6.84 (m 2H), 4.94 (s, 1H), 3.96 – 3.86 (m, 3H),
Found C, 65.41; H, 3.69; N, 14.15%.
6-amino-3-(((4-chlorophenyl)thio)methyl)-4-(4-fluorophenyl)- 157.3, 145.4, 144.6, 138.2, 133.4, 131.1, 130.2, 130.3, 130.2,
1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 129.5, 129.5, 128.9, 128.6, 127.7, 127.4, 122.6, 121.3, 121.0,
1.15 (t, J = 6.3 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ: 160.9,
(6o). Isolated as white solid; Rf = 0.40 (3:7 EtOAc/pet-ether); 113.2, 99.7, 64.1, 58.0, 29.5, 15.3; Anal. Calcd for:
°
mp 182–184 C; 1H NMR (300 MHz, DMSO-d6) δ: 7.72 (d, J = C28H23BrN4O2S: C, 60.11; H, 4.14; Br, N, 10.01%; Found C,
8.1 Hz, 2H), 7.50 (t, J = 7.8 Hz, 2H), 7.37 – 7.25 (m, 10H), 7.14 60.14; H, 4.18; Br, N, 10.03%; * One of the ethyl –SCH2 proton
(t, J = 8.7 Hz, 2H), 4.73 (s, 1H), 3.92 (d, J = 14.1 Hz, 1H); 13C was merged with ethyl-CH2 and another one –SCH2 proton was
NMR (75 MHz, DMSO-d6) δ: 159.4, 144.7, 144.3, 139.6, 137.4, merged with water peak.
134.7, 131.1, 130.6, 130.0, 129.9, 129.5, 128.9, 126.8, 120.6, 6-amino-3-(((2-bromophenyl)thio)methyl)-4-(4-nitrophenyl)-
119.9, 115.6, 115.4, 98.6, 58.2, 36.3, 30.0; Anal. Calcd for: 1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
C26H18ClFN4OS: C, 63.87; H, 3.71; N, 11.46%; Found C, 63.89; H, (6t). Isolated as white solid; Rf = 0.30 (3:7 EtOAc/pet-ether);
1
3.74; N, 11.44%; * One of the –SCH2 proton was merged with mp 192–194 °C; H NMR (300 MHz, DMSO-d6) δ: 8.11 (d, J =
water peak.
8.4 Hz, 2H), 7.78 (d, J = 7.7 Hz, 2H), 7.52 – 7.33 (m, 10H), 7.06
(t, J = 6.0 Hz, 1H), 4.93 (s, 1H), 3.96 (d, J = 13.8 Hz, 1H), 3.70 (d,
J = 13.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 160.4, 151.7,
6-amino-3-(((4-chlorophenyl)thio)methyl)-4-(4-
ethoxyphenyl)-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (6p). Isolated as white solid; Rf = 0.43 (3:7 147.6, 145.3, 144.9, 138.0, 197.8, 133.4, 130.2, 130.1, 128.9,
1
EtOAc/pet-ether); mp 184–186 °C; H NMR (300 MHz, DMSO- 127.8, 127.7, 124.7, 122.7, 121.4, 120.3, 98.6, 58.0, 37.6, 29.7;
d6) δ: 7.72 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.5 Hz, 2H), 7.34 – ESI Calcd m/z 559, found 558 [(M-1)]+; Anal. Calcd for:
7.20 (m, 9H), 7.13 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), C26H18BrN5O3S: C, 55.72; H, 3.24; N, 12.50%; Found C, 55.75; H,
4.62 (s, 1H), 4.01 – 3.88 (m, 3H), 1.30 (t, J = 6.9 Hz, 3H); 13C 3.21; N, 12.54%.
NMR (75 MHz, DMSO-d6) δ: 160.0, 158.5, 145.5, 144.9, 138.1, 6-amino-3-(((2-bromophenyl)thio)methyl)-4-(4-fluorophenyl)-
135.8, 135.5, 131.7, 131.3, 130.2, 129.7, 127.5, 121.2, 120.7, 1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
115.2, 99.7, 63.8, 59.4, 37.0, 30.7, 15.5; Anal. Calcd for: (6u). Isolated as white solid; Rf = 0.43 (3:7 EtOAc/pet-ether);
1
C28H23ClN4O2S: C, 65.30; H, 4.50; N, 10.88%; Found C, 65.32; H, mp 180–182 °C; H NMR (300 MHz, DMSO-d6) δ: 7.74 (d, J =
4.54; N, 10.86%; * One of the ethyl –SCH2 proton was merged 7.8 Hz, 2H), 7.59 – 7.48 (m, 4H), 7.35 – 7.28 (m, 6H), 7.14 –
with ethyl-CH2 and another one –SCH2 proton was merged 7.06 (m, 3H), 4.73 (s, 1H), 3.95 (d, J = 13.8 Hz, 1H); 13C NMR (75
with water peak.
MHz, DMSO-d6) δ: 160.1, 145.0, 144.9, 140.2, 138.1, 137.9,
133.5, 130.7, 130.3, 130.0, 129.0, 127.9, 127.6, 122.9, 121.4,
120.7, 116.4, 116.1, 112.9, 99.5, 58.9, 37.1, 29.8; Anal. Calcd
6-amino-3-(((4-chlorophenyl)thio)methyl)-4-(3-nitrophenyl)-
1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
(6q). Isolated as white solid; Rf = 0.31 (3:7 EtOAc/pet-ether); for: C26H18BrFN4OS: C, 58.54; H, 3.40; N, 10.50%; Found C,
mp 186–188 °C; 1H NMR (300 MHz, DMSO-d6) δ: 8.14 (s, 1H), 58.57; H, 3.44; N, 10.52%; * One of the –SCH2 proton was
7.78 (t, J = 9.0 Hz, 3H), 7.65 (t, J = 8.2 Hz, 1H), 7.53 (t, J = 7.9 merged with water peak.
Hz, 2H), 7.44 (s, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.32 (d, J = 8.6 Hz, 6-amino-4-(4-bromophenyl)-3-(((2-
2H), 7.23 (d, J = 8.6 Hz, 2H), 5.01 (s, 1H), 3.97 (d, J = 13.9 Hz, bromophenyl)thio)methyl)-1-phenyl-1,4-dihydropyrano[2,3-
1H), 3.61 (d, J = 13.9 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ: c]pyrazole-5-carbonitrile (6v). Isolated as white solid; Rf = 0.38
158.7, 147.1, 144.7, 143.6, 143.5, 136.3, 134.0, 133.6, 130.1, (3:7 EtOAc/pet-ether); mp 196—198 °C; 1H NMR (300 MHz,
129.6, 129.4, 128.5, 127.8, 125.9, 121.6, 121.5, 119.7, 118.7, DMSO-d6) δ: 7.74 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 3.6 Hz, 2H),
96.8, 56.5, 35.7, 29.0; ESI Calcd m/z 515, found 514 [(M-1)]+; 7.53 – 7.46 (m, 4H), 7.37 – 7.31 (m, 4H), 7.21 (d, J = 8.1 Hz, 2H),
Anal. Calcd for: C26H18ClN5O3S: C, 60.52; H, 3.52; N, 13.57%; 7.11 – 7.06 (m, 1H), 4.71 (s, 1H), 3.96 (d, J = 14.1 Hz, 1H); 13C
Found C, 60.56; H, 3.50; N, 13.61%.
NMR (75 MHz, DMSO-d6) δ: 160.2, 145.0, 144.8, 143.4, 138.0,
137.8, 135.9, 133.4, 132.4, 130.9, 130.2, 130.0, 128.9, 128.2,
127.9, 127.6, 122.8, 121.3, 120.6, 112.9, 99.1, 58.5, 37.3, 29.7;
6-amino-4-(4-bromophenyl)-3-(((4-
chlorophenyl)thio)methyl)-1-phenyl-1,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile (6r). Isolated as white solid; Rf = 0.45 ESI Calcd m/z 592, found 593 [(M+1)]+; Anal. Calcd for:
(3:7 EtOAc/pet-ether); mp 208–210 °C; 1H NMR (300 MHz, C26H18Br2N4OS: C, 52.54; H, 3.05; N, 9.43%; Found C, 52.52; H,
DMSO-d6) δ: 7.72 (d, J = 6.9 Hz, 2H), 7.50 (d, J = 6.3 Hz, 5H), 3.09; N, 9.47%; * One of the –SCH2 proton was merged with
7.34 – 7.21 (m, 8H), 4.71 (s, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.46 water peak.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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DOI: 10.1039/C6NJ02313D
ARTICLE
Journal Name
6-amino-3-(((2-bromophenyl)thio)methyl)-4-(4-cyanophenyl)- Isolated as yellowish solid; Rf = 0.58 (3:7 EtOAc/pet-ether); mp
1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
152–154 °C; 1H NMR (300 MHz, CDCl3) δ: 8.01 (s, 1H), 7.67 (d, J
(6w). Isolated as white solid; Rf = 0.30 (3:7 EtOAc/pet-ether); = 6.3 Hz, 2H), 7.57 (d, J = 8.1 Hz, 3H), 7.27 (d, J = 7.1 Hz, 2H),
1
mp 194–196 °C; H NMR (300 MHz, DMSO-d6) δ: 7.76 – 7.72 7.11 (d, J = 6.7 Hz, 2H), 6.91 (t, J = 6.5 Hz, 1H); 13C NMR (75
(m, 4H), 7.57 – 7.45 (m, 5H), 7.38 – 7.32 (m, 4H), 7.10 – 7.05 MHz, CDCl3) δ: 144.2, 140.3, 134.7, 132.8, 129.8, 126.6, 121.4,
(m, 1H), 4.84 (s, 1H), 3.95 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 119.6, 113.4, 111.1; ES+ HRMS m/z calcd for C14H11N3 222.1031
Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 160.4, 149.6, 145.3, [M +H], found 221.1028 [M + H].
144.9, 138.0, 137.8, 133.5, 130.2, 129.8, 129.1, 129.0, 127.9, ethyl 4-((4-chlorophenyl)thio)-3-oxobutanoate (I)
127.7, 122.9, 121.5, 120.3, 119.6, 111.0, 98.7, 58.1, 37.8, 29.8; Isolated as yellowish liquid; Rf = 0.75 (3:7 EtOAc/pet-ether); 1H
ESI Calcd m/z 539, found 538 [(M-1)]+; Anal. Calcd for: NMR (300 MHz, CDCl3) δ: 7.29 – 7.26 (m, 4H), 4.21 (q, J= 7.1
C27H18BrN5OS: C, 60.01; H, 3.36; N, 12.96%; Found C, 60.04; H, Hz, 2H), 3.80 (s, 2H), 3.62 (s, 2H), 1.28 (d, J = 7.1 Hz, 3H); 13C
3.38; N, 12.94%.
NMR (75 MHz, CDCl3) δ: 197.9, 167.3, 133.8, 132.9, 131.7,
129.8, 62.0, 46.9, 44.4, 14.4.
6-amino-4-(4-nitrophenyl)-1-phenyl-3-((p-tolylthio)methyl)-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6x). Isolated 5-(((4-chlorophenyl)thio)methyl)-2-phenyl-2,4-dihydro-3H-
as white solid; Rf = 0.29 (3:7 EtOAc/pet-ether); mp 210–212 °C; pyrazol-3-one20 (II)
1H NMR (300 MHz, DMSO-d6) δ: 8.16 (d, J = 8.7 Hz, 2H), 7.73 Isolated as brown solid; Rf = 0.81 (3:7 EtOAc/pet-ether); mp
(d, J = 7.8 Hz, 2H), 7.54 – 7.47 (m, 4H), 7.40 – 7.35 (m, 3H), 7.09 89–91 °C; 1H NMR (300 MHz, CDCl3) δ: 7.72 (d, J = 8.1 Hz, 2H),
(q, J = 8.1 Hz, 4H), 4.80 (s, 1H), 3.85 (d, J = 13.8 Hz, 1H), 2.23 (s, 7.40 (d, J = 7.7 Hz, 2H), 7.34 – 7.28 (m, 4H), 7.19 (t, J = 7.2 Hz,
3H); 13C NMR (75 MHz, DMSO-d6) δ: 160.4, 151.7, 147.5, 145.8, 1H), 3.90 (s, 2H), 3.54 (s, 2H); 13C NMR (75 MHz, CDCl3) δ:
145.1, 138.0, 137.0, 132.3, 130.7, 130.4, 130.2, 130.1, 127.6, 170.6, 155.8, 138.1, 134.0, 132.7, 132.2, 129.9, 129.3, 125.8,
124.7, 121.3, 120.4, 98.4, 57.9, 37.5, 31.4, 21.4; ESI Calcd m/z 119.4, 40.8, 34.8; ES+ HRMS m/z calcd for C16H13ClN2OS
495, found 494 [(M-1)]+; Anal. Calcd for: C27H21N5O3S: C, 65.44; 317.0515 [M +H], found 317.0514 [M + H].
H, 4.27; N, 14.13%; Found C, 65.48; H, 4.31; N, 14.09%; * One 2-(4-cyanobenzylidene)malononitrile21 (III)
of the –SCH2 proton was merged with water peak.
Isolated as white solid; Rf = 0.85 (3:7 EtOAc/pet-ether); mp
1
154–156 °C; H NMR (300 MHz, CDCl3) δ: 8.01 (d, J = 8.4 Hz,
6-amino-4-(4-fluorophenyl)-1-phenyl-3-((p-tolylthio)methyl)-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6y). Isolated 2H), 7.84 (d, J = 7.9 Hz, 3H); 13C NMR (75 MHz, CDCl3+DMSO-
as white solid; Rf = 0.34 (3:7 EtOAc/pet-ether); mp 186–188 °C; d6) δ: 158.6, 134.8, 133.4, 133.3, 131.2, 131.1, 117.8, 117.1,
1H NMR (300 MHz, DMSO-d6) δ: 7.71 (d, J = 7.8 Hz, 2H), 7.50 113.3, 112.2, 86.5. * one of the proton was merged with
(d, J = 7.5 Hz, 2H), 7.35 – 7.25 (m, 6H), 7.16 – 7.07 (m, 5H), 4.60 aromatic proton.
(s, 1H), 3.83 (d, J = 13.2 Hz, 1H), 2.23 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) δ: 160.1, 145.8, 144.9, 140.3, 138.1, 137.0, 132.4,
Acknowledgements
130.8, 130.4, 130.2, 127.5, 121.2, 120.6, 116.3, 116.0, 99.3,
N.S.D is grateful to DST (SERB), New Delhi for Major Research
Project under the fast track scheme sanction No. SR/FT/CS-
037/2011. The authors also thank DST, New Delhi for NMR
facility under the IRHPA program.
59.0, 37.0, 31.5, 21.4; Anal. Calcd for: C27H21FN4OS: C, 69.21; H,
4.52; N, 11.96%; Found C, 69.25; H, 4.56; N, 11.98%; * One of
the –SCH2 proton was merged with water peak. ESI Calcd m/z
468, found 467 [(M-1)]+
6-amino-4-(4-bromophenyl)-1-phenyl-3-((p-tolylthio)methyl)-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6z). Isolated
as white solid; Rf = 0.34 (3:7 EtOAc/pet-ether); mp 206–208 °C;
1H NMR (300 MHz, DMSO-d6) δ: 7.71 (d, J = 7.5 Hz, 2H), 7.51 –
7.46 (m, 4H), 7.36 – 7.29 (m, 3H), 7.20 – 7.07 (m, 7H), 4.59 (s,
1H), 3.84 (d, J = 13.8 Hz, 1H), 2.24 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) δ: 160.2, 145.8, 145.0, 143.6, 138.1, 137.0, 132.4,
131.0, 130.9, 130.5, 130.2, 127.5, 121.2, 120.6, 98.9, 58.6,
37.2, 31.5, 21.4; ESI Calcd m/z 528, found 527 [(M-1)]+; Anal.
Calcd for: C27H21BrN4OS: C, 61.25; H, 4.00; N, 10.58%; Found C,
61.28; H, 4.04; N, 10.61%; * One of the –SCH2 proton was
merged with water peak.
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(E)-4-((2-phenylhydrazono)methyl)benzonitrile (B)
8 | J. Name., 2012, 00, 1-3
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Table of Contents:
A one-pot, five component domino synthesis of novel thio ether containing dihydropyrano[2,3-
c]pyrazoles under solvent-free, catalyst-free is demonstrated.