One-pot synthesis, biological evaluation, and docking study of new chromeno-annulated thiopyrano[2,3-c]pyrazoles

Article abstract of DOI:10.1007/s11030-016-9665-z

Abstract: A one-pot synthesis of new chromeno-annulated thiopyrano[2,3-c]pyrazoles has been achieved through a domino-Knoevenagel–hetero-Diels–Alder reaction after combining various pyrazol-5-thiones with O-alkenyloxy/alkynyloxy-salicylaldehydes/naphthaldehydes in a Br?nsted acidic ionic liquid, [Hmim]HSO₄, methylimidazolium hydrogen sulphate, under microwave irradiation. The method is simple and in many cases the isolated products did not require further purification. The central pyranothiopyranyl cis-fusion was confirmed by 2D NMR NOESY and single-crystal X-ray analysis suggesting that the endo-E-Syn transition state would be the most favored pathway of the reaction. Many heterocycles of this new series were found active against six bacterial and two fungal strains. In addition, all the compounds possess good anti-oxidant activity with the ferric reducing anti-oxidant power value >100mmol/100g. All new structures were docked into active site of angiotensin I converting enzyme (ACE), assuming that the compounds possessed the anti-hypertensive activity potential on the basis of prediction of activity spectra of substances prediction results. Pyranyl ring oxygen in compound 9a forms two hydrogen bonds with HIS353 and HIS513 residues in the active site of the ACE having good G score (- 4.06) of this compound, comparable to that of the reference drug captopril (- 4.93). Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11030-016-9665-z

Mol Divers
DOI 10.1007/s11030-016-9665-z
ORIGINAL ARTICLE
One-pot synthesis, biological evaluation, and docking study of new
chromeno-annulated thiopyrano[2,3-c]pyrazoles
Bhagyashri D. Parmar1 · Tushar R. Sutariya1 · Gaurangkumar C. Brahmbhatt1 ·
Narsidas J. Parmar1 · Rajni Kant2 · Vivek K. Gupta2 · Prashant R. Murumkar3 ·
Mayank Kumar Sharma3 · Mange Ram Yadav3
Received: 31 August 2015 / Accepted: 4 March 2016
© Springer International Publishing Switzerland 2016
Abstract A one-pot synthesis of new chromeno-annulated
thiopyrano[2,3-c]pyrazoles has been achieved through a
domino-Knoevenagel–hetero-Diels–Alder reaction after
combining various pyrazol-5-thiones with O-alkenyloxy/
alkynyloxy-salicylaldehydes/naphthaldehydes in a Brønsted
acidic ionic liquid, [Hmim]HSO4, methylimidazolium
hydrogen sulphate, under microwave irradiation. The method
is simple and in many cases the isolated products did
not require further purification. The central pyranothiopy-
ranyl cis-fusion was confirmed by 2D NMR NOESY and
single-crystal X-ray analysis suggesting that the endo-E-Syn
transition state would be the most favored pathway of the
reaction. Many heterocycles of this new series were found
active against six bacterial and two fungal strains. In addition,
all the compounds possess good anti-oxidant activity with the
ferric reducing anti-oxidant power value >100 mmol/100g.
All new structures were docked into active site of angiotensin
I converting enzyme (ACE), assuming that the compounds
possessed the anti-hypertensive activity potential on the basis
of prediction of activity spectra of substances prediction
results. Pyranyl ring oxygen in compound 9a forms two
hydrogen bonds with HIS353 and HIS513 residues in the
active site of the ACE having good G score (−4.06) of this
compound, comparable to that of the reference drug capto-
pril (−4.93).
Graphical Abstract
Keywords Thiopyrano[2, 3-c]pyrazole · [Hmim]HSO4 ·
Pyrazole-5-thione · Domino-Knoevenagel–hetero-Diels–
Alder reaction · Microwave synthesis · Docking · Ionic
liquid
Introduction
Electronic supplementary material The online version of this
article (doi:10.1007/s11030-016-9665-z) contains supplementary
material, which is available to authorized users.
Heterocycles containing the pyranopyrazole-fused core are
known for displaying a broad range of pharmacologi-
cal properties, such as anti-inflammatory, analgesic, anti-
hypertensive, ulcerogenic, anti-tubercular, anti-malarial,
anti-hyperglycaemic, anti-tumor, anti-oxidant, anti-proli-
ferative, vasodilating, and hypnotic [1–7]. Pyranopyrazoles
have also an important role in agrochemical research due
to their bactericidal, fungicidal, and herbicidal properties
[8–10]. Pyrazole-carbohydrazides and pyrazoles substituted
with sugars were reported as anti-cancer agents [11–15].
Narsidas J. Parmar
njpchemdeptspu@yahoo.co.in
B
1
Department of Chemistry, Sardar Patel University, Vallabh
Vidyanagar, Anand District, Gujarat 388 120, India
2
Department of Physics, University of Jammu,
Jammu Tawi 180 006, India
3
Faculty of Pharmacy, The Maharaja Sayajirao University of
Baroda, Vadodara 390 001, India
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Derivatives of thiopyran, and thiopyrano-fused pyrazoles and
other heterocycles, on the other hand, constitute a class of sul-
fur heterocycleanalogs of thepossessing significant bioactiv-
ities [16–20]. RP 49356 is a K+ channel opener [17]. Thiopy-
ran derivatives are modulators of estrogen receptors, and
possess a high dopamine receptor-binding affinity [21,22].
Pharmaceutically acceptable salts of tetrahydrothiopyrano-
fused indoles are known for their psycho-analeptic and
nootropic activities [19]. Thiopyranoquinolines exhibited
interleukin-1 inhibitory activity. Some thiopyranopyrazoles
showed non-steroidal anti-inflammatory activity, without
producing gastric or renal toxicity, as selective COX-2
enzyme inhibitors [23,24]. Thus, the development of these
heterocycles is of widespread interest, and synthetic activi-
ties targeting particularly their sulfur analogs certainly offer
a way to access new bio-molecules to the medicinal and syn-
thetic chemists.
and triethylammonium acetate (TEAA) [57–59] are the only
ILs employed in the DKHDA reaction. For enhanced reac-
tivity and better selectivity, the use of IL was therefore
continued to improve this strategy. Recently, methylimida-
zolium hydrogen sulfate, [Hmim]HSO4, has been used suc-
cessfully in the synthesis of 3,4-dihydropyrimidin-2(1H)-
ones/thiones, hydroquinazoline-2,5-diones/thiones [55], and
3,4-dihydropyrimidin-2-(1H)-ones [60]. This halogen-free,
less-toxic/carbon-containing protic IL [55,56,60–64] also
mediated synthesis of functionalized pyrroles [63],
piperidines [64], pyrazolones [61], and α-aminonitriles
[62]. As part of our continued effort and interest in the
development of new polyheterocycles [57–59,65–67], we
describe an efficient, one-pot synthesis of new thiopyrano
[2,3-c]pyrazole-heterocycles in this work, via the DKHDA
approach optimizing the reaction in [Hmim]HSO4 under
microwave irradiation.
Thedomino-Knoevenagel–hetero-Diels–Alder(DKHDA)
reaction represents a noteworthy synthetic sequence, which
has been widely used to synthesize pyran-heterocycles by
assembling olefin-tethered aldehyde substrates with dike-
tones or heterocyclic ketones including 5-pyrazolone [25–
30]. The use of aldehyde substrates except for 5-alkenyl–
sulfanyl–pyrazol–4-carbaldehyde has not been yet explored
fully, leaving many new possibilities for thiopyranopyra-
zole synthesis [31–35]. Further, the Vilsmeier–Haack reac-
tion is required to synthesize 5-alkenyl–sulfanyl–pyrazol–
4-carbaldehyde substrate [23]. With a view to develop
thiopyranopyrazole-heterocycles as new sulfur- containing
scaffolds, it was aimed to use olefin-ether-tethered alde-
hyde substrates with 5-thiopyrazol by DKHDA strategy. As
bioisosteres of pyranopyrazoles, known for their biological
significance, all of the new thiopyranopyrazoles are antic-
ipated to display newer and improved biological functions
[36,37]. In general, combining one pharmacophore with oth-
ers leads to the formation of new molecular scaffolds with
improved biological functions. Further, sulfur-heterocycles
are highly pursued synthetic targets due to their limited avail-
ability from natural sources [38–40].
Replacement of traditional toxic and volatile organic sol-
vents with non-toxic and non-volatile ionic liquids (ILs)
offers many synthetic advantages such as high thermal sta-
bility, low volatility, and recyclability of the reaction media
[41–43]. Effective interactions between the IL and MW-
radiation through high polarity and ionic conduction have
been advantageous to promote many transformations [44–
56]; the technique is called ILs on MW-assisted organic
synthesis (MAOS). The hetero-Diels–Alder reaction [44] has
also been successfully studied by this technique. MAOS
[49,50] also reduces the solvent-emission, catalyst-reuse,
and pollution problems to a larger extent [25–27,32].
To the best of our knowledge, butylmethylimidazolium
tetrafluoroborate [bmim]BF4 [52], its nitrate salts [53,54]
Results and discussion
The ionic liquid [Hmim]HSO4 was synthesized by reacting
1-methylimidazole with sulphuric acid according to the lit-
erature [55,62]. Salicylaldehyde 4a–h and naphthaldehyde
5a–h substrates were obtained by reacting salicylaldehyde
1 and 2-hydroxy-naphthaldehyde 2 with the correspond-
ing alkenyl/alkynyl chloride or bromide 3a–h in anhy-
drous K2CO3-suspended dimethylformamide (DMF) solu-
tion (Scheme 1) at room temperature as reported by our
group [67]. Thionation of 1-(4-MePh/3-ClPh/Ph)-3-Me-5-
pyrazolones with Lawesson’s reagent in refluxing toluene,
on the other hand, gave thiopyrazoles 6a–c in quantitative
yields [66].
Both the 2-allyloxy-naphthaldehyde 5a and 2-prenyloxy-
naphthaldehyde 5b were reacted with thiopyrazole 6c as
model substrates to optimize the reaction condition (Table 1).
In refluxing acetonitrile (entry 1) and xylene (entry 2), where
no catalyst was used, the reaction failed to give the products
even after 24 h. In presence of catalyst TBA-HS, averaged
40 % yield of 10a and 58 % yield of 10b were recorded
after 12 and 7 h, respectively, in these solvents (entries 3,
4). Using the same catalyst under solvent-free environment
◦
at 140 C, the yields of 10a and 10b could be improved
up to 70 % (entry 5), in addition to reducing the reaction
time. To further increase the product yield, we then exam-
ined the reaction in ionic liquid, TEAA, at 120 ◦C but failed
to achieve remarkable development in this medium (entry
6). The use of ionic liquid, [Hmim]HSO4, as a catalyst, did
not work impressively under refluxing ethanol and toluene
(entries 7, 8). The results were comparable to those obtained
in refluxing acetonitrile or xylene (entries 3 and 4). Ionic liq-
uid, [Hmim]HSO4, was then tried as a reaction medium at 80
◦C. A maximum of 82 % yield of 10a/10b was achieved in
123

Mol Divers
Scheme 1 Reagents and
conditions: i DMF, K2CO3, RT,
8–10 h
Table 1 Optimization of the
DKHDA reaction under various
conditions, 5a/5b to 6c
Entry
Solvent
Catalyst
Temp. (◦C)
Time (h)
10a/10b
Yield (%)
10a/10b
1
2
3
4
5
6
7
8
9
10
Acetonitrile
Xylene
Acetonitrile
Xylene
–
–
Reflux
Reflux
Reflux
Reflux
140
24
–
–
24
Trace
38/56
42/59
68/72
64/68
56/66
54/63
80/82
89/91
TBA–HSa
TBA–HSa
TBA–HSa
TEAAb
[Hmim]HSOc4
[Hmim]HSOc4
[Hmim]HSOc4
[Hmim]HSOc4
12.0/7.0
12.0/7.0
3.5/2.0
3.5/2.5
12.0/5.0
12.0/5.0
1.5/1.0
12 min
–
120
Ethanol
Toluene
–
Reflux
Reflux
80
MWI
280 W
a = 0.25 equiv, b = 1.68 equiv., c = 0.5 equiv
MWI microwave irradiation, TBA–HS tetrabutylammonium hydrogen sulfate, TEAA triethylammonium
acetate, [Hmim]HSO4 methylimidazolium hydrogen sulfate
1.5 h (entry 9), which under microwave irradiation improved
further to 90 % taking just 12 min to complete the reaction,
at 280 W (entry 10). Syntheses of other heterocycles were
then carried out following this optimal reaction condition
(Scheme 2).
1-thia-2,3-butadiene, converting into the cyclized product
finally.
Spectroscopic data: 1H NMR, 13C NMR, and IR spectra,
of the heterocycles are in full agreement with their proposed
structures.
Figure 1 depicts a plausible mechanism of DKHDA
reaction, showing the formation of Knoevenagel adduct,
1-thia-1,3-butadiene, from pyrazole-5-thione and the alde-
hyde substrate, along with traces of Michael adduct. These
intermediates finally convert into a cyclized product via
intramolecular hetero-Diels–Alder reaction. In the reaction
medium, abstraction of a thiopyrazolone proton by ionic liq-
uid forms an unstable methylimidazoliumthiopyrazolonate,
which after reacting with the aldehyde transforms into
Knoevenagel adduct via Michael adduct, formation releas-
ing the ionic liquid simultaneously back into the medium.
Knoevenagel adduct, under the influence of positive nitro-
gen of the ionic liquid, activates the terminal sulfur of
Figure 2 shows the characteristic δ ppm values of the
protons in their 1H NMR which are part of the com-
mon skeleton in all heterocycles. Chemical shift values
of the protons which belong to the thiopyran ring-fused
fragment in different heterocycles, on the other hand, are
mentioned in the periphery of the inner circle. Coupling
constant J = 2.8−5.2 Hz value of a doublet observed at
δ 4.06–4.95 ppm, assigned to the bridge-head proton Ha,
confirmed its cis-orientation with the bridge-head proton
Hb. Proton Hb gave a multiplet at δ 2.18–3.59 ppm. One
of the thiopyranyl –SCH2– protons gets de-shielded when
the other proton is substituted by phenyl or the ester moi-
ety, i.e., signal is shifting to higher δ ppm value. A more
123

Mol Divers
Scheme 2 DKHDA products, 7,
8 and 9, 10; as assemblies of
pyrazole-5-thiones 6a–b with
salicylaldehyde-substrates 4a–h,
and as assemblies of 6b–c with
naphthaldehyde-substrates
5a–h, respectively
pronounced effect in case of –SCH= proton was seen giving
a signal at 6.02–6.07 δ ppm, for example, in compounds
7c–10c. In this context, the carbocyclic ring fusion has
little effect on the rest of the proton signals, for exam-
ple, in compounds 7d–10d. Pyranyl –OCH2 protons gave
a multiplet at δ 3.88–4.97 ppm. Similarly, protons of Me
attached to the pyrazole showed a singlet at δ 1.37–2.53
ppm.
IR band in the 1005–1300 cm−1 range confirms the
cyclic ether linkage of pyran ring. Likewise, the thiopy-
ran ring was confirmed on the basis of characteristic
band appearing in the region 600–700 cm−1 which was
attributable to the C–S–C linkage. Molecular ion signals
observed in the mass spectra were in agreement with
the calculated molecular weights of the respective prod-
ucts.
The 2D NMR NOESY (Overhauser effect spectroscopy)
ofrepresentativecompound9bsupportedthecis-relationship
between two bridge-head protons, Ha and Hb ( Fig. 3).
Finally, the single-crystal X-ray diffraction data of rep-
resentative 10a were used to confirm unambiguously the
presence of cis-fused pyranothiopyranyl core in all heterocy-
cles. The compound crystallizes in triclinic space group P-1
with unit-cell parameters: a = 8.3316(7), b = 9.6125(6),
123

Mol Divers
Fig. 3 Characteristic NOE’s of 9b
Biological evaluation and structure–activity relationship
analysis
Table 2 lists the minimum inhibitory concentration (MIC)
values of all compounds, which were measured against a
panel of six different bacterial strains; three Gram +ve and
three Gram −ve bacteria, and two fungal strains. The Table
also incorporates % growth inhibition (GI of M. Tuberculo-
sis H37RV bacteria) and ferric reducing anti-oxidant power
(FRAP) values of all the compounds. From the MIC values,
it could be seen that the compounds are almost equivalent
to ampicillin in potency against at least one of the bacterial
strains.
Fig. 1 A plausible mechanism of DKHDA reaction
c = 13.2921(10) Å, α = 79.966(5), β = 75.636(7),
65.755(7)◦, Z = 2 (Fig. 4). The geometry of the molecule
was calculated using the WinGX28 and PARST29 software
packages [68,69].
Prediction of activity spectra for substances (PASS) study
predicted higher anti-hypertensive activity for sulfoxide, 11,
and sulfone, 12, than 10b [70]. Synthesis of 11 and 12 has
been depicted in Scheme 3 using m-CPBA as an oxidant.
Sterically more bulky compounds were more active
against Gram +ve bacteria like C. tetani and B. subtilis, while
reverse was true for the less bulky compounds which showed
better activity against Gram −ve bacteria. Compounds close
Fig. 2 1H NMR chemical
shifts of all the compounds
123

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Fig. 4 ORTEP view of the
compound 10a
bacterial inhibition against Gram −ve S. typhi, compound
8b revealed chloramphenicol-equivalent potency, with MIC
value of 50 µg/mL. Compounds such as 7a and 7h were
found active against S. pneumonia bacteria, with MIC value
of 62.5 µg/mL, close to chloramphenicol and ciprofloxacin
in potency.
Resistance power of 7b, 8b, 7f, 9b, and 10a was notice-
able against Gram −ve bacteria. Compounds 7b, 9b, and
10a were active against Gram −ve V. cholera, resembling
chloramphenicol in the resistivity. Overall, compound 7b
had very strong inhibitory effect against all bacterial strains.
Compounds 7a, 7h, 8b, 8d, and 9e were active against five
of the bacterial species, whose MIC remained comparable to
at least one of the standard drugs.
Scheme 3 Reagents and conditions: (i) Dichloromethane, 0–5 ◦C (2h)
and then at RT
Anti-fungal activity of compounds 7eꢀ, 7f, 8d, 10a, 10b,
10e, and 10f, against C. albicans fungal strain, was found
to be equal to griseofulvin. Compounds such as 7a, 7d, 7g,
8b, 8c, 8e, 8f, 8g, 9h, and 10h showed similar activity but
emerged with relatively higher potential. Activity of all of
the compounds against A. fumigatus fungal strain was found
to be very poor.
Growth inhibition (GI) value of compounds 8f and 10g
lying in the range of 90–99 % indicated good anti-tubercular
activity of these candidates against M. tuberculosis H37Rv
strain. Compounds 7e, 9e, 10f, and 10h exhibited good to
moderate anti-tubercular activity with GI lying in the range
of 80–90 %.
FRAP values of all the compounds were in the range
of 220–300, indicating good anti-oxidant potential of these
compounds.
The 3-Cl as Rꢀ relative to H or 4-Me at phenyl ring of
the pyrazol unit in many cases was found to be effective in
improving the anti-bacterial profile. Compound 8f in com-
to chloramphenicol in potency and those that were more
potent than ampicillin against Gram −ve E. coli bacteria
included 7f and 10c. Inhibitory effect of compound 8f was
found very near to the standard drugs chloramphenicol and
ciprofloxacinbothagainsttheGram+vebacterialikeS. pneu-
monia. MIC values of compounds 7e, 7g, 9c, 9e, 10a, 10e,
and 10h were found to be very close to ciprofloxacin against
C. tetani bacteria. Norfloxacin-equivalent potency of com-
pounds 8a–c, 9a, 9b, 9d, 9h, and 10b, was found against B.
subtilis bacteria. Resistivity of compound 9b was also found
near to the standard drugs chloramphenicol and norfloxacin
against C. tetani bacteria. Same was observed in the case
of compound 7a, but its activity was close to chlorampheni-
col and ciprofloxacin against B. subtilis. S. pneumonia, S.
Typhi, or V. cholera bacteria were mostly the targets for com-
pounds 7a, 7b, 7h, 8b, 9b, and 10a. Compound 7b showed
activity against all bacterial strains, and recorded a higher
resistance, even more than the reference drugs except for
gentamycin, against C. tetani and S. typhi. With a strong
123

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Table 2 Anti-microbial, anti-tubercular, and anti-oxidant activities of thiopyrano[2,3-c]pyrazole-heterocycles, 7–10
Compound
Anti-microbial activity (MIC, µgmL−1
)
Anti TBa activity
(% inhibition)
Anti-oxidant activityb
(FRAP valuec)
Gram +ve bacteria
Gram −ve bacteria
Fungi
A.F.
S.P.
C.T.
B.S.
S.T.
V.C.
E.C.
C.A.
7a
7b
7c
7d
7e
7eꢀ
7f
62.5
125
250
250
250
250
100
200
62.5
250
125
250
500
250
200
62.5
250
125
125
125
250
125
125
500
250
200
100
500
500
200
125
200
200
500
0.5
250
25
62.5
250
250
200
250
200
500
250
250
125
100
125
250
200
200
500
200
250
100
100
200
125
200
250
200
125
250
125
500
250
250
250
250
250
1
250
25
250
50
250
100
250
250
200
250
62.5
250
100
250
250
250
100
250
250
250
250
250
125
200
250
200
125
250
250
250
250
250
125
250
200
100
200
250
0.05
100
50
1000
–
500
1000
1000
500
1000
250
250
500
1000
–
20
77
58
38
86
45
58
61
74
12
54
62
45
47
40
91
55
65
46
52
42
32
85
68
58
74
74
55
35
20
56
88
90
85
–
220.48
239.96
259.56
105.35
243.88
280.07
289.12
290.12
234.63
221.49
243.18
234.43
165.07
239.66
246.09
241.07
251.92
300.18
257.84
244.38
236.64
158.03
236.64
241.47
236.24
221.76
251.61
234.34
254.13
114.00
227.80
279.47
220.16
222.77
–
250
250
125
250
500
125
250
250
250
250
200
250
200
250
250
250
250
62.5
125
200
100
250
250
250
125
250
500
200
100
250
200
100
5
250
250
200
250
250
500
125
250
50
250
200
250
250
200
200
250
200
100
125
100
200
100
250
200
125
100
50
1000
1000
500
1000
1000
1000
500
1000
1000
1000
1000
1000
500
1000
500
500
–
7g
7h
8a
8b
8c
8d
8e
8eꢀ
8f
500
500
250
500
1000
500
500
1000
–
250
100
250
200
200
125
200
200
250
125
200
125
200
200
250
500
200
200
250
125
200
200
250
5
8g
8h
9a
9b
9c
9d
9e
9f
–
1000
1000
1000
1000
1000
1000
500
250
250
–
250
200
250
250
125
200
62.5
500
200
200
200
200
500
200
5
500
500
500
500
500
–
9g
9h
10a
10b
10c
10d
10e
10f
10g
10h
A
500
1000
250
–
1000
250
250
1000
500
–
500
1000
500
1000
–
B
100
50
250
50
250
50
100
50
100
50
–
–
–
–
C
–
–
–
–
D
50
100
50
50
25
25
25
–
–
–
–
E
10
100
–
10
10
10
–
–
–
–
F
–
–
–
–
–
100
100
–
100
500
–
–
–
G
–
–
–
–
–
–
–
–
H
–
–
–
–
–
–
99
–
S.P. Streptococcus pneumoniae, C.T. Clostridium tetani, B.S. Bacillus subtilis, S.T. Salmonella typhi, V.C. Vibrio cholerae, E.C. Escherichia coli,
A.F. Aspergillus fumigatus, C.A. Candida albicans
[A] Gentamycin, [B] Ampicillin, [C] Chloramphenicol, [D] Ciprofloxacin, [E] Norfloxacin, [F] Nystatin, [G] Griseofulvin, [H] Isoniazide
a
Concentration of compounds used against M. tuberculosis H37Rv bacteria= 250 µg/mL, standard anti-microbials used: isoniazide (0.2 µg/mL)
Concentration of compounds= 200 µg/mL and standard: A.A. (ascorbic acid)= 176 µg mL
A.A. mm/100 g sample
b
c
123

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parison to 7f against S. pneumonia, 8d in comparison to 7d
against S. typhi, V. cholera, and E. coli and 8g in compar-
ison to 7g against S. typhi bacteria were more potent. 8c,
8d, 8eꢀ, and 8h against V. cholera were two times higher
in inhibitory power than the corresponding 7c, 7d, 7eꢀ, and
7h. Anti-tubercular activity of compound 8f was higher than
7f. In a few cases, 4-Me group instead of 3ꢀ Cl as Rꢀ also
improved the activity. Compound 7b was found to be ten
times more potent than 8b in its resistivity toward C. tetani,
S. typhi, and V. cholera. Compounds 7b and 7h are rela-
tively more active than 8b and 8h, respectively. Compound
7f was four times more active than 8f in inhibition against E.
coli. Compound 7eꢀ is four times more active than 8eꢀ, while
inhibiting C. albicans. Anti-tubercular activity of 7e was also
higher than 8e.
Naphthaldehyde-derived heterocycles also showed a sim-
ilar trend of anti-bacterial profile when incorporated with
1-(3-ClPh)-5-thiopyrazolone unit. Compound 9b was four
times higher in activity than 10b against both S. pneu-
monia and C. tetani. The difference in the resistivity was
however ten times between these compounds against V.
cholera. When compared to 10d, compound 9d has a lit-
tle bit more inhibitory effect against S. pneumonia bacteria.
Similarly, compound 9c was four times higher in potency
against C. tetani, compared to 10c, and almost double in
activity against B. subtilis. Compound 10a, with 1-Ph at
thiopyrazolone nitrogen, was also higher in activity com-
pared to 9a against V. cholera. Compounds 10a, 10b, 10e,
and 10f in comparison to their respective chloro deriva-
tives 9a, 9b, 9e, and 9f revealed the same pattern against
the fungus C. albicans. Inhibition of growth of mycobac-
terium by compounds 10f, 10g, and 10h (Rꢀ is taken
as H) was observed to be very strong relative to com-
pounds 9f, 9g, and 9h (3-Cl is taken as R). This trend
was however seen to be reversed in case of compound 9e,
surprisingly.
Table 3 Comparison of anti-hypertensive activity potential of
thiopyrano[2,3-c]pyrazoles 7–10, with their analogous pyrano[2,3-
c]pyrazoles, based on Pa value
Compound
Pa (For anti-hypertensive activity)
Thiopyrano(2,3-c)pyrazole
Pyrano(2,3-c)pyrazolea
7a
0.638
0.661
0.690
0.684
0.734
0.734
0.654
0.636
0.576
0.594
0.615
0.650
0.648
0.688
0.688
0.613
0.599
0.545
0.538
0.554
0.589
0.594
0.634
0.557
0.550
0.503
0.608
0.630
0.668
0.665
0.708
0.626
0.611
0.550
0.695
0.694
0.460
0.441
0.472
0.346
0.435
0.435
0.268
0.415
0.274
0.422
0.406
0.436
0.304
0.400
0.400
0.233
0.380
0.244
0.345
0.334
0.368
0.226
0.330
–
7b
7c
7d
7e
7eꢀ
7f
7g
7h
8a
8b
8c
8d
8e
8eꢀ
8f
8g
8h
9a
9b
9c
9d
9e
9f
9g
0.318
0.180
0.416
0.398
0.433
0.283
0.393
0.205
0.372
0.222
–
9h
10a
10b
10c
10d
10e
10f
10g
10h
11
Molecular docking studies
Anti-hypertensive activity was predicted for all the thiopy-
ranopyrazoles when they were evaluated using predic-
tion of activity spectra for substances (PASS) software
[70] (Table 3). Thus, all the synthesized compounds were
docked into the active site of angiotensin I-converting
enzyme (ACE), assuming that their anti-hypertensive activ-
ity was originating by ACE inhibition. It is to be noted
that although pyranopyrazoles are widely studied but any
of them is yet to be reported for its anti-hypertensive
activity.
12
–
a Oxygen analogous of thiopyrano[2,3-c]pyrazole used for comparison
reported in the literature [71] as shown in Fig. 5a. One of
the oxygen molecules of the carboxyl groups on the ter-
minal proline formed three hydrogen bonds with GLN281,
LYS511, and TYR520 residues, respectively. The G scores
obtained through docking studies are shown in Table 4. Com-
pound 9a showed the highest G score (−4.06) among all
the synthesized compounds, whereas compound 9g showed
The docking protocol was validated by observing orienta-
tion of the reference compound captopril in the active site
of ACE. Captopril showed the highest G score of −4.93
and was observed to be oriented in the same manner as
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Mol Divers
Fig. 5 a Orientation of captopril in the active site of ACE (PDB ID
4C2P), b Orientation of compound (9a) in the active site of ACE (PDB
ID 4C2P), c Orientation of compound (9a) having the highest G score
(−4.06) shown in red color and compound (9g) having the lowest G
score (−2.20) shown in green color (H-bonds are shown in red dotted
lines)
the lowest G score (−2.20). Pyranyl ring oxygen in com-
pound 9a formed two hydrogen bonds with HIS353 and
HIS513 residues in the active site of the ACE as shown
in Fig. 5b which might be a reason for it showing a good
G score. The hydrogen bond distances from compound 9a
(N of 2nd position of pyrazole) with HIS353 and HIS513
residues were found to be 1.877 and 2.643 Å, respectively.
Compound 9a showed good contacts with HIS353, ALA354,
SER355, HIS383, GLU384, HIS387, PHE512, VAL518, and
TYR523 residues. Overlay structures of compound 9a and
compound 9g are shown in Fig. 5c which clearly indicates
orientation of compound 9g in opposite side (away from
the active site) to compound 9a, and this could be one of
the reasons of its poor G score. Drug like properties were
calculated to see whether the synthesized compounds could
become drugs or not. All the synthesized compounds were
in the acceptable range for the following properties viz.
molecular weight, no. of rotatable bonds, volume, H-bond
acceptor, and PSA as shown in Table 4. In addition, all the
compounds showed high (100 %) human oral absorption
(HOA), except for compound 11, and zero H-bond donor
values. The HOA value of compound 11 is 95.686 %. Cal-
culated log P value of some of the compounds was found
to be in the acceptable range (compounds 7a, 7b, 7c, 7f,
7g, 8a, 8c, 8f, 8g, 10a, 10c, 10g, 11 , and 12) as shown in
Table 4.
Conclusion
In conclusion, we demonstrated the DKHDA reaction assem-
bling the thiopyrazole and salicylaldehyde/naphthaldehyde-
based substrates in IL, [Hmim]HSO4, under the microwave
irradiation. The method did not involve chromatographic
123

Mol Divers
Table 4 G score and other
parameters of the docked
compounds (7a–12)
Compound
M.W.
Volume
No. of rotatable
bonds
HBA
QPlogPo/w
PSA
G score
7a
348.46
376.51
346.44
388.52
424.55
424.55
438.54
420.52
444.63
368.88
396.93
366.86
408.94
444.97
444.97
458.96
440.94
465.05
418.94
446.99
416.92
459.00
495.03
509.02
491.00
515.11
384.49
412.54
382.47
424.55
460.59
474.57
456.55
480.66
428.54
444.54
1073.33
1164.55
1070.84
1196.12
1293.87
1287.27
1275.52
1289.44
1424.72
1057.39
1148.63
1051.77
1180.19
1277.98
1271.20
1259.76
1273.50
1408.80
1181.68
1268.44
1177.10
1297.51
1391.76
1383.26
1394.72
1530.34
1137.61
1224.38
1133.02
1252.97
1348.06
1339.45
1350.65
1486.28
1253.92
1267.61
0
0
0
0
0
0
0
2
3
0
0
0
0
0
0
0
2
3
0
0
0
0
0
0
2
3
0
0
0
0
0
0
2
3
0
0
2
2
2
2
2
2
3
4
2
2
2
2
2
2
2
3
4
2
2
2
2
2
2
3
4
2
2
2
2
2
2
3
4
2
2
3
5.79
6.34
5.84
6.57
7.40
7.35
6.10
5.89
8.04
5.97
6.52
6.00
6.75
7.58
7.53
6.28
6.07
8.22
6.87
7.40
6.88
7.58
8.37
7.16
6.95
9.09
6.36
6.90
6.39
7.07
7.87
6.66
6.45
8.59
4.89
4.80
23.99
23.90
24.15
23.18
24.14
23.94
49.89
57.02
24.04
23.98
23.89
24.08
23.17
24.13
23.93
49.88
57.01
24.03
24.19
23.65
24.26
24.11
22.19
49.64
55.95
24.27
24.20
23.66
24.25
24.12
22.20
49.65
55.96
24.28
41.24
57.89
−3.47
−3.28
−3.05
−2.73
−2.84
−3.26
−2.86
−3.20
−3.22
−3.44
−2.79
−3.94
−3.08
−3.19
−3.09
−2.82
−2.91
−2.26
−4.06
−3.03
−2.95
−2.63
−2.20
−2.70
−2.20
−2.56
−3.78
−3.66
−3.58
−2.89
−3.09
−3.64
−2.36
−2.65
−3.92
−3.54
7b
7c
7d
7e
7eꢀ
7f
7g
7h
8a
8b
8c
8d
8e
8eꢀ
8f
8g
8h
9a
9b
9c
9d
9e
9f
9g
9h
10a
10b
10c
10d
10e
10f
10g
10h
11
12
G score of the standard drug: Captopril= −4.93, Enalapril= −4.63
purification for product isolation in many cases. Recycla-
bility of the IL was confirmed at least three times without
loss of its efficiency. All new chromen-annulated cis-fused
thiopyranopyrazoles were evaluated biologically, in vitro.
Compounds 7a, 7b, 7f, 7h, 8b, 8f, 9b and 10a showed
good anti-bacterial activity with MIC values in the range
of 62.5–25 µg/mL, which were better than the standard
ampicillin. The compounds also exhibited anti-hypertensive
activity potential as indicated by their docking study in the
active site of ACE. This study highlighted compound 9a as
a lead molecule with good orientation in the active site of
ACE.
Experimental section
General
All solvents and reagents were used as supplied from the
commercial sources. Recorded melting points are uncor-
123

Mol Divers
rected. IR spectra were recorded on Shimadzu FT-IR 8401
spectrometer using KBr discs, and are expressed in wave
numbers (cm−1). All microwave heating experiments were
performed in a closed system, on Catalyst Scientific Micro-
wave Oven model CATA-R (2.45 GHz, 140–700 Watts) from
General experimental procedure for synthesis of
thiopyrano[2,3-c] pyrazoles (7a–h, 8a–h, 9a–h, 10a–h):
A mixture of equimolar amounts (2 mmol) of O-alkenylated/
alkynylated salicylaldehyde/naphthaldehyde and pyrazole-
5-thione, taken in 0.5 equiv. of ionic liquid [Hmim]HSO4
in a round-bottom flask was irradiated under microwave
irradiation at 280 W for 15/12 min, respectively, until the
reaction was confirmed as complete by TLC. The reac-
tion mass was washed with water (25 mL) after cooling it
to room temperature. The aqueous layer containing ionic
liquid was washed by ether in order to remove undesired
impurities, followed by drying under vacuum, which further
facilitated recovery of the ionic liquid. Ethanol was added to
the insoluble crude mass to allow the product to crystallize
into pure form. The final product was then filtered. Chro-
matographic purification was required to isolate some of the
compounds.
1
CatalystTM Systems, Pune, India. H NMR and 13C NMR
spectra were recorded on a Bruker Avance 400 spectrome-
1
ter operating at 400 MHz for H NMR and 100 MHz for
13C NMR as solutions in CDCl3, unless and otherwise indi-
cated. Chemical shifts are expressed in parts per million
(ppm, δ) and referenced to the residual protic solvent. Cou-
pling constants are expressed in Hertz (Hz). Splitting patterns
are designated as s, singlet; d, doublet; t, triplet; q, quar-
tet; and m, multiplet. The degree of substitution (C, CH,
CH2, and CH3) was determined by the APT method. The
ESI mass spectra were measured on Shimadzu LCMS-2010
spectrometer. TLC was performed on Merck 60 F254 pre-
coated silica plates, and spots were detected either by means
of UV (254, 366 nm) or permanganate solution [KMnO4
(3 g), K2CO3 (20 g), NaOH (5 mL, 5 % in H2O), H2O
(300 mL)] or 2,4-dinitrophenylhydrazine solution [2,4-DNP
(12 g), Conc. H2SO4 (6 mL), Water (8 mL), EtOH (20
mL)].
Spectroscopy data of compounds 7–10, 11, 12:
1-Methyl-3-(p-tolyl)-5,5a,6,11b-tetrahydro-3H-chro−
meno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole (7a): White
All the computational studies were carried out using Mae-
stro 9.0 version Schrödinger, LLC, New York, NY, USA
[72]. Structures of molecules were built using Chem Draw
Ultra 8.0 [73] and structures were converted into Mol2
format using Open Babel 2.3.0 [74]. The structures were
imported in Maestro 9.0. All the structures were minimized
using OPLS 2005 force field in standard option Ligprep in
Maestro 9.0 (LigPrep, version 2.3). Two well-known ACE
inhibitors, captopril and enalapril, were also minimized as
per the same protocol and added to the dataset as reference
compounds. These minimized structures were utilized for
docking in the active site of ACE using Glide 5.5 (Mae-
stro 9.0). The crystal structure of ACE co-crystallized with
captopril (PDB ID 4C2P) was downloaded from RCSB Pro-
tein Data Bank (PDB) [75]. Receptor grid was prepared,
using standard option Receptor Grid Generation in Mae-
stro 9.0. The van der Waals radii of the ligands were scaled
to 0.9 with partial charges cut-off to 0.25 [76,77]. All the
minimized compounds were docked rigidly by standard pre-
cision method. Different properties of the compounds were
calculated using standard option Qikprop in Maestro 9.0.
Acceptable range or recommended values for different prop-
erties, i.e., for molecular weight 130.0–725.0, number of
rotatable bonds 0–15, volume 500.0–2000.0, number of H-
bond donor 0.0–6.0, number of acceptor bond 2.0–20, log
P −2.0–6.5, and polar surface area 7.0–200.0. Percentage
human oral absorption indicates > 80% as high and < 25%
as poor [QikProp, version 3.2, Schrödinger, LLC, New York,
NY, 2009].
◦
solid, yield 87 %, mp 111–113 C, IR (νmax, cm−1): 3049,
2926, 1602, 1505, 1248, 1072, 1002, 765, 698, 661; 1H NMR
(400 MHz, CDCl3): δ 2.40 (s, 3H, CH3 of pyrazole), 2.46 (s,
4H, 5a-H & CH3 of phenyl ring), 2.90 (d, J = 12.8 Hz, 1H,
5-H), 3.26 (t, J = 12 Hz, 1H, 5-H), 4.24 (d, J = 4.4 Hz,
1H, 11b-H), 4.44 (d, J = 11.2 Hz, 1H, 6-H), 4.54 (d,
J = 11.2 Hz, 1H, 6-H), 6.82–7.50 (m, 8H, Ar-H); 13C NMR
(100MHz, CDCl3):δ 12.6, 21.1, 25.6, 32.8, 32.1, 70.2, 114.5,
115.9, 121.4, 122.3, 123.7, 127.6, 128.4, 129.0, 129.7, 136.5,
138.5, 150.1, 152.0; ESI-MS (m/z): 349.1 (M+H)+, Anal.
Calcd for C21H20N2OS: C, 72.38; H, 5.79; N, 8.04; S, 9.20;
Found: C, 72.49; H, 5.48; N, 7.89; S, 8.96.
1,5,5-Trimethyl-3-(p-tolyl)-5,5a,6,11b-tetrahydro-3H-
chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole
(7b):
White solid, yield 89 %, mp 118–120 ◦C, IR (νmax, cm−1):
3063, 2969, 2921, 1603, 1496, 1451, 1252, 1031, 1020, 762,
1
691, 674; H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H, 5-
CH3), 1.88 (s, 3H, 5-CH3), 2.41 (s, 3H, CH3 of pyrazole),
2.45 (s, 3H, CH3 of phenyl ring), 2.52 (m, 1H, 5a–H), 4.50
(d, J = 4.4 Hz, 1H, 11b-H), 4.57 (t, J = 10.4 Hz, 1H, 6-H),
4.74 (dd,J = 6.4, J = 2.0 Hz, 1H, 6-H), 7.18–7.90 (m,
8H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 14.3, 21.3, 26.5,
29.8, 32.4, 40.5, 45.6, 65.7, 110.4, 115.1, 118.7, 121.2, 123.4,
126.7, 128.0, 129.2, 130.8, 136.6, 140.3, 148.6, 153.2; ESI-
MS (m/z): 377.2 (M+H)+, Anal. Calcd for C23H24N2OS:
C, 73.37; H, 6.42; N, 7.44; S, 8.52; Found: C, 73.04; H, 6.14;
N, 7.21; S, 8.78.
123

Mol Divers
1-Methyl-3-(p-tolyl)-6,11b-dihydro-3H-chromeno[4ꢀ,3ꢀ: 1176, 1150, 1099, 1060, 839, 818, 793, 777, 751, 710, 685,
4,5]thiopyrano[2,3-c]pyrazole (7c): White solid, yield 86
%, mp 154–156 ◦C, IR (νmax, cm−1): 3056, 2931, 2854,
1694, 1644, 1595, 1549, 1504, 1292, 1273, 1242, 1218,
1181, 1148, 1104, 1074, 873, 840, 822, 803, 779, 757, 697,
669, 638, 618; 1H NMR (400 MHz, CDCl3): δ 2.40 (s, 3H,
CH3 of pyrazole), 2.42 (s, 3H, CH3 of phenyl ring), 4.77 (d,
J = 12 Hz, 1H, 6-H), 4.94–4.97 (m, 2H, 6-H & 11b-H),
6.07 (s, 1H, 5-H), 6.89–7.47 (m, 8H, Ar-H); 13C NMR (100
MHz, CDCl3): δ 12.6, 21.1, 35.2, 72.7, 109.4, 110.0, 117.0,
121.0, 122.7, 125.6, 127.5, 127.8, 128.0, 128.3, 129.9, 136.8,
137.4, 148.8, 153.9; ESI-MS (m/z): 347.3 (M+H)+, Anal.
Calcd for C21H18N2OS: C, 72.80; H, 5.24; N, 8.09; S, 9.26;
Found: C, 73.09; H, 4.87; N, 8.24; S, 9.39.
648, 611; 1H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H, CH3
of pyrazole), 2.39 (s, 3H, CH3 of phenyl ring), 2.84–2.94 (m,
1H, 5a-H), 3.88–3.94 (m, 1H, 6-H), 3.97–4.01 (m, 1H, 6-H),
4.04 (d, J = 10.4 Hz, 1H, 11b-H), 4.11 (d, J = 10.8 Hz,
1H, 5-H), 6.90–7.43 (m, 13H, Ar-H); 13C NMR (100 MHz,
CDCl3): δ 14.1, 21.2, 37.5, 46.6, 50.7, 71.7, 112.6, 116.8,
120.6, 122.7, 124.8, 127.8, 128.1, 128.6, 128.8, 129.2, 129.7,
133.3, 136.7, 136.7, 137.8, 148.7, 155.3; ESI-MS (m/z):
425.2 (M+H)+, Anal. Calcd for C27H24N2OS: C, 76.38; H,
5.70; N, 6.60; S, 7.55; Found: C, 76.45; H, 5.58; N, 6.90; S,
7.37.
1-Methyl-5-phenyl-3-(p-tolyl)-5,5a-dihydro-3H-chro-
meno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazol-6(11bH)-one
◦
1-Methyl-3-(p-tolyl)-3,4a,5,6,7,7a,7b,12b-octahydro-
(7f): White solid, yield 86 %, mp 217–219 C, IR (νmax
,
xantheno[9ꢀ,9aꢀ,1ꢀ:4,5,6]thiopyrano[2,3-c]pyrazole (7d): cm−1): 3011, 2921, 2850, 1771, 1691, 1627, 1541, 1501,
White solid, yield 90 %, mp 242–244 ◦C, IR (νmax, cm−1):
3061, 3035, 2955, 2929, 2899, 1608, 1581, 1512, 1450, 1302,
1279, 1230, 1204, 1179, 1150, 1108, 1081, 1070, 866, 850,
824, 780, 760, 734, 699, 654, 628, 610; 1H NMR (400 MHz,
CDCl3): δ 1.58–2.13 (m, 5H, CH2), 2.29–2.33 (m, 1H, 7b-
H), 2.37 (s, 3H, CH3 of pyrazole), 2.54 (s, 3H, CH3 of
phenyl ring), 2.65–2.69 (m, 1H, CH2), 4.04–4.06 (d, 1H,
J = 4.4 Hz, 12b-H), 4.14–4.18 (m, 1H, 4a-H), 4.29–4.30 (d,
1H, J = 2.8 Hz, 7a-H), 6.80–7.36 (m, 8H, Ar-H); 13C NMR
(100 MHz, CDCl3): δ 12.3, 17.1, 20.9, 28.6, 29.7, 33.2, 39.9,
47.4, 74.3, 116.7, 121.2, 122.0, 122.2, 126.6, 126.9, 129.3,
129.4, 135.8, 136.4, 136.7, 146.4, 156.3; ESI-MS (m/z):
389.1 (M+H)+, Anal. Calcd for C24H24N2OS: C, 74.19; H,
6.23; N, 7.21; S, 8.25; Found: C, 73.87; H, 6.47; N, 7.36; S,
8.48.
1312, 1275, 1259, 1201, 1174, 1108, 1082, 1074, 866, 836,
1
771, 738, 714, 699, 646; H NMR (400 MHz, CDCl3): δ
2.33 (s, 3H, CH3 of pyrazole), 2.39 (s, 3H, CH3 of phenyl
ring), 3.56–3.59 (m, 1H, 5a-H), 4.49 (d, J = 9.6 Hz, 1H,
5-H), 4.54 (d, J = 4.4 Hz, 1H, 11b-H), 7.12–7.51 (m, 13H,
Ar-H); 13C NMR (100 MHz, CDCl3): δ 12.5, 21.0, 32.6,
43.4, 46.9, 109.4, 117.0, 122.7, 124.6, 125.1, 128.4, 129.0,
129.1, 129.2, 129.2, 129.8, 132.0, 135.8, 136.8, 137.4, 148.5,
149.8, 166.6; ESI-MS (m/z): 439.2 (M+H)+, Anal. Calcd for
C27H22N2O2S: C, 73.95; H, 5.06; N, 6.39; S, 7.31; Found:
C, 73.64; H, 4.88; N, 6.63; S, 7.53.
Ethyl1-methyl-3-(p-tolyl)-5,5a,6,11b-tetrahydro-3H-
chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole-5-carbo-
xylate (7g): Yellow oil, yield 84 %, IR (νmax, cm−1): 3160,
3061, 2971, 2934, 1740, 1671, 1631, 1600, 1548, 1287, 1239,
1172, 1166, 1091, 1059, 1031, 860, 824, 752, 704, 660, 620;
1H NMR (400 MHz, CDCl3): δ 1.34 (s, 3H, 4ꢀ-CH3), 2.38
(s, 3H, CH3 of pyrazole), 2.42 (s, 3H, CH3 of phenyl ring),
2.44 (m, 1H, 5a-H), 3.66 (d, J = 11.2 Hz, 1H, 5-H), 4.20
(m, 2H, Two 3ꢀ-H), 4.31 (m, 1H, 6-H), 4.39 (d, J = 4 Hz,
1H, 11b-H), 4.57 (m, 1H, 6-H), 6.83–7.80 (m, 8H, Ar-H);
13C NMR (100 MHz, CDCl3): δ 13.8, 14.2, 20.7, 28.9, 35.6,
45.7, 63.0, 64.9, 118.5, 120.1, 123.4, 124.8, 125.6, 127.3,
128.0, 128.8, 129.3, 132.5, 136.8, 142.5, 150.8, 171.2; ESI-
MS (m/z): 421.2 (M+H)+, Anal. Calcd for C24H24N2O3S:
C, 68.55; H, 5.75; N, 6.66; S, 7.63; Found: C, 68.31; H, 5.53;
N, 6.38; S, 7.47.
1-Methyl-5-phenyl-3-(p-tolyl)-5,5a,6,11b-tetrahydro-
3H-chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole (7e):
White solid, yield 46 %, mp 266–268 ◦C, IR (νmax, cm−1):
3055, 3033, 2948, 2920, 2861, 1614, 1588, 1519, 1241, 1209,
1177, 1150, 1099, 1062, 839, 819, 793, 777, 750, 710, 685,
646, 609; 1H NMR (400 MHz, CDCl3): δ 2.37 (s, 3H, CH3
of pyrazole), 2.51 (s, 3H, CH3 of phenyl ring), 2.61–2.66 (m,
1H, 5a-H), 3.97–4.01 (m, 1H, 6-H), 4.24–4.27 (m, 1H, 6-H),
4.43 (d, J = 4.4 Hz, 1H, 11b-H), 4.52 (d, J = 11.2 Hz,
1H, 5-H), 6.86–7.52 (m, 13H, Ar-H); 13C NMR (100 MHz,
CDCl3): δ 12.4, 21.3, 33.2, 37.2, 43.9, 67.7, 114.0, 116.6,
121.1, 122.2, 124.0, 128.1, 128.5, 128.8, 128.9, 129.6, 129.6,
132.0, 136.8, 137.1, 137.8, 148.5, 153.1; ESI-MS (m/z):
425.2 (M+H)+, Anal. Calcd for C27H24N2OS: C, 76.38; H,
5.70; N, 6.60; S, 7.55; Found: C, 76.51; H, 5.62; N, 6.94; S,
7.34.
1,5-Dimethyl-5-(4-methylpent-3-en-1-yl)-3-(p-tolyl)-5,
5a,6,11b-tetrahydro-3H-chromeno[4ꢀ,3ꢀ:4,5]thiopyrano
[2,3-c]pyrazole (7h): Yellow oil, yield 85 %, IR (νmax
,
cm−1): 3060, 2948, 2921, 2861, 1639, 1610, 1514, 1292,
1252, 1230, 1164, 1080, 814, 739, 670, 658, 612; 1H NMR
(400 MHz, CDCl3): δ 1.30 (s, 3H, 5-CH3), 1.46 (s, 3H, 4ꢀ-
CH3), 1.51 (s, 3H, 4ꢀ-CH3), 2.10 (m, 2H, 1ꢀ-H & 2ꢀ-H), 2.23
(m, 2H, 1ꢀ-H & 2ꢀ-H), 2.44 (m, 1H, 5a-H), 2.48 (s, 3H, CH3
1-Methyl-5-phenyl-3-(p-tolyl)-5,5a,6,11b-tetrahydro-
3H-chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole (7eꢀ):
White solid, yield 43 %, mp 197–199 ◦C, IR (νmax, cm−1):
3055, 3034, 2949, 2921, 2860, 1614, 1588, 1518, 1241, 1208,
123

Mol Divers
of pyrazole), 2.51 (s, 3H, CH3 of phenyl ring), 4.04 (t, 1H,
6-H), 4.13 (m, 1H, 6-H), 4.40 (d, J = 4 Hz, 1H, 11b-H), 5.06
(t, 1H, 3ꢀ-H), 6.88–7.79 (m, 8H, Ar-H); 13C NMR (100 MHz,
CDCl3): δ 13.8, 17.2, 20.6, 21.2, 23.5, 26.0, 28.5, 40.3, 43.2,
49.4, 64.3, 120.2, 122.5, 123.0, 124.2, 124.9, 125.5, 126.8,
127.8, 128.9, 129.5, 130.4, 132.2, 136.7, 142.6, 151.4; ESI-
MS (m/z): 445.1 (M+H)+, Anal. Calcd for C28H32N2OS:
C, 75.64; H, 7.25; N, 6.30; S, 7.21; Found: C, 75.43; H, 7.46;
N, 6.03; S, 6.95.
C, 65.48; H, 4.12; N, 7.64; S, 8.74; Found: C, 65.14; H, 4.37;
N, 7.35; S, 8.46.
1-Methyl-3-(3-chlorophenyl)-3,4a,5,6,7,7a,7b,12b-octa-
hydroxantheno[9ꢀ,9aꢀ,1ꢀ:4,5,6]thiopyrano[2,3-c]pyra-
◦
zole (8d): White solid, yield 89 %, mp 178–180 C, IR
(νmax, cm−1): 3060, 3039, 2962, 2925, 2899, 1611, 1580,
1512, 1451, 1302, 1280, 1230, 1203, 1179, 1150, 1108, 1081,
1070, 868, 849, 821, 783, 764, 733, 699, 651, 628, 612; 1H
NMR (400 MHz, CDCl3): δ 1.52–1.87 (m, 3H, CH2), 1.93 (s,
3H, CH3), 1.95–1.99 (m, 1H, CH2), 2.08–2.13 (m, 1H, 7b-
H), 2.21–2.30 (m, 2H, CH2), 4.04–4.05 (d, 1H, J = 4 Hz,
12b-H), 4.10–4.11 (d, 1H, J = 2.4 Hz, 4a-H), 4.25–4.33
(m, 1H, 7a-H), 6.84–7.64 (m, 8H, Ar-H); 13C NMR (100
MHz, CDCl3): δ 15.3, 19.2, 30.1, 32.9, 35.2, 39.7, 41.6, 70.3,
112.0, 116.6, 119.0, 121.0, 121.9, 123.4, 127.2, 128.9, 130.1,
131.7, 132.4, 134.8, 140.5, 149.8, 154.1; ESI-MS (m/z):
409.2 (M+H)+, Anal. Calcd for C23H21ClN2OS: C, 67.55;
H, 5.18; N, 6.85; S, 7.84; Found: C, 67.79; H, 5.36; N, 7.08;
S, 8.04.
3-(3-Chlorophenyl)-1-methyl-5,5a,6,11b-tetrahydro-
3H-chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole (8a):
White solid, yield 88 %, mp 154–156 ◦C, IR (νmax, cm−1):
3058, 2919, 1599, 1500, 1254, 1067, 1008, 760, 692, 668; 1H
NMR (400 MHz, CDCl3): δ 2.15 (s, 3H, CH3 of pyrazole),
2.21 (m, 1H, 5a-H), 2.71 (d, J = 12.8 Hz, 1H, 5-H), 3.01
(t, J = 12.4 Hz, 1H, 5-H), 4.14 (d, J = 4 Hz, 1H, 11b-H),
4.23 (d, J = 11.2 Hz, 1H, 6ꢀ-H), 4.39 (d, J = 11.2 Hz,
1H, 6ꢀꢀ-H), 6.83–7.66 (m, 8H, Ar-H); 13C NMR (100 MHz,
CDCl3): δ 15.0, 27.5, 31.2, 33.3, 65.7, 113.1, 116.5, 119.3,
120.8, 121.5, 123.3, 127.2, 128.7, 129.7, 131.6, 132.3, 134.6,
139.8, 149.8, 154.1; ESI-MS (m/z): 369.1 (M+H)+, Anal.
Calcd for C20H17ClN2OS: C, 65.12; H, 4.65; N, 7.59; S,
8.69; Found: C, 64.97; H, 4.89; N, 7.77; S, 8.41.
3-(3-Chlorophenyl)-1-methyl-5-phenyl-5,5a,6,11b-tetr-
ahydro-3H-chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyra-
zole (8e): White solid, yield 45 %, mp 255–257 ◦C, IR (νmax
,
cm−1): 3057, 3033, 2948, 2921, 2864, 1614, 1588, 1519,
3-(3-Chlorophenyl)-1,5,5-trimethyl-5,5a,6,11b-tetrah-
1244, 1207, 1177, 1154, 1099, 1064, 839, 815, 794, 779,
1
ydro-3H-chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole 753, 712, 689, 648, 609; H NMR (400 MHz, CDCl3): δ
◦
(8b): White solid, yield 91 %, mp 116–118 C, IR (νmax
,
2.51 (s, 3H, CH3 of pyrazole), 2.63 (m, 1H, 5a-H), 3.98 (m,
1H, 6-H), 4.27 (m, 1H, 6-H), 4.44 (d, J = 4 Hz, 1H, 11b-
H), 4.51 (d, J = 11.2 Hz, 1H, 5-H), 6.83–7.64 (m, 13H,
Ar-H); 13C NMR (100 MHz, CDCl3): δ 12.5, 33.6, 37.5,
44.1, 67.2, 114.3, 116.3, 120.7, 121.1, 122.4, 123.3, 127.5,
128.6, 128.8, 128.9, 129.7, 129.8, 131.9, 133.4, 135.2, 138.3,
149.8, 152.3; ESI-MS (m/z): 445.1 (M+H)+, Anal. Calcd for
C26H21ClN2OS: C, 70.18; H, 4.76; N, 6.30; S, 7.21; Found:
C, 70.33; H, 5.05; N, 6.56; S, 6.92.
cm−1): 3064, 2965, 2928, 1597, 1488, 1450, 1254, 1031,
1
1018, 760, 694, 671; H NMR (400 MHz, CDCl3): δ 1.51
(s, 3H, 5-CH3), 1.60 (s, 3H, 5-CH3), 2.13 (s, 3H, CH3 of
pyrazole), 2.18–2.23 (m, 1H, 5a-H), 4.17 (d, J = 4 Hz, 1H,
11b-H), 4.19–4.24 (t, J = 10.8 Hz, 1H, 6-H), 4.40–4.44
(ddd, J = 11.2, J = 4, J = 1.2 Hz, 1H, 6-H), 6.85–
7.64 (m, 8H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 15.4,
27.2, 30.6, 32.8, 41.4, 45.7, 65.0, 112.2, 116.7, 119.1, 120.9,
121.9, 123.3, 127.0, 128.8, 129.9, 131.5, 132.2, 134.8, 140.4,
149.9, 154.2; ESI-MS (m/z): 397.2 (M+H)+, Anal. Calcd for
C22H21ClN2OS: C, 66.57; H, 5.33; N, 7.06; S, 8.08; Found:
C, 66.78; H, 5.56; N, 6.78; S, 8.25.
3-(3-Chlorophenyl)-1-methyl-5-phenyl-5,5a,6,11b-tetr-
ahydro-3H-chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyra-
◦
zole (8eꢀ): White solid, yield 45 %, mp 199–201 C, IR
(νmax, cm−1): 3058, 3029, 2949, 2922, 2861, 1610, 1588,
1519, 1241, 1208, 1180, 1150, 1099, 1060, 839, 815, 794,
777, 751, 712, 689, 648, 610; 1H NMR (400 MHz, CDCl3):
δ 2.39 (s, 3H, CH3 of pyrazole), 2.90 (m, 1H, 5a-H), 3.90
(m, 1H, 6-H), 3.99 (m, 1H, 6-H), 4.04 (d, J = 10.8 Hz,
1H, 11b-H), 4.11 (d, J = 10.8 Hz, 1H, 5-H), 6.84–7.65
(m, 13H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 14.3,
37.2, 46.4, 50.6, 71.0, 112.4, 116.5, 120.1, 121.2, 122.5,
124.2, 127.3, 128.2, 128.5, 128.7, 129.3, 129.6, 132.4,
133.1, 135.5, 138.3, 148.7, 154.5; ESI-MS (m/z): 445.1
(M+H)+, Anal. Calcd for C26H21ClN2OS: C, 70.18; H,
4.76; N, 6.30; S, 7.21; Found: C, 70.24; H, 5.01; N, 6.45;
S, 6.97.
3-(3-Chlorophenyl)-1-methyl-6, 11b-dihydro-3H-chro-
meno[4ꢀ, 3ꢀ : 4, 5]thiopyrano[2, 3-c]pyrazole (8c): White
◦
solid, yield 86 %, mp 176–178 C, IR (νmax, cm−1): 3060,
2929, 2850, 1694, 1644, 1601, 1549, 1504, 1290, 1270, 1240,
1218, 1179, 1154, 1101, 1073, 870, 844, 820, 802, 783, 759,
698, 669, 638, 622; 1H NMR (400 MHz, CDCl3): δ 2.17 (s,
3H, CH3 of pyrazole), 4.77 (d, J = 12.4 Hz, 1H, 6-H), 4.94–
4.97 (m, 2H, 6-H & 11b-H), 6.07 (s, 1H, 5-H), 6.83–7.62 (m,
8H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 14.2, 35.5, 71.8,
109.2, 110.0, 116.8, 119.7, 120.4, 121.3, 123.1, 127.1, 128.7,
129.5, 130.1, 131.2, 132.6, 134.2, 140.2, 149.2, 154.1; ESI-
MS (m/z): 367.1 (M+H)+, Anal. Calcd for C20H15ClN2OS:
123

Mol Divers
3-(3-Chlorophenyl)-1-methyl-5-phenyl-5,5a-dihydro-
3H-chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazol-
6(11bH)-one (8f): White solid, yield 87 %, mp 236–238 ◦C,
IR (νmax, cm−1): 3010, 2926, 2845, 1766, 1691, 1626, 1541,
1500, 1310, 1278, 1259, 1203, 1174, 1108, 1081, 1074, 869,
839, 770, 738, 714, 698, 649; 1H NMR (400 MHz, CDCl3):
δ 2.32 (s, 3H, CH3 of pyrazole), 3.57 (m, 1H, 5a-H), 4.49
(d, J = 10.4 Hz, 1H, 5-H), 4.53 (d, J = 4 Hz, 1H, 11b-H),
7.11–7.64 (m, 13H, Ar-H); 13C NMR (100 MHz, CDCl3):
δ 12.6, 32.5, 43.4, 46.9, 109.5, 112.3, 117.0, 119.3, 122.7,
124.5, 125.1, 127.5, 128.6, 129.0, 129.0, 129.1, 129.3, 131.4,
132.1, 135.8, 140.3, 148.7, 149.9, 166.5; ESI-MS (m/z):
459.3 (M+H)+, Anal. Calcd for C26H19ClN2O2S: C, 68.04;
H, 4.17; N, 6.10; S, 6.99; Found: C, 68.29; H, 4.37; N, 5.88;
S, 7.17.
13-(3-Chlorophenyl)-11-methyl-2a,3,10c,13-tetrahydro-
2H-benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]py-
◦
razole (9a): White solid, yield 89 %, mp 178–180 C, IR
(νmax, cm−1): 3055, 2984, 2930, 2901, 1599, 1515, 1500,
1
1229, 1025, 1013, 832, 764, 743, 691, 674; H NMR (400
MHz, CDCl3): δ 1.37 (s, 3H, CH3 of pyrazole), 2.92 (m, 2H,
2-H and 2a-H), 3.59 (dd, J = 12, J = 4 Hz, 1H, 2ꢀ-H), 4.21
(d, J = 8 Hz, 2H, Two 3-H), 4.63 (d, J = 3.2 Hz, 1H, 10c-
H), 7.11–7.99(m, 10H, Ar-H);13CNMR(100MHz, CDCl3):
δ 13.6, 29.5, 30.8, 31.7, 65.5, 112.4, 114.5, 118.8, 121.0,
122.6, 123.3, 123.4, 126.6, 127.0, 128.6, 128.9, 129.2, 130.0,
131.8, 133.7, 134.7, 140.6, 149.8, 151.8; ESI-MS (m/z):
419.1 (M+H)+, Anal. Calcd for C24H19ClN2OS: C, 68.81;
H, 4.57; N, 6.69; S, 7.65; Found: C, 69.08; H, 4.74; N, 6.88;
S, 7.39.
13-(3-Chlorophenyl)-2,2,11-trimethyl-2a,3,10c,13-tet-
rahydro-2H-benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano
[2,3-c]pyrazole (9b): White solid, yield 91 %, mp 232–
Ethyl3-(3-chlorophenyl)-1-methyl-5,5a,6,11b-tetrahy-
dro-3H-chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole-
5-carboxylate (8g):Yellowoil, yield81%, IR(νmax, cm−1):
3163, 3060, 2971, 2934, 1739, 1670, 1632, 1604, 1548, 1287,
1240, 1170, 1166, 1094, 1058, 1031, 860, 822, 752, 700,
◦
234 C, IR (νmax, cm−1): 3064, 2963, 2917, 1621, 1593,
1516, 1231, 1134, 1015, 831, 818, 781, 748, 686, 663,
1
1
664, 621; H NMR (400 MHz, CDCl3): δ 1.32 (s, 3H, 4ꢀ-
603; H NMR (400 MHz, CDCl3): δ 1.44 (s, 3H, 2-CH3),
1.55 (s, 3H, 2-CH3), 1.75 (s, 3H, CH3 of pyrazole), 2.22–
2.27 (m, 1H, 2a-H), 4.22 (t, J = 11.2 Hz, 1H, 3-H),
4.45–4.49 (dd, J = 10.8 HZ, J = 3.6, 1H, 3-H), 4.83
(d, J = 3.2 HZ, 1H, 10c-H), 7.09–8.10 (m, 10H, Ar-
H); 13C NMR (100 MHz, CDCl3): δ 14.3, 27.3, 27.5,
32.1, 41.6, 45.8, 64.6, 112.5, 114.5, 118.8, 121.0, 122.3,
123.2, 123.4, 126.5, 127.0, 128.6, 128.9, 129.2, 130.0, 131.7,
133.6, 134.8, 140.6, 149.8, 151.8; ESI-MS (m/z): 447.2
(M+H)+, Anal. Calcd for C26H23ClN2OS: C, 69.86; H,
5.19; N, 6.27; S, 7.17; Found: C, 70.07; H, 5.38; N, 6.42;
S, 7.22.
CH3), 2.51–2.58 (m, 4H, 5a-H & CH3 of pyrazole), 3.69
(d, J = 11.2 Hz, 1H, 5-H), 4.20–4.25 (m, 2H, Two 3ꢀ-H),
4.29–4.32 (m, 1H, 6-H), 4.40 (d, J = 4.4 Hz, 1H, 11b-
H), 4.57–4.60 (m, 1H, 6-H), 6.85–7.65 (m, 8H, Ar-H); 13C
NMR (100 MHz, CDCl3): δ 13.1, 14.2, 29.3, 36.1, 46.0, 62.6,
65.7, 112.4, 116.7, 119.3, 120.8, 121.7, 123.4, 127.1, 128.7,
128.9, 129.6, 131.4, 132.3, 134.2, 140.2, 151.6, 170.2; ESI-
MS(m/z):441.1(M+H)+, Anal. CalcdforC23H21ClN2O3S:
C, 62.65; H, 4.80; N, 6.35; S, 7.27; Found: C, 62.67; H, 4.98;
N, 6.49; S, 7.52.
3-(3-Chlorophenyl)-1,5-dimethyl-5-(4-methylpent-3-
en-1-yl)-5,5a,6,11b-tetrahydro-3H-chromeno[4ꢀ,3ꢀ:4,5]
thiopyrano[2,3-c]pyrazole (8h): Yellow oil, yield 87 %,
IR (νmax, cm−1): 3060, 2947, 2923, 2860, 1639, 1610, 1513,
1292, 1250, 1230, 1160, 1084, 812, 740, 674, 662, 611; 1H
NMR (400 MHz, CDCl3): δ 1.30 (s, 3H, 5-CH3), 1.43 (s,
3H, 4ꢀ-CH3), 1.51 (s, 3H, 4ꢀ-CH3), 2.09 (m, 2H, 1ꢀ-H & 2ꢀ-
H), 2.20 (m, 2H, 1ꢀ-H & 2ꢀ-H), 2.44 (m, 1H, 5a-H), 2.53
(s, 3H, CH3 of pyrazole), 4.02 (t, 1H, 6-H), 4.15 (m, 1H,
6-H), 4.38 (d, J = 4 Hz, 1H, 11b-H), 5.07 (t, 1H, 3ꢀ-H),
6.87–7.77 (m, 8H, Ar-H); 13C NMR (100 MHz, CDCl3):
δ 14.3, 17.7, 21.2, 22.4, 25.6, 27.2, 39.4, 43.3, 49.6, 64.9,
112.4, 116.5, 119.2, 120.8, 121.7, 123.3, 124.3, 124.9, 127.1,
128.8, 129.7, 131.4, 132.2, 134.7, 140.5, 149.7, 154.3; ESI-
MS (m/z): 465.1 (M+H)+, Anal. Calcd for C27H29ClN2OS:
C, 69.73; H, 6.29; N, 6.02; S, 6.89; Found: C, 70.04; H, 6.53;
N, 6.24; S, 7.12.
13-(3-Chlorophenyl)-11-methyl-10c,13-dihydro-3H-be-
nzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazo-
le (9c):White solid, yield 86 %, mp 218–220 ◦C, IR (νmax
,
cm−1): 3054, 2920, 2848, 1703, 1654, 1581, 1554, 1510,
1294, 1266, 1234, 1202, 1184, 1149, 1118, 1069, 864, 847,
821, 810, 780, 754, 690, 657, 628, 611; 1H NMR (400
MHz, CDCl3): δ 1.72 (s, 3H, CH3 of pyrazole), 4.72 (d,
J = 12.4 Hz, 1H, 3-H), 4.92 (m, 2H, 3-H & 10c-H), 6.02
(s, 1H, 2-H), 7.06–8.23 (m, 10H, Ar-H); 13C NMR (100
MHz, CDCl3): δ 13.4, 35.2, 72.5, 106.4, 115.5, 121.1, 122.6,
123.4, 124.6, 124.8, 127.1, 127.5, 129.7, 130.1, 131.2, 132.3,
133.7, 134.8, 136.3, 140.4, 141.7, 143.7, 149.8, 151.3; ESI-
MS (m/z): 417.2 (M+H)+, Anal. Calcd for C24H17ClN2OS:
C, 69.14; H, 4.11; N, 6.72; S, 7.69; Found: C, 69.31; H, 4.25;
N, 7.05; S, 7.86.
123

Mol Divers
1-Methyl-3-(3-chlorophenyl)-3,4a,5,6,7,7a,7b,14c-octa- 1624, 1599, 1515, 1299, 1231, 1177, 1161, 1094, 1062, 1024,
hydrobenzo[7ꢀ,8ꢀ]xantheno[9ꢀ,9aꢀ,1ꢀ:4,5,6]thiopyrano
[2,3-c]pyrazole (9d): White solid, yield 88 %, mp 194–196
◦C, IR (νmax, cm−1): 3039, 3005, 2920, 2877, 1613, 1511,
1444, 1312, 1269, 1248, 1199, 1166, 1140, 1100, 1083, 1060,
860, 839, 820, 780, 755, 721, 694, 648, 630, 613; 1H NMR
(400 MHz, CDCl3): δ 1.04–1.70 (m, 4H, CH2), 1.73 (s, 3H,
CH3 of pyrazole), 1.74–1.87 (m, 2H, CH2), 2.34 (m, 1H,
7b-H), 3.47 (m, 1H, 4a-H), 4.39 (m, 1H, 7a-H), 4.70 (d, 1H,
J = 4 Hz, 14c-H), 7.11–7.90 (m, 10H, Ar-H); 13C NMR
(100 MHz, CDCl3): δ 14.2, 20.3, 27.2, 29.7, 31.0, 42.1, 48.3,
75.0, 113.3, 119.1, 121.1, 121.7, 122.1, 123.2, 126.3, 127.0,
128.7, 129.5, 130.0, 133.1, 134.7, 135.5, 136.5, 140.6, 146.1,
149.7, 152.2; ESI-MS (m/z): 459.1 (M+H)+, Anal. Calcd for
C27H23ClN2OS: C, 70.65; H, 5.05; N, 6.10; S, 6.99; Found:
C, 70.84; H, 5.27; N, 6.27; S, 7.19.
864, 819, 752, 712, 666, 615; 1H NMR (400 MHz, CDCl3): δ
1.33 (s, 3H, 4ꢀ-CH3), 1.37 (s, 3H, CH3 of pyrazole), 3.16 (m,
1H, 2a-H), 3.69 (d, J = 4.4 HZ, 1H, 2-H), 3.98 (t, 1H, 3-H),
4.25 (m, 3H, 3-H & Two 3ꢀ-H), 4.80 (d, J = 5.2 Hz, 1H, 10c-
H), 7.11–7.97(m, 10H, Ar-H);13CNMR(100MHz, CDCl3):
δ 13.2, 14.2, 29.1, 36.3, 46.1, 62.5, 65.7, 113.3, 115.5, 118.7,
121.1, 122.4, 123.5, 126.9, 127.2, 128.6, 129.2, 129.4, 129.6,
130.2, 133.8, 134.7, 136.6, 137.2, 148.6, 151.5, 170.2; ESI-
MS(m/z):491.2(M+H)+, Anal. CalcdforC27H23ClN2O3S:
C, 66.05; H, 4.72; N, 5.71; S, 6.53; Found: C, 66.27; H, 4.53;
N, 5.54; S, 6.78.
13-(3-Chlorophenyl)-2,11-dimethyl-2-(4-methylpent-3-
en-1-yl)-2a,3,10c,13-tetrahydro-2H-benzo[5ꢀ,6ꢀ]chrom-
eno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole (9h): Yellow oil,
yield 87 %, IR (νmax, cm−1): 3066, 2954, 2926, 2859, 1626,
1605, 1523, 1299, 1258, 1236, 1164, 1092, 822, 753, 699,
13-(3-Chlorophenyl)-11-methyl-2-phenyl-2a,3,10c,13-
tetrahydro-2H-benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopy-
rano[2,3-c]pyrazole (9e): White solid, yield 89 %, mp 226–
1
664, 619; H NMR (400 MHz, CDCl3): δ 1.31 (s, 3H, 2-
CH3), 1.46 (s, 3H, 4ꢀ-CH3), 1.52 (s, 3H, 4ꢀ-CH3), 1.71 (s, 3H,
CH3 of pyrazole), 2.03–2.07 (m, 2H, 2ꢀ-H & 1ꢀ-H), 2.19–2.23
(m, 2H, 2a-H & 1ꢀ-H), 2.41 (s, 1H, 2ꢀ-H), 4.35 (t, 1H, 3-H),
4.50 (m, 1H, 3-H), 4.89 (d, J = 4.8 Hz, 1H, 10c-H), 5.17 (t,
1H, 3ꢀ-H), 7.11–8.11 (m, 10H, Ar-H); 13C NMR (100 MHz,
CDCl3): δ 14.3, 17.6, 22.1, 23.6, 25.7, 27.0, 39.9, 43.2, 49.0,
64.8, 111.8, 114.6, 118.7, 121.2, 122.5, 123.2, 123.2, 123.5,
126.5, 127.0, 128.6, 128.8, 129.5, 130.4, 131.5, 132.4, 133.6,
134.7, 137.2, 148.8, 151.7; ESI-MS (m/z): 515.2 (M+H)+,
Anal. Calcd for C31H31ClN2OS: C, 72.28; H, 6.07; N, 5.44;
S, 6.22; Found: C, 72.46; H, 6.32; N, 5.70; S, 6.48.
◦
228 C, IR (νmax, cm−1): 3055, 2924, 2862, 1651, 1621,
1599, 1518, 1283, 1260, 1234, 1177, 1164, 1141, 1090, 866,
1
823, 771, 752, 731, 699, 666, 611; H NMR (400 MHz,
CDCl3): δ 1.39 (s, 3H, CH3 of pyrazole), 3.05 (m, 1H, 2a-
H), 3.95 (d, J = 5.6 Hz, 1H, 2-H), 4.00 (t, 1H, 3-H), 4.22
(m, 1H, 3-H), 4.63 (d, J = 4 Hz, 1H, 10c-H), 7.10–7.88
(m, 15H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 13.1, 30.3,
43.2, 50.3, 66.1, 113.1, 116.9, 118.8, 121.1, 122.6, 123.5,
126.8, 127.1, 128.0, 128.2, 128.6, 128.8, 128.9, 129.7, 130.0,
131.9, 133.8, 134.7, 136.8, 136.9, 140.4, 149.7, 151.8; ESI-
MS (m/z): 495.2 (M+H)+, Anal. Calcd for C30H23ClN2OS:
C, 72.79; H, 4.68; N, 5.66; S, 6.48; Found: C, 73.04; H, 4.84;
N, 5.87; S, 6.71.
11-Methyl-13-phenyl-2a,3,10c,13-tetrahydro-2H-ben-
zo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole
◦
(10a): White solid, yield 90 %, mp 171–173 C, IR (νmax
,
13-(3-Chlorophenyl)-11-methyl-2-phenyl-10c,13-dihy-
dro-2H-benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,
3-c]pyrazol-3(2aH)-one (9f): White solid, yield 85 %, mp
202–204 ◦C, IR (νmax, cm−1): 3020, 2930, 2835, 1760, 1689,
1631, 1537, 1511, 1317, 1266, 1250, 1188, 1169, 1111,
cm−1): 3058, 2929, 2901, 1598, 1517, 1499, 1226, 1027,
1011, 813, 760, 741, 695, 670; 1H NMR (400 MHz, CDCl3):
δ 1.37 (s, 3H, CH3 of pyrazole), 2.87–2.94 (m, 2H, 2-H and
2a-H), 3.57–3.61 (dd, J = 12, J = 4 Hz, 1H, 2-H), 4.20–
4.22 (m, 2H, Two 3-H), 4.64 (d, J = 3.2 Hz, 1H, 10c-H),
7.11–7.99 (m, 11H, Ar-H); 13C NMR (100 MHz, CDCl3): δ
29.5, 30.6, 30.9, 31.7, 65.4, 114.2, 114.9, 115.5, 118.7, 119.2,
120.7, 122.4, 123.1, 126.7, 127.1, 128.6, 129.1, 130.3, 130.5,
133.7, 139.4, 151.6; ESI-MS (m/z): 385.2 (M+H)+, Anal.
Calcd for C24H20N2OS: C, 74.97; H, 5.24; N, 7.29; S, 8.34;
Found: C, 74.68; H, 5.44; N, 7.56; S, 8.59.
1
1081, 1061, 864, 844, 772, 748, 701, 690, 640; H NMR
(400 MHz, CDCl3): δ 1.41 (s, 3H, CH3 of pyrazole), 3.03
(m, 1H, 2a-H), 3.91 (d, J = 5.6 Hz, 1H, 2-H), 4.63 (d,
J = 4.4 HZ, 1H, 10c-H), 7.08–7.92 (m, 15H, Ar-H); 13C
NMR (100 MHz, CDCl3): δ 13.3, 30.2, 43.1, 50.4, 117.4,
120.1, 121.6, 122.5, 124.9, 126.9, 127.1, 127.4, 127.7, 128.8,
129.0, 129.4, 130.1, 132.7, 134.8, 136.6, 136.8, 136.9, 139.1,
140.7, 142.7, 150.9, 166.6; ESI-MS (m/z): 509.1 (M+H)+,
Anal. Calcd for C30H21ClN2O2S: C, 70.79; H, 4.16; N, 5.50;
S, 6.30; Found: C, 71.03; H, 4.34; N, 5.74; S, 6.52.
2,2,11-Trimethyl-13-phenyl-2a,3,10c,13-tetrahydro-
2H-benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]
pyrazole (10b): White solid, yield 89 %, mp 198–200
◦C, IR (νmax, cm−1): 3058, 2985, 2959, 2927, 1626, 1599,
Ethyl13-(3-chlorophenyl)-11-methyl-2a,3,10c,13-tetra- 1525, 1230, 1138, 1020, 999, 820, 755, 696, 660; 1H NMR
hydro-2H-benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano-
[2,3-c]pyrazole-2-carboxylate (9g): Yellow oil, yield 82
%, IR (νmax, cm−1): 3160, 3055, 2980, 2928, 1732, 1670,
(400 MHz, CDCl3): δ 1.46 (s, 3H, 2-CH3), 1.54 (s, 3H, 2-
CH3), 1.74 (s, 3H, CH3 of pyrazole), 2.23 (td, J = 11.6,
J = 4.4 Hz, 1H, 2a-H), 4.26 (t, J = 11.2 Hz, 1H, 3-
123

Mol Divers
H), 4.47 (ddd, J = 12 HZ, J = 5.6, J = 2.4, 1H, 3-H),
4.85 (d, J = 3.6 HZ, 1H, 10c-H), 7.11–8.13 (m, 11H, Ar-
H); 13C NMR (100 MHz, CDCl3): δ 14.4, 27.3, 27.6, 32.1,
41.6, 45.5, 64.6, 112.0, 114.6, 118.8, 122.5, 123.2, 123.4,
126.5, 127.1, 128.6, 128.8, 129.0, 129.1, 131.5, 133.7, 139.5,
149.3, 151.8; ESI-MS (m/z): 413.2 (M+H)+, Anal. Calcd for
C26H24N2OS: C, 75.70; H, 5.86; N, 6.79; S, 7.77; Found: C,
75.56; H, 6.12; N, 6.57; S, 8.06.
Calcd for C30H24N2OS: C, 78.23; H, 5.25; N, 6.08; S, 6.96;
Found: C, 78.46; H, 5.37; N, 5.87; S, 6.76.
11-Methyl-2,13-diphenyl-10c,13-dihydro-2H-benzo[5ꢀ,
6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazol-3(2aH)-
one (10f): White solid, yield 86 %, mp 196–198 ◦C, IR (νmax
,
cm−1): 3028, 2934, 2832, 1764, 1688, 1631, 1539, 1511,
1321, 1268, 1253, 1188, 1166, 1116, 1087, 1068, 864, 840,
1
777, 751, 702, 697, 641; H NMR (400 MHz, CDCl3): δ
11-Methyl-13-phenyl-10c,13-dihydro-3H-benzo[5ꢀ,6ꢀ]
chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyrazole (10c):
White solid, yield 85 %, mp 206–208 ◦C, IR (νmax, cm−1):
3059, 2927, 2842, 1708, 1650, 1588, 1557, 1516, 1299, 1266,
1237, 1201, 1186, 1149, 1118, 1066, 865, 848, 822, 816, 777,
750, 694, 660, 629, 617; 1H NMR (400 MHz, CDCl3): δ 1.72
(s, 3H, CH3 of pyrazole), 4.74 (d, J = 12.4 Hz, 1H, 3-H),
4.92 (m, 2H, 3-H & 10c-H), 6.02 (s, 1H, 2-H), 7.08–8.23
(m, 11H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 13.4, 35.3,
72.5, 106.3, 115.5, 119.2, 122.6, 123.4, 124.8, 127.2, 127.5,
129.7, 130.2, 130.5, 131.2, 132.3, 133.6, 136.4, 139.6, 141.8,
143.8, 151.4; ESI-MS (m/z): 383.1 (M+H)+, Anal. Calcd for
C24H18N2OS: C, 75.37; H, 4.74; N, 7.32; S, 8.38; Found: C,
75.64; H, 4.46; N, 7.56; S, 8.51.
1.44 (s, 3H, CH3 of pyrazole), 3.03 (m, 1H, 2a-H), 3.94 (d,
J = 5.6 Hz, 1H, 2-H), 4.62 (d, J = 4 HZ, 1H, 10c-H), 7.06–
7.91 (m, 16H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 13.1,
30.1, 43.0, 50.3, 115.6, 117.5, 120.7, 121.5, 122.6, 123.4,
124.9, 126.8, 127.5, 127.6, 127.7, 128.8, 129.3, 130.2, 132.7,
134.6, 136.6, 139.1, 142.7, 150.9, 166.6; ESI-MS (m/z):
475.1 (M+H)+, Anal. Calcd for C30H22N2O2S: C, 75.93;
H, 4.67; N, 5.90; S, 6.76; Found: C, 75.67; H, 4.46; N, 4.87;
S, 6.57.
Ethyl11-methyl-13-phenyl-2a,3,10c,13-tetrahydro-2H-
benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyraz-
ole-2-carboxylate (10g): Yellow oil, yield 84 %, IR (νmax
,
cm−1): 3166, 3062, 2982, 2933, 1737, 1678, 1620, 1601,
1512, 1299, 1235, 1179, 1162, 1097, 1065, 1022, 860, 823,
1-Methyl-3-phenyl-3,4a,5,6,7,7a,7b,14c-octahydroben- 751, 711, 668, 614; 1H NMR (400 MHz, CDCl3): δ 1.33 (s,
zo[7ꢀ,8ꢀ]xantheno[9ꢀ,9aꢀ,1ꢀ:4,5,6]thiopyrano[2,3-c]pyr-
3H, 4ꢀ-CH3), 1.37 (s, 3H, CH3 of pyrazole), 3.16 (m, 1H,
2a-H), 3.71 (d, J = 4 HZ, 1H, 2-H), 4.01 (t, 1H, 3-H), 4.25
(m, 3H, 3-H & Two 3ꢀ-H), 4.82 (d, J = 5.2 Hz, 1H, 10c-H),
7.11–7.97 (m, 11H, Ar-H); 13C NMR (100 MHz, CDCl3): δ
13.1, 14.1, 29.1, 36.3, 46.0, 62.4, 65.7, 113.3, 115.5, 118.6,
120.4, 122.6, 123.5, 126.8, 127.3, 128.6, 129.7, 130.6, 133.8,
136.5, 137.2, 139.7, 148.6, 151.5, 170.2; ESI-MS (m/z):
457.2 (M+H)+, Anal. Calcd for C27H24N2O3S: C, 71.03;
H, 5.30; N, 6.14; S, 7.02; Found: C, 71.31; H, 5.57; N, 6.42;
S, 7.29.
◦
azole (10d): White solid, yield 90 %, mp 184–186 C, IR
(νmax, cm−1): 3033, 3002, 2920, 2879, 1610, 1516, 1444,
1310, 1266, 1248, 1199, 1168, 1140, 1100, 1077, 1059, 858,
834, 824, 783, 762, 725, 696, 648, 639, 615; 1H NMR (400
MHz, CDCl3): δ 1.01–1.70 (m, 4H, CH2), 1.73 (s, 3H, CH3
of pyrazole), 1.75–1.86 (m, 2H, CH2), 3.22 (m, 1H, 7b-
H), 3.48 (m, 1H, 4a-H), 4.39 (m, 1H, 7a-H), 4.70 (d, 1H,
J = 4Hz, 14c-H), 7.11–7.90(m, 11H, Ar-H);13CNMR(100
MHz, CDCl3): δ 12.8, 20.2, 27.2, 29.7, 31.0, 42.1, 48.3, 74.9,
113.3, 115.5, 120.7, 121.7, 122.1, 123.0, 126.3, 127.1, 128.7,
129.4, 130.8, 133.5, 135.6, 136.6, 139.3, 146.2, 152.1; ESI-
MS (m/z): 425.1 (M+H)+, Anal. Calcd for C27H24N2OS:
C, 76.38; H, 5.70; N, 6.60; S, 7.55; Found: C, 76.49; H, 5.58;
N, 6.46; S, 7.34.
2,11-Dimethyl-2-(4-methylpent-3-en-1-yl)-13-phenyl-
2a,3,10c,13-tetrahydro-2H-benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,
3ꢀ:4,5]thiopyrano[2,3-c]pyrazole (10h): Yellow oil, yield
85 %, IR (νmax, cm−1): 3065, 2963, 2927, 2855, 1628, 1603,
1520, 1297, 1258, 1236, 1162, 1089, 822, 749, 699, 661, 618;
1H NMR (400 MHz, CDCl3): δ 1.29 (s, 3H, 2-CH3), 1.45 (s,
3H, 4ꢀ-CH3), 1.50 (s, 3H, 4ꢀ-CH3), 1.72 (s, 3H, CH3 of pyra-
zole), 2.06 (m, 2H, 2ꢀ-H & 1ꢀ-H), 2.22 (m, 2H, 2a-H & 1ꢀ-H),
2.40 (s, 1H, 2ꢀ-H), 4.34 (t, 1H, 3-H), 4.51 (m, 1H, 3-H), 4.88
(d, J = 2.8 Hz, 1H, 10c-H), 5.16 (t, 1H, 3ꢀ-H), 7.10–8.11
(m, 11H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 14.3, 17.7,
22.0, 23.6, 25.6, 27.0, 39.9, 43.1, 49.0, 64.7, 111.9, 114.6,
115.5, 118.8, 120.7, 122.4, 123.2, 126.5, 127.3, 128.6, 129.1,
129.6, 130.4, 131.6, 132.5, 133.7, 139.4, 148.9, 151.8; ESI-
MS (m/z): 481.2 (M+H)+, Anal. Calcd for C31H32N2OS:
C, 77.46; H, 6.71; N, 5.83; S, 6.67; Found: C, 77.65; H, 6.64;
N, 5.67; S, 6.48.
11-Methyl-2,13-diphenyl-2a,3,10c,13-tetrahydro-2H-
benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]pyra-
◦
zole (10e): White solid, yield 88 %, mp 216–218 C, IR
(νmax, cm−1): 3063, 2925, 2868, 1655, 1623, 1599, 1512,
1285, 1260, 1236, 1177, 1166, 1147, 1093, 866, 823, 770,
1
756, 733, 699, 670, 616; H NMR (400 MHz, CDCl3): δ
1.39 (s, 3H, CH3 of pyrazole), 3.04 (m, 1H, 2a-H), 3.95 (d,
J = 5.6 Hz, 1H, 2-H), 4.02 (t, 1H, 3-H), 4.24 (m, 1H, 3-H),
4.61 (d, J = 4 Hz, 1H, 10c-H), 7.10–7.87 (m, 16H, Ar-H);
13C NMR (100 MHz, CDCl3): δ 13.1, 29.9, 43.1, 50.2, 66.0,
113.2, 115.5, 116.9, 118.6, 119.3, 120.6, 122.4, 123.5, 126.6,
127.3, 128.2, 128.6, 128.7, 128.9, 130.4, 131.8, 133.4, 136.9,
140.4, 148.6, 151.8; ESI-MS (m/z): 461.2 (M+H)+, Anal.
123

Mol Divers
2,2,11-Trimethyl-13-phenyl-2a,3,10c,13-tetrahydro-
2H-benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]
ities of some 1-Aryl-1,4-dihydro-3-methyl[1]benzopyrano[2,3-
c]pyrazol-4-ones, 1-Aryl-4,9-dihydro-3-methyl-1H-pyrazolo[3,4-
b]quinolin-4-ones, and 1-Aryl-1H-imidazo[4,5-b]quinoxalines. J
Med Chem 38:1330–1336. doi:10.1021/jm00008a011
◦
pyrazole1-oxide (11): White solid, mp 208–209 C, IR
(νmax, cm−1): 3063, 2970, 2932, 2862, 1744, 1605, 1497,
1304, 1234, 1088, 1041, 818, 764, 694, 687; 1H NMR (400
MHz, CDCl3): δ 1.54 (s, 3H, 2-CH3), 1.60 (s, 3H, 2-CH3),
1.74 (s, 3H, CH3 of pyrazole), 2.57 (td, J = 12, J = 4 Hz,
1H, 2a-H), 4.56 (m, 1H, 3-H), 4.84 (d, J = 2.8, 1H, 10c-
H), 4.91 (t, 1H, 3-H), 7.12–8.01 (m, 11H, Ar-H); 13C NMR
(100 MHz, CDCl3): δ 14.5, 21.9, 23.1, 28.7, 42.3, 54.5, 63.1,
112.0, 117.0, 119.0, 120.3, 122.3, 123.3, 125.2, 126.6, 128.6,
129.0, 129.4, 129.7, 133.7, 136.5, 138.7, 148.3, 152.1; ESI-
MS (m/z): 429.4 (M+H)+, Anal. Calcd for C26H24N2O2S:
C, 72.87; H, 5.64; N, 6.54; S, 7.48; Found: C, 72.64; H, 5.83;
N, 6.79; S, 7.27.
5. Hafez HN, Abbas HS, El-Gazzar ABA (2008) Synthesis and eval-
uation of analgesic, anti-inflammatory and ulcerogenic activities
of some triazolo- and 2-pyrazolyl-pyrido[2,3-d]-pyrimidines. Acta
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6. Klein M, Dinér P, Dorin-Semblat D, Doerig C, Grøtli M
(2009) Synthesis of 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-
yl)-substituted pyrazolo[3,4-d]pyrimidin-4-amines via click chem-
istry: potential inhibitors of the Plasmodium falciparum PfPK7
protein kinase. Org Biomol Chem 7:3421–3429. doi:10.1039/
B906482F
7. Abu-Hashem AA, El-Shehry MF, Badria FA (2010) Design and
synthesis of novel thiophenecarbohydrazide, thienopyrazole and
thienopyrimidine derivatives as antioxidant and antitumor agents.
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(2002) The Diels–Alder reaction in total synthesis. Angew Chem
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2,2,11-Trimethyl-13-phenyl-2a,3,10c,13-tetrahydro-
2H-benzo[5ꢀ,6ꢀ]chromeno[4ꢀ,3ꢀ:4,5]thiopyrano[2,3-c]
◦
pyrazole-1,1-dioxide (12): White solid, mp 194–196 C,
IR (νmax, cm−1): 3063, 2970, 2932, 1744, 1736, 1620, 1597,
1381, 1288, 1234, 1157, 1119, 1026, 764, 694, 648; 1H NMR
(400 MHz, CDCl3): δ 1.50 (s, 3H, 2-CH3), 1.62 (s, 3H, 2-
CH3), 1.84 (s, 3H, CH3 of pyrazole), 2.61 (m, 1H, 2a-H), 4.57
(m, 2H, Two 3-H), 5.05 (d, J = 2.8 Hz, 1H, 10c-H), 7.12–
7.99 (m, 11H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 13.7,
18.1, 24.1, 27.8, 46.4, 60.8, 63.4, 111.8, 118.9, 120.5, 122.1,
123.6, 125.5, 126.9, 128.6, 128.9, 129.0, 129.1, 130.0, 133.5,
134.0, 139.1, 148.0, 151.9; ESI-MS (m/z): 445.4 (M+H)+,
Anal. Calcd for C26H24N2O3S: C, 70.25; H, 5.44; N, 6.30;
S, 7.21; Found: C, 70.48; H, 5.15; N, 6.51; S, 7.46.
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tives of sugars: the formation of 1-glycosyl-3-methylpyrazol-5-
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Acknowledgments We express our thanks to the Head, Department
of Chemistry, S. P. University for providing required research facilities.
We (BDP, TRS, and GCB) are grateful to UGC, New Delhi for financial
support in the form of research fellowships under the UGC scheme
of RFSMS. We thank DST, New Delhi, in general, and the PURSE
central facility for mass analysis (vide sanction letter DO. No. SR/59/Z-
23/2010/43 dated 16th March 2011).
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