Rapid and efficient microwave assisted method for the regioselective synthesis of 8,8′-methylene-bis-4-oxo-1H and 2H-chromeno[4,3-c]pyrazoles

Article abstract of DOI:10.1002/jhet.5570440619

(Chemical Equation Presented) The ethyl ester of 5,5′-methylene-bis- salicyclic acid 3 was prepared by the esterification of 5,5′-methylene- bis-salicylic acid 2. The compound 3 on reacting with ethylacetoacetate yields 6,6′-methylene-bis-(3-acetyl-4-hydr

Full text of DOI:10.1002/jhet.5570440619

Nov-Dec 2007
1357
Rapid and Efficient Microwave Assisted Method for the
Regioselective Synthesis of 8,8'-Methylene-bis-4-oxo-1H
and 2H-chromeno[4,3-c]pyrazoles
Adki Nagaraj and Cherkupally Sanjeeva Reddy*
Department of Chemistry, Kakatiya University, Warangal 506 009, India.
E-mail: chsrkuc@yahoo.co.in
Received December 16, 2006
O
O
OH
O
RHN
N
O
OH
O
O
O
4
HO
N
O
5
HO
O
O
R
N
N
NHR
3
R
9b
N
N
3a
3
9b
4
O
O
O
3a
4
O
O
O
O
N
7
N
6
R
O
N
R
N
The ethyl ester of 5,5'-methylene-bis-salicyclic acid 3 was prepared by the esterification of 5,5'-
methylene-bis-salicylic acid 2. The compound 3 on reacting with ethylacetoacetate yields 6,6'-methylene-
bis-(3-acetyl-4-hydroxycoumarin) 4. The compound 4 was regioselectively converted into either 8,8'-
methylene-bis-(4-oxo-1H-chromeno[4,3-c]pyrazoles) 6 or 8,8'-methylene-bis(-4-oxo-2H-chromeno[4,3-c]-
pyrazoles) 7 under microwave irradiation. High yields are achieved even on a gram scale, while reaction
times are considerably shortened compared to conventional heating conditions.
J. Heterocyclic Chem., 44, 1357 (2007).
pyrazole molecule has been stimulated by some promising
pharmacological, agrochemical and analytical
applications of its derivatives [20].
INTRODUCTION
Microwave assisted reactions have attracted much
interest because of the simplicity of operation and mild
reaction conditions. Salient features of the microwave
approach are improved yields, enhanced reaction rates,
formation of pure products in high yields and ease of
isolation. Heterocyclic compounds have attracted
considerable attention in the design of biologically active
molecules [1-2]. Coumarins are a class of compounds
with biological activity [3], such as analgesics [4], anti-
coagulants [5], specific inhibitors of ꢀ-chymotripsin [6],
human leukocyte elastase [7] and diuretics [8]. On the
other hand, the classes of pyrazoles possess a broad
spectrum of biological effectiveness such as antiviral [9],
antibacterial [10], antidepressants [11], inhibitors of
protein kinases [12], antiagregating [13], antiarthritic [14],
and cerebroprotectors [15]. Recently some aryl pyrazoles
[16] were reported to have non-nucleoside HIV-1 reverse
transcriptase inhibitors [17], COX-2 inhibitors [18],
potent activator of the nitric oxide receptor and soluble
guanylate cyclase [19]. Besides, great interest in the
A detailed literature survey indicates that, synthesis of
some thiochromeno[4,3-c] and [3,4-c]pyrazoles [21],
pyrazolo-pyrazoles, isoxazolo-pyrazoles, pyrazolo-
pyrimidines, pyrazolo-thiazines, pyrazolo-pyridines [22],
pyrazolo[4,3-c]diazepines, pyrazolo[3,4-d]triazines, benz-
oxaphosphino[4,3-c]pyrazoles [23] and monomeric
benzopyrano[4,3-c]pyrazoles [24] have been reported. In
view of these observations it was considered of interest to
synthesize some new dimeric chemical entities incorpor-
ating the two active pharmacophores namely coumarin
and pyrazole in a single molecular frame work.
In this article, we wish to report a novel and rapid
method for the synthesis of some new 8,8'-methylene-
bis-(4-oxo-1H-chromeno[4,3-c]pyrazoles) 6 and 8,8'-
methylene-bis-(4-oxo-2H-chromeno[4,3-c]pyrazoles)
7, in good yields, from 6,6'-methylene-bis-(3-acetyl-4-
hydroxycoumarin) 4 and a variety of hydrazines under
microwave irradiation (Scheme 1).

1358
A. Nagaraj and C. Sanjeeva Reddy
Vol 44
Scheme 1
EtOO C
COOH
OH
HOOC
HO
C2H5OH
H2SO4
HCHO
H2SO4
OH
OH
HO
2
1
3
COOEt
O
COOH
O
RHN
C2H5ONa
N
OH
OEt
O
O
OH
O
RNHNH2.HCl
C2H5OH
O
O
O
O
5
HO
O
4
HO
O
N
RNHNH2.HCl
AcOH
4% HCl
NHR
O
C2H5OH
R
R
N
N
N
N
3
3
9b
9b
3
3
4
O
O
O
O
4
O
O
6
7
R
N
O
O
N
R
N
N
RESULTS AND DISCUSSION
The rate enhancement under microwave irradiation can be
attributed to the absorption of more microwave energy by
the polar reactants, which generated sufficient heat energy
to promote the reaction.
The procedure involves esterification of 5,5'-
methylene-bis-salicylic acid 2 with absolute ethyl alcohol
in presence of an acid catalyst to afford ethyl ester of 5,5'-
methylene-bis-salicyclic acid 3 in 82% of yield.
Subsequently compound 3 reacted with ethyl acetoacetate
in presence of sodium ethoxide to afford 6,6'-methylene-
bis-(3-acetyl-4-hydroxycoumarin) 4. In the first instance
the compound 4 reacted with phenyl hydrazine hydro-
chloride to afford hydrazone 5 in excellent yields.
Compound 5a, under microwave irradiation in presence
of 4% ethanolic hydrogen chloride, regioselectively was
converted into the new 8,8'-methylene-bis-(3-methyl-1-
phenylchromeno[4,3-c]pyrazol-4(1H)-one) 6a in 84%
yield while, in presence of phenyl hydrazinium chloride in
acetic acid converted into the new 8,8'-methylene-bis-(3-
methyl-2-phenyl chromeno[4,3-c]pyrazol-4(2H)-one) 7a
in 78% yield (Table 1). The molar ratio of the isomeric
products 6 and 7 depends on the amount of nucleophilic
reagent used. Thus in presence of one equivalent of
The scope and generality of the present method was
then further demonstrated by converting compound 4 with
different hydrazines followed by cyclization under
different experimental conditions. The versatility of the
reaction is well demonstrated by the fact that both
aromatic (entries a-d, Table 1) and aliphatic (entries e-g,
Table 1) hydrazines afforded their corresponding
pyrazoles 6 and 7 in good yields.
The structures of all the new compounds were
confirmed by IR, NMR and Mass spectral studies. The
13C NMR spectra of (6a, d) and (7a, d) clearly demon-
strated their structures, by comparison of the C-3, C-3a,
C-9b, and CH3 signals (Table 2). It is known that a
carbon adjacent to a substituted nitrogen resonate up
field of the signal of the same carbon in the other
isomer (unsubstituted nitrogen). Additional support for
1
the assignments was provided by the H NMR spectra
of each isomer.
hydrazine, compound
6
and two equivalents of
hydrazines, compound 7 were formed [24g]. Further
when compound 5 alone was irradiated in acetic acid, the
methylene-bis-(hydroxybenzoylpyrazoles) [25] was
formed instead of compound 7. Under conventional
heating the same reaction required 3-5 h and afforded low
yields of desired products. The reaction rates and yields
were dramatically enhanced by microwave irradiation.
In conclusion, we have described a rapid and
efficient protocol for the regioselective synthesis of
8,8'-methylene-bis-4-oxo-1H and 2H-chromeno[4,3-c]-
pyrazoles 6 and 7 by the reaction of 6,6'-methylene-bis-
(3-acetyl-4-hydroxycoumarin) 4 and a variety of
hydrazines using microwave irradiation. The present

Nov-Dec 2007
Regioselective Synthesis of Chromeno[4,3-c]pyrazoles
1359
Table 1
Synthesis of 8,8’-methylene-bis-4-oxo-1H and 2H-chromeno[4,3-c]pyrazoles 6, 7 respectively
Reaction time (min)
Yield (%)b
Entry
Hydrazine
NHNH2
Producta, R=
C6H5-
(6)
(7)
(6)
84
(7)
78
5 (5.5h)c
4 (3.5h)c
a
NHNH2
4-(MeO)-C6H4-
3-F-C6H4-
6 (5.5h)
5 (6.0h)
4 (4.0h)
3 (4.0h)
78
80
72
76
b
MeO
NHNH2
c
F
NHNH2
4-Cl-C6H4-
C6H5-CH2-
7 (5.5h)
6 (5.0h)
5 (4.5h)
4 (4.0h)
79
78
72
71
d
e
Cl
NHNH2
NHNH2
f
Isopropyl
CH3-
5 (5.5h)
5 (5.0h)
4 (3.5h)
3 (3.5h)
76
70
73
69
CH3-NHNH2
g
aProducts were characterized by IR, NMR and Mass spectroscopy. bYields refer to pure products after chromatography. cTime reported in parenthesis
were under conventional heating.
reported procedure [26]. All other reagents were purchased
from Aldrich chemicals and were used without further
purification. Crude products were purified by column
chromatography on silica gel of 60-120 mesh.
method is a very useful process for the preparation of
fused pyrazole derivatives. The reduced reaction times
together with the minimization of thermal decom-
position of the products are the main advantages of
microwave heating.
Ethyl ester of 5,5'-methylene-bis-salicyclic acid (3). To the
solution of 2 (1 mmol) in absolute ethyl alcohol (20 mL),
concentrate sulfuric acid (1.5 mL) was added. The mixture was
refluxed for 3 h. After completion of the reaction, the mixture
was poured into the ice water. Crude product was collected by
filtration, washed with 10% NaHCO3 solution, dried and
recrystallized from ethyl alcohol to give pure 3 (82%), mp 220-
Table 2
Selected 13C NMR spectral data (ꢀ ppm).
Comp
C-3
C-3a
C-4
C-9b
CH3
6a
6d
7a
7d
149.1
149.3
144.4
144.7
107.6
107.4
106.7
105.9
156.4
156.6
157.1
158.2
137.6
137.9
152.0
151.2
14.1
14.1
13.3
13.2
1
222 °C; H NMR (DMSO-d6): ꢀ 10.2 (2H, s), 7.7-7.1 (6H, m),
4.3 (4H, q, J = 7.2 Hz), 4.00 (2H, s), 1.41 (6H, t, J = 7.2 Hz); 13
C
NMR: ꢀ 170.2, 141.1, 132.3, 121.1, 113.4, 62.7, 43.9, 16.0; IR
(KBr): ꢁ 3367, 1718, 1220 cm-1; MS: m/z 344 (M+). Anal. calcd.
for C19H20O6: C, 66.27; H, 5.85. Found: C, 66.26; H, 5.80.
6,6'-Methylene-bis-(3-acetyl-4-hydroxycoumarin) (4). To a
stirred solution of 3 (1 mmol) in absolute ethyl alcohol (10 mL)
and ethyl acetoacetate (2.5 mmol) was added sodium ethoxide
(1.5 mmol). The mixture was refluxed at 110 °C with stirring
for 3 h. After completion of the reaction, monitored by TLC
(EtOAc: hexane, 1:3), the mixture was acidified with dilute HCl
(10 mL). Crude product was filtered off, washed with water,
dried and recrystallized from ethanol to give pure 4 (86%), mp
EXPERIMENTAL
The melting points were determined using a Fischer-Johns
apparatus and were uncorrected. 1H NMR and 13C NMR spectra
were obtained on a Varian Gemini spectrometer at 300 MHz and
100 MHz respectively. Chemical shifts ware reported as ꢀ ppm
with respect to internal TMS, and J values are quoted in Hz. IR
spectra were recorded on a Perkin-Elmer BX series spectro
meter in KBr and only the most significant absorptions in cm-1
are indicated. Mass spectra were recorded on a VG-Micromass
7070H spectrometer. Satisfactory elemental analyses were
1
118-120 °C; H NMR (DMSO-d6): ꢀ 12.3 (2H, s), 7.22-7.70
(6H, m), 4.00 (2H, s), 2.32 (6H, s); 13C NMR: ꢀ 184.2, 159.7,
149.8, 137.3, 121.9, 117.2, 101.2, 45.7, 22.0; IR (KBr): ꢁ 3440,
1728, 1680, 1560, 1180 cm-1; MS: m/z 420 (M+). Anal. calcd.
for C23H16O8: C, 65.72; H, 3.84. Found: C, 65.70; H, 3.75.
obtained using a Perkin-Elmer CHN analyzer. For the
microwave irradiation, a conventional house hold microwave
oven was used. The compound 2 was prepared according to

1360
A. Nagaraj and C. Sanjeeva Reddy
Vol 44
Phenylhydrazone of 6,6'-methylene-bis-(3-acetyl-4-hy
4.0 (2H, s), 2.47 (6H, s); 13C NMR: ꢀ 156.6, 149.3, 137.9, 135.6,
131.4, 125.7, 117.9, 112.3, 107.4, 44.1, 14.1; IR (KBr): ꢀ 3080,
1721, 1570, 1557, 1187 cm-1; MS: m/z 632 (M+). Anal. calcd.
for C35H22Cl2N4O4: C, 66.36; H, 3.50; Cl, 11.19. Found: C,
66.27; H, 3.34; Cl, 11.20.
droxycoumarin) (5a). To a stirred solution of compound 4 (5
mmol) in ethyl alcohol (25 mL) was added the phenyl hydrazine
hydrochloride (11 mmol) and the reaction mixture was refluxed
for 1.5 h. After completion of the reaction (TLC), the mixture
was cooled. The precipitated hydrazones was collected by
filtration, washed with water, dried and recrystalized from ethyl
alcohol to give pure 5a (82%), mp 141-143 °C; 1H NMR
(DMSO-d6): ꢀ 11.28 (2H, s), 9.1 (2H, bs), 7.22-7.61 (6H, m),
7.00-7.16 (10H, m), 4.00 (2H, s), 2.16 (6H, s); IR (KBr): ꢁ
3450-3354, 1719, 1590, 1470, 1171 cm-1; MS: m/z 601 (M+).
Anal. calcd. for C35H28N4O6: C, 69.99; H, 4.70; N, 9.33. Found:
C, 70.00; H, 4.61; N, 9.19. The other compounds 5b-g were
also prepared by the similar procedure.
General procedure for the preparation of 8,8'-methylene-
bis-(4-oxo-1H-chromeno[4,3-c]pyrazoles) (6). To a solution of
compound 5 (1 mmol) in ethyl alcohol (5 mL) was added 4%
ethanolic hydrogen chloride (3 mL) and the reaction mixture, in
a closed vessel was subjected to microwave irradiation using a
conventional house hold microwave oven operated at 360 W for
an appropriate time (Table 1). The reaction temperature was
controlled using a pulsed irradiation technique (1 min with 20
sec intervals) and the temperature was measured after each
pulse. The lowest observed temperature was ~70 °C after
irradiation for 1 min at 320 W and the highest temperature was
~120 °C after irradiation for 3 min at the same power. After
complete conversion of the reaction as indicated by TLC
(EtOAc: hexane, 3:1), the mixture was quenched with water and
extracted with EtOAc. The combined organic layers were dried
over Na2SO4, evaporated and the crude product purified by
column chromatography on silica gel to give the corresponding
6 in excellent yields (Table 1).
8,8'-Methylene-bis-(1-benzyl-3-methylchromeno[4,3-c]pyra-
zol-4(1H)-one) (6e). This compound was obtained as pink solid,
1
mp 217-218 °C; H NMR (DMSO-d6): ꢀ 7.75-7.10 (6H, m),
7.52-7.15 (10H, m), 5.13 (4H, s), 4.0 (2H, s), 2.39 (6H, s); 13C
NMR: ꢀ 158.7, 150.2, 139.7, 135.0, 131.2, 127.9, 120.4, 112.6,
102.1, 56.1, 43.1, 15.2; IR (KBr): ꢁ 3080, 1714, 1585, 1560,
1180 cm-1; MS: m/z 592 (M+). Anal. calcd. for C37H28N4O4: C,
77.99; H, 4.76; N, 9.45. Found: C, 74.98; H, 4.73; N, 9.44.
8,8'-Methylene-bis-(1-isopropyl-3-methylchromeno[4,3-c]-
pyrazol-4(1H)-one) (6f). This compound was obtained as
yellow solid, mp 221-223 °C; 1H NMR (DMSO-d6): ꢀ 7.42 (2H,
m), 7.39 (2H, d, J = 6.8 Hz), 7.12 (2H, d, J = 6.8 Hz) 5.77 (2H,
m), 4.0 (2H, s), 2.37 (6H, s), 1.52 (12H, d, J = 6.7 Hz); 13C
NMR: ꢀ 159.1, 149.3, 138.3, 131.4, 118.1, 112.4, 101.9, 59.1,
44.4, 23.2, 15.7; IR (KBr): ꢁ 3080, 2985, 1720, 1600, 1585,
1567, 1183 cm-1; MS: m/z 496 (M+). Anal. calcd. for
C29H28N4O4: C, 70.15; H, 5.68; N, 11.28. Found: C, 70.14; H,
5.63; N, 11.26.
8,8'-Methylene-bis-(1,3-dimethylchromeno[4,3-c]pyrazol-
4(1H)-one) (6g). This compound was obtained as yellow solid,
mp 198-199 °C; 1H NMR (DMSO-d6): ꢀ 7.33 (2H, m), 7.67 (2H,
d, J = 6.8 Hz), 7.12 (2H, d, J = 6.8 Hz) 4.00 (2H, s), 3.90 (6H,s),
2.39 (6H, s); 13C NMR: ꢀ 158.3, 149.2, 138.7, 131.7, 118.6,
112.2, 102.6, 43.7, 37.1, 14.1; IR (KBr): ꢁ 3078, 2985, 1710,
1595, 1180 cm-1; MS: m/z 441 (M+). Anal. calcd. for
C25H20N4O4: C, 68.17; H, 4.58; N, 12.72. Found: C, 67.93; H,
4.43; N, 12.58.
8,8'-Methylene-bis-(3-methyl-1-phenylchromeno[4,3-c]-
pyrazol-4(1H)-one) (6a). This compound was obtained as
General procedure for the synthesis of 8,8'-methylene-bis-
(4-oxo-2H-chromeno[4,3-c]pyrazoles) (7). To a solution of
compound 5 (1 mmol) in acetic acid (5 mL) was added the
corresponding hydrazine hydrochloride (2 mmol) in acetic acid
(5 mL) and the reaction mixture, in a closed vessel was
subjected to microwave irradiation using a conventional house
hold microwave oven operated at 360 W for an appropriate time
(Table 1). The reaction temperature was controlled using a
pulsed irradiation technique (1 min with 20 sec intervals) and
the temperature was measured after each pulse. The lowest
observed temperature was ~70 °C after irradiation for 1 min at
320 W and the highest temperature was ~120 °C after irradiation
for 3 min at the same power. After completion of the reaction as
indicated by TLC (EtOAc: benzene, 3:1), the mixture was
quenched with water and extracted with dichloromethane,
washed with 10% K2CO3 solution, brine, dried over Na2SO4,
evaporated and the crude product chromatographed on silica gel
resulted 7 in excellent yields (Table 1) and 6 (7-10% yields) as
the minor products.
1
brown solid, mp 202-203 °C; H NMR (DMSO-d6): ꢀ 7.72-7.16
(16H, m), 4.0 (2H, s), 2.47 (6H, s); 13C NMR: ꢀ 156.4, 149.1,
137.6, 131.4, 128.9, 124.4, 118.9, 112.4, 107.6, 47.1, 14.1; IR
(KBr): ꢀ 3028, 1724, 1567, 1562 cm-1; MS: m/z 564 (M+). Anal.
calcd. for C35H24N4O4: C, 74.46; H, 4.26; N, 9.92. Found: C,
74.35; H, 4. 20; N, 9.91.
8,8'-Methylene-bis-(1-(4-methoxyphenyl)-3-methylchro-
meno[4,3-c]pyrazol-4(1H)-one) (6b). This compound was
1
obtained as gray solid, mp 216-218 °C; H NMR (DMSO-d6): ꢀ
7.72-7.36 (6H, m), 7.42 (4H, d, J = 8.7 Hz), 7.10 (4H, d, J = 8.7
Hz), 4.0 (2H, s), 3.90 (6H, s), 2.47 (6H, s); 13C NMR: ꢀ 158.5,
149.9, 138.4, 131.4, 129.9, 124.3, 119.1, 113.9, 107.2, 54.3,
43.9, 14.2; IR (KBr): ꢀ 3090, 1710, 1585, 1569, 1245 cm-1; MS:
m/z 624 (M+). Anal. calcd. for C37H28N4O6: C, 71.14; H, 4.52;
N, 8.97. Found: C, 71.13; H, 4.49; N, 8.94.
8,8'-Methylene-bis-(1-(3-fluorophenyl)-3-methylchromeno-
[4,3-c]pyrazol-4(1H)-one) (6c). This compound was obtained as
1
8,8'-Methylene-bis-(3-methyl-2-phenylchromeno[4,3-c]-
pyrazol-4(2H)-one) (7a). This compound was obtained as
pink solid, mp 233-234 °C; H NMR (DMSO-d6): ꢀ 7.8-6.63
(10H, m), 7.68 (2H, d, J = 6.2 Hz), 7.27 (2H, d, J = 6.2 Hz), 4.0
(2H, s), 2.47 (6H, s); 13C NMR: ꢀ 166.2, 154.5, 147.2, 138.9,
130.4, 120.3, 119.2, 111.9, 106.2, 44.54, 14.32; IR (KBr): ꢀ
3080, 1715, 1569, 1584 cm-1; MS: m/z 600 (M+). Anal. calcd.
for C35H22F2N2O4: C, 70.00; H, 3.69; N, 9.33. Found: C, 69.99;
H, 3.59; N, 9.32.
1
brown solid, mp 211-212 °C; H NMR (DMSO-d6): ꢀ 7.8-6.9
(6H, m), 7.26-7.52 (10H, s), 4.0 (2H, s), 2.69 (6H, s); 13C NMR:
ꢀ 157.1, 152.0, 149.3, 144.4, 136.2, 131.2, 127.2, 120.1, 106.2,
40.8, 13.3; IR (KBr): ꢀ 1732, 1590, 1600 cm-1; MS: m/z 564
(M+). Anal. calcd. for C35H24N4O4: C, 74.46; H, 4.28; N, 9.92.
Found: C, 74.4; H, 4.22; N, 9.9.
8,8'-Methylene-bis-(1-(4-chlorophenyl)-3-methylchromeno-
[4,3-c]pyrazol-4(1H)-one) (6d). This compound was obtained
8,8'-Methylene-bis-(2-(4-methoxyphenyl)-3-methylchro-
meno[4,3-c]pyrazol-4(2H)-one) (7b). This compound was
1
as yellow solid, mp 209-211 °C; H NMR (DMSO-d6): ꢀ 7.70-
7.10 (6H, m), 7.62 (4H, d, J = 8.3 Hz), 7.54 (4H, d, J = 8.3 Hz),
1
obtained as brown solid, mp 221-223 °C; H NMR (DMSO-d6):

Nov-Dec 2007
Regioselective Synthesis of Chromeno[4,3-c]pyrazoles
1361
Indian J. Chem. 2005, 44B, 2412. d) Lokhande, P. D.; Waghamere, R.
Y.; Sakate, S. Indian J. Chem. 2005, 44B, 2338.
[3a] Gearr, G. R.; Evans, M.; Vong, A. K. Comprehensive
Heterocyclic Chem. 1984, 5, 469. b) Biuers, D.; Blondeau, D.; Sliwa, H.
J. Heterocyclic. Chem. 1993, 30, 671.
[4] Vallet, F. M. J. Ger. Offen. 1978, 2, 751.
[5] Suzmann, M. M. IV World Congress of Cardiology, Mexico.
1962, 344.
[6] Doucet, C.; Pochet, L.; Thierry, N.; Pirotte, B.; Delarge, J.;
Rebound, R. M. J. Med. Chem. 1999, 42, 4161.
ꢀ 7.72-7.36 (6H, m), 7.42 (4H, d, J = 8.3 Hz), 7.10 (4H, d, J =
8.3 Hz), 4.0 (2H, s), 3.9 (6H, s), 2.67 (6H, s); 13C NMR: ꢀ 158.5,
150.3, 144.3, 134.7, 131.4, 127.1, 120.9, 106.2, 55.3, 40.7, 13.1;
IR (KBr): ꢀ 1730, 1587, 1610 cm-1; MS: m/z 624 (M+). Anal.
calcd. for. C37H28N4O6: C, 71.14; H, 4.52; N, 8.97. Found: C,
71.12; H, 4.40; N, 8.95.
8,8'-Methylene-bis-(2-(3-fluorophenyl)-3-methylchromeno-
[4,3-c]pyrazol-4(2H)-one) (7c). This compound was obtained as
1
brown solid, mp 202-204 °C; H NMR (DMSO-d6): ꢀ 7.7-6.20
[7] Pochet, L.; Doucet, C.; Scynts, M.; Therry, N.; Boggeto, N.;
Pirotte, B. J. Med. Chem. 1996, 39, 2579.
[8] Spiro, V.; Madonia, P. Atti. Acad. Sci. Lett. Antipalermo.
1959, A95920187.
[9] Storer, R.; Ashton, C. J.; Baxter, A. D.; Hann, M. M.; Marr,
C. L. P. Nucleosides Nucleotides. 1999, 203, 1812.
[10a] Baraldi, P. G.; Pavani, M. G.; Nunez, M.; Brigidi, P.; Vitali,
B.; Gambari, R.; Romagnoli, R. Biorg. Med. Chem. 2002, 449, 1012. b)
Lee, K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron Lett. 2003, 44, 6737.
[11] Erhan, P.; Mutlu, A.; Tayfun, U.; Dilek, E. Eur. J. Med.
Chem. 2001, 36, 539.
(10H, m), 7.67 (2H, d, J = 6.2 Hz), 7.12 (2H, d, J = 6.2 Hz), 4.0
(2H, s), 2.68 (6H, s); 13C NMR: ꢀ 168.1, 157.2, 152.0, 143.4,
132.7, 122.7, 112.1, 104.7, 40.7, 13.1; IR (KBr): ꢀ 1728, 1591,
1602 cm-1; MS: m/z 600 (M+). Anal. calcd. for C35H22F2N2O4: C,
70.00; H, 3.69; N, 9.33. Found: C, 69.9; H, 3.62; N, 9.30.
8,8'-Methylene-bis-(2-(4-chlorophenyl)-3-methylchromeno-
[4,3-c]pyrazol-4(2H)-one) (7d). This compound was obtained
1
as yellow solid, mp 227-228 °C; H NMR (DMSO-d6): ꢀ 7.70-
7.10 (6H, m), 7.52 (4H, d, J = 8.3 Hz), 7.60 (4H, d, J = 8.3 Hz),
4.0 (2H, s), 2.68 (6H, s); 13C NMR: ꢀ 158.1, 151.2, 144.7, 135.3,
130.2, 126.7, 120.5, 105.9, 42.3, 13.2; IR (KBr): ꢀ 1727, 1586,
1601 cm-1; MS: m/z 633 (M+). Anal. calcd. for C35H22Cl2N4O4: C,
66.36; H, 3.50; Cl, 11.19. Found: C, 66.31; H, 3.45; Cl, 11.19.
8,8'-Methylene-bis-(2-benzyl-3-methylchromeno[4,3-c]-
pyrazol-4(2H)-one) (7e). This compound was obtained as
[12] Giesc, N. A.; Lokker, N.; Laibelman, A. M.; Searbrough, R.
M. Chem. Absrt. 1996, 135, 105089p.
[13] Bruno, O.; Ranise, A.; Bonduvalli, F.;Schenone, S.; Amico,
M.; Falciani, M.; Vacca, C.; Filippli, A. Il Farmaco. 1994, 49, 533.
[14] Nugen, R. A.; Megan, M. J. Med. Chem. 1993, 36, 134.
[15] Hiroshi, K.; Yasuhiro, T.; Yoshio, S.; Fumiki, S.; Norio, O.;
Akira, J. Jpn. J. Pharmacol. 1997, 73, 317.
1
brown solid, mp 197-200 °C; H NMR (DMSO-d6): ꢀ 7.75-7.0
(16H, m), 5.31 (4H, s), 4.0 (2H, s), 2.57 (6H, s); 13C NMR: ꢀ
158.0, 150.9, 144.7, 133.2, 128.7, 120.3, 102.4, 55.2, 42.0, 13.1;
IR (KBr): 1728, 1587, 1602 cm-1; MS: m/z 592 (M+). Anal.
calcd. for C37H28N4O4: C, 74.99; H, 4.76; N, 9.45. Found: C,
74.9; H, 4.71; N, 9.43.
[16] Jamode, V. S.; Chandak, H. S.; Bhagat, P. R.; Tambekar, D.
H. Indian. J. Heterocycl. Chem. 2003, 12, 323.
[17] Genin, M. J.; Bilers, C.; Keiser, B. J.; Poppe, S. M.; Swaney, S.
M.; Tarpley, W. G.; Yagi, Y.; Romero, D. L. J. Med. Chem. 2000, 43, 1034.
[18a] Habeb, A. G.; Rao, P. N. P.; Knaus, E. E. J. Med. Chem.
2001, 44, 3039. b) Hashimoto, H.; Imamura, K.; Haruta, J. I.; Wakitani,
K. J. Med. Chem. 2002, 45, 1511. c) Sakya, S. M.; Rast, B. Tetrahedron
Lett. 2003, 44, 7629.
[19] David, L.; Selwood David, G. B. J. Med. Chem. 2001, 44, 78.
[20a] Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles
Structure, Reaction Synthesis and Applications, Georg Thime Stuttgart,
1995, p 184. b) Elguero, J. Comprehensive Heterocyclic Chemistry II,
Katritzky, A. R.; Pees, C. W.; Scriven, E. F. Ed, Pergamon Press,
Oxford, 1996, Vol 3, p 1. c) Onoa, G. B.; Moreno, V.; Font-Bardia, M.;
Solans, X.; Peter, J. M.; Alonso, C. J. Inorg. Biochem. 1999, 75, 205. d)
Al-Allaf, T. A. K.; Rashan, L. J. Boll. Chim. Farm. 2001, 140, 205.
[21] Vitvitsakaya, A. S.; Noskova, M. P.; Kvitro, I. Y.; Efros, L.
S. Chemistry of Heterocycl. Comp. 1973, 9, 911.
8,8'-Methylene-bis-(2-isopropyl-3-methylchromeno[4,3-c]-
pyrazol-4(2H)-one) (7f). This compound was obtained as
1
yellow solid, mp 212-213 °C; H NMR (DMSO-d6): ꢀ 7.7-6.9
(6H, m), 5.70 (2H, m), 4.0 (2H, s), 2.52 (6H, s), 1.35 (12H, d, J
= 6.7 Hz); 13C NMR: ꢀ 159.1, 150.7, 140.3, 131.7, 119.8, 101.7,
57.2, 41.9, 22.3, 13.1; IR (KBr): ꢀ 1729, 1587, 1601 cm-1; MS:
m/z 496 (M+). Anal. calcd. for C29H28N4O4: C, 70.15; H, 5.68;
N, 11.28. Found: C, 70.12; H, 5.61; N, 11.27.
8,8'-Methylene-bis-(2,3-dimethylchromeno[4,3-c]pyrazol-
4(2H)-one) (7g). This compound was obtained as yellow solid,
mp 186-188 °C; 1H NMR (DMSO-d6): ꢀ 7.76-6.92 (6H, m), 4.00
(2H, s), 3.71 (6H,s), 2.52 (6H, s); 13C NMR: ꢀ 158.2, 150.6,
142.1, 133.6, 119.4, 101.8, 41.9, 32.5, 11.2; IR (KBr): ꢀ 3050,
2985, 1710, 1595, 1590, 1180 cm-1; MS: m/z 441 (M+). Anal.
calcd. for C25H20N4O4: C, 68.17; H, 4.58; N, 12.72. Found: C,
67.99; H, 4.49; N, 12.62.
[22] Christopher, D.; Gabbytt, H. J. D.; Mark, H. B.; Simon, J.;
Coles, M. B. J. Chem. Soc., Perkin. Trans. I 2000, 2930.
[23] Malecka, M.; Massa, W.; Harms, K.; Budzisz, E. J. Mol. Str.
2005, 259, 737.
[24a] Bernard, C.; Abdel, I. N.; Suzanne, G. Tetrahedron Lett.
1983, 24, 381. b) Vittoria, C.; Lucia, C.; Guido, F.; Fabrizio, M.;
Giovanna, P.; Claudia, M.; Gino, G.; Antonio, L. J. Med. Chem. 1988,
31, 1. c) Vittoria, C.; Lucia, C.; Fabrizio, M.; Guido, F.; Claudia, M.;
Sabrina, G.; Antonio, L. J. Pharm. Sci. 1991, 80, 276. d) Vittoria, C.;
Lucia, C.; Daniela, C.; Fabrizio, M.; Guido, F.; Claudia, M.; Paolo, T.;
Antonio, L. Receptors and Channels. 1993, 1, 111. e) Cacic, M.;
Trkovnik, M.; Has-Schon, E. J. Heterocyclic. Chem. 2003, 40, 833. f)
Stadlbauer, W.; Hojas, G. J. Heterocyclic. Chem. 2004, 41, 681. g)
Budzisz, E.; Malecka, M.; Nowrott, B. Tetrahedron. 2004, 60, 1749.
[25] Chantegrel, B.; Nadi, A.; Gelin, S. Synthesis. 1983, 3.
[26] Clemenson, H. J. Am. Chem. Soc., 1911, 33, 737.
REFERENCES AND NOTES
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