Design and synthesis of novel sulfone-containing pyrazolo[1,5-a]- pyrimidines and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones

Article abstract of DOI:10.1002/jhet.5570420421

A series of novel sulfone-containing pyrazolo[1,5-a]pyrimidines (2-3) and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones (5a-5k) were designed and efficiently synthesized, some of which have been identified as being potential rape inhibitors. These results

Full text of DOI:10.1002/jhet.5570420421

May-Jun 2005
609
Design and Synthesis of Novel Sulfone-containing Pyrazolo[1,5-a]-
pyrimidines and Pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones
Yan-Chao Wu, Xiao-Mao Zou, Fang-Zhong Hu and Hua-Zheng Yang *
State Key Laboratory of Element-Organic Chemistry, Institute of Element-Organic Chemistry,
Nankai University, Tianjin 300071, China
Received November 1, 2004
A series of novel sulfone-containing pyrazolo[1,5-a]pyrimidines (2-3) and pyrazolo[5,1-d][1,2,3,5]tetra-
zine-4(3H)-ones (5a-5k) were designed and efficiently synthesized, some of which have been identified as
being potential rape inhibitors. These results widen the structural diversity of rape inhibitors and confirm the
perspectives of further investigations in this area. Moreover, a plausible reaction mechanism is outlined.
J. Heterocyclic Chem., 42, 609 (2005).
Heterocyclic nitrogen compounds and their fused
pharmaceutical activities such as antitumor, anti-HIV and
protein kinase inhibitors [12-14]. They are also widely
used as important intermediates in organic synthesis due to
the chemical versatility of the sulfone moiety [15]. For
example, they can be eliminated to introduce a new bond
into an organic molecule when appropriate [16]. Therefore
the development of synthetic methods for sulfone-contain-
ing compounds has been an important field in both multi-
step synthetic chemistry and pharmaceutics.
As a result of these interesting properties, it is important
to design and synthesize new sulfone-containing hetero-
cyclic nitrogen compounds possessing potential pharma-
ceutical activities. So it is our interest to develop a facile
method for introducing the sulfone moiety to heterocyclic
nitrogen compounds and study their potential pharmaceu-
tical activities. To the best of our knowledge, there are no
reports involving the synthesis of sulfone-containing pyra-
zolo[1,5-a]pyrimidines and pyrazolo[5,1-d][1,2,3,5]-
tetrazine-4(3H)-ones. Herein, we report our strategy for
the synthesis of these sulfone-containing heterocyclic
nitrogen compounds (2, 3 and 5a-5k), which are illustrated
in Scheme 1, and the results of their biological and phar-
maceutical activities.
analogs have attracted considerable attention because of
their presence in numerous natural products [1-2] and
their potential in various applications as pharmaceuticals
and materials [3-4]. For example, indolo[1,2-c]benzo-
[1,2,3]triazines exhibit antitumor and antimicrobial
activity [5]. Pyrazolo[1,5-a]-1,3,5-triazines are portent,
orally bioavailable CRF1 receptor antagonists [6].
Pyrazolo[1,5-a]pyrimidines are a new class of COX-2-
selective inhibitors [7], and imidazo[5,1-d]-1,2,3,5-
tetrazine-4(3H)-ones exhibit antitumour activity [8]. So
it is attractive to discover novel heterocyclic nitrogen
compounds possessing potential pharmaceutical activi-
ties and representing new chemical classes that operate
by modes of action different from those already existing,
which will consequently lack cross-resistance to chemi-
cals currently used [9].
Moreover, a common method to vary the characteristic
of interesting molecules is by the introduction of sulfone
moiety. One may also use the sulfone moiety as a key
intermediate to prepare certain compounds [10]. The sul-
fone nucleus is a key unit distributed in the plant kingdom
[11] and possesses a broad spectrum of biological and
Scheme 1
Reaction conditions: a AcOH, H SO , pentane-2,4-dione, reflux; b toluene, 4-bromophenol, NaH, reflux;
2
4
c (1) NaNO , HCl, -5°C; (2) Na CO ; d CH Cl , aryl isocyanates.
2
2
3
2
2
Ar: 5a = 4-FC H ; 5b = 2-FC H ; 5c = 3-ClC H ; 5d = 4-ClC H ; 5e = 2,4-Cl C H ; 5f = 4-CNC H ;
6
4
6
4
6
4
6
4
2
6
3
6 4
5g = 4-NO C H ; 5h = 2-NO C H ; 5i = 2-CF C H ; 5j = 4-EtO CC H . 5k = H-C H
2
6
4
2
6
4
3
6
4
2
6
4
6 4

610
Y.-C. Wu, X.-M. Zou, F.-Z. Hu and H.-Z. Yang
Vol. 42
Scheme 2
Proposed mechanism of the cycloaddition
Table
1
Ethyl 5-amino-3-(methylsulfonyl)-1H-pyrazole-4-car-
Synthesis of Compounds 5 via Cycloaddition of Compound 4 with
boxylate (1) was easily prepared according to the reported
method [17]. Since compound (1) has two strong electron-
attracting groups, ethoxycarboryl and methylsulfonyl, the
density of electron cloud in the 1 and 5-position is low and
therefore the nucleophilic ability is weak. As a result, it is
not easy to complete the condensation of compound (1)
with pentane-2,4-dione under usual way. After screening
various reaction conditions, we found that ethyl 5,7-
dimethyl-2-(methylsulfonyl)pyrazolo[1,5-a]pyrimidine-3-
carboxylate (2) can be easily obtained by the condensation
of compound (1) with pentane-2,4-dione in boiling acetic
acid with the addition of two drops of concentrated vitriol.
Since methylsulfonyl eliminates easily to introduce a new
bond, ethyl 2-(4-bromophenoxy)-5,7-dimethylpyra-
zolo[1,5-a]pyrimidine-3-carboxylate (3) can be synthe-
sized efficiently by the condensation of compound (2) with
sodium 4-bromophenoxide in boiling toluene.
The diazotization of compound (1) using nitrous acid at
-5 °C followed by neutralization with saturated aqueous
sodium carbonate to give ethyl 5-diazo-3-(methylsul-
fonyl)-1H-pyrazole-4-carboxylate (4), and ethyl 3-aryl-
3,4-dihydro-7-(methylsulfonyl)-4-oxopyrazolo[5,1-
d][1,2,3,5]tetrazine-8-carboxylate (5a-5k) were obtained
by the cycloaddition of compound (4) and aryl iso-
cyanates.
Various aryl isocyanates were examined to investigate
the scope and limitation of this cycloaddition. As Table 1
indicates, the yields were good when aryl isocyanates
bearing weak electron-attracting groups such as halogen
(entry 1-5) are used. Pure products were obtained via
recrystallization from dichloromethane/diethyl ether. High
yields were also obtained when using aryl isocyanates
bearing strong electron-attracting groups such as ethoxy-
carboryl, nitro, cyano, etc. (entry 6-10). Pure products
were obtained via recrystallization from DMSO/ethanol.
When phenyl isocyanate was used, the yield decreased
dramatically (entry 11). In this case pure products were
obtained by flash chromatography on silica gel (200-300
mesh). The reaction failed to give any product at all when
aryl isocyanates bearing electron-donating groups such as
methoxy (entry 12) were used.
Aryl Isocyanates
Entry
Ar
4-FC H
Time (days)
5
m.p. (°C)
Yield (%)
1
2
3
4
5
6
7
8
7
8
6
5
3
0.5
0.5
1
5a
5b
5c
5d
5e
5f
5g
5h
5i
168-169
152-153
162-163
178-179
144-145
162-163
142-143
152-153
162-163
154-155
166-167
86
82
89
93
91
97
96
94
98
97
50
0
6
4
4
2-FC H
6
3-ClC H
6
4
4-ClC H
6
4
2,4-Cl C H
2
6 3
4-CNC H
6
4
4-NO C H
2
6 4
2-NO C H
2 6 4
9
2-CF C H
6 4
1
3
10
11
12
4-EtO CC H
0.5
10
10
5j
5k
2
6 4
H-C H
6
4
4-MeOC H
6
4
A plausible reaction mechanism is outlined in Scheme 2
according to the reported paper [18]. The cycloaddition of
ethyl 5-diazo-3-(methylsulfonyl)-1H-pyrazole-4-carboxy-
late (4) to the electron deficient C=N double bond of vari-
ous aryl isocyanates can be understood as a [7+2] cycload-
dition consisting of a ring nitrogen acylation to a 1,9-
dipole followed by intramolecular coupling.
The preliminary biological activity of these sulfone-con-
taining heterocyclic nitrogen compounds was evaluated
against barnyard grass and rape using a previously
reported procedure [20]. All of the compounds possess
some herbicide activity against rape with no activity
against barnyard grass. For example, the herbicide activi-
ties of compound 5a to compound 5e against rape at 200
ppm are 54.3%, 66.5%, 52.7%, 52.8%, and 49.6% respec-
tively, which were illustrated in Table 2.
Table 2
Bioassay Test of Compounds 5a-e Against Rape
Compound
5a
5b
5c
5d
5e Atriazine
49.6 100
Activity (%)
54.3
66.5
52.7
52.8
Due to the continuing evolution of herbicide resistance
in agriculture, discovery of new herbicides such as potent

May-Jun 2005
Design and Synthesis of Novel Sulfone
611
(75MHz, dimethylsulfoxide-d ): δ 164.88 (CO), 161.09, 154.69,
barnyard grass inhibitors is an important research objec-
tive. These results widen the structural diversity of anti-
rape and confirm the perspectives of further investigations
in this area. Further bioassay test, other biological and
pharmaceutical activities test, structure modifications as
well as synthetic applications of this new strategy are in
progress in our laboratory.
6
148.14, 147.51, 113.39, 100.40, 61.12 (CH -CH ), 43.26
2
3
(SO CH ), 25.27(CH ), 16.79 (CH ), 14.49 (CH -CH ).
2
3
3
3
2
3
Anal. Calcd. For C H N O S: C, 48.47; H, 5.08; N, 14.13.
12 15
3 4
Found: C, 48.42; H, 4.90; N, 14.25.
Preparation of Ethyl 2-(4-Bromophenoxy)-5,7-dimethylpyra-
zolo[1,5-a]pyrimidine-3-carboxylate (3).
The mixture of 4-bromophenol (0.61 g, 3.5 mmol), 85%
sodium hydrid (0.12 g, 3.5 mmol) in 20 ml boiling toluene was
stirred for 1 hour, and compound (2) (0.30 g, 1.0 mmol) was
added. After the reaction was completed as monitored by TLC
EXPERIMENTAL
General Methods.
(ethyl acetate:petroleum ether = 4:1, v/v, R (4) = 0.8), the solu-
f
tion was cooled to room temperature. The crude product was col-
lected by filtration and was washed by diethyl ether to give pure
white solid in 71.8% yield; mp 179-180 °C; ir (potassium bro-
mide): 3390, 3043, 2914, 1703 (CO), 1619, 1561, 1479, 1448,
All reactions were performed using oven-dried glassware
under a positive atmosphere of dry nitrogen. Common reagents
and materials were purchased from commercial sources and puri-
fied by recrystallization or distillation. Analytical thin layer chro-
matography was performed with 0.2 mm coated commercial sil-
-1
1
1368, 1198, 1135, 1085, 830 cm ; H nmr (200MHz, deuteri-
ochloroform): δ 1.25 (t, 3H, CH -CH , J = 6.97Hz), 2.62 (s, 3H,
ica gel plates (Kiesselgel 60 GF ). NMR spectra were mea-
2
3
254
1
13
CH ), 2.66 (s, 3H, CH ), 4.29 (q, 2H, CH -CH J = 6.97 Hz),
sured on a Bruker XL-300 ( H, 300 MHz and C, 75 MHz) or
3
3
2
3,
1
1
7.10 (s, 1H, Ar-H) , 7.24 (d, 2H, Ar-H, J = 8.40 Hz) , 7.45 (d, 2H,
Ar-H, J = 8.40 Hz).
Bruker AC-P200 ( H, 200 MHz). Data for H are reported as fol-
lows: chemical shift (δ ppm), number, multiplicity (s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet, br = broad), inte-
Anal. Calcd. For C H BrN O : C, 52.32; H, 4.13; N, 10.77.
17 16
3 3
13
Found: C, 52.25; H, 4.05; N, 10.75.
gration and coupling constant (Hz). Data for C NMR are
reported in terms of chemical shift (δ ppm). Infrared (IR) spectra
Preparation of Ethyl 5-Diazo-3-(methylsulfonyl)-1H-pyrazole-4-
carboxylate (4).
were recorded on a Shimadzu-435 spectrophotometer and are
-1
reported in terms of frequency of absorption (cm ). Elemental
To a solution of compound (1) (1.47 g, 6.3 mmol) and
hydrochloric acid (1.52 g, 36.5%) in 10 ml ethanol at -5 °C, 10 ml
5 % aqueous sodium nitrite was added slowly. After the reaction
was completed as monitored by TLC (ethyl acetate:petroleum
analyses were performed on Yanaco-CHN CORDER elementary
analyzer. Mass spectra were obtained from VG ZAB-HS instru-
ment. Melting points were measured on a Thomas-Hoover appa-
ratus and were not corrected.
ether = 1:2, v/v, R (4) = 0.6), 40 ml dichloromethane was added
f
Preparation of Ethyl 5-Amino-3-(methylsulfonyl)-1H-pyrazole-
4-carboxylate (1).
and then the mixture was neutralized with saturated aqueous
sodium carbonate until Ph = 8. The organic layer was separated,
and the aqueous solution was extracted with 40 ml
dichloromethane. The combined organic layer was dried over
anhydrous sodium sulfate, filtered, and the solvent was removed
in vacuo. The crude product was washed by diethyl ether to give
pure pale crystals in 78.0% yield; mp 132-133 °C; ir (potassium
bromide): 2967, 2236 (N≡N), 1703 (CO), 1523, 1324, 1162,
According to our previous method [18]. To a solution of ethyl
5-amino-3-(methylthio)-1H-pyrazole-4-carboxylate (10.05 g, 50
mmol) and Na WO •2H O (1.00 g, 3 mmol) in 40 ml acetic acid
2
4
2
at 40 °C, 15 ml 30% hydrogen peroxide (H O ) was added drop-
2
2
wise. After this dropping, the mixture was stirred at 55 °C and 15
ml 30% H O was added slowly. Then the mixture was stirred
2
2
-1
1
1088, 1020, 766 cm ; H nmr (200MHz, deuteriochloroform): δ
1.39 (t, 3H, CH -CH , J = 7.12 Hz), 3.41 (s, 3H, SO CH ), 4.41
vigorously at 70 °C until the reaction was completed as moni-
tored by TLC (ethyl acetate, R (1) = 0.4.), the crude product was
2
3
2
3
f
(q, 2H, CH -CH J = 7.12 Hz).
isolated by filtering and washed by ethanol to give pure white
crystals in 74.3% yield; mp 223-224 °C; H nmr (200 MHz,
2
3,
1
Anal. Calcd. For C H N O S: C, 34.42; H, 3.30; N, 22.94.
7
8 4 4
dimethylsulfoxide-d ): δ 1.25 (t, 3H, CH -CH , J = 7.10 Hz),
Found: C, 34.20; H, 3.40; N, 22.94.
6
2
3
3.27 (s, 3H, SO CH ), 4.19 (q, 2H, CH -CH , J = 7.10 Hz), 6.41
(s, 1H, N-H).
2
3
2
3
Preparation of Ethyl 3-Aryl-3,4-dihydro-7-(methylsulfonyl)-4-
oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5a-5j).
Preparation of Ethyl 5,7-Dimethyl-2-(methylsulfonyl)pyra-
zolo[1,5-a]pyrimidine-3-carboxylate (2).
The mixture of 2 mmol aryl isocyanates and 2 mmol com-
pound (4) in 5 ml dichloromethane was stirred at room tempera-
ture. After the reaction was completed as monitored by TLC
The mixture of compound (1) (0.23 g, 1.0 mmol), pentane-2,4-
dione (0.12 g, 1.2 mmol) and two drops of concentrated vitriol in
20 ml boiling acetic acid was stirred until the reaction was com-
(ethyl acetate:petroleum ether = 1:2, v/v, R (4) = 0.6.), the sol-
f
vent was removed in vacuo. The crude product was recrystallized
with DMSO/ethanol or dichloromethane/diethyl ether to give
pure crystals (5a-5j)
pleted as monitored by TLC (ethyl acetate, R (2) = 0.2). The
f
solution was washed with 10 ml water, dried over anhydrous
sodium sulfate, filtered, and evaporated under reduced pressure.
The crude product was washed by diethyl ether to give pure white
Ethyl 3-(4-Fluorophenyl)-3,4-dihydro-7-(methylsulfonyl)-4-
oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5a).
1
solid in 84.1% yield; mp 154-155 °C; H nmr (300MHz,
This compound was obtained as white solids, mp 168-169 °C;
ir (potassium bromide): 2959, 1778 (CO), 1725 (CO), 1566,
1330, 1152, 1051, 948 cm ; H nmr (300MHz, deuteriochloro-
dimethylsulfoxide-d ): δ 1.32 (t, 3H, CH -CH , J = 7.09 Hz,),
6
2
3
2.60 (s, 3H, CH ), 2.70 (s, 3H, CH ), 3.50 (s, 3H, SO CH ), 4.32
3
3
2
3
-1
1
13
(q, 2H, CH -CH , J = 7.09 Hz), 7.30 (s, 1H, Ar-H) ; C nmr
2
3

612
Y.-C. Wu, X.-M. Zou, F.-Z. Hu and H.-Z. Yang
Vol. 42
form): δ 1.45 (t, 3H, CH -CH , J = 6.85 Hz), 3.50 (s, 3H,
129.07, 120.87, 118.28, 108.60, 62.19 (CH -CH ), 42.80
2 3
2
3
SO CH ), 4.52 (q, 2H, CH -CH J = 6.85 Hz), 7.28~7.67 (m,
(SO CH ), 13.52 (CH -CH ).
Anal. Calcd. For C H Cl N O S: C, 38.90; H, 2.57; N,
14 11 2 5 5
2
3
2
3,
2 3 2 3
13
4H, Ar-H); C nmr (75MHz, dimethylsulfoxide-d ): δ 164.83
6
(CO), 162.91 (CO), 159.52, 145.14, 140.63, 139.42, 130.99,
16.20. Found: C, 38.87; H, 2.69; N, 15.84.
130.17, 126.76, 112.56, 106.56, 61.82 (CH -CH ), 41.19
2
3
Ethyl 3-(4-Cyanophenyl)-3,4-dihydro-7-(methylsulfonyl)-4-
oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5f).
(SO CH ), 14.0 (CH -CH ).
2
3
2
3
Anal. Calcd. For C H FN O S: C, 44.09; H, 3.17; N, 18.37.
14 12
5 5
This compound was obtained as white solids, mp 162-163 °C;
ir (potassium bromide): 2960, 1778 (CO), 1731 (CO), 1569,
Found: C, 44.28; H, 3.34; N, 18.69.
Ethyl 3-(2-Fluorophenyl)-3,4-dihydro-7-(methylsulfonyl)-4-
oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5b).
-1
1
1329, 1281, 1151, 1055, 958 cm ; H nmr (300MHz, dimethyl-
sulfoxide-d ): δ 1.38 (t, 3H, CH -CH , J = 7.00 Hz), 3.62 (s, 3H,
6
2
3
This compound was obtained as white solids, mp 152-153 °C;
ir (potassium bromide): 2933, 1778 (CO), 1723 (CO), 1575,
SO CH ), 4.47 (q, 2H, CH -CH J = 7.00 Hz), 7.91 (d, 2H, Ar-
H, J = 8.31 Hz), 8.15 (d, 2H, Ar-H, J = 8.31 Hz); C nmr
2 3 2 3,
13
-1
1
1322, 1188, 1050, 958 cm ; H nmr (300MHz, deuteriochloro-
form): δ 1.46 (t, 3H, CH -CH , J = 7.13 Hz), 3.52 (s, 3H,
(75MHz, dimethylsulfoxide-d ): δ 159.14 (CO), 155.86 (CO),
6
145.73, 140.78, 139.69, 134.18, 127.79, 118.44, 113.38, 108.43,
2
3
SO CH ), 4.54 (q, 2H, CH -CH J = 7.13 Hz), 7.37 (t, 1H, Ar-H,
62.87 (CH -CH ), 43.22 (SO CH ), 14.33 (CH -CH ).
2
3
2
3,
2 3 2 3 2 3
J = 8.54 Hz), 7.41 (t, 1H, Ar-H, J = 7.92 Hz ), 7.58-7.65 (m, 2H,
Ar-H); C nmr (75MHz, deuteriochloroform): δ 158.42 (CO),
Anal. Calcd. For C H N O S: C, 46.39; H, 3.11; N, 21.64.
15 12 6 5
Found: C, 46.18; H, 3.27; N, 21.75.
13
157.34 (CO), 155.39, 145.01, 137.98, 133.09, 132.98, 128.81,
Ehyl 3,4-Dihydro-7-(methylsulfonyl)-3-(4-nitrophenyl)-4-
oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5g).
125.31, 125.26, 117.37, 117.12, 110.03, 63.08 (CH -CH ), 42.73
2
3
(SO CH ), 14.03 (CH -CH ).
2
3
2
3
This compound was obtained as yellow solids, mp 142-143
°C; ir (potassium bromide): 2923, 1774 (CO), 1727 (CO), 1529,
Anal. Calcd. For C H FN O S: C, 44.09; H, 3.17; N, 18.37.
Found: C, 43.86; H, 3.04; N, 18.28.
14 12
5 5
-1
1
1350, 1148, 1042, 951 cm ; H nmr (200MHz, dimethylsulfox-
ide-d ): δ 1.37 (t, 3H, CH -CH , J = 7.02 Hz), 3.62 (s, 3H,
Ethyl 3-(3-Chlorophenyl)-3,4-dihydro-7-(methylsulfonyl)-4-
oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5c).
6
2
3
SO CH ), 4.46 (q, 2H, CH -CH J = 7.02 Hz), 7.95 (d, 2H, Ar-
2
3
2
3,
13
This compound was obtained as white solids, mp 162-163 °C;
ir (potassium bromide): 2930, 1787 (CO), 1729 (CO), 1578,
H, J = 8.39 Hz), 8.52 (d, 2H, Ar-H, J = 8.39 Hz); C nmr
(75MHz, dimethylsulfoxide-d ): δ 159.14 (CO), 155.82 (CO),
6
-1
1
148.41, 142.09, 139.70, 128.14, 125.37, 108.43, 62.87 (CH -
1319, 1150, 1059, 967 cm ; H nmr (300MHz, dimethylsulfox-
2
CH ), 43.23 (SO CH ), 14.33 (CH -CH ).
ide-d ): δ 1.36 (t, 3H, CH -CH , J = 6.87 Hz), 3.61 (s, 3H,
3
2
3
2
3
6
2
3
Anal. Calcd. For C H N O S: C, 41.18; H, 2.96; N, 20.58.
Found: C, 40.93; H, 3.00; N, 20.58.
SO CH ), 4.45 (q, 2H, CH -CH J = 6.87 Hz ), 7.68-7.73 (m,
14 12
6 7
2
3
2
3,
13
4H, Ar-H); C nmr (75MHz, dimethylsulfoxide-d ): δ 159.19
6
(CO), 155.74 (CO), 145.79, 139.80, 138.38, 133.87, 131.77,
Ethyl 3,4-Dihydro-7-(methylsulfonyl)-3-(2-nitrophenyl)-4-
oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5h).
130.80, 126.92, 125.98, 108.19, 68.82 (CH -CH ), 43.24
2
3
(SO CH ), 14.35 (CH -CH ).
2
3
2
3
This compound was obtained as yellow solids, mp 152-153
°C; ir (potassium bromide): 2925, 1773 (CO), 1720 (CO), 1536,
Anal. Calcd. For C H ClN O S: C, 42.27; H, 3.04; N, 17.61.
14 12
5 5
Found: C, 42.29; H, 3.37; N, 17.94.
-1
1
1324, 1149, 1054, 956 cm ; H nmr (200MHz, dimethylsulfox-
ide-d ): δ 1.37 (t, 3H, CH -CH , J = 6.98 Hz), 3.61 (s, 3H,
Ethyl 3-(4-Chlorophenyl)-3,4-dihydro-7-(methylsulfonyl)-4-
oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5d).
6
2
3
SO CH ), 4.46 (q, 2H, CH -CH J = 6.98 Hz), 7.91~8.42 (m,
2
3
2
3,
13
4H, Ar-H); C nmr (75MHz, dimethylsulfoxide-d ): δ 163.76
This compound was obtained as white solids, mp 178-179 °C;
ir (potassium bromide): 2929, 1771 (CO), 1730 (CO), 1568,
6
(CO), 161.12 (CO), 149.50, 144.26, 140.95, 137.91, 135.73,
-1
1
134.20, 131.31, 130.58, 114.17, 67.65 (CH -CH ), 47.98
1327, 1148, 1053, 950 cm ; H nmr (300MHz, dimethylsulfox-
2
3
(SO CH ), 19.09 (CH -CH ).
ide-d ): δ 1.38 (t, 3H, CH -CH , J = 6.97 Hz), 3.49 (s, 3H,
2
3
2
3
6
2
3
Anal. Calcd. For C H N O S: C, 41.18; H, 2.96; N, 20.58.
Found: C, 41.22; H, 3.06; N, 20.70.
SO CH ), 4.41 (q, 2H, CH -CH J = 6.97 Hz ), 7.69-7.76 (m,
14 12
6 7
2
3
2
3,
13
4H, Ar-H); C nmr (75MHz, dimethylsulfoxide-d ): δ 163.39
6
(CO), 160.05 (CO), 145.70, 140.00, 136.32, 135.18, 129.97,
Ethyl 3-(2-(Trifluoromethyl)phenyl)-3,4-dihydro-7-(methylsul-
fonyl)-4-oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5i).
128.94, 106.97, 68.33 (CH -CH ), 40.98 (SO CH ), 14.49 (CH -
2
3
2
3
2
CH ).
3
This compound was obtained as white solids, mp 162-163 °C;
ir (potassium bromide): 2926, 1786 (CO), 1719 (CO), 1575,
Anal. Calcd. For C H ClN O S: C, 42.27; H, 3.04; N, 17.61.
14 12
5 5
Found: C, 42.05; H, 2.97; N, 17.72.
-1
1
1320, 1178, 1052, 955 cm ; H nmr (300MHz, dimethylsulfox-
ide-d ): δ 1.35 (t, 3H, CH -CH , J = 7.10 Hz), 3.59 (s, 3H,
Ehyl 3-(2,4-Dichlorophenyl)-3,4-dihydro-7-(methylsulfonyl)-4-
oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5e).
6
2
3
SO CH ), 4.45 (q, 2H, CH -CH J = 7.10 Hz ), 7.93 (t, 2H, Ar-
2
3
2
3,
This compound was obtained as white solids, mp 144-145 °C;
ir (potassium bromide): 2928, 1774 (CO), 1717 (CO), 1523,
H, J = 8.08 Hz), 8.02 (d, 1H, Ar-H, J = 7.64 Hz), 8.09 (d, 1H, Ar-
13
H, J = 8.07 Hz); C nmr (75MHz, dimethylsulfoxide-d ): δ
6
-1
1
1320, 1161, 1005, 959 cm ; H nmr (200MHz, deuteriochloro-
form): δ 1.44 (t, 3H, CH -CH , J = 7.06 Hz), 3.51 (s, 3H,
159.09 (CO), 156.09 (CO), 145.94, 139.79, 135.19, 134.08,
132.73, 131.35, 126.70, 109.40, 62.86 (CH -CH ), 43.25
2
3
2
3
SO CH ), 4.53 (q, 2H, CH -CH J = 7.06 Hz), 7.51~7.67 (m,
(SO CH ), 14.36 (CH -CH ).
Anal. Calcd. For C H F N O S: C, 41.77; H, 2.80; N, 16.24.
15 12 3 5 5
2
3
2
3,
2 3 2 3
13
3H, Ar-H); C nmr (75MHz, dimethylsulfoxide-d ): δ 158.62
6
(CO), 157.73 (CO), 150.99, 136.67, 132.88, 132.34, 130.22,
Found: C, 41.55; H, 2.77; N, 16.17.

May-Jun 2005
Design and Synthesis of Novel Sulfone
613
REFERENCES AND NOTES
Ethyl 3-(4-(Ethoxycarbonyl)phenyl)-3,4-dihydro-7-(methylsul-
fonyl)-4-oxopyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5j).
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This compound was obtained as white solids, mp 154-155 °C;
ir (potassium bromide): 2933, 1780 (CO), 1726 (CO), 1563,
-1
1
1329, 1281, 1150, 1054, 966 cm ; H nmr (300MHz, dimethyl-
sulfoxide-d and deuteriochloroform): δ 1.36 (t, 3H, CH -CH , J
6
2
3
= 7.00 Hz), 1.38 (t, 3H, CH -CH , J = 7.02 Hz), 3.51 (s, 3H,
2
3
[3] F. A. El-Essawy and A. F. Khattab, J. Heterocyclic. Chem.,
41, 311 (2004).
SO CH ), 4.35 (q, 2H, CH -CH J = 7.00 Hz), 4.44 (q, 2H, CH -
2
3
2
3,
2
CH J = 7.02 Hz), 7.78 (d, 2H, Ar-H, J = 8.40 Hz), 8.17 (d, 2H,
3,
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Shafiee, J. Heterocyclic. Chem., 41, 201 (2004).
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Chem., 44, 350 (2001).
13
Ar-H, J = 8.40 Hz); C nmr (75MHz, dimethylsulfoxide-d and
6
deuteriochloroform): δ 165.08 (CO), 158.98 (CO), 155.90,
145.66, 140.74, 139.48, 131.69, 130.50, 126.71, 108.39, 62.54
(CH -CH ), 61.45 (CH -CH ), 43.13 (SO CH ), 14.47 (CH -
2
3
2
3
2
3
2
CH ), 14.23 (CH -CH ).
3
2
3
Anal. Calcd. For C H N O S: C, 46.89; H, 3.94; N, 16.08.
17 17
5 7
Found: C, 46.72; H, 3.86; N, 15.93.
Preparation of Ethyl 3,4-Dihydro-7-(methylsulfonyl)-4-oxo-3-
phenylpyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (5k).
The mixture of 2 mmol phenyl isocyanate and 2 mmol com-
pound (4) in 5 ml dichloromethane was stirred at room tempera-
ture. After the reaction was completed as monitored by TLC
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(ethyl acetate:petroleum ether = 1:2 v/v, R = 0.8.), the solvent
f
was removed in vacuo. The white product was isolated by flash
chromatography on silica gel (200-300 mesh) with ethyl
acetate:petroleum ether (33:67, v/v), R = 0.8. mp 166-167 °C; ir
f
(potassium bromide): 3043, 2932, 1790 (CO), 1728 (CO), 1558,
-1
1
1435, 1330, 1150, 1111, 1064, 951 cm ; H nmr (300MHz,
dimethylsulfoxide-d and deuteriochloroform): δ 1.45 (t, 3H,
6
CH -CH , J = 7.12 Hz), 3.52 (s, 3H, SO CH ), 4.49 (q, 2H, CH -
2
3
2
3
2
13
CH J = 7.12 Hz), 7.60-7.70 (m, 5H, Ar-H); C nmr (75MHz,
3,
dimethylsulfoxide-d and deuteriochloroform): δ 163.60 (CO),
6
160.94 (CO), 150.29, 144.01, 141.67, 135.03, 134.23, 131.10,
113.31, 67.33 (CH -CH ), 47.70 (SO CH ), 18.87 (CH -CH );
2
3
2
3
2
3
+
ms (EI): m/z 363 (M ), 335, 290, 119, 91, 44, 29.
Anal. Calcd. For C H N O S: C, 46.28; H, 3.61; N, 19.27.
14 13
5
5
Found: C, 45.99; H, 3.58; N, 19.29.
Acknowledgement.
We thank the National Key Project for Basic Research on Tibetan
Plateau (G1998040800) the National Natural Science Foundation
of China (No.20172031) and the Chinese Research Fund for the
Doctoral Program of High Education for financial supports.
[19] G. Ege and K. Gilbert, Tetrahedron Lett., 44, 4253 (1979).
[20] R. M. Jacobson and L. T. Nguyen, U. S. Patent 6, 147, 062
(2000).