A novel synthesis and herbicidal activity of fluorine-containing pyrazolo[3,4-d]pyrimidin-4-one derivatives

Article abstract of DOI:10.1016/j.jfluchem.2006.08.008

The 6-(4-alkoxycarbonylalkoxy)phenoxy-3-alkylthio-5-(fluoro-substituted)phenyl-1-phenylpyrazolo[3,4-d]pyrimidin-4-ones 6 have been successfully synthesized via a tandem aza-Wittig and annulation reactions of the corresponding iminophosphorances 4, aromatic isocyanate, and substituted phenols 2 in 59-69% isolated yields using actonitrile as solvent. These novel compounds 6 could be oxidized to sulfones 7 by hydrogen peroxide in satisfactory yields (57-93%). Their structures were clearly verified by spectroscopic data (IR, ¹H NMR, ¹³C NMR, MS, Elemental analysis or X-ray diffraction crystallography). The results of preliminary bioassay indicated that these compounds possess herbicidal activity against the root of rape and barnyard grass.

Full text of DOI:10.1016/j.jfluchem.2006.08.008

Journal of Fluorine Chemistry 127 (2006) 1584–1590
www.elsevier.com/locate/fluor
A novel synthesis and herbicidal activity of fluorine-containing
pyrazolo[3,4-d]pyrimidin-4-one derivatives
*
Hui Liu, Hong-Qing Wang, Ming-Wu Ding, Zhao-Jie Liu , Wen-Jing Xiao
**
The Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China
Received 14 May 2006; received in revised form 15 August 2006; accepted 25 August 2006
Available online 6 September 2006
Abstract
The 6-(4-alkoxycarbonylalkoxy)phenoxy-3-alkylthio-5-(fluoro-substituted)phenyl-1-phenylpyrazolo[3,4-d]pyrimidin-4-ones 6 have been suc-
cessfully synthesized via a tandem aza-Wittig and annulation reactions of the corresponding iminophosphorances 4, aromatic isocyanate, and
substituted phenols 2 in 59–69% isolated yields using actonitrile as solvent. These novel compounds 6 could be oxidized to sulfones 7 by hydrogen
1
peroxide in satisfactory yields (57–93%). Their structures were clearly verified by spectroscopic data (IR, H NMR, 13C NMR, MS, Elemental
analysis or X-ray diffraction crystallography). The results of preliminary bioassay indicated that these compounds possess herbicidal activity
against the root of rape and barnyard grass.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Pyrazolo[3,4-d]pyrimidin-4-one; Aza-Wittig reaction; Synthesis; Herbicide
1. Introduction
employed as herbicides, insecticides and fungicides [7].
Recently, aza-Wittig reactions of iminophosphoranes have
received increasing attention in view of their utility in the
synthesis of nitrogen-containing heterocyclic compounds [8].
As part of our ongoing project aimed at investigating new
herbicidal activity heterocycles [9], we have designed a series
of novel fluorine-containing compounds which have both the
skeletons of pyrazolo[3,4-d]pyrimidin-4-one and aryloxyphe-
noxypropionate (APP) based on biochemical rations. Herein,
we would like to describe the use of a new annulation process
(Scheme 1), the tandem aza-Wittig and cyclization reaction, to
synthesize the title compounds, 6-(4-alkoxycarbonylalkoxy)-
phenoxy-3-alkylthio(alkylsulfonyl)-5-(fluoro-substituted)phe-
nyl-1-phenylpyrazolo[3,4-d]pyrimidin-4-ones 6 and 7. The
results of bioassay indicated that these title compounds possess
herbicidal activity against the root of rape and barnyard grass.
Pyrazolo[3,4-d]pyrimidin-4-one derivatives have extremely
rich biological activities because of their structural similarity
with purines [1]. They exhibit excellent antibacterial, anti-
phlogistic, and antitumor activities [2]. Accordingly, they are
often employed in the treatment of erectile dysfunction in male
animals [3]. Aryloxyphenoxypropionate (APP) derivatives have
been found to be strong inhibitor of acetyl-coacarboxylase
(ACCase) and used as a very important class of herbicides in the
market [4]. In recent years, heterocycles were introduced to the
structures of APP, which lead to the development of a new series
of highly efficient herbicides. The heterocyclic units include
whip, fenthiaprop-ethyl, quizalofop-ethyl, and two well-know
fluorinatedherbicides, fluazifop-butyland heloxyfop-methyl[5].
It is well known that fluorine can affect the biological
activity of compounds in a number of important ways.
Therefore, fluorinated compounds in general and fluorinated
heterocycles are the focus of many researches [6]. In the area of
modern crop protection, fluoro agrochemicals are widely
2. Results and discussion
The iminophosphorane 4 [10], which was prepared by the
reaction of 3-alkylthio-5-amino-4-ethoxycarbonyl-1-phenyl-
pyrazole 3 [11] with triphenylphosphine and bromine using
triethylamine as base in dichloromethane, reacted with 1
equivalent of aromatic isocyanate to afford carbodiimide 5. The
* Corresponding author.
** Corresponding author. Tel.: +86 27 67862041; fax: +86 27 67862041.
E-mail address: wxiao@mail.ccnu.edu.cn (W.-J. Xiao).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.08.008

H. Liu et al. / Journal of Fluorine Chemistry 127 (2006) 1584–1590
1585
Scheme 1. Synthesis of the title compounds 6 and 7. Reagents and conditions: (a) R1ONa, R1OH, 0–35 8C, 6 h, yield 57–66%. (b) Et3N, CH2Cl2, 0 8C for 30 min then
25 8C for 26 h, yield 84%. (c) CH2Cl2, rt, 2–5 h. (d) K2CO3, CH3CN, reflux, 5 h, yield 59–69%. (e) Na2WO4ÁH2O, AcOH, 30% H2O2, 50 8C, 5 h, yield 57–93%.
Scheme 2. The cyclization of carbodiimide 5 to synthesize the title compounds 6.
Table 1
Optimization of the reaction conditions
Entry
Solvent
Temperature (8C)
Yield (%)
1
2
3
4
5
CH3CN
CH2Cl2
Toluene
CH3CN
CH3CN
80
40
80
25
40
65
11
13
20
30

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H. Liu et al. / Journal of Fluorine Chemistry 127 (2006) 1584–1590
˚
C(3) C(4), C(12) N(1) are 1.311(3) A, 1.381(3) A, 1.289(3) A,
˚
respectively, are longer than that of the typical C N (1.28 A) and
˚
C C (1.34 A), whilethe single bond lengthsof C(4)–N(5), C(2)–
˚
˚
Table 2
Yields of compounds 6 and 7
Compound
R3
R2 R1
Yields
Yields
of 6 (%) of 7 (%)
˚
C(3), C(3)–C(11), C(12)–N(2), C(4)–N(1), are 1.358(3) A,
˚
1.408(3) A, 1.439(3) A, 1.366(3) A, 1.357(3) A, respectively,
˚
˚
˚
6a, 7a
6b, 7b
6c, 7c
6d, 7d
6e, 7e
6f, 7f
6g, 7g
6h, 7h
6i, 7i
m-F–
o-F–
p-F–
m-F–
o-F–
p-F–
o-F–
p-F–
o-F–
p-F–
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
Et
Et
Et
65
69
69
65
61
63
72
93
69
82
88
85
71
62
57
88
2
are significantly shorter than the typical C(sp ) N (1.426 A) and
˚
˚
C–C (1.53 A), showing a degree of delocalization.
Me Et
Me Et
Me Et
The herbicidal activity of all compounds 6 and 7 against
Brassica napus (rape) and Echinochloa crus-galli (barnyard
grass) has been investigated at the dosage of 100 mg/L and
10 mg/L using known procedure [14] compared with distilled
water and 2,4-dichlorophenoxy acetic acid (2,4-D), a commer-
cially available herbicide. The results of bioassay showed that
many of them exhibit good herbicidal activity when fluorine
atom is introduced [9] (the inhibition rates are listed in Tables 3
and 4). It showed that the role of the fluorine position (m-, p-, o-)
has not obvious influence on herbicidal activity, but it is worthy
to note that the inhibition rates of 7 have gone up greatly when
the sulfide group was oxidized to the sulfonyl group. Most of
compounds 7 in the Table 4 exhibit good inhibition rates (80–
98%) against the root of rape and barnyard grass at 100 mg/L.
For example, 7a, 7c, 7d, 7e, 7f showed >90% inhibitory rate to
root of rape and barnyard grass. It is also interesting, that ethyl
ester show higher herbicidal activity than the corresponding
methyl ester and n-propyl ester in general. This may be due to
the hydrolysis of the product [15]. The investigations on R and S
isomers of products are going on further.
Me n-Pr 61
Me n-Pr 62
PhCH2 Me Me
PhCH2 Me Me
59
66
6j, 7j
reaction of 2-(4-hydroxyphenoxy)-carboxylate 2 [9,12] with 5
generated 6 in the presence of catalytic amount of potassium
carbonate via guanidine intermediates 8. This process can be
rationalized in Scheme 2.
Optimization of the reaction conditions showed that better
yield was obtained when polar solvent acetonitrilewas used [13].
During the process, it is essential to control reaction temperature
to in order to get good yields. A favourable temperature for the
reaction was 80 8C (Table 1). Then, compound 6 were oxidized
by hydrogen peroxide (H2O2) using sodium wolframate
(Na2WO4) as the catalyst to give compounds 7 at about
40 8C. The results are summarized in Table 2.
The structures of compounds 6 and 7 were deduced from their
spectra data (IR, 1H NMR, 13C NMR, MS, Elemental analyses).
7b was recrystallized by slow evaporation from CH2Cl2, which
afforded single crystal that is analyzed by X-ray diffraction
crystallography. The corresponding structure is shown in Fig. 1.
X-ray structure analysis verified again the proposed structure,
and showed that ring atoms in pyrazolo[3,4-d]pyrimidin-4-one
moiety are essentially planar. The bond lengths of C(2) N(4),
In summary, we have developed a novel approach to 6-(4-
alkoxycarbonylalkoxy)phenoxy-3-alkylthio(alkylsulfonyl)-5-
(fluoro-substituted)phenyl-1-phenylpyrazolo[3,4-d]pyrimidin-
4-one derivatives via a tandem aza-Wittig and annulation
reactions. The structures of the title compounds possess both
the skeletons of pyrazolo[3,4-d]pyrimidin-4-one and arylox-
yphenoxypropionate (APP). The biological evalution showed
Fig. 1. View and atom labelling of 7b.

H. Liu et al. / Journal of Fluorine Chemistry 127 (2006) 1584–1590
1587
Table 3
Herbicidal comparison with unfluorinated compounds
Compounds
R1
R2
R3
R4
Relative inhibition (root %/stalk %)
Rape
Barnyard grass
100 mg/L
100 mg/L
10 mg/L
10 mg/L
6a
6k
6l
6d
6m
6n
Et
Et
Et
Et
Et
Et
H
Me
Me
Me
Me
Me
Me
m-F
H
78.4/48.7
74.3/36.5
65.3/21.1
93.1/73.1
85.1/55.8
50.0/11.1
46.1/25.6
53.5/13.5
35.6/17.3
59.4/32.7
70.3/30.8
19.6/11.1
95.6/62.1
88.5/22.6
80.8/32.3
88.5/25.8
82.7/22.6
64.4/À31.6
60.9/55.2
40.4/9.7
H
H
m-Cl
m-F
m-Cl
p-Me
59.6/19.4
75.0/0.0
Me
Me
Me
73.1/12.9
53.3/10.5
that these compounds have good herbicidal activity and could
be further developed as potential herbicides.
imimophosphoranes 4 [10] were prepared according to
literature procedures.
3.2. Measurements and instruments
3. Experimental
IR was recorded on a Perkin-Elmer PE-983 infrared
1
3.1. Materials
spectrometer as KBr film with absorption in cmÀ1. H NMR
spectra were recorded on Mercury Plus-400 (400 MHz)
spectrophotometers. Chemical shifts are reported in ppm from
TMS with the solvent resonance as the internal standard
(CDCl3: d 7.26). 13C NMR spectra were recorded on Mercury
Plus-400 (100 MHz) spectrophotometers with complete proton
decoupling spectrophotometers (CDCl3: 77.2). Mass spectra
were measured on a Finnigan Trace MS spectrometer.
Elementary analyses were taken on a Vario EL III elementary
analysis instrument. X-ray diffraction crystallography was
measured on Bruker Smart Apex Area CCD.
All the solvent and materials are reagent grades and purified
before use. 2-(4-Hydroxyphenoxy)-carboxylates 2 [9,12], 3-
alkylthio-5-amino-4-ethoxycarbonyl-1-phenylpyrazole 3 [11],
Table 4
The herbicidal activity of compounds 6 and 7
Compounds
Relative inhibition (root %/stalk %)
Rape
Barnyard grass
100 mg/L
10 mg/L
100 mg/L
10 mg/L
6a
6b
6c
6d
6e
6f
6g
6h
6i
78.4/48.7
79.4/33.3
81.2/42.3
93.1/73.1
84.2/63.5
97.0/65.4
25.5/10.6
40.0/4.3
46.1/25.6
34.3/33.3
47.5/15.4
59.4/32.7
43.6/23.1
51.5/11.5
10.0/19.1
À10.0/À10.6
5.5/8.5
95.6/62.1
82.6/20.7
90.4/19.4
88.5/25.8
82.7/12.9
98.1/54.8
61.9/16.1
54.8/3.2
60.9/55.2
54.3/10.3
59.6/À6.5
75.0/0.0
3.3. Preparation of 2-(4-hydroxyphenoxy)-carboxylates 2
Compound 2wereprepared accordingtoliteratureprocedures
[9,12]. Ethyl 2-(4-hydroxyphenoxy)-acetate was obtained after
recrystallized with ether as white solid in 66% yield, mp 124–
126 8C. Methyl-2-(4-hydroxyphenoxy)-propionate was got by
distilling under reduced pressure in 62% yield as light yellow
thick liquid, bp 165–167 8C/42 Pa, M+ = 196; ethyl-2-(4-
hydroxyphenoxy)-propionate was got in 59% yield, bp 135–
138 8C/22 Pa, M+ = 210; n-propyl-2-(4-hydroxyphenoxy)-pro-
pionate was got in 57% yield, bp 139–142 8C/38 Pa, M+ = 224.
57.7/À6.4
75.0/16.1
33.3/9.7
42.8/0.0
56.7/68.1
33.3/12.8
98.0/84.6
88.2/71.8
97.1/64.1
97.1/74.4
91.2/64.1
97.1/82.5
27.2/8.9
78.6/74.2
47.6/35.5
97.8/75.9
91.3/58.6
93.5/62.1
93.5/51.7
91.3/44.8
95.6/72.5
50.0/13.3
87.5/10.0
57.5/6.7
42.8/29.0
52.4/32.2
78.3/51.7
67.4/6.9
6j
31.1/8.5
7a
7b
7c
7d
7e
7f
7g
7h
7i
44.1/7.7
21.6/7.7
46.1/7.7
67.4/À3.4
69.6/20.7
73.9/27.6
74.1/58.0
15.0/10.0
37.5/0
45.1/30.8
13.7/7.7
50.0/30.8
11.9/13.3
17.4/6.7
3.4. General procedure for the preparation of
imimophosphoranes 4
83.7/42.2
51.1/11.1
79.3/40.0
99.0/91.2
28.3/11.1
27.2/6.7
45.0/13.3
57.5/À10.0
97.5/30.8
7j
2,4-D
75.0/13.3
97.5/33.3
Imimophosphoranes 4 were prepared according to the
98.1/91.2
reported procedures [10]. When R3 is Me, a pale yellow crystal

1588
H. Liu et al. / Journal of Fluorine Chemistry 127 (2006) 1584–1590
in 84% yield was obtained, mp 192–194 8C, 1H NMR (CDCl3,
TMS, 400 MHz) d 7.70–7.16 (m, 20H), 3.61 (q, 2H,
J = 7.2 Hz), 2.51 (s, 3H), 1.44 (t, 3H, J = 7.2 Hz). When R3
is benzyl, a pale yellow crystal in 86% yield was got, mp 86–
87 8C, MS: (m/z) 613 (M+), 614 (M+ + 1), 615 (M+ + 2).
3.5.5. 6-[4-(1-Ethoxycarbonylethoxy)]phenoxy-5-(2-
fluorophenyl)-3-methylthio-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (6e)
White crystals, mp 201–203 8C, yield, 61%; IR (KBr) n
(cmÀ1): 2990, 2932, 1739, 1704, 1601, 1577, 1545, 1500, 1399,
1350, 1193, 1135, 1036, 896, 757; 1H NMR (CDCl3, 400 MHz)
d 7.90 (d, 2H, J = 8.0 Hz, Ar), 7.26–7.49 (m, 6H, Ar), 7.20 (t,
1H, J = 7.2 Hz, Ar), 7.10 (d, 2H, J = 8.8 Hz, OC6H4O), 6.91 (d,
2H, J = 8.8 Hz, OC6H4O), 4.75 (q, 1H, J = 6.8 Hz, OCH), 4.22
(q, 2H, J = 7.2 Hz, OCH2), 2.68 (s, 3H, SCH3), 1.65 (d, 3H,
J = 6.4 Hz, CH3CH), 1.23 (t, 3H, J = 6.4 Hz, CH2CH3); EI-MS
(70 eV, m/z): 560 (M+), 561 (M+ + 1); Elemental Anal. Calcd.
for C29H25FN4O5S: C, 62.13; H, 4.49; N, 9.99; Found: C,
62.44; H, 4.38; N, 10.05.
3.5. General procedure for the preparation of 6-(4-
alkoxycarbonylalkoxy)phenoxy-3-alkylthio-5-(fluoro-
substituted)phenyl-1-phenylpyrazolo[3,4-d]pyrimidin-4-
ones 6a–6j
To a solution of iminophosphorane 4 (2 mmol) in dry
dichloromethane (25 mL), aromatic isocyanate (2 mmol) was
added under nitrogen at room temperature. After the reaction
mixture was stirred for 2–5 h, the solvent was removed under
reduced pressure and then 25 mL anhydrous accetonitrile,
2.0 mmol 2-(4-hydroxyphenoxy)-carboxylates 2 and 0.05 g
anhydrous potassium carbonate were added to the mixture.
Stirring for another 5 h at refluxing, the mixture was cooled to
room temperature and then filtered. The filtration was
condensed under reduce pressure, and the residue was
recrystallized with ethanol to give pure 6-(4-alkoxycarbony-
lalkoxy) phenoxy-3-alkylthio-5-(fluoro-substituted)phenyl-1-
phenylpyrazolo[3,4-d]pyrimidin-4-ones 6a–6j.
3.5.6. 6-[4-(1-Ethoxycarbonylethoxy)phenoxy-5-(4-
fluorophenyl)-3-methylthio-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (6f)
White crystals, mp 198–199 8C, yield, 63%; IR (KBr) n
(cmÀ1): 2988, 2935, 1751, 1704, 1603, 1576, 1549, 1504, 1350,
1190, 1132, 1030, 896, 829, 758; 1H NMR (CDCl3, 400 MHz) d
7.90 (d, 2H, J = 8.0 Hz, Ar), 7.18–7.36 (m, 7H, Ar), 7.07 (d, 2H,
J = 9.2 Hz, OC6H4O), 6.90 (d, 2H, J = 8.8 Hz, OC6H4O), 4.75
(q, 1H, J = 6.8 Hz, OCH), 4.21 (q, 2H, J = 6.8 Hz, OCH2), 2.64
(s, 3H, SCH3), 1.65 (d, 3H, J = 7.2 Hz, CH3CH), 1.23 (t, 3H,
J = 7.2 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3): d 13.4,
14.3, 18.6, 61.5, 73.3, 102.2, 115.9, 116.5, 116.7, 120.2, 122.6,
126.2, 128.9, 130.3, 130.4, 138.7, 145.8, 147.4, 151.1, 155.8,
156.2, 157.5, 161.6, 164.1, 171.9; EI-MS (70 eV, m/z): 560
(M+), 561 (M+ + 1); Elemental Anal. Calcd. for
C29H25FN4O5S: C, 62.13; H, 4.49; N, 9.99; Found: C,
61.86; H, 4.28; N, 9.76.
3.5.1. 6-(4-Ethoxycarbonylmethoxy)phenoxy-5-(3-
fluorophenyl)-3-methylthio-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (6a)
Spectral date are reference to [9c]; 13C NMR (100 MHz,
CDCl3): d 13.5, 14.3, 61.6, 66.0, 102.2, 115.5, 116.3, 116.6,
120.4, 122.7, 124.6, 126.3, 129.0, 130.7, 135.8, 138.7, 145.9,
147.6, 151.1, 154.1, 156.0, 157.3, 163.1, 168.7.
3.5.2. 6-(4-Ethoxycarbonylmethoxy)phenoxy-5-(2-
fluorophenyl)-3-methylthio-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (6b)
3.5.7. 5-(2-Fluorophenyl)-3-methylthio-1-phenyl-6-[4-(1-
propoxycarbonylethoxy)]phenoxy pyrazolo[3,4-
d]pyrimidin-4-one (6g)
Spectral date are consistent with reference to [9c].
White crystals, mp 185–187 8C; yield, 61%; IR (KBr) n
(cmÀ1): 2988, 1743, 1702, 1601, 1576, 1500, 1398, 1190, 896,
1
757; H NMR (CDCl3, 400 MHz) d 7.90 (d, 2H, J = 8.0 Hz,
3.5.3. 6-(4-Ethoxycarbonylmethoxy)phenoxy-5-(4-
fluorophenyl)-3-methylthio-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (6c)
Ar), 7.20–7.46 (m, 7H, Ph), 7.09 (d, 2H, J = 9.2 Hz, OC6H4O),
6.91 (d, 2H, J = 9.2 Hz, OC6H4O), 4.76 (q, 1H, J = 7.2 Hz,
CHC O), 4.11 (t, 2H, J = 6.8 Hz, OCH2Et), 2.68 (s, 3H,
SCH3), 1.60–1.66 (m, 5H, CH3CHO and CH2CH2CH3), 0.87
(t, 3H, J = 7.2 Hz, CH3); 13C NMR (100 MHz, CDCl3): d 10.4,
13.6, 18.7, 22.1, 67.1, 73.3, 102.2, 116.0, 116.6, 116.8, 120.4,
122.2, 122.7, 124.8, 126.3, 129.0, 130.6, 131.3, 138.7, 145.9,
147.6, 151.4, 155.9, 156.1, 156.8, 172.1; EI-MS (70 eV, m/z):
575 (M+); Elemental Anal. Calcd. for C30H27FN4O5S: C, 62.71;
H, 4.74; N, 9.75; Found: C, 62.93; H, 4.81; N, 9.92.
Spectral date are consistent with reference to [9c].
3.5.4. 6-[4-(1-Ethoxycarbonylethoxy)]phenoxy-5-(3-
fluorophenyl)-3-methylthio-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (6d)
White crystals, mp 209–210 8C; yield, 65%; IR (KB) n
(cmÀ1): 2991, 2928, 1743, 1704, 1600, 1575, 1549, 1502, 1349,
1195, 1134, 829, 779, 679; 1H NMR (CDCl3, 400 MHz) d 7.90
(d, 2H, J = 8.4 Hz, Ar), 7.51 (q, 1H, J = 8.4 Hz, Ar), 7.33 (t, 2H,
J = 8.0 Hz, Ar), 7.12–7.26 (m, 4H, Ar), 7.08 (d, 2H, J = 8.8 Hz,
OC6H4O), 6.91 (d, 2H, J = 8.8 Hz, OC6H4O), 4.75 (q, 1H,
J = 6.8 Hz, OCH), 4.22 (q, 2H, J = 7.2 Hz, OCH2), 2.66 (s, 3H,
SCH3), 1.65 (d, 3H, J = 6.4 Hz, CH3CH), 1.24 (t, 3H,
J = 7.2 Hz, CH2CH3); EI-MS (70 eV, m/z): 560 (M+), 562
(M+ + 2); Elemental Anal. Calcd. for C29H25FN4O5S: C, 62.13;
H, 4.49; N, 9.99; Found: C, 62.32; H, 4.57; N, 10.02.
3.5.8. 5-(4-Fluorophenyl)-3-methylthio-1-phenyl-6-[4-(1-
propoxycarbonylethoxy)]phenoxy pyrazolo[3,4-
d]pyrimidin-4-one (6h)
White crystals, mp 188–189 8C; yield, 62%; IR (KBr) n
(cmÀ1): 2971, 2930, 1752, 1702, 1603, 1576, 1505, 1349, 1132,
1
895, 830, 758; H NMR (CDCl3, 400 MHz) d 7.90 (d, 2H,
J = 7.6 Hz, Ar), 7.20–7.36 (m, 7H, Ph), 7.07 (dd, 2H,

H. Liu et al. / Journal of Fluorine Chemistry 127 (2006) 1584–1590
1589
J = 6.8 Hz and 2.8 Hz, OC6H4O), 6.91 (dd, 2H, J = 9.2 Hz and
3.6.4. 6-[4-(1-Ethoxycarbonylethoxy)]phenoxy-5-(3-
fluorophenyl)-3-methylsulfonyl-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (7d)
2.8 Hz, OC6H4O), 4.76 (q, 1H, J = 6.8 Hz, CHC O), 4.11 (t,
2H, J = 6.6 Hz, OCH2Et), 2.68 (s, 3H, SCH3), 1.60–1.66 (m,
5H, CH3CHO and CH2CH2CH3), 0.87 (t, 3H, J = 7.4 Hz,
CH3); EI-MS (70 eV, m/z): 575 (M+); Elemental Anal. Calcd.
for C30H27FN4O5S: C, 62.71; H, 4.74; N, 9.75; Found: C,
62.59; H, 4.65; N, 9.88.
White crystals, mp 212–213 8C; yield 82%; IR (KBr) n
(cmÀ1): 3118, 2990, 2928, 1720, 1600, 1579, 1558, 1502, 1327,
1
1197, 1134, 1095, 881, 770, 682, 571, 522; H NMR (CDCl3,
400 MHz) d 7.87 (d, 2H, J = 8.0 Hz, Ar), 7.56 (q, 1H,
J = 6.4 Hz, Ar), 7.14–7.40 (m, 6H, Ar), 7.06 (d, 2H, J = 8.8 Hz,
OC6H4O), 6.91 (d, 2H, J = 8.8 Hz, OC6H4O), 4.74 (q, 1H,
J = 6.8 Hz, OCH), 4.21 (q, 2H, J = 7.2 Hz, OCH2), 3.50 (s, 3H,
S (O2) CH3), 1.65 (d, 3H, J = 6.4 Hz, CH3CH), 1.24 (t, 3H,
J = 7.2 Hz, CH2CH3); EI-MS (70 eV, m/z): 592 (M+ À 1), 593
(M+); Elemental Anal. Calcd. for C29H25FN4O7S: C, 58.78; H,
4.25; N, 9.45; Found: C, 58.88; H, 4.23; N, 9.50.
3.5.9. 3-Benzylsulfanyl-5-(2-fluorophenyl)-6-[4-(1-
methoxycarbonylethoxy)]phenoxy-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (6i)
Spectral date are consistent with reference to [9a].
3.5.10. 3-Benzylsulfanyl-5-(4-fluorophenyl)-6-[4-(1-
methoxycarbonylethoxy)]phenoxy-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one e (6j)
Spectral date are reference to [7a]; 13C NMR (100MHz,
CDCl3):d 18.7, 35.2, 52.5, 73.3, 102.5, 116.0, 116.6, 116.8,
120.4, 122.6, 126.3, 127.4, 128.5, 129.0, 129.4, 130.3, 130.4,
137.7, 138.7, 145.9, 146.3, 151.1, 155.8, 156.2, 157.5, 161.7,
164.1, 172.4.
3.6.5. 6-[4-(1-Ethoxycarbonylethoxy)]phenoxy-5-(2-
fluorophenyl)-3-methylsulfonyl-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (7e)
White crystals, mp 233–235 8C, yield 88%; IR (KBr) n
(cmÀ1): 3120, 2987, 2925, 1744, 1728, 1599, 1578, 1545, 1501,
1
1327, 1192, 1137, 1096, 905, 775, 696, 574, 523; H NMR
(CDCl3, 400 MHz)d 7.87 (d, 2H, J = 8.0 Hz, Ar), 7.27-7.47 (m,
7H, Ar), 7.08 (d, 2H, J = 9.2 Hz, OC6H4O), 6.91 (d, 2H,
J = 9.2 Hz, OC6H4O), 4.75 (q, 1H, J = 6.4 Hz, OCH), 4.21 (q,
2H, J = 7.2 Hz, OCH2), 3.51 (s, 3H, S (O2) CH3), 1.65 (d, 3H,
J = 6.4 Hz, CH3CH), 1.23 (t, 3H, J = 6.4 Hz, CH2CH3); EI-MS
(70 eV, m/z): 592 (M+ À 1), 593 (M+); Elemental Anal. Calcd.
for C29H25FN4O7S: C, 58.78; H, 4.25; N, 9.45; Found: C,
58.82; H, 4.27; N, 9.51.
3.6. General procedure for the preparation of 6-(4-
alkoxycarbonylalkoxy)phenoxy-3-alkylsulfonyl-5-(fluoro-
substituted)phenyl-1-phenylpyrazolo[3,4-d]pyrimidin-4-
ones 7a–7j
To a 25 mL flask, 1.5 mmol 6 and 15 ml acetic acid
were added at room temperature, and then 0.002 g
(0.06 mmol) Na2WO4ÁH2O was added with stirring. The
reaction mixture was heated to 40 8C with vigorous stirring.
To the reaction mixture, 0.51 g (4.5 mmol) 30% H2O2 was
added slowly. After addition was completed, the mixture was
heated to 50 8C and stirred for another 5 h. The reaction
mixture was chilled to room temperature and dumped to a
solution that was dispensed by 0.25 g Na2SO3 and 20 mL
water. A lot of white solid was precipitated with stirring.
Pure compounds 7 were obtained after recrystallization with
ethanol.
3.6.6. 6-[4-(1-Ethoxycarbonylethoxy)]phenoxy-5-(4-
fluorophenyl)-3-methylsulfonyl-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (7f)
White crystals, mp 231–232 8C, yield 85%; IR (KBr) n
(cmÀ1): 3117, 3006, 2925, 1749, 1720, 1605, 1577, 1546, 1504,
1
1328, 1201, 1137, 1098, 904, 775, 695, 560, 524; H NMR
(CDCl3, 400 MHz) d 7.87 (d, 2H, J = 8.0 Hz, Ar), 7.24–7.40
(m, 7H, Ar), 7.05 (d, 2H, J = 9.2 Hz, OC6H4O), 6.90 (d, 2H,
J = 9.2 Hz, OC6H4O), 4.74 (q, 1H, J = 6.4 Hz, OCH), 4.21 (q,
2H, J = 6.8 Hz, OCH2), 3.50 (s, 3H, S(O2)CH3), 1.64 (d, 3H,
J = 7.0 Hz, CH3CH), 1.23 (t, 3H, J = 7.2 Hz, CH2CH3); 13C
NMR (100 MHz, CDCl3):d 14.2, 18.6, 42.6, 61.6, 73.3, 100.9,
116.1, 116.9, 117.1, 121.7, 122.4, 128.0, 129.2, 130.2, 130.3,
137.6, 145.5, 147.6, 151.8, 156.0, 156.3, 156.9, 161.8, 164.3,
171.9; EI-MS (70 eV, m/z): 592 (M+ À 1), 593 (M+); Elemental
Anal. Calcd. for C29H25FN4O7S: C, 58.78; H, 4.25; N, 9.45;
Found: C, 58.85; H, 4.24; N, 9.53.
3.6.1. 6-(4-Ethoxycarbonylmethoxy)phenoxy-5-(3-
fluorophenyl)-3-methylsulfonyl-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (7a)
Spectral date are reference to [9c]. 13C NMR (100 MHz,
CDCl3):d 14.3, 42.7, 61.7, 65.9, 100.9, 115.6, 116.3, 117.1,
121.8, 122.5, 124.4, 128.1, 129.2, 131.0, 135.8, 137.5, 145.6,
147.6, 151.8, 156.1, 156.3, 156.7, 163.6, 168.6.
3.6.2. 6-(4-Ethoxycarbonylmethoxy)phenoxy-5-(2-
fluorophenyl)-3-methylsulfonyl-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (7b)
3.6.7. 5-(2-Fluorophenyl)-3-methylsulfonyl-1-phenyl-6-[4-
(1-propoxycarbonylethoxy)]phenoxy pyrazolo[3,4-
d]pyrimidin-4-one (7g)
Spectral date are consistent with reference to [9c].
White crystals, mp 172–176 8C; yield, 71%; IR (KBr) n
(cmÀ1): 3120, 2971, 1732, 1599, 1578, 1550, 1501, 1196, 1137,
1038, 903, 761, 574, 519; 1H NMR (CDCl3, 400 MHz) d 7.88
(d, 2H, J = 8.0 Hz, Ar), 7.24–7.39 (m, 8H, Ar), 7.06 (d, 2H,
J = 8.8 Hz, OC6H4O), 6.91 (d, 2H, J = 9.2 Hz, OC6H4O), 4.75
(q, 1H, J = 6.8 Hz, CHC O), 4.11 (t, 2H, J = 7.6 Hz,
3.6.3. 6-(4-Ethoxycarbonylmethoxy)phenoxy-5-(4-
fluorophenyl)-3-methylsulfonyl-1-phenylpyrazolo[3,4-
d]pyrimidin-4-one (7c)
Spectral date are consistent with reference to [9c].

1590
H. Liu et al. / Journal of Fluorine Chemistry 127 (2006) 1584–1590
OCH2CH2CH3), 3.50 (s, 3H, S(O2)CH3), 1.60–1.66 (m, 5H,
OCHCH3 and OCH2CH2CH3), 0.87 (t, 3H, J = 7.6 Hz,
OCH2CH2CH3); 13C NMR (100 MHz, CDCl3): d 10.4, 18.7,
22.1, 42.7, 67.1, 73.3, 100.8, 116.1, 116.6, 116.8, 121.1, 122.5,
125.1, 128.1, 129.2, 130.4, 131.7, 137.6, 145.6, 146.6, 147.7,
152.0, 155.6, 156.1, 156.8, 172.0; EI-MS (70 eV, m/z): 606
(M+ À 1), 607 (M+); Elemental Anal. Calcd. for
C30H27FN4O7S: C, 59.40; H, 4.49; N, 9.24; Found: C,
59.51; H, 4.54; N, 9.18.
3.8. Crystal structure determination
Single crystal X-ray diffraction data for 7b at 292 K on a
Bruker Smart Apex Area CCD equipped with Mo Ka radiation
˚
(l = 0.71073 A). Crystallographic data (excluding structure
factors) for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-604929. Copies of the data can be
obtained, free of charge, on application to CCDC, Cambridge,
UK (fax: +44 1223 336033 or email: deposit@ccdc.cam.ac.uk).
3.6.8. 5-(4-Fluorophenyl)-3-methylsulfonyl-1-phenyl-6-[4-
(1-propoxycarbonylethoxy)]phenoxy pyrazolo[3,4-
d]pyrimidin-4-one (7h)
Acknowledgment
We are grateful to the National Natural Science Foundation
of China (no. 20101001).
White crystals, mp 211–213 8C; yield, 62%; IR (KBr) n
(cmÀ1): 3979, 2969, 2919, 1721, 1605, 1579, 1558, 1504, 1194,
1137, 1093, 1034, 902, 763, 558, 521; 1H NMR (CDCl3,
400MHz) d 7.88 (d, 2H, J = 8.0 Hz, Ar), 7.24–7.39 (m, 8H, Ar),
7.05 (d, 2H, J = 8.8 Hz, OC6H4O), 6.90 (d, 2H, J = 8.8 Hz,
OC6H4O), 4.75 (q, 1H, J = 6.8 Hz, CHC O), 4.11 (t, 2H,
J = 7.6 Hz, OCH2CH2CH3), 3.50 (s, 3H, S(O2)CH3), 1.59–1.66
(m, 5H, OCHCH3 and OCH2CH2CH3), 0.87 (t, 3H, J = 7.6 Hz,
OCH2CH2CH3); EI-MS (70 eV, m/z): 606 (M+ À 1), 607 (M+);
Elemental Anal. Calcd. for C30H27FN4O7S: C, 59.40; H, 4.49;
N, 9.24; Found: C, 59.52; H, 4.56; N, 9.20.
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