Synthesis of new fluorine-containing pyrazolo[3,4-b]pyridinones as promising drug precursors

Article abstract of DOI:10.1007/s11172-011-0114-y

Methods for the synthesis of 4-R-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6- ones (R = CF₂SAr and 4-CFHSAr) were developed. The derivatives with R = CF₂SAr were obtained by both heterocyclization of 1-substituted 5-aminopyrazoles with ethyl 4,4-difluoro-3-oxo-4-phenylsulfanylbutanoate and replacement of the Br atom in 4-bromodifluoromethyl-6,7-dihydro-1H-pyrazolo[3,4- b]pyridin-6-ones by sodium arenethiolates. The fragment 4-CF-HSAr was introduced by replacement of the Cl atom in 4-chlorofluoromethyl-6,7-dihydro-1H- pyrazolo[3,4-b]pyridin-6-ones by sodium arenethiolates. Oxidation of 4-CF ₂SPh-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-ones gave the corresponding sulfoxides; their structures were confirmed by X-ray diffraction data.

Full text of DOI:10.1007/s11172-011-0114-y

Russian Chemical Bulletin, International Edition, Vol. 60, No. 4, pp. 733—745, April, 2011
733
Synthesis of new fluorineꢀcontaining pyrazolo[3,4ꢀb]pyridinones
as promising drug precursors
A. S. Golubev,a G. S. Starostin,a K. S. Chunikhin,a A. S. Peregudov,a K. C. Rodygin,b S. A. Rubtsova,b
P. A. Slepukhin,c A. V. Kuchin,b and N. D. Chkanikova
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: nchkan@ineos.ac.ru
bInstitute of Chemistry, Komi Research Center, Ural Branch of the Russian Academy of Sciences,
48 ul. Pervomaiskaya, 167982 Syktyvkar, Komi Republic, Russian Federation
cI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620990 Ekaterinburg, Russian Federation
Methods for the synthesis of 4ꢀRꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones
(R = CF2SAr and 4ꢀCFHSAr) were developed. The derivatives with R = CF2SAr were obꢀ
tained by both heterocyclization of 1ꢀsubstituted 5ꢀaminopyrazoles with ethyl 4,4ꢀdifluoroꢀ3ꢀ
oxoꢀ4ꢀphenylsulfanylbutanoate and replacement of the Br atom in 4ꢀbromodifluoromethylꢀ
6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones by sodium arenethiolates. The fragment 4ꢀCFꢀ
HSAr was introduced by replacement of the Cl atom in 4ꢀchlorofluoromethylꢀ6,7ꢀdihydroꢀ1Hꢀ
pyrazolo[3,4ꢀb]pyridinꢀ6ꢀones by sodium arenethiolates. Oxidation of 4ꢀCF2SPhꢀ6,7ꢀdihydroꢀ
1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones gave the corresponding sulfoxides; their structures were conꢀ
firmed by Xꢀray diffraction data.
Key words: pyrazolo[3,4ꢀb]pyridines, fluorineꢀcontaining 6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridinꢀ6ꢀones, 1ꢀsubstituted 5ꢀaminopyrazoles, heterocyclization, fluorineꢀcontaining ethyl
acetoacetates, microwave irradiation, arylsulfanyl(difluoro)methyl group, arylsulfinyl(difluoro)ꢀ
methyl group.
The pyrazolo[3,4ꢀb]pyridine framework is a key strucꢀ
tural fragment of many heterocyclic compounds showing
a broad spectrum of biological activity.1 In the last deꢀ
cade, some heterocycles of this class have been found to
regulate the cardiovascular system2 and possess antiviral,3
antitumor,4 antiinflammatory,5 antimicrobial,6 and antiꢀ
parasitic properties.7 Fluoroalkylꢀcontaining pyrazoloꢀ
[3,4ꢀb]pyridines are also believed to be candidates for medꢀ
ications and considered to be potential inhibitors of adeꢀ
nosine deaminase and inosine 5´ꢀmonophosphate dehyꢀ
drogenase.8 Primary attention has been given to the synꢀ
thesis of CF3ꢀcontaining pyrazolo[3,4ꢀb]pyridines 1,9
while derivatives containing the fragment CF2 were repreꢀ
sented by CF2Hꢀcontaining pyrazolo[3,4ꢀb]pyridines.8 At
the same time, the structural fragment CF2, which is sterꢀ
ically similar to the CH2 group, contrasts sharply with the
latter in polarity and reactivity.10 In particular, this fragꢀ
ment is thought to be an isopolar and isosteric substitute
for oxygen.11 Some CF2ꢀcontaining compounds exhibit
high physiological activity,12 including antitumor13 and
antifungal effects14 and inhibition of HIVꢀ1 reverse tranꢀ
scriptase15 and various protein kinases.16 Thus, developꢀ
ment of synthetic routes to compounds with functionalꢀ
ized fragments CF2 is an important step in searching for
novel biologically active molecules. Recently, we have pubꢀ
lished a method for the synthesis of 4ꢀ[(difluoro)(phenꢀ
oxy)methyl]ꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀ
one (2) from ethyl 4,4ꢀdifluoroꢀ4ꢀphenoxyacetoacetate
and 5ꢀaminoꢀ1ꢀ(3ꢀchlorophenyl)ꢀ3ꢀmethylpyrazole.17
The goal of the present work was to develop methods
for the synthesis of earlier unknown 6,7ꢀdihydroꢀ1Hꢀpyrꢀ
azolo[3,4ꢀb]pyridinꢀ6ꢀones 3 containing arylsulfanyl(diꢀ
fluoro)methyl (ArSCF2—) and arylsulfanyl(fluoro)methyl
groups (ArSCHF—) at position 4.
Within the scope of the present work, we studied two
synthetic routes to target compounds 3. The first route
involves heterocyclization of 1ꢀsubstituted 5ꢀaminopyrꢀ
azoles with acyclic compounds already containing the fragꢀ
ment ArSCF2 or ArSCHF (e.g., earlier unknown esters of
4ꢀarylthioꢀ4,4ꢀdifluoroacetoacetic and 4ꢀarylthioꢀ4ꢀfluoroꢀ
acetoacetic acid 4) (Scheme 1). The second route involves
the formation of the fragments ArSCF2 and ArSCHF in
a heteromolecule via substitution of the arylsulfanyl group
for the halogen atom in 4ꢀCF2Brꢀ (or 4ꢀCF2Clꢀ) and
4ꢀCHFClꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones
(see Scheme 1).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 718—730, April, 2011.
1066ꢀ5285/11/6004ꢀ733 © 2011 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Golubev et al.
Scheme 2
Conditions: NaH, Et2O or LDA, –75 °C.
Ethyl 4ꢀfluoroꢀ4ꢀphenylthioacetoacetate (4b) was obꢀ
tained as shown in Scheme 3. Following this scheme, we
also obtained known18 ethyl 4ꢀbromoꢀ4,4ꢀdifluoroacetoꢀ
acetate (4c) and ethyl 4ꢀchloroꢀ4,4ꢀdifluoroacetoacetate
(4d) and undocumented ethyl 4ꢀchloroꢀ4ꢀfluoroacetoꢀ
acetate (4e).
X = F, H
Scheme 1
Scheme 3
4
b
c
X
H
F
Y
4
d
e
X
F
H
Y
Cl
Cl
PhS
Br
Conditions: LDA, MeCO2Et, Et2O, –75 °C.
Then we studied heterocyclization reactions of acetoꢀ
acetic derivatives 4a—e with 1ꢀsubstituted 5ꢀaminoꢀ
pyrazoles 5a—c.
A: X = F, Y = Br (Cl); X = H, Y = Cl
3, 4: X = F, H
Results and Discussion
For the first approach, we should previously synthesize
4ꢀarylthioꢀ4,4ꢀdifluoroacetoacetic and 4ꢀarylthioꢀ4ꢀfluoroꢀ
acetoacetic acid esters 4 (see Scheme 1). Ethyl 4,4ꢀdiꢀ
fluoroꢀ4ꢀphenylthioacetoacetate (4a) was obtained in two
ways: (1) condensation of ethyl difluoro(phenylthio)ꢀ
acetate with ethyl acetate in the presence of NaH and (2)
lithiation of ethyl acetate with lithium diisopropylamide
(LDA) at –75 °C followed by acylation of the lithium
derivative with ethyl difluoro(phenylthio)acetate at the
same temperature (Scheme 2).
A reaction of ethyl 4,4ꢀdifluoroꢀ4ꢀphenylthioacetoꢀ
acetate 4a with pyrazole 5a in boiling acetic acid gave
a complex mixture of products precluding isolation of the

Fluorinated 1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
735
Scheme 5
target pyrazolo[3,4ꢀb]pyridine (3a). A decrease in the reꢀ
action temperature to 70 °C, as well as heating in DMF at
80 °C, was ineffective. The target pyrazolo[3,4ꢀb]pyridines
3a—c were obtained when solutions of oxo ester 4a and
pyrazoles 5a—c in acetic acid were exposed to microwave
irradiation for 7 min (Scheme 4).
Scheme 4
Comꢀ
pound
6a
6b
6c
7a
7b
7c
8a
X
Y
R1
R2
F
F
F
F
F
F
H
H
H
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Ph
4ꢀFC6H4
4ꢀMeOC6H4CH2
Ph
4ꢀFC6H4
4ꢀMeOC6H4CH2
Ph
Me
Me
H
Me
Me
H
Me
Me
H
8b
8c
4ꢀFC6H4
4ꢀMeOC6H4CH2
R1 = Ph, R2 = Me (3a); R1 = 4ꢀFC6H4, R2 = Me (3b);
R
1 = 4ꢀMeOC6H4CH2, R2 = H (3c)
MW denotes microwave irradiation
the reduction19 of the 4ꢀCF2Br group to the 4ꢀCF2H group:
in all cases, difluoromethylpyrazolopyridine 9 was formed
as a byꢀproduct. Compound 9 was also obtained by conꢀ
densation of aminopyrazole 5a with ethyl 4,4ꢀdifluoroacꢀ
etoacetate 4f in boiling acetic acid.
With ethyl 4ꢀfluoroꢀ4ꢀphenylthioacetoacetate 4b, all
our attempts to obtain the target 4ꢀArSCHFꢀ6,7ꢀdihydroꢀ
1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones 3 from oxo ester 4b and
pyrazoles 5a—c, including heating in acetic acid under
microwave irradiation, were unsuccessful.
Ethyl 4ꢀbromoꢀ4,4ꢀdifluoroacetoacetate (4c) reacts
with aminopyrazoles 5a—c in boiling acetic acid for 3 h to
give pyrazolo[3,4ꢀb]pyridines 6a—c in high yields. Similar
reactions of ethyl 4ꢀchloroꢀ4,4ꢀdifluoroacetoacetate (4d)
and ethyl 4ꢀchloroꢀ4ꢀfluoroacetoacetate (4e) produce
pyrazolo[3,4ꢀb]pyridines 7a—c and 8a—c, respectively, in
high yields (Scheme 5).
Scheme 6
Pyrazolopyridines 6a—8a were used for the synthesis
of the target products 3 according to the second approach.
For instance, pyrazolo[3,4ꢀb]pyridine 3a was obtained by
a reaction of 4ꢀCF2Brꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridinꢀ6ꢀone (6a) with an excess of PhSNa in DMF, in
which the Br atom is replaced by the arylsulfanyl group.
For this transformation to occur, we accurately selected
appropriate reaction conditions. It turned out that the
complete conversion of compound 6a, as well as high yields
of the target products, cannot be achieved unless oxygen is
thoroughly removed from the solutions of the reagents in
DMF. Under these conditions, the reaction was completꢀ
ed with mild heating (50 °C) in 2 h; pyrazolo[3,4ꢀb]ꢀ
pyridine 3a and its 4ꢀArSCF2 analogs 3d,e were isolated in
high yields (Scheme 6). Nevertheless, we failed to avoid
Ar = Ph (3a), 4ꢀClC6H4 (3d), 4ꢀMeC6H4 (3e)
The Cl atom in 4ꢀCF2Clꢀ6,7ꢀdihydroꢀ1Hꢀpyrazoloꢀ
[3,4ꢀb]pyridinꢀ6ꢀone 7a was not replaced by the arylthio

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Golubev et al.
group under the action of excess PhSNa in DMF at
20—130 °C.
13C NMR spectroscopy and 2D NMR experiments (NOESY,
HSQC, and HMBC).
However, with 4ꢀCHFClꢀ6,7ꢀdihydroꢀ1Hꢀpyrazoloꢀ
[3,4ꢀb]pyridinꢀ6ꢀone 8a, this replacement easily occurred
in the presence of a threefold excess of sodium benzeneꢀ
thiolate or sodium 4ꢀchlorobenzenethiolate in DMF at
20 °C; compounds 3f and 3g were isolated in high yields
(Scheme 7). Thus, the target compounds 4ꢀArSCHFꢀ6,7ꢀ
dihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones 3f,g were obꢀ
tained according to the second approach.
It should be noted that the discussed8,9c,9e,17,20 trends
for the 1D 13C NMR spectra of 4ꢀmethylꢀ and 4ꢀfluoroꢀ
methylꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones and
related 4ꢀtrifluoromethylquinolinꢀ2ꢀones, which confirm
the presence of the methyl (fluoromethyl) substituent at
the γꢀposition of the pyridine ring of the 1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridinꢀ2ꢀone (quinolinꢀ2ꢀone) system, are true for the
compounds obtained here. For instance, the signals for the
C(6) atom in their 13C NMR spectra appear at δ 160—165,
while the chemical shifts of the C(4) atom are δ 135—143
(see Table 2).
Scheme 7
The IR absorption spectra of compounds 3a—g, 6a—c,
7a—c, 8a—c, and 9 (KBr pellets) differ from those
of compounds 10a,b. For instance, the IR spectra of
the compounds of the former group contain very intense
bands due to the C=O stretching vibrations (ν(CO) ≈
≈ 1653—1667 cm–1, see Table 3) and a wide band with
several peaks at 3300—2400 cm–1 21
. At the same time, the
IR spectra of compounds 10a,b show very weak bands in
the range of the C=O vibrations. The spectrum of comꢀ
pound 10b contains a wide band of medium intensity with
a peak at 3208 cm–1, which can be assigned to the OH
stretching vibrations. A similar mediumꢀintensity wide
band with a peak at 3064 cm–1 appears in the IR spectrum
of compound 10a. This spectral pattern for compounds
10a,b agrees with the Xꢀray diffraction data (see above):
according to them, both compounds in the crystal exist in
the tautomeric hydroxy (or lactim) form, while compounds
3a—g, 6a—c, 7a—c, 8a—c, and 9 in the solid state mainly
exist in the keto (or lactam) form.9d Apparently, the
4ꢀdifluoro(phenylsulfinyl)methyl group (PhSOCF2ꢀ) in
6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones is a strucꢀ
tural element enabling variation of the tautomeric nature
Ar = Ph (3f), 4ꢀClC6H4 (3g)
Pyrazolo[3,4ꢀb]pyridines containing the arylsulfinylꢀ
(difluoro)methyl group (ArSOCF2—) are unknown.
We demonstrated that the difluoro(phenylsulfanyl)ꢀ
methyl group (PhSCF2—) in compounds 3a,b can be oxiꢀ
dized with MCPBA into the difluoro(phenylsulfinyl)ꢀ
methyl group (PhSOCF2—). This transformation gave
the corresponding sulfoxides 10a,b in good yields
(Scheme 8).
Scheme 8
of the heterocycle.22
*
The general view of structure 10b with the atomic numꢀ
bering adopted in crystallographic experiments is shown
in Fig. 1, b. The molecule exists in a tweezersꢀlike conforꢀ
mation folded along the bonds C(11)—C(8)—S(1)—C(1).
The distance between the centroids of the phenyl substituꢀ
ent at the sulfinyl group and of the pyridine ring is 4.135 Å.
The torsion angle O(1)—S(1)—C(8)—C(11) is 165.55°.
The phenyl substituent at the N(1) atom is virtually coplaꢀ
nar with the pyrazolo[3,4ꢀb]pyridine framework: the maxꢀ
imum deviation of the atoms from the meanꢀsquare plane
does not exceed 0.130 Å. The bond lengths have nearly
standard values. The C(1)—S(1) bond between the sulfur
atom and the phenyl substituent is substantially shorter
R = Ph (3a, 10a), 4ꢀFC6H4 (3b, 10b)
The structures of the compounds obtained were conꢀ
firmed by elemental analysis (Table 1), NMR spectroscopy
(Table 2), IR spectroscopy, mass spectrometry (Table 3),
and Xꢀray diffraction (for 10a,b only). Clearly, the last
data also provide evidence for the 1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridine structure of, and the presence of the 4ꢀfluoroalkyl
substituent in, compounds 3a,b, 6a,b, and 7a,b (precurꢀ
sors of sulfoxides 10a,b) and compounds 3d,e and 9. The
structures of 1Hꢀpyrazolo[3,4ꢀb]pyridines 8a—c, their deꢀ
rivatives 3f,g, and compounds 3c, 6c, 7c, notably the presꢀ
ence of the 4ꢀfluoroalkyl substituent, were confirmed by
* NꢀOxide is a structural fragment that shifts the tautomeric equiꢀ
librium in 3ꢀoxoꢀ1Hꢀpyrazolo[4,3ꢀc]pyridines toward the lactim
form.22a Attempts to change the tautomeric form in quinolinꢀ2ꢀ
ones by introduction of structural fragments have been desꢀ
cribed.22b

Fluorinated 1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
737
Table 1. Yields and selected physicochemical characteristics of compounds 3a—g, 6a—c, 7a—c,
8a—c, 9, and 10a,b
Comꢀ
pound
Yield
(%)
M.p./°C
(LP—EA)*
Found
Calculated
Molecular
formula
(%)
С
Н
N
3a
3b
3с
3d
3e
3f
65
67
70
77
77
89
85
77
73
85
70
74
87
72
74
79
76
65
60
179—180
196—198
156—157
199—200
214—215
173—174
195—196
156—157
170—171
205—206
157—158
184—185
197—198
182—183
223—224
187—188
184—185
157—158
188—189
62.85
62.65
59.64
59.84
60.78
61.01
57.12
57.49
63.77
63.46
65.67
65.74
60.21
60.07
47.60
47.48
45.32
45.19
47.07
46.90
54.43
54.30
51.15
51.31
52.89
53.03
57.86
57.64
54.42
54.30
56.00
56.00
60.87
61.09
60.11
60.14
57.45
57.55
3.71
3.94
3.34
3.52
4.06
4.14
3.09
3.38
4.21
4.31
4.37
4.41
3.88
3.78
2.82
2.85
2.33
2.44
3.08
3.15
3.23
3.25
2.88
2.77
3.66
3.56
3.68
3.80
3.24
3.25
4.03
4.07
3.89
4.03
3.67
3.79
3.27
3.38
10.96
10.96
10.29
10.47
10.18
10.16
9.88
C20H15F2N3OS
C20H14F3N3OS
C21H17F2N3O2S
C20H14СlF2N3OS
C21H17F2N3OS
C20H16FN3OS
10.06
10.38
10.57
11.32
11.50
10.30
10.51
11.87
11.86
11.09
11.29
10.92
10.94
13.55
13.57
12.78
12.82
12.24
12.37
14.35
14.40
13.56
13.57
12.97
13.06
15.45
15.27
10.48
10.52
10.02
10.07
3g
6a
6b
6c
7a
7b
7c
8a
8b
8c
9
C20H15ClFN3OS
C14H10BrF2N3O
C14H9BrF3N3O
C15H12BrF2N3O2
C14H10ClF2N3O
C14H9ClF3N3O
C15H12ClF2N3O2
C14H11ClFN3O
C14H10ClF2N3O
C15H13ClFN3O2
C14Н11F2N3O
10a
10b
C20H15F2N3O2S
C20H14F3N3O2S
* The solvent system is light petroleum—ethyl acetate.
O(2)
C(9)
a
b
C(4)
C(3)
C(19)
C(3)
N(3)
N(1)
C(5)
C(6)
F(3)
C(2)
C(17)
C(16)
C(20)
O(2)
C(4)
C(5)
C(1)
C(7)
C(15)
C(18)
C(17)
C(10)
C(2)
N(3)
C(18)
C(7)
C(15)
C(1)
C(11)
C(9)
C(10)
C(6)
F(1)
S(1)
S(1)
C(19)
C(20)
C(12)
C(8)
C(12)
N(1)
N(2)
C(16)
C(11)
C(8)
C(13)
N(2)
C(14)
C(13)
O(1)
O(1)
F(1)
F(2)
F(2)
C(14)
Fig. 1. General view of structures 10a (a) and 10b (b) with thermal displacement ellipsoids (p = 50%).

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Golubev et al.
Table 2. 1H, 13C, and 19F NMR spectra of compounds 3a—c, 3f, 6a—c, 7a—c, 8a—c, 9, and 10a
Comꢀ
pound
NMR (DMSOꢀd6, δ, J/Hz)
1H
13C
19F
3а
2.71 (s, 3 H, Me);
6.61 (s, 1 Н, Н(5));
16.29 (СH3); 103.77 (C(5)); 105.66 (C(3a)); 121.60
(С(2´)(NPh)); 125.61 (С1´(SPh)), 126.05 (t, CF2S,
JC,F = 277.5); 126.42 (С(4´)(NPh)); 129.47, 130.13
(С(3´)(NPh), С(3´)(SPh)); 131.37 (С(4´)(SPh));
136.71 (С(2´)(SPh)); 139.12 (С(1´)(NPh)); 139.91
(t, C(4), JC,F = 26.5); 141.52 (C(3)), 150.93 (C(7a));
163.65 (C(6))
7.70 (s, CF2SPh)
7.32 (t, 1 H, Ar, J = 6.7);
7.46—7.57 (m, 5 H, Ar);
7.62 (d, 2 Н, Ar, J = 7.0);
8.12 (d, 2 H, Ar, J = 7.4);
12.03 (br.s, 1 H, NН)
3b
2.72 (s, 3 H, Me);
6.62 (s, 1 Н, Н(5));
16.01 (СH3); 103.61 (C(5)); 105.47 (C(3a)); 115.86
(d, С(3´)(NAr), JC,F = 23.2); 123.19 (d, С(2´)(NAr),
JC,F = 7.8); 125.50 (С(1´)(SPh)); 125.75 (t, CF2S,
JC,F = 278.0); 129.75 (С(3´)(SPh)); 131.03
(С(4´)(SPh)); 135.31 (С(1´)(NAr)); 136.46
(С(2´)(SPh)); 139.90 (t, C(4), JC,F = 26.5); 141.48
(C(3)); 150.54 (C(7a)); 160.18 (d, С(4´)(NAr),
JC,F = 241.2); 163.46 (C(6))
–38.04 (m, 1 F, ArF);
7.44 (s, CF2SPh, 2 F)
7.40 (t, 2 H, Ar, J = 8.8);
7.52 (t, 2 H, Ar, J = 7.5);
7.58 (d, 1 Н, Ar, J = 7.5);
7.65 (d, 2 Н, Ar, J = 7.0);
8.15 (m, 2 H, Ar); 12.07
(br.s, 1 H, NН)
3c*
3.83 (s, 3 H, OМе);
5.56 (s, 2 H, CH2);
6.50 (s, 1 Н, Н(5));
51.23 (СH2); 55.27 (OCH3); 102.98 (C(3a)); 109.90
(C(5)); 114.11 (C(3´)(NCH2Ar)); 125.59 (t, CF2S,
JC,F = 279.7); 125.85 (С(1´)(SPh)); 127.68
3.05 (s, CF2SPh)
6.91 (d, 2 H, Ar, J = 8.7);
7.41—7.54 (m, 5 H, Ar);
7.66 (d, 2 Н, Ar, J = 8.7);
7.93 (s, 1 H, HC(3));
13.69 (br.s, 1 H, NН)
(C(1´)(NCH2Ar)); 129.29 (С(3´)(SPh)); 129.62
(C(2´)(NCH2Ar)); 130.59 (С(4´)(SPh)); 134.15 (C(3));
136.70 (С(2´)(SPh)); 141.62 (C(7a)), 142.63 (t, С(4),
JC,F = 27.7); 159.52 (C(4´)(NCH2Ar)); 164.88 (С(6))
3f
2.68 (s, 3 H, Ме); 6.58
(s, 1 Н, Н(5)); 7.32 (t, 1 H,
Ar, J = 7.3); 7.44—7.60
(m, 7 H, Ar); 7.68 (d, 1 H,
CHF, JH,F = 53.4); 8.17
(d, 2 H, Ar, J = 7.8);
15.60 (СH3); 97.80 (d, CHFS, JC,F = 224.5); 103.23
(d, C(5), JC,F = 7.7); 106.40 (C(3a)); 121.69
(C(2´)(NPh)); 125.81 (C(4´)(NPh)); 128.87
(C(3´)(NPh)); 128.98 (C(4´)(SPh)); 129.41
(C(3´)(SPh)); 131.74 (C(1´)(SPh)); 132.63 (C(2´)(SPh));
139.24 (C(1´)(NPh)); 141.66 (C(3)); 142.52 (d, C(4),
JC,F = 24.3); 149.96 (C(7a)); 163.93 (C(6))
–75.79 (d, JH,F = 53.4)
11.70 (br.s, 1 H, NН)
6a
2.61 (s, 3 H, Ме);
6.80 (s, 1 Н, Н(5));
7.34 (t, 1 H, Ar, J = 7.15);
7.53 (t, 2 Н, Ar, J = 7.5);
8.09 (d, 2 H, Ar, J = 7.8);
12.21 (br.s, 1 H, NН)
16.00 (t, СH3, JC,F = 4.5); 101.88 (t, C(5), JC,F = 6.6);
104.14 (C(3a)); 115.39 (t, CF2Br, JC,F = 302.0); 121.83
(C(2´)); 126.62 (C(4´)); 129.48 (C(3´)); 138.94 (C(1´));
140.82 (C(3)); 141.35 (t, C(4), JC,F = 26.5); 151.07
(C(7a)); 163.80 (C(6))
30.06 (s, CF2Br)
6b
2.67 (s, 3 H, Ме);
15.80 (СH3); 101.90 (t, C(5), JC,F = 6.3); 103.90
(C(3a)); 115.25 (t, CF2Br, JC,F = 302.6); 116.14
(d, C(3´), JC,F = 23.0); 123.65 (d, C(2´), JC,F = 8.3);
135.19 (C(1´)); 140.93 (C(3)); 141.33 (t, C(4),
JC,F = 26.2); 150.81 (C(7a)); 160.42 (d, C(4´),
JC,F = 243.7); 163.80 (C(6))
–37.73 (m, 1 F, ArF);
31.35 (s, 2 F, CF2Br)
6.87 (s, 1 Н, Н(5));
7.44 (t, 2 H, Ar, J = 8.5);
8.16 (m, 2 H, Ar);
12.21 (br.s, 1 H, NН)
6c**
3.83 (s, 3 H, OМе);
5.58 (s, 2 H, CH2);
6.64 (s, 1 H, Н(5));
6.92 (d, 2 H, Ar, J = 8.4);
7.47 (d, 2 H, Ar, J = 8.4);
7.96 (s, 1 H, HC(3));
13.59 (br.s, 1 H, NН)
50.24 (CH2); 55.24 (OCH3); 102.65 (C(3a)); 104.22
(C(5)); 114.04 (C(3´)); 115.68 (t, CF2Br, JC,F = 303.5);
128.81 (C(1´)); 129.14 (C(2´)); 131.66 (C(3)); 141.05
(t, C(4), JC,F = 26.2); 147.48 (C(7a)); 159.17 (C(4´));
163.48 (C(6))
28.11 (s, СF2Br)
7a
2.54 (s, 3 H, Ме),
15.33 (СH3); 102.69 (t, C(5), JC,F = 6.5); 104.37
23.45 (s, СF2Сl)
6.85 (s, 1 Н, Н(5));
(C(3a)); 121.71 (C(2´)); 124.17 (t, CF2Cl, JC,F =
7.34 (t, 1 H, Ar, J = 7.3);
7.53 (t, 2 Н, Ar, J = 7.5);
8.05 (d, 2 H, Ar, J = 7.8);
12.31 (br.s, 1 H, NН)
289.4); 126.64 (C(4´)); 129.47 (C(3´)); 138.77 (C(1´));
139.30 (t, C(4), JC,F = 28.7); 140.93 (C(3)); 150.93
(C(7a)); 163.76 (C(6))
(to be continued)

Fluorinated 1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
739
Table 2 (continued)
Comꢀ
NMR (DMSOꢀd6, δ, J/Hz)
pound
1H
13C
19F
7b
2.63 (s, 3 H, Ме);
15.25 (СH3); 102.71 (t, C(5), JC,F = 2.0); 104.22
(C(3a)); 116.10 (d, C(3´), JC,F = 22.7); 123.54
(d, C(2´), JC,F = 8.1); 124.13 (t, CF2Cl, JC,F = 289.7);
135.17 (C(1´)); 139.27 (t, C(4), JC,F = 28.7); 140.92
(C(3)); 150.77 (C(7a)); 160.39 (d, C(4´), JC,F = 243.1);
163.80 (C(6))
–37.84 (m, 1 F, ArF);
28.41 (s, 2 F, CF2Cl)
6.94 (s, 1 Н, Н(5));
7.44 (t, 2 H, Ar, J = 8.5);
8.15 (m, 2 H, Ar);
12.31 (br.s, 1 H, NН)
7c**
3.83 (s, 3 H, OМе);
5.59 (s, 2 H, CH2);
6.69 (s, 1 H, Н(5));
6.92 (d, 2 H, Ar, J = 6.4);
7.48 (d, 2 H, Ar, J = 6.4);
7.94 (s, 1 H, H—C(3));
13.59 (br.s, 1 H, NН)
50.31 (CH2); 55.24 (OCH3); 102.96 (C(3a)); 105.29
(t, C(5), JC,F = 5.2); 114.06 (C(3´)); 124.40 (t, CF2Cl,
JC,F = 290.2); 128.77 (C(1´)); 129.09 (C(2´)); 131.72
(C(3)); 139.52 (t, C(4), JC,F = 29.0); 147.43 (C(7a));
159.25 (C(4´)); 163.54 (C(6))
23.96 (s, СF2Сl)
8a
2.63 (s, 3 H, Ме); 6.80
(s, 1 Н, Н(5)); 7.31 (t, 1 H,
Ar, J = 6.8); 7.52 (t, 2 Н,
Ar, J = 7.2); 7.98 (d, 1 H,
CHFCl, J = 48.1); 8.13
(d, 2 H, Ar, J = 7.4);
15.53 (d, СH3, JC,F = 2.2); 98.13 (d, CHFCl,
JC,F = 241.0); 103.03 (d, C(5), JC,F = 4.4); 106.14
(C(3a)); 121.41 (C(2´)); 126.29 (C(4´)); 129.49
(C(3´)); 139.28 (C(1´)); 141.69 (C(3)); 143.03
(d, C(4), JC,F = 22.1); 150.84 (C(7a)), 164.13 (C(6))
–56.88 (d, JH,F = 48.1)
11.95 (br.s, 1 H, NН)
8b
2.67 (s, 3 H, Ме); 6.84
(s, 1 Н, Н(5)); 7.43
(t, 2 H, Ar, J = 8.2);
8.04 (d, 1 H, CHFCl,
J = 48.2); 8.19 (m, 2 H,
Ar); 12.02 (br.s, 1 H, NН)
15.35 (d, СH3, JC,F = 2.3); 97.93 (d, CHFCl, JC,F
=
–56.93 (d, 1 F, CHFCl,
JH,F = 48.1); –38.28
(m, 1 F, ArF)
242.0); 103.01 (d, C(5), JC,F = 9.5); 105.85 (d, C(3a),
JC,F = 3.2); 116.14 (d, C(3´), JC,F = 22.7); 123.32
(d, C(2´), JC,F = 8.3); 135.44 (d, C(1´), JC,F = 2.3);
141.76 (C(3)); 143.03 (d, C(4), JC,F = 22.7); 150.50
(C(7a)); 160.26 (d, C(4´), JC,F = 243.1); 164.10 (C(6))
8c**
3.79 (s, 3 H, OМе);
49.36 (CH2); 54.24 (OCH3); 96.93 (d, CHFCl, JC,F
242.8); 102.29 (C(3a)); 105.90 (d, C(5), JC,F = 7.8);
112.96 (C(3´)); 127.65 (C(1´)); 128.15 (C(2´)); 131.41
(C(3)); 141.44 (d, C(4), JC,F = 23.0); 144.70 (C(7a));
158.13 (C(4´)); 162.72 (C(6))
=
–59.15 (d, JH,F = 48.1)
5.54 (s, 2 H, CH2); 6.50
(s, 1 H, Н(5)); 6.87 (d,
2 H, Ar, J = 9.0); 7.11
(d, 1 H, CHFCl, J = 49.3);
7.44 (d, 2 H, Ar, J = 9.0);
7.91 (s, 1 H, HC(3));
13.59 (br.s, 1 H, NН)
9
2.64 (s, 3 H, Ме); 6.65
(s, 1 Н, Н(5)); 6.84 (t, 1 H,
CF2H, J = 54.6); 7.34 (t,
1 H, Ar, J = 7.15); 7.44
(t, 2 Н, Ar, J = 7.5); 7.68
(d, 2 H, Ar, J = 7.5); 12.30
(br.s, 1 H, NН)
14.70 (СH3); 104.88 (t, C(5), JC,F = 8.8); 106.39
(C(3a)); 112.75 (t, CF2H, JC,F = 239.9); 121.79
(C(2´)); 125.86 (C(4´)); 128.71 (C(3´)); 138.56
(t, C(4), JC,F = 21.3); 138.86 (C(1´)); 141.66 (C(3));
149.89 (C(7a)); 163.62 (C(6))
–35.93 (d, JH,F = 54.6)
10a*
2.52 (dd, 3 Н, Ме, J = 2.3,
J = 3.7); 6.32 (s, 1 Н, Н(5));
7.30 (m, 1 Н, Ar); 7.42
(m, 2 Н, Ar); 7.59 (m, 2 Н,
Ar); 7.68 (m, 3 Н, Ar); 7.80
(m, 2 Н, Ar); 9.59 (br.s,
1 Н, ОH)
15.23 (d, AB system, JАВ = 4.5); 15.33 (d, АВꢀ
systеmа, JАВ = 4.5); 105.57, 108.17 (t, JС,F = 8.0);
122.23, 122.40 (d, AB system, JC,F = 291);
126.31, 126.35 (d, AB system, JC,F = 291); 126.98,
129.11, 129.23, 133.32, 135.12 (t, JС,F = 23.5);
136.44, 137.60, 142.82, 146.57, 161.71
–27.72 (d, AB system,
JАВ = 223.1);
–20.00 (d, AB system,
JАВ = 223.1)
* In CDCl3.
** In CDCl3 (1H and 19F) and CDCl3—10% DMSOꢀd6 (13C).
than the S(1)—C(8) bond between sulfur and the fluoroꢀ
alkyl group (Tables 4, 5). The molecular packing is made
up of oppositely directed chains of molecules, the chains
being held together by intermolecular hydrogen bonds beꢀ
tween the sulfinyl and hydroxy groups. The parameters of
these bonds are given in Table 6.

740
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Golubev et al.
Table 3. IR and mass spectra of compounds 3a—c, 3f, 6a—c, 7a—c, 8a—c, 9, and 10a
Comꢀ
pound
IR (KBr),
ν/cm–1
MS (EI, 70 eV),
m/z (Irel (%))
3a
3b
3c
3f
1661 vs (С=О)
1667 vs (С=О)
1661 vs (С=О)
1653 vs (С=О)
384 [M + Н]+ (13), 383 [M]+ (53), 275 (19), 274 (100), 226 (7), 206 (9)
402 [M + Н]+ (13), 401 [M]+ (66), 293 (15), 292 (100), 244 (6), 224 (9)
413 [M]+ (11), 305 (13), 304 (57), 303 (7), 149 (8), 122 (10), 121 (100)
366 [M + Н]+ (14), 365 [M ]+ (51), 257 (18), 256 (100), 218 (14), 208 (10),
149 (16), 109 (11)
6a
6b
1653 vs (С=О)
1662 vs (С=О)
356 [M + Н]+ (5), 355 [M]+ (24), 354 [M + Н]+ (5), 353 [M]+ (28),
275 (19), 274 (100), 247 (4), 226 (7), 206 (8)
374 [M + Н]+ (6), 373 [M]+ (31), 372 [M + Н]+ (6), 371 [M]+ (33), 293 (18),
292 (100), 265 (3), 244 (7), 224 (10)
6c
7a
1658 vs (С=О)
1655 vs (С=О)
385 [M]+ (8), 383 [M]+ (8), 305 (13), 304 (62), 303 (7), 122 (9), 121 (100)
311 [M]+ (37), 310 [M – Н]+ (22), 309 [M]+ (100), 308 [M – Н]+ (22),
294 (11), 274 (28), 268 (17), 267 (13), 246 (9), 226 (8)
329 [M]+ (37), 328 [M – Н]+ (22), 327 [M]+ (100), 326 [M – Н]+ (22),
293 (15), 292 (38), 286 (14), 265 (10), 244 (9), 224 (8)
341 [M]+ (6), 340 [M – Н]+ (9), 339 [M]+ (20), 338 [M – Н]+ (18), 305 (9),
304 (45), 303 (12), 122 (10), 121 (100)
7b
7c
8a
8b
8c
9
1660 vs (С=О)
1661 vs (С=О)
1654 vs (С=О)
1661 vs (С=О)
1653 vs (С=О)
1662 vs (С=О)
3064 m, br (ОН)
293 [M]+ (35), 292 [M – Н]+ (24), 291 [M]+ (100), 290 [M – Н]+ (22),
257 (8), 256 (33), 236 (9), 208 (11)
311 [M]+ (32), 310 [M – Н]+ (21), 309 [M]+ (100), 308 [M – Н]+ (15),
275 (11), 274 (41), 254 (8), 246 (8), 226 (12)
323 [M]+ (7), 322 [M – Н]+ (8), 321 [M]+ (16), 320 [M – Н]+ (14), 287 (12),
286 (64), 285 (16), 122 (10), 121 (100)
276 [M + Н]+ (17), 275 [M]+ (100), 274 [M – Н]+ (41), 260 (12), 234 (15),
226 (7), 206 (6)
10a
399 [M ]+ (7), 275 (20), 274 (77), 272 (19), 271 (100), 270 (27), 256 (15),
230 (21), 223 (10), 222 (13), 195 (13), 194 (14)
The general view of structure 10a with the atomic
hetaryl) substituents R in the sulfurꢀcontaining fragments
CF2SR and CHFSR.
Oxidation of 4ꢀArSCF2ꢀ6,7ꢀdihydroꢀ1Hꢀpyrazoloꢀ
[3,4ꢀb]pyridinꢀ6ꢀones yielded the corresponding sulfꢀ
oxides; their structures were confirmed by Xꢀray diffraction.
numbering is shown in Fig. 1, a. The molecule exists
in a tweezersꢀlike conformation folded along the
C(11)—C(8)—S(1)—C(6) bond. However, the phenyl subꢀ
stituent at the sulfoxide group is substantially shifted relaꢀ
tive to the pyridine ring: the distance between the cenꢀ
troids of these rings is 4.476 Å and the torsion angle
O(1)—S(1)—C(8)—C(11) is 51.90°. The phenyl substituꢀ
ent at the N(1) atom makes an angle of –22.86° with the
plane of the fused heterocycle. The bond lengths in sulfꢀ
oxide 10a are close to those in structure 10b. The C(15)
and C(16) atoms (1 – x, 1 – у, –z) are linked by a shortꢀ
ened intermolecular π—πꢀcontact. The molecules form
helical chains along the axis b, which are held together by
intermolecular hydrogen bonds, thereby producing the moꢀ
lecular packing (see Table 6).
To sum up, we developed novel approaches to the
synthesis of earlier unknown 6,7ꢀdihydroꢀ1Hꢀpyrazoloꢀ
[3,4ꢀb]pyridinꢀ6ꢀones containing the 4ꢀArSCF2 and
4ꢀArSCHF groups. The approaches involve (1) direct anꢀ
nulation of 1ꢀsubstituted 5ꢀaminopyrazoles with ethyl
4,4ꢀdifluoroꢀ4ꢀphenylthioacetoacetate 4a and (2) replaceꢀ
ment of the Br atom of 4ꢀCF2Br group (or the Cl atom of
the 4ꢀCFHCl group) by sodium arenethiolates. Using these
procedures, one can obtain 6,7ꢀdihydroꢀ1Hꢀpyrazoloꢀ
[3,4ꢀb]pyridinꢀ6ꢀones with various (including aryl and
Experimental
1
H and 13C{1H} NMR spectra were recorded on a Bruker
AvanceTM600 spectrometer (600.22 and 150.925 MHz, respecꢀ
tively). The H and 13C chemical shifts were referenced to the
1
residual signal of chloroform (δ 7.27) or CDCl3 (δ 77.0), respecꢀ
tively, and converted to SiMe4. The accuracy of δ determination
is no less than 0.001 and 0.03 ppm, respectively. 19F and 19F{1H}
NMR spectra were recorded on a Bruker AvanceTM300 spectroꢀ
meter (288.38 MHz). The 19F chemical shifts were referenced to
trifluoroacetic acid as the external standard. The accuracy of δ
determination is no less than 0.01 ppm.
Single crystals of compounds 10a and 10b were grown by
crystallization from light petroleum—diethyl ether. Xꢀray difꢀ
fraction experiments were carried out on an Xcaliburꢀ3 diffracꢀ
tometer fitted with a CCD detector (graphite monochromator,
ω scan mode, scan step 1°). The structures were solved by the
direct methods and refined by the fullꢀmatrix leastꢀsquares method
on F2 with the SHELX program package.23 The coordinates and
thermal parameters of the nonꢀhydrogen atoms were refined
isotropically and then anisotropically by the fullꢀmatrix leastꢀ

Fluorinated 1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
741
Table 4. Selected crystallographic parameters and the data collection and refinement statistics for structures
10a and 10b
Parameter
10a
10b
Molecular formula
Molecular mass
C20H15F2N3O2S
399.41
C20H14F3N3O2S
417.40
T/K
295(2)
295(2)
λ/Å
Crystal system
Space group
0.71073
Monoclinic
P21/n
0.71073
Triclinic
P–1
a/Å
b/Å
c/Å
α/deg
β/deg
γ/deg
10.594(3)
15.264(2)
11.651(3)
90
103.73(2)
90
9.122(2)
9.429(2)
11.047(2)
89.828(19)
78.62(2)
79.05(2)
2
Z
4
dcalc/g cm–3
1.449
0.218
1.517
0.230
μ/mm–1
F(000)
824
428
Crystal dimensions/mm
θ scan range/deg
Completeness at θmax (%)
Ranges of h, k, l indices
0.46×0.37×0.18
2.67—26.37
99.8
–12 < h < 13
–18 < k < 19
–8 < l < 14
7860
0.43×0.36×0.28
2.84—26.39
99.4
–11 < h < 11
–10 < k < 11
–13 < l < 13
5335
Number of measured reflections
Number of independent reflections
Number of reflections with I > 2σ(I)
3728 (Rint = 0.0483)
1343
3716 (Rint = 0.0243)
1442
Number of parameters refined
257
266
Absorption correction
GOOF (on F2)
—
1.004
—
1.003
R Factors (for reflections with I > 2σ(I))
R1
wR2
0.0398
0.0521
0.0463
0.0780
R Factors (for all reflections)
R1
wR2
0.1215
0.0546
0.212/–0.229
0.1111
0.0818
0.584/–0.437
–3
Δρmax/Δρmin/e Å
squares method. The hydrogen atoms were located from the
electron density maxima and refined using a riding model. Seꢀ
lected crystallographic parameters, data collection and refineꢀ
ment statistics, bond lengths, and hydrogen bond parameters for
structures 10a and 10b are given in Tables 4—6.
water <50 ppm) was purchased from Acros. Elemental analysis
was carried out at the Microanalysis Laboratory of the A. N.
Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences. Light petroleum (LP), ethyl acetate (EA),
and diethyl ether (DE) were used as solvents.
IR absorption spectra were recorded on a Magna IRꢀ750
Nicolet FTIR spectrometer (KBr pellets) in the 4000—400 cm–1
range. Nujol was also used for compounds 3b and 10a,b. Mass
spectra were recorded on a Finnigan Polaris Q instrument (ion
trap, ionizing energy 70 eV, direct inlet probe). Syntheses inꢀ
volving microwave radiation were carried out in a Milestone
MicroSynth system (radiation power 600 W, closed test tube,
heating mode: 25—120 °C for 5 min and 120 °C for 7 min. For
column chromatography, Kieselgel 60 silica gel (0.06—0.20 mm,
Merck) was used. Compounds were detected by visualization on
TLC plates covered with Kieselgel 60 F254 (Merck). nꢀButylꢀ
lithium (a 1.6 M solution in hexane) was purchased from Acros.
Sodium hydride (a 60% dispersion in mineral oil) was purchased
from Aldrich. Ethyl acetate (extra dry, with molecular sieves,
Table 5. Selected bond lengths (d) in compounds 10a,b
10a
10b
Bond
d/Å
Bond
d/Å
S(1)—O(1)
S(1)—C(6)
S(1)—C(8)
C(8)—F(2)
F(1)—C(8)
N(1)—N(2)
O(2)—C(9)
1.4878(16)
1.788(2)
1.890(3)
1.363(2)
1.373(3)
1.375(2)
1.339(3)
S(1)—O(1)
S(1)—C(1)
S(1)—C(8)
F(2)—C(8)
F(1)—C(8)
F(3)—C(18)
O(2)—C(9)
1.454(2)
1.772(3)
1.901(3)
1.349(3)
1.338(3)
1.361(3)
1.345(3)

742
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Golubev et al.
Table 6. Parameters of the intermolecular hydrogen bonds in compounds 10a,b
Comꢀ
pound
D—H
d(D—H)
d(H..A)
d(D..A) Angle D—H—A
A
10a
10b
O(2)—H(2)
O(2)—H(2)
O(2)—H(2)
0.70(3)
0.70(3)
0.73(3)
2.02(3)
3.02(3)
1.97(3)
2.669(3)
3.663(3)
2.660(3)
153(1)
153(1)
156(1)
O(1) [–x + 1/2, y + 1/2, –z + 1/2]
S(1) [–x + 1/2, y + 1/2, –z + 1/2]
O(1) [x, y – 1, z]
Compounds 3a—f, 6a—c, 7a—c, 8a—c, and 9 are colorless
4ꢀ[Difluoro(phenylsulfanyl)methyl]ꢀ1ꢀ(4ꢀmethoxybenzyl)ꢀ
6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (3c) was obtained
from oxo ester 4a and 5ꢀaminoꢀ1ꢀ(4ꢀmethoxybenzyl)pyrazole
5c as described for compound 3a (method A).
crystalline solids; compounds 10a,b are light yellow crystals.
Ethyl fluoro(phenylsulfanyl)acetate was prepared from ethyl
chloro(fluoro)acetate and benzenethiol as described earlier.24
The reaction time was 3 h. The yield was 89%, light yellow lowꢀ
viscosity liquid, b.p. 104—105 °C (1 Torr). The spectroscopic
characteristics of ethyl fluoro(phenylsulfanyl)acetate are identiꢀ
cal with the literature data.24
Ethyl difluoro(phenylsulfanyl)acetate was prepared from
chloro(difluoro)acetic acid according to a known procedure.25
The spectroscopic and physicochemical characteristics of ethyl
difluoro(phenylsulfanyl)acetate are identical with the literaꢀ
ture data.26
4ꢀ[4ꢀChlorophenylsulfanyl(difluoro)methyl]ꢀ3ꢀmethylꢀ1ꢀpheꢀ
nylꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (3d) was obꢀ
tained from pyrazolopyridine 6a and 4ꢀchlorobenzenethiol as
described for compound 3a (method B). IR (KBr), ν/cm–1: 1660
vs (C=O). 1H NMR (CDCl3), δ: 2.78 (s, 3 H, Me); 6.61 (s, 1 H,
HC(5)); 7.34 (t, 1 H, Ar, J = 7.5 Hz); 7.41—7.50 (m, 4 H, Ar);
7.60 (d, 2 H, Ar, J = 8.0 Hz); 7.77 (d, 2 H, Ar, J = 8.0 Hz).
19F NMR (CDCl3), δ: 5.1 (s). MS (EI, 70 eV), m/z (Irel (%)): 420
[M + H]+ (2), 419 [M]+ (11), 418 [M + H]+ (7), 417 [M]+ (27),
275 (22), 274 (100).
4ꢀ[Difluoro(4ꢀmethylphenylsulfanyl)methyl]ꢀ3ꢀmethylꢀ1ꢀpheꢀ
nylꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (3e) was obꢀ
tained from pyrazolopyridine 6a and 4ꢀmethylbenzenethiol as
described for compound 3a (method B). IR (KBr), ν/cm–1: 1662
vs (C=O). 1H NMR (CDCl3), δ: 2.46 (s, 3 H, Me); 2.82 (s, 3 H,
Me); 6.60 (s, 1 H, H(5)); 7.26—7.34 (m, 3 H, Ar); 7.45 (t, 1 H,
Ar, J = 7.8 Hz); 7.57 (d, 2 H, Ar, J = 7.9 Hz); 7.75 (d, 2 H, Ar,
J = 7.9 Hz). 19F NMR (CDCl3), δ: 4.7 (s). MS (EI, 70 eV), m/z
(Irel (%)): 398 [M + H]+ (11), 397 [M]+ (46), 275 (27), 274
(100), 226 (6), 206 (6).
4ꢀ[Fluoro(phenylsulfanyl)methyl]ꢀ3ꢀmethylꢀ1ꢀphenylꢀ6,7ꢀdiꢀ
hydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (3f). Benzenethiol (0.66 g,
6 mmol) was added to a suspension of NaH (60% dispersion,
0.24 g, 6 mmol) in DMF (10 mL). The reaction mixture was
stirred until gas evolution ceased. This resulted in a transparent
solution to which pyrazolopyridine 8a (0.6 g, 2 mmol) was addꢀ
ed. The reaction mixture was stirred at 20 °C for ~3 h until the
starting compound 8a was completely consumed (19F NMR data)
and poured into a cooled saturated solution of NH4Cl (100 mL).
The product was extracted with EA (3×40 mL). The organic
extracts were combined, washed with brine, dried over MgSO4,
and concentrated. The residue was chromatographed on silica
gel with LP—EA (2 : 1) as an eluent. The yield of compound 3f
was 0.67 g (89%).
4ꢀ[4ꢀChlorophenylsulfanyl(fluoro)methyl]ꢀ3ꢀmethylꢀ1ꢀpheꢀ
nylꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (3g) was obꢀ
tained from pyrazolopyridine 8a and 4ꢀchlorobenzenethiol as
described for compound 3f. IR (KBr), ν/cm–1: 1657 vs (C=O).
1H NMR (CDCl3), δ: 2.70 (s, 3 H, Me); 6.52 (s, 1 H, H(5)); 7.00
(d, 1 H, CHF, JH,F = 54.0 Hz); 7.34—7.60 (m, 7 H, Ar); 7.74
4ꢀ[Difluoro(phenylsulfanyl)methyl]ꢀ3ꢀmethylꢀ1ꢀphenylꢀ6,7ꢀ
dihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (3a). A. A solution of
oxo ester 4a (1.3 g, 4.7 mmol) and 5ꢀaminoꢀ3ꢀmethylꢀ1ꢀphenylꢀ
pyrazole 5a (0.8 g, 4.7 mmol) in acetic acid (5 mL) was irradiatꢀ
ed in a microwave oven (the heating conditions are described in
the preamble to the Experimental). The reaction mixture was
cooled, diluted with water (50 mL), and kept in a refrigerator for
16 h. The crystals that formed were filtered off, washed repeatꢀ
edly with water on the filter, dried in air, and recrystallized from
LP—EA (1 : 1). The yield of compound 3a was 0.8 g. An addiꢀ
tional crop (0.4 g) was obtained by column chromatography of
the mother liquor with LP—EA (3 : 1) as an eluent.
B. A flask with an inert gas outlet was charged with a 60%
dispersion of NaH (0.24 g, 6 mmol). Then DMF (10 mL) and
benzenethiol (0.5 g, 4.5 mmol) were added. The reaction mixꢀ
ture was stirred until gas evolution ceased. The resulting transꢀ
parent solution was degassed several times by passing an inert gas
in vacuo. Then pyrazolopyridine 6a (0.5 g, 1.5 mmol) was added
under an inert gas. The reaction mixture was stirred at 50 °C for
2 h until the starting compound 6a was completely consumed
(19F NMR data), cooled to 20 °C, and poured into a saturated
solution of NH4Cl (100 mL). The products were extracted with
EA (3×40 mL). The organic extracts were combined, washed
with brine, dried over MgSO4, and concentrated. The residue
was chromatographed on silica gel with LP—EA (3 : 1) as an
eluent. The first eluted fraction contained compound 3a (0.41 g,
76%). Its spectroscopic and physicochemical characteristics are
identical with those of pyrazolopyridine 3a obtained according
to method A. Further elution gave 4ꢀdifluoromethylꢀ3ꢀmethylꢀ1ꢀ
phenylꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (9) (0.07 g).
Its spectroscopic and physicochemical characteristics are idenꢀ
tical with those of pyrazolopyridine 9 obtained by condensation
of oxo ester 4f with 5ꢀaminoꢀ3ꢀmethylꢀ1ꢀphenylpyrazole (5a)
(see above).
(d, 2 H, Ar, J = 8.0 Hz). 19F NMR (CDCl3), δ: –75.60 (d, JH,F
=
= 54.0 Hz). MS (EI, 70 eV), m/z (Irel (%)): 402 [M + H]+ (2),
401 [M]+ (13), 400 [M + H]+ (8), 399 [M]+ (32), 257 (19),
256 (100).
4ꢀ[Difluoro(phenylsulfanyl)methyl]ꢀ1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ
methylꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (3b) was
obtained from oxo ester 4a and 5ꢀaminoꢀ1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ
methylpyrazole 5b as described for compound 3a (method A).
Ethyl 4,4ꢀdifluoroꢀ3ꢀoxoꢀ4ꢀphenylsulfanylbutanoate (4a). A.
Sodium hydride as a 60% dispersion in mineral oil (1.80 g,
0.045 mol) was added to an iceꢀcooled (5 °C) solution of ethyl

Fluorinated 1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
743
1
difluoro(phenylthio)acetate (9.6 g, 0.042 mol) in ethyl acetate
(10.2 g, 0.123 mol). The resulting suspension was warmed to
20 °C and vigorously stirred for ~15 min. This resulted in a violent
reaction with a sharp temperature rise and foaming. The reacꢀ
tion mixture was stirred to complete homogenization. When the
temperature decreased to 30 °C, diethyl ether (150 mL) was
added. The reaction mixture was refluxed for 12 h and concenꢀ
trated. The residue was dissolved in diethyl ether and treated
with precooled 20% H2SO4. The organic layer was separated
and the product from the aqueous layer was extracted with diethyl
ether (3×70 mL). The combined organic extracts were dried
over MgSO4 and concentrated. The residue was distilled in vacꢀ
uo to give ethyl 4,4ꢀdifluoroꢀ3ꢀoxoꢀ4ꢀphenylsulfanylbutanoate
(9.1 g, 80%) as a yellowish viscous liquid, b.p. 148—150 °C
(1 Torr). The keto/enol ratio for compound 4a in CDCl3 was 59 : 41.
Keto form. H NMR (CDCl3), δ: 1.31 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 3.50 (AB system, 2 H, COCH2); 4.22 (q, 2 H,
OCH2CH3, J = 7.5 Hz); 6.27 (d, 1 H, CHFSPh, J = 51.7 Hz);
7.37—7.62 (m, 5 H, Ph). 13C NMR (CDCl3), δ: 14.05, 45.41,
61.74, 99.09 (d, JC,F = 235.6 Hz); 129.17, 129.49, 129.67, 134.12
(d, JC,F = 1.5 Hz); 166.08, 194.17 (d, JC,F = 27.6 Hz). 19F NMR
(CDCl3), δ: –82.96 (d, JH,F = 51.7 Hz).
1
Enol form. H NMR (CDCl3), δ: 1.33 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 4.22 (q, 2 H, OCH2CH3, J = 7.5 Hz); 5.30 (dd, 1 H,
CH=, J = 1.3 Hz, J = 0.7 Hz); 6.16 (dd, 1 H, CHFSPh, J = 51.7 Hz,
J = 0.7 Hz); 7.37—7.62 (m, 5 H, Ph); 12.23 (d, 1 H, OH,
J = 1.8 Hz). 13C NMR (CDCl3), δ: 14.14, 60.76, 90.42 (d, JC,F
=
= 5.5 Hz); 97.06 (d, JC,F = 225.0 Hz); 128.89, 129.17, 129.28,
133.84 (d, JC,F = 1.7 Hz); 168.78 (d, JC,F = 28.7 Hz); 172.03.
19F NMR (CDCl3), δ: –80.66 (d, JH,F = 51.7 Hz). Found (%):
C, 55.87; H, 5.03. C12H13FO3S. Calculated (%): C, 56.24;
H, 5.11.
Ethyl 4ꢀbromoꢀ4,4ꢀdifluoroꢀ3ꢀoxobutanoate (4c), ethyl 4ꢀchloroꢀ
4,4ꢀdifluoroꢀ3ꢀoxobutanoate (4d), ethyl 4ꢀchloroꢀ4ꢀfluoroꢀ3ꢀoxoꢀ
butanoate (4e), and ethyl 4,4ꢀdifluoroꢀ3ꢀoxobutanoate (4f) were
obtained according to method B from ethyl bromo(difluoro)ꢀ
acetate, ethyl chloro(difluoro)acetate, ethyl chloro(fluoro)ꢀ
acetate, and ethyl difluoroacetate, respectively.
1
(According to H and 19F NMR data, compound 4a also conꢀ
tains the gemꢀdiol form PhSCF2C(OH)2CH2CO2Et (~7%).18a
)
1
Keto form. H NMR (CDCl3), δ: 1.31 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 3.71 (s, 2 H, COCH2); 4.24 (q, 2 H, OCH2CH3,
J = 7.5 Hz); 7.39—7.68 (m, 5 H, Ph). 19F NMR (CDCl3), δ:
–8.55 (s, CF2SPh).
1
Enol form. H NMR (CDCl3), δ: 1.32 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 4.26 (q, 2 H, OCH2CH3, J = 7.5 Hz); 5.40 (s, 1 H,
CH=); 7.39—7.68 (m, 5 H, Ph); 12.03 (s, 1 H, OH). 19F NMR
(CDCl3), δ: –5.02 (s, CF2SPh).
Ethyl 4ꢀbromoꢀ4,4ꢀdifluoroꢀ3ꢀoxobutanoate (4c). Yield 87%,
colorless lowꢀviscosity liquid, b.p. 80—84 °C (12 Torr; cf. Ref. 27:
b.p. 78—82 °C (10 Torr)). The keto/enol/gemꢀdiol18a ratio for
compound 4c in CDCl3 was 35 : 50 : 15.
Both forms. 13C NMR (CDCl3), δ: 13.98, 14.03, 43.21, 61.31,
62.04, 91.27 (t, JC,F = 4.3 Hz); 121.94 (t, JC,F = 291.1 Hz);
122.89 (t, JC,F = 279.3 Hz); 123.92, 125.38, 129.17, 129.51,
130.47, 130.85, 136.76, 136.81, 164.92 (t, JC,F = 30.0 Hz); 165.49,
171.76, 188.26 (t, JC,F = 31.3 Hz). MS (EI, 70 eV), m/z (Irel (%)):
275 [M + H]+ (6), 274 [M]+ (35), 228 (10), 227 (19), 209 (17),
189 (13), 181 (47), 165 (29), 164 (34), 161 (16), 160 (39),
159 (100). Found (%): C, 52.06; H, 4.13. C12H12F2O3S. Calcuꢀ
lated (%): C, 52.55; H, 4.41.
1
Keto form. H NMR (CDCl3), δ: 1.40 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 3.86 (s, 2 H, COCH2); 4.27 (q, 2 H, OCH2CH3,
J = 7.5 Hz). 19F NMR (CDCl3), δ: 12.62 (s).
1
Enol form. H NMR (CDCl3), δ: 1.38 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 4.36 (q, 2 H, OCH2CH3, J = 7.5 Hz); 5.61 (s, 1 H,
CH=); 12.09 (s, 1 H, OH). 19F NMR (CDCl3), δ: 18.52 (s).
gemꢀDiol form. 1H NMR (CDCl3), δ: 1.39 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 2.92 (s, 2 H, C(OH)2CH2); 4.27 (q, 2 H, OCH2CH3,
J = 7.5 Hz); 4.93 (br.s, 2 H, 2 OH). 19F NMR (CDCl3), δ: 13.67 (s).
Ethyl 4ꢀchloroꢀ4,4ꢀdifluoroꢀ3ꢀoxobutanoate (4d). Yield 85%,
colorless lowꢀviscosity liquid, b.p. 59—63 °C (12 Torr; cf.
Ref. 18b: b.p. 96 °C (70 Torr)). The keto/enol/gemꢀdiol18a ratio
for compound 4d in CDCl3 was 33 : 53 : 14.
B. A 1.6 M solution of nꢀbutyllithium (56.3 mL) in hexane
was added to a solution of diisopropylamine (9.11 g, 90 mmol) in
anhydrous diethyl ether (60 mL), while maintaining the temperꢀ
ature in a range from –5 to 0 °C. The reaction mixture was
stirred at 0 °C for 1 h. Ethyl acetate (7.93 g, 90 mmol) in diethyl
ether (20 mL) was added at –75 °C and the reaction mixture was
stirred at this temperature for 20 min. Then ethyl difluoroꢀ
(phenylthio)acetate (10.45 g, 45 mmol) in diethyl ether (20 mL)
was added and the reaction mixture was stirred at –75 °C for 3 h.
A saturated solution of NH4Cl (20 mL) was added and the reacꢀ
tion mixture was warmed to 0 °C. The organic layer was separatꢀ
ed and the product from the aqueous layer was extracted with
diethyl ether (3×40 mL). The organic extracts were combined
and washed with precooled 1 M HCl to a distinct acid reaction.
The organic layer was washed with brine, dried over MgSO4,
and concentrated. The residue was distilled in vacuo to give ethyl
4,4ꢀdifluoroꢀ3ꢀoxoꢀ4ꢀphenylsulfanylbutanoate 4a (10.1 g, 82%)
as a yellowish liquid. The spectroscopic and physicochemical
characteristics of oxo ester 4a obtained according to methods A
and B are identical.
1
Keto form. H NMR (CDCl3), δ: 1.40 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 3.84 (s, 2 H, COCH2); 4.27 (q, 2 H, OCH2CH3,
J = 7.5 Hz). 19F NMR (CDCl3), δ: 9.54 (s).
1
Enol form. H NMR (CDCl3), δ: 1.38 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 4.36 (q, 2 H, OCH2CH3, J = 7.5 Hz); 5.64 (s, 1 H,
CH=); 12.09 (s, 1 H, OH). 19F NMR (CDCl3), δ: 14.63 (s).
gemꢀDiol form. 1H NMR (CDCl3), δ: 1.39 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 2.92 (s, 2 H, C(OH)2CH2); 4.27 (q, 2 H, OCH2CH3,
J = 7.5 Hz); 4.90 (br.s, 2 H, 2 OH). 19F NMR (CDCl3), δ: 6.89 (s).
Ethyl 4ꢀchloroꢀ4ꢀfluoroꢀ3ꢀoxobutanoate (4e). Yield 89%, colꢀ
orless lowꢀviscosity liquid, b.p. 96—98 °C (20 Torr). The keto/
enol ratio for compound 4e in CDCl3 was 65 : 35.
1
Keto form. H NMR (CDCl3), δ: 1.31 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 3.76 (AB system, 2 H, COCH2); 4.24 (q, 2 H,
Ethyl 4ꢀfluoroꢀ3ꢀoxoꢀ4ꢀphenylsulfanylbutanoate (4b) was obꢀ
tained from ethyl fluoro(phenylsulfanyl)acetate according to
method B. The yield was 87%. Crude compound 4b was used in
heterocyclization reactions. Its analytically pure sample (as
a yellow viscous liquid) was isolated using column chromatograꢀ
phy on silica gel with LP—EA (10 : 1) as an eluent. The keto/
enol ratio for compound 4b in CDCl3 was 4 : 1.
OCH2CH3, J = 7.5 Hz); 6.37 (d, 1 H, CHFCl, J = 51.0 Hz).
13C NMR (CDCl3), δ: 13.96, 42.73, 61.96, 95.52 (d, JC,F
=
= 256.0 Hz); 165.65, 191.60 (d, JC,F = 26.4 Hz). 19F NMR
(CDCl3), δ: –70.29 (d, JH,F = 51.0 Hz).
1
Enol form. H NMR (CDCl3), δ: 1.32 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 4.26 (q, 2 H, OCH2CH3, J = 7.5 Hz); 5.49 (s, 1 H,
CH=); 6.41 (d, 1 H, CHFCl, J = 49.0 Hz); 11.97 (br.s, 1 H,

744
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Golubev et al.
OH). 13C NMR (CDCl3), δ: 14.03, 61.15, 90.18 (d, JC,F
=
(fluoro)methyl]ꢀ1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀmethylꢀ6,7ꢀdihydroꢀ1Hꢀ
pyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (8b), and 4ꢀ[(chloro)(fluoro)ꢀ
methyl]ꢀ1ꢀ(4ꢀmethoxybenzyl)ꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridinꢀ6ꢀone (8c) were obtained by reactions of ethyl 4ꢀchloroꢀ
4ꢀfluoroꢀ3ꢀoxobutanoate 4e with pyrazoles 5a—c, respectively.
In a similar way, 4ꢀdifluoromethylꢀ3ꢀmethylꢀ1ꢀphenylꢀ6,7ꢀdiꢀ
hydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (9) was obtained from
ethyl 4,4ꢀdifluoroꢀ3ꢀoxobutanoate 4f and pyrazole 5a.
4ꢀ[(Difluoro)(phenylsulfinyl)methyl]ꢀ1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ
methylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀol (10b). mꢀChloroperoxyꢀ
benzoic acid (17.3 mg, 0.1 mmol) in anhydrous CH2Cl2 (10 mL)
was added at 20 °C for 1 h to a solution of pyrazolopyridine 3b
(40 mg, 0.1 mmol) in anhydrous CH2Cl2 (5 mL). The resulting
solution was stirred for 1 h and treated with 5% Na2S2O3. The
organic layer was separated, dried over MgSO4, and concentratꢀ
ed. The residue was chromatographed on silica gel with LP—DE
(5 : 2) as an eluent. The yield of compound 10b was 25 mg. IR
(KBr), ν/cm–1: 3208 m, br (OH). 1H NMR (CDCl3—CD3OD),
δ: 2.52 (t, 3 H, Me, J = 3.0 Hz); 6.14 (s, 1 H, H(5)); 7.09 (m, 2 H,
Ar); 7.42 (d, 4 H, Ar, J = 4.4 Hz); 7.52 (m, 1 H, Ar); 7.90 (m, 2 H,
Ar). 19F{1H} NMR (CDCl3—CD3OD), δ: –38.06 (s, 1 F, Ar—F);
–27.19 (d, AB system, 1 F, JAB = 223.1 Hz); –19.85 (d, AB
system, 1 F, JAB = 223.1 Hz). MS (EI, 70 eV), m/z (Irel (%)): 417
[M]+ (9), 293 (22), 292 (100), 290 (13), 289 (60), 288 (9), 274
(6), 248 (6), 241 (11), 213 (9).
= 7.0 Hz); 94.80 (d, JC,F = 244.3 Hz); 167.32 (d, JC,F = 25.3 Hz);
171.83. 19F NMR (CDCl3), δ: –68.83 (d, JH,F = 49.0 Hz). MS
(EI, 70 eV), m/z (Irel (%)): 185 [M + H]+ (5), 183 [M]+ (12), 139
(16), 137 (55), 119 (20), 115 (68), 91 (29), 89 (20), 87 (100).
Found (%): C, 39.88; H, 4.83. C6H8ClFO3. Calculated (%):
C, 39.47; H, 4.42.
Ethyl 4,4ꢀdifluoroꢀ3ꢀoxobutanoate (4f). Yield 77%, colorless
lowꢀviscosity liquid, b.p. 50—53 °C (12 Torr; cf. Ref. 18b: b.p.
100 °C (100 Torr)). The keto/enol/gemꢀdiol18a ratio for comꢀ
pound 4f in CDCl3 was 27 : 56 : 17.
1
Keto form. H NMR (CDCl3), δ: 1.35 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 3.75 (s, 2 H, COCH2); 4.28 (q, 2 H, OCH2CH3,
J = 7.5 Hz); 5.95 (t, 1 H, CHF2, J = 54.0 Hz). 19F NMR
(CDCl3), δ: –50.11 (d, JH,F = 54.0 Hz).
1
Enol form. H NMR (CDCl3), δ: 1.37 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 4.31 (q, 2 H, OCH2CH3, J = 7.5 Hz); 5.54 (s, 1 H,
CH=); 6.08 (t, 1 H, CHF2, J = 54.0 Hz); 11.84 (s, 1 H, OH).
19F NMR (CDCl3), δ: –48.78 (d, JH,F = 54.0 Hz).
gemꢀDiol form. 1H NMR (CDCl3), δ: 1.33 (t, 3 H, CH3CH2O,
J = 7.5 Hz); 2.78 (s, 2 H, C(OH)2CH2); 4.25 (q, 2 H, OCH2CH3,
J = 7.5 Hz); 4.60 (br.s, 2 H, 2 OH); 5.63 (t, 1 H, CHF2, J = 55.5 Hz).
19F NMR (CDCl3), δ: –56.96 (d, JH,F = 55.5 Hz).
5ꢀAminoꢀ1ꢀ(4ꢀmethoxybenzyl)pyrazole (5c) was obtained as
described earlier28 for 5ꢀaminoꢀ1ꢀbenzylpyrazole. At the final
step of the synthesis, nꢀBuONa in nꢀbutanol4d was used instead
of solidꢀstate NaOH in nꢀpropanol. 5ꢀAminoꢀ1ꢀ(4ꢀmethoxyꢀ
benzyl)pyrazole was isolated by column chromatography on silica
4ꢀ[(Difluoro)(phenylsulfinyl)methyl]ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀ
pyrazolo[3,4ꢀb]pyridinꢀ6ꢀol (10a) was obtained from pyrazolꢀ
opyridine 3a as described for compound 10b.
1
gel with LP—EA (3 : 1) as an eluent, m.p. 70—71 °C. H NMR
We are grateful to L. L. Gervits (A. N. Nesmeyanov
Institute of Organoelement Compounds, Russian Acadeꢀ
my of Sciences) for his assistance in microwave experiꢀ
ments.
This work was financially supported by the Ministry of
Education and Science of the Russian Federation (State
Contract No. 02.512.11.2043; the Federal Target Scienꢀ
tific and Technical Program "Investigations and Developꢀ
ments in the Priority Areas of the Scientific and Engineerꢀ
ing Facilities of Russia for 2007—2012").
(CDCl3), δ: 3.44 (br.s, 2 H, NH2); 3.84 (s, 3 H, OMe); 5.21
(s, 2 H, CH2); 5.61 (d, 1 H, H(4), J = 1.8 Hz); 6.92 (d, 2 H, Ar,
J = 8.6 Hz); 7.18 (d, 2 H, Ar, J = 8.6 Hz); 7.36 (d, 1 H, H(3),
J = 1.8 Hz). 13C NMR (CDCl3), δ: 51.22, 55.30, 91.77, 114.30,
128.27, 128.63, 138.53, 144.37, 159.19. MS (EI, 70 eV), m/z
(Irel (%)): 203 [M]+ (21), 122 (9), 121 (100), 91 (12), 77 (14).
4ꢀ[(Bromo)(difluoro)methyl]ꢀ3ꢀmethylꢀ1ꢀphenylꢀ6,7ꢀdihyꢀ
droꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (6a). A solution of ethyl
4ꢀbromoꢀ4,4ꢀdifluoroꢀ3ꢀoxobutanoate 4c (2.45 g, 0.01 mol) and
5ꢀaminoꢀ3ꢀmethylꢀ1ꢀphenylpyrazole 5a (1.7 g, 0.01 mol) in glaꢀ
cial acetic acid (30 mL) was refluxed for 3 h, cooled, poured into
water with ice (100 mL), and kept in a refrigerator for 16 h. The
precipitate that formed was filtered off, dried in air, and recrysꢀ
tallized from LP—EA (1 : 1). The yield of compound 6a was
1.9 g. An additional crop (0.8 g) was obtained by column chroꢀ
matography of the mother liquor with LP—EA (3 : 1) as an eluent.
In a similar way, 4ꢀ[(bromo)(difluoro)methyl]ꢀ1ꢀ(4ꢀfluoroꢀ
phenyl)ꢀ3ꢀmethylꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone
(6b) and 4ꢀ[(bromo)(difluoro)methyl]ꢀ1ꢀ(4ꢀmethoxybenzyl)ꢀ6,7ꢀ
dihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (6c) were obtained by
reactions of ethyl 4ꢀbromoꢀ4,4ꢀdifluoroꢀ3ꢀoxobutanoate 4c with
5ꢀaminoꢀ1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀmethylpyrazole 5b and 5ꢀaminoꢀ
1ꢀ(4ꢀmethoxybenzyl)pyrazole 5c, respectively. In a similar way,
4ꢀ[(chloro)(difluoro)methyl]ꢀ3ꢀmethylꢀ1ꢀphenylꢀ6,7ꢀdihydroꢀ
1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (7a), 4ꢀ[(chloro)(difluoro)ꢀ
methyl]ꢀ1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀmethylꢀ6,7ꢀdihydroꢀ1Hꢀpyrazoꢀ
lo[3,4ꢀb]pyridinꢀ6ꢀone (7b), and 4ꢀ[(chloro)(difluoro)methyl]ꢀ1ꢀ
(4ꢀmethoxybenzyl)ꢀ6,7ꢀdihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀ
one (7c) were obtained by reactions of ethyl 4ꢀchloroꢀ4,4ꢀdifluꢀ
oroꢀ3ꢀoxobutanoate 4d with pyrazoles 5a—c, respectively. In
a similar way, 4ꢀ[(chloro)(fluoro)methyl]ꢀ3ꢀmethylꢀ1ꢀphenylꢀ6,7ꢀ
dihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (8a), 4ꢀ[(chloro)ꢀ
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Received September 6, 2010;
in revised form February 28, 2011