A convenient synthesis of fluorinated pyrazolo[3,4-b]pyridine and Pyrazolo[3,4-d]pyrimidine nucleosides

Article abstract of DOI:10.1055/s-0028-1083365

Starting from 5-amino-1-(2,3-0-isopropylidene-β-D-ri- bofuranosyl)-1H-pyrazole, fluorine-containing 1,3-CCC-, 1,3-CNC- dielectrophiles and 2,4,6-tris(trifluoromethyl)-1,3,5-triazine, a set of fluorinated pyrazolo[3,4-b]pyridine and pyrazolo[3,4-d]pyrimi-

Full text of DOI:10.1055/s-0028-1083365

PAPER
731
A Convenient Synthesis of Fluorinated Pyrazolo[3,4-b]pyridine and
Pyrazolo[3,4-d]pyrimidine Nucleosides
F
luorinatedPyrazo
i
lo[3,4-
k
b
]pyridine
a
t
nd Pyra
o
zolo[3,4-
d
]p
r
yrimidine
NucO
leosides . Iaroshenko,*a,b Dmitri V. Sevenard,e Anton Kotljarov,d Dmitriy M. Volochnyuk,b,c
Andrei O. Tolmachev,a,b Vyacheslav Ya. Sosnovskikhf
a
National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
Enamine Ltd., 23 A. Matrosova st., 01103 Kyiv, Ukraine
b
Fax +380(44)5373253; E-mail: yaroshenko@enamine.net
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, Kyiv-94, 02094, Ukraine
c
d
Institute of Organic and Bioorganic Chemistry, University of Tartu, Jakobi 2, 51014 Tartu, Estonia
Hansa Fine Chemicals GmbH, BITZ, Fahrenheitstr. 1, 28359 Bremen, Germany
Department of Chemistry, Ural State University, 51 Lenina Ave., 620083 Ekaterinburg, Russian Federation
e
f
Received 26 September 2008; revised 15 October 2008
Dedicated to Professor V. P. Khilya on the occasion of his 70th birthday
tostatin and their analogues with a trifluoromethyl group
should thus increase the stability of the corresponding hy-
drates, and would be expected to change the metabolic
pathway that governs the toxicity of the substrates.12
Abstract: Starting from 5-amino-1-(2,3-O-isopropylidene-b-D-ri-
bofuranosyl)-1H-pyrazole, fluorine-containing 1,3-CCC-, 1,3-CNC-
dielectrophiles and 2,4,6-tris(trifluoromethyl)-1,3,5-triazine, a set
of fluorinated pyrazolo[3,4-b]pyridine and pyrazolo[3,4-d]pyrimi-
dine nucleosides was obtained. Synthetic access to stable 4-(poly-
On the other hand, in our opinion, purines and their isos-
teres bearing polyfluoroalkyl substituents in positions two
and six should also be considered as potential IMPDH in-
hibitors, due to the possibility of covalent binding be-
tween the Cys 331 residue of the active site of the enzyme
with the more electrophilic C-6 (C-2) atoms, forming sta-
ble Meisenheimer-type adducts. It was shown that, for
example, the 6-chloro-substituted purine base3 is dehalo-
genated by IMPDH and a covalent bond is formed at C-6
with Cys 331.
fluoroalkyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-ole
was
elaborated, which can be considered to be mimetics of the putative
transition state involved in adenosine deaminase activity.
Key words: pyrazole, pyridine, pyrimidine, fluorine, annulation,
electrophilic aromatic substitution
Adenosine deaminase (ADA) and inosine 5¢-monophos-
phate dehydrogenase (IMPDH) are two groups of en-
zymes that play a key role in purine de novo
biosynthesis.1–4 In the last two decades ADA and IMPDH
have become important target enzymes for drug design,
since it was found that a deficiency of ADA impairs the
function of the human immune system, resulting in severe
combined immunodeficiency (SCID), characterized by
severe T-lymphocyte dysfunction and agammaglobuline-
mia.5 Furthermore, ADA enzyme abnormalities have also
been reported in acquired immunodeficiency syndrome
(AIDS),6 in tuberculosis,7 Parkinson’s disease,8a in viral
hepatitis,8b some leukaemia diseases,9 and many others in-
cluding cancer.2
In this publication we report a facile synthesis of pyrazo-
lo[3,4-b]pyridine and pyrazolo[3,4-d]pyrimidine nucleo-
sides, which are promising scaffolds for potential ADA
and IMPDH inhibitors.
We report two general synthetic routes to pyrazolo[3,4-
b]pyridine and pyrazolo[3,4-d]pyrimidine nucleosides
starting from iso-AIRs 5-amino-1-(2,3-O-isopropylidene-
b-D-ribofuranosyl)-1H-pyrazole (1; Figure 1). The first
involves regiospecific annulation of the pyridine and py-
rimidine rings to give the aminoheterocyclic moiety using
a number of 1,3-CCC- and 1,3-CNC-fluoro-containing di-
electrophiles 3–11 (Figure 2). The second approach is
based on an inverse electron-demand Diels–Alder reac-
tion.13
Electron-withdrawing trifluoromethyl groups facilitate
water addition to the 6-position of purine (purine isosters)
and maintains the stability of the formed 6-hydrates. Re-
cently, a theoretical study has been carried out that estab-
lished 6-trifluoromethyl-substituted purine isosteres as
promising inhibitors of ADA.10 Since the trifluoromethyl
group is isosterically comparable to the amino group,11
modification of compounds that imitate the putative tran-
sition-state involved in ADA activity should not cause
problems with substrate recognition, and should thus lead
to enzyme inhibition. Modification of Coformycin, Pen-
R1
R1
+
X
N
+
X
N
N
+
NH2
R2
O
N
R2
N
O
HO
2
HO
1
O
O
HO
OH
iso-AIRs-riboside
SYNTHESIS 2009, No. 5, pp 0731–0740
Advanced online publication: 11.02.2009
x
x
.
x
x
.2
0
0
9
Figure 1 Retrosynthetic analysis
DOI: 10.1055/s-0028-1083365; Art ID: P09708SS
© Georg Thieme Verlag Stuttgart · New York

732
V. O. Iaroshenko et al.
PAPER
RF
X
RF
R
F3C
R
F3C
O
O
O
N
3
6a: R = Me
b: R = Ph
N
3a: RF = CF3, R = CF3
b: RF = CF3, R = Ph
7a: X = CH2
b: X = S
N
R
i
O
O
O
c: RF = CF3, R = 2-thienyl
d: RF = CF3, R = 4-pyridyl
4a: RF = CF3, R = OMe
b: RF = CF2H, R = OMe
5a: RF = C2F5, R = Me
b: RF = C2F4H, R = Et
c: RF = C4F9, R = Et
HO
O
O
O
13a–d
O
O
Table 1
OH
CF3
8
CF3
iii
iii
9
O
14a
13g
MeO
CF3
RF
CO2Me
CF3
13e,f
15a,b
N
CF3
+
N
N
N
5
Me2N
NMe2
1
N
Cl
N
R
O
ii
F3C
N
H
CF3
–
10
PF6
HO
11
12
14a: RF = C2F5, R = Me 68%
b: RF = C2F4H, R = Et 70%
O
O
Figure 2 Variety of 1,3-CCC- and 1,3-CNC-dielectrophiles used
for building pyrazolo[3,4-b]pyridine and pyrazolo[3,4-d]pyrimidine
nucleosides
c: RF = C4F9, R = Et
71%
We started our investigation by optimising the reaction of
iso-AIRs 1 with dicarbonyls 3–5. The previously reported
possibility of conducting this reaction in acetic acid
media14a was not possible in the case of 1, since refluxing
in acetic acid caused a deglycosylation reaction to take
place. However, the desired pyridine ring annulation did
proceed smoothly in absolute DMF at 130 °C in the ab-
sence of acid under inert atmosphere for 12 hours. These
conditions gave the set of pyrazolo[3,4-b]pyridines 13a–
d in good to excellent yields (Scheme 1, Table 1). As re-
ported previously, the reaction proceeds via formation of
the corresponding hydrates, which can be detected by 19F
NMR,14b however, the presence of the trifluoromethyl
group was not enough to stabilize the hydrates. The intro-
duction of more electron-withdrawing polyfluoroalkyl
groups (C2F5, C2F4H and C4F9) enabled isolation and
identification of the hydrates by NMR methods. Keto es-
ters 4 and ketones 6 reacted with 1 under milder condi-
tions (DMF, 80 °C), delivering stable acyclic carbinols
15. Since compounds 15a and 15b appeared to be stable,
ring formation to give 13e and 13f, respectively, required
relatively harsh conditions such as heating at 180 °C with-
out solvent. The dehydration of 14a and cyclization of 15a
and 15b proceeded smoothly in absolute methanol under
reflux with a catalytic amount of p-toluenesulfonic acid
(PTSA), however, under these conditions a cleavage of
the iso-propylidene protection group took place, deliver-
ing the ribosides 16e–g in good yields (Scheme 2,
Table 2).
RF
OH
R
N
4, 6
N
NH2
O
ii
HO
15a: RF = CF3, R = CH2CO2Me 72%
b: RF = CF2H, R = CH2CO2Me 49%
c: RF = CF3, R = Me 89%
O
O
d: RF = CF3, R = Ph 87%
Scheme 1 Reagents and conditions: (i) DMF, N2, 125 °C, 12 h; (ii)
DMF, N2, 80 °C, 12 h; (iii) no solvent, reduced pressure, 180 °C, 1 h.
Table 1 Yields of Pyrazolo[3,4-b]pyridines 13a–g
Product
13a
RF
R
Yield (%)a
CF3
CF3
CF3
CF3
CF3
CF2H
C2F5
CF3
94
81
86
91
65
37
69
13b
13c
Ph
2-thienyl
4-pyridyl
OH
13d
13e
13f
OH
13g
Me
a Pure isolated product.
dine 20 in 80% yield. After deprotecting 20, the pyrazo-
lo[3,4-b]pyridine 21 was obtained in 78% yield.
When diketones 7 were also tested for pyridine ring for-
mation we obtained satisfactory results for the condensed
pyrazolo[3,4-b]pyridines 17, which were obtained in
yields of 69–72%. Deprotection of 17 led to nucleosides
18.
It was expected that 3-(trifluoroacetyl)chromone 9,15
which is a 1,3-CCC-dielectrophile, would react with the
aminopyrazole moiety of 22 resulting in pyridine ring an-
nulation. However, instead of delivering pyrazolo[3,4-
b]pyridines, the reaction gave the corresponding 2-(tri-
fluoromethyl)chroman-4-ones 23a and 23b. Such chemi-
cal behaviour of 9 was already reported,15 and is typical
for aromatic and aliphatic amines. Single crystal X-ray
The reaction of compound 1 with 8 afforded the N-adduct
19 (Scheme 3). This intermediate underwent a 6-exo-trig
cyclisation (180 °C) to give 6-unsubstituted pyrazolopyri-
Synthesis 2009, No. 5, 731–740 © Thieme Stuttgart · New York

PAPER
Fluorinated Pyrazolo[3,4-b]pyridine and Pyrazolo[3,4-d]pyrimidine Nucleosides
733
O
i
CF3
N
13a–g
CF3
N
N
8
N
N
1
N
H
O
O
i
ii
Rf
HO
HO
C2F5 OH
O
O
OR
OR
N
N
19 92%
N
N
N
R
N
H
Me
O
20 R = 2,2-propylidene 80%
21 R = H 78%
ii
O
iii
6-exo-trig
HO
HO
16a–g
14a
Table 2
X
HO
OH
O
O
N
N
CF3
N
NH
O
O
9
N
R
a: R = H, 72%
b: R = Et, 75%
i
N
N
NH2
R
N
F3C
HO
O
O
OH
Rf
HO
22
23
OMe
N
OR
OR
Scheme 3 Reagents and conditions: (i) DMF, inert atmosphere,
80 °C, 12 h; (ii) no solvent, reduced pressure, 180 °C, 1 h; (iii) TFA–
H2O (9:1), r.t., 45 min.
N
NH2
O
17a: X = CH2
R = 2,2-propylidene 72%
b: X = S
R = 2,2-propylidene
HO
15a,b
ii
69%
O
O
18
X = S, R = H
79%
Scheme 2 Reagents and conditions: (i) TFA–H2O (9:1), r.t., 45
min; (ii) MeOH, PTSA, reflux, 1 h.
Table 2 Yields of Pyrazolo[3,4-b]pyridines 16a–g
Starting material Product
RF
R
Yield (%)a
13a
13b
13c
13d
13e
15a
13f
16a
16b
16c
16d
16e
16e
16f
16f
16g
16g
CF3
CF3
CF3
CF3
CF3
CF3
CF2H
CF2H
C2F5
C2F5
CF3
Ph
84
71
2-thienyl 85
4-pyridyl 74
Figure 3 Molecular structure of compound 23b
OH
OH
OH
OH
Me
Me
64
73
61
70
77
83
(HPLC, mass detection), however our attempts to isolate
it failed.
The structure of the pyrazolopyridines were confirmed by
1H, 13C, and 19F NMR spectroscopies. The most convinc-
ing evidence for the formation of 4-trifluoromethyl iso-
mers were the chemical shift of C(4) (dc= ~133 ppm) with
a coupling constant of ~37 Hz; for the 6-trifluoromethyl
isomer, one would expect the signal of C(6) to be situated
at dc = ~147 ppm.
15b
13g
14a
a Pure isolated product.
Concerning the structures of 14 and 15, the resonance of
the sp3-carbon atom was observed at d = ~91 ppm (2JC–F
=
analysis unambiguously revealed the chroman structure
of molecule 23b (Figure 3).
24 Hz) and d = ~72 ppm (2JC–F = ~28 Hz), respectively;
the 19F chemical shifts of 15a, 15c and 15d were found at
around d = –83 ppm.
Vinamidinium hexafluorophosphate (10; Figure 2) has re-
cently been used in the synthesis of nitrogen-containing
heterocycles such as pyrimidines,16 however, the reaction
of aminopyrazole 1 with 10 (DMF, 80–125 °C) led to the
formation of a mixture products. According to 19F NMR,
nearly a dozen components were detected. A 10% yield of
1-(2,3-O-isopropylidene-b-D-ribofuranosyl)-5-(trifluoro-
In order to confirm the structure of hydrates 14 by means
of H–H, C–H (HMQC, HMBC, ROESY) correlation
spectroscopy, the model compound 14b (R = C2F4H) was
synthesized (Figure 4). A correlation of the CF2H proton
at d = 6.12 ppm with the H-3 proton at d = 7.60 ppm and
H-5 at d = 6.17 ppm was observed in the ROESY spectra.
Furthermore, in the HMQC spectrum, H-3 and H-5 inter-
methyl)-1H-pyrazolo[3,4-b]pyridine
was
detected
Synthesis 2009, No. 5, 731–740 © Thieme Stuttgart · New York

734
V. O. Iaroshenko et al.
PAPER
O
ROESY
O
ROESY
CF2CF2H
6.12
ROESY
6.17
H-1' (5.81) --- H-7 (12.15)
H-2' (5.15) --- Me (1.34)
H-3' (5.01) --- Me (1.34)
HO
7.60
H
NH
CF3
N
OMe
CF3
N
H
N
11
4
3
5
6
N
HMBC
N
ROESY
N
N
(3.67 + 3.81)
N
O
i
ii
O
H-1' (5.81) --- C-7a (173.0)
H
H
H
Me
N
7a
N
H
12.15
C
5'
HO
HMQC
HO
1.13
2.33
HO
O
H2
H-3 (7.60) --- C-3 (136.2)
H-5 (6.17) --- C-5 (103.2)
H-1' (5.81) --- C-1' (91.6)
H-2' (5.15) --- C-2' (85.6)
H-3' (5.01) --- C-3' (82.4)
H-4' (4.49) --- C-4' (88.5)
H-5' (3.67 + 3.81) --- C-5' (64.1)
4'
H
H
H
1'
4.49
H
24 32%
OR
OR
O
O
5.14
2'
3'
5.01
5.81
ROESY
25 R = 2,2-propylidene
26 R = H 52%
64%
O
O
113.0
14b
iii
1
1.54
25.3
Me
Me 1.34
27.1
6-exo-trig
CF3
Figure 4 Significant NMR data of compound 14b
N
N
N
12
N
iii
CF3
O
acted with carbon atoms at d = 103.2 and d = 136.2 ppm,
which were assigned as C-5 and C-3, respectively. Further
evidence confirming the structure of 14b is depicted in
Figure 3. The formation of a stable molecular ion of hy-
drates 14 by electron ionization (70 eV) is also in accor-
dance with structure 14.
iv
27 R = 2,2-propylidene 97%
28 R = H 85%
HO
OR
OR
N
CF3
F3C
CF3
4
F3C
N
H
N
N
N
The allopurinol riboside is a known pharmaceutical
agent.17 Herein, we would like to present a novel three-
step synthetic route to 2-trifluoromethyl-allopurinol ribo-
side 26 from iso-AIRs 1 and building block 11
(Scheme 4). Aminopyrazole 1 reacts with two equivalents
of 11 under mild conditions (CH2Cl2, Et3N), affording the
product bearing two methyl 1,1,1-trifluoropropan-2-
ylidenecarbamate groups, which were detected by HPLC.
It should be noted that several by-products were also de-
tected by 19F NMR. During the elution with ethyl acetate,
the methyl 1,1,1-trifluoropropan-2-ylidenecarbamate
group on the 5-position of the sugar residue was removed
to give a relatively stable intermediate 24, which hydro-
lysed slowly in air. Amidine 24 appeared to be stable to
the ring cyclization and required heating at 180 °C for one
hour.
Het
H
N
Het
CF3
CF3
H2N
NH2
B
A
N-4
Scheme 4 Reagents and conditions: (i) Et3N (2 equiv), CH2Cl2,
0 °C, 30 min then r.t., 2 h, then reflux, 3 h; (ii) no solvent, reduced
pressure, 180 °C, 1 h; (iii) TFA–H2O (9:1), r.t., 45 min; (iv) CH2Cl2,
N2, r.t., 36 h.
pyrazolo[3,4-d]pyrimidine nucleosides were elaborated.
The simple synthesis and purification procedures and the
high yields of the target compounds allow synthesis of
functionally diverse pyrazolo[3,4-b]pyridine and pyrazo-
lo[3,4-d]pyrimidine nucleosides, which are potential in-
hibitors of ADA and IMPDH receptors.
The inverse electron-demand Diels–Alder reaction is a
powerful method for assembling heterocycles.18 Recently,
we have applied this method14b to the synthesis of fluori-
nated purines and 7-thiopurines starting from the N2,N2-
dialkyl-1,3-thiazole-2,4-diamines and 1,2-dimethyl-1H-
imidazol-5-amine.
All solvents were purified and dried by standard methods. NMR
spectra were recorded on Jeol JNM-LA 400, Varian VXR-300 or
Varian Mercury-400 spectrometers. 1H and 13C NMR spectra (300
and 100 MHz, respectively) were recorded using TMS as an internal
standard; 19F NMR spectra (282 MHz) with CFCl3 as an internal
standard. Mass spectra were obtained on a Hewlett–Packard HP
GC/MS 5890/5972 instrument (EI, 70 eV) using a GC inlet, or on a
MX-1321 instrument (EI, 70 eV) by direct inlet. Column chroma-
tography was performed on silica gel (63–200 mesh, Merck). Silica
gel Merck 60F 254 plates were used for TLC. The solvent systems
used for chromatographic separation were those indicated for the
given Rf values. For compounds that were purified by recrystalliza-
tion, the solvent system is indicated with the mp data. Satisfactory
microanalysis obtained: C 0.33; H 0.45; N 0.25.
Reaction of 1 with 2,4,6-tris(trifluoromethyl)-1,3,5-triaz-
ine (12) provides 1-(2,3-O-isopropylidene-b-D-ribofura-
nosyl)-4,6-bis(trifluoromethyl)-1H-pyrazolo[3,4-d]pyr-
imidine (27), the deprotection of which delivers 28, which
is the fluorinated analogue of Nebularine.19 As for all the
previous ribosides, the deprotection of the sugar group
was carried out in a mixture of trifluoroacetic acid and wa-
ter (9:1). Several other reagents for the deprotection of the
2,2¢-isopropylidene protection group were tried, however,
the method described here gave the best results.
X-ray Crystallography of 23b
Crystallographic measurements were performed at r.t. on an Enraf–
Nonius CAD4 diffractometer operating in the w-2q scan mode
(scanning rate ratio: w/2q = 1.2). The structure was solved by direct
methods and refined by full-matrix least-squares technique in aniso-
tropic approximation using SHELXS97 and SHELXL9720 program
packages. Hydrogen atoms were placed at calculated position and
refined using the ‘riding’ model.
In conclusion, the reactions of 5-amino-1-(2,3-O-isopro-
pylidene-b-D-ribofuranosyl)-1H-pyrazole (1) with a range
of fluorinated 1,3-CCC- and 1,3-CNC-dielectrophiles 3–
11, and 2,4,6-tris(trifluoromethyl)-1,3,5-triazine (12)
were studied systematically. Facile methods for the syn-
thesis of the fluorinated pyrazolo[3,4-b]pyridine and
Synthesis 2009, No. 5, 731–740 © Thieme Stuttgart · New York

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Fluorinated Pyrazolo[3,4-b]pyridine and Pyrazolo[3,4-d]pyrimidine Nucleosides
735
X-ray crystal data for 23b; Crystal system: monoclinic; Space
group: P21/c; Unit cell dimensions: a = 8.0430(16) Å, b = 12.352(3)
Å, c = 16.384(3) Å, b = 101.14(3)°; V = 1597.1(6) Å3; Z = 4;
m(Mo-Ka) = 0.126 mm–1. 21982 reflections collected, 3197 unique
reflections, (Rint = 0.0541); Mo-Ka radiation (l = 0.71073 Å); 226
parameters, R1 = 0.0375, wR2 = 0.0878, S = 1.112 [2864 reflec-
tions with I > 2s(I)].
MS: m/z (%) = 436 (10) [M+ + 1], 435 (39) [M+], 420 (26), 417 (21),
411 (13), 351 (14), 350 (56), 317 (14), 291 (35), 277 (27), 144
(100), 123 (10), 124 (76), 85 (19), 66 (14).
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-6-(thiophen-2-yl)-
4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (13c)
Yield: 0.76 g (86%); colourless solid; mp 135–137 °C; Rf = 0.70
(hexane–EtOAc, 1:1).
Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication no.
CCDC 699062 and can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
1H NMR (DMSO-d6): d = 1.34 (s, 3 H, CH3), 1.62 (s, 3 H, 3-CH3),
3.35–3.39 (m, 1 H, CH), 3.49–3.53 (m, 1 H, CH), 4.20 (td, JH–H
=
7.0, 2.3 Hz, 1 H, CH), 4.87 (t, 3JH–H = 5.9 Hz, 1 H, CH), 5.10 (dd,
JH–H = 6.5 Hz, JH–H = 2.4 Hz, 1 H, CH), 5.46 (d, 3JH–H = 5.9 Hz, 1 H,
CH), 6.56 (br s, 1 H, CH), 7.22 (dd, 3JH–H = 5.1 Hz, 3JH–H = 3.9 Hz,
1 H, CH), 7.81 (dd, 3JH–H = 5.1 Hz, 3JH–H = 1.2 Hz, 1 H, CH), 8.20
3
3
Compounds 13a–d and 17; General Procedure
(dd, JH–H = 3.9 Hz, JH–H = 1.2 Hz, 1 H, CH), 8.23 (s, 1 H, CH),
A mixture of iso-AIRs 1 (2 mmol) and 1,3-dielectrophile (2.1
mmol) in DMF (15 mL) under an inert atmosphere was stirred for
12 h at 125 °C. The reaction mixture was then concentrated under
reduced pressure and the dark material was purified by column
chromatography over silica gel.
8.38 (s, 1 H, CH).
13C NMR (DMSO-d6): d = 25.0, 26.9, 61.7, 82.0, 83.6, 87.9, 89.6,
108.9, 110.9, 112.7, 122.2 (q, 1JC–F = 275 Hz), 128.9, 129.3, 131.1,
131.2 (q, 2JC–F = 35 Hz), 132.3, 142.6, 150.6, 152.5.
MS: m/z (%) = 442 (16) [M+ + 1], 441 (62) [M+], 426 (17), 423 (13),
413 (11), 412 (35), 411 (100), 353 (15), 352 (70), 325 (11), 324
(28), 298 (28), 297 (25), 292 (12), 282 (26), 271 (23), 270 (97), 269
(72), 84 (36), 66 (23).
Formation of 20, 13e–g and 25; General Procedure
Initial compound (14a for 13g, 15a for 13e, 15b for 13f, 19 for 20,
24 for 25; 2 mmol) in a 10 mL round-bottom flask was kept for 1 h
at 180 °C (temperature of the oil bath) under reduced pressure (0.02
mmHg). When the reaction was complete, the dark-brown material
was purified by column chromatography over silica gel.
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-6-(pyridin-4-yl)-4-
(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (13d)
Yield: 0.79 g (91%); colourless solid; mp 169–172 °C; Rf = 0.40
(hexane–EtOAc, 1:1).
1H NMR (DMSO-d6): d = 1.36 (s, 3 H, CH3), 1.56 (s, 3 H, 3-CH3),
3.31–3.52 (m, 1 H, CH), 4.18 (t, 3JH–H = 7.0 Hz, 1 H, CH), 4.91 (t,
3JH–H = 5.4 Hz, 1 H, CH), 5.04 (dd, 3JH–H = 6.6 Hz, 3JH–H = 2.4 Hz,
1 H, CH), 5.46 (d, 3JH–H = 5.2 Hz, 1 H, CH), 6.75 (s, 1 H, CH), 8.25
(d, 3JH–H = 5.0 Hz, 2 H, CH), 8.38 (s, 1 H, CH), 8.52 (s, 1 H, CH),
8.75 (d, 3JH–H = 5.0 Hz, 2 H, CH).
13C NMR (DMSO-d6): d = 25.1, 26.8, 61.6, 82.1, 83.7, 88.0, 89.3,
110.3, 112.3 (q, 3JC–F = 4.7 Hz), 112.7, 121.5, 122.3 (q, 1JC–F = 275
Hz), 131.9 (q, 2JC–F = 37 Hz), 132.3, 143.7, 150.6, 151.0, 154.4.
MS: m/z (%) = 436 (2) [M+], 421 (33), 418 (17), 407 (63), 406 (100),
378 (11), 348 (13), 347 (51), 320 (13), 319 (27), 293 (25), 277 (14),
265 (50), 68 (13).
4,6-Bis(trifluoromethyl)-1-(2,3-O-isopropylidene-b-D-ribofura-
nosyl)-1H-pyrazolo[3,4-b]pyridine (13a)
Yield: 0.8 g (94%); yellow oil; Rf = 0.40 (hexane–EtOAc, 3:1).
1H NMR (CDCl3): d = 1.38 (s, 3 H CH3), 1.65 (s, 3 H, 3-CH3), 3.68
2
3
2
(dd, JH–H = 12.8 Hz, JH–H = 3.2 Hz, 1 H, CH), 3.86 (dd, JH–H
=
12.8 Hz, 3JH–H = 2.7 Hz, 1 H, CH), 4.53 (br s, 1 H, CH), 5.11 (dd,
3JH–H = 5.9 Hz, 3JH–H = 1.6 Hz, 1 H, CH), 5.27 (dd, 3JH–H = 5.5 Hz,
3JH–H = 2.8 Hz, 1 H, CH), 6.82 (d, 3JH–H = 2.8 Hz, 1 H, CH), 7.78 (s,
1 H, CH), 8.35 (s, 1 H, CH).
13C NMR (CDCl3): d = 25.2, 27.2, 63.8, 81.9, 85.0, 88.0, 91.8,
1
110.8, 112.7, 113.7, 113.8, 119.4 (q, JC–F = 275 Hz), 122.3 (q,
1JC–F = 275 Hz), 132.8, 134.1 (q, 2JC–F = 37 Hz), 148.2 (q, 2JC–F = 37
Hz), 150.3.
19F NMR (CDCl3): d = –60.9, –66.8.
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-4-(trifluorometh-
yl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (13e)
Yield: 0.49 g (65%); colourless solid; mp 139–141 °C; Rf = 0.75
(hexane–EtOAc, 1:1).
MS: m/z (%) = 412 (41), 398 (12), 397 (51), 338 (20), 310 (37), 284
(11), 268 (17), 256 (54), 255 (46), 236 (17), 186 (10), 157 (30), 100
(16), 88 (11), 86 (77), 85 (17), 84 (100), 69 (12), 68 (25), 59 (24),
57 (11), 49 (13), 47 (17), 43 (23).
1H NMR (DMSO-d6): d = 1.30 (s, 3 H, CH3), 1.49 (s, 3 H, 3-CH3),
2
3
3.58 (dd, JH–H = 12.8 Hz, JH–H = 3.2 Hz, 1 H, CH), 3.72 (dd,
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-6-phenyl-4-(triflu-
oromethyl)-1H-pyrazolo[3,4-b]pyridine (13b)
Yield: 0.71 g (81%); colourless solid; mp 129–131 °C; Rf = 0.65
(hexane–EtOAc, 1:1).
2JH–H = 12.8 Hz, 3JH–H = 2.7 Hz, 1 H, CH), 4.30 (s, 1 H, OH), 4.39
(br s, 1 H, CH), 4.99 (d, 3JH–H = 5.9 Hz, 1 H, CH), 5.19 (d, 3JH–H
=
6.2 Hz, 1 H), 5.30 (d, 3JH–H = 2.4 Hz, 1 H), 5.45 (d, 3JH–H = 3.9 Hz,
1 H), 5.81 (d, 3JH–H = 2.8 Hz, 1 H, CH), 7.37 (s, 1 H, CH).
1H NMR (CDCl3): d = 1.34 (s, 3 H, CH3), 1.62 (s, 3 H, 3-CH3), 3.71
13C NMR (DMSO-d6): d = 25.6, 27.0, 63.4, 81.8, 85.1, 88.4, 91.7,
2
3
2
(dd, JH–H = 12.8 Hz, JH–H = 3.2 Hz, 1 H, CH), 3.84 (dd, JH–H
=
3
1
12.8 Hz, 3JH–H = 2.7 Hz, 1 H, CH), 4.49 (br s, 1 H, CH), 5.09 (dd,
3JH–H = 5.9 Hz, 3JH–H = 1.6 Hz, 1 H, CH), 5.25 (dd, 3JH–H = 5.5 Hz,
104.3 (q, JC–F = 4.4 Hz), 112.9, 113.4, 124.3 (q, JC–F = 275 Hz),
132.8, 134.0 (q, 2JC–F = 35 Hz), 142.1, 164.0.
3JH–H = 2.8 Hz, 1 H, CH), 6.88 (d, JH–H = 2.8 Hz, 1 H, CH), 7.45
3
19F NMR (DMSO-d6): d = –60.8.
MS: m/z (%) = 376 (10) [M+ + 1], 375 (24) [M+], 370 (11), 343 (34),
320 (12), 319 (100), 297 (69), 211 (75), 201 (49), 189 (13), 125
(17), 77 (25), 64 (36).
(m, 3 H, CH), 7.82 (s, 1 H, CH), 8.06 (d, 3JH–H = 7.8 Hz, 2 H, CH),
8.14 (s, 1 H, CH).
13C NMR (DMSO-d6): d = 25.0, 26.9, 62.0, 72.0, 73.7, 85.2, 88.7,
3
1
109.3, 111.7 (q, JC–F = 4.7 Hz), 123.1 (q, JC–F = 275 Hz), 127.2,
2
127.5, 130.9, 132.7, 131.2 (q, JC–F = 37 Hz), 132.7, 137.1, 151.0,
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-4-(difluorometh-
yl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (13f)
Yield: 0.26 g (37%); colourless solid; mp 147–149 °C; Rf = 0.50
(EtOAc).
156.4.
19F NMR (CDCl3): d = –60.7.
Synthesis 2009, No. 5, 731–740 © Thieme Stuttgart · New York

736
V. O. Iaroshenko et al.
PAPER
1H NMR (DMSO-d6): d = 1.28 (s, 3 H, CH3), 1.50 (s, 3 H, 3-CH3),
1 H, CH), 5.81 (br s, 1 H, CH), 6.12 (tt, 2JH–F = 53.0 Hz, 3JH–F = 5.1
Hz, 1 H, CF2H), 6.17 (d, JH–H = 2.0 Hz, 1 H, CH), 7.60 (s, 1 H,
CH), 12.15 (br s, 1 H, NH).
2
3
3
3.54 (dd, JH–H = 12.8 Hz, JH–H = 3.2 Hz, 1 H, CH), 3.74 (dd,
2JH–H = 12.8 Hz, 3JH–H = 2.7 Hz, 1 H, CH), 4.19 (s, 1 H, OH), 4.38
(br s, 1 H, CH), 4.96 (d, 3JH–H = 5.9 Hz, 1 H, CH), 5.16 (d, 3JH–H
=
13C NMR (CDCl3): d = 11.4, 25.0, 25.3, 27.1, 64.1, 82.4, 85.6, 88.5,
6.2 Hz, 1 H), 5.32 (d, 3JH–H = 2.4 Hz, 1 H), 5.44 (d, 3JH–H = 3.9 Hz,
1 H), 5.81 (d, 3JH–H = 2.8 Hz, 1 H, CH), 6.11 (t, 3JH–F = 55 Hz, 1 H,
CF2H), 7.38 (s, 1 H, CH).
2
1
91.5 (t, JC–F = 24.0 Hz), 91.6, 91.9, 109.2 (tt, JC–F = 250 Hz,
2JC–F = 34.3 Hz), 109.7 (tt, JC–F = 258 Hz, JC–F = 26 Hz), 113.4,
1
2
136.2, 140.7, 173.0.
13C NMR (DMSO-d6): d = 25.3, 27.1, 63.7, 81.3, 85.2, 88.8, 91.1,
MS: m/z (%) = 419 (8) [M+], 401 (10), 400 (100), 390 (17), 309 (30),
297 (25), 183 (27), 179 (39), 171 (50), 149 (11), 101 (11), 84 (11),
43 (12).
1
2
102.4, 111.7, 112.8, 115.9 (t, JC–F = 240 Hz), 126.4 (t, JC–F = 25
Hz), 134.3, 142.5, 165.0.
MS: m/z (%) = 356 (3), 331 (31), 188 (15), 177 (12), 160 (22), 159
(100), 126 (17), 86 (18).
6-Ethyl-1-(2,3-O-isopropylidene-b-D-ribofuranosyl)-4-(perfluo-
robutyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-ol (14c)
Yield: 0.78 g (71%); yellow oil; Rf = 0.20 (hexane–EtOAc, 3:1).
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-6-methyl-4-(per-
fluoroethyl)-1H-pyrazolo[3,4-b]pyridine (13g)
Yield: 0.59 g (69%); yellow oil; Rf = 0.55 (hexane–EtOAc, 3:1).
3
1H NMR (CDCl3): d = 1.08 (t, JH–H = 7.4 Hz, 3 H, CH3), 1.29 (s,
3 H, CH3), 1.48 (s, 3 H, 3-CH3), 2.26 (q, 3JH–H = 7.4 Hz, 2 H), 3.62
1H NMR (CDCl3): d = 1.33 (s, 3 H, CH3), 1.64 (s, 3 H, 3-CH3), 2.37
(s, 3 H, CH3), 3.64 (dd, 2JH–H = 12.8 Hz, 3JH–H = 3.2 Hz, 1 H, CH),
3.88 (dd, 2JH–H = 12.8 Hz, 3JH–H = 2.7 Hz, 1 H, CH), 4.50 (br s, 1 H,
(dd, JH–H = 12.8 Hz, JH–H = 3.1 Hz, 1 H, CH), 3.86 (dd, JH–H =
3
3
2
12.8 Hz, 3JH–H = 2.0 Hz, 1 H, CH), 4.44 (br s, 1 H, CH), 4.96 (d,
3JH–H = 5.8 Hz, 1 H, CH), 5.01 (dd, 3JH–H = 5.8 Hz, 3JH–H = 3.1 Hz,
1 H, CH), 5.68 (s, 1 H, CH), 5.73 (d, 3JH–H = 2.8 Hz, 1 H, CH), 6.12
3
OH), 5.10 (dd, JH–H = 5.9 Hz, 3JH–H = 1.6 Hz, 1 H, CH), 5.23 (dd,
3
3
3
3
3JH–H = 5.5 Hz, JH–H = 2.8 Hz, 1 H, CH), 6.82 (d, JH–H = 2.8 Hz,
(d, JH–H = 2.0 Hz, 1 H, CH), 7.55 (d, JH–H = 2.0 Hz, 1 H, CH),
1 H, CH), 7.78 (s, 1 H, CH), 8.20 (s, 1 H, CH).
12.03 (br s, 1 H, NH).
13C NMR (CDCl3): d = 24.3, 25.4, 27.0, 63.0, 82.5, 85.1, 88.4, 91.7,
110.9, 111.1 (tq, 1JC–F = 215 Hz, 2JC–F = 38 Hz), 113.4, 114.5, 120.1
(qt, 1JC–F = 285 Hz, 2JC–F = 38 Hz), 132.0, 133.4 (t, 2JC–F = 25 Hz),
148.6, 152.7.
13C NMR (CDCl3): d = 11.6, 25.1, 25.8, 26.9, 64.0, 82.3, 85.4, 88.3,
91.7 (t, JC–F = 24 Hz), 91.9, 92.1, 103.2, 113.3, 136.9, 140.5, 173.2.
MS: m/z (%) = 555 (24) [M+], 525 (61), 384 (27), 383 (64), 173 (11),
164 (100), 126 (36), 83 (11), 71 (14), 69 (18), 59 (23), 43 (17).
MS: m/z (%) = 424 (22) [M+ + 1], 423 (42) [M+], 407 (19), 379 (15),
351 (17), 299 (100), 271 (67), 203 (57), 123 (11), 89 (33), 64 (20).
Methyl 3-[5-Amino-1-(2,3-O-isopropylidene-b-D-ribofurano-
syl)-1H-pyrazol-4-yl]-4,4,4-trifluoro-3-hydroxybutanoate (15a)
Yield: 0.61 g (72%); yellow oil; Rf = 0.60 (EtOAc).
Synthesis of Compounds 14, 15, 19, 23; General Procedure
A mixture of iso-AIRs 1 (2.0 mmol) and 1,3-dielectrophile (2.1
mmol) in DMF (15 mL) under an inert atmosphere was stirred for
24 h at 80 °C. The reaction mixture was then concentrated under re-
duced pressure (0.02 mmHg) and the brown oil was purified by col-
umn chromatography over silica gel.
1H NMR (CDCl3): d = 1.30 (s, 3 H, CH3), 1.47 (s, 3 H, 3-CH3), 3.21
(m, 2 H, CH2), 3.58 (dd, 2JH–H = 12.8 Hz, 3JH–H = 3.2 Hz, 1 H, CH),
3.67 (s, 3 H, OCH3), 3.89 (dd, 2JH–H = 12.8 Hz, 3JH–H = 2.6 Hz, 1 H,
CH), 4.71 (br s, 4 H, NH2 and OH), 4.90 (dd, 3JH–H = 6.0 Hz, 3JH–H
1.4 Hz, 1 H, CH), 5.20 (dd, JH–H = 6.0 Hz, JH–H = 2.6 Hz, 1 H,
CH), 5.65 (d, 3JH–H = 7.4 Hz, 1 H, CH), 5.87 (d, 3JH–H = 2.5 Hz, 1 H,
CH), 6.35 (s, 1 H, CH).
=
3
3
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-6-methyl-4-(per-
fluoroethyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-ol (14a)
Yield: 0.6 g (68%); yellow oil; Rf = 0.50 (hexane–EtOAc, 1:1).
13C NMR (CDCl3): d = 25.4, 26.9, 43.1, 50.9, 63.4, 73.0 (q, 2JC–F
=
1
28 Hz), 82.5, 87.9, 92.7, 98.0, 111.0, 113.9, 127.1 (q, JC–F = 278
1H NMR (CDCl3): d = 1.29 (s, 3 H, CH3), 1.49 (s, 3 H, 3-CH3), 2.00
Hz), 146.3, 147.9, 175.3.
19F NMR (CDCl3): d = –84.2.
MS: m/z (%) = 439 (9) [M+], 422 (53), 420 (26), 403 (70), 374 (47),
366 (18), 365 (90), 307 (67), 222 (50), 173 (21), 174 (100), 108
(10), 77 (34), 54 (11).
3
(s, 1 H, CH3), 2.26 (q, 3JH–H = 7.4 Hz, 2 H), 3.63 (dd, JH–H = 12.8
Hz, 3JH–H = 3.1 Hz, 1 H, CH), 3.79 (dd, 2JH–H = 12.8 Hz, 3JH–H = 2.0
3
Hz, 1 H, CH), 4.45 (br s, 1 H, CH), 4.96 (d, JH–H = 5.8 Hz, 1 H,
CH), 5.01 (dd, 3JH–H = 5.8 Hz, 3JH–H = 3.1 Hz, 1 H, CH), 5.70 (br s,
1 H, CH), 5.75 (d, 3JH–H = 2.7 Hz, 1 H), 6.11 (3JH–H = 2.0 Hz, 1 H),
7.55 (d, 3JH–H = 2.4 Hz, 1 H, CH), 12.04 (br s, 1 H, NH).
13C NMR (CDCl3): d = 20.2, 25.1, 26.9, 64.0, 82.3, 85.3, 88.3, 92.0
Methyl 3-[5-Amino-1-(2,3-O-isopropylidene-b-D-ribofurano-
syl)-1H-pyrazol-4-yl]-4,4-difluoro-3-hydroxybutanoate (15b)
Yield: 0.40 g (49%); yellow oil; Rf = 0.30 (EtOAc).
2
1
(t, JC–F = 24 Hz), 92.1, 93.8, 102.9, 107.6 (tq, JC–F = 263 Hz,
1
2
2JC–F = 37 Hz), 113.3, 118.2 (qt, JC–F = 285 Hz, JC–F = 34 Hz),
1H NMR (CDCl3): d = 1.31 (s, 3 H, CH3), 1.50 (s, 3 H, 3-CH3), 3.27
(m, 2 H, CH2), 3.57 (dd, 2JH–H = 12.7 Hz, 3JH–H = 3.2 Hz, 1 H, CH),
3.66 (s, 3 H, OCH3), 3.87 (dd, 2JH–H = 12.7 Hz, 3JH–H = 2.6 Hz, 1 H,
136.4, 140.6, 168.0.
MS: m/z (%) = 441 (24) [M+], 411 (13), 352 (14), 269 (100), 173
(13), 150 (87), 122 (13), 108 (13), 85 (13), 84 (23), 73 (12), 71 (22),
69 (26), 66 (20), 59 (31), 57 (12), 55 (12), 45 (21), 43 (24).
CH), 4.55 (br s, 4 H, NH2 and OH), 4.87 (dd, 3JH–H = 6.0 Hz, 3JH–H
=
3
3
1.4 Hz, 1 H, CH), 5.19 (dd, JH–H = 5.8 Hz, JH–H = 2.6 Hz, 1 H,
CH), 5.53 (d, 3JH–H = 7.2 Hz, 1 H, CH), 5.78 (d, 3JH–H = 2.5 Hz, 1 H,
CH), 6.39 (s, 1 H, CH), 7.17 (t, 1JH–F = 54 Hz, 1 H, CF2H).
6-Ethyl-1-(2,3-O-isopropylidene-b-D-ribofuranosyl)-4-(1,1,2,2-
tetrafluoroethyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-ol
(14b)
13C NMR (CDCl3): d = 25.1, 26.0, 43.0, 51.1, 63.7, 70.3 (q, 2JC–F
=
1
Yield: 0.61 g (70%); yellow oil; Rf = 0.75 (hexane–EtOAc, 1:1).
27 Hz), 82.3, 87.0, 92.2, 98.0, 110.2, 113.0, 125.1 (q, JC–F = 256
1H NMR (CDCl3): d = 1.13 (t, 3JH–H = 7.4 Hz, 3 H, CH3), 1.34 (s,
Hz), 146.0, 147.2. 178.1.
3 H, CH3), 1.54 (s, 3 H, 3-CH3), 2.33 (q, 3JH–H = 7.4 Hz, 2 H), 3.67
MS: m/z (%) = 420 (12) [M+ – 1], 404 (33), 391 (44), 351 (99), 333
(100), 281 (71), 207 (10), 205 (39), 173 (29), 171 (19), 121 (11), 86
(21).
3
3
2
(dd, JH–H = 12.8 Hz, JH–H = 3.1 Hz, 1 H, CH), 3.81 (dd, JH–H
=
12.8 Hz, 3JH–H = 2.0 Hz, 1 H, CH), 4.49 (br s, 1 H, CH), 5.01 (d,
3JH–H = 5.8 Hz, 1 H, CH), 5.14 (dd, 3JH–H = 5.8 Hz, 3JH–H = 3.1 Hz,
Synthesis 2009, No. 5, 731–740 © Thieme Stuttgart · New York

PAPER
Fluorinated Pyrazolo[3,4-b]pyridine and Pyrazolo[3,4-d]pyrimidine Nucleosides
737
2-[5-Amino-1-(2,3-O-isopropylidene-b-D-ribofuranosyl)-1H-
pyrazol-4-yl]-1,1,1-trifluoropropan-2-ol (15c)
Yield: 0.65 g (89%); yellow oil; Rf = 0.35 (EtOAc).
19F NMR (DMSO-d6): d = –61.0, –66.5.
MS: m/z (%) = 387 (5) [M+], 358 (15), 357 (77), 310 (14), 285 (22),
284 (39), 256 (20), 132 (100).
1H NMR (CDCl3): d = 1.33 (s, 3 H, CH3), 1.57 (s, 3 H, 3-CH3), 1.67
(s, 3 H, CH3), 3.61 (dd, 2JH–H = 12.8 Hz, 3JH–H = 3.2 Hz, 1 H, CH),
3.84 (dd, 2JH–H = 12.8 Hz, 3JH–H = 2.6 Hz, 1 H, CH), 4.17 (br s, 3 H,
l-(b-D-Ribofuranosyl)-6-phenyl-4-(trifluoromethyl)-1H-pyra-
zolo[3,4-b]pyridine (16b)
Yield: 0.28 mg (71%); colourless solid; mp 189–191 °C; Rf = 0.60
(EtOAc).
NH2 and OH), 4.61 (br s, 1 H, CH), 4.97 (dd, 3JH–H = 6.0 Hz, 3JH–H
=
3
3
1.4 Hz, 1 H, CH), 5.25 (dd, JH–H = 6.0 Hz, JH–H = 2.6 Hz, 1 H,
CH), 5.67 (d, 3JH–H = 7.4 Hz, 1 H, CH), 5.81 (d, 3JH–H = 2.5 Hz, 1 H,
CH), 6.11 (s, 1 H, CH).
3
1H NMR (DMSO-d6): d = 3.50 (q, JH–H = 6.2 Hz, 1 H, CH), 3.64
(m, 1 H, CH), 4.02 (q, 3JH–H = 5.7 Hz, 1 H, CH), 4.35 (q, 3JH–H = 5.1
Hz, 1 H, CH), 4.78–4.83 (br m, 2 H, CH), 5.29 (d, 3JH–H = 5.4 Hz,
1 H, OH), 5.52 (d, 3JH–H = 5.8 Hz, 1 H, OH), 6.56 (d, 3JH–H = 4.3 Hz,
1 H, CH), 7.62 (m, 3 H, CH), 8.29 (s, 1 H, CH), 8.36 (d, 3JH–H = 7.8
Hz, 2 H, CH), 8.50 (s, 1 H, CH).
2
13C NMR (CDCl3): d = 24.5, 25.9, 27.0, 63.5, 73.1 (q, JC–F = 28
Hz), 82.4, 88.0, 92.7, 98.1, 111.1, 114.3, 127.7 (q, 1JC–F = 278 Hz),
147.1, 149.8.
19F NMR (CDCl3): d = –83.7.
MS: m/z (%) = 367 (12) [M+], 367 (89), 350 (100), 317 (37), 288
(68), 254 (78), 88 (79).
13C NMR (DMSO-d6): d = 62.7, 70.9, 73.3, 85.3, 88.2, 109.2, 111.7
1
(q, 3JC–F = 4.7 Hz), 123.0 (q, JC–F = 275 Hz), 127.0, 127.7, 130.7,
132.8, 131.1 (q, 2JC–F = 37 Hz), 132.8, 137.0, 151.6, 156.7.
1-[5-Amino-1-(2,3-O-isopropylidene-b-D-ribofuranosyl)-1H-
pyrazol-4-yl]-2,2,2-trifluoro-1-phenylethanol (15d)
Yield: 0.75 g (87%); yellow oil; Rf = 0.65 (EtOAc).
MS: m/z (%) = 395 (9) [M+], 365 (33), 318 (14), 306 (33), 293 (32),
292 (100), 276 (12), 265 (19), 264 (89), 263 (12), 190 (90), 171
(11), 76 (20).
1H NMR (CDCl3): d = 1.37 (s, 3 H, CH3), 1.50 (s, 3 H, 3-CH3), 3.64
l-(b-D-Ribofuranosyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridine (16c)
Yield: 0.34 g (85%); colourless solid; mp 194–195 °C; Rf = 0.68
2
3
2
(dd, JH–H = 12.8 Hz, JH–H = 3.2 Hz, 1 H, CH), 3.85 (dd, JH–H
=
3
12.8 Hz, JH–H = 2.6 Hz, 1 H, CH), 4.69 (br s, 4 H, NH2 and OH),
4.99 (dd, 3JH–H = 6.0 Hz, 3JH–H = 1.4 Hz, 1 H, CH), 5.25 (dd, 3JH–H
=
(EtOAc).
6.0 Hz, 3JH–H = 2.6 Hz, 1 H, CH), 5.61 (d, 3JH–H = 7.4 Hz, 1 H, CH),
5.79 (d, 3JH–H = 2.5 Hz, 1 H, CH), 6.13 (s, 1 H, CH), 7.37 (d, 3JH–H
=
1H NMR (DMSO-d6): d = 3.46–3.52 (m, 1 H, CH), 3.63–3.69 (m,
1 H, CH), 4.02 (q, 3JH–H = 5.7 Hz, 1 H, CH), 4.35 (q, 3JH–H = 5.1 Hz,
1 H, CH), 4.79–4.83 (br m, 2 H, CH), 5.31 (d, 3JH–H = 5.4 Hz, 1 H,
OH), 5.55 (d, 3JH–H = 5.8 Hz, 1 H, OH), 6.40 (d, 3JH–H = 4.3 Hz, 1 H,
CH), 7.30 (dd, 3JH–H = 5.1 Hz, 3JH–H = 3.9 Hz, 1 H, CH), 7.88 (dd,
3JH–H = 5.1 Hz, 3JH–H = 1.2 Hz, 1 H, CH), 8.28 (dd, 3JH–H = 3.9 Hz,
3JH–H = 1.2 Hz, 1 H, CH), 8.31 (s, 1 H, CH), 8.45 (s, 1 H, CH).
7.8 Hz, 2 H, CH), 7.43–7.54 (m, 3 H, CH).
2
13C NMR (CDCl3): d = 25.1, 27.0, 63.3, 73.2 (q, JC–F = 28 Hz),
83.9, 88.0, 97.4, 97.9, 111.0, 114.3, 124.2, 127.3, 127.6 (q, 1JC–F
=
278 Hz), 130.3, 137.7, 147.5, 149.9.
19F NMR (CDCl3): d = –83.5.
MS: m/z (%) = 428 (11) [M+ – 1], 412 (51), 353 (45), 359 (33), 358
(100), 289 (70), 201 (32), 158 (56), 68 (23).
13C NMR (DMSO-d6): d = 62.3, 71.0, 85.3, 88.4, 109.0, 110.8 (q,
1
3JC–F = 4.7 Hz), 122.8 (q, JC–F = 275 Hz), 129.0, 129.3, 130.6,
131.0, 131.1 (q, 2JC–F = 37 Hz), 132.1, 142.8, 151.1, 152.4.
Cleavage of 2,2¢-Propylidene Protecting Group; General Proce-
dure
MS: m/z (%) = 402 (20) [M+ + 1], 401 (61) [M+], 372 (17), 371 (62),
370 (22), 325 (14), 324 (59), 313 (27), 312 (74), 300 (24), 299 (56),
298 (87), 296 (18), 284 (26), 283 (55), 282 (77), 272 (43), 271 (70),
270 (100), 269 (84), 268 (15), 250 (18), 222 (11), 215 (13), 172
(16), 108 (11), 73 (25), 69 (13), 57 (22), 45 (18), 43 (15).
The protected substrate (1 mmol) was dissolved in a mixture of
TFA–H2O (9:1; 10–15 mL), and stirred vigorously at r.t. for 30–40
min (reaction monitored by TLC). The reaction mixture was con-
centrated under reduced pressure (the mixture should not be heated
over 40 °C) and the residue was subjected to column chromatogra-
phy over silica gel.
l-(b-D-Ribofuranosyl)-6-(pyridin-4-yl)-4-(trifluoromethyl)-1H-
pyrazolo[3,4-b]pyridine (16d)
Yield: 0.27 g (74%); colourless solid; mp 182–183 °C (EtOH).
Synthesis of Compounds 16e–g from 14a, 15a and 15b; General
Procedure
Compound 14a, 15a or 15b (1 mmol) and PTSA (cat.), dissolved in
absolute MeOH (10 mL) was heated under reflux for 1 h. After
evaporation of the solvent, the residue was either subjected to flash
column chromatography over silica gel or recrystallized from an ap-
propriate solvent.
1H NMR (DMSO-d6): d = 3.54 (m, 1 H, CH), 3.68 (m, 1 H, CH),
4.00 (q, 3JH–H = 4.7 Hz, 1 H, CH), 4.30 (br s, 1 H, CH), 4.73 (d,
3JH–H = 4.7 Hz, 2 H, CH), 5.29 (br s, 1 H, OH), 5.48 (d, 3JH–H = 5.4
Hz, 1 H, OH), 6.49 (d, 3JH–H = 4.7 Hz, 1 H, CH), 8.03 (s, 1 H, CH),
8.14 (s, 1 H, CH), 8.20 (d, 3JH–H = 5.0 Hz, 2 H, CH), 8.79 (d, 3JH–H
=
5.0 Hz, 2 H, CH).
13C NMR (DMSO-d6): d = 61.9, 82.0, 83.5, 88.3, 89.1, 110.4, 112.4
(q, 3JC–F = 4.7 Hz), 112.7, 121.6, 122.8 (q, 1JC–F = 275 Hz), 131.7 (q,
2JC–F = 37 Hz), 132.4, 143.8, 150.2, 151.5, 154.9.
19F NMR (DMSO-d6): d = –67.1.
l-(b-D-Ribofuranosyl)-4,6-bis(trifluoromethyl)-1H-pyrazo-
lo[3,4-b]pyridine (16a)
Yield: 0.33 mg (84%); colourless solid; mp 111–112 °C; Rf = 0.75
(EtOAc).
MS: m/z (%) = 397 (18) [M+ + 1], 396 (72) [M+], 377 (88), 356 (29),
357 (89), 305 (40), 230 (100), 177 (35), 176 (90), 157 (11), 122
(19), 119 (20), 68 (10), 45 (41).
1H NMR (DMSO-d6): d = 3.49 (m, 1 H, CH), 3.63 (m, 1 H, CH),
4.02 (q, 3JH–H = 4.7 Hz, 1 H, CH), 4.34 (br s, 1 H, CH), 4.79 (d,
3JH–H = 4.7 Hz, 2 H, CH), 5.32 (br s, 1 H, OH), 5.55 (d, 3JH–H = 5.4
Hz, 1 H, OH), 6.44 (d, 3JH–H = 4.7 Hz, 1 H, CH), 8.21 (s, 1 H, CH),
8.73 (s, 1 H, CH).
13C NMR (DMSO-d6): d = 62.1, 70.8, 73.4, 85.0, 88.5, 111.0, 112.9,
119.5 (q, 1JC–F = 275 Hz), 122.2 (q, 1JC–F = 275 Hz), 132.5, 132.51
(q, 2JC–F = 37 Hz), 145.2 (q, 2JC–F = 37 Hz), 150.3.
l-(b-D-Ribofuranosyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-
b]pyridin-6(7H)-one (16e)
Yield: 0.25 g (64%); colourless solid; mp 177–180 °C (EtOH).
3
1H NMR (DMSO-d6): d = 3.55 (q, JH–H = 6.2 Hz, 1 H, CH), 3.60
(m, 1 H, CH), 4.09 (q, 3JH–H = 5.7 Hz, 1 H, CH), 4.33 (q, 3JH–H = 5.1
Synthesis 2009, No. 5, 731–740 © Thieme Stuttgart · New York

738
V. O. Iaroshenko et al.
PAPER
Hz, 1 H, CH), 4.75–4.82 (br m, 2 H, CH), 5.27 (d, 3JH–H = 5.4 Hz,
1 H, OH), 5.58 (d, 3JH–H = 5.6 Hz, 1 H, OH), 6.59 (d, 3JH–H = 4.3 Hz,
1 H, CH), 7.00 (s, 1 H, CH), 7.75 (s, 1 H, CH), 12.11 (br s, 1 H,
NH).
MS: m/z (%) = 461 (51) [M+], 447 (35), 440 (26), 401 (70), 371
(100), 365 (10), 364 (80), 287 (43), 256 (17), 209 (19), 181 (35),
119 (21), 63 (23).
10-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-(trifluorometh-
yl)-6,10-dihydro-5H-benzo[h]pyrazolo[3,4-b]quinoline-7-(tri-
fluoromethyl)-6,10-dihydropyrazolo[3,4-b]thiochromeno[3,4-
e]pyridine (17b)
13C NMR (DMSO-d6): d = 81.4, 85.7, 88.8, 91.3, 104.1 (q, 3JC–F
=
1
4.4 Hz), 112.7, 113.4, 124.3 (q, JC–F = 275 Hz), 132.2, 134.2 (q,
2JC–F = 35 Hz), 142.0, 164.9.
19F NMR (DMSO-d6): d = –61.1.
Yield: 0.66 g (69%); colourless solid; mp 131–133 °C; Rf = 0.80
MS: m/z (%) = 335 (11) [M+], 334 (28), 317 (31), 316 (16), 311 (11),
277 (33), 278 (100), 256 (69), 245 (10), 244 (74), 199 (39), 198
(11), 190 (54), 189 (17), 138 (18), 112 (21), 107 (22), 104 (14), 98
(12), 81 (13), 68 (11), 43 (19).
(hexane–EtOAc, 2:1).
1H NMR (CDCl3): d = 1.33 (s, 3 H, CH3), 1.62 (s, 3 H, CH3), 3.70
3
3
2
(dd, JH–H = 12.8 Hz, JH–H = 3.2 Hz, 1 H, CH), 3.86 (dd, JH–H
=
3
12.8 Hz, JH–H = 2.0 Hz, 1 H, CH), 4.10 (s, 2 H, CH2), 4.48 (br s,
1 H, CH), 5.07 (dd, 3JH–H = 5.9 Hz, 3JH–H = 1.6 Hz, 1 H, CH), 5.23
3
3
3
l-(b-D-Ribofuranosyl)-4-(difluoromethyl)-1H-pyrazolo[3,4-
b]pyridin-6(7H)-one (16f)
Yield: 0.19 g (61%); colourless solid; mp 184–186 °C (EtOH).
(dd, JH–H = 5.9 Hz, JH–H = 2.8 Hz, 1 H, CH), 6.80 (d, JH–H = 2.8
Hz, 1 H, CH), 7.27–7.36 (br m, 3 H, CH), 8.17 (m, 1 H, CH), 8.40
(s, 1 H, CH).
3
1H NMR (DMSO-d6): d = 3.53 (q, JH–H = 6.2 Hz, 1 H, CH), 3.61
13C NMR (CDCl3): d = 25.0, 27.0, 27.6, 63.9, 81.8, 85.1, 87.9, 90.8,
(m, 1 H, CH), 4.11 (q, 3JH–H = 5.7 Hz, 1 H, CH), 4.31 (q, 3JH–H = 5.1
Hz, 1 H, CH), 4.73–4.83 (br m, 2 H, CH), 5.20 (d, 3JH–H = 5.4 Hz,
1 H, OH), 5.59 (d, 3JH–H = 5.6 Hz, 1 H, OH), 6.50 (d, 3JH–H = 4.3 Hz,
1 H, CH), 6.25 (t, 3JH–F = 55 Hz, 1 H, CF2H), 7.00 (s, 1 H, CH), 7.75
(s, 1 H, CH), 12.11 (br s, 1 H, NH).
3
1
122.5 (q, JC–F = 3.5 Hz), 123.2 (q, JC–F = 275 Hz), 126.4, 127.3,
127.8 (q, 2JC–F = 37 Hz), 128.6, 130.4, 133.31, 133.36, 136.6, 149.8,
153.9.
19F NMR (CDCl3): d = –56.1.
MS: m/z (%) = 479 (41) [M+], 450 (70), 438 (25), 385 (23), 291 (77),
13C NMR (DMSO-d6): d = 81.2, 85.4, 88.7, 91.0, 102.1, 112.0,
187 (17), 186 (100), 169 (12), 158 (77), 137 (11), 84 (31).
1
2
112.7, 115.3 (t, JC–F = 240 Hz), 126.0 (t, JC–F = 25 Hz), 134.2,
142.7, 165.2.
10-(b-D-Ribofuranosyl)-7-(trifluoromethyl)-6,10-dihydropyra-
zolo[3,4-b]thiochromeno[3,4-e]pyridine (18)
Yield: 0.35 g (79%); colourless solid; mp 159–160 °C; Rf = 0.80
(EtOAc).
MS: m/z (%) = 317 (3) [M+], 316 (11), 302 (19), 301 (25), 300 (14),
269 (70), 280 (50), 221 (91), 184 (100), 134 (17), 133 (60), 103
(48), 64 (11).
1H NMR (DMSO-d6): d = 3.51 (q, JH–H = 6.2 Hz, 1 H, CH), 3.67
3
l-(b-D-Ribofuranosyl)-4-(perfluoroethyl)-1H-pyrazolo[3,4-
(m, 1 H, CH), 4.00 (q, 3JH–H = 5.5 Hz, 1 H, CH), 4.30 (q, 3JH–H = 5.0
Hz, 1 H, CH), 4.75–4.81 (br m, 2 H, CH), 5.33 (d, 3JH–H = 5.4 Hz,
1 H, OH), 5.50 (d, 3JH–H = 5.8 Hz, 1 H, OH), 6.59 (d, 3JH–H = 4.5 Hz,
b]pyridine (16g)
Yield: 0.30 g (77%); colourless solid; mp 122–124 °C; Rf = 0.70
(EtOAc).
3
1 H, CH), 7.30–7.41 (br m, 3 H, CH), 8.10 (d, JH–H = 7.8 Hz, 1 H,
3
1H NMR (DMSO-d6): d = 2.41 (s, 3 H, CH3), 3.58 (q, JH–H = 6.2
CH), 8.49 (s, 1 H, CH).
Hz, 1 H, CH), 3.67 (m, 1 H, CH), 4.00 (q, 3JH–H = 5.7 Hz, 1 H, CH),
4.32 (q, 3JH–H = 5.1 Hz, 1 H, CH), 4.75–4.82 (br m, 2 H, CH), 5.37
(d, 3JH–H = 5.4 Hz, 1 H, OH), 5.50 (d, 3JH–H = 5.7 Hz, 1 H, OH), 6.50
(d, 3JH–H = 4.3 Hz, 1 H, CH), 8.14 (s, 1 H, CH), 8.23 (s, 1 H, CH).
13C NMR (DMSO-d6): d = 27.3, 65.2, 83.0, 85.9, 87.1, 90.7, 122.2
(q, 3JC–F = 3.5 Hz), 124.4 (q, 1JC–F = 275 Hz), 126.0, 127.7, 128.5 (q,
2JC–F = 37 Hz), 129.1, 130.4, 134.1, 134.6, 139.0, 149.1, 155.7.
19F NMR (DMSO-d6): d = –56.5.
MS: m/z (%) = 440 (19) [M+ + 1], 439 (77) [M+], 433 (21), 431 (17),
430 (29), 392 (11), 393 (100), 392 (19), 390 (70), 388 (23), 378
(11), 337 (17), 287 (15), 286 (97), 285 (24), 189 (13), 188 (11), 187
(18), 167 (18), 165 (20), 164 (68), 157 (44), 156 (50), 119 (11), 88
(45), 67 (23), 43 (15).
13C NMR (DMSO-d6): d = 25.3, 62.7, 70.9, 73.9, 84.8, 88.3, 111.4,
1
2
112.9, 111.1, 111.2 (tq, JC–F = 215 Hz, JC–F = 38 Hz), 120.1 (qt,
1JC–F = 285 Hz, JC–F = 38 Hz), 132.48, 133.7 (t, JC–F = 25 Hz),
2
2
150.3.
MS: m/z (%) = 384 (17) [M+ + 1], 383 (70) [M+], 265 (12), 264
(100), 244 (19), 234 (13), 221 (18), 189 (54), 174 (60), 173 (10),
172 (96), 150 (61), 143 (11).
1,1,1-Trifluoro-4-[1-(2,3-O-isopropylidene-b-D-ribofuranosyl)-
1H-pyrazol-5-ylamino]but-3-en-2-one (19)
Yield: 0.69 g (92%); yellow oil; Rf = 0.45 (hexane–EtOAc, 1:1).
10-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-7-(trifluorometh-
yl)-6,10-dihydro-5H-benzo[h]pyrazolo[3,4-b]quinoline (17a)
Yield: 0.66 g (72%); colourless solid; mp 139–141 °C; Rf = 0.70
(hexane–EtOAc, 2:1).
1H NMR (CDCl3): d = 1.29 (s, 3 H, CH3), 1.53 (s, 3 H, 3-CH3), 3.57
2
3
2
(dd, JH–H = 12.8 Hz, JH–H = 3.2 Hz, 1 H, CH), 3.72 (dd, JH–H
=
12.8 Hz, 3JH–H = 2.7 Hz, 1 H, CH), 4.43 (br s, 1 H, CH), 4.92 (dd,
3JH–H = 5.9 Hz, 3JH–H = 1.6 Hz, 1 H, CH), 5.25 (dd, 3JH–H = 5.5 Hz,
3JH–H = 2.8 Hz, 1 H, CH), 5.67 (d, 3JH–H = 7.4 Hz, 1 H, CH), 5.81 (d,
3JH–H = 2.4 Hz, 1 H, CH), 6.03 (d, 3JH–H = 2.0 Hz, 1 H, CH), 7.27 (d,
3JH–H = 8.2 Hz, 1 H, CH), 8.44 (d, 3JH–H = 2.0 Hz, 1 H, CH).
1H NMR (CDCl3): d = 1.30 (s, 3 H, CH3), 1.64 (s, 3 H, CH3), 2.89
3
(br s, 2 H, CH2), 3.30 (br s, 2 H, CH2), 3.71 (dd, JH–H = 12.8 Hz,
3JH–H = 3.2 Hz, 1 H, CH), 3.86 (dd, 2JH–H = 12.8 Hz, 3JH–H = 2.0 Hz,
1 H, CH), 4.10 (s, 2 H, CH2), 4.48 (br s, 1 H, CH), 5.07 (dd, 3JH–H
5.9 Hz, 3JH–H = 1.6 Hz, 1 H, CH), 5.23 (dd, 3JH–H = 5.9 Hz, 3JH–H
=
=
2.8 Hz, 1 H, CH), 6.81 (d, 3JH–H = 2.8 Hz, 1 H, CH), 7.27–7.36 (br
13C NMR (CDCl3): d = 25.1, 27.0, 63.7, 81.7, 84.9, 88.4, 92.1, 92.5,
95.8, 113.7, 116.5 (q, 1JC–F = 287 Hz), 140.3, 140.6, 151.7, 180.7 (q,
2JC–F = 33 Hz).
MS: m/z (%) = 377 (7) [M+], 344 (27), 330 (16), 329 (92), 270 (37),
243 (15), 242 (36), 216 (26), 214 (13), 205 (30), 201 (11), 200 (20),
189 (10), 188 (100), 187 (22), 157 (18), 136 (16), 86 (30), 85 (18),
84 (36), 71 (11), 69 (17), 68 (32), 59 (34), 57 (16), 43 (24).
m, 3 H, CH), 8.23 (m, 1 H, CH), 8.44 (s, 1 H, CH).
13C NMR (CDCl3): d = 24.4, 25.9, 26.4, 27.1, 63.0, 82.2, 85.3, 87.1,
3
1
90.7, 121.8 (q, JC–F = 3.4 Hz), 123.1 (q, JC–F = 275 Hz), 126.3,
2
127.0, 127.7 (q, JC–F = 37 Hz), 128.0, 130.9, 133.7, 135.4, 136.0,
148.9, 155.1.
19F NMR (CDCl3): d = –55.3.
Synthesis 2009, No. 5, 731–740 © Thieme Stuttgart · New York

PAPER
Fluorinated Pyrazolo[3,4-b]pyridine and Pyrazolo[3,4-d]pyrimidine Nucleosides
739
Synthesis of Compounds 20 and 25; General Procedure
The initial compound 19 or 24 (2 mmol) was placed in a 10 mL flask
and melted for 1 h under reduced pressure (0.02 mmHg) at 180 °C
(temperature of the oil bath). The dark residue formed was purified
by column chromatography over silica gel.
Hz, 1 H, CH), 7.16 (t, 3JH–H = 7.3 Hz, 1 H, CH), 7.41 (s, 1 H, CH),
7.56 (t, JH–H = 7.3 Hz, 1 H, CH), 7.75 (d, JH–H = 12.5 Hz, 1 H,
CH), 7.85 (d, 3JH–H = 7.3 Hz, 1 H, CH), 9.18 (s, 1 H, OH), 12.75 (d,
3JH–H = 11.1 Hz, 1 H, NH).
13C NMR (DMSO-d6): d = 14.6, 42.9, 94.2, 97.6 (q, 2JC–F = 32 Hz),
100.7, 116.7, 119.7, 122.4, 122.7 (q, 1JC–F = 290 Hz), 125.3, 125.9,
128.2, 128.9, 135.5, 138.4, 139.0, 149.4, 156.0, 180.6.
3
3
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-4-(trifluorometh-
yl)-1H-pyrazolo[3,4-b]pyridine (20)
Yield: 0.58 g (80%); yellow oil; Rf = 0.65 (hexane–EtOAc, 2:1).
MS: m/z (%) = 353 (14) [M+], 336 (15), 335 (100), 278 (73), 257
(18), 238 (41), 178 (19).
1H NMR (CDCl3): d = 1.32 (s, 3 H, CH3), 1.63 (s, 3 H, CH3), 3.70
3
3
2
(dd, JH–H = 12.0 Hz, JH–H = 3.5 Hz, 1 H, CH), 3.81 (dd, JH–H
=
Methylethylidenecarbamate-5-amino-2,2,2-trifluoro-1-(2,3-O-
isopropylidene-b-D-ribofuranosyl)-1H-pyrazole (24)
12.0 Hz, 3JH–H = 1.3 Hz, 1 H, CH), 4.49 (br s, 1 H, CH), 5.09 (dd,
3JH–H = 5.4 Hz, 3JH–H = 1.6 Hz, 1 H, CH), 5.28 (dd, 3JH–H = 5.4 Hz,
3JH–H = 2.7 Hz, 1 H, CH), 6.43 (br s, 1 H, OH), 6.80 (d, 3JH–H = 2.7
Hz, 1 H, CH), 8.21 (d, 3JH–H = 4.8 Hz, 1 H, CH), 8.33 (s, 1 H, CH),
8.70 (d, 3JH–H = 4.8 Hz, 1 H, CH).
A mixture of 1 (4 mmol) and ethaneimidoyl chloride 11 (1.52 g, 8
mmol) in CH2Cl2 (25 mL) was stirred at 0 °C for 30 min, then a so-
lution of Et3N (8 mmol, 1.11 mL) in CH2Cl2 (10 mL) was slowly
added. The mixture was stirred at r.t. for 2 h, then refluxed for 3 h.
The solution was washed with H2O (2 × 20 mL) and the organic lay-
er was dried over Na2SO4. After evaporation of the solvent, the res-
idue was subjected to flash column chromatography over silica gel
(EtOAc) to afford 24.
13C NMR (CDCl3): d = 24.7, 26.9, 63.4, 82.1, 85.9, 87.5, 92.3,
1
111.1, 112.7, 113.78, 113.83, 123.1 (q, JC–F = 275 Hz), 130.9,
133.6 (q, 2JC–F = 37 Hz), 144.8, 150.9.
19F NMR (DMSO-d6): d = –61.4.
Yield: 0.52 g (32%); yellow oil; Rf = 0.55 (EtOAc).
MS: m/z (%) = 359 (55) [M+], 354 (18), 333 (19), 301 (22), 278 (67),
277 (23), 270 (37), 234 (67), 232 (49), 184 (100), 179 (89), 161
(60), 160 (11), 155 (21), 107 (16), 72 (78).
1H NMR (CDCl3): d = 1.33 (s, 3 H, CH3), 1.61 (s, 3 H, 3-CH3), 3.59
(dd, 2JH–H = 12.0 Hz, 3JH–H = 3.2 Hz, 1 H, CH), 3.69 (s, 3 H, OCH3),
3.77 (dd, 2JH–H = 12.0 Hz, 3JH–H = 2.5 Hz, 1 H, CH), 4.43 (br s, 1 H,
CH), 4.90 (dd, 3JH–H = 5.9 Hz, 3JH–H = 1.6 Hz, 1 H, CH), 5.21 (dd,
l-(b-D-Ribofuranosyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-
b]pyridine (21)
Yield: 0.25 g (78%); colourless solid; mp 122–124 °C; Rf = 0.55
(EtOAc).
3
3
3JH–H = 5.5 Hz, JH–H = 2.5 Hz, 1 H, CH), 5.72 (d, JH–H = 7.6 Hz,
1 H, CH), 5.77 (br s, 1 H, 5¢-OH), 5.84 (d, 3JH–H = 2.3 Hz, 1 H, CH),
6.89 (d, 3JH–H = 2.3 Hz, 1 H, CH).
1H NMR (DMSO-d6): d = 3.41 (dd, 2JH–H = 11.1 Hz, 3JH–H = 5.5 Hz,
1 H, CH), 3.54 (dd, 2JH–H = 11.1 Hz, 3JH–H = 4.9 Hz, 1 H, CH), 3.94
(q, 3JH–H = 4.9 Hz, 1 H, CH), 4.25 (t, 3JH–H = 4.7 Hz, 1 H, CH), 4.65
(t, 3JH–H = 5.0 Hz, 1 H, CH), 6.32 (d, 3JH–H = 4.4 Hz, 1 H, CH), 8.19
(d, 3JH–H = 4.8 Hz, 1 H, CH), 8.34 (s, 1 H, CH), 8.73 (d, 3JH–H = 4.8
Hz, 1 H, CH).
13C NMR (DMSO-d6): d = 25.4, 27.3, 53.3, 63.8, 82.0, 85.0, 88.3,
92.2, 111.2, 111.9, 118.5 (1JC–F = 276 Hz), 137.7 (q, 2JC–F = 37 Hz),
140.1, 149.7, 169.7.
19F NMR (DMSO-d6): d = –68.3.
MS: m/z (%) = 408 (21) [M+], 377 (35), 376 (100), 301 (29), 298
(78), 254 (16), 256 (83), 178 (56), 171 (45), 152 (10), 96 (14), 44
(37).
13C NMR (CDCl3): d = 62.7, 70.5, 73.8, 85.1, 88.8, 111.2, 113.0,
1
2
122.4 (q, JC–F = 275 Hz), 132.0, 132.5 (q, JC–F = 37 Hz), 144.4,
150.3.
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-6-(trifluorometh-
yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (25)
Yield: 0.48 g (64%); colourless solid; mp 110 °C; Rf = 0.20
(EtOAc).
13C NMR (DMSO-d6): d = 25.9, 27.0, 62.1, 81.3, 83.6, 88.7, 93.3,
109.9, 112.9, 122.4 (q, 1JC–F = 285 Hz), 131.8, 146.3 (q, 2JC–F = 33
Hz), 148.8, 167.7.
19F NMR (DMSO-d6): d = –69.0.
MS: m/z (%) = 376 (57) [M+], 375 (31), 371 (22), 355 (78), 321
(100), 287 (63), 270 (48), 205 (91), 170 (81), 168 (86), 159 (11),
112 (10), 109 (12), 43 (77).
19F NMR (DMSO-d6): d = –61.1.
MS: m/z (%) = 319 (27) [M+], 311 (12), 304 (11), 298 (17), 297 (15),
290 (12), 217 (100), 211 (19), 210 (85), 198 (73), 197 (11), 181
(43), 167 (29), 163 (89), 88 (17), 79 (15).
2-Hydroxy-3-[(1H-pyrazol-5-ylamino)methylene]-2-(trifluoro-
methyl)-2,3-dihydro-4H-chromen-4-one (23a)
Yield: 0.47 g (72%); colourless solid; mp 200–203 °C; Rf = 0.25
(EtOAc).
1H NMR (DMSO-d6): d = 6.31 (s, 1 H, CH), 7.00 (d, 3JH–H = 7.3 Hz,
1 H, CH), 7.11 (t, 3JH–H = 7.3 Hz, 1 H, CH), 7.45 (s, 1 H, CH), 7.55
3
3
(t, JH–H = 7.3 Hz, 1 H, CH), 7.80 (d, JH–H = 12.1 Hz, 1 H, CH),
l-(b-D-Ribofuranosyl)-6-(trifluoromethyl)-1H-pyrazolo[3,4-
d]pyrimidin-4(5H)-one (26)
Yield: 0.14 g (52%); colourless solid; mp 198 °C.
3
7.89 (d, JH–H = 7.3 Hz, 1 H, CH), 9.14 (s, 1 H, OH), 12.60 (d,
3JH–H = 11.7 Hz, 1 H, NH).
13C NMR (DMSO-d6): d = 94.2, 97.6 (q, JC–F = 32 Hz), 100.5,
2
13C NMR (DMSO-d6): d = 64.4, 78.3, 80.3, 85.0, 91.1, 108.0, 122.2
116.5, 119.6, 122.3, 122.7 (q, 1JC–F = 290 Hz), 125.0, 126.0, 128.0,
(q, 2JC–F = 33 Hz), 131.0, 146.0 (q, 1JC–F = 285 Hz), 148.0, 165.0.
128.7, 135.5, 138.3, 139.5, 149.7, 155.8, 180.3.
MS: m/z (%) = 325 (11) [M+], 306 (16), 307 (100), 213 (18), 181
(19), 149 (27), 117 (33), 94 (24), 67 (35).
MS: m/z (%) = 336 (4) [M+], 318 (12), 317 (19), 315 (27), 311 (11),
309 (17), 234 (31), 202 (44), 180 (100), 149 (69), 133 (97), 130
(61), 129 (57), 111 (12), 73 (34), 46 (19).
3-{[(1-Ethyl-1H-pyrazol-5-yl)amino]methylene}-2-hydroxy-2-
(trifluoromethyl)-2,3-dihydro-4H-chromen-4-one (23b)
Yield: 0.53 g (75%); colourless solid; mp 153–155 °C; Rf = 0.90
(EtOAc).
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-4,6-bis(trifluoro-
methyl)-1H-pyrazolo[3,4-d]pyrimidine (27)
A mixture of iso-AIRs 1 (2 mmol) and 2,4,6-tris(trifluoromethyl)-
1,3,5-triazine (12; 2 mmol) in CH2Cl2 (20 mL) was stirred at r.t. un-
til the initial aminoheterocycle was consumed (~36 h, monitored be
3
1H NMR (DMSO-d6): d = 1.36 (t, JH–H = 6.6 Hz, 3 H, CH3), 4.13
(q, 3JH–H = 6.6 Hz, 3 H, CH2), 6.39 (s, 1 H, CH), 7.07 (d, 3JH–H = 7.3
Synthesis 2009, No. 5, 731–740 © Thieme Stuttgart · New York

740
V. O. Iaroshenko et al.
PAPER
(5) (a) Giblett, E. R.; Anderson, J. E.; Cohen, F.; Pollara, B.;
TLC). The solution formed was evaporated and the residue was sub-
jected to column chromatography over silica gel.
Meuwissen, H. J. Lancet 1972, 2, 1067. (b) Hirshhorn, R.
Clin. Immunol. Immunopathol. 1995, 76, S219.
Yield: 0.83 g (97%); yellow oil; Rf = 0.50 (hexane–EtOAc, 2:1).
1H NMR (CDCl3): d = 1.37 (s, 3 H, CH3), 1.65 (s, 3 H, CH3), 3.75
(6) (a) Niedzwicki, J. G.; Kouttab, N. M.; Mayer, K. H.;
Carpenter, C. C.; Parks, R. E. Jr.; Abushanab, E.; Abernethy,
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Bissbort, S. H. Chest 1994, 106, 33. (b) Banales, J. L.;
Rivera Martinez, E.; Perez Gonzalez, L.; Selman, M.;
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Matsuya, M.; Kashiwagi, M. A. J. Neurol. Sci. 1995, 132,
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3
3
2
(dd, JH–H = 12.1 Hz, JH–H = 3.5 Hz, 1 H, CH), 3.86 (dd, JH–H
=
12.1 Hz, 3JH–H = 1.3 Hz, 1 H, CH), 4.53 (br s, 1 H, CH), 5.07 (dd,
3JH–H = 5.9 Hz, 3JH–H = 1.6 Hz, 1 H, CH), 5.27 (dd, 3JH–H = 5.9 Hz,
3JH–H = 2.8 Hz, 1 H, CH), 6.40 (br s, 1 H, 5¢-OH), 6.82 (d, 3JH–H
2.8 Hz, 1 H, CH), 8.35 (s, 1 H, CH).
=
13C NMR (CDCl3): d = 25.4, 27.3, 63.8, 82.0, 85.0, 88.3, 92.2,
1
111.2, 114.3, 119.2 (q, 1JC–F = 271 Hz), 120.2 (q, JC–F = 271 Hz),
134.1, 151.5 (q, 2JC–F = 39 Hz), 145.2 (q, 2JC–F = 39 Hz), 154.6.
19F NMR (CDCl3): d = –69.4, –71.8.
MS: m/z (%) = 414 (19), 413 (100), 398 (35), 339 (12), 311 (22),
257 (16), 157 (48), 100 (14).
(9) (a) Demeocq, F.; Viallard, J. L.; Boumsell, L.; Richard, Y.;
Chassgne, J.; Plagne, R.; Lemerle, J.; Bernard, A. Leuk. Res.
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(12) (a) Cristalli, G.; Costanzi, S.; Lambertucci, C.; Lupidi, G.;
Vittori, S.; Volpini, R.; Camaioni, E. Med. Res. Rev. 2001,
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see: (a) Dang, Q.; Brown, B. S.; Erion, M. D. J. Org. Chem.
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l-(b-D-Ribofuranosyl)-4,6-bis(trifluoromethyl)-1H-pyrazo-
lo[3,4-d]pyrimidine (28)
Yield: 0.33 g (85%); colourless solid; mp 99–101 °C; Rf = 0.70
(EtOAc).
1H NMR (DMSO-d6): d = 3.41 (dd, 2JH–H = 11.7 Hz, 3JH–H = 5.8 Hz,
1 H, CH), 3.54 (dd, 2JH–H = 11.7 Hz, 3JH–H = 5.1 Hz, 1 H, CH), 3.94
(q, 3JH–H = 5.1 Hz, 1 H, CH), 4.25 (t, 3JH–H = 4.7 Hz, 1 H, CH), 4.65
(t, 3JH–H = 5.1 Hz, 1 H, CH), 6.32 (d, 3JH–H = 4.3 Hz, 1 H, CH), 8.86
(s, 1 H, CH).
13C NMR (DMSO-d6): d = 61.9, 70.7, 73.5, 85.8, 88.9, 109.8, 119.2
1
1
(q, JC–F = 271 Hz), 120.2 (q, JC–F = 271 Hz), 133.9, 149.5 (q,
2JC–F = 39 Hz), 150.2 (q, 2JC–F = 39 Hz), 154.6.
19F NMR (DMSO-d6): d = –69.0, –71.1.
MS: m/z (%) = 389 (13) [M+ + 1], 359 (12), 358 (63), 312 (14), 311
(88), 299 (62), 286 (36), 285 (52), 270 (10), 269 (20), 258 (30), 257
(90), 133 (14), 132 (100), 114 (15), 104 (27), 86 (27), 84 (17), 74
(11), 73 (53), 57 (19).
(14) (a) Volochnyuk, D. M.; Pushechnikov, A. O.; Krotko, D. G.;
Sibgatulin, D. A.; Kovalyova, S. A.; Tolmachev, A. A.
Synthesis 2003, 1531. (b) Iaroshenko, V. O.; Volochnyuk,
D. M.; Wang, Y.; Vovk, M. V.; Boiko, V. J.; Rusanov, E. B.;
Groth, U. M.; Tolmachev, A. O. Synthesis 2007, 3309.
(15) (a) Sosnovskikh, V. Ya.; Irgashev, R. A.; Barabanov, M. A.
Synthesis 2006, 2707. (b) Sosnovskikh, V. Ya.; Irgashev, R.
A. Heteroat. Chem. 2006, 17, 99.
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Synthesis 2009, No. 5, 731–740 © Thieme Stuttgart · New York