Synthesis of some fluorinated heteroannulated pyrimidines - Purine isosteres - Via inverse-electron-demand Diels-Alder protocol

Article abstract of DOI:10.1055/s-0029-1217015

The inverse-electron-demand Diels-Alder reaction of electron excessive systems such as enamines, electron-enriched amino heterocycles, and anilines with 2,4,6-tris(polyfluoroalkyl)- 1,3,5-triazines was investigated. This study results in the synthesis of

Full text of DOI:10.1055/s-0029-1217015

PAPER
3967
Synthesis of Some Fluorinated Heteroannulated Pyrimidines – Purine
Isosteres – via Inverse-Electron-Demand Diels–Alder Protocol
S
ynthesis of Fluor
i
inate
d
P
k
urine
I
soste
t
re
s
or O. Iaroshenko*a,b
a
‘Enamine Ltd.’, 23 A. Matrosova st., 01103 Kyiv, Ukraine
Fax +380(44)5373253; E-mail: Yaroshenko@enamine.net
b
National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv-33, Ukraine
Received 15 June 2009; revised 13 July 2009
Dedicated to my wife Amrita Singha Roy on the occasion of her 20th birthday
applied in the total synthesis9 of nothapodytine B and (2)-
mappiline.
Abstract: The inverse-electron-demand Diels–Alder reaction of
electron excessive systems such as enamines, electron-enriched
amino heterocycles, and anilines with 2,4,6-tris(polyfluoroalkyl)-
1,3,5-triazines was investigated. This study results in the synthesis
of a set of polyfluoroalkyl containing pyrimidines, heteroannulated
pyrimidines, and quinazolines. Following the elaborated synthetic
pathway, l-(b-D-ribofuranosyl)-4,6-bis(polyfluoroalkyl)-1H-pyra-
zolo[3,4-d]pyrimidines were prepared starting from iso-AIRs.
Polyfluoroalkyl-containing azadienes, 1,2,4,5-tetra-
zines,10 were recently used by Seitz and co-workers for
the synthesis of derivatives of 1,2,4-triazines, pyridines,
and arenes. At the same time, on the basis of the fluorinat-
ed 1,3,5-triazines and some electron-rich aminoheterocy-
cles, we11 and others12 have elaborated preparative
methods for purines and purine isosteres assembling via
the annulation of the pyrimidine core to the aminohetero-
cyclic moiety.
Key words: pyrimidines, purine isosteres, heterocycles, annula-
tion, fluorine
In this publication, a preparative method for heteroannu-
lated pyrimidines is reported based on LUMOdiene-controlled
azadiene Diels–Alder reaction of fluorinated 1,3,5-tri-
azines 11 with enamines, electron-rich heterocycles,
anilines 1–9, and the iso-AIRs (AIRs = aminoimidazole
riboside) 10 (Figure 1). Due to the lowering of the
By virtue of its excellent chemo-, regio-, and diastereo-
selectivity, the Diels–Alder (DA) reaction is one of the
most important and elegant methods for the construction
of six-membered ring compounds. Application of DA
methodology led to the synthesis of many single and poly-
cyclic systems including heterocycles.1 The systematic
study of mechanistic2 and theoretical aspects3 of DA reac-
tions has been recently carried out.
O
N
Depending on the energy state of the both pairs of the
frontier orbitals in the Hückel molecular orbital (HMO)
model Diels–Alder cycloaddition reactions are divided
into three types:4(1) normal HOMOdiene-controlled; (2) neu-
tral; and (3) LUMOdiene-controlled or inverse-electron-
demand DA reactions.
N
N
N
Ph
NH2
NH2
N
N
NH2
Me
H
H
3
2
1
S
EtO2C
EtO2C
Alk2N
NC
NH2
O
N
Hetero-diene modification of the DA protocol has gained
great popularity in application to the synthesis of a num-
ber of heterocycles.5 Nowadays, an azadiene reaction1 is
one of the main synthetic pathways towards unsaturated
nitrogen-containing heterocycles bearing two or more ste-
reogenic centers because the azadiene [4+2] cycloaddi-
tions are performed at room or even lower temperatures
with a high degree of endo-selectivity.
NH2
S
NH2
4
5
6
NH2
NH2
N
t-Bu
NH2
Me2N
N
9
7
8
The inverse-electron-demand, the so-called LUMOdiene-
RF
N
azadiene protocol in Diels–Alder reactions, has
controlled
been successfully used for the synthesis of pyridines6 in-
cluding a number of complex natural products such as
streptonigrone7 and fredricamycin A.8 An inverse-elec-
tron-demand Diels–Alder protocol was also successfully
N
N
N
N
NH2
O
RF
RF
HO
11a RF = CF3
10
11b RF = CF2H
O
O
11c RF = CF2Cl
11d RF = C2F5
SYNTHESIS 2009, No. 23, pp 3967–3974
Advanced online publication: 23.09.2009
DOI: 10.1055/s-0029-1217015; Art ID: P08809SS
x
x.
x
x
.
2
0
0
9
Figure 1 Aminoheterocycles 1–9, iso-AIRs 10, and 2,4,6-tris(poly-
fluoroalkyl)-1,3,5-triazines 11.
© Georg Thieme Verlag Stuttgart · New York

3968
V. O. Iaroshenko
PAPER
RF
N
LUMOdiene energy level in the fluorinated 1,3,5-triazines
to such an extent that the azadiene [4+2] cycloaddition re-
action described proceeds at room temperature with high
regiospecificity affording only one main isomer.
N
N
RF
11
RF
RF
N
We have started our investigation with the study of the re-
action of classical enamines such as 3-aminobutenenitrile
(12a) and 3-aminobut-2-enoic acid ethyl ester (12b), with
2,4,6-tris(trifluoromethyl)-1,3,5-triazine (11a). The reac-
tion was carried out in dichloromethane at room tempera-
ture for 12 hours, which led to the formation of the
corresponding 2,4-bis(trifluoromethyl)pyrimidines 13 in
quantitative yield (Scheme 1). Since the analytically pure
precursors 12 have been used for this reaction, the formed
products 13 needed no further purification.
N
Het
Het
i
NH2
RF
1–9
74–98%
14
RF
NH
Het
N
Het
Het
N
RF
H
N
15
16
Scheme 2 Reagents and conditions: (i) CH2Cl2–AcOH (10:1), r. t.,
CF3
24–48 h.
N
N
postulated as transition states B, C, and an intermediate D
as depicted in Scheme 3. Compounds D have been isolat-
ed and characterized.12 When the reactions of heterocy-
cles 3 and 7 were run in dichloromethane without acid
catalysis, the intermediates D were observed in the reac-
tion mixture by means of HPLC. However, in some cases
we have encountered the problem of separating pyrim-
idines 14 and the corresponding intermediates D. In the
course of separation on silica gel the latter transformed
into aromatic compounds 14.
CF3
N
CF3
F3C
EWG
EWG
11a
N
i
NH2
N
CF3
12
13
Scheme 1 Reagents and conditions: (i) CH2Cl2 under N2, r.t., 24 h.
The pyrimidines containing RF substituents in positions 2
and 4 have been previously synthesized13 by addition of
trifluoroacetonitrile either to the CH2-active pattern con-
taining the CO13a or CN13b group in the a-position, or to N-
pyrimidinium salts13c containing the CH2-unsubstituted
function neighboring with the N-nuclei. Annulation of the
pyrimidine core to the enamine moiety was described as a
[2+2+2] cycloaddition reaction14 of enamine function and
two units of trifluoroacetonitrile.
In our opinion the reaction should start with the formation
of the sandwich complex with charge transfer A as the
RF
RF
RF
4
N
N
N
N
H
1'
Het
+
N
RF
N
Het
As mentioned above, the cycloaddition of the electron-
deficient 1,3,5-triazines to electron-rich aminoheterocy-
cles is a significant method11,12 of purine/(purine isostere)
assembly. The polyfluoroalkyl containing purines are a
target due to a broad spectrum of their biological activi-
ty.15
NH2
RF
RF
2'
NH2
+
A
B
N-4
Thus, this potentially powerful method can be expanded
to other heterocycles mainly through a change in the RF
group of the initial 1,3,5-triazine molecule. Aminohetero-
cycles 1–8 and 3-dimethylaminoaniline (9) react smooth-
ly with 1,3,5-triazines 11 in a 10:1 mixture of
dichloromethane and AcOH under mild condition (r.t.) to
give a set of diverse fluorinated heteroannulated pyrim-
idines 14a–u in 74–98% yields and 2,4-bis(polyfluoro-
alkyl)-7-(dimethylamino)quinazolines 14v–x in 89–91%
yields (Scheme 2). The fluorinated quinazolines are at-
tractive bioactive molecules.16 The fluorinated quinazo-
lines are mainly used for the treatment of anemia,17 and
some other diseases.18
RF
1
RF
N
1
4
RF
H
1'
2
N
2
N
N
H
RF
Het
Het
N
4
3
3
RF
2'
H2N
H2N
D
C
+
H
RF
RF
N
RF
H
Het
N
H
Het
Het
Het
The scope and mechanism of the reaction between elec-
tron-deficient dienes and electron-rich dienophiles has
been investigated.4–6 In the case of enamines and 1,3,5-tri-
azines two transition structures and one intermediate were
N
H2N
H2N
F
E
Scheme 3
Synthesis 2009, No. 23, 3967–3974 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Purine Isosteres
3969
first step. In the literature there is no information about the mixture with TFA–H2O (20:1). For the synthesis of ribo-
detection of such complexes. We have made this assump- side 22, the silyl Hilbert–Johnson reaction21 was used.
tion based on the observation of the reaction mixture in This reaction takes place in dichloromethane with BSA
dichloromethane at low temperature –10 to –25 °C. In the [O,N-bis(trimethylsilyl)acetamide] and TMS-triflate as a
first few seconds after addition of a diene to the solution catalyst.11c The subsequent acetyl moiety cleavage by am-
of the electron-rich moiety in dichloromethane, the color monia yields compound 23 in 81% yield (Scheme 5).
of the reaction mixture changes from slightly yellow to
CF3
red through blue depending on the initial amine.
CF3
N
N
N
The detailed study of the reaction mixture has revealed the
formation of two by-products 15 and 16 in an amount less
than 1–2%. Amidines 15 are hydrolytically stable prod-
ucts formed by the releasing of trifluoroacetonitrile after
the cycloaddition took place. The formation of the het-
erodiannulated pyridines 16 suggests that pyrimidines 14
are still capable of reacting with the electron-rich systems.
The reaction most likely proceeds via intermediates E and
F. However, all detected pyrimidines 14 are prone to cy-
cloaddition, even under the harsh conditions (DMF, 80–
140 °C, 24 h). Nevertheless, despite our numerous at-
tempts, only traces of diannulated pyridines 16 were ob-
served.
N
N
N
i
ii
N
N
H
NH2
N
CF3
N
CF3
PMB
in situ
PMB
20
21
77%
60%
19
OAc
OAc
O
CF3
AcO
CF3
N
N
N
AcO
N
N
N
21
N
CF3
iv
iii
AcO
O
N
CF3
O
22
90%
23
81%
HO
Very recently, the synthesis of the l-(b-D-ribofuranosyl)-
4,6-bis(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine
starting from 5-amino-1-(2,3-O-isopropylidene-b-D-ribo-
furanosyl)-1H-pyrazole (iso-AIRs, 10) and 2,4,6-tris(tri-
fluoromethyl)-1,3,5-triazine (11a) has been reported.11b
Here, we describe using the same synthetic procedure the
preparation of the compounds 18, where RF = CF2H,
CF2Cl, C2F5. The reaction proceeds in dichloromethane at
room temperature releasing protected moieties 17. Treat-
ment of 17 with TFA–H2O (9:1) then delivers the ribo-
sides 18 (Scheme 4).
AcO
OAc
HO
OH
Scheme 5 Reagents and conditions: (i) 2,4,6-tris(trifluoromethyl)-
1,3,5-triazine, CH2Cl2 under N2, r.t., 36 h; (ii) TFA–H2O (20:1), r.t.,
24 h; (iii) BSA [O,N-bis(trimethylsilyl)acetamide], TMS-triflate;
MeCN, reflux 4 h; (iv) MeOH/NH3, r.t., 12 h.
The structure of synthesized pyrimidines was confirmed
by, 13C, and 19F NMR spectroscopy. For example, in the
1H, 13C NMR spectra of compounds 14 possessing the
methyl group at the 7-position of the pseudo purine skel-
eton, the long range interaction of the methyl group and
RF substituent were clearly observed, which is one of the
features confirming the structure of the scaffold 14. More-
over, the CF2H proton of the compounds 14c,o,r,u,x, 17c
and 18c shows ROESY correlations with the protons of
the neighboring groups also confirming the constitution of
14.
RF
RF
N
N
N
N
11b–d
N
N
RF
N
N
RF
18 81–83%
10
O
O
i
ii
17 88–93%
HO
HO
O
O
HO
OH
In conclusion, a convenient synthetic approach to het-
eroannulated 2,4-bis(polyfluoroalkyl)pyrimidines was
elaborated from commercially available 2,4,6-tris(poly-
fluoroalkyl)-1,3,5-triazines and electron-rich aminohet-
erocycles. The method discovered here allows access to
libraries of compounds containing the scaffold 14.
Scheme 4 Reagents and conditions: (i) CH2Cl2 under N2, r.t., 36 h;
(ii) TFA–H2O (9:1), r.t., 40 min.
We are currently involved in the development of potential
inhibitors of adenosine deaminase (ADA) and inosine 5¢-
monophosphate dehydrogenase (IMPDH) based on poly-
fluoroalkyl-containing purines and purine isosteres. Here,
we wish to report a model synthesis of purine nucleoside
containing trifluoromethyl group in position 2 and 6 of the
purine skeleton, which are suspected to be the inhibitors
of the ADA enzyme family.19 3-(4-Methoxybenzyl)-3H-
imidazol-4-ylamine (19) generated in situ by previous re-
ported procedure20 was used for the synthesis of purine 20
bearing 4-methoxybenzyl protecting group at position 9.
Purine 20 was easily deprotected to 21 by treatment of the
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) by GC inlet or on a MX-1321
instrument (EI, 70 eV) by direct inlet. Column chromatography was
performed on silica gel (63–200 mesh, Merck). Silica gel Merck
60F254 plates were used for TLC Satisfactory microanalysis ob-
tained: C 0.33; H 0.45; N 0.25.
Synthesis 2009, No. 23, 3967–3974 © Thieme Stuttgart · New York

3970
V. O. Iaroshenko
PAPER
Compounds 13 Starting from 11a and 12; General Procedure
A mixture of initial enamine 12a,b (2 mmol) and 2,4,6-tris(trifluo-
romethyl)-1,3,5-triazine (11a; 627 mg, 2.2 mmol) in CH2Cl2 (20
mL) was stirred at r.t., until the initial aminoheterocycle vanished
(TLC) and then the solution was evaporated. The yellow oil was an-
alytically pure and no other purification steps were needed.
MS: m/z (%) = 249 (13, [M+ + 1]), 248 (100, [M+]), 247 (10, [M+ –
1]).
2-Phenyl-4,6-bis(trifluoromethyl)-1,2-dihydropyrazolo[3,4-
d]pyrimidin-3-one (14d)
Prepared from 2 and 11a; yield: 0.63 g (91%); orange solid; mp
188–189 °C; Rf = 0.60 (CHCl3–MeOH, 9:1).
4-Methyl-2,6-bis(trifluoromethyl)pyrimidine-5-carbonitrile
(13a)
Yield: 510 mg (ca. 100%); yellow oil.
1H NMR (CDCl3): d = 2.57 (3 H, s, CH3).
1H NMR (DMSO-d6): d = 7.15 (1 H, t, 3JH,H = 7.8 Hz), 7.40 (2 H, t,
3JH,H = 7.8 Hz), 8.22 (2 H, d, 3JH,H = 7.8 Hz).
13C NMR (DMSO-d6): d = 101.6, 119.4, 120.1 (q, 1JC,F = 274 Hz),
2
120.3 (q, 1JC,F = 274 Hz), 124.2, 128.6, 140.4, 150.6 (q, JC,F = 36
MS: m/z (%) = 256 (10, [M+ + 1]), 255 (100, [M+]), 240 (11), 229
Hz), 152.8 (q, 2JC,F = 36 Hz), 155.2, 156.1.
19F NMR (DMSO-d6): d = –68.0, –71.4.
(19), 186 (17, [M+ – CF3]), 112 (13), 111 (10), 87 (11).
MS: m/z (%) = 349 (18, [M+ + 1]), 348 (100, [M+]), 328 (11), 319
(17), 299 (11), 112 (14), 111 (15), 105 (10).
Ethyl 4-Methyl-2,6-bis(trifluoromethyl)pyrimidine-5-carboxy-
late (13b)
Yield: 604 mg (ca. 100%); yellow oil.
4,6-Bis(perfluoroethyl)-2-phenyl-1,2-dihydropyrazolo[3,4-
d]pyrimidin-3-one (14e)
Prepared from 2 and 11d; yield: 798 mg (89%); orange solid; mp
159–161 °C; Rf = 0.20 (EtOAc).
1H NMR (CDCl3): d = 1.39 (3 H, t, 3JH,H = 7.8 Hz, CH3), 2.55 (3 H,
s, CH3), 4.35 (2 H, q, 3JH,H = 7.8 Hz, CH3).
MS: m/z (%) = 302 (10, [M+ + 1]), 301 (100, [M+]), 257 (19), 233
(12, [M+ – CF3]), 229 (11), 215 (10), 180 (14).
1H NMR (DMSO-d6): d = 7.22 (1 H, t, 3JH,H = 7.8 Hz), 7.49 (2 H, t,
3JH,H = 7.8 Hz), 8.20 (2 H, d, 3JH,H = 7.8 Hz).
Compounds 14, 17; General Procedure
13C NMR (DMSO-d6): d = 104.1, 119.0, 111.1 (tq, 1JC,F = 215 Hz,
A mixture of initial aminoheterocycle 1–10 (2 mmol) and 2,4,6-
tris(polyfluoroalkyl)-1,3,5-triazine 11a–d (2.2 mmol) in a mixture
of CH2Cl2–AcOH (30 mL, 10:1) was stirred at r.t. for 36–48 h, until
the initial aminoheterocycle had vanished (TLC), and then the reac-
tion mixture was evaporated. The residue was purified by column
chromatography over silica gel. In the case of salts 4·HCl, NaOAc
(1.1 equiv) was added.
1
2
2JC,F = 38 Hz), 112.4 (tq, JC,F = 215 Hz, JC,F = 38 Hz), 120.3 (qt,
1JC,F = 285 Hz, 2JC,F = 38 Hz), 120.7 (qt, JC,F = 285 Hz, 2JC,F = 38
1
Hz), 125.5, 128.9, 140.0, 150.0 (t, 2JC,F = 27 Hz), 152.0 (t, 2JC,F = 27
Hz), 155.8, 158.0.
MS: m/z (%) = 449 (16, [M+ + 1]), 448 (100, [M+]), 447 (19, [M+ –
1]), 371 (21, [M+ – Ph]), 379 (38, [M+ – CF3]), 329 (17, [M+ –
C2F5]), 77 (33).
8,9-Dimethyl-2,6-bis(perfluoroethyl)-9H-purine (14a)
Prepared from 1 and 11d; yield: 692 mg (90%); colorless solid; mp
60–61 °C; Rf = 0.55 (CH2Cl2–MeOH, 15:1).
1H NMR (CDCl3): d = 2.82 (3 H, s, 2-CH3), 3.89 (3 H, s, 1-CH3).
4,6-Bis(chlorodifluoromethyl)-2-phenyl-1,2-dihydropyrazo-
lo[3,4-d]pyrimidin-3-one (14f)
Prepared from 2 and 11c; yield: 717 mg (94%); orange solid; mp
200–201 °C; Rf = 0.75 (CHCl3–MeOH, 9:1).
1H NMR (DMSO-d6): d = 7.25 (1 H, t, 3JH,H = 7.8 Hz), 7.49 (2 H, t,
3JH,H = 7.8 Hz), 8.10 (2 H, d, 3JH,H = 7.8 Hz).
1
13C NMR (CDCl3): d = 15.1, 29.9, 111.2 (tq, JC,F = 215 Hz,
1
2
2JC,F = 38 Hz), 112.4 (tq, JC,F = 215 Hz, JC,F = 38 Hz), 120.1 (qt,
1JC,F = 285 Hz, 2JC,F = 38 Hz), 120.9 (qt, JC,F = 285 Hz, JC,F = 38
Hz), 131.7, 131.9, 143.0 (2JC,F = 26 Hz), 148.8 (2JC,F = 26 Hz),
156.1, 161.3.
1
2
1
13C NMR (DMSO-d6): d = 101.0, 112.4, 120.0 (t, JC,F = 287 Hz),
1
2
121.7 (t, JC,F = 287 Hz), 124.0, 125.3, 139.1, 150.0 (t, JC,F = 32
Hz), 150.0 (t, 2JC,F = 32 Hz), 154.9, 158.2.
MS: m/z (%) = 385 (12, [M+ + 1]), 384 (100, [M+]), 315 (38, [M+ –
CF3]), 264 (44, [M+ – C2F5]).
MS: m/z (%) = 382 (63, [M+ + 2]), 381 (14, [M+ + 1]), 380 (100,
[M+]), 378 (17), 288 (10), 77 (99).
2,6-Bis(chlorodifluoromethyl)-8,9-dimethyl-9H-purine (14b)
Prepared from 1 and 11c; yield: 590 mg (93%); colorless solid; mp
97–98 °C; Rf = 0.85 (CH2Cl2–MeOH, 10:1).
1H NMR (CDCl3): d = 2.65 (3 H, s, 2-CH3), 3.80 (3 H, s, 1-CH3).
3-Methyl-4,6-bis(perfluoroethyl)-1H-pyrazolo[3,4-d]pyrimi-
dine (14g)
Prepared from 3 and 11d; yield: 718 mg (97%): colorless solid; mp
88–89 °C; Rf = 0.35 (EtOAc–hexane, 1:5).
1
13C NMR (CDCl3): d = 14.0, 29.3, 119.7 (t, JC,F = 289 Hz), 121.8
1H NMR (CDCl3): d = 2.79 (3 H, s, CH3), 12.55 (1 H, s, NH).
13C NMR (DMSO-d6): d = 14.6 (5JC,F = 4 Hz), 111.2 (tq, 1JC,F = 215
1
2
(t, JC,F = 289 Hz), 131.7, 131.9, 143.9 (t, JC,F = 33 Hz), 149.5 (t,
2JC,F = 33 Hz), 155.0, 163.0.
1
2
Hz, 2JC,F = 38 Hz), 112.5 (tq, JC,F = 215 Hz, JC,F = 38 Hz), 120.1
MS: m/z (%) = 318 (61, [M+ + 2]), 317 (11, [M+ + 1]), 316 (100,
1
2
1
[M+]).
(qt, JC,F = 285 Hz, JC,F = 38 Hz), 120.7 (qt, JC,F = 285 Hz,
2JC,F = 38 Hz), 145.4, 151.3 (t, JC,F = 25 Hz), 152.8 (t, JC,F = 25
2
2
Hz), 158.
2,6-Bis(difluoromethyl)-8,9-dimethyl-9H-purine (14c)
Prepared from 1 and 11b; yield: 457 mg (92%); colorless solid; mp
95–97 °C; Rf = 0.75 (CH2Cl2–MeOH, 8:1).
MS: m/z (%) = 371 (10, [M+ + 1]), 370 (100, [M+]), 369 (47, [M+ –
1]), 301 (92, [M+ – CF3]), 251 (17, [M+ – C2F5]).
1H NMR (CDCl3): d = 2.71 (3 H, s, 2-CH3), 3.81 (3 H, s, 1-CH3),
6.89 (1 H, t, 2JH,F = 52 Hz, CF2H), 7.01 (1 H, t, 2JH,F = 55 Hz, CF2H).
4,6-Bis(chlorodifluoromethyl)-3-methyl-1H-pyrazolo[3,4-d]py-
rimidine (14h)
Prepared from 3 and 11c; yield: 533 mg (88 %); colorless solid; mp
129–131 °C; Rf = 0.55 (EtOAc–hexane, 1:4).
1
13C NMR (CDCl3): d = 14.5, 29.9, 115.5 (t, JC,F = 248 Hz), 116.3
1
2
(t, JC,F = 248 Hz), 131.7, 133.3, 144.7 (t, JC,F = 26 Hz), 147.1 (t,
2JC,F = 26 Hz), 156.7, 159.0.
1H NMR (CDCl3): d = 2.74 (3 H, s, CH3), 12.01 (1 H, s, NH).
Synthesis 2009, No. 23, 3967–3974 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Purine Isosteres
3971
5
13C NMR (DMSO-d6): d = 14.3 (t, JC,F = 1.9 Hz), 111.1, 120.0 (t,
1H NMR (CDCl3): d = 1.46 (3 H, t, 3JH,H = 7.8 Hz, CH3), 4.38 (2 H,
q, 3JH,H = 7.8 Hz, CH2), 8.17 (1 H, s, CH).
1JC,F = 289 Hz), 121.9 (t, JC,F = 289 Hz), 143.8, 151.7 (2JC,F = 31
1
Hz), 152.8 (2JC,F = 31 Hz), 158.0.
3
13C NMR (CDCl3): d = 14.4, 63.5, 105.2 (t, JC,F = 2.1 Hz), 115.0,
MS: m/z (%) = 304 (61, [M+ + 2]), 302 (100, [M+]), 301 (13), 300
120.0 (t, 1JC,F = 287 Hz), 121.7 (t, 1JC,F = 287 Hz), 149.8, 151.0 (t,
2JC,F = 33 Hz), 155.3 (t, 2JC,F = 33 Hz), 155.9, 168.3.
(17), 299 (11), 177 (11).
MS: m/z (%) = 362 (63, [M+ + 2]), 360 (100, [M+]), 289 (17), 288
(12), 231 (14), 201 (11).
4-[5,7-Bis(perfluoroethyl)thiazolo[4,5-d]pyrimidin-2-yl]mor-
pholine (14i)
Prepared from 4 and 11d; yield: 724 mg (79%); colorless solid; mp
71–73 °C; Rf = 0.45 (EtOAc–hexane, 1:4).
1H NMR (CDCl3): d = 3.68 (4 H, br s, NCH2), 4.07 (4 H, br s,
OCH2).
Ethyl 5-Methyl-2,4-bis(trifluoromethyl)thieno[2,3-d]pyrimi-
dine-6-carboxylate (14n)
Prepared from 6 and 11a; yield: 560 mg (91%); colorless solid; mp
111–113 °C; Rf = 0.30 (EtOAc–hexane, 1:5).
1
13C NMR (CDCl3): d = 49.2, 65.1, 111.1 (tq, JC,F = 215 Hz,
1H NMR (CDCl3): d = 1.38 (3 H, t, 3JH,H = 7.8 Hz, CH3), 2.90 (3 H,
2JC,F = 38 Hz), 112.7 (tq, JC,F = 215 Hz, JC,F = 38 Hz), 120.1 (qt,
t, 3JH,H = 2.0 Hz, CH3), 4.41 (2 H, t, 3JH,H = 7.8 Hz, CH2).
1
2
1JC,F = 285 Hz, 2JC,F = 38 Hz), 120.8 (qt, JC,F = 285 Hz, JC,F = 38
1
2
13C NMR (CDCl3): d = 14.2, 14.3 (q, 3JC,F = 5.6 Hz), 62.9, 119.5 (q,
Hz), 143.4 (t, 2JC,F = 29 Hz), 154.0 (t, 2JC,F = 29 Hz), 172.0, 175.0.
1
1JC,F = 274 Hz), 120.5 (q, JC,F = 274 Hz), 128.7, 133.9, 137.3,
MS: m/z (%) = 459 (15, [M+ + 1]), 458 (100, [M+]), 339 (10, [M+ –
151.5 (q, 2JC,F = 36 Hz), 151.6 (q, 2JC,F = 36 Hz), 161.7, 171.2.
19F NMR (CDCl3): d = –64.7, –71.5.
C2F5]), 331 (18), 271 (11), 256 (13), 153 (10).
MS: m/z (%) = 359 (14, [M+ + 1]), 358 (98, [M+]), 331 (15), 330
(100), 329 (39), 314 (11), 313 (58), 312 (52), 309 (18), 286 (11),
285 (50), 284 (47), 69 (10).
4-[5,7-Bis(chlorodifluoromethyl)thiazolo[4,5-d]pyrimidin-2-
yl]morpholine (14j)
Prepared from 4 and 11c; yield: 579 mg (74%); colorless solid; mp
119–122 °C; Rf = 0.65 (EtOAc).
1H NMR (CDCl3): d = 3.67 (4 H, br s, NCH2), 3.93 (4 H, br s,
OCH2).
Ethyl 5-Methyl-2,4-bis(perfluoroethyl)thieno[2,3-d]pyrimi-
dine-6-carboxylate (14m)
Prepared from 6 and 11d; yield: 852 mg (93%); colorless solid; mp
88–89 °C; Rf = 0.80 (EtOAc–hexane 1:5).
1H NMR (CDCl3): d = 1.33 (3 H, t, 3JH,H = 7.8 Hz, CH3), 2.83 (3 H,
t, 3JH,H = 2.0 Hz, CH3), 4.49 (2 H, t, 3JH,H = 7.8 Hz, CH2).
13C NMR (CDCl3): d = 49.4, 65.9, 120.1 (t, JC,F = 288 Hz), 121.5
1
(t, 1JC,F = 288 Hz), 143.0 (t, 2JC,F = 33 Hz), 150.2 (t, 2JC,F = 33 Hz),
174.2, 175.1.
MS: m/z (%) = 392 (12, [M+ + 2]), 390 (72, [M+]), 300 (100), 78
(11).
3
13C NMR (CDCl3): d = 14.0, 15.1 (t, JC,F = 3.0 Hz), 62.0, 111.0
1
2
1
(tq, JC,F = 215 Hz, JC,F = 38 Hz), 112.3 (tq, JC,F = 215 Hz,
2JC,F = 38 Hz), 120.1 (qt, JC,F = 285 Hz, JC,F = 38 Hz), 120.9 (qt,
1
2
Ethyl 2,4-Bis(trifluoromethyl)furo[2,3-d]pyrimidine-6-carbox-
ylate (14k)
Prepared from 5 and 11a; yield: 680 mg (98%); colorless solid; mp
71 °C; Rf = 0.75 (EtOAc–hexane, 1:4).
1H NMR (CDCl3): d = 1.42 (3 H, t, 3JH,H = 7.8 Hz, CH3), 4.30 (2 H,
q, 3JH,H = 7.8 Hz, CH2), 8.31 (1 H, s, CH).
1JC,F = 285 Hz, JC,F = 38 Hz), 128.7, 133.0, 139.9, 151.9 (t,
2
2JC,F = 26 Hz), 153.4 (t, 2JC,F = 26 Hz), 161.0, 173.3.
MS: m/z (%) = 459 (15, [M+ + 1]), 458 (100, [M+]), 390 (42, [M+ +
1 – CF3]), 389 (42, [M+ – CF3]), 385 (17), 340 (10, [M+ + 1 – C2F5]),
339 (10, [M+ – C2F5]), 218 (10), 203 (11), 73 (12).
13C NMR (CDCl3): d = 14.1, 63.1, 109.3 (q, 3JC,F = 1.7 Hz), 115.8,
119.3 (q, 1JC,F = 274 Hz), 120.1 (q, 1JC,F = 274 Hz), 149.8, 151.5 (q,
2JC,F = 36 Hz), 153.7 (q, 2JC,F = 36 Hz), 157.1, 167.5.
Ethyl 2,4-Bis(difluoromethyl)-5-methylthieno[2,3-d]pyrimi-
dine-6-carboxylate (14o)
Prepared from 6 and 11b; yield: 597 mg (91%); colorless solid; mp
117–118 °C; Rf = 0.80 (EtOAc–hexane, 1:5).
MS: m/z (%) = 328 (28, [M+]), 309 (99), 301 (14), 300 (100), 283
(72), 256 (16), 235 (16), 69 (18), 45 (16).
1H NMR (CDCl3): d = 1.43 (3 H, t, 3JH,H = 7.8 Hz, CH3), 2.89 (3 H,
t, 3JH,H = 2.0 Hz, CH3), 4.45 (2 H, t, 3JH,H = 7.8 Hz, CH2), 6.99 (1 H,
t, 2JH,F = 53 Hz, CF2H), 7.11 (1 H, t, 2JH,F = 54 Hz, CF2H).
Ethyl 2,4-Bis(perfluoroethyl)furo[2,3-d]pyrimidine-6-carboxy-
late (14l)
Prepared from 5 and 11d; yield: 770 mg (90%); colorless solid; mp
59–60 °C; Rf = 0.55 (EtOAc–hexane, 1:5).
1H NMR (CDCl3): d = 1.42 (3 H, t, 3JH,H = 7.8 Hz, CH3), 4.30 (2 H,
q, 3JH,H = 7.8 Hz, CH2), 8.31 (1 H, s, CH).
13C NMR (CDCl3): d = 14.9, 14.0, 62.1, 114.7 (t, JC,F = 246 Hz),
1
1
2
115.2 (t, JC,F = 247 Hz), 128.7, 133.9, 137.3, 141.5 (t, JC,F = 26
Hz), 152.1 (t, 2JC,F = 26 Hz), 161.7, 171.2.
MS: m/z (%) = 323 (13, [M+ + 1]), 322 (100, [M+]), 321 (90, [M+ –
1]), 271 (67, [M+ – CF2H]), 277 (50), 250 (12), 249 (15), 74 (77).
3
13C NMR (CDCl3): d = 14.9, 63.4, 109.3 (t, JC,F = 2.4 Hz), 111.0
1
2
1
(tq, JC,F = 215 Hz, JC,F = 38 Hz), 112.3 (tq, JC,F = 215 Hz,
7-tert-Butyl-2,4-bis(perfluoroethyl)-7H-pyrrolo[2,3-d]pyrimi-
dine-5-carbonitrile (14p)
Prepared from 7 and 11d; yield: 829 mg (95%); colorless solid; mp
120–121 °C; Rf = 0.70 (EtOAc–hexane, 1:3).
2JC,F = 38 Hz), 117.7, 120.1 (qt, JC,F = 285 Hz, JC,F = 38 Hz),
120.9 (qt, 1JC,F = 285 Hz, 2JC,F = 38 Hz), 147.0, 151.5 (t, 2JC,F = 29
Hz), 155.2 (t, 2JC,F = 29 Hz), 159.0, 169.3.
1
2
MS: m/z (%) = 429 (14, [M+ + 1]), 428 (100, [M+]), 411 (10), 383
1H NMR (DMSO-d6): d = 1.73 (9 H, s, CH3), 8.21 (1 H, s, 2-H).
13C NMR (DMSO-d6): d = 28.9, 60.8, 85.7, 113.9, 115.0, 111.2 (tq,
(17), 355 (21), 310 (13, [M+ – C2F5]), 208 (11), 57 (33).
1
1JC,F = 215 Hz, 2JC,F = 38 Hz), 112.2 (tq, JC,F = 215 Hz, 2JC,F = 38
Ethyl 2,4-Bis(chlorodifluoromethyl)furo[2,3-d]pyrimidine-6-
carboxylate (14m)
Prepared from 5 and 11c; yield: 636 mg (88%); colorless solid; mp
Hz), 120.3 (qt, 1JC,F = 285 Hz, 2JC,F = 38 Hz), 120.9 (qt, 1JC,F = 285
2
Hz, 2JC,F = 38 Hz), 143.8, 145.0 (t, JC,F = 27 Hz), 146.0, 149.0 (t,
2JC,F = 27 Hz).
100–102 °C; Rf = 0.45 (EtOAc–hexane, 1:4).
MS: m/z (%) = 437 (16, [M+ + 1]), 436 (41, [M+]), 380 (100, [M+ +
1 – t-Bu]), 379 (76, [M+ – t-Bu]), 368 (33, [M+ + 1 – CF3]), 367 (11,
Synthesis 2009, No. 23, 3967–3974 © Thieme Stuttgart · New York

3972
V. O. Iaroshenko
PAPER
N,N-Dimethyl-2,4-bis(trifluoromethyl)quinazolin-7-amine
[M+ – CF3]), 318 (10, [M+ + 1 – C2F5]), 317 (10, [M+ – C2F5]), 57
(67).
(14v)
Prepared from 9 and 11a; yield: 561 mg (91%); colorless solid; mp
178–180 °C; Rf = 0.35 (EtOAc–hexane, 1:2).
1H NMR (CDCl3): d = 3.15 (6 H, s, CH3), 7.03 (1 H, d, 3JH,H = 2.7
Hz, CH), 7.27 (1 H, dd, 3JH,H = 9.4 Hz, 3JH,H = 2.7 Hz, CH), 7.47 (1
H, dq, 3JH,H = 9.4 Hz, JH,F = 2.0 Hz, CH).
7-tert-Butyl-2,4-bis(chlorodifluoromethyl)-7H-pyrrolo[2,3-
d]pyrimidine-5-carbonitrile (14q)
Prepared from 7 and 11c; yield: 642 mg (87%); colorless solid; mp
147–149 °C; Rf = 0.55 (EtOAc–hexane, 1:3).
1H NMR (DMSO-d6): d = 1.70 (9 H, s, CH3), 8.01 (1 H, s, 2-H).
13C NMR (DMSO-d6): d = 27.1, 60.7, 85.9, 111.1, 116.5, 120.2 (t,
13C NMR (CDCl3): d = 40.1, 104.6 (q, 3JC,F = 1.5 Hz), 112.8, 119.6
1
1
(q, JC,F = 274 Hz), 119.7, 121.0 (q, JC,F = 274 Hz), 125.5 (q,
3JC,F = 3.2 Hz), 152.1 (q, 2JC,F = 36 Hz), 153.5, 157.7 (q, 2JC,F = 36
Hz), 158.4.
1
1JC,F = 287 Hz), 121.6 (t, JC,F = 287 Hz), 140.2, 143.1 (2JC,F = 34
Hz), 144.5, 149.0 (2JC,F = 34 Hz).
MS: m/z (%) = 368 (100, [M+]), 312 (22), 57 (100).
MS: m/z (%) = 310 (17, [M+ + 1]), 309 (100, [M+]), 308 (90).
7-tert-Butyl-2,4-bis(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimi-
dine-5-carbonitrile (14r)
Prepared from 7 and 11b; yield: 547 mg (91%); colorless solid; mp
N,N-Dimethyl-2,4-bis(perfluoroethyl)quinazolin-7-amine (14w)
Prepared from 9 and 11d; yield: 728 mg (89%); colorless solid; mp
170–172 °C; Rf = 0.65 (EtOAc–hexane, 1:2).
150–152 °C (EtOH–H2O).
1H NMR (DMSO-d6): d = 1.77 (9 H, s, CH3), 6.92 (1 H, t, 2JH,F = 57
Hz, CF2H), 7.11 (1 H, t, 2JH,F = 54 Hz, CF2H), 8.11 (1 H, s, 2-H).
1H NMR (CDCl3): d = 3.19 (6 H, s, CH3), 7.13 (1 H, d, 3JH,H = 2.7
Hz, CH), 7.19 (1 H, dd, 3JH,H = 9.4 Hz, 3JH,H = 2.7 Hz, CH), 7.35 (1
H, dq, 3JH,H = 9.4 Hz, JH,F = 2.0 Hz, CH).
13C NMR (DMSO-d6): d = 28.5, 61.1, 83.2, 111.4, 114.4 (t,
13C NMR (CDCl3): d = 40.8, 104.0 (t, 3JC,F = 2.1 Hz), 112.8, 111.0
1
1
2
1
1JC,F = 243 Hz), 115.3 (t, JC,F = 245 Hz), 116.3, 142.7, 141.1
(tq, JC,F = 215 Hz, JC,F = 38 Hz), 112.6 (tq, JC,F = 215 Hz,
(2JC,F = 27 Hz), 144.0, 146.1 (2JC,F = 25 Hz).
2JC,F = 38 Hz), 120.1 (qt, JC,F = 285 Hz, JC,F = 38 Hz), 119.7,
120.5 (qt, 1JC,F = 285 Hz, 2JC,F = 38 Hz), 121.1, 127.3 (t, 3JC,F = 3.0
Hz), 152.7 (t, 2JC,F = 26 Hz), 153.7, 157.1 (t, 2JC,F = 26 Hz), 157.0.
1
2
MS: m/z (%) = 301 (15, [M+ + 1]), 300 (100, [M+]), 299 (88, [M+ –
1]), 243 (19, [M+ – t-Bu]), 249 (89, [M+ – CF2H]), 219 (42), 218
(24), 57 (78).
MS: m/z (%) = 410 (15, [M+ + 1]), 409 (100, [M+]), 340 (67, [M+ –
CF3]), 290 (19, [M+ – C2F5]).
2,4-Bis(trifluoromethyl)-9H-pyrimido[4,5-b]indole (14s)
Prepared from 8 and 11a; yield: 525 mg (86%); colorless solid; mp
207–208 °C; Rf = 0.65 (EtOAc–hexane, 1:1).
1H NMR (DMSO-d6): d = 7.34 (2 H, m), 7.77 (1 H, d, J = 7.2 Hz),
8.23 (1 H, d, J = 7.2 Hz), 12.56 (1 H, s).
2,4-Bis(difluoromethyl)-N,N-dimethylquinazolin-7-amine (14x)
Prepared from 9 and 11b; yield: 497 mg (91%); colorless solid; mp
189–190 °C; Rf = 0.75 (EtOAc–hexane, 1:2).
1H NMR (CDCl3): d = 3.11 (6 H, s, CH3), 7.01 (1 H, d, 3JH,H = 2.7
Hz, CH), 6.90 (1 H, t, 2JH,F = 54 Hz, CF2H), 7.05 (1 H, t, 2JH,F = 53
Hz, CF2H), 7.25 (1 H, dd, 3JH,H = 9.4 Hz, 3JH,H = 2.7 Hz, CH), 7.39
(1 H, dq, 3JH,H = 9.4 Hz, JH,F = 2.0 Hz, CH).
13C NMR (CDCl3): d = 40.1, 102.9 112.8, 114.7 (t, 1JC,F = 247 Hz),
115.5 (t, 1JC,F = 245 Hz), 119.9, 125.5 (t, 3JC,F = 3.2 Hz), 150.0 (q,
2JC,F = 27 Hz), 154.4, 157.0 (t, 2JC,F = 26 Hz), 157.9.
1
13C NMR (DMSO-d6): d = 110.9, 119.3 (q, JC,F = 274 Hz), 120.2
1
(q, JC,F = 274 Hz), 121.0, 125.0, 133.5, 135.1, 146.2, 147.5 (q,
2JC,F = 36 Hz), 150.6 (q, 2JC,F = 36 Hz), 151.9, 157.0.
MS: m/z (%) = 306 (14, [M+ + 1]), 305 (100, [M+]), 285 (18), 284
(39).
2,4-Bis(perfluoroethyl)-9H-pyrimido[4,5-b]indole (14t)
Prepared from 8 and 11d; yield: 705 mg (87%); colorless solid; mp
169–170 °C; Rf = 0.35 (EtOAc–hexane, 1:2).
MS: m/z (%) = 274 (14, [M+ + 1]), 273 (90, [M+]), 272 (100, [M+ –
1]), 229 (11, [M+ – NMe2]), 222 (71, [M+ – CF2H]).
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-4,6-bis(perfluoro-
ethyl)-1H-pyrazolo[3,4-d]pyrimidine (17a)
Prepared from 10 and 11d; yield: 983 mg (93%); yellow oil;
Rf = 0.30 (hexane–EtOAc, 3:1).
1H NMR (DMSO-d6): d = 7.37 (m, 2 H), 7.87 (d, J = 7.2 Hz, 1 H),
8.20 (d, J = 7.2 Hz, 1 H), 12.78 (s, 1 H)
1
13C NMR (DMSO-d6): d = 110.9, 111.1 (tq, JC,F = 215 Hz,
1
2
2JC,F = 38 Hz), 112.7 (tq, JC,F = 215 Hz, JC,F = 38 Hz), 120.4 (qt,
1H NMR (CDCl3): d = 1.33 (3 H, s, CH3), 1.61 (3 H, s, CH3), 3.77
1JC,F = 285 Hz, 2JC,F = 38 Hz), 120.9 (qt, JC,F = 285 Hz, JC,F = 38
1
2
3
3
(1 H, dd, JH,H = 11.7 Hz, JH,H = 3.7 Hz, CH), 3.76 (1 H, dd,
2JH,H = 11.7 Hz, 3JH,H = 1.4 Hz, CH), 4.57 (1 H, br s, CH), 5.04 (1
H, dd, 3JH,H = 5.5 Hz, 3JH,H = 1.7 Hz, CH), 5.20 (1 H, dd, 3JH,H = 5.5,
2
Hz), 121.5, 127.0, 133.9, 135.8, 146.7, 147.5 (q, JC,F = 27 Hz),
149.9 (q, 2JC,F = 27 Hz), 151.9, 156.1.
MS: m/z (%) = 406 (15, [M+ + 1]), 405 (100, [M+]), 405 (100, [M+
3
Hz, JH,H = 2.7 Hz, CH), 6.49 (1 H, br s, 5¢-OH), 6.88 (1 H, d,
– 1]), 286 (11, [M+ – C2F5]).
3JH,H = 2.7 Hz, CH), 8.55 (1 H, s, CH).
13C NMR (CDCl3): d = 25.0, 29.1, 63.5, 82.0, 85.9, 88.4, 92.9,
2,4-Bis(difluoromethyl)-9H-pyrimido[4,5-b]indole (14u)
Prepared from 8 and 11b; yield: 452 mg (84%); colorless solid; mp
219–221 °C; Rf = 0.45 (EtOAc–hexane, 1:1).
1H NMR (DMSO-d6): d = 7.27 (2 H, m), 6.79 (1 H, t, 2JH,F = 52 Hz,
CF2H), 6.91 (1 H, t, 2JH,F = 52 Hz, CF2H), 7.77 (1 H, d, J = 7.2 Hz),
8.17 (1 H, d, J = 7.2 Hz), 12.76 (1 H, s).
13C NMR (DMSO-d6): d = 111.1, 114.4 (t, 1JC,F = 243 Hz), 115.7 (t,
1JC,F = 245 Hz), 121.1, 124.4, 133.3, 134.7, 146.1, 145.5 (q,
2JC,F = 27 Hz), 150.0 (q, 2JC,F = 27 Hz), 151.2, 155.5.
1
2
111.7, 114.0, 111.3 (tq, JC,F = 215 Hz, JC,F = 38 Hz), 112.5 (tq,
1
1JC,F = 215 Hz, 2JC,F = 38 Hz), 120.2 (qt, JC,F = 285 Hz, 2JC,F = 38
1
2
Hz), 120.5 (qt, JC,F = 285 Hz, JC,F = 38 Hz), 134.6, 147.0 (q,
2JC,F = 28 Hz), 151.2 (q, 2JC,F = 27 Hz), 155.9.
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-4,6-bis(chloro-
difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine (17b)
Prepared from 10 and 11c; yield: 839 mg (91%); yellow oil;
Rf = 0.65 (hexane–EtOAc, 2:1).
1H NMR (CDCl3): d = 1.32 (3 H, s, CH3), 1.71 (3 H, s, CH3), 3.70
MS: m/z (%) = 270 (13, [M+ + 1]), 269 (100, [M+]), 268 (12, [M+ –
3
3
1]), 218 (11, [M+ – CF2H]).
(1 H, dd, JH,H = 12.2 Hz, JH,H = 3.3 Hz, CH), 3.86 (1 H, dd,
2JH,H = 12.2 Hz, 3JH,H = 1.1 Hz, CH), 4.55 (1 H, br s, CH), 5.04 (1
Synthesis 2009, No. 23, 3967–3974 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Purine Isosteres
3973
H, dd, 3JH,H = 5.9 Hz, 3JH,H = 1.7 Hz, CH), 5.32 (1 H, dd, 3JH,H = 5.9,
1H NMR (DMSO-d6): d = 3.50 (1 H, dd, 2JH,H = 11.1 Hz, 3JH,H = 5.5
CH), 3.53 (1 H, dd, 2JH,H = 11.1 Hz, 3JH,H = 5.0 Hz, CH), 3.93 (1 H,
q, 3JH,H = 5.0 Hz, CH), 4.24 (1 H, t, 3JH,H = 4.3 Hz, CH), 4.60 (1 H,
t, 3JH,H = 5.2 Hz, CH), 6.33 (1 H, d, 3JH,H = 4.1 Hz, CH), 6.95 (1 H,
t, 2JH,F = 54 Hz, CF2H), 7.09 (1 H, t, 2JH,F = 55 Hz, CF2H), 8.77 (1
H, s, CH).
3
Hz, JH,H = 2.5 Hz, CH), 6.43 (1 H, br s, 5¢-OH), 6.80 (1 H, d,
3JH,H = 2.5 Hz, CH), 8.44 (1 H, s, CH).
13C NMR (CDCl3): d = 25.2, 27.0, 62.3, 82.7, 85.5, 88.1, 92.0,
1
1
111.1, 113.3, 120.4 (t, JC,F = 289 Hz), 121.3 (t, JC,F = 288 Hz),
134.7, 150.0 (t, 2JC,F = 29 Hz), 146.0 (t, 2JC,F = 29 Hz), 156.7.
13C NMR (DMSO-d6): d = 63.1, 70.5, 73.0, 85.0, 88.0, 109.5, 115.0
1
1
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-4,6-bis(difluoro-
methyl)-1H-pyrazolo[3,4-d]pyrimidine (17c)
(t, JC,F = 245 Hz), 117.2 (t, JC,F = 245 Hz), 134.4, 148.1 (q,
2JC,F = 27 Hz), 150.5 (q, 2JC,F = 27 Hz), 155.5.
Prepared from 10 and 11b; yield: 691 mg (88%); yellow oil;
Rf = 0.75 (hexane–EtOAc, 1:1).
9-(4-Methoxybenzyl)-2,6-bis(trifluoromethyl)-9H-purine (20)
Following the general procedure for the preparation of 14; com-
pound 11a was reacted with the in situ generated 1920 to afford 20;
yield: 2.9 g (77%); colorless solid; mp 162–163 °C; Rf = 0.40 (hex-
ane–EtOAc, 3:1).
1H NMR (CDCl3): d = 1.38 (3 H, s, CH3), 1.68 (3 H, s, CH3), 3.77
3
3
(1 H, dd, JH,H = 11.9 Hz, JH,H = 3.7 Hz, CH), 3.83 (1 H, dd,
2JH,H = 11.9 Hz, 3JH,H = 1.3 Hz, CH), 4.51 (1 H, br s, CH), 5.04 (1
H, dd, 3JH,H = 5.9 Hz, 3JH,H = 1.4 Hz, CH), 5.22 (1 H, dd, 3JH,H = 5.9,
3
Hz, JH,H = 2.8 Hz, CH), 6.39 (1 H, br s, 5¢-OH), 6.78 (1 H, d,
1H NMR (DMSO-d6): d = 3.59 (3 H, s), 5.15 (2 H, s), 6.93 (2 H, d,
3JH,H = 2.8 Hz, CH), 6.95 (1 H, t, 2JH,F = 55 Hz, CF2H), 7.07 (1 H, t,
2JH,F = 56 Hz, CF2H), 8.41 (1 H, s, CH).
3JH,H = 7.8 Hz, CH), 7.20 (2 H, d, 3JH,H = 7.8 Hz, CH), 8.39 (1 H, s).
13C NMR (DMSO-d6): d = 54.8, 59.3, 120.1 (1JC,F = 273 Hz), 120.5
(1JC,F = 273 Hz), 122.0, 129.1, 130.7, 131.3, 131.4, 141.1 (2JC,F = 37
Hz), 147.9 (2JC,F = 37 Hz), 153.3, 155.1, 162.0.
13C NMR (CDCl3): d = 25.0, 27.0, 63.3, 82.0, 85.9, 88.8, 93.0,
1
1
111.1, 114.0, 114.2 (t, JC,F = 241 Hz), 115.1 (t, JC,F = 242 Hz),
134.6, 149.5 (q, 2JC,F = 29 Hz), 144.4 (q, 2JC,F = 27 Hz), 155.5.
MS: m/z (%) = 377 (12, [M+ + 1]), 376 (78, [M+]), 256 (37), 255
(43), 221 (11), 121 (100).
Cleavage of 2,2¢-Propylidene Protection Group; Compounds
18; General Procedure
Deprotection of Compound 20 to 2,6-Bis(trifluoromethyl)-9H-
purine (21)
The protected substrate 17 (1 mmol) was dissolved in a mixture of
CF3CO2H–H2O (9:1, 10–15 mL) and stirred vigorously for 30–40
min (controlled by TLC) at r.t. The reaction mixture was concen-
trated under reduced pressure (the mixture should not be heated
over 40 °C) and the residue was subjected to column chromatogra-
phy over silica gel.
A solution of compound 20 (5 mmol, 1.88 g) in TFA–H2O (20:1, 20
mL) was stirred for 24 h at r.t. The solvent was removed under re-
duced pressure, the formed material was kept for the next 36 h on a
vacuum line. The resulting material was purified by recrystalliza-
tion from i-PrOH; yield: 768 mg (60%); colorless solid; mp 207–
209 °C (i-PrOH).
l-(b-D-Ribofuranosyl)-4,6-bis(perfluoroethyl)-1H-pyrazolo[3,4-
d]pyrimidine (18a)
1H NMR (DMSO-d6): d = 8.41 (1 H, s), 12.01 (1 H, s, NH).
13C NMR (DMSO-d6): d = 120.1 (1JC,F = 273 Hz), 120.5
(1JC,F = 273 Hz), 131.0, 131.1, 141.0 (2JC,F = 37 Hz), 147.0
(2JC,F = 37 Hz), 152.0, 161.7.
Yield: 396 mg (81%); colorless solid; mp 73–75 °C; Rf = 0.25 (hex-
ane–EtOAc, 1:1).
1H NMR (DMSO-d6): d = 3.38 (1 H, dd, 2JH,H = 11.4 Hz, 3JH,H = 5.9
CH), 3.51 (1 H, dd, 2JH,H = 11.4 Hz, 3JH,H = 5.1 Hz, CH), 3.96 (1 H,
q, 3JH,H = 5.1 Hz, CH), 4.23 (1 H, t, 3JH,H = 4.7 Hz, CH), 4.67 (1 H,
t, 3JH,H = 5.1 Hz, CH), 6.36 (1 H, d, 3JH,H = 4.5 Hz, CH), 8.81 (1 H,
s, CH).
MS: m/z (%) = 257 (10, [M+ + 1]), 256 (100, [M+]), 255 (77).
9-(Triacetyl-b-D-ribofuranosyl)-2,6-bis(trifluoromethyl)-9H-
purine (22)
13C NMR (DMSO-d6): d = 61.4, 70.2, 73.7, 85.4, 88.6, 109.4, 111.6
The glycosylation reaction was conducted according to the proce-
dure described elsewhere.11c
1
2
1
(tq, JC,F = 215 Hz, JC,F = 38 Hz), 112.9 (tq, JC,F = 215 Hz,
2JC,F = 38 Hz), 120.4 (qt, JC,F = 285 Hz, JC,F = 38 Hz), 120.6 (qt,
1JC,F = 285 Hz, 2JC,F = 38 Hz), 133.7, 147.1 (q, 2JC,F = 29 Hz), 150.2
(q, 2JC,F = 29 Hz), 155.7.
1
2
Yield: 926 mg (90%); colorless solid; mp 98–101 °C; Rf = 0.65
(hexane–EtOAc, 1:1).
1H NMR (DMSO-d6): d = 1.97–2.10 (9 H, br s), 3.39 (1 H, m), 3.67
(1 H, m), 3.96 (1 H, q, J = 4.7 Hz), 4.39 (1 H, br s), 4.55 (1 H, d,
J = 4.7 Hz), 6.60 (1 H, d, J = 4.5 Hz), 8.34 (1 H, s),
13C NMR (DMSO-d6): d = 20.4, 20.5, 20.8, 62.9, 71.0, 72.9, 85.1,
87.0, 110.0, 120.2 (1JC,F = 273 Hz), 120.5 (1JC,F = 273 Hz), 131.4,
141.1 (2JC,F = 37 Hz), 147.2 (2JC,F = 37 Hz), 152.0, 161.7, 171.1,
171.2, 171.4.
l-(b-D-Ribofuranosyl)-4,6-bis(chlorodifluoromethyl)-1H-pyra-
zolo[3,4-d]pyrimidine (18b)
Yield: 345 mg (82%); colorless solid; mp 111–113 °C; Rf = 0.55
(EtOAc).
1H NMR (DMSO-d6): d = 3.43 (1 H, dd, 2JH,H = 11.8 Hz, 3JH,H = 5.7
CH), 3.52 (1 H, dd, 2JH,H = 11.7 Hz, 3JH,H = 5.2 Hz, CH), 3.92 (1 H,
q, 3JH,H = 5.2 Hz, CH), 4.23 (1H, t, 3JH,H = 4.7 Hz, CH), 4.61 (1 H,
t, 3JH,H = 5.2 Hz, CH), 6.30 (1 H, d, 3JH,H = 4.3 Hz, CH), 8.77 (1H,
s, CH).
Deprotection of the Acylated Nucleoside 22; 9-(b-D-Ribofurano-
syl)-2,6-bis(trifluoromethyl)-9H-purine (23)
To a solution of the acylated nucleoside 22 (1 mmol) in anhyd
MeOH (5 mL) was added dropwise a sat. solution of ammonia in
MeOH (20 mL) at 0 °C. The mixture was stirred for another 30 min
and left overnight at r.t. The solvent was removed under reduced
pressure, the formed material was kept for the next 24 h on a vacu-
um line. The resultant material formed was purified by column
chromatography on silica gel; yield: 315 mg (81%); colorless solid;
mp 142–144 °C; Rf = 0.47 (EtOAc).
13C NMR (DMSO-d6): d= 62.4, 70.5, 73.1, 85.5, 88.0, 111.1, 120.5
1
1
(t, JC,F = 287 Hz), 122.0 (t, JC,F = 287 Hz),, 133.9, 149.5 (q,
2JC,F = 28 Hz), 150.2 (q, 2JC,F = 28 Hz), 154.6.
l-(b-D-Ribofuranosyl)-4,6-bis(difluoromethyl)-1H-pyrazo-
lo[3,4-d]pyrimidine (18c)
Yield: 292 mg (83%); colorless solid; mp 120–121 °C; Rf = 0.30
(EtOAc).
Synthesis 2009, No. 23, 3967–3974 © Thieme Stuttgart · New York

3974
V. O. Iaroshenko
PAPER
1H NMR (DMSO-d6): d = 3.41 (1 H, m), 3.71 (1 H, m), 4.11 (1 H,
q, J = 4.3 Hz), 4.30 (1 H, br s), 4.39 (1 H d, J = 4.3 Hz), 5.22 (1 H,
m), 5.55 (2 H, br s), 6.53 (1 H, d, J = 5.1 Hz,), 8.31 (1H, s).
13C NMR (DMSO-d6): d = 61.0, 71.9, 75.3, 85.7, 87.1, 111.9, 120.1
(1JC,F = 273 Hz), 120.4 (1JC,F = 273 Hz), 131.5, 141.1 (2JC,F = 37
Hz), 146.4 (2JC,F = 37 Hz), 153.5, 161.0.
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(11) (a) 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. (b) Iaroshenko, V.
O.; Sevenard, D. V.; Kotljarov, A. V.; Volochnyuk, D. M.;
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731. (c) Iaroshenko, V. O.; Wang, Y.; Sevenard, D. V.;
Volochnyuk, D. M. Synthesis 2009, 1851.
Acknowledgment
The authors acknowledge Prof. V. Ya. Sosnovskikh (Ural State
University, Russia), Dr. D. V. Sevenard (Hansa Fine Chemicals
GmbH, Bremen, Germany), and Dr. D. Volochnyuk (Enamine Ltd.
Ukraine) for the discussion of the obtained results, and for the help
during the preparation of the manuscript.
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Synthesis 2009, No. 23, 3967–3974 © Thieme Stuttgart · New York