Synthesis of new fluorine containing triazolo- and tetrazolopyrimidines

Article abstract of DOI:10.1055/s-2002-28512

The reaction of 1,1,1-trifluoro-4-(sulfonyl)-but-3-ene-2,2-dioles 1a,b with corresponding aminoazoles was investigated. A new simple and efficient way for the regioselective synthesis of 5-CF₃ or 7-CF₃ triazolo- and tetrazolopyrimidines is described.

Full text of DOI:10.1055/s-2002-28512

PAPER
901
Synthesis of New Fluorine Containing Triazolo- and Tetrazolopyrimidines
Synthesis of
N
ew F
r
luorine
c
Containing
a
Triazolo-
a
d
nd Tetrazolo
y
pyrimidine
s
L. Krasovsky, Andrew M. Moiseev, Valentine G. Nenajdenko,* Elizabeth S. Balenkova
Department of Chemistry, Moscow State University, 119899 Moscow, Russia
Fax +7(095)9328846; E-mail: Nen@acylium.chem.msu.su
Received 5 February 2002
ridines,20 pyrazolo[1,5-a]pyrimidines,21 6,7-dihydro-5H-
1,3,4-thiadiazolo[3,2-a]pyrimidines,22 and 6,7-dihydro-
5H-thiazolo[3,2-a]pyrimidines23 by the reaction of sul-
fones 1a,b with various aminoheterocycles. It was there-
fore considered that the reaction of diols 1a,b with 3-
amino-1,2,4-triazoles and 5-aminotetrazole might result
in improved regioselectivity yielding only one regioiso-
mer under a particular reaction condition.
Abstract: The reaction of 1,1,1-trifluoro-4-(sulfonyl)-but-3-ene-
2,2-dioles 1a,b with corresponding aminoazoles was investigated.
A new simple and efficient way for the regioselective synthesis of
5-CF3 or 7-CF3 triazolo- and tetrazolopyrimidines is described.
Key words: cycloaddition, heterocycles, triazolopyrimidine, tetra-
zolopyrimidine, sulfones
Treatment of 1a,b with different 3-amino-1,2,4-triazoles
and 5-aminotetrazole in acetic acid at reflux gave a mix-
ture of cycloadducts 2a k and 3a k in 70 90% isolated
yields (Scheme 1, Table 1). It is worth mentioning, that in
water, under reflux, no significant difference of the ratio
of regioisomer was observed. The reaction of 1a,b with
aminotriazoles at room temperature afforded only 5%
conversion after 10 days. It should be noted that the yields
and ratio of 5- and 7-CF3 substituted azolopyrimdines do
not depend significantly on reagents 1a or 1b. Moreover,
the reaction with triazoles bearing both aliphatic and aro-
matic substituents as a rule gives a mixture of isomeric
azolopyrimdines. Only in the case of aryltriazoles f h the
highly regioselectively formation of 7-CF3 azolopyrim-
dines is observed.
Fluorine containing heterocyclic compounds are a subject
of continuous interest1,2 due to their potent pharmacolog-
ical properties. Some fluorinated pyrimidines were clini-
cally evaluated as valuable anticancer agents.3 It is known
that incorporation of a fluorine atom or CF3- group into
bioactive molecule leads to increased lipid solubility and
thereby enhances the rate of absorption and transport of
that substance in vivo.1Also, many triazolopyrimidines
have shown significant herbicidal,4 fungicidal5 activity
and are well-known as new cardiovascular agents6. The
reported methods for the synthesis of substituted azolopy-
rimidines usually involves cyclocondensation of
aminotriazoles5 12 or aminoterazoles8,13 with three carbon
1,3-electrophilic fragments.14 A drawback of these ap-
proaches is the formation of the mixture of isomers from
the reaction of non-symmetrical systems with aminoa-
zoles.4,12 Paudler at al. obtained mixtures when treating
triazolopyrimidine with phenyllithium.15 Novel methods
for the construction of the triazolopyrimidines nucleus in-
volving reactions of vinylogous iminium salts and related
analogs with 3-amino-1,2,4-triazoles have been reported
last year.16 An alternative synthetic route to different tria-
zolopyrimidines is the reaction of 2-hydrazinopyrimidine
with acylating agents and also the Dimroth-like rearrange-
ment of triazolo[4,3-a]pyrimidines to triazolo[1,5-a]pyri-
midines in acid or alkali.5,17
Scheme 1
Nevertheless, simple modification of reaction conditions
allowed us to obtain 5-CF3 triazolo[1,5-a]pyrimidines 2 as
a pure regioisomer. We have observed that the reaction of
sulfones 1a,b with 3-amino-1,2,4-triazoles in acetonitrile
at room temperature yields exclusively the 5-CF3 isomer
of tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine (4). Com-
pound 4 precipitated from the reaction mixture. None of
the isomeric 7-CF3 isomer could be detected in the reac-
tion. Moreover, this reaction proceeds stereoselectively to
give 2, the only diastereomer of triazolo[1,5-a]pyrim-
idines having diaxially oriented sulfonyl and hydroxyl
groups. Earlier, we observed the same arrangement of
these groups in analogous tetrahydropyrimidines
system22,23 and have confirmed this by X-ray crystallogra-
phy.22 We presume that, it is connected with the formation
Thus, there is a limited amount of the regiospecific syn-
thesis of 7- and 5-substituted azolopyrimidines.7,16 There
is a definite need to develop new methods for the re-
giospecific synthesis of this class of compounds.
In recent work, we have prepared some -trifluoro-
acetylvinylsulfones.18 We have found that alkenes 1a,b
are very reactive electrophiles, reacting with heteroarenes
such as pyrrole, indole and furan.19 Also, we have recently
described a new simple and efficient way for the regiospe-
cific formation of CF3-containing imidazo[1,2-a]py-
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
1437-210X,E;2002,0,07,0901,0905,ftx,en;P00302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

902
A. L. Krasovsky et al.
PAPER
Table 1 Yields and Regioisomeric Ratio of Cycloadducts 2 and 3
Table 2 Yields of Cycloadducts 4, and 2 Obtained by Method C
X
Entry Method from 1a
2:3 a
from 1b
Yield 2:3 a
X
from 1a
from 1b
entry
Yield %
85
entry
Yield %
86
Yield
%
%
HC
4a
4c
2a
2d
2e
2f
4b
4d
2a
2d
2e
2f
HC
a
A
B
B
B
B
B
B
B
B
B
B
B
100:10 83
100:15 86
88:100 80
28:100 74
10:100 78
15:100 76
100:44 80
PhC
88
90
100:50 82
95:100 75
59:100 70
38:100 74
44:100 76
24:100 78
HC
70
65
MeC
b
c
d
e
f
(1-Ad)C
t-BuC
68
72
CF3C
64
66
(1-Ad)C
t-BuC
PhC
75
70
2,4-Cl2C6H3C
2-BrC6H4C
2m
2i
61
2m
2i
63
PhC
5:100
0:100
2:100
83
70
93
65
66
4-MeOC6H4C
4-ClC6H4C
2-BrC6H4C
MeOOCC
N
g
h
i
3:100
72
est in this class of compounds.9 In the reaction of the
sulfones 1a,b with 3-amino-1H-1,2,4-triazole-5-carbox-
ylic acid in acetic acid under reflux, a mixture of triazol-
opyrimidines 2a,3a was obtained in good yield instead of
the expected product. Moreover, the ratio of isomers
2a:3a is the same as for the reaction with unsubstituted 3-
amino-1,2,4-triazole. We believe that decarboxylation of
3-amino-1H-1,2,4-triazole-5-carboxylic acid precedes the
step of heterocyclization. To avoid decarboxylation, we
performed the reaction of 1a,b with the corresponding es-
ter of [1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid.
Initially formed cycloadducts 2j,3j can be smoothly con-
verted to [1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic
acid 2l,3l (Scheme 3) by hydrolysis with lithium hydrox-
ide in methanol (method D). Alternatively, carboxylic
acid 2l can be prepared by the reaction of sulfones 1a,b
with the 3-amino-1H-1,2,4-triazole-5-carboxylic acid in
water at reflux (method A).
13:100 90
37:100 76
100:23 86
16:100 72
19:100 81
j
100:7
3:100
87
72
k
a Structure and ratios of products were determined by 1H NMR
of intramolecular hydrogen bond between sulfonyl and
hydroxyl group in 4.
Further aromatization of 4 at reflux in acetic acid provides
5-CF3 triazolo[1,5-a]pyrimidines 2 as one regioisomer
quantitatively. We have also investigated one-pot synthe-
sis of 5-CF3 triazolo[1,5-a]pyrimidines 2 in acetonitrile at
reflux (method C, Scheme 2, Table 2). This approach pro-
vides a simple way to obtain 5-CF3 triazolo[1,5-a]pyrim-
idines. We reason that, in this case the reaction is
autocatalyzed by the eliminated sulfinic acid. In spite of
slighly lower yields, the one-pot technique is attractive
due to its simplicity.
Scheme 3
Scheme 2
The regiochemistry of 5- and 7-CF3 substituted com-
pounds 2,3 can be established by 1H NMR spectroscopy.
Introduction of a polar group, such as the carboxylic acid,
at position 2 of triazolopyrimidines resulted in a greater
solubility of new potential biologically active CF3- con-
taining azolopyrimdines and therefore has increased inter-
The cycloadducts having 5-CF3-substitution have J3
HH
6.9 7.3 Hz, while those with a 7-CF3-substitution have
J3HH 4.2 4.8 Hz. (Scheme 4).7,17
Synthesis 2002, No. 7, 901–905 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of New Fluorine Containing Triazolo- and Tetrazolopyrimidines
903
precipitate of 2l was filtered, washed by H2O (2 5 mL) and air
dried. Yield 53%.
Method D: 1. As the common technique. 2. To a solution of methyl
[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (2j, 0.5 mmol) in
MeOH (5 mL) the solution of LiOH (1.1 equiv) in MeOH was add-
ed. The mixture was stirred at r.t. for 24 h. Removal of the solvent
under reduced pressure afforded products, which was dissloved in
H2O (5 mL) and the pH adjusted to 2.0 with HCl (10%). The white
precipitate of 2l was filtered, washed by H2O (2 5 mL) and dried
on air; yield 71%; white solid; mp 120 123 °C.
Scheme 4
Two types of heterocyclization in reactions of 1,3-bielec-
trophiles with aminotriazoles to form triazolo[1,5-a]pyri-
midines or triazolo[4,3-a]pyrimidines system are
described in literature. Calculations of total energy of ba-
sic states showed that triazolo[1,5-a]pyrimidines are more
stable than isomeric triazolo[4,3-a]pyrimidines.24
Kawase25 and Bouillon26 showed NH2-4-N ring atom cy-
clization with the formation of [1,2,4]triazolo[4,3-a]pyri-
midine ring by only an NOE experiment25 or by
questionable comparison of UV-VIS and 13C NMR data.
Others attribute the formation of [1,2,4]triazolo[1,5-a]py-
rimidine in the reaction of 1,2,4-triazol-3-amines to 1,3-
1
IR: 1770 cm .
1H NMR (400 MHz, CDCl3): = 7.78 (1 H, d, CH-6, J = 7.1 Hz),
9.24 (1 H, d, CH-7, J = 7.1 Hz).
13C NMR (100 MHz, DCl3) = 110.5, 128.9 (q, J = 277.0 Hz, CF3),
142.3, 153.7, 156.5, 158.3, 159.9 (q, J = 40, 1 Hz, C-CF3).
Anal. Calcd for C14H13F3O3S: C, 36.22; H, 1.30. Found: C, 36.11;
H, 1.19.
4,5,6,7-Tetrahydro[1,2,4]triazolo[1,5-a]pyrimidines (4)
To a solution of vinylsulfone 1a,b (1 mmol) in CH3CN (7 mL) the
corresponding aminoazoles (1.1 mmol) was added. The mixture
was stirred for 12 h at r.t. The precipitate was filtered, washed by
bielectrophiles and some authentic X-ray diffraction CH3CN (2 3 mL) and dried on air.
analysis12 or by independent synthesis.7,8b,16 In order to
7-(Phenylsulfonyl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-
[1,2,4]triazolo[1,5-a]pyrimidin-5-ol (4a)
White solid; mp 136 138 °C.
confirm the formation of the pair of 2,3 isomers instead of
isomers of 5, we performed an NOE experiment for the
mixture of 2b:3b (95:100) isomers and have not observed
this effect in both isomers. Therefore, at least in our case,
the formation of triazolo[1,5-a]pyrimidines system takes
place.
1
IR: 2920, 1374 cm .
1H NMR (400 MHz, CDCl3): = 2.29 (1 H, dd, CH-6, J = 12.4, 13.5
Hz), 2.63 (1 H, dd, CH-6, J = 4.8, 13.5 Hz), 5.62 (1 H, dd, CH-7,
J = 4.8, 12.4 Hz), 7.40 (1 H, m, Ph), 7.70 (2 H, m, Ph), 7.79 (2 H,
m, Ph), 9.02 (1 H, br s, CH-2).
13C NMR (100 MHz, CDCl3): 26.7, 67.8, 79.5 (COH, J = 41.2 Hz),
123.7 (CF3, J = 285.8 Hz), 129.7, 132.0, 133.0, 140.6, 150.6, 152.3.
In summary, the reaction of 1,1,1-trifluoro-4-(sulfonyl)-
but-3-ene-2,2-dioles 1a,b with 3-amino-1,2,4-triazoles
and 5-aminotetrazole was investigated. The reaction in
acetic acid leads to the mixture of 5- and 7-CF3- isomers.
We have developed a novel regiospecific technique with
simple experimental layout which allows for the prepara-
tion of pure 5-CF3-azolo[1,2-a]pyrimidines in high yields.
Anal. Calcd for C12H11F3N4O3S: C, 41.38; H, 3.18. Found: C, 41.21;
H, 3.19.
7-(Methylsulfonyl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-
[1,2,4]triazolo[1,5-a]pyrimidin-5-ol (4b)
White solid; mp 151 153 °C.
Melting points were determined in sealed capillaries and are uncor-
rected. NMR spectra were recorded on Varian VXR-400 spectrom-
eter with TMS as an internal standard. The IR spectra were obtained
with UR-20 spectrometer as films. Column chromatography was
performed on silica gel (63 200 mesh, Merck). All solvents used
were dried and distilled according to standard procedures. Silica gel
Merck 60 and Merck 60F254 plates were used for conventional and
analytical (TLC) chromatography, respectively.
1
IR: 2924, 1382 cm .
1H NMR (400 MHz, CDCl3): = 2.10 (1 H, m, CH-6), 2.67 (1 H,
m, CH-6), 3.34 (3 H, s, CH3), 5.90 (1 H, br t, CH-7, J = 6.7 Hz), 9.0
(1 H, br s, CH-2).
13C NMR (100 MHz, DCl3): = 26.4, 41.2, 67.7, 79.1 (COH,
J = 41.4 Hz), 124.0 (CF3, J = 286.0 Hz), 150.6, 152.3.
Anal. Calcd for C79F3N4O3S: C, 29.37; H, 3.17. Found: C, 29.29; H,
3.12.
Azolopyrimidines 2,3; General Procedure
To a solution of vinylsulfone 1a,b (1 mmol) in H2O (10 mL) (meth-
od A), in AcOH (5 mL) (method B) or in CH3CN (method C) the
corresponding aminoazole (1.1 mmol) was added. The mixture was
stirred at reflux at the appropriate time. Removal of the solvent un-
der reduced pressure afforded products, which were purified by col-
umn chromatography over silica gel using CH2Cl2 as eluent.
2-Phenyl-7-(phenylsulfonyl)-5-(trifluoromethyl)-4,5,6,7-tetra-
hydro[1,2,4] triazolo[1,5-a]pyrimidin-5-ol (4c)
White solid; mp 177 179 °C.
1
IR: 2921, 1373 cm .
1H NMR (400 MHz, CDCl3): = 2.24 (1 H, dd, CH-6, J = 12.4, 13.4
Hz), 2.60 (1 H, dd, CH-6, J = 4.8, 13.4 Hz), 5.60 (1 H, dd, CH-7,
J = 4.8, 12.4 Hz), 7.40 (2 H, m, Ph), 7.48 (2 H, m, Ph), 7.70 (3 H,
m, Ph), 7.79 (3 H, m, Ph), 9.11 (1 H, br s, CH-2).
13C NMR (100 MHz, CDCl3): = 26.9, 67.7, 79.0 (COH, J = 41.3
Hz), 124.0 (CF3, J = 284.1 Hz), 129.5, 132.1, 133.0, 133.6, 137.8,
140.1, 140.6, 142.4, 150.6, 152.3.
5-(Trifluoromethyl) [1,2,4]triazolo[1,5-a]pyrimidine-2-carbox-
ylic acid (2l)
Method A: To a solution of vinylsulfone 1a,b (1 mmol) in H2O (25
mL) the 3-amino-1H-1,2,4-triazole-5-carboxylic acid (1.1 mmol)
was added. The mixture was stirred for 10 h at reflux. The solution
was cooled and the pH adjusted to 2.0 with HCl (10%). The white
Synthesis 2002, No. 7, 901–905 ISSN 0039-7881 © Thieme Stuttgart · New York

904
A. L. Krasovsky et al.
PAPER
Table 3 Spectroscopic Data
1H NMR (DMSO-d6/TMS) , J (Hz)
13C NMR (DMSO-d6/TMS) , J (Hz)
Mp, °C
2a: 7.48 (d, 1 H, J = 7.1 Hz, CH-6), 8.67 (s, 1 H, CH-8), 9.11 (d, Major isomer 2a: 105.5, 119.8 (q, J = 277.1 Hz, CF3), 138.8, 128–130
1 H, J = 7.1 Hz, CH-7)
150.5 (q, J = 37.0 Hz, C-CF3), 154.5, 156.8
3a: 7.48 (d, 1 H, J = 4.3 Hz, CH-6), 8.66 (s, 1 H, CH-8), 9.01 (d,
1 H, J = 4.3 Hz, CH-5)
2b: 2.60 (s, 3 H, CH3), 7.51 (d, 1 H, J = 7.1 Hz, CH-6), 9.15 (d, 2b: 15.2, 107.5, 120.2 (q, J = 277.9 Hz, CF3), 139.4, 155.8 (q, 142–144
1 H, J = 7.1 Hz, CH-7) J = 38.3 Hz, C-CF3), 140.4, 156.5
3b: 2.60 (s, 3 H, CH3), 7.54 (d, 1 H, J = 4.2 Hz, CH-6), 8.91 (d, 3b: 15.3, 110.0, 123.8 (q, J = 276.7 Hz, CF3), 149.4 (q,
1 H, J = 4.2 Hz, CH-5)
J = 37.7 Hz, CCF3), 150.8, 154.8, 169.0
2c: 7.80 (d, 1 H, J = 7.2 Hz, CH-6), 9.39 (d, 1 H, J = 7.2 Hz,
CH-7)
3c: 7.84 (d, 1 H, J = 4.5 Hz, CH-6), 9.18 (d, 1 H, J = 4.5 Hz,
Major isomer 3c: 110.6, 120.0 (q, J = 274.8 Hz, CF3), 121.4
(q, J = 277.2 Hz, CF3), 142.9 (q, J = 37.2 Hz, C-CF3), 151.0,
151.4 (q, J = 38.0 Hz, C-CF3), 154.4
84–86
CH-5)
2d: 1.65 2.18 (m, 15 H, Ad), 7.53 (d, 1 H, J = 7.1 Hz, CH-6),
9.21 (d, 1 H, J = 7.1 Hz, CH-7)
3d: 1.65 2.18 (m, 15 H, Ad), 7.55 (d, 1 H, J = 4.3 Hz, CH-6),
8.92 (d, 1 H, J = 4.3 Hz, CH-5)
Major isomer 3d: 20.7, 29.1, 37.1, 41.8, 109.8, 120.8 (q,
J = 277.7 Hz, CF3), 140.1, 149.1 (q, J = 38.5 Hz, C-CF3),
156.4, 175.3
101–103
113–115
180–182
2e: 1.46 (s, 9 H, 3 CH3), 7.51 (d, 1 H, J = 7.1 Hz, CH-6), 9.16 (d, Major isomer 3e: 29.7, 35.7, 109.6, 121.2 (q, J = 277.0 Hz,
1 H, J = 7.1 Hz, CH-7)
3e: 1.46 (s, 9 H, 3 CH3), 7.53 (d, 1H, J = 4.4 Hz, CH-6), 8.91 (d,
1 H, J = 4.4 Hz, CH-5)
CF3), 140.0, 149.3 (q, J = 37.9 Hz, C-CF3), 154.6, 178.1
2f: 7.54 7.58 (m, 4 H, Ar + CH-6), 8.30 8.33 (m, 2 H, Ar), 9.24 2f: 113.0, 120.2 (q, J = 277.8 Hz, CF3), 130.5, 130.9, 135.1,
(d, 1 H, J = 7.1 Hz, CH-7)
3f: 7.54 7.58 (m, 3 H, Ar), 7.60 (d, 1 H, J = 4.3 Hz, CH-6),
8.30 8.33 (m, 2 H, Ar), 8.98 (d, 1 H, J = 4.3 Hz, CH-5)
135.9, 150.4, 157.9, 164.0 (q, J = 40.0 Hz, C-CF3), 170.1
3f: 110.7, 118.9 (q, J = 276.6 Hz, CF3), 129.0, 130.7, 133.0,
135.8, 150.2, 157.2, 159.4 (q, J = 39.5 Hz, C-CF3), 172.8
2g: 3.85 (s, 3 H, CH3), 6.95 (d, 2 H, Ar), 7.54 (d, 1 H, J = 7.0 Hz, Major isomer 3g: 56.46, 111.2, 116.7, 118.8 (q, J = 280.1 Hz, 195–197
CH-6), 7.94 (d, 2 H, Ar), 9.18 (d, 1 H, J = 7.0 Hz, CH-7) CF3), 129.0, 130.0, 157.6, 158.0, 159.6 (q, J = 41.0 Hz, C-
3g: 3.83 (s, 3 H, CH3), 7.05 (d, 2 H, Ar), 7.56 (d, 1 H, J = 4.4 Hz, CF3), 164.5, 175.7
CH-6), 8.21 (d, 2 H, Ar), 8.91 (d, 1 H, J = 4.4 Hz, CH-5)
2h: 7.55 (d, 2 H, Ar), 7.58 (d, 1 H, J = 6.9 Hz, CH-6), 7.96 (d, 2 Major isomer 3h: 111.0, 118.9 (q, J = 277.4 Hz, CF3), 129.4, 168–170
H, Ar), 9.23 (d, 1 H, J = 6.9 Hz, CH-7)
132.3, 132.8, 135.6, 154.2, 156.6, 159.1 (q, J = 39.7 Hz, C-
3h: 7.55 (d, 2 H Ar), 7.61 (d, 1 H, J = 4.3 Hz, CH-6), 8.27 (d, 2 CF3), 170.8
H, Ar), 8.98 (d, 1 H, J = 4.3 Hz, CH-5)
2i: 7.43 (m, 1 H, Ar), 7.53 (m, 1 H, Ar), 7.62 (d, J = 7.0 Hz, CH- Major isomer 3i: 110.1, 120.8 (q, J = 275.2 Hz, CF3), 129.5,
6), 7.80 (m, 1 H, Ar), 7.96 (m, 1 H, Ar), 9.29 (d, 1 H, J = 7.0 Hz, 130.3, 132.9, 133.5, 134.0, 135.9, 141.0, 157.3, 160.2 (q,
123–125
CH-7)
J = 39.9 Hz, C-CF3), 173.7
3i: 7.43 (m, 1 H, Ar), 7.53 (m, 1 H, Ar), 7.64 (d, J = 4.3 Hz, CH-
6), 7.80 (m, 1 H, Ar), 7.96 (m, 1 H, Ar), 9.02 (d, 1 H, J = 4.3 Hz,
CH-5)
2j: 4.00 (s, 3 H, CH3), 7.73 (d, 1 H, J = 7.1 Hz, CH-6), 9.36 (d, 1 Major isomer 2j: 54.0, 109.9, 129.7 (q, J = 276.1 Hz, CF3),
170–171
120–122
H, J = 7.1 Hz, CH-7)
142.2, 154.9, 156.2, 158.8, 161.3 (q, J = 40.4 Hz, C-CF3)
3j: 4.00 (s, 3 H, CH3), 7.77 (d, 1 H, J = 4.4 Hz, CH-6), 9.11 (d, 1
H, J = 4.4 Hz, CH-5)
2k: 7.66 (d, 1 H, J = 7.3 Hz, CH-6), 9.43 (d, 1 H, J = 7.3 Hz,
CH-7)
Major isomer 3k: 108.7, 121.2 (q, J = 277.0 Hz, CF3), 156.2
(q, J = 39.9 Hz, C-CF3), 156.2, 162.7
3k: 7.42 (d, 1 H, J = 4.8 Hz, CH-6), 8.81 (d, 1 H, J = 4.8 Hz,
CH-5)
2m:b 7.48 (d, 2 H, Ar), 7.63 (d, 2 H, Ar), 7.82 (d, 1 H, J = 6.9 Hz, 2m: 109.6, 114.3 (q, J = 283.3 Hz, CF3), 120.7, 123.7, 128.1, 160–162
CH-6), 7.84 (d, 2 H, Ar), 9.40 (d, 1 H, J = 6.9 Hz, CH-7)
131.2, 132.9, 134.4, 139.5, 151.7, 155.3 (q, J = 39.7 Hz, C-
CF3), 162.4
a Satisfactory microanalyses were obtained: C 0.28, H 0.25.
b In CDCl3/CF3COOH.
Synthesis 2002, No. 7, 901–905 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of New Fluorine Containing Triazolo- and Tetrazolopyrimidines
905
Anal. Calcd for C18H15F3N4O3S: C, 50.94; H, 3.56. Found: C, 51.03;
H, 3.49.
(5) Popova, L. M.; Trishina, A. U.; Vershilov, S. V.; Ginak, A.
L.; Maksimov, B. N. J. Fluorine Chem 1999, 96, 51.
(6) Novinson, T.; Springer, R. H.; O' Brien, D. E.; Scholten, M.
B.; Miller, J. P.; Robins, R. K. J. Med. Chem. 1982, 25, 420;
and references therein.
(7) Monte, W. T.; Kleschick, W. A.; Meikle, R. W.; Snider, S.
W.; Bordner, J. J. Heterocycl. Chem. 1989, 26, 1393.
(8) (a) Allen, C. F. H.; Beilfuss, H. R.; Burness, D. M.;
Reynolds, G. A.; Tinker, J. F.; Van Allan, J. A. J. Org.
Chem. 1959, 24, 796. (b) Bajwa, J. S.; Sykes, P. J. J. Chem.
Soc., Perkin Trans. I 1979, 3085.
(9) Okabe, T.; Bhooshan, B.; Novinson, T.; Hillyard, I. W.;
Garner, G. E.; Robins, R. K. J. Heterocycl. Chem. 1983, 20,
735.
(10) Chambers, V. C. J. Am. Chem. Soc. 1960, 82, 605.
(11) Hori, M.; Tanaka, K.; Kataoka, T.; Shimizu, H.; Imai, E.;
Kimura, K.; Hashimoto, Y. J. Chem. Soc., Perkin Trans. I
1985, 2333.
2-Phenyl-7-(methylsulfonyl)-5-(trifluoromethyl)-4,5,6,7-tetra-
hydro[1,2,4] triazolo[1,5-a]pyrimidin-5-ol (4d)
White solid; mp 184 186 °C.
1
IR: 2926, 1384 cm .
1H NMR (400 MHz, CDCl3): = 2.18 (1 H, dd, CH-6, J = 12.6, 13.3
Hz), 2.67 (1 H, dd, CH-6, J = 4.6, 13.3 Hz), 3.32 (3 H, s, CH3), 5.90
(1 H, dd, CH-7, J = 4.6, 12.6 Hz), 7.46 (2 H, m, Ph), 7.69 (1 H, m,
Ph), 7.80 (2 H, m, Ph), 9.08 (1 H, br s, CH-2).
13C NMR (100 MHz, DCl3): = 26.6, 41.4, 67.7, 80.1 (C-OH,
J = 41.0 Hz), 124.2 (CF3, J = 286.6 Hz), 133.7, 140.4, 140.8, 142.8,
150.6, 152.3.
Anal. Calcd for C7H9F3N4O3S: C, 29.37; H, 3.17. Found: C, 29.29;
H, 3.12.
(12) Kleschick, W. A.; Bordner, J. J. Heterocycl. Chem. 1989, 26,
1489.
Azolopyrimidines 2 from 4; General Procedure
The corresponding 4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimi-
dine 4 (0.5 mmol) was dissolved in HOAc (10 mL). The mixture
was stirred for 1 h under reflux. The solvent was evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy over silica gel using CH2Cl2 as eluent; yield 95 98%.
(13) (a) Buelow, C. Chem. Ber. 1909, 42, 4429.
(b) Bachkovskij, I. P.; Chuiguk, V. A. Ykr. Khim. Z. 1987,
53, 319. (c) Bajwa, J. S.; Sykes, P. J. J. Chem. Soc., Perkin
Trans. I 1980, 1019. (d) Russ, T.; Bats, J. W.; Ried, W.
Synthesis 1990, 721.
(14) (a) Mosby, W. L. In Heterocyclic Systems with Bridgehead
Nitrogen Atoms; Wiley-Interscience: New York, 1961.
(b) Wiessberger, A.; Taylor, E. C. In Special Topics in
Heterocyclic Chemistry; Wiley-Interscience: New York,
1977.
Acknowledgement
Financial support from Russian Fundamental Investigation Found-
ation (Grants 00-03-32763a and 00-03-32760) is gratefully ack-
nowledged.
(15) Paudler, W.; Chao, C.; Helmick, L. J. Heterocycl. Chem
1972, 1157.
(16) Petrich, S. A.; Qian, Z.; Santiago, L. M.; Gupton, J. T.;
Sikorski, J. A. Tetrahedron 1994, 50, 12113.
(17) Brown, D. J.; Nagamatsu, T. Aust. J. Chem. 1977, 30, 2515.
(18) Krasovsky, A. L.; Nenajdenko, V. G.; Balenkova, E. S.
Tetrahedron 2001, 1, 1349.
(19) Nenajdenko, V. G.; Krasovsky, A. L.; Lebedev, M. L.;
Balenkova, E. S. Synlett 1997, 1349.
(20) Krasovsky, A. L.; Nenajdenko, V. G.; Balenkova, E. S.
Synthesis 2002, in press.
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Synthesis 2002, No. 7, 901–905 ISSN 0039-7881 © Thieme Stuttgart · New York