Cyclization of bifunctional 3,5-diamino-1H-1,2,4-triazole-1- carboximidamide, 5-amino-3-hydrazinotriazole and 3,6-diguanidino-1,2,4,5- tetrazine: A one-step route to fluorinated heteropolycycles

Article abstract of DOI:10.1055/s-2008-1067047

A series of new fluorine-containing triazolylpyrimidines and pyrimidinoaminotetrazines results from one-pot reactions of 3,5-diamino- 1H-1,2,4-triazole-1-carboximidamide hydrochloride and l,4-diguanidino-2,3,4,5- tetrazine with fluoro-l,3-diketones. Bicyclization of a variety of fluorinated 1,3-diketones gave three fluorinated heterocyclic pyrazolo[l,2,4]triazolo[l,5-a] pyrimidines in moderate yield in a single step.

Full text of DOI:10.1055/s-2008-1067047

PAPER
1775
Cyclization of Bifunctional 3,5-Diamino-1H-1,2,4-triazole-1-carboximid-
amide, 5-Amino-3-hydrazinotriazole and 3,6-Diguanidino-1,2,4,5-tetrazine:
A One-Step Route to Fluorinated Heteropolycycles
A
O
ne-Step Rou
h
te to Fluorin
u
a
ted Hetero
o
Department of Chemistry, University of Idaho, Moscow, ID 83844-2343, USA
E-mail: jshreeve@uidaho.edu
Received 5 February 2008; revised 28 February 2008
triazolo[1,5-a]pyrimidine, a subtype of a purine bio-
Abstract: A series of new fluorine-containing triazolylpyrimidines
and pyrimidinoaminotetrazines results from one-pot reactions of
3,5-diamino-1H-1,2,4-triazole-1-carboximidamide hydrochloride
and 1,4-diguanidino-2,3,4,5-tetrazine with fluoro-1,3-diketones.
isosteric analogue, is reported to be useful in controlling
noxious fungi, and to be a potent and selective A2A ade-
nosine receptor antagonist, in addition to possessing po-
Bicyclization of a variety of fluorinated 1,3-diketones gave three tential anti-tumor activities (Figure 1).5 The properties of
fluorinated heterocyclic pyrazolo[1,2,4]triazolo[1,5-a]pyrimidines
in moderate yield in a single step.
1,2,4-triazole–iridium complexes, such as flexibility,
make them well-suited for organic light-emitting materi-
als and devices.6 The tricyclic heterocyclic tetrazine com-
Key words: cyclization, bifunctional heterocycles, fluorinated
polyheterocycles, triazolylpyrimidines, pyrazolo[1,2,4]triazo-
lo[1,5-a]pyrimidines
pound shown in Figure 1 has also been shown to retard the
ripening or senescence of fruit or other plants.7
Previously, a bicyclic triazolopyrimidine was prepared by
condensation of 3-amino-1,2,4-triazole or 3-amino-5-
It is well-known that introduction of a fluorine atom or a
fluoroalkyl group into heterocyclic compounds has a pro-
benzylthio-1,2,4-triazole and dicarbonyl compounds,8 or
by a multiple-step process.9 However, the efficient syn-
theses of fluorinated bicyclic or polycyclic triazolo-
found influence on their chemical, physical and biological
properties.1 Fluorinated heterocycles are widely recog-
aminopyrimidine,
pyrazolo-triazolopyrimidine,
or
nized as important species in the development of new
pharmaceuticals and agrochemicals.2 In the formation of
these heterocyclic compounds, cyclic addition reactions
have been mainly applied to the synthesis of fluorinated
five-membered heterocyclic rings, such as furan, pyra-
zole, isoxazole, 1,2,3-triazole, and six-membered hetero-
cyclic rings, such as pyrimidine, quinoline and pyridine.3
It is worthwhile developing new fluorinated heterocyclic
rings which may have advantageous properties. Fluorinat-
ed heteropolycyclic systems are among some new fluori-
nated heterocyclic rings that are currently attracting
attention.4 For example, the bicyclic heterocycle, 1,2,4-
pyrimidinotetrazine compounds have not been reported.
Our efforts have been directed toward the development of
new synthetic methodologies for the successful prepara-
tion of fluorinated heterocyclic compounds as bioactive
molecules as well as nitrogen-rich energetic materials.10 A
large number of fluorinated pyrazole, triazole and tetra-
zole quaternary salts are ionic liquids.11
While
3,5-diamino-1H-1,2,4-triazole-1-carboximid-
amide,12 5-amino-3-hydrazino-1,2,4-triazole13 and 1,4-
diguanidino-2,3,4,5-tetrazine14 are bifunctional heteronu-
cleophiles (Scheme 1), there appears to be no reports of
F
N
SO2NH2
N
HN
N
F
Ir
2
N
N
N
N
N
N
N
N
N
N
N
Cl
MeO
N
N
[1,2,4]triazolo[1,5-a]pyrimidine
as anticancer agenta
organic light-emitting materials
1,2,4-triazole iridium complexb
tetrazine retards ripening of
fruit and plantsc
a Ref. 5, b Ref. 6, c Ref. 7
Figure 1 Triazole and tetrazine heterocycles
SYNTHESIS 2008, No. 11, pp 1775–1782
x
x.
x
x
.
2
0
0
8
Advanced online publication: 29.04.2008
DOI: 10.1055/s-2008-1067047; Art ID: M00708SS
© Georg Thieme Verlag Stuttgart · New York

1776
Z. Zeng et al.
PAPER
NH2
N
NH2
N
N
N
.
HCl
H2N
H2N
H2N
HN
N
N
Cl
NH2
NH2
NHNH2
N
N
NCNH2
HCl
NH2
NaNO2, HCl
SnCl2, HCl
N
N
.
2HCl
NH
H2N
H2N
H
N
H
N
H
N
NH2
N
×
N.
HCl
H2N
N
H
Me
N
NH
NH
NH
N
N
N
N
N
N
H2N
NH2
N
H
Me
H2N
NH
N
NH2
N
N
Me
N
N
Me
Scheme 1 Synthesis of bifunctional heterocyclic nucleophiles
cyclization reactions of such materials to yield fluorinated the 3,5-diamino-1H-1,2,4-triazole-1-carboximidamide.17
heteropolycyclic compounds. Therefore, we now report Cyclization of 1 with fluorine-containing 1,3-diketones
the facile and straightforward syntheses of fluorinated tri- 2a–c (1:1), in acetic acid at 110 °C for 24 hours, generated
azolylaminopyrimidine, pyrazolo-triazolopyrimidine, and the fluorinated triazolylaminopyrimidines 3a–c in high
pyrimidino(amino)tetrazine heteropolycycles by cycliz- yields (Scheme 2). An attempt to form the bicyclic prod-
ing 3,5-diamino-1H-1,2,4-triazole-1-carboximidamide, uct, 4,6-bis(trifluoromethyl)-2-(1,2,4-triazolo[1,5-a]pyri-
5-amino-3-hydrazino-1,2,4-triazole, and 1,4-diguanidino- midin-5-ylamino)pyrimidine, by treating 3a with
2,3,4,5-tetrazine with fluorine-containing 1,3-diketones.
additional 1,1,1,5,5,5-hexafluoropentane-2,4-dione (2a)
in acetic acid at 110 °C was unsuccessful. After refluxing
1 and 2a (1:2 ratio) in ethanol with sulfuric acid as cata-
lyst, the 19F NMR spectrum of the reaction mixture
showed resonances at d = –68.8 ppm (3a), and at d = –69.0
ppm and –70.0 ppm (4). Separation of the reaction mix-
ture gave 3a (70% yield) and 4 (30%).
The commercially available starting material, 3,5-diami-
no-1,2,4-triazole, was reacted with cyanamide in ethanol
under reflux for six hours to form 3,5-diamino-1H-1,2,4-
triazole-1-carboximidamide, not the previously reported
product 5-amino-3-guanidino-1,2,4-triazole,15 which, af-
ter workup, was isolated as the hydrochloride salt, 1, in
75% yield (Scheme 2). Previously, 2-(3,5-diamino-1H- While no bicyclization reactions occurred, it was found
1,2,4-triazol-1-yl)-4,6-dimethylpyrimidine was isolated that 4 could also be obtained in 60% yield by reacting 3,5-
from the reaction of 4,6-dimethyl-2-hydrazinopyrimidine diamino-1,2,4-triazole with 2a under the same conditions.
hydrochloride and dicyandiamide in pyrimidine,16 or from The formation of compound 4 from the 3,5-diamino-1H-
NH2
NH2
.
N
N
N
AcOH, 110 °C, 24 h
N
H2N
HN
HCl
N
H2N
N
CF3COCH2COR
+
3a R = CF3
3b R = Me
3c R = Ph
2a R = CF3
2b R = Me
2c R = Ph
1
NH2
N
N
CF3
R
NH2
NH2
N
N
NH2
.
N
N
N
H2N
F3C
N
N
N
N
2 CF3COCH2COCF3
EtOH, H2SO4, reflux, 24 h
N
H2N
HN
HCl
+
N
N
F3C
CF3
4
CF3
N
NH2
–69.0 ppm
–70.0 ppm
NH2
3a
NH
Scheme 2 Cyclization reactions of 3,5-diamino-1H-1,2,4-triazole-1-carboximidamide.
Synthesis 2008, No. 11, 1775–1782 © Thieme Stuttgart · New York

PAPER
A One-Step Route to Fluorinated Heteropolycycles
1777
1,2,4-triazole-1-carboximidamide hydrochloride, 1, may inated group is present.18 Dehydration of 7 under the in-
involve an initial solvolysis of the guanyl moiety to yield fluence of acetic anhydride at 120 °C, gave 6 in 90%
3,5-diamino-1,2,4-triazole which would react with the yield. This is thus a simple and convenient one-step route
diketone to produce 4.
for the preparation of fluorinated heteropolycyclic deriva-
tives of pyrazolo-[1,2,4]-triazolo[1,5-a]pyrimidine.
The bicyclization of 5-amino-3-hydrazino-1,2,4-triazole
dihydrochloride (5) to three fluorinated pyrazo- The result obtained with 2a encouraged us to extend this
lo[1,2,4]triazolo[1,5-a]pyrimidine heterocycles in one approach to the synthesis of asymmetrically fluorinated
step was also investigated; the starting material, 5, was pentane-2,4-diones in order to synthesize the fluorinated
produced in two steps from 3,5-diamino-1,2,4-triazole.13 heteropolycycles, pyrazolo-1,2,4-triazolo-pyrimidines,
In an effort to prepare 5-amino-3-[3,5-bis(trifluorometh- using 1,1,1-trifluoropentane-2,4-dione (2b; Scheme 4).
yl)pyrazolo]-1,2,4-triazole, 5 was reacted with 2a to give Upon column chromatographic purification of the reac-
a mixture of 5,7-bis(trifluoromethyl)-2-[3,5-bis(trifluo- tion mixture, 7-methyl-5-trifluoromethyl-2-(5-methyl-3-
romethyl)pyrazolo]-[1,2,4]-triazolo[1,5-a]pyrimidine (6) trifluoromethylpyrazolo)-[1,2,4]-triazolo[1,5-a]pyrimi-
and the corresponding dihydro compound 7 (Scheme 3). dine (9), and a three-component isomeric mixture were
1
The mixture was easily separated by chromatography to obtained. Compound 9 was identified using H (1H–13C
give 6 (10%) and 7 (60%). The structure of compound 6 HMBC) and 19F NMR spectroscopy, mass spectra, ele-
1
was confirmed by 19F and H NMR, mass spectrometry mental analysis and single-crystal X-ray structure deter-
and elemental analysis [four 19F NMR resonances (d = mination. The 19F NMR signals at d = –69.76 and –63.46
–68.38, –68.26, –62.94 and –59.16 ppm), and aromatic ppm were assigned to the trifluoromethyl groups on the
proton signals in the 1H NMR spectrum (d = 8.21 and 7.54 pyrimidine and pyrazole rings, respectively, based on 1H–
ppm)]. The structure of 7 was unambiguously assigned 13C HMBC and 19F NMR spectroscopy; the coupling con-
using 1H (1H–13C HSQC, HMBC) and 19F NMR spectros- stants (JC–F) between the fluorine atoms of the trifluoro-
copy, mass spectrometry, and elemental analysis. In the methyl groups and the carbon atom were 275 and 266 Hz,
1
1H HSQC spectrum of 7, a clear decoupled H singlet at respectively. The mixture containing the isomeric com-
d = 6.21 ppm could be assigned to the hydroxyl group. pounds 10, 11 and 12 could not be separated by normal
When 5 and pentane-2,4-dione were heated at reflux for column chromatography because of their very similar po-
24 hours under the same conditions, only 5,7-dimethyl-2- larities. The GC-MS chromatogram, however, exhibited
(3,5-dimethylpyrazolo)-[1,2,4]-triazolo[1,5-a]pyrimidine
three peaks at 14.1 (m/z =350), 14.6 (m/z = 350) and 15.7
(8) was obtained in 70% yield. Based on the observed for- (m/z = 350) minutes, corresponding to the three isomers.
mation of a single compound, 8, it can be seen that the for- These isomeric structures were identified by comparison
mation of 7 arises either as a direct result of the presence of the 19F NMR spectra with those of 6 and 9.
of a high concentration of the enol isomer of bis(trifluo-
Furyl pyrimidine derivatives have been reported to be im-
romethyl)acetylacetone or because the dehydration step is
portant antitumor agents.19 Condensation of furyl-substi-
more difficult under the reaction conditions when a fluor-
–80.87 ppm
OH
F3C
F3C
CF3
CF3
N
N
N
N
–67.02 ppm
N
N
+
CF3COCH2COCF3
N
N
N
N
N
N
7, 60%
CF3
6, 10%
EtOH, H2SO4, reflux, 24 h
NHNH2
2HCl
F3C
N
CF3
Me
F3C
–68.35 ppm
–68.37 ppm
N
H2N
N
H
5
MeCOCH2COMe
Me
N
N
N
EtOH, H2SO4, reflux, 24 h
N
N
N
N
8
Me
Me
OH
F3C
F3C
–59.16 ppm
CF3
CF3
N
N
N
N
N
(MeCO)2O
–62.94 ppm
N
N
N
N
N
N
120 °C, 16 h
6
Scheme 3 Cyclization reactions of 5-amino-3-hydrazino-1,2,4-triazole
Synthesis 2008, No. 11, 1775–1782 © Thieme Stuttgart · New York

1778
Z. Zeng et al.
PAPER
NHNH2
2HCl
N
N
H2N
N
H
5
CF3COCH2COMe
EtOH, H2SO4, reflux, 24 h
Me
N
mixture (three isomers) (40%)
F3C
CF3
N
N
–63.46 ppm
N
Me
F3C
N
CF3
–59.23 ppm
–59.28 ppm
Me
Me
N
N
N
N
N
–63.45 ppm
N
N
N
N
N
9
Me
F3C
N
12
N
10
N
11
N
N
–69.76 ppm
N
N
N
N
CF3
Me
CF3
Me
F3C
Me
10%
–69.38 ppm
–69.33 ppm
–69.38 ppm
Scheme 4 Synthesis of asymmetrically fluorinated pyrazolo-1,2,4-triazolo-pyrimidines
NHNH2
N
N
2HCl
H2N
N
H
5
O
O
EtOH, H2SO4, reflux, 24 h
F3CCCH2C
O
mixture (two isomers) (50%)
F3C
O
N
–59.4 ppm
CF3
N
N
N
O
N
–63.5 ppm
N
N
N
N
N
N
N
13
14
F3C
CF3
–69.1 ppm
22:78
–69.2 ppm
O
O
Scheme 5 Synthesis of asymmetrically fluorinated pyrazolo-1,2,4-triazolo-pyrimidines
tuted 4,4,4-trifluoro-1-(2-furyl)butane-1,3-dione with 5,
gave a mixture of two isomers 13 and 14 (Scheme 5). The
GC-MS chromatogram exhibited two peaks at 19.9 (m/z =
CF3
F3C
N
N
NH
O
454) and 20.3 (m/z = 454) minutes. The ratio of 13 and 14
HN
HN
NH2
NH
was 22:78, based on comparison of peak intensities in the
19F NMR spectra. Their structures were assigned by com-
parison with the 19F NMR spectra of 6 and 9.
N
N
N
N
O
N
N
N
N
+
CF3COCH2COCF3
reflux, 24 h
2a
NH2
The synthesis of 3,6-bis[4,6-bis(trifluoromethyl)pyrimi-
dino-2-amino]tetrazine (16), a fluorinated heteropolycy-
clic, in 75% yield also succeeded by heating 3,6-
diguanidino-1,2,4,5-tetrazine (15)14 and 2a, at reflux in
dioxane (Scheme 6). However, no reaction occurred when
15 was heated under the same conditions with 1,1,1-tri-
fluoropentane-2,4-dione (2b).
NH
NH
N
N
15
16
CF3
F3C
Scheme 6 Synthesis of fluorinated pyrimidinotetrazine
Synthesis 2008, No. 11, 1775–1782 © Thieme Stuttgart · New York

PAPER
A One-Step Route to Fluorinated Heteropolycycles
1779
an EXETER CE-440 Elemental Analyzer. GC-MS spectra were re-
corded on a Shimadzu GCMS-QP5050A using a capillary column.
3,5-Diamino-1H-1,2,4-triazole-1-carboximidamide Hydrochlo-
ride (1)
To a round-bottom flask fitted with a reflux condenser, was added
3,5-diamino-1,2,4-triazole hydrochloride (3 mmol) and cyanamide
(3 mmol) in EtOH (30 mL). The reaction was heated at reflux for 6
h, then the mixture was filtered and washed with EtOH (15 mL), and
the white solid was recrystallized from methanol to give 1. Yield:
75% white solid; mp (DSC) 210 ºC (dec.).
1H NMR (DMSO-d6): d = 8.8 (s, 4 H), 7.4 (s, 2 H), 5.8 (s, 2 H).
13C NMR (DMSO-d6): d = 164.3, 157.6, 152.7.
Anal. Calcd for C3H8ClN7: C, 20.29; H, 4.54; N, 55.21. Found: C,
20.39; H, 4.47; N, 55.21.
Figure 2 (a) Molecular structure of 9 (30% thermal displacement)
showing the numbering scheme. Hydrogen atoms are shown (arbitra-
ry spheres) but are unlabelled for clarity. (b) Packing diagram of 9
(ball and stick) viewed down the a-axis, showing the alternating
stacks. Hydrogen atoms have been omitted for clarity.
Preparation of Fluorinated Triazolylpyrimidines 3a–c; General
Procedure
To a round-bottom flask fitted with a reflux condenser, was added
3,5-diamino-1H-1,2,4-triazole-1-carboximidamide hydrochloride
(1; 1 mmol) and fluorinated 1,3-b-diketone (1 mmol) in AcOH (10
mL). The reaction was heated at reflux for 24 h then AcOH was re-
moved under reduced pressure and the residue was recrystallized
from 1,4-dioxane to give 3a–c in good yields.
The solid-state structure of 9 was confirmed by single-
crystal X-ray diffraction as shown in Figure 2. Suitable
colorless plate crystals were obtained by slow concentra-
tion of an ethyl acetate/hexane solution of 9. A notable
feature of this molecule is the approximate co-planarity of
the pyrazole and pyrimidine moieties (only a 2.2° angle
between the pyrazole and pyrimidine mean planes). This,
as well as the short C–N bond length joining the two sys-
tems [C7–N12, 1.394(2) Å], indicates a delocalization of
the aromaticity across both ring-systems. This conforma-
tion enables the molecules to pack in alternating ABAB
2-(3,5-Diamino-1H-1,2,4-triazol-1-yl)-4,6-di(trifluorometh-
yl)pyrimidine (3a)
Yield: 80%; yellow solid; mp 319 °C.
1H NMR (DMSO-d6): d = 8.1 (s, 1 H), 7.5 (s, 2 H), 5.8 (s, 2 H).
13C NMR (DMSO-d6): d = 164.1, 159.5 (q, JC–F = 37.0 Hz, CCF3),
157.9, 156.5, 126.9 (q, JC–F = 276.0 Hz, CF3), 108.9.
19F NMR (DMSO-d6): d = –68.8 (s, 6 F).
stacks parallel to the a-axis with a gap of ~3.45 Å between GC-MS (EI): m/z = 313 [M+].
each ‘planar’ unit as shown in Figure 2b.
Anal. Calcd for C8H5F6N7: C, 30.68; H, 1.61; N, 31.31. Found: C,
30.94; H, 1.52; N, 30.91.
In conclusion, a new and highly effective one-step route
has been developed for the preparation of fluorine-con-
taining heteropolycycles. Cyclization of bifunctional nu-
cleophiles, 3,5-diamino-1H-1,2,4-triazole-1-carboximid-
amide hydrochloride and 3,6-diguanidino-1,2,4,5-tetra-
zine, with fluorine-containing 1,3-diketones results in the
formation of fluorinated triazolylaminopyrimidines and
pyrimidinoaminotetrazines in high yield. Combination of
5-amino-3-hydrazino-1,2,4-triazole dihydrochloride with
a variety of fluorinated 1,3-diketones yields three sym-
metric and asymmetric fluorinated heterocycles, pyrazo-
lo[1,2,4]triazolo[1,5-a]pyrimidines, in one step in
moderate yields.
2-(3,5-Diamino-1H-1,2,4-triazol-1-yl)-4-methyl-6-trifluoro-
methylpyrimidine (3b)
Yield: 70%; yellow solid; mp 322 °C.
1H NMR (DMSO-d6): d = 7.6 (s, 1 H), 7.5 (s, 2 H), 5.6 (s, 2 H), 2.5
(s, 3 H).
13C NMR (DMSO-d6): d = 172.6, 162.1 156.3, 155.32, 154.8 (q,
JC–F = 35.0 Hz, CCF3), 121.5 (q, JC–F = 274.0 Hz, CF3), 111.1, 24.0.
19F NMR (DMSO-d6): d = –69.0 (s, 3 F).
GC-MS (EI): m/z = 259 [M+].
Anal. Calcd for C8H8F3N7: C, 37.07; H, 3.11; N, 37.83. Found: C,
37.00; H, 2.95; N, 37.67.
2-(3,5-Diamino-1H-1,2,4-triazol-1-yl)-4-phenyl-6-trifluoro-
methylpyrimidine (3c)
Yield: 62%; yellow solid; mp 324 °C.
1H NMR (DMSO-d6): d = 8.3 (d, J = 6.8 Hz, 2 H), 8.2 (s, 1 H), 7.8
(s, 2 H), 7.6 (m, 3 H).
13C NMR (DMSO-d6): d = 169.3, 161.4, 157.4 (q, JC–F = 35.0 Hz,
CCF3), 156.7, 135.9, 134.0, 130.6, 129.3, 121.7 (q, JC–F = 275.0 Hz,
CF3), 109.5.
19F NMR (DMSO-d6): d = –68.6 (s, 3 F).
GC-MS (EI): m/z = 321 [M+].
All the reagents used were analytical reagents purchased from com-
mercial sources and used as received. The following materials were
prepared and purified according to reported procedures: 5-amino-3-
hydrazino-1,2,4-triazole dihydrochloride13 and 3,6-diguanidino-
1,2,4,5-tetrazine.14
1H, 19F and 13C NMR spectra were recorded on a Bruker 300 MHz
NMR spectrometer operating at 300.13, 282 and 75.48 MHz, re-
1
spectively. H–13C HSQC and HMBC spectra were recorded on a
Bruker Avance 500 MHz NMR spectrometer. Chemical shifts are
reported relative to TMS (1H and 13C NMR) or CCl3F (19F NMR).
The solvent used was CD3CN unless otherwise specified. Melting
points were recorded on a differential scanning calorimeter (DSC)
at a scan rate of 10 °C/min. Elemental analyses were performed on
Anal. Calcd for C13H10F3N7·0.5(C4H8O2): C, 49.32; H, 3.86; N,
26.84. Found: C, 49.08; H, 3.20; N, 26.43.
Synthesis 2008, No. 11, 1775–1782 © Thieme Stuttgart · New York

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PAPER
Preparation of 3a and 5,7-Bis(trifluoromethyl)-[1,2,4]-triazo-
lo[1,5-a]pyrimidine-2-amine (4); Method 1
Dehydration of 7 to 6
A sample of 7 (50 mg) was dissolved in Ac2O (10 mL) and heated
at 120 °C for 16 h. The solvent was removed under reduced pressure
and the residue was recrystallized (CH2Cl2–hexane) to give 6 (90%
yield).
To a round-bottom flask fitted with a reflux condenser, 1 (1 mmol),
1,1,1,5,5,5-hexafluoropentane-2,4-dione (2a; 2 mmol) and concd
H2SO4 (6 drops) in EtOH (15 mL) was brought to reflux for 24 h.
The mixture was cooled to r.t. and neutralized with sat NaHCO3.
EtOH was removed under reduced pressure, MeCN (40 mL) was
added to the residue and the solution was stirred for 1 h. The solu-
tion was filtered and the residue was recrystallized (1,4-dioxane) to
Preparation of 5,7-Dimethyl-2-[3,5-bis(trifluoromethyl)pyrazo-
lo]-[1,2,4]-triazolo[1,5-a]pyrimidine (8)
The reaction was carried out as described above with 5-amino-3-hy-
drazino-1,2,4-triazole dihydrochloride (5; l mmol) and pentane-2,4-
dione (2 mmol). The solvent was removed and the crude product
was recrystallized (EtOH) to give 8.
1
yield a yellow solid (3a), which was identified by H NMR, 19F
NMR, GC-MS. The filtrate was concentrated and the residue was
purified by column chromatography (hexane–EtOAc, 3:1) to give 4.
Yield: 30%; colorless solid; mp 252 °C.
1H NMR (CD3CN): d = 7.7 (s, 1 H), 5.7 (s, 2 H).
19F NMR (CD3CN): d = –70.0, –69.0.
GC-MS (EI): m/z = 271 [M+].
Yield: 70%; colorless solid; mp 172 °C.
1H NMR (CD3CN): d = 7.0 (s, 1 H), 6.1 (s, 1 H), 2.7 (s, 3 H), 2.6 (s,
3 H), 2.6 (s, 3 H), 2.3 (s, 3 H).
13C NMR (CD3CN): d = 165.9, 161.2, 155.5, 151.9, 148.1, 143.5,
111.8, 109.5, 24.9, 17.0, 13.6, 13.5.
GC-MS (EI): m/z = 242 [M+].
Anal. Calcd for C7H3F6N5: C, 31.01; H, 1.12; N, 25.83. Found: C,
31.16; H, 1.09; N, 25.56.
Anal. Calcd for C12H14N6: C, 59.49; H, 5.82; N, 34.69. Found: C,
59.15; H, 5.68; N, 34.64.
Preparation of 4; Method 2
The reaction was carried out as described above with 3,5-diamino-
1,2,4-triazole (1 mmol) and 2a (1 mmol). After the solvent was re-
moved, the crude product was purified by column chromatography
(hexane–EtOAc, 3:1) to give 4 (isolated yield 70%), which was
identified by 1H NMR, 19F NMR, GC-MS.
Preparation of Pyrazolo-1,2,4-triazolopyrimidines 9–12
The reaction was carried out as described above with 5 (1 mmol)
and 2b (2 mmol). After addition of NaHCO3, H2O (15 mL) was add-
ed, the solution was extracted with EtOAc (3 × 15 mL) and the or-
ganic extracts were dried over anhydrous Na2SO4. After the solvent
was removed, the crude product was purified by column chroma-
tography (hexane–EtOAc, 5:1 then 2:1) to give 9 and a mixture of
the three isomers 10, 11 and 12 (30:40:10 mixture by 19F NMR
spectra).
Preparation of 5,7-Bis(trifluoromethyl)-2-[3,5-bis(trifluoro-
methyl)pyrazolo]-[1,2,4]-triazolo[1,5-a]pyrimidine (6) and 7
The reaction was carried as described above with 5 (1 mmol) and 2a
(2 mmol). After the addition of NaHCO3, H2O (15 mL) was added,
the solution was extracted with EtOAc (3 × 15 mL) and the organic
extracts were dried over anhydrous Na2SO4. The solvent was re-
moved and the crude product was purified by column chromatogra-
phy (hexane–EtOAc, 10:1 then 5:1) to give 6 and 7.
7-Methyl-5-trifluoromethyl-2-(5-methyl-3-trifluoromethyl-
pyrazolo)-[1,2,4]-triazolo[1,5-a]pyrimidine (9)
Yield: 10%; colorless solid; mp 162 °C.
1H NMR (CD3CN): d = 7.6 (s, 1 H), 6.7 (s, 1 H), 2.9 (s, 3 H), 2.7 (s,
5,7-Bis(trifluoromethyl)-2-[3,5-bis(trifluoromethyl)pyrazolo]-
[1,2,4]-triazolo[1,5-a]pyrimidine (6)
Yield: 10%; colorless solid; mp 167 °C.
1H NMR (CD3CN): d = 8.2 (s, 1 H), 7.5 (s, 1 H).
13C NMR (CD3CN): d = 161.3, 155.9, 154.2 (q, JC–F = 38.0 Hz,
CCF3), 146.1 (q, JC–F = 40.0 Hz, CCF3), 138.7 (q, JC–F = 40.0 Hz,
CCF3), 136.6 (q, JC–F = 42.0 Hz, CCF3), 122.8 (CF3), 120.9 (CF3),
120.6 (CF3), 117.6 (CF3), 111.9, 108.7.
19F NMR (CD3CN): d = –68.4 (s, 3 F), –68.3 (s, 3 F), –62.9 (s, 3 F),
–59.2 (s, 3 F).
3 H).
13C NMR (CD3CN): d = 162.2, 153.5, 152.3 (q, JC–F = 37.0 Hz,
CCF3), 146.5, 145.5 (q, JC–F = 38.0 Hz, CCF3), 122.4 (q, JC–F
=
275.0 Hz, CF3), 121.7 (q, JC–F = 275.0 Hz, CF3), 108.6 (q, JC–F = 2.4
Hz, CHCCF3), 107.6 (q, JC–F = 1.8 Hz, CHCCF3), 18.0 (CH3), 13.9
(CH3).
19F NMR (CD3CN): d = –69.3 (s, 3 F), –63.5 (s, 3 F).
GC-MS (EI): m/z = 350 [M+].
Anal. Calcd for C12H8F6N6: C, 41.15; H, 2.30; N, 24.00. Found: C,
41.16; H, 2.34; N, 23.36.
GC-MS (EI): m/z = 458 [M+].
Anal. Calcd for C12H2F12N6: C, 31.46; H, 0.44; N, 18.34. Found: C,
31.58; H, 0.37; N, 18.06.
10, 11 and 12
Isolated as a mixture of three isomers. The yield ratio of 10:11:12
was 40:50:10.
7
Yield: 40%; colorless solid; GC peaks at 14.3 min, 14.5 min and
15.0 min.
1H NMR (CD3CN): d = 7.6 (t, J = 5.9 Hz, 1 H), 6.9 (s, 1 H), 6.7 (s,
1 H), 2.9, 2.8, 2.7, 2.4 (4 s, 3 H each).
Yield: 60%; colorless solid; mp 140 °C.
1H NMR (CDCl3): d = 7.7 (s, 1 H), 6.2 (s, 1 H, OH), 3.6 (AB,
JA–B = 53 Hz, 2 H).
13C NMR (CDCl3): d = 163.2, 154.0, 144.4 (q, JC–F = 40.0 Hz,
CCF3), 136.7 (q, JC–F = 40.0 Hz, CCF3), 123.6 (q, CF3), 121.3 (q,
CF3), 119.2 (q, CF3), 117.0 (q, CF3), 104.2, 95.7 (q, JC–F = 21.0 Hz,
CCF3), 41.7 (CH2).
19F NMR (CD3CN): d = –69.4, –69.3, –63.5, –59.3, –59.2.
GC-MS (EI): m/z = 350 [M+] (14.3 min), 350 [M+] (14.5 min), 350
[M+] (15.0 min).
19F NMR (CDCl3): d = –80.9 (s, 3 F), –68.4 (s, 3 F), –68.4 (s, 3 F),
–67.0 (s, 3 F).
Anal. Calcd for C12H8F6N6: C, 41.15; H, 2.30; N, 24.00. Found: C,
41.48; H, 2.57; N, 23.39.
GC-MS (EI): m/z = 458 [M+ – H2O].
Preparation of Pyrazolo-1,2,4-triazolopyrimidines 13 and 14
The reaction was performed as described above with 5 (1 mmol)
and 4,4,4-trifluoro-1-(2-furyl)butane-1,3-dione (2 mmol). After ad-
Anal. Calcd for C12H4F12N6O: C, 30.27; H, 0.85; N, 17.65. Found:
C, 30.37; H, 0.87; N, 17.26.
Synthesis 2008, No. 11, 1775–1782 © Thieme Stuttgart · New York

PAPER
A One-Step Route to Fluorinated Heteropolycycles
1781
dition of NaHCO3, H2O (15 mL) was added, the mixture was ex-
tracted with EtOAc (3 × 15 mL) and the organic extracts were dried
over anhydrous Na2SO4. The solvent was removed and the crude
product was purified by column chromatography (hexane–EtOAc,
5:1) to give a mixture of the two isomers 13 and 14.
Yield: 50% (isolated yield of 13 + 14 in 22:78 ratio based on 19F
NMR spectra); colorless solid; GC peaks at 19.9 min and 20.3 min.
1H NMR (CD3CN): d = 8.05 (s, 1 H), 7.90 (m, 1 H), 7.62 (d, J = 3.5
Hz, 1 H), 7.58 (m, 1 H), 7.13 (s, 1 H), 6.84 (m, 1 H), 6.77 (q, J = 1.7
Hz, 1 H), 6.54 (q, J = 1.7 Hz, 1 H).
19F NMR (CD3CN): d = –69.19, –69.14, –63.46, –59.40.
References
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GC-MS (EI): m/z = 454 [M+] (19.9 min), 454 [M+] (20.3 min).
Anal. Calcd for C18H8F6N6O2: C, 47.59; H, 1.77; N, 18.50. Found:
C, 47.62; H, 1.64; N, 18.26.
Preparation of 3,6-Bis[4,6-bis(trifluoromethyl)pyrimidino-2-
amino]tetrazine (16)
The reaction was carried out as described above with 15 (0.5 mmol)
and 2a (1 mmol) in 1,4-dioxane (10 mL) under reflux. The mixture
is refluxed for 24 h then cooled to r.t. and filtered. The residue was
washed with EtOH (3 × 15 mL) and dried in vacuo to give 16.
Yield: 75%; red solid; mp 225 °C.
1H NMR (DMSO-d6): d = 12.4 (s, 2 H), 8.0 (s, 2 H).
19F NMR (DMSO-d6): d = –68.8 (s, 6 F).
Anal. Calcd for C14H4F12N10·(C4H8O2): C, 34.41; H, 1.92; N, 22.29.
Found: C, 33.96; H, 1.61; N, 22.66.
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X-ray Crystallographic Analysis of 9
Crystals of compound 9 were removed from the flask and a suitable
crystal was selected, attached to a glass fiber and data were collect-
ed at 90(2) K using a Bruker/Siemens SMART APEX instrument
(Mo Ka radiation, l = 0.71073 Å) equipped with a Cryocool
NeverIce low-temperature device. Data were measured using ome-
ga scans of 0.3° (omega and phi scans of 0.5°) per frame for 20 s for
9, and a full sphere of data was collected. A total of 2400 (2565)
frames were collected with a final resolution of 0.83 Å. Cell para-
meters were retrieved using SMART software20 and refined using
SAINTPlus21 on all observed reflections. Data reduction and cor-
rection for Lp and decay were performed using the SAINTPlus soft-
ware. Absorption corrections were applied using SADABS.22 The
structure was solved by direct methods and refined by least-squares
method on F2 using the SHELXTL program package.23 The struc-
ture was solved by analysis of systematic absences. All non-hydro-
gen atoms were refined anisotropically. No decomposition was
observed during data collection.
X-ray crystal data for 9;24 Empirical formula: C12H8F6N6; Formula
weight 350.24; Crystal system = triclinic; Space group P1 (#2);
T = 90(2) K; a = 7.0943(4) Å, b = 7.3652(4) Å, c = 13.4329(7) Å,
a = 102.400(10)°,
b = 103.171(2)°,
g = 97.1310(10)°;
V = 656.33(6) Å3; Z = 2; F(000) = 352; m = 0.174 mm–1; reflections
collected = 7561, independent reflections = 2574 [Rint = 0.0158];
R1, wR2 [I > 2s(I)] = 0.0421, 0.0444.
Acknowledgment
The authors gratefully acknowledge the support of DTRA
(HDTRA1-07-1-0024), NSF (CHE-0315275), and ONR (N00014-
06-1-1032). The Bruker (Siemens) SMART APEX diffraction faci-
lity was established at the University of Idaho with the assistance of
the NSF-EPSCoR program and the M. J. Murdock Charitable Trust,
Vancouver, WA, USA.
Organometallics 2007, 26, 1782.
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Synthesis 2008, No. 11, 1775–1782 © Thieme Stuttgart · New York

1782
Z. Zeng et al.
PAPER
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(20) SMART: v.5.632, Bruker Molecular Analysis Research
Tool, Bruker AXS, Madison, WI, 2005
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Program, Bruker AXS, Madison, WI, 2004
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program, Bruker AXS Inc., Madison, WI, 2004
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(23) SHELXTL: v. 6.14, Structure Determination Software Suite,
Sheldrick G.M., Bruker AXS Inc., Madison, WI, 2004
(24) CCDC 666024 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data-_request/cif.
Synthesis 2008, No. 11, 1775–1782 © Thieme Stuttgart · New York