Full text of DOI:10.1007/s11172-018-2154-z

Russian Chemical Bulletin, International Edition, Vol. 67, No. 5, pp. 893—901, May, 2018
893
Synthesis and study of the azide-tetrazole tautomerism
in 2-azido-4-(trifluoromethyl)-6-R-pyrimidines (R = H, 4-ClC6H4)
Е. B. Nikolaenkova,a N. V. Aleksandrova,а V. I. Mamatyuk,а,b and V. P. Krivopalov
аN. N. Vorozhtsov Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrentieva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. E-mail: krivic@nioch.nsc.ru
bNovosibirsk State University,
2 ul. Pirogova, 630090 Novosibirsk, Russian Federation
Azide-tetrazole equilibrium in azidopyrimidines bearing trifluoromethyl group on the
example of 2-azidopyrimidines has been studied. The latter were synthesized via nitrosation
of 2-hydrazino-4-trifluoromethylpyrimidine and reaction of NaN3 with 4-trifluoromethyl-2-
chloro-6-(4-chlorophenyl)pyrimidine. The tautomeric equilibrium 5-trifluoromethyltetr-
←
azolo[1,5-a]pyrimidine
2-azido-4-trifluoromethylpyrimidine was observed in the absence
→
of solvent and in DMSO-d6 solution, whereas in CDCl3 only an azide form exists. For 2-azido-
4-trifluoromethyl-6-(4-chlorophenyl)pyrimidine, only an azide isomer was detected in CDCl3
solution, and in DMSO-d6 solution it is in equilibrium with 5-(trifluoromethyl)-7-(4-chloro-
phenyl)tetrazolo[1,5-a]pyrimidine (the tautomer ratio is 99 : 1). Thermodynamic and kinetic
←
parameters of 5-trifluoromethyltetrazolo[1,5-a]pyrimidine
2-azido-4-trifluoromethylpyr-
→
imidine tautomeric rearrangement in DMSO-d6 for 5-trifluoromethyltetrazolo[1,5-a]pyrimidine
were determined using the exchange spectroscopy (EXSY) technique.
Key words: 2-azidopyrimidines, tetrazolo[a]pyrimidines, trifluoromethylpyrimidines, azide-
tetrazole tautomerism, equilibrium constants, exchange rate constants, NMR spectroscopy,
exchange spectroscopy.
An extensive study of organic azides is still in progress due
to diversity of their thermal and photochemical transforma-
tions as well as wide spectrum of practical applications.1—5
A feature of azidopyrimidines similar to other aza-
aromatic compounds bearing the azide group in the
α-position to the nitrogen atom is an equilibrium between
opened (azide) and annulated (tetrazole) forms, that is,
the azide-tetrazole tautomerism. This tautomerism, being
controlled by a variety of external and internal factors,
represents an important reason determining biological
activity and reactivity of compounds. Results of studies of
the azide-tetrazole tautomerism have been summarized in
reviews6—8 and articles.9—17 It should be noted that in
2-azido-4-R1- and 2-azido-4-R1-6-R2-pyrimidines at
R1 ≠ R2, two types of tetrazoles can be formed by the
intramolecular cyclization of the azido group.
Earlier, studying the photochemical activity of 2- and
4-azidopyrimidines bearing aryl substituents, we have
obtained the following results: (1) substituted 2-nitro-
pyrimidines have been synthesized,18 (2) azidopyrimidines
were successfully used as a photosensitive component in
a composition comprising propylene glycol in photo-
materials with physical development,19,20 and (3) a method
to obtain positive images on porous supports using non-
silver photography technique based on changing the
photomaterial wettability (a developer is an aqueous solu-
tion of an organic dye) has been elaborated.21,22
We have experimentally found that in the above-
mentioned photochemical processes, those azide tauto-
mers are active, high-reactive nitrenes of which form
a mixture of various products generating hydrophobic
areas on porous supports. In continuation of studies of the
azide-tetrazole tautomerism as well as thermal and photo-
chemical activity of azidopyrimidines, it seems promising
to introduce electron-withdrawing and hydrophobic poly-
fluoroalkyl substituents into the structures of these com-
pounds, for example, to synthesize 2-azido-4-aryl-6-tri-
fluoromethylpyrimidines. This would offer a clearer view
of the features of the polyfluoroalkyl group effects on the
azide-tetrazole equilibrium and reactivity of azidopyr-
imidines in thermal and photochemical reactions.
The present study is directed on the synthesis of
2-azidopyrimidines bearing CF3-group in the pyrimidine
ring, study of structural aspects of azide-tetrazole tauto-
merism, and determination of thermodynamic and kinetic
parameters of the rearrangement of 5-(trifluoromethyl)-
tetrazolo[1,5-a]pyrimidine to 2-azido-4-trifluoromethyl-
pyrimidine in DMSO-d6.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 0893—0901, May, 2018.
1066-5285/18/6705-0893 © 2018 Springer Science+Business Media, Inc.

894
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
Nikolaenkova et al.
We have performed a search for 2-azidopyrimidines
bearing fluoroalkylsubstituents in a ring in Informational
Retrievals SciFinder® and Reaxys®, and found that there
are only few articles and patents devoted to such com-
pounds.23—25
azides were detected in CDCl3 (see Scheme 1), while in
the highly polar DMSO-d6, the azide-tetrazole equilibrium
was observed. Thus, for compound 1 (R = CF3), 1А : 1T
ratio (at 22 °С) is 1 : 2.3 (see Scheme 1, Eq. (1)). Therefore,
it is surprising that in studies33—35 devoted to the synthe-
sis of tetrazolo[1,5-a]pyrimidines 5, 6, and 8 bearing
an electron-withdrawing CF3 group in the pyrimidine
ring, which is more electron-deficient compared to pyri-
dine one (Scheme 2), the potential azide-tetrazole equi-
librium is not even considered and the structures provided
in these studies represent those existing under kinetically
controlled conditions. Under conditions of tautomeric
equilibrium in solution, the formation of a mixture of
azide and tetrazole forms is possible, their ratio depend-
ing on the solvent polarity. It was only the absence of
Being pioneers in studying the azide-tetrazole tautom-
←
erism between 2-azido-4,6-di-R-pyrimidine 5,7-di-R-
→
tetrazolo[1,5-a]pyrimidine (R = H, Me) using IR and
1H NMR techniques in solutions of DMSO-d6, CDCl3,
acetone-d6, and CF3COOH, the authors26,27 have found
that this equilibrium is defined by the solvent polarity, and
the presence of electron-donating Me groups stabilizes the
tetrazole form of the studied derivatives relative to the
parent 2-azidopyrimidine.
It is also known that 2-azido- and 2-azido-6-methyl-
pyridines 1 (R = Н, Me) exist in organic solvents exclu-
sively as tetrazole forms 1T (Scheme 1, equation (1)).28,29
In 1H and 13C NMR spectra of 2-azido-4- methylpyrim-
idine 2, ternary azide-tetrazole equilibrium is observed
(see Scheme 1, equation (2)).30
characteristic bands of azido groups (2100―2200 cm–1
)
in the IR spectra of solutions in СНСl3 that would allow
one to agree that one set of signals in the 1H and 13C NMR
spectra in CDCl3 relates to either of the tetrazole forms,
but the studies33—35 provided no IR spectra. Close analogs
of compounds 5 and 6 in terms of the electronic effects
of substituents on the azide-tetrazole equilibrium are
2-azido-4,6-diphenylpyrimidine36 and 2-azido-4-
(ethoxycarbonyl)-6-(phenyl)/(4-bromophenyl)pyrimid-
ines.37,38 For these compounds, the azide signals were
observed in the IR spectra (pellets in KBr and solutions
in CHCl3), whereas in 1H and 13C NMR spectra (CDCl3)
only signals of azide tautomers were found. According to
the X-ray data, the same tautomers exist also in a crystal-
line state.
Synthesis of 5-trifluoromethyl- and/or 7- trifluoro-
methyltriazolo[1,5-а]pyrimidines (Scheme 3) via cyclo-
condensation of enones 7a,b with 3-amino-1,2,4-triazoles
has been thoroughly studied.34 Intermediates of the reac-
tion were found to be 4,5,6,7-tetrahydrotriazolo[1,5-a]-
pyrimidines, the aromatization of which comprises a re-
moval of water and sulfinic acid. However, the synthesis
of isomeric 5-trifluoromethyl- and 7-trifluoromethyl-
tetrazolo[1,5-а]pyrimidines 8T and 8T´ starting from
5-aminotetrazole 3 (see Scheme 2) poses a challenge, as
these compounds will readily undergo isomerization under
the reaction conditions to give 2-azido-4-trifluoropyrim-
idine 8A, which can react with sulfinic acids in the presence
of the atmospheric oxygen and undergo 1,3-dipolar cyclo-
addition with vinyl sulfones 7a,b yielding substituted
1,2,3-triazoles. Therein lies a fundamental difference
between the above-mentioned reaction from two others
involving 5-aminotetrazole. Also, the formation of the
target compounds by condensation of 5-aminotetrazole
with 1,3-dicarbonyl compounds and their analogs upon
heating under acidic conditions consists of three inter-
mediate steps.
Scheme 1
Solvent
CDCl3
R
Ratio 1T : 1A
100 : 0
H, Me
CF3
CF3
CDCl3
0 : 100
2.3 : 1
DMCO-d6
Solvent
2T´ : 2A : 2T ratio
under equilibrium conditions
11 : 45 : 44
CDCl3
DMSO-d6
28 : 2 : 70
When studying trifluoro-substituted 2-azidopyridines/
tetrazolo[1,5-a]pyridines, it was found31,32 that in the
NMR spectra of 2-azido-6-trifluoromethyl- and 2-azido-
4,6-bis(trifluoromethyl)pyridines isolated as oils, only
In the present study, compounds 6aT and 8T and/or
8T´ were synthesized by the reaction of chloropyrimidine
9 with NaN3/LiCl in DMF at 40—50 °С and nitrosation

2-Azido-4-(trifluoromethyl)pyrimidines
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
895
Scheme 2
6: R = 4-ClC6H4 (a), Me (b), 4-FC6H4, 4-BrC6H4, 4-IC6H4, 4-MeC6H4, 4-MeOC6H4, etc.
7: R = Ph (a), Me (b)
Reagents and conditions: i. [bmim][BF4], HCl (0.1%), 6 h, 120 °C; ii. microwave irradiation, [bmim][BF4], HCl (0.1%), 12 min,
120 °C.
of 2-hydrazino-6-trifluoromethylpyrimidine 12 in diluted
НCl at 0—5 °С (Schemes 4 and 5) (see, e.g., Refs 6, 31,
32, 36, 39, and 40).
These synthetic approaches to 2-azidopyrimidines/
tetrazolo[a]pyrimidines bearing the trifluoromethyl group
allows one to exclude the dehydration step involving the
geminal С(ОН)СF3 moiety in the parent tetrazolo[a]-
pyrimidines (see Schemes 2 and 3), since perfluoroalkyl
substitutents inhibit elimination of the water molecule in
contrast to non-fluorinated alkyl analogs.
We have studied the azide-tetrazole equilibrium of
2-azidopyrimidines bearing the trifluoromethyl group by
the example of compounds 6a and 8 (see Schemes 4 and 5)
using IR and 1H, 13C, and 19F NMR spectroscopy tech-
niques in DMSO-d6 and СDCl3 solutions.
be noted that the signal of the carbon atom involved in the
annulation of the tetrazole ring is shifted upfield in tetra-
zoles (Δδ ≈ 20 ppm) compared to the signal of the corre-
sponding carbon atom in an azide.30 Moreover, the
IR spectrum (KBr) of compound 6a shows the characteris-
tic adsorption band of the azide group at 2140 cm–1
.
According to the NMR spectra, in a solution of highly
polar DMSO-d6, tetrazole tautomer 6aT appears along
with azide form 6aA in an amount of 1%. The main cri-
terion for assigning the structure of this tautomer to
tetrazole 6aТ, rather than to 6aT´, was a 1Н—13С HMBC
correlation between upfield shifted carbon atom at
δС(7) 148.06, and aromatic protons (see Scheme 4).
Melting points and 1H and 13C NMR (CDCl3) spectral
data for compound 6а obtained by us (see Scheme 4) and
those for 7-(trifluoromethyl)-5-(4-chlorophenyl)tetr-
azolo[1,5-a]pyrimidine described in a study33 (see Scheme 2)
were identical.
It was found that similar to compound 1a, compound
6a exists in СDCl3 only in the azide form 6aA. Thus, in
1
the Н and 13С NMR spectra (CDCl3), a set of signals
corresponding only to tautomer 6aA is observed, as indi-
cated by characteristic downfield shifts of pyrimidine cyclic
carbon atoms at δС 163.15, 167.53, and 158.34. It should
We assume that in CDCl3 cyclization of the previously
studied39 2-azido-6-methyl-4-chloropyrimidine 10 and
its 4-trifluoromethyl analog 6b (Scheme 6)33 should follow
Scheme 3

896
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
Nikolaenkova et al.
Scheme 4*
* For structures 6aT and 6aA, the main correlations in the 1H—13C HMBC spectrum are denoted by arrows.
the same route and have the close ratio of azide and tetr-
azole tautomers.33 This is supported by the characteristic
downfield shift of the Me protons up to δ 3.00—3.30 when
annulation of the tetrazole ring occurs at the nitrogen atom
adjacent to the Me group. Thus, for example, in the
1H NMR spectra (CDCl3), chemical shifts of the Me
protons for compounds 10T and 11T (see Scheme 6) ap-
pear at δ 3.04 and 3.05, respectively, and those for the
Me group protons of C(5)Me and C(7)Me in 2-azido-4,6-
dimethylpyrimidine being in a tautomeric equilibrium with
5,7-dimethyltetrazolo[1,5-a]pyrimidine26,27 appear at
δ 2.78 and 3.00, respectively.
at δН 7.22 and 2.61 correspond to 2-azido-4-methyl-6-
trifluoromethylpyrimidine 6bA rather than to 5-methyl-
7-trifluoromethyltetrazolo[1,5-a]pyrimidine 6bT´. Also,
low-intensity signals at δН ~3.15 and ~7.45 are observed
in the spectrum that can be attributed to 7-methyl-5-
trifluoromethyl[1,5-a]pyrimidine 6bТ.
It was of interest for us to compare tautomeric com-
positions for compound 6a and its methyl analog 11 for
which ternary azide-tetrazole equilibrium in solutions
is also possible (see Scheme 6). Recently,15 the azide-
tetrazole equilibrium of isotopically-labeled compound
15N(2),15N(3)-11 in solutions of DMSO-d6 and CF3COOD
was studied using NMR spectroscopy technique. Joint
analysis of 1H—15N and 13C—15N spin-spin coupling
constants indicated that only tautomer 15N(1),15N(2)-11T
There are two sets of signals in the 1H NMR spectrum
(CDCl3) of compound 6b provided in the supporting
information of a study.33 In our opinion, intensive signals
Scheme 5*
* For structures 8A and 8T, the main correlations in the 1H—13C HMBC spectrum are denoted by arrows.

2-Azido-4-(trifluoromethyl)pyrimidines
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
897
Scheme 6*
* For structures 11A and 11T, the main correlations in the 1H—13C HMBC spectrum are denoted by arrows. Chemical shifts of pro-
tons and carbon atoms of the heterocyclic moieties are given in the δ scale.
is presented in DMSO-d6, while in CF3COOD, an azide
form of 11A is observed. Structures of compound 11
tautomers have been defined based on the chemical
shift values of the 13С atoms taking into account corr-
dine 1А, published prior to the studies on the synthesis of
trifluoromethyltetrazolo[1,5-а]pyrimidines.33—35
Tautomer structures were determined on the basis of
the NMR spectroscopy data. As a criterion for an assigne-
ment of signals of compound 8 in the 1Н NMR spectrum
1
elations in the Н—13С HMBC spectra. We have deter-
3
mined tautomer ratio for compound 11 in different solvents
(Table 1).
(DMSO-d6) to a specific tautomer, the JН,Н value was
Comparing tautomeric compositions for compound 11
with those for 2-azido-4-phenyl-40 and 2-azido-4-methyl-
pyrimidines30 in DMSO-d6, acetone-d6, and CDCl3
(see Table 1), the following conclusions may be drawn:
(1) a consistent increase of the electron density at the N(3)
atom of azide 11A caused by the presence of Ph and Me
groups contributes a lot to stabilization of tetrazole isomer
11T resulting in the absence of isomer 11Т´ in solutions
and (2) content of azide tautomer 11A is higher in low
polar solvents.
Table 1. Azide-tetrazole equilibrium for compounds 6a,
8, and 11
Сompound
Solvent
Tautomer
ratioa
T : T´ : A
6a
6a
8
8
8
DMSO-d6
CDCl3
1 : 0 : 99
0 : 0 : 100
32 : 0 : 68b
0 : 0 : 100
4 : 0 : 96
DMSO-d6
CDCl3
c
One-step synthesis and spectral studies of 2-azido-4-
(trifluoromethyl)pyrimidines 8 have demonstrated that
this compound exists in azide form 8A in CDCl3 solutions,
—
11
11
11
DMSO-d6
Acetone-d6
CDCl3
100 : 0 : 0
84 : 0 : 16
49 : 0 : 51
while in solution of highly polar DMSO-d6, a binary
←
equilibrium 8T
8A is established wherein tautomers
→
a
A tautomer ratio in the mixtures was determined from
the 1Н NMR spectra measured at 23—26 °С.
b At 50 °С.
present in comparable amounts (see Scheme 5). Our data
are consistent with the results of studies31,32 of the azide-
tetrazole equilibrium for 2-azido-6-trifluoromethylpyri-
c Without solvent (in an oily state).

898
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
Nikolaenkova et al.
used.6 Thus, protons at δН 8.12 and 10.15 were attributed
to tetrazole tautomer 8T based on 3J = 7.1 Hz. Other
lgk
0.4
3
protons at δН 7.79 and 9.09 with J = 5.0 Hz correspond
0.2
to azide form 8A. Analysis of cross peaks in two-dimen-
1
sional Н—13С HMBC and 1Н—13С HSQC spectra sup-
0
ported the correctness of such signal assignment (see
Scheme 5). Thus, the H(6) proton (δ 9.09) corresponding
to tautomer 8A correlates to downfiled signals of the carbon
atoms, namely, to a direct coupling with the C(6) atom at
δ 163.4 and with long range coupling with the C(2) atom
at δ 162.1, the chemical shifts of which are characteristic
of an azide form. The proton H(7) (δ 10.15) according to
the direct coupling constant value is bonded to the C(7)
carbon atom (δ 138.9), the upfield chemical shift value of
which compared to the corresponding chemical shift for
the carbon atom in an azide unambiguously confirms an
isomerization of azide 8A to tetrazol 8T. Compound 8 is
an oil, therefore, it was possible to measure its NMR
spectrum without any solvent. The presence of two forms
wherein azide form 8A was dominating has been revealed.
Identification was performed as described above based on
–0.2
–0.4
–0.6
–0.8
–1.0
–1.2
–0.150
–0.145 –1000•(2.3RT)–1
Fig. 1. Dependence of the rearrangement rate constant for
a tetrazole form of 5-(trifluoromethyl)tetrazolo[1,5-а]pyrimidine
(8T) in DMSO-d6 on temperature in Arrhenius coordinates. This
dependence is described by the equation y = 131.5692x + 18.8773
(correlation coefficient R = 1.0000).
3
3
the JH,H values (for the form 8T, JH,H ≈ 7 Hz30).
Tautomer ratio 8T : 8A was 4 : 96 at room temperature (see
Table 1).
R•(lnK)
Тhus, 6-(4-ClC6H4)group in compound 6а shifts
considerably the azide-tetrazole equilibrium towards an
azide tautomer compared to compound 8.
16
14
12
10
8
According to 1Н and 19F NMR spectra of compound 8
measured in DMSO-d6 at temperatures ranging from room
one to 100 °C, the azide-tetrazole rearrangement of this
compound is a slow process in the NMR time scale, hav-
ing no influence on signal broadening in the spectra.
However, at temperatures ranging from 70 to 100 °C, the
rearrangement becomes rapid enough for the exchange
cross peaks to appear in the EXSY spectrum along with
diagonal peaks. Earlier,41 we have successfully used the
EXSY technique to study kinetic characteristics of ex-
change processes in a series of substituted 4-azido-
pyrimidines. This enabled us to apply this technique in
calculation of the rate constants at four different tem-
peratures such as 70, 80, 90, and 100 °C (Fig. 1).
Temperature dependence of the equilibrium constant
of the azido-tetrazole tautomerism for 2-azido-4-
(trifluoromethyl)pyrimidine (8) was determined from
integral intensity of signals in 19F NMR spectra (Fig. 2).
Thermodynamic and kinetic parameters of the azide-
tetrazole tautomerism for 8 are given in Table 2.
6
4
Temperature rise
2
–3.1
–3.0
–2.9
–2.8
–1000•T–1
Fig. 2. Temperature dependence of the equilibrium constant (K)
for the azide-tetrazole tautomerism of 5-(trifluoromethyl)-
tetrazolo[1,5-а]pyrimidine (8T) in DMSO-d6. Rising the tem-
perature results in a growth of the equilibrium constant of isom-
erization of the tetrazole to an azide K = [8A]/[8T]. This depen-
dence is described by the equation y = 19.1349x + 65.6042
(correlation coefficient R = 0.9969).
(6а), H (8)). It was found that compound 6а exists in an
azide form in CDCl3, and only in DMSO-d6 a trace
amount of 5-(trifluoromethyl)-7-(4-chlorophenyl)tetr-
azolo[1,5-a]pyrimidine (6аТ) can be detected. Compound
8 exists in CDCl3 exclusively in an azide form, while
without solvent, 5-(trifluoromethyl)tetrazolo[1,5-a]pyr-
imidine (8Т) is also observed together with a dominant
tautomer, namely, 2-azido-4-(trifluoromethyl)pyrimidine
(8А), and the content of the former in DMSO-d6 increases
According to Table 2, the rate constant for the tetr-
azole-azide rearrangement for compound 8 at room tem-
perature was k298 = 6.23 0.06•105 s–1, corresponding to
the half-reaction time τ1/2 of about 30 h. Thus, to obtain
an equilibrium tautomeric mixture of compound 8 at room
temperature, a prolonged storage is needed.
We have studied a tautomeric equilibrium in a series
of 2-azido-4-(trifluoro)-6-R-pyrimidines (R = 4-ClC6H4

2-Azido-4-(trifluoromethyl)pyrimidines
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
899
1
Table 2. Thermodynamic and kinetic parameters of
rearrangement of 5-(trifluoromethyl)tetrazolo[1,5-a]-
pyrimidine (8T) into 2-azido-4-trifluoromethyl-
pyrimidine (8А) in DMSO-d6
120.3 (q, CF3, JС,F = 275.5 Hz); 129.2 (С(2,6-Ph)); 129.5
(С(3,5-Ph)); 132.8 (С(1-Ph)); 137.7 (С(4-Ph)); 156.9 (q, С(6),
2JС,F = 35.8 Hz); 162.1 (С(2)); 167.1 (С(4)). 19F NMR (282.37
MHz, DMSO-d6), δ: –71.0. 1Н NMR (600.30 MHz, CDCl3),
δ: 7.49 (m, 2 H, m-Ph); 7.68 (s, 1 H, H(5)); 8.07 (m, 2 H, o-Ph).
13C NMR (150.95 MHz, CDCl3), δ: 107.7 (q, С(5), 3JС,F = 2.9 Hz);
Parameter
Value
1
120.0 (q, CF3, JС,F = 275.5 Hz); 128.7 (С(2,6-Ph)); 129.5
ΔH/kJ mol–1
ΔS/J mol–1 К–1
ΔG298/J mol–1
Еа/kJ mol–1
lgA*
19.4 0.4
(С(3,5-Ph)); 132.9 (С(1-Ph)); 139.0 (С(4-Ph)); 158.3 (q, С(6),
2JС,F = 36.5 Hz); 163.2 (С(2)); 167.5 (С(4)). 19F NMR (282
MHz, CDCl3), δ: –73.2.
66
1
–268
9
131.6 0.6
18.9 0.1
6.23 0.06
30
5-(Trifluoromethyl)-7-(4-chlorophenyl)tetrazolo[1,5-a]pyr-
imidine (6aT). 1Н NMR (600.30 MHz, DMSO-d6), δ: 7.80
(m, 2 H, H(m-Ph)); 8.37 (m, 2 H, H(o-Ph)); 8.45 (s, 1 H, H(6)).
13C NMR (150.95 MHz, DMSO-d6), δ: 107.5 (С(6)); 120.2
(q, CF3); 132.0 (С(2,6-Ph)); 129.2 (С(3,5-Ph)); 126.7 (С(1-Ph));
138.2 (С(4-Ph)); 148.1 (С(7)); 154.3 (q, С(5), 2JС,F = 36.7 Hz);
154.8 (С(3а)). 19F NMR (282.37 MHz, DMSO-d6), δ: –69.7.
Synthesis of compound 8. To a stirred solution of 2-hydr-
azino-6-(trifluoromethyl)pyrimidine (0.356 g, 2 mmol) in
a mixture of concentrated HCl (1 mL) and water (6 mL) on
cooling (ice—water), a solution of NaNO2 (0.1 g, 1.5 mmol) in
water (1.5 mL) was added dropwise. The reaction mixture was
stirred for 2 h, diluted with water, neutralized with aqueous NH3,
extracted with CHCl3, and dried over MgSO4. The solvent was
evaporated, and the residue was purified by column chromato-
graphy on SiO2 (eluent — CHCl3). Product 8 was obtained as an
oil (0.220 g, 58%). IR (thin film), ν/cm–1: 2149 (N3). Found:
m/z 189.0252 [M]+. C5H2F3N5. Calculated: M = 189.0257. The
ratio of tautomers 8A and 8T are given in Table 1.
k298•105/s–1
τ1/2/h
* A is Pre-exponential factor in the Arrhenius equa-
tion.
with time. For compound 8, kinetic rearrangement para-
meters have been determined using EXSY, and the rate
constant for the conversion of 5-(trifluoromethyl)tetr-
azolo[1,5-a]pyrimidine (8Т) to 2-azido-4-(trifluoro-
methyl)pyrimidine (8А) at room temperature has been
evaluated, being equal to k298 = 6.23 0.06•105 s–1
.
Experimental
Melting points were determined on a Mettler Toledo FP-900
apparatus. IR spectra were obtained on a Vector-22 Fourier
transform spectrometer. High-resolution mass spectra were re-
corded on DFS-Termoelectron apparatus (ionization energy
70 eV, direct injection of a sample, ion source temperature 50 °C).
Elemental analysis was performed using a Euro EA3000 CHNS-
analyzer. NMR spectra were recorded on Bruker AV-600 (600.30,
150.95, and 564.81 MHz for 1Н, 13С, and 19F, respectively),
Bruker AV-400 (400.13 MHz for 1Н), Bruker AV-300 (300.13 and
282.37 MHz for 1Н and 19F, respectively), and Bruker DRX-500
2-Azido-4-(trifluoromethyl)pyrimidine (8A). 1H NMR
3
(600.30 MHz, DMSO-d6), δ: 7.79 (d, 1 Н, Н(5), JH(5),H(6)
= 5.0 Hz); 9.09 (dq, 1 Н, Н(6), 3JH(6),H(5) = 5.0 Hz, 5JH(6),F
=
=
= 0.4 Hz). 13С NMR (150.95 MHz, DMSO-d6), δ: 113.5 (q, С(5),
3JC,F = 2.6 Hz); 119.9 (q, СF3, 1JC,F = 276.2 Hz); 155.7 (q, С(4),
2JC,F = 36.0 Hz); 162.1 (С(2)); 163.4 (С(6)). 19F NMR
(564.81 MHz, DMSO-d6), δ: –69.2. 1H NMR (300.13 MHz,
CDCl3), δ: 7.35 (d, 1 Н, Н(5), 3JH(5),H6 = 5.0 Hz); 8.83 (dq, 1 Н,
Н(6), JH(6),H(5) = 5.0 Hz, JH(6),F = 0.4 Hz). 13С NMR
3
5
(125.75 MHz, CDCl3), δ: 112.3 (q, С(5), 3JC,F = 2.7 Hz); 119.8
1
1
2
(500.13 and 125.75 MHz for Н and 13С, respectively) spectro-
(q, СF3, JC,F = 275.7 Hz); 157.6 (q, С(4), JC,F = 37.1 Hz);
161.6 (С(6)); 163.0 (С(2)). 19F NMR (282.37 MHz, CDCl3, δ,
м.д.): –73.3. 1H NMR (400.13 MHz, without solvent), δ: 7.35
meters in DMSO-d6 (δН 2.50, δС 39.50), acetone-d6 (δН 2.04,
δС 29.80), and CDCl3 (δН 7.24, δС 76.90). Chemical shifts in
1H and 13С spectra are given relative to the residual solvent sig-
nals (an internal standard). Chemical shifts in 19F spectra are
given relative to trichlorofluoromethane (δF 0 ppm) (an external
standard).
Synthesis of compound 6a. To a solution of 2-chloro-4-(4-
chlorophenyl)-6-(trifluoromethyl)pyrimidine (0.586 g, 2 mmol)
in anhydrous DMF (15 mL), NaN3 (0.16 g, 2.5 mmol) and
anhydrous LiCl (0.11 g, 2.5 mmol) were added. The resulting
mixture was stirred for 14 h at 40—50 °C, then cooled and poured
into water. The precipitate was filtered, washed with water, and
air-dried to a constant weight. Product 6a was obtained (0.46 g,
77%), m.p. 89—90 °C. IR (KBr), ν/сm–1: 2141 (N3). Found (%):
С, 44.11; H, 1.72; Сl, 11.86; F, 19.04; N, 23.42. C11H5ClF3N5.
Calculated (%): С, 44.09; H, 1.68; Cl, 11.83; F, 19.02; N, 23.37.
Ratio of tautomers 6aА and 6aT are given in Table 1.
(d, 1 Н, Н(5), 3JH(5),H6 = 5.0 Hz; 8.78 (d, 1 Н, Н(6), 3JH(6),H5
=
= 5.0 Hz). 13С NMR (125.75 MHz, without solvent), δ: 113
3
1
(q, С(5), JC,F = 2.6 Hz); 121 (q, СF3, JC,F = 276 Hz); 158
(q, С(4), 2JC,F = 36.0 Hz); 163(С(6)); 164 (С(2)).
5-(Trifluoromethyl)tetrazolo[1,5-a]pyrimidine (8T). 1H NMR
3
(600.13 MHz, DMSO-d6), δ: 8.12 (d, 1 Н, Н(6), JH(6),H(7)
= 7.1 Hz); 10.15 (dq, 1 Н, Н(7), 3JH(6),H(7) = 7.1 Hz, 5JH(7),F
=
=
= 0.3 Hz). 13С NMR (150.95 MHz, DMSO-d6), δ: 109.5 (q, С(6),
3JC,F = 1.4 Hz); 120.1 (q, СF3, 1JC,F = 275.0 Hz); 138.9 (C(7));
153.8 (C(3a)); 154.5 (q, С(5), JC,F = 36.8 Hz). 19F NMR
2
(564.81 MHz, DMSO-d6), δ: –68.0. 1H NMR (400.13 MHz,
3
without solvent), δ: 7.84 (d, 1 Н, Н(6), JH(7),H(6) = 7.1); 9.78
(d, 1 Н, Н(7), 3JH(6),H7 = 7.1 Hz).
Synthesis of compound 11. To a solution of 2-hydrazino-4-
methyl-6-phenylpyrimidine (0.6 g, 3 mmol) in 70% acetic acid
(15 mL), a solution of NaNO2 (0.42 g, 6 mmol) in water (5 mL)
was added over ~15 min on cooling with ice water. The reaction
mixture was stirred further for 1.5 h at ~0 °C, diluted with ~15 mL
of water, in a while, the precipitate was filtered, washed with
2-Azido-4-(4-chlorophenyl)-6-(trifluoromethyl)pyrimidine
(6aA). 1Н NMR (600.30 MHz, DMSO-d6), δ: 7.60 (m, 2 H,
m-Ph); 8.27 (m, 2 H, o-Ph); 8.31 (s, 1 H, H(5)). 13C NMR
3
(150.95 MHz, DMSO-d6), δ: 109.0 (q, С(5), JС,F = 2.6 Hz);

900
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
Nikolaenkova et al.
water, and dried. Compound 11T was obtained (0.45 g, 71%),
m.p. 186—189 °C (EtOH―dioxane). Found (%): С, 62.49;
H, 4.22; N, 33.27. C11H9N5. Calculated (%): С, 62.49; H, 4.14;
N, 33.16.
which are comparable with those of the spin-lattice relaxation.
Because of an exchange in the EXSY spectra, cross peaks, being
indicative of signals, become to appear together with diagonal
ones.42,43 General view of the EXSY spectra is illustrated in
Fig. 3 by the example of 19F—19F EXSY spectrum of compound 8.
The rate constant for the tetrazole-azide transition was cal-
culated from an integral intensity of cross and diagonal peaks in
NOESY/EXSY spectrum providing the balance of the spin-spin
relaxation of atoms under consideration by the equation44
2-Azido-4-methyl-6-phenylpyrimidine (11A). 1H NMR
(500.13 MHz, CDCl3), δ: 2.53 (s, 3 Н, СН3); 7.30 (s, 1 H, Н(5));
7.48 (m, 3 Н, H(m-Ph), H(p-Ph)); 8.06 (m, 2 Н, H(о-Ph)).
13С NMR (125.75 MHz, CDCl3), δ: 24.1 (СН3); 111.9 (С(5));
127.1 (С(2,6-Ph)); 128.8 (С(3,5-Ph)); 131.2 (С(4-Ph)); 135.7
(С(1-Ph)); 162.0 (С(2)); 165.5 (C(6)); 170.1 (С(4)). 1H NMR
(600.30 MHz, acetone-d6), δ: 2.52 (s, 3 Н, СН3); 7.69 (s, 1 H,
Н(5)); 7.53—7.56 (m, 3 Н, H(m,p-Ph)); 8.19 (m, 2 Н, H(o-Ph)).
13С NMR (125.75 MHz, acetone-d6), δ: 24.1 (СН3); 113.1 (С(5));
128.0 (С(2,6-Ph)); 129.8 (С(3,5-Ph)); 132.2 (С(4-Ph)); 136.8
(С(1-Ph)); 162.8 (С(2)); 166.3 (C(6)); 171.7 (С(4)).
,
(1)
where K is an equilibrium constant for the azide-tetrazole tauto-
merism; τ is a mixing (exchange) time, s; ITT and IAA are inten-
sities of diagonal peaks; Icross = 0.5(ITA + IAT) is a half-sum of
cross peak intensities.
The values of ΔH, ΔS, and Еа, lgА and the accuracy thereof
were calculated by the least square method using the Excel software.
7-Methyl-5-phenyltetrazolo[1,5-a]pyrimidine (11T). 1H NMR
4
(500.13 MHz, CDCl3), δ: 3.04 (d, 3 Н, СН3, JH,H = 1.0 Hz);
4
7.51 (q, 1 H, Н(6), JH,H = 1.0 Hz); 7.56 (m, 2 Н, H(m-Ph));
7.59 (m, 1 Н, H(p-Ph)); 8.21 (m, 2 Н, H(o-Ph)). 13С NMR
(125.75 MHz, CDCl3), δ: 17.3 (СН3); 108.9 (С(6)); 128.1 (С(2,6-Ph));
129.2 (С(3,5-Ph)); 132.3 (С(4-Ph)); 135.1 (С(1-Ph)); 145.3
(С(7)); 155.3 (С(3a)); 164.6 (С(5)). 1H NMR (600.30 MHz,
The authors gratefully acknowledge the Chemical
Service Center of Collective Use of the Siberian Branch
of Russian Academy of Sciences for spectral and analyti-
cal measurements.
The present study was financially supported by the
Ministry of Education and Science of the Russian Feder-
ation (Competitiveness Enhancement Program for Lead-
ing Universities of Russian Federation among Leading
World Research and Educational Centers, Project No. 5-100)
and the Russian Foundation for Basic Research (Project
No. 18-33-00172mol_а).
4
acetone-d6), δ: 3.05 (d, 3 Н, СН3, JH,H = 1.0 Hz); 7.60—7.66
(m, 3 Н, H(m,p-Ph)); 8.04 (q, 1 H, Н(6), 4JH,H = 1.0 Hz); 8.36
(m, 2 Н, H(o-Ph)). 13С NMR (125.75 MHz, acetone-d6), δ: 17.2
(СН3); 110.0 (С(6)); 129.0 (С(2,6-Ph)); 130.0 (С(3,5-Ph)); 132.9
(С(4-Ph)); 136.8 (С(1-Ph)); 147.5 (С(7)); 156.5 (С(3a)); 165.2
(С(5)). 1H NMR (600.30 MHz, DMSO-d6), δ: 2.96 (d, 3 Н,
СН3, 4JH,H = 1.00 Hz); 8.17 (q, 1 H, Н(6), 4JH,H = 1.0 Hz); 7.64
(m, 3 Н, H(m,p-Ph)); 8.33 (m, 2 Н, H(o-Ph)). 13С NMR
(150.75 MHz, DMSO-d6), δ: 16.8 (СН3); 109.5 (С(6)); 128.1
(С(2,6-Ph)); 129.3 (С(3,5-Ph)); 132.2 (С(4-Ph)); 135.2 (С(1-Ph));
146.7 (С(7)); 155.0 (С(3a)); 163.8 (С(5)).
Calculation of rate constants. In the present study, rate con-
stants for a tautomeric rearrangement were determined using
NOESY/EXSY technique. This method allows the most precise
study of relatively slow reversible processes, the rates of
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Received June 30, 2017;
in revised form December 5, 2017;
accepted March 19, 2018