New approach to the synthesis of azauracils and azaisocytosines

Article abstract of DOI:10.1007/s11172-006-0550-2

A new procedure was developed for the synthesis of 6-phenyltetrazolo[1,5-b] triazin-7-one. Aza analogs of uracil and isocytosine were prepared by the tetrazole ring cleavage. It was demonstrated that these transformations can be used in the synthesis of a

Full text of DOI:10.1007/s11172-006-0550-2

Russian Chemical Bulletin, International Edition, Vol. 55, No. 11, pp. 2071—2080, November, 2006
2071
New approach to the synthesis of azauracils and azaisocytosines*
b
c
T. S. Shestakova,a S. L. Deev,b E. N. Ulomsky,a V. L. Rusinov,a O. N. Chupakhin, O. A. D´yachenko,
ꢀ
O. N. Kazheva,c A. N. Chekhlov,c P. A. Slepukhin,b and M. I. Kodessb
aUral State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 0458. Eꢀmail: rusinov@htf.ustu.ru
bI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 1189. Eꢀmail: chupakhin@ios.uran.ru
cInstitute of Problems of Chemical Physics, Russian Academy of Sciences,
1 prosp. Akad. Semenova, 142432 Chernogolovka, Moscow Region, Russian Federation.
A new procedure was developed for the synthesis of 6ꢀphenyltetrazolo[1,5ꢀb]triazinꢀ7ꢀone.
Aza analogs of uracil and isocytosine were prepared by the tetrazole ring cleavage. It was
demonstrated that these transformations can be used in the synthesis of anomalous nucleoꢀ
sides.
Key words: tetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriazine, azauracil, azaisocytosine, alkylation, azidoꢀ
tetrazole rearrangement, destruction.
3,5ꢀDioxoꢀ1,2,4ꢀtriazine derivatives (6ꢀazauracils)
have been widely described in the literature. For example,
anomalous nucleosides and nucleotides based on azaꢀ
uracils have antiviral and antitumor activity.1—3 The
azauracil fragment is present in the structure, which is
a promising ligand for positron emission tomography.4
A glutamate receptor antagonist was designed based on
3,5ꢀdioxoꢀ1,2,4ꢀtriazines.5 In addition, compounds havꢀ
ing antiasthmatic activity were found among azauracils.6,7
Hence, the development of new procedures for the synꢀ
thesis of aza derivatives of pyrimidine bases is an imporꢀ
tant problem.
Earlier, we have described various procedures for
partial destruction of azoloannelated pyrimidines and
1,2,4ꢀtriazines,8—11 which were used as nontrivial synꢀ
thetic approaches for the synthesis of substituted nonfused
1,2,4ꢀtriazines, including the synthesis of the antiepileptic
drug lamotrigine.11 The efficiency and advantages of this
procedure over conventional synthesis methods were
demonstrated.11
occur selectively. It should be noted that direct alkylaꢀ
tion of 3,5ꢀdioxoꢀ1,2,4ꢀtriazines at the N(2) atom giving
rise to N,Nꢀdialkyl derivatives as byꢀproducts is generꢀ
ally used.12,13 To synthesize alkylation products at the
N(4) atom, it is necessary to initially acylate the starting
triazine at the N(2) atom.4,14
The synthesis of 6ꢀphenyltetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriꢀ
azinꢀ7ꢀone (1) by annulation of the tetrazole ring in the
reaction of 3ꢀhydrazinoꢀ5ꢀoxoꢀ6ꢀphenylꢀ2,5ꢀdihydroꢀ
1,2,4ꢀtriazine with nitric acid was documented.15 We deꢀ
veloped an alternative procedure for the synthesis of comꢀ
pound 1 based on the reaction of diazotetrazole 3 with
ethyl phenyl(formyl)acetate 4 (Scheme 1).
We used formyl derivative 4 because ethyl phenylꢀ
acetate is not involved in the azoꢀcoupling reaction,
whereas the introduction of the electronꢀwithdrawing
formyl group leads to an increase in CHꢀacidity. The
reaction of diazotetrazole 3 with CHꢀactive compound 4
produced hydrazone 5, the azoꢀcoupling reaction
being accompanied by elimination of the formyl group.
After further refluxing in acetic acid, compound 5
was transformed into 6ꢀphenyltetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriꢀ
azinone (1). It should be noted that hydrazone 5 can
undergo cyclization to give exclusively tetrazolo[5,1ꢀc]ꢀ
1,2,4ꢀtriazinone 6, whose transformation into tetrꢀ
azolo[1,5ꢀb]ꢀ1,2,4ꢀtriazinone (1) can occur only with the
involvement of the azidoꢀtetrazole rearrangement, i.e.,
through the formation of azide 7.
In the present study, we extended the scope of this
synthetic approach and used it for introducing an alkyl
substituent at the N(4) position of 3,5ꢀdioxoꢀ and 3ꢀamiꢀ
noꢀ5ꢀoxoꢀ1,2,4ꢀtriazines, which are aza analogs of uracil
and isocytosine, respectively. This became possible due to
the fact that Nꢀalkylation of tetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriazinꢀ
7ꢀone (1) and subsequent cleavage of the tetrazole ring
The mass spectrum of compound 1 has a molecular
ion peak (Table 1). The IR spectrum shows an absorption
* Dedicated to Academician O. M. Nefedov on the occasion of
his 75th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1993—2001, November, 2006.
1066ꢀ5285/06/5511ꢀ2071 © 2006 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 55, No. 11, November, 2006
Shestakova et al.
Scheme 1
band at 1711 cm–1 assigned to the carbonyl group.
The absence of the signal of the azide group at
2210—2240 cm–1 in the IR spectrum of compound 1
indicates that this heterocycle has a bicyclic structure.
The 1H NMR spectrum of heterocycle 1 shows signals
for the protons of the phenyl substituent at δ 7.40—8.10
(Table 2).
Both the protonꢀcoupled and protonꢀdecoupled
13C NMR spectra of compound 1 contain signals of the
tetrazolotriazine system and the phenyl substituent at low
field (Table 3).
tetrazole and triazine rings in compounds 1 and 6 (parꢀ
ticularly, in solution). Although the structure of comꢀ
pound 1 was discussed in the literature, the proof of the
mode of fusion of the azole and azine rings based on
13C NMR spectroscopic data seems to be unconvincing.15
Hence, to solve this problem, we synthesized 5ꢀaminoꢀ
tetrazole 2* with the use of 15Nꢀlabeled aminoguanidine
bicarbonate 8* (the isotope abundance was 87 %)
(Scheme 2).
The position of the isotope label in aminoguanidine
8* and the method used for the synthesis of compound 2*
enabled the introduction of the 15N isotope at the
N(2) position of the tetrazole ring. The subsequent use of
amine 2* in diazotization and azoꢀcoupling reactions alꢀ
lowed us to prepare hydrazone 5*.
However, all these data did not allow us to unambiguꢀ
ously conclude whether cyclization of hydrazone 5 is acꢀ
companied by the azidoꢀtetrazole rearrangement. These
data are insufficient to establish the mode of fusion of the
Scheme 2

Synthesis of azauracils and azaisocytosines
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 11, November, 2006 2073
Table 1. Melting points, yields, molecular weights (massꢀspecꢀ
trometric data), and IR spectroscopic data for compounds 1, 5,
9, 10a—e, 12a—d, 13a—e, and 14
nonequivalent interactions between the carbon atom and
the 15N isotope, which can occur both in a mixture of
compounds 6a* and 6b* and in a mixture of heterocycles
1a* and 1b*. In this spectrum, the signal at δ 151.69
belonging to the C(6) atom has a simpler multiplet strucꢀ
ture due to a longꢀrange interaction with one 15N atom,
and a signal for the C(7) atom appears as a singlet because
it does not interact with the 15N isotope (see Table 3).
This spectral pattern corresponds only to structure 1b*.
We unambiguously established that compound 1 exists in
solution as tetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriazine, and its formaꢀ
tion from hydrazone 5 occurs through the azidoꢀtetrazole
rearrangement involving bicyclic compound 6 and azide 7.
8ꢀAlkyl derivatives of compound 1 were synthesized
with the use of the sodium salt of tetrazolotriazine 9,
which was prepared by the treatment of NHꢀheterocycle 1
Comꢀ
pound
M.p.a
/°C
Yield
(%)
[M]+,
m/z (I (%))
IR,
ν/cm–1
1
5
9
10a
10b
10c
10d
10e
225
172—174
311b
182c
159
80
86
87
56
45
50
65
40
214 (25.19)
260 (23.19)
236 (1.44)
228 (18.54)
242 (7.03)
256 (11.80)
254 (7.88)
328 (11.93)
1711 (СО)
1632 (СО)
1630 (СО)
1730 (CO)
1696 (CO)
1697 (CO)
1700 (CO)
1700 (СO)
1750 (СО)
1676 (CO)
137c
93
67
12a
12b
12c
12d
13a
13b
13c
13d
13e
14
265
221
149d
165e
199
164
154c
149
138
174
35
49
39
32
49
57
41
39
34
29
202 (100.00)
216 (56.21)
230 (40.95)
228 (100.00)
203 (100.00)
217 (75.90)
231 (44.73)
229 (88.69)
261 (30.49)
263 (9.59)
3340 (NH2)
3387 (NH2)
1679 (CO)
3320 (NH2)
3393 (NH2)
1684 (CO)
3310 (NH2)
3399 (NH2)
1679 (CO)
3332 (NH2)
3421 (NH2)
1705 (CO)
1722 (СО)
3204 (NH)
1697 (CO)
1717 (CO)
3200 (NH)
1676 (CO)
1720 (CO)
3196 (NH)
1680 (CO)
1715 (CO)
3200 (NH)
1670 (CO)
1704 (CO)
3160 (NH)
1666 (CO)
1708 (CO)
3200 (NH)
with a sodium carbonate solution (Scheme 3). The reacꢀ
tion of compound 9 with various alkylating agents in DMF
at 100 °C was completed in a few hours. The yields of
alkyl derivatives 10a—e were 40—65%.
Scheme 3
X = Br, I
10: R = Me (a), Et (b), Pr (c), CH2—CH=CH2 (d),
CH2—(CH2)3—OAc (e)
The structure of salt 9 (Na+[C9H5N6O]–•3H2O,
Fig. 1) was established by singleꢀcrystal Xꢀray diffraction
study of the product prepared by the reaction of heteroꢀ
cycle 1 with sodium carbonate. The geometric parameters
of the organic ion are similar to those typical of tetrꢀ
azolo[1,5ꢀb]ꢀ1,2,4ꢀtriazines (Table 4).16,11 The azole and
azine rings form a virtually planar heterocyclic system, in
which the phenyl substituent deviates from the conjugaꢀ
tion system. The dihedral angle between the triazine ring
and the phenyl group is 43.4°. The N(1) atom of the
tetrazole ring is coordinated to the sodium ion, which, in
turn, is surrounded by water molecules. The sodium ions
are linked to each other through the oxygen bridges to
a After recrystallization from ethanol.
b After recrystallization from water.
c After recrystallization from isopropyl alcohol.
d After recrystallization from acetic acid
e After recrystallization from benzene.
Cyclization of compound 5* afforded a mixture of two
derivatives, whose structures differ only in the position of
the isotope label. This was established by 13C NMR specꢀ
troscopy. For example, the signal for the C(8a) bridgeꢀ
head atom (δ 145.54) in the fully protonꢀdecoupled
13C NMR spectrum of this mixture (see Table 3) has a
complex multiplet structure. This is indicative of several

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Shestakova et al.
Table 2. 1H NMR spectroscopic data for compounds 1, 5, 10a—e, 12a—d, 13a—e, and 14
Comꢀ
pound
δ
1
5
7.47—7.58 (m, 3 Н, Ph); 8.05—8.09 (m, 2 Н, Ph);
1.30 (t, 3 H, O—CH2—CH3); 4.42 (q, 2 Н, О—СН2—Me); 7.42—7.50 (m, 3 Н, Ph); 7.74—7.77 (m, 2 Н, Ph);
11.93 (br.s, 1 Н, NH); 15.71 (br.s, 1 Н, NH)
9
7.41—7.44 (m, 3 Н, Ph); 8.14—8.18 (m, 2 Н, Ph);
10a
10b
10c
3.62 (s, 3 H, N—Me); 7.48—7.59 (m, 3 H, Ph); 8.04—8.08 (m, 2 H, Ph)
1.34 (t, 3 Н, N—CH2—CH3); 4.16 (q, 2 Н, N—CH2—Me); 7.50—7.60 (m, 3 Н, Ph); 8.05—8.09 (m, 2 Н, Ph)
0.97 (t, 3 Н, N—CH2—CH2—CH3); 1.76—1.85 (m, 2 Н, N—СН2—СН2—Me); 4.08 (t, 2 Н,
N—CH2—CH2—Me); 7.55—7.65 (m, 3 Н, Ph); 8.00—8.04 (m, 2 Н, Ph)
10d
10e
4.47 (d, 2 Н, N—CH2—CH=CH2); 5.26, 5.46 (both dd, 1 H each, N—CH2—CH=CH2);
5.90—5.97 (m, 1 H, N—CH2—CH=CH2); 7.53—7.64 (m, 3 Н, Ph); 8.00—8.04 (m, 2 Н, Ph)
1.64—1.74 (m, 2 Н, СН2—СН2—СН2—О—СО—Me); 1.76—1.89 (m, 2 Н, СН2—СН2—СН2—О—СО—Me);
1.96 (s, 3 Н, СН2—СН2—СН2—О—СО—Me); 4.02 (t, 2 Н, СН2—СН2—СН2—О—СО—Me); 4.16 (t, 2 Н,
N—CH2—CH2); 7.48—7.63 (m, 3 Н, Ph); 8.04—8.10 (m, 2 Н, Ph)
12a
12b
3.37 (s, 3 H, N—Me); 7.30—7.40 (m, 3 H, Ph and 2H, NH2); 8.02—8.06 (m, 2 H, Ph)
1.24 (t, 3 Н, N—CH2—Me); 4.00 (q, 2 Н, N—CH2—Me); 7.30—7.37 (m, 3 Н, Ph + 2 Н, NH2);
8.01—8.06 (m, 2 Н, Ph)
12c
12d
0.96 (t, 3 Н, N—CH2—CH2—CH3); 1.64—1.69 (m, 2 Н, N—CH2—CH2—Me); 3.90 (t, 2 Н,
N—CH2—CH2—Me); 7.20—7.40 (m, 3 Н, Ph and 2 Н, NH2); 8.00—8.06 (m, 2 Н, Ph)
4.59 (d, 2 Н, N—CH2—CH=CH2); 5.15, 5.18 (both dd, 1 H each, N—CH2—CH=CH2);
5.82—5.91 (m, 1 Н, N—CH2—CH=CH2); 7.34—7.44 (m, 3 Н, Ph and 2 Н, NH2); 8.00—8.04 (m, 2 Н, Ph)
3.27 (s, 3 Н, N—Me); 7.37—7.42 (m, 3 Н, Ph); 7.88—7.93 (m, 2 Н, Ph); 12.60 (br.s, 1 Н, NH)
1.22 (t, 3 Н, N—CH2—CH3); 3.93 (q, 2 Н, N—CH2—Me); 7.38—7.41 (m, 3 Н, Ph); 7.87—7.92 (m, 2 Н, Ph);
12.61 (br.s, 1 Н, NH)
13a
13b
13c
13d
0.95 (t, 3 Н, N—CH2—CH2—CH3); 1.61—1.70 (m, 2 Н, N—CH2—CH2—Me); 3.83 (t, 2 Н, N—CH2—CH2—Me);
7.38—7.42 (m, 3 Н, Ph); 7.87—7.92 (m, 2 Н, Ph); 12.61 (br.s, 1 Н, NH)
4.47 (d, 2 Н, N—CH2—CH=CH2); 5.18, 5.24 (both dd, 1 H each, N—CH2—CH=CH2);
5.81—5.89 (m, 1 H, N—CH2—CH=CH2); 7.36—7.50 (m, 3 Н, Ph); 7.80—7.92 (m, 2 Н, Ph);
12.68 (br.s, 1 Н, NH)
13e
14
1.46—1.54 (m, 2 Н, СН2—СН2—СН2—ОН); 1.61—1.73 (m, 2 Н, СН2—СН2—СН2—ОН); 3.44 (q, 2 Н,
СН2—СН2—ОН); 3.88 (t, 2 Н, N—CH2—CH2); 4.08 (t, 1 Н, СН2—ОН); 7.37—7.41 (m, 3 Н, Ph);
7.88—7.93 (m, 2 Н, Ph); 12.57 (br.s, 1 Н, NH)
3.41 (t, 2 Н, СН(ОН)—СН2—ОН); 3.76—3.91 (m, 2 Н, N—CH2—CH(OH)); 4.00—4.06 (m, 1 Н,
N—CH2—CH(OH)); 4.27 (t, 1 Н, СН2—ОН); 4.52 (d, 1 Н, СН—ОН); 7.38—7.41 (m, 3 Н, Ph);
7.88—7.94 (m, 2 Н, Ph); 12.65 (br.s, 1 Н, NH)
O(1)
C(8)
O(2S)
N(6)
C(7)
C(6)
C(5)
C(4)
C(9)
Na(1)
O(1S)
C(1)
N(1)
N(2)
C(3)
N(4)
N(3)
N(5)
O(3S)
C(2)
Fig. 1. Structure of the Na+[C9H5N6O]–•3H2O salt (9).
form polymeric chains with an Na—Na distance of 3.765 Å
(Fig. 2). As a result, sodium forms an octahedral comꢀ
plex, in which the metal ion is linked to one heterocyclic
ligand and five water molecules (Table 5). This is a conseꢀ
quence of a weak πꢀπ interaction and an extensive hydroꢀ
gen bond network in the crystal structure (Table 6). The
πꢀπ overlap of the phenyl substituents is evident from the
distance between the tetrazolotriazine ligands in the stacks
(3.765 Å).17
The mass spectra of compounds 10a—e have molecuꢀ
lar ion peaks (see Table 1). In the IR spectra, the stretchꢀ
ing vibrations in the 1690—1750 cm–1 region (see Table 1)

Synthesis of azauracils and azaisocytosines
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 11, November, 2006 2075
Table 3. 13C NMR spectroscopic data for compound 1, a mixture of 1a* and 1b*, and compounds 10a—e
Comꢀ
pound
δ (J/Hz)
C(6)
C(7)
C(8a)
Ph
R
1
151.66
153.94 (s)
145.62 (s)
131.51, 130.87,
129.49, 128.26
131.53, 130.84,
129.50, 128.28
131.73, 130.69,
129.51, 128.40
131.65, 130.77,
129.56, 128.33
(t, 3JСН = 3.8)
151.69 (m)
1а*, 1b*
10a
153.94 (s)
145.54 (m)
150.63
(t, 3JСН = 3.7)
151.02
(t, 3JСН = 3.7)
152.95
(q, 3JСН = 2.9)
152.41
(t, 3JСН = 3.8)
146.72
(q, 3JСН = 3.3)
146.11
30.16 (q, 1JCH = 144.0)
10b
11.64 (qt, 1JCH = 128.6,
3JCH = 3.4); 38.28 (tq,
1JCH = 143.9, 3JCH = 4.6)
11.11 (qm, 1JCH = 126.1);
3
(t, JСН = 4.4)
10c
10d
150.97
152.67
146.45
(t, JСН = 4.3)
131.64, 130.79,
129.56, 128.31
3
1
(t, 3JСН = 4.0)
(t, 3JСН = 3.7)
19.79 (tm, JCH = 129.1);
45.68 (tm, 1JCH = 142.9)
46.04 (tm, 1JCH = 143.6);
118.90 (ddt, 1JCH = 159.2,
1JCH = 156.1, 3JCH = 5.4);
129.60*
150.98
(t, 3JСН = 3.5)
152.37
(t, 3JСН = 3.7)
146.23
(t, JСН = 4.1)
131.71, 130.72,
129.58, 128.35
3
10e
150.99
(t, 3JСН = 3.7)
152.72
(t, 3JСН = 3.7)
146.23
(t, JСН = 4.3)
131.69, 130.78,
129.59, 129.35
20.67 (q, 1JCH = 129.3);
23.06 (dm, 1JCH = 133.5);
25.32 (tm, 1JCH = 127.7);
43.71 (tm, 1JCH = 143.6);
63.31 (tm, 1JCH = 147.0)
3
* The signal overlaps with the signal for the orthoꢀcarbons of the phenyl substituent.
Table 4. Selected bond lengths and bond angles in the organic ion of the Na+[C9H5N6O]–•3H2O salt (9)
Parameter
Value
Parameter
Value
Parameter
Value
Bond
d/Å
Bond
d/Å
Bond
d/Å
C(7)—N(1)
C(7)—N(6)
C(7)—N(4)
C(8)—O(1)
1.335(3)
1.344(3)
1.349(2)
1.241(3)
ω/deg
C(8)—N(6)
C(8)—C(9)
C(9)—N(5)
C(9)—C(1)
1.350(2)
1.514(2)
1.302(3)
1.482(2)
ω/deg
N(1)—N(2)
N(2)—N(3)
N(3)—N(4)
N(4)—N(5)
1.363(3)
1.293(3)
1.359(2)
1.356(2)
ω/deg
Angle
Angle
Angle
N(1)—C(7)—N(6)
N(1)—C(7)—N(4)
N(6)—C(7)—N(4)
O(1)—C(8)—N(6)
O(1)—C(8)—C(9)
N(6)—C(8)—C(9)
130.12(2)
107.49(2)
122.39(2)
121.53(2)
119.72(2)
118.73(2)
N(5)—C(9)—C(1)
N(5)—C(9)—C(8)
C(1)—C(9)—C(8)
C(7)—N(1)—N(2)
N(3)—N(2)—N(1)
N(2)—N(3)—N(4)
115.45(2)
123.08(2)
121.42(2)
104.82(2)
113.46(2)
103.99(2)
C(7)—N(4)—N(5)
C(7)—N(4)—N(3)
N(5)—N(4)—N(3)
C(9)—N(5)—N(4)
C(7)—N(6)—C(8)
126.47(2)
110.24(2)
123.29(2)
113.15(2)
116.14(2)
Table 5. Coordination environment of the sodium cation in the Na+[C9H5N6O]–•3H2O salt (9)
Bond
d/Å
Angle
ω/deg
Angle
ω/deg
Na(1)—N(1)
2.513(2) O(2SA)—Na(1)—O(3SA)
2.464(3) O(2SB)—Na(1)—O(3SB)
2.502(2) O(2SB)—Na(1)—O(3SB)
2.319(2) O(3SA)—Na(1)—O(3SB) 100.20(7)
2.637(3) N(1)—Na(1)—O(3SB) 95.10(8)
2.405(2) O(3SA)—Na(1)—O(3SB) 100.20(7)
81.57(8)
83.09(9)
95.14(7)
N(1)—Na(1)—O(3SB)
N(1)—Na(1)—O(2SA)
N(1)—Na(1)—O(3SA)
N(1)—Na(1)—O(3SB)
N(1)—Na(1)—Na(1)
95.14(7)
83.80(8)
79.94(7)
98.43(8)
80.02(6)
Na(1)—O(2SA)
Na(1)—O(3SA)
Na(1)—O(1S)
Na(1)—O(2SВ)
Na(1)—O(3SB)

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Shestakova et al.
Table 6. Hydrogen bond parameters for the Na+[C9H5N6O]–•3H2O salt (9)
D—H
d(D—H)
d(H..A)
d(D..A)
DHA Angle
/deg
Atom
Transformation
Å
O(3S)—H(3SB)
O(2S)—H(2SB)
O(3S)—H(3SA)
O(2S)—H(2SA)
O(1S)—H(1SA)
O(1S)—H(1SB)
0.918
0.957
1.022
0.833
0.851
0.961
2.045
1.928
1.871
2.343
1.909
2.162
2.840
2.861
2.802
3.079
2.747
2.831
144.05
164.31
149.79
147.67
167.94
125.53
N(2)
N(6)
O(1)
O(2)S
O(1)
(x – 1, y, z)
(x + 1/2, –y + 1/2, –z)
(x, y – 1, z)
(x – 1/2, –y + 1/2, –z)
(x + 1/2, –y + 1/2, –z)
(x – 1/2, –y – 1/2, –z)
O(1)S
Fig. 2. Structure of the stack formed by the Na+[C9H5N6O]–•3H2O salt (9).
are assigned to the carbonyl group. This is evidence of
Nꢀalkylation of salt 9.
The tetrazole and triazine rings in compound 10c form
a planar heterocyclic system, which is not conjugated
with the phenyl substituent. The dihedral angle between
the planes of the triazine and benzene rings is 30.4°. The
dihedral angle between the planes of the propyl substituꢀ
ent and the triazine ring is 89.9°. The N(6)C(1)C(2)C(3)
torsion angle is 176.4°.
The 1H NMR spectra of heterocycles 10a—e show
signals for both the protons of the phenyl substituent and
the alkyl fragment (see Table 2).
To unambiguously determine the alkylation site and
confirm the mode of fusion of the azole and azine rings in
heterocycles 10a—e in the solid phase, we studied the
product of the reaction of sodium salt 9 with propyl broꢀ
mide by Xꢀray diffraction. It was established that this
reaction produces 6ꢀphenylꢀ8ꢀpropyltetrazolo[1,5ꢀb]ꢀ
1,2,4ꢀtriazinꢀ7ꢀone (10c) (Fig. 3, Table 7).
The 13C NMR spectra of compounds 10a—e show
signals of the tetrazolotriazine system, the phenyl subꢀ
stituent, and the alkyl fragment (see Table 3). The assignꢀ
ment of the signals was made based on the analysis of the
fine structure of the signals for the carbon atoms in the
Table 7. Selected bond lengths and bond angles in compound 10c
Bond
d/Å
Angle
ω/deg
Angle
ω/deg
O(1)—C(7)
N(1)—N(2)
N(1)—C(5)
N(2)—N(3)
N(3)—N(4)
N(4)—N(9)
N(4)—C(5)
N(6)—C(1)
N(6)—C(5)
N(6)—C(7)
C(7)—C(8)
N(9)—C(8)
C(8)—C(11)
C(1)—C(2)
C(2)—C(3)
1.208(2)
1.374(2)
1.306(2)
1.287(2)
1.352(2)
1.353(2)
1.343(2)
1.478(2)
1.354(2)
1.377(2)
1.507(2)
1.293(2)
1.481(2)
1.493(2)
1.505(3)
C(5)—N(1)—N(2)
N(3)—N(2)—N(1)
N(2)—N(3)—N(4)
C(5)—N(4)—N(3)
C(5)—N(4)—N(9)
N(3)—N(4)—N(9)
N(1)—C(5)—N(4)
N(1)—C(5)—N(6)
N(4)—C(5)—N(6)
C(5)—N(6)—C(7)
C(5)—N(6)—C(1)
C(7)—N(6)—C(1)
O(1)—C(7)—N(6)
O(1)—C(7)—C(8)
N(6)—C(7)—C(8)
104.3(1)
112.5(1)
104.9(1)
108.8(1)
127.6(1)
123.5(1)
109.4(1)
131.6(1)
119.0(1)
119.7(1)
119.9(1)
120.2(1)
121.2(1)
123.4(1)
115.5(1)
N(9)—C(8)—C(11)
N(9)—C(8)—C(7)
C(11)—C(8)—C(7)
C(8)—N(9)—N(4)
N(6)—C(1)—C(2)
116.2(1)
124.0(1)
119.6(1)
114.1(1)
112.5(1)
111.4(2)
118.7(1)
122.8(1)
118.4(1)
120.4(2)
120.1(2)
120.2(2)
120.2(2)
120.3(1)
C(1)—C(2)—C(3)
C(12)—C(11)—C(16)
C(12)—C(11)—C(8)
C(16)—C(11)—C(8)
C(13)—C(12)—C(11)
C(14)—C(13)—C(12)
C(15)—C(14)—C(13)
C(14)—C(15)—C(16)
C(15)—C(16)—C(11)

Synthesis of azauracils and azaisocytosines
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 11, November, 2006 2077
Scheme 4
C(13)
C(3)
O(1)
C(14)
C(2)
C(12)
C(7)
C(8)
N(6)
C(1)
C(15)
C(11)
C(5)
C(16)
N(9)
N(1)
N(2)
N(4)
N(3)
Fig. 3. Molecular structure of Nꢀpropyltetrazolotriazinone 10c.
spectra recorded without suppression of the 13C—1H couꢀ
pling constants. In the spectrum of Nꢀmethyl derivaꢀ
tive 10a, the signals for the C(7) and C(8a) atoms are
observed as quartets (3J = 2.9 Hz and 3J = 3.3 Hz, respecꢀ
tively). The signal for the C(6) atom appears as a triplet
(3J = 3.7 Hz).
10—13: R = Me (a), Et (b), Pr (c), CH2—CH=CH2 (d),
R = CH2—(CH2)3—OAc (10e, 11e), CH2—(CH2)3—OH (13e)
For alkyl derivatives 10b—e, all signals for the carbon
atoms of the tetrazoloꢀ1,2,4ꢀtriazine system in the spectra
recorded without 13C—1H decoupling, appear as triplets
due to the presence of the Nꢀmethylene fragment in the
alkyl substituent. Hence, the assignment of the signals of
the carbon atoms of the heterocyclic moiety in compounds
10b—e was made based on a comparison of the chemical
shifts with those for compound 10a. The assignment of
the signals in the 13C NMR spectra of compounds 10a—e
was confirmed by correlation 2D HSQC and HMBC exꢀ
periments for heterocycle 10e and the 13C NMR spectroꢀ
scopic data for compounds 1a* and 1b* (see Table 3).
Study of destruction of tetrazolotriazines 10a—d
(Scheme 4) demonstrated that the treatment of these comꢀ
pounds with copper in acetic acid affords azaisocytosines
12a—d. Most likely, the synthesis of amines 12a—d proꢀ
ceeds through the formation of azides 11a—d.
It should be noted that compounds 10a—e are abnorꢀ
mally stable to acid hydrolysis. The formation of azauracils
13a—e was observed only upon prolonged refluxing in
a sodium methoxide solution. In the case of comꢀ
pound 10e, cleavage of the tetrazole ring is accompanied
by removal of the acyl protecting group to give anomalous
nucleoside 13e.
Oxidation of allyl derivative 13d with iodine in the
presence of silver acetate also afforded acyclic nucleoꢀ
side 14 (Scheme 5).
Therefore, we synthesized azaisocytosine derivatives
12a—d and azauracil derivatives 13a—e and 14 containꢀ
ing the alkyl substituent at the N(4) atom of the 1,2,4ꢀtriꢀ
azine ring.
The 1H NMR spectra of 1,2,4ꢀtriazine derivatives
12a—d, 13a—e, and 14 show signals for the protons of the
phenyl fragment and the Nꢀalkyl substituent (see Table 2).
Scheme 5
The IR spectra of triazinones 12a—d show absorption
bands in the 3310—3430 and 1670—1700 cm–1 regions,
which is indicative of the presence of the amino and
carboxy groups, respectively. The IR spectra of azauracils
13a—e and 14 are characterized by the presence of two
pronounced absorption bands in the 1660—1730 cm–1
region, which were assigned to stretching vibrations of the
carbonyl groups. The appearance of the signals of the
second carbonyl group for compounds 13a—e and the
detection of the amino group in heterocycles 12a—d indiꢀ
cate that the tetrazole ring in azoloazines 10a—e was
cleaved (see Table 1).
The formation of 1,2,4ꢀtriazine derivatives 12a—d and
13a—e from annulated tetrazolotriazines 10a—e is addiꢀ
tionally confirmed by m/z for the molecular ion peaks in
the mass spectra (see Table 1).
To summarize, a principally new procedure was deꢀ
veloped for the synthesis of various derivatives of azauracils
and azaisocytosines, including those with the desired poꢀ
sition of the Nꢀalkyl substituent, by destruction of the
azole fragment in tetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriazinꢀ7ꢀones.

2078
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 11, November, 2006
Shestakova et al.
Table 8. Elemental analysis data for compounds 1, 5, 9, 10a—e,
12a—d, 13a—e, and 14
This synthetic methodology from "complex to simple" is
more efficient than conventional approaches from "simple
to complex" and can be used in the nucleoside synthesis.
Comꢀ
pound
Found
Calculated
Molecular
formula
(%)
Experimental
С
Н
N
The IR spectra were recorded in KBr pellets on a Specord 75
IR spectrometer. The H NMR spectra (in DMSOꢀd6 + CCl4)
1
50.44
50.47
50.54
50.77
41.71
41.07
52.54
52.63
54.40
54.54
56.00
56.24
56.49
56.69
54.89
54.87
59.37
59.40
61.05
61.10
62.61
62.59
63.00
63.15
59.05
59.11
60.63
60.82
62.32
62.33
62.74
62.87
59.50
59.76
54.50
54.75
2.72
2.82
4.61
4.65
2.94
3.06
3.54
3.53
4.13
4.16
4.68
4.72
3.79
3.96
4.97
4.91
5.14
4.98
5.63
5.59
6.51
6.13
5.30
5.30
4.45
4.46
5.15
5.10
5.84
5.67
4.72
4.84
5.84
5.79
5.02
4.98
39.27
39.24
32.43
32.29
32.35
31.94
36.75
36.83
34.63
34.69
32.80
32.79
33.15
33.05
25.34
25.60
27.59
27.71
25.99
25.91
24.26
24.33
24.38
24.55
20.49
20.68
19.18
19.34
18.16
18.17
17.99
18.33
16.09
16.08
15.52
15.96
C9H6N6O
1
were measured on a Bruker WM ꢀ250 instrument with SiMe4 as
the internal standard. The 13C 2D NMR spectra (100 MHz)
were recorded on a Bruker DRXꢀ400 spectrometer in DMSOꢀd6.
The mass spectra were obtained on a Varian MATꢀ311A instruꢀ
ment; samples were introduced by a direct inlet system; the
ionizing electron energy was 70 eV; the ionization chamber temꢀ
perature was 100—300 °C. The melting points were determined
on a Boetius apparatus. Thinꢀlayer chromatography was carried
out on Silufol UVꢀ254 plates using ethyl acetate as the eluent;
spots were visualized by exposing to UV radiation and iodine
vapor. Column chromatography was performed on Kieseligelꢀ60
silica gel (Merck, Germany).
5
C11H12N6O2
9
C9H5N6NaO
•1.5H2O
C10H8N6O
10а
10b
10c
10d
10e
12a
12b
12c
12d
13a
13b
13c
13d
13e
14
C11H10N6O
C12H12N6O
C12H10N6O
C15H16N6O3
C10H10N4O
C11H12N4O
C12H14N4O
C12H12N4O
C10H9N3O2
C11H11N3O2
C12H13N3O2
C12H11N3O2
C13H15N3O3
C12H13N3O4
5ꢀAminotetrazole, ethyl phenylacetate, and 60% sodium
hydride in oil were purchased from Aldrich. All other reagents
and solvents used in experiments were commercial Russianꢀ
made products.
The yields and solvents used for crystallization are listed in
Table 1. The elemental analysis data are given in Table 8.
[
15N]ꢀAminoguanidine bicarbonate (8*) was prepared accordꢀ
ing to a procedure described earlier.18
6ꢀPhenyltetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriazinꢀ7ꢀone (1). A solution
of hydrazone 5 (1 g) in acetic acid (7 mL) was refluxed for 2 h.
After cooling, the precipitate that formed was filtered off and
dried.
A mixture of [15N]ꢀlabeled compounds 1a* and 1b*. Concenꢀ
trated HCl (0.5 mL) was added to a solution of aminotetrazole 2*
(0.2 g, 2 mmol) in water (10 mL). After cooling of the reaction
mixture to –2 °C, a solution of NaNO2 (0.14 g, 2 mmol) in
water (2 mL) was added dropwise with vigorous stirring. The
reaction mixture was kept at –2 °C for 30 min. A mixture of
ethyl phenyl(formyl)acetate (4) (2 mmol) and sodium carbonꢀ
ate (0.6 g) in water (3 mL) and ethanol (2 mL) was added to the
resulting diazonium salt. The resulting mixture was stirred at
room temperature for 2 h, concentrated HCl (1 mL) was added,
and the mixture was filtered. The precipitate that formed was
dissolved in acetic acid (2 mL). The solution was refluxed for 2 h,
cooled, and filtered. A mixture of compounds 1a* and 1b* was
obtained in a yield of 0.2 g (46 %), M+ 215.
[2ꢀ15N]ꢀ5ꢀAminotetrazole (2*). Aminoguanidine 15N (8*)
(0.69 g) was stirred in 5 N nitric acid (2 mL). Then a 5 N NaNO2
solution (1 mL) was added at a temperature no higher than
40 °C. Sodium acetate (1.4 g) was added to the resulting yellow
solution. The mixture was refluxed for 5 min and then cooled.
The precipitate that formed was filtered off. The yield was 0.43 g
(88%), m.p. 200 °C, M+ 86.
and the mixture was treated with diethyl ether (4×15 mL). The
organic layer was separated, dried with Na2SO4, and concenꢀ
trated. The residue was distilled off in vacuo, and the fraction
with 105—112 °C was collected at 5 Torr.
Ethyl αꢀ(tetrazolꢀ5ꢀylhydrazono)phenylacetate (5). Concenꢀ
trated HCl (5 mL) was added to a solution of aminotetrazole (2)
(2 g, 20 mmol) in water (100 mL). The reaction mixture was
cooled to –2 °C, a solution of NaNO2 (1.4 g, 20 mmol) in water
(20 mL) was added dropwise with vigorous stirring, and the
reaction mixture was kept at –2 °C for 30 min. A mixture of
ethyl phenyl(formyl)acetate (4) (20 mmol) and sodium carbonꢀ
ate (6 g) in water (30 mL) and ethanol (15 mL) was added to the
resulting diazonium salt. The reaction mixture was stirred at
room temperature for 2 h, and concentrated HCl (5 mL) was
added. The precipitate that formed was filtered off and recrysꢀ
tallized.
Ethyl αꢀformylphenylacetate (4). A 60% NaH oily suspenꢀ
sion (6.60 g) was added to a mixture of anhydrous hexane (60 mL)
and ethyl formate (8.8 mL, 0.11 mol), and the reaction mixture
was stirred for 10 min. Then ethyl phenylacetate (15 mL, 0.1 mol)
was added dropwise for 40 min. The precipitate was filtered off,
washed with hexane (20 mL), dried, and dissolved in water
(40 mL). Then HCl was added to the resulting solution to pH 2,

Synthesis of azauracils and azaisocytosines
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 11, November, 2006 2079
Sodium salt of 7ꢀoxoꢀ6ꢀphenyltetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriazine
(9). Tetrazolotriazine 1 (2.14 g, 10 mmol) was suspended in a
17% sodium carbonate solution (5 mL). The precipitate was
filtered off and recrystallized.
8ꢀSubstituted 7ꢀoxoꢀ6ꢀphenyltetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriꢀ
azines (10a—e). Sodium salt 9 (0.24 g, 1 mmol) was dissolved in
DMF (5 mL), alkyl bromide or iodide (2 mmol) was added, and
the mixture was heated on a water bath for 2 h. Water (40 mL)
was added to the cooled reaction mixture. The precipitate that
formed was filtered off and recrystallized.
4ꢀSubstituted 3ꢀaminoꢀ5ꢀoxoꢀ6ꢀphenylꢀ1,2,4ꢀtriazines
(12a—d). A mixture of 8ꢀRꢀ6ꢀphenylꢀ7ꢀoxoꢀtetrazolo[1,5ꢀb]ꢀ
1,2,4ꢀtriazine 10a—d (2 mmol) and a copper powder (0.252 g,
4 mmol) freshly prepared according to a known procedure19 was
refluxed in acetic acid (5 mL) for 2 h. Then the reaction mixture
was cooled and aqueous (25%) ammonium (15 mL) was added.
The precipitate that formed was filtered off, dried, and recrysꢀ
tallized.
4ꢀSubstituted 3,5ꢀdioxoꢀ6ꢀphenylꢀ1,2,4ꢀtriazines (13a—d).
Triazine 10a—d (1 mmol) was added to a sodium methoxide
solution, which was prepared from sodium (0.027 g, 1.2 mmol)
and methanol (6 mL). The reaction mixture was refluxed for
2 h, cooled, and poured into water. Acetic acid was added to
neutral pH. The precipitate that formed was filtered off and
recrystallized.
and methanol (6 mL). The reaction mixture was refluxed for
2 h, cooled, and poured into water. Acetic acid was added to
neutral pH, and the mixture was concentrated. The product was
isolated by silica gel column chromatography using ethyl acetate
as the eluent (Rf = 0.3).
4ꢀ(2,3ꢀDihydroxypropyl)ꢀ3,5ꢀdioxoꢀ6ꢀphenylꢀ1,2,4ꢀtriazine
(14). Water (0.03 mL) was added to a solution of dione 13d
(0.25 g, 1 mmol) in acetic acid (10 mL). Silver acetate (0.46 g,
2.75 mmol) and iodine (0.3 g, 1.2 mmol) were added portionwise
to the reaction mixture. The resulting suspension was refluxed
for 3 h, cooled, and filtered. The filtrate was concentrated
in vacuo, the residue was dissolved in ethanol (10 mL), and
acetyl chloride (0.5 mL) was added. The resulting solution was
kept at room temperature for 48 h and then evaporated. The
product was isolated by column chromatography in a 1 : 1 chloꢀ
roform : ethyl acetate system (Rf = 0.2).
Xꢀray diffraction data sets for compounds 9 and 10c were
collected on an automated Xcalibur 3 diffractometer equipped
with a CCD detector (9) and on an automated EnrafꢀNonius
CADꢀ4 diffractometer (10c) (ω/2θꢀscanning technique,
λMoꢀKα radiation, graphite monochromator).
Both structures were solved by direct methods and refined
by the leastꢀsquares method using the SHELXSꢀ9720 and
SHELXLꢀ9721 program packages with anisotropic (isotropic for
H atoms) displacement parameters.
4ꢀ(4ꢀHydroxybutyl)ꢀ3,5ꢀdioxoꢀ6ꢀphenylꢀ1,2,4ꢀtriazine (13e).
Triazine 10e (0.33 g, 1 mmol) was added to a sodium methoxide
solution, which was prepared from sodium (0.027 g, 1.2 mmol)
Selected bond lengths and bond angles for the structures of 9
and 10c are given in Tables 4 and 7, respectively. The geometric
data for the coordination environment of the sodium cation in
Table 9. Crystallographic data and the Xꢀray data collection and refinement statistics
Parameter
9
10c
Molecular formula
Molecular weight
Crystal system
Space group
a/Å
b/Å
c/Å
α/deg
Na+[C9H5N6O]–•3H2O
290.23
C12H12N6O
256.28
Monoclinic
C2/c
16.026(2)
6.992(1)
22.788(4)
90
Orthorhombic
P2(1)2(1)2(1)
3.7652(2)
9.8696(11)
33.529(4)
90
β/deg
γ/deg
90
90
93.43(3)
90
Z
4
8
λ/Å
U/Å
0.71073
1246.0(2)
–5 < h < 5
–13 < k < 14
–46 < l < 49
1.547
0.71073
2548.9(7)
0 < h < 18
0 < k < 8
–27 < l < 27
1.34
Ranges of measured indices
dcalc/g cm–3
µ/mm–1
0.152
0.093
Number of measured reflections
Number of independent reflections
Number of reflections with I2 > 4σ(I2
R
1968
2409
1868
0.0424
2275
2192
1770
0.038
)
0
wR2
0.1091
0.104
Number of parameters in refinement
GOOF
225
1.002
221
1.053
Residual electron
density/e Å–3 (min/max)
–0.219/0.270
–0.134/0.163

2080
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 11, November, 2006
Shestakova et al.
the structure of 9 are given in Table 5. The hydrogen bond
parameters are listed in Table 6. The results of Xꢀray diffraction
study of compounds 9 and 10c are presented in Table 9.
8. V. L. Rusinov, E. N. Ulomsky, D. N. Kozhevnikov, O. N.
Chupakhin, and G. G. Aleksandrov, Zh. Org. Khim., 1996,
32, 770 [Russ. J. Org. Chem., 1996, 32 (Engl. Transl.)].
9. V. V. Voronin, E. N. Ulomsky, V. L. Rusinov, and O. N.
Chupakhin, Mendeleev Commun., 1999, 5, 200.
10. E. N. Ulomsky, V. V. Voronin, V. L. Rusinov, and O. N.
Chupakhin, Izv. Akad. Nauk, Ser. Khim., 2001, 655 [Russ.
Chem. Bull., Int. Ed., 2001, 50, 682].
11. E. N. Ulomsky, T. S. Shestakova, S. L. Deev, V. L. Rusinov,
and O. N. Chupakhin, Izv. Akad. Nauk, Ser. Khim., 2005,
713 [Russ. Chem. Bull., Int. Ed., 2005, 54, 726].
12. J. Gutt, M. Prystaš, and F. Šorm, Coll. Czech. Chem. Comm.,
1961, 26, 974.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ
32792ꢀa), the Council on Grants of the President of the
Russian Federation (Program for State Support of Young
Scientists, Grant MKꢀ1707.2005.3), and the Ministry of
Education and Science of the Russian Federation (State
Contract No. 02.435.11.3017, the HighꢀPriority Field
"Living Systems" ZhSꢀ13.2/005, "Design of Antiviral
Drugs for Treatment and Prophylaxis of Viral Diseases by
Chemical Synthesis Methods").
13. A. Nová ek and P. Fiedler, Coll. Czech. Chem. Comm., 1971,
36, 3507.
14. M. Prystaš, J. Gutt, and F. Šorm, Coll. Czech. Chem. Comm.,
1962, 27, 1572.
15. M. M. Goodman and W. W. Paudler, J. Org. Chem., 1977,
42, 1866.
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Received October 2, 2006;
in revised form October 18, 2006