Nucleophilic ring-opening of the azole and azine moieties in 6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-ones

Article abstract of DOI:10.1023/A:1011373131012

The effects of the nature of the nucleophile and the structure of 6-nitrotriazolo[1,5-a]pyrimidinones on the direction of the ring opening were investigated. The triazole ring is opened under the action of strong bases, such as alkoxides or alkalis, to form 2-cyanoaminopyrimidinones and then 2-aminopyrimidinones. The results of the reactions with N-nucleophiles depend on the accessibility of position 5 of the heterocycle. Thus, sterically hindered secondary amines react with 5-methyltriazolopyrimidinones to give 2-guanidinopyrimidinones and then 2-aminopyrimidinones. In the absence of a substituent at position 5, the azine ring is opened to form 4-alkyl-3-amino-1,2,4-triazoles and 3-amino-2-nitroacrylamides. Under the action of primary amines, only the pyrimidine fragment is cleaved.

Full text of DOI:10.1023/A:1011373131012

682
Russian Chemical Bulletin, International Edition, Vol. 50, No. 4, pp. 682—688, April, 2001
Nucleophilic ring-opening of the azole and azine moieties
in 6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-ones*
E. N. Ulomsky, V. V. Voronin, V. L. Rusinov,« and O. N. Chupakhin
Ural State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 0458. E-mail: rusinov@htf.ustu.ru
The effects of the nature of the nucleophile and the structure of 6-nitrotriazolo[1,5-a]pyri-
midinones on the direction of the ring opening were investigated. The triazole ring is opened
under the action of strong bases, such as alkoxides or alkalis, to form 2-cyanoamino-
pyrimidinones and then 2-aminopyrimidinones. The results of the reactions with N-nucleo-
philes depend on the accessibility of position 5 of the heterocycle. Thus, sterically hindered
secondary amines react with 5-methyltriazolopyrimidinones to give 2-guanidinopyrimidinones
and then 2-aminopyrimidinones. In the absence of a substituent at position 5, the azine ring is
opened to form 4-alkyl-3-amino-1,2,4-triazoles and 3-amino-2-nitroacrylamides. Under the
action of primary amines, only the pyrimidine fragment is cleaved.
Key words: 6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-ones, 3-amino-1,2,4-triazoles, 3-ami-
no-2-nitrocrotonamide, 3-amino-2-nitroacrylamides, N-alkyl-N-hetarylcyanamides, 2-alkyl-
amino-4-methyl-5-nitropyrimidin-7-ones, ring opening, nucleophiles.
Azaindolizines are characterized by the ability to
and 2-(alkylamino)-4-methyl-5-nitro-1,6-dihydropyri-
undergo ring opening of their azine or azole moieties
under the action of nucleophiles. The major regularities
of these processes were successfully generalized in the
context of consonant and dissonant series in heterocy-
clic systems.1,2 However, this concept does not reflect
the effects of the nature of the nucleophile and its
structure on the direction of the reaction. To reveal the
characteristic features of the nucleophilic scission of
6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-ones, we stud-
ied the reactions of these heterocycles with C-, O-, and
N-nucleophiles, which was of interest from the view-
point of simulation of the reactivity and investigation of
the metabolism of azaindolizines among which biologi-
cally active compounds have been found.3
midin-6-ones (3a—d), the ratio between these products
depending on the reaction time. Thus, the 2 : 3 ratio was
1 : 1 after 30 min, whereas aminopyrimidinones 3a—d
were obtained exclusively after 2 h. Apparently, the first
stage of the reaction yielded cyanamide 2, which was
then converted into product 3.
The IR spectra of compounds 2 have intense absorp-
tion bands corresponding to stretching vibrations of the
CN group (Table 1) and stretching vibration bands of
the —NO2 and —CO groups. The data from mass spec-
trometry indicate that the molecular masses of triazolo-
pyrimidines 1 are identical to those of cyanides 2.
Stretching vibration bands of the —NO2 and —CO
groups and of the secondary amine fragment can be
identified in the IR spectra of compounds 3.
1
In the H NMR spectra of aminopyrimidinones 3,
Results and Discussion
the resonance signals of the NCH2 fragment of the R1
substituents are observed at higher field than those in the
spectra of compounds 1 and 2 (δ 3.2—3.5 as opposed to
δ 4.0—4.2, see Table 1). The NMR spectra also have
three-proton singlet signals belonging to the C-methyl
groups and broadened signals of the NH groups.
Reactions with CH-active compounds. The reactions
of 3-alkyl-1,2,4-triazolo[1,5-a]pyrimidinones 1 with
nitromethane, ethyl acetoacetate, or ethyl cyanoacetate
in the presence of acid catalysts did not proceed even on
heating. However, the reactions with the use of sodium
derivatives of cyanoacetic or acetoacetic esters afforded
cyanamides 2 (see Scheme 1).
Reactions with O-nucleophiles. The reactions of 3-al-
kyl-1,2,4-triazolo[1,5-a]pyrimidin-7-ones (1a—d) with
magnesium methoxide afforded N-alkyl-N-(4-me-
thyl-5-nitro-6-oxopyrimidin-2-yl)cyanamides (2a—d)
(Scheme 1). By analogy with the scission of 5-chloro-3-
(β-D-ribofuranosyl)-1,2,4-triazolo[1,5-a]pyrimidin-7-
one,1,4 it can be assumed that the destruction of the
azole fragment involves the formation of anion A,1,2,5
which is isomerized to cyanamide 2.
Heating of triazolopyrimidinones 1a—d with ethanolic
alkali afforded two types of products, viz., cyanamides 2
Reactions with amines. We have surveyed the se-
lected aspects of conversions of triazolopyrimidinones 1
* Dedicated to Prof. H. Neunhoeffer on the occasion of his
65th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 655—661, April, 2001.
1066-5285/01/5004-682 $25.00 © 2001 Plenum Publishing Corporation

Nucleophilic ring-opening of triazolopyrimidinones Russ.Chem.Bull., Int.Ed., Vol. 50, No. 4, April, 2001
683
Scheme 1
It can be assumed that the formation of products
4—8, like the reactions with alkoxides and alkalis, pro-
ceeds through cyanamides 2. However, treatment of
compounds 2 with secondary amines both at room
temperature and on heating gave rise to aminopyrimi-
dinones 3 rather than to guanidines 4—8. Therefore, the
involvement of compound 2 in the formation of prod-
ucts 4—8 is unlikely and it is possible that conversions
proceed according to another mechanism. Apparently,
the low basicity of the amine prevents the formation of
the anion of the type A and the reaction proceeds
through the nucleophilic addition at C(2) to form adduct
B followed by its transformation into pyrimidinyl-
guanidines 4—8 (Scheme 2).
O
O
O2N
Me
1
N
O2N
Me
6
7
N
N
N
i, ii or iv
–
5
3
C
2
N
N
N
N
4
R1
R1
1a—d
A
iii
O
O
O2N
O2N
Me
NH NH
NH
iii
R3
CN
Me
N
N
N
N
N
Scheme 2
R1
R1
R3
4a—d—8a—d
2a—d
O
iii
O2N
Me
ii or iii
–
N
N
H
1
R2
O
O
N
N
N
O2N
Me
O2N
Me
R1
R2
N
N
NH
iii
B
R2
NHR1
O
N
N
N
R1
O2N
N
NH
1e—h
3a—d
R2
–
N
C
R1 = Et (a), Pr (b), Bu (c), n-C5H11 (d);
Me
N
N
R1 = Et, R2 = Me (e); R1 = Pr, R2 = Me (f);
R1 = R2 = Et (g); R1 = Pr, R2 = Et (h);
R1
R2
O
R3
O2N
Me
–
N
NH
(5);
N
(4);
N
N
=
4—8
R2
R3
N
N
N
R1
R2
(6);
(8)
(7);
O
N
N
N
With the aim of elucidating the mechanism of the
2
azine ring-opening, we studied the reactions of 2,3-di-
alkyl-1,2,4-triazolopyrimidinones 1e—h with secondary
amines. We believed that the results of the reactions of
this type should be unambiguous because it was stated
that opening of the C-alkyl-substituted azole ring cannot
occur in compounds of this group.1 However, we ob-
tained amines 3a—d (see Scheme 1) instead of acyclic
products although heating was more prolonged than that
in the case of compounds 1a—d. Such decrease in the
reactivity can be explained by steric hindrances provided
that an adduct of the type B is formed (see Scheme 2).
However, the triazole ring-opening remains the only
direction of the reaction.
The direction of the nucleophilic attack changes if
the C-methyl group is removed from the pyrimidine
ring. In the reaction of 3-ethyl-6-nitro-1,2,4-triazo-
lo[1,5-a]pyrimidin-7-one (9) with pyrrolidine, only the
azine ring was opened to form 2-nitro-3-pyrrolidino-
acrylopyrrolidide (10) and 3-amino-4-ethyl-1,2,4-triazole
(11a) (Scheme 3). The spectral characteristics and physi-
Regents and conditions: i. (MeO)2Mg, MeOH; ii. NaOH, EtOH,
∆; iii. R32NH, ∆; iv. Na, NCCH2COOEt, or AcCH2COOEt.
under the action of amines in a brief communication.6
In the present study, we examined this type of reac-
tions in more detail. Heating of 3-alkyl-1,2,4-triazo-
lo[1,5-a]pyrimidinones 1a—d with secondary amines for
30 min afforded 1-alkyl-1-(4-methyl-5-nitro-6-oxo-1,6-
dihydropyrimidin-2-yl)guanidines (4—8), which were
converted into aminopyrimidinones 3a—d upon further
heating (see Scheme 1). The identity of products 3
obtained through different paths (ii and iii) was proved
by comparing their spectral characteristics and physico-
chemical properties. The 1H NMR spectra of com-
pounds 4—8 have signals of the alkyl fragment, the
methyl group of the pyrimidine ring, and the secondary
amino group (see Table 1) and are in complete agree-
ment with the proposed structures.

684
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 4, April, 2001
Ulomsky et al.
Table 1. Data from mass spectrometry and IR and 1H NMR spectroscopy of the synthesized compounds
–1
Com-
pound
m/z (Irel (%))
IR, ν/cm
1H NMR, δ
2a
2b
2c
197 (4), 97 (28), 70 (13), 55 (100)
1320, 1510 (NO2);
1620 (CO); 2280 (CN)
1320, 1520 (NO2);
1620 (CO); 2270 (CN)
1310, 1520 (NO2);
1610 (CO); 2270 (CN)
1.23 (t, 3 Í); 2.12 (s, 3 Í); 4.10 (q, 2 Í);
9.53 (br.s, 1 Í)
0.92 (t, 3 Í); 1.41 (qt, 2 Í); 2.12 (s, 3 Í);
4.10 (t, 2 Í); 10.30 (br.s, 1 Í)
0.91 (t, 3 Í); 1.32 (qt, 2 Í);
1.61 (tt, 2 Í); 2.11 (s, 3 Í); 4.08 (t, 2 Í);
10.65 (br.s, 1 Í)
197 (16), 183 (100), 137 (28),
109 (13), 55 (31)
209 (51), 183 (100), 137 (30),
109 (11), 55 (31)
2d
3a
223 (54), 197 (15), 183 (100),
137 (29), 109 (13), 67 (23), 55 (25)
198 [M]+ (11), 181 (93), 183 (100),
170 (27), 166 (15), 137 (78),
109 (26), 69 (56), 55 (54)
1320, 1520 (NO2);
1610 (CO); 2280 (CN)
1320, 1510 (NO2);
1680 (CO); 1250,
3280 (NH)
0.88 (t, 3 Í); 1.00—2.00 (m, 6 Í);
2.20 (s, 3 Í); 4.06 (t, 2 Í); 10.10 (br.s, 1 Í)
1.18 (t, 3 Í); 2.28 (s, 3 Í); 3.20—3.50
(m, 2 Í); 7.33 (br.s, 1 Í);
11.43 (br.s, 1 Í)
3b
3c
3d
4a
4b
4c
4d
5a
5b
212 [M]+ (14), 195 (85), 183 (100),
170 (18), 166 (22), 137 (58),
109 (32), 69 (39), 55 (48)
226 [M]+ (9), 209 (93), 183 (100),
137 (42), 109 (18), 69 (28),
55 (40)
240 [M]+ (12), 223 (91), 211 (15),
183 (100), 170 (33), 166 (32),
137 (69), 109 (30), 69 (41), 55 (55)
294 [M]+ (3), 183 (32), 181 (35),
137 (13), 123 (19), 96 (43),
70 (48), 55 (100)
308 [M]+ (3), 212 (15), 195 (47),
183 (100), 170 (15), 137 (34),
96 (46), 70 (28), 55 (43)
322 [M]+ (3), 226 (15), 209 (63),
183 (100), 170 (13), 166 (14),
137 (29), 96 (51), 70 (34), 55 (51)
336 [M]+ (2), 240 (5), 223 (60),
183 (100), 170 (12), 166 (12),
137 (29), 96 (43), 70 (15), 55 (40)
308 [M]+ (2), 198 (30), 183 (31),
181 (36), 137 (13), 110 (47),
109 (38), 85 (41), 69 (100), 55 (57)
322 [M]+ (2), 305 (4), 212 (12),
195 (52), 183 (100), 137 (45),
110 (55), 109 (53), 84 (47),
69 (68), 67 (49), 55 (89)
1310, 1500 (NO2);
1680 (CO);
1260, 3300 (NH)
1320, 1500 (NO2);
1680 (CO); 1250,
3300 (NH)
1310, 1510 (NO2);
1680 (CO);
1280, 3320 (NH)
1330, 1530 (NO2);
1680 (CO)
0.92 (t, 3 Í); 1.30—1.55 (m, 2 Í);
2.28 (s, 3 Í); 3.20—3.40 (m, 2 Í);
7.28 (br.s, 1 H); 11.40 (br.s, 1 H)
0.89 (t, 3 Í); 1.20—1.60 (m, 4 Í);
2.28 (s, 3 Í); 3.20—3.40 (m, 2 Í); 7.09 (br.s, 1 Í);
11.38 (br.s, 1 Í)
0.87 (t, 3 Í); 1.15—1.80 (m, 6 Í); 2.28 (s, 3 Í);
3.10—3.50 (m, 2 Í); 7.26 (br.s, 1 Í);
11.45 (br.s, 1 Í)
1.17 (t, 3 H); 1.80—2.00 (m, 4 H); 2.08 (s, 3 H);
3.30—3.50 (m, 4 Í); 3.78 (q, 2 H);
8.78 (br.s, 2 Í)
0.88 (t, 3 Í); 1.62 (tq, 2 Í); 1.80—2.00 (m, 4 H);
2.08 (s, 3 H); 3.30—3.50 (m, 4 Í); 3.69 (t, 2 Í);
8.73 (br.s, 2 Í)
0.92 (t, 3 Í); 1.30 (qt, 2 Í); 1.59 (tt, 2 Í);
1.80—2.00 (m, 4 H); 2.08 (s, 3 H); 3.30—3.50 (m, 4 Í);
3.72 (t, 2 Í); 8.75 (br.s, 2 Í)
0.89 (t, 3 Í); 1.20—1.40 (m, 4 Í); 1.59 (tt, 2 Í);
1.80—2.00 (m, 4 H); 2.07 (s, 3 H); 3.30—3.50 (m, 4 Í);
3.72 (t, 2 Í); 8.77 (br.s, 2 Í)
1.16 (t, 3 H); 1.50—1.70 (m, 6 H); 2.09 (s, 3 H);
3.30—3.50 (m, 4 Í); 3.78 (q, 2 H);
8.71 (br.s, 2 Í)
0.89 (t, 3 Í); 1.50—1.70 (m, 8 H);
2.09 (s, 3 H); 3.30—3.50 (m, 4 Í);
3.68 (t, 2 Í);
1310, 1510 (NO2);
1670 (CO)
1320, 1510 (NO2);
1680 (CO)
1320, 1510 (NO2);
1680 (CO)
1320, 1530 (NO2);
1670 (CO)
1330, 1520 (NO2);
1670 (CO)
8.85 (br.s, 2 Í)
5c
336 [M]+ (2), 319 (2), 305 (3),
212 (13), 195 (45), 183 (100),
137 (37), 110 (58), 109 (42),
84 (36), 69 (72), 67 (51), 55 (92)
223 (32), 183 (58), 137 (25),
84 (100), 67 (33), 55 (49)
1330, 1520 (NO2);
1680 (CO)
0.90 (t, 3 Í); 1.28 (qt, 2 Í);
1.50—1.70 (m, 8 H); 2.08 (s, 3 H);
3.30—3.50 (m, 4 Í); 3.72 (t, 2 Í);
8.80 (br.s, 2 Í)
0.88 (t, 3 Í); 1.20—1.40 (m, 4 Í);
1.50—1.70 (m, 8 H); 2.08 (s, 3 H); 3.30—3.50 (m, 4 Í);
3.71 (t, 2 Í); 8.77 (br.s, 2 Í)
1.09 (t, 3 H); 2.28 (s, 3 H); 3.30—3.40 (m, 4 H);
3.60—3.70 (m, 4 Í); 3.80 (q, 2 H);
8.41 (br.s, 1 H); 9.81 (br.s, 1 H)
0.89 (t, 3 Í); 1.59 (tq, 2 Í); 2.14 (s, 3 H);
3.40—3.50 (m, 4 H); 3.62—3.72 (m, 4 Í);
3.72 (t, 2 Í); 9.03 (br.s, 2 Í)
5d
6a
6b
6ñ
1320, 1520 (NO2);
1680 (CO)
310 [M]+ (2), 198 (19), 181 (26),
142 (19), 123 (20), 113 (24),
86 (100), 69 (91)
324 [M]+ (1), 307 (6), 212 (12),
195 (56), 183 (100), 166 (17),
137 (39), 112 (41), 67 (28)
338 [M]+ (2), 251 (32), 234 (17),
209 (100), 196 (30), 183 (15),
165 (14), 124 (18), 109 (25),
95 (18), 67 (27)
1310, 1530 (NO2);
1670 (CO)
1330, 1520 (NO2);
1670 (CO)
1320, 1510 (NO2);
1680 (CO)
0.90 (t, 3 Í); 1.28 (q, 2 Í); 1.59 (tt, 2 Í);
2.15 (s, 3 Í); 3.40—3.50 (m, 4 Í); 3.62—3.72 (m, 4 Í);
3.74 (t, 2 Í); 8.60 (br.s, 1 Í); 9.78 (br.s, 1 Í)
6d
209 (8), 196 (30), 183 (100),
165 (14), 124 (17), 109 (26),
95 (15), 67 (28)
1330, 1510 (NO2);
1680 (CO)
0.89 (t, 3 Í); 1.20—1.40 (m, 4 Í); 1.60 (tt, 2 Í);
2.13 (s, 3 H); 3.40—3.48 (m, 4 H); 3.60—3.70 (m, 4 Í);
3.76 (t, 2 Í); 9.08 (br.s, 2 Í)
(to be continued)

Nucleophilic ring-opening of triazolopyrimidinones Russ.Chem.Bull., Int.Ed., Vol. 50, No. 4, April, 2001
685
Table 1 (continued)
–1
Com-
pound
m/z (Irel (%))
IR, ν/cm
1H NMR, δ
7a
322 [M]+ (2), 305 (12), 261 (9),
198 (36), 183 (46), 181 (58),
125 (16), 123 (41), 98 (43),
69 (58), 55 (100)
1320, 1510 (NO2);
1680 (CO)
1.17 (t, 3 H); 1.50—1.62 (m, 4 Í); 1.62—1.80 (m, 4 Í);
2.08 (s, 3 H); 3.40—3.60 (m, 4 Í);
3.79 (q, 2 H); 8.89 (br.s, 2 H)
7b
7c
7d
8a
8b
8c
8d
10
336 [M]+ (2), 212 (14), 198 (38),
1320, 1510 (NO2);
0.89 (t, 3 Í); 1.50—1.62 (m, 6 Í); 1.62—1.80 (m, 4 Í);
2.09 (s, 3 Í); 3.40—3.60 (m, 4 Í); 3.68 (t, 2 Í);
8.85 (br.s, 2 H)
0.90 (t, 3 Í); 1.28 (qt, 2 Í); 1.50—1.62 (m, 6 Í);
1.62—1.80 (m, 4 Í); 2.08 (s, 3 H); 3.40—3.60 (m, 4 Í);
3.72 (t, 2 Í); 8.80 (br.s, 2 H)
0.88 (t, 3 Í); 1.20—1.40 (m, 4 Í); 1.50—1.62 (m, 6 Í);
1.62—1.80 (m, 4 Í); 2.08 (s, 3 H, Me); 3.40—3.60
(m, 4 Í); 3.71 (t, 2 Í); 8.77 (br.s, 2 H, NH)
1.00—1.40 (m, 10 Í); 1.18 (t, 3 H); 1.57—1.80 (m, 6 Í);
1.95—2.00 (m, 4 Í); 2.10 (s, 3 H, Me); 3.05—3.20
(m, 2 Í); 3.68 (q, 2 H); 8.10 (br.s, 2 H, NH)
0.89 (t, 3 Í); 1.00—1.40 (m, 10 Í); 1.57—1.80 (m, 8 Í);
1.95—2.00 (m, 4 Í); 2.09 (s, 3 H, Me); 3.05—3.20
(m, 2 Í); 3.69 (t, 2 Í); 8.12 (br.s, 2 H, NH)
0.91 (t, 3 Í); 1.00—1.40 (m, 12 Í); 1.57—1.80 (m, 8 Í);
1.95—2.00 (m, 4 Í); 2.10 (s, 3 H, Me); 3.05—3.20
(m, 2 Í); 3.66 (t, 2 Í); 7.78 (br.s, 2 H, NH)
0.89 (t, 3 Í); 1.00—1.40 (m, 14 Í); 1.57—1.80 (m, 8 Í);
1.95—2.00 (m, 4 Í); 2.10 (s, 3 H, Me);
181 (64), 167 (14), 124 (43), 98 (45), 1690 (CO)
69 (61), 55 (100)
350 [M]+ (1), 226 (12), 198 (41),
181 (55), 124 (49), 98 (48), 69 (52),
55 (100)
240 (13), 198 (35), 181 (68),
167 (12), 124 (44), 98 (42),
69 (50), 55 (100)
404 [M]+ (3), 300 (8), 261 (5),
223 (51), 181 (71),
1320, 1510 (NO2);
1690 (CO)
1320, 1510 (NO2);
1600, 1690 (CO)
1340, 1530 (NO2);
1680 (CO)
138 (100), 56 (98)
418 [M]+ (2), 233 (2), 195 (9),
183 (12), 181 (12),
1320, 1520 (NO2);
1680 (CO)
138 (100), 56 (73)
195 (5), 183 (16), 181 (10),
138 (100), 82 (21),
67 (23), 56 (83)
236 (9), 181 (10), 138 (100),
82 (19), 67 (20)
1330, 1520 (NO2);
1680 (CO)
1320, 1520 (NO2);
1680 (CO)
3.05—3.20 (m, 2 Í); 3.65 (t, 2 Í); 8.10 (br.s, 2 H, NH)
1.80—2.20 (m, 8 Í); 3.20—3.80 (m, 8 Í);
8.35 (s, 1 Í)
193 (13), 124 (23), 97 (65),
72 (100)
1310, 1530 (NO2);
1670 (CO)
1330, 1650, 3210,
11b 126 [M]+ (100), 84 (77), 57 (16)
0.87 (t, 3 H); 1.71 (tq, 2 H); 3.67 (t, 2 H);
3450 (NH2); 2870 (Alk) 4.58 (br.s, 2 Í); 7.73 (s, 1 H)
11c 140 [M]+ (100), 84 (69), 57 (12)
1340, 1645, 3210,
0.92 (t, 3 H); 1.33 (tq, 2 H); 1.68 (tt, 2 H);
3430 (NH2); 2890 (Alk) 3.73 (t, 2 H); 4.77 (br.s, 2 Í); 7.56 (s, 1 H)
11d 154 [M]+ (100), 130 (6), 98 (9),
84 (67), 57 (14)
11å 126 [M]+ (100), 98 (81), 71 (14)
1330, 1650, 3212,
0.88 (t, 3 Í); 1.00—2.00 (m, 6 Í); 3.68 (t, 2 Í);
3445 (NH2); 2890 (Alk) 4.42 (br.s, 2 Í); 7.55 (s, 1 H)
1330, 1650, 3445 (NH2); 1.14 (t, 3 Í); 2.17 (s, 3 Í); 3.71 (q, 2 Í);
2920, 2890 (Alk)
1040, 1180, 1330, 1650, 2.75 (d, 3 Í); 5.90 (br.s, 1 Í); 7.35 (br.s, 1 Í);
2870, 3210, 3450 12.10 (br.s, 1 Í)
1270, 1370, 1510 (NO2); 2.14 (s, 3 Í); 7.35 (br.s, 1 Í); 7.75 (br.s, 1 Í);
5.53 (br.s, 2 Í)
13à 98 [M]+ (100), 97 (100), 70 (69),
57 (54)
14
15
16
17
18
145 [M]+ (48), 129 (9), 128 (100),
127 (38), 85 (76), 83 (18), 69 (17)
1650 (CO); 3150,
3300 (NH)
8.90 (br.s, 1 Í); 9.80 (br.s, 1 Í)
225 [M]+ (46), 179 (66), 165 (100),
124 (62), 109 (25), 96 (30), 82 (83),
67 (37), 56 (67)
309 [M]+ (39), 263 (12), 211 (34),
185 (75), 139 (42), 99 (100)
1350, 1550 (NO2);
1600, 1650 (CO);
3450 (NH)
2.07 (s, 3 Í); 3.72—3.82 (m, 2 Í); 4.10—4.18 (m, 2 Í);
5.00—5.30 (m, 4 Í); 5.75—6.05 (m, 2 Í); 8.56 (t, 1 Í);
10.79 (t, 1 Í)
1360, 1540 (NO2);
1610, 1650 (CO);
3230, 3350 (NH)
1320, 1530 (NO2);
1650 (CO); 3380 (NH)
1.10—1.40 (m, 12 Í); 1.60—1.80 (m, 8 Í);
2.09 (s, 3 Í); 3.00—3.20 (m, 2 Í); 8.70 (br.s, 1 Í);
9.40 (br.s, 1 Í)
3.72—3.85 (m, 4 Í); 4.10—4.20 (m, 2 Í);
5.03—5.30 (m, 4 Í); 8.31 (s, 1 Í); 8.60 (br.s, 1 Í);
10.50 (br.s, 1 Í)
211 [M]+ (43), 165 (72), 151 (100),
96 (32), 56 (54)
143 [M]+ (100), 125 (36), 96 (11),
83 (30), 67 (86)
1080, 1470 (NO2);
1680 (CO);
2.23 (s, 3 Í);
7.23 (br.s, 2 Í)
3200, 3380 (NH)
cochemical properties of aminotriazole 11a are identical
with those reported previously.7
It also appeared that the presence of the N-alkyl
group has no effect on the scission of the pyrimidine ring
because the reactions of 4-methyltriazolopyrimidinones
12a,b with pyrrolidine also afforded acrylamide 10 and
3-methylamino-5-R-1,2,4-triazoles (13a,b). The spec-
tral characteristics and the melting point of triazole 13b
are in complete agreement with those reported previ-
ously8 (Table 2).
Apparently, the pyrimidine ring-opening involves two
processes, viz., the reaction of amine with the carbonyl

686
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 4, April, 2001
Ulomsky et al.
Scheme 3
whose nucleophilic centers are more accessible com-
pared to those in secondary amines.
O
Ammonia, cyclohexylamine, and allylamine reacted
with 5-methyl-6-nitrotriazolopyrimidinones 1a—e to
form 4-alkyl- and 4,5-dialkyl-3-amino-1,2,4-triazoles
(11a—d and 11e) and 3-amino-2-nitrocrotonamides
(14—16) (Scheme 5). The reaction of allylamine with
triazolopyrimidinone 9 gave rise to nitroacrylamide 17
and aminotriazole 11a, which is in complete agreement
with the proposed mechanism.
O2N
N
N
NH
N
N
Et
9
O
N
N
N
N
+
NO2
10
H2N
N
Scheme 5
Et
11a
R3
O
O
N
N
O2N
NHR4
+
R4NH
HN
N
N
N
R2
H2N
N
10
+
NO2
14, 15, 16, 17
R4NH2
R1
R
HN
Me
N
R
N
N
11a—e
Me
1a—e, 9
12a,b
13a,b
R = H (a), Me (b)
HN
NH
H2NNH2
11a—d
+
group and the attack at the C(5) atom (Scheme 4).
According to earlier studies,9 the first stage of conver-
sions involves the reversible reaction of the nucleophile
with the carbonyl C(7) atom followed by the reaction of
amide C 10 with the second amine molecule to form
intermediate D and its decomposition into acrylamide
10 and triazole 11.
Me
O
NO2
18
HN
N
12a,b
17
+
R2
HN
Me
N
13a,b
Scheme 4
14
Me
15
Me
16
Me
17
H
R3
R4
O
NO2
H
All
All
NH
NH
N
N
N
9
+
–H
As expected, a change of the position of the N-methyl
group in the heterocycle did not change the direction of
its decomposition. The reactions of 4-methyl-6-
nitrotriazolo[1,5-a]pyrimidinones (12a,b) with allylamine
gave rise to acrylamide 17 and 3-methylamino-1,2,4-
triazoles (13a,b) as well (see Scheme 5).
N
N
H
Et
C
O
N
NO2
1
–
C
N
The H NMR spectra of compounds 11b—e and
N
N
10
+
11
13a,b have resonance signals for the alkyl substituents
R1, the H(2) proton, and the amino group. The charac-
teristics of aminotriazole 11a are consistent with the
published data. The mass spectra of compounds 11b—e,
13a,b, and 14—17 exhibit peaks of molecular ions. The
IR spectra of compounds 14—17 reveal the presence of
the carbonyl, nitro, and amino groups (see Table 1).
A characteristic feature of the reactions of triazolo-
pyrimidinones 1a—e with hydrazine is the formation of
5-methyl-4-nitro-1,2-dihydropyrazol-3-one (18) along
with triazoles 11a—e (see Scheme 5).
N
N
H
Et
D
Evidently, the pyrimidine ring-opening in triazolo-
pyrimidinones 9, 12, and 13 is controlled by the accessi-
bility of the C(5) atom for the nucleophilic attack in the
stage of formation of the anion of the type D. The
absence of the C-methyl group in the pyrimidine ring in
compounds 9, 12, and 13 favors their scission.
1
This assumption was confirmed by the reactions of
N-alkyltriazolo[1,5-a]pyrimidinones with primary amines
The H NMR and IR spectra of pyrazolone 18 do
not contradict the proposed structure. The mass spec-

Nucleophilic ring-opening of triazolopyrimidinones Russ.Chem.Bull., Int.Ed., Vol. 50, No. 4, April, 2001
Table 2. Yields, melting points, and data from elemental analysis of the synthesized compounds
687
Com- Yield M.p.a
Found
Calculated
Molecular
formula
Com- Yield M.p.a
pound (%) /°Ñ
Found
Calculated
Molecular
formula
(%)
(%)
pound (%)
/°Ñ
C
H
N
C
H
N
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
78
72
67
54
87
83
77
79
55
63
58
43
68
71
63
54
73
70
64
48
250
210
180
155
285
270
240
174
270
270
260
255
250
255
260
260
180b
235b
162b
218b
43.20 3.98 31.51
43.05 4.06 31.38
45.44 4.82 29.37 C9H11N5O3
45.57 4.67 29.52
47.76 5.16 28.01 C10H13N5O3
47.81 5.22 27.87
49.93 5.74 26.46 C11H15N5O3
49.81 5.66 26.40
42.36 5.00 28.21 C7H10N4O3
42.42 5.09 28.27
45.11 5.79 26.28 C8H12N4O3
45.28 5.70 26.40
47.92 5.98 24.69 C9H14N4O3
47.79 6.19 24.78
50.04 6.65 23.37 C10H16N4O3
50.00 6.67 23.33
48.90 6.36 28.62 C12H18N6O3
48.97 6.16 28.55
50.46 6.72 27.18 C13H20N6O3
50.64 6.54 27.26
52.00 6.93 25.98 C14H22N6O3
52.16 6.88 26.07
53.58 7.00 24.98 C15H24N6O3
53.56 7.19 24.98
50.58 6.73 27.22 C13H20N6O3
50.64 6.54 27.26
52.07 6.90 26.04 C14H22N6O3
52.16 6.88 26.07
53.53 7.22 24.90 C15H24N6O3
53.56 7.19 24.98
54.78 7.55 23.92 C16H26N6O3
54.84 7.48 23.98
C8H9N5O3
7a
7b
7c
7d
8a
8b
8c
8d
10
83
76
80
52
59
64
55
43
53
270 52.07 6.75 26.01 C14H22N6O3
52.16 6.88 26.07
275
53.52 7.21 25.02 C15H24N6O3
53.56 7.19 24.98
270
54.79 7.60 23.87 C16H26N6O3
54.84 7.48 23.98
260 55.99 7.80 23.12 C17H28N6O3
56.03 7.74 23.06
230 59.37 7.94 20.84 C20H32N6O3
59.39 7.97 20.78
210 60.15 8.28 20.14 C21H34N6O3
60.26 8.19 20.08
190 60.99 8.23 19.46 C22H36N6O3
61.09 8.39 19.43
170 61.96 8.62 18.98 C23H38N6O3
61.86 8.58 18.82
—
55.16 6.98 17.66 C11H17N3O3
55.22 7.16 17.56
11a
11b
82
77
195c
—
—
—
—
180d 47.54 8.06 44.37
47.60 7.99 44.41
C5H10N4
11c
11d
11å
13à
74
64
91
87
132e 51.25 8.78 39.78
51.41 8.63 39.97
C6H12N4
C7H14N4
C5H10N4
C3H6N4
108 54.69 9.24 36.21
54.52 9.15 36.33
144d 47.49 7.92 44.52
47.60 7.99 44.41
112d 36.80 6.14 57.02
36.73 6.16 57.11
13b
14
92
77
138
202
—
—
—
—
33.13 4.82 28.84
33.11 4.86 28.96
C4H7N3O3
46.52 5.93 26.94 C12H18N6O4
46.45 5.85 27.08
48.10 6.31 26.02 C13H20N6O4
48.14 6.22 25.91
49.58 6.54 24.82 C14H22N6O4
49.70 6.55 24.84
51.11 6.93 23.91 C15H24N6O4
51.13 6.86 23.85
15
16
17
62
43
59
65
22
47
53.47 6.83 18.46 C10H15N3O3
53.32 6.71 18.65
62.19 8.66 13.45 C16H27N3O3
62.11 8.80 13.58
51.22 6.34 19.77 C9H13N3O3
51.18 6.20 19.89
18
1
78—86 273c
—
—
—
—
a From a 1 : 1 water—propan-2-ol mixture.
b From a 1 : 2 ether—dichloromethane mixture.
6,7
c Lit. data: m.p. of compounds 11a
and 18 11 are 200—201 °C and 276 °C, respectively.
d From ethanol.
e
From chloroform.
trum has a molecular ion peak [M]+ (m/z 143). The
spectral characteristics of compound 18 correspond to
those of the specimens obtained by nitration of 5-methyl-
1,2-dihydropyrazol-3-one. The melting point of 18
(273—275 °C) is consistent with the published data11
(276 °C).
No changes were observed upon heating of 1,2,4-tri-
azolo[1,5-a]pyrimidin-7-ones 1a—h with tertiary amines,
such as triethylamine or N,N,N´,N´-tetramethyl-
ethylenediamine.
Thus, the predominant direction of decomposition of
6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-ones under the
action of amines involves the pyrimidine ring-opening to
form hetarylaminoacrylamides of the type C, the sec-
ondary nucleophilic attack at the enamine C atom, and
the scission of the anion of the type D to form amides 10
and 14—17 and aminotriazoles 11 and 13. Since the
presence of the bulky methyl group in the azine frag-
ment hinders the second stage of conversion to form
intermediate D, the azine ring-opening occurs only in

688
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 4, April, 2001
Ulomsky et al.
was filtered off, the filtrate was concentrated, and the residue
was crystallized from EtOH.
the reactions with primary amines. Due to steric hin-
drances, secondary amines cannot react with triazolo-
pyrimidinones 1 giving rise to anions of the type D and
the reactions follow a different pathway resulting in
decomposition of the azole fragment to form hetaryl-
guanidines 4—8 and then amines 3. Alkalis, alkoxides,
and C-nucleophiles act as bases and decompose exclu-
sively the azole ring in triazolopyrimidinones, decompo-
sition proceeding only in the absence of substituents in
this ring.
4-Alkyl- and 4,5-dialkyl-3-amino-1,2,4-triazoles (11),
N-allyl- and N-cyclohexyl-3-(allyl- and cyclohexylamino)-2-
nitrobut-2-enamides (15 and 16), and N-allyl-3-allylamino-2-
nitroacrylamide (17). A mixture of compound 1 or 9 (1.8 mmol)
and the amine (3 mL) was refluxed for 10—15 min. Product 11
was precipitated from the solution by the addition of EtOH
(15 mL), filtered off, and crystallized from EtOH. The filtrate
was concentrated and the residue was triturated with hexane.
Amides 15, 16, or 17 were crystallized from n-octane.
3-Methylamino- and 5-methyl-3-methylamino-1,2,4-tri-
azoles (13a,b) and 3-pyrrolidino- or 3-allylamino-2-nitro-
acrylamides (10 and 17). A mixture of compounds 12a,b
(1.8 mmol) in pyrrolidine or allylamine (3 mL) was refluxed for
10—15 min. Products 13a,b were precipitated from the solution
by the addition of EtOH (15 mL), filtered off, and crystallized
from EtOH. Amides 10 and 17 were isolated as described above.
5-Methyl-4-nitro-1,2-dihydropyrazol-3-one (18). Hydrazine
hydrate (4 mmol) was added to a solution of compound 1
(2 mmol) in EtOH (15 mL). The reaction mixture was kept at
∼20 °C for 2 days and concentrated to dryness. Pyrazolone 18
was crystallized from a 1 : 2 ethanol—water mixture.
Experimental
The 1H NMR spectra were recorded on a Bruker WH-250
spectrometer (250 MHz) in DMSO-d6 with Me4Si as the
internal standard. The mass spectra were obtained on a Varian
MAT-311A instrument (70 eV, EI). The IR spectra were mea-
sured on a Specord IR-75 instrument in KBr pellets. The course
of the reaction and the purities of the products were monitored
by TLC on Silufol UV-254 plates using CHCl3—EtOH (2 : 1) as
the eluent; visualization was carried out with UV light.
N-Alkyl-N-(4-methyl-5-nitro-6-oxopyrimidin-2-yl)cyan-
amides (2). A. A solution of NaOH (0.08 g, 2 mmol) in EtOH
(2 mL) was added to a solution of compound 1 (1.35 mmol) in
EtOH (3 mL). The reaction mixture was refluxed for 20 min,
neutralized, and concentrated in vacuo. The residue was dis-
solved in a minimum volume of hot water. The precipitate that
formed upon cooling was filtered off.
This work was financially supported by the U.S.
Civilian Research and Development Foundation for the
Independent States of the Former Soviet Union (CRDF)
(Grant REC-005) and by the Russian Foundation for
Basic Research (the Program "Leading Scientific
Schools," Project No. 00-15-37390).
B. Triazolopyrimidinone 1 (1.35 mmol) was added to a
solution of Mg(OMe)2 (5 mol L–1) in MeOH (5 mL). The
reaction mixture was refluxed for 1 h and then neutralized. The
solvent was evaporated in vacuo. The product was isolated as
described above.
2-(Alkylamino)-4-methyl-5-nitropyrimidin-7-ones (3). A. A
solution of NaOH (0.08 g, 2.03 mmol) in EtOH (2 mL) was
added to a solution of compound 1 (1.35 mmol) in hot EtOH
(3 mL). The reaction mixture was refluxed for 2 h and then
concentrated in vacuo. The residue was dissolved in a minimum
volume of hot water and cooled. The precipitate that formed
was filtered off.
B. A mixture of compound 1 (2 mmol) and secondary
amine (10 mmol) was refluxed for 2 h. Then EtOH (15 mL) was
added. The reaction mixture was neutralized and the precipitate
that formed was crystallized from water.
1-Alkyl-1-(4-methyl-5-nitro-6-oxopyrimidin-2-yl)guanidines
(4—8) (general procedure). A mixture of 3-alkyl-5-methyl-6-
nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one (1) (1.35 mmol) and
secondary amine (10 mmol) was heated to obtain a solution
(10—30 min) and then concentrated in vacuo. The residue was
crystallized (see Table 2).
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Received November 15, 2000