C-C recyclizations of some 2,7-disubstituted 6-ethoxycarbonylpyrazolo[1,5- a]pyrimidines

Article abstract of DOI:10.1007/s10593-011-0760-x

Condensation of ethyl ethoxymethyleneacetoacetate and ethyl ethoxymethylenecyanoacetate in ethanol with 3-substituted 3-aminopyrazoles and 5-amino-1,2,4-triazole gave the 2-substituted 6-ethoxy- carbonyl-7-methyl- and 7-amino-6-ethoxycarbonylpyrazolo[1,5-

Full text of DOI:10.1007/s10593-011-0760-x

Chemistry of Heterocyclic Compounds, Vol. 47, No. 3, June, 2011 (Russian Original Vol. 47, No. 3, March, 2011)
C–C RECYCLIZATIONS OF SOME 2,7-DISUBSTITUTED
6-ETHOXYCARBONYLPYRAZOLO[1,5-a]PYRIMIDINES
G. G. Danagulyan1,2*, A.P. Boyakhchyan2, A. G. Danagulyan2, and H. A. Panosyan3
Condensation of ethyl ethoxymethyleneacetoacetate and ethyl ethoxymethylenecyanoacetate in ethanol
with 3-substituted 3-aminopyrazoles and 5-amino-1,2,4-triazole gave the 2-substituted 6-ethoxy-
carbonyl-7-methyl- and 7-amino-6-ethoxycarbonylpyrazolo[1,5-a]pyrimidines as well as 7-amino-
6-ethoxycarbonyl-1,2,4-triazolo[1,5-a]pyrimidine. In the presence of alkali these rearranged to
2-substituted 6-acetyl-7-hydroxy- and 6-carbamoyl-7-hydroxypyrazolo[1,5-a]pyrimidines respectively
and also to 6-carbamoyl-7-hydroxy-1,2,4-triazolo[1,5-a]pyrimidine. According to 1H (including
NOESY) NMR spectroscopic data there were formed, along with the cyclization products, noncyclic
condensation adducts (as cyano derivatives) from ethyl ethoxymethylenecyanoacetate with
5-aminopyrazoles. In the presence of alcoholic alkaline solution these were also transformed in high
yield to 6-carbamoyl-7-hydroxypyrazolopyrimidines. When refluxed for a longer time in 12% aqueous
alcoholic alkaline solution the 6-ethoxycarbonyl-2,7-dimethylpyrazolo[1,5-a]pyrimidine and 6-acetyl-
7-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine recyclize to give 6-carboxy-2,7-dimethyl- and 2,7-di-
methylpyrazolo[1,5-a]pyrimidines.
Keywords: pyrazolo[1,5-a]pyrimidine, 1,2,4-triazolo[1,5-a]pyrimidine, rearrangement, recyclization.
The report concerns a study of the recyclization of condensed pyrimidines containing a bridging
nitrogen atom which, on the basis of the atom substitution proceeding in the heterocycle, is a C–C recyclization,
i.e. it is accompanied by substitution of the carbon atom of the heterocycle by another (exo ring) carbon atom. A
similar rearrangement has previously been reported in a series of noncondensed 2-substituted 5-ethoxy-carbonyl-
4-methyl(4-amino)pyrimidines. Upon heating in sodium ethylate or alkaline solution they are converted to the
corresponding 2-substututed 5-acetyl(carbamoyl)-4-hydroxypyrimidines [1-4] as well as in a series of condensed
pyrimidine systems, viz. pyrazolo[1,5-a]pyrimidines and 1,2,4-triazolo[1,5-a]pyrimidines [5].
_______
* To whom correspondence should be addressed, e-mail: gdanag@email.com.
1Russian-Armenian (Slavonic) State University, 123 Hovsep Emin St., Yerevan 0091, Republic of Armenia.
2Institute of Organic Chemistry, Scientific-Technological Center of Organic and Pharmaceutical Chemistry of
the National Academy of Sciences of the Republic of Armenia, 167-A Zakariya Kanakertsi St., Yerevan 0094,
Republic of Armenia.
3Molecular Structure Research Center, Scientific-Technological Center of Organic and Pharmaceutical
Chemistry of the National Academy of Sciences of the Republic of Armenia, 26 Azatunyan Ave, Yerevan 0014,
Republic of Armenia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 393-405, March, 2011. Original
article submitted October 30, 2009.
0009-3122/11/4703-0321©2011 Springer Science+Business Media, Inc.
321

We have previously shown [5] that certain 6-ethoxycarbonyl-7-methylpyrazolo[1,5-a]pyrimidines and
6-ethoxycarbonyl-7-methyl-1,2,4-triazolo[1,5-a]pyrimidine are converted by treatment with alkali to the
corresponding 6-acetyl-7-hydroxyazolo[1,5-a]pyrimidines.
In extending these studies we have examined the possibility of carrying out similar rearrangements
amongst a series of condensed bicyclic pyrimidines containing a methyl or amino group in the pyrimidine ring,
specifically in the case of 2-substituted 6-ethoxycarbonyl-7-methylpyrazolo[1,5-a]- and 7-amino-6-ethoxy-
carbonylpyrazolo[1,5-a]pyrimidines and also 7-amino-6-ethoxycarbonyl-1,2,4-triazolo[1,5-a]pyrimidine. Models
of the studied compounds 6-8 containing a methyl group in position 7 of the pyrazolo[1,5-a]pyrimidine have been
synthesized by condensation of the ethyl ethoxymethyleneacetoacetate with the 3-substituted 5-aminopyrazoles 1,
3, and 4 in ethanol. The 7-aminoazolo[1,5-a]pyrimidines 9-11 were prepared by reaction of ethyl
ethoxymethylenecyanoacetate with aminoazoles containing an amidine or guanidine fragment, specifically, with
5-amino-3-methyl- and 5-amino-3-phenylpyrazoles 1 and 2 and also 5-amino-1,2,4-triazole (5).
R
2
R
X 3
CHOEt
CHOEt
X
R
1 N
N4
5
X
N
MeCOCCO2Et
NCCCO2Et
N
N
N
N
NH2
N
6
Me
7
H
H2N
9–11
CO2Et
CO2Et
6–8
1–5
14, 610 X = CH, 1, 6, 9 R = Me, 2, 10 R = Ph, 3, 7 R = o-ClC6H4, 4, 8 R = o-BrC6H4;
5, 11 R = H, X = N
The structure of compounds 6-8 including the presence of ethoxycarbonyl and methyl groups in the
pyrimidine ring (i.e. condensation proceeds on account of the acetyl and ethoxymethylene fragments of the
reagent) was confirmed through their 1H NMR spectra. The position of the methyl group in the pyrimidine ring
1
of compounds 6-8 (position 5 or 7) was determined using the NOESY H NMR method for the iodomethylates
of these systems. In particular, in the spectrum of compound 12 (the iodomethylate of compound 6) a clear
interaction was noted between the protons of the N-methyl group and the pyrazole ring CH and this pointed to
alkylation at the N(4) atom. In the spectrum of this compound there was observed an obvious cross peak
between the signal for this same N-methyl group and the pyrimidine ring proton which is unambiguous evidence
for their closely related position in the molecule. It is significant that any kind of interaction of the two
Me
Me
H
+
MeI
MeI
N
+
Me
N
Me
6
N
N
N
N
–
I
–
I
EtI
H
H
Me
Me
CO2Et
CO2Et
12
Me
+
N
CH2Me
N
N
–
I
H
Me
CO2Et
13
322

methyl groups in the molecule is absent and this is additional evidence that the methyl group in compound 6, as
also in compounds 7 and 8, is at position 7 of the pyrazolo[1,5-a]pyrimidine, i.e. distant from the N(4) atom. A
1
similar interaction was also noted by us in the H NMR spectrum of compound 13 (the iodoethylate of the
pyrazolo[1,5-a]pyrimidine 6).
In the realization of the condensation of the 5-aminoazoles 1, 2, and 5 with ethyl ethoxymethylene-
cyanoacetate we have proposed (or at least not ruled out) that the reaction could occur by different routes both
from the viewpoint of the groups taking part in the cyclization and by the direction of cyclization. In our opinion
there may be 8 or more substances as cyclization products bearing in mind the presence of three reactive centers
in the molecule of the ethoxymethylene derivative and also the ambident nature of the -aminoazoles (with,
correspondingly, possible cyclization to form a pyrimidine or pyridine ring with aminopyrazoles or isomeric
1,2,4-triazolopyrimidines with 1,2,4-triazoles). Hence, in these reactions of forming the azolo[1,5-a]pyrimidines
(taking into account the undoubtedly greater activity of the ethoxymethylene group when compared to the nitrile
and ester groups) the cyclization can lead to one of the azolopyrimidines A-D given below.
R
R
X
X
N
N
N
N
N
N
NH2
A
B
H2N
CO2Et
CO2Et
R
X
CO2Et
CN
+
N
EtO
N
N
R
H
R
X
X
N
N
N
N
N
N
OH
HO
D
C
CN
CN
It was turned out that the spectrum of the triazolo[1,5-a]pyrimidine 11 showed signals for the ester
group protons, a triazole ring proton singlet, and also two proton doublets with a broadened signal for a further
proton (proposed to be NH groups). On the basis of this data we consider that compound 11 exists in the
tautomeric form 11a, which explains the splitting of the signals of the H-5 proton and the neighboring NH
group.
A more complex picture is noted in the 1H NMR spectra of compounds 9 and 10. The 1H NMR spectrum
of the condensation product of 5-amino-3-phenylpyrazole (2) with ethyl ethoxymethylenecyanoacetate shows, in
place of spectrum of the expected compound 10, two sets of signals pointing to the presence in
N
N
H
H
N
N
N
N
N
N
H2N
HN
CO2Et
CO2Et
11a
11
323

solution of two compounds (possibly two conformer forms of the same compound). In addition to signals for
ethyl and phenyl group protons there are observed two doublet signals which we assign to the proton of the
exocyclic double bond and the NH (3J = 13.5 Hz). The spectrum of the material isolated also shows the presence
of two pairs of doublets for the pyrazole ring protons H-4 and NH (4J = 2.1 Hz). Evidently the compound
produced is the noncyclic cyano derivative 14 without closure of the pyrimidine ring. The proposal was
confirmed by the presence in the IR spectrum of nitrile stretching vibrations at 2220 cm-1 and also by the
presence in the mass spectrum of a fragment corresponding to cleavage of this group. The presence in the
spectrum of two sets of signals, the changes in intensities of which alter with the nature of the solvent used, is
explained by the potential existence of hindered rotation around the exocyclic C(3)–N partial double bond in
compound 14 and hence giving the forms 14a and 14b.
Ph
Ph
N
N
NH
N
N
N
CO2Et
CN
+
2
EtO
C
H
HN
H2N
CO2Et
CO2Et
10
H
N
H
N
H
H
H
H
CN
H
H
HN
HN
N
N
14
CO2Et
H
H
NC
CO2Et
14b
14a
As is evident from the NOESY 2D spectrum for this compound, the phenyl group is found at position 5
of the pyrazole ring and is confirmed by the presence of a strong NOE for the phenyl ring ortho protons both
with the NH proton and also with H-4. An NOE is observed in conformer 14a between the H-4 and exocyclic
NH proton and in conformer 14b between the H-4 and the N–CH.
1
Study of the H NMR spectra of the compound separated as a result of treating the 5-amino-
3-methylpyrazole (1) with ethyl ethoxymethylenecyanoacetate showed three sets of signals corresponding to the
pyrazolopyrimidine 9 (about 20%) with two conformational forms of the noncyclic cyano derivative 15 (about
40% of each). The NOESY spectrum of compounds 15a and 15b repeats the relationship found in the spectrum
of compound 14, in fact showing the presence of an NOE between the methyl group protons at position 5 of the
pyrazole ring and the NH and H-4 protons. An NOE is also seen between the pyrazole H-4 ring proton and a
proton of the exocyclic multiple bond.
The existence of a nitrile group in this sample (i.e. the presence of the noncyclic compound) is noted in
the IR spectrum. The mass spectrometric study carried out to clarify the structure of the condensation product
might be uninformative since the molecular weights of compounds 9 and 15 are identical. However, in the mass
spectrum, a fragment which corresponded to cleavage of a CN group was observed and this points the presence
of the open form 15.
The synthesis of all of the azolopyrimidines listed occurs in quite high yield (60-86%) with short
refluxing of the aminoazoles 1-5 in alcohol with the corresponding ethoxymethylene derivatives. The triazolo
derivative 11 is the exception and is formed (in 79% yield) only by refluxing the reagents in alcohol for 5 h. As
noted above, however, reaction with the cyanoacetate derivative is markedly more difficult.
324

Me
Me
N
N
NH
N
N
N
HN
H2N
CO2Et
CN
CO2Et
CO2Et
1
EtO CH
+
9
H
Me
HN
H
Me
HN
H
H
H
CN
CO2Et
N
N
H
N
N
NC
CO2Et
15a
15b
Rearrangement of the pyrazolo[1,5-a]pyrimidines 6-8 to give the corresponding 6-acetyl-7-hydroxy-
pyrazolo[1,5-a]pyrimidines 16-18 generally proceeds rapidly at room temperature in the presence of an
alcoholic alkaline solution over several minutes, even at room temperature. A salt of the 7-hydroxy derivative is
initially formed and acidification gives the 7-hydroxy derivatives 16-18.
The rearrangement product of the triazolopyrimidine 11 (the 6-carbamoyl-7-hydroxy-1,2,4-triazolo-
[1,5-a]pyrimidine (19)) is prepared in 51% yield only by refluxing compound 11 for 5 h in alcoholic alkaline
solution. In the short term (within minutes) in refluxing alkaline solution of the triazolo[1,5-a]pyrimidine 11 the
reaction does not go to completion and gives a mixture of the starting and final reaction products.
R
N
N
N
NaOH
KOH
N
N
N
N
6–8, 11
HO
HO
COMe
CONH2
16–18
19
16 R = Me, 17 R = o-ClC6H4, 18 R = o-BrC6H4
It should be noted that reaction of compound 16 in an alcoholic solution of sodium ethylate gave the
water soluble sodium salt of the 6-acetyl-7-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine (20).
1
The H NMR spectra of all of the recyclization products showed the absence of signals for the ester
protons which characterize the starting materials and the appearance of a broadened signal for a hydroxyl group
proton.
We were unable to synthesize the pyrazolopyrimidines 9 and 10 in a pure state (without the formation of
the corresponding non cyclic forms). Hence in the reaction with alcoholic base solution we have introduced the
samples separated, in fact the phenyl derivative 14 and the 2-methyl derivative of the pyrazolopyrimidine 9 as a
mixture with the corresponding cyano derivative 15.
Short heating in base of the phenyl derivative 14 and the mixture of the pyrazolo[1,5-a]pyrimidine 9
with the noncyclic cyano derivatives 15 gave high yields of the corresponding 6-carbamoyl-7-hydroxy-
325

TABLE 1. Characteristics of the Synthesized Compounds 6-24
Found, %
——————
Yield,
%
Com-
pund
Empirical
formula
mp, °C
Rf*
Calculated, %
H
С
N
C11H13N3O2
60.03
60.26
5.71
5.98
19.40
19.17
111-112
0.69
86
6
C16H14ClN3O2
C16H14BrN3O2
C10H12N4O2
60.59
60.86
53.51
53.35
54.29
54.54
4.60
4.47
3. 70
3. 92
5.31
5.46
13.49
13.31
11.41
11.67
25.71
25.44
124-125
109-110
191-192
0.80
0.9
63
60
77
7
8
9, 15a,
and 15b
11
0.56
C8H9N5O2
46.04
46.38
4.18
4.37
4.26
4.47
5.05
4.84
5.17
5.00
34.04
33.81
11.41
11.63
10.98
11.20
19.56
19.85
235-236
167-168
154-155
206-207
0.61
—
69
95
75
75
C11H13N3O2 MeI 40.13
12
13
39.90
41.39
41.61
64.09
63.82
C11H13N3O2 EtI
—
C15H14N4O2
0.38
14a
and 14b
16
C9H9N3O2
56.78
56.54
58.19
58.45
50.41
50.62
39.97
40.23
4.50
4.74
3.59
3.50
3.27
3.03
2.98
2.81
22.21
21.98
14.87
14.61
12.89
12.65
38.85
39.10
>300
0.63
0.60
0.60
0.36
—
93
57
76
51
90
86
94
C14H10ClN3O2
C14H10BrN3O2
C6H5N5O2
221–222
233–234
>300
17
18
19
20
21
22
23
C9H8N3NaO2
C8H8N4O2
—
50.15
50.00
61.68
61.41
56.29
56.54
4.03
4.17
4.11
3.96
4.51
4.74
29.39
29.16
22.30
22.04
22.19
21.98
>300
0.45
0.54
0.65
C13H10N4O2
C9H9N3O2
>300
>330 (subl.)
48 (A)
25 (B)
C8H9N3
65.54
65.29
6.01
6.16
28.38
28.55
220 (subl.)
0.68
37 (A)
58 (B)
24
_______
* Systems: benzene-acetone, 3: 1 (compounds 6, 9, 14a,b, 15a,b, 24) and 1:1
(compounds 7, 8, 11, 16-19, 21-23).
2-substituted pyrazolo[1,5-a]pyrimidines 21 and 22. Evidently the action of base occurs initially to give
cyclization of compounds 14 and 15 to the corresponding 7-aminopyrazolo[1,5-a]pyrimidines 9 and 10 which
readily cyclize in the reaction conditions to compounds 21 and 22.
R
N
N
N
14a, 9 + 15a
HO
CONH2
21, 22
21 R = Me, 22 R = Ph
326

A possible scheme for the conversion of compounds 6-11 is given below.
R
N
R
N
R
N
R
N
X
X
X
X
–
OH
N
N
N
N
6–11
N
N
16–19, 21, 22
N
–
N
–
–
O
HO
–OEt
EtO
O
Y
Y
COY
O
CO2Et
CO2Et
COY
Y = Me, NH2
In the recyclization process using hydroxide ion there evidently occurs opening of the pyrimidine ring at
the N–C(7) bond, subsequent rotation around the C(5)–C(6) bond and a repeated cyclization involving a
nucleophilic attack of a triazole ring nitrogen atom such that a carbon of the ester group is included in the newly
formed pyrimidine ring while the C(7) atom (which was in the pyrimidine ring) proves to be outside the
heterocycle. The relatively low yield of the rearrangement product in the case of recyclization of
triazolopyrimidine 11 is possibly related to the lowering of the electron density at the N(1) atom in the
intermediate due to the (-M) effect of the N(3) triazole ring atom.
12% KOH
Me
Me
6
EtOH/H2O
N
N
N
N
N
N
–
CO2
12% KOH
EtOH/H2O
Me
Me
16
CO2H
24
23
We have previously reported that prolonged refluxing of the 6-ethoxycarbonyl-7-methyl-2-phenyl- or
6-acetyl-7-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidines in a 12% aqueous alcoholic solution of potassium
hydroxide causes rearrangement to give in both cases 7-methyl-2-phenylpyrazolo[1,5-a]pyrimidine [5]. The
formation of the latter indirectly points to the occurrence of a repeated, two-stage rearrangement of both starting
compounds to the 6-carboxy-7-methyl-2-phenylpyrazolo[1,5-a]pyrimidine which undergoes decarboxylation
under these reaction conditions. We have also recorded similar recyclizations in the case of the corresponding
Me
Me
Me
–
OH
N
N
N
N
–
N
N
–
N
16
N
H
–
N
HO
HO
HO
O
Me
O
H
COMe
N
COMe
CO2H
Me
N
N
23
24
Me
–
–CO2
– OH
H
–
O
CO2H
327

2-methyl derivatives 6 and 16. Moreover, under these conditions (in contrast to those reported before) we have
been able to separate and to identify the product of the noted two-stage C–C recyclization as the 6-carboxy-
2,7-dimethylpyrazolo[1,5-a]pyrimidine (23) and the final reaction product, i.e. the 2,7-dimethylpyrazolo-
[1,5-a]pyrimidine (24). Separation of the 6-carboxy-2,7-dimethylpyrazolo[1,5-a]pyrimidine (23) is a direct,
rather than indirect, proof of the existence of a two-stage C–C recyclization.
TABLE 2. 1H and 13C NMR Spectra of the Condensed Pyrimidines 6-24
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1.44 (3Н, t, J = 7.1, ОСН2СH3); 2.56 (3Н, s, 2-СН3); 3.20 (3Н, s, 7-СН3);
4.44 (2Н, q, J = 7.1, ОСН2СН3); 6.55 (1Н, s, Н-3); 8.91 (1Н, s, Н-5)
6*
7
1.47 (3Н, t, J = 7.1, ОСН2СH3); 3.28 (3Н, s, 7-СН3); 4.47 (2Н, q, J = 7.1, ОСН2CH3);
7.30 (1Н, s, Н-3); 7.37-7.41 (2Н, m, С6Н4); 7.53 (1H, m, C6H4); 7.97 (1H, m, C6H4),
8.99 (1Н, s, Н-5)
1.44 (3Н, t, J = 7.1, ОСН2СH3); 3.26 (3Н, s, 7-СН3); 4.46 (2Н, q, J = 7.1, ОСН2);
7.30 (1Н, s, Н-3); 7.41-7.79 (4Н, m, С6Н4); 8.99 (1Н, s, Н-5)
8
1.40 (0.6H, t, J = 7.1, OСН2СH3); 2.45 (0.6H, s, CH3); 4.34 (0.4H, q, J = 7.1, OСН2СH3);
9
6.19 (0.2H, s, H-3); 8.13 (0.2H, br. s, NH2) and 8.36 (0.2H, br. s, NH2); 8.53 (0.2H, s, H-5)
1.35 (3Н, t, J = 7.1, ОСН2СH3); 4.21 (2Н, q, J = 7.1, ОСН2СH3); 8.18 (1H, br. s, H-2);
8.61 (1H, d, J = 13.5, H-5); 11.35 (1H, d, J = 13.5, NH); 13.65 (1H, br. s, NH)
11
12
13
1.47 (3Н, t, J = 7.1, ОСН2СH3); 2.67 (3H, s, 2-CH3); 3.37 (3H, s, 7-CH3);
4.45 (3H, s, N-CH3); 4.51 (2Н, q, J = 7.1, ОСН2СH3); 7.33 (1H, s, H-3); 9.78 (1H, s, H-5)
1.51 (3Н, t, J = 7.1, ОСН2СH3); 1.65 (3Н, t, J = 7.1, NСН2СH3); 2.65 (3H, s, 2-CH3);
3.35 (3H, s, 7-CH3); 4.50 (2Н, q, J = 7.1, ОСН2СH3); 4.91 (2Н, q, J = 7.1, NСН2СH3);
7.43 (1H, s, H-3); 9.84 (1H, s, H-5)
1.33 and 1.37 (3H, t, J = 7.1, CH3); 4.21 and 4.28 (2H, q, J = 7.1, OCH2);
6.32 and 6.64 (1H, d, J = 2.1, H-4); 7.26-7.42 (3H, m, C6H5) and 7.64-7.69 (2H, m, C6H5);
8.27 and 8.57 (1H, d, J = 13.8, =CHNH); 10.75 (1H, d, J = 13.8, =CHNH);
12.82 and 12.94 (1H, d, J = 2.1, NH)
14a
and
14b
1.31 and 1.35 (2.4H, t, J = 7.1, OCH2CH3); 2.23 and 2.25 (2.4H, s, CH3);
4.19 and 4.25 (1.6H, q, J = 7.1, OCH2); 5.74 and 5.95 (0.8H, br. s, H-4 pyrazole);
8.14 and 8.49 (0.8H, d, J = 13.8, =CHNH); 10.56 and 10.62 (0.8H, d, J = 13.8, =CHNH);
11.98 and 12.12 (0.8H, br. s, NH)
15a
and
15b
2.49 (3H, s, 2-CH3); 3.13 (3H, s, COCH3); 6.41 (1H, s, H-3); 7.00 (1H, br. s, OH);
8.79 (1H, s, H-5)
16
17
18
19
3.23 (3H, s, CH3); 5.8-6.3 (1Н, br. s, ОН); 7.17 (1Н, s, Н-3); 7.38 (2Н, m, С6Н4);
7.51 (1Н, m, С6Н4); 7.98 (1Н, m, С6Н4); 8.90 (1Н, s, Н-5)
3.22 (3H, s, CH3); 7.17 (1H, s, H-3); 7.40-7.97 (4H, m, C6H4);
8.91 (1H, s, H-5); 12.4-13.3 (1H, br. s, OH)
8.34 (1Н, s, H-2); 8.62 (1Н, br. s, NH); 8.83 (1Н, s, Н-5); 8.88 (1Н, br. s, NH);
12.4-13.4 (1Н, br. s, ОН)
2.55 (3H, s, 2-CH3); 2.97 (3H, s, COCH3); 6.57 (1H, s, H-3); 8.68 (1H, s, H-5)
20
21*2
2.41 (3Н, s, СН3); 6.18 (1Н, s, Н-3); 8.03 (1Н, br. s, NH); 8.43 (1Н, br. s, NH);
8.55 (1Н, s, Н-5); 11.0-13.0 (1Н, br. s, ОН)
6.78 (1Н, s, Н-3); 7.4-8.0 (5Н, m, С6Н5); 8.18 (1Н, br. s, NH); 8.58 (1Н, br. s, NH);
8.59 (1Н, s, Н-5); 11.4-13.1 (1Н, br. s, ОН)
22
23
24
2.49 (3H, s, 2-CH3); 3.13 (3H, s, 7-CH3); 6.41 (1H, s, H-3); 8.79 (1H, s, H-5);
12.92 (1Н, br. s, COОН)
2.48 (3H, s, 2-CH3); 2.72 (3H, d, J = 0.9, 7-CH3); 6.37 (1H, s, H-3);
6.68 (1H, dq, J = 4.2, J = 0.9, H-6); 8.24 (1H, d, J = 4.2, H-5)
_______
*
13C spectrum, δ, ppm: 14.43 (СН3СН2О); 14.99 (2-СН3); 15.19 (7-СН3);
61.54 (ОСН2); 97.76 (С-3); 109.89 (С-2); 149.51 (С-ipso); 149.78 (С-5);
150.98 (С-7); 157.38 (С-6); 165.10 (СОО).
*
2 13C spectrum, δ, ppm: 14.11 (CH3); 89.88 (CO–C); 95.94 (=CH); 148.70 (C-
7); 149.53 (C-4); 150.34 (N=CH), 154.36 (C-2); 167.99 (CO).
328

The formation of compounds 23 and 24 from pyrazolopyrimidines 6 and 16 can be explained by the
occurrence of a series of successive reactions which include the opening of the pyrimidine ring, its cyclization,
and then decarboxylation. The scheme given below shows The scheme for the transformation of the acetyl
derivative 16 is given above. According to the scheme reported previously the transformation of compound 6 to
compounds 23 and 24 initially forms the acetyl derivative 16 (C–C recyclization) but in this case a normal
hydrolysis of the ester group is not excluded. Compound 16 then again undergoes rearrangement to the final
compounds 23 and 24.
EXPERIMENTAL
1
IR spectra were obtained on a UR-20 spectrometer using vaseline oil. H and 13C NMR spectra were
recorded at the Molecular Structure Research Center, National Academy of Sciences of Armenia (US CRDF
RESC 17-5 program) on a Varian Mercury 300 instrument (300 and 75 MHz respectively) using CDCl3
(compounds 6-8), DMSO-d6 (compounds 9-19, 21-24) or D2O (compound 20) with TMS as standard. The
sample temperature was 303 K. Mass spectra were recorded on an MK-1321 spectrometer with direct insertion
of the sample into the ion source and an ionization energy of 70 eV. TLC was performed on Silufol UV-254
plates and revealed using iodine vapor and the Ehrlich reagent.
5-Amino-3-methylpyrazole (1) and 5-amino-1,2,4-triazole (5) used in the synthesis of the
azolopyrimidines were obtained from the Aldrich company and the 5-amino-3-phenylpyrazole (2), 5-amino-
3-(o-chlorophenyl)pyrazole (3), and 5-amino-3-(o-bromophenyl)pyrazole (4) were prepared by method [6].
The physicochemical and spectroscopic characteristics of the compounds synthesized are given in
Tables 1 and 2.
6-Ethoxycarbonyl-2,7-dimethylpyrazolo[1,5-a]pyrimidine (6). A solution of ethyl ethoxymethylene-
acetoacetate (18.6 g, 100 mmol) in ethanol (20 ml) was added to a solution of 5-amino-3-methylpyrazole (9.7 g,
100 mmol) in ethanol (30 ml). Over 3-5 min the temperature of the reaction mixture increased. It was then
refluxed for 15 min, cooled, and the precipitate formed was filtered off to give the product (18.8 g, 86%) as
shining white crystals of the pyrazolo[1,5-a]pyrimidine 6.
2-(o-Chlorophenyl)-6-ethoxycarbonyl-7-methylpyrazolo[1,5-a]pyrimidine (7).
A
mixture of
5-amino-3-(o-chlorophenyl)pyrazole (1.4 g, 7 mmol), ethyl ethoxymethyleneacetoacetate (1.5 g, 8 mmol), and
absolute ethanol (10 ml) was refluxed for 1 h. The precipitate formed on cooling was filtered off to give
compound 7 (1.4 g, 63%).
2-(o-Bromophenyl)-6-ethoxycarbonyl-7-methylpyrazolo[1,5-a]pyrimidine (8). A mixture of ethyl
ethoxymethyleneacetoacetate (0.85 g, 4.5 mmol), 5-amino-3-(o-bromophenyl)pyrazole (1.0 g, 4.2 mmol), and
absolute alcohol (10 ml) was refluxed for 1 h. The precipitate formed on cooling was filtered off to give the
pyrazolo[1,5-a]pyrimidine 8 (0.9 g, 60%).
7-Amino-6-ethoxycarbonyl-2-methylpyrazolo[1,5-a]pyrimidine (9). A solution containing 5-amino-
3-methylpyrazole (2.0 g, 20 mmol) in absolute ethanol (20 ml) was added to a solution of ethyl
ethoxymethylenecyanoacetate (3.4 g, 20 mmol) in absolute ethanol (5 ml). An increase in temperature of
10-15ºC was observed almost at once. The solution was refluxed for 15 h. After cooling, the precipitate was
filtered off to give 3.4 g (77%) of a mixture of compound 9 and ethyl 2-cyano-3-(5-methylpyrazol-
3-yl)aminopropenoate (15). IR spectrum, , cm-1: 1500, 1570, 1625, 1630, 1678 (C=C and C=N), 1710 (C=O),
2210 (cyano), 3200 (NH). Mass spectrum, m/z (Irel, %): 221 [M++1] (16), 220 [M]+ (100), 193 (15), 192 (16),
186 (17), 175 (23), 174 (69), 148 (12), 120 (15).
Ethyl 2-Cyano-3-(5-phenylpyrazol-3-yl)aminopropenoate (14). Similarly as above. A solution
containing 5-amino-3-phenylpyrazole (4.0 g, 25 mmol) in absolute ethanol (30 ml) was added to a solution of
329

ethyl ethoxymethylenecyanoacetate (4.2 g, 25 mmol) in absolute ethanol (5 ml). Formation of a precipitate was
noted almost at once. The precipitate was filtered off to give compound 14 (5.25 g, 75%) which was
recrystallized from ethanol. IR spectrum, , cm-1: 1565 and 1583, 1630, 1675 (C=C and C=N), 1703 (C=O),
2220 (CN), 3270 (NH). Mass spectrum, m/z (Irel, %): 283 [M++1] (20), 282 [M+] (100), 237 (20), 236 (58), 210
(33), 209 (30), 182 (11).
7-Amino-6-ethoxycarbonyl-1,2,4-triazolo[1,5-a]pyrimidine (11). A solution containing 5-amino-
1,2,4-triazole (1.8 g, 20 mmol) in absolute ethanol (35 ml) was added to a solution of ethyl
ethoxymethylenecyanoacetate (3.4 g, 20 mmol) in absolute ethanol (5 ml). The mixture was refluxed for 5 h.
The precipitate formed after cooling was filtered off and washed with cold alcohol to give compound 11 (2.86 g,
69%) which was recrystallized from ethanol.
6-Ethoxycarbonyl-2,4,7-trimethylpyrazolo[1,5-a]pyrimidinium Iodide (12). A mixture of the
pyrazolo[1,5-a]pyrimidine 6 (2 g, 9 mmol) and methyl iodide (4 ml, 9.12 g, 64 mmol) was heated in a sealed
ampule for 5 h. The crystals formed were filtered off, washed with hexane, and dried to give the iodide 12
(3.1 g, 95%).
6-Ethoxycarbonyl-4-ethyl-2,7-dimethylpyrazolo[1,5-a]pyrimidinium Iodide (13). Similarly to the
above. A mixture of the pyrazolo[1,5-a]pyrimidine 6 (1.8 g, 8 mmol) and ethyl iodide (5 ml, 9.66 g, 62 mmol)
was heated in a sealed ampule on a water bath for 8 h. The crystals formed were filtered off, washed with hot
hexane, and dried to give the iodide 13 (2.3 g, 75%).
6-Acetyl-7-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine (16). A solution of potassium hydroxide
(1.0 g) in ethanol (10 ml) was added to a solution of the 6-ethoxycarbonyl derivative 6 (1.1 g, 5 mmol) in
ethanol (5 ml). The color changed from yellow to blue after addition of alkali and crystals of the potassium salt
of the product began to precipitate from the solution. The crystals were filtered off, dissolved in water, and
acidified to pH 5-6. The precipitate was then filtered off and washed with water and acetone to give the 6-acetyl
derivative 16 (0.88 g, 93%).
6-Acetyl-2-(o-chlorophenyl)-7-hydroxypyrazolo[1,5-a]pyrimidine (17). A solution of compound 7
(1.26 g, 4 mmol) in ethanol (15 ml) was added to a solution of KOH (2.0 g, 36 mmol) in aqueous ethanol (70%,
15 ml). After stirring for several minutes a precipitate began to appear. The mixture was refluxed for 1 h, cooled,
and acidified with dilute hydrochloric acid (1: ) to pH 5-6 to give compound 17 (0.65 g, 57%).
6-Acetyl-2-(o-bromophenyl)-7-hydroxypyrazolo[1,5-a]pyrimidine (18). Analogously to the above. A
solution of compound 8 (1.44 g, 4 mmol) in ethanol (15 ml) was added to a solution of KOH (2.0 g, 36 mmol) in
70% aqueous ethanol (15 ml). A dark-violet coloration was produced instantaneously and this then disappeared.
The solution was acidified with dilute hydrochloric acid to pH 6-7 and the precipitate formed was filtered off
and washed on the filter with water to give grayish crystals of compound 18 (1.0 g, 76%) which were
recrystallized from ethanol.
6-Carbamoyl-7-hydroxy-1,2,4-triazolo[1,5-a]pyrimidine (19). A solution of sodium hydroxide (0.4 g,
10 mmol) in ethanol (5 ml) was added to a suspension of compound 11 (1.04 g, 5 mmol) in ethanol (10 ml) and
refluxed for 5 h. The precipitate formed after cooling was filtered off, dissolved in water, and acidified using
dilute hydrochloric acid to pH 5-6. The precipitate then produced was filtered off and washed with cold water to
give the triazolo[1,5-a]pyrimidine 19 (0.45 g, 51%).
Sodium Salt of 6-Acetyl-7-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine (20). A solution of sodium
ethylate (prepared from sodium (0.21 g, 9 mmol) and absolute alcohol (5ml)) was added to a suspension of
6-acetyl-7-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine 16 (1.7 g, 9 mmol) in absolute alcohol (10 ml). The
mixture was left for several hours at room temperature and the precipitate was filtered off to give the sodium salt
of 20 (1.7 g, 90%).
6-Carbamoyl-7-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine (21). A solution of sodium hydroxide
(1.0 g, 25 mmol) in absolute ethanol (5 ml) was added to a solution of a mixture of compound 9 and the acyclic
330

cyano derivative 15 (0.5 g, 2.2 mmol) in absolute ethanol (15 ml) and refluxed for 10 min. The solution changed
color and a precipitate was formed. Solvent was evaporated and the residue was washed with
absolute benzene. The precipitate remaining was filtered off, dissolved in water, and acidified using dilute
hydrochloric acid (1:1) to pH 4. The precipitate was filtered and washed with cold water to give the
pyrazolo[1,5-a]pyrimidine 21 (0.36 g, 86%).
6-Carbamoyl-7-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidine (22). A solution of potassium hydroxide
(2.0 g, 36 mmol) in ethanol (20 ml) was added to a solution of the cyano derivative 14 (2.0 g, 7 mmol) in
ethanol (15 ml) and refluxed for 15 min. A change in color was noted and a precipitate was formed which was
filtered off, dissolved in water, and acidified with dilute hydrochloric acid (1:1) to pH 5-6. The precipitate
formed was filtered off and washed with cold water to give compound 22 (1.65 g, 94%).
6-Carboxy-2,7-dimethylpyrazolo[1,5-a]pyrimidine (23) and 2,7-Dimethylpyrazolo[1,5-a]pyrimidine
(24). A. A solution of potassium hydroxide (1.2 g, 20 mmol) in water (5 ml) was added to a solution of the
6-ethoxycarbonyl derivative 6 (1.1 g, 5 mmol) in ethanol (5 ml) and refluxed for 20 h. Solvent was evaporated
to dryness and the residue was washed twice with benzene collecting the benzene extracts. Removal of the
benzene gave compound 24 (0.27 g, 37%). The residue formed after treatment of the reaction mixture with
benzene was dissolved in water (5 ml) and acidified using hydrochloric acid to pH 4-5. The crystals formed
were filtered off and recrystallized from benzene to give compound 23 (0.46 g, 48%).
B. Similarly to the above, refluxing a mixture of the 6-acetyl derivative 16 (0.96 g, 5 mmol) and
potassium hydroxide (1.68 g, 30 mmol) in aqueous alcohol solution (13 ml) for 30 h. Treatment with benzene
then gave compound 24 (0.43 g, 58%) and the acid 23 (0.24 g, 25%). According to melting point,
chromatographic mobility, and 1H NMR spectrum the sample obtained agreed with that prepared by the counter
synthesis of ester 6 using method A.
This work was carried out with the financial support of a USA Civil Research and Dvelopment Fund
(US CRDF, grant ARB2-2640-YE-5) and also through topic 326 funded by the Armenian Republic Ministry of
Science and Education.
REFERENCES
1.
2.
R. S. Vartanyan, Zh. V. Kazaryan, and S. A. Vartanyan, Khim. Geterotsikl. Soedin., 1558 (1982).
[Chem. Heterocycl. Comp., 18, 1212 (1982)].
G. G. Danagulyan and A. D. Mkrtchyan, Khim. Geterotsikl. Soedin., 1735 (2003). [Chem. Heterocycl.
Comp., 39, 1529 (2003)].
3.
4.
G. G. Danagulyan and A. D. Mkrtchyan, Khim. Zh. Armenii, 58, 70 (2005).
R. S. Vartanyan (Vardanyan), V. J. Hruby, G. G. Danagulyan, and A. D. Mkrtchyan, J. Heterocycl.
Chem., 42, 557 (2005).
5.
6.
G. G. Danagulyan, A. A. Mkrtchyan, and G. A. Panosyan, Khim. Geterotsikl. Soedin., 569 (2005).
[Chem. Heterocycl. Comp., 41, 485 (2005)].
I. I. Grandberg, Wei-p' i Ting, and A. N. Kost, Zh. Obshch. Khim., 31, 2311 (1961).
331