Cyclocondensation of N-aryl-3-oxobutanethioamides with 5-amino-3-R-4-R 1-pyrazoles

Article abstract of DOI:10.1007/s10593-009-0168-z

The cyclocondensation products of N-aryl-3-oxobutanethioamides with 5-amino-3-R-4-R¹-pyrazoles are 4-(arylamino)-2-methyl-7-R-8-R ¹-pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine-4-thione derivatives, the ratio of which depends on the nucleophilicity of the starting 5-amino-3-R-4-R¹-pyrazoles and the presence of a proton donor solvent.

Full text of DOI:10.1007/s10593-009-0168-z

Chemistry of Heterocyclic Compounds, Vol. 44, No. 10, 2008
CYCLOCONDENSATION OF N-ARYL-
3-OXOBUTANETHIOAMIDES WITH
5-AMINO-3-R-4-R1-PYRAZOLES
V. N. Britsun
The cyclocondensation products of N-aryl-3-oxobutanethioamides with 5-amino-3-R-4-R1-pyrazoles are
4-(arylamino)-2-methyl-7-R-8-R1-pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine-4-thione
derivatives, the ratio of which depends on the nucleophilicity of the starting 5-amino-3-R-4-R1-
pyrazoles and the presence of a proton donor solvent.
Keywords: 5-amino-3-R-4-R1-pyrazoles, N-aryl-3-oxobutanethioamides, 4-(arylamino)-2-methyl-7-R-
8-R1-pyrazolo[1,5-a]pyrimidines, 2,7-dimethyl-1,4-dihydropyrazolo[1,5-a]pyrimidine-4-thione, 2-methyl-
1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine-4-thione, 2-methyl-4-(phenylamino)pyrido-
[2',3':3,4]pyrazolo[1,5-a]pyrimidine, heterocyclization, [3+3] cyclocondensation.
We have recently shown that N-aryl-3-oxobutanethioamides react with such 2-aminoazoles (azines) as
3-amino-5-R-1,2,4-triazoles [1], 2-amino-5-R-pyridines [2], 2-amino-4-R-5-R1-thiazoles [3], and 5-amino-
tetrazole [4] via a [3+3] cycloaddition scheme to form two groups of compounds (pyrimidine-4-thione and
4-(arylamino)pyrimidine derivatives) the ratio of which depends on the basicity of the heterocyclic
1,3-dinucleopile and the acidity of the solvent [1-4].
The aim of this work is to continue our investigation [1-4] and study of the regioselectivity of the
cyclization of the N-aryl-3-oxobutanethioamides 1a-d with such 1,3-dinucleophiles as the 5-amino-3-R-4-R1-
pyrazoles, viz 5-amino-3-methylpyrazole (2a), 5-amino-4-cyanopyrazole (2b), and 3-amino-2H-pyrazolo-
[3,4-b]pyridine (2c) in the absence and the presence of a proton donor solvent. Such a course should prove an
addition to the general results of preceding work [1-4], in particular the observation of the effect of the
nucleophilicity of the 2-aminoazole and the acidity of the solvent on the regioselectivity of the process.
Since the [3+3] cyclocondensation can occur at three reaction centers in the N-aryl-3-oxobutane-
thioamides 1a-d and at two in the 5-amino-3-R-4-R1-pyrazoles 2a-c the reaction products can be four groups of
compounds i.e. 2(4)-methyl-7-R-8-R1-1,4(1,2)-dihydropyrazolo[1,5-a]pyrimidine-4(2)-thiones and 4(2)-aryl-
amino-2(4)-methyl-7-R-8-R1-pyrazolo[1,5-a]pyrimidines.
It was shown that two groups of compounds are the result of the reaction, i.e. the pyrimidine thiones 3a,b
and the 4-(arylamino)pyrazolo[1,5-a]pyrimidines 4a-f. The structure of the dihydropyrazolo[1,5-a]pyrimidine
thiones 3a,b was proved by thionation of the 2,7-dimethyl-1,4-dihydropyrazolo-[1,5-a]pyrimidin-4-one 5 (the
structure of which had been proved using X-ray analysis [5]) to give the 2,7-dimethyl-1,4-dihydropyrazolo-
[1,5-a]pyrimidine-4-thione (3a). Since the 5-amino-3-R-4-R1-pyrazoles are isoelectronic with 3-amino-
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02660; e-mail:
bvn1967@rambler.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1550-1555,
October, 2008. Original article submitted February 5, 2008.
1262
0009-3122/08/4410-1262©2008 Springer Science+Business Media, Inc.

5-R-1,2,4-triazoles and characterized by approximately the same basicity (for R = R1 = H the pKa's are 4.11 and
4.17 respectively [6]) then, on the basis of the X-ray structural analysis the products of the reaction of the latter
with N-aryl-3-oxobutanethioamides [1], it can be assumed that compounds 4a-f are 4-arylamino-2-methyl-7-R-
8-R1-pyrazolo[1,5-a]pyrimidines (Tables 1-3).
S
O
N
HN
H2N
Ar
Me
+
N
R
–H2O, –H2S
–ArNH2
H
R1
1a–d
2a–c
Ar
S
HN
N
N
N
N
+
R
R
Me
N
H
Me
N
R1
R1
3a,b
4a–f
O
N
P2S5
N
3a
Me
Me
N
H
5
1a, 4a,b,f Ar = Ph; 1b, 4c Ar = 4-MeOC6H4; 1c, 4d Ar = 3-CF3C6H4; 1d, 4e Ar = 4-O2NC6H4;
2a−4a R = Me, R1 = H; 2b, 4b–e R = H, R1 = CN; 2c, 3b, 4f R + R1 = N=CH−CH=CH
1
The characteristic H NMR spectroscopic signals for the products 3a,b and 4a-f are the singlets for
2-CH3, H-3, and the NH groups (2.30-2.46, 6.56-7.29, 13.06-13.10 and 2.40-2.57, 6.16-6.86, 10.16-10.84 ppm).
It follows from Table 2 that the yield and ratio of compounds 3a,b and 4a-f depend both on the presence
of a protonating solvent and on the nucleophilicity of the 5-amino-3-R-4-R1-pyrazoles 2a-c. The aminopyrazoles
2a-c show an increasing nucleophilicity of their exo- and endocyclic amino groups in the order 2a > 2c > 2b.
When the reaction is carried out without a protonating solvent the interaction of the starting 1a-d with
the aminopyrazoles 2a-c occurs selectively in all cases (experiments 1-6) to give the 4-arylamino-2-methyl-
7-R-8-R1-pyrazolo[1,5-a]pyrimidines 4a-e and the 2-methyl-4-(phenylamino)pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimi-
dine (4f).
The nucleophilicity value of the exo- and endocyclic amino groups in the aminopyrazoles 2a-c affects
the regioselectivity of the cyclocondensation in acetic acid. In the case of the 5-amino-4-cyanopyrazole (2b),
which is the weakest base, the regioselectivity of the process is the same both in the presence of a proton donor
solvent and without it (experiments 2-5). This fact suggest that the starting aminopyrazole 2b and the reaction
intermediates are not protonated by acetic acid. For the more basic aminopyrazoles 2a,c the regioselectivity of
the process in AcOH is changed when compared with the selectivity of the reaction without it. The
dihydropyrazolo[1,5-a]pyrimidine-4-thione 3a is the single condensation product of the starting reagents 1a and
2a whereas the 2-methyl-1,4-dihydropyrido[2',3',:3,4]pyrazolo[1,5-a]pyrimidine-4-thione (3b) is the dominant
product in the reaction of the starting 1a and 2c.
It has been proposed [7, 8] that the thioamides 1a-d react with aminopyrazoles 2a-c, initially to form the
enamino thioamides 6a-f which are reversibly converted to the tetrahedral intermediates 7a-f [9].
Because cleavage of a C–S bond occurs more readily than a C–N bond (formation energies respectively
272 and 285 kJ/mol) [10] heating the intermediate 7a-f causes elimination of hydrogen sulfide to give the 4-aryl-
1263

It should be noted that the 2-R-1,4-dihydropyrazolo[1,5-a]pyrimidine-4-thiones (R = H, Ph), prepared
from the corresponding 2-R-4-chloropyrazolo[1,5-a]pyrimidines and thiourea, show a high activity towards
Schistosoma mansoni while the structurally similar 2-R-1,4-dihydropyrazolo[1,5-a]pyrimidin-4-ones do not
show anthelmintic activity [11].
Me
HN
Me
HN
SH
S
2a–c
H
N
Ar
N
N
N
1a–d
H
4a–f
Ar
H
R1
–H2S
1
R
N
N
R
R
6a–f
7a–f
H+
–H+
Me
+
SH
HN
R 1
+
Ar
3a,b
N
N
H
–ArNH2
–H+
H
N
R
8a,b
6a,b,f, 7a,b,f, 8a,b Ar = Ph; 6c, 7c Ar = 4-MeOC6H4; 6d, 7d Ar = 3-CF3C6H4;
6e, 7e Ar = 4-O2NC6H4; 6a–8a R = Me; 6b–e, 7b–e R = H; 6a–8a R1 = H;
6b-e, 7b–e R1 =CN; 6f, 7f, 8b R + R1 = N=CH–CH=CH
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical formula
mp, °С*
С
H
N
3a
3b
4a
4b
4c
4d
4e
4f
C8H9N3S
53.47
53.61
55.79
55.54
70.42
70.57
67.39
67.46
64.42
64.51
56.86
56.79
56.96
57.14
69.53
69.80
5.29
5.06
3.55
3.73
6.06
5.92
4.38
4.45
4.76
4.69
2.89
3.18
3.27
3.43
4.55
4.76
23.31
23.44
26.07
25.91
23.72
23.51
27.93
28.09
24.82
25.07
21.90
22.07
28.81
28.56
25.30
25.44
304-306
341-345
145-147
180-182
161-163
157-159
315-317
207-210
C10H8N4S
C14H14N4
C14H11N5
C15H13N5O
C15H10F3N5
C14H10N6O2
C16H13N5
_______
Compounds 3a,b, 4e were recrystallized from DMSO, 4a,c,d from ethanol,
and 4b,f from nitromethane.
1264

TABLE 2. Yields of the Reaction Products of the N-Aryl-3-oxobutane-
thioamides 1a-d with 5-Amino-3-R-4-R1-pyrazoles 2a-c
Experiment
number
Starting
reagents
Reaction
products
Yield of compounds 4a–f (3a,b), %
AcOH
Without solvent
1
2
3
4
5
6
1a, 2a
1a, 2b
1b, 2b
1c, 2b
1d, 2b
1a, 2c
4a (3a)
4b
0 (66)
61
62
59
47
58
51
63
4c
49
4d
54
4e
55
4f (3b)
13 (47)
TABLE 3. 1H NMR Spectra of Compounds 3a,b and 4a-f
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
3a
3b
4a
4b
4c
2.30 (3Н, s, 7-CH3); 2.35 (3H, s, 2-CH3); 6.11 (1Н, s, H-8); 6.56 (1Н, s, H-3);
13.06 (1H, br. s, H-1)
2.46 (3Н, s, 2-CH3); 7.29 (2Н, m, H-3,9); 8.78 (1Н, d, J = 5.4, H-10);
8.88 (1Н, d, J = 8.1, H-8); 13.10 (1H, br. s, H-1)
2.33 (3Н, s, 7-CH3); 2.44 (3Н, s, 2-CH3); 6.12 (1Н, s, Н-8); 6.14 (1Н, s, Н-3);
7.24 (1H, m, C6H5); 7.43 (4Н, m, C6H5); 9.64 (1Н, s, NН)
2.43 (3Н, s, 2-CH3); 6.37 (1Н, s, Н-3); 7.31 (1H, m, C6H5); 7.46 (4Н, m, C6H5);
8.64 (1Н, s, H-7), 10.35 (1Н, s, NН)
2.40 (3Н, s, 2-CH3); 3.80 (3Н, s, CH3O); 6.16 (1Н, s, Н-3);
7.03 (1H, d, J = 9.0, 4-С6Н4); 7.32 (1H, d, J = 9.0, 4-С6Н4);
8.62 (1Н, s, H-7), 10.16 (1Н, s, NН)
4d
2.46 (3Н, s, 2-CH3); 6.49 (1Н, s, Н-3); 7.62 (1H, m, 3-CF3С6Н4);
7.71 (1H, m, 3-CF3С6Н4); 7.79 (2H, m, 3-CF3С6Н4); 8.67 (1Н, s, H-7);
10.54 (1Н, s, NН)
4e
4f
2.50 (3Н, s, 2-CH3); 6.86 (1Н, s, Н-3); 7.75 (1H, d, J = 8.9, 4-С6Н4);
8.31 (1H, d, J = 8.9, 4-С6Н4); 8.76 (1Н, s, H-7); 10.84 (1Н, s, NН)
2.57 (3Н, s, 2-CH3); 6.77 (1Н, s, H-3); 7.22 (1H, m, H-9); 7.32 (1H, m, C6H5);
7.53 (4Н, m, C6H5); 8.64 (1Н, d, J = 8.1, H-10); 8.82 (1Н, d, J = 4.9, H-8);
10.41 (1Н, s, NН)
The cyclocondensation of the thioamide 1a with aminopyrazole 2c occurs nonselectively in acid
medium, likely as a result of the realization of two reaction paths one of which (conversion of 7f via 8b and 3b)
dominates.
Hence the products of the reaction of the N-aryl-3-oxobutanethioamides 1a-d with the 5-amino-3-R-
4-R1-pyrazoles 2a-c without proton donor solvent are only the 4-arylamino-2-methyl-7-R-8-R1-pyrazolo-
[1,5-a]pyrimidines 4a-f while carrying out the cyclocondensation reaction of 1a with pyrazoles 2a,c in AcOH
preferably gives the 1,4-dihydropyrazolo[1,5-a]pyrimidine-4-thiones 3a,b.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian-300 instrument (300 MHz) using DMSO-d6 and with TMS
as internal standard. 2,7-Dimethyl-1,4-dihydropyrazolo[1,5-a]pyrimidin-4-one 5 was prepared by method [5].
Reaction of N-aryl-3-oxobutanethioamides 1a-d with 5-Amino-3-R-4-R1-pyrazoles 2a-c. A. A solution
of N-aryl-3-oxobutane thioamide 1a-d (2 mmol) and 5-amino-3-R-4-R1-pyrazole 2a-c (2 mmol) was heated in
AcOH (5 ml) for 6 h at 100-110°C, cooled, and the 2,7-dimethyl-1,4-dihydropyrazolo[1,5-a]pyrimidine-4-thione 3a
(2-methyl-1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine-4-thione 3b) were filtered off.
1265

The filtrate was evaporated, triturated with diethyl ether (3ml), and 4-(arylamino)-2-methyl-7-R-8-R1-
pyrazolo[1,5-a]pyrimidine 4a-e (2-methyl-4-phenylaminopyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine 4f) were
filtered off.
B. A mixture of finely powdered N-aryl-3-oxobutanethioamide 1a-d (2 mmol) and 5-amino-3-R-4-R1-
pyrazole 2a-c (2 mmol) was heated for 0.5 h at 100-110°C, cooled, and treated with refluxing 2-propanol (3 ml).
The suspension was cooled and the precipitated compound 4a-e (mixture of compounds 3b and 4f) filtered off.
1
The ratio of the 3b and 4f products was measured using H NMR spectroscopy. Compounds 3b and 4f were
separated by treatment of the mixture with a 10% aqueous solution of KOH., The insoluble pyrazolo-
[1,5-a]pyrimidine 4f was filtered off and the basic solution was acidified with AcOH and the thione 3b was
filtered off.
Thionation of 2,7-Dimethyl-1,4-dihydropyrazolo[1,5-a]pyrimidin-4-one (5). A solution of the
pyrazolo[1,5-a]pyrimidin-4-one 5 (1.63 g, 10 mmol) and P2S5 (2.22 g, 10 mmol) in pyridine (8 ml) was refluxed
for 10 h, cooled, diluted with water (30 ml), and extracted with chloroform (2×15 ml). The chloroform solution
was dried over MgSO4, evaporated in vacuo on a water pump, and compound 3a was recrystallized from
1
DMSO. The yield of thione 3a was 0.63 g (35%). The melting point and H NMR spectra of compound 3a
prepared by reaction of the N-phenyl-3-oxobutane thioamide 1a with 5-amino-3-methylpyrazole 2a and by
sulfurization of the pyrazolo[1,5-a]pyrimidin-4-one 5 were identical.
REFERENCES
1.
2.
V. N. Britsun, A. N. Borisevich, A. N. Chernega, and M. O. Lozinskii, Zh. Org. Khim., 42, 1529 (2006).
V. N. Britsun, A. N. Borisevich, V. V. Pirozhenko, and M. O. Lozinskii, Zh. Org. Khim,, 43, 283
(2007).
3.
4.
5.
V. N. Britsun, A. N. Borisevich, A. N. Esipenko, and M. O. Lozinskii, Zh. Org. Khim., 43, 99 (2007).
V. N. Britsun, A. N. Borisevich, and M. O. Lozinskii, Zh. Org. Khim., 43, 1552 (2007).
N. L. Nam, I. I. Grandberg, and V. I. Sorokin, Khim. Geterotsikl. Soedin., 1379 (2003). [Chem.
Heterocycl. Comp., 39, 1210 (2003)].
6.
7.
8.
J. Catalan, J. L. Abboud, and J. Elguero, Adv. Heterocycl. Chem., 41, 248 (1987).
V. N. Britsun, A. N. Borisevich, and M. O. Lozinskii, Zh. Org. Khim, 43, 908 (2007).
A. N. Borisevich and P. S. Pel'kis, Zh. Org. Khim., 3, 1339 (1967).
9.
10.
J. March, Organic Chemistry [Russian translation], Vol. 2, Mir, Moscow (1987), p. 55.
Z. Hauptmann, J. Graefe, and H. Remane, Organic Chemistry [Russian translation], Khimiya, Moscow
(1979), p. 52.
11.
K. Senga, T. Novinson, H. R. Wilson, and R. K. Robins, J. Med. Chem., 24, 610 (1981); Chem. Abstr.,
94, 192258 (1981).
1266