Pyrazolopyrimidines based on 5-aminopyrazoles unsubstituted at the position 1

Article abstract of DOI:10.1023/A:1022186627777

By condensation of various symmetric β-diketones with a series of 5-aminopyrazoles that are unsubstituted at the position 1, we have obtained a series of pyrazolo[1,5-a]pyrimidines that are of interest as physiologically active compounds. Hexafluoroacetylacetone reacts in another direction, forming pyrazolo[4,5-b]pyridine.

Full text of DOI:10.1023/A:1022186627777

Chemistry of Heterocyclic Compounds, Vol. 38, No. 11, 2002
PYRAZOLOPYRIMIDINES BASED ON
5-AMINOPYRAZOLES UNSUBSTITUTED
AT THE POSITION 1
N. L. Nam, I. I. Grandberg, and V. I. Sorokin
By condensation of various symmetric β-diketones with a series of 5-aminopyrazoles that are
unsubstituted at the position 1, we have obtained a series of pyrazolo[1,5-a]pyrimidines that are of
interest as physiologically active compounds. Hexafluoroacetylacetone reacts in another direction,
forming pyrazolo[4,5-b]pyridine.
Keywords: aminopyrazoles, β-diketones, pyrazolopyrimidines.
It was shown earlier [1] that 5-amino-3-phenylpyrazole (1), when heated up to 140°C with
acetylacetone, forms 5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine (2). Unfortunately, that paper did not
indicate the yield and other characteristics, except for C, H, N analyses.
Me
Ph
N
Ph
CH2(COMe)2
N
H2N
ON
N
H
N
H
Me
Me
N
1
4
Ph
Ph
HNO2
N
N
N
N
N
N
Me
Me
Me
2
3
Proof that condensation occurred at the position 1 (and not at the position 4) of the pyrazole ring was
the facile nitrosation of compound 2 to form nitroso derivative 3. The nitrosation reaction would be less likely if
structure 4 were formed.
We decided to extend the scope of this condensation by using a series of other 5-aminopyrazoles and
symmetric β-diketones (asymmetric diketones, of course, would give a mixture of isomers).
We should note that condensation with acetylacetone 6a, methylacetylacetone 6b, and
hexafluoroacetylacetone 6c is an exothermic reaction (when the components are mixed, we observe appreciable
heating), but for high yield they must be heated for 2 h with bath temperature up to 140°C. With
dibenzoylmethane, the reaction proceeds significantly more slowly and the bath temperature must be maintained
at a level of 160 to 170°C.
__________________________________________________________________________________________
K. A. Timiryazev Moscow Agricultural Academy, Moscow 127550, Russia; e-mail:
intelbioscan@mtu-net.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1555-1558,
November, 2002. Original article submitted March 2, 2000.
0009-3122/02/3811-1371$27.00©2002 Plenum Publishing Corporation
1371

1
R
R
R1
R
N
N
N
R2COCH(R3)COR2
+
N
2
R2
H2N
N
H
6a–d
R
R3
7a–h
5a–c
5a R = Me, b R = Ph, c R = Et, a, b R1 = H, c R1 = Me; 6 a, b R2 = Me, c R2 = CF3, d R2 = Ph,
a, c, d R3 = H, b R3 = Me; 7 a, b, d R = Me, c, e R = Et, f-h R = Ph, a, b, d, f-h R1 = H, c, e, R1 = Me,
a, c-g R2 = Me, b, h R2 = Ph, a-c, f, h R3 = H, d, e, g R3 = Me
Additional although indirect evidence for the reaction occurring at the position 1 is the fact that the
process also easily occurs for 4-substituted 5-aminopyrazole 5c, forming derivatives 7c and 7e. Conclusive
confirmation of structure 7 came from analysis of the 1H NMR spectra. The signal for the proton at the position
4 of the pyrazole ring is registered in the 5.8-7 ppm region and can be easily distinguished. Furthermore, if
structures of type 8 were formed, then a signal for the NH proton should be present in the spectrum in the
1
9.5-14 ppm region. The H NMR spectra (see experimental section) suggest that in all cases of condensation,
except when hexafluoroacetylacetone is used, the reaction proceeds to form pyrazolo[1,5-a]-pyrimidines. But in
the case of reaction between hexafluoroacetylacetone and 3-methylaminopyrazole 5a, 3-methyl-4,6-
ditrifluoromethylpyrazolo[4,5-b]pyridine (8) was formed. We observed such condensation earlier for
N-substituted 5-aminopyrazoles [2].
CF3
Ph
Me
CF3COCH2COCF3
N
+
N
H2N
N
H
F3C
N
N
H
5c
5a
8
The structure of compound 8 is confirmed by 1H NMR spectral data, which showed a singlet for the Me
group in the 2.65 ppm region, only one singlet in the aromatic proton region 7.75 ppm (5-H), and a broadened
singlet for the NH proton in the 14.3 ppm region. Such a change in direction of cyclization may be due to the
higher electronegativity of the carbon atom for the C=O group in 6c, which is sufficient for electrophilic attack
at the reactive 4 position of the aminopyrazole ring.
EXPERIMENTAL
The IR spectra were taken on a Perkin-Elmer in KBr tablets; the UV spectra were taken on a Specord
M-40 spectrometer in alcohol; the NMR spectra were recorded on a Bruker AM-300 (300 MHz) in DMSO-d6.
TLC was performed on Silufol plates.
5-Amino-3-methylpyrazole (5a). A mixture of β-aminocrotononitrile (24.6 g, 0.3 mol) and hydrazine
hydrate (50 ml), containing 0.8 mol of hydrazine, was heated to boiling under reflux. Then the excess hydrazine
hydrate was distilled off from the reaction mass under vacuum, and the residue was distilled. Obtained 22.6 g
(77.7%) of aminopyrazole 5a; bp 152-153°C (6 torr); crystallizes on standing; mp 48-49°C. Rf 0.52 (methanol–
acetone, 1:1), visualized by iodine. IR spectrum, ν, cm-1: 1490, 1580, 3250. UV spectrum, λmax: 232 nm, log ε
3.84. Found, %: C 49.2; H 7.4; N 43.6. C4H7N3. Calculated, %: C 49.48; H 7.72; N 43.30.
1372

5-Amino-3-phenylpyrazole (5b). A mixture of benzoylacetonitrile (8.7 g, 0.06 mol), methylcellosolv
(15 ml), and 85% hydrazine hydrate (4 ml) was heated under reflux to boiling. The reaction mixture was
evaporated down on a rotary evaporator to dryness and the residue was recrystallized from a 1:2 benzene–
hexane mixture. Obtained 7.4 g (77.6%) of aminopyrazole 5b; mp 123°C (mp 123°C [3]). Rf 0.13 (benzene–
acetone, 2.5:1), visualization by iodine. IR spectrum, ν, cm-1: 1500, 1560, 1610, 3240. UV spectrum,
λmax 254 nm, log ε 3.84. Found, %: C 49.2; H 5.7; N 26.3. C9H9N3. Calculated, %: C 67.92; H 5.66; N 26.42.
5-Amino-3-ethyl-4-methylpyrazole (5c) was obtained analogously to 5-amino-3-methylpyrazole from
α-methyl-β-iminobutyronitrile (0.1 mol) and 85% hydrazine hydrate (0.4 mol) in 79% yield; bp 141-143°C
(2 torr) in the form of a thick yellow oil. Rf 0.50 (methanol–acetone, 1:1), visualization by iodine. IR spectrum,
ν, cm-1: 1500, 1590, 3300. UV spectrum, λmax: 231 nm, log ε (3.77). Found, %: C 57.4; H 8.8; N 32.9. C6H11N3.
Calculated, %: C 57.60; H 8.81; N 33.60.
General Condensation Procedure. A mixture of the corresponding aminopyrazole (0.05 mol) and
β-dicarbonyl compound (0.051 mol) was heated in an open flask on a metallic bath with a bath temperature of
140-150°C, making it possible to distill off the cleaved water (in the case of dibenzoylmethane, the bath
temperature was 160-170°C). After this, the crystallized mixture was recrystallized from 80% alcohol and again
as needed from a benzene–hexane mixture.
a
Yield 92%; mp 69-70°C. Rf 0.51 (benzene–acetone,
2,5,7-Trimethylpyrazolo[1,5- ]pyrimidine (7a).
5:1), visualization by iodine. IR spectrum, ν, cm-1: 1450, 1560, 1620. UV spectrum, λmax, nm (log ε): 234 (4.73);
1
265 (3.43); 267 (3.48); 282 (3.64); 312 (3.43). H NMR spectrum, δ, ppm: 2.44 (3H, s, 2-CH3); 2.47 (3H, s,
5-CH3); 2.66 (3H, s, 7-CH3); 6.22 (s, 3-H); 6.66 (s, 6-H). Found, %: C 66.9; H 6.9; N 25.8. C9H11N3.
Calculated, %: C 67.08; H 6.83; N 26.09.
a
Yield 98%; mp 112-113°C. R 0.31 (benzene),
2-Methyl-5,7-diphenylpyrazolo[1,5- ]pyrimidine (7b).
f
visualization by iodine. IR spectrum, ν, cm-1: 1495, 1560, 1610. UV spectrum, λmax, nm (log ε): 236 (4.23);
267 (4.60); 321 (3.83); 367 (3.53). 1H NMR spectrum, δ, ppm: 2.47 (3H, s, 2-CH3); 7.50 (s, 6-H); 7.47-8.25 (m,
aromatic protons); 6.52 (s, 3-H). Found, %: C 79.6; H 5.2; N 15.1. C19H15N3. Calculated, %: C 80.00; H 5.26;
N 14.74.
a
Yield 85%; mp 50-51°C, R 0.62 (benzene–
2-Ethyl-3,5,7-trimethylpyrazolo[1,5- ]pyrimidine (7c).
f
acetone, 5:1), visualization by iodine. IR spectrum, ν, cm-1: 1510, 1545, 1590, 1630, 1670 (weak). UV spectrum,
λmax, nm (log ε): 238 (4.35), 278 (3.27), 289 (3.25). 1H NMR spectrum, δ, ppm: 1.28 (3H, t, 2-CH3); 2.74 (2H, q,
2-CH2); 2.20 (3H, s, 3-CH3); 2.46 (5H, s, 5-CH3); 2.63 (3H, s, 7-CH3); 6.75 (s, 6-H). Found, %: C 70.0; H 8.2;
N 22.4. C11H15N3. Calculated, %: C 69.84; H 7.94; N 22.22.
a
Yield 86%; mp 126-127°C. Rf 0.67 (benzene–
2,5,6,7-Tetramethylpyrazolo[1,5- ]pyrimidine (7d).
acetone, 5:1), visualization by iodine. IR spectrum, ν, cm-1: 1450, 1490, 1525, 1620. UV spectrum, λmax, nm
1
(log ε): 235 (4.50); 269 (3.38); 284 (3.23); 294 (3.23). H NMR spectrum, δ, ppm: 2.42 (3H, s, 2-CH3); 2.68
(3H, s, 5-CH3); 2.28 (3H, s, 6-CH3); 3.08 (3H, s, 7-CH3); 6.18 (s, 3-H). Found, %: C 68.7; H 7.7; N 24.2.
C10H13N3. Calculated, %: C 68.57; H 7.43; N 24.00.
a
Yield 79%; mp 72-73°C. Rf 0.51
2-Ethyl-3,5,6,7-tetramethylpyrazolo[1,5- ]pyrimidine (7e).
(benzene–acetone, 4:1), visualization by iodine followed by heating. IR spectrum, ν, cm-1: 1450, 1505, 1530,
1580, 1630, 1675 (weak). UV spectrum, λmax, nm (log ε): 239 (4.78), 281 (3.33), 291 (3.39), 333 (3.59).
1H NMR spectrum, δ, ppm: 1.28 (3H, t, 2-CH3); 2.74 (2H, q, 2-CH2); 2.21 (3H, s, CH3); 2.46 (3H, s, 5-CH3);
2.25 (3H, s, 6-CH3); 2.65 (3H, s, 7-CH3). Found, %: C 70.9; H 8.2; N 21.0. C12H17N3. Calculated, %: C 70.94;
H 8.37; N 20.69.
a
Yield 97%; mp 155-156°C. R 0.53 (benzene–
5,7-Dimethyl-2-phenylpyrazolo[1,5- ]pyrimidine (7f).
f
acetone, 4:1), visualization by iodine followed by heating. IR spectrum, ν, cm-1: 1440, 1470, 1525, 1560, 1625.
1
UV spectrum, λmax, nm (log ε): 239 (4.42), 259 (4.77), 283 (4.04), 299 (3.98). H NMR spectrum, δ, ppm: 2.48
(3H, s, 5-CH3); 2.73 (3H, s, 7-CH3); 6.76 (s, 3-H); 7.37 (t, p-H arom.); 7.47 (dd, m-H arom.); 8.00 (d,
o-H arom.). Found, %: C 75.2; H 5.9; N 19.1. C14H13N3. Calculated, %: C 75.34; H 5.83; N 18.83.
1373

a
Yield 90%; mp 187-188°C. Rf 0.57
5,6,7-Trimethyl-2-phenylpyrazolo[1,5- ]pyrimidine (7g).
(benzene–acetone, 4:1), visualization by iodine followed by heating. IR spectrum, ν, cm-1: 1430, 1465, 1520,
1630. UV spectrum, λmax, nm (log ε): 235 (4.24), 244 (4.37), 254 (4.56), 262 (4.63), 272 (4.54), 299 (3.87),
1
310 (3.83). H NMR spectrum, δ, ppm: 2.47 (3H, s, 5-CH3); 2.30 (3H, s, 6-CH3); 2.77 (3H, s, 7-CH3); 6.81 (s,
3-H); 7.37 (t, p-H arom.); 7.48 (dd, m-H arom.); 7.98 (d, o-H arom.). Found, %: C 76.3; H 6.3; N 18.1.
C15H15N3. Calculated, %: C 75.95; H 6.33; N 17.72.
a
Yield 94%; mp 153-155°C. Rf 0.64 (benzene),
2,5,7-Triphenylpyrazolo[1,5- ]pyrimidine (7h).
visualization by iodine followed by heating. IR spectrum, ν, cm-1: 1450, 1470, 1500, 1560, 1580, 1615.
1
UV spectrum, λmax, nm (log ε): 236 (4.78), 260 (4.96), 342 (4.20). H NMR spectrum, δ, ppm: 7.07 (s, 3-H);
7.4-8.3 (m, protons of phenyl rings and 6-H). Found, %: C 83.1; H 4.8; N 12.3. C24H17N3. Calculated, %:
C 82.90; H 4.90; N 12.10.
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