Condensation of 5-aminopyrazoles unsubstituted in position 1 with β-keto esters

Article abstract of DOI:10.1023/B:COHC.0000008268.94940.5c

Condensation of β-keto esters with 5-aminopyrazoles unsubstituted in position 1 gives 7-oxopyrazolo[1, 5-a]pyrimidines.

Full text of DOI:10.1023/B:COHC.0000008268.94940.5c

Chemistry of Heterocyclic Compounds, Vol. 39, No. 9, 2003
CONDENSATION OF 5-AMINOPYRAZOLES
UNSUBSTITUTED IN POSITION 1
WITH β-KETO ESTERS
N. L. Nam, I. I. Grandberg, and V. I. Sorokin
Condensation of β-keto esters with 5-aminopyrazoles unsubstituted in position 1 gives
7
-oxopyrazolo[1,5-a]pyrimidines.
Keywords: 5-aminopyrazoles, β-keto esters, pyrazolopyrimidones.
S. Checchi and coworkers investigated in 1955 [1] the condensation of 5-amino-3-phenylpyrazole with
acetoacetic ester and, without evidence, assigned the structure of the product as 7-oxopyrazolo[1,5-a]pyrimidine
(
see below, structure type 5).
We have previously reported [2] that the condensation of 5-aminopyrazoles 1 (unsubstituted in
position 1) with symmetrical β-diketones gives pyrazolo[1,5-a]pyrimidines 4. Only in the case of
hexafluoroacetylacetone did the condensation occur via another route to give the pyrazolo[4,5-b]pyridine 3.
R2
R1
R2
R1
N
O
HN
N
3
4
+
R COCH(R )COOEt
N
H N
N
H
2a–f
R3
2
4
R
1
a–c
4
a–h
R2
R1
R3
R1
N
N
R4
HN
N
O
R3
N
H
O
N
H
R4
5
3
1
2
1
2
1
2
3
4
3
1
a R = Me, R = H; b R = Et, R = Me; c R = Ph, R = H; 2 a R = Me, R = H; b R = Me,
4
3
4
3
4
3
4
3
R = Et; c R = Me, R = CH
R = HOCH
2
COOEt; d R = CF
3
, R = H; e R = Ph, R = H; f R = Me,
4
1
3
2
4
1
2
3
4
1
2
CH . 4 a R = R = Me, R = R = H; b R = Et, R = R = Me, R = H; c R = Ph,
2
2
4
3 1 3 2 4 1 2 4
R = R = H, R = Me; d R = R = Me, R = H, R = CH COOEt; e R = Me, R = R = H,
2
3
1
3
2
4
1
3
2 4
R = Ph; f R = R = Me, R = H, R = Et; g R = R = Me, R = H, R = HOCH
2
CH ;
2
1
2
3
4
h R = Et, R = Me, R = CF
3
, R = H
_
_________________________________________________________________________________________
K. A. Timiryazev Agricultural Academy, Moscow 127550, Russia; e-mail: interbioscan@mtu-net.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1379-1382, September, 2003. Original
article submitted September 5, 2000; revision submitted February 19, 2003.
1
210
0009-3122/03/3909-1210$25.00©2003 Plenum Publishing Corporation

Fig. 1. Structure of compound 4a.
In this work we have studied the condensation of 5-aminopyrazoles unsubstituted in position 1 with
various β-keto esters by heating both components without solvent at 150°C. 5-Amino-3-methylpyrazole (1a),
5
-amino-3-ethyl-4-methylpyrazole (1b), and 5-amino-3-phenylpyrazole (1c) were used in the reactions.
The question regarding the direction of condensation at the C or N atoms of the pyrazole ring to give
1
compounds of type 3 or of type 4,5 respectively was readily resolved using H NMR spectroscopy. Since a
1
distinction between the structures 4 and 5 was practically impossible using H NMR we have used X-ray
structural analysis*. In the example of the condensation of acetoacetic ester with 5-amino-3-methylpyrazole the
product was 3,5-dimethyl-7-oxopyrazolo[1,5-a]pyrimidine (4a) without an admixture of the isomeric compound
5
(see Fig. 1).
Because the spectroscopic data and the physical characteristics for the compounds obtained are similar
(
see Experimental) we propose that in the other examples the reaction occurs with the formation of the
1
7
-oxopyrazolo[1,5-a]pyrimidines 4a-h. The H NMR spectra and the TLC data point to the absence of isomeric
products. The yields are 65-99%.
EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer 577 instrument (using KBr). UV spectra were taken on a
1
Specord M-40 spectrophotometer using alcohol and H NMR spectra on a Bruker AM-300 instrument
(
300 MHz) using DMSO-d . TLC was carried out on Silufol plates in methanol and revealed using iodine vapor
6
or an alcoholic solution of FeCl with subsequent heating. The synthesis of the aminopyrazoles used in the
3
reaction has previously been reported by us [2].
General Condensation Method. A mixture of the corresponding 5-aminopyrazole (50 mmol) and the
β-dicarbonyl compound (55 mmol) in a flask (30 ml) was heated on a metal bath at 140-150°C for 3 h, allowing
elimination of the water and alcohol evolved (in the case of the benzoylacetic ester the bath temperature was
held at 165-170°C). The crystallized mixture was recrystallized from 80% alcohol.
_
*
______
X-ray analysis was carried out at Institute of Organoelement Compounds of the Russian Academy of Sciences
by O. Ya. Burbulevich. A crystal was grown from 80% acetic acid. Detailed X-ray analytical data will be the
subject of a separate communication.
1
211

Compounds 4a-h were prepared using this method.
,5-Dimethyl-7-oxopyrazolo[1,5-a]pyrimidine (4a). Yield 99%; mp 245-246°C. R
0.59. UV spectrum,
2
f
-1
1
λ
max, nm (log ε): 249 (4.42); 255 (3.92); 294 (4.02). IR spectrum, ν, cm : 1630, 1680. H NMR spectrum,
δ, ppm: 2.26 (3H, s, 2-CH ); 2.28 (3H, s, 5-CH ); 5.85 (s, 3H); 5.40 (s, 6-H); 11.85 (s, NH). Found, %: C 58.5;
H 5.7; N 25.8. C O. Calculated, %: C 58.5; H 6.1; N 25.6.
3
3
8
H
10
N
3
2
-Ethyl-3,5-dimethyl-7-oxopyrazolo[1,5-a]pyrimidine (4b). Yield 73%; mp 243-244°C. R
0.70.
f
-
1
UV spectrum, λmax, nm (log ε): 220 (4.48); 253 (4.11); 261 (4.15); 288 (3.95). IR spectrum, ν, cm : 1630, 1670.
1
H NMR spectrum, δ, ppm: 1.23 (3H, t, 2-CH
2
CH
3
); 2.61 (2H, q, 2-CH
2
CH
3
); 2.09 (3H, s, 3-CH
3
); 2.29 (3H, s,
O. Calculated, %: C 62.8;
5
-CH
H 6.8; N 22.0.
-Methyl-7-oxo-2-phenylpyrazolo[1,5-a]pyrimidine (4c). Yield 64%; mp 308-310°C (with decomp.).
3
); 5.36 (s, 6-H); 11.50 (s, NH). Found, %: C 62.6; H 6.8; N 22.0. C10
H N
13 3
5
-1
1
R
f
0.72. UV spectrum, λmax, nm (log ε): 258 (4.47); 299 (3.90). IR spectrum, ν, cm : 1630, 1685. H NMR
spectrum, δ, ppm: 2.31 (3H, s, 5-CH ); 6.42 (s, 3-H); 5.50 (s, 6-H); 12.10 (s, NH); 7.35-7.96 (m, Harom).
Found, %: C 68.9; H 4.9; N 18.6. C13 O. Calculated, C 69.3; H 4.9; N 18.7.
3
H
11
N
3
6
-Carbethoxymethyl-2,5-dimethyl-7-oxopyrazolo[1,5-a]pyrimidine (4d). Yield 76% (acetosuccinate
-1
ester was used as the β-keto ester); mp 233-234°C. R
f
0.80. IR spectrum, ν, cm : 1615, 1665, 1730.
1
UV spectrum, λmax, nm (log ε): 252 (3.95); 257 (3.96); 266 (3.68); 297 (3.85). H NMR spectrum, δ, ppm: 1.27
(
5
3H, t, O–CH
.82 (s, 3-H). Found, %: C 57.7; H 6.2; N 17.0. C12
-Methyl-7-oxo-5-phenylpyrazolo[1,5-a]pyrimidine (4e). Yield 67%; mp 261-263°C. R
2
3
CH ); 4.10 (2H, q, O–CH
2
CH
3
); 2.26 (3H, s, 2-CH
3
); 2.30 (3H, s, 5-CH
3
); 3.82 (2H, s, 6-CH );
2
H N
15 3
O
3
. Calculated, %: C 57.8; H 6.2; N 16.9.
2
f
0.70.
UV spectrum, λmax, nm (log ε): 248 (4.72); 297 (4.11); 319 (3.86). IR spectrum, ν, cm : 1630, 1680. H NMR
spectrum, δ, ppm: 2.36 (3H, s, 2-CH ); 5.90 (3-H); 5.99 (s, 6-H); 12.60 (s, NH); 7.56-7.84 (m, Harom). Found, %:
C 69.2; H 5.1;N 18.3. C13 O. Calculated, %: C 69.3; H 4.9; N 18.7.
-Ethyl-2,5-dimethyl-7-oxopyrazolo[1,5-a]pyrimidine (4f). Yield 73%; mp 220-222°C. R
-1
1
3
H
13
N
3
6
f
0.68.
UV spectrum, λmax, nm (log ε): 254 (3.93); 260 (3.94); 301 (2.91). IR spectrum, ν, cm : 1630, 1675. H NMR
spectrum, δ, ppm: 2.28 (3H, s, 2-CH ); 2.29 (3H, s, 5-CH ); 1.06 (3H, t, 6-CH CH ); 2.48 (2H, q, 6-CH CH );
.76 (s, 3-H); 11.68 (s, NH). Found, %: C 62.7; H 6.8; N 22.00. C10 O. Calculated, %: C 62.8; H 6.8;
N 22.00.
-1
1
3
3
2
3
2
3
5
H
13
N
3
6
-β-Hydroxyethyl-2,5-dimethyl-6-oxopyrazolo[1,5-a]pyrimidine (4g). Yield 92% (α-acetylbutyro-
-1
lactone was used as the β-keto ester); mp 219-221°C. R
f
0.66. IR spectrum, ν, cm : 1600, 1670. UV spectrum,
); 2.32 (3H, s,
); 5.78 (s, 3-H); 11.68 (s, NH). Found, %: C 58.00; H 6.3;
. Calculated, %: C 58.0; H 6.3; N 20.3.
1
λ
5
max, nm (log ε): 256 (4.38); 260 (4.40); 298 (4.31). H NMR spectrum, δ, ppm: 2.28 (3H, s, 2-CH
3
-CH
3
); 2.61 (2H, t, 6-α-CH
2
); 3.48 (2H, t, 6-β-CH
2
N 20.0. C10
H
13
N
3
O
2
2
-Ethyl-3-methyl-7-oxo-5-trifluoromethylpyrazolo[1,5-a]pyrimidine (4h). Yield 73%; mp 202-
-1
2
03°C. R
f
0.71. IR spectrum, ν, cm : 1640, 1675. UV spectrum, λmax, nm (log ε): 223 (4.29); 269 (3.79); 279
1
(
3.90); 299 (3.85); 314 (3.80); 327 (3.77). H NMR spectrum, δ, ppm: 1.28 (3H, t, 2-CH
2
CH
3
); 2.78 (2H, q,
O.
2
-CH
2
CH
3
); 2.18 (3H, s, 3-CH
3
); 6.09 (s, 6-H); 10.35 (s, NH). Found, %: C 49.0; H 4.2; N 17.5. C10
H
10
F
N
3 3
Calculated, %: C 49.0; H 4.1; N 17.1.
REFERENCES
1
2
.
.
S. Checchi, P. Papini, and M. Ridi, Gazz. Chim. Ital., 85, 1160 (1955).
N. L. Nam. I. I. Grandberg, and V. I. Sorokin, Khim. Geterotsikl. Soedin., 1555 (2002).
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