α-Aminoazoles in syntheses of heterocycles. 3(5)-Aminopyrazole-4- carbonitriles in the synthesis of pyrazolo[1,5-α]pyrimidines

Full text of DOI:10.1134/S1070428007030281

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 3, pp. 471–473. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © E.E. Emelina, A.A. Petrov, A.V. Firsov, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 3, pp. 470–472.
SHORT
COMMUNICATIONS
α-Aminoazoles in Syntheses of Heterocycles. 3(5)-Aminopyrazole-
4
-carbonitriles in the Synthesis of Pyrazolo[1,5-a]pyrimidines
E. E. Emelina, A. A. Petrov, and A. V. Firsov
St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
e-mail: emelina@hotmail.ru
Received September 16, 2006
DOI: 10.1134/S1070428007030281
Broad spectrum of biological activity of functional-
ly substituted pyrazolopyrimidines stimulates develop-
ment of new methods for the synthesis of these com-
pounds [1–3]. In the past 10–15 years, new sedative
and soporific medical agents have been found among
pyrazolopyrimidine derivatives; among these, Zaleplon
of mixtures of two regioisomeric pyrazolo[1,5-a]pyri-
midines due to comparable reactivities of the two
electrophilic centers in the initial diketone. Reactions
of benzoylacetones IIa–IIc with 3(5)-aminopyrazole-
4-carbonitriles Ia and Ib, performed according to
the procedures described in [6, 7] (fusion or heating in
acetic acid or ethanol), give almost inseparable mix-
tures of regioisomeric pyrazolopyrimidines III and IV
{N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-
N-ethylacetamide}is one of the most efficient [4, 5].
We have developed a procedure for the regioselec-
tive synthesis of substituted 7-aryl-5-methylpyrazolo-
(
fraction of IV ~10–30%). We have succeeded in ob-
taining compounds IVa and IVb as the only products
by reaction of 3(5)-aminopyrazole-4-carbonitriles Ia
and Ib with 4-phenylbut-3-yn-2-one (V), following the
procedure described by us previously [8].
[
1,5-a]pyrimidine-3-carbonitriles that are structurally
related to Zaleplon. The procedure is based on cyclo-
condensation of 3(5)-aminopyrazole-4-carbonitriles
with 1-arylbutane-1,3-diones in ethanol at a tempera-
ture not exceeding 0°C in the presence of trifluoro-
acetic acid as catalyst. The only products of these re-
actions are 7-aryl-5-methylpyrazolo[1,5-a]pyrimidine-
The structure of regioisomers IIIa, IIIb, IVa, and
1
13
IVb was determined on the basis of the H and
C
NMR data, taking into account characteristic chemical
shifts of protons and carbon atom of the methyl group
i
3
-carbonitriles IIIa–IIIf; they are isolated in high
and C in the phenyl group of both compounds, δ ,
C
i
i
yields as high-melting crystalline substances.
ppm: 5-CH ~25, 7-CH ~17, 5-C ~136.5, 7-C ~131
3
3
Reactions of unsymmetrical 1,3-diketones with
[8, 9]. In all cases, the 5-CH signal appears in
3
3
(5)-aminopyrazoles [6, 7] often lead to the formation
a stronger field than that from 7-CH by about 0.1 ppm.
3
NC
NC
N
Ar
N
Me
MeCOCH COAr (IIa–IIc)
2
AcOH, Δ
R
R
+
N
N
N
N
Me
Ar
R
CN
IIIa–IIIf
IVa, IVb, IVe, IVf
IIa–IIc, EtOH
N
CF COOH, 0°C
3
NH2
N
H
IIIa–IIIf
Ia, Ib
Ph–C C–COMe (V)
EtOH, CF COOH, 0°C
3
IVa, IVb
I, R = H (a), Me (b); II, Ar = Ph (a), 4-i-PrOC
6
H
4
(b), 4-ClC
6
H
4
(c); III, IV, Ar = Ph, R = H (a), Me (b), Ar = 4-i-PrOC
6 4
H ,
R = H (c), Me (d), Ar = 4-ClC
6
4
H , R = H (e), Me (f).
471

4
72
EMELINA et al.
6
3
7
-Aryl-5-methylpyrazolo[1,5-a]pyrimidine-3-
(OCH), 81.0 (CN), 110.19 (C ), 114.12 (C ), 115.84,
i
2
carbonitriles IIIa–IIIf (general procedure). A solu-
tion of 2.5 mmol of benzoylacetone IIa–IIc in 3 ml of
ethanol was added to a solution of 2.5 mmol of amino-
pyrazole Ia or Ib in 2 ml of ethanol containing 3 drops
of trifluoroacetic acid at a temperature not exceeding
121.78, 132.15 (C ), 160.97 (C H ), 146.55 (C ), 152.25
6 4
3
a
7
5
(C ), 157.06 (C ), 163.34 (C ). Found, %: C 70.41;
H 6.09. C H N O. Calculated, %: C 70.57; H 5.92.
1
8
18
4
7
-(4-Chlorophenyl)-5-methylpyrazolo[1,5-a]pyr-
imidine-3-carbonitrile (IIIe). Yield 92%, mp 292°C
decomp.). H NMR spectrum (DMSO-d ), δ, ppm:
6
.70 (3H, CH ), 7.47 (1H, 6-H), 7.67 d and 8.12 d
C H ), 8.68 (1H, 2-H). Found, %: C 62.40; H 3.52.
C H ClN . Calculated, %: C 62.58; H 3.38.
0
°C. The mixture was stirred at 0°C until the reaction
1
(
was complete (TLC, Silufol UV-254), and the precip-
itate was filtered off, treated with boiling ethanol, and
filtered off again.
2
3
(
6 4
1
4
9
4
5
-Methyl-7-phenylpyrazolo[1,5-a]pyrimidine-3-
1
7-(4-Chlorophenyl)-2,5-dimethylpyrazolo[1,5-a]-
pyrimidine-3-carbonitrile (IIIf). Yield 90%,
mp 207°C. H NMR spectrum (CDCl ), δ, ppm: 2.58
3H, 2-CH ), 2.71 (3H, 5-CH ), 6.94 (1H, 6-H), 7.56 d
H ). C NMR spectrum (CDCl ),
6 4 3
δ , ppm: 14.18 (2-CH ), 25.33 (5-CH ), 82.21 (CN),
110.60 (C ), 113.94 (C ), 128.58, 129.56, 131.20 (C ),
138.33 (C H ), 146.02 (C ), 152.13 (C ), 158.26 (C ),
carbonitrile (IIIa). Yield 85%, mp 214°C. H NMR
spectrum, δ, ppm: in CDCl : 2.76 s (3H, CH ), 7.03 s
1H, 6-H), 7.59-7.90 m (5H, Ph), 8.34 s (1H, 2-H); in
DMSO-d : 2.69 s (3H, CH ), 7.42 s (1H, 6-H), 7.59–
.06 m (5H, Ph), 8.69 s (1H, 2-H). C NMR spectrum
3
3
1
3
(
(
3 3
6
3
13
1
3
and 7.97 d (4H, C
8
(
(
(
C
3
3
DMSO-d ), δ , ppm: 25.25 (CH ), 81.15 (CN), 112.22
6
C
3
6
3
i
6
3
i
C ), 114.39 (C ), 129.33, 130.32 (C), 130.45, 133.32
7
3a
2
2
7
3a
6 4
5
Ph), 147.40 (C ), 147.70 (C ), 151.62 (C ), 164.75
5
163.36 (C ). Found, %: C 63.50; H 4.05. C15
Calculated, %: C 63.72; H 3.92.
H11ClN .
4
(
C ). Found, %: C 71.68; H 4.55. C H N . Calculat-
14
10
4
ed, %: C 71.78; H 4.30.
7
-Methyl-5-phenylpyrazolo[1,5-a]pyrimidine-3-
1
2
,5-Dimethyl-7-phenylpyrazolo[1,5-a]pyrimi-
carbonitrile (IVa). Yield 90%, mp 164°C. H NMR
spectrum (DMSO-d ), δ, ppm: 2.86 s (3H, CH ),
.54 m and 8.24 m (5H, Ph), 7.85 (1H, 6-H), 8.58 (1H,
dine-3-carbonitrile (IIIb). Yield 81%, mp 179°C.
H NMR spectrum (DMSO-d ), δ, ppm: 2.55 (3H,
-CH ), 2.76 (3H, 5-CH ), 7.30 (1H, 6-H), 7.58–
.05 (Ph). C NMR spectrum (DMSO-d ), δ , ppm:
1
6
3
6
7
2
(
1
(
2
8
1
(
1
3 3
1
3
13
-H). C NMR spectrum (DMSO-d ), δ , ppm: 17.68
6
C
6
C
6
3
CH ), 82.47 (CN), 108.47 (C ), 113.88 (C ), 128.40,
4.15 (2-CH ), 25.14 (5-CH ), 80.99 (CN), 111.59
3
3
3
i
7
6
3
i
29.60, 131.94, 136.36 (C ) (Ph), 147.90 (C ), 148.92
C ), 114.32 (C ), 129.25, 130.32 (C ), 132.15 (Ph),
3
a
2
5
7
3a
2
5
C ), 150.60 (C ), 159.26 (C ). Found, %: C 71.60;
46.77 (C ), 152.03 (C ), 157.34 (C ), 164.03 (C ).
Found, %: C 72.40; H 4.95. C H N . Calculated, %:
H 4.50. C H N . Calculated, %: C 71.78; H 4.30.
14 10
4
1
5
13
4
C 72.56; H 4.87.
-(4-Isopropoxyphenyl)-5-methylpyrazolo-
1,5-a]pyrimidine-3-carbonitrile (IIIc). Yield 87%,
2
,7-Dimethyl-5-phenylpyrazolo[1,5-a]pyrimi-
7
dine-3-carbonitrile (IVb). Yield 85%, mp 213°C.
1
[
H NMR spectrum (DMSO-d
2-CH ), 2.76 (3H, 7-CH ), 7.70 (1H, 6-H), 7.58–
8.02 (Ph). C NMR spectrum (DMSO-d ), δ , ppm:
14.15 (2-CH ), 17.63 (7-CH ), 81.72 (CN), 107.90
6
), δ, ppm: 2.52 (3H,
1
mp 108°C. H NMR spectrum (DMSO-d ), δ, ppm
3
3
6
1
3
(
J, Hz): 1.37 d [6H, (CH ) CH, J = 5.9], 2.70 (3H,
6
C
3
2
5
7
-CH ), 4.74 sept (1H, CH, J = 5.9), 7.25 (1H, 6-H),
3
3
3
13
6
3
i
.03 d and 8.08 d (2H each, C H ). C NMR spectrum
(C ), 114.30 (C ), 128.21, 129.63, 131.92, 136.30 (C )
6
4
7
3a
2
(
(
1
(
DMSO-d ), δ , ppm: 22.55 [(CH ) CH], 25.17
(Ph), 148.48 (C ), 150.60 (C ), 157.94 (C ), 158.67
6
C
3 2
6
5
5-CH ), 70.31 (OCH), 81.32 (CN), 110.65 (C ),
(C ). Found, %: C 72.49; H 4.92. C H N . Calculat-
3
15 13
4
3
i
13.90 (C ), 115.87, 121.63, 132.23 (C ), 161.09
C H ), 147.13 (C ), 151.77 (C ), 147.13 (C ), 163.86
C ). Found, %: C 69.96; H 5.67. C H N O. Calculat-
ed, %: C 72.56; H 4.87.
2
3a
7
6 4
5
-(4-Chlorophenyl)-7-methylpyrazolo[1,5-a]-
5
(
1
17
16
4
pyrimidine-3-carbonitrile (IVe). H NMR spectrum
DMSO-d ), δ, ppm: 2.85 (3H, CH ), 7.65 d and 8.28 d
C H ), 7.95 (1H, 6-H), 8.78 (1H, 2-H).
6
ed, %: C 69.85; H 5.52.
(
(
6
3
7
-(4-Isopropoxyphenyl)-2,5-dimethylpyrazolo-
4
[
1,5-a]pyrimidin-3-carbonitrile (IIId). Yield 82%,
mp 112°C. H NMR spectrum (DMSO-d ), δ, ppm
1
5-(4-Chlorophenyl)-2,7-dimethylpyrazolo[1,5-a]-
1
6
pyrimidine-3-carbonitrile (IVf). H NMR spectrum
(
J, Hz): 1.38 d [6H, (CH ) CH, J = 5.9], 2.54 (3H,
3
2
(
7
CDCl ), δ, ppm: 2.65 (3H, 2-CH ), 2.87 (3H, 7-CH ),
.29 (1H, 6-H), 7.50 d and 8.13 d (4H, C H ).
3 3 3
2
-CH ), 2.66 (3H, 5-CH ), 4.74 sept (1H, CH, J = 5.9),
3 3
6 4
7
.25 (1H, CH), 7.03 d and 8.07 d (2H each, C H ).
6
4
1
3
1
13
C NMR spectrum (DMSO-d ), δ , ppm: 14.13
The H and C NMR spectra were recorded on
a Bruker DPX-300 spectrometer at 300 and 75 MHz,
6
C
(
2-CH ), 22.57 [(CH ) CH], 25.07 (5-CH ), 70.30
3
3 2
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 3 2007

α-AMINOAZOLES IN SYNTHESES OF HETEROCYCLES.
473
respectively, using CDCl and DMSO-d as solvents.
3. Zaharan, M.A., El-Sharief, A.M.Sh., El-Gaby, M.S.A.,
Ammar, Y.A.A., and El-Said, U.H., Farmaco, 2001,
vol. 56, p. 277.
3
6
Signals from protons in compounds IVe and IVf were
1
identified in the H NMR spectrum of the correspond-
4
. George, C.F.P., Lancet, 2001, vol. 357, p. 1623.
ing isomer mixture III/IV. Aminopyrazoles Ia and Ib
were synthesized according to the procedure reported
in [10]. Pyrazolo[1,5-a]pyrimidines IVa and IVb were
prepared as described in [8].
5
. Moore, K.A., Zemrus, T.L., Ramcharitar, V., Levine, B.,
and Fowler, D.R., Forensic Sci. Int., 2003, vol. 134,
p. 120.
6
. Elnagdi, M.H., Elmoghayar, M.R.H., and Elge-
meie, G.E.H., Advances in Heterocyclic Chemistry,
Katritzky, A.R., Ed., New York: Academic, 1987,
vol. 41, p. 319.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 3 2007