α-aminoazoles in the Synthesis of heterocycles: V. Synthesis of azolo[1,5-a]pyrimidines from 2-ethoxyvinyl trifluoromethyl ketones and 2,2-diethoxyvinyl trifluoromethyl ketone

Article abstract of DOI:10.1134/S1070428009030117

A procedure was proposed for the synthesis of 7-trifluoromethylazolo[1,5-a] pyrimidines by reactions of 2-ethoxyvinyl trifluoromethyl ketones and 2,2-diethoxyvinyl trifluoromethyl ketone with 5(3)-aminoazoles. The reactions occurred under mild conditions,

Full text of DOI:10.1134/S1070428009030117

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 3, pp. 417–420. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © E.E. Emelina, A.A. Petrov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 3, pp. 427–430.
α-Aminoazoles in the Synthesis of Heterocycles: V.* Synthesis
of Azolo[1,5-a]pyrimidines from 2-Ethoxyvinyl Trifluoromethyl
Ketones and 2,2-Diethoxyvinyl Trifluoromethyl Ketone
E. E. Emelina and A. A. Petrov
St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
e-mail: emelina@hotmail.ru
Received May 28, 2008
Abstract—A procedure was proposed for the synthesis of 7-trifluoromethylazolo[1,5-a]pyrimidines by reac-
tions of 2-ethoxyvinyl trifluoromethyl ketones and 2,2-diethoxyvinyl trifluoromethyl ketone with 5(3)-amino-
azoles. The reactions occurred under mild conditions, and the products were formed with high yield and
regioselectivity.
DOI: 10.1134/S1070428009030117
Functionally substituted pyrazolo[1,5-a]pyrimi-
dines exhibit a broad spectrum of biological and
pharmacological activity [2–5]. Some pyrazolo[1,5-a]-
pyrimidines, namely Zaleplon, Indiplon, and Ocina-
plon [6] that belong to non-benzodiazepine sedative
and hypnotic agents, are used in medical practice.
Therefore, studies in this field of synthetic organic
chemistry continuously attract researchers’ attention
and imply both development of new procedures and
modification of already known ones.
showed that O–N exchange follows vinylic substitu-
tion pattern (replacement of the alkoxy group by
amino). It is known that introduction of a trifluoro-
methyl group into organic molecules often increases
their lipophilicity and decreases toxicity, which could
modify or enhance their biological activity [12].
In the present work we examined reactions of
4-ethoxy-1,1,1-trifluoropent-3-en-2-one (IIa), 4-eth-
oxy-1,1,1-trifluoro-4-phenylbut-3-en-2-one (IIb), and
4,4-diethoxy-1,1,1-trifluoropent-3-en-2-one (IIc) with
5(3)-aminopyrazoles Ia–Ie and 5-amino-1,2,4-triazole
(If) (Scheme 1). The reactions occurred under mild
conditions to give compounds IIIa–IIIj as the only
products. It should be noted that the cyclocondensation
of aminotriazole If with 1,1,1-trifluoromethyl-4-phen-
ylbutane-2,4-dione was reported to afford a mixture of
regioisomeric triazolopyrimidines [13]. Unlike known
schemes for the introduction of an ethoxy group into
We previously proposed an effective regioselective
method for the synthesis of 7-trifluoromethyl-substitut-
ed azolopyrimidines from trifluoroacetylvinyl ethers.
The latter were also used as starting compounds in
regioselective syntheses of trifluoromethyl-containing
β-acylvinylamines [7–9], 2-trifluoromethylpyrazolo-
[1,5-a]pyrimidines [10], pyrido[3,4-b]pyrimidines, and
pyrazolo[3,4-b]pyridines [11]. Hojo et al. [8, 9]
Scheme 1.
CF3
OEt
O
N
NH
N
Z
MeCN
N
R1
+
R1
NH2
R2
CF3
Z
N
IIIa–IIIj
R2
Ia–If
IIa–IIc
I, Z = CH, R1 = Me (a), 4-ClC6H4 (b); Z = CPh, R1 = Me (c); Z = CCN, R1 = H (d); Z = CBr, R1 = Me (e); Z = N, R1 = H (f); II, R2 =
Me (a), Ph (b), EtO (c); III, Z = CH: R1 = Me, R2 = OEt (a); R1 = 4-ClC6H4, R2 = Me (b), Ph (c), EtO (d); Z = CPh, R1 = R2 =
Me (e), Ph (f), EtO (g); Z = CCN, R1 = H, R2 = EtO (h); Z = CBr, R1 = Me, R2 = EtO (i); Z = N, R1 = H, R2 = Ph (j).
* For communication IV, see [1].
417

EMELINA, PETROV
418
pyrazolopyrimidines [14–16], the proposed procedure
ensures regioselective preparation of 5-ethoxy-7-tri-
fluoromethylpyrazolopyrimidines IIIa–IIIj in one
other species, stable diol V [18] and spectrally detect-
able 2,5-dimethyl-7-trifluoromethyl-3-phenyl-6,7-di-
hydropyrazolo[1,5-a]pyrimidin-7-ol (VI) having
N4=C5 double bond [19] (Scheme 2). Compound VI is
isomeric to intermediate IV.
1
step. The H and 13C NMR spectra and physical
constants of compounds IIIb, IIIc, IIIe, and IIIf coin-
cided with those reported previously for the same com-
pounds synthesized by reactions of 1,1,1-trifluoropen-
tane-2,4-dione and 4,4,4-trifluoro-1-phenylbutane-1,3-
dione with the corresponding aminoazoles [17]. The
structure of compounds IIIa, IIId, and IIIg–IIIi was
determined by comparing chemical shifts of the carbon
atoms contiguous to the CF3 group (δC 134–135 ppm,
2J = 37–38 Hz) with those typical of pyrazolopyrimi-
dines and pyrazolopyridines [δC 134 ppm, =C(CF3)N=;
145.5 ppm [–C(CF3)=N–] which were determined with
account taken of long-range couplings [1, 17].
Scheme 2.
Ph
Ph
H
Me
OH
N
N
Me
Me
Me
N
N
N
N
F3C
OH
F3C
OH
V
VI
1H NMR spectrum, δ, ppm: 1H NMR spectrum, δ, ppm:
2.25 and 2.42 (CH2, AB system, 2.95 and 3.20 (CH2, AB system,
JAB = 13.7 Hz) JAB = 18.9 Hz)
Ph
4,4-Diethoxy-1,1,1-trifluoropent-3-en-2-one (IIc)
was brought into reaction with 3-methyl-1-phenyl-1H-
pyrazol-5-amine (Ig) to obtain 4-trifluoromethylpyra-
zolo[3,4-b]pyridine (VII) (Scheme 3). The reaction
was carried out both in acetonitrile and under the
conditions reported in [11] (a mixture of toluene and
acetic acid). Comparison of the 13C chemical shifts for
the C–CF3 fragment in VII [δC 133.7 q (C4CF3),
160.0 ppm (C6)] with those reported by us previously
[1, 17] for trifluoromethyl-substituted pyrazolo[3,4-b]-
pyridines {δC ~147.5 [C6(CF3)=N], ~132–133 ppm
[C4(CF3)=C]} allowed us to unambiguously identify
compound VII as 6-ethoxy-3-methyl-1-phenyl-4-tri-
N
CF3
145.5
N
Ph
155.2
103.3
134.2 q
Ph
Me
N
101.8
N
N
N
135.1 q
CF3
CF3
Ph
Ph
N
Me
158.4
N
OEt
160.4
Me
Me
N
106.9
N
99.7
N
N
133.5 q
136.0 q
CF3
CF3
1H and 13C NMR monitoring of the reaction of
3(5)-methyl-4-phenyl-1H-pyrazol-5(3)-amine (Ia) with
4-ethoxy-1,1,1-trifluoropent-3-en-2-one (IIa) in CDCl3
allowed us to detect only one intermediate product,
2,5-dimethyl-7-trifluoromethyl-3-phenyl-4,7-dihydro-
pyrazolo[1,5-a]pyrimidin-7-ol (IV) having C5=C6
double bond in the pyrimidine ring; intermediate IV
was gradually transformed into pyrazolo[1,5-a]pyrimi-
dine (IIIe).
1
fluoromethylpyrazolo[3,4-b]pyridine. The H and 13C
NMR spectra of VII coincided with the data given in
[11] for the product which was erroneously assigned
the structure of 6-ethoxy-3-methyl-1-phenyl-6-tri-
fluoromethylpyrazolo[3,4-b]pyridine.
Scheme 3.
Ph
OEt
O
N
N
Ph
19.3
Me
H
+
N
Me
NH2
EtO
CF3
128.9
Me
N
90.2
Ig
IIc
N
82.2
F3C
OH
CF3
Me
IV
MeCN
N
1H NMR spectrum, δ, ppm: 4.55 (6-H),
N
N
OEt
9.31 (4-H), 1.97 (5-CH3)
Ph
VII
On the other hand, the formation of pyrazolo-
[1,5-a]pyrimidines from 5(3)-aminopyrazoles and
1,1,1-trifluoropentane-2,4-dione was mediated by
We can conclude that cyclocondensation of
α-aminoazoles with 2-ethoxyvinyl trifluoromethyl
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α-AMINOAZOLES IN THE SYNTHESIS OF HETEROCYCLES: V.
419
ketones and 2,2-diethoxyvinyl trifluoromethyl ketone
occurs strictly regioselectively via replacement of the
ethoxy group at the vinylic double bond by the amino
group in the azole and reaction of the trifluoroacetyl
group at the endocyclic nitrogen atom. Analogous
scheme was proposed previously for the reaction of
3(5)-aminoazoles with trifluoromethyl-containing
1,3-diketones [16, 17].
CH3, J = 7.0 Hz), 2.42 s (3H, 2-CH3), 4.42 q (2H,
OCH2, J = 7.0 Hz), 6.20 s (1H, 3-H), 6.72 s (1H, 6-H).
13C NMR spectrum (DMSO-d6), δC, ppm: 13.78 (CH3),
3
14.10 (2-CH3), 62.61 (OCH2), 98.17 q (C6, JCF
=
4.0 Hz), 94.55 (C3), 118.78 q (CF3, JCF = 274.3 Hz),
134.62 q (C7, JCF = 36.9 Hz), 148.23 (C3a), 154.87
2
(C2), 162.12 (C5). Found, %: C 48.72; H 4.27.
C10H10F3N3O. Calculated, %: C 48.98; H 4.11.
2-(4-Chlorophenyl)-5-ethoxy-7-trifluoromethyl-
Probable biological activity of the synthesized com-
pounds was predicted using PASS program. This pro-
gram makes it possible to predict 3300 kinds of bio-
logical activity with an average accuracy of ~95% on
the basis of the structure of a chemical compound
[20–22]. The results showed that pyrazolopyrimidines
III could inhibit cyclic AMP phosphodiesterase, cyclic
GMP phosphodiesterase, and cyclooxygenase, act as
interleucin-5 antagonists, and exhibit analgesic, anti-
arthritic, and anxiolytic properties.
pyrazolo[1,5-a]pyrimidine (IIId). Yield 93%,
1
mp 176°C. H NMR spectrum (CDCl3), δ, ppm: 1.47 t
(3H, CH3, J = 6.5 Hz), 4.50 q (2H, OCH2, J = 6.5 Hz),
6.69 s (1H), 6.72 s (1H), 7.42–7.94 m (4H, C6H4).
13C NMR spectrum (CDCl3), δC, ppm: 14.12 (CH3),
63.39 (OCH2), 92.54 (C3), 99.66 q (C6, 3JCF = 3.9 Hz),
2
119.10 q (CF3, JCF = 274.2 Hz), 135.97 q (C7, JCF
=
37.6 Hz), 149.46 (C3a), 155.64 (C2), 160.40 (C5);
127.78, 128.88, 131.00, 134.94 (C6H4). Found, %:
C 52.55; H 3.50. C15H11ClF3N3O. Calculated, %:
C 52.72; H 3.24.
Thus we have proposed an efficient procedure for
the synthesis of 5-alkoxy-7-trifluoromethylpyrazolo-
and 5-alkoxy-7-trifluoromethyltriazolo[1,5-a]pyrimi-
dines with high yield and regioselectivity and simple
isolation of the products.
5-Ethoxy-2-methyl-3-phenyl-7-trifluoromethyl-
pyrazolo[1,5-a]pyrimidine (IIIg). Yield 91%,
1
mp 146°C. H NMR spectrum (CDCl3), δ, ppm: 1.45 t
(3H, CH3, J = 6.5 Hz), 2.65 s (3H, 2-CH3), 4.49 q (2H,
OCH2, J = 6.5 Hz), 6.67 s (1H), 7.31–7.72 m (5H, Ph).
EXPERIMENTAL
13C NMR spectrum (CDCl3), δC, ppm: 14.05 (CH3),
1
The H and 13C NMR spectra were recorded at
3
14.56 (2-CH3), 63.27 (OCH2), 98.91 q (C6, JCF
=
3.9 Hz), 108.24 (C3), 119.18 q (CF3, JCF = 274.9 Hz),
22°C on a Bruker DPX-300 spectrometer (300.13 and
75.47 MHz, respectively); the chemical shifts were
measured relative to the residual proton or carbon
signals of deuterated solvents (CDCl3, δ 7.28 ppm,
δC 76.90 ppm; DMSO-d6, δ 2.50 ppm, δC 39.50 ppm).
1H-1,2,4-Triazol-3-amine (Ic) was commercial prod-
uct (Acros Organics). 5(3)-Aminopyrazoles Ia and Ib
were synthesized according to the procedures reported
in [23, 24]. Trifluoromethyl ketones IIa–IIc were
prepared by trifluoroacetylation of the corresponding
ketone diethyl acetals [7]. The physical constants and
spectral parameters of pyrazolo[1,5-a]pyrimidines IIIb,
IIIc, IIIe, and IIIf were consistent with published
data [16].
135.65 q (C7, JCF = 36.6 Hz), 145.56 (C3a), 153.70
2
(C2), 160.32 (C5), 126.21, 128.21, 128.50, 131.98 (Ph).
Found, %: C 59.60; H 4.60. C16H14F3N3O. Calculated,
%: C 59.81; H 4.39.
5-Ethoxy-7-trifluoromethylpyrazolo[1,5-a]py-
rimidine-3-carbonitrile (IIIh). Yield 74%, mp 148°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.47 t (3H,
CH3, J = 7.0 Hz), 4.60 q (2H, OCH2, J = 7.0 Hz),
7.22 s (1H, 6-H), 8.54 s (1H, 2-H). 13C NMR spectrum
(DMSO-d6), δC, ppm: 13.72 (CH3), 64.46 (OCH2),
3
81.17 (C3), 102.86 q (C6, JCF = 5.0 Hz), 111.20 (CN),
2
118.39 q (CF3, JCF = 275.3 Hz), 136.10 q (C7, JCF
=
38.9 Hz), 147.02 (C3a), 150.30 (C2), 162.99 (C5).
Found, %: C 46.61; H 2.86. C10H7F3N4O. Calculated,
%: C 46.88; H 2.75.
Azolopyrimidines IIIa–IIIj (general procedure).
A solution of 5 mmol of 5(3)-aminoazole Ia–Ie and
5.5 mmol of trifluoromethyl ketone IIa–IIc in 10 ml of
acetonitrile or chloroform was stirred for 1 h at room
temperature and was then heated for 1 h under reflux.
The solvent was distilled off under reduced pressure,
and the residue was recrystallized from ethanol.
3-Bromo-5-ethoxy-2-methyl-7-trifluoromethyl-
pyrazolo[1,5-a]pyrimidine (IIIi). Yield 91%,
mp 80°C. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.43 t
(3H, CH3, J = 7.0 Hz), 2.40 s (3H, 2-CH3), 4.52 q (2H,
OCH2, J = 7.0 Hz), 6.80 s (1H, 6-H). 13C NMR spec-
trum (DMSO-d6), δC, ppm: 12.74 (2-CH3), 13.70 (CH3),
5-Ethoxy-2-methyl-7-trifluoromethylpyrazolo-
[1,5-a]pyrimidine (IIIa). Yield 91%, mp 80°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.41 t (3H,
63.17 (OCH2), 83.04 (C3), 99.62 q (C6, 3JCF = 4.0 Hz),
2
118.48 q (CF3, JCF = 273.2 Hz), 135.12 q (C7, JCF
=
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EMELINA, PETROV
420
37.9 Hz), 144.70 (C3a), 153.05 (C2), 160.44 (C5).
Found, %: C 36.83; H 3.40. C10H9BrF3N3O. Calculat-
ed, %: C 37.06; H 2.80.
9. Hojo, M., Masuda, R., and Okada, E., Synthesis, 1989,
p. 215.
10. Martins, M.A.P., Cunico, W., Scapin, E., Emme-
rich, D.J., Fiss, G.F., Rosa, F.A., Bonacorso, H.G.,
Zanatta, N., and Flores, A.F.C., Lett. Org. Chem., 2006,
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12. Fuller, R. and Kobayashi, Y., Biomedicinal Aspects of
Fluorine Chemistry, Amsterdam: Elsevier, 1982.
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Chem., 1995, vol. 32, p. 407.
5-Phenyl-7-trifluoromethyl[1,2,4]triazolo[1,5-a]-
pyrimidine (IIIj). Yield 79%, mp 143–146°C (sub-
1
limes). H NMR spectrum (DMSO-d6), δ, ppm: 8.38 s
(1H, 6-H), 7.60–8.32 m (5H, C6H5), 8.80 s (1H, 2-H).
13C NMR spectrum (DMSO-d6), δC, ppm: 107.12 (C6),
2
119.18 (CF3, JCF = 273.1 Hz), 134.60 (C7, JCF
=
38.5 Hz), 155.89 (C2), 157.08 (C3a), 161.59 (C5);
128.26, 129.38, 132.34, 135.24 (C6H5). Found, %:
C 54.63; H 2.82. C12H7F3N4. Calculated, %: C 54.55;
H 2.67.
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