Synthesis of new pyrazolo[1,5-a]pyrimidines by reaction of β,γ-unsaturated γ-alkoxy-α-keto esters with N-unsubstituted 5-aminopyrazoles

Article abstract of DOI:10.1055/s-0032-1318329

The reaction of β,γ-unsaturated γ-alkoxy-α-keto esters with N-unsubstituted 5-aminopyrazoles was investigated. The reaction proceeds with high regioselectivity and is considered as an effective- method for the preparation of new pyrazolo[1,5-a]pyrimidines bearing an ester function in the 7-position. The obtained drug-like compounds have a great potential for medicinal chemistry as they closely resemble the structure of several marketed pharmaceuticals. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318329

PAPER
▌925
paper
Synthesis of New Pyrazolo[1,5-a]pyrimidines by Reaction of β,γ-Unsaturated
γ-Alkoxy-α-keto Esters with N-Unsubstituted 5-Aminopyrazoles
Functionalized Heterocycles
Oleksandr O. Stepaniuk,a,b Vitalii O. Matviienko,a,b Ivan S. Kondratov,*b,c Igor V. Vitruk,a,b Andrei O. Tolmacheva,b
a
Kyiv National Taras Shevchenko University, 64 Volodymirska st., 01033 Kyiv-33, Ukraine
b
Enamine Ltd., 23 A. Matrosova st., 01103 Kyiv, Ukraine
c
Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, Murmanska 1, 02660 Kyiv-94, Ukraine
Fax +380(44)537325; E-mail: vanya_ko@mail.ru
Received: 05.12.2012; Accepted after revision: 08.02.2013
R2
Y
Abstract: The reaction of β,γ-unsaturated γ-alkoxy-α-keto esters
R2
R1
R4
X
with N-unsubstituted 5-aminopyrazoles was investigated. The reac-
tion proceeds with high regioselectivity and is considered as an
effective method for the preparation of new pyrazolo[1,5-a]pyrimi-
dines bearing an ester function in the 7-position. The obtained drug-
like compounds have a great potential for medicinal chemistry as
they closely resemble the structure of several marketed pharmaceu-
ticals.
OR3
acylation
R1
OR3
O
1a–c
2a–c
3a–c
R1
R4
R1
R4
X
or/and
R2
Y
R2
Key words: heterocycles, esters, regioselectivity, pyrazolo[1,5-
a]pyrimidines, 5-aminopyrazoles
X
Y
a R1 = R2 = H, R3 = Et
b R1 = H, R2 = R3 = Me
c R1 = Me, R2 = H, R3 = Et
1 R4 = CO2Et
β,γ-Unsaturated γ-alkoxy-α-keto esters of general struc-
tures 1–3 are widely used as building blocks for the prep-
aration of fused heterocyclic compounds (Scheme 1).
They can be easily obtained by acylation of the corre-
sponding α,β-unsaturated ethers, namely, ethyl vinyl ether
(a), 2-methoxypropene (b), and 1-ethoxypropene (c).1
Compounds 1–3 can be considered as synthetic equiva-
lents of β-dicarbonyl compounds and often their applica-
tion is more suitable than usage of the corresponding
diketones or keto aldehydes. Compounds 2 and 3 can be
mentioned as the most popular among other β-alkoxyvi-
nyl ketones and were widely used as starting materials in
numerous syntheses of heterocyclic compounds.2
2 R4 = CF3
3 R4 = CCl3
Scheme 1 Synthesis and application of compounds 1a–c to 3a–c in
heterocyclic chemistry
were published properties of pyrazolo[1,5-a]pyrimidines
as corticotropin-releasing factor (CRF),5 GABA and
GABAA receptors,6 neuropeptide Y1 receptor,7 KCa-chan-
nels,8 an estrogen receptor,9 a histamine H3 receptor,10 and
a nicotinic acid receptor11 ligands. Derivatives of pyrazo-
lo[1,5-a]pyrimidines are also inhibitors of kinase-insert
domain-containing receptor tyrosine kinase (KDR),12 cy-
clin-dependent kinase-2 (CDK-2),13 c-Src kinase,14 B-Raf
kinase,15 serine/threonine-protein kinase (CHK1),16 mito-
gen-activated protein kinase 2 (MAPKAP-K2),17 lympho-
cyte-specific protein tyrosine kinase (Lck),18 bone
morphogenetic protein (BMP) signaling,19 and dipeptidyl
peptidase IV,20 as well as effective anti-inflammatory,21
antiprolifirative,22 and antiviral23 agents. In addition, the
pyrazolo[1,5-a]pyrimidine framework was recently iden-
tified as a privileged structure in drug discovery.24 Anxio-
lytic and sedative agents Zaleplon, Indiplon, and
Ocinaplon can be mentioned as the representative exam-
ples of approved drugs containing pyrazolo[1,5-a]pyrim-
idine core (Figure 1).
At the same time, the corresponding heterocyclizations of
compounds 1a–c, unexpectedly, despite the great poten-
tial, attracted almost no attention so far. Application of
these compounds for the preparation of ethoxycarbonyl
containing heterocycles by the reaction with binucleo-
philes is much less precedented in the literature.3
Recently, we have presented a regioselective reaction of
cyclic alkoxyenones – ethyl (4,5-dihydrofuran-3-yl)- and
(5,6-dihydropyran-3-yl)-2-oxoacetates – with N-unsub-
stituted aminoazoles.4 In this context, in the present work
we describe our results on the reaction of enones 1a–c
with 1-unsubstituted aminopyrazoles to provide pyrazo-
lo[1,5-a]pyrimidines, bearing an ethoxycarbonyl group.
Pyrazolo[1,5-a]pyrimidines are present in a large number
of compounds possessing a broad range of biological ac-
tivity. Only during the last five years, among others, there
The first part of our research was devoted to the optimiza-
tion of the literature protocol for the synthesis of the cor-
responding starting materials.
Compound 1a was synthesized using the method of Tietze
et al.1a by the acylation of ethyl vinyl ether with ethyl 2-
chloro-2-oxoacetate without using solvent and base.
Compounds 1b,c were earlier obtained using CHCl3 as
SYNTHESIS 2013, 45, 0925–0930
Advanced online publication: 04.03.2013
DOI: 10.1055/s-0032-1318329; Art ID: SS-2012-T0927-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

926
O. O. Stepaniuk et al.
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corresponding products 5a–o in good yields (Scheme 3,
Table 1). The reaction of β-alkoxy enones 1a–c with 5-
aminoazoles 4a–e is a successful example of a regioselec-
tive heterocyclization in comparison with same interac-
tion of other 1,3-dielectrophiles – 1,3-dicarbonyl
compounds, which usually proceeds with low regioselec-
tivity.25 For instance, the earlier investigated reaction of
ethyl 2,4-dioxopentanoate with 5-aminopyrazole (4a) led
to a mixture of regeoisomers 5b and 5p in a ratio of 27:73
(Scheme 4).26
Me
N
N
N
Et
N
O
O
N
N
N
N
N
N
N
O
S
N
O
CN
N
Indiplon
Zaleplon
Ocinaplon
Figure 1 FDA-approved drugs containing pyrazolo[1,5-a]pyrimi-
dine motif
R2
O
R2
EtO2CCOCl, Py
CH2Cl2
OR3
EtO2C
OR3
65–90%
solvent and pyridine as base.3e Similar conditions (which
were earlier used for acylation of cyclic α,β-unsaturated
ethers4) were applied performing the reaction at room
temperature in dichloromethane using pyridine as a base
and increasing the reaction time up to 7 days. This proce-
dure allowed the preparation of the products 1b,c on a
large scale (>120 g) and isolation in a rather good yield of
90% and 65%, respectively (Scheme 2).
R1
R1
1b,c
b R1 = H, R2 = R3 = Me
c R1 = Me, R2 = H, R3 = Et
Scheme 2 Synthesis of compounds 1b,c
CO2Et
N
R4
N
O
R2
R5
EtOH
reflux, 10 h
R1
R2
N
OR3
+
R4
EtO2C
74–95%
Next, the reaction of compounds 1a–c with various 5-ami-
noazoles 4a–e was investigated. It was shown that upon
refluxing in ethanol N-unsubstituted 5-aminopyrazoles
4a–e and esters 1a–c led to regioselective formation of
R1
1a–c
N
H2N
N
H
R5
4a–e
5a–o
Scheme 3 Synthesis of pyrazolo[1,5-a]pyrimidines 5a–o (see Table 1)
Table 1 Reaction of Compounds 1a–c with 5-Aminopyrazoles 4a–e
Entry
Substrate 1
R1, R2, R3
Substrate 4
R4, R5
H, H
Product (yield, %)
CO2Et
5a
(74)
N
1
1a
H, H, Et
4a
N
N
CO2Et
N
5ba
(86)
N
N
2
3
4
5
6
1b
1c
1a
1b
1c
H, Me, Me
Me, H, Et
H, H, Et
4a
4a
4b
4b
4b
H, H
N
CO2Et
5c
(79)
N
N
H, H
CO2Et
N
5d
(68)
N
Me, H
Me, H
Me, H
N
CO2Et
N
5eb
(91)
N
N
H, Me, Me
Me, H, Et
N
CO2Et
5f
(95)
N
N
Synthesis 2013, 45, 925–930
© Georg Thieme Verlag Stuttgart · New York

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Functionalized Heterocycles
927
Table 1 Reaction of Compounds 1a–c with 5-Aminopyrazoles 4a–e (continued)
Entry
7
Substrate 1
R1, R2, R3
Substrate 4
R4, R5
Product (yield, %)
CO2Et
N
5g
(95)
N
1a
H, H, Et
4c
H, CN
N
CN
CO2Et
N
N
N
5h
(74)
8
9
1b
1c
1a
H, Me, Me
Me, H, Et
H, H, Et
4c
4c
4d
H, CN
CN
CO2Et
N
N
N
5i
(87)
H, CN
CN
CO2Et
N
N
5j
(92)
10
H, CO2Et
N
CO2Et
CO2Et
N
N
5k
11
12
13
14
15
1b
1c
1a
1b
1c
H, Me, Me
Me, H, Et
H, H, Et
4d
4d
4e
4e
4e
H, CO2Et
H, CO2Et
H, CONH2
H, CONH2
H, CONH2
(92)
N
CO2Et
CO2Et
N
N
N
5l
(88)
CO2Et
CO2Et
N
N
5m
(89)
N
CONH2
CO2Et
N
N
N
5n
(88)
H, Me, Me
Me, H, Et
CONH2
CO2Et
N
N
N
5o
(92)
CONH2
a Compound 5b was earlier obtained by other method in 15% yield.26
b Compound 5e was earlier obtained under other conditions in 92% yield.3a
It should be mentioned that the same regioselectivity as While in the case of ethyl 2,4-dioxopentanoate (Scheme
enones 1a–c was also demonstrated in the case of reaction 4) the low regioselelectivity is due to an only slightly dif-
of similar cyclic alkoxyenones with N-unsubstituted ami- ferent reactivity of the two carbonyl groups, in the case of
noazoles.4
enones 1a–c the reason of high regioselectivity can be ex-
plained by formation of intermediate enaminones 6 (ini-
tial highly regioselective attack at 4-position, Figure 2).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 925–930

928
O. O. Stepaniuk et al.
PAPER
as potential pathway to functionalized pyrazoles, ami-
dines, and pyrazolo[1,5-a]pyrimidines, respectively. The
reaction can be considered as general effective regioselec-
tive approach to pyrazolo[1,5-a]pyrimidines 5a–o, which
are expected to be potential building blocks since they
possess the heterocyclic cores, which are similar/identical
to those found within several FDA-approved drugs, and
hence are of great potential for medicinal chemistry.
CO2Et
N
N
N
N
N
5b (27%)
H2N
H
O
O
4a
+
EtOH, reflux
30 min
CO2Et
N
N
Solvents were purified according to standard procedures. Chemi-
cals (highest commercial quality) were purchased from Acros,
Sigma-Aldrich, Merck, and Enamine Ltd. Compound 1a was syn-
thesized by the published procedure.1a The progress of reactions
was monitored by TLC analysis (silica gel 60 F254, Merck). Melt-
ing points were obtained using a Büchi melting point apparatus and
are uncorrected. IR spectra were recorded on Bruker Vertex 70
spectrometer. NMR spectra were recorded on Bruker Avance DRX
spectrometer at 500 MHz (1H), 126 MHz (13C), and 470 MHz (19F)
N
CO2Et
5p (73%)
Scheme 4 Reaction of ethyl 2,4-dioxopentanoate with 5-aminopyr-
azole (4a) described in the literature26
These compounds were mostly observed by NMR analy-
sis of the mixtures and were isolated in several cases when
the reaction was carried out under mild conditions (EtOH,
–10 to 0 °C, 2 h): reaction of enone 1b with 5-aminoazole
(4a) (compound 6a) and reaction of enone 1a with 5-ami-
no-3-methylaminoazole (4b) (compound 6b). Isolated
compounds were found to be unstable under heating or
standing at room temperature (partially transformed to
compounds 5b and 5d, respectively) and were character-
ized by recording their 1H NMR spectra in acetone-d6.
1
at 25 °C. SiMe4 (for H and 13C NMR) and CCl3F (for 19F NMR)
were used as internal standards. Mass spectra were recorded on
Agilent 1100 LCMSD SL instrument with chemical ionization (CI).
Enones 1b,c; General Procedure
A solution of the corresponding alkoxyalkene (1 mol) and pyridine
(79 g, 1 mol) in CH2Cl2 (600 mL) was cooled to 0–5 °C and a solu-
tion of ethyl 2-chloro-2-oxoacetate (136.5 g, 1 mol) in CH2Cl2 (600
mL) was added to the mixture under stirring at 0–10 °C. During the
addition the precipitation of pyridine hydrochloride was observed.
The reaction mixture was left stirring for 7 d at r.t. Then, it was
washed with H2O (5 × 200 mL) until pH ~7. The organic layer was
dried (Na2SO4), evaporated, and the residue was distilled under vac-
uum.
R4
O
R2
6a R2 = Me, R4 = H
6b R2 = H, R4 = Me
N
N
Ethyl (E)-4-Methoxy-2-oxopent-3-enoate (1b)
Prepared from 2-methoxypropene (72.1 g, 1 mol); yield: 154.8 g
(90%); light yellow solid; mp 37–39 °C; bp 83 °C/0.5 mmHg. NMR
data are identical (differences are insignificant) to those reported
previously.3e
EtO2C
NH
H
Figure 2 Structure of isolated intermediates 6a,b
The reaction of enones 1a–c was also carried out with sev-
eral 3-substituted 5-amino-1H-1,2,4-triazoles. In these
cases complex inseparable mixtures were formed and
only in the case of the reaction of enone 1c with 5-amino-
3-trifluoromethyl-1H-1,2,4-triazole (7) the single product
8 was isolated in 47% yield (Scheme 5).
IR (ATR): 1018, 1055, 1098, 1247, 1294, 1368, 1401, 1442, 1568,
1681, 1725, 1786, 2984 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.37 (t, J = 7.2 Hz, 3 H, CH3),
2.38 (s, 3 H, CH3), 3.78 (s, 3 H, OCH3), 4.31 (q, J = 7.2 Hz, 2 H,
CH2O), 6.24 (s, 1 H, CH).
13C NMR (126 MHz, CDCl3): δ = 14.0, 20.7, 56.2, 62.1, 94.8,
163.2, 179.3, 180.8.
MS (CI): m/z (%) = 173 (100, [M + 1]+).
CF3
N
Anal. Calcd for C8H12O4 (172.07): C, 55.81; H, 7.02. Found: C,
55.68; H, 7.06.
N
CO2Et
N
H2N
O
H
N
N
7
N
Pyrazolo[1,5-a]pyrimidines 5a–o; General Procedure
A solution of compound 1a–c (10 mmol) and 4a–e (10 mmol) in
EtOH (10 mL) were stirred for 2 h at r.t and then refluxed for 10 h.
Then, the solution was cooled, evaporated, and the residue was pu-
rified by appropriate method.
F3C
EtO2C
OEt
EtOH, reflux
36 h, 47%
N
8
1c
Scheme 5 Reaction of enone 1c with aminotriazole 7
Ethyl Pyrazolo[1,5-a]pyrimidine-7-carboxylate (5a)
Prepared from enone 1a (1.72 g, 10 mmol) and 5-aminopyrazole
(4a; 0.83 g, 10 mmol), and purified by crystallization from hexane;
yield: 1.41 g (74%); yellow solid; mp 39 °C.
The structure of compound 8 as well as structures of com-
pounds 5a–o were confirmed by close similarity of 1H and
13C NMR data of compounds synthesized with the data of
earlier obtained [1,2,4]triazolo[1,5-a]pyrimidines4 and
pyrazolo[1,5-a]pyrimidines3a,4,26 bearing alkoxycarbonyl
group in 7-position (see Supporting Information).
IR (ATR): 1128, 1221, 1295, 1338, 1458, 1516, 1536, 1609, 1723,
2984, 3060 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.48 (t, J = 7.0 Hz, 3 H, CH3),
4.54 (q, J = 7.0 Hz, 2 H, CH2O), 6.97 (s, 1 Harom), 7.59 (d, J = 7.3
Hz, 1 Harom), 8.25 (s, 1 Harom), 8.82 (d, J = 7.3 Hz, 1 Harom).
In summary, we have investigated the reaction of com-
pounds 1a–c with N-unsubstituted 5-aminopyrazoles 4a–e
Synthesis 2013, 45, 925–930
© Georg Thieme Verlag Stuttgart · New York

PAPER
Functionalized Heterocycles
929
13C NMR (126 MHz, CDCl3): δ = 14.3, 62.7, 99.7, 107.4, 135.5,
146.4, 146.6, 147.6, 163.7.
MS (CI): m/z (%) = 192 (100, [M + 1]+).
P.; Muraro, P.; Beck, P.; Machado, P.; Frizzo, C. P.; Zanatta,
N.; Bonacorso, H. G. Synth. Commun. 2008, 38, 3465.
(g) Zanatta, N.; Faoro, D.; da S. Fernandes, L.; Brondani, P.
B.; Flores, D. C.; Flores, A. F. C.; Bonacorso, H. G.;
Martins, M. A. P. Eur. J. Org. Chem. 2008, 5832.
(h) Zanatta, N.; Madruga, C. C.; Marisco, P. C.; da Rosa, L.
S.; da Silva, F. M.; Bonacorso, H. G.; Martins, M. A. P.
J. Heterocycl. Chem. 2010, 47, 1234. (i) Moreira, D. N.;
Frizzo, C. P.; Longhi, K.; Soares, A. B.; Morzari, M. R. B.;
Buriol, L.; Brondani, S.; Zanatta, N.; Bonacorso, H. G.;
Martins, M. A. P. Monatsh. Chem. 2011, 142, 1265. (j) Xin,
Y.; Zhao, J.; Gu, J.; Zhu, S. J. Fluorine Chem. 2011, 132,
402. (k) Xin, Y.; Zhao, J.; Zhu, S. J. Fluorine Chem. 2012,
133, 98.
Anal. Calcd for C9H9N3O2 (191.07): C, 56.54; H, 4.74; N, 21.98.
Found: C, 56.63; H, 4.65; N, 22.05.
Enaminones 6a,b; General Procedure
To a solution of the corresponding 5-aminopyrazole 4 (10 mmol) in
EtOH (15 mL) was added compound 1 dissolved in EtOH (10 mL)
dropwise at –10 °C. The mixture was stirred for 2 h at 0 °C and the
residue formed was filtered, washed with cold EtOH (5 mL) and
dried.
Ethyl (E)-2-Oxo-4-(1H-pyrazol-5-ylamino)pent-3-enoate (6a)
Prepared from enone 1b (1.72 g, 10 mmol) and 5-aminopyrazole
(4a; 0.83 g, 10 mmol); yield: 2.0 g (90%); light yellow solid; mp
>50 °C (dec.).
1H NMR (500 MHz, acetone-d6): δ = 1.33 (t, J = 7.2 Hz, 3 H, CH3),
2.37 (s, 3 H, CH3), 4.25 (q, J = 7.2 Hz, 2 H, CH2O), 5.92 (s, 1 H,
CH), 6.28 (d, J = 1.8 Hz, 1 Harom), 7.78 (d, J = 1.8 Hz, 1 Harom),
12.04 (br s, 1 H, NH), 13.11 (br s, 1 H, NH).
(3) See for example: (a) Frizzo, C. P.; Martins, M. A. P.;
Marzari, M. R. B.; Campos, P. T.; Claramunt, R. M.; García,
M. Á.; Sanz, D.; Alkorta, I.; Elguero, J. J. Heterocycl. Chem.
2010, 47, 1259. (b) Moreira, D. N.; Frizzo, C. P.; Longhi, K.;
Zanatta, N.; Bonacorso, H. G.; Martins, M. A. P. Monatsh.
Chem. 2008, 139, 1049. (c) Nesi, R.; Chimichi, S.; Scotton,
M.; Degl’Innocenti, A.; Adembri, G. J. Chem. Soc., Perkin
Trans. 1 1980, 1667. (d) Dyachenko, V. D.; Tkachev, R. P.;
Dyachenko, A. D. Russ. J. Gen. Chem. 2009, 79, 121.
(e) Machado, P.; Rosa, F. A.; Rossatto, M.; Sant’Anna, G..
da S.; Sauzem, P. D.; Siqueira da Silva, R. M.; Rubin, M. A.;
Ferreira, J.; Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P.
ARKIVOC 2007, (xvi), 281.
(4) Stepaniuk, O. O.; Matvienko, V. O.; Kondratov, I. S.;
Shishkin, O. V.; Volochnyuk, D. M.; Mykhailiuk, P. K.;
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MS (CI): m/z (%) = 224 (100, [M + 1]+).
Anal. Calcd for C10H13N3O3 (223.10): C, 53.80; H, 5.87; N, 18.82.
Found: C, 54.01; H, 5.90; N, 18.69.
Acknowledgment
We would like to thank Dr. Sergey I. Vdovenko and O. A. Fedoren-
ko (Institute of Bioorganic Chemistry and Petrochemistry NAS of
Ukraine) for their help in recording the IR spectra.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are spectroscopic and mass spectrometric data, elemental analyses,
and copies of 1H and 13C NMR spectra of all new compounds 1b,c,
5a–o, 6a,b, 8, as well as comparison of 13C NMR data of com-
pounds 5a–o and pyrazolo[1,5-a]pyrimidine-7-carboxylates descri-
bed in the literature.SunogIpifrmntiratuoSpIg
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