Regioselective synthesis of novel substituted pyrazolo[1,5-a]pyrimidines under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2008.08.044

A series of 6-(2-hydroxybenzoyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines 5 have been synthesized directly by the solvent-free reaction between 5-amino-1H-pyrazoles 1 and 3-benzoyl-2-methyl-4H-chromen-4-one 4. This solvent-free reaction proceeds in a regiospecific fashion by intramolecular opening of the γ-pyrone ring in a Michael-type reaction, that followed by cyclization via nucleophilic attack of endocyclic pyrazole nitrogen toward benzoyl group gives the pyrazolo[1,5-a]pyrimidines 5. The use of this method affords high yields in short reaction times.

Full text of DOI:10.1016/j.tetlet.2008.08.044

Tetrahedron Letters 49 (2008) 6254–6256
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of novel substituted pyrazolo[1,5-a]pyrimidines
under solvent-free conditions
b
a
a
c
c
Jairo Quiroga a, , Jaime Portilla , Rodrigo Abonía , Braulio Insuasty , Manuel Nogueras , Justo Cobo
*
a Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A. A. 25360 Cali, Colombia
b Bioorganic Compounds Research Group, Department of Chemistry, Universidad de los Andes, Carrera 1 N° 18A 10, Bogotá, Colombia
c Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2008
Revised 8 August 2008
Accepted 11 August 2008
Available online 15 August 2008
A series of 6-(2-hydroxybenzoyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines 5 have been synthe-
sized directly by the solvent-free reaction between 5-amino-1H-pyrazoles 1 and 3-benzoyl-2-methyl-
4H-chromen-4-one 4. This solvent-free reaction proceeds in a regiospecific fashion by intramolecular
opening of the c-pyrone ring in a Michael-type reaction, that followed by cyclization via nucleophilic
attack of endocyclic pyrazole nitrogen toward benzoyl group gives the pyrazolo[1,5-a]pyrimidines 5.
The use of this method affords high yields in short reaction times.
Ó 2008 Published by Elsevier Ltd.
Keywords:
5-Amino-1H-pyrazole
3-Benzoyl-2-methyl-4H-chromen-4-one
Pyrazolo[15-a]pyrimidine
Solvent-free reaction
Pyrazole and pyrimidine derivatives have attracted the atten-
tion of organic chemists very much due to their biological and che-
motherapeutic importance. Pyrazolopyrimidines and related fused
heterocycles are of interest as potential bioactive molecules. They
are known to exhibit a wide range of biological activities, such as
cSRC kinase inhibitors involved with ischemic brain pathology,1
cyclin dependent kinase 1 (CDK1) inhibitor,2 HIV reverse trans-
criptase inhibitors,3 CCR1 antagonists,4 protein kinase inhibitors,5
cGMP degradation inhibitors, or herbicidal and fungicidal activi-
ties.6 These compounds can also be used as intermediates in the
dyestuff industry.7 Numerous methods for the synthesis of pyr-
azolo[1,5-a]pyrimidines have been reported in the last twenty
years, which involved the reaction between 5-aminopyrazoles
and 1,3-bis-electrophilic compounds, such as b-dicarbonyl, alk-
oxymethylene-b-dicarbonyl, and b-enaminone compounds.8,9
We have already reported studies on reactions involving some
alkoxymethylene-b-dicarbonyl compounds, that if containing a
cyclic structure may allow the introduction of polyfunctionality
in the pyrazolo[1,5-a]pyrimidine system, such as the phenolic9a
or benzoic acid9b residues. Recently, we have described the synthe-
sis of new 2-(pyrazolo[1,5-a]pyrimidin-5-yl)benzoic acids 3 by the
solvent-free cyclocondensation between 5-amino-1H-pyrazoles 1
R
N
R
fusion
1.5 min
N
O
N
CO2H
O
O
+
HN
NH2
N
1
O
O
2
3
R = CH3, t-Bu, C6H5, 4-CH3C6H4, 4-CH3OC6H4, 4-O2NC6H4, 4-ClC6H4, 4-BrC6H4
Scheme 1.
Accordingly, the 1,3-biselectrophilic analogous like chromones
(see 4 in Scheme 2) represent a very reactive system owing to
the presence of an unsaturated b-diketone moiety, which makes
the position C2 sensitive to Michael addition of nucleophiles with
opening of the c-pyrone ring and followed by a new cycloconden-
sation via one of those carbonyl groups.9,10
Continuing our studies on the application of solvent-free cyclo-
condensation methodology to the synthesis of fused pyrazoles,11
we described here the solvent-free reaction between 5-amino-
1H-pyrazoles
1 and 3-benzoyl-2-methyl-4H-chromen-4-one 4,
and 3-(3-oxo-2-benzofuran-1(3H)-ylidene)-pentane-2,4-dione
2
which afforded successfully an interesting series of 6-(2-hydr-
oxybenzoyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines 5a–h
after just a few minutes12 (Scheme 2). The synthesis has been car-
ried out using two different methods. In the first (method A), the
reaction mixture was placed in an air open Pyrex-tube and the
system was heated in an oil-bath at 180 °C for 2.0 min to give 5
in good to excellent yields and short reaction times (Scheme 1).9b
* Corresponding author. Fax: +57 2 33392440.
E-mail address: jaiquir@univalle.edu.co (J. Quiroga).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.08.044

J. Quiroga et al. / Tetrahedron Letters 49 (2008) 6254–6256
6255
4
N
cludes this carbonyl for the nucleophilic addition, favoring so the
regioselectivity in the reaction.
The structures of new pyrazolo[1,5-a]pyrimidines were appro-
priately established by the usual spectroscopic methods. Single
crystal X-ray diffraction analysis of some selected compounds
was used to corroborate the postulated structures.13
3
NH2
NH
5
6
2
R
R
N
N
N
7
1
1a-h
fusion or
Ph
O
OH
R
N
MW, 2 min
+
5a-h
-H2O
O
N
N
O
O
Concluding, we have developed a simple, efficient, and versatile
one-step method for the synthesis of functionalized pyrazolo-
[1,5-a]pyrimidines 5a–h in a regiochemical manner by reaction
between aminopyrazole 1 with the chromenone 4. These com-
pounds present a privileged core from a biological point of view.
The reaction induced by microwave offered better yields than the
reaction carried out by heating in an oil-bath.
3
Ph
4
4'
HO
Ph
6
2
O1
4
Entry
5a
5b
5c
5d
5e
5f
R
Yield., %*
75/93
73/92
72/90
70/91
72/89
75/88
76/91
70/91
CH3
t-Bu
C6H5
4-CH3C6H4
Acknowledgments
4-CH3OC6H4
4-O2NC6H4
4-ClC6H4
Authors are grateful to COLCIENCIAS, to Universidad del Valle,
to Universidad de los Andes, to the Spanish ‘Consejería de Innova-
ción, Ciencia y Empresa, Junta de Andalucía’, and ‘Servicios Técni-
cos de la Universidad de Jaén’ for financial support.
5g
5h
4-BrC6H4
* Yield by fusion/MW
Scheme 2.
References and notes
1. Mukaiyama, H.; Nishimura, T.; Kobayashi, S.; Komatsu, Y. Bioorg. Med. Chem.
2008, 16, 909–921.
2. Huang, S.; Lin, R.; Yu, Y.; Lu, Y.; Connolly, P.; Chiu, G.; Li, S.; Emanuel, S.;
Middleton, S. Bioorg. Med. Chem. Lett. 2007, 17, 1243–1245.
3. Saggar, S.; Sisko, J.; Tucker, T.; Tynebor, R.; Su, D.; Anthony, N. U.S. Patent Appl.
US 2,007,021,442, 2007.
in good isolated yield (70–76%). In the second (Method B), the
reaction mixture was placed in an air open Pyrex-erlenmeyer flask
and the system was irradiated in a multimode microwave oven
during 2 min (at 600 W) to give 5 in excellent yield (88–93%).
The reactions were repeated in different domestic microwave
ovens to prove reproducibility, and no significant deviation was
found.
4. Zhang, P.; Pennell, M.; Wright, J.; Chen, W.; Leleti, M.; Li, Y.; Li, L.; Xu, Y. PCT Int.
Appl. WO 2007002293, Chemocentryx, U.S.A.
5. (a) Chiu, G.; Li, S.; Connolly, P.; Middleton, S.; Emanuel, S.; Huang, S.; Lin, R.; Lu,
Y. PCT Int. Appl. WO 2006130673, Janssen Pharmaceutica, N.V., Belgium; (b)
Dwyer, M.; Paruch, K.; Alvarez, C.; Doll, R.; Keertikar, K.; Duca, J.; Fischmann, T.;
Hruza, A.; Madison, V.; Lees, E.; Parry, D.; Seghezzi, W.; Sgambellone, N.;
Shanahan, F.; Wiswellb, D.; Guzia, T. Bioorg. Med. Chem. Lett. 2007, 17, 6216–
6219.
6. Feurer, A.; Luithle, J.; Wirtz, S.; Koenig, G.; Stasch, J.; Stahl, E.; Schreiber, R.;
Wunder, F.; Lang, D. PCT Int. Appl. WO 2004009589, Bayer Healthcare AG,
Germany.
7. (a) Demircali, A.; Karci, F. Dyes Pigments 2005, 64, 259–264; (b) Tsai, P. C.;
Wang, I. J. Dyes Pigments 2007, 74, 288–297; (c) Tsai, P. C.; Wang, I. J. Dyes
Pigments 2008, 76, 575–581.
8. (a) Elnagdi, M. H.; Elmoghayar, M. R. H.; Elgemeie, G. H. Adv. Heterocycl. Chem.
1987, 41, 319–376; (b) Quiroga, J.; Hormaza, A.; Insuasty, B.; Saitz, C.; Jullian,
C.; Canñete, A. J. Heterocycl. Chem. 1998, 35, 61–64; (c) El-Taweel, F.; Abu
Elmaati, T. J. Chin. Chem. Soc. 2002, 49, 1051–1055; (d) Daniels, R.; Kim, K.;
Lebois, E.; Muchalski, H.; Hughes, M.; Lindsley, C. Tetrahedron Lett. 2008, 49,
305–310.
9. (a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957–4980;
(b) Quiroga, J.; Portilla, J.; Abonía, R.; Insuasty, B.; Nogueras, M.; Cobo, J.
Tetrahedron Lett. 2007, 48, 6352–6355; (c) Quiroga, J.; Mejía, D.; Insuasty, B.;
Abonía, R.; Nogueras, M.; Sanchez, A.; Cobo, J. J. Heterocycl. Chem. 2002, 39, 51–
54.
10. (a) Basinski, W.; Jerzmanowska, Z. Pol. Med. Chem. 1983, 57, 471–474; (b)
Quiroga, J.; Rengifo, A.; Insuasty, B.; Abonía, R.; Nogueras, M.; Sánchez, A.
Tetrahedron Lett. 2002, 43, 9061–9063.
It is worthy of mentioning that the goodness and simplicity of
this process is due to the fact that these new compounds are iso-
lated in good yields as stable crystalline solids and easily purified
by recrystallization from ethanol. These reactions proceed in a
regioselective fashion, with no evidence of formation of the regio-
isomer derivatives 6; and the use of the 3-benzoyl-2-methyl-4H-
chromen-4-one 4 allows the introduction of polyfunctionality in
the pyrazolo[1,5-a]pyrimidines, such as the 2-hydroxybenzoyl
group.
Taking into account the reports of the literature,9,10 we have
postulated a route for the formation of pyrazolo[1,5-a]pyrimidines
5a–h. As initial stage, we assume a Michael-type nucleophilic
addition of NH2-group of amine 1 towards the C2 of compound
4, as explained above. The addition is followed with ring-opening
of the c-pyrone to give the intermediate A, which can then evolve
by cyclocondensation via attack of the nucleophilic nitrogen at the
pyrazole toward the carbonyl group of the benzoyl group to form
the isolated compounds 5 (Scheme 3).
It is quite evident that the last step of cyclocondensation occurs
with the participation of the carbonyl at benzoyl group (C40)
instead of carbonyl group at 2-hydroxybenzoyl (C4). The reason
is the electron releasing effect of the phenolic group which pre-
11. (a) Quiroga, J.; Cruz, S.; Insuasty, B.; Abonıía, R. Heterocycl. Commun. 2000, 6,
275–282; (b) Quiroga, J.; Cisneros, C.; Insuasty, B.; Abonía, R.; Nogueras, M.;
Sánchez, A. Tetrahedron Lett. 2001, 42, 5625–5627; (c) Quiroga, J.; Portilla, J.;
Insuasty, B.; Abonía, R.; Nogueras, M.; Sortino, M.; Zacchino, S. J. Heterocycl.
Chem. 2005, 42, 61–66; (d) Quiroga, J.; Cruz, S.; Insuasty, B.; Abonía, R.;
Nogueras, M.; Cobo, J. Tetrahedron Lett. 2006, 47, 27–30; (e) Quiroga, J.; Portilla,
J.; Serrano, H.; Abonía, R.; Insuasty, B.; Nogueras, M.; Cobo, J. Tetrahedron Lett.
2007, 48, 1987–1990.
R
6-(20-hydroxybenzoyl)-5-methyl-7-phenyl-pyrazolo[1,5-a]-
mixture of equimolar amounts of 5-amino-3-R-1H-
R
R
N
12. Preparation
pyrimidines 5a–h:
pyrazole
of
A
1
(10 mmol) and 3-benzoyl-2-methyl-4H-chromen-4-one 4 (2.64 g,
HN
N
NH2
H
N
H
N
O
10 mmol) was heated in an oil-bath at 180 °C for 2 min (Method A) or was
placed in an air open Pyrex-erlenmeyer flask, and the system was irradiated in
a multimode microwave oven during 2 min (at 600 W) (Method B). It was then
stirred and allowed to cool to room temperature till it solidified. The solid
material was treated with ethanol. After the solvent was removed by filtration,
the products formed were recrystallized from ethanol. Data for 6-(20-hydro-
xybenzoyl)-5-methyl-2-(4-methylphenyl)-7-phenylpyrazolo[1,5-a]pyrimidine 5d:
This compound was obtained according to general procedure as yellow
crystals. Mp 198–199 °C, yield 70/91%. IR (KBr) = 3423 cmꢀ1 (OH), 1698 cmꢀ1
(C@O), 1595 cmꢀ1 (C@N); 1H NMR (DMSO-d6, 400 MHz) d: 2.33 (s, 3H, p-CH3),
NH
N
O
N
fusion
or M W
Ph
1a-h
O
+
2
-H2O
5a-h
1O
4'
HO
A
3
Ph
4
2
3
Ph
4
4'
1
HO
HO
O
O
4
Scheme 3.

6256
J. Quiroga et al. / Tetrahedron Letters 49 (2008) 6254–6256
2.42 (s, 3H, 5-CH3), 6.76 (t, 1H, H-5Bz, J = 7.45 and 7.44 Hz), 6.83 (d, 1H, H-3Bz,
C6Bz, 138.6 CpR, 142.6 C7, 148.9 C3a, 155.1 C5, 155.7 C2, 159.8 C2Bz, 193.6
C@O; MS (70 eV) m/z (%): 419 (89, M+), 404 (19), 298 (42), 299 (100), 77 (19),
39 (29). HRMS: calcd for C27H21N3O2: m/z = 419.1634; found: 419.1639.
13. Portilla, J.; de la Torre, J.; Cobo, J.; Low, J.; Glidewell, C. Acta Crystallogr., Sect. E
2006, 62, 03195–03197.
J = 8.28 Hz), 7.21 (s, 1H, H-3), 7.25 (d, 2H, HmR, J = 7.86 Hz), 7.40 (m, 4H, HmPh,
H-4Bz and H-6Bz), 7.54 (m, 3H, HpPh and HoPh), 7.81 (d, 2H, HoR, J = 7.85 Hz),
10.95 (s, 1H, OH); 13C NMR (DMSO-d6, 100 MHz) d: 20.9 p-CH3, 23.2 5-CH3,
92.7 C3, 117.4 C3Bz, 119.4 C5Bz, 121.4 C6, 122.4 C1Bz, 126.1 CoR, 128.1 CmPh,
129.2 CiPh, 129.3 CmR, 129.6 CiR, 129.7 CoPh, 130.4 C4Bz, 131.8 CpPh, 136.5