A convenient synthesis of pyrazole-substituted heterocycles

Article abstract of DOI:10.3184/030823409X12608188070442

(E)-1-(5-Methyl-1-phenylpyrazol-4-yl)-3-(N,N-dimethylamino)-2-propen-1-one reacts with hydrazine, hydroxylamine, guanidine and aminopyrazole derivatives to afford the corresponding 3,4p-bipyrazole, pyrazolylisoxazole, pyrazolylpyrimidine and pyrazolo[1,5-a]pyrimidine derivatives, respectively. It reacts also with benzoquinone, naphthoquinone and N-benzoylglycine to give the corresponding benzofuran and pyrazolylpyranone derivatives, respectively.

Full text of DOI:10.3184/030823409X12608188070442

8
RESEARCH PAPER
JANUARY, 8–11
JOURNAL OF CHEMICAL RESEARCH 2010
A convenient synthesis of pyrazole-substituted heterocycles
Mohamed R. Shaaban, Taha M. A. Eldebss, Ahmed F. Darweesh and Ahmad M. Farag*
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
(E)-1-(5-Methyl-1-phenylpyrazol-4-yl)-3-(N,N-dimethylamino)-2-propen-1-one reacts with hydrazine, hydroxylamine, guanidine
and aminopyrazole derivatives to afford the corresponding 3,4p-bipyrazole, pyrazolylisoxazole, pyrazolylpyrimidine and
pyrazolo[1,5-a]pyrimidine derivatives, respectively. It reacts also with benzoquinone, naphthoquinone and N-benzoylglycine to
give the corresponding benzofuran and pyrazolylpyranone derivatives, respectively.
Keywords: 3,4p-bipyrazole, isoxazole, pyrimidine, pyrazolo[1,5-a]pyrimidine, benzofuran, pyranone
The pyrazole ring is a prominent structural motif found in
numerous pharmaceutically active compounds. Due to the
easy preparation and rich biological activity, the pyrazole
framework plays an essential role in many biologically active
compounds and therefore represents an interesting template
for combinatorial1–4 as well as medicinal chemistry.5–7 Indeed,
pyrazole-based derivatives have shown several biological
activities as seen in COX-2,5 p38 MAP kinase,6 and CDK2/
Cyclin A inhibitors.7 Many of them were tested and/or
evaluated in potential drug discovery.8–11
Our attention was focused on functionalised pyrazole scaf-
folds, which produce a variety of heterocyclic compounds.
Thus, (E)-1-(5-methyl-1-phenylpyrazol-4-yl)-3-(N,N-dimeth-
ylamino)-2-propen-1-one (2) was obtained from the reaction
of 4-acetyl-5-methyl-1-phenyl-1H-pyrazole (1) with N,
N-dimethylformamide dimethyl acetal (DMF-DMA) and
has recently been reported as a useful precursor for the
synthesis of many interesting heterocycles.12
In continuation of our interest in the synthesis of a variety
of pyrazole-based heterocyclic systems for biological evalua-
tion,13–15 we report here on the behaviour of the versatile enami-
none 2 towards some nitrogen nucleophiles, p-benzoquinone
and 1,4-naphthoquinone, as a facile and convenient route to
novel 3,4p-bipyrazole, pyrazolylisoxazole, pyrazolylpyri-
midine, pyrazolo[1,5-a]pyrimidines, pyrazolylbenzo- furan
and pyrazolylpyranone derivatives of anticipated biological
and pharmaceutical activities.
When compound 2 was treated with guanidine, it afforded
an excellent yield of a single product (as examined by TLC).
The reaction product was identified as 4-(5-methyl-1-phenyl-
1H-pyrazol-4-yl)pyrimidin-2-amine (5) on the basis of its
spectral data (see Experimental). Compounds 3, 4 and 5
are assumed to be formed via addition of the amino group
of hydrazines, hydroxylamine, and guanidine to the activated
ethylenic double bond of enaminone 2 followed by intra-
molecular cyclisation and elimination of water and
dimethylamine.
The behaviour of compound 2 towards some aminopyrazole
derivatives, as potential precursors for the interesting biologi-
cally active pyrazolo[1,5-a]pyrimidines, was also investigated.
Thus, when the enaminone 2 was treated with 5-amino-
1H-pyrazole derivatives 6a–c, in the presence of piperidine,
it afforded the pyrazolo[1,5-a]pyrimidine derivatives 8a–c via
the non-isolable intermediates 7a–c (Scheme 2). The struc-
tures of compounds 8a–c were established on the basis of their
elemental analyses and spectral data (see Experimental).
Benzofurans are widely distributed in nature and of estab-
lished biological activities,11 therefore, a novel route to
biologically interesting 5-hydroxy-3-aroylbenzofurans bear-
ing a substituted pyrazole moiety was investigated. Thus, it
was found that the enaminone 2 reacts readily with p-
benzoquinone in acetic acid at room temperature, yielding a
single product which was assigned as (5-hydroxybenzofuran-
3-yl)(5-methyl-1-phenyl-1H-pyrazol-4-yl)methanone (10).
The latter product was assumed to be formed via initial addi-
tion of the electron-rich moiety C2 in the enaminone 2 to the
activated electron-poor double bond system in the quinone
to afford the product 10 via the non-isolable intermediate 9.
In a similar manner, the enaminone 2 reacts with 1,4-
naphthoquinone to afford (5-hydroxynaphtho[1,2-b]furan-
3-yl)(5-methyl-1-phenyl-1H-pyrazol-4-yl) methanone (11)
(Scheme 3).
Results and discussion
Treatment of 1-(5-methyl-1-phenylpyrazol-4-yl)-3-(N,N-
dimethylamino)-2-propen-1-one (2) with hydrazine hydrate
and with phenylhydrazine in refluxing ethanol, led to the
formation of the novel 5p-methyl-1p-phenyl-1pH,2H-3,4p-
bipyrazole (3a) and 5p-methyl-1p,2-diphenyl-1pH,2H-3,4p-
bipyrazole (3b), respectively (Scheme 1).
Treatment of the enaminone 2 with N-benzoylglycine
(12) in refluxing acetic anhydride led to the formation of a
product that was assigned as 3-benzoylamino-6-(5-methyl-1-
phenylpyrazol-4-yl))-2H-pyran-2-one (15). The structure of
the latter product was established on the basis of its elemental
analysis and spectral data (see Experimental). Compound 15
is assumed to be formed via the reaction of the intermediate
oxazolone 13, which is formed in situ, with the enaminone
2, yielding the non-isolable intermediate 14, that further
rearranges into the corresponding pyranone derivative 15
(Scheme 4).
The IR spectra of the products 3a and 3b were free of
a carbonyl function. In addition, compound 3a exhibited an
1
absorption band at 3425 cm−1 due to a NH function. The H
NMR spectrum of the same compound revealed a singlet signal
at δ 2.61 due to methyl protons, two doublet signals at δ 6.46
and 7.70 (J = 2.33 Hz) due to pyrazole protons, a singlet signal
at δ 8.05 due to pyrazole-3H and D O-exchangeable signal at
δ 12.81 due to the NH proton, in2 addition to an aromatic
multiplet at δ 7.42–7.55.
In conclusion, we have investigated the synthetic potential
of (E)-1-(5-methyl-1-phenylpyrazol-4-yl)-3-(N,N-dimethyl-
amino)-2-propen-1-one (2) as a versatile, readily accessible
building block for the synthesis of new pyrazole-substituted
heterocyclic compounds of biological and pharmaceutical
importance.
Similarly, the enaminone 2 reacts with hydroxylamine,
to afford only one isolable product identified as 5-(5-methyl-
1
1-phenyl-1H-pyrazol-4-yl)isoxazole (4) (Scheme 1). The H
NMR spectrum of the latter product exhibited a singlet signal
at δ 2.51 due to methyl protons, two doublets at δ 6.68 and 8.61
(J = 1.23 Hz) due to two isoxazole protons, a singlet signal
at δ 8.12 due to a pyrazole-3H and an aromatic multiplet at
δ 7.50–7.58.
Experimental
All melting points were measured with a Gallenkamp apparatus. The
IR spectra were recorded of samples in KBr on a Shimadzu FT-IR
8101 PC IR spectrophotometer. 1H spectra were run at 300 MHz and
* Correspondent. E-mail: afarag49@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2010
9
Scheme 1
Scheme 2

10 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 3
Scheme 4
(M+). Found: C, 69.55 H, 5.44; N, 24.95%. C13H12N4 requires C,
69.62; H, 5.39; N, 24.98%.
13C spectra were run at 75.46 MHz in dimethyl sulfoxide (DMSO-d6).
Chemical shifts were related to that of the solvent. Mass spectra were
measured on a GCMS-QP1000 EX spectrometer at 70 eV. Elemental
analyses were carried out at the Microanalytical Center of Cairo
University, Giza, Egypt.
1-(5-Methyl-1-phenylpyrazol-4-yl)-3-(N,N-dimethylamino)-
2-propen-1-one (2)12 and aminopyrazoles 7a–c16–18 were prepared
following the literature procedures.
5p-Methyl-1p,2-diphenyl-1pH,2H-3,4p-bipyrazole (3b): Yield (74%);
m.p. 195–197 °C; IR (KBr) υmax/cm−1 1594 (C=N); 1H NMR (DMSO-
d ) δ 2.60 (s, 3H, CH ), 6.53 (d, 1H, J = 2.41 Hz, pyrazole-4-CH),
76.37–7.75 (m, 10H, Ar3H), 7.92 (d, 1H, J = 2.41 Hz, pyrazole-5-CH),
8.23 (s, 1H, pyrazole-3p-CH); MS, m/z 300 (M+). Found: C, 75.90; H,
5.41; N, 18.69. C H16N requires C, 75.98; H, 5.37; N, 18.65%.
5-(5-Methyl-1-1p9henyl4-1H-pyrazol-4-yl)isoxazole (4): A solution of
the enaminone 2 (2.55 g, 10 mmol) in ethanol (50 mL) was treated
with hydroxylamine hydrochloride (0.7 g, 10 mmol) in the presence
of ammonium acetate (1.5 g). The reaction mixture was heated under
reflux for 2 h. then poured into ice-cold water. The resulting solid
product was filtered off washed with water dried and recrystallised
from DMF. Yield (86%); m.p. 159–161 °C; IR (KBr) υmax/cm−1 1595
(C=N); 1H NMR (DMSO-d ) δ 2.51(s, 3H, CH3), 6.68 (d, 1H, J = 1.23,
isoxazole-4-CH), 7.50–7.568 (m, 5H, ArH), 8.12 (s, 1H, pyrazole-
3-CH), 8.61 (d, 1H, J = 1.23, isoxazole-3-CH); MS, m/z 225 (M+).
Found: C, 69.27; H, 4.96; N, 18.61%. C13H16N3O requires C, 69.32;
H, 4.92; N, 18.66%.
3,4p-Bipyrazole derivatives 3a, b; general procedure
Hydrazine hydrate (2 mL) or phenylhydrazine (1.5 mL), was added
to a stirred solution of the enaminone 2 (2.55g, 10 mmol) dissolved
in acetic acid (30 mL). Stirring was continued overnight at room
temperature for 12 h. The solid product was filtered off washed with
water dried and recrystallised from DMF.
5p-Methyl-1p-phenyl-1pH,2H-3,4p-bipyrazole (3a): Yield (78%); m.
p. 160–162 °C; IR (KBr) υmax/cm−1 3425 (NH), 1597 (C=N); 1H NMR
(DMSO-d ) δ 2.61 (s, 3H, CH3), 6.46 (d, 1H, J = 2.33 Hz, pyrazole-4-
CH), 7.426–7.55 (m, 5H, ArH), 7.70 (d, 1H, J = 2.33 Hz, pyrazole-
5-CH), 8.05 (s, 1H, pyrazole-3p-CH), 12.81 (s, 1H, NH); MS, m/z 224

JOURNAL OF CHEMICAL RESEARCH 2010 11
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine (5): To
a mixture of the enaminone 2 (0.51 g, 2 mmol) and guanidine nitrate
(2.3 mmol) in ethanol (30 mL), anhydrous potassium carbonate
(0.55 g, 4 mmol) was added. The resulting mixture was refl formed
solid products was collected by filtration, washed with water and
dried. Recrystallisation from DMF afforded 2-amino-4-(5-methyl-1-
phenyl-pyrazol-4-yl)pyrimidine (6). Yield (79%); m.p. 220–222°C;
IR (KBr) υ /cm−1 3471, 3286 (NH2), 1585 (C=N); 1H NMR (DMSO-
d6) δ 2.65 m(asx, 3H, CH3), 6.47(s, 2H, NH2), 6.88 (d, 1H, J = 5.4 Hz
pyrimidine-5-CH), 7.48–7.56 (m, 5H, ArH), 8.17 (s, 1H, pyrazole-3-
CH), 8.20 (d, 1H, J = 5.4 Hz pyrimidine-6-CH); 13CNMR δ 9.98,
93.73,104.74, 108.26, 124.12 125.16, 129.33, 139.71, 142.23, 155.48,
161.29, 164.39; MS, m/z 251(M+). Found: C, 66;98 H, 5;19 N, 27.79%.
C14H23N5 requires: C, 66.92 H, 5.21 N, 27.87%.
υ
/cm−1 3218 (OH), 1624 (C=O), 1594 (C=N); 1H NMR (DMSO-d6)
δm2ax.60 (s, 3H, CH3), 3.39 (s, 1H, OH), 7.54–8.37 (m, 10H, ArH), 8.91
(s, 1H, pyrazole-3-CH), 10.23 (s, 1H, furan-2-CH); MS, m/z 368 (M+).
Found: C, 74.95; H, 4.36; N, 7.57%. C23H16N2O3 requires C, 74.99;
H, 4.38; N, 7.60%.
N-(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-oxo-2H-pyran-3-yl)
benzamide (15): A solution of the enaminone 2 (2.55 g, 10 mmol) and
N-benzoylglycine (12) (1.7 g, 10 mmol) in acetic anhydride (50mL)
was heated under reflux for 2 h. The reaction mixture was concen-
trated in vacuo and the solid product obtained upon cooling was fil-
tered off washed with water and recrystallised from DMF. Yield
(85%); m.p. 288–290 °C; IR (KBr) υmax/cm−1 3406 (NH), 1699, 1672
1
(two C=O), 1561 (C=N); H NMR (DMSO-d ) δ 2.57 (s, 3H, CH ),
6.70 (d, 1H, J = 5.2 Hz, pyran-5-CH), 6.89 (d,61H, J = 5.2 Hz, pyra3n-
4-CH), 7.31–7.94 (m, 10H, ArH), 8.06 (s, 1H, pyrazole-3-CH), 9.69
(s, 1H, NH); 13C NMR δ 12.1, 101.35, 111.43, 113.64, 120.76, 125.22,
126.63, 127.54, 128.49, 129.25, 133.46, 134.99, 138.91, 140.02,
146.96, 151.28, 158.89, 166.30; MS, m/z 371 (M+). Found: C, 71.19;
H, 4.57; N, 11.26%. C22H17N3O3 requires C, 71.15; H, 4.61; N,
11.31%.
Pyrazolo[1,5-a]pyrimidine derivatives 8a–c; general procedure
To a mixture of the enaminone 2 (2.55 g, 10 mmol) and appropriate
aminopyrazole derivatives 6a–c (10 mmol) in absolute ethanol
(25 mL) and few drops of piperidine was refluxed for 3 h. The formed
solid product was filtered off washed with ethanol,dried and recrystal-
lised from ethanol/DMF to afford pyrazol[1,5-a]pyrimidine deriva-
tives 8a–c in 65-70% yield. The physical and spectra data of
compound 8a–c are listed below.
Received 2009; accepted 31 November 2009
Paper 090841 doi: 10.3184/030823409X12608188070442
Published online: 20 January 2010
7-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylpyrazolo[1,5-a]
pyrimidine (8a): Yield (70%); m.p. 216–218°C; IR (KBr) υmax/cm−1
1
1596 (C=N); H NMR (DMSO-d6) δ 2.57 (s, 3H, CH3), 7.14 (s, 1H,
pyrazole-3 CH), 7.30–8.57 (m, 13H, ArH); 13C NMR δ 11.98, 88.74,
93.73, 108.10, 122.26, 124.90, 125.25, 126.21, 127.53, 128.16,
129.33, 137.12, 138.90, 140.71, 142.23, 149.3, 152.48, 157.29; MS,
m/z 351 (M+). Found: C, 75.23; H, 4.81; N, 19.99%. C22H17N5 requires
C, 75.19; H, 4.88; N, 19.93%.
References
1
2
3
4
5
L.F. Tietze, A. Steinmetz and F. Balkenhohl, Bioorg. Med. Chem. Lett.,
1997, 7, 1303.
P. Brooking, A. Doran, P. Grimsey, N.W. Hird, W.S. MacLachlan and
M. Vimil, Tetrahedron Lett., 1999, 40, 1405.
P. Grosche, A. Holtzel, T. B. Walk, A.W. Trautwein and G. Jung, Synthesis,
1999, 1961.
S.P. Watson, R.D. Wilson, D.B. Judd and S.A Richards. Tetrahedron Lett.,
1997, 38, 9065.
T.D. Penning, J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W. Collins,
S. Docter, M.J. Graneto, L.F. Lee, J.W. Malecha, J.M. Miyashiro, R.S.
Rogers, D.J. Rogier, S.S. Yu, G.D. Anderson, E.G. Burton, J.N. Cogburn,
S.A. Gregory, C.M. Koboldt, W.E. Perkins, K. Seibert, A.W. Veenhuizen,
Y.Y. Zhang and P.C. Isakson, J. Med. Chem., 1997, 40, 1347.
J. Regan, S. Breitfelder, P. Cirillo, T. Gilmore, A.G. Graham, E. Hickey,
B. Klaus, J. Madwed, M. Moriak, N. Moss, C. Pargellis, S. Pav, A. Proto,
A. Swinamer, L. Tang and C. Torcellini, J. Med. Chem., 2002, 45, 2994.
P. Pevarello, M.G. Brasca, R. Amici, P. Orsini, G. Traquandi, L. Corti,
C. Piutti, P. Sansonna, M. Villa, B.S. Pierce, M. Pulici, P. Giordano, K.
Martina, E.L. Fritzen, R.A. Nugent, E. Casale, A. Cameron, M. Ciomei,
F. Roletto, A. Isacchi, G. Fogliatto, E. Pesenti, W. Pastori, A. Marsiglio,
K.L. Leach, P.M. Clare, F. Fiorentini, M. Varasi, A. Vulpetti and M.A.
Warpehoski, J. Med. Chem., 2004, 47, 3367.
2-Methyl-7-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-
a]pyrimidine (8b): Yield (76%); m.p. 202–204 °C; IR (KBr) υmax/cm−1
1
1594 (C=N); H NMR (DMSO-d6) δ 2.61 (s, 3H, CH3), 2.69 (s, 3H,
CH3), 7.01 (s, 1H, pyrazole-4-CH), 7.36–8.61 (m, 7H, ArH), 8.12
(s, 1H, pyrazole-3-CH); MS, m/z 289 (M+). Found: C, 70.52; H, 5.20;
N, 24.26%. C17H15N requires C, 70.57; H, 5.23; N, 24.21%.
3-Methyl-7-(5-m5ethyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylpyr-
azolo[1,5-a]pyrimidine (8c): Yield (68%); m.p. 226–228 °C; IR
1
(KBr) υ /cm−1 1596 (C=N); H NMR (DMSO-d ) δ 2.05 (s, 3H,
6
7
CH3), 2.m5a4x (s, 3H, CH3), 7.21–8.66 (m, 12H, ArH),68.16 (s, 1H, pyr-
azole-3-CH); MS, m/z 365 (M+). Found: C, 75.53; H, 5.21; N, 19.19%.
C23H19N5 requires C, 75.59; H, 5.24; N, 19.16%.
(5-Hydroxybenzo]furan-3-yl)(5-methyl-1-phenyl-1H-pyrazol-
4-yl)methanone (10) and (5-Hydroxynaphtho[1,2-b]furan-3-yl)
(5-methyl-1-phenyl-1H-pyrazol-4-yl)methanone
procedure
(11);
general
8
9
F. Popowycz, G. Fournet, C. Schneider, K. Bettayeb, Y. Ferandin,
C. Lamigeon, O.M. Tirado and B. Joseph, J. Med. Chem., 2009, 52, 655.
A.A.M. Eissa, N.A.H. Farag and G.A.H. Soliman, Bioorg. Med. Chem.,
2009, 17, 5059.
To a stirred solution of the enaminone 2 (2.55 g, 10 mmol) in acetic
acid (50 mL), each of p-benzoquinone or1,4-naphthoquinone
(10 mmol) was added and stirring continued at room temperature
for 12h. The reaction mixture was evaporated in vacuo, and the
solid product obtained was triturated with ethanol, filtered off, and
recrystallised from DMF to afford (5-hydroxybenzo]furan-3-yl)
(5-methyl-1-phenyl-1H-pyrazol-4-yl)methanone (10) and (5-
hydroxynaphtho[1,2-b]furan-3-yl)(5-methyl-1-phenyl-1H-pyrazol-4-
yl)methanone (11).
10 X. Li, L. Wang, L. Long, J. Xiao, Y. Hu and S. Li, Bioorg. Med. Chem.
Lett., 2009, 19, 4868.
11 N. Siddiqui, P. Alam and W. Ahsan, Arch. Pharm., 2009, 342, 173.
12 M. R. Shaaban, T.M.A. Eldebss, A.F. Darweesh and A.M. Farag,
J. Heterocycl. Chem., 2008, 45, 1739.
13 K.M. Dawood, E.A. Ragab and A.M. Farag, J. Chem. Res., 2009, 630.
14 A.M. Farag, A.S. Mayhoub, S.E. Barakat and A.H. Bayomi, Bioorg. Med.
Chem., 2008, 16, 4569.
15 A.M. Farag, A.S. Mayhoub, S.E. Barakat and A.H. Bayomi, Bioorg. Med.
Chem., 2008, 16, 881.
(5-Hydroxybenzo[1,2-a]furan-3-yl)(5-methyl-1-phenyl-1H-pyrazol-
4-yl)methanone (10): Yield (72%); m.p. 240–242°C; IR (KBr)
υ
/cm−1 3209 (OH), 1627 (C=O), 1596 (C=N); 1H NMR (DMSO-d6)
δm2ax.60 (s, 3H, CH3), 3.31 (s, 1H, OH), 6.87–8.38 (m, 8H, ArH), 8.78
(s, 1H, pyrazole-3-CH), 9.41 (s, 1H, furan-2-CH); MS, m/z 318 (M+).
Found: C, 71.64; H, 4.46; N, 8.85%. C19H14N2O3 requires C, 71.69;
H, 4.43; N, 8.80%.
16 A. Takamizawa and Y. Hamashima, Yakugaku Zasshi 1964, 84, 1113;
Chem. Abstr., 1965, 62, 5276.
17 M.H. Elnagdi, H.A. Elfahham, S.A.S. Ghozlan and G.E. Elgemeie,
J. Chem. Soc., Perkin Trans.1, 1982, 2663.
(5-Hydroxynaphtho[1,2-b]furan-3-yl)(5-methyl-1-phenyl-1H-pyr-
azol-4-yl)methanone (11): Yield (76%); m.p. 264–266 °C; IR (KBr)
18 M.H. Elnagdi, E.M. Kandeel, E.M. Zayed and Z.E. Kandeel, J. Heterocycl.
Chem., 1977, 14, 155.

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