Novel regiospecific method for synthesis of 2-(3,5-diaryl-4,5-dihydro-1H- pyrazol-1-yl)-4,6-diarylpyrimidines

Article abstract of DOI:10.1080/00397910701845555

The facile, regiospecific, one-pot synthesis of 2-(3,5-diaryl-4,5-dihydro- 1H-pyrazol-1-yl)-4,6-diarylpyrimidines derivatives has been described, involving a [3+2] and [3+3] cyclocondensation between the α,β-unsaturated ketones and aminoguanidine bicarbonate. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701845555

This article was downloaded by: [University Library Utrecht]
On: 22 July 2013, At: 19:13
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Novel Regiospecific Method for Synthesis of
2‐(3,5‐Diaryl‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)‐4,6‐dia
Ranjeet Bairwa a & Mariam S. Degani a
a Department of Pharmaceutical Sciences and Technology, Institute of
Chemical Technology, Mumbai University, Matunga, Mumbai, India
Published online: 22 Feb 2008.
To cite this article: Ranjeet Bairwa & Mariam S. Degani (2008) Novel Regiospecific Method for Synthesis
of 2‐(3,5‐Diaryl‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)‐4,6‐diarylpyrimidines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:6, 943-952, DOI:
10.1080/00397910701845555
To link to this article: http://dx.doi.org/10.1080/00397910701845555
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 38: 943–952, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845555
Novel Regiospecific Method for Synthesis of
2-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-1-yl)-
4,6-diarylpyrimidines
Ranjeet Bairwa and Mariam S. Degani
Department of Pharmaceutical Sciences and Technology, Institute of
Chemical Technology, Mumbai University, Matunga, Mumbai, India
Abstract: The facile, regiospecific, one-pot synthesis of 2-(3,5-diaryl-4,5-dihydro-1H-
pyrazol-1-yl)-4,6-diarylpyrimidines derivatives has been described, involving a [3 þ 2]
and [3 þ 3] cyclocondensation between the a,b-unsaturated ketones and aminoguani-
dine bicarbonate.
Keywords: aminoguanidine bicarbonate, 2-(pyrazol-1-yl)pyrimidines, a,b-unsatu-
rated ketones
INTRODUCTION
The structurally novel 2-(1H-pyrazol-1-yl)-pyrimidine derivatives have been
reported to have interesting bioactive profiles.[1–4] For example, 4-methoxy-
2-(5-methoxy-3-methyl-1H-pyrazol-1-yl)-6-methylpyrimidine (epirizole) is
a nonsteroidal anti-inflammatory and analgesic agent therapeutically used in
Japan.[5] Many analogs of 2-(1H-pyrazol-1-yl)-pyrimidine show potent inhi-
bition of HCl-ethanol-induced and water-immersion stress-induced ulcers in
rats.[6] Moreover, 2-(3,4,-diethyl-1-pyrazolyl)-pyrimidine and 2-(4,5-
dihydro-4-methyl-3-arylpyrazol-1-yl)-4,6-dimethylpyrimidines were found
to possess herbicidal and fungicidal activity.[3,7] It is pertinent to mention
that 1-(pyrimidin-2-yl)-3-pyrazolin-5-one derivatives such as 2-(4,5-
Received in India September 26, 2007
Address correspondence to Mariam S. Degani, Department of Pharmaceutical
Sciences and Technology, UICT, Matunga, Mumbai 400019, India. E-mail: msdegani@
udct.org
943

944
R. Bairwa and M. S. Degani
dimethyl-pyrazol-1-yl)-4-thioxo-6-methyl-4H-pyrimidine are associated with
cardiotonic activity with an ED50 value close to that of milrinone.[8]
Although the 2-(1H-pyrazol-1-yl)-pyrimidine core seems important for
imparting several biological properties, the scope in designing simple and
efficient synthetic routes still exists. The first synthesis of 2-(pyrazol-1-yl)pyr-
imidine was reported in 1963.[9] Later, many routes were described, but all
of them are fraught with difficulties and modest yields.[10–13] A one-
step method was reported in which cyclocondensation of 4-alkoxy-1,1,1-
trifluoro-3-alken-2-one and aminoguanidine bicarbonate was carried out
wherein 5-hydroxy-substituted 2-(5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)
pyrimidine derivatives were formed.[14]
The present work reports a regiospecific one-pot synthesis involving a
[3 þ 2] and [3 þ 3] cyclocondensation between a,b-unsaturated aromatic
ketones and aminoguanidine bicarbonate to obtain several novel 2-(3,5-
diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4,6-diarylpyrimidine derivatives in a
regiospecific manner.[15,16]
The a,b-unsaturated ketones (1a–k) were prepared according to literature
methods.[17–19] The advantage of using substituted a,b-unsaturated aromatic
ketones was that a wide variety of end products can be synthesized, as variations
can be made at both the aromatic rings of the ketones. Subsequent condensation
reactions of alcoholic solutions of a,b-unsaturated ketones (1a–k) with amino-
guanidine bicarbonate (2) gave 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4,6-
diarylpyrimidine derivatives (3a–k) (Scheme 1). Initially, experiments with a
variety of solvents including N,N-dimethyl formamide (DMF), dimethyl
sulfoxide (DMSO), and acetonitrile did not yield the product. Alcoholic
solvents were found to be suitable, with ethanol giving optimum yield. Other
salts of aminoguanidine including HCl and H2SO4 salts also did not give the
final products in a one-pot scheme, indicating that the slow release of free
base from the H2CO3 salt was required for the reaction. Addition of a
catalyst like Lewis acid did not yield product, whereas addition of sodium
acetate resulted in no substantial improvement of yields. Thus condensation
of alcoholic solutions of a,b-unsaturated ketones (1a–k) with aminoguanidine
Scheme 1.

2-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4,6-diarylpyrimidines
945
bicarbonate (2) in a simple one-pot reaction gave 2-(3,5-diaryl-4,5-dihydro-1H-
pyrazol-1-yl)-4,6-diarylpyrimidine derivatives (3a–k) (Scheme 1).
The versatility of this methodology was expanded with a number of a,b-
unsaturated ketones (1a–k) being used to prepare 2-(3,5-diaryl-4,5-dihydro-
1H-pyrazol-1-yl)-4,6-diarylpyrimidines (3a–k) (Table 1).
Although we have not yet established the mechanism of the cycloconden-
sation reaction between a,b-unsaturated ketones and aminoguanidine bicar-
bonate in an experimental manner, a possible explanation is proposed in
Scheme 2. It involves either a [3 þ 2] or [3 þ 3] cyclocondensation to give
intermediate I or II, respectively, which again undergoes [3 þ 3] or [3 þ 2]
cyclocondensation, leading to 4,5-dihydropyrimidine-pyrazoline (III).
Under alkaline conditions, the 4,5-dihydropyrimidine-pyrazoline undergoes
aromatization to form the final product, 3 (Scheme 2).
In conclusion, this regiospecific method of synthesis of 2-(3,5-diaryl-4,5-
dihydro-1H-pyrazol-1-yl)-4,6-diarylpyrimidines in one pot is simple and novel.
EXPERIMENTAL
The reagents and solvents were obtained from commercial sources. The
melting points of the compounds synthesized were uncorrected and were
recorded by the open glass capillary method on an Oswald Precision
melting-point apparatus. All the NMR spectra were recorded on a Jeol
Table 1. Yields and melting points of synthesized 2-(3,5-diaryl-4,5-dihydro-1H-pyr-
azol-1-yl)-4,6-diarylpyrimidines (3a–k)
Yield
(%)b
Compounda
Ar
Ar0
M.P. (8C)
3a
3b
3c
3d
3e
3f
Phenyl
4-Methoxyphenyl
Phenyl
4-Bromophenyl
4-Bromophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
45
40
45
42
47
55
46
42
32
33
48
226–228
234–236
235–238
254–255
240–242
225–228
214–216
207–209
230–232
239–241
242–244
4-Methoxyphenyl
3,4-Dimethoxy phenyl
Phenyl
3g
3h
3i
4-Methoxyphenyl
3,4-Dimethoxy phenyl
Phenyl
3j
3k
4-Methoxyphenyl
4-Chlorophenyl
aAll the synthesized 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4,6-diarylpyrimi-
dines were characterized spectroscopically (IR, 1H NMR, 13C NMR, MS, and
elemental analysis).
bYields indicate isolated yields after column chromatography.

946
R. Bairwa and M. S. Degani
Scheme 2. Proposed reaction mechanism of synthesis of 2-(3,5-diaryl-4,5-dihydro-
1H-pyrazol-1-yl)-4,6-diarylpyrimidines (3).
FT-NMR (1H NMR and 13C NMR at 300 MHz) in 5-mm sample tubes in
CDCl3 using TMS as internal reference. IR spectra were recorded on a
Perkin-Elmer Fourier transform infrared spectrometer or Buck Scientific
infrared spectroscopy M500 spectrophotometer using KBr-based pellets.
The CHN analysis was recorded on a Perkin-Elmer series 2–2400. Analytical
thin-layer chromatography (TLC) was carried out on precoated plates SiO2
(silica gel 60, F 254, Merck). SiO2 (Silica gel 60–80 mesh, Merck) was
used for column chromatography. Commercial reagents and solvents were
used without further purification unless stated. All the products gave
1
melting points and spectral (IR, H NMR, 13C NMR, MS, and elemental
analysis) data consistent with the assigned structures.
General Procedure for the Synthesis of 2-(3,5-Diaryl-4, 5-dihydro-
1H-pyrazol-1-yl)-4,6-diarylpyrimidines (3a–k)
A mixture of 1a–k (5 mmol) and aminoguanidine bicarbonate, 2 (3 mmol),
contained in a 50-ml, round-bottom flask was suspended in 30 ml of
ethanol, and the mixture was refluxed with stirring. The reaction was

2-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4,6-diarylpyrimidines
947
monitored by TLC and continued until the a,b-unsaturated ketone was
completely consumed or did not react further. The solvent was evaporated,
and the residue thus obtained was suspended in dichloromethane. The
insoluble part was filtered off, and the solvent was evaporated under
vacuum. The product thus obtained contained impurities (base spot) and
some amount of the starting material, and hence it was purified by silica-gel
column chromatography to obtain pyrazolyl-pyrimidine (3a–k) as the major
isolable product. The synthesized compounds were characterized using IR,
1H NMR, 13C NMR, and MS spectroscopy and elemental analysis.
Spectral Data of 2-(3,5-Diaryl-4, 5-dihydro-1H-pyrazol-1-yl)-4,6-
diarylpyrimidines
4-(4-Bromophenyl)-2-[3-(4-bromophenyl)-5-phenyl-4,5-dihydro-1H-
pyrazol-1-yl]- 6-phenylpyrimidine (3a)
Yield 45%; yellow solid; mp 226–2288C. IR (KBr): 3071.7, 2936.8,
1590.7, 1529.2, 1472.2, 808.0 cm21
;
1H NMR (300 MHz, CDCl3): d
2
3
(ppm) ¼ 3.23–3.15 (dd, JHH ¼ 17.4 Hz, JHH ¼ 6.0 Hz, 1H, pyrazoline
2
3
H-4 trans), 385–3.75 (dd, JHH ¼ 17.2 Hz, JHH ¼ 12.3 Hz, 1H, pyrazoline
H-4 cis), 5.83–5.77 (dd, 3JHH ¼ 12.3 Hz, 3JHH ¼ 6.0 Hz, 1H,
pyrazoline H-5), 7.17 (s, 1H, pyrimidine H-5), 7.91–7.24 (m, 18H, Ar); 13C
NMR (300 MHz, CDCl3): d ¼ 42.39 (C4-pyrazoline), 63.10 (C5-pyrazoline),
103.54 (C5-pyrimidine), 127.29, 127.36, 128.07, 128.51, 128.63, 128.78,
129.01, 130.02, 130.63, 131.73, 131.79, 131.94, 132.11, 136.61, 137.51
(Ar), 150.89 (C3-pyrazoline), 158.92, 164.48, 165.02 (C4-pyrimidine, C2-
pyrimidine, C6-pyrimidine); MS (ES þ 4.27e4): m/z (%) 608.32, 610.31
(100) [Mþ, 612.31. Anal. calcd. for C31H22Br2N4 (610.34): C, 61.10; H,
3.63; N, 9.18. Found: C, 61.00; H, 3.72; N, 9.20.
4-(4-Bromophenyl)-2-[3-(4-bromophenyl)-5-(4-methoxyphenyl)-4,5-
dihydro-1H-pyrazol-1-yl]-6-(4-methoxyphenyl)-pyrimidine (3b)
Yield 40%; yellow solid; mp 234–2368C. IR (KBr): 2978.3, 2916.0, 2853.8,
1
1586.3, 1539.2, 1243.9, 1005.2, 818 cm21; H NMR (300 MHz, CDCl3): d
2
3
(ppm) ¼ 3.31–3.26 (dd, JHH ¼ 17.2 Hz, JHH ¼5.5 Hz, 1H, pyrazoline
H-4 trans), 3.88–3.73 (m, 7H, OCH3 pyrazoline H-4 cis), 5.88–5.83 (dd,
3JHH ¼ 11.9 Hz, 3JHH ¼ 5.5 Hz, 1H, pyrazoline H-5), 7.26 (s, 1H, pyrimidine
H-5), 8.03–6.85 (m, 16H, Ar); 13C NMR (300 MHz, CDCl3): d ¼ 42.62

948
R. Bairwa and M. S. Degani
(C4-pyrazoline), 55.28, 55.43, (OCH3), 62.76 (C5-pyrazoline), 103.54
(C5-pyrimidine), 113.95, 114.03, 114.46, 119.90, 120.38, 127.78, 128.58,
128.82, 130.66, 135.47, 136.23, 136.62, 137.53, 159.03, 164.48 (Ar),
150.81 (C3-pyrazoline), 151.44, 156.54, 165.02 (C4-pyrimidine, C2-pyrimi-
dine, C6-pyrimidine). Anal. calcd. for C31H22Br2N4O2 (670.39): C, 59.12;
H, 3.91; N, 8.36. Found: C, 59.09; H, 3.83; N, 8.30.
4-(4-Chlorophenyl)-2-[3-(4-chlorophenyl)-5-phenyl-4,5-dihydro-1H-
pyrazol-1-yl]-6-phenyl pyrimidine (3c)
Yield 45%; yellow solid; mp 235–2388C. IR (KBr): 3033, 2932, 1572, 1530,
1
1476, 1563 cm21; H NMR (300 MHz, CDCl3): d (ppm) ¼ 3.22–3.15 (dd,
3
2JHH ¼ 17.1 Hz, JHH ¼5.7 Hz, 1H, pyrazoline H-4 trans), 3.84–3.75
2
3
(dd, JHH ¼17.1 Hz, JHH ¼12.1 Hz, 1H, pyrazoline H-4 cis), 5.83–5.77
3
3
(dd, JHH ¼ 12.1 Hz, JHH ¼ 5.5 Hz, 1H, pyrazoline H-5), 7.27 (s, 1H, pyri-
midine H-5), 7.90–7.19 (m, 18H, Ar); 13C NMR (300 MHz, CDCl3):
d ¼ 42.45 (C4-pyrazoline), 63.10 (C5-pyrazoline), 104.09 (C5-pyrimidine),
127.27 127.82, 128.07, 128.51, 128.55, 128.63, 128.78, 129.21, 131.19,
131.78, 131.79, 131.94, 132.11, 136.60, 137.40, 137.51, (Ar), 150.86 (C3-pyr-
azoline), 158.84, 164.48, 165.32 (C4-pyrimidine, C2-pyrimidine, C6-pyrimi-
dine). Anal. calcd. for C31H22Cl2N4 (521.44): C, 73.01; H, 4.25; N, 10.74.
Found: C, 73.00; H, 4.29; N, 10.70.
4-(4-Chlorophenyl)-2-[3-(4-chlorophenyl)-5-(4-methoxyphenyl)-4,5-
dihydro-1H-pyrazol-1-yl]-6-(4-methoxyphenyl)-pyrimidine (3d)
Yield 42%; yellow solid; mp 254–2558C. IR (KBr): 3016, 2955, 1533, 1475,
820 cm21
;
1H NMR (300 MHz, CDCl3): d (ppm) ¼ 3.27–3.19 (dd,
3
2JHH ¼ 17.1 Hz, JHH ¼ 5.4 Hz, 1H, pyrazoline H-4 trans), 3.87–3.76
3
(m, 7H, OCH3, pyrazoline H-4 cis), 5.87–5.81 (dd, JHH ¼ 12.0 Hz,
3JHH ¼ 5.4 Hz, 1H, pyrazoline H-5), 7.25 (s, 1H, pyrimidine H-5), 8.01–
6.84 (m, 16H, Ar); 13C NMR (300 MHz, CDCl3): d ¼ 42.44 (C4-pyrazoline),
56.02, 56.54, (OCH3) 63.07 (C5-pyrazoline), 104.00 (C5-pyrimidine), 117.82,
120.38, 125.85, 127.27, 127.84, 128.55, 128.62, 128.77, 130.62, 150.81,
135.43, 136.14, 136.02, 137.53, 143.41, 159.19, 164.39 (Ar), 150.81 (C3-pyr-
azoline), 151.19, 158.93, 165.92 (C4-pyrimidine, C2-pyrimidine, C6-pyrimi-
dine). Anal. calcd. for C33H26Cl2N4O2 (581.50): C, 68.16; H, 4.51; N, 9.64.
Found: C, 68.10; H, 4.45; N, 9.62.
4-(4-Chlorophenyl)-2-[3-(4-chororophenyl)-5-(3,4-dimethoxyphenyl)-
4,5-dihydro-1H-pyrazol-1-yl]-6-(3,4-dimethoxyphenyl) pyrimidine (3e)
Yield 47%; yellow solid; mp 240–2428C. IR (KBr): 3027, 3025, 2936, 1575,
1
1566, 1531 cm21; H NMR (300 MHz, CDCl3): d (ppm) ¼ 3.28–3.21 (dd,
3
2JHH ¼ 17.3 Hz, JHH ¼ 6.0 Hz, 1H, pyrazoline H-4 trans), 3.95–3.80

2-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4,6-diarylpyrimidines
949
3
(m, 13H, OCH3, pyrazoline H-4 cis), 5.88–5.82 (dd, JHH ¼ 12.5 Hz,
3JHH ¼ 6.0 Hz, 1H, pyrazoline H-5), 7.26 (s, 1H, pyrimidine H-5),
8.01–6.80 (m, 14H, Ar); 13C NMR (300 MHz, CDCl3): 42.62 (C4-pyrazo-
line), 53.63, 55.28, 55.40, 56.02, (OCH3), 62.76 (C5-pyrazoline), 103.54
(C5-pyrimidine), 110.27, 110.84, 111.35, 117.82, 120.38, 127.78, 128.58,
128.82, 149.42, 130.37, 130.66, 135.47, 136.23, 136.58, 149.18 (Ar),
150.81 (C3-pyrazoline), 151.44, 156.54, 159.03 (C4-pyrimidine, C2-pyrimi-
þ
dine, C6-pyrimidine); MS (ES þ 1.85e3): m/z (%) 641 (100) [M]
,
643.29. Anal. calcd. for C35H30Cl2N4O4 (641.54): C, 65.53; H, 4.71; N,
8.73. Found: C, 65.36; H, 4.66; N, 8.69.
4-(4-Fluorophenyl)-2-[3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-
pyrazol-1-yl]-6-phenylpyrimidine (3f)
Yield 55%; pale yellow solid; mp 225–2288C. IR (KBr): 3050.9, 2926.4,
1568.4, 1508.5, 1472.2, 1352 cm21
;
1H NMR (300 MHz, CDCl3): d
2
3
(ppm)¼ 3.31–3.23 (dd, JHH ¼ 17.3 Hz, JHH ¼5.7 Hz, 1H, pyrazoline H-4
2
3
trans), 3.92–3.82 (dd, JHH ¼17.1 Hz, JHH ¼12.0 Hz, 1H, pyrazoline H-4
3
3
cis), 5.89–5.84 (dd, JHH ¼ 11.5 Hz, JHH ¼ 5.4 Hz, 1H, pyrazoline H-5),
7.24 (s, 1H, pyrimidine H-5), 8.00–7.24 (m, 18H, Ar); 13C NMR
(300 MHz, CDCl3): d ¼ 42.60 (C4-pyrazoline), 63.07 (C5-pyrazoline),
104.00 (C5-pyrimidine), 114.03 114.46, 119.90, 125.85, 127.27, 127.84,
128.55, 128.65, 128.77, 130.62, 135.43, 136.14, 136.62, 137.53, 159.03,
164.39 (Ar), 150.81 (C3-pyrazoline), 156.54, 158.93, 165.39 (C4-pyrimidine,
C2-pyrimidine, C6-pyrimidine). Anal. calcd. for C31H22F2N4 (488.52): C,
76.21; H, 4.54; N, 11.47. Found: C, 76.21; H, 4.47; N, 11.35.
4-(4-Fluorophenyl)-2-[3-(4-fluorophenyl)-5-(4-methoxyphenyl)-4,5-
dihydro-1H-pyrazol-1-yl]-6-(4-methoxyphenyl) pyrimidine (3g)
Yield 46%; pale yellow solid; mp 214–2168C. IR (KBr): 3070.9, 2935.6,
1585.2, 1508, 1476.7, 1413.1 cm21
;
1H NMR (300 MHz, CDCl3): d
2
3
(ppm)¼ 3.28–3.20 (dd, JHH¼ 17.1 Hz, JHH ¼ 5.4 Hz, 1H, pyrazoline H-4
trans), 3.87–3.75 (m, 7H, OCH3, pyrazoline H-4 cis), 5.86–5.80 (dd,
3JHH ¼ 12.0 Hz, 3JHH ¼ 5.4 Hz, 1H, pyrazoline H-5), 7.25 (s, 1H, pyrimidine
H-5), 8.03–6.83 (m, 16H, Ar); 13C NMR (300 MHz, CDCl3): d¼ 42.30 (C4-
pyrazoline), 56.02, 56.07 (OCH3), 62.52 (C5-pyrazoline), 103.24 (C5-pyrimi-
dine), 111.34, 117.92, 120.29, 126.59, 127.22, 129.22, 129.30, 129.51, 130.84,
132.39, 135.14, 136.79, 148.10, 149.12, 158.70, 165.03 (Ar), 151.19 (C3-pyr-
azoline), 151.83, 159.19, 165.07 (C4-pyrimidine, C2-pyrimidine, C6-pyrimi-
dine); MS (ES þ 1.85e3): m/z (%) 549.31 (100) [M þ H]þ, 550.31. Anal.
calcd. for C33H26F2N4O2 (548.58): C, 72.25; H, 4.78; N, 10.21. Found: C,
72.30; H, 4.74; N, 10.18.

950
R. Bairwa and M. S. Degani
4-(3,4-Dimethoxyphenyl)-2-[5-(3,4-dimethoxyphenyl)-3-(4-
fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-6-(4-
fluorophenyl)pyrimidine (3h)
Yield 42%; pale yellow solid; mp 207–2098C. IR (KBr): 3058.9, 2967.9,
1
1570, 1529.2, 1472, 1399.5 cm21; H NMR (300 MHz, CDCl3): d (ppm)¼
2
3
3.28–3.20 (dd, JHH ¼ 17.4 Hz, JHH ¼ 6.3 Hz, 1H, pyrazoline H-4 trans),
3.95–3.80 (m, 13H, OCH3, pyrazoline H-4 cis), 5.88–5.82 (dd,
3JHH ¼ 12.6 Hz, 3JHH ¼ 6.3 Hz, 1H, pyrazoline H-5), 7.26 (s, 1H, pyrimidine
H-5), 8.01–6.80 (m, 14H, Ar); 13C NMR (300 MHz, CDCl3): d ¼ 42.81 (C4-
pyrazoline), 53.63, 55.28, 56.02, 56.07, (OCH3) 62.52 (C5-pyrazoline),
103.24 (C5-pyrimidine), 117.92, 120.29, 126.59, 127.22, 129.22, 129.30,
129.51, 130.84, 135.14, 136.79, 139.66, 140.64, 148.10, 149.12, 149.32,
165.00 (Ar), 151.19 (C3-pyrazoline), 151.83, 159.19, 165.37 (C4-pyrimidine,
C2-pyrimidine, C6-pyrimidine). Anal. calcd. for C35H30F2N4O4 (608.63): C,
69.07; H, 4.97; N, 9.21. Found: C, 69.10; H, 4.87; N, 9.16.
4-(4-Methoxyphenyl)-2-[3-(4-methoxyphenyl)-5-phenyl-4,5-dihydro-
1H-pyrazol-1-yl]-6-phenylpyrimidine (3i)
Yield 32%; yellow solid; mp 230–2328C. IR (KBr): 3061.3, 2926.4, 1581.1,
1529.2, 1467, 1342 cm21
;
1H NMR (300 MHz, CDCl3):
d
2
3
(ppm) ¼ 3.28–3.20 (dd, JHH ¼ 17.4 Hz, JHH ¼ 5.4 Hz, 1H, pyrazoline
H-4 trans), 3.87–3.75 (m, 7H, OCH3, pyrazoline H-4 cis), 5.86–5.80 (dd,
3JHH ¼ 12.0 Hz, 3JHH ¼ 5.1 Hz, 1H, pyrazoline H-5), 7.22 (s, 1H, pyrimidine
H-5), 8.03–6.83 (m, 16H, Ar); 13C NMR (300 MHz, CDCl3): d ¼ 42.60 (C4-
pyrazoline), 55.28, 55.40, (OCH3), 62.26 (C5-pyrazoline), 103.33 (C5-pyrimi-
dine), 114.03, 114.46, 119.90, 126.64, 127.22, 127.29, 128.47, 128.56, 128.82,
129.41, 130.31, 132.39, 136.02, 138.01, 158.77, 160.07, (Ar-C), 151.63
(C3-pyrazoline), 151.83, 161.69, 165.37 (C4-pyrimidine, C2-pyrimidine,
C6-pyrimidine). Anal. calcd. for C33H28N4O2 (512.60): C, 77.32; H, 5.51;
N, 10.93, Found: C, 77.21; H, 5.60; N, 10.83.
2-[3,5-Bis-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]-4,6-bis-
(4-methoxy-phenyl) pyrimidine (3j)
Yield 33%; yellow solid; mp 239–2418C. IR (KBr): 3009.4, 2905.7, 2833.0,
1565.6, 1534.4, 1477.4, 1238.7, 1031.1 cm21; 1H NMR (300 MHz, CDCl3): d
(ppm) ¼ 3.29–3.22 (dd, 2JHH ¼ 17.4 Hz, 3JHH ¼ 5.7 Hz, 1H, pyrazoline H-4
trans), 3.94–3.80 (m, 13H, OCH3, pyrazoline H-4 cis), 5.86–5.80 (dd,
3JHH ¼ 12.2 Hz, 3JHH ¼ 5.7 Hz, 1H, pyrazoline H-5), 7.22(s, 1H, pyrimidine
H-5), 7.97–6.79 (m, 16H, Ar); 13C NMR (300 MHz, CDCl3): d ¼ 42.66 (C4-
pyrazoline), 55.28, 55.38, 56.02, 56.07, (OCH3) 62.14 (C5-pyrazoline),
102.89 (C5-pyrimidine), 113.90, 113.98, 126.62, 127.18, 127.22, 128.79,
129.18, 129.26, 129.63, 130.45, 135.20, 136.21, 139.53, 140.51, 159.05,

2-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4,6-diarylpyrimidines
951
164.92, (Ar-C), 151.61 (C3-pyrazoline), 158.71, 161.59, 165.24 (C4-pyrimi-
dine, C2-pyrimidine, C6-pyrimidine). Anal. calcd. for C35H32N4O4 (572.65):
C, 73.41; H, 5.63; N, 9.78. Found: C, 73.35; H, 5.69; N, 9.74.
4-(4-Chlorophenyl)-2-[5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-
dihydro-1H-pyrazol-1-yl]-6-(4-methoxyphenyl)-pyrimidine (3k)
Yield 48%; yellow solid; mp 242–2448C. IR (KBr): 3016, 2955, 1533, 1475,
820 cm21
;
1H NMR (300 MHz, CDCl3): d (ppm)¼ 3.31–3.23 (dd,
3
3JHH ¼ 17.3 Hz, JHH ¼ 5.4 Hz, 1H, pyrazoline H-4 trans), 3.88–3.73
3
(m, 7H, OCH3, pyrazoline H-4 cis), 5.89–5.83 (dd, JHH ¼ 12.0 Hz,
3JHH ¼ 5.4 Hz, 1H, pyrazoline H-5), 7.26 (s, 1H, pyrimidine H-5), 8.04–
6.85 (m, 16H, Ar); 13C NMR (300 MHz, CDCl3): d ¼ 42.44 (C4-pyrazoline),
56.02, 56.54, (OCH3), 63.11 (C5-pyrazoline), 104.00 (C5-pyrimidine),
117.82, 120.38, 125.92, 127.29, 127.81, 128.66, 128.64, 128.77, 130.65,
135.43, 136.14, 136.02, 137.53, 143.41, 159.19, 164.26, (Ar-C), 150.80
(C3-pyrazoline), 151.19, 158.93, 165.90 (C4-pyrimidine, C2-pyrimidine,
C6-pyrimidine). Anal. calcd. for C33H26Cl2N4O2 (581.49): C, 68.16; H,
4.51; N, 9.64. Found: C, 68.12; H, 4.41; N, 9.52.
ACKNOWLEDGEMENT
The authors thank M. K. Gurjar, deputy director and head of the Division of
Organic Chemistry Technology, National Chemical Laboratory, Pune, and
S. Joshi, vice president, R&D Synthetics, FDC Ltd., Mumbai, for their
valuable suggestions. Ranjeet Bairwa thanks the Institute of Science,
Mumbai, India, for recording 1H NMR and 13C NMR, and UGC, New
Delhi, for financial support.
REFERENCES
1. Naito, T.; Yoshikawa, T.; Kitahara, S. I.; Aoki, N. E. Studies on pyrimidinylpyr-
azoles, I: Syntheses of 1-and 2-pyrimidinyl-3-methylpyrazolin-5-one derivatives.
Chem. Pharm. Bull. 1969, 17, 1467.
2. (a) Konish, K.; Kuragano, T. Nippon Noyaku Gakkaishi 1990, 15, 13; (b) Chem.
Abstr. 1990, 113, 36297.
3. (a) Konish, K.; Kuragano, T.; Matsura, K. Jpn. Kokai Tokkyo Koho JP 6 1987, 200,
404; (b) Chem. Abstr. 1987, 106, 171125.
4. Oshima, Y.; Akimoto, T.; Tsukada, W.; Yamasaki, T.; Yamaguchi, K.; Kojima, H.
Studies on pyrimidinylpyrazoles, IV: Pharmacological activities of 1-(4-methoxy-
6-methyl-2-pyrimidinyl)-3-methyl-5-methoxypyrazole and its related compounds.
Chem. Pharm. Bull. 1969, 17, 1492.

952
R. Bairwa and M. S. Degani
5. Ikeda, M.; Maruyama, K.; Nobuhara, Y.; Yamada, T.; Okabe, S. Synthesis and
cytoprotective antiulcer activity of 2- or 4-(1H-pyrazol-1-yl)pyrimidine deriva-
tives related to mepirizole and dulcerozine. Chem. Pharm. Bull. 1996, 44, 1700.
6. Ikeda, M.; Maruyama, K.; Nobuhara, Y.; Yamada, T.; Okabe, S. Cytoprotective
effects of 4,6-bis(1H-pyrazol-1-yl)pyrimidine and related compounds on HCI-
ethanol-induced gastric lesions in rats. Chem. Pharm. Bull. 1997, 45, 549.
7. Chang, Z. Y.; Hanagan, M. A.; Selby, T. P.; Frasier, D. A. Preparation of
pyrazoles, pyrazolines and tetrahydropyridazines as agrochemical fungicides.
PCT Int. Appl. US1992/003103, 2004.
8. Sedereviciute, V.; Garaliene, V.; Vainilavicius, P.; Hetzheim, A. Synthese und kar-
¨
diotone Aktivitat von Pyrazolylpyrimidinen (Synthesis and cardiotonic activity of
pyrazolylpyrimidines). Pharmazie 1998, 33, 349.
9. (a) Shirakava, K.; Tsujikawa, T. Takeda Kenkyusho Nempo 1963, 22, 19;
(b) Chem. Abstr. 1964, 55, 10450.
10. Badawey, E.-S. A. M. Synthesis and in vitro evaluation of some new pyrimidines
and related condensed ring systems as potential anticancer agents. J. Heterocycl.
Chem. 1996, 33, 229.
11. Zanatta, N.; Flores, D. C.; Madruga, C. C.; Faoro, D.; Flores, A. F. C.;
Bonacorso, H. G.; Martins, M. A. P. Regiospecific cyclization of 4-alkoxyvinyl tri-
fluoro[chloro]methyl ketones with 6-trifluoro[chloro]methyl-2-hydrazine pyrimi-
dines: A convenient method to obtain trifluoro[chloro]methylated 2-(5-hydroxy-
5-trifluoro[chloro]methyl-4,5-dihydro1H-pyrazol-1-yl]-pyrimidines.
2003, 894–898.
Synthesis
12. Bonacorso, H. G.; Martins, M. A. P.; Marcos, A. P. M.; Zanatta, N.; Flores, A. F. C.
Synthesis of alkyl-, aryl- and heteroaryl-substituted 2-[3-oxo-2,3-dihydro-1H-
pyrazol-2-yl]-6(4)-trifluoromethylpyrimidines from b-alkoxyvinyl trifluoromethyl
ketones. Synthesis 2005, 809–813.
13. Flores, D. C.; Fissa, F. G.; Wbatuba, S. L.; Martins, M. A. P.; Burrow, R. A.;
Flores, A. F. C. Synthesis of new 2-(5-aryl-3-styryl-4,5-dihydro-1H-pyrazol-1-
yl)-4-(trifluoromethyl)pyrimidines. Synthesis 2006, 2349–2356.
14. Bonacorso, H. G.; Wentz, A. P.; Zanatta, N.; Martins, M. A. P. Regiospecific cycli-
zation of b-methoxyvinyl trifluoromethyl ketones with aminoguanidine: A con-
venient method to obtain trifluoromethylated 2-[1H-pyrazol-1-yl]pyrimidines.
Synthesis 2001, 10, 1505–1508.
15. Alan, R. K.; Mingyi, W.; Suoming, Z.; Michael, V. V. Regioselective synthesis of
polysubstituted pyrazoles and isoxazoles. J. Org. Chem. 2001, 66, 6787–6791.
16. Vimesh, M. P.; Kishor, R. D. Eco-friendly synthesis of fluorine-containing pyrazo-
line derivatives over potassium carbonate. Arkivoc 2004 (1), 123–129.
17. Robert, E. L.; Leo, P. P. Acid-catalyzed condensations. II. The condensation of
benzaldehyde with substituted acetophenones. J. Am. Chem. Soc. 1955, 77,
6667–6668.
18. Babu, G.; Perumal, P. T. Convenient synthesis of a,a-1-bis (substituted furfuryli-
dene) cycloalkanones and chalcones under microwave irradiation. Synth.
Commun. 1997, 27, 3677–3682.
19. Huang, D.; Wang, J.; Zhang, Y.; Tang, J. A new solvent-free synthesis of a,b-
unsaturated ketones from acetals with aryl ketones under microwave irradiation.
Synthetic Communications 2002, 32 (7), 971–979.