Structural identification of pyrazoles and pyrimidines using 2D HMBC NMR and single-crystal X-ray diffraction

Article abstract of DOI:10.14233/ajchem.2015.19251

A facile and highly efficient microwave-assisted synthesis of functionalized pyrazoles and pyrimidines based on the regiospecific synthesis is reported. The present work provides unambiguous evidence of the pyrazoles was determined using 2D HMBC NMR. The structure for pyrimidine have been confirmed by single-crystal X-ray diffraction.

Full text of DOI:10.14233/ajchem.2015.19251

Asian Journal of Chemistry; Vol. 27, No. 12 (2015), 4611-4614
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.19251
Structural Identification of Pyrazoles and Pyrimidines Using
2D HMBC NMR and Single-Crystal X-Ray Diffraction
A.S. AL-BOGAMI
Department of Chemistry, Faculty of Science, University of Jeddah, P.O. Box 80327, Jeddah 21589, Saudi Arabia
Corresponding author: Tel: +966 554433416; E-mail: chem_org@hotmail.com
Received: 14 April 2015;
Accepted: 15 May 2015;
Published online: 29 August 2015;
AJC-17517
A facile and highly efficient microwave-assisted synthesis of functionalized pyrazoles and pyrimidines based on the regiospecific synthesis
is reported. The present work provides unambiguous evidence of the pyrazoles was determined using 2D HMBC NMR. The structure for
pyrimidine have been confirmed by single-crystal X-ray diffraction.
Keywords: Microwave irradiation, Isoniazid, Pyrazoles, Pyrimidines.
Chalcones 3a-d were prepared according to the litera-
ture13.
Synthesis of pyrazoles (5a-d): A mixture of chalcones
3a-d (1 mmol), isoniazid (4) (1mmol) and AcOH (5 mL) was
subjected to microwave heating for several minutes to afford
pyrazoles.
INTRODUCTION
Among the many heterocyclic compounds that have been
explored as potential pharmacologically active compounds,
pyrazoles are known to have chemotherapeutic effects and
function as antimicrobial1, antifungal2 and antiviral agents3.
Pyrazoles are an important class of five-membered heterocyclic
compounds and are widely found as the core structure in many
agrochemicals and pharmaceuticals. Recently, pyrazole synthesis
has been of interest because of their prevalence as scaffolds in
the syntheses of bioactive compounds. Pyrazole derivatives have
diverse biological activities4-7 and are known as anticarcinogens8.
Pyrimidines are also hetrocycles of interest because of their
antimicrobial9, antioxidant10, antiinflammatory11, antiallergic12
and anticancer10,13 activities.
The aim of the present study was to develop a facile and
highly efficient microwave-assisted synthesis of functionalized
pyrazoles and pyrimidines. The structures of the pyrazoles were
determined using two-dimensional heteronuclear multiple-
bond correlation nuclear magnetic resonance spectroscopy (2D
HMBC NMR), and those of the pyrimidines were determined
by X-ray crystallography.
(3-(4-Chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydro-
1H-pyrazolyl)(pyridin-4- yl)methanone (5a): m.p. 205-206
°C; IR (KBr, νmax, cm-1): 1642 (C=O), 1553 (C=N); 1H NMR
(400 MHz, CDCl3), δ: 3.10 (dd, 1HA), 3.66 (dd, 1HB), 5.70
(dd, 1HX) , 7.01-8.69 (m, 11H,ArH); 13C NMR δ: 41.33, 59.80,
123.21, 126.05 ,126.33, 126.90, 127.78, 128.11, 128.34,
128.70, 128.90, 132.91, 138.30, 142.46, 148.34, 148.50,
152.71, 164.33; MS: (%) 368 (M + 2, 75), 369 (M+, 80). Calcd.
for C19H14N3OSCl: C, 62.11; H, 2.82; N, 10.42; Found: C,
61.77; H, 2.71; N, 9.87.
[3-(4-Hydroxyphenyl)-5-(thiophen-2-yl)-4,5-dihydro-
1H-pyrazolyl](pyridin-4-yl)methanone (5b): m. p. 168-170
°C; IR (KBr, νmax, cm-1): 1660 (C=O), 1560 (C=N); 1H NMR
(400 MHz, CDCl3), δ: 3.12 (dd, HA), 3.55 (dd, 1HB), 5.68 (dd,
1HX), 7.01-8.69 (m.11H, ArH); 13C NMR δ: 42.31, 60.01,
122.96, 125.89, 126.30, 126.93, 127.81, 128.18, 128.44,
128.71, 128.93, 133.05, 137.50, 143.40, 147.80, 149.50,
153.88, 165.31; MS: (%) 349 (M+, 85). Calcd. for C19H15N3O2S:
C, 67.31; H, 3.33; N, 11.03; Found: C, 66.08; H,2.89; N, 10.88.
Pyridin-4-yl[5-(thiophen-2-yl)-3-p-tolyl-4,5-dihydro-
EXPERIMENTAL
The IR spectra were run on a Smart iTR 100. NMR spectra
were performed on Bruker 400 MHz. Mass spectra were
recorded on Thermo Scientific QuantumAccess. The elemental
compositions were determined on a on a EuroVector instrument.
Microwave experiments were performed using CEM Discover
(300 W). Single crystal X-ray analyses were performed using
Bruker APEX2 instrument.
1H-pyrazolyl]methanone (5c): m.p. 172-173 °C, IR (KBr,
1
ν
max, cm-1): 1662 (C=O), 1573 (C=N); H NMR (400 MHz,
CDCl3), δ: 2.30 (s, 3H, Me), 3.29 (dd, HA), 3.91(dd, HB), 5.21
(dd, HX), 7.01-8.69 (m.11H, ArH); 13C NMR δ: 44.30, 61.11,

4612 Al-Bogami
Asian J. Chem.
122.90, 125.77, 126.33, 126.90, 127.83, 128.92, 128.50,
128.78, 128.90, 133.15, 138.44, 142.54, 146.19, 149.88,
154.88, 166.33; MS: (%) 347 (M+, 90). Calcd. for C20H17 N3OS:
C, 69.13; H,4.94; N, 11.19; Found: C, 68.02; H, 4.85; N, 10.72.
[3-Phenyl-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-
RESULTS AND DISCUSSION
Chalcones (3a-d) for heterocyclic compounds synthesis
were prepared by base catalyzed condensation of 2-acetylthio-
phene ketone (1) with appropriately substituted benzaldehydes
(2). The synthetic routes to our prepared compounds are shown
in (Scheme-I, Table-1).
yl](pyridin-4-yl)methanone (5d): m.p. 183-185 °C; IR (KBr,
1
ν
max, cm-1): 1669 (C=O), 1560 (C=N); H NMR (400 MHz,
CDCl3), δ: 3.36 (dd, HA), 3.90 (dd, HB), 5.11 (1H, HX) , 7.01-
8.69 (m.12H,ArH); 13C NMR δ: 41.53, 60.20, 121.91, 124.79,
125.93, 126.91, 127.81, 128.92, 128.51, 128.78, 128.94,
132.16, 133.85, 139.43, 143.55, 146.43, 150.03, 154.59,
166.32; MS: (%) 333 (M+, 80). Calcd. for C19H15N3OS: C,
68.55; H, 2.53; N, 16.60; Found: C, 66.80; H, 2.18; N, 15.11.
Synthesis of pyrimidines (8a-d): A mixture of chalcones
3a-d (1 mmol), guanidine hydrochloride (7) (1 mmol) and
potassium hydroxide (4 mmol) in methanol (3 mL) was
subjected to microwave heating for several minutes to afford
pyrimidines.
TABLE-1
CHALCONES (3) DERIVATIVES
Compound
R
Cl
Yield (%)*
98
96
94
91
3a
3b
3c
3d
OH
CH3
H
*Isolated yield
Pyrazoles (5a-5d) were respectively obtained from the
reactions of each of chalcones (3a-3d) with isoniazid (4). These
reactions immediately cyclized to give a pyrazole ring under
microwave irradiation (Scheme-II, Table-2).
4-(4-Chlorophenyl)-6-(thiophen-2-yl)pyrimidin-2-
amine (8a): m.p. 164-165 °C; IR (KBr, νmax, cm-1): 3433 (NH2),
1451 (C=N); 1H NMR (400 MHz, CDCl3), δ: 7.03 (s, 2H, NH2),
7.93 (s, 1H, Hpyrimidin), 7.15-8.11 (m, 7HAr); 13C NMR δ: 94.17,
127.33, 127.65, 128.21, 128.83, 130.51, 132.52, 135.52,
137.19, 142.60, 159.54, 163.14, 164.50; MS (%): 289 (M+2,
28), 287 (M+, 80). Calcd. for C14H10N3SCl: C, 59.44; H, 2.50;
N, 15.55; Found: C, 58.43; H, 2.10; N,14.87.
TABLE-2
SYNTHESIS OF PYRAZOLES FROM ISONIAZID
Microwave
irradiation
Conventional
method
Compound
Time
Yield
(%)*
Time
(h)
Yield
(%)*
(min)
4-(4-Hydroxyphenyl)-6-(thiophen-2-yl)pyrimidin-2-
amine (8b): m.p. 139-140 °C; IR (KBr, νmax, cm-1): 3465 (NH2),
1455 (C=N), 1H NMR (400 MHz, CDCl3), δ: 7.11 (s, 2H, NH2),
7.89 (s, 1H, Hpyrimidin), 7.10-7.99 (m, 7HAr); 13C NMR δ: 93.54,
127.30, 127.55, 128.71, 128.82, 130.51, 132.42, 134.92,
136.29, 142.50, 158.94, 162.94, 164.53; MS: (%) 269 (M+,
95). Calcd. for C14H11N3OS: C, 62.98; H,3.11; N, 14.50; Found:
C, 62.18; H, 3.02; N, 13.17.
4-(Thiophen-2-yl)-6-p-tolylpyrimidin-2-amine (8c): m.p.
166-168 °C; IR (KBr, νmax, cm-1): 3454 (NH2), 1465 (C=N);
1H NMR (400 MHz, CDCl3), δ: 2.33 (s, 3H, Me), 7.01 (s,
2HAmine), 7.88 (s, 1H, Hpyrimidin), 7.31-8.09 (m, 7HAr); 13C NMR
δ: 93.50, 127.41, 127.57, 128.66, 128.92, 130.71, 132.92,
135.92, 136.31, 142.60, 159.84, 162.84, 165.02; MS (%): 267
(M+, 85). Calcd. % C15H13N3S: C, 68.67; H, 4.16; N, 14.72;
Found: C, 67.75; H, 4.11; N, 13.95.
7
79
4.0
46
5a
5b
5c
4
84
81
3.5
5.5
44
43
11
4-Phenyl-6-(thiophen-2-yl)pyrimidin-2-amine (8d): m.p.
208-210 °C; IR (KBr, νmax, cm-1): 3462 (NH2), 1445 (C=N);
1H NMR (400 MHz, CDCl3), δ: 7.03 (s, 2H, NH2), 8.05 (s,
1H, Hpyrimidin), 7.31-8.09 (m, 8HAr); 13C NMR δ: 94.70, 127.33,
127.67, 128.56, 128.81, 130.91, 133.80, 135.62, 136.21,
142.50, 160.74, 162.74, 164.02; MS: (%) 253 (M+, 90). Calcd.
% C14H11N3S: C, 69.65;H 3.53;N, 14.85; Found: C, 69.08; H,
3.16; N, 14.10.
5d
12
77
7.0
49
*Isolated yield
Scheme-I: Synthesis of chalcones (3a-d)

Vol. 27, No. 12 (2015)
Structural Identification of Pyrazoles and Pyrimidines 4613
Scheme-II: Regiospecific synthesis of pyrazoles (5a-d)
Based on the elemental analysis results and spectroscopic
data from the isolated products, the product could be one of
the two possible isomers 5 or 6 (Scheme-II). Scheme-II show
that the product may be one of the two possible isomers 5 or 6.
Through our research in previously studies14,15 for identical
reactions depends on 1D NMR spectroscopy, in our opinion
we cannot depend on 1D NMR to decide which isomer formed.
Therefore, we studied here facile and highly efficient 2D NMR
experiment to determine the structure of the isomer. The
present work provides unambiguous evidence of the obtained
pyrazoles on the basis of the long-range C-H connectivity’s
Pyrazole proton
20
40
60
(a)
(b)
80
100
120
140
160
8
6
4
2
0
ppm
via H-13C HMBC in which it used to study J and 3J corre-
lations between 13C and 1H, multiple bonds away that can shows
connectivity with through nuclei without attached protons.
Fig. 1a show the full spectrum of 1H-13C HMBC for isolated
product 5a or 6a, depend on the number of correlations between
the H-pyrazole toward carbons that are five and six bonds away
(Fig. 1b). Being of five correlations in 2D NMR spectrum of
the isolated product is prove conclusively for the proposed
structure 5a (Fig. 1c). Therefore, formation of pyrazole isomers
(5a-d) is assumed to be formed via the above green path
illustrated in Scheme-II.
1
2
Pyrazole proton
correlate to five
carbon atoms
20
40
60
80
100
120
140
160
(c)
Pyrimidine compounds (8a-8d) show the IR spectra
absorbance for amino group at about 3440 cm-1 and C=N at
1
1450 cm-1. Their H NMR spectra are characterized by the
presence of a singlet for two protons at about δ = 7.0 ppm is
assigned to the amino protons.The singlet for Hpyrimidin is observed
at about δ = 8.05 ppm (Scheme-III, Table-3).
Finally, the structure of products (8a-d) was ascertained
utilizing X-ray diffraction.
8
6
4
2
0
ppm
Fig. 1. (a) 2D-HMBC NMR of the compound 5a or 6a and assignment for
pyrazole proton (b) Number of correlations between pyrazole proton
toward carbons in the possible regiospecific products 5a and 6a;
(c) number of correlation between pyrazole proton and carbon atoms
Conclusion
A simple and efficient microwave irradiation protocol was
developed for the synthesis of pyrazoles and pyrimidines with

4614 Al-Bogami
Asian J. Chem.
Scheme-III: Synthesis of pyrimidines (8a-d)
TABLE-3
SYNTHESIS OF PYRIMIDINE FROM
GUANIDINE HYDROCHLORIDE
high yields and short reaction times. Structural identification
of the pyrazoles and pyrimidines was achieved using 2D
HMBC NMR and single-crystal X-ray diffraction.
Microwave
irradiation
Conventional
method
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*Isolated yield
Fig. 2. X-ray crystal structure of the compound 8b