A Convenient Synthesis of Pyrazole-imidazoline Derivatives by Microwave Irradiation

Article abstract of DOI:10.1002/jhet.3557

A series of 28 hybrids pyrazole-imidazolines 1a–n and 2a–n were synthesized by a new methodology using microwave irradiation, in short time (20–30?min), in low power (50–70?W), and in 34–92% yield. Among all methodologies evaluated, no side products were obtained. All derivatives were completely characterized by FT–IR, ¹H and ¹³C NMR, GC–MS, and HRMS.

Full text of DOI:10.1002/jhet.3557

Month 2019
A Convenient Synthesis of Pyrazole-imidazoline Derivatives by
Microwave Irradiation
*
Cynthia N. Pereira, Bruna C. Teixeira, and Maurício S. dos Santos
Getúlio de S. Rosa, Bernardo A. Souto,
Laboratório de Síntese Orgânica (LABSINTO), Instituto de Física e Química, Universidade Federal de Itajubá, 1303 BPS
Avenue, Itajubá-, MG 37500-903, Brazil
*E-mail: mauriciosantos@unifei.edu.br
Received October 19, 2018
DOI 10.1002/jhet.3557
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A series of 28 hybrids pyrazole-imidazolines 1a–n and 2a–n were synthesized by a new methodology
using microwave irradiation, in short time (20–30 min), in low power (50–70 W), and in 34–92% yield.
Among all methodologies evaluated, no side products were obtained. All derivatives were completely char-
1
acterized by FT–IR, H and 13C NMR, GC–MS, and HRMS.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
expensive reagents, toxic metals, long time reaction, and
poor yields.
Pyrazole is a five-membered heterocycle ring widely
found in a large variety of compounds that possess
important biological activities, such as antileishmanial,
analgesic, anti-inflammatory, antibacterial, antifungal,
antitumoral, and antiviral [1–6]. Because of the wide
range of applications involving compounds containing
pyrazole moiety, many publications concerning
methodologies to obtain this heterocycle have been
reported [7–9]. Most of them are based on two classical
methods: Knorr’s and Pechmann’s syntheses [10,11].
On the other hand, 2-imidazoline ring, an azole
derivative from imidazole, also named as cyclic amidine,
is of considerable importance because the derivatives
have been employed against several diseases, such as
hyperglycemia, hypertension, and cancer [12–15]. The
main synthetic route to 2-imidazoline formation is based
on cyclization from nitriles and ethylenediamine (EDA)
with different catalysts, solvents, and reaction conditions
[16–19]. There are some reports showing carboxylic
acids [20], amides [21], and esters [22] as raw materials
instead of nitriles. Many of these protocols have some
disadvantages, such as the use of strong Lewis acid,
In the last 8 years, few papers related to new synthetic
methodologies to obtain 2-imidazoline were published.
Zhow et al. synthesized 14 2-imidazolines from olefins,
amines, NBS, and acetonitrile as solvent, with reaction
time from 4 to 16 h, in 45–99% yield [23]. Wróbel and
colleagues obtained six new 2-imidazoline derivatives
using
N1-(4-nitrophenyl)ethylenediamine,
cyanogen
bromide (Br─CN), isopropanol, and six substituted
isocyanates. The global reaction time was approximately
3.5 h, and the yields were not cited on the paper [24]. A
series of six novel hybrids benzofuran/2-imidazoline was
reported by Giorgioni et al. from esters, EDA derivatives,
NaH (in mineral oil), trimethylaluminum as catalyst and
inert atmosphere. The reaction time was approximately
12h, andthecompoundswereisolatedin40–58%yield[25].
Microwave irradiation is an important technique to
access many functional groups, including heterocyclic
systems [26]. Zhang et al. reported the synthesis of 2-
imidazolines from the reaction of aromatic nitriles with
EDA or N-(2-aminoethyl)ethanolamine, using cupric
indole-3-acetate (Cu (II)-(IAA)2) as catalyst under
microwave irradiation, in good to excellent yields
© 2019 Wiley Periodicals, Inc.

G. d. S. Rosa, B. A. Souto, C. N. Pereira, B. C. Teixeira, and M. S. dos Santos
Vol 000
(79–94%) and reaction time from 5 to 20 min. The power
applied was very high: 1000 W [27]. De La Hoz and
coworkers obtained seven compounds containing 2-
imidazoline linked to pyrazole, imidazole, and benzene
rings, under microwave irradiation. They used nitriles,
EDA, and elemental sulfur under solvent-free conditions.
The power was 30 W, during 3 to 30 min, in 18–98%
yields [28].
yields as well: 68–92%. Both methodologies have been
reported by our research group previously [29,30].
Finally, the targets 1a–n and 2a–n were obtained from
4a–n and 3a–n, respectively, EDA, CS2 under mild
conditions employing microwave irradiation, in 44–92%
and 34–84% yields, respectively, and they are shown in
Table 1. The structures could be assigned on the basis of
1
its Fourier transform infrared (FT–IR), H and 13C NMR
Our research group have synthesized pyrazoles
containing 2-imidazoline moiety using carbon disulfide
(CS2) and EDA, under reflux, with a long reaction time
(14–15 h), in moderate to good yields (65–77%) [29].
In search for new methodologies to obtain 2-
imidazolines, in better yields, shorter reaction time, and
milder reaction conditions, we planned to synthesize 1-
aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles 1a–n
and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-
pyrazoles 2a–n, from key intermediates 1-aryl-1H-
pyrazole-4-carbonitriles 3a–n and 5-amino-1-aryl-1H-
spectra, and high-resolution mass spectrometry (HRMS)
data.
We investigated the influence of CS2 and EDA in the
reaction. The optimal reaction conditions with regard to
reagents quantities were 2.0 mL of EDA and 4 mmol of
CS2 for each mmol of 3a–n and 4a–n, raw materials to
synthesize 1a–n and 2a–n, respectively. The power was
also optimized. For the synthesis of 1a–n, the best results
were obtained when 50 W, a very low power, was
employed. After 10 min, the thin layer chromatography
(TLC) analysis showed that the reactions had not been
completed yet. However, the corresponding raw material
3a–n was not identified by TLC after 20 min. In an
attempt to evaluate the influence of the power, a new
procedure increasing the power to 70 W was made, but
the reaction time did not reduce, and no side products
were identified by TLC and gas chromatography coupled
to mass spectrometry. To synthesize 2a–n, first of all we
used 50 W, but a long time reaction was required. So a
little higher power, 70 W, was enough to complete the
reaction in 30 min. Samples were collected to accompany
the reaction by TLC as well as in the reaction to obtain
1a–n.
pyrazole-4-carbonitriles
4a–n,
respectively,
by
microwave irradiation. The compounds 1a–d,g–i and
2a–d,g–i are reported for the first time. The synthesis of
the compounds is summarized in Scheme 1.
Results and Discussion. We have synthesized the key
intermediates 4a–n starting from commercially available
arylhydrazine hydrochlorides 5a–n. First of all, 5a–n were
converted to the unprotonated arylhydrazines by treatment
with sodium acetate in ethanol, under reflux, for 20 min.
After that, ethoxymethylenemalononitrile was added to
give the corresponding 4a–n, after 1 h, in good to excellent
yields: 70–93%. The aprotic deamination of 4a–n with t-
butyl nitrite and tetrahydrofuran, under reflux for 2 h,
afforded the desired compounds 3a–n in good to excellent
A characteristic band in 1620 cmÀ1 approximately was
revealed using FT–IR spectra, attributed to C═N
stretching of imidazoline ring. It was not observed any
absorption band in the 2200 cmÀ1 region related to nitrile
group. The 1H NMR spectra of 1a–n showed two
singlets at 7.98–8.16 ppm and 8.31–8.99 corresponding
Scheme 1. Synthetic route to obtain the compounds 1(a–n) and 2(a–n).
Reagents and conditions: (i) sodium acetate, ethanol, 20 min, reflux; (ii)
ethoxymethylenemalononitrile, 1 h, reflux; (iii) t-butyl nitrite, THF, 2 h,
reflux; (iv) ethylenediamine, CS2, MW irradiation (50 W), 20 min; (v)
ethylenediamine, CS2, MW irradiation (70 W), 30 min.
Table 1
Isolated yields of 1a–n and 2a–n.
R
Product
Yield (%)
Product
Yield (%)
3-Cl-4-CH3
4-Cl-2-CH3
2,4-diCl
2,6-diCl
3,4-diCl
3,5-diCl
4-OCH3
4-F
4-Cl
4-Br
3-F
3-Cl
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
92
45
70
76
79
80
57
87
78
65
55
47
61
44
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
79
76
53
34
71
83
50
66
42
84
67
74
47
55
3-Br
H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
A Convenient Synthesis of Pyrazole-imidazoline Derivatives by Microwave
Irradiation
to pyrazole protons, while only one singlet at 7.64–
7.76 ppm was identified for 2a–n. The phenyl protons
were assigned according to standard coupling/integration
expected. The presence of just one signal for two CH2
groups at 3.55–3.58 and 3.49–3.65 ppm for 1a–n and
2a–n, respectively, indicates the prototropic tautomerism
in the imidazoline ring. It is important to highlight that
all NMR spectra for 1a–n were recorded in DMSO-d6,
while for 2a–n, either in DMSO-d6 (2a–f,k) or MeOH-d4
(2g–j,l–n), which explain the wide range of chemical
shifts for methylene protons of 2a–n. For 1a, 1b, 1g, 2a,
2b, and 2g, a singlet corresponding to methyl group was
identified. The amine protons (NH2) were assigned as
broad at 6.29–6.85 ppm for compounds 2a–f,k, only on
spectra recorded in DMSO-d6, an aprotic solvent; in
methanol, a protic solvent, this signal was not observed.
The 13C NMR spectra of 1a–n and 2a–n showed a broad
signal in 48.35–49.93 ppm corresponding for the two
CH2 groups in the imidazoline ring. The carbons of the
aromatic rings were identified as expected. HRMS
ionization). The HRMS was performed using
Micromass/Waters ZQ-4000 Spectrometer, capillary
3.0 kV, cone 30.0 V, extrator 1 V, RF lens 1.0 V, source
temperature 150°C, desolvation temperature 300°C
(electrospray ionization [ESI]).
The
key
intermediates
1-aryl-1H-pyrazole-4-
carbonitriles 3a–n and 5-amino-1-aryl-1H-pyrazole-4-
carbonitriles 4a–n were synthesized by our research
group according to the previously described [29,30].
General procedure for the synthesis of 1-aryl-4-(4,5-
dihydro-1H-imidazol-2-yl)-1H-pyrazoles 1a–n. A mixture
of 1-aryl-1H-pyrazole-4-carbonitriles 3a–n (0.001 mol),
2.0 mL of EDA (1,2-diaminoethane), and CS2
(0.004 mol), in a 50 mL round-bottom flask adapted with
a glass condenser, was irradiated with microwave (CEM–
Discover apparatus), power 50 W, during 20 min. Then,
the reaction mixture was poured into cold water; the
precipitate was filtered out and washed with cold water.
The reactions were accompanied by means of TLC and
dichloromethane as eluent.
1-(3-Chloro-4-methylphenyl)-4-(4,5-dihydro-1H-imidazol-2-
yl)-1H-pyrazole (1a). Yield: 92%; mp: 168–170°C; FT–IR
1
confirmed all structures 1a–n and 2a–n, after FT–IR, H
NMR, and 13C NMR analyses.
ν (cmÀ1): 3199, 3122, 2941, 2879, 1627, 1604, 1583, 1564.
1H NMR (500 MHz, DMSO-d6): δ = 8.85 (s, 1H), 8.02 (s,
1H), 7.92 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 8.3, 2.2 Hz,
1H), 7.50 (d, J = 8.3 Hz, 1H), 3.55 (s, 4H), 2.36 (s, 3H).
13C NMR (126 MHz, DMSO-d6): δ = 157.58, 140.25,
138.27, 134.00, 133.79, 132.10, 127.64, 118.68, 117.06,
116.27, 49.26, 19.02. HRMS (ESI): m/z [M + H]+: Calcd
CONCLUSION
In this work, we have reported an efficient and highly
selective microwave irradiation method to obtain
imidazoline linked to different 1-aryl-1H-pyrazoles.
Twenty-eight compounds, 1a–n and 2a–n, were
synthesized and characterized. The derivatives 1a–d,g–i
and 2a–d,g–i have been reported for the first time. Most
reactions have high yields, no side products were
identified, and the reaction time was no longer than
30 min in low power: 50 and 70 W. This new
methodology can be applied in the synthesis of
imidazoline ring in future works.
for C13H13ClN4: 261.0907; found: 261.0927.
1-(4-Chloro-2-methylphenyl)-4-(4,5-dihydro-1H-imidazol-2-
yl)-1H-pyrazole (1b). Yield: 37%; mp: 174–176°C; FT–IR
1
ν (cmÀ1): 3108, 2962, 2921, 2869, 1621, 1547. H NMR
(500 MHz, DMSO-d6): δ = 8.35 (s, 1H), 8.02 (s, 1H),
7.54 (s, 1H), 7.42 (s, 2H), 3.56 (s, 4H), 2.21 (s, 3H). 13C
NMR (126 MHz, DMSO-d6): δ = 157.65, 139.50,
137.94, 135.08, 132.66, 131.21, 130.84, 127.31, 126.63,
114.75, 48.89, 17.56. HRMS (ESI): m/z [M + H]+: Calcd
for C13H13ClN4: 261.0907; found: 26.0927.
1-(2,4-Dichlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-
1H-pyrazole (1c). Yield: 70%; mp: 110–111°C; FT–IR ν
EXPERIMENTAL
1
(cmÀ1): 3239, 3110, 2935, 2873, 1626, 1570, 1483. H
All commercial reagents were used as received unless
otherwise noted. The reaction progress was monitored by
TLC with precoated 60 F254 silica gel plates. The melting
points were determined on a Fisatom 430 apparatus. FT–
IR were recorded on a PerkinElmer Spectrum 100, ATR
diamond-ZnSe apparatus, wave numbers expressed in
cmÀ1. NMR spectra were recorded on a Bruker Avance
(500 MHz), at 298 K, in methanol-d4 or DMSO-d6.
Chemical shifts (δ) are expressed in parts per million
(ppm) and coupling constants (J) in Hertz (Hz). Gas
chromatography coupled to mass spectrometry was
executed on an Agilent equipment, column HP-5 Agilent,
30 m, split ratio 20:1, operating at 70 eV (electron impact
NMR (500 MHz, DMSO-d6): δ = 8.49 (s, 1H), 8.08 (s,
1H), 7.92 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H),
7.62 (dd, J = 8.6, 1.8 Hz, 1H), 3.58 (s, 4H). 13C NMR
(126 MHz, DMSO-d6): δ = 158.06, 140.67, 136.79,
134.36, 132.52, 130.56, 129.78, 129.55, 128.98, 115.29,
49.26. HRMS (ESI): m/z [M
C12H10Cl2N4: 281.0361; found: 281.0357.
+
H]+: Calcd for
1-(2,6-Dichlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-
1H-pyrazole (1d). Yield: 76%; mp: 221–223°C; FT–IR ν
(cmÀ1): 3116, 3069, 2941, 2869, 2800, 1620, 1568,
1
1550. H NMR (500 MHz, DMSO-d6): δ = 8.31 (s, 1H),
8.06 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.62 (t,
J = 8.3 Hz, 1H), 3.55 (s, 4H). 13C NMR (126 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. d. S. Rosa, B. A. Souto, C. N. Pereira, B. C. Teixeira, and M. S. dos Santos
Vol 000
DMSO-d6): δ = 157.49, 140.04, 135.38, 133.17, 132.29,
1-(4-Bromophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-
pyrazole (1j).
Yield: 65%; mp: 228–230°C (lit. 222–
132.00, 128.99, 115.17, 49.09. HRMS (ESI): m/z
223°C [29]); FT–IR ν (cmÀ1): 3144, 3110, 2931, 2863,
1632, 1589, 1565. 1H NMR (500 MHz, DMSO-d6):
δ = 8.83 (s, 1H), 8.04 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H),
7.72 (d, J = 8.8 Hz, 2H), 3.56 (s, 4H). 13C NMR
(126 MHz, DMSO-d6): δ = 157.54, 140.38, 138.47,
132.49, 127.53, 120.48, 119.09, 116.43, 49.15. HRMS
(ESI): m/z [M + H]+: Calcd for C12H11BrN4: 291.0245;
found: 291.0256.
[M + H]+: Calcd for C12H10Cl2N4: 281.0361; found:
281.0373.
À1-(3,4-Dichlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-
1H-pyrazole (1e). Yield: 79%; mp: 185–186°C (lit. 187–
188°C [29]); FT–IR ν (cmÀ1): 3200, 3120, 2952, 2862,
1628, 1596, 1581. 1H NMR (500 MHz, DMSO-d6):
δ = 8.94 (s, 1H), 8.16 (d, J = 2.5 Hz, 1H), 8.07 (s, 1H),
7.88 (dd, J = 8.8, 2.5 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H),
3.57 (s, 4H). 13C NMR (126 MHz, DMSO-d6):
δ = 157.37, 140.67, 138.74, 132.05, 131.48, 128.75,
128.03, 120.08, 118.46, 116.47, 49.01. HRMS (ESI): m/z
[M + H]+: Calcd for C12H10Cl2N4: 281.0361; found:
4-(4,5-Dihydro-1H-imidazol-2-yl)-1-(3-fluorophenyl)-1H-
pyrazole (1k).
Yield: 55%; mp: 164–167°C (lit. 155–
156°C [29]); FT–IR ν (cmÀ1): 3170, 3111, 3075, 2934,
2880, 2852, 1631, 1600, 1564. 1H NMR (500 MHz,
DMSO-d6): δ = 8.88 (s, 1H), 8.05 (s, 1H), 7.72–7.75 (m,
2H), 7.54–7.59 (m, 1H), 7.18–7.21 (m, 1H), 3.56 (s, 4H).
13C NMR (126 MHz, DMSO-d6): δ = 162.58 (d,
281.0362.
1-(3,5-Dichlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-
1H-pyrazole (1f).
Yield: 80%; mp: 83–84°C (lit. 170–
171°C [29]); FT–IR ν (cmÀ1): 3174, 3140, 3098, 3079,
2944, 2870, 1629, 1579, 1552. 1H NMR (500 MHz,
DMSO-d6): δ = 8.99 (s, 1H), 8.08 (s, 1H), 7.97 (d,
J = 1.5 Hz, 2H), 7.60 (s, 1H), 3.57 (s, 4H). 13C NMR
(126 MHz, DMSO-d6): δ = 157.40, 140.97, 135.11,
128.40, 125.98, 117.26, 117.12, 116.71, 49.26. HRMS
(ESI): m/z [M + H]+: Calcd for C12H10Cl2N4: 281.0361;
3
1J = 244.0 Hz), 157.53, 140.65 (d, J = 10.6 Hz), 140.44,
131.55 (d, 3J = 9.4 Hz), 127.81, 116.46, 114.34 (d,
4J = 2.6 Hz), 113.34 (d, 2J = 21.1 Hz), 105.89 (d,
2J = 26.7 Hz), 49.30. HRMS (ESI): m/z [M + H]+: Calcd
for C12H11FN4: 231.1046; found: 231.1048.
1-(3-Chlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-
pyrazole (1l).
Yield: 47%; mp: 120–124°C (lit. 175–
177°C [29]); FT–IR ν (cmÀ1): 3198, 3113, 2941, 2873,
1633, 1589, 1566. 1H NMR (400 MHz, DMSO-d6):
δ = 8.91 (s, 1H), 8.06 (s, 1H), 7.95 (t, J = 2.0 Hz, 1H),
7.84 (dd, J = 8.0, 2.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H),
7.42 (dd, J = 8.0, 2.0 Hz, 1H), 3.57 (s, 4H). 13C NMR
(101 MHz, DMSO-d6): δ = 158.01, 141.00, 140.79,
134.54, 131.88, 128.37, 126.97, 118.78, 117.50, 116.83,
found: 281.0363.
4-(4,5-Dihydro-1H-imidazol-2-yl)-1-(4-methoxyphenyl)-1H-
pyrazole (1g).
Yield 57%; mp: 196–197°C; FT–IR
(cmÀ1): 3142, 3101, 2934, 2873, 2844, 1631, 1562,
1
1518. H NMR (500 MHz, DMSO-d6): δ = 8.68 (s, 1H),
7.98 (s, 1H), 7.74 (d, J = 9.0 Hz, 2H), 7.07 (d,
J = 9.0 Hz, 2H), 3.80 (s, 3H), 3.55 (s, 4H). 13C NMR
(126 MHz, DMSO-d6): δ = 158.44, 158.27, 140.02,
133.38, 127.64, 120.64, 116.11, 115.16, 55.92, 49.68.
HRMS (ESI): m/z [M + H]+: Calcd for C13H14N4O:
243.1246; found: 243.1255.
49.64. HRMS (ESI): m/z [M
C12H11ClN4: 247.0750; found: 247.0752.
+
H]+: Calcd for
1-(3-Bromophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-
pyrazole (1m). Yield: 61%; mp: 116–120°C (lit. 180–
181°C [29]); FT–IR ν (cmÀ1): 3178, 3139, 3099, 2936,
2867, 1627, 1590, 1551. 1H NMR (500 MHz,
DMSO-d6): δ = 8.91 (s, 1H), 8.07 (t, J = 1.8 Hz, 1H),
8.06 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.55 (d,
J = 8.1 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 3.58 (s,
4H). 13C NMR (126 MHz, DMSO-d6): δ = 157.56,
140.56, 140.38, 131.65, 129.45, 127.99, 122.38,
121.13, 117.44, 116.15, 49.04. HRMS (ESI): m/z
[M + H]+: Calcd for C12H11BrN4: 291.0245; found:
4-(4,5-Dihydro-1H-imidazol-2-yl)-1-(4-fluorophenyl)-1H-
pyrazole (1h).
Yield: 87%; mp: 210–212°C; FT–IR ν
(cmÀ1): 3142, 3105, 2934, 2882, 2848, 1632, 1563,
1
1516. H NMR (500 MHz, DMSO-d6): δ = 8.78 (s, 1H),
8.02 (s, 1H), 7.87 (dd, J = 9.0, 4.7 Hz, 2H), 7.37 (t,
J = 9.0 Hz, 2H), 3.55 (s, 4H). 13C NMR (126 MHz,
DMSO-d6): δ = 160.51 (d, 1J = 243.6 Hz), 157.64,
140.07, 135.86 (d, 4J = 2.6 Hz), 127.57, 120.64 (d,
2
3J = 8.6 Hz), 116.39 (d, J = 23.1 Hz), 116.19, 49.93.
HRMS (ESI): m/z [M + H]+: Calcd for C12H11FN4:
231.1046; found: 231.1040.
291.0253.
4-(4,5-Dihydro-1H-imidazol-2-yl)-1-phenyl-1H-pyrazole
(1n). Yield: 44%; mp: 149–150°C (lit. 185–186°C [29]);
1-(4-Chlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-
FT–IR ν (cmÀ1): 3142, 3105, 3075, 2934, 2848, 1630,
pyrazole (1i).
Yield: 78%; mp: 214–216°C; FT–IR ν
1
(cmÀ1): 3151, 3111, 3071, 2934, 2878, 1629, 1567, 1504.
1H NMR (500 MHz, DMSO-d6): δ = 8.83 (s, 1H), 8.04 (s,
1H), 7.88 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 8.9 Hz, 2H),
3.56 (s, 4H). 13C NMR (126 MHz, DMSO-d6):
δ = 157.55, 140.35, 138.07, 130.86, 129.58, 127.58,
120.18, 116.38, 49.14. HRMS (ESI): m/z [M + H]+: Calcd
for C12H11ClN4: 247.0750; found: 247.0749.
1597, 1562. H NMR (500 MHz, DMSO-d6): δ = 8.80 (s,
1H), 8.03 (s, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.53 (t,
J = 7.8 Hz, 2H), 7.35 (t, J = 7.8 Hz, 1H), 3.56 (s, 4H).
13C NMR (126 MHz, DMSO-d6): δ = 158.16, 140.53,
139.73, 130.13, 127.79, 127.22, 119.01, 116.62, 49.56.
HRMS (ESI): m/z [M + H]+: Calcd for C12H12N4:
213.1140; found: 213.1151.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
A Convenient Synthesis of Pyrazole-imidazoline Derivatives by Microwave
Irradiation
General procedure for synthesis of 5-amino-1-aryl-4-(4,5-
dihydro-1H-imidazol-2-yl)-1H-pyrazoles 2a–n. A mixture
197–199°C (lit. 190–192°C [29]); FT–IR ν (cmÀ1): 3418,
3298, 3074, 2935, 2873, 1611, 1560, 1522. 1H NMR
(500 MHz, DMSO-d6): δ = 7.85 (d, J = 2.5 Hz, 1H),
7.78 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 7.63 (dd, J = 8.7,
2.5 Hz, 1H), 6.77 (br, 2H), 3.51 (s, 4H). 13C NMR
(126 MHz, DMSO-d6): δ = 159.89, 147.98, 139.22,
138.37, 131.63, 131.17, 128.88, 124.01, 122.56, 94.89.
HRMS (ESI): m/z [M + H]+: Calcd for C12H11Cl2N5:
of
5-amino-1-aryl-1H-pyrazole-4-carbonitriles
4a–n
(0.001 mol), 2.0 mL of EDA (1,2-diaminoethane), and
CS2 (0.004 mol), in a 50 mL round-bottom flask adapted
with a glass condenser, was irradiated with microwave
(CEM–Discover apparatus), power 70 W, during 30 min.
Then, the reaction mixture was poured into cold water;
the precipitate was filtered out and washed with cold
water. The reactions were accompanied by means of TLC
and dichloromethane as eluent.
296.0470; found: 296.0472.
5-Amino-1-(3,5-dichlorophenyl)-4-(4,5-dihydro-1H-
imidazol-2-yl)-1H-pyrazole (2f). Yield: 83%; mp: 96–98°C
5-Amino-1-(3-chloro-4-methylphenyl)-4-(4,5-dihydro-1H-
(lit. 109–111°C [29]); FT–IR ν (cmÀ1): 3420, 3282, 3083,
2946, 2873, 1619, 1583, 1568. 1H NMR (500 MHz,
DMSO-d6): δ = 7.76 (s, 1H), 7.67 (d, J = 1.8 Hz, 2H),
7.62 (t, J = 1.8 Hz, 1H), 6.85 (br, 2H), 3.53 (s, 4H). 13C
NMR (126 MHz, DMSO-d6): δ = 160.12, 148.60,
140.88, 140.20, 135.09, 126.73, 121.63, 94.65, 48.35.
HRMS (ESI): m/z [M + H]+: Calcd for C12H11Cl2N5:
imidazol-2-yl)-1H-pyrazole (2a).
Yield: 79%; mp: 188–
190°C; FT–IR ν (cmÀ1): 3384, 3261, 3115, 2924, 2853,
1603, 1581, 1566. 1H NMR (500 MHz, DMSO-d6):
δ = 7.69 (s, 1H), 7.62 (s, 1H), 7.49 (s, 2H), 6.64 (br, 2H),
3.50 (s, 4H), 2.37 (s, 3H). 13C NMR (126 MHz,
DMSO-d6): δ = 159.93, 147.60, 138.58, 137.48, 133.77,
133.42, 131.59, 122.54, 121.06, 94.58, 43.95, 19.03.
HRMS (ESI): m/z [M + H]+: Calcd for C13H14ClN5:
276.1016; found: 276.1022.
296.0470; found: 296.0474.
5-Amino-4-(4,5-dihydro-1H-imidazol-2-yl)-1-(4-
methoxyphenyl)-1H-pyrazole (2g). Yield: 50%; mp: 171–
5-Amino-1-(4-chloro-2-methylphenyl)-4-(4,5-dihydro-1H-
173°C; FT–IR ν (cmÀ1): 3263, 2940, 2857, 2837, 1602,
1
imidazol-2-yl)-1H-pyrazole (2b).
Yield: 76%; mp: 144–
1561, 1510. H NMR (500 MHz, MeOH-d4): δ = 7.65 (s,
146°C; FT–IR ν (cmÀ1): 3411, 3262, 3205, 3127, 2925,
2851, 1596, 1570, 1524. 1H NMR (500 MHz,
DMSO-d6): δ = 7.64 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H),
7.40 (dd, J = 8.5, 2.0 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H),
6.29 (br, 2H), 3.49 (s, 4H), 2.05 (s, 3H). 13C NMR
(126 MHz, DMSO-d6): δ = 160.65, 148.91, 139.13,
138.75, 138.10, 136.20, 133.75, 129.98, 127.09, 93.41,
49.39, 18.04. HRMS (ESI): m/z [M + H]+: Calcd for
C13H14ClN5: 276.1016; found: 276.1032.
1H), 7.41 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H),
3.85 (s, 3H), 3.64 (s, 4H). 13C NMR (126 MHz, MeOH-
d4): δ = 162.80, 161.19, 148.85, 139.60, 131.88, 127.47,
115.85, 95.34, 56.10, 49.76. HRMS (ESI): m/z [M + H]+:
Calcd for C13H15N5O: 258.1355; found: 258.1366.
5-Amino-4-(4,5-dihydro-1H-imidazol-2-yl)-1-(4-
fluorophenyl)-1H-pyrazole (2h).
Yield: 66%; mp: 164–
166°C; FT–IR ν (cmÀ1): 3280, 3075, 2943, 2872, 1611,
1
1598, 1567. H NMR (500 MHz, MeOH-d4): δ = 7.68 (s,
5-Amino-1-(2,4-dichlorophenyl)-4-(4,5-dihydro-1H-
1H), 7.55 (dd, J = 9.0, 4.8 Hz, 2H), 7.28 (t, J = 9.0 Hz,
2H), 3.65 (s, 4H). 13C NMR (126 MHz, MeOH-d4):
imidazol-2-yl)-1H-pyrazole (2c).
Yield: 53%; mp: 167–
169°C; FT–IR ν (cmÀ1): 3437, 3240, 3098, 2929, 2862,
1598, 1572, 1524. 1H NMR (500 MHz, DMSO-d6):
δ = 7.87 (d, J = 2.2 Hz, 1H), 7.65 (s, 1H), 7.59 (dd,
J = 8.5, 2.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.44 (br,
2H), 3.49 (s, 4H). 13C NMR (126 MHz, DMSO-d6):
δ = 160.09, 148.95, 139.26, 138.20, 134.51, 132.95,
130.63, 130.48, 129.03, 92.73. HRMS (ESI): m/z
[M + H]+: Calcd for C12H11Cl2N5: 296.0470; found:
296.0499.
1
δ = 163.61 (d, J = 244.2.3 Hz), 162.56, 149.02, 140.10,
135.50 (d, 4J = 2.9 Hz), 127.90 (d, 3J = 8.9 Hz), 117.47 (d,
2J = 23.3 Hz), 95.61, 49.77. HRMS (ESI): m/z [M + H]+:
Calcd for C12H12FN5: 246.1155; found: 246.1062.
5-Amino-1-(4-chlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-
yl)-1H-pyrazole (2i). Yield: 42%; mp: 179–181°C; FT–IR
ν (cmÀ1): 3397, 3265, 3122, 2932, 2852, 1606, 1568,
1
1523. H NMR (500 MHz, MeOH-d4): δ = 7.69 (s, 1H),
7.54 (s, 4H), 3.65 (s, 4H). 13C NMR (126 MHz,
MeOH-d4): δ = 162.65, 148.99, 140.39, 138.09, 134.77,
5-Amino-1-(2,6-dichlorophenyl)-4-(4,5-dihydro-1H-
130.81, 126.85, 95.81, 49.77. HRMS (ESI): m/z [M + H]+:
Calcd for C12H12ClN5: 262.0859; found: 262.0861.
5-Amino-1-(4-bromophenyl)-4-(4,5-dihydro-1H-imidazol-2-
imidazol-2-yl)-1H-pyrazole (2d).
Yield: 34%; mp: 126–
128°C; FT–IR ν (cmÀ1): 3275, 3170, 3129, 2940, 2866,
1604, 1566, 1531. 1H NMR (500 MHz, DMSO-d6):
δ = 7.68 (s, 2H), 7.67 (s, 1H), 7.58 (t, J = 8.2 Hz, 1H),
6.48 (br, 2H), 3.50 (s, 4H). 13C NMR (126 MHz,
DMSO-d6): δ = 160.09, 149.02, 139.19, 134.78, 133.10,
132.01, 129.05, 92.34, 44.04. HRMS (ESI): m/z
[M + H]+: Calcd for C12H11Cl2N5: 296.0470; found:
yl)-1H-pyrazole (2j).
Yield: 84%; mp: 184–188°C (lit.
189–191°C [29]); FT–IR ν (cmÀ1): 3387, 3260, 3119,
2926, 2852, 1605, 1566, 1523. 1H NMR (400 MHz,
MeOH-d4): δ = 7.68–7.70 (m, 3H), 7.49 (d, J = 8.9 Hz,
2H), 3.65 (s, 4H). 13C NMR (101 MHz, MeOH-d4):
δ = 161.16, 147.51, 138.99, 137.10, 132.40, 125.61,
121.11, 94.29. HRMS (ESI): m/z [M + H]+: Calcd for
C12H12BrN5: 306.0354; found: 306.0365.
296.0499.
5-Amino-1-(3,4-dichlorophenyl)-4-(4,5-dihydro-1H-
imidazol-2-yl)-1H-pyrazole (2e).
Yield: 71%; mp:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. d. S. Rosa, B. A. Souto, C. N. Pereira, B. C. Teixeira, and M. S. dos Santos
Vol 000
[2] El-Sehemi, A. G.; Bondock S; Ammar, Y. A. Med Chem Res
2013, 827.
5-Amino-4-(4,5-dihydro-1H-imidazol-2-yl)-1-(3-
fluorophenyl)-1H-pyrazole (2k).
Yield: 67%; mp: 164–
[3] Küçükgüzel, S. G.; Senkardes, S. Eur J Med Chem 2015, 97,
166°C (lit. 169–171°C [29]); FT–IR ν (cmÀ1): 3388,
3269, 3206, 3162, 2936, 2877, 1603, 1575, 1521. 1H
NMR (500 MHz, DMSO-d6): δ = 7.72 (s, 1H), 7.55–7.56
(m, 1H), 7.46–7.49 (m, 2H), 7.19–7.22 (m, 1H), 6.73 (br,
2H), 3.51 (s, 4H). 13C NMR (126 MHz, DMSO-d6):
786.
[4] Zhang, J.; Tan, D.; Wang, T.; Jing, S.; Kang, Y.; Zhang, Z. J
Mol Struct 2017, 1149, 235.
[5] Sankappa, R. U.; Isloor, A. M.; Shetty, P.; Pai, K. S. R.; Fun,
H. K. Arab J Chem 2015, 8, 317.
[6] Khan, M. F.; Alam, M. M.; Vera, G.; Akhtar, W.; Akhter, M.;
Shaquiquzzaman, M. Eur J Med Chem 2016, 120, 170.
[7] Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes,
A. Chem Rev 2011, 111, 6984.
[8] Li, M.; Zhao, B. Eur J Med Chem 2014, 85, 311.
[9] Fustero, S.; Simon-Fuentes, A.; Sanz-Cervera, J. F. Org Prep
Proced Int 2011, 41, 253.
[10] Knorr, L. Ber Dtsch Chem Ges 1884, 17, 1635.
[11] Pechmann, H. V. Ber Dtsch Chem Ges 1894, 27, 1888.
[12] Krasavin, M. Eur J Med Chem 2015, 97, 525.
[13] Bihan, G.; Rondu, F.; Pele-Tounian, A.; Wang, X.; Lidy, S.;
Touboul, E.; Lamouri, A.; Dive, G.; Huet, J.; Pfeiffer, B.; Renard, P.;
Guardiola-Lemaitre, B.; Manechez, D.; Penicaud, L.; Ktorza, A.;
Godfroid, J. J Med Chem 1999, 42, 1587.
1
δ = 162.10 (d, J = 244.0 Hz), 159.91, 147.68, 139.98 (d,
3
3J = 10.3 Hz), 138.78, 130.96 (d, J = 9.2 Hz), 118.16
4
2
(d, J = 2.7 Hz), 113.24 (d, J = 21.0 Hz), 109.42 (d,
2J = 25.3 Hz), 94.69. HRMS (ESI): m/z [M + H]+: Calcd
for C12H12FN5: 246.1155; found: 246.1163.
5-Amino-1-(3-chlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-
yl)-1H-pyrazole (2l).
Yield: 74%; mp: 160–162°C (lit.
127–128°C [29]); FT–IR ν (cmÀ1): 3376, 3280, 3222,
3171, 2948, 2922, 2876, 1632, 1609, 1594, 1569. 1H
NMR (500 MHz, MeOH-d4): δ = 7.70 (s, 1H), 7.61–7.62
(m, 1H), 7.52–7.53 (m, 2H), 7.42–7.44 (m, 1H), 3.65 (s,
4H). 13C NMR (126 MHz, MeOH-d4): δ = 162.74,
149.16, 140.76, 140.67, 136.29, 132.12, 129.18, 125.40,
123.48, 96.09. HRMS (ESI): m/z [M + H]+: Calcd for
[14] Yu, A.; Frishman, W. H. J Clin Pharmacol 1996, 36, 98.
[15] Sun, M.; Wu, X.; Chen, J.; Cai, J.; Cao, M.; Ji, M. Eur J Med
Chem 2010, 45, 2299.
[16] Ferm, R. J.; Riebsomer, J. L. Chem Rev 1954, 54, 593.
[17] Korshin, E. E.; Sabirova, L. I.; Akhmadullin, A. G.; Levin, Y.
A. Russian Chem Bull 1994, 43, 431.
C12H12ClN5: 262.0859; found: 262.0877.
5-Amino-1-(3-bromophenyl)-4-(4,5-dihydro-1H-imidazol-2-
yl)-1H-pyrazole (2m). Yield: 47%; mp: 88–92°C (lit. 143–
[18] Rousselet, G.; Capdeviell, P.; Maumy, M. Tetrahedron Lett
1993, 34, 6395.
[19] Spychala, J. Tetrahedron Lett 1999, 40, 2841.
[20] Vorbriiggen, H.; Krolikiewicz, K. Tetrahedron Lett 1981, 22,
4471.
[21] Welsch, S. J.; Umkehrer, M.; Kalinski, C.; Ross, G.; Burdack,
C.; Kolb, J.; Wild, M.; Ehrlich, A.; Wessjohann, L. A. Tetrahedron Lett
2015, 56, 1025.
[22] Neef, G.; Eder, U.; Sauer, G. J Org Chem 1981, 46, 2826.
[23] Zhou, L.; Zhou, J.; Tan, C. K.; Chen, J.; Yeung, Y. Org Lett
2011, 13, 2448.
[24] Wrobel, T. M.; Kosikowska, U.; Kaczor, A. A.; Andrzejczuk,
S.; Karczmarzyk, Z.; Wysocki, W.; Urbanczyk-Lipkowska, Z.; Morawiak,
M.; Matosiuk, D. Molecules 2015, 20, 14761.
[25] Giorgioni, G.; Ambrosini, D.; Vesprini, C.; Hudson, A.;
Nasuti, C.; Stefano, A.; Sozio, P.; Ciampi, O.; Costa, B.; Martini, C.;
Carrieri, A.; Carbonara, G.; Enzensperger, C.; Pigini, M. Bioorg Med
Chem 2010, 18, 7085.
[26] Romanova, N. N.; Kudan, P. V.; Gravis, A. G.; Bundel, Y. G.
Chem Heterocyc Compd 2000, 36, 1130.
[27] Zhang, J.; Wang, X.; Yang, M.; Wan, K.; Yin, B.; Wang, Y.;
Li, J.; Shi, Z. Tetrahedron Lett 2011, 52, 1578.
145°C [29]); FT–IR ν (cmÀ1): 3442, 3321, 3249, 3088,
3063, 2941, 2869, 1614, 1592, 1527. 1H NMR
(400 MHz, MeOH-d4): δ = 7.76 (t, J = 1.9 Hz, 1H), 7.70
(s, 1H), 7.56–7.60 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 3.65
(s, 4H). 13C NMR (101 MHz, MeOH-d4): δ = 161.14,
147.61, 139.25, 139.13, 130.77, 130.63, 126.79, 122.39,
122.37, 94.42. HRMS (ESI): m/z [M + H]+: Calcd for
C12H12BrN5: 306.0354; found: 306.0357.
5-Amino-4-(4,5-dihydro-1H-imidazol-2-yl)-1-phenyl-1H-
pyrazole (2n).
Yield: 55%; mp: 138–140°C (lit. 135–
136°C [29]); FT–IR ν (cmÀ1): 3351, 3264, 3149, 3074,
934, 2885, 2864, 1595, 1567. 1H NMR (500 MHz,
MeOH-d4): δ = 7.69 (s, 1H), 7.53–7.54 (m, 4H), 7.42–7.45
(m, 1H), 3.65 (s, 4H). 13C NMR (126 MHz, MeOH-d4):
δ = 162.83, 148.92, 140.18, 139.40, 130.87, 129.43,
125.60, 95.68, 49.82. HRMS (ESI): m/z [M + H]+: Calcd
for C12H13N5: 228.1249; found: 228.1261.
[28] De La Hoz, A.; Díaz-Ortiz, A.; Carmen, M. M.; Moral, M.;
Moreno, A.; Elguero, J.; Foces-Foces, C.; Rodriguez, M. L.; Sánches-
Migállon, A. Tetrahedron 2006, 62, 5868.
[29] Santos, M. S.; Oliveira, M. L. V.; Bernardino, A. M. R.; Léo,
R. M.; Amaral, V. R.; Carvalho, F. T.; Leon, L. L.; Canto-Cavalheiro, M.
M. Bioorg Med Chem 2011, 21, 7451.
[30] Santos, M. S.; Bernardino, A. M. R.; Pinheiro, L. C. S.; Canto-
Cavalheiro, M. M.; Leon, L. L. J Heterocyclic Chem 2012, 49, 1425.
Acknowledgments. This work is a collaboration research project
of the members of the Rede Mineira de Química (RQ-MG)
supported by FAPEMIG (Project: CEX – RED-00010-14). The
authors thank CAPES, CNPq, and the Program for
Technological Development in Tools for Health-RPT-
FIOCRUZ for allowing the use of their facilities.
SUPPORTING INFORMATION
REFERENCES AND NOTES
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[1] Faria, J. V.; Vergi, P. F.; Miguita, A. G. C.; Santos, M. S.;
Boechat, N.; Bernardino, A. M. R. Bioorg Med Chem 2017, 25, 5891.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet