Microwave assisted regioselective synthesis of novel pyrazoles and pyrazolopyridazines via fluorine containing building blocks

Article abstract of DOI:10.1016/j.molstruc.2017.04.047

A facile regioselective synthesis of novel pyrazole derivatives containing a fluorophenyl moiety via the 1,3-dipolar cycloaddition of nitrileimines and enamines using conventional as well as microwave irradiation conditions have been achieved. Fluorine-co

Full text of DOI:10.1016/j.molstruc.2017.04.047

Journal of Molecular Structure 1142 (2017) 122e129
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Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Microwave assisted regioselective synthesis of novel pyrazoles and
pyrazolopyridazines via fluorine containing building blocks
, b, *
Ismail I. Althagafi a, Mohamed R. Shaaban a
a Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukaramah 715, Saudi Arabia
b Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile regioselective synthesis of novel pyrazole derivatives containing a fluorophenyl moiety via the
1,3-dipolar cycloaddition of nitrileimines and enamines using conventional as well as microwave irra-
diation conditions have been achieved. Fluorine-containing building blocks methodology was used in
order to access the targeted fluorinated compounds. The structures of the synthesized products were
confirmed by 1H NMR, FT-IR, mass spectrometry, and elemental analyses. Furthermore, the synthesized
pyrazoles have been used in the synthesis of some new pyrazolo pyidazines containing pendent to
fluorophenyl moiety. An unambiguous structural assignment of the obtained pyrazole regioisomers was
determined using the 1H NMR analysis as a valuable tool.
Received 12 December 2016
Received in revised form
8 April 2017
Accepted 12 April 2017
Available online 18 April 2017
Keywords:
Microwave irradiations
1,3-dipolar cycloaddition
Regioselectivity
© 2017 Published by Elsevier B.V.
Pyrazoles
Pyrazolo pyridazines
1. Introduction
of selectivity of reaction products [17e19]. Currently, other alter-
native routes are used including green methodologies such as
The presence of fluorinated moieties in organic molecules may
dramatically modifies the physicochemical profile of organic
compounds [1]. Thus, fluorine containing heterocycles have
attracted much interest because of their potent biological and
pharmacological activities [2e4], and their role in the development
of many functional materials [5e11]. Among these heterocycles,
pyrazoles have been reported to have important biological activ-
ities [12], including; anti-nociceptive activities [13]; in some drugs
for Parkinson's diseases [14] and cytotoxicity against cancer cell
lines [15]. Also, many fluoro compounds are well-known
commercialized drugs, such as Prozac, Casodex, Arava and Cele-
brex can be represented as shown in Fig. 1 [16].
Due to this chemotherapeutic importance, much more attention
has been paid to develope of new synthetic methodologies to
heterocycles pendent to fluorinated organic groups. However, most
of the known methodologies applied to the synthesis of fluorinated
organic molecules suffer from serious disadvantages. For example,
common fluorinating agents are highly toxic and difficult to be
handled at ambient conditions. Also, direct fluorination always lake
electrochemical fluorination and using fluorine-containing build-
ing blocks which can be considered to be a cornerstone in the field
of fluoro-organic compounds synthesis including our contribution
in these fields [20e26]. On the other hand, microwave irradiation
has been recently demonstrated its utility as an energy source to
improve yields and/or save reaction conditions, especially in the
field of heterocyclic synthesis [27]. The use of the pressurized mi-
crowave irradiation can be very advantageous to many synthetic
approaches where the solvent can be heated up to temperatures
that are 2e4 times their respective boiling points and thus
providing large rate enhancement. In addition, keeping the atmo-
sphere from moisture that may affect the moisture sensitive re-
agents decreases the possibility of formation of the undesired
byproducts. Motivated by the aforementioned findings and as a
part of our interest in the study and synthesis of a wide range of
fluorinated heterocyclic systems, we report on the easy access of
new pyrazoles and pyrazolo pyridazines pendent to fluorophenyl
moiety via 1,3-dipolar cycloaddition of nitrileimines to the versatile
3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (3) under
both microwave irradiation and conventional methods. Also
unambiguously proof the structure of the obtained regioisomers
utilizing the chemical evidences as well as spectral data.
* Corresponding author. Department of Chemistry, Faculty of Applied Science,
Umm Al-Qura University, Makkah Almukaramah, Saudi Arabia.
http://dx.doi.org/10.1016/j.molstruc.2017.04.047
0022-2860/© 2017 Published by Elsevier B.V.

I.I. Althagafi, M.R. Shaaban / Journal of Molecular Structure 1142 (2017) 122e129
123
H
N
HO
H
O
O2
S
F3C
NC
N
CF3
O
F
Fluoxetine (Prozac)TM
Bicalutamide (Casodex)TM
H2NOS
F3C
O
N
N
O
N
H
CF3
N
Celecoxib (Celebrex)TM
Leflunomide (Arava)TM
Fig. 1. Fluorinated commercialized drugs.
2. Experimental section
synthesized compound are listed below.
Mp.: 64e65 ꢁC; IR (KBr) cmꢀ1: 1664 (C]O), 1598 (C]N); 1H
NMR (CDCl3):
eCOeCH]), 7.10 (d, 2H, AreH), 7.80 (d, J ¼ 12.3 Hz,1H, ¼CHeN), 7.92
(d, 2H, AreH).; MS (m/z): 193 (Mþ); C11H12FNO:Anal. Calcd: C,
68.38; H, 6.26; N, 7.25. Found C, 68.28; H, 6.16; N, 7.35. %.
2.1. Materials and methods
d
3.02 (s, 6H, N(CH3)2), 5.67 (d, 1H, J ¼ 12.3 Hz,
All melting points were measured on a Gallenkamp melting
point apparatus. The infrared spectra were recorded on Shi-
madzu IR-3600 spectrometer (potassium bromide) ύ/cmꢀ1. The
NMR spectra were recorded on a Varian Mercury VXR-300 NMR
spectrometer (1H NMR (300 MHz) and 13C NMR (75.46 MHz))
were run in deuterated chloroform (CDCl3) or dimethyl sulfoxide
(DMSO-d6). Chemical shifts were related to that of the solvent.
Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX
mass spectrometer at 70 eV. Elemental analyses were carried out
at the Micro-analytical Center of Cairo University, Giza, Egypt and
recorded on Elementar-Vario EL automatic analyzer. The Micro-
wave reactor was used in this work is the CEM mars machine.
CEM has several vessel types that are designed for their ovens:
Closed-system vessels including the HP-500 (500 psig material
design pressure and 260 ꢁC), pictured below, have liners are
composed of PFA. Each reaction vessel fits within a microwave-
transparent sleeve made of Kevlar, and each vessel-sleeve as-
sembly gets clamped within a carriage or 'support module'
with 5 foot-pounds of torque applied to the clamping bolt.
Hydrazonoyl halides were prepared according to the reported
literature [28].
2.1.2. Reactivity of 1-(4-fluorophenyl)-3-(dimethylamino)prop-2-
en-1-one (3) towards nitrileimines: synthesis of novel pyrazoles
2.1.2.1. General procedure
2.1.2.1.1. Thermal method. To a mixture of 1-(4-fluorophenyl)-3-
(dimethylamino)prop-2-en-1-one (3) (2 mmol) and the appro-
priate hydrazonoyl chloride 4a-i or 11 (2 mmol), in benzene
(20 mL), an equivalent amount of triethylamine was added. The
reaction mixture was stirred at room temperature overnight or
under reflux and followed by TLC then the solvent was distilled off
under reduced pressure. The residual brown viscous liquid was
taken in methanol and purified through a flash column of silica gel
with ethyl acetate as an eluent. Evaporation of the solvent under
reduced pressure afforded a pure solid, dried and finally recrys-
tallized from heptane to afford corresponding pyrazole derivatives
7a-i or 14.
2.1.2.1.2. Microwave
method. To
a
mixture of 1-(4-
fluorophenyl)-3-(dimethylamino)prop-2-en-1-one (3) (2 mmol)
and the appropriate hydrazonyl chloride 4a-i or 11 (2 mmol), in
benzene (20 mL), an equivalent amount of triethylamine was
added. The reaction mixture was mixed in a HP-500 Plus process
vessel. The vessel was capped properly and irradiated by micro-
waves under pressurized conditions (600 W, 17.2 bar, 85 ꢁC) for a
given time (followed by TLC). The solvent was distilled off under
reduced pressure then the residual brown viscous liquid was taken
in methanol and purified through a flash column of silica gel with
ethyl acetate as an eluent. Evaporation of the solvent under reduced
pressure afforded a pure solid, dried and finally recrystallized from
heptane or hexane to afford corresponding pyrazole derivatives.
The physical and spectral data of the synthesized compound are
listed below.
2.1.1. Synthesis of 1-(4-fluorophenyl)-3-(dimethylamino)prop-2-
en-1-one (3)
To a solution of p-fluoroacetophenone (1) (10 mmol) in xylene
or without solvent was added dimethylformamide-dimethylacetal
(DMF-DMA) (12 mmol) and the mixture was mixed in a HP-500
Plus process vessel. The vessel was capped properly and irradi-
ated by microwaves under pressurized conditions (17.2 bar, 110 ꢁC)
for 10 min. The excess DMF-DMA was evaporated in vacuo and the
residue was dissolved in ether (50 mL) and dried over MgSO4. After
evaporation of the solvent the resulting solid was recrystallized
from hexane to afford (E)-1-(4-fluorophenyl)-3-(dimethylamino)
prop-2-en-1-one (2), The physical and spectral data of the

124
I.I. Althagafi, M.R. Shaaban / Journal of Molecular Structure 1142 (2017) 122e129
2.1.2.1.2.1. 4-(4-Fluorobenzoyl)-1-(1-(4-methoxyphenyl)-
1H-
2.1.2.1.2.8. 4-(4-Fluorobenzoyl)-N,1-diphenyl-1H-pyrazole-3-
pyrazol-3-yl)ethanone (7a)
carboxamide (7h)
Mp.: 132e133 ꢁC; IR (KBr) cmꢀ1: 1681, 1661 (2 C]O), 1597 (C]
Mp.: 195e197 ꢁC; IR (KBr) cmꢀ1: 3356 (NH), 1690 (C]O), 1635
N); 1H NMR (CDCl3):
2H), 7.68 (d, 2H), 7.87 (dd, 2H), 8.09 (s, 1H); 13C NMR (DMSO-d6):
d
2.62 (s, 3H), 3.87 (s, 3H), 7.03 (d, 2H), 7.13 (t,
(C]O), 1598 (C]N); 1H NMR (CDCl3):
d 7.10e7.53 (m, 3H), 7.77 (m,
9H), 7.91e7.96 (m, 2H), 8.23 (s, 1H), 10.74 (s, 1H, NH); MS (m/z): 385
(Mþ); C23H16FN3O2:Anal. Calcd: C, 71.68; H, 4.18; N, 10.90. Found C,
71.65; H, 4.13; N, 10.88%.
d
27.37, 55.85, 114.99, 115.75 (d, 2JCF, 21.25 Hz), 121.45, 122.79,
131.38, 132.31, 132.36 (d, 3JCF, 8.75 Hz), 134.75, 149.89, 159.31,
165.54 (d, 1JCF, 251.25 Hz), 188.43, 192.83; MS (m/z): 338 (Mþ);
2.1.2.1.2.9. (3-(4-Chlorobenzoyl)-1-p-tolyl-1H-pyrazol-4-yl) (4-
fluorophenyl)methanone (7i)
C
19H15FN2O3:Anal. Calcd: C, 67.45; H, 4.47; N, 8.28. Found C, 67.48;
H, 4.44; N, 8.25%.
Mp.: 164e165 ꢁC; IR (KBr) cmꢀ1: 1690, 1635 (2 C]O), 1598 (C]
2.1.2.1.2.2. 4-(4-Fluorobenzoyl)-1-(1-(4-tolyl)- 1H-pyrazol-3-yl)
ethanone (7b)
N); 1H NMR (CDCl3):
d
2.44 (s, 3H), 7.12 (t, 2H), 7.34 (d, 2H), 7.45 (d,
2H), 7.64 (d, 2H), 7.87 (dd, 2H), 8.12 (d, 2H), 8.27 (s, 1H); 13C NMR
Mp.: 154e156 ꢁC; IR (KBr) cmꢀ1: 1683, 1664 (2 C]O), 1592 (C]
(DMSO-d6): d
27.54, 116.07 (d, 2JCF, 20.00 Hz), 118.78, 122.54,
N); 1H NMR (CDCl3):
d
2.43 (s, 3H), 2.63 (s, 3H), 7.11 (t, 2H), 7.31 (d,
122.92, 123.13, 131.07, 132.17, 132.65 (d, 2JCF, 8.75 Hz), 134.42,
140.24, 150.59, 165.65 (d, 1JCF, 247.50 Hz), 188.16, 193.10; MS (m/z):
418 (Mþ); C24H16ClFN2O2:Anal. Calcd: C, 68.82; H, 3.85; N, 6.69.
Found C, 68.80; H, 3.83; N, 6.64%.
2H), 7.64 (d, 2H), 7.88 (t, 2H), 8.14 (s, 1H); 13C NMR (DMSO-d6):
d
21.04, 27.39, 116.01 (d, 2JCF, 22.50 Hz), 119.76, 122.89, 130.40,
131.45, 132.36 (d, 3JCF, 8.75 Hz), 134.56, 136.87, 137.91, 150.05,
165.57 (d, 1JCF, 251.27 Hz), 188.41, 192.89; MS (m/z): 322 (Mþ);
2.1.2.1.2.10. Ethyl 4-(4-fluorobenzoyl)-1-(4-methoxyphenyl)-1H-
pyrazole-3-carboxylate (13)
C
19H15FN2O2: Anal. Calcd: C, 70.80; H, 4.69; N, 8.69. Found C, 70.78;
H, 4.72; N, 8.64%.
Mp.: 177e179 ꢁC; IR (KBr) cmꢀ1: 1731 (C]O), 1665 (C]O), 1591
2.1.2.1.2.3. 4-(4-Fluorobenzoyl)-1-(1-(4-nitrophenyl)-
azol-3-yl)ethanone (7c)
1H-pyr-
(C]N); 1H NMR (CDCl3):
d 1.07 (t, 3H, CH3), 3.80 (s, 3H, OCH3), 4.14
(q, 2H, CH2), 6.92 (d, 2H), 7.07 (d, 2H), 7.63 (d, 2H), 7.85 (dd, 2H),
8.14 (s, 1H, pyrazole-5-CH); MS (m/z): 368 (Mþ); C20H17FN2O4:Anal.
Calcd: C, 65.21; H, 4.65; N, 7.60. Found C, 65.23; H, 4.62; N, 7.64%.
Mp.: 190e192 ꢁC; IR (KBr) cmꢀ1: 1686, 1665 (2 C]O), 1593 (C]
N); 1H NMR (CDCl3):
2H), 8.29 (s, 1H), 8.44 (d, 2H); 13C NMR (DMSO-d6):
d
2.66 (s, 3H), 7.12 (t, 2H), 7.86 (dd, 2H), 7.98 (d,
27.60, 115.51,
d
116.25 (d, 2JCF, 22.50 Hz), 120.53, 123.65, 125.98, 132.76 (d, 3JCF,
10.00 Hz), 134.38, 143.47, 146.67, 151.25, 165.74 (d, 1JCF, 251.25 Hz),
188.25, 193.19; MS (m/z): 353 (Mþ); C18H12FN3O4:Anal. Calcd: C,
61.19; H, 3.42; N, 11.89. Found C, 61.14; H, 3.44; N, 11.85%.
2.1.2.1.2.4. 1-(1-(3-Bromophenyl)-4-(4-fluorobenzoyl)-1H-pyr-
azol-3-yl)ethanone (7d)
2.1.3. Synthesis of pyrazolopyridazine derivatives 10 and 14
2.1.3.1. General procedure
2.1.3.1.1. Thermal method. A mixture of the appropriate pyrazole
derivatives 7 or 13 (1 mmol) and hydrazine hydrate (98%), (2 mL)
was heated under reflux in ethanol (20 mL) for 4 h then left to cool
to room temperature. The formed precipitates were collected by
filtration, washed with ethanol and dried. Recrystallization from
EtOH/DMF afforded yellow crystals of the corresponding pyrazolo
[3,4-d]pyridazine derivatives 10a-f and 14.
2.1.3.1.2. Microwave method. To a solution of appropriate pyr-
azole derivatives 7 or 13 (1 mmol) in ethanol (10 mL), hydrazine
hydrate (98%), (2 mL) was added. The total mixture was placed in a
HP-500 Plus process vessel. The vessel was capped properly and
irradiated by microwaves under pressurized conditions (600 W,
17.2 bar, 120 ꢁC) for a given time. The formed solid was filtered off,
washed with ethanol and recrystallized from EtOH/DMF to afford
the corresponding pyrazolo [3,4-d]pyridazine derivatives 10a-f and
14. The compounds synthesized together with their physical data
are listed below:
Mp.: 133e135 ꢁC; IR (KBr) cmꢀ1: 1689, 1664 (2 C]O), 1597 (C]
N); 1H NMR (CDCl3):
d
2.64 (s, 3H, CH3CO), 7.12 (t, 2H), 7.41 (t, 1H),
7.58 (d, 1H), 7.71 (d, 1H), 7.87 (dd, 2H), 8.00 (s, 1H), 8.17 (s, 1H); 13
C
NMR (DMSO-d6):
d
27.44, 116.02 (d, 2JCF, 20.00 Hz), 118.75, 122.54,
122.02, 123.43, 131.00, 132.11, 132.15 (d, 2JCF, 8.75 Hz), 134.40,
140.14, 150.19, 165.25 (d, 1JCF, 247.50 Hz), 188.10, 192.86; MS (m/z):
386 (Mþ); C18H12BrFN2O2:Anal. Calcd: C, 55.83; H, 3.12; N, 7.23.
Found C, 55.80; H, 3.14; N, 7.20%.
2.1.2.1.2.5. 4-(4-Fluorobenzoyl)-1-(1-(3-tolyl)-1H-pyrazol-3-yl)
ethanone (7e)
Mp.: 110e111 ꢁC; IR (KBr) cmꢀ1: 1689, 1653 (2 C]O), 1596 (C]
N); 1H NMR (CDCl3):
d
2.47 (s, 3H), 2.64 (s, 3H), 7.10 (t, 2H), 7.25 (d,
1H), 7.43 (t,1H), 7.56 (d,1H), 7.60 (s,1H), 7.88 (t, 2H), 8.16 (s,1H); 13
C
NMR (DMSO-d6):
d
21.68, 27.35, 115.79 (d, 2JCF, 18.50 Hz), 117.21,
2.1.3.1.2.1. 4-(4-Fluorophenyl)-7-methyl-2-4-tolyl-2H-pyrazolo
[3,4-d]pyridazine(10a)
120.79, 123.61, 129.30, 129.80, 130.27, 132.15 (d, 2JCF, 8.12 Hz),
134.62, 139.17, 140.27, 150.53, 166.01 (d, 1JCF, 243.10 Hz), 188.88,
193.16; MS (m/z): 322 (Mþ); C19H15FN2O2:Anal. Calcd: C, 70.80; H,
4.69; N, 8.69. Found C, 70.84; H, 4.71; N, 8.72%.
Mp.: 00e009 ꢁC; IR (KBr) cmꢀ1: 1598 (C]N); 1H NMR (CDCl3):
d
2.47 (s, 3H), 3.04 (s, 3H), 7.23 (t, 2H), 7.26 (d, 2H), 7.82 (d, 2H), 8.09
(t, 2H), 8.66 (s, 1H); 13C NMR (DMSO-d6):
d
18.47, 21.10, 115.44,
116.31 (d, 2JCF, 21.25 Hz), 121.65, 125.05, 130.67, 130.56 (d, 3JCF,
8.75 Hz), 133.19, 137.40, 139.60, 144.24, 151.77, 152.79, 163.01 (d,
1JCF, 246.25 Hz); MS (m/z): 318 (Mþ); C19H15FN4:Anal. Calcd: C,
71.68; H, 4.75; N, 17.60. Found C, 71.67; H, 4.73; N, 17.57%.
2.1.3.1.2.2. 4-(4-Fluorophenyl)-7-methyl-2-m-tolyl-2H-pyrazolo
[3,4-d]pyridazine(10b)
2.1.2.1.2.6. 4-(4-Fluorobenzoyl)-1-(1-(3-methoxyphenyl)-
pyrazol-3-yl)ethanone (7f)
1H-
Mp.: 105e107 ꢁC; IR (KBr) cmꢀ1: 1688, 1665 (2 C]O), 1592 (C]
N); 1H NMR (CDCl3):
d 2.64 (s, 3H), 3.91 (s, 3H), 6.97 (d, 1H), 7.13 (t,
2H), 7.35e7.46 (m, 3H), 7.87 (dd, 2H), 8.17 (s, 1H); MS (m/z): 338
(Mþ); C19H15FN2O3:Anal. Calcd: C, 67.45; H, 4.47; N, 8.28. Found C,
67.41; H, 4.50; N, 8.32%.
Mp.: 198e199 ꢁC; IR (KBr) cmꢀ1: 1591 (C]N); 1H NMR (CDCl3):
2.1.2.1.2.7. 1-(1-(3-Chlorophenyl)-4-(4-fluorobenzoyl)-1H-pyr-
azol-3-yl)ethanone (7g)
d
2.50 (s, 3H), 3.02 (s, 3H), 7.21 (t, 2H), 7.31 (d, 1H), 7.46 (t, 1H), 7.74
(d, 1H), 7.78 (s, 1H), 8.07e8.12 (m, 2H), 8.66 (s, 1H); MS (m/z): 318
(Mþ); C19H15FN4:Anal. Calcd: C, 71.68; H, 4.75; N, 17.60. Found C,
71.65; H, 4.73; N, 17.57%.
Mp.: 128e129 ꢁC; IR (KBr) cmꢀ1: 1689, 1664 (2 C]O), 1591 (C]
N); 1H NMR (CDCl3):
d
2.65 (s, 3H), 7.13 (t, 2H), 7.27 (s, 1H), 7.43 (m,
2H), 7.64 (d, 1H), 7.87 (m, 2H), 8.18 (s, 1H); MS (m/z): 342 (Mþ);
18H12ClFN2O2:Anal. Calcd: C, 63.08; H, 3.53; N, 8.17. Found C, 63.11;
H, 3.51; N, 8.21%.
2.1.3.1.2.3. 2-(3-Chlorophenyl)-4-(4-fluorophenyl)-7-methyl-2H-
pyrazolo[3,4-d]pyridazine(10c)
C
Mp.: 203e205 ꢁC; IR (KBr) cmꢀ1: 1593 (C]N); 1H NMR (CDCl3):

I.I. Althagafi, M.R. Shaaban / Journal of Molecular Structure 1142 (2017) 122e129
125
d
3.03 (s, 3H), 7.24 (t, 2H), 7.52 (m, 2H), 7.86 (d,1H), 7.87 (d, 1H), 8.10
dimethylacetal (2). The structure of the enaminone 3 was confirmed
(m, 2H), 8.71 (s, 1H); MS (m/z): 338 (Mþ); C18H12ClFN4:Anal. Calcd:
C, 63.82; H, 3.57; N, 16.540. Found C, 63.79; H, 3.54; N, 16.50%.
2.1.3.1.2.4. 2-(3-Bromophenyl)-4-(4-fluorophenyl)-7-methyl-2H-
pyrazolo[3,4-d]pyridazine (10d)
by its elemental analysis and spectral data. Its 1H nmr spectrum
displayed a singlet signal at
two doublets at
5.67 ppm and 7.10 ppm (J¼12.3 Hz) due to olefinic
protons, in addition to an aromatic multiplets in the region
d 3.02 ppm due to N,N-dimethyl protons,
d
Mp.: 204e206 ꢁC; IR (KBr) cmꢀ1: 1597 (C]N); 1H NMR (CDCl3):
3.02 (s, 3H), 7.22 (t, 2H), 7.44 (t, 2H), 7.65 (d, 1H), 7.91 (d, 1H), 8.10
d
7.80e7.92 ppm. The value of the coupling constant (J¼12.3 Hz) for
d
the ethylenic protons indicates that the enaminone 2 exists exclu-
sively in the E-configuration. The reactivity of enaminone 3, in
general, can be attributed to the fact that their molecules have two
electron poor centers at C-1 and C-3 in addition to one electron rich
center at C-2 which is due to the delocalization of the lone pair of
electrons on the nitrogen atom as shown in (Chart 1).
(dd, 2H), 8.18 (s, 1H), 8.70 (s, 1H); 13C NMR (DMSO-d6):
d 18.49,
115.46, 116.35 (d, 2JCF, 21.25 Hz), 120.95, 122.91, 124.35, 126.02,
130.50 (d, 3JCF, 8.75 Hz), 132.26, 132.55, 133.09, 140.80, 144.42,
151.92, 152.92, 164.02 (d, 1JCF, 240.00 Hz); MS (m/z): 383 (Mþ);
C
18H12BrFN4:Anal. Calcd: C, 56.42; H, 3.16; N, 14.62. Found C, 56.40;
O
H
O
H
O
H
CH3
CH3
CH3
N
N
N
CH3
CH3
CH3
F
F
F
Electron rich
carbon
O
CH3
N
CH3
Electron difficient
F
carbon
Chart 1. Structures of enaminone 3.
H, 3.18; N, 14.60%.
Thus, the unique structure of enaminone 3 (Chart 1), which
facilitates 1,3-dipolar cycloaddition reactions with nitrileimines, is
considered to be one of the most convenient approaches to syn-
thesis pyrazoles. In this context, when compound 3 was allowed to
react with nitrileimines 5 (liberated, in situ, from the corresponding
hydrazonoyl halide 4 by the action of triethylamine) in a given
solvent under conventional conditions, it afforded the novel pyr-
azole derivatives 7a-i as shown in (Scheme 1). The reaction pro-
ceeds at room temperature and followed by TLC via overnight
stirring of the reaction mixture to give good yields of the reaction
product. Also, performing the cycloaddition under reflux using
same experimental conditions gives a moderate yield of the tar-
geted pyrazoles within 2e5 h. On the other hand, when carrying
out the reaction under microwave conditions the yields have been
enhanced to be excellent and in a short time of reaction as
mentioned in Table 1.
2.1.3.1.2.5. 4-(4-Fluorophenyl)-2-(3-methoxyphenyl)-7-methyl-
2H-pyrazolo[3,4-d]pyridazine (10e)
Mp.: 144e146 ꢁC; IR (KBr) cmꢀ1: 1598 (C]N); 1H NMR (CDCl3):
d
3.08 (s, 3H), 3.94 (s, 3H), 7.07 (d, 1H), 7.26 (t, 2H), 7.51 (m, 3H), 8.13
(dd, 2H), 8.73 (s, 1H); MS (m/z): 334 (Mþ); C19H15FN4O:Anal. Calcd:
C, 68.25; H, 4.52; N, 16.76. Found C, 68.22; H, 4.50; N, 16.74%.
2.1.3.1.2.6. 4-(4-Fluorophenyl)-7-methyl-2-(2-nitrophenyl)-2H-
pyrazolo[3,4-d]pyridazine (10e)
Mp.: 250e252 ꢁC; IR (KBr) cmꢀ1: 1590 (C]N); 1H NMR (CDCl3):
d
2.94 (s, 3H), 7.22 (t, 2H), 7.77e7.87 (m, 3H), 8.08e8.16 (m, 3H),
8.58 (s, 1H); 13C NMR (DMSO-d6): 18.31, 115.87 (d, 2JCF, 21.25 Hz),
d
119.78, 121.52, 124.63, 129.16, 130.50 (d, 3JCF, 8.75 Hz), 131.04,
132.80, 135.09, 140.55, 144.51, 151.97, 152.95, 163.92 (d, 1JCF,
247.50 Hz); MS (m/z): 349 (Mþ); C18H12FN5O2:Anal. Calcd: C, 61.89;
H, 3.46; N, 20.05. Found C, 61.88; H, 3.43; N, 20.01%.
2.1.3.1.2.7. 4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-2H-pyr-
azolo[3,4-d]pyridazin-7(6H)-one (14)
The double bond in the enaminone 3 can be looked on as an
electron rich one that may enter in 1,3-dipolar cycloaddition re-
actions. Nitrileimines have been reported to add to a,b-unsaturated
Mp.: 200e202 ꢁC; IR (KBr) cmꢀ1: 1635 (C]O), 1592 (C]N); 1H
NMR (CDCl3):
d
3.89 (s, 3H, OCH3), 7.04 (d, 2H), 7.21 (d, 2H), 7.73 (d,
carbonyl compounds to yield a mixture of isomeric pyrazolines. In
the present work, the reaction of the nitrileimines 5a-i with the
enaminone 3 afforded, in each case, only one isolable product as
tested by TLC analysis of the crude reaction product. The reaction
products were identified as 1-aryl-3-acetyl-4-(4-fluorophenylyl)
pyrazoles 7a-i. The latter products were assumed to be formed via
1,3-dipolar cycloaddition of the nitrileimines 5a-i to the activated
double bond in the enaminone 3 to afford the non-isolable dihy-
dropyrazole intermediates 6a-i which then lose dimethylamine
molecule yielding the pyrazole derivatives 7a-i. The other possible
isomeric structure 9 was excluded initially on the basis of the
2H), 7.86 (dd, 2H), 8.39 (s, 1H, pyrazole-5-CH), 10.04 (br, NH); MS
(m/z): 336 (Mþ); C18H13FN4O2:Anal. Calcd: C, 64.28; H, 3.90; N,
16.66. Found C, 64.25; H, 3.88; N, 16.60%.
3. Results and discussion
Solvent free synthesis of the 3-(dimethylamino)-1-(4-
fluorophenyl)prop-2-en-1-one (3) as a versatile fluorine-containing
building block have been achieved by microwave irradiation of a
mixture of 4-fluoroacetophenone (1) and dimethylformamide

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I.I. Althagafi, M.R. Shaaban / Journal of Molecular Structure 1142 (2017) 122e129
Scheme 1. 1,3-dipolar cycloaddition of enaminone 3 with nitrilimines 5.
spectral data of the isolated products. For example, in the pyrazole
ring system, C-4 is the most electron-rich carbon; thus, H-4 is ex-
More deep analysis of the 1H NMR spectra of the isolated pyr-
azoles showed more evidences for the formation of the
regioisomers of pyrazole derivatives 7 rather than 9. Based on the
pected to appear at
hand, H-5 is linked to the carbon attached to the nitrogen atom and
it is expected to appear typically in the region 7.53e8.59 ppm
(Fig. 2). The 1H NMR spectra of the isolated reaction products
revealed, in each case, singlet signal in the region of
8.20e8.75 ppm which indicates the presence of the pyrazole H-5
d
6.31 ppm in 1H NMR spectrum. On the other
chemical shift (d) of the 5-H pyrazole protons, we found that the
d
value of d is affected by the substuents in the phenyl ring at
position-1 through the pyrazole ring. Thus, examine the 1H NMR
a
spectra for pyrazoles 7a-c we have noticed that the value of the
chemical shift (d) of 5-H pyrazole increases according to the nature
d
rather than H-4 in the structure of the isolated products.
of the substituent group at the para position in the phenyl ring. The
5-H pyrazole proton in 7c is resonating at higher value than the
other isomer due to the electron withdrawing effect of the nitro
group located at the para position in the phenyl ring.
On the other hand, the 5-H pyrazole proton in 7a is resonating at
lower value than the other isomer due to the electron releasing
effect of the methoxy group located at the para position in the
phenyl ring (Fig. 3). The latter results is not observed when the
substituent groups are located in the meta position in the phenyl
group with respect to the pyrazole ring as in pyrazoles 7 d-f (Fig. 4).
This pronounced effect on the 5-H pyrazole proton chemical shift
reinforce the structure of the regioisomers 7 over 9.
Table 1
Thermal and MW yields of the synthesized pyrazoles 7a-i.
4, 7 R
Ar
Conventional
MW
Reflux
stirring at rt.
Time (h) Yield % Yield %
Time (min) Yield %
a
b
c
d
e
f
g
h
i
CH3
C6H4MeO-p
C6H4Me-p
C6H4NO2-p
C6H4Br-m
C6H4Me-m
2
3
3
3
3
54
45
39
58
46
54
45
55
53
72
65
45
68
76
64
65
56
63
20
25
15
20
25
25
20
30
15
79
76
76
80
85
88
65
71
81
CH3
CH3
CH3
CH3
CH3
CH3
These spectral evidences was further confirmed chemically.
Thus, the position of the two carbonyl functions in the pyrazole 7
are in the favored position for the condensation with hydrazine in
order to annulate the pyridazine ring in fusion to the pyrazole ring
C6H4MeO-m 2
C6H4Cl-m
2
5
2
C6H5NH C6H5
C6H4Cl-p C6H4Me-p

I.I. Althagafi, M.R. Shaaban / Journal of Molecular Structure 1142 (2017) 122e129
127
O
O
O
F
F
H
R
4
5
3
4
N
1
5
Ar
N
2
H
O
N
2
3
N
1
R
Ar
7
9
Fig. 2. The pyrazole H-5 rather than H-4 in the structure of pyrazoles.
Scheme 2. Synthesis of pyrazolopyridazine derivatives 10.
Fig. 3. Comparison of pyrazole H-5 chemical shifts the structure of pyrazoles and the
effect of neighboring para-substituted phenyl ring.
Table 2
Thermal and MW yields of the synthesized pyrazolopyridazines 10a-f.
10
Ar
Yield %
Conventional
MW
a
b
c
d
e
f
C6H4CH3-p
C6H4CH3-m
C6H4Cl-m
C6H4Br-m
C6H4OCH3-m
C6H4NO2-o
46
56
43
46
58
42
56
76
73
66
78
52
disappearance of the two carbonyl absorption bands.
It is obvious that the microwave irradiation yields are quite
better than that the corresponding thermal reactions and in highly
comparable shorter time of reactions as shown in Table 2.
In the same manner, the enaminone 3 reacts with C-1-(ethox-
ycarbonyl)-N-4-arylnitrilimines 12 [liberated, in situ, from the
corresponding hydrazonoyl chlorides 11] under the same reaction
conditions to afford a product that may be formulated as the pyr-
azole structure 13 or their regioisomer 14. Structure 14 was
excluded on the basis of spectroscopic data of the isolated product.
For example, the 1H NMR spectra of the reaction products revealed,
Fig. 4. Comparison of pyrazole H-5 chemical shifts the structure of pyrazoles and the
effect of neighboring meta-substituted phenyl ring.
the pyrazole CH-5 in the region of
d 8.31 ppm which is in accor-
dance with structure 13 (Scheme 3).
Also, a chemical confirmation of the proposed structure 13
based on reaction of 13 with hydrazine hydrate in ethanol under
reflux or using microwave conditions to afford the pyrazolo [3,4-d]
pyridazinone derivative 14 (Scheme 4). The latter pyrazolopyr-
idazinone structure was further established on the basis of the IR
spectrum of 14 which was found to be free from the ester carbonyl
function frequency and appearance of the new amide carbonyl at
to afford the corresponding pyrazolo pyridazine ring system. The
reaction of pyrazoles 7 with hydrazine hydrate, in refluxing ethanol
afforded the corresponding pyrazolo [3,4-d]pyridazine derivatives
10a-f, in almost good yields under both thermal and microwave
conditions (Scheme 2, Table 2). The structures of the products 10a-f
were confirmed based on their elemental analyses and spectro-
scopic data. The IR spectra of compounds 10a-f showed the

128
I.I. Althagafi, M.R. Shaaban / Journal of Molecular Structure 1142 (2017) 122e129
O
O
Cl
EtO
Et3N
3
EtO
N
N
NH
Ar
N
Ar
12
11
O
F
O
O
EtO
F
N
Ar
N
N
O
N
Ar
OEt
14
13
Ar = C6H4OMe-p
Scheme 3. 1,3-dipolar cycloaddition of enaminone 3 with C-1-(ethoxycarbonyl)-N-4-arylnitrilimines 12.
Acknowledgements
The authors are greatly appreciative to Umm Al-Qura University
for funding this research (Project No. 43305028).
References
[1] J. Wang, M. Sanchez-Rosello, J.L. Acena, C. del Pozo, A.E. Sorochinsky,
S. Fustero, V.A. Soloshonok, H. Liu, Chem. Rev. 114 (2014) 2432.
[2] G. Resnati, Tetrahedron 49 (1993) 9385.
[3] L. Kenneth, J. Kirk, Fluor. Chem. 127 (2006) 1013.
[4] G. Lal, S. Pez, G.P. Syvret, Chem. Rev. 96 (1996) 1737.
[5] J. Mann, Chem. Soc. Rev. 16 (1987) 381.
[6] K. Burger, U. Wucherpfennig, E. Brunner, Adv. Heterocycl. Chem. 60 (1994) 1.
[7] R. Filler, Y. Kobayashi (Eds.), Biomedicinal Aspects of Fluorine Chemistry,
Kondansha and Elsevier Biomedical, Tokyo, 1982.
[8] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, Wiley, New
York, 1991.
Scheme 4. Synthesis of pyrazolopyridazinone derivatives 14.
[9] I. Ojima, J.R. McCarthy, J.T. Welch (Eds.), Biomedical Frontiers of Fluorine
Chemistry. ACS Symposium Series 639, American Chemical Society, Wash-
ington, DC, 1996.
[10] S. Narizuka, T. Fuchigami, Bioorg. Med. Chem. Lett. 5 (1995) 1293.
[11] T. Hiyama, Organofluorine Compounds: Chemistry and Applications, Springer,
Berlin, 2000.
1635 cmꢀ1. The 1H NMR spectra of the reaction products also
revealed, in each case, the presence of NH proton in the region of
d
10.04 ppm and H-5 pyrazole in the region of d 8.35 ppm in
addition to the signals of aromatic protons.
[12] (a) A. Chauhan, P.K. Sharma, N. Kaushik, Int. J. ChemTech. Res. 3 (2011) 11;
(b) S. Fustero, M. Sanchez-Rosello, P. Barrio, A. Simon-Fuentes, Chem. Rev. 111
(2011) 6984;
(c) L. Yet, in: A.R. Katritzky, C.A. Ramsden, E.F.V. Scriven, R.J.K. Taylor (Eds.),
Pyrazoles, Comprehensive Heterocyclic Chemistry III, 4, Elsevier, Oxford,
2008, p. 1e141;
4. Conclusion
(d) K.S. Patel, K.N. Raval, S.P. Patel, A.G. Patel, S.V. Patel, Int. J. Pharma. Biol. Sci.
2 (2012) 170;
Regioselective synthesis of novel pyrazoles scaffolds containing
a fluorophenyl moiety have been achieved using microwave irra-
diation. High yields of pyrazoles and short reaction times compared
with the conventional conditions were observed in this developed
method. 1H NMR measurements have been readily utilized for the
unambiguous structural characterization of the regioselectivity in
the 1,3-dipolar cycloaddition reaction of hydrazonoyl halides with
the activated alkene. The synthesis of pyrazolopyridazines is
considered as an alternative tool to confirm the structure of the
synthesized pyrazoles in a regioselective manner.
(e) P.S. Lobanov, D.V. Dar’in, Chem. Heterocycl. Compd. 49 (2013) 507.
[13] (a) L. Nagarapu, H.K. Gaikwad, K. Sarikonda, J. Mateti, R. Bantu, P.S. Raghu,
K.M. Manda, S.V. Kalvendi, Eur. J. Med. Chem. 45 (2010) 4720;
(b) J.L. Malavolta, A.A. Souto, D.L. de Mello, D.C. Flores, A.F.C. Flores, J. Fluor.
Chem. 158 (2014) 16.
[14] (a) F. Chimenti, E. Maccioni, D. Secci, A. Bolasco, P. Chimenti, A. Granese,
O. Befani, P. Turini, S. Alcaro, F. Ortuso, R. Cirilli, F. La Torre, M.C. Cardia,
S. Distinto, J. Med. Chem. 48 (2005) 7113;
(b) N. Das, B. Dash, M. Dhanawat, S.K. Shrivastava, Chem. Pap. 66 (2012) 67.
[15] D. Kaushik, R. Kumar, S. Ahmed Khan, G. Chawla, Med. Chem. Res. 21 (2012)
3646.

I.I. Althagafi, M.R. Shaaban / Journal of Molecular Structure 1142 (2017) 122e129
129
[16] (a) L. Zhu, Z. Miao, C. Sheng, J. Yao, C. Zhuang, W. Zhang, J. Fluor. Chem. 131
[23] M.R. Shaaban, T. Fuchigami, Tetrahedron Lett. 43 (2002) 273.
[24] M.R. Shaaban, H. Ishii, T. Fuchigami, Synlett 10 (2001) 1644.
[25] M.R. Shaaban, T. Fuchigami, J. Org. Chem. 65 (2000) 8685.
[26] M.R. Shaaban, H. Ishii, T. Fuchigami, J. Org. Chem. 66 (2000) 5633.
[27] (a) C.O. Kappe, A. Stadler, Microwaves in Organic and Medicinal Chemistry,
Wiley-VCH, Weinheim, 2005;
(b) C.O. Kappe, D. Dallinger, S.S. Murphree, Practical Microwave Synthesis for
Organic Chemists, Wiley-VCH, Weinheim, 2009.
[28] A.M. Farag, M.S. Algharib, Org. Prep. Proced. Int. 20 (1988) 521.
(2010) 800;
(b) M. Abid, B. TVorVok, Adv. Synth. Catal. 347 (2005) 1797.
[17] V.G. Nenajdenko, A.V. Sanin, E.S. Balenkova, Molecules 2 (1997) 186.
[18] V.G. Nenajdenko, A.V. Sanin, E.S. Balenkova, Russ. Chem. Rev. 68 (1999) 483.
[19] K. Prabakaran, F.N. Khan, J. Jin, P. Manivel, Res. Chem. Intermed. 38 (2012)
429.
[20] M.R. Shaaban, S. Inagi, T. Fuchigami, Electrochim. Acta 54 (2009) 2635.
[21] M.R. Shaaban, J. Fluor. Chem. 129 (2008) 115.
[22] N. Iwayasu, M.R. Shaaban, T. Fuchigami, Heterocycl. Comm. 57 (2002) 623.