Synthesis of novel pyrazoles incorporating a phenothiazine moiety: Unambiguous structural characterization of the regioselectivity in the 1,3-dipolar cycloaddition reaction using 2D HMBC NMR spectroscopy

Article abstract of DOI:10.1016/j.tet.2013.06.028

An efficient and attractive regioselective synthesis of a series of novel pyrazoles containing a phenothiazine moiety was achieved utilizing microwave irradiation. Unambiguous structural assignment of the obtained regioisomers was determined utilizing 2D

Full text of DOI:10.1016/j.tet.2013.06.028

Accepted Manuscript
Synthesis of novel pyrazoles incorporating a phenothiazine moiety: Unambiguous
structural characterization of the regioselectivity in the 1,3-dipolar cycloaddition
reaction using 2D HMBC NMR spectroscopy
Ahmed E.M. Mekky, Tamer S. Saleh, Abdullah S. Al-Bogami
PII:
S0040-4020(13)00958-7
10.1016/j.tet.2013.06.028
TET 24504
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 April 2013
Revised Date: 29 May 2013
Accepted Date: 10 June 2013
Please cite this article as: Mekky AEM, Saleh TS, Al-Bogami AS, Synthesis of novel pyrazoles
incorporating a phenothiazine moiety: Unambiguous structural characterization of the regioselectivity
in the 1,3-dipolar cycloaddition reaction using 2D HMBC NMR spectroscopy, Tetrahedron (2013), doi:
10.1016/j.tet.2013.06.028.
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ACCEPTED MANUSCRIPT
Synthesis of novel pyrazoles incorporating a phenothiazine moiety: Unambiguous
structural characterization of the regioselectivity in the 1,3-dipolar cycloaddition
reaction using 2D HMBC NMR spectroscopy
1
,2
1,3
1,∗
Ahmed E. M. Mekky , Tamer S. Saleh , Abdullah S. Al-Bogami
1
Chemistry Department, Faculty of Science, King Abdulaziz University, North Jeddah, P.O. Box 80203, Jeddah
21589, Saudi Arabia
2
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
Green Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
3
∗
Corresponding author. Fax: +966 26400376; Tel: +966 554433416; E-mail: chem_org@hotmail.com
1

ACCEPTED MANUSCRIPT
Synthesis of novel pyrazoles incorporating a phenothiazine moiety:
Unambiguous structural characterization of the regioselectivity in the 1,3-
dipolar cycloaddition reaction using 2D HMBC NMR spectroscopy
1
,2
1,3
1,∗
Ahmed E. M. Mekky , Tamer S. Saleh , Abdullah S. Al-Bogami
1
Chemistry Department, Faculty of Science, King Abdulaziz University, North Jeddah, P.O. Box 80203, Jeddah
21589, Saudi Arabia
2
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
Green Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
3
ABSTRACT
An efficient and attractive regioselective synthesis of a series of novel pyrazoles
containing a phenothiazine moiety was achieved utilizing microwave irradiation.
Unambiguous structural assignment of the obtained regioisomers were
determined utilizing 2D HMBC NMR techniques as a valuable tool.
Keywords
microwave irradiation; phenothiazine; pyrazole; hydrazonyl halides; HMBC;
regioselectivity
∗
Corresponding author. Fax: +966 26400376; Tel: +966 554433416; E-mail: chem_org@hotmail.com
2

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1
. Introduction
The phenothiazine structure occurs in various neuroleptic drugs, e.g.
1
2
chlorpromazine, and antihistaminic drugs, e.g. promethazine. The term
phenothiazines" describes the largest of the five main classes of neuroleptic
"
antipsychotic drugs. These drugs have antipsychotic, and often antiemetic
properties, although they may also cause severe side effects such as
extrapyramidal symptoms (including akathisia and tardive dyskinesia),
hyperprolactinaemia, and the rare but potentially fatal neuroleptic malignant
3
syndrome, as well as substantial weight gain. These side effects associated with
phenothiazine drugs have raised a cautionary flag on these drugs.
Phenothiazine antipsychotics are classified into three groups that differ
with respect to the substituent on the ring. Hence, there remains a demand for
more efficacious and safer phenothiazine derivatives; this can be attained by the
synthesis of a large number of novel phenothiazine derivatives for biological
screening programmes.
On the other hand, enaminones have proven to be valuable synthons for a
4
-8
wide variety of biologically active heterocyclic ring systems. One of these
9
-12
important classes is the pyrazole system.
Literature reports reveal many
synthetic approaches used for the synthesis of pyrazole derivatives, one of the
most important approach being the 1,3-dipolar cycloaddition utilizing
nitrilimines (generated insitu by the action of base on the hydrazonoyl halide)
13-15
and α,β-unsaturated carbonyl compounds (Scheme 1).
3

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O
O
R
R'
R
R'
R
X
-
Me NH
2
N
N
N
NMe2
N
NH
Ar
N
Ar
Ar
A
Base
HX
Ar
O
R
N
OR
C
N
+
R'
NMe2
R
R
NMe2
-
Me NH
2
R'
R'
N
N
N
N
O
O
Ar
Ar
B
Scheme 1: 1,3-Dipolar cycloaddation reaction
The above reaction proceeds regioselectively to give only one product A or B.
However, to the best of our knowledge, it is frequently difficult to present
unequivocal proof of the reaction product structures for this 1,3-dipolar
cycloaddition reaction. Therefore, it is crucial to rationalize the observed
regioselectivity. Single crystal X-ray is a useful tool for the unambiguous
structure determination of the obtained products, but it is sometimes difficult to
access a single crystal of the formed product.
Motivated by the aforementioned findings, and in a continuation of our interest
in the synthesis of a wide range of heterocyclic systems for biological screening
1
6-31
in our laboratory,
we report herein on the 1,3-dipolar cycloaddition of some
nitrilimines to the versatile, hitherto unreported E-3-(dimethylamino)-1-(10H-
phenothiazin-2-yl) prop-2-en-1-one (2) under both microwave irradiation and
conventional methods. This provides a convenient route for obtaining the novel
phenothiazine derivatives bearing a pyrazole moiety. Unambiguous structure
determination of the obtained regioisomers utilizing 2D NMR techniques as a
valuable tool for the identification and characterization of pyrazoles was
employed which could facilitate the work of the pharmacologist in the study of
the structure activity relationship of bioactive molecules.
4

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2
. Results and discussion
The reaction of equimolar quantities of 1-(10H-phenothiazin-2-yl)ethanone (1)
and dimethylformamide-dimethylacetal (DMF-DMA) was carried out in toluene
under microwave irradiation. The key intermediate E-3-(dimethylamino)-1-
(10H-phenothiazin-2-yl)prop-2-en-1-one (2) was obtained within 45 min. as
evidenced by TLC (Scheme 2), while the same reaction carried out via reflux in
toluene required 18 h.
O
O
H
N
H
N
OMe
OMe
Me
Toluene
NMe2
+
Me2N
M.W or Reflux
S
S
1
2
Scheme 2: Synthesis of enaminone 2
The structure of the enaminone 2 was confirmed by its elemental analysis and
1
spectroscopic data. Its H NMR spectrum displayed two singlet signals at δ 2.88
and 3.13, due to the N,N-dimethyl protons, two doublets at δ 5.69 and 7.70 (J
=
12.4 Hz), due to the olefinic protons, in addition to aromatic proton signals in
the region δ 6.66-7.30 and D O exchangeable singlet signal, due to the NH
2
proton at δ 8.68. The value of the coupling constant (J =12.4 Hz) for the
ethylenic protons indicates that the enaminone 2 exists exclusively in the E-
configuration. The reactivity of enaminones, in general, can be attributed to the
fact that they have two electron poor centers at C-1 and C-3 in addition to one
electron-rich center at C-2, attributed by the delocalization of the lone pair of
electrons on the nitrogen atom (Figure 1).
Figure 1: Structure of Enaminone 2
5

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The double bond in compound 2 can be looked on as an electron-rich one
that may enter into 1,3-dipolar cycloaddition reactions with hydrazonyl halides.
On the other hand, there are many types of hydrazonyl halides as represented in
Figure 2. Type I are α-ketohydrazonoyl halides, type II are N-
arylbenzenecarbohydrazonoyl halide, type III are oxalodihydrazonyl dihalides
and type IV are N-aryltrifluoromethylcarbohydrazonoyl halides
Figure 2: Some types of hydrazonyl halides
These hydrazonyl halides in presence of a base liberate in situ, intermediates
known as nitrilimines. These can react easily with α,β-unsaturated ketones such
as enaminones to afford a pyrazole via a 1,3-dipolar cycloaddition reaction.
Therefore, our current research is directed to the study of the regioselectivity in
the 1,3-dipolar cycloaddition of some nitrilimines (liberated in situ for
hydrazonyl halides types I and III) with enaminone 2. Thus, when compound 2
was allowed to react with the nitrilimine 4 (liberated, in situ, from the
corresponding hydrazonyl halides (Type I) 3 by the action of triethylamine in
dioxane under microwave irradiation), it afforded in each case, only one isolable
product as shown by TLC analysis (Scheme 3). The times of reactions and
yields are shown in Table 1.
6

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O
Ar
N
N
R
O
O
H
N
S
NMe2
Cl
R
-HCl
N
NH
Ar
5
3
a-h
TEA, Dioxane
H
O
N
O
O
H
N
R
O
O
R
3
4
MW or Reflux
Dioxane
S
+
2
R
N
-Me2NH
N
S
2
N
1
5
N
Ar
N
NMe2
N
Ar
4a-h
Ar
7a-h
6
O
O
NMe2
R
R
3
4
O
O
2
N
N
5
N
N
2
-Me NH
1
Ar
Ar
NH
NH
S
S
9a-h
8
Scheme 3: Reaction of hydrazony halids (type I) with enaminone 2
We have three possible products 5, 7 or 9. Amidrazone structure 5 was easily
1
ruled out on the basis of the H NMR spectra of the reaction products. In
principle, two isomeric structures, 7a-h or 9a-h are possible for the product on
the basis of elemental analysis and spectroscopic data of the isolated products.
1
For example, the H NMR spectra of the isolated products show, in each case,
disappearance of NMe signals, and the two doublets of the olefinic protons, and
2
appearance of a singlet signal corresponding to pyrazole proton in the region δ
8
.96-9.23. The IR spectra of the isolated products, in each case, showed the
presence of two carbonyl absorption bands, and the presence of a band due to a
NH group (Scheme 3).
3
2-34
To our knowledge, the previously reported results
for similar reactions based
1
on one dimension H NMR spectroscopy assume that in the pyrazole ring
system, C-4 is more electron-rich carbon than C-5; thus, H-4 is expected to
appear at a higher field, typically at a lower chemical shift than H-5, which is
7

ACCEPTED MANUSCRIPT
linked to a carbon attached to a nitrogen atom, and therefore is deshielded and
typically appeared at a higher chemical shift.
We agree with this assumption to some extent, if we can compare the
1
spectra of two regioisomers. In the present case, we have only one H NMR
spectrum in view of the fact that the reaction proceeded in a regioselective
manner. The chemical shift in NMR spectroscopy is considered a tensor not a
scalar, so we can not decide if the obtained chemical shift of the pyrazole proton
is a lower or higher value.
Therefore, distinction between the two possible regioisomers is very important,
so we introduce here, a simple 2D-NMR experiment to unambiguouly elucidate
the structure of the obtained regioisomer.
Structure elucidation was conveniently achieved on the basis of the long-range
1
13
C–H connectivities via H- C HMBC, (Figure 3a) depending on the correlation
between the pyrazole proton with the carbons of the two carbonyl groups. For
1
13
example, the H- C HMBC spectrum of the isolated product 7a or 9a, shows a
signal at δ 193.14 ppm corresponding to the carbonyl carbon due to its
correlation peak with the signal at δ 2.59 ppm assigned to the methyl protons of
the acetyl group (Figure 3b).
pyrazole proton
methyl protons
a
8

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methyl protons
methyl protons correlate to carbonyl
carbonyl group
carbon of acetyl group
b
pyrazole proton
pyrazole proton correlates
to only one carbonyl group
carbonyl group
c
d
1
13
Figure 3: (a) the H- C HMBC spectrum of the isolated regioisomer 7a or 9a
b) correlation between methyl protons and carbonyl group (c) correlation
between pyrazol proton and carbonyl group (d) diagnostic correlations in the
(
1
13
H- C HMBC (red arrows) for two regioisomer 7a and 9a
9

ACCEPTED MANUSCRIPT
On the other hand, the signal at δ 188.96 ppm is attributed to the other carbonyl
group, owing to its correlation peak with the signal at δ 9.02 ppm, easily
assigned to the pyrazole proton (Figure 3C). These observations indicate that
3
only one carbonyl functional group correlates to the pyrazole proton ( J ), in
H-C
accordance with the structure 7a, in addition to the other observed correlations
2
3
of the pyrazole protons with C-4 pyrazole ( J ), C-3 pyrazole ( J ) and the
H-C
H-C
3
desheilded quaternary carbon of the phenyl group ( J ) (Figure 3c and Figure
H-C
3
d). Therefore, these results confirm the existence of regioisomer 7a and rule
out the alternative structure 9a.
The formation of novel pyrazole derivatives 7a-h were assumed to be formed
via initial 1,3-dipolar cycloaddition of the nitrilimines 4a-h to the activated
double bond in the enaminone 2 to afford the non-isolable dihydropyrazole
intermediates 8, followed by elimination of dimethylamine, yielding the
pyrazole derivative 7a-h.
It is noteworthy that the structure of pyrazole derivatives 7a-h resulting from
type I hydrazonyl halides can be confirmed chemically via the reaction of
compounds 7a-h with hydrazine to afford the pyrazolo[3,4-d] pyridazine
derivatives 10a-h in almost quantitative yields (Scheme 4). The time of
reactions and yields are shown in Table 1.
O
CH3
N
N
NH
N
N
Ar
N
Ar
N
N
MW or Reflux
Ethanol
MW or Reflux
Ethanol
7e-h
7a-d
NH NH .H O
NH NH .H O
2
2
2
2 2 2
HN
HN
S
S
10e-h
10a-d
Scheme 4: Synthesis of pyrazolo[3,4-d] pyridazine derivatives 10a-h
The structures of the products 10a-h were confirmed based on their elemental
analysis and spectrscopic data. The IR spectra of compounds 10a-d showed
disappearance of the two carbonyl absorption bands. Also, the IR spectra of
1
0

ACCEPTED MANUSCRIPT
compounds 10e-h showed appearance of two bands due to the two NH groups.
The mass spectra of 10a showed a peak corresponding to the molecular ion at
1
4
07 and its H NMR spectrum revealed a singlet at δ 2.49 due to the methyl
protons, a D O exchangeable singlet signal at δ 8.79 and a singlet signal at δ
2
9
.56 due to the pyrazole H-5 proton in addition to aromatic multiplets.
In order to address the advantage of microwave irradiation on the above
mentioned reactions, all the previously mentioned reaction were carried out
using conventional method via reflux in dioxane and/or ethanol (Table 1). The
obtained results revealed that the reactions are took a longer time to attain a
much lower yield than that obtained using the microwave protocol.
Table 1: Synthesis of pyrazole 7a-h pyrazolo[3,4-d]pyridazine derivatives
1
0a-h under both Microwave irradiation and conventional method
Entry
1
Product
Microwave Irradiation Conventional Condition
Time (min.) Yield % Time (h)
Yield %
1
1
20
20
91
93
48
48
69
7
a
H
2
N
O
O
H3C
S
N
N
70
CH3
7
b
1
1

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H
3
4
N
O
O
H3C
S
N
N
F
1
20
93
89
48
48
65
62
7
c
9
0
7
d
5
6
1
1
20
00
90
91
48
48
65
62
7
e
7
f
7
8
1
1
20
90
88
48
48
62
58
7
g
20
1
2

ACCEPTED MANUSCRIPT
7
h
9
3
0
93
95
3
3
88
85
1
0a
CH3
1
0
30
N
N
H C
N
3
N
HN
S
1
0b
1
1
30
92
3
81
1
0c
CH3
1
2
30
89
3
85
N
N
F3C
N
N
HN
S
1
0d
1
3

ACCEPTED MANUSCRIPT
O
1
3
30
88
3
80
N
NH
N
N
HN
S
1
0e
O
1
4
30
87
3
79
N
NH
H C
N
3
N
HN
S
1
0f
1
5
30
90
3
77
1
0g
1
6
30
93
3
83
1
0h
Thus, microwave irradiation was found to have a beneficial effect on the
synthesis of pyrazole derivatives7a-h and pyrazolo[3,4-d]pyridazine derivatives
1
0a-h, in which there was a substantial decrease in the time of above reactions
1
4

ACCEPTED MANUSCRIPT
from 3-48 h under conventional heating to 30min.-2 h. In addation there was a
noticeable improvement in the yields of the reactions under microwave
irradiations.
Encouraged by the successful characterization of pyrazole derivatives 7a-h, the
reaction protocol was further extended to the reaction of other hydrazonyl
halides of type III with enaminone 2, in order to provide unambiguous structure
determination of the obtained regioisomers. It is worth mentioning that the
regioisomeric products in this case can not be proved chemically like the
regioisomeric product of type I hydrazonyl halides with enaminone 2.
It is important to mention here, that the reaction of oxalodihydrazonyl
dichlorides (11) (Type III) with enaminone 2 afforded the regioselective bis
pyrazole product 13 or 14; however, oxalodihydrazonyl dichlorides (11) (Type
III) were relatively more reactive and sensitive to heat than type I; it required
less exposure time to MW irradiation at lower power for completion of the
reaction.
The reaction was also performed under conventional conditions, by stirring the
reactant at room temperature (Scheme 5).
Reaction of oxalodihydrazonyl dichlorides (11) (Type III) with enaminone 2
under microwave irradiation also resulted in exclusive formation of a single
regioisomer that may have structure 13 or 14 (Scheme 5). The challenge was to
differentiate and determine its structure by NMR spectroscopy.
1
5

ACCEPTED MANUSCRIPT
Scheme 5: Regioselective synthesis of bis-Pyrazole derivative 13
1
13
We found that H- C HMBC is also a useful tool to unambigously assign the
structure of isolated regioisomers unambiguously.
Structure elucidation of the isolated product 13 or 14 was achieved on the basis
1
13
of the long-range C–H connectivities via H- C HMBC, based on the number of
correlations between the pyrazole proton towards carbons that are two and three
1
13
bonds away (Figure 4a). The presence of four correlations in H- C HMBC
spectrum of the isolated product is conclusive evidence for the proposed
structure 13 (Figure 4b).
a
1
6

ACCEPTED MANUSCRIPT
b
Figure 4: (a) number of correlations between pyrazole proton towards carbons
in the possible regioselective products 13 and 14
1
13
(
b) H- C HMBC spectrum of the isolated product
Finally, our efforts will be extended to encompass unambiguous structural
charactraization of the regioselectivity in 1,3-dipolarcycloaddation reactions
with other types of hydrazonyl halides.
3
. Conclusion
An efficient microwave-assisted protocol for the regioselective synthesis of a
series of novel pyrazoles incorporating a phenothiazine moiety is reported.
Microwave irradiation offered high yields of pyrazoles in a short reaction time,
1
13
compared with classical heating. 2D ( H– C) HMBC measurements can be
readily utilized for the unambiguous structural characterization of the
regioselectivity in the 1,3-dipolar cycloaddition reaction of hydrazonyl halides,
type I and type III with enaminones.
4
. Experimental section
4
.1. General
1
7

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All organic solvents were purchased from commercial sources and used as
received unless otherwise stated. All other chemicals were purchased from
Merck, Aldrich or Acros and used without further purification. Thin-layer
chromatography (TLC) was performed on precoated Merck 60 GF254 silica gel
plates with a fluorescent indicator, and detection by means of UV light at 254
and 360 nm. The melting points were measured on a Stuart melting point
apparatus and are uncorrected. IR spectra were recorded on a Smart iTR which
is an ultra-high-performance, versatile Attenuated Total Reflectance (ATR)
sampling accessory on the Nicolet iS10 FT-IR spectrometer. The NMR spectra
1
were recorded on on a Bruker Avance III 400 (9.4 Tesla, 400.13 MHz for H
1
3
and 100.62 MHz for C) spectrometer with a 5-mm BBFO probe, at 298 K.
Chemical shifts (δ in ppm) are given relative to internal solvent, CDCl 7.26 for
3
1
13
1
13
H and 77.0 for C. ( H– C) gs-HMBC was acquired and processed using
standard Bruker NMR software (Topspin 3.2). Mass spectra were recorded on a
Thermo ISQ Single Quadrupole GC-MS. Elemental analyses were carried out
on a EuroVector instrument C, H, N, S analyzer EA3000 Series.
Microwave experiments were performed using CEM Discover & Explorer SP
microwave apparatus (300 W), utilizing 35 ml capped glass reaction vessels
Automated power control based on temperature feedback.
3
5
α-Ketohydrazonoyl halides 3a-h
and N,N-diphenyloxalodi-hydrazonoyl
3
6
dichloride (11) were prepared according to the reported literature.
4
.2. General procedure and characterization data
4
1
.2.1. Synthesis of E-3-(dimethylamino)-1-(10H-phenothiazin-2-yl)prop-2-en-
-one (2):
Method A: To a solution of 1-(10H-phenothiazin-2-yl)ethanone (1) (2.41g, 10
mmol) in toluene (30 mL), dimethylformamide-dimethylacetal (DMF-DMA)
1
8

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(2.62 mL, 20 mmol) was added and refluxed for 18 h (untill no starting materials
showed by in TLC). The excess toluene and DMF-DMA was distilled off under
reduced pressure. The residual solid was taken up in ether (20 mL) and the
resulting crystals were collected by filtration, washed thoroughly with ether,
dried and finally recrystallized from dry benzene to afford the enaminone 3 in
(2.58g, 87 % yield).
Method B: This process was performed using microwave irradiation (300 Watt,
o
1
00 C) on the same scale described above. Here the reactants were dissolved in
toluene and subjected to microwave irradiation for 45 min. until the starting
materials were no longer detectable by TLC. The product was obtained and
purified (2.75 g, 93% yield) as described above in conventional reaction .
-1
1
Orange solid, mp 249-251 °C; IR (KBr) ν/cm : 3256 (NH), 1636 (CO); H NMR (DMSO-d ):
6
3 3
δ 2.88 (s, 3H, CH ), 3.13 (s, 3H, CH ), 5.69 (d, 1H, =CH-CO, J = 12.4 Hz), 6.66 (d, 1H, ArH,
J = 8 Hz), 6.75 (t, 1H, ArH, J = 8 Hz), 6.91 (d, 1H, ArH, J = 8 Hz), 6.94 (d, 1H, ArH, J = 8
Hz), 6.99 (t, 1H, ArH, J = 8 Hz), 7.22 (s, 1H, ArH), 7.30 (d, 1H, ArH, J = 8 Hz), 7.70 (d, 1H,
1
3
=
2 6
CH-N, J = 12.4 Hz), 8.68 (s, 1H, NH, D O-exchangeable); C NMR (DMSO-d ): δ 14.16,
3
1
9.35, 62.14, 64.86, 116.03, 122.73, 124.31, 131.34, 132.36, 134.11, 137.80, 145.80, 146.31,
+
56.68, 161.47, 166.13; MS: M (296); C H N OS (296.39): Anal. Calcd: C, 68.89; H, 5.44;
17
16
2
N, 9.45; S, 10.82. Found C, 68.83; H, 5.38; N, 9.40; S, 10.78%.
4
.2.2.Typical procedure for the synthesis of pyrazole derivatives 7a-h
Method A: To a mixture of enaminone 2 (2.96g, 10 mmol) and the appropriate
hydrazonyl chloride 3a-h (10 mmol) in dioxane (15 mL), an equivalent amount
of triethylamine (10 mmol) was added. The total mixture was placed in a
process vial in the microwave, and was irradiated with a power of 300 W to
o
reach a reaction temperature of 140 C under auto generated pressure. The vial
was exposed to microwaves for the required time to complete the reaction. The
progress of the reaction was monitored by TLC (eluent; ethylacetate:
chloroform). Upon completion of the reaction, the solvent was evaporated under
1
9

ACCEPTED MANUSCRIPT
reduced pressure. The obtained solid product was crystallized using ethanol to
afford the corresponding pyrazole derivatives 7a–h.
Method B: To a hot solution of enaminone 2 (10 mmol) and the appropriate
hydrazonyl halides 3a-h (1.39 mL, 10 mmol) in dioxane (25 mL), triethylamine
(10 mmol) was added. The reaction mixture was refluxed for 48 h. The solvent
was evaporated under reduced pressure. The solid product was crystallized from
ethanol to afford the corresponding pyrazole derivatives 7a–h.
4
.2.2.1.
1-(4-(10H-phenothiazine-2-carbonyl)-1-phenyl-1H-pyrazol-3-
yl)ethanone (7a)
-
1
Orange solid, mp 258-260 °C; IR (KBr) ν/cm : 3406 (NH), 1682, 1645 (CO),
1
1
593 (C=N); H NMR (DMSO-d ): δ 2.59 (s, 3H, CH CO), 6.61 (d, 1H, ArH, J
6
3
=
8 Hz), 6.76 (t, 1H, ArH, J = 8 Hz), 6.92 (d, 1H, ArH, J = 8 Hz), 6.97-7.02 (m,
2
7
H, ArH), 7.07 (s, 1H, ArH), 7.17 (d, 1H, ArH, J = 8 Hz), 7.47 (t, 1H, ArH, J =
.6 Hz), 7.60 (t, 2H, ArH, J = 7.6 Hz), 7.99 (d, 2H, ArH, J = 8 Hz), 8.73 (s, 1H,
1
3
NH, D O-exchangeable), 9.02 (s, 1H, pyrazole-5-CH); C NMR (DMSO-d ): δ
2
6
2
1
1
4
7.50, 114.59, 114.98, 115.55, 119.85, 122.63, 123.11, 123.19, 124.09, 126.60,
26.75, 128.49, 130.28, 131.56, 136.91, 137.06, 139.02, 141.59, 142.40, 150.30,
+
88.96, 193.14; MS: M (411); C H N O S (411.48): Anal. Calcd: C, 70.05; H,
2
4
17
3
2
.16; N, 10.21; S, 7.79. Found C, 69.98; H, 4.12; N, 10.11; S, 7.71%.
4
3
.2.2.2. 1-(1-(4-methylphenyl)-4-(10H-phenothiazine-2-carbonyl)-1H-pyrazol-
-yl)ethanone (7b)
-
1
Orange solid, mp 218-220 °C; IR (KBr) ν/cm : 3402 (NH), 1682, 1647 (CO) ,
1
1
6
585 (C=N); H NMR (DMSO-d ): δ 2.38 (s, 3H, CH ), 2.58 (s, 3H, CH CO),
6
3
3
.60 (d, 1H, ArH, J = 8 Hz), 6.76 (t, 1H, ArH, J = 8 Hz), 6.91 (d, 1H, ArH, J = 8
Hz), 6.97-7.02 (m, 2H, ArH), 7.06 (s, 1H, ArH), 7.17 (d, 1H, ArH, J = 8 Hz),
.40 (d, 2H, ArH, J = 8.4 Hz), 7.87 (d, 2H, ArH, J = 8.4 Hz), 8.74 (s, 1H, NH,
7
13
D O-exchangeable), 8.96 (s, 1H, pyrazole-5-CH); C NMR (DMSO-d ): δ
2
6
2
0

ACCEPTED MANUSCRIPT
2
1
1
0.99, 27.49, 114.60, 114.98, 115.55, 119.71, 122.62, 123.01, 123.16, 124.03,
26.60, 126.75, 128.48, 130.62, 131.36, 136.81, 137.09, 138.06, 141.59, 142.38,
+
50.08, 189.01, 193.12; MS: m/z 425 (M ); C H N O S (425.50): Anal. Calcd:
2
5
19
3
2
C, 70.57; H, 4.50; N, 9.88; S, 7.54. Found C, 70.50; H, 4.46; N, 9.83; S, 7.48%.
4
3
.2.2.3. 1-(1-(4-fluorophenyl)-4-(10H-phenothiazine-2-carbonyl)-1H-pyrazol-
-yl)ethanone (7c)
-
1
Red solid, mp 253-255 °C; IR (KBr) ν/cm : 3345 (NH), 1690, 1636 (CO) , 1594
1
(
C=N); H NMR (DMSO-d ): δ 2.60 (s, 3H, CH CO), 6.59 (d, 1H, ArH, J = 8
6
3
Hz), 6.75 (t, 1H, ArH, J = 8 Hz), 6.91 (d, 1H, ArH, J = 8 Hz), 6.98-7.03 (m, 2H,
ArH), 7.10 (s, 1H, ArH), 7.19 (d, 1H, ArH, J = 8 Hz), 7.45 (d, 2H, ArH, J = 8
Hz), 7.83 (d, 2H, ArH, J = 8 Hz), 8.75 (s, 1H, NH, D O-exchangeable), 9.02 (s,
2
1
3
1
1
1
H, pyrazole-5-CH); C NMR (DMSO-d ): δ 27.45, 114.63, 115.09, 115.65,
6
19.82, 122.60, 122.89, 123.19, 124.16, 126.66, 127.31, 128.51, 131.01, 131.43,
37.18, 141.05, 141.50, 142.41, 150.16, 160.97, 188.91, 193.14; MS: m/z 429
+
(
M ); C H FN O S (429.47): Anal. Calcd: C, 67.12; H, 3.76; N, 9.78; S, 7.47.
2
4
16
3
2
Found C, 67.06; H, 3.70; N, 9.75; S, 7.42%.
4
1
.2.2.4. 1-(4-(10H-phenothiazine-2-carbonyl)-1-(4-(trifluoromethyl)phenyl)-
H-pyrazol-3-yl)ethanone (7d)
-
1
Red solid, mp 270-272 °C; IR (KBr) ν/cm : 3413 (NH), 1983, 1640 (CO) , 1606
1
(
C=N); H NMR (DMSO-d ): δ 2.61 (s, 3H, CH CO), 6.61 (d, 1H, ArH, J = 8
6
3
Hz), 6.76 (t, 1H, ArH, J = 8 Hz), 6.91 (d, 1H, ArH, J = 8 Hz), 6.98-7.03 (m, 2H,
ArH), 7.08 (s, 1H, ArH), 7.18 (d, 1H, ArH, J = 8 Hz), 7.99 (d, 2H, ArH, J = 8.4
Hz), 8.24 (d, 2H, ArH, J = 8.4 Hz), 8.74 (s, 1H, NH, D O-exchangeable), 9.16
2
13
(
s, 1H, pyrazole-5-CH); C NMR (DMSO-d ): δ 27.54, 114.46, 115.00, 115.53,
6
1
1
20.30, 122.65, 123.31, 123.49, 124.29, 126.62, 126.75, 127.58, 127.61, 128.50,
32.11, 136.91, 137.06, 141.54, 141.83, 142.42, 150.85, 188.72, 193.12; MS:
2
1

ACCEPTED MANUSCRIPT
+
m/z 479 (M ); C H F N O S (479.47): Anal. Calcd: C, 62.62; H, 3.36; N, 8.76;
2
5
16
3
3
2
S, 6.69. Found C, 62.57; H, 3.30; N, 8.73; S, 6.64%.
4
.2.2.5. Ethyl 4-(10H-phenothiazine-2-carbonyl)-1-phenyl-1H-pyrazole-3-
carboxylate (7e)
-
1
Yellow solid, mp 185-187 °C; IR (KBr) ν/cm : 3302 (NH), 1717, 1671 (CO) ,
1
1
599 (C=N); H NMR (DMSO-d ): δ 1.14 (t, 3H, CH , J = 7.2 Hz), 4.21 (q, 2H,
6
3
CH , J = 7.2 Hz), 6.51 (d, 1H, ArH, J = 8 Hz), 6.78 (t, 1H, ArH, J = 8 Hz), 6.90
2
(d, 1H, ArH, J = 8 Hz), 6.92-6.96 (m, 2H, ArH), 7.11 (s, 1H, ArH), 7.21 (d, 1H,
ArH, J = 8 Hz), 7.37 (t, 1H, ArH, J = 8 Hz), 7.46 (t, 2H, ArH, J = 8 Hz), 7.72 (d,
2
5
1
1
H, ArH, J = 8 Hz), 8.76 (s, 1H, NH, D O-exchangeable), 9.19 (s, 1H, pyrazole-
2
1
3
-CH); C NMR (DMSO-d ): δ 13.82, 61.75, 114.13, 114.64, 116.65, 120.06,
6
22.40, 122.72, 123.80, 124.39, 125.92, 126.55, 127.78, 128.29, 129.64, 129.95,
+
37.19, 139.57, 141.41, 141.68, 143.83, 161.53, 188.43; MS: m/z 441 (M );
C H N O S (441.50): Anal. Calcd: C, 68.01; H, 4.34; N, 9.52; S, 7.26. Found
2
5
19
3
3
C, 67.94; H, 4.29; N, 9.47; S, 7.22%.
4
.2.2.6. Ethyl 1-(4-methylphenyl)-4-(10H-phenothiazine-2-carbonyl)-1H-
pyrazole-3-carboxylate (7f)
-
1
Orange solid, mp 210-212 °C; IR (KBr) ν/cm : 3290 (NH), 1717, 1669 (CO) ,
1
1
603 (C=N); H NMR (DMSO-d ): δ 1.13 (t, 3H, CH , J = 7.2 Hz), 2.39 (s, 3H,
6
3
CH ), 4.24 (q, 2H, CH , J = 7.2 Hz), 6.52 (d, 1H, ArH, J = 8 Hz), 6.76 (t, 1H,
3
2
ArH, J = 8 Hz), 6.88 (d, 1H, ArH, J = 8 Hz), 6.90-6.99 (m, 2H, ArH), 7.09 (s,
1
2
H, ArH), 7.19 (d, 1H, ArH, J = 8 Hz), 7.40 (d, 2H, ArH, J = 8.4 Hz), 7.79 (d,
H, ArH, J = 8.4 Hz), 8.71 (s, 1H, NH, D O-exchangeable), 9.16 (s, 1H,
2
1
3
pyrazole-5-CH); C NMR (DMSO-d ): δ 13.79, 20.89, 61.70, 114.09, 114.60,
6
1
1
16.39, 119.88, 122.34, 122.67, 124.02, 124.41, 125.90, 126.48, 127.79, 128.11,
29.24, 130.10, 137.07, 139.23, 141.50, 141.80, 143.91, 161.37, 188.22; MS:
2
2

ACCEPTED MANUSCRIPT
+
m/z 455 (M ); C H N O S (455.53): Anal. Calcd: C, 68.55; H, 4.65; N, 9.22; S,
2
6
21
3
3
7
.04. Found C, 68.49; H, 4.58; N, 9.17; S, 7.00%.
4
.2.2.7. Ethyl 1-(4-fluorophenyl)-4-(10H-phenothiazine-2-carbonyl)-1H-
pyrazole-3-carboxylate (7g)
-
1
Red solid, mp 196-198 °C; IR (KBr) ν/cm : 3289 (NH), 1721, 1663 (CO) , 1601
1
(
C=N); H NMR (DMSO-d ): δ 1.17 (t, 3H, CH , J = 7.2 Hz), 4.24 (q, 2H, CH ,
6
3
2
J = 7.2 Hz), 6.58 (d, 1H, ArH, J = 8 Hz), 6.82 (t, 1H, ArH, J = 8 Hz), 6.92-7.00
m, 3H, ArH), 7.11 (s, 1H, ArH), 7.18 (d, 1H, ArH, J = 8 Hz), 7.61 (d, 2H, ArH,
J = 8.4 Hz), 8.98 (d, 2H, ArH, J = 8.4 Hz), 8.75 (s, 1H, NH, D O-exchangeable),
(
2
1
3
9
1
1
.23 (s, 1H, pyrazole-5-CH); C NMR (DMSO-d ): δ 13.83, 61.80, 113.98,
6
14.62, 116.47, 121.61, 122.05, 122.80, 123.86, 124.49, 125.82, 126.61, 127.53,
27.81, 130.07, 137.17, 139.60, 141.39, 141.82, 143.92, 160.90, 161.42, 188.29;
+
MS: m/z 459 (M ); C H FN O S (459.49): Anal. Calcd: C, 65.35; H, 3.95; N,
2
5
18
3
3
9
.14; S, 6.98. Found C, 65.29; H, 3.88; N, 9.09; S, 6.92%.
4
.2.2.8.
Ethyl
4-(10H-phenothiazine-2-carbonyl)-1-(4-(trifluoromethyl)
phenyl)-1H-pyrazole-3-carboxylate (7h)
-
1
Orange solid, mp 202-204 °C; IR (KBr) ν/cm : 3311 (NH), 1720, 1673 (CO) ,
1
1
606 (C=N); H NMR (DMSO-d ): δ 1.13 (t, 3H, CH , J = 7.2 Hz), 4.19 (q, 2H,
6
3
CH , J = 7.2 Hz), 6.66 (d, 1H, ArH, J = 8 Hz), 6.75 (t, 1H, ArH, J = 8 Hz), 6.90
2
(d, 1H, ArH, J = 8 Hz), 6.97-7.02 (m, 2H, ArH), 7.11 (s, 1H, ArH), 7.29 (d, 1H,
ArH, J = 8 Hz), 7.98 (d, 2H, ArH, J = 8.4 Hz), 8.21 (d, 2H, ArH, J = 8.4 Hz),
13
8
.77 (s, 1H, NH, D O-exchangeable), 9.22 (s, 1H, pyrazole-5-CH); C NMR
2
(
DMSO-d ): δ 14.13, 61.69, 114.46, 115.01, 115.52, 120.36, 121.34, 122.29,
6
1
1
22.67, 123.27, 124.34, 124.45, 126.68, 127.54, 128.20, 128.51, 132.34, 137.08,
+
40.02, 141.51, 142.13, 144.55, 161.30, 188.85; MS: m/z 509 (M );
C H F N O S (509.50): Anal. Calcd: C, 61.29; H, 3.56; N, 8.25; S, 6.29.
2
6
18
3
3
3
Found C, 61.22; H, 3.49; N, 8.20; S, 6.23%.
2
3

ACCEPTED MANUSCRIPT
4
.2.3. Synthesis of pyrazolo[3,4-d]pyridazine derivatives 10a-h
Method A: To a solution of appropriate pyrazole derivatives 7a-h (1 mmol) in
ethanol (10 mL), hydrazine hydrate (98%) (2mL, 10 mmol) was added. The total
mixture was placed in a process vial and was irradiated by microwaves with a
power of 300 W to reach a reaction temperature of 140 °C under auto generated
pressure for 30 min. The solid was filtered off, washed with ethanol and
recrystallized from DMF to afford the corresponding pyrazolo[3,4-d]pyridazine
derivatives 10a-h.
Method B: A mixture of the appropriate pyrazole derivatives 7a-g (1 mmol) and
hydrazine hydrate (98%), (2mL, 10 mmol) was heated under reflux in ethanol
(20 mL) for 3 hour then left to cool to room temperature. The precipitates were
collected by filtration, washed with ethanol and dried. Recrystallization from
dimethylformamide (DMF) afforded yellow crystals of the corresponding
pyrazolo[3,4-d]pyridazine derivatives 10a-h.
4
.2.3.1.
2-(7-methyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-4-yl)-10H-
phenothiazine (10a)
-
1
1
Orange solid, mp 284-286 °C; IR (KBr) ν/cm : 1590 (C=N); H NMR (DMSO-
d ): δ 2.87 (s, 3H, CH ), 6.71 (d, 1H, ArH, J = 8 Hz), 6.78 (t, 1H, ArH, J = 8
6
3
Hz), 6.95 (d, 1H, ArH, J = 8 Hz), 7.02 (t, 1H, ArH, J = 8 Hz), 7.10 (d, 1H, ArH,
J = 8 Hz), 7.55-7.58 (m, 2H, ArH), 7.60-7.67 (m, 3H, ArH), 8.20 (d, 2H, ArH, J
1
3
=
8 Hz), 8.79 (s, 1H, NH, D O-exchangeable), 9.56 (s, 1H, pyrazole-5-CH); C
2
NMR (DMSO-d ): δ 18.48, 113.69, 115.01, 115.29, 116.20, 119.79, 121.85,
6
1
1
22.18, 122.40, 125.08, 126.75, 126.91, 128.24, 129.75, 130.24, 135.94, 139.59,
+
42.00, 142.78, 144.34, 151.76, 153.07; MS: m/z 407 (M ); C H N S (407.49):
24
17
5
2
4

ACCEPTED MANUSCRIPT
Anal. Calcd: C, 70.74; H, 4.21; N, 17.19; S, 7.87. Found C, 70.69; H, 4.14; N,
1
7.14; S, 7.83%.
4
1
.2.3.2.
2-(7-methyl-2-(4-methylphenyl)-2H-pyrazolo[3,4-d]pyridazin-4-yl)-
0H-phenothiazine (10b)
-
1
1
Orange solid, mp 256-258 °C; IR (KBr) ν/cm : 1587 (C=N); H NMR (DMSO-
d ): δ 2.40 (s, 3H, CH ), 2.88 (s, 3H, CH ), 6.70 (d, 1H, ArH, J = 8 Hz), 6.79 (t,
6
3
3
1
7
H, ArH, J = 8 Hz), 6.94 (d, 1H, ArH, J = 8 Hz), 7.01 (t, 1H, ArH, J = 8 Hz),
.12 (d, 1H, ArH, J = 8 Hz), 7.56-7.59 (m, 2H, ArH), 7.61 (d, 2H, ArH, J = 8
Hz), 8.10 (d, 2H, ArH, J = 8 Hz), 8.79 (s, 1H, NH, D O-exchangeable), 9.56 (s,
2
1
3
1
1
1
H, pyrazole-5-CH); C NMR (DMSO-d ): δ 18.46, 20.87, 113.65, 115.01,
6
15.17, 116.18, 119.71, 121.83, 122.11, 122.38, 125.10, 126.76, 126.87, 128.25,
29.80, 130.33, 135.84, 140.06, 142.09, 142.71, 144.39, 151.75, 153.01; MS:
+
m/z 421 (M ); C H N S (421.52): Anal. Calcd: C, 71.23; H, 4.54; N, 16.61; S,
2
5
19
5
7
.61. Found C, 71.15; H, 4.50; N, 16.56; S, 7.57%.
4
1
.2.3.3.
2-(2-(4-fluorophenyl)-7-methyl-2H-pyrazolo[3,4-d]pyridazin-4-yl)-
0H-phenothiazine (10c)
-
1
1
Red solid, mp 261-263 °C; IR (KBr) ν/cm : 1595 (C=N); H NMR (DMSO-d ):
6
δ 2.89 (s, 3H, CH ), 6.73 (d, 1H, ArH, J = 8 Hz), 6.79 (t, 1H, ArH, J = 8 Hz),
3
6
.95 (d, 1H, ArH, J = 8 Hz), 7.02 (t, 1H, ArH, J = 8 Hz), 7.13 (d, 1H, ArH, J = 8
Hz), 7.60 (s, 1H, ArH), 7.63 (d, 1H, ArH, J = 8 Hz), 7.78 (d, 2H, ArH, J = 8.4
Hz), 8.04 (d, 2H, ArH, J = 8.4 Hz), 8.78 (s, 1H, NH, D O-exchangeable), 9.61
2
13
(
s, 1H, pyrazole-5-CH); C NMR (DMSO-d ): δ 18.51, 113.67, 115.01, 115.38,
6
1
1
16.17, 119.90, 122.45, 125.40, 126.10, 126.76, 126.93, 128.26, 129.61, 129.94,
35.77, 139.62, 142.34, 142.75, 144.39, 151.93, 153.31, 160.97; MS: m/z 425
+
(
M , 22%); C H FN S (425.48): Anal. Calcd: C, 67.75; H, 3.79; N, 16.46; S,
2
4
16
5
7
.54. Found C, 67.70; H, 3.72; N, 16.41; S, 7.49%.
2
5

ACCEPTED MANUSCRIPT
4
.2.3.4.
2-(7-methyl-2-(4-(trifluoromethyl)phenyl)-2H-pyrazolo[3,4-
d]pyridazin-4-yl)-10H-phenothiazine (10d)
-
1
1
Red solid, mp 290-292 °C; IR (KBr) ν/cm : 1600 (C=N); H NMR (DMSO-d ):
6
δ 2.88 (s, 3H, CH ), 6.72 (d, 1H, ArH, J = 8 Hz), 6.79 (t, 1H, ArH, J = 8 Hz),
3
6
.96 (d, 1H, ArH, J = 8 Hz), 7.03 (t, 1H, ArH, J = 8 Hz), 7.12 (d, 1H, ArH, J = 8
Hz), 7.57 (s, 1H, ArH), 7.63 (d, 1H, ArH, J = 8 Hz), 8.06 (d, 2H, ArH, J = 8.4
Hz), 8.49 (d, 2H, ArH, J = 8.4 Hz), 8.81 (s, 1H, NH, D O-exchangeable), 9.75
2
13
(
s, 1H, pyrazole-5-CH); C NMR (DMSO-d ): δ 18.49, 113.62, 115.03, 115.44,
6
1
1
16.15, 119.99, 122.42, 125.64, 126.00, 126.76, 126.94, 127.54, 127.57, 128.27,
29.50, 129.83, 135.78, 141.96, 142.41, 142.81, 144.58, 151.94, 153.27; MS:
+
m/z 475 (M ); C H F N S (475.49): Anal. Calcd: C, 63.15; H, 3.39; N, 14.73;
2
5
16
3
5
S, 6.74. Found C, 63.09; H, 3.32; N, 14.68; S, 6.70%.
4
7
.2.3.5.
4-(10H-phenothiazin-2-yl)-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-
(6H)-one (10e)
-
1
Yellow solid, mp 281-283 °C; IR (KBr) ν/cm : 3309, 3291 (NH), 1653 (CO) ,
1
1
601 (C=N); H NMR (DMSO-d ): δ 6.70 (d, 1H, ArH, J = 8 Hz), 6.80 (t, 1H,
6
ArH, J = 8 Hz), 6.95 (d, 1H, ArH, J = 8 Hz), 7.02 (t, 1H, ArH, J = 8 Hz), 7.07
d, 1H, ArH, J = 8 Hz), 7.28 (s, 1H, ArH), 7.39 (d, 1H, ArH, J = 8 Hz), 7.54 (t,
(
1
8
H, ArH, J = 8 Hz), 7.64 (t, 2H, ArH, J = 8 Hz), 8.13 (d, 2H, ArH, J = 8 Hz),
.75 (s, 1H, NH, D O-exchangeable), 9.35 (s, 1H, pyrazole-5-CH), 12.65 (s, 1H,
2
1
3
NH, D O-exchangeable); C NMR (DMSO-d ): δ 113.02, 115.00, 116.24,
2
6
1
1
18.57, 118.73, 121.20, 122.32, 126.31, 126.76, 126.90, 128.22, 129.34, 130.25,
34.78, 139.45, 141.21, 141.99, 142.75, 143.24, 144.56, 156.36; MS: m/z 409
+
(
M , 22%); C H N OS (409.46): Anal. Calcd: C, 67.47; H, 3.69; N, 17.10; S,
2
3
15
5
7
.83. Found C, 67.39; H, 3.60; N, 17.06; S, 7.75%.
4
.2.3.6.
2-(4-methylphenyl)-4-(10H-phenothiazin-2-yl)-2H-pyrazolo[3,4-
d]pyridazin-7(6H)-one (10f)
2
6

ACCEPTED MANUSCRIPT
-
1
Yellow solid, mp > 300 °C; IR (KBr) ν/cm : 3311, 3294 (NH), 1657 (CO) ,
1
1
603 (C=N); H NMR (DMSO-d ): δ 2.40 (s, 3H, CH ), 6.68 (d, 1H, ArH, J = 8
6
3
Hz), 6.81 (t, 1H, ArH, J = 8 Hz), 6.95 (d, 1H, ArH, J = 8 Hz), 7.01 (t, 1H, ArH,
J = 8 Hz), 7.09 (d, 1H, ArH, J = 8 Hz), 7.25 (s, 1H, ArH), 7.37 (d, 1H, ArH, J =
8
Hz), 7.42 (d, 2H, ArH, J = 8 Hz), 7.66 (d, 2H, ArH, J = 8 Hz), 8.72 (s, 1H,
NH, D O-exchangeable), 9.32 (s, 1H, pyrazole-5-CH), 12.61 (s, 1H, NH, D O-
2
2
1
3
exchangeable); C NMR (DMSO-d ): δ 18.47, 113.01, 115.05, 116.22, 118.53,
6
1
1
18.70, 121.24, 122.29, 126.27, 126.76, 126.91, 128.24, 129.32, 130.28, 134.75,
+
39.48, 141.26, 142.10, 142.83, 143.31, 144.55, 155.53; MS: m/z 423.49 (M );
C H N OS (423): Anal. Calcd: C, 68.07; H, 4.05; N, 16.54; S, 7.57. Found C,
2
4
17
5
6
8.00; H, 4.01; N, 16.45; S, 7.51%.
4
.2.3.7.
2-(4-fluorophenyl)-4-(10H-phenothiazin-2-yl)-2H-pyrazolo[3,4-
d]pyridazin-7(6H)-one (10g)
-
1
Orange solid, mp > 300 °C; IR (KBr) ν/cm : 3315, 3301 (NH), 1660 (CO) ,
1
1
595 (C=N); H NMR (DMSO-d ): δ 6.73 (d, 1H, ArH, J = 8 Hz), 6.80 (t, 1H,
6
ArH, J = 8 Hz), 6.95 (d, 1H, ArH, J = 8 Hz), 7.03 (t, 1H, ArH, J = 8 Hz), 7.12
d, 1H, ArH, J = 8 Hz), 7.30 (s, 1H, ArH), 7.41 (d, 1H, ArH, J = 8 Hz), 7.76 (d,
H, ArH, J = 8.4 Hz), 8.05 (d, 2H, ArH, J = 8.4 Hz), 8.76 (s, 1H, NH, D O-
(
2
2
exchangeable), 9.32 (s, 1H, pyrazole-5-CH), 12.68 (s, 1H, NH, D O-
2
1
3
exchangeable); C NMR (DMSO-d ): δ 113.11, 115.16, 116.18, 118.46, 119.02,
6
1
1
22.42, 126.11, 126.75, 126.93, 128.27, 129.51, 129.98, 134.86, 139.60, 141.32,
+
42.05, 142.75, 143.30, 144.50, 155.59, 161.09; MS: m/z 427 (M );
C H FN OS (427.45): Anal. Calcd: C, 64.63; H, 3.30; N, 16.38; S, 7.50. Found
2
3
14
5
C, 64.57; H, 3.26; N, 16.36; S, 7.47%.
4
.2.3.8.
4-(10H-phenothiazin-2-yl)-2-(4-(trifluoromethyl)phenyl)-2H-
pyrazolo[3,4-d]pyridazin-7(6H)-one (10h)
2
7

ACCEPTED MANUSCRIPT
-
1
Orange solid, mp > 300 °C; IR (KBr) ν/cm : 3321, 3314 (NH), 1662 (CO) ,
1
1
603 (C=N); H NMR (DMSO-d ): δ 6.71 (d, 1H, ArH, J = 8 Hz), 6.79 (t, 1H,
6
ArH, J = 8 Hz), 6.96 (d, 1H, ArH, J = 8 Hz), 7.05 (t, 1H, ArH, J = 8 Hz), 7.15
d, 1H, ArH, J = 8 Hz), 7.33 (s, 1H, ArH), 7.46 (d, 1H, ArH, J = 8 Hz), 8.09 (d,
H, ArH, J = 8.4 Hz), 8.43 (d, 2H, ArH, J = 8.4 Hz), 8.76 (s, 1H, NH, D O-
(
2
2
exchangeable), 9.34 (s, 1H, pyrazole-5-CH), 12.64 (s, 1H, NH, D O-
2
1
3
exchangeable); C NMR (DMSO-d ): δ 113.12, 115.10, 116.17, 118.85, 119.93,
6
1
1
21.20, 122.44, 124.60, 126.31, 126.76, 126.91, 128.23, 129.42, 130.11, 135.06,
+
39.66, 141.41, 142.09, 142.77, 143.34, 144.56, 155.54; MS: m/z 477 (M );
C H F N OS (477.46): Anal. Calcd: C, 60.37; H, 2.96; N, 14.67; S, 6.72.
2
4
14
3
5
Found C, 60.31; H, 2.90; N, 14.62; S, 6.68%.
4
1
.2.4. Synthesis of 4,4'-di(10H-phenothiazine-2-carbonyl)-1,1'-diphenyl-
H,1'H-3,3'-bipyrazole (13)
Method A: To a mixture of enaminone 2 (2.96 g, 10 mmol) and the appropriate
N,N'-diphenyloxalodihydrazonoyl dichloride (11) (1.54 g, 5 mmole) in dioxane
(15 ml), an equivalent amount of triethylamine (10 mmol) was added. The total
mixture was placed in a process vial and was irradiated by microwaves with a
o
power of 50 W to reach a reaction temperature of 70 C under auto generated
pressure. The vial was exposed to microwaves for the required time to complete
the reaction. The progress of the reaction was monitored by TLC (eluent;
ethylacetate: chloroform). Upon completion of the reaction, the solvent was
evaporated under reduced pressure to obtain the solid product in (3.28 g, 89%
yield). The obtained solid product was crystallized using ethanol to afford the
corresponding bipyrazole derivative 13.
Method B: This process was performed with stirring at room temperature on the
same scale described above for the microwave reaction. The reactants were
stirred in dioxane for 24 h until the starting materials were no longer detectable
2
8

ACCEPTED MANUSCRIPT
by TLC. The product was obtained and purified (2.43 g, 66% yield) as
described above in microwave reaction .
-
1
Brown solid, mp 152-154 °C; IR (KBr) ν/cm : 3394 (NH), 1651 (CO), 1590
1
(
C=N); H NMR (DMSO`-d ): δ 6.61 (d, 1H, ArH, J = 8 Hz), 6.76 (t, 1H, ArH,
6
J = 8 Hz), 6.91 (d, 1H, ArH, J = 8 Hz), 6.98-7.03 (m, 2H, ArH), 7.08 (s, 1H,
ArH), 7.18 (d, 1H, ArH, J = 8 Hz), 7.47 (t, 1H, ArH, J = 7.6 Hz), 7.60 (t, 2H,
ArH, J = 7.6 Hz), 8.00 (d, 2H, ArH, J = 8 Hz), 8.74 (s, 1H, NH, D O-
2
1
3
exchangeable), 9.03 (s, 1H, pyrazole-5-CH); C NMR (DMSO-d ): δ 114.55,
6
1
1
14.98, 115.56, 119.85, 122.68, 123.19, 123.24, 124.19, 126.65, 126.74, 128.49,
30.34, 131.66, 136.99, 137.08, 139.06, 142.56, 142.63, 143.42, 195.34; MS:
+
M (736); C H N O S (736.86): Anal. Calcd: C, 71.72; H, 3.83, N, 11.41; S,
44
28
6
2 2
8
.70. Found C, 71.66; H, 3.78; N, 11.39; S, 8.62%.
References
[1] Liu, X; De Haan, S. Cochrane Database Syst Rev, 2009, 2, CD007778.
[2] Tarkkila, P; Tôrn, K; Tuominen, M; Lindgren, L. Acta Anaesthesiol Scand
1
995, 39, 983–986.
th
[
3] Dale, M.M.; Rang, H. P. in Rang & Dale's pharmacology, 7 edition,
Elsevier/Edinburgh : Churchill Livingstone, 2012.
[
[
[
4] Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433-2480.
5] Stanovnik, B.; Svete, J. Synlett 2000, 1077-1091.
6] Selic, L.; Jaksˇe, R.; Lampic, K.; Golic, L.; Golic Grdadolnik, S.; Stanovnik,
B. Helv. Chim. Acta 2000, 83, 2802-2811
[7] Selic, L.; Stanovnik, B. Tetrahedron 2001, 57, 3159-3164.
[8] Selic, L.; Recnik, S.; Stanovnik, B. Heterocycles, 2002, 58, 577-585.
2
9