Chemistry of Phosphorus Ylides: Part 46—Efficient Synthesis and Biological Evaluation of New Phosphorus, Sulfur, and Selenium Pyrazole Derivatives

Article abstract of DOI:10.1002/jhet.3361

1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde was allowed to react with different phosphorus, sulfur, and selenium reagents. The reaction products depend on the nature of the reagent and the condition of the reaction used. Treatment of the carbaldehyde with the active phosphacumulene ylides afforded the phosphoranylidene pyranopyrazoles. On the other hand, its reaction with the stable phosphonium ylides gave the oxaphosphetanes. Sulfidodithiaphosphetane pyrazole was generated from the reaction of Japanese reagent with the carbaldehyde. Selenido-oxaselenaphosphetane and dioxaphospholane pyrazoles were obtained from the reaction of the carbaldehyde with Woolin's reagent and phosphorus triamide, respectively. The antimicrobial screening of the synthesized compounds was also evaluated.

Full text of DOI:10.1002/jhet.3361

Month 2018
Chemistry of Phosphorus Ylides: Part 46—Efficient Synthesis and
Biological Evaluation of New Phosphorus, Sulfur, and Selenium
Pyrazole Derivatives
Mansoura A. Abd-El-Maksoud,a
Tamer K. Khatab,a
Soher S. Maigali,a
Fouad M. Soliman,
and
a
*
Ahmed A. Hamedb
aOrganometallic and Organometalloid Chemistry Department, National Research Centre, 33-El-Buhouth Street, P.O. Box
12622, Dokki, Giza, Egypt
bMicrobial Chemistry Department, National Research Centre, 33-El-Buhouth Street, P.O. Box 12622, Dokki, Giza, Egypt
*E-mail: solimanfma2@yahoo.com
Received May 27, 2018
DOI 10.1002/jhet.3361
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde was allowed to react with differ-
ent phosphorus, sulfur, and selenium reagents. The reaction products depend on the nature of the reagent and
the condition of the reaction used. Treatment of the carbaldehyde with the active phosphacumulene ylides
afforded the phosphoranylidene pyranopyrazoles. On the other hand, its reaction with the stable phospho-
nium ylides gave the oxaphosphetanes. Sulfidodithiaphosphetane pyrazole was generated from the reaction
of Japanese reagent with the carbaldehyde. Selenido-oxaselenaphosphetane and dioxaphospholane pyrazoles
were obtained from the reaction of the carbaldehyde with Woolin’s reagent and phosphorus triamide, respec-
tively. The antimicrobial screening of the synthesized compounds was also evaluated.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
molluscicidal activities [12]. Moreover, some of these
analogues have shown promising human Ch K1 kinase
growth inhibition [13].
Pyrazole and its derivatives constitute an important
compound covering a broad range of synthetic as well as
natural products that display innumerable chemical,
biological,
agrochemical,
and
pharmacological
RESULTS AND DISCUSSION
properties [1–7]. Moreover, considerable amount of work
has been carried out in the synthetic development of
envisaging the pyrazole fusion with the pyran
heterocyclic unit with potential applications in medicinal
chemistry. Pyranopyrazole derivatives have been
particularly found to exhibit anticancer [8], antimicrobial
[9], insecticidal [10], anti-inflammatory [11], and
Chemistry.
In our continuing studies, we have
described the development of new biomolecules of
therapeutic interest from the reaction of active and
stabilized phosphonium ylides with bioactive natural and
unnatural products with potential applications in
medicinal chemistry [14–21].
© 2018 Wiley Periodicals, Inc.

M. A. Abd-El-Maksoud, T. K. Khatab, S. S. Maigali, F. M. Soliman, and A. A. Hamed
Vol 000
By
reacting
1,5-dimethyl-3-oxo-2-phenyl-2,3-
1H, 13C, 31P NMR, and mass spectral data. The mass
spectrum of 6a showed the molecular ion peak at m/z 550
(M)+ and a signal in the 31P NMR spectrum at δ
31.79 ppm, which supports the oxaphosphetane
structure [23,24]. On the other hand, in the mass
spectrum of the oxobutene 7c, the molecular ion peak
was found at m/z (%) = 256 (M+, 100) (Scheme 2).
The reaction of phosphinimine 8 was studied with the
carbaldehyde 1, too. In their reactivity, the
iminophosphoranes are inferior to phosphinalkylenes
[25–27]. We have found that the carbaldehyde 1 reacted
with N-(triphenylphosphoranylidene) aniline (8) in
boiling toluene for 20 h, to give 1,5-dimethyl-2-phenyl-
dihydro-1H-pyrazole-4-carbaldehyde (1) with (N-
phenyliminovinylidene)-triphenylphosphorane (2a) in
tetrahydrofuran (THF), compound 1,7a-dimethyl-2-
phenyl-6-(phenylimino)-7-(triphenylphosphoranylidene)-1,
6,7,7a-tetrahydropyrano[4,3-c]pyrazol-3(2H)-one (3a) was
obtained. The phosphacumulene ylides can be represented
by the resonance structures 2A and 2B. They react with
some unsaturated compounds with the resonance structure
2A and with carbonyl compounds the resonance structure
2B (Wittig reaction). Thus, the reaction of the
carbaldehyde 1 with the cumulated phosphonium ylide 2a
run by [4 + 2]-cycloaddition and gave the pyran 3a. No
triphenylphosphane oxide was isolated from the reaction,
which means that no [2 + 2]-cycloaddition of 2a to the
aldehyde group of 1 occurred. The structure of product 3a
was confirmed on the basis of the respective spectral data.
4-((phenylimino)methyl)-1H-pyrazol-3(2H)-one
together with triphenylphosphane oxide.
(9),
The
mass spectrum of 9 showed an molecular ion peak at
m/z = (291, [M]+) (Scheme 3).
1
In the H NMR spectrum of 3a signals appeared at δ 1.62
P-S heterocycles have been well established, and they
are widely used [28–31]. In the present study, we
investigated the reactions of some thionating agents on
the carbaldehyde 1. When phosphorus pentasulfide was
allowed to react with carbaldehyde 1 in THF at room
temperature, 1,5-dimethyl-2-phenyl-3-thioxo-2,3-dihydro-
1H-pyrazole-4-carbothialdehyde (10) was obtained. The
IR spectrum of 10 showed the characteristic band due to
the C═S at 1185 and 1120 cmꢀ1, and in its MS, an ion
peak was observed at m/z 247 [M–H]+.
(s, 3 H, CH3), 3.10 (s, 1 H, N–CH3), 6.16 (s, 1 H,
CH═C), 6.79–7.77 (m, 25 H, Ar–H). The 13C NMR
spectrum of 3a showed signals at δ 162.46 (C═O,
pyrazolone), 154.15 (C═N), 148.86 (C═P), 111.17–
143.84 (arom.-C), 39.96 (N–CH3), and 27.50 ppm (CH3).
Moreover, a signal at δ 28.79 ppm was observed in its
31P NMR spectrum [22].
When the reaction of the carbaldehyde 1 with (2-
oxovinylidene) triphenylphosphorane (2b) was carried out in
boiling
toluene,
1,7a-dimethyl-2-phenyl-7-
Chemistry of Japanese reagent (JR) (2,4-bis(phenylthio)-
1,2,3,4-dithiaphosphetane-2,4-disulfide) (11a) has been
studied for many years. This reagent 11a exists in
equilibrium with the monomeric form 11b, which can be
incorporated with the substrate [32–35]. When the
carbaldehyde 1 reacted with JR 11b in THF at room
(triphenylphosphoranylidene)-1,2,7,7a-tetrahydropyrano[4,3-
c]pyrazole-3,6-dione (3b) was obtained (Scheme 1).
The behavior of the stabilized phosphonium ylides 4a–
4f toward the carbaldehyde 1 was studied, too, to
determine the site of attack. It was found that
methoxycarbonyl-(4a), ethoxycarbonyl-(4b), acetyl-(4c),
benzoyl-(4d), formyl-(4e), and nitrile-(4f) methylene
triphenylphosphorane react with the carbaldehyde 1 to
give the intermediates betains 5a–5f, by addition of the
ylide carbon atom to the carbonyl group of the
carbaldehyde 1. In the second step, a four-membered ring
6 is formed. Compounds 6a and 6b are stable, but the
intermediates 6c–6f decompose into the olefins 7c–7f and
triphenylphosphane oxide. The structure of the
oxaphosphetane 6a was established on the basis of IR,
temperature,
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazole-4-carbothialdehyde (12) was isolated. The
mass spectrum of 12 showed an ion peak m/z (%) at 232
(M+, 15), and its IR spectrum showed the (C═O, pyrazole)
and the C═S at 1649 and 1159 cmꢀ1, respectively. On the
other hand, when the carbaldehyde 1 reacted with JR in
dry boiling toluene for 10 h, 1,5-dimethyl-2-phenyl-
4-(2-(phenylthio)-2-sulfido-1,3,2-dithiaphosphetan-4-yl)-
1H-pyrazol-3(2H)-one (13b) was formed. It could be
concluded that formation of the dithiaphosphetane 13b
Scheme 1. Synthesis of pyranopyrazole derivatives (3a,b) from the reaction of carbaldehyde 1 and phosphacumulene (2a,b).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Efficient Synthesis and Biological Evaluation of New Phosphorus, Sulfur and
Selenium Pyrazole Derivatives
Scheme 2. Synthesis of oxaphosphetane (6a, 6b) and olfin derivatives 7c–7f from the reaction of carbaldehyde 1 and stabilized phosphonium ylides 4a–
4b. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 3. Synthesis of iminopyrazole derivative 9.
from the reaction of JR 11b and carbaldehyde 1, firstly,
thionation reaction occurred to the oxygen atom of
carbaldehyde 1 followed by the nucleophilic attack of the
sulfur center of compound 1 on the electron-deficient
center of the monomeric species of JR 11b to give the
zwitterionic adduct 13a, which cyclizes to give the
dithiaphosphetane 13b. Upon treatment of the
carbaldehyde 1 with phosphorus pentasulfide or JR on
cold temperature, thionation reactions occur, and we
isolate only compound 10 or 12, respectively. But when
the reaction of 1 with JR was performed on hot
temperature, the new heterocyclic sulfur compound 13b
was obtained (Scheme 4). The most important feature in
the spectroscopic data of compound 13b is that an ion
peak at m/z (20%) 436 (M)+ was found in the MS.
Selenium is an essential element for life; selenocysteine
is viewed as the 21st amino acid in the natural
repertoire, and the importance of selenium-containing
enzymes in redox processes has been increasingly
recognized
[36–38].
Moreover,
organoselenium
compounds have been studied as biological models that
are capable of simulating catalytic functions demonstrated
by natural enzymes [39–41].
Woolin’s reagent (14a ⇌ 14b), just like JR, dissociates,
and as a result in the solution, there is diselenophosphine
ylide, which is the appropriate nucleophilic reagent (14b)
[42]. So the present study was extended also to the
reaction of the carbaldehyde 1 with Woolin’s reagent in
boiling toluene. 1,5-Dimethyl-2-phenyl-4-(2-phenyl-2-
selenido-1,3,2-oxaselenaphosphetan-4-yl)-1H-pyrazol-3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Abd-El-Maksoud, T. K. Khatab, S. S. Maigali, F. M. Soliman, and A. A. Hamed
Vol 000
Scheme 4. Synthesis of organophosphorus and sulfur pyrazole derivatives 10, 12, and 13b from the reaction of carbon disulfide and Japanese reagent 11a
with pyrazolone carbaldehyde 1.
(2H)-one (15) was obtained (Scheme 5). The structure of
compound 15 was confirmed through its MS; it showed
the m/z (%) at 482 (M+, 8).
against Gram-positive bacteria Staphylococcus aureus
and Gram-negative bacteria Pseudomonas aeruginosa by
using acetyltetracyclene as reference standard. The
solvent control used was dimethyl sulfoxide (DMSO).
The yeast and antifungal activities were screened against
Candida albicans and Aspergillus niger. The inhibition
zone for each compound was measured and compared
with the reference. The results of antimicrobial screening
are illustrated in Table 1 and show that most of the tested
compounds have excellent to good antimicrobial interest.
Compounds 3a, 3b, 6a, 7c, 10, 13b, and 15 are the most
active compounds against the yeast C. albicans,
exceeding the inhibitory effect of the reference drug; the
clear inhibition zone reached from 6 to 11 mm, while the
inhibition zone for the reference was zero, and it is
considered an excellent result. Moreover, compounds 3a
and 7c showed good inhibition zone that reached 7 mm
for both compounds and 6 mm for compound 13b equal
to that of the reference antibiotic against the fungus
A. niger. On the other hand, excellent antimicrobial
activity was also achieved by compounds 6b and 7c
against the Gram-negative strain pathogen P. aeruginosa
with clear zone higher than that of the reference drug. It
is well known that pyrazole derivatives have a big
diversity in antimicrobial activity [47], especially
pyranopyrazoles. Therefore, compound 3a showed a
good result; the clear inhibition zone reached 21 mm, and
it is a good result, near to the inhibitory effect of the
reference against Gram-positive bacteria S. aureus
because it contains phosphopyranpyrazole, which is
Hexamethylphosphorus triamide (16) is
a strong
nucleophile used to synthesize epoxides and arene oxides
from aldehydes [43–45]. Thus, the reagent also replaces
triphenylphosphane in the Wittig reaction [46].
Now, the reaction of the aldehyde 1 with the phosphorus
triamide reagent 16 was performed in boiling toluene. The
product of the reaction depends upon the electronegativity
of the aldehyde and the mode of carrying out the
reaction. Compound 4,40-(dimethylamino)-2-oxido-1,4,2-
dioxaphospholane-3,5-diyl)bis(1,5-dimethyl-2-phenyl-1H-
pyrazol-3(H)-one (20) was only isolated. The mechanism
of this reaction can be explained by initial nucleophilic
attack of the aldehyde 1 by the phosphorus triamide 16 to
form the phosphonium 1:1 adduct 17. This adduct 17
reacted with a second aldehyde molecule to form the 2:1
adduct 18, which cyclizes to the dioxaphospholane 19.
The intermediate 19 adds molecule of water in the
presence of unavoidable moisture to give the final stable
oxaphospholane pyrazole 20 along with dimethylamine
1
(Scheme 6). The H NMR of 20 shows signals at δ 1.74
(s, 6 H, C–CH3), 2.01 (d, 6 H, P–N–CH3), 2.51 (s, 6H,
2
N–CH3), 5.45 (d, 1H, JHP = 6 Hz, O–CH–P), 6.49 (d,
3
1H, JHP = 3 Hz, O–CH–O), and 7.31–7.81 ppm (m, 10
H, aromatics).
Antimicrobial evaluation.
The newly prepared
compounds 3a, 3b, 6a, 6b, 7c, 7d, 7e, 10, 12, 13b, 15,
and 20 were screened for their antimicrobial activity
Scheme 5. Synthesis of selenido-oxaselenaphosphetane derivative 15.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Efficient Synthesis and Biological Evaluation of New Phosphorus, Sulfur and
Selenium Pyrazole Derivatives
Scheme 6. Synthesis of dioxaphospholane derivative 20 from the reaction of pyrazolone carbaldehyde 1 and hexamethylphosphorus triamide 16.
Table 1
Antimicrobial activities of the new compounds.
Inhibition clear zone (mm)
Gram
stain
Compound no.
Reference
antibiotic
Microorganism
reaction
3a
21
3b
6a
6b
7c
7d
7e
10
12
13b
15
20
(acetyltetracyclene)
Staphylococcus
aureus
Pseudomonas
aeruginosa
Candida
albicans
Aspergillus
niger
Positive
Negative
Yeast
11
6
6
NA NA NA
6
9
15
NA
NA
25
10
0
9
8
7
6
8
15
11
11
7
NA NA
NA NA
6
6
7
11
6
8
6
NA
NA
NA
9
7
NA
6
NA
Fungus
NA NA NA
NA NA NA NA
NA
7
NA, no activity.
bioactive against these pathogens [48]. Moreover, the
skeleton of 6a includes the oxaphosphetane group, which
increases the physiological properties. In addition, a few
of the tested compounds appeared to have moderate
inhibitory effect; some of them had no inhibitory effect
as well.
CONCLUSION
The synthesis of pyrazole derivatives containing
phosphorus, sulfur, and selenium reagents represent an
interesting approach to the preparation of new bioactive
heterocyclic compounds. The reaction of pyrazole
Journal of Heterocyclic Chemistry
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M. A. Abd-El-Maksoud, T. K. Khatab, S. S. Maigali, F. M. Soliman, and A. A. Hamed
Vol 000
carbaldehyde 1 with the active phosphacumulenes 2a,b
took place smoothly with the formation of the
Elemental analysis (C, H, N) results were recorded with
Elementar Vario EL Germany, and all of these agreed sat-
isfactory with the calculated values. The reported yields are
of pure isolated materials obtained by column chromatog-
raphy silica gel 60 (Merck) and thin-layer chromatography
(TLC), which was performed on Merck Kiesel gel F254
precoated plates (Merck, Darmstadt, Germany). The
starting material, no. 1, was purchased from Aldrich Com-
pany under CAS no. 950-81-2; compound 8 was from Al-
drich Company CAS no. 2325-27-1; compound 14 was
from Aldrich Company CAS no. 122039-27-4; and com-
pound 16 was from Merck Company CAS no. 680-31-9.
Solvents were dried/purified according to literature proce-
dures [49].
phosphoranylidene
pyranopyrazoles
3a,b,
while
the reaction of the stable phosphonium ylides 4a–b with
the aldehyde 1 afforded the oxaphosphetanes 6a,b, and the
phosphonium ylides 4c–f gave the olefins 7c–f. On
the other hand, the phosphinimine 8, which is less reactive
than are the phosphinalkylenes 4a–f, afforded the
iminomethylpyrazole 9, on reaction with the carbaldehyde
1. Moreover, the reaction of the sulfur reagents
phosphorus pentasulfide and JR 11 with the carbaldehyde
1 resulted in the formation of the thioxopyrazole 10,
pyrazole carbothialdehyde 12, and sulfidodithiaphosphetane
pyrazole 13. The present investigation afforded also the
selenido-oxaselenaphosphetane pyrazole 15 from the
reaction of Woolin’s reagent 14 with the carbaldehyde 1.
Finally, the oxaphospholane pyrazole 20 was isolated from
the reaction of hexamethylphosphorus triamide 16 and the
carbaldehyde 1. These reactions supply direct route for the
synthesis of phosphorus, sulfur, and selenium derivatives.
Moreover, the antimicrobial activity of the synthesized
compounds showed that compounds 3a, 3b, 6a, 7c, 10,
13b, and 15 recorded a marked high activity against the
yeast C. albicans, while compounds 3a, 7c, and 13b were
the most active with the fungus than was the reference
drug, and compounds 6b and 7c have the highest activity
against the Gram-negative bacteria P. aeruginosa. In
addition, compound 3a recorded moderate activity with
S. aureus, the Gram-positive bacteria.
Interaction
triphenylphosphorane (2a) with 1,5-dimethyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde (1).
of
(N-phenyliminovinylidene)
A
solution
of
(N-phenyliminovinylidene)
triphenylphosphorane (2a) [50] (0.377 g, 1 mmol) in
20 mL of THF was added dropwise with stirring at room
temperature to a solution of 1,5-dimethyl-3-oxo-2-phenyl-
2,3-dihydro-1H-pyrazole-4-carbaldehyde (1) (0.216 g,
1 mmol) in 20 mL of THF. The reaction mixture was
stirred for 10 h, during which the color changed from
buff to red (the progress of the reaction was monitored by
TLC). THF was distilled under reduced pressure, and the
residue was chromatographed on silica gel column using
petroleum ether (60–80°C)/ethyl acetate (60:40, v/v) as
an eluent; product 3a was isolated.
1,7a-Dimethyl-2-phenyl-6-(phenylimino)-7-
(triphenylphosphoranylidene)-1,6,7,7a-tetrahydropyrano[4,3-c]
pyrazol-3(2H)-one (3a). Yield 55%, yellow crystals, m.p.
EXPERIMENTAL
238–240°C, IR (KBr, ev, cmꢀ1): 1727 (C═O, pyrazolone),
1
1653 (C═N), 1589 (C═P), 1495, 1449 (P-aryl). H NMR
Chemistry. Melting points were determined with an
(300 MHz, DMSO, δ, ppm): 1.62 (s, 3 H, CH3), 3.10 (s,
1 H, N–CH3), 6.16 (s, 1 H, CH═C), 6.79–7.77 (m, 25 H,
Ar–H). 13C NMR (75 MHz, DMSO-d6, δ, ppm): 162.46
(C═O, pyrazolone), 154.15 (C═N), 148.86 (C═P),
111.17–143.84 (arom.-C), 39.96 (N–CH3), 27.5 (CH3).
31P NMR (202.4 MHz, DMSO-d6, δ, ppm): 28.79. MS
(m/z, %): 315 [M–(Ph3P═O) 100]+, 300 [M–
(Ph3P═O + CH3), 65]+, 285 [M–(Ph3P═O + 2 CH3), 5]+.
Anal. Calcd for C38H32N3O2P (593.65). Calcd: C, 76.88;
H, 5.43; N, 7.08; P, 5.22. Found: C, 76.79; H, 5.33; N,
electrothermal
digital
melting
point
apparatus
(Electrothermal Engineering Ltd., Essex, UK). The IR
spectra were recorded in KBr discs on a Pye Unicam SP
3300 and Shimadzu FTIR 8101 PC Infrared
Spectrophotometers (Pye Unicam Ltd., Cambridge, UK,
and Shimadzu, Tokyo, Japan, respectively). H and 13C
1
NMR spectra were obtained from a JEOL ECA 500 MHz
(Tokyo, Japan), Bruker Avance 300 MHz, and a Varian
Mercury VXR-300 MHz NMR spectrometers using
hexadeuterated DMSO (DMSO-d6) as a solvent and
tetramethylsilane as an internal reference at 500 and
300 MHz (1H NMR) and at 125 and 75.46 MHz (13C
NMR), respectively. 31P NMR spectra were obtained from
Bruker Avance 300 MHz and a JEOL ECA 500 MHz
NMR spectrometer at 121 and 202 MHz using DMSO-d6
as a solvent and tetramethylsilane as an internal reference.
Chemical shifts were related to those of the solvent. Mass
spectra (electron-impact mass spectrometry) were obtained
with ISQ (single quadrupole MS, Thermo Scientific) and
Shimadzu GCMS-QP EX mass spectrometer at 70 eV.
6.55; P, 5.10.
Reaction of (2-oxovinylidene) triphenylphosphorane (2b)
with 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-
4-carbaldehyde (1).
A solution of (2-oxovinylidene)
triphenylphosphorane (2b) [51] (0.302 g, 1 mmol) in
20 mL of dry toluene was added to a solution of 1
(0.216 g, 1 mmol) in 20 mL of dry toluene and refluxed
for 12 h, during which the color was changed from
colorless to brown and precipitate formed (the progress of
the reaction was monitored by TLC). Filter and
recrystallize by ethyl acetate to give compound 3b.
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Month 2018
Efficient Synthesis and Biological Evaluation of New Phosphorus, Sulfur and
Selenium Pyrazole Derivatives
1,7a-Dimethyl-2-phenyl-7-(triphenylphosphoranylidene)-
1,2,7,7a-tetrahydropyrano[4,3-c]pyrazole-3,6-dione (3b).
pyrazole). 31P NMR (121 MHz, DMSO-d6, δ, ppm):
33.34. MS (m/z, %): 565 [M + H]+, 550 [M–CH3]+, 286
[M–Ph3P═O]+, 277 (Ph3P═O). Anal. Calcd for
C34H33N2O4P (564.61). Calcd: C, 72.33; H, 5.89; N,
4.96; P, 5.49. Found: C, 72.19; H, 5.82; N, 4.88; P, 5.37.
Yield 70%, colorless crystals, m.p. 106–108°C, IR (KBr,
ev, cmꢀ1): 1624 (br, 2 C═O), 1483 (C═P), 1431, 1381 (P-
1
aryl). H NMR (300 MHz, DMSO, δ, ppm): 2.51 (s, 3 H,
CH3), 3.13 (s, 3 H, N–CH3), 7.37–8.34 (m, 21 H, Ar–H).
13C NMR (75 MHz, DMSO-d6, δ, ppm): 172.80 (C═O,
pyrazol), 158.58 (C═O, pyranone), 151.79 (C═P),
119.79–135.29 (arom.-C), 79.67 (CH–O), 39.10 (N–
CH3), 8.01 (CH3). 31P NMR (202.4 MHz, DMSO-d6, δ,
ppm): 29.64. MS (m/z, %): 433 [M–(2 CO + 2 CH3)+
15], 417 [(M–CO2+ CO+ 2 CH3)+, 80], 263 [(PPh3) 7],
215 [pyrazole carbaldehyde, 100]. Anal. Calcd for
C32H27N2O3P (518.54). Calcd: C, 74.12; H, 5.25; N,
5.40; P, 5.97. Found: C, 73.99; H, 5.18; N, 5.33; P, 5.85.
The reaction of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1
H-pyrazole-4-carbaldehyde (1) with stabilized phosphonium
ylides (4c–f). General procedure.
A mixture of 1
(0.216 g, 0.001 mol) and stabilized phosphonium ylides
(4c–f) (0.001 mol) [53] was refluxed in dry toluene
(50 mL) for 10 h. The solvent was distilled under
reduced pressure, and the remaining residue was purified
on silica gel column chromatography to give compounds
(7c–f) and triphenylphosphane oxide (m.p. and mixed m.
p. 151°C).
The reaction of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1
1,5-Dimethyl-4-(3-oxobut-1-en-1-yl)-2-phenyl-1H-pyrazol-
H-pyrazole-4-carbaldehyde
phosphonium ylide (4a, 4b). General procedure.
(1)
with
stabilized
3(2H)-one
(7c).
It was isolated by using
petroleum ether (60–80°C)/ethyl acetate as an eluent
(80:20, v/v), from the reaction of with
A
mixture of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazole-4-carbaldehyde (1) (0.216 g, 0.001 mol) and
stabilized phosphonium ylides (4a,b) [52] (0.001 mol) in
30 mL of dry toluene was boiled for 10 h. The colors
changed to yellow, and the precipitates are formed in
both reactions. The precipitate was filtered and
1
acetylmethylenetriphenylphosphorane (4c). Yield 35%,
colorless crystals, m.p. 165–167°C, IR (KBr, ev, cmꢀ1):
1648 (C═O, pyrazole), 1608 (C═O). 1H NMR
(500 MHz, DMSO, δ, ppm): 2.27 (s, 3 H, COCH3), 2.38
(s, 3 H, CH3), 3.25 (s, 3 H, N–CH3), 7.31–7.48 (m, 7 H,
Ar–H). MS (m/z, %): 256 [[M]+ 100], 241 [(M–CH3)+
40], 213 [(M–COCH3)+ 65], 198 [M–(2CH3 + CO)+ 7].
Anal. Calcd for C15H16N2O2 (256.30). Calcd: C, 70.29;
crystallized from benzene to give 6a and 6b, respectively.
Methyl-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)-2,2,2-triphenyl-1,2λ5-oxaphosphetane-3-
carboxylate (6a).
It was isolated from the reaction of
H, 6.29; N, 10.93. Found: C, 69.89; H, 6.21; N, 10.80.
1,5-Dimethyl-4-(3-oxo-3-phenylprop-1-en-1-yl)-2-phenyl-
the
carbaldehyde and methoxycarbonyl-
1
methylenetriphenylphosphorane (4a). Yield 55%,
colorless crystals, m.p. 133–135°C, IR (KBr, ev, cmꢀ1):
1665 (C═O, pyrazole), 1615 (C═O), 1485, 1433 (P-
1H-pyrazol-3(2H)-one (7d).
It was obtained by using
petroleum ether (60–80°C)/ethyl acetate as an eluent
(65:35, v/v), from the reaction of and
1
1
phenyl). H NMR (300 MHz, DMSO, δ, ppm): 2.39 (s, 3
benzoylmethylenetriphenylphosphorane (4d). Yield 40%,
colorless crystals, m.p. 273–275°C, IR (KBr, ev, cmꢀ1):
1663 (C═O, pyrazole), 1598 (C═O). 1H NMR
(500 MHz, DMSO, δ, ppm): 2.44 (s, 3 H, CH3), 3.28 (s,
3 H, N–CH3), 7.37–7.68 (m, 12 H, Ar–H). MS (m/z, %):
318 [[M]+ 100], 213 [[M–(COPh)]+ 40], 105 [COPh, 70].
Anal. Calcd for C20H18N2O2 (318.37). Calcd: C, 75.45;
H, CH3), 3.24 (s, 3 H, N–CH3), 3.77 (s, 3 H, O–CH3),
7.03–7.72 (m, 22 H, Ar–H). 13C NMR (75 MHz,
DMSO-d6, δ, ppm): 169.11 (2 C═O), 125.14–133.24
(arom.-C), 115.52 (CH), 51.38 (OCH3), 34.5 (N–CH3),
10.84 (CH3). 31P NMR (121 MHz, DMSO-d6, δ, ppm):
31.79. MS (m/z, %): 550 [M]+, 272 [M–(Ph3P═O), 60]+,
277 (Ph3P═O, 9). Anal. Calcd for C33H31N2O4P
(550.58). Calcd: C, 71.99; H, 5.68; N, 5.09; P, 5.63.
H, 5.70; N, 8.80. Found: C, 75.33; H, 5.58; N, 8.77.
(3-(1,5-Dimethyl-3-oxo-2-phenyl 2,3-dihydro-1H-pyrazol-4-
yl) acrylaldehyde (7e). It was isolated by using petroleum
Found: C, 71.79; H, 5.63; N, 5.01; P, 5.57.
Ethyl-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)-2,2,2-triphenyl-1,2
ether (60–80°C)/ethyl acetate as an eluent (35:65, v/v),
from the reaction of 2-(triphenylphosphoranylidene)
acetaldehyde (4e). Yield 35%, yellow crystals, m.p. 241–
243°C, IR (KBr, ev , cmꢀ1): 3425 (OH), 1657 (C═O,
λ5-oxaphosphetane-3-
carboxylate (6b). It was obtained from the reaction of 1
and ethoxycarbonylmethylenetriphenylphosphorane (6b).
Yield 45%, colorless crystals, m.p. 158–160°C, IR (KBr,
ev, cmꢀ1): 1700 (C═O, pyrazole), 1661 (C═O), 1485 (br,
1
pyrazole), 1598 (C═O). H NMR (500 MHz, DMSO, δ,
ppm): 2.42 (s, 3 H, CH3), 3.15 (s, 3 H, N–CH3), 7.21–
7.66 (m, 7 H, Ar–H), 9.86 (s, 1 H, CHO). MS (m/z, %):
242 [[M]+ 5], 188 [[M–CHCHCHO]+ 55]. Anal. Calcd
for C14H14N2O2 (242.27). Calcd: C, 69.41; H, 5.82; N,
1
p-Phenyl). H NMR (300 MHz, DMSO, δ, ppm): 1.28 (t,
3 H, CH3–CH2), 2.35 (s, 3 H, CH3), 3.21 (s, 3 H, N–
CH3), 4.17–7.25 (m, 4 H, CH3CH2 + CHO–P + CH–
COO), 6.98–7.71 (m, 20 H, Ar–H). 13C NMR (75 MHz,
DMSO-d6, δ, ppm): 168.60 (C═O, ester), 163.44, (C═O,
pyrazole), 125.16–134.27 (arom.-C), 115.84 (CH), 59.98
(CH2), 34.92 (N–CH3), 14.37 (CH3), 10.84 (CH3,
11.56. Found: C, 69.32; H, 5.75; N, 11.49.
3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl) acrylonitrile (7f). It was obtained by using petroleum
ether (60–80°C)/ethyl acetate as an eluent (90:10, v/v)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Abd-El-Maksoud, T. K. Khatab, S. S. Maigali, F. M. Soliman, and A. A. Hamed
Vol 000
from the reaction of 1 and 2-(triphenylphosphoranylidene)
acetonitrile (4f). Yield 43%, colorless crystals, m.p. 175–
177°C, IR (KBr, ev, cmꢀ1): 2196 (C ≡ N), 1658 (C═O,
temperature to a solution of 1 (0.216 g, 1 mmol) in
20 mL of THF. The reaction mixture was stirred for 12 h
during which the color changed from brown to black (the
progress of the reaction was monitored by TLC). THF
was distilled under reduced pressure, and the residue was
chromatographed on silica gel column using petroleum
ether (60–80°C)/ethyl acetate (20: 80, v/v) as an eluent;
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-
carbothialdehyde (12) was isolated. Yield 55%, colorless
crystals, m.p. 208–210°C, IR (KBr, ev, cmꢀ1): 1649 (C═O,
1
pyrazole). H NMR (500 MHz, DMSO, δ, ppm): 2.16 (s,
3 H, CH3), 3.25 (s, 3 H, N–CH3), 6.58 (d, 1H, CH, JH–
= 15 Hz), 7.45 (d, 1H, CH, JH–H = 15 Hz), 7.46–7.63
H
(m, 5 H, Ar–H). MS (m/z, %): 238 [M–H]+. Anal. Calcd
for C14H13N3O (239.27). Calcd: C, 70.28; H, 5.48; N,
17.56. Found: C, 70.13; H, 5.45; N, 17.49.
Interaction of N-(triphenylphosphoranylidene) aniline (8)
with 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-
1
pyrazole), 1159 (C═S). H NMR (500 MHz, DMSO, δ,
4-carbaldehyde
(1).
This is
a
mixture of
ppm): 2.50 (s, 3 H, CH3), 3.24 (s, 3 H, N–CH3), 5.76 (s, 1
H, CH), 7.25–7.60 (m, 5 H, Ar–H). MS (m/z, %): 232 [[M]+
15], 202 [[(M)+ꢀ2CH3] 5]. Anal. Calcd for C12H12N2OS
(232.30). Calcd: C, 62.04; H, 5.21; N, 12.06; S, 13.80.
Found: C, 61.90; H, 5.19; N, 11.95; S, 13.69.
N-(triphenylphosphoranylidene) aniline (8) (0.353 g,
0.001 mol) and pyrazole carbaldehyde (1) (0.216 g,
0.001 mol) in 20 mL of dry toluene. The reaction mixture
was refluxed for 20 h. The color changed to yellow until
no more starting materials could be detected (TLC). The
solvent was distilled under reduced pressure, and the
remaining residue was purified on silica gel column
chromatography using petroleum ether (60–80°C)/ethyl
acetate as an eluent (35:65, v/v) to give
triphenylphosphane oxide (m.p. and mixed m.p. 151°C)
and 1,5-dimethyl-2-phenyl-4-((phenylimino)methyl)-1H-
pyrazol-3(2H)-one (9). Yield 43%, brown crystals, m.p.
172–174°C, IR (KBr, ev, cmꢀ1): 1698 (C═O, pyrazole),
Interaction of Japanese and Woolin’s reagents with
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-
carbaldehyde (1). A mixture of 1 (0.216 g, 0.001 mol)
and JR 11 or Woolin’s reagents 14 (0.001 mol) was
refluxed in dry toluene (50 mL) for 10 h in the case of 11
and 20 h in the case 14 until no more starting materials
could be detected (TLC). The solvent was distilled under
reduced pressure, and the remaining residue was purified
on silica gel column chromatography to give compounds
1
1608 (C═N). H NMR (500 MHz, DMSO, δ, ppm): 2.62
13 and 15, respectively.
1,5-Dimethyl-2-phenyl-4-(2-(phenylthio)-2-sulfido-1,3,2-
(s, 3 H, CH3), 3.31 (s, 3 H, N–CH3), 7.21–7.75 (m, 10
H, Ar–H), 9.90 (s, 1H, CH═N). MS (m/z, %): 291 ([M]+,
4), 290 ([M–H]+, 20), 261 (M+–2CH3), 35). Anal. Calcd
for C18H17N3O (291.35). Calcd: C, 74.20; H, 5.88; N,
14.42. Found: C, 74.08; H, 5.85; N, 14.39.
dithiaphosphetan-4-yl)-1H-pyrazol-3(2H)-one
(13b).
Petroleum ether (60–80°C)/acetone (45: 55, v/v) was
used as an eluent. Yield 72%, buff crystals, m.p. 122–
1
125°C. H NMR (500 MHz, DMSO-d6, δ, ppm): 2.27 (s,
3 H, CH3), 3.65 (s, 3 H, N–CH3), 5.74 (s, 1 H, CH),
7.15–7.73 (m, 10 H, Ar–H). MS (m/z, %): 436 [[M]+ 20],
434 [[M–(2H)] 100]+, 264 [[M–PhPS2]+ 50], 188 [[M–
PhPCS4]+ 10]. Anal. Calcd for C18H17N2OPS4 (436.57).
Calcd: C, 49.52; H, 3.92; N, 6.42; P, 7.09; S, 29.38.
Found: C, 49.44; H, 3.89; N, 6.38; P, 7.00; S, 29.32.
1,5-Dimethyl-2-phenyl-4-(2-phenyl-2-selenido-1,3,2-
oxaselenaphosphetan-4-yl)-1H-pyrazol-3(2H)-one (15).
Reaction
of
phosphorus
pentasulfide
with
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-
carbaldehyde (1). A solution of phosphorus pentasulfide
(0.22 g, 1 mmol) was added dropwise with stirring at
room temperature to a solution of 1 (0.216 g, 1 mmol) in
20 mL of THF. The reaction mixture was stirred for 10 h
during which the color changed to black and the
precipitate formed and then crystallized from benzene
to give 1,5-dimethyl-2-phenyl-3-thioxo-2,3-dihydro-1H-
pyrazole-4-carbothialdehyde (10). Yield 65%, colorless
crystals, m.p. > 300°C, IR (KBr, ev, cmꢀ1): 1185, 1120
Petroleum ether (60–80°C)/acetone (20: 80, v/v) was
used as an eluent. Yield 85%, gray crystals, m.p. 228–
230°C, IR (KBr,
ev, cmꢀ1): 1633 (C═O, pyrazole), 608
1
1
(P═Se). H NMR (300 MHz, DMSO-d6, δ, ppm): 1.46
(2 C═S). H NMR (500 MHz, DMSO, δ, ppm): 2.39 (s,
(s, 3 H, CH3), 2.07 (s, 3 H, N–CH3), 5.20 (s, 1 H, CH),
7.46–7.70 (m, 10 H, Ar–H). MS (m/z, %): 482 [[M]+ 8],
467 [[M–CH3]+ 4]. Anal. Calcd for C18H17N2O2PSe2
(482.23). Calcd: C, 44.83; H, 3.55; N, 5.81; P, 6.42.
Found: C, 44.75; H, 3.51; N, 5.73; P, 6.33.
3 H, CH3), 3.07 (s, 3 H, N–CH3), 5.56 (s, 1H, CH),
7.29–7.67 (m, 5 H, Ar–H). 13C NMR (75 MHz,
DMSO-d6, δ, ppm): 201.48 (HC═S), 190.74 (C═S),
125.97–133.45 (arom.-C), 24.25 (N–CH3), 14.15 (CH3).
MS (m/z, %): 247 [(M–H)+, 5]. Anal. Calcd for
C12H12N2S2 (248.37). Calcd: C, 58.03; H, 4.87; N,
11.28;S, 25.82. Found:C, 57.93;H, 4.83;N,11.21;S, 25.75.
Interaction of hexamethylphosphorus triamide (16) with
4-hydroxy-3-methoxybenzaldehyde (1).
A mixture of
hexamethylphosphorus triamide (16) (0.163 g, 1 mmol)
in 20 mL of dry boiling toluene was added to a solution
of compound 1 (0.216 g, 1 mmol) in 20 mL of dry
toluene and refluxed for 3 h. Toluene is distilled, and the
residue was crystallized from ethanol to form adduct 20.
Interaction
of
(2,4-bis(phenylthio)-1,3,2,4-
dithiadiphosphetane-2,4-disulfide) Japanese reagent (11)
with 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-
4-carbaldehyde (1). A solution of JR 11 [54] (0.404 g,
1 mmol) was added dropwise with stirring at room
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Efficient Synthesis and Biological Evaluation of New Phosphorus, Sulfur and
Selenium Pyrazole Derivatives
4,40-(2-(Dimethylamino)-2-oxido-1,4,2-dioxaphospholane-
3,5-diyl)bis(1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one)
(20). Yield 77%, yellowish brown crystals, m.p. 105–
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1
107°C. H NMR (300 MHz, DMSO-d6, δ, ppm): 1.74 (s,
6H, C–CH3), 2.01 (d, 6H, P–N–CH3), 2.51 (s, 6H, N–
CH3), 5.45 (d, 1H, JHP = 6 Hz, O–CH–P), 6.49 (d, 1H,
[10] Ismail, Z. H.; Aly, G. M.; El-Degwi, M. S.; Heiba, H. I.;
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2
3JHP = 3 Hz, O–CH–O), and 7.31–7.81 (m, 10 H, Ar–H).
13C NMR (75 MHz, DMSO-d6, δ, ppm): 177.71 (2
C═O), 120.16–133.45 (arom.-C), 106.50 (O–CH–O),
89.41 (O–CH–P), 38.76 (P–N–CH3), 21.32 (N–CH3),
14.15 (CH3, pyrazole). 31P NMR (121 MHz, DMSO-d6,
δ, ppm): 21.59. MS (m/z, %): 445 [M–(Ph) 3]+, 417 [M–
(Ph + CO)]+, 216 [pyrazolone carbaldehyde]. Anal. Calcd
for C26H30N5O5P (523.52). Calcd: C, 59.65; H, 5.78; N,
13.38; P, 5.92. Found: C, 59.55; H, 5.73; N, 13.27; P, 5.87.
[14] Abd-El-Maksoud, M. A.; Maigali, S. S.; Soliman, F. M. J
Heterocycl Chem 2014, 51, 1830. https://doi.org/10.1002/jhet.2205.
[15] Maigali, S. S.; Abd-El-Maksoud, M. A.; El-Hussieny, M.; So-
liman, F. M.; Abdel-Aziz, M. S.; Shalaby, S. M. J Chem Res 2014, 38 754
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[16] Abd-El-Maksoud, M. A.; El-Hussieny, M.; Maigali, S. S.; So-
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[18] El-Hussieny, M.; Abd-El-Maksoud, M. A.; Maigali, S. S.; So-
liman, F. M.; Soliman, A. M. Phosphorus, Sulfur, and Silicon 2015, 190,
1845 https://doi.org/10.1080/10426507.2015.1025904.
[19] El-Hussieny, M.; Abd-El-Maksoud, M. A.; Maigali, S. S.; So-
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Journal of Heterocyclic Chemistry
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