Synthesis of some new triphenylphosphanylidenes, alkylphosphonates, and heterocycles of pyrazole derivatives and their antimicrobial activity

Article abstract of DOI:10.1080/10426507.2012.704104

The reaction of 5(4H)-pyrazolone with phosphorus ylides afforded new triphenylphosphanylidene alkanone derivatives. Moreover, its benzylidene derivative reacted with Wittig-Horner reagents to give the corresponding dialkoxyphosphoryl, alkyl phosphonate, a

Full text of DOI:10.1080/10426507.2012.704104

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Some New
Triphenylphosphanylidenes,
Alkylphosphonates, and Heterocycles
of Pyrazole Derivatives and Their
Antimicrobial Activity
Leila S. Boulos a , Ewies F. Ewies a , Amin F. M. Fahmy b & Maysa E.
Mohram c
a Department of Organometallic and Organometalloid Chemistry ,
National Research Centre , Dokki , Cairo , Egypt
b Department of Chemistry, Faculty of Science , Ain Shams
University , Abbassia , Cairo , Egypt
c Department of Microbial Chemistry , National Research Centre ,
Dokki , Cairo , Egypt
Published online: 31 May 2013.
To cite this article: Leila S. Boulos , Ewies F. Ewies , Amin F. M. Fahmy & Maysa E. Mohram (2013)
Synthesis of Some New Triphenylphosphanylidenes, Alkylphosphonates, and Heterocycles of Pyrazole
Derivatives and Their Antimicrobial Activity, Phosphorus, Sulfur, and Silicon and the Related Elements,
188:6, 790-803, DOI: 10.1080/10426507.2012.704104
To link to this article: http://dx.doi.org/10.1080/10426507.2012.704104
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Phosphorus, Sulfur, and Silicon, 188:790–803, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.704104
SYNTHESIS OF SOME NEW
TRIPHENYLPHOSPHANYLIDENES,
ALKYLPHOSPHONATES, AND HETEROCYCLES
OF PYRAZOLE DERIVATIVES AND THEIR
ANTIMICROBIAL ACTIVITY
Leila S. Boulos,1 Ewies F. Ewies,1 Amin F. M. Fahmy,2
and Maysa E. Mohram3
1Department of Organometallic and Organometalloid Chemistry,
National Research Centre, Dokki, Cairo, Egypt
2Department of Chemistry, Faculty of Science, Ain Shams University,
Abbassia, Cairo, Egypt
3Department of Microbial Chemistry, National Research Centre, Dokki,
Cairo, Egypt
GRAPHICAL ABSTRACT
H3C
Ph
O
OH
P(OCH3)2
H3C
N
COCH3
PPh3
N
COOCH3
N
Ph
O
N
O
7a
Ph
8b
Ph
H3C
OH O
P(OC2H5)2
H3C
O
OH
CH N
N
COOC2H5
Cl
N
N
O
O
P(OC2H5)2
N
Ph
8c
Ph
9
Abstract The reaction of 5(4H)-pyrazolone with phosphorus ylides afforded new triph-
enylphosphanylidene alkanone derivatives. Moreover, its benzylidene derivative reacted with
Wittig–Horner reagents to give the corresponding dialkoxyphosphoryl, alkyl phosphonate, and
heterocyclic products. Treatment of pyrazole-4-carbaldehyde with Wittig–Horner reagents and
trialkyl phosphites gave the respective alkyl phosphonate adducts. Mechanisms accounting for
Received 9 April 2012; accepted 14 June 2012.
Address correspondence to Leila S. Boulos, Department of Organometallic and Organometalloid Chemistry,
National Research Centre, El-Behoos St., P.O. 12622, Dokki, Cairo, Egypt. E-mail: leilagoubran@yahoo.com
790

SYNTHESIS OF SOME NEW TRIPHENYLPHOSPHANYLIDENES
791
the formation of the new products are discussed. The biological activity of some of the newly
synthesized compounds was also examined.
Keywords Pyrazoles; phosphorus ylides; Wittig–Horner reagents; alkyl phosphites; triph-
enylphosphanylidenes
INTRODUCTION
The pyrazole ring system is frequently used in the synthesis of pharmaceuticals. A
literature survey reveals that pyrazole derivatives are well known to have antibacterial,1
antifungal,2 antitubercular,3 anticancer,4 analgesic,5 anti-inflammatory,5 antipyretic,6 and
anticonvulsant activities.7 In view of this, and as a continuation of our work in organophos-
phorus chemistry,8–14 it was of considerable interest to synthesize new triphenylphos-
phanylidenes, alkyl phosphonates, and heterocycles of pyrazole derivatives to obtain potent
biologically active compounds. The present study deals with the reaction of substituted
pyrazole derivatives 1–3 with phosphorus ylides 4a,b, Wittig–Horner reagents 5a–e, and
trialkyl phosphites 6a,b.
RESULTS AND DISCUSSION
Chemistry
We have found that 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1) reacted with 1 mol
equivalent of 1-triphenylphosphoranylidene-2-propanone (4a) in refluxing tetrahydrofuran
(THF) to give the triphenylphosphanylidene pyrazolyl pyranone 7a (35% yield) and the
dipyrazolyl ethylenic product (7c) (15% yield). Triphenylphosphane oxide was also isolated
from the reaction medium and identified (mixed mp; mass spectral: MS) (Scheme 1).
Similarly, carbethoxymethylenetriphenylphosphorane 4b reacted with 1 (1:1) molar
ratio, in THF at r.t. for 6 h to give product 7b (60% yield) and 7c (15% yield). Triphenylphos-
phane oxide was also isolated from the reaction mixture (Scheme 1). The structures of 7a,b
and 7c were deduced from correct elemental analyses, IR, 1H, 13C, 31P NMR, and MS data
(cf. Experimental Section).
We propose the reaction course depicted in Scheme 1. The products 7a,b were
presumably formed through addition of alkylidene phosphoranes 4a,b to the carbonyl
carbon of pyrazolone 1. Since the stabilized phosphonium ylides 4a,b act as a Lewis base
that facilitate also the dimerization of the starting pyrazolone 1 via dehydration process,
the dimeric structure 7c was also obtained15 (Scheme 1).
Next, when 4-benzylidene-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2) was treated
with 1 mol equivalent of triethylphosphonoacetate (5a) in the presence of an alcoholic
sodium ethoxide solution at r.t. for 6 h, adduct 8a was isolated in a 75% yield (Scheme 2).
The structure of 8a is deduced from its spectroscopic data (Scheme 2, Experimental Sec-
tion). Similarly, compound 2 reacted with 2 mol equivalents of trimethylphosphonoacetate
(5b) in the presence of methanolic sodium methoxide solution at the reflux temperature
for 4 h to give a colorless crystalline compound assigned the pyranopyrazole structure 8b
(Scheme 2), which was established from its elemental analyses, IR, 1H, 13C, 31P NMR, and
MS data (cf. Experimental Section).
Similarly, pyrazolone 2 reacted with one molar equivalent of diethyl(1,3-
dioxoisoindolin-2-yl)methylphosphonate (5c) in the presence of an ethanolic sodium

792
L. S. BOULOS ET AL.
H3C
Ph3P=CHCOR
+
− TPPO
N
O
N
4a, R = CH3
4b, R = OC2H5
Ph
1
H3C
H3C
Ph3P
O
COR
+
N
Ph
N
N
OH
N
N
N
Ph
Ph
H3C
7a, R = CH3
7b, R = OC2H5
7c
Scheme 1
ethoxide solution at the reflux temperature for 12 h to give two crystalline compounds
assigned structures 8c,d (Scheme 2), which were established on the basis of their spectral
data (cf. Experimental Section).
Also, when pyrazolone 2 was allowed to react with 1 mol equivalent of 2-
methylallylphosphonate 2d, in the presence of an alcoholic sodium ethoxide solution,
products 8e (major) and 8d (minor) were isolated (Scheme 2). Moreover, pyrazolone 2 re-
acted with one molar equivalent of 5e in the presence of alcoholic sodium ethoxide solution
for 15 h to give 8f in a 70% yield together with 8d (20% yield, Scheme 2). The structure of
4-benzylidene-3-methyl-5-(4-methylbenzylidene)-1-phenyl-4,5-dihydro-1H-pyrazole (8f)
is assigned from its spectral data (cf. Experimental Section).
A possible explanation for the reaction course of 2 with Wittig–Horner reagents 5a,b
is shown in Scheme 3. Initial attack of triethylphosphonoacetate (5a) on the most reactive
center of 2 gave the stable phosphonate product 8a. Compound 8b is presumably formed via
intermediate A. Under the influence of the base present in the reaction medium, elimination
of dialkyl phosphite followed by addition of another molecule of Wittig–Horner reagent
5b together with cyclization via loss of one molecule alcohol gave the final phosphonate
product 8b (Scheme 3). The liberated dimethyl phosphite was detected in the water layer
by the development of a violet color on addition of 3,5-dinitrobenzoic acid.16
Formation of compound 8d can be explained by alkylation process. Since the en-
hanced reactivity of the phosphonate carbanions allows the α-carbon to be elaborated by
alkylation,17,18 we suggest that the steric hindrance provided by dioxoisoindolinyl, p-methyl
phenyl, methyl allyl groups inhibits the intramolecular displacement reaction and leads in-
stead to the formation of 8d. A similar alkylation was also observed in the reaction of
Wittig–Horner reagents 5c–e with pyrroles,19 quinoneimines,20 and nitronaphthols.21

SYNTHESIS OF SOME NEW TRIPHENYLPHOSPHANYLIDENES
793
O
Ph
P(OC2H5)2
H3C
O
OC2H5
(C2H5O)2PCH2COOC2H5
O
HN
O
N
5a
Ph
O
P
8a
(OCH3)2
Ph
H3C
N
COOCH3
O
(CH3O)
2 PCHCOOCH3
O
5b
O
N
8b
Ph
Ph
H3C
Ph
O
O
OC2H5
OC2H5
Ph
O
H3C
H2
C
OH
H3C
OC2H5
(C2H5O)2P
N
P
N
N
O
N
O
O
HN
N
+
N
5c
O
Ph
O
N
Ph
H3C
Ph
8d
8c
2
H3C
CH2
Ph
CH2
H3C
(OC2H5)2
P
8d
+
(OC H )
O
P
2
5 2
O
5d
N
O
N
8e
Ph
H3C
Ph
O
(C2H5O)2P
C
CH3
H2
H
+
8d
N
C
CH3
5e
N
Ph
8f
Scheme 2
Furthermore, this study was extended to include the behavior of 5-chloro-3-methyl-1-
phenyl-1H-pyrazole-4-carbaldehyde (3) toward triethylphosphonoacetate (5a) and trialkyl
phosphites 6a,b to determine the preferential site of attack. We have found that when 3 was
allowed to react with one molar equivalent of triethylphosphonoacetate (5a) in the presence
of an alcoholic sodium ethoxide solution, adduct 9 was isolated in a 75% yield (Scheme 4).
The structure of ethoxyphosphono pyrazole derivative (9) is assigned from its spectral data
(cf. Experimental Section).

794
L. S. BOULOS ET AL.
H3C
H3C
CHPh
O
CHPh
O
−
N
N
N
N
2
Ph
Ph
Ph
COOCH3
OCH3
H3C
Ph
O
P
O
O
OCH3
H3C
P(OC2H5)2
N
OH
HN
COOC2H5
N
N
Ph
Ph
8a
A
O
− HP(OCH3)2
Ph
O
Ph
COOCH3
P(OCH3)2
H3C
H3C
H
COOCH3
COOCH3
+ 5b
N
−
N
N
O
OH
N
Ph
Ph
C
B
− MeOH
Ph
O
P(OCH3)2
H3C
COOCH3
N
O
N
Ph
O
8b
Scheme 3

SYNTHESIS OF SOME NEW TRIPHENYLPHOSPHANYLIDENES
795
O
HO
P(OC2H5)2
H3C
CHO
Cl
H3C
O
( C2H5O)2PCH2COOHC2H5
COOC2H5
N
5a
N
N
Cl
N
Ph
Ph
3
9
Scheme 4
Also, the reaction of pyrazole-4-carbaldehyde 3 with trialkyl phosphites 6a,b was
also investigated. We have found that the reaction of 3 with one molar equivalent of 6a,b
in dry toluene at r.t. afforded products 10a,b (Scheme 5). The structures of compounds
10a,b were attested by their elemental analyses, IR, 1H, 13C, 31P NMR, and MS data (cf.
Experimental Section).
−
H
O
OR3
OR3
OR3
−
H3C
H3C
O
C
P
CH
OR3
OR3
OR3
+
P
N
N
Cl
Cl
N
N
6a, R3 = C2H5
b, R3 = CH(CH3)2
Ph
Ph
(A)
3
HOH
H
HO
CH
O
OR3
OR3
OR3
O
H3C
P
P(OR3 )2
H3C
− R3OH
OH
N
Cl
N
N
Cl
N
Ph
(B)
Ph
10a, R3 = C2H5
b, R3 = CH(CH3)2
Scheme 5

796
L. S. BOULOS ET AL.
The formation of compounds 10a,b involves Michael addition22,23 by the tertiary
phosphite ester on the active carbonyl carbon in 3 to give the dipolar intermediate A.
Addition of unavoidable moisture to intermediate A produces a transient intermediate B
with pentacovalent phosphorus.24 The latter collapses via loss of an alcohol molecule to
give the dialkyl phosphonate products 10a,b25 (Scheme 5).
BIOLOGICAL ACTIVITY
The antibacterial and antifungal activities26–29 were carried out in the Microbial
Chemistry Department, National Research Centre, Egypt, using the diffusion plate method.
The obtained results are compared with the reference antibiotics that were purchased from
Egyptian markets.26–29 The obtained results revealed that the tested compounds had different
antimicrobial responses.
As shown in Table S1 (Supplemental Materials, available online), compounds 7a and
10b are active against both Gram-positive and Gram-negative bacteria. Moreover, they have
antifungal activity against the pathogen Candida albicans. At the same time, compound
8f exhibited antimicrobial activity against only Gram-positive bacteria; other compounds
showed antibacterial activity to different extents.
CONCLUSION
From the results of the present investigation, it can be concluded that the reactions
of pyrazolone 1 with phosphorus ylides 4 lead to different products, depending on the
nature of the phosphorus ylide as well as the stability of the intermediate. Moreover, when
4-benzylidene-pyrazolone 2 was reacted with Wittig–Horner reagents 5a–c, diethoxyphos-
phoryl 8a, the cyclic dimethoxyphosphoryl 8b, methylphosphonate 8c, and the phosphonate
product 8e were obtained. We have noted that formation of 8a–f depends on the nature
of the phosphonate anion, the base used, as well as on the reactivity of the intermediate.
Moreover, pyrazolone 3 reacted with Wittig–Horner reagents and trialkyl phosphites to
give the respective alkyl phosphonate products.
Significantly, the reactions of phosphorus ylides and Wittig–Horner reagents with
pyrazolone 1–3 are indicative of the broad reaction spectrum of which ylides and phospho-
nate anions are capable in addition to the usual olefin-forming reactions. Also, this finding
which represents a new route to 8b is a supplement to the expanded utility of reagents 5a–e
for the production of the new products.
In addition, some of the newly synthesized compounds were selected and screened
for their antibacterial activity. The tested compounds 7a–c, 8a–c,e,f, 9, 10b revealed an-
tibacterial activity to different extents.
EXPERIMENTAL
Melting points were determined in open glass capillaries using Electrothermal IA
9000 series digital melting point apparatus (Electrothermal, Essex, UK) and are uncor-
rected. The IR spectra were measured in KBr pellets with a Perkin-Elmer Infracord spec-
trophotometer model 157(Grating). The 1H and 13C NMR spectra were recorded in CDCl3
and/or dimethyl sulfoxide (DMSO) as solvent on Joel-500 MHz spectrometer, and the
chemical shifts were recorded in δ values relative to tetramethylsilane (TMS). The 31P

SYNTHESIS OF SOME NEW TRIPHENYLPHOSPHANYLIDENES
797
NMR spectra were recorded with a Varian CFT-20 (vs. external 85% H3PO4 standard).
The MS were performed at 70 eV on a Shimadzu GCS-OP 1000 Ex spectrometer. Elemen-
tal analyses were performed using Elmenter Varu EL Germany Instrument. The reported
yields are based upon pure materials isolated by column chromatography. Solvents were
dried/purified according to the literature procedures. Starting materials were prepared ac-
cording to the literature procedures.30 Sample spectra for compounds 8a and 10a are shown
in Figures S1–S6 (in the Supplemental Materials, available online).
General Procedure for the Reaction of Phosphonium Ylides 4a,b with
3-Methyl-1-phenyl-5(4H)-pyrazolone (1)
One mmol of 4a (0.31 g) or 4b (0.34 g) and one mmol pyrazolone 1 (0.17 g) in
dry THF (30 mL) were refluxed for 6 h (4a with 1) or 10 h (4b with 1). The reaction was
preceded with thin layer chromatography (TLC). The volatile materials were evaporated
under reduced pressure. The residue was subjected to silica gel column chromatography
to give 7a,c or 7b,c; triphenylphosphine oxide was also isolated from the reaction medium
and identified (mix mp, MS).
1-(5-Hydroxy-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-yl)-1-
(triphenyl-λ5-phosphanylidene)propan-2-one (7a, C31H29N2O2P)
Eluent: petroleum ether/ethyl acetate (65/35, v/v). Product 7a was separated as pink
crystals, yield 35%; mp 195–197◦C; IR (KBr): v˜ = 3429 (OH), 1674 (C O), 1538 (C N),
1
1482 (aryl-P), 1105 (P C) cm−1; H NMR (500.14 MHz, DMSO): δ = 1.65 (s, 3H,
4
pyrazolyl-CH3), 1.84, 1.85 (d, JHH = 15 Hz, JHP = 4.2 Hz, 2H, CH2), 2.67 (s, 3H,
COCH3), 6.07–7.57 (m, 20H, Harom), 8.01 (d, 4JHP = 4.20 Hz, 1H, OH, exchangeable with
D2O) ppm; 13C NMR (125.76 MHz, DMSO): δ = 18.5, 20.5 (2CH3), 44.5 (d, 3JCP = 8.1 Hz,
2
CH2), 71.5 (d, JCP = 28.5 Hz, cyclic C OH), 113.5, 114.3, 114.7, 117.0, 119.3, 120.5,
121.2, 124.7, 128.8, 129.2, 129.6, 133.1, 133.5, 144.7 (Ar C), 133.5 (d, JCP = 90.2, C P),
165.5 (C O) ppm; 31P NMR: δ = 18.5 ppm; MS (EI, 70 eV): m/z (%) = 494 (5) [M+2H]+,
477 (15), [M−CH3]+; Anal. for C31H29N2O2P (492.2): calcd C 75.59, H 5.93, N 5.69, P
6.29; found: C 75.55, H 5.94, N 5.68, P 6.30.
(5-Hydroxy-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-yl)
(triphenyl-λ5-phosphanylidene)methyl propanoate (7b, C32H31N2O3P)
Eluent: petroleum ether/ethyl acetate (65/35, v/v). Product 7b was separated as yel-
low crystals, yield 45%; mp 138–140◦C; IR (KBr): v˜ = 3423 (OH), 1641 (C O), 1590
1
(C N), 1425 (aryl-P), 1025 (P C) cm−1; H NMR (500.14 MHz, CDCl3): δ = 0.52 (t,
JHH = 13.8 Hz, CH2CH3, 3H), 1.75 (d, JHH = 8.8 Hz, 4JHP = 4.23 Hz, 2H, CH3CH2), 2.31,
2.33 (q, JHH = 8.8 Hz, 2H, CH2), 2.65 (s, 3H, CH3), 6.79–7.21 (m, 20H, Harom), 10.06
(s, 1H, OH, exchangeable with D2O) ppm; 13C NMR (125.76 MHz, CDCl3): δ = 12.2
3
(CH3), 14.8 (pyrazolyl-CH3), 29.8 (CH2), 44.5, 45.6 (d, JCP = 7.20 Hz, CH2), 82.5 (d,
2JCP = 29.1 Hz, cyclic C OH), 103.9, 112.4, 114.3, 114.7, 117.0, 119.3, 120.5, 121.2,
124.7, 128.8, 129.2, 129.6, 133.1, 133.5, 144.7 (Ar C), 144.5, 145.4 (d, JCP = 112.5 Hz,
C P), 147.9 (C N), 161.7 (C O) ppm; 31P NMR: δ = 23.8 ppm; MS (EI, 70 eV): m/z

798
L. S. BOULOS ET AL.
(%) = 524 (5) [M+2H]+, 451 (35) [M−73, (OCOEt)], 262 (100) [TPP]+, 174 (40), [pyra-
zolone]+; Anal. for C32H31N2O3P (522.21): calcd C 73.55, H 5.98, N 5.36, P 5.93; found:
C 73.50, H 5.97, N 5.38, P 5.95.
5-Methyl-4-(5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-ylidene)-2-
phenyl-2,4-dihydro-3H-pyrazol-3-one (7c, C20H20N4O)
Eluent: petroleum ether/ethyl acetate (60/40, v/v). Product 7c was separated as yellow
crystals, yield 15%; mp 115–117◦C; IR (KBr): v˜ = 1651 (C O), 1623 (C C), 1590 (C N)
cm−1; 1H NMR (500.14 MHz, CDCl3): δ = 2.31, 2.38 (d, JHH = 13.8 Hz, 2H, CH2), 2.71,
2.75 (2 s, 6H, 2CH3), 7.13–7.93 (m, 10H, Harom) ppm; 13C NMR (125.76 MHz, CDCl3):
δ = 18.5, 23.2 (2CH3), 24.7 (CH2), 96.8, 163.7 (C C), 112.4, 114.3, 114.7, 117.0, 119.3,
120.5, 121.2, 124.7, 128.8, 129.2, 129.6, 133.1, 133.5, 144.7 (Ar C), 148.1 (C N), 166.1
(C O) ppm; MS (EI, 70 eV): m/z (%) = 334 (10) [M+2H]+, 315 (15) [M−15]+, 198 (75)
[M−132, (PhN N C CH3)]+; Anal. for C20H20N4O (332.16): calcd C 72.27, H 6.06, N
16.86; found: C 72.30, H 6.02, N 16.88.
Reaction of 4-Benzylidene-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2)
with Trialkylphosphonoacetate (5a,b)
A solution of 1 mmol of sodium methoxide (0.54 g) or sodium ethoxide (0.68 g) in
absolute alcohol (30 mL) was treated with an equimolar amount of the trialkylphospho-
noacetate 5a (0.22 mL) or 5b (0.18 mL), and then pyrazolone 2 (1 mmol, 0.26 g) was
added. The resulting reaction mixture was allowed to stir at r.t. for 6 h (5a with 2) or the
resulting mixture was refluxed for 4 h (5b with 2) (TLC). Thence, the reaction mixture
was poured onto a small amount of water, extracted with ethyl acetate; the extracts were
dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residual
material was recrystallized from ethyl acetate to give products 8a or 8b.
Ethyl 2-(Diethoxyphosphoryl)-3-(3-oxo-2-phenyl-4-methyl-2,3-dihydro-
1H-pyrazol-4-yl)3-phenylpropanoate (8a, C25H31N2O6P)
Product 8a was precipitated as colorless crystals, yield 80%; mp 150–152◦C; IR
(KBr): v˜ = 3448 (NH), 1732 (ester C O), 1651 (C O), 1610 (C C), 1228 (P O), 980
(P O C) cm−1; 1H NMR (500.14 MHz, CDCl3): δ = 0.80, 1.02, 1.05 (3 t, JHH = 13.8 Hz,
9H, 3CH2CH3,), 2.22 (s, 3H, pyrazolyl-CH3), 2.46 (t, 2JHP = 15.5 Hz, 1H, CH P), 3.79,
3.88 (2 q, JHH = 8.8 Hz, 4H, P (O CH2 )2), 4.20 (t, 3JHP = 11.5 Hz, 1H, CH CH P),
4.59 (q, JHH = 8.8 Hz, 2H, COO CH2), 7.10 7.66 (m, 10H, Harom), 10.95 (1H, NH,
exchangeable with D2O) ppm; 13C NMR (125.76 MHz, CDCl3): δ = 14.1, 14.8, 14.8
(4CH3), 18.3 (CH Ph), 40.7 (d, JCP = 88.2 Hz, C P), 61.3, 62.3, 62.4 (3CH2), 107.3
(cyclic C CH Ph), 112.4, 114.3, 114.7, 117.0, 119.3, 120.5, 121.2, 124.7, 128.8, 129.2,
129.6, 133.1, 133.5, 144.7 (Ar C), 166.2 (C O), 170.7 (ester C O) ppm; 31P NMR:
δ = 23.0 ppm. MS (EI, 70 eV): m/z (%) = 486 (65) [M]+, 458 (5) [M−28]+; Anal. for
C25H31N2O6P (486.19): calcd C 61.72, H 6.42, N 5.76, P 6.37; found: C 61.74, H 6.40, N
5.79, P 6.32.

SYNTHESIS OF SOME NEW TRIPHENYLPHOSPHANYLIDENES
799
Methyl (dimethoxyphosphoryl)(1,4-dimethyl-3-methyl-6-oxo-1,4,5,6-
tetrahydropyrano[2,3-c]pyrazol-5-yl)acetate (8b, C24H25N2O7P)
Product 8b was precipitated as colorless crystals, yield 75%; mp 143 144◦C; IR
(KBr): v˜ = 1741 (ester C O), 1647 (C O), 1612 (C C), 1547 (C N), 1221 (P O),
985 (P O C) cm−1; 1H NMR (500.14 MHz, CDCl3): δ = 2.49 (s, 3H, pyrazolyl-CH3),
3
2.62, 2.88 (2 d, JHP = 11.5 Hz, 6H, 2P(O)(OCH3), 3.08 (s, 3H, COOCH3), 3.10 (ddd,
3JHP = 11.5 Hz, JHH = 7.8 Hz, 1H, CHCH P), 3.86 (dd, 2JHP = 21.3 Hz, JHH = 7.8 Hz, 1H,
CH P), 4.23 (d, 1H, CH Ph), 6.70–7.06 (m, 10H, Harom) ppm; 13C NMR (125.76 MHz,
CDCl3): δ = 10.8 (pyrazolyl-CH3), 39.4 (d, JCP = 102.20, C P), 40.1 (d, 2JCP = 35.37 Hz,
3
2
C C P), 51.2 (d, JCP = 9.37 Hz, C Ph), 52.3, 53.3 (OCH3, JCP = 37.37 Hz), 54.4
(s, COOCH3), 107.8 (cyclic C C Ph), 112.4, 114.3, 114.7, 117.0, 119.3, 120.5, 121.2,
124.7, 128.8, 129.2, 129.6, 133.1, 133.5, 144.7 (Ar C), 153.1 (C N), 164.7 (C O), 168.1
(ester C O) ppm; 31P NMR = 29.2 ppm; MS (EI, 70 eV): m/z (%) = 484 (60) [M]+, 363
(50), 283 (100) [pyranopyrazole]+; Anal. for C24H25N2O7P (484.14): calcd C 59.50, H
5.20, N 5.78, P 6.39; found: C 59.54, H 5.22, N 5.76, P 6.35.
Reaction of 4-Benzylidene-3-methyl-1-phenyl-1H-pyrazol-5(4H)-
one (2) with diethyl substituted phosphonate (5c–e)
General procedure. A solution of 1 mmol of sodium methoxide (0.54 g) or sodium
ethoxide (0.68 g) in absolute alcohol (30 mL) was treated with an equimolar amount of
the diethyl-substituted phosphonate (5c–e), and then the pyrazolone 2 (1 mmol, 0.26 g)
was added. The resulting reaction mixture was allowed to heat on steam bath for 12–16 h
(TLC). Thence, the reaction mixture was poured onto a small amount of water, extracted
with ethyl acetate; the extracts were dried over anhydrous sodium sulfate and evaporated
under reduced pressure. The residual material was chromatographed on silica gel column to
give products 8c–f. Compound 8d was separated as pink crystals from all reaction mixtures.
Diethyl (4-Benzylidene-4,5-dihydro-5-hydroxy-3-methyl-1-phenyl-1H-
pyrazol-5-yl)(1,3-dioxoisoindolin-2-yl)methylphosphonate (8c, C30H30N3O6P)
Eluent: petroleum ether/ethyl acetate (60/40, v/v). Product 8c was separated as brown
crystals, yield 35%; mp 183–185◦C; IR (KBr): v˜ = 3447 (OH), 1653 (C O), 1612
(C C), 1555 (C N), 1239 (P O), 967 (P O C) cm−1; 1H NMR (500.14 MHz, CDCl3):
δ = 1.12, 1.24 (2 t, JHH = 13.8 Hz, 6H, 2CH2CH3), 2.30 (s, 3H, pyrazolyl-CH3), 3.97 (d,
2JHP = 23.6 Hz, 1H, CH P), 4.19, 4.63 (2 q, JHH = 8.8 Hz, 3JHP = 10.3 Hz, 4H, CH2CH3),
5.9 (s, 1H, CH Ph), 6.43–8.73 (m, 14H, Harom) ppm; 13C NMR (125.76 MHz, CDCl3):
δ = 14.8 (s, 2(O CH2 CH3), 18.7 (pyrazolyl-CH3), 50.2 (d, JCP = 133 Hz, C P), 62.3
2
(d, JCP = 20.20 Hz, 2CH2), 75.2 (cyclic C OH), 112.4, 114.3, 114.7, 117.0, 119.3,
120.5, 121.2, 124.7, 128.8, 129.2, 129.6, 133.1, 133.5, 147.5 (Ar C), 155.6 (C N), 167.9
(2C O) ppm; 31P NMR: δ = 27.4 ppm; MS (EI, 70 eV): m/z (%) = 561 (5) [M+2H]+,
501 (35), 185 (20) [pyrazole]+; Anal. for C30H30N3O6P (559.19): calcd C 64.39, H 5.40,
N 7.51, P 5.54; found: C 64.35, H 5.44, N 7.50, P 5.52.

800
L. S. BOULOS ET AL.
4-(Ethoxy(phenyl)methyl)-1,2-dihydro-5-methyl-2-phenylpyrazol-3-one
(8d, C19H20N2O2)
Eluent: petroleum ether/ethyl acetate (95/5, v/v). Product 8d was separated as pink
crystals, yield 20%; mp 175–176◦C; IR (KBr): v˜ = 3442 (NH), 1663 (C O), 1610 (C C)
1
cm−1; H NMR (500.14 MHz, CDCl3): δ = 1.30 (t, JHH = 13.8 Hz, 3H, CH3), 2.25
(s, 3H, pyrazolyl-CH3), 4.15 (q, JHH = 8.8 Hz, 2H, CH2), 5.8 (s, 1H, CH CH Ph),
7.16–7.83 (m, 10H, Harom), 9.01 (s, 1H, NH, exchangeable with D2O) ppm; 13C NMR
(125.76 MHz, CDCl3): δ = 15.6 (CH3), 18.3 (pyrazolyl-CH3), 65.1 (CH2), 75.7 (CH Ph),
107.7 (C CH Ph), 112.4, 114.3, 114.7, 117.0, 119.3, 120.5, 121.2, 124.7, 128.8, 129.2,
129.6, 133.1, 133.5, 144.7 (Ar C), 150.7 (C N), 166.2 (C O) ppm; MS (EI, 70 eV): m/z
(%) = 310 (10) [M+2H]+, 281 (50) [M−29]+; Anal. for C19H20N2O2 (308.15): calcd C
74.00, H 6.54, N 9.08; found: C 74.01, H 6.55, N 9.05.
Diethyl 1-(2,3-Dihydro-5-methyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)-3-
methyl-1-phenylbut-3-en-2-ylphosphonate (8e, C25H31N2O4P)
Eluent: petroleum ether/ethyl acetate (60/40, v/v). Product 8e was separated as brown
crystals, yield 55%; mp 228–230◦C; IR (KBr): v˜ =1638 (C O), 1628 (C C), 1599 (C N),
1244 (P O), 963 (P O C) cm−1; 1H NMR (500.14 MHz, CDCl3): δ = 0.96, 1.03 (2 t,
4
JHH = 13.8 Hz, JHP = 4.2 Hz, 6H, 2O C CH3), 1.11 (s, 3H, C CH3), 2.04 (s,
pyrazolyl-CH3), 2.84 (d, 2JHP = 28.5 Hz, 1H, CH CH P), 3.78 (d, 3JHP = 8.5 Hz, 1H,
CH CH P), 4.67, 4.75 (2 q, JHH = 8.8 Hz, 4H, CH2), 5.11, 5.15 (d, 2H, CH2), 6.8–7.42
(m, 10H, Harom) ppm; 13C NMR (125.76 MHz, CDCl3): δ = 14.8 (2CH3), 18.7 (pyrazolyl-
2
CH3), 20.4 (d, JCP = 23 Hz, CH Ph), 23.0 (C CH3), 40.9 (d, JCP = 133 Hz, CH P)
2
151.1 (C N), 111.0, 147.7 (C CH2), 62.7 (2CH2, JCP = 23 Hz), 112.4, 114.3, 114.7,
117.0, 119.3, 120.5, 121.2, 124.7, 128.8, 129.2, 129.6, 133.1, 133.5, 144.7, 147.5 (Ar C),
166.9 (2C O) ppm; 31P NMR = 22.9 ppm; MS (EI, 70 eV): m/z (%) = 453 (5) [M−H]+,
396 (35) [M−58]+; Anal. for C25H31N2O4P (454.2): calcd C 66.07, H 6.87, N 6.16, P 6.81;
found: C 66.07, H 6.85, N 6.19, P 6.80.
4-Benzylidene-3-methyl-5-(4-methylbenzylidene)-1-phenyl-4,5-dihydro-
1H-pyrazole (8f, C25H22N2)
Eluent: petroleum ether/ethyl acetate (60/40, v/v). Product 8f was separated as brown
crystals, yield 70%; mp 165–166◦C; IR (KBr): v˜ = 1616 (C C), 1590 (C N) cm−1
;
1H NMR (500.14 MHz, DMSO): δ = 1.60, 1.87 (2 s, 6H, 2CH3), 6.66 (s, 1H, C CH),
7.09–8.65 (m, 14H, Harom) ppm; 13C NMR (125.76 MHz, DMSO): δ = 11.4 (pyrazolyl-
CH3), 21.07 (CH3), 102.6 (CH Ph), 112.4, 114.3, 114.7, 117.0, 119.3, 120.5, 121.2, 124.7,
128.8, 129.2, 129.6, 133.1, 133.5, 144.7 (Ar C), 144.7 (C N) ppm; MS (EI, 70 eV): m/z
(%) = 350 (M+, 5), 335 (M−CH3, 5), 273 (M−C6H5), 100; Anal. for C25H22N2 (350.18):
calcd C 85.68, H 6.33, N 7.99; found: C 85.62, H 6.35, N 7.95.
Reaction of 5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3)
with Triethylphosphonoacetate (5b)
A solution of 1 mmol of sodium ethoxide (0.68 g) in absolute alcohol (30 mL) was
treated with an equimolar amount of triethylphosphonoacetate (5b), and then pyrazole 3

SYNTHESIS OF SOME NEW TRIPHENYLPHOSPHANYLIDENES
801
(1 mmol, 0.22 g) was added. The resulting reaction mixture was allowed to heat on steam
bath for 12 h (TLC). The reaction mixture was poured into a small amount of water, extracted
with ethyl acetate; the extracts were dried over anhydrous sodium sulfate and evaporated
under reduced pressure. The residual material was recrystallized from acetone/petroleum
ether to give product 9.
Ethyl 1-(Ethoxyphosphono)-2-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-
4-yl)-2-hydroxyethanoate (9, C19H26ClN2O6P)
Eluent: petroleum ether/acetone (85/15, v/v). Product 9 was separated as colorless
crystals, yield 75%; mp 210–212◦C; IR (KBr): v˜ = 3248 (OH), 1732 (ester C O),
1
1226 (P O), 1610 (C C), 1554 (C N), 959 (P O C), 763 (C Cl) cm−1; H NMR
(500.14 MHz, CDCl3): δ = 0.83, 1.25, 1.29 (3 t, JHH = 13.8 Hz, 9H, 3CH3), 2.60 (s, 3H,
pyrazolyl-CH3), 3.60, 3.62 (dd, 2JHP = 23 Hz, JHH = 8.6 Hz, 1H, CH P), 3.62, 4.07, 4.11
(3 q, JHH = 8.8 Hz, 6H, 3CH2), 5.42, 5.50 (d, 3JHP = 9.6 Hz, 1H, CH CH P), 6.46 (1H,
OH, exchangeable with D2O), 6.64–8.09 (m, 5H, Harom), ppm; 13C NMR (125.76 MHz,
CDCl3): δ = 14.3, 20.1, 31.8 (4CH3), 40.2 (C OH), 56.2 (d, C P, JCP = 88.2 Hz), 60.5,
3
62.3 (3CH2), 107.2, 107.4 (cyclic C CH OH, JCP = 10.38 Hz), 112.4, 114.3, 114.7,
117.0, 119.3, 120.5, 121.2, 124.7, 128.8, 129.2, 129.6, 133.1, 133.5, 144.7 (Ar C), 153.1
(C N), 168.4 (ester C O) ppm; 31P NMR: δ = 26.29 ppm; MS (EI, 70 eV): m/z (%) = 446
(5) [M+H]+, 400 (5) [M−45, (OEt)]+; Anal. for C19H26ClN2O6P (445.12): calcd C 51.30,
H 5.89, Cl 7.97, N 6.30, P 6.96; found: C 51.35, H 5.87, Cl 7.94, N 6.32, P 6.97.
Reaction of 5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3)
with Trialkylphosphite (6a,b)
A mixture of 3 (1 mmol, 0.22 g) and 6a (1 mmol, 0.16 mL) or 6b (1 mmol, 0.20 mL)
in dry toluene (30 mL) was stirred for 7 h (3 with 6a) or 10 h (3 with 6b) (TLC). The volatile
materials were evaporated under reduced pressure. The residue was chromatographed on
silica gel column to give products 10a,b together with unchanged pyrazole-4-carbaldehyde
3 (ca, 10%).
Diethyl (5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)(hydroxy)
methylphosphonate (10a, C15H20ClN2O4P)
Eluent: petroleum ether/acetone (75/25, v/v). Product 10a was separated as colorless
crystals, yield 45%; mp 188–190◦C; IR (KBr): v˜ = 3282 (OH), 1596 (C C), 1550 (C N),
1240 (P O), 969 (P O C), 725 (C Cl) cm−1; 1H NMR (500.14 MHz, CDCl3): δ = 1.22,
1.27 (2 t, JHH = 13.8 Hz, 6H, 2CH2CH3), 2.00 (1H, OH, exchangeable with D2O), 2.41
(pyrazolyl-CH3), 4.12, 4.14 (2 q, JHH = 8.8 Hz, 4H, 2CH2CH3), 5.06 (d, 2JHP = 25.6 Hz,
1H, CH P), 7.41–7.46 (m, 5H, Harom) ppm; 13C NMR (125.76 MHz, CDCl3): δ = 11.3
(pyrazolyl-CH3), 14.8 (2CH3), 53.8 (d, JCP = 88.20, C P), 62.6 (CH2), 119.6, 128.0
(cyclic C C), 112.4, 114.3, 114.7, 117.0, 119.3, 120.5, 121.2, 124.7, 128.8, 129.2, 129.6,
133.1, 133.5, 144.7 (Ar C), 152.3 (C N) ppm; 31P NMR: δ = 20.7 ppm; MS (EI, 70 eV):
m/z (%) = 358 (5) [M]+, 343 (60) [M−CH3]+, 221 (45) [M−137, P(O)(OC2H5)2]+; Anal.
for C15H20ClN2O4P (358.780): calcd C 50.22, H 5.62, Cl 9.88, N 7.81, P 8.63; found: C
50.23, H 5.60, Cl 9.88, N 7.85, P 8.65.

802
L. S. BOULOS ET AL.
Dipropan-2-yl [(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)(hydroxy)
methyl] phosphonate (10b, C17H24ClN2O4P)
Eluent: petroleum ether/acetone (75/25, v/v). Product 10b was separated as golden
brown crystals, yield 45%; mp 178–180◦C; IR (KBr): v˜ = 3282 (OH), 1555 (C N), 1236
(P O), 952 (P O C), 730 (C Cl) cm−1; 1H NMR (500.14 MHz, CDCl3): δ = 0.99, 1.27
(2 d, 12H, 4CH3), 2.05–2.17 (2 septets, 2H, 2 isopropyl-CH), 2.46 (s, 3H, pyrazolyl-CH3),
4.41 (d, 2JHP = 30.6 Hz, 1H, CH P), 4.71 (1H, OH, exchangeable with D2O), 7.02–7.97
(m, 5H, Harom) ppm; 13C NMR (125.76 MHz, CDCl3): δ = 11.3 (pyrazolyl-CH3), 24.8
(4CH3), 54.5 (d, JCP = 90.20, C P), 72.6 (2CH), 119.6, 128.0 (cyclic C C), 112.4, 114.3,
114.7, 117.0, 119.3, 120.5, 121.2, 124.7, 128.8, 129.2, 129.6, 133.1, 144.7 (Ar C), 147.3
(C N) ppm; 31P NMR: δ = 25.1 ppm; MS (EI, 70 eV): m/z (%) = 386 (5) [M]+, 221
(25) [M−165, P(O)(OCH(CH3)2)2]+; Anal. for C17H24ClN2O4P (387.12): calcd C 52.79,
H 6.25, Cl 9.17, N 7.24, P 8.01; found: C 52.80, H 6.22, Cl 9.15, N 7.25, P 8.04.
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