Chemistry of phosphorus ylides. Part 38: Synthesis and anticancer activity of cyclobutane, oxaphosphetane, oxaphosphinine, azaphosphetidene, and pyridazine derivatives

Article abstract of DOI:10.1007/s00706-013-1124-2

The reactions of nucleophilic active phosphacumulene, phosphallene, and stable phosphonium ylides with quinones, cyclobutenone, α,β- unsaturated compounds, quinone monoanil, and monohydrazone were investigated. Carbocyclic and heterocyclic patterns such a

Full text of DOI:10.1007/s00706-013-1124-2

Monatsh Chem
DOI 10.1007/s00706-013-1124-2
ORIGINAL PAPER
Chemistry of phosphorus ylides. Part 38: Synthesis and anticancer
activity of cyclobutane, oxaphosphetane, oxaphosphinine,
azaphosphetidene, and pyridazine derivatives
•
Ibrahim F. Zeid Medhat M. Said
•
•
Shaban A. Darwish Fouad M. Soliman
Received: 8 October 2013 / Accepted: 13 November 2013
Ó Springer-Verlag Wien 2013
Abstract The reactions of nucleophilic active phospha-
cumulene, phosphallene, and stable phosphonium ylides
with quinones, cyclobutenone, a,b-unsaturated compounds,
quinone monoanil, and monohydrazone were investigated.
Carbocyclic and heterocyclic patterns such as phosphany-
lidene cyclobutanones, oxaphosphetane, oxaphosphinines,
azaphosphetidenes, and pyridazines were obtained. The
cytotoxic activity of some new products was evaluated
against human cervical and breast carcinoma cell lines.
Certain tested compounds showed promising results.
human carcinoma cell lines [10]. In conclusion of our work
aimed at the synthesis of carbocyclic and heterocyclic
systems containing phosphorus moieties with remarkable
biological importance [11–17], we report here on the utility
of phosphacumulated and phosphallene ylides as building
blocks for the synthesis of phosphanylidene cyclobutylid-
ene, oxabicyclo compounds, spiro-oxetanone, spiro-
oxaphosphetanone, oxaphosphinine, azaphosphetidenes,
and pyridazines. The cytotoxicity of the synthesized com-
pounds was evaluated against cervical and breast
carcinoma cell lines in order to explore their potential as a
new class of potent anticancer agents.
Keywords Phosphanylidene cyclobutanones ꢀ
Oxaphosphetanes ꢀ Oxaphosphinines ꢀ Azaphosphetidenes ꢀ
Pyridazines ꢀ Antitumor activity
Results and discussion
Introduction
Treatment of naphthalene-1,2-dione (1) with (N-phenyl-
iminovinylidene)triphenylphosphorane (2a) in tetrahydro-
furan (THF) at room temperature afforded the target
carbocyclic compounds, namely 1-[2,4-bis(phenylimino)-
3-(triphenylphosphanylidene)cyclobutylidene]naphthalen-
2(1H)-one (6a) together with triphenylphosphine oxide.
A distinguishing feature in the IR spectrum of 6a is the
There has been considerable interest in the development of
novel compounds with antitumor activity. A variety of
antitumor drugs such as quinines [1, 2], indandiones [3, 4],
a,b-unsaturated compounds [5, 6], and hydrazones [7–9]
are currently in clinical use. Moreover, triaziquone deriv-
atives displayed significant cytotoxic activities against
presence of only one carbonyl signal at 1,577 cm-1
.
Moreover, signals at d = 187.78 (C=O), 164.20 (C=N),
and 153.23 (C=P) were recorded in the 13C NMR spectrum.
In the 31P NMR spectrum of 6a a signal at d = 29.74 ppm
was recorded which fits with the presence of a phosphorane
on a four-membered ring [18]. The product 6a is assumed
to be formed via the reaction of the phosphacumulene 2a
with naphthalene-1,2-dione (1) by a [2?2]-cycloaddition
of the C-1 carbonyl group [19, 20] in compound 1 to the
ylidic C–P bond of the reagent 2a to give the oxapho-
sphetane 4 through the dipolar intermediate 3 [21–23]. The
intermediate 4 is decomposed to the unstable ketene 5 [24]
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-013-1124-2) contains supplementary
material, which is available to authorized users.
M. M. Said ꢀ S. A. Darwish ꢀ F. M. Soliman (&)
Department of Organometallic and Organometalloid Chemistry,
National Research Centre, Dokki, Cairo, Egypt
e-mail: solimanfma2@yahoo.com
I. F. Zeid
Department of Chemistry, Faculty of Science,
Menoufiya University, Shebin El-Kom, Egypt
123

I. F. Zeid et al.
and triphenylphosphine oxide which is a good leaving
group. [2?2]-Cyclization of a second molecule of 2a to the
ketene 5 afforded the four-membered ring phosphanylidene
cyclobutylidene 6a. Similarly, when the naphthalenedione
was treated with (oxovinylidene)triphenylphosphane (2b)
the corresponding 2-(2-oxonaphthalen-1(2H)-ylidene)-4-
(triphenylphosphanylidene)cyclobutane-1,3-dione (6b) and
triphenylphosphine oxide were obtained (Scheme 1).
A comparative study between the active phosphacu-
mulene 2a and a stabilized phosphonium ylide, acetyl-
methylenetriphenylphosphorane (9), towards 3,4-diphe-
nylcyclobut-3-ene-1,2-dione (7) was also investigated.
Thus, when compound 7 was treated with (N-phenylimi-
novinylidene)triphenylphosphorane (2a) in boiling toluene,
2,3-diphenyl-4-[2,4-bis(phenylimino)-3-(triphenylpho-
sphanylidene)cyclobutylidene]cyclobut-2-en-1-one (8) and
triphenylphosphine oxide were isolated. The IR spectrum
of the reaction product 8 revealed bands at 1,650 (C=O),
1,593 (C=N), 1,491 (C=P), and 1,441 cm-1 (P–Ar).
Moreover, the 13C NMR spectrum of 8 displayed distinct
resonances at 170.10 (C=O), 166.65 (C=N), and 153.83
(C=P) ppm. A signal at 30.07 ppm was observed in its 31P
NMR spectrum. The mass spectrum indicated the presence
of an ion peak at m/z = 710 [M?]. On the other hand, when
compound 7 was treated with equimolar amounts of acet-
ylmethylenetriphenylphosphorane (9) in refluxing toluene,
the corresponding 4-(2-oxopropylidene)-2,3-diphenylcy-
clobut-2-en-1-one (10) and triphenylphosphine oxide were
obtained. A [2?2]-cycloaddition of the C=O bond of
compound 7 to the ylidic C–P bond of 9 is proposed to
123

Chemistry of phosphorus ylides
1
generate the unstable oxaphophetane [22, 23, 25]. In
the case of weakly nucleophilic stabilized ylide 9, the
first stage of the reaction is the threo-betaine which is
more stable than the erythro-betaine [26, 27]. By this
means subsequent formation of the intermediate four-
membered ring [28] and its decomposition into the trans-
olefin [29] and triphenylphosphine oxide are mainly
formed.
(3JHP = 13.5 Hz) in its H NMR spectrum. The 13C NMR
spectrum of 11 displayed distinct resonances of the methyl
groups at 24.20, the CH methine at 29.00, the C=P at
166.15, the C=N at 169.80, and the acetyl C=O at
199.00 ppm. Moreover, a signal at 26.26 ppm was
observed in its 31P NMR spectrum and the mass spectrum
indicated the presence of an ion peak at m/z = 652
[(M?1)?] (Scheme 2).
The IR spectrum of 10 showed bands at 1,689 (C=O,
acetyl) and 1,637 cm-1 (C=O, cyclobutenone). The 1H
NMR spectrum of 10 revealed signals at d = 2.70 (s, 3H,
CH3), 6.00 (s, 1H, CH), and 7.50–8.00 (m, 10H, Ar) ppm.
The 13C NMR displayed distinct resonances of the methyl
group at d = 29.30, the CH methine at 153.50, the cyc-
lobutenone C=O at 187.60, and the acetyl C=O at
193.07 ppm. In addition, when the product 10 was treated
with the active phosphacumulene 2a in boiling toluene,
1-[7,8-diphenyl-3-(phenylimino)-4-(triphenylphosphany-
lidene)-2-oxabicyclo[4.2.0]octa-1(6),7-dien-5-yl]ethanone
(11) was isolated. Formation of compound 11 is proposed
to occur by [2?4]-cycloaddition of the ylide 2a to com-
pound 10. The most important features of structure 11 are
the presence of signals at 2.70 ppm (s) for the methyl
protons and 3.75 ppm (d) for the methine proton
When 2,5-diphenylcyclohexa-2,5-diene-1,4-dione (12)
was treated with the phosphacumulene 2a in THF at room
temperature, 4-[2,4-bis(phenylimino)-3-(triphenylphosph-
anylidene)cyclobutylidene]-2,5-diphenylcyclohexa-2,5-
dienone (13) and triphenylphosphine oxide were isolated.
The 13C NMR spectrum of compound 13 possess three
signals at 187.33, 165.35, and 158.60 ppm belonging to
C=O, C=N, and C=P, respectively. Moreover, the 31P NMR
spectrum revealed a singlet signal at 29.93 ppm and the
mass spectrum of 13 showed the presence of an ion peak at
m/z = 734 [(M-2)?]. On the other hand, compound 12
was boiled in toluene with the stabilized phosphonium
ylide benzoylmethylenetriphenylphosphorane (14) to give
4-(2-oxo-2-phenylethylidene)-2,5-diphenylcyclohexa-2,5-
dienone (15) and triphenylphosphine oxide. The IR spec-
trum of 15 revealed bands at 1,747 and 1,596 cm-1 due to
Scheme 2
123

I. F. Zeid et al.
Scheme 3
benzoyl and cyclohexanone carbonyl functions. Treatment
of compound 15 with the phosphacumulene 2a gave 2-[4-
[2,4-bis(phenylimino)-3-(triphenylphosphanylidene)cyclo-
butylidene]-2,5-diphenylcyclohexa-2,5-dienylidene]-1-phe-
nylethanone (16) and triphenylphosphine oxide. The 13C
NMR spectrum of 16 revealed the C=O and C=N signals at
182.73 and 168.90 ppm, respectively, and a signal at
29.78 ppm was found in its 31P NMR spectrum
(Scheme 3).
which is transformed to the four-membered stable oxaph-
osphetane 20. The 31P NMR shifts of 20 were 21.23 (O–P)
and 15.98 (P=C) ppm which fits with the presence of
a
phosphorane on a four-membered ring [30, 31]
(Scheme 4).
The behavior of 2-benzylidene-1H-indene-1,3(2H)-dione
(21a) and 2-(1,3-dioxo-1H-inden-2(3H)-ylidene)malononit-
rile (21b) towards hexaphenylcarbodiphosphorane (19) was
studied, too. The reaction was performed in THF at room
temperature and proceeded by [4?2]-cycloaddition rather
than [2?2]-cycloaddition to give the pyran form. In case of
the reaction of 21a with 19 the corresponding pyran 22a was
initially formed which loses triphenylphosphane by Hoff-
mann degradation due to the presence of a hydrogen atom in
the a-position to give 2,2,2,4-tetraphenylindeno[2,1-e]
[1,2]oxaphosphinin-5(2H)-one (23) and triphenylphosphane,
whereas the stable 5-oxo-2,2,2-triphenyl-3-(triphenylpho-
sphanylidene)-2,3-dihydroindeno[2,1-e][1,2]oxaphosphinine-
4,4(5H)-dicarbonitrile (22b) was isolated from the reaction
of compound 21b and the bisphosphorane 19. The 31P
NMR spectrum of the pyran 22b revealed two singlet
signals at 26.10 (O–P) and 21.23 ppm (C=P) which fits
with the presence of a phosphorane on a six-membered
ring, whereas the pyran 23 revealed a singlet signal at
21.26 ppm (O–P) (Scheme 5).
The reaction of 2,3-dimethylanthracene-9,10-dione (17)
with the phosphacumulene 2a was performed in toluene at
room temperature to give 10-[2,4-bis(phenylimino)-3-
(triphenylphosphanylidene)cyclobutylidene]2,3-dimethyl-
anthracen-9(10H)-one (18) and triphenylphosphine oxide.
A signal at 19.21 ppm in its 31P NMR spectrum was found
which supports the assigned structure of 18. In addition, the
behavior of the anthracenedione 17 towards the bisphos-
phorane hexaphenylcarbodiphosphorane (19) was studied.
When 17 was treated with 19 in toluene at room temper-
ature, 2,3-dimethyl-20,20,20-triphenyl-30-(triphenylphospha-
nylidene)-10H-spiro[anthracene-9,40-[1,2]oxaphosphetan]-
10-one (20) was obtained. The formation of 20 from the
reaction of 17 with 19 can be explained by initial nucleo-
philic attack at the carbanion center in the bisylide 19 on
the carbonyl function in 17 to give the phosphobetaine,
123

Chemistry of phosphorus ylides
Scheme 4
Scheme 5
123

I. F. Zeid et al.
Scheme 6
The behavior of hexaphenylcarbodiphosphorane (19)
towards the monoanil 2-(phenylimino)naphthalen-1(2H)-
one (24) was also studied to determine the site of attack.
We found that phosphorane 19 reacts with the anil 24 in
boiling THF to give 1,2,2,2-tetraphenyl-3-(triphenylpho-
sphanylidene)-10H-spiro[1,2]azaphosphetidene-4,20-naph-
thalen]-10-one (25). The initial step in this reaction is
nucleophilic attack by the carbanion center of the phos-
phorane preferentially at the electron-deficient carbon–
nitrogen double bond [32–35], rather than the carbonyl
group of the bifunctional monoanil. The IR and 31P NMR
were reasons for assigning structure 25. The IR spectrum of
compound 25 showed bands at 1,660 (C=O), 1,592 (C=P),
and 1,435 cm-1 (P–Ar). In the 31P NMR of 25, two signals
were observed at 21.23 (C=P) and 29.84 ppm (N–P–C)
(Scheme 6).
As a point of interest to prepare heterocyclic pyridazines,
the behavior of 2-(2-phenylhydrazono)naphthalen-1(2H)-
one (26) towards (N-phenyliminovinylidene)triphenyl-
phosphorane (2a) was investigated, too. Thus, compound 26
was reacted with the phosphacumulene 2a in boiling toluene,
yielding N-(3-phenylbenzo[f]cinnolin-2(3H)-ylidene)ani-
line (28) and triphenylphosphine oxide. Michael addition of
the phenylhydrazone 26 to the phosphacumulene afforded
firstly the complicated phosphorane 27a, which cyclized
directly according to an intramolecular Wittig reaction to
yield the compound 28. On the other hand, (oxovinylid-
ene)triphenylphosphorane (2b) react less rapidly with the
phenylhydrazone 26 to yield the respective resonance-sta-
bilized phosphorane 27b. The most important features in the
spectroscopic data of N0-(1-oxonaphthalen-2(1H)-ylidene)-
N-phenyl-2-(triphenylphosphanylidene)acetohydrazide
(27b) are that the IR spectrum showed two C=O bands at
1,627 cm-1 (broad band) and the 1H NMR exhibits
Fig. 1 Molecular structure of pyridazinone 30 with 50 % probability
ellipsoids
reaction of 2-(2-phenylhydrazono)-1H-indene-1,3(2H)-
dione (29) with the phosphacumulene 2a. Compound 29 and
the reagent 2a react in a molar ratio of 1:1 in boiling toluene
to give 2-phenyl-3-(phenylimino)-2H-indeno[2,1-c]pyrida-
zin-9(3H)-one (30) together with triphenylphosphine oxide.
The mass spectrum of the pyridazinone 30 showed a peak at
m/z = 349 corresponding to its molecular ion. Moreover,
the proposed structure 30 was unequivocally confirmed by
x-ray crystallography (Fig. 1; Table 1).
Therefore, it is safe to state that the reaction course
between phosphacumulene ylides and monophenylhydraz-
one 29 is rather dependent on a number of parameters.
These include the nature of the reactant, the type of the
solvent, and the reaction temperature (Scheme 7).
absorption at 4.20 ppm (d, 2JHP = 19.1 Hz, CH=P). The 13
C
Biology
NMR of 27b disclosed the presence of the oxonaphthalene
C=O at 167.20, N–C=O at 152.00, and CH at 68.64 ppm. A
signal was observed at 29.80 ppm in its 31P NMR spectrum,
and an ion peak at m/z = 549 [(M-1)?] was observed in the
MS. Besides, the MS of the cyclic compound 28 showed a
peak at m/z = 346 [(M-1)?]. We also examined the
Chemotherapy is a major approach for both localized and
metastasized cancers [36]. Therefore, eight of the newly
synthesized compounds were screened for their in vitro
cytotoxic and growth inhibitory activities against two cell
lines tested, namely HELA (cervical carcinoma cell line)
123

Chemistry of phosphorus ylides
and MCF-7 (breast carcinoma cell line), in comparison
with the activity of the known anticancer reference drug
doxorubicin. The cytotoxic activities of the tested com-
pounds expressed as IC50 (the dose that reduces survival to
50 %) were compiled in Table 2.
considerably more active when compared with doxorubi-
cin. In case of the HELA carcinoma cell line, the indenone
23 bearing an oxaphosphinine exhibited a significant
inhibitory effect at low concentration (IC50 = 2.70 lg/
cm3) compared with doxorubicin (IC50 = 4.19 lg/cm3),
followed by 28, 20, 6a, and 25, recording IC50 = 2.85,
3.00, 3.45, and 3.90 lg/cm3, respectively. Besides, com-
pound 27b showed a remarkable growth inhibition but at a
slightly higher concentration (IC50 = 4.20 lg/cm3) than
the reference drug. On the contrary, the inhibition activity
was observed for 8 and 30 at higher concentration
(IC50 = 10.50 and 16.80 lg/cm3, respectively), which are
approximately twofold (for the former) and fourfold (for
the latter) less active than doxorubicin.
From Table 2, it is evident that all of the tested new
compounds reveal survival reduction in breast and cervical
carcinoma cell lines up to 50 % at different IC50 doses. In
general, compounds 6a, 20, 23, 25, and 28 appeared
˚
Table 1 Selected bond length/A and angles/° for compound 30
N1–N2
1.355 (12)
1.298 (13)
1.440 (13)
1.412 (12)
1.388 (2)
N2–N1–C13
116.05 (8)
120.48 (8)
107.59 (8)
133.15 (9)
127.93 (8)
129.70 (10)
125.59 (9)
104.35 (9)
0.24 (13)
177.20 (2)
-2.77 (13)
0.00 (13)
69.500 (2)
6.1 (2)
N1–C13
N2–C19
C3–N4
C3–N4–C8
C13–C7–C14
Promising results were also obtained against breast car-
cinoma cell line MCF-7. It is worth noticing that compounds
20, 23, 27b, and 28 have a growth inhibitory pattern on
MCF-7 like that on HELA, showing IC50 = 3.15, 2.85, 3.45,
and 3.60 lg/cm3, respectively, higher than the growth
inhibition for doxorubicin, IC50 = 4.35 lg/cm3. Moreover,
compound 25 showed an inhibitory effect on MCF-7, but in
this case at higher concentration (IC50 = 4.65 lg/cm3) than
the reference (IC50 = 4.35 lg/cm3).
C14–C7–C15
C3–C5
N4–C8–C15
C5–C24
O6–C18
C7–C13
C7–C15
C8–C15
C10–C19
C11–C14
C22–H22
1.379 (14)
1.215 (13)
1.434 (14)
1.341 (14)
1.452 (13)
1.374 (2)
C18–C11–C25
N1–C13–C18
C11–C18–C13
N2–N1–C13–C7
N2–N1–C13–C18
C8–N2–N1–C13
C19–N2–C8–N4
C8–N2–C19–C10
N1–C13–C18–O6
1.410 (14)
0.960 (12)
The above outlined results indicate that increasing the
aromaticity of the compounds may be the key factor for the
cytotoxicity activity against HELA and MCF-7 cell lines,
Scheme 7
123

I. F. Zeid et al.
Ltd., Essex, UK). The IR spectra were recorded in KBr
disks on Pye Unicam SP 3300 and Shimadzu FT IR 8101
PC infrared spectrophotometers (Pye Unicam Ltd. Cam-
bridge, England and Shimadzu, Tokyo, Japan,
respectively). 1H, 13C, and 31P NMR spectra were obtained
from a Jeol ECA 500 MHz NMR spectrometer (Tokyo,
Japan) using deuterated chloroform (CDCl3) as a solvent
and TMS as internal reference at 500, 125, and 200 MHz,
respectively. Mass spectra (EI-MS) were obtained at 70 eV
with a Finnegan MAT SSQ 7000 spectrometer (England).
Elemental analysis (C, H, N) results were recorded with an
Elementar Vario EL (Germany), phosphorus was measured
by spectrophotometric methods, and all of them agreed
satisfactory with the calculated values. X-ray crystallogra-
phy was carried out on a Kappa CCD Enraf–Nonius FR 590
diffractometer at the National Research Center, Dokki,
Cairo, Egypt. The reported yields are of pure isolated
materials obtained by column chromatography (silica gel
60, Merck). Thin layer chromatography (TLC) was per-
formed on Kieselgel F254 precoated plates (Merck).
Solvents were dried/purified according to literature
procedures.
Table 2 Cytotoxic activity of the synthesized compounds against
HELA and MCF-7
Compound
IC50/lg cm-3
HELA
MCF-7
DXR
6a
4.19
3.45
10.50
3.00
2.70
3.90
4.20
2.85
16.80
4.35
7.35
19.50
3.15
2.85
4.65
3.45
3.60
17.00
8
20
23
25
27b
28
30
IC50 value is defined as the concentration at which 50 % survival of
cells was observed
Negative control DMSO, no reactivity
particularly when the tested compounds contain one or two
triphenylphosphane groups.
Conclusion
1-[2,4-Bis(phenylimino)-3-(triphenylphosphanylidene)
cyclobutylidene]naphthalen-2(1H)-one
The reactions of nucleophilic active phosphacumulene,
phosphallene, and stable phosphonium ylides with qui-
nones, cyclobutendione, a,b-unsaturated compounds,
quinone monoanil, and monohydrazone represent an
interesting approach to the synthesis of new carbocyclic
and heterocyclic bioactive compounds. Cycloaddition
reactions took place and the reaction products depend on
the nature of the reagent used. Moreover, differences in the
nucleophilic character and reactivity of the phosphorus
reagents were noticed: phosphacumulene [ phosphal-
lene [ stable phosphonium ylides. Whereas the
phosphacumulene reacts smoothly with the reactants, the
phosphallene and stable phosphonium ylides react less
rapidly [37, 38]. This process can be considered as a simple
and efficient route for the formation of phosphanylidenes,
cyclobutanones, oxaphosphetanes, oxaphosphinines, az-
aphosphetidenes, and pyridazines. The preliminary
biological screening of certain compounds as anticancer
agents suggests that 6a, 20, 23, 25, and 28 emerge as the
most active, showing strong cytotoxicity which is higher
than the reference drug, doxorubicin. These findings could
provide a relevant basis for the development of the tested
compounds as anticancer drugs.
(6a, C44H31N2OP)
A mixture of 158 mg naphthalene-1,2-dione (1, 1 mmol)
and 754 mg (N-phenyliminovinylidene)triphenylphospho-
rane (2a, 2 mmol) [39] in 50 cm3 dry THF was stirred at
room temperature for 8 h. The solvent was evaporated under
reduced pressure to give a brown precipitate which was
recrystallized by plate TLC using petroleum ether (60–
80 °C)/chloroform (1:1, v/v) as an eluent to give 410 mg
ꢀ
(65 %) of 6a. M.p.: 155 °C; IR: m = 1,577 (C=O), 1,435 (P–
Ar) cm-1; 1H NMR (CDCl3): d = 7.05–7.80 (m, 31H, ArH)
ppm; 13C NMR (CDCl3): d = 120.76, 120.54, 122.09,
122.90, 123.87, 128.54, 128.64, 132.22, 132.14, 137.32,
138.66, 142.01, 143.85 (Ar C), 153.23 (C=P), 164.20 (C=N),
187.78 (C=O) ppm; 31P NMR (CDCl3): d = 29.74 ppm;
MS: m/z (%) = 634.7 (M?, 10). Triphenylphosphine oxide
was isolated, m.p. and mixed m.p.: 151 °C.
2-(2-Oxonaphthalen-1(2H)-ylidene)-4-
(triphenylphosphanylidene)cyclobutane-1,3-dione
(6b, C32H21O3P)
A mixture of 158 mg naphthalene-1,2-dione (1, 1 mmol)
and 604 mg (oxovinylidene)triphenylphosphorane (2b,
2 mmol) [40] in 50 cm3 dry THF was stirred at room
temperature for 12 h. The crude brown precipitate obtained
was filtered off and recrystallized from methylene chloride
Experimental
and ether to afford 300 mg (62 %) of 6b. M.p.: 160 °C; IR:
1
Melting points were determined with an electrothermal
digital melting point apparatus (Electrothermal Engineering
m = 1,623 (2C=O, a broad band), 1,434 (P–Ar) cm-1; H
ꢀ
NMR (CDCl3): d = 7.00–7.90 (m, 21H, ArH) ppm; 13C
123

Chemistry of phosphorus ylides
NMR (CDCl3): d = 124.09, 128.55, 128.66, 132.10,
132.18, 132.90, 133.29, 140.21, 143.65, 143.88, 144.49,
146.65 (Ar C), 155.78 (C=P), 187.00 (C=O, naphthale-
none), 199.45 (C=O, cyclobutanone) ppm; 31P NMR
(CDCl3): d = 29.95 ppm; MS: m/z (%) = 484.4 ([M-
1]?, 10). Triphenylphosphine oxide was isolated, m.p. and
mixed m.p.: 151 °C.
precipitate which upon recrystallization from ether gave
ꢀ
370 mg (56 %) of 11. M.p.: 120 °C; IR: m = 1,583 (C=O, a
broad band), 1,436 (P–Ar) cm-1
;
1H NMR (CDCl3):
3
d = 2.70 (s, 3H, CH3), 3.75 (d, 1H, JPH = 13.5 Hz,
CH=P), 7.30–7.90 (m, 30H, ArH) ppm; 13C NMR (CDCl3):
d = 24.20 (CH3), 29.00 (CH), 114.37, 122.09, 123.12,
124.86, 125.54, 130.94, 131.77, 134.58, 136.27, 143.21,
145.02 (Ar C), 166.15 (C=P), 169.80 (C=N), 199.00 (C=O)
ppm; 31P NMR (CDCl3): d = 26.26 ppm; MS: m/z (%) =
652.7 ([M?1]?, 4).
2,3-Diphenyl-4-[2,4-bis(phenylimino)-3-(triphenylphosphan-
ylidene)cyclobutylidene]cyclobut-2-en-1-one
(8, C50H35N2OP)
A mixture of 234 mg 3,4-diphenylcyclobut-3-ene-1,2-dione
(7, 1 mmol) [41] and 754 mg (N-phenyliminovinylidene)tri-
phenylphosphorane (2a, 2 mmol)wererefluxedin30 cm3 dry
toluene for 8 h. The solvent was evaporated under reduced
pressure to give a brown precipitate, which was recrystallized
from ethanol to afford 490 mg (69 %) of 8. M.p.: 235 °C; IR:
4-[2,4-Bis(phenylimino)-3-(triphenylphosphanylidene)
cyclobutylidene]-2,5-diphenylcyclohexa-2,5-dienone
(13, C52H37N2OP)
A mixture of 260 mg 2,5-diphenylcyclohexa-2,5-diene-
1,4-dione (12, 1 mmol) [44, 45] and 754 mg (N-pheny-
liminovinylidene)triphenylphosphorane (2a, 2 mmol) in
50 cm3 dry THF was stirred at room temperature for
10 h. The brown precipitate obtained was filtered off and
recrystallized from ether to afford 510 mg (69 %) of 13.
ꢀ
m = 1,650 (C=O), 1,593 (C=N), 1,491 (C=P), 1,441 (P–Ar)
cm-1; 1H NMR (CDCl3):d = 7.47–7.72 (m, 35H, ArH) ppm;
13C NMR (CDCl3): d = 114.76, 116.56, 116.99, 118.07,
120.49, 121.63, 122.33, 124.12, 125.20, 125.54, 131.96,
136.27, 144.01 (Ar C), 153.82 (C=P), 166.65 (C=N), 170.10
(C=O) ppm; 31P NMR (CDCl3): d = 30.07 ppm; MS:
m/z (%) = 710.8 (M?, 7). Triphenylphosphine oxide was
isolated, m.p. and mixed m.p.: 151 °C.
ꢀ
M.p.: 215 °C; IR: m = 1,593 (C=O and C=N, a broad
band), 1,434 (P–Ar) cm-1 1H NMR (CDCl3):
;
d = 7.13–7.71 (m, 37H, ArH) ppm; 13C NMR (CDCl3):
d = 118.87, 119.23, 122.09, 126.34, 128.04, 128.94,
129.25, 129.34, 130.65, 131.22, 132.08, 138.64, 145.21,
146.45 (Ar C), 158.60 (C=P), 165.35 (C=N), 187.33 (C=O)
ppm; 31P NMR (CDCl3): d = 29.93 ppm; MS: m/z (%) =
734.8 ([M-2]?, 3). Triphenylphosphine oxide was iso-
lated, m.p. and mixed m.p.: 151 °C.
4-(2-Oxopropylidene)-2,3-diphenylcyclobut-2-en-1-one
(10, C44H14O2)
A solution of 318 mg acetylmethylenetriphenylphosphor-
ane (9, 1 mmol) [42] in 30 cm3 of dry toluene was added
dropwise to a stirred solution of 234 mg 3,4-diphenylcy-
clobut-3-ene-1,2-dione (7, 1 mmol). The reaction mixture
refluxed for 20 h. After toluene was distilled off under
reduced pressure, the residue was treated with dry ether,
filtered off, and recrystallized from benzene/petroleum
ether (40–60 °C) to give brown crystals, 188 mg (65 %) of
2-[4-[2,4-Bis(phenylimino)-3-(triphenylphosphanylidene)-
cyclobutylidene]-2,5-diphenylcyclohexa-2,5-dienylidene]-
1-phenylethanone (16, C60H43N2OP)
A mixture of 362 mg 4-(2-oxo-2-phenylethylidene)-2,5-diphe-
nylcyclohexa-2,5-dienone (15, 1 mmol) [43] and 754 mg (N-
phenyliminovinylidene)triphenylphosphorane (2a, 2 mmol) in
50 cm3 dry toluene was refluxed for 8 h. The solvent was
evaporated under reduced pressure to afford a pale yellow
precipitate which was recrystallized from ethanol to give
ꢀ
10. M.p.: 162 °C; IR: m = 1,689 (C=O, acetyl), 1,637
1
(C=O, cyclobutenone) cm-1; H NMR (CDCl3): d = 2.70
(s, 3H, CH3), 6.00 (s, 1H, CH), 7.50–8.00 (m, 10H, ArH
and cyclobutylidene H) ppm; 13C NMR (CDCl3):
d = 29.30 (CH3), 122.99, 124.11, 124.86, 127.54,
128.04, 136.28, 137.29 (Ar C), 153.50 (CH–C=O) 187.60
(C=O, cyclobutenone), 193.07 (C=O, acetyl) ppm; MS:
m/z (%) = 274.3 (M?, 7). Triphenylphosphine oxide was
isolated, m.p. and mixed m.p.: 151 °C.
ꢀ
430 mg (51 %) of 16. M.p.: 180 °C; IR: m = 1,648 (C=O and
C=N, a broad band), 1,401 (P–Ar) cm-1; 1H NMR (CDCl3):
d = 6.90 (s, 1H, CH), 7.30–7.80 (m, 43H, ArH) ppm; 13C
NMR (CDCl3): d = 117.19, 122.03, 123.10, 126.16, 128.27,
128.51, 129.44, 129.50, 129.59, 132.82, 133.26, 133.26,
133.34, 141.65, 143.33 (Ar C), 147.5 (C=P), 168.90 (C=N),
182.73 (C=O) ppm; 31P NMR (CDCl3): d = 29.78 ppm; MS:
m/z (%) = 836.8 ([M-2]?, 3). Triphenylphosphine oxide was
isolated, m.p. and mixed m.p.: 151 °C.
1-[7,8-Diphenyl-3-(phenylimino)-4-(triphenylphosphan-
ylidene)-2-oxabicyclo[4.2.0]octa-1(6),7-dien-5-yl]-
ethanone (11, C45H31NO2P)
A mixture of 274 mg 4-(2-oxopropylidene)-2,3-diphenyl-
cyclobut-2-en-1-one (10, 1 mmol) [43] and 377 mg (N-
phenyliminovinylidene)triphenylphosphorane (2a, 1 mmol)
in 50 cm3 dry toluene was refluxed for 12 h. The solvent was
evaporated under reduced pressure to afford a brown
10-[2,4-Bis(phenylimino)-3-(triphenylphosphanylidene)-
cyclobutylidene]-2,3-dimethylanthracen-9(10H)-one
(18, C50H37N2OP)
A mixture of 236 mg 2,3-dimethylanthracene-9,10-dione
(17, 1 mmol) [46] and 754 mg (N-phenyliminovinylid-
123

I. F. Zeid et al.
ene)triphenylphosphorane (2a, 2 mmol) in 50 cm3 dry
toluene was stirred at room temperature for 15 h. The
solvent was evaporated under reduced pressure to give a
green precipitate which was recrystallized from benzene to
2,2,2,4-Tetraphenylindeno[2,1-e][1,2]oxaphosphinin-
5(2H)-one (23, C35H25O2P)
A mixture of 234 mg 2-benzylidene-1H-indene-1,3(2H)-
dione (21a, 1 mmol) [49] and 536 mg hexaphenylcarbodi-
phosphorane (19, 1 mmol) in 50 cm3 dry THF was stirred
at room temperature for 8 h. The solvent was evaporated
under reduced pressure and the remaining residue was
chromatographed on silica gel using chloroform/ethyl
acetate (8:2, v/v) as an eluent to afford 280 mg (55 %) of
ꢀ
afford 460 mg (65 %) of 18. M.p.: 160 °C; IR: m = 1,597
(C=O), 1,434 (P–Ar) cm-1; 1H NMR (CDCl3): d = 2.16 (s,
3H, CH3), 2.20 (s, 3H, CH3), 7.25–8.06 (m, 26H, ArH) ppm;
13C NMR (CDCl3): d = 20.05 (CH3), 23.00 (CH3), 120.11,
122.19, 126.95, 127.46, 128.37, 128.56, 128.66, 129.54,
132.05, 132.14, 132.22, 134.46, 139.54, 140.67 (Ar C),
151.87 (C=P), 162.20 (C=N), 182.00 (C=O) ppm; 31P NMR
(CDCl3): d = 19.21 ppm; MS: m/z (%) = 710.8 ([M-2]?,
3). Triphenylphosphine oxide was isolated, m.p. and mixed
m.p.: 151 °C.
ꢀ
23. M.p.: 152 °C; IR: m = 1,640 (C=O), 1,434 (P–Ar)
cm-1; H NMR (CDCl3): d = 4.73 (d, 1H, JHP = 17 Hz,
CH=P), 7.42–7.60 (m, 24H, ArH) ppm; 13C NMR (CDCl3):
d = 105.56 (CH–P), 122.37, 123.89, 123.19, 125.33,
126.04, 129.52, 132.69, 132.73, 132.78, 133.39 (Ar C),
177.10 (C=O) ppm; 31P NMR (CDCl3): d = 21.26 ppm;
MS: m/z (%) = 506.5 ([M-2]?). Triphenylphosphane was
isolated, m.p. and mixed m.p.: 78 °C.
1
2
2,3-Dimethyl-20,20,20-triphenyl-30-(triphenylphosphan-
ylidene)-10H-spiro[anthracene-9,40-[1,2]oxaphosphetan]-
10-one (20, C53H42O2P2)
A mixture of 236 mg 2,3-dimethylanthracene-9,10-dione
(17, 1 mmol) and 536 mg hexaphenylcarbodiphosphorane
(19, 1 mmol) [47] in 40 cm3 dry toluene was stirred at
room temperature for 1 h. The precipitate obtained was
filtered off and recrystallized from ether to afford 430 mg
1,2,2,2-Tetraphenyl-3-(triphenylphosphanylidene)-10H-
spiro[1,2]azaphosphetidine-4,20-naphthalen]-10-one
(25, C53H41NOP2)
A mixture of 233 mg 2-(phenylimino)naphthalen-1(2H)-
one (24, 1 mmol) [50] and 536 mg hexaphenylcarbodipho-
sphorane (19, 1 mmol) in 50 cm3 dry THF was refluxed for
8 h. The solvent was evaporated under reduced pressure to
give a brown precipitate which was crystallized from ether
to afford 550 mg (71 %) of 25. M.p.: 202 °C; IR:
ꢀ
(55 %) of 20. M.p.: 145 °C; IR: m = 1,625 (C=O), 1,435
1
(P–Ar) cm-1; H NMR (CDCl3): d = 2.32 (s, 3H, CH3),
2.41 (s, 3H, CH3) 7.16–7.57 (m, 36H, ArH) ppm; 13C NMR
(CDCl3): d = 18.80 (CH3), 19.01 (CH3), 71.40 (O–C–
C=P), 117.23, 119.89, 125.12, 126.26, 128.74, 129.59,
132.81, 133.47, 133.30, 135.99, 137.08, 138.67, 143.11 (Ar
C), 152.63 (C=P), 182.40 (C=O) ppm; 31P NMR (CDCl3):
d = 15.98 (C=P), 21.23 (O–P–C) ppm; MS: m/
z (%) = 770.8 ([M-2]?).
mꢀ = 1,660 (C=O), 1,592 (C=P), 1,435 (P–Ar) cm-1; H
1
NMR (CDCl3): d = 7.22–7.41 (m, 41H, ArH) ppm; 13C
NMR (CDCl3): d = 119.07, 119.22, 121.12, 122.29,
124.33, 125.67, 126.53, 128.42, 128.51, 129.43, 131.92,
133.28, 137.08, 138.43, 140.44 (Ar C), 148.55 (C=P),
181.29 (C=O) ppm; 31P NMR (CDCl3): d = 21.23 (C=P),
29.84 (N–P–C) ppm; MS: m/z (%) = 767.8 ([M-2]?).
5-Oxo-2,2,2-triphenyl-3-(triphenylphosphanylidene)-2,3-
dihydroindeno-[2,1-e][1,2]oxaphosphinine-4,4(5H)-
dicarbonitrile (22b, C49H34N2O2P2)
N0-(1-Oxonaphthalen-2(1H)-ylidene)-N-phenyl-2-
(triphenylphosphanylidene)acetohydrazide
A mixture of 208 mg 2-(1,3-dioxo-1H-inden-2(3H)-yli-
dene)malononitrile (21b, 1 mmol) [48] and 536 mg
hexaphenylcarbodiphosphorane (19, 1 mmol) in 50 cm3
dry THF was stirred at room temperature for 8 h. The
solvent was evaporated under reduced pressure to give a
brown precipitate which was chromatographed on silica gel
using chloroform/ethyl acetate (6:4, v/v) as an eluent to
afford 450 mg (60 %) of 22b. M.p.: [350 °C; IR:
(27b, C36H27N2O2P)
A mixture of 248 mg 2-(2-phenylhydrazono)naphthalen-
1(2H)-one (26, 1 mmol) [51] and 302 mg (oxovinylid-
ene)triphenylphosphorane (2b, 1 mmol) in 50 cm3 dry
toluene was refluxed for 15 h. The solvent was evaporated
under reduced pressure to give a yellow precipitate which
was chromatographed on silica gel using chloroform/
acetone (6:4, v/v) as an eluent to afford 366 mg (66 %) of
ꢀ
m = 2,193 (C:N), 1,666 (C=O), 1,621 (C=P), 1,435 (P–
ꢀ
27b. M.p.: 172 °C; IR: m = 1,627 (2C=O, a broad band),
Ar) cm-1 1H NMR (CDCl3): d = 7.44–7.73 (m, 34H,
;
1,591 (C=P), 1,435 (P–Ar) cm-1
;
1H NMR (CDCl3):
ArH) ppm; 13C NMR (CDCl3): d = 119.20 (C:N),
122.55, 128.90, 128.98, 129.07, 129.25, 132.15, 132.22,
132.30, 132.84, 134.18, 134.80, 140.67, 143.265, 144.43
(Ar C), 156.21 (C=P), 182.97 (C–O), 196.08 (C=O) ppm;
31P NMR (CDCl3): d = 21.23 (C=P), 26.10 (O–P–C) ppm;
MS: m/z (%) = 742.7 ([M-2]?).
2
d = 4.20 (d, 1H, JHP = 19.1 Hz, CH=P), 7.23–7.69 (m,
26H, ArH) ppm; 13C NMR (CDCl3): d = 118.22, 120.09,
122.33, 123.26, 124.64, 128.53, 128.63, 128.88, 130.99,
134.39, 139.58, 142.07 (Ar C), 152.02 (C=P), 157.80 (C=O,
acetamide), 167.20 (C=O, naphthalenone) ppm; 31P NMR
(CDCl3): d = 29.80 ppm; MS: m/z (%) = 549 ([M-1]?, 6).
123

Chemistry of phosphorus ylides
N-(3-Phenylbenzo[f]cinnolin-2(3H)-ylidene)aniline
(28, C24H17N3)
Table 3 Crystal structure and data refinement parameters for com-
pound 30
A mixture of 248 mg 2-(2-phenylhydrazono)naphthalen-
1(2H)-one (26, 1 mmol) and 377 mg (N-phenyliminoviny-
lidene)triphenylphosphorane (2a, 1 mmol) in 50 cm3 dry
toluene was refluxed for 8 h. The solvent was evaporated
under reduced pressure to give an orange precipitate which
was chromatographed on silica gel using acetone/chloro-
form (8:2, v/v) as an eluent to afford 180 mg (52 %) of 28.
Empirical formula
C23H15N3O
349.393
Monoclinic
23.9632(5)
9.2543(2)
17.0030(4)
90.00
Formula weight
Crystal system/space group
˚
a/A
˚
b/A
˚
c/A
a/°
b/°
c/°
-1
M.p.: 108 °C; IR: m = 1,590 (C=N) cm
;
1H NMR
ꢀ
115.5013(9)
90.00
(CDCl3): d = 7.22–7.54 (m, 17H, ArH) ppm; 13C NMR
(CDCl3): d = 116.88, 120.09, 121.33, 123.42, 128.22,
128.42, 128.51, 129.16, 131.92, 131.97, 132.06, 133.24,
137.21, 138.98 (Ar C), 155.00 (C=N) ppm; MS: m/
z (%) = 346 ([M-1]?, 12). Triphenylphosphine oxide
was isolated, m.p. and mixed m.p.: 151 °C.
3
˚
V/A
3,403.28(13)
8
Z
Dx/Mg cm-3
l/mm-1
1.364
0.09
Color/shape
Dark brown/prismatic
298
Temp./K
2-Phenyl-3-(phenylimino)-2H-indeno[2,1-c]pyridazin-
9(3H)-one (30, C23H15N3O)
h range for collection
Reflection collected
Independent reflections
Data/restraints/
parameters
2.910–27.51
2,528
A mixture of 250 mg 2-(2-phenylhydrazono)-1H-indene-
1,3(2H)-dione (29, 1 mmol) [52] and 377 mg (N-pheny-
liminovinylidene)triphenylphosphorane (2a, 1 mmol) in
50 cm3 dry toluene was refluxed for 7 h. The solvent
was evaporated under reduced pressure to give an orange
precipitate, which was chromatographed on silica gel
using petroleum ether (60–80 °C)/chloroform (7:3, v/v)
as an eluent to afford 30, then recrystallized from a
mixture of dichloromethane and ether (1:3) to afford,
after standing overnight and cooling, orange crystals;
4,248
0
244
R(gt)
0.038
Final R indices [I [ 3(I)]
Rint 0.024
Cytotoxicity screening
The present study aimed to illustrate the effect of some
newly synthesized compounds on the human cervical car-
cinoma cell line (HELA) and human breast carcinoma cell
line (MCF-7) in comparison with doxorubicin (DXR), in a
trial to get more effective and less toxic agents. Experi-
ments were set up using the two human carcinoma cell lines
to identify the potential toxicity of eight selected newly
synthesized compounds (6a, 8, 20, 23, 25, 27b, 28, and 30)
along with DXR as a standard reference compound in the
sulforhodamine B (SRB) assay reported by Skehan et al.
[54]. Cells were plated in 96-multiwell plates (104 cells/
well) for 24 h before treatment with compounds to allow
attachment of cells to the wells. Different concentrations of
the compound under test (0, 1, 2.5, 5, and 10 lg/well) were
added to the cell monolayer. Each concentration was eval-
uated three times (each dose was incubated with the cells in
three different wells). Monolayer cells were incubated with
the compounds for 48 h at 37 °C and in an atmosphere of
5 % CO2. After 48 h, the cells were fixed, washed, and
stained with SRB. Excess stain was washed with acetic acid
and the attached stain was recovered with a tris EDTA
buffer. The color intensity was measured using an ELISA
reader. The relation between the surviving fraction and the
concentration (lg cm-3) was plotted to obtain the survival
ꢀ
230 mg (66 %) of 30. M.p.: 255 °C; IR: m = 1,705
(C=O), 1,640 (C=N) cm-1 1H NMR (CDCl3):
;
d = 6.90–7.78 (m, 15H, ArH) ppm; 13C NMR (CDCl3):
d = 111.08 (C–C=NPh), 114.56, 121.75, 121.32, 122.26,
122.87, 124.94, 126.84, 128.16, 135.90, 138.39, 1,389.34,
140.67, 143.81, 143.98, 145.02 (Ar C), 162.20 (C=N),
185.08 (C=O) ppm; MS: m/z (%) = 349 (M?, 33).
Triphenylphosphine oxide was isolated, m.p. and mixed
m.p.: 151 °C.
A single crystal of compound 30 was grown by slow
crystallization in a mixture of CH2Cl2 and ether (1:3). The
crystal structure was solved and refined using maxus (no-
nius, Deflt and MacScience, Japan) [53]. Mo-Ka radiation
˚
(k = 71,073 A) and a graphite monochromator were used
for data collection. The chemical formula and ring labeling
system are shown in Table 3. Crystallographic data
(excluding structure factors) for the structure in this paper
have been deposited with the Cambridge Crystallographic
Data Center as supplementary publication number CCDC-
860453. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: ?44-(0)1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk).
123

I. F. Zeid et al.
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23. Schlosser M, Iskala A, Tarchini C, Tuong HB (1975) Chimia
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24. Bestmann HJ, Schmid G (1974) Angew Chem Int Ed 13:273
25. Vedejs E, Marth CF (1989) J Am Chem Soc 111:1519
26. Schlosser M, Christmann KF (1967) Liebigs Ann Chem 708:1
27. Schlosser M, Christmann KF (1965) Angew Chem Int Ed 4:689
28. Fliszar S, Hudson RF, Salvadori G (1963) Helv Chim Acta
46:1580
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