Reactions of 5(4H)-oxazolones with Wittig-Horner reagents: Novel synthesis of dioxopyrrolidinephosphonates and phosphonoalkanoates with anticipated schistosomicidal activity

Article abstract of DOI:10.1515/znb-2008-1012

4-Benzylidene-2-phenyl-5(4H)-oxazolones react with Wittig-Horner reagents in the presence of alcoholic sodium alkoxide to give novel dioxopyrrolidinephosphonates, diethyl [3-(benzoylamino)-1-cyano-2-oxo-4- phenylbut-3-en-1-yl]phosphonate and phosphonoalkenoate derivatives. Both the phosphonate adducts and the ester products were also isolated from the reaction of oxazolones with triethyl phosphonoacetate using alcoholic sodium ethoxide and/or sodium hydride as a base. Possible reaction mechanisms are considered, and the structural assignments are based on analytical and spectroscopic results. The biological evaluation of the new compounds is reported.

Full text of DOI:10.1515/znb-2008-1012

Reactions of 5(4H)-Oxazolones with Wittig-Horner Reagents:
Novel Synthesis of Dioxopyrrolidinephosphonates and Phosphono-
alkanoates with Anticipated Schistosomicidal Activity
Leila S. Boulosa, Mona H. N. Arsaniousa, Ewies F. Ewiesa, and Fatem Ramzyb
a National Research Centre, Dokki, Cairo, Egypt
b Parasitology Department, Theodor Bilharz Research Institute, Imbaba, Egypt
Reprint requests to Prof. Dr. Leila S. Boulos. E-mail: leilagoubran@yahoo.com
Z. Naturforsch. 2008, 63b, 1211 – 1218; received June 6, 2008
4-Benzylidene-2-phenyl-5(4H)-oxazolones react with Wittig-Horner reagents in the presence of
alcoholic sodium alkoxide to give novel dioxopyrrolidinephosphonates, diethyl [3-(benzoylamino)-
1-cyano-2-oxo-4-phenylbut-3-en-1-yl]phosphonate and phosphonoalkenoate derivatives. Both the
phosphonate adducts and the ester products were also isolated from the reaction of oxazolones with
triethyl phosphonoacetate using alcoholic sodium ethoxide and/or sodium hydride as a base. Possi-
ble reaction mechanisms are considered, and the structural assignments are based on analytical and
spectroscopic results. The biological evaluation of the new compounds is reported.
Key words: 5(4H)-Oxazolones, Wittig-Horner Reagents, Dioxopyrrolidinephosphonates
Introduction
idin-3-yl]-phosphonate (3a) is deduced from its spec-
troscopic data (Scheme 1, Experimental Section).
Similarly, compound 2a reacts with trimethyl phos-
phonoacetate (1b), in the presence of methano-
lic sodium methoxide solution, to give a color-
less crystalline compound formulated as dimeth-
yl [1-benzoyl-5-benzylidene-2,4dioxopyrrolidin-3-yl]-
phosphonate (3b) (Scheme 1). Structure 3b was es-
tablished on the basis of its spectral data (cf. Experi-
mental Section). A possible explanation for the reac-
tion course of 2a with Wittig-Horner reagents 1a and
1b is shown in Scheme 1. Initial attack of the phos-
phonate carbanion 1a and/or 1b on the lactone car-
bonyl group in 2a followed by azlactone ring open-
ing (under the influence of the alkoxide present in
the reaction medium) [15, 16] accompanied by elim-
ination of the appropriate alcohol molecule from the
intermediate A, gives the cyclic products 3a and 3b
(Scheme 1).
Oxazolones exhibit a wide spectrum of pharmaco-
logical activities including anticancer, antimicrobial,
antifungal, and antagonistic [1 – 3] activity. 5(4H)-
Oxazolones that are internal anhydrides of acyl amino
acids make an important class of five-membered hete-
rocycles which are also used for the synthesis of sev-
eral organic molecules, including amino acids, pep-
tides [4 – 6], antimicrobial or antitumor agents [7, 8].
This together with our interest in organophosphorus
chemistry [9 – 14] triggered the synthesis of new phos-
phorus compounds incorporating such important units
that may possibly lead to biological activity.
The present study deals with the reaction of Wittig-
Horner reagents 1a – c with 5(4H)-oxazolones 2a – e
(Fig. 1). The purpose of this study was to determine
the preferential site of attack by these reagents and to
synthesize new phosphonate adducts with anticipated
schistosomicidal activity.
Next, when 2a was allowed to react with one equiv-
alent of diethyl (cyanomethyl)phosphonate (1c), in
the presence of alcoholic sodium ethoxide solution,
Results and Discussion
When 4-benzylidene- 2 - phenyl- 5(4H)- oxazolone adduct 4 was isolated in 75 % yield (Scheme 1). The
(2a) was treated with one equivalent of triethyl structure of diethyl [3-(benzoylamino)-1-cyano-2-oxo-
phosphonoacetate (1a) in the presence of alco- 4-phenylbut-3-en-1-yl]phosphonate(4) is derived from
holic sodium ethoxide solution at r. t. for 4 h, its spectral data (cf. Experimental Section).
adduct 3a was isolated (Scheme 1). The structure
Furthermore, this study has been extended to in-
of diethyl [1-benzoyl-5-benzylidene-2,4-dioxopyrrol- clude the reaction of triethyl phosphonoacetate (1a)
c
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L. S. Boulos et al. · Reactions of 5(4H)-Oxazolones with Wittig-Horner Reagents
Fig. 1.
Scheme 1.
with 2b – c. When 2b was allowed to react with one the full set of its spectral data (cf. Experimental Sec-
equivalent of 1a, in the presence of alcoholic sodium tion). Compounds 4, 5a, and 5b are possibly obtained
ethoxide solution at r. t. for 8 h, adduct 5a was isolated through addition of the carbanion reagents 1c and 1a
(Scheme 2, Experimental Section).
to the lactone carbonyl group of the azlactone ring fol-
lowed by ring opening [15] due to the presence of a
base to give the final products 4, 5a, and 5b, respec-
tively.
Similarly, 2c reacts with triethyl phosphonoacet-
ate (1a) in alcoholic sodium ethoxide solution to
give a colorless crystalline compound formulated as
ethyl 1-(ethoxyphosphono)-3-benzamido-3-cyclohex-
When 4-[(4-methoxyphenyl)methylidene]-2-phen-
yl-2-oxopropanoate (5b) (Scheme 2). The structure of yl-1,3-oxazol-5(4H)-one (2d) was allowed to react
the new compound 5b is assigned on the basis of with one mole equivalent of 1a in alcoholic sodium
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L. S. Boulos et al. · Reactions of 5(4H)-Oxazolones with Wittig-Horner Reagents
1213
Scheme 2.
Scheme 3.
ethoxide solution at r. t. for 5 h, two adducts formulated instead of alcoholic sodium ethoxide, led to the for-
as compounds 6a and 7a were obtained (Scheme 3). mation of ethyl 1-(ethoxyphosphono)-3-benzamido-
Compound 6a (major product) was formulated as the 4-(4-methoxyphenyl)-2-oxobut-3-enoate (7a) in good
known ethyl 3-(4-methoxyphenyl)-2-[(phenylcarbon- yields together with ethyl 3-(4-methoxyphenyl)-2-
yl)amino]prop-2-enoate [16]. Carrying out the reac- [(phenylcarbonyl)amino]prop-2-enoate (6a) as the mi-
tion using sodium hydride in dry toluene as a base nor product (Scheme 3, Experimental Section).
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L. S. Boulos et al. · Reactions of 5(4H)-Oxazolones with Wittig-Horner Reagents
Table 1. In vitro evaluation of compounds for schistosomicidal activity at 10 µg mL−1
.
Compound
1st day
No. of worms (12)
2nd day
No. of worms (12)
3rd day
No. of worms (12)
4th day
No. of worms (12)
Dead
Mortality (%)
Dead
Mortality (%)
Dead
Mortality (%)
Dead
Mortality (%)
3a
4
0
0
0
0
0
12
0
33.3
0
0
0
0
0
100
0
9
0
0
0
0
0
12
0
75
0
0
0
0
0
100
0
10
7
2
3
0
1
12
0
100
58.3
16.7
25
12
12
2
3
1
5
12
0
100∗
100∗
16.7
25
3b
5a
5b
6a
0
8.3
6b
8.3
100
0
41.7
100
0
PZQ (+ve) control
DMSO (−ve) control
Table 2. In vitro antischis-
tosomal effect (IC50 and
IC90) of compounds com-
pared to PZQ.
We found that, when 2e reacts with triethyl phos- Compound
IC50 IC90
5.74 7.78
7.04 9.01
3a
phonoacetate (1a) in alcoholic sodium ethoxide so-
3b
lution, ethyl-2-(benzoylamino)-3-[4-(dimethylamino)-
PZQ(+ve) control 0.4
0.64
phenyl]acrylate (6b) is the sole reaction product. When
2e reacts with 1a using sodium hydride in toluene in-
stead of alcoholic sodium ethoxide, two products for-
mulated as 6b (12 %) and 7b (75 %) were obtained
(Scheme 3).
Asia, Central and South America [19]. It is a para-
sitic uncontrolled disease and represents an interna-
tional as well as an important national health problem
in Egypt. One of the most important methods for con-
trolling schistosomiasis is through its intermediate host
by using a chemical molluscidal agent. Therefore, the
present work aimed to introduce oxazolone derivatives
and test them for new antischistosomal activity in vitro
on Schistosoma mansoni worms.
The organophosphorus and ester compounds were
tested in a concentration of 10 µg mL−1 for in vitro
bioactivity on viable Schistosoma mansoni mature
worms in culture medium (RPMI 1640). Three repli-
cates were used for each compound, and three pairs of
worms, males and females equally represented, were
placed in each vial containing the medium and the
compound. The worms were considered dead when
they did not show mobility for one minute. The vi-
ability ratio of worms was determined by calculating
the number of dead worms relative to the total number
of worms. The results were compared with negative
dimethylsulfoxide (DMSO) and positive (praziquan-
tel) controls. Praziquantel (PZQ) is the mainstay of
schistosomiasis control programs worldwide, in other
words an enormous investment in terms of money,
manpower and training rests on the efficacy of a sin-
gle synthetic compound.
From the results of the present investigation, it can
be concluded that the reactions of oxazolones 2 with
Wittig-Horner reagents 1 lead to different products,
depending on the nature of the phosphonate anion,
the base used, as well as on the reactivity of the cor-
responding benzylidene moiety. We have noted that,
when electron donating groups are attached to the
arylidene ring as in compounds 2b and 2c the reac-
tion was directed to form the phosphonate products 5a
and 5b. However, when only an electron-donating sys-
tem is attached to the arylidene ring as in compounds
2d and 2e, both the phosphonate adducts (7a, 7b) and
the ester products (6a, 6b) were isolated. The yields
of products 6a, b and 7a, b depend markedly on the
substituents of the arylidene moiety as well as on the
base used. The significance of these findings is not
only the discovery of a new reactivity pattern for the
Wittig-Horner reagents but also the establishment of
a novel method for the synthesis of dioxopyrrolidine-
phosphonate, phosphonopropanoate, and phosphono-
butenoate derivatives.
Biological evaluation
The antischistosomal activity of the newly prepared
The present data revealed that both compounds
organophosphorus and ester compounds was tested in 3a and 3b induced in vitro antischistosomal activ-
vitro on Schistosoma mansoni worms. Schistosomia- ity (100 % mortality). Compounds 4a, 4b, 5a and 5b
sis is a disease related to water contact in agriculture showed various degrees of lethal effect (8.3 – 41.7 %
fields and is affecting millions of people in developing mortality) on worms at 10 µg mL−1 of the compounds
countries in tropical and subtropical parts of Africa, after 4 d of exposure (Table 1).
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L. S. Boulos et al. · Reactions of 5(4H)-Oxazolones with Wittig-Horner Reagents
1215
The two active compounds were further subjected ocyclic), 7.30 – 7.99 (m, 10H, 2 × Ph-H). – 13C{H} NMR
3
(125.76 MHz, CDCl3): δ = 14.1, 14.3 (2 × CH3, JCP
=
to determination of their inhibitory concentration (IC50
and IC90) values (Table 2). The compounds 3a and 3b
possess the strongest antischistosomal activity (IC50
values equal to or less than 10 µg mL−1) (Table 2),
and they are considered as promising bioactive com-
pounds which deserve further investigation. Therefore,
the present study is a trial to throw light on some new
chemotherapeutic antischistosomal drugs.
17.9 Hz), 33.7, 34.8 (d, JCP =133.53 Hz, C–P), 61.8, 62.7
2
(2 × CH2, JCP = 27.5 Hz), 127.6 – 133.0 (Ar-C), 132.1,
2
133.9 (C=CH), 165.5 (NCOPh), 166.8 (COCHP, JCP
=
25.5 Hz), 187.5 (C=O) [23]. – 31P NMR: δ = 20.34 [24]. –
MS (EI, 70 eV): m/z (%) = 427 (20) [M]+, 295 (95) [M–CO–
Ph–CO]+. – C22H22NO6P (427.38): calcd. C 61.83, H 5.19,
N 3.28, P 7.25; found C 61.90, H 5.25, N 3.35, P 7.30.
Reaction of trimethyl phosphonoacetate (1b) with
4-benzylidene-2-phenyl-5(4H)-oxazolone (2a)
Experimental Section
General remarks
A solution of sodium methoxide (0.054 g, 1 mmol) in
Melting points were determined in open glass capillar- absolute methanol (30 mL) was treated with an equimo-
ies using an Electrothermal IA 9000 Series digital melting lar amount of 1b, and then the oxazolone compound 2a
point apparatus (Electrothermal, Essex, U. K.) and are uncor- (0.16 g, 1 mmol) was added. The resulting reaction mix-
rected. Elemental analyses were performed with an Elemen- ture was stirred at r. t. for 4 h and then poured into a small
tar Vario EL, (Microanalytical Unit, National Research Cen- amount of water (2 mL) and extracted with ethyl acetate.
tre, Cairo, Egypt) and were in good agreement ( 0.2 %) with The extracts were dried and the solvents evaporated under
the calculated values. The IR spectra (KBr) were recorded on reduced pressure. The residue was crystallized from diethyl
an FT IR-8201 PC spectrophotometer (Schimadzu, Japan). ether to give 3b. M. p. 133 – 135 ◦C (diethyl ether). – IR
The 1H and 13C NMR spectra were measured on a Jeol (film): ν = 1135 (P–O), 1269 (P=O), 1579 (C=C, exo-
500 MHz spectrometer in [D6]DMSO or CDCl3. The chem- cyclic), 1627 (amide C=O), 1715 (C=O) cm−1. – 1H NMR
ical shifts were recorded relative to TMS. The 31P NMR (500 MHz, CDCl3): δ = 3.77, 3.84 (2d, 6H, JHH = 7.2,
spectra were taken with a Varian CFT-20 instrument vs. ex- 3JHP = 10.9 Hz, 2 × CH3O), 2.95, 3.03 (d, 1H, JHP
=
ternal 85 % H3PO4 as the standard. The mass spectra (EI) 21.6 Hz, CH–P), 7.26 (s, 1H, exocyclic CH), 7.32 – 7.88 (m,
were run at 70 eV on a Finnegan SSQ 7000 spectrometer 10H, 2 × Ph-H). – 13C{H} NMR (125.76 MHz, CDCl3):
2
(Thermo-instrument System Incorp., USA), m/z values are δ = 52.7, 52.8 (2 × CH3O, JCP = 28.5 Hz), 54.3, 56.4 (d,
given in Dalton. TLC (silica gel, aluminum sheets 60 F254
,
JCP = 130.4 Hz, C–P), 128.0 – 132.5 (Ar-C), 133.5 – 133.8
2
Merck, Darmstadt, Germany) was used for tracing the reac- (C=C), 164.3 (NCOPh), 165.4 (d, JCP = 26.35 Hz, amide
tions. Wittig-Horner reagents 1a – c and 5(4H)-oxazolones C=O), 190.3 (d, CO, JCP = 30.54 Hz). – 31P NMR: δ =
2
2a – e were prepared according to reported procedures [20 – 22.95. – MS (EI, 70 eV): m/z (%) = 399 (5) [M]+, 339 (100)
22].
[M–(CH3O)2]+. – C20H18NO6P (399.33): calcd. C 60.15,
H 4.54, N 3.51, P 7.76; found C 60.25, H 4.60, N 3.56,
P 7.82.
Reaction of triethyl phosphonoacetate (1a) with 4-benzylid-
ene-2-phenyl-5(4H)-oxazolone (2a)
Reaction of diethyl (cyanomethyl)phosphonate (1c) with 2a
A solution of sodium ethoxide (0.068 g, 1 mmol) in
absolute ethanol (30 mL) was treated with an equimolar
A solution of sodium ethoxide (0.068 g, 1 mmol) in abso-
amount of triethyl phosphonoacetate (1a), and then the ox- lute ethanol (30 mL) was treated with 1c (0.18 g, 1 mmol).
azolone 2a (0.16 g, 1 mmol) was added. The resulting re- Compound 2a (0.16 g, 1 mmol) was added, and the reaction
action mixture was stirred at r. t. for 4 h. Then the re- mixture was stirred at r. t. for 5 h, then poured into a small
action mixture was poured into a small amount of water, amount of water (2 mL). The mixture was extracted with
extracted with ethyl acetate, and the extracts were dried chloroform, dried, and the solvents were evaporated under
over anhydrous sodium sulfate and the solvents evaporated reduced pressure. The residue was washed with petroleum
◦
under reduced pressure. The residual material was recrys- ether (b. p. 40 – 60 C) and recrystallized from diethyl ether
tallized from ethyl acetate to give 3a. M. p. 130 – 132 ◦C to give 4. M. p. 136 – 137 ◦C (diethyl ether). – IR (film):
(ethyl acetate). – IR (film): ν = 1100 (P–O), 1245 (P=O), ν = 1129 (P–O), 1252 (P=O), 1590 (C=CH), 1690 (COPh),
1622 (C=C, exocyclic), 1645, 1650 (2 amide C=O), 1712 2230 (CN), 3235 (NH) cm−1. – 1H NMR (500 MHz,
(C=O) cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.23, CDCl3): δ = 1.36, 1.39 (2dt, 6H, JHH = 4.9, 4JHP = 4.85 Hz,
4
1.29 (2dt, 6H, 2 × CH3, JHH = 6.8, JHP = 4.1 Hz), 2.90 2 × CH3), 2.85 – 2.89 (d, 1H, JHP = 25 Hz, CH–P), 4.32, 4.35
3
(d, 1H, JHP = 21.20, CH–P), 4.16, 4.28 (2dq, 4H, 2 × CH2– (2dq, 4H, JHH = 7.6, JHP = 5.15 Hz, 2 × CH2–O–P), 6.89
3
O–P, JHH = 6.8, JHP = 5.9 Hz), 7.29 (s, 1H, C=CH ex- (s, 1H, C=CH), 8.15 (s, 1H, NH, exchangeable with D2O),
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L. S. Boulos et al. · Reactions of 5(4H)-Oxazolones with Wittig-Horner Reagents
7.28 – 7.95 (m, 10H, Ph-H). – 13C{H} NMR (125.76 MHz, 34.1 (d, JCP = 137.5 Hz, C–P), 59.7, 60.9 (ester CH2), 61.8,
[D6]DMSO): δ = 14.7 (s, 2 × CH3), 39.8 (d, JCP = 133 Hz, 61.9 (2 × CH2–O–P, 2JCP = 12.5 Hz), 120.3, 146.2 (C=CH),
C–P), 61.4 (s, 2 × CH2), 109.5 (C=CH), 114.9 (CN), 128.2 – 127.4 – 133.7 (Ar-C), 164.7 (amide, C=O), 165.6 (ester
2
133.7 (Ar-C), 165.4 (amide CO) 196.5 (d, C=O, JCP
=
C=O), 165.7 (COCH). – 31P NMR: δ = 23.02. – MS (EI,
31.05 Hz). – 31P NMR: δ = 14.96. – MS (EI, 70 eV): m/z 70 eV): m/z (%) = 465 (15) [M]+, 388 (10) [M–Ph]+, 345
(%) = 426 (8) [M]+, 306 (15) [M–NHCOPh]+, 295 (60) [M– (30) [M–NHCOPh]+, 287 (100) [(C2H5)2P(O)CHCO]+. –
PhCO–CN]+, 249 (15) [M–(C2H5O)2P(O)–CHCN]+, 105 C23H32NO7P (465.47): calcd. C 59.35, H 6.93, N 3.01,
(100) [PhCO]+. – C22H22NO6P (427.38): calcd. C 61.97, P 6.65; found C 59.44, H 7.10, N 3.07, P 6.71.
H 5.44, N 6.57, P 7.26; found C 62.03, H 5.49, N 6.62,
P 7.32.
General procedure for the reaction of triethyl phosphono-
acetate (1a) with 2d, 2e
General procedure for the reaction of triethyl phosphono-
acetate (1a) with 2b, c
a) In the presence of alcoholic sodium ethoxide
Sodium ethoxide (0.068 g, 1 mmol) in absolute alcohol
(30 mL) was added to a solution of an equimolar amount
of 1a, and then the starting material (2d, 2e) (1 mmol) was
added. The reaction mixture was stirred for 8 h at r. t., then
poured into water (1 – 2 mL). The mixture was extracted with
ethyl acetate (3 × 20 mL), and the extracts were dried over
anhydrous sodium sulfate and the solvents evaporated under
reduced pressure. The residue was subjected to silica gel col-
umn chromatography to give the products 6a, 7a and 5b.
A solution of sodium ethoxide (0.068 g, 1 mmol) in abso-
lute ethanol (30 mL) was treated with an equimolar amount
of the phosphonate 1a (0.22 g,1 mmol). After 5 min, 2b
or 2c (1 mmol) was added, and the reaction mixture was
stirred at r. t. for 8 h. The solution was poured into water (1 –
2 mL), the mixture extracted with ethyl acetate (3 × 20 mL),
the solution was dried, and the solvents were evaporated un-
der reduced pressure. The residue was recrystallized to give
adducts 5a, b.
◦
Adduct 5a: M. p. 105 – 107 ◦C (ethyl acetate). – IR (film)
ν = 1127 (P–O), 1239 (P=O), 1654, 1660 (amide C=O),
1711 (C=C), 1730 (CO), 3271 (broad band, NH) cm−1. –
1H NMR (500 MHz, CDCl3): δ = 1.29, 1.30 (2 × dt, 6H,
Adduct 6a: M. p. 99 – 101 C (ethyl acetate), eluent (ace-
tone : petroleum ether, 5 : 95, v : v). – IR (film) ν = 1609
(C=C), 1644 (amide CO), 1707 (ester CO), 3290 (broad
1
band, NH) cm−1. – H NMR (500 MHz, CDCl3): δ = 1.31
4
(t, 3H, CH3), 3.74 (s, 3H, OMe), 4.29 (q, 2H, CH2), 6.82 (s,
1H, C=CH), 7.24 – 7.86 (m, 9H, 2 × Ph-H), 8.2 (s, 1H, NH,
exchangeable with D2O). – 13C{H} NMR (125.76 MHz,
CDCl3): δ = 13.91 (Me), 40.6 (OCH3), 61.2 (CH2), 127.9 –
131.6 (Ar-C), 164.3 (amide CO), 165.2 (ester CO), 121.1,
134.2 (C=CH). – MS (EI, 70 eV): m/z (%) = 325 (20) [M]+,
280 (35) [M–C2H5O]+, 220 (10) [M–COPh]+, 105 (100)
[PhCO]+. – C19H19NO4 (325.35): calcd. C 70.14, H 5.89,
N 4.31; found C 70.21, H 5.95, N 4.38.
JHH = 6.8, JHP = 3.75 Hz, 2 × CH3), 1.31 (t, 3H, ester
CH3), 2.88, 2.93 (d, 1H, JHP = 26.15 Hz, CH–P), 3.7 (s,
3
9H, 3 × OCH3), 4.26, 4.27 (2 × dq, 4H, JHH = 6.8, JHP
=
5.1 Hz, 2 × CH2–O–P), 6.74 (s, 1H, C=CH), 7.20 – 7.52 (m,
7H, 2 × Ph-H), 7.86 (s, 1H, NH, exchangeable with D2O). –
13C{H} NMR (125.76 MHz, CDCl3): δ = 14.2 (s, 3 × CH3),
32.5, 33.0 (d, JCP = 125 Hz, C–P), 55.6 (s, 3 × OMe), 60.0,
61.9 (s, 3 × CH2), 125.9, 138.7 (C=CH), 127.5 – 133.5 (m,
2
Ar-C), 164.9, 165.6, 166.0 (3 × C=O, JCP = 28.27 Hz). –
31P NMR: δ = 22.3 ppm. – MS (EI, 70 eV): m/z (%) = 563
Adduct 7a: M. p. 198 – 201 ◦C, eluent (acetone : petroleum
(10) [M]+, 486 (40) [M–Ph]+, 458 (20) [M–COPh]+, 443 ether) (20 : 80, v/v). – IR (film): ν = 1109 (P–O), 1252
(15) [M–NHCOPh]+, 386 (85) [M–(3OCH3C6H2)]+, 105
(100) [PhCO]+. – C27H34NO10P (563.53): calcd. C 57.55,
H 6.08, N 2.49, P 5.50; found C 57.60, H 6.14, N 2.55,
P 5.56.
(P=O), 1622 (C=C), 1640, 1645 (amide C=O), 1720 (ester,
1
CO), 3310 (broad band, NH) cm−1. – H NMR (500 MHz,
4
CDCl3): δ = 1.03 – 1.6 (2 × dt, 6H, JHH = 6.9, JHP
=
5.2 Hz, 2 × CH3), 1.11 (t, 3H, ester CH3), 2.6, 2.7 (d, 1H,
Adduct 5b: M. p. 106 – 108 ◦C (ethyl acetate). – IR JHP = 20.1 Hz, CH–P), 3.6 (s, 3H, OMe), 3.65, 3.85 (2 × dq,
3
(film): ν = 1032 (P–O), 1219 (P=O), 1640, 1648 (amide 4H, JHH = 6.9, JHP = 6 Hz, 2 × CH2), 3.85 (q, 2H, es-
C=O), 1620 (C=C), 1722 (ester CO), 3324 (broad band ter CH2), 6.2 (s, 1H, C=CH), 7.1 – 7.8 (m, 9H, 2 × Ph-H),
NH) cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.09, 1.13, 9.04 (s, 1H, NH exchangeable with D2O). – 13C{H} NMR
1.57 (cyclohexylidene, CH2), 1.17, 1.19 (2 × dt, 6H, JHH
=
(125.76 MHz, CDCl3): δ = 7.6, 14.8 (3 × CH3), 54.4 (d,
4
7, JHP = 4 Hz, 2 × CH3), 1.20 (t, 3H, ester CH3), 3.04, JCP = 132 Hz, C–P), 61.6 (3 × CH2), 40.6 (OMe), 121.3,
3.15 (d, 1H, JHP = 21.4 Hz, CH–P), 4.04, 4.05 (2 × dq, 134.6 (C=CH), 127.4, 133.7 (Ar-C), 163.6 (amide C=O),
4H, JHH = 7, JHP = 5.2 Hz, 2 × CH2–O–P), 4.1 (q, 2H, 196.5, 207.1 (2 × CO). – 31P NMR: δ = 21.53. – MS
3
ester CH2), 7.48 – 7.91 (m, 5H, Ar-H), 9.7 (s, 1H, NH, (EI, 70 eV): m/z (%) = 503 (15) [M]+, 426 (10) [M–
exchangeable with D2O). – 13C{H} NMR (125.76 MHz, Ph]+, 398 (25) [M–COPh]+, 383 (20) [M–NHCOPh]+,
[D6]DMSO): δ = 13.8, 14.0 (2 × CH3, JHP = 14.3 Hz), 279 (65) [M–(C2H5O)2P(O)CH–COOC2H5]+, 105 (100)
3
16.09 (ester CH3), 27.5 – 32.4 (cyclohexylidene C), 33.0, [PhCO]+. – C25H30NO8P (503.48): calcd. C 59.64, H 6.01,
Unauthenticated
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L. S. Boulos et al. · Reactions of 5(4H)-Oxazolones with Wittig-Horner Reagents
1217
N 2.78, P 6.15; found C 59.73, H 6.07, N 2.85, P 8.21.
4.5 Hz, 2 × CH2), 4.21 (q, 2H, ester CH2), 6.6 (s, 1H,
C=CH), 6.84 – 7.79 (m, 9H, 2 × Ph-H), 7.91 (s, 1H, NH
exchangeable with D2O). – 13C{H} NMR (125.76 MHz,
CDCl3): δ = 14.6, 14.8 (3 × CH3), 39.8 (N(CH3)2), 52.8 (d,
JCP = 133.2 Hz, C–P), 61.6, 61.8 (3 × CH2), 114 (C=C),
164.6, 165.3 (amide C=O), 196 (ester CO), 120.59 – 134.80
(Ar-C). – 31P NMR: δ = 23.2. – MS (EI, 70 eV): m/z
(%) = 516 (10) [M]+, 472 (15) [M–N(CH3)2]+, 439 (30)
[M–Ph]+, 411 (25) [M–COPh]+, 396 (40) [M–NHCOPh]+,
292 (30) [M–(C2H5O)2P(O)CHCOO C2H5]+, 105 (100)
[PhCO]+. – C26H33N2O7P (516.52): calcd. C 60.46, H 6.44,
N 5.42, P 6.00; found C 60.53, H 6.48, N 5.48, P 6.07.
◦
Adduct 6b: M. p. 96 – 98 C (ethyl acetate). – IR (film):
ν = 1609 (amide CO), 1644 (C=C), 1707 (ester CO), 3295
(broad band NH) cm−1. – 1H NMR (500 MHz, CDCl3):
δ = 1.23 (t, 3H, CH3), 2.27 (s, 6H, N(CH3)2), 4.21 (q, 2H,
CH2), 6.67 (s, 1H, C=CH), 7.39 – 7.81 (m, 9H, 2 × Ph-H),
8.1 (s, 1H, NH, exchangeable with D2O). – 13C{H} NMR
(125.76 MHz, CDCl3): δ = 14.15 (Me), 39.6 (N(CH3)2),
60.26 (CH2), 120.50, 134.8 (C=CH), 121.3 – 131.6 (Ar-C),
165.3, 165.8 (2 × CO). – MS (EI, 70 eV): m/z (%) = 338 (5)
[M]+, 309 (10) [M–C2H5]+, 292 (30) [M–OC2H5]+, 264
(15) [M–COOC2H5]+, 105 (100) [PhCO]+. – C20H22N2O3
(338.40): calcd. C 70.99, H 6.55, N 8.28; found C 71.06,
H 6.60, N 8.34.
Biological evaluation of the tested compounds
Adult worms of Schistosoma mansoni (Egyptian strain)
were obtained by infecting Syrian golden hamsters
(Mesocricetus auratus) by percutaneous infection of 350 cer-
cariae per animal, freshly shed from infected Biomphalaria
alexandrina snails [17]. The animal experiments were car-
ried out according to the internationally valid guidelines in
an institution coping with biological ethics (Theodor Bilharz
Research Institute) [18]. Worms were obtained, by porto-
b) In the presence of sodium hydride
Triethyl phosphonoacetate (1a) (0.068 g, 1 mmol) was
dissolved in very dry toluene (25 mL), and then sodium hy-
dride (0.024 g, 1 mmol) was added carefully with stirring.
Then, the starting material (2d, e) (1 mmol) was added to
the mixture which was refluxed for 8 h. The volatile mate-
rials were evaporated under reduced pressure to give 6a, b
and 7a, b. Compounds 6a, b and 7a are the same products as
those obtained in the presence of sodium ethoxide.
mesenteric perfusion, 45 d post infection using citrated saline
1
(7.5 g L−1 Na citrate + 8.59 g L− NaCl).
Adduct 7b: M. p. 136 – 138 ◦C. Eluent (ace-
tone : petroleum ether, 20 : 80, v : v). – IR (film): ν =
1137 (P–O), 1223 (P=O), 1609 (C=C), 1640, 1644 (amide
C=O), 1707 (ester CO), 3309 (broad band, NH) cm−1. –
1H NMR (500 MHz, CDCl3): δ = 1.23, 1.24 (2 × t, 6H,
The worms in small sterilized sieves were washed three
times with phosphate buffer (pH = 7.4), then three times with
RPMI-1640 medium with L-glutamine containing antibiotics
(300 µg Streptomycin, 300 units Penicillin and 160 µg Gen-
tamycin) + 20 % foetal calf serum, inside a sterilization
laminar flow. Then the worms were poured into a small
4
JHH = 7.45, JHP = 3.7 Hz, 2 × CH3), 1.31 (t, 3H, ester
◦
petri dish. Compound samples were kept at −20 C in the
CH3), 2.26 (s, 6H, N(CH3)2), 2.71, 2.72 (d, 1H, JHP
20.19 Hz, CH–P), 4.13, 4.18 (2 × q, 4H, JHH = 7.45, 3JHP
=
=
dark.
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