Synthesis of novel 1,2-diphenylpyrrole derivatives using organophosphorus reagents and their antitumour activities

Article abstract of DOI:10.3184/174751914X13976652851990

The reactions are reported of 4-(furan-3-ylcarbonyl)-1,5- diphenylpyrrolidine-2,3-dione with six classes of organophosphorus reagents: carboalkoxymethylene triphenylphosphoranes, triphenyl (phenylimino)-λ5- phosphane, trialkylphosphonoacetates, trialkylph

Full text of DOI:10.3184/174751914X13976652851990

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 JUNE, 325–330
RESEARCH PAPER 325
Synthesis of novel 1,2-diphenylpyrrole derivatives using organophosphorus
reagents and their antitumour activities
Ewies F. Ewiesa, Naglaa F. Elsayeda, Leila S. Boulosa* and Abdel-Mohsen M. Solimanb
aDepartment of Organometallic and Organometalloid Chemistry, and bTherapeutic Chemistry Department, National Research Centre, El‑Buhouth
St, PO 12622, Dokki, Giza, Egypt
The reactions are reported of 4-(furan-3-ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione with six classes of organophosphorus
reagents: carboalkoxymethylene triphenylphosphoranes, triphenyl (phenylimino)-λ5-phosphane, trialkylphosphonoacetates,
trialkylphosphites, tris (dialkylamino)phosphines, and Lawesson’s reagent. Several of the products showed antitumour activity.
Keywords: pyrrolidine-2,3-dione, trialkylphosphites, Wittig reaction, ylides, antitumour agents
Compounds containing the pyrrolidine ring are widely
distributed in nature.1 Moreover, the pyrrolidine ring is present
as the main part in the pyrrolidine alkaloids such as hygrine2 and
cuscohygrine,3 and also in various types of alkaloidal skeletons
such as nicotine4 and the physostigma venenosum alkaloids.5
Previously, it has been reported that 1,5-diphenylpyrrole-
2,3-dione derivatives possess analgesic,6 notropic,6 anti-
inflammatory,7 antibacterial,8 and antiviral activities.9 This
together with our interest in organophosphorus chemistry10–14
has encouraged the synthesis of new organophosphorus
compounds incorporating such structural units that may
possibly lead to further biological activity.
4-(Furan-3-ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-
dione 1 reacted with 1 equiv. of carbomethoxymethylene
triphenylphosphorane 2a in refluxing benzene for 12 h to
give methyl [4-(furan-3-ylcarbonyl)-2-oxo-1,5-diphenyl-2,5-
dihydro-1H-pyrrol-3-yl]acetate 8a in 6o% yield (Scheme 1).
Similarly, 1 reacted with 1 equiv. of the carboethoxy analogue
2b in refluxing benzene for 12 h to give product 8b also in 60%
yield (Scheme 1).We propose the reaction course depicted in
Scheme 1. The reaction was assumed to involve interaction of the
ylide at the keto group at position 3 of the pyrrolidine ring to form
the olefinic compound A with expulsion of triphenylphosphane
oxide (TPPO), which was followed by migration of the α-proton
to give the stable compounds 815 (Scheme 1). Note that when
compound 1 was allowed to react with 3 equiv. 2a in refluxing
benzene for 20 h, only the same product 8a was obtained in
75% yield which excluded the possibility that the reaction could
proceed either via attack at the side-chain C=O group or via
the (unlikely) attack at the amide C=O group (in position 4) of
the heterocycle. There is precedent for this, for it was earlier
reported that the reaction of 4-aroyl-1,5-diphenylpyrrolidine-
2,3-dione with butylamine and ethanolamine involved exclusive
attack at the 3-position to produce the corresponding 4-aroyl-3-
alkylamino-1,5-diphenyl-2,5-dihydropyrrole-2-ones.16,17
The present study deals with the reaction of 4-(furan-3-
ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione
1
with six
classes of organophosphorus reagent: carboalkoxymethylene
triphenylphosphoranes 2a,b, triphenyl (phenylimino)-λ5-
phosphane 3, trialkylphosphonoacetates 4a,b, trialkyl-
phosphites 5a–c, tris (dialkylamino)phosphines 6a,b, and
Lawesson’s reagent 7 (Fig. 1).
Results and discussion
All the synthesised compounds described here are new and
were characterised from their IR, MS, 1H, 13C, 31P NMR spectral
data and their elemental analyses. Only selected spectral data
of some the new compounds will be discussed.
When 1 was treated with 1 equiv. of triphenyl (phenylimino)-
λ5-phosphane 3 in refluxing benzene for 10 h, product 9 was
isolated from the reaction medium (Scheme 1).
O
O
Ph3P=CHCOOR
Ph3P=N-Ph
O
Ph
N
O
2a, R = CH3
b, R = C2H5
3
Ph
1
X
X
O
P
(RO)2PCH2COOR
S
P
S
X
MeO
P
S
OMe
5a, X = OMe
5b, X = OEt
5c, X = OPri
6a, X = NMe2
6b, X = NEt2
4a, R = CH3
b, R = C2H5
S
7
Fig. 1 Reactant materials (1–7).
* Correspondent. E-mail: leilagoubran@yahoo.com
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326 JOURNAL OF CHEMICAL RESEARCH 2014
O
O
H
O
CHCOOR
O
benzene, reflux
- TPPO
+
Ph3P=CHCOOR
12 h
O
Ph
O
O
N
Ph
N
2a, R = CH3
b, R = C2H5
Ph
Ph
(A)
1
Ph3P=N-Ph
benzene, reflux
10 h, - TPPO
3
O
O
H
O
R
N-Ph
O
O
Ph
O
O
N
Ph
N
O
Ph
(B)
Ph
8a, R = CH3
b, R = C2H5
O
NHPh
O
Ph
O
N
Ph
9
Scheme 1
Similarly, product 9 was presumably formed through
addition of iminophosphorane 3 to the ketonic carbonyl of the
pyrrolidine 1 with expulsion of TPPO to give the intermediate
B followed by migration of the α-proton to give 4-(furan-3-
ylcarbonyl)-1,5-diphenyl-3-(phenylamino)-1,5-dihydro-2H-
pyrrol-2-one 9 as shown in Scheme 1.15,18
The reaction of 4-(furan-3-ylcarbonyl)-1,5-diphenyl-
pyrrolidine-2,3-dione 1 with Wittig–Horner reagents 4a,b
was also studied. When 1 was treated with 1 mole equiv. of
trimethylphosphonoacetate 4a in the presence of alcoholic
sodium methoxide solution at reflux temperature for 6 h,
of alkylphosphonate 4 to give intermediate C followed by
elimination of water to afford the final product 10 respectively
(Scheme 2).
The behaviour of 4-(furan-3-ylcarbonyl)-1,5-diphenyl-
pyrrolidine-2,3-dione
1 towards trialkylphosphites 5a–c
was investigated to determine the preferential site of attack.
We found that the reaction of 1 with 5a was successfully
completed (TLC) by using an excess of phosphite 5a as solvent
and warming the mixture for 1 h. Chromatography of the
mixture yielded product 11a in 60% yield. Similarly, when
1 was allowed to react with excess of triethylphosphite 5b or
triisopropylphosphite 5c, adducts 11b or 11c were isolated
(Scheme 3). The formation of 11a–c involves nucleophilic
attack22,23 by the phosphite on the active carbonyl carbon in 1
to give the zwitterionic intermediate D. Addition of a molecule
water (unavoidable moisture) to intermediate D produces a
transient intermediate E with pentacovalent phosphorus.24,25
The latter collapses through loss of dialkylphosphite, followed
by loss of one molecule of water to give the final products 11a–
c. The dialkylphosphites were detected in the water layer by the
development of a violet colour on addition of 3,5-dinitrobenzoic
acid.26
The reaction of 4-(furan-3-ylcarbonyl)-1,5-diphenyl-
pyrrolidine-2,3-dione 1 with tris (dialkylamino)phosphines
6a,b was also investigated. We found that the reaction of 1 with
excess of 6a,b at reflux temperature for 0.5 h, gave products
12a,b (Scheme 3). Products 12a,b were presumably formed
through nucleophilic attack22,23 of 6a,b on the carbonyl group
in 1. Since dialkylaminophosphite is a good leaving group,
methyl
(dimethoxyphosphoryl)[4-(furan-2-ylcarbonyl)-1,5-
diphenyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]acetate 10a was
isolated in 80% yield (Scheme 2).
The IR spectrum of 10a revealed the presence of strong
absorption bands at 927 (P–O–C),19 1229 (P=O),19 1566
(C=C), 1644 (amide C=O), 1684 cm–1 (side chain C=O), and
1741 cm–1 (C=O, ester). 10a also exhibited a positive shift in
its 31P NMR spectrum (δ=23.2, 85% H3PO4).20,21 Similarly,
triethylphosphonoacetate 4b reacts with 1 in the presence of
ethanolic sodium ethoxide solution at reflux temperature to
give ethyl (diethoxyphosphoryl)[4-(furan-2-ylcarbonyl)-1,5-
diphenyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]acetate 10b in 75%
1
yield (Scheme 3). The elemental microanalysis, IR, H, 13C,
31P NMR and mass spectral data agreed with structure 10b
(Scheme 2).
A possible explanation for the course of the reaction of 1
with 4a,b is shown in Scheme 3. 4-(furan-3-ylcarbonyl)-1,5-
diphenylpyrrolidine-2,3-dione 1 reacts with 1 mol of the anion
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JOURNAL OF CHEMICAL RESEARCH 2014 327
O
OR
O
O
O
H
OH
O
O
ROH, NaOR
reflux temp
P(OR)2
(RO) PCH COOR
+
2
2
O
Ph
N
O
a, R = CH3
b, R = C2H5
O
Ph
4a, R = CH3
b, R = C2H5
N
O
Ph
Ph
(C)
1
- H2O
O
OR
O
O
P(OR)2
O
Ph
N
O
Ph
10a, R = CH3
b, R = C2H5
Scheme 2
compounds 12a,b could be formed through rapid hydrolysis
due to the presence of unavoidable moisture followed by loss of
one molecule water (Scheme 3).
We also investigated the behaviour of diphenylpyrrolidine-
2,3-dione 1 towards Lawesson’s reagent 7. We found that when
1 was allowed to react with a 0.5 equiv. of Lawesson’s reagent
7 in dry toluene at room temperature for 5 h, the expected
product 13 was isolated in 85% yield (Scheme 4). Compound
13 was chromatographically pure and showed a sharp melting
point. It is well known that Lawesson’s reagent [2,4-bis
(4-methoxyphenyl)-1,3,2,4-dithiaphosphatane-2,4-disulfuide]
exists in equilibrium with the monomeric form which reacted
with 1 to give the product of thionation, 4-(furan-3-ylcarbonyl)-
1,5-diphenyl-3-thioxopyrrolidin-2-one 13.27,28
Cytotoxic and biological activity
Cytotoxic drugs remain the main stay of cancer chemotherapy
and are being employed in novel ways of therapy such as
inhibitors of signals.29 It is therefore important to discover
O
O
O
X
O
X
toluene, stirring
+
HOH
P
X
P
X
or neat, warming
X
unavoidable moisture
X
O
Ph
N
Ph
1
O
O
Ph
N
O
5a, X = OMe
5b, X = OEt
5c, X = OPri
6a, X = NMe2
6b, X = NEt2
Ph
D
O
OH
H
O
OH
OH
X
H
OH
P
X
X
X
P
X
P
+
X
X
X
O
O
Ph
N
O
O
Ph
X = OMe, OEt, OPri, NMe2, NEt2
N
O
Ph
Ph
F
E
- H2O
O
X
O
Ph
N
O
Ph
11a, X = OMe
11b, X = OEt
11c, X = OPri
12a, X = NMe2
12b, X = NEt2
Scheme 3
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328 JOURNAL OF CHEMICAL RESEARCH 2014
O
S
P
S
S
O
S
O
S
Ar
P
S
Ar
Ar
P
S
7, Ar= 4-OCH3-C6H4,
O
O
Ph
N
Ph
N
O
O
Ph
Ph
1
13
Scheme 4
novel cytotoxic agents possessing a broader spectrum of
antitumour activity and fewer toxic side effects than current
agents. Moreover, chemotherapy is a major approach for both
localised and metastasised cancers,30 and pyrrole derivatives
have proved to have significant therapeutic potentials.1–8
Based on these considerations, eight of the newly synthesised
compounds 8a,b, 10a,b, 11a,b, 12a,b were subjected to
screening for evaluation of their in vitro antitumour activity
against liver HEPG2 cancer cell lines in comparison to the
known anticancer drugs: 5-flurouracil (5-FU) and doxorubicin
(DOX) using a SRB assay. The substances used are supposed
to target mainly the cancer cells and doses are calculated to
minimise the collateral damage to surrounding tissues which,
nevertheless, occurs.31 This kind of treatment increases the
entropy of the organism, suppresses the immune system, and
forms a toxic cell environment which may destroy surrounding
healthy cells.32 So it is important to minimise therapeutic doses
to the least amount possible as well as trying to minimise the
side effects of these drugs.
Preliminary screening of the selected 1,5-diphenylpyrrole-
2-one derivatives showed that all the compounds exhibited a
moderate to strong growth inhibition activity on the tested cell
line between 1 and 10 µg mL–1 concentrations in comparison
to the known anticancer drugs: 5-Flurouracil (5-FU) and
Doxorubicin (DOX). As Table 1 shows, compounds 10a,b, 12a,b
were the most active and showed growth inhibition against
liver (HEPG2) human solid tumour cell lines comparable to
5-flurouracil (5-FU) and doxorubicin (DOX).
dialkylaminophosphanes 6a,b, the alkylated products 11a–c,
12a,b were isolated. Lawesson’s reagent (LR) reacted with 1 to
give the thione product 13 through a thionation reaction.
Experimental
Melting points were determined in open glass capillaries using
Electrothermal IA 9000 series digital melting point apparatus
(Electrothermal, Essex, UK) and are uncorrected. 4-(Furan-3-
ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione 1 was easily prepared in
85% yield according to the literature.33 The IR spectra were measured
in KBr pellets with a PerkinElmer Infracord spectrophotometer
model 157 (Grating). NMR spectra were obtained on a Joel-500 MHz
spectrometer (1H NMR at 500 MHz, 13C NMR at 125 Hz) in CDCl3
using TMS as internal standard. Chemical shifts δ were given in ppm
and coupling constants J in Hz. 31P NMR spectra were taken on a Varian
CFT-20 (using 85% H3PO4 as an external standard). The mass spectra
were performed at 70eV on a Shimada GCS-OP 1000 Ex Spectrometer
provided with a data system. Elemental analyses were performed using
Elmenter Vario EL Germany Instrument. The reported yields are based
upon pure materials isolated by column chromatography. Solvents were
dried/purified according to conventional procedures.
Reaction of 4-(furan-3-ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione
1 with phosphonium ylides 2a,b; general procedure
Pyrrolidine-2,3-dione 1 (0.34 g, 1 mmol) and of 2a (0.31 g, 1 mmol) or
2b (0.34 g, 1 mmol) in dry benzene (30 mL) were refluxed for 12 h. The
reaction was followed by TLC. When the reaction was complete, the
volatile materials were evaporated under reduced pressure. The residue
was subjected to silica gel column chromatography to give 8a or 8b;
triphenylphosphane oxide was also isolated from the reaction medium
and identified (mixed m.p., MS).
Methyl [4-(furan-3-ylcarbonyl)-2-oxo-1,5-diphenyl-2,5-dihydro-1H-
pyrrol-3-yl]acetate (8a): Eluent: petroleum ether (60–80°C)/ acetone
(95/5, v/v). Yellow crystals, 0.38 g, yield 60%; m.p. 168–170 °C; IR: 1622
(amide C=O), 1677 (side chain C=O), 1730 (ester C=O) cm–1; 1H NMR
δ 3.62 (s, 3H, CH3), 3.79 (s, 2H, CH2), 5.14 (s, 1H, cyclic CH), 6.28, 6.51
(3H, furan H), 7.17–7.62 (m, 10 H, Harom.) ppm; 13C NMR δ 30.7 (CH2),
52.5 (CH3), 66.3 (cyclic CH), 113.1, 147.9, 150.6 (furan), 120.7–133.5
(aromatic, C–H), 162.4 (amide C=O), 169.8 (ester C=O), 193.3 (side
chain C=O) ppm; MS (EI 70 eV): m/z (%)401 (55) [M]+. Anal. calcd for
C24H19NO5: C, 71.81; H, 4.77; N, 3.49; found: C, 70.91; H, 4.85; N, 3.78%.
Ethyl [4-(furan-3-ylcarbonyl)-2-oxo-1,5-diphenyl-2,5-dihydro-1H-
pyrrol-3-yl]acetate (8b): Eluent: petroleum ether (60–80°C)/ acetone
(90/10, v/v). Yellow crystals, 0.38 g, yield 60%; m.p. 133–135 °C;
IR:1622 (amide C=O), 1689 (side chain C=O), 1735 (ester C=O) cm–1; 1H
NMR δ 1.25 (t, 3H, CH3), 3.60 (s, 2H, CH2), 4.16 (q, 2 H, CH2CH3), 5.14
Table 1 Effect of some selected newly synthesised compounds on liver
carcinoma cell line (HEPG2)
Compound
IC50 (µg mL–1)
5-Flurouracil
Doxorubicin
8a
8b
10a
10b
11a
11b
12a
5
3.56
8.48
8.26
3.56
3.74
8.54
7.43
4.31
4.1
12b
IC50 =dose of the compounds which reduces survival to 50%.
Conclusion
(s, 1H, cyclic CH), 6.26, 6.50 (3H, furan H), 7.17–7.65 (m, 10 H, Harom.
)
ppm; 13C NMR δ 14.2 (CH3), 31.1 (CH2, ethyl), 61.5 (cyclic CH), 66.3
(OCH2), 113.2, 147.9, 150.5, 152.1 (furan), 122.0–136.6 (aromatic, C–H),
169.4 (amide C=O), 177.4 (ester C=O), 193.3 (side chain C=O) ppm; MS
(EI 70 eV): m/z (%) 415 (45) [M]+. Anal. calcd for C25H21NO5: C, 72.28;
H, 5.10; N, 3.37; found: C, 72.31; H, 5.15; N, 3.25%.
Based on the results of the present investigation, it could be
concluded that the reaction of 4-(furan-3-ylcarbonyl)-1,5-
diphenylpyrrolidine-2,3-dione 1 with phosphonium ylides
2a,b and (phenylimino)-λ5-phosphane 3 proceeds according
to the Wittig reaction to give the olefinic products followed
by migration of the α-proton to give the stable compounds
8,9. Moreover, the reaction of 4-(furan-3-ylcarbonyl)-
Reaction of 4-(furan-3-ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione
1 with triphenyl (phenylimino)-λ5-phosphane 3
1,5-diphenylpyrrolidine-2,3-dione
reagents 4a,b led to the dialkoxyphosphoryl derivatives
10a,b. In the reaction of 1 with trialkylphosphites 5a–c and
1
with Wittig–Horner
Pyrrolidine-2,3-dione 1 (0.34 g, 1 mM) and 3 (0.35 g, 1 mM) in dry
benzene (30 mL) were refluxed for 10 h. The reaction was followed by
TLC. The volatile materials were evaporated under reduced pressure.
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The residue was subjected to silica gel column chromatography to
give 9; triphenylphosphane oxide was also isolated from the reaction
medium and identified (mixed m.p., MS).
3-Ethoxy-4-(furan-3-ylcarbonyl)-1,5-diphenyl-1,5-dihydro-2H-
pyrrol-2-one (11b): Eluent: petroleum ether (60–80°C)/ethyl acetate
(95/5, v/v). Yellow crystals, 0.30 g, yield 60%; m.p. 136–137 °C; IR:
1562 (C=C), 1627 (amide C=O), 1684 (side chain C=O) cm–1; 1H NMR
δ 1.34 (t, 3H, CH3), 4.54 (q, 2H, CH2 ethyl), 6.11 (s, 1H, cyclic CH), 6.50,
6.57 (3H, furan H), 7.12–7.60 (m, 10 H, Harom.) ppm; 13C NMR δ 15.6
(CH3), 62.4 (cyclic CH), 68.6 (CH2 ethyl), 112.3 (cyclic C=C), 112.5,
147.3 (furan), 120.5–134.9 (aromatic, C–H), 165.7 (amide C=O), 176.7
(cyclic =C–O), 195.7 (side chain C=O) ppm; MS (EI 70 eV): m/z (%) 373
(70) [M]+. Anal. calcd for C23H19NO4: C, 73.98; H, 5.13; N, 3.75; found:
C, 74.08; H, 5.12; N, 3.95%.
4-(Furan-3-ylcarbonyl)-1,5-dimethyl-3-(propan-2-yloxy)-1,5-
dihydro-2H-pyrrol-2-one (11c): Eluent: petroleum ether (60–80°C)/
ethylacetate (93/7, v/v). Pale yellow crystals, 0.33 g (60%); m.p.
136–137 °C; IR: 1560 (C=C), 1623 (amide C=O), 1685 (side chain C=O)
cm–1; 1H NMR δ 1.39 (s, 6H, CH3), 5.57 (sep, 1H, CH), 6.14 (s, 1H, cyclic
CH), 6.50, 6.57 (3H, furan H), 7.16–7.58 (m, 10 H, Harom.) ppm; 13C NMR
δ 22.8 (CH3), 62.1 (CH), 74.9 (cyclic CH), 111.5 (cyclic C=C), 111.2,
147.2 (furan), 120.9–141.9 (aromatic, C–H), 165.6 (amide C=O), 175.1
(cyclic =C–O), 191.8 (side chain C=O) ppm; MS (EI 70 eV): m/z (%) 387
(70) [M]+. Anal. calcd for C24H21NO4: C, 74.40; H, 5.46; N, 3.62; found:
C, 74.81; H, 5.11; N, 4.02%.
4-(Furan-3-ylcarbonyl)-1,5-diphenyl-3-(phenylamino)-1,5-dihydro-
2H-pyrrol-2-one (9): Eluent: petroleum ether (60–80°C)/ acetone
(95/5, v/v). Yellow crystals, 0.38 g, yield 55%; m.p. 125–127°C; IR: 1635
(amide C=O), 1675 (side chain C=O), 3325 (NH) cm–1; 1H NMR δ 2.75
(s, 1H, NH, exchangeable with D2O), 5.62 (cyclic CH), 5.92, 6.32 (3H,
furan H), 7.08–7.76 (m, 15 H, Harom.) ppm; 13C NMR δ 51.3 (cyclic CH),
113.1, 147.9, 150.6 (furan), 120.7–133.5 (aromatic, C–H), 145.8 (=C–N),
161.4 (amide C=O), 184.3 (side chain C=O) ppm; MS (EI 70 eV): m/z
(%) 420 (45) [M]+. Anal. calcd for C27H20N2O3: C, 77.13; H, 4.79; N, 6.66;
found: C, 77.45; H, 4.85; N, 6.65%.
Reaction of 4-(furan-3-ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione
1 with trialkylphosphonoacetate 4a,b in the presence of sodium alkoxide
A solution of sodium alkoxide (1 mmol) in absolute alcohol (30 mL) was
treated with trialkylphosphonoacetate 4a or 4b (1 mmol) then 1 mmol
of pyrrolidine-2,3-dione 1 was added and the resulting reaction mixture
was refluxed for 6 h (TLC), evaporated then poured on a small amount
of water (1–2 mL), extracted with ethyl acetate (3×20 mL), dried over
anhydrous sodium sulfate, filtered and the extracts were evaporated
under reduced pressure to give 10a or 10 b.
Methyl (dimethoxyphosphoryl)[4-(furan-2-ylcarbonyl)-1,5-diphenyl-
2-oxo-2,5-dihydro-1H-pyrrol-3-yl]acetate (10a): Colourless crystals
(ethyl acetate), 0.45 g, yield 80%; m.p. 248–250 °C; IR: 927 (P–O–C),
1229 (P=O), 1566 (C=C), 1644 (amide C=O), 1684 (side chain C=O),
1741 (ester C=O) cm–1; 1H NMR δ 3.06 (d, 2JHP =21.3 Hz, JHH =7.8 Hz,
1 H, CH–P), 3.39–3.67 (2s, 9H, 3CH3), 5.54 (s, 1H, cyclic CH), 6.48,
6.517 (3H, furan H), 6.95–7.81 (m, 10 H, Harom) ppm; 13C NMR δ 31.3
(d, JCP =102.20, C–P), 52.0, 53.2 (CH3), 54.2 (cyclic CH), 70.1 (cyclic
C–C–P), 111.8, 146.4 (furan), 121.7–136.5 (aromatic, C–H), 166.4
(amide C=O), 176.6 (ester C=O), 179.6 (side chain C=O) ppm; 31P
NMR=23.2 ppm; MS (EI, 70 eV): m/z (%) 509 (30) [M]+. Anal. calcd for
C26H24NO8P: C, 61.30; H, 4.75; N, 2.75; P, 6.08; found: C, 60.90; H, 3.95;
N, 2.57; P, 6.12%.
Ethyl (diethoxyphosphoryl)[4-(furan-2-ylcarbonyl)-1,5-diphenyl-
2-oxo-2,5-dihydro-1H-pyrrol-3-yl]acetate (10b): Colourless crystals
(ethyl acetate), yield 75%; m.p. 220–222 °C; IR: 930 (P–O–C), 1230
(P=O), 1645 (amide C=O), 1684 (side chain C=O), 1745 (ester C=O)
cm–1; 1H NMR δ 1.11–1.31 (3t, 9 H, CH3), 4.07–4.12 (3 q, 6H, CH2), 3.06
(d, 2JHP =21.3 Hz, JHH =7.8 Hz, 1 H, CH–P), 5.65 (s, 1H, cyclic CH), 6.51,
6.57 (3H, furan H), 6.70–7.06 (m, 10 H, Harom) ppm; 13C NMR δ 14.1,
14.8 (CH3), 32.3 (d, JCP =102.20, C–P), 54.4 (cyclic CH), 61.5, 62.2 (3d,
2JCP =35.37 Hz, CH2 ethyl), 70.1 (cyclic C–C–P), 111.8, 146.4 (furan),
119.5–136.5 (aromatic, C–H), 166.4 (amide C=O), 176.6 (ester C=O),
185.6 (side chain C=O) ppm; 31P NMR=29.2 ppm; MS (EI, 70 eV): m/z
(%) 551 (20) [M]+. Anal. calcd for C29H30NO8P: C, 63.15; H, 5.48; N,
2.54; P, 5.62; found: C, 62.95; H, 5.59; N, 2.83; P, 5.60%.
Reaction of 4-(furan-3-ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione
1 with trisdialkylaminophosphines 6a,b
1 (0.34 g, 1 mmol) and excess of trisdialkylaminophosphines 6a,b were
refluxed for 0.5 h. The reaction was followed by TLC. The volatile
materials were evaporated under reduced pressure. The residue was
subjected to silica gel column chromatography to give 12a,b.
3-(Dimethylamino)-4-(furan-3-ylcarbonyl)-1,5-diphenyl-1,5-
dihydro-2H-pyrrol-2-one (12a): Eluent: petroleum ether (60–80°C)/
acetone (90/10, v/v). Yellow crystals, 0.33 g, yield 65%; m.p.
1
168–170 °C; IR: 1622 (amide C=O), 1683 (side chain C=O) cm–1; H
NMR δ 3.14 (s, 6H, CH3), 5.57 (s, 1H, CH), 6.18, 6.42 (3H, furan H),
6.88–7.53 (m, 10 H, Harom.) ppm; 13C NMR δ 42.7 (CH3), 55.6 (cyclic CH),
119.5, 153.1 (cyclic C=C–N), 116.0, 145.0, 154.3, (furan), 123.9–137.0
(aromatic, C–H), 165.5 (amide C=O), 177.2 (side chain C=O) ppm; MS
(EI 70 eV): m/z (%) 372 (55) [M]+. Anal. calcd for C23H20N2O3: C, 74.18;
H, 5.41; N, 7.52; found: C, 73.98; H, 5.39; N, 8.14%.
3-(Diethylamino)-4-(furan-3-ylcarbonyl)-1,5-diphenyl-1,5-dihydro-
2H-pyrrol-2-one (12b): Eluent: petroleum ether (60–80°C)/ acetone
(93/7, v/v). Yellow crystals, 0.36 g, yield 67%; m.p. 145–147 °C; IR:
1620 (amide C=O), 1685 (side chain C=O) cm–1; 1H NMR δ 1.14 (t, 6H,
CH3), 2.25 (q, 4H, CH2), 6.10 (d, 1 H, cyclic CH), 6.25, 6.42 (3H, furan
H), 6.67–7.53 (m, 10 H, Harom.) ppm; 13C NMR δ 13.0 (CH3), 45.2 (CH2),
52.6 (cyclic CH), 111.5, 152.3 (cyclic C=C–N), 116.0, 145.0, 154.3,
(furan), 123.9–138.1 (aromatic, C–H), 165.5 (amide C=O), 187.2 (side
chain C=O) ppm; MS (EI 70 eV): m/z (%) 402 (65) [M]+. Anal. calcd
for C25H24N2O3: C, 74.98; H, 6.04; N, 7.00; found: C, 75.01; H, 5.94; N,
7.11%.
Reaction of 4-(furan-3-ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione
1 with trialkylphosphites 5a–c
Excess trialkylphosphites 5a–c) was added to 1 (0.34 g, 1 mmol)
without solvent. The reaction mixture was warmed for 0.5–1 h (TLC).
After evaporation of the volatile material under reduced pressure, the
residue was submitted to silica gel column chromatography to give
11a–c.
The same products were obtained when the reaction of 5a–c (1 mmol)
and 1 (1 mmol) in dry toluene (30 mL) was stirred at room temperature
for 4–5 h.
Reaction of 4-(furan-3-ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione
1 with Lawesson’s reagent 7
A mixture of 0.34 g of 1 (1 mmol) and Lawesson’s reagent 7 (0.5 mmol)
in dry toluene (30 mL) is stirred at room temperature for 5 h (TLC). The
volatile materials were evaporated under reduced pressure. The residue
was washed with cyclohexane (3×20 mL) to give the product 13 in pure
form.
4-(Furan-3-ylcarbonyl)-3-methoxy-1,5-diphenyl-1,5-dihydro-2H-
pyrrol-2-one (11a): Eluent: petroleum ether (60–80°C)/ethylacetate
(97/3, v/v). Yellow crystals, 0.28 g, yield 60%; m.p. 170–171 °C; IR:
1560 (C=C), 1624 (amide C=O), 1684 (side chain C=O) cm–1; 1H NMR
δ 4.10 (s, 3H, CH3), 6.12 (s, 1H, cyclic CH), 6.51, 6.57 (3H, furan H),
7.15–7.60 (m, 10 H, Harom.) ppm; 13C NMR δ 59.9 (cyclic CH), 62.6 (CH3),
112.8 (cyclic C=C), 112.52, 147.5 (furan), 120.5–136.5 (aromatic, C–H),
165.6 (amide C=O), 176.6 (cyclic =C–O), 195.6 (side chain C=O) ppm;
MS (EI 70 eV): m/z (%) 359 (30) [M]+. Anal. calcd for C22H17NO4: C,
73.53; H, 4.77; N, 3.90; found: C, 73.66; H, 4.67; N, 3.96%.
4-(Furan-3-ylcarbonyl)-1,5-diphenyl-3-thioxopyrrolidin-2-one
(13): Green crystals; 0.33 g, yield 60%; m.p. 73–75 °C (benzene); IR:
1276 (C=S), 1623 (amide C=O), 1683 (side chain C=O) cm–1; 1H NMR
δ 3.09 (d, 1 H, cyclic CH), 4.78 (d, 1 H, cyclic CH), 6.30, 6.42 (3H, furan
H), 6.97–8.01 (m, 10 H, Harom.) ppm; 13C NMR δ 45.4 (cyclic CH), 62.2
(cyclic CH), 111.2, 143.8, 153.3 (furan), 111.3–144.9 (aromatic, C–H),
165.4 (amide C=O), 181.8 (side chain C=O) ppm; MS (EI, 70 eV): m/z
361 (35) [M]+; Calcd. for C21H15NO3S: C, 69.79; H, 4.18; N, 3.88; S, 8.87;
found C, 69.09; H, 4.25; N, 3.50; S, 9.07%.
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330 JOURNAL OF CHEMICAL RESEARCH 2014
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Cytotoxic and biological activity
Measurement of potential cytotoxicity by SRB assay: Potential
cytotoxicity of the selected pyrrole derivatives was tested using the
method of Skehan et al. 34
Cells were plated in 96-multiwell plate (104 cells/well) for 24 h
before treatment with the compound (s) to allow attachment of cells
to the wall of the plate. Different concentrations of the compound
under test (0, 1, 2.5, 5, 10 µg mL–1) were added to the cell monolayer.
Triplicate wells were prepared for each individual dose. Monolayer
cells were incubated with the compound (s) for 48 h at 37°C and in an
atmosphere of 5% CO2. Cultures were then fixed with trichloroacetic
acid and stained for 30 min with 0.4% (wt/vol) sulforhodamine B
(SRB) dissolved in 1% acetic acid. Unbound dye was removed by four
washes with 1% acetic acid, and protein-bound dye was extracted with
10 mmol unbuffered Tris base [tris (hydroxymethyl) aminomethane]
for determination of optical density in a computer-interfaced, 96-well
microtiter plate reader. The SRB assay results were linear with the
number of cells and with values for cellular protein measured by
both the Lowry and Bradford assays at densities ranging from sparse
subconfluence to multilayered supraconfluence. The signal-to-noise
ratio at 564 nm was approximately 1.5 with 1,000 cells per well. The
relation between surviving fraction and drug concentration is plotted
to obtain the survival curve of both cancer cell lines for each tested
compound.
18 L.S. Boulos, M.H.N. Arsanious and E.F. Ewies, Phosphorus Sulfur Silicon
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22 R.F. Hudson, Structure and mechanism in organic phosphorus chemistry.
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23 R.G. Harvey and E.D. Desombe, Topics in phosphorus chemistry, eds M.
Grayson and E.G. Griffith. John Wiley and Sons Inc., New York, 1964 pp.
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Received 25 February 2014; accepted 26 March 2014
Paper 1402489 doi: 10.3184/174751914X13976652851990
Published online: 10 June 2014
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