Efficient synthesis of highly functionalised 5-oxo-4,5-dihydro-1H-pyrroles and 5-oxo-2,5-dihydro-1H-pyrroles derivatives

Article abstract of DOI:10.3184/030823410X12744391095257

Methyl 2-(2-benzoylphenylamino)-2-oxoacetate and dimethyl 2,2'-(4,4'-methylenebis(4,1- phenylene)bis(azanediyl)) bis(2-oxoacetate) undergo a smooth reaction with triphenylphosphine and dialkyl acetylenedicarboxylates to produce corresponding highly functionalised 5-oxo-4,5-dihydro-1H-pyrroles and 5-oxo-2,5-dihydro-1H-pyrroles derivatives.

Full text of DOI:10.3184/030823410X12744391095257

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 315
JUNE, 315–317
Efficient synthesis of highly functionalised 5-oxo-4,5-dihydro-1H-pyrroles
and 5-oxo-2,5-dihydro-1H-pyrroles derivatives
Ali Souldozia*, Ali Reza Dadrassb and Zahra Ranjdostc
aDepartment of Chemistry, IAU-Urmia Branch, P.O. Box 969, Urmia, Iran
bChemistry Department, Faculty of Science, Urmia University, Urmia 57159-165, Iran
cChemistry Department, Faculty of Science, Znjan University, Zanjan 45195-313, Iran
Methyl 2-(2-benzoylphenylamino)-2-oxoacetate and dimethyl 2,2’-(4,4’-methylenebis(4,1- phenylene)bis(azanediyl))
bis(2-oxoacetate) undergo a smooth reaction with triphenylphosphine and dialkyl acetylenedicarboxylates to
produce corresponding highly functionalised 5-oxo-4,5-dihydro-1H-pyrroles and 5-oxo-2,5-dihydro-1H-pyrroles
derivatives.
Keywords: NH-acid, dialkyl acetylenedicarboxylates, triphenylphosphine, 5-oxo-4,5-dihydropyrrole, 5-oxo-2,5-dihydropyrrole
N-Substituted pyrrolines derivatives are important starting
materials for the preparation of a variety of biologically active
compounds due to their ability to react as acceptors in con-
jugate addition reactions of organocuprates, enolates and
nitrogen nucleophiles, beyond suffering hydroxylation, epoxi-
dation, cyclopropanation and cycloaddition reactions.1–6 Five-
membered ring lactams have successfully been used in routes
to various alkaloids and are suitable precursors for unusual
γ-amino acids such as statine and its analogues.7–17
Despite their wide applicability, available routes for the
synthesis of N-substituted pyrrolines derivatives are limited.
As part of our current studies on the development of new routes
to heterocyclic and carbocyclic systems, we now report a facile
one-pot synthesis of highly functionalised 5-oxo-4,5-dihydro-
1H-pyrroles and 5-oxo-2,5-dihydro-1H-pyrroles derivatives.
Thus, reactions of compounds 3 and 7 with dialkyl acetyl-
enedicarboxylate in the presence of triphenylphosphine lead to
the corresponding synthetic compounds 4a, 4b, 8a, 8b and 9 in
fairly good yields (Schemes 1 and 3).
Compound 4 is readily prepared via an intramolecular Wittig
reaction. Thus, triphenylphosphine and dialkyl acetylenedicar-
boxylates (2) in the presence of a strong NH-acid, such
as methyl 2-(2-benzoylphenylamino)-2-oxoacetate undergo a
smooth reaction at ambient temperature to produce a phospho-
rus ylide. This, in turn, experiences an intramolecular Wittig
reaction under the reaction conditions employed to produce
dialkyl 1-(2-benzoylphenyl)-4-methoxy-5-oxo-4,5-dihydro-
1H-pyrrole-2,3-dicarboxylate (4) (Scheme 1). No other
products could be detected by NMR spectroscopy.
The structures of compounds 4a and 4b were deduced from
their elemental analyses and their high-field 1H and 13C NMR
and IR spectral data. The mass spectra of these compounds
displayed molecular ion peaks at m/z = 411 and 439. Although
we have not yet established the mechanism of the reaction
between triphenylphosphine and dialkyl acetylenedicarboxyl-
ates in the presence of methyl 2-(2-benzoylphenylamino)-
2-oxoacetate in an experimental manner, but a possible
explanation of reactions is proposed in Scheme 2.
On the basis of the well-established chemistry of trivalent
phosphorus nucleophiles, it is reasonable to assume that the
initial addition of triphenylphosphine to the acetylenic ester
and subsequent protonation of the 1:1 adduct by the NH-acid
leads to compound 4. Then, the positively charged ion might
be attacked by the conjugate base of the NH-acid to form
phosphorane (5), which is converted to pyrrole derivative (6).
Compound 6 apparently isomerises under the reaction condi-
tions to produce the 5-oxo-4,5-dihydropyrrole ring system (4)
(Scheme 2).
1H NMR spectroscopy was used to distinguish structure 4
from the primary adduct, the 5-oxo-2,5-dihydropyrrole deriva-
tive (6). Thus, each of the products exhibited a methine hydro-
gen resonance at about δ = 5.16 and 5.12 ppm. The chemical
shift of the methine hydrogen in 6 is expected to appear at
about δ = 5.3–5.5 ppm.18,19
We have also used dimethyl 2,2′-(4,4′-methylenebis(4,1-
phenylene)bis(azanediyl))bis(2-oxoacetate) (7) in this reaction
(Scheme 3).
The reaction of dialkyl acetylenedicarboxylates with di-
methyl 2,2′-(4,4′-methylenebis(4,1-phenylene)bis(azanediyl))
bis(2-oxoacetate) in the presence of triphenylphosphine pro-
ceeded spontaneously at ambient temperature in chloroform
and was completed within a few hours. 1H and 13C NMR spec-
tra of the crude products clearly indicated the formation of 8a,
8b and 9 (Scheme 3).
On the basis of the chemistry of trivalent phosphorus nucleo-
philes it is reasonable to assume that compound 8 results from
the initial addition of triphenylphosphine to the acetylenic
ester and subsequent protonation of the 1:1 adduct by dimethyl
Scheme 1
* Correspondent. E-mail: alisouldozi@yahoo.com

316 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2
Scheme 3
Bruker DRX-300 Avance spectrometer at 300.13 and 75.467 MHz,
respectively. Elemental analyses were performed using a Heraeus
CHN-O-Rapid analyzer. Mass spectra were recorded on a Finnigan-
Matt 8430 mass spectrometer operating at an ionisation potential of
20 eV. Flash chromatography columns were prepared from Merck
silica gel powder.
2,2′-(4,4′-methylenebis(4,1-phenylene)bis(azanediyl))bis(2-
oxoacetate). Then, the positively charged ion is attacked by the
conjugate base of the NH-acid to form phosphorane 10, which
is converted to pyrrole derivative 8.
1H NMR spectroscopy was used to distinguish structure 8
from the 5-oxo-4,5-dihydropyrrole derivative. Thus, each of
the products exhibited a methine hydrogen resonance at about
δ = 5.34, 5.32 and 5.33 ppm. The chemical shift of the methine
hydrogen in 8 and 9 are expected to appear at about δ = 5.1–
5.2 ppm.20,21
General procedure for preparation of methyl 2-(2-benzoylphenyl-
amino)-2-oxoacetate (3) To a magnetically stirred solution of the
2-aminobenzophenone (2 mmol, 0.39 g) and 0.20 g of triethylamine
(2 mmol) in 20 mL of CHCl3 was added, dropwise, a solution of 0.24
g of methyl chloroglyoxylate (2 mmol) in 10 mL of CHCl3. After 24 h
stirring at reflux, the mixture was washed three times with the same
volume of 6 M HCl solution. The organic phase was dried over MgSO4
and evaporated. The product was recrystalised from ethanol.
Methyl 2-(2-benzoylphenylamino)-2-oxoacetate (3): White powder,
0.485 g, m.p. 126 °C, yield 91%. IR (KBr)(vmax, cm−1): 3234.68
(N–H), 3075.06, 2954.72, 1728.93, 1712.02, 1633.27, 1577.97,
1445.75, 1295.81, 1264.77, 1200.89, 1170.03, 981.07, 939.92, 770.21,
710.53, 697.95. 1H NMR (CDCl3) δH: 4.00 (3H, s, OCH3), 7.22 (1H,
t, 3JHH = 7.6 Hz, arom), 7.50 (2H, t, 3JHH = 7.6 Hz, arom), 7.75 (2H, d,
3JHH = 7.8 Hz, arom), 7.60–7.68 (3H, m, arom), 8.70–8.73 (1H, m,
arom), 12.24 (N–H). 13C NMR (CDCl3) δC: 53.98 (1C, OCH3), 121.52,
123.64, 128.34, 130.02, 132.68, 133.65, 134.26 (9C of = CH), 124.25,
138.23, 138.57 (3C), 154.63, 160.83, 199.05 (3C=O). Anal. Calcd
for C16H13NO4 (283.28): C, 67.84; H, 4.63; N, 4.94. Found: C, 67.61;
H, 4.56; N, 4.90%.
In addition, the reaction of diethyl acetylenedicarboxylate
with 7 in the presence of triphenylphosphine in ratios of 1:1:1
and 2:1:2 produced the compounds 8b and 9. In this connec-
tion, when we used dimethyl acetylenedicarboxylate in place
of diethyl acetylenedicarboxylate only compound 8a was
obtained.
Experimental
Starting materials and solvents were obtained from Merck (Germany)
and Fluka (Switzerland) and were used without further purification.
TLC and NMR indicated that there is no side product. Melting points
were measured on an Electrothermal 9100 apparatus and are uncor-
rected. IR spectra were measured on a Shimadzu IR-460 spectrometer.
1H and 13C NMR spectra were measured (CDCl3 solution) with a

JOURNAL OF CHEMICAL RESEARCH 2010 317
General procedure for preparation of dimethyl 2,2′-(4,4′-methy-
lenebis(4,1-phenylene)bis(azanediyl))bis(2-oxoacetate) (7)
Diethyl 4-methoxy-1-{4-[4-(2-methoxy-2-oxoacetamido)benzyl]
phenyl}-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate (8b): Vis-
cous oil, 0.33 g, yield 63%.IR (KBr)(vmax, cm−1): 3348.36 (NH),
3055.91, 2989.93, 1701 (br), 1648.15,1512.94, 1438.22, 1190.17,
1120.36, 721.56, 696.66. 1H NMR (CDCl3) δH: 1.08 (3H, t, 3JHH = 7.0
To a magnetically stirred solution of the 4,4′-methylenedianiline
(2 mmol, 0.40 g) and 0.40 g of triethylamine (4 mmol) in 20 mL of
CHCl3 was added, dropwise, a solution of 0.49 g of methyl chlorogly-
oxylate (4 mmol) in 10 mL of CHCl3. After 24 h stirring at reflux, the
mixture was washed three times with the same volume of 6 M HCl
solution. The organic phase was dried over MgSO4 and evaporated.
The product was recrystallised from ethanol.
Dimethyl 2,2′-(4,4′-methylenebis(4,1-phenylene)bis(azanediyl))bis
(2-oxoacetate) (7): White powder, 0.62 g, m.p. 140 °C, yield 84%.
IR (KBr)(vmax, cm−1): 3338.46 (N–H), 3041.31, 2951.46, 2925.86,
1754.79, 1731.67, 1715.67, 1686.17, 1523.58, 1413.90, 1297.85,
1267.11, 1162.64, 984.21, 764.11, 703.65. 1H NMR (CDCl3) δH: 3.97
(6H, s, 2OCH3), 3.97 (2H, s, CH2), 7.19 (4H, d, 3JHH = 8.4 Hz, arom),
7.57 (4H, 3JHH = 8.4, arom), 8.82 (2 N-H). 13C NMR (CDCl3) δC: 38.74
(1C of CH2), 54.02 (2C of CH3), 120.07 and 129.63 (8C of =CH),
134.46 and 138.26 (4C), 153.48 and 161.49 (4C=O). Anal. Calcd for
C19H18N2O6 (370.36): C, 61.62; H, 4.90, 7.56. Found: C, 61.55; H,
4.81; N, 7.49%.
3
Hz, CH3), 1.32 (3H, t, JHH = 7.0 Hz, CH3), 3.96 (5H, br, CH2 and
OCH3 of oxoacetate), 4.39 (3H, s, OCH3), 4.10 (2H, q, 3JHH= 7.0 Hz,
OCH2), 4.27 (2H, q, 3JHH= 7.0 Hz, OCH2), 5.32 (1H, s, CH of methine),
7.15–7.21 (1H, m, arom), 7.43–7.49 (3H, m, arom), 7.52–7.58 (2H,
m, arom), 7.67–7.71 (2H, m, arom), 8.89 (NH). 13C NMR (CDCl3) δC:
13.89 and 14.10 (2C, 2CH3), 40.82 (1C, CH2), 53,98 and 60.49 (2C,
2OCH3), 61.17 and 61.32 (2C, 2OCH2), 62.12 (1C, CH of methine),
111.37, 133.27, 134.50, 138.07, 139.13, 153.56 (6C), 154.71, 161.46,
162.54, 163.54, 167.53 (5C=O). MS: m/z (%); 526 (M+, 10), 253
(100), 167 (41), 104 (16), 87 (23). Anal. Calcd for C27H28N2O9
(524.18): C, 61.83; H, 5.38; N, 5.34. Found: C, 61.68; H, 5.27; N,
5.28%.
Tetraethyl 1,1′-[4,4′-methylenebis(4,1-phenylene)]bis(4-methoxy-
5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate) (9): Viscous oil,
0.163 g, yield 24%. IR (KBr)(vmax, cm−1):3132.01, 2982.56, 1746.00,
1
1720.20, 1648.17, 1514.17, 1369.66, 1208.64, 1026.86, 763.08. H
General procedure for preparation of 4a, 4b, 8a, 8b and 9
3
NMR (CDCl3) δH: 1.09 (6H, t, JHH = 7.2 Hz, 2 CH3), 1.33 (6H, t,
To a magnetically stirred solution of N–H acid (1 mmol) and triphe-
nylphosphine (1 mmol) in 20 mL of CHCl3 was added a solution of
dialkyl acetylenedicarboxylate (1 mmol) in 3mL of CHCl3 at −5 °C
over 10 min. The reaction mixure was then allowed to warm to room
temperature and stirred for 24 h. The solvent was removed under
reduced pressure and the residue was purified by column chromatog-
raphy using petroleum ether:ethyl acetate (10:2) as eluent. The solvent
was removed under reduced pressure to afford the products.
3
3JHH = 7.2, 2CH3), 3.96 (2H, s, CH2), 4.09 (4H, q, JHH = 7.2Hz,
2OCH2), 4.29 (4H, q, 3JHH = 7.2Hz), 4.39 (6H, s, OCH3), 5.33 (2H of
3
3
methine), 7.19 (4H, d, JHH = 8.4 Hz, arom), 7.47 (4H, d, JHH = 8.4
Hz, arom). 13C NMR (CDCl3) δC: 13.90 and 14.11 (4C of 4 CH3),
40.80 (C of CH2), 60.49 (2C of 2 OCH3), 61.17 and 61.31 (4C of 4
OCH2), 62.14 (2CH of methine), 129.66 and 122.22 (8C of =CH),
111.36, 134.46, 138.94, 154.72 (8C), 161.26, 163.55, 167.52 (6C=O).
MS: m/z (%); 680 (M+, 15), 424 (52), 258 (66), 168 (61), 134 (84),
92(100). Anal. Calcd for C35H38N2O12 (678.24): C, 61.94; H, 5.64; N,
4.13. Found: C, 61.89; H, 5.61; N, 3.97%.
Dimethyl 1-(2-benzoylphenyl)-4-methoxy-5-oxo-4,5-dihydro-1H-
pyrrole-2,3-dicarboxylate (4a): Viscous oil, 0.30g, yield 73%. IR
(KBr)(vmax, cm−1): 2957.92, 1750.11, 1720.27, 1666.35, 1647.84,
1596.22, 1447.16, 1359.99, 1292.04, 1233.04, 1157.40, 761.02,
1
This work was supported by the IAU-Urmia Branch, Urmia
Research Council.
714.72, 700.83. H NMR (CDCl3) δH: 3.696, 3.78 and 4.24 (9H, s,
3
3OCH3), 5.16 (1H, s, CH of methine), 7.30 (1H, d, JHH = 7.8 Hz,
arom), 7.42–7.62 (6H, m, arom), 7.79 (2H, d, 3JHH = 7.8Hz, arom). 13
C
NMR (CDCl3) δC: 52.04, 52.94, 60.21 (3C of OCH3), 63.29 (1C,
of methine), 128.17, 128.35, 128.78, 130.19, 130.87, 131.90, 133.28
(9C of =CH), 112.20, 134.37, 136.78, 137.12, 154.29 (5C), 161.95,
164.42, 168.14, 195.47 (4C=O). MS: m/z (%); 411 (M+, 18), 230 (62),
182 (43), 166 (100), 135 (65), 80 (76). Anal. Calcd for C22H19NO7
(409.12): C, 64.54; H, 4.68; N, 3.42. Found: C, 64.21; H, 4.31; N,
3.19%.
Received 6 April 2010; accepted 7 May 2010
Paper 1000053 doi: 10.3184/030823410X12744391095257
Published online: 2 July 2010
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3
3
δH: 1.15 (3H, t, JHH =7.2 Hz, CH3), 1.28 (3H, t, JHH = 7.2Hz, CH3),
4.08–4.25 (7H, m, 2OCH2 and OCH3), 5.12 (1H, s, CH of methine),
7.32 (1H, d, 3JHH = 7.8 Hz, arom), 7.42–7.60 (6H, m, arom), 7.79 (2H,
3
d, JHH = 7.2 Hz, arom). 13C NMR (CDCl3) δC: 13.94, 14.07 (2C of
CH3), 60.36 (1C of OCH3), 61.00 and 62.01 (2C of OCH2), 63.76 (1C,
of methine), 128.09, 128.33, 128.92, 130.15, 130.53, 131.79, 133.24
(9CH of =CH), 112.40, 134.45, 136.82, 137.08, 154.29 (5C), 161.34,
164.50, 167.60 and 195.47 (4C=O). MS: m/z (%); 439 (M+, 15), 256
(54), 182 (38), 166 (100), 135 (72), 80 (84).Anal. Calcd for C24H23NO7
(437.15): C, 65.90; H 5.30; N 3.20. Found: C, 65.76; H, 5.15; N,
2.99%.
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phenyl}-5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylate (8a): Vis-
cous oil, 0.45 g, yield 91%. IR (KBr)(vmax, cm−1): 3386.51, 3053.68,
2952.50, 1749.44, 1761.68, 1647.94, 1513.12, 1437.13, 1394.61,
1287.34, 1235.23, 1195.35, 1118.93, 721.69, 695.31. 1H NMR
(CDCl3) δH: 3.65, 3.83, 4.39 (9H, s, 3OCH3), 3.96 (5H, br, CH2 and
OCH3 of oxalate), 5.34 (1H, s, CH of methine), 7.16–7.21 (1H, m,
arom), 7.43–7.49 (3H, m, arom), 7.52–7.58 (2H, m, arom), 7.64–7.71
(2H, m, arom), 8.90(NH). 13C NMR (CDCl3) δC: 52.14, 53.13, 53.99,
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163.46, 168.13 (C=O). MS: m/z (%); 498 (M+, 7), 231 (100), 167
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