Triphenylphosphine-catalyzed simple synthesis of dimethyl 1-aryl-4-ethoxy-5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylates

Article abstract of DOI:10.1080/10426500211717

Ethyl 2-arylamino-2-oxo-acetates undergo a complex reaction with dimethyl acetylenedicarboxylate in the presence of triphenylphosphine to produce dimethyl 1-aryl-4-ethoxy-5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylates in good yields. Dynamic NMR study of

Full text of DOI:10.1080/10426500211717

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Triphenylphosphine-Catalyzed Simple Synthesis of
Dimethyl 1-Aryl-4-ethoxy-5-oxo-4,5-dihydro-1 H -
pyrrole-2,3-dicarboxylates
Issa Yavari a , Mansoureh Aghazadeh a & Mohsen Tafazzoli b
a Department of Chemistry , University of Tarbiat Modarres , Tehran, Iran
b Department of Chemistry , Sharif University of Technolog , Tehran, Iran
Published online: 27 Oct 2010.
To cite this article: Issa Yavari , Mansoureh Aghazadeh & Mohsen Tafazzoli (2002) Triphenylphosphine-Catalyzed Simple
Synthesis of Dimethyl 1-Aryl-4-ethoxy-5-oxo-4,5-dihydro-1 H -pyrrole-2,3-dicarboxylates, Phosphorus, Sulfur, and Silicon and
the Related Elements, 177:5, 1101-1107, DOI: 10.1080/10426500211717
To link to this article: http://dx.doi.org/10.1080/10426500211717
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1101–1107
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290092370
TRIPHENYLPHOSPHINE-CATALYZED SIMPLE
SYNTHESIS OF DIMETHYL 1-ARYL-4-ETHOXY-5-OXO-
4,5-DIHYDRO-1H-PYRROLE-2,3-DICARBOXYLATES
Issa Yavari,a Mansoureh Aghazadeh,a and Mohsen Tafazzolib
Department of Chemistry, University of Tarbiat Modarres,
Tehran, Irana and Department of Chemistry, Sharif University
of Technolog, Tehran, Iranb
(Received December 27, 2001)
Ethyl 2-arylamino-2-oxo-acetates undergo a complex reaction with
dimethyl acetylenedicarboxylate in the presence of triphenylphos-
phine to produce dimethyl 1-aryl-4-ethoxy-5-oxo-4,5-dihydro-1H-
pyrrole-2,3-dicarboxylates in good yields. Dynamic NMR study of
dimethyl 1-(2-methylphenyl)-4-ethoxy-5-oxo-4,5-dihydro-1H-pyrrole-
2,3-dicarboxylate shows
a
fairly high energy barrier (1G= =
53.2 kJmol 1) for rotation around the N-aryl single bond, which
leads to an observable atropisomerism.
Keywords: Acetylenic ester; NH-acid; restricted rotation; stereo-
chemistry; triphenylphosphine
INTRODUCTION
It is perhaps unnecessary to emphasize the importance of the pyr-
role nucleus in organic chemistry, especially in natural products
such as chlorophyll, hemoglobin, bile pigments and mold metabolites.
N-Substituted 2-pyrrolines are an important class of heterocyclic com-
pounds that exhibit biological activity1 and serve as useful synthetic
intermediates.2,3 Despite their wide applicability, available routes for
the synthesis of 2-pyrrolin-5-ones are limited.4 6 As part of our current
studies on the development of new routes to heterocyclic and carbo-
10
cyclic systems,7
we now report a simple one-pot synthesis of highly
functionalized 2-pyrrolin-5-ones 2. Thus, reaction of ethyl 2-arylamino-
2-oxo-acetates 1 with dimethyl acetylenedicarboxylate (DMAD) in the
Address correspondence to I. Yavari, Department of Chemistry, University of Tarbiat
Modarres, PO Box 14115-175, Tehran, Iran. E-mail: isayavar@yahoo.com
1101

1102
I. Yavari et al.
SCHEME 1
presence of triphenylphosphine leads to the corresponding dimethyl
1-aryl-4-ethoxy-5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylates 2a–c
in good yields (see Scheme 1).
RESULTS AND DISCUSSION
The reaction of ethyl 2-arylamino-2-oxo-acetates (1) with DMAD
in the presence of triphenylphosphine proceeded spontaneously at
room temperature in dichloromethane and was finished within 24 h.
1H and 13C NMR spectra of the crude product clearly indicated the for-
mation of dimethyl 1-aryl-4-ethoxy-5-oxo-4,5-dihydro-1H-pyrrole-2,3-
dicarboxylates (2). Any product other than 2 could not be detected by
NMR spectroscopy.
Reactions are known in which an unsaturated heterocyclic com-
pound is produced from a phosphorane connected with a carbonyl
12
group by a chain containing a heteroatom.7
Thus the 4,5-
dihydropyrrole derivative 2 may be regarded as the product of an in-
tramolecular Wittig reaction. Such addition-cyclization products ap-
parently result from an initial addition of triphenylphosphine to the
acetylenic ester and subsequent protonation of the 1:1 adduct by ethyl
2-aryl-2-oxo-acetate. Then, the positively charged ion is attacked by
the nitrogen atom of the conjugate base of the NH-acid to form
the phosphorane 3, which is converted to the 2,5-dihydropyrrole
derivative 4. Compound 4 apparently isomerizes under the reac-
tion conditions employed to produce the 4,5-dihydropyrrole isomer 2
(see Scheme 2).

1H-pyrrole Derivatives
1103
SCHEME 2
The structures of compounds 2a–c were deduced from their elemen-
tal analyses and their IR, 1H, and 13C NMR spectra. The mass spectra
of these compounds are fairly similar, as expected, and confirm their
molecular weights. Initial fragmentations involve loss from or com-
plete loss of the side chains and scission of the heterocyclic ring system.
13C NMR spectroscopy was used to distinguish structure 2 from the
primary product, 2,5-dihydropyrrole derivative 4. Thus, the 13C NMR
spectrum of each of the isolated products exhibited a methine carbon
resonance at about = 69. The chemical shift for the methine carbon in
4 is expected to appear at about = 52–56.13,14
The 1H NMR spectrum of 2a exhibited four single sharp lines, read-
ily recognized as arising from methyl ( = 3.65 and 3.84 ppm) and me-
thine ( = 5.15 ppm) protons, along with characteristic multiplets for the
ethoxy and phenyl groups. The 13C NMR spectrum of 2a showed sev-
enteen distinct resonances in agreement with the 4,5-dihydropyrrole
1
structure. The H and 13C NMR spectra of 2b and 2c are similar to
those of 2a, except for the ester moieties, which exhibited characteris-
tic resonances with appropriate chemical shift.
The most noteworthy feature of the 1H NMR spectrum of 2a in CDCl3
at room temperature (25 C) is the methoxy region which exhibits a
slightly broad and a sharp single at = 3.65 and 3.84 ppm respectively.
At 50 C, both singlets are sharp. Decreasing the temperature results in
splitting of the signal at = 3.65 ppm (T = 18 1 C), and at 50 C,
c
two sharp singlets ( = 3.62 and 3.68 ppm) in nearly 1:1 ratio, together
with a slightly broad singlet ( = 3.82 ppm) are observed.

1104
I. Yavari et al.
Although an extensive line-shape analysis in relation to the dynamic
1H NMR effect observed for 2a was not undertaken, the variable tem-
perature spectra allowed to calculate the free energy barrier (if not the
enthalpy or entropy of activation) for the dynamic NMR process in 2a.
From coalescence of the methyl proton resonances and using the ex-
√
pression, k = 1 / 2, we calculate that the first-order rate constant
1
(k) for the dynamic NMR effect in 2a is 67 s at 255 K. Application
of the absolute rate theory with a transmission coefficient of 1 gives a
free-energy of activation (1G=) of 53.2 2 kJmol 1, where all known
sources of errors are estimated and included.15 The experimental data
available are not suitable for obtaining meaningful values of 1H= and
1S=, even though the errors in 1G= are not large.16
The dynamic NMR effect observed for 2a can be attributed to re-
stricted rotation around the aryl-nitrogen single bond as a result of
the steric effect of the methyl group (see Scheme 3), which exhibits
a sharp singlet at room temperature, and two singlets ( = 2.205 and
2.223 ppm) in 1:1 ratio at 60 C (T = 245 K). For compound 2b, with
c
two methyl groups, rotation around the aryl-nitrogen bond is slow at
ambient temperature and two sharp singlets ( = 2.02 and 2.12 ppm)
are observed for the CH3-aryl groups, together with two sharp singlets
( = 3.56 and 3.74 ppm) for the methoxy protons. These signals exhibit
little broadening at 50 C, the highest temperature investigated. The 1H
NMR spectrum of 2c shows two sharp singlets ( = 3.58 and 3.74 ppm)
for the methoxy groups. The high-field signal exhibits little broadening
at 60 C, the lowest temperature investigated. Thus, rotation around
the aryl-nitrogen bond in 3c is fast on the NMR timescale at 60 C, as
a result of smaller steric interaction of the chlorine atom compared to
that of the methyl group in 2a.
SCHEME 3
In summary, the reaction of ethyl 2-arylamino-2-oxo-acetates with
dimethyl acetylenedicarboxylate in the presence of triphenylphosphine
provide a simple one-pot entry into the synthesis of polyfunctionalized
5-oxo-4,5-dihydro-1H-pyrrole derivatives of potential synthetic inter-
1
est. Dynamic NMR effects are observed in the H NMR spectra of 2a
and are attributed to restricted rotation around the aryl-nitrogen bond.

1H-pyrrole Derivatives
1105
EXPERIMENTAL
Melting points were measured on Buchi B-540 apparatus. Elemental
analyses were performed using a Heraeus CHN-O-Rapid analyser. IR
spectra were recorded on a Shimadzu IR-460 spectrometer. 1H and
13C NMR spectra were measured with Bruker DRX-500 AVANCE in-
strument with CDCl3 as solvent at 500.1 and 125.8 MHz, respectively.
The mass spectra were recorded on a FINNIGAN-MAT 8430 mass spec-
trometer operating at an ionization potential of 70 eV. Ethyl oxalyl chlo-
ride, triphenylphosphine, dimethyl acetylenedicarboxylate, and aniline
derivatives were obtained from Fluka (Buchs Switzerland) and used
without further purification.
Preparation of Ethyl Arylamino-2-oxo-acetates (1)
General Procedure
To a magnetically stirred solution of the aniline derivative (2 mmol)
and 0.20 g of triethylamine (2 mmol) in 20 mL of CH2Cl2 was added,
dropwise, a solution of 0.27 g of ethyl oxalyl chloride (2 mmol) in 10 mL
of CH2Cl2. 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 recrystalized
from ethanol.
Ethyl 2-(2-Methylanilino)-2-oxo-acetate (1a)
White powder, 0.34 g, m.p. 35–36 C, yield 85%. IR (KBr) ( max/cm 1):
1731 and 1706 (C O), 3255 (N H). Analyses: Calcd for C11H13NO3
(208.1): C, 63.75; H, 6.32; N, 6.75%. Found: C, 63.5; H, 6.4; N, 6.7%.
3
1H NMR (500 MHz, CDCl3): 1.36 (3 H, t, JHH = 7.2 Hz, CH3); 2.25
(3 H, s, CH3); 4.34 (2 H, q, 3 JHH = 7.2 Hz, CH2); 7.04–7.19 (3 H, m, Ar);
3
7.93 (1 H, d, JHH = 7.4 Hz, CHortho); 8.83 (H, s, NH); 13C NMR
(125.8 MHz, CDCl3): 13.98 and 17.44 (2 CH3); 63.63 (OCH2); 121.83
(C-6); 125.88 (C-4); 126.92 and 128.67 (C-3,5); 130.60 (C-2); 134.42 (C-1);
153.99 and 161.10 (2 C O).
Ethyl 2-(2,6-Dimethylanilino)-2-oxo-acetate (1b)
White powder, 0.40 g, m.p. 75–76 C, yield 90%. IR (KBr) ( max/cm 1):
1724 and 1674 (C O); 1523 (N H). Analyses: Calcd for C12H15NO3
(221.2): C, 65.14; H, 6.83; N 6.33%. Found: C, 65.3; H, 6.9; N, 6.3%.
3
1H NMR (500 MHz, CDCl3):
1.41 (3 H, t, JHH = 7.1 Hz, CH3);
3
2.22 (6 H, s, CH3); 4.38 (2 H, q, JHH = 7.1 Hz, CH2); 7.06–7.14

1106
I. Yavari et al.
(3 H, m, Ar); 8.47 (1 H, s, NH). 13C NMR (125.8 MHz, CDCl3): 14.01
and 18.43 (2 CH3); 63.56 (CH2); 127.93 (C-4); 128.36 (C-3,5); 132.27
(C-2,6); 135.04 (C-1); 154.68 and 160.94 (C O).
Ethyl 2-(2,4-Dichloroanilino)-2-oxo-acetate (1c)
White powder, 0.48 g, m.p. 117–118 C, yield 90%. IR (KBr) ( max/cm 1):
1723 (C O); 1521 (N H). Analyses: Calcd for C10H9NO3Cl2 (262.1):
1
C, 45.82; H, 3.46; N, 5.34%. Found: C, 46.0; H, 3.5; N, 5.4% H NMR
3
(500.1 MHz, CDCl3): 1.25 (3 H, t, JHH = 7.2 Hz, CH3); 4.25 (2 H, q,
3
3 JHH = 7.2 Hz, CH2); 7.03–7.24 (2 H, m, Ar); 8.21 (1 H, d, JHH = 8.8
Hz, Hortho); 9.23 (1 H, s, NH). 13C NMR (125.8 MHz, CDCl3); 14.07
(CH3); 64.02 (CH2); 121.81(C-6); 124.03 (C-2); 128.14 (C-5); 129.02
(C-3); 130.43 (C-4); 132.17 (C-1); 153.83 and 160.30 (C O).
Preparation of Dimethyl 1-(2-Methylphenyl)-4-ethoxy-
5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylate (2a)
General Procedure
To a magnetically stirred solution of 1 (2 mmol) and 0.78 g of triph-
enylphosphine (3 mmol) in 20 mL of CH2Cl2 was added a solution of
0.31 g of dimethyl acetylenedicarboxylate (2.2 mmol) in 3 mL of CH2Cl2
at 0 C. After 24 h the solvent was removed under reduced pressure and
the viscous residue was purified by column chromatography (silica gel,
70-230 mesh, CH2Cl2 eluent). The solvent was removed and the prod-
uct was obtained as white crystals, 0.46 g, m.p. 78–79 C, yield 70%.
IR (KBr) ( max/cm 1): 1749, 1708, and 1636 (C O). MS, m/z (%): M+,
333 (12), 274 (19), 91 (62), 118 (100). Analyses: Calcd for C17H19NO6
(333.3): C, 61.26; H, 5.74; N, 4.20%. Found: C, 61.3; H, 5.8; N, 4.2%.
3
1H NMR (500 MHz, CDCl3): 1.47 (3 H, t, JHH = 7.0 Hz, CH3); 2.24
(3 H, s, CH3); 3.65 and 3.84 (2 OCH3); 4.88 (2 H, q, 3 JHH = 7.0 Hz, CH2);
5.15 (1 H, s, CH); 7.10–7.31 (4 H, m, Ar). 13C NMR (20.1 MHz, CDCl3):
15.68 and 17.83 (2 CH3); 51.92 and 52.74 (2 OCH3); 62.52 (CH2); 68.62
(CH); 112.79 (C); 126.91 (C-6); 127.26 (C-4); 128.90 and 131.35 (C-3,5);
134.36 (C-2); 136.56 (C-1); 154.34 (C); 162.18, 163.60 and 168.19 (C O).
Dimethyl 1-(2,6-Dimethylphenyl)-4-ethoxy-5-oxo-
4,5-dihydro-1H-pyrrole-2,3-dicarboxylate (2b)
White powder, 0.66 g, m.p. 78–79 C, yield 95%. IR (KBr) ( max/cm 1):
1751, 1714, and 1694 (C O). MS, m/z (%): M+, 347 (16.7), 348 (100),
288 (67); 105 (18.7), 228 (35). Analyses: Calcd for C18H21NO6 (347.3):
1
C, 62.24; H, 6.09; N, 4.03%. Found: C, 62.3; H, 6.6; N, 3.9%. H NMR

1H-pyrrole Derivatives
1107
3
(500 MHz, CDCl3): 1.34 (3 H, t, JHH = 7.0 Hz, CH3); 2.02 and 2.12
3
(2 CH3); 3.56 and 3.74 (2 OCH3); 4.71 (2 H, q, JHH = 7.0 Hz, CH2);
5.12 (1 H, s, CH); 7.14–7.25 (3 H, m, Ar). 13C NMR (128.5 MHz, CDCl3):
15.67, 17.78 and 18.04 (3 CH3); 51.99 and 52.76 (2 OCH3); 61.35 (CH2);
68.73 (CH); 112.53 (C); 128.92 (C-4); 132.97 (C-3,5); 135.74 (C-1); 137.59
(C-2,6); 154.39 (C); 162.27, 163.81 and 167.96 (C O).
Dimethyl 1-(2,4-Dichlorophenyl)-4-ethoxy-5-oxo-
4,5-dihydro-1H-pyrrole-2,3-dicarboxylate (2c)
White powder, 0.48 g, m.p. 85–86 C, yield 70%. IR (KBr) ( max/cm 1):
1755, 1722, and 1689 (C O). MS, m/z (%): M+, 388 (38), 400 (25), 268
(100), 145 (14.6), 59 (65). Analyses Calcd for C16H15NO6Cl2 (388.2):
1
C, 49.50; H, 3.89; N, 3.60%. Found: C, 49.6; H, 3.9; N, 3.6%. H NMR
3
(500 MHz, CDCl3): 1.37 (3 H, t, JHH = 7.0 Hz, CH3); 3.58 and 3.74
3
(2 OCH3); 4.74 (2 H, q, JHH = 7.0 Hz, CH2); 5.18 (1 H, s, CH); 7.12
3
3
(1 H, d, JHH = 8.5 Hz, Hortho); 7.23–7.26 (1 H, d, d, JHH = 8.5 Hz,
4 JHH = 2.3 Hz, Hmeta); 7.44 (1 H, d, JHH = 2.3 Hz, Hmeta). 13C NMR
4
(125.8 MHz, CDCl3): 15.47 (CH3); 51.89 and 52.82 (2 OCH3); 61.40
(CH2); 68.60 (CH); 112.89 (C); 130.35 (C-6); 130.99 and 131.58 (C-3,5);
133.24 (C-2); 133.56 (C-4); 135.45 (C-1); 153.76 (C); 161.92, 163.99 and
167.58 (C O).
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