A one-pot synthesis of functionalised 3-pyrolin-2-ones by a four-component reaction between triphenylphosphine, primary amines, dimethyl acetylenedicarboxylate and ethyl chlorooxoacetate

Article abstract of DOI:10.3184/030823407X255542

Reaction between triphenylphosphine, dimethy acetylenedicarboxylate and amines produces phosphorus ylids which undergo a smooth reaction with ethyl chlorooxoacetate and triethylamine to produce dimethyl N-aryl-(or alkyl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-2,3-dicarboxylates in high yields.

Full text of DOI:10.3184/030823407X255542

574 RESEARCH PAPER
OCTOBER, 574–576
JOURNAL OF CHEMICAL RESEARCH 2007
A one-pot synthesis of functionalised 3-pyrolin-2-ones by a four-
component reaction between triphenylphosphine, primary amines,
dimethyl acetylenedicarboxylate and ethyl chlorooxoacetate
Mohammad Anary-Abbasinejada*, Hossein Anaraki-Ardakania, Alimohammad Dehghana,
Alireza Hassanabadia and Mohammad Reza Seyedmirb
aDepartment of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
bIslamic Azad University, Yazd Branch, R&D Unit, PO Box 89195-155, Yazd, Iran
Reaction between triphenylphosphine, dimethy acetylenedicarboxylate and amines produces phosphorus ylids
which undergo a smooth reaction with ethyl chlorooxoacetate and triethylamine to produce dimethyl N-aryl-(or
alkyl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-2,3-dicarboxylates in high yields.
Keywords: primary amines, dimethyl acetylenedicarboxylate, ethyl chlorooxoacetate, 3-pyrolin-2-ones, multi component
reactions
N-Substituted 3-pyrrolines are important compounds which
exhibit neuritogenic activity1 and serve as useful synthetic
intermediates.2 Despite their wide applicability, available
routes for the synthesis of 3-pyrolin-2-ones are limited.3,4
PPh3
PPh3
CO2CH3
1
PhHN
+ H3CO2C
CO2CH3
PhNH2
CO2CH3
Reaction
between
triphenylphosphine,
dimethyl
3
acetylenedicarboxylate (DMAD) and primary amines was
previously reported to produce β-amino phosphoranes 4
(Scheme 1).5 Following our previous work on the reaction
between phosphorus nucleophiles and acetylenic esters in the
presence of organic acids,6-10 we decided to investigate the
reaction of these phosphorus ylids with ethyl chlorooxoacetate
and triethylamine. Ylid 4 was expected to react with ethyl
chlorooxoacetate to produce oxamate 5 which may then
undergo intramolecular Wittig reaction to produce dimethyl
N-phenyl-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-2,3-
dicarboxylate 6a (Scheme 2). Thus, ylid 4 was prepared by the
reaction between triphenylphosphine, DMAD and aniline by
the previously reported procedure.5 When phosphorane 4 was
stirred with an equimolar amount of ethyl chlorooxoacetate
and triethylamine in dichloromethane, a smooth reaction
took place. After completion of the reaction (monitored by
TLC) N-phenyl-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-2,3-
dicarboxylate 6a was obtained in nearly quantitative yield.
Being successful in this reaction, we decided to investigate
the one-pot synthesis of 3-pyrolin-2-one 6a (Scheme 3). Thus,
equimolar amounts of triphenylphosphine, aniline and DMAD
were mixed in dichloromethane as solvent. After stirring for
1 min, triethylamine and ethyl chlorooxoacetate were added
and the progress of the reaction was monitored by TLC. After
24 hours theTLC of the mixture of the reaction showed only the
presence of product 6a and triphenylphosphine oxide. Silica-
gel chromatography afforded the product N-phenyl-4-ethoxy-
5-oxo-2,5-dihydro-1H-pyrole-2,3-dicarboxylate 6a in 98%
yield. To investigate the scope of the reaction, different aryl and
alkyl amines were reacted with triphenylphosphine, DMAD
and ethyl chlorooxoacetate. As showed in Scheme 3, different
amines may be used to produce the corresponding 3-pyrrolin-
2-ones in good yields. Most of the compounds reported here
are known compounds, which were previously reported to be
prepared by the reaction between triphenylphosphine, DMAD
and N-substituted oxamates.11 Compounds 6a and 6c–i were
compared with the corresponding compounds prepared by the
reported procedure.11 Compound 6b was new and its structure
was deduced by elemental and spectral analysis.
2
4
Scheme 1
O
OEt
Cl
PPh3
CO2CH3
O
OEt
O
Et3N, - Et3NHCl
O
PPh3
CO2CH3
PhHN
N
Ph
CO2CH3
CO2CH3
4
5
OEt
O
CO2CH3
-Ph3PO
N
Ph
CO2CH3
6a
Scheme 2
report that the reaction between DMAD and N-aryl (or alkyl)
ethyloxamate in the presence of trialkyl phosphite leads to
N-aryl-(or alkyl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-2,3-
dicarboxylates in good yields (Scheme 4). When a solution
of trimethyl phosphite, DMAD and N-phenyl ethyloxamate
in dichloromethane was stirred at room temperature for
24 hours, dimethyl N-phenyl-4-ethoxy-5-oxo-2,5-dihydro-
1H-pyrole-2,3-dicarboxylate 6a was obtained as the only
product in 97% yield (Scheme 1). This reaction could be
carried out with other N-alkyl or N-aryl oxamates to produce
dimethyl N-aryl-(or alkyl)-4-ethoxy-5-oxo-2,5-dihydro-
1H-pyrole-2,3-dicarboxylates in good yields. As showed in
Scheme 4 this reaction could also be carried out with triethyl-
or tributyl phosphite as well, but when triphenyl phosphite
was used the yields were low. The advantage of the method
reported here over the previously reported reaction between
triphenylphosphine,DMADandN-substitutedethyloxamates11
is that here the by-product is trimethyl phosphate, which could
be easily removed by washing the reaction mixture with water.
In contrast, one of the most important drawbacks of the Wittig
reaction is the separation of products from triphenylphosphine
The reaction of trialkyl phosphites and DMAD in the
presence of organic NH acidic compounds lead to phosphite
ylides as intermediate or final product.6,9 Here, we also
* Correspondent. E-mail: mohammadanary@yahoo.com
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JOURNAL OF CHEMICAL RESEARCH 2007 575
OEt
PPh3
1
O
O
CO2CH3
Et3N, - Et3NHCl
-Ph3PO
OEt
+
+
H3CO2C
CO2CH3
Cl
N
R
CO2CH3
RNH2
O
3
2
6
2 , 6
a
%Yield of 6
R
C6H5
98
2-C2H5C6H4
4-CH3C6H4
4-BrC6H4
b
c
95
95
d
e
95
94
4-NO2C6H4
f
g
h
i
C6H5CH2
95
96
98
90
C6H5CH2CH2
n-Bu
CH3
Scheme 3
oxide. This is usually done by chromatographic methods,
which are especially difficult for large-scale preparations.
It is rational to assume that compounds 6a–i are produced
from the intramolecular Wittig reaction of phosphite ylide
intermediates 9 (Scheme 5).
In conclusion, we here report a four-component reaction
between triphenylphosphine, DMAD, primary amines and
ethyl chlorooxoacetate to produce functionalised 3-pyrolin-2-
ones in high yields. The reaction between trimethyl phosphite,
DMAD, and N-substituted ethyloxamates also leads to
functionalised 3-pyrolin-2-ones in high yields The present
method carries the advantage that not only is the reaction
performed under neutral conditions but also that the substances
can be mixed without any activation or modification.
Experimental
All melting points are uncorrected. Elemental analyses were
performed using a Heraeus CHN-O-Rapid analyser. Mass spectra
were recorded on a FINNIGAN-MAT 8430 mass spectrometer
operating at an ionisation potential of 70 eV. IR spectra were recorded
1
on a Shimadzu IR-470 spectrometer. H and 13C NMR spectra were
recorded on Bruker DRX-500 Avance spectrometer at 500 and
125.8 MHz, respectively. 1H and 13C NMR spectra were obtained
on solution in CDCl3 using TMS as internal standard. Column
OEt
(R'O)3P
7
O
CO2CH3
O
H3CO2C
CO2CH3
+
N
OEt
3
R
CO2CH3
RNH
O
6
8
%Yield* of 6
R' = Et
R' = Me
97
8 , 6
a
R' = n-Bu R' = Ph
R
C6H5
93
90
55
2-C2H5C6H4
4-CH3C6H4
4-BrC6H4
4-NO2C6H4
C6H5CH2
C6H5CH2CH2
n-Bu
b
c
90
95
90
90
95
95
49
37
d
e
f
g
h
i
94
90
92
95
94
93
95
91
89
95
90
90
97
95
95
98
94
90
60
35
40
40
30
35
CH3
*Isolated yield
Scheme 4
OEt
(CH3O)3P
O
O
_
O
P(OCH3)3
CO2CH3
OP(OCH3)3
6
H3CO2C
CO2CH3
+
N
Ph
OEt
RNH
3
CO2CH3
O
9
8
Scheme 5
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576 JOURNAL OF CHEMICAL RESEARCH 2007
chromatography was performed with Merck silica gel 60, 230–
400 mesh. The chemicals used in this work purchased from Fluka
(Buchs, Switzerland) and were used without further purification.
Method a: To a magnetically stirred solution of triphenylphosphine
(0.26 g, 1 mmol) and aniline (0.09 g, 1 mmol) in dichloromethane
(10 ml) was added dropwise a mixture of dimethyl acetylene-
dicarboxylate (0.14 g, 1 mmol) in dichloromethane (3 ml) at room
temperature over 2 min. The reaction mixture was then stirred for
one minute. Triethylamine (1 mmol) and ethyl chlorooxoacetate
(1.1 mmol) was added, respectively. The reaction mixture was then
stirred for 24 hours. Solvent was evaporated and the residue was
purified by column chromatography on silica-gel using ethyl acetate-
hexane (1:4) mixture as eluent.
Method b: to a magnetically stirred solution of trimethyl phosphite
(1 mmol) and N-phenyl ethyloxamate (1 mmol) in dichloromethane
(10 ml) was added a mixture of dimethyl acetylenedicarboxylate
(1 mmol) in dichloromethane (1 ml) at room temperature.
The reaction mixture was then stirred for 24 h. The reaction mixture
was washed with water to remove trimethyl phosphate. The organic
layer was then concentrated and passed trough a silica gel pad eluting
by hexane–ethyl acetate (4:1) mixture. Solvent was evaporated and
the product was obtained as a white powder.
5.41 (1H, s, CH), 7.22–8.36 (4 CH, arom.). 13C NMR (125.8 MHZ,
CDCl3): δ 15.71 (CH3), 52.41 and 53.61 (2 OCH3), 61.25 (OCH2),
69.35 (C–H), 112.47 (C=C), 119.88, 125.12, 142.62, 145.12
(C, arom), 153.52 (C=C), 162.34 and 163.82 (2 CO2 Me), 167.89
(C=O).
Dimethyl N-benzyl-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-2,3-
dicarboxylate (6f): White crystals, m.p. 52–54°C, yield (95%).
IR (KBr) (νmax/cm-1): 1749, 1732 and 1706 (C=O), 1640 (C=C).
3
1H NMR (500 MHZ, CDCl3): δ 1.31 (3H, t, JHH = 7.05 Hz, CH3),
3.52 and 3.57 (6H, 2 s, 2 OCH3), 4.16 (1H, d, JAB = 15 Hz, CH2,
Bn.), 4.49 (1H, s, CH), 4.64–4.71 (2H, m, OCH2), 4.77 (1H, d,
JAB = 15 Hz, CH2, Bn.), 7.15–7.92 (5H, m, arom.). 13C NMR (125.8
MHZ, CDCl3): δ 15.64 (CH3), 54.73 (CH2, Bn.), 51.82 and 52.14
(2 OCH3), 59.69 (OCH2), 68.57 (CH), 111.37 (C=C), 128.11, 128.55,
128.77, 135.48 (C, arom), 154.58 (C=C), 162.13 and 164.72 (2 CO2
Me), 168.22 (C=O).
Dimethyl N-(2-phenylethyl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-
2,3-dicarboxylate (6g): Pale yellow oil, yield (96%). IR (KBr)
(νmax/cm-1): 1752, 1722 and 1698(C=O), 1625(C=C). 1H NMR
3
(500 MHZ, CDCl3): δ 1.38 (3H, t, JHH = 7.05 Hz, CH3), 2.78 (1H,
m, CH2, Bn.), 2.89 (1H, m, CH2, Bn.), 3.25 (1H, m, CHN), 3.72 and
3.74(6H, 2 s, 2 OCH3), 3.96 (1H, m, CHN), 4.58 (1H, s, CH), 4.73
(2H, m, OCH2), 7.14–7.30 (5H, m, arom.). 13C NMR (125.8 MHZ,
CDCl3): δ 15.28 (CH3), 33.36 (NCH2), 42.79 (CH2, Bn.), 51.37 and
52.63 (2 OCH3), 59.87(OCH2), 67.88 (CH), 111.17(C=C), 126.22,
128.12, 128.16, 137.30(C, arom), 154.58 (C=C), 162.23 and 164.72
(2 CO2 Me), 168.14 (C=O).
Dimethyl
N-phenyl-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-2,3-
dicarboxylate (6a): White solid, m.p. 82–83°C, yield (98%).
IR (KBr) (νmax/cm-1): 1748, 1716 and 1696 (C=O), 1644 (C=C).
3
1H NMR (500 MHZ, CDCl3): δ 1.40(3H, t, JHH = 7.05 Hz, CH3),
3.59 and 3.77 (6H, 2 s, 2 OCH3), 4.79 (2H, q, 3JHH = 7.05 Hz, OCH2),
5.34(1H, s, C–H), 7.19–7.53 (5H, m, arom.). 13C NMR (125.8 MHZ,
CDCl3): δ 16.02 (CH3), 52.44 and 53.45 (2 OCH3), 61.31 (OCH2),
69.19 (CH), 112.03 (C=C) 122.15, 126.81, 129.64, 136.67 (C, arom),
154.77 (C=C), 162.51 and 163.97 (2 CO2 Me), 168.58(C=O).
Dimethyl
N-butyl-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-2,3-
dicarboxylate (6h): Yellow oil, yield (98%). IR (KBr) (νmax/cm-1):
1745, 1721 and 1698(C=O), 1635 (C=C). 1H NMR (500 MHZ,
CDCl3): δ 0.93 (3H, t, 3JHH = 7.05 Hz, CH3), 1.32(2H, m, CH2), 1.42
(3H, t, 3JHH = 7.05 Hz, CH3), 1.54 (2H, m, CH2), 3.04 (1H, m, CHN),
3.72 (1H, m, CHN), 3.54 and 3.79 (6H, 2 s, 2 OCH3), 4.75 (1H, s, CH),
4.79 (2H, q, OCH2). 13C NMR (125.8 MHZ, CDCl3): δ 13.07 (CH3),
15.13 (CH3), 19.34 (CH2), 29.29(CH2), 41.09 (NCH2), 51.49 and
52.49 (2 OCH3), 59.86 (OCH2), 67.92 (CH), 110.86, 154.19 (C=C),
162.23 and 164.53 (2 CO2 Me), 168.89(C=O).
DimethylN-(2-ethylphenyl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-
2,3-dicarboxylate (6b): Yellow solid, m.p. 86–87°C, yield (95%). IR
(KBr) (νmax/cm-1): 1742, 1726 and 1698 (C=O), 1654 (C=C).
Anal. Calcd for C18H21NO6 (347.36): C, 62.24; H, 6.09; N, 4.03.
Found: C, 62.21; H, 6.14; N, 4.02%.,1H NMR (500 MHZ, CDCl3):
3
3
δ 1.19(3H, t, JHH = 7.52 Hz, CH3), 1.43(3H, t, JHH = 7.05 Hz,
CH3), 2.59 (2H, m, CH2), 3.60 and 3.78 (6H, 2 s, 2 OCH3), 4.84
Dimethyl N-methyl-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-2,3-
dicarboxylate (6i): Yellow oil, yield (90%). IR (KBr) (νmax/cm-1):
1751, 1722 and 1695(C=O), 1642 (C=C). 1H NMR (500 MHZ,
3
(2H, q, JHH = 7.05 Hz, OCH2), 5.14(1H, s, C–H), 7.03–7.33 (4H,
m, arom.). 13C NMR (125.8 MHZ, CDCl3): δ 14.66 (CH3), 16.05
(CH3), 24.02(CH2), 52.40 and 53.24 (2 OCH3), 63.32 (OCH2),
69.08 (CH), 112.62 (C=C), 122.14, 127.24, 129.68, 133.87,
136.21,142.61 (C, arom), 154.77 (C=C), 162.64 and 164.12 (2 CO2
Me), 168.55(C=O). MS (m/z,%): 347 (M, 1).
3
CDCl3): δ 1.36 (3H, t, JHH = 7.05 Hz, CH3), 2.96(3H, s, CH3N),
3.68 and 3.78 (6H, 2 s, 2 OCH3), 4.72 (1H, s, CH), 4.81 (2H, q, 3JHH
= 7 Hz, OCH2). 13C NMR (125.8 MHZ, CDCl3): δ 15.71 (CH3),
28.54 (NCH3), 52.08 and 53.41(2 OCH3), 61.79 (OCH2), 68.52
(CH), 111.32, 154.94 (C=C), 163.54 and 165.21 (2 CO2 Me), 169.31
(C=O).
Dimethyl N-(4-methylphenyl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-
2,3-dicarboxylate (6c): Yellow crystals, m.p. 73–75°C, yield
(95%). IR (KBr) (νmax/cm-1): 1751 and 1721 (C=O), 1642 (C=C).
3
1H NMR (500 MHZ, CDCl3): δ 1.43 (3H, t, JHH = 7.05 Hz, CH3),
Received 21 August 2007; accepted 10 October 2007
Paper 07/4805 doi: 10.3184/030823407X255542
2.36 (3H, s, CH3), 3.61 and 3.76 (6H, 2 s, 2 OCH3), 4.83 (2H, q,
3J
= 7.05 Hz, OCH2), 5.32 (1H, s, CH), 7.06–742 (4H, m,
aroHmH.). 13C NMR (125.8 MHZ, CDCl3): δ 15.74 (CH3), 20.96 (CH3),
52.14 and 53.06 (2 OCH3), 61.32 (OCH2), 67.86 (CH), 111.82 (C=C),
122.12, 129.71, 133.49, 136.48(C, arom), 154.61 (C=C), 163.23 and
164.35 (2 CO2 Me), 169.17(C=O).
References
1
H. Kakeya, C. Onozawa, M. Sato, K. Arai and H. Osada, J. Med. Chem.,
1997, 40, 391, and references therein.
2
(a) B.A. Kulkarani andA. Ganesan, Angew. Chem. Int. Ed. Engl., 1997, 36,
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111, 1905; (c) B. Tarnchompoo, C. Thebtaranonth and Y. Thebtaranonth,
Tetrahedron Lett.,1987, 28, 6675.
Dimethyl N-(4-bromophenyl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-
2,3-dicarboxylate (6d): White crystals, m.p. 81–83°C, yield (95%).
IR (KBr) (νmax/cm-1): 1745, 1723 and 1694 (C=O), 1640 (C=C).
3
1H NMR (500 MHZ, CDCl3): δ 1.52(3H, t, JHH = 7.1 Hz, CH3),
3
4
J. Barluenga, F. Palacios, S. Fustero and V. Gotor, Synthesis, 1981, 200.
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3.59 and 3.72 (6H, 2 s, 2 OCH3), 4.83 (2H, q, 3JHH = 7 Hz, OCH2),
5.79 (1H, s, C–H), 7.12–7.53 (4H, m, arom.). 13C NMR (125.8
MHZ, CDCl3) δ 15.68 (CH3), 52.39 and 53.26 (2 OCH3), 60.67
(OCH2), 67.69 (C–H), 111.82 (C=C), 119.37, 125.67, 129.63,
135.59 (C, arom), 154.43 (C=C), 162.13 and 163.55 (2 CO2 Me),
168.99 (C=O).
5
6
7
I. Yavari, M. Adib and L. Hojabri, Tetrahedron, 2002, 58, 7213.
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9
M. Anary-abbasinejad and S. Tahan, Phosphorus, Sulfur and Silicon,
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J. Chem. Res., 2007, 455.
DimethylN-(4-nitrophenyl)-4-ethoxy-5-oxo-2,5-dihydro-1H-pyrole-
2,3-dicarboxylate (6e): Yellow solid, m.p. 146–147°C, yield
(94%). IR (KBr) (νmax/cm-1): 1738, 1723 and 1705 (C=O).
3
1H NMR (500 MHZ, CDCl3): δ 1.48 (3H, t, JHH = 7.05 Hz, CH3),
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11 I. Yavari and M. Bayat, Synthetic Commun., 2002, 32, 2527.
3.69 and 3.73 (6H, 2 s, 2 OCH3), 4.84 (2H, q, 3JHH = 7.05 Hz, OCH2),
PAPER: 07/4805