Synthesis of functionalized 5-oxo-2,5-dihydro-1H-pyrroles from primary alkylamines, oxalyl chloride, and dimethyl acetylenedicarboxylate

Article abstract of DOI:10.1055/s-2008-1072657

An efficient synthesis of dimethyl 1-alkyl-2,4-dihydroxy-5-oxo-2,5-dihydro- 1H-pyrrole-2,3-dicarboxylates is described via a three-component reaction between primary alkylamines, oxalyl chloride, and dimethyl acetylenedicarboxylate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072657

1208
LETTER
Synthesis of Functionalized 5-Oxo-2,5-dihydro-1H-pyrroles from Primary
Alkylamines, Oxalyl Chloride, and Dimethyl Acetylenedicarboxylate
S
ynthesi
s
s
of Funct
s
ionalized
a5-Oxo-2,5-dihydr
Y
o-1
H
-pyrroles avari,* Sanaz Souri
Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: yavarisa@modares.ac.ir
Received 14 January 2008
CO2Me
O
MeO2C
OH
Abstract: An efficient synthesis of dimethyl 1-alkyl-2,4-dihy-
droxy-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylates is de-
CH2Cl2
H2O
Cl
RNH2
+
+
Cl
MeO2C
HO
scribed via
a three-component reaction between primary
O
N
R
O
CO2Me
alkylamines, oxalyl chloride, and dimethyl acetylenedicarboxylate.
1
2
3
4
Key word: oxalyl chloride, 3-pyrroline-2-one, enaminone, acety-
lenic ester, multicomponent reaction, alkylamines
Yield (%) of 4
1, 4
R
a
b
c
d
e
f
Bn
90
4-MeC6H4CH2
4-MeOC6H4CH2
4-ClC6H4CH2
2-ClC6H4CH2
1-Naphthylmethyl
n-Bu
95
95
90
95
98
90
The importance of substituted pyrrolidines in the chemi-
cal synthesis of biologically interesting molecules is well
recognized.1,2 The development of new synthetic proce-
dures for preparation of 3-pyrrolin-2-ones has gained
great interest in organic synthesis. The most investigated
approaches to polysubstituted 3-pyrrolin-2-ones rely on
multicomponent reactions.3–5 Other recently reported
methodologies include cyclization of a,b-unsaturated g-
aminoesters,6 rearrangement of chlorinated pyrrolin-2-
ones,7 ruthenium-catalyzed cyclocarbonylation of a-al-
lenic sulfonamides,8 cyclization of 3-phenylsulfanyl-2-
propenamides,9 reaction of g-keto thioesters with
amines,10 oxidative cyclization of phenacyl amide in the
presence of atmospheric oxygen,11 alkaline hydrolysis of
N-substituted 2-acetoxypyrroles,12 intramolecular aldol
condensation,13 and cyclization of 3-aryl-4,4-dichlorobu-
tanamides.14
g
Scheme 1
the experimental section.16 The H NMR and 13C NMR
spectra of 4b–g are similar to those for 4a except for the
alkyl moieties, which showed characteristic resonances in
appropriate regions of the spectrum.
1
A tentative mechanism for this transformation is proposed
in Scheme 2. It is conceivable that the initial event is the
formation of enaminoester 5 from the alkylamine and
DMAD,9,10 which is subsequently attacked by oxalyl
chloride to produce 6. Intermediate 6 undergoes cycliza-
tion to produce 7, which is converted to 8 by elimination
of HCl. Compound 4 is apparently formed by addition of
adventitious water to 8.
As part of our current studies on the development of new
routes in heterocyclic synthesis,15 we report an efficient
synthetic route to 1,5-dihydro-2H-pyrrole-2-ones. Thus,
the reaction between alkylamines 1, dimethyl acetylenedi-
carboxylate (DMAD, 2), and oxalyl chloride (3) in
CH2Cl2 led to dimethyl 1-alkyl-2,4-dihydroxy-5-oxo-2,5-
dihydro-1H-pyrrole-2,3-dicarboxylates (4) in good
yields16 (Scheme 1).
In conclusion, we have described a convenient route to
functionalized 3-pyrroline-2-ones, from oxalyl chloride
and DMAD in the presence of primary alkylamines. The
advantage of the present procedure is that the reaction is
The structures of compounds 4a–g were apparent from
CO2Me
their mass spectra, which showed, in each case, the molec-
CO2Me
CO2Me
R
CO2Me
1
3
ular ion peak at the appropriate m/z value. The H NMR
N
R
H
1 + 2
and 13C NMR spectroscopic data, as well as IR spectra,
N
– HCl
H
Cl–
O
Cl
1
H
are in agreement with the proposed structures. The H
O
NMR spectrum of 4a in CDCl3 showed four singlets for
methoxy (d = 3.19 and 3.73 ppm) and OH (d = 4.77 and
9.09 ppm) protons. The 13C NMR spectrum of 4a exhibit-
ed thirteen signals in agreement with the proposed struc-
ture. Partial assignments of these resonances are given in
5
6
CO2Me
CO2Me
CO2Me
R
CO2Me
R
N
H2O
N
4
Cl–
– HCl
O
O
O
O
SYNLETT 2008, No. 8, pp 1208–1210
Advanced online publication: 16.04.2008
x
x.
x
x.
2
0
0
8
7
8
DOI: 10.1055/s-2008-1072657; Art ID: D04608ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

LETTER
Synthesis of Functionalized 5-Oxo-2,5-dihydro-1H-pyrroles
1209
ppm. 13C NMR (125.7 MHz, CDCl3): d = 20.4 (Me), 41.5
(NCH2), 51.6 (OMe), 53.0 (OMe), 83.5 (COH), 110.2 (C),
128.3 (CH), 128.4 (CH), 131.6 (C), 137.0 (C), 157.9
(=COH), 162.5 (C=O), 163.6 (C=O), 169.3 (CON) ppm.
MS: m/z (%) = 335 (18) [M+], 276 (70), 244 (100), 91 (50),
77 (64). Anal. Calcd (%) for C16H17NO7 (335.31): C, 57.31;
H, 5.11; N, 4.18. Found: C, 57.46; H, 5.06; N, 4.23.
Compound 4c: white powder; 157–158 °C (decomp.); yield:
0.63 g (90%). IR (KBr): nmax = 3363, 3130, 1745, 1710,
1674, 1425, 1308, 1236 cm–1. 1H NMR (500.1 MHz,
CDCl3): d = 3.23 (3 H, s, OMe), 3.74 (3 H, s, OMe), 3.76 (3
H, s, OMe), 4.21 (1 H, d, 3J = 15.2 Hz, CH), 4.70 (1 H, br s,
OH), 4.74 (1 H, d, 3J = 15.2 Hz, CH), 6.85 (2 H, d, 3J = 8.5
Hz, CH), 7.19 (1 H, d, 3J = 8.5 Hz, CH), 9.09 (1 H, br s, OH)
ppm. 13C NMR (125.7 MHz, CDCl3): d = 42.2 (NCH2), 51.8
(OMe), 53.3 (OMe), 55.5 (OMe), 85.6 (COH), 112.3 (C),
114.4 (CH), 129.2 (C), 130.8 (CH), 156.3 (C), 160.1
(=COH), 163.4 (C=O), 164.4 (C=O), 169.8 (CON) ppm.
MS: m/z (%) = 351 (18) [M+], 292 (70), 244 (100), 91 (50),
77 (64). Anal. Calcd (%) for C16H17NO8 (351.31): C, 54.70;
H, 4.88; N, 3.99. Found: C, 54.50; H, 4.96; N, 4.08.
Compound 4d: white powder; 160–162 °C (decomp.); yield
0.64 g (90%). IR (KBr): nmax = 3365, 3135, 1743, 1700,
1671, 1428, 1310, 1237 cm–1. 1H NMR (500.1 MHz,
CDCl3): d = 3.27 (3 H, s, OMe), 3.81 (3 H, s, OMe), 4.17 (1
H, d, 3J = 15.3 Hz, CH), 4.72 (1 H, br s, OH), 4.88 (1 H, d,
3J = 15.3 Hz, CH), 7.22 (2 H, d, 3J = 8.3 Hz, CH), 7.27 (2 H,
d, 3J = 8.3 Hz, CH), 9.10 (1 H, br s, OH) ppm. 13C NMR
(125.7 MHz, CDCl3): d = 42.5 (NCH2), 53.1 (OMe), 54.7
(OMe), 84.9 (COH), 111.8 (C), 129.4 (CH), 131.2 (CH),
134.7 (C), 156.4 (C), 159.6 (=COH), 163.8 (C=O), 165.1
(C=O), 170.8 (CON) ppm. MS: m/z (%) = 355 (18) [M+],
296 (100), 276 (70), 91 (50), 77 (64). Anal. Calcd (%) for
C15H14ClNO7 (355.72): C, 50.65; H, 3.97; N, 3.94. Found: C,
50.52; H, 4.03; N, 3.91.
performed under neutral conditions by simple mixing of
the starting materials. The procedure described here pro-
vides an acceptable one-pot method for the preparation of
functionalized 3-pyrroline-2-ones.
References and Notes
(1) Ikeguky, S. M.; Sawaki, M.; Yoshii, H.; Maeda, K.;
Morishima, Y. J. Pestic. Sci. 2000, 25, 107.
(2) Broggini, G.; Zecchini, G. Synthesis 1999, 905.
(3) Beck, B.; Picard, A.; Herdtweck, E.; Dömling, A. Org. Lett.
2004, 6, 39.
(4) Nair, V.; Mathen, J. S.; Viji, S.; Srinivas, R.; Nandakumar,
M. V.; Varma, L. Tetrahedron 2002, 58, 8113.
(5) Yavari, I.; Bayat, M. Synth. Commun. 2002, 32, 2527.
(6) Grison, C.; Genève, S.; Coutrot, P. Tetrahedron Lett. 2001,
42, 3831.
(7) Ghelfi, F.; Stevens, C. V.; Laureyn, I.; Van Meenen, E.;
Rogge, T. M.; De Buyck, L.; Nikitin, K. V.; Grandi, R.;
Libertini, E.; Pagnoni, U. M.; Schenetti, L. Tetrahedron
2003, 59, 1147.
(8) Kang, S. K.; Kim, K. J.; Yu, C. M.; Hwang, J. W.; Do, Y. K.
Org. Lett. 2001, 3, 2851.
(9) Naitoh, R.; Nakamura, Y.; Katano, E.; Nakamura, Y.;
Okada, E.; Asaoka, M. Heterocycles 2004, 63, 1009.
(10) Bouillon, J. P.; Tinant, B.; Nuzillard, J. M.; Portella, C.
Synthesis 2004, 711.
(11) Pal, M.; Swamy, N. K.; Hameed, P. S.; Padakanti, S.;
Yeleswarapu, K. R. Tetrahedron 2004, 60, 3987.
(12) Tsolomiti, G.; Tsolomitis, A. Tetrahedron Lett. 2004, 45,
9353.
(13) Snider, B. B.; Neubert, B. J. J. Org. Chem. 2004, 69, 8952.
(14) Verniest, G.; Boterberg, S.; Bombeke, F.; Stevens, C. V.; De
Kimpe, N. Synlett 2004, 1059.
Compound 4e: white powder; 160–164 °C (decomp.); yield
0.64 g (90%). IR (KBr): nmax = 3310, 3305, 1747, 1680,
1675, 1462, 1430, 1400 cm–1. 1H NMR (500.1 MHz,
CDCl3): d = 3.39 (3 H, s, OMe), 3.75 (3 H, s, OMe), 4.64 (1
H, d, 3J = 16.3 Hz, CH), 4.70 (1 H, d, 3J = 16.3 Hz, CH), 4.75
(1 H, br s, OH), 7.26–7.29 (3 H, m, CH), 7.39 (1 H, m, CH),
9.12 (1 H, br s, OH) ppm. 13C NMR (125.7 MHz, CDCl3):
d = 40.5 (NCH2), 51.9 (OMe), 53.4 (OMe), 86.1 (COH),
112.8 (C), 127.8 (CH), 129.8 (CH), 130.1 (CH), 130.4 (CH),
133.6 (C), 134.4 (C), 156.1 (=COH), 163.4 (C=O), 164.7
(C=O), 169.5 (CON) ppm. MS: m/z (%) = 355 (18) [M+],
296 (100), 276 (70), 91 (50), 77 (64). Anal. Calcd (%) for
C15H14ClNO7 (355.72): C, 50.65; H, 3.97; N, 3.94. Found: C,
50.73; H, 4.02; N, 3.90.
Compound 4f: white powder; 166–167.5 °C (decomp.);
yield 0.72 g (98%). IR (KBr): nmax = 3330, 3140, 1747, 1676,
1671, 1462, 1399, 1363 cm–1. 1H NMR (500.1 MHz,
CDCl3): d = 2.54 (3 H, s, OMe), 3.77 (3 H, s, OMe), 4.59 (1
H, d, 3J = 14.9 Hz, CH), 4.81 (1 H, br s, OH), 5.63 (1 H, d,
3J = 14.9 Hz, CH), 7.39–7.57 (4 H, m, CH), 7.84 (2 H, m,
CH), 8.15 (1 H, m, CH), 9.18 (1 H, br s, OH) ppm. 13C NMR
(125.7 MHz, CDCl3): d = 41.2 (NCH2), 52.1 (OMe), 52.8
(OMe), 84.5 (COH), 111.2 (C), 124.0 (CH), 125.0 (CH),
126.1 (CH), 126.8 (CH), 128.3 (CH), 129.3 (CH), 129.4
(CH), 129.9 (C), 131.6 (C), 133.6 (C), 158.8 (=COH), 162.7
(C=O), 164.3 (C=O), 169.4 (CON) ppm. MS: m/z (%) = 371
(18) [M+], 312 (100), 276 (70), 91 (50), 77 (64). Anal. Calcd
(%) for C19H17NO7 (371.34): C, 61.46; H, 4.61; N, 3.77.
Found: C, 61.59; H, 4.65; N, 3.82.
(15) Yavari, I.; Souri, S. Synlett 2007, 19, 2969.
(16) Dimethyl 1-Benzyl-2,4-dihydroxy-5-oxo-2,5-dihydro-
1H-pyrrole-2,3-dicarboxylate (4a)
To a stirred solution of DMAD (0.34 g, 2.4 mmol) and
alkylamine (0.20 g, 2 mmol) in CH2Cl2 (10 mL) was added
oxalyl chloride (0.17 mL, 2 mmol) at r.t. The reaction
mixture was then stirred for 24 h. The solvent was removed
under reduced pressure and the precipitate was purified by
recrystallization from Et2O to give 4a.
Compound 4a: white powder; 170–171 °C (decomp.); yield
0.57 g (90%). IR (KBr): nmax = 3360, 3135, 1741, 1705,
1674, 1425, 1311 cm–1. 1H NMR (500.1 MHz, CDCl3):
d = 3.19 (3 H, s, OMe), 3.73 (3 H, s, OMe), 4.28 (1 H, d,
3J = 15.5 Hz, CH), 4.77 (1 H, br s, OH), 4.80 (1 H, d, 3J =
15.5 Hz, CH), 7.24–7.30 (5 H, m, CH), 9.09 (1 H, br s, OH)
ppm. 13C NMR (125.7 MHz, CDCl3): d = 42.7 (NCH2), 51.8
(OMe), 53.2 (OMe), 85.7 (C-OH), 112.4 (C), 128.2 (CH),
129.0 (CH), 129.3 (CH), 137.4 (C), 156.4 (=COH), 163.3
(C=O), 164.6 (C=O), 169.7 (CON) ppm. MS: m/z (%) = 321
(8) [M+], 262 (70), 244 (100), 91 (50), 77 (64). Anal. Calcd
(%) for C15H15NO7 (321.28): C, 56.08; H, 4.71; N, 4.36.
Found: C, 56.31; H, 4.82; N, 4.39.
Similarly, the following compounds were prepared. All
compounds gave satisfactory analytical and spectroscopic
data.
Compound 4b: white powder; 150–152 °C (decomp.); yield
0.63 g (95%). IR (KBr): nmax = 3380, 3140, 1744, 1699,
1671, 1429, 1388, 1234 cm–1. 1H NMR (500.1 MHz,
CDCl3): d = 2.29 (3 H, s, Me), 3.17 (3 H, s, OMe), 3.80 (3 H,
s, OMe), 4.13 (1 H, d, 3J = 14.6 Hz, CH), 4.74 (1 H, br s,
OH), 4.93 (1 H, d, 3J = 14.6 Hz, CH), 7.06 (2 H, d, 3J = 7.9
Hz, CH), 7.15 (1 H, d, 3J = 7.9 Hz, CH), 9.07 (1 H, br s, OH)
Compound 4g: white powder; 132–133 °C (decomp.); yield
0.51 g (90%). IR (KBr): nmax = 3350, 3140, 1745, 1674,
1670, 1460, 1389, 1360 cm–1. 1H NMR (500.1 MHz,
Synlett 2008, No. 8, 1208–1210 © Thieme Stuttgart · New York

1210
I. Yavari, S. Souri
LETTER
CDCl3): d = 0.85 (3 H, t, 3J = 7.0 Hz, Me), 1.26 (2 H, q, 3J =
7.3 Hz, CH2), 1.42 (2 H, m, CH2), 3.23 (2 H, m, CH2), 3.78
(3 H, s, OMe), 3.79 (3 H, s, OMe), 4.77 (1 H, s, OH), 9.12 (1
H, br s, OH) ppm. 13C NMR (125.7 MHz, CDCl3): d = 13.5
(CH3), 20.0 (CH2), 30.1 (CH2), 39.5 (NCH2), 52.1 (OMe),
54.1 (OMe), 85.3 (COH), 110.5 (C), 157.4 (=COH), 163.7
(C=O), 163.8 (C=O), 170.4 (CON) ppm. MS: m/z (%) = 287
(18) [M+], 276 (70), 228 (100), 91 (50), 77 (64). Anal. Calcd
(%) for C12H17NO7 (287.26): C, 50.17; H, 5.96; N, 4.88.
Found: C, 50.00; H, 5.91; N, 4.92.
Synlett 2008, No. 8, 1208–1210 © Thieme Stuttgart · New York

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