Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones

Article abstract of DOI:10.1007/s11164-013-1102-7

Uncatalyzed one-pot pseudo-four-component reaction of ethyl pyruvate, anilines, and aldehydes in n-hexane as solvent, under reflux, affords a variety of 3-amino-1,5-dihydro-2H-pyrrol-2-ones in high yield. n-Hexane is an excellent driving force in preparat

Full text of DOI:10.1007/s11164-013-1102-7

Res Chem Intermed
DOI 10.1007/s11164-013-1102-7
Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-
pyrrol-2-ones
•
Hamid Reza Shaterian Mohammad Ranjbar
Received: 14 December 2012 / Accepted: 4 February 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Uncatalyzed one-pot pseudo-four-component reaction of ethyl pyruvate,
anilines, and aldehydes in n-hexane as solvent, under reflux, affords a variety of
3-amino-1,5-dihydro-2H-pyrrol-2-ones in high yield. n-Hexane is an excellent
driving force in preparation of the desired products. These compounds have bio-
logical and pharmacological properties and are also used in medicinal chemistry.
Use of a non-toxic and inexpensive solvent, simple and efficient synthesis, clean
work-up, and high yields of the products are the advantages of this method. We
report the first catalyst-free method for synthesis this class of compounds.
Keywords Uncatalyzed Á Ethyl pyruvate Á Anilines Á Aldehydes Á
3-Amino-1,5-dihydro-2H-pyrrol-2-ones
Introduction
1,5-Dihydro-2H-pyrrol-2-ones, particularly their 3-amino-substituted derivatives,
interesting lactams found in many natural products, have promising biological and
pharmacological properties [1–7]. Examples include the lipopeptides microcolin A
and B [8, 9]. When an amino substituent is present at the 3-position, these
heterocycles are also enamines; these have attracted much attention and have
applications in organic and medicinal chemistry [10–19]. For construction of this
class of molecules, two-component condensation of aromatic aniline derivatives
with b,c-unsaturated a-oxo esters has been reported [6]. Literature survey also
revealed three-component coupling of aniline, aldehyde, and pyruvate in the
presence of stoichiometric amount of Ti(OEt)4 and sulfuric acid [7] and
H. R. Shaterian (&) Á M. Ranjbar
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan,
98135-674 Zahedan, Iran
e-mail: hrshaterian@chem.usb.ac.ir
123

H. R. Shaterian, M. Ranjbar
organocatalytic hydrogen-bonding of phosphoric acid and thiourea [20] for
synthesis of these lactams. To the best of our knowledge, this is the first report of
catalyst-free preparation of 3-amino-1,5-dihydro-2H-pyrrol-2-ones (Scheme 1).
Experimental
General
All reagents were purchased from Merck and Sigma-Aldrich and were used without
further purification. All yields refer to isolated products after purification. Products
were characterized by comparison of physical and spectroscopic (IR and NMR) data
with those of authentic samples. NMR spectra were recorded on a Bruker Advance
DPX 500 MHz instrument. The spectra were measured in DMSO relative to TMS
(0.00 ppm). IR spectra were recorded on a Jasco FT-IR 460 plus spectrophotometer.
TLC was performed on Polygram SIL G/UV254 silica gel plates.
General experimental procedure for uncatalyzed synthesis
of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
n-Hexane (5 mL) was added to a mixture of ethyl pyruvate (10 mmol), aniline
(20 mmol), and aldehyde (10 mmol). The reaction mixture was stirred at reflux for
appropriate time (Table 1) and monitored by TLC analysis using 4:1 n-hexane–
EtOAc as mobile phase. On completion, the reaction mixture was cooled to room
temperature. Recrystallization from n-hexane afforded the corresponding products.
The desired pure products were characterized by comparison of their physical
data with those of known compounds. Spectral data for unknown products are given
below:
1-(4-Methoxyphenyl)-3-(4-methoxyphenylamino)-5-(propyl)-1H-pyrrol-2(5H)-
1
one (Table 1, Entry 24): H NMR (500 MHz, CDCl3): d = 1.22 (t, J = 7.6 Hz,
3H), 1.51–1.59 (m, 4H), 3.78 (s, 3H), 3.80 (s, 3H), 4.13–4.18 (m, 1H), 5.81 (s, 1H),
6.43 (s, 1H), 6.87 (d, J = 6.9 Hz, 2H), 6.92 (d, J = 6.9 Hz, 2H), 7.01 (d,
J = 6.8 Hz, 2H), 7.24 (d, J = 6.9 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3):
d = 14.0, 14.1, 21.4, 55.4, 55.6, 62.0, 105.8, 114.5, 114.8, 118.7, 124.7, 128.1,
G
O
NH2
CHO
O
H
G
N
OEt
n-Hexane
N
H3C
+
+
2
Reflux
O
G
G'
G'
Scheme 1 Catalyst-free preparation of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
123

Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
123

H. R. Shaterian, M. Ranjbar
123

Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
123

H. R. Shaterian, M. Ranjbar
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Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
123

H. R. Shaterian, M. Ranjbar
123

Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
123

H. R. Shaterian, M. Ranjbar
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Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
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H. R. Shaterian, M. Ranjbar
123

Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
G
NH2
O
NH
OEt
OEt
H3C
H2C
+
-H2O
O
O
G
I
NH2
CHO
G
+
CH=N
-H2O
G'
G
G'
II
G
NH
G
O
G
OEt
Intramolecular amidation
andTautomerism
OEt
N
+
CH=N
H2C
G'
N
H
O
II
I
G'
G
G
O
H
G
N
N
G'
Scheme 2 Suggested mechanism for preparation of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
134.5, 154.7, 158.6, 167.7, 171.6 ppm; FT-IR (KBr): 3,309, 2,991, 2,935, 1,694,
1,650, 1,609, 1,538, 1,513, 1,462, 1,372, 1,297, 1,246, 1,177, 1,111, 1,031, 834,
780, 726 cm-1; MS (EI, 70 eV) m/z (%) = 396 (70), 352 (14), 323 (100), 309 (12),
279 (13), 246 (6), 202 (5), 148 (35),132 (5),107 (4), 92 (8), 77 (12), 64 (3); calcd. for
[C21H24N2O3]: C, 71.57; H, 6.86; N, 7.95 %; Found: C, 71.67; H, 6.93; N, 8.01 %.
5-(2,3-Dichlorophenyl)-1-(4-methoxyphenyl)-3-(4-methoxyphenylamino)-1H-
1
pyrrol-2(5H)-one (Table 1, Entry 25): H NMR (500 MHz, CDCl3): 3.78 (s, 3H),
3.80 (s, 3H), 5.99 (d, J = 2.6 Hz, 1H), 6.24 (d, J = 2.3 Hz, 1H), 6.47 (s, 1H),
6.86–6.92 (m, 4H), 6.94 (d, J = 1.25 Hz, 1H), 7.04 (d, J = 8.9 Hz, 2H), 7.09 (t,
J = 8.2 Hz, 1H), 7.34–7.36 (dd, J = 1.6, 7.8 Hz, 1H), 7.47 (d, J = 9.1 Hz, 2H)
ppm; 13C NMR (125 MHz, CDCl3): d = 55.4, 55.6, 60.9, 103.6, 114.4, 114.8,
118.6, 118.7, 122.4, 125.2, 128.0, 129.7, 130.2, 133.4, 133.8, 134.5, 137.7, 154.7,
156.8, 167.0 ppm; IR (KBr): 3,329, 3,052, 3,003, 2,903, 1,680, 1,654, 1,616, 1,606,
1,512, 1,422, 1,299, 1,249, 1,105, 1,035, 810, 781, 728, 670 cm-1; MS (EI, 70 eV)
m/z (%) = 304 (2), 269 (1), 254 (6), 149 (9), 134 (27), 122 (51), 106 (12), 92 (14),
77 (30), 57 (18), 43 (100); calcd. for [C24H20Cl2N2O3]: C, 63.31; H, 4.43; N,
6.15 %; Found: C, 63.40; H, 4.48; N, 6.23 %.
1-(4-Methoxyphenyl)-3-(4-methoxyphenylamino)-5-(3,4,5-trimethoxyphenyl)-
1
1H-pyrrol-2(5H)-one (Table 1, Entry 26): H NMR (500 MHz, CDCl3): 3.74 (s,
3H), 3.75 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 3.78 (s, 3H), 5.46 (d, J = 2.5 Hz, 1H),
123

H. R. Shaterian, M. Ranjbar
5.90 (d, J = 2.6 Hz, 1H), 6.36 (s, 2H), 6.44 (s, 1H), 6.81–6.85 (m, 4H), 7.02 (d,
J = 8.9 Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3):
d = 55.4, 55.6, 56.2, 60.8, 62.0, 65.1, 103.8, 106.0, 114.2, 114.7, 118.7, 123.9,
128.1, 130.4, 133.9, 133.3, 134.8, 153.6, 154.5, 157.1, 167.2 ppm; IR (KBr): 3,905,
3,855, 3,752, 3,650, 3,317, 2,938, 1,660, 1,591, 1,541, 1,519, 1,459, 1,399, 1,335,
1,302, 1,252, 1,184, 1,129, 1,032, 824, 789, 671, 524 cm-1; MS (EI, 70 eV) m/
z (%) = 476 (93), 396(5), 354 (38), 326 (100), 300(6), 238 (8), 194(4), 148 (7), 122
(17),92 (5), 77(10); calcd. for [C27H28N2O6]: C, 68.05; H, 5.92; N, 5.88 % Found:
C, 68.11; H, 5.99; N, 5.91 %.
5-(4-Bromophenyl)-1-(4-methoxyphenyl)-3-(4-methoxyphenylamino)-1H-pyr-
rol-2(5H)-one (Table 1, Entry 27):1H NMR (500 MHz, CDCl3): 1.23 (s, 3H,
J = 7.13), 1.6 (s, 3H), 5.50 (d, J = 2.5 Hz, 1H), 5.86 (d, J = 2.6 Hz, 1H), 6.4 (s,
1H), 6.86–6.88 (m, 3H), 6.92–7.01 (m, 4H), 7.24-7.25 (m, 4H), 7.37 (d, 1H,
J = 6.6) ppm; 13C NMR (125 MHz, CDCl3): d = 55.3, 55.4, 61.9, 64.1, 68.8,
105.8, 107.6, 114.7, 118.7, 121.9, 123.8, 128.6, 129.0, 129.3, 129.4, 132.1, 133.3,
136.9, 154.7, 158.6, 171.5, ppm; IR (KBr): 3,905, 3,855, 3,762, 3,309, 1,728, 1,600,
1,648, 1,542, 1,510, 1,459, 1,440, 1,399, 1,298, 1,248, 1,178, 1,111, 1,032, 830,
525 cm-1; MS (EI, 70 eV) m/z (%) = 466 (6), 396 (18), 323 (100), 279 (3),235
(2),220 (3),189 (1), 148 (16),122 (4),107 (3),92 (5), 77(6); calcd. for
[C24H21BrN2O3]: C, 61.95; H, 4.55; N, 6.02 % Found: C, 61.90; H, 4.62; N,
6.10 % .
3-(4-Chlorophenylamino)-1,5-bis(3-chlorophenyl)-1H-pyrrol-2(5H)-one (Table 1,
1
Entry 28): H NMR (500 MHz, CDCl3): 1.53 (s, 1H), 5.6 (s, 1H), 6.02 (s, 1H), 6.6
(s, 1H), 6.97 (d, J = 8.80 Hz, 2H), 7.10 (d, J = 8.30 Hz, 2H), 7.23–7.26 (m, 5H),
7.43 (d, J = 8.85 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3): d = 63.5, 107.8,
117.9, 122.5, 126.4, 127.5, 128.1, 129.1, 129.4, 131.3, 132.7, 133.2, 135.4, 139.5,
166.7, ppm; IR (KBr): 3,905, 3,855, 3,752, 3,650, 331, 1,670, 1,647, 1,601, 1,533,
1,492, 1,422, 1,384, 1,089, 814, 624, 470 cm-1
;
MS (EI, 70 eV)
m/z (%) = 430 (100), 302 (54),274 (98), 253 (6), 239 (16), 218 (3), 204 (22),
177 (4),162 (6), 89 (5), 138 (22), 111 (31), 75 (124), 51 (5); calcd. for
[C22H15Cl3N2O]: C, 61.49; H, 3.52; N, 6.52 % Found: C, 61.52; H, 3.55; N, 6.60 %.
Results and discussion
We were interested in preparation of 3-amino-1,5-dihydro-2H-pyrrol-2-one deriv-
atives by pseudo four-component reaction of ethyl pyruvate, anilines, and
aldehydes. First, several catalysts (Al(HSO4)3, silica–sulfuric acid, FeCl3–SiO2,
and P2O5–SiO2), different solvents (ethanol, dichloromethane, chloroform, ethyl
acetate, diethyl ether, and n-hexane), and solvent-free conditions were studied. We
found the catalysts performed better in n-hexane under reflux conditions than under
other conditions. The heterogeneous catalysts were not all soluble in n-hexane but
the reactions were complete. We then decided to perform the reaction in n-hexane
under reflux conditions without use of any catalyst. The reactions were complete in
the absence of the catalysts in n-hexane. It seems that n-hexane provides a good
driving force for completion of the reaction because the product is not soluble in the
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Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
solvent and heterogeneous catalysts did not act efficiently in n-hexane as nonpolar
solvent.
To investigate the range of anilines and aldehydes suitable for the reaction, a
variety of substituted anilines and aldehydes bearing either electron-withdrawing or
electron-donating groups were used in the reaction; all led to the desired products in
high yields (Table 1). Reaction of aliphatic aldehydes, for example n-butyaldehyde,
afforded the desired product in moderate yield (Table 1, Entry 24).
The mechanism proposed for reaction of ethyl pyruvate, aniline, and aldehyde
are shown in Scheme 2. Two equivalents of aniline first react with the ethyl
pyruvate and the aldehyde to form enamine I and imine II, respectively (Scheme 2).
Subsequent condensation of I and II followed by the intramolecular amidation with
loss of ethanol afforded the 3-amino-1,5-dihydro-2H-pyrrol-2-one as product. This
proposed mechanism was confirmed in the literature [7, 20].
Literature survey revealed little research on synthesis of this class of compounds.
We compared the suitability of our method with results reported in the literature, for
example Ti(OEt)4 (200 mol %) with sulfuric acid [7] and organocatalytic hydrogen-
bonding of phosphoric acid and thiourea (10 mol %, 18 h) [20], and found that this
catalyst-free method is most efficient in respect of reaction times and temperature
and has broad applicability in terms of yield.
Conclusions
We report, for the first time, an uncatalyzed one-pot, pseudo-four-component
reaction of ethyl pyruvate, anilines, and aldehydes, under reflux conditions in
n-hexane, which affords a variety of 3-amino-1,5-dihydro-2H-pyrrol-2-ones in high
yield. Use of a non-toxic and inexpensive solvent, simple reaction, and clean work-
up are advantages of this method.
Acknowledgments We are grateful to the University of Sistan and Baluchestan Research Council for
partial support of this research.
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