Synthesis and NMR spectroscopic studies of optically active derivatives of γ-aminobutenoic acids and 2-amino-pyrrolin-4-ones

Article abstract of DOI:10.1002/jhet.5570380416

An efficient method for the preparation of optically active derivatives of γ-amino-butenoic acids and their cyclic derivatives, 2-amino-pyrrolin-4-ones, from α-amino acids is described. Partial racemization accompanies the formation of initial unsaturated

Full text of DOI:10.1002/jhet.5570380416

Jul-Aug 2001
Synthesis and NMR Spectroscopic Studies of Optically Active
Derivatives of γ-Aminobutenoic Acids and 2-Amino-pyrrolin-4-ones
Margarita Petroliagi and Olga Igglessi-Markopoulou*
917
Laboratory of Organic Chemistry, Department of Chemical Engineering,
National Technical University of Athens, Zografou Campus, 157 73 Athens, GREECE
Received September 5, 2000
An efficient method for the preparation of optically active derivatives of γ-amino-butenoic acids and their
cyclic derivatives, 2-amino-pyrrolin-4-ones, from α-amino acids is described. Partial racemization accom-
panies the formation of initial unsaturated γ-amino-β-hydroxy esters 5-8, as determined by chiral HPLC.
J. Heterocyclic Chem., 38, 917 (2001).
Recent synthetic work and structure-activity studies on
Another important class of potential medicinal agents that
have been identified as efficacious antiviral drugs are the
nitrogen heterocyclic compounds possessing the pyrroline
ring system. Especially, the derivatives of 2-amino-pyrroles
exhibit antiallergic, local anaesthetic, antiarrythmic,
hypotensive and anticonvulsant properties [4]. Recently,
these compounds have been used as important heterocyclic
building blocks of antibiotics for the treatment of osteoporo-
sis, breast cancer and cardiovascular disorder, e.g., thrombo-
sis [5]. Analogues of 2-amino-pyrroles have been synthe-
sized by a standard Dieckmann condensation using ethyl
α-cyano-γ-chloroacetoacetates as precursors, either by a
thermal condensation of α-aminoketones with t-butyl-
cyanoacetate, or by reaction of primary and secondary
amines with oxazolin-2-ylidene-malonitriles [6].
β-hydroxy-γ-amino acids, analogues of statine, have
revealed that these compounds are of increased pharmaco-
logical significance due to their participation in the bioac-
tivity of peptides and their ability to act as selective renin
inhibitors [1]. Especially, the difunctionalised enols of
type I (Figure I) possessing topographical similarities with
Boc-statine, have attracted much attention after clinical
evaluation as they constitute potent, powerful inhibitors
against HIV protease [2].
In continuation of our studies on the use of N-hydroxysuc-
cinimide esters of N-acetyl-α-amino acids [7], as precursors
for the synthesis of compounds with interesting biological
properties, we propose here an efficient methodology for the
construction of optically active 4-amino-3-hydroxy-2-cyano-
2-butenoates 5-8 as useful synthons for the synthesis of
A key feature of rationally designed HIV inhibitors has
been the introduction of substituents to these derivatives
that mimic natural substrate side chains, whilst retaining or
improving activity against both the enzyme and the virus.
Extensive screening and modeling studies have revealed
that the presence of two electron-withdrawing substituents
at the positions E,E' modulate the electron density of the
electrophilic center at the vinylic position that interacts
with the nucleophilic groups at the active site of enzymes,
favoring in this way enzyme-inhibitor interaction.
In the light of this relevance of β-hydroxy-γ-amino acids
the development of efficient methods for their asymmetric
construction is of great importance to organic synthesis in
general and to natural product and medicinal chemistry in
particular. G.Sauvé and co-workers [2] have reported a syn-
thetic sequence to optically active difunctionalised enols of
type I (Figure I) which involves the condensation of an
appropriate active methylene compound with an activated
acyl-imidazole intermediate. Another strategy for the con-
struction of compounds of this class involves the C-acyla-
tion reactions of ethyl cyanoacetic esters with N-hydroxy-
succinimide esters of N-substituted-α-amino acids, as it has
been recently reported by our laboratory [3].

918
M. Petroliagi and O. Igglessi-Markopoulou
Vol. 38
chiral 2-amino-pyrrolin-4-ones 9-16. For our starting
reagents, we have chosen N-hydroxysuccinimide esters of
four different optically active N-acetyl-α-amino acids
(L-alanine, L-phenylalanine, L-valine, L-leucine).
Employment of the anion of ethyl cyanoacetate (sodium
hydride, tetrahydrofuran, 0 °C) with N-hydroxysuccinimide
esters 1-4, the novel optically active γ-acetamino-β-hydroxy-
butenoates 5-8 have been formed (Scheme I).
In a typical C-acylation reaction 3 equivalents of the
ethyl cyanoacetate were treated with 2 equivalents of
sodium hydride in tetrahydrofuran at 0 °C. After stirring of
the reaction mixture for 1 hour, N-hydroxysuccinimide
ester 1-4 was added and stirring was continued for further
3hours, at 0 °C. After workup of the reaction mixture, as it
is described in the experimental section, the difunction-
alised enols 5-8 were isolated without further cylclization
in good yields. The enantiomeric ratio, e.r., of the com-
pounds was 78-94% (Table 1), as determined by means of
HPLC using a chiral stationary phase.
ratio of these
compounds, by means of HPLC were unsuccessful.
tions. Any effort to determine the enatiomeric
The structure of the newly prepared C-acylation com-
pounds 5-8 and 2-aminopyrrolin-4-ones 13-16 has been
elucidated using NMR and IR spectroscopy. The difunc-
tionalised enols 5-8 can occur in two enolic forms, Z and E,
from which the Z-enol form should be the most stable due
to the presence of intramolecular hydrogen bonding (Figure
1
13
II). The H and C NMR spectra of these compounds
confirm their existence, in deuteriochloroform solution, in
Table 1
Physical properties of the C-acylation compounds 5-8
Compound
Enant. ratio(t, min) [a]
[α] [b]
mp (°C)
Yield(%)
e.e
D
5
6
7
8
84 (6.22) : 16(7.83)
78 (5.82) : 22 (7.62)
94 (6.00) : 6(7.57)
92 (5.88) : 8(7.60)
+21.4 (c1, MeOH)
+130.5 (c1.32, MeOH)
+8.2 (c1.05, CHCl )
+28.4 (c1.3, MeOH)
128-132
164-165
102-105
89-93
50
77
45
65
68
56
88
84
3
[a]The enantiomeric ratios were determined by HPLC analysis with a CHIRALPAK AS column (4.6x250mm), [245nm, 0.55
ml/min, ethanol-hexane (90:10)]; [b]Optical rotations were recorded on a Perkin-Elmer 241 polarimeter.
An important feature for the proposal methodology has
been the use of N-hydroxysuccinimide esters of N-acetyl-
L-amino acids as acylating agents. These esters are stable,
can be stored for a long time and are easily prepared, there-
fore are useful precursors for the synthesis of optically
active functionalized enols.
enolic form (Tables 2,3). In addition, due to the electron-
withdrawing character of CN group, the enol population is
increased in these compounds and thus the OH chemical
shift is decreased (δ ~13-14 ppm) [9].
Η
The 2-amino-pyrrolin-4-ones can occur in the following
tautomeric forms AB[C/D] (Scheme II) [3c].
Then, our attention was concentrated on the use of the
C-acylation compounds 5-8 as synthons for the construc-
tion of novel optically active 2-amino-pyrrolin-4-ones. As
it has been reported, nitrogen heterocycles possessing one
or more stereogenic centers constitute important subunits
of natural products which exhibit a broad range of biologi-
cal activities [8]. Ring closure to 2-amino-pyrrolin-4-ones
9-12 was achieved by refluxing the C-acylation com-
pounds 5-8 in a solution of 8% hydrochloric acid in
ethanol for 3 hours. When the reaction mixture was con-
centrated in vacuo, the hydrochloride salts of 2-amino-
pyrrolin-4-ones 9-12, with a small amount of the corre-
sponding amines, were obtained.
1
The H NMR spectra of 2-amino-pyrrolin-4-ones 13-16
in hexadeuteriodimethylsulfoxide solution confirmed that
the predominant form should be the tautomer C, as there is
not any characteristic resonance of a methine proton at C-3
corresponding to the tautomer B, or any signals of OH group
corresponding to the tautomer A (Tables 4,5). The signals of
-NH appear upfield and are exchangeable with D O.
The IR spectra of the C-acylation compounds 5-8 show
Treatment of the hydrochlorde salts 9-12 with a solution of
1% sodium hydroxide at 0 °C for 1 hour, the free enamines,
2-amino-3-ethoxycarbonylpyrrolin-4-ones 13-16, showed an
optical rotation confirming that the pyrrolinone nucleus pos-
sess a stereogenic center, under these experimental condi-
2
2
-1
absorptions bands at 3295-3210 and 2220-2210 cm

Jul-Aug 2001
Synthesis and NMR Spectroscopic Studies of Optically Active Derivatives
919
Table 2
1
H NMR Spectra of Compounds 5-8 (300MHz, CDCl )
3
Compound
R
CO CH CH
CH-R
COCH
CO CH CH
CHR
NH
OH
2
2
3
3
2
2
3
5
CH
1.31
CH 1.53
1.98
4.29
4.83
6.60
13.75
3
3
(3H, t, J 6.8)
1.35
(3H, t, J 7.3)
(3H, d, J 7.3)
(3H, s)
1.96
(3H, s)
(2H, q, J 6.8)
4.32
(2H, q, J 6.8)
(1H, m)
5.14
(1H, dd, J 7.3) (1H, bs)
(1H, bs)
5.92
(1H, br)
13.90
(1H, br)
6
7
8
CH C H
CH C H
2
6
5
2 6 5
3.18, 3.04 (1H, dd, J 6, 8.4)
3.13, 2.99 (1H, dd, J 5.7, 8.4)
C H 7.20-7.35 (5 H, m)
6
5
CH(CH )
1.36
(3H, t, J 6.8)
CH(CH )
2.05
(3H, s)
4.34
(2H, q, J 7.3)
4.71
(1H, t, J 8.0)
5.95
(1H, bs)
13.94
(1H, br)
3 2
3 2
1.03(6 H, d, J 6.59)
CH(CH )
3 2
2.09-2.16 (1H, m)
CH CH(CH ) 1.34
CH CH(CH )
2.02
(3H, s)
4.32
(2H, q, J 7.3)
4.84-4.91
(1H, m)
6.16
(1H, bs)
14.24
(1H, br)
2
3 2
2
3 2
(3H, t, J 7.33) 0.95,0.98(6H, dd, J 4.4)
CH CH
2
1.58-1.72 (3H, m,)
Table 3
C NMR Spectra of Compounds 5-8 (CDCl )
13
3
Compound
R
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10 C-11
C-12
------
C-13
------
C-14
------
5
CH
10
113.49 78.97 190.31 48.12 170.28 22.12 170.44 62.62 13.65 17.53 ------
3
6
113.40 80.80 188.32 53.61 169.83 22.49 170.50 62.87 13.79 38.49 135.09 129.19 128.97 127.65
7
8
CH(CH )
113.74 80.95 188.53 57.60 170.13 22.24 170.81 62.60 13.61 30.81
18.73
18.26
------
------
------
3 2
10 11,12
CH CH(CH )
113.72 72.62 190.09 51.06 170.36 21.39 170.49 62.77 13.82 41.39 24.77
22.71
22.51
2
3 2
10 11 12,13
purity as the enantiomeric ratios of such difunctionalised
enols are reported for first time. The merits of this syn-
thetic route are the mild reaction conditions, the short
reaction times, the high yields in which the products were
isolated with partial racemization. The procedure is
directed towards extending the previous one reported
recently by our laboratory [3] as it includes modifications
on the reaction conditions and is applied on the prepara-
tion of more aminoacids derivatives. Furthermore, it
extends the usefulness of novel synthesized difunction-
alised enols as precursors for the construction of optically
active 2-amino-pyrrolin-4-ones whose enantiomeric ratio
determination is under investigation.
which are attributed to the NH and C≡N stretching,
respectively. In the carbonyl region, only the com-
pounds 6 and 8 exhibit absorption band for the CO
-1
group of the keto form at 1720–1710 cm , whereas all
the C-acylation compounds 5-8 show a characteristic
-1
absorption band at 1665-1640 cm for the CO group of
the enol form of the β-dicarbonyl system CO-CH-
-1
CO↔C(OH)=C-CO. The band at 1585 cm is attrib-
uted to the carbon-carbon double bond. These results
indicate that the C-acylation compounds 6 and 8 exist as
a mixture of the keto- and enol- form, whereas the C-
acylation compounds 5 and 7 predominate in their eno-
lic form, in the solid state.
In the work described above we have developed a con-
cise and versatile approach to optically active cyano
derivatives of β-hydroxy-γ-amino acids and we have been
innovative in the determination of their enantiomeric
In conclusion, the reported novel class of optically
active difunctionalised enols and aminopyrrolinones may
serve as useful probes for studying structure-activity rela-
tionships in medicinal chemistry.

920
M. Petroliagi and O. Igglessi-Markopoulou
Vol. 38
Table 4
1
2
H NMR of Compounds 13-16 (300MHz, [ H ]DMSO)
6
Compound
OCH CH
OCH CH
C-R
CH
CHR
NH
NH
2
2
3
2
3
13
1.16
4.04
3.5
7.38
7.99
3
R=CH
14
(3H, t, J 7.0)
1.15
(3H, t, J 7.0)
(2 H, q, J 6.8)
4.03
2 H, bq, J 6.8)
1.09 (3 H, d, J 6.8)
CH C H
2.57, 2.62 (1H,dd, J 5.7, 2.4)
2.97, 3.02 (1H, dd, J 6.3, 3.0)
(1 H, q, J 6.8)
3.79-3.83
(1 H, m)
(1 H, bs)
7.48
(1 H, bs)
(2 H, bs)
3
C H and NH
2
6
5
6 5 2
R=C H CH
7.18-7.28 (~7 H, m)
6
5
2
C H and NH
6
5
2
7.18-7.28 (~7 H, m)
CH(CH )
15
1.15
(3H, t, J 7.0)
3.98-4.09
(2 H, m)
3.41
(1 H, d, J 3.4)
7.68
(1 H, bs)
7.4
(2 H, bs)
3 2
R=(CH ) CH
0.66, 0.92 (3H, dd, J 6.8)
CH(CH )
3 2
3 2
1.94-2.02 (1 H, m)
16
1.15
(3H, t, J 7.0)
4.04
(2H, q, J 7.3)
CH CH(CH )
0.86 (6 H, d, J 6.6)
3.49-3.53
(1 H, m)
7.76
(1 H, bs)
7.39
(2 H, bs)
2
3 2
R=(CH ) CHCH
3 2
2
CH CH(CH )
2
3 2
1.40-1.76 (3 H, m)
Table 5
13
2
C NMR of Compounds 14-16 ([ H ]DMSO)
6
Compound
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-11
C-12
C-13
14 R=
164.99
85.84
190.17 62.41 169.76
57.73 14.53
37.24
137.76
129.39
128.29
126.42
15 R= (CH ) CH
165.01
165.18
86.13
85.41
190.79 66.41 170.40
191.56 60.14 169.73
57.71 14.50
57.72 14.54
29.36
41.05
19.19
15.43
------
------
------
3 2
11, 10
9
16 R= (CH ) CHCH
24.48
23.31
21.69
3 2
12, 11 10
2
9
EXPERIMENTAL
The N-acetyl-L-alanine and N-acetyl-L-phenylalanine were
commercially available. The requisite N-acetyl-L-leucine and L-
valine were prepared using the method of H. D. DeWitt and A.
W. Ingersoll [11].
Melting points were determined on a Gallenkamp MF13-595
melting point apparatus and are uncorrected. The ir spectra were
recorded on a Perkin Elmer 267 spectrometer. The H nmr spectra
1
General Procedure for the Synthesis of Optically Active N-
Hydroxysuccinimide Esters of N-Acetyl-α-amino Acids 1-4.
were recorded on a Varian Gemini-2000 300 MHz spectrometer;
chemical shifts are quoted in ppm (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad); J values are given in Hz.
Optical rotations were recorded on a Perkin-Elmer 241 polarimeter,
at 25 °C. The Mass spectra were recorded on a VG 7070 E/DEC
VAX 4000,60 Instrument using Fast Atom Bombardment (FAB),
University of Liverpool. HPLC has been carried out on a Varian
2501, using a packed column, [CHIRALPAK AS (4.6x250mm)].
The mobile phase was ethanol-hexane (90:10). Elemental analyses
were obtained from the University of Liverpool, Chemistry
Department. Solvents and reagents were dried or purified according
to the procedure described by Perrin and Armarego [10].
The requisite N-hydroxysuccinimide esters of N-acetyl-α-
amino acids 1-4 were prepared according to a method which has
been recently reported [7], with minor modifications: the mixture
of N-acetyl-α-amino acid (50 mmoles), N-hydroxysuccinimide
(50 mmoles) and N,N'-dicyclohexylcarbodiimide (50 mmoles) in
tetrahydrofuran (160 ml) was stirred at 0 °C. After the filtration
of N,N'-dicyclohexylurea, the solution was concentrated in vacuo
giving either a solid or an oily product.
N-Hydroxysuccinimide Ester of N-Acetyl-L-alanine (1).
According to the previous procedure compound (1) was obtained
Preparation of Optically Active N-Acetyl-α-amino Acids.
after concentration in vacuo as a solid, mp 119-122 °C (65%), [α]
D

Jul-Aug 2001
Synthesis and NMR Spectroscopic Studies of Optically Active Derivatives
921
1
Ethyl 4-Acetylamino-2-cyano-3-hydroxy-5-methylhex-2-enoate
(7).
+71.5 (c4.0, MeOH); H nmr (deuteriochloroform): δ 1.58 (3 H, d,
J = 7.3, CHCH ), 2.03 (3 H, s, COCH ), 2.84 (4 H, s,
3
3
CO(CH ) CO), 4.99 (1 H, q, J = 7.3, CHCO) and 6.09 (1 H, br, NH).
2 2
According to the previous procedure the title compound was
obtained as a solid (0.89 g, 45%) mp 102-105 °C (from chloro-
N-Hydroxysuccinimide Ester of N-Acetyl-L-phenylalanine (2).
form-light petroleum ether), [α] +8.17 (c1.05, CHCl );
3
D
According to the previous procedure the title compound was
ir(Nujol): 3240m,br (NH), 2218s,sh (CN), 1655w,br (CO ester,
obtained as a solid, mp 152-154 °C (85%), [α] -39 (c1.0,
-1
1
D
enol form), 1585w,br (C=C), 1540w,br (amide II) cm ; H nmr
(deuteriochloroform) see Table 2; C nmr (deuteriochloroform)
see Table 3; ms: m/z 254 (M , 0.19), 211 (2.72), 183 (5.38),
1
MeOH); H nmr (deuteriochloroform): δ 1.94 (3 H, s, COCH ),
3
13
2.79 (4 H, s, CO(CH ) CO), 3.18, 3.30 (2 H, 2dd, J 5.7 and 6.0,
2 2
+
CH C H ), 5.24 (1 H, m, CHCO), 6.11 (1 H, br, NH) and 7.22-
2 6 5
139(52.14), 68(100), 43(30).
7.34 (5 H, m, C H ).
6 5
Anal. Calcd. for C
H O N : C, 56.88; H, 7.13; N, 11.01.
12 18 4 2
Found C, 56.83; H, 7.12; N, 11.04.
N-Hydroxysuccinimide Ester of N-Acetyl-L-valine (3).
Ethyl 4-Acetylamino-2-cyano-3-hydroxy-6-methyl-2-heptenoate
According to the previous procedure the title compound was
(8).
obtained as a solid, mp 136-140 °C (84%), [α] -55.43 (c1.6,
D
1
MeOH); H nmr (deuteriochloroform): δ 1.06 and 1.03 [6 H, two
According to the previous procedure the title compound was
obtained as a solid (1.54 g, 65%) mp 89-93 °C (from chloroform-
light petroleum ether), [α] +28.4 (c1.3, MeOH); ir(Nujol):
3210s,sh (NH), 2220s,sh (CN), 1710w,sh (CO ester, keto form),
1655s,sh (CO ester, enol form), 1590m,br (C=C), 1545s,sh
(amide II) cm ; H nmr (deuteriochloroform) see Table 2;
nmr (deuteriochloroform) see Table 3; ms: m/z 268 (M , 35%),
269 (21), 225 (100).
Anal. Calcd. for C
Found C, 58.12; H, 7.52; N, 10.49.
d, J 2.1, CH(CH ) ], 2.05 (3 H, s, COCH ), 2.32 [1 H, m,
3 2
3
CH(CH ) ], 2.83 (4 H, s, CO(CH ) CO), 4.92 (1 H, d, J 5.1,
3 2
2 2
D
CHCO) and 6.09 (1 H, br, NH).
N-Hydroxysuccinimide Ester of N-Acetyl-L-leucine (4).
-1
1
13
C
According to the previous procedure the title compound was
+
1
obtained as a waxy solid (85%), [α] -18.94 (c1.28, MeOH); H
D
nmr (deuteriochloroform): δ 0.93 [6 H, m, CH(CH ) ], 1.74 (3
H, m, CH CH), 2.00 (3 H, s, COCH ), 2.79 [4 H, s,
CO(CH ) CO], 4.97 (1 H, m, CHCO) and 6.47 (1 H, br, NH).
2 2
3 2
H O N : C, 58.19; H, 7.51; N, 10.44.
13 20 4 2
2
3
General Method for the Preparation of Compounds 9-12.
General Method for the Preparation of Compounds 5-8.
The C-acylation compound 5-8 (14 mmoles) was added in a
solution of 8% hydrogen chloride in ethanol, prepared from the
addition of acetyl chloride (11 ml) in anhydrous ethanol (113 ml).
The reaction mixture was refluxed for 3 hours and set aside
overnight at room temperature. Then it was evaporated in vacuo
to give the hydrochloric salt of compounds 9-12.
The ethyl cyanoacetate (26.4 mmoles) was added dropwise to
a suspension of sodium hydride (55-60 % sodium hydride in oil;
17.6 mmoles) in anhydrous tetrahydrofuran (20 ml) and the thick
slurry thus formed was stirred at 0 °C for 1 hour. The N-hydroxy-
succinimide ester of N-acetyl-α-amino acid 1-4 (8.8 mmoles)
was then added to the mixture and stirring continued for 3 hours,
at 0 °C. The reaction mixture was concentrated in vacuo and the
solid obtained was diluted in water and washed with diethyl
ether. The aqueous layer was separated, acidified with 10%
hydrochloric acid in an ice-water bath giving a solid that was
washed with light petroleum ether.
General Method for the Preparation of Compounds 13-16 as Free
Amines.
The Hydrochloric salt 9-12 (1.14 mmoles) was added to a solu-
tion of sodium hydroxide 1% (3 ml) and the reaction mixture was
stirred for 1 hour at 0 °C. The solid product so formed was iso-
lated by filtration.
Ethyl-4-acetylamino-2-cyano-3-hydroxypent-2-enoate (5).
2-Amino-3-ethoxycarbonyl-5-methylpyrrolin-4-one (13).
According to the previous procedure the title compound (5) was
obtained as a solid (1.9 g, 50%) mp 128-132 °C (from chloroform-
According to the previous procedure the title compound was
obtained after extraction of the aqueous solution with ethyl
light petroleum ether), [α] +21.4 (c1.0, MeOH); ir(Nujol):
D
3280s,sh (NH), 2210m,sh (CN), 1640m,br (CO ester, enol form),
acetate as a waxy solid (0.17 g, 35%), [α] +10 (c0.2, MeOH);
D
-1
1
1
1585w,br (C=C), 1545m,br (amide II) cm ; H nmr (deuteriochlo-
H nmr (dimethyl-d sulfoxide) see Table 4.
6
13
roform) see Table 2; C nmr (deuteriochloroform) see Table 3; ms:
2-Amino-3-ethoxycarbonyl-5-benzylpyrrolin-4-one (14).
+
m/z 226 (M , 4.71%), 184 (10.03), 112 (6.56), 86(100), 44(98.15).
According to the previous procedure the title compound was
Ethyl 4-Acetylamino-2-cyano-3-hydroxy-5-phenylpent-2-enoate
(6).
obtained as a solid (0.09 g, 52%) mp 202-204 °C, [α] +6.6
D
(c0.3, MeOH); ir(Nujol): 3440m,sh and 3320w,br (NH and
According to the previous procedure the title compound was
obtained as a solid (0.95 g, 77 %) mp 164-165 °C (from chloro-
NH ), 1690w,br (CO ketone and COester), 1625m,sh (C=C)
2
-1
1
13
cm ; H nmr (dimethyl-d6 sulfoxide) see Table 4; C nmr
(dimethyl-d6 sulfoxide) see Table 5; ms: m/z 243 (15.23), 216
(31.51), 188 (74.79), 91(100), 43(14.50).
form-light petroleum ether), [α] +130.5 (c1.32, MeOH);
D
ir(Nujol): 3295s,sh (NH), 2220m,sh (CN), 1720w,br (CO ester,
keto form), 1650m,br (CO ester, enol form), 1585m,br (C=C),
2-Amino-3-ethoxycarbonyl-5-isopropylpyrrolin-4-one (15).
-1
1
1530m,br (amide II) cm ; H nmr (deuteriochloroform) see
13
Table 2; C nmr (deuteriochloroform) see Table 3; ms: m/z 302
According to the previous procedure the title compound was
+
(M , 1.40%), 256(10.70), 243 (22.61), 169(100), 43(79.79).
obtained as a solid (0.3 g, 59%) mp 174-176 °C, [α] +8 (c0.2,
D
Anal. Calcd. for C
H O N : C, 63.56; H, 6.00; N, 9.27.
MeOH); ir(Nujol): 3480s,sh, 3270s,sh and 3140m,br (NH and
16 18 4 2
NH ), 1685s,sh (CO ketone), 1655s,sh (CO ester), and 1615m,sh
Found C, 63.42; H, 6.02; N, 9.27.
2

922
M. Petroliagi and O. Igglessi-Markopoulou
Vol. 38
-1
1
13
[3a] A. Detsi, J. Markopoulos and O. Igglessi-Markopoulou,
Chem. Commun., 1323 (1996); [b] A. Detsi, M. Micha-Screttas and
O. Igglessi-Markopoulou, J. Chem. Soc., Perkin Trans. 1, 2443
(1998); [c] E. Samartzi, A. Gola, V. Bardakos, J. Markopoulos, M.
Petroliagi and O. Igglessi-Markopoulou, J. Heterocyclic Chem., 37,
681 (2000).
(C=C) cm ; H nmr (dimethyl-d6 sulfoxide) see Table 4;
C
nmr (dimethyl-d6 sulfoxide) see Table 5; ms: m/z 197 (0.29),
170 (88.75), 167 (23.91), 151 (20.94), 124 (100), 43(8.01).
2-Amino-3-ethoxycarbonyl-5-isobutylpyrrolin-4-one (16).
According to the previous procedure the title compound was
[4] R. J. Mattson, L.-C. Wang and J. W. Sowell Sr., J.
Heterocyclic Chem., 17, 1793 (1980).
obtained as a solid (0.2 g, 78%) mp 180-185 °C, [α] +2.6 (c0.5,
D
MeOH); ir(Nujol): 3480s,sh, 3260m,sh and 3140m,br (NH and
[5] M. Missbach, Ciba-Geiby A.-G., Switz.; Chem. Abstr.,
125, 86670 (1997).
NH ), 1700m,sh (CO ketone), 1655m,sh (CO ester), and
2
-1 1
1615m,sh (C=C) cm ; H nmr (dimethyl-d sulfoxide) see Table
6
13
[6a] J. A. S. Laks, J. R. Ross, S. M. Bayomi and J. W. Sowell
Sr., Synth. Commun., 291 (1985); [b] K.-J. Boosen, Helv. Chim. Acta,
60(4), 1256 (1977); [c] H-D. Stachel, K. K. Harigel, H.
Poschenrieder and H. Burghard, J. Heterocyclic Chem., 17, 1195
(1980); [d] M. Rehwald, H. Schäfer and K. Gewald, Monatsch.
Chem., 128, 933 (1997).
[7a] M. Petroliagi and O. Igglessi-Markopoulou, J. Chem. Soc.,
Perkin Trans. 1, 3543 (1997); [b] M. Petroliagi and O. Igglessi-
Markopoulou, Tetrahedron Asymm., 10, 1873 (1999).
[8] B. J. L. Royles, Chem. Rev., 95, 1981 (1995).
4; C nmr (dimethyl-d sulfoxide) see Table 5; ms: m/z 212
6
(1.02), 181 (15.09), 170 (100), 124 (96.23), 44 (26.89).
Ackowledgments.
We thank the Committee of Research of the National Technical
University of Athens, Greece, for a doctoral assistantship (M.P.)
REFERENCES AND NOTES
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Laboratory Chemicals, Pergamon Press, Oxford, 1988.
[11] D. DeWitt and A. W. Ingersoll, J. Am. Chem. Soc., 3359
(1951).
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