Heterocyclization of derivatives of 4-oxoalkanoic acids to 1,5-disubstituted pyrrolin-2-ones

Article abstract of DOI:10.1023/A:1011957011038

Conditions were developed for the synthesis and production of 1-aryl-5-alkyl(aryl)-3H- and 1-aryl-5-alkyl(aryl)-5H-pyrrolin-2-ones from the amides and esters of 4-oxoalkanoic acids. It was established that the yield and ratio of the 3H and 5H isomers depe

Full text of DOI:10.1023/A:1011957011038

Chemistry of Heterocyclic Compounds, Vol. 37, No. 6, 2001
HETEROCYCLIZATION OF DERIVATIVES
OF 4-OXOALKANOIC ACIDS TO
1,5-DISUBSTITUTED PYRROLIN-2-ONES
A. Yu. Egorova, V. A. Sedavkina, and Z. Yu. Timofeeva
Conditions were developed for the synthesis and production of 1-aryl-5-alkyl(aryl)-3H- and 1-aryl-5-
alkyl(aryl)-5H-pyrrolin-2-ones from the amides and esters of 4-oxoalkanoic acids. It was established
that the yield and ratio of the 3H and 5H isomers depend on the substrate employed in the reaction.
Keywords: 4-oxoalkanamides, 1-aryl-5-alkyl(aryl)-3H-pyrrolin-2-ones, 1-aryl-5-alkyl(aryl)-5H-
pyrrolin-2-ones, 4-oxoalkanoic esters.
Unsaturated five-membered nitrogen-containing 2-oxo heterocycles occupy an important place in
organic chemistry in connection with their discovery in the form of fragments of natural compounds and also the
production of substances with various types of biological activity from them [1]. The production of
1,5-disubstituted pyrrolin-2-ones in the reactions of N-substituted succinimides with the Grignard reagent and of
L-angelicolactone with primary amines has been described [2, 3].
The present paper gives the results of the synthesis of 5-alkyl(aryl)-3H- and 5-alkyl(aryl)-5H-pyrrolin-2-
ones from the amides and esters of 4-alkanoic acids and also the internal esters of these acids — 3H-furan-2-
ones — by their reaction with amines of the aromatic series under various conditions.
5-Alkyl(aryl)-3H-furan-2-ones (1a-g) react with primary aromatic amines (aniline, p-toluidine,
p-bromoaniline) in xylene solution at 120°C with the reagents in a ratio of 1:3 and form mixtures of 1-aryl-5-
alkyl(aryl)-3H-pyrrolin-2-ones (2a-g) and 1-aryl-5-alkyl(aryl)-5H-pyrrolin-2-ones (3a-f). The products were
isolated mainly in the form of the 3H isomers of 1,5-disubstituted pyrrolin-2-ones 2a-g (yields 70-75%). The
amounts of compounds 3a-f in the reaction mixtures were insignificant.
120 oC
+
+
H2N Ar
O
R
O
R
R
O
N
xylene
O
N
1a–g
Ar
Ar
3a–g
2a–g
O
80 oC
O
(CH3CO)2O
RCCH2CH2C
benzene
NHAr
4e,f,h
1-4 a R = CH3, Ar = C6H5; b R = C4H9, Ar = C6H5; c R = i-C4H9, Ar = C6H5;
d R = C5H11, Ar = C6H5; e R = C6H13, Ar = C6H5; f R = C7H15, Ar = C6H5;
g R = C6H5, Ar = C6H4CH3-p; h R = C7H15, Ar = C6H4Br-p
__________________________________________________________________________________________
N. G. Chernyshevskii Saratov State University, Saratov, Russia; e-mail: TimofijiwaSU@info.sgu.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 755-758, June, 2001. Original article
submitted June 11, 1999. Revision submitted June 22, 2000.
694
0009-3122/01/3706-0694$25.00©2001 Plenum Publishing Corporation

It should be noted that 1-(4-methylphenyl)-5-phenylpyrrolin-2-one (2g) only exists in the form of the 3H
isomer both in the solid state and in solution in deuterochloroform, and the 5H form could not be isolated.
Compounds 2a-g and 3a-f are formed through a stage involving opening of the furan ring as a result of
ammonolysis of the initial compounds 1a-g by the aromatic amines. The obtained 4-oxoalkanamides 4 undergo
successive cyclization to the tautomeric 2-aryl-5-alkyl(aryl)-5-hydroxy-2-oxopyrrolidines with further
dehydration and partial isomerization of the 3H form 2a-f to the more stable 5H isomers 3a-f. Isomerization of
compounds (2a-f to compounds 3a-f also takes place during storage in air under room conditions.
The intermediates 4e-g were obtained intentionally under milder conditions as a result of boiling the
furanones 1 with amines in benzene with reduction of the process time by half. Their physical constants are
given in Table 1.
The IR spectra of compounds 4e-g contain the absorption bands of the amide carbonyl at
1589-1540 cm-1, the carbonyl group at 1690-1660 cm-1, and the NH group at 3330-3230 cm-1.
Comparison of the IR spectra of compounds 2a-g and 3a-f shows that the largest difference in them is
observed in the region of the vibrations of the lactam carbonyl. For compounds 2a-g the absorption band of the
C=O group is observed in the region of 1690-1665 cm-1, whereas this band in the isomers 3a-f is observed in the
region of 1705-1700 cm-1.
TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Com-
Empirical
20
bp, °C/mm Hg
nD
Yield, %
Calculated, %
pound formula
C
H
S
C11H11NO
C14H17NO
C14H17NO
C15H19NO
C16H21NO
C17H23NO
C17H15NO
C11H11NO
C14H17NO
C14H17NO
C15H19NO
C16H21NO
C17H23NO
C16H23NO2
C17H25NO2
C17H24BrNO2
76.58
76.36
6.30
6.41
8.01
8.10
155-158/4
157-160/4
165-168/4
170-172/4
168-170/4
172-175/4
179-181
1.5280
1.5340
1.5328
1.5360
1.5368
1.5380
—
63
68
72
72
70
75
82
35
20
17
15
15
10
87
85
76
2a
2b
2c
78.15
7.65
6.45
78.20
7.97
6.52
78.02
78.20
7.71
7.97
6.40
6.52
78.51
8.15
6.02
2d
2e
78.67
8.36
6.12
79.18
79.08
8.80
8.71
5.60
5.76
76.40
8.52
5.30
2f
76.47
8.68
5.63
2g*
3a
3b
3c
79.98
82.00
5.72
5.07
5.61
5.63
76.21
6.35
8.15
165-167/4
165-168/4
170-173/4
175-178/4
176-178/4
178-180/4
98-100
1.5484
1.5523
1.5490
1.5510
1.5560
1.5580
—
76.36
6.41
8.10
78.25
78.20
7.80
7.97
6.50
6.52
78.01
7.57
6.42
78.20
7.97
6.52
78.15
78.67
8.10
8.36
5.98
6.12
3d
3e
78.95
8.60
5.15
79.08
8.71
5.76
76.12
76.47
8.60
8.68
5.05
5.25
3f
4e*
4f*
4h*
73.51
8.60
5.07
73.62
8.88
5.37
74.32
74.24
9.35
9.16
5.00
5.09
99-102
—
56.81
6.70
4.12
55-56
—
57.68
6.83
3.96
_______
*mp, °C
695

1
TABLE 2. The H NMR Spectra of 1-Phenyl-5R-3H-pyrrolin-2-ones 2 and
1-Phenyl-5R-5H-pyrrolin-2-ones 3
Chemical shifts, δ, ppm, J (Hz)
Com-
3-Н
5-Н
pound
R
Ph
4-Н (1H, dd)
(2H, dd)
(1Н, m)
1.60 (3Н, s)
7.15-7.46
7.45-8.00
7.30-7.90
7.25-7.46
7.40-8.00
7.30-7.80
3.00
3.10
3.02
6.07
6.10
6.18
5.20 J34 = 3.30, 3.38
—
—
2a
2b
2c
3a
3b
3c
0.81-1.92 (9Н, m)
0.80-1.94 (9Н, m)
1.60 (3H, d)
0.81-1.92 (9Н, m)
0.80-1.94 (9Н, m)
5.19 J34 = 3.44, 3.54
5.25 J34 = 3.42, 3.55
—
7.14 J45 = 5.74, J34 = 6.54
7.16 J45 = 5.70, J34 = 6.62
7.17 J45 = 5.71, J34 = 6.60
3.95
3.87
3.90
1
In the H NMR spectrum (deuterochloroform) of pyrrolin-2-ones 2a-c there is a signal for the vinyl
proton in the region of 5.19-5.25 ppm (d), and there are also signals for the protons at position 3 of the ring in
the region of 2.70-3.10 ppm, the form of which confirms the structure of the 3H form (Table 2).
In the spectra of compounds 3a-c there are signals of the vinyl protons 3-H and 4-H in the region of
6.07-6.18 and 7.14-7.17 ppm respectively and also a multiplet for the 5-H proton in the region of 2.27-2.35 ppm
(Table 2).
The reaction of the ethyl 4-oxoalkanoates 5a-c with aromatic amines on boiling in xylene leads to the
formation of the desired 1-aryl-5-alkyl(aryl)-3H-pyrrolin-2-ones 2a-c with yields of 63-75% and also the
isomeric 1-aryl-5-alkyl-5H-pyrrolin-2-ones 3a-c with yields of 10-35%.
120 oC
xylene
RCCH2CH2COOC2H5
+ H2NC6H5
5a–c
O
3a–c
2a–c
+
RC CH2CH2COOC2H5
CH CH2COOC2H5
NHAr
RC
NAr
B
A
If the reaction is carried out under mild conditions in solution in ethyl alcohol, the yields of compounds
2a-c and 3a-c in each case are no more than 18% in total, since the reaction takes place through the formation of
the intermediate enamines A and B, the cyclization of which is hindered as a result of the decrease in the
basicity of the nitrogen atom. The evidence for the formation of the intermediates A and B is based on the data
from the 1H NMR spectra recorded for the reaction mixture. Thus, for the tautomer A the signals for the protons
of the group at CH2C=O are observed in the region of 2.77 ppm (d) and those of the vinyl proton are in the
region of 6.15 ppm (t). At 8.2 ppm there is a broad signal for the NH group. In the spectra there are also signals
in the region of 2.12 (m) and 3.63 (m) ppm, corresponding to the protons of the CH2CH2C=O group belonging
to form B. The signals for the protons of the phenyl substituent are in the region of 7.01-7.10 ppm, and those for
the alkyl are in the region of 0.80-1.84 ppm.
The presence of the signal of the vinyl proton and the retention of the signals for the protons of the ester
group in the region of 4.95 (q, 2H) and 2.56 (t, 3H) ppm with spin–spin coupling constant 4.52 Hz make it
possible to conclude that the reaction takes place through a stage involving the formation of the intermediates A
and B.
The physicochemical and spectral characteristics of compounds 2a-g and 3a-f, obtained from the
3H-furanones 1a-g, the amides 4e,f,h, and the esters 5a-c agree fully (Tables 1 and 2).
Thus, it is more expedient to base the synthesis of 1,5-disubstituted 3H-pyrrolin-2-ones on the cyclic
esters of 4-oxoalkanoic acids – 3H-furan-2-ones.
696

EXPERIMENTAL
The IR spectra were recorded on an IKS-29 instrument. The 1H NMR spectra were obtained on a Varian
FT-80A instrument at 80 MHz with deuterochloroform as solvent. The chemical shifts are given on the δ scale
with TMS as internal standard. The yields and characteristics of the obtained compounds are given in Tables 1
and 2. The ethyl 4-oxoalkanoates 5 were obtained by the familiar method [4], and the 5-alkyl-3H-furan-2-ones
were obtained by the method in [5].
1-Aryl-5-alkyl(aryl)-3H-pyrrolin-2-ones (2a-g). A mixture of the compound 1a-g (0.025 mol) and the
aminating agent (0.1 mol) in absolute xylene was boiled for 3 h. The solvent was distilled, and the residue was
submitted to fractional distillation under vacuum.
1-Aryl-5-alkyl-3H-pyrrolin-2-ones (2a-c) and 1-Aryl-5-alkyl-5H-pyrrolin-2-ones (3a-c) Based on
Ethyl 4-Oxoalkanoates (5a-c). A mixture of the compound 5a-c (0.2 mol), aniline (0.3 mol), and absolute
o-xylene (80 ml) was boiled under a reflux condenser for 3 h. The product was isolated by vacuum distillation.
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1.
2.
3.
4.
A. Maxwell and D. Rampersad, J. Natur. Prod., 52, 891 (1989).
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(1960), p. 243.
V. A. Sedavkina, N. A. Morozova, A. Yu. Egorova, and I. G. Ostroumov, Khim. Geterotsikl. Soedin.,
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697