Catalytic hydrogenation of methyl esters of some 1H-pyrazoline-3-carboxylic acids

Article abstract of DOI:10.1007/s10593-010-0408-2

Hydrogenation over Raney nickel of the methyl ester of 1H-pyrazoline-3- carboxylic acid and also of its 4-phenyl and 5-methoxycarbonyl-substituted analogs, leads respectively to 3-aminopyrrolidin-2-one, its 4-phenyl- and 5-methoxycarbonyl derivatives, pre

Full text of DOI:10.1007/s10593-010-0408-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 10, 2009
CATALYTIC HYDROGENATION
OF METHYL ESTERS OF SOME
1H-PYRAZOLINE-3-CARBOXYLIC
ACIDS
V. A. Gorpinchenko1, D. V. Petrov1*, S. S. Lozhkin1,
E. G. Galkin, and V. A. Dokichev1
Hydrogenation over Raney nickel of the methyl ester of 1H-pyrazoline-3-carboxylic acid and also of its
4-phenyl and 5-methoxycarbonyl-substituted analogs, leads respectively to 3-aminopyrrolidin-2-one, its
4-phenyl- and 5-methoxycarbonyl derivatives, predominantly to the trans isomer. Under the same
conditions 1-amino-4-methoxycarbonylpyrrolidin-2-one was obtained from 3,4-di(methoxycarbonyl)-
1H-pyrazoline, but 3,4,5-tri(methoxycarbonyl)-1H-pyrazoline did not react.
Keywords: 3-aminopyrrolidin-2-ones, methyl esters of 1H-pyrazoline-3-carboxylic acids, Raney nickel,
catalytic hydrogenation, cyclocondensation.
At the present time much attention is paid to the search for new regioselective and stereoselective
methods for constructing the pyrrolidine ring, which is a pharmacophoric group of many pharmaceutical
preparations (piracetam, oxiracetam, fenotropil) and physiologically active substances (domoic acid,
oxazolomycin) [1-14]. Pyrrolidines with an amino group in position 3 are of special interest. For example,
3-aminopyrrolidin-2-one, linked with a norbornane fragment, displays antiarrhythmic, anti-inflammatory,
analgesic, and nootropic activity and in the breadth of its therapeutic action exceeds the antiarrhythmic
preparations used at the present time [15, 16].
The use of 1,3-dipolar cycloaddition of diazo compounds to olefins and subsequent catalytic
hydrogenation of the resulting pyrazolinecarboxylic acid esters is one of the most promising approaches to the
synthesis of 3-aminopyrrolidin-2-ones [15-18].
With the aim of obtaining new compounds of the series mentioned the hydrogenation has been studied
in the present work of pyrazoline-3-carboxylic acid methyl ester (1), and also its 4-phenyl- (2), 5-methoxy-
carbonyl- (3), 4-methoxycarbonyl- (4), and 4,5-di(methoxycarbonyl)- (5) substituted analogs.
_______
* To whom correspondence should be addressed, e-mail: dokichev@anrb.ru.
1Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences, Ufa 450054, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1500-1506, October, 2009.
Original article submitted May 20, 2008; revision submitted April 2, 2009.
1202
0009-3122/09/4510-1202©2009 Springer Science+Business Media, Inc.

A preliminary search for optimum reaction conditions showed that the most effective was hydrogenation
in methanol in the presence of Raney nickel at 100oC (hydrogen pressure 7.1 MPa, 5 h) [19], previously
proposed for pyrazoline-3-carboxylic acid methyl ester linked with a norbornene fragment.
Under these conditions 3-aminopyrrolidin-2-one 7 was obtained in 84% yield from ester 1, probably as a
result of cyclocondensation of the intermediate diamine 6a. Hydrogenation of the phenyl-substituted ester 2 was
effected in quantitative yield to a mixture (1.5:1, here and subsequently from 1H NMR spectra) of trans and cis
isomers of 3-amino-4-phenylpyrrolidin-2-one (8). The predominant formation of the trans isomer 9 was also
observed on reduction of the 5-methoxycarbonyl-substituted ester 3 (ratio trans-9:cis-9, 2.4:1). Probably such
stereoselectivity is caused by the fact that the catalytic addition of hydrogen to the C=N double bond occurs
mainly at the sterically least hindered side, in the trans position relative to the substituent in the ring.
CO2Me
NH2
R
NH2
O
CO2Me
R
6a
H2
N
R1
R1
Ni–Ra
NH2
N
H
N
H
7
6a–c
1–3
6b
6c
Ph
Ph
NH2
O
NH2
O
NH2
NH2
+
+
O
O
N
MeO2C
N
H
N
N
H
MeO2C
H
H
cis-9
cis-8
trans-9
trans-8
1, 6a R = R1 = H; 2, 6b R = Ph, R1 = H; 3, 6c R = H, R1 = CO2Me
In difference to esters 1-3, hydrogenation under the same conditions of 4-methoxycarbonyl-substituted
ester 4 led to 1-amino-4-methoxycarbonylpyrrolidin-2-one 10 in 87% yield. The determining stage of the
process is probably the conversion of pyrazolidine 11 into the dimethyl ester of 2-(hydrazinomethyl)fumaric
acid (12) as a result of breaking of the ring at the N(2)–C(3) bond.
MeO2C
CO2Me
CO2Me
NH
MeO2C
H2
N
Ni Ra
N
H
N
H
11
4
MeO2C
H2, Ni Ra
MeO2C
MeO2C
O
N
NH2
CO2Me
O
MeO2C
13
N
NH
NH2
4
H2, Ni Ra
NH2
10
CO2Me
NH
14
NH2
1203

It should be mentioned that under the conditions of hydrogenating compounds 1-4, 3,4,5-tri-
(methoxycarbonyl)pyrazoline 5 (mixture of trans and cis isomers in a ratio of 9:1) did not undergo any
conversion.
The composition and structure of the obtained new compounds 7-10 were confirmed by the results of
elemental analysis, and also by data of IR spectra, 1H, and 13C NMR spectra. The presence in their IR spectra of
an absorption band for the C=O group (in the 1640-1736 region) and for NH2 (in the 2856-3424 cm-1 region)
confirms the formation of an amino lactam fragment.
1
In the H NMR spectra of pyrrolidones 7-9 there were broadened signals for the protons of the NH2
group (at 1.5-2.2 ppm) and the NH ring fragment (6.8-7.7 ppm). In the case of N-aminopyrrolidone 10 the
amino group is displayed at lower field (2.57 ppm), but the signal of the NH fragment was absent. The 13C NMR
spectra of all compounds 7-10 contain a signal for the carbon atom of the C=O ring fragment (at 178.2-180.8
ppm), but in the spectra of esters 9 and 10 a signal was also observed for the C=O group of the COOMe
substituent (at 173.7-174.8 ppm). The presence in the NMR spectra of doubled signals for the H-3 and H-4
protons and the C(3), C(4) atoms in the case of compound 8, and also the H-4 proton and the C(3), C(5) atoms
for compound 9 show the formation of a mixture of two isomers. Comparison of the indicated spectra with the
spectra of the known analogs make it possible to conclude that a trans configuration is the most probable for the
main isomers of 8 and 9. The coupling constant of the main isomer of 3-amino-4-phenylpyrrolidone (8)
J3,4 = 10.1 Hz, and of the minor J3,4 = 7.4 Hz. The signals of the C(3) and C(4) atoms of the first were displaced
relative to the signals of the analogous atoms of the second towards low field (by 3.11 and 5.63 ppm
respectively). A similar picture was also observed in the spectra of the known analog 3-amino-1-benzyl-4-indol-
ylpyrrolid-2-one [20]. The J3,4 of its trans and cis isomers were 9.0 and 8.0 respectively, but the signals of the
C(3), C(4) atoms of the trans isomer were displaced relative to the signals of the analogous atoms of the cis
isomer towards low field (by 3.2 and 4.9 ppm respectively). It should also be noted that the coupling constants
of trans-, and cis-3-amino-4-indolyl-5-(tert-butyldimethylsilyloxy)methylpyrrolid-2-one J3,4 = 11.1 Hz [21], i.e.
close to the J3,4 coupling constants of the main isomer of 8. In the spectra of the main isomer of
3-amino-5-methoxycarbonylpyrrolid-2-one (9), and also of the trans and cis isomers of its analogs 3-hydroxy-
and 3-benzoyloxy-5-methoxy-carbonylpyrrolid-2-ones [22], the signals of the two H-4 protons have the form of
two doublets of doublets of doublets. The similarity of the spectra of the main isomer of 9 and the trans isomers
of the analogs is well shown from this signal, and also their difference from the spectra of the minor isomer of 9
and the cis isomers of the analogs. In the first the signals of the two H-4 protons are disposed significantly more
closely (the distance between them is 0.2-0.4 ppm) than in the second (distance is equal to 0.8-0.9 ppm). In the
first the coupling constants J4,5 (at 6.3-8.3 Hz) differ significantly but for the second this difference is smaller
(0.1-0.2 Hz). We also note that like the signals of atoms C(3), C(4) of the main isomer of 8, the signals of the
C(3), C(5) atoms of the main isomer of 9 are displaced relative to the signals of the analogous atoms of the
minor isomer towards low field (by 0.25 and 0.90 ppm respectively).
The structure of compound 10 was also confirmed by data of mass spectra, in which a peak was
recorded for the molecular ion of m/z 158.070 (21.5%) of composition C6H10N2O3 (calculated 158.16). The
breakdown of this ion was in accordance with the rules for the mass spectral behavior of esters and pyrrolidines
[23, 24]. Interpretation of the spectrum was carried out based on concepts of charge localization and the unpaired
electron [24]. Diagnostic fragments are formed on breaking the heterocycle (fragments F1, F2) and fission of
substituents (F3, F4). On localizing the charge on the carbonyl carbon atom of the ester group not only is fission of
the C–C bond ([M-CO2CH3]+ → F3) brought about but also a C–O bond is broken ([M-OCH3]+ → F5). Analogous
processes were observed on breakdown of the secondary ion F4: (F4 –(CO2CH3)+ → F6; F4 – (OCH3)+ → F7).
The character of the substitution of the studied pyrazolines 1-4 shows a decisive effect on their reactivity
on hydrogenation over Raney nickel and determines the direction of conversion of the pyrazolidine ring formed
as an intermediate. Its breakdown at the N–N or C(3)–N bond leads to a 3- or 1-aminopyrrolidin-2-one.
1204

+
O
+
O
C
C
O
O
N
N
F7
.
.
–OMe
.
NH2
F5
–OMe
+
O
110.021 (12.1)
C5H11NO2
.
O
O
.
+
127.052 (20.1)
C5H7N2O2
O
–NH3
.
O
N
O
–CO2Me
.
+
N
F4
.
NH2
–CO2Me
.
+
O
M
141.045 (31.1)
C6H7O3N
N
158.070 (21.5)
C6H10N2O3
.
+
NH2
F3
O
99.054 (29.7)
C4H7N2O
N
F1
F6
F2
101.048 (100)
C4H7NO2
115.063 (70.5)
C5H9NO2
82.092 (5.1)
C4H4NO
.
.
+
+
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Bruker AM 300 (300 and 75 MHz respectively)
spectrometer in CDCl3, C6D6, or CD3OD, internal standard was TMS. The IR spectra were recorded on UR 20
and Specord M 80 instruments in a thin film or in nujol. The mass spectra were recorded on a high resolution
Thermo Finnigan MAT 95 XP spectrometer at an ionizing voltage of 70 eV (temperature of ionizing chamber
250oC, temperature of direct insertion 50-270oC, heating rate 10oC/min). The precise values of mass numbers of
fragments formed in the source were measured with the aid of a procedure for comparing peaks with a standard
(perfluorokerosene). Melting points were determined on a Boetius microstage. Elemental analysis of compounds
was carried out on a CHN analyzer from HEKAtech Gmbh Analysen–technik's Euro-EA. Preparative separation
was effected on a column of 70-320 mesh silica gel from Lancaster.
The initial compounds 1-5 were synthesized by known procedures [17, 25].
Catalytic Hydrogenation of Pyrazolines (General Method). A solution of pyrazoline 1-5 in MeOH
(50 ml) and Raney nickel, obtained from nickel–aluminum (1:1) alloy (0.1 g), was kept in a rotating steel
autoclave of volume (100 ml) at 100oC and H2 pressure 7.09 MPa for 5 h. The reaction mixture was then cooled,
filtered, and the filtrate evaporated.
3-Aminopyrrolidin-2-one (7). Product 7 (0.85 g, 84%) was obtained from ester 1 (1.3 g, 10.14 mmol)
as colorless crystals of mp 105-106oC (sublimes). IR spectrum, ν, cm-1: 720, 916, 1008, 1040, 1240, 1264, 1288,
1376, 1460, 1676, 2856-3336. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.65 (2H, br. s, NH2); 1.78-1.81 (1H,
m, H-4); 2.42-2.47 (1H, m, H-4); 3.22-3.35 (2H, m, H-5); 3.47 (1H, dd, 3Jcis = 8.3, 3Jtrans = 10.1, H-3); 7.06 (1H,
13
br. s, NH). C NMR spectrum (CD3OD), δ, ppm: 30.96 (C-4); 38.76 (C-5); 52.16 (C-3); 179.58 (C-2). Found,
%: C 47.95; H 8.10; N 28.00. C4H8N2O. Calculated, %: C 47.99; H 8.05; N 27.98.
trans- and cis-3-Amino-4-phenylpyrrolidin-2-one (8). A mixture (0.6 g, 99%) (1.5:1) of the trans and
cis isomers of product 8 was obtained from ester 2 (0.7 g, 3.42 mmol) as colorless crystals of mp 208-209oC
(from a benzene–ether mixture). IR spectrum, ν, cm-1: 704, 760, 1168-1196, 1256, 1440, 1496, 1600,
1205

1712-1736, 3032-3256. Found, %: C 68.20; H 6.80; N 15.88. C10H12N2O. Calculated, %: C 68.16; H 6.86;
N 15.90. The ratio of isomers was determined from the ratios of the areas of the signals of the H-3 protons of the
trans and cis isomers in the 1H NMR spectrum of a mixture.
1
trans-8. H NMR spectrum (C6D6), δ, ppm (J, Hz): 1.49 (2H, br. s, NH2); 2.89 (1H, ddd, J4,3 = 10.1,
J4,5 = 8.7, J4,5 = 8.4, H-4); 3.02-3.17 (2H, m, H-5); 3.39 (1H, d, J3,4 = 10.1, H-3); 7.06-7.22 (5H, m, C6H5); 7.60
(1H, br. s, NH). 13C NMR spectrum (C6D6), δ, ppm: 45.50 (C-5); 50.99 (C-4); 59.06 (C-3); 127.21 (C Ph);
128.71 (C Ph); 128.83 (C Ph); 140.39 (C Ph); 178.25 (C-2).
1
cis-8. H NMR spectrum (C6D6), δ, ppm (J, Hz): 1.49 (2H, br. s, NH2); 2.98 (1H, ddd, J4,3 = 7.4,
J4,5 = 9.3, J4,5 = 9.2, H-4); 3.02-3.17 (2H, m, H-5); 3.46 (1H, d, J3,4 = 7.4, H-3); 7.06-7.22 (5H, m, C6H5); 7.65
(1H, br. s, NH). 13C NMR spectrum (C6D6 ), δ, ppm: 45.36 (C-4); 45.47 (C-5); 55.95 (C-3); 127.27 (C Ph);
128.71 (C Ph); 128.83 (C Ph); 139.00 (C Ph); 179.06 (C-2).
trans- and cis-3-Amino-5-methoxycarbonylpyrrolidin-2-one (9). A mixture (2.4 : 1) (0.55 g, 86%) of
the trans and cis isomers of product 9 was obtained as a colorless oily liquid from ester 3 (0.75 g, 4 mmol). IR
spectrum, ν, cm-1: 756, 800, 1016, 1096, 1440, 1688, 2880-2960, 2960-3424. Found, %: C 45.63; H 6.25;
N 17.75. C6H10N2O3. Calculated, %: C 45.57; H 6.37; N 17.71. The ratio of isomers was determined from the
ratio of the total areas of the signals of the two H-4 protons of the trans and cis isomers in the 1H NMR spectrum
of the mixture.
1
trans-9. H NMR spectrum (CD3OD), δ, ppm (J, Hz): 2.15 (2H, br. s, NH2); 2.16 (1H, ddd, J2 = 13.0,
J4,3 = 10.1, J4,5 = 9.3, H-4); 2.53 (1H, ddd, J2 = 13.0, J4,3 = 8.3, J4,5 = 2.0, H-4); 3.54 (1H, dd, J3,4 = 10.1,
J
3,4 = 8.3, H-3); 3.76 (3H, s, CH3); 4.23 (1H, dd, J5,4 = 9.3, J5,4 = 2.0, H-5); 6.80 (1H, br. s, NH). 13C NMR
spectrum (CD3OD), δ, ppm: 34.93 (C-4); 51.71 (CH3); 54.0 (C-3,5); 174.43 (CO); 180.77 (C-2).
cis-9. 1H NMR spectrum (CD3OD), δ, ppm (J, Hz): 1.81 (1H, ddd, J2 = 12.4, J4,3 = 9.5, J4,5 = 9.1, H-4);
2.15 (2H, br. s, NH2); 2.74-2.83 (1H, m, H-4); 3.54 (1H, dd, J3,4 = 7.3, J3,4 = 9.5, H-3); 3.76 (3H, s, CH3);
13
4.21-4.26 (1H, m, H-5); 6.80 (1H, br. s, NH). C NMR spectrum (CD3OD), δ, ppm: 34.93 (C-4); 51.71 (CH3);
53.10 (C-5); 53.75 (C-3); 173.74 (CO), 180.12 (C-2).
1-Amino-4-methoxycarbonylpyrrolidin-2-one (10). Compound 15 (0.81 g, 87%) was obtained from
ester 4 (1.1 g, 5.9 mmol) as a pale-blue oil, converting into a dark-blue amorphous powder of mp 105oC
1
(decomp.). IR spectrum. ν, cm-1: 676, 1200, 1440, 1640-1728, 2952, 3016-3272. H NMR spectrum (CD3OD), δ,
ppm: 2.57 (2H, br. s, NH2); 3.36-3.45 (1H, m, H-4); 3.50-3.64 (2H, m, H-3); 3.72 (3H, s, CH3); 3.72-3.77 (2H, m,
H-5). 13C NMR spectrum (CD3OD); δ, ppm: 33.91 (C-3); 39.46 (C-4); 45.41 (C-5); 52.60 (CH3); 174.81 (CO);
178.59 (C-2). Mass spectrum (EI, 70 eV), m/z (Irel, %): 158 (22) [M]+, 141 (31) [M-NH3]+, 127 (20) [M-OMe]+, 115
(71) [M-CHON]+, 110 (12) [M-NH3-OMe]+, 101 (100) [M-C2H3ON]+, 99 (30) [M-CO2Me]+, 82 (5)
[M-NH3-CO2Me]+. Found, %: C 45.63; H 6.38; N 17.84. C6H10N2O3. Calculated, %: C 45.57; H 6.37; N 17.71.
The work was carried out with the financial support of the Presidium of the Russian Academy of Sciences
(fundamental investigations programs "Directed synthesis of organic substances with given properties and the
construction of functional materials based on them" and "Fundamental sciences in medicine").
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