Synthesis and structure of aryl(hetaryl)spiropyrrolidones

Article abstract of DOI:10.1007/s11172-012-0131-5

Hydrogenation of the diastereouniform 3-[1-aryl(hetaryl)-2-nitroethyl]-3- methoxycarb-onyl-4-phenyl(3-pyridyl)-2-pyrrolidones is accompanied by intramolecular acylation of the formed amino group to afford the diastereomerically pure 4,4′-aryl(hetaryl)-3,3

Full text of DOI:10.1007/s11172-012-0131-5

Russian Chemical Bulletin, International Edition, Vol. 61, No. 5, pp. 1014—1023, May, 2012
1014
Synthesis and structure of aryl(hetaryl)spiropyrrolidones
V. M. Berestovitskaya,a I. A. Litvinov,b O. S. Vasil´eva,a A. A. Nikonorov,a E. S. Ostroglyadov,a and D. B. Krivolapovb
aA. I. Herzen State Pedagogical University of Russia,
48 nab. Moiki, 191186 Saint Petersburg, Russian Federation.
Eꢀmail: kohrgpu@yandex.ru
bA. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843) 273 1872
Hydrogenation of the diastereouniform 3ꢀ[1ꢀaryl(hetaryl)ꢀ2ꢀnitroethyl]ꢀ3ꢀmethoxycarbꢀ
onylꢀ4ꢀphenyl(3ꢀpyridyl)ꢀ2ꢀpyrrolidones is accompanied by intramolecular acylation of the
formed amino group to afford the diastereomerically pure 4,4´ꢀaryl(hetaryl)ꢀ3,3´ꢀspirobiꢀ
[2ꢀpyrrolidones]. The structures of these diastereomers were characterized by IR, 1H and
13C NMR spectroscopy using heteronuclear correlation experiments, and Xꢀray diffraction
study.
Key words: 2ꢀpyrrolidones, 3,3´ꢀspiropyrrolidones, diastereomers, catalytic hydrogenation.
Spiroconjugated heterocycles are the part of natural
compounds and synthetic medicaments. In particular, the
substances containing spiroheterocyclic systems are strucꢀ
tural components of the antibiotics griseofulvin and rifabꢀ
utin, the synthetic steroidal spironolacton, and the antiꢀ
hypertensive agent irbesartan.1 Of great importance are
compounds containing the pharmacophore heterocycle,
viz., 2ꢀpyrrolidone. They include commonly used mediꢀ
caments, such as pyracetam,1 its phenyl analog phenoꢀ
tropyl (carfedone)2—4, polyvinylpyrrolidones (hemodez,
enterodez, and polydez), the 2ꢀpyrrolidone—pyroglutamic
acid composition5 and others.
of the initially formed amino group to afford spiropyrꢀ
rolidones isolated as the diastereouniform compounds
2a—j,l—n and 2´a,b,g—i (Scheme 1).
Scheme 1
In this regard, the 3,3´ꢀspiropyrrolidone derivatives are
interesting by themselves as potential bioactive comꢀ
pounds, as well as precursors of the previously unknown
representatives of ꢀamino butyric acid and ꢀpyrrolidone
whose molecules contain several heterocycles.
The reduction of the corresponding nitroethylpyrroliꢀ
done carboxylates in the presence of a catalyst can be
a convenient method for the preparation of aryl(hetaryl)ꢀ
spiropyrrolidones, which was first shown in Ref. 6 by two
examples.
Compounds 1a—n and 1´a,b,g—i are obtained readily
by the reaction of 4ꢀaryl(hetaryl)ꢀ3ꢀmethoxycarbonylꢀ2ꢀ
pyrrolidones with 2ꢀaryl(hetaryl)ꢀ1ꢀnitroethenes and isoꢀ
lated as one or two diastereomers 1 and 1´, which are
wellꢀseparable by recrystallization.7,8
R1 = Ph, R2 = Ph (1a, 1´a, 2a, 2´a), 4ꢀMeC6H4 (1b, 1´b, 2b, 2´b),
4ꢀMeOC6H4 (1c, 2c), 4ꢀMe2NC6H4 (1d, 2d), 4ꢀClC6H4 (1e, 2e),
4ꢀO2NC6H4 (1f), 4ꢀH2NC6H4 (2f), 3ꢀpy (1g, 1´g, 2g, 2´g),
2ꢀfuryl (1h, 1´h, 2h, 2´h), 1ꢀmethylbenzimidazolꢀ2ꢀyl
(1i, 1´i, 2i, 2´i), indolꢀ3ꢀyl (1j, 2j);
R1= 3ꢀpy, R2 = Ph (1k, 2g), 4ꢀMeOC6H4 (1l, 2l),
4ꢀClC6H4 (1m, 2m), 3ꢀpy (1n, 2n)
We carried out hydrogenation of the diastereouniform
nitroethylpyrrolidone carboxylates 1a—n and 1´a,b,g—i
with electrolytic hydrogen in the presence of the nickel
catalyst under atmospheric pressure at 18—20 C. The
reduction was accompanied by intramolecular acylation
The resulted spiropyrrolidones are stable highꢀmeltꢀ
ingꢀpoint crystalline substances. Their structures were conꢀ
firmed by IR, 1H and 13C NMR spectroscopy using
heteronuclear correlation experiments (1H—13C HMQC,
1H—13C HMBC) for particular compounds, and Xꢀray
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1009—1018, May, 2012.
1066ꢀ5285/12/6105ꢀ1014 © 2012 Springer Science+Business Media, Inc.

3,3´ꢀSpiropyrrolidones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
1015
diffraction analysis. Note that the IR spectral and eleꢀ
mental analysis data have been described earlier6 for diaꢀ
stereomers 2a and 2´a obtained by hydrogenation of the
corresponding nitroethylpyrrolidone carboxylates. Howꢀ
ever, the melting points given in Ref. 6 (281 and 275 C)
do not agree with those for compounds 2a and 2´a
that were prepared and completely characterized by us
(228—230 and 210—212 C, respectively).
In the IR spectra of spiropyrrolidones 2a—j,l—n and
2´a,b,g—i, the stretching vibration bands of nitro groups
typical of nitroethylpyrrolidone carboxylates disappear
as a natural result and there are broadened absorption
bands of the NH groups in the highꢀfrequency region
(3400—3150 cm–1) (Table 1).
1
The H NMR spectra of compounds 2a—j,l—n and
2´a,b,g—i (see Table 1) contain each one signal set for the
Table 1. Melting points, yields, and IR and 1H NMR spectral data for aryl(hetaryl)ꢀ3,3´ꢀspiropyrrolidones 2a—j,l—n and 2´a,b,g—i
Comꢀ M.p.
poundꢀ /C
Yield
(%)
IR, /cm–1
1Н NMR (DMSOꢀd6),  (J/Hz)
NH C=O
R1
(m)
R2
H(1),
H(4)
H(4´)
H´(5),
H(5)
H´(5´),
H(5´)
H(1´) (s)
2a
228—230
70
85
68
72
86
50
73
71
60
65
3400, 1711,
3274 1675
7.24, 7.31, 7.55
(all m)
7.88
3.39
(d, 1 H,
J = 6.5)
3.39
(d, 1 H,
J = 6.5)
3.24 (d, 1 H,
J = 9.0); 3.80
(dd, 1 H,
J = 6.5, J = 9.0) J = 6.5, J = 9.0)
3.18 (dd, 1 H, 2.92 (dd, 1 H,
J = 9.0, J = 9.5); J = 9.0, J = 9.5);
3.49 (dd, 1 H, 3.28 (dd, 1 H,
3.24 (d, 1 H,
J = 9.0); 3.80
(dd, 1 H,
2´a 210—212
3393, 1712,
3230 1682
7.03, 7.33, 7.54
(all m)
7.97, 3.08 (dd, 4.16 (dd,
8.34
1 H,
J = 8.7,
J = 9.5)
1 H,
J = 8.7,
J = 9.5) J = 8.7, J = 9.0) J = 8.7, J = 9.0)
2b
248—250
3394, 1713,
3286 1680
7.25,
7.32,
7.53
7.00, 7.42 7.85
(both m);
3.25
3.35 (d,
1 H,
J = 6.3)
3.32 (d,
1 H,
J = 6.3)
3.22 (d, 1 H,
J = 9.3); 3.80
(dd, 1 H,
J = 6.3, J = 9.3) J = 6.3, J = 9.3)
3.19 (dd, 1 H, 2.89 (dd, 1 H,
J = 8.9, J = 9.4); J = 8.9, J = 9.4);
3.44 (dd, 1 H, 3.24 (dd, 1 H,
3.18 (d, 1 H,
J = 9.3); 3.77
(dd, 1 H,
(s, Me)
2´b 289—291
3393, 1712,
3253 1680
7.19
6.98, 7.05 7.94, 3.08 (dd, 4.11 (dd,
(both m); 8.31
3.39
(s, Me)
1 H,
J = 8.7,
J = 9.4)
1 H,
J = 8.7,
J = 9.4) J = 8.7, J = 8.9) J = 8.7, J = 8.9)
2c
2d
2e
2f
241—243
252—253
264—265
289—291
272—274
3395, 1710,
3270 1678
7.25,
7.32
7.55
6.88, 7.47 7.92
(both m);
3.71
3.37 (d,
1 H,
J = 6.4)
3.34 (d,
1 H,
J = 6.4)
3.23 (d, 1 H,
J = 9.2); 3.72
(dd, 1 H,
3.18 (d, 1 H,
J = 9.2); 3.72
(dd, 1 H,
(s, Me)
J = 6.4, J = 9.2) J = 6.4, J = 9.2)
3220, 1713,
3165 1675
7.25,
7.55,
7.64
7.33, 7.55 8.00
(both m);
3.00
3.40 (d,
1 H,
J = 6.4)
3.37 (d,
1 H,
J = 6.4)
3.24 (d, 1 H,
J = 9.3); 3.72
(dd, 1 H,
3.27 (d, 1 H,
J = 9.3); 3.75
(dd, 1 H,
(s, Me)
J = 6.4, J = 9.3) J = 6.4, J = 9.3)
3230 1725,
1675
6.55,
7.00
6.57,
6.90
8.14
3.47 (d,
1 H,
J = 6.3)
3.43 (d,
1 H,
J = 6.3)
2.86 (d, 1 H,
J = 9.4); 3.94
(dd, 1 H,
2.90 (d, 1 H,
J = 9.4); 3.94
(dd, 1 H,
(both m)
J = 6.3, J = 9.4) J = 6.3, J = 9.4)
3385, 1731,
3200 1700
7.83,
8.05
7.00,
7.21
8.00, 3.45 (d,
7.67a
3.45 (d,
1 H,
J = 6.5)
3.17 (d, 1 H,
J = 9.4); 3.85
(dd, 1 H,
3.17 (d, 1 H,
J = 9.4); 3.85
(dd, 1 H,
1 H,
J = 6.5)
(both m)
J = 6.5, J = 9.4) J = 6.5, J = 9.4)
2g
3395, 1711,
3267 1680
6.60,
6.97,
7.56
7.33, 7.64, 8.47, 3.45 (d,
8.01, 8.14, 8.69
8.24
3.73 (d,
1 H,
J = 6.6)
2.85 (d, 1 H,
J = 9.1); 3.93
(dd, 1 H,
J = 6.6, J = 9.1) J = 6.6, J = 9.1)
3.25 (dd, 1 H, 3.05 (dd, 1 H,
J = 8.9, J = 9.6); J = 8.9, J = 9.6);
3.55 (dd, 1 H, 3.25 (dd, 1 H,
2.84 (d, 1 H,
J = 9.1); 3.93
(dd, 1 H,
1 H,
J = 6.6)
(all m)
2´g 205—207
3395, 1700,
3213 1676
7.25
7.10—8.51 8.05 3.05 (dd, 4.25 (dd,
(m)
1 H,
J = 8.8,
J = 9.6)
1 H,
J = 8.8,
J = 9.6) J = 8.8, J = 8.9) J = 8.8, J = 8.9)
(to be continued)

1016
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
Berestovitskaya et al.
Table 1 (continued)
Comꢀ M.p.
Yield
IR, /cm–1
1Н NMR (DMSOꢀd6),  (J/Hz)
poundꢀ /C
(%)
NH C=O
R1
(m)
R2
H(1),
H(1´) (s)
H(4)
H(4´)
H´(5),
H(5)
H´(5´),
H(5´)
2h
235—236
72
3356, 1707,
3202 1675
7.25,
7.31,
7.47
6.33,
6.40,
7.59
7.92, 3.65 (d,
3.60 (d,
1 H,
J = 6.4)
3.37 (d, 1 H,
J = 9.0); 3.82
(dd, 1 H,
3.28 (d, 1 H,
J = 9.0); 3.65
(dd, 1 H,
8.01
1 H,
J = 6.4)
(all m)
J = 6.4, J = 9.0) J = 6.4, J = 9.0)
3.22 (dd, 1 H, 2.80 (dd, 1 H,
J = 9.0, J = 9.5); J = 9.0, J = 9.5);
3.50 (dd, 1 H, 3.30 (dd, 1 H,
2´h 215—217
72
60
68
68
63
61
45
3395, 1723,
3282 1684
7.14,
7.22
6.25,
6.49,
7.70
7.91, 3.05 (dd, 4.16 (dd,
8.26
1 H,
1 H,
J = 8.6,
J = 9.5)
J = 8.6,
(all m)
J = 9.5) J = 8.6, J = 9.0) J = 8.6, J = 9.0)
2i
285—287
310—312
170—172
243—245
176—178
333—335
3292, 1720,
3230 1667
6.52,
6.71,
6.91
7.05, 7.52 7.93, 3.70 (d,
3.67 (d,
1 H,
J = 6.7)
2.95 (d, 1 H,
J = 9.1); 4.00
(dd, 1 H,
J = 6.7, J = 9.1) J = 6.7, J = 9.1)
3.23 (dd, 1 H, 3.27 (dd, 1 H,
J = 9.1, J = 9.4); J = 9.1, J = 9.4);
3.58 (dd, 1 H, 3.54 (dd, 1 H,
2.95 (d, 1 H,
J = 9.1); 3.97
(dd, 1 H,
(both m); 8.12
2.85
1 H,
J = 6.7)
(s, Me)
2´i
2j
3230, 1727,
3150 1694
7.23,
7.47
7.23, 7.53, 7.98, 3.15 (dd, 4.52 (dd,
7.70 (all 8.41
m); 3.75
(s, Me)
1 H,
J = 8.7,
J = 9.4)
1 H,
J = 8.7,
J = 9.4) J = 8.7, J = 9.1) J = 8.7, J = 9.1)
3307, 1706,
3231 1684
7.26,
7.35,
7.51
7.05, 7.35, 7.95, 3.36 (d,
7.48, 7.57 8.00, 1 H,
(all m) 11.10b J = 6.2)
3.85 (d,
1 H,
J = 6.2)
3.25 (d, 1 H,
J = 9.6); 3.68
(dd, 1 H,
3.36 (d, 1 H,
J = 9.6); 3.64
(dd, 1 H,
J = 6.2, J = 9.6) J = 6.2, J = 9.6)
2l
3225 1703,
1680
7.33,
8.00,
8.45,
8.64
6.86, 7.48, 8.00
(both m);
3.69
3.42 (d,
1 H,
J = 6.6)
3.32 (d,
1 H,
J = 6.6)
3.21 (d, 1 H,
J = 9.0); 3.75
(dd, 1 H,
3.27 (d, 1 H,
J = 9.0); 3.75
(dd, 1 H,
(s, Me)
J = 6.6, J = 9.0) J = 6.6, J = 9.0)
2m
2n
3260, 1705,
3120 1682
7.34,
8.00,
8.45,
8.66
7.35, 7.58 8.03
(both m)
3.44 (d,
1 H,
3.42 (d,
1 H,
J = 6.7)
3.22 (d, 1 H,
J = 9.0); 3.78
(dd, 1 H,
3.25 (d, 1 H,
J = 9.0); 3.75
(dd, 1 H,
J = 6.7)
J = 6.7, J = 9.0) J = 6.7, J = 9.0)
3395, 1710,
3270 1680
7.34, 8.00, 8.45,
8.69 (all m)
8.06
3.47 (d,
1 H,
3.30 (d,
1 H,
J = 6.5)
3.30 (d, 1 H,
J = 9.1); 3.77
(dd, 1 H,
3.42 (d, 1 H,
J = 9.1); 3.77
(dd, 1 H,
J = 6.5)
J = 6.5, J = 9.1) J = 6.5, J = 9.1)
a The signal relates to the NH2 protons of the pꢀaminophenyl group. b The signal relates to the NH proton of the indole ring.
protons of all structural fragments, which evidences their
diastereo uniformities, the methylene and methyne proꢀ
tons of both rings form two threeꢀspin systems in the reꢀ
gion of  2.85—3.95. For this reason, to interpret correctly
the positions of the signals for the methylene and methyne
protons of spiropyrrolidones 2a—j,l—n and 2´a,b,g—i, we
applied the techniques of twoꢀdimensional heteronuclear
( 46.40), H(5´) ( 3.97) and C(5´) ( 46.40). The analoꢀ
gous correlation is observed in the spectrum of isomer 2´i
(Fig. 2).
Consequently, the analysis of the 1H—13C HMQC
spectra of diastereomers 2i and 2´i allowed distinguishing
the signals for the methyne (H(4) and H(4´)) and methylꢀ
ene (H´(5), H(5), H´(5´), and H(5´)) protons of the
pyrrolidone rings in the multispin systems, as well as deꢀ
termining the chemical shifts for the ipsoꢀC atom of the
phenyl group (С(6) 142.66 and 142.36, respectively) and
the C(13) atom of the benzimidazole ring (С(13) 155.74
and 151.53, respectively) (see Figs 1 and 2; Table 2).
The correctness of the signal assignment for the methꢀ
yne and methylene protons belonging to a certain pyrroliꢀ
1
correlation spectroscopy 1H—13C HMQC and H—13C
HMBC performed for isomers 2a,e,g—j,l—n and 2´a,h,i.
For example, the 1H—13C HMQC spectrum of comꢀ
pound 2i (Fig. 1) displays the correlations between H(4)
( 3.70) and C(4) atoms ( 45.22), H(4´) ( 3.67) and
C(4´) ( 36.40); H´(5) ( 2.95) and C(5) ( 48.75), H(5)
( 4.00) and C(5) ( 48.75); H´(5´) ( 2.95) and C(5´)

3,3´ꢀSpiropyrrolidones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
1017
done ring in the molecules of spiropyrrolidones 2i and 2´i
was confirmed by 1H—13C HMBC. For example, the
1H—13C HMBC spectrum of compound 2i (Fig. 3) disꢀ
plays the correlation between the
H(4) proton ( 3.70) and the ipsoꢀC
atom of the phenyl ring (C(6)
2i (H(4) 3.70 and H(4´) 3.67). Such pattern is typical of all
compounds synthesized (see Table 1).
The analysis of the 1H—13C HMQC and 1H—13C
HMBC spectra of compounds 2a,e,g—j,l—n and 2´a,h,i
allows correct highꢀprobability interpretation of the 1H
and 13C NMR spectra of all obtained spiropyrrolidones
2a—j,l—n and 2´a,b,g—i.
142.66), the H´(5) ( 2.95), H(5)
protons ( 4.00) and the C(6) atom
of the phenyl ring ( 142.66); beꢀ
tween the H(4´) proton ( 3.67) and
the C(13) atom of the benzimidꢀ
We received an important information on the strucꢀ
tures of compounds 2a—j,l—n and 2´a,b,g—i from the
Xꢀray diffraction study of diastereomers 2i and 2´i
(Figs 5—8 and Table 3).
azole ring ( 155.74); between the
H´(5´) ( 2.95), H(5´) protons
( 3.97) and the C(13) atom
( 155.74), as well as between the
H(4) proton ( 3.70) and the orthoꢀC atom of the phenyl
group (C(7) 128.59). The analogous correlation is observed
in the 1H—13C HMBC spectrum of diastereomer 2´i (Fig. 4).
The correlation spectra showed the difference in the
appearance of the H(4) and H(4´) methyne protons of the
pyrrolidone rings: in isomer 2´i, the signals for H(4) and
H(4´) are shifted upfield ( 3.15) and downfield ( 4.52),
respectively, compared to the analogous signals for isomer
Compounds 2i and 2´i crystallize as racemates and
have the following relative configuration of two asymmetꢀ
ric carbon atoms (C(4) and C(4´)): relꢀ(4S,4´S) (R,R)
and relꢀ(4S,4´R) (R,S), respectively. In both molecules,
the lactam rings of spiropyrrolidone are arranged almost
perpendicularly to each other: the dihedral angles beꢀ
tween the ring planes C(5)N(1)C(2)C(3)C(4) and
C(5´)N(1´)C(2´)C(3)C(4´) are 87.5(2) and 86.8(1) in the
molecules of 2i and 2´i, respectively. The fiveꢀmemꢀ
bered rings in both molecules have the envelope conꢀ
formation. In the molecule of 2i, the fragments
C(5)N(1)C(2)C(3) and C(5´)N(1´)C(2´)C(3) are planar
H´(5´)
H(4´)
H´(5)
Ph
H(1)
H(4)
H(1´)
Bza
H(5´)
H(5)

10
0
NCH3
C(4´)
C(4)
C(5´)
C(5)
C(3)
H(4´)/С(4´)
30
H(5´)/С(5´)
H´(5´)/С(5´)
50
70
H(5)/С(5)
H´(5)/С(5)
H(4)/С(4)
90
110
130
150
170
Bza
Bza
Bza
pꢀPh
oꢀPh
Ph
mꢀPh
C(2´)
C(2)

8
7
6
4
3
0
20
Fig. 1. 1H—13C HMQC spectrum of compound 2i in DMSOꢀd6 (here and in Figs 2—4 Bza designates the benzimidazole fragment).

1018
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
Berestovitskaya et al.
H(5)
Bza
H´(5´)
H´(5)
H(1)
H(1´)

H(5´)
Ph
H(4´)
H(4)
60
0
NCH3
30
H´(5´)/С(5´)
C(4´)
H(5´)/С(5´)
H(4´)/С(4´)
C(5´)
C(5)
50
70
H(5)/С(5)
C(4)
C(3)
H(4)/С(4)
90
110
130
150
170
Bza
Bza
mꢀPh
Ph
oꢀPh
pꢀPh
Bza
C(2)
C(2´)
8
7
6
4
3
0
20

Fig. 2. 1H—13C HMQC spectrum of compound 2´i in DMSOꢀd6.
within 0.020(2) and 0.016(2) Å and the deviations of
the C(4) and C(4´) from these planes are 0.480(2) and
0.446(3) Å, respectively. In the molecule of 2´i, the
fragments C(5)N(1)C(2)C(3) and C(5´)N(1´)C(2´)C(3)
Table 2. 13C NMR spectra of compounds 2a,e,g—j,l—n and 2´a,h,i in DMSOꢀd6
Comꢀ
pound

C(2)
C(2´)
C(3) C(4) C(4´) C(5) C(5´)
R1, R2
2а
2´a
2e
173.51 173.51
174.04 174.53
175.85 175.85
173.27 173.20
173.40 173.07
173.76 173.50
175.02 175.75
62.94 46.58 46.58 45.43 45.43 127.70, 128.50, 130.71, 136.72
63.09 45.37 44.87 45.60 42.16 127.71, 128.00, 128.27, 128.77, 129.59, 130.80, 137.23, 137.32
62.45 45.67 45.05 48.55 48.45 126.32, 126.75, 128.23, 128.31, 128.64, 131.17, 141.73, 142.67
62.76 46.86 43.86 45.40 45.00 123.59, 127.81, 128.50, 130.73, 136.43, 138.10, 148.94, 151.50
61.38 47.60 39.30 44.66 43.46 108.07, 111.08, 127.90, 128.68, 130.43, 136.50, 142.52, 152.17
62.12 46.25 39.80 45.33 41.92 108.83, 110.98, 128.00, 128.68, 129.68, 137.19, 143.44, 151.69
62.28 45.22 36.40 48.75 46.40 110.14, 118.78, 121.82, 122.01, 126.59, 128.32, 134.85, 142.66,
143.32, 155.74, 29.10 (Me)
2g
2h
2´h
2i
2´i
2j
173.01 174.25
174.31 174.69
172.98 172.70
173.10 173.10
173.14 173.14
62.64 45.84 40.00 45.43 43.12 110.86, 119.37, 122.28, 122.89, 127.80, 128.33, 130.34, 137.29,
136.75, 142.36, 151.53, 30.09 (Me)
63.00 46.69 37.89 45.41 47.18 109.55, 112.16, 118.23, 119.28, 121.49, 125.63, 127.76, 128.68,
128.76, 130.41, 136.03, 137.39
62.51 47.67 43.56 45.36 44.74 126.83, 127.55, 131.44, 138.02, 140.67, 142.94, 147.88, 159.34,
55.11 (Me)
62.71 46.12 43.90 45.26 44.93 123.65, 128.55, 132.33, 132.55, 132.89, 135.35, 138.14,
149.02, 151.51
2l
2m
2n
62.52 44.71 44.71 44.05 44.05 123.76, 132.37, 138.28, 149.11, 151.57

3,3´ꢀSpiropyrrolidones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
1019

H(4´) H´(5)
H(4)
Bza
H´(5´)
Ph
H(1)
H(1´)
H(5´)
H(5)
10
0
NCH3
H´(5´)/С(4´)
H(4´)/С(5´)
H(1´)/С(4´)
C(4´)
40
C(4)
H(1´)/С(5´)
C(5´)
H(4´)/С(3)
H´(5)/С(4)
C(5)
C(3)
H(4)/С(5)
H(4)/С(3)
60
H(5)/С(3)
H(1)/С(3)
80
100
120
140
160
H(4)/С(7)
H(4)/С(6)
Bza
H(5)/С(6)
Ph
Bza
H´(5)/С(6)
H(4´)/С(13)
H(5´)/С(13)
C(2´)
C(2)
8
7
6
4
3
0
20

Fig. 3. 1H—13C HMBC spectrum of compound 2i in DMSOꢀd6.
are planar within 0.014(3) and 0.010(2) Å and the deviaꢀ
tions of the C(4) and C(4´) atoms are 0.378(3) and 0.446(3) Å,
respectively.
The crystals of compounds 2i and 2´i are stabilized by
the N—H...Oꢀ and O—H...O hydrogen bonds. In the crysꢀ
tal of 2i, there are only the N—H...O hydrogen bonds and
Table 3. Crystallographic parameters and Xꢀray diffraction data for compounds 2i and 2´i
Parameter
2i
2´i
Parameter
2i
2´i
h, k, and l indice
measurement
interval
Number of measured/
independent
reflections
Number of observed
reflections
with I > 2(I)
R
Rw
Rall
Rw,all
Stiffness parameter
Number of refined
parameters
–12  h  13,
–12  k  12,
–20  l  20
13322/
–12  h  12,
–30  k  30,
–12  l  12
22731/
Color, habit
Molecular formula
Molecular weight
Crystal system
Space group
a/Å
Colorless prysmatic
C21H20N4O2 C21H20N4O2•C2H6O
360.41
406.48
Monoclinic
/3543
/4640
P21/n
P21/c
9.836(3)
24.132(6)
9.463(2)
108.683(3)
2128(1)
4
10.775(1)
10.017(1)
16.718(2)
91.018(2)
1804.2(3)
4
2149
2657
b/Å
c/Å
/deg
V/Å3
0.0544
0.1254
0.0955
0.1440
1.04
0.0630
0.1526
0.1164
0.1847
1.05
Z
dcalc/g cm–3
(Мо)/cm–1
F(000)
1.327
1.269
0.88
0.86
760
864
324
355
 range/deg
Rint
2.2    26.0
0.061
2.2    27.0
0.069

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Berestovitskaya et al.

Bza
H(5)
H(5´)
H´(5´)
H´(5)
H(4)
H(1)
Ph
H(1´)
60
H(4´)
0
40
NCH3
H´(5´)/С(4´)
H(1´)/С(4´)
C(4´)
C(5´)
H(4´)/С(5´)
C(5)
C(4)
H(4)/С(5)
H´(5)/С(4)
H(1´)/С(5´)
60
C(3)
H(5)/С(3)
H(4)/С(3)
H(1)/С(3)
H(4´)/С(3)
80
100
120
140
160
Bza
H(4)/С(7)
H(4)/С(6)
H´(5)/С(6)
Ph
H(5)/С(6)
Bza
H(5´)/С(13)
C(2)
H(4´)/С(13)
C(2´)
8
7
6
4
3
0
20

Fig. 4. 1H—13C HMBC spectrum of compound 2´i in DMSOꢀd6.
twoꢀdimensional grid of hydrogen bonds (see Fig. 7). In
the crystal of 2´i, there are both N—H...O and O—H...O
hydrogen bonds and the hydrogen bonding motif is a tape
(see Fig. 8). The parameters for the hydrogen bonds are
given in Table 4.
1
Since the H NMR spectral data of diastereomers 2i
and 2´i agree good with the spectra of all obtained
O(2)
N(1)
C(21)
N(12)
C(13)
C(4´)
C(15)
C(16)
C(17)
C(18)
N(1´)
O(2´)
C(16)
C(5´)
C(2)
C(3)
C(17)
N(14)
C(13)
C(15)
C(4)
C(4´)
C(5)
O(2´)
O(2)
C(2´)
C(20)
C(3´)
C(2´)
C(18)
C(19)
C(21)
C(6)
C(19)
N(1´)
C(2)
N(1)
C(11)
C(6)
C(4)
C(5)
C(20)
N(14)
C(11)
C(5´)
C(7)
C(10)
C(7)
C(8)
C(10)
C(9)
C(8)
C(9)
Fig. 6. Molecular geometry of compound 2´i in the crystal (the
solvate molecule of ethanol is not shown). Anisotropic thermal
vibrations are shown with 50% probability.
Fig. 5. Molecular geometry of compound 2i in the crystal. Anisoꢀ
tropic thermal vibrations are given with 50% probability.

3,3´ꢀSpiropyrrolidones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
1021
Fig. 7. Hydrogen bonding system in the crystal of compound 2i.
spiropyrrolidones 2a—j,l—n and 2´a,b,g—i, one can
assume that all diastereomers of the type 2 have the
configuration of two chiral centers analogous to that in
the molecule of 2i and all diastereomers of the type 2´
have the configuration analogous to that in the moleꢀ
cule of 2´i.
Fig. 8. Hydrogen bonding system in the crystal of compound 2´i.

1022
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
Berestovitskaya et al.
Table 4. Parameters of the intermolecular hydrogen bonds in the crystals of compounds 2i and 2´i
(D is a donor and A is an acceptor)
Bond
D—H...A
d/Å
DHA angle
/deg
Symmetry operation
D—H
H...A
D...A
Crystal of compound 2i
0.92(3) 1.95(3) 2.857(3) 169(3)
N(1)—H(1)...O(2´)
1 – x, –y, 1 – z
N(1´)—H(1´)...N(14)
0.98(3) 2.06(3) 3.031(3) 171.1(19) 3/2 – x, –1/2 + y, 1/2 – z
Crystal of compound 2´i
N(1)—H(1)...O(50)
N(1´)—H(1´)...O(2´)´
O(50)—H(50)...N(14)´
0.79(4) 2.08(4) 2.862(4)
0.92(4) 2.01(4) 2.919(3)
0.88(4) 2.00(4) 2.865(4)
169(3)
170(3)
173(4)
—
–x, –y, 1 – z
1 + x, y, z
Data collection and editing and refinement of the unit cell
parameters were performed by the APEX2 program.13 The analꢀ
ysis of intermolecular interactions and imaging were performed
using the PLATON program.14
The atomic coordinates of structures and their thermal paꢀ
rameters were deposited at the Cambridge Crystallographic Data
Centre (http://www.ccdc.cam.ac.uk) under Nos 883002 and
883003, respectively.
Thus, we obtained a series of novel aryl(hetaryl)ꢀ
containing spiropyrrolidones 2a—j,l—n and 2´a,b,g—i
whose structures were characterized and proved reliably
by IR, 1H and 13C NMR spectroscopy (using 1H—13C
HMQC and 1H—13C HMBC experiments) and Xꢀray difꢀ
fraction study. The 1H NMR spectral analysis showed
that the comparative values of chemical shifts of the H(4)
and H(4´) protons can be used as the analytic signs
upon determination of the stereomerism of compounds
2a—j,l—n and 2´a,b,g—i.
Melting points were measured on a PTP(M) instrument.
3ꢀAryl(hetaryl)ꢀ3ꢀmethoxycarbonylꢀ2ꢀnitroethylꢀ4ꢀphenylꢀ
2ꢀpyrrolidones 1a—j and 1´a,b,g—i and 3ꢀaryl(hetaryl)ꢀ3ꢀmethꢀ
oxycarbonylꢀ2ꢀnitroethylꢀ4ꢀ(3ꢀpyridyl)ꢀ2ꢀpyrrolidones 1k—n
were synthesized according to the published procedures.7,8
relꢀ(4S,4´R)ꢀ4,4´ꢀDiphenylꢀ3,3´ꢀspirobi[2ꢀpyrrolidone] (2a).
A suspension of skeletal nickel catalyst (2.4 g) in ethanol (15 mL)
was saturated with electrolytic hydrogen. 3ꢀMethoxycarbonylꢀ
3ꢀ(1ꢀphenylꢀ2ꢀnitroethyl)ꢀ4ꢀphenylꢀ2ꢀpyrrolidone (1a) (2.5 g,
6.7 mmol) in ethanol (80 mL) was added in the hydrogen stream
and the mixture was hydrogenized until complete absorption of
the calculated amount of hydrogen (0.460 L, 0.02 mol). The
catalyst was separated on a filter and washed by portionwise
decantation with boiling ethanol (3×100 mL). The filtrate was
concentrated by 2/3 of the initial volume under reduced pressure
(15—20 Torr). The crystalline product was separated on a filter
to yield pyrrolidone 2а (1.52 g, 5 mmol, 70%), m.p. 228—230 C
(from ethanol) (cf. Ref. 6: m.p. 281 C (from methanol)). Found (%):
C, 74.41; H, 5.61; N, 8.98. C19H18N2O2. Calculated (%):
C, 74.49; H, 5.92; N, 9.14.
Compounds 2b—n and 2´a,b,g—i were prepared according
to the procedure for compound 2a using the same molar ratios of
reagents.
relꢀ(4S,4´S)ꢀ4,4´ꢀDiphenylꢀ3,3´ꢀspirobi[2ꢀpyrrolidone] (2´a)
was obtained from compound 1´а. The yield was 85%, m.p.
210—212 C (from ethanol) (cf. Ref. 6: m.p. 275 С (from methꢀ
anol)). Found (%): C, 74.58; H, 6.08; N, 8.99. C19H18N2O2.
Calculated (%): C, 74.49; H, 5.92; N, 9.14.
relꢀ(4S,4´R)ꢀ4´ꢀ(4ꢀMethylphenyl)ꢀ4ꢀphenylꢀ3,3´ꢀspirobi[2ꢀ
pyrrolidone] (2b) was obtained from compound 1b. The yield
was 68%, m.p. 248—250 C (from ethanol). Found (%): C, 75.12;
H, 6.29; N, 8.82. C20H20N2O2. Calculated (%): C, 74.98;
H, 6.29; N, 8.74.
relꢀ(4S,4´S)ꢀ4´ꢀ(4ꢀMethylphenyl)ꢀ4ꢀphenylꢀ3,3´ꢀspirobiꢀ
[2ꢀpyrrolidone] (2´b) was obtained from compound 1´b. The
yield was 72%, m.p. 289—291 C (from ethanol). Found (%):
The obtained compounds 2a—j,l—n and 2´a,b,g—i can
be used for the synthesis of novel derivatives of ꢀamino
butyric acid and spiropyracetam and are of interest as
promising bioactive compounds.
Experimental
1
H, 13C{1H}, 1H—13C HMQC, and 1H—13C HMBC spectra
were recorded on Jeol ECX400A spectrometer (399.782 MHz
(1H) and 100. 525 MHz (13C)) in DMSOꢀd6 using the residual
signal for the nonꢀdeuterated solvent as the internal standard.
Vibrational spectra were recorded on IR Prestigeꢀ21 (Shimadzu)
Fourier spectrometer in KBr pellets.
Singleꢀcrystal Xꢀray diffraction studies of compounds 2i and
2´i were performed in the Joint Spectroanalysis Center of the
A. E. Arbuzov Institute of Organic and Physical Chemistry.
The single crystals of compounds 2i and 2´i were obtained by
crystallizaion from ethanol. The Xꢀray diffraction experiment
was performed on a Bruker Smart APEX II CCD autodiffractoꢀ
meter (graphite monochromator, (MoꢀK) = 0.71073 Å, 293 K,
ꢀscan range). The semiempirical account of absorption was
performed according to the SADABS program.9 The crystalloꢀ
graphic data and main refinement parameters for compounds 2i
and 2´i are given in Table 3. The structures were solved by the
direct method using the SIR program.10 A solvate molecule of
ethanol was found in the crystal of 2´i. Hydrogen atoms were
revealed from difference Fourier series and refined in the isoꢀ
tropic approximation. The hydrogen atoms of the ethanol moleꢀ
cule in the structure of 2´i were placed in the geometricalꢀ
ly calculated positions and refined in the riding model. All calꢀ
culations were performed using the SHELXLꢀ9711 and WinGX
programs.12

3,3´ꢀSpiropyrrolidones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
1023
C, 74.04; H, 6.24; N, 8.44. C20H20N2O2. Calculated (%):
C, 74.98; H, 6.29; N, 8.74.
was 63%, m.p. 243—245 C (from ethanol). Found (%): C, 67.36;
H, 5.78; N, 12.47. C19H19N3O3. Calculated (%): C, 67.64;
H, 5.68; N, 12.46.
relꢀ(4S,4´R)ꢀ4´ꢀ(4ꢀChlorophenyl)ꢀ4ꢀ(3ꢀpyridyl)ꢀ3,3´ꢀspiroꢀ
bi[2ꢀpyrrolidone] (2m) was obtained from compound 1m. The
yield was 61%, m.p. 176—178 C (from ethanol). Found (%):
C, 63.45; H, 4.88; N, 12.05. C18H16ClN3O2. Calculated (%):
C, 63.25; H, 4.72; N, 12.29.
relꢀ(4S,4´R)ꢀ4,4´ꢀDi(3ꢀpyridyl)ꢀ3,3´ꢀspirobi[2ꢀpyrrolidone]
(2n) was obtained from compound 1n. The yield was 45%, m.p.
333—335 C (from ethanol). Found (%): C, 66.57; H, 5.32; N, 18.15.
C17H16N4O2.Calculated (%): C, 66.23; H, 5.19; N, 18.18.
relꢀ(4S,4´R)ꢀ4´ꢀ(4ꢀMethoxyphenyl)ꢀ4ꢀphenylꢀ3,3´ꢀspiroꢀ
bi[2ꢀpyrrolidone] (2c) was obtained from compound 1c. The yield
was 86%, m.p. 241—243 C (from ethanol). Found (%): C, 71.46;
H, 5.84; N, 7.94. C20H20N2O3. Calculated (%): C, 71.41;
H, 5.99; N, 8.33.
relꢀ(4S,4´R)ꢀ4´ꢀ(4ꢀN,NꢀDimethylaminophenyl)ꢀ4ꢀphenylꢀ
3,3´ꢀspirobi[2ꢀpyrrolidone] (2d) was obtained from compound
1d. The yield was 50%, m.p. 252—253 С (from ethanol).
Found (%): C, 72.08; H, 6.67; N, 11.72. C21H23N3O2. Calculatꢀ
ed (%): C, 72.18; H, 6.63; N, 12.03.
relꢀ(4S,4´R)ꢀ4´ꢀ(4ꢀChlorophenyl)ꢀ4ꢀphenylꢀ3,3´ꢀspirobiꢀ
[2ꢀpyrrolidone] (2e) was obtained from compound 1e. The yield
was 73%, m.p. 264—265 C (from ethanol). Found (%): C, 66.85;
H, 5.25; N, 8.98. C19H17ClN2O2. Calculated (%): C, 66.96;
H, 5.03; N, 8.88.
relꢀ(4S,4´R)ꢀ4´ꢀ(4ꢀAminophenyl)ꢀ4ꢀphenylꢀ3,3´ꢀspirobiꢀ
[2ꢀpyrrolidone] (2f) was obtained from compound 1f. The yield
was 71%, m.p. 289—291 C (from ethanol). Found (%): C, 70.91;
H, 5.85; N, 13.93. C19H19N3O2. Calculated (%): C, 71.01;
H, 5.96; N, 13.08.
relꢀ(4S,4´R)ꢀ4ꢀPhenylꢀ4´ꢀ(3ꢀpyridyl)ꢀ3,3´ꢀspirobi[2ꢀpyrꢀ
rolidone] (2g). The yield was 60% and m.p. 272—274 С (from
ethanol) upon the synthesis from 1g; the yield was 55%, m.p.
270—272 C (from ethanol) upon the synthesis from 1k. The
sample mixture of the compound obtained by reduction of comꢀ
pound 1g with the sample obtained by reduction of compound
1k showed no temperature depression. Found (%): C, 70.13;
H, 5.64; N, 13.23. C18H17N3O2. Calculated (%): C, 70.34;
H, 5.58; N, 13.67.
relꢀ(4S,4´S)ꢀ4ꢀPhenylꢀ4´ꢀ(3ꢀpyridyl)ꢀ3,3´ꢀspirobi[2ꢀpyrroliꢀ
done] (2´g) was obtained from compound 1´g. The yield was
65%, m.p. 205—207 C (from ethanol). Found (%): C, 70.05;
H, 5.68; N, 13.28. C18H17N3O2. Calculated (%): C, 70.34;
H, 5.58; N, 13.67.
relꢀ(4S,4´S)ꢀ4´ꢀ(2ꢀFuryl)ꢀ4ꢀphenylꢀ3,3´ꢀspirobi[2ꢀpyrroliꢀ
done] (2h) was obtained from compound 1h. The yield was 72%,
m.p. 235—236 C (from ethanol). Found (%): C, 68.46; H, 5.98;
N, 9.47. C17H16N2O3. Calculated (%): C, 68.91; H, 5.44; N, 9.45.
relꢀ(4S,4´R)ꢀ4´ꢀ(2ꢀFuryl)ꢀ4ꢀphenylꢀ3,3´ꢀspirobi[2ꢀpyrroliꢀ
done] (2´h) was obtained from compound 1´h. The yield was
72%, m.p. 215—217 C (from ethanol). Found (%): C, 68.42;
H, 5.97; N, 9.57. C17H16N2O3. Calculated (%): C, 68.91;
H, 5.44; N, 9.45.
relꢀ(4S,4´S)ꢀ4´ꢀ(1ꢀMethylbenzimidazolꢀ2ꢀyl)ꢀ4ꢀphenylꢀ3,3´ꢀ
spirobi[2ꢀpyrrolidone] (2i) was obtained from compound 1i. The
yield was 60%, m.p. 285—287 C (from ethanol). Found (%):
C, 69.52; H, 5.94; N, 15.99. C21H20N4O2. Calculated (%):
C, 69.98; H, 5.59; N, 15.55.
relꢀ(4S,4´R)ꢀ4´ꢀ(1ꢀMethylbenzimidazolꢀ2ꢀyl)ꢀ4ꢀphenylꢀ3,3´ꢀ
spirobi[2ꢀpyrrolidone] (2´i) was obtained from compound 1´i.
The yield was 68%, m.p. 310—312 C (from ethanol). Found (%):
C, 70.02; H, 5.90; N, 15.34. C21H20N4O2. Calculated (%):
C, 69.98; H, 5.59; N, 15.55.
relꢀ(4S,4´R)ꢀ4´ꢀ(Indolꢀ3ꢀyl)ꢀ4ꢀphenylꢀ3,3´ꢀspirobi[2ꢀpyrꢀ
rolidone] (2j) was obtained from compound 1j. The yield was
68%, m.p. 170—172 C (from ethanol). Found (%): C, 73.45;
H, 5.54; N, 12.33. C21H18N3O2. Calculated (%): C, 73.24;
H, 5.27; N, 12.20.
This work was financially supported by the Saint Peꢀ
tersburg Goverment (Program for students, postgraduate
students, and young scientists, Grant 2.5/07ꢀ06/039, PSP
10517) and the Ministry of Education and Science of the
Russian Federation (State Contract No. 16.552.11.7008).
References
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Products], 15th Ed., RIA "New Wave", Moscow, 2007,
116 pp. (in Russian).
2. V. M. Berestovitskaya, M. M. Zobacheva, O. S. Vasil´eva,
Izv. RGPU im. A. I. Gertsena, Ser. Estestv. i Tochnye Nauki
[Bull. of the A. I. Herzen State Pedagogical University of
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Received June 2, 2011;
in revised form October 19, 2011