Chemical transformations of 3-aminopyrrolidin-2-ones of the norbornane and cyclopropane series

Article abstract of DOI:10.1007/s11172-010-0013-7

3-Aminopyrrolidin-2-ones containing a fused norbornane or spirocyclopropane fragment react with benzaldehyde to give azomethines, which can be transformed into N-substituted 3-aminopyrrolidin-2-ones by reduction with sodium borohydride. Diazotization of amino-pyrrolidinones with NaNO₂ in acetic acid results in the elimination of molecular nitrogen and in the formation of acetoxy or unsaturated derivatives (through stabilization of intermediate carbocations). 6-Methylidene4-azaspiro[2.4]heptan-5-one obtained by diazotization of 6-amino-6-methyl-4-azaspiro[2.4]heptan-5-one easily reacts with diazomethane, diazocyclo-propane, and benzonitrile oxide to yield heterocyclic spiranes by means of 1,3-dipolar cycloaddition.

Full text of DOI:10.1007/s11172-010-0013-7

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 339—346, February, 2009
339
Chemical transformations of 3ꢀaminopyrrolidinꢀ2ꢀones
of the norbornane and cyclopropane series*
I. V. Kostyuchenko,a† E. V. Shulishov,a R. R. Rafikov,a A. I. Novichkov,a
V. A. Dokichev,b and Yu. V. Tomilova
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6390. Eꢀmail: tom@ioc.ac.ru
bInstitute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347) 235 6066. Eꢀmail: dokichev@anrb.ru
3ꢀAminopyrrolidinꢀ2ꢀones containing a fused norbornane or spirocyclopropane fragment
react with benzaldehyde to give azomethines, which can be transformed into Nꢀsubstituted
3ꢀaminopyrrolidinꢀ2ꢀones by reduction with sodium borohydride. Diazotization of aminoꢀ
pyrrolidinones with NaNO2 in acetic acid results in the elimination of molecular nitrogen and
in the formation of acetoxy or unsaturated derivatives (through stabilization of intermediate
carbocations). 6ꢀMethylideneꢀ4ꢀazaspiro[2.4]heptanꢀ5ꢀone obtained by diazotization of
6ꢀaminoꢀ6ꢀmethylꢀ4ꢀazaspiro[2.4]heptanꢀ5ꢀone easily reacts with diazomethane, diazocycloꢀ
propane, and benzonitrile oxide to yield heterocyclic spiranes by means of 1,3ꢀdipolar cycloꢀ
addition.
Key words: 3ꢀaminopyrrolidinꢀ2ꢀones, spirocyclopropaneꢀcontaining azaheterocycles,
azomethines, diazotization, 1,3ꢀdipolar addition.
In the last few years, active interest has been shown in
Scheme 1
substituted 3ꢀaminopyrrolidinꢀ2ꢀones as promising bioꢀ
logically active compounds or synthons for target modiꢀ
fication of this heterocyclic fragment.1—5 For instance,
5ꢀaminoꢀexoꢀ3ꢀazatricyclo[5.2.1.02,6]decanꢀ4ꢀone (1)
containing a 3ꢀaminopyrrolidinꢀ2ꢀone fragment (obtained
by catalytic hydrogenation of a methyl diazoacetate—
norbornene adduct with Raney nickel2) has high antiꢀ
arrhythmic and antifibrillatory effects on simulated
arrhythmias of different types. Along with aminopyrroꢀ
lidinꢀ2ꢀones, their 5ꢀspirocyclopropaneꢀcontaining
analogs have also been tested for biological activity.6,7
Recently, we developed a method for the synthesis
of pyrrolidinꢀ2ꢀones containing the amino group and
the spirocyclopropane fragment in positions 3 and 5.8 A
general route to these compounds, in particular, 2ꢀoxospiroꢀ
[pyrrolidineꢀ5,1´ꢀcyclopropanes] 2 and 3 (Scheme 1),
involves catalytic hydrogenation of spiro[1ꢀpyrazolineꢀ
5,1´ꢀcyclopropane]ꢀ3ꢀcarboxylates or the corresponding
amides (Raney Ni, H2, 80—90 bar, 60—70 °C). As with
the formation of compound 1, the reaction occurs by
†
Deceased.
* On the occasion of the 75th anniversary of the foundation
Reagents and conditions: i. H2, Ni—Ra, 110 bar, 25—40 °C;
ii. H2, Ni—Ra, 80—90 bar, 60—70 °C.
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 337—343, February, 2009.
1066ꢀ5285/09/5802ꢀ0339 © 2009 Springer Science+Business Media, Inc.

340
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Kostyuchenko et al.
complete reduction of the pyrazolines to diamines folꢀ
lowed by intramolecular cyclocondensation of the ester
or amide fragment at the distant amino group.
In the present work, we studied some chemical transꢀ
formations of 3ꢀaminopyrrolidinꢀ2ꢀones 1—3 mainly
occurring at the amino group and obtained new spiro
structures with the retained cyclopropane fragment.
very weak coupling between the vicinal H(6) and H(7)
protons, which suggests the transoid arrangement of the
substituents in pyrrolidinone 5 and, consequently, in the
starting and substituted amines 3 and 7.
Polycyclic amine 1, in which the antiꢀisomer is domiꢀ
nant (3.2 : 1), reacts with benzaldehyde or 2,4ꢀdimethoxyꢀ
benzaldehyde in a similar way. Although both isomers are
involved in the reaction, double recrystallization from
benzene—ethyl acetate (1 : 2) gives the individual antiꢀ
isomers of azomethines 8a,b in 62—68% yields (Scheme 3).
In the 1H NMR spectra of compounds 8a,b, the signal for
the methine H(5) proton is shifted downfield by ~0.5 ppm
compared to the analogous signal for antiꢀ1 but the
coupling constant (J5,6 ≈ 3.5 Hz) has the same order of
magnitude,2 which suggests the identical arrangement
of the substituents in these compounds.
Results and Discussion
First of all, we tried to obtain azomethines under mild
conditions and reduce them to substituted amines. A simiꢀ
lar approach has been employed earlier1 for the synthesis
of substituted 3ꢀaminopyrrolidinꢀ2ꢀones acting as farnesylꢀ
transferase inhibitors. We found that condensation of
3ꢀaminopyrrolidinꢀ2ꢀone 2 or 3 with benzaldehyde in
boiling CH2Cl2 in the presence of anhydrous MgSO4
easily leads to azomethine 4 or 5, respectively, in
78—85% yields (Scheme 2). These azomethines can be
smoothly reduced with NaBH4 in methanol to substituted
3ꢀaminopyrrolidinꢀ2ꢀones 6 and 7 in high yields, the other
functional groups being intact.
Scheme 3
Scheme 2
Reagents and conditions: ArCHO, MgSO4, CH2Cl2, 40 °C, 3 h.
Ar = Ph (a), 2,4ꢀC6H3(OMe)2 (b)
Acylation of pyrrolidinones 1 and 3 with acetyl chloꢀ
ride in triethylamine involves only the amino group,
giving the corresponding Nꢀacetyl derivatives 9 and 10
in good yields (Scheme 4). As expected, the ratio of the
Scheme 4
Reagents: i. MgSO4, CH2Cl2; ii. NaBH4, MeOH
2, 4, 6: R1 = Me, R2 = H
3, 5, 7: R1 = H, R2 = CONHC6H4F
The 1H and 13C NMR spectra of azomethines 4 and 5
show signals at δH 8.3—8.4 and δC 158—164 (N=CH).
Instead, the 1H NMR spectra of reduction products 6 and
7 contain two doublets at δH 3.8—4.0 (geminal coupling
constant J = 12—13 Hz) and a broadened singlet at
δH 2.0—2.5 and their 13C NMR spectra exhibit a signal
at δC 48—51 (NH—CH2). The NOESY experiment for
compound 5 revealed a sufficiently strong coupling beꢀ
tween the H(7) proton and either a cyclopropane proton
or the amide proton of the aliphatic fragment, a coupling
between the H(6) proton and the N=CH proton, and a
Reagents and conditions: AcCl, Et3N, CH2Cl2, 10 °C.

Reactions of 3ꢀaminopyrrolidinꢀ2ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
341
antiꢀ and synꢀisomers of product 9 is the same as in the
starting pyrrolidinone 1 (~3.2 : 1). The major, antiꢀisoꢀ
mer was isolated in the individual state by preparative
TLC; in its 1H NMR spectrum, the coupling constant for
the vicinal H(5) and H(6) protons has the same order of
magnitude as in the starting antiꢀ1 (J = 4.4 Hz).
1H NMR spectrum); their structures were not determined.
The ratio of the total integral intensity of the signals
at δ 5.6—6.2 to the intensity of the signal at δ 5.30 for the
single H(5) proton in the isomer synꢀ11 is ~2.6 : 1.
Diazotization of aminopyrrolidinone 3 under similar
conditions gives acetoxy derivative 12 and dihydroꢀ
pyrrolone 13 as major products in a total yield of 70—73%
(Scheme 5). Compounds 12 and 13 were identified from
the 1H and 13C NMR spectra of the reaction mixture. The
only isomer obtained of compound 12 seems to be a
transꢀisomer since the coupling constants for the protons
of the heterocycle (J6,7 = 7.3 Hz) are close to those for
compound 10 (J6,7 = 8.4 Hz).
In contrast to amines 1 and 3, nitrosation of amine 2
with NaNO2 in acetic acid was more efficient, being
accompanied only by deprotonation of the intermediate
carbocation leading to a difficultꢀtoꢀseparate mixture of
unsaturated compounds 14 and 15 (Scheme 6). The ratio
of these isomers varies widely with the solvent and the
acidity of the medium; however, compound 14 containing
the endocyclic double bond is always dominant (Table 1).
We studied transformations of compounds 1—3 under
nitrosation conditions. It is known9 that 3ꢀaminopyrrolinꢀ
2ꢀones, which contain a double bond in the heterocycle,
can be diazotized with NaNO2 in acetic acid to give
3ꢀdiazoꢀ4ꢀpyrrolinꢀ2ꢀones as stable crystalline comꢀ
pounds. However, our attempted synthesis of diazo
compounds from aminopyrrolidinones 1—3 failed under
analogous conditions. It turned out that diazonium ions
generated in the diazotization of compounds 1—3 with
NaNO2 in acetic acid at 10 °C tend to lose a nitrogen
molecule, giving the corresponding carbocations rather
than cyclic diazo amides. Further stabilization of these
carbocations depends on the structure of the starting
aminopyrrolidinone, mainly proceeding through their
deprotonation or addition of an acetate anion. For inꢀ
stance, diazotization of amine 1 gives a mixture of prodꢀ
ucts, isomeric antiꢀ and synꢀ3ꢀacetoxypyrrolidinones 11
being dominant. Their total yield is 50—55%. According
to the 1H NMR data, the ratio of the antiꢀ and synꢀ
isomers of compound 11 is ~1.6 : 1 (for the starting
aminopyrrolidinone 1, 3.2 : 1), which agrees with the
carbocationic reaction mechanism (Scheme 5). Using
preparative TLC, we isolated a fraction containing antiꢀ
and synꢀ11 in a ratio of ~6 : 1 and a fraction with a someꢀ
what lower Rf value. The latter fraction contains synꢀ11
and probably a number of unsaturated compounds resultꢀ
ing from carbocationic rearrangements (the presence of
four signals with different intensities at δ 5.6—6.2 in the
Scheme 6
Methylidenepyrrolidinone 15 is of interest for the
synthesis of heterocyclic spiranes (e.g., by analogy with
1,3ꢀdipolar cycloaddition to 1ꢀsubstituted 5,5ꢀdimethylꢀ
3ꢀmethylidenepyrrolidinꢀ2ꢀone10,11). Its highest yield
1
(up to 20%, H NMR data) was achieved in a nonpolar
Scheme 5
solvent (CCl4) at 30 °C (see Table 1). Because isomers 14
and 15 are difficult to separate, their further transformaꢀ
tions were studied without separation of their reaction
mixture.
It turned out that the action of diazomethane or diazoꢀ
cyclopropane (generated by decomposition of Nꢀcycloꢀ
Table 1. Yields and ratios of compounds 14 and 15 for different
solvents and reaction conditions
Reagents and
solvents
Т/°С
Total
yield (%)
Ratio of
14 and 15
NaNO2/AcOH
NaNO2/(CO2H)2/
Me2CO—H2O
5
5
80
75
8 : 1
10 : 1
NaNO2/AcOH/CCl4 30
88
73
3.5 : 1
6 : 1
BuONO/CH2Cl2/
Me3COOH
5
N2O3/CHCl3
15
48
>50 : 1
Reagents and conditions: AcOH, NaNO2, 10 °C.

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Kostyuchenko et al.
propylꢀNꢀnitrosourea in the presence of Cs2CO3) on a
mixture of compounds 14 and 15 (3.5 : 1) results in
1,3ꢀdipolar cycloaddition involving only isomer 15.
In both cases, the reaction proceeds regioselectively to
give diꢀ and trispyro adducts 16 and 17 in high yields, the
conversion of 3ꢀmethylidenepyrrolidinꢀ2ꢀone (15) being
complete (Scheme 7). Products 16 and 17 can be easily
separated from the unreacted dihydropyrrolone 14 by
preparative TLC.
1,3ꢀdipolar cycloaddition of benzonitrile oxide to the
endocyclic double bond. With an equimolar ratio of
the reagents, the conversion of compound 14 is ~50%
and the yield of product 19 is ~40% (Scheme 8). Accordꢀ
ing to the NOESY data, the hydroxy and phenyl groups in
oxime 19 are on the same side of the double bond.
Scheme 8
Scheme 7
Reagents and conditions: PhCCl=NOH/NEt3, C6H6, 80 °C.
Thus, we demonstrated that 3ꢀaminopyrrolidinꢀ2ꢀones
containing a polycyclic or spirocyclopropane fragment
can be used as new structural units for the targeted synꢀ
thesis of their Nꢀsubstituted derivatives and heterocyclic
diꢀ and trispyrans containing a cyclopropane fragment,
which are of interest as potential biologically active comꢀ
pounds and as structural fragments of more complicated
polycyclic systems.
Experimental
Reagents and conditions: i. CH2N2, Et2O/CH2Cl2;
ii. PhCCl=NOH, NEt3, CH2Cl2; iii.
Cs2CO3, CH2Cl2, 5 °C.
,
1H and 13C NMR spectra were recorded on a Bruker
AVANCE II 300 spectrometer (300 and 75.5 MHz, respectively)
for solutions in CDCl3, (CD3)2CO, or (CD3)2SO with 0.05%
Me4Si as the internal standard. Mass spectra were measured on
a Finnigan MAT INCOSꢀ50 instrument (EI, 70 eV, direct inlet
probe). Elemental analysis was carried out on a Perkin—Elmer
Series II, 2400 C,H,Nꢀanalyzer. NꢀCyclopropylꢀNꢀnitrosoꢀ
urea,12 Nꢀ(4ꢀfluorophenyl)maleimide,13 5ꢀaminoꢀexoꢀ3ꢀazaꢀ
tricyclo[5.2.1.02,6]decanꢀ4ꢀone (1),2 6ꢀaminoꢀ6ꢀmethylꢀ
4ꢀazaspiro[2.4]heptanꢀ5ꢀone (2),8 and benzohydroximoyl chloꢀ
ride14 were prepared as described earlier. Compound 1 was
additionally recrystallized from ethyl acetate; the ratio of its
antiꢀ and synꢀisomers was 3.2 : 1. Thinꢀlayer chromatography
was carried out on Silica gel 60 plates (Merck); spots were
visualized with the iodine vapor. For preparative separation,
Silica gel 60 plates (0.040—0.063 mm, Merck) with a layer thickꢀ
ness of 1.5—1.8 mm were employed. Reagentꢀgrade solvents
(>99.6%) were used without additional purification.
Nꢀ(4ꢀFluorophenyl)ꢀ6ꢀaminoꢀ5ꢀoxoꢀ4ꢀazaspiro[2.4]heptaneꢀ
7ꢀcarboxamide (3). A 100ꢀcm3 steel autoclave was charged with
7ꢀ(4ꢀfluorophenyl)spiro{cyclopropaneꢀ1,4´ꢀ2,3,7ꢀtriazabicycloꢀ
[3.3.0]octꢀ2ꢀeneꢀ6,8ꢀdione} (0.52 g, 2 mmol) (prepared from
diazocyclopropane and Nꢀ(4ꢀfluorophenyl)maleimide by analogy
with the synthesis of the corresponding 4ꢀbromophenyl derivaꢀ
tive),8 ethanol (50 mL), and Raney nickel (0.05 g). Hydrogenaꢀ
tion was carried out at 60 °C and a hydrogen pressure of 80 bar
for 4 h. Then the reaction mixture was filtered and concenꢀ
In the 13C NMR spectra, the signals at δ 37.4 and
97.3 are due to the C(3) and C(5) spiro atoms in comꢀ
pound 16 and the signals at δ 37.3, 95.9, and 70.3 are due
to the C(3), C(5), and C(7) spiro atoms in compound 17,
respectively.
Nitrile oxide generated from benzohydroximoyl chloꢀ
ride and triethylamine in a mixture of compounds 14 and
15 also reacts only with the latter to give cycloadduct 18
in high yield (Scheme 7). As expected, the only one
isomer was obtained, which agrees with the literature data
on 1,3ꢀdipolar cycloaddition of benzonitrile oxide to strucꢀ
turally similar 5,5ꢀdimethylꢀ3ꢀmethylidenepyrrolidinꢀ
2ꢀone.10 The resulting dispirane 18 can easily be isolated
by precipitation from methanol at –15 °C. In the
13C NMR spectrum of this compound, the signals at
δ 35.3 and 87.9 are due to the C(3) and C(5) spiro atoms.
Dihydropyrrolꢀ2ꢀone 14, which was isolated in the
individual state from its mixtures with pyrazolines 16 and
17 by preparative TLC also reacts with benzohydroximoyl
chloride in the presence of triethylamine in boiling benꢀ
zene for 12 h. However, the reaction occurs by acylation
of the N—H bond of dihydropyrrolone 14 rather than by

Reactions of 3ꢀaminopyrrolidinꢀ2ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
343
trated, the residue was treated with ethyl acetate, and the
precipitate that formed was filtered off and dried in vacuo. The
yield of compound 3 was 0.21 g (40%), colorless crystals,
m.p. 256—258 °C. Found (%): C, 59.04; H, 5.55; N, 15.80.
C13H14FN3O2. Calculated (%): C, 59.31; H 5.36; N, 15.96.
Partial MS, m/z (Irel (%)): 263 (3) [M]+, 246 (2), 207 (5), 153
(12), 126 (42), 125 (67), 111 (100), 109 (97). 1H NMR
((CD3)2SO), δ: 0.52, 0.81 (both m, 2 H each, CH2CH2); 2.00
(br.s, 2 H, NH2); 3.11 (d, 1 H, H(7)), J = 8.8 Hz); 3.83 (d, 1 H,
H(6)), J = 8.8 Hz); 7.12, 7.60 (both m, 2 H each, C6H4); 7.81,
10.3 (both br.s, 1 H each, 2 NH). 13C NMR ((CD3)2SO), δ: 7.9,
8.7 (CH2CH2); 37.2 (C(3)); 54.8, 55.4 (C(6), C(7)); 114.8
(d, Cm, JC,F = 22.0 Hz); 128.6 (d, Co, JC,F = 7.8 Hz); 134.6
(d, Cipso, JC,F = 2.3 Hz); 157.7 (d, Cp, JC,F = 239 Hz); 167.8,
175.2 (2 CO).
Synthesis of azomethines (general procedure). A suspension
of 3ꢀaminopyrrolidinꢀ2ꢀones 1—3 (0.38 mmol), benzaldehyde
(0.4 mmol), and anhydrous MgSO4 (0.7 mmol) in CH2Cl2 (5 mL)
was stirred at 40 °C for 3—4 h. The reaction mixture was filtered
and concentrated. The product was extracted from the residue
with ethyl acetate and recrystallized from benzene—AcOEt
(1 : 2) to give azomethines 4, 5, and transꢀ8a,b.
6ꢀBenzylideneaminoꢀ6ꢀmethylꢀ4ꢀazaspiro[2.4]heptanꢀ5ꢀone
(4), 85% yield, m.p. 174—176 °C. Found (%): C, 73.31; H, 7.35;
N, 12.08. C14H16N2O. Calculated (%): C, 73.66; H 7.06;
N, 12.27. MS, m/z (Irel (%)): 228 (2) [M]+, 199 (5), 158 (17),
130 (26), 125 (100). 1H NMR ((CD3)2SO), δ: 0.56—0.77 (m,
4 H, CH2CH2); 1.42 (s, 3 H, Me); 2.19, 2.49 (both d, 1 H each,
H2C(7), 2J = 12.9 Hz); 7.43, 7.72 (both m, 3+2 H, Ph); 7.98
(br.s, 1 H, NH); 8.41 (s, HC=N). 13C NMR ((CD3)2SO), δ:
9.0, 9.3 (CH2CH2); 22.3 (Me); 35.1 (C(3)); 44.7 (C(7)); 67.1
(C(6)); 127.4 (Cm); 128.2 (Co); 130.3 (Cp); 135.8 (Cipso); 158.6
(C=N), 175.1 (CO).
Nꢀ(4ꢀFluorophenyl)ꢀtransꢀ6ꢀbenzylideneaminoꢀ5ꢀoxoꢀ4ꢀazaꢀ
spiro[2.4]heptaneꢀ7ꢀcarboxamide (5), 78% yield, m.p. 222—224 °C.
Partial MS, m/z (Irel (%)): 351 (2) [M]+, 213 (17), 137 (10), 106
(100). 1H NMR ((CD3)2SO), δ: 0.56, 0.70, 0.90 (all m, 1+1+2 H,
CH2CH2); 3.68 (d, 1 H, H(7), 3J = 7.4 Hz); 4.52 (d, 1 H, H(6),
3J = 7.4 Hz); 7.11, 7.56 (both m, 2 H each, C6H4); 7.43, 7.74
(both m, 3+2 H, Ph); 8.18, 10.2 (both br.s, 1 H each, 2 NH);
8.40 (s, HC=N). 13C NMR ((CD3)2SO), δ: 8.4, 8.7 (CH2CH2);
33.4 (C(3)); 52.9 (C(7)); 71.9 (C(6)); 114.8 (d, Cm,, JC,F = 21.7 Hz);
120.8 (d, Co, JC,F = 8.0 Hz); 127.7, 128.3 (Co, Cm); 130.7 (Cp);
134.5 (d, Cipso, JC,F = 2.2 Hz); 135.0 (Cipso); 157.5 (d, Cp,
JC,F = 238 Hz); 164.1 (C=N); 167.6, 171.0 (2 CO).
Hendo(8), Hendo(9), Hanti(10)); 1.52 (m, 3 H, Hexo(8 and 9),
Hsyn(10)); 2.20 (m, 2 H, H(6), H(7)); 2.46 (m, 1 H, H(1));
3.62 (br.d, 1 H, H(5), J5,6 = 3.4 Hz); 3.66 (br.d, 1 H, H(2),
J2,6 = 7.3 Hz); 3.83, 3.84 (both s, 3 H each, 2 OMe); 6.20 (br.s,
1 H, NH); 6.41 (dd, 1 H, H(3´), 4J = 2.3 Hz, 5J = 1.0 Hz); 6.49
(dd, 1 H, H(5´), 3J = 8.6 Hz, 4J = 2.3 Hz); 7.90 (dd, 1 H, H(6´),
3J = 8.6 Hz, 5J = 1.0 Hz); 8.65 (s, HC=N). 13C NMR (CDCl3),
δ: 25.4, 28.2 (C(8), C(9)); 32.2 (C(10)); 40.8, 41.4 (C(1), C(7));
50.2 (C(6)); 55.5, 55.6 (2 OMe); 60.5 (C(2)); 75.4 (C(5));
98.0 (C(3´)); 105.4 (C(5´)); 117.7 (C(1´)); 128.9 (C(6´)); 159.0
(C=N), 160.4, 163.4 (C(2´), C(4´)); 176.5 (CO).
6ꢀBenzylaminoꢀ6ꢀmethylꢀ4ꢀazaspiro[2.4]heptanꢀ5ꢀone (6).
Sodium borohydride (19 mg, 0.5 mmol) was added to a solution
of azomethine 4 (34 mg, 0.15 mmol) in anhydrous methanol
(3 mL). The reaction mixture was stirred at 20 °C for 12 h. The
solvent was removed in vacuo, the residue was treated with
water, and the product was extracted with CH2Cl2. The organic
layer was separated, dried with anhydrous Na2SO4, and conꢀ
centrated in vacuo. The yield of amine 6 was 29 mg (85%),
m.p. 109—111 °C. Partial MS, m/z (Irel (%)): 230 (1) [M]+, 201
(4), 173 (5), 146 (15), 125 (22), 106 (84), 91 (100). 1H NMR
(CDCl3), δ: 0.70, 0.87 (both m, 2 H each, CH2CH2); 1.46 (s,
3 H, Me); 1.88, 2.50 (both d, 1 H each, H2C(7), 2J = 13.0 Hz);
1.95 (br.s, 1 H, NH); 3.73, 3.83 (both d, 1 H each, H2CN,
2J = 12.1 Hz); 6.95 (br.s, 1 H, NH); 7.20—7.40 (m, 5 H, Ph).
13C NMR (CDCl3), δ: 9.8, 12.2 (CH2CH2); 24.6 (Me); 35.9
(C(3)); 41.4 (C(7)); 48.2 (NCH2); 62.7 (C(6)); 127.1 (Cp); 128.4,
128.5 (Co, Cm); 140.3 (Cipso); 179.8 (CO).
Nꢀ(4ꢀFluorophenyl)ꢀtransꢀ6ꢀbenzylaminoꢀ5ꢀoxoꢀ4ꢀazaspiroꢀ
[2.4]heptaneꢀ7ꢀcarboxamide (7) was obtained analogously by
reduction of azomethine 5. The yield was 88%, m.p. 146—148 °C.
Found (%): C, 67.54; H, 5.44; N, 12.12. C20H20FN3O2.
Calculated (%): C, 67.97; H, 5.70; N, 11.89. Partial MS, m/z
(Irel (%)): 353 (2) [M]+, 262 (6), 215 (10), 125 (19), 106 (34),
91 (100). 1H NMR ((CD3)2SO), δ: 0.52, 0.82, 0.96 (all m,
1+2+1 H, CH2CH2); 2.48 (br.s, 1 H, NH); 3.38 (d, 1 H, H(7),
3J = 10.4 Hz); 3.93, 4.07 (both d, 1 H each, NCH2, 2J = 12.7 Hz);
4.04 (d, 1 H, H(6), 3J = 10.4 Hz); 6.98, 7.41 (both m, 2 H each,
C6H4); 7.30 (m, 5 H, Ph); 7.10, 9.3 (both br.s, 1 H each, 2 NH).
13C NMR ((CD3)2SO), δ: 8.6, 9.7 (CH2CH2); 38.4 (C(3)); 50.7
(C(7)); 51.2 (NCH2); 61.5 (C(6)); 115.6 (d, Cm,, JC,F = 22.2 Hz);
121.7 (d, Co, JC,F = 8.0 Hz); 127.8 (Cp); 128.5, 128.8 (Co, Cm);
133.8 (d, Cipso, JC,F = 2.5 Hz); 138.7 (Cipso); 159.4 (d, Cp,
JC,F = 241 Hz); 167.4, 174.6 (2 CO).
antiꢀ and synꢀ5ꢀAcetamidoꢀexoꢀ3ꢀazatricyclo[5.2.1.02,6]ꢀ
decanꢀ4ꢀone (9). Acetyl chloride (47 mg, 0.6 mmol) in CH2Cl2
(0.5 mL) was added dropwise to a stirred solution of amine 1
(100 mg, 0.6 mmol) and triethylamine (67 mg, 0.66 mmol) in
CH2Cl2 (5 mL). The reaction mixture was stirred at 20 °C for
10 h. Then water (3 mL) was added and the product was
extracted with CH2Cl2 (3×10 mL). The combined organic
extracts were dried with anhydrous MgSO4 and concentrated
in vacuo. The yield of compound 9 as a 3.2 : 1 mixture of transꢀ
and cisꢀisomers was 116 mg (93%). The antiꢀisomer was isolated
using preparative TLC on SiO2 with benzene—AcOEt (1 : 3)
as an eluent, yellowish crystals, Rf 0.30, m.p. 64—67 °C.
antiꢀIsomer of compound 9. Found (%): C, 63.06; H, 7.89;
N, 13.16. C11H16N2O2. Calculated (%): C, 63.44; H, 7.74;
N, 13.45. Partial MS, m/z (Irel (%)): 208 (16) [M]+, 190 (5), 166
(24), 165 (70) [M – Ac]+, 150 (10) [M – NHAc]+, 43 (100).
1H NMR (CDCl3), δ: 1.19 (m, 3 H, Hendo(8), Hendo(9), Hanti(10));
antiꢀ5ꢀBenzylideneaminoꢀexoꢀ3ꢀazatricyclo[5.2.1.02,6]ꢀ
decanꢀ4ꢀone (8a), 62% yield, m.p. 168—170 °C. Partial MS,
m/z (Irel (%)): 254 (1) [M]+, 151 (100), 122 (47), 110 (23), 104
(12). 1H NMR (CDCl3), δ: 1.19 (m, 3 H, Hendo(8), Hendo(9),
Hanti(10)); 1.51 (m, 3 H, Hexo(8 and 9), Hsyn(10)); 2.21 (m, 2 H,
H(1), H(7)); 2.48 (ddd, 1 H, H(6), J2,6 = 7.2 Hz, J5,6 = 3.5 Hz,
J = 1.5 Hz); 3.65 (br.d, 1 H, H(5), J5,6 = 3.5 Hz); 3.67 (br.d,
1 H, H(2), J2,6 = 7.2 Hz); 7.08 (br.s, 1 H, NH); 7.40, 7.79
(both m, 3+2 H, Ph); 8.37 (s, HC=N). 13C NMR (CDCl3), δ:
25.3, 28.2 (C(8), C(9)); 32.2 (C(10)); 40.8, 41.2 (C(1), C(7));
49.9 (C(6)); 60.8 (C(2)); 75.3 (C(5)); 128.5 (Co, Cm); 131.0
(Cp); 135.8 (Cipso); 163.4 (C=N), 176.3 (CO).
antiꢀ5ꢀ(2,4ꢀDimethoxybenzylidene)aminoꢀexoꢀ3ꢀazatricycloꢀ
[5.2.1.02,6]decanꢀ4ꢀone (8b), 68% yield, m.p. 188—190 °C.
Partial MS, m/z (Irel (%)): 314 (9) [M]+, 218 (5), 164 (28), 151
1
(100), 122 (89), 110 (43). H NMR (CDCl3), δ: 1.18 (m, 3 H,

344
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Kostyuchenko et al.
1.41 (dq, 1 H, Hsyn(10), 2J = 10.2 Hz, J ≈ 1.8 Hz); 1.55 (m, 2 H,
Hexo(8 and 9)); 2.00 (s, 3 H, Me); 2.18 (m, 2 H, H(6), H(7));
2.44 (m, 1 H, H(1)); 3.54 (br.d, 1 H, H(2), J2,6 = 7.5 Hz); 3.81
(dd, 1 H, H(5), J5,6 = 4.4 Hz, 3J = 6.6 Hz); 6.66 (br.d, 1 H,
NHAc, 3J = 6.6 Hz); 6.70 (br.s, 1 H, NH). 13C NMR (CDCl3),
δ: 23.0 (Me); 25.4, 27.8 (C(8), C(9)); 32.0 (C(10)); 41.1, 41.3
(C(1), C(7)); 49.9 (C(6)); 56.3 (C(2)); 60.1 (C(5)); 170.8 (CO);
176.5 (C(4)). synꢀIsomer of compound 9 (in the mixture with the
transꢀisomer). 1H NMR (CDCl3), nonꢀoverlapping signals, δ:
2.07 (s, 3 H, Me); 2.59 (br.dd, 1 H, H(6), J2,6 = 6.9 Hz,
J5,6 = 10.1 Hz); 3.59 (br.d, 1 H, H(2), J2,6 = 6.9 Hz); 4.58 (dd,
1 H, H(5), J5,6 = 10.1 Hz, 3J = 6.0 Hz); 6.52 (br.d, 1 H, NHAc,
3J = 6.0 Hz); 6.60 (br.s, 1 H, NH). 13C NMR (CDCl3), δ: 22.8
(Me);24.7, 28.5 (C(8), C(9)); 29.7 (C(10)); 36.4 (C(7));
41.7 (C(1); 44.4 (C(6)); 52.3 (C(2)); 60.0 (C(5)); 171.0 (CO);
176.3 (C(4)).
(C(1), C(7)); 49.0 (C(6)); 60.5 (C(2)); 75.4 (C(5)); 170.5 (CO);
174.3 (C(4)).
synꢀIsomer of compound 11. 1H NMR (CDCl3), nonꢀoverꢀ
lapping signals, δ: 2.02, 2.09 (both m, 1 H each, H(1), H(7));
2.20 (s, 3 H, Me); 2.55 (m, 1 H, H(6)); 3.57 (br.d, 1 H, H(2),
J2,6 = 7.0 Hz); 5.30 (d, 1 H, H(5), J5,6 = 10.0 Hz); 6.85 (br.s,
1 H, NH). 13C NMR (CDCl3), δ: 20.6 (Me); 24.7 (C(9)); 28.3
(C(8)); 32.3 (C(10)); 36.2 (C(7)); 41.4 (C(1)); 44.0 (C(6));
60.0 (C(2)); 71.1 (C(5)); 170.5 (CO); 174.1 (C(4)).
Nꢀ(4ꢀFluorophenyl)ꢀtransꢀ6ꢀacetoxyꢀ5ꢀoxoꢀ4ꢀazaspiroꢀ
[2.4]heptaneꢀ7ꢀcarboxamide (12) and Nꢀ(4ꢀfluorophenyl)ꢀ5ꢀoxoꢀ
4ꢀazaspiro[2.4]heptꢀ6ꢀeneꢀ7ꢀcarboxamide (13). Sodium nitrite
(0.19 g, 2.8 mmol) was added at 10 °C to a solution of aminoꢀ
pyrrolidinone 3 (0.13 g, 0.5 mmol) in acetic acid (5 mL) conꢀ
taining CH2Cl2 (0.5 mL). The reaction mixture was stirred for
2 h. Then the acetic acid was removed in vacuo, water (1 mL)
was added, and the product was extracted with ethyl acetate.
The extract was concentrated in vacuo. A fine crystalline subꢀ
stance (0.10 g, 70—73%) consisting of compounds 12 and 13
(molar ratio 1.4 : 1) was isolated by preparative TLC on SiO2
with AcOEt as an eluent, Rf 0.26—0.35.
Nꢀ(4ꢀFluorophenyl)ꢀtransꢀ6ꢀacetamidoꢀ5ꢀoxoꢀ4ꢀazaspiroꢀ
[2.4]heptaneꢀ7ꢀcarboxamide (10). Acetyl chloride (32 mg,
0.4 mmol) in CH2Cl2 (0.5 mL) was added dropwise to a stirred
mixture of amine 3 (105 mg, 0.4 mmol) and triethylamine
(42 mg, 0.42 mmol) in CH2Cl2 (6 mL). The reaction mixture
was stirred at 20 °C for 12 h. Then 0.3 M NaOH (1.4 mL)
was added and the mixture was evaporated in vacuo almost to
dryness. The product was extracted from the residue with ethyl
acetate (3×10 mL). The combined extracts were concentrated
in vacuo. The yield of compound 10 was 110 mg (90%), colorless
small crystals, m.p. 288—290 °C. Found (%): C, 58.66; H, 5.49;
N, 13.37. C15H16FN3O3. Calculated (%): C, 59.01; H, 5.28;
N, 13.76. 1H NMR ((CD3)2SO), δ: 0.49, 0.59, 0.85 (all m,
1+1+2 H, CH2CH2); 1.82 (s, 3 H, Me); 3.52 (d, 1 H, H(7),
J6,7 = 8.4 Hz); 4.60 (dd, 1 H, H(6), J6,7 = 8.4 Hz, 3J = 8.1 Hz);
7.14, 7.59 (both m, 2 H each, C6H4); 7.99, 10.2 (both br.s,
1 H each, 2 NH); 8.44 (br.d, 1 H, NHAc, 3J = 8.1 Hz).
13C NMR ((CD3)2SO), δ: 8.7, 8.8 (CH2CH2); 22.1 (Me); 37.6
(C(3)); 51.2 (C(7)); 53.4 (C(6)); 114.9 (d, Cm,, JC,F = 22.0 Hz);
120.6 (d, Co, JC,F = 8.0 Hz); 134.5 (d, Cipso, JC,F = 2.8 Hz);
157.6 (d, Cp, JC,F = 240 Hz); 167.8, 169.0, 171.2 (3 CO).
antiꢀ and synꢀ5ꢀAcetoxyꢀexoꢀ3ꢀazatricyclo[5.2.1.02,6]decanꢀ
4ꢀone (11). Sodium nitrite (207 mg, 3 mmol) was added at 10 °C
to a solution of aminopyrrolidinone 1 (100 mg, 0.6 mmol) in
acetic acid (5 mL) containing CH2Cl2 (0.5 mL). The reaction
mixture was stirred for 2 h. Then the acetic acid was removed
in vacuo, water (1 mL) was added, and the product was extracted
with CH2Cl2. The extract was concentrated in vacuo. According
to the integral intensities of the nonꢀoverlapping signals at δ 4.82
Compound 12. 1H NMR ((CD3)2CO), δ: 0.80, 0.96 (both m,
CH2CH2); 1.96 (s, 3 H, Me); 3.53 (d, 1 H, H(7), J6,7 = 7.3 Hz);
5.82 (d, 1 H, H(6), J6,7 = 7.3 Hz); 7.08 and 7.63 (both m,
2 H each, C6H4); 7.35, 9.45 (both br.s, 1 H each, 2 NH).
13C NMR ((CD3)2CO), δ: 9.0, 9.5 (CH2CH2); 19.8 (Me); 38.4
(C(3)); 52.6 (C(7)); 73.3 (C(6)); 115.2 (d, Cm,, JC,F = 22.4 Hz);
121.4 (d, Co, JC,F = 8.2 Hz); 135.2 (d, Cipso, JC,F = 2.8 Hz);
157.4 (d, Cp, JC,F = 240 Hz); 167.2, 169.6, 175.8 (3 CO).
Compound 13. 1H NMR ((CD3)2CO), δ: 1.46, 1.91 (both m,
2 H each, CH2CH2); 6.71 (s, 1 H, H(6)); 7.06, 7.72 (both m,
2 H each, C6H4); 7.85, 9.65 (both br.s, 1 H each, 2 NH).
13C NMR ((CD3)2CO), δ: 13.4 (CH2CH2); 37.4 (C(3)); 115.1
(d, Cm,, JC,F = 22.5 Hz); 122.0 (d, Co, JC,F = 8.0 Hz);
126.8 (C(6)); 134.9 (d, Cipso, JC,F = 2.8 Hz); 158.5 (d, Cp,
JC,F = 238 Hz); 164.2, 168.1, 170.0 (C(7), 2 CO).
Nitrosation of 6ꢀaminoꢀ6ꢀmethylꢀ4ꢀazaspiro[2.4]heptanꢀ
5ꢀone (2). Sodium nitrite (1.04 g, 15 mmol) was added at 30 °C
for 30 min to an actively stirred solution of aminopyrrolidinone
2 (1.12 g, 8 mmol) in CCl4 (14 mL) and acetic acid (6 mL). The
reaction mixture was stirred for 2 h, poured into cold water, and
neutralized with K2CO3. The product was extracted with
CH2Cl2. The organic layer was dried with anhydrous Na2SO4
and concentrated in vacuo. The residue was washed with a small
amount of ether and dried in vacuo. According to 1H and
13C NMR data, the resulting colorless crystals (0.87 g, ~88%)
consisted of 6ꢀmethylꢀ4ꢀazaspiro[2.4]heptꢀ6ꢀenꢀ5ꢀone (14) and
6ꢀmethylideneꢀ4ꢀazaspiro[2.4]heptanꢀ5ꢀone (15) in a ratio of
~3.5 : 1. Compound 14 was isolated in the individual state upon
treatment of the mixture of the isomers obtained with diazoꢀ
methane or diazocyclopropane, because it was inert under those
conditions (see below).
1
and 5.30 in the H NMR spectrum of the reaction mixture, the
ratio of antiꢀ and synꢀ11 was ~1.6 : 1. Acetoxy derivatives 11
were isolated by preparative TLC on SiO2 (benzene—AcOEt,
1 : 3) as a ~5 : 1 mixture of the antiꢀ and synꢀisomers (Rf 0.32).
Another fraction with Rf 0.24 contained synꢀ11 (35—40%).
The total yield of compounds 11 was 50—55%. Partial MS, m/z
(Irel (%)): 209 (17) [M]+, 167 (40), 166 (21) [M – Ac]+, 149 (64)
[M – AcOH]+, 106 (84), 67 (90), 43 (100).
antiꢀIsomer of compound 11. 1H NMR (CDCl3), δ: 1.15
(m, 2 H, Hendo(8), Hendo(9)); 1.22 (dq, 1 H, Hanti(10),
2J = 10.8 Hz, J ≈ 1.8 Hz); 1.36 (dq, 1 H, Hsyn(10), 2J = 10.8 Hz,
J ≈ 1.8 Hz); 1.55 (m, 2 H, Hexo(8), Hexo(9)); 2.07 (m, 1 H,
H(6)); 2.14 (s, 3 H, Me); 2.20 (m, 1 H, H(7)); 2.48 (m, 1 H,
H(1)); 3.57 (br.d, 1 H, H(2), J2,6 = 7.0 Hz); 4.82 (d, 1 H, H(5),
J5,6 = 3.6 Hz); 6.98 (br.s, 1 H, NH). 13C NMR (CDCl3), δ:
20.9 (Me); 25.2 (C(9)); 27.9 (C(8)); 32.1 (C(10)); 40.1, 40.9
Compound 14. 1H NMR (CDCl3), δ: 1.23, 1.44 (both m,
2 H each, CH2CH2); 1.92 (d, 3 H, Me, J = 1.6 Hz); 6.40 (dq,
1 H, =CH, J = 1.5 Hz, J = 1.6 Hz); 8.10 (br.s, 1 H, NH).
13C NMR (CDCl3), δ: 10.8 (Me); 11.5 (CH2CH2); 43.3 (C(3));
133.0 (C(6)); 144.8 (C(7)); 175.3 (C=O).
Compound 15. 1H NMR (CDCl3), δ: 0.71, 0.95 (both m,
2 H each, CH2CH2); 2.87 (t, 2 H, H2C(7), J = 2.5 Hz); 5.36,
6.02 (both m, 1 H each, =CH2); 8.30 (br.s, 1 H, NH). 13C NMR
(CDCl3), δ: 11.8 (CH2CH2); 35.1 (C(7)); 36.8 (C(3)); 115.6

Reactions of 3ꢀaminopyrrolidinꢀ2ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
345
1
(=CH2); 140.9 (C(6)); 170.7 (C=O). The yields and ratios of
compounds 14 and 15 for different solvents and reaction condiꢀ
tions are given in Table 1.
[M]+, 214 (14), 144 (36), 117 (18), 82 (40), 77 (100). H NMR
((CD3)2SO), δ: 0.62—0.82 (m, 4 H, CH2CH2); 2.30, 2.46
(both d, 1 H each, H2C(4), 2J = 13.9 Hz); 3.52, 3.69 (both d,
1 H each, H2C(6), 2J = 17.2 Hz); 7.47, 7.69 (both m, 3+2 H,
Ph); 8.33 (br.s, 1 H, NH). 13C NMR ((CD3)2SO), δ: 8.4, 10.2
(CH2CH2); 35.3 (C(3)); 41.2, 41.5 (C(4), C(9)); 87.9 (C(5));
126.2 (Co); 128.4 (Cm); 128.5 (Cipso); 129.8 (Cp); 155.5 (C(8));
171.8 (CO).
6,7,11ꢀTriazadispiro[2.1.45.23]undecꢀ6ꢀenꢀ10ꢀone (16).
A 0.5 M solution of diazomethane (0.8 mL, 0.4 mmol) in ether
was added to a solution of a ~3.5 : 1 mixture (55.4 mg) of isoꢀ
mers 14 and 15 (this corresponds to ~0.1 mmol of compound
15) in CH2Cl2 (1 mL). The reaction mixture was kept at 18 °C
for two days. The solvents were removed in vacuo and the resiꢀ
due was separated by preparative TLC (SiO2, AcOEt). The yield
of dispirane 16 was 14.4 mg (87% with respect to compound 15),
colorless crystals, Rf 0.46, m.p. 156—157 °C The unreacted comꢀ
pound 14 (39 mg) was recovered, Rf 0.32, m.p. 123—124 °C.
Compound 16. Found (%): C, 58.46; H, 6.39; N, 25.20.
C8H11N3O. Calculated (%): C, 58.17; H, 6.71; N, 25.44. Partial
MS (EI), m/z (Irel (%)): 149 (4), 136 (25), 122 (100), 110 (12),
109 (24). 1H NMR (CDCl3), δ: 0.77, 0.96 (both m, 1+3 H,
CH2CH2); 1.46 (ddd, 1 H, Ha(9), 2J = 12.6 Hz, 3J = 8.0 Hz,
3J = 9.0 Hz); 2.28 (ddd, 1 H, Hb(9), 2J = 12.6 Hz, 3J = 6.4 Hz,
3J = 8.1 Hz); 2.37, 2.53 (both d, 1 H each, H2C(4), 2J = 13.3 Hz);
4.66 (m, 2 H, H2C(8)); 5.85 (br.s, 1 H, NH). 13C NMR (CDCl3),
δ: 10.2, 11.7 (CH2CH2); 26.4 (C(9)); 37.4 (C(3)); 40.6 (C(4));
77.6 (C(8)); 97.3 (C(5)); 173.6 (CO).
4ꢀ[Hydroxyimino(phenyl)methyl]ꢀ6ꢀmethylꢀ4ꢀazaspiroꢀ
[2.4]heptꢀ6ꢀenꢀ5ꢀone (19). A mixture of compound 14 (49 mg,
0.4 mmol), benzohydroximoyl chloride (62 mg, 0.4 mmol),
and triethylamine (46 mg, 0.45 mmol) was refluxed in benzene
(5 mL) for 12 h. On cooling, the precipitate that formed was
filtered off, the solvent was removed in vacuo, and the residue
was separated by preparative TLC (SiO2, AcOEt). The
yield of compound 19 was 39 mg (40%), yellow crystals, Rf 0.55,
m.p. 113—115 °C. MS, m/z (Irel (%)): 242 (52) [M]+, 178 (45),
123 (100), 105 (43). 1H NMR (CDCl3), δ: 1.26 (m, 2 H,
CH2CH2); 1.97 (d, 3 H, Me, 4J = 1.5 Hz); 2.48 (m, 2 H,
CH2CH2); 6.54 (q, 1 H, =CH, 4J = 1.5 Hz); 7.08 (tt, 1 H,
Hp, J = 7.7 Hz, J = 1.3 Hz); 7.31 (dd, 2 H, Hm, J = 8.4 Hz,
3J = 7.7 Hz); 7.50 (dd, 2 H, Ho, 3J = 8.4 Hz, 4J = 1.3 Hz);
11.0 (br.s, 1 H, NOH). 13C NMR (CDCl3), δ: 10.6 (Me);
11.6 (CH2CH2); 48.0 (C(3)); 120.4 (Co); 124.0 (Cp); 129.0
(Cm); 129.8 (Cipso); 137.5 (C(6)), 149.6 (C=N); 149.7 (C(7));
173.7 (CO).
3
4
3
Compound 14. Partial MS (EI), m/z (Irel(%)): 123 (100)
[M]+, 122 (38) [M – H]+, 108 (15), 94 (27). For the 1H and
13C NMR spectra, see the section “Nitrosation of compound 2”).
10,11,13ꢀTriazatrispiro[2.1.1.27.25.23]tridecꢀ10ꢀenꢀ12ꢀone
(17). NꢀCyclopropylꢀNꢀnitrosourea (20.5 mg, 0.15 mmol) and
Cs2CO3 (65 mg, 0.2 mmol) were added at 5—7 °C to a solution
of a ~3.5 : 1 mixture (55.3 mg) of isomers 14 and 15 (this correꢀ
sponds to ~0.1 mmol of compound 15) in CH2Cl2 (3 mL). The
reaction mixture was vigorously stirred for 30 min, filtered, and
concentrated in vacuo. The residue was separated by preparative
TLC (SiO2, AcOEt). The unreacted compound 14 (38 mg) was
recovered, Rf 0.32 (its characteristics are given above). The yield
of trispyran 17 was 15.8 mg (83% with respect to compound 15),
colorless crystals, Rf 0.55, m.p. 176—177 °C. Found (%):
C, 62.53; H, 6.70; N, 22.03. C10H13N3O. Calculated (%):
C, 62.81; H, 6.85; N, 21.97. Partial MS, m/z (Irel (%)): 162 (14),
148 (27), 135 (100), 120 (29), 95 (38), 79 (90). 1H NMR
(CDCl3), δ: 0.72, 0.93, 1.11, 1.23 (all m, 1+3+1+1 H, protons
of the cyclopropane rings); 1.66, 2.44 (both d, 1 H each, H2C(4),
2J = 12.7 Hz); 1.81 (m, 2 H, CHCH of the cyclopropane ring
next to the N=N fragment); 2.37, 2.53 (both d, 1 H each,
H2C(6), 2J = 13.3 Hz); 6.32 (br.s, 1 H, NH). 13C NMR (CDCl3),
δ: 10.2, 12.2, 14.6, 15.1 (2 CH2CH2); 33.6 (C(6)); 37.3 (C(3));
41.9 (C(4)); 70.3 (C(7)); 95.9 (C(5)); 173.4 (CO).
8ꢀPhenylꢀ6ꢀoxaꢀ7,11ꢀdiazadispiro[2.1.45.23]undecꢀ7ꢀenꢀ
10ꢀone (18). Benzohydroximoyl chloride (0.16 g, 1 mmol) and
triethylamine (0.11 g, 1.1 mmol) were added to a solution of a
~3.5 : 1 mixture (0.22 g) of isomers 14 and 15 (this corresponds
to ~0.4 mmol of compound 15) in CH2Cl2 (5 mL). The reaction
mixture was kept at 18 °C for 20 h and treated with water
(10 mL). The organic layer was separated and concentrated
in vacuo. The residue was dissolved in a minimum amount of
methanol at 30 °C and left at –15 °C for 12 h. The precipitate
that formed was filtered off, washed with a small amount of
chloroform, and dried in vacuo. The yield of compound 18 was
0.091 g (94%), colorless crystals, m.p. 235—236 °C. Found (%):
C, 69.15; H, 5.88; N, 11.23. C14H14N2O2. Calculated (%):
C, 69.41; H, 5.82; N, 11.56. Partial MS, m/z (Irel (%)): 242 (3)
We are grateful to O. M. Nefedov for his participation
in the discussion and preparation of this study for pubꢀ
lication.
This work was financially supported by the Council
on Grants at the President of the Russian Federation
(Program for State Support of Leading Scientific Schools,
Grant NShꢀ3237.2008.3) and the Presidium of the
Russian Academy of Sciences (Basic Research Subꢀ
program “Development of the Methodology of Organic
Synthesis and Creation of Compounds with Valuable
Applied Properties”).
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Received July 21, 2008;
in revised form December 29, 2008