Synthesis and thermal transformations of pyrazolines obtained by 1,3-dipolar addition of diazocyclopropane to maleimides

Article abstract of DOI:10.1007/s11172-008-0226-1

1-Pyrazolines, obtained by 1,3-dipolar cycloaddition of diazocyclopropane to N-phenyl- and N-cyclohexylmaleimides, undergo complete dediazoniation at 175 °C for 10-16 h with the formation of spiro[3-azabicyclo[3.1.0]hexane-6, 1′-cyclopropane]-2,4-diones 3 (80-89%) and isomeric 3-cyclopropyl-1H- pyrrole-2,5-diones 4. On the example of 3-cyclopropyl-1-phenyl-1H-pyrrole-2,5- dione, it was shown that compounds 4 are able again to enter into 1,3-dipolar cycloaddition with diazomethane or diazocyclopropane with the reaction in the case of diazocyclopropane being nonselective and leading to two regioisomeric pyrazolines in the ratio ～1.7: 1, thermolysis of which, conversely, proceeds with high selectivity and exclusively affords a spiropentane derivative. An action of the aqueous methanol solution of sodium hydroxide on the spiropentanes fused with succinimide fragment and subsequent acidification of the salts obtained lead to stable cis-amidoacids of spiropentane series.

Full text of DOI:10.1007/s11172-008-0226-1

Russian Chemical Bulletin, International Edition, Vol. 57, No. 8, pp. 1712—1717, August, 2008
1712
Synthesis and thermal transformations of pyrazolines obtained by
1,3ꢀdipolar addition of diazocyclopropane to maleimides
I. V. Kostyuchenko,† E. V. Shulishov, R. R. Rafikov, and Yu. V. Tomilov
N. 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
1ꢀPyrazolines, obtained by 1,3ꢀdipolar cycloaddition of diazocyclopropane to Nꢀphenylꢀ
and Nꢀcyclohexylmaleimides, undergo complete dediazoniation at 175 °C for 10—16 h with
the formation of spiro[3ꢀazabicyclo[3.1.0]hexaneꢀ6,1´ꢀcyclopropane]ꢀ2,4ꢀdiones 3 (80—89%)
and isomeric 3ꢀcyclopropylꢀ1Hꢀpyrroleꢀ2,5ꢀdiones 4. On the example of 3ꢀcyclopropylꢀ
1ꢀphenylꢀ1Hꢀpyrroleꢀ2,5ꢀdione, it was shown that compounds 4 are able again to enter into
1,3ꢀdipolar cycloaddition with diazomethane or diazocyclopropane with the reaction in the
case of diazocyclopropane being nonselective and leading to two regioisomeric pyrazolines
in the ratio ~1.7 : 1, thermolysis of which, conversely, proceeds with high selectivity and
exclusively affords a spiropentane derivative. An action of the aqueous methanol solution
of sodium hydroxide on the spiropentanes fused with succinimide fragment and subsequent
acidification of the salts obtained lead to stable cisꢀamidoacids of spiropentane series.
Key words: spiro[1ꢀpyrazolineꢀ3,1´ꢀcyclopropanes], spiropentanosuccinimides, spiropentaneꢀ
1,2ꢀdicarboxylic acid monoamides, diazo compounds, 1,3ꢀdipolar cycloaddition, thermolysis.
Earlier, it was shown that 1,3ꢀdipolar cycloaddition of
fragment and cyclization into imide leads to an increase
in metabolic activity of enzyme PARPꢀ1 (see Ref. 7). The
fragment of 2ꢀamidocyclopropanecarboxylic acid was used
in the development of pseudoꢀtriꢀ and pentapeptides to
make their conformational mobility limited,8,9 as well as
in the synthesis of bicyclic monothioimides, which are of
interest as chiral synthons.10
the in situ generated diazocyclopropane to unsaturated
compounds1—5 is a convenient general method for the
preparation of 1ꢀ or 2ꢀpyrazolines containing spiroꢀjointed
cyclopropane fragment. This process occurs the most
readily for sterically unhindered C=C bonds, which conꢀ
tain electronꢀwithdrawing substituents or which are a part
of strained fragments. In its turn, thermal dediazoniation
of spirocyclopropaneꢀcontaining 1ꢀpyrazolines allows
one to obtain spiropentane derivatives,3—6 though,
desired selectivity is not always achievable in such proꢀ
cesses. In a number of cases, the formation of spiroꢀ
pentanes is accompanied by side reactions, which lead
to isomeric unsaturated compounds.5,6
In the present work, a synthesis of spirocyclopropaneꢀ
containing pyrazolines fused with a succinimide fragment
has been accomplished and their thermal dediazoniaꢀ
tion has been studied in order to prepare spiropentaneꢀ
1,2ꢀdicarboxylic acid derivatives. The latter, similarly to
the cyclopropanedicarboxylic acid derivatives, can be of
interest as synthons for the synthesis of new biologycally
active compounds. Thus, for example, a modification of
4ꢀbenzylꢀ2Hꢀphthalazinꢀ1ꢀone, which is a powerful
inhibitor of poly(adenazindiphosphateribose)polymerase,
by introduction of 2ꢀamidocyclopropanecarboxylic acid
Results and Discussion
Earlier, we have shown2 that Nꢀ(4ꢀmethyl)ꢀ or
Nꢀ(4ꢀbromophenyl)maleimides are suitable substrates
for the synthesis of spirocyclopropaneꢀcontaining pyrazoꢀ
lines fused with a succinimide fragment. Similar process
also occurs on 1,3ꢀdipolar cycloaddition of the in situ
generated diazocyclopropane to Nꢀphenylꢀ and Nꢀcycloꢀ
hexylmaleimides (1a,b). The use of 1.5ꢀfold molar excess
of NꢀcyclopropylꢀNꢀnitrosourea as the source diazoꢀ
cyclopropane and potassium or cesium carbonates as the
bases leads to spirocyclopropaneꢀcontaining heterocycles
2a,b in 70 and 62% yield, respectively (Scheme 1). In this
case, the use of Cs2CO3 instead of K2CO3 decreases the
reaction time by 5—6 times, having virtually no effect on
the yields of the corresponding heterocycles 2a,b. In our
view, the somewhat lower yield of adduct 2b has a reason:
the presence of the cyclohexyl substituent instead of the
aryl one, apparently, decreases polarizability of the
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1680—1685, August, 2008.
1066ꢀ5285/08/5708ꢀ1712 © 2008 Springer Science+Business Media, Inc.

Spiropentanes from maleimides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
1713
molecule in the transition state and makes the reaction of
1,3ꢀdipolar cycloaddition less efficient.
mixture obtained on the thermolysis of pyrazoline 2b,
spiropentane 3b was isolated in 44% yield by cooling down
to –20 °C, whereas the mother liquor was a mixture of
compounds 3b and 4b in the ratio ~4 : 1. The structures
of the compounds obtained were established on the basis of
the 1H and 13C NMR spectra of individual spiropentanes
3a and 3b and their mixtures with the corresponding
cyclopropylꢀ1Hꢀpyrroleꢀ2,5ꢀdiones 4a and 4b. Spiroꢀ
pentanes 3a and 3b are characterized by the presence of
two muliplets in the region 0.9—1.2 ppm and a singlet
at 2.89 or 2.66 ppm, whereas cyclopropylꢀ1Hꢀpyrroleꢀ
2,5ꢀdiones 4a and 4b, by the presence of the signals
of equal intensities at 2.0 (CH) and 6.1 ppm (=CH).
Further, we studied the reactivity of 1ꢀphenylꢀ
1Hꢀpyrroleꢀ2,5ꢀdione 4a in the reaction of 1,3ꢀdipolar
cycloaddition with diazomethane and diazocyclopropane.
The action of ethereal solution of diazomethane (15 °C,
3 days) on the mixture of compounds 3a and 4a obtained
(ratio 1.4 : 1) leads to a complete transformation of
1Hꢀpyrroleꢀ2,5ꢀdione 4a into 2,3,7ꢀtriazabicyclo[3.3.0]ꢀ
octeneꢀ6,8ꢀdione 5 (Scheme 2). In this case, the succinꢀ
imide fused with the spiropentane fragment remains
intact. The addition of CH2N2 to the double bond of
1Hꢀpyrroleꢀ2,5ꢀdione 4a proceeds with high selectivity
with the cyclopropyl substituent being placed in position
1 of the bicyclic system, which is indicated by the presꢀ
Thermolysis of spiro[pyrazolinecyclopropanes] 2a,b
obtained was carried out by reflux of their solutions in
oꢀdichlorobenzene for 10—16 h until evolution of nitroꢀ
1
gen was stopped. According to the TLC and H NMR
spectral data, the complete conversion of starting pyrazoꢀ
lines and the formation in every case of two isomeric
compounds, viz., fused spiropentanes 3a,b and 3ꢀcycloꢀ
propylꢀ1Hꢀpyrroleꢀ2,5ꢀdiones 4a,b, are observed. The
nature of substituent in the succinimide ring has conꢀ
siderable influence on the ratio of the compounds formed:
thus, in the case of cyclohexyl substituent the selectivity
of the process with respect to the forming spiropentane 3b
is somewhat higher than in the case of phenyl substituent
(Scheme 1).
Scheme 1
1
ence of the threeꢀspin system CH2CH in the H NMR
spectrum and by position of the quaternary C atom at
103.2 ppm in the 13C NMR spectrum.
Scheme 2
O
O
Ph
N
N
CH2N2
N
Ph
N
Et2O/CH Cl2
2
O
R = Ph (a), C H (b). 3a : 4a ∼ 4 : 1; 3b : 4b ∼ 8 : 1.
6
11
O
Reagents and conditions: i, K CO (Cs CO ), CH Cl , 5—7 °C.
2
3
2
3
2
2
4a
5 ( 100%)
~
The observed dediazoniation of pyrazolines 2a,b,
despite the side formation of cyclopropylꢀ1Hꢀpyrroleꢀ
2,5ꢀdiones 4, turned out to be more selective in compariꢀ
son, for example, with the earlier described11 thermolysis
of 1ꢀpyrazoline, obtained by addition of diazomethane to
Nꢀphenylmaleimide, which resulted, along with cycloꢀ
propane derivative, in isomeric unsaturated compounds,
viz., 3ꢀmethylꢀ1ꢀphenylꢀ3ꢀpyrrolineꢀ2,5ꢀdione and
3ꢀmethyleneꢀ1ꢀphenylpyrrolidineꢀ2,5ꢀdione, as well as
2ꢀpyrazoline, the product of isomerization of starting
1ꢀpyrazoline, in the ratio 5 : 6 : 1.5 : 1, respectively.
The spiropentane derivative of succinimide 3a was
successfully isolated in the individual state by partial crysꢀ
tallization of the reaction mixture from benzene—light
petroleum (1 : 2) with the yield of the target product beꢀ
ing 52%. According to the 1H NMR spectrum, the filtrate
was a mixture of compounds 3a and 4a in the ratio 1.4 : 1.
Similarly, from the ethereal solution of the reaction
In contrast to diazomethane, 1,3ꢀdipolar cycloaddiꢀ
tion of diazocyclopropane to the double bond of 1Hꢀpyrꢀ
roleꢀ2,5ꢀdione 4a proceeds unselectively and leads
to a mixture of spiro{2,3,7ꢀtriazabicyclo[3.3.0]octeneꢀ
4,1´ꢀcyclopropanes} 6 and 7 containing the cyclopropyl
substituent in positions 1 or 5 of the bicyclic system
(Scheme 3). The lack of selectivity of the addition of
diazocyclopropane to the unsymmetrically substituted
cyclic double bond was observed earlier, for example,
during its interaction with 1ꢀmethylcyclopropeneꢀ3ꢀcarꢀ
boxylate.12 We used approximately threeꢀfold molar
excess of NꢀcyclopropylꢀNꢀnitrosourea for the generation
of diazocyclopropane and complete conversion of
1Hꢀpyrroleꢀ2,5ꢀdione 4a into adducts 6 and 7.
Isomer 6 was isolated from the reaction mixture by
crystallization from ether, whereas isomer 7 by preparaꢀ
tive TLC of the residue left after evaporation of ether.

1714
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
Kostyuchenko et al.
Scheme 3
in the case of phenyl substituent and ~3.3 : 1 in the case of
cyclohexyl one.
Scheme 4
O
CONHR
NaOH
N
R
MeOH/HO
2
CO2Na
10a,b
O
3a,b
2% HCl/H2O
MeONa (2%)
MeOH
– MeOH
∆
CONHR
CONHR
CH2N2
Et2O/MeOH
6 : 7 = 1.7 : 1
CO2H
CO2Me
9a,b
11a,b
According to the 1H and 13C NMR spectra, the signals of
the angular fragment H—C in isomer 6 have chemical
shifts of δH 2.48 and δC 72.9, whereas in isomer 7, δH 5.40
and δC 94.0, that indicates the bonding of this fragment
with the C or N atoms of the pyrazoline ring.
In contrast to pyrazoline 2a, thermal dediazoniation
of pyrazoline 6 proceeds with high selectivity and leads to
spiropentane 8 (Scheme 3), that is indicated by the only
set of signals in the 1H and 13C NMR spectra.
R = Ph (a), cycloꢀC H (b).
6
11
Interestingly, the hydrolysis of unsymmetrical spiroꢀ
pentanosuccinimide 8 upon action of NaOH in MeOH—
H2O (~2 : 1) proceeds strictly selectively and after acidifiꢀ
cation with 2% aq. HCl gives only one regioisomer of
amidoacid 12 (Scheme 5). This assignment was made
based on the literature data,14 according to which the
Cꢀsubstituted succinimide ring opening with bases always
proceeds by the nucleophilic attack at the sterically less
hindered C=O group.
It is known13 that the fused succinimide ring can be
easily opened by the action of bases. Earlier, we have
shown2 that the action of even catalytic amount of NaOH
in ethanol on the fused succinimidopyrazolines leads to
the succinimide ring opening with the formation of
Nꢀarylꢀ6ꢀethoxycarbonylꢀ4,5ꢀdiazaspiro[2.4]heptꢀ5ꢀeneꢀ
7ꢀcarboxamides. However, in contrast to succinimidoꢀ
pyrazolines, succinimides with the fused spiropentane
fragment turned out to be rather resistant to the action of
bases. Thus, the action of sodium methoxide (~2 mol. %)
in methanol on compounds 3a and 3b at room temperaꢀ
ture for 120 h leads to amidoesters of spiropentaneꢀ
1,2ꢀdicarboxylic acid 9 with conversion of 50% in the
case of compound 3a and ~10% in the case of compound
3b. Moreover, a reflux of the mixture of compounds 3a
and 9a formed with evaporation of ethanol leads to a
reverse cyclization of amidoester 9a formed back into the
starting spiropentanosuccinimide 3a. However, the
action of NaOH in aq. methanol on succinimides 3
affords the corresponding salts of spiropentanecarboxylic
acids 10, which on acidification with 2% aq. hydrochloric
acid are converted into stable amidoacids 11 in 84—87%
yield (Scheme 4). The latter upon treatment with ethereal
solution of diazomethane are converted into methyl
esters 9a and 9b, which can partially cyclize into the
corresponding succinimides 3a or 3b. According to the
1H NMR spectra of the reaction mixtures, the ratio of
amidoesters to the corresponding succinimides was ~4 : 1
Scheme 5
Thus, the methodology suggested by us for the syntheꢀ
sis of spirocyclopropaneꢀcontaining pyrazolines fused with
a succinimide fragment and their thermal dediazoniation
into the corresponding spiropentanes is rather simple
and convenient method for the preparation of new
polycyclopropane compounds, in particular, Nꢀsubstituted
monoamides of cisꢀspiropentaneꢀ1,2ꢀdicarboxylic acid as
new synthons for the modification of biologically active
compounds.
Experimental
1H and 13C NMR spectra were recorded on a Bruker ACꢀ200
(200 and 50.3 MHz) and Bruker AMꢀ300 spectrometers (300
and 75.5 MHz, respectively) for solutions in CDCl3 or (CD3)2SO

Spiropentanes from maleimides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
1715
containing 0.05% Me4Si as the internal standard. Mass spectra
were recorded on a Finnigan MAT INCOSꢀ50 instrument (EI,
70 eV, direct inlet). NꢀCyclopropylꢀNꢀnitrosourea,15 Nꢀphenylꢀ
(1a)16 and Nꢀcyclohexylmaleimides (1b)17 were obtained according
to the described procedures. Thinꢀlayer chromatography was
performed on Silica gel 60 plates (Merck) with visualization
by iodine vapors. Chromatographic plates (silica gel 60,
0.040—0.063 mm, Merck) with 1.8 mm layer were used for
preparative isolations. Solvents of chemically pure grade (>99.6%)
were used without additional purification.
Synthesis of 7ꢀarylspiro[2,3,7ꢀtriazabicyclo[3.3.0]octꢀ2ꢀeneꢀ
4,1´ꢀcyclopropane]ꢀ6,8ꢀdiones (2a,b) (general procedure). Potasꢀ
sium carbonate (4.61 g, ~26 mmol) containing ~20% H2O, or
Cs2CO3 (8.47 g, ~26 mmol) was added to a mixture of maleimide
1a (1.91 g, 11 mmol) or 1b (1.97 g, 11 mmol) and Nꢀcyclopropylꢀ
Nꢀnitrosourea (2.16 g, 16 mmol) in CH2Cl2 (30 mL) at 5—7 °C
and this was vigorously stirred at this temperature for 160—180
or 30 min, respectively. Then the reaction mixture was filtered
and washed with CH2Cl2, the solvent was evaporated in vacuo
and pyrazolines 2a,b were obtained by recrystallization of the
residue from benzene.
Compound 2a, the yield was 70%, m.p. 155—156 °C. Found
(%): C, 64.98; H, 4.79; N, 17.21; C13H11N3O2. Calculated (%):
C, 64.72; H, 4.60; N, 17.42. Partial MS, m/z (Irel (%)): 241 (1)
[M]+, 213 (7) [M – N2]+, 185 (11), 184 (14), 94 (32), 66 (100).
1H NMR (CDCl3), δ: 1.44, 1.92 (both m, 1+3 H, CH2CH2);
3.16 (d, 1 H, H(5), 3J = 8.4 Hz); 6.04 (d, 1 H, H(1), 3J = 8.4 Hz);
7.23, 7.45 (both m, 2+3 H, Ph). 13C NMR (CDCl3), δ: 11.3,
16.8 (CH2CH2); 41.6 (C(5)); 73.7 (C(4)); 91.7 (C(1)); 126.3
(oꢀC); 128.4 (ipsoꢀC); 129.1 (pꢀC); 129.3 (mꢀC); 168.7 and
173.6 (2 CO).
1.08 (m, 4 H, CH2CH2); 1.96 (m, 1 H, CH); 6.14 (s, 1 H,
=CH); 7.20—7.50 (m, Ph). 13C NMR (CDCl3), δ: 8.4 (CH);
12.0 (CH2CH2); 120.7 (C(4)); 126.0 (oꢀC); 127.6 (pꢀC); 128.6
(mꢀC); 131.6 (ipsoꢀC); 153.5 C(3); 169.2, 169.7 (2 CO).
Thermolysis of bicyclic pyrazoline 2b. A solution of pyrazoline
2b (0.99 g, 4 mmol) in oꢀdichlorobenzene (5 mL) was heated at
180 °C until the gas evolution was stopped (~16 h). Then, the
solvent was evaporated in vacuo at 0.2 Torr. According to the 1H
and 13C NMR spectra, the residue contained two compounds:
3ꢀcyclohexylspiro[3ꢀazabicyclo[3.1.0]hexaneꢀ6,1´ꢀcyclopropane]ꢀ
2.4ꢀdione (3b) and 1ꢀcyclohexylꢀ3ꢀcyclopropylꢀ1Hꢀpyrroleꢀ
2,5ꢀdione (4b) in the ratio ~8 : 1. Individual compound 3b
(0.39 g, 44%) was isolated as yellow crystals by recrystallization
from ether upon cooling to –20 °C, m.p. 107—109 °C. Found
(%): C, 71.51; H, 8.00; N, 6.31. C13H17NO2. Calculated (%):
C, 71.21; H, 7.81; N, 6.39. Partial MS (EI), m/z (Irel (%)): 219
1
(12) [M]+, 138 (100), 120 (3). H NMR (CDCl3), δ: 0.94, 1.14
(both m, 2 H each, CH2CH2); 1.2—2.1 (m, 10 H, 5 CH2);
2.66 (s, 2 H, CHCH); 3.81 (tt, 1 H, N—CH, 3J = 3.7 Hz,
3J = 11.8 Hz). 13C NMR (CDCl3), δ: 2.3, 7.0 (CH2CH2); 25.0,
25.6, 25.9 (1+2+2 CH2); 29.1 (2 CH); 30.4 (C(6)); 51.3 (NCH);
1
175.3 (2 CO). According to the H NMR spectrum, the filtrate
left after evaporation of the solvent contained a mixture of
1
compounds 3b and 4b in the ratio ~4 : 1. H NMR (CDCl3), δ:
compound 4b: 5.89 (s, =CH), other signals are overlapped with
the signals of compound 3b.
1ꢀCyclopropylꢀ7ꢀphenylꢀ2,3,7ꢀtriazabicyclo[3.3.0]octꢀ
2ꢀeneꢀ6,8ꢀdione (5). An ethereal solution of diazomethane
(0.5 M, 3 mL) was added to a mixture of isomers 3a and 4a
(0.092 g, the ratio was ~1.4 : 1, which corresponded to
~0.18 mmol of 4a) in CH2Cl2 (5 mL) and this was kept for
3 days at 15 °C. The solvent was evaporated in vacuo and the
residue was first crystallized from benzene to remove the greater
portion of compound 3a and then it was purified by preparative
TLC on silica gel (eluent, ether) to obtain pyrazoline 5 (0.039 g,
85 %). Partial MS (EI), m/z (Irel (%)): 255 (2) [M]+, 227 (5),
199 (6), 91 (20), 79 (100). 1H NMR (CDCl3), δ: 0.46, 0.76
(both m, 2 H each, CH2CH2); 1.90 (m, 1 H, CH); 2.78 (dd, 1 H,
J = 2.9 Hz, J = 9.9 Hz, H(5)); 4.83 (dd, 1 H, Ha(4), J = 9.9 Hz,
2J = 19.0 Hz); 5.13 (dd, 1 H, Hb(4), J = 2.9 Hz, J1 = 19.0 Hz);
7.23, 7.44 (both m, 2+3 H, Ph). 13C NMR (CDCl3), δ: 1.4, 1.5
(CH2CH2); 13.0 (CH); 40.1 (C(5)); 80.9 (C(4)); 103.2 (C(1));
126.3 (oꢀC); 129.0 (pꢀC); 129.1 (mꢀC); 130.9 (ipsoꢀC); 170.9,
174.2 (2 CO).
1ꢀCyclopropylꢀ (6) and 5ꢀcyclopropylꢀ7ꢀphenylspiro[2,3,7ꢀtriꢀ
azabicyclo[3.3.0]octꢀ2ꢀeneꢀ4,1´ꢀcyclopropane]ꢀ6,8ꢀdione (7).
NꢀCyclopropylꢀNꢀnitrosourea (0.13 g, 1.0 mmol) and cesium
carbonate (0.70 g, ~2 mmol) were added to a mixture of isomers
3a and 4a (0.21 g, the ratio was ~1.4 : 1 which corresponded
to ~0.41 mmol of 4a) in CH2Cl2 (10 mL) at 5—7 °C and the
mixture was stirred for 40 min at this temperature. The reaction
mixture was filtered and the solvent was evaporated in vacuo.
According to the 1H NMR spectrum, the residue was a mixture
of starting compound 3a and isomeric pyrazolines 6 and 7 in the
molar ratio ~3.8 : 1.7 : 1, respectively. Individual pyrazoline 6
(72 mg, 60%) was isolated as colorless crystals by recrystallization
from ether, m.p. 199—201 °C. Found (%): C, 68.11; H, 5.15;
N, 14.71. C16H15N3O2. Calculated (%): C, 68.31; H, 5.37; N,
14.94. Partial MS, m/z (Irel (%)): 253 (2) [M – N2]+, 224 (4),
119 (30), 106 (48), 91 (100), 77 (74). 1H NMR (CDCl3), δ: 0.49,
0.78 (both m, 2 H each, CH2CH2); 1.31 (m, 1 H, CH); 1.83—2.04
Compound 2b, the yield was 62%, m.p. 161—163 °C. Found
(%): C, 63.43; H, 7.11; N, 16.70. C13H17N3O2. Calculated (%):
C, 63.14; H, 6.93; N, 16.99. Partial MS, m/z (Irel (%)): 137 (52)
[M – N2 – C6H10]+, 109 (31), 94 (35), 66 (100). 1H NMR
(CDCl3), δ: 1.15—2.20 (m, 14 H, 7 CH2); 2.91 (d, 1 H, H(5),
3J = 8.4 Hz); 3.89 (tt, 1 H, N(7)—CH, 3J = 3.7 Hz, 3J = 12.0 Hz);
3
5.83 (d, 1 H, H(1), J = 8.4 Hz). 13C NMR (CDCl3), δ: 10.9,
16.5 (C(2´), C(3´)); 24.9, 25.7, 28.6, 28.7 (1+2+1+1 CH2); 41.1
(C(5)); 52.1 (N(7)—CH); 73.2 (C(4)); 91.4 (C(1)); 169.8, 174.5
(2 CO).
Thermolysis of bicyclic pyrazoline 2a. A solution of pyrazoline
2a (0.96 g, 4 mmol) in oꢀdichlorobenzene (5 mL) was heated at
180 °C until the gas evolution was stopped (~10 h). Then, the
solvent was evaporated in vacuo at 0.2 Torr. According to the 1H
and 13C NMR spectra, the residue contained two compounds:
3ꢀphenylspiro[3ꢀazabicyclo[3.1.0]hexaneꢀ6,1´ꢀcyclopropane]ꢀ
2.4ꢀdione (3a) and 3ꢀcyclopropylꢀ1ꢀphenylꢀ1Hꢀpyrroleꢀ
2,5ꢀdione (4a) in the ratio ~4 : 1. Individual compound 3a
(0.44 g, 52%) was isolated as yellow crystals by recrystallization
from benzene—light petroleum (1 : 2), m.p. 111—112 °C. Found
(%): C, 73.49; H, 5.35; N, 6.50. C13H11NO2. Calculated (%):
C, 73.23; H, 5.20; N, 6.57. Partial MS (EI), m/z (Irel (%)): 213
(78) [M]+, 184 (32), 156 (33), 94 (66), 66 (100). 1H NMR
(CDCl3), δ: 1.12, 1.21 (both m, 2 H each, CH2CH2); 2.89 (s,
2 H, CHCH); 7.21, 7.38, 7.46 (all m, 2+1+2 H, Ph). 13C NMR
(CDCl3), δ: 2.6, 6.9 (CH2CH2); 26.1 (2 CH); 30.2 (C(6)); 126.8
(oꢀC); 128.5 (pꢀC); 129.2 (mꢀC); 131.8 (ipsoꢀC); 174.1 (2 CO).
According to the 1H NMR spectrum, the filtrate left after
evaporation of the solvent contained a mixture of compounds 3a
and 4a in the ratio 1.4 : 1. 1H NMR (CDCl3), δ: compound 4a:

1716
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
Kostyuchenko et al.
(m, 4 H, CH2CH2); 2.48 (s, 1 H, H(5)); 7.23 and 7.43 (both m,
2+3 H, Ph). 13C NMR (CDCl3), δ: 1.3, 1.4 (CH2CH2); 11.4,
16.7 (C(2´) and C(3´)); 13.2 (CH); 44.2 (C(5)); 72.9 (C(4));
101.9 (C(1)); 126.3 (oꢀC); 129.0 (pꢀC); 129.3 (mꢀC); 131.0
(ipsoꢀC); 171.2, 173.1 (2 CO). The filtrate left after isolation of
pyrazoline 6 was concentrated and the residue was separated by
TLC on silica gel (eluent, ether) to obtain pyrazoline 7 (0.026 g,
22%) as yellowish fusible crystals, Rf = 0.74. Partial MS, m/z
(Irel (%)): 253 (2) [M – N2]+, 224 (12), 212 (9), 91 (100), 77
1ꢀMethoxycarbonylꢀ2ꢀ(phenylcarbamoyl)spiropentane (9a).
An ethereal solution of diazomethane (0.5 M, 1 mL) was added
dropwise to a solution of amidoacid 11a (0.015 g, 0.06 mmol) in
methanol (0.5 mL) at room temperature until persistent yellow
color was present and evolution of the gas was stopped. Then,
the mixture was kept for 2 h and the solvent was evaporated
in vacuo to obtain 0.016 g of the reaction mixture, which,
according to the 1H NMR spectrum, contained ~80% of methyl
spiropentanecarboxylate 9a and ~20% spiropentanosuccinimide
3a. Attempts to isolate amidoester 9a was accompanied by its
cyclization into succinimide 3a. Partial MS (EI), m/z (Irel (%)):
245 (52) [M]+, 213 (24) [M – MeOH]+, 153 (67), 93 (100).
1H NMR (CDCl3), δ (after the signals of compound 3a were
subtracted): 1.14, 1.28 (both m, 2 H each, CH2CH2); 2.50, 2.62
1
(56). H NMR (CDCl3), δ: 0.16, 0.57, 0.64 (all m, 1+1+2 H,
CH2CH2); 1.09 (m, 1 H, CH); 1.67—2.01 (m, 4 H, CH2CH2);
5.40 (s, 1 H, H(1)); 7.24, 7.44 (both m, 2+3 H, Ph). 13C NMR
(CDCl3), δ: 1.0, 1.8 (CH2CH2); 12.3 (CH); 12.4, 13.3 (CH2CH2);
49.3 (C(5)); 77.3 (C(4)); 94.0 (C(1)); 126.3 (oꢀC); 129.1 (pꢀC);
129.3 (mꢀC); 131.0 (ipsoꢀC); 168.0, 175.1 (2 CO).
3
(both d, 1 H each, H(1) and H(2), J = 8.3 Hz); 3.73 (s, 3 H,
1ꢀCyclopropylꢀ3ꢀphenylꢀ3ꢀazaspiro[bicyclo[3.1.0]hexaneꢀ
6,1´ꢀcyclopropane]ꢀ2,4ꢀdione (8). A solution of pyrazoline 6
(0.034 g, 0.12 mmol) in oꢀdichlorobenzene (5 mL) was heated at
175 °C for 10 h until the gas evolution was stopped. Then, the
solvent was evaporated in vacuo at 0.2 Torr, the residue was
treated with benzene—light petroleum (1 : 1) and filtered through
a short layer of silica gel. The filtrate was concentrated in vacuo
to obtained compound 8 (0.027 g, 88%) as beige crystals,
m.p. 127—129 °C. Found (%): C, 75.44; H, 5.54; N, 5.62.
C16H15NO2. Calculated (%):C, 75.87; H, 5.97; N, 5.53. Partial
OMe); 7.08, 7.29, 7.54 (all m, 1+2+2 H, Ph), 8.89 (s, 1 H, NH).
13C NMR (CDCl3), δ: 5.2, 8.3 (CH2CH2); 22.5 (C(3)); 27.1,
32.2 (C(1), C(2)); 52.6 (OMe); 120.0 (oꢀC); 124.1 (pꢀC); 129.0
(mꢀC); 138.1 (ipsoꢀC); 167.8 (COO); 172.8 (CONH).
2ꢀ(Cyclohexylcarbamoyl)ꢀ1ꢀmethoxycarbonylspiropentane
(9b) was synthesized similarly from amidoacid 11b (0.014 g,
0.06 mmol) and an ethereal solution of diazomethane. According
to the 1H NMR spectrum, the reaction mixture (0.015 g)
contained ~78% of methyl spiropentanecarboxylate 9b and ~22%
spiropentanosuccinimide 3b. Partial MS (EI), m/z (Irel (%)):
251 (7) [M]+, 192 (12), 138 (100). 1H NMR (CDCl3), δ:
1.02—1.48 (m, 10 H, CH2CH2 and 3 CH2 cyclohexyl); 1.52—1.94
(m, 4 H, 2 CH2 cyclohexyl); 2.41, 2.49 (both d, 1 H each, H(1)
and H(2), 3J = 8.0 Hz); 3.73 (s, 3 H, OMe); 3.75 (m, 1 H,
NCH); 6.59 (s, 1 H, NH). 13C NMR (CDCl3), δ: 4.9, 7.9 (C(4)
and C(5)); 21.4 (C(3)); 24.6, 25.6 (CH2 cyclohexyl ); 26.5, 30.9
(C(1) and C(2)); 29.1, 32.7, 33.1 (CH2 cyclohexyl ); 48.0
(NCH); 52.1 (OMe); 168.1 (COO); 172.0 (CONH).
2ꢀ(Phenylcarbamoyl)ꢀ1ꢀcyclopropylspiropentaneꢀ1ꢀcarboꢀ
xylic acid (12). A solution of NaOH (0.2 N, 0.3 mL) was added
to a solution of compound 8 (0.015 g, 0.06 mmol) in methanol
(0.3 mL) and this was kept for 16 h at 20 °C. Then, methanol
was evaporated in vacuo, the reaction mixture was acidified with
2% aq. hydrochloric acid and extracted with chloroform (1 mL).
The organic layer was dried with anhydrous Na2SO4, the solvent
was evaporated in vacuo, the reaction mixture was treated with
ether to obtain amidoacid 12 (0.014 g, 87%) as colorless crystals,
+
MS (EI), m/z (Irel (%)): 253 (8) [M] , 225 (12), 133 (17), 91
1
(100). H NMR (CDCl3), δ: 0.23, 0.49, 0.69 (all m, 1+1+2 H,
CH2CH2); 1.07, 1.20 (both m, 2 H each, CH2CH2); 1.45 (m,
1 H, CH); 2.41 (s, 1 H, H(5)); 7.22, 7.40 (both m, 2+3 H, Ph).
13C NMR (CDCl3), δ: 2.6, 2.8 (CH2CH2); 3.0, 5.9 (CH2CH2);
28.3 (C(1)); 29.7 (C(6)); 34.2 (C(5)); 126.8 (oꢀC); 128.4 (pꢀC);
129.1 (mꢀC); 132.0 (ipsoꢀC); 174.0, 175.9 (2 CO).
2ꢀ(NꢀPhenylcarbamoyl)spiropentaneꢀ1ꢀcarboxylic acid (11a).
A solution of NaOH (1 N, 0.9 mL) was added to a solution of
compound 3a (0.192 g, 0.9 mmol) in methanol (2 mL) and this
was stirred for 16 h at 20 °C. Then, methanol was evaporated,
the aqueous solution was acidified with 2% aq. hydrochloric
acid and extracted with chloroform (7 mL). The organic layer
was dried with anhydrous Na2SO4, the solvent was evaporated
in vacuo to obtained amidoacid 11a (0.181 g, 87%) as colorless
crystals, m.p. 164—166 °C. Found (%): C, 67.77; H, 5.79; N, 6.33.
C13H13NO3. Calculated (%):C, 67.52; H, 5.67; N, 6.06. Partial
MS (EI), m/z (Irel (%)): 231 (7) [M]+, 186 (4) [M – CO2H]+, 93
(100). 1H NMR (DMSOꢀd6), δ: 0.95, 1.11 (both m, CH2CH2);
m.p. 171—173 °C. Partial MS (EI), m/z (I (%)): 271 (2)
rel
[M]+, 226 (8) [M – CO2H]+, 93 (100), 77 (43). 1H NMR
(CDCl3), δ: 0.38, 0.74, 0.89, 1.18 (all m, 1+2+1+4 H,
2 CH2CH2); 1.58 (m, 1 H, CH); 2.59 (s, 1 H, H(1)); 7.21, 7.38,
7.51 (all m, 1+2+2 H, Ph); 8.61 (s, 1 H, NH); 13.2 (br.s, 1 H,
OH). 13C NMR (CDCl3), δ: 2.8, 4.7, 5.2, 7.7 (2 CH2CH2);
14.0 (CH); 27.4 (C(3)); 29.8 (C(2)); 37.3 (C(1)); 121.0 (oꢀC);
126.0 (pꢀC); 129.3 (mꢀC); 136.3 (ipsoꢀC); 167.7 (COOH); 171.8
(CONH).
3
2.39, 2.56 (both d, 1 H each, H(1), H(2), J = 8.3 Hz); 7.03,
7.28, 7.55 (all m, 1+2+2 H, Ph); 10.05 (s, 1 H, NH); 12.25
(br.s, 1 H, OH). 13C NMR (DMSOꢀd6), δ: 3.6, 5.8 (CH2CH2);
20.1 (C(3)); 26.1, 27.6 (C(1) and C(2)); 118.7 (oꢀC); 122.7
(pꢀC); 127.8 (mꢀC); 138.5 (ipsoꢀC); 167.2, 170.5 (2 CO).
2ꢀ(NꢀCyclohexylcarbamoyl)spiropentaneꢀ1ꢀcarboxylic acid
(11b) was synthesized similarly from compound 3b (0.11 g,
0.5 mmol) and the NaOH solution (1 N, 0.5 mL). After acidificaꢀ
tion with HCl, amidoacid 11b (0.10 g, 84%) was obtained
as beige crystals, m.p. 144—146 °C. Partial MS (EI), m/z
(Irel (%)): 237 (3) [M]+, 192 (10) [M – CO2H]+, 139 (15), 138
(16), 41 (100). 1H NMR (CDCl3), δ: 1.03—1.44 (m, 10 H,
CH2CH2, 3 CH2 cyclohexyl); 1.56—1.97 (m, 4 H, 2 CH2 cycloꢀ
This work was financially supported by the Presidium
of the Russian Academy of Sciences (Program for Basic
Research “Development of Methods for the Preparation
of Chemical Compounds and New Materials”, Subproꢀ
gram “Development of Methodology of Organic Syntheꢀ
sis and Preparation of Compounds with Valuable Applied
Properties”) and Federal Agency for Science and
Innovations (Russian Federation President Grant
NShꢀ6075.2006.3).
3
hexyl); 2.45, 2.49 (both d, 1 H each, H(1), H(2), J = 7.8 Hz);
3.75 (m, 1 H, NCH); 7.51 (d, 1 H, NH, J = 8.0 Hz); 13.8 (br.s,
1 H, OH). 13C NMR (CDCl3), δ: 5.4, 8.6 (C(4) and C(5)); 23.9
(C(3)); 24.8 (2 CH2); 25.4 (CH2); 29.0, 30.7 (C(1) and C(2));
32.6, 32.7 (2 CH2); 49.7 (NCH); 172.4, 173.5 (2 CO).

Spiropentanes from maleimides
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
1717
8. J. A. Miller, E. J. Hennessy, W. J. Marshall, M. A. Scialdone,
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A. Malik, M. North, Tetrahedron, 1997, 53, 17417.
10. M. J. Milewska, T. Polonski, Tetrahedron: Asymmetry, 1994,
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Received February 8, 2008