Reduction of substituted spiro[cyclopropane-3-(1-pyrazolines)] to spiro[cyclopropane-3-pyrazolidines] and 1-(2-aminoethyl)cyclopropylamine derivatives

Article abstract of DOI:10.1007/s11172-006-0156-8

Raney nickel-catalyzed hydrogenation of 5-substituted spiro[cyclopropane-3- (1-pyrazoline)]-5-carboxylates occurs with N-N bond cleavage with simultaneous cyclocondensation to give 3-aminopyrrolidin-2-ones containing a spirocyclopropane fragment. The pres

Full text of DOI:10.1007/s11172-006-0156-8

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Russian Chemical Bulletin, International Edition, Vol. 54, No. 11, pp. 2562—2570, November, 2005
Reduction of substituted spiro[cyclopropaneꢀ3ꢀ(1ꢀpyrazolines)]
to spiro[cyclopropaneꢀ3ꢀpyrazolidines] and
1ꢀ(2ꢀaminoethyl)cyclopropylamine derivatives
I. V. Kostyuchenko,a E. V. Shulishov,a V. A. Korolev,a V. A. Dokichev,b and Yu. V. Tomilova
ꢀ
aN. D. Zelinsky Institute of Organic Chemistry, Russian Aсademy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 6390. Eꢀmail: tom@ioc.ac.ru
bInstitute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences,
71 prosp. Octyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347 2) 35 6066. Eꢀmail: dokichev@anrb.ru
Raney nickelꢀcatalyzed hydrogenation of 5ꢀsubstituted spiro[cyclopropaneꢀ3ꢀ(1ꢀpyrazoꢀ
line)]ꢀ5ꢀcarboxylates occurs with N—N bond cleavage with simultaneous cyclocondensation
to give 3ꢀaminopyrrolidinꢀ2ꢀones containing a spirocyclopropane fragment. The presence of
the second ester group in the pyrazoline side chain, in the position ensuring the formation of a
fiveꢀmembered ring results in 6,11ꢀdiazadispiro[2.1.4.2]undecaneꢀ7,10ꢀdione, the product of
double cyclocondensation of the intermediate diamine. Hydrogenation of the arylꢀsubstituted
spiro[cyclopropaneꢀ3ꢀ(1ꢀpyrazolines)] in the presence of acetone affords hexahydrospiro[cycloꢀ
propaneꢀ4ꢀpyrimidines], which can be converted into the cyclopropaneꢀcontaining 1,3ꢀdiꢀ
amines in the individual state or as salts.
Key words: spiro[cyclopropaneꢀ3ꢀ(1ꢀpyrazolines)], spiro[[cyclopropaneꢀ3ꢀpyrrolidinꢀ5ꢀ
ones], hexahydrospiro[cyclopropaneꢀ4ꢀpyrimidines], 1,3ꢀdiamines, reduction, cycloconꢀ
densation.
Hydrogenolysis of 1ꢀ or 2ꢀpyrazolines gives either
ecules creates certain difficulties for the selective reducꢀ
tion of the heterocyclic N=N bond. Indeed, in none of
the experiments were we able to eliminate completely the
formation of byꢀproducts resulting from hydrogenolysis
(or isomerization) of the cyclopropane ring. However,
under certain conditions, it is possible to direct the reducꢀ
tion toward the predominant formation of pyrazolidines
or 1,3ꢀdiamines, which retain the cyclopropane fragment
in the molecule. Thus, the catalytic reduction of spiꢀ
ro[cyclopropaneꢀ3ꢀ(1ꢀpyrazoline)] 1, obtained by addiꢀ
tion of diazocyclopropane to methyl methacrylate,11 was
found to proceed most efficiently in an ethanol solution
pyrazolidines1—3 or 1,3ꢀdiamines,3—8 depending on the
nature of reducing reagents and reaction conditions; staꢀ
bilization of the pyrazolidines normally requires the inꢀ
troduction of a protecting group to a nitrogen atom. Transꢀ
formation of pyrazolines into diamines is mainly carried
out by catalytic hydrogenation of 1ꢀ or 2ꢀpyrazolines unꢀ
der a hydrogen pressure in the presence of Raney nickel.
The reduction of pyrazolines that contain an ester or amide
group in the γꢀposition to the amino group formed deꢀ
serves special consideration. In this case, the 1,3ꢀdiamines
formed initially undergo intramolecular condensation to
give 3ꢀaminoꢀ2ꢀpyrrolidone derivatives.9,10 These are of
interest as potential biologically active substances and
structural fragments of complex polycyclic systems present
in natural products.
when catalyzed by the Raney nickel (pH = 80—90 bar,
2
70 °C, 4 h). Under these conditions, spiro[cyclopropaneꢀ
3ꢀ(1ꢀpyrrolidinꢀ5ꢀone)] 2 is formed as the major reaction
product in 52—55% yield upon complete reduction of
pyrazoline 1 to diamino ester 3, which then undergoes
intramolecular condensation (Scheme 1). As the temꢀ
perature is decreased to 50 °C, a substantial portion of the
starting pyrazoline remains unchanged, while temperaꢀ
ture rise above 90 °C decreases the yield of pyrrolidinone
2 due to the formation of heavier products, apparently
upon various intermoecular transformations.
This communication reports the first study of the reꢀ
duction, under various conditions, of spirocyclopropaneꢀ
containing pyrazolines prepared either previously11—13 or
in this study.
Results and Discussion
The presence of the cyclopropane fragment as a reacꢀ
tion site in spiro[cyclopropaneꢀ3ꢀ(1ꢀpyrazoline)] molꢀ
It is noteworthy that the reaction mixture formed after
hydrogenation of pyrazoline 1 with hydrogen in the presꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2482—2490, November, 2005.
1066ꢀ5285/05/5411ꢀ2562 © 2005 Springer Science+Business Media, Inc.

Reduction of spiro[cyclopropaneꢀ3ꢀ(1ꢀpyrazolines)] Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2563
Scheme 1
Reagents and conditions: i. H2, Ni, 80 bar, 70 °C, 4 ч; ii. Zn, NH4Cl, THF/H2O.
Scheme 2
ence of Raney nickel almost does not contain spiro[cycloꢀ
propaneꢀ3ꢀ(1ꢀpyrazolidine)] 4 (according to H NMR),
1
which is either unstable under these conditions or is easily
reduced to diamine, which is then converted into pyrrolꢀ
idinone 2.
Unlike catalytic hydrogenation, the reduction of
pyrazoline 1 with zinc in aqueous THF in the presence of
NH4Cl yields mainly a mixture of two structural isomers,
spiro[cyclopropaneꢀ3ꢀpyrazolidine] (4) and ethylpyrazoꢀ
line 5 (see Scheme 1). Unfortunately, we were unable to
isolate these compounds in a pure state, but their presꢀ
ence in the reaction mixture is indicated by the full set of
nonꢀoverlapping signals of the corresponding protons in
the 1H NMR spectrum (see Experimental). According to
the integral intensity, the overall yield of compounds 4
and 5 is ~85%, while their ratio is ~1.8 : 1. The substantial
formation of pyrazoline 5 containing no cyclopropane
fragment is apparently due to isomerization of pyrazolidine
4 induced by the arising zinc salt, which acts as a Lewis
acid. The catalytic reduction of pyrazoline 1 in the presꢀ
ence of Raney nickel gives almost no ethylpyrazoline 5.
Acylation of 3ꢀaminopyrrolidinꢀ2ꢀone 2 with chloroꢀ
acetyl chloride in the presence of Et3N involves the amino
group (Scheme 2) and gives chloroacetamide derivative 6
in ~65% yield. Refluxing of this product with KOH in
MeOH does not affect the overall structure of the molꢀ
ecule, being accompanied only by hydrolysis of the C—Cl
bond to give 2ꢀhydroxyacetamide 7.
Reagents and conditions: i. ClCH2COCl, Et3N, CH2Cl2, 20 °C;
ii. KOH/MeOH, 64 °C, 2 h.
Scheme 3
Raney nickelꢀcatalyzed hydrogenation of spiro[cycloꢀ
propaneꢀ3ꢀ(1ꢀpyrazoline)] (8), synthesized in 68% yield
by cyanoethylation of pyrazoline 9 under the action of
MeONa/MeOH at –10 °C (see Ref. 12), proceeds in the
same way as the reduction of pyrazoline 1, giving rise to
3ꢀaminospiro[cyclopropaneꢀ2ꢀpyrrolidinꢀ5ꢀone] 10 in
38% yield (for the recrystallized product) (Scheme 3).
The reduction of pyrazoline 11, containing two ester
groups in the molecule,12 is accompanied by two intramoꢀ
lecular condensations of the intermediate diamine, giving
rise to 6,11ꢀdiazadispiro[2.1.4.2]undecaꢀ7,10ꢀdione (12)
(Scheme 4) in 43% yield. The 13C NMR spectrum of this
Reagents and conditions: i. CH2=CHCN, MeONa/MeOH,
–10 °C; ii. H2, Ni, 90 bar, 80 °C, 5 h.
compound shows, apart from the five CH2 groups, four
signals from the quaternary C atoms, two of these being
spiro atoms (δC 36.7 and 66.6), and the other two being
parts of carbonyl groups (δC 178.9 and 180.9).

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Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005
Kostyuchenko et al.
Scheme 4
Scheme 5
i. H2, Ni, 100 bar, 80 °C, 5 h.
Dilactam 12 is a spirocyclopropane analog of 1,7ꢀdiꢀ
azaspiro[4,4]nonaneꢀ2,6ꢀdione synthesized previously in
several step from pyroglutamic acid, in particular, as
the chiral (5R)ꢀisomer.14,15 Previously, the 1,7ꢀdiazaꢀ
spiro[4,4]nonaneꢀ2,6ꢀdione fragment has been widely
used for the design of conformationally rigid peptidoꢀ
mimetics, including analogs of the hormone thyrotropin
(TRH).15—19 The catalytic hydrogenation of pyrazolines,
containing two ester groups in definite sites of the molꢀ
ecule can serve as yet another method for the preparation
of spiroꢀbislactams.
We studied hydrogenation of fused spiro[cycloproꢀ
panepyrazolines] 13a,b, prepared by 1,3ꢀdipolar cycloꢀ
addition of diazocyclopropane generated in situ to
Nꢀ(pꢀtolyl)ꢀ and Nꢀ(4ꢀbromophenyl)maleimides. It was
found that even minor changes in the nature of the aryl
substituent have a pronounced effect on the pattern of
transformations. Thus the reduction of pyrazoline 13a
with hydrogen in the presence of thoroughly washed Raney
nickel containing no traces of alkali gives, as the major
product (63%), Nꢀ(pꢀtolyl)amide of 6ꢀaminoꢀ5ꢀoxoꢀ4ꢀ
azaspiro[2.4]heptaneꢀ7ꢀcarboxylic acid (14), whose forꢀ
mation is preceded by selective reduction of the N=N
bond to the corresponding diamino derivative (Scheme 5).
The subsequent cyclocondensation involves the amino
group located most closely to the cyclopropane ring, which
furnishes the most stable fiveꢀmembered heterocycle. In
addition to the proton signals from the aryl and cycloproꢀ
R = Me (a), Br (b)
Reagents and conditions: i. K2CO3, CH2Cl2, 5—8 °C; ii. H2, Ni,
100 bar, 80 °C, 6 h.
Treatment of pyrazoline 13b or 15 with an equivalent
amount of a base induces a more extensive transformaꢀ
tion, resulting in trisubstituted pyrazole 16 in 80—95%
yield (Scheme 6).
1
pane fragments, the H NMR spectrum of compound 14
in (CD3)2SO exhibits two doublets with δ 3.14 and 3.88
with coupling constants J = 8.5 Hz, due to the methine
protons, and three broadened singlets with δ 9.8, 7.8,
and 3.3, corresponding to the protons of two amide
and one amino groups. The 13C NMR spectrum has
two lowꢀfield signals of equal intensity (∆δ 5—7), due to
the C atoms of two different amide groups (see Experiꢀ
mental).
Attempts at reducing pyrazoline 13b into 3ꢀaminoꢀ
pyrrolidinꢀ2ꢀone under the same conditions failed due to
the easy alcoholysis of the imide ring. Indeed, even mere
refluxing of bromophenyl derivative 13b for 2 h or treatꢀ
ment of 13b with 2 mol.% NaOH in EtOH at 25 °C gives
2ꢀpyrazoline 15 (85—90% yields), which is not reduced
under the aboveꢀdescribed conditions.
Unlike hydrogenation of the aboveꢀdiscussed spiꢀ
ro[cyclopropanepyrazolines] containing electronꢀwithꢀ
drawing substituents in position 3 of the heterocycle,
which ensure further transformations of the diamines
formed, hydrogenation of 5ꢀphenylspiro[cyclopropaneꢀ
3ꢀ(1ꢀpyrazoline)] (17a)13 was expected to stop after the
formation of amines. However, no pyrazolidine 18a or
diamine 19a could be isolated in a pure state upon the
reduction of pyrazoline 17a with H2 in the presence of
Raney nickel (80 °C, 100 bar), despite the virtually comꢀ
plete conversion of the starting pyrazoline.
In order to trap the amines, we carried out hydrogenaꢀ
tion of pyrazoline 17a under the same conditions but with
preliminary addition of a 10ꢀfold molar excess of acetone.
In this case, hexahydropyrimidine 20a was isolated in

Reduction of spiro[cyclopropaneꢀ3ꢀ(1ꢀpyrazolines)] Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2565
Scheme 6
A similar strategy was used to prepare diamine 19b,
containing a pꢀfluorophenyl substituent in the molecule.
The initial 1ꢀpyrazoline 17b was prepared in ~65% yield
by 1,3ꢀdipolar cycloaddition of in situ generated diꢀ
azocyclopropane to pꢀfluorostyrene. Hydrogenation of
pyrazoline 17b with hydrogen over Raney nickel in the
presence of acetone affords hexahydropyrimidine 20b
(yield 62%), which was converted into diamine 19b in
91% yield via the dihydrochloride 21b.
In order to estimate the feasibility of preparing pyrꢀ
azolidine derivative 18a, we studied the action of other
reducing agents on pyrazoline 17a. Alkylꢀ and arylꢀsubꢀ
stituted pyrazolines can be reduced to pyrazolidines on
treatment with LiAlH4 in THF20 or to diamines with Na
in refluxing EtOH.21 It was found that spirocyclopropaneꢀ
pyrazoline 17a does not change under the action of LiAlH4
in THF, whereas treatment with Na in ethanol (Scheme 8)
gives a mixture of pyrazolidine 18a and 3(5)ꢀphenylꢀ5(3)ꢀ
ethylpyrazole (22)13 in ~4 : 1 ratio rather than diamine 19a.
Pyrazole 22 results apparently from isomerization of the
starting pyrazoline 17a taken place at at 78 °C and inꢀ
duced by the EtONa formed.
i. NaOH (1 equiv.), EtOH.
~60% yield, indicating that hydrogenation of pyrazoline
17a actually involves the N=N bond with the intermediꢀ
ate formation of diamine 19a (Scheme 7). Despite the
fact that we did not succeed in isolating diamine 19a upon
direct catalytic hydrogenation of pyrazoline 17a, this comꢀ
pound was obtained in a pure state upon decomposition
of compound 20a. Indeed, treatment of hexahydroꢀ
pyrimidine 20a with two equivalents of HCl in dioxane
results in elimination of the acetone molecule to give
diamine dihydrochloride 21a, which is converted into
free diamine 19a upon neutralization with aqueous NaOH.
On refluxing in acetone, this product is converted again
into hexahydropyrimidine 20a in ~90% yield.
Scheme 8
Scheme 7
Pyrazolidine 18a, which is readily oxidized in air to
give pyrazoline 17a, was identified by the 1H NMR specꢀ
trum of the reaction mixture. Its spectrum closely reꢀ
sembles the spectrum of the starting pyrazoline 17a, but
the signals for the cyclopropaneꢀring protons and three
interrelated heterocycle protons are somewhat shifted
upfield (see Experimental). Chromatography on SiO2 gave
only pyrazole 22.
Acyclic 1,2ꢀdisubstituted hydrazines are known22 to
react with two moles of aldehydes to give 1,3,4ꢀoxadiꢀ
azolidine derivatives. However, if the freshly obtained
reaction mixture containing ~60% pyrazolidine 18a is
made to react with acetaldehyde, 3ꢀethoxyꢀ3ꢀphenylꢀ5ꢀ
ethylpyrazole 23 is formed in ~50% yield instead of
oxadiazoline. The product structure was proved by 1H and
Ar = Ph (a), 4ꢀC6H4F (b)
i. H2, Ni, 100 bar, 80 °C, 6 h.

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Kostyuchenko et al.
13C NMR spectra and NOESY experiments (coupling of
the OCH2 group with the phenyl orthoꢀprotons is obꢀ
served). Pyrazole 23 is probably formed through oxidaꢀ
tion and condensation of pyrazolidine 18a with two acꢀ
etaldehyde molecules accompanied by cyclopropane ring
opening and yielding intermediate 24, which then isomerꢀ
izes (see Scheme 8).
Finally, we demonstrated that acyl derivatives of diꢀ
amines 19 of the cyclopropane series can be obtained
directly from hexahydropyrimidines 20 or diamine salts 21.
The reaction of compound 20a with acetic anhydride, as
in the case of hexahydropyrimidines containing no spiroꢀ
cyclopropane fragment,23 leads to 1,2´ꢀbis(acetylamino)ꢀ
1ꢀ(2´ꢀphenylethyl)cyclopropane (25) in 62% yield
(Scheme 9). It is noteworthy that the reaction of dihydroꢀ
chloride 21b with diethyl oxalate in the presence of Et3N
as the base gives bisꢀethyloxalylamide 26 rather than cyꢀ
clic oxamide. A change in the reactant ratio and the order
of addition does not give the cyclization product either,
although the reaction of usual 1,3ꢀdiamines with diethyl
oxalate or oxalyl chloride is a known method for the synꢀ
thesis of cyclic oxamides.24
Experimental
H and 13C NMR spectra were recorded on Bruker ACꢀ200
(200 and 50.3 MHz) and Bruker AMꢀ300 (300 and 75.5 MHz,
respectively) spectrometers for solutions in CDCl3, CD3OD, or
(CD3)2SO containing 0.05% Me4Si as the internal standard.
Mass spectra were run on a Finnigan MAT INCOSꢀ50 (EI,
70 eV, direct injection). Spiro[cyclopropanepyrazolines] 1, 9,
11, and 17a,c were synthesized by known procedures.11—13,20
Thin layer chromatography was performed using silica gel 60
(0.040—0.063 mm) produced by Merck.
6ꢀAminoꢀ6ꢀmethylꢀ4ꢀazaspiro[2.4]heptanꢀ5ꢀone (2). Pyrazoꢀ
line 1 (0.55 g, 3.3 mmol), EtOH (10 mL), and Raney nickel
(0.05 g) were placed in a 100ꢀmL steel autoclave and hydrogeꢀ
nated at 70 °C and at a 80 bar H2 pressure for 4 h. The reaction
mixture was filtered, the solvent was evaporated, and the residue
was treated with ether. The resulting precipitate was filtered off
and dried in vacuo to give 0.26 g (55%) of pyrrolidinꢀ2ꢀone 2 as a
colorless finely crystalline compound, m.p. 283—284 °C.
Found (%): C, 60.15; H, 8.68; N, 19.77. C7H12N2O. Calcuꢀ
lated (%): C, 59.98; H, 8.63; N, 19.98. 1H NMR (CDCl3), δ:
0.70, 0.84 (both m, 2 H each, CH2CH2); 1.38 (s, 3 H, Me); 1.80
(br.s, 2 H, NH2); 1.94, 2.22 (both d, 1 H each, H2C(7), 2J =
12.1 Hz); 6.42 (br.s, 1 H, NH). 13C NMR (DMSOꢀd6), δ: 6.6,
10.8 (CH2CH2); 20.9 (Me); 35.1 (C(3)); 40.2 (C(7)); 57.1
(C(6)); 172.6 (CO). MS, m/z (Irel (%)): 140 [M]+ (14), 123
[M – NH3]+ (4), 112 (20), 111 (38), 97 (21), 70 (31); 57 (60),
42 (100).
1
Scheme 9
Reduction of pyrazoline 1 in a Zn—NH4Cl system. Ammoꢀ
nium chloride (4.28 g, 0.08 mol) in water (10 mL) and Zn
(5.20 g, 0.08 gꢀat) were added to a solution of pyrazoline 1
(0.15 g, 0.9 mmol) in THF (10 mL), and the suspension was
stirred for 24 h at 20 °C. The mixture was filtered, and water
(30 mL) and CH2Cl2 (30 mL) were added to the filtrate. The
organic layer was separated and dried with anhydrous Na2SO4,
and the solvent was evaporated in vacuo at 20 °C. According to
1H NMR data, the residue (0.13 g) was mainly a mixture of
6ꢀmethoxycarbonylꢀ6ꢀmethylꢀ4,5ꢀdiazaspiro[2.4]heptane (4)
and 5ꢀethylꢀ3ꢀmethylꢀ3ꢀmethoxycarbonylꢀ3,4ꢀdihydroꢀ2Hꢀ
pyrazole (5) (ratio ~(1.8 : 1), overall yield ~85%). Compound 4.
1H NMR (CDCl3), δ: 0.61, 0.89 (both m, 2 H each, CH2CH2);
1.54 (s, 3 H, Me); 1.93, 2.44 (both d, 1 H each, H2C(7), 2J =
12.6 Hz); 3.78 (s, 3 H, OMe). Compound 5. 1H NMR (CDCl3),
δ: 1.12 (t, 3 H, Me, J = 7.5 Hz); 1.50 (s, 3 H, Me); 2.29 (q, 2 H,
CH2, J = 7.5 Hz); 2.58, 3.19 (both d, 1 H each, H2C(4), 2J =
16.7 Hz); 3.74 (s, 3 H, OMe).
Reagents and conditions: i. Ac2O/Et2O, 18 °C, 48 h;
ii. (CO2Et)2/Et3N, Et2O, 18 °C, 72 h.
2ꢀChloroꢀNꢀ{6ꢀmethylꢀ5ꢀoxoꢀ4ꢀazaspiro[2.4]heptꢀ6ꢀ
yl}acetamide (6). Triethylamine (0.15 g, 1.5 mmol) was added at
5 °C to a solution of amide 2 (0.10 g, 0.73 mmol) in CH2Cl2
(3 mL); then a solution of chloroacetyl chloride (0.082 g,
0.73 mmol) in CH2Cl2 (1 mL) was added. After keeping for
12 h, the reaction mixture was treated with water (20 mL), the
organic layer was separated and dried with anhydrous Na2SO4,
the solvent was removed in vacuo, and the residue was treated
with ether to give 0.102 g (65%) of acetamide 6 as colorless
crystals, m.p. 167—169 °C. Found (%): C, 50.03; H, 6.16;
Cl, 16.18; N, 12.79. C9H13ClN2O2. Calculated (%): C, 49.89;
Thus, catalytic hydrogenation of substituted spiꢀ
ro[cyclopropane(1ꢀpyrazolines)] with hydrogen in the
presence of Raney nickel provides the route to diamines;
when the molecule contains ester groups, they are immeꢀ
diately converted into pyrrolidinꢀ2ꢀones or, in the presꢀ
ence of acetone, into the corresponding hexahydroꢀ
pyrimidines containing a spirocyclopropane fragment. The
latter products are convenient synthons for the preparaꢀ
tion of new promising cyclopropaneꢀcontaining 1,3ꢀdiꢀ
amines both free and as salts.
1
H, 6.05; Cl, 16.36; N, 12.93. H NMR (CDCl3), δ: 0.60—1.02
(m, 4 H, CH2CH2); 1.59 (s, 3 H, Me); 2.18, 2.81 (both d,
1 H each, H2C(7), 2J = 12.5 Hz); 4.02 (s, 2 H, CH2Cl), 7.12,

Reduction of spiro[cyclopropaneꢀ3ꢀ(1ꢀpyrazolines)] Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2567
7.20 (both br.s, 1 H each, 2 NH). 13C NMR (CDCl3), δ: 8.0,
12.5 (CH2CH2); 22.5 (Me); 36.6 (C(3)); 42.5 (CH2Cl); 43.2
(C(7)); 59.3 (C(6)); 165.7 (NHCO); 176.9 (C(5)). Partial MS,
m/z (Irel (%)): 218 (0.1) and 216 (0.3) [M]+, 181 [M – Cl]+
(0.5), 123 (100).
the residue (0.073 g) was treated with ether. The precipitate was
filtered off. After drying, 0.032 g (40%) of compound 12
was formed as a colorless finely crystalline compound, m.p.
302—303 °C. Found (%): C, 59.67; H, 6.48; N, 15.32.
C9H14N2O2. Calculated (%): C, 59.99; H, 6.71; N, 15.55.
1H NMR (DMSOꢀd6), δ: 0.51—0.92 (m, 4 H, CH2CH2); 1.96,
2ꢀHydroxyꢀNꢀ(6ꢀmethylꢀ5ꢀoxoꢀ4ꢀazaspiro[2.4]heptꢀ6ꢀ
yl)acetamide (7). A mixture of acetamide 6 (0.016 g, 0.07 mmol)
and КOH (0.05 g, 0.1 mmol) in MeOH (1 mL) was refluxed for
4 h. The solvent was evaporated to 2/3 of the initial volume, the
precipitate was filtered off, and the filtrate was evaporated
in vacuo to give 0.013 g (94%) of hydroxyacetamide 7 as a
colorless finely crystalline compound, m.p. 301—302 °C.
Found (%): C, 54.32; H, 7.19; N, 14.01. C9H14N2O3. Calcuꢀ
2
2.36 (both d, 1 H each, H2C(7), J = 12.5 Hz); 2.02—2.29 (m,
4 H, CH2CH2); 7.89, 7.98 (both br.s, 1 H each, 2 NH). 1H NMR
(CD3OD), δ: 0.61—1.02 (m, 4 H, CH2CH2); 2.02, 2.51 (both d,
1 H each, H2C(7), 2J = 13.0 Hz); 2.30—2.48 (m, 4 H, CH2CH2).
13C NMR (CD3OD), δ: 9.0, 12.1 (CH2CH2); 31.0, 32.8 (C(8),
C(9)); 36.7 (C(3)); 43.7 (C(4)); 66.6 (C(5)); 178.9, 180.9 (2
CO). Partial MS, m/z (Irel (%)): 180 [M]+ (59), 152 (56), 97
(52), 54 (100).
1
lated (%): C, 54.53; H, 7.12; N, 14.13. H NMR (CD3OD), δ:
0.55—0.90 (m, 4 H, CH2CH2); 1.51 (s, 3 H, Me); 1.89, 2.81
(both d, 1 H each, H2C(7), 2J = 12.4 Hz); 3.42 (br.s, 2 NH,
OH); 3.91 (s, 2 H, OCH2). 13C NMR (CD3OD), δ: 8.6, 12.9
(CH2CH2); 23.3 (Me); 37.0 (C(3)); 43.3 (C(7)); 60.0 (C(6));
72.5 (OCH2); 171.6 (NHCO); 178.8 (C(5)). Partial MS,
m/z (Irel (%)): 198 [M]+ (0.6), 149 (11), 139 (1.5), 123 (100).
6ꢀ(2ꢀCyanoethyl)ꢀ6ꢀmethoxycarbonylꢀ4,5ꢀdiazaspiꢀ
ro[2.4]heptꢀ4ꢀene (8). Sodium methoxide (0.07 g, 1.2 mmol) in
MeOH (0.2 mL) was added at –10 °C to a vigorously
stirred mixture of 6ꢀmethoxycarbonylꢀ4,5ꢀdiazaspiro[2.4]heptꢀ
5ꢀene (9) (1.80 g, 12 mmol) and acrylonitrile (0.60 g, 12 mmol)
in CH2Cl2 (7 mL), and the mixture was stirred for 20 min. The
reaction mixture was treated with 10 mL of water, the organic
layer was separated, the aqueous layer was extracted with CH2Cl2
(10 mL), and the organic solution was dried with anhydrous
Na2SO4. The solvent was removed in vacuo and the residue was
recrystallized from hexane to give 1.69 g (68%) of pyrazoline 8
as yellowish crystals, m.p. 53—54 °C. 1H NMR (CDCl3), δ: 1.21
(m, 2 H, CHCH, directed away from the heterocycle N atoms);
1.78, 2.29 (both d, 1 H each, H2C(7), 2J = 13.0 Hz); 1.86 (m,
2 H, CHCH, directed toward the heterocycle N atom); 2.49 (m,
4 H, CH2CH2); 3.82 (s, 3 H, OMe). 13C NMR (CDCl3), δ:
12.7, 14.9 (CH2CH2); 14.7 (CH2CN); 31.6 (C(7)); 33.5
(CH2CH2CN); 53.1 (OMe); 70.4 (C(3)); 94.9 (C(6)); 118.8
(CN); 170.0 (CO). Partial MS, m/z (Irel (%)): 139 [C7H9NO2]+
(35), 79 [C5H5N]+ (100).
6ꢀAminoꢀ6ꢀ(2ꢀcyanoethyl)ꢀ4ꢀazaspiro[2.4]heptanꢀ5ꢀone
(10). Spiro[cyclopropanepyrazoline] 8 (1.28 g, 6.2 mmol), ethaꢀ
nol (40 mL), and Raney nickel (0.05 g) were placed in a 100ꢀcm3
steel autoclave and hydrogenated at 80 °C and at a hydrogen
pressure of 90 bar for 5 h. Then the reaction mixture was filtered
and the solvent was evaporated in vacuo. The residue (~1.2 g)
was treated with ethyl acetate at –20 °C, the precipitate was
filtered off, washed with chloroform, and dried in vacuo to give
0.42 g (38%) of compound 10 as a colorless powder, m.p.
166—168 °C. 1H NMR (CD3OD), δ: 0.72—0.91 (m, 4 H,
CH2CH2); 1.98 (m, 2 H, CH2CN); 2.10, 2.19 (both d, 1 H each,
H2C(7), 2J = 13.5 Hz); 2.60 (m, 2 H, CH2). 13C NMR
(CD3OD), δ: 8.3, 10.4 (cycloꢀCCH2CH2); 10.9 (CH2CN); 32.4
(CH2); 34.6 (C(3)); 41.3 (C(7)); 58.6 (C(6)); 120.6 (CN); 177.8
(CO). Partial MS, m/z (Irel (%)): 179 [M]+ (8), 162 [M – NH3]+
(18), 151 (19), 150 (59), 122 (46), 111 (100), 97 (82).
Synthesis of 7ꢀarylspiro[cyclopropaneꢀ2,3,7ꢀtriazabiꢀ
cyclo[3.3.0]octꢀ2ꢀeneꢀ6,8ꢀdiones] (13a,b) (general procedure).
Potassium carbonate (2.61 g, ~15 mmol) containing ~20% H2O
was added at 5—7 °C to a mixture of Nꢀarylmaleimide (2.8 mmol)
and NꢀnitrosoꢀNꢀcyclopropylurea (0.71 g, 5.5 mmol) in CH2Cl2
(20 mL), and the mixture was vigorously stirred for 3 h at the
same temperature. Then the reaction mixture was filtered, the
solvent was evaporated in vacuo, and the residue was recrystalꢀ
lized from benzene. Compound 13a, yield 63%, m.p. 145—147 °C.
Found (%): C, 65.68; H, 5.08; N, 16.32. C14H13N3O2. Calcuꢀ
lated (%): C, 65.87; H, 5.13; N, 16.46. 1H NMR (CDCl3), δ:
1.44, 1.92 (both m, 2H each, CH2CH2); 2.37 (s, 3 H, Me); 3.13
(d, 1 H, H(5), 3J = 8.5 Hz); 6.02 (d, 1 H, H(1), 3J = 8.5 Hz);
7.12, 7.28 (both d, 2H each, C6H4, J = 8.7 Hz). 13C NMR
(CDCl3), δ: 11.2, 16.8 (CH2CH2); 21.2 (Me); 41.6 (C(5)); 73.6
(C(4)); 91.7 (C(1)); 126.1 (Cm); 128.4 (Cp); 130.0 (Co); 139.2
(Cipso); 168.8 and 173.7 (2 CO). Partial MS, m/z (Irel (%)): 255
[M]+ (51), 227 (10), 133 (13), 66 (100). Compound 13b, yield
74%, m.p. 195—197 °C. Found (%): C, 48.58; H, 3.08; Br, 24.62.
C
13H10BrN3O2. Calculated (%): C, 48.77; H, 3.15; Br, 24.96.
1H NMR (CDCl3), δ: 1.48, 1.95 (both m, 2H each, CH2CH2);
3.15 (d, 1 H, H(5), 3J = 8.4 Hz); 6.02 (d, 1 H, H(1), 3J =
8.4 Hz); 7.16, 7.58 (both d, 2H each, C6H4, J = 8.7 Hz).
13C NMR (CDCl3), δ: 11.3, 16.9 (CH2CH2); 41.6 (C(5)); 73.5
(C(4)); 91.8 (C(1)); 122.9 (Cp); 127.8 (Cm); 129.9 (Cipso); 132.4
(Co); 168.3, 173.2 (2 CO). Partial MS, m/z (Irel (%)): 321 (0.5)
and 319 (0.5) [M]+, 184 (20), 94 (35), 66 (100%).
Nꢀ(pꢀTolyl)ꢀ6ꢀaminoꢀ5ꢀoxoꢀ4ꢀazaspiro[2.4]heptanꢀ7ꢀcarbꢀ
oxamide (14). Pyrazoline 13a (0.38 g, 1.5 mmol), ethanol
(50 mL), and Raney nickel (0.05 g) were placed in a 100ꢀcm3
steel autoclave and hydrogenated at 80 °C and at a hydrogen
pressure of 100 bar for 6 h. Then the reaction mixture was
filtered, the solvent was evaporated, the residue was treated with
ethyl acetate, and the precipitate was filtered off and dried
in vacuo to give 0.25 g (64%) of compound 14 as colorless crysꢀ
tals, m.p. 199—201 °C. 1H NMR (DMSOꢀd6), δ: 0.82, 1.54
(both m, 2 H each, CH2CH2); 2.24 (s, 3 H, Me); 3.14 (d, 1 H,
J = 8.5 Hz); 3.32 (br.s, 2 H, NH2); 3.88 (d, 1 H, J = 8.5 Hz);
7.11, 7.48 (both d, 2 H each, C6H4, J = 8.7 Hz); 7.82, 9.80
(both br.s, 1 H each, 2 NH). 13C NMR (DMSOꢀd6), δ: 7.9, 8.7
(CH2CH2); 19.9 (Me); 37.2 (C(3)); 54.6 (C(7)); 55.3 (C(6));
118.9 (Cm); 128.6 (Co); 132.0 (Cp); 135.7 (Cipso); 167.6, 175.2
(2 CO). Partial MS, m/z (Irel (%)): 259 [M]+ (7), 203 (4), 163
(18), 126 (64), 107 (100).
6,11ꢀDiazadispiro[2.1.4.2]undecaneꢀ7,10ꢀdione (12). Pyrꢀ
azoline 11 (0.105 g, 0.44 mmol), ethanol (6 mL), and Raney
nickel (0.02 g) were placed in a 100ꢀcm3 autoclave and hydrogeꢀ
nated at 80 °C and a hydrogen pressure of 100 bar for 5 h. The
reaction mixture was filtered, the solvent was evaporated, and
Nꢀ(4ꢀBromophenyl)ꢀ6ꢀethoxycarbonylꢀ4,5ꢀdiazaspiꢀ
ro[2.4]heptꢀ5ꢀeneꢀ7ꢀcarboxamide (15). Sodium hydroxide
(1.6 mg, 0.04 mmol) in ethanol (1 mL) was added to a suspenꢀ

2568
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005
Kostyuchenko et al.
sion of pyrazoline 13b (0.65 g, 2 mmol) in ethanol (5 mL), and
the mixture was stirred for 10 h. Then the solvent was removed
in vacuo, the residue was treated with CHCl3, and the insoluble
part, representing product 15, was filtered off and dried in air to
give 0.55 g (85%) of compound 15 as slightly yellowish crystals,
m.p. 217—219 °C. 1H NMR (DMSOꢀd6), δ: 0.88 (m, 4 H,
CH2CH2); 1.16 (t, 3 H, Me, J = 7.0 Hz); 3.92 (s, 1 H, CH); 4.11
(q, 2 H, OCH2, J = 7.0 Hz); 7.50 (m, 4 H, C6H4); 8.60 (br.s,
1 H, NH); 10.05 (br.s, 1 H, CONH). 13C NMR (DMSOꢀd6), δ:
7.9, 13.8 (CH2CH2); 13.6 (Me); 48.5 (C(3)); 54.0 (OCH2); 59.2
(C(7)); 114.5 (Cp); 120.7 (Cm); 131.0 (Co); 134.3 (Cipso); 137.5
(C(6)); 161.6, 167.2 (2 CO). Partial MS, m/z (Irel (%)): 367
(0.5) and 365 (0.5) [M]+, 168 (38), 122 (100).
reaction mixture was filtered, the solvent was evaporated in
vacuo, and the residue was recrystallized from ether.
5,5ꢀDimethylꢀ7ꢀphenylꢀ4,6ꢀdiazaspiro[2.5]octane (20a) was
prepared from pyrazoline 17a (0.57 g), yield 0.43 g (60%), colꢀ
orless crystals, m.p. 71—73 °C. Found (%): C, 77.51; H, 9.18;
N, 13.02. C14H20N2. Calculated (%): C, 77.73; H, 9.32; N, 12.95.
1H NMR (CDCl3), δ: 0.36—0.78 (m, 4 H, CH2CH2); 1.18 (dd,
1 H, HaC(8), 2J = 13.4 Hz, 3J = 11.9 Hz); 1.34, 1.53 (both s,
3 H each, 2 Me); 1.89 (dd, 1 H, HbC(8), 2J = 13.4, 3J = 3.0 Hz);
2.07 (br.s, 2 H, 2 NH); 4.28 (dd, 1 H, H(7), 3J = 3.0 and 11.9
Hz); 7.28 (m, 5 H, Ph). 13C NMR (CDCl3), δ: 11.2, 16.4
(CH2CH2); 24.3, 32.6 (2 Me); 33.2 (C(3)); 42.4 (C(8)); 54.0
(C(7)); 67.7 (C(5)); 126.6 (Cm); 127.2 (Cp); 128.5 (Co); 144.4
(Cipso). Partial MS, m/z (Irel (%)): 215 [M – H]+ (4), 187 (42),
158 (61), 106 (100).
NꢀBromophenylꢀ5ꢀethylꢀ3ꢀethoxycarbonylpyrazoleꢀ4ꢀcarbꢀ
oxamide (16). Sodium hydroxide (80 mg, 2.0 mmol) in ethanol
(1 mL) was added to a suspension of pyrazoline 13b (0.64 g,
2.0 mmol) in ethanol (5 mL) and the mixture was stirred for
10 h. The homogeneous reaction mixture was concentrated, and
the residue was dissolved in CH2Cl2 (5 mL) and washed with
water (10 mL). The organic layer was dried with anhydrous
Na2SO4. Removal of the solvent gave 0.51 g (80%) of pyrazole
5,5ꢀDimethylꢀ7ꢀ(4ꢀfluorophenyl)ꢀ4.6ꢀdiazaspiro[2.5]octane
(20b) was prepared from pyrazoline 17b (0.63 g), yield 0.48 g
(62%), colorless crystals, m.p. 74—75 °C. 1H NMR (CDCl3), δ:
0.35—0.74 (m, 4 H, CH2CH2); 1.26 (dd, 1 H, HaC(8), 2J =
13.2 Hz, 3J = 11.7 Hz); 1.32, 1.51 (both s, 3 H each, 2 Me); 1.57
(br.s, 2 H, 2 NH); 1.82 (dd, 1 H, HbC(8), 2J = 13.2 Hz, 3J =
1
3
16, m.p. 205—207 °C. H NMR (CDCl3), δ: 1.27 (t, 3 H, Me,
3.0 Hz); 4.23 (dd, 1 H, H(7), J = 3.0 and 11.7 Hz); 7.02, 7.32
J = 7.3 Hz); 1.49 (t, 3 H, Me, J = 7.5 Hz); 2.93 (q, 2 H, CH2,
J = 7.5 Hz); 4.48 (q, 2 H, OCH2, J = 7.3 Hz); 5.29 (br.s, 1 H,
NH); 7.29, 7.52 (both d, 2H each, C6H4, J = 9.0 Hz); 12.49
(br.s, 1 H, CONH). 13C NMR (DMSOꢀd6), δ: 13.5, 13.6 (2 Me);
19.9 (CH2); 59.2 (OCH2); 106.1 (C(4)); 114.4 (Cp); 120.8 (Cm);
131.2 (Co); 138.2 (Cipso); 146.9, 153.0 (C(3), C(5)); 161.1, 164.6
(2 CO). Partial MS, m/z (Irel (%)): 367 (22) and 365 (24) [M]+,
321 (25) and 319 (25) [M – EtOH]+, 195 (48), 173 (90),
171 (100).
A similar procedure starting from 2ꢀpyrazoline 15 (0.27 g,
0.73 mmol) and NaOH (0.033 g, 0.8 mmol) in ethanol (5 mL)
with a 10ꢀh stirring at room temperature gave 0.25 g (95%) of
pyrazole 16.
(both m, 2 H each, C6H4F). 13C NMR (CDCl3), δ: 11.2, 16.4
(CH2CH2); 24.3, 33.1 (2 Me); 32.6 (C(3)); 42.5 (C(8)); 53.4
(C(7)); 67.7 (C(5)); 115.2 (d, Cm, J = 21.2 Hz); 128.2 (d, Co,
J = 7.9 Hz); 140.2 (Cipso); 161.9 (d, Cp, J = 241 Hz). Partial MS,
m/z (Irel (%)): 234 [M]+ (4), 221 (23), 177 (28), 165 (100).
Reduction of phenylpyrazoline 17a with sodium in ethanol.
Sodium (1.8 g, 80 mmol) was added in small portions over a
period of 20 min to a boiling solution of pyrazoline 17a (0.34 g,
2 mmol) in ethanol (50 mL). After completion of the reaction,
the mixture was cooled to 20 °C, water (50 mL) was added, and
the mixture was extracted with CH2Cl2 (50 mL). The solution
was dried with anhydrous Na2SO4 and the solvent was evaporated
1
in vacuo. According to H NMR data, the residue (0.34 g) conꢀ
6ꢀ(4ꢀFluorophenyl)ꢀ4,5ꢀdiazaspiro[2.4]heptꢀ4ꢀene (17b).
NꢀNitrosoꢀNꢀcyclopropylurea (2.56 g, 20 mmol) was added at
–20 °C over a period of 15 min to a vigorously stirred mixture of
4ꢀfluorostyrene (3.15 g, 26 mmol) and MeONa (1.40 g, 26 mmol)
in MeOH (4 mL) and CH2Cl2 (20 mL), and the mixture was
stirred for additional 15 min. Then the temperature was inꢀ
creased to 5 °C and water (~0.5 mL) was added. The organic
layer was separated, and the solid residue was washed with
CH2Cl2 (10 mL), dried with anhydrous Na2SO4, and conꢀ
centrated in vacuo. The residue was recrystallized from an
ether—hexane mixture (1 : 3) to give 3.20 g (65%) of pyrazoline
17b as yellow crystals, m.p. 38—39 °C. 1H NMR (CDCl3), δ:
1.18 (m, 2 H, CHCH, directed away from the heterocycle
N atoms); 1.88 (m, 2 H, CHCH, directed toward the heteroꢀ
cycle N atom); 1.74 (dd, 1 H, HaC(7), 2J = 9.9 Hz, 3J = 7.1 Hz);
2.27 (dd, 1 H, HbC(7), 2J = 9.9 Hz, 3J = 12.9 Hz); 5.62 (dd,
1 H, H(6), 3J = 7.1 and 12.9 Hz); 7.05, 7.22 (both m, 2H each,
C6H4F). 13C NMR (CDCl3), δ: 14.2 (CH2CH2); 33.4 (C(7));
69.6 (C(3)); 89.2 (C(6)); 115.8 (d, Cm, J = 21.5 Hz); 128.9 (d,
Co, J = 7.6 Hz); 135.4 (Cipso); 162.3 (d, Cp, J = 246 Hz). Partial
MS, m/z (Irel (%)): 190 [M]+ (6), 161 (18), 147 (100).
tained 6ꢀphenylꢀ4,5ꢀdiazaspiro[2.4]heptane (18a) and 3(5)ꢀpheꢀ
nylꢀ5(3)ꢀethylpyrazole (22) in ~(4 : 1) ratio as the major identiꢀ
fied products (overall content ~80%). Compound 22 was identiꢀ
fied by comparison with an authentic sample.13 Compound 18a.
1H NMR (CDCl3), δ: 0.72, 0.91 (both m, 2H each, CH2CH2);
2.12 (dd, 1 H, HaC(7), 2J = 12.5 Hz, 3J = 6.5 Hz); 2.48 (dd,
1 H, HbC(7), 2J = 12.5 Hz, 3J = 8.7 Hz); 3.90 (br.s, 2 H,
NH—NH); 4.52 (dd, 1 H, H(6), 3J = 6.5 and 8.7 Hz); 7.22—7.52
(m, 5 H, Ph). 13C NMR (CDCl3), δ: 10.7, 12.7 (CH2CH2); 43.9
(C(7)); 45.9 (C(3)); 66.5 (C(6)); 126.8 (Cm); 127.3 (Cp); 128.7
(Co); 142.7 (Cipso).
3ꢀPhenylꢀ3ꢀethoxyꢀ5ꢀethylꢀ3Hꢀpyrazole (23). Petroleum
ether (b.p. 40—70 °C) (5 mL) and freshly distilled acetaldehyde
(0.075 g, 1.7 mmol) were added to the reaction mixture (0.24 g)
obtained in the previous experiment and containing ~60%
pyrazolidine 18a, and the mixture was refluxed until the starting
pyrazoline disappeared (TLC, Silufol, CHCl3—MeOH, 4 : 1, as
the eluent). After 2 h, the reaction mixture was cooled and the
solvent was evaporated in vacuo at 20 °C. Vacuum microꢀ
distillation of the residue (bath temperature 140 °C, 0.15 Torr)
gave 0.065 g of a yellowish liquid, containing, according to
1H NMR data, ~90% pyrazole 23 (yield ~50%). 1H NMR
(CDCl3), δ: 1.29 (t, 3 H, Me, J = 7.6 Hz); 1.38 (t, 3 H, Me, J =
7.3 Hz); 2.69 (q, 2 H, CH2, J = 7.6 Hz); 4.09 (q, 2 H, OCH2,
J = 7.3 Hz); 6.08 (s, H(4)); 7.32—7.48 (m, 5 H, Ph). 13C NMR
(CDCl3), δ: 14.0, 15.9 (2 Me); 21.5 (CH2); 44.1 (OCH2); 104.1
Catalytic reduction of pyrazolines 17 in the presence of acꢀ
etone (general procedure). Pyrazoline 17 (3.3 mmol), acetone
(0.38 g, 6.6 mmol), ethanol (10 mL), and Raney nickel (0.05 g)
were placed in a 100ꢀcm3 autoclave. Hydrogenation was carried
out at 80 °C and at a hydrogen pressure of 100 bar for 6 h. The

Reduction of spiro[cyclopropaneꢀ3ꢀ(1ꢀpyrazolines)] Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2569
(C(4)); 128.2, 128.6, 128.7, 131.3 (Ph); 143.7 (C(3)); 153.8
(C(5)). Partial MS, m/z (Irel (%)): 216 [M]+ (3), 200 (68), 172
(74), 77 (100).
Preparation of diammonium salts 21a,b. A 4 M solution of
HCl in dioxane (1 mL) was added in one portion to a solution of
hexahydropyrimidine 20a or 20b (1.6 mmol) in dioxane (1 mL),
and, after 15 min, the solvent was evaporated in vacuo. The
residue was dissolved in water, the solution was washed with
CH2Cl2, and water was evaporated in vacuo.
1H NMR (CDCl3), δ: 0.65, 0.79 (both m, 2H each, CH2CH2);
1.53 (dd, 1 H, Ha from CH2, 2J = 14.4 Hz, 3J = 10.5 Hz); 1.82,
2.04 (both s, 3 H each, 2 Me); 2.40 (dd, 1 H, Hb from CH2, 2J =
14.4 Hz, 3J = 4.3 Hz); 5.20 (ddd, 1 H, CH, 3J = 4.3 and 10.5 Hz,
3JHCNH = 9.0 Hz); 6.21 (br.d, 1 H, NH, 3J = 9.0 Hz); 6.62 (br.s,
1 H, NH); 7.28 (m, 5 H, Ph). 13C NMR (CDCl3), δ: 13.0,
13.4 (CH2CH2); 23.5, 23.6 (2 Me); 30.4 (C); 41.5 (CH2); 51.3
(CH); 126.6 (Cm); 127.6 (Co); 128.8 (Cp); 141.6 (Cipso); 170.3,
177.0 (2 CO). Partial MS, m/z (Irel (%)): 260 [M]+ (0.4), 217
[M – Ac]+ (12), 106 (100).
1ꢀ(2ꢀAminoꢀ2ꢀphenylethyl)cyclopropylamine dihydrochloride
(21a). Yield 73%, m.p. 267—268 °C. Found (%): C, 52.73;
H, 7.49; Cl, 11.46; N, 28.30. C11H18Cl2N2. Calculated (%):
C, 53.07; H, 7.28; Cl, 11.24; N, 28.46. 1H NMR (DMSOꢀd6), δ:
0.19, 0.89, 1.16 (all m, 1 + 2 + 1 H, CH2CH2); 2.07 (dd, 1 H,
2J = 15.5 Hz, 3J = 8.9 Hz) and 2.31 (dd, 1 H, CH2, 2J = 15.5 Hz,
3J = 6.1 Hz); 4.80 (dd, 1 H, HC, 3J = 6.1 and 8.9 Hz); 7.41, 7.69
(both m, 2 + 3 H, Ph); 8.84 (br.s, 6 H, 2 H3N+). 13C NMR
(DMSOꢀd6), δ: 8.4, 9.6 (CH2CH2); 23.4 (C); 30.0 (CH2); 50.6
(CH); 127.0 (Co); 128.1 (Cp); 128.2 (Cm); 161.6 (Cipso).
1ꢀ[2ꢀAminoꢀ2ꢀ(4ꢀfluorophenyl)ethyl]cyclopropylamine diꢀ
hydrochloride (21b). Yield 93%, colorless crystal, m.p.
141—142 °C. Found (%): C, 49.31; H, 6.32; Cl, 26.37; N, 10.30.
C11H17Cl2FN2. Calculated (%): C, 49.45; H, 6.41; Cl, 26.54;
N, 10.49. 1H NMR (DMSOꢀd6), δ: 0.19, 0.89, 1.04 (all m,
1 + 2 + 1 H, CH2CH2); 2.21 (m, 2 H, CH2); 4.81 (m, 1 H, HC);
7.71, 7.39 (both m, 2H each, C6H4F); 8.71 (br.s, 6 H, 2 H3N+).
13C NMR (DMSOꢀd6), δ: 8.4, 9.5 (CH2CH2); 25.0 (C); 30.0
(CH2); 49.8 (CH); 115.1 (d, Cm, J = 21.5 Hz); 129.3 (d, Co, J =
8.4 Hz); 134.0 (Cipso); 161.6 (d, Cp, J = 245 Hz).
1ꢀ(2ꢀAminoꢀ2ꢀphenylethyl)cyclopropylamine (19a). A 10%
aqueous solution of NaOH (1.5 mL) was added to a solution of
salt 21a (0.30 g, 1.2 mmol) in water (1 mL), and the mixture was
stirred for 5 min and extracted with CH2Cl2 (3 mL). The organic
layer was separated and dried with anhydrous Na2SO4, and the
solvent was evaporated in vacuo to give 0.21 g (98%) of diamine
19a as a slightly yellowish thick liquid. Found (%): C, 74.71;
H, 9.03; N, 15.62. C11H16N2. Calculated (%): C, 74.96; H, 9.15;
N, 15.89. 1H NMR (CDCl3), δ: 0.27, 0.52 (both m, 1 + 3 H,
CH2CH2); 1.79 (br.d, 2 H, CH2, J ≈ 7.0 Hz); 2.20 (br.s, 4 H,
2 NH2); 4.23 (br.t, 1 H, CH, J ≈ 7.0 Hz); 7.28 (m, 5 H, Ph).
13C NMR (CDCl3), δ: 14.2, 15.3 (CH2CH2); 33.0 (C);
49.4 (CH2); 55.1 (CH); 126.3 (Co); 127.1 (Cp); 128.6 (Cm);
147.0 (Cipso).
1,2´ꢀBis(ethoxyoxalylamino)ꢀ1ꢀ[2´ꢀ(4″ꢀfluoropheꢀ
nyl)ethyl]cyclopropane (26). Triethylamine (0.10 g, 1.0 mmol)
and diethyl oxalate (0.13 g, 1.3 mmol) were added successively
to a suspension of salt 19b (0.115 g, 0.43 mmol) in CH2Cl2
(5 mL), and the reaction mixture was kept for 72 h at 20 °C. The
solvent and excess diethyl oxalate was removed in vacuo and
the residue was chromatographed on a column with SiO2
(ether—AcOEt, 1 : 1, as the eluent) to give 0.094 g (59%) of
compound 26 as a resinous beigeꢀcolored liquid. Found (%):
C, 57.54; H, 5.59; N, 6.93. C17H23FN2O6. Calculated (%):
C, 57.86; H, 5.88; N, 7.10. 1H NMR (CDCl3), δ: 0.81, 0.92
(both m, 2H each, CH2CH2); 1.38 (q, 6 H, 2 Me, 3J = 7.0 Hz);
1.71 (dd, 1 H, Ha from CH2, 2J = 14.3 Hz, 3J = 9.6 Hz); 2.50
(dd, 1 H, Hb from CH2, 2J = 14.3 Hz, 3J = 4.9 Hz); 4.32 (m,
4 H, 2 OCH2); 5.18 (ddd, 1 H, CH, 3J = 4.9 and 9.6 Hz,
3JHCNH = 8.6 Hz); 7.02, 7.29 (both m, 2H each, Ph); 7.52 (br.d,
1 H, NH, 3J = 8.6 Hz); 7.79 (br.s, 1 H, NH). 13C NMR (CDCl3),
δ: 12.9, 13.4 (2 Me); 14.0 (CH2CH2); 30.8 (C); 40.7 (CH2); 51.5
(CH); 63.2, 63.5 (2 OCH2); 115.8 (d, Cm, J = 21.6 Hz); 128.5
(d, Co, J = 8.2 Hz); 135.8 (Cipso); 159.9 (d, Cp, J = 246 Hz);
160.4, 164.3 (2 CO). Partial MS, m/z (Irel (%)): 394 [M]+ (0.2),
321 [M – CO2Et]+ (7), 224 (100).
The authors are grateful to Academician O. M.
Nefedov for participation in the discussion and in the
preparation of this study for publication.
This work was supported by the Federal Agency on
Science and Innovation and the Council for Grants
at Russian Federation President (State Program for
the support of leading scientific schools, project
NShꢀ1987.2003.3) and the Presidium of the Russian Acadꢀ
emy of Sciences (Fundamental Research Program "Tarꢀ
geted Synthesis of Organic Compounds with Specified
Properties and Design of Functional Materials Based
on Them").
1ꢀ[2ꢀAminoꢀ2ꢀ(4ꢀfluorophenyl)ethyl]cyclopropylamine (19b).
A similar procedure starting from salt 21b (55 mg, 0.21 mmol)
gave diamine 19b (38 mg, 98%) as a yellowish thick liquid.
1H NMR (CDCl3), δ: 0.26, 0.52 (both m, 1 + 3 H, CH2CH2);
2
3
1.70 (dd, 1 H, CH2, J = 14.0 Hz, J = 8.1 Hz); 1.74 (dd, 1 H,
2
3
CH2, J = 14.0 Hz, J = 5.9 Hz); 1.82 (br.s, 4 H, 2 NH2); 4.26
(dd, 1 H, CH, 3J = 5.9 and 8.1 Hz); 7.01, 7.34 (both m, 2 H each,
C6H4F). 13C NMR (CDCl3), δ: 14.1, 15.2 (CH2CH2); 32.7 (C),
49.4 (CH2); 54.3 (CH); 115.2 (d, Cm, J = 21.1 Hz); 127.8 (d,
Co, J = 7.9 Hz); 142.5 (Cipso); 161.8 (d, Cp, J = 245).
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Received August 29, 2005;
in revised form October 18, 2005