Synthesis of cyclopropane derivatives of aspartic acid by thermal decomposition of substituted pyrazolines

Article abstract of DOI:10.1023/A:1015468306583

Thermal decomposition of substituted Δ¹- and Δ ²-pyrazolines was used to obtain cyclopropane derivatives of aspartic and adipic acids.

Full text of DOI:10.1023/A:1015468306583

Russian Journal of General Chemistry, Vol. 72, No. 3, 2002, pp. 460 463. Translated from Zhurnal Obshchei Khimii, Vol. 72, No. 3, 2002,
pp. 495 498.
Original Russian Text Copyright
2002 by Anisimova, Berkova, Paperno, Deiko.
Synthesis of Cyclopropane Derivatives of Aspartic Acid
by Thermal Decomposition of Substituted Pyrazolines
N. A. Anisimova, G. A. Berkova, T. Ya. Paperno, and L. I. Deiko
Mountain-Altaisk State University, Mountain-Altaisk, Russia
Gertsen Russian State Pedagogical University, St. Petersburg, Russia
Received July 22, 1998
Abstract Thermal decomposition of substituted 1- and 2-pyrazolines was used to obtain cyclopropane
derivatives of aspartic and adipic acids.
The interest in -amino acids of the cyclopropane
series, including cyclopropane analogs of glutamic
and aspartic acids, is associated with the possibility
of designing on their basis new antispasmodic and
psychotropic drugs [1]. In this connection search for
synthetic approaches to such amino acids takes on
special significance.
variable and depends on the structure of the parent
pyrazolines [2], as well as on the reaction conditions
[3, 4]. According to [5, 6], thermolysis of 1-pyra-
zolines yields mostly cyclopropane derivatives, while
2-pyrazolines, by contrast, are a source of un-
saturated compounds.
In the present work we decomposed 1- (I, II) and
2-pyrazolines III VI obtained in the previous works
[7 10].
One of the methods for preparing precursors of
cyclopropane -amino acids involves decomposition
of pyrazoline derivatives. N-Unsubstituted pyrazolines
decompose under rigid conditions; the reaction in-
volves nitrogen evolution and generally takes two
pathways to give either cyclopropane or unsaturated
compounds. The ratio of these two products is
Earlier Bregovec and Jakovcic [1] decomposed
pyrazoline I in toluene under reflux (2.5 h, argon
atmosphere). The reaction gave rise to 1-(acetylamino)-
cyclopropane-1-carboxylic acid (VII) in an yield of
70%. By changing toluene by the higher boiling di-
H
N
N
N
R1
R2
R1
R2
R1
N
NH
CO2Me
NHAc
III, IV
N
R2
CO2Me
CO2Me
NHAc
V, VI
NHAc
I, II
N+N
HB
R2
HB
R1
HA
R1
CO2Me
CO2Me
NHAc
CH3 C=C CO2Me
NHAc
R2
+
HA
Ph
VIII
NHAc
E-VII, E-X, E-XII,
E-XIV, E-XVI
Z-IX, Z-XI, Z-XIII,
Z-XV
R1 = H (I, VII, VII X), CO2Me (III, V, XI, XII, XV), CO2Et (IV, VI, XIII, XIV, XVI); R2 = H (I, III, IV, VII,
XI XIV), Ph (II, V, VI, IX, X, XV, XVI).
1070-3632/02/7203-0460$27.00 2002 MAIK Nauka/Interperiodica

SYNTHESIS OF CYCLOPROPANE DERIVATIVES OF ASPARTIC ACID
Table 1. Yields, melting points, and elemental analyses of compounds VII and IX XVI
Found, %
461
Calculated, %
H
Comp.
no.
Yield,
%
mp,
C
Formula
C
H
N
C
N
VII
IX
X
95
42
20
35
15
35
15
40
40
82 84
78 79
58 60
121 122
69 70
84 85
49 50
Oil
53.52
66.92
66.92
50.20
50.20
52.42
52.41
61.88
62.95
7.00
6.42
6.40
6.01
6.03
6.53
6.56
5.82
6.23
8.93
6.02
6.05
6.65
6.55
6.11
6.11
4.90
4.58
C7H11NO3
C13H15NO3
C13H15NO3
C9H13NO5
C9H13NO5
C10H15NO5
C10H15NO5
C15H17NO5
C16H19NO5
53.50
66.95
66.90
50.23
50.29
52.40
52.40
61.86
62.95
7.01
6.44
6.43
6.05
6.00
6.55
6.55
5.84
6.23
8.92
6.01
6.02
6.51
6.50
6.10
6.10
4.81
4.59
XI
XII
XIII
XIV
XV
XVI
methylformamide, we could not only reduce the re-
action time to 20 min, but also improve the yield of
cyclopropane VII to 95%.
with the mechanism of pyrazoline ring cleavage,
proposed by Tabushi et al. [13]. The same views
have been advanced by Thomas et al. [14 ], who
related the stability of the intermediate with the pre-
sence of electron-acceptor substituents in the 3 or 5
positions of the pyrazoline ring.
Thermolysis of 1-pyrazoline Z-II under the same
conditions allowed preparation (by contrast to data
in [2]) of cyclopropane derivatives IX and X in an
yield of 62%, along with alkene VIII.
According to [2, 13, 15], thermolysis of 1-pyra-
zolines should be considered as a stereospecific
process, where the configuration of substituents in the
decomposition products is the same as in the parent
pyrazolines. However, we found that thermolysis of
substituted 1- (II) and 2- pyrazolines (III VI) in
DMF occurs nonstereospecifically. Thus, isomer Z-II
in our conditions gives cyclopropanes Z-IX and E-X,
individual compounds III and IV give mixtures
Z-XI + E-XII and Z-XIII + E-XIV, respectively,
while individual destereomers V and VI give a mix-
ture of four different stereoisomers of compounds XV
and XVI. By column chromatography we could se-
parate Z- and E isomers IX XIV and isolate the most
stable stereoisomers E-XV and E-XVI from the
stereiosmeric mixture.
Cyclopropane derivatives from pyrazolines are
commonly prepared by catalytic thermolysis [11] or
by photolysis [12]. However, under the conditions
reported therein we failed to synthesize cyclopropane
precursors of aspartic acid from pyrazolines III and
IV. The latter could only be thermolyzed in DMF
under reflux to obtain cyclopropanes XI XIV in an
yield of 50%. We were the first to obtain compounds
XI XIV by this method. Earlier compounds XI and
XII were synthesized in another way [8].
The use of DMF for decomposing compounds V
and VI allowed us to prepare previously unknown
phenylaspartic acid derivatives XV and XVI.
It should be noted that, unlike 1-pyrazolines, the
more stable 2-pyrazolines require longer reaction
times to decompose: 40 (III, IV) and 60 min (V, VI),
instead of 20 min. This fact appears to be explained
by the additional conjugation of the C=N bond in
them with R1 and R2 (N=CHCO2R, N=CHPh) and
the change from the 2- to 1-pyrazoline structure.
The complication of the molecular structure in the
series I VI not only increases the reaction time, but
also reduces the yield of cyclopropanes from 95 and
40% (Table 1).
The nonstereospecificity of the decomposition of
1- and 2-pyrazolines can be explained by the forma-
tion of a stable intermediate and the possibility of
rotation in it of substituents about the C4 C5 bond.
The structure of amino acids XI XVI was establi-
1
shed by H NMR and IR spectroscopy and by com-
parison with model compounds VII, IX, and X
1
(Table 2). The H NMR spectra of XI XVI show
signals of all structural fragments and reveal non-
equivalence of ring protons which appear as a multi-
plet (1.1 2.2 ppm) overlapping with the NAc signal.
Stereochemical assignment of Z-XI, E-XII, Z-XIII,
and E-XIV was performed on the basis of the che-
mical shifts of NHAc protons: The signals of Z
The formation of cyclopropanes from 1- (II) and
2-pyrazolines (III VI) can be explained in terms of
the effect of solvent polarity on the stability of the
intermediate zwitter ion, which is nicely consistent
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 3 2002

462
ANISIMOVA et al.
Table 2. IR and 1H NMR spectra of cyclopropane derivatives VII and IX XVI
IR spectrum (CHCl3),
1H NMR spectrum (CDCl3),
, ppm; J, Hz
1
, cm
Comp.
no.
CH CH
(ring)
C=O N H C H CH2
R1
R2
CO2Me NHAc
NH
JAB JA,R JB,R
2
2
VII
1720, 3420
1680
1.04 m (1H) 1.44 m (1H) 1.44 m
3.62 s 1.93 s 7.49 s 7.2 8.5
(3H) (3H) (1H)
3.75 s 1.75 s 7.18 s 9.0
(3H) (3H) (1H)
3.70 s 1.82 s 7.18 s 7.0
(3H) (3H) (1H)
1.87 d.d 3.40 s 1.68 s 7.36 s 9.0 8.0
(2H) (3H) (3H) (1H)
4.5
4.5
4.3
2.5
(2H)
Z-IX
ð-X
1720, 3420 3000 1250 1.15 2.00 m 7.18 7.23 m 2.28 m
1678 (1H) (5H, Ph) (2H)
1720, 3420 3000 1260 1.12 1.98 m 7.18 8.23 m 1.70 m
1700
(1H)
(5H, Ph)
1.23 d.d
(1H)
(2H)
Z-XI
1725, 3420, 3040 1270, 3.40 s
1720, 3400
1690 3200
1225, (3H, CO2Me)
1180
E-XII 1720, 3420, 3030 1280, 3.65 s
1.78 d.d
(1H)
1.64 d.d 3.67 s 1.91 s 6.62 s 7.5 9.5
(2H) (3H) (3H) (1H)
4.5
5.0
4.5
1710, 3410
1690 3220
1210 (3H, CO2Me)
1180
3445, 1265, 1.20 t (3H), 1.74 m
3440 1230, 4.11 q (2H) (1H)
3200 1190 (CO2Et)
3443, 1270, 1.16 t (3H), 1.46 m
3400 1240, 4.09 q (2H) (1H)
3200 1170 (CO2Et)
Z-XIII 1720,
1.63 d.d 3.70 s 1.93 s 6.38 s 8.5 7.5
(2H) (3H) (3H) (1H)
1715,
1690
E-XIV 1730,
1720,
1.98 d.d 3.62 s 1.90 s 7.33 s 7.5 9.0
(2H)
(3H)
(3H)
(1H)
1695
Z-XV 1720,
1700,
3420 1150, 3.70 s
7.20 7.37 m 2.06 m
3.69 s 1.76 s 6.97 s 9.5
(3H) (3H) (1H)
1210, (3H, CO2Me) (5H, Ph)
(2H)
1680
1230
Z-XVI 1730,
1710,
3420 1155, 1.16 t (3H), 7.17 7.31 m 1.89 m
1200, 4.15 q (2H) (5H, Ph) (2H)
1230 (CO2Et)
3.70 s 1.76 s 6.94 s 7.5
(3H) (3H) (1H)
1690
isomers are downfield from those of E isomers. This
fact can be explained by the through-space electron-
acceptor effect of the CO2R group which in the former
isomers is on the same side with NHAc with respect
to the ring plane. The IR spectra display absorption
bands of the cyclopropane system at 1290 1160 (de-
hydrogenated amino acids by the procedure [7, 8].
Cyclopropanes VII, IX, and X were obtained by
modified procedures [1, 2].
Methyl 1-(acetylamino)cyclopropane-1-carboxy-
late (VII). A solution of 5 g of pyrazoline III in
50 ml of DMF was refluxed for 20 min. The solvent
was removed on a rotary evaporator, and the residue
(tarry substance) was subjected to chromatography
(eluent chloroform). Yield 4 g (95%).
1
formation vibrations) and 3040 2980 cm (stretching
vibrations) [16].
EXPERIMENTAL
Methyl 1-(acetylamino)-2-phenylcyclopropane-1-
carboxylates (Z-IX) and (E-X) were prepared by the
above procedure from 5 g of compound II. Column
chromatography gave 2.77 g (62%) of a 2:1 mixture
of isomers Z-IX and E-X (eluent chloroform). Methyl
2-(acetylamino)-3-phenyl-2-butenoate (VIII): eluent
benzene, yield 0.89 g (20%), mp 140 C (from CHCl3)
{physicochemical characteristics of compound VIII
coincide with those reported in [2]}.
The IR spectra were obtained on a UR-20 spectro-
meter in CHCl3. The H NMR spectra were measured
1
on a Tesla BS-487C spectrometer at 80 MHz in
CDCl3. Column chromatography was performed on
Silica gel L 100/250 (Chemapol). The separation of Z
and E isomers was controlled by GLC. Thin-layer
chromatography was performed on Silufol-254 plates
in a 3:2 hexane acetone mixture.
Pyrazolines I VI were prepared by cycloaddition
of aliphatic diazo compounds to corresponding de-
Dimethyl 1-(acetylamino)cyclopropane-1,2-di-
carboxylates (Z-XI) and (E-XII) and 1-(acetyl-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 3 2002

SYNTHESIS OF CYCLOPROPANE DERIVATIVES OF ASPARTIC ACID
amino)-2-(ethoxycarbonyl)-1-(methoxycarbonyl)- 5. Engel, P., Chem. Rev., 1980, vol. 80, no. 2, p. 99.
463
cyclopropanes (Z-XIII) and (E-XIV) were syn-
thesized by refluxing 5 g of pyrazolines III and IV in
DMF for 40 min and isolated like compounds IX and
X. Yield 2.21 g (50%) (esters XI and XII) and 2.23 g
(50%) (esters XIII and XIV). The products all are
colorless crystals.
6. Auwers, K. and Konig, C., Justus Liebigs. Ann. Chim.,
1932, vol. 496, no. 252, p. 100.
7. Anisimova, N.A., Deiko, L.I., Berkova, G.A., and
Perekalin, V.V., Zh. Obshch. Khim., 1999, vol. 69,
no. 9, p. 1529.
8. Anisimova, N.A., Berkova, G.A., and Deiko, L.I., Zh.
Obshch. Khim., 1998, vol. 68, no. 7, p. 1165.
Dimethyl 1-(acetylamino)-3-phenyl-2-cyclo-
propane-1,2-dicarboxylate (XV) and 1-(acetyl-
amino)-2-(ethoxycarbonyl)-1-(methoxycarbonyl)-3-
phenylcyclopropane (XVI) were obtained by reflux-
ing pyrazolines V and VI for 60 min and isolated by
chromatography (eluent toluene). Compound XV:
yield 1.83 g, colorless oil, Rf 0.65. Compound XVI:
1.84 g, Rf 0.69.
9. Anisimova, N.A., Berkova, G.A., and Deiko, L.I., Zh.
Obshch. Khim., 1998, vol. 34, no. 8, p. 1263.
10. Anisimova, N.A., Berkova, G.A., and Deiko, L.I., Zh.
Org. Khim., 1999, vol. 35, no. 1, p. 159.
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Chem., 1965, vol. 43, no. 5, p. 1407.
12. Kohler, E. and Steele, L., J. Am. Chem. Soc., 1919,
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