Catalytic cyclopropanation of alkyl 2-allyl-2-acetylaminomalonate and methyl N-(acetyl)(phenyl)dehydroalanine with alkyl diazoacetates

Article abstract of DOI:10.1023/A:1015438005249

Cyclopropane analogs of aspartic and adipic acids were prepared by catalytic cyclopropanation of dehydro amino acid derivatives with alkyl diazoacetates in the presence of catalyst (dirhodium tetraacetate).

Full text of DOI:10.1023/A:1015438005249

Russian Journal of General Chemistry, Vol. 72, No. 2, 2002, pp. 272 275. Translated from Zhurnal Obshchei Khimii, Vol. 72, No. 2, 2002,
pp. 294 298.
Original Russian Text Copyright
2002 by Anisimova, Berkova, Paperno, Deiko.
Catalytic Cyclopropanation
of Alkyl 2-Allyl-2-acetylaminomalonate
and Methyl N-(Acetyl)(phenyl)dehydroalanine
with Alkyl Diazoacetates
N. A. Anisimova, G. A. Berkova, T. Ya. Paperno, and L. I. Deiko
Gorno-Altaisk State University, Gorno-Altaisk, Altai Republic, Russia
Herzen Russian State Pedagogical University, St. Petersburg, Russia
Received June 22, 1998
Abstract Cyclopropane analogs of aspartic and adipic acids were prepared by catalytic cyclopropanation
of dehydro amino acid derivatives with alkyl diazoacetates in the presence of catalyst (dirhodium tetraacetate).
Amino acids of the cyclopropane series widely
occur in the nature; they exhibit diverse physiological
activity and accomplish important functions in plants
and animals [1, 2]. Therefore, studies in the field of
synthesis of cyclopropanes with the aim of searching
for practically useful compounds, primarily drugs,
show much promise.
acids of the cyclopropane series and their synthetic
analogs [3, 4]. There are virtually no data in the litera-
ture on catalytic cyclopropanation of dehydro amino
acids of various structures with alkyl diazoacetates.
With the aim of searching for new amino dicarbox-
ylic acids of the cyclopropane series, we have per-
formed for the first time cyclopropanation of dehydro
amino acids I IV containing isolated (I, II), activated
(III), and conjugated (IV) C=C bonds with diazo
compounds V VII.
At present, cyclopropanation of unsaturated amino
acids with aliphatic diazo compounds in the presence
of catalysts is an efficient synthetic route to amino
R1 = H (I III), Ph (IV); R2
=
(I),
(II), CO2Me (III, IV); Alk = Me (VIII,
IX, XII, XIII), Et (X, XI, XIV, XV); R3 = H (I, II), NHAc (III, IV); R4 = CO2Me (V, VIII, XI, XII, XV, XVII,
XVIII, XXI), CO2Et (VI, IX, X, XIII, XIV, XIX, XX, XXII), H (VII).
1070-3632/02/7202-0272$27.00 2002 MAIK Nauka/Interperiodica

CATALYTIC CYCLOPROPANATION
1H NMR and analytical data for cyclopropane derivatives VIII XI and XVIa
1H NMR spectrum (CDCl3), , ppm
273
NHAc
CO2Me
CO2Et
CH2
CH2 ring
1.14 m (2H)
1.21 m (2H)
1.18 m (2H)
1.18 m (2H)
CH CH
NH
VIII 1.99 s (3H) 3.71 s (3H),
2.47 m (2H)
1.60 m, 2.29 m (2H) 7.19 s (1H)
1.60 m, 2.63 m (2H) 6.70 s (1H)
1.58 m, 2.53 m (2H) 6.89 s (1H)
1.58 m, 2.73 m (2H) 6.47 s (1H)
3.67 s (3H)
IX
X
1.98 s (3H) 3.62 s (6H) 1.13 t (3H), 2.41 m (2H)
4.20 q (2H)
2.00 s (3H)
1.18 t (9H), 2.30 m (2H)
4.20 q (6H)
XI
1.98 s (3H) 3.73 s (3H) 1.18 t (6H), 2.31 m (2H)
4.20 q (4H)
XVI 2.01 s (3H) 3.72 s (6H), 1.19 t (6H), 2.29 m (2H, CH2) 1.30 m (2H, CH2) 1.30 m, 2.01 m (2H) 6.89 s (1H)
4.09 q (4H) 2.54 m (2H, CH2)
Found, %
H
Calculated, %
H
Formula
C
N
C
N
VIII
IX
X
XI
XVI
51.80, 51.85
53.32, 53.36
55.95, 55.98
54.70, 54.74
55.97, 55.99
6.30, 6.33
6.68, 6.70
7.26, 7.30
6.97, 7.00
7.28, 7.31
4.68, 4.70
4.45, 4.50
4.08, 4.10
4.25, 4.30
4.07, 4.10
C13H19NO7
C14H21NO7
C16H25NO7
C15H23NO7
C16H25NO7
51.83
53.33
55.98
54.71
55.98
6.31
6.67
7.29
6.99
7.29
4.65
4.44
4.08
4.26
4.08
a
The coupling constants were not determined, because the multiplets overlapped.
Esters I and II reacted with alkyl diazoacetates V
and VI (CH2Cl2, 0 C, palladium acetate) by two path-
ways: formation of new cyclopropane derivatives of
adipic acid VIII XI in 7% yield and of unsaturated
compounds XII XV in 10% yield. By varying the
reaction conditions, we were able to increase the yield
of one of the products. For example, replacement of
palladium(II) acetate by dirhodium tetraacetate, other
conditions being similar, increased the yield of cyclo-
propanes VIII XI to 40%, and at the reaction temper-
ature increased to 22 C unsaturated compounds XII
XV were obtained in a quantitative yield.
aspartic acid in a low yield (10%). The reaction is
accompanied by formation of a polymer. The low
yield of cyclopropane derivatives is due to weak nu-
cleophilicity of the double bond in III and to the fact
that the electron-withdrawing substituent in this case
prevents addition of carbene [5]. Compounds XVII
and XIX were prepared previously by other proce-
dures [6, 7].
Introduction of the phenyl substituents into the
-position of the double bond in dehydroalanine, as
expected, deactivates the double bond. Attempts to
perform cyclopropanation of methyl N-acetyldehydro-
phenylalaninate IV with diazo compounds V and VI
under similar and more rigorous conditions (CH2Cl2,
refluxing, 20 h) failed. This result is consistent with
the published data that trisubstituted olefins [5], in
particular, dehydrophenylalanine [8], do not react with
diazoacetates even in the presence of a catalyst. How-
ever, replacement of the solvent CH2Cl2 by more
polar CHCl3 and refluxing of the reaction mixture for
6 h in the presence of the catalyst allowed us to per-
form for the first time cycloaddition of alkyl diazo-
acetates V and VI to alkene IV. In contrast to the ini-
tial dehydro amino acids containing isolated (I, II)
or activated (III) double bonds, reaction of diazo com-
Insertion product XV does not react with alkyl
diazoacetate V, whereas with diazomethane VII it
reacts even in the absence of catalyst to give the pre-
viously unknown cyclopropane derivative of pimelic
acid XVI in 90% yield. Different reactivity of V and
VII toward XV may be due to the smaller volume and
stronger nucleophilicity of diazomethane as compared
to alkyl diazoacetate, which is consistent with pub-
lished data [5].
Methyl N-(acetyl)dehydroalaninate III reacts with
alkyl diazoacetates V and VI to give cyclopropane
derivatives Z-VII, Z-XIX, E-XVIII, and E-XX of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 2 2002

274
ANISIMOVA et al.
1
pounds with IV in the presence of a catalyst yields
1,3-dipolar cycloaddition products, 2-pyrazolines
XXI and XXII. Despite the rigorous reaction condi-
tions and the use of the catalyst, no cyclopropane
products were detected in the reaction mixture. The
structure of 2-pyrazolines XXI and XXII shows that
the cycloaddition occurs against the Auwers rule [8].
The amino group in the H NMR spectra gives a
singlet at 6.47 6.89 ppm. In the IR spectra, this
group is manifested as a narrow band in the range
3420 3410 cm , and only the vibrations of the free
amino group are observed. Thus, no absorption related
to the presence of hydrogen bonds is observed; this is
due to the presence of the methylene group between
the ring and acetamidomalonate fragment, which
makes formation of intramolecular hydrogen bonds
less probable.
1
Formation of pyrazolines in this reaction can be
due to the fact that incorporation of alkene IV into the
coordination sphere of rhodium is hindered sterically
and electronically; competing incorporation into the
rhodium coordination sphere of smaller alkyl diazo-
acetate molecules seems more probable. The resulting
diazo compound catalyst complex attacks the C=C
bond to give 2-pyrazolines. The capability of rhodi-
um to form stable complexes with diazo compounds
was proved in [5].
In cyclopropane derivatives of adipic acid VIII XI,
the substituents presumably have the E arrangement
relative to the ring.
Our study showed that preparation of aminodicar-
boxylic acids of the cyclopropane series by catalytic
cyclopropanation is feasible only if the initial substi-
tuted dehydro amino acids contain the isolated double
bond. Unsaturated amino acid derivatives with the
activated C=C bond polymerize under conditions of
this reaction, and the yield of the corresponding cyclo-
propanes is low; dehydro amino acids with the conju-
gated C=C bond yield 1,3-dipolar cycloaddition prod-
ucts, pyrazolines.
The structure of new cyclopropanes VIII XI and
1
XVI was proved by H NMR and IR spectroscopy
(see table).
Compounds VIII XI and XVI contain two geminal
and two vicinal protons giving a characteristic upfield
multiplet in the 1H NMR spectra. The geminal protons
give signals at 1.14 1.30 ppm, and the vicinal pro-
tons, which are in the geminal position in the ring
relative to the acetamidomalonate moiety, give a
multiplet ( 1.30 1.60 ppm). The signal of the HX
proton at the C3 atom of the cyclopropane ring is
shifted downfield (a multiplet at 2.01 2.73 ppm).
In the IR spectra, the geminal protons give a strong
EXPERIMENTAL
The IR spectra were taken on a UR-20 spectrom-
eter (solutions in CHCl3), and the H NMR spectra,
on a Tesla BS-487C spectrometer (80 MHz, CDCl3,
internal reference HMDS).
1
1
The compounds were isolated and purified by col-
umn chromatography on Chemapol L 100/250 silica
gel using the Trappe solvent series; separation of the
Z and E isomers was monitored by GLC. The reten-
tion factors Rf were determined on Silufol-254 plates
in a 3 : 2 hexane acetone mixture.
bending vibration band at 1310 1180 cm , and the
1
vicinal protons give a strong band at 3030 2960 cm .
Such a pattern is probably due to the high degree of
polarization of the CH bond in the strained ring.
The ester groups in these compounds give the
1
expected signals in the H NMR spectra. The ethoxy-
Cyclopropanes VIII XI and heptenedioate de-
rivatives XII XV. To a solution of 2 g of alkene I or
II in 10 ml of CH2Cl2 was added 0.2 g of dirhodium
tetraacetate. The mixture was cooled to 0 C, and a
twofold excess of diazo compounds V and VI was
added dropwise with stirring. The mixture was stirred
at 0 C for an additional 5 h and then allowed to stand
at 0 C for 12 h. The catalyst was filtered off, the
solvent was evaporated, and the oily residue was
chromatographed. From the fraction eluted with chlo-
roform, yellow oily cyclopropane derivatives VIII XI
were isolated in 38 40% yield. Methyl 2-acetylami-
no-2-methoxycarbonyl-3-(2-methoxycarbonylcyclo-
propyl)propanoate VIII: yield 1.4 g (40%); methyl
2-acetylamino-2-methoxycarbonyl-3-(2-ethoxycarbo-
nylcyclopropyl)propanoate IX: yield 1.3 g (39%);
carbonyl group gives a triplet ( 1.13 1.19 ppm) and
a quartet ( 4.09 4.21 ppm) with the coupling con-
stant J 7.0 Hz. The methoxycarbonyl group protons
give a singlet at 3.62 3.73 ppm. In the IR spectra
of VIII XI and XVI the high-frequency carbonyl band
is split; graphical resolution reveals the presence of
1
three ester groups ( , cm : 1750, 1745 1725, 1725
1
1720). The low-frequency band (1725 1720 cm )
should be assigned to vibrations of the carbonyl group
1
at the ring, and the band at 1750 cm , to vibrations
of the ester group that is most hindered sterically.
1
The acetamide protons in the H NMR spectra give
a characteristic singlet in the range 1.98 2.01 ppm.
In the IR spectra, this group gives a carbonyl band
1
at 1690 1670 cm .
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 2 2002

CATALYTIC CYCLOPROPANATION
275
ethyl 2-acetylamino-2-ethoxycarbonyl-3-(2-ethoxycar- Z-XIX, E-XX were prepared as described above by
bonylcyclopropyl)propanoate X: yield 1.37 g (38%);
ethyl 2-acetylamino-2-ethoxycarbonyl-3-(2-methoxy-
carbonylcyclopropyl)propanoate XI: yield 1.38 g
(38%).
reactions of III with V and VI. Isomers Z-XVII,
Z-XIX and E-XVIII, E-XX were isolated by column
chromatography (eluent chloroform) in a 2 : 1 ratio;
yield 10%. The physicochemical characteristics of
XVII XX coincide with those given in [6, 7]. In-
crease of the reaction temperature to 22 C results in
complete polymerization of the reaction mixture.
From the fraction eluted with benzene, yellow oily
insertion products XII XV were isolated in 22 24%
yield. Dimethyl 2-acetylamino-2-methoxycarbonyl-4-
heptenedioate XII: yield 0.66 g (22%); 1H NMR
spectrum, , ppm: 1.97 s (3H, NHAc), 3.70 s (3H,
CO2Me), 3.72 s (3H, NHAc), 2.69 m (2H, CH2),
3.0 m (2H, CH2), 5.19 d (1H, =CH), 5.50 m (1H,
=CH), 7.02 s (1H, NH)]. 1-O-Methyl 7-O-ethyl 2-ace-
tylamino-2-methoxycarbonyl-4-heptenedioate XIII:
yield 0.73 g (24%); 1H NMR spectrum, , ppm:
1.98 s (3H, NHAc), 3.73 s (3H, CO2Me), 1.22 t (3H)
and 4.20 q (2H, CO2Et), 2.67 m (2H, CH2), 3.02 m
(2H, CH2), 5.17 d (1H, =CH), 5.51 m (1H, =CH),
6.97 s (1H, NH)]. Diethyl 2-acetylamino-2-ethoxycar-
4-Acetylamino-4,5-dimethoxycarbonyl-3-phenyl-
2-pyrazoline XXI and 4-acetylamino-5-ethoxycar-
bonyl-4-methoxycarbonyl-3-phenyl- 2-pyrazoline
XXII. The preparation procedures and physicochem-
ical parameters of XXI and XXII are given in
[10, 11].
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1. Wagner, J. and Musso, H., Angew. Chem., 1983,
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1
bonyl-4-heptenedioate XIV: yield 0.90 g (24%); H
p. 2231.
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(2H) and 4.20 m (3H, CO2Et), 2.70 m (2H, CH2),
3.02 m (2H, CH2); 5.20 d (1H, =CH), 5.52 m (1H,
=CH), 6.95 s (1H, NH)]. 1-O-Ethyl 7-O-methyl 2-ace-
tylamino-2-ethoxycarbonyl-4-heptenedioate XV: yield
0.76 g (22%). The physicochemical parameters of XV
are given in [9].
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catalyst was performed similarly. Compounds VIII
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methoxycarbonylmethylcyclopropyl)propanoate
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insertion product XV with diazomethane VII in the
absence of catalyst (0 C) and isolated by column
chromatography (elution with chloroform). Yellow
oily substance; yield 1.87 g (90%), Rf 0.69.
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ethyl 1-acetylamino-1,2-cyclopropanedicarboxylate
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 2 2002