Regio- and stereoselectivity of cycloaddition of C-amidonitrones to esters of methylenecyclopropanedicarboxylic acids

Article abstract of DOI:10.1134/S1070428011020187

C-Amidonitrones add regio- and stereoselectively to esters of 3-methylenecyclopropane-1,2-dicarboxylic, 2-(diphenylmethylene)cyclopropane-1,1- dicarboxylic, and 2-(1-phenylethylidene)cyclopropane-1,1-dicarboxylic acids to form a single diastereomer of 4-spirocyclopropaneisoxazolidines.

Full text of DOI:10.1134/S1070428011020187

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 2, pp. 269276. Pleiades Publishing, Ltd., 2011.
Original Russian Text  A.P. Molchanov, Tran Q. Tung, R.R.Kostikov, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 2, pp. 277283.
Regio- and Stereoselectivity of Cycloaddition
of C-Amidonitrones to Esters
of Methylenecyclopropanedicarboxylic Acids
A. P. Molchanov, Tran Q. Tung, and R. R.Kostikov
St. Petersburg State University, St. Petersburg,198504 Russia
e-mail: s.lab@pobox.spbu.ru
Received May 26, 2010
Abstract—C-Amidonitrones add regio- and stereoselectively to esters of 3-methylenecyclopropane-1,2-
dicarboxylic, 2-(diphenylmethylene)cyclopropane-1,1-dicarboxylic, and 2-(1-phenylethylidene)cyclopropane-
1,1-dicarboxylic acids to form a single diastereomer of 4-spirocyclopropaneisoxazolidines.
DOI: 10.1134/S1070428011020187
The reaction of nitrones with unsaturated compounds
is a widely used method of building up an isoxazolidine
ring [1]. In contrast to acyclic unsaturated compounds
methylenecyclopropanes due to a significant strain energy
readily enter into the cycloaddition reactions with nitrones
to form a mixture of 4- and 5-spirocyclopropaneisoxa-
zolidines whose ratio depends on the substituents both
in the nitrone and the methylenecyclopropane [2]. We
formerly established that the reaction of C,N-diaryl- an
C-aryl-N-methylnitrones with the ester of 3-methylene-
cyclopropane-1,2-dicarboxylic acid formed exclusively
4-spirocyclopropaneisoxazolidines [3]. C-Amidonitrones
with an electron-acceptor substituent at the carbon atom
should be more reactive in the cycloaddition, but the
only example of such process is the reaction between
N-phenyl-C-(N-phenylcarbamoyl)nitrone with 2,2-dan-
dmethyl-1-methylenecyclopropane leading to 5-spirocy-
clopropaneisoxazolidine [4].
spectrum contained a cross-peak between the protons H1
and ortho-H2 of the aromatic ring. Methylenecyclopro-
panes III and IV were synthesized analogously to [7].
Methylenecyclopropane IV was obtained as a mixture of
E- and Z-isomers in the ratio 8 : 1. The configuration of
the main E-isomer was established with the help of the
1H–1H NOESYspectrum. The spectrum contained cross-
peaks corresponding to the coupling of the cyclopropane
protons H1 with the ortho-H2 proton of the aromatic ring,
and the coupling of proton H1 with the protons of the
methyl group expected in the Z-isomer was absent.
Me
Me
O
N
H2
H1
H1
E-IV
H
CO2Me
H2
N
H1
CO2Me
O
In this study the reactions were investigated of N-
aryl- (or N-methyl)-C-amidonitrones Ia–Id with dimethyl
esters of 3-methylenecyclopropane-1,2-dicarboxylic (II),
2-(diphenylmethylene)cyclopropane-1,1- dicarboxylic
(III), and 2-(1-phenylethylidene)cyclopropane-1,1-di-
carboxylic (IV) acids.
Ib
The reaction between the nitrones with the methy-
lenecyclopropanes was carried out by heating in tolu-
ene. The reaction in all events proceeded regio- and
stereo-selectively affording exclusively 4-spirocyclo
propaneisoxazolidines,with esters II and III formed a
single diastereomer Va–Vd and VIa–VId. Since ester
IV was a mixture of two isomers the reaction products
Nitrones were synthesized by procedures [5] (Ia–Ic),
[6] (Id). The Z-stereochemistry of nitrone Ib was estab-
1
lished using the H–1H NOESY NMR spectrum. The
269

MOLCHANOV et al.
CO2Me
270
CO2Me
R1
O
O
R1
H
N
Toluene,
110°C
O
+
N
NHAr
CO2Me
H
ArHN
CO2Me
O
Ia_Id
II
Va_Vd
I, V, Ar = R1 = Ph (a); Ar = Ph, R1 = 4-MeC6H4 (b), Me (d); Ar = 4-MeOC6H4, R1 = 4-MeC6H4 (c).
CO2Me
R2
Ph
CO2Me
Ph
MeO2C
MeO2C
R2
Ph
Toluene,
R2
110°C
Ia_Id
H
O
+
+
H
O
O
CO2Me
CO2Me
O
N
N
R1
ArHN
R1
ArHN
VIIIa_VIIIc
VIa_VId
,
VIIa_VIIc
III, IV
R2 = Ph (III), Me (IV); VI, R2 = Ph: Ar = Ph, R1 = Ph (a), 4-MeC6H4 (b), Me (d); Ar = 4-MeOC6H4, R1 = 4-MeC6H4 (c);
VII, VIII, R2 = Me: Ar = Ph, R1 = Ph (a), 4-MeC6H4 (b); Ar = 4-MeOC6H4, R1 = 4-MeC6H4 (c).
also were present as isomers mixtures in the same ratio
~8 : 1. The isomeric products were separated by column
chromatography.
spectrum containing cross-peaks indicated in the scheme
and corresponding to the coupling of the proton H1 with
the protons of NH and methoxycarbonyl groups, and also
with the proton in the ortho-position of the aromatic ring.
No cross-peaks were found between the proton H1 and
the cyclopropane protons H2, H3 that should be expected
for the other stereoisomer.
It was also found that N-methylnitrone Id was less
reactive than N-arylnitrones Ia–Ic, and C-amidonitrones
Ia–Id were more reactive that N,C-diarylnitrones. For
instance, the heating of C-(4-chlorophenyl)-N-phenylni-
trone with methylenecyclopropanes III and IV in toluene
at 110°C over 100 h did not result in the formation of
cycloaddition products.
H4
H
The composition and structure of obtained com-
pounds V–VIII wre established from the elemental
Me
H3
O
H5
H1
N
1
analysis and spectral data. In the H NMR spectra of
CO2Me
CO2Me
compounds Va–Vd the following signals were observed:
2 doublets from the cyclopropane protons in the region
2.06–3.44 ppm (J 5.8 Hz), 2 doublets from the protons
of the methylene group in the region 4.06–4.39 ppm
(J 8.7 Hz), and the singlet from the methane proton in
the region 3.80–4.61 ppm. The 13C NMR spectra of com-
pounds Va–Vd contained the signals of the carbon atoms
of the cyclopropane ring (2 CH at 27–28 and 32 ppm
and one quaternary carbon atom at 42–43 ppm), of the
methane carbon at 68–69 ppm, and of methylene carbon
atom linked to oxygen at 71–72 ppm. The IR spectra
contain the absorption bands of ester and amide carbonyl
groups in the range 1675–1740 cm–1 and of NH group
in the region 3350–3375 cm–1. The stereochemistry of
compound Vc was established using the 1H–1H NOESY
H2
HN
O
MeO
Vc
Ph
Ph
H1
H
O
MeO2C
MeO2C
N
Me
H3
O
H2
NHPh
VIc
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 2 2011

REGIO- AND STEREOSELECTIVITY OF CYCLOADDITION OF C-AMIDONITRONES TO ESTERS
271
In the 1H NMR spectra of compounds VIa–VId the
signals are observed from the protons of the cyclopro-
pane ring in the region 1.83–2.23 ppm and a singlet
from the methane group of the isoxazolidine ring in
the region 4.29–5.16 ppm. In the 13C NMR spectra of
compounds VIa–VId the signals appear from the carbon
atom of the methylene group of the cyclopropane ring
in the region 20.9–22.4 ppm, of methane carbon atom
at 71.4–76.3 ppm, and from the quaternary carbon atom
linked to oxygen at 89.1–91.1 ppm. The (3SR,7RS)-ste-
reochemistry of compound Vb was established using the
1H–1H NOESY spectrum (see the scheme). For another
(3RS,7RS)-diastereomer the cross-peaks should appear
between the methane group of the isoxazolidine fragment
and the protons of the cyclopropane ring.
The 1H NMR spectra of compounds VIIa–VIIc and
VIIIa–VIIIc contain doublet signals of the protons of the
cyclopropane ring in the region 1.5–2.2 ppm and a singlet
from the methane group of the isoxazolidine ring in the
region 5.27–5.37 ppm. In the 13C NMR spectra signals
appear from the carbon atoms of the methylene group of
the cyclopropane ring in the region 20.5–22.2 ppm, from
the methane carbon atom at 69.3–71.4 ppm, and from the
quaternary carbon atom of the isoxazolidine ring con-
nected to oxygen at 86.5–88.6 ppm. The (3SR,4RS,7RS)-
configuration of compound VIIb and the (3SR,4SR,7RS)-
configuration of compound VIIIb was established with
the help of the 1H–1H NOESY spectrum. In the spectrum
of compound VIIb an interaction was observed between
one cyclopropane proton H1 with the ortho-protons of the
aromatic ring, and in the spectrum of compound VIIIb
the cyclopropane proton H1 interacted with the protons of
the methyl group. At the same time in the spectra of both
compounds no interaction was found between the proton
of the methind group H3 with the cyclopropane protons
H1 or H2 that should be expected for diastereomers of
(3RS,4RS,7RS)- or (3RS,4SR,7SR)-configuration.
Hence the stereoselectivity of the addition of C-
amidonitrones to methylenecyclopropane II is similar
to the stereoselectivity that has been formerly observed
in the addition of C,N-diarylnitrones to the same methy-
lenecyclopropane [3]. The cycloaddition of the nitrone
to methylenecyclopropanes II–IV may take two routes:
through the transition state A leading to the (3SR,4RS)-
diastereomers, or through the transition state B, which
should result in (3RS,4SR)-diastereomers. Apparently
the second route is less favorable since here should arise
the steric repulsion between the syn-oriented edter and
amide groups (see the scheme). The similar effect occurs
in the reaction between methylenecyclopropane IV with
the nitrones, and the diastereomers VII form in a larger
quantity than diastereomers VIII due to the larger steri-
cal effect of the phenyl group compared to the methyl.
EXPERIMENTAL
Elemental analysis was carried out on CHN-analyzer
Hewlett Packard 185-B. Mass spectra were measured
on an instrument Bruker-micrOTOF (ESI). IR spectra
were recorded on a spectrophotometer UR-20 from 2%
solutions in chloroform. 1H and 13C NMR spectra were
registered on a spectrometer Bruker DPX-300 at operating
frequencies 300 and 75 MHz respectively. The purity and
homogeneity of compounds was checked and the reaction
progress was monitored by TLC on Silufol UV-254 plates.
H
Me
H1
H
O
N
Me
MeO2C
MeO2C
H3
NHPh
Nitrones Ia–Ic. General procedure. To 150 ml of etha-
nol solution of 20 mmol of 1-(2-aryl-amino-2-oxoethyl)
pyridinium chloride and 20 mmol of nitrosoarene cooled
to –3°C at vigorous stirring 20 ml of 1 N water solution
of sodium hydroxide was added maintaining the solution
temperature below 0°C. The mixture was kept for 2 h at
0°C, diluted with 2 volumes of cold water, the precipitated
nitrone was filtered off, washed with water, and recrystal-
lized from ethanol or 1,2-dichloroethane. Nitrones Ia–Id
are readily hydrolyzed in air.
H2
O
VIIb
Me
H1
H
O
N
Me
MeO2C
MeO2C
H3
N-Phenyl-C-(N-phenylcarbamoyl)nitrone (Ia).
Yield 54%, mp 147–148°C (1,2-dichloroethane) (149–
150°C [8]). IR spectrum, ν, cm–1: 3050, 1670 s, 1612,
NHPh
H2
O
VIIIb
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 2 2011

MOLCHANOV et al.
272
Scheme.
Ph
R2
CO2Me
H
R2
C4
C3
C7
Ph
CO2Me
H
H
H
O
N
CO2Me
H
Ph
R2
O
+N
CO2Me
C=O
R1
CO2Me
R1
H
O
H
NHAr
CO2Me
NHAr
3SR,7RS
H
+
A
O
+N
CO2Me
CO2Me
R2
Ph
R2
H
Ph
CONH2Ar
R1
C4
CO2Me
CO2Me
H
O
N
C3
H
C7
H
O
+
R1
H
C=O
N
H
O
R1
NHAr
NHAr
H
3RS,7RS
B
1561 s, 1462, 1090. 1H NMR spectrum (CDCl3), δ, ppm:
7.19 t (1H, J 7.3 Hz), 7.40 t (2H, J 8.0 Hz), 7.53–7.63
(3H), 7.73–7.78 (5H), 12.22 s (1H, NH). 13C NMR spec-
trum (CDCl3), δ, ppm: 121.1 (CH), 121.9 (CH), 125.4
(CH), 129.5 (CH), 130.0 (CH), 131.4 (CH), 132.2 (CH),
137.5 (C), 147.5 (C), 158.8 (CO).
N-Methyl-C-(N-phenylcarbamoyl)nitrone (Id) was
synthesized by procedure [6]. Yield 37%, mp 109–111°C.
IR spectrum, ν, cm–1: 3030, 1670 s, 1610, 1561 s, 1462,
1429, 1158. 1H NMR spectrum (CDCl3), δ, ppm: 3.89 s
(3H, CH3), 7.16 t (1H, J 8.0 Hz), 7.21 s (1H, =CH), 7.36 t
(2H, J 8.0 Hz), 7.67 d (2H, J 8.0 Hz), 11.92 s (1H, NH).
13C NMR spectrum (CDCl3), δ, ppm: 55.0 (CH3), 121.0
(CH), 125.3 (CH), 129.4 (CH), 133.3 (CH), 137.4 (C),
158.4 (CO).
(Z)-N-(p-Tolyl)-C-(N-phenylcarbamoyl)nitrone
(Ib). Yield 81%, mp 156–157°C (ethanol). IR spectrum,
ν, cm–1: 3058, 1670 s, 1612 s, 1561 s, 1519, 1462,
1
1090. H NMR spectrum (CDCl3), δ, ppm: 2.46 s (3H,
Methylenecyclopropanes III and IV. General proce-
dure. To a solution of 30 mmol of 1,1-diphenylpropa-1,2-
diene (3-phenylbuta-1,2-diene) and 30 mg of Rh2(OAc)4
in 5 ml of anhydrous dichloromethane was added at heat-
ing a solution of 20 mmol of dimethyl diazomalonate in
14 ml of anhydrous dichloromethane (~4 h). The mixture
was heated for 3 h, cooled, the solvent was evaporated,
and the residue was subjected to chromatography on silica
gel (eluent ethyl acetate–petroleum ether).
CH3), 7.21 t (1H, J 7.3 Hz), 7.32–7.42 (4H), 7.66 d (2H,
J 8.7 Hz), 7.73–7.75 (3H), 12.24 s (1H, NH). 1H NMR
spectrum (DMSO-d6), δ, ppm: 2.38 s (3H, CH3), 7.17 m
(1H), 7.34–7.42 (4H), 7.72 d (2H, J 8.0 Hz), 7.84 (2H,
J 8.0 Hz), 8.14 s (1H, =CH), 12.29 s (1H, NH). 13C NMR
spectrum (CDCl3), δ, ppm: 21.7 (CH3), 121.1 (CH), 121.6
(CH), 125.4 (CH), 129.5 (CH), 130.5 (CH), 130.9 (CH),
137.6 (C), 142.9 (C), 145.2 (C), 158.9 (CO).
C-(N-4-Methoxyphenylcarbamoyl)-N-(p-tolyl)-
nitrone (Ic). Yield 79%, mp 142–143°C (ethanol). IR
spectrum, ν, cm–1: 3030, 1670 s, 1610, 1561 s, 1530,
1270, 1190, 1097, 1052. 1H NMR spectrum (CDCl3), δ,
ppm: 2.46 s (3H, CH3), 3.83 s (3H, OCH3), 6.92 d (2H,
J 8.7 Hz), 7.33 d (2H, J 8.7 Hz), 7.65 d (2H, J 8.7 Hz),
7.67 d (2H, J 8.7 Hz), 7.72 s (1H, =CH), 12.17 s (1H,
NH). 13C NMR spectrum (CDCl3), δ, ppm: 21.7 (CH3),
55.9 (CH3), 114.6 (CH), 121.6 (CH), 122.6 (CH), 130.5
(CH), 130.7 (C), 130.9 (CH), 142.8 (C), 145.2 (C), 157.2
(C), 158.6 (CO).
Dimethyl 2-(diphenylmethylene)cyclopropane-
1,1-dicarboxylate (III). Yield 30%, oily substance. IR
spectrum, ν, cm–1: 3060, 1740 s, 1452, 1328, 1289, 1128.
1H NMR spectrum (CDCl3), δ, ppm: 2.56 s (2H, CH2),
3.69 s (6H, 2CH3), 7.30–7.46 (10H). 13C NMR spectrum
(CDCl3), δ, ppm: 20.2 (CH2), 32.5 (C), 53.1 (CH3), 122.3
(C), 128.2 (CH), 128.4 (CH), 128.6 (CH), 128.7 (CH),
128.9 (CH), 133.2 (C), 139.0 (C), 139.3 (C), 168.7 (CO).
Dimethyl 2-(1-phenylethylidene)cyclopropane-1,1-
dicarboxylate (IV). Yield 60%, oily substance. Accord-
ing to the 1H NMR spectrum, the ratio of (E)/(Z)-isomers
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 2 2011

REGIO- AND STEREOSELECTIVITY OF CYCLOADDITION OF C-AMIDONITRONES TO ESTERS
273
was 8 : 1. IR spectrum, ν, cm–1: 3060, 1740 s, 1452,
1328 s, 1285, 1128.
cm–1: 3350, 1740 s, 1715 s, 1690 s, 1600, 1535, 1505 s,
1440 s, 1345 s, 1255, 1185, 1160. H NMR spectrum
1
(CDCl3), δ, ppm: 2.08 d (1H, CH, J 5.8 Hz), 2.34 s (3H,
CH3), 3.38 d (1H, CH, J 5.8 Hz), 3.40 s (3H, OCH3),
3.74 s (3H, OCH3), 4.21 d (1H, CH2, J 8.7 Hz), 4.37 d (1H,
CH2, J 8.7 Hz), 4.64 s (1H, CH), 6.98 d (2H, J 8.7 Hz),
7.13–7.18 (3H), 7.37 t (2H, J 8.0 Hz), 7.65 d (2H,
J 8.0 Hz), 9.14 s (1H, NH). 13C NMR spectrum (CDCl3),
δ, ppm: 21.0 (CH3), 27.7 (CH), 32.1 (CH), 42.2 (C), 52.5
(CH3), 53.0 (CH3), 68.5 (CH), 71.8 (CH2), 115.8 (CH),
120.2 (CH), 124.9 (CH), 129.4 (CH), 129.9 (CH), 133.6
(C), 137.7 (C), 146.8 (C), 167.0 (CO), 170.5 (CO), 171.1
(CO). Found, %: C 64.99; H 5.70; N 6.60. C23H24N2O6.
Calculated, %: C 65.08; H 5.70; N 6.60.
E-Isomer. 1H NMR spectrum (CDCl3), δ, ppm: 2.28 t
(3H, CH3, J 2.2 Hz), 2.55 t (2H, CH2, J 2.2 Hz), 3.78 s
(6H, 2CH3), 7.34–7.42 (3H), 7.64 d (2H, J 7.3 Hz).
13C NMR spectrum (CDCl3), δ, ppm: 19.3 (CH3), 21.2
(CH2), 31.0 (C), 53.2 (CH3), 119.9 (C), 126.5 (CH), 126.7
(C), 128.3 (CH), 128.8 (CH), 138.6 (C), 169.0 (CO).
Z-Isomer. 1H NMR spectrum (CDCl3), δ, ppm: 2.23 t
(2H, CH2, J 2.2 Hz), 2.34 t (3H, CH3, J 2.2 Hz), 3.72 s
(6H, 2CH3), 7.34–7.42 (3H), 7.55 d (2H, J 7.3 Hz).
Reactions of nitrones Ia–Id with methylenecyclo-
propanes II–IV. General procedure. A solution of
methylenecyclopropane II–IV and nitrone Ia–Id was
heated in 10 ml of anhydrous toluene. The toluene was
evaporated in a vacuum, the residue was subjected to
chromatography on silica gel. Eluent petroleum ether
(40–70°C)–ethyl acetate. The solvent was evaporated,
the residue was recrystallized from ethanol.
Dimethyl (1RS,2RS,7SR)-7-[N-(4-methoxyphenyl)
carbamoyl]-6-(4-tolyl)-5-oxa-6-aza-spiro[2.4]heptane-
1,2-dicarboxylate (Vc) was obtained from 170 mg
(1 mmol) of methylenecyclopropane II and 511 mg
(1.8 mmol) of nitrone Ic. Time of heating 11 h. Yield
140 mg (31%), mp 151–152°C. IR spectrum, ν, cm–1:
3375, 1715 s, 1680 s, 1590, 1505 s, 1435, 1340 s, 1238 s,
1165, 1150 s. 1H NMR spectrum (CDCl3), δ, ppm: 2.06 d
(1H, CH, J 5.8 Hz), 2.33 s (3H, CH3), 3.37 d (1H, CH,
J 5.8 Hz), 3.39 s (3H, OCH3), 3.73 s (3H, OCH3), 3.82 s
(3H, OCH3), 4.21 d (1H, CH2, J 8.7 Hz), 4.36 d (1H,
CH2, J 8.7 Hz), 4.61 s (1H, CH), 6.89 d (2H, J 8.7 Hz),
6.97 d (2H, J 8.7 Hz), 7.14 d (2H, J 8.0 Hz), 7.56 d (2H,
J 8.0 Hz), 9.03 s (1H, NH). 13C NMR spectrum (CDCl3),
δ, ppm: 21.0 (CH3), 27.7 (CH), 32.1 (CH), 42.2 (C), 52.5
(CH3), 53.0 (CH3), 55.9 (CH3), 68.5 (CH), 71.9 (CH2),
114.5 (CH), 115.9 (CH), 121.9 (CH), 129.9 (CH), 131.0
(C), 133.5 (C), 146.9 (C), 156.9 (C), 166.7 (CO), 170.5
(CO), 171.2 (CO). Found, %: C 63.61; H 5.69; N 6.37.
C24H26N2O7. Calculated %: C 63.43; H 5.77; N 6.16.
Dimethyl (1RS,2RS,7SR)-6-phenyl-7-(N-
phenylcarbamoyl)-5-oxa-6-azaspiro[2.4]-
heptane-1,2-dicarboxylate (Va) was obtained from
170 mg (1 mmol) of methylenecyclopropane II and
432 mg (1.8 mmol) of nitrone Ia. Time of heating 11 h.
Yield 185 mg (45%), mp 143°C. IR spectrum, ν, cm–1:
3350, 1725 s, 1700 s, 1605 s, 1545, 1505, 1450, 1350 s,
1260 s 1230 s. 1H NMR spectrum (CDCl3), δ, ppm: 2.07 d
(1H, CH, J 5.8 Hz), 3.37–3.39 (4H), 3.74 s (3H, CH3),
4.23 d (1H, CH2, J 8.7 Hz), 4.39 d (1H, CH2, J 8.7 Hz),
4.69 s (1H, CH), 7.08–7.18 (4H), 7.32–7.39 (4H), 7.65 d
1
(2H, J 7.2 Hz), 9.11 s (1H, NH). H NMR spectrum
(C6D6), δ, ppm: 2.07 d (1H, CH, J 5.8 Hz), 3.04 s (3H,
OCH3), 3.23 s (3H, OCH3), 3.90 d (1H, CH, J 5.8 Hz),
4.25 d (1H, CH2, J 8.7 Hz), 4.32 d (1H, CH2, J 8.7 Hz),
4.85 s (1H, CH), 6.84–6.94 (4H), 7.05–7.14 (4H), 7.61 d
(2H, J 7.3 Hz), 9.14 s (1H, NH). 13C NMR spectrum
(CDCl3), δ, ppm: 27.8 (CH), 32.1 (CH), 42.2 (C), 52.7
(CH3), 53.0 (CH3), 68.5 (CH), 71.9 (CH2), 115.8 (CH),
120.3 (CH), 124.1 (CH), 125.0 (CH), 129.4 (CH), 129.5
(CH), 137.7 (C), 149.2 (C), 166.9 (CO), 170.5 (CO), 171.1
(CO). Found %: C 64.26; H 5.41; N 6.83. C22H22N2O6.
Calculated %: C 64.38; H 5.40; N 6.83.
Dimethyl (1RS,2RS,7SR)-6-methyl-7-(N-phenyl-
carbamoyl)-5-oxa-6-azaspiro[2.4]-heptane-1,2-
dicarboxylate (Vd) was obtained from 340 mg
(2 mmol) of methylenecyclopropane II and
641 mg (3.6 mmol) of nitrone Id. Time of heating 22 h.
Yield 240 mg (35%). Oily substance. IR spectrum, ν,
cm–1: 3370, 1712 s, 1675 s, 1588 s, 1513 s, 1140 s, 1430 s,
1330 s, 1228 s, 1163. 1H NMR spectrum (CDCl3), δ, ppm:
2.46 d (1H, CH, J 5.8 Hz), 2.80 s (3H, CH3), 3.44 d (1H,
CH, J 5.8 Hz), 3.72 s (3H, OCH3), 3.78 s (3H, OCH3),
3.80 s (1H, CH), 4.06 d (1H, CH2, J 8.7 Hz), 4.25 d (1H,
CH2, J 8.7 Hz), 7.11 t (1H, J 7.3 Hz), 7.30 t (2H, J 7.3 Hz),
7.60 d (2H, J 7.3 Hz), 9.18 s (1H, NH). 13C NMR spec-
trum (CDCl3), δ, ppm: 27.4 (CH), 32.4 (CH), 42.6 (C),
44.2 (CH3), 52.9 (CH3), 53.0 (CH3), 68.2 (CH), 71.2
D i m e t h y l ( 1 R S , 2 R S , 7 S R ) - 6 - ( 4 - t o l y l ) -
7-(N-phenylcarbamoyl)-5-oxa-6-azaspiro[2.4]-
heptane-1,2-dicarboxylate (Vb) was obtained from
170 mg (1 mmol) of methylenecyclopropane II and
457 mg (1.8 mmol) of nitrone Ib. Time of heating 11 h.
Yield 135 mg (32%), mp 166–167°C. IR spectrum, ν,
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(CH2), 120.1 (CH), 124.7 (CH), 129.3 (CH), 137.8 (C),
167.0 (CO), 170.6 (CO), 171.1 (CO). Found [M + H]+
349.1384. C17H20N2O6. Calculated [M + H]+ 349.1400.
from 322 mg (1 mmol) of methylenecyclopropane III
and 341 mg (1.4 mmol) of nitrone Ic. Time of heating
45 h. Yield 350 mg (58%), mp 185–186°C. IR spectrum,
ν, cm–1: 3375, 1732 s, 1682 s, 1512 s, 1437, 1280, 1250 s,
1100. 1H NMR spectrum (CDCl3), δ, ppm: 1.93 d (1H,
CH2, J 6.5 Hz), 2.21 d (1H, CH2, J 6.5 Hz), 2.26 s (3H,
CH3), 3.22 s (3H, OCH3), 3.78 s (3H, OCH3), 3.86 s (3H,
OCH3), 5.02 s (1H, CH), 6.81 d (2H, J 8.7 Hz), 6.91 d
(2H, J 8.7 Hz), 7.00 d (2H, J 8.0 Hz), 7.20–7.25 (5H),
7.32–7.44 (3H), 7.52–7.55 (2H), 7.69 d (2H, J 7.3 Hz),
8.53 s (1H, NH). 13C NMR spectrum (CDCl3), δ, ppm:
21.0 (CH3), 21.1 (CH2), 39.1 (C), 50.0 (C), 53.1 (CH3),
53.5 (CH3), 55.9 (CH3), 71.7 (CH), 90.3 (C), 114.4 (CH),
115.7 (CH), 121.9 (CH), 128.0 (CH), 128.1 (CH), 128.5
(CH), 128.7 (CH), 129.2 (CH), 129.6 (CH), 130.1 (CH),
130.5 (C), 132.6 (C), 137.3 (C), 138.7 (C), 141.1 (C),
146.9 (C), 157.0 (C), 166.7 (CO), 166.9 (CO), 167.8
(CO). Found, %: C 71.49; H 5.69; N 4.66. C36H34N2O7.
Calculated, %: C 71.27; H 5.65; N 4.62.
Dimethyl (3SR,7RS)-4,4,6-triphenyl-7-(N-
phenylcarbamoyl)-5-oxa-6-azaspiro[2.4]-heptane-
1,1-dicarboxylate (VIa) was obtained from 322 mg
(1 mmol) of methylenecyclopropane III and 288 mg
(1.4 mmol) of nitrone Ia. Time of heating 17 h. Yield
440 mg (78%), mp 162–163°C. IR spectrum, ν, cm–1:
3340, 1750 s, 1725 s, 1685 s, 1600, 1160, 1515, 1495,
1440 s, 1350, 1260 s, 1190. 1H NMR spectrum (CDCl3),
δ, ppm: 1.84 d (1H, CH2, J 6.5 Hz), 2.23 d (1H, CH2,
J 6.5 Hz), 3.25 s (3H, OCH3), 3.88 s (3H, OCH3), 5.16 s
(1H, CH), 6.90 t (1H, J 7.3 Hz), 6.94 d (2H, J 8.0 Hz),
7.10–7.21 (6H), 7.30–7.43 (7H), 7.57–7.59 (2H), 7.65 d
(2H, J 7.3 Hz), 8.72 s (1H, NH). 13C NMR spectrum
(CDCl3), δ, ppm: 20.9 (CH2), 38.8 (C), 49.3 (C), 53.2
(CH3), 53.6 (CH3), 71.4 (CH), 91.1 (C), 114.9 (CH),
120.2 (CH), 122.6 (CH), 125.1 (CH), 128.0 (CH), 128.1
(CH), 128.7 (CH), 128.8 (CH), 129.0 (CH), 129.3 (CH),
129.5 (CH), 130.3 (CH), 137.3 (C), 138.4 (C), 140.7 (C),
149.3 (C), 166.7 (CO), 167.2 (CO), 167.9 (CO). Found,
%: C 72.62; H 5.37; N 4.98. C34H30N2O6. Calculated, %:
C 72.58; H 5.37; N 4.98.
Dimethyl (3SR,7RS)-6-methyl-4,4-diphenyl-7-(N-
phenylcarbamoyl)-5-oxa-6-aza-spiro[2.4]heptane-
1,1-dicarboxylate (VId) was obtained from 322 mg
(1 mmol) of methylenecyclopropane III and 214 mg
(1.4 mmol) of nitrone Id. Time of heating 144 h. Yield
70 mg (14%). Oily substance. IR spectrum, ν, cm–1:
3350, 1723, 1678 s, 1590, 1513 s, 1435 s, 1425 s, 1235 s,
1088. 1H NMR spectrum (CDCl3), δ, ppm: 1.83 d (1H,
CH2, J 7.3 Hz), 2.07 d (1H, CH2, J 7.3 Hz), 2.96 s (3H,
CH3), 3.16 s (3H, OCH3), 3.93 s (3H, OCH3), 4.29 s (1H,
CH), 7.10 t (1H, J 7.0 Hz), 7.27–7.48 (12H), 7.80 d (2H,
J 8.0 Hz), 8.52 s (1H, NH). 13C NMR spectrum (CDCl3),
δ, ppm: 22.4 (CH2), 39.8 (C), 45.2 (CH3), 52.2 (C), 53.2
(CH3), 53.5 (CH3), 76.3 (CH), 89.1 (C), 120.0 (CH),
125.0 (CH), 128.0 (CH), 128.2 (CH), 128.6 (CH), 129.3
(CH), 129.6 (CH), 137.2 (C), 140.3 (C), 140.9 (C), 166.6
(CO), 167.2 (CO), 167.3 (CO). Found [M + H]+ 501.2004.
C29H28N2O6. Calculated [M + H]+ 501.2026.
Dimethyl (3SR,7RS)-6-(4-tolyl)-4,4-diphenyl-7-(N-
phenylcarbamoyl)-5-oxa-6-aza-spiro[2.4]heptane-1,1-
dicarboxylate (VIb) was obtained from 322 mg (1 mmol)
of methylenecyclopropane III and 305 mg (1.4 mmol) of
nitrone Ib. Time of heating 20 h. Yield 330 mg (57%), mp
172–173°C. IR spectrum, ν, cm–1: 3340, 1750 s, 1725 s,
1685 s, 1600, 1510, 1440 s, 1350, 1260 s, 1200, 1160.
1H NMR spectrum (CDCl3), δ, ppm: 1.94 d (1H, CH2,
J 6.5 Hz), 2.19 d (1H, CH2, J 6.5 Hz), 2.25 s (3H, CH3),
3.21 s (3H, OCH3), 3.87 s (3H, OCH3), 5.02 s (1H, CH),
6.92 d (2H, J 8.0 Hz), 7.00 d (2H, 8.0 Hz), 7.10 t (1H,
J 7.3 Hz), 7.20–7.43 (10H), 7.52–7.55 (2H), 7.70 d (2H,
J 8.0 Hz), 8.63 s (1H, NH). 13C NMR spectrum (CDCl3),
δ, ppm: 21.0 (CH3), 21.1 (CH2), 39.1 (C), 50.0 (C), 53.2
(CH3), 53.6 (CH3), 71.9 (CH), 90.4 (C), 115.7 (CH),
120.2 (CH), 125.0 (CH), 128.0 (CH), 128.2 (CH), 128.6
(CH), 128.7 (CH), 129.2 (CH), 129.3 (CH), 129.7 (CH),
130.1 (CH), 132.7 (C), 137.3 (C), 138.7 (C), 141.0 (C),
146.8 (C), 166.7 (CO), 167.2 (CO), 167.8 (CO). Found,
%: C 73.12; H 5.53; N 4.87. C35H32N2O6. Calculated, %:
C 72.90; H 5.59; N 4.86.
Dimethyl (3SR,4RS,7RS)- and (3SR,4SR,7RS)-4-
methyl-4,6-diphenyl-7-(N-phenylcarbamoyl)-5-oxa-
6-azaspiro[2.4]heptane-1,1-dicarboxylates (VIIa)
and (VIIIa) were obtained from 520 mg (2 mmol) of
methylenecyclopropane IV and 576 mg (2.4 mmol) of
nitrone Ia. Time of heating 39 h.
Ester VIIa. Yield 590 mg (59%), mp 153–154°C. IR
spectrum, ν, cm–1: 3340, 1750 s, 1680 s, 1600 s, 1530 s,
1490 s, 1440 s, 1260 s, 1105. 1H NMR spectrum (CDCl3),
δ, ppm: 1.48 d (1H, CH2, J 6.5 Hz), 1.53 s (3H, CH3),
2.09 d (1H, CH2, J 6.5 Hz), 3.60 s (3H, OCH3), 3.85 s
Dimethyl (3SR,7RS)-7-[N-(4-methoxyphenyl)
carbamoyl]-6-(4-tolyl)-4,4-diphenyl-5-oxa-6-azaspi-
ro[2.4]heptane-1,1-dicarboxylate (VIc) was obtained
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(3H, OCH3), 5.33 s (1H, CH), 6.98 d.d (1H, J 7.3, 8.0 Hz),
7.06 d (2H, J 8.7 Hz), 7.12 t (1H, J 7.3 Hz), 7.26–7.43
(9H), 7.54 d (2H, J 8.0 Hz), 9.09 s (1H, NH). 13C NMR
spectrum (CDCl3), δ, ppm: 22.2 (CH2), 22.5 (CH3), 37.4
(C), 50.2 (C), 53.4 (CH3), 53.6 (CH3), 69.3 (CH), 88.6
(C), 113.9 (CH), 120.3 (CH), 122.4 (CH), 125.2 (CH),
128.2 (CH), 128.6 (CH), 129.0 (CH), 129.4 (CH), 129.5
(CH), 137.4 (C), 139.1 (C), 150.9 (C), 167.2 (CO), 167.7
(CO), 167.8 (CO). Found, %: C 69.41; H 5.59; N 5.59.
C29H28N2O6. Calculated, %: C 69.59; H 5.64; N 5.60.
Ester VIIIb. Yield 75 mg (9%), mp 89–90°C. IR
spectrum, ν, cm–1: 3330, 1750 s, 1720 s, 1685 s, 1600 s,
1530 s, 1505 s, 1440 s, 1260 s, 1105. 1H NMR spectrum
(CDCl3), δ, ppm: 1.99 s (3H, CH3), 2.07 d (1H, CH2,
J 6.5 Hz), 2.14 d (1H, CH2, J 6.5 Hz), 2.20 s (3H, CH3),
3.05 s (3H, OCH3), 3.94 s (3H, OCH3), 5.28 s (1H, CH),
6.66 d (2H, J 8.7 Hz), 6.87 d (2H, J 8.0 Hz), 7.11–7.18
(4H), 7.33 t (2H, J 8.0 Hz), 7.51–7.57 (4H), 8.86 s (1H,
NH). 13C NMR spectrum (CDCl3), δ, ppm: 20.7 (CH2),
20.9 (CH3), 23.9 (CH3), 38.4 (C), 49.8 (C), 53.0 (CH3),
53.6 (CH3), 71.4 (CH), 86.5 (C), 114.7 (CH), 120.4
(CH), 125.1 (CH), 128.1 (CH), 128.2 (CH), 128.4 (CH),
129.4 (CH), 129.5 (CH), 131.6 (C), 137.4 (C), 140.3 (C),
146.9 (C), 167.5 (CO), 167.6 (CO), 167.9 (CO). Found,
%: C 69.97; H 5.91; N 5.37. C30H30N2O6. Calculated, %:
C 70.02; H 5.88; N 5.44.
Ester VIIIa. Yield 80 mg (8%), mp 80–82°C. IR
spectrum, ν, cm–1: 3340, 1750 s, 1720 s, 1680 s, 1600 s,
1
1530 s, 1490 s, 1440 s, 1260 s, 1105. H NMR spec-
trum (CDCl3), δ, ppm: 1.96 s (3H, CH3), 2.06 d (1H,
CH2, J 6.5 Hz), 2.17 d (1H, CH2, J 6.5 Hz), 3.03 s (3H,
OCH3), 3.91 s (3H, OCH3), 5.37 s (1H, CH), 6.67 d
(2H, J 8.0 Hz), 6.75 t (1H, J 7.3 Hz), 7.00 d.d (2H,
J 7.3, 8.7 Hz), 7.08–7.13 (4H), 7.30 d.d (2H, J 7.3,
8.0 Hz), 7.49–7.51 (4H), 8.85 s (1H, NH). 13C NMR
spectrum (CDCl3), δ, ppm: 20.5 (CH2), 23.8 (CH3), 38.2
(C), 49.4 (C), 52.9 (CH3), 53.6 (CH3), 71.0 (CH), 87.0
(C), 114.0 (CH), 120.4 (CH), 121.8 (CH), 125.2 (CH),
128.0 (CH), 128.2 (CH), 128.5 (CH), 128.9 (CH), 129.4
(CH), 137.4 (C), 140.0 (C), 149.4 (C), 167.5 (CO), 167.7
(CO), 168.0 (CO). Found, %: C 68.71; H 5.49; N 5.46.
C29H28N2O6. Calculated, %: C 68.59; H 5.64; N 5.60.
Dimethyl (3SR,4RS,7RS)- and (3SR,4SR,7RS)-4-
methyl-6-(p-tolyl)-4-phenyl-7-[N-(4-methoxyphenyl)
carbamoyl]-5-oxa-6-azaspiro-[2.4]heptane-1,1-
dicarboxylates (VIIc) and (VIIIc) were obtained from
520 mg (2 mmol) of methylenecyclopropane IV and
795 mg (2.8 mmol) of nitrone Ic. Time of heating 41 h.
Ester VIIc. Yield 560 mg (51%), mp 170–171°C. IR
spectrum, ν, cm–1: 3363, 1738 s, 1687 s, 1530 s, 1517 s,
1
1440, 1252 s, 1185, 1105, 1185. H NMR spectrum
(CDCl3), δ, ppm: 1.52 d (1H, CH2, J 5.8 Hz), 1.57 s (3H,
CH3), 2.14 d (1H, CH2, J 5.8 Hz), 2.33 s (3H, CH3), 3.64 s
(3H, OCH3), 3.81 s (3H, OCH3), 3.88 s (3H, OCH3),
5.33 s (1H, CH), 6.89 d.d (2H, J 7.3, 2.2 Hz), 7.02 d
(2H, J 8.0 Hz), 7.14 d (2H, J 8.7 Hz), 7.38–7.50 (7H),
9.05 s (1H, NH). 13C NMR spectrum (CDCl3), δ, ppm:
20.9 (CH3), 22.2 (CH2), 22.6 (CH3), 37.6 (C), 50.4 (C),
53.3 (CH3), 53.6 (CH3), 55.9 (CH3), 69.3 (CH), 88.6
(C), 114.1 (CH), 114.6 (CH), 122.1 (CH), 128.1 (CH),
128.6 (CH), 129.0 (CH), 130.0 (CH), 130.6 (C), 131.8
(C), 139.4 (C), 148.7 (C), 157.1 (C), 167.0 (CO), 167.7
(CO), 167.9 (CO). Found, %: C 68.21; H 5.86; N 5.20.
C31H32N2O7. Calculated, %: C 68.37; H 5.92; N 5.14.
Dimethyl (3SR,4RS,7RS)- and (3SR,4SR,7RS)-4-
methyl-6-(p-tolyl)-4-phenyl-7-(N-phenylcarbamoyl)-
5-oxa-6-azaspiro[2.4]heptane-1,1-dicarboxylates
(VIIb) and (VIIIb) were obtained from 520 mg (2 mmol)
of methylenecyclopropane IV and 711 mg (2.8 mmol) of
nitrone Ib. Time of heating 42 h.
Ester VIIb. Yield 530 mg (50%), mp 166–167°C. IR
spectrum, ν, cm–1: 3330, 3040, 1750 s, 1720 s, 1685 s,
1600 s, 1530 s, 1505 s, 1440 s, 1260 s, 1105. 1H NMR
spectrum (CDCl3), δ, ppm: 1.52 d (1H, CH2, J 6.5 Hz),
1.57 s (3H, CH3), 2.12 d (1H, CH2, J 6.5 Hz), 2.33 s (3H,
CH3), 3.64 s (3H, OCH3), 3.89 s (3H, OCH3), 5.34 s (1H,
CH), 7.02 d (2H, J 8.0 Hz), 7.14 d (2H, J 8.7 Hz), 7.15 t
(1H, J 8.7 Hz), 7.33–7.48 (7H), 7.58 d (2H, J 8.0 Hz),
9.16 s (1H, NH). 13C NMR spectrum (CDCl3), δ, ppm:
20.9 (CH3), 22.2 (CH2), 22.6 (CH3), 37.5 (C), 50.4 (C),
53.4 (CH3), 53.6 (CH3), 69.4 (CH), 88.6 (C), 114.1 (CH),
120.4 (CH), 125.1 (CH), 128.2 (CH), 128.5 (CH), 129.0
(CH), 129.5 (CH), 130.0 (CH), 131.9 (C), 137.5 (C),
139.4 (C), 148.7 (C), 167.3 (CO), 167.7 (CO), 167.9
(CO). Found, %: C 70.11; H 5.71; N 5.51. C30H30N2O6.
Calculated, %: C 70.02; H 5.88; N 5.44.
Ester VIIIc. Yield 45 mg (4%), oily substance. IR
spectrum, ν, cm–1: 3350, 1713 s, 1663 s, 1585, 1495
1
s, 1420, 1283, 1228 s, 1163, 1090. H NMR spectrum
(CDCl3), δ, ppm: 1.99 s (3H, CH3), 2.08 d (1H, CH2,
J 5.8 Hz), 2.15 d (1H, CH2, J 5.8 Hz), 2.20 s (3H, CH3),
3.05 s (3H, CH3), 3.80 s (3H, CH3), 3.93 s (3H, CH3),
5.27 s (1H, CH), 6.67 d (2H, J 8.7 Hz), 6.85–6.89 (4H),
7.15–7.17 (3H), 7.42 d (2H, 8.7 Hz), 7.54–7.57 (2H),
8.76 s (1H, NH). 13C NMR spectrum (CDCl3), δ, ppm:
20.6 (CH2), 20.9 (CH3), 23.9 (CH3), 38.4 (C), 49.8 (C),
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Brandi, A., Cicchi, S., Cordero, F.M., and Goti, A., Chem.
Rev., 2003, vol. 103, p. 1213: Goti, A., Cordero, F.M., and
Brandi, A., Top. Curr. Chem., 1996, vol. 178, p. 1.
52.9 (CH3), 53.5 (CH3), 55.9 (CH3), 71.3 (CH), 86.5 (C),
114.6 (CH), 114.7 (CH), 122.2 (CH), 128.1 (CH), 128.2
(CH), 128.4 (CH), 129.5 (CH), 130.5 (C), 131.5 (C), 140.3
(C), 146.9 (C), 157.1 (C), 167.3 (CO), 167.7 (CO), 167.8
(CO). Found [M + H]+ 545.2263. C31H32N2O7. Calculated
[M + H]+ 545.2288.
3. Diev, V.V., Tran, Q.T., and Molchanov, A.P., Eur. J. Org.
Chem., 2009, p. 525.
4. Akmanova, N.A., Sagitdinova, Kh.F., and Balenkova, E.S.,
Khim. Geterotsikl. Soedin., 1982, p. 1192.
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