Regioselective cycloaddition of C-Aryl- and C-Carbamoylnitrones to methyl 2-Benzylidenecyclopropanecarboxylate

Article abstract of DOI:10.1134/S1070428012100041

C-Aryl- and C-carbamoylnitrones reacted with methyl 2- benzylidenecyclopropanecarboxylate in highly regioselective fashion to give the corresponding 1,3-dipolar cycloaddition products, substituted methyl 5-oxa-6-azaspiro[2.4]heptane-1-carboxylates as mixt

Full text of DOI:10.1134/S1070428012100041

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 10, pp. 1283–1288. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.P. Molchanov, T.Q. Tran, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 10, pp. 1289–1294.
Regioselective Cycloaddition
of C-Aryl- and C-Carbamoylnitrones to Methyl
2-Benzylidenecyclopropanecarboxylate
A. P. Molchanov and T. Q. Tran
St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
e-mail: s.lab@pobox.spbu.ru
Received April 25, 2012
Abstract—C-Aryl- and C-carbamoylnitrones reacted with methyl 2-benzylidenecyclopropanecarboxylate in
highly regioselective fashion to give the corresponding 1,3-dipolar cycloaddition products, substituted methyl
5-oxa-6-azaspiro[2.4]heptane-1-carboxylates as mixtures of two diastereoisomers.
DOI: 10.1134/S1070428012100041
1,3-Dipolar cycloaddition is one of the most power-
ful tools for the construction of five-membered N,O-
heterocyclic systems. An example of such reactions is
addition of nitrones at a double carbon–carbon bond,
which underlies a widely used method of synthesis of
isoxazolidine derivatives [1]. Isoxazolidines attract
strong interest due to their potential biological activity
and the possibility for converting them into amino
alcohols via hydrogenolysis of the N–O bond. Amino
alcohols in turn are important as initial compounds for
the synthesis of naturally occurring β-lactams and al-
kaloids. Unlike acyclic unsaturated compounds, steri-
cally strained methylidenecyclopropanes readily react
with nitrones according to the [2+3]-cycloaddition
pattern with formation of mixtures of isomeric C4- and
C5-spiro isoxazolidines whose ratio depends on the
substituents in both nitrone and methylidenecyclo-
propane components [2]. We previously found that
C,N-diaryl- and C-carbamoyl-N-arylnitrones react with
methylidenecyclopropanedicarboxylic acid esters to
produce only 4-spiro derivatives [3] and that reactions
of C,C-disubstituted nitrones with the same esters lead
to azeto- and pyrroloquinolines through intermediate
5-spiro isoxazolidines [4].
The present article reports on the reactions of
N-aryl(methyl)-C-arylnitrones Ia–Id and N-aryl-
(methyl)-C-carbamoylnitrones Ie–Ih with methyl
2-benzylidenecyclopropanecarboxylate (II). The
reactions were carried out in boiling toluene to produce
diastereoisomeric 4-spiro oxazolidine derivatives III
and IV with high regioselectivity (Scheme 1).
The structure of cycloadducts III and IV was
determined on the basis of spectral data. Compounds
1
IIIa–IIIh displayed in the H NMR spectra three
doublets of doublets at δ 0.59–2.17 ppm (J = 8.7, 5.8;
6.5, 5.8; 8.7, 6.5 Hz) from protons in the cyclopropane
ring, two singlets at δ 3.44–4.61 and 5.17–5.35 ppm
from CH protons in the oxazolidine ring, and signals
from aromatic protons and protons in the ester group.
1
The H NMR spectra of IIIe–IIIh also contained
a singlet at δ 8.99–9.13 ppm from the NH proton. The
13C NMR spectra of IIIa–IIIh contained signals from
carbon atoms in the cyclopropane ring at δC 14.6–18.7
(CH2), 24.1–28.5 (CH), and 42.6–47.3 ppm (Cspiro),
Scheme 1.
COOMe
Ph
H
H
Ph
H
H
H
COOMe
O–
N+
H
PhMe, 110°C
O
N
R1
O
N
R1
+
+
R2
Ph
R1
COOMe
R2
IIIa–IIIh
R2
Ia–Ih
II
IVa, IVb, IVe–IVh
R1 = R2 = Ph (a); R1 = Ph, R2 = 4-ClC6H4 (b); R1 = Me, R2 = Ph (c); R1 = Me, R2 = 4-ClC6H4 (d); R1 = Ph, R2 = PhNHC(O) (e);
R1 = 4-MeC6H4, R2 = PhNHC(O) (f); R1 = 4-MeC6H4, R2 = 4-MeOC6H4NHC(O) (g); R1 = Me, R2 = PhNHC(O) (h).
1283

MOLCHANOV, TRAN
1284
signals from carbon atoms in the oxazolidine ring at
δC 75.0–79.4 (NCH) and 80.3–81.7 ppm (OCH), and
other signals. In the IR spectra of IIIa–IIId, absorp-
tion bands due to ester carbonyl group were observed
in the region 1728–1720 cm–1, and the amide group in
IIIe–IIIh gave rise to absorption bands at 1686–1680
(C=O) and 3363–3344 cm–1 (NH). The elemental com-
positions or high-resolution mass spectra of IIIa–IIIh
were consistent with the assumed structure.
was also confirmed by their elemental compositions
and high-resolution mass spectra.
1
In the H NMR spectra of the reaction mixtures
only signals corresponding to 4-spiro derivatives were
detected. The stereochemical structure of adducts III
and IV was determined on the basis of 1H–1H NOESY
data (see figure). Compounds IIIb, IIId, and IIIh
showed cross peaks due to interaction between ortho-
protons (H1) in the aromatic ring on the nitrogen atom
(or protons in the N-methyl group) and H5 and H6,
indicating that these protons are located at the same
side of the isoxazolidine ring. In addition, couplings
between protons in the cyclopropane ring (H4, H7, H8),
on the one hand, and H6 and ortho-protons in other
aromatic rings (H2 and H3) were observed. No cross
peaks between H5, H6 and H7, H8, which might be
expected for the other diastereoisomer, were detected.
Analogous pattern was observed in the 1H–1H NOESY
spectrum of IVb with the difference that interaction
between H4 and H5 rather than H6 was found therein.
1
In the H NMR spectra of IVa, IVb, and IVe–IVh
we observed three doublets of doublets from protons in
the cyclopropane ring at δ 0.67–2.29 ppm (J = 8.7,
5.8; 6.5, 5.8; 8.7, 6.5 Hz), two singlets from 7-H and
4-H at δ 4.89–5.23 and 5.08–5.25 ppm, and other
signals. The NH proton in IVe–IVh resonated at
δ 9.17–9.34 ppm. The 13C NMR spectra of IVa, IVb,
and IVe–IVh contained signals from carbon atoms in
the cyclopropane ring at δC 14.8–18.2 (CH2), 25.2–
25.8 (CH), and 42.9–47.4 ppm (Cspiro), signals from
carbon atoms in the oxazolidine ring at δC 67.7–69.7
(C7) and 85.3–86.1 ppm (C4), and other signals. Com-
pounds IVa and IVb showed in the IR spectra ester
carbonyl absorption band at 1730–1720 cm–1, and the
spectra of IVe–IVh displayed amide carbonyl absorp-
tion at 1688–1680 cm–1 and NH absorption at 3363–
3340 cm–1. The structure of IVa, IVb, and IVe–IVh
The ratio of diastereoisomers III and IV depended
on the substituent in the initial nitrone. C,N-Diaryl-
nitrones Ia and Ib gave rise to equimolar mixtures of
the corresponding adducts; isomers IIIc and IIId were
formed as the only products from N-methylnitrones Ic
and Id; and the ratio of adducts III and IV in the
H2
H1
H2
H5
H5
H1
O
H2
Me
O
H2
CO2Me
H7
N
CO2Me
H7
N
H6
H6
H4
H4
H3
H9
H3
N
O
H8
H8
Ph
Cl
O
IIIb
H2
IIIh
H2
H1
O
H5
H5
H1
Me
H2
H2
H4
CO2Me
N
H6
H3
N
H6
H4
MeO2C
H3
H7
H7
H3
H3
H8
H8
Cl
Cl
IIId
IVb
Principal correlations in the 1H NOESY spectra of compounds IIIb, IIId, IIIh, and IVb.
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REGIOSELECTIVE CYCLOADDITION OF C-ARYL- AND C-CARBAMOYLNITRONES
1285
Scheme 2.
Ph
H
H
Ph
H
4
H
H
H
O
N
3
O
CO2Me
H
Ph
O
H
H
7
R1
R2
N
CO2Me
R1
R2
H
H
H
CO2Me
R2
+
A
(3SR,4RS,7SR)
Ph
H
H
H
H
N
4
R1
H
3 H
Ph
O
N
CO2Me
R2
H
O
CO2Me
7
R1
H
R2
N
H
R1
H
B
(3RS,4SR,7SR)
reactions with C-carbamoylnitrones Ie–Ih was 4:1 in
all cases.
(electrospray ionization, positive ion detection). The
IR spectra were recorded on a UR-20 spectrometer
from 2% solutions in chloroform or KBr pellets. The
1H and 13C NMR spectra were measured from solu-
tions in CDCl3 on a Bruker DPX-300 instrument at
300.13 and 75.47 MHz, respectively. The progress of
reactions and the purity of products were monitored by
TLC on Silufol UV-254 plates.
The addition of nitrone I to methylidenecyclo-
propane II may follow two paths. The first of these
involves transition state A and leads to (3SR,4RS,7SR)
stereoisomers III and IV. The second path should give
(3RS,4SR,7SR) stereoisomers through transition state
B. Presumably, the second path is less favorable since
steric repulsion between the phenyl group and R1 and
between the syn-oriented ester group and R2 is possible
in transition state B (Scheme 2).
Initial nitrones Ia–Ih were synthesized according to
the procedures described in [5].
Methyl (E)-2-benzylidenecyclopropanecarbox-
ylate (II). A solution of 1.36 g (20 mmol) of methyl
diazoacetate in 14 ml of methylene chloride was added
over a period of ~4 h to a hot solution of 4.5 g
(30 mmol) of phenylallene and 30 mg of Rh2(OAc)4 in
5 ml of anhydrous methylene chloride. The mixture
was heated for 3 h, cooled, and evaporated, and the
residue was subjected to column chromatography on
silica gel using ethyl acetate–petroleum ether as eluent.
Yield 0.87 g (23%), oily substance. IR spectrum
(CHCl3), ν, cm–1: 3064, 1724 s, 1600, 1492, 1440,
The relative reactivities of nitrones were estimated
by performing competing reactions. We found that
C-(phenylcarbamoyl)-N-phenylnitrone (Ie) is more
reactive than C,N-diphenylnitrone (Ia) toward cyclo-
propane II (chloroform, 60°C) by a factor of more
than 20 and that N-phenyl-C-(4-chlorophenyl)nitrone
(Ib) is more reactive than its N-methyl analog Id
(toluene, 110°C) by a factor 15. These findings indicat-
ed that introduction of an electron-withdrawing group
to the carbon atom increases the reactivity of nitrone
and that replacement of phenyl group on the nitrogen
atom in nitrone by alkyl substituent reduces the
reactivity.
To conclude, we have demonstrated that C-aryl-
and C-carbamoylnitrone react with methyl 2-benzyli-
denecyclopropanecarboxylate in regioselective fashion
to give substituted methyl 5-oxa-6-azaspiro[2.4]hep-
tane-1-carboxylates as mixtures of two diastereo-
isomers.
1
1363, 1334, 1276. H NMR spectrum, δ, ppm:
1.99 d.d.d (1H, CH2, J = 9.5, 8.0, 2.2 Hz), 2.16 d.d.d
(1H, CH, J = 9.5, 4.4, 2.2 Hz), 2.40 d.d.d (1H, CH2,
J = 8.0, 4.4, 2.2 Hz), 3.73 s (3H, CH3), 6.85 q (1H,
=CH, J = 2.2 Hz), 7.28 t (1H, Harom, J = 7.3 Hz), 7.37 t
(2H, Harom, J = 7.3 Hz), 7.54 d (2H, Harom, J = 7.3 Hz).
13C NMR spectrum, δC, ppm: 13.2 (CH2), 16.3 (CH),
52.4 (CH3), 120.2 (CH), 123.3 (C), 127.5 (CH), 128.0
(CH), 129.0 (CH), 137.0 (C), 173.1 (C=O). Found:
m/z 189.0886 [M + H]+. C12H12O2. Calculated:
[M + H]+ 189.0916.
EXPERIMENTAL
The elemental compositions were determined on
a Hewlett–Packard 185-B CHN analyzer. The mass
spectra were run on a Bruker microTOF instrument
Reaction of nitrones Ia–Ih with methyl 2-ben-
zylidenecyclopropanecarboxylate (II) (general
procedure). A solution of 1–3 mmol of benzylidene-
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MOLCHANOV, TRAN
1286
cyclopropane II and 1.1 equiv of nitrone Ia–Ih in
10 ml of anhydrous toluene was heated under reflux
until the reaction was complete. The solvent was re-
moved under reduced pressure, and stereoisomers III
and IV were separated by column chromatography on
silica gel using petroleum ether (bp 40–70°C)–ethyl
acetate as eluent. The eluate was evaporated, and the
residue was recrystallized from ethanol. We failed to
separate diastereoisomers IIIa and IVa.
(C=O). Found, %: C 71.49; H 5.17; N 3.66.
C25H22ClNO3. Calculated, %: C 71.51; H 5.28; N 3.34.
Methyl (1SR,3SR,4RS,7SR)-7-(4-chlorophenyl)-
4,6-diphenyl-5-oxa-6-azaspiro[2.4]heptane-1-car-
boxylate (IVb). Yield 410 mg (28%), white powder,
mp 128–130°C (from EtOH), Rf 0.37 (EtOAc–hexane,
1:7). IR spectrum (CHCl3), ν, cm–1: 3050, 2945, 1730 s,
1
1610, 1505, 1455, 1402, 1310, 1185, 1105. H NMR
spectrum, δ, ppm: 0.67 d.d (1H, CH2, J = 8.7, 5.8 Hz),
1.03 d.d (1H, CH2, J = 6.5, 5.8 Hz), 1.71 d.d (1H, CH,
J = 8.7, 6.5 Hz), 3.71 s (3H, CH3), 5.21 s (1H, CH),
5.22 s (1H, CH), 7.02 t (1H, Harom, J = 7.3 Hz), 7.15 d
(2H, Harom, J = 8.7 Hz), 7.19–7.22 m (2H, Harom),
7.29 d (2H, Harom, J = 8.0 Hz), 7.33–7.43 m (5H,
Harom), 7.75 d (2H, Harom, J = 8.7 Hz). 13C NMR spec-
trum, δC, ppm: 17.7 (CH2), 24.9 (CH), 47.0 (C), 52.0
(CH3O), 68.6 (CH), 85.0 (CH), 114.3 (CH), 122.0
(CH), 128.5 (CH), 128.6 (CH), 128.8 (CH), 129.1
(CH), 129.2 (CH), 129.4 (CH), 133.0 (C), 134.9 (C),
139.7 (C), 150.0 (C), 173.1 (C=O). Found, %: C 71.50;
H 5.28; N 3.52. C25H22ClNO3. Calculated, %: C 71.51;
H 5.28; N 3.34.
M e t h y l ( 1 R S , 3 S R , 4 R S , 7 S R ) - a n d
(1SR,3SR,4RS,7SR)-4,6,7-triphenyl-5-oxa-6-aza-
spiro[2.4]heptane-1-carboxylates (IIIa/IVa). Reac-
tion time 18 h. Yield 470 mg (63%), white powder,
Rf 0.58 (EtOAc–hexane, 1:4). IR spectrum (CHCl3), ν,
cm–1: 3068, 2952, 1720 s, 1600, 1490, 1452, 1392,
1
1292, 1168. H NMR spectrum, δ, ppm: 0.68 d.d (1H,
CH2, J = 8.7, 5.8 Hz), 0.74 d.d (1H, CH2, J = 8.7,
5.8 Hz), 1.01 d.d (1H, CH2, J = 6.5, 5.8 Hz), 1.09 d.d
(1H, CH2, J = 6.5, 5.8 Hz), 1.71 d.d (1H, CH, J = 8.7,
6.5 Hz), 1.97 d.d (1H, CH, J = 8.7, 6.5 Hz), 3.71 s (3H,
CH3), 3.72 s (3H, CH3), 4.61 s (1H, CH), 5.23 s (1H,
CH), 5.25 s (1H, CH), 5.34 s (1H, CH), 7.01–7.46 m
(26H, Harom), 7.70 d (2H, Harom, J = 7.3 Hz), 7.81 d
(2H, Harom, J = 7.3 Hz). 13C NMR spectrum, δC, ppm:
18.1 (CH2), 25.4 (CH), 25.8 (CH), 47.2 (C), 47.5 (C),
52.3 (CH3), 52.4 (CH3), 69.7 (CH), 76.2 (CH), 80.3
(CH), 85.5 (CH), 114.7 (CH), 117.2 (CH), 122.2 (CH),
123.3 (CH), 127.6 (CH), 128.1 (CH), 128.4 (CH),
128.5 (CH), 128.6 (CH), 128.7 (CH), 128.8 (CH),
129.0 (CH), 129.1 (CH), 129.2 (CH), 129.4 (CH),
129.5 (CH), 135.6 (C), 138.3 (C), 140.9 (C), 141.6 (C),
150.0 (C), 150.8 (C), 172.5 (C=O), 173.4 (C=O).
Found, %: C 77.85; H 5.94; N 3.70. C25H23NO3. Cal-
culated, %: C 77.90; H 6.01; N 3.63.
Methyl (1RS,3SR,4RS,7SR)-6-methyl-4,7-di-
phenyl-5-oxa-6-azaspiro[2.4]heptane-1-carboxylate
(IIIc). Reaction time 69 h. Yield 118 mg (23%), oily
liquid, Rf 0.48 (EtOAc–hexane, 1:5). IR spectrum
(CHCl3), ν, cm–1: 3052, 2956, 1722 s, 1604, 1492,
1444, 1392, 1168. 1H NMR spectrum, δ, ppm: 0.61 d.d
(1H, CH2, J = 8.7, 5.8 Hz), 0.85 d.d (1H, CH2, J = 6.5,
5.8 Hz), 1.77 d.d (1H, CH, J = 8.7, 6.5 Hz), 2.74 s (3H,
CH3), 3.78 s (3H, CH3), 3.82 s (1H, CH), 5.18 s (1H,
CH), 7.28–7.41 m (8H, Harom), 7.81 d (2H, Harom, J =
7.3 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 18.7
(CH2), 24.1 (CH), 44.0 (CH3), 47.3 (C), 52.3 (CH3),
79.4 (CH), 80.5 (CH), 127.7 (CH), 128.3 (CH), 128.5
(CH), 128.9 (CH), 129.1 (CH), 129.4 (CH), 135.9 (C),
143.0 (C), 173.1 (C=O). Found: m/z 324.1616 [M + H]+.
C20H21NO3. Calculated: [M + H]+ 324.1600.
Methyl (1RS,3SR,4RS,7SR)-7-(4-chlorophenyl)-
4,6-diphenyl-5-oxa-6-azaspiro[2.4]heptane-1-car-
boxylate (IIIb). Reaction time 14 h. Yield 410 mg
(28%), white powder, mp 55–56°C, Rf 0.32 (EtOAc–
hexane, 1:7). IR spectrum (CHCl3), ν, cm–1: 3060,
1
2956, 1724 s, 1600, 1492, 1444, 1392, 1165. H NMR
Methyl (1RS,3SR,4RS,7SR)-7-(4-chlorophenyl)-
6-methyl-4-phenyl-5-oxa-6-azaspiro[2.4]heptane-1-
carboxylate (IIId). Reaction time 70 h. Yield 160 mg
(32%), oily liquid, Rf 0.40 (EtOAc–hexane, 1:6). IR
spectrum (KBr), ν, cm–1: 3031, 2953, 2871, 1728 s,
spectrum (CDCl3), δ, ppm: 0.78 d.d (1H, CH2, J = 8.7,
5.8 Hz), 1.06 d.d (1H, CH2, J = 6.5, 5.8 Hz), 1.98 d.d
(1H, CH, J = 8.7, 6.5 Hz), 3.71 s (3H, CH3), 4.61 s
(1H, CH), 5.35 s (1H, CH), 7.05 t (1H, Harom, J =
7.3 Hz), 7.12 d (2H, Harom, J = 7.3 Hz), 7.26–7.32 m
(3H, Harom), 7.35–7.43 m (6H, Harom), 7.66 d (2H,
1
1599, 1491, 1444, 1391, 1197, 1168, 1091. H NMR
spectrum, δ, ppm: 0.59 d.d (1H, CH2, J = 8.7, 5.8 Hz),
0.87 d.d (1H, CH2, J = 6.5, 5.8 Hz), 1.76 d.d (1H, CH,
J = 8.7, 6.5 Hz), 2.73 s (3H, CH3), 3.78 s (3H, CH3),
H
arom, J = 6.5 Hz). 13C NMR spectrum, δC, ppm: 17.4
(CH2), 25.6 (CH), 46.5 (C), 51.9 (CH3O), 75.2 (CH),
79.9 (CH), 116.7 (CH), 123.1 (CH), 127.8 (CH), 128.1
(CH), 128.2 (CH), 128.8 (CH), 129.1 (CH), 129.4
(CH), 134.0 (C), 136.6 (C), 140.1 (C), 149.4 (C), 171.9
3.79 s (1H, CH), 5.17 s (1H, CH), 7.22 d (2H, Harom
J = 8.7 Hz), 7.32–7.43 m (5H, Harom), 7.77 d (2H,
arom, J = 8.0 Hz). 13C NMR spectrum, δC, ppm: 18.4
,
H
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REGIOSELECTIVE CYCLOADDITION OF C-ARYL- AND C-CARBAMOYLNITRONES
1287
(CH2), 24.1 (CH), 43.9 (CH3), 47.1 (C), 52.3 (CH3O),
78.6 (CH), 80.4 (CH), 127.7 (CH), 128.2 (CH), 128.4
(CH), 129.3 (CH), 130.6 (CH), 134.6 (C), 134.7 (C),
142.7 (C), 172.8 (C=O). Found: m/z 358.1225 [M + H]+.
C20H20ClNO3. Calculated: [M + H]+ 358.1210.
J = 8.7, 6.5 Hz), 2.19 d.d (1H, CH, J = 8.7, 5.8 Hz),
2.37 s (3H, CH3), 3.58 s (3H, CH3), 4.20 s (1H, CH),
5.23 s (1H, CH), 7.12 d (2H, Harom, J = 8.7 Hz), 7.18–
7.49 m (10H, Harom), 7.59 d (2H, Harom, J = 8.0 Hz),
9.08 s (1H, NH). 13C NMR spectrum, δC, ppm: 14.8
(CH2), 21.1 (CH3), 28.0 (CH), 43.1 (C), 52.1 (CH3),
75.1 (CH), 81.7 (CH), 115.8 (CH), 120.5 (CH), 125.2
(CH), 128.9 (CH), 129.0 (CH), 129.5 (CH), 130.3
(CH), 133.6 (C), 137.5 (C), 137.9 (C), 146.6 (C), 167.7
(C=O), 172.0 (C=O). Found, %: C 73.39; H 5.84;
N 6.25. C27H26N2O4. Calculated, %: C 73.28; H 5.92;
N 6.33.
Methyl (1RS,3SR,4RS,7SR)-4,6-diphenyl-7-
phenylcarbamoyl-5-oxa-6-azaspiro[2.4]heptane-1-
carboxylate (IIIe). Reaction time 70 min. Yield
275 mg (64%), white powder, mp 149–150°C (from
EtOH), Rf 0.36 (EtOAc–hexane, 1:3). IR spectrum
(CHCl3), ν, cm–1: 3356, 3064, 2956, 1724 s, 1684 s,
1
1600, 1528, 1490, 1444, 1392, 1324, 1172. H NMR
Methyl (1SR,3SR,4RS,7SR)-6-(4-methylphenyl)-
4-phenyl-7-phenylcarbamoyl-5-oxa-6-azaspiro[2.4]-
heptane-1-carboxylate (IVf). Yield 73 mg (17%),
spectrum, δ, ppm: 1.09 d.d (1H, CH2, J = 6.5, 5.8 Hz),
2.04 d.d (1H, CH2, J = 8.7, 6.5 Hz), 2.20 d.d (1H, CH,
J = 8.7, 5.8 Hz), 3.57 s (3H, CH3), 4.23 s (1H, CH),
5.25 s (1H, CH), 7.11–7.23 m (4H, Harom), 7.34–7.49 m
(9H, Harom), 7.59 d (2H, Harom, J = 8.0 Hz), 9.06 s (1H,
NH). 13C NMR spectrum, δC, ppm: 14.7 (CH2), 28.0
(CH), 43.0 (C), 52.2 (CH3), 75.1 (CH), 81.7 (CH),
115.5 (CH), 120.5 (CH), 124.0 (CH), 125.2 (CH),
128.9 (CH), 129.0 (CH), 129.5 (CH), 129.8 (CH),
137.4 (C), 137.8 (C), 149.0 (C), 167.6 (C=O), 172.0
(C=O). Found, %: C 72.79; H 5.50; N 6.45.
C26H24N2O4. Calculated, %: C 72.88; H 5.65; N 6.54.
1
waxy material, Rf 0.44 (EtOAc–hexane, 1:4). H NMR
spectrum, δ, ppm: 0.93 d.d (1H, CH2, J = 8.7, 5.8 Hz),
1.58 d.d (1H, CH2, J = 8.7, 6.5 Hz), 2.26 d.d (1H, CH,
J = 6.5, 5.8 Hz), 2.37 s (3H, CH3), 3.61 s (3H, CH3),
4.90 s (1H, CH), 5.08 s (1H, CH), 7.08–7.48 m (12H,
Harom), 7.68 d (2H, Harom, J = 8.0 Hz), 9.27 s (1H, NH).
13C NMR spectrum, δC, ppm: 15.6 (CH2), 21.1 (CH3),
25.2 (CH), 43.7 (C), 52.4 (CH3), 67.8 (CH), 86.0 (CH),
115.4 (CH), 120.4 (CH), 124.8 (CH), 128.6 (CH),
128.8 (CH), 129.3 (CH), 129.5 (CH), 130.2 (CH),
133.4 (C), 136.0 (C), 138.0 (C), 148.9 (C), 168.2
(C=O), 172.9 (C=O). Found: m/z 465.1806 [M + Na]+.
C27H26N2O4. Calculated: [M + Na]+ 465.1790.
Methyl (1SR,3SR,4RS,7SR)-4,6-diphenyl-7-phe-
nylcarbamoyl-5-oxa-6-azaspiro[2.4]heptane-1-car-
boxylate (IVe). Yield 70 mg (16%), waxy material,
Rf 0.44 (EtOAc–hexane, 1:3). IR spectrum (CHCl3), ν,
cm–1: 3356, 3036, 2956, 1722 s, 1688 s, 1600, 1528,
Methyl (1RS,3SR,4RS,7SR)-7-(4-methoxyphenyl-
carbamoyl)-6-(4-methylphenyl)-4-phenyl-5-oxa-6-
azaspiro[2.4]heptane-1-carboxylate (IIIg). Reaction
time 70 min. Yield 305 mg (68%), white powder (from
EtOH), Rf 0.35 (EtOAc–hexane, 1:4). IR spectrum
(CHCl3), ν, cm–1: 3363, 2956, 1724 s, 1680 s, 1596,
1
1490, 1444, 1394, 1174. H NMR spectrum, δ, ppm:
0.95 d.d (1H, CH2, J = 8.7, 5.8 Hz), 1.60 d.d (1H, CH2,
J = 8.7, 6.5 Hz), 2.26 d.d (1H, CH, J = 6.5, 5.8 Hz),
3.59 s (3H, CH3), 4.94 s (1H, CH), 5.11 s (1H, CH),
7.12–7.45 m (13H, Harom), 7.68 d (2H, Harom, J =
8.0 Hz), 9.25 s (1H, NH). 13C NMR spectrum, δC,
ppm: 15.6 (CH2), 25.2 (CH), 43.6 (C), 52.4 (CH3),
67.9 (CH), 86.1 (CH), 115.2 (CH), 120.4 (CH), 123.8
(CH), 124.9 (CH), 128.6 (CH), 128.9 (CH), 129.3
(CH), 129.5 (CH), 129.7 (CH), 135.9 (C), 137.9 (C),
148.9 (C), 168.1 (C=O), 172.9 (C=O). Found:
m/z 451.1641 [M + Na]+. C26H24N2O4. Calculated:
[M + Na]+ 451.1634.
1
1512, 1442, 1414, 1392, 1248, 1172. H NMR spec-
trum, δ, ppm: 1.07 d.d (1H, CH2, J = 6.5, 5.8 Hz),
2.03 d.d (1H, CH2, J = 8.7, 6.5 Hz), 2.20 d.d (1H, CH,
J = 8.7, 5.8 Hz), 2.37 s (3H, CH3), 3.58 s (3H, CH3),
3.83 s (3H, CH3), 4.19 s (1H, CH), 5.23 s (1H, CH),
6.92 d (2H, Harom, J = 8.7 Hz), 7.11 d (2H, Harom, J =
8.7 Hz), 7.18 t (2H, Harom, J = 8.7 Hz), 7.31–7.38 m
(3H, Harom), 7.46 d (2H, J = 8.7 Hz), 7.49 d (2H, J =
8.7 Hz), 8.99 s (1H, NH). 13C NMR spectrum, δC,
ppm: 14.7 (CH2), 21.1 (CH3), 28.0 (CH), 43.1 (C),
52.1 (CH3), 55.9 (CH3), 75.0 (CH), 81.6 (CH), 114.6
(CH), 115.7 (CH), 122.2 (CH), 128.9 (CH), 129.0
(CH), 129.1 (CH), 130.3 (CH), 130.6 (C), 133.6 (C),
137.9 (C), 146.6 (C), 157.1 (C), 167.4 (C=O), 172.1
(C=O). Found, %: C 71.09; H 5.96; N 5.90.
C28H28N2O5. Calculated, %: C 71.17; H 5.97; N 5.93.
Methyl (1RS,3SR,4RS,7SR)-6-(4-methylphenyl)-
4-phenyl-7-phenylcarbamoyl-5-oxa-6-azaspiro[2.4]-
heptane-1-carboxylate (IIIf). Reaction time 70 min.
Yield 290 mg (66%), white powder (from EtOH),
Rf 0.36 (EtOAc–hexane, 1:4). IR spectrum (CHCl3), ν,
cm–1: 3348, 3048, 2956, 1726 s, 1686 s, 1600, 1528,
1
1506, 1444, 1392, 1176. H NMR spectrum, δ, ppm:
1.08 d.d (1H, CH2, J = 6.5, 5.8 Hz), 2.05 d.d (1H, CH2,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 10 2012

MOLCHANOV, TRAN
1288
Methyl (1SR,3SR,4RS,7SR)-7-(4-methoxyphenyl-
3.93 s (1H, CH), 5.17 s (1H, CH), 7.15–7.19 (3H,
Harom), 7.27–7.30 m (3H, Harom), 7.37 t (2H, Harom, J =
carbamoyl)-6-(4-methylphenyl)-4-phenyl-5-oxa-
6-azaspiro[2.4]heptane-1-carboxylate (IVg). Yield
75 mg (17%), waxy material, Rf 0.44 (EtOAc–hexane,
8.0 Hz), 7.66 d (2H, Harom, J = 8.7 Hz), 9.34 s
(1H, NH). 13C NMR spectrum, δC, ppm: 14.7 (CH2),
25.4 (CH), 42.5 (C), 43.3 (CH3), 52.1 (CH3), 68.8
(CH), 84.9 (CH), 119.8 (CH), 124.2 (CH), 128.1
(CH), 128.8 (CH), 128.9 (CH), 129.0 (CH), 136.1
(C), 137.6 (C), 167.7 (C=O), 172.3 (C=O). Found:
m/z 367.1673 [M + H]+. C21H22N2O4. Calculated:
[M + H]+ 367.1658.
1
1:4). H NMR spectrum, δ, ppm: 0.92 d.d (1H, CH2,
J = 8.7, 5.8 Hz), 1.57 d.d (1H, CH2, J = 8.7, 6.5 Hz),
2.27 d.d (1H, CH, J = 6.5, 5.8 Hz), 2.37 s (3H, CH3),
3.60 s (3H, CH3), 3.83 s (3H, CH3), 4.89 s (1H, CH),
5.08 s (1H, CH), 6.92 d (2H, Harom, J = 8.7 Hz), 7.09 d
(2H, Harom, J = 8.7 Hz), 7.16–7.23 m (4H, Harom), 7.30–
7.38 m (3H, Harom), 7.59 d (2H, Harom, J = 9.5 Hz),
9.17 s (1H, NH). 13C NMR spectrum, δC, ppm: 14.8
(CH2), 21.1 (CH3), 25.2 (CH), 43.6 (C), 52.3 (CH3),
55.9 (CH3), 67.7 (CH), 86.1 (CH), 114.6 (CH), 115.4
(CH), 122.0 (CH), 128.6 (CH), 129.3 (CH), 129.6
(CH), 130.2 (CH), 133.3 (C), 136.1 (C), 136.7 (C),
145.9 (C), 156.9 (C), 166.6 (C=O), 167.8 (C=O).
Found: m/z [M + Na]+ 495.1909. C28H28N2O5. Calcu-
lated: [M + Na]+ 495.1896.
The relative reactivities of nitrones toward 2-ben-
zylidenecyclopropane were estimated by the yields of
the final products. The reaction was carried out using
1 equiv of 2-benzylidenecyclopropane and 4 equiv of
each nitrone. The ratio of adducts III and IV was
1
determined from the H NMR spectra of the reaction
mixtures.
REFERENCES
Methyl (1RS,3SR,4RS,7SR)-6-methyl-4-phenyl-
7-phenylcarbamoyl-5-oxa-6-azaspiro[2.4]heptane-
1-carboxylate (IIIh). Reaction time 9 h. Yield 295 mg
(48%), white powder, mp 121–122°C (from EtOH),
Rf 0.35 (EtOAc–hexane, 1:2). IR spectrum (CHCl3), ν,
cm–1: 3344, 3064, 2956, 1724 s, 1684 s, 1602, 1532,
1. Tufarielo, J.J., 1,3-Dipolar Cycloaddition Chemistry,
Padwa, A., Ed., New York: Wiley, 1984; Jones, R.C.F.
and Martin, J.N., Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and
Natural Products, Padwa, A. and Pearson, W.H., Eds.,
New York: Wiley, 2002, p. 1; Grigor’ev, I.A., Nitrile
Oxides, Nitrones and Nitronates in Organic Synthesis,
Feuer, H., Ed., Hoboken, NJ: Wiley, 2007, p. 129.
2. Brandi, A. and Goti, A., Chem. Rev., 1998, vol. 98,
p. 589; 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; Diev, V.V., Stetsenko, O.N., Tran, T.Q.,
Kopf, J., Kostikov, R.R., and Molchanov, A.P., J. Org.
Chem., 2008, vol. 73, p. 2396.
1
1444, 1392, 1324, 1170. H NMR spectrum, δ, ppm:
1.03 d.d (1H, CH2, J = 6.5, 5.8 Hz), 2.17 d.d (1H, CH2,
J = 8.7, 5.8 Hz), 2.27 d.d (1H, CH, J = 8.7, 6.5 Hz),
3.02 s (3H, CH3), 3.44 s (1H, CH), 3.79 s (3H, CH3),
5.19 s (1H, CH), 7.17 t (1H, Harom, J = 7.3 Hz), 7.28–
7.39 m (7H, Harom), 7.59 d (2H, Harom, J = 8.0 Hz),
9.13 s (1H, NH). 13C NMR spectrum, δC, ppm: 14.2
(CH2), 28.1 (CH), 42.2 (C), 43.9 (CH3), 52.0 (CH3),
75.5 (CH), 80.6 (CH), 120.0 (CH), 124.6 (CH), 128.3
(CH), 128.4 (CH), 128.5 (CH), 129.1 (CH), 137.2 (C),
138.1 (C), 167.2 (C=O), 171.8 (C=O). Found, %:
C 68.68; H 5.98; N 7.59. C21H22N2O4. Calculated, %:
C 68.84; H 6.05; N 7.65.
3. Diev, V.V., Tran, T.Q., and Molchanov, A.P., Eur. J. Org.
Chem., 2009, p. 525; Tran, T.Q., Diev, V.V., and Molcha-
nov, A.P., Tetrahedron, 2011, vol. 67, p. 2391; Molcha-
nov, A.P., Tran, T.Q., and Kostikov, R.R., Izv. Ross.
Akad. Nauk, Ser. Khim., 2011, p. 2253.
Methyl (1SR,3SR,4RS,7SR)-6-methyl-4-phenyl-
7-phenylcarbamoyl-5-oxa-6-azaspiro[2.4]heptane-
1-carboxylate (IVh). Yield 75 mg (12%), oily sub-
stance, Rf 0.32 (EtOAc–hexane, 1:2). IR spectrum
(CHCl3), ν, cm–1: 3340, 3068, 2956, 1724 s, 1688 s,
4. Tran, T.Q., Diev, V.V., Starova, G.L., Gurzhiy, V.V., and
Molchanov, A.P., Eur. J. Org. Chem., 2012, p. 2054.
5. Svetkin, Yu.V., Akmanova, N.A., and Karataeva, G.I.,
Zh. Org. Khim., 1972, vol. 8, p. 2431; Akmanova, N.A.,
Sagitdinova, Kh.F., and Balenkova, E.S., Khim. Getero-
tsikl. Soedin., 1982, p. 1192; Andrade, M.M.,
Barros, M.T., and Pinto, R.C., Tetrahedron, 2008, vol. 64,
p. 10521; Molchanov, A.P., Tran, T.Q., and Kosti-
kov, R.R., Russ. J. Org. Chem., 2011, vol. 47, p. 269.
1
1602, 1526, 1444, 1394, 1324, 1170. H NMR spec-
trum, δ, ppm: 0.86 d.d (1H, CH2, J = 8.7, 5.8 Hz),
1.93 d.d (1H, CH2, J = 8.7, 6.5 Hz), 2.29 d.d (1H, CH,
J = 6.5, 5.8 Hz), 2.99 s (3H, CH3), 3.79 s (3H, CH3),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 10 2012