Thermolysis of 1-phthalimidoaziridine-2-carbonitriles in the presence of dipolarophiles

Article abstract of DOI:10.1134/S1070428008120105

Thermolysis of trans-3-phenyl-1-phthalimidoaziridine-2-carbonitrile and trans-1-phthalimidoaziridine-2,3-dicarbonitrile in the presence of several dipolarophiles involves 1,3-dipolar cycloaddition to intermediate azomethine ylides and leads to 1-phthalimidopyrrolidine derivatives with good yields and high stereoselectivity. Thermally induced opening of the three-membered ring in trans-2,3-disubstituted 1-phthalimidoaziridines occurs in conrotatory mode to produce the corresponding cis-azomethine ylides in keeping with the orbital symmetry conservation rules. The relative configuration of substituents in the dipolarophiles is retained, which implies concerted mechanism of the addition.

Full text of DOI:10.1134/S1070428008120105

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1780–1788. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © M.A. Kuznetsov, A.S. Pan’kova, A.V. Ushkov, S.I. Selivanov, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44,
No. 12, pp. 1807–1815.
Thermolysis of 1-Phthalimidoaziridine-2-carbonitriles
in the Presence of Dipolarophiles
M. A. Kuznetsov, A. S. Pan’kova, A. V. Ushkov, and S. I. Selivanov
St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
e-mail: mak@mail.wplus.net
Received October 26, 2007
Abstract—Thermolysis of trans-3-phenyl-1-phthalimidoaziridine-2-carbonitrile and trans-1-phthalimidoaziri-
dine-2,3-dicarbonitrile in the presence of several dipolarophiles involves 1,3-dipolar cycloaddition to inter-
mediate azomethine ylides and leads to 1-phthalimidopyrrolidine derivatives with good yields and high stereo-
selectivity. Thermally induced opening of the three-membered ring in trans-2,3-disubstituted 1-phthalimido-
aziridines occurs in conrotatory mode to produce the corresponding cis-azomethine ylides in keeping with the
orbital symmetry conservation rules. The relative configuration of substituents in the dipolarophiles is retained,
which implies concerted mechanism of the addition.
DOI: 10.1134/S1070428008120105
Aziridines are widely used in organic synthesis, and
their transformations usually involve opening of the
energy-rich three-membered ring. Thermally or photo-
chemically induced cleavage of the C–C bond gen-
erates 1,3-dipoles, so-called azomethine ylides A [1],
and addition of the latter at multiple bonds of dipolaro-
philes provides a general method for the synthesis of
various five-membered nitrogen-containing hetero-
cycles [2] (Scheme 1). Obviously, aziridine ring open-
ing to produce azomethine ylides should be favored by
the presence of strong electron-withdrawing groups
that are capable of stabilizing partial negative charge
on the terminal carbon atoms of the 1,3-dipole thus
formed.
electron-withdrawing substituents on slight heating (or
even at room temperature!) in the presence of dipolaro-
philes are in fact converted into compounds which may
be regarded as products of intra- (dihydrooxazoles,
oxazoles) and/or intermolecular transformations (dihy-
dropyrroles, azetidines) of the corresponding N-phthal-
imidoazomethine ylides. It was also noted that the
activating effect of substituents on the aziridine carbon
atoms decreases in the series CN >> COR > COOR.
Analogous intramolecular transformations were report-
ed for N-succinimidoaziridines [5].
However, the only dipolarophile used in the above
studies on [2+3]-cycloaddition of azomethine ylides
was strongly reactive dimethyl acetylenedicarboxylate,
and the steric structure of a few isolated adducts was
not determined rigorously. Therefore, both the scope of
application of this reaction series for the synthesis of
N-aminoazoles and general relations (primarily stereo-
chemical) holding in the process remained unclear. The
goal of the present work was to examine thermal trans-
formations of much more stable trans-disubstituted
N-phthalimidoaziridines I and II in the presence of
The possibility for generation of azomethine ylides
from N-aminoaziridine derivatives has been studied
very poorly, though this process could give rise in one
step to various compounds of the N-aminodihydropyr-
role and N-aminopyrrolidine series. The only series of
studies in this field was performed about 25 years ago
by Foucaud et al. [3, 4]. These authors showed that
some N-phthalimidoaziridines having three or four
Scheme 1.
X
Y
Δ or hν
X
Y
N
N
N
N
A
1780

THERMOLYSIS OF 1-PHTHALIMIDOAZIRIDINE-2-CARBONITRILES
1781
Scheme 2.
R
Pb(OAc)4, CH2Cl2
CN
PhthN NH2
+
PhthN
N
R
CN
I (40%), II (50%)
O
b
a
c
N
I, R = CN; II, R = Ph; PhthN =
.
O
various dipolarophiles and elucidate the mechanism
and stereochemical aspects of the formation of pos-
sible 1,3-dipolar cycloaddition products.
different sources were mixtures of E and Z isomers
whose separation is quite tedious. Therefore, we pre-
pared pure (E)-cinnamonitrile from accessible (E)-cin-
namic acid through the corresponding amide.
The choice of substituents in the three-membered
ring of aziridines I and II was dictated by the follow-
ing reasons. According to published data [4], cyano
group which is known as a strong electron acceptor
maximally facilitates cleavage of aziridine ring with
formation of azomethine ylide, while phenyl group is
capable of effectively delocalizing both positive and
negative charges. As dipolarophiles we selected exten-
sively studied compounds IIIa–IIIc possessing elec-
tron-deficient double carbon–carbon bonds, which are
frequently used as “traps” and are convenient models
for studying stereochemistry of the entire transforma-
tion sequence.
The structure of aziridines I and II was confirmed
by the 1H and 13C NMR and mass spectra and elemen-
tal analyses. N-Aminoaziridine derivatives are charac-
terized by slow (on the NMR time scale) inversion of
the endocyclic nitrogen atom [7]. In the case of aziri-
dine I this process is degenerate, so that compound I
1
displays in the H NMR spectrum two doublets from
protons in the aziridine ring of a single form at δ 4.8–
1
4.9 ppm. According to the H NMR data, aziridine II
at room temperature exists as a mixture of two inverto-
mers, one of which considerably prevails (~96:4). Sig-
nals from the aziridine protons of the major invertomer
appear in a stronger field (δ 3.38 and 4.52 ppm; cf.
δ 4.12 4.73 ppm for the minor one). In the 13C NMR
spectrum of II, only signals belonging to the major
invertomer could be reliably distinguished. Taking into
account that the effective volume of the phenyl group
is clearly larger than the volume of the linear cyano
N-Phthalimidoaziridines I and II were synthesized
from N-aminophthalimide and the corresponding un-
saturated nitriles according to the standard procedure
for oxidative aminoaziridination [6] (Scheme 2). Com-
mercially available fumaronitrile was pure E isomer.
However, commercial samples of cinnamonitrile from
Scheme 3.
R'
R'
120–220°C
2.5–3.5 h
H
H
IIIa–IIIc
I, II
R
CN
R
N
CN
N
NPhth
NPhth
IVa–IVc (34–77%)
Va–Vc (21–82%)
O
N
O
MeO
MeO
OMe
Ph
OMe
O
O
O
O
IIIa
IIIb
IIIc
IV, R = CN; V, R = Ph.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

KUZNETSOV et al.
1782
group, the phenyl ring and phthalimide fragment in
the major invertomer are likely to be oriented trans.
trans Configuration of both adducts I and II with
respect to the C2–C3 bond follows from the small
vicinal coupling constant for the aziridine protons (3J =
5.1 Hz for compound I and the major invertomer of II;
3J = 5.6 Hz for the minor invertomer of II) [7].
leads to more severe conditions necessary for opening
of the aziridine ring.
In all cases, thermolysis of aziridines I and II in the
presence of dipolarophiles IIIa–IIIc led to the forma-
tion of the corresponding 1,3-dipolar cycloaddition
products, previously unknown N-phthalimidopyrroli-
dines IVa–IVc and Va–Vc (Scheme 3). The selectivity
1
of the process was confirmed by the H NMR spectra
Thermolysis of aziridines I and II was performed in
sealed ampules and/or in a hermetically closed heat-
resistant reactor in the presence of 1.5 equiv of the cor-
responding dipolarophile. As solvent we used benzene
or more polar and higher-boiling chlorobenzene.
of the reaction mixtures, which were recorded imme-
diately after thermolysis.
The assumed structure of crystalline N-phthal-
imidopyrrolidines IVa–IVc and Va–Vc was consistent
1
Preliminary experiments were carried out by heat-
ing aziridine I in the presence of dimethyl fumarate
(IIIa). Compound I is appreciably soluble in benzene
only above 150°C, and in chlorobenzene, at 110°C;
nevertheless, it was necessary to heat the reaction mix-
ture to 220°C to initiate the process. Likewise, heating
to the same temperature was required for the reactions
of I with dipolarophiles IIIb and IIIc. Therefore,
chlorobenzene was selected as solvent. Monitoring of
the reaction course by TLC showed that complete
conversion of aziridine I into thermolysis products was
attained in about 3 h. The reactions of aziridine II with
dipolarophiles IIIa–IIIc were complete in 2.5–3 h
even at 120°C, so that this series of experiments was
performed using benzene as solvent. Insofar as each of
aziridines I and II started to react with all dipolaro-
philes IIIa–IIIc at the same temperature, we presumed
that the rate-determining step in the overall process
is just opening of the aziridine ring to generate azo-
methine ylide.
with their H and 13C NMR and mass spectra and
elemental analyses. The mass spectra of IVa–IVc and
Va–Vc contained the corresponding molecular ion
peaks, strong peaks due to [M – 146]+ and/or
[M – 147]+ ions (loss of phthalimide fragment), and
ion peak with m/z 147. In the 1H NMR spectra of these
compounds, multiplets typical of phthalimido group
were located in the region δ 7.70–8.00 ppm. The imide
carbonyl carbon atoms resonated in the 13C NMR spec-
tra at δC 164–165 ppm, and carbon atoms in the six-
membered aromatic ring gave signals at δC 129–130
(Ca), 123–124 (Cb), and 134–135 ppm (Cc). The chem-
ical shifts of protons and carbon nuclei in the cyano,
methoxycarbonyl, and phenyl groups had their usual
values.
Signals from protons neighboring to the nitrogen
atom in the pyrrolidine fragments usually appear in the
1H NMR spectra of adducts IVa–IVc and Va–Vc as
doublets at δ 4.9–5.4 ppm. Protons on C3 and C4
resonate at δ 3.5–4.4 ppm, and the number and multi-
plicity of their signals depend on a particular com-
pound structure. Four protons in the pyrrolidine ring of
adducts IVa and Va–Vc form an ABXY spin system,
and the 3-H and 4-H signals appear as doublets of
doublets which sometimes degenerate into triplets.
This is consistent with magnetic nonequivalence of
those protons in molecules Va–Vc and the absence of
any symmetry elements (such as reflection plane or
second-order rotation axis) in pyrrolidine IVa mole-
cule. The four ring protons in IVb and IVc give only
two signals (AA′XX′ spin system), indicating the pres-
ence of some symmetry elements in their molecules. In
the spectrum of bicyclic adduct IVc, these signals look
like slightly broadened singlets, which corresponds to
3JAX not exceeding 1–2 Hz. The above stated is con-
sistent with the presence of four pyrrolidine carbon
signals in the 13C NMR spectrum of adduct IVa and
only two signals in the spectra of IVb and IVc.
In all cases, the thermolysis was accompanied by
tarring and formation of phthalimide. The latter may
appear in the reaction mixture as a result of elimination
from both initial aziridine and final product. However,
when aziridines I and II were heated under the same
conditions but in the absence of dipolarophile, no
decomposition was observed; therefore, elimination of
phthalimide fragment from the cycloaddition products
seems to be more probable.
Comparison of the thermolysis conditions for aziri-
dines I and II indicates more facile conversion of
phenyl-substituted compound II into azomethine ylide,
i.e., phenyl ring stabilizes intermediate dipole more
effectively than does strong electron-withdrawing
cyano group. On the other hand, published data for tri-
and tetra-substituted aziridines [4] clearly demonstrate
that, as might be expected, reduction in the number of
substituents capable of stabilizing azomethine ylide
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

THERMOLYSIS OF 1-PHTHALIMIDOAZIRIDINE-2-CARBONITRILES
1783
NC
NC
N
A fairly difficult problem was to determine steric
COOMe
COOMe
COOMe
structure of the isolated compounds. For this purpose,
dependences of vicinal coupling constants 3JHH upon
dihedral angle (like Karplus equation) are generally
PhthN
PhthN
PhthN
N
PhthN
PhthN
PhthN
COOMe
3
NC
NC
used. However, the ranges of JHH for cis- and trans-
IVa1
IVa2
oriented protons in five-membered heterocycles
3
strongly overlap each other, so that JHH values cannot
NC
N
NC
N
be regarded as reliable criteria for configuration as-
signment [8]. This is clearly demonstrated by the data
for adduct IVa obtained from aziridine I and dimethyl
fumarate (IIIa). All vicinal constants for the ring
protons in IVa are almost similar (J2,3 = J4,5 = 9.1,
J3,4 = 9.8 Hz). It would seem that equal J2,3 and J4,5
constants imply similar orientations of the H2/H3 and
H4/H5 couples (both cis or both trans). On the other
hand, examination of all six theoretically possible dia-
stereoisomers of IVa (structures IVa1, IVa2 and IVb1–
IVb4) shows that similar orientations of the above
proton couples inevitably correspond to the presence
of a symmetry element (plane or C2 axis; structures
IVb1–IVb4); this means that these protons and the
respective carbon atoms should be enantiotopic or
equivalent in pairs. In contrast, all ring protons and
carbon atoms in IVa are nonequivalent, i.e., molecule
IVa lacks any symmetry element; therefore, it may
have only asymmetric structure like IVa1 or IVa2.
COOMe
COOMe
COOMe
COOMe
σ
NC
NC
IVb1
IVb2
NC
N
NC
N
COOMe
COOMe
COOMe
COOMe
C2
NC
NC
IVb3
IVb4
Theoretically, symmetric compound IVb may have
one of the following four configurations: IVb1 and
IVb2 with a symmetry plane and pairwise enantiotopic
protons or IVb3 and IVb4 with a second-order rotation
axis and pairwise equivalent protons. These two struc-
ture types may be distinguished provided that the
rotation of the phthalimido group about the N–N bond
is slow on the NMR time scale. The reason is that dia-
stereosomers IVb3 and IVb4 retain the C2 symmetry
axis at any conformation of the phthalimide residue,
and all protons and carbon atoms therein should
remain equivalent in pairs even if the rotation is
restricted completely. On the other hand, in the most
stable conformers of structures IVb1 and IVb2 the
phthalimido group should be orthogonal to the pyrroli-
dine ring plane. In this case, provided that the rotation
about the N–N bond is restricted, two halves of the
3
Insofar as vicinal coupling constants JHH are clear-
ly unsuitable for determination of steric configuration
1
of the isolated adducts, we have resorted to 2D H
NOESY technique. Figure 1 shows the 2D 1H NOESY
spectrum of adduct IVa; it is seen that the NOEs for
H2–H3 and H4–H5 sharply differ in magnitude. The
observed pattern suggests cis orientation of H4 and H5
and trans orientation of H2 and H3. Furthermore, the
H3–H4 cross peak is very weak, which corresponds to
trans orientation of these protons. Thus the configura-
tion of molecule IVa is given by structure IVa1.
H3 H2
H3, H4
δ, ppm
H2
H3
COOMe
NC
4.0
H3, H4
PhthN
N
COOMe
H4
4.5
5.0
NC
H5
H2
H3
IVa
5.0
4.5
4.0 δ, ppm
Fig. 1. 2D 1H NOESY spectrum of dimethyl rel-(2R,3R,4R,5S)-2,5-dicyano-1-phthalimidopyrrolidine-3,4-dicarboxylate (IVa).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

KUZNETSOV et al.
1784
H1′
H1
O
H6a
H1, H3 H3′
H3a, H6a
H
3a′ H6a′
NC
δ, ppm
PhthN
N
N
Ph
H3a
H6a′
H3a′
NC
H3
IVc
O
O
4.0
H3a, H6a
4.5
5.0
5.5
O
H1'
H6a'
MeO
PhthN
MeO
N
N
Ph
H3′
H1, H3
H3a'
H3'
O
O
5.5
5.0
4.5
4.0 δ, ppm
VI
Fig. 2. 2D 1H NOESY spectrum of a mixture of compounds IVc and VI at a ratio of 1:2.
phthalimide fragment become nonequivalent, which
should be reflected in a complicated pattern of the cor-
responding signals in the NMR spectra.
that it is considerably weaker than for the cis-oriented
H3′–H3a′ and H3a′–H6a′ protons in VI. These findings
unambiguously indicate trans orientation of the cyano
groups and N-phenylmaleimide fragment in molecule
IVc, i.e., its exo configuration.
Even at room temperature, the signal from the
imide carbonyl carbon atoms in the 13C NMR spectrum
of IVb (δC 164.9 ppm) is very weak and broadened;
obviously, this is the result of a slow (on the NMR
time scale) dynamic process. Therefore, molecule IVb
possesses a symmetry plane (structure IVb1 or IVb2)
but not symmetry axis. Assuming that strained all-cis
structure IVb2 is unlikely to be formed as the only
product of intermolecular reaction at 220°C, adduct
IVb was assigned structure IVb1.
All products of cycloaddition of aziridine II to
dipolarophiles IIIa–IIIc are characterized by slow (on
the NMR time scale) rotation of the phthalimido group
about the N–N bond. As a result, the imide carbonyl
carbon signals (δC 164–165 ppm) are not observed in
the 13C NMR spectra of Va–Vc, and sometimes Ca
signals disappear; in addition, the Ca and Cb signals
broaden. Presumably, the phenyl ring in the α-position
to the former aziridine nitrogen atom creates strong
steric hindrances to rotation of the phthalimide frag-
ment (as compared to cyano-substituted analog).
The NMR spectra of bicyclic adduct IVc also in-
dicate that its molecule is symmetric. It may have con-
figurations analogous to IVb1–IVb4. However, trans-
junction of two five-membered rings is strongly unfa-
vorable; therefore, structures like IVb3 and IVb4 may
be ruled out. Structures IVb1 and IVb2 possess a sym-
metry plane and differ by orientation of the cyano
groups and N-phenylmaleimide fragment with respect
to the pyrrolidine ring plane. To distinguish between
1
In the H NMR spectra of compounds Va–Vc,
signal from the CHPh proton appears as a doublet in
a weaker field than the CHCN proton and is broader
and lower. Most probably, this is the result of long-
range interaction with ortho-protons in the benzene
ring. The most upfield signal in the spectra is that from
the proton in the vicinal position with respect to the
phenyl group. Signals from the ring protons in the
spectra of adducts Va–Vc (with account taken of their
multiplicity) were assigned, and their steric structure
1
them, we used the “intermolecular” 2D H NOESY
version and compared NOEs for couples of neighbor-
ing protons in pyrrolidine IVc and previously synthe-
sized compound VI whose configuration unambigu-
ously follows from the absence of symmetry elements
in its molecule. In order to take into account equiva-
lence of the H1–H6a and H3–H3a couplings in molecule
IVc, a twofold amount of compound VI was taken.
1
was determined, using 2D H NOESY as well. For
example, strong nuclear Overhauser effect between the
ortho-protons in the phenyl ring, on the one hand, and
spatially close 3-H and 3a-H, on the other, allowed us
1
to unambiguously assign signals in the H NMR spec-
The NOESY spectrum of a 1:2 mixture of com-
pounds IVc and VI (Fig. 2) clearly shows that the
NOE for H1–H6a/H3–H3a in IVc is comparable with the
NOE for the trans-oriented H1′ and H6a′ protons and
trum of compound Vc. In addition, the cross peak be-
tween the cis-oriented protons in the N-phenylmale-
imide fragment (H3a/H6a) is much greater than the cor-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

THERMOLYSIS OF 1-PHTHALIMIDOAZIRIDINE-2-CARBONITRILES
1785
H1
H5
H5
O
H6a
H4
COOMe
H4
COOMe
NC
NC
HN
Ph
NC
PhthN
N
PhthN
N
N
Ph
COOMe
H3
COOMe
H3
H3a
Ph
Ph
H2
H2
H3
Vc
O
Va
Vb
responding NOEs for the trans-oriented proton couples
H1–H6a and H3–H3a (the latter are approximately simi-
lar), which confirms the assumed relative arrangement
of substituents in molecule Vc.
above mechanism. This means that the cycloaddition
of azomethine ylides is stereoselective: the products
are exclusively less sterically strained adducts IVb,
IVc, Vb, and Vc having exo configuration. One more
evidence for high sensitivity of the reaction to steric
factors may be relatively low yields of adducts with di-
methyl fumarate (IIIa): three substituents in molecules
IVa and Va reside at the one side of relatively small
pyrrolidine ring.
Strong NOEs between ortho-protons in the phenyl
ring and geminal (H2) and vicinal (H3) protons were
1
also observed in the 2D H NOESY spectrum of Vb,
which clearly indicated cis orientation of the H3–H4
couple and trans orientation of H2–H3 and H4–H5.
Therefore, steric configuration of this compound is
fairly obvious.
To conclude we can state that thermolysis of disub-
stituted N-phthalimidoaziridines I and II in the pres-
ence of dipolarophiles leads to the formation of
N-aminopyrrolidine derivatives with good yields and
high stereoselectively. The described reaction may be
regarded as a general method for the synthesis of such
difficultly accessible compounds.
1
It follows from the 2D H NOESY spectrum of
adduct Va that the ortho-protons in the phenyl ring are
loated closely to only H2 and that the vicinal H3 proton
is fairly distant. This means that the phenyl and neigh-
boring ester groups are oriented cis. Correspondingly,
the H2–H3 couple shows a strong NOE. A weaker
effect is observed for H2–H5 and H3–H5. Presumably,
the H2, H3, and H5 protons reside at the same side of
the pyrrolidine ring. The cross peak for H3–H4 is rela-
tively weak, which is also consistent with the structure
assigned to Va.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker DPX-300 spectrometer at 300.13 and
75.47 MHz, respectively; the chemical shifts were
measured relative to the residual proton (CHCl3,
δ 7.26 ppm; DMSO, δ 2.50 ppm; CH3CN, δ 1.96 ppm)
and carbon signals (CDCl3, δC 77.16 ppm; DMSO-d6,
δC 39.52 ppm; CD3CN, δC 1.32 ppm) of the deuterated
solvents. The elemental compositions were determined
on an HP-185B automatic CHN analyzer. The mass
spectra (electron impact, 70 eV) were obtained on
an MKh-1321 instrument, and the ESI (electrospray
ionization) mass spectra were run on a Finnigan MAT-
90 spectrometer. The reaction mixtures were analyzed,
and the purity of the isolated products was checked, by
TLC on Alugram sil G/UV254 plates. N-Aminophthal-
imide was synthesized according to the procedure
described in [9].
Thus we can state that the NOESY method ensures
reliable determination of steric structure of the ob-
tained pyrrolidine derivatives and that the use of spin–
spin coupling constants is inappropriate.
Our results provide rigorous substantiation of the
following mechanism of the observed transformation.
The first step is conrotatory opening of the three-mem-
bered ring in trans-2,3-disubstituted 1-phthalimidoaz-
iridines I and II to generate the corresponding cis-
azomethine ylides, which is allowed by the orbital
symmetry conservation rules. Next follows concerted
cycloaddition of intermediate 1,3-dipoles at the double
C=C bond of dipolarophiles IIIa–IIIc. The complete
stereospecificity of both steps is indicated by the facts
that the substituents in the initial trans-2,3-disubsti-
tuted aziridine appear cis-oriented in adducts IVa–IVc
and Va–Vc and that the relative configuration of sub-
stituents in dipolarophiles IIIa–IIIc is retained.
(E)-Cinnamonitrile. A solution of 5.0 g (30 mmol)
of (E)-cinnamoyl chloride in 20 ml of methylene chlo-
ride was added under vigorous stirring to a mixture of
45 ml (0.6 mol) of 25% aqueous ammonia and 150 g
of ice. After 20 min, the white precipitate of (E)-cin-
namamide was filtered off and dried in air. Yield 4.0 g
(90%), mp 146°C; published data [10]: mp 149°C.
Moreover, the reactions of aziridines I and II with
dimethyl maleate (IIIb) and N-phenylmaleimide (IIIc)
gave only one stereoisomer of the two possible for the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

KUZNETSOV et al.
1786
A mixture of 4.0 g (27 mmol) of (E)-cinnamamide
itate was filtered off and dried in air. Yield 433 mg
(50%), mp 132°C. According to the 1H NMR data, the
product was a mixture of two invertomers at a ratio of
and 4.6 g (32 mmol) of P2O5 in 100 ml of toluene was
heated for 3 h under reflux, the progress of the reaction
being monitored by TLC. The solution was separated
by decanting, 50 ml of toluene was added to the solid
residue, and the mixture was heated for 1 h under
reflux. The solution was separated by decanting, com-
bined with the first solution, and passed through a thin
layer of silica gel. The solvent was distilled off under
reduced pressure to obtain 2.2 g (63%) of (E)-cin-
namonitrile as a yellow liquid with a specific odor.
1H NMR spectrum (CDCl3), δ, ppm: 5.88 d (1H,
CHCN, J = 16.7 Hz), 7.40 d (1H, CHPh, J = 16.7 Hz),
7.43–7.48 m (5H, Harom) (cf. [11]). 13C NMR spectrum
(CDCl3), δC, ppm: 96.41 (CHCN), 118.24 (CN),
127.44 (Cm), 129.20 (Co), 131.30 (Cp), 133.60 (Ci),
150.65 (CHPh).
1
96:4. H NMR spectrum (CDCl3), δ, ppm: 3.38 d and
4.52 d (J = 5.1 Hz, major invertomer), 4.12 d and
4.73 d (J = 5.6 Hz, minor invertomer) (total of 2H);
7.42 m (C6H5, major invertomer), 7.65 m (C6H5, minor
invertomer) (total of 5H); 7.74–7.88 m (4H, C6H4).
13C NMR spectrum of the major invertomer (CDCl3),
δC, ppm: 34.80 (C2), 49.48 (C3), 114.83 (CN), 123.86
(Cb), 127.21 (Cm), 129.05 (Co), 129.52 (Ca), 130.19
(Cp), 132.64 (Ci), 134.81 (Cc), 164.82 (C=O). Mass
spectrum (EI), m/z (Irel, %): 289 (31) [M]+, 143 (88)
[M – PhthN], 142 (51) [M – PhthNH], 116 (55), 104
(100) [C6H4CO], 89 (11), 84 (12), 76 (75), 51 (11), 50
(28). Found, %: C 70.41; H 3.99; N 14.73. C17H11N3O2.
Calculated, %: C 70.59; H 3.81; N 14.53.
Oxidative addition of N-aminophthalimide to
unsaturated nitriles. Potassium carbonate, 1.242 g
(9 mmol), was dispersed in a solution of 3 mmol of
fumaronitrile or cinnamonitrile in 20 ml of anhydrous
methylene chloride, and 486 mg (3 mmol) of N-amino-
phthalimide and 1.329 g (3 mmol) of lead tetraacetate
were added in small approximately equal portions over
a period of 40 min under stirring and cooling with ice
water. When the addition was complete, the mixture
was stirred for 20 min and filtered through a thin layer
of silica gel, and the precipitate was washed with
40 ml of methylene chloride or chloroform. The filtrate
was combined with the washings and treated as in-
dicated below.
Dimethyl rel-(2R,3R,4R,5S)-2,5-dicyano-1-phthal-
imidopyrrolidine-3,4-dicarboxylate (IVa). A dry
heat-resistant glass ampule was charged with 225 mg
(0.94 mmol) of aziridine I and 204 mg (1.40 mmol) of
dimethyl fumarate (IIIa) in 12 ml of anhydrous chloro-
benzene. The ampule was sealed, placed into a metal
high-pressure container with a screw cap, and heated
for 3.5 h at 220°C in a muffle furnace. After cooling,
the ampule was opened, the solvent was distilled off
under reduced pressure, and the residue was subjected
to column chromatography on 40 g of silica gel using
hexane–methylene chloride (1:1) to pure methylene
chloride as eluent (gradient elution). Yield 123 mg
1
(34%), mp 205°C. H NMR spectrum (CDCl3), δ,
ppm: 3.86 s and 3.89 s (3H each, Me), 4.06 d.d and
4.11 d.d (1H each, 3-H, 4-H, J = 9.1, 9.8 Hz), 4.79 d
and 4.92 d (1H each, 2-H, 5-H, J = 9.1 Hz), 7.80–
7.96 m (4H, C6H4). 13C NMR spectrum (DMSO-d6–
CDCl3, 1 :2), δC, ppm: 46.51, 47.24 (CH3); 52.86,
52.94, 54.32, 54.54 (C2–C5); 115.11, 115.69 (CN);
123.44 (Cb), 129.14 (Ca), 134.67 (Cc), 164.55 (C=O);
167.08, 167.38 (C=O, ester). Mass spectrum (ESI):
m/z: 382 [M]+. Found, %: C 56.62; H 3.88; N 14.72.
C18H14N4O6. Calculated, %: C 56.55; H 3.69; N 14.65.
trans-1-Phthalimidoaziridine-2,3-dicarbonitrile
(I). The solution obtained from 234 mg (3 mmol) of
fumaronitrile was evaporated under reduced pressure
until crystallization began and was left overnight in
a freezing chamber (–15 to –20°C). The white flaky
crystals were filtered off and dried in air. Yield 285 mg
1
(40%), mp 198°C. H NMR spectrum (DMSO-d6), δ,
ppm: 4.83 d and 4.92 d (1H each, CHCN, J = 5.1 Hz),
7.84–7.99 m (4H, C6H4). 13C NMR spectrum
(DMSO-d6), δC, ppm: 31.74 and 32.03 (C2, C3), 113.39
and 114.58 (CN), 123.65 (Cb), 129.62 (Ca), 135.21 (Cc),
163.74 (C=O). Mass spectrum (ESI): m/z 238 [M]+.
Found, %: C 60.40; H 2.74; N 23.85. C12H6N4O2. Cal-
culated, %: C 60.51; H 2.54; N 23.52.
Dimethyl rel-(2R,3R,4S,5S)-2,5-dicyano-1-phthal-
imidopyrrolidine-3,4-dicarboxylate (IVb). A heat-
resistant glass reactor with a screw cap was charged
with 227 mg (0.95 mmol) of aziridine I and 206 mg
(1.40 mmol) of dimethyl maleate (IIIb) in 12 ml of
anhydrous chlorobenzene and was heated for 3 h at
220°C on a silicone oil bath. After cooling, the solvent
was distilled off under reduced pressure, and the resi-
due was subjected to column chromatography on 40 g
of silica gel using hexane–ethyl acetate (2:1) to ethyl
trans-3-Phenyl-1-phthalimidoaziridine-2-carbo-
nitrile (II). The solution obtained from 387 mg
(3 mmol) of (E)-cinnamonitrile was evaporated under
reduced pressure (but not to dryness). A small amount
of diethyl ether was added to the residue, and the mix-
ture was left to stand for crystallization. The precip-
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THERMOLYSIS OF 1-PHTHALIMIDOAZIRIDINE-2-CARBONITRILES
1787
acetate–ethanol (2 :1) as eluent (gradient elution).
Yield 280 mg (77%), mp 204°C. H NMR spectrum
(3H, Me), 4.20 d.d (1H, 4-H, J = 8.2, 9.7 Hz), 5.05 d
(1H, 5-H, J = 9.7 Hz), 5.39 d (1H, 2-H, J = 10.3 Hz),
7.22–7.31 m (3H, m-H, p-H), 7.45–7.47 m (2H, o-H),
1
(CD3CN), δ, ppm: 3.80 s (6H, Me), 4.03 m (2H, 3-H,
4-H), 4.91 m (2H, 2-H, 5-H), 7.87–7.94 m (4H, C6H4).
13C NMR spectrum (CDCl3), δC, ppm: 47.56 (CH3),
53.61 and 54.49 (C2–C5), 115.81 (CN), 124.47 (Cb),
129.37 (Ca), 135.48 (Cc), 164.92 br.s (C=O), 167.77
(C=O, ester). Mass spectrum (EI), m/z (Irel, %): 382
(0.1) [M]+, 324 (10), 147 (100) [PhthNH], 105 (65), 76
(30), 59 (17), 50 (10), 43 (10). Found, %: C 56.54;
H 3.66; N 14.66. C18H14N4O6. Calculated, %: C 56.68;
H 3.86; N 14.65.
13
7.69–7.80 m (4H, C6H4). C NMR spectrum (CDCl3),
δC, ppm: 46.55, 49.49, 52.23, 53.34, 53.53 (CH3,
C3–C5); 66.68 (C2); 116.63 (CN); 123–124 br.s, 124–
125 br.s (Cb); 128.36 (Cm, Co); 129.00 (Cp); 129.64 br.s
(Ca); 134.9 br.s (Ci, Cc); 169.49, 169.56 (C=O). Mass
spectrum (EI), m/z (Irel, %): 433 (2) [M]+, 322 (22), 287
(60) [M – PhthN], 255 (73), 251 (16), 227 (56), 226
(56), 195 (42), 182 (56), 168 (15), 167 (14), 148 (10),
142 (100), 130 (20), 115 (42), 104 (71) [C6H4CO], 90
(15), 76 (56), 59 (53), 51 (12). Found, %: C 63.74;
H 4.39; N 9.70. C23H19N3O6. Calculated, %: C 63.72;
H 4.46; N 9.59.
exo,exo-4,6-Dioxo-5-phenyl-2-phthalimidoocta-
hydropyrrolo[3,4-c]pyrrole-1,3-dicarbonitrile (IVc).
A dry heat-resistant glass ampule was charged with
206 mg (0.86 mmol) of aziridine I and 224 mg
(1.30 mmol) of N-phenylmaleimide (IIIc) in 12 ml of
anhydrous chlorobenzene. The ampule was sealed,
placed into a metal high-pressure container with
a screw cap, and heated for 3 h at 220°C in a muffle
furnace. After cooling, the ampule was opened, the
solvent was distilled off under reduced pressure, and
the residue was subjected to column chromatography
on 40 g of silica gel using methylene chloride to meth-
ylene chloride–diethyl ether (10:1) as eluent (gradient
Dimethyl rel-(2R,3R,4S,5S)-5-cyano-2-phenyl-
1-phthalimidopyrrolidine-3,4-dicarboxylate (Vb).
A heat-resistant glass reactor with a screw cap was
charged with 289 mg (1.0 mmol) of aziridine II and
216 mg (1.5 mmol) of dimethyl maleate (IIIb) in
12 ml of anhydrous benzene, and the mixture was
heated for 2.5 h at 120°C. After cooling, the solvent
was distilled under reduced pressure, the oily residue
was treated with a small amount of diethyl ether, and
the white precipitate was filtered off and dried in air.
1
1
elution). Yield 206 mg (58%), mp 262°C. H NMR
Yield 221 mg (51%), mp 186°C. H NMR spectrum
spectrum (DMSO-d6), δ, ppm: 4.39 s (2H, 3a-H, 6a-H),
5.36 s (2H, 1-H, 3-H), 7.44–7.62 m (5H, C6H5), 7.89–
7.96 m (4H, C6H4). 13C NMR spectrum (DMSO-d6),
δC, ppm: 49.68 (C3a, C6a), 56.49 (C1, C3), 118.21 (CN),
123.70 (Cb), 127.08 (Cm), 129.10 (Cp), 129.25 (Co),
129.73 (Ca), 131.97 (Ci), 135.10 (Cc), 165.21 (C=O),
173.51 (C4, C6). Mass spectrum (EI), m/z (Irel, %): 411
(3) [M]+, 264 (100) [M – PhthNH], 147 (49) [PhthNH],
145 (39), 119 (55), 117 (39), 104 (55) [C6H4CO], 91
(21), 86 (13), 84 (23), 76 (59), 65 (16), 49 (35). Found,
%: C 64.38; H 3.29; N 17.22. C22H13N5O4. Calculated,
%: C 64.23; H 3.19; N 17.02.
(DMSO-d6), δ, ppm: 3.55 d.d (1H, 3-H, J = 7.3,
9.2 Hz), 3.66 s and 3.71 s (3H each, Me), 4.18 d.d (1H,
4-H, J = 8.2, 9.2 Hz), 5.14 d (1H, 5-H, J = 8.2 Hz),
5.15 d (1H, 2-H, J = 7.3 Hz), 7.24–7.37 m (3H, m-H,
p-H), 7.48–7.51 m (2H, o-H), 7.84 m (4H, C6H4).
13C NMR spectrum (DMSO-d6), δC, ppm: 46.21, 50.63,
52.45, 52.68, 53.58 (CH3, C3–C5); 67.36 (C2); 117.82
(CN); 123.51 br.s (Cb); 127.60, 128.42 (Cm, Co);
128.49 (Cp); 135.13 (Cc); 137.65 (Ci); 169.24, 170.28
(C=O). Mass spectrum (EI), m/z (Irel, %): 433 (1) [M]+,
375 (12), 322 (22), 287 (100), 286 (35) [M – PhthNH],
226 (62), 225 (55), 195 (130), 182 (59), 167 (14), 148
(10), 142 (59), 131 (16), 115 (25), 104 (48) [C6H4CO].
Found, %: C 63.74; H 4.39; N 9.70. C23H19N3O6. Cal-
culated, %: C 63.82; H 4.50; N 9.53.
Dimethyl rel-(2R,3S,4S,5S)-5-cyano-2-phenyl-
1-phthalimidopyrrolidine-3,4-dicarboxylate (Va).
A heat-resistant glass reactor with a screw cap was
charged with 289 mg (1.0 mmol) of aziridine II and
216 mg (1.5 mmol) of dimethyl fumarate (IIIa) in
12 ml of anhydrous benzene, and the mixture was
heated for 3.5 h at 120°C on a silicone oil bath. After
cooling, the solvent was distilled off under reduced
pressure, the oily residue was treated with a small
amount of diethyl ether, and the white precipitate was
filtered off and dried in air. Yield 91 mg (21%),
mp 190°C. 1H NMR spectrum (CDCl3), δ, ppm: 3.20 s
(3H, Me), 3.83 d.d (1H, 3-H, J = 8.2, 10.3 Hz), 3.83 s
exo,exo-4,6-Dioxo-3,5-diphenyl-2-phthalimido-
octahydropyrrolo[3,4-c]pyrrole-1-carbonitrile (Vc).
A heat-resistant glass reactor with a screw cap was
charged with 289 mg (1.0 mmol) of aziridine II and
260 mg (1.5 mmol) of N-phenylmaleimide (IIIc) in
12 ml of anhydrous benzene, and the mixture was
heated for 3 h at 120°C and left to stand overnight. The
white crystals were filtered off and dried in air. Yield
380 mg (82%), mp 255°C. 1H NMR spectrum (CDCl3),
δ, ppm: 3.63 d.d (1H, 3a-H, J = 8.1, 9.6 Hz), 4.05 d.d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

KUZNETSOV et al.
1788
3. Foucaud, A. and Baudru, M., C. R. Acad. Sci., Ser. C,
1970, vol. 271, p. 1613; Charier, J., Person, H., and
Foucaud, A., Tetrahedron Lett., 1979, vol. 20, p. 1381;
Charrier, J., Foucaud, A., Person, H., and Loukakou, E.,
J. Org. Chem., 1983, vol. 48, p. 481.
4. Person, H., Luanglath, K., Baudru, M., and Foucaud, A.,
Bull. Soc. Chim. Fr., 1976, p. 1989.
5. Person, H. and Foucaud, A., Bull. Soc. Chim. Fr., 1976,
(1H, 6a-H, J = 6.3, 9.6 Hz), 5.05 d (1H, 1-H, J =
6.3 Hz), 5.17 d (1H, 3-H, J = 8.1 Hz), 7.31–7.61 m
(10H, C6H5), 7.72–7.81 m (4H, C6H4). 13C NMR spec-
trum (CDCl3), δC, ppm: 46.96, 50.52, 53.78 (C1, C3a,
C6a); 68.75 (C3); 116.45 (CN); 126.52, 127.69, 129.20,
129.33, 129.45, 129.52, 131.20, 135.70 (Carom); 135.07
br.s (Cs); 172.85, 173.30 (C4, C6). Mass spectrum (EI),
m/z (Irel, %): 462 (2) [M]+, 435 (10), 316 (28), 315 (62)
[M – PhthNH], 168 (28), 147 (11) [PhthNH], 142
(100), 115 (14), 104 (21) [C6H4CO], 78 (25), 76 (19).
Found, %: C 70.13; H 3.90; N 12.12. C27H18N4O4. Cal-
culated, %: C 70.03; H 3.87; N 12.09.
p. 1119.
6. Gladstone, W.A.F. and Norman, R.O.C., J. Chem.
Soc. C, 1966, p. 1536.
7. Atkinson, R.S. and Malpass, J.R., J. Chem. Soc., Perkin
Trans. 1. 1977, p. 2242.
8. Jackman, L.M. and Sternhell, S., Applications of
Nuclear Magnetic Resonance Spectroscopy in Organic
Chemistry, London: Pergamon, 1969, 2nd ed., p. 287.
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9. Drew, N.D.K. and Hatt, N.H., J. Chem. Soc., 1937,
Padwa, A., Ed., New York: Wiley, 1984, p. 653.
p. 16.
2. Heine, H.W. and Peavy, R., Tetrahedron Lett., 1965,
vol. 6, p. 3123; Harwood, L.M. and Vickers, R.J.,
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. 169.
10. Svoistva organicheskikh soedinenii. Spravochnik (Prop-
erties of Organic Compounds. Reference Book), Pote-
khin, A.A., Ed., Leningrad: Khimiya, 1984, p. 520.
11. Organic Syntheses, Semmelhack, M.F., Ed., New York:
Wiley, 1984, vol. 62, p. 179.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008