The Curtin-Hammett principle in action: 1-amino-3H-isoindole in cycloaddition reactions

Article abstract of DOI:10.1016/j.tet.2009.11.031

Based on the spectral studies of 1-aminoisoindole we have observed that in solution the isoindolenine tautomer predominates. In spite of this fact but, taking into account the Curtin-Hammett principle, we undertaken the first study of the Diels-Alder reaction for 1-aminoisoindole as a typical representative of simple isoindoles in isoindoline form. We have studied the interaction of 1-aminoisoindole with maleimide derivates and demonstrated that the products are rearranged 1:2 composition adducts. We have proposed a rearrangement mechanism, detected and identified the intermediate Diels-Alder products containing both endo- and exo adducts.

Full text of DOI:10.1016/j.tet.2009.11.031

Tetrahedron 66 (2010) 508–512
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The Curtin–Hammett principle in action: 1-amino-3H-isoindole
in cycloaddition reactions
,
Igor V. Levkov a, Oleksandr V. Turova, Oleg V. Shishkin b, Svetlana V. Shishkina b, Zoia V. Voitenko a
*
a Kiev National Taras Shevchenko University, 64 Str Volodymyrska, 01033 Kiev, Ukraine
b STC ‘Institute for Single Crystals’ NASU, 60 Lenina ave, 61001 Kharkiv, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on the spectral studies of 1-aminoisoindole we have observed that in solution the isoindolenine
tautomer predominates. In spite of this fact but, taking into account the Curtin–Hammett principle, we
undertaken the first study of the Diels–Alder reaction for 1-aminoisoindole as a typical representative of
simple isoindoles in isoindoline form. We have studied the interaction of 1-aminoisoindole with
maleimide derivates and demonstrated that the products are rearranged 1:2 composition adducts. We
have proposed a rearrangement mechanism, detected and identified the intermediate Diels–Alder
products containing both endo- and exo adducts.
Received 18 August 2009
Received in revised form
21 October 2009
Accepted 5 November 2009
Available online 15 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
first examined reactions typical only for the isoindole tautomer and
chose an isoindole, which was prevalently in the isoindolenine
Isoindoles are promising active biological materials1,2 with in-
teresting spectral properties and are the subject of study for im-
portant theoretical questions, such as: aromaticity, tautomerism3–8
and represent the important source of the reactive compounds and
synthons used for cycloaddition reactions,9–14 the study of the or-
ganic reactions mechanisms, new rearrangements15–21 and the
creation of new colouring agents.22–24
The most typical reaction for simple isoindole systems is the
Diels–Alder reaction but previously this reaction was associated
only with isoindoles prevalently in the isoindole tautomeric form.
Our previous researches in the chemistry of the simple iso-
indoles9 have shown that the main products in the reaction with
maleimide derivates are the Diels–Alder adducts. In some cases the
rearrangement with the formation of naphthalene derivate is
possible. For condensed azolo and azinoisoindoles21 have been
found three types of rearrangements, that are uncharacteristic for
the simple isoindoles. In order to study these features we have
chosen 1-aminoisoindole as the object of our researches. It is the
basic elementary structural fragment, that enters into the structure
of condensed azolo and azinoisoindoles.
tautomeric form. In this work therefore, we have investigated the
interaction between 1-aminoisoindole and maleimide derivates.
2. Results and discussion
One of the most interesting properties of the parent isoindole 1a
is the rapid tautomeric equilibrium with isoindolenine
1b26,27(Scheme 1).
H
H
NH
N
H
H
H
1b
1a
NH2
NH
NH
NH2
NH
H
N
H
H
H
H
2c
2a
2b
Based on the study of electronic spectrums we were able to
prove the existence of a tautomeric equilibrium for 1-amono-
isoindole in spite of the fact, that is, oindole tautomer is the pre-
vailing form here. Based on the Curtin–Hammett principle25 we
Scheme 1. Tautomerism of unsubstituted isoindole 1 and 1-aminoisoindole 2.
The percentage content of the isoindole form can be increased
or reduced by adding substituents to the simple isoindole frame-
work. For isoindoles in the ortho-quinoid system, i.e., type 1 com-
position, the most studied process is the Diels–Alder reaction
which has been studied in the case of maleic acid derivates as
dienophiles. If isoindoles isolation is complicated through their
* Corresponding author. Tel.: þ38 096 449 2900; fax: þ38 044 235 1273.
E-mail address: z_voitenko@mail.univ.kiev.ua (Z.V. Voitenko).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.031

I.V. Levkov et al. / Tetrahedron 66 (2010) 508–512
509
instability, their adducts are often identified by reactions with
either maleic anhydride or N-phenylmaleimide.
An equimolar quantity of N-phenylmaleinimide was added to
the aetheric solution of 1-aminoisoindole cooled to ꢁ10 ꢀC. After
several minutes, we observed a yellow residue of the Diels–Alder
cycloaddition adduct, which could be described as endo-adduct 6c
(Scheme 3) considering the previously determined by NMR-spec-
troscopy6,10 structure of endo- and exo-isomers of 7-azabenzo-
norbornens. After gentle heating or dissolution of the endo-adduct
in different solvents, it rearranged to exo-adduct 7c with sub-
sequent rearrangement to the Michael adduct 8c. It was easy to
follow this process visually as with the formation of adduct 8c the
reaction mixture had become light pink (a colour typical for iso-
indole structures). The endo-adduct then transforms to exo-adduct
through a Diels–Alder retro-reaction with the formation of a more
thermodynamically stable isomer. We have proved this fact via
a chemical trap method: several drops of acetylenedicarboxylic
acid methylic ether (DMAD) were added to the solution of endo-
adduct, which made the mixture turn bright red in colour typical
for interaction with 1-amonoisoindole. Similarly, we determined
the mechanism of transformation of endo-adducts to exo-adducts
for the reaction between N-methylisoindole quinazolone and
maleimide derivates.21 Acetylenedicarboxylic acid ethers mixed
with this compound form Michael adducts that are red in colour. All
intermediate adducts are unstable and are quickly decomposed
even in solid state.
We were interested to see if we could extend the boundaries of
the synthetic use of the isoindoles in the isoindolenine form in
cycloaddition reactions. To answer this question we need to per-
form a detailed study of the tautomerism of this type of com-
pounds. The object of the study was 1-aminoisoindole.
1-Aminoisoindole has three theoretically possible tautomeric for-
msd2a, 2b and 2c. But only one of themd2cdcan theoretically
enter into the Diels–Alder reaction as it contains an ortho-quinoid
diene fragment.
According to the IR-spectral data27 1-aminoisoindole in solid
state and in solution prevalently exists in the 2b form. The position
of aminoisoindole characteristic frequencies depends on the sol-
vent nature and concentration as these are the factors, which de-
termine the degree of association.
According to our UV-spectral data a small amount of the iso-
indole tautomeric form is present in equilibrium and it can be
measured. This enabled us to use the Curtin–Hammett principle
and study the reaction between 1-aminoisoindole and maleimide
derivates as active dienophiles.
First we tried to perform the reaction between 1-amino-
isoindole 3 bromide and maleimides 4a–e in 1:1 and 1:2 ratios in
methanol with presence of triethylamine, at room temperature
(25 ꢀC). Irrespective of the compound ratio, in all cases we obtained
product 5a–e (Scheme 2), which was confirmed by spectral study.
H
N
NH2
H1
O
NH2
NH
NH2
H2
NPh
O
NH2 HBr
O
NPh
H3
N
MeOH
O
6c
4c
N
R
2
O
N
Ha
Hb
O
Hx
O
NEt3
N
O
O
NH2
R
N
R
O
H
NH
NH2
N
3
4a-e
O
5a-e
H1
O
NPh
H2
H3
Maleimide
Product
R
H
Yield (%)
36
O
NPh
H1
H2
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
H3
O
8c
7c
4-CH3O-C6H4 77
C6H5
81
84
39
4-CH3-C6H4
CH3
NH2
N
H
N
NH2
H
O
Ph
Scheme 2. Interaction of hydrobromide of 1-aminoisoindole 3 with maleimides 4a–e
in the ratio 1:2.
O
N
O
O
H
N
N
Ph
O
N
Ph
The yields of the obtained products strongly depend on the
substituent R. In the case of aromatic substituents the yields were
higher. We were unable to obtain the final adducts with some other
maleimide derivates, in particular with ortho- and meta-substituted
N-phenylmaleimides.
O
Ph
O
O
5c
9c
Compound
Yield (%)
It was also interesting that we could not perform the reaction
between 1-aminoisoindole and 3-methyl-N-phenylmaleimide,
which can presumably be explained by the steric complications
considering the common synchronous [4þ2]-cycloaddition mech-
anism. This may mean that the reaction goes not under a Michael
addition mechanism but through the formation of the Diels–Alder
adduct.
6c
7c
8c
9c
5c
67
43
73
-
81
To probe this statement we tried to obtain the cycloaddition
adduct. Selecting the solvent for this reaction was extremely im-
portant. First, we need the solvent to shift the equilibrium towards
the formation of the isoindole tautomeric form. Secondly, the sol-
vent had to be aprotonic as the cycloaddition adducts for 1-ami-
noisoindole readily and easily rearrange to Michael adducts.
Diethyl ether was an ideal choice as it perfectly met all these
requirements.
Scheme 3. Mechanism of interaction of 1-aminoisoindole 2 with maleimide 4c.
Adduct 8c further easily enters the next cycloaddition with an-
other maleimide molecule. After the next rearrangement, we
obtained Michael bis-adduct 5c. We were unable to obtain in-
termediate 9c.
All intermediate adducts are unstable and are quickly destroyed
even in solid state, for this reason we were only able to identify

510
I.V. Levkov et al. / Tetrahedron 66 (2010) 508–512
their structure by qa rapid measurment of their 1H NMR spectra.
endo- and exo-adducts configuration was proved in view of the
previously determined criteria.
NH26.96
7.81
121.6
7.44
137.4
165.3
129.4
We have proved the rearranged structure of the type 5 adducts
both by 1H NMR spectrums and by two-dimensional spectroscopy.
The 1H NMR spectrum of the compound 5e corresponds the for-
mula where two succinimide fragments are combined with atom
C(8) of 1-aminoisodole fragment. The aromatic protons of the iso-
indole fragment appear at the low field (7–7.8 ppm), the protons of
the amino group can be observed at 6.59 ppm, the protons of
succinimide fragments give two well-resolved AMX spin systems
and the protons of the methyl groups give singlets at 2.81 and
2.78 ppm. Two succinimide fragments are not equivalent because
of the atropoisomerism that leads to the existence of two not
equivalent AMX spin systems. It was a bit unexpected to observe
the signals of one of the protons of the methylene group of both
succinimide fragments at such strong field as 0.88 and 1.02 ppm.
The signals of the second protons of these methylene groups have
no anomalies in chemical shifts and they can be observed at 2.50
and 2.25 ppm.
As proton magnetic resonance spectrum of the obtained product
has a number of peculiarities, in order to ensure further confir-
mation of the compound structure we measured its spectrum on
nuclei 13C and made experiments on 1H–13C heteronuclear corre-
lation through one chemical bond (HMQC) and 2–3 chemical bonds
(HMBC). The coordinates of the cross-peaks found in the two-
dimensional spectrums are given in Table 1.
N
130.3
7.40
76.8
2.25
149.8
122.0
7.08
1.02
31.1
0.88
31.3
42.6
4.43
O
2.50
4.60
43.2
176.9
25.0
N
178.9
O
O
O
CH3
179.3
176.6
2.81
N
24.8
CH3
2.78
Figure 1. Coordinations of signals 13C and 1H NMR for compound 5e.
149.8 ppm, while the other signal of this proton absorbing at
4.43 ppm has no such correlation. This indicates different sizes for
the torsion angle between bond C(7)-C(8) of isoindole nucleus and
bond of C–H methine proton of succinimide fragments. The ab-
sence of the named correlation means that 3J (C, H) is approximate
to zero, which is possible if the torsion angle is approximate to 90ꢀ.
This is the situation which is observed for one of the succinimide
residues.
The fact of the anomalously strong field position of the signals of
one of the methylene protons of succinimide fragment also needs
to be explained. Most likely this is because one of the methylene
protons of succinimide fragments gets into the anisotropic mag-
netic field of C]N double bond of the isoindole fragment.
The structure of the rearrangement adducts has been confirmed
by X-ray diffraction analysis (Fig. 2).
Table 1
Coordinates of the crosspeaks in spectrums HMQC and HMBC for the compound 5c
Coordinate
1H,
, ppm
Coordinate 13C,
HMQC
d
, ppm
HMBC
d
7.81
7.44
7.40
7.08
6.96
4.60
4.43
2.81
2.78
2.50
2.25
1.02
0.88
121.6
129.4
130.3
122.0
d
165.3; 149.8; 130.3; 122.0
137.4; 122.0
149.8; 121.6; 76.8
149.8; 137.4; 129.4; 121.6; 76.8
137.4
76.8; 179.3; 149.8
76.8; 178.9
178.9; 176.9
179.3; 176.6
76.8; 41.2
76.8; 42.6
76.8; 41.2; 179.3; 176.6
76.8; 42.6; 178.9; 176.9
43.2
42.6
25.0
24.8
31.1
31.3
31.1
31.3
These experiments enabled to assign the signals in the carbon
spectrum of the compound and to make a number of conclusions
about its structure. The protonated carbon atoms are easily
assigned on the basis of the correlations existing in the HMQC
spectrum, while the quaternary carbon atoms are assigned by the
correlations through 2–3 chemical bonds in HMBC spectrum. The
signal assignments are shown in Figure 1.
The key aspect in determining the molecular structure is the
presence of a quaternary carbon atom C(8) in the isoindole frag-
ment with a chemical shift of 76.8 ppm. The HMBC spectrum has
the relevant signal correlations expected for the proton signals of
the CH and CH2 groups of succinimide fragments. This confirms
that both of the residues are bound with atom C(8). The molecular
location of this atom is proved by the correlation with the signal of
one of the aromatic protons with chemical shift of 7.08 ppm (proton
H-4).
The correlations in the HMBC spectrum also enable conclusions
on the mutual orientation of the protons in the synthesised product
molecule. One of the signals of the CH proton of the succinimide
fragments (with a chemical shift of 4.60 ppm) has intensive cor-
relation via three bonds with the C(7) signal absorbing at
Figure 2. X-ray diffraction analysis of the compound 5e.
According to the X-ray diffraction study compound 5e exists in
the crystal phase as monohydrate. Two succinimidyl substituents
have similar orientation with respect to the aminoisoindole frag-
ment (the C(2)-C(7)-C(8)-C(9) and C(2)-C(7)-C(8)-C(14) torsion
angles are ꢁ120.0(2)ꢀ and 113.9(2)ꢀ, respectively). Such arrange-
ment of the substituents is stabilised additionally by the weak
intramolecular hydrogen bond C(14)-H(14)/O(2) (H/O 2.39 Å C–
H/O 131ꢀ). Steric repulsion between atoms of the C(14)-C(15)-
C(16)-N(3)-C(17) heterocycle and aminoisoindole fragment (the
shortened intramolecular contacts: H(6)/C(17) 2.81 Å (van der
Waals radii sum28 is 2.87 Å), H(15a)/N(1) 2.63 Å (2.67 Å), H(15a)/

I.V. Levkov et al. / Tetrahedron 66 (2010) 508–512
511
C(1) 2.70 Å (2.87 Å), H(15a)/C(7) 2.80 Å (2.87 Å)) is considerably
stronger as compared to steric interactions between the C(9)-C(10)-
N(2)-C(11)-C(12) ring and the bicyclic fragment where only one
shortened intramolecular contact (the H(12a)/C(7) 2.67 Å) is ob-
served. The difference in the degree of the repulsion between
succinimidyl substituents and the bicyclic fragment results, evi-
dently, in a slightly different conformation of the five-membered
heterocycles: the C(9)/.C(12), N(2) ring is a planar within 0.01 Å
while the C(14)/C(17), N(3) ring adopts the envelope conforma-
tion where the deviation of the C(14) atom from the mean plane of
the remaining atoms of the ring is 0.13 Å. The nitrogen atom of the
amino group has the pyramidal configuration (the sum of bond
angles centred at the N(4) atom is 352ꢀ).
and the solution was boiled for 15 min in inert atmosphere. After
cooling, the water (30 mL) was added. The residue was filtered and
washed with isopropyl alcohol and gave the title compound 8c
(0.45 g, 73%) as a light pink solid. dH (400 MHz, DMSO-d6) 2.91 (1H,
dd, J 9.2, 18.0 Hz), 3.20 (1H, d, J 4.8, 18.0 Hz), 3.96 (1H, d, J 4.8,
9.2 Hz), 6.92–7.77 (9H, m), 8.89 (3H, s, NH, NH2).
4.2. Common procedure for reaction of 1-aminoisoindole
with maleimides (5a–e)
To a solution of 1-aminoisoindole hydrobromide29 3 (0.43 g,
2 mmol) in absolute methanol (5 mL) was added the relevant
maleimide 4a–e (4.2 mmol) with heating until dissolved. It was
added triethylamine (1 mL) and the flask was closed tightly. After
a while the mixture produced white plate-formed crystals. The
residue was filtered and washed with methanol. The filtrate was
left until the precipitate stopped form.
3. Conclusions
We have discovered a new transformation on the basis of the
reactions between 1-aminoisoindole and maleimide derivates in
a 1:2 ratio leading to formation of Michael bis-adducts. The fol-
lowing intermediates reactions have been defined: Diels–Alder
adducts in 1:1 composition. We have also proposed the mechanism
for the formation of rearrangement products and transformation of
endo-isomers to exo-isomers. The structure of all the obtained
substances has been studied by spectral methods including two-
dimensional NMR spectroscopy and X-ray diffraction analysis.
4.2.1. 3,3-Bis-(2,5-pyrrolidinone-1H)-1-aminoisoindole (5a). 0.23 g,
36%, white solid, mp 270 ꢀC; [Found: C, 58.89; H, 4.32; N, 17.17.
C16H14N4O4 requires C, 58.81; H, 4.41; N, 17.25]; ymax(KBr) 3456,
3368, 3236, 3068, 2725, 1708, 1636, 1556, 1344, 1172, 768 cmꢁ1
; dH
(400 MHz, DMSO-d6) 1.99 (2H, dd, J 6.0, 18.8 Hz), 2.65 (2H, dd, J 9.2,
18.8 Hz), 3.85 (2H dd, J 6.0, 9.2 Hz), 6.90 (2H, s, NH2), 7.21 (1H, d),
7.38–7.40 (2H, m), 7.71 (1H, d), 11.00 (2H, s, 2 NH); dH (400 MHz,
CF3COOD) 2.80 (2H, dd, J 6.0, 18.8 Hz), 3.42 (2H, dd, J 9.2, 18.8 Hz),
4.62 (2H, dd, J 6.0, 9.2 Hz), 7.72 (1H, d), 7.9 (1H, t), 8.0 (1H, t), 8.31
(1H, d); dC (100.7 MHz, DMSO-d6) 33.0, 46.7, 75.7, 121.1, 122.4, 128.5,
129.5, 137.4, 150.5, 164.9, 178.2, 179.1; HRMS (EI): Mþ, found 327.3.
C16H14N4O4 requires 327.3.
4. Experimental section
4.1. General
The 1H NMR spectra (400.396 MHz) were recorded with a Var-
ian Mercury 400 with TMS as internal standard. The UV-spectra
were recorded on Specord M400. The IR-spectra were recorded on
Specord M82. The chromatomass-spectra were recorded on Agilent
1100 Series with selective detector Agilent LC/MSD SL. Elemental
analysis was realised with a Carlo Erba Strumenization analyser.
4.2.2. 3,3-Bis-(2,5-pyrrolidinone-1-(4-methoxyphenil))-1-amino-
isoindole (5b). 0.83 g, 77%, white solid, mp 285 ꢀC; [Found:
C, 66.91; H, 4.87; N, 10.40. C30H26N4O6 requires C, 66.95; H, 4.93;
N, 10.51]; ymax(KBr) 3424, 3072, 2992, 2936, 2836, 1708, 1644, 1508,
1248, 1184, 832 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.08 (1H, dd, J 6.0,
18.8 Hz), 1.26 (1H, dd, J 6.0, 18.8 Hz), 2.47 (1H, dd, J 9.2, 18.8 Hz),
2.67 (1H, dd, J 9.2, 18.8 Hz), 3.79 (6H, s), 4.53 (1H dd, J 6.0, 9.2 Hz),
4.68 (1H dd, J 6.0, 9.2 Hz), 7.00–7.18 (10H, m), 7.30 (1H, d), 7.53–7.55
(2H, m), 7.89 (1H, d); dH (400 MHz, CF3COOD) 2.27 (1H, dd, J 6.0,
18.8 Hz), 2.46 (1H, dd, J 6.0, 18.8 Hz), 2.97 (1H, dd, J 9.2, 18.8 Hz),
3.40 (1H, dd, J 9.2, 18.8 Hz), 4.06 (6H, s), 5.36 (2H, dd, J 6.0, 9.2 Hz),
7.25 (8H, m), 7.86 (1H, d), 8.00 (1H, t), 8.15 (1H, t), 8.48 (1H, d); dC
(100.7 MHz, DMSO-d6) 31.4, 31.7, 42.9, 43.2, 56.1, 77.3, 114.8, 115.0,
121.8, 122.4, 125.4, 125.8, 129.0, 129.1, 129.6, 130.4, 137.6, 149.8,
159.5, 159.7, 165.4, 176.0, 176.3, 178.3, 178.5; HRMS (EI): Mþ, found
539.6. C30H26N4O6 requires 539.6.
4.1.1. endo-Adduct of 1-aminoisoindole with N-phenilmaleimide
(6c). To a solution of 1-aminoisoindole hydrobromide29 3 (1.07 g,
5 mmol) in water (10 mL) was added saturated NaOH water solu-
tion (10 mL). 1-aminoisoindole was extracted by diethyl ether
(20 mL). The ether extracts were dried over anhydrous Na2SO4. The
solution was cooled to ꢁ10 ꢀC and N-phenylmaleimide 4c (0.87 g,
5 mmol) was added. The reaction was performed for 5 h at ꢁ10 ꢀC.
The residue was filtered and washed with absolute ether and gave
the title compound 6c (1.02 g, 67%) as a light yellow solid. dH
(400 MHz, DMSO-d6) 4.15 (1H, dd, J 2.3, 8.0 Hz), 4.44 (1H, dd, J 6.0,
8.0 Hz), 5.72 (1H, dd, J 2.3, 6.0 Hz), 6.99–7.93 (9H, m), 10.2 (3H, s,
NH, NH2).
4.2.3. 3,3-Bis-(2,5-pyrrolidinone-1-phenil)-1-aminoisoindole
(5c). 0.77 g, 81%, white solid, mp 282 ꢀC; [Found: C, 70.28; H, 4.63;
N, 11.71. C28H22N4O4 requires C, 70.21; H, 4.74; N, 11.67]; ymax(KBr)
4.1.2. exo-Adduct of 1-aminoisoindole with N-phenilmaleimide
(7c). To a solution of 1-aminoisoindole hydrobromide29 3 (1.07 g,
5 mmol) in water (10 mL) was added saturated NaOH water solu-
tion (10 mL). 1-aminoisoindole was extracted by diethyl ether
(20 mL). The ether extracts were dried over anhydrous Na2SO4. To
a solution was added isopropyl alcohol and then N-phenyl-
maleimide 4c (0.87 g, 5 mmol) at room temperature. After 30 min
the residue was filtered and washed with isopropyl alcohol and
absolute ether and gave the title compound 7c (0.66 g, 43%) as
a light yellow solid. dH (400 MHz, DMSO-d6) 4.09 (1H, d, J 7.8 Hz),
4.37 (1H, d, J 7.8 Hz), 5.70 (1H, s), 7.00–8.04 (9H, m), 10.2 (3H, s, NH,
NH2).
3424, 3100, 3064, 1704, 1644, 1564, 1496, 1384, 1184, 700 cmꢁ1
; dH
(400 MHz, DMSO-d6) 1.17 (1H, dd, J 6.0, 18.8 Hz), 1.33 (1H, dd, J 6.0,
18.8 Hz), 2.42 (1H, dd, J 9.2, 18.8 Hz), 2.65 (1H, dd, J 9.2, 18.8 Hz),
4.61 (1H dd, J 6.0, 9.2 Hz), 4.77 (1H dd, J 6.0, 9.2 Hz), 6.93 (2H, s,
NH2), 7.11–7.54 (13H, m), 7.90 (1H, d); dH (400 MHz, CF3COOD) 2.26
(1H, dd, J 6.0,18.8 Hz), 2.45 (1H, dd, J 6.0,18.8 Hz), 2.95 (1H, dd, J 9.2,
18.8 Hz), 3.39 (1H, dd, J 9.2, 18.8 Hz), 5.36 (2H, dd, J 6.0, 9.2 Hz),
7.24–7.61 (10H, m), 7.85 (1H, d), 7.98 (1H, t), 8.14 (1H, t), 8.46 (1H,
d); dC (100.7 MHz, DMSO-d6) 31.5, 31.8, 43.1, 43.3, 77.4, 121.8, 122.5,
127.8, 128.0, 129.0, 129.2, 129.5, 129.7, 129.8, 130.4, 132.9, 133.3,
137.6, 149.8, 165.4, 175.8, 176.1, 178.1, 178.2; HRMS (EI): Mþ, found
479.5. C28H22N4O4 requires 479.5.
4.1.3. 3-(2,5-pyrrolidinone-1-phenil)-3H-1-aminoisoindole (8c). To
a solution of exo- 6c or endo-adduct 7c or their mixtures (0.61 g,
2 mmol) in methanol (10 mL) were added 5 drops of triethylamine
4.2.4. 3,3-Bis-(2,5-pyrrolidinone-1-tolyl)-1-aminoisoindole
(5d). 0.85 g, 84%, white solid, mp 283 ꢀC; [Found: C, 71.08; H, 5.17;

512
I.V. Levkov et al. / Tetrahedron 66 (2010) 508–512
N, 11.06. C30H26N4O4 requires C, 71.15; H, 5.22; N, 11.01]; ymax(KBr)
3424, 3064, 2920, 1700, 1644, 1508, 1384, 1180, 720 cmꢁ1
refinement against F2 in anisotropic approximation for non-hy-
drogen atoms using 5175 reflections was converged to wR2¼0.109
;
dH (400 MHz, DMSO-d6) 1.15 (1H, dd, J 6.0, 18.8 Hz), 1.36 (1H, dd, J
6.0, 18.8 Hz), 2.37 (1H, dd, J 9.2, 18.8 Hz), 2.45 (6H, s), 2.56 (1H, dd, J
9.2, 18.8 Hz), 4.59 (1H dd, J 6.0, 9.2 Hz), 4.76 (1H dd, J 6.0, 9.2 Hz),
6.92 (2H, s, NH2), 7.14–7.52 (11H, m), 7.90 (1H, d); dH (400 MHz,
CF3COOD) 2.23 (1H, dd, J 6.0, 18.8 Hz), 2.44 (1H, dd, J 6.0, 18.8 Hz),
2.46 (6H, s), 2.94 (1H, dd, J 9.2, 18.8 Hz), 3.38 (1H, dd, J 9.2, 18.8 Hz),
5.36 (2H, dd, J 6.0, 9.2 Hz), 7.07 (2H, d), 7.12 (2H, d), 7.38 (4H, d), 7.86
(1H, d), 7.98 (1H, t), 8.13 (1H, t), 8.46 (1H, d); dC (100.7 MHz, DMSO-
d6) 17.7, 17.9, 31.4, 31.7, 42.9, 43.2, 77.3, 121.8, 122.4, 125.4, 125.8,
128.0, 128.1, 129.6, 130.4, 132.7, 137.6, 138.7, 149.8, 159.5, 159.7,
165.4, 176.0, 176.3, 178.3, 178.5; HRMS (EI): Mþ, found 507.6.
C30H26N4O4 requires 507.6.
(R1¼0.060 for 2394 reflections with F>4 (F), S¼0.860). The final
s
atomic coordinates, and crystallographic data for molecule 5e have
been deposited to with the Cambridge Crystallographic Data Cen-
tre, 12 Union Road, CB2 1EZ, UK (fax: þ44-1223-336033,; e-mail:
deposit@ccdc.cam.ac.uk) and are available on request quoting the
deposition numbers CCDC 736675.
References and notes
1. Toja, E.; Omodei-Sale, A.; Favara, D.; Cattaneo, C.; Gallico, L.; Galliani, G.
Arzneim.-Forsch. 1983, 33, 1222.
2. Lerner, L. J. J. Reprod. Fertil. Suppl. 1989, 39, 251.
3. Bonnett, R.; North, S. A. Adv. Heterocycl. Chem. 1981, 29, 341.
4. Kreher, R.; Herd, K.-J. Chem. Ztg. 1982, 106, 305.
5. Kreher, R. P.; Kohl, N. Angew. Chem., Int. Ed. Engl. 1984, 23, 517.
6. Kovtunenko, V. A.; Voitenko, Z. V.; Sheptun, V. L.; Tyltin, A. K.; Chernega, I.;
Struchkov, Y. T.; Babichev, F. S. Chem. Heterocycl. Comp. 1984, 20, 1235.
7. Kreher, R. P.; Use, G. Chem. Ber. 1988, 121, 927.
8. Bonnett, R.; North, S. A.; Newton, R. F.; Scopes, D. I. Tetrahedron 1983, 39, 1401.
9. Kovtunenko, V. A.; Voitenko, Z. V. Russ. Chem. Rev. 1994, 63, 997.
10. Kovtunenko, V. A.; Voitenko, Z. V.; Tyltin, A. K.; Turov, A. V.; Babichev, F. S. Ukr.
Khim. Zh. 1983, 49, 1287.
11. Kreher, R. P.; Feldhoff, U.; Seubert, J.; Schmitt, D. Chem. Ztg. 1987, 111, 155.
12. Orti, E.; Bredas, J. L. J. Chem. Phys. 1988, 89, 1009.
13. Kreher, R. P.; Seubert, J.; Schmitt, D.; Use, G.; Kohl, N.; Muleta, T. Chem. Ber. 1990,
123, 381.
14. Zhou, Z.; Parr, R. G. J. Am. Chem. Soc. 1989, 111, 7371.
15. Kovtunenko, V. A.; Voitenko, Z. V.; Kucherenko, T. T.; Turov, A. V.; Tyltin, A. K.;
Babichev, F. S. Chem. Heterocycl. Comp. 1990, 26, 161.
16. Troll, T.; Ollmann, G. W. Tetrahedron Lett. 1981, 22, 3497.
17. Voitenko, Z. V.; Samoilenko, V. P.; Kovtunenko, V. A.; Gurkevich, V. Y.; Tyltin, A. K.;
Shcherbakov, M. V.; Shishkin, O. V. Chem. Heterocycl. Comp. 1999, 35, 600.
18. Voitenko, Z. V.; Pokholenko, A. A.; Shkarov, O. O.; Kovtunenko, V. A.; Babichev,
F. S. Chem. Heterocycl. Comp. 2002, 38, 190.
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Chima. 2006, 9, 1482.
20. Voitenko, Z.; Lyaskovskyy, V.; Wolf, J. G.; Jaud, J. ARKIVOC 2007, 15, 90.
21. Pokholenko, A. A.; Voitenko, Z. V.; Kovtunenko, V. A. Russ. Chem. Rev. 2004, 73,
771.
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23. Voitenko, Z. V.; Yegorova, T. V.; Kysil’, A. I.; Andre, C.; Wolf, J. G. Tetrahedron
2004, 60, 195.
24. Voitenko, Z. V.; Yegorova, T. V.; Kovtunenko, V. A.; Zubatyuk, R. I.; Shishkina, S. V.;
Shishkin, O. V.; Tsapko, M. D.; Turov, A. V. J. Mol. Struct. 2004, 707, 193.
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Mechanisms - 4th ed.; 2000; pp 215–261.
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27. Sieveking, H. U.; Luttke, W. Annalen 1977, 2, 189.
28. ZefirovYu, V. Kristallografiya 1997, 42, 936.
29. Ussr, P. 1166476 Byull. Izobret. 1983, 46, 68.
30. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
4.2.5. 3,3-Bis-(2,5-pyrrolidinone-1-methyl)-1-aminoisoindole
(5e). 0.28 g, 39%, white solid, mp 273 ꢀC; [Found: C, 61.01; H, 5.12;
N, 15.81. C18H18N4O4 requires C, 61.13; H, 5.07; N, 15.78]; ymax(KBr)
3440, 3108, 3068, 2948, 1688, 1648, 1432, 1380, 1276, 1120,
688 cmꢁ1
; dH (400 MHz, DMSO-d6) 0.87 (1H, dd, J 6.0, 18.8 Hz), 1.02
(1H, dd, J 6.0,18.8 Hz), 2.25 (1H, dd, J 9.2,18.8 Hz), 2.50 (1H, dd, J 9.2,
18.8 Hz), 2.79 (6H, s), 4.42 (1H dd, J 6.0, 9.2 Hz), 4.60 (1H dd, J 6.0,
9.2 Hz), 6.96 (2H, s, NH2), 7.08 (1H, d), 7.40 (1H, t), 7.46 (1H, t), 7.80
(1H, d); dH (400 MHz, CF3COOD) 2.00 (1H, dd, J 6.0, 18.8 Hz), 2.20
(1H, dd, J 6.0, 18.8 Hz), 2.79 (1H, dd, J 9.2, 18.8 Hz), 3.20 (7H, m), 5.10
(2H, dd, J 6.0, 9.2 Hz), 7.61 (1H, d), 7.90 (1H, t), 8.00 (1H, t), 8.36 (1H,
d); dC (100.7 MHz, DMSO-d6) 24.8, 25.0, 31.1, 31.3, 42.6, 43.2, 76.8,
121.6, 122.0, 129.4, 130.3, 137.4, 149.8, 165.3, 176.6, 176.9, 178.9,
179.6; HRMS (EI): Mþ, found 355.4. C18H18N4O4 requires 355.4.
4.3. X-ray diffraction study
The colourless crystals of 5e (C18H20N4O5) are orthorhombic. At
100 K a¼11.815(2), b¼14.054(2), c¼21.508(6) Å, V¼3571(1) Å3,
Mr¼372.38, Z¼8, space group Pbca, dcalcd¼1.385 g/cm3,
m
(MoK
a
)¼0.103 mmꢁ1
F(000)¼1568. Intensities of 19434, re-
,
flections (5199 independent, Rint¼0.105) were measured on the
‘Xcalibur-3’ diffractometer (graphite monochromated MoKa radia-
tion, CCD detector,
u
-scaning, 2Qmax¼60ꢀ). The structure was
solved by direct method using SHELXTL package.30 Positions of the
hydrogen atoms of water molecule were located from electron
density difference maps and refined using ‘riding’ model with
Uiso¼1.5Ueq of the carrier atom. All hydrogen atoms in molecule 5e
are refined in isotropic approximation. Full-matrix least-squares