Generation of azomethine imines via opening of the diaziridine ring in unsymmetrically substituted 6-aryl-1,5-diazabicyclo-[3.1.0]hexanes and their transformations

Article abstract of DOI:10.1134/S1070428011030171

Thermally induced opening of the diaziridine ring at the carbon-nitrogen bond in unsymmetrically substituted 6-aryl-1,5-diazabicyclo[3.1.0]hexanes is characterized by low regioselectivity which is likely to be determined by the inductive effect of substituents in the trimethylene bridge. 1,3-Dipolar cycloaddition of the resulting azomethine imines to phenyl isocyanate is regioselective: it occurs at the double carbon-nitrogen bond with predominant formation of the corresponding cis adducts due to dipolarophile approach to Z-azomethine imine at the sterically less hindered side. Analogous approach of dipolarophile is also observed in the reaction with N-arylmaleimides.

Full text of DOI:10.1134/S1070428011030171

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 3, pp. 421–432. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © Yu.B. Koptelov, S.P. Saik, A.P. Molchanov, S.I. Selivanov, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 3,
pp. 428–438.
Generation of Azomethine Imines via Opening of the Diaziridine
Ring in Unsymmetrically Substituted 6-Aryl-1,5-diazabicyclo-
[3.1.0]hexanes and Their Transformations
Yu. B. Koptelov, S. P. Saik, A. P. Molchanov, and S. I. Selivanov
St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
e-mail: koptelov@JK7283.spb.edu
Received July 5, 2010
Abstract—Thermally induced opening of the diaziridine ring at the carbon–nitrogen bond in unsymmetrically
substituted 6-aryl-1,5-diazabicyclo[3.1.0]hexanes is characterized by low regioselectivity which is likely to be
determined by the inductive effect of substituents in the trimethylene bridge. 1,3-Dipolar cycloaddition of the
resulting azomethine imines to phenyl isocyanate is regioselective: it occurs at the double carbon–nitrogen
bond with predominant formation of the corresponding cis adducts due to dipolarophile approach to Z-azo-
methine imine at the sterically less hindered side. Analogous approach of dipolarophile is also observed in the
reaction with N-arylmaleimides.
DOI: 10.1134/S1070428011030171
Azomethine imines, especially those fused to a cy-
clic system at both nitrogen atoms or nitrogen and
carbon atoms, may be useful as initial compounds for
the preparation of a wide series of fused heteropoly-
cyclic and spiro-fused heterocyclic systems [1]. A con-
venient method for the generation of azomethine
imines in which both nitrogen atoms are incorporated
into a pyrazolidine fragment is based on thermal open-
ing of the diaziridine ring in 6-aryl-1,5-diazabicyclo-
[3.1.0]hexanes at the carbon–nitrogen bond [2]. If no
1,3-dipolarophile is present in the reaction mixture,
highly reactive and labile azomethine imines thus
formed undergo isomerization into the corresponding
4,5-dihydro-1H-pyrazoles [3, 4]. Introduction of a sub-
stituent into position 2 of 6-aryl-1,5-diazabicyclo-
[3.1.0]hexane molecule violates symmetric structure of
the bicyclic system. However, opening of the diaziri-
dine ring in 2-oxo derivatives occurs strictly regio-
selectively at the carbon–nitrogen bond contiguous to
the carbonyl group [5], whereas thermolysis of 6-aryl-
2-methyl-1,5-diazabicyclo[3.1.0]hexanes is charac-
terized by low regioselectivity [6]; isomerization of
unstable intermediate azomethine imines leads to the
formation of mixtures of 1-arylmethyl-5-methyl-4,5-
dihydro-1H-pyrazoles and 1-arylmethyl-3-methyl-4,5-
dihydro-1H-pyrazoles at a ratio of ~6:5 (55:45%).
substituted 2-phenyl- and 2,2,4-trimethyl-1,5-diazabi-
cyclo[3.1.0]hexanes and the stereoselectivity in the
reactions of azomethine imines thus formed with
1,3-dipolarophiles (1,3-dipolar cycloaddition). We
were especially interested in thermal decomposition of
diazabicyclohexane Ib having three substituents in the
trimethylene bridge. On the one hand, the presence of
two methyl groups in position 2 increases strain in the
bicyclic system, which should affect the mode of
opening of the three-membered ring; on the other
hand, opening of the diaziridine fragment at the car-
bon–nitrogen bond contiguous to the quaternary car-
bon atom could give rise to azomethine imine lacking
a hydrogen atom for the subsequent 1,4-H shift leading
to 4,5-dihydro-1H-pyrazole derivative.
Unsymmetrically substituted 6-aryl-1,5-diazabicy-
clo[3.1.0]hexanes Ia–Ic were synthesized in 11–30%
yields according to known procedure involving con-
densation of 4-methoxy- and 4-bromobenzaldehydes
with substituted propane-1,3-diamines IIa and IIb and
subsequent oxidation of intermediate substituted hexa-
hydropyrimidines with sodium hypochlorite [2]
(Scheme 1). Initial propane-1,3-diamines were pre-
pared in turn by catalytic hydrogenation of dihydro-
pyrazoles [7]. It should be noted that the yields of the
corresponding symmetric analogs, 6-(4-methoxyphen-
yl)- [2] and 6-(4-bromophenyl)-1,5-diazabicyclo[3.1.0]-
hexanes [8], were considerably higher, 52 and 70%,
In the present work we examined the regioselec-
tivity in the opening of the diaziridine ring in 6-aryl-
421

KOPTELOV et al.
422
Scheme 1.
X
X
CHO
NH2 NH2
MeOH
NaOCl
+
R
R'
R'
X
HN
NH
N
N
R
R
R'
R'
R'
R'
IIa, IIb
Ia–Ic
R'
R
X
R'
N
N
+
+
HN
N
R
R'
X
X
R'
IIIa–IIIc
IVa–IVc
I, III, IV, R = Ph, R′ = H, X = Br (a); R = R′ = Me, X = Br (b), MeO (c); II, R = Ph, R′ = H (a); R = R′ = Me (b).
respectively. The structure of diazabicyclohexanes Ia–
Ic was confirmed by spectral data. The 1H NMR spec-
tra of all 6-aryl-1,5-diazabicyclo[3.1.0]hexanes Ia–Ic
in CDCl3 contained characteristic singlets at δ 3.10–
3.28 ppm from the CH proton in the diaziridine ring.
steric structure. The 1H NMR spectrum of Ia in CDCl3
contained the following signals, δ, ppm: 1.93 m (1H,
J = 8.0, 13.4 Hz) and 2.37 m (1H, J = 8.9, 13.4 Hz)
(CH2), 3.25 d.d.d (1H, J = 8.0, 8.1, 12.0 Hz) and
3.60 m (1H, J = 8.9, 12.0 Hz) (CH2), 3.28 s (1H,
NCHN), 4.83 m (1H, J = 8.6 Hz, PhCH), as well as
signals belonging to aromatic protons.
We previously showed that symmetric 6-aryl-1,5-
diazabicyclo[3.1.0]hexanes exist as exo-6 isomers due
to hindered inversion of the diaziridine ring [8] and
that 6-aryl-2-methyl-1,5-diazabicyclo[3.1.0]hexanes
have the structure of exo,exo isomers [6]. As follows
Apart from signals corresponding to compounds
Ia–Ic, the NMR spectra of the reaction mixtures
contained signals assignable to the initial aldehydes,
Schiff bases IIIa–IIIc and amidines IVa–IVc, and
compound IVa was isolated as individual substance
(yield 48%). Unlike the synthesis of symmetric 6-aryl-
1,5-diazabicyclo[3.1.0]hexanes (where the main by-
products were Schiff bases like III) [4], in our case the
main by-products were amidines IVa–IVc resulting
from oxidation of hexahydropyrimidines. A probable
reason is steric hindrances to oxidative cyclization of
hexahydropyrimidines having substituents in position
4(6) to the corresponding diaziridines Ia–Ic.
1
from analysis of the 2D H NMR (NOESY) spectrum
of compound Ic (Fig. 1), 6-aryl-2,2,4-trimethyl-1,5-di-
azabicyclo[3.1.0]hexanes Ib and Ic are also exo,exo
isomers having, like their monomethyl analogs, a boat
conformation. This is indicated by spatial interaction
between one proton in the methylene group
(δ 2.04 ppm) and the CH proton in the diaziridine ring
(δ 3.16 ppm).
Presumably, 6-(4-bromophenyl)-2-phenyl-1,5-di-
azabicyclo[3.1.0]hexane (Ia) should have a similar
Compounds Ia–Ic were subjected to thermolysis
under conditions analogous to those reported for
6-aryl-1,5-diazabicyclo[3.1.0]hexanes [2, 4, 8, 9], i.e.,
by heating in boiling p- or o-xylene (bp 138 and
144°C, respectively). In all cases the reaction was
complete in ~25 min (TLC), which is typical of diaziri-
dine ring opening in 6-aryl-1,5-diazabicyclo[3.1.0]-
hexanes. After removal of the solvent, the reaction
mixtures were analyzed by 1H NMR.
7.31
3.16
H
OCH3
2.04
H
1.39 Me
N
1.61
H
N
H
Me
1.49
3.84
Me
1.42
Fig. 1. Principal nuclear Overhauser effects in the two-
dimensional 1H NOESY spectrum of compound Ic.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

GENERATION OF AZOMETHINE IMINES
423
Scheme 2.
H
Ph
Ph
Br
Br
Br
~1,4-H
N
N
a
N
N
Va
H
a
b
N
N
H
Br
Br
~1,4-H
N
N
Ph
b
Ia
N
N
Ph
Ph
H
VIa
Opening of the three-membered ring in unsymmet-
rically substituted 1,5-diazabicyclohexanes at carbon–
nitrogen bonds can follow two pathways (a and b)
leading to the formation of the corresponding regio-
isomeric azomethine imines which then undergo iso-
merization via 1,4-H shift into 4,5-dihydro-1H-pyra-
zole derivatives. Thermolysis of 6-(4-bromophenyl)-2-
phenyl-1,5-diazabicyclo[3.1.0]hexane (Ia) in the ab-
sence of 1,3-dipolarophile gave a mixture of isomeric
dihydropyrazoles Va and VIa at a ratio of ~52 :48
(Scheme 2). The isomer ratio was determined on the
Opening of the diaziridine ring in 6-aryl-2,2,4-tri-
methyl-1,5-diazabicyclo[3.1.0]hexanes Ib and Ic along
pathway b seemed to be preferred. We believed that in
this case elimination of additional steric strain due to
the presence of two methyl groups in the α-position
with respect to the nitrogen atom (in fact, a latent tert-
butyl group) should be more efficient. The resulting
azomethine imine lacks hydrogen atom necessary for
1,4-H shift, so that isomerization into the correspond-
ing dihydropyrazole is impossible. However, the
1H NMR spectra of the reaction mixtures obtained by
thermolysis of compounds Ib and Ic showed the
presence of only dihydropyrazoles Vb and Vc (≥85–
90% of the overall amount of products) which could be
formed via cleavage of the diaziridine fragment exclu-
sively along pathway a (Scheme 3). Compounds that
could be formed according to pathway b were not
detected. The 1H NMR spectra of the reaction mixtures
also contained signals from para-substituted benzalde-
hydes (~10%); the latter may result from hydrolysis of
azomethine imines generated by cleavage of the initial
diaziridine along pathway b.
1
basis of the H NMR spectrum of the reaction mixture
from the intensities of the benzylic proton signals.
These signals appeared as a singlet at δ 4.29 ppm for
isomer Va (the corresponding signal of 1-benzyl-3-
phenyl-4,5-dihydro-1H-pyrazole in DMSO-d6 was
located at δ 4.28 ppm [10], and of 1-benzyl-3-methyl-
4,5-dihydro-1H-pyrazole, at δ 4.10 ppm [11]) and two
doublets at δ 3.79 and 4.23 ppm (2J = 14.0 Hz) for
isomer VIa. No appreciable amounts of any other
compounds were detected in the reaction mixture by
1H NMR spectroscopy.
Scheme 3.
H
Me
Me
X
X
X
~1,4-H
N
N
a
N
N
Me
Me
Me
Me
H
Vb, Vc
a
b
N
N
Me
Me
X
Me
Me
~1,4-H
N
Me
?
b
N
Ib, Ic
Me
H
X = Br (b), MeO (c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

KOPTELOV et al.
424
Scheme 4.
Ph
N
Ph
N
Ar
N
Ar
N
Ar
O
Ar
O
N
H
PhNCO
N
N
N
N
+
+
N
a
Ph
H
H
Ph
Ph
Ar
Ph
b
anti/cis-VIIa
anti/trans-VIIIa
Va
Δ
a
N
N
H
Ph
N
Ph
N
Ar
Ar
Ph
Ia
O
Ar
O
Ar
H
PhNCO
N
N
+
+
N
N
b
N
N
N
N
Ph
H
Ph
Ph
Ph
syn/cis-IXa
syn/trans-Xa
VIa
Ar = 4-BrC6H4.
Dihydropyrazoles Vb and Vc characteristically
showed in the H NMR spectra singlets from methyl
and Vc are formed. By contrast, electron-withdrawing
phenyl group stabilizes transition state with a partial
negative charge on the neighboring nitrogen atom, and
compound Va slightly prevails among the products.
1
protons at δ 1.19–1.21 (6H) and 1.91–1.94 ppm (3H)
and methylene protons at δ 2.46–2.48 (2H) and 3.90–
3.95 ppm (2H), as well as doublets from aromatic
protons at δ 7.30 (1H, J = 8.0 Hz) and 7.43 ppm (1H,
J = 8.0 Hz) for Vb and at δ 6.88 (1H, J = 8.6 Hz) and
7.37 ppm (1H, J 8.6 Hz) for Vc. The spectrum of Vc
additionally contained a singlet at δ 3.80 ppm (3H)
from protons in the methoxy group.
By thermolysis of diazabicyclohexane Ia in the
presence of phenyl isocyanate we obtained mixtures of
all four possible regio- and stereoisomeric cycloaddi-
tion products VIIa–Xa (Scheme 4). According to the
1H NMR data, the reaction mixture also contained
appreciable amounts of dihydropyrazoles Va and VIa
(~24%) at a ratio of 62:38 (52:48 in the absence of
dipolarophile). These findings are likely to indicate
somewhat higher reactivity of intermediate azomethine
imine formed according to pathway b in the cyclo-
addition to phenyl isocyanate. Thermal opening of the
diaziridine ring in compound Ia in the presence of
phenyl isocyanate was characterized by the same
regioselectivity as in the absence of dipolarophile. The
ratio of anti adducts VIIa and VIIIa and syn adducts
IXa and Xa was ~44:56, and the ratio of cis (VIIa +
IXa) and trans adducts (VIIIa + Xa) was ~62 :38.
Taking into account our previous data obtained for
2-methyl-substituted 6-aryl-1,5-diazabicyclo[3.1.0]-
hexanes [6], the observed regioselectivity of diaziri-
dine ring opening in diazabicyclohexanes Ia–Ic may
be rationalized in terms of a weak inductive effect of
the methyl or phenyl group in position 2. Assuming
thermal polarization of the C6–N5 bond (a) in Ib and
Ic, two donor methyl groups should exert a stronger
destabilizing effect on the transition state, as compared
to the effect of one methyl group upon polarization of
the C6–N1 bond (b); as a result, dihydropyrazoles Vb
Br
Br
Br
5.62
3.75
3.46
H
H
H
6.86
3.94
H
2.13
2.90
6.94
7.45
2.17
H
6.17
H
H
7.05
2.77
N
N
H
5.84
N
Ph
N
N
H
2.55 H
N
2.18
H
N
Ph
Ph
N
H
N
H3.94
H
H
H
O
H
2.56
5.28
7.33
3.46
O
4.06
O
H
3.67
VIIa
IXa
Xa
Fig. 2. Principal nuclear Overhauser effects in the 1H NOESY spectra of compounds VIIa, IXa, and Xa.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

GENERATION OF AZOMETHINE IMINES
425
Scheme 5.
Ph
Ar
N
Ar
N
N
Ar
O
H
PhNCO
N
N
N
+
N
a
Me
Me
Me
Me
H
H
Me
Me
Ar
Me
Me
Me
b
Me
Me
Δ
a
anti/cis-VIIb
Vb
Ph
N
N
H
Ph
N
Ar
N
Me
N
O
Ar
O
Ar
H
PhNCO
Ib
+
N
b
N
N
N
N
Me
Me
Me
Me
Me
Me
Me
Me
Me
syn/cis-IXb
syn/trans-Xb
Ar = 4-BrC6H4.
Figure 2 shows the main signals and spatial interac-
tions (nuclear Overhauser effects) of protons in com-
pounds VIIa, IXa, and Xa, which gave rise to cross
Xb) was 76:24, and cis isomers VIIb and IXb were
the major products: cis-(VIIb + IXb)/trans-Xb = 92:8.
Some proton chemical shifts and spatial interac-
1
peaks in the 2D H NMR spectra (NOESY) recorded
tions between protons in adducts VIIb and IXb, which
1
from solutions in CDCl3. We failed to isolate com-
pound VIIIa as individual substance, but in the
1H NMR spectrum of the product mixture enriched in
adduct VIIIa we observed multiplet signals from
methylene protons at δ 2.10 (1H), 2.35 (1H), and
2.69 ppm (2H), a multiplet at δ 5.24 ppm (1H) and
a singlet at δ 6.37 ppm (1H) from methine protons, and
signals from aromatic protons in the region δ 7.08–
7.51 ppm (14H).
were observed in their 2D H NMR spectra (NOESY)
recorded from solutions in CDCl3, are shown in Fig. 3.
Compound Xb was not isolated as analytically pure
sample, and its relative configuration was determined
1
by comparing its H NMR spectrum with those of
compound Xa and analogous thermolysis products of
2-substituted 6-aryl-1,5-diazabicyclo[3.1.0]hexanes
1
[6]. Adduct Xb displayed in the H NMR spectrum
signals from protons in the methyl groups at δ, ppm:
0.65 d (3H, J = 6.1 Hz), 1.55 s (3H), and 1.58 s (3H),
methylene protons at 1.73 d.d (1H, J = 7.9, 12.3 Hz)
and 2.14 d.d (1H, J = 7.4, 12.3 Hz), methine protons at
3.11 d.q (1H, J = 6.1, 7.4, 7.9 Hz) and 6.04 s (1H), and
aromatic protons in the region 7.02–7.49 ppm (9H).
1
According to the H NMR data, thermolysis of
6-(4-bromophenyl)-2,2,4-trimethyl-1,5-diazabicyclo-
[3.1.0]hexane (Ib) in the presence of phenyl isocyanate
gave a mixture of products containing compounds
VIIb and Vb (resulting from cleavage of the C6–N5
bond) together with adducts IXb and Xb which were
formed via opening of the C6–N1 bond (pathway b,
Scheme 5). As noted above, thermolysis of diazabicy-
clohexane Ib in the absence of dipolarophile afforded
no products corresponding to pathway b. Thus, unlike
four adducts formed by thermolysis of diazabicyclo-
hexane Ia, only three products were detected in analo-
gous transformation of compound Ib. The fraction of
dihydropyrazole Vb in the reaction mixture did not
exceed ~14%, and no protons signals assignable to
Presumably, the observed relatively high stereo-
selectivity of 1,3-dipolar cycloaddition in the thermol-
ysis of 2-substituted 6-aryl-1,5-diazabicyclohexanes Ia
Br
Br
5.61
5.62
0.98Me
1.36
Me
1.26Me
H
3.1H0
H
H
1.68
N
N
N
Ph
H
2.13
2.18
N
Ph
H
N
H
N
1
4-bromobenzaldehyde were observed in the H NMR
1.75
Me
H 4.22
O
Me
1.71
1.31
spectrum of the reaction mixture. The regioselectivity
in diaziridine ring opening in compound Ib was esti-
mated at ~78:22 in favor of pathway a (VIIb, Vb).
O
Me
1.40
VIIb
IXb
1
Fig. 3. Principal nuclear Overhauser effects in the 1H NOESY
spectra of compounds VIIb and IXb.
In keeping with the H NMR data, anti adduct VIIb
considerably prevailed: the ratio anti-VIIb/syn-(IXb +
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

KOPTELOV et al.
426
and Ib in the presence of phenyl isocyanate (cis/trans
ratio 62–92/8–38) is determined by preferential dipo-
larophile approach to intermediate azomethine imine at
the side opposite to the methyl or phenyl group in the
pyrazolidine ring, i.e., at the least sterically hindered
side (Scheme 6). Probable ways of dipolarophile ap-
proach ensuring minimal spatial interaction between
phenyl isocyanate and azomethine imine are shown in
Scheme 6. In the other cases, spatial interactions be-
tween the NCO fragment and substituent in position 2
of the pyrazolidine ring are considerably stronger.
Here, it is assumed that, like stable azomethine imines
having an oxo group in the α-position [12], non-
stabilized azomethine imine resulting from thermolysis
of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes Ia and Ib
also has Z configuration.
[3.1.0]hexane indicated higher stability of the former
(ΔΔHZ–E = –5.2 kcal/mol); and the calculated differ-
ence in the Gibbs energies (ΔΔGZ–E = –5.1 kcal/mol)
suggests insignificant contribution of the E isomer in
the equilibrium state (kZ/kE ≈ 600 at 140°C; Scheme 7).
Therefore, we believe that the reaction with phenyl
isocyanate involves azomethine imine having Z con-
figuration.
Scheme 7.
Ph
N
H
kE
kZ
H
Ph
N
N
N
Z
E
Our results led us to conclude that thermally
induced cleavage of the diaziridine ring in 2-methyl-,
2,2,4-trimethyl-, and 2-phenyl-substituted 6-aryl-1,5-
diazabicyclo[3.1.0]hexanes in the presence of phenyl
isocyanate gives mainly adducts with cis orientation of
the aryl and methyl (CHMe) or phenyl groups as
a result of dipolarophile approach at the less sterically
hindered side of intermediate unstable Z-dipole, i.e., at
the side opposite to the methyl or phenyl group.
Scheme 6.
Ph
Ph
O
N
N
C
O
Ar
Ar
N
N
H
Ph
H
N
N
Ph
anti/cis Adduct
Ph
N
Thermal decomposition of 6-(4-bromophenyl)-
2,2,4-trimethyl-1,5-diazabicyclo[3.1.0]hexane (Ib) in
the presence of N-(4-bromophenyl)maleimide gave
a mixture of compounds containing dihydropyrazole
Vb (~28%) and three cycloaddition products XIb–
XIIIb (~72%) (Scheme 8). The ratio of the adducts
was determined on the basis of the intensities of the
9-H and 3a-H signals in the 1H NMR spectra. The ratio
of the products formed along pathways a and b was
~70:30. The fraction of anti adduct XIb was slightly
greater [anti-XIb/syn-(XIIb + XIIIb) = 56:44], and
the ratio cis-(XIb + XIIb)/trans-XIIIb was ~79:21;
i.e., the major products were isomers with cis orienta-
tion of the 4-bromophenyl and methyl (CHMe) groups.
The addition of N-(4-bromophenyl)maleimide to azo-
methine imines generated by thermolysis of diazabicy-
clohexane Ib occurred exclusively as a result of exo
approach, yielding cis-fused (9-H, 9a-H) pyrrolopyra-
zoles XIb–XIIIb.
Ph
O
C
O
N
Ar
H
Ar
N
N
N
O
N
H
Ph
Ph
syn/cis Adduct
Ph
Ph
H
O
N
N
C
Ar
N
N
Ar
Me
H
N
N
Me
Me
Me
Me
Me
anti/cis Adduct
In fact, E configuration of azomethine imine should
be characterized by fairly strong destabilizing spatial
interaction between the aryl and methyl (phenyl)
groups, and the formation of cis-isomeric cycloaddi-
tion product requires phenyl isocyanate approach at the
side corresponding to the methyl (phenyl) group,
which seems to be improbable.
Figure 4 shows principal spatial interactions be-
tween protons in molecule XIb, which give rise to
1
cross peaks in the 2D H NMR spectrum (NOESY,
Quantum-chemical calculation (DFT, 6-31G basis
set, B3LYP functional, Gaussian-03 [13]) of the enthal-
pies of formation of the Z and E isomers of dipole
generated by thermolysis of 6-phenyl-1,5-diazabicyclo-
CDCl3). Adduct XIIb was not isolated as analytically
pure substance. In the H NMR spectrum (CDCl3) of
crude product XIIb we observed signals (δ, ppm) from
methyl protons at 1.21 d (3H, J = 6.2 Hz), 1.49 s (3H),
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

GENERATION OF AZOMETHINE IMINES
427
Scheme 8.
O
Ar
N
H
9a
3a
Ar
N
Ar
O
9
H
N
N
N
+
a
Me
Me
Me
H
Me
Me
Ar
Me
anti/cis/cis-XIb
O
O
, Δ
b
N
Me
Me
Vb
a
N
Ar
N
H
Ar
O
Ar
O
Me
N
N
H
H
9a
3a
Ib
Ar
Ar
O
O
9
+
H
H
b
N
N
N
N
Me
Me
syn/cis/cis-XIIb
Me
Me
syn/trans/cis-XIIIb
Me
Me
Ar = 4-BrC6H4.
and 1.52 s (3H), methylene protons at 1.67 d.d (1H,
J = 6.4, 12.8 Hz) and 2.20 d.d (1H, J = 9.6, 12.8 Hz),
methine protons at 3.00 d.d.q (1H, J = 6.2, 6.4,
9.6 Hz), 4.13 d.d (2H, J = 9.0, 9.2 Hz), 4.37 d (1H, J =
9.0 Hz), and 4.62 d (1H, J = 9.2 Hz), and aromatic
protons at 6.66–7.49 d (8H). Compound XIIIb dis-
former. exo Approach of N-mesitylmaleimide having
two substituents in the ortho positions to Z-dipole is
impossible because of strong steric interactions be-
tween the ortho substituents in the benzene ring of the
imide and benzene ring of the dipole. On the other
hand, such approach should be possible when the
dipole has E configuration; in this case, considerable
amount of the corresponding trans adduct would be
formed. However, no cycloaddition products with
N-mesitylmaleimide were detected. Likewise, N-aryl-
maleimides having no ortho substituents, e.g.,
N-(4-bromophenyl)maleimide, should react with
E-azomethine imine to give trans adducts as a result of
exo approach of the imide, but the reaction mixtures
contained only the cis adducts which could be formed
only from Z-azomethine imine.
1
played the following signals in the H NMR spectrum
of the reaction mixture (CDCl3), δ, ppm: 0.65 d (3H,
J = 6.2 Hz, Me), 3.19 m (1H), 4.20 d (1H, J = 5.0 Hz,
CH). The structures of adducts XIIb and XIIIb shown
in Scheme 8 were assigned by comparing their 1H NMR
spectra with the spectra of thermolysis products of
compound Ib in the presence of phenyl isocyanate.
Thermolysis of 6-(4-bromophenyl)- and 6-(4-me-
thoxyphenyl)-2,2,4-trimethyl-1,5-diazabicyclo[3.1.0]-
hexanes Ib and Ic in the presence of N-mesitylmale-
imide gave mixtures consisting mainly of dihydropyra-
zole Vb or Vc and the corresponding benzaldehyde
(>90%). These results indicated that the main trans-
formation pathway of labile sterically hindered azo-
methine imine in the presence of sterically hindered
maleimide is formal 1,4-H-shift. No cycloaddition
products were detected.
Analysis of possible modes of approach of N-aryl-
maleimides to azomethine imines generated from
6-aryl-2,2,4-trimethyl-1,5-diazabicyclo[3.1.0]hexanes
confirmed our above assumption that these dipoles
have Z configuration. As follows from Scheme 9, the
presence of three methyl groups in the pyrazolidine
fragment completely prevents endo approach of male-
imide to azomethine imine, regardless of the con-
figuration of the latter (E or Z) and structure of the
Thus the stereoselectivity in the cycloaddition of
N-arylmaleimides to azomethine imines generated by
Br
Br
O
N
3.85
H
N
7.31
4.63
H
O
N
H4.25
H3.20
0.85Me
Me
1.35
1.38
Me
H
H
2.27
1.69
XIb
Fig. 4. Principal nuclear Overhauser effects in the 1H NOESY
spectrum of compound XIb.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

KOPTELOV et al.
428
Scheme 9.
(Z)-Azomethine imine
Br
O
cis Adduct
O
N
Br
endo Approaches
trans Adducts
N
Me
O
H
O
N
N
Me
exo Approach
O
O
Me
N
N
O
O
cis Adduct
Br
Br
Me
O
Me
N
O
exo Approach
cis Adduct
Me
Me
Me
H
N
N
Me
O
Me
N
O
Me
Me
(E)-Azomethine imine
Br
O
Me
O
endo Approaches
N
Me
O
N
Me
Me
exo Approach
trans Adduct
O
Me
N
N
O
Me
trans Adducts
N
O
Br
thermolysis of unsymmetrically substituted 6-aryl-1,5-
diazabicyclo[3.1.0]hexanes is determined (as in the re-
actions with phenyl isocyanate) by dipolarophile ap-
proach at the less sterically hindered side of inter-
mediate azomethine imine which is likely to have Z
configuration.
diamines IIa and IIb were synthesized by hydrogena-
tion of the corresponding 4,5-dihydropyrazoles [7]
which were prepared in turn according to the proce-
dures reported in [17–19].
6-(4-Bromophenyl)-2-phenyl-1,5-diazabicyclo-
[3.1.0]hexane (Ia). A solution of 10.1 g (0.055 mol) of
4-bromobenzaldehyde in 80 ml of methanol was added
dropwise over a period of 1.5 h to 8.2 g (0.055 mol) of
1-phenylpropane-1,3-diamine (IIa), maintaining the
temperature at 0–5°C. The cooling bath was removed,
the mixture was stirred for 1 h at room temperature and
evaporated by half under reduced pressure, and 32 ml
(0.061 mol) of a 1.90 N solution of sodium hypo-
chlorite was added dropwise over a period of 1 h on
cooling with ice water. The mixture was stirred for 1 h
at room temperature, 150 ml of water and 100 ml of
benzene were added, the organic phase was separated,
and the aqueous phase was extracted with benzene
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
trometer from 1–2% solutions in chloroform. The
1H and 13C NMR spectra were measured on a Bruker
DPX-300 spectrometer at 300.130 and 75.468 MHz,
respectively, using CDCl3 as solvent and reference
(CHCl3, δ 7.26 ppm; CDCl3, δC 77.16 ppm) [14].
N-Arylmaleimides were synthesized according to
standard procedure [15]. Aqueous sodium hypochlorite
was prepared as described in [16]. Initial propane-1,3-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

GENERATION OF AZOMETHINE IMINES
429
(3×40 ml). The extracts were combined with the or-
ganic phase, dried over Na2SO4, and evaporated by
half under reduced pressure, and an equal amount of
diethyl ether was added to the residue. The precipitate
of compound IVa was filtered off, and the filtrate was
evaporated. The solid residue was purified by colum
chromatography on silica gel (Silicagel L, 35–70 μm,
substrate–sorbent weight ratio 1:7, eluent hexane–
ethyl acetate, 7:1). Diaziridine Ia isolated from the
eluate contained 90% of the main substance; it was
purified by recrystallization from diethyl ether with ad-
dition of hexane. Yield 2.6–2.8 g (15–16%), mp 143–
144°C. IR spectrum, cm–1: 3080, 3050, 2990, 2975,
2950, 1600, 1520, 1500, 1435, 1260, 1080, 1030.
1H NMR spectrum, δ, ppm: 1.93 m (1H), 2.37 m (1H,
CH2, J = 8.9, 13.4 Hz), 3.25 d.d.d (1H, CH2N, J = 8.0,
8.1, 12.0 Hz), 3.28 s (1H, NCHN), 3.60 m (1H, CH2N,
J = 8.9, 12.0 Hz), 4.83 m (1H, CHPh, J = 8.6 Hz),
7.23–7.49 m (9H, Harom). 13C NMR spectrum, δC, ppm:
30.8 (CH2), 51.4 (CH2), 57.1 (CH), 66.7 (CH), 122.7
(Carom), 126.5 (2C, CHarom), 127.1 (CHarom), 128.6 (2C,
CHarom), 129.3 (2C, CHarom), 131.5 (2C, CHarom), 136.1
(Carom), 143.6 (Carom). Found, %: C 60.96; H 4.81;
N 8.89. C16H15BrN2. Calculated, %: C 60.94; H 4.92;
N 8.74.
the residue was purified by column chromatography on
silica gel (Silicagel L, 160–200 μm, substrate–sorbent
weight ratio 1:7, gradient elution: hexane, hexane–
ethyl acetate, 15:1). We isolated 15 g of a mixture of
products containing ~90% of diaziridine Ib. Com-
pound Ib was purified by recrystallization from
hexane. Yield 7.3 g (30%), mp 73°C. IR spectrum, ν,
cm–1: 3035, 2980, 2945, 2920, 2880, 1605, 1500, 1470,
1430, 1385, 1345, 1305, 1260, 1184, 1125, 1110, 1080,
1
1050, 1025. H NMR spectrum, δ, ppm: 1.37 s (3H,
Me), 1.40 d (3H, Me, J = 7.2 Hz), 1.47 s (3H, Me),
1.61 m (1H, CH2, J = 13.6 Hz), 2.01 d.d (1H, CH2, J =
9.2, 13.6 Hz), 3.14 s (1H, NCHN), 3.84 m (1H,
CHMe, J = 7.6, 9.2 Hz), 7.24 d (2H, Harom, J = 7.9 Hz),
7.44 d (2H, Harom, J = 7.9 Hz). 13C NMR spectrum, δC,
ppm: 23.7 (CH3), 26.6 (CH3), 31.1 (CH3), 43.4 (CH2),
57.8 (CH), 62.3 (CH), 65.7 (CMe2), 122.4 (Carom),
129.1 (2C, CHarom), 131.5 (2C, CHarom), 136.8 (Carom).
Found, %: C 60.94; H 4.92; N 8.74. C16H15BrN2. Cal-
culated, %: C 60.96; H 4.81; N 8.89.
6-(4-Methoxyphenyl)-2,2,4-trimethyl-1,5-diaza-
bicyclo[3.1.0]hexane (Ic). A solution of 9.4 g
(0.069 mol) of 4-methoxybenzaldehyde in 35 ml of
methanol was added dropwise over a period of 30 min
to a solution of 8.0 g (0.069 mol) of 2-methylpentane-
2,4-diamine (IIb) in 35 ml of methanol, cooled to 0–
5°C. The cooling bath was removed, and the mixture
was stirred for 1 h at room temperature. The resulting
solution was cooled with ice water, 30 ml (0.073 mol)
of a 2.44 N solution of sodium hypochlorite was added
dropwise over a period of 20 min, and the mixture was
stirred for 1 h at room temperature. The organic phase
was separated, and the aqueous phase was treated with
chloroform (3×20 ml). The extract was dried over
Na2SO4, the solvent was distilled off, and the oily
residue was purified by column chromatography
(Silicagel L, 100–200 μm, substrate–sorbent weight
ratio 1:25, eluent hexane–ethyl acetate). The oily sub-
stance thus isolated was dissolved in a minimal amount
of ethyl acetate–hexane (1:1), and the solution was
frozen with liquid nitrogen. Yield 1.9 g (12%), mp 54–
2-(4-Bromophenyl)-4-phenyl-1,4,5,6-tetrahydro-
pyrimidine (IVa). 1H NMR spectrum, δ, ppm: 1.82 m
(1H, CH2), 2.10 m (1H, CH2), 3.50 m (2H, CH2N),
4.62 d.d (1H, CHPh, J = 5.6, 7.5 Hz), 3.95–5.21 br.s
(1H, NH), 7.28–7.41 m (5H, Harom), 7.50 d (2H, Harom
,
J = 8.4 Hz), 7.60 d (2H, Harom, J = 8.4 Hz).
6-(4-Bromophenyl)-2,2,4-trimethyl-1,5-diazabi-
cyclo[3.1.0]hexane (Ib). A solution of 10.0 g
(0.086 mol) of 2-methylpentane-2,4-diamine (IIb) in
35 ml of methanol was cooled to 0–5°C, and
0.086 mol of 4-bromobenzaldehyde was added in two
8.0-g portions: the first portion was dissolved in 50 ml
of methanol and added over a period of 0.5 h, and the
second portion was dissolved in 100 ml of methanol
and added over a period of 1.5 h. The cooling bath was
removed, the mixture was stirred for 1 h at room
temperature and evaporated by half under reduced
pressure, and 45 ml (0.106 mol) of a 2.35 N solution of
sodium hypochlorite was added dropwise to the resi-
due over a period of 0.5 h on cooling with ice water.
The mixture was stirred for 1 h at room temperature,
150 ml of water and 100 ml of benzene were added,
the organic phase was separated, and the aqueous
phase was extracted with benzene (3×40 ml). The
combined extracts were dried over sodium sulfate, the
solvent was distilled off under reduced pressure, and
1
55°C. H NMR spectrum, δ, ppm: 1.37 s (3H, Me),
1.40 d (3H, Me, J = 7.2 Hz), 1.46 s (3H, Me), 1.60 d.d
(1H, CH2, J = 1.4, 13.6 Hz), 2.01 d.d (1H, CH2, J =
9.4, 13.6 Hz), 3.14 s (1H, NCHN), 3.77 s (3H, OMe),
3.82 d.d.q (1H, CHMe, J = 1.4, 7.2, 9.4 Hz), 6.84 d
(2H, Harom, J = 8.7 Hz), 7.29 d (2H, Harom, J = 8.7 Hz).
13C NMR spectrum, δC, ppm: 23.8 (CH3), 26.6 (CH3),
31.2 (CH3), 43.5 (CH2), 55.4 (OCH3), 58.2 (CH), 62.1
(CH), 65.8 (CMe2), 113.9 (2C, CHarom), 128.5 (2C,
CHarom), 129.9 (Carom), 159.9 (Carom). Found, %:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

KOPTELOV et al.
430
C 72.37; H 8.51; N 12.14. C14H20N2O. Calculated, %:
C 72.38; H 8.68; N 12.06.
tained from 278 mg (0.88 mmol) of diazabicyclohex-
ane Ia and 105 mg (0.88 mmol) of phenyl isocyanate.
The product mixture was separated by column chroma-
tography (Silicagel L, 35–70 μm, substrate–sorbent
weight ratio 1:160, eluent hexane–ethyl acetate, 8:1).
The separation process was monitored by thin-layer
chromatography (Silufol UV-254; hexane–ethyl ace-
tate, 5:1; double elution; development with iodine
vapor). The overall preparative yield of all isomers
Thermolysis of diazabicyclohexanes Ia–Ic in the
absence of dipolarophiles. A 0.1–1.0 M solution of
diazabicyclohexane Ia–Ic in p- or o-xylene was heated
under stirring at a bath temperature of 140 and 145°C,
respectively, over a period of 20–25 min. The mixture
was cooled, and the solvent was distilled off under
reduced pressure. The ratio of isomers V and VI in the
reaction mixture did not depend on the concentration
of the initial diazabicyclohexane (according to the
1H NMR data).
1
was 297 mg (78%). According to the H NMR data,
the ratio of isomers Xa/IXa/VIIIa/VIIa was ~0.97:
1.0:0.36:1.19.
Compound VIIa. Yield 64 mg (17%), mp 168–
170°C. IR spectrum, ν, cm–1: 3080, 3040 s, 2970,
2940, 2920, 1715 s (C=O), 1600, 1530, 1510, 1425,
1380 s, 1350, 1320, 1290, 1255, 1180, 1115, 1060,
1-(4-Bromobenzyl)-3-phenyl-4,5-dihydro-1H-
pyrazole (Va) and 1-(4-bromobenzyl)-5-phenyl-4,5-
dihydro-1H-pyrazole (VIa). Isomer ratio Va/VIa
1
48:52. Compound Va: H NMR spectrum, δ, ppm:
1
1040. H NMR spectrum, δ, ppm: 2.18 m (1H, CH2),
2.95–3.04 m (2H, CH2), 3.05–3.15 m (2H, CH2), 4.29 s
(2H, CH2), 7.16 d (2H, Harom, J = 8.3 Hz), 7.27–7.50
(5H, Harom), 7.65 m (2H, Harom, J = 8.3 Hz). Compound
2.77 m (1H, CH2), 2.90 m (1H, CH2), 3.46 m (1H,
CH2), 5.28 m (1H, CHPh), 5.84 s (1H, CH), 7.05–
7.13 m (1H, Harom), 7.18–7.39 m (9H, Harom), 7.44–
7.54 m (4H, Harom). 13C NMR spectrum, δ, ppm: 36.0
(CH2), 54.4 (CH2), 59.8 (CH), 78.3 (CH), 119.7 (2C,
CHarom), 123.0 (Carom), 124.4 (CHarom), 125.9 (2C,
CHarom), 127.1 (CHarom), 128.6 (4C, CHarom), 129.3
(2C, CHarom), 132.2 (2C, CHarom), 137.1 (Carom), 137.9
(Carom), 143.1 (Carom), 161.1 (C=O). Found, %:
C 63.39; H 5.00; N 9.51. C23H20BrN3O. Calculated, %:
C 63.60; H 4.64; N 9.67.
1
VIa: H NMR spectrum, δ, ppm: 2.67 m (1H, CH2),
2.95–3.08 m (1H, CH2), 3.79 d (1H, CH2, J = 14.0 Hz),
4.04 d.d (1H, CH2, J = 14.6, 10.1 Hz), 4.23 d
(1H, CH2, J = 14.0 Hz), 6.76 s (1H, CH), 7.27–7.50
(9H, Harom).
1-(4-Bromobenzyl)-3,5,5-trimethyl-4,5-dihydro-
1
1H-pyrazole (Vb). H NMR spectrum, δ, ppm: 1.19 s
(6H, Me), 1.91 s (3H, Me), 2.47 s (2H, CH2), 3.90 s
(2H, CH2), 7.30 d (2H, Harom, J = 8.3 Hz), 7.43 d (2H,
1
Compound VIIIa. Yield 3 mg (0.8%). H NMR
Harom, J = 8.3 Hz).
spectrum, δ, ppm: 2.10 m (1H, CH2), 2.35 m (1H,
CH2), 2.69 m (2H, CH2), 5.24 m (1H, CHPh), 6.37 s
(1H), 7.08–7.51 m (14H, Harom).
1-(4-Methoxybenzyl)-3,5,5-trimethyl-4,5-dihy-
1
dro-1H-pyrazole (Vc). H NMR spectrum, δ, ppm:
1.21 s (6H, Me), 1.94 s (3H, Me), 2.48 s (2H, CH2),
Compound IXa. Yield 30 mg (8%), mp 142–143°C.
IR spectrum, ν, cm–1: 3060 s, 3040 s, 2900, 1715 s
(C=O), 1600, 1530, 1510, 1470, 1425, 1380 s, 1325,
3.80 s (3H, OMe), 3.95 s (2H, CH2), 6.88 d (2H, Harom
,
J = 8.7 Hz), 7.37 d (2H, Harom, J = 8.7 Hz).
1
Thermolysis of diazabicyclohexanes Ia and Ib in
the presence of dipolarophiles. An equivalent amount
of the corresponding dipolarophile was added to a so-
lution of diazabicyclohexane Ia or Ib in 2–3 ml of p-
or o-xylene, and the mixture was heated under stirring
at a bath temperature of 140–145°C over a period of
25 min. The mixture was cooled, and the solvent was
distilled off under reduced pressure.
1295, 1260, 1160, 1100, 1060, 1040. H NMR spec-
trum, δ, ppm: 2.17 m (1H, CH2), 2.55 m (1H, CH2),
3.46 m (1H, CH2, J = 3.1 Hz), 3.75 d.d (1H, CHPh, J =
7.1, 10.7 Hz), 4.06 m (1H, CH2), 5.62 s (1H, CH),
7.02–7.11 m (3H, Harom), 7.30 d (2H, Harom, J =
7.6 Hz), 7.40–7.49 m (9H, Harom). 13C NMR spectrum,
δC, ppm: 36.2 (CH2), 44.8 (CH2), 67.9 (CH), 75.6
(CH), 118.7 (2C, CHarom), 123.0 (Carom), 124.0
(CHarom), 128.2 (2C, CHarom), 128.3 (2C, CHarom),
128.7 (CHarom), 129.2 (2C, CHarom), 129.3 (2C,
CHarom), 132.1 (2C, CHarom), 136.5 (Carom), 137.9
(Carom), 138.2 (Carom), 161.6 (C=O). Found, %:
C 63.41; H 4.62; N 9.48. C23H20BrN3O. Calculated, %:
C 63.60; H 4.64; N 9.67.
rel-(3R,7S)-3-(4-Bromophenyl)-2,7-diphenylper-
hydropyrazolo[1,2-a][1,2,4]triazol-1-one (VIIa), rel-
(3R,7R)-3-(4-bromophenyl)-2,7-diphenylperhydro-
pyrazolo[1,2-a][1,2,4]triazol-1-one (VIIIa), rel-
(3R,5R)-3-(4-bromophenyl)-2,5-diphenylperhydro-
pyrazolo[1,2-a][1,2,4]triazol-1-one (IXa), and rel-
(3R,5S)-3-(4-bromophenyl)-2,5-diphenylperhydro-
pyrazolo[1,2-a][1,2,4]triazol-1-one (Xa) were ob-
Compound Xa. Yield 50 mg (13%), mp 121–
122°C. IR spectrum, ν, cm–1: 3090, 3045 s, 2980,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

GENERATION OF AZOMETHINE IMINES
431
2960, 1710 s (C=O), 1600, 1530, 1520, 1430, 1400 s,
1255, 1180, 1110, 1080, 1060, 1040. H NMR spec-
2870, 1705 s (C=O), 1600, 1535, 1510, 1420, 1395 s,
1365, 1300, 1280, 1260, 1240, 1200, 1110, 1080,
1020. 1H NMR spectrum, δ, ppm: 1.26 d (3H, Me, J =
5.9 Hz), 1.40 s (3H, Me), 1.71 s (3H, Me), 1.75 d.d
(1H, CH2, J = 10.0, 12.1 Hz), 2.13 d.d (1H, CH2, J =
7.0, 12.1 Hz), 3.10 d.d.q (2H, CHMe, J = 5.9, 7.0,
10.0 Hz), 5.62 s (1H, ArCH), 7.02 m (1H, Harom),
7.20–7.29 m (4H, Harom), 7.37 d (2H, Harom, J =
8.1 Hz), 7.44 d (2H, Harom, J = 8.4 Hz). 13C NMR spec-
trum, δC, ppm: 17.5 (CH3), 25.7 (CH3), 31.3 (CH3),
50.7 (CH2), 60.2 (CHMe), 61.6 (CMe2), 76.3 (CHAr),
120.0 (2C, CHarom), 122.8 (Carom), 123.8 (CHarom),
128.6 (2C, CHarom), 129.1 (2C, CHarom), 132.0 (2C,
CHarom), 137.9 (Carom), 138.3 (Carom), 157.1 (C=O).
Found, %: C 59.64; H 5.45; N 10.40. C20H22BrN3O.
Calculated, %: C 60.01; H 5.54; N 10.50.
1
trum, δ, ppm: 2.13 m (1H, CH2), 2.56 m (1H, CH2),
3.67 m (1H, CH2), 3.94 d.d (1H, CHPh, J = 7.1,
10.7 Hz), 6.17 s (1H, CH), 6.75–7.33 m (14H, Harom).
13C NMR spectrum, δC, ppm: 36.6 br.s (CH2), 44.5
(CH2), 63.3 br.s (CH), 75.0 (CH), 121.1 (2C, CHarom),
123.3 (Carom), 124.6 (CHarom), 127.0 (CHarom), 127.5
(2C, CHarom), 128.1 (2C, CHarom), 128.9 (2C, CHarom),
129.8 (2C, CHarom), 132.4 (2C, CHarom), 136.1 br.s
(Carom), 137.4 (Carom), 139.6 (Carom), 162.3 (C=O).
Found, %: C 63.62; H 4.74; N 9.55. C23H20BrN3O.
Calculated, %: C 63.60; H 4.64; N 9.67.
rel-(3R,7R)-3-(4-Bromophenyl)-5,5,7-trimethyl-
2-phenylperhydropyrazolo[1,2-a][1,2,4]triazol-1-
one (VIIb), rel-(3R,5S)-3-(4-bromophenyl)-5,7,7-tri-
methyl-2-phenylperhydropyrazolo[1,2-a][1,2,4]tri-
azol-1-one (IXb), and rel-(3R,5R)-3-(4-bromophen-
yl)-5,7,7-trimethyl-2-phenylperhydropyrazolo-
[1,2-a][1,2,4]triazol-1-one (Xb) were obtained from
267 mg (0.95 mmol) of diazabicyclohexane Ib and
114 mg (0.95 mmol) of phenyl isocyanate. The product
mixture was separated by column chromatography
(Silicagel L, 35–70 μm, substrate–sorbent weight ratio
1:125, hexane–ethyl acetate, 10:1). The separation
process was monitored by TLC (Silufol UV-254,
hexane–ethyl acetate, 5:1, double elution, develop-
ment with iodine vapor). The overall preparative yield
of all isomers was 297 mg (65%). According to the
1H NMR data, the isomer ratio Xb/IXb/VIIb was
~8.6:2.0:1.0.
Compound Xb. Yield 16 mg (4%), purity ~90%.
1H NMR spectrum, δ, ppm: 0.65 d (3H, Me, J =
6.1 Hz), 1.55 s (3H, Me), 1.58 s (3H, Me), 1.73 d.d
(1H, CH2, J = 7.9, 12.3 Hz), 2.14 d.d (1H, CH2, J =
7.4, 12.3 Hz), 3.11 d.d.q (2H, CHMe, J = 6.1, 7.4,
7.9 Hz), 6.04 s (1H, ArCH), 7.02 m (1H, Harom), 7.14–
7.35 m (6H, Harom), 7.49 d (2H, Harom, J = 8.4 Hz).
rel-(3aR,5R,9S,9aS)-2,9-Bis(4-bromophenyl)-
5,7,7-trimethylperhydropyrazolo[1,2-a]pyrrolo-
[3,4-c]pyrazole-1,3-dione (XIb), rel-(3aR,7S,9S,9aS)-
2,9-bis(4-bromophenyl)-5,5,7-trimethylperhydro-
pyrazolo[1,2-a]pyrrolo[3,4-c]pyrazole-1,3-dione
(XIIb), and rel-(3aR,7R,9S,9aS)-2,9-bis(4-bromo-
phenyl)-5,5,7-trimethylperhydropyrazolo[1,2-a]pyr-
rolo[3,4-c]pyrazole-1,3-dione (XIIIb) were obtained
from 202 mg (0.72 mmol) of diazabicyclohexane Ib
and 181 mg (0.72 mmol) of N-(4-bromophenyl)male-
imide. The isomer mixture was separated by column
chromatography (Silicagel L, 35–70 μm, substrate–
sorbent weight ratio 1:200, gradient elution with hex-
ane–ethyl acetate, 5:1 and 3:1). The separation proc-
ess was monitored by TLC (Silufol UV-254, hexane–
ethyl acetate, 3:1, development with iodine vapor).
The isomer ratio XIb/XIIb/XIIIb in the reaction mix-
ture was ~2.45:1.0:0.9 (1H NMR data).
Compound VIIb. Yield 139 mg (37%), mp 147–
148°C. IR spectrum, ν, cm–1: 3080 s, 2980 s, 2945,
2880, 1705 s (C=O), 1600, 1535, 1500, 1410, 1385 s,
1365, 1260, 1240, 1220, 1180, 1110, 1060, 1030.
1H NMR spectrum, δ, ppm: 0.98 s (3H, Me), 1.31 d
(3H, Me, J = 6.4 Hz), 1.36 s (3H, Me), 1.68 m (1H,
CH2), 2.18 d.d (1H, CH2, J = 7.7, 12.1 Hz), 4.22 m
(1H, CHMe, J = 6.4, 7.7 Hz), 5.61 s (1H, CHAr),
7.04 m (1H, Harom), 7.22–7.31 m (4H, Harom), 7.43–
7.51 m (4H, Harom). 13C NMR spectrum (CDCl3), δC,
ppm: 19.4 (CH3), 22.5 (CH3), 25.1 (CH3), 48.6 (CH2),
52.2 (CHMe), 64.3 (CMe2), 73.3 (CHAr), 118.7 (2C,
CHarom), 122.7 (Carom), 123.7 (CHarom), 128.3 (2C,
CHarom), 129.2 (2C, CHarom), 132.2 (2C, CHarom), 137.7
(Carom), 138.2 (Carom), 161.4 (C=O). Found, %:
C 59.71; H 5.29; N 10.26. C20H22BrN3O. Calculated,
%: C 60.01; H 5.54; N 10.50.
Compound XIb. Yield 70 mg (25%), mp 205–
206°C (decomp.). IR spectrum, ν, cm–1: 3030, 2970,
2880, 1800, 1720 v.s (C=O), 1600, 1495 s, 1380 s,
1300, 1250, 1230, 1190 s, 1160, 1120, 1070, 1020.
1H NMR spectrum, δ, ppm: 0.85 s (3H, Me), 1.35 d
(3H, Me, J = 6.2 Hz), 1.38 s (3H, Me), 1.69 d.d (1H,
CH2, J = 6.9, 12.7 Hz), 2.27 d.d (1H, CH2, J = 9.7,
12.7 Hz), 3.20 d.d.q (1H, CHMe, J = 6.2, 6.9, 9.7 Hz),
3.85 d.d (1H, CH, J = 7.5, 9.9 Hz), 4.25 d (1H, CH, J =
Compound IXb. Yield 20 mg (5%), mp 138–
139°C. IR spectrum, ν, cm–1: 3080 s, 2980 s, 2940,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

KOPTELOV et al.
432
8. Molchanov, A.P., Sipkin, D.I., Koptelov, Yu.B., Kopf, J.,
and Kostikov, R.R., Russ. J. Org. Chem., 2003, vol. 39,
p. 1338.
9. Molchanov, A.P., Sipkin, D.I., Koptelov, Yu.B., Kopf, J.,
and Kostikov, R.R., Russ. J. Org. Chem., 2004, vol. 40,
p. 67.
7.5 Hz), 4.63 d (1H, CHAr, J = 9.9 Hz), 7.02 d (2H,
Harom, J = 8.5 Hz), 7.31 d (2H, Harom, J = 8.2 Hz),
7.45 d (2H, Harom, J = 8.2 Hz), 7.54 d (2H, Harom, J =
8.5 Hz). 13C NMR spectrum, δC, ppm: 20.4 (CH3), 26.5
(CH3), 32.7 (CH3), 47.2 (CH2), 52.5 (CH), 59.4 (CH),
63.5 (C), 65.4 (CH), 66.4 (CH), 122.0 (Carom), 122.3
(Carom), 127.6 (2C, CHarom), 129.4 (2C, CHarom), 130.7
(Carom), 131.8 (2C, CHarom), 132.3 (2C, CHarom), 138.1
(Carom), 172.9 (C=O), 174.4 (C=O). Found, %:
C 51.66; H 4.41; N 7.58. C23H23Br2N3O2. Calculated,
%: C 51.80; H 4.35; N 7.88.
10. Gnichtel, H. and Köhler, C., Justus Liebigs Ann. Chem.,
1990, p. 775.
11. Gomtsyan, A., Koenig, R.J., and Lee, C.-H., J. Org.
Chem., 2001, vol. 66, p. 3613.
12. Turk, C., Svete, J., Stanovnik, B., Golič, L., Golič-
Grdadolnič, S., Golobič, A., and Selič, L., Helv. Chim.
Acta, 2001, vol. 84, p. 146.
Compound XIIb. Yield 15 mg (4%), purity ~85%.
1H NMR spectrum, δ, ppm: 1.21 d (3H, Me), 1.49 s
(3H, Me), 1.52 s (3H, Me), 1.67 d.d (1H, CH2, J = 6.4,
12.8 Hz), 2.20 d.d (1H, CH2, J = 9.6, 12.8 Hz),
3.00 d.d.q (1H, CHMe, J = 6.2, 6.4, 9.6 Hz), 4.13 d.d
(1H, CH, J = 9.0, 9.2 Hz), 4.37 d (1H, CH, J = 9.0 Hz),
4.62 d (1H, CHAr, J = 9.2 Hz), 6.66 d (2H, Harom, J =
7.3 Hz), 7.31 d (2H, Harom, J = 7.3 Hz), 7.43 d (2H,
Harom, J = 8.3 Hz), 7.49 d (2H, Harom, J = 8.3 Hz).
13. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuse-
ria, G.E., Robb, M.A., Cheeseman, J.R., Montgo-
mery, J.A., Vreven, T., Jr., Kudin, K.N., Burant, J.C.,
Millam, J.M., Iyengar, S.S., Tomasi, J., Barone, V.,
Mennucci, B., Cossi, M., Scalmani, G., Rega, N.,
Petersson, G.A., Nakatsuji, H., Hada, M., Ehara, M.,
Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Naka-
jima, T., Honda, Y., Kitao, O., Nakai, H., Klene, M.,
Li, X., Knox, J.E., Hratchian, H.P., Cross, J.B.,
Adamo, C., Jaramillo, J., Gomperts, R., Strat-
mann, R.E., Yazyev, O., Austin, A.J., Cammi, R.,
Pomelli, C., Ochterski, J.W., Ayala, P.Y., Morokuma, K.,
Voth, G.A., Salvador, P., Dannenberg, J.J., Zakrzew-
ski, V.G., Dapprich, S., Daniels, A.D., Strain, M.C.,
Farkas, O., Malick, D.K., Rabuck, A.D., Raghava-
chari, K., Foresman, J.B., Ortiz, J.V., Cui, Q., Ba-
boul, A.G., Clifford, S., Cioslowski, J., Stefanov, B.B.,
Liu, G., Liashenko, A., Piskorz, P., Komaromi, I.,
Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A.,
Peng, C.Y., Nanayakkara, A., Challacombe, M.,
Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W.,
Gonzalez, C., and Pople, J.A., GAUSSIAN-03, Pitts-
burgh PA: Gaussian, 2003.
1
Compound XIIIb. Some signals in the H NMR
spectrum of the reaction mixture, δ, ppm: 0.65 d (3H,
Me, J = 6.2 Hz), 4.20 d (1H, CH, J = 5.0 Hz).
REFERENCES
1. Grashey, R., 1,3-Dipolar Cycloaddition Chemistry,
Padwa, A., Ed., New York: Wiley, 1984, chap. 1, p. 733;
Rodina, L.L., Kolberg, A., and Schulze, B., Heterocycles,
1998, vol. 49, p. 587.
2. Koptelov, Yu.B., Kim, M.Kh., Molchanov, A.P., and Kos-
tikov, R.R., Russ. J. Org. Chem., 1999, vol. 35, p. 110.
3. Trofimov, V.V., Koptelov, Yu.B., Molchanov, A.P., and
Kostikov, R.R., Zh. Org. Khim., 1994, vol. 30, p. 1389.
4. Molchanov, A.P., Sipkin, D.I., Koptelov, Yu.B., and Kos-
14. Gottlieb, H.E., Kotlyar, V., and Nudelman, A., J. Org.
Chem., 1997, vol. 62, p. 7512.
15. Kanhaiya, S.R., Blanton, C., and De Witt, S., J. Org.
Chem., 1982, vol. 47, p. 502.
tikov, R.R., Russ. J. Org. Chem., 2001, vol. 37, p. 841.
5. Schulz, M. and West, G., J. Prakt. Chem., 1970, vol. 312,
p. 161; Geissler, G., Menz, I., Angermüller, K., and
Tomaschewski, G., J. Prakt. Chem., 1983, vol. 325,
p. 197; Geissler, G., Fust, W., Krüger, B., and Toma-
schewski, G., J. Prakt. Chem., 1983, vol. 325, p. 205.
16. Karyakin, Yu.V., Chistye khimicheskie reaktivy (Pure
Chemicals), Moscow: Goskhimizdat, 1947, p. 408.
17. Ioffe, B.V. and Burmanova, N.B., Khim. Geterotsikl.
Soedin., 1971, p. 1225.
6. Koptelov, Yu.B. and Saik, S.P., Russ. J. Org. Chem.,
2006, vol. 42, p. 1501.
18. Curtius, Th. and Wirsing, F., J. Prakt. Chem., 1894,
vol. 50, p. 531.
19. Denmark, S.E. and Kim, S.H., Synthesis, 1992, p. 229.
7. Kost, A.N., Golubeva, G.A., and Terent’ev, A.P., Dokl.
Akad. Nauk SSSR, 1959, vol. 129, p. 1300.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011