Generation and metathesis of azomethine imines in reaction of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with het(aryl)methylidenemalononitriles

Article abstract of DOI:10.1007/s11172-013-0143-9

A new metathesis reaction of azomethine imines is found. Catalytic or thermal diaziridine ring opening of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes leads to azomethine imines reacting further with het(aryl)methylidenemalononitriles to give in situ new azomethine imines inaccessible by common synthetic methods. New azomethine imines are detected as pyrazolines formed via a 1,4-H shift and trapped by the [3+2] cycloaddition with various dipolarophiles to yield 1,5-diazabicyclo[3.3.0]octane derivatives bearing pharmacophoric heterocycles, e.g. furan, nitrofuran, thiophene, and indole. The best results are achieved in the Et₂O·BF₃-catalyzed reactions in ionic liquids.

Full text of DOI:10.1007/s11172-013-0143-9

Russian Chemical Bulletin, International Edition, Vol. 62, No. 4, pp. 1066—1075, April, 2013
1066
Generation and metathesis of azomethine imines
in reaction of 6ꢀarylꢀ1,5ꢀdiazabicyclo[3.1.0]hexanes
with het(aryl)methylidenemalononitriles*,**
M. I. Pleshchev,a V. Yu. Petukhova,a† V. V. Kuznetsov,a D. V. Khakimov,a T. S. Pivina,a
Yu. V. Nelyubina,b and N. N. Makhovaa
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: mnn@ioc.ac.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: unelya@xrlab.ineos.ac.ru
A new metathesis reaction of azomethine imines is found. Catalytic or thermal diaziridine
ring opening of 6ꢀarylꢀ1,5ꢀdiazabicyclo[3.1.0]hexanes leads to azomethine imines reacting
further with het(aryl)methylidenemalononitriles to give in situ new azomethine imines inaccesꢀ
sible by common synthetic methods. New azomethine imines are detected as pyrazolines formed
via a 1,4ꢀH shift and trapped by the [3+2] cycloaddition with various dipolarophiles to yield
1,5ꢀdiazabicyclo[3.3.0]octane derivatives bearing pharmacophoric heterocycles, e.g. furan,
nitrofuran, thiophene, and indole. The best results are achieved in the Et2O•BF3ꢀcatalyzed
reactions in ionic liquids.
Key words: diaziridines, 6ꢀarylꢀ1,5ꢀdiazabicyclo[3.1.0]hexanes, het(aryl)methylideneꢀ
malononitriles, azomethine imines, [3+2] cycloaddition, metathesis, cycloreversion, 1,5ꢀdiꢀ
azabicyclo[3.3.0]octanes, pyrazolines, ionic liquids, boron trifluoride diethyl etherate, catalysis.
One of the key scientific interests of our research group
is the development of synthetic methods towards diaziriꢀ
dine derivatives and the study of their reactivity. We elabꢀ
orated simple and efficient synthetic procedures for both
monoꢀ and bicyclic compounds of this type2 and develꢀ
oped methods for their transformation into other nitrogen
heterocycles (by ring expansion reaction) serving for conꢀ
venient synthesis of the complex heterocyclic ring sysꢀ
tems.3 These reactions can occur due to susceptibility of
the strained diaziridines to ring opening on treatment with
electrophilic reagents providing dipolar species, which can
further undergo cycloaddition reactions with dipolaroꢀ
philes. Thus, a method for the in situ generation of azomeꢀ
thine imines 1 was developed, which involved the opening
of the diaziridine ring at 6ꢀarylꢀ1,5ꢀdiazabicyclo[3.1.0]ꢀ
hexanes 2 in ionic liquids (IL) in the presence of a catalytꢀ
ic amounts of BF3•Et2O.4—9 The reactions of azomethine
imines 1 with various dipolarophiles (CS2, ꢀnitrostyrenes,
chalcone, and activated nitriles) yielded fused heterocyclic
systems with pyrazolidine ring annulated to either 1,3,4ꢀthiꢀ
azolidineꢀ2ꢀthione, pyrazolidine, pyrazole or 1,2,4ꢀtriazolꢀ
ine ring (Scheme 1). The synthesized compounds are
of practical importance, since among these substances
ꢀlactam antibiotics and other antibacterial agents,10,11
tumor necrosis factorꢀ (TNFꢀ) inhibitors,12 herbicides,
fungicides,13,14 and highly conductive organic plastic crysꢀ
tals15 were found. These results are summarized in the
works.16,17
With the aim to synthesize derivatives containing fused
pyrazolidine and 1,3,4ꢀoxadiazolidine rings, we studied
the reaction of azomethine imines 1 with isatins 3.18 Howꢀ
ever, instead of the expected fused heterocycles 4, a mixꢀ
ture of 1ꢀsubstituted pyrazolines 5 and the corresponding
pyrazoles 6 was obtained; moreover, in all cases, aromatic
aldehydes used for the synthesis of the starting bicyclic
diaziridines 2 were isolated in high yields. Apparently, the
expected compounds 4 were initially formed, but under
the reaction conditions they underwent the 1,3,4ꢀoxadiꢀ
azolidine ring opening with the liberation of the aromatic
aldehyde and formation of the new azomethine imines 7.
A 1,4ꢀH shift in compounds 7 resulted in pyrazolines 5,
which were subsequently oxidized to pyrazoles 6 by atmoꢀ
spheric oxygen. The transformation of azomethine imines 1
* Dedicated to Academician of the Russian Academy of Sciences
I. P. Beletskaya on the occasion of her anniversary.
**For short communication on this subject, see Ref. 1.
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 1065—1074, April, 2013.
1066ꢀ5285/13/6204ꢀ1066 © 2013 Springer Science+Business Media, Inc.

New metathesis reaction of azomethine imines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1067
Scheme 1
formed in the first step of the reaction into new azomeꢀ
thine imines 7 was regarded as azomethine imine metaꢀ
thesis. A suggested mechanism was confirmed by trapping
one of azomethine imines 7 via [3+2] cycloaddition
with diethyl acetylenedicarboxylate (DEAD) to yield comꢀ
pound 8 (Scheme 2). Unfortunately, azomethine imines 1
did not react with other carbonyl compounds (aromatic
and heteroaromatic aldehydes, benzophenone, and hexaꢀ
fluoroacetone) with the exception of 4ꢀnitrobenzaldehyde
leading to the corresponding pyrazolines in low yields.
Since pyrazoline derivatives exhibit a wide range of
biological activity (antibacterial, antiꢀinflammatory, anꢀ
tidepressant, and monoamino oxidase inhibition),19 in the
present work, we continued our studies on the synthesis of
pyrazolines bearing various aromatic and heterocyclic
substituents by metathesis of azomethine imines 1 in the
reaction with dipolarophiles. Activated derivatives of
carbonyl compounds, namely, arylꢀ and hetarylmethꢀ
ylidenemalononitriles 9, were chosen as potential diꢀ
polarophiles.
withdrawing 4ꢀNO2 substituent in the aromatic ring (9a,b
were synthesized by the condensation of 4ꢀnitrobenzaldeꢀ
hyde with malonodinitrile or ethyl cyanoacetate accordꢀ
ing to the known procedures20). To find the optimal conꢀ
ditions for this reaction, we used the following methods
for the generation of azomethine imines 1a,b from biꢀ
cyclic diaziridines 2a,b: IL 1ꢀbutylꢀ3ꢀmethylimidazolium
tetrafluoroborate ([bmim][BF4]), BF3•Et2O (20 mol.%),
40 C (method A); MeCN, BF3•Et2O (20 mol.%), 40 C
(method B); toluene, reflux (method C); oꢀxylene, reflux
(method D). Methods C and D were described earlier.21
Indeed, the use of arylmethylidenemalononitriles 9a,b as
the reagents for azomethine imine metathesis was proved
to be efficient. In all cases, irrespective of the method of
generation of azomethine imines 1a,b, pyrazoline 10a was
isolated, however, the highest yield was achieved with
method A (Table 1, entries 1—4) regardless of the subꢀ
stituent in the starting bicyclic diaziridine. Along with
pyrazoline 10a, arylmethylidenemalononitriles 11a—c
(11b was a mixture of Eꢀ and Zꢀisomers) containing the
aromatic fragments of the starting bicyclic diaziridines
2a,b were isolated in high yields (Scheme 3). Compounds
10a and 11a—c were separated by silica gel column
chromatography.
We started our study from the reaction between 6ꢀarylꢀ
1,5ꢀdiazabicyclo[3.1.0]hexanes 2a,b bearing electronꢀdoꢀ
nating 4ꢀMeO and 4ꢀMe substituents in the aromatic ring
and arylmethylidenemalononitriles 9a,b with an electronꢀ

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Makhova et al.
Scheme 2
1,4ꢀH shift
Ar = 4ꢀMeOC6H4, 4ꢀEtOC6H4, 4ꢀMeC6H4
3, 5—7: R = H (a), Me (b), Pri (c)
[bmim][BF4] is the 1ꢀbutylꢀ3ꢀmethylimidazolium tetrafluoroborate
Scheme 3
Obviously, in this reaction, pyrazoline 10a is formed
following the mechanism similar to that of pyrazoline forꢀ
mation in the reaction of bicyclic diaziridines 2 with isatꢀ
ins 3 (see Scheme 2). The starting diaziridines 2a,b initialꢀ
ly undergo the diaziridine ring opening to generate azomeꢀ
thine imines 1a,b. Then, the [3+2] cycloaddition (with
Table 1. Reaction of 6ꢀarylꢀ1,5ꢀdiazabicyclo[3.1.0]hexane 2a
with het(aryl)methylidenemalononitriles 9
Entry
Comꢀ
pound 9
Method
t/h
Pyrazoline
Yield
(%)
10
1
2
3
4
5
6
7
8
a
a
a
a
b
a
c
d
d
e
e
f
A
B
C
D
B
A*
C
A
C
B
C
C
D
A—D
A—D
1
2
10a
10a
10a
10a
10a
10a
10b
10c
10c
10d
10d
10e
10f
84
60
25
56
60
63
30
30
20
60
60
60
32
0
0.5
10 min
0.5
3
1
6
2
2
Reagents and conditions: [bmim][BF4], BF3•Et2O (20 mol.%),
40 C, (method A); MeCN, BF3•Et2O (20 mol.%), 40 C (methꢀ
od B); toluene, reflux (method C); oꢀxylene, reflux (method D).
9
10
11
12
13
14
15
1, 2: Ar = 4ꢀMeOC6H4 (a), 4ꢀMeC6H4 (b)
9: X = CN (a), CO2Et (b)
11: Ar = 4ꢀMeOC6H4 (a, b), 4ꢀMeC6H4 (c); X = CN (a, c), CO2Et (b)
2
0.2
0.2
—
g
h
i
10g
10h
—
0
the Michaelꢀtype regioselectivity) of compounds 1a,b with
arylmethylidenemalononitriles 9a,b via intermediates
12a,b produces new bicyclic compounds 13a,b. Under the
* In the reaction, 6ꢀ(4ꢀmethylphenyl)ꢀ1,5ꢀdiazabicyclo[3.1.0]ꢀ
hexane (2b) was used.

New metathesis reaction of azomethine imines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1069
Scheme 4
1,4ꢀH shift
1, 11, 12, 12ґ, 13: Ar = 4ꢀMeOC6H4 (a), 4ꢀMeC6H4 (b)
9: R = 4ꢀO2NC6H4 (a, b), X = CN (a), COOEt (b)
10a, 14a: R = 4ꢀO2NC6H4
reaction conditions, compounds 13a,b decompose via inꢀ
termediates 12´a,b to give new azomethine imines 14a,b
(metathesis) and arylmethylidenemalononitriles 11a—c,
whereas azomethine imine 14a gives pyrazoline 10a through
a 1,4ꢀH shift (Scheme 4).
intermediate bicycle 13a (the bond orders are 0.893 and
0.879, respectively), thereby breaking of these bonds is
facilitated. Note that the bond b breaks first to produce
a new dipolar intermediate 12a giving via the retroꢀMichael
This mechanism (see Scheme 4) was confirmed by the
quantum chemical calculations, which were carried out
on the example of the reaction of azomethine imine 1a
with arylmethylidenemalononitrile 9a. According to calꢀ
culations, the metathesis of azomethine imines 1  14 via
the 1,3ꢀdipolar cycloreversion is thermodynamically faꢀ
vorable. The energy difference between the starting and
the final pairs 1,3ꢀdipole—arylmethylidenemalononitrile
1a + 9a and 14a + 11a is 9.47 kcal mol–1 (Fig. 1). Figure 2
shows the geometry of two transition states (TS1 and TS2)
of the cycloreversion reaction. The first transition state
(TS1) corresponds to the step of the negative pole addiꢀ
tion of the starting dipole 1a to arylmethylidenemalonoꢀ
nitrile 9a via the Michaelꢀtype reaction to give intermediꢀ
ate 12a. Subsequent ring closure of intermediate 12a yields
compound 13a. The calculations show a weakening of the
bonds a and b adjacent to the C(CN)2 fragment in the
TS1 (1a + 9a)
C
N
O
TS2 (14a + 11a)
Fig. 1. Energy profile of the reaction of azomethine imine 1a
and arylmethylidenemalononitrile 9a. Energies (kcal mol–1
)
Fig. 2. Geometry of the transition states according to the calcuꢀ
were calculated on the B3LYP6ꢀ31G(d) level of theory.
lations on the HF/STOꢀ3G level of theory.

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Makhova et al.
reaction (transition state TS2) a new pair azomethine
imine 14a—arylmethylidenemalononitrile 11a, which is
thermodynamically more favorable due to the donating
effect of the 4ꢀMeO substituent at the aromatic fragment.
The process observed22 is referred to as a cycloaddiꢀ
tion—cycloreversion cascade (Scheme 5). The cycloꢀ
reversion of 1,3ꢀdipoles (nitrones, azomethine ylides,
nitrile oxides, and carbonyl ylides) is a rather common
phenomenon.23
pounds 9, therefore, other methods were also used. Table
1 summarizes the best experimental results.
Scheme 6
Scheme 5
However, similar transformations of azomethine imines
are relatively rare. Thus, the work24 described a 1,3ꢀcycloꢀ
reversion of substituted 1,5ꢀdiazabicyclo[3.3.0]octanes to
other 1,5ꢀdiazabicyclo[3.3.0]octanes in the reaction of the
former with the substituted olefins on heating. Later,25
a 1,3ꢀcycloreversion of 1,3,4ꢀoxadiazolidines was reported;
on heating, these compounds underwent the ring opening
to form the starting carbonyl compound and azomethine
imine, which were chemically trapped. In both cases, the
cycloreversion gave the same azomethine imine, which
was used to obtain the first cycloaddition product. On the
contrary, the reactions we found represent the azomethine
imine metathesis, upon which the starting azomethine
imine reacts with dipolarophiles (isatins and arylmethylꢀ
idenemalononitriles) to generate a new azomethine imine
providing pyrazolines 5 and 10 via a subsequent 1,4ꢀH shift.
To introduce other aromatic and heterocyclic substiꢀ
tuents into the pyrazoline ring and to prepare compounds,
which synthesis by the reactions with carbonyl compounds
failed, we studied the reaction of 6ꢀ(4ꢀmethoxyphenyl)ꢀ
1,5ꢀdiazabicyclo[3.1.0]hexane (2a) with het(aryl)methylꢀ
idenemalononitriles 9c—j obtained by condensation of
malonodinitrile with the corresponding aldehydes and isꢀ
atins (Schemes 6 and 7). The studies were carried out on
the example of 6ꢀ(4ꢀmethoxyphenyl)ꢀ1,5ꢀdiazabicycloꢀ
[3.1.0]hexane (2a), since the yields of pyrazoline 10a and
arylidenemalononitriles 11a—c did not depend on the
structure of the starting bicyclic diaziridine. We did not
succeed in the synthesis of all target pyrazolines, only comꢀ
pounds 10b—f were obtained in the yields from moderate
to good (see Scheme 6 and Table 1, entries 5—13). The
reaction of bicyclic diaziridine 2a with compounds 9h,i
results exclusively in arylmethylidenemalononitrile 11a in
high isolated yields (80—85%) (entries 14—15). The optiꢀ
mal conditions (method A) found earlier for the reaction
of bicyclic diaziridines 2a,b with arylmethylidenemalonoꢀ
nitriles 9a,b were turned to be not the best for all comꢀ
Compound
9c, 10b
9d, 10c
9e, 10d
9f, 10e
R
Ph
Compound
9g, 10f
9h, 10g
9i, 10h
R
2ꢀnitroꢀ5ꢀfuryl
2ꢀfuryl
2ꢀthienyl
3ꢀO2NC6H4
2ꢀO2NC6H4
4ꢀBrC6H4
Scheme 7
R = H (9j, 7a, 15a), Pri (9k, 7c, 15b)
Conditions: methods A—C for 9j, method D for 9k.
Instead of the expected pyrazolines 5a,c, the reaction
of 2a with 2ꢀoxoindolinꢀ3ꢀylidenemalononitriles 9j,k synꢀ
thesized from isatins and malonodinitrile according to the
known procedure26 surprisingly affords imines 15a,b along

New metathesis reaction of azomethine imines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1071
Scheme 8
R = 4ꢀO2NC6H4 (16a, 17a), 2ꢀfuryl (16b, 17b), 2ꢀthienyl (16c)
with arylmethylidenemalononitrile 11a regardless of the
method used for generation of azomethine imine 1a
(Scheme 7). It can be assumed that in this reaction, the
corresponding azomethine imines 7a,c are also formed,
however, they are hydrolyzed to imines 15 during silica gel
chromatography.
The high yields of arylmethylidenemalononitriles 11a—c,
the moderate yields of pyrazolines 10b,c,f, and zero yields
of 10g—k indicate a low thermal stability of some new
azomethine imines 7 and 14. In an effort to trap their
formation from azomethine imines 1 during metathesis
via the dicyanomethylene group transfer, all reactions of
bicyclic diaziridine 2a with het(aryl)methylidenemalonoꢀ
nitriles 9a,h—j were performed in the presence of different
trapping agents (DMAD, CS2, 4ꢀNO2C6H4SO2CH=CH2).
Indeed, the corresponding azomethine imines were deꢀ
tected as new fused heterocycles 16a—d, 17a,b, and
18 isolated in moderate to good yields (Scheme 8,
Table 2).aa
It is worthy to note that direct generation of azomeꢀ
thine imines 14 from bicyclic diaziridines 2 containing
electronꢀwithdrawing heterocyclic substituents at position
6 is impossible, since these diaziridine derivatives either
are unstable or do not exist. Developed by us simple proꢀ
cedure for generation of azomethine imines 14 can be used
for the synthesis of other fused heterocycles similar to
compounds 16—18.
To complete the studies on the azomethine imine meꢀ
tathesis, we attempted to use in this reaction a representaꢀ
tive of carbonyl compounds, namely, 4ꢀBrC6H4CHO, unꢀ
der conditions for the thermal generation of azomethine
imine 1a. In this case, reflux of the mixture of bicyclic
diaziridine 2a and 4ꢀBrC6H4CHO in xylene over 1 h is
required to complete the reaction (TLC monitoring). Inꢀ
deed, pyrazoline 10e is formed but only in low yield, while
pyrazoline 10i is the major reaction product formed
through a 1,4ꢀH shift in the starting azomethine imine 1a
(Scheme 9).
Table 2. Chemical trapping of azomethine imines 7 and 14
Entry
Compound 9
Trap
Reaction conditions
Product
Yield (%)
1
2
3
4
5
6
7
a
h
i
DMAD
DMAD
DMAD
DMAD
CS2
CS2
MeCN, BF3•Et2O, 40 C
Toluene, reflux
16a
16b
16c
16d
17a
17b
18
63
41
30
65
40
30
40
MeCN, BF3•Et2O, 40 C
[bmim][BF4], BF3•Et2O, 20 C
[bmim][BF4], BF3•Et2O, 20 C
[bmim][BF4], BF3•Et2O, 20 C
[emim][OTf]*, BF3•Et2O, 40 C
j
a
h
a
4ꢀO2NC6H4O2SCH=CH2
* [emim][OTf] is the 3ꢀethylꢀ1ꢀmethylimidazolium triflate.

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Makhova et al.
Scheme 9
1,4ꢀH shift
Reagents and conditions: oꢀxylene, reflux, 1 h.
All compounds synthesized are characterized by eleꢀ
mental analysis, NMR spectroscopy using, primarily, the
2D gNOESY, {1H—13C}HSQC, and {1H—15N}HMBC
techniques, and mass spectrometry. The structure of comꢀ
pound 17a is also confirmed by Xꢀray diffraction* (Fig. 3).
The molecular geometry of compound 17a is found to be
similar to that of its analog bearing the Me group instead
of NO2 group.4 Thus, both heterocycles adopt the enveꢀ
lope conformation with C(2) and C(3) atoms deviating
from the plane by 0.65(1) and 0.60 Å, respectively, the
angle between the planes of heterocycles is 10.2(1). The
sums of bond angles for N(1) and N(2) atoms are 360.0(1)
and 324.8(1), respectively, the electron density is partially
delocalized on the N(1)—C(1) bond. There is no conjugaꢀ
tion between the phenyl ring and the nitro group; the corꢀ
responding dihedral angle is equal to 16.7(1). In crystal,
the molecules of 17a form centrosymmetric dimers due to
the S...S interactions, which can be regarded as the charge
transfer from the lone electron pair of one of the sulfur
atoms to the *ꢀorbital of the S(1)—C(1) bond (distance
S...S 3.542(1) Å, angle S—S—C 149.8(1)). These supraꢀ
molecular associates are combined into the 3Dꢀcage owꢀ
ing to the weak interactions of the C—H...O, C—H...S,
and C—H... types.
In summary, replacement of carbonyl compounds with
their activated form, het(aryl)methylidenemalononitriles,
in the reaction with bicyclic diaziridines 2 is very efficient
and allows elaboration of the method for the in situ generꢀ
ation of azomethine imines 14 by a new metathesis reacꢀ
tion of azomethine imines 1 formed by the diaziridine ring
opening of 6ꢀarylꢀ1,5ꢀdiazabicyclo[3.1.0]hexanes. This
method resulted in generation of a wide range of azomeꢀ
thine imines 14 inaccessible by common methods from
the corresponding 6ꢀhet(aryl)ꢀ1,5ꢀdiazabicyclo[3.1.0]hexꢀ
anes, which are low stable or inaccesible. Azomethine
imines 14 resulted from the metathesis were either detectꢀ
ed as pyrazolines formed via the 1,4ꢀH shift or involved in
the [3+2] cycloaddition with different dipolarophiles to
give fused heterocyclic systems, viz., 1,5ꢀdiazabicycloꢀ
[3.3.0]octane derivatives containing various aromatic and
heterocyclic substituents.
Experimental
Elemental analysis was performed on a Perkin—Elmer 2400
instrument. Mass spectra (EI, 70 eV) were recorded on a MAT
INCOSꢀ50 instrument. High resolution mass spectra (ESI) were
recorded on a Bruker micrOTOF II instrument. 1H and 13C NMR
spectra were recorded on Bruker AMꢀ300 (working frequencies
of 300.13 and 75.47 MHz, respectively) and Bruker AVꢀ600
(working frequencies of 600.13 and 150.90 MHz, respectively)
spectrometers in CDCl3, the chemical shifts are given in the
 scale relative to the residual solvent signal (H 7.27 and C 77.0).
The progress of the reaction was monitored by TLC on QF 254
plates (Merck). All new compounds were isolated by preparative
chromatography on silica gel 0.060—0.200 mm, 60 A (ACROS
Organics) (elution with AcOEt—light petroleum). For the isolaꢀ
tion of some products, silica gel was deactivated by triethylamine.
S(2)
S(1)
O(1)
C(1)
C(7)
C(8)
C(2)
N(3)
C(10)
C(6)
N(1)
C(9)
C(11)
N(2)
C(3)
O(2)
C(5)
C(4)
* The structure of compound 17a was first published in Ref. 1.
Fig. 3. General view of molecule 17a.

New metathesis reaction of azomethine imines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1073
Quantum chemical calculations were performed within the
density functional theory (DFT) framework by the Gaussian 98
program.27 The search for the global minimum of compounds
and reaction products was performed by DFT calculations using
the B3LYP hybrid exchangeꢀcorrelation functional with the
6ꢀ31G(d) split valence basis set. The nature of stationary points
was determined using the Hessian matrix by the absence of imagꢀ
inary frequencies. The bond orders were generalized using the
Wiberg bond order indices.28 Transition states were localized by
the Hartree—Fock method with the STOꢀ3G (HF/STOꢀ3G)
basis set.
Synthesis of 4,5ꢀdihydroꢀ1Hꢀpyrazoles 10 and arylmethylideneꢀ
malononitriles 11a—c (general procedure). Methods A and B.
A catalytic amount of BF3·Et2O (20 mol.%) was added to a mixꢀ
ture of 6ꢀarylꢀ1,5ꢀdiazabicyclo[3.1.0]hexane 2a,b (0.5 mmol)
and het(aryl)methylidenemalononitrile 9 (0.5 mmol) in IL
[bmim][BF4] (1.5 mL, method A) or anhydrous MeCN (3 mL,
method B). The reaction mixture was stirred at 40 C until comꢀ
plete consumption of the starting compounds (TLC monitorꢀ
ing). For the reactions in IL, the products were extracted with
a mixture of CH2Cl2—Et2O, 1 : 5 (4×3 mL); MeCN was evapoꢀ
rated in vacuo. Compounds 10 and 11 were isolated by preparaꢀ
tive column chromatography. Characteristics of compounds
11a,b (see Ref. 29) and 11c (see Ref. 30) are in agreement with
published data.
13C NMR (75 MHz, CDCl3), : 143.59 (N=CH); 155.88, 148.34,
112.62, 111.90 (furyl); 52.35 (CH2Ar); 52.24 (NCH2); 34.61
(NCH2CH2). MS (EI, 70 eV), m/z (Irel (%)): 195 [M]+ (28), 149
[M – NO2]+ (37), 83 [M – nitrofuryl]+ (18). Found (%):
C, 49.19; H, 4.60; N, 21.58. C8H9N3O3. Calculated (%): C, 49.23;
H, 4.65; N, 21.53.
Synthesis of 3ꢀ[(3ꢀaminopropyl)imino]indolinꢀ2ꢀones 15.
Method A. To a mixture of 6ꢀarylꢀ1,5ꢀdiazabicyclo[3.1.0]hexane
2a (0.5 mmol) and isatinylidenemalononitriles 9j,k (0.5 mmol)
in IL [bmim][BF4] (1.5 mL), a catalytic amount of BF3•Et2O
(20 mol.%) was added. The reaction mixture was stirred at room
temperature until complete consumption of the starting comꢀ
pounds (TLC monitoring), then extracted with CH2Cl2—Et2O,
1 : 5, (4×3 mL). The solvents were evaporated in vacuo, the products
were purified by preparative column chromatography.
Methods C and D. A stirred mixture of 6ꢀarylꢀ1,5ꢀdiazaꢀ
bicyclo[3.1.0]hexane 2a (0.5 mmol) and isatinylidenemalonoꢀ
nitrile 9j,k (0.5 mmol) was refluxed in toluene (30 min, method C)
or oꢀxylene (5 mL) (10 min, method D). The reaction mixture
was cooled, the solvents were evaporated in vacuo, and the prodꢀ
ucts were purified by preparative column chromatography.
3ꢀ[(3ꢀAminopropyl)imino]indolinꢀ2ꢀone (15a) was syntheꢀ
sized by methods A, C, and D. 1H NMR (300 MHz, CDCl3),
: 8.24 (s, 1 H, NH); 7.98 (d, 1 H, CH in Ar, J = 7.3 Hz);
7.15—7.02 (m, 2 H, CH in Ar); 6.90 (d, 1 H, CH in Ar, J = 7.4 Hz);
4.97 (t, 2 H, CH2NH2, J = 8.1 Hz); 4.31 (t, 2 H, NCH2, J = 7.3 Hz);
2.30—2.20 (m, 2 H, NCH2CH2). 13C NMR (75 MHz, CDCl3),
: 161.95 (C=O); 135.76, 124.95, 120.28, 120.20, 119.86, 108.17
(Ar); 109.03 (N=C); 61.14 (CH2NH2); 59.98 (NCH2); 21.21
(NCH2CH2). MS (ESI), m/z: 202.0976 [M – H]+. Calculated
for C11H13N3O: 202.0975 [M – H]+.
(E)ꢀ3ꢀ[(3ꢀAminopropyl)imino]ꢀ1ꢀisopropylindolinꢀ2ꢀone (15b)
was synthesized by method D. 1H NMR (600 MHz, CDCl3),
: 8.07 (d, 1 H, CH in Ar, J = 7.8 Hz); 7.15 (t, 1 H, H in Ar,
J = 7.8 Hz); 7.06—7.03 (m, 2 H, H in Ar); 4.99 (t, 2 H, CH2NH2,
J = 8.4 Hz); 4.81—4.79 (m, 1 H, CH(CH3)2); 4.29 (t, 2 H,
NCH2, J = 7.2 Hz); 2.27—2.22 (m, 2 H, NCH2CH2); 1.53, 1.52
(both s, 6 H, CH(CH3)2). 13C NMR (150 MHz, CDCl3),
: 161.26 (C=O); 136.10, 125.25, 120.89, 120.84, 120.10, 108.52
(Ar); 110.13 (N=C); 61.13 (CH2NH2); 60.25 (NCH2); 43.17
(CH(CH3)2); 21.76 (NCH2CH2); 20.06 (CH(CH3)2). MS (EI,
70 eV), m/z (Irel (%)): 244 [M – H]+ (27), 243 [M – 2 H]+ (100),
200 [M – 2 H – Pri]+ (11), 173 (19). Found (%): C, 68.56;
H, 7.78; N, 17.16. C14H19N3O. Calculated (%): C, 68.54; H, 7.81;
N, 17.13.
Methods C and D. A stirred mixture of 6ꢀarylꢀ1,5ꢀdiazaꢀ
bicyclo[3.1.0]hexane 2a,b (0.5 mmol) and het(aryl)methylideneꢀ
malononitrile 9 (0.5 mmol) was refluxed in toluene (5 mL)
(0.5—2 h, method C) or oꢀxylene (5 mL) (10 min, method D).
The reaction mixture was cooled, the solvents were evaporated
in vacuo, and the products were isolated by preparative column
chromatography.
Physicochemical data of compounds 10a—c were published
in the works,18,31,32 respectively.
1ꢀ(2ꢀNitrobenzyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (10d) was obꢀ
tained by method B. 1H NMR (300 MHz, CDCl3), : 7.92 (d, 1 H,
CH in Ar, J = 8.1 Hz); 7.76 (d, 1 H, CH in Ar, J = 7.3 Hz); 7.59
(t, 1 H, CH in Ar, J = 7.3 Hz); 7.41 (t, 1 H, CH in Ar, J = 8.1 Hz);
6.83 (s, 1 H, N=CH); 4.44 (s, 2 H, CH2Ar); 3.08—3.02 (m, 2 H,
NCH2); 2.70—2.64 (m, 2 H, NCH2CH2). 13C NMR (75 MHz,
CDCl3), : 144.18 (N=CH); 149.18, 133.77, 133.45, 131.28,
128.02, 124.56 (Ar); 56.86 (CH2Ar); 53.06 (NCH2); 34.31
(NCH2CH2). MS (EI, 70 eV), m/z (Irel (%)): 205 [M]+ (8), 83
[M – 2ꢀNO2C6H4]+ (19), 69 [M – 2ꢀNO2C6H4CH2]+ (40).
Found (%): C, 58.57; H, 5.36; N, 20.43. C10H11N3O2. Calculatꢀ
ed (%): C, 58.53; H, 5.40; N, 20.48.
1ꢀ(4ꢀBromobenzyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (10e) was synꢀ
thesized by method C. 1H NMR (300 MHz, CDCl3), : 7.46,
7.26 (both d, 4 H, Ar, J = 8.0 Hz); 6.82 (s, 1 H, N=CH); 4.14
(s, 2 H, CH2Ar); 2.96—2.89 (m, 2 H, NCH2); 2.68—2.62 (m, 2 H,
NCH2CH2). 13C NMR (75 MHz, CDCl3), : 143.59 (N=CH);
136.79, 131.51, 130.70, 121.23 (Ar); 59.93 (CH2Ar); 52.18
(NCH2); 34.24 (NCH2CH2). MS (EI, 70 eV), m/z (Irel (%)):
238, 240 [M]+ (24), 171 (100), 90 (65). Found (%): C, 50.25;
H, 4.61; Br, 33.38; N, 11.73. C10H11BrN2. Calculated (%): C, 50.23;
H, 4.64; Br, 33.42; N, 11.72.
Dimethyl 3,5,6,7ꢀtetrahydroꢀ3ꢀ(4ꢀnitrophenyl)pyrazolo[1,2ꢀa]ꢀ
pyrazoleꢀ1,2ꢀdicarboxylate (16a). A mixture of compounds 2a
(0.5 mmol), 9a (0.5 mmol), and a catalytic amount of BF3•Et2O
in anhydrous MeCN (2 mL) was stirred at 40 C for 10 min.
Then DMAD (0.5 mmol) was added dropwise, and stirring was
continued for additional 1.5 h. The solvent was evaporated
in vacuo, the residue was dissolved in CH2Cl2, washed with satuꢀ
rated aq. NaHCO3, and dried with MgSO4. The product was
purified by chromatography. 1H NMR (600 MHz, CDCl3),
: 8.09, 7.63 (both d, 4 H, Ar, J = 8.8 Hz); 5.22 (s, 1 H, NCH);
3.86, 3.56 (both s, 6 H, Me); 3.48—3.43, 3.32—3.27 (both m,
2 H, MeO2CCNCH2); 3.14—3.11 (m, 1 H) and 2.85 (dd, 1 H,
ArNCH2, J = 8.8 Hz, J = 9.5 Hz); 2.12—2.07 (m, 2 H, NCH2CH2).
13C NMR (150 MHz, CDCl3), : 163.53, 162.46 (C=O); 150.63
(NCCO2Me); 148.39, 147.43, 128.06, 123.88 (Ar); 105.87
(CCO2Me); 69.81 (ArCH); 53.22, 51.52 (Me); 52.14 (ArNCH2),
1ꢀ[(5ꢀNitrofuranꢀ2ꢀyl)methyl]ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (10f)
was synthesized by method D. 1H NMR (300 MHz, CDCl3),
: 7.29 (d, 1 H, H in furan, J = 3.6 Hz); 6.87 (s, 1 H, N=CH); 6.55
(d, 1 H, H in furan, J = 3.6 Hz); 4.27 (s, 2 H, CH2 in furan);
3.12—3.06 (m, 2 H, NCH2); 2.74—2.68 (m, 2 H, NCH2CH2).

1074
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Makhova et al.
46.12 (MeO2CCNCH2); 24.69 (NCH2CH2). MS (EI, 70 eV),
m/z (Irel (%)): 347 [M]+ (10), 288 [M – Ac]+ (2), 225
[M – NO2C6H4]+ (100). Found (%): C, 55.29; H, 4.96; N, 12.08.
C16H17N3O6. Calculated (%): C, 55.33; H, 4.93; N, 12.10.
Dimethyl 3ꢀ(furanꢀ2ꢀyl)ꢀ3,5,6,7ꢀtetrahydropyrazolo[1,2ꢀa]ꢀ
pyrazoleꢀ1,2ꢀdicarboxylate (16b). A stirred mixture of comꢀ
pounds 2a (0.5 mmol) and 9h (0.5 mmol) in toluene (5 mL) was
refluxed for 5 min. Then DMAD (0.5 mmol) was added dropꢀ
wise, stirring was continued for 30 min, and the mixture was
cooled to room temperature. The solvent was evaporated in vacꢀ
uo, the residue was purified by chromatography. 1H NMR
(300 MHz, CDCl3), : 7.32 (d, 1 H, CH furyl, J = 1.9 Hz); 6.23
(dd, 1 H, CH furyl, J = 3.2 Hz, J = 1.9 Hz); 6.16 (d, 1 H,
CH furyl, J = 3.2 Hz); 5.26 (s, 1 H, NCH); 3.87, 3.59 (both s, 6 H,
Me); 3.41—3.55, 3.29—3.22 (both m, 2 H, CH2NC=C); 3.13—3.07
(m, 1 H); 2.81 (dd, 1 H, CH2NCH, J = 8.9 Hz, J = 9.2 Hz);
2.10—2.00 (m, 2 H, NCH2CH2). 13C NMR (75 MHz,
CDCl3), : 163.61, 162.59 (both C=O); 151.78 (CH2NC=C);
152.75, 142.46, 110.21, 106.57 (furan); 103.52 (CH2NC=C);
63.97 (NCH); 53.03, 51.35 (both Me); 51.24 (CH2NCH);
46.07 (CH2NC=C); 24.77 (NCH2CH2). MS (EI, 70 eV), m/z
(Irel (%)): 292 [M]+ (48), 291 [M – H]+ (100), 233 [M – Ac]+ (4),
225 [M – furyl]+ (29). Found (%): C, 57.57; H, 5.48; N, 9.61.
C14H16N2O5. Calculated (%): C, 57.53; H, 5.52; N, 9.58.
Dimethyl 3ꢀ(thiophenꢀ2ꢀyl)3,5,6,7ꢀtetrahydropyrazolo[1,2ꢀa]ꢀ
pyrazoleꢀ1,2ꢀdicarboxylate (16c) was synthesized similarly to
(0.6 mmol) and 9a (0.5 mmol) in [bmim][BF4] (1.5 mL) was
stirred for 1 h at room temperature in the presence of a catalytic
amount of BF3•Et2O. Then CS2 (5 mmol) was added and stirꢀ
ring was continued for 4.5 h. The reaction products were exꢀ
tracted with CH2Cl2—Et2O, 1 : 5 (4×3 mL) and purified by chroꢀ
matography. 1H NMR (300 MHz, CDCl3), : 8.26, 7.72 (both d,
4 H, Ar, J = 8.7 Hz); 5.88 (s, 1 H, NCH); 4.21—4.11, 3.74—3.65
(both m, 2 H, S=CNCH2); 3.26—3.20 (m, 1 H); 2.91 (dd, 1 H,
CHNCH2, J = 8.3 Hz, J = 9.7 Hz); 2.63—2.49 (m, 2 H,
NCH2CH2). 13C NMR (75 MHz, CDCl3), : 185.05 (C=S);
148.52, 143.60, 128.33, 124.29 (Ar); 72.08 (NCH); 51.21
(CHNCH2); 46.50 (S=CNCH2); 27.00 (NCH2CH2). MS (ESI),
m/z: 280.0216 [M – H]+. Calculated for C11H11N3O2S2: 280.0209
[M – H]+.
3ꢀ(Furanꢀ2ꢀyl)ꢀ3,5,6,7ꢀtetrahydropyrazolo[1,2ꢀc][1,3,4]ꢀ
thiadiazoleꢀ1(1H)ꢀthione (17b) was synthesized similarly to comꢀ
pound 17a. 1H NMR (300 MHz, CDCl3), : 7.46 (d, 1 H, CH of
furyl, J = 1.1 Hz); 6.54 (dd, 1 H, CH of furyl, J = 3.3 Hz, J = 1.1 Hz);
6.39 (m, 1 H, CH of furyl); 5.89 (s, 1 H, NCH); 4.06—3.97,
3.76—3.67 (both m, 2 H, SCNCH2); 3.21—3.15 (m, 1 H); 2.90
(dd, 1 H, CHNCH2, J = 8.2 Hz, J = 9.7 Hz); 2.53—2.40 (m, 2 H,
NCH2CH2). 13C NMR (75 MHz, CDCl3), : 185.08 (C=S);
148.22, 143.91, 110.85, 110.16 (furan); 65.61 (NCH); 50.40
(CHNCH2); 46.28 (SCNCH2); 26.84 (NCH2CH2). MS (ESI),
m/z 225.0159 [M – H]+. Calculated for C9H10N2OS2: 225.0151
[M – H]+.
1
compound 16a. H NMR (300 MHz, CDCl3), : 7.19 (d, 1 H,
1ꢀ(4ꢀNitrophenyl)ꢀ2ꢀ[(4ꢀnitrophenyl)sulfonyl]ꢀ1,2,3,5,6,7ꢀ
hexahydropyrazolo[1,2ꢀa]pyrazole (18). To a mixture of comꢀ
pound 2a (0.5 mmol) and catalytic amount of BF3•Et2O in
IL [emim]OTf (1.5 mL), arylmethylidenemalononitrile 9a
(0.5 mmol) was added. The mixture was stirred at 40 C for
10 min, followed by addition of 4ꢀnitrophenylsulfonylethylene
(0.5 mmol), and stirring was continued for 6 h at this temperaꢀ
ture. The reaction mixture was washed with saturated aq.
NaHCO3, extracted with CH2Cl2, and dried with MgSO4. The
product was purified by chromatography. M.p. 205 C (decomp.).
1H NMR (300 MHz, DMSOꢀd6), : 8.24, 8.07 (both d, 4 H,
SO2Ar, J = 8.7 Hz); 7.99, 7.48 (both d, 4 H, Ar, J = 8.5 Hz); 4.65
(dd, 1 H, CHSO2Ar, J = 14.0 Hz, J = 8.6 Hz); 4.23 (d, 1 H,
CHAr, J = 7.8 Hz); 3.59—3.47, 3.39—3.33 (both m, 2 H,
CH2CHSO2); 3.03 (t, 2 H, CH2NCH2CHSO2, J = 7.6 Hz);
2.92—2.67 (m, 2 H, ArCHNCH2); 2.32—2.23, 2.05—1.77
(both m, 1 H, NCH2CH2). 13C NMR (75 MHz, CDCl3),
: 150.96, 147.66, 147.21, 143.91, 130.33, 130.00, 124.90, 123.42
(SO2Ar and Ar); 73.79 (CHSO2Ar); 65.92 (CHAr); 51.92, 51.05
(SO2CHCH2NCH2); 49.11(CHNCH2); 24.09 (NCH2CH2). MS
(ESI), m/z 419.1016 [M + H]+. Calculated for C18H18N4O6S:
419.1020 [M + H]+.
CH of thienyl, J = 5.0 Hz); 7.06 (d, 1 H, CH of thienyl, J = 3.3 Hz);
6.94 (dd, 1 H, CH of thienyl, J = 4.0 Hz, J = 4.5 Hz); 5.50 (s, 1 H,
NCH); 3.93, 3.68 (both s, 6 H, Me); 3.54—3.45, 3.39—3.31
(both m, 2 H, CH2NC=C); 3.22—3.15 (m, 1 H); 2.87 (dd, 1 H,
CH2NCH, J = 8.9 Hz, J = 9.1 Hz); 2.18—2.09 (m, 2 H,
NCH2CH2). 13C NMR (75 MHz, CDCl3), : 163.78, 162.75
(both C=O); 150.34 (CH2NC=C); 144.42, 126.82, 124.64,
124.43 (thiophene); 106.70 (CH2NC=C); 65.91 (NCH); 53.11,
51.44 (both Me); 51.36 (CH2NCH); 46.23 (CH2NC=C); 24.93
(NCH2CH2). MS (ESI), m/z: 331.0721 [M + Na]+. Calculated
for C14H16N2O4S: 331.0723 [M + Na]+.
Dimethyl 2ꢀoxoꢀ6´,7´ꢀdihydroꢀ5´Hꢀspiro(indolineꢀ3,1´ꢀpyrꢀ
azolo[1,2ꢀa]pyrazole)ꢀ2´,3´ꢀdicarboxylate (16d). A mixture of
compounds 2a (0.6 mmol) and 9j (0.5 mmol) in [bmim][BF4]
(1.5 mL) and a catalytic amount of BF3•Et2O was stirred for 1 h
at room temperature. Then DMAD (0.5 mmol) was added dropꢀ
wise and stirring was continued for 16 h. The reaction mixture
was diluted with CH2Cl2, washed with saturated aq. NaHCO3
and brine, dried with MgSO4, and the product was purified by
chromatography. M.p. 83—84 C (decomp.). 1H NMR (600 MHz,
CDCl3), : 7.75 (br.s, 1 H, NH); 7.33 (d, 1 H, CH of indole,
J = 7.8 Hz); 7.24 (dd, 1 H, CH of indole, J = 7.8 Hz,
J = 7.2 Hz); 7.03 (dd, 1 H, CH of indole, J = 7.2 Hz, J = 7.8 Hz);
6.85 (d, 1 H, CH of indole, J = 7.8 Hz); 3.96, 3.52 (both s, 6 H,
Me); 3.49—3.46, 3.45—3.41 (both m, 2 H, CH2NC=C); 3.25
(dd, 1 H, J = 9.6 Hz, J = 7.2 Hz); 2.99—2.96 (m, 1 H, CH2NC
of indole); 2.27—2.22, 2.20—2.14 (both m, 2 H, NCH2CH2).
13C NMR (150 MHz, CDCl3), : 174.58 (NHC=O); 162.64, 162.14
(both MeOC=O); 151.94 (CH2NC=C); 140.46, 129.77, 128.96,
125.21, 122.97, 110.06, 73.44 (indole); 104.35 (CH2NC=C);
53.26, 51.41 (both Me); 47.91 (CH2NC of indole); 46.13
(CH2NC=C); 26.26 (NCH2CH2). MS (ESI), m/z 366.1060
[M + Na]+. Calculated for C17H17N3O5: 366.1060 [M + Na]+.
3ꢀ(4ꢀNitrophenyl)ꢀ3,5,6,7ꢀtetrahydropyrazolo[1,2ꢀc][1,3,4]ꢀ
thiadiazoleꢀ1(1H)ꢀthione (17a). A mixture of compounds 2a
This work was financially supported in parts by the
Russian Foundation for Basic Research (Project No. 13ꢀ03ꢀ
00153a) and the Presidium of Russian Academy of Sciꢀ
ences (Program for Basic Research No. 8 "Development
of Methods for Preparation of Chemical Substances and
Creation of New Materials").
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Received December 25, 2012;
in revised form March 6, 2013