Metathesis of azomethine imines in reaction of 6-aryl-1,5-diazabicyclo[3.1. 0]hexanes with (Het)arylidenemalononitriles

Article abstract of DOI:10.1016/j.mencom.2013.01.012

Ring opening in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes gives cyclic azomethine imines which are prone to exchange of arylidene moiety with (het)arylidenemalononitriles to form the metathesis products being new azomethine imines. These species were fixed as

Full text of DOI:10.1016/j.mencom.2013.01.012

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 34–36
Metathesis of azomethine imines in reaction of 6-aryl-1,5-diaza-
bicyclo[3.1.0]hexanes with (het)arylidenemalononitriles
Mikhail I. Pleshchev,a Vera Yu. Petukhova,a Vladimir V. Kuznetsov,a Dmitriy V. Khakimov,a
Tatyana S. Pivina,a Marina I. Struchkova,a Yulia V. Nelyubinab and Nina N. Makhova*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: mnn@ioc.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: unelya@xrlab.ineos.ac.ru
DOI: 10.1016/j.mencom.2013.01.012
Ring opening in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes gives cyclic azomethine imines which are prone to exchange of arylidene
moiety with (het)arylidenemalononitriles to form the metathesis products being new azomethine imines. These species were fixed as
pyrazolines due to the 1,4-H shift or trapped by dimethyl acetylenedicarboxylate or CS2.
One of our scientific interests is the investigation of diaziridine
ring expansion under the action of electrophilic agents.1,2 In
particular, some untrivial heterocyclic systems were accessed
by [3+2]-cycloaddition of diverse dipolarophiles to cyclic azo-
methine imines 1 generated by the diaziridine ring opening in
bicyclic diaziridines 2 in ionic liquids (ILs).3–8 The synthesized
structures relate to the classes of compounds important for
practical applications, among which g-lactam antibiotics and other
antibacterial agents,9,10 TNF-a-inhibitors,11 herbicides, fungi-
cides,12,13 and high-conductivity organic crystals were revealed.14
Note that the developed procedures are based on simple two-
step protocol – a synthesis of diaziridine derivatives15 and their
interaction with commercial reagents.
Recently,16 during the studying of reaction between bicyclic
diaziridines 2 and isatins 3 we have discovered new method for
the azomethine imine generation (Scheme 1). In these reactions,
mixtures of isatin pyrazolines 4 and pyrazoles 5 were obtained
instead of expected fused heterocyclic systems 6, with aromatic
aldehydes used for the preparation of initial bicyclic diaziridines
2 having been isolated in high yields. We supposed that expected
compounds 6 could be produced at the first reaction step. How-
ever, in the presence of BF3∙Et2O, the formed 1,3,4-oxadiazoli-
dine ring can be opened with an aromatic aldehyde release and
generation of new azomethine imines 7. The latter would trans-
form to pyrazolines 4 due to the 1,4-H shift. The transformation
of azomethine imines 1 to azomethine imines 7 may be regarded
as azomethine imine metathesis. In one case species 7 was trapped
as [3+2] adduct 8 with DEAD. Our attempts to extend this
reaction on other aromatic and heteroaromatic aldehydes failed,
except for 4-nitrobenzaldehyde.
In this work we continued researching reagents for the azo-
methine imine metathesis using (het)arylidenemalononitriles 9
as dipolarophiles. The investigations began from a reaction of
6-aryl-1,5-diazabicyclo[3.1.0]hexanes 2a,b with donor MeO and
Me substituents in the aromatic ring and available17 arylidene-
malononitriles 9a,b with an electron-withdrawing NO2 substi-
tuent in the aromatic ring (Scheme 2). To find the optimal condi-
tions, we tested different methods2,16,18 (i–iv) for azomethine imine
generation.† However, instead of anticipated bicyclic structures
Ar
Ar
O
BF3∙Et2O
N
N
N
N
[bmim][BF4]
(MeCN)
2
1
O
Ar
[1,4-H]
N
N
N
N
N
N
N
– ArCHO
6
7
4
[O]
N
EtO2CC CCO2Et
†
General procedure for the synthesis of 4,5-dihydro-1H-pyrazoles 4.
Methods i, ii. A catalytic amount (20 mol%) of BF3∙Et2O was added to
a mixture of 6-aryl-1,5-diazabicyclo[3.1.0]hexane 2a,b (0.5 mmol) and
(het)arylidenemalononitrile 9a–g (0.5 mmol) in IL [bmim][BF4] (1.5 ml,
method i) or anhydrous MeCN (3 ml, method ii). The reaction mixture
was stirred at 40°C until the disappearance of the starting material (TLC
control). The reaction products were either extracted from IL (CH2Cl2–Et2O,
1:5, 4×3 ml) or isolated by the removal of MeCN under reduced pressure.
The residue was separated by column chromatography on SiO2 (eluent,
AcOEt–light petroleum). Reaction time is indicated in Table 1.
EtO2C
EtO2C
N
Pri
N
N
5
O
8
O
Methods iii, iv: A mixture of compound 2a or 2b (0.5 mmol) and com-
pound 9 (0.5 mmol) was refluxed in 5 ml of toluene (0.5–2 h, method iii)
or xylene (10 min, method iv). The reaction mixture was allowed to cool
to room temperature. The solvent was then removed under reduced pressure
and the residue was separated by column chromatography on SiO2 (eluent,
AcOEt–light petroleum). Reaction time is specified in Table 1.
=
or 4-O NC H CHO
O
2
6 4
N
O
R
3
Ar = 4-MeOC6H4, 4-EtOC6H4, 4-MeC6H4
Scheme 1
For characteristics of products 4d–f, see Online Supplementary Materials.
© 2013 Mendeleev Communications. All rights reserved.
– 34 –

Mendeleev Commun., 2013, 23, 34–36
CN
Table 1 Reaction of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes 2a,b with com-
pounds 9a–g.
4-O2NC6H4
X
Ar
9a X = CN
9b X = CO2Et
Ar
Entry
Ar in 9
Conditions (t/h)
Yield of 4 (%)
N
N
i, ii, iii or iv
N
N
1
2
4-O2NC6H4 (9a)
4-O2NC6H4 (9a)
4-O2NC6H4 (9a)
4-O2NC6H4 (9b)
Ph (9c)
3-O2NC6H4 (9d)
3-O2NC6H4 (9d)
2-O2NC6H4 (9e)
2-O2NC6H4 (9e)
4-BrC6H4 (9f)
i (1)
4a (84)
4a (60)
4a (25)
4a (60)
4b (30)
4c (30)
4c (20)
4d (60)
4d (60)
4e (60)
4f (32)
ii (2)
1a,b
2a Ar = 4-MeOC6H4,
2b Ar = 4-MeC6H4
3
iii (0.5)
ii (0.5)
iii (1)
i (6)
4
5
C6H4NO2-4
6
CN
N
Ar
N
7
iii (2)
ii (2)
+
X
8
9
iii (2)
iii (0.2)
iv (0.2)
11a Ar = 4-MeOC6H4, X = CN
11b Ar = 4-MeOC6H4, X = CO2Et
11c Ar = 4-MeC6H4, X = CN
4a
25–84%
10
11
5-O2N-2-furyl (9g)
80–85%
In addition, quantum chemical calculations [B3LYP 6-31G(d)]
have shown that species 7 was energetically more favourable
than species 1 (see Scheme 3).
Scheme 2 Reagents and conditions: i, BF3∙Et2O, [bmim][BF4], 40°C;2
ii, BF3∙Et2O, MeCN, 40°C;16 iii, reflux in toluene;18(a),(b) iv, reflux in
xylene.18(a),(b)
Since pyrazolines occur in a number of biologically active
molecules,20(a)–(e) we continued studying reactions between 6-aryl-
1,5-diazabicyclo[3.1.0]hexanes 2 and other (het)arylidenemalono-
nitriles 9 with a view to afford new pyrazolines 4, which we had
failed to synthesize in the similar reaction from carbonyl com-
pounds. As the pyrazoline 4a and arylidenemalononitriles
11a–c yields did not depend on the structure of initial bicyclic
diaziridine 2a,b, 6-(4-methoxyphenyl)-1,5-diazabicyclo[3.1.0]-
hexane 2a was only used in further investigations.
The aforesaid methods i–iv were used to prepare azomethine
imine 1a (see Table 1). It was found that interaction of bicyclic
diaziridine 2a with arylidenemalononitriles 9c–g (Scheme 4,
Table 1) also resulted in pyrazolines 4b–f in moderate to good
yields (see Table 1, entries 5–11, only optimal conditions for each
reaction have been tabulated). Meanwhile, the corresponding
pyrazolines were not accessed under any conditions in reactions
of hetarylidenemalononitriles with furan, thiophene and isatin
substituents, whereas arylidenemalononitrile 11a was isolated
in all cases in high yields (80–85%) (Scheme 4).
10 (see Scheme 3) pyrazoline 4a was obtained regardless of a
method employed to prepare azometine imines. The best yield
of 4a was achieved in IL (method i). Along with compound 4a
other arylidenemalononitriles 11a–c containing aromatic frag-
ments of the starting bicyclic diaziridines 2a,b were isolated in
high yields (see Scheme 2).
The mechanism of this process is outlined in Scheme 3 and
is evidently similar to that of the pyrazolines 4 formation in the
reaction of 2 with carbonyl compounds (see Scheme 1). At first,
arylidenemalononitriles 9a,b are linked to the negative pole of
azomethine imines 1 in accordance with Michael-type interaction
yielding expected bicyclic products 10 through intermediate 12.
However, compounds 10 apparently generate new azomethine
imines 13 with a release of new arylidenemalononitriles 11a–c.
Probably, azomethine imines 13 are precursors of compound
4a due to the 1,4-H shift. Thus, the found reaction is also the
azomethine imine metathesis between primary azomethine imines
1 and new azomethine imines 7. Compounds 1, 7, 10–12 in the
reaction mass are evidently at equilibrium, while the driving
force of the whole process is the pyrazoline 4a formation. The
reaction runs through a transfer of cyanomethylidene fragment
from arylidenemalononitriles 9 to the ArCH fragment of initial
azomethine imines 1 with a release of new arylidenemalononitriles
11a–c. A similar transfer of the dicyanomethylene group between
arylidenemalononitriles and aldehydes has been reported.19
High yields of arylidenemalononitriles 11a–c and zero or low
yields of pyrazolines 4 in some cases testify to low thermal stability
of newly formed azomethine imines 7, especially with 2-furyl,
2-thienyl and isatin-3-yl substituents at hetarylidenemalononitriles
9h–j, under the reaction conditions. To confirm the formation of
azomethine imine 7 in these cases, we used dipolarophiles (DMAD,
CS2) for their trapping.‡ In fact, azomethine imines 7a,h–j were
CN
CN
CN
X
CN
CN
Ar
Ar2
Ar2
Ar1
Ar1
X
Ar
9
N
N
N
N
CN
2a,b
9c–g
i, ii, iii or iv
N
N
[1a]
+
2a
X = CN, CO2Et
1a,b
0 kcal mol–1
12
MeO
11a
4b–f
Scheme 4
NC
N
X
N
Ar1
Ar2
‡
Ar2
Ar2
Trapping of azomethine imines 7 with DMAD and CS2. A mixture of
[1,4-H]
N
N
N
compound 2a (0.5 mmol) and 9 (0.5 mmol) with a catalytic amount of
BF3∙Et2O in 2 ml of dry MeCN (conditions ii) for DMAD or in IL [bmim]
[BF4] (1.5 ml) (conditions i) for CS2 was stirred for 10–60 min at 20–40°C.
Then DMAD (0.5 mmol) or CS2 (5 mmol) was added dropwise, and the
reaction mixture was stirred at this temperature for 1.5 h. MeCN was
evaporated, the residue was dissolved in CH2Cl2 (the reaction mixture in
IL was dissolved in CH2Cl2), washed with NaHCO3 and brine, dried over
MgSO4 and separated by column chromatography on SiO2 (eluent,
AcOEt–light petroleum).
N
10
–21.78 kcal mol–1
7
4a
–24.47 kcal mol–1
–9.47 kcal mol–1
CN
Ar1
11a–c
Ar1 = 4-MeOC6H4
Ar2 = 4-O2NC6H4
X
For characteristics of products 13a,b and 14a,b, see Online Supple-
mentary Materials.
Scheme 3
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Mendeleev Commun., 2013, 23, 34–36
R1R2C=C(CN)2
9a,h
R1R2C=C(CN)2
9i,j
This work was partially supported by the Russian Foundation
for Basic Research (grant no. 09-03-01091) and the Program of
the Russian Academy of Sciences ‘Development of Methods for
Synthesizing Chemical Compounds and Creating New Materials’.
then CS2
then DMAD
[1a]
CO2Me
R2
R1
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.01.012.
R2
R1
S
MeO2C
S
N
N
N
N
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14a R1 = 4-O2NC6H4, R2 = H,
conditions i, 40%
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Figure 1 Molecular structure of compound 14a.
§
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Received: 27th July 2012; Com. 12/3962
– 36 –