Metathesis of azomethine imines in the reaction of 6-aryl-1,5- diazabicyclo[3.1.0]hexanes with carbonyl compounds

Article abstract of DOI:10.1016/j.mencom.2012.01.012

An interaction of carbonyl compounds (isatins, 4-nitrobenzaldehyde) with azomethine imines generated by the diaziridine ring opening in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes in the presence of BF₃· Et₂O as a catalyst induced the metathesis to other azomethine imines with the elimination of aldehydes ArCHO. New azomethine imines were trapped with diethyl acetylenedicarboxylate, otherwise they transformed to the corresponding pyrazolines due to a 1,4-H shift.

Full text of DOI:10.1016/j.mencom.2012.01.012

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 32–34
Metathesis of azomethine imines in the reaction of
6-aryl-1,5-diazabicyclo[3.1.0]hexanes with carbonyl compounds
Vera Yu. Petukhova, Mikhail I. Pleshchev, Leonid L. Fershtat,
Vladimir V. Kuznetsov, Vadim V. Kachala and Nina N. Makhova*
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
DOI: 10.1016/j.mencom.2012.01.012
An interaction of carbonyl compounds (isatins, 4-nitrobenzaldehyde) with azomethine imines generated by the diaziridine ring
opening in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes in the presence of BF3∙Et2O as a catalyst induced the metathesis to other azomethine
imines with the elimination of aldehydesArCHO. New azomethine imines were trapped with diethyl acetylenedicarboxylate, otherwise
they transformed to the corresponding pyrazolines due to a 1,4-H shift.
Over a few past years our laboratory has been engaged in inves-
tigating of 1,3-dipolar cycloaddition reactions of diverse dipolaro-
philes (carbon disulfide,1,2 activated olefins,3 activated nitriles,2,4
ketenes5) to azomethine imines 1 generated by the catalytic diazi-
ridine ring opening in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes 2
in ionic liquids (ILs) in the presence of BF3∙Et2O (Scheme 1).6
In all instances, products were bicyclic fused systems 3 where
the pyrazolidine cycle was annelated by various heterocycles.
Analogues of the synthesized structures have been reported or
patented for medical, agricultural and technology applications.7–11
the presence of various dipolarphiles yields 1,3-dipolar cyclo-
addition products 5', however, for that it has to be heated at 80°C
within 7–11 days (Scheme 2).
Isatin derivatives 6a–c substituted in different ways at the
nitrogen atom were selected as carbonyl compounds (isatins are
known to display a variety of pharmacological activity14 and
serve as a source of dyes, pesticides, insecticides, etc.15,16). We
anticipated that the interaction of 6a–c with azomethine imines
1a–c would proceed at the 3-C=O (cf. ref. 17).
Azomethine imines 1 were prepared1–6 from 6-aryl-1,5-diaza-
bicyclo[3.1.0]hexanes 2a–c in ILs catalyzed by BF3∙Et2O at
20°C. We expected that the reaction products would be bicyclic
structures 7 containing spiroconjugated indolin-2-one moieties
(Scheme 3).
Ar
Ar
N
N
Ar
A
B
BF3∙Et2O
ILs
N
N
A
N
B
N
The research started with compound 2a and isatin 6a. To
generate azomethine imine 1a the reaction was performed in the
IL 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4])
at 20°C with BF3∙Et2O (0.2 mmol per 1 mmol of 2a). Under
these conditions, the reaction was complete only in 7 days (TLC
control), however, instead of expected 7a, a mixture of two
compounds was attained in low yields. The C(3) atom of isatin
in the compounds appeared to be bound to nitrogen atoms of
pyrazoline (8a) and pyrazole (9a) cycles. A mixture of the same
compounds 8a and 9a, also in low yields, was obtained in the
reaction between isatin 6a and two other 6-aryl-1,5-diazabicyclo-
[3.1.0]hexanes 2b,c under similar conditions (Scheme 3, Table 1).†
By analogy running the reaction of compound 2a with isatins
2
1
3
A
B = EWG–CN, Ar1–CH=CHNO2, CS2, PhCH=CHCOPh
Scheme 1
In this work the research was focused on a possibility to
prepare fused systems where the pyrazolidine cycle was annelated
by the 1,3,4-oxadiazolidine heterocycle on a basis of the reaction
between azomethine imines 1 and carbonyl compounds. According
to reported data12,13 analogues of azomethine imines 1 having
the C=O group in the heterocyclic moiety (e.g., azomethines 4)
are capable of reacting with carbonyl compounds to give bicyclic
products 5. Note that compounds 5 can thermally eliminate ethyl
glyoxylate and generate initial azomethine imine 4. The latter in
†
General procedure for the interaction of 6-aryl-1,5-diazabicyclo[3.1.0]-
hexanes 2a–c with 1H-indole-2,3-diones 6a–c and 4-nitrobenzaldehyde.
A catalytic amount (0.20 mmol) of BF3∙Et2O and 1 mmol of corresponding
isatin 6a–c or 4-nitrobenzaldehyde was added to a mixture of 1 mmol of
6-aryl-1,5-diazabicyclo[3.1.0]hexane 2a–c and 1.5 ml of ([bmim][BF4])
or MeCN. The reaction mass was stirred at 18–20°C until the initial isatin
disappeared (TLC control) for ~7 days (for 4-nitrobenzaldehyde, the reaction
runs at 40–50°C for 3 days). The reaction mass was diluted with the
equal water amount and extracted with 3×5 ml CH2Cl2. The combined
extract was dried over MgSO4. The organic solvent was evaporated and
the products were separated using column chromatography (eluent: ethyl
acetate–light petroleum, 1.5:1). In all the cases, aromatic aldehydes ArCHO
(Ar = 4-MeOC6H4, 4-EtOC6H4, 4-MeC6H4) were eluted first and were
identified by comparison with the authentic samples. To regenerate the IL,
the water phase was evaporated on a rotary evaporator at 90°C to reach the
constant mass.
EtO2C
H
H
N
O
Ph
N
Ph
EtO2CCHO
EtO2CCHO
N
N
MgBr2∙Et2O
THF, 65 °C, 7 h
O
O
O
4
R
EtO2C
Ph
EtO2C
Ph
RCH=CHR
toluene, 80 °C,
7–11 days
O
CO2Et
N
O
R
N
N
N
– EtO2CCHO
O
O
O
5
5'
For characteristics of compounds 8a–c and 9a–c, see Online Supple-
mentary Materials.
Scheme 2
© 2012 Mendeleev Communications. All rights reserved.
– 32 –

Mendeleev Commun., 2012, 22, 32–34
Ar
Ar
N
N
N
Ar
N
O
Ar
O
R
N
N
12
R
2a–c
N
N
O
O
N
[bmim][BF4],
20 °C
O
BF3∙Et2O
7
6
BF3∙Et2O
2
O
N
IL or MeCN
N
[bmim][BF4],
20 °C, 7 days
Ar
R
6a–c
1
N
N
N
R
– ArCHO
N
N
O
1a–c
O
O
Ar
Ar
N
N
for 6a,c MeCN, 20 °C,
8a–c
R
N
N
7 days
N
N
R
+
O
O
1, 2: a Ar = 4-MeOC6H4
b Ar = 4-EtOC6H4
c Ar = 4-MeC6H4
10
7
N
6, 8, 9: a R = Me
b R = Pri
R
9a,c
[1,4-H]
N
R
N
N
– ArCHO
c R = H
O
N
N
O
9a–c
Scheme 3
11
Table 1 Yields of pyrazolines 8 and pyrazoles 9.
N
R
N
O
R
Starting isatin, reaction medium, yields of products 8 and 9 (%)
6a 6b 6c
[bmim][BF4] MeCN [bmim][BF4] MeCN [bmim][BF4] MeCN
[O]
O
N
N
N
N
Start-
ing 2
9
8
8a
9a
9a
8b
9b
9b
8c
9c
9c
Scheme 4
2a
2b
2c
15
14
18
12
10
37
46
31
23
49
57
25
—
—
—
15
24
42
32
42
41
overall process is the formation of pyrazolines 8 induced by a
formal 1,4-H shift in azomethine imine 11. It is obvious that
azomethine imines 11 are capable of transforming to pyrazolines
8 at room temperature whereas azomethine imines 1 give ana-
logous pyrazolines 12 only at heating.19 Pyrazoles 9 are most
likely to emerge in oxidation of pyrazolines 8 by air oxygen.20
The obtaining of sole pyrazole derivatives 9 from the reaction
in MeCN is apparently related to an easier oxidation reaction
course in organic solvents than in strongly polar ILs.
With a view to support the proposed mechanism, the reaction
mixture of 2a and 6b, after its maintaining for 2 days at 20°C,
was treated with diethyl acetylenedicarboxylate as a ‘trap’. In fact,
its 1,3-dipolar cycloaddition with azomethine imine 11b resulted in
a polycyclicproduct13(Scheme5),whosestructurewasrigorously
proved by elemental analysis and spectroscopic data.‡
6b,c afforded a mixture of pyrazolines 8b,c and pyrazoles 9b,c
but in higher yields. The interaction of compound 2b with isatin
6b resulted only in pyrazoline derivative 8b whereas both types
of compounds 8c and 9c were obtained from reactants 2b and
6c (Table 1). Furthermore, processing 6-aryl-1,5-diazabicyclo-
[3.1.0]hexanes 2 and isatins 6 in MeCN gave only pyrazole deriva-
tives 9a,c. No interaction of azomethine imines 1a,b with isatin
6b occurred in MeCN (Scheme 3).
In all cases, compounds 8 and 9 were separated by column
chromatography on SiO2 and characterized by elemental and
spectral analysis data, primarily NMR using procedures such as
COSY, {1H–1H}gNOESY, {1H–13C}HMBC, {1H–13C}HSQC, and
{
1H–15N}HMBC.Aromatic aldehydes used in the synthesis of initia
l
bicycles 2a–c and some amount of isatins were detected in all cases.
Also, noticeable resinification was observed, especially in the case of
isatin 6a. Raising the reaction temperature both in IL and in MeCN
enhanced resinification and dropped the yields of products 8 and 9.
A plausible mechanism of the reaction pathway is given in
Scheme 4. At first, the 3-C=O isatin group adds to the negative
pole of azomethine imine 1 to generate a new dipolar interme-
diate 10 that would cyclize to expected 1,3,4-oxadiazolidines 7.
However, despite the low reaction temperature (20°C), oxa-
diazolidines 7 appeared insufficiently stable. Their decay was
probably caused by BF3∙Et2O, which promoted the oxadiazolidine
cycle opening and splitting-off the aromatic aldehydes followed
by the generation of other azomethine imines 11. 1,3,4-Oxa-
diazolidines are known18 to be acid-sensitive.
Ar
Pri
N
BF3∙Et2O
IL
6b
N
N
2a
– ArCHO
O
N
N
1a
Ar = 4-MeOC6H4
11b
EtO2C
EtO2C
EtO2CC CCO2Et
N
Pri
N
N
O
13
Most likely, compounds 1, 10, 7 and 11 are in balance with
each other in the ongoing reaction and the driving force of the
Scheme 5
– 33 –

Mendeleev Commun., 2012, 22, 32–34
Online Supplementary Materials
Ar
Ar
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2012.01.012.
BF3∙Et2O
4-NO2C6H4CHO
N
N
N
IL, 40–50 °C
N
1a–c
2a–c
References
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Scheme 6
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The discovered metathesis of azomethine imines proved to be
of rather general nature. The interaction of 2a–c with 4-nitrobenz-
aldehyde in [bmim][BF4] with a catalytic amount of BF3∙Et2O at
gentle heating (40–50°C) withing 3 days afforded pyrazoline 14
in 30–44% yield. Maximum yield of 14 was achieved in the reac-
tion with azomethine imine 1a. In MeCN, compounds 2a–c and
4-nitrobenzaldehyde did not react. The generation of pyrazoline
14 evidently proceeds analogously to that of pyrazolines 8 via
oxadiazolidine 7d and azomethine imine 11d (Scheme 6).‡
Summing up, the metathesis of azomethine imines (the genera-
tion of new azomethine imines 11 instead of original azomethine
imines 1) was revealed in the interaction of 6-aryl-1,5-diaza-
bicyclo[3.1.0]hexanes with isatins and 4-nitrobenzaldehyde in
ILs (with isatins in MeCN as well) catalyzed by BF3∙Et2O under
mild conditions. The transformation may be of use in the pre-
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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
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20 L. C. Behr, R. Fusco and C. H. Jarboe, in The Chemistry of Heterocyclic
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‡
For the synthesis of compound 13 and characteristics of compounds 13
and 14, see Online Supplementary Materials.
Received: 8th July 2011; Com. 11/3758
– 34 –