Bicyclization involving pseudo-intramolecular imination with diamines

Article abstract of DOI:10.1039/c1cc10705d

α-Nitro-δ-keto nitriles and α-nitro-δ-keto ester were readily converted to diazabicyclo compounds having vicinal functionality upon treatment with diamines. The keto nitrile attracts the diamine nearby to an acidic hydrogen to cause the pseudo-intramolecu

Full text of DOI:10.1039/c1cc10705d

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COMMUNICATION
Bicyclization involving pseudo-intramolecular imination with diaminesw
Nagatoshi Nishiwaki,* Shotaro Hirao, Jun Sawayama, Kazuhiko Saigo and Kazuya Kobiro
Received 6th February 2011, Accepted 11th March 2011
DOI: 10.1039/c1cc10705d
a-Nitro-d-keto nitriles and a-nitro-d-keto ester were readily
converted to diazabicyclo compounds having vicinal functionality
upon treatment with diamines. The keto nitrile attracts the
diamine nearby to an acidic hydrogen to cause the pseudo-
intramolecular imination which proceeds efficiently without
any catalyst at room temperature.
group bites it; this process is similar to the manner in which a
football fish attracts its prey (Scheme 1). We considered that
this new concept is applicable to efficient syntheses of various
kinds of polyfunctionalized compounds under mild conditions.
For example, the pseudo-intramolecular reaction took place
for substrates such as a-nitro-d-keto nitrile 1 with amines,5
which affords the corresponding 2-amino-3-nitro-1,4-dihydro-
pyridine 26 in the following manner. Treatment of 1 with an
amine results in the formation of an intermediate ammonium
salt 3; then, the liberated amine attacks the nearby cyano
group to cause cyclization (Scheme 2). From the point aimed
at bifunctionality of the substrate 1, we considered that the
pseudo-intramolecular reaction surely proceeds at the carbonyl
group if amines having a nucleophilic functional group such as
diamines 4 are employed, which leads to multiply functionalized
1,7-diazabicyclo[4.3.0]nonanes (DBNs) and their homologs.
Several synthetic routes to DBN frameworks have been
established with the aim of studying the biological activities
of these DBNs7 and for producing DBN-based agrochemicals.8
The DBN framework can be constructed by the intermolecular
condensation of 1,2-diaminoethanes with 5-chloropentanal,9
g-acyl (or g-cyano) butylates,10 or glutaraldehyde.11 Intra-
molecular cyclization of 5-amino-1-pentanols,7 or dipeptides12
is another for the direct synthesis of DBNs from acyclic
starting materials. Pyridines and piperidines can be used as
scaffolds for the synthesis of [a]-fused rings by intramolecular
nucleophilic reaction,13 1,3-dipolar cycloaddition14 etc. DBNs
can also be synthesized by constructing a second ring on an
imidazolidine ring, i.e., by the formation of a fused ring
compound.8,15 Although these methods are of great synthetic
importance, they are not effective for the synthesis of
multifunctionalized DBN derivatives because of the following
drawbacks: (1) these methods involve multistep reactions
Development of synthetic methods satisfying as many criteria
as possible among the twelve principles of green chemistry1 is
highly demanded in organic chemistry. Improving the efficiency
of reactions is one of the main approaches to environmentally
benign methods, in which increase of the collision frequency of
the reactants should be considered as a significant factor.
Intramolecular reactions proceed faster than intermolecular
reactions because of the high collision frequency of the reac-
tion sites, which can be attributed to the spatial proximity.
With regard to intermolecular process, employment of reac-
tion fields, such as capsules, cages, bowls, and micelles, has
been recognized as a useful method in organic synthesis to
come close to one another, so that the reaction proceeds
rapidly to afford the product.2
To the contrary, we previously proposed a new protocol, a
pseudo-intramolecular reaction, which efficiently proceeds to
completion under mild conditions even when no catalyst,
additive, or special manipulation is employed; in particular,
this reaction can be carried out even in the absence of the
above mentioned reaction fields.3,4 Compounds having an
acidic hydrogen as well as an appropriate functionality can
be used as substrates for the pseudo-intramolecular reaction,
and they readily form ammonium salts upon treatment with
amines. When the amine is liberated from the salt under
equilibrium, the nucleophilic moiety (amine) and the electro-
philic functionality come close to each other. Because of this
spatial proximity, the reaction, which is actually intermolecular,
behaves like an intramolecular reaction, and side reactions are
suppressed. In the present process, the acidic hydrogen atom is
used as a lure for attracting the amine, and the functional
School of Environmental Science and Engineering,
Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502,
Japan. E-mail: nishiwaki.nagatoshi@kochitech.ac.jp;
Fax: +81-887-57-2520; Tel: +81-887-57-2517
w Electronic supplementary information (ESI) available: Spectral and
analytical data of compounds 1, 5a, 7, 8, 9 and 13. X-ray crystallo-
graphic data of 7a and 13. CCDC 804331–804332. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc10705d
Scheme 1 Pseudo-intramolecular process.
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4938 Chem. Commun., 2011, 47, 4938–4940
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Table 1 Bicyclization using other diamines
Run
R1
R2
R3
n
Diamine
Product
Yield/%
1
2
3
4
5
6
Me
H
Me
Me
Me
Me
H
H
H
Et
H
H
H
H
Me
H
H
1
1
1
1
2
3
4a
4a
4b
4c
4d
4e
7a
9
76
26
65a
79
85
23
Scheme 2 Synthesis of 2,3-difunctionalized 1,4-dihydropyridine 2.
a
7b, 7b0
7c
7d
and (2) the starting materials are not readily available. To the
best of our knowledge, there is only one report on the synthesis
of DBNs possessing two functional groups at the 2- and the
3-positions.8 Therefore, there is increased demand for the
development of an easy synthetic method that affords vicinally
functionalized DBNs via simple manipulations, even when no
special reagents or reaction conditions are employed. In this
study, we have developed a facile method for the synthesis of
DBNs and their homologs; in our method, pseudo-intramolecular
imination is a key step, and the diamines 4 used show acrobatic
behavior.
H
7e
a
A mixture of two regioisomers 7b (8-methyl isomer) and 7b0
(9-methyl isomer) was formed in a 1 : 1 ratio.
hydrogen atoms (i.e. compound 8); however, 8 was unstable
and decomposed within a few days even when stored in a
refrigerator. When 1,2-diaminopropane 4b was employed, an
equimolar mixture of regioisomers 7b and 7b0 was formed,
indicating that the initial imination was unaffected by the
presence of the methyl group on the ethylene chain (run 3).
The reactivity of diamine 4c, which had an N-ethyl group, was
similar to that of the unsubstituted diamine 4a; the N-ethyl
group in 4c did not interfere with the reaction, and a bicyclic
product 7c was obtained (run 4). This is notable because
the present reaction completely recognized the primary
amino group from the secondary amino one having similar
basicity. It was also possible to construct relatively larger
condensed rings by employing diamines 4d and 4e. When
using 1,3-diaminopropane 4d, bicyclization proceeded in the
same way to afford diazabicyclo[4.4.0]decane 7d in 85% yield
(run 5). The use of 1,4-diaminobutane 4e resulted in the
formation of a seven-membered ring (run 6).
When 1,2-diaminoethane 4a was added to a solution of keto
nitrile 1 in acetonitrile, a white precipitate was immediately
formed. The results of elemental analyses and HRMS revealed
that the molecular formula of the precipitated compound was
C10H18N4O2, which corresponded to a dehydrated form of the
adduct obtained from 1 and 4a. The IR spectrum of the
precipitate showed a strong absorption at 2190 cmꢀ1 and a
relatively weak absorption at 1672 cmꢀ1; these two absorptions
could be assigned to the cyano group of a-cyanonitronate9 and
an imino group, respectively. On the basis of these spectral and
analytical data, the product was confirmed to be the zwitterionic
imine 5a, and not the ammonium salt 6a (Fig. 1). However,
when the 1H NMR spectrum of the precipitate was recorded in
DMSO-d6 (in which the precipitate was readily soluble) instead
of CD3CN (in which the precipitate was insoluble), signals due
to 5a as well as 6a were observed; these NMR signals could be
ascribed to the equilibrium shift from 5a to 6a in DMSO. It is
noteworthy that imination proceeded quantitatively at room
temperature to afford 5a even in the absence of a catalyst.
Under reflux conditions, imine 5a could be easily transformed
to the DBN derivative 7a (yield: 76%; Table 1, run 1), whose
structure was determined by X-ray crystallography as well as
from spectral and analytical data. Interestingly, the bridgehead
nitrogen and the three adjacent carbons in 7a were located
in a plane within 0.025 A; this was thought to be due to the
conjugation with the a-iminonitronic acid moiety. For the
formation of 9 via bicyclization (run 2), the two methyl groups
at the b-position of the d-keto nitrile were replaced with
While a-nitro-d-keto nitrile 1 quantitatively affords 5a,
d-keto nitrile 10, which has no nitro group, remains unreacted
even after treatment with diamine 4a under the same con-
ditions used for the formation of 5a (Scheme 3). This result
indicates that the presence of a nitro group is necessary for the
initial imination step. Since there are three carbons between
the two functional groups (the cyano group and the keto
group) in 1, the nitro group cannot activate the carbonyl
group by the electron-withdrawing inductive effect. The main
role of the nitro group is to make the a-hydrogen acidic so that
it can attract diamine 4a to form ammonium salt 6a, which is
essential for triggering the pseudo-intramolecular process, as
shown in Scheme 1.
A plausible mechanism for the present reaction is illustrated
in Scheme 4. One of the amino groups (blue) in 4a deproto-
nates the a-carbon of d-keto nitrile 1 to afford ammonium salt
6a, which realizes two reactants, 1 and 4a, are closed together
Fig. 1 Plausible structures for the precipitates.
Scheme 3 Reaction of keto nitrile 10 with diamine 4a
Chem. Commun., 2011, 47, 4938–4940 4939
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The pseudo-intramolecular process is well suited for the
synthesis of vicinally bifunctional compounds, which can be
converted into a variety of new compounds.16 Molecular
design of the substrates with an acidic hydrogen and a
functionality, is easy. Hence, the pseudo-intramolecular reac-
tion is expected to emerge as a powerful tool for the synthesis
of polyfunctionalized compounds that cannot be prepared by
alternative methods.
This work was supported by Grants-in-Aid for Scientific
Research (No. 22550043) and by Kyoto-Advanced Nano-
technology Network from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
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4940 Chem. Commun., 2011, 47, 4938–4940
This journal is The Royal Society of Chemistry 2011