A catalyst and additive-free three-component reaction of highly electrophilic azides with cyclic ketones and cycloaliphatic amines. Synthesis of novel N-heteroaryl amidines

Article abstract of DOI:10.1016/j.tetlet.2016.03.058

Highly electrophilic 5-azido-1-methyl-4-nitro-1H-imidazole and sulfonyl azides were demonstrated to react with alicyclic amines and cyclic ketones in the absence of any catalyst or additive to afford novel N-(4-nitroimidazol-5-yl)- or N-sulfonylamidines respectively. Based on single crystal X-ray analysis, a revision of the previously reported data of Gao and co-workers on the direction of the reaction of sulfonyl azides with endocyclic enamines was made. The reaction of 2,6-diazidopyridine with an enamine, 4-(cyclohex-1-en-1-yl)morpholine, proceeded with cyclization of the azide moiety onto the pyridine C=N bond to form an amidine bearing the tetrazolo[1,5-a]pyridine fragment.

Full text of DOI:10.1016/j.tetlet.2016.03.058

Accepted Manuscript
A Catalyst and Additive-Free Three-Component Reaction of Highly Electro-
philic Azides with Cyclic Ketones and Cycloaliphatic Amines. Synthesis of
Novel N-Heteroaryl Amidines
Ilya Efimov, Nikolai Beliaev, Tetyana Beryozkina, Pavel Slepukhin, Vasiliy
Bakulev
PII:
S0040-4039(16)30280-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.058
TETL 47446
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
4 February 2016
10 March 2016
17 March 2016
Please cite this article as: Efimov, I., Beliaev, N., Beryozkina, T., Slepukhin, P., Bakulev, V., A Catalyst and
Additive-Free Three-Component Reaction of Highly Electrophilic Azides with Cyclic Ketones and Cycloaliphatic
Amines. Synthesis of Novel N-Heteroaryl Amidines, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.03.058
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A Catalyst and Additive-Free Three-
Component Reaction of Highly Electrophilic
Azides with Cyclic Ketones and
Leave this area blank for abstract info.
Cycloaliphatic Amines. Synthesis of Novel N-
Heteroaryl Amidines
Ilya Efimov , Nikolai Beliaev , Tetyana Beryozkina , Pavel Slepukhin , Vasiliy Bakulev *
a
a
a
a,b
a

1
Tetrahedron Letters
A Catalyst and Additive-Free Three-Component Reaction of Highly
Electrophilic Azides with Cyclic Ketones and Cycloaliphatic Amines. Synthesis
of Novel N-Heteroaryl Amidines
a
a
a
b
a*1
Ilya Efimov , Nikolai Beliaev , Tetyana Beryozkina , Pavel Slepukhin , Vasiliy Bakulev
a
TOS Department, Ural Federal University named after the first President of Russia B.N. Yeltsin, 19 Mira str., 620002 Yekaterinburg, Russia
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of Russian Academy of Sciences, 20 S. Kovalevskaya str., 620990 Yekaterinburg, Russia
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Highly electrophilic 5-azido-1-methyl-4-nitro-1H-imidazole and sulfonyl azides were
demonstrated to react with alicyclic amines and cyclic ketones in the absence of any catalyst or
additive to afford novel N-(4-nitroimidazol-5-yl)- or N-sulfonylamidines respectively. Based on
single crystal X-ray analysis, a revision of the previously reported data of Gao and co-workers
on the direction of the reaction of sulfonyl azides with endocyclic enamines was made. The
reaction of 2,6-diazidopyridine with an enamine, 4-(cyclohex-1-en-1-yl)morpholine, proceeded
with cyclization of the azide moiety onto the pyridine C=N bond to form an amidine bearing the
tetrazolo[1,5-a]pyridine fragment.
Available online
Keywords:
Azide
Amine
Amidine
2
009 Elsevier Ltd. All rights reserved.
Triazoline
Multicomponent reaction
Amidines represent a structural motif present in a variety of
biologically active compounds and many natural products. N-
for the synthesis of N-heteroaryl amidines, we studied the
reactions of 5-azido-1-methyl-4-nitroimidazole (1a) or 2,6-
diazidopyridine (1b) with enamines generated in situ from cyclic
ketones 2a-d and cycloaliphatic amines 3a-c.
1
Sulfonyl amidines were demonstrated to inhibit a dopamine
2
a
2b
transporter and various types of osteoclast differentiations. On
the other hand, nitroimidazole and nitropyridine derivatives
exhibit antibacterial, and antiviral activities as well as
The basic idea was that the enamines, formed in situ from the
reaction of ketones with amines, might react with highly
electrophilic azides in the absence of any catalyst or additive. The
reaction conditions were optimized using 5-azido-1-methyl-4-
nitroimidazole 1a, morpholine (3a) and cyclohexanone (2a) as
model substrates. We found that the best conditions involved a
one-pot 3CR procedure and the use of 1a, 2b and 3a in a molar
ratio 1:2:2 in methanol at 50 °C under an air atmosphere. The
desired product 4a was obtained in 86% yield with 5-amino-4-
nitro-1-methylimidazole (5) as a by-product, which was most
likely formed by the hydrolysis of amidine 4. Encouraged by this
result we used the optimized conditions in the reactions of azide
1a with the following ketones: cyclohexanone (2a),
cycloheptanone (2b), cyclooctanone (2c) and acetone (2d) and
amines: morpholine (3a), piperidine (3b) and N-methylpiperazine
3
protistocidal effects. Heteroaryl amidines are less reported in the
literature in comparison to alkyl and aryl amidines. It is
4
noteworthy that there are only two reports to date for the
5
synthesis of imidazole and pyridine containing amidines. To the
best of our knowledge, N-imidazole and N-pyridine amidines of
alicyclic acids are not known. The introduction of an alicyclic
moiety to the amidine could increase the lipophilicity of
compounds, facilitating the transportation via cell membranes.
Therefore, it is a challenging task to develop a new efficient
synthetic method for the preparation of N-heteroaryl substituted
amidines containing an alicyclic counterpart. Based on
6
experiences of using a multicomponent approach, herein, we
proposed to develop a three-component reaction (3CR) to
synthesize highly substituted N-heteroaryl amidines from
heteroaryl azides, cyclic ketones and nitropyridines. We turned
our attention to the reaction of sulfonyl azides with enamines
(3c) (Scheme 1). The N-imidazolyl amidines 4a-g were isolated
in 60-90% yields. It is notable that pyrrolidine and diethylamine
failed to give the desired product probably because of the
instability of the intermediate triazolines (Scheme 2) that might
further proceed to form a mixture of non-identified products.
5b,7
which is widely used for preparing N-sulfonyl amidines. The
reactions of aryl and heteroaryl azides lead to another type of
8
compound, mainly 1-aryl(heteroaryl)-1,2,3-triazoles and only a
few examples of N-heteroaryl amidines prepared by this reaction
5a
are known so far. To develop an efficient and simple method
—
——
*
Corresponding author. Tel.:+73433745483; E-mail: v.a.bakulev@urfu.ru

2
Tetrahedron Letters
Scheme 1. A. Scope of the multicomponent reaction of azide 1a with cyclic ketones 2a-d and amines 3a-c leading to amidines
4
a-g. В. Synthesis of sulfonyl amidines 4h-j from sulfonyl azides 1b-d, cyclohexanone and morpholine
1
The structures of amidines 4a–g were confirmed by H and
additive to form N-sulfonyl amidines 4h-j in good yields
1
3
C NMR spectroscopy, including 2D HMBC and HSQC
(Scheme 1). In principle, the formation of compound 4k,
isomeric to 4j might be formed by analogy with the data of Gao
1
13
methods ( H– C), and mass spectrometry, which were in good
agreement with the proposed structures. Unambiguous proof for
the structures of compounds 4 came from the single crystal X-ray
11
and co-workers for the reaction of sulfonyl azides 1b-d with
enamine 2. Though compound 4j has an NMR spectrum identical
9
11
diffraction data for 4a,e (Fig. 1, 2).
to product 4k published by Gao and co-workers, X-ray analysis
of a monocrystal of 4j (Fig. 3) provides final evidence for the
reaction products as being amidine 4j, and not β-morpholino
tosylimine 4k.
To gather insight into the reaction mechanism, one additional
experiment was performed. When azide 1a was reacted with
cycloheptanone (2b) and pyrrolidine (3d) in methanol at room
temperature, fused triazoline 6a was isolated. The latter
compound underwent smooth transformation in methanol at 50
Interestingly, in contrast to the one-pot reactions of azides
with ketones and amines leading to amidines of type 4 that
4g,7a-c,i,j,l
°
C to form amidine 4l in 25% yield (Scheme 2). The
require the use of acids and water-accepting additives,
5-
aminotriazoline of type 6 is proposed to be an intermediate in
azidoimidazole 1a and sulfonyl azides 1b-d reacted smoothly
with morpholine (3a) and cyclohexanone (2a) in methanol to
furnish amidines 4a,h-j in good yields without a catalyst or an
additive (Scheme 1).
7a,b
reactions of this type and some examples of relatively stable 5-
5a,7d,10
aminotriazolines have been published.
no data on the transformation of isolated fused triazolines of type
to give amidines. Our experiment gives some proof for the 3CR
However, there was
6
of azides with amines and ketones that proceed via unstable
aminotriazolines of type 6.
We have also demonstrated that sulfonyl azides 1b-d, similar
to 5-azidoimidazole 1a, reacted with cyclohexanone (2a) and
morpholine (3a) in methanol in the absence of a catalyst or

3
Scheme 2. Three component synthesis of aminotriazoline 6a and its transformation to amidine 4l
Scheme 3. Reaction of 2,6-diazidopyridine 1e with enamine 7 to form amidine 8
Furthermore we examined the reaction of 2,6-diazido-4-
nitropyridine (1e) with morpholine (3a) and cyclohexanone (2a)
in methanol at 50 °C, but failed to synthesize the corresponding
N-pyridylamidine. Instead, a mixture of non-identified products
was formed, probably due to hydrolysis of the intermediate
triazoline. At the same time azide 1e was found to react smoothly
with the isolated enamine 7 in 1,4-dioxane at room temperature
to form new amidine 8 in 54% yield along with tar-like by-
products. The combination of column chromatography and
double crystallization allowed us to prepare a pure sample of
compound 8.
Figure 2. Structure of compound 4e
Figure 1. Structure of compound 4a
Bis-amidine 10 was not detected in the reaction using an
excess of enamine 7 which demonstrates that intramolecular
heteroelectrocyclization of intermediate 4m is more preferable
than reaction of the second azide group with the second molecule
of enamine 7.
12
Figure 3. Structure of compound 4j
A plausible mechanism involves the formation of enamine 7,
which is in equilibrium with ketone 2a and amine 3a, and the
formation of triazoline 6c from enamine 7 and azide 1a which
can shift this equilibrium (Scheme 4).
IR, NMR, mass-spectra and single crystal X-ray analysis of 8
9
(
Fig. 4) were in accordance with the proposed structure. These
data gave evidence that the azido group in position 5 of diazide
e reacts with enamine 7 rather than that in position 2.
1

4
Tetrahedron Letters
Scheme 4. A plausible mechanism for the formation of amidines 4 from amines, ketones and azide
Elimination of dinitrogen from triazoline 6c finalizes the process
resulting in amidine 4a. We detected the presence of
cyclohexanone and morpholine by H NMR spectroscopy when
4.
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1
we treated enamine 7 in a solution of CD
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detected in a solution of 2a and 3a in CD OD at 50 °C. Both
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3
OD/water in a NMR
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synthesis of novel N-imidazol-5-yl amidines based on a catalyst
and additive-free 3CR of 5-azido-4-nitroimidazole with cyclic
ketones and cycloaliphatic amines. This method is also
applicable for the synthesis of N-sulfonyl amidines. Reaction of
2
,6-diazidopyridine with 4-(cyclohex-1-en-1-yl)morpholine was
shown to be accomplished with cyclization of the azide moiety
pyridine C=N bond to form an amidine bearing the tetrazolo[1,5-
a]pyridine fragment.
Acknowledgments
9
1
.
Deposition numbers for compounds 4a (CCDC 1451360), 4e
(
CCDC 1451362), 4j (CCDC 1451361) and 8 (CCDC 1451359)
This project was supported by the Russian Scientific
Foundation (15-13-10031).
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


A novel three-component reaction of azides
with ketones and amines has been found.
Method for the synthesis of new N-heteroaryl
amidines was elaborated.
Sulfonyl azides are shown to react with
endocyclic amines to form N-sulfonyl amidines.